EA043389B1 - 1,3,4,5-TETRAHYDRO-2H-PYRIDO[4,3-b]INDOLE DERIVATIVES FOR THE TREATMENT, RELIEF, OR PREVENTION OF TAU AGGREGATE ASSOCIATED DISORDERS, SUCH AS ALZHEIMER'S DISEASE - Google Patents

Description

Field of invention

The present invention relates to new compounds that can be used for the treatment, amelioration or prevention of a group of disorders and abnormalities associated with tau protein (tubulin-associated) aggregates, including, but not limited to, neurofibrillary tangles (NFTs), such as Alzheimer's disease (AD).

State of the art

Many age-related diseases are based on or associated with extracellular or intracellular deposits of amyloid or amyloid-like proteins, which contribute to the pathogenesis as well as disease progression. The best characterized amyloid protein that forms extracellular aggregates is amyloid beta (Ae). Other examples of amyloid proteins that form extracellular aggregates are prion, ATTR (transthyretin) or ADan (ADanPP). Amyloid-like proteins that form primarily intracellular aggregates include, but are not limited to, tau, alpha-synuclein, TAR-DNA binding protein 43 (TDP-43), and huntingtin (htt). Diseases involving tau aggregates are usually referred to as tauopathies, such as AD.

Amyloid or amyloid-like deposits result from protein misfolding followed by aggregation to form beta sheets, in which multiple peptides or proteins are held together by intermolecular hydrogen bonds. Although amyloid or amyloid-like proteins have different primary amino acid sequences, their deposits often contain many common molecular components, particularly the presence of quaternary β-sheet structures. The relationship between amyloid deposits and disease remains largely unclear. A variety of protein aggregates, including both those associated with and not associated with disease pathologies, have been found to be toxic, suggesting that common molecular features of amyloid are involved or responsible for disease (Bucciantini et al., Nature, 2002, 416, 507-11). A variety of beta-sheet multimers of aggregated peptides or proteins have also been associated with toxicity to a variety of peptides or proteins ranging from dimers to soluble low molecular weight oligomers, protofibrils, or insoluble fibrillar deposits.

Alzheimer's disease (AD) is a neurological disorder thought to be primarily caused by amyloid plaques, the extracellular accumulation of abnormal deposits (amyloid-beta) of Ae aggregates in the brain. Other major neuropathological features in AD are intracellular neurofibrillary tangles (NFTs), which arise from the aggregation of hyperphosphorylated tau, misfolded tau, or pathological tau and its conformers. AD shares its etiopathology with many neurodegenerative tauopathies, particularly certain types of frontotemporal dementia (FTD). Tau protein is a freely soluble, naturally unfolded protein that actively binds to microtubules (MTs), promoting their assembly and stability. MTs are of great importance for the integrity of the neuronal cytoskeleton - and therefore for the proper formation and functioning of neural circuits, hence for learning and memory. Tau binding to MTs is controlled by dynamic phosphorylation and dephosphorylation, as demonstrated primarily in vitro and in non-neuronal cells. In the brains of AD patients, tau pathology (tauopathy) develops later than amyloid pathology, but it is still controversial if the Ae protein is the causative agent in AD, which forms the essence of the so-called amyloid cascade hypothesis (Hardy et al., Science 1992, 256, 184-185; Musiek et al., Nature Neurosciences 2015, 18(6), 800-806). The exact mechanisms that link amyloid to tau pathology remain largely unknown, but neuronal signaling pathways that act on or through GSK3 and cdk5 as the major tau kinases have been proposed (Muyllaert et al., Rev. Neurol. (Paris) , 2006, 162, 903-7; Muyllaert et al., Genes Brain and Behav. 2008, Suppl 1, 57-66). Even if tauopathy develops later than amyloid, it is not just an innocent side effect, but also a major pathological culprit in AD. In experimental mouse models, cognitive defects caused by amyloid pathology are almost completely alleviated by the absence of tau protein (Roberson et al., Science, 2007, 316 (5825), 750-4), and the severity of cognitive dysfunction and dementia correlates with tauopathy rather than with amyloid pathology.

Diseases involving tau aggregates are commonly referred to as tauopathies, and they include, but are not limited to, Alzheimer's disease (AD), familial AD, PART (primary age-related tauopathy), Creutzfeldt-Jakob disease, Boxer's dementia, Down syndrome, Gerstmann-Straussler-Scheinker (GSS), inclusion body myositis, cerebral prion protein-induced amyloid angiopathy, traumatic brain injury (TBI), amyotrophic lateral sclerosis (ALS), Guam parkinsonism-dementia complex, non-Guam motor neuron disease with neurofibrillary tangles, disease , characterized by the appearance of argyrophilic granules, corticobasal degeneration (CBD), diffuse neurofibrillary tangles with calcification, frontotemporal dementia with parkinsonism associated with chromosome 17 (FTDP-17), Hallervorden-Spatz disease, multiple system atrophy (MSA), Niemann-Pick disease type C, pallidoponto- 1 043389 degeneration, Pick's disease (PiD), progressive subcortical gliosis, progressive supranuclear palsy (PSP), subacute sclerosing panencephalitis, tangle-predominant dementia, postencephalitic parkinsonism, myotonic dystrophy, subacute sclerosing panencephalitis, mutations in LRRK2, chronic traumatic encephalopathy (CTE), familial British dementia, familial Danish dementia, other frontotemporal lobar degenerations, Guadalupean parkinsonism, neurodegeneration with brain iron accumulation, SLC9A6-related mental retardation, white matter tauopathy with globular glial inclusions, epilepsy, dementia with Lewy bodies (LBD), mild cognitive impairment (MCI), multiple sclerosis, Parkinson's disease, HIV-associated dementia, adult-onset diabetes, senile cardiac amyloidosis, glaucoma, ischemic stroke, AD psychosis, and Huntington's disease. (Williams et al., Intern. Med. I, 2006, 36, 652-60; Kovacs et al., J Neuropathol Exp Neurol. 2008; 67 (10): 963-975; Higuchi et al., Neuropsychopharmacology - 5 ^th Generation of Progress, 2002, section 9, chapter 94: 1339-1354; Hilton et al., Acta Neuropathol. 1995; 90 (1): 101-6; Iqbal et al., Biochimica et Biophysica Acta 1739(2005) 198- 210; McQuaid et al., Neuropathol Appl Neurobiol. Apr 1994; 20(2): 103-10; Vossel et al., Lancet Neurol 2017; 16: 311-22; Stephan et al., Molecular Psychiatry (2012) 17, 1056-1076; Anderson et al., Brain (2008), 131, 1736-1748; Savica et al., JAMA Neurol. 2013; 70 (7): 859-866; Brown et al., Molecular Neurodegeneration 2014, 9:40; El Khoury et al., Front. Cell. Neurosci., 2014, volume 8, article 22: 1-18; Tanskanen et al., Ann. Med. 2008; 40 (3): 232-9; Gupta et al., CAN J OPHTHALMOL - vol. 43, no. 1, 2008: 53-60; Dickson et al., Int J Clin Exp Pathol 2010; 3 (1): 1-23; Fernandez-Nogales et al., Nature Medicine , 20, 881-885 (2014); Bi et al., Nature Communications, volume 8, article number: 473 (2017); Murray et al., Biol Psychiatry. April 1, 2014; 75 (7): 542-552).

Of all the drugs in clinical trials for Alzheimer's disease in 2017, those targeting tau are very rare, representing only 8% of phase II clinical trials (Cummings et al., Alzheimer's & Dementia: Translational Research & Clinical Interventions 3 (2017) 367-384). Current therapeutic approaches that target tau include primarily antibody-based approaches, with the major limitation of targeting only extracellular tau. Among small molecule approaches, several tau kinase inhibitors have been developed, although they are very challenging in terms of toxicity and specificity. However, currently only one kinase inhibitor, Nilotinib, is being tested in clinical trials. Finally, among the tau aggregation inhibitors, only one, LMTX, is currently in clinical trials (Cummings et al., 2017). Although tau-based therapies have received increasing attention in recent years, there is still a great need for additional therapeutic agents that target pathological tau conformers known or suspected to cause tauopathies.

WO 2011/128455 relates to specific compounds that are useful for the treatment of disorders associated with amyloid proteins or amyloid-like proteins.

WO 2010/080253 relates to dipyridylpyrrole derivatives which are useful in the treatment of diseases amenable to inhibition, regulation and/or modulation of protein kinase signal transduction.

Summary of the invention

The purpose of the present invention was to provide compounds that can be used in the treatment, amelioration or prevention of a group of disorders and abnormalities associated with tau protein aggregates, including, but not limited to, NFTs, such as Alzheimer's disease (AD). There is also a need in the art for compounds that can be used as therapeutic agents to (a) reduce tau/NFT aggregates by recognizing aggregated tau and disaggregating tau, e.g., by altering the molecular conformation of the tau aggregate, and/or (b) preventing the formation of tau aggregates and/or (c) intracellular interaction with tau aggregates, and/or (d) reducing tau misfolding and hyperphosphorylation in vivo and/or (f) reducing neuroinflammatory markers. The inventors of the present invention have surprisingly discovered that these objectives can be achieved using compounds of formula (I) as described below.

The compounds of formula (I) (a) demonstrate a high ability to reduce tau aggregates by recognizing aggregated tau and disaggregating tau, for example, by changing the molecular conformation of the tau aggregate, and/or (b) preventing the formation of tau aggregates, and/or (c) intracellular interaction with tau aggregates, and/or (d) reducing tau misfolding and hyperphosphorylation in vivo, and/or (e) reducing neuroinflammatory markers. Without wishing to be bound by theory, it is believed that the compounds of formula (I) inhibit tau aggregation or disaggregate preformed tau aggregates, including when present intracellularly. Due to their unique structural features, these compounds exhibit properties such as appropriate lipophilicity and molecular weight, brain uptake and pharmacokinetics, cell permeability, solubility and metabolic stability to be successful drugs for the treatment, amelioration or prevention of tauopathies.

Accumulation of Tau NFT lesions has been shown to correlate well with cognitive deficits in AD, both through histopathological analysis and through PET imaging of tau in

- 2 043389 vivo. The compounds of this invention can either prevent the formation of tau aggregates or disaggregate pre-existing tau aggregates, and therefore can be expected to prevent or reduce associated cognitive deficits in AD.

Ultrastructural analysis revealed that tau inclusions consist of paired helical filaments (PHF) or straight filaments (SF). High-resolution structural analysis revealed that these filaments consist of a central region containing tau amino acids 306–378, which adopt a transverse beta/beta helical structure. The compounds of this invention can recognize aggregated tau and disaggregate tau, for example, by changing the molecular conformation of the tau aggregate, and therefore can be expected to facilitate the clearance of tau.

It has also been shown that tau is capable of both proliferating from cell to cell and that certain forms of tau (acting as seeds) are able to cause a structural change in the native tau protein in a healthy cell to undergo misfolding and aggregation. Aggregated tau is thought to be responsible for seeding and therefore spreading tau pathology. The compounds of this invention can interact intracellularly with aggregated tau and, therefore, can be expected to reduce the spread of tau pathology and ultimately prevent or reduce associated cognitive deficits in AD.

The tau aggregation cascade begins with tau misfolding and hyperphosphorylation. These events are thought to precede the formation of intracellular tau neuronal inclusions and hence the establishment and spread of tau pathology. The compounds of this invention can reduce tau misfolding and hyperphosphorylation in vivo, and therefore can be expected to have a beneficial effect in the treatment, amelioration or prevention of diseases associated with tau pathology.

Finally, the link between tau pathology and neuroinflammation is now well established. Neuroinflammation is a key event already in the early stages of AD and is considered one of the causes that trigger tau aggregation in PHF. Additionally, some mouse models of tauopathy have shown significant neuroinflammation when tau pathology is well established in the brain, indicating that tau pathology may also cause neuroinflammation. These two findings indicate that tau pathology and neuroinflammation are linked in a positive feedback loop. The compounds of this invention reduce neuroinflammatory markers in the fight against taupathology.

The present invention discloses novel compounds of formula (I) having the ability to (a) reduce tau aggregates, recognize aggregated tau, and disaggregate tau, for example, by changing the molecular conformation of the tau aggregate, and/or (b) prevent the formation of tau aggregates, and/or ( c) interact intracellularly with tau aggregates, and/or (d) reduce tau misfolding and hyperphosphorylation in vivo, and/or (f) reduce neuroinflammatory markers. The present invention provides methods for treating disorders and disorders associated with tau protein aggregates, including, but not limited to, NFTs, using a compound of formula (I) or a pharmaceutical composition thereof. The present invention further provides a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier or excipient.

The present invention is summarized in the following paragraphs.

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof; where A is selected from the group consisting of

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accessible position where

R ^j , and if A represents can be attached to Q in any way substituted with one or more substituents, R ^j does not represent -CN, -halogen or -CF3, and if A represents

or

, R ^j is not -halogen; and where

may be optionally substituted with one or more R substituents;

B is selected from the group consisting of O and NR ^a ;

E and V are independently selected from the group consisting of N, O and S;

G is selected from the group consisting of a benzene ring and a pyridine ring;

J is selected from the group consisting of O and NR ¹ ;

Q represents N;

Y is selected from the group consisting of CZ and N, with the proviso that when Y is N, B is N-alkyl or O;

Y ¹ represents CZ;

Y ² represents CZ;

Y ³ represents CZ;

Z is independently selected from the group consisting of H, halogen, O-alkyl and alkyl;

R is independently selected from the group consisting of

and -NR3R ⁴ ;

R ^a is selected from the group consisting of H and alkyl;

R ^b , R ^c , R ^d , R ^e , R ^f and R ^g represent H;

R ^j is independently selected from the group consisting of -halogen, -O-alkyl, -CF3, -CN, -NR3R ⁴ , as well as (R ² )n—NJ' where a bridge containing a C _1-2 carbon atom may be present between carbon atom and carbon atom c or d, or a bridge containing a carbon atom C _1-2 may be present between carbon atom b and carbon atom c or d;

R ¹ is selected from the group consisting of H and alkyl;

R ² represents alkyl, and if two R ² are geminal, they can be connected to form a 3-6 membered ring;

R ³ and R ⁴ are independently selected from the group consisting of H and alkyl, where alkyl may be optionally substituted with -O-alkyl;

n is 0, 1, 2, 3 or 4, and where alkyl has 1 to 6 carbon atoms.

2. The connection according to claim 1, in which

^v represents

3. A compound according to claim 1, which is a compound of formula (Ia)

- 4 043389 ζ

ζ (la) where A, B, R ^b , R ^c , R ^d , R ^e , R ^f , R ^g , Y and Z have the meanings defined in paragraph 1.

4. A compound according to claim 1, which is a compound of formula (Ib)

(lb) where A, B, R ^b , R ^c , R ^d , R ^e , R ^f , R ^g and Z have the meanings defined in paragraph 1.

5. A compound according to any one of claims 1 to 4, where A is

can be attached to Q in any available position, and moreover

’ which may optionally be replaced by one or more R substituents, where G, E, V and R have the meanings defined in claim 1.

6. A compound according to any one of claims 1 to 5, which is a compound of formula (Ic)

where E, R, V and Z have the meanings defined in paragraph 1.

7. A connection selected from the group consisting of

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8. A pharmaceutical composition containing a compound according to any one of claims 1 to 7 and optionally a pharmaceutically acceptable carrier or excipient.

9. Use of the compound of formula (I)

or a pharmaceutically acceptable salt thereof;

for treating, ameliorating or preventing a disorder or abnormality associated with tau protein aggregates, wherein A is selected from the group consisting of

in a highly accessible position where it can be attached to Q or substituted with one or more substituents R ^j , moreover, if A is E

, R ^j is not -CN, -halogen or -CF ₃ , and where

^v may optionally be substituted with one or more R substituents;

B is selected from the group consisting of O and NRa;

E and V are independently selected from the group consisting of N, O and S;

G is selected from the group consisting of a benzene ring and a pyridine ring;

J is selected from the group consisting of O and NR ¹ ;

Q represents N;

Y is selected from the group consisting of CZ and N, with the proviso that when Y is N, B is N-alkyl or O;

Y ¹ represents CZ; Y ² represents CZ;

Y ³ represents CZ;

Z is independently selected from the group consisting of H, halogen, O-alkyl and alkyl;

R is independently selected from the group consisting of Ra is selected from the group consisting of H and alkyl; R ^b , R ^c , R ^d , R ^e , R ^f and R ^g represent H;

. ³ R ⁴ ;

R ^j is independently selected from the group consisting of -halogen, -O-alkyl, -CF ₃ , -CN, -NR ³ R ⁴ , as well as (R ² )n -NJ with ά „ ' where the bridge containing the carbon atom C _1-2 may be present between carbon atom and carbon atom c or d, or a bridge containing a carbon atom C _1-2 may be present between carbon atom b and carbon atom c or d;

R ¹ is selected from the group consisting of H and alkyl;

R ² represents alkyl, and if two R ² are geminal, they can be connected to form a 3-6 membered ring;

R ³ and R ⁴ are independently selected from the group consisting of H and alkyl, where alkyl may be optionally substituted with -O-alkyl;

n is 0, 1, 2, 3 or 4; and where alkyl has from 1 to 6 carbon atoms.

10. Application according to claim 9, in which

represents

11. Use according to claim 9, wherein the compound is a compound of formula (Ia)

(1a) where A, B, R ^b , R ^c , R ^d , R ^e , R ^f , R ^g , Y and Z have the meanings defined in clause 9.

12. Use according to claim 9, wherein the compound is a compound of formula (Ib)

z (Ib) where A, B, R ^b , R ^c , R ^d , R ^e , R ^f , R ^g and Z have the meanings defined in clause 9.

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13. Use according to any one of claims 9 to 12, where A is

maybe > in which

may be attached to Q in any available position, and optionally be substituted with one or more R substituents, where G, E, V and R have the meanings defined in claim 9.

14. Use according to any one of formula (Ic) claims 9 to 13, where the compound is a compound from

where E, R, V and Z have the meanings defined in paragraph 9.

15. The use of a compound or a pharmaceutically acceptable salt thereof for the treatment, amelioration or prevention of a disorder or abnormality associated with tau protein aggregates, wherein the compound is selected from the group consisting of

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16. A method of treating, preventing, or alleviating a disorder or abnormality associated with tau protein aggregates, comprising administering an effective amount of a compound according to any one of claims 17 to a subject in need thereof.

17. The method according to claim 16, characterized in that the disorder is selected from Alzheimer's disease (AD), familial AD, primary age-related tauopathy (PART), Creutzfeldt-Jakob disease, Boxer dementia, Down syndrome, Gerstmann-Straussler-Scheinker disease (GSS ), inclusion body myositis, cerebral prion protein-induced amyloid angiopathy, traumatic brain injury (TBI), amyotrophic lateral sclerosis (ALS), Guam parkinsonism-dementia complex, non-Guam motor neuron disease with neurofibrillary tangles, disease characterized by the appearance of argyrophilic grains , corticobasal degeneration (CBD), diffuse neurofibrillary tangles with calcification, frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), Hallerwarden-Spatz disease, multiple system atrophy (MSA), Niemann-Pick disease type C, pallido -ponto-nigral degeneration, Pick's disease (PiD), progressive subcortical gliosis, progressive supranuclear palsy (PSP), subacute sclerosing panencephalitis, tangle-predominant dementia, postencephalitic parkinsonism, myotonic dystrophy, subacute sclerosing panencephalitis, mutations in LRRK2, chronic traumatic encephalopathy ( CTE), familial British dementia, familial Danish dementia, other frontotemporal lobar degenerations, Guadalupean parkinsonism, neurodegeneration with brain iron accumulation, SLC9A6-related mental retardation, white matter tauopathy with globular glial inclusions, epilepsy, dementia with Lewy bodies ( LBD), mild cognitive impairment (MCI), multiple sclerosis, Parkinson's disease, HIV-associated dementia, adult-onset diabetes, frailty-related cardiac amyloidosis, glaucoma, ischemic stroke, psychosis

- 30 043389 for AD and Huntington's disease, preferably Alzheimer's disease (AD), corticobasal degeneration (CBD), Pick's disease (PiD) and progressive supranuclear palsy (PSP).

18. Use of a compound as defined in any one of claims 1 to 7 in the manufacture of a medicament for the treatment, prevention or amelioration of a disorder or abnormality associated with tau protein aggregates.

19. Use according to claim 9 or use according to claim 18, characterized in that the disorder is selected from Alzheimer's disease (AD), familial AD, primary age-related tauopathy (PART), Creutzfeldt-Jakob disease, Boxer dementia, Down syndrome, Gerstmann disease -Straussler-Scheinker (GSS), inclusion body myositis, cerebral prion protein-induced amyloid angiopathy, traumatic brain injury (TBI), amyotrophic lateral sclerosis (ALS), Guam parkinsonism-dementia complex, non-Guam motor neuron disease with neurofibrillary tangles, disease characterized by the appearance of argyrophilic granules, corticobasal degeneration (CBD), diffuse neurofibrillary tangles with calcification, frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), Hallervorden-Spatz disease, multiple system atrophy (MSA), Niemann disease -Pica type C, pallidoponto-nigral degeneration, Pick's disease (PiD), progressive subcortical gliosis, progressive supranuclear palsy (PSP), subacute sclerosing panencephalitis, tangle-predominant dementia, postencephalitic parkinsonism, myotonic dystrophy, subacute sclerosing panencephalitis, mutations in LRRK2, chronic traumatic encephalopathy (CTE), familial British dementia, familial Danish dementia, other frontotemporal lobar degenerations, Guadalupean parkinsonism, neurodegeneration with brain iron accumulation, SLC9A6-related mental retardation, white matter tauopathy with globular glial inclusions, epilepsy , Lewy body dementia (LBD), mild cognitive impairment (MCI), multiple sclerosis, Parkinson's disease, HIV-associated dementia, adult-onset diabetes, senile cardiac amyloidosis, glaucoma, ischemic stroke, AD psychosis and Huntington's disease, preferably Alzheimer's disease (AD) ), corticobasal degeneration (CBD), Pick's disease (PiD) and progressive supranuclear palsy (PSP).

20. Use of a compound according to any one of claims 1 to 7 to reduce tau aggregation.

21. Use of a compound according to any one of claims 1 to 7 for preventing the formation of tau aggregates and/or for inhibiting tau aggregation.

22. Use of a compound according to any one of claims 1 to 7 for intracellular interaction with tau aggregates.

23. Use of a compound according to any one of claims 1 to 7 for reducing tau misfolding and hyperphosphorylation in vivo.

24. A method of reducing tau aggregation, comprising administering an effective amount of a compound according to any one of claims 1 to 7 to a subject in need thereof.

25. A method of preventing the formation of tau aggregates and/or inhibiting tau aggregation, comprising administering an effective amount of a compound according to any one of claims 1 to 7 to a subject in need thereof.

26. A method of intracellular interaction with tau aggregates, comprising administering an effective amount of a compound according to any one of claims 1 to 7 to a subject in need thereof.

27. A method of reducing tau misfolding and hyperphosphorylation in vivo, comprising administering an effective amount of a compound according to any one of claims 1 to 7 to a subject in need thereof.

28. Use of a compound according to any one of claims 1 to 7 in the manufacture of a medicament for reducing tau aggregation.

29. Use of a compound according to any one of claims 1 to 7 in the manufacture of a medicinal product for preventing the formation of tau aggregates and/or for inhibiting tau aggregation.

30. Use of a compound according to any one of claims 1 to 7 in the manufacture of a medicinal product for intracellular interaction with tau aggregates.

31. Use of a compound according to any one of claims 1 to 7 in the manufacture of a medicament for reducing tau misfolding and hyperphosphorylation in vivo.

32. Use of a compound as defined in any one of claims 1 to 7 for characterizing tissue with tau pathology.

33. Use of a compound as defined in any one of claims 1 to 7 for testing compounds targeting tau pathology in tissue with tau pathology.

Definitions.

For the purposes of the present invention, the following definitions apply.

Alkyl refers to a saturated straight or branched chain organic moiety consisting of carbon and hydrogen atoms. Examples of suitable alkyl groups have from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms, and include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl and isobutyl. The alkyl may optionally be substituted with halogen (preferably F), -OH or -O-alkyl (preferably -OMe).

Hal or halogen refers to F, Cl, Br and I.

3-8 membered ring refers to a three-, four-, five-, six-, seven-, or eight-membered ring where none, one or more carbon atoms in the ring are replaced by 1 or 2 (for a three-membered ring), 1. 2 or 3 (for a four-membered ring), 1, 2, 3 or 4 (for a five-membered ring) or 1, 2, 3, 4 or 5 (for a six-membered ring) 1, 2, 3, 4, 5 or 6 (for a seven-membered ring) rings) or 1, 2, 3, 4, 5, 6 or 7 (for an eight-membered ring) with the same or different heteroatoms, the heteroatoms being selected from O, N and S.

The compounds of the present invention having one or more optically active carbon atoms may exist as racemates and racemic mixtures (including mixtures in all proportions), stereoisomers (including diastereomeric mixtures and individual diastereomers, enantiomeric mixtures and individual enantiomers, mixtures of conformers and individual conformers ), tautomers, atropoisomers and rotamers. All isomeric forms are included in the present invention. The compounds described in this invention containing olefinic double bonds include the geometric isomers E and Z. Also included in this invention are all pharmaceutically acceptable salts, prodrugs, polymorphs, hydrates and solvates.

The term polymorphs refers to the different crystal structures of the compounds of the present invention. This may include, but is not limited to, crystal (and amorphous materials) morphology and all crystal lattice shapes. The salts of the present invention may be crystalline and may exist as more than one polymorph.

