1,5-naphtyridine and quinoline based inhibitors of ALK5

Abstract

The present invention relates to compounds of formula (I) which are inhibitors of activin receptor-like kinase 5 (ALK5) and related uses.

Description

[0001] AGO-P3616PCT Application as filed

[0002] NOVEL COMPOUNDS

[0003] Field of the Invention

[0004] This invention relates to novel compounds, pharmaceutical compositions containing them and their use as medicaments, in particular in the prevention or treatment of diseases or disorders ameliorated by inhibition of activin receptor-like kinase 5 (ALK5).

[0005] Background of the Invention

[0006] Transforming growth factor-p (TGF-P) belongs to the TGF-p superfamily, which comprises TGF- i , TGF- 2, and TGF- 3, among other proteins. TGF-p is involved in many cellular processes, including cell proliferation, cell migration, invasion, epithelial-mesenchymal transition, extracellular matrix production and immune suppression. TGF-p and its receptors are often chronically overexpressed in various human diseases, including cancer, inflammation, tissue fibrosis and autoimmunity. Therefore, blockade of TGF-p signalling pathway is considered an attractive target for drug development. (Heldin C. H. et al, 2016).

[0007] TGF-p signals via two related transmembrane type I and type II serine / threonine kinase receptors. Following TGF-p binding to the constitutively active type II receptor, the type I receptor (TGFPR1 , also called activin receptor-like kinase 5 (ALK5), which term is used hereafter) is phosphorylated and creates a binding site for Smad2 and Smad3 proteins, which are further phosphorylated. Phosphorylated Smad2 / Smad3 proteins form a heteromeric complex with Smad4, which translocate into the nucleus, assembles with specific DNA-binding cofactors and co-modulators, and binds to the promoters of TGF-p target genes involved in cell differentiation, proliferation, apoptosis, migration, and extracellular matrix production. (Akhurst R. J. et al, 2012).

[0008] In most cell types, activin receptor-like kinase 5 (ALK5) is the predominant TGF-p receptor I that is activated by TGF-p through TGF-p receptor II. This interaction requires both extracellular and intracellular domains for signal transduction. ALK5 and TGF-p receptor II proteins can also form active heterooligomeric complexes in the absence of ligand. These complexes are able to transduce basal signals when both receptors are co-expressed because of their intrinsic affinity for interaction. (Bierie B. et al, 2006).

[0009] The functional TGFpRII-TGFpRI (ALK5) heteromeric signalling complex is commonly associated with human cancer, and it regulates the activation of downstream Smad-dependent AGO-P3616PCT Application as filed and Smad-independent pathways. In fact, many studies have identified mutations in components that are associated with the TGF-p pathway, and which correlate with cancer occurrence and prognosis in many human tissues. The over expression of TGF-pi has been associated with breast, colon, oesophageal, gastric, hepatocellular, lung and pancreatic cancer inter alia. Importantly, the overexpression of TGF-p in human cancer correlates with tumour progression, metastasis, angiogenesis and poor prognostic outcome. Furthermore, TGF-p inhibits alveolar epithelial cell growth and repair, so it is a key player in fibrotic processes, acting on both fibroblasts and alveolar epithelial cells (Saito A. et al, 2018). Extensive evidence suggests that the canonical ALK5 / Smad3 pathway is critically involved in the pathogenesis of fibrosis in many tissues. Oral administration of a small molecular weight selective inhibitor of the kinase activity of ALK5 inhibited fibrogenesis in a rat model of progressive TGF-pi -induced pulmonary fibrosis. Furthermore, Smad3 null mice exhibit attenuated fibrosis in a wide range of experimental models and are resistant to bleomycin- induced pulmonary fibrosis. (Biernacka, A et al, 2011). Similar to the role of TGF-p in pulmonary fibrosis, in COPD patients TGF-p promotes fibrotic airway remodelling, which can further contribute to diminished lung function. Some of the increases in TGF-pi in the airway epithelium of COPD patients may be a direct response to cigarette smoke, the most significant risk factor for development of this disease state (Aschner, Y. et al, 2016). The transforming growth factor (TGF-P) cytokines play a central role in development and progression of chronic respiratory diseases. TGF-p overexpression in chronic inflammation, remodelling, fibrotic process, and susceptibility to viral infection is established in the most prevalent chronic respiratory diseases including pulmonary fibrosis, asthma, COPD and lung cancer.

[0010] Compounds which have utility as potent inhibitors of ALK5 are described in W02021 / 105317 and W02022 / 069509 (both Origo Biopharma S.L.).

[0011] A number of activin receptor-like kinase 5 (ALK5) inhibitors are disclosed in WO2021 / 102468, WO2021 / 102468 and WO2020 / 123453 (all Theravance Biopharma R&D IP LLC).

[0012] There remains a need to provide further compounds having potent ALK5 inhibitory activity, particularly compounds with low plasma stability and which have favourable properties for use as a pharmaceutical, especially when delivered by administration to the lung. AGO-P3616PCT Application as filed

[0013] Summary of the Invention

[0014] The present invention provides a compound of formula (I): wherein:

[0015] Ri is independently selected from the group consisting of halo, Ci-4alkyl optionally substituted by hydroxy, Ci-4haloalkyl and Ci-4alkoxy; n is 1 , 2 or 3; represents the point of connection to the remainder of the compound;

[0016] R2 is independently selected from the group consisting of Ci-4alkyl optionally substituted by hydroxy, Ci-4haloalkyl and halo; p is 0, 1 or 2;

[0017] Z is CH or N; wherein:

[0018] A) when Z is N, R3 is H and R4 is -C(=O)O-Rs, or

[0019] B) when Z is CH, R3 is H and R4 is -C(=O)O-Rs or

[0020] C) when Z is CH, R4 is H and R3 is -C(=O)O-Rs; and in each of A), B) and C) above: Rs is selected from the group consisting of Ci-4alkyl, Co-salkylene-Cs-ecycloalkyl, C2- salkylene-NRsARsB, Co-3alkylene-C-linked 4-8 membered nitrogen containing heterocyclyl, and Ci-3alkylene-N-linked 4-8 membered nitrogen containing heterocyclyl, wherein the 4-8 membered nitrogen containing heterocyclyl is optionally substituted by one RSD, one, two or three RSE, and an oxo group; RSA is selected from the group consisting of H, Ci-4alkyl and C-linked 4-8 membered nitrogen containing heterocyclyl wherein the C-linked 4-8 membered nitrogen AGO-P3616PCT Application as filed containing heterocyclyl is optionally substituted by one or two Rsc, one RSF, and an oxo group;

[0021] RSB is H or Ci-4alkyl;

[0022] Rsc is selected from the group consisting of Ci-4alkyl optionally substituted by hydroxy or methoxy, Ci-4alkoxy, Ci-4haloalkyl, halo and -NRSARSB;

[0023] RSD is selected from the group consisting of 4-6 membered nitrogen containing heterocyclyl and Cs-scycloalkyl each of which being optionally substituted by one or two methyl groups and wherein the heterocyclyl is optionally substituted by an oxo group;

[0024] RSE is selected from the group consisting of Ci-4alkyl optionally substituted by hydroxy or methoxy, Ci-4alkoxy, Ci-4haloalkyl, halo and -NRSARSB;

[0025] RSF is Cs-scycloalkyl optionally substituted by one or two methyl groups; and RSA and RSB are independently selected from H and methyl; or a pharmaceutically acceptable salt and / or solvate thereof. The compounds of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof are herein referred to as “a compound of the invention”.

[0026] Detailed Description of the Invention Compounds of formulae (I), (IA), (IA), (IA”), (IB), (IB’), (IB”), (IC), (IC’), (IC”), (ID), (IE), (IF), (XVII), (XX), (XXX) and (XXXI) are herein all referred to as “compounds of the invention”. Compounds of formulae (IA), (IA), (IA”), (IB), (IB’), (IB”), (IC), (IC’), (IC”), (ID), (IE), (IF), (XVII), (XX), (XXX) and (XXXI) are sub-formulae of compounds of formula (I). Embodiments and preferences set out herein below apply equally to the compounds of formulae (I), (IA), (IA), (IA’), (IB), (IB’), (IB”), (IC), (IC’), (IC”), (ID), (IE), (IF), (XVII), (XX), (XXX) and (XXXI) except where the context indicates otherwise.

[0027] In one embodiment, the compound of the invention is provided in the form of a compound of formula (I). In one embodiment, the compound of the invention is provided in the form of a pharmaceutically acceptable salt and / or solvate. In one embodiment, the compound of the invention is provided in the form of a pharmaceutically acceptable salt and solvate (i.e. a pharmaceutically acceptable solvate of a pharmaceutically acceptable salt). In one embodiment, the compound of the invention is provided in the form of a pharmaceutically acceptable salt. In one embodiment, the compound of the invention is provided in the form of a pharmaceutically acceptable solvate. In one embodiment, the compound of the invention is provided in the form of a compound which is not a salt. In one embodiment, the compound of the invention is provided in the form of a compound which is not a solvate. In one embodiment, AGO-P3616PCT Application as filed the compound of the invention is provided in the form of a compound which is not a salt or a solvate.

[0028] Embodiments set out below relating to relative stereochemistry and the nature of groups, are envisaged as being independently, fully combinable with one another where appropriate to the circumstances (i.e. where chemically sensible) to form further embodiments of the invention.

[0029] Such embodiments apply equally to intermediates which may be of use in the synthesis of compounds of formulae (I), (IA), (IA), (IA”), (IB), (IB’), (IB”), (IC), (IC’), (IC”), (ID), (IE), (IF), (XVII), (XX), (XXX) and (XXXI) e.g. compounds of formulae (II) and (III). Embodiments and preferences set out herein with respect to the compounds of formulae (I), (IA), (IA), (IA”), (IB), (IB’), (IB”), (IC), (IC’), (IC”), (ID), (IE), (IF), (XVII), (XX), (XXX) and (XXXI) apply equally to the pharmaceutical composition, compound or pharmaceutically acceptable salt and / or solvate thereof for use, pharmaceutical composition for use, use and method aspects of the invention.

[0030] The term “alkyl”, such as “Ci-4alkyl” refers to a straight or branched fully saturated hydrocarbon group having the specified number of carbon atoms. The term encompasses methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. The term “alkyl” also encompasses “alkylene”, such as “Co-3alkylene” which is a bifunctional straight or branched fully saturated hydrocarbon group having a specified number of carbon atoms. “Coalkylene” means there is no alkylene group present; for example when Rs is Coalkylene-Cs-scycloalkyl, it means Rs is Cs-scycloalkyl. Example “alkylene” groups include methylene, ethylene, n-propylene and n- butylene. A Ci-4alkyl group may (where so indicated) be optionally substituted by hydroxy, examples include -CH2OH and -CH2CH2OH.

[0031] The term “alkoxy” refers to an alkyl group, such as “Ci-4alkyl” as defined above, singularly bonded via an oxygen atom. Examples of alkoxy groups include methoxy.

[0032] The term “halo” refers to fluoro, chloro, bromo or iodo. Particular examples of halo are fluoro and chloro, especially fluoro.

[0033] The term “hydroxy” refers to an -OH group.

[0034] The term “haloalkyl”, such as “Ci-4haloalkyl” as used herein refers to a straight or a branched fully saturated hydrocarbon chain containing the specified number of carbon atoms and at least one halogen atom, such as fluoro or chloro, especially fluoro. An example of haloalkyl is CF3. Further examples of haloalkyl are -CHF2 and -CH2CF3. AGO-P3616PCT Application as filed

[0035] The term “Cs-ecycloalkyl” (such as C3-4cycloalkyl, Cs-scycloalkyl, C^scycloalkyl, C4-6cycloalkyl and Cs-ecycloalkyl) refers to a fully saturated cyclic hydrocarbon group having from 3 to 6 carbon atoms. The term encompasses cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0036] The term “4-8 membered nitrogen containing heterocyclyl” refers to a non-aromatic monocyclic group having 4 to 8 ring atoms, at least one of which is a nitrogen atom and may include other heteroatoms selected from N, O or S. The term “heterocyclic ring” is interchangeable with “heterocyclyl”. The term encompasses pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl.

[0037] Other heterocyclyl groups, for example 5-6 membered heterocyclyl, 4 membered heterocyclyl,

[0038] 5 membered heterocyclyl, 6 membered heterocyclyl, 7 membered heterocyclyl and 8 membered heterocyclyl are as defined above but contain different numbers of ring atoms. Of particular interest are 4-8 membered nitrogen containing heterocyclyl groups, such as 4-6 membered nitrogen containing heterocyclyl groups. In some cases they may contain only N heteroatoms, suitably one or two N heteroatoms, such as azetidine, pyrrolidine, piperazine and piperidine. The 4-8 membered heterocyclyl may (where so indicated) be optionally substituted by an oxo group, which substitution will be on a carbon atom. Examples include 6 membered nitrogen-containing heterocycles selected from , AGO-P3616PCT Application as filed o represents the point of connection to the remainder of the compound.

[0039] The term “C-linked” refers to a substituent bonded to the rest of the compound through an available carbon atom via carbon-carbon single bond.

[0040] The term “N-linked” refers to a substituent bonded to the rest of the compound through an available nitrogen atom via a nitrogen-carbon single bond.

[0041] Where substituents are indicated as being optionally substituted in formula (I) in the embodiments and preferences set out below, the optional substituent may be attached to an available carbon atom, which means a carbon atom which is attached to at least one hydrogen atom i.e. a C-H group or a CH2 group, or the optional substituent may be attached to an available nitrogen atom, which means a nitrogen atom which is attached to a hydrogen atom i.e. a N-H group (save that oxo substituents are substituents on an available carbon atom). The optional substituent replaces the hydrogen atom attached to the carbon atom or the hydrogen atom attached to the nitrogen atom. Furthermore, the skilled person will appreciate that optional substitution only occurs on an available carbon atom or nitrogen atom in a manner that follows reasonable chemical rationale e.g. when Rs is 4-8 membered nitrogen containing heterocyclyl and RSE is -N RSARSB, the -N RSARSB group would not be attached to an available nitrogen atom such that formation of a nitrogen-nitrogen single bond would be avoided.

[0042] Where substituents are indicated as being independently selected from a list of possible substituents in formula (I) in the embodiments and preferences set out below (e.g. R1), this means that if more than one of the substituents is present (e.g. n is 2) then each substituent may be the same or different.

[0043] In any of the following formulae (such as (IA), (IA), (IA”), (IB), (IB’), (IB”), (IC), (IC’), (IC”), (ID), (IE), and (IF)), all variables (such as R1, R2, Rs, n and p) are as defined herein.

[0044] In one embodiment, Z is N. In another embodiment, Z is CH. AGO-P3616PCT Application as filed

[0045] In an embodiment, a compound of formula (I) is provided which is a compound of formula (IA):

[0046] In an embodiment, a compound of formula (I) is provided which is a compound of formula (IA): or a pharmaceutically acceptable salt and / or solvate thereof.

[0047] In an embodiment, a compound of formula (I) is provided which is a compound of formula (IA”): or a pharmaceutically acceptable salt and / or solvate thereof. AGO-P3616PCT Application as filed

[0048] In an embodiment, a compound of formula (I) is provided which is a compound of formula (IB):

[0049] In an embodiment, a compound of formula (I) is provided which is a compound of formula (IB’): or a pharmaceutically acceptable salt and / or solvate thereof.

[0050] In an embodiment, a compound of formula (I) is provided which is a compound of formula (IB”): or a pharmaceutically acceptable salt and / or solvate thereof.

[0051] In an embodiment, a compound of formula (I) is provided which is a compound of formula (IC): AGO-P3616PCT Application as filed or a pharmaceutically acceptable salt and / or solvate thereof.

[0052] In an embodiment, a compound of formula (I) is provided which is a compound of formula (IC’): or a pharmaceutically acceptable salt and / or solvate thereof.

[0053] In an embodiment, a compound of formula (I) is provided which is a compound of formula (IC”): or a pharmaceutically acceptable salt and / or solvate thereof. AGO-P3616PCT Application as filed

[0054] In one embodiment, a compound of formula (I) is provided which is a compound of formula (ID): or a pharmaceutically acceptable salt and / or solvate thereof.

[0055] In one embodiment, a compound of formula (I) is provided which is a compound of formula (IE): wherein R3 is H and R4 is -C(=O)-O-Rs; or a pharmaceutically acceptable salt and / or solvate thereof.

[0056] In one embodiment, a compound of formula (I) is provided which is a compound of formula wherein R3 is -C(=O)-O-Rs and R4 is H; or a pharmaceutically acceptable salt and / or solvate thereof. AGO-P3616PCT Application as filed

[0057] In one embodiment, Ri is independently halo. In another embodiment, Ri is independently fluoro or chloro. In one embodiment, Ri is independently Ci-4alkyl optionally substituted by hydroxy. In another embodiment, Ri is independently unsubstituted Ci-4alkyl. In another embodiment, Ri is independently Ci-4alkyl substituted by hydroxy. In another embodiment, Ri is methyl. In one embodiment, Ri is independently Ci-4haloalkyl. In another embodiment, Ri is CF3. In one embodiment, Ri is independently Ci-4alkoxy. In another embodiment, Ri is methoxy. Suitably, Ri is halo.

[0058] In one embodiment, n is 1. In another embodiment, n is 2. In another embodiment, n is 3. In another embodiment, n is 1 or 2. Suitably, n is 2.

[0059] In one embodiment, Ri is independently halo and n is 2. In another embodiment, Ri is independently fluoro or chloro and n is 2.

[0060] In one embodiment, Ri is independently fluoro or chloro and n is 2, such that the following moieties form: of connection to the remainder of the compound.

[0061] Suitably, Ri is independently fluoro or chloro and n is 2, such that the following moiety forms: represents the point of connection to the remainder of the compound. . , AGO-P3616PCT Application as filed represents the point of connection to the remainder of the represents the point of connection to the remainder of the compound.

[0062] In one embodiment, R2 is independently Ci-4alkyl. In another embodiment, R2 is independently Ci-4alkyl substituted by hydroxy. In another embodiment, R2 is independently methyl or ethyl. In one embodiment, R2 is independently Ci-4haloalkyl. In another embodiment, R2 is CF3. In one embodiment, R2 is independently halo. In another embodiment, R2 is independently fluoro or chloro. Suitably, R2 is methyl.

[0063] The R2 group may be bonded to either an available N or C atom on the group.

[0064] In one embodiment, p is 0 i.e. R2 is absent. In another embodiment, p is 1. In another embodiment, p is 2. Suitably p is 0 or 1.

[0065] Therefore in one embodiment, p is 0 i.e. R2 is absent, so that the following moiety is formed: represents the point of connection to the remainder of the compound.

[0066] In another embodiment, p is 0 i.e. R2 is absent, so that the following moiety is formed: represents the point of connection to the remainder of the compound. AGO-P3616PCT Application as filed

[0067] In another embodiment, the R2 group (as defined above for compounds of formula (I)) and a pyrazolyl core form the following moiety: represents the point of connection to the remainder of the compound. Suitably, R2 is methyl.

[0068] In another embodiment, the R2 group (as defined above for compounds of formula (I)) and a pyrazolyl core form the following moiety: represents the point of connection to the remainder of the compound. Suitably, R2 is methyl.

[0069] In another embodiment, the two R2 groups (as defined above for compounds of formula (I)) and a pyrazolyl core form the following moiety: represents the point of connection to the remainder of the compound. AGO-P3616PCT Application as filed

[0070] In another embodiment, the R2 group (as defined above for compounds of formula (I)) and an imidazolyl core form the following moiety: represents the point of connection to the remainder of the compound.

[0071] In another embodiment, the R2 group (as defined above for compounds of formula (I)) and an imidazolyl core form the following moiety: wherein represents the point of connection to the remainder of the compound.

[0072] In another embodiment, the two R2 groups (as defined above for compounds of formula (I)) and an imidazolyl core form the following moiety: represents the point of connection to the remainder of the compound.

[0073] In one embodiment, R2 is Ci-4alkyl and p is 1. In another embodiment, R2 is methyl, and p is

[0074] 1. In another embodiment, R2 is ethyl and p is 1. In one embodiment, R2 is Ci-4alkyl substituted AGO-P3616PCT Application as filed by hydroxy and p is 1. In one embodiment, R2 is ethyl substituted by hydroxy and p is 1. In one embodiment, R2 is Ci-4haloalkyl and p is 1. In one embodiment, R2 is methyl and p is 1.

[0075] In one embodiment, R5 is Ci-4alkyl. In another embodiment, R5 is methyl. In another embodiment, Rs is ethyl. In another embodiment, R5 is propyl. In another embodiment, R5 is butyl. Suitably, R5 is methyl or ethyl.

[0076] In one embodiment, Rsis Co-salkylene-Cs-scycloalkyl. In another embodiment, R5 is Coalkylene- Cs-ecycloalkyl. In another embodiment, Rs is Cialkylene-Cs-scycloalkyl. In another embodiment, Rs is C2alkylene-C3-6cycloalkyl. In another embodiment, Rs is Csalkylene-Cs- scycloalkyl. In another embodiment, Rs is Cialkylene-Cscycloalkyl. In another embodiment, Rs is C2alkylene-C3cycloalkyl. In another embodiment, Rs is Csalkylene-Cscycloalkyl. In another embodiment, Rs is Cialkylene-C4cycloalkyl. In another embodiment, Rs is C2alkylene- C4cycloalkyl. In another embodiment, Rs is C3alkylene-C4cycloalkyl. In another embodiment, Rs is Cialkylene-Cscycloalkyl. In another embodiment, Rs is C2alkylene-Cscycloalkyl. In another embodiment, Rs is Csalkylene-Cscycloalkyl. In another embodiment, Rs is Cialkylene- Cscycloalkyl. In another embodiment, Rs is C2alkylene-C6cycloalkyl. In another embodiment, Rs is Csalkylene-Cscycloalkyl. In one embodiment, Rs is C2-3alkylene-NRsARsB. In another embodiment, Rs is C2alkylene- NRSARSB. In another embodiment, Rs is Csalkylene-NRsARsB. In another embodiment, Rs is C2alkylene-NH2. In another embodiment, Rs is C2alkylene-N(CH3)2. In another embodiment, Rs is C2alkylene-N(C2Hs)2. In one embodiment, Rs is Co-3alkylene-C-linked 4-8 membered nitrogen containing heterocyclyl. In another embodiment, Rs is Coalkylene-C-linked 4-8 membered nitrogen containing heterocyclyl. In another embodiment, Rs is Cialkylene-C-linked 4-8 membered nitrogen containing heterocyclyl. In another embodiment, Rs is C2alkylene-C-linked 4-8 membered nitrogen containing heterocyclyl. In another embodiment, Rs is Csalkylene-C-linked 4-8 membered nitrogen containing heterocyclyl.

[0077] In another embodiment, the C-linked 4-8 membered nitrogen containing heterocyclyl is a 4 membered nitrogen containing heterocyclyl. In another embodiment, the C-linked 4-8 membered nitrogen containing heterocyclyl is a 5 membered nitrogen containing heterocyclyl. In another embodiment, the C-linked 4-8 membered nitrogen containing heterocyclyl is a 6 membered nitrogen containing heterocyclyl. In another embodiment, the C-linked 4-8 membered nitrogen containing heterocyclyl is a 7 membered nitrogen containing heterocyclyl. AGO-P3616PCT Application as filed

[0078] In another embodiment, the C-linked 4-8 membered nitrogen containing heterocyclyl is an 8 membered nitrogen containing heterocyclyl. In another embodiment, the C-linked 4-8 membered nitrogen containing heterocyclyl is a 4-6 membered nitrogen containing heterocyclyl. Suitably, the C-linked 4-8 membered nitrogen containing heterocyclyl is a 6 membered nitrogen containing heterocyclyl.

[0079] In another embodiment, Rs is Ci-salkylene-N-linked 4-8 membered nitrogen containing heterocyclyl. In another embodiment, Rs is Cialkylene-N-linked 4-8 membered nitrogen containing heterocyclyl. In another embodiment, Rs is C2alkylene-N-linked 4-8 membered nitrogen containing heterocyclyl. In another embodiment, Rs is Csalkylene-N-linked 4-8 membered nitrogen containing heterocyclyl. In another embodiment, Rs is Cialkylene-N-linked 4-6 membered nitrogen containing heterocyclyl. In another embodiment, Rs is C2alkylene-N- linked 4-6 membered nitrogen containing heterocyclyl. In another embodiment, Rs is Csalkylene-N-linked 4-6 membered nitrogen containing heterocyclyl. Suitably, Rs is C2alkylene-N-linked 4-6 (e.g. 6) membered nitrogen containing heterocyclyl.

[0080] In any one of the above embodiments, the 4-8 membered nitrogen containing heterocyclyl is optionally substituted by one RSD, by one, two or three RSE, and by an oxo group. In another embodiment, the 4-8 membered nitrogen containing heterocyclyl is not substituted.

[0081] In another embodiment, Rs is substituted by one RSD. In another embodiment, Rs is substituted by one RSE. In another embodiment, Rs is substituted by two RSE. In another embodiment, Rs is substituted by three RSE. In another embodiment, Rs is substituted by an oxo group. In another embodiment, Rs is substituted by one RSD and one RSE. In another embodiment, Rs is substituted by one RSD and two RSE. In another embodiment, Rs is substituted by one RSD and three RSE. In another embodiment, Rs is substituted by one RSD and an oxo group. In another embodiment, Rs is substituted by one RSE and an oxo group. In another embodiment, Rs is substituted by two RSE and an oxo group. In another embodiment, Rs is substituted by three RSE and an oxo group. In another embodiment, Rs is substituted by one RSD, one RSE and an oxo group. In another embodiment, Rs is substituted by one RSD, two RSE and an oxo group. In another embodiment, Rs is substituted by one RSD, three RSE and an oxo group. Suitably, Rs is substituted by one or two RSE groups. When Rs is substituted by two or three RSE groups, each RSE group may be the same or different. In one embodiment, RsAis H. In another embodiment, RsAis Ci-4alkyl. In another embodiment, RsA is methyl. In another embodiment, RsA is ethyl. In another embodiment, RsA is propyl. In another embodiment, RsA is butyl. Suitably, Rs is methyl or ethyl. AGO-P3616PCT Application as filed

[0082] In another embodiment, RSA is C-linked 4-8 membered nitrogen containing heterocyclyl which is optionally substituted by one or two Rsc, one RSF, and an oxo group. In one embodiment, the C-linked 4-8 membered nitrogen containing heterocyclyl is not substituted.

[0083] In one embodiment, RSA is substituted by one Rsc. In another embodiment, RSA is substituted by two Rsc. In another embodiment, RSA is substituted by one RSF. In another embodiment, RSA is substituted by an oxo group. In another embodiment, RSA is substituted by one RSF and one Rsc. In another embodiment, RSA is substituted by one RSF and two Rsc. In another embodiment, RSA is substituted by one RSF and an oxo group. In another embodiment, RSA is substituted by one Rsc and an oxo group. In another embodiment, RSA is substituted by two Rsc and an oxo group. In another embodiment, RSA is substituted by one RSF, one Rsc and an oxo group. In another embodiment, RSA is substituted by one RSF, two Rsc and an oxo group. When RSA is substituted by two Rsc groups, each Rsc group may be the same or different.

[0084] In one embodiment, RSB is H. In another embodiment, RSB is Ci-4alkyl. In another embodiment, R5B is Ci-2alkyl. In another embodiment, RSB is methyl.

[0085] In one embodiment, RSA and RSB are both H. In another embodiment, RSA and RSB are both methyl. In another embodiment, RSA and RSB are both ethyl. In another embodiment, RSA is C- linked 4-8 membered nitrogen containing heterocyclyl and RSB is H. In another embodiment, RSA is C-linked 4-8 membered nitrogen containing heterocyclyl and RSB is methyl. Suitably, RSA and RSB are both methyl or ethyl. In one embodiment, Rsc is Ci-4alkyl. In another embodiment, Rsc is Ci-4alkyl substituted by hydroxy. In another embodiment, Rsc is Ci-4alkyl substituted by methoxy. In one embodiment, Rsc is Ci-4alkoxy. In one embodiment, Rsc is Ci-4haloalkyl. In one embodiment, Rsc is halo. In one embodiment, Rsc is -N RSARSB. In one embodiment, RSD is 4-6 membered nitrogen containing heterocyclyl. In another embodiment, RSD is Cs-scycloalkyl. In one embodiment, RSD is unsubstituted. In another embodiment, RSD is substituted by one or two methyl groups. In another embodiment, RSD is substituted by an oxo group. In another embodiment, RSD is substituted by one or two methyl groups and an oxo group.

[0086] In one embodiment, RSE is Ci-4alkyl. In another embodiment, RSE is methyl. In another embodiment, RSE is Ci-4alkyl substituted by hydroxy. In another embodiment, RSE is Ci-4alkyl AGO-P3616PCT Application as filed substituted by methoxy. In one embodiment, RSE is Ci-4alkoxy. In one embodiment, RSE is Ci- 4haloalkyl. In one embodiment, RSE is halo. In another embodiment, RSE is fluoro. In one embodiment, RSE is -NRsAReB. Suitably, RSE is methyl.

[0087] In one embodiment, RSE is Cs-scycloalkyl. In another embodiment, RSF is Cs-scycloalkyl substituted by one methyl group. In another embodiment, RSF is Cs-scycloalkyl substituted by two methyl groups.

[0088] In one embodiment, RSA is H. In another embodiment, RSA is methyl. In one embodiment, RSB is H. In another embodiment, RSB is methyl. In one embodiment, RSA and RSB are both H. In another embodiment, RSA and RSB are both methyl. In another embodiment, one of RSA and RSB is H and the other is methyl.

[0089] In one embodiment, Rs is -Co-3alkylene-C-linked 4-8 membered nitrogen containing heterocyclyl, wherein the C-linked 4-8 membered nitrogen containing heterocyclyl is selected from the group consisting of: wherein * represents the connection of the C-linked 4-8 membered nitrogen containing heterocyclyl to the Co-3alkylene group and wherein RSD and RSE are as defined elsewhere herein. AGO-P3616PCT Application as filed

[0090] In one embodiment, Rs is -Co-3alkylene-C-linked 4-8 membered nitrogen containing heterocyclyl, wherein the C-linked 4-8 membered nitrogen containing heterocyclyl is selected from the group consisting of: wherein * represents the connection of the C-linked 4-8 membered nitrogen containing heterocyclyl to the Co-3alkylene group. Suitably, RSE is selected from the group consisting of H, halo and Ci-4alkyl.

[0091] In one embodiment, Rs is -Ci-salkylene-N-linked 4-8 membered nitrogen containing heterocyclyl, wherein the N-linked 4-8 membered nitrogen containing heterocyclyl is: wherein * represents the connection of the N-linked 4-8 membered nitrogen containing heterocyclyl to the Ci-3alkylene group and wherein RSE is as defined elsewhere herein. Suitably, RSE is selected from the group consisting of H and Ci-4alkyl.

