Novel compounds

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-P3725PCT 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-P3725PCT 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 which have favourable properties for use as a pharmaceutical. AGO-P3725PCT 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; 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; m is 0, 1 or 2;

[0017] Z is CH or N; A is -Ci-4alkylene-;

[0018] B is selected from the group consisting of phenyl optionally fused to a 5-7 membered nitrogen containing heterocyclyl, 5-6 membered heteroaryl optionally fused to a 5-7 membered nitrogen containing heterocyclyl, and 4-10 membered nitrogen containing heterocyclyl;

[0019] R3 is independently selected from the group consisting of Ci-4alkyl optionally substituted by hydroxy or methoxy, hydroxy, Ci-4alkoxy, Ci-4haloalkyl, halo and -N RSARSB;

[0020] RSA and RSB are independently selected from H and methyl;

[0021] R4 is selected from the group consisting of 4-6 membered nitrogen containing heterocyclyl and Cs-ecycloalkyl in either case optionally substituted by one or two methyl groups; p is 0, 1 or 2; q is 0 or 1 ; and

[0022] Re is H or Ci-4alkyl; AGO-P3725PCT Application as filed or a pharmaceutically acceptable salt and / or solvate thereof.

[0023] The compounds of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof are herein referred to as “a compound of the invention”.

[0024] Detailed Description of the Invention

[0025] Compounds of formulae (I), (IA), (IA), (IA”), (IB), (IB’) and (IB”) are herein all referred to as “compounds of the invention”. Compounds of formulae (IA), (IA), (IA”), (IB), (IB’) and (IB”) 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’) and (IB”) except where the context indicates otherwise.

[0026] In one embodiment, the compound of the invention is provided in the form of a compound of formula (I). The invention further provides a pharmaceutically acceptable salt and / or solvate of a compound of the invention. The invention further provides a pharmaceutically acceptable salt and solvate of a compound of the invention (i.e. a pharmaceutically acceptable solvate of a pharmaceutically acceptable salt of a compound of the invention). The invention further provides a pharmaceutically acceptable salt of a compound of the invention. The invention further provides a pharmaceutically acceptable solvate of a compound of the invention. 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, the compound of the invention is provided in the form of a compound which is not a salt or a solvate.

[0027] 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. Such embodiments apply equally to intermediates which may be of use in the synthesis of compounds of formula (I), (IA), (IA), (IA”), (IB), (IB’) and / or (IB”) e.g. compounds of formulae (II) and (III).

[0028] Embodiments and preferences set out herein with respect to the compounds of formula (I), (IA), (IA), (IA”), (IB), (IB’) and / or (IB”) 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. AGO-P3725PCT Application as filed

[0029] 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 “Ci-4alkylene” which is a bifunctional straight or branched fully saturated hydrocarbon group having a specified number of carbon atoms. 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. A Ci-4alkyl group may (where so indicated) be optionally substituted by -OMe; an example includes -CF^CFWMe.

[0030] The term “alkoxy” refers to an alkyl group, such as “Ci-4alkyl” as defined above, singularly bonded via an oxygen atom. An examples of an alkoxy group includes -OCH3.

[0031] The term “hydroxy” refers to an -OH group.

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

[0033] 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.

[0034] The term “Cs-ecycloalkyl” (such as C3-4cycloalkyl, Cs-scycloalkyl, C4-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.

[0035] The term “4-10 membered nitrogen containing heterocyclyl” refers to a non-aromatic cyclic group having 4 to 10 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 monocyclic groups such as pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl. Other heterocyclyl groups, for example 4-7 membered nitrogen containing heterocyclyl, 5-7 membered nitrogen containing heterocyclyl, 5-6 membered nitrogen containing heterocyclyl, 4 membered nitrogen containing heterocyclyl, 5 membered nitrogen containing heterocyclyl, 6 membered nitrogen containing heterocyclyl, 7 membered nitrogen containing heterocyclyl and 8 membered nitrogen containing heterocyclyl are as AGO-P3725PCT Application as filed 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 nitrogen containing heterocyclyl groups may contain only N heteroatoms, suitably one or two N heteroatoms, such as azetidine, pyrrolidine, piperazine and piperidine. The term “4-10 membered nitrogen containing heterocyclyl” as used herein also refers to a non-aromatic cyclic group having the specified number of ring atoms formed in two fused rings, at least one of which atoms is a nitrogen atom and may include other heteroatoms selected from N, O and S, such as N or O, e.g. N. Heterocyclyl groups comprising two fused rings may contain at least one nitrogen atom and may also include one other heteroatom e.g. O, N or S especially O or N such as N, or may contain at least one nitrogen atom and may also include two other heteroatoms e.g. two N atoms or a N atom and an O or S atom, or may contain at least one nitrogen atom and may also include three other heteroatoms e.g. one N atoms and two O atoms. When the heterocyclyl groups comprises two fused rings, one ring may contain at least one nitrogen atom and may also include one or more heteroatoms selected from N, O or S, or both rings may contain at least one nitrogen atom and may also include one or more heteroatoms selected from N, O or S. An example of a heterocyclyl comprising two fused rings is tetrahydro-5H-[1 ,3]dioxolo[4,5-c]pyrrol-5-yl: wherein " \ represents the point of connection to the remainder of the compound.

[0036] The term “5-6 membered heteroaryl” refers to a cyclic group with aromatic character having 5 to 6 ring atoms, at least one of which is a heteroatom independently selected from N, O and S. The term encompasses pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, oxazolyl, isoxazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyradizinyl and pyrazinyl. Where a heteroaryl group contains more than one ring, not all rings must contain a heteroatom, and not all rings must be aromatic in character.

[0037] 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. For example, where it is stated that B is N-linked, B is connected to A via an available N atom in ring B, for example when B is 4- 10 membered nitrogen containing heterocyclyl.

[0038] Where substituents are indicated as being optionally substituted in formula (I) in the AGO-P3725PCT Application as filed 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 a hydrogen atom i.e. a C-H 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. The optional substituent replaces the hydrogen atom attached to the carbon atom or the hydrogen atom attached to the nitrogen atom.

[0039] Furthermore, the skilled person will appreciate that substitution only occurs on an available carbon atom or nitrogen atom in a manner that follows reasonable chemical rationale e.g. when B is 5-7 membered nitrogen containing heterocyclyl, p is 1 or 2 and R3 is -NRSARSB, the -NRSARSB group would not be attached to an available nitrogen atom such that formation of a nitrogen-nitrogen single bond would be avoided.

[0040] 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.

[0041] In one embodiment, Z is N. In another embodiment, Z is CH.

[0042] In any of the following formulae (such as (IA), (IA), (IA”), (IB), (IB’) and (IB”), all variables (such as R1 , R2, R3, R4, Re, n, m, p and q) are as defined herein.

[0043] 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.

[0044] In an embodiment, a compound of formula (I) is provided, which is a compound of formula (IA’): AGO-P3725PCT Application as filed or a pharmaceutically acceptable salt and / or solvate thereof.

[0045] 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.

[0046] 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.

[0047] In an embodiment, a compound of formula (I) is provided, which is a compound of formula

[0048] (IB’): AGO-P3725PCT Application as filed or a pharmaceutically acceptable salt and / or solvate thereof.

[0049] In an embodiment, a compound of formula (I) is provided, which is a compound of formula

[0050] (IB”): or a pharmaceutically acceptable salt and / or solvate thereof.

[0051] 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 Ci-4alkyl substituted by hydroxy. In another embodiment, Ri is independently unsubstituted Ci-4alkyl. 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.

[0052] In one embodiment, n is 1. In another embodiment, n is 2. In one another embodiment, n is 3. In another embodiment, n is 1 or 2. Suitably, n is 2. In one embodiment, Ri is independently halo and n is 2. In another embodiment, Ri is independently fluoro or chloro and n is 2. AGO-P3725PCT Application as filed

[0053] In one embodiment, Ri is independently fluoro or chloro and n is 2, such that the following moiety forms wherein represents the point of connection to the remainder of the compound.

[0054] Suitably, R1 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.

[0055] In one embodiment, wherein represents the point of connection to the remainder of the compound. In another embodiment, represents the point of connection to the remainder of the compound. Suitably, wherein represents the point of connection to the remainder of the compound.

[0056] 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 AGO-P3725PCT Application as filed or chloro. Suitably R2 is independently selected from the group consisting of Ci -4al ky I optionally substituted by hydroxy, and Ci-4haloalkyl e.g. R2 is Ci-4alkyl such as methyl.

[0057] The R2 group may be bonded to either a N or C atom on the group.

[0058] In one embodiment, m is 0 i.e. R2 is absent. In another embodiment, m is 1. In another embodiment, m is 2. Suitably m is 0 or 1.

[0059] Therefore in one embodiment, m is 0 i.e. R2 is absent, so that the following moiety is formed: wherein " \ represents the point of connection to the remainder of the compound.

[0060] In another embodiment, m 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.

[0061] 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. AGO-P3725PCT Application as filed the R2 group (as defined

[0062] V" (R2)m

[0063] >O above for compounds of formula (I)) and a core form the following moiety: V" wherein represents the point of connection to the remainder of the compound. Suitably, R2 is methyl.

[0064] In another embodiment, the R2 group (as defined above for compounds of formula (I)) and a pyrazolyl core form the following moiety: wherein " V" \" represents the point of connection to the remainder of the compound.

[0065] 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. AGO-P3725PCT Application as filed

[0066] 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.

[0067] In another embodiment, the R2 group (as defined above for compounds of formula (I)) and a imidazolyl core form the following moiety: X wherein " \ represents the point of connection to the remainder of the compound.

[0068] In one embodiment, R2 is Ci-4alkyl, and m is 1. In another embodiment, R2 is methyl, and m is 1. In another embodiment, R2 is ethyl, and m is 1. In one embodiment, R2 is Ci-4alkyl substituted by hydroxy and m is 1. In one embodiment, R2 is ethyl substituted by hydroxy and m is 1. In one embodiment, R2 is Ci-4haloalkyl and m is 1. Suitably, R2 is methyl and m is 1.

[0069] In one embodiment, A is -Ci-2alkylene. In another embodiment, A is -CH2-. In another embodiment, A is -CH2CH2-. In one embodiment, B is phenyl optionally fused to a 5-7 membered nitrogen containing heterocyclyl. In another embodiment, B is phenyl fused to a 5-7 membered nitrogen containing heterocyclyl. In another embodiment, B is phenyl. In another embodiment, B is phenyl fused to a 5 membered nitrogen containing heterocyclyl. In another embodiment, B is phenyl fused AGO-P3725PCT Application as filed to a 6 membered nitrogen containing heterocyclyl. In another embodiment, B is phenyl fused to a piperidinyl to form tetrahydroquinolinyl. In another embodiment, B is phenyl fused to a 7 membered nitrogen containing heterocyclyl. Suitably, B is 1 ,2,3,4-tetrahydroisoquinolin-6-yl: wherein represents the point of connection to the remainder of the compound.

[0070] In one embodiment, B is 5-6 membered heteroaryl optionally fused to a 5-7 membered nitrogen containing heterocyclyl. In another embodiment, B is 5-6 membered heteroaryl fused to a 5-7 membered nitrogen containing heterocyclyl. In another embodiment, B is 5 membered heteroaryl fused to a 5-7 membered nitrogen containing heterocyclyl. In another embodiment, B is 6 membered heteroaryl fused to a 5-7 membered nitrogen containing heterocyclyl. In another embodiment, B is 5 membered heteroaryl. In another embodiment, B is 6 membered heteroaryl. In another embodiment, B is pyridinyl. In another embodiment, B is 5 membered heteroaryl fused to a 5 membered nitrogen containing heterocyclyl. In another embodiment, B is 5 membered heteroaryl fused to a 6 membered nitrogen containing heterocyclyl. In another embodiment, B is 5 membered heteroaryl fused to a 7 membered nitrogen containing heterocyclyl. In another embodiment, B is 6 membered heteroaryl fused to a 5 membered nitrogen containing heterocyclyl. In another embodiment, B is 6 membered heteroaryl fused to a 6 membered nitrogen containing heterocyclyl. In another embodiment, B is 6 membered heteroaryl fused to a 7 membered nitrogen containing heterocyclyl. Suitably, B is pyridinyl.

[0071] In one embodiment, B is 4-10 membered nitrogen containing heterocyclyl. In another embodiment, B is 5-6 membered nitrogen containing heterocyclyl. In another embodiment, B is 4 membered nitrogen containing heterocyclyl. In another embodiment, B is 5 membered nitrogen containing heterocyclyl. In another embodiment, B is pyrrolidinyl. In another embodiment, B is 6 membered nitrogen containing heterocyclyl. In another embodiment, B is piperazinyl. In another embodiment, B is 7 membered nitrogen containing heterocyclyl. In another embodiment, B is 8 membered nitrogen containing heterocyclyl. In another embodiment, B is 9 membered nitrogen containing heterocyclyl. In another embodiment, B is 10 membered nitrogen containing heterocyclyl. In one embodiment, B is monocyclic 4-10 membered nitrogen containing heterocyclyl. Suitably, B is pyrrolidinyl or piperazinyl. In another embodiment, B comprises two fused rings, such that B is bicyclic 4-10 membered nitrogen containing heterocyclyl. Suitably, B is tetrahydro-5H-[1 ,3]dioxolo[4,5-c]pyrrol-5-yl: AGO-P3725PCT Application as filed wherein " \ represents the point of connection to the remainder of the compound.

[0072] In one embodiment, Ra is independently Ci-4alkyl. In another embodiment, Ra is independently methyl or ethyl. In another embodiment, R3 is independently Ci-4alkyl substituted by hydroxy. In another embodiment, R3 is independently Ci-4alkyl substituted by methoxy. In another embodiment, R3 is independently methoxyethyl. In one embodiment, R3 is independently hydroxy. In one embodiment, R3 is independently Ci-4alkoxy. In one embodiment, R3 is independently Ci-4haloalkyl. In another embodiment, R3 is independently CF3. In one embodiment, R3 is independently halo. In another embodiment, R3 is independently fluoro or chloro. In one embodiment, R3 is independently -N RSARSB. In one embodiment, R3 is independently selected from the group consisting of Ci-4alkyl optionally substituted by hydroxy or methoxy, hydroxy and C1-4 alkoxy. In another embodiment, R3 is independently selected from Ci-4alkyl optionally substituted by hydroxy or methoxy, and hydroxy. Suitably, R3 is independently propyl, methoxyethyl or hydroxy.

[0073] In one embodiment, RSA and RSB are both independently H. In another embodiment, RSA and RSB are both independently methyl. In another embodiment, one of RSA and RSB is H and the other is methyl. In another embodiment, RSA is methyl and RSB is H. Suitably, RSA and RSB are both H.

[0074] In one embodiment, p is 0 i.e. R3 is absent. In another embodiment, p is 1. In another embodiment, p is 2. In another embodiment, p is 0 or 1 . In another embodiment, p is 1 or 2. Suitably, p is 0 or 1 .

[0075] In one embodiment, p is 1 and R3 is Ci-4alkyl. In another embodiment, p is 1 and R3 is propyl. In another embodiment, p is 2 and R3 is independently methyl. In another embodiment, p is 2 and R3 is independently hydroxy. In another embodiment, p is 1 and R3 is selected from propyl, methoxyethyl and hydroxy.

[0076] In one embodiment, q is 0, p is 0,1 or 2 and B is optionally substituted by R3 selected from the group consisting of: AGO-P3725PCT Application as filed wherein R3 is as defined elsewhere herein and wherein represents the point of connection to the remainder of the compound.

