Sulfonamide derivatives useful as GPR17 modulators

Abstract

THERAPEUTIC COMPOUNDS The present invention relates to compounds of Formula (I) which act to attenuate or block the function of the GPR17 receptor (e.g. compounds which act as GPR17 antagonists), wherein R1, R2, R3, R4, R5, X1, X2, X3, X4, X5, and X6 each have any one of the meanings defined herein. The present invention also relates to pharmaceutical compositions comprising the compounds of Formula (I), and to their use in the diseases in which GPR17 attenuation is beneficial, such as in the treatment of multiple sclerosis (MS).

Description

[0001] THERAPEUTIC COMPOUNDS

[0002] BACKGROUND

[0003] G-protein coupled receptors (GPCRs) are membrane proteins which link extracellular ligand binding to intracellular signalling predominantly through coupling with intracellular G-proteins leading to second messenger signalling and diverse downstream effects.

[0004] G-protein coupled receptor 17 (GPR17) is an orphan GPCR, without consensus on the identity of an endogenous ligand. Several putative endogenous ligands including uracil nucleotides and cysteinyl leukotrienes have been suggested (1), however other groups have been unable to verify the findings (2, 3). In cells natively expressing GPR17, signalling stimulated by a synthetic agonist MDL29.951 occurs via coupling with Gi and Gq proteins (4). Coupling with Gi causes a decrease in adenylyl cyclase and subsequently the second messenger cyclic AMP (cAMP). An analysSynthesis of Examples, general procedures the structure of the activated GPR17-Gi complex has indicated that the extracellular Ioop2 of GPR17 occupies the orthosteric binding pocket promoting selfactivation (5). Coupling with Gq results in phospholipase C (PLC) activation and calcium accumulation.

[0005] Myelin is the lipid-rich protective sheath that surrounds axons, allowing saltatory conduction of nerve impulses via nodes of Ranvier. In situations where myelin is damaged the signal fails to conduct correctly. Oligodendrocytes (ODCs) are the most common glial cell in the brain and are located throughout the white matter. They are responsible for myelination of axons during development and remyelination following injury. ODCs mature from oligodendrocyte precursor cells (OPCs) in response to both external and intrinsic factors (6). GPR17 has been demonstrated to be most highly expressed on pre-myelinating ODCs (7), also called differentiation committed-OPCs (8). A reduction in expression of GPR17 is required for maturation to myelinating-capable ODCs (9). Attenuation or blockade of GPR17 function is expected to promote remyelination.

[0006] GPR17 protein and / or mRNA expression has been shown to be elevated in rodent CNS injury settings such as in focal cerebral ischaemia (10, 11), spinal cord injury (12), cuprizone-induced demyelination (13) and has been described as a sensor for damage.

[0007] Similarly in human injury Franke etal. (14) characterised GPR17 expression in brain samples from patients with traumatic brain injury (TBI) undergoing neurosurgery for contusion removal and from autopsy TBI cases. GPR17 was expressed on OPCs, dying neurons, reactive astrocytes and activated microglia / macrophages. In autopsy cases, GPR17 expression positively correlated with death for intracranial complications. Angelini et al. (15) detected GPR17 expression in postmortem brains from multiple sclerosis patents. They showed an increase in GPR17-expressing oligodendroglial cells accumulating at inflammatory sites in normal appearing white matter (NAWM).

[0008] GPR17 antagonists have been reported by several groups. Zhou et al. (16) demonstrated binding using a frontal affinity chromatography-mass spectrometry (FAC-MS) method while Eberini et al. (17) described a series of agonist and partial agonist ligands using GTPyS binding.

[0009] Functional effects of attenuation or blockade of GPR17 function (such as through GPR17 antagonists) have been published in WO2018122232A1, WO2024017857A1 and WO2024104462. In WO2018122232A1, Mueller eta / , showed in an in vitro recombinant assay that novel GPR17 antagonists caused a reduction in MDL29, 951 -stimulated calcium accumulation and a reversal of forskolin-stimulated MDL29,951-driven reduction in cAMP. Additionally, they showed that GPR17 antagonists promoted primary rat OPC maturation measured by increased myeloid basic protein and myelination of electrospun fibres. The in vivo effect of GPR17 antagonism was shown using cuprizone-stimulated demyelination of the corpus callosum by measuring a significant increase in the percentage of myelination in mice treated with GPR17 antagonist.

[0010] In WO2024017857A1 Galley et al. showed in an in vitro recombinant assay that GPR17 antagonists caused a reversal of forskolin-stimulated MDL29,951-driven reduction in cAMP. In WO2024104462 Han et al. demonstrated in an in vitro recombinant assay that GPR17 antagonists caused a reduction in MDL29, 951 -stimulated calcium accumulation. Additionally, they showed that GPR17 antagonists promoted primary rat OPC maturation measured by increased myelin basic protein and CC1. In vivo the optic nerve crush model was used to demonstrate a significant increase in newly proliferating mature oligodendrocytes in GPR17-antagonist treated mice measured by co-expression of CC1+Edll+.

[0011] In addition to the above antagonist studies Chen et al. (9) published effects mediated by genetic knockout of GPR17. GPR17 knockout mice in the embryonic stage but not the adult stage displayed an early onset of oligodendrocyte myelination.

[0012] Primary demyelinating disorders such as multiple sclerosis (MS) and optic neuritis are currently treated with several anti-inflammatory strategies however none of the approved treatments address the potential for remyelination and associated disease reversal. Attenuating or blocking the function of GPR17 therefore has potential to compliment current treatment. Acute TBI has also been linked with both demyelination and increased GPR17 expression and may provide a further setting in which GPR17 antagonism may be of benefit. Additionally, several neurodegenerative disorders have been linked with demyelination and as such attenuating or blocking the function of GPR17 may provide benefit across a wide range of settings including Alzheimer’s disease and Parkinson’s disease.

[0013] Thus, there is strong evidence that attenuating or blocking the function of GPR17 will be efficacious in the treatment of demyelinating disorders, such as MS.

[0014] The compounds of the present invention effect attenuation or blockade of GPR17 receptor function. The compounds of the present invention are therefore likely to be particularly useful in the treatment of diseases in which modulation of GPR17 function is beneficial.

[0015] The compounds of the present invention are likely to be particularly useful in the treatment or prophylaxSynthesis of Examples, general procedures MS, situations resulting in direct damage to myelin sheaths such as carbon monoxide poisoning or virus induced demyelination, primary demyelinating disorders such as neuromyelitis optica, transverse myelitis, acute and multiphasic disseminated encephalomyelitis, and other CNS disorders associated with myelin loss such as amyotrophic lateral sclerosis (ALS), multiple system atrophy (MSA), Alzheimer’s disease, schizophrenia, Parkinson’s disease and Huntington’s disease.

[0016] DESCRIPTION OF THE INVENTION

[0017] The present invention relates to compounds which act as modulators of the GPR17 receptor. In particular, the present invention relates to compounds which act to attenuate or block the function of the GPR17 receptor (e.g. compounds which act as GPR17 antagonists).

[0018] In a first aspect of the invention, the present invention relates to compounds of Formula (I) shown below, or pharmaceutically acceptable salts, solvates or hydrates thereof:

[0019]

[0020] wherein:

[0021] R1is selected from hydrogen, halo, Ci-4alkyl and Ci-salkoxy; R2is selected from hydrogen, halo, cyano, Ci-4alkyl, C^alkenyl, C^alkynyl, Ciwalkoxy, Ci-shaloalkyl, Ciwhaloalkoxy, Ci-saminoalkyl, Ciwhydroxyalkyl, Ci-salkylamino, di(Ci.

[0022] 3alkyl)amino, nitro, hydroxyl, Ci-salkylcarbonyl, Ci-salkoxycarbonyl, Ciwalkylsulfinyl and Ci-salkylsulfonyl;

[0023] R3is selected from hydrogen, Ci-4alkyl, Ci-salkoxy, halo, hydroxyl, cyano, nitro, C2-salkenyl, C^alkynyl, Ci-shaloalkyl, Ciwhaloalkoxy, Ci-saminoalkyl, Ci-shydroxyalkyl, Ci- scyanoalkyl, C(O)Ra, C(O)NRaRb, C(O)ORa, C(O)C(O)NRaRb, OC(O)ORa, OC(O)NRaRb, NRaRb, NRaC(O)NRaRb, SRa, S(O)Ra, S(O)2Ra, C3-iocycloalkyl, Ci- 6alkylene-C3-iocycloalkyl, 3-10-membered heterocyclyl, Ce-waryl, and 4-10 membered heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl of R3is optionally substituted with 1, 2 or 3 Rxgroups, and wherein Raand Rbare independently selected from hydrogen and Ci-4alkyl;

[0024] R4is selected from a group of the formula:

[0025] -L1-L2-Z1

[0026] wherein:

[0027] Li is absent or a Ci-salkylene optionally substituted with fluoro;

[0028] l_2is absent or selected from O, N(RC), C(O), C(O)O, OC(O), C(O)N(RC), N(RC)C(O), N(Rc)C(O)N(Rd), N(RC)C(O)O, OC(O)N(RC), S(O)2N(RC) and N(RC)SO2, wherein Rcand Rdare independently selected from hydrogen and Ci-4alkyl; and

[0029] Z1 is selected from hydrogen, cyano, Ci-4alkyl, Cs-ecycloalkyl, Ci- 4alkoxy, halo, hydroxyl, nitro, C^alkenyl, C^alkynyl, Ci-shaloalkyl, Ci- shaloalkoxy, Ci-scyanoalkyl, Ci-salkoxyalkyl, Ci-saminoalkyl, Ci- shydroxyalkyl, 4-10-membered heterocyclyl, Ce- aryl, and 4-10 membered heteroaryl, wherein each alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl of Z1 is optionally substituted with 1, 2 or 3 Rygroups; R5is selected from hydrogen, Ci-4alkyl, Ci-salkoxy, Ci-shaloalkyl, halo, hydroxyl and cyano;

[0030] Xi is selected from CR7and N;

[0031] X2is absent or selected from CR8and N;

[0032] X3 is selected from CR9and N;

[0033] X4 is selected from CR10and N;

[0034] X5 is selected from CR11and N; wherein no more than two of Xi, X2, X3, X4 and X5 are N;

[0035] and wherein two of Xi, X2, X3, X4 and X5 may optionally, together with the atoms to which they are attached, be linked to form a 5-6 membered heteroaryl, phenyl, 5-7- membered heterocyclyl or Cs-ycycloalkyl;

[0036] X6 is CR12or N;

[0037] R7is selected from hydrogen, Ci-4alkyl, Ci.3alkoxy, halo, hydroxyl, cyano, nitro, C2-3alkenyl, C^alkynyl, Ci.3haloalkyl, Ci.3haloalkoxy, Ci.3aminoalkyl, Ci.3hydroxyalkyl, Ci-3cyanoalkyl, C(O)Re, C(O)NReRf, C(O)ORe, C(O)C(O)NReRf, OC(O)ORe,

[0038]

[0039] OC(O)NReRf, NReRf, SRe, S(O)Re, S(O)2Re, C3-iocycloalkyl, 3-10-membered heterocyclyl, Ce-waryl, 4-10 membered heteroaryl, and Ci-ealkyl-Q1, wherein Q1is selected from C3-10 cycloalkyl, 3-10-membered heterocyclyl, Ce- aryl, 4-10 membered heteroaryl, and wherein Reand Rfare independently selected from hydrogen and Ci- 4alkyl, and further wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl of R7, and each alkyl of Reand / or Rfis optionally substituted with 1, 2 or 3 Rxgroups;

[0040] R8, R9, R10and R11are independently selected from hydrogen, halo, cyano, Ci-4alkyl, C^alkenyl, C^alkynyl, Ci-3alkoxy, Ci.3haloalkyl, Ci-3haloalkoxy, Ci-3aminoalkyl, Ci-3hydroxyalkyl, nitro and hydroxyl;

[0041] R12is selected from hydrogen, Ci-4alkyl, Ci-3alkoxy, halo, hydroxyl, cyano, nitro, C2-3alkenyl, C^alkynyl, Ci.3haloalkyl, Ci-3haloalkoxy, Ci-3aminoalkyl, Ci-3hydroxyalkyl, Ci-3cyanoalkyl, Ci-3alkylamino, di(Ci-3alkyl)amino, C(O)R9, C(O)NR9Rh, C(O)OR9, C3- wcycloalkyl, 3-10-membered heterocyclyl, Ce-waryl, 4-10 membered heteroaryl, and CiwalkylQ2, wherein Q2is selected from C3-wcycloalkyl, 3-10-membered heterocyclyl, Ce-waryl, 4-10 membered heteroaryl, wherein R9and Rhare independently selected from hydrogen and Ci-4alkyl, and wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl of R12is optionally substituted with 1, 2 or 3 Rxgroups; Rxis selected from Ci-4alkyl, Ci.3alkoxy, Ci.3haloalkyl, Ci.3haloalkoxy, halo, hydroxyl, cyano, nitro, amino, cyclopropyl and cyclobutyl; and

[0042] Ryis selected from Ci-4alkyl, Ci.3alkoxy, Ci.3haloalkyl, Ci.3haloalkoxy, halo, hydroxyl, cyano, nitro, amino, amido, sulphamoyl, C3-6cycloalkyl, 3-6-membered heterocyclyl, phenyl, and 4-6 membered heteroaryl.

[0043] According to a further aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of Formula (I) as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in admixture with a pharmaceutically acceptable diluent or carrier.

[0044] According to a further aspect of the present invention, there is provided a method of treating a disease or disorder in which GPR17 activity is implicated in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.

[0045] Suitably, the disease or disorder in which GPR17 activity is implicated is selected from multiple sclerosis (MS), situations resulting in damage to myelin sheaths such as carbon monoxide poisoning or virus induced demyelination, primary demyelinating disorders such as neuromyelitis optica, transverse myelitis, acute and multiphasic disseminated encephalomyelitis, and other CNS disorders associated with myelin loss such as amyotrophic lateral sclerosis (ALS), multiple system atrophy (MSA), Alzheimer’s disease, schizophrenia, Parkinson’s disease and Huntington’s disease. Most suitably, the disease or disorder in which GPR17 activity is implicated is multiple sclerosis.

[0046] According to a further aspect of the present invention, there is provided a method of treating a disease or disorder related to damage to myelin sheaths in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.

[0047] According to a further aspect of the present invention, there is provided a method of treating multiple sclerosis in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.

[0048] According to a further aspect of the present invention, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein for use in therapy.

[0049] According to a further aspect of the present invention, there is provided a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein, for use in the treatment of GPR17-associated disease.

[0050] According to a further aspect of the present invention, there is provided a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein, for use in the treatment of a disease or disorder related to damage to myelin sheaths.

[0051] According to a further aspect of the present invention, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein for use in the treatment of multiple sclerosis.

[0052] According to a further aspect of the present invention, there is provided the use of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein in the manufacture of a medicament for the treatment of a GPR17-associated disease. Suitably, the GPR17-associated disease is selected from multiple sclerosis (MS), situations resulting in damage to myelin sheaths such as carbon monoxide poisoning or virus induced demyelination, primary demyelinating disorders such as neuromyelitis optica, transverse myelitis, acute and multiphasic disseminated encephalomyelitis, and other CNS disorders associated with myelin loss such as amyotrophic lateral sclerosis (ALS), multiple system atrophy (MSA), Alzheimer’s disease, schizophrenia, Parkinson’s disease and Huntington’s disease.

[0053] Most suitably, the GPR17-associated disease is multiple sclerosis.

[0054] DETAILED DESCRIPTION OF THE INVENTION

[0055] Definitions

[0056] Unless otherwise stated, the following terms used in the specification and claims have the following meanings set out below.

[0057] It is to be appreciated that references to "treating" or "treatment" include prophylaxis as well as the alleviation of established symptoms of a condition. " Treating" or "treatment" of a state, disorder or condition therefore includes: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a subject (preferably a human) that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition, (2) inhibiting the state, disorder or condition, i.e., arresting, reducing or delaying the development of the disease or a relapse thereof (in case of maintenance treatment) or at least one clinical or subclinical symptom thereof, or (3) relieving or attenuating the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.

[0058] A "therapeutically effective amount" means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.

[0059] As used herein, “patient” or “subject” refers to a mammal, including a domestic animal, animal kept as livestock and a zoo animal. Conveniently, the “patient” or “subject” is a human being. In the specification, the term " Cm-n" used as a prefix refers to the subsequent group having m to n carbon atoms.

[0060] In this specification the term "alkyl" includes both straight and branched chain alkyl groups. References to individual alkyl groups such as "propyl" are specific for the straight chain version only and references to individual branched chain alkyl groups such as "isopropyl" are specific for the branched chain version only. For example, " Ci-ealkyl" includes Ci-4alkyl, Ci -salkyl or Ci- 2alkyl. This term is exemplified by groups such as methyl, ethyl, n- propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, t-amyl, and the like. A similar convention applies to other radicals, for example "phenylCi-ealkyl" includes phenylCi.4alkyl, benzyl, 1 -phenylethyl and 2-phenylethyl.

[0061] In this specification the term “alkylene” includes both straight and branched chain divalent alkyl groups. For example, “Ci-salkylene” includes methylene (-CH2-), ethylene (-CH2CH2-), and propylene.

[0062] " Cycloalkyl" means a hydrocarbon ring. Suitably, "cycloalkyl" means a hydrocarbon ring containing from 3 to 8 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or bicyclo[2.2.1]heptyl. Most suitably, "cycloalkyl" means cyclopropyl, cyclobutyl or cyclopentyl, and preferably cyclopropyl.

[0063] The term "halo" refers to fluoro, chloro, bromo and iodo.

[0064] The term "heterocyclyl", "heterocyclic" or "heterocycle" means a non-aromatic saturated or partially saturated monocyclic, fused, bridged, or spiro ring system including at least one heteroatom such as nitrogen, oxygen, or sulfur. Monocyclic heterocyclic rings may contain from about 3 to 12 (suitably from 3 to 7) ring atoms, with from 1 to 5 (suitably 1, 2 or 3) heteroatoms selected from nitrogen, oxygen or sulfur in the ring. Bicyclic heterocycles may contain from 7 to 17 member atoms, suitably 7 to 12 member atoms, in the ring. Bicyclic heterocyclic(s) rings may be fused, spiro, or bridged ring systems. Examples of heterocyclic groups include cyclic ethers such as oxiranyl, oxetanyl, tetrahydrofuranyl, dioxanyl, and substituted cyclic ethers. Heterocycles containing nitrogen include, for example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrotriazinyl, tetrahydropyrazolyl, and the like. Sulfur containing heterocycles include, for example, tetrahydrothienyl, tetrahydro-2H-thiopyran, and hexahydrothiepine. Other heterocycles include dihydro-oxathiolyl, tetrahydro-oxazolyl, tetrahydro-oxadiazolyl, tetrahydrodioxazolyl, tetrahydro-oxathiazolyl, hexahydrotriazinyl, tetrahydro-oxazinyl, morpholinyl, thiomorpholinyl, tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, and octahydrobenzothiazolyl. For heterocycles containing sulfur, the oxidized sulfur heterocycles containing SO or SO2 groups are also included. Examples include the sulfoxide and sulfone forms of tetrahydrothienyl and thiomorpholinyl such as tetrahydrothiene-1,1-dioxide and thiomorpholinyl-1,1-dioxide. Examples of heterocyclyl groups which bear 1 or 2 oxo (=0) or thioxo (=S) substituents include 2-oxopyrrolidinyl, 2-thioxopyrrolidinyl, 2-oxoimidazolidinyl, 2-thioxoimidazolidinyl, 2-oxopiperidinyl, 2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl or 2,6-dioxopiperidinyl. Particular heterocyclyl groups are saturated monocyclic 3 to 7 membered heterocyclyls containing 1, 2 or 3 heteroatoms selected from nitrogen, oxygen or sulfur, for example azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, tetrahydrothienyl, tetrahydrothienyl-1,1-dioxide, thiomorpholinyl, thiomorpholinyl-1,1-dioxide, piperidinyl, homopiperidinyl, piperazinyl or homopiperazinyl. As the skilled person would appreciate, any heterocycle may be linked to another group via any suitable atom, such as via a carbon or nitrogen atom. However, reference herein to piperidino or morpholino refers to a piperidin-1-yl or morpholin-4-yl ring that is linked via the ring nitrogen.

[0065] The term "heteroaryl" or "heteroaromatic" means an aromatic mono-, bi-, or polycyclic group incorporating one or more (for example 1-4, particularly 1, 2 or 3) heteroatoms selected from nitrogen, oxygen or sulfur. The term heteroaryl includes both monovalent species and divalent species. Examples of heteroaryl groups are monocyclic and bicyclic groups containing from five to twelve ring members, and more usually from five to ten ring members. The heteroaryl group can be, for example, a 5- or 6-membered monocyclic group or a 9- or 10- membered bicyclic group, for example a bicyclic structure formed from fused five and six membered rings or two fused six membered rings. Each ring may contain up to about four heteroatoms typically selected from nitrogen, sulfur and oxygen. Typically, the heteroaryl group will contain up to 3 heteroatoms, more usually up to 2, for example a single heteroatom. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non-basic as in the case of an indole or pyrrole nitrogen. In general, the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five.

[0066] Examples of heteroaryl include furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3, 5- triazenyl, benzofuranyl, indolyl, isoindolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzothiazolyl, indazolyl, purinyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl, pteridinyl, naphthyridinyl, carbazolyl, phenazinyl, benzisoquinolinyl, pyridopyrazinyl, thieno[2,3-b]furanyl, 2H-furo[3,2-b]-pyranyl, 5H-pyrido[2,3-d]-oxazinyl, 4H-imidazo[4,5-d]thiazolyl, pyrazino[2,3-d]pyridazinyl, imidazo[2,1-b]thiazolyl, imidazo[1,2-b][1,2,4]triazinyl. " Heteroaryl" also covers partially aromatic bi- or polycyclic ring systems wherein at least one ring is an aromatic ring and one or more of the other ring(s) is a non-aromatic, saturated or partially saturated ring, provided at least one ring contains one or more heteroatoms selected from nitrogen, oxygen or sulfur. Examples of partially aromatic heteroaryl groups include for example, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 2-oxo-1,2,3,4-tetrahydroquinolinyl, dihydrobenzthienyl, dihydrobenzfuranyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,3]dioxolyl, 2,2-dioxo-1,3-dihydro-2-benzothienyl, 4, 5, 6, 7- tetrahydrobenzofuranyl, indolinyl, 1, 2,3,4-tetrahydro-1,8-naphthyridinyl and 1,2,3,4-tetrahydropyrido[2,3-b]pyrazinyl.

[0067] Examples of five membered heteroaryl groups include but are not limited to pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl and tetrazolyl groups.

[0068] Examples of six membered heteroaryl groups include but are not limited to pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl.

[0069] A bicyclic heteroaryl group may be, for example, a group selected from:

[0070] a benzene ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; a pyridine ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; a pyrimidine ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; a pyrrole ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms;

[0071] a pyrazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;

[0072] a pyrazine ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;

[0073] an imidazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; an oxazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;

[0074] an isoxazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; a thiazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;

[0075] an isothiazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; a thiophene ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; a furan ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; a cyclohexyl ring fused to a 5- or 6-membered heteroaromatic ring containing 1, 2 or 3 ring heteroatoms; and

[0076] a cyclopentyl ring fused to a 5- or 6-membered heteroaromatic ring containing 1, 2 or 3 ring heteroatoms.

[0077] Particular examples of bicyclic heteroaryl groups containing a six membered ring fused to a five membered ring include but are not limited to benzfuranyl, benzthiophenyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, indolinyl, isoindolinyl, purinyl (e.g., adeninyl, guaninyl), indazolyl, benzodioxolyl and pyrazolopyridinyl groups.

[0078] Particular examples of bicyclic heteroaryl groups containing two fused six membered rings include but are not limited to quinolinyl, isoquinolinyl, chromanyl, thiochromanyl, chromenyl, isochromenyl, chromanyl, isochromanyl, benzodioxanyl, quinolizinyl, benzoxazinyl, benzodiazinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl and pteridinyl groups.

[0079] The term "aryl" means a cyclic or polycyclic aromatic group having from 6 to 12 carbon atoms. The term aryl includes both monovalent species and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl and the like. In particular embodiment, an aryl is phenyl.

[0080] “Amino” means the chemical group -NH2.

[0081] “Amido” means the chemical group -C(O)NH2.

[0082] “Carboxy” means the chemical group -CO2H.

[0083] “Sulphamoyl” means the chemical group -SO2NH2.

[0084] “Cyano” means the chemical group -CN.

[0085] “Alkoxy”, means a group -OR wherein R is “alkyl” as defined and exemplified further herein. Particular alkoxy groups include, by way of example, meth(yl)oxy, eth(yl)oxy, n-prop(yl)oxy, isoprop(yl)oxy, n-but(yl)oxy, tert-but(yl)oxy, sec-but(yl)oxy, isobut(yl)oxy, and the like.

[0086] The term " Ci-shaloalkyl” refers to a “Ci-salkyl” (e.g. a methyl, ethyl or propyl group) as described herein, which is substituted with one or more halo atoms. Representative examples of " Ci-shaloalkyl” groups include Ci-sfluoroalkyl and Ci-3chloroalkyl groups. Further representative examples of Ci-sfluoroalkyl groups include, but are not limited to -CF3, -CHF2, -CHFCHF2 and -CH2CF3. Particularly preferred Ci-sfluoroalkyl groups are trifluoromethyl -CF3, and difluoromethyl -CHF2. The term " Ci-shaloalkoxy" refers to a “Ci-salkoxy” (e.g. methoxy, ethoxy or propoxy group) as described herein, which is substituted with one or more halo atoms. Representative examples of " Ci-shaloalkyl” groups include Ci-sfluoroalkoxy and Ci-3chloroalkoxy groups. Further representative examples Ci-sfluoroalkoxy groups include, but are not limited to - OCF3, -OCHF2, -OCHFCH2F and -OCH2CF3. Particularly preferred Ci-sfluoroalkoxy groups are -OCF3 and -OCHF2.

[0087] The term " Ci-shydroxyalkyl” as used refers to a “Ci-salkyl’ (e.g. a methyl, ethyl or propyl group) as described herein, which is substituted with one or more hydroxy groups. Representative examples of " Ci-shydroxyalkyl” groups include, but are not limited to -CH2CH2OH (monohydroxyethyl) -CH2CH2CH2OH (monohydroxypropyl), and -CH2CH(OH)CH2OH (dihydroxypropyl).

