Modulators of the GPR17 receptor

Abstract

The present application 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 application 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 analysis of 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. Attenuation or blockade of GPR17 function 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 attenuation or blockade of GPR17 function may provide benefit across a wide range of settings including Alzheimer’s disease and Parkinson’s disease.

[0013] Thus, there is strong evidence that attenuation or blockade 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 prophylaxis of 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: R1is selected from hydrogen, halo, Ci-4alkyl and Ciwalkoxy;

[0021] R2is selected from hydrogen, halo, cyano, Ci-4alkyl, C^alkenyl, C^alkynyl, Ci-salkoxy, Ci-shaloalkyl, Ciwhaloalkoxy, Ci-saminoalkyl, Ciwhydroxyalkyl, Ciwalkylamino, 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, 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-ealkylene-Cs- cycloalkyl, 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] L2is 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)SC>2, 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, Ciwalkoxy, Ci-shaloalkyl, halo, hydroxyl and cyano;

[0030] Xi is selected from CR7and N;

[0031] X2is absent or selected from CR8and N, wherein when X2is absent then Xi is selected from NH, S, and O;

[0032] X3 is selected from CR9and N; X4 is selected from CR10and N;

[0033] X5 is selected from CR11and N;

[0034] 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] X6is CR12or N;

[0037] R7is selected from hydrogen, Ci-4alkyl, Ci-salkoxy, halo, hydroxyl, cyano, nitro, C2-salkenyl, C^alkynyl, Ciwhaloalkyl, Ciwhaloalkoxy, Ci-saminoalkyl, Ciwhydroxyalkyl, Ci-3cyanoalkyl, C(O)Re, C(O)NReRf, 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-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;

[0038] R8, R9, R10and R11are independently selected from hydrogen, halo, cyano, Ci-4alkyl, C^alkenyl, C^alkynyl, Ciwalkoxy, Ciwhaloalkyl, Ciwhaloalkoxy, Ciwaminoalkyl, Ci-shydroxyalkyl, Cs-wcycloalkyl, nitro and hydroxyl;

[0039] R12is selected from hydrogen, Ci-4alkyl, Ciwalkoxy, halo, hydroxyl, cyano, nitro, C2-salkenyl, C^alkynyl, Ciwhaloalkyl, Ciwhaloalkoxy, Ciwaminoalkyl, Ciwhydroxyalkyl, Ci-scyanoalkyl, Ciwalkylamino, 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 Cs-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, Ciwalkoxy, Ciwhaloalkyl, Ciwhaloalkoxy, halo, hydroxyl, cyano, nitro, amino, cyclopropyl and cyclobutyl; and

[0040] Ryis selected from Ci-4alkyl, Ciwalkoxy, Ciwhaloalkyl, Ciwhaloalkoxy, halo, hydroxyl, cyano, nitro, amino, amido, carboxy, carbamoyl, sulfamoyl, C3-6 cycloalkyl, 3-6-membered heterocyclyl, phenyl, and 4-6 membered heteroaryl. 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.

[0041] 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) ora pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.

[0042] 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.

[0043] 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) ora pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.

[0044] 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.

[0045] 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.

[0046] 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. 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.

[0047] 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.

[0048] 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.

[0049] Most suitably, the GPR17-associated disease is multiple sclerosis.

[0050] DETAILED DESCRIPTION OF THE INVENTION

[0051] Definitions

[0052] Unless otherwise stated, the following terms used in the specification and claims have the following meanings set out below.

[0053] 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. 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.

[0054] 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.

[0055] 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.

[0056] 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.

[0057] "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.

[0058] The term "halo" refers to fluoro, chloro, bromo and iodo.

[0059] The term "heterocyclyl", "heterocyclic" or "heterocycle" means a non-aromatic saturated or partially saturated monocyclic, fused, bridged, or spiro bicyclic heterocyclic ring system(s). Monocyclic heterocyclic rings contain from about 3 to 12 (suitably from 3 to 7) ring atoms, with from 1 to 5 (suitably 1, 2 or 3) heteroatoms selected from nitrogen, oxygen or sulfur in the ring. Bicyclic heterocycles contain from 7 to 17 member atoms, suitably 7 to 12 member atoms, in the ring. Bicyclic heterocyclic(s) rings may be fused, spiro, or bridged ring systems. Examples of heterocyclic groups include cyclic ethers such as oxiranyl, oxetanyl, tetrahydrofuranyl, dioxanyl, and substituted cyclic ethers. Heterocycles containing nitrogen include, for example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrotriazinyl, tetrahydropyrazolyl, and the like. Typical sulfur containing heterocycles include tetrahydrothienyl, dihydro-1,3-dithiol, tetrahydro-2 / - / -thiopyran, and hexahydrothiepine. Other heterocycles include dihydrooxathiolyl, tetrahydro-oxazolyl, tetrahydro-oxadiazolyl, tetrahydrodioxazolyl, tetrahydrooxathiazolyl, hexahydrotriazinyl, tetrahydro-oxazinyl, morpholinyl, thiomorpholinyl, tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, and octahydrobenzothiazolyl. For heterocycles containing sulfur, the oxidized sulfur heterocycles containing SO or SO2 groups are also included. Examples include the sulfoxide and sulfone forms of tetrahydrothienyl and thiomorpholinyl such as tetrahydrothiene 1, 1 -dioxide and thiomorpholinyl 1, 1 -dioxide. A suitable value for a heterocyclyl group which bears 1 or 2 oxo (=0) or thioxo (=S) substituents is, for example, 2-oxopyrrolidinyl, 2-thioxopyrrolidinyl, 2-oxoimidazolidinyl, 2-thioxoimidazolidinyl, 2-oxopiperidinyl, 2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl or 2,6-dioxopiperidinyl. Particular heterocyclyl groups are saturated monocyclic 3 to 7 membered heterocyclyls containing 1, 2 or 3 heteroatoms selected from nitrogen, oxygen or sulfur, for example azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, tetrahydrothienyl, tetrahydrothienyl 1, 1 -dioxide, thiomorpholinyl, thiomorpholinyl 1, 1 -dioxide, piperidinyl, homopiperidinyl, piperazinyl or homopiperazinyl. As the skilled person would appreciate, any heterocycle may be linked to another group via any suitable atom, such as via a carbon or nitrogen atom. However, reference herein to piperidino or morpholino refers to a piperidin-1-yl or morpholin-4-yl ring that is linked via the ring nitrogen. The term "heteroaryl" or "heteroaromatic" means an aromatic mono-, bi-, or polycyclic ring incorporating one or more (for example 1-4, particularly 1, 2 or 3) heteroatoms selected from nitrogen, oxygen or sulfur. The term heteroaryl includes both monovalent species and divalent species. Examples of heteroaryl groups are monocyclic and bicyclic groups containing from five to twelve ring members, and more usually from five to ten ring members. The heteroaryl group can be, for example, a 5- or 6-membered monocyclic ring or a 9- or 10- membered bicyclic ring, for example a bicyclic structure formed from fused five and six membered rings or two fused six membered rings. Each ring may contain up to about four heteroatoms typically selected from nitrogen, sulfur and oxygen. Typically, the heteroaryl ring will contain up to 3 heteroatoms, more usually up to 2, for example a single heteroatom. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non-basic as in the case of an indole or pyrrole nitrogen. In general, the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five.

[0060] Examples of heteroaryl include furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazenyl, benzofuranyl, indolyl, isoindolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzothiazolyl, indazolyl, purinyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl, pteridinyl, naphthyridinyl, carbazolyl, phenazinyl, benzisoquinolinyl, pyridopyrazinyl, thieno[2,3-b]furanyl, 2H-furo[3,2-b]-pyranyl, 5H-pyrido[2,3-d]-o-oxazinyl, 1 / - / -pyrazolo[4,3-d]-oxazolyl, 4H-imidazo[4,5-d]thiazolyl, pyrazino[2,3-d]pyridazinyl, imidazo[2, 1 -b]thiazolyl, imidazo[1,2-b][1,2,4]triazinyl. "Heteroaryl" also covers partially aromatic bi- or polycyclic ring systems wherein at least one ring is an aromatic ring and one or more of the other ring(s) is a non-aromatic, saturated or partially saturated ring, provided at least one ring contains one or more heteroatoms selected from nitrogen, oxygen or sulfur. Examples of partially aromatic heteroaryl groups include for example, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 2-oxo- 1,2,3,4-tetrahydroquinolinyl, dihydrobenzthienyl, dihydrobenzfuranyl, 2,3-dihydro- benzo[1,4]dioxinyl, benzo[1,3]dioxolyl, 2,2-dioxo-1,3-dihydro-2-benzothienyl, 4, 5,6,7-tetrahydrobenzofuranyl, indolinyl, 1,2,3,4-tetrahydro-1,8-naphthyridinyl and 1,2,3,4-tetrahydropyrido[2,3- 5]pyrazinyl.

[0061] 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.

[0062] Examples of six membered heteroaryl groups include but are not limited to pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl.

[0063] A bicyclic heteroaryl group may be, for example, a group selected from:

[0064] 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;

[0065] a pyrazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;

[0066] a pyrazine ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;

[0067] 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;

[0068] 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;

[0069] 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

[0070] a cyclopentyl ring fused to a 5- or 6-membered heteroaromatic ring containing 1, 2 or 3 ring heteroatoms.

[0071] 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.

[0072] 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.

[0073] The term "aryl" means a cyclic or polycyclic aromatic ring 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.

[0074] “Cyano” means the chemical group -CN.

[0075] “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.

[0076] 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-schloroalkyl 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.

[0077] 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-schloroalkoxy 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. The term "Ci-shydroxyalkyl” 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 hydroxy groups. Representative examples of "Ci-shydroxyalkyl” groups include, but are not limited to - CH2OH (hydroxymethyl), -CH2CH2OH (monohydroxyethyl), -CH(OH)CH2OH (1,2-dihydroxyethyl), -CH2CH2CH2OH (monohydroxypropyl), and -CH2CH(OH)CH2OH (dihydroxypropyl).

[0078] The term "Ci-saminoalkyl” 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 -CH2NH2 and -CH2CH2NH2. The term “Ci-salkylamino” as used refers to an amino group with is substituted with a C^alkyl group, and “di(Ci-salkyl)amino” refers to an amino group with is substituted with two C^alkyl groups. Representative examples of “Ci-salkylamino” groups include, but are not limited to -NHCH3 and representative examples of “di(Ci-salkyl)amino” groups include, but are not limited to -N(CH3)2.

[0079] The term "Ci-scyanoalkyl” 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-scyanoalkyl” 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.

[0080] Where substituents are described as being substituted with “one or more” groups it is to be understood that this definition includes - but is not limited to - substituents which are substituted with one, two, three or four groups, such as substituents which are substituted with one, two, or three groups; with one or two groups; or with one group.

[0081] The phrase "compound of the invention" means those compounds which are disclosed herein, both generically and specifically.

[0082] Compounds of the Invention

[0083] In one aspect, the present invention provides compounds of Formula (I) shown below, or pharmaceutically acceptable salts, solvates or hydrates thereof:

[0084]

[0085] wherein:

[0086] R1is selected from hydrogen, halo, Ci-4alkyl and Ci-salkoxy;

[0087] 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.

[0088] 3alkyl)amino, nitro, hydroxyl, Ci-salkylcarbonyl, Ci-salkoxycarbonyl, Ci-salkylsulfinyl and Ci-salkylsulfonyl;

[0089] 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- ealkylene-Cs- cycloalkyl, 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;

[0090] R4is selected from a group of the formula:

[0091] -L1-L2-Z1

[0092] wherein:

[0093] Li is absent or a Ci-salkylene optionally substituted with fluoro;

[0094] L2is 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)SC>2, wherein Rcand Rdare independently selected from hydrogen and Ci-4alkyl; and

[0095] Zi is selected from hydrogen, cyano, Ci-4alkyl, Cswcycloalkyl, Ci- 4alkoxy, halo, hydroxyl, nitro, C^alkenyl, C^alkynyl, Ciwhaloalkyl, Ci- shaloalkoxy, Ciwcyanoalkyl, Ciwalkoxyalkyl, Ciwaminoalkyl, 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, Ci-salkoxy, Ciwhaloalkyl, halo, hydroxyl and cyano;

[0096] Xi is selected from CR7and N;

[0097] X2 is absent or selected from CR8and N, wherein when X2 is absent then Xi is selected from NH, S, and O;

[0098] X3 is selected from CR9and N;

[0099] X4 is selected from CR10and N;

[0100] X5 is selected from CR11and N;

[0101] wherein no more than two of Xi, X2, X3, X4 and X5 are N;

[0102] 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;

[0103] X6is CR12or N;

[0104] R7is selected from hydrogen, Ci-4alkyl, Ci-salkoxy, halo, hydroxyl, cyano, nitro, C2-salkenyl, C^alkynyl, Ciwhaloalkyl, Ciwhaloalkoxy, Ci-saminoalkyl, Ciwhydroxyalkyl, Ci-3cyanoalkyl, C(O)Re, C(O)NReRf, 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, 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; R8, R9, R10and R11are independently selected from hydrogen, halo, cyano, Ci-4alkyl, C^alkenyl, C^alkynyl, Ci-salkoxy, Ciwhaloalkyl, Ciwhaloalkoxy, Ciwaminoalkyl, Ci- shydroxyalkyl, Cs-wcycloalkyl, nitro and hydroxyl;

[0105] R12is selected from hydrogen, Ci-4alkyl, C1-3alkoxy, halo, hydroxyl, cyano, nitro, C2-3alkenyl, C2-3alkynyl, C1-3haloalkyl, C1-3haloalkoxy, C1-3aminoalkyl, C1-3hydroxyalkyl, Ci- scyanoalkyl, Ciwalkylamino, di(Ci-3alkyl)amino, C(O)R9, C(O)NR9Rh, C(O)OR9, C3- locycloalkyl, 3-10-membered heterocyclyl, Ce-waryl, 4-10 membered heteroaryl, and Ci-ealkylQ2, wherein Q2is selected from Cs-wcycloalkyl, 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; Rxis selected from Ci-4alkyl, Ciwalkoxy, Ciwhaloalkyl, Ciwhaloalkoxy, halo, hydroxyl, cyano, nitro, amino, cyclopropyl and cyclobutyl; and

[0106] Ryis selected from Ci-4alkyl, Ciwalkoxy, Ciwhaloalkyl, Ciwhaloalkoxy, halo, hydroxyl, cyano, nitro, amino, amido, carboxy, carbamoyl, sulfamoyl, C3-6 cycloalkyl, 3-6- membered heterocyclyl, phenyl, and 4-6 membered heteroaryl.

[0107] In an embodiment, the invention provides compounds of Formula (I) shown below, or pharmaceutically acceptable salts, solvates or hydrates thereof:

[0108]

[0109] wherein:

[0110] R1is selected from hydrogen, halo, Ci-4alkyl and Ciwalkoxy; R2is selected from hydrogen, halo, cyano, Ci-4alkyl, C^alkenyl, C^alkynyl, Ci-salkoxy, Ci-shaloalkyl, Ciwhaloalkoxy, Ci-saminoalkyl, Ciwhydroxyalkyl, Ciwalkylamino, di(Ci.

[0111] 3alkyl)amino, nitro, hydroxyl, Ci-salkylcarbonyl, Ci-salkoxycarbonyl, Ciwalkylsulfinyl and Ci-salkylsulfonyl;

[0112] 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, C3-10 cycloalkyl, Ci-ealkylene-Cs- cycloalkyl, 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;

[0113] R4is selected from a group of the formula:

[0114] -L1-L2-Z1

[0115] wherein:

[0116] Li is absent or a Ci-salkylene optionally substituted with fluoro;

[0117] L2is 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)SC>2, wherein Rcand Rdare independently selected from hydrogen and Ci-4alkyl; and

[0118] 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, Ciwalkoxy, Ci-shaloalkyl, halo, hydroxyl and cyano;

[0119] Xi is selected from CR7and N;

[0120] X2is absent or selected from CR8and N;

[0121] X3 is selected from CR9and N;

[0122] X4 is selected from CR10and N;

[0123] X5 is selected from CR11and N; wherein no more than two of Xi, X2, X3, X4 and X5 are N;

[0124] 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;

[0125] X6is CR12or N;

[0126] R7is selected from hydrogen, Ci-4alkyl, Ci-salkoxy, halo, hydroxyl, cyano, nitro, C2- salkenyl, C^alkynyl, Ciwhaloalkyl, Ciwhaloalkoxy, Ci-saminoalkyl, Ciwhydroxyalkyl, Ci-3cyanoalkyl, C(O)Re, C(O)NReRf, 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-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;

[0127] R8, R9, R10and R11are independently selected from hydrogen, halo, cyano, Ci-4alkyl, C^alkenyl, C^alkynyl, Ciwalkoxy, Ciwhaloalkyl, Ciwhaloalkoxy, Ciwaminoalkyl, Ci- shydroxyalkyl, nitro and hydroxyl;

[0128] R12is selected from hydrogen, Ci-4alkyl, C1-3alkoxy, halo, hydroxyl, cyano, nitro, C2-3alkenyl, C2-3alkynyl, C1-3haloalkyl, C1-3haloalkoxy, C1-3aminoalkyl, C1-3hydroxyalkyl, Ci- scyanoalkyl, Ciwalkylamino, 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 Cs-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, Ciwalkoxy, Ciwhaloalkyl, Ciwhaloalkoxy, halo, hydroxyl, cyano, nitro, amino, cyclopropyl and cyclobutyl; and

[0129] Ryis selected from Ci-4alkyl, Ciwalkoxy, Ciwhaloalkyl, Ciwhaloalkoxy, halo, hydroxyl, cyano, nitro, amino, amido, carboxy, carbamoyl, sulfamoyl, C3-6 cycloalkyl, 3-6- membered heterocyclyl, phenyl, and 4-6 membered heteroaryl.

[0130] 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, X6, 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 (75) 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:

[0131] (1) R1is selected from hydrogen, halo and Ci-4alkyl;

[0132] (2) R1is selected from hydrogen, halo and Ci-2alkyl;

[0133] (3) R1is selected from hydrogen, and halo;

[0134] (4) R1is selected from hydrogen, chloro, bromo and methyl;

[0135] (5) R1is hydrogen;

[0136] (6) R2is selected from hydrogen, halo, cyano, Ci-4alkyl, C^alkenyl, C^alkynyl, Ci-salkoxy, Ci-shaloalkyl, Ciwhaloalkoxy, Ci-saminoalkyl, Ci-shydroxyalkyl, Ciwalkylamino, di(Ci.

[0137] 3alkyl)amino, nitro and hydroxyl;

[0138] (7) R2is selected from hydrogen, halo, cyano, Ci-4alkyl, C^alkenyl, C^alkynyl, Ciwalkoxy, Ci-shaloalkyl and Ciwhaloalkoxy;

[0139] (8) R2is selected from hydrogen, halo, cyano, Ci-4alkyl, Ciwalkoxy, Ci-shaloalkyl and Ci- shaloalkoxy;

[0140] (9) R2is selected from hydrogen, halo, Ci-4alkyl and Ciwalkoxy;

[0141] (10) R2is selected from hydrogen and halo;

[0142] (11) R3is selected from hydrogen, Ci-4alkyl, Ci-salkoxy, halo, hydroxyl, cyano, nitro, C2- salkenyl, C^alkynyl, Ci-shaloalkyl, Ciwhaloalkoxy, Ci-saminoalkyl, Ci-shydroxyalkyl, Ci.3cyanoalkyl, C(O)Ra, C(O)NRaRb, C(O)ORa, NRaRb, C3-iocycloalkyl, Ci-6alkylene- Cs-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;

[0143] (12) R3is selected from hydrogen, Ci-4alkyl, Ci-salkoxy, halo, hydroxyl, cyano, nitro, C2- salkenyl, C^alkynyl, Ci-shaloalkyl, Ciwhaloalkoxy, Ci-saminoalkyl, Ci-shydroxyalkyl, Ci-3cyanoalkyl, 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;

[0144] (13) R3is selected from hydrogen, Ci-4alkyl, Ci-salkoxy, 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, 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, Ciwalkoxy, halo, hydroxyl, cyano, C^alkenyl, C^alkynyl, Ciwhaloalkyl, Ciwhaloalkoxy, Ciwaminoalkyl, Ciwhydroxyalkyl, Ci- scyanoalkyl, Ciwalkylamino, Cs-ecycloalkyl, 3-6-membered heterocyclyl, Ce-waryl, and 4-6 membered heteroaryl;

[0145] (15) R3is selected from hydrogen, Ci-4alkyl, Ciwalkoxy, halo, cyano, C^alkenyl, C2- salkynyl, Ciwhaloalkyl, Ciwhaloalkoxy, Ciwaminoalkyl, Ciwhydroxyalkyl, Ci- scyanoalkyl, Ciwalkylamino, Cs-ecycloalkyl and 3-6-membered heterocyclyl;

[0146] (16) R3is selected from Ci-4alkyl, Ciwalkoxy, halo, cyano, Ciwhaloalkyl, Ciwhaloalkoxy, and Cs-ecycloalkyl;

[0147] (17) R3is selected from halo, Ciwhaloalkyl, Ciwhaloalkoxy, and C3-6 cycloalkyl;

[0148] (18) R3is selected from chloro, bromo, Ciwfluoroalkyl, Ciwfluoroalkoxy, and cyclopropyl; (19) R3is selected from chloro, bromo, difluoromethyl, difluoromethoxy, and cyclopropyl; (20) R3is halo, preferably chloro or bromo;

[0149] (21) R4is selected from a group of the formula:

[0150] -L1-L2-Z1

[0151] wherein:

[0152] Li is absent or a Ciwalkylene optionally substituted with fluoro;

[0153] L2is 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

[0154] Z1 is selected from hydrogen, cyano, Ci-4alkyl, Cs-ecycloalkyl, Ci- 4alkoxy, halo, hydroxyl, nitro, C^alkenyl, C^alkynyl, Ciwhaloalkyl, 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; (22) R4is selected from a group of the formula:

[0155] -L1-L2-Z1

[0156] wherein:

[0157] Li is absent or a Ciwalkylene optionally substituted with fluoro; L2is 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

[0158] Zi is selected from hydrogen, cyano, Ci-4alkyl, Cs-ecycloalkyl, Ci- 4alkoxy, halo, hydroxyl, C^alkenyl, C^alkynyl, Ciwhaloalkyl, Ci- shaloalkoxy, Ciwcyanoalkyl, Ciwalkoxyalkyl, Ciwaminoalkyl, Ci- shydroxyalkyl, 4-6-membered heterocyclyl, Ce-waryl, and 4-6- membered heteroaryl, wherein each alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl of Zi is optionally substituted with 1, 2 or 3 Rygroups; (23) R4is selected from a group of the formula:

[0159] -L1-L2-Z1

[0160] wherein:

[0161] Li is absent or a Ciwalkylene;

[0162] L2is 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

[0163] Zi is selected from hydrogen, cyano, Ci-4alkyl, Cs-ecycloalkyl, Ci- 4alkoxy, halo, hydroxyl, C^alkenyl, C^alkynyl, Ciwhaloalkyl, Ci- shaloalkoxy, Ciwcyanoalkyl, Ciwalkoxyalkyl, Ciwaminoalkyl, Ci- shydroxyalkyl, 4-6-membered heterocyclyl, Ce- aryl, and 4-6- membered heteroaryl, wherein each alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl of Zi is optionally substituted with 1 or 2 Rygroups; (24) R4is selected from a group of the formula:

[0164] -L2-Z1

[0165] wherein:

[0166] L2is 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

[0167] Zi is selected from hydrogen, cyano, Ci-4alkyl, Cs-ecycloalkyl, Ci- 4alkoxy, halo, hydroxyl, C^alkenyl, C^alkynyl Ciwcyanoalkyl, Ci- salkoxyalkyl, Ciwaminoalkyl, Ciwhydroxyalkyl, 4-6-membered heterocyclyl, phenyl, and 5-6-membered heteroaryl, wherein each alkyl, cycloalkyl, phenyl and heteroaryl of Zi is optionally substituted with 1 or 2 Rygroups wherein Ryis selected from Ci-4alkyl, Ci-salkoxy, Ci- shaloalkyl, Ci-shaloalkoxy, halo, hydroxyl, cyano, nitro, amino, amido, carbamoyl, sulfamoyl, C3-6 cycloalkyl, 3-6-membered heterocyclyl, phenyl, and 4-6 membered heteroaryl;

[0168] (25) R4is selected from a group of the formula:

[0169] -L2-Z1

[0170] wherein:

[0171] L2is 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 C1-2alkyl; and

[0172] Z1 is selected from hydrogen, cyano, Ci-4alkyl, C3-6cycloalkyl, C1-4alkoxy, halo, hydroxyl, C2-3alkenyl, C1-3cyanoalkyl, C1-3alkoxyalkyl, C1-3aminoalkyl, C1-3hydroxyalkyl, and a 5-membered heteroaryl, wherein each cycloalkyl, and heteroaryl of Z1 is optionally substituted with 1 or 2 Rygroups;

[0173] (26) R4is selected from a group of the formula:

[0174] -L2-Z1

[0175] wherein:

[0176] L2is 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 C1-2alkyl; and

[0177] Z1 is selected from hydrogen, cyano, Ci-4alkyl, C3-6cycloalkyl, C1-4alkoxy, halo, hydroxyl, C2-3alkenyl, C1-3cyanoalkyl, C1-3alkoxyalkyl, C1-3aminoalkyl, C1-3hydroxyalkyl, and a 5-membered heteroaryl, wherein each cycloalkyl, and heteroaryl of Z1 is optionally substituted with 1 or 2 Rygroups;

[0178] (27) R4is selected from hydrogen, cyano, Ci-4alkyl, C3-6cycloalkyl, C1-4alkoxy, halo, hydroxyl, C2-3alkenyl, C1-3cyanoalkyl, C1-3alkoxyalkyl, C1-3aminoalkyl, C1-3hydroxyalkyl, 5-membered heteroaryl, C(O)ORC, C(O)N(Rc)(Rd), 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 wherein Ryis selected from Ci-4alkyl, Ci-salkoxy, Ci-shaloalkyl, Ci- shaloalkoxy, halo, hydroxyl, cyano, nitro, amino, amido, carbamoyl, sulfamoyl, C3-6 cycloalkyl, 3-6-membered heterocyclyl, phenyl, and 4-6 membered heteroaryl; (28) R4is selected from cyano, Ci-4alkyl, C3-6cycloalkyl, C1-4alkoxy, halo, hydroxyl, C2-3alkenyl, C1-3cyanoalkyl, C1-3alkoxyalkyl, C1-3aminoalkyl, C1-3hydroxyalkyl, 5- membered heteroaryl, C(O)ORC, C(O)N(Rc)(Rd), 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 wherein Ryis selected from C1-4alkyl, C1-3alkoxy, C1-3haloalkyl, C1-3haloalkoxy, halo, hydroxyl, cyano, nitro, amino, amido, carbamoyl, sulfamoyl, C3-6cycloalkyl, 3-6-membered heterocyclyl, phenyl, and 4-6 membered heteroaryl;

[0179] (29) R4is selected from cyano, Ci-salkoxy, halo, Ci-shydroxyalkyl, Ci-salkoxyalkyl, 5- membered heteroaryl, 4-6-membered heterocyclyl, C0-2alkyleneC(O)OC1-2alkyl, C(O)OH, C0-2alkyleneC(O)Rc, C0-2alkyleneC(O)N(Rc)(Rd), C0-2alkyleneN(Rc)(Rd), and C0-2alkyleneN(Rc)C(O)Rdwherein Rcand Rd are independently selected from hydrogen and Ci-2alkyl, and wherein said 5-membered heteroaryl is optionally substituted with 1 or 2 Rygroups wherein Ryis selected from C1-4alkyl, C1-3haloalkyl, halo, and C3-6cycloalkyl;

[0180] (30) R4is selected from cyano, methoxy, bromo, Ci.2hydroxyalkyl, Ci.2alkoxyalkyl, 5- membered heteroaryl, 5-6-membered heterocyclyl, C0-2alkyleneC(O)OC1-2alkyl, C(O)OH, C0-2alkyleneC(O)Rc, C0-2alkyleneC(O)N(Rc)(Rd), C0-2alkyleneN(Rc)(Rd), and C0-2alkyleneN(Rc)C(O)Rdwherein Rcand Rd are independently selected from hydrogen and Ci-2alkyl, and wherein said 5-membered heteroaryl is optionally substituted with Ci-3alkyl;

[0181] (31) 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;

[0182] (32) R4is selected from cyano, Ci-shydroxyalkyl, 5-membered heteroaryl and C(O)ORC, wherein Rcand Rdare independently selected from hydrogen and Ci-2alkyl;

[0183] (33) R4is selected from cyano, C(O)ORC, C(O)NHRC, CH2OH and a 5-membered heteroaryl (such as oxazolyl, pyrazolyl, oxadiazolyl, triazolyl and tetrazolyl), wherein Rcis selected from hydrogen and methyl;

[0184] (34) R4is hydrogen;

[0185] (35) R5is selected from hydrogen, Ci.salkoxy, Ci-shaloalkyl, halo, hydroxyl and cyano; (36) R5is selected from hydrogen, Ci-4alkyl, Ci.salkoxy, Ci-shaloalkyl and halo;

[0186] (37) R5is selected from hydrogen, Ci-4alkyl and halo;

[0187] (38) R5is hydrogen;

[0188] (39) Xi is selected from CR7and N;

[0189] X2 is selected from CR8and N;

[0190] X3 is selected from CR9and N; X4 is selected from CR10and N;

[0191] X5 is selected from CR11and N;

[0192] 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;

[0193] (40) Xi is selected from CR7;

[0194] X2 is selected from CR8and N;

[0195] X3 is selected from CR9and N;

[0196] X4 is selected from CR10and N;

[0197] X5 is selected from CR11and N;

[0198] (41) Xi is selected from NH, S, and O;

[0199] X2 is absent;

[0200] X3 is selected from CR9and N;

[0201] X4 is selected from CR10and N;

[0202] X5 is selected from CR11and N;

[0203] (42) Xi is selected from NH, S, and O;

[0204] X2 is absent;

[0205] X3 is selected from CR9and N;

[0206] X4is N;

[0207] X5 is selected from CR11and N;

[0208] (43) X6is CR12;

[0209] (44) X6is N;

[0210] (45) R7is selected from hydrogen, Ci-4alkyl, Ci-salkoxy, halo, hydroxyl, cyano, nitro, C2-3alkenyl, C2-3alkynyl, C1-3haloalkyl, C1-3haloalkoxy, C1-3aminoalkyl, C1-3hydroxyalkyl, C1-3cyanoalkyl, C(O)Re, C(O)NReRe, C(O)ORe, NReRf, C3-10cycloalkyl, 3-10-membered heterocyclyl, C6-10aryl, 4-10 membered heteroaryl, and C1-6alkyl-Q1, wherein Q1is selected from C3-10cycloalkyl, 3-10-membered heterocyclyl, C6-10aryl, 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;

