Inhibitory compounds

Abstract

The present invention relates to certain compounds that function as inhibitors of DHX9 activity (RNA Helicase A / RHA or Nuclear DNA Helicase II / NDH II). The present invention also relates to processes for the preparation of these compounds, to pharmaceutical compositions 5 comprising them, and to their use in the treatment of proliferative disorders, such as cancer, autoimmune and infectious diseases, as well as other diseases or conditions in which DHX9 activity is implicated.

Description

INHIBITORY COMPOUNDSFIELD OF THE INVENTION

[0001] The present invention relates to certain compounds that function as inhibitors of DHX9 activity (RNA Helicase A I RHA or Nuclear DNA Helicase II I NDH II). The present invention also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them, and to their use in the treatment of proliferative disorders, such as cancer, autoimmune and infectious diseases, as well as other diseases or conditions in which DHX9 activity is implicated.BACKGROUND OF THE INVENTION

[0002] DHX9 (RNA Helicase A I RHA or Nuclear DNA Helicase II I NDH II) is a NTP- dependent DExH-box helicase capable of unwinding both RNA and DNA as well as aberrant polynucleotide structures (Lee and Pelletier, Bohnsack et al). DHX9 can bind to and unwind or resolve dsDNA / RNA, ssDNA / RNA, DNA:RNA hybrids (such as R-loops), circular RNA, and DNA / RNA G quadruplexes. While it can act on multiple nucleotide structures, DHX9 has a preference for RNA displacement loops (R-loops), and both RNA and DNA G-quadruplexes (Liu et al).

[0003] DHX9 therefore has an important role in various RNA and DNA related cellular processes, such as transcription, translation, RNA splicing, editing, RNA transport and processing, microRNA genesis, and maintenance of genomic stability (Aktas et al). Genomic integrity is maintained through the DNA damage response, whereby cells undergo cell cycle arrest to initiate repair pathways or, if irreparable, induce cell death. DHX9 can mediate genomic stability via resolution of R-loop-associated DNA damage (Chakraborty et al). Through these various cellular roles, DHX9 has been shown to be a key regulator in a variety of cancer types and its deregulated activity can cause alterations in cellular growth and formation of tumors (Shi et al). For example, DHX9 has demonstrated regulation of genes associated with sustained proliferative signaling, evasion of growth suppressors, evasion of apoptosis, angiogenesis, and metastasis, all of which are hallmarks of cancer (Gulliver et al). The overexpression and upregulated activity of DHX9 has been observed in several cancer types including lung and colorectal cancers, prostate cancer, glioma and hepatocellular carcinoma (Wang et al).

[0004] Microsatellite instable cancers and tumors with defective MisMatch Repair (dMMR) exhibit a particularly strong dependence on DHX9 (Bonneville et al). It has been demonstratedthat DHX9 knockdown leads to replication stress, cell cycle arrest and apoptosis in CRC-MSI cancer cells with defective MMR (Castro et al, 2023). MSI cancers with a high potential dependency on DHX9 are colorectal, ovarian and gastric cancers (Deshpande et al, Liu S et al, Pelosov et al). A similar dependency on DHX9 is observed in other cancers (eg breast cancer) beyond dMMR, where there are defective DNA damage repair pathways eg through BRCA1 and / or BRCA2 mutations (Chakraborty and Hiom, Castro et al, 2024).

[0005] Recent studies have also suggested that depletion of DHX9 activity is able to trigger viral mimicry in cold tumors such as small cell lung cancer and boost responsiveness to immunotherapy treatments such as checkpoint inhibitors (Cottrel et al, Murayama et al).

[0006] DHX9 has also been implicated in Ewing’s sarcoma (Fidaleo et al).

[0007] DHX9 has been implicated in other diseases involving gene replication, translation or regulation including viral infections and autoimmune disease. Many of the biological processes in which DHX9 participates are utilised by viruses to promote their own replication.

[0008] DHX9 has been implicated in atherosclerosis progression (Huangfu et al).

[0009] There is therefore a need for DHX9 inhibitors as potential therapeutic agents for treating diseases or disorders that show a dependency on DHX9.References• Akta§ T, 111 k IA, Maticzka D, Bhardwaj V, Rodrigues CP, Mittler G, Manke T, Backofen R, Akhtar A. Nature, 2017, 544, 115-142.• Bohnsack KE , Yi S, Venus S, Jankowsky E, Bohnsack MT. Nature Reviews Molecular Cell Biology, 2023, 24, 749-769.• Bonneville R, Krook MA, Kautto EA, Miya J, Wing MR, Chen H-Z, Reeser JW, Yu L, Roychowdhury S. Precision Oncology, 2017, 1-15.• Castro J, Daniels MH, Lu C, Brennan D, Gotur D, Lee Y-T, Knockenhauer K, Case A, Wu J, Buker SM, Liu J, Sparling BA, Sickmier EA, Blakemore SJ, Boriack-Sjodin PA, Duncan KW, Ribich S, Copeland RA. Cancer Res, 2023, 83 (7_Supplement): 1136• Castro J, Daniels M, Nayak S, Laidlaw M, Brennan D, Johnston BT, Wu J, Raman A, Lu C, Blakemore SJ, Silver SJ, Boriack-Sjodin P, Duncan KW, Sagar JA, Copeland RA. Cancer Res, 2024, 84 (6_Supplement): 3908.• Chakraborty P, Hiom K. Nature Communications, 2021 , 12:4126, 1-18.• Chakraborty P, Huang J, Hiom K. Nat Commun. 2018, 9(1):4346• Cottrell KA, Ryu S, Torres LS, Schab AM, Weber JD. Cancer Res Commun, 2024, 4(4), 986-1003.• Deshpande M, Romanski PA, Rosenwaks Z, Gerhardt J. Cancers, 2020, 12, 3319- 3343.• Shi F, Cao S, Zhu Y, Yu Q, Guo W, Zhang S. J Clin Lab Anal. 2021 , 35:e24052, 1-11.• Gulliver C, Hoffmann R, Baillie GS. Future Science OA, 2020, FSO650.• Lee T, Pelletier, J. Oncotarget, 2016, 7(27)42716-42739• Liu M-Y, Keng-Ru Lin K-R, Chien Y-L, Yang B-Z, Tsui L-Y, Chu H-P, Wu C-S. Nucleic Acids Research, 2024, 52, 204-222.• Liu S, He L, Wu J, Wu X, Xie L, Dai L, Chen L, Xie F, Liu Z. Cellular and Molecular Life Sciences, 2021, 78:8261-8281• Murayama T, Nakayama J, Jiang X, Miyata K, Morris AD, Cai KQ, Prasad RM, Ma X, Efimov A, Belani N, Gerstein ER, Tan Y, Zhou Y, Kim W, Maruyama R, Campbell KS, Chen L, Yang Y, Balachandran S, Canadas I, Cancer Discov. 2024, 14, 468-491.• Pelosof L, Yerram SR, Ahuja N, Delmas A, Danilova L, Herman JG, and Azad NS. Int J Cancer, 2013, 134(3), 1-23.• Wang Y, Guo Y, Song Y, Zou W, Zhang J, Yi Q, Xiao Y, Peng J, Li Y, Yao L. Frontiers in Pharmacology, 2023, 14:1153067, 1-16• Fidaleo M., Svetoni F., Volpe E., Mihana B., Caporossi D., Paronetto M. Oncotarget. 2015; 6: 31740-31757.• Huangfu N, Ma H, Tian M, Zhang J, Wang Y, Li Z, Chen X, Cui H. Inflammation. 2023 Oct; 46(5): 1725-1738.

[0010] An object of this invention is to provide inhibitors of DHX9 activity.SUMMARY OF THE INVENTION

[0011] In one aspect, the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt thereof.

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

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

[0014] In another aspect, the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in the treatment of a proliferative condition.

[0015] In another aspect, the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in the treatment of cancer. In a particular embodiment, the cancer is a human cancer.

[0016] In another aspect, the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in the inhibition of DHX9 activity.

[0017] In another aspect, the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in promoting an immune response (e.g. anti-viral or anti-tumour immune response).

[0018] In another aspect, the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in increasing or enhancing an anti-tumour immune response during immune-oncology therapy.

[0019] In another aspect, the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in the treatment of an autoimmune disease. Suitably, the autoimmune disease is selected from colitis, multiple sclerosis, rheumatoid arthritis, lupus (e.g. systemic lupus erythematosus (SLE)), cirrhosis, dermatitis or inflammatory bowel disease.

[0020] In another aspect, the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in the treatment of an infectious disease, e.g. a viral infection.

[0021] In another aspect, the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in the treatment of a viral infection. Suitably, the viral infection is selected from a RNA viral infection, a DNA viral infection, HIV-1, Simian type D retrovirus, hepatitis, cytomegalovirus, adenovirus, hepatitis E, influenza A, classical swine fever, foot and mouth, Encephalomyocarditis virus (EMCV), norovirus, herpes simplex virus 1 (HSV-1), COVID-19, lymphocytic choriomeningitis virus (LCMV), listeria, myxoma virus, chikungunya virus.

[0022] In another aspect, the present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of a proliferative condition.

[0023] In another aspect, the present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of cancer. In a particular embodiment, the medicament is for use in the treatment of human cancers.

[0024] In another aspect, the present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the inhibition of DHX9 activity.

[0025] In another aspect, the present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for promoting an immune response (e.g. anti-viral or anti-tumour immune response).

[0026] In another aspect, the present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for for use in increasing an innate immune response in a subject.

[0027] In another aspect, the present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in increasing or enhancing an anti-tumour immune response during immune-oncology therapy.

[0028] In another aspect, the present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of an autoimmune disease. Suitably, the autoimmune disease is selected from colitis, multiple sclerosis, rheumatoid arthritis, lupus (e.g. systemic lupus erythematosus (SLE)), cirrhosis, dermatitis or inflammatory bowel disease.

[0029] In another aspect, the present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of an infectious disease.

[0030] In another aspect, the present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of a viral infection. Suitably, the viral infection is a RNA viral infection, a DNA viral infection, HIV-1 , Simian type D retrovirus, hepatitis, cytomegalovirus, adenovirus, hepatitis E, influenza A, classical swine fever, foot and mouth, Encephalomyocarditis virus (EMCV), norovirus, herpes simplex virus 1 (HSV-1), COVID-19, lymphocytic choriomeningitis virus (LCMV), listeria, myxoma virus, chikungunya virus.

[0031] In another aspect, the present invention provides a method of inhibiting DHX9 activity in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0032] In another aspect, the present invention provides a method of inhibiting cell proliferation in vitro or in vivo, said method comprising contacting a cell with an effective amountof a compound as defined herein, or a pharmaceutically acceptable salt, or a pharmaceutical composition as defined herein.

[0033] In another aspect, the present invention provides a method of inhibiting metastasis in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, or a pharmaceutical composition as defined herein.

[0034] In another aspect, the present invention provides a method of promoting an immune response (e.g. anti-viral or anti-tumour immune response) in a subject in need thereof, said method comprising administering to the subject a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, or a pharmaceutical composition as defined herein.

[0035] In another aspect, the present invention provides a method of increasing an innate immune response in a subject in need thereof, said method comprising administering to the subject a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, or a pharmaceutical composition as defined herein.

[0036] In another aspect, the present invention provides a method of increasing or enhancing an anti-tumour immune response during immune-oncology therapy, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, or a pharmaceutical composition as defined herein.

[0037] In another aspect, the present invention provides a method of treating a proliferative disorder, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, or a pharmaceutical composition as defined herein.

[0038] In another aspect, the present invention provides a method of treating cancer, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, or a pharmaceutical composition as defined herein.

[0039] In another aspect, the present invention provides a method of treating an autoimmune disease, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, or a pharmaceutical composition as defined herein.

[0040] In another aspect, the present invention provides a method of treating an infectious disease, said method comprising administering to a subject in need thereof a therapeuticallyeffective amount of a compound as defined herein, or a pharmaceutically acceptable salt, or a pharmaceutical composition as defined herein.

[0041] In another aspect, the present invention provides a method of treating a viral infection, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, or a pharmaceutical composition as defined herein. Suitably, the viral infection is a RNA viral infection, a DNA viral infection, HIV-1 , Simian type D retrovirus, hepatitis, cytomegalovirus, adenovirus, hepatitis E, influenza A, classical swine fever, foot and mouth, Encephalomyocarditis virus (EMCV), norovirus, herpes simplex virus 1 (HSV-1), COVID-19, lymphocytic choriomeningitis virus (LCMV), listeria, myxoma virus, chikungunya virus.

[0042] In one aspect, the present invention provides a combination comprising a compound as defined herein, or a pharmaceutically acceptable salt thereof, with one or more additional therapeutic agents.

[0043] The present invention further provides a method of synthesising a compound, or a pharmaceutically acceptable salt, as defined herein.

[0044] In another aspect, the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt, obtainable by, or obtained by, or directly obtained by a method of synthesis as defined herein.

[0045] In another aspect, the present invention provides novel intermediates as defined herein which are suitable for use in any one of the synthetic methods as set out herein.

[0046] Preferred, suitable, and optional features of any one particular aspect of the present invention are also preferred, suitable, and optional features of any other aspect.DETAILED DESCRIPTION OF THE INVENTIONDefinitions

[0047] Unless otherwise stated, the following terms used in the specification and claims have the following meanings set out below.

[0048] 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 diseaseor 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.

[0049] 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.

[0050] 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, “Ci-ealkyl” includes Ci-4alkyl, Ci-3alkyl, propyl, isopropyl and f-butyl. A similar convention applies to other radicals, for example “phenyl(Ci-6alkyl)” includes phenyl(Ci-4alkyl), benzyl, 1-phenylethyl and 2-phenylethyl.

[0051] The term "(m-nC)" or “Cm-n”, or "(m-nC) group" or “Cm-n” used alone or as a prefix, refers to any group having m to n carbon atoms.

[0052] The term "alkenyl", as used herein, refers to an aliphatic group containing at least one double bond and is intended to include both "unsubstituted alkenyls" and "substituted alkenyls", the latter of which refers to alkenyl moieties having substituents replacing a hydrogen on one or more carbons of the alkenyl group. Such substituents may occur on one or more carbons that are included or not included in one or more double bonds. Moreover, such substituents include all those contemplated for alkyl groups, as discussed below, except where stability is prohibitive. For example, substitution of alkenyl groups by one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated.

[0053] The term "alkynyl", as used herein, refers to an aliphatic group containing at least one triple bond and is intended to include both "unsubstituted alkynyls" and "substituted alkynyls", the latter of which refers to alkynyl moieties having substituents replacing a hydrogen on one or more carbons of the alkynyl group. Such substituents may occur on one or more carbons that are included or not included in one or more triple bonds. Moreover, such substituents include all those contemplated for alkyl groups, as discussed above, except where stability is prohibitive. For example, substitution of alkynyl groups by one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated.

[0054] An “alkylene” group is an alkyl group that is positioned between and serves to connect two other chemical groups. Thus, “Ci-salkylene” means a linear saturated divalenthydrocarbon radical of one to three carbon atoms or a branched saturated divalent hydrocarbon radical of three atoms, for example, methylene, ethylene, propylene, and the like.

[0055] The term “Cm-ncycloalkyl” means a hydrocarbon ring containing from m to n carbon atoms, for example “Cs-ecycloalkyl” means a hydrocarbon ring containing from 3 to 6 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. The term “Cm-ncycloalkyl” also encompasses non-aromatic saturated or partially saturated monocyclic, fused, bridged, or spiro bicyclic carbocyclic ring system(s). The term “Cm-ncycloalkyl” includes both monovalent species and divalent species. Monocyclic “Cm-ncycloalkyl” rings contain from about 3 to 12 (suitably from 3 to 8, most suitably from 5 to 6) ring carbon atoms. Bicyclic “Cm- ncycloalkyl” contain from 5 to 17 ring carbon atoms, suitably 5 to 12 ring carbon atoms. Bicyclic “Cm-ncycloalkyl” rings may be fused, spiro, or bridged ring systems.

[0056] The term "cycloalkoxy" means a cycloalkyl-O-group in which the cycloalkyl group is as previously defined, for example C^cycloalkoxy (or -O-C3-4cycloalkyl) means a hydrocarbon ring containing from 3 to 4 carbon atoms, linked to an O atom e.g.

[0057] The term “halo” or “halogeno” refers to fluoro, chloro, bromo and iodo.

[0058] The term “heterocyclyl”, “heterocyclic” or “heterocycle” means a non-aromatic saturated or partially saturated monocyclic, fused, bridged, or spiro bicyclic heterocyclic ring system(s). The term heterocyclyl includes both monovalent species and divalent species. Monocyclic heterocyclic rings contain from about 3 to 12 (suitably from 3 to 7, most suitably from 5 to 6) 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 4 to 17 member atoms, suitably 5 to 12 member atoms, in the ring, with from 1 to 5 (suitably 1 , 2 or 3) heteroatoms selected from nitrogen, oxygen or sulfur in the ring. Bicyclic heterocycles contain from about 5 to about 17 ring atoms, suitably from 5 to 12 ring atoms. Bicyclic heterocyclic(s) rings may be fused, spiro, or bridged ring systems. Examples of heterocyclic groups include cyclic ethers such as oxiranyl, oxetanyl, tetrahydrofuranyl, dioxanyl, and substituted cyclic ethers. Heterocycles containing nitrogen include, for example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrotriazinyl, tetrahydropyrazolyl, and the like. Typical sulfur containing heterocycles include tetrahydrothienyl, dihydro-1 , 3-dithiol, tetrahydro-2 / 7-thiopyran, and hexahydrothiepine. Other heterocycles include dihydro-oxathiolyl, tetrahydro-oxazolyl,tetrahydro-oxadiazolyl, tetrahydrodioxazolyl, tetrahydro-oxathiazolyl, hexahydrotriazinyl, tetrahydro-oxazinyl, morpholinyl, thiomorpholinyl, tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, and octahydrobenzothiazolyl. For heterocycles containing sulfur, the oxidized sulfur heterocycles containing SO or SO2 groups are also included. Examples include the sulfoxide and sulfone forms of tetrahydrothienyl and thiomorpholinyl such as tetrahydrothiene 1 ,1 -dioxide and thiomorpholinyl 1 ,1 -dioxide. A suitable value for a heterocyclyl group which bears 1 or 2 oxo (=0) or thioxo (=S) substituents is, for example, 2-oxopyrrolidinyl, 2-thioxopyrrolidinyl, 2-oxoimidazolidinyl, 2-thioxoimidazolidinyl, 2-oxopiperidinyl, 2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl or 2,6-dioxopiperidinyl. Particular heterocyclyl groups are saturated monocyclic 3 to 7 membered heterocyclyls containing 1 , 2 or 3 heteroatoms selected from nitrogen, oxygen or sulfur, for example azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, tetrahydrothienyl, tetrahydrothienyl 1 ,1-dioxide, thiomorpholinyl, thiomorpholinyl 1 ,1-dioxide, piperidinyl, homopiperidinyl, piperazinyl or homopiperazinyl. As the skilled person would appreciate, any heterocycle may be linked to another group via any suitable atom, such as via a carbon or nitrogen atom. However, reference herein to piperidino or morpholino refers to a piperidin-1-yl or morpholin-4-yl ring that is linked via the ring nitrogen.

[0059] A “carbon-linked heterocyclyl” means a heretocycle group as defined above that is connected via a carbon atom, rather than a heteroatom such as nitrogen.

[0060] By “spirocyclic ring systems” it is meant a compound which at least two rings which have only one atom in common and are not linked by a bridge.

[0061] By “fused ring systems” it is meant a compound in which two rings share two adjacent atoms. In other words, the rings share one covalent bond.

[0062] 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.

[0063] The term “heteroaryl” or “heteroaromatic” means an aromatic mono-, bi-, or polycyclic ring incorporating one or more (for example 1-4, 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 sixmembered 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.

[0064] 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[2,3-b]furanyl, 2H-furo[3,2-b]-pyranyl, 5H-pyrido[2,3-d]-o-oxazinyl, 1 H-pyrazolo[4,3-d]-oxazolyl, 4H-imidazo[4,5-d]thiazolyl, pyrazino[2,3-d]pyridazinyl, imidazo[2,1-b]thiazolyl, imidazo[1 ,2-b][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 non-aromatic, 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 and 3,4-dihydro-2 / 7-pyrido[3,2-b][1 ,4]oxazinyl.

[0065] 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.

[0066] Examples of six membered heteroaryl groups include but are not limited to pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl.

[0067] 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.

[0068] 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.

[0069] 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.

[0070] 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 a particular embodiment, an aryl is phenyl.

[0071] The term "optionally substituted" refers to either groups, structures, or molecules that are substituted and those that are not substituted.

[0072] 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.

[0073] The phrase “compound of the invention” means those compounds which are disclosed herein, both generically and specifically.Compounds of the invention

[0074] In one aspect, the present invention relates to compounds of formula (I) or (Q) shown below, or a pharmaceutically acceptable salt thereof:wherein:Ring A is phenyl or 5- or 6-membered heteroaryl; wherein Ring A is optionally substituted by one or more substituents RA, wherein each RAis independently selected from halo (e.g. Cl, F), cyano, (1-4C)alkyl, (1-4C)haloalkyl, (3-6C)cycloalkyl or ORA1, where RA1is selected from (1-4C)alkyl, (1-4C)haloalkyl, (3-6C)cycloalkyl;Y is absent or a group of the formula:Y1-Y2wherein:Y1is absent or [CRYaRYb]n, wherein n is an integer from 1 to 4, wherein each occurrence of RYaand RYbis independently selected from hydrogen or (1- 2C)alkyl;Y2is absent or selected from -O-, -S-, -SO-, -SO2-, -C(O)-, -0(0)0-, -00(0)-, - N(RY1)-, -N(RY1)-C(O)-, -N(RY1)-C(O)O- or -C(O)-N(RY1)-, wherein RY1is selected from hydrogen or (1 -2C)alkyl;Z is selected from (1-4C)alkyl, (3-12C)cycloalkyl, 4 to 12 membered heterocyclyl (including monocyclic, spirocyclic, fused and bridged heterocycles), phenyl, naphthyl or 5 to 10 membered heteroaryl, wherein any of which may be optionally substituted by one or more substituents selected from hydroxy, halo, cyano, (1 -4C)alkyl or (1-4C)alkoxy, wherein the (1- 4C)alkyl or (1-4C)alkoxy are optionally further substituted by one or more substituents selected from halo, hydroxy or cyano;Ring B is a 5- or 6-membered heteroaryl or 5- or 6- membered heterocyclyl; wherein 5- or 6-membered heteroaryl is optionally substituted with one or more substituents RB, and 5- or 6-membered heterocyclyl is optionally substituted with oxo or one or more substituents RB; wherein each RBis independently selected from halo, cyano, hydroxy, (1-4C)alkyl, (1-4C)alkoxy, (3-8C)cycloalkyl, wherein any (1 -4C)alkyl, (1-4C)alkoxy or (3-8C)cycloalkyl may be optionally further substituted by one or more substituents selected from hydroxy, halo, (1-4C)alkoxy, (1-4C)haloalkoxy, cyano, NRB1RB2, NRB1C(O)RB2or C(O)NRB1RB2, wherein RB1and RB2are independently selected from hydrogen or (1 -4C)alkyl;W is absent or is methylene optionally substituted by hydroxy;Ring C is selected from phenyl, naphthyl, 5 to 10-membered heteroaryl, (3- 10C)cycloalkyl or 4 to 10-membered heterocyclyl; wherein Ring C is optionally substituted by one or more substituents independently selected from halo, cyano, oxo, (1-6C)alkyl, (1-4C)haloalkyl, halo, cyano, (3-8C)cycloalkyl, 3 to 8 membered heterocyclyl, or ORc1, wherein RC1is selected from hydrogen, (1 -4C)alkyl, (3-8C)cycloalkyl, 3 to 8 membered heterocyclyl, phenyl, 5 or 6 membered heteroaryl, wherein any (1 -6C)alkyl, (3-8C)cycloalkyl, 3 to 8 membered heterocyclyl, phenyl or 5 or 6 membered heteroaryl in a substituent group on Ring C, including those in a group RC1, are optionally further substituted with one or more substituents selected from halo, cyano, oxo, hydroxy (1-4C)alkyl, (1-4C)haloalkyl, (1-4C)alkoxy or (1-4C)haloalkoxy; andX is a group of the formula:X1 - X2 - X3 wherein:Xi is absent or selected from -C(O)-, -C(O)-N(Rx1)-, -N(Rx2)-C(O)-N(Rx1)- or -N(Rx2)- C(O)-, wherein Rx1and R’'2are each independently selected from hydrogen or (1- 3C)alkyl;X2 is absent or is -[CR^R^Jq, wherein Rx1and R’'2are each independently selected from hydrogen or (1 -2C)alkyl, and q is an integer selected from 1 or 2;X3 is selected from (1-4C)alkyl, (3-10C)cycloalkyl or 4 to 12-membered heterocyclyl; andX3 is optionally substituted by one or more substitutents independently selected from halo, (1-2C)alkyl, (1-2C)alkoxy, (1-2C)haloalkyl or (1-2C)haloalkoxy.

[0075] In a preferred embodiment, W is absent, thus the compound has a structure according to Formula (la) below:wherein Ring A, Ring B, Ring C, Y and Z are each as defined anywhere herein.

[0076] In another aspect, the present invention relates to compounds of formula (I) shown below, or a pharmaceutically acceptable salt thereof:wherein:Ring A is phenyl or 5- or 6-membered heteroaryl; wherein Ring A is optionally substituted by one or more substituents RA, wherein each RAis independently selected from halo (e.g. Cl, F), cyano, (1-4C)alkyl, (1-4C)haloalkyl, (3-6C)cycloalkyl or ORA1, where RA1is selected from (1-4C)alkyl, (1-4C)haloalkyl, (3-6C)cycloalkyl;Y is absent or a group of the formula:Y1-Y2wherein:Y1is absent or [CRYaRYb]n, wherein n is an integer from 1 to 4, wherein each occurrence of RYaand RYbis independently selected from hydrogen or (1- 2C)alkyl;Y2is absent or selected from -O-, -S-, -SO-, -SO2-, -C(O)-, -0(0)0-, -00(0)-, - N(RY1)-, -N(RY1)-C(O)-, -N(RY1)-C(O)O- or -C(O)-N(RY1)-, wherein RY1is selected from hydrogen or (1 -2C)alkyl;Z is selected from (1-4C)alkyl, (3-12C)cycloalkyl, 4 to 12 membered heterocyclyl (including monocyclic, spirocyclic, fused and bridged heterocycles), phenyl, naphthyl or 5 to 10 membered heteroaryl, wherein any of which may be optionally substituted by one or more substituents selected from hydroxy, halo, cyano, (1 -4C)alkyl or (1-4C)alkoxy, wherein the (1- 4C)alkyl or (1-4C)alkoxy are optionally further substituted by one or more substituents selected from halo, hydroxy or cyano;Ring B is a 5-membered heteroaryl or 5-membered heterocyclyl; wherein Ring B is optionally substituted with one or more substituents RB, wherein each RBis independently selected from halo, cyano, hydroxy, (1 -4C)alkyl, (3-8C)cycloalkyl, wherein any (1-4C)alkyl or (3-8C)cycloalkyl may be optionally further substituted by one or more substituents selected from hydroxy, halo, (1-4C)alkoxy, (1-4C)haloalkoxy, cyano, NRB1RB2, NRB1C(O)RB2or C(O)NRB1RB2, wherein RB1and RB2are independently selected from hydrogen or (1-4C)alkyl;Ring C is selected from phenyl, naphthyl, 5 to 10-membered heteroaryl, (3- 10C)cycloalkyl or 4 to 10-membered heterocyclyl; wherein Ring C is optionally substituted by one or more substituents independently selected from halo, cyano, oxo, (1-4C)alkyl, (1-4C)haloalkyl, halo, cyano, (3-8C)cycloalkyl, 3 to 8 membered heterocyclyl, or ORC1, wherein RC1is selected from hydrogen, (1-4C)alkyl, (3-8C)cycloalkyl, 3 to 8 membered heterocyclyl, phenyl, 5 or 6 membered heteroaryl, wherein any (1 -4C)alkyl, (3-8C)cycloalkyl, 3 to 8 membered heterocyclyl, phenyl or 5 or 6 membered heteroaryl in a substituent group on Ring C, including those in a group RC1, are optionally further substituted with one or more substituents selected from halo, cyano, oxo, hydroxy (1 -4C)alkyl, (1-4C)haloalkyl, (1-4C)alkoxy or (1-4C)haloalkoxy.

[0077] Particular compounds of the invention include, for example, compounds of formula (I) or (Q), or pharmaceutically acceptable salts thereof, wherein, unless otherwise stated, each of Ring A, Ring B, Ring C, W, X, Y, Z, and any associated substituent groups has any of the meanings defined hereinbefore or in any one of paragraphs (1) to (37) hereinafter: -(1) Ring A is selected from phenyl or 5- or 6-membered heteroaryl; wherein Ring A is optionally substituted by one or more substituents RA, wherein each RAis independently as defined herein.(2) Ring A has a formula selected from:wherein:A1 , A2, A3, A4 and As form a 5-membered heteroaryl ring, which is optionally substituted by 1 or 2 independently selected RAgroups; andAs, A7, As, Ag, A10 and An form a phenyl ring or a 6-membered heteroaryl ring (e.g. pyridyl or pyrimidyl), which is optionally substituted by 1 , 2 or 3 independently selected RAgroups; and each RAis independently as defined anywhere herein.(3) Ring A has a formula selected from:wherein:Ai , A2, A3, A4 and As form a thiazole, imidazole, pyraxole or oxazole ring, any of which may be optionally substituted by 1 or 2 independently selected RAgroups;Ae, A7, As, Ag, A10 and An form a phenyl ring, a pyridyl ring or a pyrimidyl ring, any of which may be optionally substituted by 1 , 2 or 3 independently selected RAgroups; and each RAis independently as defined anywhere herein.(4) Ring A has a formula selected from:wherein:Qi is selected from CH or N; n is an integer selected from 0, 1 , 2 or 3X2 is selected from CH or N; m is an integer selected from 0, 1 or 2;X3 is selected from CH or N;X4 is selected from CH or N;X5 is selected from CH or N; p is an integer selected from 0, 1 or 2; wherein at least one of X3, X4 and X5 is not CH; and any available carbon atom, including those in Qi , X2, X3, X4 and X5, may be optionally substituted by a group RA; wherein each RAis independently as defined anywhere herein.(5) Ring A has a formula selected from:wherein:X2 is selected from CH or N;X3 is selected from CH or N;X4 is selected from CH or N; wherein at least one of X3 and X4 is not CH; andRA2, RAS, RA4, RAS, RA6 and RA? are each independently selected from hydrogen or a group RAas defined anywhere herein.(6) Ring A has a formula selected from:wherein RA2, RAS, RA4 and RAS are each independently selected from hydrogen or a group RAas defined anywhere herein.(7) Ring A has a formula selected from:wherein:RA2 is selected from hydrogen or a group RAas defined anywhere herein;RAS, RA4 and RAS are each independently selected from hydrogen, halo (e.g. F or Cl) or methyl.(7A) Ring A has a formula selected from:wherein RA2 is selected from hydrogen or a group RAas defined anywhere herein.(7B) Ring A has a formula selected from:wherein RA2 is selected from hydrogen or chloro.(8) RAis selected from halo (e.g. Cl, F), cyano, (1-2C)alkyl, (1-2C)haloalkyl, (3- 6C)cycloalkyl or ORA1, where RA1is selected from hydrogen, (1-2C)alkyl, (1- 2C)haloalkyl or (3-6C)cycloalkyl.(9) RAis selected from chloro, fluoro, cyano, methyl, fluoromethyl (e.g. CHF2, CF3), methoxy or fluoromethoxy (e.g. OCF3).(10) RAis selected from chloro, fluoro, methyl, fluoromethyl (e.g. CHF2 CF3) or methoxy.(10A) RAis chloro.(11) Ring B is a 5-membered heteroaryl or 5- or 6-membered heterocyclyl; wherein Ring B is optionally substituted with oxo or one or more substituents RB, wherein each RBis independently selected from halo, cyano, hydroxy, (1-2C)alkyl, (1-2C)alkoxy, (3-8C)cycloalkyl, wherein any (1 -2C)alkyl or (3-8C)cycloalkyl may be optionally further substituted by one or more substituents selected from hydroxy, halo, (1-2C)alkoxy, (1-2C)haloalkoxy, cyano, NRB1RB2, NRB1C(O)RB2or C(O)NRB1RB2, wherein RB1and RB2are independently selected from hydrogen or (1- 2C)alkyl,(12) Ring B is a 5-membered heteroaryl or 5- or 6-membered heterocyclyl; wherein Ring B is optionally substituted with oxo or one or more substituents RB, wherein each RBis independently selected from halo, cyano, hydroxy, methoxy or (1- 2C)alkyl, wherein the (1 -2C)alkyl may be optionally further substituted by one or more substituents selected from hydroxy, halo, (1-2C)alkoxy, (1-2C)haloalkoxy, cyano, NH2or C(O)NH2or NHC(O)H.(12A) Ring B is a is a 5-membered heteroaryl, 5-membered heterocyclyl or pyridonyl; wherein Ring B is optionally substituted with one or more substituents RB, wherein each RBis independently selected from halo, cyano, hydroxy, methoxy or (1- 3C)alkyl, and wherein (1 -3C)alkyl is optionally substituted by hydroxy.(12B) Ring B is a 5-membered heteroaryl comprising from 1-3 nitrogen atoms, a 5- membered heterocyclyl comprising from 1-2 nitrogen atoms, thiophene or pyridonyl; wherein Ring B is optionally substituted with one or more substituents RB, wherein each RBis independently selected from halo, cyano, hydroxy, methoxy or (1 -3C)alkyl, wherein (1-3C)alkyl is optionally substituted by hydroxy.(13) Ring B is a 5-membered heteroaryl or 5-membered heterocyclyl; wherein Ring B is optionally substituted with one or more substituents RB, wherein each RBis independently selected from halo, cyano, hydroxy or (1 -2C)alkyl.(13A) Ring B has a formula selected from:wherein any of the above rings may be optionally substituted on an available carbon atom by a substituent RB, wherein each RBis independently as defined herein; and RC2is selected from hydrogen or (1 -3C)alkyl, wherein (1-3C)alkyl is optionally substituted by hydroxy.(14) Ring B has a formula selected from:wherein any of the above rings may be optionally substituted on an available carbon atom by a substituent RB, wherein each RBis as defined anywhere herein; and RC2is selected from hydrogen or (1 -3C)alkyl, wherein (1-3C)alkyl is optionally substituted by hydroxy.(14A) Ring B has a formula selected from:wherein:RB2is selected from hydrogen or (1 -2C)alkyl; andRC2is (1 -2C)alkyl, wherein (1-2C)alkyl is optionally substituted by hydroxy.(14B) Ring B has a formula selected from:wherein:RB2is selected from hydrogen or methyl; andRC2is methyl.(15) Ring C is selected from phenyl, naphthyl, 5 to 10-membered heteroaryl, (3- 10C)cycloalkyl or 3 to 10-membered heterocyclyl; wherein Ring C is optionally substituted by one or more substituents independently selected from halo, cyano, oxo, (1-4C)alkyl, (1-2C)haloalkyl, (1- 2C)alkoxy, (1-2C)haloalkoxy, (3-8C)cycloalkyl, 3 to 8 membered heterocyclyl, C(O)NRc1RC3or ORC1, wherein RC1is selected from hydrogen, (1-2C)alkyl, (3-8C)cycloalkyl, 3 to 8 membered heterocyclyl, phenyl, 5-membered heteroaryl or 6- membered heteroaryl, and RC3is selected from hydrogen or (1 -2C)alkyl; wherein any alkyl, cycloalkyl, heterocyclyl, phenyl, or heteroaryl present in a substituent group on Ring C, including those in a group RC1, are optionally further substituted with one or more substituents selected from halo, cyano, oxo, hydroxy, (1-2C)alkyl, (1-2C)haloalkyl, (1-2C)alkoxy or (1-2C)haloalkoxy.(16) Ring C is selected from 5- to 6-membered heteroaryl or 5 to 6-membered heterocyclyl; wherein Ring C is optionally substituted by one or more substituents independently selected from halo, cyano, oxo, (1-4C)alkyl (e.g. (1 -2C)alkyl, (1- 2C)haloalkyl, (3-8C)cycloalkyl, 3 to 8 membered heterocyclyl, C(O)NRc1RC3or ORC1, wherein RC1is selected from hydrogen, (1 -2C)alkyl, (3-8C)cycloalkyl or 3 to 8 membered heterocyclyl, and RC3is selected from hydrogen or (1 -2C)alkyl; wherein any alkyl, cycloalkyl, heterocyclyl, phenyl, or heteroaryl present in a substituent group on Ring C, including those in a group RC1, are optionally further substituted with one or more substituents selected from halo, cyano, oxo, hydroxy, (1-2C)alkyl or (1-2C)haloalkyl.(17) Ring C is selected from a 5-membered heteroaryl, pyridyl or or pyrimdyl; wherein Ring C is optionally substituted by one or more substituents independently selected from halo, (1 -4C)alkyl (e.g. (1 -2C)alkyl), 3 to 8 membered heterocyclyl (including monocyclic, spirocyclic, bridged and fused heterocyclyl), C(O)NRC1RC3or ORC1, wherein RC1is selected from hydrogen, (1-2C)alkyl or 3 to 8 membered heterocyclyl, and RC3is selected from hydrogen or (1 -2C)alkyl; wherein any alkyl, cycloalkyl, heterocyclyl, phenyl, or heteroaryl present in a substituent group on Ring C, including those in a group RC1, are optionally further substituted with one or more substituents selected from halo, cyano, oxo, hydroxy or methyl.(17A) Ring C is selected from:wherein any of the above rings are optionally substituted on an available carbon atom by one or more substituents independently selected from halo, cyano, oxo, (1 -2C)alkyl, (1- 2C)haloalkyl, (3-8C)cycloalkyl, 3 to 8 membered heterocyclyl, C(O)NRC1RC3or ORC1, wherein RC1is selected from hydrogen, (1 -2C)alkyl, (3-8C)cycloalkyl or 3 to 8 membered heterocyclyl, and RC3is selected from hydrogen or (1 -2C)alkyl; wherein any alkyl, cycloalkyl, heterocyclyl, phenyl, or heteroaryl present in a substituent group on Ring C, including those in a group RC1, are optionally further substituted with one or more substituents selected from halo, cyano, oxo, hydroxy, (1- 2C)alkyl or (1-2C)haloalkyl;RN1is selected from hydrogen or (1 -4C)alkyl (e.g. methyl, ethyl or isopropyl);RN2is selected from hydrogen or (1-4C)alkyl (e.g. methyl, ethyl or isopropyl); RCNis selected from hydrogen or (1-4C)alkyl; preferably RCNis methyl(18) Ring C is selected from:wherein any of the above rings are optionally substituted on an available carbon atom by one or more independently selected Ring C substituents as defined in any one of paragraphs (14) to (16);RN1is selected from hydrogen or (1 -3C)alkyl; andRCNis selected from hydrogen or (1-3C)alkyl; preferably RCNis methyl.(18A) Ring C is selected from:wherein any of the above rings are optionally substituted on an available carbon atom by one or more independently selected Ring C substituents as defined in any one of paragraphs (14) to (16); andRN1is selected from hydrogen or (1 -3C)alkyl.(18B) Ring C is:wherein RN1is (1-3C)alkyl (e.g methyl).(18C) Ring C is selected from:P388833WO(18D) Ring C is selected from:(19A) Y is absent or a group of the formula:Y1- Y2- Y3wherein:Y1is absent or [CRYaRYb]n, wherein n is an integer from 1 to 2, wherein each occurrence of RYaand RYbis independently selected from hydrogen or methyl;Y2is absent or selected from -O-, -C(O)-, -C(O)O-, -OC(O)- or -N(RY1)-, wherein RY1is selected from hydrogen or (1 -2C)alkyl;Y3is absent or [CRYaRYb]n, wherein n is an integer from 1 to 2, wherein each occurrence of RYaand RYbis independently selected from hydrogen or methyl; Z is selected from (1 -4C)alkyl, (3-8C)cycloalkyl, 4 to 8 membered heterocyclyl (including monocyclic, spirocyclic, fused and bridged heterocycles), phenyl or 5 or 6 membered heteroaryl, wherein any of which may be optionally substituted by one or more substituents selected from hydroxy, halo, cyano, (1 -2C)alkyl, (1-2C)alkoxy, wherein the (1 -2C)alkyl or (1-2C)alkoxy are optionally further substituted by one or more substituents selected from halo, hydroxy or cyano.(20) Y is absent or a group of the formula:Y1-Y2wherein:Y1is absent or [CRYaRYb]n, wherein n is an integer from 1 to 2, wherein each occurrence of RYaand RYbis independently selected from hydrogen or methyl;Y2is absent or selected from -O-, -C(O)-, -C(O)O-, -OC(O)- or -N(RY1)-, wherein RY1is selected from hydrogen or (1 -2C)alkyl.(21) Y is absent or a group of the formula:Y1-Y2wherein:Y1is absent or selected from [CH2] or [CHMe];Y2is absent or selected from -O- or -N(RY1)-, wherein RY1is selected from hydrogen or methyl.(22) Y is absent or is selected from -CH2-, -CHMe-, -O- or -N(RY1)-, wherein RY1is selected from hydrogen or methyl.(23) Y is selected from -O- or -N(RY1)-, wherein RY1is selected from hydrogen or methyl.(23A) Y is selected from -O- or -NH-.(24) Z is selected from (1 -4C)alkyl, (3-8C)cycloalkyl, 4 to 8 membered heterocyclyl (including monocyclic, spirocyclic, fused and bridged heterocycles), phenyl or 5 or 6 membered heteroaryl, wherein any of which may be optionally substituted by one or more substituents selected from hydroxy, halo, cyano, (1 -2C)alkyl, (1-2C)alkoxy and NRZ2RZ3, wherein the (1 -2C)alkyl or (1-2C)alkoxy are optionally further substituted by one or more substituents selected from halo, hydroxy or cyano, and RZ2and RZ3are independently selected from hydrogen or (1 -2C)alkyl.(25) Z is selected from (1 -4C)alkyl, (3-6C)cycloalkyl, 4 to 8 membered heterocyclyl (including monocyclic, spirocyclic, fused and bridged heterocycles) or 5-membered heteroaryl, wherein any of which may be optionally substituted by one or more substituents selected from hydroxy, halo, (1 -2C)alkyl, (1-2C)alkoxy and NRZ2RZ3, wherein the (1 -2C)alkyl or (1-2C)alkoxy are optionally further substituted by one or more substituents selected from halo or hydroxy, and RZ2and RZ3are independently selected from hydrogen or (1 -2C)alkyl.(25A) Z is selected from (1 -3C)alkyl, (4-6C)cycloalkyl, 4 to 6 membered monocyclic heterocyclyl or 5-membered heteroaryl, wherein any of which may be optionally substituted by one or more substituents selected from hydroxy, fluoro, (1 -2C)alkyl or NHRZ3, wherein the (1 -2C)alkyl may be optionally further substituted by one or more substituents selected from fluoro or hydroxy, and RZ3is selected from methyl or ethyl.(26) Z is selected from (1 -2C)alkyl, (4-6C)cycloalkyl, 4 to 6 membered monocyclic heterocyclyl or 5-membered heteroaryl, wherein any of which may be optionally substituted by one or more substituents selected from hydroxy, fluoro or (1 -2C)alkyl, wherein the (1 -2C)alkyl may be optionally further substituted by one or more substituents selected from fluoro or hydroxy.(27) Z is a 4 to 6 membered monocyclic heterocyclyl, which may be optionally substituted by one or more substituents selected from hydroxy, fluoro or (1 -2C)alkyl, wherein the (1 -2C)alkyl may be optionally further substituted by one or more substituents selected from fluoro or hydroxy.(27A) Z is a 4 to 6 membered monocyclic oxygen containing heterocyclyl, which may be optionally substituted by one or more substituents selected from hydroxy, fluoro or (1 -2C)alkyl, wherein the (1-2C)alkyl may be optionally further substituted by one or more substituents selected from fluoro or hydroxy.(28) Z has a formula:wherein: z1 is an integer selected from 0, 1 or 2 z2 is an integer selected from 1 or 2; z3 is an integer selected from 1 , 2 or 3; each occurrence of Rziis independently selected from any of the optional Z group substituents as defined anywhere herein.wherein: z1 is an integer selected from 0 or 1 ; z2 is an integer selected from 1 or 2; z3 is an integer selected from 1 or 2; each occurrence of Rzi , if present, is independently selected from hydrogen, hydroxy, halo, cyano, methyl, methoxy, wherein the methyl or methoxy are optionally further substituted by one or more substituents selected from halo or hydroxy.(29A) Z has a formula:wherein: z1 is an integer selected from 0 or 1 ; z2 is 2; z3 is 1 ;Rzi , if present, is selected from hydroxy, fluoro or (1-2C)alkyl, wherein the (1 -2C)alkyl may be optionally further substituted by one or more substituents selected from fluoro or hydroxy.(29B) Z has a formula:wherein: z1 is an integer selected from 0, 1 or 2; each occurrence of Rzi, if present, is independently selected from any of the Z group substituents as defined anywhere herein.(29C) Z has a formula:wherein: z1 is an integer selected from 0, 1 or 2; each occurrence of Rzi, if present, is independently selected from hydrogen, hydroxy, halo, cyano, methyl, methoxy, wherein the methyl or methoxy are optionally further substituted by one or more substituents selected from halo or hydroxy.(29D) Z has a formula:wherein: z1 is an integer selected from 0, 1 or 2; each occurrence of Rzi , if present, is independently selected from hydroxy, fluoro or (1 -2C)alkyl, wherein the (1 -2C)alkyl may be optionally further substituted by one or more substituents selected from fluoro or hydroxy.(30) Z has a formula selected from:(31) W is absent or is methylene substituted by hydroxy.(32) W is absent.(33) X is a group of the formula:X1 - X2 - X3 wherein:Xi is absent or selected from -C(O)-, -C(O)-N(Rx1)-, -N(Rx2)-C(O)-N(Rx1)- or - N(Rx2)-C(O)-, wherein Rx1and R’'2are each independently selected from hydrogen or (1-3C)alkyl, ;X2 is absent or is -[CR^R^Jq, wherein Rx1and R’'2are independently selected from hydrogen or (1 -3C)alkyl, and q is an integer selected from 1 or 2;X3 is selected from (1-4C)alkyl, (3-10C)cycloalkyl or 4 to 12-membered heterocyclyl; andX3 is optionally substituted by one or more substituents independently selected from halo, hydroxy, NH2, (1-4C)alkyl, (1-4C)hydroxyalkyl, (1- 2C)alkoxy, (1-2C)haloalkyl or (1-2C)haloalkoxy.(34) X is a group of the formula:X1 - X2 - X3 wherein:Xi is absent or selected from -C(O)- or -C(O)-N(Rx1)-, wherein Rx1is selected from hydrogen or (1 -2C)alkyl;X2 is absent or is -[CRx3Rx4]q-, wherein Rx1and R’'2are independently selected from hydrogen or methyl, and q is an integer selected from 1 or 2;X3 is selected from (1-4C)alkyl, monocyclic (3-6C)cycloalkyl, bicyclic (4- 8C)cycloalkyl, 4 to 6-membered monocyclic heterocyclyl or 5- to 10- membered bicyclic heterocyclyl; andX3 is optionally substituted by one or more substituents independently selected from halo, hydroxy, NH2, (1-2C)alkyl, (1-2C)hydroxyalkyl, (1- 2C)alkoxy, (1-2C)haloalkyl or (1-2C)haloalkoxy.(35) X is a group of the formula:X1 - X2 - X3 wherein:Xi is absent or selected from -C(O)- or -C(O)-N(Rx1)-, wherein Rx1is selected from hydrogen or (1 -2C)alkyl;X2 is absent or is -[CRx3Rx4]q-, wherein Rx1and R’'2are independently selected from hydrogen or methyl, and q is 1 ;X3 is selected from (1-3C)alkyl, monocyclic (3-6C)cycloalkyl, bicyclic (4- 8C)cycloalkyl, 4 to 6-membered monocyclic heterocyclyl or 5- to 10- membered bicyclic heterocyclyl; andX3 is optionally substituted by one or more substituents independently selected from halo (e.g. fluoro), hydroxy, (1-2C)alkyl, (1-2C)hydroxyalkyl, (1- 2C)alkoxy or (1-2C)haloalkyl.(36) X is a group of the formula:X1 - X2- X3 wherein either: i) Xi is absent or selected from -C(O)-N(Rx1)-, wherein Rx1is selected from hydrogen or (1 -2C)alkyl;X2 is absent or is -[CRx3Rx4]q-, wherein Rx1and R’'2are independently selected from hydrogen or methyl, and q is 1 ;X3 is selected from (1-3C)alkyl, monocyclic (3-6C)cycloalkyl, bicyclic (4- 8C)cycloalkyl, 4 to 6-membered monocyclic heterocyclyl or 5- to 10- membered bicyclic heterocyclyl; andX3 is optionally substituted by one or more substituents independently selected from halo, hydroxy, NH2, (1-2C)alkyl, (1-2C)hydroxyalkyl, (1- 2C)alkoxy, (1-2C)haloalkyl or (1-2C)haloalkoxy; or ii) Xi is -C(O)-;X2 is absent;X3 is selected from a nitrogen-linked 4 to 6-membered monocyclic heterocyclyl or a nitrogen-linked 5- to 10-membered bicyclic heterocyclyl; and X3 is optionally substituted by one or more substituents independently selected from halo, hydroxy, (1 -2C)alkyl, (1-2C)hydroxyalkyl, (1-2C)alkoxy or (1-2C)haloalkyl.(37) X is selected from:

[0078] Suitably, a heteroaryl or heterocyclyl group as defined herein is a monocyclic heteroaryl or heterocyclyl group comprising one, two or three heteroatoms selected from N, O or S.

[0079] Suitably, a heteroaryl is a 5- or 6-membered aryl or heteroaryl ring comprising one, two or three heteroatoms selected from N, O or S.

[0080] Suitably, a heterocyclyl group is a 4-, 5- or 6-membered heterocyclyl ring comprising one, two or three heteroatoms selected from N, O or S. Most suitably, a heterocyclyl group is a 5- or 6-membered ring comprising one, two or three heteroatoms selected from N, O or S (preferably N or O), [e.g. morpholinyl (e.g. 4-morpholinyl), oxetane, methyloxetane (e.g. 3- methyloxetane), pyrrolidinone (e.g. pyrrolidin-2-one)].

[0081] Suitably, an aryl group is phenyl.

[0082] Suitably, Ring A is as defined in any one of paragraphs (1) to (7) above. More suitably, Ring A is as defined in any one of paragraphs (5) to (7) above. Most suitably, Ring A is as defined in paragraph (6) or (7) above.

[0083] Suitably, Ring A is as defined in any one of paragraphs (1) to (7B) above. More suitably, Ring A is as defined in any one of paragraphs (7), (7B) or (7A) above. Most suitably, Ring A is as defined in paragraph (7A) or (7B) above.

[0084] Suitably, RAis as defined in any one of paragraphs (8) to (10) or (10A) above. More suitably, RAis as defined in paragraph (9), (10) or (10A) above. Most suitably, RAis is as defined in paragraph (10) or (10A) above.

[0085] Suitably, Ring B is as defined in any one of paragraphs (11) to (14) above. More suitably, Ring B is as defined in paragraph (13) or (14) above. Most suitably, Ring B is as defined in paragraph (14) above.

[0086] Suitably, Ring B is as defined in any one of paragraphs (11) to (14B) above. More suitably, Ring B is as defined in any one of paragraphs (13A), (14), (14A) or (14B) above. Most suitably, Ring B is as defined in paragraph (14A) or (14B) above.

[0087] Suitably, Ring C is as defined in any one of paragraphs (15) to (19) above. More suitably, Ring C is as defined in any one of paragraphs (17) to (19) above. Most suitably, Ring C is as defined in paragraph (18) or (19) above.

[0088] Suitably, Ring C is as defined in any one of paragraphs (15) to (19) above. More suitably, Ring C is as defined in any one of paragraphs (17), (17A), (17B), (18), (18A), (18B) or (19) above. Most suitably, Ring C is as defined in paragraph (18D) or (19) above.

[0089] Suitably, Y is as defined in any one of paragraphs (20) to (23) above. More suitably,Y is as defined in paragraph (22) or (23) above. Most suitably, Y is as defined in paragraph (23) above.

[0090] Suitably, Y is as defined in any one of paragraphs (19A) to (23A) above. More suitably,Y is as defined in paragraph (23) or (23A) above. Most suitably, Y is as defined in paragraph (23A) above.

[0091] Suitably, Z is as defined in any one of paragraphs (24) to (30) above. More suitably, Z is as defined in any one of paragraphs (26) to (30) above. Most suitably, Z is as defined in paragraph (27), (28), (29) or (30) above.

[0092] Suitably, Z is as defined in any one of paragraphs (24), (25), (25A), (26), (27), (27A), (28), (29), (29A), (29B), (29C) or (30) above. More suitably, Z is as defined in any one of paragraphs (29A), (29B), (29C), (29D) or (30) above. Most suitably, Z is as defined in paragraph (29C) or (30) above.

[0093] Suitably, z1 is as defined in any one of paragraphs (28), (29) or (29a) above. Most suitably, z1 is as defined in paragraph (29).

[0094] Suitably, z2 is as defined in any one of paragraphs (28), (29) or (29a) above. More suitably, z2 is as defined in paragraph (29) or (29a) above. More suitably, z2 is as defined in paragraph (29a) above.

[0095] Suitably, z3 is as defined in any one of paragraphs (28), (29) or (29a) above. More suitably, z3 is as defined in paragraph (29) or (29a) above. More suitably, z3 is as defined in paragraph (29a) above.

[0096] Suitably, each occurrence of Rziis independently selected from any of the Z group substituents as defined in any one of paragraphs (24) to (27) above. More suitably, each occurrence of Rziis independently selected from any of the Z group substituents as defined in paragraph (27) or (28) above. Most suitably, each occurrence of Rziis independently selected from any of the Z group substituents as defined in paragraph (27) above.

[0097] Suitably, each occurrence of Rziis independently selected from any of the optional Z group substituents as defined in any one of paragraphs (24) to (29D) above. More suitably, each occurrence of Rziis independently selected from any of the optional Z group substituents as defined in paragraph (29C) or (27D) above. Most suitably, each occurrence of Rziis independently selected from any of the optional Z group substituents as defined in paragraph (29D) above.

[0098] Suitably, W is as defined in paragraph (31) or (32) above. Most suitably, W is as defined in paragraph (32) above.

[0099] Suitably, X is as defined in any one of paragraphs (33) to (37) above. More suitably, X is as deined in paragraph (36) or (37) above. Most suitably, X is as defined in paragraph (37) above.

[0100] In a particular group of compounds of the invention, Ring A is phenyl, i.e. the compounds have the structural formula (Ila) (a sub-definition of formula (I)) shown below:wherein Ring B, Ring C, Y and Z have any one of the meanings defined herein; and RA2 is selected from hydrogen or a group RAas defined anywhere herein; or a pharmaceutically acceptable salt thereof.

[0101] In an embodiment of the compounds of formula (Ila):RA2 is selected from hydrogen or a group RA; wherein RAis as defined in any one of paragraphs (8) to (10) above;Ring B is as defined in any one of paragraphs (11) to (14) above;Ring C is as defined in any one of paragraphs (15) to (19) above;Y is as defined in any one of paragraphs (20) to (23) above; andZ is as defined in any one of paragraphs (24) to (30) above.

[0102] In an embodiment of the compounds of formula (Ila):RA2 is selected from hydrogen or a group RA; wherein RAis as defined in paragraph (9) or (10) above;Ring B is as defined in paragraph (13) or (14) above;Ring C is as defined in any one of paragraphs (17) to (19) above;Y is as defined in paragraph (22) or (23) above; andZ is as defined in any one of paragraphs (26) to (30) above.

[0103] In an embodiment of the compounds of formula (Ila):RA2 is selected from hydrogen or a group RA; wherein RAis as defined in paragraph (10) above;Ring B is as defined in paragraph (14) above;Ring C is as defined in paragraph (18) or (19) above;Y is as defined in paragraph (22) or (23) above; andZ is as defined in paragraph (27) above.

[0104] In an embodiment of the compounds of formula (Ila):RA2 is selected from hydrogen or a group RA; wherein RAis as defined in paragraph (10) above;Ring B is as defined in paragraph (14) above;Ring C is as defined in paragraph (18) or (19) above;Y is as defined in paragraph (22) or (23) above; andZ is as defined in paragraph (28) above.

[0105] In an embodiment of the compounds of formula (Ila):RA2 is selected from hydrogen or a group RA; wherein RAis as defined in paragraph (10) above;Ring B is as defined in paragraph (14) above;Ring C is as defined in paragraph (18) or (19) above;Y is as defined in paragraph (22) or (23) above; andZ is as defined in paragraph (29) above.

[0106] In an embodiment of the compounds of formula (Ila):RA2 is selected from hydrogen or a group RA; wherein RAis as defined in paragraph (10) above;Ring B is as defined in paragraph (14) above;Ring C is as defined in paragraph (18) or (19) above;Y is as defined in paragraph (22) or (23) above; andZ is as defined in paragraph (30) above.

[0107] In an embodiment of the compounds of formula (Ila):RA2 is selected from hydrogen or a group RA; wherein RAis as defined in paragraph (10A) above;Ring B is as defined in paragraph (14A) or (14B) above;Ring C is as defined in paragraph (18D) or (19) above;Y is as defined in paragraph (23) or (23A) above; andZ is as defined in paragraph (29A), (29B), (29C), (29D) or (30), above.

[0108] In an embodiment of the compounds of formula (Ila):RA2 is selected from hydrogen or a group RA; wherein RAis as defined in paragraph (10A) above;Ring B is as defined in paragraph (14A) or (14B) above;Ring C is as defined in paragraph (18D) or (19) above;Y is as defined in paragraph (23) or (23A) above; andZ is as defined in paragraph (29D) or (30) above.

[0109] In a particular group of compounds of the invention, Ring A is pyridyl, i.e. the compounds have the structural formula (lib) (a sub-definition of formula (I)) shown below:wherein Ring B, Ring C, Y and Z have any one of the meanings defined herein; and RA2 is selected from hydrogen or a group RAas defined anywhere herein; or a pharmaceutically acceptable salt thereof.

[0110] In an embodiment of the compounds of formula (lib):Qi is selected from CH or N;RA2 is selected from hydrogen or a group RA; wherein RAis as defined in any one of paragraphs (8) to (10) above;Ring B is as defined in any one of paragraphs (11) to (14) above;Ring C is as defined in any one of paragraphs (15) to (19) above;Y is as defined in any one of paragraphs (20) to (23) above; andZ is as defined in any one of paragraphs (24) to (30) above.

[0111] In an embodiment of the compounds of formula (lib):RA2 is selected from hydrogen or a group RA; wherein RAis as defined in any one of paragraphs (8) to (10A) above;Ring B is as defined in any one of paragraphs (11) to (14B) above;Ring C is as defined in any one of paragraphs (15) to (19) above;Y is as defined in any one of paragraphs (19A) to (23A) above; andZ is as defined in any one of paragraphs (24), (25), (25A), (26), (27), (27A), (28), (29), (29A), (29B), (29C) or (30) above.

[0112] In an embodiment of the compounds of formula (lib):RA2 is selected from hydrogen or a group RA; wherein RAis as defined in paragraph (9) or (10) above;Ring B is as defined in paragraph (13) or (14) above;Ring C is as defined in any one of paragraphs (17) to (19) above;Y is as defined in paragraph (22) or (23) above; andZ is as defined in any one of paragraphs (26) to (30) above.

[0113] In an embodiment of the compounds of formula (lib):RA2 is selected from hydrogen or a group RA; wherein RAis as defined in paragraph (9), (10) or (10A) above;Ring B is as defined in paragraph (13A), (14), (14A) or (14B) above;Ring C is as defined in any one of paragraphs (17), (17A), (17B), (18), (18A), (18B), (18C), (18D) or (19) above;Y is as defined in paragraph (23) or (23A) above; andZ is as defined in any one of paragraphs (29A), (29B), (29C), (29D) or (30) above.

[0114] In an embodiment of the compounds of formula (lib):RA2 is selected from hydrogen or a group RA; wherein RAis as defined in paragraph (10) above;Ring B is as defined in paragraph (14) above;Ring C is as defined in paragraph (18) or (19) above;Y is as defined in paragraph (22) or (23) above; andZ is as defined in paragraph (27) above.

[0115] In an embodiment of the compounds of formula (lib):RA2 is selected from hydrogen or a group RA; wherein RAis as defined in paragraph (10) above;Ring B is as defined in paragraph (14) above;Ring C is as defined in paragraph (18) or (19) above;Y is as defined in paragraph (22) or (23) above; andZ is as defined in paragraph (28) above.

[0116] In an embodiment of the compounds of formula (lib):RA2 is selected from hydrogen or a group RA; wherein RAis as defined in paragraph (10) above;Ring B is as defined in paragraph (14) above;Ring C is as defined in paragraph (18) or (19) above;Y is as defined in paragraph (22) or (23) above; andZ is as defined in paragraph (29) above.

[0117] In an embodiment of the compounds of formula (lib):RA2 is selected from hydrogen or a group RA; wherein RAis as defined in paragraph (10) above;Ring B is as defined in paragraph (14) above;Ring C is as defined in paragraph (18) or (19) above;Y is as defined in paragraph (22) or (23) above; andZ is as defined in paragraph (30) above.

[0118] In an embodiment of the compounds of formula (lib):RA2 is selected from hydrogen or a group RA; wherein RAis as defined in paragraph (10A) above;Ring B is as defined in paragraph (14A) or (14B) above;Ring C is as defined in paragraph (18D) or (19) above;Y is as defined in paragraph (23) or (23A) above; andZ is as defined in paragraph (29A), (29B), (29C), (29D) or (30), above.

[0119] In an embodiment of the compounds of formula (lib):RA2 is selected from hydrogen or a group RA; wherein RAis as defined in paragraph (10A) above;Ring B is as defined in paragraph (14A) or (14B) above;Ring C is as defined in paragraph (18D) or (19) above;Y is as defined in paragraph (23) or (23A) above; andZ is as defined in paragraph (29D) above.

[0120] In an embodiment of the compounds of formula (lib):RA2 is selected from hydrogen or a group RA; wherein RAis as defined in paragraph (10A) above;Ring B is as defined in paragraph (14A) or (14B) above;Ring C is as defined in paragraph (18D) or (19) above;Y is as defined in paragraph (23) or (23A) above; andZ is as defined in paragraph (30) above.

[0121] In a particular group of compounds of the invention, Ring A is a 5-membered heterocyclic ring, i.e. the compounds have the structural formula (He) (a sub-definition of formula (I)) shown below:wherein Ring B, Ring C, Y and Z have any one of the meanings defined herein;Ai , A2, A3, A4 and As form a 5-membered heteroaryl ring, which is optionally substituted by 1 or 2 independently selected RAgroups.

[0122] In an embodiment of the compounds of formula (He): each occurrence of RAis independently as defined in any one of paragraphs (8) to (10) above;Ring B is as defined in any one of paragraphs (11) to (14) above;Ring C is as defined in any one of paragraphs (15) to (19) above;Y is as defined in any one of paragraphs (20) to (23) above; andZ is as defined in any one of paragraphs (24) to (30) above.

[0123] In an embodiment of the compounds of formula (He): each occurrence of RAis independently as defined in paragraph (9) or (10) above;Ring B is as defined in paragraph (13) or (14) above;Ring C is as defined in any one of paragraphs (17) to (19) above;Y is as defined in paragraph (22) or (23) above; andZ is as defined in any one of paragraphs (26) to (30) above.

[0124] In an embodiment of the compounds of formula (He): each occurrence of RAis independently as defined in paragraph (10) above;Ring B is as defined in paragraph (14) above;Ring C is as defined in paragraph (18) or (19) above;Y is as defined in paragraph (22) or (23) above; andZ is as defined in paragraph (27) above.

[0125] In an embodiment of the compounds of formula (He): each occurrence of RAis independently as defined in paragraph (10) above;Ring B is as defined in paragraph (14) above;Ring C is as defined in paragraph (18) or (19) above;Y is as defined in paragraph (22) or (23) above; andZ is as defined in paragraph (28) above.

[0126] In an embodiment of the compounds of formula (He): each occurrence of RAis independently as defined in paragraph (10) above;Ring B is as defined in paragraph (14) above;Ring C is as defined in paragraph (18) or (19) above;Y is as defined in paragraph (22) or (23) above; andZ is as defined in paragraph (29) above.

[0127] In an embodiment of the compounds of formula (He): each occurrence of RAis independently as defined in paragraph (10) above;Ring B is as defined in paragraph (14) above;Ring C is as defined in paragraph (18) or (19) above;Y is as defined in paragraph (22) or (23) above; andZ is as defined in paragraph (30) above.

[0128] In an embodiment of the compounds of formula (He): each occurrence of RAis independently as defined in paragraph (10) above;Ring B is as defined in paragraph (14A) or (14B) above;Ring C is as defined in paragraph (18D) or (19) above;Y is as defined in paragraph (23) or (23A) above; andZ is as defined in paragraph (29A), (29B), (29C), (29D) or (30), above.

[0129] In an embodiment of the compounds of formula (Hb): each occurrence of RAis independently as defined in paragraph (10) above;Ring B is as defined in paragraph (14A) or (14B) above;Ring C is as defined in paragraph (18D) or (19) above;Y is as defined in paragraph (23) or (23A) above; andZ is as defined in paragraph (29D) or (30) above.

[0130] In a particular group of compounds of the invention, i.e. the compounds have the structural formula (III) (a sub-definition of formula (I)) shown below, or a pharmaceutically acceptable salt thereof:wherein Ring A, Ring B, Ring C, W and Y have any one of the meanings defined herein; z1 is an integer selected from 0, 1 or 2; and each occurrence of Rziis selected from hydrogen or a group RAas defined anywhere herein; z2 is an integer selected from 1 or 2; z3 is an integer selected from 1 , 2 or 3; each occurrence of Rzi, if present, is independently selected from any of the Z group substituents as defined anywhere herein.

[0131] In an embodiment of the compounds of formula (III):Ring A is as defined in any one of paragraphs (1) to (7B) above;Ring B is as defined in any one of paragraphs (11) to (14) above;Ring C is as defined in any one of paragraphs (15) to (19) above;W is as defined in paragraph (31) or (32) above;Y is as defined in any one of paragraphs (20) to (23) above; z1 is an integer selected from 0, 1 or 2; z2 is an integer selected from 1 or 2; z3 is an integer selected from 1 , 2 or 3;each occurrence of Rzi, if present, is independently selected from any of the optional Z group substituents as defined in any one of paragraphs (24) to (27) above.

[0132] In an embodiment of the compounds of formula (III):Ring A is as defined in any one of paragraphs (5) to (7B) above;Ring B is as defined in paragraph (13) or (14) above;Ring C is as defined in any one of paragraphs (17) to (19) above;W is as defined in paragraph (31) or (32) above;Y is as defined in paragraph (22) or (23) above; and z1 is an integer selected from 0 or 1 ; z2 is an integer selected from 1 or 2; z3 is an integer selected from 1 or 2; each occurrence of Rzi, if present, is independently selected from any of the optional Z group substituents as defined in paragraph (27) or (28) above.

[0133] In an embodiment of the compounds of formula (III):Ring A is as defined in paragraph (7A) or (7B) above;Ring B is as defined in paragraph (14) above;Ring C is as defined in paragraph (18) or (19) above;W is as defined in paragraph (31) or (32) above;Y is as defined in paragraph (22) or (23) above; and z1 is an integer selected from 0 or 1 ; z2 is an integer selected from 1 or 2; z3 is an integer selected from 1 or 2; each occurrence of Rzi, if present, is independently selected from any of the optional Z group substituents as defined in paragraph (27) above.

[0134] In an embodiment of the compounds of formula (III):Ring A is as defined in any one of paragraphs (1) to (7B) above;Ring B is as defined in any one of paragraphs (11) to (14B) above;Ring C is as defined in any one of paragraphs (15) to (19) above;W is as defined in paragraph (31) or (32) above;Y is as defined in any one of paragraphs (19A) to (23A) above; z1 is as defined in any one of paragraphs (28), (29) or (29A) above; z2 is as defined in any one of paragraphs (28), (29) or (29A) above; z3 is as defined in any one of paragraphs (28), (29) or (29A) above; each occurrence of Rziis independently selected from any of the optional Z group substituents as defined in any one of paragraphs (24) to (29D) above.

[0135] In an embodiment of the compounds of formula (III):Ring A is as defined in any one of paragraphs (7), (7B) or (7A) above;Ring B is as defined in paragraph (13A), (14), (14A) or (14B) above;Ring C is as defined in any one of paragraphs (17), (17A), (17B), (18), (18A), (18B), (18C), (18D) or (19) above;W is as defined in paragraph (31) or (32) above;Y is as defined in paragraph (23) or (23A) above; and z1 is as paragraph (29a) above; z2 is as defined in paragraph (29) or (29A) above. z3 is as defined in paragraph (29) or (29A) above; and each occurrence of Rz1 is independently selected from any of the optional Z group substituents as defined in paragraph (29C) or (27D) above.

[0136] In an embodiment of the compounds of formula (III):Ring A is as defined in paragraph (7A) or (7B) above;Ring B is as defined in paragraph (14A) or (14B) above;Ring C is as defined in paragraph (18D) or (19) above;W is as defined in paragraph (32) above;Y is as defined in paragraph (23A) above; z1 is as defined in paragraph (29A); z2 is as defined in paragraph (29A) above; z3 is as defined in paragraph (29A) above; each occurrence of Rzi, if present, is independently selected from any of the optional Z group substituents as defined in paragraph (29A) above.

[0137] In any of the embodiments of Formula (III) described above, W may be absent, thus the compounds have the structural formula (Illa) (a sub-definition of formula (I)) shown below, or a pharmaceutically acceptable salt thereof:wherein Ring A, Ring B, Ring C, Y, z1 , z2, z3 and Rzihave any one of the meanings defined herein.

[0138] In a particular group of compounds of the invention, i.e. the compounds have the structural formula (IV) (a sub-definition of formula (I)) shown below, or a pharmaceutically acceptable salt thereof:wherein Ring B, Ring C, W, Qi , RA2, Y, Z1 , RZI , z2 and z3 are as defined anywhere herein.

[0139] In an embodiment of the compounds of formula (IV):Qi is selected from CH or N;RA2 is a group RAas defined in any one of paragraphs (8) to (10) or (10A) above;Ring B is as defined in any one of paragraphs (11) to (14B) above;W is as defined in paragraph (31) or (32) above;Ring C is as defined in any one of paragraphs (15) to (19) above;Y is as defined in any one of paragraphs (20) to (23) above; and z1 is as defined in any one of paragraphs (28), (29) or (29A) above; z2 is as defined in any one of paragraphs (28), (29) or (29A) above;z3 is as defined in any one of paragraphs (28), (29) or (29A) above; and each occurrence of Rziis independently selected from any of the optional Z group substituents as defined in any one of paragraphs (24) to (29D) above.

[0140] In an embodiment of the compounds of formula (IV):Qi is selected from CH or N;RA2 is a group RAas defined in paragraph (9), (10) or (10A) above;Ring B is as defined in any one of paragraphs (13A), (14), (14A) or (14B) above;Ring C is as defined in any one of paragraphs (17), (17A), (17B), (18), (18A), (18B) or (19) above;W is as defined in paragraph (31) or (32) above;Y is as defined in paragraph (22) or (23) above; and z1 is as paragraph (29A) above; z2 is as defined in paragraph (29) or (29A) above. z3 is as defined in paragraph (29) or (29A) above; and each occurrence of Rz1 is independently selected from any of the optional Z group substituents as defined in paragraph (29) or (29A) above.

[0141] In an embodiment of the compounds of formula (IV):Qi is selected from CH or N;RA2 is a group RAas defined in paragraph (10) or (10A) above;Ring A is as defined in paragraph (7A) or (7B) above;Ring B is as defined in paragraph (14A) or (14B) above;W is as defined in paragraph (32) above;Ring C is as defined in paragraph (18D) or (19) above;Y is as defined in paragraph (23A) above; z1 is as defined in paragraph (29A); z2 is as defined in paragraph (29A) above; z3 is as defined in paragraph (29A) above; and each occurrence of Rziis independently selected from any of the optional Z group substituents as defined in paragraph (29A) above.

[0142] In any of the embodiments of Formula (IV) described above, W may be absent, thus the compounds have the structural formula (IVa) (a sub-definition of formula (I)) shown below, or a pharmaceutically acceptable salt thereof:wherein Ring B, Ring C, Qi, RA2, Y, Z1 , RZI , z2 and z3 are as defined anywhere herein.

[0143] In a particular group of compounds of the invention, i.e. the compounds have the structural formula (V) or (VI) (sub-definitions of formula (I)) shown below, or a pharmaceutically acceptable salt thereof:wherein Ring B, Ring C, RA2, RB2QI, Y, Z and RB2have any one of the meanings defined herein.

[0144] In an embodiment of the compounds of formula (V) or (VI):Qi is selected from CH or N;RA2 is a group RAas defined in any one of paragraphs (8) to (10) or (10A) above;RB2is selected from hydrogen or (1 -2C)alkyl;W is as defined in paragraph (31) or (32) above;Ring C is as defined in any one of paragraphs (15) to (19) above;Y is as defined in any one of paragraphs (19A) to (23A) above; andZ is as defined in any one of paragraphs (24), (25), (25A), (26), (27), (27A), (28), (29), (29A), (29B), (29C) or (30) above.

[0145] In an embodiment of the compounds of formula (V) or (VI):Qi is selected from CH or N;RA2 is a group RAas defined in paragraph (9), (10) or (10A) above;RB2is selected from hydrogen or (1 -2C)alkyl;W is as defined in paragraph (31) or (32) above;Ring C is as defined in any one of paragraphs (17), (17A), (17B), (18), (18A), (18B), or (19) above;Y is as defined in paragraph (23) or (23A) above; andZ is as defined in any one of paragraphs (29A), (29B), (29C), (29D) or (30) above.

[0146] In an embodiment of the compounds of formula (V) or (VI):Qi is selected from CH or N;RA2 is a group RAas defined in paragraph (10) above;RB2is selected from hydrogen or methyl;W is as defined in paragraph (31) or (32) above;Ring C is as defined in paragraph (18D) or (19) above;Y is as defined in paragraph (23) or (23A) above; andZ is as defined in paragraph (29D) or (30) above.

[0147] In an embodiment of the compounds of formula (V) or (VI):Qi is selected from CH or N;RA2 is a group RAas defined in paragraph (10) above;RB2is selected from hydrogen or methyl;W is as defined in paragraph (32) above;Ring C is as defined in paragraph (18D) above;Y is as defined in paragraph (23A) above; and Z is as defined in paragraph (29D) above.

[0148] In a particular group of compounds of the invention, i.e. the compounds have the structural formula (Vila) or (Villa) (sub-definitions of formula (I)) shown below, or a pharmaceutically acceptable salt thereof:wherein wherein Ring C, Qi, W, Y, RA2, RB2, Z1 , RZI , z2 and z3 are as defined anywhere herein.

[0149] In an embodiment of the compounds of formula (VII) or (VIII):Qi is selected from CH or N;RA2 is a group RAas defined in any one of paragraphs (8) to (10) or (10A) above;RB2is selected from hydrogen or (1 -2C)alkyl;W is as defined in paragraph (31) or (32) above;Ring C is as defined in any one of paragraphs (15) to (19) above;Y is as defined in any one of paragraphs (19A) to (23A) above; z1 is as defined in any one of paragraphs (28), (29) or (29A) above; z2 is as defined in any one of paragraphs (28), (29) or (29A) above; z3 is as defined in any one of paragraphs (28), (29) or (29A) above; and each occurrence of Rziis independently selected from any of the optional Z group substituents as defined in any one of paragraphs (24) to (29D) above.

[0150] In an embodiment of the compounds of formula (VII) or (VIII):Qi is selected from CH or N;RA2 is a group RAas defined in paragraph (9), (10) or (10A) above;RB2is selected from hydrogen or (1 -2C)alkyl;W is as defined in paragraph (31) or (32) above;Ring C is as defined in any one of paragraphs (17), (17A), (17B), (18), (18A), (18B), or (19) above;Y is as defined in paragraph (23) or (23A) above; z1 is as paragraph (29A) above; z2 is as defined in paragraph (29) or (29A) above. z3 is as defined in paragraph (29) or (29A) above; and each occurrence of Rz1 is independently selected from any of the optional Z group substituents as defined in paragraph (29) or (29A) above.

[0151] In an embodiment of the compounds of formula (VII) or (VIII):Qi is selected from CH or N;RA2 is a group RAas defined in paragraph (10) above;RB2is selected from hydrogen or methyl;W is as defined in paragraph (31) or (32) above;Ring C is as defined in paragraph (18D) or (19) above;Y is as defined in paragraph (23) or (23A) above; z1 is as defined in paragraph (29A);z2 is as defined in paragraph (29A) above; z3 is as defined in paragraph (29A) above; and each occurrence of Rziis independently selected from any of the optional Z group substituents as defined in paragraph (29A) above.

[0152] In an embodiment of the compounds of formula (VII) or (VIII):Qi is selected from CH or N;RA2 is a group RAas defined in paragraph (10) above;RB2is selected from hydrogen or methyl;W is as defined in paragraph (32) above;Ring C is as defined in paragraph (18D) above;Y is as defined in paragraph (23A) above; z1 is as defined in paragraph (29A); z2 is as defined in paragraph (29A) above; z3 is as defined in paragraph (29A) above; and each occurrence of Rziis independently selected from any of the optional Z group substituents as defined in paragraph (29A) above.

[0153] In a particular group of compounds of the invention, i.e. the compounds have the structural formula (QI) (a sub-definition of formula (Q)) shown below, or a pharmaceutically acceptable salt thereof:wherein Ring B, Ring C, Qi, RA2, X, Y, z1 , Rzi, z2 and z3 are as defined anywhere herein.

[0154] In an embodiment of the compounds of formula (QI):Qi is selected from CH or N;RA2 is a group RAas defined in any one of paragraphs (8) to (10) or (10A) above;Ring B is as defined in any one of paragraphs (11) to (14B) above;X is as defined in any one of paragraphs (33) to (37) above;Y is as defined in any one of paragraphs (19A) to (23A) above; andZ is as defined in any one of paragraphs (24), (25), (25A), (26), (27), (27A), (28), (29), (29A), (29B), (29C) or (30) above.

[0155] In an embodiment of the compounds of formula (QI):Qi is selected from CH or N;RA2 is a group RAas defined in paragraph (9), (10) or (10A) above;Ring B is as defined in paragraph (13A), (14), (14A) or (14B) above;X is as deined in paragraph (36) or (37) above;Y is as defined in paragraph (23) or (23A) above; andZ is as defined in any one of paragraphs (29A), (29B), (29C), (29D) or (30) above.

[0156] In an embodiment of the compounds of formula (QI):Qi is selected from CH or N;RA2 is a group RAas defined in paragraph (10) above;Ring B is as defined in paragraph (14A) or (14B) above;X is as defined in paragraph (37) above;Y is as defined in paragraph (23) or (23A) above; andZ is as defined in paragraph (29D) or (30) above.

[0157] In an embodiment of the compounds of formula (QI):Qi is selected from CH or N;RA2 is a group RAas defined in paragraph (10) above;Ring B is as defined in paragraph (14A) or (14B) above;X is as defined in paragraph (37) above;Y is as defined in paragraph (23A) above; andZ is as defined in paragraph (29D) above.

[0158] In a particular group of compounds of the invention, i.e. the compounds have the structural formula (QI I) (a sub-definition of formula (Q)) shown below, or a pharmaceutically acceptable salt thereof:wherein Ring B, Qi, RA2, QI , X, Y, z1 , RA2, zi, Z2 and z3 are as defined anywhere herein.

[0159] In an embodiment of the compounds of formula (Qll):Qi is selected from CH or N;RA2 is a group RAas defined in any one of paragraphs (8) to (10) or (10A) above;Ring B is as defined in any one of paragraphs (11) to (14B) above;X is as defined in any one of paragraphs (33) to (37) above;Y is as defined in any one of paragraphs (19A) to (23A) above; z1 is as defined in any one of paragraphs (28), (29) or (29A) above; z2 is as defined in any one of paragraphs (28), (29) or (29A) above; z3 is as defined in any one of paragraphs (28), (29) or (29A) above; each occurrence of Rziis independently selected from any of the optional Z group substituents as defined in any one of paragraphs (24) to (29D) above.

[0160] In an embodiment of the compounds of formula (Qll):Qi is selected from CH or N;RA2 is a group RAas defined in paragraph (9), (10) or (10A) above;Ring B is as defined in paragraph (13A), (14), (14A) or (14B) above;X is as deined in paragraph (36) or (37) above;Y is as defined in paragraph (23) or (23A) above; z1 is as paragraph (29a) above; z2 is as defined in paragraph (29) or (29A) above. z3 is as defined in paragraph (29) or (29A) above; andeach occurrence of Rz1 is independently selected from any of the optional Z group substituents as defined in paragraph (29C) or (27D) above.

[0161] In an embodiment of the compounds of formula (QI I):Qi is selected from CH or N;RA2 is a group RAas defined in paragraph (10) above;Ring B is as defined in paragraph (14A) or (14B) above;X is as defined in paragraph (37) above;Y is as defined in paragraph (23) or (23A) above; and z1 is as defined in paragraph (29A); z2 is as defined in paragraph (29A) above; z3 is as defined in paragraph (29A) above; each occurrence of Rzi, if present, is independently selected from any of the optional Z group substituents as defined in paragraph (29A) above.

[0162] In an embodiment of the compounds of formula (QI I):Qi is selected from CH or N;RA2 is a group RAas defined in paragraph (10) above;X is as defined in paragraph (37) above;Y is as defined in paragraph (23A) above; and z1 is as defined in paragraph (29A); z2 is as defined in paragraph (29A) above; z3 is as defined in paragraph (29A) above; each occurrence of Rzi, if present, is independently selected from any of the optional Z group substituents as defined in paragraph (29A) above.