Solvates, hydrates, as well as anhydrous salt forms are also covered by this invention. The solvent included in the solvates is not particularly limited and may be any pharmaceutically acceptable solvent. Examples include water and C1. ₄ alcohols (such as methanol or ethanol).

Pharmaceutically acceptable salts are defined as derivatives of the disclosed compounds in which the parent compound is modified by producing acidic or basic salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic moieties such as amines, alkali metal salts or organic salts of acidic moieties such as carboxylic acids, etc. Pharmaceutically acceptable salts include conventionally accepted non-toxic salts or quaternary ammonium salts of the parent compound, obtained, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include salts derived from inorganic acids such as, but not limited to, hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric acid and the like; and salts derived from organic acids such as, but not limited to, acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isethionic acid, etc. Pharmaceutically acceptable salts of the present invention can be synthesized from the starting compound which contains a basic or acid moiety by conventional chemical methods. Typically, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture of the two. Organic solvents include, but are not limited to, non-aqueous media such as ethers, ethyl acetate, ethanol, isopropanol or acetonitrile. Lists of suitable salts can also be found in Remington Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, PA, 1990, page 1445, the disclosure of which is incorporated herein by reference.

The compounds of the present invention may also be provided in the form of a prodrug, namely a compound that is metabolized in vivo to an active metabolite. As used hereinafter in the specification and claims, the term prodrug means any covalently linked compound that releases the active parent pharmaceutical drug through in vivo biotransformation. Reference Goodman and Gilman (The Pharmacological Basis of Therapeutics, 8th ed., McGraw-Hill, Int. Ed. 1992, Biotransformation of Drugs, pp. 13-15) describing prodrugs is generally incorporated herein by reference.

As used herein, the phrase pharmaceutically acceptable refers to compounds, materials, compositions and/or dosage forms that, based on careful medical evaluation, are suitable for use in contact with human and animal tissue without causing excessive toxicity, irritation, allergic response or other problem or complication. and have an acceptable benefit/risk ratio.

The patients or subjects of the present invention are typically animals, especially mammals, more particularly humans.

As used herein, the term tau refers to a highly soluble microtubule-binding protein primarily found in neurons and includes the major 6 isoforms, cleaved or processed forms, and other modified forms such as those resulting from phosphorylation, glycosylation, glycation, prolyl isomerization, nitration, acetylation, polyamination, ubiquitination, sumoylation and oxidation.

Aggregated tau refers to aggregated monomers of tau peptides or proteins that are folded into oligomeric or polymeric structures.

Neurofibrillary tangles (NFTs) as used herein refer to insoluble aggregates of hyperphosphorylated tau protein containing paired helical filaments and (PHF) and straight filaments. Their presence is a hallmark of AD and other diseases known as tauopathies.

As used herein, the terms antibody or antibodies are a term generally recognized in the art and are intended to refer to molecules or active fragments of molecules that bind known antigens, or specifically to immunoglobulin molecules and the antigen-binding portions of immunoglobulin molecules. In particular, the mixture of the present invention includes the compounds of the present invention and anti-tau antibodies or anti-Abeta antibodies.

As used herein, the term functionally equivalent antibody or functional portion thereof is meant to refer to an equivalent molecule or active fragments of a molecule that binds to a known antigen, or to refer in particular to an immunoglobulin molecule and antigen-binding portions of an immunoglobulin molecule and has essentially the same properties. the same (biological) activity as the antibody from which it is derived.

The vaccine or vaccines specified in the mixtures of the present invention are, in particular, tau or Abeta vaccines.

The definitions and preferred definitions given in the Definition section apply to all embodiments described below unless otherwise noted.

Brief description of graphic materials

Fig. 1: CSF tau was quantified in rTg4510 mice treated with the compound of Example 12 and Example 45.

Fig. 2: Quantification of tau misfolding in rTg4510 mice treated with the compound of Example 12 and Example 45.

Fig. 3: Quantification of Iba1 (A) and CD68 (B) in rTg4510 mice treated with the compound of Example 12 and Example 45.

Fig. 4: Reduction of misfolding in NFTs in human AD and PSP brain slices using the compound of Example 45.

Fig. 5: High resolution autoradiography in human brain sections using ^3H -example 45 (A) and ^3H -example 45 and radioactive free example 45 (B).

Detailed description of the invention

The compounds of the present invention will be described below. It should be understood that all possible combinations of the following definitions are also provided.

The present invention relates to a compound of formula (I) (A j R ^{b R} 4—Q _Rd /~R ^e ϊ GU-U (I) or a pharmaceutically acceptable salt thereof; where A is selected from the group consisting of O o O OG Al O (U S UGU V/ V_7 _rae VV Ch/Chh / U- / 3 fyjjo) can be attached to Q in

- 33 043389 any available position where

, and

substituted with one or more substituents R ^j , and if A is

CF ₃ , and if A is

E

' R ^j is not -CN, -halogen or ' R ^j is not -halogen; and where

or

^V may optionally be substituted with one or more R substituents;

B is selected from the group consisting of O and NR ^a ;

E and V are independently selected from the group consisting of N, O and S;

G is selected from the group consisting of a benzene ring and a pyridine ring;

J is selected from the group consisting of O and NR ¹ ;

Q represents N;

Y is selected from the group consisting of CZ and N, with the proviso that when Y is N, B is N-alkyl or O;

Y ¹ represents CZ;

Y ² represents CZ;

Y ³ represents CZ;

Z is independently selected from the group consisting of H, halogen, O-alkyl and alkyl;

(R ² ) -O

R is independently selected from the group consisting of and -NR ³ R ⁴ ;

R ^a is selected from the group consisting of H and alkyl;

R ^b , R ^c , R ^d , R ^e , R ^f and R ^g represent H;

R ^j is independently selected from the group consisting of -halogen, -O-alkyl, -CF ₃ , -CN, -NR ³ R ⁴ , as well as (R ² )n —NJ cd ___ ____ - _ ____ _ ___ ____ ' where a bridge containing a C _1-2 carbon atom may be present between carbon atom and carbon atom c or d, or a bridge containing carbon atom C _1-2 may be present between carbon atom b and carbon atom c or d;

R ¹ is selected from the group consisting of H and alkyl;

R ² represents alkyl, and if two R ² are geminal, they can be connected to form a 3-6 membered ring;

R ³ and R ⁴ are independently selected from the group consisting of H and alkyl, where alkyl may be optionally substituted with -O-alkyl;

n is 0, 1, 2, 3 or 4, and where alkyl has 1 to 6 carbon atoms.

_x V represents .

In one embodiment, the compound is a compound of formula (Ia)

where A, B, R ^b , R ^c , R ^d , R ^e , R ^f , R ^g , Y and Z have the meanings defined in paragraph 1.

In one embodiment, the compound is a compound of formula (Ib)

- 34 043389

where A, B, R ^b , R ^c , R ^d , R ^e , R ^f , R ^g and Z have the meanings defined in paragraph 1.

B A B In one embodiment, A is . wherein ^v may be _x , x ^V may be optionally substituted with one or more substituents R, wherein G, E, V and R have the meanings defined in claim 1.

In one embodiment, the compound is a compound of formula (Ic)

where E, R, V and Z have the meanings defined in paragraph 1.

In one embodiment, the compound is a compound selected from the group consisting of

- 35 043389

- 36 043389

- 37 043389

- 38 043389

- 39 043389

- 40 043389

- 41 043389

- 42 043389

- 43 043389

- 44 043389

- 45 043389

In one embodiment, the present invention also relates to a pharmaceutical composition comprising a compound according to any one of claims 1 to 7 and optionally a pharmaceutically acceptable carrier or excipient.

In one embodiment, the present invention also relates to the use of a compound of formula (I)

or a pharmaceutically acceptable salt thereof;

for treating, ameliorating or preventing a disorder or abnormality associated with tau protein aggregates, wherein A is selected from the group consisting of

- 46 043389

may be attached to Q in any available position where R ^j is present, wherein A is substituted with one or more substituents > R ^j is not -CN, -halogen or -CF ₃ , and

where ^v may optionally be substituted with one or more R substituents;

B is selected from the group consisting of O and NR ^a ;

E and V are independently selected from the group consisting of N, O and S;

G is selected from the group consisting of a benzene ring and a pyridine ring;

J is selected from the group consisting of O and NR ¹ ;

Q represents N;

Y is selected from the group consisting of CZ and N, with the proviso that when Y is N, B is N-alkyl or O;

Y ¹ represents CZ;

Y ² represents CZ;

Y ³ represents CZ;

Z is independently selected from the group consisting of H, halogen, O-alkyl and alkyl;

R is independently selected from the group consisting of

and -NR ³ R ⁴ ;

R ^a is selected from the group consisting of H and alkyl;

R ^b , R ^c , R ^d , R ^e , R ^f and R ^g represent H;

R ^j is independently selected from the group consisting of -halogen, -O-alkyl, -CF ₃ , -CN, -NR ³ R ⁴ , as well as (R ² )n -NJ with

' wherein a bridge containing a C _1-2 carbon atom may be present between carbon atom and carbon atom c or d, or a bridge containing carbon atom C _1-2 may be present between carbon atom b and carbon atom c or d;

R ¹ is selected from the group consisting of H and alkyl;

R ² represents alkyl, and if two R ² are geminal, they can be connected to form a 3-6 membered ring;

R ³ and R ⁴ are independently selected from the group consisting of H and alkyl, where alkyl may be optionally substituted with -O-alkyl;

n is 0, 1, 2, 3 or 4; and where alkyl has from 1 to 6 carbon atoms.

In one embodiment

represents

In one embodiment, the compound is a compound of formula (Ia)

- 47 043389

(la) where A, B, R ^b , R ^c , R ^d , R ^e , R ^f , R ^g , Y and Z have the meanings defined above.

In one embodiment, the compound is a compound of formula (Ib)

where A, B, R ^b , R ^c , R ^d , R ^e , R ^f , R ^g and Z have the meanings defined above.

In one embodiment, A is to be attached to Q in any available position, and wherein

’ in which may be optional

may be substituted with one or more R substituents, where G, E, V and R are as defined above.

In one embodiment, the compound is a compound of formula (Ic)

where E, R, V and Z have the meanings defined above.

In one embodiment, the present invention also relates to the use of a compound or a pharmaceutically acceptable salt thereof for the treatment, amelioration or prevention of a disorder or abnormality associated with tau protein aggregates, wherein the compound is selected from the group consisting of

- 48 043389

- 49 043389

- 50 043389

- 51 043389

- 52 043389

- 53 043389

- 54 043389

- 55 043389

- 56 043389

- 57 043389

- 58 043389

- 59 043389

In one embodiment, the invention also provides a method of treating, preventing, or ameliorating a disorder or abnormality associated with tau protein aggregates, comprising administering an effective amount of any of the foregoing compounds to a subject in need thereof.

In one embodiment, the disorder is selected from Alzheimer's disease (AD), familial AD, primary age-related tauopathy (PART), Creutzfeldt-Jakob disease, Boxer dementia, Down syndrome, Gerstmann-Straussler-Scheinker disease (GSS), inclusion body myositis, cerebral amyloid angiopathy caused by prion protein, traumatic brain injury (TBI), amyotrophic lateral sclerosis (ALS), Guam parkinsonism-dementia complex, non-Guam motor neuron disease with neurofibrillary tangles, disease characterized by the appearance of argyrophilic granules, corticobasal degeneration (CBD), diffuse neurofibrillary tangles with calcification, frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), Hallerwarden-Spatz disease, multiple system atrophy (MSA), Niemann-Pick disease type C, pallidopontigral degeneration, disease Pica (PiD), progressive subcortical gliosis, progressive supranuclear palsy (PSP), subacute sclerosing panencephalitis, tangle-predominant dementia, postencephalitic parkinsonism, myotonic dystrophy, subacute sclerosing panencephalitis, LRRK2 mutations, chronic traumatic encephalopathy (CTE), familial British dementia, familial Danish dementia, other frontotemporal lobar degenerations, Guadalupean parkinsonism, neurodegeneration with brain iron accumulation, SLC9A6-related mental retardation, white matter tauopathy with globular glial inclusions, epilepsy, Lewy body dementia (LBD), mild cognitive impairment (MCI) , multiple sclerosis, Parkinson's disease, HIV-associated dementia, adult-onset diabetes, senile cardiac amyloidosis, glaucoma, ischemic stroke, AD psychosis and Huntington's disease, preferably Alzheimer's disease (AD), corticobasal degeneration (CBD), Pick's disease (PiD) and progressive supranuclear palsy (PSP).

In one embodiment, the present invention also relates to the use of any of the above compounds in the manufacture of a medicament for the treatment, prevention or amelioration of a disorder or abnormality associated with tau protein aggregates.

In one embodiment, the disorder is selected from Alzheimer's disease (AD), familial AD, primary age-related tauopathy (PART), Creutzfeldt-Jakob disease, Boxer dementia, Down syndrome, Gerstmann-Straussler-Scheinker disease (GSS), inclusion body myositis, cerebral amyloid angiopathy caused by prion protein, traumatic brain injury (TBI),

- 60 043389 amyotrophic lateral sclerosis (ALS), Guam parkinsonism-dementia complex, non-Guam motor neuron disease with neurofibrillary tangles, disease characterized by the appearance of argyrophilic grains, corticobasal degeneration (CBD), diffuse neurofibrillary tangles with calcification, frontotemporal dementia with parkinsonism, associated with chromosome 17 (FTDP-17), Hallervorden-Spatz disease, multiple system atrophy (MSA), Niemann-Pick disease type C, pallidopontongigral degeneration, Pick disease (PiD), progressive subcortical gliosis, progressive supranuclear palsy ( PSP), subacute sclerosing panencephalitis, tangle-predominant dementia, postencephalitic parkinsonism, myotonic dystrophy, subacute sclerosing panencephalitis, LRRK2 mutations, chronic traumatic encephalopathy (CTE), familial British dementia, familial Danish dementia, other frontotemporal lobar degenerations, Guadalupean parkinsonism, neurodegener ations with iron accumulation in the brain, SLC9A6-related mental retardation, white matter tauopathy with globular glial inclusions, epilepsy, dementia with Lewy bodies (LBD), mild cognitive impairment (MCI), multiple sclerosis, Parkinson's disease, HIV-associated dementia, diabetes in adults, senile cardiac amyloidosis, glaucoma, ischemic stroke, psychosis in AD and Huntington's disease, preferably Alzheimer's disease (AD), corticobasal degeneration (CBD), Pick's disease (PiD) and progressive supranuclear palsy (PSP).

In one embodiment, the present invention also relates to the use of any of the above compounds to reduce tau aggregation.

In one embodiment, the present invention also provides the use of any of the above compounds to prevent the formation of tau aggregates and/or to inhibit tau aggregation.

In one embodiment, the present invention also relates to the use of any of the above compounds for intracellular interaction with tau aggregates.

In one embodiment, the present invention also provides the use of any of the above compounds to reduce tau misfolding and hyperphosphorylation in vivo.

In one embodiment, the present invention also provides a method of reducing tau aggregation, comprising administering an effective amount of any of the foregoing compounds to a subject in need thereof.

In one embodiment, the present invention also provides a method for preventing the formation of tau aggregates and/or inhibiting tau aggregation, comprising administering an effective amount of any of the foregoing compounds to a subject in need thereof.

In one embodiment, the present invention also provides a method of intracellular interaction with tau aggregates, comprising administering an effective amount of any of the foregoing compounds to a subject in need thereof.

In one embodiment, the present invention also provides a method of reducing tau misfolding and hyperphosphorylation in vivo, comprising administering an effective amount of any of the foregoing compounds to a subject in need thereof.

In one embodiment, the present invention also relates to the use of any of the above compounds in the manufacture of a medicament for reducing tau aggregation.

In one embodiment, the present invention also relates to the use of any of the above compounds in the manufacture of a medicament for preventing the formation of tau aggregates and/or for inhibiting tau aggregation.

In one embodiment, the present invention also relates to the use of any of the above compounds in the manufacture of a drug for intracellular interaction with tau aggregates.

In one embodiment, the present invention also relates to the use of any of the above compounds in the manufacture of a medicament for reducing tau misfolding and hyperphosphorylation in vivo.

In one embodiment, the present invention also relates to the use of any of the above compounds to characterize tissue with tau pathology.

In one embodiment, the present invention also relates to the use of any of the above compounds for testing compounds that target tau pathology in tissue with tau pathology.

Preferred compounds of formula (I) are

- 61 043389

- 62 043389

- 63 043389

- 64 043389

n

- 65 043389

- 66 043389

Preferred compounds are also illustrated in the examples.

Any combination of embodiments, preferred embodiments and more preferred embodiments disclosed herein are also provided herein.

Pharmaceutical compositions.

Although the compounds of the present invention should be administered separately, they are preferably formulated into a pharmaceutical composition in accordance with standard pharmaceutical practice. Thus, the present invention also relates to a pharmaceutical composition that contains a therapeutically effective amount of a compound of formula (I), optionally in admixture with a pharmaceutically acceptable carrier, diluent, adjuvant or excipient.

Pharmaceutically acceptable excipients are well known in the pharmaceutical art and are described, for example, in Remington Pharmaceutical Sciences, ^15th edition, Mack Publishing Co., New Jersey (1975). The pharmaceutical excipient may be selected based on the intended route of administration and standard pharmaceutical practice. The excipient must be acceptable in the sense that it is not harmful to the recipient.

Pharmaceutically suitable excipients that can be used in the pharmaceutical composition of the present invention may include, for example, carriers, carrier vehicles, diluents, solvents such as monohydric alcohols such as ethanol, isopropanol, and polyhydric alcohols such as glycols and edible oils such as soybean oil, coconut oil,

- 67 043389 olive oil, safflower oil, cottonseed oil, fatty acid esters such as ethyl oleate, isopropyl myristate, binders, adjuvants, solubilizers, thickeners, stabilizers, disintegrants, glidants, lubricants, buffering agents, emulsifiers, wetting agents, suspending agents agents, sweeteners, colors, flavors, coating agents, preservatives, antioxidants, glazing agents, drug delivery modifiers and enhancers such as calcium phosphate, magnesium stearate, talc, monosaccharides, disaccharides, starch, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose, dextrose , hydroxypropyl-b-cyclodextrin, polyvinylpyrrolidone, low-melting waxes and ion exchange resins.

Routes of administration (delivery) of the compounds of this invention include, but are not limited to, one or more of: oral (e.g., as a tablet, capsule, or ingestible solution), topical, transmucosal (e.g., as a nasal inhalation spray or aerosol), nasal, parenteral (eg, injectable), gastrointestinal, intraspinal, intraperitoneal, intramuscular, intravenous, intrauterine, intraocular, intradermal, intracranial, intratracheal, intravaginal, intracerebroventricular, intracerebral, subcutaneous, ophthalmic (including intravitreal or intracameral), transdermal, rectal, buccal, epidural and sublingual.

For example, the compounds may be administered orally in the form of tablets, capsules, ovules, elixirs, solutions or suspensions, which may contain flavorings or colors, for immediate, sustained, modified, sustained, pulsed or controlled release.

Tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine, disintegrants such as starch (preferably corn, potato or tapioca starch), sodium starch glycolate, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. In addition, lubricants such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included. Solid compositions of this type can also be used as fillers in gelatin capsules. Preferred excipients in this regard include lactose, starch, cellulose, milk sugar or high molecular weight polyethylene glycols. For aqueous suspensions and/or elixirs, the agent may be combined with a variety of sweeteners or flavoring agents, coloring agents or dyes, emulsifying and/or suspending agents, and diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof.

When the compounds of the present invention are administered parenterally, examples of such administration include one or more of: intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, or subcutaneous administration of the compounds; and/or using infusion methods. For parenteral administration, the compounds are best used in the form of a sterile aqueous solution, which may contain other substances, such as sufficient salts or glucose, to render the solution isotonic with blood. Aqueous solutions should be suitably buffered (preferably to a pH of 3 to 9) if necessary. The preparation of suitable parenteral compositions under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.

As stated, the compounds of the present invention can be administered intranasally or by inhalation and are conveniently delivered in the form of a dry powder inhaler or aerosol dispenser from a pressurized container, pump, spray or nebulizer using a suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, hydrofluoroalkane, such such as 1,1,1,2-tetrafluoroethane (HFA134AT) or 1,1,1,2,3,3,3-heptafluoropropane (HFA 227EA), carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver the metered amount. The pressurized container, pump, nebulizer or nebulizer may contain a solution or suspension of the active compound, for example using a mixture of ethanol and a propellant as a solvent, which may further contain a lubricant such as sorbitan trioleate. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator can be formulated to contain a powder mixture of the compound and a suitable powder base such as lactose or starch.

Alternatively, the compounds of the present invention can be administered in the form of a suppository or pessary, or it can be applied topically in the form of a gel, hydrogel, lotion, solution, cream, ointment or powder. The compounds of the present invention can also be administered transdermally or transdermally, for example, using a skin patch.

They can also be administered by the pulmonary or rectal route. They can also be administered through the eye. For ophthalmic use, the compounds can be prepared as micronized suspensions in isotonic, pH-adjusted, sterile saline.

- 68 043389 or, preferably, in the form of solutions in isotonic, pH-adjusted, sterile saline, optionally in combination with a preservative such as benzylalkonium chloride.

Alternatively, they may be formulated as an ointment such as Vaseline.

For topical application to the skin, the compounds of the present invention may be formulated as a suitable ointment containing the active compound suspended or dissolved, for example, in a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, emulsifying wax and water. Alternatively, they may be formulated as a suitable lotion or cream, suspended or dissolved, for example, in a mixture of one or more of the following: mineral oil, sorbitan monostearate, polyethylene glycol, liquid paraffin, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

Typically, the physician will determine the actual dosage that will be most appropriate for the individual subject. The specific dosage level and frequency of administration for any given individual may vary and will depend on a variety of factors, including the potency of the particular compound used, the metabolic stability and duration of action of that compound, age, body weight, general health, gender, diet, route and time of administration, rate of elimination, combination of drugs, severity of the specific condition and individual receiving therapy.

A suggested dose of the compounds of the present invention for administration to a human (approximately 70 kg body weight) is 0.1 mg to 3 g, 0.1 mg to 2 g, 0.1 mg to 1 g, preferably 1 mg to 500 mg of active ingredient per dose unit. A unit dose may be administered, for example, 1 to 4 times a day. The dose will depend on the route of administration. It is understood that regular dosage adjustments may be required depending on the age and weight of the patient and the severity of the condition being treated. The exact dose and route of administration will ultimately be left to the discretion of the treating physician or veterinarian.

The compounds of this invention can also be used in combination with other therapeutic agents. When a compound of this invention is used in combination with a second therapeutic agent active against the same disease, the dose of each compound may differ from the dose when the compound is used alone.

The above combinations may conveniently be presented for use in the form of a pharmaceutical composition. The individual components of such combinations can be administered sequentially or simultaneously in separate or combined pharmaceutical compositions in any convenient manner. When administration is sequential, both the compound of this invention and the second therapeutic agent may be administered first. When administration is simultaneous, the combination can be administered in either one or another pharmaceutical composition. When combined in the same composition, it is understood that the two compounds must be stable and compatible with each other and the other components of the composition. When formulated separately, they may be provided in any convenient composition, generally in a manner known for such compounds in the art.

The pharmaceutical compositions of this invention can be prepared in a manner well known to one skilled in the art, as described, for example, in Remington Pharmaceutical Sciences, ^15th edition, Mack Publishing Co., New Jersey (1975).

Diseases or pathological conditions that can be treated, alleviated or prevented by the compounds of the present invention are disorders or abnormalities associated with tau protein aggregates, such as neurodegenerative disorders. Examples of diseases and conditions that can be treated, ameliorated, or prevented are caused by or are associated with the formation of neurofibrillary lesions. This is the predominant brain pathology in tauopathy. The diseases and conditions include a heterogeneous group of neurodegenerative diseases or conditions, including diseases or conditions that show the coexistence of tau and amyloid pathologies.

Examples of diseases and conditions that may be treated, ameliorated, or prevented include, but are not limited to, Alzheimer's disease (AD), familial AD, PART (primary age-related tauopathy), Creutzfeldt-Jakob disease, Boxer's dementia, Down syndrome, Gerstmann-Streissler-Scheinker disease (GSS), inclusion body myositis, prion cerebral amyloid angiopathy, traumatic brain injury (TBI), amyotrophic lateral sclerosis (ALS), parkinsonism-dementia complex Guam, non-Guam motor neuron disease with neurofibrillary tangles, disease, characterized by the appearance of argyrophilic granules, corticobasal degeneration (CBD), diffuse neurofibrillary tangles with calcification, frontotemporal dementia with parkinsonism associated with chromosome 17 (FTDP-17), Hallervorden-Spatz disease, multiple system atrophy (MSA), Niemann-Pick disease type C, pallidopontonigral degeneration, Pick's disease (PiD), progressive subcortical gliosis, progressive supranuclear palsy (PSP), subacute sclerosing panencephalitis, tangle-predominant dementia, post- 69 043389 stencephalitic parkinsonism, myotonic dystrophy, Subacute sclerosing panencephalitis, mutations in LRRK2, chronic traumatic encephalopathy (CTE), familial British dementia, familial Danish dementia, other frontotemporal lobar degenerations, Guadalupean parkinsonism, neurodegeneration with brain iron accumulation, SLC9A6-related mental retardation, white matter tauopathy with globular glial inclusions, epilepsy , diffuse Lewy body disease (LBD), mild cognitive impairment (MCI), multiple sclerosis, Parkinson's disease, HIV-related dementia, adult-onset diabetes, senile cardiac amyloidosis, glaucoma, ischemic stroke, AD psychosis, and Huntington's disease. Preferably, diseases and pathological conditions that can be treated, ameliorated or prevented include Alzheimer's disease (AD), as well as other neurodegenerative tauopathies such as Creutzfeldt-Jakob disease, boxer dementia, amyotrophic lateral sclerosis (ALS), a disease characterized by the appearance of argyrophilic granules , corticobasal degeneration (CBD), frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), Pick's disease (PiD), progressive supranuclear palsy (PSP), tangle-predominant dementia, dementia with Guam parkinsonian syndrome, disease

Hallervorden-Spatz, chronic traumatic encephalopathy, traumatic brain injury (TBI) and other frontotemporal lobar degeneration. More preferably, Alzheimer's disease (AD), corticobasal degeneration (CBD), Pick's disease (PiD) and progressive supranuclear palsy (PSP).