[0211] (46) R7is selected from hydrogen, Ci-4alkyl, Ciwalkoxy, halo, hydroxyl, cyano, nitro, C2-3alkenyl, C2-3alkynyl, C1-3haloalkyl, C1-3haloalkoxy, C1-3aminoalkyl, C1-3hydroxyalkyl, C1-3cyanoalkyl, C(O)Re, C(O)NReRe, C(O)ORe, NReRf, C3-10cycloalkyl, 3-10-membered heterocyclyl, C6-10aryl, 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; (47) R7is selected from hydrogen, Ci-4alkyl, Ci-salkoxy, halo, hydroxyl, cyano, nitro, C2-3alkenyl, C2-3alkynyl, C1-3haloalkyl, C1-3haloalkoxy, C1-3aminoalkyl, C1-3hydroxyalkyl, C1-3cyanoalkyl, 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;

[0212] (48) R7is selected from hydrogen, Ci-4alkyl, Ci-salkoxy, halo, hydroxyl, cyano, nitro, C2-3alkenyl, C2-3alkynyl, C1-3haloalkyl, C1-3haloalkoxy, C1-3aminoalkyl, C1-3hydroxyalkyl, C1-3cyanoalkyl, C1-3alkylamino, C3-6cycloalkyl and 3-6-membered heterocyclyl;

[0213] (49) R7is selected from hydrogen, Ci-4alkyl, Ci-salkoxy, halo, cyano, C2-3alkenyl, C2-3alkynyl, C1-3haloalkyl, Ci-shaloalkoxy, Ci-saminoalkyl, Ci-shydroxyalkyl, Ci- scyanoalkyl, Ci-salkylamino and C3-6 cycloalkyl;

[0214] (50) R7is selected from hydrogen, Ci-4alkyl, Ci-salkoxy, halo, cyano, Ci-shaloalkyl, Ci- shaloalkoxy, Ci-saminoalkyl, Ci-shydroxyalkyl, Ci-scyanoalkyl, Ci-salkylamino and cyclopropyl;

[0215] (51) R7is selected from Ci-4alkyl, Ci-salkoxy, Ci-salkoxy substituted with Ci.2alkoxy, halo, Ci-shaloalkyl, Ci-shaloalkoxy, and Ci-scyanoalkyl;

[0216] (52) R7is selected from Ci-salkyl, Ci-salkoxy, Ci.2alkoxy substituted with methoxy, bromo, Ci-sfluoroalkyl, Ci-sfluoroalkoxy, and Ci-scyanoalkyl;

[0217] (53) R7is selected from Ci-salkoxy, halo, Ci-shaloalkoxy and Ci-scyanoalkyl;

[0218] (54) R8, R9, R10and R11are independently selected from hydrogen, halo, cyano, Ci-4alkyl, C2-3alkenyl, C2-3alkynyl, C1-3alkoxy, C1-3haloalkyl, C1-3haloalkoxy, and C3-10cycloalkyl; (55) R8, R9, R10and R11are independently selected from hydrogen, halo, cyano, Ci-4alkyl, Ci-salkoxy, Ci-shaloalkyl and Ci-shaloalkoxy;

[0219] (56) R8, R9, R10and R11are independently selected from hydrogen, halo, Ci-salkoxy, Ci- salkyl, and Cs-ecycloalkyl;

[0220] (57) R8, R9, R10and R11are independently selected from hydrogen, fluoro, chloro, methoxy, methyl, and cyclopropyl;

[0221] (58) R8, R9, R10and R11are independently selected from hydrogen, halo, Ci-4alkyl, and Ci- salkoxy;

[0222] (59) R12is selected from hydrogen, Ci-4alkyl, Ci-salkoxy, halo, hydroxyl, cyano, nitro, C2- salkenyl, C2-3alkynyl, C1-3haloalkyl, C1-3haloalkoxy, C1-3aminoalkyl, C1-3hydroxyalkyl, C1-3cyanoalkyl C1-3alkylamino, di(C1-3alkyl)amino, C(O)Rg, C(O)NRgRh, C(O)ORg, C3-6cycloalkyl, 3-6-membered heterocyclyl, phenyl and 4-6 membered heteroaryl, wherein Rgand 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;

[0223] (60) R12is selected from hydrogen, C1-4alkyl, C1-3alkoxy, halo, hydroxyl, cyano, nitro, C2-3alkenyl, C2-3alkynyl, 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;

[0224] (61) 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 and 4-6 membered heteroaryl;

[0225] (62) R12is selected from hydrogen, halo, cyano, Ci-4alkyl, C^alkenyl, C2-3alkynyl, C1-3alkoxy, C1-3haloalkyl, C1-3haloalkoxy, C1-3aminoalkyl, C1-3hydroxyalkyl, nitro, hydroxyl, and 4-6 membered heteroaryl;

[0226] (63) R12is selected from hydrogen, halo, Ci-4alkyl, Ci-salkoxy, Ci-shaloalkyl, Ci- shaloalkoxy, Ci-saminoalkyl, Ci-shydroxyalkyl and 5-6 membered heteroaryl;

[0227] (64) R12is selected from hydrogen, halo, Ci-4alkyl, Ci-salkoxy, Ci-shaloalkyl and 5-6 membered heteroaryl;

[0228] (65) R12is selected from hydrogen, halo, Ci-salkoxy, and 5-membered heteroaryl;

[0229] (66) R12is selected from hydrogen, bromo, and 5-membered heteroaryl;

[0230] (67) R12is hydrogen;

[0231] (68) Rxis selected from Ci-4alkyl, Ci-salkoxy, Ci-shaloalkyl, Ci-shaloalkoxy, halo, hydroxyl, cyano, and amino;

[0232] (69) Rxis selected from Ci-4alkyl, Ci-salkoxy, Ci-shaloalkyl, halo and cyano;

[0233] (70) Rxis selected from Ci-4alkyl, Ci-salkoxy, and halo;

[0234] (71) Rxis selected from methyl, methoxy, fluoro, chloro and bromo;

[0235] (72) Ryis selected from Ci-4alkyl, Ci-salkoxy, Ci-shaloalkyl, Ci-shaloalkoxy, halo, hydroxyl, cyano, nitro, amino, C3-6 cycloalkyl, 3-6-membered heterocyclyl, phenyl and 4-6 membered heteroaryl;

[0236] (73) Ryis selected from Ci-4alkyl, Ci-salkoxy, Ci-shaloalkyl, Ci-shaloalkoxy, halo, hydroxyl, cyano, C3-6 cycloalkyl and 3-6-membered heterocyclyl;

[0237] (74) Ryis selected from Ci-4alkyl, Ci-salkoxy, halo, cyano, cyclopropyl and 3-4-membered heterocyclyl;

[0238] (75) Ryis selected from methyl, methoxy, fluoro, chloro, bromo and cyclopropyl.

[0239] 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.

[0240] Suitably, a heteroaryl is a 5- or 6-membered heteroaryl ring comprising one, two or three heteroatoms selected from N, O or S. 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 pyrrolidinyl]. Suitably an aryl group is phenyl.

[0241] Suitably, R1is as defined in any one of paragraphs (1) to (5). Most suitably, R1is as defined in paragraph (5).

[0242] Suitably, R2is as defined in any one of paragraphs (6) to (10). Most suitably, R2is as defined in paragraph (10).

[0243] Suitably, R3is as defined in any one of paragraphs (11) to (20). Most suitably, R3is as defined in paragraph (19) or paragraph (20).

[0244] Suitably, R4is as defined in any one of paragraphs (21) to (34). Most suitably, R4is as defined in paragraphs (29) to (33). In certain embodiments, R4is not hydrogen. Thus, in some embodiments, Z1is not hydrogen when L1and L2are both absent.

[0245] Suitably, R5is as defined in any one of paragraphs (35) to (38). Most suitably, R5is as defined in paragraph (38).

[0246] Suitably, Xi, X2, X3, X4 and X5 are each independently as defined in any one of paragraphs (39) to (42). Most suitably, Xi, X2, X3, X4 and X5 are as defined in paragraph (40). 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 heteroaryl ring.

[0247] Suitably, Xe is as defined in paragraph (43) or paragraph (44).

[0248] Suitably, R7is as defined in any one of paragraphs (45) to (53). Most suitably, R7is as defined in paragraphs (51) to (53).

[0249] Suitably, R8’ R9, R10and R11are each independently as defined in any one of paragraphs (54) to (58). Most suitably, R8’ R9, R10and R11are as defined in paragraph (57) or paragraph (58). Suitably, R12is as defined in any one of paragraphs (59) to (67). Most suitably, R12is as defined in paragraph (66) or paragraph (67).

[0250] Suitably, Rxis as defined in any one of paragraphs (68) to (71). Most suitably, Rxis as defined in paragraph (71).

[0251] Suitably, Ryis as defined in any one of paragraphs (72) to (75). Most suitably, Ryis as defined in paragraph (75). In certain embodiments, the compound of the invention is not one or both of the following compounds:

[0252] methyl 6-chloro-1-(N-(5-(2,2-difluoroethoxy)-3-fluoro-6-methoxypyridin-2- yl)sulfamoyl)indolizine-3-carboxylate; or

[0253] methyl 6-chloro-1-(N-(5-(2-fluoroethoxy)-4-methoxypyrimidin-2- yl)sulfamoyl)indolizine-3-carboxylate.

[0254] 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:

[0255]

[0256] wherein R1, R2, R3, R4, X1, X2, X3, X4, X5and X6each have any one of the meanings defined herein.

[0257] In an embodiment of the compounds of Formula (la) to Formula (le):

[0258] R1is as defined in any one of paragraphs (1) to (5);

[0259] R2is as defined in any one of paragraphs (6) to (10);

[0260] R3is as defined in any one of paragraphs (11) to (20);

[0261] R4is as defined in any one of paragraphs (21) to (34); Xi, X2, X3, X4 and X5 are each independently as defined in any one of paragraphs (39) to (42):

[0262] X6is as defined in paragraph (43) or (44):

[0263] R7is as defined in any one of paragraphs (45) to (53):

[0264] R8, R9, R10and R11are each independently as defined in any one of paragraphs (54) to (58):

[0265] R12is as defined in any one of paragraphs (59) to (67):

[0266] Rxis as defined in any one of paragraphs (68) to (71): and

[0267] Ryis as defined in any one of paragraphs (72) to (75).

[0268] In an embodiment of the compounds of Formulae (la) to (le) R4is hydrogen.

[0269] 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:

[0270]

[0271]

[0272] wherein R1, R2, R3, R4, X6, R7, R8, R9, R10, and R11each have any one of the meanings defined herein.

[0273] In an embodiment of the compounds of Formulae (If) to (Ij):

[0274] R1is as defined in any one of paragraphs (1) to (5);

[0275] R2is as defined in any one of paragraphs (6) to (10);

[0276] R3is as defined in any one of paragraphs (11) to (20);

[0277] R4is as defined in any one of paragraphs (21) to (34);

[0278] X6is as defined in paragraph (43) or (44):

[0279] R7is as defined in any one of paragraphs (45) to (53):

[0280] R8, R9, R10and R11are each independently as defined in any one of paragraphs (54) to (58):

[0281] Rxis as defined in any one of paragraphs (68) to (71): and

[0282] Ryis as defined in any one of paragraphs (72) to (75).

[0283] In an embodiment of the compounds of Formulae (If) to (Ij) R4is hydrogen.

[0284] 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:

[0285]

[0286] herein.

[0287] In an embodiment of the compounds of Formulae (Ik) to (Io):

[0288] R3is as defined in any one of paragraphs (11) to (20);

[0289] R4is as defined in any one of paragraphs (21) to (34);

[0290] R7is as defined in any one of paragraphs (45) to (53): R8, R9, R10and R11are each independently as defined in any one of paragraphs (54) to (58):

[0291] Rxis as defined in any one of paragraphs (68) to (71): and

[0292] Ryis as defined in any one of paragraphs (72) to (75).

[0293] In an embodiment of the compounds of Formulae (Ik) to (Io) R4is hydrogen.

[0294] 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:

[0295]

[0296] wherein R3and R4each have any one of the meanings defined herein and RQis selected from:

[0297]

[0298]

[0299] In an embodiment of the compounds of Formula (Ip):

[0300] R3is as defined in any one of paragraphs (11) to (20); and

[0301] R4is as defined in any one of paragraphs (21) to (34).

[0302] In an embodiment of the compounds of Formula (Ip) R4is hydrogen.

[0303] 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:

[0304]

[0305] wherein R3, X₁, X₂, X₃, X₄, X₅ and X₆ each have any one of the meanings defined herein, and Q¹ is a 5-membered heteroaryl group, such as oxazolyl, oxadiazolyl, pyrazolyl, triazolyl and tetrazolyl (preferably oxazolyl or pyrazolyl) optionally substituted with C₁₋₃alkyl.

[0306] In an embodiment of the compounds of Formulae (Iq) to (Iv):

[0307] R3is as defined in any one of paragraphs (11) to (20);

[0308] X₁, X₂, X₃, X₄ and X₅ are each independently as defined in any one of paragraphs (39) to (42): X₆ is as defined in paragraph (43) or paragraph (44):

[0309] R7is as defined in any one of paragraphs (45) to (53):

[0310] R8, R9, R10and R11are each independently as defined in any one of paragraphs (54) to (58):

[0311] R12is as defined in any one of paragraphs (59) to (67):

[0312] Rxis as defined in any one of paragraphs (68) to (71): and

[0313] Ryis as defined in any one of paragraphs (72) to (75). 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:

[0314]

[0315] wherein R³ and X₆ each have any one of the meanings defined herein, Q¹ is a 5-membered heteroaryl group such as oxazolyl, oxadiazolyl, pyrazolyl, triazolyl and tetrazolyl (preferably oxazolyl or pyrazolyl) optionally substituted with C₁₋₃alkyl, and R^Q is selected from:

[0316]

[0317] wherein R7, R8, R9, R10and R11each have any one of the meanings defined herein. In an embodiment of the compounds of Formulae (Iw) to (laa):

[0318] R3is as defined in any one of paragraphs (11) to (20); X₆ is as defined in paragraph (43) or paragraph (44): R⁷ is as defined in any one of paragraphs (45) to (53): R⁸, R⁹, R¹⁰ and R¹¹ are each independently as defined in any one of paragraphs (54) to (58): R¹² is as defined in any one of paragraphs (59) to (67): Rˣ is as defined in any one of paragraphs (68) to (71): and Rʸ is as defined in any one of paragraphs (72) to (75). In a particular group of compounds of the invention, the compounds have the one of structural Formulae (Iab) to (Iaf) (sub-definitions of Formula (I)) shown below, or a pharmaceutically acceptable salt, solvate or hydrate thereof:

[0319]

[0320] wherein R³ has any one of the meanings defined herein, Q¹ is a 5-membered heteroaryl group (such as oxazolyl, oxadiazolyl, pyrazolyl, triazolyl or tetrazolyl) optionally substituted with C₁₋₃alkyl, and R^Q is selected from:

[0321]

[0322] 

[0323]

[0324] In an embodiment of the compounds of Formulae (lab) to (laf), R3is as defined in any one of paragraphs (11) to (20).

[0325] In a particular group of compounds of the invention, the compounds have the one of structural Formulae (lag) to (Ian) (sub-definitions of Formula (I)) shown below, or a pharmaceutically acceptable salt, solvate or hydrate thereof:

[0326]

[0327]

[0328] wherein R1, R2, R3, R4, X3, X4, X5, Xe, R9, and R11each have any one of the meanings defined herein.

[0329] In an embodiment of the compounds of Formula (lag) to Formula (Ian):

[0330] R1is as defined in any one of paragraphs (1) to (5);

[0331] R2is as defined in any one of paragraphs (6) to (10);

[0332] R3is as defined in any one of paragraphs (11) to (20);

[0333] R4is as defined in any one of paragraphs (21) to (34);

[0334] X3, X4 and X5 are each independently as defined in any one of paragraphs (39) to (42): X6is as defined in paragraph (43) or (44):

[0335] R9and R11are each independently as defined in any one of paragraphs (54) to (58): R12is as defined in any one of paragraphs (59) to (67):

[0336] Rxis as defined in any one of paragraphs (68) to (71): and

[0337] Ryis as defined in any one of paragraphs (72) to (75).

[0338] In an embodiment of the compounds of Formulae (lag) to (Ian), R⁹ is C₁₋₃alkyl (such as methyl) or C₃₋₆cycloalkyl (such as cyclopropyl). In an embodiment of the compounds of Formulae (Iag) to (Ian), R¹¹ is halo (such as chloro). In an embodiment of the compounds of Formulae (Iag) to (Ian), R⁹ is C₁₋₃alkyl (such as methyl) or C₃₋₆cycloalkyl (such as cyclopropyl), and R¹¹ is halo (such as chloro).

[0339] In an embodiment of the compounds of Formulae (lag) to (Ian), R4is hydrogen.

[0340] 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:

[0341]

[0342]

[0343]

[0344]

[0345]

[0346]

[0347]

[0348]

[0349]

[0350]

[0351]

[0352]

[0353]

[0354]

[0355]

[0356]

[0357]

[0358] The various functional groups and substituents making up the compounds of the Formula (I), and sub-formulae (la) to (Ian), 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.

[0359] 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.

[0360] 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 centre, 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 centre 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 laevorotatory (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".

[0361] The compounds of this invention may possess one or more asymmetric centres; 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.

[0362] 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).

[0363] It is also to be understood that certain compounds of the Formula (I), or sub-formulae (la) to (Ian), 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.

[0364] It is also to be understood that certain compounds of the Formula (I), or sub-formulae (la) to (Ian), may exhibit polymorphism, and that the invention encompasses all such forms that possess antiproliferative activity. Compounds of the Formula (I), and sub-formulae (la) to (Ian), may exist in a number of different tautomeric forms and references to compounds of the Formula (I), and sub-formulae (la) to (Ian), 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 (Ian). 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.

[0365]

[0366] keto enol enolate

[0367] Compounds of the Formula (I), and sub-formulae (la) to (Ian), containing an amine function may also form N-oxides. A reference herein to a compound of the Formula (I), or sub-formulae (la) to (Ian), 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.

[0368] 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.

[0369] Suitably, the present invention excludes any individual compounds not possessing the biological activity defined herein.

[0370] Synthesis

[0371] 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. 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.

[0372] 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.

[0373] It will be appreciated that during the synthesis of the compounds of the invention in the processes defined herein, or during the synthesis of certain starting materials, it may be desirable to protect certain substituent groups to prevent their undesired reaction. The skilled chemist will appreciate when such protection is required, and how such protecting groups may be put in place, and later removed.

[0374] 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.

[0375] 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.

[0376] 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.

[0377] 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.

[0378] Resins may also be used as a protecting group.

[0379] 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.

[0380] 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:

[0381] (i) removing any protecting groups present;

[0382] (ii) converting the compound Formula (I) into another compound of Formula (I); and / or (iii) forming a pharmaceutically acceptable salt, hydrate or solvate thereof.

[0383] 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.

[0384] The resultant compounds of Formula (I) can be isolated and purified using techniques well known in the art. Biological Activity

[0385] The biological assays described in the Examples section herein may be used to measure the pharmacological effects of the compounds of the present invention.

[0386] 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.

[0387] 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. Pharmaceutical Compositions

[0388] 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 the Formula (I), or sub-formulae (la) to (Ian)), or a pharmaceutically acceptable salt, hydrate or solvate thereof, in association with a pharmaceutically acceptable diluent or carrier.

[0389] 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).

[0390] 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.

[0391] 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.

[0392] 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.

[0393] 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.

[0394] 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.

[0395] Routes of Administration

[0396] 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).

[0397] 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.

[0398] Therapeutic Uses and Applications

[0399] 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).

[0400] 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.

[0401] 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.

[0402] 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.

[0403] 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.

[0404] 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.

[0405] In certain embodiments, there is provided a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, ora pharmaceutical composition as defined herein, for use in the treatment and / or prevention of multiple sclerosis (MS).

[0406] 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.

[0407] 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.

[0408] 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) ora pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.

[0409] 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.

[0410] 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) ora pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.

[0411] 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.

[0412] 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).

[0413] 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.

[0414] 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).

[0415] 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.

[0416] 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.

[0417] 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.

[0418] 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.

[0419] 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.

[0420] EXAMPLES

[0421] Abbreviations

[0422] Aq = aqueous

[0423] COMU = (1-Cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate

[0424] CuBr = Copper(l) bromide

[0425] Cui = Copper(I) iodide

[0426] Cu2O = Copper(l) oxide

[0427] DCE = dichloroethane

[0428] DCM = dichloromethane

[0429] DIPEA = N, N-diisopropylethylamine

[0430] DMAP = 4-Dimethylaminopyridine

[0431] DMF = dimethylformamide

[0432] DMSO = dimethyl sulfoxide

[0433] ES+ / - = electro spray ionization, positive or negative

[0434] EtOAc = ethyl acetate

[0435] EtOH = ethanol

[0436] Et2O = diethyl ether

[0437] FA = formic acid h = hour(s)

[0438] HATU = 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate

[0439] H2O = water

[0440] HCI = hydrogen chloride, hydrochloric acid

[0441] (prep) HPLC = (preparative) high performance liquid chromatography

[0442] I PA = propan-2-ol

[0443] K₂CO₃ = potassium carbonate

[0444] KF = potassium fluoride

[0445] K3PO4 = potassium phosphate tribasic

[0446] LC / MS = liquid chromatography mass spectrometry

[0447] LiOH.H2O = lithium hydroxide mono hydrate

[0448] MeCN = acetonitrile

[0449] MeMgBr = methylmagnesium bromide

[0450] MeOH = methanol

[0451] MgSC>4= magnesium sulfate

[0452] min(s) = minute(s)

[0453] MS = mass spectrometry

[0454] NaBH₄ = sodium borohydride

[0455] NaHCO3 = sodium hydrogen carbonate

[0456] NaOAc = sodium acetate

[0457] NaOH = sodium hydroxide

[0458] Na2SC>3 = Sodium sulfite

[0459] Na2SC>4= sodium sulfate

[0460] NBS = / V-bromosuccinimide

[0461] NH3 = ammonia

[0462] NH4CI = ammonium chloride

[0463] NIS = / V-iodosuccinimide

[0464] NMP = N-methyl-2-pyrrolidone

[0465] NMR = nuclear magnetic resonance

[0466] Pd(PPh3)Ch = Bis(triphenylphosphine)palladium(ll) dichloride

[0467] Pd(dppf)Ch = [1, T-bis(diphenylphosphino)ferrocene]dichloropalladium(ll)

[0468] Pd(Ph3P)4 = tetrakis(triphenylphosphine)palladium (0)

[0469] POCI3 = phosphorus oxychloride

[0470] Rf = retention factor

[0471] RT = room temperature

[0472] sat. = saturated

[0473] SFC = supercritical fluid chromatography

[0474] SOCl₂ = thionyl chloride

[0475] TFA = trifluoroacetic acid

[0476] THF = tetrahydrofuran

[0477] TLC = thin layer chromatography

[0478] UPLC = ultra performance liquid chromatography

[0479] Preparations of the compounds of the invention

[0480] 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 synthesis of 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.

[0481] 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-de (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.

[0482] General chromatography procedures

[0483] LC / MS:

[0484] Method A

[0485] 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]: [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.

[0486] Method B

[0487] 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.

[0488] Method C

[0489] Instrument: Agilent Technologies 1290 Infinity II Series LC I 6125 Quadrupole MSD SL, Column: Zorbax extend C18 5p, 4.6 x 50mm. Gradient [time (min) / solvent B (%)]: [0.0 / 10], [4.0 / 95], [5.0 / 95], [5.0 / 10], [6.0 / 10], (Solvent A = 770.08 mg of Ammonium acetate in 1000 mL of Milli-Q Water; Solvent B= MeCN); Injection volume 1pL (may vary); UV detection 210 to 400 nm; column temperature 25°C; 1.2 mL / min. Method D

[0490] Instrument: Waters Acquity H-Class plus UPLC, Column: BEH C18, 1.7 pm, 50 x 2.1mm. Solvent A- H2O + 0.1% aqueous ammonium hydroxide, Solvent B- acetonitrile. Gradient [Time (min) / % A: % B]: [[0.0 / 95:5], [0.1 / 95:5], [2.0 / 5:95], [2.3 / 0:100], [2.32 / 95:5], [2.5 / 95:5], Injection volume 0.5 pL (may vary); UV detection 200 to 400 nm; Column temperature 40 °C; 0.6 mL / min.

[0491] Prep-HPLC conditions:

[0492] Method A

[0493] Instrument: Agilent Technologies 1260 Infinity II Series LC / 6125 Quadrupole MSD. Solvent: A- 10 mM NH4HCO3 in H2O, B- acetonitrile, Column: X Bridge C8 (19 mm X 150mm), 5pm. Gradient [time (min) / solvent B (%)]: [0.0 / 10], [15 / 95], [18 / 95], [19 / 10], [21 / 10],

[0494] Method B

[0495] Instrument: Agilent Technologies 1260 Infinity II Series LC / 6125 Quadrupole MSD. Solvent: A- 0.1% HCOOH in H2O, B- acetonitrile, Column: X Bridge C8 (19 mm X 150mm), 5pm. Gradient [time (min) / solvent B (%)]: [0.0 / 10], [15 / 95], [18 / 95], [19 / 10], [21 / 10],

[0496] Method C

[0497] Instrument: Waters 2545 quartenery system with Waters 2489 UV Detector. Solvent: A- H2O, B- MeCN, Column: Sunfire Prep C18 (150 x 19 mm, 5um). Gradient [time (min) / solvent B (%)]:

[0498] [0 / 40], [16.0 / 45],

[0499] Method D

[0500] Instrument: Gilson Semi Preparative HPLC, Solvent: A- H2O + 0.2% trifluoroacetic acid, B -acetonitrile, Column: Kinetix C18. Gradient [time (min) / solvent B (%)]: [0 / 40], [11.5 / 70], Method E

[0501] Instrument: Waters Prep HPLC with MS detector. Solvent: A- 0.1% formic acid in H2O, B-acetonitrile, Column: Gemini NX, C18, (250 x 21.2 mm), 5um, 110A. Flow rate 28.5 mL / min. Gradient [time (min) / solvent B (%)]: [0.0 / 30], [6.0 / 60], [8 / 60],

[0502] Method F

[0503] Instrument: Shimadzu LC20AP with UV detector. Solvent: A- 0.1% methanolic ammonia in methanol, Column: Chiralpak IH (250 x 30mm, 5pm). Flow rate 20 mL / min. Isocratic, 100% solvent A.

[0504] Method G

[0505] Instrument: Shimadzu LC20AP with UV detector. Solvent: A- 0.1% formic acid in H2O, B-acetonitrile, Column: Gemini NX, C18, 250X21.2 mm, 5um, 110A. Flow rate 30 mL / min. Gradient [time (min) / solvent B (%)]: [0.0 / 40], [6.0 / 50], [13 / 50],

[0506] Method H Instrument: Shimadzu LC20AP with UV detector. Solvent: A- 0.1% methanolic ammonia in n-hexane, B-0.1% methanolic ammonia in IPA: MeCN (70:30) Column: Chiralpak IK (250 x 30mm, 5pm). Flow rate 30 mL / min. Isocratic, 75% solvent A.

[0507] Method I

[0508] Instrument: Waters 2545 binary system with Waters 2489 UV Detector. Solvent: A- H2O + 0.05% formic acid, B- MeCN, Column: Shim-pack GIST C18 (250 x 20 mm, 5um). Flow rate 20 mL / min. Gradient [time (min) / solvent B (%)]: [0 / 40], [15.0 / 55], [19.0 / 55],

[0509] Method J

[0510] Instrument: Shimadzu LC20AP with UV detector. Solvent: A- 0.1% formic acid in H2O, B-acetonitrile, Column: Gemini NX, C18, 250X21.2 mm, 5um, 110A. Flow rate 30 mL / min. Gradient [time (min) / solvent B (%)]: [0.0 / 40], [6.0 / 57], [9 / 57],

[0511] Prep-SFC conditions:

[0512] Method A

[0513] Instrument: Waters SFC 350 with 2489 UV Detector. Solvent: 0.1% methanolic ammonia in MeOH: MeCN (50:50) in CO2, (40% isocratic), Column: LuxAmylose-1, 5 pm, 250 x21.2 mm. Flow rate 150 mL / min.

[0514] Synthesis of intermediates

[0515] Synthesis of Intermediate 1, methyl 6-chloroindolizine-3-carboxylate

[0516]

[0517] Step 1: To a solution of tributyl(vinyl)tin (214.28 g, 675.74 mmol)) in toluene (1000 ml) was added 2,5-dichloropyridine (CAS 16110-09-1,100.0 g, 675.74 mmol). The reaction mixture was degassed for 30 minutes by purging nitrogen and added Pd(PPh3)Cl2 (14.23 g, 20.27 mmol), heated mixture to 100 °C for 4 hours. The reaction mixture was concentrated under reduced pressure at 35 °C. This residue was slowly added in to 10% aqueous potassium fluoride (2000 ml) followed by ethyl acetate (1000 ml) and stirred for 1h. The white precipitates were filtered off and the filtrate was collected. Aqueous layer was further extracted with ethyl acetate (1000 ml) and the combined organic layers were dried over sodium sulfate and concentrated. The crude product was purified by silica gel chromatography (hexane I ethyl acetate, 10 / 2), to afford 5-chloro-2-vinylpyridine (60 g, 63.61%) as light-yellow oil.1H NMR: (400 MHz, CDCh): 6: 8.53 (d, J = 2 Hz, 1 H), 7.64 (dd, J = 2.4, 6 Hz, 1 H), 7.29 (t, J = 8 Hz, 1 H), 6.83-6.76 (m, 1 H), 6.22 (d, J = 17.2 Hz, 1H), 5.54 (d, J = 10.8 Hz, 1H).

[0518] Step 2: To a stirred solution of NIS (161.19 g, 716.42 mol) and NaOAc (51.42 g, 626.87 mol) in Acetonitrile (750 ml), was slowly added 3-Ethoxy-3-oxopropanoic acid (63.45 g, 537.32 mol) and 2-vinylpyridine (2.0 g, 0.014 mol). The reaction mixture was stirred overnight at 95 °C. The reaction was, cooled to room temperature and quenched with saturated aqueous Na2SO3 (2000 ml). This mixture was extracted with Hexane (3 X 1000 mL) and the organic layers were combined and dried over anhydrous Na2SO4. The crude product was purified by silica gel chromatography (ethyl acetate: hexane 1:99) to afford methyl 6-chloroindolizine-3-carboxylate (18.0 g, 47.94%).