[0088] The term " Ci-3aminoalkyl” as used refers to a “Ci-salkyl’ (e.g. a methyl, ethyl or propyl group) as described herein, which is substituted with one or more amino groups. Representative examples of " Ci-saminoalkyl” groups include, but are not limited to -CH2NH2and -CH2CH2NH2. The term “Ci-salkylamino” as used refers to an amino group with is substituted with a Ci-salkyl group, and “di(Ci-salkyl)amino” refers to an amino group with is substituted with two Ci -salkyl groups. Representative examples of “Ci-salkylamino” groups include, but are not limited to -NHCH3and representative examples of “di(Ci-salkyl)amino” groups include, but are not limited to -N(CH3)2.

[0089] The term " Ci-3cyanoalkyl” as used refers to a “Ci-3alkyl’ (e.g. a methyl, ethyl or propyl group) as described herein, which is substituted with one or more cyano groups. Representative examples of " Ci-3cyanoalkyl” groups include, but are not limited to -CH2CN and -CH2CH2CN. The term "optionally substituted" refers to either groups, structures, or molecules that are substituted and those that are not substituted.

[0090] The phrase "compound of the invention" means those compounds which are disclosed herein, both generically and specifically.

[0091] Compounds of the Invention

[0092] In one aspect, the present invention provides compounds of Formula (I) shown below, or pharmaceutically acceptable salts, solvates or hydrates thereof:

[0093]

[0094] wherein:

[0095] R1is selected from hydrogen, halo, Ci-4alkyl and Ci-salkoxy;

[0096] R2is selected from hydrogen, halo, cyano, Ci-4alkyl, C^alkenyl, C^alkynyl, Ci-salkoxy, Ci-shaloalkyl, Ci-shaloalkoxy, Ci-saminoalkyl, Ci-shydroxyalkyl, Ci-salkylamino, di(Ci.

[0097] 3alkyl)amino, nitro, hydroxyl, Ci-3alkylcarbonyl, Ci-salkoxycarbonyl, Ci-salkylsulfinyl and Ci-salkylsulfonyl;

[0098] R3is selected from hydrogen, Ci-4alkyl, Ci^alkoxy, halo, hydroxyl, cyano, nitro, C2- salkenyl, C^alkynyl, Ci-shaloalkyl, Ci-shaloalkoxy, Ci-saminoalkyl, Ci-shydroxyalkyl, Ci-3cyanoalkyl, C(O)Ra, C(O)NRaRb, C(O)ORa, C(O)C(O)NRaRb, OC(O)ORa, OC(O)NRaRb, NRaRb, NRaC(O)NRaRb, SRa, S(O)Ra, S(O)2Ra, C3-10 cycloalkyl, Ci-6alkylene-C3- locycloalkyl, 3-10-membered heterocyclyl, Ce- aryl, and 4-10 membered heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl of R3is optionally substituted with 1, 2 or 3 Rxgroups, and wherein Raand Rbare independently selected from hydrogen and Ci-4alkyl;

[0099] R4is selected from a group of the formula:

[0100] -L1-L2-Z1

[0101] wherein:

[0102] Li is absent or a Ci-salkylene optionally substituted with fluoro;

[0103] l_2is absent or selected from O, N(RC), C(O), C(O)O, OC(O), C(O)N(RC), N(RC)C(O), N(Rc)C(O)N(Rd), N(RC)C(O)O, OC(O)N(RC), S(O)2N(RC) and N(RC)SO2, wherein Rcand Rdare independently selected from hydrogen and Ci -4alkyl; and Zi is selected from hydrogen, cyano, Ci-4alkyl, Cs-ecycloalkyl, Ci.4alkoxy, halo, hydroxyl, nitro, C^alkenyl, C^alkynyl, Ci-shaloalkyl, Ci-shaloalkoxy, Ci-scyanoalkyl, Ci-salkoxyalkyl, Ci-3aminoalkyl, Ci-shydroxyalkyl, 4-10-membered heterocyclyl, Ce- waryl, and 4-10 membered heteroaryl, wherein each alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl of Zi is optionally substituted with 1, 2 or 3 Rygroups;

[0104] R5is selected from hydrogen, Ci-4alkyl, Ci-salkoxy, Ci-shaloalkyl, halo, hydroxyl and cyano;

[0105] Xi is selected from CR7and N;

[0106] X2 is absent or selected from CR8and N;

[0107] X3 is selected from CR9and N;

[0108] X4 is selected from CR10and N;

[0109] X5 is selected from CR11and N;

[0110] wherein no more than 2 of Xi, X2, X3, X4 and X5 are N;

[0111] and wherein two of Xi, X2, X3, X4 and X5 may optionally, together with the atoms to which they are attached, be linked to form a 5-6 membered heteroaryl, phenyl, 5-7-membered heterocyclyl or Cs-ycycloalkyl;

[0112] Xe is CR12or N;

[0113] R7is selected from hydrogen, Ci-4alkyl, Ci-salkoxy, halo, hydroxyl, cyano, nitro, C2-salkenyl, C^alkynyl, Ci-shaloalkyl, Ci-shaloalkoxy, Ci-3aminoalkyl, Ci-shydroxyalkyl, Ci-3cyanoalkyl, C(O)Re, C(O)NReRe, C(O)ORe, C(O)C(O)NReRf, OC(O)ORe, OC(O)NReRf, NReRf, SRe, S(O)Re, S(O)2Re, Cs-wcycloalkyl, 3-10-membered heterocyclyl, Ce- aryl, 4-10 membered heteroaryl, and Ci-ealkyl-Q1, wherein Q1is selected from C3-10 cycloalkyl, 3-10-membered heterocyclyl, Ce- aryl, 4-10 membered heteroaryl, and wherein Reand Rfare independently selected from hydrogen and Ci-4alkyl, and further wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl of R7, and each alkyl of Reand / or Rfis optionally substituted with 1, 2 or 3 Rxgroups;

[0114] R8, R9, R10and R11are independently selected from hydrogen, halo, cyano, Ci-4alkyl, C2-salkenyl, C^alkynyl, Ci-salkoxy, Ci-shaloalkyl, Ci-shaloalkoxy, Ci-saminoalkyl, Ci. shydroxyalkyl, nitro and hydroxyl;

[0115] R12is selected from hydrogen, Ci-4alkyl, Ciwalkoxy, halo, hydroxyl, cyano, nitro, C2-salkenyl, C^alkynyl, Ci-shaloalkyl, Ci-shaloalkoxy, Ci-saminoalkyl, Ciwhydroxyalkyl, Ci- scyanoalkyl Ci-salkylamino, di(Ci-3alkyl)amino, C(O)R9, C(O)NR9Rh, C(O)OR9, C3-wcycloalkyl, 3-10-membered heterocyclyl, Ce- aryl, 4-10 membered heteroaryl, and Ci- ealkylQ2, wherein Q2is selected from Cs- cycloalkyl, 3-10-membered heterocyclyl, Ce- aryl, 4-10 membered heteroaryl, wherein R9and Rhare independently selected from hydrogen and Ci-4alkyl, and wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl of R12is optionally substituted with 1, 2 or 3 Rxgroups

[0116] Rxis selected from Ci-4alkyl, Ci-salkoxy, Ci-shaloalkyl, Ci-shaloalkoxy, halo, hydroxyl, cyano, nitro, amino, cyclopropyl and cyclobutyl; and

[0117] Ryis selected from Ci-4alkyl, Ci-salkoxy, Ci-shaloalkyl, Ci-shaloalkoxy, halo, hydroxyl, cyano, nitro, amino, amido, carboxy, sulphamoyl, Cs-ecycloalkyl, 3-6-membered heterocyclyl, phenyl, and 4-6 membered heteroaryl.

[0118] In an embodiment, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein when Li is Ci.3alkylene and L2 is C(O)O, then Z1 is not hydrogen. In an embodiment, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein when Li is Ci alkylene (e.g. CH2) and L2 is C(O)O, then Z1 is not hydrogen.

[0119] Particular compounds of the invention include, for example, compounds of the Formula (I), pharmaceutically acceptable salts, solvates or hydrates thereof, wherein, unless otherwise stated, each of R1, R2, R3, R4, R5, Xi, X2, X3, X4, X5, Xs, R7, R8, R9, R10, R11, R12, Rxand Ryand any associated substituent groups has any of the meanings defined hereinbefore or in any of paragraphs (1) to (67) hereinafter. For the avoidance of doubt, the scope of the present invention encompasses compounds of Formula (I), or pharmaceutically acceptable salts, solvates or hydrates thereof, wherein any of the substituent definitions defined herein may be combined with any of the other substituent definitions also defined herein:

[0120] (1) R1is selected from hydrogen, halo and Ci-4alkyl;

[0121] (2) R1is selected from hydrogen, halo and Ci-2alkyl;

[0122] (3) R1is selected from hydrogen, chloro, bromo and methyl;

[0123] (4) R1is hydrogen;

[0124] (5) R2is selected from hydrogen, halo, cyano, Ci-4alkyl, C^alkenyl, C^alkynyl, Ci-salkoxy, Ci-shaloalkyl, Ci-shaloalkoxy, Ci-saminoalkyl, Ci-shydroxyalkyl, Ci-3alkylamino, di(Ci.

[0125] 3alkyl)amino, nitro and hydroxyl;

[0126] (6) R2is selected from hydrogen, halo, cyano, Ci-4alkyl, C^alkenyl, C^alkynyl, Ci-salkoxy, Ci-shaloalkyl and Ci-shaloalkoxy;

[0127] (7) R2is selected from hydrogen, halo, cyano, Ci-4alkyl, Ci-salkoxy, Ci-shaloalkyl and Ci- shaloalkoxy;

[0128] (8) R2is selected from hydrogen, halo, Ci-4alkyl and Ci-salkoxy;

[0129] (9) R2is selected from hydrogen and halo; (10) R2is hydrogen;

[0130] (11) R3is selected from hydrogen, Ci-4alkyl, Ci.3alkoxy, halo, hydroxyl, cyano, nitro, C2-3alkenyl, C^alkynyl, Ci.3haloalkyl, Ci.3haloalkoxy, Ci.3aminoalkyl, Ci.3hydroxyalkyl, Ci-3

[0131]

[0132] cyanoalkyl, C(O)Ra, C(O)NRaRb, C(O)ORa, NRaRb, C3-i0cycloalkyl, Ci-6alkylene-C3. locycloalkyl, 3-10-membered heterocyclyl, Ce-waryl, and 4-10 membered heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl of R3is optionally substituted with 1, 2 or 3 Rxgroups, and wherein Raand Rbare independently selected from hydrogen and Ci-4alkyl;

[0133] (12) R3is selected from hydrogen, Ci-4alkyl, Ci.3alkoxy, halo, hydroxyl, cyano, nitro, C2-3alkenyl, C^alkynyl, Ci.3haloalkyl, Ci.3haloalkoxy, Ci.3aminoalkyl, Ci.3hydroxyalkyl, Ci-3

[0134]

[0135] cyanoalkyl, C(O)Ra, C(O)NRaRb, C(O)ORa, NRaRb, C3.iocycloalkyl, 3-6-membered heterocyclyl, Ce- aryl, and 4-10 membered heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl of R3is optionally substituted with 1, 2 or 3 Rxgroups, and wherein Raand Rbare independently selected from hydrogen and Ci-4alkyl;

[0136] (13) R3is selected from hydrogen, Ci-4alkyl, Ci-3alkoxy, halo, hydroxyl, cyano, C^alkenyl, C^alkynyl, Ci.3haloalkyl, Ci-3haloalkoxy, Ci-3aminoalkyl, Ci-3hydroxyalkyl, Ci-3cyanoalkyl, Ci-3alkylamino, Cs-ecycloalkyl, 3-6-membered heterocyclyl, Ce-waryl, and 4-6 membered heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl of R3is optionally substituted with 1, 2 or 3 Rxgroups; (14) R3is selected from hydrogen, Ci-4alkyl, Ci.3alkoxy, halo, hydroxyl, cyano, C^alkenyl, C^alkynyl, Ci.3haloalkyl, Ci.3haloalkoxy, Ci.3aminoalkyl, Ci.3hydroxyalkyl, Ci-3cyanoalkyl, Ci.3alkylamino, C3.ecycloalkyl, 3-6-membered heterocyclyl, Ce-waryl, and 4-6 membered heteroaryl;

[0137] (15) R3is selected from hydrogen, Ci-4alkyl, Ci.3alkoxy, halo, cyano, C^alkenyl, C^alkynyl, Ci.3haloalkyl, Ci.3haloalkoxy, Ci.3aminoalkyl, Ci.3hydroxyalkyl, Ci.3cyanoalkyl, Ci-3alkylamino, C3.ecycloalkyl and 3-6-membered heterocyclyl;

[0138] (16) R3is selected from Ci-4alkyl, Ci.3alkoxy, halo, Ci.3haloalkyl, cyano, and C3.6 cycloalkyl; (17) R3is selected from halo, Ci.3fluoroalkyl and C3.6 cycloalkyl;

[0139] (18) R3is selected from chloro and cyclopropyl;

[0140] (19) R3is halo, preferably chloro or bromo;

[0141] (20) R4is selected from a group of the formula:

[0142] -L1-L2-Z1

[0143] wherein:

[0144] Li is absent or a Ci.3alkylene optionally substituted with fluoro; l_2 is absent or selected from O, N(RC), C(O), C(O)O, OC(O), C(O)N(RC), N(RC)C(O), N(RC)C(O)O, and OC(O)N(RC), wherein Rcis selected from hydrogen and Ci-4alkyl; and

[0145] Zi is selected from hydrogen, cyano, Ci-4alkyl, Cs-ecycloalkyl, Ci- 4alkoxy, halo, hydroxyl, nitro, C^alkenyl, C^alkynyl, Ciwhaloalkyl, Ci- shaloalkoxy, Ci-scyanoalkyl, Ciwalkoxyalkyl, Ci-saminoalkyl, Ci- shydroxyalkyl, 4-10-membered heterocyclyl, Ce-waryl, and 4-10 membered heteroaryl, wherein each alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl of Zi is optionally substituted with 1, 2 or 3 Rygroups; (21) R4is selected from a group of the formula:

[0146] -L1-L2-Z1

[0147] wherein:

[0148] Li is absent or a Ci.3alkylene optionally substituted with fluoro;

[0149] l_2is absent or selected from N(RC), C(O), C(O)O, OC(O), C(O)N(RC), N(RC)C(O), N(RC)C(O)O, and OC(O)N(RC), wherein Rcis selected from hydrogen and Ci-4alkyl; and

[0150] Zi is selected from hydrogen, cyano, Ci-4alkyl, Cs-ecycloalkyl, Ci- 4alkoxy, halo, hydroxyl, C^alkenyl, C^alkynyl, Ciwhaloalkyl, Ci- shaloalkoxy, Ci-scyanoalkyl, Ciwalkoxyalkyl, Ci-saminoalkyl, Ci- shydroxyalkyl, 4-6-membered heterocyclyl, Ce- aryl, and 4- 6membered heteroaryl, wherein each alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl of Zi is optionally substituted with 1, 2 or 3 Rygroups;

[0151] (22) R4is selected from a group of the formula:

[0152] -L1-L2-Z1

[0153] wherein:

[0154] Li is absent or a Ci-salkylene;

[0155] l_2is absent or selected from N(RC), C(O), C(O)O, OC(O), C(O)N(RC), N(RC)C(O), N(RC)C(O)O, and OC(O)N(RC), wherein Rcis selected from hydrogen and Ci-4alkyl; and

[0156] Zi is selected from hydrogen, cyano, Ci-4alkyl, Cs-ecycloalkyl, Ci- 4alkoxy, halo, hydroxyl, C^alkenyl, C^alkynyl, Ciwhaloalkyl, Ci- shaloalkoxy, Ci-3cyanoalkyl, Ciwalkoxyalkyl, Ciwaminoalkyl, Ci- shydroxyalkyl, 4-6-membered heterocyclyl, Ce-waryl, and 4- 6membered heteroaryl, wherein each alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl of Zi is optionally substituted with 1 or 2 Rygroups; (23) R4is selected from a group of the formula:

[0157] -L2-Z1

[0158] wherein:

[0159] L2 is absent, or selected from O, N(RC), C(O), C(O)O, OC(O), C(O)N(RC), N(RC)C(O), N(Rc)C(O)N(Rd), N(RC)C(O)O, OC(O)N(RC), S(O)2N(RC) and N(RC)SO2, wherein Rcand Rdare independently selected from hydrogen and Ci-4alkyl; and

[0160] Z1 is selected from hydrogen, cyano, Ci-4alkyl, Cs-ecycloalkyl, Ci- 4alkoxy, halo, hydroxyl, nitro, C^alkenyl, C^alkynyl, Ci-shaloalkyl, Ci- shaloalkoxy, Ciwcyanoalkyl, Ci-salkoxyalkyl, Ciwaminoalkyl, Ci- shydroxyalkyl, 4-10-membered heterocyclyl, Ce- aryl, and 4-10 membered heteroaryl, wherein each alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl of Z1 is optionally substituted with 1, 2 or 3 Rygroups; (24) R4is selected from a group of the formula:

[0161] -L2-Z1

[0162] wherein:

[0163] L2 is absent or selected from N(RC), C(O), C(O)O, C(O)N(RC), N(RC)C(O) and N(RC)C(O)O, wherein Rcis selected from hydrogen and Ci-4alkyl; and

[0164] Z1 is selected from hydrogen, cyano, Ci-4alkyl, Cs-ecycloalkyl, Ci- 4alkoxy, halo, hydroxyl, C^alkenyl, C^alkynyl Ciwcyanoalkyl, Ci- salkoxyalkyl, Ciwaminoalkyl, Ciwhydroxyalkyl, phenyl, and 5-6- membered heteroaryl, wherein each alkyl, cycloalkyl, phenyl and heteroaryl of Z1 is optionally substituted with 1 or 2 Rygroups;

[0165] (25) R4is selected from a group of the formula:

[0166] -L2-Z1

[0167] wherein:

[0168] L2 is absent or selected from N(RC), C(O), C(O)O, C(O)N(RC), N(RC)C(O) and N(RC)C(O)O, wherein Rcis selected from hydrogen and Ci-2alkyl; and Zi is selected from hydrogen, cyano, Ci-4alkyl, Cs-ecycloalkyl, Ci- 4alkoxy, halo, hydroxyl, C^alkenyl, Ci-scyanoalkyl, Ci-salkoxyalkyl, Ci- saminoalkyl, Ci-shydroxyalkyl, and a 5-membered heteroaryl, wherein each alkyl, cycloalkyl, and heteroaryl of Zi is optionally substituted with 1 or 2 Rygroups;

[0169] (26) R4is selected from a group of the formula:

[0170] -L2-Z1

[0171] wherein:

[0172] L2 is absent or selected from N(RC), C(O), C(O)O, C(O)N(RC), N(RC)C(O) and N(RC)C(O)O, wherein Rcis selected from hydrogen and Ci-2alkyl; and

[0173] Zi is selected from hydrogen, cyano, Ci-4alkyl, Cs-ecycloalkyl, Ci- 4alkoxy, halo, hydroxyl, C^alkenyl, Ci-scyanoalkyl, Ci-salkoxyalkyl, Ci- saminoalkyl, Ci-shydroxyalkyl, and a 5-membered heteroaryl, wherein each alkyl, cycloalkyl, and heteroaryl of Zi is optionally substituted with 1 or 2 Rygroups;

[0174] (27) R4is selected from hydrogen, cyano, Ci-4alkyl, Cs-ecycloalkyl, Ci.4alkoxy, halo, hydroxyl, C^alkenyl, Ci-scyanoalkyl, Ci-salkoxyalkyl, Ci-saminoalkyl, Ci-shydroxyalkyl, 5-membered heteroaryl, C(O)ORC, C(O)N(Rc)(Rd) and N(Rc)C(O)Rd, wherein Rcand Rd are independently selected from hydrogen and Ci-2alkyl, and wherein each alkyl, cycloalkyl, and heteroaryl is optionally substituted with 1 or 2 Rygroups;

[0175] (28) R4is selected from cyano, Ci-4alkyl, Cs-ecycloalkyl, Ci.4alkoxy, halo, hydroxyl, C2- salkenyl, Ci-scyanoalkyl, Ci-salkoxyalkyl, Ci-saminoalkyl, Ci-shydroxyalkyl, 5- membered heteroaryl, C(O)ORC, C(O)N(Rc)(Rd), and N(Rc)C(O)Rdwherein Rcand Rd are independently selected from hydrogen and Ci-2alkyl, and wherein each alkyl, cycloalkyl, and heteroaryl is optionally substituted with 1 or 2 Rygroups;

[0176] (29) R4is selected from cyano, Ci-shydroxyalkyl, 5-membered heteroaryl, C(O)ORCand C(O)N(Rc)(Rd), wherein Rcand Rdare independently selected from hydrogen and Ci- 2alkyl;

[0177] (30) R4is selected from cyano, Ci-shydroxyalkyl, 5-membered heteroaryl and C(O)ORC, wherein Rcand Rdare independently selected from hydrogen and Ci -2alkyl;

[0178] (31) R4is selected from cyano, C(O)ORC, C(O)NHRC, CH2OH and a 5-membered heteroaryl (such as oxazolyl, isoxazolyl, pyrazolyl, oxadiazolyl, triazolyl and tetrazolyl), wherein Rcis selected from hydrogen and methyl;

[0179] (32) R4is hydrogen; (33) R5is selected from hydrogen, Ci-4alkyl, Ci-salkoxy, Ci-shaloalkyl and halo;

[0180] (34) R5is selected from hydrogen, Ci-4alkyl and halo;

[0181] (35) R5is hydrogen;

[0182] (36) Xi is selected from CR7and N;

[0183] X2 is selected from CR8and N;

[0184] X3 is selected from CR9and N;

[0185] X4 is selected from CR10and N;

[0186] X5 is selected from CR11and N;

[0187] and wherein two of Xi, X2, X3, X4 and X5 may optionally, together with the atoms to which they are attached, be linked to form a 5-6 membered heteroaryl;

[0188] (37) Xi is selected from CR7;

[0189] X2 is selected from CR8and N;

[0190] X3 is selected from CR9and N;

[0191] X4 is selected from CR10and N;

[0192] X5 is selected from CR11and N;

[0193] (38) X6is CR12or N, preferably CR12;

[0194] (39) R7is selected from hydrogen, Ci-4alkyl, Ciwalkoxy, halo, hydroxyl, cyano, nitro, C2- salkenyl, C^alkynyl, Ci-shaloalkyl, Ci-shaloalkoxy, Ci-saminoalkyl, Ci-shydroxyalkyl, Ci- scyanoalkyl, C(O)Re, C(O)NReRe, C(O)ORe, NReRf, C3-10 cycloalkyl, 3-10-membered heterocyclyl, Ce- aryl, 4-10 membered heteroaryl, and Ci-ealkyl-Q1, wherein Q1is selected from Cs-wcycloalkyl, 3-10-membered heterocyclyl, Ce- aryl, 4-10 membered heteroaryl, and wherein Reand Rfare independently selected from hydrogen and Ci- 4alkyl, and further wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl of R7, and each alkyl of Reand / or Rfis optionally substituted with 1, 2 or 3 Rxgroups;

[0195] (40) R7is selected from hydrogen, Ci-4alkyl, Ciwalkoxy, halo, hydroxyl, cyano, nitro, C2- salkenyl, C^alkynyl, Ci-shaloalkyl, Ci-shaloalkoxy, Ci-saminoalkyl, Ci-shydroxyalkyl, Ci- scyanoalkyl, C(O)Re, C(O)NReRe, C(O)ORe, NReRf, C3-10 cycloalkyl, 3-10-membered heterocyclyl, Ce- aryl, and 4-10 membered heteroaryl, wherein Reand Rfare independently selected from hydrogen and Ci-4alkyl, and further wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl of R7, and each alkyl of Reand / or Rfis optionally substituted with 1, 2 or 3 Rxgroups;

[0196] (41) R7is selected from hydrogen, Ci-4alkyl, Ci-salkoxy, halo, hydroxyl, cyano, nitro, C2- salkenyl, C^alkynyl, Ci-shaloalkyl, Ci-shaloalkoxy, Ci-saminoalkyl, Ci-shydroxyalkyl, Ci- scyanoalkyl, C(O)Re, C(O)NReRe, C(O)ORe, NReRf, C3-6 cycloalkyl, 3-6-membered heterocyclyl, phenyl, and 5-6 membered heteroaryl, wherein Reand Rfare independently selected from hydrogen and Ci-4alkyl, and further wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, phenyl and heteroaryl of R7, and each alkyl of Reand / or Rfis optionally substituted with 1, 2 or 3 Rxgroups;

[0197] (42) R7is selected from hydrogen, Ci-4alkyl, Ci-salkoxy, halo, hydroxyl, cyano, nitro, C2- salkenyl, C^alkynyl, Ci-shaloalkyl, Ci-shaloalkoxy, Ci-saminoalkyl, Ci-shydroxyalkyl, Ci- scyanoalkyl, Ci-salkylamino, C3-6 cycloalkyl and 3-6-membered heterocyclyl;

[0198] (43) R7is selected from hydrogen, Ci-4alkyl, Ci-salkoxy, halo, cyano, C^alkenyl, C2- salkynyl, Ci-shaloalkyl, Ci-shaloalkoxy, Ci-3aminoalkyl, Ci-shydroxyalkyl, Ci- scyanoalkyl, Ci-salkylamino and C3-6 cycloalkyl;

[0199] (44) R7is selected from hydrogen, Ci-4alkyl, Ci-salkoxy, halo, cyano, Ci-shaloalkyl, Ci- shaloalkoxy, Ci-3aminoalkyl, Ci-shydroxyalkyl, Ci-scyanoalkyl, Ci-salkylamino and cyclopropyl;

[0200] (45) R7is selected from Ci-salkoxy, halo, Ci-shaloalkoxy and Ci-scyanoalkyl;

[0201] (46) R7is selected from Ci-salkoxy (such as methoxy), bromo, Ci-sfluoroalkoxy and Ci- scyanoalkyl;

[0202] (47) R8, R9, R10and R11are independently selected from hydrogen, halo, cyano, Ci-4alkyl, C^alkenyl, C^alkynyl, Ci-salkoxy, Ci-shaloalkyl and Ci-shaloalkoxy;

[0203] (48) R8, R9, R10and R11are independently selected from hydrogen, halo, cyano, Ci-4alkyl, Ci-salkoxy, Ci-shaloalkyl and Ci-shaloalkoxy;

[0204] (49) R8, R9, R10and R11are independently selected from hydrogen, halo, Ci-4alkyl, and Cisalkoxy;

[0205] (50) R8, R9, R10and R11are independently selected from hydrogen, fluoro, and methoxy; (51) R12is selected from hydrogen, Ci-4alkyl, Ci-salkoxy, halo, hydroxyl, cyano, nitro, C2- salkenyl, C^alkynyl, Ci-shaloalkyl, Ci-shaloalkoxy, Ci-saminoalkyl, Ci-shydroxyalkyl, Ci- scyanoalkyl Ci-salkylamino, di(Ci-salkyl)amino, C(O)R9, C(O)NR9Rh, C(O)OR9, C3-6 cycloalkyl, 3-6-membered heterocyclyl, phenyl and 4-6 membered heteroaryl, wherein R9and Rhare independently selected from hydrogen and Ci-4alkyl, and wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, phenyl and heteroaryl of R12is optionally substituted with 1, 2 or 3 Rxgroups;

[0206] (52) R12is selected from hydrogen, Ci-4alkyl, Ci-salkoxy, halo, hydroxyl, cyano, nitro, C2- salkenyl, C^alkynyl, Ci-shaloalkyl, Ci-shaloalkoxy, Ci-saminoalkyl, Ci-shydroxyalkyl, Ci- scyanoalkyl Ci-salkylamino, C3-6 cycloalkyl, 3-6-membered heterocyclyl, phenyl and 4- 6 membered heteroaryl;

[0207] (53) R12is selected from hydrogen, Ci-4alkyl, Ci-salkoxy, halo, hydroxyl, cyano, nitro, C2- salkenyl, C^alkynyl, Ci-shaloalkyl, Ci-shaloalkoxy, Ci-saminoalkyl, Ci-shydroxyalkyl, Ci- scyanoalkyl Ci-salkylamino and C3-6 cycloalkyl; (54) R12is selected from hydrogen, halo, cyano, Ci-4alkyl, C^alkenyl, C^alkynyl, Ci- salkoxy, Ci-shaloalkyl, Ci-shaloalkoxy, Ci-saminoalkyl, Ci-shydroxyalkyl, nitro and hydroxyl;

[0208] (55) R12is selected from hydrogen, halo, Ci-4alkyl, Ci-salkoxy, Ci-shaloalkyl, Ci-shaloalkoxy, Ci-3aminoalkyl and Ci-shydroxyalkyl;

[0209] (56) R12is selected from hydrogen, halo, Ci-4alkyl, Ci-salkoxy and Ci-shaloalkyl;

[0210] (57) R12is selected from hydrogen, halo, and Ci-salkoxy;

[0211] (58) R12is selected from hydrogen and fluoro;

[0212] (59) R12is hydrogen;

[0213] (60) Rxis selected from Ci-4alkyl, Ci-salkoxy, Ci-shaloalkyl, Ci-shaloalkoxy, halo, hydroxyl, cyano, and amino;

[0214] (61) Rxis selected from Ci-4alkyl, Ci-salkoxy, Ci-shaloalkyl, halo and cyano;

[0215] (62) Rxis selected from Ci-4alkyl, Ci-salkoxy, and halo;

[0216] (63) Rxis selected from methyl, methoxy, fluoro, chloro and bromo;

[0217] (64) Ryis selected from Ci-4alkyl, Ci-salkoxy, Ci-shaloalkyl, Ci-shaloalkoxy, halo, hydroxyl, cyano, nitro, amino, Cs-ecycloalkyl, 3-6-membered heterocyclyl, phenyl and 4-6 membered heteroaryl;

[0218] (65) Ryis selected from Ci-4alkyl, Ci-salkoxy, Ci-shaloalkyl, Ci-shaloalkoxy, halo, hydroxyl, cyano, Cs-ecycloalkyl and 3-6-membered heterocyclyl;

[0219] (66) Ryis selected from Ci-4alkyl, Ci-salkoxy, halo, hydroxyl, cyano, cyclopropyl and 3-4- membered heterocyclyl;

[0220] (67) Ryis selected from methyl, methoxy, fluoro, chloro, bromo, hydroxyl, and cyclopropyl. Suitably, a heteroaryl or heterocyclyl group as defined herein is a monocyclic heteroaryl or heterocyclyl group comprising one, two or three heteroatoms selected from N, O or S.