[0077] In one embodiment, R4 is 4-6 membered nitrogen containing heterocyclyl optionally substituted by one or two methyl groups. In another embodiment, R4 is 4-6 membered nitrogen containing heterocyclyl substituted by one methyl group. In another embodiment, R4 is 4-6 membered nitrogen containing heterocyclyl substituted by two methyl groups. In another embodiment, R4 is unsubstituted 4-6 membered nitrogen containing heterocyclyl. In one embodiment, R4 is Cs-ecycloalkyl optionally substituted by one or two methyl groups. In another embodiment, R4 is Cs-ecycloalkyl substituted by one methyl group. In another embodiment, R4 is Cs-ecycloalkyl substituted by two methyl groups. In another embodiment, R4 is unsubstituted Cs-ecycloalkyl.

[0078] In one embodiment, q is 0 i.e. R4 is absent. In another embodiment, q is 1 . Suitably, q is 0.

[0079] In one embodiment, R4 is 4-6 membered nitrogen containing heterocyclyl and q is 1. In another embodiment, R4 is Cs-ecycloalkyl and q is 1. When p is 0 and q is 1 , B may be any one of the following groups: AGO-P3725PCT Application as filed connection to the remainder of the compound.

[0080] Suitably, q is 1 when B is selected from the group consisting of phenyl, 5-6 membered heteroaryl, and 4-10 membered nitrogen containing heterocyclyl.

[0081] In one embodiment, Re is H. In another embodiment, Re is Ci-4alkyl. In another embodiment, Re is methyl. Suitably, Re is H.

[0082] In one embodiment, A is -Ci-2alkylene-, Re is H and B is selected from the group consisting of phenyl optionally fused to a 5-7 membered nitrogen containing heterocyclyl, 5-6 membered heteroaryl optionally fused to a 5-7 membered nitrogen containing heterocyclyl, and 4-8 membered nitrogen containing heterocyclyl.

[0083] 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: tert-Butyl (2S,6R)-4-(2-(6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)-1 ,5-naphthyridine-3- carboxamido)ethyl)-2,6-dimethylpiperazine-1 -carboxylate;

[0084] 6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)-N-((1 ,2,3,4-tetrahydroisoquinolin-6- yl)methyl)-1 ,5-naphthyridine-3-carboxamide;

[0085] 6-(3-(5-Chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)-N-(pyridin-3-ylmethyl)-1 ,5-naphthyridine-3- carboxamide; N-Benzyl-6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)-1 ,5-naphthyridine-3-carboxamide;

[0086] 6-(3-(5-Chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)-N-(2-((3aR,6aS)-2-(2- methoxyethyl)tetrahydro-5H-[1 ,3]dioxolo[4,5-c]pyrrol-5-yl)ethyl)-1 ,5-naphthyridine-3- carboxamide; AGO-P3725PCT Application as filed

[0087] 6-(3-(5-Chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)-N-(2-((3aR,6aS)-2-propyltetrahydro-5H- [1,3]dioxolo[4,5-c]pyrrol-5-yl)ethyl)-1 ,5-naphthyridine-3-carboxamide;

[0088] 6-(3-(5-Chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)-N-(2-((3S,4R)-3,4-dihydroxypyrrolidin-1- yl)ethyl)-1,5-naphthyridine-3-carboxamide; 6-(3-(5-Chloro-2-fluorophenyl)-5-methyl-1 H-pyrazol-4-yl)-N-((6-hydroxypyridin-3- yl)methyl)quinoline-3-carboxamide; 6-(3-(5-Chloro-2-fluorophenyl)-5-methyl-1 H-pyrazol-4-yl)-N-((2-oxo-1 ,2-dihydropyridin-4- yl)methyl)quinoline-3-carboxamide; 6-(3-(5-Chloro-2-fluorophenyl)-1-methyl-1 H-pyrazol-4-yl)-N-((6-oxo-1 ,6-dihydropyridin-3- yl)methyl)quinoline-3-carboxamide;

[0089] 6-(3-(5-Chloro-2-fluorophenyl)-5-methyl-1 H-pyrazol-4-yl)-N-((6-oxo-1 ,6-dihydropyridin-2- yl)methyl)quinoline-3-carboxamide;

[0090] 6-(3-(5-Chloro-2-fluorophenyl)-5-methyl-1 H-pyrazol-4-yl)-N-((2-oxo-1 ,2-dihydropyridin-3- yl)methyl)quinoline-3-carboxamide; 6-(3-(5-Chloro-2-fluorophenyl)-1-methyl-1 H-pyrazol-4-yl)-N-((2-oxo-1 ,2-dihydropyridin-4- yl)methyl)quinoline-3-carboxamide; 6-(3-(5-Chloro-2-fluorophenyl)-1-methyl-1 H-pyrazol-4-yl)-N-((6-oxo-1 ,6-dihydropyridin-2- yl)methyl)quinoline-3-carboxamide; 6-(3-(5-Chloro-2-fluorophenyl)-1-methyl-1 H-pyrazol-4-yl)-N-((2-oxo-1 ,2-dihydropyridin-3- yl)methyl)quinoline-3-carboxamide;

[0091] N-benzyl-6-(3-(5-chloro-2-fluorophenyl)-5-methyl-1 H-pyrazol-4-yl)quinoline-3-carboxamide; 6-(3-(5-Chloro-2-fluorophenyl)-5-methyl-1 H-pyrazol-4-yl)-N-(pyridin-3-ylmethyl)quinoline-3- carboxamide;

[0092] N-Benzyl-6-(3-(5-chloro-2-fluorophenyl)-1-methyl-1 H-pyrazol-4-yl)quinoline-3-carboxamide; 6-(3-(5-Chloro-2-fluorophenyl)-1-methyl-1 H-pyrazol-4-yl)-N-(pyridin-3-ylmethyl)quinoline-3- carboxamide; 6-(3-(5-Chloro-2-fluorophenyl)-1-methyl-1 H-pyrazol-4-yl)-N-((1,2,3,4-tetrahydroisoquinolin-6- yl)methyl)quinoline-3-carboxamide; and 6-(3-(5-Chloro-2-fluorophenyl)-5-methyl-1 H-pyrazol-4-yl)-N-((1,2,3,4-tetrahydroisoquinolin-6- yl)methyl)quinoline-3-carboxamide; or a pharmaceutically acceptable salt and / or solvate thereof.

[0093] 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 AGO-P3725PCT Application as filed 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.

[0094] 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.

[0095] 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.

[0096] 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.

[0097] 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 AGO-P3725PCT Application as filed 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.

[0098] 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), oxygen-17 (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.

[0099] In one embodiment, the compounds of the invention are conveniently provided in a natural isotopic form.

[0100] 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. AGO-P3725PCT Application as filed

[0101] 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.

[0102] 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.

[0103] 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.

[0104] 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.

[0105] Processes of the invention

[0106] 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.

[0107] 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-P3725PCT Application as filed an activated derivative thereof or a salt and / or solvate thereof; with a compound of formula (III): wherein A, B, R3, R4, Re, p and q are as defined above, or an activated derivative thereof or a salt and / or solvate thereof.

[0108] 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 DIPEA or HATLI) in a polar solvent (such as DCM or DMF).

[0109] 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).

[0110] All variables shown in the following schemes are as defined herein unless stated otherwise.

[0111] Compounds of formula (II) wherein and / or solvate thereof e.g. a pharmaceutically acceptable salt and / or solvate thereof may be AGO-P3725PCT Application as filed prepared by the synthetic route outlined in Scheme 1 below.

[0112] Scheme 1 : is of com of formula (II) wherein Z = N, m = 0 and wherein PG1= carboxylic acid protecting group (such as methyl).

[0113] Step 1 : Compounds of formula (IV), 3-amino-5-bromopyridine (CAS: 13535-01-8), are reacted with the compound of formula (V), 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 (VI), 7- bromo-2-methyl-1 ,5-naphthyridine.

[0114] Step 2: Compounds of formula (VI) are reacted with a halogenated benzoate ester (i.e. compounds of formula (VII)) in a polar solvent (such as THF) in the presence of a base (such as KHMDS) to give compounds of formula (VIII).

[0115] Step 3: Compounds of formula (VIII) 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 (IX).

[0116] Step 4: Compounds of formula (IX) 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 (X). AGO-P3725PCT Application as filed

[0117] Step 5: Compounds of formula (X) 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, m = 0 and

[0118] Compounds of formula (II) wherein 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 (VI) i.e. 3-bromo-6-methyl-1 ,5-naphthyridine.

[0119] Compounds of formula (II) wherein

[0120] 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.

[0121] AGO-P3725PCT Application as filed

[0122] Scheme 2: Synthesis of compounds of formula (II) wherein Z = N, m = wherein X is halo (e.g. Br).

[0123] Step 1 : Compounds of formula (X), 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 (XI).

[0124] Step 2: Compounds of formula (XI) 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 (XII).

[0125] Step 3: Compounds of formula (XII) 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, m = 1 and

[0126] In the instance wherein R2 is halo, Step 2 of Scheme 2 above is redundant and X is R2 compounds of formula (XI) are converted directly to compounds of formula (II) as per Step 3. AGO-P3725PCT Application as filed

[0127] Compounds of formula (II) wherein

[0128] R2is 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 (X) as shown in Scheme 1 above, with compounds of formula (XXIII):

[0129] R2-X (XXIII)

[0130] (wherein X is halo e.g. Br) in the presence of an appropriate base. Such products then may be further reacted in an analogues 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 R2is halo, Step 2 of Scheme 2 above is redundant and X becomes R2; compounds analogous to compounds of formula (XI) are converted directly to compounds of formula (II) as per Step 3.

[0131] Alternatively compounds of formula (II) wherein wherein both R2are 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 (XII) as shown in Scheme 2 above, with compounds of formula (XXIII):

[0132] R2-X (XXIII)

[0133] (wherein X is halo e.g. Br) in the presence of an appropriate base, followed by the reaction as outlined in Step 3. AGO-P3725PCT Application as filed

[0134] Compounds of formula (II) wherein 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 (X) wherein Z = CH rather than Z = N, the synthesis of which is outlined in the supporting text provided for Scheme 1 above.

[0135] Compounds of formula (II) wherein wherein R2 is Ci-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 3 below. of com of formula (II) wherein Z = CH and R2 is Ci- substituted AGO-P3725PCT Application as filed wherein X1and X2are halo (e.g. Br) and PG2is a carboxylic acid protecting group (such as methyl).

[0136] Step 1 : Compounds of formula (XIII) 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 (XIV).

[0137] Step 2: Compounds of formula (XIV) are reacted with compounds of formula (XV) 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 (XVI).

[0138] Step 3: Compounds of formula (XVI) 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

[0139] Compounds of formula (II) wherein

[0140] (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 prepared according to Scheme 3 above may also be further reacted in an analogues manner to Scheme 2, starting from compounds that are analogous to compounds of formula (X) wherein Z = CH, p = 1 and pharmaceutically acceptable salt and / or solvate thereof.

[0141] Compounds of formula (III) or a salt and / or solvate thereof e.g. a pharmaceutically acceptable salt and / or solvate thereof are commercially available or, particularly wherein Re is H and B is linked via an N atom to A, may be prepared by the synthetic route outlined in Scheme 4 below. AGO-P3725PCT Application as filed

[0142] Scheme 4: Synthesis of compounds of formula (III) wherein Re is H and B is linked via an N atom to A. wherein LG3is a leaving group (such as a halide e.g. Br) and is N protected by an amine protecting group (such as 2, 3-dihydro-1 H-isoindole-1 , 3-dione).

[0143] Step 1 : Compounds of formula (XVII) are reacted with compounds of formula (XVIII) in a polar solvent (such as MeCN) in the presence of a base (such as K2CO3) to give compounds of formula (XIX).

[0144] Step 2: Compounds of formula (XIX) are reacted with hydrazine in a polar solvent (such as EtOH) to give compounds of (III) wherein Re is H and B is N-linked.

[0145] Compounds of formula (III) wherein Re is Ci-4alkyl may be prepared by reductive amination with an appropriate aldehyde. Alternatively, compounds of formula (I) wherein Re is H may be N-alkylated to provide compounds of formula (I) wherein Re is Ci-4alkyl.

[0146] Compounds of formula (XVII) or a salt and / or solvate thereof e.g. a pharmaceutically acceptable salt and / or solvate thereof are generally commercially available. Otherwise, compounds of formula (XVII) wherein B is 4-10 membered nitrogen containing heterocyclyl (for example, Intermediate s and Intermediate 10) may be synthesised as outlined elsewhere herein.

[0147] Compounds of formula (XV) 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 5 below. AGO-P3725PCT Application as filed

[0148] Scheme 5: Synthesis of compounds of formula (XV) wherein R2 is Ci^alkyl optionally substituted by hydroxy, or Ci-4haloalkyl. wherein X4and X2are halo (e.g. Br).

[0149] Step 1 : Compounds of formula (XX) are reacted with compounds of formula (XXI) 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 (XXII).

[0150] Step 2: Compounds of formula (XXII) are reacted with a halogenating group (such as NBS) to give compounds of formula (XV).

[0151] Compounds of formula (II) wherein

[0152] 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 6 below.

[0153] AGO-P3725PCT Application as filed

[0154] Scheme 6: Synthesis of compounds of formula (II) wherein Z = CH and wherein X1and X5are halo (e.g. Br) and PG2is a carboxylic acid protecting group (such as methyl).

[0155] 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).

[0156] 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).

[0157] 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 AGO-P3725PCT Application as filed wherein X5is halo e.g. Br.

[0158] Step 1 : Compounds of formula (XXXI) 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 (XXXII).

[0159] Step 2: Compounds of formula (XXXII) are reacted with an activating group (such as POCI3) in the presence of a base (such as 2,6-lutidine) to give compounds of formula (XXXIII).

[0160] Step 3: Compounds of formula (XXXIII) are reacted with glycolic acid and compounds of formula (XXXIV) in a polar solvent (such as DMF) in the presence of a base (such as K2CO3) to give compounds of formula (XXXV).

[0161] Step 4: Compounds of formula (XXXV) are reacted with a halogenating agent (such as NBS) in an polar aprotic solvent (such as DCM) to give compounds of formula (XXIX). AGO-P3725PCT Application as filed

[0162] 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 8 below. of formula (II) wherein Z = N, m = 0 and

[0163] Step 1 : Compounds of formula (VIII) are reacted with an oxidising agent (such as SeCh) to give compounds of formula (XXXVI).

[0164] Step 2: Compounds of formula (XXXVI) are reacted with urotropine and ammonium acetate to give compounds of formula (XXXVII)

[0165] Step 3: Compounds of formula (XXXVII) 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 (XXXVIII). AGO-P3725PCT Application as filed

[0166] Step 4: Compounds of formula (XXXVIII) 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, m = 0 and

[0167] Step 1 and Step 2 of Scheme 8 above are analogous to those described in WO2021 / 102468 (Theravance Biopharma R&D IP LLC, page 49, Scheme 1).

[0168] 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 8 above starting from compounds that are analogous to compounds of formula (VII) 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 WO2021 / 102468 (Theravance Biopharma R&D IP LLC, page 50, Scheme 3).

[0169] Compounds of formula (II) wherein and / or solvate thereof e.g. a pharmaceutically acceptable salt and / or solvate thereof as prepared from Scheme 8 above may be further reacted either:

[0170] (a) with compounds of formula (XXIII):

[0171] R2-X (XXIII)

[0172] (wherein X is halo e.g. Br) in the presence of an appropriate base to afford compounds of formula (II) wherein salt and / or solvate thereof e.g. a pharmaceutically acceptable salt and / or solvate thereof; or AGO-P3725PCT Application as filed

[0173] (b) in an analogous manner to Scheme 9 below, 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.

[0174] Compounds of formula (II) wherein and / or solvate thereof e.g. a pharmaceutically acceptable salt and / or solvate thereof may be further reacted in an analogues manner to Scheme 9 below, wherein Step 3 is omitted, to afford compounds of formula (II) wherein Z = CH, m = 2 salt and / or solvate thereof e.g. a pharmaceutically acceptable salt and / or solvate thereof.

[0175] Compounds of formula (II) wherein 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-P3725PCT Application as filed

[0176] Scheme 9: Synthesis of compounds of formula (II) wherein Z = N, m = 1 wherein X5is halo (e.g. Br).