[0519] 1H NMR: (400 MHz, CDCI3): 5: 9.52 (s, 1H), 7.50-7.43 (m, 2H), 7.00 (m, 1H), 6.53 ((d, J = 4.4 Hz,1H), 3.92 (s, 3H).

[0520] Synthesis of Intermediate 2, methyl 6-chloro-1-sulfamoylindolizine-3-carboxylate

[0521]

[0522] Intermediate 1 Intermediate 2 Step 1: Methyl 6-chloroindolizine-3-carboxylate (Intermediate 1, 1.50 g, 7.17 mmol) was dissolved in THF (15 ml). To it, Burgess reagent (2.22 g, 9.32 mmol) was 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). The aqueous layer was further extracted with EtOAc (2 x 100 ml). Organic layers were combined, dried (Na2SO4) and concentrated in vacuo. The crude product was purified by normal phase gradient flash column chromatography (silica), 0% to 40% EtOAc in hexane to afford 6-chloro-1-(N-(methoxycarbonyl)sulfamoyl)indolizine-3-carboxylate (0.75 g, 30.21%) as off white solid. TLC: (5:5, EtOAc / Hexane, Rf: 0.3)

[0523] LCMS: (Method A): m / z 345.06 (ES-), at 1.588min.

[0524] Step 2: 6-chloro-1-(N-(methoxycarbonyl)sulfamoyl)indolizine-3-carboxylate (0.75 g, 2.16 mmol) was dissolved in pyridine (4 ml) and water (4 ml) and stirred at 80 °C for 16 h. The solvent was removed in vacuo to afford methyl 6-chloro-1-sulfamoylindolizine-3-carboxylate (0.55 g, 88.10%) as brown solid. TLC: (5:5, EtOAc / Hexane, Rf: 0.5).

[0525] 1H-NMR: (400MHz, DMSO) δ 9.45 (dd, J = 1.9, 0.9 Hz, 1H), 8.07 (dd, J = 9.6, 0.9 Hz, 1H), 7.73 (s, 1H), 7.57 (dd, J = 9.6, 1.9 Hz, 1H), 7.48 (s, 2H), 3.89 (s, 3H).

[0526] Synthesis of Intermediate 3, methyl 6-chloro-1 -(chlorosulfonyl) indolizine-3-carboxylate

[0527]

[0528] Methyl 6-chloroindolizine-3-carboxylate (Intermediate 1, 10.00 g, 47.85 mmol) was dissolved in chlorosulfonic acid (30 ml) at 0°C. Reaction mixture was stirred at room temperature for 2h. Reaction mixture was quenched with ice cold water (500 ml) and extracted by EtOAc (500 ml). Aqueous layer further extracted with EtOAc (2 x 500 ml). Organic layers were combined and dried (Na2SO4). Solvent was removed in vacuo, to afford crude methyl 6-chloro-1-(chlorosulfonyl) indolizine-3-carboxylate (10.00 g, 68.11%) as light brown compound which was used without further purification.

[0529] 1H-NMR: (400MHz, DMSO) δ 9.35 (dd, J = 2.0, 0.9 Hz, 1H), 8.01 (dd, J = 9.5, 0.9 Hz, 1H), 7.41 (s, 1H), 7.30 (dd, J = 9.5, 1.9 Hz, 1H), 3.84 (s, 3H).

[0530] LCMS: (Method A): Product mass was confirmed as sulfonic acid m / z 288.0 (ES-), at 2.580 min.

[0531] Synthesis of Intermediate 4, 6-chloro-3-cyanoindolizine-1-sulfonyl chloride

[0532]

[0533] Step 1: methyl 6-chloroindolizine-3-carboxylate (Intermediate 1, 1.00 g, 4.78 mmol) was dissolved in THF (5 ml) and water (5 ml). LiOH monohydrate (1.00 g, 23.90 mmol) was added at room temperature and the reaction was stirred at 60 °C for 16 h. Reaction mixture was partitioned between water (150 ml) and EtOAc (2 x 50 ml). Combined organic layers were discarded. Aqueous layer was acidified with 1N HCI (50 ml) up to pH ~2 and extracted with EtOAc (2 x 70 ml). Organic layers were combined and dried (Na2SO4). Solvent was removed in vacuo to afford crude 6-chloroindolizine-3-carboxylic acid (0.80 g, 85.74%) as off white solid which was used without purification.

[0534] TLC: (2:8; EtOAc / Hexane, Rf: 0.4).

[0535] LCMS: (Method A): m / z 194.08 (ES-), at 1.512 min.

[0536] Step 2: 6-chloroindolizine-3-carboxylic acid (0.80 g, 4.10 mmol) was dissolved in DCM (8 ml). To it HATU (3.90 g, 10.25 mmol) and DIPEA (2.86 ml, 16.40 mmol) were added at 0°C. Reaction mixture was stirred at 0 °C for 20 min. NH4CI (3.26 g, 61.53 mmol) was added and reaction mixture was stirred at room temperature 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 10% EtOAc in hexane to afford 6-chloroindolizine-3-carboxamide (0.70 g, 87.94%) as grey solid.

[0537] TLC: (1:9; EtOAc / Hexane, Rf: 0.3).

[0538] LCMS: (Method A): m / z 195.06 (ES+), at 1.861min.

[0539] Step 3: 6-chloroindolizine-3-carboxamide (0.60 g, 4.10 mmol) was dissolved in DCM (6 ml). DMF (3.90 g, 10.25 mmol) and POCl3(2.86 ml, 16.40 mmol) were added at 0 °C. Reaction mixture was stirred at room temperature for 10 min. Reaction mixture was directly injected onto normal phase gradient flash column chromatography, product eluted at 0% to 10% EtOAc in hexane to afford 6-chloroindolizine-3-carbonitrile (0.23 g, 42.25%) as a white solid.

[0540] TLC: (1:9; EtOAc / Hexane, Rf: 0.5).

[0541] LCMS: (Method A): major peak rt 2.02 min, but product mass was not observed.

[0542] Step 4: 6-chloroindolizine-3-carbonitrile (0.23 g, 1.30 mmol) was dissolved in MeCN (6 ml). Chlorosulfonic acid (0.43 ml, 6.53 mmol) was added at 0 °C. The reaction was stirred at room temperature for 1 h, then poured into ice cold water (150 ml) and extracted with EtOAc (50 ml). Aqueous layer was further extracted with EtOAc (2 x 50 ml). Organic layers were combined, dried (Na2SO4) and concentrated to afford 6-chloro-3-cyanoindolizine-1 -sulfonyl chloride (0.3 g, 83.80%) as a yellow solid which was used without purification.

[0543] LCMS: (Method A): m / z 255.00 (mass of sulfonic acid observed) (ES-), at 1.538 min.

[0544] 1H-NMR: (400MHz, DMSO): δ 8.57 (dd, J = 1.9, 0.9 Hz, 1H), 7.98 (dd, J = 9.6, 0.9 Hz, 1H), 7.51 (s, 1H), 7.27 (dd, J= 9.6, 1.8 Hz, 1H).

[0545] is of Intermediate 5, 6-chloro-3-i

[0546]

[0547] i-1 -sulfonamide

[0548]

[0549] Intermediate 4 Intermediate 5

[0550] 6-chloro-3-cyanoindolizine-1-sulfonyl chloride (Intermediate 4, 0.30 g, 1.10 mmol) was dissolved in THF (3 ml) at -78°C. NH3(g) was purged through reaction mixture for 1 h at -78 °C. Reaction mixture was concentrated in vacuo. The crude product was purified by normal phase gradient flash column chromatography (normal phase, silica), product eluted at O% to 50% EtOAc in hexane to afford 6-chloro-3-cyanoindolizine-1 -sulfonamide (0.22 g, 78.78%) as an off white solid.

[0551] LCMS: (Method A): m / z 254.02 (ES-), at 1.808 min.

[0552] 1H-NMR: (400MHz, DMSO): δ 8.78 - 8.73 (m, 1H), 8.06 - 8.00 (m, 1H), 7.89 (s, 1H), 7.60 -7.47 (m, 3H).

[0553] is of Intermediate 6, 2,5-dibromo-3-fluoro-6-

[0554]

[0555]

[0556] 5-bromo-3-fluoro-6-methoxypyridin-2-amine (CAS 1402921-50-9, 1.70 g, 7.73 mmol) was dissolved in dibromoethane (17 ml). To it, copper(ll) bromide (5.17 g, 23.18 mmol) was added at room temperature. Reaction mixture was stirred at 0 °C for 10min. Isoamyl nitrite (3.11 ml, 23.18 mmol) was added and reaction mixture was stirred at room temperature for 16h. Reaction mixture was diluted with water (200 ml) and extracted with EtOAc (100 ml). Aqueous layer was further extracted with EtOAc (2 x 100 ml). Organic layers were combined and dried (Na2SO4). Solvent was removed in vacuo to afford crude product which was purified by normal phase gradient column chromatography (silica), product eluted at 0% to 10% EtOAc in Hexane to afford 2,5-dibromo-3-fluoro-6-methoxypyridine (1.00 g, 45.73%) as yellow solid.

[0557] TLC: (2:8; EtOAc / Hexane, Rf: 0.5).

[0558] 1H-NMR: (400MHz, DMSO): δ 8.35 (d, J= 6.9 Hz, 1H), 3.92 (s, 3H).

[0559] 3-i

[0560]

[0561]

[0562]

[0563] Step 1: 2,5-dibromopyridine (CAS 624-28-2, 36.00 g, 153.19 mmol), potassium trifluoro(vinyl)borate (24.63 g, 183.80 mmol) and triethylamine (66.3 ml, 459.57 mmol) were dissolved in I PA (250 ml). N2 gas was purged through reaction mixture for 30 min at room temperature. PdCl2(dppf)DCM (6.94 g, 8.51 mmol) was added and again N2 gas was purged through reaction mixture for 30 min. Reaction mixture was stirred at 90 °C for 1h. Reaction mixture was filtered via celite bed and washed with water (500 ml) and EtOAc (500 ml). Aqueous layer was further extracted with EtOAc (2 x 500 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 1% EtOAc in hexane to afford 5-bromo-2-vinylpyridine (29.00 g, Quantitative) as yellow oil.

[0564] LCMS: (Method A): m / z 184.0 (ES+), at 2.047 min.

[0565] Step 2: 5-bromo-2-vinylpyridine (20.00 g, 109.28 mmol) was dissolved in MeCN (300 ml). 3-methoxy-3-oxopropanoic acid (38.68 g, 327.86 mmol) and NaOAc (26.88 g, 327.86 mmol) were added at room temperature. After this, N-iodosuccinamide (86.06 g, 382.51 mmol) was added portion-wise at room temperature and reaction mixture was stirred at 100 °C for 16 h. Reaction mixture quenched with saturated sodium thiosulfate solution (500 ml) and product was extracted with EtOAc (4 x 500 ml). Organic layers were combined, dried (Na2SO4) and concentrated. The crude product was purified by reverse phase gradient flash column chromatography (C18-silica, 320 g column), product eluted at 100% MeCN to afford methyl 6-bromoindolizine-3-carboxylate (14.00 g, 50.63%) as a brown solid.

[0566] LCMS: (Method A): m / z 254.0 (ES+) at 2.026 min.

[0567] 1H-NMR: (400MHz, DMSO): δ 3.84 (s, 3H), 6.69 (d, 1H, J= 2.2Hz), 7.28-7.26 (dd, 1H, J= 1.6Hz and J= 9.2Hz), 7.49 (d, 1H, J= 4.8Hz), 7.71 (d, 1H, J= 9.2Hz), 9.47 (s, 1H).

[0568] Synthesis of Intermediate 8, 2-bromo-5-(difluoromethoxy)-3-methoxypyrazine

[0569]

[0570] Intermediate 8 Step 1: 5-bromo-6-chloropyrazin-2(1H)-one (CAS 913282-74-3, 1.0g, 4.81 mmole) was dissolved in 1,4-Dioxane (15mL). To it, potassium terf-butoxide (5.38g, 48.10mmole) and methanol (1.95mL, 48.10mmole) were added at 0 °C. Reaction mixture was stirred at 60 °C for 16h. Reaction mixture was diluted with ice cold water (100mL) and pH adjusted to ~7 using 1N HCI solution. Aqueous layer was extracted with DCM (70mL). Aqueous layer was further extracted with DCM (2 x 50mL). Organic layers were combined, dried (Na2SO4) and concentrated to afford 5-bromo-6-methoxypyrazin-2(1H)-one (0.80g, 81.63%) as a white solid which was used without purification.

[0571] LCMS: (Method A): m / z 205.0 (ES+), at 1.285 min.

[0572] Step 2: 5-bromo-6-methoxypyrazin-2(1H)-one (0.80g, 3.94mmole) and K₂CO₃ (0.54g, 3.94mmole) was dissolved in DMF (15mL) at room temperature and reaction mixture was stirred for 10min at room temperature. To it, sodium 2-chloro-2,2-difluoroacetate (0.71g, 4.70mmole) was added and reaction mixture was allowed to stir at 100 °C for 2h. Reaction mixture was diluted with water (50mL) and extracted with n-hexane (50mL). Aqueous layer was further extracted with n-hexane (2 x 50mL). Organic layers were combined and dried (Na2SO4). Solvent was removed in vacuo to obtain crude, which was purified by normal phase column chromatography (silica) product eluted at 0% to 2% EtOAc in n-hexane to afford 2-bromo-5-(difluoromethoxy)-3-methoxypyrazine (0.52g, 52.20%) as colourless liquid.

[0573] 1H-NMR: (400MHz, DMSO): δ 4.01 (s, 3H), 7.73 (t, 1H, J= 71.8Hz), 7.99 (s, 1H).

[0574] Synthesis of Intermediate 9, 2-bromo-5-(2,2-difluoroethoxy)-3-fluoro-6-methoxypyridine

[0575]

[0576] Step 1: 5-(2,2-difluoroethoxy)-3,6-difluoropyridin-2-amine (CAS 2404661-28-3, 0.70 g, 3.33 mmol) was dissolved in acetonitrile (4 ml). To it, CuBr (2.30 g, 16.66 mmol) was added at 0 °C. Terf-butylnitrite (1.98 ml, 16.66 mmol) was added at room temperature and reaction mixture was stirred at room temperature for 16h. Reaction mixture partitioned between cold water (50 ml) and EtOAc (40 ml). Aqueous layer was further extracted with EtOAc (2 x 30 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 12% EtOAc in hexane to afford 2-bromo-5-(2,2-difluoroethoxy)-3,6-difluoropyridine (0.30 g, 32.98%) as a brown solid.

[0577] TLC: (3:7; EtOAc / Hexane, Rf: 0.6).

[0578] LCMS: (Method A): Product m / z was not supported for major peak at 1.380 min.

[0579] Step 2: 2-bromo-5-(2,2-difluoroethoxy)-3,6-difluoropyridine (0.30 g, 1.09 mmol) was dissolved in MeOH (5 mL) at room temperature. To it, sodium methoxide (30% solution in MeOH) (1.04 ml, 5.49 mmol) was added at room temperature. Reaction mixture was stirred at 60 °C for 16h. Reaction mixture was partitioned between water (70 ml) and EtOAc (60 ml). Aqueous layer was further extracted with EtOAc (2 x 50ml). 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 2-bromo-5-(2,2-difluoroethoxy)-3-fluoro-6-methoxypyridine (0.30 g, 95.78%) as an off white solid.1H-NMR: (400MHz, DMSO): δ 7.74 (d, J = 9.0 Hz, 1H), 6.43 (tt, J = 54.2, 3.6 Hz, 1H), 4.40 (td, J = 14.5, 3.6 Hz, 2H), 3.88 (s, 3H).

[0580] Synthesis of Intermediate 10, 2-bromo-5-(2-fluoroethoxy)-4-methoxypyrimidine

[0581]

[0582] 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.

[0583] LCMS: (Method A): m / z 251.00 (ES+) at 1.416 min.

[0584] 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).

[0585] Synthesis of Intermediate 11, 2-(4-amino-2-fluoro-5-methoxyphenyl)acetonitrile

[0586]

[0587] 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, PdCI2(dppf) (0.17 g, 0.23 mmol) was added and reaction mixture was stirred at 120 °C for 16h. 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.

[0588] LCMS: (Method A): m / z 181.15 (ES+), at 1.850 min.

[0589] 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).

[0590] Synthesis of Intermediate 12, 2-(6-bromo-5-fluoro-2-methoxypyridin-3-yl)acetonitrile

[0591]

[0592] 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 10min. After this, isoamyl nitrite (0.44 ml, 3.31 mmol) was added at 0 °C. Reaction mixture was stirred at room temperature for 16h. 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.

[0593] LCMS: (Method A): Product mass was not observed in the major peak at 2.160 min.

[0594] 1H-NMR: (400MHz, DMSO): δ 7.89 (d, J = 7.7 Hz, 1H), 3.98 - 3.86 (m, 5H).

[0595] Synthesis of Intermediate 13, 6-chloroindolizine

[0596]

[0597] To a solution of 6-chloroindolizine-2-carboxylic acid (CAS 1206974-04-0, 1.4 g, 7.16 mmol) in quinoline (20 mL, 7.16 mmol) was added copper powder (4.55 g, 71.6 mmol) at RT. Reaction mixture was stirred at 200 °C for 3 h. The reaction mixture was concentrated on high vacuum, filtered through celite bed, and bed was washed with EtOAc (20 mL) and filtrate was concentrated under reduced pressure to afford crude. Crude product was purified by flash column chromatography (silica) eluting 0-5% EtOAc in petroleum ether to afford 6-chloroindolizine (0.3 g, 1.959 mmol, 27.4 % yield) as an off-white solid.1H-NMR: (400MHz, DMSO): δ 8.53 (s, 1 H), 7.56 (s, 1 H), 7.47 (d, J = 12.40 Hz, 1H), 6.78 (d, J = 3.60 Hz, 1H), 6.68 (d, J = 2.40 Hz, 1H), 6.48 (d, J = 5.20 Hz, 1H).

[0598] LCMS: (Method C) [M+H]+: 152.0, at 2.31 min.

[0599] Synthesis of Intermediate 14, 6-chloroindolizine-1-sulfonamide

[0600]

[0601] Step 1: To a solution of 6-chloroindolizine (Intermediate 13, 1.0 g, 6.6mmol) in THF (15 mL) was added Burgess' reagent (1.73g, 7.26mmol). The reaction mixture was stirred at room temperature for 48h. The reaction mixture was diluted with DCM (50 mL) and washed with 1M aqueous HCI solution (2 x 40 mL), the organic layer dried (Na2SO4) and concentrated to afford 1.3g of crude product as a mixture of methyl ((6-chloroindolizin-1-yl)sulfonyl)carbamate (Intermediate 14) and the regioisomer methyl ((6-chloroindolizin-3-yl)sulfonyl)carbamate, which was carried onto the next step without purification.

[0602] LCMS (Method D) [M+H+J: 288.85 at 0.22 min.

[0603] Step 2: A solution of methyl N-(6-chloroindolizin-1-yl)sulfonylcarbamate (as a mixture also containing the undesired regioisomer, 170 mg, 0.590 mmol) in pyridine (5 mL) and water (5 mL) was stirred at 100 °C overnight. The reaction was evaporated in vacuo to afford the product as a mixture of 6-chloroindolizine-1-sulfonamide (Intermediate 14) and the regioisomer 6-chloroindolizine-3-sulfonamide (640 mg, 2.77mmol, 61.62% yield), which was carried onto the next step without purification.

[0604] LCMS (Method D) [M+H+] 230.91, at 0.93 min.

[0605] If desired the regioisomers can be separated by reverse phase gradient flash column chromatography (C18 silica) product eluted at 0% to 30% Acetonitrile in water.

[0606] Synthesis of Intermediate 15, 6-bromo-3-(2-fluoroethoxy)-2-methoxypyridine

[0607]

[0608] 6-bromo-2-methoxypyridin-3-ol (CAS 1823333-27-2, 0.50 g, 2.46 mmol) was dissolved in DMF (4 ml). To it, K₂CO₃ (0.40 g, 2.96 mmol) and 1-fluoro-2-iodoethane (0.72 g, 4.19 mmol) were added at room temperature and the reaction mixture was irradiated to 70 °C for 30 min in the microwave. The reaction mixture was partitioned between water (50 ml) and EtOAc (50 ml). The aqueous layer was further extracted with EtOAc (2 x 50 ml). Organic layers were combined and dried (Na2SO4). Solvent was removed in vacuo and the crude product was purified by normal phase gradient flash column chromatography (silica), product eluted at 0% to 8% EtOAc in Hexane to afford 6-bromo-3-(2-fluoroethoxy)-2-methoxypyridine (0.26 g, 42.39%) as an off-white solid.

[0609] TLC: (2:8, EtOAc / Hexane, Rf: 0.6).

[0610] LCMS: (Method A): m / z 250.03 (ES+) at 1.732 min.

[0611] Synthesis of Intermediate 16, 2-chloropyrrolo[1,2-b]pyridazine

[0612]

[0613] Intermediate 16

[0614] Step 1: A solution of 3,6-dichloropyridazine (CAS 141-30-0, 2 g, 13.43 mmol) in 1,4-dioxane (5 mL) was purged for 10 min. To this reaction mixture, Tetrakis(triphenylphosphine)palladium(0) (1.55 g, 1.34 mmol) and tri butyl-(1-propynyl)tin (4.49 mL, 14.77 mmol) were added at RT, and the reaction mixture was stirred at 100 °C for 3 h. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2 x 50 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the crude as a brown liquid. The crude was purified by normal phase gradient flash column chromatography (silica), product eluted at 0-20% EtOAc in petroleum ether to afford 3-chloro-6-(prop-1-yn-1-yl)pyridazine as a pale yellow solid (1.5 g, 9.63 mmol, 71.8% yield).

[0615] 1H-NMR: (400MHz, DMSO): δ 7.94 (d, J= 12.00 Hz, 1H), 7.85 (d, J= 12.00 Hz, 1H), 2.18 (s, 3H).

[0616] Step 2: To a microwave vial, 3-chloro-6-(prop-1-yn-1-yl)pyridazine (500 mg, 3.28 mmol), triethylamine (1.42 mL, 9.83 mmol) and copper(l) chloride (324 mg, 3.28 mmol) were added. Then, DMA (4 mL) was added at RT, and the resultant reaction mixture was irradiated at 140 °C in the microwave for 6 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with water (3 x 10 mL), dried over anhydrous sodium sulfate, and concentrated. The crude was purified by flash column chromatography (silica) 0-10% Ethyl acetate / petroleum ether to afford 2-chloropyrrolo[1,2-b]pyridazine as a pale yellow gummy liquid. (118 mg, 0.77 mmol, 23.55% yield).1H-NMR: (400MHz, DMSO): δ 8.07 (d, J= 9.20 Hz, 1H), 7.91 (t, J= 1.60 Hz, 1H), 6.92 (dd, J = 2.80, 4.40 Hz, 1H), 6.77 (d, J = 9.20 Hz, 1H), 6.67 (dd, J= 1.60, 4.40 Hz, 1H).

[0617] Synthesis of Intermediate 17, 2-chloropyrrolo[1,2-b]pyridazine-5-sulfonyl chloride

[0618]

[0619] Intermediate 16 Intermediate 17 Step 1: To a stirred solution of 3-chloropyrrolo[1,2-a]pyrazine (Intermediate 16, 80 mg, 0.524 mmol) in MeCN (2 mL) was added chlorosulfonic acid (61.1 mg, 0.524 mmol) at RT. The reaction mixture was stirred at 70 °C for 1 hour and concentrated. The crude was purified by prep-HPLC purification (Method A) to afford 3-chloropyrrolo[1,2-a]pyrazine-8-sulfonic acid (90 mg, 0.336 mmol, 64.1 %).

[0620] 1H-NMR: (400MHz, DMSO): δ 8.26 (d, J = 9.60 Hz, 1H), 7.76 (d, J = 2.80 Hz, 1H), 6.90 (d, J = 2.80 Hz, 1 H), 6.85 (d, J = 9.20 Hz, 1 H). -OH was not observed.

[0621] Step 2: To a stirred solution of 2-chloropyrrolo[1,2-b]pyridazine-5-sulfonic acid (90 mg, 0.387 mmol) in Toluene (5 mL), was added PCI5 (403 mg, 1.934 mmol) and the resultant reaction mixture was stirred at 90 °C for 16 hours. The reaction mixture was directly concentrated under reduced pressure and used without purification.

[0622] Synthesis of Intermediate 18, methyl 6-(difluoromethyl)-1-sulfamoylindolizine-3-carboxylate

[0623]

[0624] Intermediate 18

[0625] Step 1: 2-bromo-5-(difluoromethyl) pyridine (CAS 1221272-81-6, 10 g, 48.32 mmol), potassium trifluoro(vinyl)borate (7.76 g, 57.99 mmol) and triethylamine (20.5 ml, 144.96 mmol) were dissolved in I PA (100 ml). N2 gas was purged through reaction mixture for 30 min at room temperature. After this, PdCl2(dppf)DCM (1.97 g, 2.42 mmol) was added and reaction mixture was stirred at 90 °C for 4h. Reaction mixture was filtered via celite bed and washed with water (300 ml) and EtOAc (200 ml). Aqueous layer was further extracted with EtOAc (2 x 100 ml). Organic layers were combined and dried (Na2SO4). Solvent was removed in vacuo at 30°C to afford crude product which was purified by normal phase gradient column chromatography (silica), product eluted at 0% to 4% EtOAc in hexane to afford 5-(difluoromethyl)-2-vinylpyridine (6.00 g, 80%) as colourless oil.

[0626] LCMS: (Method A): m / z 156.08 (ES+) at 1.883 min.

[0627] Step 2: 5-(difluoromethyl)-2-vinyl pyridine (6.00 g, 38.70 mmol) was dissolved in MeCN (60 ml). 3-methoxy-3-oxopropanoic acid (9.13 g, 77.39 mmol) and sodium acetate (9.52 g, 116.09 mmol) were added at room temperature. After this, N-iodosuccinimide (30.46 g, 135.44 mmol) was added portion-wise at room temperature and reaction mixture was stirred at 100 °C for 6 h. The reaction mixture was quenched with saturated aqueous sodium bisulfite solution (300 ml) and product was extracted with EtOAc (3 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 2% EtOAc in hexane to afford methyl 6-(difluoromethyl)indolizine-3-carboxylate (4.00 g, 45.93%) as a brown solid.

[0628] LCMS: (Method A): m / z 226.12 (ES+) at 2.395 min.

[0629] Step 3: Methyl 6-(difluoromethyl)indolizine-3-carboxylate (4.00 g, 17.77 mmol) was dissolved in MeCN (40 ml). To it, chlorosulfonic acid (5.91 ml, 88.87 mmol) was added at 0 °C. The reaction mixture was stirred at room temperature for 4 h, then poured into ice cold water (400 ml) and extracted with DCM (400 ml). Aqueous layer was further extracted with DCM (2 x 100 ml). Organic layers were combined, dried (Na2SO4) and concentrated to afford crude methyl 1-(chlorosulfonyl)-6-(difluoromethyl)indolizine-3-carboxylate (4.00 g, 69.68%) as a brown solid.

[0630] LCMS: (Method A): m / z 304.06 (ES-, observed as sulfonic acid) at 1.631 min.

[0631] Step 4: Methyl 1-(chlorosulfonyl)-6-(difluoromethyl)indolizine-3-carboxylate (4.00 g, 12.38 mmol) was dissolved in THF (40 ml) at -78 °C. NH3 (g) was purged through reaction mixture for 4 h at -78 °C. Reaction mixture was concentrated in vacuo to afford crude product which was purified by normal phase gradient flash column chromatography (silica), product eluted at 0% to 50% EtOAc in hexane to afford methyl 6-(difluoromethyl)-1-sulfamoylindolizine-3-carboxylate (3.40 g, 90.31%) as a brown solid.

[0632] LCMS: (Method A): m / z 303.06 (ES-) at 2.015 min.

[0633] 1H-NMR: (400MHz, DMSO): 59.69 (s, 1H), 8.17 (d, J = 9.4 Hz, 1H), 7.80 (s, 1H), 7.61 (dd, J = 9.3, 1.5 Hz, 1H), 7.49 (s, 2H), 7.29 (t, J = 54.9 Hz, 1H), 3.90 (s, 3H).

[0634] Synthesis of Intermediate 19, methyl 6-(difluoromethoxy)-1-sulfamoylindolizine-3-carboxylate

[0635]

[0636] Prepared in a similar fashion to Intermediate 18 (steps 1-4) from CAS 845827-14-7, to afford methyl 6-(difluoromethoxy)-1-sulfamoylindolizine-3-carboxylate (1.00 g) as a brown solid. LCMS: (Method A): m / z 321.0 (ES+) at 1.915 min.

[0637] 1H-NMR: (400MHz, DMSO): 59.37 (d, J= 2.1 Hz, 1H), 8.10 (dd, J= 9.7, 0.9 Hz, 1H), 7.74 (s, 1 H), 7.54 - 7.09 (m, 4H), 3.88 (s, 3H).

[0638] Synthesis of Intermediate 20, 2-bromo-5-(2-fluoroethoxy)-3-methoxypyrazine

[0639]

[0640] Step 1: 5-bromo-6-chloropyrazin-2(1H)-one (CAS 913282-74-3, 1.0g, 4.81 mmole) was dissolved in 1,4-Dioxane (15mL). To it, potassium terf-butoxide (5.38g, 48.10mmole) and methanol (1.95mL, 48.10mmole) were added at 0 °C. Reaction mixture was allowed to stir at 60 °C for 16 h. Reaction mixture was diluted with ice cold water (100 mL) and adjust pH up to ~7 using 1N HCI solution. Aqueous layer was extracted with DCM (70mL). Aqueous layer was further extracted with DCM (2 x 50mL). The combined organic layers were dried (Na2SO4) and concentrated to afford 5-bromo-6-methoxypyrazin-2(1H)-one (0.80g, 81.63%) as white solid which was used for next step without any purification.

[0641] LCMS: (Method A): m / z 205.0 (ES+), at 1.285 min.

[0642] Step 2: 5-bromo-6-methoxypyrazin-2(1H)-one (0.45 g, 2.20 mmol) was dissolved in MeCN (5 ml). To it, potassium carbonate (0.91 g, 6.61 mmol) and 1-fluoro-2-iodoethane (0.23 ml, 2.64 mmol) were added at room temperature. Reaction mixture was irradiated to 100 °C in the microwave for 1 h. The reaction mixture was partitioned between water (50 ml) and EtOAc (30 ml). The aqueous layer was further extracted with EtOAc (2 x 30 ml). The combined organic layers were dried (Na2SO4) and concentrated. The crude was purified by normal phase gradient flash column chromatography (silica), product eluted at 0% to 10% EtOAc in hexane to afford 2-bromo-5-(2-fluoroethoxy)-3-methoxypyrazine (0.40 g, 72.50%) as a white solid. LCMS: (Method A): m / z 251.10 (ES+), at 1.620 min.