[0221] Suitably, a heteroaryl is a 5- or 6-membered heteroaryl ring comprising one, two or three heteroatoms selected from N, O or S.

[0222] Suitably, a heterocyclyl group is a 4-, 5- or 6-membered heterocyclyl ring comprising one, two or three heteroatoms selected from N, O or S. Most suitably, a heterocyclyl group is a 5-, 6-or 7-membered ring comprising one, two or three heteroatoms selected from N, O or S [e.g. morpholinyl (e.g. 4-morpholinyl), pyridinyl, piperazinyl, homopiperazinyl or pyrrolidinonyl]. Suitably an aryl group is phenyl.

[0223] Suitably, R1is as defined in any one of paragraphs (1) to (4). Most suitably, R1is as defined in paragraph (4).

[0224] Suitably, R2is as defined in any one of paragraphs (5) to (10). Most suitably, R2is as defined in paragraph (9) or (10). Suitably, R3is as defined in any one of paragraphs (11) to (19). Most suitably, R3is as defined in paragraph (18) or (19).

[0225] Suitably, R4is as defined in any one of paragraphs (20) to (32). Most suitably, R4is as defined in paragraph (32). In certain embodiments, R4is not hydrogen. Thus, in some embodiments, Z1is not hydrogen when L1and L2are both absent.

[0226] Suitably, R5is as defined in any one of paragraphs (33) to (35). Most suitably, R5is as defined in paragraph (35).

[0227] Suitably, Xi, X2, X3, X4 and X5 are each independently as defined in any one of paragraphs (36) to (37). Most suitably, Xi, X2, X3, X4 and X5 are as defined in paragraph (37).

[0228] Suitably, Xe is as defined in paragraph (38). It will be appreciated that when X2 is absent the ring system comprising the remaining Xi, X3, X4 and X5 groups will form a 5-membered aryl or 5-membered heteroaryl.

[0229] Suitably, R7is as defined in any one of paragraphs (39) to (46). Most suitably, R7is as defined in paragraph (46).

[0230] Suitably, R8’ R9, R10and R11are each independently as defined in any one of paragraphs (47) to (50). Most suitably, R8’ R9, R10and R11are as defined in paragraph (50).

[0231] Suitably, R12is as defined in any one of paragraphs (51) to (59). Most suitably, R12is as defined in paragraph (59).

[0232] Suitably, Rxis as defined in any one of paragraphs (60) to (63). Most suitably, Rxis as defined in paragraph (63).

[0233] Suitably, Ryis as defined in any one of paragraphs (64) to (67). Most suitably, Rxis as defined in paragraph (67).

[0234] In a particular group of compounds of the invention, the compounds have one of the structural Formulae (la) to (le) (sub-definitions of formula (I)) shown below, or a pharmaceutically acceptable salt, solvate or hydrate thereof:

[0235]

[0236] (Ic)

[0237]

[0238] wherein R1, R2, R3, R4, Xi, X2, X3, X4, X5 and Xeeach have any one of the meanings defined herein.

[0239] In an embodiment of the compounds of Formula (la) to Formula (le):

[0240] R1is as defined in any one of paragraphs (1) to (4);

[0241] R2is as defined in any one of paragraphs (5) to (10);

[0242] R3is as defined in any one of paragraphs (111) to (19);

[0243] R4is as defined in any one of paragraphs (20) to (32);

[0244] Xi, X2, X3, X4 and X5 are each independently as defined in any one of paragraphs (36) to (37):

[0245] X6is as defined in paragraph (38):

[0246] R7is as defined in any one of paragraphs (39) to (46):

[0247] R8, R9, R10and R11are each independently as defined in any one of paragraphs (47) to (50):

[0248] R12is as defined in any one of paragraphs (51) to (59):

[0249] Rxis as defined in any one of paragraphs (60) to (63): and

[0250] Ryis as defined in any one of paragraphs (64) to (67).

[0251] In an embodiment of the compounds of Formulae (la) to (le) R4is hydrogen.

[0252] In a particular group of compounds of the invention, the compounds have one of the structural Formulae (If) to (Ij) (sub-definitions of formula (I)) shown below, or a pharmaceutically acceptable salt, solvate or hydrate thereof:

[0253]

[0254] wherein R1, R2, R3, R4, X6, R7, R8, R9, R10and R11each have any one of the meanings defined herein.

[0255] In an embodiment of the compounds of Formulae (If) to (Ij):

[0256] R1is as defined in any one of paragraphs (1) to (4);

[0257] R2is as defined in any one of paragraphs (5) to (10);

[0258] R3is as defined in any one of paragraphs (11) to (19);

[0259] R4is as defined in any one of paragraphs (20) to (32); X6is as defined in paragraph (38):

[0260] R7is as defined in any one of paragraphs (39) to (46):

[0261] R8, R9, R10and R11are each independently as defined in any one of paragraphs (47) to (50):

[0262] Rxis as defined in any one of paragraphs (60) to (63): and

[0263] Ryis as defined in any one of paragraphs (64) to (67).

[0264] In an embodiment of the compounds of Formulae (If) to (Ij) R4is hydrogen.

[0265] In a particular group of compounds of the invention, the compounds have one of the structural Formulae (Ik) to (Io) (sub-definitions of Formula (I)) shown below, or a pharmaceutically acceptable salt, solvate or hydrate thereof:

[0266]

[0267]

[0268] (lo-a) (lo-b)

[0269] wherein R3, R4, R7, R8, R9R10and R11each have any one of the meanings defined herein.

[0270] In an embodiment of the compounds of Formulae (Ik) to (Io):

[0271] R3is as defined in any one of paragraphs (11) to (19);

[0272] R4is as defined in any one of paragraphs (20) to (32);

[0273] R7is as defined in any one of paragraphs (39) to (46):

[0274] R8, R9, R10and R11are each independently as defined in any one of paragraphs (47) to (50):

[0275] Rxis as defined in any one of paragraphs (60) to (63): and

[0276] Ryis as defined in any one of paragraphs (64) to (67).

[0277] In an embodiment of the compounds of Formulae (Ik) to (Io) R4is hydrogen.

[0278] In a particular group of compounds of the invention, the compounds have the structural Formula (Ip) (a sub-definition of Formula (I)) shown below, or a pharmaceutically acceptable salt, solvate or hydrate thereof:

[0279] RQHN\ SC=OO

[0280]

[0281] R4

[0282] Formula (Ip)

[0283] wherein R3, and R4each have any one of the meanings defined herein and RQis selected from:

[0284]

[0285] R3is as defined in any one of paragraphs (11) to (19); and

[0286] R4is as defined in any one of paragraphs (20) to (32).

[0287] In a particular group of compounds of the invention, the compounds have the one of structural Formulae (Iq) to (Iv) (sub-definitions of Formula (I)) shown below, or a pharmaceutically acceptable salt, solvate or hydrate thereof:

[0288]

[0289] wherein R3, Xi, X2, X3, X4, X5 and X6each have any one of the meanings defined herein, and Q1is a 5-membered heteroaryl group, such as oxazolyl, oxadiazolyl, pyrazolyl, triazolyl and tetrazolyl (preferably oxazolyl or pyrazolyl), and wherein Q1 is optionally substituted with one or more substituent groups selected from Ci-4alkyl, Ci-salkoxy, halo, cyano and cyclopropyl.

[0290] In an embodiment of the compounds of Formulae (Iq) to (Iv):

[0291] R3is as defined in any one of paragraphs (11) to (19);

[0292] Xi, X2, X3, X4 and X5 are each independently as defined in any one of paragraphs (36) to (37):

[0293] X6is as defined in paragraph (38):

[0294] R7is as defined in any one of paragraphs (39) to (46):

[0295] R8, R9, R10and R11are each independently as defined in any one of paragraphs (47) to (50):

[0296] R12is as defined in any one of paragraphs (51) to (59):

[0297] Rxis as defined in any one of paragraphs (60) to (63): and

[0298] Ryis as defined in any one of paragraphs (64) to (67).

[0299] In a particular group of compounds of the invention, the compounds have the one of structural Formulae (Iw) to (laa) (sub-definitions of Formula (I)) shown below, or a pharmaceutically acceptable salt, solvate or hydrate thereof:

[0300]

[0301] wherein R3and X6each have any one of the meanings defined herein, Q1is a 5- membered heteroaryl group such as oxazolyl, oxadiazolyl, pyrazolyl, triazolyl and tetrazolyl (preferably oxazolyl or pyrazolyl), and RQis selected from:

[0302]

[0303] wherein R7, R8, R9, R10and R11each have any one of the meanings defined herein.

[0304] In an embodiment of the compounds of Formulae (Iw) to (laa):

[0305] R3is as defined in any one of paragraphs (11) to (19);

[0306] X6is as defined in paragraph (38):

[0307] R7is as defined in any one of paragraphs (39) to (46):

[0308] R8, R9, R10and R11are each independently as defined in any one of paragraphs (47) to (50):

[0309] Rxis as defined in any one of paragraphs (60) to (63): and

[0310] Ryis as defined in any one of paragraphs (64) to (67). In a particular group of compounds of the invention, the compounds have the one of structural Formulae (lab) to (lae) (sub-definitions of Formula (I)) shown below, or a pharmaceutically acceptable salt, solvate or hydrate thereof:

[0311]

[0312] wherein R3has any one of the meanings defined herein, Q1is a 5-membered heteroaryl group (such as oxazolyl, oxadiazolyl, pyrazolyl, triazolyl or tetrazolyl), and RQis selected from:

[0313]

[0314] In an embodiment of the compounds of Formulae (lab) to (lae):

[0315] R3is as defined in any one of paragraphs (11) to (19). Particular compounds of the present invention include any of the compounds exemplified in the present application, or a pharmaceutically acceptable salt, solvate, hydrate, isotope or tautomer thereof, and, in particular, any of the following:

[0316] OMe

[0317] NA, bA,

[0318] J? p ff 7 > N

[0319] zO..0HA

[0320] p s<< P A0r T'S

[0321] cr-0>0H <^NH2Example A1 Example A2 Example A3

[0322] O e phfeFv-— r

[0323] M /

[0324] itA N Axp

[0325] / A- A T

[0326] HN.00

[0327] ,cp

[0328] 1^0 cr \ AfA

[0329] CN '■-OH

[0330] Example A4 Example A5 z>-Q

[0331] (.> \ Example A6 VF F

[0332] /

[0333] \ 0 Sp

[0334] . * 4^

[0335] N rV z o

[0336] t> A^ \ 7--- jNxHN* P HN o HKA°

[0337] j!

[0338] Fo

[0339] 05 AkA

[0340] cr' 7 Jk jQ

[0341] Vcr pi^^A 0H

[0342] o

[0343] Exam Example A9

[0344]

[0345] Example A7 ple A8

[0346]

[0347]

[0348] Example A28 Example 29

[0349] If'A- HH o

[0350] f"

[0351] Br

[0352] Example A32

[0353] Example A31

[0354] 'O

[0355] HIM. 9. „ 'ft'ssO

[0356] F

[0357] Example B1 Example B2 Example A34

[0358] Br

[0359] Example B4

[0360]

[0361] Example B3

[0362]

[0363] The various functional groups and substituents making up the compounds of Formula (I), and sub-formulae (la) to (lae), are typically chosen such that the molecular weight of the compound of the Formula (I) does not exceed 1000. More usually, the molecular weight of the compound will be less than 900, for example less than 800, or less than 750, or less than 700, or less than 650. More preferably, the molecular weight is less than 600 and, for example, is 550 or less.

[0364] A suitable pharmaceutically acceptable salt of a compound of the invention is, for example, an acid-addition salt of a compound of the invention, which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic, formic, citric methane sulfonate or maleic acid. In addition, a suitable pharmaceutically acceptable salt of a compound of the invention which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a pharmaceutically acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.

[0365] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed "isomers". Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers". Stereoisomers that are not mirror images of one another are termed "diastereomers" and those that are non-superimposable mirror images of each other are termed "enantiomers". When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a "racemic mixture". The compounds of this invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of " Advanced Organic Chemistry", 4th edition J. March, John Wiley and Sons, New York, 2001), for example by synthesis from optically active starting materials or by resolution of a racemic form. Some of the compounds of the invention may have geometric isomeric centres (E- and Z- isomers). It is to be understood that the present invention encompasses all optical, diastereoisomers and geometric isomers and mixtures thereof that possess antiproliferative activity.

[0366] The present invention also encompasses compounds of the invention as defined herein which comprise one or more isotopic substitutions. For example, H may be in any isotopic form, including1H,2H (D) and3H (T); C may be in any isotopic form including12C,13C, and14C; and O may be in any isotopic form, including16O and18O; and the like. In an embodiment, the present invention also encompasses deuterated analogues of the compounds of the invention defined by Formula (I).

[0367] It is also to be understood that certain compounds of Formula (I), or sub-formulae (la) to (lae), may exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms that possess antiproliferative activity.

[0368] It is also to be understood that certain compounds of the Formula (I), or sub-formulae (la) to (lae), may exhibit polymorphism, and that the invention encompasses all such forms that possess antiproliferative activity.

[0369] Compounds of Formula (I), and sub-formulae (la) to (lae), may exist in a number of different tautomeric forms and references to compounds of Formula (I), and sub-formulae (la) to (lae), include all such forms. For the avoidance of doubt, where a compound can exist in one of several tautomeric forms, and only one is specifically described or shown, all others are nevertheless embraced by Formula (I), and sub-formulae (la) to (lae). Examples of tautomeric forms include keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto / enol (illustrated below), imine / enamine, amide / imino alcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, and nitro / aci-nitro. |,0x zOH H’ x O'

[0370] — c—cz=== c-c

[0371] / zc=c

[0372] I X \z

[0373]

[0374] H+ / \

[0375] keto eno enolate

[0376] Compounds of Formula (I), and sub-formulae (la) to (lae), containing an amine function may also form N-oxides. A reference herein to a compound of Formula (I), or sub-formulae (la) to (lae), that contains an amine function also includes the N-oxide. Where a compound contains several amine functions, one or more than one nitrogen atom may be oxidised to form an N-oxide. Particular examples of N-oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle. N-Oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a per-acid (e.g. a peroxycarboxylic acid), see for example Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages. More particularly, N-oxides can be made by the procedure of L. W Deady (Syn. Comm. 1977, 7, 509-514) in which the amine compound is reacted with m-chloroperoxybenzoic acid (mCPBA), for example, in an inert solvent such as dichloromethane.

[0377] Though the present invention may relate to any compound or particular group of compounds defined herein by way of optional, preferred or suitable features or otherwise in terms of particular embodiments, the present invention may also relate to any compound or particular group of compounds that specifically excludes said optional, preferred or suitable features or particular embodiments.

[0378] Suitably, the present invention excludes any individual compounds not possessing the biological activity defined herein.

[0379] Synthesis

[0380] The compounds of the present invention can be prepared by any suitable technique known in the art. Particular processes for the preparation of these compounds are described further in the accompanying examples.

[0381] In the description of the synthetic methods described herein and in any referenced synthetic methods that are used to prepare the starting materials, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be selected by a person skilled in the art.

[0382] It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reaction conditions utilised. It will be appreciated that during the synthesSynthesis of Examples, general procedures the compounds of the invention in the processes defined herein, or during the synthesSynthesis of Examples, general procedures certain starting materials, it may be desirable to protect certain substituent groups to prevent their undesired reaction. The skilled chemist will appreciate when such protection is required, and how such protecting groups may be put in place, and later removed.

[0383] For examples of protecting groups see one of the many general texts on the subject, for example, 'Protective Groups in Organic Synthesis' by Theodora Green (publisher: John Wiley & Sons). Protecting groups may be removed by any convenient method described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with the minimum disturbance of groups elsewhere in the molecule.

[0384] Thus, if reactants include, for example, groups such as amino, carboxy or hydroxy it may be desirable to protect the group in some of the reactions mentioned herein.

[0385] By way of example, a suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed by, for example, hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl group such as a tert-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulfuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine. A suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium, sodium hydroxide or ammonia. Alternatively an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.

[0386] A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a t-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.

[0387] Resins may also be used as a protecting group.

[0388] The methodology employed to synthesise a compound of Formula (I) will vary depending on the nature of R1, R2, R3, R4, R5, X1, X2, X3, X4, X5, X6, R7, R8, R9, R10, R11, R12, Rxand Ryand any substituent groups associated therewith. Suitable processes for their preparation are described further in the accompanying Examples.

[0389] Once a compound of Formula (I) has been synthesised by any one of the processes defined herein, the processes may then further comprise the additional steps of:

[0390] (i) removing any protecting groups present;

[0391] (ii) converting the compound Formula (I) into another compound of Formula (I); and / or (iii) forming a pharmaceutically acceptable salt, hydrate or solvate thereof.

[0392] An example of (ii) above is when a compound of Formula (I) is synthesised and then one or more of the groups of R1, R2, R3, R4, R5, X1, X2, X3, X4, X5, X6, R7, R8, R9, R10, R11, R12, Rxand Ry, may be further reacted to change the nature of the group and provide an alternative compound of Formula (I). For example, the compound can be reacted to convert any R group into a substituent group other than hydrogen.

[0393] The resultant compounds of Formula (I) can be isolated and purified using techniques well known in the art.

[0394] Biological Activity

[0395] The biological assays described in the Examples section herein may be used to measure the pharmacological effects of the compounds of the present invention.

[0396] Although the pharmacological properties of the compounds of Formula (I) vary with structural change, as expected, the compounds of the invention were found to be active in the GPR17 attenuation functional IP-one Gq assay described in the Examples section. In general, the compounds of the invention demonstrate an fpKb value of 5.5 or greater in the GPR17 attenuation functional IP-one Gq assay described in the Examples section, with preferred compounds of the invention demonstrating an fpKb value of 6.5 or greater and the most preferred compounds of the invention demonstrating an fpKb value of 7.0 or greater.

[0397] Pharmaceutical Compositions

[0398] According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of the invention as defined hereinbefore (e.g. a compound of Formula (I), or sub-formulae (la) to (lae)), or a pharmaceutically acceptable salt, hydrate or solvate thereof, in association with a pharmaceutically acceptable diluent or carrier.

[0399] The compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular dosing or as a suppository for rectal dosing).

[0400] The compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and / or preservative agents.

[0401] An effective amount of a compound of the present invention for use in therapy is an amount sufficient to treat or prevent a condition referred to herein, slow its progression and / or reduce the symptoms associated with the condition.

[0402] The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the individual treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 0.5 g of active agent (more suitably from 0.5 to 100 mg, for example from 1 to 30 mg) compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.

[0403] The size of the dose for therapeutic or prophylactic purposes of a compound of the Formula I will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well-known principles of medicine.

[0404] In using a compound of the invention for therapeutic or prophylactic purposes it will generally be administered so that a daily dose in the range, for example, 0.1 mg / kg to 75 mg / kg body weight is received, given if required in divided doses. In general lower doses will be administered when a parenteral route is employed. Thus, for example, for intravenous or intraperitoneal administration, a dose in the range, for example, 0.1 mg / kg to 30 mg / kg body weight will generally be used. Similarly, for administration by inhalation, a dose in the range, for example, 0.05 mg / kg to 25 mg / kg body weight will be used. Oral administration may also be suitable, particularly in tablet form. Typically, unit dosage forms will contain about 0.5 mg to 0.5 g of a compound of this invention.

[0405] Routes of Administration

[0406] The compounds of the invention or pharmaceutical compositions comprising these compounds may be administered to a subject by any convenient route of administration, whether systemically / peripherally or topically (i.e., at the site of desired action).

[0407] Routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intra-arterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; by implant of a depot or reservoir, for example, subcutaneously or intramuscularly.

[0408] Therapeutic Uses and Applications

[0409] In one aspect, the invention relates to anyone of the compounds described herein, for use in therapy or diagnosis, particularly in the therapy of animals, in particular humans. Because of their GPR17 modulating properties, the compounds of the present invention can be used as medicine and may be used for the treatment and / or prevention of various diseases of the central nervous system (CNS).

[0410] In one aspect of the present invention, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein for use in therapy. According to a further aspect of the present invention, there is provided a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein, for use in the treatment of a disease or disorder related to damage to myelin sheaths.

[0411] In another aspect of the present invention, there is provided a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein, for use in the treatment and / or prevention of a GPR17-associated disease or disorder.

[0412] A GPR17 associated disease or disorder is disease which is associated with a dysfunction of the GPR17 signalling system such as, for example, an overexpression and / or overactivity of GPR17 receptors.

[0413] Examples of a GPR17-associated disease include, for example, multiple sclerosis (MS), situations resulting in direct damage to myelin sheaths such as carbon monoxide poisoning or virus induced demyelination, primary demyelinating disorders such as neuromyelitis optica, transverse myelitis, acute and multiphasic disseminated encephalomyelitis, and other CNS disorders associated with myelin loss such as amyotrophic lateral sclerosis (ALS), multiple system atrophy (MSA), Alzheimer’s disease, schizophrenia, Parkinson’s disease and Huntington’s disease.

[0414] In certain embodiments, there is provided a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein, for use in the treatment and / or prevention of multiple sclerosis (MS).

[0415] The treatment or prevention of a CNS disease such as a demyelination disease, also includes the treatment of the signs and symptoms associated with such a disease.

[0416] For example, the use of the compounds of the present invention for the treatment and / or prevention of MS also includes the treatment and / or prevention of one or more of the signs and symptoms associated with MS such as negative effects on optic nerves (vision loss, double vision), dorsal columns (loss of sensation), corticospinal tract (spastic weakness), cerebellar pathways (incoordination, dysarthria, vertigo, cognitive impairment), medial longitudinal fasciculus (double vision on lateral gaze), spinal trigeminal tract (face numbness or pain), muscle weakness (impaired swallowing, control of the bladder or gut, spasms), or psychological effects associated with the underlying disease such as depression, anxiety or other mood disorders, general weakness or sleeplessness.

[0417] According to a further aspect of the present invention, there is provided a method of treating a disease or disorder in which GPR17 activity is implicated in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.

[0418] Suitably, the disease or disorder in which GPR17 activity is implicated is selected from multiple sclerosis (MS), situations resulting in direct damage to myelin sheaths such as carbon monoxide poisoning or virus induced demyelination, primary demyelinating disorders such as neuromyelitis optica, transverse myelitis, acute and multiphasic disseminated encephalomyelitis, and other CNS disorders associated with myelin loss such as amyotrophic lateral sclerosis (ALS), multiple system atrophy (MSA), Alzheimer’s disease, schizophrenia, Parkinson’s disease and Huntington’s disease.

[0419] According to a further aspect of the present invention, there is provided a method of treating a disease or disorder related to damage to myelin sheaths in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.

[0420] According to a further aspect of the present invention, there is provided a method of treating multiple sclerosis in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.

[0421] Additionally, GPR17 modulation has been associated with stroke, haemorrhagic stroke, ischemic stroke, and traumatic brain injury (1) and also metabolic disorders including diabetes, obesity, hyperlipidaemia, and cardiovascular disorders (18, 19).