[0092] In one embodiment, there is provided a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof, which is selected from the list consisting of: Methyl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)-1 ,5-naphthyridine-3-carboxylate; Piperidin-4-ylmethyl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)-1,5-naphthyridine-3- carboxylate;

[0093] 2-(Dimethylamino)ethyl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)-1,5-naphthyridine-3- carboxylate;

[0094] 1 - M ethy I py rro I id i n-3-y I 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)-1,5-naphthyridine-3- carboxylate;

[0095] 2-(Diethylamino)ethyl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)-1,5-naphthyridine-3- carboxylate; AGO-P3616PCT Application as filed

[0096] 2-(Piperidin-4-ylamino)ethyl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)-1 ,5- naphthyridine-3-carboxylate;

[0097] (4-Amino-1-methylpiperidin-4-yl)methyl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)-1 ,5- naphthyridine-3-carboxylate;

[0098] 1 - ( P i perid i n-4-y l)azeti d i n-3-y I 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)-1 ,5- naphthyridine-3-carboxylate;

[0099] 2-(4-Aminopiperidin-4-yl)ethyl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)-1 ,5- naphthyridine-3-carboxylate;

[0100] 2-(4-Aminopiperidin-1-yl)ethyl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)-1 ,5- naphthyridine-3-carboxylate;

[0101] 3-(4-Aminopiperidin-1-yl)propyl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)-1 ,5- naphthyridine-3-carboxylate;

[0102] 2-(Methyl(piperidin-4-yl)amino)ethyl 6-(3-(5-chloro-2-fluorophenyl)-1 / 7-pyrazol-4-yl)-1 ,5- naphthyridine-3-carboxylate; 2-(((2S,6R)-2,6-Dimethylpiperidin-4-yl)amino)ethyl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-

[0103] 4-yl)-1 ,5-naphthyridine-3-carboxylate;

[0104] 2-(((2R,6R)-2,6-Dimethylpiperidin-4-yl)amino)ethyl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol- 4-yl)-1 ,5-naphthyridine-3-carboxylate;

[0105] 2-(2S,6R)-2,6-Diethylpiperidin-4-yl)amino)ethyl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4- yl)-1 ,5-naphthyridine-3-carboxylate;

[0106] 2-(Piperidin-4-ylamino)ethyl 6-(3-(5-chloro-2-fluorophenyl)-5-methyl-1 H-pyrazol-4-yl)-1 ,5- naphthyridine-3-carboxylate;

[0107] 1 -Methylpiperidin-4-yl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)-1 ,5-naphthyridine-3- carboxylate; Piperidin-4-yl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)-1 ,5-naphthyridine-3- carboxylate; Azetidin-3-yl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)-1 ,5-naphthyridine-3-carboxylate;

[0108] 1-Methylazetidin-3-yl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)-1 ,5-naphthyridine-3- carboxylate; 2-((3S,5R)-3,5-Dimethylpiperazin-1-yl)ethyl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)- 1 ,5-naphthyridine-3-carboxylate;

[0109] 2-(3S,5R)-3,5-Dimethylpiperazin-1-yl)ethyl 6-(3-(5-chloro-2-fluorophenyl)-5-methyl-1 H- pyrazol-4-yl)-1 ,5-naphthyridine-3-carboxylate;

[0110] 2-(Piperazin-1-yl)ethyl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)-1 ,5-naphthyridine-3- carboxylate;

[0111] 2-(Dimethylamino)ethyl 6-(3-(5-chloro-2-fluorophenyl)-5-methyl-1 H-pyrazol-4-yl)-1 ,5- naphthyridine-3-carboxylate; AGO-P3616PCT Application as filed

[0112] 1 -Methylpyrrolidin-3-yl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)quinoline-4- carboxylate; Azetidin-3-yl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)quinoline-4-carboxylate; (R)-Pyrrolidin-3-yl 6-(3-(5-chloro-2-fluorophenyl)-1H-pyrazol-4-yl)quinoline-4-carboxylate;

[0113] 2.2-Dimethylazetidin-3-yl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)quinoline-4- carboxylate;

[0114] (2S,4R,6R)-2,6-Dimethylpiperidin-4-yl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4- yl)quinoline-4-carboxylate;

[0115] 3.3-Dimethylpiperidin-4-yl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)quinoline-4- carboxylate;

[0116] 3-Methylazetidin-3-yl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)quinoline-4-carboxylate;

[0117] 3-Azabicyclo[3.1 ,0]hexan-6-yl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)quinoline-4- carboxylate;

[0118] 3,3-Difluoro-1-methylpiperidin-4-yl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)quinoline-4- carboxylate;

[0119] (2R,3S)-2-Methylazetidin-3-yl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)quinoline-4- carboxylate;

[0120] (2S,3S)-2-Methylazetidin-3-yl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)quinoline-4- carboxylate; 2-(Piperidin-4-ylamino)ethyl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)quinoline-4- carboxylate;

[0121] 2-((3S,5R)-3,5-Dimethylpiperazin-1-yl)ethyl 6-(3-(5-chloro-2-fluorophenyl)-5-methyl-1 H- pyrazol-4-yl)quinoline-4-carboxylate;

[0122] 1-Methylazetidin-3-yl 6-(3-(5-chloro-2-fluorophenyl)-5-methyl-1 H-pyrazol-4-yl)quinoline-4- carboxylate;

[0123] 1 -Methylpiperidin-4-yl 6-(3-(5-chloro-2-fluorophenyl)-5-methyl-1 H-pyrazol-4-yl)quinoline-4- carboxylate;

[0124] 1 -lsopropylpiperidin-4-yl 6-(3-(5-chloro-2-fluorophenyl)-5-methyl-1 H-pyrazol-4-yl)quinoline-4- carboxylate; Piperidin-4-ylmethyl 6-(3-(5-chloro-2-fluorophenyl)-1-methyl-1 H-pyrazol-4-yl)quinoline-3- carboxylate;

[0125] 2-((3S,5R)-3,5-Dimethylpiperazin-1-yl)ethyl 6-(3-(5-chloro-2-fluorophenyl)-1-methyl-1 H- pyrazol-4-yl)quinoline-3-carboxylate; 2-((3S,5R)-3,5-Dimethylpiperazin-1-yl)ethyl 6-(3-(5-chloro-2-fluorophenyl)-5-methyl-1 H- pyrazol-4-yl)quinoline-3-carboxylate; Azetidin-3-yl 6-(3-(5-chloro-2-fluorophenyl)-5-methyl-1 H-pyrazol-4-yl) quinoline-3- carboxylate; AGO-P3616PCT Application as filed

[0126] Piperidin-4-yl 6-(3-(5-chloro-2-fluorophenyl)-5-methyl-1 H-pyrazol-4-yl)quinoline-3- carboxylate; (Piperidin-4-yl)aminoethyl 6-(3-(5-Chloro-2-fluorophenyl)-5-methyl-1 H-pyrazol-4-yl)quinoline-

[0127] 3-carboxylate;

[0128] 2-Aminoethyl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)quinoline-4-carboxylate;

[0129] Piperidin-4-ylmethyl 6-(3-(5-chloro-2-fluorophenyl)-5-methyl-1 H-pyrazol-4-yl)quinoline-4- carboxylate; 2-(Piperidin-4-ylamino)ethyl 6-(3-(5-chloro-2-fluorophenyl)-5-methyl-1 H-pyrazol-4- yl)quinoline-4-carboxylate; Methyl 6-(3-(5-Chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)quinoline-4-carboxylate;

[0130] Methyl 6-(3-(5-Chloro-2-fluorophenyl)-1-methyl-1 H-pyrazol-4-yl)quinoline-4-carboxylate;

[0131] Methyl 6-(3-(5-Chloro-2-fluorophenyl)-5-methyl-1 H-pyrazol-4-yl)quinoline-4-carboxylate;

[0132] Ethyl 6-(3-(5-Chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)quinoline-3-carboxylate; 2-dimethylaminoethyl 6-(3-(5-Chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)quinoline-4-carboxylate; 2-(4-methylpiperazin-1-yl)ethyl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)quinoline-4- carboxylate; 2-(4-Methylpiperazin-1 -y I) ethyl 6-(3-(5-chloro-2-fluorophenyl)-5-methyl-1 H-pyrazol-4- yl)quinoline-4-carboxylate;

[0133] 1 - M ethy I py rro I id i n-3-y I 6-(3-(5-chloro-2-fluorophenyl)-5-methyl-1 H-pyrazol-4-yl)quinoline-4- carboxylate;

[0134] 1 - M ethy I py rro I id i n-3-y I 6-(3-(5-chloro-2-fluorophenyl)-5-methyl-1 H-pyrazol-4-yl)quinoline-3- carboxylate;

[0135] 1 - M ethy I py rro I id i n-3-y I 6-(3-(5-chloro-2-fluorophenyl)-1-methyl-1 H-pyrazol-4-yl)quinoline-3- carboxylate;

[0136] 4-piperidinylmethyl 6-(3-(5-Chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)quinoline-4-carboxylate; 2-((3S,5R)-3,5-Dimethylpiperazin-1-yl)ethyl 6-(3-(5-Chloro-2-fluorophenyl)-1 H-pyrazol-4- yl)quinoline-4-carboxylate;

[0137] 2-(Piperazin-1-yl)ethyl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)quinoline-4- carboxylate; Piperidin-4-ylmethyl 6-(3-(5-chloro-2-fluorophenyl)-5-methyl-1 H-pyrazol-4-yl)quinoline-3- carboxylate;

[0138] 1 -Methylpiperidin-4-yl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)quinoline-4-carboxylate;

[0139] (R)-1 -Methylpyrrolidin-3-yl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)quinoline-4- carboxylate;

[0140] (S)-1 -Methylpyrrolidin-3-yl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)quinoline-4- carboxylate; AGO-P3616PCT Application as filed

[0141] 1-lsopropylazetidm-3-yl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)quinoline-4- carboxylate;

[0142] 1 -lsopropylpiperidin-4-yl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)quinoline-4- carboxylate;

[0143] 1 -Cyclopropylpiperidin-4-yl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)quinoline-4- carboxylate;

[0144] 2-(Diethylamino)ethyl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)quinoline-4-carboxylate; 1-Methylazetidin-3-yl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)quinoline-4-carboxylate;

[0145] 1 -Methylpiperidin-4-yl 6-(3-(5-chloro-2-fluorophenyl)-5-methyl-1 H-pyrazol-4-yl)quinoline-3- carboxylate;

[0146] 1-Methylazetidin-3-yl 6-(3-(5-chloro-2-fluorophenyl)-5-methyl-1 H-pyrazol-4-yl)quinoline-3- carboxylate;

[0147] Piperidin-4-yl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)quinoline-4-carboxylate;

[0148] 1 ,4-Diazepan-6-yl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)-1 ,5-naphthyridine-3- carboxylate;

[0149] Methyl 6-(4-(3-chloro-4-fluorophenyl)-1-(2-hydroxyethyl)-1 H-imidazol-5-yl)quinoline-4- carboxylate;

[0150] Ethyl 6-(4-(3-chloro-4-fluorophenyl)-1-(2-hydroxyethyl)-1 H-imidazol-5-yl)quinoline-3- carboxylate; 2-(Bis(methyl-d3)amino)ethyl-1 ,1 ,2,2-d4 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)-1 ,5- naphthyridine-3-carboxylate;

[0151] 2-(Bis(methyl-d3)amino)ethyl-1 ,1 ,2,2-d4 6-(3-(5-chloro-2-fluorophenyl)-5-methyl-1 H-pyrazol- 4-yl)quinoline-3-carboxylate; and

[0152] 2-((3F?,5F?)-3,5-Dimethylpiperazin-1-yl)ethyl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)- 1 ,5-naphthyridine-3-carboxylate; or a pharmaceutically acceptable salt and / or solvate thereof.

[0153] It will be appreciated that for use in medicine the salts of the compounds of the invention should be pharmaceutically acceptable. Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art. Pharmaceutically acceptable salts include those described by Berge, 1977. Such pharmaceutically acceptable salts include acid addition salts formed with inorganic acids e.g. hydrochloric, hydrobromic, sulphuric, nitric or phosphoric acid and organic acids e.g. succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid. Non-pharmaceutically acceptable salts may be used, for example, in the isolation of compounds of the invention and are included within the scope of this invention. For example, in one embodiment, there is provided a compound of the invention or salt thereof. AGO-P3616PCT Application as filed

[0154] Certain of the compounds of the invention may form acid addition salts with one or more equivalents of the acid. The present invention includes within its scope all possible stoichiometric and non-stoichiometric forms.

[0155] The compounds of the invention may be prepared in crystalline or non-crystalline form and, if crystalline, may optionally be solvated, e.g. as the hydrate. This invention includes within its scope stoichiometric solvates (e.g. hydrates) as well as compounds containing variable amounts of solvent (e.g. water). It will be appreciated that for use in medicine the solvates of the compounds of the invention should be pharmaceutically acceptable.

[0156] It is to be understood that the present invention encompasses all isomers of compounds of the invention and their pharmaceutically acceptable derivatives, including all geometric, tautomeric and optical forms, and mixtures thereof (e.g. racemic mixtures). Where additional chiral centres are present in the compounds of the invention, the present invention includes within its scope all possible diastereoisomers, including mixtures thereof. The different isomeric forms may be separated or resolved one from the other by conventional methods, or any given isomer may be obtained by conventional synthetic methods or by stereospecific or asymmetric syntheses.

[0157] The present disclosure includes all isotopic forms of the compounds of the invention provided herein, whether in a form (i) wherein all atoms of a given atomic number have a mass number (or mixture of mass numbers) which predominates in nature (referred to herein as the “natural isotopic form”) or (ii) wherein one or more atoms are replaced by atoms having the same atomic number, but a mass number different from the mass number of atoms which predominates in nature (referred to herein as an “unnatural variant isotopic form”). It is understood that an atom may naturally exist as a mixture of mass numbers. The term “unnatural variant isotopic form” also includes embodiments in which the proportion of an atom of given atomic number having a mass number found less commonly in nature (referred to herein as an “uncommon isotope”) has been increased relative to that which is naturally occurring e.g. to the level of >20%, >50%, >75%, >90%, >95% or >99% by number of the atoms of that atomic number (the latter embodiment referred to as an "isotopically enriched variant form"). The term “unnatural variant isotopic form” also includes embodiments in which the proportion of an uncommon isotope has been reduced relative to that which is naturally occurring. Isotopic forms may include radioactive forms (i.e. they incorporate radioisotopes) and non-radioactive forms. Radioactive forms will typically be isotopically enriched variant forms. AGO-P3616PCT Application as filed

[0158] An unnatural variant isotopic form of a compound may thus contain one or more artificial or uncommon isotopes such as deuterium (2H or D), carbon-11 (11 C), carbon-13 (13C), carbon- 14 (14C), nitrogen-13 (13N), nitrogen-15 (15N), oxygen-15 (150), (170), oxygen- 18 (180), phosphorus-32 (32P), sulphur-35 (35S), chlorine-36 (36CI), chlorine-37 (37CI), fluorine-18 (18F) iodine-123 (1231), iodine-125 (1251) in one or more atoms or may contain an increased proportion of said isotopes as compared with the proportion that predominates in nature in one or more atoms. Unnatural variant isotopic forms comprising radioisotopes may, for example, be used for drug and / or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. 3H, and carbon-14, i.e. 14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Unnatural variant isotopic forms which incorporate deuterium i.e. 2H or D may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. Further, unnatural variant isotopic forms may be prepared which incorporate positron emitting isotopes, such as 11 C, 18F, 150 and 13N, and would be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.

[0159] In one embodiment, the compounds of the invention are conveniently provided in a natural isotopic form.

[0160] In one embodiment, the compounds of the invention are provided in an unnatural variant isotopic form. In a specific embodiment, the unnatural variant isotopic form is a form in which deuterium (i.e. 2H or D) is incorporated where hydrogen is specified in the chemical structure in one or more atoms of a compound of the invention. In one embodiment, the atoms of the compounds of the invention are in an isotopic form which is not radioactive. In one embodiment, one or more atoms of the compounds of the invention are in an isotopic form which is radioactive. Suitably radioactive isotopes are stable isotopes. Suitably the unnatural variant isotopic form is a pharmaceutically acceptable form.

[0161] In one embodiment, a compound of the invention is provided whereby a single atom of the compound exists in an unnatural variant isotopic form. In another embodiment, a compound of the invention is provided whereby two or more atoms exist in an unnatural variant isotopic form. AGO-P3616PCT Application as filed

[0162] Unnatural isotopic variant forms can generally be prepared by conventional techniques known to those skilled in the art or by processes described herein e.g. processes analogous to those described in the accompanying Examples for preparing natural isotopic forms. Thus, unnatural isotopic variant forms could be prepared by using appropriate isotopically variant (or labelled) reagents in place of the normal reagents employed in the Examples.

[0163] Since the compounds of the invention are intended for use in pharmaceutical compositions it will readily be understood that they are each preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure and preferably at least 85%, especially at least 98% pure (% are on a weight for weight basis). Impure preparations of the compounds may be used for preparing the more pure forms used in the pharmaceutical compositions.

[0164] In general, the compounds of the invention may be made according to the organic synthesis techniques known to those skilled in this field, as well as by the representative methods set forth below, those in the Examples and modifications thereof. For each scheme, variables are as defined above unless otherwise stated.

[0165] Processes of the invention

[0166] According to further aspects of the present invention are provided processes for the preparation of compounds or a salt and / or solvate thereof e.g. a pharmaceutically acceptable salt and / or solvate thereof of the invention, as well as processes for preparing intermediates or salts thereof in the synthesis of compounds of the invention.

[0167] Thus, in one embodiment there is provided a process for preparing a compound of formula (I) or a salt and / or solvate thereof such as a pharmaceutically acceptable salt and / or solvate thereof, which comprises reacting: a compound of formula (II): AGO-P3616PCT Application as filed wherein are as defined above, or an activated derivative thereof or a salt and / or solvate thereof; or or a salt and / or solvate thereof; with a compound of formula (IV):

[0168] Rs-OH (IV) wherein R5 is as defined above, or an activated derivative thereof or a salt and / or solvate thereof.

[0169] Suitably, compounds of formula (II) or (III) or an activated derivative thereof or a salt and / or solvate thereof are converted to compounds of formula (I) or a salt and / or solvate thereof under basic conditions (such as DI PEA, DMAP or 2,6-lutidine) in a polar solvent (such as DCM).

[0170] The term activated derivative means that the reactivity of the carboxylic acid group is increased by being converted to a more reactive functional group, such as by formation of an acid halide (such as chloride) or anhydride. The carboxylic acid group can be activated in situ by the presence of an activator (such as HATLI, EDC or Muk).

[0171] All variables shown in the following schemes are as defined herein unless otherwise stated. AGO-P3616PCT Application as filed

[0172] Compounds of formula (II) wherein salt and / or solvate thereof e.g. a pharmaceutically acceptable salt and / or solvate thereof may be prepared by the synthetic route outlined in Scheme 1 below. wherein PG1= carboxylic acid protecting group (such as methyl).

[0173] Step 1 : Compound of formula (V), 3-amino-5-bromopyridine (CAS: 13535-01-8), is reacted with the compound of formula (VI), crotonaldehyde, in a non-polar solvent (such as toluene) in the presence of an acid (such as 6M aqueous HCI) to give the compound of formula (VII), 7-bromo-2-methyl-1 ,5-naphthyridine.

[0174] Step 2: Compounds of formula (VII) are reacted with a halogenated benzoate ester (i.e. compounds of formula (VIII)) in a polar solvent (such as THF) in the presence of a base (such as KHMDS) to give compounds of formula (IX).

[0175] Step 3: Compounds of formula (IX) are heated in DMF.DMA followed by reaction with hydrazine in a polar solvent (such as MeCN) in the presence of an organic acid (such as AcOH) to give compounds of formula (X). AGO-P3616PCT Application as filed

[0176] Step 4: Compounds of formula (X) are reacted with Zn(CN)2 in a polar solvent (such as DMF) in the presence of Pd catalyst (such as Pd(PPh3)4) to give compounds of formula (XI).

[0177] Step 5: Compounds of formula (XI) are reacted with a base (such as NaOH) in a polar protic solvent (such as EtOH) to give compounds of formula (II), wherein Z = N, p = 0 and

[0178] Compounds of formula (II) wherein salt and / or solvate thereof e.g. a pharmaceutically acceptable salt and / or solvate thereof may be also prepared by an analogous synthetic route to that outlined in Scheme 1 above, wherein the compounds are prepared starting from Step 2 using commercially available 3-bromo-6- methylquinoline (CAS: 66438-78-6) as the starting material in place of the compound of formula (VII) i.e. 3-bromo-6-methyl-1 ,5-naphthyridine.

[0179] Compounds of formula (III) wherein salt and / or solvate thereof e.g. a pharmaceutically acceptable salt and / or solvate thereof may be also prepared by an analogous synthetic route to that outlined in Scheme 1 above, wherein the compounds are prepared starting from Step 2 using commercially available 4-bromo-6- methylquinoline (CAS: 1070879-23-0) as the starting material in place of the compound of formula (VII) i.e. 3-bromo-6-methyl-1 ,5-naphthyridine.

[0180] Compounds of formula (II) wherein

[0181] R2 is attached to the C atom of the pyrazolyl) or a salt and / or solvate thereof e.g. a pharmaceutically acceptable salt and / or solvate thereof may be prepared by the synthetic route outlined in Scheme 2 below. AGO-P3616PCT Application as filed

[0182] Scheme 2: Synthesis of compounds of formula (II) wherein Z = N, p = 1 wherein X is halo (e.g. Br).

[0183] Step 1 : Compounds of formula (XI), as prepared in Scheme 1 , are reacted with a halogenating agent (such as NBS) in a polar solvent (such as DMF) to give compounds of formula (XII).

[0184] Step 2: Compounds of formula (XII) are reacted with an organometallic coupling reagent (such as SnMe4 when R2 is methyl) in a polar solvent (such as DMF) in the presence of Pd catalyst (such as Pd(PPh3)4) to give compounds of formula (XIII).

[0185] Step 3: Compounds of formula (XIII) are reacted with a base (such as NaOH) in a polar protic solvent (such as EtOH) to give compounds of formula (II), wherein Z = N, p = 1 and

[0186] In the instance wherein R2 is halo, Step 2 of Scheme 2 above is redundant and X becomes AGO-P3616PCT Application as filed

[0187] R2; compounds of formula (XII) are converted directly to compounds of formula (II) as per Step 3.

[0188] Compounds of formula (II) wherein

[0189] (i.e. R2 is attached to the N atom of the pyrazolyl) or a salt and / or solvate thereof e.g. a pharmaceutically acceptable salt and / or solvate thereof may also be prepared by reaction of compounds of formula (XI) as shown in Scheme 1 above, with compounds of formula (XXXXII):

[0190] R2-X (XXXXII)

[0191] (wherein X is halo e.g. Br) in the presence of an appropriate base. Such products then may be further reacted in an analogous manner to Scheme 2 to afford compounds of formula (II) wherein salt and / or solvate thereof e.g. a pharmaceutically acceptable salt and / or solvate thereof. In the instance wherein R2 is halo, Step 2 of Scheme 2 above is redundant and X becomes R2; compounds analogous to compounds of formula (XII) are converted directly to compounds of formula (II) as per Step 3.

[0192] Alternatively compounds of formula (II) wherein wherein both R2 are Ci-4alkyl optionally substituted by hydroxy or C1- 4haloalkyl or a salt and / or solvate thereof e.g. a pharmaceutically acceptable salt and / or solvate thereof may also be prepared by reaction of compounds of formula (XIII) as shown in Scheme 2 above, with compounds of formula (XXXXII):

[0193] R2-X (XXXXII) AGO-P3616PCT Application as filed

[0194] (wherein X is halo e.g. Br) in the presence of an appropriate base, followed by the reaction as outlined in Step 3.

[0195] Compounds of formula (II) wherein or a salt and / or solvate thereof e.g. a pharmaceutically acceptable salt and / or solvate thereof may be also prepared by an analogous synthetic route to that outlined in Scheme 2 above starting from compounds that are analogous to compounds of formula (XI) wherein Z = CH rather than Z = N, the synthesis of which is outlined in the supporting text provided for Scheme 1 above.

[0196] Compounds of formula (II) wherein wherein R2 is Ci -4al ky I optionally substituted by hydroxy or Ci-4haloalkyl or a salt and / or solvate thereof e.g. a pharmaceutically acceptable salt and / or solvate thereof may be prepared by the synthetic route outlined in Scheme 3 below.

[0197] AGO-P3616PCT Application as filed

[0198] Scheme 3: Synthesis of compounds of formula (II) wherein Z = CH a wherein X1and X2are halo (e.g. Br) and PG2is a carboxylic acid protecting group (such as methyl).

[0199] Step 1 : Compounds of formula (XIV) are reacted with a boron coupling agent (such as B2(pin)2) in a polar solvent (such as dioxane) in the presence of a base (such as KOAc) and a Pd catalyst (such as PdCya) to give compounds of formula (XV).

[0200] Step 2: Compounds of formula (XV) are reacted with compounds of formula (XVI) in a polar solvent (such as dioxane) in the presence of a base (such as K3PO4) and a Pd catalyst (such as Pd(dtbpf)Ch) to give compounds of formula (XVII).

[0201] Step 3: Compounds of formula (XVII) are reacted with a base (such as NaOH) in a polar protic solvent (such as EtOH) to give compounds of formula (II), wherein Z = CH and AGO-P3616PCT Application as filed

[0202] Compounds of formula (II) wherein Z CH, p salt and / or solvate thereof e.g. a pharmaceutically acceptable salt and / or solvate thereof prepared according to Scheme 3 above may also be further reacted in an analogous manner to Scheme 2, starting from compounds that are analogous to compounds of formula (XI) wherein Z = CH, p pharmaceutically acceptable salt and / or solvate thereof.

[0203] Compounds of formula (II) wherein salt and / or solvate thereof e.g. a pharmaceutically acceptable salt and / or solvate thereof prepared from Scheme 3 above may also be further reacted in an analogous manner to Scheme 2, wherein

[0204] Step 3 is omitted, to afford compounds of formula (II) wherein AGO-P3616PCT Application as filed and R2 is halo, or a salt and / or solvate thereof e.g. a pharmaceutically acceptable salt and / or solvate thereof.

[0205] Compounds of formula (III) wherein

[0206] 4alkyl optionally substituted by hydroxy or Ci-4haloalkyl or a salt and / or solvate thereof e.g. a pharmaceutically acceptable salt and / or solvate thereof may be prepared by the synthetic route outlined in Scheme 4 below. wherein X1and X2are leaving groups (such as halo e.g. Br) and PG3is a carboxylic acid protecting group (such as methyl). AGO-P3616PCT Application as filed

[0207] Step 1 : Compounds of formula (XVIII) are reacted with a boron coupling agent (such as B2(pin)2) in a polar solvent (such as dioxane) in the presence of a base (such as KOAc) and a Pd catalyst (such as PdCya) to give compounds of formula (XIX).

[0208] Step 2: Compounds of formula (XIX) are reacted with compounds of formula (XVI) in a polar solvent (such as dioxane) in the presence of a base (such as K3PO4) and a Pd catalyst (such as Pd(dtbpf)Ch) to give compounds of formula (XX).

[0209] Step 3: Compounds of formula (XX) are reacted with a base (such as NaOH) in a polar protic solvent (such as EtOH) to give compounds of formula (III), wherein Z = CH and optionally substituted by hydroxy or

[0210] Ci-4haloalkyl.

[0211] Compounds of formula (III) wherein salt and / or solvate thereof e.g. a pharmaceutically acceptable salt and / or solvate thereof prepared from Scheme 4 above may also be further reacted in an analogous manner to Scheme 2, wherein Step 3 is omitted, to afford compounds of formula (III) wherein p = 2 and or a salt and / or solvate thereof e.g. a pharmaceutically acceptable salt and / or solvate thereof.

[0212] Compounds of formula (III) wherein salt and / or solvate thereof e.g. a pharmaceutically acceptable salt and / or solvate thereof prepared from

[0213] Scheme 4 above may also be further reacted in an analogous manner to Scheme 2, wherein

[0214] Step 3 is omitted, to afford compounds of formula (III) wherein AGO-P3616PCT Application as filed and R2 is halo, or a salt and / or solvate thereof e.g. a pharmaceutically acceptable salt and / or solvate thereof.

[0215] Compounds of formula (IV) or a salt and / or solvate thereof e.g. a pharmaceutically acceptable salt and / or solvate thereof are commercially available or may be prepared by one of the synthetic routes outlined in Scheme 5 below.

[0216] Scheme 5: Synthesis of compounds of formula (IV) , represents a C-linked 4-8 membered heterocyclyl, t is the number of repeat -CH2- units and LG5is a leaving group (such as a halide e.g. Br).

[0217] (a) Compounds of formula (XXI) are reacted with compounds of formula (XXII) in a polar solvent (such as MeCN) in the presence of a base (such as K2CO3) to give compounds of formula (IV).

[0218] (b) Compounds of formula (XXIII) are reacted with compounds of formula (XXIV) in a polar protic solvent (such as MeOH) in the presence of a reducing agent (such as NaBHsCN) to give compounds of formula (IV). Compounds of formula (XVI) wherein R2 is Ci-4alkyl optionally substituted by hydroxy or C1- 4haloalkyl or a salt and / or solvate thereof e.g. a pharmaceutically acceptable salt and / or solvate thereof may be prepared by the synthetic route outlined in Scheme 6 below. AGO-P3616PCT Application as filed

[0219] Scheme 6: Synthesis of compounds of formula (XVI) wherein R2 is Ci^alkyl optionally substituted by hydroxy or Ci-4haloalkyl. wherein X4and X2are halo (e.g. Br).

[0220] Step 1 : Compounds of formula (XXV) are reacted with compounds of formula (XXVI) in a polar solvent (such as dioxane) in the presence of a base (such as K3PO4) and a Pd catalyst (such as Pd(dtbf)Ch) to give compounds of formula (XXVII).

[0221] Step 2: Compounds of formula (XXVII) are reacted with a halogenating group (such as NBS) to give compounds of formula (XVI).

[0222] Compounds of formula (II) wherein Z = CH, p is 0 or 1 wherein R2 is Ci^alkyl optionally substituted by hydroxy or Ci-4haloalkyl or a salt and / or solvate thereof e.g. a pharmaceutically acceptable salt and / or solvate thereof may be prepared by the synthetic route outlined in Scheme 7 below.

[0223] AGO-P3616PCT Application as filed

[0224] Scheme 7: Synthesis of compounds of formula (II) wherein Z = CH, p is 0 or 1 and wherein X1and X5are leaving groups (such as halo e.g. Br) and PG2is a carboxylic acid protecting group (such as methyl).

[0225] Step 1 : Compounds of formula (XIV) are reacted with a boron coupling agent (such as B2(pin)2) in a polar solvent (such as dioxane) in the presence of a base (such as KOAc) and a Pd catalyst (such as PdCya) to give compounds of formula (XV).

[0226] Step 2: Compounds of formula (XV) are reacted with compounds of formula (XXIX) in a polar solvent (such as dioxane) in the presence of a base (such as K3PO4) and a Pd catalyst (such as Pd(dtbpf)Ch) to give compounds of formula (XXX).

[0227] Step 3: Compounds of formula (XXX) are reacted with a base (such as NaOH) in a polar protic solvent (such as EtOH) to give compounds of formula (II), wherein Z = CH p is 0 or 1 and AGO-P3616PCT Application as filed

[0228] Compounds of formula (III) wherein wherein R2 is Ci .4a! ky I optionally substituted by hydroxy or Ci-4haloalkyl or a salt and / or solvate thereof e.g. a pharmaceutically acceptable salt and / or solvate thereof may be prepared by the synthetic route outlined in Scheme 8 below. of formula (III) wherein p is 0 or 1 and wherein X1and X5are halo (e.g. Br). wherein PG3is a carboxylic acid protecting group (such as methyl ester).

[0229] Step 1 : Compounds of formula (XVIII) are reacted with a boron coupling agent (such as B2(pin)2 in a polar solvent (such as dioxane) in the presence of a base (such as KOAc) and a Pd catalyst (such as PdCya) to give compounds of formula (XIX).

[0230] Step 2: Compounds of formula (XIX) are reacted with compounds of formula (XXIX) in a polar solvent (such as dioxane) in the presence of a base (such as K2CO3) and a Pd catalyst (such as Pd(PPh3)4) to give compounds of formula (XXXI). AGO-P3616PCT Application as filed

[0231] Step 3: Compounds of formula (XXXI) are reacted with a base (such as NaOH) in a polar protic solvent (such as EtOH) to give compounds of formula (III), wherein Z = CH p is 0 or 1

[0232] Alternatively, compounds of formula (III) wherein salt and / or solvate thereof e.g. a pharmaceutically acceptable salt and / or solvate thereof, as prepared according to Scheme 8 above or in an analogous route to Scheme 10 below, may be further reacted either:

[0233] (a) with compounds of formula (XXXXII):

[0234] R2-X (XXXXII)

[0235] (wherein X is halo e.g. Br) in the presence of an appropriate base, to afford compounds of formula (III) wherein to the N atom of the imidazolyl) or a salt and / or solvate thereof e.g. a pharmaceutically acceptable salt and / or solvate thereof; or

[0236] (b) in an analogous manner to Scheme 11 below, wherein Step 3 is omitted, to afford compounds of formula (III) wherein

[0237] (i.e. R2is linked to C atom of imidazolyl) or a salt and / or solvate thereof e.g. a pharmaceutically acceptable salt and / or solvate thereof.