[0643] 1H-NMR: (400MHz, DMSO): 5 3.98 (s, 3H), 4.55-4.53 (m, 1H), 4.64-4.60 (m, 1H), 4.74-4.72 (m, 1H), 4.86-4.84 (m, 1H), 7.77 (s, 1H).

[0644] Synthesis of Intermediate 21, 2-bromo-5-(2,2-difluoroethoxy)-3-methoxypyrazine

[0645]

[0646] Step 1: Synthesis described in synthesis of intermediate 20.

[0647] Step 2; performed in a similar fashion to synthesis of intermediate 20, step 2, using 2,2-difluoroethyl trifluoromethanesulfonate (CAS 67579-81-1).

[0648] LCMS: (Method A): m / z 268.97 (ES+) at 2.077 min.

[0649] Synthesis of Intermediates 22 and 23, 2-chloro-7-cyanopyrrolon,2-blpyridazine-5-sulfonyl chloride and 2-chloro-7-cyanopyrrolon,2-blpyridazine-5-sulfonamide

[0650]

[0651] Intermediate 22 Intermediate 23 Step 1: 3-chloro-6-ethenylpyridazine (CAS 223445-04-3, 4.2 g, 29.58 mmol, 1.0 eq) was dissolved in anhydrous acetonitrile (59.16 ml, 0.5 M). Cyanoacetic acid (CAS 372-09-8, 5.032 g, 59.159 mmol, 2.0 eq) and sodium acetate (7.28 g, 88.739 mmol, 3.0 eq) were added at room temperature. N-iodosuccinimide (23.292 g, 103.529 mmol, 3.5 eq) was added portion wise at room temperature and reaction mixture was stirred at 95 °C for 16 h. Reaction mixture was quenched with saturated aqueous sodium bisulfite solution and extracted with EtOAc (3x). Organic layers were combined and dried (Na2SO4to afford crude product which was purified by normal phase gradient flash column chromatography (silica), eluted at 0% to 50% EtOAc in cyclohexane to afford 2-chloropyrrolo[1,2-b]pyridazine-7-carbonitrile (2.903 g, 15.529 mmol, 52%) as a light yellow solid.

[0652] 1H-NMR: (300MHz, DMSO): 5 8.31 (d, J = 9.4 Hz, 1H), 7.68 (d, J = 4.8 Hz, 1H), 7.24 (d, J = 9.4 Hz, 1H), 6.85 (d, J = 4.8 Hz, 1H). Step 2: 2-chloropyrrolo[1,2-b]pyridazine-7-carbonitrile (2.903 g, 15.529 mmol, 1.0 eq) in anhydrous MeCN (14.52 ml, 5.0 vol) was cooled in an ice-bath and chlorosulfonic acid (10.34 ml, 155.293 mmol, 10.0 eq) was added dropwise. The reaction mixture was slowly allowed to warm to RT and stirred overnight. The mixture was poured into water and the precipitate was collected by filtration and washed with water, then cyclohexane to afford 2-chloro-7-cyanopyrrolo[1,2-b]pyridazine-5-sulfonyl chloride (3.993 g, 13.74 mmol, 88%) as a light yellow solid.

[0653] 1H-NMR: (300MHz, DMSO): 58.39 (d, J = 9.6 Hz, 1H), 7.62 (s, 1H), 7.27 (d, J = 9.6 Hz, 1H).

[0654] Step 3: 2-chloro-7-cyanopyrrolo[1,2-b]pyridazine-5-sulfonyl chloride (1.9 g, 6.538 mmol, 1.0 eq) was dissolved in dioxane (25 ml) and cooled to 0 °C. A mixture of dioxane and concentrated aqueous ammonia (2:3, (12.5 ml, 12.5 vol)) was added dropwise. The reaction mixture was stirred at room temperature for 15 minutes, then diluted with water, extracted with EtOAc (3x), dried and concentrated. Trituration with cyclohexane afforded 2-chloro-7-cyanopyrrolo[1,2-b]pyridazine-5-sulfonamide (1.635 g, 5.415 mmol, 83%) as a light yellow solid.

[0655] 1H-NMR: (300MHz, DMSO): 58.47 (d, J = 9.6 Hz, 1H), 7.99 (s, 1H), 7.65 (s, 2H), 7.58 (d, J = 9.6 Hz, 1H).

[0656] Synthesis of Intermediate 24, 5-ethoxy-3-methoxypyrazin-2-amine

[0657]

[0658] Intermediate 24 Step 1: To an argon flushed microwave vial containing tert-butyl N-(5-bromo-3-methoxypyrazin-2-yl)-N-[(tert-butoxy)carbonyl]carbamate (CAS 815610-15-2, 0.500 g, 1.175 mmol, 1.000 eq), CS2CO3 (0.574 g, 1.762 mmol, 1.500 eq) and ethanol (0.217 g, 0.275 ml, 4.700 mmol, 4.000 eq) in toluene (2.450 ml, 0.5 M) was added RockPhos Pd G3 (CAS 2009020-38-4, 0.008 g, 0.009 mmol, 0.020 eq). The reaction was irradiated to 90 °C for 6 h in the microwave. The reaction mixture was diluted with ethyl acetate, then filtered through Celite bed and concentrated. The crude product was purified by normal phase silica chromatography to afford tert-butyl N-[(tert-butoxy)carbonyl]-N-(5-ethoxy-3-methoxypyrazin-2-yl)carbamate (0.362 g, 67%) as a yellow solid.

[0659] 1H-NMR: (300MHz, DMSO): 5 7.70 (s, 1H), 4.39 (q, J = 7.0 Hz, 2H), 3.94 (s, 3H), 1.38-1.34 (m, 21H).

[0660] Step 2: tert-butyl N-[(tert-butoxy)carbonyl]-N-(5-ethoxy-3-methoxypyrazin-2-yl)carbamate (0.362 g, 0.931 mmol, 1.00 eq) was dissolved in anhydrous DCM (6.0 ml, 0.2 M) and stirred. TFA (2.793 g, 1.781 ml, 24.498 mmol, 25.00 eq) was added dropwise and reaction was stirred at room temperature for 2 h. The reaction mixture was diluted with DCM and concentrated. The residue was diluted with water (15 ml), cooled with ice bath, basified with 1 M solution of NaOH to pH=14 and extracted with DCM (3x 30 ml). The combined organics were dried (Na2SC>4) and concentrated to afford 5-ethoxy-3-methoxypyrazin-2-amine (0.161 g, 94%) as a yellow solid.

[0661] 1H-NMR: (300MHz, DMSO): 57.14 (s, 1H), 5.56 (s, 2H), 4.13 (q, J = 7.0 Hz, 2H), 3.88 (s, 3H), 1.29 (t, J = 7.0 Hz, 3H).

[0662] Synthesis of Intermediate 25, 3-cyano-6-(difluoromethyl)indolizine-1 -sulfonyl chloride

[0663]

[0664] Intermediate 25 Step 1: To a solution of N-iodosuccinimide (15.4 g, 68.3 mmol, 4.00 equiv.) in MeCN (22.5 mL), sodium acetate (5.04 g, 61.5 mmol, 3.60 equiv.) was added, and the reaction mixture was purged with argon for 10 minutes. Cyanoacetic acid (5.23 g, 61.5 mmol, 3.60 equiv.) was added portionwise followed by 5-(difluoromethyl)-2-ethenylpyridine (CAS 1424375-82-5, 2.65 g, 17.1 mmol, 1.00 equiv.) and the mixture was then purged again with argon for 10 minutes. The reaction was stirred at 85 °C for 20 h. The reaction mixture was quenched by the addition of a saturated sodium thiosulfate (Na2S2O3) solution and extracted with diethyl ether. The combined organic layers were dried (Na2SO4) and concentrated. The crude product was purified by flash column chromatography (silica) eluted at 2-20% EtOAc in cyclohexane to afford 6-(difluoromethyl)indolizine-3-carbonitrile (1.60 g, 8.33 mmol).

[0665] 1H-NMR: (300MHz, DMSO): 5 8.86 - 8.79 (m, 1H), 7.84 (d, J = 9.3 Hz, 1H), 7.68 (d, J = 4.4 Hz, 1H), 7.36 -6.93 (m, 2H), 6.73 (d, J = 4.3 Hz, 1H).

[0666] Step 2: 6-(difluoromethyl)indolizine-3-carbonitrile (1.60 g, 8.33 mmol, 1.00 equiv.) was dissolved in acetonitrile (27 mL) and the solution was cooled to 0 °C. Chlorosulfonic acid (3.33 mL, 50.0 mmol, 6.00 equiv.) was added dropwise and the mixture was allowed to slowly warm up to room temperature and stirred for 2.5 h. The reaction mixture was poured onto ice (CAUTION, exothermic). The precipitate was collected by filtration, washed with water (3 x) and cyclohexane (3 x) to afford 3-cyano-6-(difluoromethyl)indolizine-1 -sulfonyl chloride (2.00 g, 6.54 mmol, 79%) as a green powder.1H-NMR: (300MHz, DMSO): 58.78 (s, 1H), 8.10 (d, J = 9.4 Hz, 1H), 7.60 (s, 1H), 7.44 -6.95 (m, 2H).

[0667] Synthesis of Intermediate 26, 5-(2-fluoroethoxy)-3-methoxypyrazin-2-amine

[0668]

[0669] Intermediate 26 Step 1: To an argon flushed pressure vessel containing terf-butyl A / -(5-bromo-3-methoxypyrazin-2-yl)-A / -[(tert-butoxy)carbonyl]carbamate (CAS 815610-15-2, 0.500 g, 1.20 mmol, 1.00 equiv.), CS2CO3 (0.586 g, 1.80 mmol, 1.50 equiv.) and 2-fluoroethanol (0.084 ml, 1.44 mmol, 1.20 equiv.) in toluene (2.45 ml, 0.5 M) was added RockPhos Pd G3 (20.1 mg, 0.024 mmol, 0.020 equiv.). The reaction was stirred at 90 °C overnight. The reaction mixture was diluted with ethyl acetate and washed with water (2x). The organic layer was dried (Na2SC>4) and concentrated to afford 1 g of the crude terf-butyl A / -[(tert-butoxy)carbonyl]-A / -[5-(2-fluoroethoxy)-3-methoxypyrazin-2-yl]carbamate as a mixture of primary amine, mono- and di-protected amine. A purification was performed by flash column chromatography (silica) eluting at 0-60% EtOAc in cyclohexane to afford 252 mg of terf-butyl A / -[(tert-butoxy)carbonyl]-A / -[5-(2-fluoroethoxy)-3-methoxypyrazin-2-yl]carbamate as an orange oil and as a mixture of primary amine, mono- and di-protected amine.

[0670] 1H-NMR: (300MHz, DMSO): 57.77 (s, 1H), 4.86 (q, J= 5.6, 4.7 Hz, 1H), 4.74-4.67 (m, 1H), 4.67 - 4.62 (m, 1H), 4.58 -4.52 (m, 1H), 3.95 (s, 3H), 1.35 (s, 18H).

[0671] Step 2: terf-Butyl A / -[(tert-butoxy)carbonyl]-A / -[5-(2-fluoroethoxy)-3-methoxypyrazin-2-yl]carbamate from the previous step (0.252 g, 0.650 mmol, 1.00 equiv.) was dissolved in anhydrous DCM (4.22 mL) and stirred. TFA (1.24 ml, 16.3 mmol, 25.0 equiv.) was added dropwise and reaction was stirred at room temperature for 2 h. The reaction mixture was diluted with DCM and concentrated. The residue was diluted with water, cooled with ice bath, basified with 1 M solution of NaOH to pH 14 and extracted with DCM (3x). The organic layer was then dried (Na2SO4) and concentrated to afford 5-(2-fluoroethoxy)-3-methoxypyrazin-2-amine (120 mg, 45% over 2 steps) as a brownish solid.

[0672] 1H-NMR: (300MHz, DMSO): 57.19 (s, 1H), 5.64 (s, 2H), 4.83-4.75 (m, 1H), 4.65-4.61 (m, 1 H), 4.42 - 4.37 (m, 1 H), 4.32 - 4.26 (m, 1 H), 3.88 (s, 3H).

[0673] Synthesis of Intermediate 27, 5-(2,2-difluoroethoxy)-3-methoxypyrazin-2-amine

[0674]

[0675] Intermediate 27 Performed in a similar fashion to the synthesis of Intermediate 26, using difluoroethanol to afford 5-(2,2-difluoroethoxy)-3-methoxypyrazin-2-amine as a brown solid.

[0676] 1H-NMR: (300MHz, DMSO): 57.24 (s, 1H), 6.38 (tt, J = 54.8, 3.7 Hz, 1H), 5.74 (s, 2H), 4.41 (td, J = 14.8, 3.7 Hz, 2H), 3.91 (s, 3H).

[0677] Synthesis of Intermediate 28, 3-methoxy-5-(2-methoxyethoxy)pyrazin-2-amine

[0678]

[0679] Boc Boc

[0680] Intermediate 28 Performed in a similar fashion to the synthesis of Intermediate 26, using 2-methoxymethanol to afford 3-methoxy-5-(2-methoxyethoxy)pyrazin-2-amine as a brown solid.

[0681] 1H-NMR: (300MHz, DMSO): 5 7.16 (s, 1H), 5.59 (s, 2H), 4.26 - 4.16 (m, 2H), 3.88 (s, 3H), 3.67 - 3.58 (m, 2H), 3.30 (s, 3H).

[0682] Synthesis of Intermediate 29, 6-bromo-3-cyanoindolizine-1 -sulfonyl chloride

[0683]

[0684] Intermediate 29 Performed in a similar fashion to Intermediate 25 using 5-bromo-2-ethenylpyridine (CAS 226883-52-9) to afford 6-bromo-3-cyanoindolizine-1 -sulfonyl chloride as a grey powder.1H-NMR: (300MHz, DMSO): 58.60 (t, J = 1.4 Hz, 1H), 8.11 (d, J = 9.4 Hz, 1H), 7.81 (s, 1H), 7.65 (dd, J = 9.4, 1.4 Hz, 1H).

[0685] Synthesis of Intermediate 30, 6-bromo-3-cyanoindolizine-1-sulfonamide

[0686]

[0687] Intermediate 29 Intermediate 30

[0688] 6-bromo-3-cyanoindolizine-1-sulfonyl chloride (Intermediate 29, 0.40 g, 1.26 mmol) was dissolved in THF (8 ml) at -78 °C. NH3 (g)was purged through reaction mixture for 1 h at -78 °C. The reaction mixture was concentrated to afford 6-bromo-3-cyanoindolizine-1 -sulfonamide (0.25 g, 66.48%) as a white solid that was used without further purification.

[0689] LCMS: (Method A): m / z 298.0 (ES-) at 1.833 min.

[0690] Synthesis of Intermediate 31, 3-cyano-6-(difluoromethoxy) indolizine-1 -sulfonyl chloride and Intermediate 32, 3-cyano-6-(difluoromethoxy)indolizine-1 -sulfonamide

[0691]

[0692] step 1 product

[0693] Intermediate 31

[0694]

[0695] Intermediate 32

[0696] Intermediate 31 was prepared in a similar fashion to Intermediate 29 using 5-(difluoromethoxy)-2-vinylpyridine (Intermediate 19 step 1 product) to afford 3-cyano-6-(difluoromethoxy)indolizine-l-sulfonyl chloride (0.30 g, 40.80%) as white solid.

[0697] LCMS: (Method A): m / z 287.05 (ES-) as sulfonic acid at 2.305 min.

[0698] Intermediate 32 was prepared in a similar fashion to Intermediate 30 using Intermediate 31 to afford 3-cyano-6-(difluoromethoxy)indolizine-1 -sulfonamide (0.24 g, 85.28%) as a white solid. LCMS: (Method A): m / z 286.07 (ES-) at 1.828 min.

[0699] Synthesis of Intermediate 33, 5-(2,2-difluoroethoxy)-2-iodo-4,6-dimethoxypyrimidine

[0700]

[0701] Intermediate 33

[0702] 5-(2,2-difluoro ethoxy)-4,6-dimethoxypyrimidin-2-amine (CAS 2827058-60-4, 0.25 g, 1.06 mmol), Cui (0.20 g, 1.06 mmol) and I2 (0.27 g, 1.06 mmol) were dissolved in diiodomethane (5 ml). The reaction mixture was stirred at 55 °C for 10 min. Isoamyl nitrite (0.14 ml, 1.06 mmol) was added at room temperature and reaction mixture was stirred at 55 °C for 10 min. The reaction mixture was partitioned between water (70 ml) and EtOAc (70 ml). Aqueous layer was further extracted using EtOAc (2 x 60 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 10% EtOAc in hexane to afford 5-(2,2-difluoroethoxy)-2-iodo-4,6-dimethoxypyrimidine (0.12 g, 32.62%) as a brown solid.

[0703] LCMS: (Method A): m / z 346.87 (ES+) at 2.423 min.

[0704] Synthesis of Intermediate 34, 2-bromo-5-(2,2-difluoroethyl)-3-fluoro-6-methoxypyridine

[0705]

[0706] Intermediate 34

[0707] 5-(2,2-difluoroethyl)-3-fluoro-6-methoxypyridin-2-amine (CAS 2827059-87-8, 0.40 g, 1.94 mmol) was dissolved in dibromoethane (4 ml). Copper (II) bromide (1.30 g, 5.82 mmol) was added at 0 °C and reaction mixture was stirred at 0 °C for 30 min. Isoamyl nitrite (0.79 ml, 5.82 mmol) was added at 0 °C and reaction mixture was stirred at room temperature for 16 h. Reaction mixture was diluted with water (200 ml) and EtOAc (200 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 eluted 0% to 8% EtOAc in hexane to afford 2-bromo-5-(2,2-difluoroethyl)-3-fluoro-6-methoxypyridine (0.25 g, 47.88%) as a brown sticky solid.

[0708] TLC: (2:8; EtOAc / Hexane, Rf: 0.7).

[0709] LCMS: (Method A): Product mass was not observed, major peak at 2.423 min. Synthesis of Intermediate 35, 2-bromo-3-fluoro-5-(2-fluoroethoxy)-6-methoxypyridine

[0710]

[0711] Intermediate 35

[0712] Step 1: To a solution of 5-fluoro-2-methoxypyridin-3-ol (CAS 1233025-58-5, 0.500 g, 3.494 mmol, 1.000 eq) in DMF (10 ml) was added potassium carbonate anhydrous (966 mg, 6.987 mmol, 2.000 eq) and 1-bromo-2-fluoro-ethane (CAS 762-49-2, 0.31 mL, 4.193 mmol, 1.200 eq) and the resulting suspension was stirred overnight at 30 °C. The reaction mixture was diluted with 80 mL of DCM and 10 mL of MeOH. The organic layer was washed with brine and dried over sodium sulfate. The crude was purified by flash chromatography (silica) 5-40% EtOAc in hexane to afford 5-fluoro-3-(2-fluoroethoxy)-2-methoxypyridine (248 mg, 1.285 mmol, 37%).

[0713] 1H-NMR: (300MHz, CDCI3): 5 7.64 (d, J = 2.6 Hz, 1H), 6.94 (dd, J = 9.0, 2.6 Hz, 1H), 4.80 (dd, J = 47.5, 4.0 Hz, 2H), 4.26 (dd, J = 27.6, 4.0 Hz, 2H), 3.99 (s, 3H).

[0714] Step 2: To a solution of 5-fluoro-3-(2-fluoroethoxy)-2-methoxypyridine (175 mg, 0.907 mmol, 1.000 eq) in acetonitrile (5 ml) was added N-Bromosuccinimide (0.178 g, 0.997 mmol, 1.100 eq) portion-wise, followed by a drop of DMF. The reaction mixture was stirred at 60 °C for 6 h. Volatiles were removed under vacuum and the residue purified by normal phase flash column chromatography (silica) 3-30% EtOAc in hexane to afford 2-bromo-3-fluoro-5-(2-fluoroethoxy)-6-methoxypyridine (195 mg, 0.727 mmol, 80%) as a white solid.

[0715] Synthesis of Intermediate 36, 6-(difluoromethyl)indolizine-1-sulfonamide

[0716]

[0717] Intermediate 36 Step 1: 3-cyano-6-(difluoromethyl)indolizine-1-sulfonyl chloride (Intermediate 25, 500 mg, 1.63 mmol, 1.00 equiv.) was dissolved in 1,4-dioxane (5.0 ml, 0.34 M) and cooled to 10 °C before ammonia (0.50 M in 1,4-dioxane, 32.7 ml, 16.3 mmol, 10.0 equiv.) was added dropwise. The reaction was allowed to slowly warm up to room temperature and it was stirred for 23 h at room temperature. The reaction mixture was evaporated to dryness, and the crude was suspended in water, sonicated, filtered, and washed with cold water to give 3-cyano-6-(difluoromethyl)indolizine-l -sulfonamide (443 mg, 1.63 mmol, 100%) as an off-white solid.1H-NMR: (300MHz, DMSO): 58.94 (s, 1H), 8.15 (d, J = 9.5 Hz, 1H), 7.96 (s, 1H), 7.63 (d, J = 9.5 Hz, 1H), 7.52 (s, 2H), 7.21 (t, J = 54.5 Hz, 1H).

[0718] Step 2: 3-cyano-6-(difluoromethyl)indolizine-1 -sulfonamide (443 mg, 1.63 mmol, 1.00 equiv.) was mixed with absolute EtOH (4.43 ml, 0.36 M) and NaOH (85.0 mg, 2.12 mmol, 1.30 equiv.) and water (0.89 ml) were added to this mixture. The reaction was stirred at 78 °C for 2 h, evaporated to dryness and taken onto the next step without further purification. 472 mg of the crude 6-(difluoromethyl)-1-sulfamoylindolizine-3-carboxamide was obtained as a yellow solid.

[0719] Step 3: A solution of 6-(difluoromethyl)-1-sulfamoylindolizine-3-carboxamide (472 mg, 1.63 mmol, 1.00 equiv.) in MeOH (42.5 mL) was treated with 6 M aqueous NaOH solution (6.00 g NaOH in 25 mL water). The mixture was heated at reflux for 18 h. The methanol was removed by careful evaporation under reduced pressure and the residual aqueous phase was washed with EtOAc (3x). The aqueous phase was then cooled to 5 °C and concentrated HCl solution was slowly added to the reaction mixture until pH = 2. The aqueous phase was extracted with EtOAc (3x.) The combined organic extracts were then dried (Na2SO4) and concentrated to afford 6-(difluoromethyl)-1-sulfamoylindolizine-3-carboxylic acid as a greyish powder (355 mg, 1.22 mmol, 75%).

[0720] 1H-NMR: (300MHz, CDCI3): 59.74 (s, 1H), 8.15 (d, J = 9.5 Hz, 1H), 7.76 (s, 1H), 7.57 (dd, J = 9.5, 1.5 Hz, 1H), 7.43 (s, 2H), 7.18 (d, J = 55.0 Hz, 1H).

[0721] Step 4: 6-(difluoromethyl)-1-sulfamoylindolizine-3-carboxylic acid (100 mg, 0.345 mmol, 1.00 equiv.) and LiCI (77.4 mg, 1.83 mmol, 5.30 equiv.) in DMSO (0.80 ml) were irradiated at 100 °C for 1 h in the microwave. The mixture was diluted with water and extracted with 2-MeTHF (3x). The combined organic layers were dried (Na2SO4) and concentrated to afford 119 mg of crude 6-(difluoromethyl)indolizine-1 -sulfonamide as a brown oil which was used in the next step without further purification.

[0722] 1H-NMR: (300MHz, CDCI3): 58.79 (s, 1H), 7.95 (d, J = 9.5 Hz, 1H), 7.75 (d, J = 3.0 Hz, 1H), 7.18 (d, J = 2.5 Hz, 3H), 7.12 (d, J = 3.0 Hz, 1H), 7.06 (s, 1H).

[0723] Synthesis of examples, general procedures

[0724] Route A Synthesis of Example A1, methyl 6-chloro-1-(N-(3,5-dimethoxypyrazin-2-yl)sulfamoyl)indolizine-3-carboxylate

[0725]

[0726] Methyl 6-chloro-1-sulfamoylindolizine-3-carboxylate (Intermediate 2, 0.55 g, 1.90 mmol), 2-bromo-3,5-dimethoxypyrazine (CAS 1033610-34-2, 0.41 g, 1.90 mmol) and K₂CO₃ (0.65 g, 4.77 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 (0.36 ml, 2.29 mmol) and Cui (0.07 g, 0.38 mmol) were added and reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was partitioned between water (100 ml) and EtOAc (100 ml). The aqueous layer was further extracted with EtOAc (3 x 100 ml). Organic layers were combined, dried (Na2SO4) and concentrated. The crude product was purified by reverse phase gradient flash column chromatography (reverse phase, C18 silica, 24g column), 0% to 42% MeCN in water using 0.05% formic acid as a modifier to afford methyl 6-chloro-1-(N-(3,5-dimethoxypyrazin-2-yl)sulfamoyl)indolizine-3-carboxylate (0.45g, 55.31%) as off white solid.

[0727] 1H-NMR: (400MHz, DMSO): 53.83 (s, 6H), 3.88 (s, 3H), 7.43 (s, 1H), 7.61-7.7.58 (dd, 1H J= 9.6Hz and J= 1.6Hz), 7.75 (s, 1H), 8.09-8.07 (dd, 1H, J= 9.6Hz and J= 0.8Hz), 9.44 (s, 1H), 10.38 (s, 1H).

[0728] LCMS: (Method B): m / z 427.02 (ES+) at 1.85 min.

[0729] Route B

[0730] Synthesis of Example A2, 6-chloro-1-(N-(3,5-dimethoxypyrazin-2-yl)sulfamoyl)indolizine-3-carboxylic acid and Example A3, 6-chloro-1-(N-(3,5-dimethoxypyrazin-2-yl)sulfamoyl)indolizine-3-carboxamide

[0731]

[0732] Example A1 Example A2 Example A3 Step 1: Methyl 6-chloro-1-(N-(3,5-dimethoxypyrazin-2-yl)sulfamoyl)indolizine-3-carboxylate (Example A1, 0.35 g, 0.82 mmol) was dissolved in THF (4 ml) and water (1 ml). Lithium hydroxide monohydrate (0.13 g, 3.28 mmol) was added and the reaction mixture was allowed to stir at room temperature for 16 h. The reaction mixture was concentrated in vacuo. The crude product was partitioned between water (30 ml) and EtOAc (30 ml). The aqueous layer was extracted with EtOAc (2 X 30 ml). Combined organic layer was discarded. The aqueous layer was then acidified with aqueous citric acid solution (2 ml) up to pH ~4. The aqueous layer was further extracted with EtOAc (2 X 10mL). Organic layers were combined, dried (Na2SO4) and concentrated to afford 6-chloro-1-(N-(3,5-dimethoxypyrazin-2-yl)sulfamoyl)indolizine-3-carboxylic acid (0.31 g, 91.59%) as off white solid.

[0733] 1H-NMR: (400MHz, DMSO): 5 13.29 (br s, 1H), 10.33 (s, 1H), 9.52 (d, J = 1.8 Hz, 1H), 8.05 (d, J = 9.6 Hz, 1H), 7.70 (s, 1H), 7.55 (dd, J = 9.6, 1.9 Hz, 1H), 7.44 (s, 1H), 3.83 (d, J = 5.3 Hz, 6H).

[0734] LCMS: (Method B): m / z 413.03 (ES+) at 1.40 min.

[0735] Step 2: 6-chloro-1-(N-(3,5-dimethoxypyrazin-2-yl)sulfamoyl)indolizine-3-carboxylic acid (Example A2, 0.30 g, 0.72 mmol) was dissolved in DMF (3 ml). HATU (0.33 g, 0.87 mmol) was added and the reaction mixture was stirred under nitrogen atmosphere for 30 min at room temperature. After this, NH4CI (0.15 g, 2.91 mmol) and DIPEA (0.64 ml, 3.64 mmol) were added and reaction mixture was stirred at room temperature for 16 h. The reaction mixture was partitioned between water (50 ml) and EtOAc (50 ml). The aqueous layer was further extracted with EtOAc (2 X 30 ml). Organic layers were combined dried (Na2SO4) and concentrated. The crude product was purified by reverse phase gradient flash column chromatography (silica C18, 24 g column), 0% to 44% MeCN in water using 0.05% formic acid as a modifier to afford 6-chloro-1-(N-(3,5-dimethoxypyrazin-2-yl)sulfamoyl)indolizine-3-carboxamide (0.08 g, 26.73%) as off white solid.

[0736] LCMS: (Method B): m / z 412.06 (ES+) at 1.59 min.

[0737] 1H-NMR: (400MHz, DMSO): 53.78 (s, 3H), 3.82 (s, 3H), 7.44-7.41 (m, 3H), 8.06-7.99 (m, 3H), 9.84 (s, 1H), 10.27 (brs, 1H). Route C

[0738] Synthesis of Example A4, 6-chloro-3-cyano-N-(3,5-dimethoxypyrazin-2-yl)indolizine-1-sulfonamide

[0739]

[0740] Example A3 Example A4

[0741] 6-chloro-1-(N-(3,5-dimethoxypyrazin-2-yl)sulfamoyl)indolizine-3-carboxamide (Example A3, 0.08 g, 0.19 mmol) was dissolved in DMF (0.1 ml). To it, POCl₃ (0.1 ml, 1.16 mmol) was added at 0 °C and reaction mixture was stirred at room temperature for 1h. The reaction mixture was quenched with saturated aqueous NaHCO₃ solution (10mL) and then partitioned between water (10 ml) and EtOAc (20 ml). The aqueous layer was further extracted with EtOAc (2 X 20 ml). The combined organic layers were dried (Na2SO4) and concentrated. The crude product was purified by reverse phase gradient flash column chromatography (C18 silica), 0% to 68% MeCN in water using 0.05% formic acid as a modifier to afford 6-chloro-3-cyano-N-(3,5-dimethoxypyrazin-2-yl)indolizine-1-sulfonamide (0.012 g, 15.82 %) as white solid.

[0742] LCMS: (Method B): m / z 394.06 (ES+) at 1.88 min.

[0743] 1H-NMR: (400Mz, DMSO): 5 3.83 (s, 3H), 3.85 (s, 3H), 7.46 (s, 1 H), 7.59 (d, 1 H, J= 9.6Hz), 7.96 (s, 1 H), 8.04 (d, 1 H, J= 9.6Hz), 8.75 (s, 1 H), 10.43 (s, 1H).