[0422] Another embodiment of the present invention provides a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein, for use in treating or preventing a condition, disease, or disorder selected from diabetes [e.g. Type 1 diabetes mellitus (T1D), Type 2 diabetes mellitus (T2DM), including pre-diabetes], idiopathic T1D (Type 1b), latent autoimmune diabetes in adults (LADA), early-onset T2DM (EOD), youth-onset atypical diabetes (YOAD), maturity onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, hyperglycaemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease [e.g., acute kidney disorder, tubular dysfunction, proinflammatory changes to the proximal tubules, or chronic kidney disease (CKD)], diabetic retinopathy, adipocyte dysfunction, visceral adipose deposition, sleep apnoea [e.g. obstructive sleep apnoea (OSA)], obesity (including hypothalamic obesity and monogenic obesity) and related comorbidities (e.g., osteoarthritis and urine incontinence), eating disorders (including binge eating syndrome, bulimia nervosa, and syndromic obesity such as Prader-Willi and Bardet-Biedl syndromes), weight gain such as weight gain caused by use of other agents (e.g., caused by use of steroids and / or antipsychotics, or caused by treatment of depression, or caused by use of agents on cognitive function), excessive sugar craving, dyslipidaemia [including hyperlipidaemia, hypertriglyceridemia, increased total cholesterol, high LDL (low-density lipoprotein) cholesterol, and low HDL (high- density lipoprotein) cholesterol], hyperinsulinemia, nonalcoholic fatty liver disease [NAFLD, including related diseases such as steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma], cardiovascular disease, atherosclerosis (including coronary artery disease), peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular compliance, heart failure [e.g. congestive heart failure, heart failure with preserved ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF)], myocardial infarction (e.g. necrosis and apoptosis), stroke, haemorrhagic stroke, ischemic stroke, traumatic brain injury, Parkinson’s disease, metabolic syndrome, impaired glucose metabolism, conditions of impaired fasting plasma glucose, Alzheimer’s Disease, and schizophrenia.

[0423] According to a further aspect of the present invention, there is provided a combination for use in the treatment of in the treatment and / or prevention of a GPR17-associated disease or disorder (e.g. a myelination disease or disorder, such as multiple sclerosis) comprising a compound of Formula (I) as defined herein, or a pharmaceutically acceptable salt, solvate or hydrate thereof, and any other medicament for treating a GPR17-associated disease (e.g. a myelination disease or disorder, such as multiple sclerosis).

[0424] Non-limiting examples of other medicaments for treating a GPR17-associated disease (e.g. a myelination disease or disorder, such as multiple sclerosis), include: (1) an anti-inflammatory or immunosuppressive drug, such as: (i) corticosteroids such as prednisone, methylprednisone or dexamethasone, (ii) beta interferons such as interferon beta-1 a, interferon beta- 1b or peginterferon beta- 1a, (iii) anti-CD20 antibodies such as ocrelizumab rituximab and ofatumumab, (iv) glatiramer salts such as glatiramer acetate, (v) dimethyl fumarate, (vi) fingolimod and other sphingosine-1 -phosphate receptor modulators such as ponesimod, siponimod, ozanimod or laquinimod, (vii) dihydro-orotate dehydrogenase inhibitors such as teriflunomide or leflunomide, (viii) anti-integrin alpha4 antibodies such as natalizumab, (ix) anti CD52 antibodies such as alemtuzumab, (x) mitoxantrone, (xi) anti Lingo antibodies such as opicinumab, or (xii) other immunomodulatory therapies such as masitinib; (2) analgesic drugs, such as: (i) nonsteroidal anti-inflammatory drugs such as aspirin, ibuprofen, naproxen and diclofenac, (ii) COX-2 inhibitors, and (iii) opioids such as codeine, oxycodone, hydrocodone and dihydromorphine; and (3) antidepressants.

[0425] In a further aspect of the invention there is provided a compound of Formula (I), or a pharmaceutically acceptable salt, solvate or hydrate thereof, in combination with one or more additional therapeutic agents.

[0426] According to another aspect of the invention there is provided a pharmaceutical composition which comprises a compound of Formula (I), or a pharmaceutically acceptable salt, solvate or hydrate thereof, in combination with one or more additional therapeutic agents in association with a pharmaceutically acceptable diluent or carrier.

[0427] The one or more additional therapeutic agents may comprise a further compound of Formula (I), or alternatively may comprise medicaments listed above as suitable for treating a GPR17-associated disease.

[0428] Herein, the term “combination” will be understood to refer to each of simultaneous, separate or sequential administration of the compound of the invention as defined herein, or a pharmaceutically acceptable salt, solvate or hydrate thereof, and the other medicament for treating a GPR17-associated disease as defined above.

[0429] EXAMPLES

[0430] Abbreviations

[0431] COMU = (1-Cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbenium

[0432] Cu = copper

[0433] Cui = Copper(l) iodide

[0434] Cu2O = Copper(l) oxide

[0435] Cs2CO3= Cesium carbonate

[0436] DABCO = 1,4-diazabicyclo[2.2. 2]octane

[0437] DCM = dichloromethane

[0438] DIPEA = N, N-diisopropylethylamine

[0439] DMF = dimethylformamide

[0440] DMSO = dimethyl sulfoxide

[0441] ES+ / - = electro spray ionization, positive or negative

[0442] EtOAc = ethyl acetate

[0443] EtOH = ethanol

[0444] h = hour(s)

[0445] H2= hydrogen

[0446] HATU = 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate

[0447] HBr = hydrogen bromide

[0448] HCI = hydrogen chloride, hydrochloric acid

[0449] H2O = water

[0450] HNO3= nitric acid

[0451] (prep) HPLC = (preparative) high performance liquid chromatography

[0452] I PA = propan-2-ol K2CO3= potassium carbonate

[0453] KF = potassium fluoride

[0454] K3PO4= potassium phosphate tribasic

[0455] LC / MS = liquid chromatography mass spectrometry

[0456] LiBr = lithium bromide

[0457] LiOH.H2O = lithium hydroxide mono hydrate

[0458] MeCN = acetonitrile

[0459] MeOH = methanol

[0460] MgSO4= magnesium sulfate

[0461] min(s) = minute(s)

[0462] MS = mass spectrometry

[0463] N2= nitrogen

[0464] Na2CO3= sodium carbonate

[0465] NaHCO3= sodium hydrogen carbonate

[0466] NaOAc = sodium acetate

[0467] NaOH = sodium hydroxide

[0468] Na2SO4= sodium sulfate

[0469] NBS = / V-bromosuccinimide

[0470] NH3= ammonia

[0471] NH4CI = ammonium chloride

[0472] NMP = N-methyl-2-pyrrolidone

[0473] NMR = nuclear magnetic resonance

[0474] PCy3= tricyclohexylphosphine

[0475] Pd / C = palladium on carbon

[0476] Pd(dppf)CI2= [1,1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(l I)

[0477] Pd(OAc)2= Palladium(ll) acetate

[0478] Pd(Ph3P)4= tetrakis(triphenylphosphine)palladium (0)

[0479] POCI3= phosphorus oxychloride

[0480] Rf = retention factor

[0481] RT = room temperature

[0482] sat. = saturated

[0483] SFC = supercritical fluid chromatography

[0484] THF = tetrahydrofuran

[0485] TLC = thin layer chromatography

[0486] UPLC = ultra performance liquid chromatography

[0487] Preparations of the compounds of the invention

[0488] Compounds of Formula (I) can be prepared in accordance with synthetic methods known to the skilled person. The invention also provides a process for the preparation of a compound as defined in Formula (I) above. Where intermediates are commercially available, they are identified by their chemical abstracts service (CAS) reference number, where not commercially available the synthesSynthesis of Examples, general procedures the intermediates using standard transformations is detailed herein, or a CAS number provided to link to literature syntheses. Commercial reagents were utilized without further purification.

[0489] Final compounds and intermediates are named using ChemDraw Professional. Room temperature (RT) refers to approximately 20-27 °C.1H NMR spectra were recorded at 400 or 500 MHz on either a Bruker, Varian or Jeol instrument. Chemical shift values are expressed in parts per million (ppm), i.e. (5), relative to a deuterated solvent, such as chloroform-d (7.26 ppm), DMSO-d6(2.50 ppm), or methanol-d4(3.31 ppm). The following abbreviations are used for the multiplicity of the NMR signals: s=singlet, br=broad, d=doublet, t=triplet, q=quartet, m=multiplet. Coupling constants are listed as J values, measured in Hz. NMR and mass spectroscopy results were corrected to account for background peaks. Chromatography refers to column chromatography performed using silica gel and executed under nitrogen pressure (flash chromatography) conditions or automated flash chromatography using Biotage Isolera equipment. Microwave-mediated reactions were performed in Biotage Initiator or CEM Discover microwave reactors.

[0490] General

[0491]

[0492] LC / MS:

[0493] Method A

[0494] Instrument: Waters Acquity with PDA detector and QDA performance, Column: X-bridge BEH C18, 50*2.1mm, 2.5 pm. Solvent A- (A) 2 mM Ammonium Acetate + 0.1% Formic acid in Milli-Q water, Solvent B- 0.1% Formic acid in Acetonitrile. Gradient [Time (min) / % A: % B]:

[0495] [0.00 / 95:5], [0.4 / 95:5], [0.8 / 65:35], [1.2 / 45:55], [2.5 / 0:100], UV detection 200 to 500 nm; Column temperature ambient; 0.55 mL / min.

[0496] Method B

[0497] Instrument: Waters Acquity H-Class LC / MS, Column: Gemini-NX C18, 3 pm, 30 x 2mm. Solvent A- 50 mM ammonium acetate aqueous solution at pH 7.40, Solvent B- acetonitrile. Gradient [Time (min) / % A: % B]: [0.00 / 100:0], [1.30 / 0:100], [1.55 / 0:100], [1.60 / 100:0], [3.00 / 100:0], Injection volume 1 pL (may vary); UV detection 200 to 500 nm; Column temperature 40 C; 0.5 mL / min.

[0498] Method C

[0499] Instrument: Waters Acquity with PDA detector and QDA performance, Column: X-bridge BEH C18, 50*2.1mm, 2.5 pm. Solvent A- (A) 5 mM ammonium bicarbonate in Milli-Q water, Solvent B- Acetonitrile. Gradient [Time (min) / % A: % B]: [0.00 / 95:5], [0.4 / 95:5], [0.8 / 65:35], [1.2 / 45:55], [2.5 / 0:100], UV detection 200 to 500 nm; Column temperature ambient; 0.55 mL / min.

[0500] Prep-HPLC Conditions:

[0501] Method A

[0502] Instrument: Waters 2545 quaternary system with Waters 2489 UV Detector. Solvent: A- H2O, B- MeCN, Column: Shim-Pack GIST C18 (250 x 20 mm, 5um). Flow rate 15 mL / min. Gradient [time (min) / solvent B (%)]: [0 / 20], [16.0 / 50], [23.0 / 50], Method B

[0503] Instrument: Waters 2545 binary system with Waters 2489 UV Detector. Solvent: A- H2O + 0.05% formic acid, B- MeCN, Column: Sunfire Prep C18 (150 x 19 mm, 5um). Flow rate 18 mL / min. Gradient [time (min) / solvent B (%)]: [0 / 20], [16.0 / 50], [18.0 / 50], [18.01 / 0], [20 / 100],

[0504] SynthesSynthesis of Examples, general procedures Intermediates

[0505] SynthesSynthesis of Examples, general procedures Intermediate 1, methyl 7-chloroindolizine-1 -carboxylate

[0506]

[0507] MeO Intermediate 1 Step 1; 2-bromo-4-chloropyridine (CAS 22918-01-0, 10.00 g, 52.40 mmol) was dissolved in DMF (50 ml). To it, Cs2CO3(68.29 g, 209.60 mmol) and dimethyl malonate (9.44 ml, 78.60 mmol) were added and nitrogen gas was purged through reaction mixture for 30 min at room temperature. To it, Cu2O (0.46 g, 10.40 mmol) and picolinic acid (2.60 g, 20.90 mmol) were added. Reaction mixture was stirred at 130 °C for 16 h. The reaction mixture was partitioned between water (800 ml) and EtOAc (800 ml). Aqueous layer was further extracted with EtOAc (2 x 400 ml). Organic layers were combined, dried (Na2SO4) and concentrated. The crude product was purified by normal phase gradient flash column chromatography (silica), product was eluted at 0% to 18% EtOAc in hexane to afford methyl 2-(4-chloropyridin-2-yl)acetate (4.00 g, 41.08%) as a yellow liquid.

[0508] TLC: (3:7; EtOAc / Hexane, Rf: 0.4)

[0509] LCMS: (Method_A): m / z 186.07 (ES+), at 1.241 min.

[0510] Step 2; Methyl 2-(4-chloropyridin-2-yl)acetate (4.00 g, 21.60 mmol) was dissolved in acetone (40 ml). To it, NaHCO3(7.25 g, 86.4 mmol), LiBr (1.87 g, 21.60 mmol) and chloroacetaldehyde (6.20 ml, 97.20 mmol) were added. The reaction mixture was stirred at 60 °C for 16 h. The reaction mixture was partitioned between water (500 ml) and EtOAc (500 ml). Aqueous layer was further extracted with EtOAc (2 x 200 ml). Organic layers were combined, dried (Na2SO4) and concentrated. The crude product was purified by reverse phase gradient flash column chromatography (C18 silica), product eluted at 0% to 28% MeCN in water to afford methyl 7-chloroindolizine-1 -carboxylate (3.30 g, 73.02%) as a light brown solid.

[0511] 1H NMR (400 MHz, DMSO-cQ 5: 3.80 (s, 3H), 6.96-6.94 (m, 1H), 7.17 (d, 1H, J= 2.8Hz), 7.66 (d, 1H, J= 2.8Hz), 8.02 (d, 1H, J= 2.0Hz), 8.53 (d, 1H, J= 7.2Hz).

[0512] SynthesSynthesis of Examples, general procedures Intermediate 2, methyl 7-chloro-3-sulfamoylindolizine-1 -carboxylate

[0513]

[0514] hitermedkite 1 Intermedsate 2 Step-1; Methyl 7-chloroindolizine-1-carboxylate (Intermediate 1, 1.80 g, 8.61 mmol) was dissolved in THF (18 ml). To it, Burgess reagent (2.40 g, 10.3 mmol) was added at room temperature. Reaction mixture was stirred at 60 °C for 16 h. Reaction mixture was quenched with 1M HCI solution (50 ml) and extracted with EtOAc (100 ml). Aqueous layer was further extracted with EtOAc (2 x 50 ml). The combined organics were dried (Na2SO4) and concentrated. The crude product was purified by normal phase gradient flash column chromatography (silica), eluted at 0% to 20% EtOAc in hexane to afford methyl 7-chloro-3-(N-(methoxycarbonyl)sulfamoyl)indolizine-1 -carboxylate (1.50 g, 50.33%) as a brown solid. LCMS: (Method A): m / z 347.14 (ES+), at 1.578 min.

[0515] Step-2; Methyl 7-chloro-3-(N-(methoxycarbonyl)sulfamoyl)indolizine-1-carboxylate (1.50 g, 4.33 mmol) was dissolved in pyridine (15 ml) and water (15 ml). Reaction mixture was stirred at 70 °C for 16 h. Reaction mixture was directly concentrated under reduced pressure to afford crude, which was purified by normal phase gradient flash column chromatography (silica), eluted at 0% to 15% EtOAc in hexane to afford methyl 7-chloro-3-sulfamoylindolizine-1-carboxylate (Intermediate 2, 0.30 g, 24.02%) as light yellow solid.

[0516] LCMS: (Method A): m / z 287.01 (ES-), at 1.448 min.

[0517] 1H NMR (400 MHz, DMSO-d6) δ 8.68 (d, J = 7.5 Hz, 1H), 8.22 (d, J = 2.3 Hz, 1H), 7.96 (s, 2H), 7.56 (s, 1H), 7.34 (dd, J= 7.5, 2.3 Hz, 1H), 3.84 (s, 3H).

[0518] SynthesSynthesis of Examples, general procedures Intermediate 3, methyl 7-chloro-3-(chlorosulfonyl) indolizine-1 -carboxylate

[0519]

[0520] Intermediate 1 Intermediate 3 Step 1; Methyl 7-chloroindolizine-1-carboxylate (Intermediate 1, 5.00 g, 23.92 mmol) was dissolved in MeCN (100 ml). To it, pyridine sulfur trioxide (11.42 g, 71.76 mmol) was added and reaction mixture was stirred at 110 °C for 16 h. Reaction mixture was concentrated in vacuo to afford crude product which was purified by reverse phase gradient flash column chromatography (C18 silica) product eluted at 0% to 13% acetonitrile in water to afford 7-chloro-1 -(methoxycarbonyl) indolizine-3-sulfonic acid (5.0 g, 72.33%) as a light brown solid. TLC: (5:5, EtOAc / Hexane, Rf: 0.1).

[0521] LCMS: (Method A): m / z 288.0 (ES-), at 1.176 min.

[0522] Step 2; 7-chloro-1-(methoxycarbonyl) indolizine-3-sulfonic acid (5.00 g, 17.30 mmol) was dissolved in MeCN (100 ml). To it, POCI3(8.09 ml, 86.51 mmol) was added at 0 °C. The reaction mixture was stirred at 90 °C for 1 h, then poured into cold ice water (500 ml) and extracted with EtOAc (500 ml). Aqueous layer further extracted with EtOAc (2 x 200 ml). Organic layers were combined, dried (Na2SO4) and concentrated. The crude product was purified by normal phase gradient flash column chromatography (silica), product eluted at 0% to 10% EtOAc in hexane to afford methyl 7-chloro-3-(chlorosulfonyl) indolizine-1 -carboxylate (2.20 g, 41.42%) as a light yellow solid.

[0523] LCMS: (Method A): m / z 287.99 (ES-) (Sulfonic acid observed), at 2.534 min.

[0524] 1H NMR (400 MHz, DMSO-d₆) δ 8.66 (d, J= 7.4 Hz, 1H), 8.07 (d, J= 2.2 Hz, 1H), 7.15 (s, 1H), 7.09 (dd, J= 7.4, 2.2 Hz, 1H), 3.80 (s, 3H).

[0525] SynthesSynthesis of Examples, general procedures Intermediate 4, 2-bromo-5-(2-fluoroethoxy)-4-methoxypyrimidine

[0526] F

[0527]

[0528] 5-(2-fluoroethoxy)-4-methoxypyrimidin-2-amine (CAS 2827057-55-4, 0.70g, 3.74mmole) was dissolved in HBr in H2O (47%, 10mL). To it, sodium bromide (3.85g, 37.43mmole) was added at room temperature and reaction mixture was cooled up to -5°C. A solution of sodium nitrite (2.58g, 37.43mmole) in water (2mL) was added drop wise at -5°C and reaction mixture was stirred at room temperature for 16h. Reaction mixture quenched with 40% aqueous NaOH solution (20mL) to adjust pH up to ~9 and reaction mixture was partitioned between water (70mL) and EtOAc (50mL). Aqueous layer was further extracted with EtOAc (2 X 30mL). Organic layers were combined, dried (Na2SO4) and concentrated. The crude product was purified by normal phase gradient flash column chromatography (silica), product eluted at 0% to 20% EtOAc in hexane to afford 2-bromo-5-(2-fluoroethoxy)-4-methoxypyrimidine (0.25g, 26.73%) as a pale yellow solid.

[0529] LCMS: (Method A): m / z 251.00 (ES+) at 1,416min.1H-NMR: (400MHz, DMSO): δ 3.97 (s, 3H), 4.40-4.31 (m, 2H), 4.83-4.69 (m, 2H), 8.18 (s, 1H).

[0530] SynthesSynthesis of Examples, general procedures Intermediate 5, 2-(4-amino-2-fluoro-5-methoxyphenyl)acetonitrile

[0531] NO

[0532]

[0533] 4-bromo-5-fluoro-2-methoxyaniline (CAS 330794-03-1, 0.50 g, 2.28 mmol), 4-(4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (0.53 g, 2.74 mmol) and KF (0.39 g, 6.85 mmol) were dissolved in DMSO (5 ml) and water (1 ml) at room temperature. Nitrogen gas was purged through reaction mixture for 15 min at room temperature. To it, PdCl2(dppf) (0.17 g, 0.23 mmol) was added and reaction mixture was stirred at 120 °C for 16 h. Reaction mixture was partitioned between water (100 ml) and EtOAc (50 ml). Aqueous layer was further extracted with EtOAc (2 x 50 ml). Organic layers were combined, dried (Na2SO4) and concentrated. The crude product was purified by normal phase gradient flash column chromatography (silica), product eluted at 0% to 15% EtOAc in hexane to afford 2-(4-amino-2-fluoro-5-methoxyphenyl)acetonitrile (0.25 g, 60.80%) as a brown oil.

[0534] LCMS: (Method A): m / z 181.15 (ES+), at 1.850min.

[0535] 1H-NMR: (400MHz, DMSO): δ 6.79 (d, J = 7.1 Hz, 1H), 6.46 (d, J = 11.6 Hz, 1H), 5.13 (s, 2H), 3.82 - 3.77 (m, 2H), 3.74 (s, 3H).

[0536] SynthesSynthesis of Examples, general procedures Intermediate 6, 5-fluoro-4-(fluoromethoxy)-2-methoxyaniline

[0537] F F OH J J OHFQ-' 1 p Step 1 Y Step 2 I Step 3 | p r j K * F' A

[0538] FY J —* fv

[0539] F Y Y

[0540] "' Y'" O' x ' -J

[0541] O£1O2

[0542] F

[0543] Step 4 Y, F

[0544] -*

[0545] O' Y

[0546] Intermediate 6

[0547] Step 1; 2,5-difluorophenol (CAS 2713-31-7, 1.00 g, 7.69 mmol) was dissolved in DCM (15ml). To it, fuming HNO3(0.32 ml, 7.69 mmol) was added dropwise at 0°C. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was partitioned between water (100ml) and DCM (100ml). Aqueous layer was further extracted with DCM (2 X 100ml). The combined organic layers were dried (Na2SO4) and concentrated. The crude product was purified by normal phase gradient flash column chromatography (silica), product eluted at 0% to 5% EtOAc in Hexane to afford 2,5-difluoro-4-nitrophenol (0.85g, 62.96%) as a yellow solid. TLC: (1:9; EtOAc / Hexane, Rf: 0.3)

[0548] LCMS: (Method_A): m / z 174.04 (ES-) at 1.389min

[0549] Step 2; 2,5-difluoro-4-nitrophenol (0.65 g, 3.71 mmol) was dissolved in MeCN (5ml). To it, K2CO3(1.55 g, 11.14 mmol) and fluoroiodomethane (0.71 g, 4.45 mmol) were added at room temperature. The reaction was irradiated to 80 °C for 1 h in microwave. The reaction mixture was partitioned between water (60 ml) and EtOAc (50 ml). Aqueous layer was further extracted with EtOAc (2 x 50 ml). The combined organic layers were dried (Na2SO4) and concentrated. The crude product was purified by normal phase gradient flash column chromatography (silica), product eluted at 0% to 5% EtOAc in hexane to afford 1,4-difluoro-2-(fluoromethoxy)-5-nitrobenzene (0.37 g, 48.05%) as an orange sticky material.

[0550] TLC: (1:9; EtOAc / Hexane, Rf: 0.6)

[0551] LCMS: (Method_A): Product m / z was not supported in the major peak (ES+), at 1.596min.

[0552] Step 3; 1,4-difluoro-2-(fluoromethoxy)-5-nitrobenzene (0.20 g, 0.97 mmol) was dissolved in MeOH (2mL) at room temperature. To it, sodium methoxide (30% solution in MeOH) (0.17 ml, 0.97 mmol) was added dropwise at 0°C. Reaction mixture was stirred at 0°C for 1 h, then partitioned between water (50ml) and EtOAc (30ml). The aqueous layer was further extracted with EtOAc (2 x 50ml). The combined organic layers were dried (Na2SO4) and concentrated. The crude product was purified by normal phase gradient flash column chromatography (silica), product eluted at 0% to 10% EtOAc in hexane to afford 1-fluoro-2-(fluoromethoxy)-4-methoxy-5-nitrobenzene (0.15 g, 71.09%) as a white solid.

[0553] TLC: (1:9; EtOAc / Hexane, Rf: 0.3)

[0554] LCMS: (Method_A): Product m / z was not supported in the major peak (ES+), at 1.579min.

[0555] Step 4; 1-fluoro-2-(fluoromethoxy)-4-methoxy-5-nitrobenzene (0.15 g, 0.68 mmol) was dissolved in THF (1mL) and MeOH (1mL). To it, Pd / C (10% w / w) (0.15 g) was added at room temperature. H2gas was purged through reaction mixture for 1 h at room temperature. The reaction mixture was filtered through celite bed and washed with MeOH (2 x 50ml). Solvent was removed in vacuo. Crude product was purified by normal phase gradient flash column chromatography (silica), product eluted at 0% to 5% EtOAc in hexane to afford 5-fluoro-4-(fluoromethoxy)-2-methoxyaniline (0.12 g, 92.31%) as a brown liquid. LCMS: (Method_A): m / z 190.10 (ES+) at 1.249min.

[0556] 1H NMR: (400 MHz, DMSO-d₆) δ: 6.75 (d, J = 7.7 Hz, 1H), 6.51 (d, J= 12.6 Hz, 1H), 5.68 (d, J = 54.8 Hz, 2H), 4.86 (s, 2H), 3.74 (s, 3H).

[0557] SynthesSynthesis of Examples, general procedures Intermediate 7, 7-chloroindolizine- 1 -carbonitrile

[0558]

[0559] Intermediate 1 Intermediate 7 Step 1; Methyl 7-chloroindolizine- 1 -carboxylate (1.00 g, 4.78 mmol) was dissolved in THF (5 ml) and water (5 ml). To it, lithium hydroxide monohydrate (1.00 g, 23.92 mmol) was added and reaction mixture was stirred at 60 °C for 48 h then concentrated in vacuo. The crude product was partitioned between water (70 ml) and EtOAc (70 ml). The aqueous layer was extracted with EtOAc (2 X 50 ml). Combined organic layer was discarded. The aqueous layer was then acidified with 1N HCI solution (6 ml) up to pH ~4. The aqueous layer was further extracted with EtOAc (2 X 80 ml). The organic layers were combined, dried (Na2SO4) and concentrated to afford 7-chloroindolizine-1-carboxylic acid (0.90 g, 96.46%) as an off white solid.

[0560] TLC: (8:2; EtOAc / Hexane, Rf: 0.4).