The compounds of the present invention can also be used to reduce protein aggregation, in particular tau aggregation. The ability of a compound to reduce tau aggregation can, for example, be determined using a ThT assay (Hudson et al., FEBS J., 2009, 5960-72).

The compounds of this invention can be used to treat a wide range of disorders in which the process of neuroinflammation is associated with misfolding and/or pathological aggregation of tau protein.

The compounds of the present invention can be used as an analytical standard or in vitro screening tool to characterize tissue with tau pathology and to test compounds targeting tau pathology in such tissue.

The compounds of the present invention can be used as photoprobes to crosslink a compound to a target, for use in in vitro screening assays, to identify and characterize the mode of action of a compound, including binding site mapping. The following are some examples of photoprobe compounds of the present invention:

The compounds of the present invention may also be provided in the form of a mixture with at least one additional biologically active compound and/or a pharmaceutically acceptable carrier and/or diluent and/or excipient. The compound and/or additional biologically active compound is preferably present in a therapeutically effective amount.

The nature of the additional biologically active compound will depend on the intended use of the mixture. The additional biologically active substance or compound may exert its biological action by the same or similar mechanism as the compound of the invention, or by an unrelated mechanism of action, or by multiple related and/or unrelated mechanisms of action.

Typically, the additional biologically active compound may include neutron transmission enhancers, psychotherapeutic drugs, acetylcholinesterase inhibitors, calcium channel blockers, biogenic amines, benzodiazepine tranquilizers, acetylcholine synthesis, release or release enhancers, acetylcholine postsynaptic receptor agonists, monoamine oxidase-A inhibitors, or - B, N-methyl-D-aspartate glutamate receptor antagonists, non-steroidal anti-inflammatory drugs, antioxidants and serotonergic receptor antagonists. In particular, the additional biologically active compound may be selected from the group consisting of a compound used in the treatment of amyloidosis, anti-oxidative stress compounds, anti-apoptotic compounds, metal chelators, DNA repair inhibitors such as pirenzepine and metabolites, 3-amino-1-propanesulfonic acid. acids (3APS), 1.3

- 70 043389 propane disulfonate (1,3PDS), α-secretase activators, β- and γ-secretase inhibitors, glycogen synthase kinase 3 inhibitors, O-N-acetylglucosaminase (OGA) inhibitors, neurotransmitter, β-sheet disruptors, attractants for cellular components, purifying/ beta-amyloid depleting inhibitors, N-terminally truncated beta-amyloid including amyloid beta pyroglutamate 3-42, anti-inflammatory molecules or cholinesterase inhibitors (ChEI) such as tacrine, rivastigmine, donepezil and/or galantamine, Ml agonists, others drugs, including any amyloid or tau-modifying drug and dietary supplements, antibody, including any functionally equivalent antibody or functional parts thereof, or vaccine.

In a further embodiment, mixtures of the invention may contain niacin or memantine together with a compound of the present invention and, optionally, a pharmaceutically acceptable carrier and/or diluent and/or excipient.

In yet another embodiment, the invention provides mixtures that include, as an additional biologically active compound, an atypical antipsychotic, such as, for example, clozapine, ziprasidone, risperidone, aripiprazole, or olanzapine, for the treatment of positive and negative psychotic symptoms, including hallucinations, delusions, delusions, disorders (manifested by marked incoherence, confusion, tangency) and strange or disorganized behavior, as well as anhedonia, affective flattening, apathy and social withdrawal, together with a compound of this invention and, optionally, a pharmaceutically acceptable carrier and/or diluent and/or excipient.

Other compounds which may suitably be used in mixtures in combination with a compound of the present invention are described, for example, in WO 2004/058258 (see especially pages 16 and 17), including therapeutic drug targets (pages 36-39), alkanesulfonic acid and alkanol sulfonic acids (pages 39-51), cholinesterase inhibitors (pages 51-56), NMDA receptor antagonists (pages 56-58), estrogens (pages 58-59), non-steroidal anti-inflammatory drugs (pages 60 and 61), antioxidants (pages 61 and 62), peroxisome proliferator-activated receptor (PPAR) agonists (pages 63-67), cholesterol-lowering agents (pages 68-75), amyloid inhibitors (pages 75-77), amyloid inhibitors (pages 77-78) , metal chelators (pages 78 and 79), antipsychotics and antidepressants (pages 80-82), dietary supplements (pages 83-89) and compounds that increase the availability of bioactive substances in the brain (see pages 89 to 93) and prodrugs (pages 93 and 94), incorporated herein by reference.

This invention also includes all suitable isotopic variants of the compounds of this invention. An isotopic variant of a compound of this invention is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass typically found in nature. Examples of isotopes that may be included in the compounds of this invention include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine and chlorine ^, such as ^2H , ^3H , 13C, ^14C , ^15N , ^17O , ¹⁸ O, ³⁵ S, ¹⁸ F and ³⁶ Cl, respectively. Certain isotopic embodiments of the invention, for example those that include a radioactive isotope such as ³ H or ¹⁴ C, are useful in drug and/or substrate tissue distribution studies. Tritiated, i.e. ³ H, and carbon-14, i.e. ¹⁴ C isotopes are particularly preferred because of their ease of preparation and detectability. ¹⁸ F-labeled compounds are particularly suitable for imaging applications such as PET. Substitution with heavier isotopes such as deuterium, i.e. ^2H may provide certain therapeutic benefits due to greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and may therefore be preferred in some cases. Isotopic variations of the compounds of the present invention can generally be prepared by conventional methods, such as the illustrative methods or the methods described below in the Examples and Preparation Methods, using suitable isotopic variations of suitable reagents.

The compounds of the present invention can be synthesized by one of the general methods illustrated in the following schemes. These methods are for illustrative purposes only and should not be construed as limiting.

General synthetic schemes for obtaining the building blocks of this invention:

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1. acid, solvent

N-Vos

Scheme 1

Z = H, F, Cl, Me, OMe 2. base Z = H, F, CI, Me, OMe

R ^a = H, Me 3. solvent

Z=H, F, Cl, Me, OMe

2. base Z - H, F, OMe

3. solvent

Heating commercially available phenylhydrazine derivatives (Z =H, F, Cl, Me or OMe; R ^a =H, CH3) with commercially available tert-butyl-4-oxopiperidine-1-carboxylate in a suitable solvent under acidic conditions (Fischer indole synthesis ) upon purification yielded tricyclic 2,3,4,5tetrahydro-1H-pyrido[4,3-b]indole building blocks. In the case of using 2- or 3-substituted phenylhydrazine derivatives, regioisomers were separated using supercritical fluid chromatography (SFC). Tricyclic building blocks bearing an NH moiety in the indole ring were additionally treated with Boc ₂ O to selectively protect the aliphatic secondary amine moiety and were obtained after purification.

Scheme 2

To avoid the formation of a regioisomer by using 2- or 3-substituted phenylhydrazine derivatives, corresponding phenylhydrazine derivatives having an additional halogen atom (Br, Cl) adjacent to the hydrazine moiety were used. Thus, the Fischer synthesis of indole with commercially available tert-butyl-4-oxopiperidine-1-carboxylate in a suitable solvent under acidic conditions yielded after purification only one product with an additional halogen atom. The aliphatic secondary amine was protected by Boc and the products were obtained after purification. The additional halogen atom was then removed by hydrogenation with a palladium catalyst using a suitable base in a suitable solvent to obtain the desired tricyclic 2,3,4,5 tetrahydro-1H-pyrido[4,3-b]indole building blocks after purification.

Scheme 3

The NH moiety of the indole moiety was then treated with either methyl iodide or tosyl chloride in a suitable solvent using a suitable base to obtain the N-methyl or Ntosyl derivatives after purification. The Boc-protecting group was removed by acid treatment in a suitable solvent to obtain the desired tricyclic 2,3,4,5-tetrahydro-1H-pyrido[4,3b]indole building blocks after purification. In the absence of base treatment, the corresponding salts were obtained.

- 72 043389

Scheme 4

Commercially available fluoropyrdine derivatives with an F atom in the 3-, 4-, or 5-position and an additional halogen atom (Br, Cl) in the 2-position were treated with methylhydrazine in a suitable solvent to obtain the corresponding N-methylhydrazine derivatives after purification. Fischer synthesis of indoles with commercially available tert-butyl-4-oxopiperidine-1-carboxylic acid in a suitable solvent under acidic conditions after purification gave the desired tricyclic 9methyl-6,7,8,9-tetrahydro-5H-pyrrolo[2,3- b:4,5-c']dipyridine derivatives.

Scheme 5

Heating commercially available phenylhydrazine derivatives (Z=F) with commercially available tert-butyl-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate in a suitable solvent under acidic conditions (Fischer indole synthesis) after purification gave tricyclic 5 ,6,7,8,9,10-hexahydro-7,10epiminocyclohepta[b]indole derivatives. In the case of 2- or 3-substituted phenylhydrazine derivatives, the regioisomers must be separated using supercritical fluid chromatography (SFC). The aliphatic secondary amine moiety was then protected with Boc and the products were obtained after purification. The NH moiety of the indole moiety was then treated with tosyl chloride in a suitable solvent using a suitable base to obtain the N-tosyl derivatives after purification. The Boc-protecting group was removed by acid treatment in a suitable solvent to provide the desired tricyclic 5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole building blocks after purification. In the absence of base treatment, the corresponding salts were obtained.

Scheme 6

CuCI, pyridine solvent molecular sieves

-HE

ABOUT

1. N ₂ H ₄ xH ₂ O solvent

2. 2 M HCI/Et ₂ O z

_o .NH ₂ z = f xHCI

1. acid solvent

2. base

3. solvent

Commercially available phenylboronic acid ester derivatives (Z=F) were treated with N-hydroxyphthalimide and copper(I) chloride and pyridine in a suitable solvent to, upon purification, yield the corresponding hydroxylamine derivatives containing the phthalimide protecting group. The phthalimide protecting group was cleaved with hydrazine hydrate and the corresponding hydroxylamine derivatives were obtained as salts. Heating hydroxylamine derivatives with commercially available 1,4-dioxa-8-azaspiro[4.5]decane in a suitable solvent under acidic conditions (Fischer indole synthesis) after purification gave tricyclic 1,2,3,4-tetrahydrobenzofuro[3,2-73 043389

c]pyridine derivatives.

Scheme 7

microwave radiation, solvent

G = Ph, Ru, pyrimidine

R= Morpholine, (R/S-2-methylmorpholine, (I5)-3-methylmorpholine, -N(alk) ₂ ,-NH(alk) ₄ 5-oxa-8-azaspiro[3,5]nonane

R ^x = Hal

E and V = N, O, S

G = Ph, Ru, pyrimidine

Commercially available benzo[d]thiazole (G=Ph) or benzo[d]oxazole (G=Ph) derivatives containing two halogen atoms (Br, Cl) were treated with primary or secondary amines in a suitable solvent and an additional base. Leaving group X was replaced by nucleophilic substitution with primary or secondary amines to obtain, after purification, the corresponding amino-substituted benzo[4]thiazole or benzo[d]oxazole derivatives. For less reactive amines, the desired benzo[d]thiazole or benzo[d]oxazole derivatives were prepared by performing a nucleophilic substitution reaction under microwave conditions. The corresponding thiazolo[5,4-b]pyridine (G=Py) and thiazolo[4,5-b]pyridine (G=Py) derivatives containing two halogen atoms (Br, Cl) were treated with morpholine in a suitable solvent and an additional base to obtain, after purification, the corresponding derivatives of morpholinothiazolo[5,4-b]pyridine (G=Py) and morpholinothiazolo[4,5-b]pyridine (G=Py). The corresponding thiazolo[5,4-4]pyrimidine derivatives (G=pyrimidine) containing two halogen atoms (Br, Cl) were treated with morpholine in a suitable solvent and an additional base to obtain morpholino-thiazolo[5,4-d]pyrimidine (G =pyrimidine).

Scheme 8 after purification of the corresponding derivatives

Commercially available [1,2,4]triazolo[1,5-a]pyridine derivatives containing two halogen atoms (Br, Cl) were treated with morpholine under microwave conditions to obtain zeroophilic substitution products after purification.

Scheme 8a H.HCI n U K~L Vg A M i ⁰ ___________° ^H ί Ί [IN

ΒγΛ ^{Ν 0Γ} Μ ^OG M base, solvent vg

R= morpholine, 3-oxa-8-azabicyclo[3,2,1] octane,

8-oxa-3-azabicyclo[3,2,1]octane

R ^x = Hal

Commercially available derivatives of 3,6-dibromopyridazine and 2,5-dibromopyridazine containing two bromine atoms were treated with morpholine, 3-oxa-8-azabicyclo[3.2.1]octane or 8-oxa-3azabicyclo[3.2.1]octane in the microwave. conditions in order to obtain products of zeroophilic substitution after purification.

Scheme 8b

Commercially available derivatives of 2,7-dichloroquinoline, 2-bromo-6-chloro-1,7-naphthyridine, 2 bromo-6-chloro-1,8-naphthyridine and 2,6-dichloroquinoline containing two halogens (Br, Cl) atoms were treated with morpholine under microwave conditions to obtain zeroophilic substitution products after purification.

General synthetic scheme for preparing the compounds of this invention.

- 74 043389

Scheme 9

-N(alk) ₂ , -NH(alk)

R'=morpholine

R ^x = Hal

E and V = N, O, S

G = Ph, Py

G* = Py

Tricyclic building blocks with B=NCH ₃ or B=O have been cross-coupled with amino-substituted benzo[d]thiazole or benzo[d]oxazole derivatives or substituted pyridine derivatives via palladium chemistry with a suitable palladium catalyst (chloro(2-) adduct dicyclohexylphosphino)-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2-aminoethyl)phenyl]palladium (II) with methyl tert-butyl ether; Pd(RuPhos) G1), ligand (2-dicyclohexylphosphino-2',6'diisopropoxybiphenyl; RuPhos) and base (lithium bis(trimethylsilyl)amide; LiHMDS) in a suitable solvent (tetrahydrofuran; THF) to obtain, after purification, the desired compounds of formula ( I).

Scheme 10

Tricyclic building blocks containing an N-tosyl group in the indole/azaindole moiety were cross-coupled with amino-substituted derivatives of benzo[d]thiazole, benzo[d]oxazole, thiazolo[5,4-b]pyridine (G=Py ), thiazolo[4,5-b]pyridine (G=Py), thiazolo[5,4-d]pyrimidine (G=pyrimidine), or amino-substituted derivatives of [1,2,4]triazole[1,5a]pyridine, or amino-substituted derivatives of pyridine (L=Py), pyrazine (L=pyrazine), pyridazine (L=pyridazine), pyrimidine (L=pyrimidine) or amino-substituted derivatives of isoquinoline, naphthyridine, quinazoline by palladium chemistry with a suitable palladium catalyst (Tris (dibenzylideneacetone) dipalladium (0); Pd ₂ (dba) ₃ ), ligand (2-dicyclohexylphosphino-2',6'diisopropoxybiphenyl); and a base (sodium tert-butoxide; NaOtBu) in a suitable solvent (1,4dioxane) to obtain, after purification, the desired compounds of formula (I). Alternatively, tricyclic building blocks containing an N-tosyl group in the indole/azaindole moiety have been cross-coupled with amino-substituted derivatives of benzo[d]thiazole, benzo[d]oxazole, thiazolo[5,4-b]pyridine (G =Py), thiazolo[4,5-b]pyridine (G=Py), thiazolo[5,4d]pyrimidine (O=pyrimidine), or amino-substituted derivatives [1,2,4]triazolo[1,5-a] pyridine, or amino-substituted derivatives of pyridine (L=Py), pyrazine (L=pyrazine), pyridazine (L=pyridazine), pyrimidine (L=pyrimidine) or amino-substituted derivatives of isoquinoline, naphthyridine, quinazoline by palladium chemistry with a suitable palladium catalyst (Tris

- 75 043389 (dibenzylideneacetone)dipalladium (0); Pd ₂ (dba) ₃ ), ligand (2-dicyclohexylphosphino-2',6'diisopropoxybiphenyl); and a weaker base (cesium carbonate; Cs ₂ CO ₃ ) in a suitable solvent (1,4-dioxane) to obtain N-tosyl-protected compounds after purification. The tosyl protecting group was then removed using a suitable base (cesium carbonate; Cs ₂ CO ₃ ) in a suitable solvent (2-methyl-THF, methanol) at elevated temperature (boiling) to obtain the desired compounds of formula (I) after purification.

Scheme 11

Tricyclic building blocks containing an N-tosyl group in the indole moiety were cross-coupled with dihalogenated benzo[d]thiazole and dihalogenated benzo[d]oxazole with a suitable base (potassium carbonate; K2CO3) in a suitable solvent (DMF), to obtain products of zeroophilic substitution. The product was then cross-coupled via palladium chemistry with a suitable palladium catalyst (tris(dibenzylideneacetone)dipalladium(0); Pd ₂ (dba) ₃ ), ligand (2-dicyclohexylphosphino-2',6'diisopropoxybiphenyl; RuPhos) and base ( sodium tert-butoxide; NaOtBu) in a suitable solvent (1,4-dioxane) to obtain, after purification, the desired compounds of formula (I).

General synthesis scheme for the preparation of tritium-labeled compounds of this invention.

Scheme 12

The catalyst was added to the reaction vessel with tritium, followed by the addition of a solution of the compound of the present invention in dichloromethane. The vessel was connected to the tritium line and was pressurized with tritium gas at -200°C. The solution was stirred for 8 hours at room temperature, cooled to -200°C, and excess gas was removed. The reaction flask was rinsed with methanol and the combined organic phase was evaporated in vacuo. The crude material was purified by HPLC, the mobile phase was evaporated in vacuo, and the product was redissolved in absolute ethanol. Specific activity was determined by mass spectrometry.

The breakdown of K18 Tau and full length Tau (fl) can be measured using any suitable assay known in the art. A standard in vitro assay for measuring disaggregation ability is described.

Examples

All reagents and solvents were obtained from commercial sources and were used without further purification. ^1H -NMR spectra were recorded on Bruker AV 300 and 400 MHz spectrometers in deuterated solvents. Chemical shifts (δ) are presented in ppm and coupling constants (J values) are in hertz. Spin multiplicities are denoted by the following symbols: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), bs (broad singlet). Mass spectra were obtained on an Agilent 1290 Infinity II spectrometer with Chemstation 6130 and on an Agilent 1200 Infinity II spectrometer with Chemstation 6130. GC-MS data were collected using an Agilent 7890B gas chromatograph and a 5977B mass spectrometer. Infrared spectra were obtained on a PerkinElmer spectrometer. Chromatography was carried out using silica gel (Fluka: silica gel 60, 0.063-0.2 mm) and suitable solvents as indicated in the specific examples. Flash purification was performed using Biotage Isolera with HP-Sil or KP-NH SNAP cartridges (Biotage), and the solvent gradient was specified in the specific examples. Thin layer chromatography (TLC) was performed on silica gel plates with UV detection.

- 76 043389

Preparative example 1.

Stage A.

Conc. H2SO4 (1 ml) at ice bath temperature. The reaction mixture was heated at 110°C for 3 hours. The reaction mixture was cooled to room temperature, and the precipitate was filtered off. The solid was dissolved in water, made basic with NaOH solution and extracted with DCM (dichloromethane). The organic phase was separated and dried over Na ₂ SO ₄ and the solvent was removed to give the title compound as a pale yellow solid (950 mg, 59%).

MS: 191 (M+H)+.

'H-NMR (400 MHz, DMSO-d ₆ ) δ=10.91 (s, 1H), 7.23-7.24 (m, 1H), 7.09-7.09 (m, 1H), 6.80-6.81 (m, 1H), 3.91 (s, 2H), 3.11 (t, J=5.56 Hz, 2H), 2.75 (d, J=4.96 Hz , 2H).

Stage B.

To a solution of the title compound from Step A above (0.95 g, 4.77 mmol) in THF (tetrahydrofuran) was added di-tert-butyl dicarbonate (Boc ₂ O) (1.5 g) and the mixture was stirred overnight . Once the reaction was complete as indicated by TLC, the solvent was removed and the crude reaction mixture was purified on a silica gel column using a Biotage Isolera One purification system using an EtOAc/heptane gradient (20/80^80/20) to give the title compound in the form of a sticky pale yellow liquid (1.1 g, 78%).

MS: 291 (M+H) ⁺ .

'H-NMR (400 MHz, DMSO-d6) δ=11.00 (s, 1H), 7.26 (q, J=4.52 Hz, 1H), 7.18 (t, J=8.12 Hz, 1H), 6.836.83 (m, 1H), 4.49 (s, 2H), 3.69 (t, J=5.64 Hz, 2H), 2.76 (s, 2H), 1, 43 (s, 9H).

Stage C.

To a solution of the title compound from Step B above (0.41 g, 1.41 mmol) in THF (5 ml) was added sodium hydride (0.15 g, 6.25 mmol) followed by p-toluenesulfonyl chloride (TsCl) (0.29 g, 1.45 mmol). The reaction mixture was stirred for 10 minutes. The mixture was dissolved in EtOAc (20 ml) and washed with water and brine, and dried over Na ₂ SO ₄ . The crude product was purified on a silica gel column using the Biotage Isolera One purification system using an EtOAc/heptane gradient (20/80^80/20) to give the title compound (0.45 g, 72%).

MS: 445 (M+H) ⁺ .

'H-NMR (400 MHz, DMSOD ₆ ) δ=8.03-8.04 (m, 1H), 7.77 (d, J=8.20 Hz, 2H), 7.36-7.38 ( m, 3H), 7.157.16 (m, 1H), 4.43 (s, 2H), 3.69 (t, J=5.64 Hz, 2H), 3.08 (s, 2H), 2, 32 (s, 3H), 1.43 (s, 9H).

Stage D

To a solution of the title compound from Step C above (0.42 g, 0.915 mmol) in dichloromethane was added 2N HCl (5 mL) in 1,4-dioxane. The reaction mixture was stirred overnight. After completion of the reaction, the reaction mixture was evaporated to remove the solvent and washed with diethyl ether to obtain the title compound as a white metallic solid (0.2 g, 58%).

MS: 345 (M+H) ⁺ .

'H-NMR (400 MHz, DMSO-d ₆ ) δ=9.61 (s, 1H), 8.01-8.02 (m, 1H), 7.82 (d, J=8.40 Hz, 2H), 7.45-7.45 (m, 1H), 7.39 (d, J=8.40 Hz, 2H), 7.20-7.21 (m, 1H), 4.25 (s , 2H), 3.49 (s, 2H), 3.35 (d, J=3.60 Hz, 2H), 2.34 (s, 3H).

Stage E.

To a solution of the title compound from Step D above (5.0 g, 13 mmol) in dichloromethane (50 ml) was added triethylamine (5 ml) and stirred for 10 minutes. The reaction mixture was diluted with dichloromethane (20 ml), washed with water (2x30 ml) and saturated NaCl solution (30 ml). The combined organic layer was dried over sodium sulfate and concentrated in vacuo to give the title compound as the free base (quantitative yield).

- 77 043389

Preparative example 2.

HCI/DXM ~ ΊΓΥλ-/ x Hei

Stage B\-N

P2'

Stage A.

To a solution of the title compound from Preparation 1, Step B (0.41 g, 1.41 mmol) in THF (5 ml) was added sodium hydride (0.067 g, 2.82 mmol) and the suspension was stirred at room temperature for 20 min. The reaction mixture was cooled again to 0°C and methyl iodide (0.24 g, 1.45 mmol) was added. The reaction mixture was stirred for 3 hours. The reaction mixture was dissolved in EtOAc (15 ml) and washed with water and brine and dried over Na ₂ SO ₄ . The crude product was purified on a silica gel column using the Biotage Isolera One purification system using an EtOAc/hexane gradient (20/80^80/20) to give the title compound (0.3 g, 70%). MS: 304 (M+H)+.

'H-NMR (400 MHz, DMSO-d ₆ ) δ=7.38-7.39 (m, 1H), 7.22 (dd, J=2.40, 10.00 Hz, 1H), 6, 90-6.91 (m, 1H), 4.49 (s, 2H), 3.71 (t, J=6.00 Hz, 2H), 3.62 (s, 3H), 2.79 (t , J=5.20 Hz, 2H), 1.40 (s, 9H).

Stage B.

To a solution of the title compound from Step A above (0.3 mg, 0.986 mmol) in dichloromethane was added 2N HCl (5 mL) in 1,4-dioxane. The reaction mixture was stirred overnight. The reaction mixture was evaporated to remove the solvent and washed with diethyl ether to give the title compound as a white metallic solid (0.12 g, 60%).

MS: 205.08 (M+H) ⁺ .

'H-NMR (400 MHz, DMSO-d ₆ ) δ=9.45 (br, 1H), 7.45-7.46 (m, 1H), 7.30-7.31 (m, 1H), 6.98-7.00 (m, 1H), 4.26 (s, 2H), 3.66 (s, 3H), 3.49 (d, J=4.80 Hz, 2H), 3.06 (t, J=6.00 Hz, 2H), 2.50 (s, 9H).