[0744] Route D

[0745] Synthesis of Example A5, 6-chloro-N-(3,5-dimethoxypyrazin-2-yl)-3- (hydroxymethyl)indolizine-l -sulfonamide

[0746]

[0747] Methyl 6-chloro-1-(N-(3,5-dimethoxypyrazin-2-yl)sulfamoyl)indolizine-3-carboxylate (Example A1, 0.05 g, 0.12 mmol) was dissolved in THF (2 ml). To it, Lithium aluminium hydride (1M in THF) (0.17 ml, 0.17 mmol) was added dropwise at -78 °C under nitrogen atmosphere. The reaction mixture was stirred at -78 °C for2h, then poured in a solution of sodium sulfate (50 ml) and extracted by EtOAc (50 ml). The aqueous layer further extracted with EtOAc (2 x 50 ml). Organic layers were combined and dried (Na2SO4). Solvent was removed in vacuo and crude product was purified by reverse phase gradient flash column chromatography (C18 silica, 12 g column), 0% to 62% acetonitrile in water to afford 6-chloro-N-(3,5-dimethoxypyrazin-2-yl)-3-(hydroxymethyl)indolizine-1-sulfonamide (5.5 mg, 11.77%) as a white solid.

[0748] LCMS: (Method B): m / z 399.11 (ES+) at 1.62 min.

[0749] 1H-NMR: (400MHz, DMSO): 53.81 (s, 3H), 3.82 (s, 3H), 4.76 (d, 2H, J= 4Hz), 5.33 (t, 1H, J= 6.4Hz), 7.06 (s, 1H), 7.21 (d, 1H, J= 10Hz), 7.4 (s, 1H), 7.9 (d, 1H, J= 9.6Hz), 8.47 (s, 1H), 9.99 (brs, 1H).

[0750] Route E

[0751] Synthesis of Example A10, methyl 6-chloro-1-(N-(6-(difluoromethoxy)-5-fluoro-2-methoxypyridin-3-yl)sulfamoyl)indolizine-3-carboxylate

[0752]

[0753] Intermediate 3 Example A10

[0754] 6-chloro-1-(chlorosulfonyl)indolizine 3-carboxylate (Intermediate 3, 1.50 g, 4.88 mmol) and 6-(difluoromethoxy)-5-fluoro-2-methoxypyridin-3-amine (CAS 2407470-90-8, 1.00 g, 4.88 mmol) were dissolved in pyridine (15 ml) at room temperature. The reaction mixture was allowed to stir at room temperature for 4 h. Reaction mixture was partitioned between water (50 ml) and EtOAc (50 ml). Aqueous layer was further extracted with EtOAc (2 x 50 ml). Organic layers were combined and dried (Na2SO4). Solvent was removed in vacuo to obtain crude product which was purified by flash column chromatography (normal phase, silica), 0% to 30% EtOAc in hexane afford methyl 6-chloro-1-(N-(6-(difluoromethoxy)-5-fluoro-2-methoxypyridin-3-yl)sulfamoyl)indolizine-3-carboxylate (1.30 g, 56.52%) as light brown solid.

[0755] LCMS: (Method B): m / z 477.9 (ES-) at 1.95 min.

[0756] 1H-NMR: (400Mz, DMSO): 53.44 (s, 3H), 3.87 (s, 3H), 7.77-7.43 (m, 1 H, J= 66.6Hz), 7.63-7.59 (m, 2H), 7.78 (d, 1 H, J= 10Hz), 7.94 (d, 1 H, J= 9.6Hz), 9.45 (s, 1 H), 10.11 (s, 1H). Examples

[0757] The following examples were prepared in a similar fashion to those previously described above.

[0758]

[0759]

[0760]

[0761]

[0762]

[0763]

[0764]

[0765]

[0766]

[0767]

[0768]

[0769]

[0770]

[0771]

[0772]

[0773]

[0774]

[0775]

[0776]

[0777]

[0778]

[0779]

[0780]

[0781]

[0782]

[0783]

[0784]

[0785]

[0786]

[0787]

[0788] Synthesis of Example A38, 3-acetyl-6-chloro-N-(3,5-dimethoxypyrazin-2-yl)indolizine-1-sulfonamide

[0789]

[0790] Example A2 Example A38 Step 1: 6-chloro-1-(N-(3,5-dimethoxypyrazin-2-yl)sulfamoyl)indolizine-3-carboxylic acid (Example A2, 0.05 g, 0.12 mmol) was dissolved in DMF (0.5 ml). After this, N, O-dimethylhydroxylamine hydrochloride (0.012 g, 0.12 mmol) and HATU (0.05 g, 0.14 mmol) were added and reaction mixture was stirred at 0 °C for 5min. After 5min, DIPEA (0.06 ml, 0.36 mmol) was added dropwise at 0 °C and reaction mixture was stirred at room temperature for 16h. The reaction mixture was partitioned between water (50 ml) and EtOAc (30 ml). Aqueous layer was further extracted with EtOAc (2 x 30 ml). Organic layers were combined and dried (Na₂SO₄) and concentrated. The crude product was purified by reverse phase gradient flash column chromatography (C18 silica), product eluted at 0% to 55% MeCN in water to afford 6-chloro-1-(N-(3,5-dimethoxypyrazin-2-yl)sulfamoyl)-N-methoxy-N-methylindolizine-3-carboxamide (0.03 g, 54.32%) as off-white solid.

[0791] TLC: (7:3; EtOAc / Hexane, Rf: 0.5).

[0792] LCMS: (Method A): m / z 454.15 (ES-) at 1.712 min.

[0793] Step 2: 6-chloro-1-(N-(3,5-dimethoxypyrazin-2-yl)sulfamoyl)-N-methoxy-N-methylindolizine-3-carboxamide (0.03 g, 0.066 mmol) was dissolved in THF (0.6 ml). To it, MeMgBr (3.0M in Diethyl ether) (0.066 ml, 0.19 mmol) was added at room temperature and reaction mixture was stirred at 60 °C for 2 h. The reaction mixture was partitioned between water (30 ml) and EtOAc (30 ml). Aqueous layer was further extracted with EtOAc (2 x 30 ml). Organic layers were combined, dried (Na₂SO₄) and concentrated. The crude product was purified by reverse phase gradient flash column chromatography (C18 silica, 12 g column), product eluted at 0% to 60% MeCN in water to afford 3-acetyl-6-chloro-N-(3,5-dimethoxypyrazin-2-yl)indolizine-1-sulfonamide (7 mg, 25.90%) as off white solid.

[0794] LCMS: (Method B): m / z 411.05 (ES+) at 1.77 min.

[0795] 1H-NMR: (400MHz, DMSO): 5 2.58 (s, 3H), 3.82-8.88 (m, 6H), 7.37 (s, 1H), 7.53 (d, 1H, J=9.6Hz), 8.08 (s, 1H), 8.16 (d, 1H, J= 9.2Hz), 9.94 (s, 1H). NH proton not observed. Synthesis of Example A39, (±)-6-chloro-N-(3,5-dimethoxypyrazin-2-yl)-3-(1-hydroxyethyl)indolizine-1 -sulfonamide

[0796]

[0797] Example A38 Example A39

[0798] 3-acetyl-6-chloro-N-(3,5-dimethoxypyrazin-2-yl)indolizine-1 -sulfonamide (Example A38, 0.07 g, 0.17 mmol) was dissolved in MeOH (0.4 ml) and THF (0.4 ml). To it, NaBH₄ (0.032 g, 0.85 mmol) was added at 0 °C and reaction mixture was stirred at room temperature for 1h. Reaction mixture was partitioned between water (50 ml) and EtOAc (50 ml). Aqueous layer was further extracted with EtOAc (1 x 50 ml). Organic layers were combined, dried (Na₂SO₄) and concentrated. The crude product was purified by reverse phase gradient flash column chromatography (C18 silica, 24 g column), eluted at 0% to 55% MeCN in water to afford (±)-6-chloro-N-(3,5-dimethoxypyrazin-2-yl)-3-(1-hydroxyethyl)indolizine-1 -sulfonamide (0.02 g, 28.43%) as off-white solid.

[0799] LCMS: (Method B): m / z 413.07 (ES+) at 1.67 min.

[0800] 1H-NMR: (400MHz, DMSO): 5 1.55 (d, 3H, J= 6.4Hz), 3.81 (s, 3H), 3.83 (s, 3H), 5.10 (t, 2H, J= 6.4Hz), 5.43 (d, 1H, J= 6.4Hz), 7.01 (s, 1H), 7.21 (d, 1H, J= 9.6Hz), 7.43 (s, 1H), 7.89 (d, 1H, J= 9.6Hz), 8.53 (s, 1H), 10.02 (br s, 1H).

[0801] Synthesis of Example A40, 6-chloro-N-(3,5-dimethoxypyrazin-2-yl)-3- (methoxymethyl)indolizine-l -sulfonamide

[0802]

[0803] Step 1: 6-chloro-N-(3,5-dimethoxypyrazin-2-yl)-3-(hydroxymethyl) indolizine-1-sulfonamide (Example A5, 0.25 g, 0.63 mmol) was dissolved in MeCN (5 ml). To it, DIPEA (0.32 ml, 1.88 mmol) was added at 0 °C and reaction mixture was allowed to stir at 0 °C for 30 min. After this, mesyl chloride (0.06 ml, 0.81 mmol) was added at 0 °C and reaction mixture was allowed to stir at room temperature for 3h. Reaction mixture was diluted with water (50 ml) and extracted with EtOAc (50 ml). Aqueous layer further extracted with EtOAc (2 x 50 ml). The organic layers were combined, dried (Na₂SO₄) and concentrated, to afford crude (6-chloro-1-(N-(3,5-dimethoxypyrazin-2-yl) sulfamoyl) indolizin-3-yl) methyl methanesulfonate (0.15 g, 50.33%) as brown sticky solid which was used for next step without any purification.

[0804] TLC: (5:5 EtOAc / Hexane, Rf: 0.5).

[0805] LCMS: (Method A): m / z 477.16 (ES+) at 1.636 min.

[0806] Step 2: (6-chloro-1-(N-(3,5-dimethoxypyrazin-2-yl) sulfamoyl) indolizin-3-yl) methyl methanesulfonate (0.15 g, 0.31 mmol) was dissolved in MeOH (2 ml). To it, K₂CO₃ (0.13 g, 0.94 mmol) was added at room temperature and reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was concentrated and then purified by reverse phase gradient flash column chromatography (C18 silica, 24 g column), product eluted at 0% to 40% acetonitrile in water to afford 6-chloro-N-(3,5-dimethoxypyrazin-2-yl)-3-(methoxymethyl) indolizine-1 -sulfonamide (3.03 mg, 2.32%) as light brown sticky solid.

[0807] LCMS: (Method B): m / z 413.08 (ES+) at 1.78 min.

[0808] 1H-NMR: (400MHz, MeOD): 5 3.33 (s, 3H, merged with MeOD residual peak), 3.81 (s, 3H), 3.86 (s, 3H), 4.73 (s, 2H), 7.19-7.16 (m, 2H), 7.37 (s, 1H), 7.96 (d, 1H, J= 9.6Hz), 8.34 (s, 1H).

[0809] Synthesis of Example A42, N-((6-chloro-1-(N-(3,5-dimethoxypyrazin-2-yl)sulfamoyl)indolizin- 3-yl)methyl)acetamide

[0810]

[0811] Example A5 Example A42 Step 1: 6-chloro-N-(3,5-dimethoxypyrazin-2-yl)-3-(hydroxymethyl)indolizine-1 -sulfonamide (Example A5, 0.50 g, 1.26 mmol) was dissolved in THF (20 ml). SOCl₂ (0.18 ml, 2.51 mmol) was added at 0 °C under nitrogen atmosphere. Reaction mixture was stirred at 0 °C for 1 h, then concentrated to afford 6-chloro-3-(chloromethyl)-N-(3,5-dimethoxypyrazin-2- yl)indolizine-1 -sulfonamide (0.50 g, 95.68%) as brown solid which was immediately used for next step.

[0812] TLC: (5:5, EtOAc / Hexane, Rf: 0.6).

[0813] LCMS: (Method A): Product was confirmed as methyl ether m / z 413.17 (ES+) at 2.170 min.

[0814] Step 2: THF (10 ml) was taken and NH₃ gas was purged at -78 °C for 30 min. To it, a solution of 6-chloro-3-(chloromethyl)-N-(3,5-dimethoxypyrazin-2-yl)indolizine-1 -sulfonamide (0.50 g, 1.20 mmol) in THF (10 ml) was added dropwise and reaction mixture was allowed to stir at -78 °C for 1h. Reaction was concentrated in vacuo to obtain crude, which was purified by reverse phase gradient flash column chromatography (C18 silica, 12g column), product eluted at 0% to 50% MeCN in water to afford 3-(aminomethyl)-6-chloro-N-(3,5-dimethoxypyrazin-2-yl)indolizine-1-sulfonamide (0.22 g, 46.10%) as white solid.

[0815] LCMS: (Method A): m / z 381.21 (ES+, M-16) at 1.624 min.

[0816] 1H-NMR: (400MHz, DMSO): δ 3.80 (s, 3H), 3.81 (s, 3H), 4.13 (s, 2H), 6.17 (br s, 2H), 7.09 (s, 1H), 7.18-7.15 (dd, 1H, J= 9.6Hz and J= 1.6Hz), 7.35 (s, 1H), 7.92 (d, 1H, J= 9.6Hz), 8.62 (s, 1H).

[0817] Step 3: 3-(aminomethyl)-6-chloro-N-(3,5-dimethoxypyrazin-2-yl)indolizine-1 -sulfonamide (0.2 g, 0.50 mmol) was dissolved in THF (1 ml). To it, pyridine (0.06 ml, 0.75 mmol) was added and reaction mixture was stirred at room temperature for 10 min. After this, acetyl chloride (0.039 ml, 0.55 mmol) was added dropwise at 0 °C. Reaction mixture was stirred at room temperature for 1h then concentrated. The crude product was purified by reverse phase gradient flash column chromatography (C18 silica, 12 g column), product was eluted at 0% to 64% MeCN in water to afford N-((6-chloro-1-(N-(3,5-dimethoxypyrazin-2-yl)sulfamoyl)indolizin-3-yl)methyl)acetamide (0.041 g, 18.93%) as off white solid.

[0818] LCMS: (Method B): m / z 440.13 (ES+) at 1.58 min.

[0819] 1H-NMR: (400MHz, DMSO): 5 1.85 (s, 3H), 3.81 (s, 3H), 3.84 (s, 3H), 4.55 (d, 2H, J= 6Hz), 7.04 (s, 1H), 7.22-7.19 (dd, 1H, J= 9.6Hz and J= 1.6Hz), 7.42 (s, 1H), 7.88 (d, 1H, J= 9.6Hz), 8.40 (t, 1H, J= 5.6Hz), 8.54 (s, 1H), 10.04 (br s, 1H).

[0820] Synthesis of Example A43, methyl (6-chloro-1-(N-(3,5-dimethoxypyrazin-2-yl)sulfamoyl)indolizin-3-yl)carbamate

[0821]

[0822] Example A2 Example A43

[0823] 6-chloro-1-(N-(3,5-dimethoxypyrazin-2-yl)sulfamoyl)indolizine-3-carboxylic acid (Example A2, 0.20 g, 0.48 mmol) was dissolved in THF (2 ml). To it, diphenylphosphorylazide (0.15 ml, 0.72 mmol) and triethylamine (0.10 ml, 0.72 mmol) were added dropwise at 0 °C under nitrogen. The reaction mixture was stirred at 60 °C for2h. MeOH (1 ml) was added and reaction mixture was stirred at 60 °C for 16h, than concentrated. The crude product was purified by reverse phase gradient flash column chromatography (C18 silica, 12 g column), product was eluted at 0% to 40% Acetonitrile in water to afford (6-chloro-1-(N-(3,5-dimethoxypyrazin-2-yl)sulfamoyl)indolizin-3-yl)carbamate (3 mg, 1.4%) as a light brown solid.

[0824] LCMS: (Method B): m / z (ES+) 442.06 at 1.67 min.

[0825] 1H-NMR: (400MHz, MeOD): 53.80 (s, 6H), 3.87 (s, 3H), 6.98 (s, 1H), 7.11 (d, 1H, J= 9.8Hz), 7.39 (s, 1H), 7.91 (d, 1H, J= 9.6Hz), 8.13 (s, 1H).

[0826] Synthesis of Example A44, 6-chloro-N-(3,5-dimethoxypyrazin-2-yl)-3-methoxyindolizine-1-sulfonamide

[0827]

[0828] Example A44 Step 1: Reaction performed in a similar fashion to Route A. Using Intermediate 14 (purified material) and CAS 1033610-34-2.

[0829] LCMS: (Method A): m / z 369.18 (ES+), at 2.099 min.

[0830] Step 2: 6-chloro-N-(3,5-dimethoxypyrazin-2-yl)indolizine-1 -sulfonamide (0.80 g, 2.17 mmol) was dissolved in THF (8 ml). To it, N-bromosuccinimide (0.46 g, 2.60 mmol) was added. Reaction mixture was stirred at room temperature for 16 h then concentrated. The crude product was purified by reverse phase gradient flash column chromatography (C18 silica, 80 g column), product eluted at 0% to 70% MeCN in water to afford 3-bromo-6-chloro-N-(3,5-dimethoxypyrazin-2-yl)indolizine-1 -sulfonamide (0.9 g, 92.84%) as off-white solid.

[0831] TLC: (5:5; EtOAc / Hexane, Rf: 0.7).

[0832] LCMS: (Method A): m / z 447.0 (ES+), at 2.400 min.

[0833] Step 3: 3-bromo-6-chloro-N-(3,5-dimethoxypyrazin-2-yl)indolizine-1 -sulfonamide (0.10 g, 0.22 mmol) was dissolved in MeOH (1 ml). Cu Powder (0.085 g, 1.34 mmol) and NaOMe (30% in MeOH, 0.28 ml, 1.34 mmol) were added at room temperature. The reaction mixture was stirred at 140 °C for 16 h. The reaction mixture was partitioned between water (50 ml) and DCM (20 ml). Aqueous layer was further extracted using DCM (3 x 10 ml). Organic layers were combined, dried (Na2SO4) and concentrated. The crude product was purified by reverse phase gradient flash column chromatography (C18 silica, 12 g column), product was eluted at 0% to 44% MeCN in water to afford 6-chloro-N-(3,5-dimethoxypyrazin-2-yl)-3-methoxyindolizine-1-sulfonamide (0.012 g, 13.59%) as a light-yellow solid.

[0834] LCMS: (Method B): m / z 399.12 (ES+) at 1.89 min.

[0835] 1H-NMR: (400MHz, DMSO): 5 3.81 (s, 3H), 3.83 (s, 1H), 4.01 (s, 3H), 6.51 (s, 1H), 6.99 (d, 1H, J= 9.6Hz), 7.43 (s, 1H), 7.76 (d, 1H, J= 10Hz), 8.15 (s, 1H), 9.96 (br s, 1H).

[0836] Synthesis of Example A45, 3-amino-6-chloro-N-(3,5-dimethoxypyrazin-2-yl)indolizine-1-sulfonamide

[0837]

[0838] Example A2 Example A45

[0839] 6-chloro-1-(N-(3,5-dimethoxypyrazin-2-yl)sulfamoyl)indolizine-3-carboxylic acid (Example A2, 0.10 g, 0.24 mmol) was dissolved in THF (2 ml). Diphenylphosphorylazide (0.06 ml, 0.36 mmol) and triethylamine (0.05 ml, 0.36 mmol) were added dropwise at 0 °C under nitrogen atmosphere. The reaction mixture was allowed stirred at 80 °C for 16h, then concentrated in vacuo. The crude product was purified by reverse phase gradient flash column chromatography (C18 silica, 12 g column), product was eluted at 0% to 40% Acetonitrile in water. The product was further purified by reverse phase preparative HPLC (Method C) to afford 3-amino-6-chloro-N-(3,5-dimethoxypyrazin-2-yl)indolizine-1 -sulfonamide (12.7 mg, 13.85 %) as a white solid.

[0840] LCMS: (Method B): m / z 384.11 (ES+) at 1.79 min.

[0841] 1H-NMR: (400MHz, DMSO): 53.80 (s, 3H), 3.83 (s, 3H), 5.37 (s, 2H), 6.25 (s, 1H), 6.86-6.83 (m, 1H), 7.41 (s, 1H), 7.69 (d, 1H, J= 8.0Hz), 8.12 (s, 1H), 9.85 (s, 1H).

[0842] Synthesis of Example A47, 6-chloro-1-(N-(5-(cyanomethyl)-3-fluoro-6-methoxypyridin-2-yl)sulfamoyl)indolizine-3-carboxamide

[0843]

[0844] Example A47

[0845] Step 1: Reaction performed in a similar fashion to Route A. Using Intermediate 2 and Intermediate 6.

[0846] LCMS: (Method A): m / z 490.00 (ES-) at 2.566 min.

[0847] Step 2: methyl 1-(N-(5-bromo-3-fluoro-6-methoxypyridin-2-yl)sulfamoyl)-6-chloroindolizine-3-carboxylate (0.70 g, 1.42 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (CAS 928664-98-6, 0.36 g, 1.85 mmol) and KF (0.25 g, 4.28 mmol) were dissolved in water (3 ml) and DMSO (7 ml). Nitrogen gas was purged through reaction mixture for 15min at room temperature. PdCh(dppf) (0.21 g, 0.28 mmol) was added and reaction mixture was stirred at 100 °C for 16h. Reaction mixture was partitioned between water (100 ml) and EtOAc (100 ml). Aqueous layer was further extracted with EtOAc (3 x 70 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 18% EtOAc in Hexane to afford methyl 6-chloro-1-(N-(5-(cyanomethyl)-3-fluoro-6-methoxypyridin-2-yl)sulfamoyl)indolizine-3-carboxylate (0.20 g, 31.03%) as off white solid.

[0848] TLC: (5:5; EtOAc / Hexane, Rf: 0.3).

[0849] LCMS: (Method A): m / z 453.15 (ES+) at 2.253 min.

[0850] Steps 3 and 4 were performed in a similar fashion to route B to afford 6-chloro-1-(N-(5-(cyanomethyl)-3-fluoro-6-methoxypyridin-2-yl)sulfamoyl)indolizine-3-carboxamide as an off white solid.

[0851] LCMS: (Method B): m / z 438.11 (ES+) at 1.61 min.

[0852] 1H-NMR: (400MHz, DMSO): 53.58 (s, 3H), 3.71 (s, 2H), 7.44 (brs, 1H), 7.49 (d, 1H, J= 9.2Hz), 7.65 (d, 1H, J= 8.4Hz), 8.04 (d, 1H, J= 9.2Hz), 8.07 (brs, 1H), 8.19 (s, 1H), 9.88 (s, 1H), 11.18 (s, 1H).

[0853] Synthesis of Examples A49, 6-bromo-3-cyano-N-(3,5-dimethoxypyrazin-2-yl)indolizine-1-sulfonamide and Example A56, 6-bromo-1-(N-(3,5-dimethoxypyrazin-2-yl)sulfamoyl)indolizine-3-carboxamide

[0854]

[0855] Example A56 Example A49

[0856] Step 1: methyl 6-bromoindolizine-3-carboxylate (Intermediate 7, 5.00 g, 19.77 mmol) was dissolved in chlorosulfonic acid (15 ml, 3 vol) at 0 °C and reaction mixture stirred at room temperature for 2 h. Reaction mixture was poured in ice cold water (400 ml) and extracted with DCM (400 ml). Aqueous layer was further extracted with DCM (2x200 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 methyl 6-bromo-1-(chlorosulfonyl)indolizine-3-carboxylate (4.50 g, 64.88%) as light brown solid.

[0857] LCMS: (Method A): m / z 333.88 (ES+) as sulfonic acid at 1.604 min.

[0858] Step 2: 6-bromo-1-(chlorosulfonyl)indolizine-3-carboxylate (2.00 g, 5.70 mmol) was dissolved in THF (20 ml) at room temperature. NH3 (g) was purged through reaction mixture for 2h at -78 °C. Reaction mixture was concentrated in vacuo to afford methyl 6-bromo-1-sulfamoylindolizine-3-carboxylate (1.50 g, 79.28%) as a light brown solid which was used without purification.

[0859] TLC: (3:7; EtOAc / Hexane, Rf: 0.5).

[0860] 1H-NMR: (400MHz, DMSO): 59.53 (d, J = 1.7 Hz, 1H), 8.01 (d, J = 9.5 Hz, 1H), 7.70 (s, 1H), 7.63 (dd, J = 9.5, 1.7 Hz, 1H), 7.47 (s, 2H), 3.88 (s, 3H).

[0861] Step 3: Reaction performed in a similar fashion to Route A using 2-Bromo-3,5-dimethoxypyrazine (CAS 1033610-34-2). Product was purified by normal phase gradient flash column chromatography (silica), product eluted at 0% to 30% EtOAc in hexane.

[0862] LCMS: (Method A): m / z 471.10 (ES+) at 2.357 min.

[0863] Steps 4 and 5: Reactions performed in a similar fashion to Route B to afford Example A56, 6-bromo-1-(N-(3,5-dimethoxypyrazin-2-yl)sulfamoyl)indolizine-3-carboxamide.

[0864] LCMS: (Method A): m / z 456.10 (ES+) at 1.926 min.

[0865] 1H-NMR: (400MHz, DMSO): 5 10.25 (s, 1H), 9.93 (s, 1H), 8.00 (s, 2H), 7.93 (d, J = 9.6 Hz, 1H), 7.52 (dd, J = 9.6, 1.8 Hz, 1H), 7.44 (s, 1H), 3.83 (s, 3H), 3.78 (s, 2H).

[0866] Step 6: 6-bromo-1-(N-(3,5-dimethoxypyrazin-2-yl)sulfamoyl)indolizine-3-carboxamide (0.10 g, 0.22 mmol) was dissolved in DCM (2 ml) and DMF (0.08 ml, 1.09 mmol). To it, oxalyl chloride (0.09 ml, 1.09 mmol) was added at 0 °C. Reaction mixture was stirred at room temperature for 15min. Reaction mixture was concentrated in vacuo to afford crude, which was purified by normal phase gradient flash column chromatography (silica), product eluted at 0% to 48% EtOAc in hexane to afford impure compound (0.06 g) which was re-purified by prep SFC (Method A) to afford 6-bromo-3-cyano-N-(3,5-dimethoxypyrazin-2-yl)indolizine-1-sulfonamide (0.02 g, 20.82%) as a light brown solid.

[0867] LCMS: (Method B): m / z 438.02 (ES+) at 1.89 min.

[0868] 1H-NMR: (400MHz, DMSO): 53.83 (s, 3H), 3.85 (s, 3H), 7.46 (s, 1H), 7.68-7.65 (m, 1Hz), 7.94 (s, 1H), 7.98 (d, 1H, J= 9.6Hz), 8.78 (s, 1H), 10.43 (s, 1H).

[0869] Synthesis of Examples A50, 3-cvano-6-cvclopropyl-N-(3,5-dimethoxypyrazin-2-yl)indolizine-1 -sulfonamide and A 57, 6-cvclopropyl-1-(N-(3,5-dimethoxypyrazin-2-yl)sulfamoyl)indolizine-3-carboxamide

[0870]

[0871] Example A56 Example A57 Example A50 Step 1: 6-bromo-1-(N-(3,5-dimethoxypyrazin-2-yl)sulfamoyl)indolizine-3-carboxamide (Example A56, 0.10 g, 0.22 mmol), potassium cyclopropyltrifluoroborate (0.04 g, 0.24 mmol) and K₂CO₃ (0.09 g, 0.66 mmol) were dissolved in 1,4-dioxane (2 ml) and water (0.5 ml) at room temperature. Nitrogen gas was purged through reaction mixture for 15 min at room temperature. PdCh(dppf)DCM (0.02 g, 0.02 mmol) was added and reaction mixture was irradiated at 100 °C for 1 h in the microwave. Reaction mixture was partitioned between water (40 ml) and EtOAc (40 ml). Aqueous layer was further extracted with EtOAc (2 x 30 ml). Organic layers were combined, dried (Na2SO4) and concentrated. The crude product was purified by reverse phase flash column chromatography (C18 silica, 24 g column) product was eluted at 0% to 50% MeCN in water to afford Example A57, 6-cyclopropyl-1-(N-(3,5-dimethoxypyrazin-2-yl)sulfamoyl)indolizine-3-carboxamide (0.035 g, 38.18%) as a brown solid.

[0872] LCMS: (Method A): m / z 418.19 (ES+) at 1.962 min.

[0873] 1H-NMR: (400MHz, DMSO): 5 10.16 (s, 1H), 9.58 (s, 1H), 8.01 - 7.74 (m, 2H), 7.42 (s, 1H), 7.22 (s, 1H), 7.07 (d, J = 9.4 Hz, 1H), 3.82 (d, J = 2.9 Hz, 3H), 3.75 (s, 3H), 2.00 (tt, J = 8.8, 5.1 Hz, 1H), 0.97 (h, J = 4.4 Hz, 2H), 0.69 (dd, J = 6.6, 4.6 Hz, 2H).

[0874] Step 2: 6-cyclopropyl-1-(N-(3,5-dimethoxypyrazin-2-yl)sulfamoyl)indolizine-3-carboxamide (0.035 g, 0.08 mmol) was dissolved in DCM (1 ml). To it, DMF (0.02 ml, 0.25 mmol) and POCI3 (0.02 ml, 0.25 mmol) were added at 0 °C. Reaction mixture was stirred at 0 °C for 30 min. Solvent was removed in vacuo to obtain crude which was purified by reverse phase gradient flash column chromatography (C18 silica, 12 g column), product eluted at 0% to 45% MeCN in water using 0.05% formic acid in water as a modifier to afford 3-cyano-6-cyclopropyl-N-(3,5-dimethoxypyrazin-2-yl)indolizine-1-sulfonamide (0.005 g, 14.93%) as a white solid.

[0875] LCMS: (Method B): m / z 400.17 (ES+) at 1.94 min.