[0163] Particular compounds of the present invention include any of the compounds exemplified in the present application, or a pharmaceutically acceptable salt thereof, and, in particular, any of the following:4-(3-Methylpyridin-2-yl)-N-(4-((tetrahydrofuran-3-yl)-methyl)thiazol-2-yl)thiophene-2- carboxamide;4-(3-Methylpyridin-2-yl)-N-(4-(((3R)-tetrahydrofuran-3-yl)-methyl)thiazol-2-yl)thiophene-2- carboxamide;4-(3-Methylpyridin-2-yl)-N-(4-(((3S)-tetrahydrofuran-3-yl)-methyl)thiazol-2-yl)thiophene-2- carboxamide;5-(5-(3,3-Difluoroazetidin-1-yl)pyridin-2-yl)-1-methyl-N-(4-((tetrahydrofuran-3- yl)methyl)thiazol-2-yl)-1 H-pyrrole-3-carboxamide;5-(3,5-difluoropyridin-2-yl)-1-methyl-N-(4-((tetrahydrofuran-3-yl)methyl)thiazol-2-yl)-1H- pyrrole-3-carboxamide;5-Methyl-4-(5-((1-methylazetidin-3-yl)oxy)pyrimidin-2-yl)-N-(4-((tetrahydrofuran-3- yl)methyl)thiazol-2-yl)thiophene-2-carboxamide;1-Methyl-5-(pyrimidin-2-yl)-N-(4-((tetrahydrofuran-3-yl)methyl)thiazol-2-yl)-1 H-pyrrole-3- carboxamide;1-(Pyridin-2-yl)-N-(4-((tetrahydrofuran-3-yl)methyl)thiazol-2-yl)-1H-pyrazole-4-carboxamide;5-Methyl-1-(pyrimidin-2-yl)-N-(4-((tetrahydrofuran-3-yl)methyl)thiazol-2-yl)-1 H-pyrrole-3- carboxamide;4-(4-methyl-3-oxopiperazin-1-yl)-N-(4-((tetrahydrofuran-3-yl)methyl)thiazol-2-yl)thiophene-2- carboxamide;5-(5-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyridin-2-yl)-1-methyl-N-(4-((tetrahydrofuran-3- yl)methyl)thiazol-2-yl)-1 H-pyrrole-3-carboxamide;5-(5-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyridin-2-yl)-1-methyl-N-(4-(((3R)-tetrahydrofuran-3- yl)methyl)thiazol-2-yl)-1 H-pyrrole-3-carboxamide;5-(5-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyridin-2-yl)-1-methyl-N-(4-(((3S)-tetrahydrofuran-3- yl)methyl)thiazol-2-yl)-1 H-pyrrole-3-carboxamide;5-(Hydroxymethyl)-4-(3-methylpyridin-2-yl)-N-(4-((tetrahydrofuran-3-yl)methyl)thiazol-2- yl)thiophene-2-carboxamide;4-(3-(Hydroxymethyl)pyridin-2-yl)-N-(4-((tetrahydrofuran-3-yl)methyl)thiazol-2-yl)thiophene-2- carboxamide;4-(3-(Hydroxymethyl)pyridin-2-yl)-N-(4-(((3R)-tetrahydrofuran-3-yl)methyl)thiazol-2- yl)thiophene-2-carboxamide;4-(3-(Hydroxymethyl)pyridin-2-yl)-N-(4-(((3S)-tetrahydrofuran-3-yl)methyl)thiazol-2- yl)thiophene-2-carboxamide;N-(5-Methyl-4-((tetrahydrofuran-3-yl)methyl)thiazol-2-yl)-4-(3-methylpyridin-2-yl)thiophene-2- carboxamide;4-(3-Methylpyridin-2-yl)-N-(4-(tetrahydrofuran-3-yl)thiazol-2-yl)thiophene-2-carboxamide;4-(3-Methylpyridin-2-yl)-N-(4-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl)thiophene-2- carboxamide;3-(5-Methyl-1 ,2,4-oxadiazol-3-yl)-N-(4-((tetrahydrofuran-3-yl)methyl)thiazol-2-yl)pyrrolidine- 1 -carboxamide;3-(5-methyl-1 ,2,4-oxadiazol-3-yl)-N-(5-methyl-4-((tetrahydrofuran-3-yl)methyl)thiazol-2- yl)pyrrolidine-1 -carboxamide;3-(3-methylpyridin-2-yl)-N-(4-((tetrahydrofuran-3-yl)methyl)thiazol-2-yl)pyrrolidine-1- carboxamide;3-(5-Methyl-1 ,2,4-oxadiazol-3-yl)-N-(3-((tetrahydrofuran-3-yl)methyl)phenyl)pyrrolidine-1- carboxamide;4-(3-Methylpyridin-2-yl)-N-(3-((tetrahydrofuran-3-yl)methyl)phenyl)thiophene-2-carboxamide;4-(3-Methylpyridin-2-yl)-N-(6-((tetrahydrofuran-3-yl)methyl)pyridin-2-yl)thiophene-2- carboxamide;4-(3-Methylpyridin-2-yl)-N-(3-((tetrahydrofuran-3-yl)amino)phenyl)thiophene-2-carboxamide;4-(3-Methylpyridin-2-yl)-N-(3-(((3R)-tetrahydrofuran-3-yl) amino) phenyl) thiophene-2- carboxamide;4-(3-Methylpyridin-2-yl)-N-(3-(((3S)-tetrahydrofuran-3-yl) amino) phenyl) thiophene-2- carboxamide;4-(3-Methylpyridin-2-yl)-N-(3-(oxetan-3-ylamino)phenyl)thiophene-2-carboxamide;4-(3-Methylpyridin-2-yl)-N-(6-((tetrahydrofuran-3-yl)amino)pyridin-2-yl)thiophene-2- carboxamide;4-(3-Methylpyridin-2-yl)-N-(3-((tetrahydrofuran-3-yl)oxy)phenyl)thiophene-2-carboxamide;N-(3-Chloro-5-((tetrahydrofuran-3-yl)amino)phenyl)-4-(3-methylpyridin-2-yl)thiophene-2- carboxamide;N-(3-Chloro-5-(((3R)-tetrahydrofuran-3-yl)amino)phenyl)-4-(3-methylpyridin-2-yl)thiophene-2- carboxamide;N-(3-Chloro-5-(((3S)-tetrahydrofuran-3-yl)amino)phenyl)-4-(3-methylpyridin-2-yl)thiophene-2- carboxamide;N-(3-Chloro-5-(oxazol-2-ylamino)phenyl)-4-(3-methylpyridin-2-yl)thiophene-2-carboxamide;N-(3-Chloro-5-((2-hydroxyethyl)amino)phenyl)-4-(3-methylpyridin-2-yl)thiophene-2- carboxamide;N-(3-Chloro-5-((3-methyltetrahydrofuran-3-yl)amino)phenyl)-4-(3-methylpyridin-2- yl)thiophene-2-carboxamide;N-(3-Chloro-5-((tetrahydrofuran-3-yl)amino)phenyl)-5-methyl-4-(pyrimidin-2-yl)thiophene-2- carboxamide;N-(3-Chloro-5-((tetrahydrofuran-3-yl)amino)phenyl)-5-methyl-4-(5-((1-methylazetidin-3- yl)oxy)pyrimidin-2-yl)thiophene-2-carboxamide;N-(3-Chloro-5-((tetrahydrofuran-3-yl)amino)phenyl)-5-(3,5-difluoropyridin-2-yl)-1-methyl-1 H- pyrrole- 3-carboxamide;N-(3-Chloro-5-((tetrahydrofuran-3-yl)amino)phenyl)-4-(3-(hydroxymethyl)pyridin-2- yl)thiophene-2-carboxamide;A / -(3-(lsoxazol-3-yl)phenyl)-4-(3-methylpyridin-2-yl)thiophene-2-carboxamide;4-(3-Methylpyridin-2-yl)-N-(3-(pyrrolidin-3-ylmethyl)phenyl)thiophene-2-carboxamide; or4-(3-Methylpyridin-2-yl)-N-(1-((tetrahydrofuran-3-yl)methyl)-1H-pyrazol-4-yl)thiophene-2- carboxamide.

[0164] Further particular compounds of the present invention include any of the compounds exemplified in the present application, or a pharmaceutically acceptable salt thereof, and, in particular, any of the following:N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-methyl-4-[5-(1-methylazetidin-3- yl)oxypyrimidin-2-yl]thiophene-2-carboxamide;N-[3-chloro-5-[[(3R)-tetrahydrofuran-3-yl]amino]phenyl]-5-methyl-4-[5-(1-methylazetidin-3- yl)oxypyrimidin-2-yl]thiophene-2-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-(3,5-difluoro-2-pyridyl)-1 -methylpyrrole- 3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-4-[3-(methoxymethyl)-2- pyridyl]thiophene-2-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-4-(3-methoxy-2-pyridyl)thiophene-2- carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-4-(3-cyano-2-pyridyl)thiophene-2- carboxamide;2-[5-[[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]carbamoyl]-3-thienyl]-N-methyl- pyridine-3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-1-methyl-5-(1-methyltriazol-4- yl)pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-1-methyl-5-[5-(1-methylazetidin-3- yl)oxypyrimidin-2-yl]pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-1-methyl-5-pyrimidin-2-yl-pyrrole-3- carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-[3-(hydroxymethyl)-2-pyridyl]-1- methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-(3-cyano-5-fluoro-2-pyridyl)-1- methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-(5-fluoro-3-methoxy-2-pyridyl)-1- methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-(5-fluoropyrimidin-2-yl)-1 -methylpyrrole- 3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-(3-fluoro-5-methoxy-2-pyridyl)-1- methyl-pyrrole- 3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-1-methyl-5-(1-methyl-1,2,4-triazol-3- yl)pyrrole- 3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-1-methyl-5-(1-methylpyrazol-3- yl)pyrrole- 3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-1-methyl-5-(1-methylpyrazol-4- yl)pyrrole- 3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-1-methyl-5-(5-methyl-1,2,4- oxadiazol-3-yl)pyrrole- 3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-1-methyl-5-(1-methylimidazol-4- yl)pyrrole- 3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-[5-fluoro-3-(hydroxymethyl)-2- pyridyl]-1-methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-[3-(1-hydroxy-1-methyl-ethyl)-2- pyridyl]-1-methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-cyclopropyl-1-methyl-pyrrole-3- carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-5-methyl-4-pyrimidin-2-yl- thiophene-2-carboxamide;N-[4-chloro-6-[[(3R)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-5-methyl-4-pyrimidin-2-yl- thiophene-2-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-5-(3,5-difluoro-2-pyridyl)-1-methyl- pyrrole- 3-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-5-(5-fluoro-3-methoxy-2-pyridyl)-1- methyl-pyrrole- 3-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-5-(3-cyano-5-fluoro-2-pyridyl)-1- methyl-pyrrole- 3-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-5-(5-fluoropyrimidin-2-yl)-1- methyl-pyrrole- 3-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-5-(3-fluoro-5-methoxy-2-pyridyl)-1- methyl-pyrrole- 3-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-1-methyl-5-(1-methyltriazol-4- yl)pyrrole- 3-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-1-methyl-5-(1-methylpyrazol-3- yl)pyrrole- 3-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-1-methyl-5-(1-methylpyrazol-4- yl)pyrrole- 3-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-1-methyl-5-(1-methyl-1 ,2,4-triazol- 3-yl)pyrrole- 3-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-1-methyl-5-(1-methylimidazol-4- yl)pyrrole- 3-carboxamide;5-[5-(azetidin-3-yloxy)-3-fluoro-2-pyridyl]-N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2- pyridyl]- 1-methyl-pyrrole-3-carboxamide;5-[5-(azetidin-3-yloxy)-3-fluoro-2-pyridyl]-N-[3-chloro-5-[[(3S)-tetrahydrofuran-3- yl]amino]phenyl]-1-methyl-pyrrole- 3-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-5-[3-fluoro-5-(1-methylazetidin-3- yl)oxy-2-pyridyl]-1 -methyl-pyrrole- 3-carboxamide;5-[5-(azetidin-3-yloxy)pyrimidin-2-yl]-N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2- pyridyl]-1-methyl-pyrrole-3-carboxamide;5-[5-(azetidin-3-yloxy)pyrimidin-2-yl]-N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]- 1 -methyl-pyrrole- 3-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-5-[5-fluoro-3-(hydroxymethyl)-2- pyridyl]-1-methyl-pyrrole-3-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-1-methyl-5-[5-(1-methylazetidin-3- yl)oxypyrimidin-2-yl]pyrrole-3-carboxamide;N-[3-chloro-5-(oxetan-3-ylamino)phenyl]-4-(3-methyl-2-pyridyl)thiophene-2-carboxamide;N-[3-chloro-5-(oxetan-3-ylamino)phenyl]-5-(3,5-difluoro-2-pyridyl)-1-methyl-pyrrole-3- carboxamide;N-[3-chloro-5-(oxetan-3-ylamino)phenyl]-5-methyl-4-pyrimidin-2-yl-thiophene-2-carboxamide;N-[3-chloro-5-[methyl(tetrahydrofuran-3-yl)amino]phenyl]-4-(3-methyl-2-pyridyl)thiophene-2- carboxamide;N-(3-chloro-5-tetrahydrofuran-3-yloxy-phenyl)-4-(3-methyl-2-pyridyl)thiophene-2- carboxamide;N-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-5-(3,5-difluoro-2-pyridyl)-1-methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-5-(3,5-difluoro-2-pyridyl)-1-methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S,4R)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-5-(3,5-difluoro-2-pyridyl)-1-methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3R,4R)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-5-(3,5-difluoro-2-pyridyl)-1-methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S,4R)-4-hydroxytetrahydrofuran-3-yl]amino]phenyl]-5-(3,5-difluoro-2- pyridyl)-1-methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3R,4S)-4-hydroxytetrahydrofuran-3-yl]amino]phenyl]-5-(3,5-difluoro-2- pyridyl)-1-methyl-pyrrole-3-carboxamide;N-[4-chloro-6-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]-2-pyridyl]-1-methyl-5-(1- methyltriazol-4-yl) pyrrole-3-carboxam ide;N-[4-chloro-6-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]-2-pyridyl]-1-methyl-5-(1- methyltriazol-4-yl) pyrrole-3-carboxam ide;N-[4-chloro-6-[[(3S,4R)-4-fluorotetrahydrofuran-3-yl]amino]-2-pyridyl]-1-methyl-5-(1- methyltriazol-4-yl) pyrrole-3-carboxam ide;N-[3-chloro-5-[[(3S,4S)-4-methyltetrahydrofuran-3-yl]amino]phenyl]-5-(3,5-difluoro-2-pyridyl)-1-methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3R,4S)-4-methoxytetrahydrofuran-3-yl]amino]phenyl]-5-(3,5-difluoro-2- pyridyl)-1-methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S,4S)-4-hydroxytetrahydrofuran-3-yl]amino]phenyl]-4-(3-methyl-2- pyridyl)thiophene-2-carboxamide;N-[3-chloro-5-[[(3S,4R)-4-hydroxytetrahydrofuran-3-yl]amino]phenyl]-4-(3-methyl-2- pyridyl)thiophene-2-carboxamide;N-[3-chloro-5-(tetrahydrofu ran-3-ylamino)phenyl]-5-[3- fluoro- 5-(1-methylazetidin-3-yl)oxy-2- pyridyl]- 1-methyl-pyrrole-3-carboxamide;N-[3-chloro-5-(tetrahydrofuran-3-ylamino)phenyl]-1-methyl-5-[5-(1-methylazetidin-3-yl)oxy-2- pyridyl]pyrrole-3-carboxamide;4-[5-(azetidin-3-yloxy)pyrimidin-2-yl]-N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-methyl-thiophene-2-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-methyl-4-(1-methyltriazol-4- yl)thiophene-2-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-5-methyl-4-(1-methyltriazol-4- yl)thiophene-2-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-1-methyl-5-(1-methylimidazol-2- yl)pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-1-methyl-5-(1-methylimidazol-2- yl)pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-1-methyl-5-(2-methyltriazol-4- yl)pyrrole-3-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-1-methyl-5-(2-methyltriazol-4- yl)pyrrole- 3-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-1-methyl-5-(4-methyl-1 ,2,4-triazol- 3-yl)pyrrole- 3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-1-methyl-5-(4-methyl-1 ,2,4-triazol-3- yl)pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-(2,5-dimethyltriazol-4-yl)-1-methyl- pyrrole- 3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-(1 ,5-dimethyltriazol-4-yl)-1-methyl- pyrrole- 3-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-5-(1 ,5-dimethyltriazol-4-yl)-1- methyl-pyrrole- 3-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-5-(2,5-dimethyltriazol-4-yl)-1- methyl-pyrrole- 3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-(3,5-difluoro-2-pyridyl)-1-(2- hydroxyethyl)pyrrole-3-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-5-(1-isopropyltriazol-4-yl)-1- methyl-pyrrole- 3-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-5-(2-isopropyltriazol-4-yl)-1- methyl-pyrrole- 3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-(1-isopropyltriazol-4-yl)-1-methyl- pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-(2-isopropyltriazol-4-yl)-1-methyl- pyrrole- 3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-[5-(1-cyclopropylazetidin-3- yl)oxypyrimidin-2-yl]-1-methyl-pyrrole- 3-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-5-[5-(1-cyclopropylazetidin-3- yl)oxypyrimidin-2-yl]-1-methyl-pyrrole- 3-carboxamide;4-[5-(azetidin-3-yloxy)pyrimidin-2-yl]-N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2- pyridyl]-5-methyl-thiophene-2-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-5-cyclopropyl-1-methyl-pyrrole-3- carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-5-[3-(1-hydroxy-1-methyl-ethyl)-2- pyridyl]- 1-methyl-pyrrole-3-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-4-(5-isopropoxypyrimidin-2-yl)-5- methyl-thiophene-2-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-4-(5-isopropoxypyrimidin-2-yl)-5- methyl-thiophene-2-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-4-(4-methyl-3-oxo-piperazin-1- yl)thiophene-2-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-4-(4-methyl-2-oxo-piperazin-1- yl)thiophene-2-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-4-(4-methyl-3-oxo-piperazin-1- yl)thiophene-2-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-methyl-4-(3-methyl-2-oxo- imidazolidin-1-yl)thiophene-2-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-5-methyl-4-(3-methyl-2-oxo- imidazolidin-1-yl)thiophene-2-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-5-methyl-4-(2-oxopyrrolidin-1- yl)thiophene-2-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-methyl-4-(2-oxopyrrolidin-1- yl)thiophene-2-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-4-(4-methyl-2-oxo-piperazin-1- yl)thiophene-2-carboxamide;N-[3-cyano-5-(tetrahydrofuran-3-ylamino)phenyl]-4-(3-methyl-2-pyridyl)thiophene-2- carboxamide;4-(3-methyl-2-pyridyl)-N-[3-(tetrahydrofuran-3-ylamino)-5-(trifluoromethoxy)phenyl]thiophene-2-carboxamide4-(3-methyl-2-pyridyl)-N-[3-(tetrahydrofuran-3-ylamino)-5-(trifluoromethyl)phenyl]thiophene-2-carboxamide;N-[3-fluoro-5-(tetrahydrofuran-3-ylamino)phenyl]-4-(3-methyl-2-pyridyl)thiophene-2- carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-1-methyl-5-(4-methyl-2-oxo- piperazin-1-yl)pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-1-methyl-5-(3-methyl-2-oxo- imidazolidin-1-yl)pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-(3,5-difluoro-2-pyridyl)-1-(2- methoxyethyl)pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-1-isopropyl-5-(1-methyltriazol-4- yl)pyrrole-3-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-1-isopropyl-5-(1-methyltriazol-4- yl)pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-(2-cyclopropyltriazol-4-yl)-1- methyl-pyrrole-3-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-5-(2-cyclopropyltriazol-4-yl)-1- methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-[1-[2-(dimethylamino)ethyl]pyrazol-4-yl]-1-methyl-pyrrole-3-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-5-[1-[2-(dimethylamino)ethyl]pyrazol-4-yl]-1-methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[(3-methyltetrahydrofuran-3-yl)amino]phenyl]-1-methyl-5-(1-methyltriazol-4- yl)pyrrole-3-carboxamide;N-[4-chloro-6-[(3-methyltetrahydrofuran-3-yl)amino]-2-pyridyl]-1-methyl-5-(1-methyltriazol-4- yl)pyrrole-3-carboxamide;N-[3-chloro-5-[(3-methyltetrahydrofuran-3-yl)amino]phenyl]-1-methyl-5-[5-(1-methylazetidin-3-yl)oxypyrimidin-2-yl]pyrrole-3-carboxamide;N-[4-chloro-6-[(3-methyltetrahydrofuran-3-yl)amino]-2-pyridyl]-1-methyl-5-[5-(1- methylazetidin-3-yl)oxypyrimidin-2-yl]pyrrole-3-carboxamide;5-[5-(azetidin-3-yloxy)pyrimidin-2-yl]-N-[4-chloro-6-[(3-methyltetrahydrofuran-3-yl)amino]-2- pyridyl]- 1-methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-1-methyl-5-(1- methyltriazol-4-yl) pyrrole-3-carboxam ide;N-[3-chloro-5-[(4,4-difluorotetrahydrofuran-3-yl)amino]phenyl]-1-methyl-5-(1-methyltriazol-4- yl)pyrrole-3-carboxamide;N-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-1-methyl-5-(1- methylpyrazol-4-yl)pyrrole-3-carboxamide;N-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-1-methyl-5-(1- methylpyrazol-3-yl)pyrrole-3-carboxamide;N-[4-chloro-6-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]-2-pyridyl]-1-methyl-5-(1- methylpyrazol-4-yl)pyrrole-3-carboxamide;N-[4-chloro-6-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]-2-pyridyl]-1-methyl-5-[5-(1- methylazetidin-3-yl)oxypyrimidin-2-yl]pyrrole-3-carboxamide;N-[6-chloro-2-[[(3S)-tetrahydrofuran-3-yl]amino]pyrimidin-4-yl]-5-(3,5-difluoro-2-pyridyl)-1- methyl-pyrrole-3-carboxamide;N-[2-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]pyrimidin-4-yl]-5-(3,5-difluoro-2-pyridyl)-1- methyl-pyrrole-3-carboxamide;N-[4-chloro-3-fluoro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-5-(3,5-difluoro-2-pyridyl)-1-methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-methyl-1-(1-methyltriazol-4- yl)pyrrole-3-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-5-methyl-1-(1-methyltriazol-4- yl)pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-methyl-1-(1-methylpyrazol-3- yl)pyrrole-3-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-5-methyl-1-(1-methylpyrazol-3- yl)pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-[4-(difluoromethyl)-1-methyl- pyrazol-3-yl]-1-methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-(1-ethylpyrazol-3-yl)-1-methyl- pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-(1,3-dimethylpyrazol-4-yl)-1- methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-1-methyl-5-[1-(oxetan-3-yl)pyrazol-4- yl]pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-[1-(2-methoxyethyl)pyrazol-4-yl]-1- methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-(1-cyclopropylpyrazol-4-yl)-1- methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-(1,4-dimethylpyrazol-3-yl)-1- methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-1-methyl-5-(1,3,5-trimethylpyrazol-4- yl)pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-1-phenyl-imidazole-4-carboxamideN-[5-fluoro-4-(tetrahydrofuran-3-ylmethyl)thiazol-2-yl]-4-[3-(hydroxymethyl)-2- pyridyl]thiophene-2-carboxamide;N-[5-chloro-4-(tetrahydrofuran-3-ylmethyl)thiazol-2-yl]-5-methyl-4-[5-(1-methylazetidin-3- yl)oxypyrimidin-2-yl]thiophene-2-carboxamide;N2-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-N4,N4-dimethyl-thiophene-2,4- dicarboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-[hydroxy(3- pyridyl)methyl]thiophene-2-carboxamide;N-[3-chloro-5-(tetrahydropyran-4-ylamino)phenyl]-5-(3,5-difluoro-2-pyridyl)-1-methyl-pyrrole- 3-carboxamide;N-[3-chloro-5-(tetrahydropyran-3-ylamino)phenyl]-5-(3,5-difluoro-2-pyridyl)-1-methyl-pyrrole- 3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-3-(3-methyl-2-pyridyl)pyrrolidine-1- carboxamide;(3R)-N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-3-(3-methyl-2- pyridyl)pyrrolidine-1 -carboxamide;(3S)-N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-3-(3-methyl-2- pyridyl)pyrrolidine-1 -carboxamide;N2-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-N4,N4-dimethyl-thiophene-2,4- dicarboxamide;N2-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-N4,N4-dimethyl- thiophene-2,4-dicarboxamide ;N2-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-N4,N4,5-trimethyl-thiophene-2,4- dicarboxamide;N4-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-N2,N2,1-trimethyl-pyrrole-2,4- dicarboxamide;N4-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-N2,N2,1-trimethyl-pyrrole-2,4- dicarboxamide;N4-[3-chloro-5-[(4,4-difluorotetrahydrofuran-3-yl)amino]phenyl]-N2,N2,1-trimethyl-pyrrole- 2,4-dicarboxamide;N4-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-N2,N2,1-trimethyl- pyrrole-2,4-dicarboxamide;N4-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-N2,N2,1-trimethyl- pyrrole-2,4-dicarboxamide;N4-[3-chloro-5-[[(3S,4R)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-N2,N2,1-trimethyl- pyrrole-2,4-dicarboxamide;N4-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-N2,N2-dimethyl-1-(2,2,2- trifluoroethyl)pyrrole-2,4-dicarboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-5-(1-hydroxy-1-methyl-ethyl)-1- methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-(1-hydroxy-1-methyl-ethyl)-1- methyl-pyrrole- 3-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-5-[5-(3-hydroxy-1-methyl-azetidin-3-yl)pyrimidin-2-yl]-1-methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-[5-(3-hydroxy-1-methyl-azetidin-3- yl)pyrimidin-2-yl]-1-methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3R)-tetrahydrofuran-3-yl]amino]phenyl]-5-(3,5-difluoro-2-pyridyl)-1-methyl- pyrrole- 3-carboxamide;N-[4-chloro-6-[[(3R)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-1-methyl-5-(1-methyltriazol-4- yl)pyrrole- 3-carboxamide;N-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-1-methyl-5-(1 ,3,5- trimethylpyrazol-4-yl)pyrrole- 3-carboxamide;N-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-5-(1-isopropyltriazol-4-yl)-1-methyl-pyrrole- 3-carboxamide;N-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-1-methyl-5-(2- methyltriazol-4-yl)pyrrole-3-carboxamide;N-[4-chloro-6-[(4,4-difluorotetrahydrofuran-3-yl)amino]-2-pyridyl]-1-methyl-5-(1-methyltriazol-4-yl)pyrrole- 3-carboxamide;N-[6-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]-2-pyridyl]-1-methyl-5-(1-methyltriazol-4- yl)pyrrole- 3-carboxamide;5-(3,5-difluoro-2-pyridyl)-N-[6-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]-2-pyridyl]-1- methyl-pyrrole- 3-carboxamide;5-(3,5-difluoro-2-pyridyl)-N-[3-[[(3S,4R)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-1 -methylpyrrole- 3-carboxamide;N-[3-chloro-4- fluoro- 5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-(3, 5-difluoro-2-pyridyl)-1 - methyl-pyrrole- 3-carboxamide;N4-[4-chloro-6-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]-2-pyridyl]-N2,N2,1-trimethyl- pyrrole-2,4-dicarboxamide;N4-[4-chloro-6-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]-2-pyridyl]-N2,N2,1-trimethyl- pyrrole-2,4-dicarboxamide;N4-[4-chloro-6-[[(3S,4R)-4-fluorotetrahydrofuran-3-yl]amino]-2-pyridyl]-N2,N2,1-trimethyl- pyrrole-2,4-dicarboxamide;5-(3-azabicyclo[3.1.0]hexane-3-carbonyl)-N-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3- yl]amino]phenyl]-1-methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-5-(3,3-dimethylazetidine-1-carbonyl)-1-methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-1-methyl-5-(3- methylazetidine-1-carbonyl)pyrrole-3-carboxamide;N-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-5-(3-methoxypiperidine-1- carbonyl)-1-methyl-pyrrole-3-carboxamide;N4-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-N2,1-dimethyl-N2- tetrahydropyran-4-yl-pyrrole-2,4-dicarboxamide;N4-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-N2-(1-cyclopropylethyl)-1-methyl-pyrrole-2,4-dicarboxamide;N-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-5-[4-(2- hydroxyethyl)piperidine-1-carbonyl]-1-methyl-pyrrole-3-carboxamide;N4-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-N2-(3,3- difluorocyclobutyl)-1-methyl-pyrrole-2,4-dicarboxamide;N4-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-1-methyl-N2-(3-methyl-1-bicyclo[1.1.1]pentanyl)pyrrole-2,4-dicarboxamide;N-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-1-methyl-5-(3, 3,4,4- tetrafluoropyrrolidine-1-carbonyl)pyrrole-3-carboxamide;N4-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-N2-[(1- fluorocyclopropyl)methyl]-1-methyl-pyrrole-2,4-dicarboxamideN4-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-1-methyl-N2-[(1S)-2,2,2- trifluoro-1-methyl-ethyl]pyrrole-2,4-dicarboxamide;N-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-1-methyl-5-[(2R)-2-(trifluoromethyl)pyrrolidine-1-carbonyl]pyrrole-3-carboxamide;N-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-5-[(3R)-3-fluoro-3-methyl- pyrrolidine-1-carbonyl]-1-methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-1-methyl-5-[(2S)-2-(trifluoromethyl)pyrrolidine-1-carbonyl]pyrrole-3-carboxamide;N4-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-N2,1-dimethyl-N2-(2,2,2- trifluoroethyl)pyrrole-2,4-dicarboxamide;N-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-5-(2,2- dimethylpyrrolidine-1-carbonyl)-1-methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-1-methyl-5-(morpholine-4- carbonyl)pyrrole-3-carboxamide;N-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-5-(3,3-difluoroazetidine-1- carbonyl)-1-methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-1-methyl-5-(8-oxa-3- azabicyclo[3.2.1 ]octane-3-carbonyl)pyrrole-3-carboxamide;N-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-5-[(2R,6S)-2,6- dimethylmorpholine-4-carbonyl]-1-methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-1-methyl-5-(2- methylmorpholine-4-carbonyl)pyrrole-3-carboxamide;5-(4-azaspiro[2.4]heptane-4-carbonyl)-N-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3- yl]amino]phenyl]-1-methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-5-(4,4-difluoropiperidine- 1-carbonyl)-1-methyl-pyrrole-3-carboxamide;N4-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-N2,N2-diethyl-1-methyl- pyrrole-2,4-dicarboxamide; or(S)-N-(3-Chloro-5-((tetrahydrofuran-3-yl)amino)phenyl)-5-(1-(difluoromethyl)-1 H-pyrazol-4- yl)- 1 -methyl- 1 H-pyrrole-3-carboxamide.

[0165] The various functional groups and substituents making up the compounds of the formula (I) or (Q) are typically chosen such that the molecular weight of the compound of the formula (I) or (Q) does not exceed 1000. More usually, the molecular weight of the compound will be less than 900, for example less than 800, or less than 750, or less than 700, or less than 650. More preferably, the molecular weight is less than 600 and, for example, is 550 or less.

[0166] 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 methane sulfonate 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 pharmaceutically acceptable cation, for examplea salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.

[0167] 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 non-superimposable 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 S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.

[0168] The compounds of this invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of “Advanced Organic Chemistry”, 4th edition J. March, John Wiley and Sons, New York, 2001), for example by synthesis from optically active starting materials or by resolution of a racemic form. Some of the compounds of the invention may have geometric isomeric centres (E- and Z- isomers). It is to be understood that the present invention encompasses all optical, diastereoisomers and geometric isomers and mixtures thereof that possess antiproliferative activity.

[0169] The present invention also encompasses compounds of the invention as defined herein which comprise one or more isotopic substitutions. For example, H may be in any isotopic form, including1H,2H(D), and3H (T); C may be in any isotopic form, including12C,13C, and14C; and O may be in any isotopic form, including16O and18O; and the like.

[0170] It is also to be understood that certain compounds of the formula (I) or (Q) (and subformulae 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 antiproliferative activity.

[0171] It is also to be understood that certain compounds of the formula (I) or (Q) (and subformulae thereof) may exhibit polymorphism, and that the invention encompasses all such forms that possess antiproliferative activity.

[0172] Compounds of the formula (I) or (Q) (and sub-formulae thereof) may exist in a number of different tautomeric forms and references to compounds of the formula (I) or (Q) 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) or (Q). Examples of tautomeric forms include keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto / enol (illustrated below), imine / enamine, amide / imino alcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, and nitro / aci-nitro.keto enol enolate

[0173] Compounds of the formula (I) or (Q) containing an amine function may also form N- oxides. A reference herein to a compound of the formula (I) or (Q) that contains an amine function also includes the N-oxide. Where a compound contains several amine functions, one or more than one nitrogen atom may be oxidised to form an N-oxide. Particular examples of N-oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle. N-Oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as 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 dichloromethane.

[0174] The compounds of formula (I) or (Q) 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) or (Q) 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) or (Q).

[0175] Accordingly, the present invention includes those compounds of the formula (I) or (Q) or (Q) 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) or (Q) that are produced by organic synthetic means and also such compounds that are produced in the human or animal body by way of metabolism of a precursor compound, that is a compound of the formula (I) or (Q) may be a synthetically-produced compound or a metabolically-produced compound.

[0176] A suitable pharmaceutically acceptable pro-drug of a compound of the formula (I) or (Q) 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.

[0177] 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.

[0178] A suitable pharmaceutically acceptable pro-drug of a compound of the formula (I) or (Q) 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) or (Q) 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 includeCi-ealkyl esters such as methyl, ethyl and terf-butyl, Ci-ealkoxymethyl esters such asmethoxymethyl esters, Ci-ealkanoyloxymethyl esters such as pivaloyloxymethyl esters,3-phthalidyl esters, Cs-scycloalkylcarbonyloxy- Ci-ealkyl esters such as cyclopentylcarbonyloxymethyl and 1 -cyclohexylcarbonyloxyethyl esters, 2-oxo-1 ,3-dioxolenylmethyl esters such as 5-methyl-2-oxo-1 ,3-dioxolen-4-ylmethyl esters and Ci-ealkoxycarbonyloxy- Ci-ealkyl esters such as methoxycarbonyloxymethyl and 1- methoxycarbonyloxyethyl esters.

[0179] A suitable pharmaceutically acceptable pro-drug of a compound of the formula (I) or (Q) 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) or (Q) 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 phosphate esters (including phosphoramidic cyclic esters). Further suitable pharmaceutically acceptable ester forming groups for a hydroxy group include Ci-ioalkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, Ci-ioalkoxycarbonyl groups such as ethoxycarbonyl, N, N -(Ci-6)2carbamoyl, 2- dialkylaminoacetyl and 2-carboxyacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, / V-alkylaminomethyl, N,N- dialkylaminomethyl, morpholinomethyl, piperazin-1 -ylmethyl and 4-(Ci-4alkyl)piperazin-1- ylmethyl. Suitable pharmaceutically acceptable ether forming groups for a hydroxy group include a-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.

[0180] A suitable pharmaceutically acceptable pro-drug of a compound of the formula (I) or (Q) that possesses a carboxy group is, for example, an in vivo cleavable amide thereof, for example an amide formed with an amine such as ammonia, a Ci-4alkylamine such as methylamine, a (Ci-4alkyl)2amine such as dimethylamine, / V-ethyl- / V-methylamine or diethylamine, a Ci-4alkoxy- C^alkylamine such as 2-methoxyethylamine, a phenyl-Ci- 4alkylamine such as benzylamine and amino acids such as glycine or an ester thereof.

[0181] A suitable pharmaceutically acceptable pro-drug of a compound of the formula (I) or (Q) that possesses an amino group is, for example, an in vivo cleavable amide derivative thereof. Suitable pharmaceutically acceptable amides from an amino group include, for example an amide formed with Ci- alkanoyl groups such as an acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, / V-alkylaminomethyl, N,N- dialkylaminomethyl, morpholinomethyl, piperazin- 1 -ylmethyl and4-(Ci-4alkyl)piperazin-1 -ylmethyl.

[0182] The in vivo effects of a compound of the formula (I) or (Q) 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) or (Q). As stated hereinbefore, the in vivo effects of a compound of the formula (I) or (Q) may also be exerted by way of metabolism of a precursor compound (a pro-drug).

[0183] 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.

[0184] Suitably, the present invention excludes any individual compounds not possessing the biological activity defined herein.Synthesis

[0185] The compounds of the present invention can be prepared by any suitable technique known in the art. Particular processes for the preparation of these compounds are described further in the accompanying examples.

[0186] 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.

[0187] 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.

[0188] 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.

[0189] 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 protectinggroup 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.

[0190] 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.

[0191] 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 acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl 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 an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl group such as a terf-butoxycarbonyl 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.

[0192] 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.

[0193] 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 f-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.

[0194] Resins may also be used as a protecting group.

[0195] The methodology employed to synthesise a compound of formula (I) or (Q) will vary depending on the nature of the variable groups. Suitable processes for their preparation are described further in the accompanying Examples.

[0196] Once a compound of formula (I) or (Q) has been synthesised by any one of the processes defined herein, the processes may then further comprise the additional steps of:(i) removing any protecting groups present;(ii) converting the compound formula (I) or (Q) into another compound of formula (I) or (Q);(iii) forming a pharmaceutically acceptable salt, hydrate or solvate thereof; and / or(iv) forming a prodrug thereof.

[0197] The resultant compounds of formula (I) or (Q) can be isolated and purified using techniques well known in the art.Biological Activity

[0198] The DHX9 enzyme and cell assays described in accompanying Example section may be used to measure the pharmacological effects of the compounds of the present invention.

[0199] Although the pharmacological properties of the compounds of formula (I) or (Q) vary with structural change, as expected, the compounds of the invention were found to be active in these DHX9 assays.

[0200] In general, the compounds of the invention demonstrate an IC50 of 10 pM or less in the DHX9 screening assays described herein, with preferred compounds of the invention demonstrating an IC50 of 1.0 pM or less and the most preferred compounds of the invention demonstrating an IC50 of 0.1 pM or less.

[0201] In the DHX9 split beacon unwinding screening assay described in the Biological Examples section, the compounds of formula (I) or (Q) suitably possess an activity of less than 10 pM, with preferred compounds of the invention demonstrating an IC50 of 1.0 pM or less and the most preferred compounds demonstrating an activity of 0.1 pM or less.

[0202] In CTG assay described in the Biological Examples section, the compounds of formula (I) or (Q) suitably possess an activity of 1000 nM or less, with preferred compounds of the invention demonstrating an IC50 of 100 nM or less, and the most preferred compounds demonstrating an activity of 10 nM or less.Pharmaceutical Compositions

[0203] 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 thereof, and one or more pharmaceutically acceptable excipients.

[0204] 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).

[0205] 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.

[0206] An effective amount of a compound of the present invention for use in therapy is an amount sufficient to treat or prevent any of the conditions and / or diseases described herein, e.g. a (proliferative condition and / or an autoimmune disease), slow its progression and / or reduce the symptoms associated with the condition and / or disease.

[0207] 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 0.5 g of active agent (more suitably from 0.5 to 100 mg, for example from 1 to 30 mg) compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.

[0208] The size of the dose for therapeutic or prophylactic purposes of a compound of the formula (I) or (Q) 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.

[0209] 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 intravenousor 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. Oral administration may also be suitable, particularly in tablet form. Typically, unit dosage forms will contain about 0.5 mg to 0.5 g of a compound of this invention.Therapeutic Uses and Applications

[0210] The present invention provides compounds that function as inhibitors of DHX9 activity. The compounds, or pharmaceutically acceptable salts thereof described herein may be used to decrease the expression or activity of DHX9, or to otherwise affect the properties and / or behavior of DHX9 in a cell.

[0211] The present invention therefore provides a method of inhibiting DHX9 activity in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0212] The present invention therefore provides a method of decreasing the expression of DHX9 in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0213] The present invention therefore provides a method of decreasing the expression or activity of DHX9 in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0214] The present invention therefore provides a method of affecting the properties and / or behavior of DHX9 in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0215] The present invention also provides a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in inhibiting DHX9 activity in a subject.

[0216] The present invention also provides a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in decreasing the expression of DHX9 in a subject.

[0217] The present invention also provides a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use indecreasing the expression or activity of DHX9 in a subject.

[0218] The present invention also provides a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in affecting the properties and / or behavior of DHX9 in a subject.

[0219] The present invention also provides a method of treating a disease or disorder in which DHX9 activity is implicated in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0220] In certain embodiments, the DHX9 mediated disease or disorder is selected from cancer, viral infections, and autoimmune disease. Suitably, the disease or disorder in which DHX9 activity is implicated is cancer, such as colorectal, endometrial, ovarian, gastric, hematopoietic, breast, brain, skin, lung, blood, prostate, head and neck, pancreatic, bladder, bone, soft-tissue, kidney or liver cancer.

[0221] In some embodiments, the present disclosure provides a method of treating cancer. In some embodiments, the cancer is selected from colorectal cancer, endometrial cancer, ovarian cancer, gastric cancer, hematopoietic cancer (blood cancer), breast cancer, brain cancer, skin cancer, lung cancer, prostate cancer, head and neck cancer, pancreatic cancer, bladder cancer, bone cancer, soft-tissue cancer, kidney cancer, or liver cancer. In some embodiments the cancer is selected from colorectal cancer, endometrial cancer, ovarian cancer, hematopoietic cancer, and gastric cancer.

[0222] In some embodiments, the cancer is lung cancer, e.g. small cell lung cancer.

[0223] In some embodiments, the cancer is colorectal cancer.

[0224] In some embodiments, the cancer is Ewing's Sarcoma.

[0225] In some embodiments, the cancer is a microsatellite instable (MSI) cancer. In some embodiments, the cancer is MSI-high cancer. In other embodiments, the cancer is MSI- low cancer. MSI is determined by PCR analysis of 5 different nucleotide repeats, which is dependent on the cancer type. MSI-low cancers are characterized by instability at only 1 of the 5 sites; while MSI-high cancers are characterized by instability at 2 or more of the 5 sites (G. Yang et al. Correlations between microsatellite instability and the biological behavior of tumors. Journal of Cancer Research and Clinical Oncology, 2019).

[0226] MSI-high cancer is additionally characterized by defective mismatch repair (dMMR) (M. Lorenzi, et al. Epidemiology of Microsatellite Instability High (MSI-H) and Deficient Mismatch Repair (dMMR) in Solid Tumors: A Structured Literature Review. Journal ofOncology, Volume 2020, Article ID 1897929). For example, dMMR in colorectal cancer can be determined by MLH1 promoter hypermethylation, rendering MLH1 inactive, which comprises about 80-90% of MSI-high colorectal cancers. MSI-high colorectal cancer with inactivated MLH1 is also named sporadic MSI-high colorectal cancer. Alternatively, dMMR can be determined by immunohistochemistry mutation status of MLH1 , MSH2, MSH6, MSH3, PMS1 and / or PMS2 mismatch repair (MMR) proteins. In MSI-high colorectal cancer, MLH1 and MSH2 are the 2 predominantly mutated MMR proteins. They are mutated in about 10- 20% of MSI-high colorectal cancers. MSI-high colorectal cancers with these mutations are also known as Lynch Syndrome cancers.

[0227] In some embodiments, the cancer is a MSI cancer and / or has mutations or defects in DNA mis-match repair (MMR), and / or mutations or defects in RNA splicing and the kinetochore.

[0228] In some embodiments, the cancer is a MSI high cancer, e.g. a Lynch syndrome cancer.

[0229] In some embodiments, the cancer is a MSI low cancer.

[0230] In some embodiments, the cancer is a cancer which has mutations or defects in DNA mis-match repair (MMR).

[0231] In some embodiments, the cancer is a DNA Damage Response / Repair (DDR) deficient cancer.

[0232] In some embodiments, the cancer is a replication stress high cancer. Replication stress high cancers may be any cancers defined by dysregulated activities or dysregulated / abnormal presence of a gene or set of genes that includes MLH1 , MLH3, MLH6, MSH6, MSH4, MSH5, PSM1 , PSM2, EPCAM, PARP1.POLE, POLD, PTEN, MUTYH, OGG1.APEX1 , CDC25A, PIK3CA, APC, PARP1 , BRCA1 , BRCA2, PALB2, WEE1 , RPA, ATM, ATR, DNA-PKcs, XRCC5 (Ku80), XRCC6 (Ku70),LIG4, XLF PARG, MRE11 , NBN1 , BAP1 , BRIP1 , ARID1 , BLM, BARD1 , RAD51 B, RAD51C, CHEK1 , CHEK2, 53BP1 , FANCA, FANCD2, FANCC, FANCE, FANCF, FANCG, RNASEH, SETX, FANCM, PIF1 , WRN, TOP1 , Top2, ERCC, XPG, SLX4, THO, TREX, XRCC1 , CLSPN, HUS1 , FAN1 , SLFN11 , CCNE1 , MYC, CCND1 , MDM2, EGFR, FGFR, CDK4, CDK6, KRAS, MET, ERBB2, BRAF, TP53, NRAS, CDKN2A, SOX2, FBXW7 and / or STK11.

[0233] In some embodiments, the cancer has a measurable presence of extra chromosomal DNA (ecDNA). For example, the cancer may comprise a quantitatively elevated amount or proportion of oncogene ecDNA in tumor cells, relative to normal levels or other tumors measured either by Copy Number Amplification, Genomic Fraction or cellular distribution or other technical tools. The ecDNA amplified oncogenes may include but notlimited to MYC, MYCN EGFR, ERBB2 (HER2), CCND1 , CDK4, MDM2, MET, PDGFRA, PDGFRA, CDK6, KRAS, AKT2 and / or TERT.