[0177] Step 1 : Compounds of formula (XXXVIII), as prepared in Scheme 8, are reacted with a halogenating agent (such as NBS) in a polar solvent (such as DMF) to give compounds of formula (XXXIX).

[0178] Step 2: Compounds of formula (XXXIX) 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 (XXXX).

[0179] Step 3: Compounds of formula (XXXX) 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, m is 1 and

[0180] In the instance wherein R2 is halo, Step 2 of Scheme 9 above is redundant and X5becomes R2; compounds of formula (XXXIX) are converted directly to compounds of formula (II) as per Step 3. AGO-P3725PCT Application as filed

[0181] Compounds of formula (II) wherein and / or solvate thereof e.g. a pharmaceutically acceptable salt and / or solvate thereof may also be prepared by reaction of compounds of formula (XXXVIII) as shown in Scheme 8 above, with compounds of formula (XXIII):

[0182] R2-X (XXIII)

[0183] (wherein X is halo e.g. Br) in the presence of an appropriate base. Such products may be further reacted in an analogues manner to Scheme 9, wherein Step 3 is omitted, to afford compounds of formula (II) wherein a salt and / or solvate thereof e.g. a pharmaceutically acceptable salt and / or solvate thereof.

[0184] Alternatively compounds of formula (II) wherein wherein both R2are Ci-4alkyl optionally substituted by hydroxy or Ci-

[0185] 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 (XXXX) as shown in Scheme 9 above, with compounds of formula (XXIII):

[0186] R2-X (XXIII)

[0187] (wherein X is halo e.g. Br) in the presence of an appropriate base, followed by the reaction as outlined in Step 3. AGO-P3725PCT Application as filed

[0188] Compounds of formula (II) wherein 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 9 above starting from compounds that are analogous to compounds of formula (XXXVIII) wherein Z = CH rather than Z = N, the synthesis of which is outlined in the supporting text provided for Scheme 8 above.

[0189] In the instance wherein R2 is halo, Step 2 of Scheme 9 above is redundant and X5becomes R2; compounds of formula (XII) are converted directly to compounds of formula (II) as per Step 3.

[0190] Compounds of formula (IV), (V), (VII), (XIII), (XVII) (unless otherwise stated), (XVIII), (XX), (XXI) and (XXIII) are either known or may be prepared by methods known to the skilled person. If appropriate or convenient, compounds of formula (II), (III), (IX), (X), (XI) (XII), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), (XXIX), (XXX), (XXXVII), (XXXVIII), (XXXIX) and (XXXX) 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.

[0191] Novel intermediate compounds, such as compounds of formula (II), (III), (VIII), (IX), (X), (XI), (XII), (XV), (XVI), (XVII), (XVIII), (XIX), (XXX), (XXXVIII), (XXXIX) and (XXX) and salts and / or solvates thereof e.g. pharmaceutically acceptable salts and / or solvated thereof are provided as an aspect of the invention.

[0192] 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 nitrogen protecting groups include tetrahydropyranyl (THP), tert-butyloxycarbonyl (BOG), benzyloxycarbonyl (Cbz) and allyloxycarbonyl (Alloc) groups. Examples of oxygen protecting AGO-P3725PCT Application as filed 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 Ci-ealkyl e.g. Ci-4alkyl esters), benzyl esters and allyl esters. Medical Uses

[0193] Compounds of the invention are of use in therapy, particularly for treating or preventing a disease or pathological disorder susceptible to amelioration by inhibition of ALK5. 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 good stability in human plasma. As shown in Biological Example 4, at least some of the compounds of the invention demonstrate low or very low metabolic stability. Thus, the compounds of the present invention are expected to exhibit good gastro-intestinal exposure and low systemic exposure, because they have good plasma stability and low metabolic stability.

[0194] Thus, in a first aspect, the present invention provides a compound of the invention for use as a medicament.

[0195] 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.

[0196] The term "treatment" or "treating" as used herein includes the control, mitigation, reduction, or modulation of the disease state or its symptoms.

[0197] 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-P3725PCT Application as filed

[0198] A subject will typically be a subject in need of treatment or prevention according to the invention. Suitably the subject is a human.

[0199] 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).

[0200] 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.

[0201] The term “lung diseases” includes chronic obstructive pulmonary disease (COPD) and asthma. Also included are fibrotic lung diseases (discussed further below), interstitial lung diseases (discussed further below), pulmonary arterial hypertension and lung cancer.

[0202] 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.

[0203] 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 lung fibrosis and idiopathic pulmonary fibrosis.

[0204] 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-P3725PCT 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

[0205] (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, atopic dermatitis, nephrogenic fibrosing dermopathy, mixed connective tissue disease, scleromyxedema, scleredema, 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.

[0206] 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.

[0207] 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).

[0208] 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-P3725PCT Application as filed

[0209] Pharmaceutical Compositions

[0210] 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 oral administration.

[0211] 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. 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.

[0212] 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.

[0213] 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.

[0214] 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. 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 AGO-P3725PCT Application as filed 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.

[0215] Suitably the pharmaceutically acceptable (e.g. topically acceptable) diluent is an aqueous diluent i.e. it is or comprises water.

[0216] 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.

[0217] 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).

[0218] Topical administration by inhalation may also be achieved by use of a non-pressurised formulation such as an aqueous solution or suspension.

[0219] 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 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 AGO-P3725PCT Application as filed 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.

[0220] 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 1-6pm or around 1-5 pm.

[0221] 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.

[0222] 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. Dry powder formulations may also contain other excipients such as sodium stearate, calcium stearate or magnesium stearate.

[0223] 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 delivery systems include ECLIPSE, NEXT, ROTAHALER, HANDIHALER, AEROLISER, CYCLOHALER, BREEZHALER / NEOHALER, MONODOSE, FLOWCAPS, TWINCAPS, X- AGO-P3725PCT Application as filed

[0224] 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.

[0225] 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.

[0226] Liquid suspension and aerosol formulations (whether pressurised or unpressurised) will typically contain a compound of the invention in particulate form, for example with a D50 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 D10 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 Dm, 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, Dm and D90 values, used in the context of laser diffraction, are taken to mean Dv and DV90 values and refer to the particle size whereby 10% of the distribution lies below the Dm value, and 90% of the distribution lies below the D90 value, respectively.

[0227] 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 (such as sodium chloride), pH adjusting agents, viscosity modifiers, co-solvents (such as propylene glycol) and surfactants (such as Lipoid S100). AGO-P3725PCT Application as filed

[0228] 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. 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.

[0229] 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. 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.

[0230] 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 .

[0231] 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 AGO-P3725PCT Application as filed 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. 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.

[0232] 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.

[0233] 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.

[0234] Second or further active ingredients

[0235] 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 AGO-P3725PCT Application as filed 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.

[0236] 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.

[0237] 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;

[0238] (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.

[0239] Potential desirable properties 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:

[0240] • High potency of inhibition of ALK5 activity in cells;

[0241] • High stability in human plasma;

[0242] • High stability in experimental animal species plasma (e.g. mouse plasma); • Low or very low metabolic stability e.g. as determined in human liver microsomes;

[0243] • Low or absent inhibition of CYP enzymes, such as CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4 (BFC) and / or CYP3A4 (DBF) enzymes;

[0244] • Low or absent hERG binding affinity; and

[0245] • 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

[0246] TGFp inhibition in TGFp-stimulated normal human lung fibroblasts (NHLF) assay. AGO-P3725PCT Application as filed

[0247] Abbreviations

[0248] In the present application are used the following abbreviations, with the corresponding definitions: AcOH Acetic Acid

[0249] ACVR2B Activin A receptor, type II B

[0250] B2pin2 Bis(pinacolato)diboron

[0251] BOC2O tert-Butyl dicarbonate

[0252] Boc tert-Butoxycarbonyl Cbz Benzyloxycarbonyl

[0253] CbzOSu / V-(Benzyloxycarbonyloxy)succinimide

[0254] DCM Dichloromethane

[0255] DHP 3,4-Dihydropyran

[0256] DIPEA / V, / V-Diisopropylethylamine DMA Dimethylacetamide

[0257] DMAP 4-Dimethylaminopyridine

[0258] DMF / V, / V-Dimethylformamide

[0259] DMF DMA N,N-Dimethylformamide dimethyl acetal

[0260] DMSO Dimethyl sulfoxide EDCi 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide

[0261] Et3N Triethylamine

[0262] Et2O Diethyl ether

[0263] EtOAc Ethyl acetate

[0264] EtOH Ethanol eq Equivalent

[0265] FBS Fetal bovine serum

[0266] GS / MS Gas chromatography / Mass spectrometry h hour

[0267] HATU 1-[Bis(dimethylamino)methylene]-1 / 7-1,2,3-triazolo[4,5-b]pyridinium 3- oxide hexafluorophosphate

[0268] HOBt Hydroxybenzotriazole

[0269] HPLC High-performance liquid chromatography

[0270] 1H-NMR Proton nuclear magnetic resonance

[0271] / PrOH Isopropanol KHMDS Potassium bis(trimethylsilyl)amide

[0272] L Litre

[0273] LC Liquid chromatography AGO-P3725PCT Application as filed

[0274] M Molar concentration MeCN Acetonitrile MeOH Methanol Mel Methyl iodide MsOH Methanesulfonic acid min minutes MS Mass spectroscopy Muk 2-Chloro-1 -methylpyridinium iodide NBS N-Bromosuccinimide NMR Nuclear Magnetic Resonance

[0275] PdCI2(dtbpf) [1 ,T-Bis(di-tert-butylphosphino)ferrocene]dichloropalladium(ll)

[0276] PCy3T ricyclohexylphosphine

[0277] Pd2(dba)3Tris(dibenzylideneacetone)dipalladium(0)

[0278] Pd(PPh3)4Tetrakis(triphenylphosphine)palladium(0) pH Potential of Hydrogen

[0279] PTFE Polytetrafluoroethylene p-TsOH para-Toluenesulfonic acid

[0280] Rt retention time r.t. room temperature SnMe4Tetramethyltin

[0281] TBAF tert-Butylammonium fluoride

[0282] TBDMS tert-Butyldimethylsilyl

[0283] TFA Trifluoroacetic acid

[0284] TGFp Transforming growth factor-p THF Tetrahydrofuran

[0285] THP 2-tetrahydropyranyl

[0286] LIPLC Ultra high-performance liquid chromatography

[0287] UV Ultraviolet

[0288] Experimental

[0289] 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-P3725PCT Application as filed

[0290] 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.

[0291] Analytical Equipment

[0292] 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 refers to a 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. INTERMEDIATES

[0293] Intermediate 1 (lnt-1): 5-(Aminomethyl)pyridin-2-ol

[0294] A solution of (6-methoxypyridin-3-yl)methylamine 95% (153 pL, 1.207 mmol, 1 eq) in hydrobromic acid, solution in water 48% (3.403 mL, 62.666 mmol, 25 eq) was stirred at 100 °C for 16 h. EtOAc (30 mL) was added and the resulting precipitate was collected by filtration to obtain 5-(aminomethyl)pyridin-2-ol dihydrobromide (342 mg, 99%) as a white solid.1H-NMR (300 MHz, DMSO-d6): 5 = 8.01 (s, 2H), 7.62 - 7.47 (m, 2H), 6.40 (d, J = 10.2 Hz, 1 H), 3.81 (q, J = 5.7 Hz, 2H). HPLC-MS: Rt 0.394 m / z 125.0 [M+H]+. (Method A-HPLC) AGO-P3725PCT Application as filed

[0295] Intermediate 2 (lnt-2): tert-Butyl (2S,6R)-4-(2-(1,3-dioxoisoindolin-2-yl)ethyl)-2,6- dimethylpiperazine-1 -carboxylate

[0296] Tert-butyl cis-2,6-dimethylpiperazine-1-carboxylate (300 mg, 1.399 mmol, 1 eq), 2-(2- bromoethyl)-2,3-dihydro-1 / - / -isoindole-1 , 3-dione (561 mg, 2.097 mmol, 1.5 eq) and K2CO3 (483 mg, 3.494 mmol, 2.5 eq) were mixed in MeCN (15 mL) and the solution was stirred at reflux for 48 h. The mixture was poured over water (50 mL) and EtOAc (50 mL) was added. The mixture was left stir for 10 minutes and then extracted with more EtOAc (50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and volatiles were removed under reduced pressure. The crude was purified by column chromatography on SiO2 (20% EtOAc / hexanes) to afford tert-butyl (2S,6 / ?)-4-(2-(1 ,3-dioxoisoindolin-2-yl)ethyl)-2,6- dimethylpiperazine-1-carboxylate (530 mg, 97%) as a white solid. HPLC-MS: Rt 3.248 m / z 388.3 [M+HJ+. (Method B-HPLC)

[0297] Intermediate 3 (lnt-3): tert-Butyl (2S,6R)-4-(2-aminoethyl)-2,6-dimethylpiperazine-1- carboxylate

[0298] To a solution of tert-butyl (2S,6 / ?)-4-(2-(1 ,3-dioxoisoindolin-2-yl)ethyl)-2,6-dimethylpiperazine- 1-carboxylate (lnt-2) (1.260 g, 2.113 mmol, 1 eq) in EtOH (23 mL) was added NH2NH2 H2O (1.5 mL, 30.862 mmol, 14.6 eq). The solution was stirred at 70 °C for 16 h. The crude volatiles were removed under reduced pressure. The crude residue was slurred with Et20 (20 mL). The suspension was filtered and washed with Et20. The filtrates were concentrated to afford tert- butyl (2S,6 / ?)-4-(2-aminoethyl)-2,6-dimethylpiperazine-1 -carboxylate (430 mg, 79%) as a pale yellow oil. GC-MS: Rt 8.043 m / z 257.2 [MJ. (Method A-GC-MS)

[0299] Intermediate 4 (lnt-4): Benzyl (3R,4S)-3,4-dihydroxypyrrolidine-1 -carboxylate c / s-Pyrrolidine-3,4-diol hydrochloride (3.000 g, 21.492 mmol, 1 eq), Et3N (9.00 mL, 64.571 mmol, 3 eq) and CbzOSu (5.900 g, 23.673 mmol, 1.1 eq) were mixed in CH2CI2 (107 mL) and AGO-P3725PCT Application as filed the solution was stirred at room temperature for 20 h. Then, NH4CI (saturated aqueous solution, 200 mL) and CH2CI2 (50 mL) were added. The aqueous layer was extracted with more CH2CI2 (3 x 100 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 (Silica, 4-8% MeOH / CH2Cl2, liquid loading in CH2CI2) afforded benzyl (3R,4S)-3,4-dihydroxypyrrolidine-1-carboxylate (4,34 g, 85%) as a beige solid.1H NMR (300 MHz, CDCI3) 5 7.36 (d, J = 4.4 Hz, 5H), 5.12 (s, 2H), 4.25 (s, 2H), 3.65 (dd, J = 11.2, 5.3 Hz, 2H), 3.56 - 3.31 (m, 2H), 2.61 (s, 2H). HPLC-MS: Rt 2.216 m / z 238.0 [M+HJ+. (Method A-HPLC)

[0300] Intermediate 5 (lnt-5): Benzyl (3a / ?,6aS)-2-propyltetrahydro-5H-[1,3]dioxolo[4,5- c]pyrrole-5-carboxylate