[0238] Compounds of formula (III) wherein AGO-P3616PCT Application as filed wherein R2is Ci -4al ky I optionally substituted by hydroxy or Ci-4haloalkyl or a salt and / or solvate thereof e.g. a pharmaceutically acceptable salt and / or solvate thereof may be prepared either by:

[0239] (a) further reaction of compounds of formula (III) wherein attached to the N atom of the imidazolyl) or a salt and / or solvate thereof e.g. a pharmaceutically acceptable salt and / or solvate thereof in an analogous manner to Scheme 11 , wherein Step 3 is omitted; or

[0240] (b) further reaction of compounds of formula (III) wherein attached to the C atom of the imidazolyl) or a salt and / or solvate thereof e.g. a pharmaceutically acceptable salt and / or solvate thereof with compounds of formula (XXXXII):

[0241] R2-X (XXXXII)

[0242] (wherein X is halo e.g. Br) in the presence of an appropriate base.

[0243] Compounds of formula (XXIX) or a salt and / or solvate thereof e.g. a pharmaceutically acceptable salt and / or solvate thereof may be prepared by the synthetic route outlined in Scheme 9 below. AGO-P3616PCT Application as filed wherein X5is halo e.g. Br.

[0244] Step 1 : Compounds of formula (XXXII) are reacted with p-toluenesulfonic acid sodium salt and formamide in a polar solvent (such as MeCN) in the presence of an activating agent (such as TMSCI) to give compounds of formula (XXXIII).

[0245] Step 2: Compounds of formula (XXXIII) are reacted with an activating group (such as POCh) in the presence of a base (such as 2,6-lutidine) to give compounds of formula (XXXIV).

[0246] Step 3: Compounds of formula (XXXIV) are reacted with glycolic acid and compounds of formula (XXXV) in a polar solvent (such as DMF) in the presence of a base (such as K2CO3) to give compounds of formula (XXXVI).

[0247] Step 4: Compounds of formula (XXXVI) are reacted with a halogenating agent (such as NBS) in a polar aprotic solvent (such as DCM) to give compounds of formula (XXIX).

[0248] Compounds of formula (II) wherein AGO-P3616PCT Application as filed and / or solvate thereof e.g. a pharmaceutically acceptable salt and / or solvate thereof may be prepared by the synthetic route outlined in Scheme 10 below.

[0249] Step 1 : Compounds of formula (IX) are reacted with an oxidising agent (such as SeCh) to give compounds of formula (XXXVII).

[0250] Step 2: Compounds of formula (XXXVII) are reacted with urotropine and ammonium acetate to give compounds of formula (XXXVIII)

[0251] Step 3: Compounds of formula (XXXVIII) are reacted with Zn(CN)2 in a polar solvent (such as DMF) in the presence of Pd catalyst (such as Pd(PPha)4) to give compounds of formula (XXXIX).

[0252] Step 4: Compounds of formula (XXXIX) are reacted with a base (such as NaOH) in a polar protic solvent (such as EtOH) to give compounds of formula (II), wherein Z = N, p = 0 and AGO-P3616PCT Application as filed

[0253] Step 1 and Step 2 of Scheme 10 above are analogous to those described in WO2021102468

[0254] (Theravance Biopharma R&D IP LLC, page 49, Scheme 1).

[0255] Compounds of formula (II) wherein salt and / or solvate thereof e.g. a pharmaceutically acceptable salt and / or solvate thereof may be also prepared by an analogous synthetic route to that outlined in Scheme 10 above starting from compounds that are analogous to compounds of formula (IX) wherein Z = CH instead of Z = N, the synthesis of which is described in the supporting text provided for Scheme 1 above. Step 1 and Step 2 are analogous to those described in WO2021102468 (Theravance Biopharma R&D IP LLC, page 50, Scheme 3).

[0256] Compounds of formula (II) wherein salt and / or solvate thereof e.g. a pharmaceutically acceptable salt and / or solvate thereof as prepared from Scheme 10 may be further reacted either:

[0257] (a) with compounds of formula (XXXXII):

[0258] R2-X (XXXXII)

[0259] (wherein X is halo e.g. Br) in the presence of an appropriate base, to afford compounds of formula (II) wherein to N atom of the imidazolyl) or a salt and / or solvate thereof e.g. a pharmaceutically acceptable salt and / or solvate thereof; or

[0260] (b) in an analogous manner to Scheme 11 below, wherein Step 3 is omitted, to afford compounds of formula (II) wherein

[0261] (i.e. R2is linked to C atom of imidazolyl) or a salt and / or solvate thereof e.g. a pharmaceutically acceptable salt and / or solvate thereof. AGO-P3616PCT Application as filed

[0262] Compounds of formula (II) wherein

[0263] R2 is N-linked to imidazole) or a salt and / or solvate thereof e.g. a pharmaceutically acceptable salt and / or solvate thereof may be further reacted in an analogous manner to Scheme 11 below, wherein Step 3 is omitted, to afford compounds of formula (II) wherein Z = N, p = 2 and or a salt and / or solvate thereof e.g. a pharmaceutically acceptable salt and / or solvate thereof.

[0264] Compounds of formula (II) wherein or a salt and / or solvate thereof e.g. a pharmaceutically acceptable salt and / or solvate thereof may be prepared by the synthetic route outlined in Scheme 11 below.

[0265] AGO-P3616PCT Application as filed

[0266] Scheme 11 : Synthesis of compounds of formula (II) wherein Z = N, p = 1 and wherein Z = N and p = 1 wherein X5is halo (e.g. Br)

[0267] Step 1 : Compounds of formula (XXXIX), as prepared in Scheme 10, are reacted with a halogenating agent (such as NBS) in a polar solvent (such as DMF) to give compounds of formula (XXXX).

[0268] Step 2: Compounds of formula (XXXX) are reacted with a organometallic coupling reagent (such a SnMe4) in a polar solvent (such as DMF) in the presence of Pd catalyst (such as Pd(PPh3)4) to give compounds of formula (XXXXI).

[0269] Step 3: Compounds of formula (XXXXI) are reacted with a base (such as NaOH) in a polar protic solvent (such as EtOH) to give compounds of formula (II), wherein Z = N, p is 1 and

[0270] In the instance wherein R2 is halo, Step 2 of Scheme 11 above is redundant and X5becomes R2; compounds of formula (XII) are converted directly to compounds of formula (II) as per Step 3. AGO-P3616PCT Application as filed

[0271] Compounds of formula (II) wherein is N-linked to imidazolyl) or a salt and / or solvate thereof e.g. a pharmaceutically acceptable salt and / or solvate thereof may also be prepared by reaction of compounds of formula (XXXIX) as shown in Scheme 10 above, with compounds of formula (XXXXII):

[0272] R2-X (XXXXII)

[0273] (wherein X is halo e.g. Br) in the presence of an appropriate base. Such products may be further reacted in an analogous manner to Scheme 11 , wherein Step 3 is omitted, to afford compounds of formula (II) wherein or a salt and / or solvate thereof e.g. a pharmaceutically acceptable salt and / or solvate thereof.

[0274] Alternatively compounds of formula (II) wherein wherein both R2are Ci-4alkyl optionally substituted by hydroxy or Ci¬

[0275] 4haloalkyl or a salt and / or solvate thereof e.g. a pharmaceutically acceptable salt and / or solvate thereof may also be prepared by reaction of compounds of formula (XXXXI) as shown in Scheme 11 above, with compounds of formula (XXXXII):

[0276] R2-X (XXXXII)

[0277] (wherein X is halo e.g. Br) in the presence of an appropriate base, followed by the reaction as outlined in Step 3. Compounds of formula (II) wherein Z = CH, p = 1 AGO-P3616PCT Application as filed salt and / or solvate thereof e.g. a pharmaceutically acceptable salt and / or solvate thereof may be also prepared by an analogous synthetic route to that outlined in Scheme 11 above starting from compounds that are analogous to compounds of formula (XXXIX) wherein Z = CH rather than Z = N, the synthesis of which is outlined in the supporting text provided for Scheme 10 above.

[0278] In the instance wherein R2 is halo, Step 2 of Scheme 11 above is redundant and X5becomes R2; compounds of formula (XII) are converted directly to compounds of formula (II) as per Step 3.

[0279] Compounds of formula (V), (VI), (VIII), (XIV), (XXI), (XXII), (XXIII), (XXIV), (XXV), (XXVI) and (XXXII) are either known or may be prepared by methods known to the skilled person. For example, compounds of formula (XXV) the skilled person may perform routine screening of different transition metal catalysed (e.g. Pd-catalysed) cross-coupling conditions and reagents (e.g. SnEt4 when R2 is ethyl) to introduce the R2 group from a readily available pyrazolyl compound.

[0280] If appropriate or convenient, compounds of formula (II), (III), (IV), (X), (XI), (XII), (XIII), (XVI), (XVII), (XX), (XXI), (XXIII), (XXV), (XXVII), (XXIX), (XXX) and (XXXI), (XXXVIII), (XXXIX), (XXXX), (XXXXI) and (XXXXII) may be protected in the synthetic method to protect potentially reactive groups such as oxygen and nitrogen containing groups. Further, structures shown as containing protecting groups may be successfully deployed without such protecting groups. Salt interconversion may be performed as required. Novel intermediate compounds, such as compounds of formula (II), (III), (IX), (X), (XI), (XII), (XIII), (XVI), (XVII), (XX) and (XXIX), (XXX), (XXXI), (XXXX) and (XXXXI), and salts and / or solvates thereof e.g. pharmaceutically acceptable salts and / or solvates thereof are provided as an aspect of the invention. The skilled person will appreciate that protecting groups may be used throughout the synthetic schemes described herein to give protected derivatives of any of the above compounds or generic formulae. Protective groups and the means for their removal are described in “Protective Groups in Organic Synthesis", by Theodora W. Greene and Peter G. M. Wuts, published by John Wiley & Sons Inc; 4th Rev Ed., 2006, ISBN-10: 0471697540. Examples of AGO-P3616PCT Application as filed nitrogen protecting groups include tetrahydropyranyl (THP), tert-butyloxycarbonyl (BOC), benzyloxycarbonyl (Cbz) and allyloxycarbonyl (Alloc) groups. Examples of oxygen protecting groups include benzyl, ethyl, chloro acetyl, and silyl ethers and esters (such as tertbutyldimethylsilyl (TBS). Specific examples of carboxylic acid protecting groups include alkyl esters (such as C1-6 alkyl e.g. C1-4 alkyl esters), benzyl esters and allyl esters.

[0281] Medical Uses

[0282] Compounds of the invention are for use in therapy, particularly for treating or preventing a disease or pathological disorder susceptible to amelioration by inhibition of ALK5.

[0283] As shown in Biological Example 1 and Biological Example 2 below, the compounds of the present invention are potent inhibitors of ALK5 when tested in Human TGFpR-1 inhibition experiments, as demonstrated by low IC50 values. Furthermore, as shown in Biological Example 3, at least some of the compounds of the invention demonstrate poor stability in human plasma. Such compounds when administered by inhalation may be expected to have a particularly favourable safety profile due to the expected absence of systemic activity.

[0284] Thus, in a first aspect, the present invention provides a compound of the invention for use as a medicament.

[0285] In particular, the invention provides a compound of the invention for use in the treatment or prevention of a disease or pathological disorder susceptible to amelioration by inhibition of ALK5. The invention also provides use of a compound of the invention in the manufacture of a medicament for the treatment and / or prevention of a disease or pathological disorder susceptible to amelioration by inhibition of ALK5. The invention also provides a method of treating or preventing a disease or pathological disorder which is susceptible to amelioration by inhibition of ALK5 which comprises administering a compound of the invention to a subject in need thereof.

[0286] The term "treatment" or "treating" as used herein includes the control, mitigation, reduction, or modulation of the disease state or its symptoms.

[0287] The term "prevention" or “preventing” is used herein to mean preventing the disease state or disorder, or its symptoms, in a subject, or preventing recurrence of symptoms of a disease or disorder in an afflicted subject and is not limited to complete prevention of an affliction. AGO-P3616PCT Application as filed

[0288] A subject will typically be a subject in need of treatment or prevention according to the invention. Suitably the subject is a human.

[0289] Such a disease or pathological disorder may for example be selected from the group consisting of gastrointestinal diseases, lung diseases, fibrotic diseases, fibroproliferative disorders, cancer and graft vs. host disease (GVHD).

[0290] The term “gastrointestinal diseases” refers to diseases which affect the gastro-intestinal tract, specifically the small and / or large intestine. The small intestine refers to the duodenum, jejunum, and ileum and the large intestine refers to the cecum (including the appendix), colon, rectum, and anal canal. In particular, the term gastrointestinal diseases includes inflammatory bowel diseases (IBD), post-radiation enteritis, complicated celiac disease and intestinal fibrosis. The term “inflammatory bowel diseases” or “IBD” refers to Crohn's disease (CD) (which includes inflammatory CD, fibrostenosing CD (FSCD), fistulizing CD, and perianal CD) and ulcerative colitis (UC). In particular, the term IBD includes fibrostenosing CD.

[0291] The term “lung diseases” includes chronic obstructive pulmonary disease (COPD) and asthma. Also included are fibrotic lung diseases, interstitial lung diseases, pulmonary arterial hypertension and lung cancer.

[0292] The term “fibrotic lung diseases” may fall under the category of “lung diseases” or “fibrotic diseases”. Examples of fibrotic lung disease include idiopathic pulmonary fibrosis and upper airway stenosis including idiopathic subglottic stenosis, iatrogenic laryngotracheal stenosis, and autoimmune upper airway stenosis.

[0293] The term “interstitial lung diseases” refers to lung disease of the pulmonary interstitium, e.g. as described in more detail in Wijsenbeek et al (2022). Most interstitial lung diseases are characterised by inflammation or fibrosis of the interstitial space, the primary consequence of which is impaired gas exchange, resulting in breathlessness, diminished exercise tolerance and decreased quality of life. Specific example diseases of this type include sarcoidosis, hypersensitivity pneumonitis, rheumatoid arthritis associated pulmonary fibrosis and idiopathic pulmonary fibrosis.

[0294] The term “fibrotic disease(s)” refers to diseases characterized by excessive scarring due to excessive production, deposition, and contraction of extracellular matrix, and that are associated with the abnormal accumulation of cells and / or fibronectin and / or collagen and / or increased fibroblast recruitment and include but are not limited to fibrosis of individual organs AGO-P3616PCT Application as filed or tissues such as the heart, kidney, liver, joints, lung, pleural tissue, peritoneal tissue, skin, cornea, retina, musculoskeletal and digestive tract. The term fibrotic diseases includes (i) fibrosis of the digestive tract or intestinal fibrosis, such as fibrostenosing Crohn’s disease (FSCD); (ii) hepatic fibrosis, also known as liver fibrosis, such as cirrhosis, alcohol induced liver fibrosis, toxic / drug induced liver fibrosis, hemochromatosis, non-alcoholic steatohepatitis

[0295] (NASH) (in particular F4 NASH), biliary duct injury, primary biliary cirrhosis, primary sclerosing cholangitis, infection induced liver fibrosis, viral induced liver fibrosis, and autoimmune hepatitis; (iii) fibrotic skin diseases or fibrotic diseases with a skin component such as scleroderma, nephrogenic fibrosing dermopathy, mixed connective tissue disease, scleromyxedema, scleredema, atopic dermatitis and eosinophilic fasciitis; (iv) fibrotic renal diseases such as glomerulonephritis (GN) (e.g. mesangial proliferative GN, immune GN and crescentic GN), diabetic nephropathy, renal interstitial fibrosis and renal fibrosis in transplant patients; (v) fibrotic eye diseases such as dry eyes, age-related macular degeneration, scarring of the cornea and conjunctiva, post-cataract fibrosis, proliferative vitreoretinopathy, and proliferative diabetic retinopathy; and (vi) fibrotic lung diseases.

[0296] The disease “non-alcoholic steatohepatitis (NASH)” is also known as metabolic dysfunction- associated steatohepatitis (MASH); the terms are interchangeable. The term “fibroproliferative disorders” refers to autoimmune diseases associated with fibroproliferative characteristics such as systemic lupus erythematosus (SLE), systemic sclerosis and rheumatoid arthritis and also refers to myelofibrosis.

[0297] The term “cancer” includes cancer of the breast, colon (including colorectal cancer), oesophagus, stomach, lung (including non-small cell lung cancer), pancreas, skin, prostate, liver (including hepatocellular carcinoma) and brain (including meningioma).

[0298] In particular, the compound of invention is provided for use in the treatment or prevention of a fibrotic disease selected from intestinal fibrosis, hepatic fibrosis, fibrotic skin diseases, fibrotic renal diseases, fibrotic eye diseases and fibrotic lung diseases. In particular, the fibrotic disease is intestinal fibrosis. In particular, the fibrotic disease is fibrostenosing Crohn’s disease (FSCD). In particular, the fibrotic disease is a fibrotic lung disease. In particular the fibrotic disease is idiopathic pulmonary fibrosis. AGO-P3616PCT Application as filed

[0299] Pharmaceutical Compositions

[0300] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of the invention in combination with one or more pharmaceutically acceptable diluents or carriers. The pharmaceutical composition may, for example, be adapted for oral administration or administration by inhalation. Suitably, the pharmaceutical composition may be adapted for administration by inhalation.

[0301] At least some compounds of the invention have low plasma stability. Such compounds when administered by inhalation may be expected to have a particularly favourable safety profile due to the expected absence of systemic activity.

[0302] The pharmaceutical compositions may conveniently be administered in unit dosage form and may be prepared by any of the methods well-known in the pharmaceutical art, for example as described in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA., (1985). The compositions may also conveniently be administered in unit dosage form, multiple unit dosage form or reservoir dosage form.

[0303] In one embodiment, a compound of the invention (for example, formulated as a pharmaceutical composition as defined herein) is administered by the oral route. Thus, in one embodiment there is provided a pharmaceutical composition comprising a compound of the invention optionally in combination with one or more pharmaceutically acceptable diluents, excipients, or carriers, wherein the pharmaceutical composition is suitable for oral administration.

[0304] The pharmaceutical composition comprising a compound of the invention can be formulated for oral administration as a liquid or solid, e.g. as a syrup, suspension, emulsion, tablet, capsule or lozenge. A liquid formulation suitable for oral administration will generally consist of a suspension or solution of a compound of the invention in a suitable liquid carrier(s). Suitably, the carrier is non-aqueous e.g. polyethylene glycol or an oil. The formulation may also contain a suspending agent, preservative, flavouring and / or colouring agent. A composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations, such as magnesium stearate, starch, lactose, sucrose and cellulose. AGO-P3616PCT Application as filed

[0305] Alternatively, a compound of the invention (for example, formulated as a pharmaceutical composition as defined herein) is administered by inhalation such as topically to the lung or nose, particularly, topically to the lung. Thus, in an embodiment there is provided a pharmaceutical composition comprising a compound of the invention optionally in combination with one or more topically acceptable diluents, excipients or carriers wherein the pharmaceutical composition is suitable for administration by inhalation.

[0306] Suitably the pharmaceutically acceptable (e.g. topically acceptable) diluent is an aqueous diluent i.e. it is or comprises water.

[0307] The pharmaceutical composition comprising a compound of the invention can be formulated for administration by inhalation as a liquid or solid and presented e.g. as a capsule, suspension, solution or powder.

[0308] Topical administration by inhalation may be achieved by use of a pressurised aerosol formulation. Aerosol formulations typically comprise the active ingredient suspended or dissolved in a suitable aerosol propellant, such as a hydrofluorocarbon (HFC) or hydrofluoroolefin (HFO) propellant. Suitable HFC propellants include tetrafluoroethane (HFC- 134a), heptafluoropropane (HFC-227) and 1 ,1 -difluoroethane (HFC-152a). Suitably HFO propellants include 1 ,3,3,3-tetrafluoropropene (HFO1234ze). The propellant typically comprises 40%-99.5%, e.g. 40%-90%, by weight of the total inhalation composition. The formulation may comprise excipients including co-solvents (e.g. ethanol) and surfactants (e.g. lecithin, sorbitan trioleate and the like). Other possible excipients include polyethylene glycol, polyvinylpyrrolidone, glycerine and the like. Aerosol formulations are packaged in canisters and a suitable dose is delivered by means of a metering valve (e.g. as supplied by Bespak, Valois or 3M or alternatively by Aptar, Coster or Vari).

[0309] Topical administration by inhalation may also be achieved by use of a non-pressurised formulation such as an aqueous solution or suspension.

[0310] Thus, a pharmaceutical composition comprising the compound of the invention may also be administered by inhalation using a nebuliser inhaler. Such nebuliser devices typically produce a stream of high velocity air that causes the pharmaceutical composition to spray as a mist that is carried into the patient's respiratory tract. Accordingly, when formulated for use in a nebuliser inhaler, the therapeutic agent can be dissolved in a suitable carrier to form a solution. Alternatively, the therapeutic agent can be micronized or nano-milled and combined with a AGO-P3616PCT Application as filed suitable carrier to form a suspension. The formulation may comprise excipients such as water, buffers, tonicity adjusting agents (such as sodium chloride), pH adjusting agents, viscosity modifiers, surfactants (such as Lipoid S100) and co-solvents (such as ethanol or propylene glycol). A nebuliser inhaler may be hand-held and portable or for home or hospital use (i.e. non-portable). An example of such a device is a RESPIMAT inhaler.

[0311] Suspension liquid and aerosol formulations (whether pressurised or unpressurised) will typically contain the compound of the invention in finely divided form, for example having a mass median aerodynamic diameter (MMAD) with a D50 of 0.5-10 pm e.g. around 1-5 pm.

[0312] Administration by inhalation may also be achieved by use of a dry-powder formulation. A dry powder formulation will contain a compound of the invention in particulate form, typically with an mass median aerodynamic diameter (MMAD) of 1-10 pm or a Dso of 0.5-10 pm e.g. around 1-5 pm. Powders of a compound of the invention in particulate form may be prepared by a micronisation process or similar size reduction process. Micronisation may be performed and measured as described above. The formulation will typically contain a pharmaceutically acceptable (e.g. a topically acceptable) diluent such as lactose, glucose or mannitol (preferably lactose), usually of comparatively large particle size e.g. an MMAD of 50 pm or more, e.g. 100 pm or more or a Dso of 40-150 pm. As used herein, the term “lactose” refers to a lactose-containing component, including a-lactose monohydrate, p-lactose monohydrate, a- lactose anhydrous, p-lactose anhydrous and amorphous lactose. Lactose components may be processed by micronisation, sieving, milling, compression, agglomeration or spray drying. Commercially available forms of lactose in various forms are also encompassed, for example Lactohale® (inhalation grade lactose; DFE Pharma), lnhaLac®70 (sieved lactose for dry powder inhaler; Meggle), Pharmatose® (DFE Pharma) and Respitose® (sieved inhalation grade lactose; DFE Pharma) products. In one embodiment, the lactose component is selected from the group consisting of a-lactose monohydrate, a-lactose anhydrous and amorphous lactose. Preferably, the lactose is a-lactose monohydrate. Powders for inhalation can include spray dried powders (including blends of such). For some delivery devices the powders are presented in a capsule.

[0313] Dry powder formulations may also contain other excipients such as sodium stearate, calcium stearate or magnesium stearate. A dry powder formulation is typically delivered using a dry powder inhaler (DPI) device. Example dry powder delivery systems include SPINHALER, DISKHALER, TURBOHALER, DISKUS, SKYEHALER, ACCUHALER and CLICKHALER. Further examples of dry powder AGO-P3616PCT Application as filed delivery systems include ECLIPSE, NEXT, ROTAHALER, HANDIHALER, AEROLISER, CYCLOHALER, BREEZHALER / NEOHALER, MONODOSE, FLOWCAPS, TWINCAPS, X- CAPS, TURBOSPIN, ELPENHALER, MIATHALER, TWISTHALER, NOVOLIZER, PRESSAIR, ELLIPTA, ORIEL dry powder inhaler, MICRODOSE, PULVINAL, EASYHALER, ULTRAHALER, TAIFUN, PULMOJET, OMNIHALER, GYROHALER, TAPER, CONIX, XCELOVAIR and PROHALER.

[0314] A composition presented in the form of a capsule can be prepared using routine encapsulation procedures, e.g. powders containing the active ingredient (such as a compound of the invention) can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), e.g. aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule. Capsules can also be made from HPMC. Liquid suspension and aerosol formulations (whether pressurised or unpressurised) will typically contain a compound of the invention in particulate form, for example with a Dso of 0.5- 10 pm, suitably around 1-5 pm, such as 1-2 pm. Suitably, a compound of the invention in particulate form has a Dw of 0.2 to 1 pm, such as 0.2 to 0.5 pm. Suitably, a compound of the invention in particulate form has a D90 of 2 to 6 pm such as 3 to 4 pm. The particulate form of the compound may, for example, be a micronised form. Micronisation may be performed using a jet mill such as those manufactured by Hosokawa Alpine. The resultant particle size distribution may be measured using laser diffraction (e.g. with a Malvern Mastersizer 2000S instrument). Particle size distributions may be represented using D10, D50 and D90 values. The D50 median value of particle size distributions is defined as the particle size in microns that divides the distribution in half. The measurement derived from laser diffraction is more accurately described as a volume distribution and consequently the D50 value obtained using this procedure is more meaningfully referred to as a Dvso value (median for a volume distribution). As used herein Dv values refer to particle size distributions measured using laser diffraction. Similarly, Dw and D90 values, used in the context of laser diffraction, are taken to mean Dvw and DV90 values and refer to the particle size whereby 10% of the distribution lies below the Dw value, and 90% of the distribution lies below the D90 value, respectively.

[0315] According to one embodiment of the invention there is provided a pharmaceutical composition comprising a compound of the invention as an aqueous suspension i.e. in particulate form suspended in an aqueous medium or as an aqueous solution. The aqueous medium typically comprises water and one or more excipients selected from buffers, tonicity adjusting agents AGO-P3616PCT Application as filed

[0316] (such as sodium chloride), pH adjusting agents, viscosity modifiers, co-solvents (such as propylene glycol) and surfactants (such as Lipoid S100).

[0317] Suitably, the aqueous medium comprises at least about 40% water such as at least about 60% water, at least about 80% water, at least about 95% water, or at least about 99% water, such as at least about 99% water.

[0318] Thus, according to one embodiment, there is provided a pharmaceutical composition comprising a compound of the invention in particulate form suspended in an aqueous medium.

[0319] The pharmaceutical compositions according to the present invention may also include various other ingredients, including, but not limited to, tonicity agents, buffers, surfactants, stabilizing polymer, preservatives, co-solvents and viscosity building agents. Suitable pharmaceutical compositions of the present invention include a compound of the invention formulated with a tonicity agent and a buffer. The pharmaceutical compositions of the present invention may further optionally include a surfactant and / or a palliative agent and / or a stabilizing polymer.

[0320] Various tonicity agents may be employed to adjust the tonicity of the composition. For example, sodium chloride, potassium chloride, magnesium chloride, calcium chloride, simple sugars such as dextrose, fructose, galactose, and / or simply polyols such as the sugar alcohols mannitol, sorbitol, xylitol, lactitol, isomaltitol, maltitol, and hydrogenated starch hydrolysates may be added to the composition to approximate physiological tonicity. Such an amount of tonicity agent will vary, depending on the particular agent to be added. In general, however, the compositions will have a tonicity agent in an amount sufficient to cause the final composition to have an acceptable osmolality (generally about 150-450 mOsm, preferably 250-350 mOsm and most preferably at approximately 290 mOsm). In general, the tonicity agents of the invention will be present in the range of 2 to 4% w / w. Preferred tonicity agents of the invention include the simple sugars or the sugar alcohols, such as D-mannitol. An appropriate buffer system (e.g. sodium phosphate, sodium acetate, sodium citrate, sodium borate or boric acid) may be added to the compositions to prevent pH drift under storage conditions. The particular concentration will vary, depending on the agent employed. The particular pH will depend on the route of administration. Preferably, for aqueous formulations intended for administration by inhalation, the buffer will be chosen to maintain a target pH within the range of pH 2 to 4, and more preferably to a target pH of pH 2.5-3.5 e.g. 2.9-3.1 . AGO-P3616PCT Application as filed

[0321] Surfactants may optionally be employed to deliver higher concentrations of compound of the present invention. The surfactants function to solubilise the compound and stabilise colloid dispersion, such as micellar solution, microemulsion, emulsion and suspension. Examples of surfactants which may optionally be used include polysorbate, poloxamer, polyosyl 40 stearate, polyoxyl castor oil, tyloxapol, Triton, and sorbitan monolaurate. Preferred surfactants to be employed in the invention have a hydrophile / lipophile / balance "HLB" in the range of 12.4 to 13.2, such as TritonX114 and tyloxapol.

[0322] In further embodiments, a compound of the invention may be administered by other routes, such as parenteral or ocular routes. A pharmaceutical composition comprising a compound of the invention may, for example, be adapted for parenteral administration or ocular administration. Pharmaceutical compositions for parenteral and ocular administration include aqueous formulations discussed above with adaptations appropriate for the route. For example, parenteral compositions will typically have an approximately neutral pH (e.g. pH 7.0- 7.4) and have an osmolarity in the range 100-300 mOsmol / L.

[0323] The composition may contain from 0.1% to 100% by weight, for example from 10 to 60% by weight, of the active material, depending on the method of administration. The composition may contain from 0% to 99% by weight, for example 40% to 90% by weight, of the carrier, depending on the method of administration. In some cases the formulation may contain 100% by weight of a compound of the invention. The composition may contain from 0.05 mg to 1000 mg, for example from 1.0 mg to 500 mg, of the active material, depending on the method of administration. The composition may contain from 50 mg to 1000 mg, for example from 100 mg to 400 mg of the carrier, depending on the method of administration. The dose of the compound used in the treatment of the aforementioned disorders will vary in the usual way with the seriousness of the disorders, the weight of the sufferer, and other similar factors. However, as a general guide, suitable unit doses may be 0.05 mg to 1000 mg, more suitably 1.0 mg to 500 mg, and such unit doses may be administered more than once a day, for example two or three a day. Such therapy may extend for a number of weeks, months or years.

[0324] The active compound will be administered to a patient in need thereof (for example a human or animal patient) in an amount sufficient to achieve the desired therapeutic effect. AGO-P3616PCT Application as filed

[0325] Second or further active ingredients

[0326] In a further embodiment, a compound of the invention is administered in combination with a second or further active ingredient. Administration may be simultaneous, separate or sequential. Suitably, the second or further active ingredient is an agent useful for the treatment of disease or pathological disorder that can be ameliorated by inhibition of ALK5 wherein the disease or pathological disorder is defined elsewhere herein. Thus, the invention also provides a combination therapy comprising the invention and a therapeutic agent used for the prevention or treatment of a disease or pathological disorder that can be ameliorated by inhibition of ALK5, such as a disease selected from the group consisting of gastrointestinal diseases, lung diseases, fibrotic diseases, fibroproliferative disorders, cancer and graft vs. host disease (GVHD). For example, the second or further active ingredient is an agent useful for the treatment of idiopathic pulmonary fibrosis (I PF) e.g. is selected from nintedanib and pirfenidone.

[0327] A compound of the invention may be co-formulated with a second or further active ingredient or the second or further active ingredient may be formulated to be administered separately by the same or a different route. For example, a compound of the invention may be administered to patients already being treated systemically with the second or further active ingredient.