Preparative example 3.

Stage A RD

Stage A.

To a solution of 1-(4-fluorophenyl)-1-methylhydrazine (2 g, 14.0 mmol) and tert-butyl-4-oxopiperidine-1-carboxylate (2.84 g, 14.0 mmol) in 1,4-dioxane ( 10 ml) and added conc. H ₂ SO ₄ (1 ml) at ice bath temperature. The reaction mixture was then heated at 110°C overnight. The reaction mixture was cooled to room temperature, and the precipitate was filtered off. The filtrate was discarded. The solid was dissolved in water (10 ml), the pH was adjusted to 14 with NaOH solution and the mixture was extracted with dichloromethane (150 ml).

The organic phase was washed with water and brine and dried over Na ₂ SO ₄ .

The solvent was removed to give the title compound as the free base (1.3 g, 46%).

MS: 205.08 (M+H) ⁺ .

Preparative example 4.

Stage A.

Conc. . H ₂ SO ₄ (1 ml) at ice bath temperature. Then the reaction mixture was heated at 110°C for 3 hours. The reaction mixture was cooled to room temperature, and the precipitate was filtered off. The solid was dissolved in water, made basic with NaOH solution and extracted with dichloromethane. The organic phase was separated and dried over Na ₂ SO ₄ , filtered and the solvent was removed to give the title compound as a pale yellow sticky liquid (0.60 g, 53%). The crude product was taken as such for the next

- 78 043389 stages.

MS: 203 (M+H)+.

Stage B.

To a solution of the title compound from Step A above (0.60 mg, 2.9 mmol) in THF was added di-tert-butyl dicarbonate (0.65 g, 2.9 mmol) and the mixture was stirred overnight. The solvent was removed and the crude product was purified on a silica gel column using the Biotage Isolera One purification system using an EtOAc/Ahexane (80/20) gradient to give the title compound as a pale yellow solid (0.55 g, 62%).

MS: 303 (M+H)+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ=10.71 (bs, 1H), 7.17 (d, J=8.40 Hz, 1H), 6.89 (s, 1H), 6 .65-6.66 (m, 1H), 4.49 (s, 2H), 3.75 (s, 3H), 3.69 (t, J=5.60 Hz, 2H), 2.74 ( t, J=5.60 Hz, 2H), 1.44 (s, 9H).

Stage C.

To a solution of the title compound from Step B above (0.55 g, 1.8 mmol) in THF (5 mL) was added sodium hydride (0.087 g, 3.6 mmol), followed by p-toluenesulfonyl chloride (0.342 g, 1 .8 mmol). The reaction mixture was stirred for 45 minutes. After completion of the reaction, the reaction mixture was dissolved in EtOAc (200 ml) and washed with water and brine and dried over Na ₂ SO ₄ . The crude product was purified on a silica gel column using the Biotage Isolera One purification system using a 20/80 EtOAc/hexane gradient to give the title compound as a white metallic solid (0.45 g, 45%). MS: 457 (M+H)+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ=7.92 (d, J=9.20 Hz, 1H), 7.71 (d, J=8.40 Hz, 2H), 7.35 (d, J=8.00 Hz, 2H), 7.01 (s, 1H), 6.91-6.92 (m, 1H), 4.42 (s, 2H), 3.77 (s, 3H), 3.68 (t, J=5.60 Hz, 2H), 3.05 (bs, 2H), 2.31 (s, 3H), 1.43 (s, 9H).

Stage D

To a solution of the title compound from Step C above (0.450 g, 0.986 mmol) in dichloromethane was added 2N HCl (5 mL) in 1,4-dioxane. The reaction mixture was stirred overnight. After completion of the reaction, the reaction mixture was evaporated to remove the solvent and washed with diethyl ether to give the compound as a white metallic solid (0.23 g, 65%).

MS: 357 (M+H)+.

¹ H-NMR (400 MHz, DMSO-d6) δ=9.67 (bs, 1H), 7.89 (d, J=9.20 Hz, 1H), 7.77 (d, J=8.40 Hz, 2H), 7.36 (d, J=8.00 Hz, 2H), 7.11 (d, J=2.40 Hz, 1H), 6.93-6.94 (m, 1H), 4.24 (s, 2H), 3.77 (s, 3H), 3.48-3.49 (m, 2H), 3.343.35 (m, 2H), 2.33 (s, 3H).

Preparative example 5.

Stage A.

To a solution of the title compound of Preparation 4, Step B (0.55 g, 1.8 mmol) in THF (5 mL) was added sodium hydride (0.087 g, 3.6 mmol) at 0°C. The suspension was stirred at room temperature for 20 minutes. The reaction mixture was again cooled to 0°C and methyl iodide (0.255 g, 1.8 mmol) was added. The reaction mixture was stirred for 45 minutes. After completion of the reaction, the reaction mixture was dissolved in EtOAc (20 ml) and washed with water and brine, and dried over Na2SO4, filtered and concentrated. The crude mixture was purified on a silica gel column using a Biotage Isolera One purification system using an EtOAc/hexane (80/20) gradient to give the title compound as a light brown solid (0.40 g, 45%).

MS: 317 (M+H)+.

1H-NMR (400 MHz, DMSO) δ=7.29 (d, J=8.80 Hz, 2H), 6.93 (s, 1H), 6.72-6.73 (m, 1H), 4 .50 (s, 2H), 3.76 (s, 3H), 3.70-3.72 (m, 2H), 3.59 (s, 3H), 2.78-2.79 (m, 2H ), 1.44 (s, 9H).

Stage B.

To a solution of the title compound from Step A above (0.4 g, 1.26 mmol) in dichloromethane was added 2N HCl (5 mL) in 1,4-dioxane. The reaction mixture was stirred overnight. After completion of the reaction, the reaction mixture was evaporated to remove the solvent and washed with diethyl ether to obtain the title compound as a white solid (0.2 g, 73%).

MS: 217 (M+H)+.

- 79 043389

Preparative example 6.

Stage A.

A mixture of 2-chloro-5-fluoropyridine (10 g, 76.34 mmol) and N-ethylhydrazine (6 ml) was irradiated at 180°C for 1 hour in a microwave oven. After completion of the reaction, the reaction mixture was cooled and the reaction mixture was poured into ice water and extracted with dichloromethane (2x50 ml). The organic phase was separated and dried over Na ₂ SO ₄ and the solvent was removed to give the title compound as a pale brown solid (10 g, crude). The crude product was taken as such for the next step. MS: 143 (M+H)+.

Stage B.

To a solution of the title compound from Step A above (10 g, 70.84 mmol) in methanol (100 ml) was added tert-butyl-4-oxopiperidine-1-carboxylate (16.9 g, 85 mmol) and stirred for nights. The solvent was removed and the crude reaction mixture was purified on a silica gel column using a Biotage Isolera One purification system using a methanol/DCM gradient (1/99) to give the title compound as a brown sticky oil (5 g, 22%).

MS: 323 (M+H)+.

¹ H-NMR (400 MHz, DMSO-I6) δ=7.82-7.84 (m, 1H), 7.13-7.14 (m, 1H), 6.72-6.73 (m, 1H), 4.51 (bs, 2H), 3.77 (s, 3H), 3.71-3.73 (m, 2H), 2.76-2.78 (m, 2H), 1.43 (s, 9H).

Stage C.

A mixture of the title compound from Step B above (5 g, 15.50 mmol) and diethylene glycol (5 ml) was irradiated at 180° C. for 1 hour in a microwave oven. After completion of the reaction, the reaction mixture was cooled and the reaction mixture was poured into ice water and extracted with dichloromethane (2x50 ml). The organic phase was separated and dried over Na ₂ SO ₄ and the solvent was removed, the crude mixture was purified by preparative HPLC (column: Phenomenex Gemini C18 (150x4.6) mm, 3.0 μm). Mobile phase A: 10 mM ammonium acetate in Milli-Q water. Mobile phase B: acetonitrile. Flow rate: 1.0 ml/min) to obtain the title compound as a brown solid (0.9 g, 29%).

MS: 206 (M+H)+.

¹ H-NMR (400 MHz, DMSO-th ₆ ) δ=7.87-7.89 (m, 1H), 7.46-7.47 (m, 1H), 4.53 (bs, 2H), 3.77 (s, 3H), 3.713.73 (m, 2H), 2.76-2.78 (m, 2H).

Preparative example 7.

Stage A.

To a solution of 3-(fluorophenyl)hydrazine (1 g, 6.1 mmol) and tert-butyl-4-oxopiperidine-1-carboxylate (1.2 g, 6.1 mmol) in 1,4-dioxane (10 ml) added conc. H ₂ SO ₄ (1 ml) at 0°C. The reaction mixture was then heated to 25°C and heated at 110°C for 3 hours. The reaction mixture was cooled to room temperature and the precipitate was filtered off. The solid was dissolved in water, made basic with NaOH solution and extracted with dichloromethane. The organic phase was separated and dried over Na2SO4 and the solvent was removed to give a mixture of regioisomers as a pale yellow solid (0.65 g,

56%). MS: 191.1 (M+H)+.

¹ H-NMR (400 MHz, DMSO-d6) δ=10.87 (bs, 1H), 7.26-7.30 (m, 1H), 7.02-7.05 (m, 1H), 6 .74-6.79 (m, 1H), 3.83 (bs, 2H), 2.99-3.02 (m, 2H), 2.65-2.66 (m, 2H).

Stage B.

Di-tert-butyl dicarbonate (0.757 g, 3.47 mmol) was added to a solution of the regioisomer mixture (0.65 g, 3.15 mmol) in THF and the mixture was stirred for 12 hours. After completion of the reaction (monitored by TLC) the solvent was concentrated under reduced pressure to obtain the crude product. This was purified by silica gel column chromatography (60-120 mesh) using hexane:EtOAc (70:30) to give a mixture of tert-butyl-7-fluoro-1,3,4,5-tetrahydro-2Hpyrido[4,3] regioisomers -b]indole-2-carboxylate and tert-butyl-9-fluoro-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2carboxylate as a yellow solid (0.750 g, 61%) in a ratio of ~ 70:30, respectively.

MS: 291.2 (M+H) ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ) 6=11.01 (bs, 1H), 7.36-7.39 (m, 1H), 7.06-7.09 (m, 1H), 6.79-6.84 (m, 1H), 4.51 (bs, 2H), 3.68-3.71 (m, 2H), 2.74-2.76 (m, 2H), 1. 38 (s, 9H).

Stage C.

A mixture of regioisomers (0.750 mg, 70:30) was separated using a chiral SFC column (Chiracel OJH; column: X-bridge C8 (50x4.6) mm, 3.5 μm, mobile phase A: 0.1% TFA in water, mobile phase B: 0.1% TFA in acetonitrile), yielding the second eluted title compound tert-butyl7-fluoro-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2- carboxylate as a pale yellow solid with 100% chiral purity (0.4 mg, 53%). The first eluted title compound, tert-butyl-9-fluoro-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate, was isolated as a pale yellow solid with 100 % chiral purity (0.25 g, 33%).

Second title compound eluted:

MS: 291.2 (M+H) ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ) 6=11.01 (bs, 1H), 7.36-7.39 (m, 1H), 7.06-7.09 (m, 1H), 6.79-6.84 (m, 1H), 4.51 (bs, 2H), 3.68-3.71 (m, 2H), 2.74-2.77 (m, 2H), 1. 44 (s, 9H).

RT=2.08 min.

First title compound eluted:

MS: 291.2 (M+H) ⁺ .

¹ H-NMR (400 MHz, DMSO-d6) 6=11.22 (s, 1H), 7.13 (d, J=8.08 Hz, 1H), 6.96-6.97 (m, 1H ), 6.69-6.71 (m, 1H), 4.63 (s, 2H), 3.69-3.70 (m, 2H), 2.68-2.76 (m, 2H), 1.44(s,9H).

RT=1.74 min.

Stage D

To a solution of the second elutable title compound from Step C above (0.4 g, 1.37 mmol) in THF (5 mL) was added sodium hydride (0.099 mg, 4.137 mmol) followed by ptoluenesulfonyl chloride (0.288 g, 1.51 mmol). The reaction mixture was stirred for 30 minutes. The mixture was dissolved in EtOAc (20 ml) and washed with water and brine and dried over Na ₂ SO ₄ . The crude product was purified on a silica gel column using a Biotage Isolera One purification system using an EtOAc/heptane gradient (20/80^80/20) to give the title compound (0.3 g, 49%).

MS: 445 (M+H) ⁺ .

¹ H-NMR (400 MHz, chloroform-chloroform-d) 6=7.92-7.94 (m, 1H), 7.68-7.70 (m, 1H), 7.25-7.29 ( m, 4H), 7.00-7.04 (m, 1H), 4.50 (bs, 2H), 3.76 (bs, 2H), 3.12 (bs, 2H), 2.38 (s , 3H), 1.51 (s, 9H).

Stage E.

To a solution of the title compound from Step D above (0.3 g, 0.676 mmol) in dichloromethane was added 2N HCl (5 mL) in 1,4-dioxane. The reaction mixture was stirred for 12 hours. After completion of the reaction, the reaction mixture was evaporated to remove the solvent and washed with diethyl ether to obtain the title compound as a white metallic solid (0.2 g 78%).

MS: 345 (M+H) ⁺ .

¹ H-NMR (400 MHz, DMSO-d6) 6=9.50 (bs, 2H), 7.80-7.87 (m, 2H), 7.78 (d, J=2.00 Hz, 1H ), 7.57-7.61 (m, 1H), 7.40 (d, J=8.16 Hz, 2H), 7.18-7.23 (m, 1H), 4.27 (bs, 2H), 3.56 (bs, 2H), 3.47 (bs, 2H), 2.34 (s, 3H).

- 81 043389

Preparative example 8.

1. NaH, THF Stage D

2.Tos-CI

Stage A.

To a solution of (2-chloro-3-fluorophenyl)hydrazine (10 g, 62.5 mmol) and tert-butyl-4-oxopiperidine-1-carboxylate (12 g, 62.5 mmol) in 1,4-dioxane (100 ml) added conc. H2SO4 (10 ml) at 0°C. The reaction mixture was then heated to 25°C and heated at 110°C for 3 hours. The reaction mixture was cooled to room temperature and the precipitate was filtered off. The solid was dissolved in water, made basic with NaOH solution and extracted with dichloromethane. The organic phase was separated and dried over Na ₂ SO ₄ and the solvent was removed to give the title compound as a pale yellow solid (10 g, 72%).

MS: 225 (M+H)+.

¹ H-NMR (400 MHz, DMSO-d6) δ=11.23 (bs, 1H), 7.27-7.28 (m, 1H), 6.94-6.96 (m, 1H), 3 .82 (s, 2H), 2.98-3.00 (m, 2H), 2.68 (d, J=4.72 Hz, 2H).

Stage B.

To a solution of the title compound from Step A above (10 g, 44.5 mmol) in THF (100 ml) was added di-tert-butyl dicarbonate (10.5 g, 46.5 mmol) and the mixture was stirred for 12 hours. After completion of the reaction (monitored by TLC), the solvent was concentrated under reduced pressure to obtain the crude product. This was purified by silica gel column chromatography (60-120 mesh) to give the title compound as a yellow solid (12 g, 85%).

MS: 325.1 (M+H) ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ=11.43 (s, 1H), 7.36-7.38 (m, 1H), 6.97-7.00 (m, 1H), 4 .51 (s, 2H), 3.683.69 (m, 2H), 2.76-2.78 (m, 2H), 1.43 (s, 9H).

Stage C.

To a solution of the title compound from Step B above (5 g, 15.3 mmol) in dry methanol (50 ml) was added triethylamine (6.74 ml, 46.18 mmol) and 10% Pd/C (0.2 mg , 20 wt.%). Hydrogenation was carried out under 10 bar for 16 hours. The reaction mixture was filtered through a pad of celite and concentrated in vacuo to give the title compound (4 g, 90%).

MS: 291.2 (M+H) ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ=11.01 (bs, 1H), 7.36-7.39 (m, 1H), 7.06-7.09 (m, 1H), 6 .79-6.84 (m, 1H), 4.51 (bs, 2H), 3.68-3.71 (m, 2H), 2.74-2.77 (m, 2H), 1.44 (s, 9H).

Stage D

To a solution of the title compound from Step C above (4 g, 13.7 mmol) in THF (40 mL) was added sodium hydride (9.9 g, 41.23 mmol), followed by p-toluenesulfonyl chloride (2.88 g, 15.1 mmol). The reaction mixture was stirred for 30 minutes. The mixture was dissolved in EtOAc (200 ml) and washed with water and brine, and dried over Na ₂ SO ₄ . The crude product was purified on a silica gel column using a Biotage Isolera One purification system using an EtOAc/heptane gradient (20/80 >80/20) to give the title compound (5 g, 82%).

MS: 445 (M+H) ⁺ .

1H-NMR (400 MHz, chloroform-d) δ=7.92-7.94 (m, 1H), 7.68-7.70 (m, 1H), 7.25-7.29 (m, 4H ), 7.00-7.04 (m, 1H), 4.50 (bs, 2H), 3.76 (bs, 2H), 3.12 (bs, 2H), 2.38 (s, 3H) , 1.51 (s, 9H).

Stage E.

To a solution of the title compound from Step D above (3 g, 6.76 mmol) in dichloromethane (30 ml) was added 2N HCl (15 ml) in 1,4-dioxane. The reaction mixture was stirred for 12 hours. After completion of the reaction, the reaction mixture was evaporated to remove the solvent and washed with diethyl ether to obtain the title compound as a white metallic solid (2 g, 78%).

MS: 345 (M+H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ=9.50 (bs, 2H), 7.80-7.87 (m, 2H), 7.78 (d, J=2.00 Hz, 1H ), 7.57-7.61 (m, 1H), 7.40 (d, J=8.16 Hz, 2H), 7.18-7.23 (m, 1H), 4.27 (bs, 2H), 3.56 (bs, 2H), 3.47 (bs, 2H), 2.34 (s, 3H).

- 82 043389

Receipt example 9.

Stage A.

To a solution of the title compound of Preparation 8, Step C (0.4 mg, 1.37 mmol) in THF (5 ml) was added sodium hydride (0.099 g, 4.137 mmol) followed by methyl iodide (0.102 ml, 1. 64 mmol). The reaction mixture was stirred for 2 hours. The mixture was dissolved in EtOAc (20 ml) and washed with water and brine and dried over Na ₂ SO ₄ . The crude product was purified on a silica gel column using the Biotage Isolera One purification system using a gradient

EtOAc/heptane (20/80^80/20) to give the title compound (0.3 mg, 73%).

MS: 305.37 (M+H)+.

Stage B.

To a solution of the title compound from Step A above (0.3 mg, 0.986 mmol) in dichloromethane was added 2N HCl (5 mL) in 1,4-dioxane. The reaction mixture was stirred overnight. After completion of the reaction, the reaction mixture was evaporated to remove the solvent and washed with diethyl ether to obtain the title compound as a white metallic solid (0.18 g, 75%).

MS: 205 (M+H)+.

Preparative example 10.

Stage A.

To a solution of the first eluted title compound from Preparation 7, Step C (0.2 mg, 0.67 mmol) in THF (5 mL) was added sodium hydride (0.048 g, 2.137 mmol), followed by p-toluenesulfonyl chloride (0.144 g, 0.76 mmol). The reaction mixture was stirred for 30 minutes. The mixture was dissolved in EtOAc (20 ml) and washed with water and brine and dried over Na ₂ SO ₄ . The crude product was purified on a silica gel column using the Biotage Isolera One purification system using an EtOAc/heptane gradient (20/80^80/20) to give the title compound (0.155 g, 50%).

MS: 445 (M+H)+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ=7.80-7.82 (m, 3H), 7.31-7.32 (m, 3H), 7.07-7.09 (m , 1H), 4.56 (s, 2H), 3.68-3.69 (m, 2H), 3.09 (bs, 2H), 2.33 (s, 3H), 1.43 (s, 9H).

Stage B.

To a solution of the title compound from Step A above (0.15 g, 0.337 mmol) in dichloromethane was added 2N HCl (5 mL) in 1,4-dioxane. The reaction mixture was stirred for 12 hours. After completion of the reaction, the reaction mixture was evaporated to remove the solvent and washed with diethyl ether to obtain the title compound as a white metallic solid (0.1 g, 71%).

MS: 345 (M+H)+.

1H-NMR (400 MHz, DMSO-06) δ=9.49 (bs, 2H), 7.85-7.87 (m, 3H), 7.35-7.36 (m, 3H), 7, 12-7.14 (m, 1H), 4.39 (s, 2H), 3.48 (bs, 2H), 3.17 (bs, 2H), 2.35 (s, 3H).

Preparative example 11.

Stage A.

N-Hydroxyphthalimide (7.34 g, 45.03 mmol), copper(I) chloride (2.22 g, 22.51 mmol), pyridine (2.75 ml, 33.75 mmol), molecular sieves (5 g), and the reaction mixture was heated to 70°C for 12 hours. After completion of the reaction, the reaction mixture was filtered through a pad of celite and washed

- 83 043389 ethyl acetate. The ethyl acetate layer was concentrated and the crude product was purified on silica gel using the Biotage Isolera One purification system using a hexane/EtOAc gradient (90/10^80/20) to give the title compound as a white solid (1.4 g, 24%).

MS: 258.22 (M+H)+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) 5=7.92-7.93 (m, 4H), 7.33-7.34 (m, 2H), 7.20-7.22 (m , 2H).

Stage B.

To a solution of the title compound from Step A above (1.4 g, 5.44 mmol) in chloroform:methanol (9:1, 100 ml) was added hydrazine hydrate (0.81 g, 16.32 mmol), and the reaction mixture was stirred at 25°C for 12 hours. After completion of the reaction, the reaction mixture was filtered through a pad of celite and washed with dichloromethane. The dichloromethane layer was concentrated and the crude product was added to ether (5 ml) and 2N HCl in ether (2 ml) at 0°C, then the reaction mixture was stirred at 25°C for 30 minutes. After completion of the reaction, the reaction mixture was filtered, dried in vacuo to obtain a white metallic solid (0.44 g, 50%).

MS: 128.12 (M+H) ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ=8.03-8.04 (m, 2H), 7.76-7.76 (m, 2H).

Stage C.

To a solution of the title compound from Step B above (0.44 g, 2.7 mmol) and 1,4-dioxa-8azaspiro[4,5]decane (0.44 g, 3.07 mmol) in 1.4 -dioxane (5 ml) was added conc. H2SO4 (0.5 ml) at 0°C. The reaction mixture was heated to 25°C and then further heated at 150°C for 1 hour under microwave conditions. The reaction mixture was cooled to 25°C, and the precipitate was filtered off. The solid was dissolved in water, made basic with NaOH solution and extracted with dichloromethane. The organic phase was separated and dried over Na ₂ SO ₄ and the solvent was concentrated, the crude product being taken as such for the next step (0.270 g, 52%).

MS: 192.21 (M+H) ⁺ .

Preparative example 12.

m ns|/dioxane

CH ₂ C| ₂

Stage D

Stage A.

To a solution of 4-(fluorophenyl)hydrazine hydrochloride (10 g, 0.061 mol) and tert-butyl-3-oxo-8azabicyclo[3.2.1]octane-8-carboxylate (13.9 g, 0.61 mol) in 1, 4-dioxane (100 ml) was added conc. H ₂ SO ₄ (10 ml) at 0°C, and then the mixture was heated to 100°C for 12 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and the solvent was removed under high vacuum to obtain the crude material. The crude material was made alkaline using 30% sodium hydroxide solution and the solid precipitated. The precipitated solid was filtered, washed with water (100 mL) and diethyl ether (100 mL), then the solid was dried in vacuo for 16 hours to give the title compound as a light brown solid (11 g, 83%) .

MS: 216.10 (M+H) ⁺ .

Stage B.

To a solution of the title compound from Step A above (11 g, 0.051 mol) in THF (50 ml) was added triethylamine (11 ml, 0.076 mol) and di-tert-butyl dicarbonate (11.13 g, 0.051 mol) at 0° C and then stirred at room temperature for 12 hours. After completion of the reaction as evidenced by TLC, the solvent was removed and the crude reaction mixture was purified by a silica gel column using 40 to 50% ethyl acetate in petroleum ether to give the title compound as a pale yellow solid (7.4 g, 46%). MS: 316.15 (M+H) ⁺ .

1H-NMR (400 MHz, DMSO) 5=10.94 (bs, 1H), 7.23-7.24 (m, 2H), 6.80-6.81 (m, 1H), 5.09- 5.11 (m, 1H), 4.46 (bs, 1H), 3.23-3.27 (m, 1H), 2.51-2.57 (m, 1H), 2.22-2, 26 (m, 1H), 2.00-2.07 (m, 1H), 1.59-1.60 (m, 1H), 1.41-1.44 (m, 2H), 1.20- 1.27 (m, 9H).

Stage C.

To a solution of the title compound from Step B above (3 g, 0.009 mol) in THF (30 ml)

- 84 043389 sodium hydride (60% in mineral oil; 0.57 g, 0.014 mol) was added in portions at 0°C. After the addition was complete, the reaction mixture was left stirring at room temperature for 30 minutes, and then the reaction mixture was cooled again to 0°C. To this mixture was added dropwise p-toluenesulfonyl chloride (2.16 g, 0.11 mol) dissolved in THF (20 ml) at 0°C. After the addition was complete, the reaction mixture was left stirring at room temperature for 2 hours. After completion of the reaction, as indicated by TLC, the reaction mixture was cooled to 0°C and quenched with ice water, followed by extraction with ethyl acetate (100 ml). The ethyl acetate layer was washed with water (30 ml) and saline (30 ml). The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated to give the crude product, which was purified on a silica gel column using 15 to 25% ethyl acetate in petroleum ether to give the title compound as a white solid with a metallic tint ( 2.9 g, 65%).