[0876] 1H-NMR: (400MHz, DMSO): 50.83-0.79 (m, 2H), 1.01-0.98 (m, 2H), 2.16-2.12 (m, 1H), 3.80 (s, 3H), 3.84 (s, 3H), 7.18 (d, 1H, J= 8.8Hz), 7.45 (s, 1H), 7.84 (s, 1H), 7.93 (d, 1H, J= 9.2Hz), 8.39 (s, 1H), 10.30 (br s, 1H). Synthesis of Example A51, 6-chloro-N-(3,5-dimethoxypyrazin-2-yl)-3-(1H-pyrazol-4-yl)indolizine-1 -sulfonamide

[0877]

[0878] step 2 product

[0879] 3-bromo-6-chloro-N-(3,5-dimethoxypyrazin-2-yl)indolizine-1 -sulfonamide (Example A44 step 2 product, 0.10 g, 0.22 mmol) and4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.11 g, 0.56 mmol) were dissolved in 1,4-dioxane (2 ml). To it, 2M aqueous Na2COs solution (0.50 ml, 5V) was added at room temperature. Nitrogen gas was purged through reaction mixture for 30 min at room temperature. PdCh(dppf) (0.01 g, 0.01 mmol) was added and reaction mixture was irradiated at 100 °C for 5 h in the microwave. Reaction mixture was partitioned between water (30 ml) and EtOAc (30 ml). Aqueous layer was further extracted with EtOAc (2 x 20 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 55% EtOAc in hexane to afford 6-chloro-N-(3,5-dimethoxypyrazin-2-yl)-3-(1H-pyrazol-4-yl)indolizine-1 -sulfonamide (0.01 g, 10.27%) as off white solid.

[0880] LCMS: (Method B): m / z 435.25 (ES+) at 1.78 min.

[0881] 1H-NMR: (400MHz, DMSO): 53.81 (s, 3H), 3.83 (s, 3H), 7.20-7.19 (m, 2H), 7.46 (s, 1H), 7.94-7.90 (m, 2H), 8.37 (br s, 2H), 10.10 (s, 1H), 13.30 (br s, 1H).

[0882] Synthesis of Example A52, 6-chloro-N-(3,5-dimethoxypyrazin-2-yl)-3-(oxazol-2-yl)indolizine- 1 -sulfonamide

[0883]

[0884] step 2 product 3-bromo-6-chloro-N-(3,5-dimethoxypyrazin-2-yl)indolizine-1 -sulfonamide (Example A44 step 2 product, 0.10 g, 0.22 mmol) and 2-(tributylstannyl)oxazole (0.40 g, 1.12 mmol) were dissolved in 1,4-Dioxane (2 ml). To it, Tetrakis(triphenylphosphine)palladium(0) (0.03 g, 0.02 mmol) was added and nitrogen gas was purged through reaction mixture for 15 min at room temperature. Reaction mixture was irradiated at 150 °C for 1h in the microwave. Reaction mixture was filtered via celite bed and washed with aqueous KF solution (60 ml) and EtOAc (50 ml). Aqueous layer was further extracted with EtOAc (2 x 20 ml). Organic layers were combined, dried (Na2SO4) and concentrated. The crude product was purified by reverse phase gradient column chromatography (C18 silica, 24 g column), product eluted at 0% to 47% MeCN in water using 0.05% FA as modifier to afford 6-chloro-N-(3,5-dimethoxypyrazin-2-yl)-3-(oxazol-2-yl)indolizine-1-sulfonamide (0.032 g, 32.81%) as a white solid.

[0885] LCMS: (Method B): m / z 436.06 (ES+) at 2.06 min.

[0886] 1H-NMR: (400MHz, DMSO): 5 3.83 (s, 6H), 7.44 (s, 1H), 7.52-7.49 (m, 1H), 7.53 (d, 1H, J= 0.8Hz), 7.73 (s, 1H), 8.09-8.07 (m, 1H), 8.29 (d, 1H, J= 0.8Hz), 9.72-9.71 (m, 1H), 10.37 (br s, 1H).

[0887] Synthesis of Example A53, 6-chloro-N-(3,5-dimethoxypyrazin-2-yl)-3-(1H-pyrazol-5-yl)indolizine-1 -sulfonamide

[0888]

[0889] Example A44 Example A53

[0890] step 2 product

[0891] 3-bromo-6-chloro-N-(3,5-dimethoxypyrazin-2-yl)indolizine-1 -sulfonamide (Example A44 step 2 product, 0.15 g, 0.34 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.33 g, 1.68 mmol) were dissolved in 1,4-dioxane (2 ml). To it, 2M aqueous Na2COs (0.75 ml, 5 volume) was added at room temperature. Nitrogen gas was purged through reaction mixture for 30 min at room temperature. PdCl2(dppf) (0.007 g, 0.01 mmol) was added and reaction mixture was irradiated at 100 °C for 5h 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 reverse phase gradient flash column chromatography (C18 silica, 24 g column), product was eluted at 0% to 40% MeCN in water to afford 6-chloro-N-(3,5- dimethoxypyrazin-2-yl)-3-(1H-pyrazol-5-yl)indolizine-1-sulfonamide (0.008 g, 5.48%) as an off white solid.

[0892] LCMS: (Method B): m / z (ES+) 435.12 at 1.88 min.

[0893] 1H-NMR: (400MHz, DMSO): 53.79 (s, 3H), 3.82 (s, 3H), 6.91 (s, 1H), 7.29-7.27 (m, 1H), 7.44 (s, 1H), 7.59 (s, 1H), 7.98-7.93 (m, 2H), 9.75 (s, 1H), 10.15 (br s, 1H), 13.17 (s, 1H).

[0894] Synthesis of Example A54, 6-chloro-N-(3,5-dimethoxypyrazin-2-yl)-3-(1H-pyrazol-1-yl)indolizine-1 -sulfonamide

[0895]

[0896] Example A44 Example A54

[0897] step 2 product

[0898] 3-bromo-6-chloro-N-(3,5-dimethoxypyrazin-2-yl)indolizine-1 -sulfonamide (Example 44, step 2 product, 0.15 g, 0.33 mmol), 1H-pyrazole (0.23 g, 3.36 mmol) and K3PO4 (0.36 g, 1.68 mmol) were dissolved in DMF (3 ml). N2 gas was purged through reaction mixture for 15 min at room temperature. Trans-N, N'-dimethylcyclohexane-1,2-diamine (0.10 ml, 0.67 mmol) and Cui (0.03 g, 0.17 mmol) were added and reaction mixture was irradiated at 160 °C for 1 h in the microwave. Reaction mixture was partitioned between water (40 ml) and EtOAc (40 ml). Aqueous layer was further extracted with EtOAc (2 x 30 ml). Organic layers were combined, dried (Na2SO4) and concentrated. The crude product was purified by reverse phase gradient flash column chromatography (C18 silica, 24 g column), product eluted at 0% to 80% MeCN in water to afford 6-chloro-N-(3,5-dimethoxypyrazin-2-yl)-3-(1H-pyrazol-1-yl)indolizine-1-sulfonamide (0.028 g, 19.18%) as white solid.

[0899] LCMS: (Method B): m / z 435.1 (ES+) at 1.96 min.

[0900] 1H-NMR: (400MHz, DMSO): 5 3.83 (s, 3H), 3.84 (s, 3H), 6.64 (t, 1H, J= 2.2Hz), 7.32 (d, 1H, J= 1.6Hz), 7.35 (s, 1H), 7.47 (s, 1H), 7.95 (d, 1H, J= 1.6Hz), 7.99 (d, 1H, J= 9.6Hz), 8.23 (s, 1H), 8.24 (d, 1H, J= 9.6Hz), 10.28 (s, 1H).

[0901] Synthesis of Example A55, 3,6-dichloro-N-(3,5-dimethoxypyrazin-2-yl)indolizine-1-sulfonamide

[0902]

[0903] Example A55

[0904] Step 1: 6-chloroindolizine-1-sulfonamide (Intermediate 14, purified material, 300mg, 1.3mmol) was dissolved inTHF (10 mL). N-chlorosuccinimide (208.4mg, 1.56mmol) was added and the reaction mixture stirred at room temperature overnight. The solvent was removed in vacuo and the crude was extracted with EtOAc and washed with 5% sodium thiosulfate. The organic layer was concentrated in vacuo to give 3, 6-dichloroindolizine-1 -sulfonamide (312 mg, 1.18mmol, 90.49% yield) as a navy blue solid.

[0905] 1H-NMR: (400MHz, DMSO): 5 8.50 (dd, J = 1.8, 0.9 Hz, 1H), 7.95 (dd, J = 9.7, 0.9 Hz, 1H), 7.34 (s, 2H), 7.26 (dd, J = 9.7, 1.8 Hz, 1H), 7.20 (s, 1H).

[0906] Step 2: 6-chloroindolizine-1-sulfonamide (50 mg, 0.22mmol), 2-bromo-3,5-dimethoxypyrazine (47.48mg, 0.22mmol), potassium carbonate (74.9mg, 0.54mmol), and trans-N, N'-dimethylcyclohexane-1,2-diamine (0.04mL, 0.26mmol) were added to MeCN (5 mL). The reaction mixture was flushed with nitrogen for 10 minutes. Copper(I) iodide (4.13mg, 0.02mmol) was added and the reaction mixture was heated at 80 °C overnight. Reaction mixture diluted with ethyl acetate and washed with 1M HCI and NaCCh. The organic layer was dried (phase separator) and concentrated. The residue was purified by reverse phase HPLC (Phenomenex Kinetex column, 100 x 30 mm, 5pm, 30 mL / min, gradient of 40% to 70% (over 8.7 min) then a 100 % hold (1 min), solvents: Aqueous = Water with 0.1 % TFA, Organic = Acetonitrile) to afford 3, 6-dichloro-N-(3,5-dimethoxypyrazin-2-yl)indolizine-1 -sulfonamide (5.1 mg, 0.01 mmol, 6.71% yield).

[0907] LCMS: (Method B): m / z 403.08 (ES+) at 1.82 min.

[0908] 1H-NMR: (400MHz, DMSO): 5 10.21 (s, 1H), 8.48 (dd, J = 1.8, 0.9 Hz, 1H), 7.94 (dd, J = 9.6, 0.9 Hz, 1H), 7.40 (s, 1H), 7.26 (dd, J = 9.7, 1.8 Hz, 1H), 7.23 (s, 1H), 3.82 (s, 3H), 3.81 (s, 3H).

[0909] Synthesis of Example A62, (±) 6-chloro-3-(1,2-dihvdroxyethyl)-N-(3,5-dimethoxypyrazin-2-yl)indolizine-1 -sulfonamide

[0910]

[0911] Example A44,

[0912] step 2 product Example A62 Step 1: 3-Bromo-6-chloro-N-(3,5-dimethoxypyrazin-2-yl)indolizine-1-sulfonamide (Example A44, step 2 product, 250 mg, 0.558 mmol), potassium vinyltrifluoroborate (0.090 g, 0.670 mmol) and triethylamine (0.236 ml, 1.675 mmol) were dissolved in IPA (2.5 ml). Argon was purged through reaction mixture for 15 min at room temperature. After this, 1,1'-bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane (0.023 g, 0.028 mmol) was added and reaction mixture was stirred at 80 °C for 16h. Reaction mixture was filtered via Celite bed and washed with water (100 mL) and EtOAc (30 ml). Aqueous layer was further extracted with EtOAc (2 x 50 ml). Organic layers were combined and dried (Na2SO4), filtered and concentrated to afford 6-chloro-N-(3,5-dimethoxypyrazin-2-yl)-3-ethenylindolizine-1 -sulfonamide (196 mg, 0.437 mmol, 78.23%) as a brown solid. Product was used in the next step without further purification.

[0913] 1H-NMR: (300MHz, DMSO): δ 9.98 (s, 1H), 8.83 (s, 1H), 7.87 (d, J = 9.5 Hz, 1H), 7.43 (d, J = 4.6 Hz, 1H), 7.20 (td, J = 10.5, 10.1, 8.6 Hz, 2H), 5.87 (d, J = 17.3 Hz, 1H), 5.32 (d, J = 11.4 Hz, 1H), 3.84 (s, 3H), 3.81 (s, 3H).

[0914] Step 2: N-oxide morpholine (0.050 g, 0.425 mmol) was dissolved in acetone (6.4 ml) and water (2.7 ml). Osmium tetroxide, 4 wt.% in water (24 pl) was added followed by 6-chloro-N-(3, 5-dimethoxypyrazin-2-yl)-3-ethenylindolizine-1 -sulfonamide (152 mg, 0.386 mmol). The reaction mixture was stirred at RT overnight then filtered through Celite and washed with acetone. Filtrate was concentrated yielding 179 mg of brown solid which was purified by preparative HPLC (Method E) to afford 6-chloro-3-(1,2-dihydroxyethyl)-N-(3,5-dimethoxypyrazin-2-yl)indolizine-1-sulfonamide (41.2 mg, 0.094 mmol, 24.32%) as a white powder.

[0915] LCMS: (Method B): m / z 429.21 (ES+) at 1.67 min.

[0916] 1H-NMR: (400MHz, DMSO): δ 10.00 (s, 1H), 8.59 (dd, J = 1.8, 0.9 Hz, 1H), 7.87 (dd, J = 9.7, 0.9 Hz, 1H), 7.42 (s, 1H), 7.18 (dd, J = 9.6, 1.8 Hz, 1H), 7.05 (s, 1H), 5.57 (d, J = 5.8 Hz, 1H), 4.97 (t, J = 5.7 Hz, 1H), 4.93 (q, J = 5.7 Hz, 1H), 3.83 (s, 3H), 3.80 (s, 3H), 3.75 (t, J = 5.8 Hz, 2H). Synthesis of Example A63, 6-chloro-N-(3,5-dimethoxypyrazin-2-yl)-3-(hydroxymethyl)-5-(2H- 1, 2, 3-triazol-2-yl)indolizine-1 -sulfonamide

[0917]

[0918]

[0919] Example A63

[0920] Step 1: 5-Chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine (CAS 1832583-43-3, 3.00 g, 15.38 mmol) was dissolved in MeCN (100 ml) at room temperature. To it, NBS (2.74 g, 15.38 mmol) was added and reaction mixture was stirred at room temperature for 2 h. Reaction mixture was partitioned between water (200 ml) and EtOAc (200 ml). Aqueous layer was further extracted using EtOAc (2 x 150 ml). Combined organic layers were dried (Na2SO4) and concentrated. The crude was purified by normal phase gradient flash column chromatography (silica), product was eluted at 0% to 40% EtOAc in hexane to afford 2-bromo-5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine (1.90 g, 45.26%) as a brown solid.

[0921] LCMS: (Method A): m / z 274.00 (ES+) at 1.813 min.

[0922] Step 2: 2-bromo-5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine (1.90 g, 6.96 mmol) was dissolved in 1,4-Dioxane (20 ml) at room temperature. To it, isoamyl nitrite (1.87 ml, 13.92 mmol) was added at room temperature and reaction mixture was stirred at 100°C for 6h. Reaction mixture was partitioned between water (150 ml) and EtOAc (150 ml). Aqueous layer was further extracted using EtOAc (2 x 100 ml). The combined organic layers were dried (Na2SO4) and concentrated. The crude was purified by normal phase gradient flash column chromatography (silica), product was eluted at 0% to 30% EtOAc in hexane to afford 6-bromo-3-chloro-2-(2H-1,2,3-triazol-2-yl)pyridine (1.00 g, 55.69%) as a brown solid.

[0923] LCMS: (Method A): m / z 259.0 (ES+) at 1.962 min.

[0924] Step 3: 6-bromo-3-chloro-2-(2H-1,2,3-triazol-2-yl)pyridine (1.00 g, 3.88 mmol), potassium trifluoro(vinyl)borate (1.03 g, 7.75 mmol) and Et3N (1.62 ml, 11.63 mmol) were dissolved in I PA (10 ml). Nitrogen gas was purged through reaction mixture for 15 min at room temperature. Pd(dppf)Cl2(0.31 g, 0.39 mmol) was added and reaction mixture was stirred at 80 °C for 6h. Reaction mixture was partitioned between water (100 ml) and EtOAc (80 ml). Aqueous layer was further extracted with EtOAc (2 x 70 ml). Combined organic layers were dried (Na2SO4) and concentrated. The crude was purified by normal phase gradient flash column chromatography (silica), eluted at 0% to 32% EtOAc in hexane to afford 3-chloro-2-(2H-1,2,3-triazol-2-yl)-6-vinylpyridine (0.70 g, 87.63%) as a brown sticky solid.

[0925] LCMS: (Method A): m / z 207.09 (ES+) at 1.940 min.

[0926] Step 4: Performed in a similar fashion to Intermediate 1, Step 2. Purification was by normal phase gradient flash column chromatography (silica), product was eluted at 0% to 30% EtOAc in hexane to afford methyl 6-chloro-5-(2H-1,2,3-triazol-2-yl)indolizine-3-carboxylate (0.6 g, 19.47%) as brown sticky solid. LCMS: (Method A): m / z 276.92 (ES+) at 2.048 min.

[0927] Step 5: Methyl 6-chloro-5-(2H-1,2,3-triazol-2-yl)indolizine-3-carboxylate (0.60 g, 2.17 mmol) was dissolved in MeCN (5 ml). To it, chlorosulfonic acid (0.30 ml, 4.56 mmol) was added at 0 °C and reaction mixture was stirred at room temperature for 6 h. Reaction mixture was partitioned between water (150 ml) and EtOAc (120 ml). Aqueous layer was further extracted using EtOAc (2 x 100 ml). The combined organic layer was discarded. Aqueous layer was concentrated in vacuo to afford crude 6-chloro-3-(methoxycarbonyl)-5-(2H-1,2,3-triazol-2-yl)indolizine-1 -sulfonic acid (0.60 g, 77.54%) as a brown sticky solid which was used in next step without any purification.

[0928] LCMS: (Method A): m / z 356.95 (ES+) at 1.505 min.

[0929] Step 6: 6-chloro-3-(methoxycarbonyl)-5-(2H-1, 2, 3-triazol-2-yl)indolizine-1 -sulfonic acid (0.60 g, 1.68 mmol) was dissolved in MeCN (6 ml). To it, POCl3(0.8 ml, 8.42 mmol) was added at room temperature and reaction mixture was stirred at 100 °C for 12h. Reaction mixture was poured into ice cold water (100 ml) and then extracted with EtOAc (80 ml). Aqueous layer was further extracted with EtOAc (2 x 60 ml). Combined organic layers were dried (Na2SO4) and concentrated to afford methyl 6-chloro-1-(chlorosulfonyl)-5-(2H-1,2,3-triazol-2-yl)indolizine-3-carboxylate (0.5 g, 79.33%).

[0930] LCMS: (Method A): m / z 355.01 (ES-) (Sulfonic acid) at 2.310 min. Step 7: Methyl 6-chloro-1-(chlorosulfonyl)-5-(2H-1,2,3-triazol-2-yl)indolizine-3-carboxylate (0.5 g, 1.33 mmol) was dissolved in THF (10 ml) at -78°C. NH3 (g) was purged through reaction mixture for 8h 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% acetonitrile in water to afford methyl 6-chloro-1-sulfamoyl-5-(2H-1,2,3-triazol-2-yl)indolizine-3-carboxylate (0.25 g, 52.67%) as a brown solid.

[0931] 1H-NMR: (400MHz, DMSO): δ 8.30 (s, 2H), 8.25 (d, J= 9.6 Hz, 1H), 7.72 (d, J= 9.6 Hz, 1H), 7.64 (s, 1H), 7.59 (s, 2H), 3.43 (s, 3H).

[0932] Step 8: Performed in a similar fashion to Route A, using CAS 1033610-34-2. Purification was by normal phase gradient flash column chromatography (silica), product was eluted at 0% to 35% EtOAc in hexane to afford methyl 6-chloro-1-(N-(3,5-dimethoxypyrazin-2-yl)sulfamoyl)-5-(2H-1,2,3-triazol-2-yl)indolizine-3-carboxylate (0.25 g, 72.00%) as a brown solid.

[0933] LCMS: (Method A): m / z 494.09 (ES+) at 2.093 min.

[0934] Step 9: Performed in a similar fashion to route D, to afford 6-chloro-N-(3,5-dimethoxypyrazin-2-yl)-3-(hydroxymethyl)-5-(2H-1, 2, 3-triazol-2-yl)indolizine-1 -sulfonamide (8.0 mg, 8.51%) as white solid.

[0935] LCMS: (Method B): m / z (ES+) 466.18 at 1.76 min.

[0936] 1H-NMR: (400MHz, DMSO): δ 3.53 (s, 2H), 3.77 (s, 3H), 3.80 (s, 3H), 5.16 (brs, 1H), 7.13 (s, 1H), 7.27-7.25 (m, 2H), 8.29-8.25 (m, 2H), 8.41 (s, 2H).

[0937] Synthesis of Example A66, 6-chloro-3-cvano-N-(3,5-dimethoxypyrazin-2-yl)-5-(2H-1,2,3-tri azol-2-yl)indolizine-1 -sulfonamide

[0938]

[0939] Example A66 Step 1: 3-chloro-2-(2H-1,2,3-triazol-2-yl)-6-vinylpyridine (Example A63, step 3 product, 0.15 g, 0.73 mmol), cyanoacetic acid (0.12 g, 1.46 mmol) and sodium acetate (0.18 g, 2.18 mmol) were dissolved in MeCN (4 ml). N-lodosuccinimide (0.57 g, 2.55 mmol) was added at room temperature and reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was partitioned between water (70 ml) and EtOAc (60 ml) and the aqueous layer was further extracted using 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 was eluted at 0% to 35% EtOAc in hexane to afford 6-chloro-5-(2H-1,2,3-triazol-2-yl)indolizine-3-carbonitrile (0.07 g, 39.56%) as a brown solid.

[0940] LCMS: (Method A): m / z 241.9 (ES-) at 2.018 min.

[0941] Step 2: 6-chloro-5-(2H-1,2,3-triazol-2-yl)indolizine-3-carbonitrile (0.07 g, 0.29 mmol) was dissolved in MeCN (2 ml). Chlorosulfonic acid (0.03 ml, 0.58 mmol) was added at 0 °C and reaction mixture was stirred at room temperature for 6 h. The mixture was partitioned between water (50 ml, CAUTION, exothermic) and EtOAc (40 ml), aqueous layer was further extracted using EtOAc (2 x 40 ml). The combined organic layer was discarded. Aqueous layer was concentrated in vacuo to afford crude 6-chloro-3-cyano-5-(2H-1,2,3-triazol-2-yl)indolizine-1-sulfonic acid (0.07 g, 75.24%) as an off white solid that was used without further purification. LCMS: (Method A): m / z 321.98 (ES-) at 1.515 min.

[0942] Step 3: 6-chloro-3-cyano-5-(2H-1,2,3-triazol-2-yl) indolizine-1 -sulfonic acid (0.07 g, 0.22 mmol) was dissolved in MeCN (2 ml). POCl3(0.10 ml, 1.08 mmol) was added at room temperature and the reaction mixture was stirred at 100 °C for 12 h. The reaction mixture was poured into ice cold water (70 ml) and then extracted with EtOAc (60 ml). Aqueous layer was further extracted with EtOAc (2 x 50 ml). Organic layers were combined and dried (Na2SO4). Solvent was removed in vacuo to afford 6-chloro-3-cyano-5-(2H-1,2,3-triazol-2-yl) indolizine-1 -sulfonyl chloride (0.05 g, 67.67%) as off white solid that was used without further purification. LCMS: (Method A): m / z 322.01 (ES-) (Sulfonic acid) at 1.531 min.

[0943] Step 4: 6-chloro-3-cyano-5-(2H-1, 2, 3-triazol-2-yl)indolizine-1 -sulfonyl chloride (0.05 g, 0.15 mmol) was dissolved in THF (18 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% acetonitrile in water to afford 6-chloro-3-cyano-5-(2H-1,2,3-triazol-2-yl)indolizine-1-sulfonamide (0.04 g, 84.71%) as a brown solid.

[0944] LCMS: (Method A): m / z 321.01 (ES-) at 1.766 min.

[0945] Step 5: Performed in a similar fashion to Route A, using CAS 1033610-34-2. Additional purification via prep HPLC (Method F). LCMS: (Method B): m / z (ES+) 461.19 at 1.79 min.

[0946] 1H-NMR: (400 MHz, DMSO) δ 3.82 (s, 3H), 3.83 (s, 3H), 7.39 (s, 1H), 7.81 (d, 1H, J= 9.6Hz), 8.01 (s, 1H), 8.37 (d, 1H, J= 9.6Hz), 8.48 (s, 2H), 10.71 (brs, 1H).

[0947] Synthesis of Example A67, 6-chloro-N-(6-(cyanomethyl)-5-fluoro-2-methoxypyridin-3-yl)-3- (1H-pyrazol-5-yl)indolizine-1 -sulfonamide

[0948]

[0949] Example A67

[0950] Step 1: Performed in a similar fashion to Route E, using Intermediate 3 and CAS 3026463-64-6.

[0951] Step 2: Performed in a similar fashion to Route B step 1.

[0952] Step 3: To a solution of 6-chloro-1-{[6-(cyanomethyl)-5-fluoro-2-methoxypyridin-3-yl]sulfamoyl}indolizine-3-carboxylic acid (0.671 g, 1.529 mmol, 1.00 eq) inTHF (10 mL, 0.2 M) was added lithium bromide (0.186 g, 2.141 mmol, 1.4 equiv.) and iodobenzene diacetate (0.690 g, 2.141 mmol, 1.4 equiv.). The mixture was stirred at 0 °C for 30 minutes. Water and EtOAc were added, and the phases separated. The aqueous layer was extracted 3 times with EtOAc, and the combined organic layers were dried (Na2SO4) and concentrated. The crude was purified by flash column chromatography (silica) eluted at 0 to 40% ethyl acetate in hexane to afford 3-bromo-6-chloro-N-[6-(cyanomethyl)-5-fluoro-2-methoxypyridin-3-yl]indolizine-1-sulfonamide (0.245 g, 0.517 mmol, 33.82%).1H-NMR: (300 MHz, DMSO) 6 10.11 (s, 1H), 8.44 (dd, J = 1.8, 0.9 Hz, 1H), 7.89 (dd, J = 9.6, 0.9 Hz, 1H), 7.58 (d, J = 9.9 Hz, 1H), 7.38 - 7.28 (m, 2H), 4.08 (d, J = 2.0 Hz, 2H), 3.62 (s, 3H).

[0953] Step 4: 3-bromo-6-chloro-N-[6-(cyanomethyl)-5-fluoro-2-methoxypyridin-3-yl]indolizine-1-sulfonamide (60 mg, 0.127 mmol, 1.0 eq), 3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (CAS 844501-71-9, 0.049 g, 2.0 eq), sodium carbonate (0.054 g, 0.507 mmol, 4.0 eq), 1,4-dioxane (1.2 ml, 20 vol) and water (0.4 ml, 6.6 vol) were placed in a sealed tube, then degassed with argon. 1,1'-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane (0.010 g, 0.013 mmol, 0.10 eq) was added. The reaction was stirred at 100 °C overnight. Additional 1,1'-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane (0.005 g, 0.006 mmol, 0.05 eq) and 3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.025 g, 1.0 eq) were added and the reaction was stirred for 4 h. The reaction was filtered through Celite cake, then concentrated to dryness. Crude product was purified by preparative HPLC (Method G) to afford 6-chloro-N-[6-(cyanomethyl)-5-fluoro-2-methoxypyridin-3-yl]-3-(1H-pyrazol-5-yl)indolizine-1-sulfonamide (21.7 mg, 0.046 mmol, 36.30%) as a white solid.

[0954] LCMS: (Method B): m / z (ES+) 461.18 at 1.92 min.

[0955] 1H-NMR: (400 MHz, DMSO) δ 12.97 (s, 1H), 9.67 (s, 1H), 7.97 (d, J = 9.6 Hz, 1H), 7.89 – 7.80 (m, 1H), 7.48 (t, J = 5.2 Hz, 2H), 7.25 – 7.16 (m, 1 H), 6.78 (d, J = 2.4 Hz, 1H), 3.94 (d, J = 2.1 Hz, 2H), 3.69 (s, 3H).

[0956] Synthesis of Example A68, 6-chloro-N-(6-(cvanomethyl)-5-fluoro-2-methoxypyridin-3-yl)-3-(1H-pyrazol-4-yl)indolizine-1 -sulfonamide

[0957]

[0958] Performed in a similar fashion to Example A67 using 1-Boc-4-Pyrazoleboronic acid pinacol ester in the final step (CAS 552846-17-0) to afford 6-chloro-N-(6-(cyanomethyl)-5-fluoro-2-methoxypyridin-3-yl)-3-(1H-pyrazol-4-yl)indolizine-1 -sulfonamide.

[0959] LCMS: (Method B): m / z (ES+) 461.21 at 1.83 min.1H NMR: (300 MHz, CD3OD) δ 8.26 (s, 1H), 7.94 – 7.90 (m, 3H), 7.66 (d, J = 9.9 Hz, 1 H), 7.12 (d, J = 10.2 Hz, 2H), 3.89 (d, J = 2.1 Hz, 2H), 3.73 (s, 3H).

[0960] Synthesis of Example A77, 3-cvano-6-cvclopropyl-N-(5-(2,2-difluoroethoxy)-3-methoxypyrazin-2-yl)indolizine-1 -sulfonamide

[0961]

[0962] Example A75 Example A77

[0963] 6-bromo-3-cyano-N-(5-(2,2-difluoroethoxy)-3-methoxypyrazin-2-yl)indolizine-1 -sulfonamide (Example A75, 0.10 g, 0.21 mmol), potassium cyclopropyltrifluoroborate (CAS 1065010-87-8, 0.06 g, 0.41 mmol) and K₂CO₃ (0.08 g, 0.62 mmol) were dissolved in toluene (0.9 ml) and water (0.1 ml). Nitrogen gas was purged through reaction mixture for 10 min. PdCh(dppf)DCM (0.02 g, 0.02 mmol) was added and reaction mixture was stirred at 120 °C for 4 h. 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 gradient flash column chromatography (C18 silica), product eluted at 0% to 60% ACN in water to afford 3-cyano-6-cyclopropyl-N-(5-(2,2-difluoroethoxy)-3-methoxypyrazin-2-yl)indolizine-1 -sulfonamide (0.046 g, 50%) as a white solid.

[0964] LCMS: (Method B): m / z (ES+) 450.26 at 1.98 min.

[0965] 1H-NMR: (400 MHz, DMSO) δ 0.79-0.83 (m, 2H), 0.98-1.03 (m, 2H), 2.12-2.17 (m, 1H), 3.84 (s, 3H), 4.49-4.57 (m, 2H), 6.25-6.53 (m, 1H), 7.19 (d, 1H, J= 9.4Hz), 7.53 (s, 1H), 7.87 (s, 1H), 7.96 (d, 1H, J= 9.4Hz), 8.39 (s, 1H), 10.46 (s, 1H).