[0328] In a further embodiment the invention provides a kit of parts comprising: (a) a pharmaceutical composition comprising a compound of the invention optionally in combination with one or more diluents, excipients, or carriers; (b) a pharmaceutical composition comprising a second active ingredient optionally in combination with one or more diluents, excipients, or carriers; (c) optionally one or more further pharmaceutical compositions each comprising a third or further active ingredient optionally in combination with one or more diluents, excipients, or carriers and (d) instructions for the administration of the pharmaceutical compositions to a subject in need thereof. Potential desirable properties

[0329] The compounds of the invention are potent inhibitors of ALK5 enzyme in vitro and in at least some embodiments may display one or more of the following desirable properties:

[0330] • High potency of inhibition of ALK5 activity in cells; • Low stability in human plasma;

[0331] • Low stability in experimental animal species plasma (e.g. mouse plasma); AGO-P3616PCT Application as filed

[0332] • Metabolic stability e.g. as determined in human liver microsomes which is neither too high nor too low;

[0333] • Low clearance from lung e.g. as determined in the metabolic stability (Lung S9) assay;

[0334] • Low or absent hERG binding affinity; and

[0335] • Good target engagement e.g. as determined by level of TGFp inhibition in TGFp- stimulated rat precision-cut lung slices (PCLS) assay and / or level of TGFp inhibition in TGFp inhibition in TGFp-stimulated normal human lung fibroblasts (NHLF) assay.

[0336] Abbreviations

[0337] In the present application are used the following abbreviations, with the corresponding definitions:

[0338] AcOH Acetic Acid

[0339] ACVR2B Activin A receptor, type 11 B

[0340] B2pin2 Bis(pinacolato)diboron

[0341] BOC2O tert-Butyl dicarbonate

[0342] Boc tert-Butoxycarbonyl

[0343] DCM Dichloromethane

[0344] DHP 3,4-Dihydropyran

[0345] DI PEA / V, / V-Diisopropylethylamine

[0346] DMA Dimethylacetamide

[0347] DMAP 4-Dimethylaminopyridine

[0348] DMF / V, / V-Dimethylformamide

[0349] DMF.DMA / V, / V-Dimethylformamide dimethyl acetal

[0350] DMSO Dimethyl sulfoxide

[0351] EDCi 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide

[0352] Et3N Triethylamine

[0353] EtOAc Ethyl acetate

[0354] EtOH Ethanol eq Equivalent

[0355] FBS Fetal bovine serum

[0356] GO Gas Chromatography h hour

[0357] HATU 1-[Bis(dimethylamino)methylene]-1 / 7-1 ,2,3-triazolo[4,5-b]pyridinium 3- oxide hexafluorophosphate

[0358] HOBt Hydroxybenzotriazole AGO-P3616PCT Application as filed

[0359] HPLC High-performance liquid chromatography

[0360] 1H-NMR Proton nuclear magnetic resonance

[0361] / PrOH Isopropanol

[0362] KHMDS Potassium bis(trimethylsilyl)amide

[0363] L Litre

[0364] LC Liquid chromatography

[0365] M Molar concentration

[0366] MeCN Acetonitrile

[0367] MeOH Methanol

[0368] MsOH Methanesulfonic acid min minutes

[0369] MS Mass spectroscopy

[0370] Muk 2-Chloro-1 -methylpyridinium iodide

[0371] NBS / V-Bromosuccinimide PdCI2(dtbpf) [1,T-Bis(di-tert-butylphosphino)ferrocene]dichloropalladium(ll)

[0372] PCy3T ricyclohexylphosphine

[0373] Pd2(dba)3Tris(dibenzylideneacetone)dipalladium(0)

[0374] Pd(PPh3)4Tetrakis(triphenylphosphine)palladium(0) pH Potential of Hydrogen PTFE Polytetrafluoroethylene

[0375] Rt Retention time

[0376] TFA Trifluoroacetic acid

[0377] TGF Transforming growth factor-p

[0378] THF Tetrahydrofuran THP 2-Tetrahydropyranyl

[0379] UPLC Ultra high-performance liquid chromatography

[0380] UV Ultraviolet

[0381] Experimental

[0382] The invention is illustrated by the compounds described below. The following examples describe the laboratory synthesis of specific compounds of the invention and are not meant to limit the scope of the invention in any way with respect to compounds or processes. It is understood that, although specific reagents, solvents, temperatures and time periods are used, there are many possible equivalent alternatives that can be used to produce similar results. This invention is meant to include such equivalents. AGO-P3616PCT Application as filed

[0383] Starting materials, reagents and solvents were obtained from commercial suppliers and used without further purification unless otherwise stated. Unless otherwise stated, all compounds with chiral centres are racemic. Where reactions are described as having been carried out in a similar manner to earlier more completely described reactions, the general reaction conditions used were essentially the same. Work up conditions used were of the types standard in the art, but may have been adapted from one reaction to another. The starting material may not necessarily have been prepared from the batch referred to. Compounds synthesised may have various purities, ranging from for example 85% to 99%. Calculations of number of moles and yield are in some cases adjusted for this.

[0384] Analytical Equipment

[0385] Reagents, solvents and starting products were acquired from commercial sources. The term “concentration” refers to the vacuum evaporation using a Buchi rotavapor. When indicated, the reaction products were purified by using Biotage Selekt. automated flash system with the indicated solvent system. The spectroscopic data were measured in a Varian Mercury 300 spectrometer. The HPLC-MS were performed on a Waters instrument equipped with an Alliance 2795 separation module, a UV-Vis W 2996 detector and a micromass ZQ 200 with electrospray ionization. The UPLC-MS were performed on a Water Acquity H-Class system, equipped with a PDA detector and a QDa detector with electrospray ionization. The GC-MS were performed on a Agilent 7820A instrument equipped with an 5977E mass spectrometer.

[0386] INTERMEDIATES Intermediate 1 (lnt-1): tert-butyl (2R,6S)-4-(2-hydroxyethyl)-2,6-dimethylpiperazine-1- carboxylate

[0387] A solution of tert-butyl cis-2,6-dimethylpiperazine-1-carboxylate (700 mg, 3.26 mmol, 1 eq), 2- Bromoethanol (300 pL, 4.232 mmol, 1.3 eq) and K2CO3 (1.33 g, 9.62 mmol, 2.95 eq) in MeCN (14mL) was stirred at reflux for 22 h. The reaction mixture was filtered and washed with MeCN (20 mL). The filtrates were concentrated under vacuum and the residue was dissolved in MeCN and concentrated under vacuum again to obtain tert-butyl (2R,6S)-4-(2-hydroxyethyl)- 2, 6-dimethylpiperazine-1 -carboxylate (848 mg, 100%) as a yellow oil, which was then used in AGO-P3616PCT Application as filed the next step without further purification.1H-NMR (300 MHz, CDCh): 6 = 4.13 (t, J = 6.2 Hz, 2H), 3.64 (s, 2H), 2.68 (d, J = 11.3 Hz, 2H), 2.53 (d, J = 5.8 Hz, 2H), 2.34 - 2.16 (m, 2H), 1.46 (s, 9H), 1.30 (d, J = 6.9 Hz, 6H). GC-MS: Rt 8.028 m / z 258.2 [M], (Method A-GC-MS)

[0388] Intermediate 2 (lnt-2): tert-butyl 4-((2-hydroxyethyl)amino)piperidine-1 -carboxylate MeOH

[0389] 2 -Aminoethanol (364 pL, 6.018 mmol, 1.2 eq) and NaBHsCN (474 mg, 7.527 mmol, 1.5 eq) were added to a cooled solution of / V-Boc-piperidin-4-one (1 g, 5.018 mmol, 1 eq) in MeOH (32 mL). The reaction mixture was stirred at 0 °C for 15 min and then at room temperature for 17 h. The crude volatiles were removed under reduced pressure, water (60 mL) was added, and the aqueous layer was extracted with a mixture of CH2Ch / iPrOH 30% (4 x 60 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and volatiles were removed under reduced pressure to yield the crude of fert-butyl 4-((2- hydroxyethyl)amino)piperidine-1 -carboxylate (1.226 g, 100%) as a yellow oil, which was used in the next step without further purification.

[0390] Table 1 : Intermediates 12, 52 and 53 were synthesised via an analogous route to

[0391] Intermediate 2. AGO-P3616PCT Application as filed

[0392] Intermediate 3 (lnt-3): tert-butyl 4-((tert-butoxycarbonyl)amino)-4-(2- hydroxyethyl)piperidine-1 -carboxylate oc

[0393] BOC2O (500 mg, 2.29 mmol, 2.09 eq) and Et3N (690 pL, 4.95 mmol, 4.53 eq) were added to an ice cooled suspension of 2-(4-Aminopiperidin-4-yl)ethan-1-ol dihydrochloride (250 mg, 1.093 mmol, 1 eq) in CH2CI2 (15 mL) and was stirred at room temperature for 16 h. Reaction mixture was poured into brine (50 mL) and the aqueous layer was extracted with CH2CI2 (2x50 mL). Combined organic layers were dried over anhydrous sodium sulfate, filtered and volatiles were removed under reduced pressure. The crude product was purified by flash column chromatography (Silica, ChLCh / MeOH 5-8%, dry loading) afforded tert-butyl 4-((tert- butoxycarbonyl)amino)-4-(2-hydroxyethyl)piperidine-1 -carboxylate (290 mg, 77%) as a clear oil.1H NMR (300 MHz, CDCI3) 6 = 4.43 (s, 1 H), 4.31 (t, J = 5.6 Hz, 1 H), 3.83 - 3.70 (m, 4H), 3.47 (t, J = 6.3 Hz, 2H), 2.07 (d, J = 14.0 Hz, 2H), 1.91 (d, J = 5.9 Hz, 2H), 1.61 - 1.52 (m, 2H), 1.52 - 1.40 (m, 18H). HPLC-MS: Rt 2.813 M / Z 345.1 [M+HJ+. (Method A-HPLC) AGO-P3616PCT Application as filed

[0394] Table 2: Intermediates 4-11 were synthesised via an analogous route to Intermediate 3. AGO-P3616PCT Application as filed AGO-P3616PCT Application as filed

[0395] Intermediate 13 (lnt-13): 7-bromo-2-methyl-1,5-naphthyridine

[0396] A solution of crotonaldehyde (12.02 mL, 145.07 mmol, 2.51 eq) in toluene (50 mL) was dropwise added to a solution of 3-amino-5-bromopyridine (10 g, 57.78 mmol, 1 eq) in HCI (aqueous solution 6M, 1 L). The resulting mixture was stirred at reflux for 16 h. The reaction was allowed to reach room temperature and was slowly poured to an ice bath cooled solution of NaOH (aqueous solution 6N, 1 L), then it was extracted with CH2CI2 (2x500 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The crude was purified by flash chromatography on SiC>2 (5%-10% EtOAc / hexanes) to afford 7-bromo-2-methyl-1 ,5-naphthyridine (3.4 g, 26%) as a brown solid.1H-NMR (300 MHz, DMSO-cfe): 6 = 8.97 (s, 1 H), 8.60 (s, 1 H), 8.30 (d, J = 8.6 Hz, 1 H), 7.70 (d, J = 8.6 Hz, 1 H), 2.85 - 2.56 (m, 3H). HPLC-MS: Rt 2.493 m / z 223.0-225.0 [M+H]+. (Method B-HPLC)

[0397] Intermediate 14 (lnt-14): 2-(7-bromo-1,5-naphthyridin-2-yl)-1-(5-chloro-2- fluorophenyl)ethan-1 -one

[0398] Described in WO 2020 / 123453 page 149

[0399] To a solution of 7-bromo-2-methyl-1 ,5-naphthyridine (lnt-13) (6 g, 26.897 mmol, 1 eq) in THF (162 mL) was added methyl 5-chloro-2-fluorobenzoate (15.217 g, 80.691 mmol, 3 eq) under

[0400] N2 atmosphere. The solution was cooled at -78 °C (internal temperature -70°C) and then KHMDS (solution 1M in THF, 53.8 mL, 53.795 mmol, 2 eq) was dropwise added keeping the internal temperature bellow -50 °C. The suspension was stirred at -78 °C (-65 °C) for 20 min and then at room temperature (Ta< 15 °C) for another 1 h. The mixture was quenched with H2O (300 mL) keeping the internal temperature bellow 15 °C. Suspension was filtered and the AGO-P3616PCT Application as filed filter cake was triturated with 15% EtOAc / Hexanes (2x30 mL) and rinsed with n-pentane (2x80 mL) to afford 2-(7-bromo-1 ,5-naphthyridin-2-yl)-1-(5-chloro-2-fluorophenyl)ethan-1-one (9 g, 88%) as an orange-yellowish solid.1H-NMR (300 MHz, CDCI3): 6 = 8.70 (d, J = 2.1 Hz, 1 H), 8.09 (s, 1 H), 7.98 (d, J = 9.2 Hz, 1 H), 7.92 (dd, J = 6.5, 2.7 Hz, 1 H), 7.35 (dd, J = 7.9, 4.2 Hz, 1 H), 7.22 (d, J = 9.3 Hz, 1 H), 7.13 - 7.04 (m, 1 H), 6.28 (s, 1 H), 3.89 (s, 1 H). HPLC-MS: Rt 3.504 m / z 379.0-381.0 [M+HJ+. (Method B-HPLC)

[0401] Intermediate 15 (lnt-15): 7-bromo-2-(3-(5-chloro-2-fluorophenyl)-1H-pyrazol-4-yl)-1,5- naphthyridine

[0402] Described in WO 2020 / 123453 page 150

[0403] A solution of 2-(7-bromo-1 ,5-naphthyridin-2-yl)-1-(5-chloro-2-fluorophenyl)ethan-1-one (Int- 14) (3.79 g, 9.98 mmol, 1 eq) in DMF.DMA (95 mL) was stirred at reflux for 16 h. The reaction mixture was concentrated to dryness, redissolved in MeCN (20 mL) and concentrated again. This procedure was repeated two more times. The crude was dissolved in MeCN (69 mL) and AcOH (4.17 mL, 72.87 mmol, 7.3 eq) and NH2NH2H2O (2.77 mL, 56.91 mmol, 5.7 eq) were added to reaction mixture. The suspension resulting was stirred at room temperature for 48 h, filtered and was washed with H2O (3x40 mL), MeCN (3x10 mL) and then rinsed with n-pentane (2x 20 mL) to afford 7-bromo-2-(3-(5-chloro-2-fluorophenyl)-1 / 7-pyrazol-4-yl)-1 ,5- naphthyridine (2.68 g, 67%) as an ochre solid.1H-NMR (300 MHz, DMSO-cfe): 5 = 13.60 (s, 1 H), 8.93 (d, J = 2.2 Hz, 1 H), 8.65 (s, 1 H), 8.34 (d, J = 8.9 Hz, 1 H), 8.13 (s, 1 H), 7.93 (d, J = 8.8 Hz, 1 H), 7.86 - 7.12 (m, 3H). HPLC-MS: Rt 3.017 m / z 383.0-385.1 [M+HJ+. (Method B- HPLC)

[0404] Intermediate 16 (lnt-16): 7-bromo-2-(3-(5-chloro-2-fluorophenyl)-1-(tetrahydro-2H- pyran-2-yl)-1H-pyrazol-4-yl)-1,5-naphthyridine

[0405] A solution of 7-bromo-2-(3-(5-chloro-2-fluorophenyl)-1 / 7-pyrazol-4-yl)-1 ,5-naphthyridine (lnt- 15) (2.79 g, 6.91 mmol, 1 eq), DHP (9.46 mL, 103.68 mmol, 15 eq) and MsOH (269 pL, 4.14 mmol, 0.6 eq) in THF (31 mL) was stirred at reflux for 20 h. The reaction mixture was allowed to reach room temperature, diluted with NaHCCh (aqueous saturated solution, 100 mL) and AGO-P3616PCT Application as filed extracted with EtOAc (3x75 mL). The crude product was purified by flash column chromatography on silica gel (15— >30% EtOAc / Hexanes) afforded 7-Bromo-2-(3-(5-chloro-2- fluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1 / 7-pyrazol-4-yl)-1,5-naphthyridine (3.06 g, 91%) as an orange solid.1H-NMR (300 MHz, DMSO-cfe): 6 = 8.95 (d, J = 2.3 Hz, 1 H), 8.81 (s, 1 H), 8.36 (d, J=8.9Hz, 1H), 8.13 (d, J= 2.3 Hz, 1H), 7.95 (d, J=8.9Hz, 1H), 7.63- 7.51 (m, 2H), 7.29 (t, J= 9.1 Hz, 1H), 5.55 (d, J= 9.6 Hz, 1H), 3.99 (d, J= 11.7 Hz, 1H), 3.69 (dt, J= 11.9, 6.4 Hz, 1H), 2.18 (d, J= 12.1 Hz, 2H), 2.09-1.91 (m, 1H), 1.58 (s, 3H).HPLC-MS: Rt 3.649 m / z 488.8 [M+H]+. (Method A-HPLC)

[0406] Table 3: Intermediates 18, 23, 25 and 26 were synthesised via an analogous route to

[0407] Intermediate 16. AGO-P3616PCT Application as filed

[0408] Intermediate 17 (lnt-17): 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)-1 ,5- naphthyridine-3-carbonitrile

[0409] A suspension of 7-bromo-2-(3-(5-chloro-2-fluorophenyl)-1 / 7-pyrazol-4-yl)-1 ,5-naphthyridine (lnt-15) (3.63 g, 8.99 mmol, 1 eq) and Zn(CN)2(1.60 g, 13.62 mmol, 1.52 eq) in DMF (33 mL) was degassed for 5 min. Then, Pd(PPha)4 (1.04 g, 0.90 mmol, 0.1 eq) was added and the suspension was stirred under microwave irradiation at 150 °C for 45 min. The reaction mixture was allowed to reach room temperature, EtOAc (100 mL) was added, and the suspension was filtered through celite washing with EtOAc (2 x 50 mL). The filtrates were washed with water (2 x 50 mL). The aqueous layer was extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by flash column chromatography on silica gel (2^6% MeOH / CH2Cl2, dry loading). The obtained solid was slurred with CH2Cl2 (30 mL), filtered, and washed with CH2CI2 (2 x 15 mL) to afford 6-(3-(5-Chloro-2-fluorophenyl)-7 / 7-pyrazol-4-yl)-1 ,5-naphthyridine-3- carbonitrile (1.43 g, 45%) as a beige solid.1H-NMR (300 MHz, DMSO-cfe): 6 = 9.14 (d, J = 1.9 Hz, 1 H), 8.60 (s, 1 H), 8.50 (d, J = 1 .9 Hz, 1 H), 8.42 (d, J = 8.9 Hz, 1 H), 8.04 (d, J = 9.0 Hz, 1 H), 7.66 - 7.49 (m, 2H), 7.30 (t, J= 9.1 Hz, 1 H). UPLC-MS: Rt 1.851 m / z 350.1-352.1 [M+H]+. (Method A-UPLC) AGO-P3616PCT Application as filed

[0410] Intermediate 19 (lnt-19): 6-(3-(5-chloro-2-fluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)- 1H-pyrazol-4-yl)-1,5-naphthyridine-3-carboxylic acid

[0411] To a solution of 6-(3-(5-chloro-2-fluorophenyl)-1-(tetrahydro-2 / 7-pyran-2-yl)-1 / 7-pyrazol-4-yl)- 1 ,5-naphthyridine-3-carbonitrile (lnt-18) (0.98 g, 2.26 mmol, 1 eq) in EtOH (25 mL) was added NaOH (aqueous solution 2.5M, 6.34 mL, 15.84 mmol, 7 eq). The solution was stirred at reflux for 16 h and allowed to reach room temperature. Water (50 mL) and EtOAc (50 mL) were added, and the layers were separated. The aqueous layer was extracted with EtOAc (2 x 20 mL). The aqueous layer was treated with HCI (aqueous solution 10%) until pH 5-6 was reached and extracted with EtOAc (3 x 40 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to yield crude 6-(3-(5-chloro-2- fluorophenyl)-1-(tetrahydro-2 / 7-pyran-2-yl)-1 / 7-pyrazol-4-yl)-1 ,5-naphthyridine-3-carboxylic acid (775 mg, 76%) as a beige solid, which was then used in the next step without further purification.1H-NMR (300 MHz, DMSO-cfe): 6 = 9.27 (d, J = 2.0 Hz, 1 H), 8.88 (s, 1 H), 8.42 (d, J = 8.9 Hz, 1 H), 8.29 (d, J = 2.1 Hz, 1 H), 8.06 (d, J= 8.9 Hz, 1 H), 7.71 - 7.51 (m, 2H), 7.30 (t, J = 9.1 Hz, 1 H), 5.62 - 5.50 (m, 1 H), 4.06 - 3.94 (m, 1 H), 3.77 - 3.60 (m, 1 H), 2.28 -1.65 (d, J = 42.0 Hz, 6H). HPLC-MS: Rt 2.715 m / z 452.9-454.8 [M+H]+. (Method A-HPLC)

[0412] Table 4: Intermediates 22 and 24 were synthesised via an analogous route to Intermediate 19. AGO-P3616PCT Application as filed

[0413] Intermediate 20 (lnt-20): 6-(3-bromo-5-(5-chloro-2-fluorophenyl)-1H-pyrazol-4-yl)-1,5- naphthyridine-3-carbonitrile

[0414] To a solution of 6-(3-(5-Chloro-2-fluorophenyl)-1 / 7-pyrazol-4-yl)-1 ,5-naphthyridine-3- carbonitrile (lnt-17) (55 mg, 0.157 mmol, 1 eq) in DMF (1 mL) was added NBS (55 mg, 0.309 mmol, 2 eq). The solution was stirred at 80 °C for 2 h. The reaction mixture was diluted with CH2CI2 and concentrated to dryness. The crude product was purified by flash column chromatography on silica gel (MeOH:CH2Ch 2% to 10%) to give 6-(5-bromo-3-(5-chloro-2- fluorophenyl)-1 / 7-pyrazol-4-yl)-1 ,5-naphthyridine-3-carbonitrile (51 mg, 76%) as a beige solid.1H NMR (300 MHz, DMSO-cfe) 6 = 9.22 (d, J = 1.9 Hz, 1 H), 8.77 (s, 1 H), 8.53 (d, J = 8.8 Hz, 1 H), 8.01 (d, J = 8.9 Hz, 1 H), 7.72 (d, J = 5.8 Hz, 1 H), 7.55 (s, 1 H), 7.24 (t, J = 9.3 Hz, 1 H). UPLC-MS: Rt 2.338 min m / z 426.0-428.0 [M-H]-. (Method B-UPLC)

[0415] Intermediate 21 (lnt-21): 6-(3-(5-chloro-2-fluorophenyl)-5-methyl-1H-pyrazol-4-yl)-1,5- naphthyridine-3-carbonitrile AGO-P3616PCT Application as filed

[0416] SnMe4 (200 pL, 1.443 mmol, 3.09 eq) was added to a degassed solution of 6-(5-bromo-3-(5- chloro-2-fluorophenyl)-1 / 7-pyrazol-4-yl)-1 ,5-naphthyridine-3-carbonitrile (lnt-20) (200 mg, 0.466 mmol, 1 eq) and Pd(PhaP)4 (50 mg, 0.043 mmol, 0.09 eq) in DMF (2 mL). The solution was stirred at 110 °C for 16 h. The reaction mixture was diluted with CH2CI2 (10mL) and was filtered through a PTFE 0.45 urn syringe filter, washing with more CH2CI2 (5 mL). The volatiles were removed under reduced pressure. The crude product was purified by flash column chromatography on silica gel (MeOH / CFLCh 0% to 5%, dry loading) afforded 6-(3-(5-Chloro- 2-fluorophenyl)-5-methyl-1 / 7-pyrazol-4-yl)-1 ,5-naphthyridine-3-carbonitrile (192 mg, 98%) as a white solid.1H NMR (300 MHz, DMSO-cfe) 5 = 13.39 (s, 1 H), 9.18 (d, J = 2.0 Hz, 1 H), 8.84 (s, 1 H), 8.37 (d, J = 8.9 Hz, 1 H), 7.61 - 7.44 (m, 3H), 7.20 (t, J = 9.5 Hz, 1 H), 2.56 (s, 3H). HPLC-MS: Rt 2.883 min m / z 362.2-364.0 [M-H]-. (Method A-HPLC)

[0417] Intermediate 27 (lnt-27): 3-Bromo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole A mixture of 3-Bromopyrazole 95% (3 g, 20.411 mmol, 1 eq), 5-Chloro-2-fluorophenylboronic acid (4.271 g, 24.494 mmol, 1.2 eq), PdCI2(dtbpf) (3.326 g, 5.103 mmol, 0.25 eq) and K3PO4(8.666 g, 40.826 mmol, 2 eq) in a mixture of dioxane (140 mL) and H2O (15 mL), was degassed and stirred at 90 °C for 16 h. The crude volatiles were removed under reduced pressure. Then, the mixture was diluted with EtOAc (80 mL) and washed with H2O (80 mL). The aqueous layer was extracted with EtOAc (3x80 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and volatiles were removed under reduced pressure. The crude product by purified by flash column chromatography on silica gel (EtOAc / hexane 10% to 40%) afforded 3-(5-chloro-2-fluorophenyl)-1 / 7-pyrazole (2.415 g, 60%) as a white solid.1H NMR (300 MHz, CDCh) 5= 7.88 (dd, J = 6.5, 2.7 Hz, 1 H), 7.67 (d, J = 2.3 Hz, 1 H), 7.29 - 7.21 (m, 1 H), 7.10 (dd, J = 10.6, 8.8 Hz, 1 H), 6.76 (t, J = 2.5 Hz, 1 H). GC-MS: Rt 8.161 m / z 196.1 [MJ.

[0418] (Method A-GC) AGO-P3616PCT Application as filed

[0419] Table 5: Intermediates 28-31 were synthesised via an analogous route to Intermediate 27. AGO-P3616PCT Application as filed

[0420] Intermediate 32 (lnt-32): 4-bromo-3-(5-chloro-2-fluorophenyl)-1H-pyrazole

[0421] To a solution of 3-(5-chloro-2-fluorophenyl)-1 / 7-pyrazole (lnt-27) (2.81 g, 14.292 mmol, 1 eq) in CH2CI2 (71 mL) was added NBS (2.544 g, 14.293 mmol, 1 eq). The solution was stirred at room temperature for 3 hv More NBS (254.4 mg, 1.429 mmol, 0.1 eq) was added continue with the stirring for another 2 h. The crude product was purified by flash column chromatography on silica gel (EtOAc / hexane 10% to 50%) afforded 4-bromo-3-(5-chloro-2-fluorophenyl)-1 / 7- pyrazole (3.44 g, 87%) as a white solid.1H NMR (300 MHz, CDCI3) 6= 7.81 (dd, J = 6.4, 2.6 Hz, 1 H), 7.68 (s, 1 H), 7.37 (ddd, J = 8.8, 4.4, 2.7 Hz, 1 H), 7.15 (dd, J= 10.1 , 8.9 Hz, 1 H). GC- MS: Rt 9.216 m / z 276.0 [MJ.Method A-GC-MS

[0422] Table 6: Intermediates 33-36 were synthesised via an analogous route to Intermediate 32. AGO-P3616PCT Application as filed

[0423] Intermediate 37 (lnt-37): methyl 6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)quinoline-4-carboxylate

[0424] A suspension of methyl 6-bromoquinoline-4-carboxylate (320 mg, 1.202 mmol, 1 eq), B2pin2 (320 mg, 1.26 mmol, 1.05 eq), KOAc (177 mg, 1.803 mmol, 1.5 eq), PCys (40 mg, 0.142 mmol, 0.12 eq) and Pd2(dba)s (57 mg, 0.059 mmol, 0.05 eq) dioxane (in 8 mL) was degassed and stirred at 100 °C for 16 h After cooling to room temperature, the reaction mixture was filtered through Celite and the filtrate was concentrated to give methyl 6-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)quinoline-4-carboxylate as an orange oil which was used in the next step without further purification. GC-MS: Rt 10.816 m / z 313.2[M], Method A-GC-MS AGO-P3616PCT Application as filed

[0425] Intermediate 38 (lnt-38): Ethyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline- 3-carboxylate

[0426] Intermediate 38 was prepared following the procedure as described for Intermediate 37.

[0427] GC-MS: Rt 11.391 m / z 327.2[M], Method A-GC-MS

[0428] Intermediate 39 (lnt-39): Methyl 6-(3-(5-chloro-2-fluorophenyl)-1-(tetrahydro-2H-pyran-

[0429] 2-yl)-1H-pyrazol-4-yl)quinoline-4-carboxylate

[0430] To a solution of 4-Bromo-3-(5-chloro-2-fluorophenyl)-1-(tetrahydro-2 / 7-pyran-2-yl)-1 / 7- pyrazole (lnt-33) (4.094 g, 11.384 mmol, 1.15 eq), methyl 6-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)quinoline-4-carboxylate (lnt-37) (3.1 g, 9.899 mmol, 1 eq) and PdCh(dtbpf) (645.2 mg, 0.989 mmol, 0.1 eq) in a mixture of dioxane (85 mL) and H2O (9 mL), degassed, K3PO4 (4.203 g, 19.8 mmol, 2 eq) was added and the reaction mixture was stirred at 90 °C for 16 h. The crude volatiles were removed under reduced pressure, diluted with EtOAc (80 mL) and washed with H2O (100 mL). The aqueous layer was extracted with EtOAc (2 x 80 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and volatiles were removed under reduced pressure. The crude product was purified by flash column chromatography on silica gel (EtOAc / Hexane 10% to 100%) afforded methyl 6-(3-(5-chloro-2- fluorophenyl)-1-(tetrahydro-2 / 7-pyran-2-yl)-1 / 7-pyrazol-4-yl)quinoline-4-carboxylate (4.01 g, 87%) as a brown solid.1H NMR (300 MHz, DMSO-cfe) 6= 8.98 (d, J = 4.5 Hz, 1 H), 8.54 (s, 1 H), 8.31 (s, 1 H), 8.07 (d, J = 8.8 Hz, 1 H), 7.88 - 7.77 (m, 2H), 7.64 - 7.52 (m, 2H), 7.28 (t, J = 9.0 Hz, 1 H), 5.54 (d, J = 9.7 Hz, 1 H), 4.08 - 3.96 (m, 1 H), 3.83 (s, 3H), 3.77 - 3.62 (m, 1 H), 2.29 - 2.12 (m, 1 H), 2.07 - 1.95 (m, 2H), 1.80 - 1.53 (m, 3H). HPLC-MS: Rt 3.363 m / z 466.2- 468.0 [M+HJ+. (Method A-HPLC) AGO-P3616PCT Application as filed

[0431] Table 7: Intermediate 40 was synthesised via an analogous route to Intermediate 39. AGO-P3616PCT Application as filed

[0432] Intermediate 41 (lnt-41): 6-(3-(5-Chloro-2-fluorophenyl)-1H-pyrazol-4-yl)quinoline-4- carboxylic acid

[0433] To a solution of methyl 6-(3-(5-chloro-2-fluorophenyl)-1 / 7-pyrazol-4-yl)quinoline-4-carboxylate (Ex-50) (1.705 g, 4.465 mmol, 1 eq) in EtOH (30 mL) was added NaOH (aqueous solution 2,5M, 17.863 mL, 44.657 mmol, 10 eq). The solution was stirred at room temperature for 2 h, and the crude volatiles were removed under reduced pressure. The reaction mixture was diluted with H2O (100 mL), washed with CH2CI2 (3 x 80 mL) and then acidified until pH = 4. The aqueous layer was extracted with a 30% iPrOH / CH2Ch mixture (4 x 100 mL) and the combined organic layers were dried over Na2SO4, filtered and volatiles were removed under reduced pressure to yield the crude 6-(3-(5-chloro-2-fluorophenyl)-1 / 7-pyrazol-4-yl)quinoline- 4-carboxylic acid (1.552 g, 94%) as a beige solid.1H NMR (300 MHz, DMSO-cfe) 6= 8.77 (d, J = 4.3 Hz, 1 H), 8.67 (s, 1 H), 8.09 (s, 1 H), 7.86 (d, J = 8.7 Hz, 1 H), 7.60 - 7.43 (m, 4H), 7.26 (t, J = 9.2 Hz, 1 H). HPLC-MS: Rt 2.270 m / z 368.1-370.0 [M+HJ+. (Method A-HPLC).