[0301] A mixture of benzyl (3R,4S)-3,4-dihydroxypyrrolidine-1 -carboxylate (lnt-4) (300 mg, 1.264 mmol, 1 eq), butyraldehyde (341 pL, 3.783 mmol, 2.99 eq), PTSOH.H2O (25 mg, 0.131 mmol, 0.1 eq) and Na2SO4 (540 mg, 3.801 mmol, 3.01 eq) in toluene (5 mL). was stirred at reflux for 16 h. After the reaction mixture was cooled to room temperature, water (15 mL) and CH2CI2 (15 mL) were added. The aqueous layer was extracted with CH2CI2 (3 x 15 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 20g, EtOAc / Hexanes 0-100% 10CV, A 220-480 nm, dry loading) afforded benzyl (3aR,6aS)-2-propyltetrahydro-5 / 7- [1 ,3]dioxolo[4,5-c]pyrrole-5-carboxylate (348 mg, 94%) as a yellow oil.1H-NMR (300 MHz, CDCI3): 5 = 7.43 - 7.29 (m, 5H), 5.14 (s, 2H), 4.90 (t, J = 4.6 Hz, 1 H), 4.60 (d, J = 4.0 Hz, 2H), 3.87 (t, J = 13.0 Hz, 2H), 3.47 - 3.26 (m, 2H), 1.72 - 1.61 (m, 2H), 1.42 (h, J = 7.4 Hz, 2H), 0.92 (t, J = 7.4 Hz, 3H). HPLC-MS: Rt 3.078 m / z 292.3 [M+HJ+. (Method A-HPLC)

[0302] Intermediate 6 (lnt-6): Benzyl (3a / ?,6aS)-2-(2-((tert- butyldimethylsilyl)oxy)ethyl)tetrahydro-5H-[1,3]dioxolo[4,5-c]pyrrole-5-carboxylate AGO-P3725PCT Application as filed

[0303] Intermediate 6 was prepared from Intermediate 4 and 3-[(tert-butyldimethylsilyl)oxy]propanal in an analogous manner to the synthesis of Intermediate 5.1H NMR (300 MHz, CDCh) 6 7.36 (d, J = 4.5 Hz, 5H), 5.13 (s, 2H), 5.03 (d, J = 5.3 Hz, 1 H), 4.61 (s, 2H), 4.02 - 3.54 (m, 4H), 3.36 (d, J = 12.6 Hz, 2H), 1.88 (d, J = 5.8 Hz, 2H), 0.88 (s, 9H), 0.07 (s, 6H). HPLC-MS: Rt 3.734 m / z 408.4 [M+HJ+. (Method A-HPLC)

[0304] Intermediate 7 (lnt-7): Benzyl (3a / ?,6aS)-2-(2-hydroxyethyl)tetrahydro-5H-

[0305] [1,3]dioxolo[4,5-c]pyrrole-5-carboxylate

[0306] To a cooled solution of benzyl (3aR,6aS)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)tetrahydro- 5 / 7-[1 ,3]dioxolo[4,5-c]pyrrole-5-carboxylate (lnt-6) (2.900 g, 5.142 mmol, 1 eq) in THF (45 mL) was added TBAF (solution 1M in THF, 9.7 mL, 9.7 mmol, 1.51 eq) and the mixture was stirred at low temperature for 15 min and then at room temperature for 18 h. Then, NH4CI (saturated aqueous solution, 150 mL) and CH2CI2 (100 mL) were added. The aqueous layer was extracted with more CH2CI2 (2 x 100 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 (silica, 0-10% MeOH / CH2Ch, dry loading) afforded benzyl (3aR,6aS)-2-(2-hydroxyethyl)tetrahydro-5 / 7- [1 ,3]dioxolo[4,5-c]pyrrole-5-carboxylate (1.61 g, 107%) as a yellow oil.1H NMR (300 MHz, CDCh) 6 7.44 - 7.31 (m, 5H), 5.15 (s, 2H), 5.06 (t, J = 4.2 Hz, 1 H), 4.64 (d, J = 3.6 Hz, 2H), 3.92 (s, 2H), 3.76 (t, J = 5.6 Hz, 2H), 3.35 (d, J = 12.9 Hz, 2H), 1.96 (q, J = 5.1 Hz, 2H). HPLC- MS: Rt 2.470 m / z 294.0 [M+HJ+. (Method A-HPLC)

[0307] Intermediate 8 (lnt-8): Benzyl (3a / ?,6aS)-2-(2-methoxyethyl)tetrahydro-5H- [1 ,3]dioxolo[4,5-c]pyrrole-5-carboxylate

[0308] Benzyl (3aR,6aS)-2-(2-hydroxyethyl)tetrahydro-5 / 7-[1 ,3]dioxolo[4,5-c]pyrrole-5-carboxylate (lnt-7) (2.520 g, 8.591 mmol, 1 eq), NaH 60% (412 mg, 10.3 mmol, 1.2 eq) and Mel (640 pL, 10.28 mmol, 1.2 eq) were mixed in THF (80 mL) and the solution was stirred at low temperature for 5 min and then at room temperature for 16 h. The reaction mixture was poured into NH4CI (saturated aqueous solution, 200 mL) and extracted with CH2CI2 (3 x 100 mL). Combined organic layers were dried over anhydrous sodium sulfate and concentrated under AGO-P3725PCT Application as filed vacuum. The crude product was purified by flash column chromatography (silica, MeOH / CH2Cl2 0-10%, dry loading). The purified product was dissolved in CH2CI2 (50 mL) and washed with Na2S20s (saturated aqueous solution, 2 x 40 mL). Organic layer were dried over anhydrous sodium sulfate, and concentrated under vacuum to afford benzyl (3aR,6aS)-2-(2- methoxyethyl)tetrahydro-5 / 7-[1 ,3]dioxolo[4,5-c]pyrrole-5-carboxylate (2.32 g, 88%) as a yellow oil.1H NMR (300 MHz, CDCI3) 5 7.43 - 7.27 (m, 5H), 5.13 (s, 2H), 5.01 (t, J = 4.8 Hz, 1 H), 4.68 - 4.51 (m, 2H), 4.03 - 3.65 (m, 2H), 3.49 (t, J = 6.4 Hz, 2H), 3.41 - 3.14 (m, 5H), 1.95 (q, J = 6.1 Hz, 2H).HPLC-MS: Rt 2.779 m / z 308.1 [M+HJ+. (Method A-HPLC)

[0309] Intermediate 9 (lnt-9): (3a / ?,6aS)-2-Propyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyrrole

[0310] To a solution of benzyl (3aR,6aS)-2-propyltetrahydro-5 / 7-[1 ,3]dioxolo[4,5-c]pyrrole-5- carboxylate (lnt-5) (340 mg, 1.167 mmol, 1 eq) in EtOAc (12 mL) was added Pd / C (10%, wet) 5% (249 mg, 0.116 mmol, 0.1 eq). The solution was stirred at room temperature for 17 h. The mixture was filtrated through a PTFE syringe filter washing with EtOAc (2 x 10 mL). The volatiles were removed under reduced pressure to yield crude (3aR,6aS)-2-propyltetrahydro- 4 / 7-[1 ,3]dioxolo[4,5-c]pyrrole (183 mg, 100%) as a colourless oil, which was then used in the next step without further purification.1H-NMR (300 MHz, CDCI3): 6 = 4.75 (t, J = 4.6 Hz, 1 H), 4.53 (d, J = 2.6 Hz, 2H), 3.15 (d, J = 13.6 Hz, 2H), 2.50 (d, J = 13.4 Hz, 2H), 1.72 - 1.57 (m, 2H), 1.43 (h, J = 7.2 Hz, 2H), 0.94 (t, J = 7.3 Hz, 3H). HPLC: Rt 3.049 (Method A-HPLC) Note: No ionization, so only HPLC is indicated.

[0311] Intermediate 10 (lnt-10): (3a / ?,6aS)-2-(2-Methoxyethyl)tetrahydro-4H-[1,3]dioxolo[4,5- c]pyrrole

[0312] Intermediate 10 was prepared from Intermediate 8 in an analogous manner to the synthesis of Intermediate 9.1H NMR (300 MHz, CDI3) 5 4.87 - 4.84 (m, 1 H), 4.55 - 4.54 (m, 2H), 3.50 (td, J = 6.5, 2.0 Hz, 2H), 3.32 (s, 3H), 3.18 - 3.13 (m, 2H), 2.51 - 2.46 (m, 2H), 2.07 (brs, 1 H), 1.94 (tdd, J = 6.4, 4.6, 1.8 Hz, 2H). GC-MS: Rt 6.895. HPLC-MS: m / z 174.0 [M+HJ+. (Method A-HPLC) AGO-P3725PCT Application as filed

[0313] Intermediate 11 (lnt-11): 2-(2-((3a / ?,6aS)-2-Propyltetrahydro-5H-[1,3]dioxolo[4,5- c]pyrrol-5-yl)ethyl)isoindoline-1, 3-dione

[0314] 2-(2-Bromoethyl)-2,3-dihydro-1 / - / -isoindole-1 , 3-dione (242 mg, 0.952 mmol, 1.25 eq), (3a / ?,6aS)-2-propyltetrahydro-4 / 7-[1 ,3]dioxolo[4,5-c]pyrrole (lnt-9) (120 mg, 0.763 mmol, 1 eq) and K2CO3 (220 mg, 1.591 mmol, 2.09 eq) were mixed in MeCN (3.2 mL) and the solution was stirred at reflux for 19 h. The mixture was poured over water (10 mL) and EtOAc (10 mL) was added. The mixture was left to stir for 10 minutes and then extracted with more EtOAc (20 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 (silica 20g, EtOAc / Hexanes 0-50% 12CV, A 254 nm, dry loading) afforded 2-(2-((3a / ?,6aS)-2-Propyltetrahydro-5 / 7-[1 ,3]dioxolo[4,5-c]pyrrol-5- yl)ethyl)isoindoline-1 , 3-dione (145 mg, 57%) as a yellow oil.1H-NMR (300 MHz, CDCI3): 6 = 7.83 (dd, J = 5.5, 3.1 Hz, 2H), 7.69 (dd, J = 5.5, 3.1 Hz, 2H), 4.79 (t, J = 4.6 Hz, 1 H), 4.48 (d, J = 3.1 Hz, 2H), 3.81 (t, J = 6.7 Hz, 2H), 3.19 (d, J = 10.8 Hz, 2H), 2.72 (t, J = 6.7 Hz, 2H), 2.17 (t, J = 6.2 Hz, 2H), 1.59 - 1.44 (m, 2H), 1.30 (tt, J = 13.7, 7.1 Hz, 2H), 0.79 (t, J = 7.3 Hz, 3H). HPLC-MS: Rt 2.457 m / z 331.2 [M+HJ+. (Method A-HPLC)

[0315] Intermediate 12 (lnt-12): 2-(2-((3a / ?,6aS)-2-(2-Methoxyethyl)tetrahydro-5H- [1 ,3]dioxolo[4,5-c]pyrrol-5-yl)ethyl)isoindoline-1 ,3-dione

[0316] Intermediate 12 was prepared from Intermediate 10 and 2-(2-Bromoethyl)-2,3-dihydro-1 / 7- isoindole-1 , 3-dione in an analogous manner to the synthesis of Intermediate 11.1H-NMR (300 MHz, CDCI3): 5 = 7.93 - 7.62 (m, 4H), 4.93 (t, J = 4.9 Hz, 1 H), 4.51 (s, 2H), 3.81 (t, J =

[0317] 6.7 Hz, 2H), 3.41 (t, J = 6.4 Hz, 2H), 3.32 - 3.10 (m, 5H), 2.72 (t, J = 6.9 Hz, 2H), 2.18 (d, J =

[0318] 10.7 Hz, 2H), 1.83 (q, J = 5.9 Hz, 2H). HPLC-MS: Rt 2.158 m / z 347.0 [M+HJ+. (Method A- HPLC) AGO-P3725PCT Application as filed

[0319] Intermediate 13 (lnt-13): 2-((3a / ?,6aS)-2-Propyltetrahydro-5H-[1,3]dioxolo[4,5-c]pyrrol-5- yl)ethan-1 -amine

[0320] To a solution of 2-(2-((3aR,6aS)-2-propyltetrahydro-5 / 7-[1,3]dioxolo[4,5-c]pyrrol-5- yl)ethyl)isoindoline-1, 3-dione (lnt-11) (145 mg, 0.438 mmol, 1 eq) in EtOH (4.4 mL) was added NH2NH2 H2O (319 pL, 6.563 mmol, 15 eq). The solution was stirred at 70 °C for 17 h. The crude volatiles were removed under reduced pressure. The crude residue was slurred with Et20 (5 mL). The suspension was filtered and washed with Et20. The filtrates were concentrated to afford 2-((3aR,6aS)-2-propyltetrahydro-5 / 7-[1,3]dioxolo[4,5-c]pyrrol-5- yl)ethan-1-amine (75 mg, 85%) as a yellow oil.1H-NMR (300 MHz, CDCI3): 5 = 4.82 (t, J = 4.8 Hz, 1H), 4.50 (d, J = 2.8 Hz, 2H), 3.11 (d, J = 11.0 Hz, 2H), 2.77 (t, J = 6.1 Hz, 2H), 2.48 (t, J = 6.1 Hz, 2H), 2.10 (d, J = 10.8 Hz, 2H), 1.75 - 1.63 (m, 2H), 1.45 (h, J = 7.4 Hz, 2H), 0.94 (t, J = 7.4 Hz, 3H). GC-MS: Rt 6.715 m / z 199.2 [MJ. (Method A-GC-MS)

[0321] Intermediate 14 (lnt-14): 2-((3aR,6aS)-2-(2-Methoxyethyl)tetrahydro-5H-[1,3]dioxolo[4,5- c]pyrrol-5-yl)ethan-1 -amine

[0322] Intermediate 14 was prepared from Intermediate 12 in an analogous manner to the synthesis of Intermediate 13.1H-NMR (300 MHz, CDCI3): 5 = 4.96 (t, J = 4.7 Hz, 1 H), 4.52 (s, 2H), 3.53 (t, J = 6.5 Hz, 2H), 3.33 (s, 3H), 3.12 (d, J = 10.9 Hz, 2H), 2.77 (t, J = 6.1 Hz, 2H), 2.48 (t, J = 6.1 Hz, 2H), 2.09 (d, J = 10.8 Hz, 1H), 2.01 (q, J = 5.8 Hz, 2H). GC-MS: Rt 7.519. (Method A- GC)

[0323] Intermediate 15 (lnt-15): 7-Bromo-2-methyl-1,5-naphthyridine

[0324] 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 AGO-P3725PCT Application as filed of NaOH (aqueous solution 6N, 1 L), then it was extracted with CH2CI2 (2x500 mL). The organic layer was dried over Na2SC>4 (anhydrous), filtered and concentrated. The crude was 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-d6): 5 = 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+HJ+. (Method B-HPLC)

[0325] Intermediate 16 (lnt-16): 2-(7-Bromo-1,5-naphthyridin-2-yl)-1-(5-chloro-2- fluorophenyl)ethan-1 -one

[0326] To a solution of 7-bromo-2-methyl-1 ,5-naphthyridine (lnt-15) (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 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 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 solid.1H-NMR (300 MHz, CDCI3): 5 = 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).