[0234] In some embodiments, the cancer is a cancer with an alternate mechanism of telomere maintenance, i.e. cancers dependent on a mechanism called alternative lengthening of telomeres (ALT) to maintain telomere length and attain immortality. These cancers do not use the usual telomerase enzyme dependent extension of telomeres but rather use homologous recombination based ALT mechanism which is telomerase independent.

[0235] In some embodiments, the cancer is a cold tumor. Cold tumors are cancers that have a low response rate and are difficult to mobilize an immune response against. They show resistance to immune checkpoint inhibitors (ICP) inhibitors and a paucity of tumor T cell infiltration. Small cell lung cancer is an example of a cold tumor.

[0236] The present invention provides a method of inhibiting cell proliferation, in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as defined herein.

[0237] The present invention provides a method of treating an autoimmune disease, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein. Suitably, the autoimmune disease is selected from colitis, multiple sclerosis, rheumatoid arthritis, lupus (e.g. systemic lupus erythematosus (SLE)), cirrhosis, dermatitis or inflammatory bowel disease.

[0238] The present invention provides a method of treating atherosclerosis, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0239] The present invention provides a method of treating coronary artery disease, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0240] The present invention provides a method of treating a proliferative disorder, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0241] The present invention provides a method of treating cancer, said method comprising administering to a subject in need thereof a therapeutically effective amount of acompound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein. Suitably the cancer is colorectal cancer, endometrial cancer, ovarian cancer, gastric cancer, hematopoietic cancer (blood cancer), breast cancer, brain cancer, skin cancer, lung cancer (e.g. small cell lung cancer), prostate cancer, head and neck cancer, pancreatic cancer, bladder cancer, bone cancer, soft-tissue cancer, kidney cancer, or liver cancer.

[0242] The present invention provides a method of treating a cold tumor (e.g. small cell lung cancer), said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0243] The present invention provides a method of treating: i) a MSI high cancer, e.g. a Lynch Syndrome cancer; ii) a MSI low cancer; iii) a cancer which has mutations or defects in DNA mis-match repair (MMR); iv) a DNA damage response / repair (DDR) deficient cancer; v) a replication stress high cancer; vi) a cancer with an alternate mechanism of telomere maintenance; vii) a cancer which comprises mutations or defects in RNA splicing and the kinetochore complex; viii) a cold tumor (e.g. small cell lung cancer); and / or ix) a cancer with a measurable presence of extra chromosomal DNA (ecDNA); said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0244] The present invention provides a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein for use in therapy.

[0245] The present invention provides a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein for use in the treatment of a proliferative condition.

[0246] The present invention provides a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein for use in the treatment of cancer. In a particular embodiment, the cancer is human cancer. Suitably the cancer is selected from colorectal cancer, endometrial cancer, ovarian cancer, gastric cancer, hematopoietic cancer (blood cancer), breast cancer, brain cancer, skin cancer, lung cancer, prostate cancer, head and neck cancer, pancreatic cancer, bladder cancer, bone cancer, soft-tissue cancer, kidney cancer, lymphoma, non-Hodgkin's lymphomas, myeloma, sarcomas (including osteosarcoma and Ewing's Sarcoma), thymoma, Wilms' tumour, cervical cancer, prostate cancer, glioma, hepatocellular carcinoma and liver cancer. More suitably, the cancer is selected from lung cancer, colorectal cancer, endometrial cancer, ovarian cancer, hematopoietic cancer, bone cancer and gastric cancer. More suitably, the cancer is selected from colorectal cancer or bone cancer, such as Ewing's Sarcoma.

[0247] The present invention provides a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein for use in the treatment of a cold tumor (e.g. small cell lung cancer).

[0248] The present invention therefore provides a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein for use in the treatment of: i) a MSI high cancer, e.g. a Lynch Syndrome cancer; ii) a MSI low cancer; iii) a cancer which has mutations or defects in DNA mis-match repair (MMR); iv) a DNA damage response / repair (DDR) deficient cancer; v) a replication stress high cancer; vi) a cancer with an alternate mechanism of telomere maintenance; vii) a cancer which comprises mutations or defects in RNA splicing and the kinetochore complex; viii) a cold tumor (e.g. small cell lung cancer); and / or ix) a cancer with a measurable presence of extra chromosomal DNA (ecDNA).

[0249] The present invention provides a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein for use in the inhibition of DHX9 activity.

[0250] The present invention provides a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein for use in the treatment of an autoimmune disease. Suitably, the autoimmune disease is selected from colitis, multiple sclerosis, rheumatoid arthritis, lupus (e.g. systemic lupus erythematosus (SLE)), cirrhosis, dermatitis or inflammatory bowel disease.

[0251] The present invention provides a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein for use in the treatment of atherosclerosis.

[0252] The present invention provides a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein for use in the treatment of coronary artery disease.

[0253] The present invention provides a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein for use in the treatment of an infectious disease.

[0254] In another aspect, the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in the treatment of a viral infection.

[0255] Suitably, the viral infection is selected from RNA viral infection, a DNA viral infection, HIV-1 , Simian type D retrovirus, hepatitis, cytomegalovirus, adenovirus, hepatitis E, influenza A, classical swine fever, foot and mouth, Encephalomyocarditis virus (EMCV), norovirus, herpes simplex virus 1 (HSV-1), COVID-19, lymphocytic choriomeningitis virus (LCMV), listeria, myxoma virus, chikungunya virus.

[0256] The present invention provides a compound, or a pharmaceutically acceptable salt thereof, as defined herein for use in the treatment of a disease or disorder in which DHX9 activity is implicated. Suitably, the disease or disorder in which DHX9 activity is implicated is cancer, such as colorectal cancer, endometrial cancer, ovarian cancer, gastric cancer, hematopoietic cancer (blood cancer), breast cancer, brain cancer, skin cancer, lung cancer, prostate cancer, head and neck cancer, pancreatic cancer, bladder cancer, bone cancer, soft- tissue cancer, kidney cancer, or liver cancer.

[0257] The present invention provides a use of a compound, or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for the treatment of a proliferative condition.

[0258] The present invention provides a use of a compound, or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for the treatment of cancer. Suitably, the medicament is for use in the treatment of human cancers. Suitably the cancer is colorectal cancer, endometrial cancer, ovarian cancer, gastric cancer, hematopoietic cancer (blood cancer), breast cancer, brain cancer, skin cancer, lung cancer, prostate cancer, head and neck cancer, pancreatic cancer, bladder cancer, bone cancer, soft- tissue cancer, kidney cancer, or liver cancer.

[0259] The present invention provides a use of a compound, or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for the treatment of a cold tumor (e.g. small cell lung cancer).

[0260] The present invention provides a use of a compound, or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for the treatment of: i) a MSI high cancer, e.g. a Lynch Syndrome cancer; ii) a MSI low cancer; iii) a cancer which has mutations or defects in DNA mis-match repair (MMR); iv) a DNA damage response / repair (DDR) deficient cancer; v) a replication stress high cancer; vi) a cancer with an alternate mechanism of telomere maintenance; vii) a cancer which comprises mutations or defects in RNA splicing and the kinetochore complex; viii) a cold tumor (e.g. small cell lung cancer); and / or ix) a cancer with a measurable presence of extra chromosomal DNA (ecDNA).

[0261] The present invention provides a use of a compound, or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for the treatment of an autoimmune disease. Suitably, the autoimmune disease is selected from colitis, multiple sclerosis, rheumatoid arthritis, lupus (e.g. systemic lupus erythematosus (SLE)), cirrhosis, dermatitis or inflammatory bowel disease.

[0262] The present invention provides a use of a compound, or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for the treatment of atherosclerosis.

[0263] The present invention provides a use of a compound, or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for the treatment of coronary artery disease.

[0264] In another aspect, the present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of a viral infection. Suitably, the viral infection is a RNA viral infection, a DNA viral infection, HIV-1, Simian type D retrovirus, hepatitis, cytomegalovirus, adenovirus, hepatitis E, influenza A, classical swine fever, foot and mouth, Encephalomyocarditis virus (EMCV), norovirus, herpes simplex virus 1 (HSV-1), COVID-19, lymphocytic choriomeningitis virus (LCMV), listeria, myxoma virus, chikungunya virus.

[0265] The present invention provides a use of a compound, or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for the treatment of an infectious disease.

[0266] The present invention provides a use of a compound, or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for the inhibition of DHX9 activity.

[0267] The present invention provides a use of a compound, or a pharmaceutically acceptable salt thereof, as defined herein in the manufacture of a medicament for the treatment of a disease or disorder in which DHX9 activity is implicated. Suitably, the disease or disorder in which DHX9 activity is implicated is cancer, such as colorectal cancer, endometrial cancer, ovarian cancer, gastric cancer, hematopoietic cancer (blood cancer), breast cancer, brain cancer, skin cancer, lung cancer, prostate cancer, head and neck cancer, pancreatic cancer, bladder cancer, bone cancer, soft-tissue cancer, kidney cancer, or liver cancer.

[0268] The term "proliferative disorder" are used interchangeably herein and pertain to an unwanted or uncontrolled cellular proliferation of excessive or abnormal cells which is undesired, such as, neoplastic or hyperplastic growth, whether in vitro or in vivo. Examples of proliferative conditions include, but are not limited to, pre-malignant and malignant cellular proliferation, including but not limited to, malignant neoplasms and tumours, cancers, leukemias, psoriasis, bone diseases, fibroproliferative disorders (e.g., of connective tissues), and atherosclerosis. Any type of cell may be treated, including but not limited to, lung, colon, breast, ovarian, prostate, liver, pancreas, brain and skin.

[0269] The anti-proliferative effects of the compounds of the present invention have particular application in the treatment of human cancers (by virtue of their inhibition of DHX9 activity).

[0270] The anti-cancer effect may arise through one or more mechanisms, including but not limited to, the regulation of cell proliferation, the inhibition of angiogenesis (the formation of new blood vessels), the inhibition of metastasis (the spread of a tumour from its origin), the inhibition of invasion (the spread of tumour cells into neighbouring normal structures), or the promotion of apoptosis (programmed cell death).

[0271] In a particular embodiment of the invention, the proliferative condition to be treated is cancer.

[0272] In certain embodiments, the present disclosure relates to the aforementioned methods, wherein said subject is a mammal.

[0273] In certain embodiments, the present disclosure relates to the aforementioned methods, wherein said subject is a primate.

[0274] In certain embodiments, the present disclosure relates to the aforementioned methods, wherein said subject is a human.Routes of Administration

[0275] 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).

[0276] Routes of administration include, but are not limited to, oral (e.g, by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intra-arterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; by implant of a depot or reservoir, for example, subcutaneously or intramuscularly.Combination Therapies

[0277] The antiproliferative treatment defined hereinbefore may be applied as a sole therapy or may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy. Such chemotherapy may include one or more of the following categories of anti-tumour agents:-(i) other antiproliferative / antineoplastic drugs and combinations thereof, as used in medical oncology, such as alkylating agents (for example cis-platin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan, temozolamide and nitrosoureas); antimetabolites (for example gemcitabine and antifolates such as 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);(ii) cytostatic agents such as antioestrogens (for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene, iodoxyfene, elacestrant and camizestrant), antiandrogens (for example bicalutamide, flutamide, nilutamide, cyproterone acetate, enzalutamide, darolutamide and apalutamide), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromataseinhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5a-reductase such as finasteride;(iii) anti-invasion agents [for example c-Src kinase family inhibitors like 4- (6- ch I oro-2, 3- methylenedioxyanilino)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4- yloxyquinazoline (saracatinib, AZD0530; International Patent Application WO 01 / 94341), / V- (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];(iv) inhibitors of growth factor function: for example such inhibitors include growth factor antibodies and growth factor receptor antibodies (for example the anti-erbB2 antibody trastuzumab [Herceptin™], the anti-EGFR antibody panitumumab, the anti-erbB1 antibody cetuximab [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 A / -(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-A / -(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine (Cl 1033), erbB2 tyrosine kinase inhibitors such as 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 imatinib and / or nilotinib (AMN107); inhibitors of serine / threonine kinases (for example Ras / Raf signalling inhibitors such as farnesyl transferase inhibitors, for example sorafenib (BAY 43-9006), tipifarnib (R115777) and lonafarnib (SCH66336)), inhibitors of cell signalling through MEK and / or AKT kinases, c-kit inhibitors, abl kinase inhibitors, PI3 kinase inhibitors, Plt3 kinase inhibitors, CSF-1 R kinase inhibitors, IGF receptor (insulin-like growth factor) kinase inhibitors; aurora kinase inhibitors (for example AZD1152, PH739358, VX-680, MLN8054, R763, MP235, MP529, VX-528 AND AX39459) and cyclin dependent kinase inhibitors such as CDK2 and / or CDK4 inhibitors;(v) antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, [for example the anti-vascular endothelial cell growth factor antibody bevacizumab (Avastin™) and for example, a VEGF receptor tyrosine kinase inhibitor such as 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 those disclosed in International Patent Applications WO97 / 22596, WO 97 / 30035, WO97 / 32856 and WO 98 / 13354 and compounds that work by other mechanisms (for example linomide, inhibitors of integrin avp3 function and angiostatin)];(vi) vascular damaging agents such as 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;(vii) an endothelin receptor antagonist, for example zibotentan (ZD4054) or atrasentan;(viii) antisense therapies, for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense;(ix) gene therapy approaches, including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as 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;(x) immunotherapy approaches, including for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as 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 cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies such as antibodies targeting PD-1 (e.g. pembrolizumab, nivolumab, cemiplimab, dostarlimab), PD-L1 (e.g. atezolizumab, durvalumab and avelumab), and PD-1 / VEGF bispecific antibodies, e.g. ivonescimab; and(xi) Agents used to treat AML leukaemia, including for example, cytarabine, FLT3 inhibitors, BCL2 inhibitors (e.g. venetoclax) or I DH 1 / 2 inhibitors.

[0278] 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.

[0279] 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.

[0280] 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 saltthereof, and another anti-tumour agent.

[0281] According to this aspect of the invention there is provided a combination for use in the treatment of a proliferative condition, such as cancer (for example a cancer involving a solid tumour), comprising a compound of the invention as defined hereinbefore, or a pharmaceutically acceptable salt thereof, and any one of the anti-tumour agents listed herein above.

[0282] In a further aspect of the invention there is provided a compound of the invention or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer in combination with another anti-tumour agent, optionally selected from one listed herein above.

[0283] 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.

[0284] 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 thereof, in combination with an anti-tumour agent (optionally selected from one listed herein above), in association with a pharmaceutically acceptable diluent or carrier.Numbered Embodiments

[0285] The following paragraphs define particular aspects and embodiments of the invention.Embodiment 1. A compound according to Formula (I) below, or a pharmaceutically acceptable salt thereof:wherein:Ring A is phenyl or 5- or 6-membered heteroaryl; wherein Ring A is optionally substituted by one or more substituents RA, wherein each RAis independently selected from halo (e.g. Cl, F), cyano, (1-4C)alkyl, (1-4C)haloalkyl, (3-6C)cycloalkyl or ORA1, where RA1is selected from (1-4C)alkyl, (1-4C)haloalkyl, (3-6C)cycloalkyl;Y is absent or a group of the formula:Y1-Y2wherein:Y1is absent or [CRYaRYb]n, wherein n is an integer from 1 to 4, wherein each occurrence of RYaand RYbis independently selected from hydrogen or (1- 2C)alkyl;Y2is absent or selected from -O-, -S-, -SO-, -SO2-, -C(O)-, -C(O)O-, -OC(O)-, -N(RY1)-, -N(RY1)-C(O)-, -N(RY1)-C(O)O- or -C(O)-N(RY1)-, wherein RY1is selected from hydrogen or (1 -2C)alkyl;Z is selected from (1 -4C)alkyl, (3-12C)cycloalkyl, 4 to 12 membered heterocyclyl (including monocyclic, spirocyclic, fused and bridged heterocycles), phenyl, naphthyl or 5 to 10 membered heteroaryl, wherein any of which may be optionally substituted by one or more substituents selected from hydroxy, halo, cyano, (1 -4C)alkyl or (1-4C)alkoxy, wherein the (1- 4C)alkyl or (1-4C)alkoxy are optionally further substituted by one or more substituents selected from halo, hydroxy or cyano;Ring B is a 5-membered heteroaryl or 5-membered heterocyclyl; wherein Ring B is optionally substituted with one or more substituents RB, wherein each RBis independently selected from halo, cyano, hydroxy, (1 -4C)alkyl, (3-8C)cycloalkyl, wherein any (1-4C)alkyl or (3-8C)cycloalkyl may be optionally further substituted by one or more substituents selected from hydroxy, halo, (1-4C)alkoxy, (1-4C)haloalkoxy, cyano, NRB1RB2, NRB1C(O)RB2or C(O)NRB1RB2, wherein RB1and RB2are independently selected from hydrogen or (1-4C)alkyl;Ring C is selected from phenyl, naphthyl, 5 to 10-membered heteroaryl, (3- 10C)cycloalkyl or 4 to 10-membered heterocyclyl; wherein Ring C is optionally substituted by one or more substituents independently selected from halo, cyano, oxo, (1-4C)alkyl, (1-4C)haloalkyl, halo, cyano, (3-8C)cycloalkyl, 3 to 8 membered heterocyclyl, or ORC1, wherein RC1is selected from hydrogen, (1-4C)alkyl, (3-8C)cycloalkyl, 3 to 8 membered heterocyclyl, phenyl, 5 or 6 membered heteroaryl, wherein any (1 -4C)alkyl, (3-8C)cycloalkyl, 3 to 8 membered heterocyclyl, phenyl or 5 or 6 membered heteroaryl in a substituent group on Ring C, including those in a group RC1, are optionally further substituted with one or more substituents selected from halo, cyano, oxo, hydroxy (1 -4C)alkyl, (1-4C)haloalkyl, (1-4C)alkoxy or (1-4C)haloalkoxy.Embodiment 2. A compound according to embodiment 1 , or a pharmaceutically acceptable salt thereof, wherein Ring A phenyl or 5- or 6-membered heteroaryl; wherein Ring A is optionally substituted by one or more substituents RA, wherein each RAis independently selected from halo (e.g. Cl, F), cyano, (1 -2C)alkyl, (1-2C)haloalkyl, (3- 6C)cycloalkyl or ORA1, where RA1is selected from hydrogen, (1-2C)alkyl, (1-2C)haloalkyl or (3-6C)cycloalkyl.Embodiment 3. A compound according to embodiment 1 or embodiment 2, or a pharmaceutically acceptable salt thereof, wherein each RAis independently selected from chloro, fluoro, cyano, methyl, fluoromethyl (e.g. CF3), methoxy or fluoromethoxy (e.g. OCF3); optionally wherein RAis selected from chloro, fluoro, methyl, fluoromethyl (e.g. CHF2 CF3) or methoxy.Embodiment 4. A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein Ring A has a formula selected from:wherein:Ai , A2, A3, A4 and As form a 5-membered heteroaryl ring, which is optionally substituted by 1 or 2 independently selected RAgroups; andAe, A7, As, Ag, A10 and An form a phenyl ring or a 6-membered heteroaryl ring, which is optionally substituted by 1 , 2 or 3 independently selected RAgroups; and each RAis independently as defined in any one of the preceding embodiments; optionally wherein:A1 , A2, A3, A4 and As form a thiazole, imidazole, pyraxole or oxazole ring, any of which may be optionally substituted by 1 or 2 independently selected RAgroups;As, A7, As, Ag, A10 and An form a phenyl ring, pyridyl ring or pyrimidyl ring; any of which may be optionally substituted by 1 , 2 or 3 independently selected RAgroups; and each RAis independently as defined in any one of the preceding embodiments.Embodiment 5. A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein Ring A has a formula selected from:wherein:Qi is selected from CH or N; n is an integer selected from 0, 1 , 2 or 3X2 is selected from CH or N; m is an integer selected from 0, 1 or 2;X3 is selected from CH or N;X4 is selected from CH or N;X5 is selected from CH or N; p is an integer selected from 0, 1 or 2; wherein at least one of X3, X4 and X5 is not CH; and any available carbon atom, including those in Qi , X2, X3, X4 and X5, may be optionally substituted by a group RA; wherein each RAis independently as defined in any one of the preceding embodiments.Embodiment 6. A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein Ring A has a formula selected from:wherein:X2 is selected from CH or N;X3 is selected from CH or N;X4 is selected from CH or N; wherein at least one of X3 and X4 is not CH; and A2, AS, A4 and RAS are each independently selected from hydrogen or a group RAas defined in any one of the preceding embodiments.Embodiment 7. A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein Ring A has a formula selected from:wherein RA2, RAS, RA4 and RAS are each independently selected from hydrogen or a group RAas defined in any one of the preceding embodiments; optionally wherein RA2, RAS, RA4 and RAS are independently selected from hydrogen, halo or methyl.Embodiment 8. A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein Ring B is a 5-membered heteroaryl or 5- membered heterocyclyl; wherein Ring B is optionally substituted with one or more substituents RB, wherein each RBis independently selected from halo, cyano, hydroxy, (1- 2C)alkyl, (3-8C)cycloalkyl, wherein any (1 -2C)alkyl or (3-8C)cycloalkyl may be optionally further substituted by one or more substituents selected from hydroxy, halo, (1-2C)alkoxy, (1-2C)haloalkoxy, cyano, NRB1RB2, NRB1C(O)RB2or C(O)NRB1RB2, wherein RB1and RB2are independently selected from hydrogen or (1 -2C)alkyl,Embodiment 9. A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein Ring B is a 5-membered heteroaryl or 5- membered heterocyclyl; wherein Ring B is optionally substituted with one or more substituents RB, wherein each RBis independently selected from halo, cyano, hydroxy or (1- 2C)alkyl, wherein the (1 -2C)alkyl may be optionally further substituted by one or more substituents selected from hydroxy, halo, (1-2C)alkoxy, (1-2C)haloalkoxy, cyano, NH2 or C(O)NH2or NHC(O)H.Embodiment 10. A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein Ring B is a 5-membered heteroaryl or 5- membered heterocyclyl; wherein Ring B is optionally substituted with one or more substituents RB, wherein each RBis independently selected from halo, cyano, hydroxy or (1- 2C)alkyl; optionally wherein Ring B has a formula selected from:wherein any of the above rings may be optionally substituted on an available carbon atom by a substituent RB, wherein each RBis independently as defined in any one of the preceding embodiments; andRC2is selected from hydrogen or methyl.Embodiment 11. A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein Ring C is selected from phenyl, naphthyl, 5 to 10-membered heteroaryl, (3-10C)cycloalkyl or 3 to 10-membered heterocyclyl; wherein Ring C is optionally substituted by one or more substituents independently selected from halo, cyano, oxo, (1-2C)alkyl, (1-2C)haloalkyl, (1-2C)alkoxy, (1-2C)haloalkoxy, (3- 8C)cycloalkyl, 3 to 8 membered heterocyclyl, or ORC1, wherein RC1is selected from hydrogen, (1 -2C)alkyl, (3-8C)cycloalkyl, 3 to 8 membered heterocyclyl, phenyl, 5-membered heteroaryl or 6-membered heteroaryl; wherein any alkyl, cycloalkyl, heterocyclyl, phenyl, or heteroaryl present in a substituent group on Ring C, including those in a group RC1, are optionally further substituted with one or more substituents selected from halo, cyano, oxo, hydroxy, (1-2C)alkyl, (1-2C)haloalkyl, (1- 2C)alkoxy or (1-2C)haloalkoxy.Embodiment 12. A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein Ring C is selected from 5- to 6-membered heteroaryl or 5 to 6-membered heterocyclyl; wherein Ring C is optionally substituted by one or more substituents independently selected from halo, cyano, oxo, (1-2C)alkyl, (1-2C)haloalkyl, (3-8C)cycloalkyl, 3 to 8 membered heterocyclyl, or ORc1, wherein RC1is selected from hydrogen, (1-2C)alkyl, (3-8C)cycloalkyl or 3 to 8 membered heterocyclyl; wherein any alkyl, cycloalkyl, heterocyclyl, phenyl, or heteroaryl present in a substituent group on Ring C, including those in a group RC1, are optionally further substituted with one or more substituents selected from halo, cyano, oxo, hydroxy, (1-2C)alkyl or (1-2C)haloalkyl.Embodiment 13. A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein Ring C is selected from pyridyl or or pyrimdyl; wherein Ring C is optionally substituted by one or more substituents independently selected from halo, (1-2C)alkyl, 3 to 8 membered heterocyclyl, or ORC1, wherein RC1is selected from hydrogen, (1 -2C)alkyl or 3 to 8 membered heterocyclyl; wherein any alkyl, cycloalkyl, heterocyclyl, phenyl, or heteroaryl present in a substituent group on Ring C, including those in a group RC1, are optionally further substituted with one or more substituents selected from halo, cyano, oxo, hydroxy or methyl.Embodiment 14. A compound according to any one of embodiments 1 to 12, or a pharmaceutically acceptable salt thereof, wherein Ring C is selected from:wherein any of the above rings are optionally substituted on an available carbon atom by one or more substituents independently selected from halo, cyano, oxo, (1 -2C)alkyl, (1- 2C)haloalkyl, (3-8C)cycloalkyl, 3 to 8 membered heterocyclyl, or ORC1, wherein RC1is selected from hydrogen, (1 -2C)alkyl, (3-8C)cycloalkyl or 3 to 8 membered heterocyclyl; wherein any alkyl, cycloalkyl, heterocyclyl, phenyl, or heteroaryl present in a substituent group on Ring C, including those in a group RC1, are optionally further substituted with one or more substituents selected from halo, cyano, oxo, hydroxy, (1- 2C)alkyl or (1-2C)haloalkyl; and RCNis selected from hydrogen or (1 -2C)alkyl; preferably RCNis methyl; optionally wherein Ring C is selected from:Embodiment 15. A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein:Y is absent or a group of the formula:Y1-Y2wherein:Y1is absent or [CRYaRYb]n, wherein n is an integer from 1 to 2, wherein each occurrence of RYaand RYbis independently selected from hydrogen or methyl;Y2is absent or selected from -O-, -C(O)-, -C(O)O-, -OC(O)- or -N(RY1)-, wherein RY1is selected from hydrogen or (1 -2C)alkyl;Z is selected from (1 -4C)alkyl, (3-8C)cycloalkyl, 4 to 8 membered heterocyclyl (including monocyclic, spirocyclic, fused and bridged heterocycles), phenyl or 5 or 6 membered heteroaryl, wherein any of which may be optionally substituted by one or more substituents selected from hydroxy, halo, cyano, (1 -2C)alkyl, (1-2C)alkoxy, wherein the (1 -2C)alkyl or (1-2C)alkoxy are optionally further substituted by one or more substituents selected from halo, hydroxy or cyano.Embodiment 16. A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein:Y is absent or a group of the formula:Y1-Y2wherein:Y1is absent or [CH2];Y2is absent or selected from -O- or -N(RY1)-, wherein RY1is selected from hydrogen or methyl;Z is selected from (1 -4C)alkyl, (3-6C)cycloalkyl, 4 to 8 membered heterocyclyl (including monocyclic, spirocyclic, fused and bridged heterocycles) or 5-membered heteroaryl, wherein any of which may be optionally substituted by one or more substituents selected from hydroxy, halo, (1 -2C)alkyl or (1-2C)alkoxy, wherein the (1- 2C)alkyl or (1-2C)alkoxy are optionally further substituted by one or more substituents selected from halo or hydroxy.Embodiment 17. A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein:Y is selected from -CH2-, -CHMe-, -O- or -N(RY1)-, wherein RY1is selected from hydrogen or methyl; andZ is selected from (1 -2C)alkyl, 4 to 6 membered monocyclic heterocyclyl or 5- membered heteroaryl, wherein any of which may be optionally substituted by one or more substituents selected from hydroxy, fluoro or (1 -2C)alkyl, wherein the (1 -2C)alkyl may be optionally further substituted by one or more substituents selected from fluoro or hydroxy.Embodiment 18. A compound, or a pharmaceutically acceptable salt thereof, selected from any one of the following: 4-(3-Methylpyridin-2-yl)-N-(4-((tetrahydrofuran-3-yl)-methyl)thiazol-2-yl)thiophene-2- carboxamide;4-(3-Methylpyridin-2-yl)-N-(4-(((3R)-tetrahydrofuran-3-yl)-methyl)thiazol-2-yl)thiophene-2- carboxamide;4-(3-Methylpyridin-2-yl)-N-(4-(((3S)-tetrahydrofuran-3-yl)-methyl)thiazol-2-yl)thiophene-2- carboxamide;5-(5-(3,3-Difluoroazetidin-1-yl)pyridin-2-yl)-1-methyl-N-(4-((tetrahydrofuran-3- yl)methyl)thiazol-2-yl)-1 H-pyrrole-3-carboxamide;5-(3,5-difluoropyridin-2-yl)-1-methyl-N-(4-((tetrahydrofuran-3-yl)methyl)thiazol-2-yl)-1 H- pyrrole-3-carboxamide;5-Methyl-4-(5-((1-methylazetidin-3-yl)oxy)pyrimidin-2-yl)-N-(4-((tetrahydrofuran-3- yl)methyl)thiazol-2-yl)thiophene-2-carboxamide;1-Methyl-5-(pyrimidin-2-yl)-N-(4-((tetrahydrofuran-3-yl)methyl)thiazol-2-yl)-1 H-pyrrole-3- carboxamide;1-(Pyridin-2-yl)-N-(4-((tetrahydrofuran-3-yl)methyl)thiazol-2-yl)-1H-pyrazole-4-carboxamide;5-Methyl-1-(pyrimidin-2-yl)-N-(4-((tetrahydrofuran-3-yl)methyl)thiazol-2-yl)-1 H-pyrrole-3- carboxamide;4-(4-methyl-3-oxopiperazin-1-yl)-N-(4-((tetrahydrofuran-3-yl)methyl)thiazol-2-yl)thiophene-2- carboxamide;5-(5-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyridin-2-yl)-1-methyl-N-(4-((tetrahydrofuran-3- yl)methyl)thiazol-2-yl)-1 H-pyrrole-3-carboxamide;5-(5-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyridin-2-yl)-1-methyl-N-(4-(((3R)-tetrahydrofuran-3- yl)methyl)thiazol-2-yl)-1 H-pyrrole-3-carboxamide;5-(5-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyridin-2-yl)-1-methyl-N-(4-(((3S)-tetrahydrofuran-3- yl)methyl)thiazol-2-yl)-1 H-pyrrole-3-carboxamide;5-(Hydroxymethyl)-4-(3-methylpyridin-2-yl)-N-(4-((tetrahydrofuran-3-yl)methyl)thiazol-2- yl)thiophene-2-carboxamide;4-(3-(Hydroxymethyl)pyridin-2-yl)-N-(4-((tetrahydrofuran-3-yl)methyl)thiazol-2-yl)thiophene-2- carboxamide;4-(3-(Hydroxymethyl)pyridin-2-yl)-N-(4-(((3R)-tetrahydrofuran-3-yl)methyl)thiazol-2- yl)thiophene-2-carboxamide;4-(3-(Hydroxymethyl)pyridin-2-yl)-N-(4-(((3S)-tetrahydrofuran-3-yl)methyl)thiazol-2- yl)thiophene-2-carboxamide;N-(5-Methyl-4-((tetrahydrofuran-3-yl)methyl)thiazol-2-yl)-4-(3-methylpyridin-2-yl)thiophene-2- carboxamide;4-(3-Methylpyridin-2-yl)-N-(4-(tetrahydrofuran-3-yl)thiazol-2-yl)thiophene-2-carboxamide;4-(3-Methylpyridin-2-yl)-N-(4-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl)thiophene-2- carboxamide;3-(5-Methyl-1 ,2,4-oxadiazol-3-yl)-N-(4-((tetrahydrofuran-3-yl)methyl)thiazol-2-yl)pyrrolidine- 1 -carboxamide;3-(5-methyl-1 ,2,4-oxadiazol-3-yl)-N-(5-methyl-4-((tetrahydrofuran-3-yl)methyl)thiazol-2- yl)pyrrolidine-1 -carboxamide;3-(3-methylpyridin-2-yl)-N-(4-((tetrahydrofuran-3-yl)methyl)thiazol-2-yl)pyrrolidine-1 - carboxamide;3-(5-Methyl-1 ,2,4-oxadiazol-3-yl)-N-(3-((tetrahydrofuran-3-yl)methyl)phenyl)pyrrolidine-1- carboxamide;4-(3-Methylpyridin-2-yl)-N-(3-((tetrahydrofuran-3-yl)methyl)phenyl)thiophene-2-carboxamide;4-(3-Methylpyridin-2-yl)-N-(6-((tetrahydrofuran-3-yl)methyl)pyridin-2-yl)thiophene-2- carboxamide;4-(3-Methylpyridin-2-yl)-N-(3-((tetrahydrofuran-3-yl)amino)phenyl)thiophene-2-carboxamide;4-(3-Methylpyridin-2-yl)-N-(3-(((3R)-tetrahydrofuran-3-yl) amino) phenyl) thiophene-2- carboxamide;4-(3-Methylpyridin-2-yl)-N-(3-(((3S)-tetrahydrofuran-3-yl) amino) phenyl) thiophene-2- carboxamide;4-(3-Methylpyridin-2-yl)-N-(3-(oxetan-3-ylamino)phenyl)thiophene-2-carboxamide;4-(3-Methylpyridin-2-yl)-N-(6-((tetrahydrofuran-3-yl)amino)pyridin-2-yl)thiophene-2- carboxamide;4-(3-Methylpyridin-2-yl)-N-(3-((tetrahydrofuran-3-yl)oxy)phenyl)thiophene-2-carboxamide;N-(3-Chloro-5-((tetrahydrofuran-3-yl)amino)phenyl)-4-(3-methylpyridin-2-yl)thiophene-2- carboxamide;N-(3-Chloro-5-(((3R)-tetrahydrofuran-3-yl)amino)phenyl)-4-(3-methylpyridin-2-yl)thiophene-2- carboxamide;N-(3-Chloro-5-(((3S)-tetrahydrofuran-3-yl)amino)phenyl)-4-(3-methylpyridin-2-yl)thiophene-2- carboxamide;N-(3-Chloro-5-(oxazol-2-ylamino)phenyl)-4-(3-methylpyridin-2-yl)thiophene-2-carboxamide;N-(3-Chloro-5-((2-hydroxyethyl)amino)phenyl)-4-(3-methylpyridin-2-yl)thiophene-2- carboxamide;N-(3-Chloro-5-((3-methyltetrahydrofuran-3-yl)amino)phenyl)-4-(3-methylpyridin-2- yl)thiophene-2-carboxamide;N-(3-Chloro-5-((tetrahydrofuran-3-yl)amino)phenyl)-5-methyl-4-(pyrimidin-2-yl)thiophene-2- carboxamide;N-(3-Chloro-5-((tetrahydrofuran-3-yl)amino)phenyl)-5-methyl-4-(5-((1-methylazetidin-3- yl)oxy)pyrimidin-2-yl)thiophene-2-carboxamide;N-(3-Chloro-5-((tetrahydrofuran-3-yl)amino)phenyl)-5-(3,5-difluoropyridin-2-yl)-1-methyl-1 H- pyrrole- 3-carboxamide;N-(3-Chloro-5-((tetrahydrofuran-3-yl)amino)phenyl)-4-(3-(hydroxymethyl)pyridin-2- yl)thiophene-2-carboxamide;A / -(3-(lsoxazol-3-yl)phenyl)-4-(3-methylpyridin-2-yl)thiophene-2-carboxamide;4-(3-Methylpyridin-2-yl)-N-(3-(pyrrolidin-3-ylmethyl)phenyl)thiophene-2-carboxamide;4-(3-Methylpyridin-2-yl)-N-(1-((tetrahydrofuran-3-yl)methyl)-1H-pyrazol-4-yl)thiophene-2- carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-methyl-4-[5-(1-methylazetidin-3- yl)oxypyrimidin-2-yl]thiophene-2-carboxamide;N-[3-chloro-5-[[(3R)-tetrahydrofuran-3-yl]amino]phenyl]-5-methyl-4-[5-(1-methylazetidin-3- yl)oxypyrimidin-2-yl]thiophene-2-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-(3,5-difluoro-2-pyridyl)-1 -methylpyrrole- 3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-4-[3-(methoxymethyl)-2- pyridyl]thiophene-2-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-4-(3-methoxy-2-pyridyl)thiophene-2- carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-4-(3-cyano-2-pyridyl)thiophene-2- carboxamide;2-[5-[[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]carbamoyl]-3-thienyl]-N-methyl- pyridine- 3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-1-methyl-5-(1-methyltriazol-4- yl)pyrrole- 3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-1-methyl-5-[5-(1-methylazetidin-3- yl)oxypyrimidin-2-yl]pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-1-methyl-5-pyrimidin-2-yl-pyrrole-3- carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-[3-(hydroxymethyl)-2-pyridyl]-1- methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-(3-cyano-5-fluoro-2-pyridyl)-1- methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-(5-fluoro-3-methoxy-2-pyridyl)-1- methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-(5-fluoropyrimidin-2-yl)-1 -methylpyrrole- 3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-(3-fluoro-5-methoxy-2-pyridyl)-1- methyl-pyrrole- 3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-1-methyl-5-(1-methyl-1,2,4-triazol-3- yl)pyrrole- 3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-1-methyl-5-(1-methylpyrazol-3- yl)pyrrole- 3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-1-methyl-5-(1-methylpyrazol-4- yl)pyrrole- 3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-1-methyl-5-(5-methyl-1,2,4- oxadiazol-3-yl)pyrrole- 3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-1-methyl-5-(1-methylimidazol-4- yl)pyrrole- 3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-[5-fluoro-3-(hydroxymethyl)-2- pyridyl]-1-methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-[3-(1-hydroxy-1-methyl-ethyl)-2- pyridyl]-1-methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-cyclopropyl-1-methyl-pyrrole-3- carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-5-methyl-4-pyrimidin-2-yl- thiophene-2-carboxamide;N-[4-chloro-6-[[(3R)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-5-methyl-4-pyrimidin-2-yl- thiophene-2-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-5-(3,5-difluoro-2-pyridyl)-1-methyl- pyrrole- 3-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-5-(5-fluoro-3-methoxy-2-pyridyl)-1- methyl-pyrrole-3-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-5-(3-cyano-5-fluoro-2-pyridyl)-1- methyl-pyrrole-3-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-5-(5-fluoropyrimidin-2-yl)-1- methyl-pyrrole-3-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-5-(3-fluoro-5-methoxy-2-pyridyl)-1- methyl-pyrrole-3-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-1-methyl-5-(1-methyltriazol-4- yl)pyrrole-3-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-1-methyl-5-(1-methylpyrazol-3- yl)pyrrole-3-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-1-methyl-5-(1-methylpyrazol-4- yl)pyrrole-3-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-1-methyl-5-(1-methyl-1 ,2,4-triazol- 3-yl)pyrrole-3-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-1-methyl-5-(1-methylimidazol-4- yl)pyrrole-3-carboxamide;5-[5-(azetidin-3-yloxy)-3-fluoro-2-pyridyl]-N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2- pyridyl]- 1-methyl-pyrrole-3-carboxamide;5-[5-(azetidin-3-yloxy)-3-fluoro-2-pyridyl]-N-[3-chloro-5-[[(3S)-tetrahydrofuran-3- yl]amino]phenyl]-1-methyl-pyrrole-3-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-5-[3-fluoro-5-(1-methylazetidin-3- yl)oxy-2-pyridyl]-1-methyl-pyrrole-3-carboxamide;5-[5-(azetidin-3-yloxy)pyrimidin-2-yl]-N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2- pyridyl]- 1-methyl-pyrrole-3-carboxamide;5-[5-(azetidin-3-yloxy)pyrimidin-2-yl]-N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]- 1-methyl-pyrrole-3-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-5-[5-fluoro-3-(hydroxymethyl)-2- pyridyl]- 1-methyl-pyrrole-3-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-1-methyl-5-[5-(1-methylazetidin-3- yl)oxypyrimidin-2-yl]pyrrole-3-carboxamide;N-[3-chloro-5-(oxetan-3-ylamino)phenyl]-4-(3-methyl-2-pyridyl)thiophene-2-carboxamide;N-[3-chloro-5-(oxetan-3-ylamino)phenyl]-5-(3,5-difluoro-2-pyridyl)-1-methyl-pyrrole-3- carboxamide;N-[3-chloro-5-(oxetan-3-ylamino)phenyl]-5-methyl-4-pyrimidin-2-yl-thiophene-2-carboxamide;N-[3-chloro-5-[methyl(tetrahydrofuran-3-yl)amino]phenyl]-4-(3-methyl-2-pyridyl)thiophene-2- carboxamide;N-(3-chloro-5-tetrahydrofuran-3-yloxy-phenyl)-4-(3-methyl-2-pyridyl)thiophene-2- carboxamide;N-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-5-(3,5-difluoro-2-pyridyl)- 1-methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-5-(3,5-difluoro-2-pyridyl)- 1-methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S,4R)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-5-(3,5-difluoro-2-pyridyl)- 1-methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3R,4R)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-5-(3,5-difluoro-2-pyridyl)- 1-methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S,4R)-4-hydroxytetrahydrofuran-3-yl]amino]phenyl]-5-(3,5-difluoro-2- pyridyl)-1-methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3R,4S)-4-hydroxytetrahydrofuran-3-yl]amino]phenyl]-5-(3,5-difluoro-2- pyridyl)-1-methyl-pyrrole-3-carboxamide;N-[4-chloro-6-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]-2-pyridyl]-1-methyl-5-(1- methyltriazol-4-yl)pyrrole-3-carboxamide;N-[4-chloro-6-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]-2-pyridyl]-1-methyl-5-(1- methyltriazol-4-yl)pyrrole-3-carboxamide;N-[4-chloro-6-[[(3S,4R)-4-fluorotetrahydrofuran-3-yl]amino]-2-pyridyl]-1-methyl-5-(1- methyltriazol-4-yl) pyrrole-3-carboxam ide;N-[3-chloro-5-[[(3S,4S)-4-methyltetrahydrofuran-3-yl]amino]phenyl]-5-(3,5-difluoro-2-pyridyl)- 1-methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3R,4S)-4-methoxytetrahydrofuran-3-yl]amino]phenyl]-5-(3,5-difluoro-2- pyridyl)-1-methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S,4S)-4-hydroxytetrahydrofuran-3-yl]amino]phenyl]-4-(3-methyl-2- pyridyl)thiophene-2-carboxamide;N-[3-chloro-5-[[(3S,4R)-4-hydroxytetrahydrofuran-3-yl]amino]phenyl]-4-(3-methyl-2- pyridyl)thiophene-2-carboxamide;N-[3-chloro-5-(tetrahydrofu ran-3-ylamino)phenyl]-5-[3- fluoro- 5-(1-methylazetidin-3-yl)oxy-2- pyridyl]- 1-methyl-pyrrole-3-carboxamide;N-[3-chloro-5-(tetrahydrofuran-3-ylamino)phenyl]-1-methyl-5-[5-(1-methylazetidin-3-yl)oxy-2- pyridyl]pyrrole-3-carboxamide;4-[5-(azetidin-3-yloxy)pyrimidin-2-yl]-N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-methyl-thiophene-2-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-methyl-4-(1-methyltriazol-4- yl)thiophene-2-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-5-methyl-4-(1-methyltriazol-4- yl)thiophene-2-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-1-methyl-5-(1-methylimidazol-2- yl)pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-1-methyl-5-(1-methylimidazol-2- yl)pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-1-methyl-5-(2-methyltriazol-4- yl)pyrrole-3-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-1-methyl-5-(2-methyltriazol-4- yl)pyrrole- 3-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-1-methyl-5-(4-methyl-1 ,2,4-triazol- 3-yl)pyrrole- 3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-1-methyl-5-(4-methyl-1 ,2,4-triazol-3- yl)pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-(2,5-dimethyltriazol-4-yl)-1-methyl- pyrrole- 3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-(1 ,5-dimethyltriazol-4-yl)-1-methyl- pyrrole- 3-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-5-(1 ,5-dimethyltriazol-4-yl)-1- methyl-pyrrole- 3-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-5-(2,5-dimethyltriazol-4-yl)-1- methyl-pyrrole- 3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-(3,5-difluoro-2-pyridyl)-1-(2- hydroxyethyl)pyrrole-3-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-5-(1-isopropyltriazol-4-yl)-1- methyl-pyrrole-3-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-5-(2-isopropyltriazol-4-yl)-1- methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-(1-isopropyltriazol-4-yl)-1-methyl- pyrrole- 3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-(2-isopropyltriazol-4-yl)-1-methyl- pyrrole- 3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-[5-(1-cyclopropylazetidin-3- yl)oxypyrimidin-2-yl]-1-methyl-pyrrole- 3-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-5-[5-(1-cyclopropylazetidin-3- yl)oxypyrimidin-2-yl]-1-methyl-pyrrole- 3-carboxamide;4-[5-(azetidin-3-yloxy)pyrimidin-2-yl]-N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2- pyridyl]-5-methyl-thiophene-2-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-5-cyclopropyl-1-methyl-pyrrole-3- carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-5-[3-(1-hydroxy-1-methyl-ethyl)-2- pyridyl]- 1-methyl-pyrrole-3-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-4-(5-isopropoxypyrimidin-2-yl)-5- methyl-thiophene-2-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-4-(5-isopropoxypyrimidin-2-yl)-5- methyl-thiophene-2-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-4-(4-methyl-3-oxo-piperazin-1- yl)thiophene-2-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-4-(4-methyl-2-oxo-piperazin-1- yl)thiophene-2-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-4-(4-methyl-3-oxo-piperazin-1- yl)thiophene-2-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-methyl-4-(3-methyl-2-oxo- imidazolidin-1-yl)thiophene-2-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-5-methyl-4-(3-methyl-2-oxo- imidazolidin-1-yl)thiophene-2-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-5-methyl-4-(2-oxopyrrolidin-1- yl)thiophene-2-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-methyl-4-(2-oxopyrrolidin-1- yl)thiophene-2-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-4-(4-methyl-2-oxo-piperazin-1- yl)thiophene-2-carboxamide;N-[3-cyano-5-(tetrahydrofuran-3-ylamino)phenyl]-4-(3-methyl-2-pyridyl)thiophene-2- carboxamide;4-(3-methyl-2-pyridyl)-N-[3-(tetrahydrofuran-3-ylamino)-5- (trifluoromethoxy)phenyl]thiophene-2-carboxamide;4-(3-methyl-2-pyridyl)-N-[3-(tetrahydrofuran-3-ylamino)-5-(trifluoromethyl)phenyl]thiophene- 2-carboxamide;N-[3-fluoro-5-(tetrahydrofuran-3-ylamino)phenyl]-4-(3-methyl-2-pyridyl)thiophene-2- carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-1-methyl-5-(4-methyl-2-oxo- piperazin-1-yl)pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-1-methyl-5-(3-methyl-2-oxo- imidazolidin-1-yl)pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-(3,5-difluoro-2-pyridyl)-1-(2- methoxyethyl)pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-1-isopropyl-5-(1-methyltriazol-4- yl)pyrrole-3-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-1-isopropyl-5-(1-methyltriazol-4- yl)pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-(2-cyclopropyltriazol-4-yl)-1- methyl-pyrrole-3-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-5-(2-cyclopropyltriazol-4-yl)-1- methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-[1-[2-(dimethylamino)ethyl]pyrazol- 4-yl]-1-methyl-pyrrole-3-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-5-[1-[2-(dimethylamino)ethyl]pyrazol-4-yl]-1-methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[(3-methyltetrahydrofuran-3-yl)amino]phenyl]-1-methyl-5-(1-methyltriazol-4- yl)pyrrole-3-carboxamide;N-[4-chloro-6-[(3-methyltetrahydrofuran-3-yl)amino]-2-pyridyl]-1-methyl-5-(1-methyltriazol-4- yl)pyrrole-3-carboxamide;N-[3-chloro-5-[(3-methyltetrahydrofuran-3-yl)amino]phenyl]-1-methyl-5-[5-(1-methylazetidin-3-yl)oxypyrimidin-2-yl]pyrrole-3-carboxamide;N-[4-chloro-6-[(3-methyltetrahydrofuran-3-yl)amino]-2-pyridyl]-1-methyl-5-[5-(1- methylazetidin-3-yl)oxypyrimidin-2-yl]pyrrole-3-carboxamide;5-[5-(azetidin-3-yloxy)pyrimidin-2-yl]-N-[4-chloro-6-[(3-methyltetrahydrofuran-3-yl)amino]-2- pyridyl]- 1-methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-1-methyl-5-(1- methyltriazol-4-yl)pyrrole-3-carboxamide;N-[3-chloro-5-[(4,4-difluorotetrahydrofuran-3-yl)amino]phenyl]-1-methyl-5-(1-methyltriazol-4- yl)pyrrole-3-carboxamide;N-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-1-methyl-5-(1- methylpyrazol-4-yl)pyrrole-3-carboxamide;N-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-1-methyl-5-(1- methylpyrazol-3-yl)pyrrole-3-carboxamide;N-[4-chloro-6-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]-2-pyridyl]-1-methyl-5-(1- methylpyrazol-4-yl)pyrrole-3-carboxamide;N-[4-chloro-6-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]-2-pyridyl]-1-methyl-5-[5-(1- methylazetidin-3-yl)oxypyrimidin-2-yl]pyrrole-3-carboxamide;N-[6-chloro-2-[[(3S)-tetrahydrofuran-3-yl]amino]pyrimidin-4-yl]-5-(3,5-difluoro-2-pyridyl)-1- methyl-pyrrole-3-carboxamide;N-[2-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]pyrimidin-4-yl]-5-(3,5-difluoro-2-pyridyl)-1- methyl-pyrrole-3-carboxamide;N-[4-chloro-3-fluoro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-5-(3,5-difluoro-2-pyridyl)-1-methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-methyl-1-(1-methyltriazol-4- yl)pyrrole-3-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-5-methyl-1-(1-methyltriazol-4- yl)pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-methyl-1-(1-methylpyrazol-3- yl)pyrrole-3-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-5-methyl-1-(1-methylpyrazol-3- yl)pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-[4-(difluoromethyl)-1-methyl- pyrazol-3-yl]-1-methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-(1-ethylpyrazol-3-yl)-1-methyl- pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-(1,3-dimethylpyrazol-4-yl)-1- methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-1-methyl-5-[1-(oxetan-3-yl)pyrazol-4- yl]pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-[1-(2-methoxyethyl)pyrazol-4-yl]-1- methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-(1-cyclopropylpyrazol-4-yl)-1- methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-(1,4-dimethylpyrazol-3-yl)-1- methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-1-methyl-5-(1,3,5-trimethylpyrazol-4- yl)pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-1-phenyl-imidazole-4-carboxamide;N-[5-fluoro-4-(tetrahydrofuran-3-ylmethyl)thiazol-2-yl]-4-[3-(hydroxymethyl)-2- pyridyl]thiophene-2-carboxamide;N-[5-chloro-4-(tetrahydrofuran-3-ylmethyl)thiazol-2-yl]-5-methyl-4-[5-(1-methylazetidin-3- yl)oxypyrimidin-2-yl]thiophene-2-carboxamide;N2-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-N4,N4-dimethyl-thiophene-2,4- dicarboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-[hydroxy(3- pyridyl)methyl]thiophene-2-carboxamide;N-[3-chloro-5-(tetrahydropyran-4-ylamino)phenyl]-5-(3,5-difluoro-2-pyridyl)-1-methyl-pyrrole- 3-carboxamide;N-[3-chloro-5-(tetrahydropyran-3-ylamino)phenyl]-5-(3,5-difluoro-2-pyridyl)-1-methyl-pyrrole- 3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-3-(3-methyl-2-pyridyl)pyrrolidine-1- carboxamide;(3R)-N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-3-(3-methyl-2- pyridyl)pyrrolidine-1 -carboxamide;(3S)-N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-3-(3-methyl-2- pyridyl)pyrrolidine-1 -carboxamide;N2-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-N4,N4-dimethyl-thiophene-2,4- dicarboxamide;N2-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-N4,N4-dimethyl- thiophene-2,4-dicarboxamide;N2-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-N4,N4,5-trimethyl-thiophene-2,4- dicarboxamide;N4-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-N2,N2,1-trimethyl-pyrrole-2,4- dicarboxamide;N4-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-N2,N2,1-trimethyl-pyrrole-2,4- dicarboxamide;N4-[3-chloro-5-[(4,4-difluorotetrahydrofuran-3-yl)amino]phenyl]-N2,N2,1-trimethyl-pyrrole- 2,4-dicarboxamide;N4-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-N2,N2,1 -trimethyl- pyrrole-2,4-dicarboxamide;N4-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-N2,N2,1 -trimethyl- pyrrole-2,4-dicarboxamide;N4-[3-chloro-5-[[(3S,4R)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-N2,N2,1 -trimethyl- pyrrole-2,4-dicarboxamide;N4-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-N2,N2-dimethyl-1-(2,2,2- trifluoroethyl)pyrrole-2,4-dicarboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-5-(1-hydroxy-1-methyl-ethyl)-1- methyl-pyrrole- 3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-(1-hydroxy-1-methyl-ethyl)-1- methyl-pyrrole- 3-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-5-[5-(3-hydroxy-1-methyl-azetidin-3-yl)pyrimidin-2-yl]-1-methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-[5-(3-hydroxy-1-methyl-azetidin-3- yl)pyrimidin-2-yl]-1-methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3R)-tetrahydrofuran-3-yl]amino]phenyl]-5-(3,5-difluoro-2-pyridyl)-1-methyl- pyrrole- 3-carboxamide;N-[4-chloro-6-[[(3R)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-1-methyl-5-(1-methyltriazol-4- yl)pyrrole- 3-carboxamide;N-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-1-methyl-5-(1 ,3,5- trimethylpyrazol-4-yl)pyrrole- 3-carboxamide;N-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-5-(1-isopropyltriazol-4-yl)- 1-methyl-pyrrole- 3-carboxamide;N-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-1-methyl-5-(2- methyltriazol-4-yl) pyrrole-3-carboxam ide;N-[4-chloro-6-[(4,4-difluorotetrahydrofuran-3-yl)amino]-2-pyridyl]-1-methyl-5-(1-methyltriazol-4-yl)pyrrole- 3-carboxamide;N-[6-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]-2-pyridyl]-1-methyl-5-(1-methyltriazol-4- yl)pyrrole- 3-carboxamide;5-(3,5-difluoro-2-pyridyl)-N-[6-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]-2-pyridyl]-1- methyl-pyrrole- 3-carboxamide;5-(3,5-difluoro-2-pyridyl)-N-[3-[[(3S,4R)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-1 -methylpyrrole- 3-carboxamide;N-[3-chloro-4- fluoro- 5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-(3, 5-difluoro-2-pyridyl)-1 - methyl-pyrrole- 3-carboxamide;N4-[4-chloro-6-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]-2-pyridyl]-N2,N2,1-trimethyl- pyrrole-2,4-dicarboxamide;N4-[4-chloro-6-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]-2-pyridyl]-N2,N2,1-trimethyl- pyrrole-2,4-dicarboxamide;N4-[4-chloro-6-[[(3S,4R)-4-fluorotetrahydrofuran-3-yl]amino]-2-pyridyl]-N2,N2,1-trimethyl- pyrrole-2,4-dicarboxamide;5-(3-azabicyclo[3.1.0]hexane-3-carbonyl)-N-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3- yl]amino]phenyl]-1-methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-5-(3,3-dimethylazetidine-1-carbonyl)-1-methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-1-methyl-5-(3- methylazetidine-1-carbonyl)pyrrole-3-carboxamide;N-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-5-(3-methoxypiperidine-1- carbonyl)-1-methyl-pyrrole-3-carboxamide;N4-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-N2,1-dimethyl-N2- tetrahydropyran-4-yl-pyrrole-2,4-dicarboxamide;N4-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-N2-(1-cyclopropylethyl)- 1-methyl-pyrrole-2,4-dicarboxamide;N-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-5-[4-(2- hydroxyethyl)piperidine-1-carbonyl]-1-methyl-pyrrole-3-carboxamide;N4-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-N2-(3,3- difluorocyclobutyl)-1-methyl-pyrrole-2,4-dicarboxamide;N4-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-1-methyl-N2-(3-methyl-1-bicyclo[1.1.1]pentanyl)pyrrole-2,4-dicarboxamide;N-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-1-methyl-5-(3, 3,4,4- tetrafluoropyrrolidine-1-carbonyl)pyrrole-3-carboxamide;N4-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-N2-[(1- fluorocyclopropyl)methyl]-1-methyl-pyrrole-2,4-dicarboxamide;N4-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-1-methyl-N2-[(1S)-2,2,2- trifluoro-1-methyl-ethyl]pyrrole-2,4-dicarboxamide;N-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-1-methyl-5-[(2R)-2- (trifluoromethyl)pyrrolidine-1-carbonyl]pyrrole-3-carboxamide;N-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-5-[(3R)-3-fluoro-3-methyl- pyrrolidine- 1 -carbonyl]- 1-methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-1-methyl-5-[(2S)-2- (trifluoromethyl)pyrrolidine-1-carbonyl]pyrrole-3-carboxamide;N4-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-N2,1-dimethyl-N2-(2,2,2- trifluoroethyl)pyrrole-2,4-dicarboxamide;N-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-5-(2,2- dimethylpyrrolidine-1-carbonyl)-1-methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-1-methyl-5-(morpholine-4- carbonyl)pyrrole-3-carboxamide;N-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-5-(3,3-difluoroazetidine-1- carbonyl)-1-methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-1-methyl-5-(8-oxa-3- azabicyclo[3.2.1 ]octane-3-carbonyl)pyrrole-3-carboxamide;N-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-5-[(2R,6S)-2,6- dimethylmorpholine-4-carbonyl]-1-methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-1-methyl-5-(2- methylmorpholine-4-carbonyl)pyrrole-3-carboxamide;5-(4-azaspiro[2.4]heptane-4-carbonyl)-N-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3- yl]amino]phenyl]-1-methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-5-(4,4-difluoropiperidine- 1-carbonyl)-1-methyl-pyrrole-3-carboxamide;N4-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-N2,N2-diethyl-1-methyl- pyrrole-2,4-dicarboxamide; andN-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-[1-(difluoromethyl)pyrazol-4-yl]-1- methyl-pyrrole-3-carboxamide.Embodiment 19. A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 18, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.Embodiment 20. A compound according to any one of embodiments 1 to 18, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 19, for use in therapy.Embodiment 21. A compound according to any one of embodiments 1 to 18, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 19, for use in the treatment of a proliferative condition, viral infection or autoimmune disease.Embodiment 22. A compound according to any one of embodiments 1 to 18, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 19, for use in the treatment of cancer.Embodiment 23. A compound according to any one of embodiments 1 to 18, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 19, for use in the treatment of a cancer selected from colorectal cancer, endometrial cancer, ovarian cancer, gastric cancer, hematopoietic cancer, breast cancer, brain cancer, skin cancer, lung cancer, blood cancer, prostate cancer, head and neck cancer, pancreatic cancer, bladder cancer, bone cancer, soft-tissue cancer, kidney cancer, lymphoma, non-Hodgkin's lymphomas, myeloma, osteosarcoma, Wilms' tumour, cervical cancer, prostate cancer, glioma, hepatocellular carcinoma and liver cancer; optionally wherein the cancer is selected from colorectal, endometrial, ovarian, hematopoietic, bone and gastric cancer; further optionally wherein the cancer is selected from colorectal cancer or bone cancer, such as Ewing's Sarcoma.Embodiment 24. A compound according to any one of embodiments 1 to 18, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 19, for use in the treatment of: i) a MSI high cancer, e.g. a Lynch Syndrome cancer; ii) a MSI low cancer; iii) a cancer which has mutations or defects in DNA mis-match repair (MMR); iv) a DNA damage response / repair (DDR) deficient cancer; v) a replication stress high cancer; and vi) a cancer with an alternate mechanism of telomere maintenance; vii) a cancer which comprises mutations or defects in RNA splicing and the kinetochore complex; and / or viii) a cold tumor.Embodiment 25. A compound according to any one of embodiments 1 to 18, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 19, for use in: decreasing the expression or activity of DHX9; or affect the properties and / or behavior of DHX9.ExamplesThe following abbreviations have been used in the Examples:Ac AcetylACN AcetonitrileATP Adenosine triphosphateB2Pin2 Bis(pinacolato)diboronBn benzylBOC terf-butyloxycarbonyl br broadBrettPhos 2-(dicyclohexylphosphino)3,6-dimethoxy-2',4',6'-tri- / so-propyl-1 , 1 biphenylBrettPhos. Pd G3 [(2-di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'-tri- / so-propyl-1 ,T- biphenyl)-2-(2'-amino-1,T-biphenyl)]palladium(ll) methanesulfonateBu Butyl ca. circaCAS# CAS Registry numberCOMII (1-Cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino- morpholino-carbenium hexafluorophosphate cone concentratedCTG Cell titre glow dba dibenzylideneacetoneDCM dichloromethaneDEA diethylamineDIAD Di-isopropyl-azodicarboxylateDI PEA / V, / V-di- / so-propylethylamineDMA dimethylacetamideDM EDA dimethylethylenediamineDMF dimethylformamideDMSO dimethylsulfoxideDNA Deoxyribonucleic acid dppf 1 , 1 '-bis(diphenylphosphino)ferrocene dtbpy 4,4'-di-tert-butyl-2,2'-bipyridineELS electrosprayEtOAc ethyl acetateEtOH ethanolFl Fluorescence intensityh hourHATU (1-[bis(dimethylamino)methylene]-1 / 7-1,2,3-triazolo[4,5-d]pyridinium 3- oxide hexafluorophosphateHCI hydrochloric acidHPLC high pressure liquid chromatographyHz HertzIPA / so-propyl alcoholL litresLAH Lithium aluminium hydrideLC liquid chromatographyLDA lithium di- / so-propylamideLCMS liquid chromatography - mass spectrometryKd Dissociation constantM MolarMe methylMeCN acetonitrileMeOH methanolMesyl methanesulphonylMHz mega Hertz min minutes mL millilitre mmol millimoleMS mass spectrometryMTBE methyl terf-butyl etherMW microwaveN normalNBS / V-bromosuccinimide nM nanomolarNMP A / -methyl-2-pyrrolidoneNMR Nuclear Magnetic ResonanceOtBu tert-butoxidePd-118 [1 , 1-Bis(di tert butylphosphino)ferrocene] dichloropalladium (II)Pd-C palladium on charcoalPEPPSI IHEPT- palladium(3+) 1 ,3-bis[2,6-bis(heptan-4-yl)phenyl]-4,5-dichloro-1 ,2-Cl didehydro-1A5-imidazole 3-chloropyridine dichloridePPA polyphosphoric acidprep Preparative psi Pound per square inch Py pyridine quant quantitative ref relative centrifugal force RNA ribonucleic acidRT room temperature s secondSelecttfluor™ 1-chloromethyl-4-fluoro-1 ,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborateSCX strong cation exchangeSFC supercritical fluid chromatographySPHOS Dicyclohexyl(2',6'-dimethoxy[1 , 1 '-biphenyl]-2-yl)phosphaneSPR Surface Plasmon ResonanceSTAB Sodium (triacetoxy)borohydrideT3P propylphosphonic anhydrideTPP TriphenylphosphineTBAC / V, / V, / V-tributylbutan-1-aminium chloride t-Bu-BIPPY-Phos 5-(Di-tert-butylphosphino)-1 ', 3', 5'-triphenyl-1 'H-[1 ,4']bipyrazoleTCFH Chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphateTEA Triethylamine tetrakis Pd(PhsP)4, tetrakis(triphenylphosphine)palladium (0)Tf triflateTFA trifluoroacetic acidTHF tetra hydrofuranTMA trimethylaluminiumTol toluene tR retention timeLIHPLC ultra high performance liquid chromatographyLIPLC ultra performance liquid chromatographyXantPhos 4,5-bis(diphenylphosphino)-9,9-dimethylxantheneGeneral Methods and InstrumentsLCMS methods