MS: 470.16 (M+H)+.

Stage D

To a solution of the title compound from Step C above (2.9 g, 0.006 mol) in dichloromethane (10 ml) at 0° C. was added 4N HCl (20 ml) in 1,4-dioxane. The reaction mixture was left stirring at ambient temperature for 12 hours. After completion of the reaction, the reaction mixture was evaporated to remove the solvent and washed with diethyl ether (10 ml), giving the title compound as a white metallic solid (2.4 g, 98%).

MS: 370.15 (M+H)+.

¹ H-NMR (400 MHz, DMSO-d6) δ=8.07-8.08 (m, 1H), 7.78-7.80 (m, 1H), 7.30-7.31 (m, 3H), 7.10-7.11 (m, 1H), 5.13 (d, J=4.80 Hz, 1H), 4.52 (d, J=4.80 Hz, 1H), 3, 64-3.65 (m, 4H), 3.30-3.30 (m, 1H), 2.22-2.24 (m, 7H), 1.92 (bs, 1H).

Preparative example 13.

O ...N » ILM /° θ ¹ ^^ ⁸ CH ₂ Ci ₂ , TEA

Stage A P13

Stage A.

To a solution of 2,6-dichlorobenzo[d]thiazoleα (5 g, 24.5 mmol) in dry dichloromethane (50 ml) was added morpholine (3.19 g, 36.6 mmol) and the mixture was cooled to 0°C. Triethylamine (3.71 g, 36.7 mmol) was added dropwise to this cold reaction mixture and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was treated with H ₂ O (2x20 ml) and extracted with dichloromethane. The organic layer was separated, dried over Na2SO4, filtered and evaporated to give a white solid which was triturated with diethyl ether to give the title compound (5 g, 96%).

MS: 213.4 (M+H)+.

¹ H-NMR (400 MHz, DMSO-06) δ=7.80 (d, J=8.00 Hz, 1H), 7.53 (d, J=2.00 Hz, 1H), 7.13- 7.14 (m, 1H), 3.74-3.75 (m, 4H), 3.56-3.57 (m, 4H).

Preparative example 14.

Stage A.

To a solution of 2,5-dichlorobenzo[d]thiazoleα (5 g, 24.5 mmol) in dry dichloromethane (50 ml) was added morpholine (3.19 g, 36.6 mmol) and the mixture was cooled to 0°C. Triethylamine (3.71 g, 36.7 mmol) was added dropwise to this cold reaction mixture and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was treated with H2O (2x20 ml) and extracted with dichloromethane. The organic layer was separated, dried over Na2SO4, filtered and evaporated to give a white solid which was triturated with diethyl ether to give the title compound (4.5 g, 86%).

MS: 255.4 (M+H)+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ=7.82 (d, J=8.00 Hz, 1H), 7.50 (d, J=2.00 Hz, 1H), 7.11- 7.11 (m, 1H), 3.72-3.73 (m, 4H), 3.55-3.56 (m, 4H).

- 85 043389

Preparative example 15.

HN O

G G % ^C|

CH ₂ C1 ₂ , TEL

Stage A

Χ,-Ν /ELL R ⁰

P15

Stage A.

To a solution of 2,6-dichlorobenzo[d]oxazole (5 g, 26.8 mmol) in dry dichloromethane (50 ml) was added morpholine (3.50 g, 40.3 mmol) and the mixture was cooled to 0°C. Triethylamine (4.0 g, 39.6 mmol) was added dropwise to this cold reaction mixture and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was treated with H ₂ O (2x20 ml) and extracted with dichloromethane. The organic layer was separated, dried over Na ₂ SO ₄ , filtered and evaporated to give a white solid, which was triturated with diethyl ether to give the title compound (5 g, 78%).

MS: 239.2 (M+H)+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ=7.59 (d, J=2.80 Hz, 1H), 7.30 (d, J=11.20 Hz, 1H), 7.21 (dd, J=2.80, 11.20 Hz, IH), 3.71-3.74 (m, 4H), 3.57-3.60 (m, 4H).

Preparative example 16.

HN^0

Ck,~^ _N Ck^N

L l^ ^ci L G I

O CH ₂ CI ₂ , TEA%. ·

Stage A PI6

Stage A.

To a solution of 2,5-dichlorobenzo[d]oxazole (5 g, 26.8 mmol) in dry dichloromethane (50 ml) was added morpholine (3.50 g, 40.3 mmol) and the mixture was cooled to 0°C. Triethylamine (4.0 g, 39.6 mmol) was added dropwise to this cold reaction mixture and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was treated with H2O (2x20 ml) and extracted with dichloromethane. The organic layer was separated, dried over Na2SO4, filtered and evaporated to give a white solid which was triturated with diethyl ether to give the title compound (5.2 g, 81%).

MS: 239.2 (M+H)+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ=7.44 (d, J=8.40 Hz, IH), 7.36 (d, J=2.40 Hz, IH), 7.06 (dd, J=2.00, 8.40 Hz, 1H), 3.71-3.73 (m, 4H), 3.59-3.61 (m, 4H).

Preparative example 17.

_{CH2CI2 ,} ^TEACl

P17

N,>-N

S'

Stage A

Stage A.

To a solution of 2,6-dichlorobenzo[d]thiazoleα (5 g, 24.5 mmol) in dry dichloromethane (50 ml) was added 2M dimethylamine in THF (18.37 ml, 36.65 mol) and the mixture was cooled to 0° WITH. Triethylamine (6.8 mL, 49 mmol) was added dropwise to this cold reaction mixture and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was treated with H2O (2x20 mL) and extracted with dichloromethane. The organic layer was separated, dried over Na2SO4, filtered and evaporated to give a white solid which was triturated with diethyl ether to give the title compound (4.8 g, 94%).

MS: 213.4 (M+H)+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ=7.88 (d, J=2.10 Hz, 1H), 7.41 (d, J=8.70 Hz, IH), 7.25- 7.26 (m, IH), 3.14 (s, 6H).

Preparative example 18.

Η

ΪΎ ^ _Cl it

CH ₂ CI ₂ , TEA WS\

Stage A PI 8

Stage A.

To a solution of 2,5-dichlorobenzo[d]thiazole (5 g, 24.5 mmol) in dry dichloromethane (50 ml) was added 2M dimethylamine in THF (18.37 ml, 36.65 mol) and the mixture was cooled to 0° WITH. Triethylamine (6.8 mL, 49 mmol) was added dropwise to this cold reaction mixture and the mixture was left stirring at room temperature for 4 hours. After completion of the reaction, the reaction mixture was treated with H2O

- 86 043389 (2x20 ml) and extracted with dichloromethane. The organic layer was separated, dried over Na ₂ SO ₄ , filtered and evaporated to give a white solid, which was triturated with diethyl ether to give the title compound (4.5 g, 88%).

MS: 213.4 (M+H) ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ=7.77 (d, J=11.20 Hz, 1H), 7.46 (d, J=2.40 Hz, 1H), 7.05- 7.05 (m, 1H), 3.14 (s, 6H).

Preparative example 19.

Br ci

EtOH

Stage A

P19

Stage A.

To a solution of 6-bromo-2-chlorobenzo[d]thiazole (0.45 g, 1.81 mmol) in ethanol (12 ml) was added 2M dimethylamine (3 ml) and the mixture was heated for 60 min using a microwave oven Biotage at 100°C. The reaction mixture was cooled to room temperature. The solvent was removed and the crude product was purified on a silica gel column using a gradient of ethyl acetate and heptane (40/60^60/40) to give the title compound as a solid (0.441 g, 95%).

1H-NMR (400 MHz, Chloroform-d) δ=7.70 (d, J=1.9 Hz, 1H), 7.43 - 7.35 (m, 2H), 3.20 (s, 6H) .

Preparative example 20.

With Τχα

С1^°

_CH2CI2 , _TEACl

Stage A

P20

Stage A.

To a solution of 2,6-dichlorobenzo[d]oxazole (5 g, 26.6 mmol) in dry dichloromethane (50 ml) was added 2M dimethylamine in THF (26.6 ml, 53.2 mmol) and the mixture was cooled to 0° WITH. Triethylamine (5.6 mL, 39.9 mmol) was added dropwise to this cold reaction mixture and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was treated with H ₂ O (2x20 mL) and extracted with dichloromethane. The organic layer was separated, dried over Na ₂ SO ₄ , filtered and evaporated to give a white solid, which was triturated with diethyl ether to give the title compound (5 g, 96%).

MS: 197.2 (M+H) ⁺ .

¹ H-NMR (400 MHz, DMSO^) δ=7.56 (s, 1H), 7.23-7.24 (m, 1H), 7.16-7.16 (m, 1H), 3, 13 (s, 6H).

Preparative example 21.

Stage A.

To a solution of 2,5-dichlorobenzo[d]oxazole (5 g, 26.6 mmol) in dry dichloromethane (50 ml) was added 2M dimethylamine in THF (26.6 ml, 53.2 mmol) and the mixture was cooled to 0° WITH. Triethylamine (5.6 mL, 39.9 mmol) was added dropwise to this cold reaction mixture and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was treated with H ₂ O (2x20 mL) and extracted with dichloromethane. The organic layer was separated, dried over Na ₂ SO ₄ , filtered and evaporated to give a white solid, which was triturated with diethyl ether to give the title compound (4.9 g, 94%).

MS: 197.2 (M+H) ⁺ .

¹ H-NMR (400 MHz, DMSOC) δ=7.40 (d, J=8.40 Hz, 1H), 7.30 (d, J=2.00 Hz, 1H), 6.99-6, 99 (m, 1H), 3.13 (s, 6H).

Preparative example 22.

Stage A.

To a solution of 6-bromo-2-chlorobenzo^]thiazole (0.8 g, 3.2 mmol) in ethanol (12 ml) was added a solution of isopropylamine (1 ml) and the mixture was heated for 45 min using a Bio-microwave oven. 87 043389 tag at 100°C. The reaction mixture was cooled to room temperature. The solvent was removed and the crude product was crystallized from a mixture of EtOAc and n-heptane to give the title compound as a solid (0.663 g, 75.8%).

¹ H-NMR (400 MHz, Chloroform-d) δ=7.69 (t, J=1.3 Hz, 1H), 7.38 (d, J=1.3 Hz, 2H), 7.27 ( s, 1H), 5.515.26 (m, 1H), 3.92 (h, J=6.5 Hz, 1H), 1.33 (d, J=6.4 Hz, 6H).

Preparative example 23.

Stage A.

To a solution of 6-bromo-2-chlorobenzo^]thiazole (1 g, 4.0 mmol) in ethanol (6 ml), a solution of isopropylamine (1.5 ml) was added and the mixture was heated for 90 minutes using a Biotage microwave oven at 100°C. The reaction mixture was cooled to room temperature. The solvent was removed and the crude product was dissolved in dichloromethane (150 ml) and washed with 1 M NaOH, water and brine, and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure to give the crude product, which was purified on a silica gel column using a gradient of EtOAc and heptane (20/80^50/50) to give the title compound as a solid (0.35 g, 36% ).

¹ H-NMR (400 MHz, Chloroform-d) δ=7.72 (s, 1H), 7.41 (s, 1H), 7.29 (d, J=3.3 Hz, 1H), 5, 40 (s, 1H), 3.13 (s, 3H).

Preparative example 24.

Stage A.

To a solution of 5-bromo-2-chlorobenzo[d]thiazole (0.9 g, 3.62 mmol) in ethanol (12 ml) was added 4 M methylamine (1 ml) and the mixture was heated for 90 min using a microwave oven Biotage at 100°C. The reaction mixture was cooled to room temperature. The solvent was removed and the crude product was purified on a silica gel column using a gradient of EtOAc and heptane (20/80^50/50) to give the title compound as a solid (0.57 g, 65%).

1H-NMR (400 MHz, Chloroform-d) δ=7.68 (t, J=2.0 Hz, 1H), 7.46 (d, J=8.3 Hz, 1H), 7.22 (dd , J=8.4, 1.9 Hz, 1H), 5.90 (s, 1H), 3.13 (s, 3H).

Preparative example 25.

A JL ^z ^~ ^ci ---------** ί I ^z ^nh

Br^'N EtOH Br^-N

Stage A P25

Stage A.

To a solution of 5-bromo-2-chlorobenzo[d]thiazole (0.87 g, 3.5 mmol) in ethanol (12 ml) was added a solution of isopropylamine (1.5 ml) and the mixture was heated for 60 min using a microwave Biotage oven at 100°C. The reaction mixture was cooled to room temperature. The solvent was removed and the crude product was dissolved in dichloromethane (150 ml) and washed with 1 M NaOH, water and brine, and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure to give the crude product, which was purified on a silica gel column using a gradient of EtOAc and heptane (20/80^50/50) to give the title compound as a solid (0.75 g, 79% ).

¹ H-NMR (400 MHz, Chloroform-d) δ=7.67 (d, J=1.9 Hz, 1H), 7.43 (d, J=8.5 Hz, 1H), 7.19 ( dd, J=8.3, 1.9 Hz, 1H), 5.47 (s, 1H), 4.04 - 3.79 (m, 1H), 1.34 (d, J=6.5 Hz , 6H).

- 88 043389

Preparative example 26.

Stage A.

A solution of 5-bromo-3-iodopyridin-2-amine (5 g, 16.72 mmol) and benzoyl isothiocyanate (3.29 g, 20.07 mmol) in acetone (10 ml) was stirred at 60 °C for 12 h, the reaction was monitored by TLC. The solvent was evaporated and the solid was filtered, washed with n-hexane (200 ml) and dried to give the title compound as a white metallic solid (4 g, 52%).

MS: 461.5 (M+H)+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ=12.35 (s, 1H), 11.86 (s, 1H), 8.64-8.65 (m, 2H), 7.99- 7.99 (m, 2H), 7.67 (s, 1H), 7.56 (d, J=9.40 Hz, 2H).

Stage B.

To a solution of the title compound from Step A above (4 g, 12.1 mmol) in 1,4-dioxane (60 ml) was added potassium carbonate (2.5 g, 18.15 mmol), L-proline (0. 28 g, 2.43 mmol) and copper(I) iodide (0.462 g, 2.43 mmol). The reaction mixture was then stirred at 80°C for 16 hours, and the progress of the reaction was monitored by TLC. The reaction mixture was poured into 1.0 L of water and 1.0 L of an aqueous saturated solution of NH4Cl. The mixture was stirred at room temperature for 1 hour. The solid was filtered, washed with saturated aqueous NH4Cl (2x300 ml) and water (2x300 ml) and dried to give the title compound as a white metallic solid (2.5 g , unrefined). MS: 334.51 (M+H)+.

Stage C.

A suspension of the title compound from Step B above (2 g, 5.98 mmol) in 70% H ₂ SO ₄ (6 g, 3.0 vol) was heated at 120° C. for 2 hours. The reaction mixture was cooled to room temperature temperature, and the reaction mixture was slowly poured into 100 ml of cold water (0°C). The reaction mixture was then adjusted to alkaline pH by adding 50% aqueous NaOH. The compound was then extracted with EtOAc (6x150 ml). The combined organic layers were dried over Na ₂ SO ₄ and filtered, then the solution was concentrated to give the title compound as a light yellow solid (0.3 g, 23%).

MS: 230.4 (M) ⁺ .

1H-NMR (400 MHz, DMSO-b6) δ=8.27-8.31 (m, 2H), 8.11 (s, 2H).

Stage D

To a suspension of the title compound from Step C above (0.3 mg, 1.3 mmol) in acetonitrile (5 ml) at 0° C. was added tert-butyl nitrite (0.2 ml, 1.95 mmol) over 10 min. using a syringe. Copper(II) chloride (0.2 g, 1.56 mmol) was then added in portions. After 30 min at 0°C, the reaction mixture was allowed to warm to room temperature over 1 hour and warmed to 65°C, then stirred for 4 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the solvent was evaporated and the product was diluted with water (20 ml) and 5% MeOH/DCM (3x20 ml). The combined organic layers were washed with brine (10 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The crude compound was purified by silica gel column chromatography (60-120), eluting with 1% methanol/dichloromethane to give the title compound (0.15 g, 46%) as a white metallic solid.

MS: 250.9 (M+H)+.

¹ H-NMR (400 MHz, DMSO-06) δ=8.91 (d, J=2.40 Hz, 1H), 8.82 (d, J=1.60 Hz, 1H).

Stage E.

To a solution of the title compound from Step D above (0.18 g, 0.72 mmol) in dry dichloromethane (5 ml) was added triethylamine (0.3 ml, 2.16 mmol) and morpholine (0.074 g, 0.86 mmol), and the mixture was stirred at room temperature for 6 hours. The reaction mixture was concentrated in vacuo. The crude compound was purified by silica gel column chromatography (60-120), eluting with petroleum ether/ethyl acetate to give the title compound (0.18 g, 83%) in

- 89 043389 in the form of a yellow solid.

MS: 300.0 (M+H)+.

¹ H-NMR (400 MHz, DMSO-d6) δ=8.49 (d, J=2.00 Hz, 1H), 8.38 (d, J=1.60 Hz, 1H), 3.72- 3.74 (m, 4H),

3.61-3.62 (m, 4H).

Preparative example 27.

h ₂ n

HCl/boiling (reflux ^N condenser

Stage A

S -N ci ^{0 h} 2 ⁿ y IT —

CuBr ₂

Stage B

S Nci .0.

Step C ° _v “YJ Υ

P27

Stage A.

A solution of 2-bromo-6-chloropyridin-3-amine (5 g, 24.1 mmol) and potassium thiocyanate (7 g, 72.3 mmol) in ethanol (50 ml) and conc. hydrochloric acid (37%, 100 ml) was stirred at 100°C for 40-45 hours. Completion of the reaction was confirmed by TLC (PE/EA=7.5/2.5). The reaction mixture was cooled to room temperature and concentrated to give a brown solid, which was partitioned in dichloromethane (150 ml) and aqueous 1 N NaOH (50 ml). The solid was filtered and dried to give the title compound (3.5 g, 79% yield) as a light yellow solid.

MS: 186.1 (M+H)+.

Stage B.

To a suspension of the title compound from Step A above (1.5 g, 8.08 mmol) in acetonitrile (25 ml) at 0° C. was added tert-butyl nitrite (1.4 ml, 12.12 mmol) over 10 min. using a syringe. Copper(II) bromide (2.16 g, 9.69 mmol) was then added in portions. After 30 min at 0°C, the reaction mixture was allowed to warm to room temperature over 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the solvent was evaporated and the mixture was diluted with water (20 ml) and 5% MeOH/DCM (3x20 ml). The combined organic layers were washed with brine (10 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography (60-120) and eluted with 1% methanol/dichloromethane to give the title compound (0.65 g, 32%) as a pale yellow solid.

MS: 248.5 (M+H)+.

Stage C.

To a solution of the title compound from Step B above (0.65 g, 2.61 mmol) in dry dichloromethane (5 mL) was added triethylamine (1.1 mL, 7.83 mmol) and morpholine (0.34 g, 3 .91 mmol), and the mixture was stirred at room temperature for 6 hours. The reaction mixture was concentrated in vacuo. The crude compound was purified by silica gel column chromatography (60-120) eluting with petroleum ether/ethyl acetate to give the title compound (0.6 g, 90%) as a yellow solid.

MS: 256.0 (M+H)+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ=7.83 (d, J=8.40 Hz, 1H), 7.41 (d, J=8.44 Hz, 1H), 3.72 -3.74 (m, 2H), 3.59-3.60 (m, 2H).

Preparative example 28.

Stage A.

A mixture of 2,7-dibromo-[1,2,4]triazolo[1,5-a]pyridine (0.4 g, 1.44 mmol) and morpholine (4 ml) was refluxed for 4 h under atmosphere N2. The reaction mixture was concentrated to dryness. The crude compound was purified by silica gel column chromatography (60-120) eluting with 10-100% petroleum ether/ethyl acetate as eluent to give the title compound (0.27 g, 66%) as a white solid.

MS: 285.0 (M+H) ⁺ .

D-NMR (400 MHz, DMSO-d6) δ=8.64 (d, J=7.08 Hz, 1H), 7.83 (s, 1H), 7.13-7.14 (m, 1H) , 3.69-3.71 (m,

- 90 043389

2H), 3.45-3.46 (m, 2H).

Preparative example 29.

3,6-Dibromopyridazine (0.2 g, 0.841 mmol) was dissolved in acetonitrile (2.5 ml). Morpholine (0.110 ml, 1.261 mmol) and triethylamine (0.176 ml, 1.261 mmol) were then added and the suspension was irradiated in a microwave oven at 160°C for 1 hour and 20 minutes. The reaction mixture was diluted with dichloromethane and water. The organic layer was separated, and the aqueous layer was extracted with dichloromethane twice. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude product was purified on a silica gel column using a Biotage Isolera One purification system using an n-heptane/ethyl acetate gradient (100/0^0/100) to obtain the title compound as a white solid (0.168 g, 82%) .

MS: 245.2 (M+H)+.

¹ H-NMR (400 MHz, Chloroform-d) δ=7.35 (d, J=9.5 Hz, 1H), 6.79 (d, J=9.5 Hz, 1H), 3.88 - 3.79 (m, 4H), 3.66 - 3.55 (m, 4H).

Preparative example 30.

To a suspension of sodium hydride (0.0404 g, 1.682 mmol) in dry THF (3 ml) was added morpholine (0.146 ml, 1.682 mmol) under a nitrogen atmosphere at 0°C. The reaction mixture was stirred at 0°C for 15 min, then 2,5-dibromopyrazine (0.400 g, 1.682 mmol) dissolved in dry THF (3 ml) was added. The reaction mixture was left to stir at reflux overnight. It was quenched with water and the product was extracted three times with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude product was purified on a silica gel column using a Biotage Isolera One purification system using a ngeptane/ethyl acetate gradient (100/0^0/100) to obtain the title compound as a white solid (0.245 g, 60%).

¹ H-NMR (400 MHz, Chloroform-d) δ=8.15 (d, J=1.5 Hz, 1H), 7.86 (d, J=1.5 Hz, 1H), 3.89 - 3.76 (m, 4H), 3.60 - 3.45 (m, 4H).

Preparative example 31.

Stage A.

Iron (15.47 g, 277 mmol) was added to a hot solution of 2-chloro-5-nitro-4-thiocyanatopyrimidine (10 g, 46.2 mmol) in acetic acid (264 mL, 4617 mmol) at 120°C. The mixture was stirred for 1 hour at the same temperature. The mixture was allowed to cool to room temperature and insoluble material was removed by filtration and washed with acetic acid. The filtrate was concentrated under reduced pressure and dissolved in THF (200 ml) and EtOAc (400 ml) and washed with saturated aqueous NH ₄ Cl (100 ml), saturated NaHCO ₃ solution (100 ml), dried over Na ₂ SO ₄ and the solvent was removed under reduced pressure to obtain the title compound (6.82 g, 79%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ=9.42 (s, 1H).

Stage B.

To a suspension of the title compound from Step A above (8.2 g, 43 mmol) in acetonitrile (20 ml) at 0° C. was added tert-butyl nitrite (6.8 g, 65.9 mmol) over 30 minutes. Copper(II) bromide (11.78 g, 52.8 mmol) was then added in portions. After 30 minutes at 0°C, the reaction mixture was allowed to warm to room temperature and stirred for 12 hours. Water (50 ml) and EtOAc (100 ml) were added and the phases were separated. The aqueous layer was extracted twice with EtOAc, the organic layers were combined, dried over Na ₂ SO ₄ and the solvent was evaporated under reduced pressure. The residue was purified on HPSil SNAP cartridges using the Biotage Isolera One purification system using EtOAc/n-heptane (20/80), with

- 91 043389 by obtaining the title compound (4.94 g, 45%).

¹ H-NMR (400 MHz, DMSO) δ=8.54 (s, 1H), 8.30 (s, 2H).

Stage C.

The title compound from Step B above (0.157 g, 0.627 mmol) was dissolved in morpholine (3 mL, 0.627 mmol) and stirred at room temperature for 2 hours. The reaction mixture was diluted with dichloromethane and water. The organic layer was separated and the aqueous layer was extracted with dichloromethane twice. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude product was purified on a silica gel column using the Biotage Isolera One purification system using an n-heptane/ethyl acetate gradient (100/0^0/100) to give the title compound as a white solid (0.048 g, 30% ).

MS: 258.6 (M+H)+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ=8.71 (s, 1H), 3.74 (dd, J=6.0, 3.6 Hz, 4H), 3.70 - 3, 58 (m, 4H).

Preparative example 32.

To a suspension of sodium hydride (0.077 g, 3.21 mmol) in dry THF (5 ml), (1R,5S)-3-α-oxa-8azabicyclo[3.2.1]octane hydrochloride (0.457 g, 3.06 mmol) was added to nitrogen atmosphere at 0°C. The reaction mixture was stirred for 15 min, then 2,5-dibromopyrazine (0.800 g, 3.36 mmol) dissolved in dry THF (5 ml) was added. The reaction mixture was left to stir at reflux overnight. The reaction mixture was quenched with water and the product was extracted three times with ethyl acetate. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude product was purified on a silica gel column using the Biotage Isolera One purification system using an n-heptane/ethyl acetate gradient (100/0^0/100) to obtain the title compound as a white solid (0.038 mg, 5%) .

MS: 271.8 (M+H) ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ=8.24 (d, J=1.4 Hz, 1H), 8.11 (d, J=1.4 Hz, 1H), 4.49 (s, 2H), 3.62 (d, J=10.9 Hz, 2H), 3.52 (d, J=11.0 Hz, 2H), 2.02 - 1.95 (m, 2H) , 1.91 (m, 2H).