[0561] LCMS: (Method A): m / z 196.01 (ES+) at 1.819 min.

[0562] Step 2; 7-chloroindolizine-1-carboxylic acid (0.90 g, 4.62 mmol) was dissolved in DMF (9 ml). To it, HATU (5.26 g, 13.85 mmol) was added and the reaction mixture was stirred under nitrogen atmosphere for 10 min at room temperature. After this, NH4CI (3.70 g, 69.23 mmol) and DIPEA (4.81 ml, 27.69 mmol) were added and reaction mixture was stirred at room temperature for 16 h. Reaction mixture was partitioned between water (70 ml) and DCM (70 ml). Aqueous layer was further extracted with DCM (2 X 50 ml). Organic layers were combined, dried (Na2SO4) and concentrated. The crude product was purified by normal phase gradient flash column chromatography (silica), product was eluted at 0% to 95% EtOAc in hexane to afford 7-chloroindolizine-1 -carboxamide (0.60 g, 67.01%) as a light brown solid. TLC: (8:2; EtOAc / Hexane, Rf: 0.3)

[0563] LCMS: (Method A): m / z 195.02 (ES+) at 1.674 min.

[0564] Step 3; 7-chloroindolizine-1 -carboxamide (0.60 g, 3.09 mmol) was dissolved in DCM (6 ml) and DMF (0.72 ml, 9.28 mmol). To it, POCl₃ (0.87 ml, 9.28 mmol) was added at 0 °C. Reaction mixture was stirred at 0 °C for 30 min. Reaction mixture was concentrated in vacuo to obtain crude which was purified by normal phase gradient flash column chromatography (silica), product was eluted at 0% to 20% EtOAc in hexane to afford 7-chloroindolizine-1 -carbonitrile (Intermediate 7, 0.30 g, 55.11%) as a white solid.

[0565] 1H NMR: (400 MHz, DMSO-d₆) δ: 8.56 (d, J= 7.3 Hz, 1H), 7.78 (d, J= 2.2 Hz, 1H), 7.72 (d, J = 3.1 Hz, 1H), 7.24 (d, J= 3.1 Hz, 1H), 6.99 (dd, J= 7.3, 2.2 Hz, 1H).

[0566] SynthesSynthesis of Examples, general procedures Intermediate 8, 7-chloro- 1-cyanoindolizine-3-sulfonamide

[0567]

[0568] Intermediate 7 Intermediate 8 Step 1; 7-chloroindolizine-1-carbonitrile (Intermediate 7, 0.20 g, 1.14 mmol) was dissolved in MeCN (2 ml). To it, Sulfur trioxide pyridine complex (CAS 26412-87-3, 0.35 g, 2.27 mmol) was added and the reaction mixture was stirred at 90 °C for 16 h. The reaction mixture was partitioned between water (60 ml) and DCM (50 ml). The aqueous layer was further extracted using DCM (2 x 40 ml). The combined organic layer was discarded. The aqueous layer was concentrated in vacuo to afford 7-chloro-1-cyanoindolizine-3-sulfonic acid (0.15 g, 51.57%) as a brown sticky solid, which was directly used for next step reaction without any purification. TLC: (Neat EtOAc, Rf: 0.2).

[0569] LCMS: (Method A): m / z 255.01 (ES-) at 1.603 min.

[0570] Step 2; 7-chloro-1-cyanoindolizine-3-sulfonicacid (0.15 g, 0.59 mmol) was dissolved in MeCN (0.7 ml). To it, POCI3(0.16 ml, 1.76 mmol) was added atO °C. The reaction mixture was stirred at 90 °C for 3 h. The reaction mixture was poured into crushed ice in water (60 ml) and extracted with EtOAc (60 ml). The aqueous layer further extracted with EtOAc (2 x 30 ml). Organic layers were combined, dried (Na2SO4) and concentrated to afford crude 7-chloro-1-cyanoindolizine-3-sulfonyl chloride (0.13 g, 80.98%) as yellow sticky solid.

[0571] TLC: (5:5; EtOAc / Hexane, Rf: 0.5)

[0572] LCMS: (Method A): Product mass was not supported in major peak at 2.338 min.

[0573] Step 3; 7-chloro-1-cyanoindolizine-3-sulfonyl chloride (0.13 g, 0.47 mmol) was dissolved in THF (1 ml) at -78°C. NH3 (g)was purged through reaction mixture for 2 h at -78 °C. Reaction mixture was concentrated in vacuo to afford crude which was purified by reverse phase gradient flash column chromatography (C18 silica), product eluted at 0% to 30% MeCN in water to afford 7-chloro-1-cyanoindolizine-3-sulfonamide (0.08 g, 66.11%) as a brown solid. LCMS: (Method A): m / z 253.99 (ES-) at 1.873 min

[0574] 1H NMR: (400 MHz, DMSO-d₆) δ: 8.69 (dd, J = 7.5, 0.9 Hz, 1 H), 8.08 - 8.00 (m, 3H), 7.79 (s, 1H), 7.39 (dd, J= 7.5, 2.2 Hz, 1H).

[0575] SynthesSynthesis of Examples, general procedures Intermediate 9, 2-(6-bromo-5-fluoro-2-methoxypyridin-3-yl)acetonitrile

[0576]

[0577] Br

[0578] 2-(6-amino-5-fluoro-2-methoxypyridin-3-yl)acetonitrile (CAS 2231233-87-5, 0.20 g, 1.10 mmol) was dissolved in dibromoethane (2 ml). To it, copper(ll) bromide (0.74 g, 3.31 mmol) was added and reaction mixture was stirred at 0 °C for 10 min. After this, isoamyl nitrite (0.44 ml, 3.31 mmol) was added at 0 °C. The reaction mixture was stirred at room temperature for 16 h. Reaction mixture was diluted with water (70 ml) and extracted with EtOAc (60 ml). Aqueous layer was further extracted with EtOAc (2 x 50 ml). Organic layers were combined, dried (Na2SO4) and concentrated. The crude product was purified by normal phase gradient flash column chromatography (silica), product eluted at 0% to 20% EtOAc in Hexane to afford 2-(6-bromo-5-fluoro-2-methoxypyridin-3-yl)acetonitrile (0.15 g, 55.67%) as a brown solid. LCMS: (Method A): Product mass was not observed in the major peak at 2.160min.

[0579] 1H-NMR: (400MHz, DMSO): δ 7.89 (d, J = 7.7 Hz, 1H), 3.98 - 3.86 (m, 5H).

[0580] SynthesSynthesis of Examples, general procedures Intermediate 10, 7-chloroindolizine

[0581]

[0582] Intermediate 10

[0583] To a stirred solution of 7-chloroindolizine-2-carboxylic acid (CAS 1206974-14-2, 20.0 g, 0.1025 mol) in quinoline (200 mL) was added Cu powder (65.17 g, 1.025 mol) and the reaction mixture was heated to 200 °C and stirred for 24 h. The reaction was filtered on celite bed washed with ethyl acetate (100 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by normal phase gradient flash column chromatography (silica), product eluted with hexane to afford 7-chloroindolizine (5.8 g, 36.46%).

[0584] 1H-NMR: (400MHz, DMSO): δ 8.29 (d, J = 7.2 Hz, 1H), 7.56 (d, J = 14.4 Hz, 2H), 6.77 (t, J = 3.2 Hz, 1H), 6.55-6.53 (d, J = 2.0 & 7.6 Hz, 1H), 6.37 (d, J = 4.0 Hz, 1H).

[0585] SynthesSynthesis of Examples, general procedures Intermediate 11, 7-chloroindolizine-3-sulfonamide f*-'" Step 1

[0586] *

[0587]

[0588] Intermediate 10 Intermediate 11 Step 1; To a stirred solution of 7-chloroindolizine (Intermediate 10, 2.5 g, 0.0164 mol) in Tetrahydrofuran (25 mL) was added Burgess reagent (5.86 g, 0.0246 mol) and the reaction mixture stirred at room temperature for 16 h. The reaction mixture was quenched with water (10.0 V) and extracted with ethyl acetate (10.0 V). The aqueous layer was further extracted with ethyl acetate (10.0 V) and all organic layers were combined, dried (Na2SO4) and concentrated. The crude product was slurried in ethyl acetate (10 V) and filtered. The filtrate was concentrated to obtain mixture of desired product and the regioisomer. The crude product was purified by normal phase gradient flash column chromatography (silica), product eluted at 0-70 % ethyl acetate in hexane to afford methyl ((7-chloroindolizin-3-yl)sulfonyl)carbamate (0.4 g, 8.4%).

[0589] 1H-NMR: (400MHz, DMSO): δ: 12.26 (s, 1H), 8.65-8.63 (d, 1H), 7.89 (s, 1H), 7.45-7.46 (d, 1H), 7.13-7.11 (q, 1H), 6.64-6.62 (s, 1H), 3.54 (s, 3H).

[0590] Step 2; A stirred solution of methyl ((7-chloroindolizin-3-yl)sulfonyl)carbamate (1.0 g, mol) in pyridine (4.0 mL, 4.0 V) and water (4.0 mL, 4.0 V)) stirred at 100 °C for 4 h. The reaction mixture was concentrated to afford crude product and was slurried with ethyl acetate and hexane (1:1, 10V), filtered and dried under reduced pressure to afford 7-chloroindolizine-3-sulfonamide (0.6 g, 75%).

[0591] 1H-NMR: (400MHz, DMSO): δ: 8.53 (d, 1H), 7.836-7.831 (d, 1H), 7.68 (d, 2H), 7.25-7.26 (d, 1H), 7.01-6.98 (d, 1H), 6.53-6.54 (d, 1H).

[0592] SynthesSynthesis of Examples, general procedures Intermediate 12, 3-bromo-6-(difluoromethoxy)-5-fluoro-2-methoxypyridine

[0593] w

[0594]

[0595] Intermediate 12

[0596] 6-(difluoromethoxy)-5-fluoro-2-methoxypyridin-3-amine (CAS 2407470-90-8, 3.10 g, 14.90 mmol) was dissolved in MeCN (30 ml). To it, copper(l) bromide (2.56 g, 17.88 mmol) was added at room temperature. Reaction mixture was stirred at 0 °C for 10 min. After this, tertbutyl nitrite (2.65 ml, 22.35 mmol) was added at 0 °C. Reaction mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with water (100 ml) and extracted with EtOAc (100 ml). Aqueous layer was further extracted with EtOAc (2 x 100 ml). Organic layers were combined, dried (Na2SO4) and concentrated. The crude product was purified by normal phase gradient column chromatography (silica), product eluted at 0% to 12% EtOAc in hexane to afford 3-bromo-6-(difluoromethoxy)-5-fluoro-2-methoxypyridine (1.00 g, 25.00%) as a yellow liquid.

[0597] TLC: (3:7; EtOAc / Hexane, Rf: 0.7)

[0598] LCMS: (Method A): Product m / z was not supported in major peak at 2.374 min.

[0599] SynthesSynthesis of Examples, general procedures Intermediate 13, methyl 3-(chlorosulfonyl)-7-cyclopropylindolizine-1 -carboxylate

[0600]

[0601] Intermediate 13

[0602] Step 1; Methyl 7-bromoindolizine-1 -carboxylate (CAS 1354021-08-1, 10.00 g, 43.67 mmol) was dissolved in acetone (10 ml). Sodium bicarbonate (14.67 g, 174.69 mmol), chloroacetaldehyde (3.16 ml, 47.96 mmol) and lithium bromide (3.75 g, 43.67 mmol) were added sequentially at room temperature. The reaction mixture was stirred at 60 °C for 16 h. Reaction mixture was diluted with water (200 ml) and extracted with EtOAc (200 ml). Aqueous layer further extracted with EtOAc (2 x 100 ml). Organic layers were combined, dried (Na2SO4) and concentrated. The crude product was purified by normal phase gradient flash column chromatography (silica), product was eluted at 0% to 40% ethyl acetate in hexane to afford methyl 7-bromoindolizine-1 -carboxylate (7.50 g, 67.87 %) as a white solid.

[0603] 1H-NMR: (400MHz, DMSO): 5 3.80 (s, 3H), 7.01-7.03 (m, 1H), 7.15 (d, 1H, J= 3.0 Hz), 7.66 (d, 1H, J= 3.0 Hz), 8.19 (s, 1H), 8.46 (d, 1H, J= 7.2 Hz).

[0604] Step 2; Methyl 7-bromoindolizine-1 -carboxylate (5.00 g, 19.76 mmol), cyclopropyl boronic acid (4.24 g, 49.41 mmol) and K3PO4(10.49 g, 49.41 mmol) were dissolved in toluene (45 ml) and water (5 ml). N2 gas was purged through reaction mixture for 30 min at room temperature. Tricyclohexylphosphine (1.11 g, 3.95 mmol) and Pd(OAc)2 (1.32 g, 5.90 mol) were added and the reaction was stirred at 100 °C for 16 h. Reaction mixture was partitioned between water (500 ml) and EtOAc (500 ml). Aqueous layer was further extracted with EtOAc (2 x 250 ml). Organic layers were combined and dried (Na2SO4). The crude was purified by normal phase gradient flash column chromatography (silica), product eluted at 0% to 30% EtOAc in hexane to afford methyl 6-cyclopropylindolizine-3-carboxylate (4.0 g, 94.09%) as a brown sticky liquid. LCMS: (Method A): m / z 216.21 (ES+) at 1.716 min.

[0605] Step 3; Methyl 6-cyclopropylindolizine-3-carboxylate (4.00 g, 18.59 mmol) was dissolved in MeCN (40 ml). Sulfur trioxide pyridine complex (8.87 g, 55.79 mmol) was added at room temperature and stirred at 100 °C for 16 h. The reaction mixture was concentrated in vacuo to afford crude which was purified by reverse phase gradient flash column chromatography (C18 silica), product eluted at 0% to 10% MeCN in water to afford 7-cyclopropyl-1-(methoxycarbonyl)indolizine-3-sulfonic acid (3.5 g, 63.79%) as a white solid.

[0606] LCMS: (Method A): m / z 296.04 (ES+) at 1.176 min

[0607] Step 4; 7-cyclopropyl-1-(methoxycarbonyl)indolizine-3-sulfonic acid (3.5 g, 11.86 mmol) was dissolved in DCE (35 ml) at room temperature. Et3N (8.33 ml, 59.31 mmol) and POCl₃ (6.63 ml, 71.17 mmol) were added sequentially at 0 °C. The reaction was stirred at 90 °C for 1 h, then quenched with ice cold water (200 ml) and extracted with DCM (200 ml). Aqueous layer further extracted with EtOAc (2 x 100 ml). Organic layers were combined and dried (Na2SO4). The crude was purified by normal phase gradient flash column chromatography (silica) product eluted at 0% to 40% ethyl acetate in hexane to afford methyl 3-(chlorosulfonyl)-7-cyclopropylindolizine-1 -carboxylate (2.5 g, 67.31%) as an off white solid.

[0608] LCMS: (Method A): Product mass was confirmed as sulfonic acid m / z 296.01 (ES+), at 1.185 min.

[0609] SynthesSynthesis of Examples, general procedures Intermediate B1, 6-(chlorosulfonyl)-2-oxo-1,2-dihydropyrrolo[1,2-a]pyrimidine-8-carboxylic acid

[0610]

[0611] Intermediate Bl Step 1; To the stirred solution of ethyl 2-amino-1H-pyrrole-3-carboxylate (CAS 108290-86-4, 2 g, 12.97 mmol) in DMF (15 ml), at 0 °C, was added sodium hydride 60% dispersion in mineral oil, 1.090 g, 27.2 mmol) portion wise then ethyl 3-ethoxyacrylate (2.81 g, 19.46 mmol). The reaction mixture was stirred at 0 °C for 30 min then at RT for 12 h. The reaction mixture was diluted with cold water and extracted with ethyl acetate. The extracted organic layer was washed with cold brine to remove DMF. Organic layer was dried (Na2SO4) and concentrated. The crude product was purified by normal phase gradient flash column chromatography (silica), product eluted at 35% EtOAc in petroleum ether to afford ethyl 2-oxo-1,2- dihydropyrrolo[1,2-a]pyrimidine-8-carboxylate (900 mg, 4.32 mmol, 33.3 % yield) as a light brown solid.

[0612] 1H-NMR: (400MHz, DMSO): 5: 10.55 (s, 1H), 8.32 (d, J = 8.00 Hz, 1H), 7.01 (d, J= 3.60 Hz, 1 H), 6.63 (d, J = 3.20 Hz, 1 H), 6.04 (d, J = 7.60 Hz, 1 H), 4.24 (q, J = 7.30 Hz, 2H), 1.28 (t, J = 7.20 Hz, 3H).

[0613] Step 2; Chlorosulfonic acid (5 mL, 4.85 mmol) was added to a stirred solution of ethyl 2-oxo- 1,2-dihydropyrrolo[1,2-a]pyrimidine-8-carboxylate (1 g, 4.85 mmol) at room temperature, then stirred at 70 °C for 2 h. The reaction mixture was quenched with crushed ice, the precipitate was filtered and dried to afford 6-(chlorosulfonyl)-2-oxo-1,2-dihydropyrrolo[1,2-a]pyrimidine-8- carboxylic acid (900 mg) as a light brown solid that was used crude, without purification.

[0614] Synthesis of Examples, general procedures

[0615] Route A

[0616] Synthesis of Example A1, methyl 7-chloro-3-(N-(3,5-dimethoxypyrazin-2-yl)sulfamoyl)indolizine-1-carboxylate

[0617] HN

[0618] ....

[0619] r** 'if

[0620] J'-'OMe

[0621]

[0622] 0

[0623] Example A1

[0624] Methyl 7-chloro-3-sulfamoylindolizine-1 -carboxylate (Intermediate 2, 0.30 g, 1.04 mmol), 2- bromo-3,5-dimethoxypyrazine (CAS 1033610-34-2, 0.22 g, 1.04 mmol) and K2CO3(0.43 g, 3.12 mmol) were dissolved in MeCN (5 ml). N2gas was purged through the reaction mixture for 30 min at room temperature, then trans-N, N'-dimethylcyclohexane-1,2-diamine (0.2 ml, 1.24 mmol) and Cui (0.1 g, 0.52 mmol) were added and reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was partitioned between water (80 ml) and EtOAc (80 ml). The aqueous layer was further extracted with EtOAc (2 x 40 ml). The combined organic layers were dried (Na2SO4) and concentrated. The crude product was purified by reverse phase gradient flash column chromatography (C18 silica), eluted at 0% to 30% MeCN in water to afford methyl 7-chloro-3-(N-(3,5-dimethoxypyrazin-2-yl)sulfamoyl)indolizine-1 -carboxylate (0.20 g, 45.07%) as a light brown solid.

[0625] LCMS: (Method B): m / z 426.98 (ES+) at 1.65 min.

[0626] 1H NMR: (400 MHz, DMSO-d6) δ: 3.73 (s, 3H), 3.84 (s, 6H), 7.39-7.37 (m, 1H), 7.45 (s, 1H), 7.57 (s, 1H) 8.23 (d, 1H, J= 2.0 Hz), 8.86 (d, 1H, J= 7.2 Hz), 10.86 (s, 1H).

[0627] Route B

[0628] SynthesSynthesis of Examples, general procedures Example A2, 7-chloro-3-(N-(3.5-dimethoxypyrazin-2-yl)sulfamoyl)indolizine-1-carboxylic acid and Example A3, 7-chloro-3-(N-(3.5-dimethoxypyrazin-2-yl)sulfamoyl)indolizine-1 -carboxamide

[0629]

[0630] Example A 1 Example A2 Example A3 Step 1; Methyl 7-chloro-3-(N-(3,5-dimethoxypyrazin-2-yl)sulfamoyl)indolizine-1 -carboxylate (Example A1, 0.05 g, 0.12 mmol) was dissolved in THF (0.5 ml) and water (0.5 ml). To it, LiOH monohydrate (0.02 g, 0.59 mmol) was added at room temperature. Reaction mixture was stirred at 50 °C for 16 h. The reaction mixture was diluted with water (50 ml), acidified with 1M HCI (2 ml) up to pH ~4 and extracted with EtOAc (50 ml). The aqueous layer was further extracted with EtOAc (2 x 30ml). The organic layers were combined, dried (Na2SO4) and concentrated to afford 7-chloro-3-(N-(3,5-dimethoxypyrazin-2-yl)sulfamoyl)indolizine-1-carboxylic acid (0.01g, 21.42%) as an off white solid.

[0631] LCMS: (Method B): m / z 412.94 (ES+) at 1.32 min.

[0632] 1H NMR: (400 MHz, DMSO-d6) δ: 3.72 (s, 3H), 3.85 (s, 3H), 7.37-7.35 (m, 1H), 7.49 (s, 1H), 7.55 (s, 1H) 8.24 (d, 1H, J= 1.6Hz), 8.84 (d, 1H, J= 7.6Hz), 10.82 (s, 1H), 10.66 (br s, 1H).

[0633] Step 2; 7-chloro-3-(N-(3,5-dimethoxypyrazin-2-yl)sulfamoyl)indolizine-1-carboxylic acid (Example A2, 0.40 g, 0.97 mmol) was dissolved in DMF (5 ml). To it, HATU (0.44 g, 1.16 mmol) was added and the reaction mixture was stirred for 10 min at room temperature. After this, NH4CI (0.20 g, 3.88 mmol) and DIPEA (0.83 ml, 4.85 mmol) were added and reaction mixture was stirred at room temperature for 16 h. The reaction mixture was partitioned between water (100 ml) and EtOAc (100 ml). Aqueous layer was further extracted with EtOAc (2 x 50 ml). The organic layers were combined, dried (Na2SO4) and concentrated. The crude product was purified by reverse phase gradient flash column chromatography (C18 silica), eluted at 0% to 25% MeCN in water to afford 7-chloro-3-(N-(3,5-dimethoxypyrazin-2-yl)sulfamoyl)indolizine-1 -carboxamide (0.03 g, 7.51%) as a white solid.

[0634] LCMS: (Method B): m / z 412.09 (ES+) at 1.42 min.

[0635] 1H NMR: (400 MHz, DMSO-d6) δ: 3.71 (s, 3H), 3.73 (s, 3H), 6.93 (brs, 1H), 7.05-7.03 (m, 1H), 7.11 (br s, 1H) 7.69 (br s, 1H), 7.77 (s, 1H), 8.34 (d, 1H, J= 2.0Hz), 8.85 (d, 1H, J= 7.6Hz), 10.72 (br s, 1H).

[0636] Route C

[0637] SynthesSynthesis of Examples, general procedures Example A4, 7-chloro-1-cvano-N-(3,5-dimethoxypyrazin-2-yl)indolizine-3-sulfonamide

[0638] HN

[0639]

[0640] Example A4

[0641] 7-chloro-3-(N-(3,5-dimethoxypyrazin-2-yl)sulfamoyl)indolizine-1-carboxamide (Example A3, 0.07 g, 0.17 mmol) was dissolved in DCM (2 ml). To it, DMF (0.04 ml, 0.51 mmol) and oxalyl chloride (0.04 ml, 0.51 mmol) were added at 0°C. Reaction mixture was stirred at room temperature for 2 h. The reaction mixture was partitioned between water (50 ml) and EtOAc (50 ml). The aqueous layer was further extracted with EtOAc (2 x 25 ml) and the combined organic layers were dried (Na2SO4) and concentrated. The crude product was purified by reverse phase gradient flash column chromatography (C18 silica), eluted at 0% to 30% MeCN in water to afford methyl 7-chloro-1-cyano-N-(3,5-dimethoxypyrazin-2-yl)indolizine-3-sulfonamide (0.01 g, 14.94%) as an off white solid.

[0642] LCMS: (Method B): m / z 394.08 (ES+) at 1.56 min.

[0643] 1H NMR: (400 MHz, DMSO-d6) δ: 3.70 (s, 3H), 3.72 (s, 3H), 7.01 (br s, 1H), 7.16 (br s, 1H), 7.40 (br s, 1H) 7.82 (br s, 1H), 8.16 (br s, 1H), 8.95 (d, 1H, J= 7.6Hz).

[0644] Route D

[0645] SynthesSynthesis of Examples, general procedures Example A5, 7-chloro-N-(3,5-dimethoxypyrazin-2-yl)-1- (hydroxymethyl)indolizine-3-sulfonamide OMe

[0646] MeO" J\'S J

[0647] HN „a

[0648]

[0649] "" OH

[0650] Example A5

[0651] Methyl 7-chloro-3-(N-(3,5-dimethoxypyrazin-2-yl)sulfamoyl)indolizine-1 -carboxylate (Example A1, 0.05 g, 0.12 mmol) was dissolved in THF (2 ml). To it, Lithium aluminium hydride (1 M in THF, 0.35 ml, 0.35 mmol) was added dropwise at -78 °C under nitrogen atmosphere. The reaction mixture was stirred at -78 °C for 3 h. The reaction mixture was poured in wet sodium sulphate (50 ml), filtered and washed with EtOAc (50 ml). The aqueous layer was further extracted with EtOAc (2 x 50 ml). The organic layers were combined, dried (Na2SO4) and concentrated. The crude product was purified by reverse phase gradient flash column chromatography (C18 silica), eluted at 0% to 62% Acetonitrile in water to afford 7-chloro-N-(3,5-dimethoxypyrazin-2-yl)-1-(hydroxymethyl)indolizine-3-sulfonamide (0.016 g, 34.04%) as a white solid.

[0652] LCMS: (Method B): m / z 399.01 (ES+) at 1.55 min.

[0653] 1H NMR: (400 MHz, DMSO-d6) δ: 3.72 (s, 3H), 3.78 (s, 3H), 4.59 (d, 2H, J= 5.0Hz), 4.95 (t, 1H, J= 5.0Hz), 6.89 (d, 1H, J= 4.0Hz), 7.13 (s, 1H), 7.23 (s, 1H), 7.75 (s, 1H), 8.72 (d, 1H, J= 8.0Hz), 10.57 (brs, 1H).

[0654] Route E

[0655] SynthesSynthesis of Examples, general procedures Example A6, methyl 7-chloro-3-(N-(6-(2,2-difluoroethoxy)-5-fluoro-2-methoxypyridin-3-yl)sulfamoyl)indolizine-1-carboxylate

[0656]

[0657] Example A6 Methyl 7-chloro-3-(chlorosulfonyl) indolizine-1 -carboxylate (Intermediate 3, 1.50 g, 4.88 mmol) and 6-(2,2-difluoroethoxy)-5-fluoro-2-methoxypyridin-3-amine (CAS 2407471-07-0, 1.08 g, 4.88 mmol) were dissolved in pyridine (10 ml) at room temperature. Reaction mixture was stirred at 80 °C for 1 h. The reaction mixture was diluted with water (200 ml) and extracted with EtOAc (3 x 200 ml). The combined organic layers were dried (Na2SO4) and concentrated. The crude product purified by normal phase gradient flash column chromatography (silica), product eluted at 0% to 30% EtOAc in hexane to afford methyl 7-chloro-3-(N-(6-(2,2-difluoroethoxy)-5-fluoro-2-methoxypyridin-3-yl)sulfamoyl)indolizine-1-carboxylate (1.30 g, 53.96%) as a light brown solid.