[0286] LCMS-FAR1 (UC05_FAR1 / UC01_FAR1 / UC04_FAR1 / UC06_FAR1) LCMS were performed in reverse phase using a Waters LIPLC® BEHTM C18 (2.1 mm x 50 mm, 2.5 pm; temperature: Ambient), with an injection volume of 10 pL maximum at a flow rate of 0.8mL / min and a gradient of 3-100% of water over 3.00 min at a flow rate of 0.8 mL / min than 100 % B over 0.5min with 1 ml / min flow, where A = 0.1% Formic Acid in water, and B = 0.1% Formic Acid in Water: Acetonitrile (10:90). A second gradient of 100-3% was then applied over 0.01 min and hold for 0.49 min. UV spectra were recorded in spectrum range :200 -400 nm. Mass spectra were obtained using a Acquity Qda detector; ionization mode electrospray positive or negative. Data were integrated and reported using Waters Acquity LIPLC and Empower 3 software.

[0287] LCMS-FAR1 (UC02_FAR1) LCMS were performed in reverse phase using a Waters LIPLC® BEHTM C18 (2.1 mm x 50 mm, 2.5 pm; temperature: Ambient), with an injection volume of 10 pL maximum at a flow rate of 0.8 mL / min and a gradient of 3-100% of water over 3.00 min at a flow rate of 0.8 mL / min than 100 % B over 0.5min with 1 ml / min flow, where A = 0.1% Formic Acid in water, and B = 0.1% Formic Acid in Water: Acetonitrile (10:90). A second gradient of 100-3% was then applied over 0.01 min and hold for 0.49 min. UV spectra were recorded in spectrum range :200 -400 nm. Mass spectra were obtained using a Acquity SQD detector; ionization mode electrospray positive or negative. Data were integrated and reported using Waters Acquity UPLC and Empower 3 software.

[0288] LCMS-ABR2 (UC03_ABR2) LCMS were performed in reverse phase using a Welch Xtimate C18 (4.6mm x 50 mm, 5 pm; temperature: Ambient), with an injection volume of 10 pL maximum at a flow rate of 0.8 mL / min and a gradient of 3-100% of water over 3.00 min at a flow rate of 0.8 mL / min than 100 % B over 0.5min with 1 ml / min flow, where A = 2 mm Ammonium bicarbonate in water, and B = Acetonitrile. A second gradient of 100-3% was then applied over 0.01 min and hold for 0.49 min. UV spectra were recorded in spectrum range :200 -400 nm. Mass spectra were obtained using an Acquity SQD detector; ionization mode electrospray positive or negative. Data were integrated and reported using Waters Acquity UPLC and MassLynx software.

[0289] LCMS-MSR2 (LC05_MSR2) LCMS were performed in reverse phase using a Waters Sunfire C18 (4.6mm x 150 mm, 3.5 pm; temperature: Ambient), with an injection volume of 100 pL maximum at a flow rate of 1 mL / min and a gradient of 10-100% of water over 9.00 min at a flow rate of 1 mL / min than 100 % B over 5 min with 1 ml / min flow, where A = 0.1% Formic Acid + 5 mm Ammonium Acetate in water, and B = Acetonitrile. A second gradient of 100-10% was then applied over 0.01 min and hold for 2.59 min. UV spectra were recorded in spectrum range :200 -400 nm. Mass spectra were obtained using an Infinity Lab LC / MSD G6125C detector; ionization mode electrospray positive or negative. Data were integrated and reported using Agilent 1260 infinity-ll HPLC and Openlab software.

[0290] LCMS-MSS1 (LC05_MSS1) LCMS were performed in reverse phase using a Waters Sunfire C18 (4.6mm x 150 mm, 3.5 pm; temperature: Ambient), with an injectionvolume of 100 pL maximum at a flow rate of 1 mL / min and a gradient of 0-100% of water over 9.00 min at a flow rate of 1 mL / min than 100 % B over 5 min with 1 ml / min flow, where A = 0.1 % Formic Acid + 5 mm Ammonium Acetate in water, and B = Acetonitrile. A second gradient of 100-0% was then applied over 0.01 min and hold for 2.59 min. UV spectra were recorded in spectrum range :200 -400 nm. Mass spectra were obtained using an Infinity Lab LC / MSD G6125C detector; ionization mode electrospray positive or negative. Data were integrated and reported using Agilent 1260 infinity-ll HPLC and Openlab software.

[0291] LCMS-MSR2 (LC01_MSR2) LCMS were performed in reverse phase using a Welch Xtimate C18 (4.6mm x 150 mm, 5 pm; temperature: Ambient), with an injection volume of 50 pL maximum at a flow rate of 1 mL / min and a gradient of 10-100% of water over 9.00 min at a flow rate of 1 mL / min than 100 % B over 5 min with 1 ml / min flow, where A = 0.1% Formic Acid + 5 mm Ammonium Acetate in water, and B = Acetonitrile. A second gradient of 100-10% was then applied over 0.01 min and hold for 2.59 min. UV spectra were recorded in spectrum range :200 -400 nm. Mass spectra were obtained using a Waters Micromass- ZQ 2000 MSD detector; ionization mode electrospray positive or negative. Data were integrated and reported using Waters alliance HPLC and Empower software.

[0292] LCMS-MSS1 (LC01_MSS1) LCMS were performed in reverse phase using a Welch Xtimate C18 (4.6mm x 150 mm, 5 pm; temperature: Ambient), with an injection volume of 50 pL maximum at a flow rate of 1 mL / min and a gradient of 0-100% of water over 9.00 min at a flow rate of 1 mL / min than 100 % B over 5 min with 1 ml / min flow, where A = 0.1 % Formic Acid + 5 mm Ammonium Acetate in water, and B = Acetonitrile. A second gradient of 100-0% was then applied over 0.01 min and hold for 2.59 min. UV spectra were recorded in spectrum range :200 -400 nm. Mass spectra were obtained using a Waters Micromass- ZQ 2000 MSD detector; ionization mode electrospray positive or negative. Data were integrated and reported using Waters alliance HPLC and Empower software.

[0293] LCMS-FAR1 (UC08_TFAS1) Water Acquity UPLC- H Class equipped with PDA and attached with QDa detector, column: Welch Xtimate C18, 150*4.6 mm, 5 micron, Column temperature: Ambient, Auto sampler temperature: 150C, Mobile Phase A : 2 mM ammonium acetate followed by 0.1%Formic acid in water, Mobile Phase B : 0.1% Formic acid in Acetonitrile, Mobile phase gradient details: T = 0 min (50% A, 50% B); T = 7.0 min (10% A, 90% B); gradient to T = 9.0 min (0% A, 100% B); gradient to T = 14.00 min (0% A, 100% B); T = 14.01 min (50% A, 50% B); end of run at T = 17 min (50% A, 50% B), Flow rate: 1.00 mL / min, Run Time: 17 min. UV Detection Method: - PDA Mass parameter: Probe: ESI, Mode of Ionisation : positive and negative, Cone voltage : 10V and 30V, capillary voltage: 0.8 KV, Extractor Voltage: 1 KV, Rf Lens: 0.1 , Temperature of source: 120°C, Temperature of Probe: 600°C, Cone Gas Flow:- Default , Desolvation Gas flow:-Default.

[0294] LCMS-FAR1 (UC07_FAR1) Water Acquity UPLC- H Class equipped with PDA and attached with QDa detector, column: Welch Xtimate C18, 150*4.6 mm, 5 micron, Column temperature: Ambient, Auto sampler temperature: 150C, Mobile Phase A : 2 mM ammonium acetate followed by 0.1%Formic acid in water, Mobile Phase B : 0.1% Formic acid in Acetonitrile, Mobile phase gradient details: T = 0 min (50% A, 50% B); T = 7.0 min (10% A, 90% B); gradient to T = 9.0 min (0% A, 100% B); gradient to T = 14.00 min (0% A, 100% B); T = 14.01 min (50% A, 50% B); end of run at T = 17 min (50% A, 50% B), Flow rate: 1.00 mL / min, Run Time: 17 min. UV Detection Method: - PDA Mass parameter: Probe: ESI, Mode of Ionisation : positive and negative, Cone voltage : 10V and 30V, capillary voltage: 0.8 KV, Extractor Voltage: 1 KV, Rf Lens: 0.1 , Temperature of source: 120°C, Temperature of Probe: 600°C, Cone Gas Flow:- Default , Desolvation Gas flow:-Default.

[0295] o2h_LCMS_Method-A:Water Acquity UPLC- H Class equipped with PDA and attached with QDa detector, column: X-Bridge BEH C18, 50 x 2.1 mm, 2.5 micron, Column temperature: Ambient, Auto sampler temperature: 150C, Mobile Phase A : 2 mM ammonium acetate followed by 0.1%Formic acid in water, Mobile Phase B : 0.1% Formic Acid in Acetonitrile, Mobile phase gradient details: T = 0 min (95% A, 5% B) flow; T = 0.4 min (95% A, 5% B) ; gradient to T = 0.8 min (65% A, 35% B) ; gradient to T = 1.20 min (45% A, 55% B) ; T = 2.5 min (0% A, 100% B) ; gradient to T= 3.30 min (0% A, 100% B) ; gradient to T= 3.31 min to end of run at T = 4 min (95% A, 5% B), Flow rate: 0.55 mL / min, Run Time: 4 min. UV Detection Method: PDA Mass parameter: Probe: ESI, Mode of Ionisation : positive and negative, Cone voltage : 10V and 30V, capillary voltage: 0.8 KV, Extractor Voltage: 1 KV, Rf Lens: 0.1 , Temperature of source: 120°C, Temperature of Probe: 600°C, Cone Gas Flow:- Default , Desolvation Gas flow:-Default.

[0296] o2h_LCMS_Method-B: Water Acquity UPLC- H Class equipped with PDA and attached with QDa detector, column: X-Bridge BEH C18, 50 x 2.1 mm, 2.5 micron, Column temperature: Ambient, Auto sampler temperature: 150C, Mobile Phase A : 5mM Ammonium Bicarbonate in Milli Q water, Mobile Phase B : Acetonitrile, Mobile phase gradient details: T = 0 min (95% A, 5% B) flow; T = 0.4 min (95% A, 5% B) ; gradient to T = 0.8 min (65% A, 35% B) ; gradient to T = 1.20 min (45% A, 55% B) ; T = 2.5 min (0% A, 100% B) ; gradient to T= 3.30 min (0% A, 100% B) ; gradient to T= 3.31 min to end of run at T = 4 min (95% A, 5% B), Flow rate: 0.55 mL / min, Run Time:- 4 min. UV Detection Method: PDA Mass parameter: Probe:ESI, Mode of Ionisation positive and negative, Cone voltage : 10V and 30V, capillary voltage: 0.8 KV, Extractor Voltage: 1 KV, Rf Lens: 0.1 , Temperature of source: 120°C, Temperature of Probe: 600°C, Cone Gas Flow:- Default , Desolvation Gas flow:- Default.

[0297] o2h_LCMS_DEV_22: LCMS were performed in reverse phase using a POROSHEL120 C18 100*4.6mm 4 urn temperature: Ambient, Mobile Phase A : 0.1% FA in Milli Q water, Mobile Phase B : (90:10 Acetonitrile: A line), Mobile phase gradient details: T = 0 min (80% A, 20% B) gradient to T =8.0 min (50% A, 50% B) ; gradient to T =10 min (0% A, 100% B) ; T = 12.0 min (0% A, 100% B) ; T = 12.01 min (80% A, 20% B); gradient to end of run at T = 14 min(80% A, 20%B), Run Time:- 14 min. Mass spectra were obtained using an Infinity Lab LC / MSD G6125C detector; ionization mode electrospray positive or negative. Data were integrated and reported using Agilent 1260 infinity-ll HPLC and OpenLAB software.

[0298] o2h_LCMS_DEV_27: LCMS were performed in reverse phase using a Waters Sunfire C18 (150mm x 4.6mm)3.5pm temperature: Ambient, Mobile Phase A: 0.1% Formic Acid in Milli Q water, Mobile Phase B: Acetonitrile, Mobile phase gradient details: T = 0 min (80% A, 20% B); gradient to T =8.0 min (50% A, 50% B); gradient to T = 0 min (90% A, 10% B) T = 7 min (10%A, 90% B) T = 9 min (0% A, 100% B) T = 14 min (0% A, 100% B) T = 14.01 min (90% A, 10% B) gradient to T= 17 min (90% A, 10% B). Run Time: - 17 min. Mass spectra were obtained using an Infinity Lab LC / MSD G6125C detector; ionization mode electrospray positive or negative. Data were integrated and reported using Agilent 1260 infinity-ll HPLC and OpenLAB software.

[0299] LC05_MSF1 :- LCMS were performed in reverse phase using a Waters SunfireC18 (4.6mm x 150 mm, 3.5 pm; temperature: Ambient) Mobile phase where A = 0.1% Formic Acid + 5 mm Ammonium Acetate in water, and B = Methanol & gradient details: T = 0 min (50% A, 50% B); T = 7.0 min (10% A, 90% B); gradient to T = 9.0 min (0% A, 100% B); gradient to T = 14.00 min (0% A, 100% B); T = 14.01 min (50% A, 50% B); end of run at T = 17 min (50% A, 50% B), Flow rate: 1.00 mL / min, Run Time: 17 min. UV spectra were recorded in spectrum range :200 -400 nm. Mass spectra were obtained using an Infinity Lab LC / MSD G6125C detector; ionization mode electrospray positive or negative. Data were integrated and reported using Agilent 1260 infinity-ll HPLC and Openlab software.

[0300] LC05_ISOCRATIC-B: - LCMS were performed in reverse phase using a Waters Sunfire C18 (4.6mm x 150 mm, 3.5 pm; temperature: Ambient) Mobile phase where A = 0.1 % Formic Acid + 5 mm Ammonium Acetate in water, and B = Methanol & gradient details: T = 0 min (50% A, 50% B) to T = 20 min (50% A, 50% B). Flow rate: 0.8 mL / min, Run Time: 20 min.

[0301] o2h_LCMS_Method-F: Water Acquity UPLC-H Class equipped with PDA and attached with SQd detector, column: Sunfire C18, 150*4.6 mm, 3.5 micron, Column temperature: Ambient, Auto sampler temperature: 150C, Mobile Phase A : 0.05% Trifluoro Acetic Acid in Milli Q water, Mobile Phase B: Acetonitrile, Mobile phase gradient details: T = 0 min (100% A, 0% B); T = 7.0 min (50% A, 50% B); gradient to T = 9.0 min (0% A, 100% B);gradient to T = 14.00 min (0% A, 100% B); T = 14.01 min (100% A, 0% B); end of run at T = 17 min (100% A, 0% B), Flow rate: 1.00 mL / min, Run Time: 17 min. Injection volume: 2-1 OpL, UV Detection Method: - PDA, Mass parameter: Probe: ESI, Mode of Ionisation : positive and negative, Cone voltage : 10V and 30V, capillary voltage: 3.0 KV, Extractor Voltage: 1 KV, Rf Lens: 0.1 , Temperature of source: temperature of source and probe were 120°C and 400 °C respectively. Cone Gas Flow: Default, Desolvation Gas flow: Default.HPLC methods

[0302] HPLC-TFAR1 (HP07_TFAR1 / HP05_TFAR1) HPLC were performed in reverse phase using a Welch Xtimate C18 (4.6mm x 150 mm, 5 pm; temperature: Ambient), with an injection volume of 100 pL maximum at a flow rate of 1 mL / min and a gradient of 10-100% of water over 9.00 min at a flow rate of 1 mL / min than 100 % B over 5 min with 1 ml / min flow, where A = 0.05% Trifluoroacetic Acid in water, and B = Acetonitrile. A second gradient of 100- 10% was then applied over 0.01 min and hold for 2.59 min. UV spectra were recorded in spectrum range :200 -400 nm. Data were integrated and reported using Agilent 1260 infinity- II HPLC and Openlab software.

[0303] HPLC-TFAS1 (HP07_TFAS1 / HP05_TFAS1) HPLC were performed in reverse phase using a Welch Xtimate C18 (4.6mm x 150 mm, 5 pm; temperature: Ambient), with an injection volume of 100 pL maximum at a flow rate of 1 mL / min and a gradient of 0-100% of water over 9.00 min at a flow rate of 1 mL / min than 100 % B over 5 min with 1 ml / min flow, where A = 0.05% Trifluoroacetic Acid in water, and B = Acetonitrile. A second gradient of 100- 0% was then applied over 0.01 min and hold for 2.59 min. UV spectra were recorded in spectrum range :200 -400 nm. Data were integrated and reported using Agilent 1260 infinity- II HPLC and Openlab software.

[0304] HPLC-FAR1 (HP07_FAR1 / HP05_FAR1) HPLC were performed in reverse phase using a Welch Xtimate C18 (4.6mm x 150 mm, 5 pm; temperature: Ambient), with an injection volume of 100 pL maximum at a flow rate of 1 mL / min and a gradient of 10-100% of water over 9.00 min at a flow rate of 1 mL / min than 100 % B over 5 min with 1 ml / min flow, where A = 0.1 % Formic Acid in water, and B = Acetonitrile. A second gradient of 100-10% was then applied over 0.01 min and hold for 2.59 min. UV spectra were recorded in spectrum range :200 -400 nm. Data were integrated and reported using Agilent 1260 infinity-ll HPLC and Openlab software.

[0305] HPLC-FAR1 (HP07_FAS1 / HP05_FAS1) HPLC were performed in reverse phase using a Welch Xtimate C18 (4.6mm x 150 mm, 5 pm; temperature: Ambient), with an injection volume of 100 pL maximum at a flow rate of 1 mL / min and a gradient of 0-100% of water over 9.00 min at a flow rate of 1 mL / min than 100 % B over 5 min with 1 ml / min flow, where A = 0.1% Formic Acid in water, and B = Acetonitrile. A second gradient of 100-0% wasthen applied over 0.01 min and hold for 2.59 min. UV spectra were recorded in spectrum range :200 -400 nm. Data were integrated and reported using Agilent 1260 infinity-ll HPLC and Openlab software.

[0306] HPLC-BR1 (HP04_BR1) HPLC were performed in reverse phase using a Waters AtlantisTM C18 (4.6mm x 150 mm, 5 pm; temperature: Ambient), with an injection volume of 100 pL maximum at a flow rate of 1 mL / min and a gradient of 10-100% of water over 9.00 min at a flow rate of 1 mL / min than 100 % B over 5 min with 1 ml / min flow, where A = 0.1 % Ammonia in water, and B = Acetonitrile. A second gradient of 100-10% was then applied over 0.01 min and hold for 2.59 min. UV spectra were recorded in spectrum range :200 -400 nm. Data were integrated and reported using Waters Alliance e2695 HPLC and Empower 3 software.

[0307] HPLC-BS1 (HP04_BS1) HPLC were performed in reverse phase using a Waters AtlantisTM C18 (4.6mm x 150 mm, 5 pm; temperature: Ambient), with an injection volume of 100 pL maximum at a flow rate of 1 mL / min and a gradient of 0-100% of water over 9.00 min at a flow rate of 1 mL / min than 100 % B over 5 min with 1 ml / min flow, where A = 0.1 % Ammonia in water, and B = Acetonitrile. A second gradient of 100-0% was then applied over 0.01 min and hold for 2.59 min. UV spectra were recorded in spectrum range :200 -400 nm. Data were integrated and reported using Waters Alliance e2695 HPLC and Empower 3 software.

[0308] o2h_HPLC_Method-A: Agilent 1260 infinity-ll equipped with DAD column:Sunfire C18, 150*4.6 mm, 3.5 micron, Column temperature: Ambient , Auto sampler temperature: 15°C, Mobile Phase A : 0.1%Formic acid in water, Mobile Phase B : Acetonitrile, Mobile phase gradient details: T = 0 min (90% A, 10% B); T = 7.0 min (10% A, 90% B); gradient to T = 9.0 min (0% A, 100% B); gradient to T = 14.00 min (0% A, 100% B); T = 14.01 min (90% A, 10% B); end of run at T = 17 min (90% A, 10% B), Flow rate: 1 .00 mL / min, Run Time: 17 min. UV Detection Method: - DAD

[0309] o2h_HPLC_Method-B: Agilent 1260 infinity-ll equipped with DAD column: Welch Xtimate C18, 150*4.6 mm, 5 micron, Column temperature: Ambient , Auto sampler temperature: 15°C, Mobile Phase A : 5mM Ammonium bicarbonate in water, Mobile Phase B : Acetonitrile, Mobile phase gradient details: T = 0 min (90% A, 10% B); T = 7.0 min (10% A, 90% B); gradient to T = 9.0 min (0% A, 100% B); gradient to T = 14.00 min (0% A, 100% B); T = 14.01 min (90% A, 10% B); end of run at T = 17 min (90% A, 10% B), Flow rate: 1.00 mL / min, Run Time: 17 min. UV Detection Method: - DADAdditional Analytical Methods

[0310] NMR spectra were recorded using a Bruker400MHz Avance Neo spectrometer fitted with a Bruker 5mm iProbe. Spectra were measured at 298 K, unless indicated otherwise,and were referenced relative to the solvent resonance. The chemical shifts are reported in parts per million. Data were acquired using Bruker TopSpin software and processed using MestreNova software.LCMS methods

[0311] Method X = acidic: Column: Cortecs C18, 90A, 2.7pm, 30 x 2.1 mm, at 40 °C, Detection: UV at 260nm + / - 90nm unless otherwise indicated, MS by electrospray ionization, Solvents: A: 0.1% formic acid in water, B: Acetonitrile. Mobile phase gradient details: T = 0.00 min (98% A, 2% B); T = 2.50 min (0% A, 100% B); T = 3.00 min (100% A, 0% B). Flow rate: 1.35 mL / min.