Preparative example 33.

Stage A.

Palladium(II) acetate (0.00651 g, 0.029 mmol) and 2-dicyclohexylphosphino-2',4',6'triisopropylbiphenyl (XPhos) (0.0415 g, 0.087 mmol) were placed in the reaction vessel and degassed 1,4 -dioxane (2 ml). The resulting solution was quickly degassed. The suspension was heated at 100°C (on a preheated heating block) for less than 1 min until the color of the solution changed from orange to dark pink. The vessel was then removed from the heating block and the title compound of Preparation 1 (0.110 g, 0.290 mmol) and the title compound of Preparation 29 (0.078 g, 0.319 mmol) and cesium carbonate (0.331 g, 1.015 mmol) were added. . The reaction vessel was filled with argon before being sealed. The reaction mixture was heated at 100°C for 12 hours. The reaction mixture was diluted with ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate two more times. The combined organic layers were dried over Na ₂ SO ₄ , filtered, and the solvents were evaporated under reduced pressure. The crude product was purified on a silica gel column using the Biotage Isolera One purification system using a n heptane/ethyl acetate gradient (90/10^0/100) to obtain the title compound as a yellow solid (0.072 g, 49%) .

MS: 508.2 (M+H) ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ=8.03 (dd, J=9.1, 4.5 Hz, 1H), 7.70 (d, J=8.4 Hz, 2H) , 7.42 (d, J=9.9 Hz, 1H), 7.38 (dd, J=8.9, 2.6 Hz, 1H), 7.32 (dd, J=9.0, 6 ,1 Hz, 2H), 7.17 (td, J=9.2, 2.6 Hz, 1H), 6.93 (s, 1H), 4.55 (s, 2H), 3.88 (t , J=5.6 Hz, 2H), 3.78 - 3.65 (m, 4H), 3.41 - 3.34 (m, 4H), 3.21 - 3.14 (m, 2H), 2.30(s, 3H).

Preparative examples 34 to 41f.

Following the palladium cross-coupling procedure as described in Preparative Example 33, with the exception of the use of the tricyclic amino and bromo/chloro derivatives listed in the table below, the following compounds were prepared:

Table 1

Preparative example Tricyclic amino derivative Bromine or chloroproiz aqueous Product 1. Output 2. ¹ H-NMR 3. MH ⁺ (ESI) 34 H.HCI Λ ^Ν Ts "AND F. ^Ts QrV Ν Ts 1. 68% 3. 645.1 35 R/NH.HC CrO N Ts ide 0 F. #==/ UO N'Ts 1. 80% 2. Ή-NMR (400 MHz, DMSO-de) δ = 8.08 - 7.99 (m, 1H), 7.96 (d, J = 5.9 Hz, 1H), 7.75 (d, J = 8.4 Hz, 2H), 7.44 (dd, J = 8.9, 2.7 Hz, 1H), 7.34 (d, J = 8.2 Hz, 2H), 7.18 ( td, J = 9.2, 2.7 Hz, 1H), 6.28 (d, J = 6.0 Hz, 1H), 4.62 (s, 2H), 4.01 - 3.96 (m , 2H), 3.76 - 3.53 (m, 8H), 3.15 (s, 2H), 2.30 (s, 3H). 3. 508.1 36 ^Ъднс ' Ts n F Sem N Ts 1. 52% 2. Ή-NMR (400 MHz, DMS0-<7b) δ = 8.09 (d, J = 1.5 Hz, 1H), 8.03 (dd, J = 9.1, 4.4 Hz, 1H ), 7.93 (d, J = 1.5 Hz, 1H), 7.71 (d, J = 8.4 Hz, 2H), 7.40 (dd, J = 8.9, 2.7 Hz , 1H), 7.33 (d, J= 8.1 Hz, 2H), 7.17 (td, J = 9.2, 2.7 Hz, 1H), 4.46 (s, 2H), 3 .85 (t, J= 5.7 Hz, 2H), 3.77 - 3.67 (m, 4H), 3.30 - 3.28 (m, 4H), 3.20 -3.15 (m , 2H), 2.30 (s, 3H). 3. 508.5

- 93 043389

37 H.HCI d Br—N=N ^x ' ^-o N-> \Nrv/y F-WJ N Ts 1. 62% 3. 354.5 38 H.HCI r ^N X^NF Ts CHU© Ts 1. 22% 3. 534.7 39 H.HCI XX< ^F Ts Ts 1. 45% 2. 'H-NMR (400 MHz, DMSO-<7b) δ = 8.10 (d, J= 1.5 Hz, 1H), 7.92 (d, J= 1.5 Hz, 1H), 7 .80 (dd, J = 10.3, 2.4 Hz, 2H), 7.78 - 7.74 (m, 2H), 7.58 (dd, J = 8.6, 5.5 Hz, 1H ), 7.46 - 7.27 (m, 2H), 7.18 (ddd, J = 9.4, 8.6, 2.4 Hz, 1H), 4.49 (s, 2H), 3, 84 (t, J= 5.6 Hz, 2H), 3.72 (t, J= 4.9 Hz, 4H), 3.29 (d, J = 4.9 Hz, 4H), 3.16 ( s, 2H), 2.31 (s, 3H). 3. 508.6 40 E yyZ'NH.HCI 11· Ts w TS 1. 24% 2. 'H-NMR (400 MHz, DMSO-<7b) δ = 8.53 (s, 1H), 8.04 (dd, J = 9.1, 4.4 Hz, 1H), 7.74 ( d, J = 8.4 Hz, 2H), 7.48 (dd, J = 8.9, 2.7 Hz, 1H), 7.32 (d, J = 8.2 Hz, 2H), 7, 17 (td, J = 9.2, 2.7 Hz, 1H), 4.75 (s, 2H), 4.14 (t, J = 5.6 Hz, 2H), 3.72 (t, J = 5.0 Hz, 4H), 3.53 (t, J = 4.9 Hz, 4H), 3.22 - 3.11 (m, 2H), 2.29 (s, 3H). 3. 508.5 41 Ts θ2ζ ^Ν 4Ζ> ^Β F 1. 39% 2. 'H-NMR (400 MHz, DMSO-<7b) δ = 8.07 - 7.99 (m, 2H), 7.95 (d, J = 1.5 Hz, 1H), 7.71 ( d, J= 8.4 Hz, 2H), 7.40 (dd, J= 8.9, 2.7 Hz, 1H), 7.33 (d, J= 8.1 Hz, 2H), 7, 17 (td, J = 9.2, 2.7 Hz, 1H), 4.45 (s, 2H), 4.34 (d, J = 4.6 Hz, 2H), 3.85 (t, J = 5.6 Hz, 2H), 3.67 (d, J = 10.7 Hz, 2H), 3.55 - 3.46 (m, 2H), 3.17 (t, J = 6.2 Hz , 2H), 2.30 (s, 3H), 1.95 1.87 (m, 2H), 1.85 - 1.74 (m, 2H). 3. 508.5

-94043389

41a ^NH.HCI Ts ^ ^Г °Ts 1. 29% 2. Ή-NMR (400 MHz, DMSO-b7b) δ = 8.54 (s, 1H), 7.82 (dd, J = 9.3, 6.4 Hz, ZN), 7.65 (dd, J = 8.7, 5.4 Hz, 1H), 7.36 (d, J= 8.1 Hz, 2H), 7.26 - 7.13 (m, 1H), 4.79 (s, 2H ), 4.15 (t, J= 5.6 Hz, 2H), 3.74 (t, J= 4.9 Hz, 4H), 3.55 (d, J = 4.9 Hz, 4H), 3.18 (s, 2H), 2.31 (s, 3H). 3. 565.21 41b 'w Ts “Sh _about 0 ..8 tw Ts 1. 31% 2. Ή-NMR (400 MHz, DMSO-<7b) δ = 8.06 (dd, J = 9.1, 4.4 Hz, 1H), 7.91 - 7.80 (m, 2H), 7 .73 (d, J= 8.3 Hz, 1H), 7.57 - 7.41 (m, 3H), 7.39 - 7.27 (m, 3H), 6.94 (s, 1H), 4.71 (s, 2H), 4.09 (t, J = 5.6 Hz, 2H), 3.75 (t, J = 4.7 Hz, 4H), 3.57 (t, J = 4 .8 Hz, 4H), 3.25 (d, J = 5.7 Hz, 2H), 2.28 (s, 3H). 3. 558.28 41c 00 Ts Ύ T Ί " O 0 8 .-0-0 ы^ ⁷ Ts 1. 13% 2. Ή-NMR (400 MHz, DMSO-<7b) δ = 7.87 - 7.82 (m, 2H), 7.79 (d, J = 8.4 Hz, 2H), 7.63 (dd , J = 8.6, 5.5 Hz, 1H), 7.55 - 7.43 (m, 2H), 7.33 (dd, J = 8.9, 4.0 Hz, ZN), 6, 94 (s, 1H), 4.74 (s, 2H), 4.12 - 4.04 (m, 2H), 3.74 (t, J = 4.8 Hz, 4H), 3.56 (t , J = 4.8 Hz, 4H), 3.22 (s, 2H), 2.29 (s, 3H). 3. 558.28 41d .00I ___J I I d d ΌΌ N 1. 42% 2. Ή-NMR (400 MHz, DMSO-<7b) δ = 7.97 (d, J = 2.9 Hz, 1H), 7.79 (dd, J = 10.3, 2.3 Hz, 1H ), 7.75 (d, J = 8.2 Hz, 2H), 7.56 (dd, J = 8.6, 5.5 Hz, 1H), 7.42 (dd, J = 9.1, 3.0 Hz, 1H), 7.36 (d, J= 8.1 Hz, 2H), 7.18 (td, J = 9.1, 2.3 Hz, 1H), 6.79 (d, J = 9.1 Hz, 1H), 4.18 (s, 2H), 3.48 (t, J = 5.7 Hz, 2H), 3.41 - 3.33 (m, 4H), 3, 14 (d, J = 5.7 Hz, 2H), 2.40 (t, J = 5.0 Hz, 4H), 2.32 (s, 3H), 2.21 (s, 3H). 3. 520.33

- 95 043389

1. 67%

2. ¹ H-NMR (400 MHz, DMSO-<7b) δ = 7.93 (d, J = 2.9 Hz, 1H), 7.81 (dd, J = 10.3, 2.3 Hz, 1H), 7.78 7.74 (m, 2H), 7.55 (dd, J= 8.6, 5.5 Hz, 1H), 7.44 - 7.39 (m, 1H), 7, 40 - 7.32 (m, 2H), 7.18 (td, J = 9.1, 2.4 Hz, 1H), 6.53 (d, J = 9.0 Hz, 1H), 4.73 (d, J = 2.0 Hz, 1H), 4.61 (s, 1H), 4.16 (s, 2H), 3.75 (dd, J = 7.4, 1.5 Hz, 1H) , 3.62 (d, J = 7.4 Hz, 1H), 3.52 - 3.39 (m, 3H), 3.24 3.08 (m, 3H), 2.33 (s, 3H) , 1.93 1.78 (m, 2H).

3, 519.14_________________________ 1. 95%

2. 'H-NMR (400 MHz, DMSO-<7b) δ = 7.93 (d, J = 2.9 Hz, 1H), 7.80 (dd, J = 10.3, 2.4 Hz, 1H), 7.77 (d, J = 8.4 Hz, 2H), 7.55 (dd, J = 8.6, 5.6 Hz, 1H), 7.43 (dd, J = 9.1 , 3.0 Hz, 1H), 7.37 (d, J = 8.2 Hz, 2H), 7.18 (td, J = 9.0, 2.3 Hz, 1H), 6.53 (d , J = 9.0 Hz, 1H), 4.72 (s, 1H), 4.61 (s, 1H), 4.16 (s, 2H), 3.79 3.71 (m, 1H), 3.62 (d, J= 7.3 Hz, 1H), 3.50 - 3.40 (m, 3H), 3.22 3.09 (m, 3H), 2.33 (s, 3H), 1.93 1.76 (m, 2H).

3, 519,14_________________________

Preparative example 42.

Stage A.

Palladium(II) acetate (0.0045 g, 0.020 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (XANTPHOS) (0.035 g, 0.061 mmol) were placed in the reaction vessel and degassed 1,4dioxane ( 4 ml). The resulting solution was quickly degassed. The suspension was heated at 100°C (on a preheated heating block) for less than 1 min until the color of the solution changed from orange to dark pink. The vessel was then removed from the heating block and the title compound of Preparation 1, Step E (70 mg, 0.203 mmol) and the title compound of Preparation 26 (0.067 g, 0.224 mmol) and cesium carbonate (0.232 g) were added , 0.771 mmol). The reaction vessel was filled with argon before being sealed. The reaction mixture was heated at 100°C for 18 hours. The reaction mixture was diluted with ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate two more times. The combined organic layers were dried over Na ₂ SO ₄ , filtered, and the solvents were evaporated under reduced pressure. The crude product was purified on a silica gel column using a Biotage Isolera One purification system using dichloromethane/ethylmethanol (100/00^95/05) to obtain the title compound as a yellow solid (0.052 g, 45%).

1H NMR (400 MHz, Chloroform-d) δ=8.24 (d, J=2.7 Hz, 1H), 8.16-8.03 (m, 1H), 7.64-7.59 (m , 2H), 7.55 (d, J=2.7 Hz, 1H), 7.18 (d, J=8.2 Hz, 2H), 7.02 (dd, J=8.6, 1, 9 Hz, 2H), 4.23 (d, J=2.0 Hz, 2H), 3.84-3.78 (m, 4H), 3.69-3.63 (m, 4H), 3, 59 (t, J=5.6 Hz, 2H), 3.48 (s, 1H), 3.25 (dq, J=5.7, 3.5, 2.8 Hz, 2H), 2.33 (s, 3H).

- 96 043389

Preparative example 43.

Stage A.

Palladium(II) acetate (0.0045 g, 0.020 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (XANTPHOS) (0.035 g, 0.061 mmol) were placed in the reaction vessel and degassed 1,4dioxane ( 4 ml). The resulting solution was quickly degassed. The suspension was heated at 100°C (on a preheated heating block) for less than 1 min until the color of the solution changed from orange to dark pink. The vessel was then removed from the heating block and the title compound of Preparation 1, Step E (70 mg, 0.203 mmol) and the title compound of Preparation 27 (0.067 g, 0.224 mmol) and cesium carbonate (0.232 g) were added , 0.771 mmol). The reaction vessel was filled with argon before being sealed. The reaction mixture was heated at 100°C for 18 hours. The reaction mixture was diluted with ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate two more times. The combined organic layers were dried over Na ₂ SO ₄ , filtered, and the solvents were evaporated under reduced pressure. The crude product was purified on a silica gel column using a Biotage Isolera One purification system using dichloromethane/ethylmethanol (100/00^95/05) to obtain the title compound as a yellow solid (0.048 g, 42%).

^1H NMR (400 MHz, Chloroform-d) δ=8.10 (dd, J=9.0, 4.4 Hz, 1H), 7.65 (d, J=8.9 Hz, 1H), 7 .63 - 7.57 (m, 2H), 7.15 (d, J=8.2 Hz, 2H), 7.09 - 6.97 (m, 2H), 6.75 (d, J=8 .9 Hz, 1H), 4.51 (d, J=2.0 Hz, 2H), 3.94 (t, J=5.6 Hz, 2H), 3.82 (q, J=5.2 Hz, 4H), 3.57 (dd, J=5.8, 4.0 Hz, 4H), 3.25 (td, J=5.5, 2.7 Hz, 2H), 2.31 (s , 3H).

Preparative example 44.

_{BrEt3N _}

Br% ^N f| CH ₃ CN

Stage A

Stage A.

3,6-Dibromopyridazine (0.2 g, 0.841 mmol) was dissolved in acetonitrile (2.5 ml). 8oxa-3-azabicyclo[3.2.1]octane (0.105 g, 0.925 mmol) and triethylamine (0.176 mL, 1.261 mmol) were then added and the suspension was microwaved to 160°C for 1 hour and 20 minutes. The reaction mixture was diluted with dichloromethane and water. The organic layer was separated, and the aqueous layer was extracted twice with dichloromethane. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude product was purified on a silica gel column using the Biotage Isolera One purification system using an n-heptane/ethyl acetate gradient (100/0^0/100) to obtain the title compound as a beige solid (0.152 g, 67% ).

MS: 271.5 (M+H)+.

¹ H-NMR (400 MHz, Chloroform-d) δ=7.32 (d, J=9.5 Hz, 1H), 6.70 (d, J=9.5 Hz, 1H), 4.60 - 4.43 (m, 2H), 3.83 (d, J=12.8 Hz, 2H), 3.23 (dd, J=12.4, 2.7 Hz, 2H), 2.08 - 1 .94 (m, 2H), 1.90 - 1.76 (m, 2H).

Preparative example 45.

P44

^{Stage A} Stage B

Stage A.

To a solution of 2,6-dichlorobenzo[d]oxazole (1.2 g, 6.3 mmol) was added a solution of 33 wt% methylamine in absolute ethanol (8 ml), and the mixture was heated for 30 min at 100 °C using Biotage microwave oven. The reaction mixture was cooled to room temperature and dissolved in dichloromethane (150 ml). The organic phase was washed with water, 1 N NaOH and brine and then dried over Na ₂ SO ₄ . The solvent was removed to give the title compound (1.08 g, 94%).

1H NMR (400 MHz, Chloroform-d) δ 7.30 - 7.24 (m, 2H), 7.16 (dd, J=8.4, 1.9 Hz, 1H), 5.35 (s, 1H), 3.14 (s, 3H).

- 97 043389

Stage B.

To a stirred suspension of the title compound from Step A above (39 mg, 1.663 mmol) in dry THF (1.5 ml) at 0° C. was slowly added a solution of 6-chloro-N-methylbenzo[d]oxazol-2amine (100 mg , 0.548 mmol) in dry THF (2 ml) and stirred at the same temperature for 30 min. A solution of 4-methylbenzene-1-sulfonyl chloride (107 mg, 0.561 mmol) in dry THF (1.5 ml) was then added dropwise at 0°C and the reaction mixture was stirred at 0°C for 2 hours. The reaction mixture was quenched at 0°C ice water (4 ml). The product was then extracted three times with ethyl acetate. The combined organic extracts were washed with water, brine, dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure to give the title compound as a beige solid (154 mg, 83%).

MS: 337.14 (M+H)+.

¹ H-NMR (400 MHz, DMSO) δ=7.93 - 7.89 (m, 2H), 7.88 (d, J=2.0 Hz, 1H), 7.58 (d, J=8 .5 Hz, 1H), 7.49 - 7.44 (m, 2H), 7.36 (dd, J=8.5, 2.0 Hz, 1H), 3.49 (s, 3H), 2 .39 (s, 3H).

Preparative example 46.

Stage A.

To a suspension of NaH (0.47 g, 19.55 mmol) in THF (20 ml) was added dropwise commercially available tert-butyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole -2-carboxylate (2.0 g, 7.35 mmol) (dissolved in THF) at 0°C. The mixture was then stirred at room temperature for 1 hour. After this, tosyl chloride (1.5 g, 7.82 mmol) (dissolved in THF) was added at 0° C., and then the mixture was stirred at room temperature for 2 hours. Once complete reactions as verified by TLC, the reaction mixture was quenched with ice water followed by extraction with ethyl acetate. The organic layer was concentrated to give the title compound (1.8 g, 65%). The product was taken as such for the next stage.

MS: 427.1 (M+H)+.

Stage B.

To a solution of the title compound from Step A above (1.8 g, 4.22 mmol) in DCM (20 mL) was added 4M HCl (5 mL) in dioxane. The reaction mixture was stirred overnight at room temperature. After completion of the reaction, the reaction mixture was evaporated to remove the solvent, and the residue was washed with diethyl ether to obtain the title compound as a white metallic solid (1.0 g, 66%).

MS: 361.3 (M+H)+.

Preparative example 47.

Stage A.

To a solution of commercially available (2-fluorophenyl)hydrazine hydrochloride (2 g, 12.34 mmol) and tert-butyl-4-oxopiperidine-1-carboxylate (2.45 g, 12.34 mmol) in dioxane (20 ml) was added concentrated H2SO4 (2 ml), 0°C. The reaction mixture was then heated at 120°C for 4 hours. After completion of the reaction, as evidenced by TLC, the reaction mixture was cooled to 25°C and then concentrated. The crude mixture was made alkaline with 10% NaOH solution, and the precipitate was filtered off. The solid was washed with water and dried in vacuo to give the title compound (1.7 g, 75%).

MS: 191.0 (M+H)+.

Stage B.

To a stirred solution of the title compound from Step A above (1.7 g, pure

- 98 043389 nachennoe) in THF (20 ml) was added TEA (3.76 ml, 26.82 mmol) and di-tert-butyl dicarbonate (2.34 ml, 10.73 mmol) at room temperature. The mixture was stirred for 12 hours. Once the reaction was complete as indicated by TLC, the solvent was removed and the crude reaction mixture was purified on a silica gel column using a Biotage Isolera One purification system using an EtOAc/heptane (20/80^80/20) gradient with obtaining the title compound as a pale yellow solid (700 mg, 27%).

MS: 291.1 (M+H)+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ=11.38 (bs, 1H), 7.22 (d, J=7.60 Hz, 1H), 6.96-6.85 (m, 2H), 4.53 (s, 2H), 3.70-3.71 (m, 2H), 2.78 (bs, 2H), 1.44 (s, 9H).

Stage C.

To a suspension of NaH (144 mg, 3.61 mmol) in THF (15 ml) dropwise the title compound from Step B above (700 mg, 2.41 mmol) (dissolved in THF) at 0°C. The mixture was then stirred at room temperature for 1 hour. After this, tosyl chloride (549 mg, 2.89 mmol) (dissolved in THF) was added at 0°C, and then the mixture was stirred at room temperature for 2 hours. After completion of the reaction, As evidenced by TLC, the reaction mixture was quenched with ice water followed by extraction using ethyl acetate. The organic layer was concentrated and the crude reaction mixture was purified on a silica gel column using a Biotage Isolera One purification system using an EtOAc/hexane gradient (20/80^80/20) to give the title compound (900 mg, 84%).

MS: 345.1 (M-Vos).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ=7.79 (d, J=8.04 Hz, 2H), 7.41 (d, J=8.24 Hz, 2H), 7.34 (d, J=7.68 Hz, 2H), 7.22-7.23 (m, 1H), 7.07-7.09 (m, 1H), 4.50 (s, 2H), 3, 70-3.72 (m, 2H), 3.17 (bs, 2H), 2.36 (s, 3H), 1.40 (s, 9H).

Stage D

To a solution of the title compound from Step C above (900 mg, 2.02 mmol) in DCM (10 mL) was added 4 N HCl (5 mL) in dioxane. The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was evaporated to remove the solvent, and the residue was washed with diethyl ether to obtain the title compound as a light brown solid (450 mg, 65%).

MS: 345.1 (M+H) ⁺ .

Preparative example 48.

Stage A.

To a suspension of NaH (300 mg, 12.39 mmol) in THF (15 ml) was added dropwise the title compound from Preparation 47, Step B (1.2 g, 4.13 mmol) (dissolved in THF) at 0 °C. The reaction mixture was then stirred at room temperature for 1 hour. After this, iodomethane (0.5 ml, 8.26 mmol) was added at 0°C, and then the mixture was stirred at room temperature for 2 hours. Once complete, the reaction mixture was quenched in ice-cold water followed by extraction with ethyl acetate. The organic layer was concentrated and the crude reaction mixture was purified on a silica gel column using a Biotage Isolera One purification system using an EtOAc/hexane gradient (20/80^80/20) to give the title compound (900 mg, 72%).

MS: 305.3 (M+H)+.

¹ H-NMR (400 MHz, DMSO-d6) δ=7.23 (d, J=9.60 Hz, 1H), 6.88-6.91 (m, 2H), 4.51 (s, 2H ), 3.71-3.73 (m, 5H), 2.73-2.77 (m, 2H), 1.50 (s, 9H).

Stage B.

To a solution of the title compound from Step A above (900 mg, 2.96 mmol) in DCM (10 mL), 4M HCl (5 mL) in dioxane was added. The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was evaporated to remove the solvent, and the residue was washed with diethyl ether to obtain the title compound as a light brown solid (500 mg, 83%).

MS: 205.1 (M+H) ⁺ .

- 99 043389

Preparative example 49.

Stage A.

To a solution of commercially available 2-bromo-6-chloro-1,8-naphthyridine (0.2 g, 0.821 mmol) in dry acetonitrile (5 ml) was added potassium carbonate (0.335 mg, 2.46 mmol) and morpholine (0. 11 g, 1.23 mmol). The reaction mixture was heated to 100°C for 3 hours. The reaction mixture was concentrated in vacuo and the crude reaction mixture was purified on a silica gel column using a Biotage Isolera One purification system using an EtOAc/hexane gradient (20/80^80/20), to obtain the title compound as a pale yellow solid (170 mg, 83%).

MS: 250.1 (M+H)+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ=8.71 (s, 1H), 8.07-8.08 (m, 1H), 7.82-7.95 (m, 1H), 7.55-7.56 (m, 1H), 3.72 (s, 8H).

Preparative example 50.

Stage A.

To a solution of commercially available 2-bromo-6-chloro-1,7-naphthyridine (0.5 g, 2.05 mmol) in dry acetonitrile (5 ml), potassium carbonate (0.837 mg, 6.16 mmol) and morpholine ( 0.27 g, 3.08 mmol). The reaction mixture was heated to 100°C for 3 hours. The reaction mixture was concentrated in vacuo and the crude reaction mixture was purified on a silica gel column using a Biotage Isolera One purification system using an EtOAc/hexane gradient (20/80^80/20), to obtain the title compound as a pale yellow solid (270 mg, 53%).