[0434] Table 8: Intermediates 42-46 were synthesised via an analogous route to Intermediate 41. AGO-P3616PCT Application as filed AGO-P3616PCT Application as filed

[0435] Intermediate 47 (lnt-47): A / -((3-chloro-4-fluorophenyl)(tosyl)methyl)formamide

[0436] 3-Chloro-4-fluorobenzaldehyde (38 g, 227.678 mmol, 1 eq), p-toluenesulfinic acid sodium salt (62.000 g, 330.557 mmol, 1.45 eq), formamide (21.7 mL, 546.347 mmol, 2.4 eq) and TMSCI (67.00 mL, 527.898 mmol, 2.32 eq) were mixed in MeCN (295 mL). The solution was stirred at 55 °C for 18 h, cooled with the aid of an ice / water bath and water (700 mL) was added over a period of 30 min. The mixture was stirred at room temperature for 1 h and the precipitated was filtered, washing with water (3x200 mL) and with n-heptane (200 mL). The solid was slurried in MTBE (200 mL), stirred at low temperature for 1 h, filtered and washed with MTBE (100 mL) and with n-pentane (2x200 mL). The solid was slurried again in MTBE (140 mL) and stirred at low temperature for 1 h, filtered, washing with MTBE (20 mL) and with n-pentane (2x100 mL) to afford N-((3-chloro-4-fluorophenyl)(tosyl)methyl)formamide (32.37 g, 42%) as a white solid.1H NMR (300 MHz, CDCI3) 5 8.12 (s, 1 H), 7.73 (d, J = 7.9 Hz, 2H), 7.53 - 7.43 (m, 1 H), 7.35 (d, J = 8.1 Hz, 2H), 7.15 (q, J = 7.8 Hz, 2H), 6.27 (d, J = 10.4 Hz, 1 H), 2.45 (s, 3H). HPLC-MS: Rt 2.847 m / z 359.0-361.5 [M+H]+ (Method A-HPLC).

[0437] Intermediate 48 (lnt-48): 2-chloro-1-fluoro-4-(isocyano(tosyl)methyl)benzene

[0438] To an ice cooled solution of / V-((3-chloro-4-fluorophenyl)(tosyl)methyl)formamide (lnt-47) (23.6 g, 69.049 mmol, 1 eq) in THF (170 mL) POOL (19.367 mL, 207.144 mmol, 3 eq) was added follow by the addition of 2,6-lutidine (96.507 mL, 828.594 mmol, 12 eq) over a period of 30 min, keeping the internal temperature below 15 °C and the reaction was stirred at room temperature for 20 h. The reaction mixture was cooled to an internal temperature of 10 °C with the aid of an ice / water bath and diluted with EtOAc (480 mL). Na^PCL (aqueous solution 10%, 480 mL), was slowly added over a period of 30 min and keeping the internal temperature below 15°C and the layers were separated. Organic layer was washed with water (480 mL) and with NaCI (aqueous solution 5%, 480 mL), dried over anhydrous sodium sulfate, filtered and concentrated to a final volume of ca. 300 mL and n-heptane was added (250 mL). This AGO-P3616PCT Application as filed procedure was repeated twice. To the resulting suspension n-heptane (100 mL) was added and the mixture was stirred overnight at room temperature. Solid was filtered washing with n- heptane dried to afford 2-chloro-1-fluoro-4-(isocyano(tosyl)methyl)benzene (19.6 g, 88%) as a cream solid.1H NMR (300 MHz, CDCI3) 5 7.66 (d, J = 8.0 Hz, 2H), 7.38 (d, J = 7.6 Hz, 3H), 7.19 (t, J = 8.4 Hz, 2H), 5.54 (s, 1 H), 2.49 (s, 3H). HPLC-MS: Rt 3.143 m / z 322.1-324.0 [M- H]+. (Method B-HPLC)

[0439] Intermediate 49 (lnt-49): 2-(4-(3-Chloro-4-fluorophenyl)-1H-imidazol-1-yl)ethan-1-ol

[0440] 2-Aminoethanol (1.401 mL, 23.165 mmol, 1.5 eq) was added to an ice cooled suspension of glyoxylic acid (aqueous solution 50%, 9,07M, 2.043 mL, 18.53 mmol, 1.2 eq) and K2CO3 (5.336 g, 38.609 mmol, 2.5 eq) in DMF (10 mL). The reaction was stirred at room temperature for 4 h. 2-Chloro-1-fluoro-4-(isocyano(tosyl)methyl)benzene (5.000 g, 15.443 mmol, 1 eq) was added and reaction mixture was stirred at room temperature for 20 h. H2O (100 mL) was added and extracted with CH2CI2 (2x100 mL) The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. Purification of the crude product by flash column chromatography (Silica, 2-10% MeOH / CH2CI2, dry loading) afforded 2-(4-(3- Chloro-4-fluorophenyl)-1 / 7-imidazol-1-yl)ethan-1-ol (1.96 g, 53%) as a beige solid.1H NMR (300 MHz, DMSO-d6) 5 7.87 (dd, J = 7.3, 2.2 Hz, 1 H), 7.81 - 7.57 (m, 3H), 7.37 (t, J = 9.0 Hz, 1 H), 4.98 (t, J = 5.2 Hz, 1 H), 4.00 (t, J = 5.4 Hz, 2H), 3.67 (q, J = 5.3 Hz, 2H). HPLC-MS: Rt 2.363 m / z 241.0-242.9 [M+HJ+. (Method A-HPLC)

[0441] Intermediate 50 (lnt-50): 2-(5-bromo-4-(3-chloro-4-fluorophenyl)-1H-imidazol-1-yl)ethan- 1-ol

[0442] To an ice cooled suspension of 2-(4-(3-chloro-4-fluorophenyl)-1 / 7-imidazol-1-yl)ethan-1-ol (lnt-49) (1.02 g, 4.238 mmol, 1 eq) in CH2CI2 (34 mL) was added a solution of NBS (754 mg, 4.236 mmol, 1 eq) in CH2CI2 (34 mL) over a period of 10 min. The solution was stirred at 0 °C AGO-P3616PCT Application as filed for 1 h, quenched with saturated aqueous solution of Na2S20s (50 mL), extracted with CH2CI2 (2x50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. Purification of the crude product by flash column chromatography (SiC>2, 3-10% MeOH / CH2CI2) afforded 2-(5-bromo-4-(3-chloro-4- fluorophenyl)-1 / 7-imidazol-1-yl)ethan-1-ol (1.32 g, 97%) as a beige solid.1H NMR (300 MHz, DMSO-d6) 5 8.06 - 7.80 (m, 3H), 7.47 (t, J = 9.0 Hz, 1 H), 5.03 (t, J = 5.4 Hz, 1 H), 4.05 (t, J = 5.5 Hz, 2H), 3.66 (q, J = 5.4 Hz, 2H). HPLC-MS: Rt 2.694 m / z 319.1-322.9 [M+HJ+. (Method B-HPLC)

[0443] Intermediate 51 (lnt-51): tert-butyl (2 / ?,6 / ?)-4-(2-hydroxyethyl)-2,6-dimethylpiperazine-1- carboxylate

[0444] Intermediate 51 was synthesised in an analogous manner to Intermediate 1.

[0445] 1H NMR (300 MHz, CDCI3) 5 3.90 (td, J = 6.3, 3.9 Hz, 2H), 3.60 (t, J = 5.3 Hz, 2H), 2.53 (dtd, J = 22.8, 12.0, 4.6 Hz, 4H), 2.32 (dd, J = 11.4, 6.1 Hz, 2H), 1.47 (s, 9H), 1.31 (d, J = 6.4 Hz, 6H).GC-MS: Rt 8.073 m / z 258.2 [M], Method A-GC-MS

[0446] EXAMPLES

[0447] Example 1 (Ex-1): Methyl 6-(3-(5-chloro-2-fluorophenyl)-1H-pyrazol-4-yl)-1,5- naphthyridine-3-carboxylate

[0448] To a solution of 6-(3-(5-Chloro-2-fluorophenyl)-1-(tetrahydro-2 / 7-pyran-2-yl)-1 / 7-pyrazol-4-yl)- 1 ,5-naphthyridine-3-carboxylic acid (lnt-19) (70 mg, 0.154 mmol, 1 eq) in MeOH (1.5 mL) was added SOCI2 (33 mL, 0.454 mmol, 3 eq) at 0 °C. The solution was stirred at room temperature for 19 h. More SOCI2 (33 mL, 0.454 mmol, 3 eq) was added at 0 °C and then the mixture was stirred at 50 °C for 24 h. More SOCI2 (33 mL, 0.454 mmol, 3 eq) was added at 0 °C and then the mixture was stirred at 50 °C for 3 days. The crude volatiles were removed under reduced pressure. The residue was triturated with MeOH (2 mL) and filtered. The crude product was purified by flash column chromatography (C18, NH4HCO2+HCOOH (pH=4) / MeOH 35-55%, dry loading) and slurried with MeOH (1 mL) to afford methyl 6-(3-(5-chloro-2-fluorophenyl)-1- AGO-P3616PCT Application as filed

[0449] (tetrahydro-2 / 7-pyran-2-yl)-1 / 7-pyrazol-4-yl)-1 ,5-naphthyridine-3-carboxylate (31 mg, 52%) as a beige solid.1H NMR (300 MHz, DMSO-cfe) 6 = 13.62 (s, 1 H), 9.28 (s, 1 H), 8.71 (s, 1 H), 8.51 - 8.27 (m, 2H), 8.06 (d, J = 8.9 Hz, 1 H), 7.61 (d, J = 20.8 Hz, 2H), 7.48 - 7.19 (m, 1 H), 3.95 (s, 3H). UPLC-MS: Rt 3.553 m / z 383.1-385.1 [M+H]+. (Method C-UPLC)

[0450] Example 2 (Ex-2): Piperidin-4-ylmethyl 6-(3-(5-chloro-2-fluorophenyl)-1H-pyrazol-4-yl)- 1 ,5-naphthyridine-3-carboxylate

[0451] Step 1 :

[0452] 6-(3-(5-Chloro-2-fluorophenyl)-1-(tetrahydro-2 / 7-pyran-2-yl)-1 / 7-pyrazol-4-yl)-1 ,5- naphthyridine-3-carboxylic acid (lnt-19) (100 mg, 0.22 mmol, 1 eq), EDCi (67 mg, 0.33 mmol, 1.5 eq), DMAP (27 mg, 0.221 mmol, 1 eq) and 1- / V-Boc-4-Hydroxymethyl-piperidine (57 mg, 0.264 mmol, 1.2 eq) were mixed in CH2CI2 (2 mL). The solution was stirred at room temperature for 3,5 h under N2 atmosphere. The volatiles were removed under reduced pressure and the crude product was purified by flash column chromatography (C18, H2O+HCOOH (0.1 %) / MeCN 15% to100%, dry loading) afforded (1-(tert- butoxycarbonyl)piperidin-4-yl)methyl 6-(3-(5-chloro-2-fluorophenyl)-1-(tetrahydro-2 / 7-pyran- 2-yl)-1 / 7-pyrazol-4-yl)-1 ,5-naphthyridine-3-carboxylate (134 mg, 93%) as a yellowish oil.1H- NMR (300 MHz, DMSO-cfe): 6 = 9.28 (s, 1 H), 8.89 (s, 1 H), 8.43 (d, J = 8.6 Hz, 1 H), 8.19 - 7.95 (m, 1 H), 7.78 - 7.40 (m, 2H), 7.30 (s, 1 H), 5.57 (d, J = 9.4 Hz, 1 H), 4.23 (d, J = 6.5 Hz, 2H), 4.01 (d, J = 12.3 Hz, 3H), 3.72 (s, 1 H), 2.78 (s, 2H), 2.29 - 1.91 (m, 5H), 1.75 (d, J = 12.8 Hz, 3H), 1.60 (s, 2H), 1.41 (d, J = 4.0 Hz, 9H), 1.21 (d, J = 12.5 Hz, 2H). HPLC-MS: Rt 3.864 m / z 650.2-652.3 [M+H]+. (Method A-HPLC)

[0453] To a solution of (1-(tert-butoxycarbonyl)piperidin-4-yl)methyl 6-(3-(5-chloro-2-fluorophenyl)-1- (tetrahydro-2 / 7-pyran-2-yl)-1 / 7-pyrazol-4-yl)-1 ,5-naphthyridine-3-carboxylate (130 mg, 0.199 mmol, 1 eq) in dioxane (2 mL) was added HCI (dioxane solution 4M, 1.00 mL, 4 mmol, 20 eq). AGO-P3616PCT Application as filed

[0454] The solution was stirred at room temperature for 5,5 h, 4 mL of hexanes were added to the mixture and the solvent was decanted off. This operation was repeated 4 times, to afford the HCI salt of piperidin-4-ylmethyl 6-(3-(5-chloro-2-fluorophenyl)-1 / 7-pyrazol-4-yl)-1 ,5- naphthyridine-3-carboxylate (101 mg, 94%) as a yellow solid.1H NMR (300 MHz, DMSO-cfe) 5 = 9.32 (s, 1 H), 8.87 (s, 1 H), 8.63 (s, 2H), 8.48 - 8.36 (m, 2H), 8.05 (d, J = 9.0 Hz, 1 H), 7.78 - 7.50 (m, 2H), 7.33 (t, J = 9.2 Hz, 1 H), 4.28 (d, J = 6.0 Hz, 2H), 3.33 (d, J = 12.7 Hz, 4H), 2.92 (q, J = 11.7 Hz, 2H), 2.12 (s, 1H), 1.93 (d, J = 13.9 Hz, 2H), 1.68 - 1.47 (m, 2H). UPLC- MS: Rt 2.83 m / z 466.3 - 468.2 [M+HJ+. (Method C-UPLC)

[0455] Table 9: Examples 3-16 and 78 were synthesised via an analogous route to Example 2. AGO-P3616PCT Application as filed AGO-P3616PCT Application as filed AGO-P3616PCT Application as filed AGO-P3616PCT Application as filed AGO-P3616PCT Application as filed

[0456] Example 17 (Ex-17): 1-Methylpiperidin-4-yl 6-(3-(5-chloro-2-fluorophenyl)-1H-pyrazol-4- yl)-1,5-naphthyridine-3-carboxylate

[0457] Step 1 :

[0458] 6-(3-(5-Chloro-2-fluorophenyl)-1-(tetrahydro-2 / 7-pyran-2-yl)-1 / 7-pyrazol-4-yl)-1 ,5- naphthyridine-3-carboxylic acid (lnt-19) (100 mg, 0.22 mmol, 1 eq), HATLI (101 mg, 0.265 mmol, 1 .2 eq), DIPEA (56 pL, 0.327 mmol, 1.48 eq) and A / -Methyl-4-piperidinol (31 mg, 0.269 mmol, 1.22 eq) were mixed in CH2CI2 (2.2 mL) and the solution was stirred at room temperature for 20 h. The crude volatiles were removed under reduced pressure. Purification of the crude product by flash column chromatography (C18 20 g, 15% to100% H2O+0.1% HCOOH / MeCN, dry loading) afforded 1 -Methylpiperidin-4-yl 6-(3-(5-chloro-2-fluorophenyl)-1- (tetrahydro-2 / 7-pyran-2-yl)-1 / 7-pyrazol-4-yl)-1 ,5-naphthyridine-3-carboxylate (64 mg, 53%) as a white solid. UPLC-MS: Rt 3.717 m / z 550.3-552.3 [M+H]+. (Method C-UPLC)

[0459] A solution of 1 -Methylpiperidin-4-yl 6-(3-(5-chloro-2-fluorophenyl)-1-(tetrahydro-2 / 7-pyran-2- yl)-1 / 7-pyrazol-4-yl)-1 ,5-naphthyridine-3-carboxylate (64 mg, 0.116 mmol, 1 eq) and HCL (solution 4M in dioxane, 600 pL, 2.4 mmol, 20.63 eq) in dioxane (1.2 mL) was stirred at room temperature for 22 h. More HCI dioxane (solution 4M in dioxane, 150 pL, 0.6 mmol, 5.16 eq) was added and the mixture was stirred at room temperature for 1 h, filtered and washed with 5 mL of hexanes to afford the hydrochloride salt of 1 -Methylpiperidin-4-yl 6-(3-(5-chloro-2- fluorophenyl)-1 / 7-pyrazol-4-yl)-1 ,5-naphthyridine-3-carboxylate (56 mg, 103%) as a yellow solid.1H NMR (500 MHz, DMSO-cfe, 80 °C) 5= 10.51 (s, 1 H), 9.46 - 9.25 (m, 1 H), 8.53 (s, 1 H), 8.39 (dd, J = 8.9, 0.9 Hz, 1 H), 7.98 (d, J = 8.9 Hz, 1 H), 7.68 (dd, J = 6.5, 2.7 Hz, 1 H), 7.58 AGO-P3616PCT Application as filed

[0460] (ddd, J = 8.8, 4.3, 2.7 Hz, 1 H), 7.30 (t, J = 9.2 Hz, 1 H), 5.41 - 5.16 (m, 1 H), 3.58 - 3.12 (m, 4H), 2.92 - 2.75 (m, 3H), 2.36 - 2.07 (m, 4H). UPLC-MS: Rt 2.814 m / z 466.3-468.3 [M+H]+. (Method C-UPLC)

[0461] Table 10: Examples 18-20 were synthesised via an analogous route to Example 17. AGO-P3616PCT Application as filed

[0462] Example 21 (Ex-21): 2-((3S,5 / ?)-3,5-Dimethylpiperazin-1-yl)ethyl 6-(3-(5-chloro-2- fluorophenyl)-1H-pyrazol-4-yl)-1,5-naphthyridine-3-carboxylate

[0463] Step 1 :

[0464] 6-(3-(5-Chloro-2-fluorophenyl)-1-(tetrahydro-2 / 7-pyran-2-yl)-1 / 7-pyrazol-4-yl)-1 ,5- naphthyridine-3-carboxylic acid (lnt-19) (500 mg, 1.104 mmol, 1 eq), tert-butyl (2R,6S)-4-(2- hydroxyethyl)-2,6-dimethylpiperazine-1 -carboxylate (lnt-1) (356 mg, 1.377 mmol, 1.25 eq), 2- Chloro-1 -methylpyridinium iodide (Muk) (352 mg, 1.377 mmol, 1.25 eq) and DIPEA (387 pL, 2.26 mmol, 2.05 eq) were mixed in CH2CI2 (20 mL). The solution was stirred at 35 °C for 25 h under N2 atmosphere. More tert-butyl (2R,6S)-4-(2-hydroxyethyl)-2,6-dimethylpiperazine-1- carboxylate (171 mg, 0.661 mmol, 0.60 eq), Muk (169 mg, 0.661 mmol, 0.60 eq) and DIPEA (189 pL, 1.104 mmol, 1.00 eq) were added and the solution was stirred at 35 °C for 18 h under N2 atmosphere. NH4CI (aqueous saturated solution, 30 mL) and CH2CI2 (15 mL) were added, and the layers were separated. The aqueous layer was extracted with CH2CI2 (3 x 15 mL) and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Purification of the crude product by flash column chromatography (C18, H2O + HCOOH (pH 3) / MeCN 80% to 100%, dry loading) to afford 2- ((3S,5R)-4-(tert-butoxycarbonyl)-3,5-dimethylpiperazin-1-yl)ethyl 6-(3-(5-chloro-2- fluorophenyl)-1-(tetrahydro-2 / 7-pyran-2-yl)-1 / 7-pyrazol-4-yl)-1 ,5-naphthyridine-3-carboxylate (555 mg, 73%) as a yellow foam.1H-NMR (300 MHz, CDCI3): 5 = 9.42 (d, J = 2.0 Hz, 1 H), 8.82 (s, 1 H), 8.36 (s, 1 H), 8.28 (d, J = 8.8 Hz, 1 H), 7.77 - 7.63 (m, 1 H), 7.60 (d, J = 8.9 Hz, 1 H), 7.45 - 7.29 (m, 1 H), 7.13 - 6.82 (m, 1 H), 5.69 - 5.35 (m, 1 H), 4.56 (t, J = 5.7 Hz, 2H), 4.27 - 3.93 (m, 3H), 3.78 (s, 1 H), 2.96 - 2.57 (m, 4H), 2.38 - 2.03 (m, 5H), 1.86 - 1.50 (m, 3H), 1.45 (d, J = 3.2 Hz, 9H), 1.29 - 1.19 (m, 6H). UPLC-MS: Rt 3.292 m / z 693.5-695.5 [M+H]+. (Method B-UPLC) AGO-P3616PCT Application as filed

[0465] To a solution of 2-((3S,5R)-4-(tert-butoxycarbonyl)-3,5-dimethylpiperazin-1-yl)ethyl 6-(3-(5- chloro-2-fluorophenyl)-1-(tetrahydro-2 / 7-pyran-2-yl)-1 / 7-pyrazol-4-yl)-1 ,5-naphthyridine-3- carboxylate (555 mg, 0.8 mmol, 1 eq) in dioxane (8 mL) was added HCI (dioxane solution 4M, 4.00 mL, 16 mmol, 19.98 eq). The solution was stirred at room temperature for 17 h, 10 mL of hexanes were added to the mixture and the solvent was decanted off. This operation was repeated 4 times. Purification of the crude product by flash column chromatography (C18, NH4HCO2+HCOOH (pH 4) / MeCN 25% to 45%, dry loading) to afford the formate salt of 2- ((3S,5R)-3,5-dimethylpiperazin-1-yl)ethyl 6-(3-(5-chloro-2-fluorophenyl)-1 / 7-pyrazol-4-yl)-1 ,5- naphthyridine-3-carboxylate (368 mg, 76%) as a white solid.1H NMR (300 MHz, DMSO-cfe) 5= 9.25 (d, J = 2.1 Hz, 1 H), 8.61 (s, 1 H), 8.41 (d, J = 9.0 Hz, 1 H), 8.37 - 8.25 (m, 3H), 8.05 (d, J = 8.9 Hz, 1 H), 7.68 (dd, J = 6.2, 2.7 Hz, 1 H), 7.57 (ddd, J = 8.9, 4.3, 2.7 Hz, 1 H), 7.30 (t, J = 9.2 Hz, 1 H), 4.44 (t, J = 5.7 Hz, 2H), 2.85 (d, J = 9.3 Hz, 4H), 2.72 (t, J = 5.6 Hz, 2H), 1.77 (t, J = 11.1 Hz, 2H), 0.99 (d, J = 6.2 Hz, 6H). UPLC-MS: Rt 2.61 m / z 509.3 - 511 .3 [M+HJ+. (Method C-UPLC)

[0466] Table 11 : Examples 22 and 23 were synthesised via an analogous route to Example 21. AGO-P3616PCT Application as filed

[0467] Example 24 (Ex-24): 2-(Dimethylamino)ethyl 6-(3-(5-chloro-2-fluorophenyl)-5-methyl- 1H-pyrazol-4-yl)-1,5-naphthyridine-3-carboxylate 6-(3-(5-chloro-2-fluorophenyl)-5-methyl-1 / 7-pyrazol-4-yl)-1 ,5-naphthyridine-3-carboxylic acid (lnt-22) (80 mg, 0.208 mmol, 1 eq), 2-dimethylaminoethanol (43 mL, 0.427 mmol, 2.05 eq), Muk (74.8 mg, 0.292 mmol, 1.4 eq) and lutidine (49 mL, 0.42 mmol, 2.05 eq) were mixed CH2CI2 (in 18 mL)and the solution was stirred at 35 °C NH4CI (aqueous saturated solution, 10 mL) and CH2CI2 (12 mL) were added and the layers were separated. The aqueous layer was extracted with more CH2CI2 (30 mL) and the combined organic layers were washed with NaHCOs (aqueous saturated solution, 10 mL). The aqueous layer was extracted with CH2CI2 (2 x 30 mL), the combined organic layers were dried over anhydrous sodium sulfate, filtered and volatiles were removed under reduced pressure. Purification of the crude product by flash column chromatography (C18, 25% to45% MeCN / pH = 4 buffer) afforded the desired compound together with a small amount of the corresponding carboxylic acid. The solid was dissolved in a mixture of NaHCCh (aqueous saturated solution, 10 mL) and CH2CH2 (30 mL) and the layers were separated. The aqueous layer was extracted with more CH2CH2 (2 x 30 mL) and the combined organic layers were dried over anhydrous sodium sulfate, filtered and volatiles were removed under reduced pressure to yield 2-(dimethylamino)ethyl 6-(3-(5-chloro- 2-fluorophenyl)-5-methyl-1 / 7-pyrazol-4-yl)-1 ,5-naphthyridine-3-carboxylate (55 mg, 58%) as a white solid.1H NMR (300 MHz, DMSO-cfe) 6= 13.35 (s, 1 H), 9.33 - 9.27 (m, 1 H), 8.63 - 8.58 AGO-P3616PCT Application as filed

[0468] (m, 1 H), 8.37 (d, J = 8.9 Hz, 1 H), 7.70 - 7.58 (m, 2H), 7.56 - 7.46 (m, 1 H), 7.22 (t, J = 9.3 Hz, 1 H), 4.46 (t, J = 5.7 Hz, 2H), 2.68 (t, J = 5.7 Hz, 2H), 2.58 (s, 3H), 2.24 (s, 6H). UPLC-MS: Rt 2.779 m / z 454.3-456.3 [M+H]+. (Method C-UPLC)

[0469] Example 80 (Ex-80): 2-((3R,5R)-3,5-Dimethylpiperazin-1-yl)ethyl 6-(3-(5-chloro-2- fluorophenyl)-1H-pyrazol-4-yl)-1,5-naphthyridine-3-carboxylate

[0470] Step 1 :

[0471] 6-(3-(5-Chloro-2-fluorophenyl)-1-(tetrahydro-2 / 7-pyran-2-yl)-1 / 7-pyrazol-4-yl)-1 ,5- naphthyridine-3-carboxylic acid (lnt-19) (100 mg, 0.22 mmol, 1 eq), tert-Butyl (2R,6R)-4-(2- hydroxyethyl)-2,6-dimethylpiperazine-1 -carboxylate (lnt-51) (71 mg, 0.274 mmol, 1.24 eq), Muk (70 mg, 0.273 mmol, 1.24 eq) and DIPEA (78 mL, 0.447 mmol, 2.03 eq) were mixed in CH2CI2 (4.5 mL). The solution was stirred at 35 °C for 17 h and at room temperature for 3 days. NH4CI (saturated aqueous solution, 15 mL) and CH2CI2 (10 mL) were added, and the layers were separated. The aqueous layer was extracted with CH2CI2 (3 x 10 mL), the combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by flash column chromatography (C18, H2O + HCOOH (pH=3) / MeCN 15-100%, dry loading) to give 2-((3R,5R)-4-(tert-butoxycarbonyl)-3,5- dimethylpiperazin-1-yl)ethyl 6-(3-(5-chloro-2-fluorophenyl)-1-(tetrahydro-2 / 7-pyran-2-yl)-1 / 7- pyrazol-4-yl)-1 ,5-naphthyridine-3-carboxylate (45 mg, 29%) as a yellow solid.1H NMR (300 MHz, CDCh) 6= 9.41 (s, 1 H), 8.82 (s, 1 H), 8.36 (d, J = 1.3 Hz, 1 H), 8.27 (d, J = 8.9 Hz, 1H), 7.76 - 7.67 (m, 1H), 7.59 (d, J = 8.7 Hz, 1H), 7.44 - 7.33 (m, 1H), 7.01 (t, J = 9.2 Hz, 1H), 5.52 (t, J = 6.1 Hz, 1H), 4.62 - 4.45 (m, 2H), 4.15 (d, J = 11.6 Hz, 1 H), 3.96 - 3.72 (m, 3H), 2.93 - 2.61 (m, 4H), 2.40 (dd, J = 11.2, 6.0 Hz, 2H), 2.29 - 2.03 (m, 3H), 1.85 - 1.70 (m, 3H), 1.46 (s, 9H), 1.29 (d, J = 6.9 Hz, 6H). UPLC-MS: Rt 4.077 m / z 693.3-695.2 [M+HJ+. (Method A-HPLC)

[0472] Step 2: AGO-P3616PCT Application as filed

[0473] To a solution of 2-((3R,5R)-4-(tert-butoxycarbonyl)-3,5-dimethylpiperazin-1-yl)ethyl 6-(3-(5- chloro-2-fluorophenyl)-1-(tetrahydro-2 / 7-pyran-2-yl)-1 / 7-pyrazol-4-yl)-1 ,5-naphthyridine-3- carboxylate (43 mg, 0.062 mmol, 1 eq) in dioxane (0.6 mL) was added HCI (solution 4M in dioxane, 310 mL, 1.24 mmol, 20 eq). The solution was stirred at room temperature for 42 h. More HCI (solution 4M in dioxane, 310 mL, 1.24 mmol, 20 eq) and dioxane (0.6 mL) were added and the suspension was stirred at room temperature for 5 days. Hexanes (5 mL) were added to the mixture and the solvent was poured off. This procedure was repeated 3 times and volatiles were removed under reduced pressure. The crude product was purified by preparative HPLC (acetonitrile: 10 mM NH4HCO2 buffer with HCOOH (pH = 4)) to give 2- ((3R,5R)-3,5-dimethylpiperazin-1-yl)ethyl 6-(3-(5-chloro-2-fluorophenyl)-1 / 7-pyrazol-4-yl)-1 ,5- naphthyridine-3-carboxylate (27 mg, 86%) as a white solid.1H NMR (300 MHz, DMSO-cfe) 5= 9.28 (s, 1 H), 8.63 (s, 1 H), 8.40 (m, 5H), 8.07 (d, J = 8.9 Hz, 1 H), 7.74 - 7.55 (m, 1 H), 7.31 (t, J = 9.1 Hz, 1 H), 4.46 (m, 2H), 3.18 (m, 2H), 2.70 (m, 2H), 2.62 - 2.52 (m, 2H), 2.29 - 2.19 (m, 2H), 1.08 (d, J = 6.4 Hz, 6H). UPLC-MS: Rt 2.938 m / z 509.3-511 .2 [M+H]+ (Method C-UPLC).