[0327] Intermediate 17 (lnt-17): 7-Bromo-2-(3-(5-chloro-2-fluorophenyl)-1H-pyrazol-4-yl)-1,5- naphthyridine

[0328] A solution of 2-(7-bromo-1 ,5-naphthyridin-2-yl)-1-(5-chloro-2-fluorophenyl)ethan-1-one (lnt-

[0329] 16) (3.79 g, 9.98 mmol, 1 eq) in DMF DMA (95 mL) was stirred at reflux for 16 h. The reaction AGO-P3725PCT Application as filed 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 washed with H2O (3x40 mL), MeCN (3x10 mL) and then rinsed with n-pentane (2x20 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-de): 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)

[0330] Intermediate 18 (lnt-18): 6-(3-(5-Chloro-2-fluorophenyl)-1H-pyrazol-4-yl)-1,5- naphthyridine-3-carbonitrile A suspension of 7-bromo-2-(3-(5-chloro-2-fluorophenyl)-1 / 7-pyrazol-4-yl)-1 ,5-naphthyridine (lnt-17) (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(PPh3)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 a plug of 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 (silica, 2^6% MeOH / CH2CI2, dry loading). The obtained solid was slurred with CH2CI2(30 mL), filtered, and washed with CH2CI2(2 x 15 mL) to afford 6-(3-(5-Chloro-2-fluorophenyl)-1 / 7-pyrazol-4-yl)-1 ,5- naphthyridine-3-carbonitrile (1.43 g, 45%) as a beige solid.1H-NMR (300 MHz, DMSO-de): 5 = 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+HJ+. (Method A-UPLC) AGO-P3725PCT Application as filed

[0331] Intermediate 19 (lnt-19): 6-(3-(5-Chloro-2-fluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H- pyrazol-4-yl)-1,5-naphthyridine-3-carbonitrile

[0332] A solution of 6-(3-(5-Chloro-2-fluorophenyl)-1 / 7-pyrazol-4-yl)-1 ,5-naphthyridine-3-carbonitrile (lnt-18) (1.00 g, 2.60 mmol, 1 eq), DHP (3.80 mL, 41.63 mmol, 16 eq) and MsOH (135 pL, 2.08 mmol, 0.8 eq) in THF (30 mL) was stirred at 70 °C for 17 h. The reaction mixture was allowed to reach room temperature, water (50 mL) and CH2CI2 (50 mL) were added, and the layers were separated. The aqueous layer was extracted with CH2CI2 (2 x 30 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 (EtOAc / hexanes 0% to 100%, liquid loading) to afford 6-(3-(5-chloro-2-fluorophenyl)-1- (tetrahydro-2 / 7-pyran-2-yl)-1 / 7-pyrazol-4-yl)-1 ,5-naphthyridine-3-carbonitrile (982 mg, 87%) as an orange foam.1H-NMR (300 MHz, CDCI3): 5 = 9.00 (d, J = 2.0 Hz, 1 H), 8.48 (d, J = 2.1 Hz, 1 H), 8.37 (s, 1 H), 8.28 (d, J = 8.9 Hz, 1 H), 7.67 (t, J = 7.5 Hz, 2H), 7.40 (dd, J = 8.4, 4.0 Hz, 1 H), 7.15 - 6.86 (m, 1 H), 5.52 (dd, J = 8.1 , 4.1 Hz, 1 H), 4.14 (t, J = 10.3 Hz, 1 H), 3.80 (d, J = 12.2 Hz, 1 H), 2.28 - 1.90 (m, 2H), 1.93 - 1.28 (m, 4H). HPLC-MS: Rt 3.331 m / z 434.1 [M+H]+. (Method A-HPLC)

[0333] Intermediate 20 (lnt-20): 6-(3-(5-Chloro-2-fluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H- pyrazol-4-yl)-1,5-naphthyridine-3-carboxylic acid

[0334] 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-19) (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 washed 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 (3x40 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 AGO-P3725PCT Application as filed 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)

[0335] Intermediate 21 (lnt-21): 6-(3-(5-Chloro-2-fluorophenyl)-1H-pyrazol-4-yl)-1,5- naphthyridine-3-carboxylic acid

[0336] Intermediate 21 was prepared from Intermediate 18 in an analogous manner to the synthesis of Intermediate 20.1H NMR (300 MHz, DMSO-d6) 5 9.27 (d, J = 2.0 Hz, 1 H), 8.59 (s, 1 H), 8.35 (d, J = 8.9 Hz, 1 H), 8.26 (d, J = 2.0 Hz, 1 H), 7.97 (d, J = 8.8 Hz, 1 H), 7.73 - 7.52 (m, 2H), 7.32 (t, J = 9.2 Hz, 1 H). UPLC-MS: Rt 2.469 m / z 369.3-371 .2 [M+H]+. (Method C-UPLC)

[0337] Intermediate 22 (lnt-22): 3-(5-Chloro-2-fluorophenyl)-1-methyl-1H-pyrazole

[0338] PdCh(dtbpf) (3.200 g, 4.909 mmol, 0.2 eq) was added to a cloudy solution of 3-bromo-1- methylpyrazole (2.5 mL, 24.611 mmol, 1 eq), 5-Chloro-2-fluorophenylboronic acid (4.700 g, 26.954 mmol, 1.1 eq) and K3PO4 (10.500 g, 49.466 mmol, 2.01 eq) in a mixture of dioxane (120 mL) and water (14 mL). The solution was stirred at 90 °C for 16 h, the crude was poured over brine (150 mL) and extracted with EtOAc (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 column chromatography (silica, 100% of CH2CI2) afforded 3-(5-chloro-2-fluorophenyl)-1-methyl-1 / 7-pyrazole (2.42 g, 47%) as a brown solid.1H NM R (300 MHz, CDCI3) 6= 7.99 (dd, J = 6.5, 2.7 Hz, 1 H), 7.41 (d, J = 2.3 Hz, 1 H), 7.23 - 7.15 (m, 1 H), 7.05 (dd, J = 10.5, 8.8 Hz, 1 H), 6.71 - 6.65 (m, 1 H), 3.97 (s, 3H). GC-MS: Rt 7.770 m / z 210.1 [MJ. Method A-GC AGO-P3725PCT Application as filed

[0339] Intermediate 23 (lnt-23): 3-(5-Chloro-2-fluorophenyl)-5-methyl-1H-pyrazole

[0340] Intermediate 23 was synthesised in an analogous manner to the synthesis of Intermediate 22.1H NMR (300 MHz, CDCI3) 6= 7.85 (dd, J = 6.5, 2.7 Hz, 1 H), 7.26 - 7.18 (m, 1H), 7.07 (dd, J= 10.6, 8.8 Hz, 1 H), 6.49 (d, J= 3.0 Hz, 1H), 2.37 (s, 3H). GC-MS: Rt8.618 m / z 210.1[M], Method A-GC

[0341] Intermediate 24 (lnt-24): 3-(5-Chloro-2-fluorophenyl)-5-methyl-1-(tetrahydro-2H-pyran- 2-yl)-1H-pyrazole

[0342] Intermediate 24 was synthesised in an analogous manner to the synthesis of Intermediate

[0343] 22. GC-MS: Rt 10.602 m / z 210.1[M], Method A-GC

[0344] Intermediate 25 (lnt-25): 4-Bromo-3-(5-chloro-2-fluorophenyl)-1-methyl-1H-pyrazole

[0345] To a solution of 3-(5-chloro-2-fluorophenyl)-1-methyl-1 / 7-pyrazole (lnt-22) (1.870 g, 8.877 mmol, 1 eq) in CH2CI2 (45 mL) was added NBS (1.58 g, 8.877 mmol, 1 eq) and the solution was stirred at 40 °C for 4 h Purification of the crude product by flash column chromatography (Silica, 10-60% EtOAc / hexane) afforded 4-bromo-3-(5-chloro-2-fluorophenyl)-1-methyl-1 / 7- pyrazole (2.443 g, 95%) as a beige solid.1H NMR (300 MHz, CDCh) 6= 7.58 - 7.45 (m, 2H), 7.41 - 7.30 (m, 1H), 7.11 (t, J = 9.1 Hz, 1H), 3.95 (s, 3H). GC-MS: Rt 9.046 m / z 290.0 [MJ. Method A-GC-MS AGO-P3725PCT Application as filed

[0346] Intermediate 26 (lnt-26): 4-Bromo-3-(5-chloro-2-fluorophenyl)-5-methyl-1H-pyrazole

[0347] Intermediate 26 was prepared from Intermediate 23 in an analogous manner to the synthesis of Intermediate 25.1H NMR (300 MHz, CDCI3) 6= 10.59 (s, 1 H), 7.77 - 7.69 (m, 1 H), 7.35 (ddd, J = 8.8, 4.3, 2.7 Hz, 1 H), 7.18 - 7.07 (m, 1 H), 2.33 (s, 3H). HPLC-MS: Rt 3.025 m / z 289.0-291.1 [M+HJ+. (Method A-HPLC)

[0348] Intermediate 27 (lnt-27): Ethyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline- 3-carboxylate

[0349] B2pin2Pd2(dba)3

[0350] Ethyl 6-bromoquinoline-3-carboxylate (500 mg, 1.695 mmol, 1 eq), B2pin2 (473 mg, 1.862 mmol, 1.1 eq), Pd2(dba)3(81 mg, 0.084 mmol, 0.05 eq), PCy3100% (57 mg, 0.203 mmol, 0.12 eq) and KOAc 100% (249 mg, 2.537 mmol, 1.5 eq) were mixed in dioxane (11 mL). The suspension was degassed and stirred at 100 °C for 5 h. After cooling to room temperature, the reaction mixture was filtered through a pad of Celite washing with MeCN (5 x 50 mL). The filtrate was concentrated to dryness to yield crude ethyl 6-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)quinoline-3-carboxylate (850 mg, > theoretical) as a yellow solid, which was then used in the next step without further purification. GC-MS: Rt 11.391 m / z 327.2[M], (Method A-GC-MS)

[0351] Intermediate 28 (lnt-28): Ethyl 6-(3-(5-chloro-2-fluorophenyl)-1-methyl-1H-pyrazol-4- yl)quinoline-3-carboxylate

[0352] 4-bromo-3-(5-chloro-2-fluorophenyl)-1-methyl-1 / 7-pyrazole (lnt-25) (2.440 g, 8.427 mmol, 1.08 eq), ethyl 6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)quinoline-3-carboxylate (lnt(lnt 27) (2.552 g, 7.799 mmol, 1 eq) and PdCh(dtbpf) (762.5 mg, 1.169 mmol, 0.15 eq) were mixed AGO-P3725PCT Application as filed in a mixture of dioxane (65 mL) and H2O (7 mL). The solution was degassed, K3PO4 (3.31 g, 15.6 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. Then, the mixture was diluted with CH2Cl2 / / PrOH 30% (80 mL) and washed with H2O (80 mL). The aqueous layer was extracted with ChLCh / fPrOH 30% (4x80 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, 40-70% MeCN / hLO) afforded ethyl 6-(3-(5-chloro-2-fluorophenyl)-1-methyl-1 / 7-pyrazol-4-yl)quinoline-3-carboxylate (2.421 g, 76%) as a beige solid.1H NMR (300 MHz, DMSO-cfe) 6= 9.25 (s, 1 H), 8.83 (s, 1 H), 8.25 (s, 1 H), 8.06 - 7.95 (m, 2H), 7.70 (d, J = 8.6 Hz, 1 H), 7.60 - 7.46 (m, 2H), 7.25 (t, J = 9.2 Hz, 1 H), 4.41 (q, J = 7.1 Hz, 2H), 3.99 (s, 3H), 1.38 (t, J = 7.1 Hz, 3H). HPLC-MS: Rt 3.241 m / z 410.2-412.1 [M+HJ+. (Method A-HPLC)

[0353] Intermediate 29 (lnt-29): Ethyl 6-(3-(5-Chloro-2-fluorophenyl)-5-methyl-1H-pyrazol-4- yl)quinoline-3-carboxylate

[0354] Intermediate 29 was synthesised in an analogous manner to the synthesis of Intermediate 28.1H-NMR (300 MHz, DMSO-cfe): 6 = 9.26 (d, J = 2.1 Hz, 1 H), 8.93 (d, J = 2.2 Hz, 1 H), 8.05 - 7.96 (m, 2H), 7.62 - 7.40 (m, 3H), 7.17 (t, J = 9.3 Hz, 1 H), 4.41 (q, J = 7.1 Hz, 2H), 2.39 (s, 3H), 1.38 (t, J = 7.1 Hz, 3H). HPLC-MS: Rt 3.025 m / z 410.2-412.0 [M+HJ+. (Method A-HPLC)

[0355] Intermediate 30 (lnt-30): 6-(3-(5-Chloro-2-fluorophenyl)-5-methyl-1H-pyrazol-4- yl)quinoline-3-carboxylic acid

[0356] To a solution of ethyl 6-(3-(5-chloro-2-fluorophenyl)-5-methyl-1 / 7-pyrazol-4-yl)quinoline-3- carboxylate (lnt-29) (223 mg, 0.544 mmol, 1 eq) in EtOH (5.5 mL) was added NaOH (aqueous solution 2,5M, 3.3 mL, 8.16 mmol, 15 eq). The solution was stirred at room temperature for 3 h and the crude volatiles were removed under reduced pressure. The reaction mixture was AGO-P3725PCT Application as filed diluted with CH2CI2 (30 mL) and extracted with H2O (30 mL). The aqueous layer was washed with CH2CI2 (30 mL), acidified until pH = 4, and extracted with a 30% / PrOH / CH2Cl2 mixture (3x30 mL). The combined organic layers were dried anhydrous sodium sulfate, filtered and volatiles were removed under reduced pressure to yield the crude 6-(3-(5-chloro-2- fluorophenyl)-5-methyl-1 / 7-pyrazol-4-yl)quinoline-3-carboxylic acid (198 mg, 95%) as a beige solid.1H NMR (300 MHz, DMSO-cfe) 6= 9.28 (d, J = 2.0 Hz, 1 H), 8.72 (s, 1 H), 7.94 (d, J = 8.7 Hz, 1 H), 7.87 (s, 1 H), 7.54 - 7.40 (m, 3H), 7.17 (t, J = 9.2 Hz, 1 H), 2.38 (s, 3H). HPLC-MS: Rt 2.422 m / z 382.2-384.0 [M+HJ+. (Method A-HPLC)

[0357] Intermediate 31 (lnt-31): 6-(3-(5-Chloro-2-fluorophenyl)-1-methyl-1H-pyrazol-4- yl)quinoline-3-carboxylic acid

[0358] Intermediate 31 was prepared from Intermediate 28 in an analogous manner to the synthesis of Intermediate 30.1H NMR (300 MHz, DMSO-cfe) 6= 9.24 (s, 1 H), 8.78 (s, 1 H), 8.26 (s, 1 H), 8.00 (d, J = 8.8 Hz, 1 H), 7.95 (s, 1 H), 7.68 (d, J = 9.2 Hz, 1 H), 7.61 - 7.47 (m, 2H), 7.26 (t, J = 9.3 Hz, 1 H), 3.99 (s, 3H).