MS: 250.1 (M+H)+.

¹ H-NMR (400 MHz, DMSO-06) δ=9.01 (s, 1H), 7.91-7.93 (m, 2H), 6.92-6.93 (m, 1H), 3 .71(s,8H).

Preparative example 51.

Stage A

Stage A.

To a solution of commercially available 2,7-dichloroquinoline (0.5 g, 2.52 mmol) in dry DMF (5 ml) was added potassium carbonate (1 g, 7.52 mmol) and morpholine (0.32 g, 3.78 mmol). The reaction mixture was heated to 100°C for 3 hours. The reaction mixture was concentrated in vacuo to give the title compound as a pale yellow solid (500 mg, 80%).

MS: 249.1 (M+H)+.

Preparative example 52.

Stage A.

To a solution of commercially available 2,6-dichloroquinoline (0.5 g, 2.52 mmol) in dry DMF (5 ml) was added potassium carbonate (1 g, 7.52 mmol) and morpholine (0.32 g, 3.78 mmol). The reaction mixture was heated to 100°C for 3 hours. The reaction mixture was concentrated in vacuo and the crude reaction mixture was purified on a silica gel column using a Biotage Isolera One purification system using an EtOAc/hexane gradient (20/80^80 /20) to obtain the title compound as a pale yellow solid (500 mg, 80%).

MS: 249.1 (M+H)+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ=8.06 (d, J=12.40 Hz, 1H), 7.84 (d, J=2.40 Hz, 1H), 7.51 -7.52 (m, 2H), 7.31 (d, J=12.40 Hz, 1H), 3.66-3.67 (m, 8H).

Preparative example 53.

Stage A.

A solution of commercially available 4,6-dichloropyridin-3-amine (8.0 g, 49.07 mmol) and benzoyl isothiocyanate (7.3 mL, 53.98 mmol) in acetone (120 mL) was stirred at 60°C for 3 h. The reaction was monitored by TLC. The solvent was evaporated and the solid was filtered, washed with n-hexane (100 ml) and dried to obtain the desired product as a white metallic solid (14.0 g, 87%).

MS: 328.0 (M+H)+.

¹ H-NMR (400 MHz, DMSO-d6) δ=12.39 (s, 1H), 12.02 (s, 1H), 8.74 (s, 1H), 7.98-7.99 (m , 3H), 7.67-7.68 (m, 1H), 7.56 (t, J=7.60 Hz, 2H).

Stage B.

To a solution of the title compound from Step A above (14.0 g, 42.94 mmol) in N-methyl-2-pyrrolidone (NMP) (70 ml) was added sodium methoxide (NaOMe) (4.6 g, 85.88 mmol ) at 0°C. The mixture was then heated to 120°C and stirring was continued for 4 hours. The progress of the reaction was monitored by TLC. The reaction mixture was poured into cold water (300 ml) and a white precipitate was obtained. The solid was filtered, washed with water (300 ml) and n-hexane (200 ml). The compound was dried under vacuum for 6 hours to give the desired product as a white solid (14.0 g, crude). The product was taken as such for the next stage.

MS: 290.0 (M+H)+.

Stage C.

A suspension of the title compound from Step B above (14.0 g, 48.4 mmol) in 70% H2SO4 (50.0 ml) was heated at 110°C for 4 hours. The reaction mixture was cooled to room temperature, and the reaction mixture slowly poured into 200 ml of cold water (0°C). The reaction mixture was then adjusted to alkaline pH by adding 50% aq. NaOH. The compound was then extracted with EtOAc (6x100 ml). The combined organic layers were dried over Na ₂ SO ₄ and filtered, then the solvent was concentrated to give the desired product as a light yellow solid (6 g, 67%).

MS: 186.1 (M+H)+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ=8.30 (s, 1H), 7.86 (s, 1H).

Stage D

To a suspension of the title compound from Step C above (5.0 g, 27.02 mmol) in acetonitrile (120 mL) at 0° C. was added tert-butyl nitrite (4.8 mL, 40.54 mmol) over 10 min. using a syringe. Copper(II) bromide (9.0 g, 40.54 mmol) was then added in portions. After 30 min at 0°C, the reaction mixture was allowed to warm to room temperature over 2.5 h, and the progress of the reaction was monitored by TLC. After completion of the reaction, the solvent was evaporated and diluted with water (200 ml) and 5% MeOH/DCM (3x200 ml). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound as a white solid (6.5 g). The product was taken as such for the next stage.

MS: 250.9 (M+H)+.

Stage E.

To a solution of the title compound from Step D above (6.5 g, 26.09 mmol) in dry DCM (100 mL) was added triethylamine (11.2 mL, 81.5 mmol) and morpholine (2.8 mL, 28 .13 mmol). Reactionary

- 101 043389 the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under vacuum. The crude reaction mixture was purified on a silica gel column using a Biotage Isolera One purification system using an EtOAc/hexane gradient (20/80^80/20) to obtain the title compound as a pale yellow solid (4.7 g , 71%).

MS: 256.1 (M+H)+.

¹ H-NMR (400 MHz, DMSO-d6) δ=8.48 (s, IH), 8.05 (s, 1H), 3.73-3.74 (m, 4H), 3.60-3 .61 (m, 4H).

Preparative example 54.

hn ^{7 4} o

LCl~\

LI ^ ^Cl ____________- L [ Νλ p acetonitrile,//

70°C, 12 hP54

Stage A

To a stirred solution of 2,5-dichloro-1,3-benzoxazole (0.25 g, 0.0013 mol) in acetonitrile (15 ml) was added K2CO3 (0.538 g, 0.0039 mol) and 5-oxa-8-azaspiro [3.5]nonane (0.178 g, 0.0014 mol). Thereafter, the reaction mixture was heated to 70°C for 12 hours. After completion of the reaction according to TLC, DCM and water (50 ml) were added to the reaction mixture. The organic layer was separated, dried over sodium sulfate, filtered and then concentrated to give the title compound (0.30 g, 80.21%) as a white solid.

MS: 279.1 (M+H)+.

¹ H-NMR (400 MHz, DMSO-d6) δ=7.44 (d, J=8.40 Hz, IH), 7.36-7.37 (m, IH), 7.06 (dd, J =2.00, 8.40 Hz, IH), 3.64-3.65 (m, 2H), 3.60 (s, 2H), 3.54-3.55 (m, 2H), 1, 96-1.97 (m, 4H), 1.71-1.74 (m, 2H).

Preparative example 55.

L II /U-ci L £ /^nh p acetonitrile, K2CU3 ⁷ °' ^C ' ¹² ' P5S

Stage A

To a stirred solution of 2,5-dichloro-1,3-benzoxazole (0.60 g, 0.0032 mol) in acetonitrile (15 ml) was added K2CO3 (1.32 g, 0.0096 mol) and 2-methoxyethane-1 -amine (0.266 g, 0.0035 mol). The reaction mixture was then heated to 70°C for 12 hours. After completion of the reaction by TLC, DCM and water (50 ml) were added to the reaction mixture. The organic layer was separated, dried over sodium sulfate, filtered and then concentrated to give the title compound (0.41 g, 56.24%) as a brown solid.

MS: 226.9 (M+H)+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ=8.26 (s, 1H), 7.35 (d, J=11.20 Hz, 1H), 7.28 (d, J=2.80 Hz, IH), 6.99 (dd, J=2.80, 11.20 Hz, 1H), 3.48 (d, J=7.20 Hz, 4H), 3.27 (s, 3H).

Preparative example 56.

To a stirred solution of 2,5-dichloro-1,3-benzoxazole (0.719 g, 0.0038 mol) in DCM (15 ml) was added TEA (2.67 ml, 0.0191 mol) and (2R)-2-methylmorpholine (0.5 g, 0.00494 mol) and stirred for 12 hours at 25°C. After completion of the reaction according to TLC, DCM and water (50 ml) were added to the reaction mixture. The organic layer was separated, dried over sodium sulfate, filtered and then concentrated to give the title compound (0.6 g, 45.4%) as a white solid.

MS: 253.2 (M+H)+.

1H-NMR (400 MHz, DMSO-d6) δ=7.43 (d, J=11.20 Hz, IH), 7.35 (d, J=2.40 Hz, IH), 7.05 (dd , J=2.80, 11.20 Hz, 1H), 3.89-3.90 (m, 3H), 3.56-3.59 (m, 2H), 3.17-3.18 (m , IH), 2.86-2.89 (m, IH), 1.15 (d, J=8.40 Hz, 3H).

Preparative example 57.

To a stirred solution of 2,5-dichloro-1,3-benzoxazole (0.360 g, 0.0019 mol) in DCM (15 ml) to

- 102 043389 TEA (1.33 ml, 0.0095 mol) and (2S)-2-methylmorpholine (0.25 g, 0.00247 mol) were added and stirred for 12 hours at 25°C. After completion of the reaction according to TLC, DCM and water (50 ml) were added to the reaction mixture. The organic layer was separated, dried over sodium sulfate, filtered and then concentrated. The crude reaction mixture was purified on a silica gel column using a Biotage Isolera One purification system using 20-25% ethyl acetate in petroleum ether to give the title compound as a white solid (0.3 g, 45.5%).

MS: 253.1 (M+H)+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ=7.43 (d, J=8.48 Hz, 1H), 7.34-7.35 (m, 1H), 7.05 (dd, J=2.08, 8.46 Hz, 1H), 3.90-3.90 (m, 3H), 3.61-3.62 (m, 2H), 3.24-3.25 (m, 1H), 2.87-2.89 (m, 1H), 1.15 (d, J=6.20 Hz, 3H).

Preparative example 58.

To a solution of 2,5-dichloro-1,3-benzoxazole (1.20 g, 6.38 mmol) in dry DCM (50 ml) at 0°C was added (3R)-3-methylmorpholine (0.775 g, 7.65 mmol) and Et ₃ N (1.94 g, 19.10 mmol) and stirred at 25°C for 4 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water (20 ml) and extracted with DCM (20 mlx2). The combined organic extracts were dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure.

The crude reaction mixture was purified on a silica gel column using a Biotage Isolera One purification system using 10-20% ethyl acetate in petroleum ether to give the title compound (1.0 g, 59.9%).

MS: 252.9 (M+H)+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ=7.43 (d, J=11.20 Hz, 1H), 7.35 (d, J=2.80 Hz, 1H), 7.04 (dd, J=2.80, 11.40 Hz, 1H), 4.17-4.19 (m, 1H), 3.69-3.76 (m, 3H), 3.42-3.43 (m , 5H), 1.30 (d, J=9.20 Hz, 3H).

Preparative example 59.

hn^ * i G Zha _____________► L £ o ^CI ^ ^N DXM, TEA M

25°C, 4 hours

P59

Stage A

To a solution of 2,5-dichloro-1,3-benzoxazole (1.20 g, 6.38 mmol) in dry DCM (50 ml) at 0°C was added (3S)-3-methylmorpholine (0.775 g, 7.65 mmol) and Et ₃ N (1.94 g, 19.10 mmol) and stirred at 25°C for 4 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with H ₂ O (20 ml) and extracted with DCM ( 20 mlx2). The combined organic extracts were dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure.

The crude reaction mixture was purified on a silica gel column using a Biotage Isolera One purification system using 10-20% ethyl acetate in petroleum ether to give the title compound (0.8 g, 49.6%).

MS: 252.9 (M+H)+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ=7.43 (d, J=11.20 Hz, 1H), 7.35 (d, J=2.80 Hz, 1H), 7.04 (dd, J=2.80, 11.20 Hz, 1H), 4.17-4.19 (m, 1H), 3.73-3.75 (m, 4H), 3.46-3.47 (m, 2H), 1.30 (d, J=9.20 Hz, 3H).

Preparative example 60.

To a stirred solution of 2,5-dichloro-1,3-benzoxazole (0.5 g, 0.00265 mol) in acetonitrile (10 ml) was added K2CO3 (1.1 g, 0.00797 mol) and 2-methoxy-N -methylethan-1-amine (0.284 g, 0.00319 mol). Thereafter, the reaction mixture was heated to 70°C for 12 hours. After completion of the reaction according to TLC, DCM and water (50 ml) were added to the reaction mixture. The organic layer was separated, dried over sodium sulfate, filtered and then concentrated to give the title compound (0.61 g, 95%) as a brown liquid.

MS: 241.1 (M+H)+.

- 103 043389

Ή-NMR (400 MHz, DMSO-d6) δ=7.40 (d, J=11.20 Hz, 1H), 7.30 (d, J=2.80 Hz, 1H), 7.00 (dd , J=2.80,

11.20 Hz, 1H), 3.68 (t, J=6.40 Hz, 2H), 3.58 (t, J=7.20 Hz, 2H), 3.27 (s, 3H), 3 .16(s, 3H).

Preparative example 61.

s

KS'^'O'^ DCM, Oxalyl chloride,x

LX ^SH kJ- A_/°

EtOH, 85°C, 12 h ci TEA ^NG \Зу° Cl

P61

Stage A Stage B

Stage A.

Potassium O-ethylcarbonidithioate (4.49 g, 0.0280 mol) was added to a stirred solution of 2-amino-3-chlorophenol (4 g, 0.0280 mol) in ethanol (80 ml), then heated to 85°C for 12 hours in N2 atmosphere. After completion of the reaction according to LCMS, the reaction mixture was concentrated, the crude product was acidified using acetic acid (pH 5), and the solid was filtered, washed with water, dried in vacuum for 6 hours, yielding 4-chlorobenzo[d]oxazole-2-thiol ( 4.6 g, 89%) as a pale brown solid.

MS: 186.0 (M+H)+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) 5=14.44 (bs, 1H), 7.46 (d, J=10.80 Hz, 1H), 7.35 (d, J=11, 20 Hz, 1H), 7.23 (t, J=10.80 Hz, 1H).

Stage B.

To a solution of the title compound from Step A above (4.6 g, 0.0244 mol) in DCM (90 ml) was added oxalyl chloride (3.20 ml, 0.0374 mol) followed by DMF (1 ml) at 0 °C, then stirred at 25 °C for 1 hour. TEA (10 ml, 0.0734 mol) and morpholine (2.5 ml, 0.0293 mol) were then added at 0 °C and stirred at 25 °C in for 2 hours in a nitrogen atmosphere. After completion of the reaction according to TLC, water (40 ml) was added and extracted with DCM (2x50 ml). The organic layer was concentrated and the crude product was purified on a silica gel column using a Biotage Isolera One purification system using 10-15% ethyl acetate in petroleum ether to give the title compound (3.4 g, 58%) as a pale solid -yellow color.

MS: 239.1 (M+H)+.

¹ H-NMR (400 MHz, DMSO-d6) 5=7.40 (d, J=10.80 Hz, 1H), 7.23 (d, J=10.40 Hz, 1H), 7.03 ( t, J=10.80 Hz, 1H), 3.71-3.73 (m, 4H), 3.60-3.62 (m, 4H).

Preparative example 62.

Stage A.

Tert-butyl 1,3,4,5tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate was added dropwise to a suspension of NaH (0.47 g, 19.8 mmol) in THF (10 ml). (1.8 g, 6.61). mmol) (dissolved in THF) at 0°C, and then stirred at room temperature for 1 hour. Iodomethane (0.7 ml, 11.76 mmol) was then added at 0°C, and then stirred at room temperature. rate for 2 hours. After completion of the reaction, the progress of which was monitored using TLC, the reaction mixture was quenched with ice water, followed by extraction using ethyl acetate. The organic layer was concentrated to give the crude reaction mixture of tert-butyl-5-methyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2carboxylate (1.5 g, crude). The product was taken as such for the next step. MS: 287.2 (M+H)+.

Stage B.

To a solution of the title compound from Step A above (1.5 g, 5.24 mmol) in DCM (20 mL) was added 4.0 M HCl (5 mL) in dioxane. The reaction mixture was stirred overnight. After completion of the reaction, the reaction mixture was evaporated to remove the solvent and washed with diethyl ether to obtain the title compound as a brown solid (800 mg, crude).

MS: 187.1 (M+H)+.

- 104 043389

Preparative example 63.

Stage A.

Tartaric acid was added to a solution of (3-methoxyphenyl)hydrazine hydrochloride (10 g, 57.4 mmol) and tert-butyl-4oxopiperidine-1-carboxylate (11.3 g, 57.4 mmol) in ethanol (100 ml). Dimethylurea (30:70, 10 g) was added and heated at 70°C for 16 hours. The reaction mixture was cooled to 25°C and concentrated in vacuo. The residue was dissolved in water and made alkaline to pH 14 with NaOH (30%) and extracted with DCM. The organic phase was separated and dried over Na ₂ SO ₄ , filtered and the solvent was evaporated under reduced pressure to give 7-methoxy-2,3,4,5-tetrahydro-1Hpyrido[4,3-b]indole as a pale yellow resin colors (2.5 g, 21%). The crude product was taken as such for the next step. MS: 203.0 (M+H) ⁺ .

Stage B.

To a solution of the title compound from Step A above (600 mg, 2.9 mmol) in THF (6 mL) at 25° C. was added triethylamine (0.8 mL, 5.8 mmol) and Boc anhydride (650 mg, 3 mmol) and stirred for 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure and the crude product was purified by flash column chromatography using hexane:EtOAc (80:20) to give tert-butyl-7 -methoxy-1,3,4,5-tetrahydro-2Hpyrido[4,3-b]indole-2-carboxylate as a pale yellow solid (610 mg, 68%).

MS: 303.2 (M+H) ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ=10.69 (bs, 1H), 7.25 (d, J=11.60 Hz, 1H), 6.80 (d, J=2.80 Hz, 1H), 6.61 (dd, J=2.80, 11.60 Hz, 1H), 4.48 (s, 2H), 3.81 (s, 3H), 3.67-3.68 (m, 2H), 2.73 (bs, 2H), 1.44 (s, 9H).

MS: 187.1 (M+H) ⁺ .

Stage C.

To a solution of the title compound from Step B above (550 mg, 1.8 mmol) in THF (5 ml). At 0°C, NaH (60%, mineral oil, 0.14 g, 3.6 mmol) was added and stirred for 30 min. p-Toluenesulfonyl chloride (342 mg, 1.8 mmol) was then added and stirred for 45 minutes. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with water and extracted with EtOAc (20 mlx3). The combined organic extracts were washed with water, brine and dried over Na ₂ SO ₄ . Filter and the solvents are evaporated under reduced pressure to give tert-butyl-7methoxy-5-tosyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate as a white solid with a metallic tint (550 mg, 66%). The product was taken as such for the next step.

MS: 357.0 (M+H) ⁺ -Vos.

Stage D

To a solution of the title compound from Step C above (550 mg, 1.204 mmol) in dry DCM (5 mL) at 0° C., HCl (g) in dioxane (2 M, 5 mL) was slowly added and stirred at 25° C. for 12 hours After completion of the reaction (monitored by TLC), the reaction mixture was evaporated under reduced pressure to obtain the crude product. This was washed with diethyl ether to give 7methoxy-5-tosyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as a white metallic solid (350 mg, 81%).

MS: 357.2 (M+H) ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ=7.73 (d, J=8.40 Hz, 1H), 7.56 (s, 1H), 7.37 (d, J=8.00 Hz, 2H), 7.27 (d, J=8.40 Hz, 1H), 6.85-6.86 (m, 1H), 3.82 (s, 3H), 3.72 (s, 2H ), 2.90-2.97 (m, 4H), 2.32 (s, 3H).

Preparative example 64.

- 105 043389

Stage A.

To a stirred solution of 8-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1 g, 5.37 mmol) in DCM (20 ml) was added TEA (2.25 ml , 16.1 mmol) and Boc anhydride (1.85 ml, 8.05 mol) at 0°C, then stirred at 25°C for 12 hours. After completion of the reaction according to TLC, water was added to the reaction mixture, followed by extraction using DXM. The organic layer was separated and washed with brine, concentrated and washed with hexane to give the title compounds (1.1 g, 71%) as a white metallic solid.

MS: 287.1 (M+H)+.

'H-NMR (400 MHz, DMSO-d6) δ 10.74 (s, 1H), 7.16 (d, J=8.44 Hz, 1H), 6.85 (d, J 8.28 Hz, 1H), 4.49 (s, 2H), 3.69 (t, J=5.64 Hz, 2H), 2.74 (t, J=5.28 Hz, 2H), 2.35 (s, 3H), 1.47 (s, 9H).

Stage B.

To a suspension of sodium hydride (0.125 g, 3.13 mmol) in THF (10 ml) was added dropwise the title compound from Step A above (0.6 g, 2.08 mmol) (dissolved in 20 ml THF) at 0 °C, then stirred at room temperature for 30 minutes. Tosyl chloride (1.19 g, 6.25 mmol) was then added dropwise at 0° C. (dissolved in 20 mL THF) and then stirred at room temperature for 3 hours. After completion of the reaction by TLC, the reaction mixture was quenched with ice water The resulting solid was filtered and washed with water and dried to give the title compound (0.550 g, 57%) as a white solid.

MS: 341.1 (M+H) ⁺ -Voc.

'H-NMR (400 MHz, DMSOC) δ=7.91 (d, J=8.52 Hz, 1H), 7.73 (d, J=8.20 Hz, 2H), 7.34 (d, J=8.40 Hz, 2H), 7.26 (s, 1H), 7.15 (d, J=8.56 Hz, 1H), 4.41 (s, 2H), 3.68 (t, J=5.60 Hz, 2H), 3.06 (s, 2H), 2.29-2.30 (m, 6H), 1.43 (s, 9H),

Stage C.

To a solution of the title compound from Step B above (0.55 g, 1.20 mmol) in DCM was added 4M HCl (4 ml) in dioxane at 0°C. The reaction mixture was stirred for 2 hours. After completion of the reaction, the reaction mixture was evaporated to remove the solvent and filtered with diethyl ether to obtain the title compound as a white solid (0.40 g, 85.9%).

Preparative example 65.

Stage C HCI, I dxm

Stage A.

To a stirred solution of 8-chloro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1 g, 4.84 mmol) in DCM (20 ml) was added TEA (2.02 ml , 14.5 mmol) and Boc anhydride (1.67 ml, 7.26 mmol) at 0°C, then stirred at 25°C for 12 hours. After completion of the reaction according to TLC, water was added to the reaction mixture, followed by extraction using DXM. The organic layer was separated and washed with brine, concentrated to give tert-butyl-8-chloro-1,3,4,5tetrahydropyrido[4,3-b]indole-2-carboxylate (1 g, 66.5%) as white solid matter.

MS: 305.1 (M+H) ⁺ .

'H-NMR (400 MHz, DMSO-d6) δ=11.12 (bs, 1H), 7.46 (d, J=1.68 Hz, 1H), 7.30 (d, J=8.56 Hz, 1H), 7.03 (dd, J=1.96, 8.52 Hz, 1H), 4.51 (s, 2H), 3.70 (t, J=5.64 Hz, 2H), 2.77 (t, J=5.32 Hz, 2H), 1.47 (s, 9H).

Stage B.

To a suspension of sodium hydride (0.096 g, 2.42 mmol) in THF (10 ml) cooled to 0° C., the title compound from Step A above (0.5 g, 1.61 mol) (dissolved) was added dropwise in 20 ml THF) at 0°C, then stirred at room temperature for 30 min. Tosyl chloride (0.921 g, 48.3 mol) was then added dropwise at 0° C. (dissolved in 20 mL THF) and then stirred at room temperature for 3 hours. After completion of the reaction by TLC, the reaction mixture was quenched with ice water followed by extraction using ethyl acetate (100 ml). The organic layer was separated, dried over sodium sulfate, filtered and then concentrated. The product was purified by silica gel column chromatography using petroleum ether in ethyl acetate (75:25) to give tert-butyl-8-chloro-5-(p-tolylsulfonyl)-3,4-dihydro-1H-pyrido[4,3-b ]indole-2-carboxylate (0.450 g, 60%) as a white solid.

MS: 361.1 (M+H) ⁺ -Voc.

'H-NMR (400 MHz, DMSO-d ₆ ) δ=8.05 (d, J=8.88 Hz, 1H), 7.78 (d, J=8.16 Hz, 2H), 7.64 (d, J=1.96 Hz, 1H), 7.35-7.36 (m, 3H), 4.44 (s, 2H), 3.68 (t, J=5.60 Hz, 2H) , 3.08 (bs, 2H), 2.32 (s, 3H), 1.43 (s, 9H).

- 106 043389

Stage C.

To a solution of the title compound from Step B above (0.45 g, 0.97 mol) in DCM was added 4M HCl (3 ml) in dioxane at 0°C. The reaction mixture was stirred for 2 hours. After completion of the reaction, the reaction mixture was evaporated to remove the solvent and concentrated with diethyl ether to obtain the title compound as a white solid (0.32 g, 91%). The product was taken as such for the next step. MS: 361.1 (M+H)+.

Preparative example 66.

ΗΝ ^λ O

GT >“ ^C| -------Et ₃ N, DCM, room temp., 4 h

P66

Stage A

Stage A.

To a solution of 5-bromo-2-chlorobenzo[d]oxazole (1 g, 4.30 mmol) in dry DCM (10 ml) at 0°C was added morpholine (0.56 g, 6.42 mmol) and Et ₃ N (1.7 ml, 12.9 mmol) and stirred at 25°C for 4 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with H2O (10 ml) and extracted with DCM (10 mlx2). The combined organic extracts were dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure to obtain the crude product. It was triturated with diethyl ether (100 ml), filtered, washed with diethyl ether (5 ml) and dried to give the title compound (0.85 g, 71%) as a white metallic solid.

¹ H-NMR (400 MHz, DMSO-de) δ=7.48 (d, J=2.40 Hz, 1H), 7.34-7.38 (m, 1H), 7.16-7.17 (m, 1H), 3.703.72 (m, 4H), 3.58-3.59 (m, 4H).