[0474] Example 25 (Ex-25): 1-methylpyrrolidin-3-yl 6-(3-(5-chloro-2-fluorophenyl)-1H-pyrazol- 4-yl)quinoline-4-carboxylate

[0475] 6-(3-(5-Chloro-2-fluorophenyl)-1-(tetrahydro-2 / 7-pyran-2-yl)-1 / 7-pyrazol-4-yl)quinoline-4- carboxylic acid (lnt-42) (300 mg, 0.663 mmol, 1 eq), EDCi (191 mg, 0.946 mmol, 1.43 eq), DMAP (81 mg, 0.663 mmol, 1 eq) and 1 -Methylpyrrolidin-3-ol (108 mL, 0.983 mmol, 1.48 eq) were mixed in CH2CI2 (7 mL). The solution was stirred at room temperature for 19 h and then at 50 °C for 6 h. More EDCi (134 mg, 0.664 mmol, 1.00 eq), DMAP (25 mg, 0.204 mmol, 0.31 eq) and 1 -Methylpyrrolidin-3-ol (21 mL, 0.191 mmol, 0.29 eq) were added and the mixture was stirred at room temperature for 17 h. The crude volatiles were removed under reduced pressure. Purification of the crude product by flash column chromatography (C18 40g, NH4HCO3 / HCOOH (pH 7) / MeCN 45% to 65%, dry loading) afforded 1 -Methylpyrrolidin-3-yl 6- (3-(5-chloro-2-fluorophenyl)-1-(tetrahydro-2 / 7-pyran-2-yl)-1 / 7-pyrazol-4-yl)quinoline-4- carboxylate (360 mg, 100%) as a yellow oil.1H NMR (300 MHz, CDCh) 6= 8.98 (d, J = 4.5 Hz, 1 H), 8.69 (s, 1 H), 8.08 (d, J = 8.7 Hz, 1 H), 8.02 (s, 1 H), 7.92 (d, J = 4.5 Hz, 1 H), 7.63 (d, J = 8.1 Hz, 2H), 7.38 - 7.29 (m, 1 H), 6.96 (t, J = 8.9 Hz, 1 H), 5.63 (s, 1 H), 5.51 (t, J= 6.1 Hz, 1 H), AGO-P3616PCT Application as filed

[0476] 4.16 (d, J = 12.1 Hz, 1 H), 3.84 - 3.68 (m, 2H), 3.46 - 3.33 (m, 3H), 2.86 (s, 4H), 2.69 - 2.51 (m, 1 H), 2.41 - 2.27 (m, 1 H), 2.21 (s, 2H), 2.16 - 2.04 (m, 1 H), 1.86 - 1.59 (m, 3H), 1.25 (s, 1 H). HPLC-MS: Rt 2.694 m / z 535.4-537.3 [M+HJ+. (Method A-HPLC)

[0477] Step 2:

[0478] To a solution of 1 -Methylpyrrolidin-3-yl 6-(3-(5-chloro-2-fluorophenyl)-1-(tetrahydro-2 / 7-pyran- 2-yl)-1 / 7-pyrazol-4-yl)quinoline-4-carboxylate (360 mg, 0.672 mmol, 1 eq) in dioxane (6.7 mL) was added HCI (solution 4M in dioxane, 3.36 mL, 13.44 mmol, 19.97 eq). The solution was stirred at r.t. for 23 h, 5 mL of hexanes were added to the mixture and the solvent was decanted off. This operation was repeated 4 times. The crude product was purified by flash column chromatography (C18, NH4HCO2 / HCOOH (pH 4) / MeCN 25% to 45%, dry loading) to afford 1- methylpyrrolidin-3-yl 6-(3-(5-chloro-2-fluorophenyl)-1 / 7-pyrazol-4-yl)quinoline-4-carboxylate (168 mg, 55%) as a yellow solid.1H NMR (300 MHz, DMSO-cfe) 6= 8.97 (d, J = 4.4 Hz, 1 H), 8.43 - 8.23 (m, 2H), 8.06 (d, J = 8.7 Hz, 1 H), 7.89 - 7.76 (m, 2H), 7.57 (ddd, J = 10.9, 5.5, 2.1 Hz, 2H), 7.30 (t, J = 9.1 Hz, 1 H), 5.38 - 5.24 (m, 1 H), 2.81 - 2.65 (m, 3H), 2.39 - 2.23 (m, 5H), 1.81 (dtt, J = 13.4, 6.0, 3.2 Hz, 1 H). UPLC-MS: Rt 2.825 m / z 451.3-453.4 [M+HJ+. (Method C-UPLC) Table 12: Examples 26-46 were synthesised via an analogous route to Example 25. AGO-P3616PCT Application as filed AGO-P3616PCT Application as filed AGO-P3616PCT Application as filed AGO-P3616PCT Application as filed AGO-P3616PCT Application as filed AGO-P3616PCT Application as filed AGO-P3616PCT Application as filed

[0479] Example 47 (Ex-47): 2-Aminoethyl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4- yl)quinoline-4-carboxylate

[0480] Step 1 : AGO-P3616PCT Application as filed

[0481] 6-(3-(5-chloro-2-fluorophenyl)-1 / 7-pyrazol-4-yl)quinoline-4-carboxylic acid (lnt-41) (80 mg, 0.217 mmol, 1 eq), EDCi (66 mg, 0.327 mmol, 1.5 eq), DMAP (27 mg, 0.221 mmol, 1.02 eq) and Boc-Glycinol (50 mL, 0.323 mmol, 1.49 eq) were mixed in CH2CI2 (11 mL). The solution was stirred at room temperature for 21 h. Water (15 mL) was added and the aqueous layer was extracted with CH2CI2 (3 x 10 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by flash column chromatography (C18 20 g, H2O + 0.1 % HCOOH / MeCN 20% to100% 12CV, A 215 nm, 260 nm and 345 nm, dry loading) to afford 2-((Tert-butoxycarbonyl)amino)ethyl 6- (3-(5-chloro-2-fluorophenyl)-1 / 7-pyrazol-4-yl)quinoline-4-carboxylate (75 mg, 67%) as a yellow solid.1H NMR (300 MHz, DMSO-d6) 5= 13.48 (s, 1 H), 8.96 (d, J = 4.4 Hz, 1 H), 8.37 (d, J = 11.2 Hz, 1 H), 8.03 (d, J = 8.8 Hz, 1 H), 7.91 (d, J = 4.4 Hz, 1 H), 7.76 (dd, J = 8.7, 2.0 Hz, 1 H), 7.56 (s, 2H), 7.24 (s, 1 H), 7.08 (s, 1 H), 4.28 - 4.19 (m, 2H), 3.30 - 3.25 (m, 2H), 1.32 (s, 9H). HPLC-MS: Rt 3.003 m / z 511.3-513.3 [M+H]+.(Method A-HPLC)

[0482] To a solution of 2-((tert-butoxycarbonyl)amino)ethyl 6-(3-(5-chloro-2-fluorophenyl)-1 / 7- pyrazol-4-yl)quinoline-4-carboxylate (72 mg, 0.14 mmol, 1 eq) in CH2CI2 (1.4 mL) was added TFA (107 pL, 1.397 mmol, 10 eq) and the solution was stirred at room temperature for 7 h. The crude volatiles were removed under reduced pressure, and the crude product was purified by flash column chromatography (C18 20g, H2O + 0.2% TFA / MeCN, 20% to 100%, dry loading) to afford 2-aminoethyl 6-(3-(5-chloro-2-fluorophenyl)-1 / 7-pyrazol-4-yl)quinoline-4- carboxylate (95 mg, 90%) as a yellow sticky solid.1H NMR (300 MHz, DMSO-cfe) 5= 9.05 (d, J = 4.4 Hz, 1 H), 8.53 (d, J = 2.0 Hz, 1 H), 8.28 (s, 1 H), 8.17 - 7.87 (m, 5H), 7.81 (dd, J = 8.8, 2.0 Hz, 1 H), 7.67 - 7.49 (m, 2H), 7.31 (t, J = 9.1 Hz, 1 H), 4.49 (t, J = 5.1 Hz, 2H), 3.28 (m,

[0483] 2H). UPLC-MS: Rt 2.663 m / z 411.3-413.3 [M+HJ+. (Method C-UPLC)

[0484] Example 48 (Ex-48): Piperidin-4-ylmethyl 6-(3-(5-chloro-2-fluorophenyl)-5-methyl-1H- pyrazol-4-yl)quinoline-4-carboxylate

[0485] Example 48 was prepared via an analogous route to Example 47.

[0486] 1H NMR (300 MHz, DMSO-cfe) 6= 13.22 (s, 1 H), 9.02 (d, J = 4.5 Hz, 1 H), 8.39 (d, J = 1.9 Hz, 1 H), 8.05 (d, J = 8.7 Hz, 1 H), 7.93 (d, J = 4.4 Hz, 1 H), 7.67 - 7.41 (m, 3H), 7.17 (t, J = 9.2 Hz, AGO-P3616PCT Application as filed

[0487] 1 H), 4.23 (d, J = 6.2 Hz, 2H), 3.36-3.26 (m, 2H), 2.92 - 2.76 (m, 2H), 2.40 (s, 3H), 2.03 (d, J = 7.6 Hz, 1 H), 1.83 (d, J = 12.7 Hz, 2H), 1.42 (tt, J = 13.7, 7.1 Hz, 2H). UPLC-MS: Rt 2.963 m / z 479.3-481.3 [M+H]+. (Method C-UPLC)

[0488] Example 49 (Ex-49): 2-(piperidin-4-ylamino)ethyl 6-(3-(5-chloro-2-fluorophenyl)-5- methyl-1H-pyrazol-4-yl)quinoline-4-carboxylate

[0489] Step 1 :

[0490] 6-(3-(5-chloro-2-fluorophenyl)-5-methyl-1-(tetrahydro-2 / 7-pyran-2-yl)-1 / 7-pyrazol-4- yl)quinoline-4-carboxylic acid (lnt-40) (110 mg, 0.236 mmol, 1 eq), tert-butyl 4-((tert- butoxycarbonyl)(2-hydroxyethyl)amino)piperidine-1 -carboxylate (lnt-9) (122 mg, 0.354 mmol, 1.5 eq), Muk (84.4 mg, 0.33 mmol, 1.4 eq) and lutidine (56 mL, 0.48 mmol, 2.05 eq) were mixed CH2CI2 (2.4 mL). The solution was stirred at 35 °C for 23 h and then at room temperature for 68 h. Then, tert-butyl 4-((tert-butoxycarbonyl)(2-hydroxyethyl)amino)piperidine-1- carboxylate (81.3 mg, 0.236 mmol, 1 eq) in CH2CH2 (0.5 mL) was added and the solution was stirred at room temperature for 96 h. The volatiles were removed under reduced pressure and the crude product was purified by flash column chromatography (C18, H2O+HCOOH 0.1 % / MeCN 15% to 100%) and flash column chromatography (C18, NH4HCO2+HCOOH (pH 4) / MeCN 15% to 100%) to afford 2-((tert-butoxycarbonyl)(1-(tert-butoxycarbonyl)piperidin-4- yl)amino)ethyl 6-(3-(5-chloro-2-fluorophenyl)-5-methyl-1-(tetrahydro-2 / 7-pyran-2-yl)-1 / 7- pyrazol-4-yl)quinoline-4-carboxylate (73 mg, 39%) as a white solid.1H NMR (300 MHz, CDCI3) 5= 8.97 (d, J = 4.5 Hz, 1 H), 8.63 (s, 1 H), 8.05 (d, J = 8.7 Hz, 1 H), 7.89 (d, J = 4.4 Hz, 1 H), 7.60 (d, J = 5.5 Hz, 1 H), 7.47 (d, J = 8.8 Hz, 1 H), 7.22 (s, 1 H), 6.82 (t, J = 9.0 Hz, 1 H), 5.44 (d, J = 9.8 Hz, 1 H), 4.43 - 4.39 (m, 2H), 4.20 - 4.09 (m, 3H), 3.73 (t, J = 10.7 Hz, 1 H), 3.56 - 3.41 (m, 2H), 2.71 - 2.49 (m, 6H), 2.20 - 2.07 (m, 2H), 1.82 - 1.57 (m, 8H), 1.46 - 1.42 (m, 18H). HPLC-MS: Rt 4.257 m / z 792.5-794.4 [M-H]-(Method A)

[0491] Step 2: AGO-P3616PCT Application as filed

[0492] To a solution of 2-((tert-butoxycarbonyl)(1-(tert-butoxycarbonyl)piperidin-4-yl)amino)ethyl 6- (3-(5-chloro-2-fluorophenyl)-5-methyl-1-(tetrahydro-2 / 7-pyran-2-yl)-1 / 7-pyrazol-4-yl)quinoline- 4-carboxylate (73 mg, 0.092 mmol, 1 eq) in dioxane (0.9 mL) was added HCL (solution 4M in dioxane, 461 pL, 1.844 mmol, 20 eq). The solution was stirred at room temperature for 4 h under N2 atmosphere. Then, 5 mL of hexanes were added to the mixture and the solvent was decanted off. This operation was repeated 5 times to afford 2-(piperidin-4-ylamino)ethyl 6-(3- (5-chloro-2-fluorophenyl)-5-methyl-1 / 7-pyrazol-4-yl)quinoline-4-carboxylate tri hydrochloride (50 mg, 88%) as a pale orange solid.1H NMR (300 MHz, DMSO-cfe) 6= 9.69 (s, 2H), 9.09 (p, J = 12.9 Hz, 3H), 8.55 (d, J = 1 .9 Hz, 1 H), 8.26 (d, J = 4.5 Hz, 1 H), 8.06 (d, J = 8.7 Hz, 1 H), 7.68 - 7.36 (m, 3H), 7.19 (t, J = 9.1 Hz, 1 H), 4.65 (t, J = 5.1 Hz, 2H), 3.41 (s, 5H), 2.91 (d, J = 12.1 Hz, 2H), 2.42 (s, 3H), 2.25 (d, J = 13.0 Hz, 2H), 1.92 (q, J = 11.5 Hz, 2H). UPLC-MS: Rt 2.586 m / z 508.3-510.3 [M+HJ+. (Method C-UPLC)

[0493] Example 50 (Ex-50): Methyl 6-(3-(5-chloro-2-fluorophenyl)-1H-pyrazol-4-yl)quinoline-4- carboxylate

[0494] To a solution of 4-bromo-3-(5-chloro-2-fluorophenyl)-1 / 7-pyrazole (lnt-32) (2.567 g, 9.317 mmol, 1.25 eq), methyl 6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)quinoline-4-carboxylate (lnt-37) (2.331 g, 7.443 mmol, 1 eq) and PdCh(dtbpf) (970.3 mg, 1.488 mmol, 0.2 eq) in a mixture of dioxane (65 mL) and H2O (8 mL), degassed, K3PO4 (3.16 g, 14.886 mmol, 2 eq) was added and the reaction mixture was stirred at 90 °C for 16 h The crude volatiles were removed under reduced pressure and the mixture was diluted with C^Ch / iPrOH 30% (80 mL) and washed with H2O (100 mL). The aqueous layer was extracted with C^Ch / iPrOH 30% (5 x 50 mL), the combined organic layers were dried over anhydrous sodium sulfate, filtered and volatiles were removed under reduced pressure. Purification of the crude product by flash column chromatography (C18, 20-50% MeCN / H2O) afforded methyl 6-(3-(5-chloro-2- fluorophenyl)-1 / 7-pyrazol-4-yl)quinoline-4-carboxylate (1.414 g, 50) as a brown solid.1H NMR (300 MHz, DMSO-cfe) 6= 8.96 (d, J = 4.4 Hz, 1 H), 8.34 - 8.25 (m, 2H), 8.06 (d, J = 8.8 Hz, 1 H), 7.87 - 7.80 (m, 2H), 7.64 - 7.53 (m, 2H), 7.29 (t, J = 9.1 Hz, 1 H), 3.83 (s, 3H). UPLC- MS: Rt 3.627 m / z 382.3-384.3 [M+H]+. (Method C-UPLC)_ AGO-P3616PCT Application as filed

[0495] Table 13: Examples 51-53 were synthesised via an analogous route to Example 50. AGO-P3616PCT Application as filed

[0496] Example 54 (Ex-54): 2-Dimethylaminoethyl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4- yl)quinoline-4-carboxylate

[0497] A solution of 6-(3-(5-chloro-2-fluorophenyl)-1 / 7-pyrazol-4-yl)quinoline-4-carboxylic acid (lnt- 41) (90 mg, 0.244 mmol, 1 eq), 2-dimethylaminoethanol (29 mL, 0.288 mmol, 1.2 eq) and HATLI (111.7 mg, 0.293 mmol, 1.2 eq) in a mixture of CH2CI2 (2.5 mL) and DMF (0.5 mL) was stirred at room temperature for 16 h The crude product was purified by flash column chromatography (C18, 20g, Formic acid 0.1 % v / v (pH = 2.6) : (MeCN + Formic acid 0.1 % v / v), 15-80%), by semipreparative HPLC (MeCN:(Water + 0.2% HCO2H)) and by semipreparative HPLC (MeCN: (10 mM NH4HCO3, pH 4 with HCOOH)) afforded 2-(dimethylamino)ethyl 6-(3- (5-chloro-2-fluorophenyl)-1 / 7-pyrazol-4-yl)quinoline-4-carboxylate (30 mg, 28%) as a yellow solid.1H NMR (300 MHz, DMSO-cfe) 6= 9.01 (d, J = 4.4 Hz, 1 H), 8.48 (s, 1 H), 8.32 (s, 1 H), 8.13 (s, 1 H), 8.06 (d, J = 8.8 Hz, 1 H), 7.95 (d, J = 4.4 Hz, 1 H), 7.79 (dd, J = 8.8, 2.0 Hz, 1 H), 7.65 - 7.45 (m, 2H), 7.36 - 7.20 (m, 1 H), 4.50 (t, J = 5.2 Hz, 2H), 3.19 - 3.05 (m, 2H), 2.58 (s, 6H). UPLC-MS: Rt 2.752 m / z 439.3-441.3 [M+H]+. (Method C-UPLC)

[0498] Table 14: Examples 55-59 were synthesised via an analogous route to Example 54. AGO-P3616PCT Application as filed AGO-P3616PCT Application as filed

[0499] Example 60 (Ex-60): 4-Piperidinylmethyl 6-(3-(5-Chloro-2-fluorophenyl)-1H-pyrazol-4- yl)quinoline-4-carboxylate

[0500] Step 1 :

[0501] 6-(3-(5-chloro-2-fluorophenyl)-1 / 7-pyrazol-4-yl)quinoline-4-carboxylic acid (lnt-41) (200 mg, 0.543 mmol, 1 eq), HATU (248.1 mg, 0.652 mmol, 1.2 eq), DIPEA (232 mL, 1.355 mmol, 2.5 eq) and 1-N-Boc-4-Hydroxymethyl-piperidine (175.6 mg, 0.815 mmol, 1.5 eq) were mixed DMF (in 5.43 mL). The solution was stirred at room temperature for 19 h. The crude volatiles were removed under reduced pressure. Purification of the crude product by flash column chromatography (C18 20 g, H2O+0.1% HCOOH / MeCN 20% to100% 12 CV, 255 nm and 350 nm, dry loading) afforded (1-(tert-butoxycarbonyl)piperidin-4-yl)methyl 6-(3-(5-chloro-2- fluorophenyl)-1 / 7-pyrazol-4-yl)quinoline-4-carboxylate (206 mg, 67%) as a brown oil.1H NMR (300 MHz, DMSO-d6) 5= 13.50 (s, 1 H), 8.95 (d, J = 4.4 Hz, 1 H), 8.33 (s, 2H), 8.05 (d, J = 8.7 Hz, 1 H), 7.83 (dd, J = 12.2, 6.5 Hz, 2H), 7.57 (s, 2H), 7.27 (s, 1 H), 4.12 (d, J = 6.4 Hz, 2H), 3.95 (d, J = 13.2 Hz, 2H), 2.71 (s, 2H), 1.88 (s, 1 H), 1.68 (d, J = 12.6 Hz, 2H), 1.37 (s, 9H), 1.12 (d, J = 10.3 Hz, 2H).HPLC-MS: Rt 3.303 m / z 565.3-567.1 [M+H]+. (Method A-HPLC) AGO-P3616PCT Application as filed

[0502] Step 2:

[0503] To a solution of (1-(tert-butoxycarbonyl)piperidin-4-yl)methyl 6-(3-(5-chloro-2-fluorophenyl)- 1 / 7-pyrazol-4-yl)quinoline-4-carboxylate (205 mg, 0.362 mmol, 1 eq) in CH2CI2 (3.6 mL) was added TFA (277 pL, 3.617 mmol, 10 eq). The solution was stirred at room temperature for 3,5 h. The crude volatiles were removed under reduced pressure. Purification of the crude product by flash column chromatography (C18 20g, H2O+0.1% HCOOH / MeCN 20% to100% 12 CV, 260 nm and 340 nm, dry loading) to afford the 2,2,2-trifluoroacete salt of 4-piperidinylmethyl 6-(3-(5-Chloro-2-fluorophenyl)-1 / 7-pyrazol-4-yl)quinoline-4-carboxylate (111 mg, 53%) as a yellow solid.1H NMR (300 MHz, DMSO-cfe) 6= 13.50 (s, 1 H), 9.00 (d, J = 4.4 Hz, 1 H), 8.43 - 8.24 (m, 2H), 8.08 (d, J = 8.7 Hz, 1 H), 7.94 - 7.77 (m, 2H), 7.59 (t, J = 6.9 Hz, 2H), 7.30 (t, J = 9.0 Hz, 1 H), 4.19 (d, J = 6.1 Hz, 2H), 3.30 (d, J = 12.1 Hz, 2H), 2.89 (dd, J = 13.9, 10.9 Hz, 2H), 2.06 (d, J = 10.4 Hz, 1 H), 1.87 (d, J = 13.8 Hz, 2H), 1.58 - 1.35 (m, 2H). UPLC-MS: Rt 2.849 m / z 465.3-467.3 [M+HJ+. (Method C-UPLC)

[0504] Table 15: Examples 61-63 were synthesised via an analogous route to Example 60. AGO-P3616PCT Application as filed

[0505] Example 64 (Ex-64): 1-Methylpiperidin-4-yl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4- yl)quinoline-4-carboxylate

[0506] 6-(3-(5-chloro-2-fluorophenyl)-1 / 7-pyrazol-4-yl)quinoline-4-carboxylic acid (lnt-41) (80 mg, 0.217 mmol, 1 eq), N-Methyl-4-piperidinol (37.6 mg, 0.326 mmol, 1.5 eq), EDCi (65.8 mg, 0.326 mmol, 1.5 eq) and DMAP (26.6 mg, 0.217 mmol, 1 eq) were mixed in CH2CI2 (10 mL). The solution was stirred at room temperature DMF (1 mL) was added, and the reaction was stirred at 40 °C for 5 h. Additional A / -Methyl-4-piperidinol (24.1 mg, 0.209 mmol, 1 eq) was added and the reaction was stirred overnight. Purification of the crude product by flash column chromatography (C18, (H2O + 0.1 % v / v HCOOH): MeCN, 5% to 30%) and by flash column chromatography (C18, (pH = 7 buffer : MeCN, 15% to 50%),) afforded 1 -Methylpiperidin-4-yl 6-(3-(5-chloro-2-fluorophenyl)-1 / 7-pyrazol-4-yl)quinoline-4-carboxylate (53 mg, 48%) as a white solid.1H NMR (300 MHz, DMSO-cfe) 6= 8.97 (d, J = 4.4 Hz, 1 H), 8.29 (d, J = 7.3 Hz, AGO-P3616PCT Application as filed

[0507] 2H), 8.07 (d, J = 8.8 Hz, 1 H), 7.86 - 7.78 (m, 2H), 7.63 - 7.48 (m, 2H), 7.28 (t, J = 9.2 Hz, 1 H), 4.98 - 4.83 (m, 1 H), 2.69 - 2.57 (m, 2H), 2.36 - 2.17 (m, 5H), 1.98 - 1.82 (m, 2H), 1.77

[0508] - 1.59 (m, 2H). UPLC-MS: Rt 2.866 m / z 465.2-467.2 [M+HJ+. (Method C-UPLC)

[0509] Table 16: Examples 65-73 and 79 were synthesised via an analogous route to Example 64. AGO-P3616PCT Application as filed AGO-P3616PCT Application as filed AGO-P3616PCT Application as filed

[0510] Example 74 (Ex-74): Piperidin-4-yl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4- yl)quinoline-4-carboxylate

[0511] Step 1 :

[0512] DIAD (182 mL, 0.927 mmol, 3.6 eq) was added to a solution of tert-butyl 4-hydroxypiperidine- 1-carboxylate (lnt-11) (171 mg, 0.849 mmol, 3.3 eq) and PhaP (243 mg, 0.926 mmol, 3.6 eq) in THF (19 mL) at 0 °C. After 15 min at room temperature, a solution of 6-(3-(5-chloro-2- fluorophenyl)-1 / 7-pyrazol-4-yl)quinoline-4-carboxylic acid (lnt-41) (95 mg, 0.258 mmol, 1 eq) in THF (29 mL) was slowly added and the resulting reaction mixture was stirred at room temperature for 16 h. The reaction crude was mixed with other bathes and the mixed crudes were purified by flash column chromatography (C18, (H2O + 0.1% v / v HCOOH): MeCN, 35% to65%) afforded 1-(tert-butoxycarbonyl)piperidin-4-yl 6-(3-(5-chloro-2-fluorophenyl)-1 / 7- pyrazol-4-yl)quinoline-4-carboxylate (174 mg, 122%) as a white solid. HPLC-MS: Rt 3.230 m / z 549.8-551.5 [M-H]- (Method A- HP LC) AGO-P3616PCT Application as filed

[0513] Step 2:

[0514] To a solution of 1-(tert-butoxycarbonyl)piperidin-4-yl 6-(3-(5-chloro-2-fluorophenyl)-1 / 7- pyrazol-4-yl)quinoline-4-carboxylate (174 mg, 0.315 mmol, 1 eq) in dioxane (3.2 mL) was added HCI dioxane 4M (1.6 mL, 6.4 mmol, 20.27 eq). The solution was stirred at room temperature for 3,5 h. The reaction mixture was filtered and washed with 10 mL of hexanes, to afford Piperidin-4-yl 6-(3-(5-chloro-2-fluorophenyl)-1 / 7-pyrazol-4-yl)quinoline-4-carboxylate dihydrochloride (155 mg, 94%) as a yellow solid.1H NMR (300 MHz, DMSO-cfe) 6= 9.25 - 9.04 (m, 1 H), 9.02 (d, J = 4.5 Hz, 1 H), 8.38 (d, J = 1.9 Hz, 1 H), 8.28 (s, 1 H), 8.10 (d, J = 8.8 Hz, 1 H), 7.99 (d, J = 4.5 Hz, 1 H), 7.85 (dd, J = 8.8, 2.0 Hz, 1 H), 7.65 - 7.51 (m, 2H), 7.29 (t, J = 9.0 Hz, 1 H), 5.20 (dt, J = 7.7, 3.8 Hz, 1 H), 3.38 - 3.01 (m, 4H), 2.23 - 2.05 (m, 2H), 2.03 - 1.84 (m, 2H). UPLC-MS: Rt 2.840 m / z 451.3-453.3 [M+HJ+. (Method C-UPLC)

[0515] Example 75 (Ex-75): 1,4-diazepan-6-yl 6-(3-(5-chloro-2-fluorophenyl)-1H-pyrazol-4-yl)- 1 ,5-naphthyridine-3-carboxylate

[0516] Step 1 :

[0517] 6-(3-(5-Chloro-2-fluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1 / 7-pyrazol-4-yl)-1 ,5- naphthyridine-3-carboxylic acid (lnt-19) (100 mg, 0.22 mmol, 1 eq), EDCi (67 mg, 0.332 mmol, 1.5 eq), DMAP (27 mg, 0.221 mmol, 1 eq) and 1 ,4-di-tert-butyl 6-hydroxy-1 ,4-diazepane-1 ,4- dicarboxylate (88 mg, 0.264 mmol, 1.2 eq) were mixed in CH2CI2 (2 mL). The solution was stirred at room temperature for 96 h under N2 atmosphere. The crude volatiles were removed under reduced pressure. Purification of the crude product by flash column chromatography (C18, NH4HCO2+HCOOH (pH 4) / MeCN 70-90%, dry loading) afforded di-tert-butyl 6-((6-(3- (5-chloro-2-fluorophenyl)-1-(tetrahydro-2 / 7-pyran-2-yl)-1 / 7-pyrazol-4-yl)-1 ,5-naphthyridine-3- carbonyl)oxy)-1 ,4-diazepane-1 ,4-dicarboxylate (132 mg, 80%) as a pale yellow solid.1H NMR (300 MHz, CDCh) 6 9.41 (s, 1 H), 8.86 (s, 1 H), 8.37 (s, 1 H), 8.27 (s, 1 H), 7.70 (s, 1 H), 7.58 (s, AGO-P3616PCT Application as filed

[0518] 1 H), 7.38 (s, 1 H), 7.02 (s, 1 H), 5.61 - 5.47 (m, 1 H), 5.41 (s, 1 H), 4.23 - 4.09 (m, 1 H), 3.96 - 3.45 (m, 9H), 2.32 - 1.96 (m, 4H), 1.42 (d, J = 34.8 Hz, 18H). HPLC-MS: Rt 3.831 m / z 751.3- 753.3 [M+H]+. (Method A-HPLC)

[0519] Step 2:

[0520] To a solution of di-tert-butyl 6-((6-(3-(5-chloro-2-fluorophenyl)-1-(tetrahydro-2 / 7-pyran-2-yl)- 1 / 7-pyrazol-4-yl)-1 ,5-naphthyridine-3-carbonyl)oxy)-1 ,4-diazepane-1 ,4-dicarboxylate (100 mg, 0.133 mmol, 1 eq) in 1.3 mL of dioxane was added HCI (solution 4M in dioxane, 670 mL, 2.68 mmol, 20.13 eq). The solution was stirred at room temperature for 7 h under N2 atmosphere. More HCI dioxane 4M (130 mL, 0.52 mmol, 3.91 eq) was added and the suspension was stirred at room temperature for 21 h under N2 atmosphere. 5 mL of hexanes were added to the mixture and the solvent was decanted off. This operation was repeated 4 times. The solid was triturated with Et20 (3 x 5 mL) and dried under high vacuum to afford 1 ,4- diazepan-6-yl 6-(3-(5-chloro-2-fluorophenyl)-1 / 7-pyrazol-4-yl)-1 ,5-naphthyridine-3- carboxylate trihydrochloride (67 mg, 87%) as a yellow solid.

[0521] 1H-NMR (300 MHz, DMSO-cfe + D2O drops): 5 = 9.51 (d, J = 2.1 Hz, 1 H), 8.76 - 8.31 (m, 3H), 8.01 (d, J = 8.9 Hz, 1 H), 7.82 - 7.46 (m, 2H), 7.30 (t, J = 9.2 Hz, 1 H), 5.74 (s, 1 H), 3.83 - 3.53 (m, 8H). UPLC-MS: Rt 2.518 m / z 467.3-469.3 [M+H]+. (Method C-UPLC)

[0522] Example 76 (Ex-76): Methyl 6-(4-(3-chloro-4-fluorophenyl)-1-(2-hydroxyethyl)-1H- imidazol-5-yl)quinoline-4-carboxylate

[0523] 2-(5-bromo-4-(3-chloro-4-fluorophenyl)-1 / 7-imidazol-1-yl)ethan-1-ol (lnt-50) (250 mg, 0.782 mmol, 1 eq), methyl 6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)quinoline-4-carboxylate (lnt-37) (318.5 mg, 1.017 mmol, 1.3 eq), Pd(Ph3P)4(180.8 mg, 0.156 mmol, 0.2 eq) and K2CO3 (270.3 mg, 1.955 mmol, 2.5 eq) were mixed in a mixture of dioxane (7 mL) and H2O (0.7 mL). The suspension was degassed and stirred at 100 °C for 16 h, filtered through a plug of celite, AGO-P3616PCT Application as filed washing with 10% MeOH / C ^Ch (4 x 20 mL). The crude product was purified by flash column chromatography (C18, 40g, 15%to 50% MeCN / FW) and by semipreparative HPLC (MeCN: (H2O + 0.2% HCOOH, pH = 3)) to give methyl 6-(4-(3-chloro-4-fluorophenyl)-1-(2- hydroxyethyl)-1 / 7-imidazol-5-yl)quinoline-4-carboxylate (17 mg, 5%) as a yellow solid. 1 H NMR (300 MHz, DMSO-d6) 5 9.15 (d, J = 4.4 Hz, 1 H), 8.68 (d, J = 1.9 Hz, 1 H), 8.25 (d, J = 8.7 Hz, 1 H), 8.02 (d, J = 4.4 Hz, 1 H), 7.93 (s, 1 H), 7.82 (dd, J = 8.7, 1 .9 Hz, 1 H), 7.60 - 7.55 (m, 1 H), 7.24 - 7.19 (m, 2H), 5.00 (s, 1 H), 3.98 - 3.84 (m, 5H), 3.50 (t, J = 5.6 Hz, 2H). UPLC- MS: Rt 2.363 m / z 426.3-428.2 [M+H]+. (Method C-UPLC)

[0524] Example 77 (Ex-77): Ethyl 6-(4-(3-chloro-4-fluorophenyl)-1-(2-hydroxyethyl)-1H- imidazol-5-yl)quinoline-3-carboxylate

[0525] Ethyl 6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)quinoline-3-carboxylate (lnt-38) (490 mg, 1.497 mmol, 1 eq), 2-(5-bromo-4-(3-chloro-4-fluorophenyl)-1 / 7-imidazol-1-yl)ethan-1-ol (Int- 50) (622 mg, 1.946 mmol, 1.3 eq), PdCh(dtbpf) (165 mg, 0.253 mmol, 0.17 eq) and K3PO4

[0526] (635 mg, 2.991 mmol, 2 eq) were mixed in a mixture of dioxane (14 mL) and H2O (1.4 mL). The suspension was degassed and stirred at 90 °C for 19 h, cooled to room temperature and volatiles were removed under reduced pressure. Purification of the crude product by flash column chromatography (Silica, 5% MeOH / DCM, dry loading) afforded ethyl 6-(4-(3-chloro-4- fluorophenyl)-1-(2-hydroxyethyl)-1 / 7-imidazol-5-yl)quinoline-3-carboxylate (595 mg, 90%) as a dark brown foam. 1 H NMR (300 MHz, dmso) 5 9.39 (d, J = 2.1 Hz, 1 H), 9.07 (d, J = 2.1 Hz, 1 H), 8.35 (d, J = 1 .9 Hz, 1 H), 8.23 (d, J = 8.7 Hz, 1 H), 7.99 - 7.81 (m, 2H), 7.65 - 7.46 (m, 1 H), 7.28 - 7.13 (m, 2H), 4.93 (t, J = 5.3 Hz, 1 H), 4.44 (q, J = 7.1 Hz, 2H), 3.92 (t, J = 5.6 Hz, 2H), 3.49 (q, J = 5.6 Hz, 2H), 1.39 (t, J = 7.1 Hz, 3H). UPLC-MS: Rt 3.715 m / z 440.2-442.2 [M+H]+. (Method C-UPLC)

[0527] Comparator 1 (Comp-1): 2-Piperazin-1-ylethyl 6-[5-(6-methyl-2-pyridyl)-1H-pyrazol-4- yl]-1,5-naphthyridine-3-carboxylate

[0528] Comparator 1 may be prepared from the route as outlined in WO2021102468 (Theravance Biopharma R&D LLC, page 91 , Example 277). AGO-P3616PCT Application as filed

[0529] Analytical Methods:

[0530] HPLC-MS Methods

[0531] The LC conditions and MS parameters of both methods are indicated in the following tables:

[0532] LC Conditions AGO-P3616PCT Application as filed

[0533] MS Parameters (Micromass ZQ 2000)

[0534] UPLC-MS Methods

[0535] LC Conditions AGO-P3616PCT Application as filed

[0536] MS PARAMETERS (Acquity QDa detector):

[0537] GC-MS Method AGO-P3616PCT Application as filed

[0538] Flame ionization detector (FID)

[0539] Mass spectrometer

[0540] Commercial Materials

[0541] Unless otherwise stated, all starting materials are commercially available.