[0658] LCMS: (Method B): m / z 494.15 (ES+) at 2.04 min.

[0659] 1H NMR: (400 MHz, DMSO-d6) δ: 3.15 (s, 3H), 3.80 (s, 3H), 4.60-4.52 (m, 2H), 6.51-6.22 (m, 1H), 7.37 (s, 1H), 7.45-7.43 (dd, 1H, J= 7.2Hz and J= 2Hz), 7.72 (d, 1H, J= 10Hz), 8.25 (s, 1H), 8.80 (d, 1H, J= 7.2Hz), 10.43 (s, 1H). Examples

[0660] The following examples were prepared in a similar fashion to those previously described above.

[0661] Example Synthetic Analytical data

[0662] Name Structure Reaction details

[0663] Number Route LCMS 1H NMR

[0664] F'V-F

[0665] / 1H NMR: (400 MHz, DMSO-de) b LCMS: 6: 3.27 (s, 3H), 4.58-4.49 (m, 7-chloro-N-(6-(2,2-difluoroethoxy)-5- (Method B): 4H), 4.96 (t, 1 H, J= 5.6Hz), 6.50- fluoro-2-methoxypyridin-3-yl)-1 - Starting material m / z 466.05 6.22 (m, 1H), 7.02 (s, 1H), 7.04 A7 D

[0666] (hydroxymethyl)indolizine-3- HN p example A6 (ES+) at 1.91 (s, 1H), 7.59 (d, 1H, J= 10.4Hz), sulfonamide min. 7.85 (s, 1H), 8.62 (d, 1H, J=

[0667] 7.2Hz), 10.11 (s, 1H).

[0668] "'-OH

[0669] )1H NMR: (400 MHz, DMSO-de) d LCMS: 6: 3.81 (s, 3H), 4.20-4.11 (m, 7-chloro-3-(N-(5-(2-fluoroethoxy)-4- (Method B): 2H), 4.59 (t, 1H, J= 3.2Hz), 4.71 methoxypyrimidin-2- N \^ / -4XA followed Starting materials m / z 444.07 (t, 1H, J= 3.6Hz), 7.09 (s, 1H), A8 /

[0670] yl)sulfamoyl)indolizine-1 - HM 0 by B. intermediates 2 and 4. (ES+) at 1.49 7.20 (s, 1H), 7.81 (s, 1H), 7.86 carboxamide Co min. (s, 1H), 8.16 (s, 1H), 8.42 (s,

[0671] 1H), 8.66 (s, 1H), 12.30 (s, 1H). Co

[0672] cr \

[0673] 0

[0674]

[0675] Starting material

[0676] example A8. POCh1H NMR: (400 MHz, DMSO-de)

[0677] LCMS:

[0678] used instead of oxalyl 6: 3.81 (s, 3H), 4.20-4.11 (m,

[0679] (Method B):

[0680] 7-chloro-1 -cyano-N-(5-(2- chloride. Purification by 2H), 4.72-4.59 (m, 2H), 7.31 (br m / z 426.06

[0681] A9 fluoroethoxy)-4-methoxypyrimidin-2- C normal phase gradient s, 1H), 7.85 (s, 1 H), 7.90 (br s,

[0682] (ES+) at 1.64

[0683] yl)indolizine-3-sulfonamide flash column 1 H), 7.98 (s, 1H), 8.70 (brs, 1H), min.

[0684] chromatography (silica), 12.90 (br s, 1H).

[0685] product eluted at 0% to

[0686] 30% EtOAc in hexane.

[0687] F

[0688] f X

[0689] p

[0690] LCMS:1H NMR: (400 MHz, DMSO-de) methyl 7-chloro-3-(N-(6- \ / / {Starting materials

[0691] (Method B): δ: 3.37 (s, 3H), 3.8 (s, 3H), (difluoromethoxy)-5-fluoro-2- r intermediate 2 and

[0692] 0 479.97 m / z 7.35-7.33 (m, 1H), 7.40 (s, 1H), A10 methoxypyridin-3- A intermediate 12.

[0693] (ES+) at 1.957.53 (s, 1H), 7.70-7.67 (m, 1H), yl)sulfamoyl)indolizine-1 - Reaction temperature

[0694] min. 8.18 (d, 1H, J= 1.6Hz), 8.83 (d, carboxylate was 80 °C.

[0695] 1H, J= 7.6Hz), 10.63 (s, 1H).z..p--o

[0696] 0 \

[0697]

[0698] D'"

[0699] R..:„z-P

[0700] IrV M I*

[0701] X

[0702] % /

[0703]

[0704]

[0705]

[0706] \ *1H NMR: (400 MHz, DMSO-de)

[0707] LCMS:

[0708] 6: 3.16 (s, 3H), 3.96 (s, 2H), 6.93 7-ch loro- 1 -cyano-N-(4- £ / Starting material (Method B):

[0709] (d, 1H, J= 6.8 Hz), 7.21 (d, 1H, (cyanomethyl)-5-fluoro-2- ■“■'■O \ 0 example A16. Reaction m / z 419.21

[0710] A17 c J= 10.0Hz), 7.49-7.47 (m, 1H), methoxyphenyl)indolizine-3- was performed at 0 °C (ES+) at 1.85

[0711] 7.75 (s, 1H), 8.06 (s, 1H), 8.88 sulfonamide for 15 minutes. min.

[0712] cr (d, 1H, J=7.6Hz), 10.56 (s, 1H).

[0713] N

[0714] 1H NMR: (400 MHz, DMSO-de) Starting materials LCMS:

[0715] 6: 3.29 (s, 3H), 3.94 (s, 2H), 4.56 7-chloro-N-(4-(cyanomethyl)-5- intermediates 3 and 5. (Method B):

[0716] (d, 2H, J= 5.6Hz), 4.99 (t, 1H, J= fluoro-2-methoxyphenyl)-1 - E, followed In route D reaction was m / z 424.22

[0717] A18 5.6Hz), 6.91 (d, 1H, J= 6.8Hz), (hydroxymethyl)indolizine-3- y $ o-% by D performed at 0 °C. (ES+) at 1.81

[0718] 7.06 (d, 1 H, J= 7.6Hz), 7.17- sulfonamide Purification by prep min.

[0719] 7.14 (m, 2H), 7.86 (s, 1H), 8.69 HPLC method A.

[0720] (d, 1H, J= 7.6Hz), 10.21 (s, 1H). o o

[0721]

[0722] 1H NMR (400 MH DMSOd):ze-,

[0723] 6349 ( 3H) 409 ( 2H) 456ss:.,,.,,.

[0724] LCMS:

[0725] (d 2H J 52H) 500 ( 1H J 7hlN(6(hl)5ttcorocanome=z=yy------,,.,.,,

[0726] (Mhd B) Siiltttteoarng maeras:

[0727] 52H) 710707 ( 1H) 725 E flld fl2hidi3l)1tmooeoromeoprnzwuxyyy------ -.,..,,.

[0728] / 42508 idi 3d CAS A19tt mnermeae anz.

[0729] ( 1H) 759 (d 1H J 96H) b D (hdhl)idlii3tsromenone=zyyxyyz--,,.,,.,

[0730] (ES) 1713026463646t+ a--..

[0731] 787 ( 1H) 869 (d 1H Jlfids soname=u.,,.,,

[0732] i mn.

[0733] 76H) 1054 (b 1H)rsz.,.,.

[0734] F X Siilttt rarng maera.,

[0735] O1H NMR (400 MH DMSOd):ze-,

[0736] LCMSl A14 eampe:x.

[0737] N 6323 ( 3H) 750747 ( Fsm:-.,,..,

[0738] T (Mhd B) Pifii b 7hl1N(6tteorcaon reersecorocano:uyvy-- ---- 1H) 764 ( 1H J 718H)t=z,.,,.,

[0739] / 44489hdi flh (diflh)5fl2tt m pase graenasoromeoorozuxyu----.

[0740] 774 ( 1H) 789 (d 1H J A20 HN Om=.,,.,,

[0741] (ES) 186lhhhidi3l)idlii3ttt+ a comn cromaograp meoprnnoneuyxyyyz----.

[0742] 96H) 809 (d 1HJ 20H)z=z.,.,,., i (C18ili)ldlfidtt mn sca ee a sonameuu., 883 (d 1H J 72H) 1069=z.,,.,.

[0743] 0% 70% MCN i toen \ cr ( 1H)s,. taer w. N

[0744] o

[0745] ZU

[0746] A 1

[0747] " \ / /

[0748] A *i“ <£—“\

[0749] P < v # J

[0750] □

[0751]

[0752] Starting materials

[0753] intermediate 3 and CAS

[0754] 3026463-64-6. In route

[0755] B step 1 reaction was1H NMR: (400 MHz, DMSO-de) performed at room LCMS: 6: 3.39 (s, 3H), 4.12 (s, 2H), 7.11 7-chloro-3-(N-(6-(cyanomethyl)-5- x temperature for 16 h. In (Method B): (s, 1H), 7.35-7.32 (m, 1H), 7.67 fluoro-2-methoxypyridin-3- E followed route B step 2 coupling m / z 438.09 (d, 1H, J= 9.2Hz), 7.72 (s, 1H), A21

[0756] yl)sulfamoyl)indolizine-1 - by B agent was COMU and (ES+) at 1.58 7.93 (s, 1H), 8.47 (d, 1H, J= carboxamide ' A. purification by reverse min. 1.6Hz), 8.80 (d, 1H, J= 7.2Hz), cr A- AJ \ phase column 10.70 (s, 1H).

[0757] chromatography (C18

[0758] 0 silica), product eluted at

[0759] 0% to 95% MeCN in

[0760] water.

[0761] J. J Starting material1H NMR: (400 MHz, DMSO-de)

[0762] LCMS:

[0763] example A21. 6: 3.39 (s, 3H), 4.15 (s, 2H), 7-chloro-1 -cyano-N-(6- 0 (Method B):

[0764] Purification by normal 7.51-7.49 (m, 1H), 7.71 (d, 1H, (cyanomethyl)-5-fluoro-2- m / z 420.08

[0765] A22 C phase gradient flash J= 9.6Hz), 7.87 (s, 1H), 8.09 (d, methoxypyridin-3-yl)indolizine-3- (ES+) at 1.72

[0766] column chromatography 1H, J= 1.6Hz), 8.88 (d, 1H, J= sulfonamide AN A min.

[0767] cA^A (silica), eluted at 0% to 7.6Hz), 10.86 (s, 1H).

[0768] 56% EtOAc.

[0769] N

[0770]

[0771] Starting materials

[0772] LCMS:1H NMR: (400 MHz, DMSO-de) intermediate 3 and CAS

[0773] (Method B): 6: 7.13 (br s, 1H), 7.35-7.29 (m, 3-(N-(4-bromo-2,5- 112279-60-4. Route E

[0774] E, followed m / z 463.89 2H), 7.65 (t, 1H, J= 7.6Hz), A23 difluorophenyl)sulfamoyl)-7- performed at room

[0775] by B. (ES+) at 1.67 7.75 (s, 1H), 7.97 (s, 1H), 8.45 chloroindolizine-1 -carboxamide temperature for 16 h. In

[0776] min. (s, 1H), 8.73 (d, 1H, J= 7.6Hz), cK route B step 2 coupling

[0777] 11.04 (br s,1H).

[0778] agent was COMU.

[0779] 1H NMR: (400 MHz, DMSO-de) 6: 3.06 (s, 3H), 5.78 (s, 1H), 5.91 Starting materials

[0780] LCMS: (s, 1H), 6.76 (d, 1H, J= 7.6Hz), intermediates 3 and 6.

[0781] 7-chloro-3-(N-(5-fluoro-4- (Method B): 7.05 (br s, 1H), 7.22 (d, 1 H, J=

[0782] In route E the reaction

[0783] (fluoromethoxy)-2- E followed m / z 446.07 11.6Hz), 7.31-7.29 (dd, 1H, J= A24 was performed at room

[0784] methoxyphenyl)sulfamoyl)indolizine- by B. (ES+) at 1.79 7.2Hz, J= 2.0Hz), 7.68 (br s, temperature. In route B,

[0785] 1 -carboxamide min. 1H), 7.78 (s, 1H), 8.46 (s, 1H), step 2 the coupling

[0786] 8.77 (d, 1H, J= 7.6Hz), 10.21 (s, cK agent was COMU.

[0787] 1H).

[0788]

[0789] a I ( Xs Lk ss

[0790] 5

[0791] / / / / AO A o ' T "" "

[0792] 1

[0793] £ P

[0794]

[0795] A27, 7-chloro-N-(3,5-dh in-2-vl)-1-(1H-t

[0796] ‘-3-sulfonamide

[0797]

[0798] Example A32 Example A27

[0799] 1-bromo-7-chloro-N-(3,5-dimethoxypyrazin-2-yl) indolizine-3-sulfonamide (Example A32, 0.15 g, 0.34 mmol), 1H-pyrazole (0.46 g, 6.73 mmol) and K3PO4(0.36 g, 1.68 mmol) were dissolved in DMF (2 ml). N2 gas was purged through reaction mixture for 15 min at room temperature. After that, trans-N, N'-dimethylcyclohexane-1,2-diamine (0.10 ml, 0.67 mmol) and Cui (0.06 g, 0.34 mmol) were added and reaction mixture was stirred at 160 °C for 1.5 h under microwave irradiation. Reaction mixture was partitioned between water (60 ml) and EtOAc (60 ml). Aqueous layer was further extracted with EtOAc (2 x 40 ml). Organic layers were combined, dried (Na2SO4) and concentrated. The crude product was purified by reverse phase gradient flash column chromatography (C18 silica), product was eluted at 0% to 90% acetonitrile in water using 0.05% formic acid as modifier to afford 7-chloro-N-(3,5-dimethoxypyrazin-2-yl)-1-(1H-pyrazol-1-yl) indolizine-3-sulfonamide (0.01 g, 6.85%) as an off white solid.

[0800] LCMS: (Method B): m / z 435.2 (ES+) at 1.87 min.

[0801] 1H NMR: (400 MHz, DMSO-d₆) δ: 3.72 (s, 3H), 3.83 (s, 3H), 6.52 (t, 1H, J= 2.4Hz), 7.17-7.14 (m, 1H), 7.49 (s, 1H), 7.75 (s, 1H), 7.77 (d, 1H, J= 1.6Hz), 8.25 (d, 1H, J= 1.6Hz), 8.43 (d, 1H, J= 2.4Hz), 8.72 (d, 1H, J= 7.6Hz), 10.80 (s, 1H).

[0802]

[0803] A28, 7-chloro-N-(3,5-dii in-2-yl)- 1-(oxazol-2-' 3-sulfonamide

[0804]

[0805] Example A32 Example A28

[0806] 1-bromo-7-chloro-N-(3,5-dimethoxypyrazin-2-yl)indolizine-3-sulfonamide (Example A32, 0.20 g, 0.45 mmol) and 2-Tributylstannanyl-oxazole (0.80 g, 2.24 mmol) were dissolved in 1,4-dioxane (5 ml) at room temperature. To it, Pd(Ph3P)4(0.05 g, 0.04 mmol) was added and reaction mixture was irradiated to 150 °C for 1 h in the microwave. The reaction mixture was partitioned between water (50 ml) and EtOAc (50 ml). Aqueous layer was further extracted with EtOAc (2 x 30 ml). Solvent was removed in vacuo to afford crude, which was purified by reverse phase column chromatography (C18 silica), product was eluted at 0% to 45% MeCN in water using 0.05% formic acid as a modifier to afford 7-chloro-N-(3,5-dimethoxypyrazin-2-yl)-1-(oxazol-2-yl)indolizine-3-sulfonamide (0.021 g, 10.76%) as an off white solid.

[0807] LCMS: (Method B): m / z 436.21 (ES+) at 1.82 min.

[0808] 1H NMR: (400 MHz, DMSO-cfe) 6: 3.73 (s, 3H), 3.83 (s, 3H), 7.33-7.31 (m, 1H), 7.37 (s, 1H), 7.47 (s, 1H), 7.65 (s, 1H), 8.16 (s, 1H), 8.37 (d, 1H, J= 2.0Hz), 8.84 (d, 1H, J= 7.6Hz), 10.86 (s, 1H).

[0809] SynthesSynthesis of Examples, general procedures Example A29, 7-chloro-N-(3,5-dimethoxypyrazin-2-yl)-1-(1H-pyrazol-5-yl)indolizine-3-sulfonamide

[0810]

[0811] Example A 32 Example A29

[0812] 1-bromo-7-chloro-N-(3,5-dimethoxypyrazin-2-yl)indolizine-3-sulfonamide (Example A32, 0.20 g, 0.45 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.44 g, 2.24 mmol) were dissolved in 1,4-dioxane (2 ml). To it, 2M aqueous Na2CO3(1 ml) was added at room temperature. Nitrogen gas was purged through reaction mixture for 30 min at room temperature. After that, PdCl2(dppf) (0.01 g, 0.01 mmol) was added and reaction mixture was irradiated at 100 °C for 1.5 h in the microwave. Reaction mixture was partitioned between water (50 ml) and EtOAc (50 ml). Aqueous layer was further extracted with EtOAc (3 x 30 ml). Organic layers were combined, dried (Na2SO4) and concentrated. The crude product was purified by normal phase gradient column chromatography (silica), product eluted at 0% to 25% EtOAc in hexane to afford compound which was further purified by reverse phase gradient flash column chromatography (C18 silica), product was eluted at 0% to 42% acetonitrile in water to afford 7-chloro-N-(3,5-dimethoxypyrazin-2-yl)-1-(1H-pyrazol-5-yl)indolizine-3-sulfonamide (0.003 g, 1.54%) as a white solid.

[0813] LCMS: (Method B): m / z 435.21 (ES+) at 1.78 min.

[0814] 1H NMR: (400 MHz, MeOD) 5: 3.70 (s, 3H), 3.86 (s, 3H), 6.58 (d, 1H, J= 2.4Hz), 6.98 (d, 1H, J= 7.2Hz), 7.41 (s, 1 H), 7.58 (s, 1 H), 7.70 (s, 1 H), 8.24 (br s, 1 H), 8.83 (d, 1 H, J= 7.6Hz). SynthesSynthesis of Examples, general procedures Example A30, 7-chloro-N-(3,5-dimethoxypyrazin-2-yl)-1-(1H-pyrazol-4-yl)indolizine-3-sulfonamide

[0815] O'”

[0816]

[0817] H

[0818] Example A32 Example 30

[0819] 1-bromo-7-chloro-N-(3,5-dimethoxypyrazin-2-yl)indolizine-3-sulfonamide (Example A32, 0.25 g, 0.56 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.54 g, 2.80 mmol) were dissolved in 1,4-dioxane (2.5 ml). To it, 1M aqueous Na2CO3(2.5 ml) was added at room temperature. Nitrogen gas was purged through reaction mixture for 10 min at room temperature. After that, PdCl2(dppf) (0.02 g, 0.03 mmol) was added and reaction mixture was irradiated to 150 °C for 2 h in the microwave. Reaction mixture was partitioned between water (50 ml) and EtOAc (50 ml). Aqueous layer was further extracted with EtOAc (3 x 20 ml). Organic layers were combined, dried (Na2SO4) and concentrated. The crude product was purified by reverse phase gradient flash column chromatography (C18 silica), product was eluted at 0% to 35% MeCN in water. The product was further purified by prep HPLC (Method B) to afford 7-chloro-N-(3,5-dimethoxypyrazin-2-yl)-1-(1H-pyrazol-4-yl)indolizine-3-sulfonamide (4.1 mg, 1.68%) as an off white solid.

[0820] LCMS: (Method B): m / z 435.23 (ES+) at 1.74 min.

[0821] 1H NMR: (400 MHz, MeOD) 5: 3.72 (s, 3H), 3.87 (s, 3H), 6.94-6.92 (m, 1H), 7.41 (s, 1H), 7.43 (s, 1H), 7.79 (d, 1H, J= 1.2Hz), 7.91 (br s, 2H), 8.81 (d, 1H, J= 7.6Hz).

[0822] SynthesSynthesis of Examples, general procedures Example A31, 7-chloro-N-(3, 5-dimethoxypyrazin-2-yl)- 1-(isoxazol-4-yl)indolizine-3-sulfonamide

[0823] OMe

[0824]

[0825] Example A32 Example 31

[0826] 1-bromo-7-chloro-N-(3,5-dimethoxypyrazin-2-yl)indolizine-3-sulfonamide (Example A32, 0.11 g, 0.25 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (0.06 g, 0.32 mmol) and Na2CC>3 solution (1M in H2O, 0.60 ml) were dissolved in MeCN (3 ml). N2 gas was purged through reaction mixture for 15 min at room temperature. After this, PdCl2(dppf) (0.03 g, 0.05 mmol) was added and reaction mixture was irradiated to 100 °C for 15 min in microwave. The reaction mixture was partitioned between water (70 ml) and EtOAc (70 ml). Aqueous layer was further extracted with EtOAc (2 x 50 ml). Organic layers were combined, dried (Na2SO4) and concentrated. The crude product was purified by normal phase gradient flash column chromatography (silica), product eluted at 0% to 30% EtOAc in hexane to afford 7-chloro-N-(3,5-dimethoxypyrazin-2-yl)-1-(isoxazol-4-yl)indolizine-3-sulfonamide (2.41 mg, 2.25%) as a brown solid.

[0827] LCMS: (Method B): m / z 436.09 (ES+) at 1.72 min.

[0828] 1H NMR: (400 MHz, MeOD) 5: 3.74 (s, 3H), 3.87 (s, 3H), 7.02-6.99 (m, 1H), 7.39 (s, 1H), 7.57 (s, 1H), 7.86 (d, 1H, J= 1.2Hz), 8.23 (s, 1H), 8.85 (d, 1H, J= 7.6Hz), 9.11 (s, 1H).

[0829] SynthesSynthesis of Examples, general procedures Example A32, 1-bromo-7-chloro-N-(3.5-dimethoxypyrazin-2-yl)indolizine-3-sulfonamide

[0830]

[0831] Intermediate 11

[0832] Example A32

[0833] Step 1; 7-chloroindolizine-3-sulfonamide (Intermediate 11, 0.80 g, 3.48 mmol), 2-bromo-3,5-dimethoxypyrazine (CAS 1033610-34-2, 0.99 g, 4.52 mmol) and K2CO3(1.44 g, 10.44 mmol) were dissolved in MeCN (15 ml). Nitrogen gas was purged through reaction mixture for 15 min at room temperature. After that, trans-N, N'-dimethylcyclohexane-1,2-diamine (0.65 ml, 4.17 mmol) and Cui (0.33 g, 1.74 mmol) were added and reaction mixture was stirred at 80 °C for 16h. Reaction mixture was partitioned between water (30 ml) and EtOAc (30 ml). The aqueous layer was further extracted with EtOAc (3 x 30 ml). Organic layers were combined, dried (Na2SO4) and concentrated. The crude was purified by reverse phase gradient flash column chromatography (C18 silica), product eluted at 0% to 58% MeCN in water using 0.1% formic acid as a modifier to afford 7-chloro-N-(3,5-dimethoxypyrazin-2-yl)indolizine-3-sulfonamide (0.80 g, 62.50%) as a brown solid.

[0834] LCMS: (Method A): m / z 369 (ES+) at 2.304 min

[0835] Step 2; 7-chloro-N-(3,5-dimethoxypyrazin-2-yl) indolizine-3-sulfonamide (0.35 g, 0.95 mmol) was dissolved in THF (5 ml). To it, NBS (0.18 g, 1.04 mmol) was added at room temperature and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was partitioned between water (70 ml) and EtOAc (60 ml). The aqueous layer was further extracted with EtOAc (2 x 50 ml). Organic layers were combined, dried (Na2SO4) and concentrated. The crude was purified by normal phase gradient flash column chromatography (silica), product eluted at 0% to 30% EtOAc in hexane to afford 1-bromo-7-chloro-N-(3,5-dimethoxypyrazin-2-yl) indolizine-3-sulfonamide (0.15 g, 35.36%) as a brown sticky material.

[0836] LCMS: (Method A): m / z 447.0 (ES+), at 2.332min.

[0837] SynthesSynthesis of Examples, general procedures Example A33, N-(6-(cyanomethyl)-5-fluoro-2-methoxypyridin-3-yl)-7-cyclopropyl- 1-( 1H-pyrazol- 1-yl)indolizine-3-sulfonamide

[0838]

[0839] Step 1; N-(6-(cyanomethyl)-5-fluoro-2-methoxypyridin-3-yl)-7-cyclopropylindolizine-3-sulfonamide (Example B5, 0.10 g, 0.25 mmol) was dissolved in THF (1 ml). Pyridinium tribromide (0.13 g, 0.50 mmol) was added at -10 °C. The reaction mixture was stirred at -10 °C for 10 min. The reaction mixture was partitioned between water (100 ml) and EtOAc (100 ml). Aqueous layer was further extracted with EtOAc (2 x 50 ml). Organic layers were combined and dried (Na2SO4) to afford crude product which was purified by normal phase gradient flash column chromatography (silica), product eluted at 0% to 25% EtOAc in hexane to afford 1-bromo-N-(6-(cyanomethyl)-5-fluoro-2-methoxypyridin-3-yl)-7-cyclopropyl-indolizine-3-sulfonamide (0.06 g, 50.22%) as a brown solid.

[0840] LCMS: (Method A): m / z 479.0 (ES+) at 2.102 min.

[0841] Step 2; 1-bromo-N-(6-(cyanomethyl)-5-fluoro-2-methoxypyridin-3-yl)-7-cyclopropylindolizine-3-sulfonamide (0.04 g, 0.08 mmol), 1H-pyrazole (0.06 g, 0.83 mmol) and K2CO3(0.03 g, 0.25 mmol) were dissolved in MeCN (0.4 ml). N2 gas was purged through reaction mixture for 15 min at room temperature. trans-N, N'-dimethylcyclohexane-1,2-diamine (0.02 ml, 0.10 mmol) and Cui (0.01 g, 0.04 mmol) were added and the reaction mixture was irradiated to 90 °C for 1 h in the microwave. The reaction mixture was partitioned between water (100 ml) and EtOAc (100 ml). Aqueous layer was further extracted with EtOAc (2 x 50 ml). Organic layers were combined and dried (Na2SO4). The crude was purified by reverse phase gradient flash column chromatography (C18 silica), product eluted at 0% to 60% MeCN in water to afford N-(6-(cyanomethyl)-5-fluoro-2-methoxypyridin-3-yl)-7-cyclopropyl-1-(1H-pyrazol-1-yl)indolizine-3-sulfonamide (0.07 g, 17.95%) as a light brown solid.