[0359] EXAMPLES

[0360] Example 1 (Ex-1): 6-(3-(5-chloro-2-fluorophenyl)-1H-pyrazol-4-yl)- / V-(2-((3S,5R)-3,5- dimethylpiperazin-1-yl)ethyl)-1,5-naphthyridine-3-carboxamide

[0361] Step 1 :

[0362] 6-(3-(5-Chloro-2-fluorophenyl)-1 / 7-pyrazol-4-yl)-1 ,5-naphthyridine-3-carboxylic acid (lnt-21) (85 mg, 0.23 mmol, 1 eq), tert-butyl (2S,6R)-4-(2-aminoethyl)-2,6-dimethylpiperazine-1- carboxylate (lnt-3) (77 mg, 0.299 mmol, 1.3 eq) and HATU (113.9 mg, 0.299 mmol, 1.3 eq) were mixed in DMF (2 mL) and the solution was stirred at room temperature for 17 h. The crude volatiles were removed under reduced pressure and the crude product was purified by flash column chromatography (C18 12 g, H2O / MeCN 20-100%, dry loading) to afford tert-butyl (2S,6R)-4-(2-(6-(3-(5-chloro-2-fluorophenyl)-1 / 7-pyrazol-4-yl)-1 ,5-naphthyridine-3- AGO-P3725PCT Application as filed carboxamido)ethyl)-2,6-dimethylpiperazine-1 -carboxylate (78 mg, 56%) as a white solid.1H NMR (300 MHz, DMSO-d6) 5 9.20 (s, 1 H), 8.81 (s, 1 H), 8.49 - 8.22 (m, 2H), 7.96 (d, J = 9.1 Hz, 1 H), 7.78 - 7.38 (m, 2H), 7.27 (s, 1 H), 3.93 (s, 2H), 3.44 (s, 2H), 2.70 (d, J = 10.9 Hz, 2H), 2.08 (d, J = 12.1 Hz, 2H), 1.38 (s, 9H), 1.14 (d, J = 6.7 Hz, 6H).HPLC-MS: Rt 2.997 m / z 608.5- 610.4 [M+H]+. (Method B-HPLC)

[0363] Step 2:

[0364] To a solution of tert-butyl (2S,6R)-4-(2-(6-(3-(5-chloro-2-fluorophenyl)-1 / 7-pyrazol-4-yl)-1 ,5- naphthyridine-3-carboxamido)ethyl)-2,6-dimethylpiperazine-1-carboxylate (75 mg, 0.123 mmol, 1 eq) in CH2CI2 (4 mL) was added TFA (0.3 pL, 0.004 mmol, 0.04 eq). The solution was stirred at room temperature for 5 h. The crude volatiles were removed under reduced pressure and the crude product was purified by flash column chromatography (C18 12g, (H2O+NH4HCO3 10 mM pH7) / MeCN, 20-100% 10CV, 220 nm, 260 nm and 340 nm, dry loading) and by preparative HPLC (MeCN: NH4HCO3IO mM pH7) to afford 6-(3-(5-Chloro-2- fluorophenyl)-1 / 7-pyrazol-4-yl)- / V-(2-((3S,5R)-3,5-dimethylpiperazin-1-yl)ethyl)-1 ,5- naphthyridine-3-carboxamide (48 mg, 77%) as a yellow solid.1H NMR (300 MHz, DMSO-de) 5 9.20 (d, J = 2.1 Hz, 1 H), 8.83 (s, 1 H), 8.56 (s, 1 H), 8.34 (dd, J = 14.4, 7.3 Hz, 3H), 7.95 (d, J = 8.9 Hz, 1 H), 7.69 - 7.52 (m, 2H), 7.29 (t, J = 9.2 Hz, 1 H), 2.83 (t, J = 9.8 Hz, 4H), 1 .65 (t, J = 10.6 Hz, 2H), 0.99 (d, J = 6.2 Hz, 6H). UPLC-MS: Rt 2.550 m / z 508.4-510.4 [M+H]+. (Method C-UPLC)

[0365] Example 2 (Ex-2): 6-(3-(5-chloro-2-fluorophenyl)-1H-pyrazol-4-yl)- / V-((1, 2,3,4- tetrahydroisoquinolin-6-yl)methyl)-1,5-naphthyridine-3-carboxamide

[0366] Example 2 was prepared from Intermediate 20 and tert-butyl 6-(aminomethyl)-3,4- dihydroisoquinoline-2(1h)-carboxylate in an analogous manner to the synthesis of Example 1.1H NMR (300 MHz, DMSO-d6) 5 9.48 (t, J = 5.9 Hz, 1 H), 9.27 (d, J = 2.1 Hz, 1 H), 9.00 (s, 2H), 8.65 (s, 1 H), 8.39 (d, J = 9.0 Hz, 2H), 7.97 (d, J = 8.9 Hz, 1 H), 7.81 - 7.49 (m, 2H), 7.23 AGO-P3725PCT Application as filed

[0367] (dd, J = 13.1 , 5.4 Hz, 4H), 4.50 (d, J = 5.8 Hz, 2H), 4.26 (s, 2H), 3.38 (t, J = 5.8 Hz, 2H), 2.99

[0368] (t, J = 6.3 Hz, 2H).UPLC-MS: Rt 2.687 m / z 513.3-515.3 [M+H]+. (Method C-UPLC)

[0369] Example 3 (Ex-3): 6-(3-(5-Chloro-2-fluorophenyl)-1H-pyrazol-4-yl)- / V-(pyridin-3- ylmethyl)-1,5-naphthyridine-3-carboxamide

[0370] Step 1 :

[0371] A mixture 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-20) (150 mg, 0.331 mmol, 1 eq), HATU (151 mg, 0.397 mmol, 1.2 eq) and 3-(aminomethyl)pyridine (51 mL, 0.5 mmol, 1.51 eq) in CH2CI2 (3.3 mL) was stirred at room temperature for 20 h. Then, DMF (0.2 mL) was added, continuing the stirring at room temperature for 28 h. The crude volatiles were removed under reduced pressure and the crude product was purified by flash column chromatography (C18 20g, H2O / MeCN 20-100% 12 CV, 250 nm and 340 nm, dry loading) to give 6-(3-(5-Chloro-2- fluorophenyl)-1-(tetrahydro-2 / 7-pyran-2-yl)-1 / 7-pyrazol-4-yl)- / \ / -(pyridin-3-ylmethyl)-1 ,5- naphthyridine-3-carboxamide (144 mg, 80%) as a yellow sticky solid.1H-NMR (300 MHz, CDCI3): 5 = 9.31 (d, J = 2.1 Hz, 1 H), 8.70 - 8.45 (m, 3H), 8.39 - 8.19 (m, 2H), 7.83 - 7.50 (m, 3H), 7.34 (tt, J = 7.9, 4.1 Hz, 1 H), 7.07 - 6.85 (m, 2H), 5.61 - 5.43 (m, 1 H), 4.73 (d, J = 5.8 Hz, 2H), 4.14 (d, J = 11.9 Hz, 1 H), 3.76 (t, J = 9.7 Hz, 1 H), 2.26 - 2.05 (m, 2H), 1.95 - 1.58 (m, 4H). HPLC-MS: Rt 2.917 m / z 543.3-545.2 [M+H]+. (Method A-HPLC)

[0372] Step 2:

[0373] A solution of 6-(3-(5-Chloro-2-fluorophenyl)-1-(tetrahydro-2 / 7-pyran-2-yl)-1 / 7-pyrazol-4-yl)- / \ / - (pyridin-3-ylmethyl)-1 ,5-naphthyridine-3-carboxamide (140 mg, 0.257 mmol, 1 eq) in dioxane (2.6 mL) was added HCI (solution 4M in dioxane, 1.25 mL, 5 mmol, 19.39 eq), the mixture was stirred at room temperature for 24 h and the volatiles were removed under reduced pressure The crude residue was slurred with hexanes (35 mL). The solid was collected by filtration, washed with hexane (3 x 4 mL) and with Et20 (3 x 4 mL) and dried under high vacuum. The crude product was purified by flash column chromatography (C18 20 g, NH4HCO3+HCOOH (pH 7) 25-55%, 12CV, 250 nm and 340 nm, dry loading) to afford 6-(3-(5-Chloro-2- AGO-P3725PCT Application as filed f I uoropheny I)- 1 / 7-py razol-4-y I)- / -(py rid i n-3-y I methy I)- 1 ,5-naphthyridine-3-carboxamide (75 mg, 63%) as a white solid.1H NMR (300 MHz, DMSO-d6) 5 13.61 (s, 1 H), 9.50 (t, J = 5.8 Hz, 1 H), 9.28 (d, J = 1.8 Hz, 1 H), 8.60 (s, 1 H), 8.53 - 8.29 (m, 3H), 7.96 (d, J = 9.0 Hz, 1 H), 7.82 - 7.48 (m, 3H), 7.45 - 7.19 (m, 2H), 4.56 (d, J = 5.7 Hz, 2H).. UPLC-MS: Rt 2.864 m / z 459.3- 461.3 [M+H]+. (Method C-HPLC)

[0374] Table 1 : Examples 4-6 were synthesised in an analogous manner to Example 3. AGO-P3725PCT Application as filed

[0375] Example 7 (Ex-7): 6-(3-(5-Chloro-2-fluorophenyl)-1H-pyrazol-4-yl)-A / -(2-((3S,4R)-3,4- dihydroxypyrrolidin-1-yl)ethyl)-1,5-naphthyridine-3-carboxamide

[0376] To a solution of 6-(3-(5-chloro-2-fluorophenyl)-1-(tetrahydro-2 / 7-pyran-2-yl)-1 / 7-pyrazol-4-yl)- / V-(2-((3aR,6aS)-2-propyltetrahydro-5 / - / -[1 ,3]dioxolo[4,5-c]pyrrol-5-yl)ethyl)-1 ,5- naphthyridine-3-carboxamide (Ex-6) (135 mg, 0.159 mmol, 1 eq) in THF (0.5 mL) was added HCI (aqueous solution 2.73 M, 1.00 mL, 2.73 mmol, 17.12 eq). The solution was stirred at room temperature for 17 h and then at 60 °C for 24 h. The crude volatiles were removed under reduced pressure. The crude product was purified by flash column chromatography (C18, NH4HCO3+HCOOH (pH 7) / MeCN 20-40%, dry loading) to afford 6-(3-(5-Chloro-2- fluorophenyl)-1 / 7-pyrazol-4-yl)- / V-(2-((3S,4R)-3,4-dihydroxypyrrolidin-1-yl)ethyl)-1 ,5- naphthyridine-3-carboxamide (22 mg, 28%) as a yellow solid.1H NMR (300 MHz, DMSO-de) 5 9.19 (d, J = 2.1 Hz, 1 H), 8.54 (s, 1 H), 8.40 - 8.30 (m, 2H), 8.20 (s, 1 H), 7.94 (d, J = 8.9 Hz, 1 H), 7.71 - 7.47 (m, 2H), 7.26 (s, 1 H), 3.96 (s, 2H), 3.40 (d, J = 7.3 Hz, 2H), 3.02 (s, 2H), 2.82 - 2.68 (m, 2H), 2.56-2.46 (m, 2H). UPLC-MS: Rt 2.461 m / z 497.3-499.3 [M+H]+. (Method C- UPLC)

[0377] Example 8 (Ex-8): 6-(3-(5-Chloro-2-fluorophenyl)-5-methyl-1H-pyrazol-4-yl)- / V-((6- hydroxypyridin-3-yl)methyl)quinoline-3-carboxamide

[0378] 6-(3-(5-chloro-2-fluorophenyl)-5-methyl-1 / 7-pyrazol-4-yl)quinoline-3-carboxylic acid (lnt-30) (50 mg, 0.13 mmol, 1 eq), 5-(Aminomethyl)pyridin-2-ol dihydrobromide (lnt-1) (44.9 mg, 0.157 mmol, 1.2 eq), DIPEA (89 mL, 0.519 mmol, 4 eq) and HATLI (83.7 mg, 0.22 mmol, 1.2 eq) AGO-P3725PCT Application as filed were mixed in CH2CI2 ( 2.6 mL) and DMF (1 mL) and the resulting solution was stirred at room temperature for 16 h Purification of the crude product by flash column chromatography (C18, 12g, H2O / MeCN, 10-40%) afforded 6-(3-(5-chloro-2-fluorophenyl)-5-methyl-1 / 7-pyrazol-4-yl)- / V-((6-hydroxypyridin-3-yl)methyl)quinoline-3-carboxamide (25 mg, 39%) as a beige solid.1H- NMR (300 MHz, DMSO-d6): 5 = 9.23 (d, J=2.1 Hz, 1H), 9.21 -9.13 (m, 1H), 8.73 (d, J = 2.3 Hz, 1H), 7.98 (d, J= 8.6 Hz, 1H), 7.82 (s, 1H), 7.59-7.40 (m, 4H), 7.38-7.32 (m, 1H), 7.17 (t, J= 9.3 Hz, 1H), 6.32 (d, J= 9.4 Hz, 1H), 4.26 (d, J= 5.3 Hz, 2H), 2.37 (s, 3H). UPLC-MS: Rt 2.812 m / z 488.3-490.3 [M+HJ+. (Method C-UPLC)

[0379] Table 2: Examples 9-15 were synthesised in an analogous manner to Example 8. AGO-P3725PCT Application as filed AGO-P3725PCT Application as filed

[0380] Example 16 (Ex-16): A / -benzyl-6-(3-(5-chloro-2-fluorophenyl)-5-methyl-1H-pyrazol-4- yl)quinoline-3-carboxamide

[0381] A solution of 6-(3-(5-chloro-2-fluorophenyl)-5-methyl-1 / 7-pyrazol-4-yl)quinoline-3-carboxylic acid (lnt-30) (40 mg, 0.104 mmol, 1 eq), HATU (50 mg, 0.131 mmol, 1.26 eq) and benzylamine (15 pL, 0.137 mmol, 1.31 eq) in a mixture of CH2CI2 (3.5 mL) and DMF (1 mL) was stirred at room temperature for 22 h. Water (30 mL) and CH2CI2 (10 mL) were added to the reaction mixture and the layers were separated. The aqueous layer was extracted with CH2CI2 (3x 0 mL) and 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 20g, H2O / MeCN 20 -100% 12 CV, A = 265 nm, 300 nm, dry loading) afforded / \ / -benzyl-6-(3-(5-chloro-2-fluorophenyl)-5-methyl-1 / 7-pyrazol-4-yl)quinoline- 3-carboxamide (35 mg, 71 %) as a beige solid.1H NMR (300 MHz, DMSO-d6) 5 13.18 (s, 1 H), 9.39 - 9.23 (m, 2H), 8.77 (d, J = 2.2 Hz, 1 H), 7.99 (d, J = 8.7 Hz, 1 H), 7.89 - 7.78 (m, 1 H), AGO-P3725PCT Application as filed

[0382] 7.70 - 7.01 (m, 9H), 4.55 (d, J = 5.9 Hz, 2H), 2.38 (s, 3H).. UPLC-MS: Rt 3.805 m / z 471.3-

[0383] 473.3 [M+H]+. (Method C-UPLC)

[0384] Table 3: Examples 17-19 were synthesised in an analogous manner to Example 16. AGO-P3725PCT Application as filed

[0385] Example 20 (Ex-20): 6-(3-(5-chloro-2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)- / V-

[0386] ((1,2,3,4-tetrahydroisoquinolin-6-yl)methyl)quinoline-3-carboxamide

[0387] Step 1 :

[0388] 6-(3-(5-chloro-2-fluorophenyl)-1-methyl-1 / 7-pyrazol-4-yl)quinoline-3-carboxylic acid (lnt-31) (90 mg, 0.235 mmol, 1 eq), HATU (107 mg, 0.281 mmol, 1.19 eq), DIPEA (60 pL, 0.35 mmol, 1.49 eq) and tert-Butyl 6-(aminomethyl)-3,4-dihydroisoquinoline-2(1 / 7)-carboxylate (80 mg, 0.289 mmol, 1.23 eq) were mixed in CH2CI2 (2.4 mL) and the solution resulting was stirred at room temperature for 17 h. Water (15 mL) and CH2CI2 (15 mL) were added and the layers were separated. The aqueous layer was extracted with CH2CI2 (3x10 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, acetone / hexanes 30- 60%) afforded tert-Butyl 6-((6-(3-(5-chloro-2-fluorophenyl)-1-methyl-1 / 7-pyrazol-4- yl)quinoline-3-carboxamido)methyl)-3,4-dihydroisoquinoline-2(1 / 7)-carboxylate (135 mg, 91%) as a beige solid.1H NMR (300 MHz, DMSO-d6) 6 9.29 (m, 1 H), 9.22 (s, 1 H), 8.65 (s, 1 H), 8.25 (s, 1 H), 7.98 (d, J = 8.7 Hz, 1 H), 7.78 (s, 1 H), 7.66 (d, J = 8.7 Hz, 1 H), 7.63 - 7.45 (m, 2H), 7.37 - 7.06 (m, 4H), 4.46 (d, J = 8.1 Hz, 4H), 3.97 (s, 3H), 3.52 (d, J = 5.8 Hz, 2H), 2.74 (s, 2H), 1.40 (s, 9H). HPLC-MS: Rt 3.298 m / z 626.4-628.2 [M+H]+. (Method A-HPLC)

[0389] To a solution of tert-butyl 6-((6-(3-(5-chloro-2-fluorophenyl)-1-methyl-1 H-pyrazol-4- yl)quinoline-3-carboxamido)methyl)-3,4-dihydroisoquinoline-2(1 / 7)-carboxylate (135 mg, 0.215 mmol, 1 eq) in dioxane (1 mL) was added HCI (solution 4M in dioxane, 1.00 mL, 4 mmol,