[0542] BIOLOGICAL EXAMPLES

[0543] Biological Example 1 - Biochemical assay ALK5

[0544] Method A

[0545] Human TGFpR-1 inhibition experiments were carried out in a white 384-microplate low flange (Corning 3572) with ADP-Glo kinase Assay Kit (Promega V9101) and TGFpR-1 Kinase Enzyme System (Promega V4092). Test compounds and standard Galunisertib (Cayman AGO-P3616PCT Application as filed

[0546] 15312), 50 ng / well TGFpR-1 kinase and 50pM ATP were added in a final volume of 10pL / well; using Reaction buffer supplied by kit as assay buffer. The reaction mixture was incubated in gentle shaking for 120 min at RT, after incubation of 10pL of ADP-Glo Reagent was added and incubated in gentle shaking for 40 min at RT. 20pL of Kinase Detection Reagent was added and plate was incubated in gentle shaking for 30 min at RT. Luminescence (1000 ms) was measured in Perkin Elmer EnSpire Multimode plate reader.

[0547] Method B

[0548] Human ALK5 inhibition experiments were carried out in Labcyte 384-well microplate (Labcyte, Catalog# LP-0200) using HotSpotTM Kinase profiling services. N-terminal GST-tagged recombinant human ALK5 / TGFBR1 (C-terminal fragment, amino acids T200-M503; ProQinase. cat# 0397-0000-1) was incubated at 30 nM with 20 pM Casein substrate (dephosphorylated, SignalChem cat# C03-54BN) and 2 mM MnCI2 along with test compound in a buffer consisting of 20 mM Hepes (pH 7.5), 10 mM MgCI2, 1 mM EGTA, 0.01 % Brij35, 0.02 mg / ml BSA, 0.1 mM Na3VO4, 2 mM DTT, 1% DMSO. Compounds were typically prepared in a three-fold serial dilution in DMSO over 10-doses starting at 10 pM final concentration and added to the assay by acoustic technology (Beckman Coulter Life Sciences Echo550; nanoliter range) and pre-incubated for 20 min at room temperature. Then, 5 pM [33P]-ATP (Hartman Analytic Cat# SCF-301-12) was added to initiate the reaction. After 2- hour incubation at room temperature, the reaction was spotted to P81 ion exchange filter paper (Whatman Inc., Piscataway, NJ). Unbound phosphate was removed by extensive washing in 0.75% phosphoric acid. After subtraction of background derived from control reactions containing inactive enzyme, kinase activity was expressed as the percent remaining kinase activity in test samples compared to vehicle (dimethyl sulfoxide, Sigma Aldrich #472301) reactions. Values were fit to a 4-parameter logistic curve and IC50 values determined using Prism (GraphPad Software).

[0549] Results

[0550] Data for compounds of the invention that were tested in this assay are shown in Table 17 below. AGO-P3616PCT Application as filed

[0551] Table 17 AGO-P3616PCT Application as filed

[0552] Conclusion

[0553] As can be seen from the results described in Table 17, the compounds of the present invention that were tested in this assay are potent inhibitors of ALK5. The compounds tested were, save for one, more potent than the comparator compound in this assay.

[0554] Biological Example 2 - Cellular assay ALK5

[0555] The experiments were carried out in A549 cell line. 30000 cells were seeded in 200pl of culture medium (Sigma D6046) supplemented with L-Glutamine (Sigma G7513), Penicillin / Streptomycin (Invitrogen 11058) and FBS (Sigma F9665) on a 96 wells microplate (Becton Dickinson 353072). After 16 hours medium was changed to serum free medium. Compounds, Galunisertib, as inhibitor ligand (Cayman CAY-15312) and recombinant Human TGF-P2 (R&D Systems 302-B2-002) as activator of the ALK-5, were added in their corresponding wells and incubated following the instructions of the Alpahscreen AlphaLISA® SureFire® Ultra™ p- SMAD3 (Ser423 / 425) Kit (Perkin Elmer ALSU-PSM3-A500).

[0556] Results

[0557] Data for compounds of the invention that were tested in this assay are shown in Table 18 below. AGO-P3616PCT Application as filed

[0558] Table 18

[0559] Conclusion

[0560] As can be seen from the results described in Table 18, the compounds of the present invention that were tested in this assay are potent inhibitors of ALK5. A clear majority of the compounds tested were more potent than the comparator compound in this assay. AGO-P3616PCT Application as filed

[0561] Biological Example 3 - Plasma Stability

[0562] Method A

[0563] Materials (plasma):

[0564] • Matrix - Mouse and human plasma, subjected to not more than one freeze-thaw cycle will be used

[0565] • Anticoagulant - K2EDTA

[0566] • Species - Swiss Albino (male) and Caucasian (male), plasma will be a pool from at least 3 donors

[0567] Method:

[0568] Briefly, the pH of the plasma were adjusted to 7.4 prior to use. Subsequently, 995 pL of plasma were incubated in an orbital incubator shaker maintained at 37 °C and 5% carbon dioxide for 10 min.

[0569] Reactions were initiated by the addition of 5 pL of 1 mM test item stock solutions into 995 pL plasma to prepare 5 pM solution. The microfuge tubes were inverted for uniform mixing and then incubated in an orbital incubator shaker maintained at 37 °C and 5% carbon dioxide. Aliquots (50 pL) were withdrawn from the reaction tube at 0 and 60 min and the reaction was immediately terminated by collecting the samples in 96 well plates containing 150 pL of acetonitrile. All assays were performed in duplicate. The quenched samples were stored at - 70 °C until analysis.

[0570] To the quenched samples internal standard was added, vortex mixed and centrifuged at 4000 rpm for 10 minutes and an aliquot of supernatant was used for LC-MS / MS analysis.

[0571] Procaine hydrochloride and diltiazem at 1 pM was used as a positive control in plasma.

[0572] Bioanalysis: The experimental samples were analysed for test items by employing a suitable fit-for-purpose multiple reaction monitoring method developed on LC-MS / MS using an API 4000 mass spectrometer to estimate the area ratio (peak area / internal standard peak area). AGO-P3616PCT Application as filed

[0573] Data Reporting:

[0574] The data was reported as percentage of parent compound remaining at each time point considering the zero min sample as 100%. The first order decay equation (A = AOe-kt) was used to estimate half-life using GraphPad Prism® software.

[0575] Method B

[0576] Rat, human, mouse and dog plasma pooled from healthy donors extracted in citrate tubes was employed in the assay.

[0577] Brief protocol:

[0578] Plates containing 5pM compounds in plasma (total volume: 100pL) were incubated at 37 °C at the different times (0, 60, 120 and 360 min). Then 300 pl Acetonitrile were added for precipitating plasma protein, and the plate was centrifuged at 4000 g for 60 min at 4 °C. Supernatant was taken and analysed by UPLC / MS / MS for sample quantification.

[0579] Stationary phase: Reverse phase ACQUITY BEH C18 1.7pm 2.1x50mm (Waters)

[0580] Mobile phase: 0.1% Formic acid water / 0.1 % formic acid in acetonitrile

[0581] Gradient: Flow: 0.6 ml / min

[0582] The chromatographic equipment employed was an LIPLC QSM Waters Acquity. Compound concentrations were calculated from the MS peak areas. AGO-P3616PCT Application as filed

[0583] Method C

[0584] Materials (plasma):

[0585] • Pooled mixed gender human plasma (BiolVT) was used in the assay.

[0586] 4 non-coded push cap tubes (1.4 ml) were prepared for each compound / control (two for time point 0 min, TO, and other two for 60 min time point, T60), and 250 pl of plasma were added to each tube. TO and T60 tubes were treated as follows:

[0587] • T60 tubes: compound’s or control’s work solution (1.25 pl) were added to plasma and incubated for 1h or 4h at 37°C. At the end of incubation, 750 pl of STOP solution were added to the tubes. • TO tubes: 750 pl of STOP solution were added to the tubes, followed by compound’s / control’s work solution (1.25 pl); after proper mixing, TO tubes were kept at +4°C until the end of incubation.

[0588] All tubes were centrifuged at 4500 rpm, at +4°C for 30 minutes. The resulting supernatants were analysed by LC-MS / MS.

[0589] Data analysis:

[0590] Plasma stability, expressed as the percentage of remaining parent compound, was calculated from the ratio of peak area of the remaining compound and peak area of the internal standard after 60 min of incubation compared to the same ratio at the t=0 min (100%). Value at t=0 min (100%) was calculated as average of two replicas.

[0591] A “low” plasma stability is defined as less than 50% of the compound remaining after 60 mins as tested in this assay. A “very low” plasma stability is defined as less than 20% of the compound remaining after 60 mins as tested in this assay.

[0592] Results

[0593] Data for compounds of the invention that were tested in this assay are shown in Table 19 below.

[0594] Table 19 AGO-P3616PCT Application as filed AGO-P3616PCT Application as filed

[0595] *Data of Examples with apparent plasma stability of more than 100% is a result of limitations of the assay, and should be treated as having 100% plasma stability for the purposes of this analysis.

[0596] Conclusion

[0597] As can be seen from the results described in Table 19, at least some of the compounds of the present invention that were tested in this assay show low or very low plasma stability. Preferable compounds have a plasma stability of less than 5% as tested in this assay.

[0598] Biological Example 4 - Metabolic Stability (Liver Microsomes)

[0599] Method A

[0600] Human, rat, mice and dog microsomes from Tebu-Xenotech were employed in the assay. They contained 20 mg / ml of protein.

[0601] Brief protocol:

[0602] The following quantities were added to each well of a 96-well microplate.

[0603] Plates were incubated at 37 °C and 75 pL samples were taken at 0, 10, 20, 40 and 60 minutes. Samples were transferred to a microplate and 75 pl Acetonitrile + IS(Rolipram) were added for inactivating the microsomes, and 30 pl of H2O with 0.5% formic acid for improving the AGO-P3616PCT Application as filed chromatographic conditions and kept at 4 °C. When all the samples were taken the plate was centrifuged at 46000 g for 30 min at 15oC.

[0604] Stationary phase: Acquity LIPLC® BEHC18 1 ,7 pm (2.1 mm x 50 mm) (Waters)

[0605] Mobile phase: A: 0.1% formic; B: acetonitrile+0.1% formic acid

[0606] Gradient:

[0607] Flow: 0.6 ml / min

[0608] The chromatographic equipment employed was an LIPLC QSM Waters Acquity.

[0609] Metabolic stability was calculated from the logarithm of the remaining compound at each of the times evaluated.

[0610] Method B

[0611] Intrinsic clearance studies were performed with mouse and human liver microsomes at 0.55 mg / mL protein concentration.

[0612] Briefly, for protein concentration of 0.5 mg / mL assay, liver microsomal protein (12.5 pL), NADPH (50 pL) and phosphate buffer (435 pL) were co-incubated (pre-incubation) in a 96-well deep well plate in an orbital incubator (10 min, 37°C). 0

[0613] Reactions were initiated by the addition of 2.5 pL of 100 pM test item working stock solution to give a final test item concentration of 0.5 pM. Aliquots (50 pL) were withdrawn from the reaction tube at 0 and 60 min and the reaction was immediately terminated by transferring to a 96-deep well plate containing 150 pL of acetonitrile. b

[0614] NADPH-free control incubations were performed by mixing liver microsomes (12.5 pL) and phosphate buffer (485 pL) and incubating at 37°C for 10 minutes. Reaction were initiated by addition of 2.5 pL of test item working stock solution, and aliquots (50 pL) were withdrawn at AGO-P3616PCT Application as filed

[0615] 0 and 60 min and reaction was terminated with 150 pL of acetonitrile. All experiments were performed in duplicate for the test item.

[0616] Verapamil at 0.5 pM was used as the positive control in mouse and human liver microsomes. All experiments were performed in singlet for the positive control.

[0617] To the quenched samples internal standard was added and vortex mixed followed by centrifugation at 4,000 rpm for 20 minutes and an aliquot of supernatant was taken for LC- MS / MS analysis.

[0618] Bioanalysis:

[0619] The experimental samples were analysed by employing a suitable fit-for-purpose multiple reaction monitoring method developed on LC-MS / MS using an API 4000 mass spectrometer to estimate the area ratio (analyte peak area / internal standard peak area). The % parent remaining was monitored for the test items and the intrinsic clearance was determined.

[0620] Data Analysis:

[0621] The data was fitted to the one phase exponential decay equation (A = Aoe'kt) using GraphPad Prism® software. The half-life (ti / 2) generated by the software was reported. Intrinsic clearance was calculated using the formula k x volume of reaction mixture (pL)

[0622] CLint = - protem content (mg) where, k = decay rate constant (min-1)

[0623] Method C

[0624] Liver microsomes from Corning / Discovery Life Sciences were employed in the assay:

[0625] • Human liver microsomes, pooled donors

[0626] • Mouse pooled liver microsomes, male, CD-1 • Rat pooled liver microsomes, male, Sprague Dawley

[0627] • Dog pooled liver microsomes, male; Beagle

[0628] Stock concentration of liver microsomes was 20 mg / mL. AGO-P3616PCT Application as filed

[0629] Methods:

[0630] Solutions:

[0631] 50mM PBS Buffer:

[0632] • Dissolve 1 tablet in 40 ml of mqH20

[0633] • Adjust pH to 7.4

[0634] • Store at 2-8°C and discard if turbidity develops

[0635] STOP solution -

[0636] • ACN:MeOH = 2:1 with appropriate amount of internal standard (final: 100 ng / ml of diclofenac and 10 ng / ml of warfarin sodium)

[0637] Procedure:

[0638] Compounds and positive controls dilutions were prepared starting from the 10 mM DMSO stock solutions. A 2-step dilution was performed to obtain 1 pM final concentration (0.03% DMSO):

[0639] Step 1) 3x dilution of stock solution in DMSO, 2.5pL of 10mM stock solution + 5pL DMSO

[0640] Step 2) 333.3x dilution in PBS, 1 ,5pL of 3.33mM stock + 498.5pL PBS

[0641] Microsomal dilutions were prepared in PBS to obtain 0.625 mg / ml working solution. Final concentration in incubation mix - 0.5 mg / mL. Co-factors solutions in 50mM PBS pH 7.4 were prepared as follows:

[0642] Equal volumes of aliquoted co-factors were combined. The Tecan EVO instrument was set according to worktable layout and the following script was run:

[0643] • Cofactor transfer (60pL) to Cofactor / PCR plate

[0644] • Buffer transfer (60pL) to Cofactor / PCR plate AGO-P3616PCT Application as filed

[0645] • Microsomes transfer to Incubation plate (2x160pL for incubation with cofactors and 160pL for incubation without cofactor)

[0646] • Compound dilution 2 mix and transfer to Incubation plate (40pL for incubation with cofactors and 20pL for incubation without cofactor) • Pre-incubation: 37 °C, mix 900 rpm, 5 min

[0647] • Dispense 120pL of Stop solution to Quench plate

[0648] • Start reaction: transfer 40pL / 20pL from Cofactor plate to Incubation plate

[0649] • Incubation at 37°C with shaking 500 rpm

[0650] • Sample quench: transfer 40 pL from Incubation plate to Quench plate • Time-points: 0.3, 10, 20, 30, 45 and 60 min

[0651] • Time-points for incubation without cofactor: 0.3 and 60 min

[0652] • At the end of script seal Quench plate

[0653] Quench plate was centrifuged at 4500 rpm for 30 minutes at 4-8°C. Supernatant was transferred into two LCMS plates using TECAN EVO. Samples were analysed using LC- MS / MS methods. If not analysed immediately, LCMS plates were stored at -80°C until analysis.

[0654] Data Analysis:

[0655] Metabolic stability, expressed as the percentage of remaining parent compound, was calculated from the ratio of peak area of the remaining compound and peak area of the internal standard after different time of incubation compared to the same ratio at the t=0 min (100%):

[0656] % remaining peak area ratios of test compound vs. IS at appointed time

[0657] = - x 100. peak area ratios of test compound vs. IS at 0 min The half-life (t1 / 2) is calculated in GraphPad Prism software from % remaining vs. time regression using non-linear regression fit (one phase exponential decay with following constrain parameters: Span=100, Plateau=0, K=no constraint).

[0658] In vitro intrinsic clearance (CLint) is calculated from half-life using following equation: CLint[pl / min / mg] = 0.693 / t1 / 2 / min x (mL of incubation / mg protein) x 1000

[0659] Results

[0660] Data for compounds of the invention that were tested in this assay are shown in Table 20 below. AGO-P3616PCT Application as filed

[0661] Table 20 (Human) AGO-P3616PCT Application as filed

[0662] Biological Example 5 - Metabolic Stability (Lung S9)

[0663] Materials (Lung S9 Fractions):

[0664] Mouse, rat and human lung S9 procured from XenoTech LLC (Kansas, USA) were used in the assay. The final protein concentration to assess intrinsic clearance were 0.5 mg / mL.

[0665] • Mouse Lung S9 Fraction - CD1 , untreated, Male, pool of 400, 5 mg protein / mL, M1000.PS9.

[0666] • Rat Lung S9 Fraction - SD, male, pool of 150, 5 mg protein / mL, R1000.PS9.

[0667] • Human Lung S9 Fraction - Mixed gender, pool of 4, 5 mg protein / mL, H0610.PS9 (NS).

[0668] • Phosphate Buffer (50 mM, pH 7.4): Disodium hydrogen phosphate (3.6 g) and sodium dihydrogen phosphate (3.0 g) were weighed and dissolved separately in Milli-Q® water to make volume up to 500 mL. The pH of disodium hydrogen phosphate solution was adjusted to 7.4 by adding sodium dihydrogen phosphate solution. • p-Nicotinamide Adenine Dinucleotide 2'-Phosphate (NADPH): NADPH (Catalog number: 481973, Source: Merck) was weighed and dissolved in required amount of phosphate buffer solution to obtain final stock solution concentration of 10 mM. The solution was stored below -20 °C until use. Method:

[0669] Intrinsic clearance studies were performed individually with mouse, rat, and human lung S-9 fractions at 0.5 mg / mL protein concentration.

[0670] Lung S9 fraction (50 pL), NADPH (50 pL) and phosphate buffer (397.5 pL) were co-incubated (pre-incubation) in a 96-well deep well plate in an orbital incubator (preincubation for 10 min at 37 °C). Reactions were initiated by the addition of 2.5 pL of 200 pM working stock solution of the test item. Aliquots (50 pL) were withdrawn from the reaction tube at 0, 15, 30, 45, 60, 90 and 120 min and the reaction was immediately terminated by transferring to a 96 deep well plate containing 200 pL of acetonitrile.

[0671] NADPH-free control incubations were performed by mixing lung S9 fraction (25 pL) and phosphate buffer (223.75 pL) and incubating at 37 °C for 10 minutes. Reaction was initiated by addition of 1.25 pL of test item. Aliquots (50 pL) were withdrawn at 0 and 120 minutes and reaction was terminated with 200 pL of acetonitrile. Reaction and control experiments were performed in duplicate. Phenacetin and 7 Ethoxy resorufin (0.5 pM each) were used as AGO-P3616PCT Application as filed positive controls in mouse, rat and human lung S9 fractions. Reaction and control experiments were performed in singlet.

[0672] The experiment conditions were modified based on the initial experiment and all modifications if any were presented in the report. To the quenched samples, internal standard was added and vortex mixed followed by centrifugation at 4,000 rpm for 10 min and an aliquot of supernatant was stored at -70 °C until LC-MS / MS analysis.

[0673] Bioanalysis: The experimental samples were analysed by employing a suitable multiple reaction monitoring method developed on LC-MS / MS using an API 4000 mass spectrometer to estimate the area ratio (analyte peak area / internal standard peak area). The method for bioanalysis was included in the final report. Data Analysis:

[0674] The data was fitted to the one phase exponential decay equation (A = Aoe'kt) using GraphPad Prism® software. The half-life (ti / 2) generated by the software was reported. Intrinsic clearance was calculated using the formula where, k = decay rate constant (min-1) x volumeofreactionmixture( / zL) mtproteincontent(mg)

[0675] Biological Example 6 - hERG Binding Affinity

[0676] Compound preparation: Mother plate with control compound and test compounds was prepared in Storplate-384-deep- well-V-bottom plate. Test compounds were prepared as 100x concentrated by diluting 10 mM DMSO stock 3.33x in DMSO and 9 more three-fold consecutive dilutions were prepared by mixing 5 pL of compound solution with 10 pL of DMSO. Compounds were tested in triplicates and diluted 100x in test plate for a final starting concentration of 30 pM. Control compound E- 4031 was prepared from 3 mM stock by diluting it 6x in DMSO in order to prepare 500 pM concentration. E-4031 was tested on each assay plate in triplicates in concentration response at 10 consecutive three-fold dilutions starting from 5 pM final concentration.

[0677] An aliquot of 100 nL of compound solution was transferred from the mother plate to the test plate using a Mosquito nanoliter liquid handling system (STP labtech). The assay was AGO-P3616PCT Application as filed performed in 384-well Greiner low volume black test plates using a 10 pL assay volume. The total percentage of DMSO was 1%. 5 pM E-4031 was used as 100% inhibition control, while 0% inhibition control contained membrane, Tracer Red and DMSO.

[0678] Certain test compounds at higher concentrations can cause light scatter in FP experiments (which is highly polarized) or can exhibit an additional, non-hERG-specific reduction or increase in the observed polarization. In order to exclude the interference with the FP assay, correction method was applied and test compounds were tested in the presence and in the absence of saturating control inhibitor (5 pM E-4031). In the presence of saturating amount of inhibitor any non-specific changes in polarization due to test compound can then be observed and subtracted. For this purpose, compounds were prepared in the mother plate as 200x concentrated solutions (10 mM stock solutions were diluted 1.67x in DMSO) and 50 nL of the solution was added by Mosquito to the assay plate in triplicates, final starting compound concentration was 30 pM. E-4031 was also prepared as 200x concentrated solution (40 pL of 3 mM stock was mixed with 80 pL of DMSO, 10 pL per well was added in mother plate) and 50 nL of the solution was added by Mosquito to the assay plate in the wells with test compounds, final concentration of E-4031 in the presence of test compounds was 5 pM.

[0679] Biological Example 7 - TGFp-stimulated rat precision-cut lung slices (PCLS)

[0680] Materials:

[0681] Preparing murine PCLS -

[0682] • Advanced DMEM / F-12 medium, Gibco, Cat. No. 12634-010

[0683] • Antibiotic / Antimycotic (A / A), 100x, Gibco, Cat. No. 15240-062

[0684] • Agarose type I, low EED, Sigma, Cat. No. A6013

[0685] • Dulbecco's Modified Eagle Medium (DMEM), no phenol red, Gibco, Cat. No. 31053- 044

[0686] • Dimethyl sulfoxide (DMSO), Sigma, Cat. No. D2650

[0687] • Recombinant human TGFp, R&D Systems, Cat. No. 240-B

[0688] • RNA Later Stabilization Solution, Invitrogen, Cat. No. AM7021

[0689] RNA isolation -

[0690] • Precellys Hard Tissue CK28 tubes, Bertin Technologies, Cat. No. P000911-LYSK1-A

[0691] • Ethanol, > 99.8 A. R., LachNer, Cat. No. 20025-A99

[0692] • Trizol Reagent, Ambion, Cat. No. 15596018

[0693] • Chloroform, LachNer, Cat. No. 20034-AT1 AGO-P3616PCT Application as filed

[0694] • Isopropyl alcohol, LachNer, Cat. No. 20037-ATO

[0695] • Buffer NTC, Macherey-Nagel, Cat. No. 740654

[0696] • NucleoSpin Gel and PCR Clean-up kit, Macherey-Nagel, Cat. No. 740609

[0697] • Quant-iT RiboGreen RNA kit, Invitrogen, Cat. No. R11490

[0698] Gene expression analysis -

[0699] • SuperScript III Reverse Transcriptase, Invitrogen, Cat. No. 18080-044

[0700] • dNTP Mix, Invitrogen, Cat. No. 18427-088

[0701] • Random primers, Invitrogen, Cat. No. 48190011 • RNase Out, Invitrogen, Cat. No. 10777-019

[0702] • TaqMan Fast Advanced Master Mix, Thermo Fisher, Cat. No. 4444557

[0703] • Pre-designed, pre-optimized primers and TaqMan probe for genes of interest from Thermo Fisher Methods:

[0704] Preparing rat POLS and treatment with compounds and TGF / 3 -

[0705] Male CD(SD) rats are anesthetized with ketamine hydrochloride (Narkamon) and xylazine (Xylazine) and lungs are filled through trachea with 1.5% warm agarose solution in Advanced DMEM / F-12 medium + 1% antibiotic / antimycotics (A / A). After trachea ligation, lungs are excised from the thoracic cavity and placed into Advanced DMEM / F-12 medium + 1% A / A on ice. Agarose filled lungs are cut into cylindrical shapes (8 mm diameter) and used for cutting into -250 pm thick PCLS using Alabama R&D live tissue microtome.

[0706] After preparing all PCLS they are transferred into 24-well plates and treated with test compounds or vehicle in Advanced DMEM / F-12 medium + 1% A / A and then treated with test compounds or vehicle. After 1 h of pre-incubation with compounds or vehicle, PCLS are treated with TGFp at final concentration 20 ng / mL. PCLS are incubated for 72 h at 37°C, 5% CO2, 95% humidity. After end of incubation, PCLS are collected into RNA later stabilization solution and stored at -20°C until RNA isolation.

[0707] RNA isolation and RNA concentration measurement -

[0708] PCLS samples are homogenized in 750 pL of Trizol reagent using Precellys Hard Tissue Tubes and Precellys instrument. To homogenized samples 150 pL of chloroform is added, thoroughly mixed and centrifuged for 15 min at 12,000 g, 4°C. Aqueous phase is collected, followed by addition of 375 pLof isopropanol. Samples are incubated for 10 min at RT, followed by centrifugation for 10 min at 12,000 g, 4°C. Supernatant is discarded and RNA pellet is AGO-P3616PCT Application as filed washed with 750 pL of 75% ethanol, vortexed and then centrifuged for 5 min at 7,500 g, 4°C. Pellet is dissolved in 200 pL of NTC buffer and incubated for 10 min at 50°C with occasional vortexing. 200 pL of 70% ethanol is then added and samples are loaded to NucleoSpin Gel and PCR Clean-up columns. After RNA binding to the membrane, columns are washed with 700 pL of Buffer NT3 and centrifuged for 30 sec at 11 ,000 g. Flowthrough is discarded and washing step is repeated. Then, columns are completely dried by centrifugation for 1 min at 11 ,000 g. RNA is finally eluted by adding 25 pL of Buffer NE directly onto the membrane of the column and centrifuged for 1 min at 11 ,000 g. RNA samples are stored at -80°C until use for RNA concentration measurement, reverse transcription, and gene expression analysis.

[0709] RNA concentrations are determined using Quant-iT RiboGreen kit, following manufacturers’ instructions. RNA is diluted 200x in TE buffer. Standard is prepared in concentrations 2000, 1000, 200 and 40 ng / mL in TE buffer. 100 pL of samples or standards are added to black 96- well plate. 100 pL of TE Buffer is used as blank. Quant-iT RiboGreen reagent is diluted 200x and then 100 pL is added to each well with samples or standards. Plate is incubated for 5 min at RT, in the dark. Fluorescent signals are measured at 490 nm excitation and 590 nm emission using EnVision instrument. RNA concentrations in samples are calculated by interpolation from standard curve using Microsoft Excel software. Gene expression analysis -

[0710] Reverse transcription is performed using SuperScript III RT kit following manufacturer’s instructions (Invitrogen). 1 pL of Random primers and 1 pL of 10 mM dNTP are mixed, with 11 pL of RNA. Plate is then incubated for 5 min at 65°C, followed by incubation on ice for 1 min. The rest of the reverse transcription mix is prepared by mixing 4 pL of 5x First strand buffer, 1 pL of 0.1 M DTT, 1 pL of RNAse Out and 1 pL of Superscript III with previously mixed RNA, random primers and dNTPs. Final volume in each well is 20 pL. Program for reverse transcription reaction is: 5 min at 25°C, 60 min at 50°C, 15 min at 70°C and °° at 4°C. After end of reverse transcription reaction, all samples are diluted 5x by adding 80 pL of RNAse free water to 20 pL of prepared cDNA.

[0711] Expression of genes of interest is determined using real-time PCR analysis, and normalized to expression of housekeeping genes. qPCR mix for each gene is prepared separately by mixing 0.5 pL of 20X primers and probe mix, 1 .5 pL of RNase free water and 5 pL of TaqMan Master Mix. Then, 7 pL of each prepared qPCR mix is added to 3 pL of cDNA. qPCR reaction is as follows: 2 min at 50°C (1 cycle), 10 min at 95°C (1 cycle), 15 sec at 95°C (40 cycles) and 60 sec at 60°C (40 cycles). AGO-P3616PCT Application as filed

[0712] Data Analysis:

[0713] Expression of genes of interest is normalized to expression of housekeeping genes. First, geometric mean is calculated from Ct values of housekeeping genes, which is then subtracted from obtained Ct values of test genes using equation: ACt (test gene) = Ct (test gene) - GeoMean Ct (housekeeping genes). Relative gene expression is further calculated from ACt using equation 2A(-ACt) x 1000. All calculations are performed using Microsoft Office Excel software. Calculated relative gene expression is used to prepare graphs using GraphPad Prism software.