[0842] LCMS: (Method B): m / z 467.26 (ES+) at 1.92 min.

[0843] 1H NMR: (400 MHz, DMSO-cfe) 6: 0.78-0.82 (m, 2H), 1.01-1.44 (m, 2H), 2.04-2.08 (m, 1H), 3.48 (s, 3H), 4.07 (s, 2H), 6.48 (t, 1H, J= 2.0Hz), 6.76 (d, 1H, J= 6.8Hz), 7.60-7.63 (m, 2H), 7.73 (d, 1H, J= 1.6Hz), 7.84 (s, 1H), 8.27 (d, 1H, J= 2.4Hz), 8.64 (d, 1H, J= 7.2Hz), 10.59 (s, 1H). SynthesSynthesis of Examples, general procedures Example A34, N-(4-(cyanomethyl)-5-fluoro-2-methoxyphenyl)-7-cyclopropyl-1- ( 1H-pyrazol- 1-yl)indolizine-3-sulfonamide

[0844] Step 1 Step 2

[0845]

[0846] Example B6 Example A34 Prepared in a similar 2-step fashion to example A33, using as starting material Example B6 to afford N-(4-(cyanomethyl)-5-fluoro-2-methoxyphenyl)-7-cyclopropyl-1-(1 H-pyrazol-1-yl)indolizine-3-sulfonamide (0.008 g, 4.83%) as a white solid.

[0847] LCMS: (Method B): m / z 400.27 (ES+) at 2.01 min.

[0848] 1H NMR: (400 MHz, DMSO-d₆) δ: 0.77-0.81 (m, 2H), 1.00-1.04 (m, 2H), 2.01-2.08 (m, 1H), 3.27 (s, 3H), 3.89 (s, 2H), 6.44-6.47 (m, 1H), 6.72 (d, 1H, J= 6.0Hz), 6.87 (d, 1H, J= 6.8Hz), 7.16 (d, 1H, J= 10.8Hz), 7.51 (s, 1H), 7.71 (s, 1H), 7.82 (s, 1H), 8.25 (d, 1H, J= 2.4Hz), 8.63 (d, 1H, J= 7.6Hz), 10.25 (bs, 1H).

[0849] SynthesSynthesis of Examples, general procedures Example B1, 7-cyclopropyl-N-(3,5-dimethoxypyrazin-2-yl)indolizine-3-sulfonamide

[0850]

[0851] Example B1

[0852] Step 1; 7-bromoindolizine-2-carboxylic acid (CAS 1206981-92-1, 11.00 g, 46.03 mmol) and quinoline (55 ml) were dissolved in NMP (165 ml). Nitrogen gas was purged through reaction mixture for 10 min at room temperature. To it, CU2O (0.66 g, 4.60 mmol) and 4,7-diphenyl-1,10-phenanthroline (3.06 g, 9.21 mmol) were added at room temperature. Again, nitrogen gas was purged through reaction mixture for 10 min at room temperature. The reaction mixture was then irradiated at 200 °C for 1 h in the microwave. The reaction mixture was diluted with water (150 ml) and extracted with EtOAc (130 ml). Aqueous layer was further extracted with EtOAc (2 x 100 ml). Organic layers were combined, dried (Na2SO4) and concentrated. The crude was purified by normal phase gradient column chromatography (silica), product was eluted at 0% to 8% EtOAc in hexane to afford 7-bromoindolizine (3.70 g, 41.22%) as a brown sticky solid.

[0853] Note: Reaction was carried out in 22 divided batches on 0.50 g scale (22 x 0.50 g= 11.00 g). Workup and purification were done after combining all the batches.

[0854] TLC: (3:7; EtOAc / Hexane, Rf: 0.8).

[0855] LCMS: (Method A): m / z 196.08 (ES+), at 2.350 min.

[0856] Step 2; 7-bromoindolizine (3.70 g, 18.97 mmol), cyclopropyl boronic acid (4.07 g, 47.44 mmol) and K3PO4(10.07 g, 47.44 mmol) were dissolved in toluene (50 ml) and water (10 ml). Nitrogen gas was purged through reaction mixture at room temperature for 15 min. To it, Pd(OAc)2 (1.28 g, 1.90 mmol) and PCy₃ (1.06 g, 3.79 mmol) were added. The reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was diluted with water (100 ml) and extracted with EtOAc (80 ml). Aqueous layer was further extracted with EtOAc (2 x 80 ml). Organic layers were combined, dried (Na2SO4) and concentrated. The crude product was purified by normal phase gradient flash column chromatography (silica), product was eluted at 0% to 8% EtOAc in hexane to afford 7-cyclopropylindolizine (2.00 g, 67.08%) as a brown solid.

[0857] TLC: (1:9; EtOAc / Hexane, Rf: 0.8)

[0858] LCMS: (Method B): m / z 158.20 (ES+), at 1.76 min.

[0859] Step 3; 7-cyclopropylindolizine (2.00 g, 12.74 mmol) was dissolved in THF (30 ml). To it, Burgess reagent (3.33 g, 14.00 mmol) was added at room temperature and reaction mixture was stirred at room temperature for 48 h. The reaction mixture was diluted with water (100 ml) and extracted with EtOAc (80 ml). Aqueous layer was further extracted with EtOAc (2 x 80 ml). Organic layers were combined, dried (Na2SO4) and concentrated. The crude product (and regioisomer) was purified by normal phase gradient flash column chromatography (silica), product was eluted at 0% to 40% EtOAc in hexane to afford methyl ((7-cyclopropylindolizin-3-yl)sulfonyl)carbamate (0.50 g, 13.35%) as brown solid.

[0860] LCMS: (Method A): m / z 295.10 (ES+), at 1.669 min.1H NMR: (400 MHz, MeOD) 6: 8.67 - 8.61 (m, 1H), 7.43 (d, J= 4.5 Hz, 1H), 7.37 - 7.30 (m, 1 H), 6.64 (dd, J = 7.4, 1.9 Hz, 1 H), 6.44 (dd, J = 4.6, 0.8 Hz, 1 H), 3.61 (s, 3H), 1.98 (tt, J = 8.4, 5.0 Hz, 1H), 1.10 - 1.01 (m, 2H), 0.85 - 0.77 (m, 2H).

[0861] Step 4; Methyl ((7-cyclopropylindolizin-3-yl)sulfonyl)carbamate (0.50 g, 1.70 mmol) was dissolved in pyridine (3 ml) and water (3 ml). Reaction mixture was stirred at 100 °C for 4 h. The reaction mixture was concentrated to afford crude, which was purified by reverse phase gradient flash column chromatography (reverse phase), product was eluted at 0% to 40% MeCN in water to afford 7-cyclopropylindolizine-3-sulfonamide (0.38 g, 94.67%) as a brown solid.

[0862] LCMS: (Method A): m / z 237.11 (ES+), at 1.492 min.

[0863] 1H NMR: (400 MHz, DMSO-d₆) δ: 0.78-0.74 (m, 2H), 1.01-0.96 (m, 2H), 1.99-1.94 (m, 1H), 6.36 (d, 1H, J= 4.0Hz), 6.65-6.63 (dd, 1H, J= 7.6Hz and J= 2.0Hz), 7.16 (d, 1H, J= 4.4Hz), 7.37 (s, 1H), 7.52 (s, 2H), 8.42 (d, 1H, J= 7.6Hz).

[0864] Step 5; 7-cyclopropylindolizine-3-sulfonamide (0.10 g, 0.42 mmol), 2-bromo-3,5- dimethoxypyrazine (CAS 1033610-34-2, 0.10 g, 0.46 mmol) and K2CO3 (0.17 g, 1.27 mmol) were dissolved in MeCN (5 ml). Nitrogen gas was purged through reaction mixture for 15 min at room temperature. After this, trans-N, N'-dimethylcyclohexane-1,2-diamine (0.10 ml, 0.63 mmol) and Cui (0.04 g, 0.21 mmol) were added and reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was partitioned between water (60 ml) and EtOAc (50 ml). Aqueous layer was further extracted using EtOAc (2 x 40 ml). Organic layers were combined, dried (Na2SO4) and concentrated. The crude product was purified by normal phase gradient flash column chromatography (silica), product eluted at 0% to 40% EtOAc in hexane to afford 7- cyclopropyl-N-(3,5-dimethoxypyrazin-2-yl)indolizine-3-sulfonamide (0.065 g, 41.03%) as an off white solid.

[0865] LCMS: (Method B): m / z 375.17 (ES+) at 1.82 min.

[0866] 1H NMR: (400 MHz, DMSO-d₆) δ: 0.80-0.76 (m, 2H), 1.02-0.97 (m, 2H), 2.00-1.96 (m, 1H), 3.65 (s, 3H), 3.83 (s, 3H), 6.34 (d, 1H, J= 4.4Hz), 6.69-6.67 (dd, 1H, J= 7.6Hz and J= 1.6Hz), 7.16 (d, 1H, J= 4.4Hz), 7.38 (s, 1H), 7.46 (s, 1H), 8.59 (d, 1H, J= 7.2Hz), 10.37 (s, 1H).

[0867]

[0868] Synthesis of Example B2, 7-chloro-N-(3,5-dimethoxypyrazin-2-yl)-8-fluoroindolizine-3-sulfonamide

[0869]

[0870] Step 1; 4-chloro-3-fluoropicolinaldehyde (CAS 1260878-78-1, 8.50 g, 53.46 mmol) was dissolved in dioxane (50 ml) and water (35 ml). To it, methyl acrylate (12.54 ml, 160.39 mmol) and DABCO (0.60 g, 5.35 mmol) were added sequentially at room temperature. Reaction mixture was stirred at 60 °C for 16 h. The reaction mixture was partitioned between water (450 ml) and EtOAc (450 ml). Aqueous layer was further extracted with EtOAc (2 x 400 ml). Organic layers were combined, dried (Na2SO4) and concentrated. The crude was purified by normal phase gradient flash column chromatography (silica), product was eluted at 0% to 12% EtOAc in hexane to afford methyl 2-((4-chloro-3-fluoropyridin-2-yl)(hydroxy)methyl)acrylate (2.30 g, 17.56%) as a brown solid.

[0871] TLC: (2:8; EtOAc / Hexane, Rf: 0.3).

[0872] LCMS: (Method A): m / z 246.06 (ES+) at 1.269min.

[0873] Step 2; methyl 2-((4-chloro-3-fluoropyridin-2-yl)(hydroxy)methyl)acrylate (2.30 g, 9.39 mmol) was dissolved in DCM (20 ml). To it, pyridine (1.24 ml, 14.08 mmol) was added and reaction mixture stirred for 15 min. After this, acetyl chloride (1.00 ml, 14.00mmole) was added dropwise at 0 °C and reaction mixture was stirred at room temperature for 30 min. Reaction mixture was diluted with water (150 ml) and extracted with EtOAc (150 ml). Aqueous layer was further extracted with EtOAc (2 x 100 ml). Organic layers were combined, dried (Na2SO4) and concentrated to afford methyl 2-(acetoxy(4-chloro-3-fluoropyridin-2-yl)methyl)acrylate (2.30 g, 85.36%) as a brown sticky solid. TLC: (3:7, EtOAc / Hexane, Rf: 0.5).

[0874] LCMS: (Method A): m / z 288.10 (ES+) at 1.520 min

[0875] Step 3; Methyl 2-(acetoxy(4-chloro-3-fluoropyridin-2-yl)methyl)acrylate (2.30 g, 8.01 mmol) was dissolved in toluene (50 ml). Reaction mixture was stirred at 100 °C for 16 h. Solvent was removed in vacuo to afford crude which was purified by normal phase gradient flash column chromatography (silica), product was eluted at 0% to 12% EtOAc in hexane to afford methyl 7-chloro-8-fluoroindolizine-2-carboxylate (0.50 g, 27.49%) as an off white solid.

[0876] TLC: (2:8; EtOAc / Hexane, Rf: 0.6).

[0877] LCMS: (Method A): m / z 228.10 (ES+) at 1.820 min.

[0878] Step 4; methyl 7-chloro-8-fluoroindolizine-2-carboxylate (0.50 g, 2.20 mmol) was dissolved in THF (5 ml) and water (5 ml). To it, lithium hydroxide monohydrate (0.18 g, 4.40 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. Reaction mixture was concentrated in vacuo. Crude product was partitioned between water (70 ml) and EtOAc (70 ml). The aqueous layer was extracted with EtOAc (2 x 60 ml). Combined organic layers were discarded. The aqueous layer was then acidified with aqueous 1N HCI solution (4 ml) up to pH ~4. The aqueous layer was further extracted with EtOAc (2 x 70 ml). Organic layers were combined, dried (Na2SO4) and concentrated to afford 7-chloro-8-fluoroindolizine-2-carboxylic acid (0.40 g, 85.26%) as an off white solid.

[0879] TLC: (1:9; MeOH / DCM, Rf: 0.2)

[0880] 1H NMR: (400 MHz, DMSO-d₆) δ: 12.68 (s, 1H), 8.29 - 8.15 (m, 2H), 6.88 -6.76 (m, 2H). Step 5; 7-chloro-8-fluoroindolizine-2-carboxylic acid (0.40 g, 1.87 mmol) was dissolved in quinoline (2.5 ml) and NMP (7.5 ml). Nitrogen gas was purged through reaction mixture for 15 min at room temperature. After this, CU2O (0.013 g, 0.093 mmol) and 4,7-Diphenyl-1,10-phenanthroline (0.062 g, 0.18 mmol) were added at room temperature. Again, nitrogen gas was purged through reaction mixture for 15 min and reaction mixture was irradiated to 200 °C for 1 h in the microwave. The reaction mixture partitioned between water (70 ml) and EtOAc (100 ml). Aqueous layer was further extracted with EtOAc (2 x 50 ml). Organic layers were combined, dried (Na2SO4) and concentrated. The crude product was purified by normal phase gradient column chromatography (silica), product eluted at 0% to 12% EtOAc in hexane to afford 7-chloro-8-fluoroindolizine (0.20 g, 63.01%) as a brown solid.

[0881] LCMS: (Method A): Product mass was not observed in major peak at 1.896min.

[0882] 1H NMR: (400 MHz, DMSO-d₆) δ: 6.58 (d, 1H, J= 3.6Hz), 6.67 (t, 1H, J= 7.2Hz), 6.84 (t, 1H, J= 3.2Hz), 7.72 (brs, 1H), 8.22 (d, 1H, J= 7.2Hz). Step 6; 7-chloro-8-fluoroindolizine (1.25 g, 7.39 mmol) was dissolved in THF (15 ml). To it, Burgess reagent (1.93 g, 8.13 mmol) was added at room temperature and reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water (100 ml) and extracted with EtOAc (80 ml). Aqueous layer was further extracted using EtOAc (2 x 70 ml). Organic layers were combined dried (Na2SO4) and concentrated. The crude product (containing regioisomer) was purified by normal phase gradient flash column chromatography (silica), product was eluted at 0% to 30% EtOAc in hexane to afford methyl ((7-chloro-8-fluoroindolizin-3-yl)sulfonyl)carbamate (0.50 g, 22.09%) as a brown solid.

[0883] LCMS: (Method A): m / z 305.00 (ES-), at 1.608 min.

[0884] 1H NMR: (400 MHz, DMSO-d₆) δ: 8.51 (d, J= 7.4 Hz, 1H), 7.51 (d, J= 4.6 Hz, 1H), 7.25 (t, J = 7.4 Hz, 1H), 6.84 (d, J= 4.6 Hz, 1H), 3.55 (s, 3H).

[0885] Step 7; methyl ((7-chloro-8-fluoroindolizin-3-yl)sulfonyl)carbamate (0.50 g, 1.63 mmol) was dissolved in pyridine (3 ml) and water (3 ml). Reaction mixture was stirred at 100 °C for 16 h. Reaction mixture was concentrated in vacuo to afford crude, which was purified by normal phase gradient flash column chromatography (silica), product was eluted at 0% to 28% EtOAc in hexane to afford 7-chloro-8-fluoroindolizine-3-sulfonamide (0.06 g, 14.80%) as a brown solid.

[0886] LCMS: (Method A): m / z 246.90 (ES+), at 2.040 min.

[0887] Step 8; Prepared in a similar fashion to Route A, using starting material CAS 1033610-34-2. LCMS: (Method B): m / z 386.93 (ES+) at 1.79 min.

[0888] 1H NMR: (400 MHz, DMSO-d₆) δ: 3.72 (s, 3H), 3.85 (s, 3H), 6.75 (d, 1H, J= 4.4Hz), 7.17 (t, 1H J= 7.2Hz), 7.32 (d, 1H, J= 4.4Hz), 7.47 (s, 1H), 8.57 (d, 1H, d= 7.6Hz), 10.71 (s, 1H). SynthesSynthesis of Examples, general procedures Example B3, 2-chloro-N-(5-fluoro-2.6-dimethoxypyridin-3-yl)pyrrolo[1.2-a ]p yrimidine- 6-sulfonamide

[0889] P O

[0890]

[0891] Intermediate B1 Example B3 Step 1; A solution of 6-(chlorosulfonyl)-2-oxo-1,2-dihydropyrrolo[1,2-a]pyrimidine-8-carboxylic acid (Intermediate B1, 1 g, 3.61 mmol) and 5-fluoro-2,6-dimethoxypyridin-3-amine (CAS 2407470-86-2, 0.311 g, 1.807 mmol) in Pyridine (5 ml) was stirred at 100 °C for 8 h. The reaction mixture was concentrated, diluted with water and extracted with ethyl acetate. Extracted organic layer was dried (NaSO₄) and concentrated. The crude product was purified by normal phase gradient flash column chromatography (silica), product eluted at 40% EtOAc in petroleum ether to afford N-(5-fluoro-2,6-dimethoxypyridin-3-yl)-2-oxo-1,2-dihydropyrrolo[1,2-a]pyrimidine-6-sulfonamide (5 mg, 0.011 mmol, 0.3%) as a brown solid.

[0892] 1H NMR: (400 MHz, DMSO-d₆) δ: 12.14 (s, 1H), 9.85 (s, 1H), 8.47 (d, J = 8.00 Hz, 1H), 7.56 (d, J = 10.00 Hz, 1H), 6.74 (d, J = 4.00 Hz, 1H), 6.17 (d, J = 8.00 Hz, 1H), 5.56 (d, J = 3.60 Hz, 1H), 3.89 (s, 3H), 3.33 (s, 3H).

[0893] Step 2; A solution of N-(5-fluoro-2,6-dimethoxypyridin-3-yl)-2-oxo-1,2-dihydropyrrolo[1,2-a]pyrimidine-6-sulfonamide (100 mg, 0.271 mmol) in POCh (4 ml, 42.9 mmol) was stirred at 70 °C for 2 h. The reaction mixture was quenched with ice, extracted with ethyl acetate and the organic layer was washed with saturated sodium bicarbonate, dried (Na2SO4) and concentrated. The crude was purified by normal phase gradient flash column chromatography (silica), product eluted at 15% EtOAc in petroleum ether to afford 2-chloro-N-(5-fluoro-2,6-dimethoxypyridin-3-yl)pyrrolo[1,2-a]pyrimidine-6-sulfonamide (27 mg, 0.069 mmol, 25%) as a pale yellow solid.

[0894] LCMS: (Method B): m / z 387.21 (ES+) at 1.78 min.

[0895] 1H NMR: (400 MHz, DMSO-d₆) δ: 10.15 (s, 1H), 8.99 (d, J = 8.0 Hz, 1H), 7.61 (d, J = 10.0 Hz, 1H), 7.32 (d, J = 7.6 Hz, 1H), 7.27 (d, J = 4.4 Hz, 1H), 6.58 (d, J = 5.2 Hz, 1H), 3.86 (s, 3H), 3.16 (s, 3H).

[0896] SynthesSynthesis of Examples, general procedures Example B4, N-(4-bromo-2, 5-difluorophenyl)-2-chloropyrrolo[ 1,2-alpyrimidine-6-sulfonamide

[0897] Br

[0898] *

[0899] FV--F

[0900] Jr" ”

[0901] HiM P

[0902] /

[0903]

[0904] Example B4

[0905] Prepared in a similar fashion to example B3, using as starting materials intermediate B1 and CAS 112279-60-4. (In step 1, purification was by normal phase gradient flash column chromatography (silica), product eluted at 2% MeOH in DCM)

[0906] LCMS: (Method B): m / z 420.02 (ES+) at 1.62 min.1H NMR: (400 MHz, DMSO-d₆) δ: 10.92 (s, 1H), 8.99 (d, J = 0.80 Hz, 1H), 7.71-7.67 (m, 1H), 7.53 (d, J = 4.40 Hz, 1H), 7.33-7.30 (m, 2H), 6.65 (d, J = 4.00 Hz, 1H).

[0907] SynthesSynthesis of Examples, general procedures Example B5, N-(6-(cvanomethyl)-5-fluoro-2-methoxypyridin-3-yl)-7-cvclopropylindolizine-3-sulfonamide

[0908]

[0909] Example B5

[0910] Step 1; methyl 3-(chlorosulfonyl)-7-cyclopropylindolizine-1-carboxylate (Intermediate 13, 1.00 g, 3.19 mmol) and 2-(5-amino-3-fluoro-6-methoxypyridin-2-yl)acetonitrile (CAS 3026463-64-6, 0.67 g, 3.83 mmol) were dissolved in pyridine (10 ml). The reaction was stirred at rt for 4 h. Reaction mixture was partitioned between water (300 ml) and EtOAc (300 ml). Aqueous layer was further extracted with EtOAc (2 x 150 ml). Organic layers were combined and dried (Na2SO4). The crude was purified by normal phase gradient flash column chromatography (silica), product eluted at 0% to 50% EtOAc in hexane to afford methyl 3-(N-(6-(cyanomethyl)-5-fluoro-2-methoxypyridin-3-yl)sulfamoyl)-7-cyclopropylindolizine-1 -carboxylate (0.80 g, 54.68%) as a brown solid.

[0911] LCMS: (Method A): m / z 458.10 (ES+) at 1.815 min.

[0912] Step 2; Methyl 3-(N-(6-(cyanomethyl)-5-fluoro-2-methoxypyridin-3-yl)sulfamoyl)-7-cyclopropylindolizine-1-carboxylate (0.80 g, 1.74 mmol) was dissolved in THF: MeOH:water (10 mL, ratio 6:2:2). Lithium hydroxide monohydrate (2.21 g, 12.22 mmol) was added and the reaction mixture was stirred at 60 °C for 16 h, then concentrated. The crude product was partitioned between water (100 ml) and EtOAc (100 ml). The aqueous layer was extracted with EtOAc (2 x 50 ml). Combined organic layer was discarded. The aqueous layer was then acidified with 1N HCI solution (15 ml) up to pH ~4. The aqueous layer was further extracted with EtOAc (2 x 100 ml). Organic layers were combined and dried (Na2SO4). The crude was purified by reverse phase gradient flash column chromatography (C18 silica), product eluted at 0% to 50% MeCN in water to afford 3-(N-(6-(cyanomethyl)-5-fluoro-2-methoxypyridin-3-yl)sulfamoyl)-7-cyclopropylindolizine-1 -carboxylic acid (0.30 g, 38.68%) as a brown solid. LCMS: (Method A): m / z 445.10 (ES+) at 1.512 min.

[0913] Step 3; 3-(N-(6-(cyanomethyl)-5-fluoro-2-methoxypyridin-3-yl)sulfamoyl)-7-cyclopropyl-indolizine-1-carboxylic acid (0.10 g, 0.23 mmol) was dissolved in TFA (1 ml). The reaction mixture was stirred under nitrogen atmosphere for 30 min at 60 °C. The reaction mixture was basified by saturated aqueous NaHCCh solution (10 ml) up to pH~9, then partitioned between water (100 ml) and EtOAc (100 ml). Organic layer was dried (Na2SO4) to give crude product which was purified by reverse phase gradient flash column chromatography (C18 silica), product eluted at 0% to 50% MeCN in water to afford N-(6-(cyanomethyl)-5-fluoro-2-methoxypyridin-3-yl)-7-cyclopropylindolizine-3-sulfonamide (0.035 g, 38.84%) as a light brown solid.

[0914] LCMS: (Method B): m / z 401.24 (ES+) at 1.99 min.

[0915] 1H NMR: (400 MHz, DMSO-d₆) δ: 0.77-0.80 (m, 2H), 0.98-1.03 (m, 2H), 1.97-2.01 (m, 1H), 3.46 (s, 3H), 4.08 (s, 2H), 6.33 (d, 1H, J= 4.4Hz), 6.72-6.74 (m, 1H), 7.22 (d, 1H, J= 4.4Hz), 7.39 (s, 1H), 7.54 (d, 1H, J= 9.6Hz), 8.61 (d, 1H, J= 7.6Hz), 10.41 (s, 1H).

[0916] SynthesSynthesis of Examples, general procedures Example B6, N-(4-(cyanomethyl)-5-fluoro-2-methoxyphenyl)-7-cyclopropylindolizine-3-sulfonamide

[0917]

[0918] Performed in a similar 2-step fashion to Example B5, using starting materials Intermediates 13 and 5 to afford N-(4-(cyanomethyl)-5-fluoro-2-methoxyphenyl)-7-cyclopropylindolizine-3-sulfonamide (0.027 g, 29.97%) as a white solid.

[0919] LCMS: (Method B): m / z 400.27 (ES+) at 2.01 min.1H NMR: (400 MHz, DMSO-d₆) δ: 0.76-0.80 (m, 2H), 0.97-1.02 (m, 2H), 1.95-1.99 (m, 1H), 3.27 (s, 3H), 3.91 (s, 2H), 6.29 (d, 1H, J= 4.4Hz), 6.68-6.70 (m, 1H), 6.87 (d, 1H, J= 6.8Hz), 7.08-7.13 (m, 2H), 7.36 (s, 1H), 8.60 (d, 1H, J= 7.2Hz), 10.03 (s, 1H).

[0920] Biological Data

[0921] Human GPR17 blockade functional IP-one Gq assay

[0922] U2OS cells (obtained from the American Tissue Culture Collection, ATCC) were infected for 24 h with 1% v / v human long form GPR17 expressing BacMam virus. Following BacMam infection cells were pelleted by centrifugation (335 g, 5 min), resuspended in freezing medium (FBS + 10% DMSO) and frozen at -150 °C until required.