[0966] Synthesis of Example B1, N-(4-bromo-2,5-difluorophenyl)-6-chloroindolizine-1-sulfonamide

[0967]

[0968] A solution of 4-bromo-2,5-difluorobenzeneboronic acid (328.52mg, 1.39 mmol), Tetrakis(acetonitrile)copper(l) tetrafluoroborate (110 mg, 0.350 mmol), potassium phosphate tribasic (1.21 g, 5.55mmol), 6-chloroindolizine-3-sulfonamide (Intermediate 14, 160 mg, 0.6900mmol) in MeCN (10 mL) was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc and washed with 1M aq. HCI solution, sat. aq. NaHCO₃ solution, brine, dried over MgSC, passed over hydrophobic frit and evaporated in vacuo. The residue was purified by flash column chromatography (reverse phase, 30g, Biotage® SfarCI 8 D -Duo 100A 30 pm silica, 50 mL per min) gradient 0% to 100% MeOH in H2O + 0.2% TFA modifier, to give N-(4-bromo-2,5-difluoro-phenyl)-6-chloro-indolizine-1 -sulfonamide (40.8 mg, 44.64%).

[0969] LCMS: (Method B): m / z 418.93 (ES-) at 1.83 min.

[0970] 1H-NMR: (400 MHz, Acetonitrile-d3) 5 8.34 (dd, J = 1.8, 0.9 Hz, 1H), 7.80 (ddd, J = 9.7, 0.6 Hz, 1H), 7.44 (dd, J = 3.1, 0.6 Hz, 1H), 7.40 (dd, J = 9.8, 6.9 Hz, 1H), 7.33 (ddd, J = 9.5, 6.3, 0.3 Hz, 1H), 7.12 (dd, J = 9.7, 1.8 Hz, 1H), 7.05 (d, J = 3.1 Hz, 1H).

[0971] Synthesis of Example B2, N-(5-bromo-4-methoxypyrimidin-2-yl)-6-chloroindolizine-1-sulfonamide

[0972]

[0973] 6-chloroindolizine-1-sulfonamide (Intermediate 14, 50 mg, 0.22mmol), 5-bromo-2-iodo-4-methoxy-pyrimidine (CAS 1443792-51-5, 88 mg, 0.28mmol), potassium carbonate (75 mg, 0.54mmol), and trans-N, N'-dimethylcyclohexane-1,2-diamine (0.04mL, 0.26mmol) were added to MeCN (5 mL). The reaction mixture was flushed with nitrogen for 10 minutes. Copper(I) iodide (4.13mg, 0.02mmol) was added and the reaction mixture was then heated at 80 °C overnight. Reaction mixture diluted with ethyl acetate and washed with HCl and NaCO3. The organic layer was dried (phase separator) and evaporated to dryness. The residue was purified by reverse phase HPLC (Phenomenex Kinetex column, 100 x 30 mm, 5pm, 30 mL / min, gradient of 40% to 70% (over 8.7 min) then a 100 % hold (1 min), solvents: Aqueous = Water with 0.1 % TFA, Organic = Acetonitrile) to give N-(5-bromo-4-methoxy-pyrimidin-2-yl)-6-chloro-indolizine-1-sulfonamide (30.1 mg, 0.07mmol, 33.25% yield).

[0974] LCMS: (Method B): m / z 417.03 (ES+) at 1.65 min.

[0975] 1H-NMR: (400 MHz, DMSO) 5 11.70 (s, 1H), 8.77 (dd, J = 1.8, 0.9 Hz, 1H), 8.36 (s, 1H), 7.98 (dt, J = 9.6, 0.8 Hz, 1H), 7.62 (dd, J = 3.1, 0.5 Hz, 1H), 7.26 (dd, J = 9.7, 1.8 Hz, 1H), 7.23 (d, J = 3.0 Hz, 1H), 3.83 (s, 3H).

[0976] Synthesis of Example B3, 6-chloro-N-(4-(difluoromethoxy)-5-fluoro-2-methoxyphenyl)indolizine-1 -sulfonamide

[0977]

[0978] 1-bromo-4-(difluoromethoxy)-5-fluoro-2-methoxybenzene (CAS 2091708-41-5, 130. mg, 0.48mmol), 6-chloroindolizine-1-sulfonamide (Intermediate 14, 90 mg, 0.39 mmol), potassium carbonate (200 mg, 1.45 mmol) and trans-N, N'-dimethylcyclohexane-1,2-diamine (100 mg, 0.7mmol) were added to MeCN (10 mL) and stirred under N2 (10 mins). Copper(I) iodide (11 mg, 0.06mmol) was added and the reaction mixture was heated to 90 °C overnight. The reaction mixture was filtered through a celite cartridge, and concentrated. The residue was purified by flash-column chromatography (silica) 0-40% EtOAc in iso-hexane to give 6-chloro-N-[4-(difluoromethoxy)-5-fluoro-2-methoxy-phenyl]indolizine-1 -sulfonamide (34 mg, 0.08 mmol, 20.71% yield) as an off-white solid.

[0979] LCMS: (Method B): m / z 421.06 (ES+) at 1.88 min.

[0980] 1H-NMR: (400 MHz, DMSO) δ 9.53 (s, 1H), 8.75 (dd, J = 1.5, 0.7 Hz, 1H), 7.73 (d, J = 0.7 Hz, 1H), 7.59 (d, J = 3.0 Hz, 1H), 7.21 (d, J = 11.7 Hz, 1H), 7.17 (dd, J = 9.7, 1.8 Hz, 1H), 7.14 (t, J = 73.4 Hz, 1H), 7.01 (d, J = 0.5 Hz, 1H), 6.87 (d, J = 7.4 Hz, 1H), 3.43 (s, 3H).

[0981] Synthesis of Example B4, 6-chloro-N-(4-(difluoromethoxy)-2,5-difluorophenyl)indolizine-1-sulfonamide

[0982]

[0983] 6-chloroindolizine-1-sulfonamide (Intermediate 14, 73 mg, 0.32mmol), 1-bromo-4-(difluoromethoxy)-2,5-difluorobenzene (CAS 1394130-50-7, 90 mg, 0.35mmol), potassium carbonate (110 mg, 0.8 mmol) and trans-N, N'-dimethylcyclohexane-1,2-diamine (55 mg, 0.39 mmol) were dissolved in MeCN (10 mL) and stirred under N2 (10 mins). Copper(I) iodide (25 mg, 0.13mmol) was added, and the reaction mixture was heated to 100 °C over the weekend. The reaction mixture was passed through celite and concentrated. The crude solid was purified by flash-column chromatography (silica) 10-30 % EtOAc in iso-hexane with dryloading. The crude was further purified by prep HPLC (Method D) to give 6-chloro-N-[4-(difluoromethoxy)-2,5-difluoro-phenyl]indolizine-1 -sulfonamide (15 mg, 0.04 mmol, 11.6% yield) as a brown solid.

[0984] LCMS: (Method B): m / z 409.17 (ES+) at 1.85 min.

[0985] 1H-NMR: (400 MHz, DMSO) 5 10.22 (s, 1H), 8.77 (dd, J = 1.8, 0.9 Hz, 1H), 7.70 (dt, J = 9.6, 0.8 Hz, 1H), 7.63 (dd, J = 3.1, 0.6 Hz, 1H), 7.35-7.24 (m, 2H), 7.20 (dd, 1H), 7.18 (t, J = 72.9 Hz, 1H), 7.04 (d, J = 3.0 Hz, 1H).

[0986] Synthesis of Example B5, 6-cyclopropyl-N-(5-(2-fluoroethoxy)-6-methoxypyridin-2-yl)indolizine-1 -sulfonamide

[0987]

[0988] Step 1: Methyl 6-cyclopropylindolizine-2-carboxylate (CAS 2376496-92-1, 5.50 g, 25.58 mmol) was dissolved in THF (50 mL) and water (50 mL). To it, LiOH monohydrate (2.14 g, 51.16 mmol) was added at room temperature and reaction mixture was stirred for 16 h. Reaction mixture was diluted with water (100 mL), acidified with 1N HCI (70 mL) up to pH ~2 and product was extracted with EtOAc (300 mL). Aqueous layer was further extracted using EtOAc (2 x 100 mL). Organic layers were combined and dried (Na2SO4). Solvent was removed to afford 6-cyclopropylindolizine-2-carboxylic acid (3.50 g, 68.07%) as a light brown solid. LCMS: (Method A): m / z 202.10 (ES+), at 1.516 min.

[0989] Step 2: 6-cyclopropylindolizine-2-carboxylic acid (3.50 g, 17.41 mmol) was dissolved in quinoline (17.5 mL) and NMP (52.5 mL). Nitrogen gas was purged through reaction mixture at room temperature for 20 min. To it, Cu2O (0.25 g, 1.74 mmol) and 4,7-Diphenyl-1,10-phenanthroline (1.16 g, 3.48 mmol) were added at room temperature. Nitrogen gas was purged through reaction mixture at room temperature for 10 min. Reaction mixture was then irradiated at 200 °C for 1 h in microwave. Reaction mixture was diluted with water (500 mL) and extracted with 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 normal phase gradient column chromatography (silica), product was eluted at 0% to 12% EtOAc in hexane to afford 6-cyclopropylindolizine (2.30 g, 84.13%) as off white solid. LCMS: (Method A): m / z 158.10 (ES+), at 1.935 min.

[0990] Step 3: 6-cyclopropylindolizine (2.30 g, 14.65 mmol) was dissolved in THF (30 mL). To it, burgess reagent (4.18 g, 17.58 mmol) was added at room temperature and reaction mixture was stirred at room temperature for 48 h. Reaction mixture was diluted with water (200 mL) and extracted with EtOAc (200 mL). Aqueous layer was further extracted using 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 8% EtOAc in hexane to afford methyl ((6-cyclopropylindolizin-1-yl)sulfonyl)carbamate (0.90 g, 20.89%) as off white solid.

[0991] LCMS: (Method A): m / z 295.11 (ES+), at 1.467 min.

[0992] Step 4: Methyl ((6-cyclopropylindolizin-1-yl)sulfonyl)carbamate (0.90 g, 3.06 mmol) was dissolved in pyridine (3 mL) and water (3 mL). Reaction mixture was stirred at 100 °C for 16h. Reaction mixture was concentrated under vacuo to afford crude, which was purified by normal phase gradient flash column chromatography (silica), product was eluted at 0% to 29% EtOAc in hexane to afford 6-cyclopropylindolizine-1-sulfonamide (0.50 g, 69.21%) as brown solid. LCMS: (Method A): m / z 237.10 (ES+), at 1.357 min.1H-NMR: (400 MHz, DMSO) 60.71-0.67 (m, 2H), 0.95-0.90 (m, 2H), 1.93-1.89 (m, 1H), 6.86-6.84 (d, 1H, J= 8.8Hz), 6.96 (d, 1H, J= 2.8Hz), 7.04 (s, 2H), 7.49 (d, 1H, J= 2.8Hz), 7.75 (d, 1H, J= 9.2Hz), 8.26 (s, 1H).

[0993] Step 5: 6-cyclopropylindolizine-1 -sulfonamide (0.05 g, 0.20 mmol), 6-bromo-3-(2-fluoroethoxy)-2-methoxypyridine (Intermediate 15, 0.05 g, 0.20 mmol) and K₂CO₃ (0.08 g, 0.63 mmol) were dissolved in MeCN (2 ml). N2 gas was purged through reaction mixture for 30min at room temperature. After this, trans-N, N'-dimethylcyclohexane-1,2-diamine (0.04 ml, 0.25 mmol) and Cui (0.02 g, 0.11 mmol) were added and reaction mixture was stirred at 100 °C for 16h. Reaction mixture was partitioned between water (50 ml) and EtOAc (50 ml). Aqueous layer was further extracted with EtOAc (2 x 25 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 50% MeCN in water to afford 6-cyclopropyl-N-(5-(2-fluoroethoxy)-6-methoxypyridin-2-yl) indolizine-1 -sulfonamide (0.004 g, 44.29%) as an off white solid.

[0994] LCMS: (Method B): m / z 406.19 (ES+) at 1.78 min.

[0995] 1H-NMR: (400 MHz, DMSO) 50.69-0.67 (m, 2H), 0.93-0.88 (m, 2H), 1.92-1.86 (m, 1H), 3.65 (s, 3H), 4.04-4.02 (m, 1H), 4.12-4.10 (m, 1H), 4.58 (m, 1H), 4.71-4.69 (m, 1H), 6.48 (d, 1H, J= 8.0Hz), 6.87 (d, 1H, J= 9.6Hz), 6.98 (d, 1H, J= 2.8Hz), 7.15 (d, 1H, J= 8.0Hz), 7.45 (d, 1H, J= 2.4Hz), 7.77 (d, 1H, J= 9.2Hz), 8.24 (s, 1H), 10.14 (brs, 1H).

[0996] Synthesis of Example B6, 2-chloro-N-(5-fluoro-2,6-dimethoxypyridin-3-yl)pyrrolon,2-blpyridazine-5-sulfonamide

[0997]

[0998] To a stirred solution of 2-chloropyrrolo[1,2-b]pyridazine-5-sulfonyl chloride (Intermediate 17, 60 mg, 0.239 mmol) in DCE (3 mL) and pyridine (0.096 mL, 1.195 mmol), was added 5-fluoro-2,6-dimethoxypyridin-3-amine (CAS 2407470-86-2, 49.4 mg, 0.287 mmol) and the resultant reaction mixture was stirred at RT for 16 hours then concentrated. The crude was purified by prep-HPLC (Method A) to afford 2-chloro-N-(5-fluoro-2,6-dimethoxypyridin-3-yl)pyrrolo[1,2-b]pyridazine-5-sulfonamide, (10 mg, 0.024 mmol, 10.06%) as an off-white solid.

[0999] LCMS: (Method B): m / z 387.22 (ES+) at 1.79 min.1H-NMR: (400 MHz, DMSO) 6 9.60 (s, 1 H), 8.09 (d, J = 9.60 Hz, 1 H), 7.98 (d, J = 3.20 Hz, 1 H), 7.51 (d, J = 10.40 Hz, 1H), 7.20 (d, J = 9.20 Hz, 1H), 7.05 (d, J = 3.20 Hz, 1H), 3.87 (s, 3H), 3.39 (s, 3H).

[1000] Synthesis of Example B7, N-(4-bromo-2,5-difluorophenyl)-2-chloropyrrolon,2-blpyridazine-5-sulfonamide

[1001]

[1002] To a stirred solution of 2-chloropyrrolo[1,2-b]pyridazine-5-sulfonyl chloride (Intermediate 17, 60 mg, 0.239 mmol) and pyridine (0.096 mL, 1.195 mmol) in DCE (2 mL), was added 4-bromo-2,5-difluoroaniline (CAS 112279-60-4, 59.6 mg, 0.287 mmol) and the resultant reaction mixture was stirred at RT for 16 hours then concentrated. The crude product was purified by prep-HPLC purification (Method B) to afford N-(4-bromo-2,5-difluorophenyl)-2-chloropyrrolo[1,2-b]pyridazine-5-sulfonamide (4 mg, 9.04 umol, 3.80 % yield) as a yellow solid. LCMS: (Method B): m / z 419.98 (ES-) at 1.79 min.

[1003] 1H-NMR: (400 MHz, DMSO) 5 10.50 (s, 1H), 8.20 (d, J = 9.60 Hz, 1H), 7.99 (d, J = 2.80 Hz, 1H), 7.63-7.60 (m, 1H), 7.29-7.16 (m, 3H).

[1004] Synthesis of Example B8, 6-chloro-N-(3,5-dimethoxypyrazin-2-yl)indolizine-1 -sulfonamide

[1005]

[1006] Reaction performed in a similar fashion to Route A, using Intermediate 14 (purified material) and CAS 1033610-34-2.

[1007] LCMS: (Method A): m / z 369.18 (ES+), at 2.099 min.

[1008] 1H-NMR: (400 MHz, DMSO) 5 10.01 (s, 1H), 8.74 (dd, J = 1.9, 0.9 Hz, 1H), 7.83 (d, J = 9.6 Hz, 1H), 7.59 (d, J = 3.0 Hz, 1H), 7.42 (s, 1H), 7.17 (dd, J = 9.6, 1.8 Hz, 1H), 7.09 (d, J = 3.0 Hz, 1H), 3.82 (s, 3H), 3.80 (s, 3H).

[1009] Synthesis of Example B11, 6-chloro-N-(5-(cyanomethyl)-3-fluoro-6-methoxypyridin-2-yl)indolizine-1 -sulfonamide

[1010]

[1011] B11

[1012] Step 1: Performed in a similar fashion to route E using Intermediates 3 and 12, with the addition of DMAP (0.5 eq) and with heating to 80 °C for 16 h.

[1013] LCMS: (Method A): m / z 453.07 (ES+), at 2.336 min.

[1014] Step 2: Performed in a similar fashion to route B, step 1.

[1015] LCMS: (Method A): m / z 437.0 (ES-), at 2.127 min.

[1016] Step 3: 6-chloro-1-(N-(5-(cyanomethyl)-3-fluoro-6-methoxypyridin-2-yl)sulfamoyl)indolizine-3-carboxylic acid (0.03 g, 0.068 mmol) was dissolved in DMSO (0.2 ml). To it, a solution of sodium chloride (0.019 g, 0.34 mmol) in water (0.2 ml) was added at room temperature and reaction mixture was stirred at 100 °C for 16h. Reaction mixture was diluted with water (30 ml) and extracted with EtOAc (20 ml). Aqueous layer was further extracted with EtOAc (2 x 20 ml). The combined organic layers were dried (Na2SO4) and concentrated. The crude product was purified by reverse phase gradient flash column chromatography (C18 silica), product eluted at 0% to 30% MeCN in water to afford 6-chloro-N-(5-(cyanomethyl)-3-fluoro-6-methoxypyridin-2-yl)indolizine-1 -sulfonamide (3.1 mg, 9.92%) as a light yellow solid.

[1017] LCMS: (Method B): m / z 395.19 (ES+) at 1.84 min.

[1018] 1H-NMR: (400 MHz, DMSO) 53.63 (s, 2H), 3.70 (s, 3H), 7.11 (d, 1H, J= 9.6Hz), 7.25 (d, 1H, J= 3.2Hz), 7.48 (d, 1H, J= 9.6Hz), 7.52 (d, 1H, J= 2.8Hz), 7.97 (d, 1H, J= 9.6Hz), 8.49 (s, 1H).

[1019] Synthesis of Example B13, 6-chloro-N-(4-(cyanomethyl)-2,5-difluorophenyl)indolizine-1-sulfonamide

[1020]

[1021] Performed in a similar fashion to Example B11 using intermediate 3 and CAS 2092112-51-9. Further purification of the final compound by prep HPLC (Method I) to afford 6-chloro-N-(4-(cyanomethyl)-2,5-difluorophenyl)indolizine-1-sulfonamide (0.02g, 27.89%) as a white solid. LCMS: (Method B): m / z 382.16 (ES+) at 1.89 min.

[1022] 1H-NMR: (400 MHz, DMSO) 53.95 (s, 2H), 7.07 (d, 1H, J= 3.2Hz), 7.18-7.23 (m, 3H), 7.62 (d, 1H, J= 2.8Hz), 7.78 (d, 1H, J= 9.6Hz), 8.77 (d, 1H, J= 0.8Hz), 10.04 (brs, 1H).

[1023] Synthesis of Example B14, 6-chloro-N-(5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidin-2-yl)indolizine-1 -sulfonamide

[1024]

[1025] Example B14

[1026] Step 1: Performed in a similar fashion to Route A using intermediates 2 and 33.

[1027] Step 2: Performed in a similar fashion to Route B, step 1. Step 3: Performed in a similar fashion to Example B11 step 3, with heating in the microwave at 100 °C for 1 hour to afford 6-chloro-N-(5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidin-2-yl)indolizine-1 -sulfonamide (0.021 g, 23.06%) as an off-white solid.

[1028] LCMS: (Method B): m / z 449.16 (ES+) at 1.96 min.

[1029] 1H-NMR: (400 MHz, DMSO) 53.77 (s, 6H), 3.92-4.00 (m, 2H), 6.02-6.30 (m, 1H), 7.21-7.23 (m, 2H), 7.61 (d, 1H, J= 2.8Hz), 7.94 (d, 1H, J= 9.6Hz), 8.77 (s, 1H), 11.44 (bs, 1H). Additional examples were synthesised using methods similar to those described.

[1030]

[1031]

[1032]

[1033]

[1034]

[1035]

[1036]

[1037]

[1038]

[1039]

[1040]

[1041]

[1042]

[1043]

[1044]

[1045]

[1046]

[1047]

[1048]

[1049]

[1050]

[1051]

[1052]

[1053]

[1054]

[1055]

[1056]

[1057]

[1058]

[1059]

[1060]

[1061]

[1062]

[1063]

[1064]

[1065] Biological data

[1066] Human GPR17 blockade functional IP-one Gq assay

[1067] 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.

[1068] 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 WO 2018 / 122232A1), 3 uM) 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.

[1069] 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 as mean values (n > 2); wherein fpKb values refer to functional pKb, where pKb = -log10(Kb) and Kb is the binding constant.

[1070] Table A - GPR17 in vitro functional activity

[1071]

[1072]

[1073]

[1074] Pharmacokinetic profiling

[1075] The pharmacokinetic profiles of two GPR17 antagonists according to the present invention were assessed in rats via intravenous (IV) and oral (PO) routes of delivery. Pharmacokinetic data (mean values ± standard deviation) derived from these experiments for Examples A4 and A60 are detailed in Table B.

[1076] Methods’. For pharmacokinetic analysis, groups of three male Sprague-Dawley rats, were administered a single dose of the test compounds via IV or PO route at 1 and 3 mg / kg, respectively. For IV dosing, test compounds were formulated in 10% DMAC + 10% Solutol HS15 + 80% saline (0.2 mg / mL) and administered at 5 mL / kg and for PO dosing they were formulated in 10% DMAC + 10% Solutol HS15 + 80% water (1 mg / mL) and administered at 5 mL / kg. Following dosing, blood samples were collected at serial time points out to either 24 or 48 h via the jugular vein and centrifuged to separate plasma for analysis by LC-MS / MS. WinNonlin v8.2 statistics software (Pharsight Corporation, California, USA) was used to generate pharmacokinetic parameters using non-compartmental analysis.

[1077] Table B - PK Profiles of Examples A4 and A60

[1078]

[1079]

[1080] Brain penetration

[1081] Plasma, brain and CSF exposure were evaluated to assess the brain penetration of sixGPR17 antagonists according to the present invention (Examples A4, A49, A59, A60, A74 & A78) following IV administration. Unbound brain-to-plasma ratio (Kp.uu) was calculated (mean values ± standard deviation) following experimental determination of binding in rat plasma and brain homogenate, as shown in Table C.

[1082] Methods’. For brain penetration assessment, groups of three male Sprague-Dawley rats were administered a single 1 mg / kg dose of test compound (formulated in 10% DMAC + 10% Solutol HS15 + 80% saline) via the IV route. At 1 h post-dose, animals were sacrificed and brains extracted, homogenised with 2 volumes (w / v) of methanol + phosphate buffered saline pH 7.4 (1:1) and analysed by LC-MS / MS. Blood and CSF samples were removed at the same time point, centrifuged and the plasma and CSF analysed by LC-MS / MS.

[1083] To permit calculation of unbound brain-to-plasma ratio (Kp,uu), non-specific binding of test compound in rat plasma and brain homogenate was performed, using Rapid Equilibrium Dialysis (RED). Test compounds were prepared in DMSO (1 pM final, 0.2% DMSO) and added to (i) undiluted rat plasma and (ii) rat brain tissue homogenised with 2 volumes (w / v) of sodium phosphate buffer (pH 7.4) and dialysed against phosphate buffer for either 24 h (plasma) or 5 h (brain homogenate) at 37 °C. After incubation, the contents of each plasma / brain and buffer compartment were removed and mixed with equal volumes of control dialysed buffer or plasma / brain to maintain matrix similarity for analysis. Proteins were then precipitated by the addition of acetonitrile containing an analytical internal standard (allowing ratio of test compound versus internal standard to be derived), centrifuged and the supernatant removed for analysis by LC-MS / MS. Fraction unbound (fu) in plasma and brain was calculated using the following formula, then used to correct total plasma and brain concentrations to derive the Kp,uu:

[1084] Fraction bound = (Total plasma or brain ratio) - (Total buffer ratio) / Total plasma or brain ratio Fraction unbound (fu, brain or plasma) = 1 - Fraction bound

[1085] For correction of dilution in brain binding assay:

[1086] Undiluted Fu, brain = (1 / dilution factor) / ((1 / fu diluted)) - 1) + (1 / dilution factor) Where dilution factor = 4

[1087] Table C - Brain / plasma PK parameters for test compounds following IV administration

[1088]

[1089] *corrected for residual blood in the brain which was assumed to be 15 μL / g brain

[1090] 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.

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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-salkylcarbonyl, 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- ealkylene-Cs- cycloalkyl, 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 selected from a group of the formula:-L1-L2-Z1wherein:Li is absent or a Ciwalkylene optionally substituted with fluoro;L2is 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)SC>2, 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, Ciwhaloalkyl, Ci- shaloalkoxy, Ciwcyanoalkyl, Ciwalkoxyalkyl, Ciwaminoalkyl and 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, Ci-salkoxy, Ciwhaloalkyl, halo, hydroxyl and cyano;Xi is selected from CR7and N;X2is absent or selected from CR8and N, wherein when X2is absent then Xi is selected from NH, S, and O;X3 is 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;X6is CR12or N;R7is selected from hydrogen, Ci-4alkyl, Ci-salkoxy, halo, hydroxyl, cyano, nitro, C2. salkenyl, C2.3alkynyl, Ciwhaloalkyl, Ciwhaloalkoxy, Ci-saminoalkyl, Ciwhydroxyalkyl, 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, C3-10 cycloalkyl, 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, R10and R11are independently selected from hydrogen, halo, cyano, Ci-4alkyl, C^alkenyl, C^alkynyl, Ci-salkoxy, Ciwhaloalkyl, Ciwhaloalkoxy, Ciwaminoalkyl, Ci- shydroxyalkyl, Cs-wcycloalkyl, nitro and hydroxyl;R12is selected from hydrogen, Ci-4alkyl, C1-3alkoxy, halo, hydroxyl, cyano, nitro, C2-3alkenyl, C2-3alkynyl, C1-3haloalkyl, C1-3haloalkoxy, C1-3aminoalkyl, C1-3hydroxyalkyl, Ci- scyanoalkyl, Ciwalkylamino, 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 C3-10 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; Rxis selected from Ci-4alkyl, Ciwalkoxy, Ciwhaloalkyl, Ciwhaloalkoxy, halo, hydroxyl, cyano, nitro, amino, cyclopropyl and cyclobutyl; andRyis selected from Ci-4alkyl, Ciwalkoxy, Ciwhaloalkyl, Ciwhaloalkoxy, halo, hydroxyl, cyano, nitro, amino, amido, carboxy, carbamoyl, sulfamoyl, 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, such as wherein R1is hydrogen.

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, such as wherein R2is hydrogen.

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, Ciwhaloalkyl, Ciwhaloalkoxy, Ciwaminoalkyl, Ciwhydroxyalkyl, Ciwcyanoalkyl, Ciwalkylamino, C3-6 cycloalkyl, 3-6- membered heterocyclyl, Ce-waryl, 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 3, wherein R3is selected from halo, Ciwhaloalkyl, Ciwhaloalkoxy, and C3-6 cycloalkyl.

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

7. A compound, or a pharmaceutically acceptable salt, solvate or hydrate thereof, according to claim 6, 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.

8. A compound, or a pharmaceutically acceptable salt, solvate or hydrate thereof, according to claim 6, wherein R12is selected from hydrogen, halo, Ci-4alkyl, Ci-salkoxy and Ci-shaloalkyl.

9. A compound, or a pharmaceutically salt, solvate or hydrate thereof, according to any one of claims 1 to 8, wherein R4is selected from a group of the formula:-L1-L2-Z1wherein:Li is absent or a Ci-salkylene optionally substituted with fluoro;L2is 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.

10. A compound, or a pharmaceutically acceptable salt, solvate or hydrate thereof, according to any one of claims 1 to 8, 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.

11. A compound, or a pharmaceutically acceptable salt, solvate or hydrate thereof, according to any one of claims 1 to 8, wherein R4is selected from cyano, Ci-salkoxy, halo, Ci-shydroxyalkyl, Ci-salkoxyalkyl, 5-membered heteroaryl, 4-6-memberedheterocyclyl, Co-2alkyleneC(0)OCi-2alkyl, C(O)OH, Co-2alkyleneC(0)Rc, C0-2alkyleneC(O)N(Rc)(Rd), C0-2alkyleneN(Rc)(Rd), and C0.2alkyleneN(Rc)C(O)Rdwherein Rcand Rd are independently selected from hydrogen and Ci-2alkyl, and wherein said 5-membered heteroaryl is optionally substituted with 1 or 2 Rygroups wherein Ryis selected from Ci-4alkyl, Ci-shaloalkyl, halo, and C3-6 cycloalkyl.

12. A compound, or a pharmaceutically acceptable salt, solvate or hydrate thereof, according to any one of claims 1 to 8, 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.

13. A compound, or a pharmaceutically acceptable salt, solvate or hydrate thereof, according to any one of claims 1 to 12, wherein R5is hydrogen.

14. A compound, or a pharmaceutically acceptable salt, solvate or hydrate thereof, according to any one of claims 1 to 13, wherein R7is selected from hydrogen, Ci -4al kyl, 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.

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

16. A compound, or a pharmaceutically acceptable salt, solvate or hydrate thereof, according to any one of claims 1 to 15, wherein R8, R9, R10and R11are independently selected from hydrogen, halo, Ci-salkoxy, Ci-salkyl, and Cs-ecycloalkyl.

17. A compound, or a pharmaceutically acceptable salt, solvate or hydrate thereof, according to any one of claims 1 to 15, wherein R8, R9, R10and R11are independently selected from hydrogen, halo, cyano, Ci-4alkyl, Ci-salkoxy, Ci-shaloalkyl and Ci- shaloalkoxy.

18. A compound, or a pharmaceutically acceptable salt, solvate or hydrate thereof, according to any one of claims 1 to 17, wherein:Rxis selected from Ci-4alkyl, Ci-salkoxy, Ci-shaloalkyl, halo and cyano; andRyis selected from Ci-4alkyl, Ci-salkoxy, halo, cyano, cyclopropyl and 3-4-membered heterocyclyl.