[0312] Method Y = basic: Column: Kinetex Evo C18, 100A, 2.6pm, 30 x 2.1 mm, at 40 °C, Detection: UV at 260nm + / - 90nm unless otherwise indicated, MS by electrospray ionization, Solvents: A: 0.1 % Ammonia in water, B: Acetonitrile. Mobile phase gradient details: T = 0.00 min (98% A, 2% B); T = 2.50 min (0% A, 100% B); T = 3.00 min (0% A, 100% B). Flow rate: 1.35 mL / min.Synthesis of IntermediatesSynthesis of Methyl 4-(3-methylpyridin-2-yl)thiophene-2-carboxylate (Intermediate A) and 4-(3-Methylpyridin-2-yl)thiophene-2-carboxylic acid (Intermediate B).Step 1 : Methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) thiophene-2-carboxylate.

[0313] To a stirred solution methyl 4-bromothiophene-2-carboxylate (CAS# 62224-16- 2) (20.0 g, 90.94 mmol) in 1 ,4-dioxane (200 mL) were added bis(pinacolato)diborane (34.6 g, 136.4 mmol) followed by addition of potassium acetate (26.7 g, 272.8 mmol) at room temperature. The resulting reaction mixture was degassed with nitrogen gas for 15 min. PdCh(dppf) (3.28 g, 4.547 mmol) was added at room temperature and the resulting reaction mixture was heated at 85°C for 16 h. The reaction mixture was cooled at room temperatureand reaction mixture was poured in water (200 mL) and extracted ethyl acetate (2 x 80 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain the crude. The crude material was purified by column chromatography on silica gel (60-120 mesh size) using 20% ethyl acetate in hexane to afford methyl 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl) thiophene -2-carboxylate (19.0 g, 79%); 1 H-NMR (400 MHz, DMSO-d6) 5 8.32 (s, 1 H), 7.85 (s, 1 H), 3.82 (s, 3H), 1.28 (s, 12H).Step-2: Methyl 4-(3-methylpyridin-2-yl) thiophene-2-carboxylate (Intermediate A).Intermediate ATo a stirred mixture of 2-bromo-3-methylpyridine (CAS # 3430-17-9) (10.0 g, 58.13 mmol) in 1 , 4 -Dioxane (80 mL) and water (20 mL) were added methyl 4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl) thiophene -2-carboxylate (18.0 g, 69.73 mmol) followed by potassium carbonate (24.0 g, 174.4 mmol) at room temperature. The reaction mixture was purged with nitrogen gas for 10 mins. PdCl2(dppf) (2.52 g, 2.906 mmol) was added and the resulting reaction mixture was stirred at 90°C for 4 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to afford crude material. The obtained crude material was purified by column chromatography on silica gel (60-120 mesh size) using 30% ethyl acetate in hexane to afford methyl 4-(3-methylpyridin-2-yl) thiophene- 2-carboxylate (9.0 g, 58%); 1 H-NMR (400 MHz, DMSO-d6) 5 8.48 - 8.46 (m, 1 H), 8.23 (d, J = 1.6 Hz, 1 H), 8.15 (d, J = 1.6 Hz, 1 H), 7.73 - 7.71 (m, 1 H), 7.30 - 7.27 (m, 1 H), 3.86 (s, 3H), 2.45 (s, 3H); LCMS: 1.628 min, MS: ES+ 234.1 (M+1) (Method -o2h_LCMS_Method_A).Step-3: 4-(3-Methylpyridin-2-yl) thiophene-2-carboxylic acid (Intermediate B).Intermediate BTo a stirred solution of methyl 4-(3-methylpyridin-2-yl) thiophene-2-carboxylate (7.5 g, 36.48 mmol) in a mixture of methanol (85 mL) and water (85 mL) was added lithium hydroxide (15.3 g, 364.8 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated to remove organics and diluted with water (50 mL). The aqueous layer was acidified to pH~2 using 1M HCI solution to obtain the precipitation.The solid material was filtered off and dried under reduced pressure to afford 4-(3- methylpyridin-2-yl) thiophene-2-carboxylic acid (7.5 g, 88%); 1 H-NMR (400 MHz, DMSO-de) 5 13.22 (br s, 1 H), 8.46 (d, J = 4.0 Hz, 1 H), 8.17 (d, J = 0.8 Hz, 1 H), 8.07 (d, J = 0.8 Hz, 1 H), 7.72 (d, J = 7.6 Hz, 1 H), 7.30 - 7.27 (dd, J = 7.6 Hz, 4.8 Hz, 1 H), 2.46 (s, 3H); LCMS: 1.275 min, MS: ES+ 220.0 (M+1) (Method -o2h_LCMS_Method_A).Synthesis of methyl 5-(3,5-difluoropyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxylate (Intermediate C).Intermediate C

[0314] To a stirred solution of 2-bromo-3,5-difluoropyridine (CAS# 660425-16-1) (0.1 g, 0.5154 mmol) in a mixture of 1 , 4 dioxane (3.0 mL) and water (0.6 mL) were added methyl 1-methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrrole-3-carboxylate (CAS# 2377610-99-4) (0.14 g, 0.5669 mmol) followed by tri-potassium phosphate (0.32 g, 1.546 mmol) at room temperature. The reaction mixture was degassed with nitrogen gas for 10 mins. PdCh(dppf)2 (0.037 g, 0.0515 mmol) was added and the resulting reaction mixture was stirred at 100°C for 3 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to afford crude material. The obtained crude material was purified by column chromatography on silica gel (60-120 mesh size) using 100% dichloromethane to afford methyl 5-(3,5-difluoropyridin-2-yl)-1-methyl-1 H-pyrrole-3-carboxylate (0.25 g, 96% ); 1 H-NMR (400 MHz, DMSO-d6) 5 8.58 (d, J = 1 Hz, 1 H), 8.10 - 8.04 (m, 1 H), 7.70 (s, 1 H), 6.88 (d, J = 6.88 Hz, 1 H), 3.86 (s, 3H), 3.73 (s, 3H); LCMS: 2.111 min, MS: ES+ 253.1 (M+1) (Method -o2h_LCMS_Method_A).Synthesis of methyl 5-(5-(3,3-difluoroazetidin-1-yl)pyridin-2-yl)-1-methyl-1 H-pyrrole-3- carboxylate (Intermediate D) and 5-(5-(3,3-difluoroazetidin-1-yl)pyridin-2-yl)-1-methyl- 1 H-pyrrole-3-carboxylic acid (Intermediate E)Intermediate E Intermediate DStep-1 : Methyl 1-methyl-1H-pyrrole-3-carboxylate

[0315] To a stirred solution of methyl 1 H-pyrrole-3-carboxylate (10.0 g, 80.00 mmol) in N,N-dimethylformamide (100 mL) was added sodium hydride (7.68 g, 160.0 mmol) portion wise at 0°C. Methyl iodide was added (22.72 g, 160.0 mmol) at 0°C and the resulting reaction mixture was stirred at room temperature for 3 h. The reaction mixture was poured into ice cold water (300 mL) and extracted with ethyl acetate (400 mL x 3). The combined organic layer was dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to afford methyl 1 -methyl- 1 H-pyrrole-3-carboxylate (10 g, 89.92 %);1 H-NMR (400 MHz, DMSO-de) 5 7.40 (t, J = 2.0 Hz, 1 H), 6.77 (t, J = 2.8 Hz, 1 H), 6.38 (dd, J = 2.8 Hz, 1.6 Hz, 1 H), 3.67 (s, 3H), 3.65 (s, 3H); LCMS: 1.735 min, MS: ES+ 140.1 (M+1), (o2h_LCMS_Method_A).Step-2: Methyl 1 -methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrrole-3- carboxylateM OOC

[0316] To a stirred solution of methyl 1 -methyl- 1 H-pyrrole-3-carboxylate (6.0 g, 43.16 mmol) in 1 ,4 Dioxane (60 mL) was added bis(pinacolato)diboron (13.15 g, 51.79 mmol). The reaction mixture was purged with nitrogen gas for 15 minutes. Bis(1 ,5- cyclooctadiene)dimethoxydiiridium (CAS# 12148-71-9) (0.428 g, 0.647 mmol) and 4,4'-Di- tert-butyl-2,2'-bipyridine (0.347 g, 1.294 mmol) were added into reaction mixture and stirred at100°C for 3 h. The reaction mixture was passed though celite and the resulting filtrate was concentrated under reduced pressure to afford crude material. The obtained crude material was purified by column chromatography on silica gel (100-200 mesh size) using 8% ethyl acetate in hexane methyl 1-methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H- pyrrole-3-carboxylate (6.0 g, 52.49%); 1 H-NMR (400 MHz, CDCI3) 5 7.39 (d, J = 1.6 Hz, 1 H), 7.22 (d, J = 2.0 Hz, 1 H), 3.84 (s, 3H), 3.72 (s, 3H), 1.32 (s, 12 H).Step-3: Methyl 5-(5-bromopyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxylate

[0317] To a stirred solution of 5-bromo-2-iodopyridine (CAS # 223463-13-6) (6.0 g, 21.12 mmol) in 1 , 4 Dioxane (60 mL) were added methyl 1-methyl-5-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-1 H-pyrrole-3-carboxylate (6.7 g, 25.34 mmol) followed by potassium phosphate tribasic (13.4 g, 63.36 mmol) and water (1.2 mL) at room temperature. The reaction mixture was degassed with nitrogen gas for 15 minutes. PdCh(dppf)2 (0.155 g, 0.2112 mmol) was added and the resulting reaction mixture was stirred at 80°C for 1 h. The reaction mixture was cooled to room temperature and passed though celite. The resulting filtrate was concentrated under reduced pressure to afford crude material. The obtained crude material was purified by column chromatography on silica gel (100-200 mesh size) using 10% ethyl acetate in hexane to afford methyl 5-(5-bromopyridin-2-yl)- 1 -methyl- 1 H-pyrrole-3-carboxylate (2.5 g, 37.43%); 1 H-NMR (400 MHz, DMSO-d6) 58.68 (d, J = 2.0 Hz, 1 H), 8.03 (dd J = 8.8 Hz, 2.4 Hz, 1 H), 7.75 (d, J = 8.4 Hz, 1 H), 7.65 (d, J = 1.6 Hz, 1 H), 7.08 (d, J = 2.0 Hz, 1 H), 3.95 (s, 3H), 3.73 (s, 3H); LCMS: 2.334 min, MS: ES+ 295.1 (M+1), 297 (M+3), (o2h_LCMS_Method_A).Step-4: Methyl 5-(5-(3,3-difluoroazetidin-1 -y I ) py ri d i n-2-y I )-1 -methyl-1 H-pyrrole-3- carboxylate (Intermediate D)

[0318] To a stirred solution of methyl 5-(5-bromopyridin-2-yl)- 1 -methyl- 1 H-pyrrole-3- carboxylate (2.5 g, 8.503 mmol) in 1 ,4-dioxane (25 mL) were added 3,3-difluoroazetidine HCI salt (CAS# 288315-03-7) (3.29 g, 25.51 mmol) and cesium carbonate (8.28 g, 25.51 mmol) atroom temperature. The reaction mixture was degassed with nitrogen gas for 15 minutes. PEPPSI IHEPT-CI (0.413 g, 0.4237 mmol) was added and the resulting reaction mixture was stirred at 120°C for 1 h. The reaction mixture was passed though celite and the resulting filtrate was concentrated under reduced pressure to afford crude material. The obtained crude material was purified by column chromatography on silica gel (100-200 mesh size) using 25% ethyl acetate in hexane to afford methyl 5-(5-(3,3-difluoroazetidin-1-yl)pyridin-2-yl)-1-methyl- 1 H-pyrrole-3-carboxylate (2.0 g, 76.83 %); 1 H-NMR (400 MHz, DMSO-d6) 5 7.96 (d, J = 2.8 Hz, 1 H), 7.60 (d, J = 8.4 Hz, 1 H), 7.54 (d, J = 1.6 Hz, 1 H), 7.05 (dd, J = 8.4 Hz, 2.4 Hz, 1 H), 6.79 (d, J = 2 Hz, 1 H), 4.38 (t, J = 12 Hz, 4H), 3.90 (s, 3H), 3.71 (s, 3H); LCMS: 2.078 min, MS: ES+ 308.2 (M+1), (o2h_LCMS_Method_A).Step-5: 5-(5-(3,3-Difluoroazetidin-1-yl)pyridin-2-yl)-1-methyl-1H-pyrrole-3-carboxylic acid (Intermediate E)Intermediate E

[0319] To a stirred solution of methyl 5-(5-(3,3-difluoroazetidin-1 -yl)pyridin-2-yl)-1 - methyl- 1 H-pyrrole-3-carboxylate (1.25 g, 4.071 mmol) in mixture of tetrahydrofuran (7.0 mL) and methanol (7.0 mL) was added a solution of lithium hydroxide monohydrate (0.85 g, 20.35 mmol) in water (7.0 mL) at room temperature. The reaction mixture was stirred at 60°C for 3 h. The reaction mixture was concentrated to remove organics and diluted with water (50 mL). The aqueous layer was acidified to pH~2 using 1M HCI solution (60 mL) to obtain the precipitation. The solid material was filtered off and dried under reduced pressure to afford methyl 5-(5-(3,3-difluoroazetidin-1-yl)pyridin-2-yl)-1-methyl-1 H-pyrrole-3-carboxylate (1.1 g, 92.21 %);1H-NMR (400 MHz, DMSO-d6) 5 11.83 - 11.78 (m, 1 H), 7.96 (s, 1 H), 7.59 (d, J = 8.4 Hz, 1 H), 7.45 (s, 1 H), 7.05 (d, J = 8.4 Hz, 1 H), 6.74 (s, 1 H), 4.38 (t, J = 12.4 Hz, 4H), 3.88 (s, 3H); LCMS: 1.767 min, MS: ES+ 294.2 (M+1) (o2h_LCMS_Method_A); HPLC: 5.729 min, o2h_HPLC_Method_A).Synthesis of methyl 1-methyl-5-(pyrimidin-2-yl)-1 H-pyrrole-3-carboxylate (Intermediate F) and 1-methyl-5-(pyrimidin-2-yl)-1 H-pyrrole-3-carboxylic acid (Intermediate G)Intermediate F Intermediate G

[0320] Methyl 1-methyl-5-(pyrimidin-2-yl)-1 H-pyrrole-3-carboxylate (Intermediate F) was prepared according to the procedure described for Intermediate D but using 2- bromopyrimidine (CAS # 4595-60-2) in step 3. 1 H-NMR (400 MHz, DMSO-d6) 5 8.80 (d, J = 4.8 Hz, 2H), 7.70 (d, J = 1.6 Hz, 1 H), 7.32 - 7.29 (m, 2H), 4.07 (s, 3H), 3.74 (s, 3H); LCMS: 1.812 min, MS: ES+ 218.2 (M+1) (o2h_LCMS_Method_A).

[0321] To a stirred solution of methyl 1-methyl-5-(pyrimidin-2-yl)-1 H-pyrrole-3- carboxylate (0.25 g, 1.152 mmol) in tetrahydrofuran (2.5 mL) and methanol (2.5 mL) was added a solution of sodium hydroxide (0.23 g, 5.760 mmol) in water (2.5 mL) at room temperature. The reaction mixture was left to stir at 60°C for 3 h. The reaction mixture was concentrated to remove organics and diluted with water (50 mL). The aqueous layer was acidified to pH ~2 using 1 M HCI solution to obtain the precipitation. The solid material was filtered off and dried under reduced pressure to afford 1-methyl-5-(pyrimidin-2-yl)-1 H-pyrrole- 3-carboxylic acid (0.3 g, 61.14%); 1 H-NMR (400 MHz, DMSO-d6) 5 12.0 (s, 1 H), 8.79 (d, J = 4.8 Hz, 2H), 7.61 (d, J = 1 .6 Hz, 1 H), 7.30 - 7.29 (m, 2H), 4.06 (s, 3H); LCMS: 1.600 min, MS: ES+ 204.2 (M+1) (o2h_LCMS_Method_A).Synthesis of Methyl 5-methyl-4-(5-((1-methylazetidin-3-yl)oxy)pyrimidin-2-yl)thiophene- 2-carboxylate (Intermediate H) and 5-methyl-4-(5-((1-methylazetidin-3-yl)oxy)pyrimidin- 2-yl)thiophene-2-carboxylic acid (Intermediate I)Step 1 : methyl 5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2- carboxylate.CAS# 12148-71-9 B2Pin2,dtbpy , Heptane, 100°C, rv _ sih _ ,MeOOC^

[0322] To a stirred solution methyl 5-methylthiophene-2-carboxylate (CAS# 19432-69- 0) (15.0 g, 96.15 mmol) in heptane (150 mL) were added bis(pinacolato)diborane (29.3 g, 115.3 mmol) followed by 4,4'-Di-tert-butyl-2,2'-bipyridine (0.10 g, 0.3846 mmol) at room temperature. The resulting reaction mixture was degassed with nitrogen gas for 15 min. Bis(1 ,5-cyclooctadiene) dimethoxydiiridium (CAS# 12148-71-9) (0.12 g, 0.192 mmol) was added at room temperature. The resulting reaction mixture was stirred at 100°C for 24 h. The reaction mixture was cooled at room temperature and filtered through celite, washed with ethyl acetate (200 mL x 2). The resulting filtrate was directly concentrated under vacuum to afford crude material. The obtained crude was purified by column chromatography on silica gel (60 - 120 mesh size) using 5% ethyl acetate in hexane to afford methyl 5-methyl-4-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate (20 g, 73.81 %); 1 H-NMR (DMSO-d6) (400 MHz); 5 7.70 (s, 1 H), 3.79 (s, 3H), 2.65 (s, 3H), 1.28 (s, 12H); LCMS: 2.745 min, MS: ES+ 283.1 (M+1) (o2h_LCMS_Method_A).Step 2: Methyl 4-(5-hydroxypyrimidin-2-yl)-5-methylthiophene-2-carboxylate.CAS# 1240621-87-7 fTo a stirred solution of 2-Bromo-5-hydroxypyrimidine (CAS# 1240621-87-7) (12.4 g, 70.92 mmol) in a mixture of 1 ,4- dioxane (400 mL) and water (120 mL) were added methyl 5-methyl- 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate (20 g, 70.92 mmol) and tribasic potassium phosphate (45.1 g, 212.7 mmol) at room temperature. The resulting reaction mixture was degassed with N2 gas for 20 min. Pd(dppf)Cl2 (5.18 g, 7.092 mmol) was added at room temperature. The resulting reaction mixture was stirred at 80°C for 12 h. The reaction mixture was poured in ice cold water (800 mL) and extracted with ethyl acetate (1000 mL x 5). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under vacuum to afford crude. The obtained crude was purified by column chromatography on silica gel (60 - 120 mesh size) using 70% ethyl acetate in hexane to afford methyl 4-(5-hydroxypyrimidin-2-yl)-5-methylthiophene-2-carboxylate (7.5 g, 42.28%), 1 H- NMR (DMSO-d6) (400 MHz); 5 10.60 (s, 1 H), 8.42 (s, 2H), 8.22 (s, 1 H), 3.82 (s, 3H), 2.81 (s, 3H); LCMS: 1.945 min, MS: ES+ 251.1 (M+1) (o2h_LCMS_Method_A).Step 3: Methyl 5-methyl-4-(5-((1-methylazetidin-3-yl)oxy)pyrimidin-2-yl)thiophene-2- carboxylate (Intermediate H).

[0323] To a stirred solution of methyl 4-(5-hydroxypyrimidin-2-yl)-5-methylthiophene-2-carboxylate (7.50 g, 30.00 mmol) in tetrahydrofuran (75 mL) were added 1-methylazetidin-3-ol (CAS# 111043-48-2) (2.61 g, 30.0 mmol) and triphenylphosphine (23.5 g, 90.00 mmol) at room temperature. Diisopropyl azodicarboxylate (18.1 g, 90.00 mmol) was added drop-wise at room temperature. The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was poured into water (500 mL) and extracted with ethyl acetate (300 mL x 3). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude. The obtained crude was purified by reverse phase flash chromatography (C18 silica) using 60% acetonitrile in water to afford methyl 5-methyl-4- (5-((1-methylazetidin-3-yl)oxy)pyrimidin-2-yl)thiophene-2-carboxylate; (1.0 g, 10.45%); LCMS: 1.709 min, MS: ES+ 320.2 (M+1) (o2h_LCMS_Method_A).Step 4: 5-Methyl-4-(5-((1-methylazetidin-3-yl)oxy)pyrimidin-2-yl)thiophene-2-carboxylic acid (Intermediate I).

[0324] To a stirred solution of methyl 5-methyl-4-(5-((1-methylazetidin-3- yl)oxy)pyrimidin-2-yl)thiophene-2-carboxylate (1.0 g, 3.134 mmol) in mixture of tetra hydrofuran (5 mL), methanol (5 mL) and water (5 mL) was added sodium hydroxide (0.62 g, 15.67 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated to remove organics and acidified to pH ~2 using 2M HCI (80 mL) solution with stirring to obtain the precipitate. The solid was filtered off and dried under vacuum to afford 5-methyl-4-(5-((1-methylazetidin-3-yl)oxy)pyrimidin-2- yl)thiophene-2-carboxylic acid; (0.2 g, 20.92% Yield). LCMS: 1.573 min, MS: ES+ 306.1 (M+1) (o2h_LCMS_Method_A).Synthesis of 5-methyl-3-(pyrrolidin-3-yl)-1,2,4-oxadiazole HCI salt (Intermediate J).Step 1 : Tert-butyl-3-(N'-hydroxycarbamimidoyl) pyrrolidine-1 -carboxylate.

[0325] To a stirred solution of tert-butyl 3-cyanopyrrolidine-1 -carboxylate (20.0 g, 102.0 mmol) in methanol (200 mL) was added hydroxylamine (50% solution in water) (21 mL, 306.1 mmol) and the resulting reaction mixture was stirred at 80°C temperature for 2 h. The reaction mixture was directly concentrated under reduced pressure to afford tert-butyl-3-(N'- hydroxycarbamimidoyl)pyrrolidine-1-carboxylate (21.0 g, 90%); 1 H-NMR (400 MHz, DMSO- d6) 6 8.97 (d, J = 5.2 Hz, 1 H), 5.43 (s, 2H), 3.743 - 3.23 (m, 4H), 2.81 - 2.75 (m, 1 H), 1.99 - 1.89 (m, 2H), 1.39 (s, 9H); LCMS: 1.420 min, MS: ES+ 174.0 (M-tBu) (o2h_LCMS_Method_A).Step-2: Tert-butyl-3-(N'-acetoxycarbamimidoyl) pyrrolidine-1 -carboxylate.To a stirred solution of tert-butyl-3-(N'-hydroxycarbamimidoyl) pyrrolidine-1-carboxylate (20.0 g, 87.33 mmol)) in dichloromethane (400 mL) were added triethylamine (17.6 g, 174.6 mmol) followed by dropwise addition of acetyl chloride (CAS# 75-36-5) (6.81 g, 87.33 mmol) at 0°C temperature. The resulting reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with saturated sodium bicarbonate solution (200 mL) and extracted with dichloromethane (100 mLx 2). The layers were separated and the organic layer was washed with water (200 mL) and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford tert-butyl (Z)-3-(N'-acetoxycarbamimidoyl) pyrrolidine- 1- carboxylate (20.0 g, 84%); LCMS: 1.730 min, MS: ES+ 172.1 (M-100)(o2h_LCMS_Method_A).Step-3: Tert-butyl 3-(5-methyl-1,2,4-oxadiazol-3-yl) pyrrolidine-1 -carboxylate.To a stirred solution of tert-butyl-3-(N'-acetoxycarbamimidoyl)pyrrolidine-1-carboxylate (20 g, 73.80 mmol) in xylene (200 mL) was stirred at 130°C temperature for 24 h. The resulting reaction mixture directly concentrated under reduced pressure to obtain the crude. The crude was purified by column chromatography on silica gel (60-120 mesh size) in 30% ethyl acetate in hexane to tert-butyl 3-(5-methyl-1 ,2,4-oxadiazol-3-yl) pyrrolidine- 1 -carboxylate (15 g, 80%); 1 H-NMR (400 MHz, DMSO-d6) 5 3.66 - 3.53 (m, 2H), 3.42 - 3.30 (m, 3H), 2.57 (s, 3H), 2.26 - 2.20 (m, 1 H), 2.08 - 2.01 (m, 1 H), 1 .403 (s, 9H); LCMS: 1.983 min, MS: ES+ 254.2 (M+1) (o2h_LCMS_method-A).Step-4: 5-Methyl-3-(pyrrolidin-3-yl)-1,2,4-oxadiazol HCI salt (Intermediate J)Intermediate J

[0326] To a stirred solution of tert-butyl 3-(5-methyl-1 ,2,4-oxadiazol-3-yl) pyrrolidine- 1-carboxylate (10.0 g, 39.52 mmol) in 4M HCI in 1 ,4 dioxane (100 mL) and the resulting reaction mixture was stirred at room temperature for 2 h. The resulting reaction mixture concentrated under reduced pressure to obtain the crude. The crude was triturated by n- pentane (100 mL) to afford 5-methyl-3-(pyrrolidin-3-yl)-1 ,2,4-oxadiazol HCI salt (5.0 g, 82 %); 1 H-NMR (400 MHz, DMSO-d6) 5 9.53 (br s, 2H), 3.71 - 3.66 (m, 1 H), 3.61 - 3.56 (m, 1 H), 3.33 - 3.25 (m, 3H), 2.59 (s, 3H), 2.36 - 2.31 (m, 1 H), 2.12 - 2.05 (m, 1 H); LCMS: 0.314 min, MS: ES+ 154.1 (M+1) (o2h_LCMS_method-B).Synthesis of 4-((Tetrahydrofuran-3-yl)methyl)thiazol-2-amine (Intermediate K).

[0327] To a stirred solution of 2-(tetrahydrofuran-3-yl)acetic acid (CAS# 138498-97-2) (5.0 g, 38.46 mmol) in thionyl chloride (50 mL) was stirred at 85°C for 2 h. The reaction mixture was directly concentrated under reduced pressure. The obtained crude was dissolved in tetra hydrofuran (50 mL) and added trimethylsilyl diazomethane (2.0 M in Hexane) (38.46 mL, 76.92 mmol) at 0°C temperature. The resulting reaction mixture was allowed to stirred at room temperature for 30 h. Hydrogen bromide (63 % in water) (10 mL) was added at 0°C temperature and reaction mixture was allowed to stirred at room temperature for 1 h. The reaction mixture was poured into saturated sodium bicarbonate solution (500 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford 1-bromo-3- (tetrahydrofuran-3-yl)propan-2-one (3.0 g, 37.71%).Step 2: 4-((Tetrahydrofuran-3-yl)methyl)thiazol-2-amine (Intermediate K).Intermediate K

[0328] To a stirred solution of 1-bromo-3-(tetrahydrofuran-3-yl)propan-2-one (3.0 g, 14.56 mmol) in methanol (30 mL) was added thiourea (CAS# 62-56-6) (0.88 g, 11.65 mmol) at room temperature. The resulting reaction mixture was stirred at 65°C for 4 h. The reaction mixture was directly concentrated under reduced pressure to afford crude. The obtained crude was purified by column chromatography on basic alumna (100-200 mesh size) using 2% methanol in dichloromethane to afford 4-((tetrahydrofuran-3-yl)methyl)thiazol-2-amine (1.2 g, 44.95%); 1 H-NMR (400 MHz, DMSO-d6) 5 6.81 (s, 2H), 6.15 (s, 1 H), 3.72- 3.70 (m, 2H), 3.61 (q, J = 7.2, 7.6 Hz, 1 H), 3.33 - 3.30 (m, 1 H), 2.44 (br s, 3H), 1.97 - 1.89 (m, 1 H), 1.56 - 1.48 (m, 1 H); LCMS: 1.108 min, MS: ES+ 185.0 (M+1), (o2h_LCMS_Method_B); HPLC: 4.692 minutes, (Method - o2h_HPLC_Method_B).Synthesis of 5-Chloro-N1-(tetrahydrofuran-3-yl) benzene-1,3-diamine (Intermediate L)Step-1 : N-(3-chloro-5-nitrophenyl) tetrahydrofuran-3-amine.

[0329] To a stirred solution of 1-chloro-3-fluoro-5-nitrobenzene (0.7 g, 4.000 mmol) (CAS# 4815-64-9) in dimethyl sulfoxide (7 mL) were added tetrahydrofuran-3-amine (CAS# 88675-24-5) (0.41 g, 4.800 mmol) and potassium carbonate (2.76 g, 20.00 mmol) at room temperature. The resulting reaction mixture was stirred at 100°C temperature for 5 h. The reaction mixture was poured into water (200 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude. The obtained crude was purified by column chromatography (60-120 mesh size) using 45% ethyl acetate in hexane to afford N-(3-chloro- 5-nitrophenyl)tetrahydrofuran-3-amine; (0.5 g, 51.67%); 1 H-NMR (400 MHz, DMSO-de) 57.33 (dd, J = 6.8 Hz, J = 2.0 Hz, 2H), 7.00 (s, 1 H), 6.93 (d, J = 6.8 Hz, 1 H), 4.12 - 4.09 (m, 1 H), 3.88 - 3.71 (m, 3H), 3.55 (dd, J = 9.2 Hz, J = 3.2 Hz, 1 H), 2.23 - 2.18 (m, 1 H), 1.76 - 1.72 (m, 1 H); LCMS: 2.004 min, MS: material doesn’t ionize, (o2h_LCMS_Method_A)Step 2: 5-Chloro-N1-(tetrahydrofuran-3-yl) benzene-1,3-diamine (Intermediate L)Intermediate L

[0330] To a stirred solution of N-(3-chloro-5-nitrophenyl) tetrahydrofuran-3-amine (0.5 g, 2.066 mmol) in mixture of methanol (10 mL) and water (10 mL) were added iron powder (1.1 g, 20.66 mmol) and NH4CI (1.1 g, 20.66 mmol) at room temperature. The resulting reaction mixture was stirred at 80°C for 1 h. The reaction mixture was poured into saturated sodium bicarbonate solution (100 mL) and extracted with ethyl acetate (40 mL x 3). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the crude. The combined organic layer was dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to afford 5-chloro-N1- (tetrahydrofuran-3-yl) benzene-1 ,3-diamine (0.2 g, 45.64%); LCMS: 1.614 min, MS: ES+ 213.1 (M+1), 215.1 (M+3) (o2h_LCMS_Method_A).Synthesis of 3-((Tetrahvdrofuran-3-vl)methvl)aniline (Intermediate M)Step-1 : (2-Oxotetrahydrofuran-3-yl)triphenylphosphonium bromide.

[0331] To a stirred solution of 3-bromodihydrofuran-2(3H)-one (CAS# 5061-21-2) (40 g, 243.9 mmol) in ethyl acetate (200 mL) were added triphenylphosphine (67.0 g, 256.1 mmol) at room temperature. The reaction mixture was stirred at 80°C for 18 h. The reaction mixture was filtered out and solid material was dry under reduce pressure to afford (2- oxotetrahydrofuran-3-yl)triphenyl phosphonium bromide (40 g, 39%); 1 H-NMR (400 MHz, DMSO-d6) 6 7.96 - 7.88 (m, 9H), 7.82 - 7.77 (m, 6H), 6.43 - 6.34 (m, 1 H), 4.47 - 4.41 (q, J = 8.8 Hz, 16 Hz, 1 H), 4.34 - 4.30 (m, 1 H), 2.92 - 2.85 (m, 1 H), 2.67 - 2.57 (m, 1 H); LCMS: 1.684 min, MS: ES+, 347.2, (Method -o2h_LCMS_Method_A).Step 2: 3-(3-Nitrobenzylidene)dihydrofuran-2(3H)-one.

[0332] To a stirred solution of (2-oxotetrahydrofuran-3-yl)triphenyl phosphonium bromide (40 g, 93.89 mmol) in tetrahydrofuran (340 mL) was added n-BuLi (2.5 M in Hexane) (37.5 mL, 93.89 mmol) dropwise at -78°C temperature and the resulting reaction mixture was stirred at 0°C for 30 mins. A solution of 3-nitrobenzaldehyde (CAS# 99-61-6) (11.3 g, 75.11 mmol) in tetrahydrofuran (340 mL) was added dropwise at -78°C temperature and the resulting reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with NH4CI solutions (500 mL) and extracted with ethyl acetate (300 mL x 3). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the crude. The obtained crude was purified by column chromatography on silica gel (60-120 mesh size) using 30% ethyl acetate in hexane to afford (Z)-3-(3- nitrobenzylidene)dihydrofuran-2(3H)-one (10 g, 49%); 1 H-NMR (400 MHz, DMSO-d6) 5 8.38 (s, 1 H), 8.27 (d, J = 8.4 Hz, 1 H), 7.82 (d, J = 7.6 Hz, 1 H), 7.86 - 7.56 (m, 2H), 4.57 - 4.47 (m, 2H), 3.37 - 3.33 (m, 2H).Step 3: 3-(3-Aminobenzyl)dihydrofuran-2(3H)-one.

[0333] To a stirred solution of 3-(3-nitrobenzylidene) dihydrofuran-2(3H)-one (10.0 g, 45.66 mmol) in methanol (300 mL) was added 10% Pd / C (10 g, w / w) at room temperature. The reaction mixture was stirred at room temperature under H2<g) pressure (20 psi) for 18 h. The reaction mixture was filtered off and the resulting filtrate was concentrated under reduce pressure to afford 3-(3-aminobenzyl)dihydrofuran-2(3H)-one (5 g, 57%); LCMS: 1.207 min, MS: ES+, 192.0 (M+1), (Method -o2h_LCMS_Method_B).Step 4: 3-((Tetrahydrofuran-3-yl)methyl)aniline (Intermediate M).CAS# 27607-77-8Intermediate M

[0334] To a stirred solution of titanium tetrachloride (4.57 mL, 41.88 mmol) in anhydrous dichloromethane (50 mL) was added a solution of trimethylsilyl trifluoromethanesulfonate (CAS# 27607-77-8) (13.4 mL, 83.76 mmol) in dichloromethane (50 mL) dropwise at 0°C temperature. The resulting reaction mixture was stirred at room temperature for 4 h. 3-(3-aminobenzyl)dihydrofuran-2(3H)-one (5.0 g, 26.17 mmol) and triethyl silane (23.8 mL, 130.8 mmol) were added at 0°C temperature and the resulting reaction mixture was stirred at 50°C temperature for 16 h. The reaction mixture was diluted with saturated NaHCOs solution (500 mL) and extracted with ethyl acetate (300 mL x 3). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the crude. The obtained crude was purified by reverse phase chromatography (C18 silica gel) using 20% acetonitrile in 0.1 % ammonia in water to afford 3- ((tetrahydrofuran-3-yl)methyl)aniline (0.7 g, 15%); 1 H-NMR (400 MHz, DMSO-d6) 56.90 (t, J = 8.0 Hz, 1 H), 6.39 - 6.33 (m, 3H), 4.98 (br s, 2H), 3.76 - 3.59 (m, 3H), 3.34 - 3.28 (m, 1 H), 2.49 - 2.37 (m, 3H), 1.91 - 1.87 (m, 1 H), 1.53 - 1.50 (m, 1 H); LCMS: 1.286 min, MS: ES+ 178.0 (M+1) (Method-o2h_LCMS_method-B).Synthesis of 5-Methyl-4-((tetrahydrofuran-3-yl)methyl)thiazol-2-amine (Intermediate N)Step-1 : 5-Bromo-4-((tetrahydrofuran-3-yl)methyl)thiazol-2-amine.NBS ACNIntermediate K

[0335] To a stirred solution of 4-((tetrahydrofuran-3-yl)methyl)thiazol-2-amine (Intermediate K) (0.5 g, 2.717 mmol) in acetonitrile (5.0 mL) was added N-Bromosuccinimide (0.48 g, 2.717 mmol) at room temperature. The resulting reaction mixture was allowed to stir at room temperature for 3 h. The reaction mixture was directly evaporated under reduced pressure to afford the crude material. The obtained crude material was purified by column chromatography on silica gel (60-120 mesh size) using 30 % ethyl acetate in hexane to afford 5-bromo-4-((tetrahydrofuran-3-yl)methyl)thiazol-2-amine (0.3 g, 42.01 %); 1 H-NMR (400 MHz, DMSO-d6) 5 7.14 (s, 2H), 3.75 - 3.59 (m, 3H), 3.38 - 3.32 (m, 1 H), 2.44 - 2.42 (m, 3H), 1.95 - 1.87 (m, 1 H), 1.58 - 1.52 (m, 1 H); LCMS: 1.654 min, MS: ES+ 263.0 (M+1) (o2h_LCMS_Method_A).Step 2: 5-Methyl-4-((tetrahydrofuran-3-yl)methyl)thiazol-2-amine.CAS#823-96-1 Pd2(dba)3,Sphos, K3PO4, Toluene, / S"rrrr-O 100°C, 16 hur-OH2NX H r \ H2N— JI f \ N^' ^X / N"X^X / Intermediate N

[0336] To a stirred solution of 5-bromo-4-((tetrahydrofuran-3-yl) methyl)thiazol-2- amine (0.02 g, 0.0763 mmol) in anhydrous toluene (1.0 mL) were added trimethyl boroxine (CAS# 823-96-1) (0.047 g, 0.381 mmol) and potassium phosphate tribasic (0.048 g, 0.2289 mmol) at room temperature. The reaction mixture was degassed with N2gas for 15 minutes. S-Phos (0.006 g, 0.0152 mmol) and Pd2(dba)s (0.0069 g, 0.0076 mmol) were added and the resulting reaction mixture was stirred at 100°C for 16 h. The reaction mixture was passed through the celite bed and washed with ethyl acetate (300 mL) and concentrated under reduced pressure to afford the crude material. The obtained crude material was purified by column chromatography on neutral alumna (100-200 mesh size) using 30 % ethyl acetate in hexane to afford 5-methyl-4-((tetrahydrofuran-3-yl)methyl)thiazol-2-amine (0.120 g, 53.09%); 1 H-NMR (400 MHz, DMSO-d6) 5 6.55 (s, 2H), 3.74 - 3.58 (m, 4H), 2.45 - 2.33 (m, 3H), 2.10(s, 3H), 1.92 - 1.86 (m, 1H), 1.54 - 1.48 (m, 1 H); LCMS: 1.283 min, MS: ES+ 199.1 (M+1), (o2h_LCMS_Method_A).Synthesis of 6-((Tetrahydrofuran-3-yl)methyl)pyridin-2-amine (Intermediate 0).

[0337] To a stirred solution of tetrahydrofuran-3-carboxylic acid (5.0 g, 43.31 mmol) in in mixture of dichloromethane (50 mL) and ethyl acetate (50 mL) was added triethylamine (18.13 mL, 129.3 mmol) at 0°C. The reaction mixture was stirred at 0°C for 5 minutes. T3P (50% in ethyl acetate) (41.1 g, 64.65 mmol) was added slowly at 0°C followed by N,O- dimethylhydroxylamine hydrochloride (CAS# 6638-79-5) (45 mmol). The resulting reaction mixture was left to stir at room temperature for 12 h. The reaction mixture was poured into ice cold water (500 mL) and extracted ethyl acetate (3 x 200 mL). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure to afford N-methoxy-N- methyltetrahydrofuran-3-carboxamide (20 g, 72.94%; 1 H-NMR (400 MHz, CDCI3) 5 4.05 (t, J = 8.4 Hz, 1 H), 3.94 - 3.80 (m, 3H), 3.72 (s, 3H), 3.46 - 3.39 (m, 1 H), 3.22 (s, 3H), 2.29 - 2.20 (m, 1 H), 2.14 - 2.05 (m, 1H); LCMS: 1.294 min, MS: ES+ 160.1 (M+1), (o2h_LCMS_Method_A).Step-1 : N-(6-Bromopyridin-2-yl)pivalamide.

[0338] To a stirred solution of 6-bromopyridin-2-amine (5.0 g, 29.06 mmol) in dichloromethane (50 mL) was added triethylamine (12.22 mL, 87.20 mmol) at 0°C. Pivaloyl chloride (CAS# 3282-30-2) (4.18 g, 34.87 mmol) was added slowly at 0°C. The resulting reaction mixture was stirred at room temperature for 12 h. The reaction mixture was poured into ice cold water (600 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford N-(6-bromopyridin-2-yl)pivalamide (20 g, 67.29%); 1 H-NMR (400 MHz, DMSO-d6) 5 10.13 (s, 1 H), 8.07 (d, J = 8 Hz, 1 H), 7.71 - 7.69 (t, J = 8 Hz, 1 H), 7.32 (d, J = 7.6 Hz, 1 H), 1.23 (s, 9H); LCMS: 2.230 min, MS: ES+ 257.1 (M+1), 259.0 (M+3) (o2h_LCMS_Method_A).Step-2: N-(6-(Tetrahydrofuran-3-carbonyl)pyridin-2-yl)pivalamide.To a stirred solution of N-(6-bromopyridin-2-yl)pivalamide (5.0 g, 19.53 mmol) in toluene (50 mL) was added isopropyl magnesium chloride solution (CAS# 1068-55-9) (2.0 M in THF) (11.7 mL, 23.43 mmol) at 0°C dropwise in 30 minutes. The reaction mixture was stirred at 0°C for 12 h. A solution of N-methoxy-N-methyltetrahydrofuran-3-carboxamide (3.73 g, 23.43 mmol) in tetrahydrofuran was added at 0°C. The resulting reaction mixture was stirred at room temperature for 24 h. The reaction mixture was quenched with water (400 mL) and then extracted with ethyl acetate (100 mL x 3). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material. The obtained crude material was purified by column chromatography on silica gel (100-200 mesh size) using 12% ethyl acetate in hexane to N-(6-(tetrahydrofuran-3-carbonyl)pyridin-2- yl)pivalamide (6.0 g, 55.83%); 1 H-NMR (400 MHz, CDCh) 6 8.46 (d, J = 8 Hz, 1 H), 8.01 (br s, 1 H), 7.88 - 7.79 (m, 2H), 4.45 - 4.40 (m, 1 H), 4.20 (t, J = 8.8 Hz, 1 H), 3.95 - 3.85 (m, 3H), 2.33 - 2.27 (m, 1 H), 2.21 - 2.14 (m, 1 H), 1.37 (s, 9H); LCMS: 2.063 min, MS: ES+ 277.1 (M+1) (o2h_LCMS_Method_A).Step-3: N-(6-(Hydroxy(tetrahydrofuran-3-yl)methyl)pyridin-2-yl)pivalamide.To a stirred solution of N-(6-(tetrahydrofuran-3-carbonyl)pyridin-2-yl)pivalamide (2.6 g, 9.420 mmol) in methanol (26 mL) was added sodium borohydride (1.78 g, 47.10 mmol) portion wise at room temperature. The resulting reaction mixture was stirred at room temperature for 10 h. The reaction mixture was cooled to room temperature, poured into ice cold water (600 mL) and extracted with ethyl acetate (150 mL x 3). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material. The obtained crude material was purified by column chromatography on silica gel (100-200 mesh size) using 30% ethyl acetate in hexane to afford N-(6-(hydroxy(tetrahydrofuran-3- yl)methyl)pyridin-2-yl)pivalamide (3.0 g, 57.27%); 1 H-NMR (400 MHz, CDCh) 5 8.18 (d, J = 8 Hz, 1 H), 7.99 (br s, 1 H), 7.74 - 7.70 (m, 1 H), 7.01 (d, J = 7.6 Hz, 1 H), 4.65 - 4.61 (m, 1 H), 3.94 - 3.88 (m, 1 H), 3.82 - 3.72 (m, 3H), 3.64 - 3.51 (m, 1 H), 3.22 (s, 1 H), 1.92 - 1 .85 (m, 2H), 1.37 (s, 9H); LCMS: 1.699 and 1.675 min, MS: ES+ 279.1 (M+1) (o2h_LCMS_Method_A).Step-4: N-(6-((Tetrahydrofuran-3-yl)methyl)pyridin-2-yl)pivalamide.