[0923] On experiment day, a serial dilution of GPR17 antagonists, high (DMSO) and low (IC100 reference GPR17 antagonist, CAS number 2231230-59-2 (prepared according to the procedure described in WO2018122232A1), 3uM controls, agonist control (starting at 30 uM), and agonist EC80 MDL29951 (1uM) (Cambridge Bioscience) were prepared in DMSO and stamped into proxiplates (PerkinElmer) by a LabCyte ECHO acoustic dispenser.

[0924] Frozen cells were thawed and resuspended in assay stimulation buffer (Revvity) to achieve a density of 2500 cells per well. 14 uL cells were added to assay plates stamped above using a Multidrop Combi Reagent Dispenser (ThermoFisher) before centrifugation (335 g, 1 min). Cells were incubated with compounds at 37°C for 2 h prior to addition of IP-one detection reagents (IP-one Gq kit, Revvity) which were prepared according to the manufacturer’s instructions. Plates were incubated for 1 h at room temperature before reading on a PHERAstar FS plate reader (BMG) using standard HTRF settings. HTRF ratios were obtained by dividing the acceptor emissions (665 nm) by the donor emissions (620 nm) and multiplying by 10,000. Data were normalised to IC100 response from reference GPR17 antagonist and EC80 concentration of MDL29951 and fit to a 4-parameter logistical fit to generate fpKb values which are presented in Table A below wherein fpKb values refer to functional pKb, where pKb = -log10(Kb) and Kb is the binding constant.

[0925] Table A - GPR17 in vitro functional activity

[0926] GPR17 GPR17 Example number Example number

[0927] fpKb fpKb

[0928] A1 7.18 A21 8.76 A2 7.26 A22 8.77 A3 7.64 A23 7.64 A4 7.71 A24 8.39 A5 7.97 A25 7.74 A6 7.95 A26 8.57

[0929]

[0930] A7 9.21 A27 8.00 A8 6.85 A28 7.34 A9 7.19 A29 8.33 A10 7.81 A30 8.00 A11 9.10 A31 8.00 A12 9.24 A33 8.27 A13 9.14 A34 8.04 A14 8.83 B1 7.51 A15 6.92 B2 8.08 A16 8.72 B3 7.42 A17 9.34 B4 6.90 A18 9.08 B5 8.53 A19 8.91 B6 8.41

[0931]

[0932] A20 8.57

[0933] While specific embodiments of the invention have been described herein for the purpose of reference and illustration, various modifications will be apparent to a person skilled in the art without departing from the scope of the invention as defined by the appended claims.

[0934] REFERENCES

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[0936] (2) Simon K et al. The Orphan Receptor GPR17 Is Unresponsive to Uracil Nucleotides and Cysteinyl Leukotrienes. Mol Pharmacol. 2017 May;91(5):518-532. doi: 10.1124 / mol.116.107904.

[0937] (3) Qi AD et al. Is GPR17 a P2Y / leukotriene receptor? examination of uracil nucleotides, nucleotide sugars, and cysteinyl leukotrienes as agonists of GPR17. J Pharmacol Exp Ther. 2013 Oct; 347(1): 38-46. doi: 10.1124 / jpet.113.207647.

[0938] (4) Simon K et al. The Orphan G Protein-coupled Receptor GPR17 Negatively Regulates Oligodendrocyte Differentiation via Gai / o and Its Downstream Effector Molecules. J Biol Chem. 2016 Jan 8;291(2):705-18. doi: 10.1074 / jbc. M 115.683953.

[0939] (5) Ye F et al. Cryo-EM structure of G-protein-coupled receptor GPR17 in complex with inhibitory G protein. Med. Comm. 2022; 3:e159. https: / / doi.org / 10.1002 / mco2.159. (6) Adams KL et al. Intrinsic and extrinsic regulators of oligodendrocyte progenitor proliferation and differentiation. Semin Cell Dev Biol. 2021 Aug;116:16-24. doi: 10.1016 / j.semcdb.2020.10.002.

[0940] (7) Jakel S et al. Altered human oligodendrocyte heterogeneity in multiple sclerosis.

[0941] Nature. 2019 Feb;566(7745):543-547. doi: 10.1038 / s41586-019-0903-2.

[0942] (8) Rivera AD etal. Keeping the ageing brain wired: a role for purine signalling in regulating cellular metabolism in oligodendrocyte progenitors. Pflugers Arch. 2021 May;473(5):775-783. doi: 10.1007 / s00424-021-02544-z.

[0943] (9) Chen Y et al. The oligodendrocyte-specific G protein-coupled receptor GPR17 is a cell- intrinsic timer of myelination. Nat Neurosci. 2009 Nov;12(11):1398-406. doi: 10.1038 / nn.2410. (10) Lecca D et al. The recently identified P2Y-like receptor GPR17 is a sensor of brain damage and a new target for brain repair. PLoS One. 2008;3(10):e3579. doi: 10.1371 / journal. pone.0003579.

[0944] (11) B. Zhao etal. The new P2Y-like receptor G protein-coupled receptor 17 mediates acute neuronal injury and late microgliosis after focal cerebral ischemia in rats, Neuroscience, 202, 2012, 42-57. doi. org / 10.1016 / j. neuroscience.2011.11.066.

[0945] (12) Stefania Ceruti et al. The P2Y-like receptor GPR17 as a sensor of damage and a new potential target in spinal cord injury, Brain, 132 (8), 2009, 2206–2218, https: / / doi.org / 10.1093 / brain / awp147.

[0946] (13) Nyamoya, S et al. G-Protein-Coupled Receptor Gpr17 Expression in Two Multiple Sclerosis Remyelination Models. Mol Neurobiol 56, 1109–1123 (2019). https: / / doi.org / 10.1007 / s12035-018-1146-1.

[0947] (14) Franke H, et al. Changes of the GPR17 receptor, a new target for neurorepair, in neurons and glial cells in patients with traumatic brain injury. Purinergic Signal. 2013 Sep;9(3):451-62. doi: 10.1007 / s11302-013-9366-3

[0948] (15) Angelini J, et al. The Distribution of GPR17-Expressing Cells Correlates with White Matter Inflammation Status in Brain Tissues of Multiple Sclerosis Patients. Int J Mol Sci. 2021 Apr 27;22(9):4574. doi: 10.3390 / ijms22094574.

[0949] (16) Zhuo T, et al. Synthesis and Ability of New Ligands for G Protein-Coupled Receptors 17 (GPR17). Med Sci Monit. 2017 Feb 22;23:953-959. doi: 10.12659 / msm.902048. (17) Eberini I, etal. In silico identification of new ligands forGPR17: a promising therapeutic target for neurodegenerative diseases. J Comput Aided Mol Des. 2011 Aug;25(8):743- 52. doi: 10.1007 / s10822-011-9455-8.

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Claims

CLAIMS1. A compound of Formula (I) shown below, or a pharmaceutically acceptable salt, solvate or hydrate thereof:wherein:R1is selected from hydrogen, halo, Ci-4alkyl, and Ci-salkoxy;R2is selected from hydrogen, halo, cyano, Ci-4alkyl, C^alkenyl, C^alkynyl, Ci-salkoxy, Ci-shaloalkyl, Ci-shaloalkoxy, Ci-saminoalkyl, Ci-shydroxyalkyl, Ci-salkylamino, di(Ci.3alkyl)amino, nitro, hydroxyl, Ci-3alkylcarbonyl, Ci-salkoxycarbonyl, Ci-salkylsulfinyl, and Ci-salkylsulfonyl;R3is selected from hydrogen, Ci-4alkyl, Ci-salkoxy, halo, hydroxyl, cyano, nitro, C2- salkenyl, C^alkynyl, Ci-shaloalkyl, Ci-shaloalkoxy, Ci-saminoalkyl, Ci-shydroxyalkyl, Ci-3cyanoalkyl, C(O)Ra, C(O)NRaRb, C(O)ORa, C(O)C(O)NRaRb, OC(O)ORa, OC(O)NRaRb, NRaRb, NRaC(O)NRaRb, SRa, S(O)Ra, S(O)2Ra, C3-iocycloalkyl, Ci- 6alkylene-C3-iocycloalkyl, 3-10-membered heterocyclyl, Ce- aryl, and 4-10 membered heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl of R3is optionally substituted with 1, 2 or 3 Rxgroups, and wherein Raand Rbare independently selected from hydrogen and Ci-4alkyl;R4is a group of the formula:-L1-L2-Z1wherein:Li is absent, or a Ci-salkylene optionally substituted with fluoro;l_2is absent, or selected from O, N(RC), C(O), C(O)O, OC(O), C(O)N(RC), N(RC)C(O), N(Rc)C(O)N(Rd), N(RC)C(O)O, OC(O)N(RC), S(O)2N(RC), and N(RC)SO2, wherein Rcand Rdare independently selected from hydrogen and Ci-4alkyl; andZi is selected from hydrogen, cyano, Ci-4alkyl, Cswcycloalkyl, Ci- 4alkoxy, halo, hydroxyl, nitro, C^alkenyl, C^alkynyl, Ci-shaloalkyl, Ci- shaloalkoxy, Ciwcyanoalkyl, Ci-salkoxyalkyl, Ci-saminoalkyl, Ci- shydroxyalkyl, 4-10-membered heterocyclyl, Ce-waryl, and 4-10 membered heteroaryl, wherein each alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl of Zi is optionally substituted with 1, 2 or 3 Rygroups; R5is selected from hydrogen, Ci-4alkyl, Ciwalkoxy, Ciwhaloalkyl, halo, hydroxyl, and cyano;Xi is selected from CR7and N;X2is absent, or selected from CR8and N;X3is selected from CR9and N;X4 is selected from CR10and N;X5 is selected from CR11and N;wherein no more than 2 of Xi, X2, X3, X4 and X5 are N;and wherein two of Xi, X2, X3, X4 and X5 may optionally, together with the atoms to which they are attached, be linked to form a 5-6 membered heteroaryl, phenyl, 5-7-membered heterocyclyl, or Cs-ycycloalkyl;Xe is CR12or N;R7is selected from hydrogen, Ci-4alkyl, Ci-salkoxy, halo, hydroxyl, cyano, nitro, C2-salkenyl, C^alkynyl, Ciwhaloalkyl, Ciwhaloalkoxy, Ci-saminoalkyl, Ci-shydroxyalkyl, Ci-3cyanoalkyl, C(O)Re, C(O)NReRe, C(O)ORe, C(O)C(O)NReRf, OC(O)ORe, OC(O)NReRf, NReRf, SRe, S(O)Re, S(O)2Re, C3-iocycloalkyl, 3-10-membered heterocyclyl, Ce- aryl, 4-10 membered heteroaryl, and Ci-ealkyl-Q1, wherein Q1is selected from C3-10 cycloalkyl, 3-10-membered heterocyclyl, Ce-waryl, and 4-10 membered heteroaryl, and wherein Reand Rfare independently selected from hydrogen and Ci-4alkyl, and further wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl of R7, and each alkyl of Reand / or Rf, is optionally substituted with 1, 2, or 3 Rxgroups;R8, R9, R10, and R11are independently selected from hydrogen, halo, cyano, Ci-4alkyl, C^alkenyl, C^alkynyl, Ciwalkoxy, Ci-shaloalkyl, Ci-shaloalkoxy, Ci-3aminoalkyl, Ci- shydroxyalkyl, nitro, and hydroxyl;R12is selected from hydrogen, Ci-4alkyl, Ciwalkoxy, halo, hydroxyl, cyano, nitro, C2- salkenyl, C^alkynyl, Ci-shaloalkyl, Ci-shaloalkoxy, Ci-3aminoalkyl, Ci-shydroxyalkyl, Ci- scyanoalkyl Ci-3alkylamino, di(Ci-3alkyl)amino, C(O)R9, C(O)NR9Rh, C(O)OR9, C3- locycloalkyl, 3-10-membered heterocyclyl, Ce- aryl, 4-10 membered heteroaryl, and Ci-ealkylQ2, wherein Q2is selected from Cs-wcycloalkyl, 3-10-membered heterocyclyl, Ce- aryl, and 4-10 membered heteroaryl, wherein R9and Rhare independently selected from hydrogen and Ci-4alkyl, and wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl of R12is optionally substituted with 1, 2, or 3 Rxgroups;Rxis selected from Ci-4alkyl, Ciwalkoxy, Ci-shaloalkyl, Ci-shaloalkoxy, halo, hydroxyl, cyano, nitro, amino, cyclopropyl, and cyclobutyl; andRyis selected from Ci-4alkyl, Ci.3alkoxy, Ci-shaloalkyl, Ci-shaloalkoxy, halo, hydroxyl, cyano, nitro, amino, amido, sulphamoyl, Cs-ecycloalkyl, 3-6-membered heterocyclyl, phenyl, and 4-6 membered heteroaryl.

2. A compound, or a pharmaceutically acceptable salt, solvate or hydrate thereof, according to claim 1, wherein R1is selected from hydrogen, chloro, bromo, and methyl.

3. A compound, or a pharmaceutically acceptable salt, solvate or hydrate thereof, according to claim 1 or claim 2, wherein R2is selected from hydrogen, halo, Ci-4alkyl, and Ciwalkoxy.

4. A compound, or a pharmaceutically acceptable salt, solvate or hydrate thereof, according to any one of claims 1 to 3, wherein R3is selected from hydrogen, Ci-4alkyl, Ciwalkoxy, halo, hydroxyl, cyano, C^alkenyl, C^alkynyl, Ci-shaloalkyl, Ci-shaloalkoxy, Ci-saminoalkyl, Ci-shydroxyalkyl, Ci-scyanoalkyl, Ci-salkylamino, Cs-ecycloalkyl, 3-6- membered heterocyclyl, Ce- aryl, and 4-6 membered heteroaryl.

5. A compound, or a pharmaceutically acceptable salt, solvate or hydrate thereof, according to any one of claims 1 to 4, wherein Xe is CR12.

6. A compound, or a pharmaceutically acceptable salt, solvate or hydrate thereof, according to claim 5, wherein R12is selected from hydrogen, halo, cyano, Ci-4alkyl, C2- salkenyl, C^alkynyl, Ci-salkoxy, Ci-shaloalkyl, Ci-shaloalkoxy, Ci-saminoalkyl, Ci- shydroxyalkyl, nitro, and hydroxyl.

7. A compound, or a pharmaceutically acceptable salt, solvate or hydrate thereof, according to claim 5, wherein R12is selected from hydrogen, halo, Ci-4alkyl, Ci-salkoxy, and Ci-shaloalkyl.

8. A compound, or a pharmaceutically salt, solvate or hydrate thereof, according to any one of claims 1 to 7, wherein R4is selected from a group of the formula:-L1-L2-Z1wherein:Li is absent, or a Ci-salkylene optionally substituted with fluoro;l_2is absent, or selected from N(RC), C(O), C(O)O, OC(O), C(O)N(RC), N(RC)C(O), N(RC)C(O)O, and OC(O)N(RC), wherein Rcis selected from hydrogen and Ci-4alkyl; andZ1 is selected from hydrogen, cyano, Ci-4alkyl, Cs-ecycloalkyl, Ci- 4alkoxy, halo, hydroxyl, C^alkenyl, C^alkynyl, Ci-shaloalkyl, Ci- shaloalkoxy, Ci-scyanoalkyl, Ci-salkoxyalkyl, Ci-saminoalkyl, Ci- shydroxyalkyl, 4-6-membered heterocyclyl, Ce- aryl, and 4-6 membered heteroaryl, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl of Z1 is optionally substituted with 1, 2, or 3 Rygroups.

9. A compound, or a pharmaceutically acceptable salt, solvate or hydrate thereof, according to any one of claims 1 to 7, wherein R4is selected from hydrogen, cyano, Ci-4alkyl, Cs-ecycloalkyl, Ci.4alkoxy, halo, hydroxyl, C^alkenyl, Ci-scyanoalkyl, Ci- salkoxyalkyl, Ci-saminoalkyl, Ci-shydroxyalkyl, 5-membered heteroaryl, C(O)ORC, and C(O)N(RC)(RC), wherein Rcis selected from hydrogen and Ci-2alkyl, and wherein each alkyl, cycloalkyl, and heteroaryl is optionally substituted with 1 or 2 Rygroups.

10. A compound, or a pharmaceutically acceptable salt, solvate or hydrate thereof, according to any one of claims 1 to 7, wherein R4is selected from cyano, C(O)ORC, C(O)NHRC, CH2OH, and a 5-membered heteroaryl (such as oxazolyl, pyrazolyl, oxadiazolyl, triazolyl and tetrazolyl), and wherein Rcis selected from hydrogen and methyl.

11. A compound, or a pharmaceutically acceptable salt, solvate or hydrate thereof, according to any one of claims 1 to 10, wherein R5is hydrogen.

12. A compound, or a pharmaceutically acceptable salt, solvate or hydrate thereof, according to any one of claims 1 to 11, wherein R7is selected from hydrogen, Ci-4alkyl,Ci-salkoxy, halo, hydroxyl, cyano, nitro, C^alkenyl, C^alkynyl, Ci-shaloalkyl, Ci- shaloalkoxy, Ci-saminoalkyl, Ci-shydroxyalkyl, Ci-scyanoalkyl, C(O)Re, C(O)NReRe, C(O)ORe, NReRf, Cs- cycloalkyl, 3-10-membered heterocyclyl, Ce- aryl, and 4-10 membered heteroaryl, wherein Reand Rfare independently selected from hydrogen and Ci-4alkyl, and further wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl of R7, and each alkyl of Reand / or Rf, is optionally substituted with 1, 2, or 3 Rxgroups.

13. A compound, or a pharmaceutically acceptable salt, solvate or hydrate thereof, according to any one of claims 1 to 11, wherein R7is selected from hydrogen, Ci-4alkyl, Ci^alkoxy, halo, hydroxyl, cyano, nitro, C^alkenyl, C^alkynyl, Ci-shaloalkyl, Ci- shaloalkoxy, Ci-3aminoalkyl, Ci-shydroxyalkyl, Ci-scyanoalkyl, Ci-salkylamino, C3- ecycloalkyl, and 3-6-membered heterocyclyl.

14. A compound, or a pharmaceutically acceptable salt, solvate or hydrate thereof, according to any one of claims 1 to 13, wherein R8, R9, R10, and R11are independently selected from hydrogen, halo, cyano, Ci-4alkyl, Ci-salkoxy, Ci-shaloalkyl, and Ci- shaloalkoxy.

15. A compound, or a pharmaceutically acceptable salt, solvate or hydrate thereof, according to any one of claims 1 to 14, wherein:Rxis selected from Ci-4alkyl, Ci^alkoxy, Ci-shaloalkyl, halo, and cyano; andRyis selected from Ci-4alkyl, Ci^alkoxy, halo, cyano, cyclopropyl, and 3-4-membered heterocyclyl.

16. A compound, or a pharmaceutically acceptable salt, solvate or hydrate thereof, which is selected from any one of the following:methyl 7-chloro-3-(N-(3,5-dimethoxypyrazin-2-yl)sulfamoyl)indolizine-1 -carboxylate; 7-chloro-3-(N-(3,5-dimethoxypyrazin-2-yl)sulfamoyl)indolizine-1-carboxylic acid; 7-chloro-3-(N-(3,5-dimethoxypyrazin-2-yl)sulfamoyl)indolizine-1-carboxamide;7-chloro-1-cyano-N-(3,5-dimethoxypyrazin-2-yl)indolizine-3-sulfonamide;7-chloro-N-(3,5-dimethoxypyrazin-2-yl)-1-(hydroxymethyl)indolizine-3-sulfonamide; methyl 7-chloro-3-(N-(6-(2,2-difluoroethoxy)-5-fluoro-2-methoxypyridin-3- yl)sulfamoyl)indolizine-1 -carboxylate;7-chloro-N-(6-(2,2-difluoroethoxy)-5-fluoro-2-methoxypyridin-3-yl)-1- (hydroxymethyl)indolizine-3-sulfonamide;7-chloro-3-(N-(5-(2-fluoroethoxy)-4-methoxypyrimidin-2-yl)sulfamoyl)indolizine-1- carboxamide;7-chloro-1-cyano-N-(5-(2-fluoroethoxy)-4-methoxypyrimidin-2-yl)indolizine-3-sulfonamide;methyl 7-chloro-3-(N-(6-(difluoromethoxy)-5-fluoro-2-methoxypyridin-3-yl)sulfamoyl)indolizine-1 -carboxylate;7-chloro-N-(6-(difluoromethoxy)-5-fluoro-2-methoxypyridin-3-yl)-1- (hydroxymethyl)indolizine-3-sulfonamide;7-chloro-3-(N-(6-(2,2-difluoroethoxy)-5-fluoro-2-methoxypyridin-3-yl)sulfamoyl)indolizine-1 -carboxamide;7-chloro-1-cyano-N-(6-(2,2-difluoroethoxy)-5-fluoro-2-methoxypyridin-3-yl)indolizine- 3-sulfonamide;7-chloro-3-(N-(6-(difluoromethoxy)-5-fluoro-2-methoxypyridin-3-yl)sulfamoyl)indolizine-1 -carboxamide;7-chloro-N-(5-(2-fluoroethoxy)-4-methoxypyrimidin-2-yl)-1-(hydroxymethyl)indolizine- 3-sulfonamide;7-chloro-3-(N-(4-(cyanomethyl)-5-fluoro-2-methoxyphenyl)sulfamoyl)indolizine-1-carboxamide;7-chloro-1-cyano-N-(4-(cyanomethyl)-5-fluoro-2-methoxyphenyl)indolizine-3-sulfonamide;7-chloro-N-(4-(cyanomethyl)-5-fluoro-2-methoxyphenyl)-1-(hydroxymethyl)indolizine- 3-sulfonamide;7-chloro-N-(6-(cyanomethyl)-5-fluoro-2-methoxypyridin-3-yl)-1- (hydroxymethyl)indolizine-3-sulfonamide;7-chloro-1-cyano-N-(6-(difluoromethoxy)-5-fluoro-2-methoxypyridin-3-yl)indolizine-3-sulfonamide;7-chloro-3-(N-(6-(cyanomethyl)-5-fluoro-2-methoxypyridin-3-yl)sulfamoyl)indolizine-1-carboxamide;7-chloro-1-cyano-N-(6-(cyanomethyl)-5-fluoro-2-methoxypyridin-3-yl)indolizine-3-sulfonamide;3-(N-(4-bromo-2,5-difluorophenyl)sulfamoyl)-7-chloroindolizine-1-carboxamide;7-chloro-3-(N-(5-fluoro-4-(fluoromethoxy)-2-methoxyphenyl)sulfamoyl)indolizine-1-carboxamide;7-chloro-3-(N-(4-(difluoromethoxy)-2,5-difluorophenyl)sulfamoyl)indolizine-1-carboxamide;7-chloro-1-cyano-N-(5-(cyanomethyl)-3-fluoro-6-methoxypyridin-2-yl)indolizine-3-sulfonamide;7-chloro-N-(3,5-dimethoxypyrazin-2-yl)-1-(1H-pyrazol-1-yl)indolizine-3-sulfonamide; 7-chloro-N-(3,5-dimethoxypyrazin-2-yl)-1-(oxazol-2-yl)indolizine-3-sulfonamide;7-chloro-N-(3,5-dimethoxypyrazin-2-yl)-1-(1H-pyrazol-5-yl)indolizine-3-sulfonamide; 7-chloro-N-(3,5-dimethoxypyrazin-2-yl)-1-(1H-pyrazol-4-yl)indolizine-3-sulfonamide; 7-chloro-N-(3,5-dimethoxypyrazin-2-yl)-1-(isoxazol-4-yl)indolizine-3-sulfonamide; 1-bromo-7-chloro-N-(3,5-dimethoxypyrazin-2-yl)indolizine-3-sulfonamide;N-(6-(cyanomethyl)-5-fluoro-2-methoxypyridin-3-yl)-7-cyclopropyl-1-(1H-pyrazol-1- yl)indolizine-3-sulfonamide;N-(4-(cyanomethyl)-5-fluoro-2-methoxyphenyl)-7-cyclopropyl-1-(1H-pyrazol-1- yl)indolizine-3-sulfonamide;7-cyclopropyl-N-(3,5-dimethoxypyrazin-2-yl)indolizine-3-sulfonamide;7-chloro-N-(3,5-dimethoxypyrazin-2-yl)-8-fluoroindolizine-3-sulfonamide;2-chloro-N-(5-fluoro-2,6-dimethoxypyridin-3-yl)pyrrolo[1,2-a]pyrimidine-6- sulfonamide;N-(4-bromo-2,5-difluorophenyl)-2-chloropyrrolo[1,2-a]pyrimidine-6-sulfonamide;N-(6-(cyanomethyl)-5-fluoro-2-methoxypyridin-3-yl)-7-cyclopropylindolizine-3- sulfonamide; andN-(4-(cyanomethyl)-5-fluoro-2-methoxyphenyl)-7-cyclopropylindolizine-3- sulfonamide.

17. A pharmaceutical composition comprising a compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt, solvate or hydrate thereof, and a pharmaceutically acceptable carrier or excipient.

18. A compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt, solvate or hydrate thereof, or a pharmaceutical composition according to claim 17, for use in the treatment of a GPR17-associated disease.

19. A compound or pharmaceutical composition for use according to claim 18, wherein the GPR17-associated disease is selected from multiple sclerosis, multiple sclerosis (MS), situations resulting in damage to myelin sheaths such as carbon monoxide poisoning or virus induced demyelination, primary demyelinating disorders such as neuromyelitis optica, transverse myelitis, acute and multiphasic disseminated encephalomyelitis, and other CNS disorders associated with myelin loss such as amyotrophic lateral sclerosis (ALS), multiple system atrophy (MSA), Alzheimer’s disease, schizophrenia, Parkinson’s disease, and Huntington’s disease.

20. A compound or pharmaceutical composition for use according to claim 18, wherein the GPR17-associated disease is multiple sclerosis.

21. A method for the treatment of a disease or disorder in which GPR17 activity is implicated in a subject in need of such treatment, said method comprising administering a therapeutically effective amount of a compound according to any of claims 1 to 16, or a pharmaceutically acceptable salt, solvate or hydrate thereof, or a pharmaceutical composition according to claim 17.

22. A method according to claim 21, wherein said disease or disorder in which GPR17 activity is implicated is selected from multiple sclerosis, multiple sclerosis (MS), situations resulting in damage to myelin sheaths such as carbon monoxide poisoning or virus induced demyelination, primary demyelinating disorders such as neuromyelitis optica, transverse myelitis, acute and multiphasic disseminated encephalomyelitis, and other CNS disorders associated with myelin loss such as amyotrophic lateral sclerosis (ALS), multiple system atrophy (MSA), Alzheimer’s disease, schizophrenia, Parkinson’s disease, and Huntington’s disease.

23. A method according to claim 21, wherein the disease or disorder in which GPR17 activity is implicated is multiple sclerosis.

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