[0714] Percentages of inhibition of test compound are calculated for each test gene using calculated relative gene expression data. First, values of vehicle samples are subtracted from TGFp vehicle and compound treated samples. Then, percentage of inhibition over TGFp vehicle is calculated. Graphs are prepared using GraphPad Prism software, and IC50 values are determined using non-linear, four parameter curve fit.

[0715] Biological Example 8 - TGFp-stimulated normal human lung fibroblasts (NHLF)

[0716] Materials:

[0717] Cell culture -

[0718] • Normal Human Lung Fibroblasts (NHLF), Lonza, Cat. No. CC-2515

[0719] • Fibroblast Basal Medium, Lonza, Cat. No. CC-3131

[0720] • FGM-2 SingleQuots Kit (hFGF-B, Insulin, FBS, gentamicin / amphotericin-B), Lonza, Cat. No. CC-4126,

[0721] • Pure Col (Bovine Collagen Solution type I), Advanced BioMatrix, Cat. No. 5005

[0722] • Recombinant human TGFp, R&D Systems, Cat. No. 240-B

[0723] RNA isolation -

[0724] • RLT buffer, Qiagen, Cat. No. 1015762

[0725] • p-Mercaptoethanol, Sigma, Cat. No. M3148

[0726] • RNeasy Mini Kit, Qiagen, Cat. No. 74106

[0727] • Ethanol, > 99.8 A. R., LachNer, Cat. No.20025-A99

[0728] • High Capacity RT Kit, Applied Biosystems, Cat. No. 4368813

[0729] • TaqMan Fast Advanced Master Mix, Thermo Fisher, Cat. No. 4444557

[0730] • Primers and TaqMan probe for genes of interest, Thermo Fisher

[0731] • Primers and TaqMan probe for genes of interest, Microsynth AGO-P3616PCT Application as filed

[0732] Methods:

[0733] Testing compounds in TGF / 3 stimulated NHLF -

[0734] 96-well plates are coated with 3 pg / mL PureCol by incubation for 2 h at 37°C, 5% CO2, 95% humidity. Afterwards, plates are washed with PBS and 8000 cells / well are seeded in fibroblast basal medium supplemented with FGM-2 SingleQuots (hFGF, Insulin, FBS and gentamicin / amphotericin-B). Cells are incubated overnight at 37°C, 5% CO2, 95% humidity.

[0735] The day after, cell medium is aspirated, cells are washed with fibroblast basal medium supplemented with FGM-2 SingleQuots without FBS (starvation medium) and then incubated overnight in starvation medium at 37°C, 5% CO2, 95% humidity.

[0736] The day after, compounds or vehicle are added to the cells and pre-incubated for 1 h at 37°C, 5% CO2, 95% humidity. After 1 h pre-incubation, cells are stimulated with TGFp at final concentration of 1 ng / mL. Cells are then incubated for 48 h (or as required) at 37°C, 5% CO2, 95% humidity.

[0737] After end of incubation, cells are washed with PBS and then lysed in 150 pL / well of RLT buffer with 1% p-mercaptoethanol and stored at -20°C until further use for RNA isolation. RNA isolation and gene expression analysis -

[0738] RNA is isolated from cells using RNeasy Mini Kit from Qiagen, following manufacturers’ instructions. 150 pL of 70% ethanol is added to each well containing 150 pL of RLT buffer + 1 % p-mercaptoethanol and then 300 pL is transferred to RNeasy Mini column. Samples are centrifuged for 30 s at 8,000 x g after which the flow through is discarded. 500 pL of Buffer RW1 is added to each column and samples are centrifuged for 30 s at 8,000 x g after which the flow through is discarded again. Then, the column are washed by adding 500 pL of Buffer RPE and centrifuged for 30 s at 8,000 x g. The flow through is discarded and the column is again washed by adding another 500 pL of Buffer RPE and centrifuged for 2 min at 8,000 x g to dry the membrane. The flow through is discarded and the columns are centrifuged for 1 min at 12,000 x g to completely remove any residual ethanol from the columns. After that, RNA is eluted in 30 pL of RNase free water by centrifugation for 1 min at 8,000 x g.

[0739] Isolated RNA is reverse transcribed to cDNA using High Capacity RT Kit from Applied Biosystems, following manufacturer’s instructions. 2 pL of 10x RT Buffer, 0.8 pL of dNTP Mix (100 mM), 2 pL of 10x Random Primers, 1 pL of Multiscribe RT, 4.2 pL of RNase free water are mixed with 10 pL of RNA. Reverse transcription reaction is as follows: 10 min at 25°C, 120 AGO-P3616PCT Application as filed min at 37°C, 5 min at 85°C. Obtained cDNA is diluted 5x by adding 80 pL of RNase free water to 20 pL of cDNA.

[0740] Expression of genes of interest is determined using real-time PCR analysis, and normalized to expression of housekeeping genes. Primers and probes from Microsynth are diluted to optimized concentrations in RNase free water and then mixed with 5 pL of TaqMan Master and 3 pL of cDNA. Primers and probes from Thermo Fisher are mixed at volume of 0.5 pL of 20X primers and probe mix, 1 .5 pL of RNase free water, 5 pL of TaqMan Master Mix and 3 pL of cDNA. qPCR reaction is as follows: 2 min at 50°C (1 cycle), 10 min at 95°C (1 cycle), 15 sec at 95°C (40 cycles) and 60 sec at 60°C (40 cycles).

[0741] Data Analysis:

[0742] Expression of genes of interest is normalized to expression of housekeeping genes. First, geometric mean is calculated from Ct values of housekeeping genes, which is then subtracted from obtained Ct values of test genes using equation: ACt (test gene) = Ct (test gene) - GeoMean Ct (housekeeping genes). Relative gene expression is further calculated from ACt using equation 2A(-ACt) x 1000. All calculations are performed using Microsoft Office Excel software. Calculated relative gene expression is used to prepare graphs using GraphPad Prism software.

[0743] Percentages of inhibition of test compound are calculated for each test gene using calculated relative gene expression data. First, values of vehicle samples are subtracted from TGFp vehicle and compound treated samples. Then, percentage of inhibition over TGFp vehicle is calculated. Graphs are prepared using GraphPad Prism software, and IC50 values are determined using non-linear, four parameter curve fit.

[0744] Biological Example 9 - Bleomycin-induced lung fibrosis model

[0745] Compounds may be tested in the bleomycin challenge rodent model e.g. as described in Murgo et al (2023).

[0746] The bleomycin-induced lung fibrosis model in mouse is recognized as adequate to evaluate the potential of novel therapeutics for the treatment of I PF patients. The translational value of this model towards human disease has been well documented (Murgo et al., 2023).

[0747] In brief, a possible protocol for testing candidate treatments for I PF in a therapeutic setting of the bleomycin model is as follows. On day 0, animals are challenged with a single intranasal AGO-P3616PCT Application as filed administration of 1 mg / kg of bleomycin. On day 6, the oral administration of test compounds is initiated in the animals pretreated with a single dose of bleomycin 6 days earlier. A negative control group is included in the study, in which bleomycin-pretreated animals are administered orally vehicle only. A positive control group is included in the study, where bleomycin- pretreated animals are dosed orally a with a compound that has known activity in the model, e.g. Nintedanib (60 mg / kg twice a day). Daily treatment is maintained until day 21. At termination of the study, animals a sacrificed and lungs sampled and weighed. A lung lobe is collected and stored in RNAIater for future gene expression studies. Remaining lungs are stored in 10% buffered formalin and ultimately embedded in paraffin for sectioning using a microtome. Lungs sections stained using the trichrome method are then used to score disease severity, typically using the Ashcroft score.

[0748] REFERENCES Akhurst, R. J. et al, Targeting the TGFp signalling pathway in disease, Nature Reviews, 2012, 11 (10), 790-811.

[0749] Aschner, Y. et al, Transforming Growth Factor-p: Master Regulator of the Respiratory System in Health and Disease, American Journal of Respiratory Cell and Molecular Biology, 2016, 54(5), 647-655. Bierie, B. et al, TGF-p: the molecular Jekyll and Hyde of cancer, Nature Reviews Cancer, 2006, 6, 506-520.

[0750] Biernacka, A. et al, TGF-p signalling in fibrosis, Growth Factors, 2011 , 29(5), 196-202.

[0751] Heldin, C. H. et al, Signalling Receptors for TGF-b Family Members, Cold Spring Harb Perspect Biol, 2016, 8(8), 1-33. Howell, J. E. etal, TGF-p: Its Role in Asthma and Therapeutic Potential, Current Drug Targets, 2006, 7(5), 547-565.

[0752] Li, S. W. et al, SARS coronavirus papain-like protease induces Egr-1 -dependent up-regulation of TGF-pi via ROS / p38 MAPK / STAT3 pathway, Sci Rep., 2016, 6, 25754.

[0753] Murgo, A. et al, Harnessing the translational power of bleomycin model: new insights to guide drug discovery for idiopathic pulmonary fibrosis. Front Pharmacol., 2023, 14, 1303646.

[0754] Saito, A. et al, TGF-p Signaling in Lung Health and Disease, Int. J. Mol. Sci., 2018, 19(8), 2460.

[0755] Wang, J. et al, Targeting Transforming Growth Factor-b Signalling in Primary Open-Angle Glaucoma, J Glaucoma, 2017, 26(4), 390-395. Xia, Y. C. et al, Glucocorticoid Insensitivity in Virally Infected Airway Epithelial Cells Is Dependent on Transforming Growth Factor-p Activity, PLoS Pathog, 2017, 13(1), 1006138. AGO-P3616PCT Application as filed

[0756] All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth.

[0757] Throughout the specification and the claims which follow, unless the context requires otherwise, the word ‘comprise’, and variations such as ‘comprises’ and ‘comprising’, will be understood to imply the inclusion of a stated integer, step, group of integers or group of steps but not to the exclusion of any other integer, step, group of integers or group of steps.

[0758] The application of which this description and claims forms part may be used as a basis for priority in respect of any subsequent application. The claims of such subsequent application may be directed to any feature or combination of features described herein. They may take the form of product, composition, process, or use claims and may include, by way of example and without limitation, the claims which follow.

Claims

AGO-P3616PCT Application as filedCLAIMS1. A compound of formula (I):wherein:Ri is independently selected from the group consisting of halo, Ci-4alkyl optionally substituted by hydroxy, Ci-4haloalkyl and Ci-4alkoxy; n is 1 , 2 or 3;represents the point of connection to the remainder of the compound;R2 is independently selected from the group consisting of Ci-4alkyl optionally substituted by hydroxy, Ci-4haloalkyl and halo; p is 0, 1 or 2;Z is CH or N; wherein:A) when Z is N, R3 is H and R4 is -C(=O)O-Rs, orB) when Z is CH, R3 is H and R4 is -C(=O)O-Rs orC) when Z is CH, R4 is H and R3 is -C(=O)O-Rs; and in each of A), B) and C) above: Rs is selected from the group consisting of Ci-4alkyl, Co-salkylene-Cs-ecycloalkyl, C2- salkylene-NRsARsB, Co-3alkylene-C-linked 4-8 membered nitrogen containing heterocyclyl, and Ci-3alkylene-N-linked 4-8 membered nitrogen containing heterocyclyl, wherein the 4-8 membered nitrogen containing heterocyclyl is optionally substituted by one RSD, one, two or three RSE, and an oxo group; RSA is selected from the group consisting of H, Ci-4alkyl and C-linked 4-8 membered nitrogen containing heterocyclyl wherein the C-linked 4-8 membered nitrogenAGO-P3616PCT Application as filed containing heterocyclyl is optionally substituted by one or two Rsc, one RSF, and an oxo group;RSB is H or Ci-4alkyl;Rsc is selected from the group consisting of Ci-4alkyl optionally substituted by hydroxy or methoxy, Ci-4alkoxy, Ci-4haloalkyl, halo and -NRSARSB;RSD is selected from the group consisting of 4-6 membered nitrogen containing heterocyclyl and Cs-scycloalkyl each of which being optionally substituted by one or two methyl groups and wherein the heterocyclyl is optionally substituted by an oxo group;RSE is selected from the group consisting of Ci-4alkyl optionally substituted by hydroxy or methoxy, Ci-4alkoxy, Ci-4haloalkyl, halo and -NRSARSB;RSF is Cs-scycloalkyl optionally substituted by one or two methyl groups; andRSA and RSB are independently selected from H and methyl; or a pharmaceutically acceptable salt and / or solvate thereof.

2. The compound or pharmaceutically acceptable salt and / or solvate thereof according to claim 1 , wherein Z is N.

3. The compound or pharmaceutically acceptable salt and / or solvate thereof according to claim 1 , wherein Z is CH.

4. The compound according to claim 1 or claim 2, which is a compound of formula (IA): whereinor a pharmaceutically acceptable salt and / or solvate thereof.

5. The compound according to claim 4, which is a compound of formula (IA):AGO-P3616PCT Application as filedor a pharmaceutically acceptable salt and / or solvate thereof.

6. The compound according to claim 4, which is a compound of formula (IA”):wherein Ri, R2, Rs, n and p are as defined in claim 1 ; or a pharmaceutically acceptable salt and / or solvate thereof.

7. The compound according to claim 1 or claim 3, which is a compound of formula (IB):AGO-P3616PCT Application as filed whereinor a pharmaceutically acceptable salt and / or solvate thereof.

8. The compound according to claim 7, which is a compound of formula (IB’):wherein R1, R2, Rs, n and p are as defined in claim 1 ; or a pharmaceutically acceptable salt and / or solvate thereof.

9. The compound according to claim 7, which is a compound of formula (IB”):wherein R1, R2, Rs, n and p are as defined in claim 1 ; or a pharmaceutically acceptable salt and / or solvate thereof.

10. The compound according to claim 1 or claim 3, which is a compound of formula (IC):AGO-P3616PCT Application as filed whereinor a pharmaceutically acceptable salt and / or solvate thereof.

11. The compound according to claim 10, which is a compound of formula (IC’):or a pharmaceutically acceptable salt and / or solvate thereof.

12. The compound according to claim 10 which is a compound of formula (IC”):AGO-P3616PCT Application as filed wherein Ri, R2, Rs, n and p are as defined in claim 1 ; or a pharmaceutically acceptable salt and / or solvate thereof.

13. The compound or pharmaceutically acceptable salt and / or solvate thereof according to any one of claims 1 to 12, wherein R1 is independently halo.

14. The compound or pharmaceutically acceptable salt and / or solvate thereof according to claim 13, wherein R1 is independently fluoro or chloro.

15. The compound or pharmaceutically acceptable salt and / or solvate thereof according to any one of claims 1 to 14, wherein n is 2.

16. The compound or pharmaceutically acceptable salt and / or solvate thereof according to claim 15, wherein the following moiety forms:whereinrepresents the point of connection to the remainder of the compound.

17. The compound or pharmaceutically acceptable salt and / or solvate thereof according to any one of claims 1 to 16, wherein p is 0.

18. The compound or pharmaceutically acceptable salt and / or solvate thereof according to any one of claims 1 to 16, wherein p is 1.

19. The compound or pharmaceutically acceptable salt and / or solvate thereof according to any one of claims 1 to 16 or 18, wherein R2 is C1-4 alkyl.

20. The compound or pharmaceutically acceptable salt and / or solvate thereof according to claim 19, wherein R2 is methyl.

21. The compound according to claim 1 , which is a compound of formula (ID):AGO-P3616PCT Application as filedwherein R3 is H and R4 is -C(=O)-O-Rs wherein Rs is as defined in claim 1 : or a pharmaceutically acceptable salt and / or solvate thereof.

22. The compound according to claim 1 , which is a compound of formula (IE):wherein R3 is H and R4 is -C(=O)-O-Rs wherein Rs is as defined in claim 1 : or a pharmaceutically acceptable salt and / or solvate thereof.

23. The compound according to claim 1 , which is a compound of formula (IF):wherein R4 is H and R3 is -C(=O)O-Rs wherein Rs is as defined in claim 1 : or a pharmaceutically acceptable salt and / or solvate thereof.AGO-P3616PCT Application as filed24. The compound or pharmaceutically acceptable salt and / or solvate thereof according to any one of claims 1 to 23, wherein Rs is selected from the group consisting of Ci-4alkyl, C2- salkylene-NRsA sB, Co-3alkylene-C-linked 4-8 membered nitrogen containing heterocyclyl, and Ci-3alkylene-N-linked 4-8 membered nitrogen containing heterocyclyl, wherein the 4-8 membered nitrogen containing heterocyclyl is optionally substituted by one RSD and one, two or three RSE.

25. The compound or pharmaceutically acceptable salt and / or solvate thereof according to claim 24, wherein Rs is selected from the group consisting of methyl or ethyl.

26. The compound or pharmaceutically acceptable salt and / or solvate thereof according to claim 24, wherein Rs is C2alkylene-NRsARsB.

27. The compound or pharmaceutically acceptable salt and / or solvate thereof according to claim 26, wherein RSA selected from the group consisting of H, Ci-4alkyl and C-linked 4-8 membered nitrogen containing heterocyclyl wherein the C-linked 4-8 membered nitrogen containing heterocyclyl is optionally substituted by one or two Rsc.

28. The compound or pharmaceutically acceptable salt and / or solvate thereof according to claim 27, wherein RSA is C-linked 4-8 membered nitrogen containing heterocyclyl.

29. The compound or pharmaceutically acceptable salt and / or solvate thereof according to any one of claims 26 to 28, wherein RSB is H or methyl.

30. The compound or pharmaceutically acceptable salt and / or solvate thereof according to claim 29, wherein RSA and RSB are each H or methyl.

31. The compound or pharmaceutically acceptable salt and / or solvate thereof according to claim 1 , which is selected from the group consisting of:Methyl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)-1 ,5-naphthyridine-3-carboxylate;Piperidin-4-ylmethyl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)-1 ,5-naphthyridine-3- carboxylate;2-(Dimethylamino)ethyl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)-1 ,5-naphthyridine-3- carboxylate;1 - M ethy I py rro I id i n-3-y I 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)-1 ,5-naphthyridine-3- carboxylate;AGO-P3616PCT Application as filed2-(Diethylamino)ethyl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)-1 ,5-naphthyridine-3- carboxylate;2-(Pipendin-4-ylammo)ethyl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)-1 ,5- naphthyridine-3-carboxylate;(4-Amino-1-methylpiperidin-4-yl)methyl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)-1 ,5- naphthyridine-3-carboxylate;1 - (pi pe ri d i n-4-y I) azetid i n-3-y I 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)-1 ,5- naphthyridine-3-carboxylate;2-(4-Aminopiperidin-4-yl)ethyl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)-1 ,5- naphthyridine-3-carboxylate;2-(4-Aminopiperidin-1-yl)ethyl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)-1 ,5- naphthyridine-3-carboxylate;3-(4-Aminopiperidin-1-yl)propyl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)-1 ,5- naphthyridine-3-carboxylate;2-(Methyl(piperidin-4-yl)amino)ethyl 6-(3-(5-chloro-2-fluorophenyl)-1 / 7-pyrazol-4-yl)-1 ,5- naphthyridine-3-carboxylate; 2-(((2S,6R)-2,6-Dimethylpiperidin-4-yl)amino)ethyl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol- 4-yl)-1 ,5-naphthyridine-3-carboxylate; 2-(((2R,6R)-2,6-Dimethylpiperidin-4-yl)amino)ethyl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol- 4-yl)- 1 ,5-naphthyridine-3-carboxylate;2-(2S,6R)-2,6-Diethylpiperidin-4-yl)amino)ethyl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4- yl)-1 ,5-naphthyridine-3-carboxylate;2-(Piperidin-4-ylamino)ethyl 6-(3-(5-chloro-2-fluorophenyl)-5-methyl-1 H-pyrazol-4-yl)-1 ,5- naphthyridine-3-carboxylate; 1 -Methylpiperidin-4-yl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)-1 ,5-naphthyridine-3- carboxylate;Piperidin-4-yl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)-1 ,5-naphthyridine-3- carboxylate; Azetidin-3-yl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)-1 ,5-naphthyridine-3-carboxylate; 1-Methylazetidin-3-yl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)-1 ,5-naphthyridine-3- carboxylate; 2-((3S,5R)-3,5-Dimethylpiperazin-1-yl)ethyl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)- 1 ,5-naphthyridine-3-carboxylate; 2-(3S,5R)-3,5-Dimethylpiperazin-1-yl)ethyl 6-(3-(5-chloro-2-fluorophenyl)-5-methyl-1 H- pyrazol-4-yl)-1 ,5-naphthyridine-3-carboxylate; 2-(Piperazin-1-yl)ethyl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)-1 ,5-naphthyridine-3- carboxylate;AGO-P3616PCT Application as filed2-(Dimethylamino)ethyl 6-(3-(5-chloro-2-fluorophenyl)-5-methyl-1 H-pyrazol-4-yl)-1 ,5- naphthyridine-3-carboxylate;1 -Methylpyrrolidin-3-yl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)quinoline-4- carboxylate; Azetidin-3-yl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)quinoline-4-carboxylate;(R)-Pyrrolidin-3-yl 6-(3-(5-chloro-2-fluorophenyl)-1H-pyrazol-4-yl)quinoline-4-carboxylate;2,2-Dimethylazetidin-3-yl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)quinoline-4- carboxylate;(2S,4R,6R)-2,6-Dimethylpiperidin-4-yl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4- yl)quinoline-4-carboxylate;3,3-Dimethylpiperidin-4-yl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)quinoline-4- carboxylate;3-Methylazetidin-3-yl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)quinoline-4-carboxylate;3-Azabicyclo[3.1 ,0]hexan-6-yl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)quinoline-4- carboxylate;3,3-Difluoro-1-methylpiperidin-4-yl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)quinoline-4- carboxylate;(2R,3S)-2-Methylazetidin-3-yl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)quinoline-4- carboxylate;(2S,3S)-2-Methylazetidin-3-yl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)quinoline-4- carboxylate;2-(Piperidin-4-ylamino)ethyl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)quinoline-4- carboxylate; 2-((3S,5R)-3,5-Dimethylpiperazin-1-yl)ethyl 6-(3-(5-chloro-2-fluorophenyl)-5-methyl-1 H- pyrazol-4-yl)quinoline-4-carboxylate;1-Methylazetidin-3-yl 6-(3-(5-chloro-2-fluorophenyl)-5-methyl-1 H-pyrazol-4-yl)quinoline-4- carboxylate;1 -Methylpiperidin-4-yl 6-(3-(5-chloro-2-fluorophenyl)-5-methyl-1 H-pyrazol-4-yl)quinoline-4- carboxylate; 1 -lsopropylpiperidin-4-yl 6-(3-(5-chloro-2-fluorophenyl)-5-methyl-1 H-pyrazol-4-yl)quinoline-4- carboxylate;Piperidin-4-ylmethyl 6-(3-(5-chloro-2-fluorophenyl)-1-methyl-1 H-pyrazol-4-yl)quinoline-3- carboxylate;2-((3S,5R)-3,5-Dimethylpiperazin-1-yl)ethyl 6-(3-(5-chloro-2-fluorophenyl)-1-methyl-1 H- pyrazol-4-yl)quinoline-3-carboxylate;2-((3S,5R)-3,5-Dimethylpiperazin-1-yl)ethyl 6-(3-(5-chloro-2-fluorophenyl)-5-methyl-1 H- pyrazol-4-yl)quinoline-3-carboxylate;AGO-P3616PCT Application as filedAzetidin-3-yl 6-(3-(5-chloro-2-fluorophenyl)-5-methyl-1 H-pyrazol-4-yl) quinoline-3- carboxylate;Piperidin-4-yl 6-(3-(5-chloro-2-fluorophenyl)-5-methyl-1 H-pyrazol-4-yl)quinoline-3- carboxylate; (Piperidin-4-yl)aminoethyl 6-(3-(5-Chloro-2-fluorophenyl)-5-methyl-1 H-pyrazol-4-yl)quinoline- 3-carboxylate; 2-Aminoethyl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)quinoline-4-carboxylate; Piperidin-4-ylmethyl 6-(3-(5-chloro-2-fluorophenyl)-5-methyl-1 H-pyrazol-4-yl)quinoline-4- carboxylate; 2-(Piperidin-4-ylamino)ethyl 6-(3-(5-chloro-2-fluorophenyl)-5-methyl-1 H-pyrazol-4- yl)quinoline-4-carboxylate; Methyl 6-(3-(5-Chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)quinoline-4-carboxylate; Methyl 6-(3-(5-Chloro-2-fluorophenyl)-1-methyl-1 H-pyrazol-4-yl)quinoline-4-carboxylate; Methyl 6-(3-(5-Chloro-2-fluorophenyl)-5-methyl-1 H-pyrazol-4-yl)quinoline-4-carboxylate; Ethyl 6-(3-(5-Chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)quinoline-3-carboxylate;2-dimethylaminoethyl 6-(3-(5-Chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)quinoline-4-carboxylate; 2-(4-methylpiperazin-1-yl)ethyl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)quinoline-4- carboxylate; 2-(4-Methylpiperazin-1-yl)ethyl 6-(3-(5-chloro-2-fluorophenyl)-5-methyl-1 H-pyrazol-4- yl)quinoline-4-carboxylate;1 -Methylpyrrolidin-3-yl 6-(3-(5-chloro-2-fluorophenyl)-5-methyl-1 H-pyrazol-4-yl)quinoline-4- carboxylate;1 -Methylpyrrolidin-3-yl 6-(3-(5-chloro-2-fluorophenyl)-5-methyl-1 H-pyrazol-4-yl)quinoline-3- carboxylate; 1 -Methylpyrrolidin-3-yl 6-(3-(5-chloro-2-fluorophenyl)-1-methyl-1 H-pyrazol-4-yl)quinoline-3- carboxylate;4-piperidinylmethyl 6-(3-(5-Chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)quinoline-4-carboxylate;2-((3S,5R)-3,5-Dimethylpiperazin-1-yl)ethyl 6-(3-(5-Chloro-2-fluorophenyl)-1 H-pyrazol-4- yl)quinoline-4-carboxylate;2-(Piperazin-1-yl)ethyl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)quinoline-4- carboxylate; Piperidin-4-ylmethyl 6-(3-(5-chloro-2-fluorophenyl)-5-methyl-1 H-pyrazol-4-yl)quinoline-3- carboxylate;1 -Methylpiperidin-4-yl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)quinoline-4-carboxylate; (R)-1 -Methylpyrrolidin-3-yl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)quinoline-4- carboxylate;AGO-P3616PCT Application as filed(S)-1-Methylpyrrohdm-3-yl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)quinoline-4- carboxylate;1-lsopropylazetidin-3-yl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)quinoline-4- carboxylate;1 -lsopropylpiperidin-4-yl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)quinoline-4- carboxylate;1 -Cyclopropylpiperidin-4-yl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)quinoline-4- carboxylate;2-(Diethylamino)ethyl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)quinoline-4-carboxylate; 1-Methylazetidin-3-yl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)quinoline-4-carboxylate;1 -Methylpiperidin-4-yl 6-(3-(5-chloro-2-fluorophenyl)-5-methyl-1 H-pyrazol-4-yl)quinoline-3- carboxylate;1-Methylazetidin-3-yl 6-(3-(5-chloro-2-fluorophenyl)-5-methyl-1 H-pyrazol-4-yl)quinoline-3- carboxylate;Piperidin-4-yl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)quinoline-4-carboxylate;1 .4-Diazepan-6-yl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)-1 ,5-naphthyridine-3- carboxylate;Methyl 6-(4-(3-chloro-4-fluorophenyl)-1-(2-hydroxyethyl)-1 H-imidazol-5-yl)quinoline-4- carboxylate;Ethyl 6-(4-(3-chloro-4-fluorophenyl)-1-(2-hydroxyethyl)-1 H-imidazol-5-yl)quinoline-3- carboxylate;2-(Bis(methyl-d3)amino)ethyl-1 ,1 ,2,2-d4 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)-1 ,5- naphthyridine-3-carboxylate;2-(Bis(methyl-d3)amino)ethyl-1 ,1 ,2,2-d4 6-(3-(5-chloro-2-fluorophenyl)-5-methyl-1 H-pyrazol- 4-yl)quinoline-3-carboxylate; and2-((3R,5R)-3,5-Dimethylpiperazin-1-yl)ethyl 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)-1.5-naphthyridine-3-carboxylate; or a pharmaceutically acceptable salt and / or solvate of any one thereof.

32. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt and / or solvate thereof according to any one of claims 1 to 31 and a pharmaceutically acceptable diluent or carrier.

33. The compound or pharmaceutically acceptable salt and / or solvate thereof according to any one of claims 1 to 31 , or pharmaceutical composition according to claim 32, for use as a medicament.AGO-P3616PCT Application as filed34. The compound or pharmaceutically acceptable salt and / or solvate thereof according to any one of claims 1 to 31 , or pharmaceutical composition according to claim 32, for use in the treatment or prevention of a disease or pathological disorder susceptible to amelioration by inhibition of ALK5.

35. Use of the compound or pharmaceutically acceptable salt and / or solvate thereof according to any one of claims 1 to 31 , or pharmaceutical composition according to claim 32, in the manufacture of a medicament for the treatment or prevention of a disease or pathological disorder susceptible to amelioration by inhibition of ALK5.

36. A method of treatment or prevention of a disease or pathological disorder susceptible to amelioration by inhibition of ALK5 comprising the administration to a subject in need thereof of the compound or pharmaceutically acceptable salt and / or solvate thereof according to any one of claims 1 to 31 , or pharmaceutical composition according to claim 32.

37. The compound or pharmaceutically acceptable salt and / or solvate thereof according to any one of claims 1 to 31 , or pharmaceutical composition according to claim 32, for use in the treatment or prevention of lung diseases such as idiopathic pulmonary fibrosis.

38. The compound or pharmaceutically acceptable salt and / or solvate thereof according to any one of claims 1 to 31 , or pharmaceutical composition according to claim 32, for administration by inhalation as a liquid or solid.

39. A compound or a salt and / or solvate thereof, which is selected from the group consisting of: a compound formula (II):wherein Ri, R2, Z, n and p are as defined in any one of claims 1 to 31 or a salt and / or solvate thereof; a compound formula (III):AGO-P3616PCT Application as filedwherein Ri, R2, n and p are as defined in any one of claims 1 to 31 or a salt and / or solvate thereof; a compound formula (IX):wherein R1 and n are as defined in any one of claims 1 to 31 or a salt and / or solvate thereof; a compound formula (X):wherein R1 and n are as defined in any one of claims 1 to 31 or a salt and / or solvate thereof; a compound formula (XI):wherein R1 and n are as defined in any one of claims 1 to 31 or a salt and / or solvate thereof; a compound formula (XII):AGO-P3616PCT Application as filedwherein Ri and n are as defined in any one of claims 1 to 31 and X is halo (e.g. Br) or a salt and / or solvate thereof; a compound formula (XIII):wherein Ri, R2 and n are as defined in any one of claims 1 to 31 or a salt and / or solvate thereof; a compound formula (XVII):wherein Ri, R2, n and p are as defined in any one of claims 1 to 31 and PG2is a carboxylic acid protecting group such as methyl, or a salt and / or solvate thereof; and a compound formula (XX):wherein Ri, R2, n and p are as defined in any one of claims 1 to 31 and PG3is a carboxylic acid protecting group such as methyl, or a salt and / or solvate thereof.AGO-P3616PCT Application as filed40. A process for the preparation of the compound of formula (I) or a salt and / or solvate thereof such as a pharmaceutically acceptable salt and / or solvate thereof as defined in any one of claims 1 to 31 , comprising reacting either: a compound of formula (II):wherein Ri , R2, Z, n and p are as defined in any one of claims 1 to 31 , or an activated derivative thereof or a salt and / or solvent thereof; or a compound of formula (III):wherein R1, R2, n and p are as defined in any one of claims 1 to 31 , or an activated derivative thereof or a salt and / or solvent thereof; with a compound of formula (IV):Rs-OH (IV) wherein R5 is as defined in claim 1 or an activated derivative thereof or a salt and / or solvate thereof.

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