19. A compound, or a pharmaceutically acceptable salt, solvate or hydrate thereof, which is selected from any one of the following:methyl 6-chloro-1-(N-(3,5-dimethoxypyrazin-2-yl)sulfamoyl)indolizine-3-carboxylate; 6-chloro-1-(N-(3,5-dimethoxypyrazin-2-yl)sulfamoyl)indolizine-3-carboxylic acid; 6-chloro-1-(N-(3,5-dimethoxypyrazin-2-yl)sulfamoyl)indolizine-3-carboxamide;6-chloro-3-cyano-N-(3,5-dimethoxypyrazin-2-yl)indolizine-1 -sulfonamide;6-chloro-N-(3,5-dimethoxypyrazin-2-yl)-3-(hydroxymethyl)indolizine-1 -sulfonamide; methyl 6-chloro-1-(N-(6-(difluoromethoxy)-5-fluoro-2-methoxypyridin-3- yl)sulfamoyl)indolizine-3-carboxylate;methyl 6-chloro-1-(N-(5-(difluoromethoxy)-3-methoxypyrazin-2- yl)sulfamoyl)indolizine-3-carboxylate;6-chloro-N-(5-(difluoromethoxy)-3-methoxypyrazin-2-yl)-3-(hydroxymethyl)indolizine- 1-sulfonamide;6-chloro-1-(N-(5-(difluoromethoxy)-3-methoxypyrazin-2-yl)sulfamoyl)indolizine-3- carboxylic acid;6-chloro-1-(N-(5-(difluoromethoxy)-3-methoxypyrazin-2-yl)sulfamoyl)indolizine-3- carboxamide;methyl 6-chloro-1-(N-(5-(2,2-difluoroethoxy)-3-fluoro-6-methoxypyridin-2- yl)sulfamoyl)indolizine-3-carboxylate;6-chloro-N-(6-(difluoromethoxy)-5-fluoro-2-methoxypyridin-3-yl)-3- (hydroxymethyl)indolizine-l -sulfonamide;methyl 6-chloro-1-(N-(6-(2,2-difluoroethoxy)-5-fluoro-2-methoxypyridin-3- yl)sulfamoyl)indolizine-3-carboxylate;6-chloro-N-(6-(2,2-difluoroethoxy)-5-fluoro-2-methoxypyridin-3-yl)-3- (hydroxymethyl)indolizine-l -sulfonamide;methyl 6-chloro-1-(N-(5-(2-fluoroethoxy)-4-methoxypyrimidin-2- yl)sulfamoyl)indolizine-3-carboxylate;6-chloro-N-(5-(2,2-difluoroethoxy)-3-fluoro-6-methoxypyridin-2-yl)-3- (hydroxymethyl)indolizine-l -sulfonamide;6-chloro-1-(N-(6-(2,2-difluoroethoxy)-5-fluoro-2-methoxypyridin-3- yl)sulfamoyl)indolizine-3-carboxylic acid;6-chloro-1-(N-(6-(2,2-difluoroethoxy)-5-fluoro-2-methoxypyridin-3-yl)sulfamoyl)indolizine-3-carboxamide;6-chloro-1-(N-(6-(difluoromethoxy)-5-fluoro-2-methoxypyridin-3-yl)sulfamoyl)indolizine-3-carboxylic acid;6-chloro-1-(N-(6-(difluoromethoxy)-5-fluoro-2-methoxypyridin-3-yl)sulfamoyl)indolizine-3-carboxamide;6-chloro-1-(N-(5-(2,2-difluoroethoxy)-3-fluoro-6-methoxypyridin-2-yl)sulfamoyl)indolizine-3-carboxamide;6-chloro-3-cyano-N-(6-(2,2-difluoroethoxy)-5-fluoro-2-methoxypyridin-3-yl)indolizine- 1-sulfonamide;6-chloro-3-cyano-N-(5-(difluoromethoxy)-3-methoxypyrazin-2-yl)indolizine-1-sulfonamide;6-chloro-N-(5-(2-fluoroethoxy)-4-methoxypyrimidin-2-yl)-3-(hydroxymethyl)indolizine- 1-sulfonamide;6-chloro-3-cyano-N-(6-(difluoromethoxy)-5-fluoro-2-methoxypyridin-3-yl)indolizine-1-sulfonamide;6-chloro-3-cyano-N-(5-(2,2-difluoroethoxy)-3-fluoro-6-methoxypyridin-2-yl)indolizine- 1-sulfonamide;6-chloro-1-(N-(5-(2-fluoroethoxy)-4-methoxypyrimidin-2-yl)sulfamoyl)indolizine-3-carboxamide;6-chloro-3-cyano-N-(5-(2-fluoroethoxy)-4-methoxypyrimidin-2-yl)indolizine-1-sulfonamide;6-chloro-1-(N-(4-(cyanomethyl)-5-fluoro-2-methoxyphenyl)sulfamoyl)indolizine-3-carboxamide;6-chloro-3-cyano-N-(4-(cyanomethyl)-5-fluoro-2-methoxyphenyl)indolizine-1-sulfonamide;6-chloro-N-(4-(cyanomethyl)-5-fluoro-2-methoxyphenyl)-3-(hydroxymethyl)indolizine- 1-sulfonamide;6-chloro-N-(6-(cyanomethyl)-5-fluoro-2-methoxypyridin-3-yl)-3-(hydroxymethyl)indolizine-l -sulfonamide;6-chloro-1-(N-(6-(cyanomethyl)-5-fluoro-2-methoxypyridin-3-yl)sulfamoyl)indolizine-3-carboxamide;6-chloro-3-cyano-N-(6-(cyanomethyl)-5-fluoro-2-methoxypyridin-3-yl)indolizine-1-sulfonamide;1-(N-(4-bromo-2,5-difluorophenyl)sulfamoyl)-6-chloroindolizine-3-carboxamide;6-chloro-N-(4-(difluoromethoxy)-2,5-difluorophenyl)-3-(hydroxymethyl)indolizine-1-sulfonamide;6-chloro-1-(N-(4-(difluoromethoxy)-2,5-difluorophenyl)sulfamoyl)indolizine-3-carboxamide;3-acetyl-6-chloro-N-(3,5-dimethoxypyrazin-2-yl)indolizine-1 -sulfonamide;6-chloro-N-(3,5-dimethoxypyrazin-2-yl)-3-(1-hydroxyethyl)indolizine-1 -sulfonamide; 6-chloro-N-(3,5-dimethoxypyrazin-2-yl)-3-(methoxymethyl)indolizine-1 -sulfonamide; 6-chloro-1-(N-(3,5-dimethoxypyrazin-2-yl)sulfamoyl)-N-methylindolizine-3-carboxamide;N-((6-chloro-1-(N-(3,5-dimethoxypyrazin-2-yl)sulfamoyl)indolizin-3-yl)methyl)acetamide;methyl (6-chloro-1-(N-(3,5-dimethoxypyrazin-2-yl)sulfamoyl)indolizin-3-yl)carbamate; 6-chloro-N-(3,5-dimethoxypyrazin-2-yl)-3-methoxyindolizine-1 -sulfonamide;3-amino-6-chloro-N-(3,5-dimethoxypyrazin-2-yl)indolizine-1 -sulfonamide;6-chloro-3-cyano-N-(5-(cyanomethyl)-3-fluoro-6-methoxypyridin-2-yl)indolizine-1-sulfonamide;6-chloro-1-(N-(5-(cyanomethyl)-3-fluoro-6-methoxypyridin-2-yl)sulfamoyl)indolizine-3-carboxamide;6-chloro-N-(5-(cyanomethyl)-3-fluoro-6-methoxypyridin-2-yl)-3-(hydroxymethyl)indolizine-l -sulfonamide;6-bromo-3-cyano-N-(3,5-dimethoxypyrazin-2-yl)indolizine-1 -sulfonamide;3-cyano-6-cyclopropyl-N-(3,5-dimethoxypyrazin-2-yl)indolizine-1 -sulfonamide;6-chloro-N-(3,5-dimethoxypyrazin-2-yl)-3-(1H-pyrazol-4-yl)indolizine-1 -sulfonamide; 6-chloro-N-(3,5-dimethoxypyrazin-2-yl)-3-(oxazol-2-yl)indolizine-1 -sulfonamide; 6-chloro-N-(3,5-dimethoxypyrazin-2-yl)-3-(1H-pyrazol-5-yl)indolizine-1 -sulfonamide; 6-chloro-N-(3,5-dimethoxypyrazin-2-yl)-3-(1H-pyrazol-1-yl)indolizine-1 -sulfonamide; 3, 6-dichloro-N-(3,5-dimethoxypyrazin-2-yl)indolizine-1 -sulfonamide;6-bromo-1-(N-(3,5-dimethoxypyrazin-2-yl)sulfamoyl)indolizine-3-carboxamide;6-cyclopropyl-1-(N-(3,5-dimethoxypyrazin-2-yl)sulfamoyl)indolizine-3-carboxamide; 3-cyano-6-(difluoromethyl)-N-(3,5-dimethoxypyrazin-2-yl)indolizine-1 -sulfonamide; 3-cyano-6-(difluoromethoxy)-N-(3,5-dimethoxypyrazin-2-yl)indolizine-1 -sulfonamide; 6-chloro-3-cyano-N-(5-(2-fluoroethoxy)-3-methoxypyrazin-2-yl)indolizine-1-sulfonamide;6-chloro-3-cyano-N-(5-(2,2-difluoroethoxy)-3-methoxypyrazin-2-yl)indolizine-1-sulfonamide;(±) 6-chloro-3-(1,2-dihydroxyethyl)-N-(3,5-dimethoxypyrazin-2-yl)indolizine-1-sulfonamide;6-chloro-N-(3,5-dimethoxypyrazin-2-yl)-3-(hydroxymethyl)-5-(2H-1,2,3-triazol-2-yl)indolizine-1 -sulfonamide;2-chloro-7-cyano-N-(3,5-dimethoxypyrazin-2-yl)pyrrolo[1,2-b]pyridazine-5-sulfonamide;2-chloro-7-cyano-N-(6-(2,2-difluoroethoxy)-5-fluoro-2-methoxypyridin-3-yl)pyrrolo[1,2-b]pyridazine-5-sulfonamide;6-chloro-3-cyano-N-(3,5-dimethoxypyrazin-2-yl)-5-(2H-1,2,3-triazol-2-yl)indolizine-1-sulfonamide;6-chloro-N-(6-(cyanomethyl)-5-fluoro-2-methoxypyridin-3-yl)-3-(1H-pyrazol-5-yl)indolizine-1 -sulfonamide;6-chloro-N-(6-(cyanomethyl)-5-fluoro-2-methoxypyridin-3-yl)-3-(1H-pyrazol-4-yl)indolizine-1 -sulfonamide;6-chloro-3-cyano-N-(5-ethoxy-3-methoxypyrazin-2-yl)indolizine-1 -sulfonamide;3-cyano-6-(difluoromethyl)-N-(5-(2-fluoroethoxy)-3-methoxypyrazin-2-yl)indolizine-1-sulfonamide;3-cyano-N-(5-(2,2-difluoroethoxy)-3-methoxypyrazin-2-yl)-6-(difluoromethyl)indolizine-l -sulfonamide;3-cyano-6-(difluoromethyl)-N-(3-methoxy-5-(2-methoxyethoxy)pyrazin-2-yl)indolizine-1-sulfonamide;6-chloro-3-cyano-N-(3-methoxy-5-(2-methoxyethoxy)pyrazin-2-yl)indolizine-1-sulfonamide;6-bromo-3-cyano-N-(5-(2-fluoroethoxy)-3-methoxypyrazin-2-yl)indolizine-1-sulfonamide;6-bromo-3-cyano-N-(5-(2,2-difluoroethoxy)-3-methoxypyrazin-2-yl)indolizine-1-sulfonamide;3-cyano-N-(5-(2,2-difluoroethoxy)-3-methoxypyrazin-2-yl)-6-(difluoromethoxy)indolizine-l -sulfonamide;3-cyano-6-cyclopropyl-N-(5-(2,2-difluoroethoxy)-3-methoxypyrazin-2-yl)indolizine-1-sulfonamide;3-cyano-6-(difluoromethoxy)-N-(5-(2-fluoroethoxy)-3-methoxypyrazin-2-yl)indolizine- 1-sulfonamide;6-bromo-3-cyano-N-(3-methoxy-5-(2-methoxyethoxy)pyrazin-2-yl)indolizine-1-sulfonamide;6-bromo-3-cyano-N-(5-ethoxy-3-methoxypyrazin-2-yl)indolizine-1 -sulfonamide;3-cyano-6-(difluoromethyl)-N-(5-ethoxy-3-methoxypyrazin-2-yl)indolizine-1-sulfonamide;3-cyano-6-(difluoromethoxy)-N-(5-ethoxy-3-methoxypyrazin-2-yl)indolizine-1-sulfonamide;6-chloro-N-(3,5-dimethoxypyrazin-2-yl)-3-methylindolizine-1 -sulfonamide;methyl 2-(6-chloro-1-(N-(3,5-dimethoxypyrazin-2-yl)sulfamoyl)indolizin-3-yl)acetate; 6-chloro-N-(3,5-dimethoxypyrazin-2-yl)-3-(2-hydroxyethyl)indolizine-1 -sulfonamide; 2-(6-chloro-1-(N-(3,5-dimethoxypyrazin-2-yl)sulfamoyl)indolizin-3-yl)acetic acid; 2-(6-chloro-1-(N-(3,5-dimethoxypyrazin-2-yl)sulfamoyl)indolizin-3-yl)acetamide; 6-chloro-1-(N-(5-fluoro-4-(fluoromethoxy)-2-methoxyphenyl)sulfamoyl)indolizine-3-carboxamide;N-(4-bromo-2,5-difluorophenyl)-6-chloro-3-(hydroxymethyl)indolizine-1 -sulfonamide; 6-chloro-N-(3,5-dimethoxypyrazin-2-yl)-3-(thiazol-2-yl)indolizine-1 -sulfonamide; 6-chloro-N-(3,5-dimethoxypyrazin-2-yl)-3-(2H-1,2,3-triazol-2-yl)indolizine-1-sulfonamide;6-chloro-N-(3,5-dimethoxypyrazin-2-yl)-3-(1H-1,2,4-triazol-5-yl)indolizine-1-sulfonamide;2-chloro-7-cyano-N-(4-(cyanomethyl)-5-fluoro-2-methoxyphenyl)pyrrolo[1,2-b]pyridazine-5-sulfonamide;2-chloro-7-cyano-N-(6-(difluoromethoxy)-5-fluoro-2-methoxypyridin-3-yl)pyrrolo[1,2-b]pyridazine-5-sulfonamide;6-chloro-N-(3,5-dimethoxypyrazin-2-yl)-3-(1,2,4-oxadiazol-5-yl)indolizine-1-sulfonamide;6-chloro-N-(4-(difluoromethoxy)-2,5-difluorophenyl)-3-(1H-pyrazol-5-yl)indolizine-1-sulfonamide;2-chloro-N-(5-(2,2-difluoroethoxy)-3-fluoro-6-methoxypyridin-2-yl)-7- (hydroxymethyl)pyrrolo[1,2-b]pyridazine-5-sulfonamide;2-chloro-N-(6-(2,2-difluoroethoxy)-5-fluoro-2-methoxypyridin-3-yl)-7- (hydroxymethyl)pyrrolo[1,2-b]pyridazine-5-sulfonamide;2-chloro-N-(6-(difluoromethoxy)-5-fluoro-2-methoxypyridin-3-yl)-7- (hydroxymethyl)pyrrolo[1,2-b]pyridazine-5-sulfonamide;2-chloro-N-(4-(cyanomethyl)-5-fluoro-2-methoxyphenyl)-7- (hydroxymethyl)pyrrolo[1,2-b]pyridazine-5-sulfonamide;6-chloro-N-(5-fluoro-4-(fluoromethoxy)-2-methoxyphenyl)-3-(1H-pyrazol-5-yl)indolizine-1 -sulfonamide;6-chloro-N-(4-(difluoromethoxy)-2,5-difluorophenyl)-3-(1H-pyrazol-4-yl)indolizine-1-sulfonamide;N-(4-bromo-2,5-difluorophenyl)-6-chloro-3-(1H-pyrazol-5-yl)indolizine-1 -sulfonamide; 6-chloro-3-cyano-N-(5-(cyanomethyl)-3-methoxypyrazin-2-yl)indolizine-1-sulfonamide;6-chloro-3-cyano-N-(5-ethyl-3-methoxypyrazin-2-yl)indolizine-1 -sulfonamide;6-chloro-N-(3,5-dimethoxypyrazin-2-yl)-3-(1-methyl-1H-pyrazol-4-yl)indolizine-1-sulfonamide;2-bromo-7-cyano-N-(3,5-dimethoxypyrazin-2-yl)pyrrolo[1,2-b]pyridazine-5-sulfonamide;N-(4-bromo-2,5-difluorophenyl)-6-chloro-3-(1H-pyrazol-4-yl)indolizine-1 -sulfonamide; 6-chloro-N-(5-(difluoromethoxy)-3-methoxypyrazin-2-yl)-3-methoxyindolizine-1-sulfonamide;6-chloro-N-(3,5-dimethoxypyrazin-2-yl)-3-(1-methyl-1H-pyrazol-3-yl)indolizine-1-sulfonamide;6-chloro-N-(5-(2-fluoroethoxy)-3-methoxypyrazin-2-yl)-3-(1H-pyrazol-1-yl)indolizine- 1-sulfonamide;6-chloro-N-(5-(2,2-difluoroethoxy)-3-methoxypyrazin-2-yl)-3-(1H-pyrazol-1-yl)indolizine-1 -sulfonamide;6-chloro-N-(5-(2,2-difluoroethoxy)-3-methoxypyrazin-2-yl)-3-(1H-1,2,4-triazol-1-yl)indolizine-1 -sulfonamide;6-chloro-N-(5-(difluoromethoxy)-3-methoxypyrazin-2-yl)-3-(1H-pyrazol-1-yl)indolizine- 1-sulfonamide;6-chloro-N-(5-(2-fluoroethoxy)-3-methoxypyrazin-2-yl)-3-(1H-1,2,3-triazol-1-yl)indolizine-1 -sulfonamide;6-chloro-N-(5-(2-fluoroethoxy)-3-methoxypyrazin-2-yl)-3-(2H-1,2,3-triazol-2-yl)indolizine-1 -sulfonamide;6-chloro-N-(5-(2,2-difluoroethoxy)-3-methoxypyrazin-2-yl)-3-(1H-1,2,3-triazol-1-yl)indolizine-1 -sulfonamide;6-chloro-N-(5-(2,2-difluoroethoxy)-3-methoxypyrazin-2-yl)-3-(2H-1,2,3-triazol-2-yl)indolizine-1 -sulfonamide;6-chloro-N-(5-(difluoromethoxy)-3-methoxypyrazin-2-yl)-3-(1H-1,2,3-triazol-1-yl)indolizine-1 -sulfonamide;6-chloro-N-(5-(difluoromethoxy)-3-methoxypyrazin-2-yl)-3-(2H-1,2,3-triazol-2-yl)indolizine-1 -sulfonamide;6-chloro-N-(5-(2-fluoroethoxy)-3-methoxypyrazin-2-yl)-3-methoxyindolizine-1-sulfonamide;6-chloro-N-(4-(cyanomethyl)-5-fluoro-2-methoxyphenyl)-3-(1H-pyrazol-5-yl)indolizine- 1-sulfonamide;6-chloro-N-(4-(cyanomethyl)-5-fluoro-2-methoxyphenyl)-3-(1H-pyrazol-4-yl)indolizine- 1-sulfonamide;6-chloro-N-(3,5-dimethoxypyrazin-2-yl)-3-(1H-imidazol-2-yl)indolizine-1 -sulfonamide; 5-bromo-6-chloro-3-cyano-N-(3,5-dimethoxypyrazin-2-yl)indolizine-1 -sulfonamide;3-bromo-6-chloro-N-(3,5-dimethoxypyrazin-2-yl)indolizine-1 -sulfonamide;6-chloro-N-(2-(2,2-difluoroethoxy)-4-methoxypyrimidin-5-yl)-3-(1H-pyrazol-5-yl)indolizine-1 -sulfonamide;6-chloro-3-cyano-N-(4-(cyanomethyl)-2,5-difluorophenyl)indolizine-1 -sulfonamide; 3-cyano-N-(4-(cyanomethyl)-2,5-difluorophenyl)-6-(difluoromethyl)indolizine-1-sulfonamide;6-chloro-N-(3,5-dimethoxypyrazin-2-yl)-3-(1,4-dioxan-2-yl)indolizine-1-sulfonamide; 3-cyano-N-(6-(cyanomethyl)-5-fluoro-2-methoxypyridin-3-yl)-6-(difluoromethyl)indolizine-l -sulfonamide;3-cyano-N-(4-(cyanomethyl)-5-fluoro-2-methoxyphenyl)-6-(difluoromethyl)indolizine-1-sulfonamide;6-chloro-3-cyano-N-(5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidin-2-yl)indolizine-1-sulfonamide;6-chloro-3-cyano-N-(5-(2,2-difluoroethyl)-4,6-dimethoxypyrimidin-2-yl)indolizine-1-sulfonamide;3-cyano-N-(5-(2,2-difluoroethyl)-4,6-dimethoxypyrimidin-2-yl)-6-(difluoromethyl)indolizine-l -sulfonamide;3-cyano-N-(5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidin-2-yl)-6- (difluoromethyl)indolizine-l -sulfonamide;3-cyano-N-(4-(cyanomethyl)-5-fluoro-2-methoxyphenyl)-6-(difluoromethoxy)indolizine-l -sulfonamide;6-chloro-N-(4-(cyanomethyl)-5-fluoro-2-methoxyphenyl)-3-(1,2-dihydroxyethyl)indolizine-1 -sulfonamide;6-chloro-N-(4-chloro-5-cyclopropylisothiazol-3-yl)-3-cyanoindolizine-1 -sulfonamide; 6-chloro-3-cyano-N-(5-(2,2-difluoroethyl)-3-fluoro-6-methoxypyridin-2-yl)indolizine-1-sulfonamide;6-chloro-N-(6-(cyanomethyl)-5-fluoro-2-methoxypyridin-3-yl)-3-(1,2-dihydroxyethyl)indolizine-1 -sulfonamide;3-cyano-N-(6-(cyanomethyl)-5-fluoro-2-methoxypyridin-3-yl)-6-(difluoromethoxy)indolizine-l -sulfonamide;3-cyano-N-(5-(2,2-difluoroethyl)-3-fluoro-6-methoxypyridin-2-yl)-6-(difluoromethyl)indolizine-l -sulfonamide;6-chloro-3-cyano-N-(5-(cyanomethyl)-6-fluoro-3-methoxypyridin-2-yl)indolizine-1-sulfonamide;N-(4-chloro-5-cyclopropylisothiazol-3-yl)-3-cyano-6-(difluoromethyl)indolizine-1-sulfonamide;3-cyano-N-(6-(2,2-difluoroethyl)-5-fluoro-2-methoxypyridin-3-yl)-6-(difluoromethyl)indolizine-l -sulfonamide;3-cyano-N-(5-(cyanomethyl)-6-fluoro-3-methoxypyridin-2-yl)-6- (difluoromethyl)indolizine-l -sulfonamide;3-cyano-6-cyclopropyl-N-(5-(2-fluoroethoxy)-3-methoxypyrazin-2-yl)indolizine-1-sulfonamide;3-cyano-N-(4-(2,2-difluoroethyl)-2,5-difluorophenyl)-6-(difluoromethyl)indolizine-1-sulfonamide6-chloro-3-cyano-N-(6-(2,2-difluoroethyl)-5-fluoro-2-methoxypyridin-3-yl)indolizine-1-sulfonamide;3-cyano-N-(4-(2,2-difluoroethyl)-5-fluoro-2-methoxyphenyl)-6-(difluoromethyl)indolizine-l -sulfonamide;6-chloro-3-cyano-N-(4-(2,2-difluoroethyl)-5-fluoro-2-methoxyphenyl)indolizine-1-sulfonamide;3-cyano-N-(4-(2,2-difluoroethyl)-5-fluoro-2-methoxyphenyl)-6-(difluoromethoxy)indolizine-l -sulfonamide;6-chloro-3-(1,2-dihydroxyethyl)-N-(5-(2-fluoroethoxy)-3-methoxypyrazin-2-yl)indolizine-1 -sulfonamide;6-chloro-3-cyano-N-(5-fluoro-2-methoxy-6-(2,2,2-trifluoroethyl)pyridin-3-yl)indolizine- 1-sulfonamide;6-bromo-3-cyano-N-(4-(2,2-difluoroethyl)-5-fluoro-2-methoxyphenyl)indolizine-1-sulfonamide;6-bromo-3-cyano-N-(6-(2,2-difluoroethyl)-5-fluoro-2-methoxypyridin-3-yl)indolizine-1-sulfonamide;3-cyano-N-(6-(2,2-difluoroethyl)-5-fluoro-2-methoxypyridin-3-yl)-6-(difluoromethoxy)indolizine-l -sulfonamide;3-cyano-6-(difluoromethyl)-N-(5-fluoro-2-methoxy-6-(2,2,2-trifluoroethyl)pyridin-3-yl)indolizine-1 -sulfonamide;6-chloro-N-(3,5-dimethoxypyrazin-2-yl)-3-(2-methyl-2H-tetrazol-5-yl)indolizine-1-sulfonamide;6-chloro-N-(5-(2,2-difluoroethoxy)-3-fluoro-6-methoxypyridin-2-yl)-3-(1,2-dihydroxyethyl)indolizine-1 -sulfonamide;6-chloro-N-(5-(cyanomethyl)-3-fluoro-6-methoxypyridin-2-yl)-3-(1,2-dihydroxyethyl)indolizine-1 -sulfonamide;6-chloro-N-(4-chloro-5-methylisoxazol-3-yl)-3-cyanoindolizine-1 -sulfonamide N-(4-bromo-2,5-difluorophenyl)-6-chloroindolizine-1 -sulfonamide;N-(5-bromo-4-methoxypyrimidin-2-yl)-6-chloroindolizine-1 -sulfonamide;6-chloro-N-(4-(difluoromethoxy)-5-fluoro-2-methoxyphenyl)indolizine-1 -sulfonamide; 6-chloro-N-(4-(difluoromethoxy)-2,5-difluorophenyl)indolizine-1 -sulfonamide;6-cyclopropyl-N-(5-(2-fluoroethoxy)-6-methoxypyridin-2-yl)indolizine-1 -sulfonamide; 2-chloro-N-(5-fluoro-2,6-dimethoxypyridin-3-yl)pyrrolo[1,2-b]pyridazine-5-sulfonamide;N-(4-bromo-2,5-difluorophenyl)-2-chloropyrrolo[1,2-b]pyridazine-5-sulfonamide; 6-chloro-N-(3,5-dimethoxypyrazin-2-yl)indolizine-1-sulfonamide;6-chloro-N-(5-(difluoromethoxy)-3-methoxypyrazin-2-yl)indolizine-1 -sulfonamide; 6-chloro-N-(5-(2,2-difluoroethoxy)-3-fluoro-6-methoxypyridin-2-yl)indolizine-1-sulfonamide;6-chloro-N-(5-(cyanomethyl)-3-fluoro-6-methoxypyridin-2-yl)indolizine-1 -sulfonamide; 6-chloro-N-(5-(2-fluoroethoxy)-3-methoxypyrazin-2-yl)indolizine-1 -sulfonamide;6-chloro-N-(4-(cyanomethyl)-2,5-difluorophenyl)indolizine-1 -sulfonamide;6-chloro-N-(5-(2,2-difluoroethoxy)-4,6-dimethoxypyrimidin-2-yl)indolizine-1-sulfonamide;6-chloro-N-(5-(2,2-difluoroethyl)-3-fluoro-6-methoxypyridin-2-yl)indolizine-1-sulfonamide;6-chloro-N-(3-fluoro-5-(2-fluoroethoxy)-6-methoxypyridin-2-yl)indolizine-1-sulfonamide;6-(difluoromethyl)-N-(3-fluoro-5-(2-fluoroethoxy)-6-methoxypyridin-2-yl)indolizine-1-sulfonamide;6-chloro-N-(5-(2-fluoroethoxy)-4-methoxypyrimidin-2-yl)indolizine-1 -sulfonamide; 6-cyclopropyl-N-(5-(difluoromethoxy)-3-methoxypyrazin-2-yl)indolizine-1-sulfonamide;N-(4-bromo-2,5-difluorophenyl)-6-cyclopropylindolizine-1 -sulfonamide;6-cyclopropyl-N-(5-(2-fluoroethoxy)-4-methoxypyrimidin-2-yl)indolizine-1-sulfonamide;6-bromo-N-(3,6-difluoro-5-(2-fluoroethoxy)pyridin-2-yl)indolizine-1 -sulfonamide; 6-bromo-N-(3,5-dimethoxypyrazin-2-yl)indolizine-1-sulfonamide;6-chloro-N-(6-(2,2-difluoroethoxy)-5-fluoro-2-methoxypyridin-3-yl)indolizine-1-sulfonamide;6-chloro-N-(6-(cyanomethyl)-5-fluoro-2-methoxypyridin-3-yl)indolizine-1 -sulfonamide; 6-chloro-N-(4-(cyanomethyl)-5-fluoro-2-methoxyphenyl)indolizine-1 -sulfonamide; 6-chloro-N-(5-(2,2-difluoroethyl)-4,6-dimethoxypyrimidin-2-yl)indolizine-1-sulfonamide;6-chloro-N-(5-ethoxy-3-methoxypyrazin-2-yl)indolizine-1 -sulfonamide;6-chloro-N-(3-methoxy-5-(2-methoxyethoxy)pyrazin-2-yl)indolizine-1 -sulfonamide;6-chloro-N-(4-chloro-5-cyclopropylisothiazol-3-yl)indolizine-1 -sulfonamide;6-chloro-N-(6-(2,2-difluoroethyl)-5-fluoro-2-methoxypyridin-3-yl)indolizine-1- sulfonamide;6-chloro-N-(4-(2,2-difluoroethyl)-2,5-difluorophenyl)indolizine-1 -sulfonamide; and 6-chloro-N-(5-(cyanomethyl)-6-fluoro-3-methoxypyridin-2-yl)indolizine-1 -sulfonamide.

20. A pharmaceutical composition comprising a compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt, solvate or hydrate thereof, and a pharmaceutically acceptable carrier or excipient.

21. A compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt, solvate or hydrate thereof, or a pharmaceutical composition according to claim 20, for use in the treatment of a GPR17-associated disease.

22. A compound or pharmaceutical composition for use according to claim 21, 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.

23. A compound or pharmaceutical composition for use according to claim 21, wherein the GPR17-associated disease is multiple sclerosis.

24. 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 19, or a pharmaceutically acceptable salt, solvate or hydrate thereof, or a pharmaceutical composition according to claim 20.

25. A method according to claim 24, 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 lateralsclerosis (ALS), multiple system atrophy (MSA), Alzheimer’s disease, schizophrenia, Parkinson’s disease and Huntington’s disease.

26. A method according to claim 24, wherein the disease or disorder in which GPR17 activity is implicated is multiple sclerosis.

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