[0339] To a stirred solution of N-(6-(hydroxy(tetrahydrofuran-3-yl)methyl)pyridin-2- yl)pivalamide (3.0 g, 10.86 mmol) in dichloromethane (30 mL) were added triethylamine (4.57 mL, 32.60 mmol) followed by mesyl chloride (3.73 mL, 32.60 mmol) at 0°C. The resulting reaction mixture was stirred at room temperature for 1 h. The reaction mixture was directly concentrated under reduced pressure to afford crude material which was used in next step without purification.

[0340] The above material was dissolved in acetic acid (40 mL) was added Zn metal (3.5 g, 54.34 mmol) and resulting reaction mixture was stirred 40°C for 12 h. The reaction mixture was cooled to room temperature and poured into ice cold water (300 mL) and extracted with ethyl acetate (180 mL x 3). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material. The obtained crude material was purified by column chromatography on silica gel (100-200 mesh size) using 15% ethyl acetate in hexane to afford N-(6-((tetrahydrofuran-3- yl)methyl)pyridin-2-yl)pivalamide (2.0 g, 70.73%); LCMS: 1.872 min, MS: ES+ 263.2 (M+1) (o2h LCMS Method A).6-((Tetrahydrofuran-3-yl)methyl)pyridin-2-amine (Intermediate O).

[0341] To a stirred solution of N-(6-((tetrahydrofuran-3-yl)methyl)pyridin-2- yl)pivalamide (2.0 g, 7.633 mmol) in water (20 mL) was added potassium hydroxide (4.27 g, 76.33 mmol) at room temperature. The resulting reaction mixture was heated at 100°C for 12 h. The reaction mixture was cooled to room temperature, poured into ice cold water (350 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material. The obtained crude material was purified by column chromatography on basic aluminum (100- 300 mesh size) using 30% ethyl acetate in hexane afford 6-((tetrahydrofuran-3- yl)methyl)pyridin-2-amine (1.0 g, 73.60%); 1 H-NMR (400 MHz, CDCI3) 6 7.36 (t, J = 15.6 Hz, 1 H), 6.51 (d, J = 7.6 Hz, 1 H), 6.36 (d, J = 8.4 Hz, 1 H), 4.38 (br s, 2H), 3.94 - 3.86 (m, 2H), 3.81 - 3.75 (m, 1 H), 3.51 - 3.48 (m, 1 H), 2.07 - 1.99 (m, 1 H), 1.67-165 (m, 2H); LCMS: 0.718 min, MS: ES+ 179.1 (M+1), (o2h_LCMS_Method_A).Synthesis of (S)-5-Chloro-N1-(tetrahydrofuran-3-yl)benzene-1,3-diamine (Intermediate P).Step 1 : (S)-N-(3-Chloro-5-nitrophenyl)tetrahydrofuran-3-amine.

[0342] To a stirred solution of 1-bromo-3-chloro-5-nitrobenzene (CAS# 219817-43-3) (30.0 g, 127.71 mmol) in anhydrous 1 ,4-dioxane (600 mL) were added (S)-tetrahydrofuran-3- amine (HCI Salt) (CAS# 204512-95-8) (18.80 g, 153.25 mmol) and cesium carbonate (124.5 g, 383.14 mmol) at room temperature. Xantphos (14.76 g, 25.54 mmol) and Pd2(dba)s (11.68 g, 12.77 mmol) were added and the resulting reaction mixture allowed to stirred at 100°C for 24 h. The resulting reaction mixture was filtered through celite, washed with ethyl acetate (1000 mL) and the filtrate was concentrated under reduced pressure to afford the crude. The crude product was purified by column chromatography on silica gel (60-120 mesh size) using 15% ethyl acetate in hexane to afford (S)-N-(3-chloro-5-nitrophenyl)tetrahydrofuran-3-amine as brown solid (25.0 g, 40.60%); 1 H-NMR (400 MHz, DMSO-d6) 6 7.34 - 7.30 (m, 2H), 6.99(t, J = 2.0 Hz, 1 H), 6.93 (d, J = 6.4 Hz, 1 H), 4.11 - 4.07 (m, 1 H), 3.88 - 3.79 (m, 2H), 3.76 - 3.71 (m, 1 H), 3.55 (dd, J = 8.8 Hz, J = 3.2 Hz, 1 H), 2.25 - 2.16 (m, 1 H), 1.77 - 1.70 (m, 1 H); LCMS: 2.185 min, MS: ES+ 243.0 (M+1) (Method -o2h_LCMS_Method_A).Step 2: (S)-5-Chloro-N1-(tetrahydrofuran-3-yl)benzene-1,3-diamine (Intermediate P).

[0343] To a stirred solution of (S)-N-(3-chloro-5-nitrophenyl) tetrahydrofuran-3-amine (25.0 g, 103.28 mmol) in a mixture of tetrahydrofuran (250 mL) and water (250 mL) were added zinc dust (33.7 g, 516.42 mmol) and ammonium chloride (27.6 g, 516.42 mmol) at room temperature. The resulting reaction mixture was allowed to stirred at room temperature for 2 h. The reaction mixture was filtered through celite and the filtrate was diluted with water (500 mL) and extracted with ethyl acetate (500 mL x 2). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford (S)-5-chloro- N1-(tetrahydrofuran-3-yl)benzene-1 ,3-diamine as yellow oil (20.0 g, 91.28); 1 H-NMR (400 MHz, DMSO-d6) 5 5.83 - 5.71 (m, 4H), 5.07 (s, 2H), 3.84 - 3.68 (m, 4H), 3.48 (t, J = 6.0 Hz, 1 H), 2.15 - 2.07 (m, 1 H), 1.75 - 1.68 (m, 1 H); LCMS: 1.622 min, MS: ES+ 213.1 (M+1), 215.1 (M+3) (Method -o2h_LCMS_Method_A).Alternative Synthesis of (S)-5-Chloro-N1-(tetrahydrofuran-3-yl)benzene-1,3-diamine(Intermediate P).Step-1 : (S)-N-(3-Chloro-5-nitrophenyl)tetrahydrofuran-3-amine.

[0344] To a 3 L four-neck round-bottom flask was added a stirred solution of 1-chloro- 3-fluoro-5-nitrobenzene (150 g, 857.24 mmol) in dimethyl sulfoxide (DMSO, 1500 mL) at room temperature. To this solution was added (S)-tetrahydrofuran-3-amine hydrochloride (264.9 g, 2143.1 mmol) followed by potassium carbonate (591.92 g, 4286.2 mmol). The resulting reaction mixture was stirred at 80°C for 72 h. The resulting reaction mixture was poured in to ice-cold water (1 L) and stirred continuously for 1h to obtain precipitated. The solid material was filtered and dry under reduced pressure to afford (S)-N-(3-chloro-5-nitrophenyl)tetrahydrofuran-3-amine as dark yellow solid (300 g, 72.34%); 1 H-NMR (400 MHz, DMSO-d6) 5 7.35 - 7.30 (m, 2H), 7.00 (t, J = 1.6 Hz, 1 H), 6.93 (d, J = 6.4 Hz, 1 H), 4.12 - 4.08 (m, 1 H), 3.89 - 3.71 (m, 3H), 3.56 - 3.53 (m, 1 H), 2.25 - 2.17 (m, 1 H), 1.78 - 1.71 (m, 1 H); LCMS: 1.701 min, MS: ES- 241.0 (M-1) (o2h_LCMS_Method_B).Step-2: (S)-5-Chloro-N1-(tetrahydrofuran-3-yl)benzene-1,3-diamine.

[0345] To a 2 L three-neck round-bottom flask was added a stirred solution of (S)-N- (3-chloro-5-nitrophenyl)tetrahydrofuran-3-amine (95.0 g, 392.48 mmol) in a mixture of tetra hydrofuran (950 mL) and water (950 mL). The solution was cooled to 0°C and zinc dust (128.3 g, 1962.4 mmol) followed by ammonium chloride (104.79 g, 1962.4 mmol) were added portion-wise. The resulting reaction mixture was stirred at 60°C for 6 h. The reaction mixture was filtered through a celite bed to remove solid residues, and the filtrate was diluted with water (2000 mL) and extracted with ethyl acetate (2 x 2000 mL). The combined organic layers were concentrated under reduced pressure to afford a crude. The resulting organic residue was then diluted with water (1000 mL) and ethyl acetate (1000 mL) and acidified with concentrated hydrochloric acid until the aqueous layer reached pH~1-2. The layers were separated and the organic layer (non-polar impurities) was discarded. The aqueous layer was subsequently neutralized with saturated sodium bicarbonate solution (1000 mL) and extracted with ethyl acetate (2 x 2000 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford (S)-5-chloro-N1- (tetrahydrofuran-3-yl)benzene-1 ,3-diamine as a brown liquid (277 g, 94.88%); 1 H-NMR (400 MHz, DMSO-d6) 5 5.83 (s, 1 H), 5.79 (s, 1 H), 5.75 (d, J = 6.0 Hz,1 H) 5.71 (s, 1 H) 5.07 (s, 2H), 3.86 - 3.66 (m, 4H), 3.47 (d, J = 5.2 Hz, 1 H), 2.14 - 2.09 (m, 1 H), 1.73 - 1.70 (m, 1 H);13C- NMR (100 MHz, DMSO-d6) 5 150.99, 150.35, 134.20, 102.71 , 101.31 , 96.32, 73.03, 66.85, 53.22, 33.07; LCMS: 1.652 min, MS: ES+ 213.1 (M+1), 215.1 (M+3) (o2h_LCMS_Method_A).Synthesis of (R)-5-Chloro-N1-(tetrahydrofuran-3-yl)benzene-1,3-diamine (Intermediate Q).Step-1 : (R)-N-(3-Chloro-5-nitrophenyl)tetrahydrofuran-3-amine.

[0346] To a stirred solution of 1-bromo-3-chloro-5-nitrobenzene (CAS# 219817-43-3) (0.50 g, 2.127 mmol) in anhydrous 1 ,4-dioxane (5 mL) were added (R)-tetrahydrofuran-3- amine HCI salt (CAS# 1072015-52-1) (0.52 g, 4.255 mmol) and cesium carbonate (2.08 g, 6.382 mmol) at room temperature. 5-(di-tert-Butylphosphino)-1',3',5'-triphenyl-TH-1 ,4'- bipyrazole (CAS# 894086-00-1) (0.21 g, 0.425 mmol) and Pd2(dba)3(0.19 g, 0.212 mmol) were added and the resulting reaction mixture allowed to stirred at 100°C for 4 h. The resulting reaction mixture was passed through celite, washed with ethyl acetate (500 mL) and the filtrate was concentrated under reduced pressure to afford the crude. The obtained crude was purified by column chromatography on silica gel (60-120 mesh size) using 15% ethyl acetate in hexane to afford (R)-N-(3-chloro-5-nitrophenyl)tetrahydrofuran-3-amine (0.75 g, 48.72%); 1 H-NMR (400 MHz, DMSO-d6) 6 7.46 - 7.31 (m, 2H), 6.99 (t, J = 2.0 Hz, 1 H), 6.95 (d, J = 6.8 Hz, 1 H), 4.13 - 4.08 (m, 1 H), 3.88 - 3.73 (m, 3H), 3.55 (dd, J = 9.2, J = 3.2 Hz, 1 H), 2.25 - 2.16 (m, 1 H), 1.99 - 1.71 (m, 1 H); LCMS: 1.729 min, MS: ES+ 243.1 (M+1), 245.1 (M+3) (o2h_LCMS_Method_B).Step-2: (R)-5-Chloro-N1-(tetrahydrofuran-3-yl)benzene-1,3-diamine (Intermediate Q).

[0347] To a stirred solution of (R)-N-(3-chloro-5-nitrophenyl)tetrahydrofuran-3-amine (0.50 g, 2.066 mmol) in a mixture of tetrahydrofuran (5 mL) and water (5 mL) were added zinc dust (0.67 g, 10.33 mmol) and ammonium chloride (0.55 g, 10.33 mmol) at room temperature. The resulting reaction mixture was allowed to stirred at room temperature for 2 h. The reaction mixture was filtered through celite and the resulting filtrate was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford (R)-5-chloro- N1-(tetrahydrofuran-3-yl)benzene-1 ,3-diamine (0.30 g, 68.46%); 1 H-NMR (400 MHz, DMSO- d6) 6 5.82 - 5.70 (m, 4H), 5.06 (s, 2H), 3.85 - 3.67 (m, 4H), 3.47 - 3.33 (m, 1 H), 2.13 - 2.08 (m, 1 H), 1.72 - 1.70 (m, 1 H); LCMS: 1.328 min, MS: ES+ 213.1 (M+1), 215.0 (M+3) (o2h_LCMS_Method_B).Synthesis of (S)-4-Chloro-N2-(tetrahydrofuran-3-yl) pyridine-2,6-diamine (Intermediate R).Step-1 : tert-Butyl (6-bromo-4-chloropyridin-2-yl) carbamate.

[0348] To a stirred solution of 2,6-dibromo-4-chloropyridine (CAS# 1196156-59-8) (100 g, 371.7 mmol) in 1 ,4-dioxane (1000 mL) were added tert-butyl carbamate (30.4 g, 260.2 mmol) and cesium carbonate (242.3 g, 743.4 mmol) at room temperature. The resulting reaction mixture was degassed with nitrogen gas for 15 minutes. Pd2(dba)s (34.01 g, 37.17 mmol) and xantphos (42.97 g, 74.34 mmol) were added at room temperature. The resulting reaction mixture was stirred at 100°C for 4 h. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure to afford crude. The obtained crude was purified by reverse phase flash chromatography on (C silica gel) using 68% acetonitrile in water to afford tert-butyl (6-bromo-4-chloropyridin-2-yl) carbamate (50 g, 44.11 %); 1 H-NMR (400 MHz, DMSO-d6) 5 10.48 (s, 1 H), 7.86 (d, J = 1.6 Hz, 1 H), 7.47 (d, J = 1.6 Hz, 1 H), 1.45 (s, 9H); LCMS: 2.755 min, MS: ES+ 251.0 (M-tBu) (o2h_LCMS_Method_A).Step-2: tert-Butyl (S)-(4-chloro-6-((tetrahydrofuran-3-yl)amino)pyridin-2-yl)carbamate.

[0349] To a stirred solution of tert-butyl (6-bromo-4-chloropyridin-2-yl) carbamate (50 g, 163.3 mmol) in 1 ,4 dioxane (500 mL) were added (S)-tetrahydrofuran-3-amine hydrochloride (CAS# 204512-95-8) (20.09 g, 163.3 mmol) and cesium carbonate (159.8 g, 490.1 mmol) at room temperature. The resulting reaction mixture was degassed with nitrogen gas for 15 minutes. Pd2(dba)s (14.95 g, 16.33 mmol) and xantphos (9.44 g, 16.33 mmol) were added at room temperature and the resulting reaction mixture was stirred at 100°C for 14 h. The reaction mixture was poured into water (1000 mL) and extracted with ethyl acetate (500 mL x 3). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude. The obtained crude was purified by column chromatography on silica gel (60-120 mesh size) using 30% ethyl acetate in n-hexaneto afford tert-butyl (S)-(4-chloro-6-((tetrahydrofuran-3-yl)amino)pyridin-2-yl)carbamate (35 g, 68.61 %); 1 H-NMR (400 MHz, DMSO-d6) 5 9.41 (s, 1 H), 6.97 - 6.94 (m, 2H), 6.17 (d, J = 1.6 Hz, 1 H), 4.26 - 4.25 (m, 1 H), 3.96 - 3.93 (m, 1 H), 3.83 - 3.77 (m, 1 H), 3.72 - 3.68 (m, 1 H), 3.43 - 3.33 (m, 1 H), 2.19 - 2.14 (m, 1 H), 1.77 - 1.71 (m, 1 H), 1.46 (s, 9H); LCMS: 2.366 min, MS: ES+ 314.1 (M+1), 258.1 (M-tBu) (o2h_LCMS_Method_A).Step-3: (S)-4-Chloro-N2-(tetrahydrofuran-3-yl) pyridine-2,6-diamine (Intermediate R).

[0350] To a stirred solution of tert-butyl (S)-(4-chloro-6-((tetrahydrofuran-3-yl) amino) pyridin-2-yl)carbamate (35 g, 111.8 mmol) in DCM (175 mL) was added trifluoroacetic acid (175 mL) at room temperature. The resulting reaction mixture was stirred at room temperature for 6 h. The resulting reaction mixture was concentrated under reduced pressure and basified to pH~8 using saturated aqueous NaHCOs solution (500 mL) and extracted with ethyl acetate (500 mL x 2). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude. The obtained crude was purified by reverse phase flash column chromatography on (Cis silica gel) using 35% acetonitrile in water (0.1% NH4OH) to afford (S)-4-chloro-N2-(tetrahydrofuran-3-yl)pyridine-2,6-diamine (20 g, 83.92%); 1 H-NMR (400 MHz, DMSO-d6) 5 6.49 (d, J = 6.4 Hz, 1 H), 5.74 (s, 2H), 5.65 - 5.62 (m, 2H), 4.30 - 4.20 (m, 1 H), 3.85 - 3.75 (m, 2H), 3.70 - 3.64 (m, 1 H), 3.43 - 3.32 (m, 1 H), 2.14 - 2.05 (m, 1 H), 1.75 - 1.67 (m, 1 H); LCMS: 1.442 min, MS: ES+ 214.1 (M+1), 216.1 (M+3) (o2h_LCMS_Method_A); HPLC: 3.316 min, (o2h_HPLC_Method_A).Alternative synthesis of (S)-4-Chloro-N2-(tetrahydrofuran-3-yl) pyridine-2,6-diamine(Intermediate R).Step-1 : Tert-butyl (4,6-dichloropyridin-2-yl)bis-carbamate.

[0351] To a 10 L four-neck round-bottom flask, a stirred solution of 4,6-dichloropyridin- 2-amine (375 g, 2315 mmol) in dichloromethane (3750 mL). To this solution were added di-tert-butyl dicarbonate (Boc)2O (1263 g, 5787 mmol), 4-(dimethylamino)pyridine (DMAP) (28.28 g, 231.5 mmol) and triethylamine (702.7 g, 6945 mmol) sequentially at room temperature. The resulting reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water (5000 mL) and extracted with dichloromethane (4000 mL x 2). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude. The obtained crude was purified by column chromatography on silica gel (60-120 mesh size) using 20% ethyl acetate in n-hexane to afford tert-butyl (4,6-dichloropyridin-2-yl)bis-carbamate as off-white solid (1490 g, 66.86%); 1 H-NMR (400 MHz, DMSO-d6) 5 7.80 - 7.77 (m, 2H), 1.42 (s, 18H); LCMS: 2.839 min, MS: ES+ 363.1 (M+1), 263.1 (M-100), 206.9 (M-156) (o2h_LCMS_Method_A).Step-2: Tert-butyl (S)-(4-chloro-6-((tetrahydrofuran-3-yl)amino)pyridin-2-yl)bis- carbamate.

[0352] To a 3 L four neck round bottom flask to a stirred solution of tert-butyl (4,6- dichloropyridin-2-yl)bis-carbamate (100 g, 276.1 mmol) in 1 ,4 dioxane (1000 mL) were added (S)-tetrahydrofuran-3-amine hydrochloride (33.9 g, 276.1 mmol), cesium carbonate (269.9 g, 828.5 mmol), Pd2(dba)s (12.6 g, 13.80 mmol) and Xantphos (15.9 g, 27.61 mmol) at room temperature and the resulting reaction mixture was stirred at 100°C for 3 h. After this period, an additional portion of cesium carbonate (89.9 g, 276.18 mmol) was added at 100°C, and the reaction mixture was stirred at the same temperature for 13 h. The reaction mixture was filtered through celite bed and washed with ethyl acetate (3000 mL). The combined filtrate was concentrated under reduced pressure to afford crude. The obtained crude was purified by column chromatography on silica gel (60-120 mesh size) using 30% ethyl acetate in n-hexane to afford tert-butyl (S)-(4-chloro-6-((tetrahydrofuran-3-yl)amino)pyridin-2-yl)bis-carbamate as brown semi-solid (945 g, 55.66%); 1 H-NMR (400 MHz, DMSO-d6) 5 7.24 (d, J = 6.0 Hz, 1 H), 6.61 (d, J = 1.2 Hz, 1 H), 6.43 (d, J = 1.2 Hz, 1 H), 3.84 - 3.78 (m, 2H), 3.73 - 3.66 (m, 2H), 3.48 - 3.45 (m, 1 H), 2.17 - 2.12 (m, 1 H), 1.78 - 1.70 (m, 1 H), 1.49 (s, 18H); LCMS: 2.558 min, MS: ES+ 414.3 (M+1), 416.2 (M+3) (o2h_LCMS_Method_A).Step-3: (S)-4-Chloro-N2-(tetrahydrofuran-3-yl)pyridine-2,6-diamine.

[0353] To a 5 L four neck round bottom flask to a stirred solution of tert-butyl (S)-(4- chloro-6-((tetrahydrofuran-3-yl)amino)pyridin-2-yl)bis-carbamate (450 g, 1089 mmol) in DCM (1350 mL) was added trifluoroacetic acid (1350 mL) drop wise at room temperature. The resulting reaction mixture was stirred at room temperature for 16 h. The resulting reaction mixture was diluted with water (7000 mL) and basified to pH~8 using solid NaHCOs (3000 g) and extracted with ethyl acetate (5000 mL x 3). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude. The obtained crude was purified by reverse phase flash column chromatography on (C silica gel) using 34% acetonitrile in water (0.1 % Aq. NH4OH solution) to afford (S)-4-chloro-N2- (tetrahydrofuran-3-yl)pyridine-2,6-diamine as brown sticky liquid (280 g, 57.40%); 1 H-NMR (400 MHz, DMSO-d6) 5 6.49 (d, J = 6.8 Hz, 1 H), 5.74 (s, 2H), 5.67 - 5.64 (m, 2H), 4.27 - 4.26 (m, 1 H), 3.86 - 3.78 (m, 2H), 3.71 - 3.67 (m, 1 H), 3.45 - 3.34 (m, 1 H), 2.15 - 2.07 (m, 1 H), 1.76 - 1.69 (m, 1 H);13C-NMR (100 MHz, DMSO-d6) 5 160.06, 159.02, 143.50, 94.89, 94.52, 73.34, 66.78, 51.56, 32.94; LCMS: 1.409 min, MS: ES+ 214.1 (M+1), 216.0 (M+3) (o2h_LCMS_Method_A); HPLC: 5.763 min, (o2h_HPLC_Method_B).Synthesis of (R)-4-Chloro-N2-(tetrahydrofuran-3-yl) pyridine-2,6-diamine (Intermediate S).Step-1 : tert-Butyl (R)-(4-chloro-6-((tetrahydrofuran-3-yl)amino)pyridin-2-yl)carbamate.

[0354] To a stirred solution of (R)-tetrahydrofuran-3-amine hydrochloride (CAS # 1072015-52-1) (0.25 g, 2.03 mmol) in 1 ,4 dioxane (10 mL) were added tert-butyl (6-bromo-4- chloropyridin-2-yl)carbamate (0.80 g, 2.642 mmol) and cesium carbonate (1.98 g, 6.097 mmol) at room temperature. Pd2(dba)s (0.18 g, 0.203 mmol) and Xantphos (0.23 g, 0.406 mmol) were added at room temperature. The resulting reaction mixture was stirred at 100°C temperature for 16 h. The reaction mixture was passed through the celite and washed with ethyl acetate (200 mL), concentrated under reduced pressure to afford crude. The obtained crude was purified by column chromatography on silica gel (60-120 mesh size) using 12% ethyl acetate in n-hexane to afford tert-butyl (R)-(4-chloro-6-((tetrahydrofuran-3-yl)amino)pyridin-2-yl)carbamate (0.30 g, 36.39%); 1 H-NMR (400 MHz, DMSO-d6) 5 9.41 (s, 1 H), 6.95 - 6.85 (m, 2H), 6.15 (d, J = 1.6 Hz, 1 H), 4.26 - 4.24 (m, 1 H), 3.94 - 3.91 (m, 1 H), 3.79 - 3.75 (m, 1 H), 3.70 - 3.65 (m, 1 H), 3.41 - 3.37 (m, 1 H), 2.17 - 2.12 (m, 1 H), 1.72 - 1.71 (m, 1 H), 1.45 (s, 9H); LCMS: 2.407 min, MS: ES+ 314.0 (M+1), 258.03 (M-tBu) (o2h_LCMS_Method_A).Step-2: (R)-4-Chloro-N2-(tetrahydrofuran-3-yl)pyridine-2,6-diamine (Intermediate S).

[0355] To a stirred solution of tert-butyl (R)-(4-chloro-6-((tetrahydrofuran-3- yl)amino)pyridin-2-yl)carbamate (0.30 g, 0.958 mmol) in DCM (6 mL) was added 4M HCI in 1 ,4-dioxane (6 mL) at room temperature. The resulting reaction mixture was allowed to stir at room temperature for 16 h. The resulting reaction mixture was concentrated under reduced pressure and basified with NaHCOs solution (100 mL) and extracted with dichloromethane (50 mL x 3). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford (R)-4-chloro-N2-(tetrahydrofuran-3-yl)pyridine- 2,6-diamine (0.150 g, 73.43%); 1 H-NMR (400 MHz, DMSO-d6) 5 8.42 (br s, 1 H), 7.84 (br s, 2H), 6.04 (d, J = 2.0 Hz, 1 H), 5.94 (d, J = 2.0 Hz, 1 H), 4.37 (br s, 1 H), 3.92 - 3.80 (m, 1 H), 3.73 - 3.66 (m, 1 H), 3.61 - 3.58 (m, 1 H), 1.27 (s, 1 H), 2.28 - 2.23 (m, 1 H), 1.82 - 1.74 (m, 1 H); LCMS: 1.708 min, MS: ES+ 214.2 (M+1), 216.1 (M+3) (o2h_LCMS_Method_B).Synthesis of Methyl 1-methyl-5-(5-((1-methylazetidin-3-yl)oxy)pyrimidin-2-yl)-1H- pyrrole-3-carboxylate (Intermediate T)Step-1 : Tert-butyl 3-((2-chloropyrimidin-5-yl)oxy)azetidine-1 -carboxylate.

[0356] To a 3 L four-neck round-bottom flask was added a stirred solution of 2- chloropyrimidin-5-ol (150.0 g, 1153.9 mmol) and tert-butyl 3-iodoazetidine-1 -carboxylate (489.9 g, 1730.9 mmol) in N, N-dimethylformamide (1500 mL, 10 v) under a nitrogen atmosphere. To this solution, potassium carbonate (478.4 g, 3461.8 mmol) was added in one portion at room temperature. The resulting heterogeneous mixture was heated to 100 °C and stirred for 16 h. The reaction mixture was poured in ice cold water (2000 mL) to obtain precipitated. The solid material was filtered out and dried under reduced pressure to afford tert-butyl 3-((2-chloropyrimidin-5-yl)oxy)azetidine-1-carboxylate (110 g, 33.50%); 1 H-NMR (400 MHz, DMSO-d6) 5 8.41 (s, 2H), 5.15 - 5.12 (m, 1 H), 4.32 (t, J = 7.6 Hz, 2H), 3.86 (d, J = 7.6 Hz, 2H), 1.38 (s, 9H); LCMS: 2.095 min, MS: ES+ 286.2 (M+1), 288.2 (M+3) (o2h_LCMS_Method_A).Step-2: Methyl 5-(5-((1-(tert-butoxycarbonyl)azetidin-3-yl)oxy)pyrimidin-2-yl)-1-methyl- 1 H-pyrrole-3-carboxylate.

[0357] To a 3 L four-neck round-bottom flask was added a stirred solution of tert-butyl 3-((2-chloropyrimidin-5-yl)oxy)azetidine-1 -carboxylate (85.0 g, 298.2 mmol) in 1 ,4-dioxane (1700 mL) and water (340 mL) under a nitrogen atmosphere were added methyl 1-methyl-5- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrrole-3-carboxylate (intermediate V) (79.05 g, 298.2 mmol) followed by cesium carbonate (291.43 g, 896.9 mmol), and PdCI2(dppf) DCM (12.17 g, 14.91 mmol) at room temperature. The resulting reaction mixture was stirred at 100°C for 3 h. The resulting reaction mixture was poured in water (700 mL) and extracted with ethyl acetate (700 mL x 2). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the crude. The obtained crude material was purified by column chromatography on silica gel (100-200 mesh size) using 100% ethyl acetate to afford methyl 5-(5-((1-(tert- butoxy carbonyl) azetidin-3- yl)oxy)pyrimidin-2-yl)-1-methyl-1 H-pyrrole-3-carboxylate (57 g, 49.33%); 5 8.47 (s, 2H), 7.65 (d, J = 1.6 Hz, 1 H), 7.16 (d, J = 2.0 Hz, 1 H), 5.18 - 5.14 (m, 1 H), 4.35 (t, J = 8.4 Hz, 2H), 4.02 (s, 3H), 3.87 (d, J = 7.2 Hz, 2H), 3.72 (s, 3H), 1.39 (s, 9H); LCMS: 2.274 min, MS: ES+ 389.3 (M+1) (o2h_LCMS_Method_A).Step-3: Methyl 5-(5-(azetidin-3-yloxy)pyrimidin-2-yl)-1-methyl-1H-pyrrole-3-carboxylate hydrochloride salt.

[0358] To a 2 L four-neck round-bottom flask, charged with a stirred solution of methyl 5-(5-((1-(tert-butoxycarbonyl)azetidin-3-yl)oxy)pyrimidin-2-yl)-1-methyl-1 H-pyrrole-3- carboxylate (57.0 g, 149.4 mmol) in dichloromethane (570 mL), was added 4M HCI in 1 ,4- dioxane (285 mL, 5 V) dropwise at room temperature under a nitrogen ...

Claims

CLAIMS1. A compound according to Formula (I) or (Q) below, or a pharmaceutically acceptable salt thereof:wherein:Ring A is phenyl or 5- or 6-membered heteroaryl; wherein Ring A is optionally substituted by one or more substituents RA, wherein each RAis independently selected from halo (e.g. Cl, F), cyano, (1-4C)alkyl, (1-4C)haloalkyl, (3-6C)cycloalkyl or ORA1, where RA1is selected from (1-4C)alkyl, (1-4C)haloalkyl, (3-6C)cycloalkyl;Y is absent or a group of the formula:Y1-Y2wherein:Y1is absent or [CRYaRYb]n, wherein n is an integer from 1 to 4, wherein each occurrence of RYaand RYbis independently selected from hydrogen or (1- 2C)alkyl;Y2is absent or selected from -O-, -S-, -SO-, -SO2-, -C(O)-, -0(0)0-, -00(0)-, -N(RY1)-, -N(RY1)-C(O)-, -N(RY1)-C(O)O- or -C(O)-N(RY1)-, wherein RY1is selected from hydrogen or (1 -2C)alkyl;Z is selected from (1 -4C)alkyl, (3-12C)cycloalkyl, 4 to 12 membered heterocyclyl (including monocyclic, spirocyclic, fused and bridged heterocycles), phenyl, naphthyl or 5 to 10 membered heteroaryl, wherein any of which may be optionally substituted by one or more substituents selected from hydroxy, halo, cyano, (1 -4C)alkyl or (1-4C)alkoxy, wherein the (1 -4C)alkyl or (1-4C)alkoxy are optionally further substituted by one or more substituents selected from halo, hydroxy or cyano;Ring B is a 5- or 6-membered heteroaryl or 5- or 6-membered heterocyclyl; wherein 5- or 6-membered heteroaryl is optionally substituted with one or more substituents RB, and 5- or 6-membered heterocyclyl is optionally substituted with oxo or one or more substituents RBwherein each RBis independently selected from halo, cyano, hydroxy, (1 -4C)alkyl, (1- 4C)alkoxy, (3-8C)cycloalkyl, wherein any (1 -4C)alkyl, (1-4C)alkoxy, or (3-8C)cycloalkyl may be optionally further substituted by one or more substituents selected from hydroxy, halo, (1- 4C)alkoxy, (1-4C)haloalkoxy, cyano, NRB1RB2, NRB1C(O)RB2or C(O)NRB1RB2, wherein RB1and RB2are independently selected from hydrogen or (1 -4C)alkyl;W is absent or is methylene optionally substituted by hydroxy;Ring C is selected from phenyl, naphthyl, 5 to 10-membered heteroaryl, (3- 10C)cycloalkyl or 4 to 10-membered heterocyclyl; wherein Ring C is optionally substituted by one or more substituents independently selected from halo, cyano, oxo, (1-6C)alkyl, (1-4C)haloalkyl, halo, cyano, (3-8C)cycloalkyl, 3 to 8 membered heterocyclyl, or ORc1, wherein RC1is selected from hydrogen, (1 -4C)alkyl, (3-8C)cycloalkyl, 3 to 8 membered heterocyclyl, phenyl, 5 or 6 membered heteroaryl, wherein any (1 -6C)alkyl, (3-8C)cycloalkyl, 3 to 8 membered heterocyclyl, phenyl or 5 or 6 membered heteroaryl in a substituent group on Ring C, including those in a group RC1, are optionally further substituted with one or more substituents selected from halo, cyano, oxo, hydroxy (1-4C)alkyl, (1-4C)haloalkyl, (1-4C)alkoxy or (1-4C)haloalkoxy;X is a group of the formula:X1 - X2 - X3 wherein:Xi is absent or selected from -C(O)-, -C(O)-N(Rx1)-, -N(Rx2)-C(O)-N(Rx1)- or -N(Rx2)- C(O)-, wherein Rx1and R’'2are each independently selected from hydrogen or (1 -3C)alkyl;X2 is absent or is -[CR^R^Jq, wherein Rx1and R’'2are each independently selected from hydrogen or (1 -2C)alkyl, and q is an integer selected from 1 or 2;X3 is selected from (1 -4C)alkyl, (3-10C)cycloalkyl or 4 to 12-membered heterocyclyl; andX3 is optionally substituted by one or more substitutents independently selected from halo, (1-2C)alkyl, (1-2C)alkoxy, (1-2C)haloalkyl or (1-2C)haloalkoxy.

2. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ring A phenyl or 5- or 6-membered heteroaryl; wherein Ring A is optionally substituted by one or more substituents RA, wherein each RAis independently selected from halo (e.g. Cl, F), cyano, (1-2C)alkyl, (1-2C)haloalkyl, (3-6C)cycloalkyl or ORA1, where RA1is selected from hydrogen, (1 -2C)alkyl, (1-2C)haloalkyl or (3-6C)cycloalkyl.

3. A compound according to claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein each RAis independently selected from chloro, fluoro, cyano, methyl, fluoromethyl (e.g. CF3), methoxy or fluoromethoxy (e.g. OCF3); optionally wherein RAis selected from chloro, fluoro, methyl, fluoromethyl (e.g. CHF2 CF3) or methoxy; further optionally wherein RA is chloro.

4. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein Ring A has a formula selected from:wherein:Ai , A2, A3, A4 and As form a 5-membered heteroaryl ring, which is optionally substituted by 1 or 2 independently selected RAgroups; andAe, A7, As, Ag, A10 and An form a phenyl ring or a 6-membered heteroaryl ring (e.g. pyridyl or pyrimidyl), which is optionally substituted by 1 , 2 or 3 independently selected RAgroups; and each RAis independently as defined in any one of the preceding claims; optionally wherein:A1 , A2, A3, A4 and As form a thiazole, imidazole, pyraxole or oxazole ring, any of which may be optionally substituted by 1 or 2 independently selected RAgroups;As, A7, As, Ag, A10 and An form a phenyl ring, pyridyl ring or pyrimidyl ring; any of which may be optionally substituted by 1 , 2 or 3 independently selected RAgroups; andeach RAis independently as defined in any one of the preceding claims.

5. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein Ring A has a formula selected from:wherein:Qi is selected from CH or N;n is an integer selected from 0, 1 , 2 or 3X2 is selected from CH or N; m is an integer selected from 0, 1 or 2;X3 is selected from CH or N;X4 is selected from CH or N;X5 is selected from CH or N; p is an integer selected from 0, 1 or 2; wherein at least one of X3, X4 and X5 is not CH; and any available carbon atom, including those in Qi , X2, X3, X4 and X5, may be optionally substituted by a group RA; wherein each RAis independently as defined in any one of the preceding claims; optionally wherein Ring A has a formula selected from:wherein:X2 is selected from CH or N;X3 is selected from CH or N;X4 is selected from CH or N; wherein at least one of X3 and X4 is not CH; andRA2, RAS, RA4 and RAS are each independently selected from hydrogen or a group RAas defined in any one of the preceding claims.

6. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein Ring A has a formula selected from:wherein RA2, RAS, RA4 and RAS are each independently selected from hydrogen or a group RAas defined in any one of the preceding claims; optionally wherein RA2, RAS, RA4 and RAS are independently selected from hydrogen, halo or methyl; further optionally wherein Ring A has a formula selected from:wherein:RA2 is selected from hydrogen or a group RAas defined in any one or the preceding claims, preferably RA2 is selected from hydrogen or chloro.

7. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein Ring B is a 5-membered heteroaryl or 5- or 6-membered heterocyclyl; wherein Ring B is optionally substituted with oxo or one or more substituents RB, wherein each RBis independently selected from halo, cyano, hydroxy, (1-2C)alkyl, (1- 2C)alkoxy, (3-8C)cycloalkyl, wherein any (1 -2C)alkyl or (3-8C)cycloalkyl may be optionallyfurther substituted by one or more substituents selected from hydroxy, halo, (1-2C)alkoxy, (1-2C)haloalkoxy, cyano, NRB1RB2, NRB1C(O)RB2or C(O)NRB1RB2, wherein RB1and RB2are independently selected from hydrogen or (1 -2C)alkyl; optionally wherein Ring B is a 5-membered heteroaryl or 5- or 6-membered heterocyclyl; wherein Ring B is optionally substituted with oxo or one or more substituents RB, wherein each RBis independently selected from halo, cyano, hydroxy, methoxy or (1- 2C)alkyl, wherein the (1 -2C)alkyl may be optionally further substituted by one or more substituents selected from hydroxy, halo, (1-2C)alkoxy, (1-2C)haloalkoxy, cyano, NH2 or C(O)NH2or NHC(O)H; further optionally wherein Ring B is a 5-membered heteroaryl, 5-membered heterocyclyl or pyridonyl; wherein Ring B is optionally substituted with one or more substituents RB, wherein each RBis independently selected from halo, cyano, hydroxy or (1- 3C)alkyl,and wherein (1 -3C)alkyl is optionally substituted by hydroxy; further optionally wherein Ring B is a 5-membered heteroaryl comprising from 1-3 nitrogen atoms, a 5-membered heterocyclyl comprising from 1-2 nitrogen atoms, thiophene or pyridonyl; wherein Ring B is optionally substituted with one or more substituents RB, wherein each RBis independently selected from halo, cyano, hydroxy, methoxy or (1- 3C)alkyl, wherein (1-3C)alkyl is optionally substituted by hydroxy.

8. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein Ring B has a formula selected from:wherein any of the above rings may be optionally substituted on an available carbon atom by a substituent RB, wherein each RBis independently as defined in any one of the preceding claims; andRC2is selected from hydrogen or (1 -3C)alkyl, wherein (1-3C)alkyl is optionally substituted by hydroxy;optionally wherein Ring B has a formula selected from:wherein any of the above rings may be optionally substituted on an available carbon atom by a substituent RB, wherein each RBis as defined anywhere herein; and RC2is selected from hydrogen or (1 -3C)alkyl, wherein (1-3C)alkyl is optionally substituted by hydroxy9. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein Ring B has a formula selected from:wherein the above rings may be optionally substituted on an available carbon atom by a substituent RB, wherein each RBis independently selected from (1 -2C)alkyl; and RC2is (1 -2C)alkyl, wherein (1-2C)alkyl is optionally substituted by hydroxy.

10. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein Ring C is selected from phenyl, naphthyl, 5 to 10-membered heteroaryl, (3-10C)cycloalkyl or 3 to 10-membered heterocyclyl; wherein Ring C is optionally substituted by one or more substituents independently selected from halo, cyano, oxo, (1-4C)alkyl, (1-2C)haloalkyl, (1-2C)alkoxy, (1-2C)haloalkoxy, (3- 8C)cycloalkyl, 3 to 8 membered heterocyclyl, C(O)NRc1RC3or ORC1, wherein RC1is selected from hydrogen, (1 -2C)alkyl, (3-8C)cycloalkyl, 3 to 8 membered heterocyclyl, phenyl, 5- membered heteroaryl or 6-membered heteroaryl, and RC3is selected from hydrogen or (1- 2C)alkyl; wherein any alkyl, cycloalkyl, heterocyclyl, phenyl, or heteroaryl present in a substituent group on Ring C, including those in a group RC1, are optionally further substituted with one ormore substituents selected from halo, cyano, oxo, hydroxy, (1-2C)alkyl, (1-2C)haloalkyl, (1- 2C)alkoxy or (1-2C)haloalkoxy; optionally wherein Ring C is selected from 5- to 6-membered heteroaryl or 5 to 6-membered heterocyclyl; wherein Ring C is optionally substituted by one or more substituents independently selected from halo, cyano, oxo, (1-4C)alkyl, (1-2C)haloalkyl, (3-8C)cycloalkyl, 3 to 8 membered heterocyclyl, C(O)NRc1RC3or ORC1, wherein RC1is selected from hydrogen, (1-2C)alkyl, (3- 8C)cycloalkyl or 3 to 8 membered heterocyclyl, and RC3is selected from hydrogen or (1- 2C)alkyl; wherein any alkyl, cycloalkyl, heterocyclyl, phenyl, or heteroaryl present in a substituent group on Ring C, including those in a group RC1, are optionally further substituted with one or more substituents selected from halo, cyano, oxo, hydroxy, (1-2C)alkyl or (1-2C)haloalkyl. further optionally wherein Ring C is selected from a 5-membered heteroaryl, pyridyl or or pyrimdyl; wherein Ring C is optionally substituted by one or more substituents independently selected from halo, (1-4C)alkyl, 3 to 8 membered heterocyclyl, C(O)NRc1RC3or ORC1, wherein RC1is selected from hydrogen, (1 -2C)alkyl or 3 to 8 membered heterocyclyl, and RC3is selected from hydrogen or (1 -2C)alkyl; wherein any alkyl, cycloalkyl, heterocyclyl, phenyl, or heteroaryl present in a substituent group on Ring C, including those in a group RC1, are optionally further substituted with one or more substituents selected from halo, cyano, oxo, hydroxy or methyl.

11. A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein Ring C is selected from:wherein any of the above rings are optionally substituted on an available carbon atom by one or more substituents independently selected from halo, cyano, oxo, (1 -2C)alkyl, (1- 2C)haloalkyl, (3-8C)cycloalkyl, 3 to 8 membered heterocyclyl, C(O)NRC1RC3or ORC1, wherein RC1is selected from hydrogen, (1 -2C)alkyl, (3-8C)cycloalkyl or 3 to 8 membered heterocyclyl, and RC3is selected from hydrogen or (1 -2C)alkyl; wherein any alkyl, cycloalkyl, heterocyclyl, phenyl, or heteroaryl present in a substituent group on Ring C, including those in a group RC1, are optionally further substituted with one or more substituents selected from halo, cyano, oxo, hydroxy, (1- 2C)alkyl or (1-2C)haloalkyl;RN1is selected from hydrogen or (1 -4C)alkyl (e.g. methyl, ethyl or isopropyl);RN2is selected from hydrogen or (1-4C)alkyl (e.g. methyl, ethyl or isopropyl); RCNis selected from hydrogen or (1 -4C)alkyl; preferably RCNis methyl;optionally wherein Ring C is selected from:wherein any of the above rings are optionally substituted on an available carbon atom by one or more independently selected Ring C substituents as defined in any one of the preceding claims; and RCNis selected from hydrogen or (1 -2C)alkyl; preferably RCNis methyl further optionally wherein Ring C is selected from:wherein any of the above rings are optionally substituted on an available carbon atom by one or more independently selected Ring C substituents as defined in any one of the preceding claims; and RCNis selected from hydrogen or (1 -2C)alkyl ; preferably RCNis methyl.

12. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein Ring C is selected from:P388833WOoptionally wherein Ring C has a structure selected from:

13. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein:Y is absent or a group of the formula:Y1-Y2-Y3wherein:Y1is absent or [CRYaRYb]n, wherein n is an integer from 1 to 2, wherein each occurrence of RYaand RYbis independently selected from hydrogen or methyl; Y2is absent or selected from -O-, -C(O)-, -C(O)O-, -OC(O)- or -N(RY1)-, wherein RY1is selected from hydrogen or (1 -2C)alkyl;Y3is absent or [CRYaRYb]n, wherein n is an integer from 1 to 2, wherein each occurrence of RYaand RYbis independently selected from hydrogen or methyl; optionally wherein Y is absent or a group of the formula: Y1-Y2wherein:Y1is absent or [CRYaRYb]n, wherein n is an integer from 1 to 2, wherein each occurrence of RYaand RYbis independently selected from hydrogen or methyl; Y2is absent or selected from -O-, -C(O)-, -C(O)O-, -OC(O)- or -N(RY1)-, wherein RY1is selected from hydrogen or (1 -2C)alkyl; further optionally wherein Y is absent or a group of the formula: Y1-Y2wherein:Y1is absent, -CH2- or -CHMe-;Y2is absent or selected from -O- or -N(RY1)-, wherein RY1is selected from hydrogen or methyl; further optionally wherein Y is selected from -CH2-, -CHMe-, -O- or -N(RY1)-, wherein RY1is selected from hydrogen or methyl.

14. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein Z is selected from (1 -4C)alkyl , (3-8C)cycloalkyl, 4 to 8 membered heterocyclyl (including monocyclic, spirocyclic, fused and bridged heterocycles), phenyl or 5 or 6 membered heteroaryl, wherein any of which may be optionally substituted by one or more substituents selected from hydroxy, halo, cyano, (1 -2C)alkyl, (1-2C)alkoxy, wherein the (1 -2C)alkyl or (1-2C)alkoxy are optionally further substituted by one or more substituents selected from halo, hydroxy or cyano; optionally wherein Z is selected from (1-4C)alkyl, (3-8C)cycloalkyl, 4 to 8 membered heterocyclyl (including monocyclic, spirocyclic, fused and bridged heterocycles), phenyl or 5or 6 membered heteroaryl, wherein any of which may be optionally substituted by one or more substituents selected from hydroxy, halo, cyano, (1 -2C)alkyl, (1-2C)alkoxy, wherein the (1 -2C)alkyl or (1-2C)alkoxy are optionally further substituted by one or more substituents selected from halo, hydroxy or cyano; further optionally wherein Z is selected from (1 -4C)alkyl, (3-6C)cycloalkyl, 4 to 8 membered heterocyclyl (including monocyclic, spirocyclic, fused and bridged heterocycles) or 5-membered heteroaryl, wherein any of which may be optionally substituted by one or more substituents selected from hydroxy, halo, (1-2C)alkyl, (1-2C)alkoxy and NRZ2RZ3, wherein the (1 -2C)alkyl or (1-2C)alkoxy are optionally further substituted by one or more substituents selected from halo or hydroxy, and RZ2and RZ3are independently selected from hydrogen or (1 -2C)alkyl.

15. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein Z is selected from (1 -3C)alkyl, (4- 6C)cycloalkyl, 4 to 6 membered monocyclic heterocyclyl or 5-membered heteroaryl, wherein any of which may be optionally substituted by one or more substituents selected from hydroxy, fluoro, (1-2C)alkyl or NHRZ2, wherein the (1 -2C)alkyl may be optionally further substituted by one or more substituents selected from fluoro or hydroxy, and RZ2is selected from methyl or ethyl; optionally wherein Z is selected from (1 -2C)alkyl, (4-6C)cycloalkyl, 4 to 6 membered monocyclic heterocyclyl or 5-membered heteroaryl, wherein any of which may be optionally substituted by one or more substituents selected from hydroxy, fluoro or (1 -2C)alkyl, wherein the (1 -2C)alkyl may be optionally further substituted by one or more substituents selected from fluoro or hydroxy; further optionally wherein Z is a 4 to 6 membered monocyclic oxygen containing heterocyclyl, which may be optionally substituted by one or more substituents selected from hydroxy, fluoro or (1 -2C)alkyl, wherein the (1-2C)alkyl may be optionally further substituted by one or more substituents selected from fluoro or hydroxy16. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein Z is a group of the formula:wherein: z1 is an integer selected from 0, 1 or 2z2 is an integer selected from 1 or 2; z3 is an integer selected from 1, 2 or 3; each occurrence of Rziis independently selected from any of the Z group substituents as defined in any one of the preceding claims; optionally wherein: z1 is an integer selected from 0 or 1 ; z2 is an integer selected from 1 or 2; z3 is an integer selected from 1 or 2; each occurrence of Rzi, if present, is independently selected from hydrogen hydroxy, halo, cyano, methyl, methoxy, wherein the methyl or methoxy are optionally further substituted by one or more substituents selected from halo or hydroxy; further optionally wherein Z is a group of the formula:wherein: z1 is an integer selected from 0 or 1 ; each occurrence of Rzi, if present, is independently selected from hydrogen hydroxy, halo, cyano, methyl, methoxy, wherein the methyl or methoxy are optionally further substituted by one or more substituents selected from halo or hydroxy; further optionally wherein Z is selected from:

17. A compound according to any one of the preceding claims, wherein W is absent or is methylene substituted by hydroxy; optionally wherein W is absent.

18. A compound according to any one of the preceding claims, whereinX is a group of the formula:X1 - X2 - X3 wherein:Xi is absent or selected from -C(O)-, -C(O)-N(Rx1)-, -N(Rx2)-C(O)-N(Rx1)- or - N(Rx2)-C(O)-, wherein Rx1and R’'2are each independently selected from hydrogen or (1-3C)alkyl, ;X2 is absent or is -[CR^R^Jq, wherein Rx1and R’'2are independently selected from hydrogen or (1 -3C)alkyl, and q is an integer selected from 1 or 2;X3 is selected from (1-4C)alkyl, (3-10C)cycloalkyl or 4 to 12-membered heterocyclyl; andX3 is optionally substituted by one or more substituents independently selected from halo, hydroxy, NH2, (1-4C)alkyl, (1-4C)hydroxyalkyl, (1- 2C)alkoxy, (1-2C)haloalkyl or (1-2C)haloalkoxy; optionally wherein X is selected from:

19. A compound according to any one of the preceding claims, wherein the compound has a structural formula (Ila), (lib), (He), (III), (Illa), (IV), (IVa), (V), (VI), (VII), (VIII), (QI) or (QI II), shown below:P388833WOP388833WOP388833WOwherein Ring A, Ring B, Ring C, Qi, W, X, Y, Z, RA2, RB2, Z1 , Z2, Z3 and Rziare as defined in any one of the preceding claims.

20. A compound, or a pharmaceutically acceptable salt thereof, selected from any one of the following:4-(3-Methylpyridin-2-yl)-N-(4-((tetrahydrofuran-3-yl)-methyl)thiazol-2-yl)thiophene-2- carboxamide;4-(3-Methylpyridin-2-yl)-N-(4-(((3R)-tetrahydrofuran-3-yl)-methyl)thiazol-2-yl)thiophene-2- carboxamide;4-(3-Methylpyridin-2-yl)-N-(4-(((3S)-tetrahydrofuran-3-yl)-methyl)thiazol-2-yl)thiophene-2- carboxamide;5-(5-(3,3-Difluoroazetidin-1-yl)pyridin-2-yl)-1-methyl-N-(4-((tetrahydrofuran-3- yl)methyl)thiazol-2-yl)-1 H-pyrrole-3-carboxamide;5-(3,5-difluoropyridin-2-yl)-1-methyl-N-(4-((tetrahydrofuran-3-yl)methyl)thiazol-2-yl)-1H- pyrrole-3-carboxamide;5-Methyl-4-(5-((1-methylazetidin-3-yl)oxy)pyrimidin-2-yl)-N-(4-((tetrahydrofuran-3- yl)methyl)thiazol-2-yl)thiophene-2-carboxamide;1-Methyl-5-(pyrimidin-2-yl)-N-(4-((tetrahydrofuran-3-yl)methyl)thiazol-2-yl)-1 H-pyrrole-3- carboxamide;1-(Pyridin-2-yl)-N-(4-((tetrahydrofuran-3-yl)methyl)thiazol-2-yl)-1H-pyrazole-4-carboxamide;5-Methyl-1 -(pyrimidin-2-yl)-N-(4-((tetrahydrofuran-3-yl)methyl)thiazol-2-yl)-1 H-pyrrole-3- carboxamide;4-(4-methyl-3-oxopiperazin-1-yl)-N-(4-((tetrahydrofuran-3-yl)methyl)thiazol-2-yl)thiophene-2- carboxamide;5-(5-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyridin-2-yl)-1-methyl-N-(4-((tetrahydrofuran-3- yl)methyl)thiazol-2-yl)-1 H-pyrrole-3-carboxamide;5-(5-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyridin-2-yl)-1-methyl-N-(4-(((3R)-tetrahydrofuran-3- yl)methyl)thiazol-2-yl)-1 H-pyrrole-3-carboxamide;5-(5-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyridin-2-yl)-1-methyl-N-(4-(((3S)-tetrahydrofuran-3- yl)methyl)thiazol-2-yl)-1 H-pyrrole-3-carboxamide;5-(Hydroxymethyl)-4-(3-methylpyridin-2-yl)-N-(4-((tetrahydrofuran-3-yl)methyl)thiazol-2- yl)thiophene-2-carboxamide;4-(3-(Hydroxymethyl)pyridin-2-yl)-N-(4-((tetrahydrofuran-3-yl)methyl)thiazol-2-yl)thiophene-2- carboxamide;4-(3-(Hydroxymethyl)pyridin-2-yl)-N-(4-(((3R)-tetrahydrofuran-3-yl)methyl)thiazol-2- yl)thiophene-2-carboxamide;4-(3-(Hydroxymethyl)pyridin-2-yl)-N-(4-(((3S)-tetrahydrofuran-3-yl)methyl)thiazol-2- yl)thiophene-2-carboxamide;N-(5-Methyl-4-((tetrahydrofuran-3-yl)methyl)thiazol-2-yl)-4-(3-methylpyridin-2-yl)thiophene-2- carboxamide;4-(3-Methylpyridin-2-yl)-N-(4-(tetrahydrofuran-3-yl)thiazol-2-yl)thiophene-2-carboxamide;4-(3-Methylpyridin-2-yl)-N-(4-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl)thiophene-2- carboxamide;3-(5-Methyl-1 ,2,4-oxadiazol-3-yl)-N-(4-((tetrahydrofuran-3-yl)methyl)thiazol-2-yl)pyrrolidine- 1 -carboxamide;3-(5-methyl-1 ,2,4-oxadiazol-3-yl)-N-(5-methyl-4-((tetrahydrofuran-3-yl)methyl)thiazol-2- yl)pyrrolidine-1 -carboxamide;3-(3-methylpyridin-2-yl)-N-(4-((tetrahydrofuran-3-yl)methyl)thiazol-2-yl)pyrrolidine-1- carboxamide;3-(5-Methyl-1 ,2,4-oxadiazol-3-yl)-N-(3-((tetrahydrofuran-3-yl)methyl)phenyl)pyrrolidine-1- carboxamide;4-(3-Methylpyridin-2-yl)-N-(3-((tetrahydrofuran-3-yl)methyl)phenyl)thiophene-2-carboxamide;4-(3-Methylpyridin-2-yl)-N-(6-((tetrahydrofuran-3-yl)methyl)pyridin-2-yl)thiophene-2- carboxamide;4-(3-Methylpyridin-2-yl)-N-(3-((tetrahydrofuran-3-yl)amino)phenyl)thiophene-2-carboxamide;4-(3-Methylpyridin-2-yl)-N-(3-(((3R)-tetrahydrofuran-3-yl) amino) phenyl) thiophene-2- carboxamide;4-(3-Methylpyridin-2-yl)-N-(3-(((3S)-tetrahydrofuran-3-yl) amino) phenyl) thiophene-2- carboxamide;4-(3-Methylpyridin-2-yl)-N-(3-(oxetan-3-ylamino)phenyl)thiophene-2-carboxamide;4-(3-Methylpyridin-2-yl)-N-(6-((tetrahydrofuran-3-yl)amino)pyridin-2-yl)thiophene-2- carboxamide;4-(3-Methylpyridin-2-yl)-N-(3-((tetrahydrofuran-3-yl)oxy)phenyl)thiophene-2-carboxamide;N-(3-Chloro-5-((tetrahydrofuran-3-yl)amino)phenyl)-4-(3-methylpyridin-2-yl)thiophene-2- carboxamide;N-(3-Chloro-5-(((3R)-tetrahydrofuran-3-yl)amino)phenyl)-4-(3-methylpyridin-2-yl)thiophene-2- carboxamide;N-(3-Chloro-5-(((3S)-tetrahydrofuran-3-yl)amino)phenyl)-4-(3-methylpyridin-2-yl)thiophene-2- carboxamide;N-(3-Chloro-5-(oxazol-2-ylamino)phenyl)-4-(3-methylpyridin-2-yl)thiophene-2-carboxamide;N-(3-Chloro-5-((2-hydroxyethyl)amino)phenyl)-4-(3-methylpyridin-2-yl)thiophene-2- carboxamide;N-(3-Chloro-5-((3-methyltetrahydrofuran-3-yl)amino)phenyl)-4-(3-methylpyridin-2- yl)thiophene-2-carboxamide;N-(3-Chloro-5-((tetrahydrofuran-3-yl)amino)phenyl)-5-methyl-4-(pyrimidin-2-yl)thiophene-2- carboxamide;N-(3-Chloro-5-((tetrahydrofuran-3-yl)amino)phenyl)-5-methyl-4-(5-((1-methylazetidin-3- yl)oxy)pyrimidin-2-yl)thiophene-2-carboxamide;N-(3-Chloro-5-((tetrahydrofuran-3-yl)amino)phenyl)-5-(3,5-difluoropyridin-2-yl)-1-methyl-1 H- pyrrole- 3-carboxamide;N-(3-Chloro-5-((tetrahydrofuran-3-yl)amino)phenyl)-4-(3-(hydroxymethyl)pyridin-2- yl)thiophene-2-carboxamide;A / -(3-(lsoxazol-3-yl)phenyl)-4-(3-methylpyridin-2-yl)thiophene-2-carboxamide;4-(3-Methylpyridin-2-yl)-N-(3-(pyrrolidin-3-ylmethyl)phenyl)thiophene-2-carboxamide;4-(3-Methylpyridin-2-yl)-N-(1-((tetrahydrofuran-3-yl)methyl)-1H-pyrazol-4-yl)thiophene-2- carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-methyl-4-[5-(1-methylazetidin-3- yl)oxypyrimidin-2-yl]thiophene-2-carboxamide;N-[3-chloro-5-[[(3R)-tetrahydrofuran-3-yl]amino]phenyl]-5-methyl-4-[5-(1-methylazetidin-3- yl)oxypyrimidin-2-yl]thiophene-2-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-(3,5-difluoro-2-pyridyl)-1 -methylpyrrole- 3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-4-[3-(methoxymethyl)-2- pyridyl]thiophene-2-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-4-(3-methoxy-2-pyridyl)thiophene-2- carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-4-(3-cyano-2-pyridyl)thiophene-2- carboxamide;2-[5-[[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]carbamoyl]-3-thienyl]-N-methyl- pyridine- 3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-1-methyl-5-(1-methyltriazol-4- yl)pyrrole- 3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-1-methyl-5-[5-(1-methylazetidin-3- yl)oxypyrimidin-2-yl]pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-1-methyl-5-pyrimidin-2-yl-pyrrole-3- carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-[3-(hydroxymethyl)-2-pyridyl]-1- methyl-pyrrole- 3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-(3-cyano-5-fluoro-2-pyridyl)-1- methyl-pyrrole- 3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-(5-fluoro-3-methoxy-2-pyridyl)-1- methyl-pyrrole- 3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-(5-fluoropyrimidin-2-yl)-1 -methylpyrrole- 3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-(3-fluoro-5-methoxy-2-pyridyl)-1- methyl-pyrrole- 3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-1-methyl-5-(1-methyl-1,2,4-triazol-3- yl)pyrrole- 3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-1-methyl-5-(1-methylpyrazol-3- yl)pyrrole- 3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-1-methyl-5-(1-methylpyrazol-4- yl)pyrrole- 3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-1-methyl-5-(5-methyl-1,2,4- oxadiazol-3-yl)pyrrole- 3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-1-methyl-5-(1-methylimidazol-4- yl)pyrrole- 3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-[5-fluoro-3-(hydroxymethyl)-2- pyridyl]-1-methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-[3-(1-hydroxy-1-methyl-ethyl)-2- pyridyl]-1-methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-cyclopropyl-1-methyl-pyrrole-3- carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-5-methyl-4-pyrimidin-2-yl- thiophene-2-carboxamide;N-[4-chloro-6-[[(3R)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-5-methyl-4-pyrimidin-2-yl- thiophene-2-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-5-(3,5-difluoro-2-pyridyl)-1-methyl- pyrrole- 3-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-5-(5-fluoro-3-methoxy-2-pyridyl)-1- methyl-pyrrole- 3-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-5-(3-cyano-5-fluoro-2-pyridyl)-1- methyl-pyrrole- 3-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-5-(5-fluoropyrimidin-2-yl)-1- methyl-pyrrole- 3-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-5-(3-fluoro-5-methoxy-2-pyridyl)-1- methyl-pyrrole- 3-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-1-methyl-5-(1-methyltriazol-4- yl)pyrrole- 3-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-1-methyl-5-(1-methylpyrazol-3- yl)pyrrole-3-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-1-methyl-5-(1-methylpyrazol-4- yl)pyrrole-3-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-1-methyl-5-(1-methyl-1 ,2,4-triazol-3-yl)pyrrole-3-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-1-methyl-5-(1-methylimidazol-4- yl)pyrrole-3-carboxamide;5-[5-(azetidin-3-yloxy)-3-fluoro-2-pyridyl]-N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2- pyridyl]- 1-methyl-pyrrole-3-carboxamide;5-[5-(azetidin-3-yloxy)-3-fluoro-2-pyridyl]-N-[3-chloro-5-[[(3S)-tetrahydrofuran-3- yl]amino]phenyl]-1-methyl-pyrrole-3-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-5-[3-fluoro-5-(1-methylazetidin-3- yl)oxy-2-pyridyl]-1-methyl-pyrrole-3-carboxamide;5-[5-(azetidin-3-yloxy)pyrimidin-2-yl]-N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2- pyridyl]- 1-methyl-pyrrole-3-carboxamide;5-[5-(azetidin-3-yloxy)pyrimidin-2-yl]-N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-1-methyl-pyrrole-3-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-5-[5-fluoro-3-(hydroxymethyl)-2- pyridyl]- 1-methyl-pyrrole-3-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-1-methyl-5-[5-(1-methylazetidin-3- yl)oxypyrimidin-2-yl]pyrrole-3-carboxamide;N-[3-chloro-5-(oxetan-3-ylamino)phenyl]-4-(3-methyl-2-pyridyl)thiophene-2-carboxamide;N-[3-chloro-5-(oxetan-3-ylamino)phenyl]-5-(3,5-difluoro-2-pyridyl)-1-methyl-pyrrole-3- carboxamide;N-[3-chloro-5-(oxetan-3-ylamino)phenyl]-5-methyl-4-pyrimidin-2-yl-thiophene-2-carboxamide;N-[3-chloro-5-[methyl(tetrahydrofuran-3-yl)amino]phenyl]-4-(3-methyl-2-pyridyl)thiophene-2- carboxamide;N-(3-chloro-5-tetrahydrofuran-3-yloxy-phenyl)-4-(3-methyl-2-pyridyl)thiophene-2- carboxamide;N-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-5-(3,5-difluoro-2-pyridyl)-1-methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-5-(3,5-difluoro-2-pyridyl)-1-methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S,4R)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-5-(3,5-difluoro-2-pyridyl)-1-methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3R,4R)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-5-(3,5-difluoro-2-pyridyl)-1-methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S,4R)-4-hydroxytetrahydrofuran-3-yl]amino]phenyl]-5-(3,5-difluoro-2- pyridyl)-1-methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3R,4S)-4-hydroxytetrahydrofuran-3-yl]amino]phenyl]-5-(3,5-difluoro-2- pyridyl)-1-methyl-pyrrole-3-carboxamide;N-[4-chloro-6-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]-2-pyridyl]-1-methyl-5-(1- methyltriazol-4-yl) pyrrole-3-carboxam ide;N-[4-chloro-6-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]-2-pyridyl]-1-methyl-5-(1- methyltriazol-4-yl) pyrrole-3-carboxam ide;N-[4-chloro-6-[[(3S,4R)-4-fluorotetrahydrofuran-3-yl]amino]-2-pyridyl]-1-methyl-5-(1- methyltriazol-4-yl) pyrrole-3-carboxam ide;N-[3-chloro-5-[[(3S,4S)-4-methyltetrahydrofuran-3-yl]amino]phenyl]-5-(3,5-difluoro-2-pyridyl)-1-methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3R,4S)-4-methoxytetrahydrofuran-3-yl]amino]phenyl]-5-(3,5-difluoro-2- pyridyl)-1-methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S,4S)-4-hydroxytetrahydrofuran-3-yl]amino]phenyl]-4-(3-methyl-2- pyridyl)thiophene-2-carboxamide;N-[3-chloro-5-[[(3S,4R)-4-hydroxytetrahydrofuran-3-yl]amino]phenyl]-4-(3-methyl-2- pyridyl)thiophene-2-carboxamide;N-[3-chloro-5-(tetrahydrofu ran-3-ylamino)phenyl]-5-[3- fluoro- 5-(1-methylazetidin-3-yl)oxy-2- pyridyl]- 1-methyl-pyrrole-3-carboxamide;N-[3-chloro-5-(tetrahydrofuran-3-ylamino)phenyl]-1-methyl-5-[5-(1-methylazetidin-3-yl)oxy-2- pyridyl]pyrrole-3-carboxamide;4-[5-(azetidin-3-yloxy)pyrimidin-2-yl]-N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-methyl-thiophene-2-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-methyl-4-(1-methyltriazol-4- yl)thiophene-2-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-5-methyl-4-(1-methyltriazol-4- yl)thiophene-2-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-1-methyl-5-(1-methylimidazol-2- yl)pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-1-methyl-5-(1-methylimidazol-2- yl)pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-1-methyl-5-(2-methyltriazol-4- yl)pyrrole-3-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-1-methyl-5-(2-methyltriazol-4- yl)pyrrole- 3-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-1-methyl-5-(4-methyl-1 ,2,4-triazol-3-yl)pyrrole- 3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-1-methyl-5-(4-methyl-1,2,4-triazol-3- yl)pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-(2,5-dimethyltriazol-4-yl)-1-methyl- pyrrole- 3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-(1,5-dimethyltriazol-4-yl)-1-methyl- pyrrole- 3-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-5-(1 ,5-dimethyltriazol-4-yl)-1- methyl-pyrrole- 3-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-5-(2,5-dimethyltriazol-4-yl)-1- methyl-pyrrole- 3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-(3,5-difluoro-2-pyridyl)-1-(2- hydroxyethyl)pyrrole-3-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-5-(1-isopropyltriazol-4-yl)-1- methyl-pyrrole- 3-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-5-(2-isopropyltriazol-4-yl)-1- methyl-pyrrole- 3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-(1-isopropyltriazol-4-yl)-1-methyl- pyrrole- 3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-(2-isopropyltriazol-4-yl)-1-methyl- pyrrole- 3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-[5-(1-cyclopropylazetidin-3- yl)oxypyrimidin-2-yl]-1-methyl-pyrrole- 3-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-5-[5-(1-cyclopropylazetidin-3- yl)oxypyrimidin-2-yl]-1-methyl-pyrrole- 3-carboxamide;4-[5-(azetidin-3-yloxy)pyrimidin-2-yl]-N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2- pyridyl]-5-methyl-thiophene-2-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-5-cyclopropyl-1-methyl-pyrrole-3- carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-5-[3-(1-hydroxy-1-methyl-ethyl)-2- pyridyl]- 1-methyl-pyrrole-3-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-4-(5-isopropoxypyrimidin-2-yl)-5- methyl-thiophene-2-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-4-(5-isopropoxypyrimidin-2-yl)-5- methyl-thiophene-2-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-4-(4-methyl-3-oxo-piperazin-1- yl)thiophene-2-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-4-(4-methyl-2-oxo-piperazin-1- yl)thiophene-2-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-4-(4-methyl-3-oxo-piperazin-1- yl)thiophene-2-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-methyl-4-(3-methyl-2-oxo- imidazolidin-1-yl)thiophene-2-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-5-methyl-4-(3-methyl-2-oxo- imidazolidin-1-yl)thiophene-2-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-5-methyl-4-(2-oxopyrrolidin-1- yl)thiophene-2-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-methyl-4-(2-oxopyrrolidin-1- yl)thiophene-2-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-4-(4-methyl-2-oxo-piperazin-1- yl)thiophene-2-carboxamide;N-[3-cyano-5-(tetrahydrofuran-3-ylamino)phenyl]-4-(3-methyl-2-pyridyl)thiophene-2- carboxamide;4-(3-methyl-2-pyridyl)-N-[3-(tetrahydrofuran-3-ylamino)-5-(trifluoromethoxy)phenyl]thiophene-2-carboxamide4-(3-methyl-2-pyridyl)-N-[3-(tetrahydrofuran-3-ylamino)-5-(trifluoromethyl)phenyl]thiophene- 2-carboxamide;N-[3-fluoro-5-(tetrahydrofuran-3-ylamino)phenyl]-4-(3-methyl-2-pyridyl)thiophene-2- carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-1-methyl-5-(4-methyl-2-oxo- piperazin-1-yl)pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-1-methyl-5-(3-methyl-2-oxo- imidazolidin-1-yl)pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-(3,5-difluoro-2-pyridyl)-1-(2- methoxyethyl)pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-1-isopropyl-5-(1-methyltriazol-4- yl)pyrrole-3-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-1-isopropyl-5-(1-methyltriazol-4- yl)pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-(2-cyclopropyltriazol-4-yl)-1- methyl-pyrrole-3-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-5-(2-cyclopropyltriazol-4-yl)-1- methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-[1-[2-(dimethylamino)ethyl]pyrazol-4-yl]-1-methyl-pyrrole-3-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-5-[1-[2-(dimethylamino)ethyl]pyrazol-4-yl]-1-methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[(3-methyltetrahydrofuran-3-yl)amino]phenyl]-1-methyl-5-(1-methyltriazol-4- yl)pyrrole-3-carboxamide;N-[4-chloro-6-[(3-methyltetrahydrofuran-3-yl)amino]-2-pyridyl]-1-methyl-5-(1-methyltriazol-4- yl)pyrrole-3-carboxamide;N-[3-chloro-5-[(3-methyltetrahydrofuran-3-yl)amino]phenyl]-1-methyl-5-[5-(1-methylazetidin- 3-yl)oxypyrimidin-2-yl]pyrrole-3-carboxamide;N-[4-chloro-6-[(3-methyltetrahydrofuran-3-yl)amino]-2-pyridyl]-1-methyl-5-[5-(1- methylazetidin-3-yl)oxypyrimidin-2-yl]pyrrole-3-carboxamide;5-[5-(azetidin-3-yloxy)pyrimidin-2-yl]-N-[4-chloro-6-[(3-methyltetrahydrofuran-3-yl)amino]-2- pyridyl]- 1-methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-1-methyl-5-(1- methyltriazol-4-yl) pyrrole-3-carboxam ide;N-[3-chloro-5-[(4,4-difluorotetrahydrofuran-3-yl)amino]phenyl]-1-methyl-5-(1-methyltriazol-4- yl)pyrrole-3-carboxamide;N-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-1-methyl-5-(1- methylpyrazol-4-yl)pyrrole-3-carboxamide;N-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-1-methyl-5-(1- methylpyrazol-3-yl)pyrrole-3-carboxamide;N-[4-chloro-6-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]-2-pyridyl]-1-methyl-5-(1- methylpyrazol-4-yl)pyrrole-3-carboxamide;N-[4-chloro-6-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]-2-pyridyl]-1-methyl-5-[5-(1- methylazetidin-3-yl)oxypyrimidin-2-yl]pyrrole-3-carboxamide;N-[6-chloro-2-[[(3S)-tetrahydrofuran-3-yl]amino]pyrimidin-4-yl]-5-(3,5-difluoro-2-pyridyl)-1- methyl-pyrrole-3-carboxamide;N-[2-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]pyrimidin-4-yl]-5-(3,5-difluoro-2-pyridyl)-1- methyl-pyrrole-3-carboxamide;N-[4-chloro-3-fluoro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-5-(3,5-difluoro-2-pyridyl)-1-methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-methyl-1-(1-methyltriazol-4- yl)pyrrole-3-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-5-methyl-1-(1-methyltriazol-4- yl)pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-methyl-1-(1-methylpyrazol-3- yl)pyrrole-3-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-5-methyl-1-(1-methylpyrazol-3- yl)pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-[4-(difluoromethyl)-1-methyl- pyrazol-3-yl]-1-methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-(1-ethylpyrazol-3-yl)-1-methyl- pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-(1,3-dimethylpyrazol-4-yl)-1- methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-1-methyl-5-[1-(oxetan-3-yl)pyrazol-4- yl]pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-[1-(2-methoxyethyl)pyrazol-4-yl]-1- methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-(1-cyclopropylpyrazol-4-yl)-1- methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-(1,4-dimethylpyrazol-3-yl)-1- methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-1-methyl-5-(1,3,5-trimethylpyrazol-4- yl)pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-1-phenyl-imidazole-4-carboxamideN-[5-fluoro-4-(tetrahydrofuran-3-ylmethyl)thiazol-2-yl]-4-[3-(hydroxymethyl)-2- pyridyl]thiophene-2-carboxamide;N-[5-chloro-4-(tetrahydrofuran-3-ylmethyl)thiazol-2-yl]-5-methyl-4-[5-(1-methylazetidin-3- yl)oxypyrimidin-2-yl]thiophene-2-carboxamide;N2-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-N4,N4-dimethyl-thiophene-2,4- dicarboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-[hydroxy(3- pyridyl)methyl]thiophene-2-carboxamide;N-[3-chloro-5-(tetrahydropyran-4-ylamino)phenyl]-5-(3,5-difluoro-2-pyridyl)-1-methyl-pyrrole- 3-carboxamide;N-[3-chloro-5-(tetrahydropyran-3-ylamino)phenyl]-5-(3,5-difluoro-2-pyridyl)-1-methyl-pyrrole- 3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-3-(3-methyl-2-pyridyl)pyrrolidine-1- carboxamide;(3R)-N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-3-(3-methyl-2- pyridyl)pyrrolidine-1 -carboxamide;(3S)-N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-3-(3-methyl-2- pyridyl)pyrrolidine-1 -carboxamide;N2-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-N4,N4-dimethyl-thiophene-2,4- dicarboxamide;N2-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-N4,N4-dimethyl- thiophene-2,4-dicarboxamide ;N2-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-N4,N4,5-trimethyl-thiophene-2,4- dicarboxamide;N4-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-N2,N2,1-trimethyl-pyrrole-2,4- dicarboxamide;N4-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-N2,N2,1-trimethyl-pyrrole-2,4- dicarboxamide;N4-[3-chloro-5-[(4,4-difluorotetrahydrofuran-3-yl)amino]phenyl]-N2,N2,1-trimethyl-pyrrole-2,4-dicarboxamide;N4-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-N2,N2,1 -trimethyl- pyrrole-2,4-dicarboxamide;N4-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-N2,N2,1 -trimethyl- pyrrole-2,4-dicarboxamide;N4-[3-chloro-5-[[(3S,4R)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-N2,N2,1 -trimethyl- pyrrole-2,4-dicarboxamide;N4-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-N2,N2-dimethyl-1-(2,2,2- trifluoroethyl)pyrrole-2,4-dicarboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-5-(1-hydroxy-1-methyl-ethyl)-1- methyl-pyrrole- 3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-(1-hydroxy-1-methyl-ethyl)-1- methyl-pyrrole- 3-carboxamide;N-[4-chloro-6-[[(3S)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-5-[5-(3-hydroxy-1-methyl-azetidin-3-yl)pyrimidin-2-yl]-1-methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-[5-(3-hydroxy-1-methyl-azetidin-3- yl)pyrimidin-2-yl]-1-methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3R)-tetrahydrofuran-3-yl]amino]phenyl]-5-(3,5-difluoro-2-pyridyl)-1-methyl- pyrrole-3-carboxamide;N-[4-chloro-6-[[(3R)-tetrahydrofuran-3-yl]amino]-2-pyridyl]-1-methyl-5-(1-methyltriazol-4- yl)pyrrole-3-carboxamide;N-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-1-methyl-5-(1 ,3,5- trimethylpyrazol-4-yl)pyrrole-3-carboxamide;N-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-5-(1-isopropyltriazol-4-yl)-1-methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-1-methyl-5-(2- methyltriazol-4-yl) pyrrole-3-carboxam ide;N-[4-chloro-6-[(4,4-difluorotetrahydrofuran-3-yl)amino]-2-pyridyl]-1-methyl-5-(1-methyltriazol-4-yl)pyrrole- 3-carboxamide;N-[6-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]-2-pyridyl]-1-methyl-5-(1-methyltriazol-4- yl)pyrrole-3-carboxamide;5-(3,5-difluoro-2-pyridyl)-N-[6-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]-2-pyridyl]-1- methyl-pyrrole-3-carboxamide;5-(3,5-difluoro-2-pyridyl)-N-[3-[[(3S,4R)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-1 -methylpyrrole- 3-carboxamide;N-[3-chloro-4- fluoro- 5-[[(3S)-tetrahydrofuran-3-yl]amino]phenyl]-5-(3,5-difluoro-2-pyridyl)-1- methyl-pyrrole- 3-carboxamide;N4-[4-chloro-6-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]-2-pyridyl]-N2,N2,1-trimethyl- pyrrole-2,4-dicarboxamide;N4-[4-chloro-6-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]-2-pyridyl]-N2,N2,1-trimethyl- pyrrole-2,4-dicarboxamide;N4-[4-chloro-6-[[(3S,4R)-4-fluorotetrahydrofuran-3-yl]amino]-2-pyridyl]-N2,N2,1-trimethyl- pyrrole-2,4-dicarboxamide;5-(3-azabicyclo[3.1.0]hexane-3-carbonyl)-N-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3- yl]amino]phenyl]-1-methyl-pyrrole- 3-carboxamide;N-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-5-(3,3-dimethylazetidine- 1 -carbonyl)- 1-methyl-pyrrole- 3-carboxamide;N-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-1-methyl-5-(3- methylazetidine-1-carbonyl)pyrrole-3-carboxamide;N-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-5-(3-methoxypiperidine-1- carbonyl)-1-methyl-pyrrole-3-carboxamide;N4-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-N2,1-dimethyl-N2- tetrahydropyran-4-yl-pyrrole-2,4-dicarboxamide;N4-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-N2-(1-cyclopropylethyl)-1-methyl-pyrrole-2,4-dicarboxamide;N-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-5-[4-(2- hydroxyethyl)piperidine-1-carbonyl]-1-methyl-pyrrole-3-carboxamide;N4-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-N2-(3,3- difluorocyclobutyl)-1-methyl-pyrrole-2,4-dicarboxamide;N4-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-1-methyl-N2-(3-methyl-1-bicyclo[1.1.1]pentanyl)pyrrole-2,4-dicarboxamide;N-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-1-methyl-5-(3, 3,4,4- tetrafluoropyrrolidine-1-carbonyl)pyrrole-3-carboxamide;N4-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-N2-[(1- fluorocyclopropyl)methyl]-1-methyl-pyrrole-2,4-dicarboxamideN4-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-1-methyl-N2-[(1S)-2,2,2- trifluoro-1-methyl-ethyl]pyrrole-2,4-dicarboxamide;N-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-1-methyl-5-[(2R)-2-(trifluoromethyl)pyrrolidine-1-carbonyl]pyrrole-3-carboxamide;N-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-5-[(3R)-3-fluoro-3-methyl- pyrrolidine-1-carbonyl]-1-methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-1-methyl-5-[(2S)-2-(trifluoromethyl)pyrrolidine-1-carbonyl]pyrrole-3-carboxamide;N4-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-N2,1-dimethyl-N2-(2,2,2- trifluoroethyl)pyrrole-2,4-dicarboxamide;N-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-5-(2,2- dimethylpyrrolidine-1-carbonyl)-1-methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-1-methyl-5-(morpholine-4- carbonyl)pyrrole-3-carboxamide;N-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-5-(3,3-difluoroazetidine-1- carbonyl)-1-methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-1-methyl-5-(8-oxa-3- azabicyclo[3.2.1 ]octane-3-carbonyl)pyrrole-3-carboxamide;N-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-5-[(2R,6S)-2,6- dimethylmorpholine-4-carbonyl]-1-methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-1-methyl-5-(2- methylmorpholine-4-carbonyl)pyrrole-3-carboxamide;5-(4-azaspiro[2.4]heptane-4-carbonyl)-N-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3- yl]amino]phenyl]-1-methyl-pyrrole-3-carboxamide;N-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-5-(4,4-difluoropiperidine- 1-carbonyl)-1-methyl-pyrrole-3-carboxamide;N4-[3-chloro-5-[[(3R,4S)-4-fluorotetrahydrofuran-3-yl]amino]phenyl]-N2,N2-diethyl-1-methyl- pyrrole-2,4-dicarboxamide; or (S)-N-(3-Chloro-5-((tetrahydrofuran-3-yl)amino)phenyl)-5-(1-(difluoromethyl)-1 H-pyrazol-4- yl)- 1 -methyl- 1H-pyrrole-3-carboxamide.

21. A pharmaceutical composition comprising a compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

22. A compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 21, for use in therapy.

23. A compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 21, for use in the treatment of a proliferative condition, viral infection or autoimmune disease.

24. A compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 21, for use in the treatment of cancer; optionally wherein the cancer selected is from colorectal cancer, endometrial cancer, ovarian cancer, gastric cancer, hematopoietic cancer, breast cancer, brain cancer, skin cancer, lung cancer, prostate cancer, head and neck cancer, pancreatic cancer, bladder cancer, bone cancer, soft-tissue cancer, kidney cancer, lymphoma, non-Hodgkin's lymphomas, myeloma, osteosarcoma, Wilms' tumour, cervical cancer, prostate cancer, glioma, hepatocellular carcinoma and liver cancer; optionally wherein the cancer is selected from colorectal, endometrial, ovarian, hematopoietic, bone and gastric cancer; further optionally wherein the cancer is selected from colorectal cancer or bone cancer, such as Ewing's Sarcoma.

25. A compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 21, for use in the treatment of:i) a MSI high cancer, e.g. a Lynch Syndrome cancer; ii) a MSI low cancer; iii) a cancer which has mutations or defects in DNA mis-match repair (MMR); iv) a DNA damage response / repair (DDR) deficient cancer; v) a replication stress high cancer; and vi) a cancer with an alternate mechanism of telomere maintenance; vii) a cancer which comprises mutations or defects in RNA splicing and the kinetochore complex; and / or viii) a cold tumor.

26. A compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 21, for use in: decreasing the expression or activity of DHX9; affect the properties and / or behavior of DHX9.

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