[0390] 18.55 eq) and the resulting suspension was stirred at room temperature for 22 h. Hexanes (3 AGO-P3725PCT Application as filed x 2 mL) were added to the mixture and the solvent was decanted off. The compound was dissolved in MeCN (3x3 mL) and concentrated to dryness. to afford 6-(3-(5-chloro-2- fluorophenyl)-1-methyl-1 / 7-pyrazol-4-yl)- / \ / -((1,2,3,4-tetrahydroisoquinolin-6- yl)methyl)quinoline-3-carboxamide (75 mg, 58%) as a yellow solid.1H-NMR (300 MHz, DMSO-d6): 5 = 9.55 - 9.15 (m, 4H), 8.76 (s, 1 H), 8.29 (s, 1H), 8.03 (d, J = 8.7 Hz, 1 H), 7.83 (s, 1 H), 7.76 - 7.45 (m, 3H), 7.33 - 7.12 (m, 4H), 4.50 (d, J = 5.7 Hz, 2H), 4.22 (m, 2H), 3.99 (s, 3H), 3.34 (m, 2H), 2.99 (d, J = 6.6 Hz, 2H). UPLC-MS: Rt 3.244 m / z 526.4-528.3 [M+HJ+. (Method C-UPLC)

[0391] Example 21 (Ex-21): 6-(3-(5-chloro-2-fluorophenyl)-5-methyl-1H-pyrazol-4-yl)-Af-

[0392] ((1,2,3,4-tetrahydroisoquinolin-6-yl)methyl)quinoline-3-carboxamide

[0393] Example 21 was prepared from Intermediate 30 and tert-butyl 6-(aminomethyl)-3,4- dihydroisoquinoline-2(1 / - / )-carboxylate in an analogous manner to the synthesis of Example 20.1H-NMR (300 MHz, DMSO-d6): 5 = 9.71 - 9.28 (m, 4H), 9.17 - 8.90 (m, 1 H), 8.21 - 7.86 (m, 2H), 7.79 - 7.36 (m, 3H), 7.21 (m, 4H), 4.51 (d, J = 5.8 Hz, 2H), 4.22 (brs, 2H), 3.34 (m, 2H), 2.99 (m, 2H), 2.39 (s, 3H). UPLC-MS: Rt 2.965 m / z 526.4-528.4 [M+H]+. (Method C- UPLC) Analytical Methods:

[0394] HPLC-MS Methods AGO-P3725PCT Application as filed

[0395] The LC conditions and MS parameters of both methods are indicated in the following tables: LC Conditions

[0396] MS Parameters (Micromass ZQ 2000) AGO-P3725PCT Application as filed

[0397] UPLC-MS Methods

[0398] LC Conditions AGO-P3725PCT Application as filed

[0399] MS PARAMETERS (Acquity QDa detector):

[0400] GC-MS Method

[0401] Flame ionization detector (FID)

[0402] Mass spectrometer AGO-P3725PCT Application as filed

[0403] Commercial Materials

[0404] Unless otherwise stated, all starting materials are commercially available. BIOLOGICAL EXAMPLES

[0405] Biological Example 1 - Biochemical assay ALK5

[0406] Method A

[0407] 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 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.

[0408] Method B

[0409] 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;

[0410] 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). AGO-P3725PCT Application as filed

[0411] Results

[0412] Data for compounds of the inventions that were tested in this assay are shown in Table 4 below.

[0413] Table 4

[0414] Conclusion

[0415] As can be seen from the results described in Table 4, the compounds of the present invention that were tested in this assay are potent inhibitors of ALK5.

[0416] Biological Example 2 - Cellular assay ALK5

[0417] 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). AGO-P3725PCT Application as filed

[0418] Results

[0419] Data for compounds of the inventions that were tested in this assay are shown in Table 5 below.

[0420] Table 5

[0421] Conclusion

[0422] As can be seen from the results described in Table 5, the compounds of the present invention that were tested in this assay are potent inhibitors of ALK5.

[0423] Biological Example 3 - Plasma Stability

[0424] Method

[0425] Human and mouse plasma pooled from healthy donors extracted in citrate tubes was employed in the assay.

[0426] Brief protocol:

[0427] Plates containing 5pM compounds in plasma (total volume: 1OOpL) 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.

[0428] Stationary phase: Reverse phase ACQUITY BEH C18 1.7pm 2.1x50mm (Waters)

[0429] Mobile phase: 0.1% Formic acid water / 0.1 % formic acid in acetonitrile

[0430] Gradient: AGO-P3725PCT Application as filed

[0431] Flow: 0.6 ml / min

[0432] The chromatographic equipment employed was an LIPLC QSM Waters Acquity. Compound concentrations were calculated from the MS peak areas.

[0433] A “high” plasma stability is defined as more than 80% of the compound remaining after 60 mins as tested in this assay. A “very high” plasma stability is defined as more than 90% of the compound remaining after 60 mins as tested in this assay.

[0434] Results

[0435] Data for compounds of the inventions that were tested in this assay are shown in Table 6 below.

[0436] Table 6 (Human)

[0437] *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.

[0438] Conclusion As can be seen from the results described in Table 6, the compounds of the present invention that were tested in this assay have high or very high plasma stability. This behaviour could be advantageous according to the route of administration (e.g. oral administration). AGO-P3725PCT Application as filed

[0439] Biological Example 4 - Metabolic Stability (Liver Microsomes)

[0440] Method A

[0441] Human and mice microsomes from Tebu-Xenotech were employed in the assay. They contained 20 mg / ml of protein.

[0442] Brief protocol:

[0443] The following quantities were added to each well of a 96-well microplate.

[0444] 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 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.

[0445] Stationary phase: Acquity LIPLC® BEHC18 1 ,7 pm (2.1 mm x 50 mm) (Waters)

[0446] Mobile phase: A: 0.1 % formic; B: acetonitrile+0.1 % formic acid

[0447] Gradient: AGO-P3725PCT Application as filed

[0448] Flow: 0.6 ml / min

[0449] The chromatographic equipment employed was an LIPLC QSM Waters Acquity.

[0450] Metabolic stability was calculated from the logarithm of the remaining compound at each of the times evaluated.

[0451] Method B

[0452] Intrinsic clearance studies were performed with mouse and human liver microsomes at 0.5 mg / mL protein concentration. 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).

[0453] 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.

[0454] 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 0 and 60 min and reaction was terminated with 150 pL of acetonitrile. All experiments were performed in duplicate for the test item.

[0455] Verapamil at 0.5 pM was used as the positive control in mouse and human liver microsomes.

[0456] All experiments were performed in singlet for the positive control.

[0457] 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.

[0458] Bioanalysis:

[0459] 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. AGO-P3725PCT Application as filed

[0460] Data Analysis:

[0461] 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 (uL)

[0462] CLint = - protem content (mg) where, k = decay rate constant (min-1)

[0463] A “low” metabolic stability is defined as less than 30% of the compound remaining after 60 mins as tested in this assay. A “very low” metabolic stability is defined as less than 10% remaining after 60 mins as tested in this assay.

[0464] Results

[0465] Data for compounds of the inventions that were tested in this assay are shown in Table 7 below.

[0466] Table 7 (Human) 0 Conclusion

[0467] As can be seen from the results described in Table 7, some of the compounds of the present invention that were tested in this assay show low or very low metabolic stability. This behaviour could be advantageous where the compound is metabolised to an inactive metabolite, thereby reducing systemic exposure. t) AGO-P3725PCT Application as filed

[0468] Biological Example 5 - CYP Inhibition

[0469] The objective of the studies was to screen the inhibition potential of the compounds using recombinant human cytochrome P450 enzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4 (BFC) and CYP3A4 (DBF)) and probe substrates with fluorescent detection. Method A

[0470] Incubations were conducted in a 200 pl volume in 96 well microtiter plates (COSTAR 3915). Addition of cofactor-buffer mixture (KH2PO4 buffer, 1.3mM NADP, 3.3mM MgCI2, 3.3 mM Glucose-6-phosphate and 0.4U / mL Glucose-6-phosphate Dehydrogenase), supersomes control, standard inhibitors (Furafyline, Tranylzypromine, Ketoconazole, Sulfaphenazole and Quinidine; from Sigma Aldrich) previously diluted and compounds to plates were carried out by a liquid handling station (Zephyr Caliper). The plate was then pre-incubated at 37°C for 5 min, and the reaction initiated by the addition of pre-warmed enzyme / substrate (E / S) mix. The E / S mix contained buffer (KH2PO4), c-DNA-expressed P450 in insect cell microsomes, substrate (3-cyano-7-ethoxycoumarin (CEC) for CYP1A2 and CYP2C19, 7-Methoxy-4- (trifluoromethyl)coumarin (7-MFC) for CYP2C9, 3-[2-(N,N-Diethyl-N-methylammonium)ethyl]- 7-Methoxy-4- Methylcoumarin (AMMC) for CYP2D6 and 7-benzyloxytrifluoromethyl coumarin (7-BFC) and Dibenzylfluorescein (DBF) for CYP3A4) and other components to give the final assay concentrations in a reaction volume of 200 pl. Reactions were terminated after various times (a specific time for each cytochrome) by addition of STOP solution (ACN / TrisHCI 0.5M 80:20, and NaOH 2N for CYP3A4 (DBF).

[0471] Fluorescence per well was measured using a fluorescence plate reader (EnVision 2104 multilabel Reader) and percentage of inhibition was calculated.

[0472] Method B:

[0473] Assay procedure • Preparation of master plate (dilution plate for test compounds): o each test compound prepared / provided as 10 mM DMSO stock solution o each test compound is assayed in duplicate; final compound concentration of 10 pM

[0474] • Preparation of master plate (serial dilution plate for controls): • Serial dilution of controls is carried out in a 96-well plate o 50 pL of DMSO to wells A1-G12 o 50 pL of appropriate control to well H1-H12 o dilute (1 :3) master plate by transferring 25 pL in the order from H to B well o further dilute 10x in buffer (A1 to A1 , B1 to B1 , etc.) • Preparation of incubation mix (for one full plate): AGO-P3725PCT Application as filed

[0475] • Incubation steps: o transfer 195 pL of incubation mixture into each well of 96-well plate (reaction plate) o transfer 5pL from each well of the master plate into the equivalent well of the incubation plate (i.e. A1 to A1 , B1 to B1 , etc.)

[0476] Test compounds:

[0477] • transfer 199.5 pL of incubation mixture into each well of 96-well plate (reaction plate)

[0478] • transfer 0.5pL from each well of 5 mM working solution (n=2)

[0479] • DMSO control and blank samples: • transfer 199.5 pL of incubation mixture into 2 columns of the reaction plate

[0480] • add 0.5pL of DMSO to each well

[0481] • pre-warm incubation plate for 5 minutes at 37°C

[0482] • start the reaction by adding 50pL of cofactor solution to each well of the reaction plate (except for 2 wells of DMSO blank samples (row H)) • incubate plates at 37°C for the substrate specific time

[0483] • terminate the reaction by collecting 75 pl from each well and adding to 225 pl acetonitrile: methanol (2:1) solution with internal standard (100 ng / ml diclofenac + 10 ng / ml warfarin -> warfarin used for 2C9 isoform or in case any variation is observed with diclofenac) • ctfg: 4000 rpm, 30 minutes, +4°C

[0484] • transfer supernatants to a new plate for LC-MS / MS analysis

[0485] Data Analysis: a) control inhibitors The instrument responses (analyte peak area / internal standard peak area) were referenced to those for solvent controls (as 100%) in order to determine the percentage reduction in probe metabolism.

[0486] Percent of control activity of probe metabolism versus Log concentration plots were generated using GraphPad Prism software or similar software that can perform nonlinear regression. The AGO-P3725PCT Application as filed sigmoidal dose response model was fitted to the data in order to determine the IC50 for each compound. b) tested compounds

[0487] The instrument responses (analyte peak area / internal standard peak area) for DMSO control were defined as maximum activation (calculated as average of 14 samples). PIN (percentage of inhibition) for each compound replica was calculated as follows:

[0488] PIN = 100 - [(analyte peak area / internal standard peak area)*1001 maximum activation]

[0489] Results

[0490] Data for compounds of the inventions that were tested in this assay are shown in Tables 8-10 below.

[0491] Table 8 (Method A)

[0492] Table 9 (Method B) AGO-P3725PCT Application as filed

[0493] Table 10 (Method B)

[0494] Conclusion

[0495] As can be seen from the results described in Tables 8-10, at least some of the compounds of the present invention that were tested in this assay showed only weak CYP inhibition and compounds are expected to show only weak CYP inhibition at relevant concentrations following administration.

[0496] Biological Example 6 - hERG Binding Affinity 0 Compound preparation:

[0497] 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 triplicates5 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. 0 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 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. t) AGO-P3725PCT Application as filed

[0498] 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.

[0499] Biological Example 7 - TGFp-stimulated rat precision-cut lung slices (PCLS)

[0500] Materials:

[0501] Preparing murine PCLS -

[0502] • Advanced DMEM / F-12 medium, Gibco, Cat. No. 12634-010

[0503] • Antibiotic / Antimycotic (A / A), 100x, Gibco, Cat. No. 15240-062

[0504] • Agarose type I, low EED, Sigma, Cat. No. A6013

[0505] • Dulbecco's Modified Eagle Medium (DMEM), no phenol red, Gibco, Cat. No. 31053- 044

[0506] • Dimethyl sulfoxide (DMSO), Sigma, Cat. No. D2650

[0507] • Recombinant human TGFp, R&D Systems, Cat. No. 240-B

[0508] • RNA Later Stabilization Solution, Invitrogen, Cat. No. AM7021

[0509] RNA isolation -

[0510] • Precellys Hard Tissue CK28 tubes, Bertin Technologies, Cat. No. P000911-LYSK1-A

[0511] • Ethanol, > 99.8 A. R., LachNer, Cat. No. 20025-A99

[0512] • Trizol Reagent, Ambion, Cat. No. 15596018

[0513] • Chloroform, LachNer, Cat. No. 20034-AT1

[0514] • Isopropyl alcohol, LachNer, Cat. No. 20037-ATO

[0515] • Buffer NTC, Macherey-Nagel, Cat. No. 740654

[0516] • NucleoSpin Gel and PCR Clean-up kit, Macherey-Nagel, Cat. No. 740609

[0517] • Quant-iT RiboGreen RNA kit, Invitrogen, Cat. No. R11490 AGO-P3725PCT Application as filed

[0518] Gene expression analysis -

[0519] • SuperScript III Reverse Transcriptase, Invitrogen, Cat. No. 18080-044

[0520] • dNTP Mix, Invitrogen, Cat. No. 18427-088

[0521] • Random primers, Invitrogen, Cat. No. 48190011 • RNase Out, Invitrogen, Cat. No. 10777-019

[0522] • TaqMan Fast Advanced Master Mix, Thermo Fisher, Cat. No. 4444557

[0523] • Pre-designed, pre-optimized primers and TaqMan probe for genes of interest from Thermo Fisher Methods:

[0524] Preparing rat POLS and treatment with compounds and TGF / 3 -

[0525] 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.

[0526] 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.

[0527] RNA isolation and RNA concentration measurement -

[0528] 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 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 AGO-P3725PCT Application as filed 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.

[0529] 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.

[0530] Gene expression analysis -

[0531] 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 O.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.

[0532] 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).

[0533] Data Analysis:

[0534] 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 AGO-P3725PCT Application as filed 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.

[0535] 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.

[0536] Biological Example 8 - TGFp-stimulated normal human lung fibroblasts (NHLF) Materials:

[0537] Cell culture -

[0538] • Normal Human Lung Fibroblasts (NHLF), Lonza, Cat. No. CC-2515

[0539] • Fibroblast Basal Medium, Lonza, Cat. No. CC-3131

[0540] • FGM-2 SingleQuots Kit (hFGF-B, Insulin, FBS, gentamicin / amphotericin-B), Lonza, Cat. No. CC-4126,

[0541] • Pure Col (Bovine Collagen Solution type I), Advanced BioMatrix, Cat. No. 5005

[0542] • Recombinant human TGFp, R&D Systems, Cat. No. 240-B

[0543] RNA isolation -

[0544] • RLT buffer, Qiagen, Cat. No. 1015762

[0545] • p-Mercaptoethanol, Sigma, Cat. No. M3148

[0546] • RNeasy Mini Kit, Qiagen, Cat. No. 74106

[0547] • Ethanol, > 99.8 A. R., LachNer, Cat. No.20025-A99

[0548] • High Capacity RT Kit, Applied Biosystems, Cat. No. 4368813

[0549] • TaqMan Fast Advanced Master Mix, Thermo Fisher, Cat. No. 4444557

[0550] • Primers and TaqMan probe for genes of interest, Thermo Fisher

[0551] • Primers and TaqMan probe for genes of interest, Microsynth

[0552] Methods:

[0553] Testing compounds in TGFp stimulated NHLF -

[0554] 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. AGO-P3725PCT Application as filed

[0555] 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. 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. 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.

[0556] RNA isolation and gene expression analysis -

[0557] 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.

[0558] 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 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.

[0559] 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 AGO-P3725PCT Application as filed 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).

[0560] Data Analysis:

[0561] 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.

[0562] 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.

[0563] REFERENCES

[0564] Akhurst, R. J. et al, Targeting the TGFp signalling pathway in disease, Nature Reviews, 2012, 11 (10), 790-811.

[0565] 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.

[0566] Bierie, B. et al, TGF-p: the molecular Jekyll and Hyde of cancer, Nature Reviews Cancer, 2006, 6, 506-520.

[0567] Biernacka, A. et al, TGF-p signalling in fibrosis, Growth Factors, 2011 , 29(5), 196-202.

[0568] Heldin, C. H. et al, Signalling Receptors for TGF-b Family Members, Cold Spring Harb Perspect Biol, 2016, 8(8), 1-33.

[0569] Howell, J. E. etal, TGF-p: Its Role in Asthma and Therapeutic Potential, Current Drug Targets, 2006, 7(5), 547-565.

[0570] 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.

[0571] Saito, A. et al, TGF-p Signaling in Lung Health and Disease, Int. J. Mol. Sci., 2018, 19(8), 2460. AGO-P3725PCT Application as filed

[0572] Wang, J. et al, Targeting Transforming Growth Factor-b Signalling in Primary Open-Angle Glaucoma, J Glaucoma, 2017, 26(4), 390-395.

[0573] 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.

[0574] 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.

[0575] 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.

[0576] 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-P3725PCT 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;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; m is 0, 1 or 2;Z is CH or N; A is -Ci-4alkylene-;B is selected from the group consisting of phenyl optionally fused to a 5-7 membered nitrogen containing heterocyclyl, 5-6 membered heteroaryl optionally fused to a 5-7 membered nitrogen containing heterocyclyl, and 4-10 membered nitrogen containing heterocyclyl;R3 is independently selected from the group consisting of Ci-4alkyl optionally substituted by hydroxy or methoxy, hydroxy, Ci-4alkoxy, Ci-4haloalkyl, halo and -N RSARSB;RSA and RSB are independently selected from H and methyl;R4 is selected from the group consisting of 4-6 membered nitrogen containing heterocyclyl and Cs-ecycloalkyl in either case optionally substituted by one or two methyl groups; p is 0, 1 or 2; q is 0 or 1 ; andRe is H or Ci-4alkyl;AGO-P3725PCT Application as filed or a pharmaceutically acceptable salt and / or solvate thereof.

2. The compound according to claim 1 , which is a compound of formula (IA):wherein A, B, C, R1, R2, R3, R4, Re, n, m, p and q are as defined in claim 1 ; or a pharmaceutically acceptable salt and / or solvate thereof.

3. The compound according to claim 2, which is a compound of formula (IA):wherein A, B, Ri, R2, R3, R4, Re, n, m, p and q are as defined in claim 1 ; or a pharmaceutically acceptable salt and / or solvate thereof.

4. The compound according to claim 2, which is a compound of formula (IA”):wherein A, B, R1, R2, R3, R4, Re, n, m, p and q are as defined in claim 1 ;AGO-P3725PCT Application as filed or a pharmaceutically acceptable salt and / or solvate thereof.

5. The compound according to claim 1 , which is a compound of formula (IB):wherein A, B, C, R1, R2, R3, R4, Re, n, m, p and q are as defined in claim 1 ; or a pharmaceutically acceptable salt and / or solvate thereof.

6. The compound according to claim 5, which is a compound of formula (IB’):wherein A, B, Ri, R2, R3, R4, Re, n, m, p and q are as defined in claim 1 ; or a pharmaceutically acceptable salt and / or solvate thereof.

7. The compound according to claim 5, which is a compound of formula (IB”):wherein A, B, R1, R2, R3, R4, Re, n, m, p and q are as defined in claim 1 ;AGO-P3725PCT Application as filed or a pharmaceutically acceptable salt and / or solvate thereof.

8. The compound or pharmaceutically acceptable salt and / or solvate thereof according to any one of claims 1 to 7, wherein Ri is independently halo.

9. The compound or pharmaceutically acceptable salt and / or solvate thereof according to claim 8, wherein Ri is independently fluoro or chloro.

10. The compound or pharmaceutically acceptable salt and / or solvate thereof according to any one of claims 1 to 9, wherein n is 2.

11. The compound or pharmaceutically acceptable salt and / or solvate thereof according to claim 10, wherein the following moiety forms:wherein " \ represents the point of connection to the remainder of the compound.

12. The compound or pharmaceutically acceptable salt and / or solvate thereof according to any one of claims 1 to 11 , wherein m is 0.

13. The compound or pharmaceutically acceptable salt and / or solvate thereof according to any one of claims 1 to 11 , wherein m is 1.

14. The compound or pharmaceutically acceptable salt and / or solvate thereof according to any one of claims 1 to 11 or 13, wherein R2 is Ci-4alkyl.

15. The compound or pharmaceutically acceptable salt and / or solvate thereof according to claim 14, wherein R2 is methyl.

16. The compound or pharmaceutically acceptable salt and / or solvate thereof according to any of claims 1 to 15, wherein A is -Ci-2alkylene.

17. The compound or pharmaceutically acceptable salt and / or solvate thereof according to claim 16, wherein A is -CH2- or -CH2CH2-.AGO-P3725PCT Application as filed18. The compound or pharmaceutically acceptable salt and / or solvate thereof according to any of claims 1 to 17, wherein B is phenyl optionally fused to a 5-7 membered nitrogen containing heterocyclyl.

19. The compound or pharmaceutically acceptable salt and / or solvate thereof according to claim 18, wherein B is phenyl.

20. The compound or pharmaceutically acceptable salt and / or solvate thereof according to claim 19, wherein B is phenyl fused to a 6 membered nitrogen containing heterocyclyl.

21. The compound or pharmaceutically acceptable salt and / or solvate thereof according to claim 20, wherein B is 1,2,3,4-tetrahydroisoquinolin-6-yl:wherein " \ represents the point of connection to the remainder of the compound.

22. The compound or pharmaceutically acceptable salt and / or solvate thereof according to claim 17, wherein B is 5-6 membered heteroaryl optionally fused to a 5-7 membered nitrogen containing heterocyclyl.

23. The compound or pharmaceutically acceptable salt and / or solvate thereof according to claim 22, wherein B is pyridinyl.

24. The compound or pharmaceutically acceptable salt and / or solvate thereof according to claim 17, wherein B is 4-10 membered nitrogen containing heterocyclyl.

25. The compound or pharmaceutically acceptable salt and / or solvate thereof according to claim 24, wherein B is selected from the group consisting of pyrrolidinyl, piperazinyl and tetrahydro-5H-[1,3]dioxolo[4,5-c]pyrrol-5-yl.

26. The compound or pharmaceutically acceptable salt and / or solvate thereof according to any one of claims 1 to 25, wherein R3 is independently selected from the group consisting of Ci-4alkyl optionally substituted by hydroxy or methoxy, hydroxy and C1-4 alkoxy.AGO-P3725PCT Application as filed27. The compound or pharmaceutically acceptable salt and / or solvate thereof according to claim 26, wherein R3 is selected from the group consisting of methyl, propyl, methoxyethyl and hydroxy.

28. The compound or pharmaceutically acceptable salt and / or solvate thereof according to any one of claims 1 to 25, wherein p is 0.

29. The compound or pharmaceutically acceptable salt and / or solvate thereof according to any one of claims 1 to 27, wherein p is 1.

30. The compound or pharmaceutically acceptable salt and / or solvate thereof according to any one of claims 1 to 27, wherein p is 2.

31. The compound or pharmaceutically acceptable salt and / or solvate thereof according to any one of claims 1 to 30, wherein q is 0.

32. The compound or pharmaceutically acceptable salt and / or solvate thereof according to any of claims 1 to 31 , wherein Re is H.

33. The compound or pharmaceutically acceptable salt and / or solvate thereof according to any of claims 1 to 31 , wherein Re is Ci-4al kyl .

34. The compound or pharmaceutically acceptable salt and / or solvate thereof according to claim 1 , which is selected from the group consisting of: tert-Butyl (2S,6R)-4-(2-(6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)-1 ,5-naphthyridine-3- carboxamido)ethyl)-2,6-dimethylpiperazine-1 -carboxylate;6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)-N-((1,2,3,4-tetrahydroisoquinolin-6- yl)methyl)-1 ,5-naphthyridine-3-carboxamide;6-(3-(5-Chloro-2-fluorophenyl)-1H-pyrazol-4-yl)-N-(pyridin-3-ylmethyl)-1,5-naphthyridine-3- carboxamide;N-Benzyl-6-(3-(5-chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)-1 ,5-naphthyridine-3-carboxamide;6-(3-(5-Chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)-N-(2-((3aR,6aS)-2-(2- methoxyethyl)tetrahydro-5H-[1,3]dioxolo[4,5-c]pyrrol-5-yl)ethyl)-1,5-naphthyridine-3- carboxamide; 6-(3-(5-Chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)-N-(2-((3aR,6aS)-2-propyltetrahydro-5H- [1,3]dioxolo[4,5-c]pyrrol-5-yl)ethyl)-1 ,5-naphthyridine-3-carboxamide;AGO-P3725PCT Application as filed6-(3-(5-Chloro-2-fluorophenyl)-1 H-pyrazol-4-yl)-N-(2-((3S,4R)-3,4-dihydroxypyrrolidin-1- yl)ethyl)-1,5-naphthyridine-3-carboxamide;6-(3-(5-Chloro-2-fluorophenyl)-5-methyl-1 H-pyrazol-4-yl)-N-((6-hydroxypyridin-3- yl)methyl)quinoline-3-carboxamide; 6-(3-(5-chloro-2-fluorophenyl)-5-methyl-1 H-pyrazol-4-yl)-N-((2-oxo-1 ,2-dihydropyridin-4- yl)methyl)quinoline-3-carboxamide;6-(3-(5-chloro-2-fluorophenyl)-1-methyl-1 H-pyrazol-4-yl)-N-((6-oxo-1,6-dihydropyridin-3- yl)methyl)quinoline-3-carboxamide;6-(3-(5-chloro-2-fluorophenyl)-5-methyl-1 H-pyrazol-4-yl)-N-((6-oxo-1,6-dihydropyridin-2- yl)methyl)quinoline-3-carboxamide;6-(3-(5-chloro-2-fluorophenyl)-5-methyl-1 H-pyrazol-4-yl)-N-((2-oxo-1,2-dihydropyridin-3- yl)methyl)quinoline-3-carboxamide;6-(3-(5-Chloro-2-fluorophenyl)-1-methyl-1 H-pyrazol-4-yl)-N-((2-oxo-1 ,2-dihydropyridin-4- yl)methyl)quinoline-3-carboxamide; 6-(3-(5-Chloro-2-fluorophenyl)-1-methyl-1 H-pyrazol-4-yl)-N-((6-oxo-1 ,6-dihydropyridin-2- yl)methyl)quinoline-3-carboxamide;6-(3-(5-Chloro-2-fluorophenyl)-1-methyl-1 H-pyrazol-4-yl)-N-((2-oxo-1 ,2-dihydropyridin-3- yl)methyl)quinoline-3-carboxamide;N-benzyl-6-(3-(5-chloro-2-fluorophenyl)-5-methyl-1 H-pyrazol-4-yl)quinoline-3-carboxamide; 6-(3-(5-Chloro-2-fluorophenyl)-5-methyl-1 H-pyrazol-4-yl)-N-(pyridin-3-ylmethyl)quinoline-3- carboxamide; N-Benzyl-6-(3-(5-chloro-2-fluorophenyl)-1-methyl-1 H-pyrazol-4-yl)quinoline-3-carboxamide; 6-(3-(5-Chloro-2-fluorophenyl)-1-methyl-1 H-pyrazol-4-yl)-N-(pyridin-3-ylmethyl)quinoline-3- carboxamide; 6-(3-(5-chloro-2-fluorophenyl)-1-methyl-1 H-pyrazol-4-yl)-N-((1 ,2,3,4-tetrahydroisoquinolin-6- yl)methyl)quinoline-3-carboxamide; and 6-(3-(5-chloro-2-fluorophenyl)-5-methyl-1 H-pyrazol-4-yl)-N-((1 ,2,3,4-tetrahydroisoquinolin-6- yl)methyl)quinoline-3-carboxamide; or a pharmaceutically acceptable salt and / or solvate of any one thereof.

35. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt and / or solvate thereof according to any one of claims 1 to 34 and a pharmaceutically acceptable diluent or carrier.

36. The compound or pharmaceutically acceptable salt and / or solvate thereof according to any one of claims 1 to 34, or pharmaceutical composition according to claim 35, for use as a medicament.AGO-P3725PCT Application as filed37. The compound or pharmaceutically acceptable salt and / or solvate thereof according to any one of claims 1 to 34, or pharmaceutical composition according to claim 35, for use in the treatment or prevention of a disease or pathological disorder susceptible to amelioration by inhibition of ALK5.

38. Use of the compound or pharmaceutically acceptable salt and / or solvate thereof according to any one of claims 1 to 34, or pharmaceutical composition according to claim 35, 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.

39. 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 34, or pharmaceutical composition according to claim 35.

40. The compound or pharmaceutically acceptable salt and / or solvate thereof according to any one of claims 1 to 34, or pharmaceutical composition according to claim 35, for use in the treatment or prevention of lung diseases such as idiopathic pulmonary fibrosis.

41. The compound or pharmaceutically acceptable salt and / or solvate thereof according to any one of claims 1 to 34, or pharmaceutical composition according to claim 35, for use as a medicament for oral administration.

42. 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 m are as defined in any one of claims 1 to 34 or a salt and / or solvate thereof;AGO-P3725PCT Application as filed a compound of formula (III):wherein A, B, R3, R4, p and q are as defined in any one of claims 1 to 34 or a salt and / or solvate thereof; a compound formula (VIII):wherein R1 and n are as defined in any one of claims 1 to 34 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 34 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 34 or a salt and / or solvate thereof; a compound formula (XI):AGO-P3725PCT Application as filedwherein R1 and n are as defined in any one of claims 1 to 34 and X is halo (e.g. Br) or a salt and / or solvate thereof; a compound formula (XII):wherein Ri, R2 and n are as defined in any one of claims 1 to 34 or a salt and / or solvate thereof; and a compound formula (XVI):wherein R1, R2, n and m are as defined in any one of claims 1 to 34 and PG2is a carboxylic acid protecting group such as methyl or a salt and / or solvate thereof.

43. 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 34, comprising reacting a compound of formula (II):AGO-P3725PCT Application as filedwherein R1, R2, Z, n and m are as defined in any one of claims 1 to 34, or an activated derivative thereof or a salt and / or solvate thereof; with a compound of formula (III):wherein A, B, R3, R4, Re, p and q are as defined in claim 1, or an activated derivative thereof or a salt and / or solvate thereof.

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