Preparative example 67.

Stage A.

To a stirred solution of 4,6-dichloropyridin-3-amine (2.5 g, 15.3 mmol) in THF (50 mL), triphosgene (4.55 g, 15.3 mol) in THF was added dropwise, followed by TEA. (4.28 ml, 30.7 mol) and refluxed for 2 hours. The reaction mixture was concentrated in vacuo. The residue was dissolved in acetonitrile (50 ml) and toluene (50 ml) and morpholine (1.34 g, 15.3 mmol) were added and heated to 110°C for 12 hours. After checking by TLC, the crude product was concentrated and purified by column chromatography on silica gel using petroleum ether:ethyl acetate (20:80) to give N-(4,6-dichloro-3-pyridyl)morpholine-4-carboxamide (3.0 g, 70.1%) as a white solid.

MS: 276.0 (M+H) ⁺ .

¹ H-NMR (400 MHz, DMSO-de) δ=8.55 (s, 1H), 8.38-8.40 (m, 1H), 7.78-7.79 (m, 1H), 3 .57-3.58 (m, 4H), 3.40-3.42 (m, 4H).

Stage B.

To a solution of the title compound from Step A above (3.0 g, 10.8 mmol) in 1,4-dioxane (5 ml) was added Cs ₂ CO ₃ (10.5 g, 32.4 mol), 1. 10-phenanthroline (0.972 g, 5.40 mol) and copper iodide (1.03 g, 5.40 mol) were then heated to 120°C for 12 hours. The reaction mixture was filtered through celite and washed with DCM/MeOH, concentrated , and the crude product was purified on a silica gel column using a Biotage Isolera One purification system using a 40/60 EtOAc/hexane gradient to give the title compound as a white metallic solid (0.150 g, crude). The crude product was taken as such for the next step. MS: 240.1 (M+H) ⁺ .

Preparative example 68.

- 107 043389

Stage A.

To a stirred solution of 8-ethoxy-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1 g, 4.62 mmol) in DCM (20 ml) was added TEA (1.97 ml , 13.87 mmol) and Boc anhydride (1.5 ml, 6.93 mol) at 0°C, then stirred at 25°C for 12 hours. After completion of the reaction according to TLC, water was added to the reaction mixture, followed by extraction using DXM. The organic layer was separated and washed with brine, concentrated and washed with hexane to give tert-butyl-8ethoxy-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (0.8 g , 54%) in the form of a brown solid.

MS: 317.2 (M+H)+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ=10.69 (bs, 1H), 7.16 (d, J=8.68 Hz, 1H), 6.87 (s, 1H), 6 .66 (t, J=6.76 Hz, 1H), 4.48 (s, 1H), 3.97-3.99 (m, 2H), 3.69 (t, J=5.48 Hz, 2H), 2.74 (bs, 2H), 1.44 (s, 9H), 1.23 (t, J=6.84 Hz, 3H).

Stage B.

To a suspension of sodium hydride (0.136 g, 2.84 mmol) in THF (5 ml) was added dropwise the title compound from Step A above (0.3 g, 0.95 mmol) (dissolved in 10 ml THF) at 0 °C, then stirred at room temperature for 30 minutes. Tosyl chloride (0.27 g, 1.42 mmol) was then added dropwise at 0° C. (dissolved in 10 mL THF) and then stirred at room temperature for 3 hours. After completion of the reaction by TLC, the reaction mixture was quenched with ice water , the resulting solid was filtered and washed with water and dried to give tert-butyl-8-ethoxy-5-tosyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (0. 32 g, 72%) as a white solid. The product was taken as such for the next step.

MS: 371.2 (M+H)+-Voc.

Stage C.

To a solution of the title compound from Step B above (0.32 g, 0.68 mmol) in DCM was added 4M HCl (4 ml) in dioxane at 0°C. The reaction mixture was stirred for 2 hours. After completion of the reaction, the reaction mixture was evaporated to remove the solvent and filtered with diethyl ether to obtain the title compound as a brown solid (0.13 g, 56%). The product was taken as such for the next step.

MS: 371.2 (M+H) ⁺ .

Preparative example 69.

but O.

o ^N °n % b

JL NHjOH HCl K

[J CH ₃ COONa i] NaH, DMF

Ν I -----------------* . '

Stage A Stage B

Stage C

Stage A.

To a stirred solution of tert-butyl-4-oxopiperidine-1-carboxylate (10.00 g, 0.0502 mol) in ethanol (100 ml) was added hydroxylamine hydrochloride (6.98 g, 0.100 mol) and CH ₃ COONa (8, 23 g, 0.100 mol), then heated to 90°C for 12 hours under nitrogen. After completion of the reaction according to LCMS, the reaction mixture was concentrated and water (100 ml) was added to the crude material, followed by extraction with dichloromethane (250 ml). The organic layer was concentrated and the crude product was purified by a silica gel column (Biotage) using 1830% ethyl acetate in petroleum ether to give tert-butyl 4-(hydroxyimino)piperidine-1-carboxylate (5 g, 46.4%) as a white solid substances.

MS: 159.1 (M+H)+-tert-butyl.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ=10.45 (s, 1H), 3.33-3.36 (m, 4H), 2.42-2.44 (m, 2H), 2.20-2.22 (m, 2H), 1.41 (s, 9H).

Stage B.

To a suspension of sodium hydride (0.268 g, 7.00 mmol) in DMF (3 ml), the title compound from Step A above (0.500 g, 2.33 mmol) was added dropwise (dissolved in 5 ml DMF) at 0°C , then stirred at room temperature for 60 minutes. Thereafter, 2-fluoropyridine (0.340 g, 3.50 mmol) was added dropwise at 0°C (dissolved in 2 ml DMF) and then stirred at room temperature for 3 hours. After completion of the reaction according to TLC, the reaction mixture was quenched with ice water followed by extraction using ethyl acetate (30 ml). Organic

- 108 043389 the layer was separated, dried over sodium sulfate, filtered and then concentrated to give tert-butyl 4-oxo-3-(2-oxo-1,2-dihydropyridin-3-yl)piperidin-1-carboxylate (300 mg, crude) as a pale brown solid. The crude product was taken as such for the next step.

MS: 293.2 (M+H)+.

Stage C.

A suspension of the title compound from Step B above (0.5 g, 1.71 mmol) in concentrated H2SO4 (2.0 ml) was stirred at room temperature for 16 hours under a nitrogen atmosphere. After this, LCMS was checked, which indicated only the presence of the starting material, then the reaction mixture was heated to 60°C for 16 hours under a nitrogen atmosphere. After this, LCMS was checked, which indicated the presence of 80% by weight of the product. The reaction mixture was cooled to room temperature, 10% acetonitrile in water (20.0 ml) was added to it, and the reaction mixture was made basic using solid K2CO3, then the solid was filtered. The filtrate was concentrated to give the title compound (250 mg, crude) as a brown sticky oil. The product was taken as such for the next step.

MS: 175.1 (M+H)+.

Stage D

To a stirred solution of the title compound from Step C above (0.6 g, 3.15 mmol) in tetrahydrofuran (10.0 ml) was added TEA (1.32 ml, 9.46 mol) and Boc anhydride (0.869 ml , 3.78 mmol) at 0°C, then stirred at 25°C for 12 hours under a nitrogen atmosphere. After completion of the reaction by TLC, the reaction mixture was concentrated and the crude product was purified on a silica gel column (Biotage) using 15-20% ethyl acetate in petroleum ether to give tert-butyl7,8-dihydrofuro[2,3-b:4,5- c']dipyridine-6(5H)-carboxylate (500 mg, 53%) as a white solid with a metallic tint.

MS: 275.2 (M+H)+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ=8.21-8.22 (m, 1H), 8.05-8.06 (m, 1H), 7.30-7.31 (m , 1H), 4.51 (s, 2H), 3.76 (t, J=5.60 Hz, 2H), 2.86 (t, J=5.60 Hz, 2H), 1.44 (s , 9H).

Stage E

To a stirred solution of the title compound from Step D above (0.5 g, 1.67 mmol) in dichloromethane (5 ml) was added 4.0 M HCl in dioxane (2 ml) at 0° C., then stirred for 2 h at 0°C-20°C. After completion of the reaction by TLC and LCMS, the reaction mixture was concentrated to obtain the title compound (350 mg, quantitative) as a white solid with a metallic tint.

MS: 175.1 (M+H)+.

Preparative example 70.

Гΐ^ ^С1

Stage A.

To a stirred solution of 2,5-dichloro-1,3-benzoxazole (0.25 g, 0.0013 mol) in acetonitrile (15 ml) was added K2CO3 (0.55 g, 0.0040 mol) and (2S,6R) -2,6-dimethylmorpholine (0.17 g, 0.0014 mol). Thereafter, the reaction mixture was heated to 70°C for 12 hours. After completion of the reaction according to TLC, DCM and water (50 ml) were added to the reaction mixture. The organic layer was separated, dried over sodium sulfate, filtered and then concentrated to the title compound (0.2 g, 56%) as a white solid.

MS: 267.0 (M+H)+.

¹ H-NMR (400 MHz, DMSO-Y6) δ=7.43 (d, J=8.44 Hz, 1H), 7.34 (d, J=1.96 Hz, 1H), 7.04- 7.04 (m, 1H), 3.99 (d, J=13.16 Hz, 2H), 3.66-3.67 (m, 2H), 2.82 (t, J=10.84 Hz , 2H), 1.00 (d, J=6.28 Hz, 6H).

Preparative example 71.

- 109 043389

Stage A.

To a stirred solution of 2,5-dichloro-1,3-benzoxazole (0.6 g, 0.0032 mol) in acetonitrile (15 ml) was added K ₂ CO ₃ (1.32 g, 0.0096 mol) and tert. butylamine (0.255 g, 0.0035 mol). After this, the reaction mixture was heated to 70°C for 12 hours. After completion of the reaction according to TLC, DCM and water (50 ml) were added to the reaction mixture. The organic layer was separated, dried over sodium sulfate, filtered and then concentrated to give the title compound (0.4 g, 55%) as a brown solid.

MS: 225.0 (M+H)+.

¹ H-NMR (400 MHz, DMSO-d6) δ=7.97 (s, 1H), 7.31-7.32 (m, 2H), 6.96-6.97 (m, 1H), 1 .40 (s, 9H).

Preparative example 72.

Stage A.

To a stirred solution of 6-bromo-2-chloroquinazoline (0.3 g, 1.234 mmol) in acetonitrile was added (10 ml) K ₂ CO ₃ (0.34 g, 2.467 mmol) and morpholine (0.17 g, 1.85 mmol). Thereafter, the reaction mixture was heated to 70°C for 12 hours. After completion of the reaction according to TLC, DCM and water (50 ml) were added to the reaction mixture. The organic layer was separated, dried over sodium sulfate, filtered and then concentrated to give the title compound (0.25 g, 69%) as a pale yellow solid. The product was taken as such for the next stage.

MS: 294.0 (M+H)+.

Preparative example 73.

Dioxane Et ₃ N _{С( N}

IKFC, overnight at ΥΊ kxO

Stage A P73

Stage A.

Triethylamine (0.210 mL, 1.507 mmol) and morpholine (0.052 mL, 0.603 mmol) were added to a stirred solution of 2,6-dichloro-1,5-naphthyridine (100 mg, 0.502 mmol) in dioxane (3 mL). The reaction mixture was stirred at 110°C. After 4 hours the reaction was not complete, so triethylamine (0.210 ml, 1.507 mmol) was added and the reaction mixture was further stirred at 110°C overnight. Reactionary

The mixture was concentrated to dryness and then dissolved in dichloromethane and washed with a saturated aqueous NH4Cl solution. The aqueous layer was extracted twice with DCM. The combined organic layers were dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure to give the title product as a beige solid (93 mg, 74%).

MS: 250.02 (M+H)+.

¹ H-NMR (400 MHz, DMSO-d6) δ=8.05 (d, J=9.4 Hz, 1H), 7.98 (d, J=8.8 Hz, 1H), 7.59 ( d, J=8.7 Hz, 1H), 7.53 (d, J=9.5 Hz, 1H), 3.71 (hept, J=3.3, 2.6 Hz, 8H).

Preparative example 74.

MeCN Et ₃ N MW 160°C, _1h 20 ί| Ί l\O ------------cih.hn;>. _s .

Cl Stage A

P74

Stage A.

2-Bromo-5-chloropyridine (200 mg, 1.039 mmol) was dissolved in acetonitrile (2.5 ml), to which (18.48)-2-oxa-5-azabicyclo[2.2.1]heptanhydrochloride (211 mg, 1.559 mmol) and triethylamine (0.362 ml, 2.60 mmol), and the suspension was irradiated in a microwave oven to 160°C for 1 hour 20 minutes. The sample was then extracted between water (20 ml) and dichloromethane (20 ml). The aqueous layer was washed twice with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified on a silica gel column using the Biotage Isolera One purification system with a dichloromethane/methanol gradient (100/0^90/10) to obtain the product as a beige solid (57 mg, 26%).

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MS: 211.03 (M+H)+.

1H-NMR (400 MHz, DMSO-d6) δ=8.06 (d, J=2.6 Hz, 1H), 7.56 (dd, J=9.0, 2.7 Hz, 1H), 6 .57 (d, J=9.0 Hz, 1H), 4.80 (d, J=2.3 Hz, 1H), 4.65 (d, J=2.4 Hz, 1H), 3.76 (dd, J=7.3, 1.5 Hz, 1H), 3.61 (d, J=7.3 Hz, 1H), 3.43 (dd, J=10.1, 1.5 Hz, 1H), 3.20 (d, J=10.3 Hz, 1H), 1.90 (dd, J=9.7, 2.3 Hz, 1H), 1.87-1.81 (m, 1H ).

Preparative example 75.

_ MeCN Et ₃ N

MW16O°C,U2Q CMHnX, —Stage A

Stage A.

2-Bromo-5-chloropyridine (200 mg, 1.039 mmol) was dissolved in acetonitrile (2.5 ml), to which (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptanhydrochloride (211 mg, 1.559 mmol) and triethylamine (0.362 ml, 2.60 mmol), and the suspension was irradiated in a microwave oven to 160°C for 1 hour 20 minutes. The sample was then extracted between water (20 ml) and dichloromethane (20 ml). The aqueous layer was washed twice with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified on a silica gel column using the Biotage Isolera One purification system with a dichloromethane/methanol gradient (100/0^90/10) to obtain the product as a beige solid (51 mg, 23%).

MS: 211.04 (M+H)+.

¹ H-NMR (400 MHz, DMSO-d6) δ=8.06 (dd, J=2.7, 0.7 Hz, 1H), 7.56 (dd, J=9.0, 2.7 Hz , 1H), 6.63 - 6.50 (m, 1H), 4.80 (s, 1H), 4.64 (s, 1H), 3.75 (dd, J=1.6, 1.5 Hz, 1H), 3.61 (d, J=7.3, 0.9 Hz, 1H), 3.43 (dd, J=10.1, 1.6 Hz, 1H), 3.20 (d , J=10.1, 1.1 Hz, 1H), 1.94 - 1.78 (m, 2H).

Example 1.

Stage A.

Chloro-(2-dicyclohexylphosphino2',6'-diisopropoxy-1,1'-biphenyl)[2-(2-aminoethyl)phenyl]palladium (P)-methyl-tert-butyl ether adduct was added to degassed tetrahydrofuran (5 ml). (PdRuPhos G1) (0.017 g, 0.024 mmol), 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (RuPho) (0.011 g, 0.024 mmol), title compound from Preparation Example 2 (0.05 g, 0.024 mmol ) and commercially available 4-(6-bromobenzo[d]thiazol-2-yl)morpholine (0.073 g, 0.029 mmol). A 1 M solution of lithium bis(trimethylsilyl)amide (LiHMDS) in tetrahydrofuran (1 mL, 1 mmol) was then added. The resulting reaction mixture was heated at reflux for 2 hours. The reaction mixture was cooled to room temperature, dissolved in dichloromethane (100 ml). The organic phase was washed with water and brine, and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure. The crude product was purified on a silica gel column using a Biotage Isolera One purification system using an ethyl acetate/n-heptane gradient (80/20^100/0) to give the title compound (0.070 g, 69%).

1H-NMR (400 MHz, Chloroform-d) δ=7.51 (d, J=8.8 Hz, 1H), 7.31 (d, J=2.4 Hz, 1H), 7.27 (s , 1H), 7.20 (dd, J=8.8, 4.2 Hz, 1H), 7.14 (td, J=8.6, 2.4 Hz, 2H), 6.94 (td, J=9.1, 2.5 Hz, 1H), 4.40 (s, 2H), 3.88 - 3.81 (m, 4H), 3.70 (t, J=5.7 Hz, 2H ), 3.64 (s, 3H), 3.59 (t, J=4.9 Hz, 4H), 2.92 (t, J=5.7 Hz, 2H).

Example 2.

Stage A.

To a stirred solution of the title compound of Preparative Example 1 (0.150 g, 1 eq.) in dry 1,4-dioxane (5 ml) was added commercially available 4-(6-bromobenzo[d]thiazol-2yl)morpholine (1 eq. ), sodium tert-butoxide (3 eq.), and the mixture was degassed for 10 minutes under N ₂ atmosphere. Pd ₂ (dba) ₃ (0.05 eq.) and Ru-Phos (0.1 eq.) were added to this reaction mixture, and the mixture was heated to 100° C. until the reaction was complete. After completion of the reaction, the reaction mixture was filtered through a pad of celite and washed with EtOAc. The filtrate was concentrated and the crude product was purified by column chromatography or preparative HPLC to give the title compound 6 as listed in Table. 2.

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Examples from 3 to 96e.

Following the procedures for the palladium cross-coupling reaction as described in Examples 1 and 2, except for the use of the tricyclic amino and bromo/chloro derivatives listed in the table below, the following compounds were prepared. Examples 71 and 72 were prepared according to the procedures described in Preparative Examples 42 and 43, respectively, followed by deprotection described in Example 97.

table 2

Example Tricyclic amino derivative Bromine or chlorine derivative, aqueous Product 1. Output 2. Ή-NMR 3. MH ⁺ (ESI) 4. Synthesis procedure 3 F fl_ All NH νΊΙ / ήη 1. 63% 2. Ή-NMR (400 MHz, Chloroform-7) δ = 7.50 (d, J = 8.8 Hz, 1H), 7.31 (d, 7 = 2.5 Hz, 1H), 7.27 (s, 1H), 7.23 - 7.08 (m, 3H), 6.93 (td, J = 9.1, 2.5 Hz, 1H), 4.47 - 4.20 (m, 2H ), 3.68 (t, J= 5.7 Hz, 2H), 3.64 (s, 2H), 3.19 (s, 6H), 2.92 (dq, J = 5,3,2, 9, 1.7 Hz, 2H). 4. Example 1 4 F fl All NH n-V / ΒγΌ^νΥ 1. 49% 2. Ή-NMR (400 MHz, DMSO7b) δ = 7.59 (d, 7 = 7.4 Hz, 1H), 7.43 - 7.35 (m, 2H), 7.26 (dd, J = 9.3, 2.1 Hz, 2H), 7.02 (dd, J= 8.8, 2.5 Hz, 1H), 6.92 (td, J = 9.2, 2.6 Hz, 1H ), 4.30 (s, 2H), 4.05 - 3.80 (m, 1H), 3.63 (d, J= 4.3 Hz, 5H), 2.99 - 2.79 (m, 2H), 1.19 (d, J = 6.5 Hz, 6H). 4. Example 1 5 Ffl All NH nAJ / f ^sis %-N BrAAf-DN tAA ν·Α> / 1. 33% 2. Ή-NMR (400 MHz, Chloroform-d) δ = 7.51 (d, J= 8.8 Hz, 1H), 7.32 (d, J= 2.5 Hz, 1H), 7.22 (dd, J = 8.8, 4.3 Hz, 1H), 7.15 (ddd, 7 = 12.9, 9.1,2.5 Hz, 2H), 6.96 (td, J = 9 ,1, 2.6 Hz, 1H), 5.13 (s, 1H), 4.41 (t, J = 1.7 Hz, 2H), 3.72 (t, J = 5.7 Hz, 2H ), 3.67 (s, 3H), 3.12 (s, 3H), 2.94 (dd, J = 6.5, 4.7 Hz, 2H). 4. Example 1

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6 ^F O^ ts NH.HCI erOJ-O 1. 20% 2. Ή-NMR (400 MHz, DMSOd ₆ ) δ = 10.96 (s, 1H), 7.51-7.51 (m, 1H), 7.37-7.40 (m, 1H), 7.22-7.29 (m, 2H), 7.10-7.13 (m, 1H), 6.88-6.88 (m, 1H), 4.33 (s, 2H) , 3.73 (t, J = 5.20 Hz, 4H), 3.63 (t, J = 5.60 Hz, 2H), 3.48 (t, J = 4.80 Hz, 4H), 2 .90 (s, 2H). 3. 410.5 4. Example 2 7 XXn ts H.HCI eHGUCH 1. 16% 2. Ή-NMR (400 MHz, DMSOd ₆ ) δ = 10.95 (s, 1H), 7.48 (s, 1H), 7.33-7.36 (m, 1H), 7.217 .33 (m, 2H), 7.07-7.09 (m, 1H), 6.82-6.88 (m, 1H), 4.31 (m, 2H), 3.60 (s, 2H ), 3.10 (m, 6H), 2.90 (s, 2H). 3. 367.5 4. Example 2 8 w ts H.HCI sLFo n 1. 24% 2. Ή-NMR (400 MHz, DMSOde) δ = 7.29-7.23 (m, ZN), 7.04 (d, J = 1.8 Hz, 1H), 6.88-6.83 ( m, 1H), 6.80-6.77 (m, 1H), 4.31 (s, 2H), 3.73-3.71 (m, 4H), 3.64-3.61 (m, 2H), 3.56 (t, J = 9.2 Hz, 4H), 2.88-2.87 (m, 2H). 3. 393.4 4. Example 2 9 ts H.HCI LE) 1. 20% 2. Ή-NMR (400 MHz, DMSOde) δ = 10.95 (s, 1H), 7.59 (d, J = 8.40 Hz, 1H), 7.30-7.25 (m, 2H) , 3.52 (d, 7 =2.00 Hz, 1H), 6.93 (dd,7 = 2.40, 8.80 Hz, 1H), 6.88-6.83 (m, 1H), 4.37 (s, 2H), 3.74-3.68 (m, 6H), 3.51 (t, 7 = 4.80 Hz, 4H), 2.88 (t, 7 = 4.80 Hz , 2H). 3. 409.5 4. Example 2

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10 ύΥ” Ts H 1. 12% 2. Ή-NMR (400 MHz, DMSO7 ₆ ) δ =10.95 (s, 1H), 7.28-7.22 (m, 3H), 7.00 (s, 1H), 3 .52 (t, J = 8.92 Hz, 1H), 6.72 (d, J = 8.68 Hz, 1H), 3.12 (s, 2H), 3.61 (t, J = 4, 72 Hz, 2H), 3.10 (d, J= 1.24 Hz, 6H), 2.88 (s, 2H). 3. 351.4 4. Example 2 eleven Ts _c ,JOX ^4cYN'H 1. 32% 2. Ή-NMR (400 MHz, DMSO7 ₆ ) δ = 10.95 (s, 1H), 7.54 (d, J = 8.68 Hz, 1H), 7.30-7.25 (m, 2H), 3.52 (d, J = 2.00 Hz, 1H), 6.89-6.85 (m, 2H), 3.12 (s, 2H), 3.68 (t, J = 5.44 Hz, 2H), 3.12 (s, 6H), 2.89 (d, J = 5.00 Hz, 2H). 3. 367.5 4. Example 2 12 /—NH.HCI Ts _FROM TO Yy<x?-O 1. 27% 2. Ή-NMR (400 MHz, DMSO7 ₆ ) δ =10.96 (s, 1H), 7.29-7.18 (m, ZN), 6.95 (dd, J= 2, 08, 8.58 Hz, 1H), 3.52 (t, J = 2.32 Hz, 1H), 4.31 (s, 2H), 3.12 (t, J = 5.00 Hz, 4H) , 3.62 (t, J = 5.52 Hz, 2H), 3.53 (t, J = 4.52 Hz, 4H), 2.89 (t, 7 = 5.16 Hz, 2H). 3. 393.4 4. Example 2 13 ^NH.HCI Y ts Cl-^^o / 47½S H 1. 28% 2. Ή-NMR (400 MHz, DMSOde) δ =10.94 (s, 1H), 7.28-7.11 (m, 4H), 6.92-6.84 (m, 2H), 3, 52 (s, 2H), 3.59 (s, 2H), 3.12 (d, J = 2.00 Hz, 6H), 2.88 (s, 2H). 3. 351.4 4. Example 2

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14 F^ ^NHYMJ \ szh) ^QrOj’O’ 1. 22% 2. Ή-NMR (400 MHz, DMSOd ₆ ) δ = 7.42-7.39 (m, IH), 7.317.26 (m, 2H), 7.05 (s, IH), 6.956 .91 (m, IH), 6.79 (d, J = 8.6 Hz, IH), 4.33 (s, 2H), 3.72-3.71 (m, 4H), 3.67- 3.64 (m, 5H), 3.57-3.57 (m, 4H), 2.90-2.98 (m, 2H). 3. 407.5 4. Example 2 15 F^^t ¹ Pr\ ο,ΠΤΟ 1. 30% 2. Ή-NMR (400 MHz, DMSOd ₆ ) δ = 7.42-7.39 (m, IH), 7.307.27 (m, IH), 7.22-7.18 (m, 2H), 6.97-6.91 (m, 2H), 4.33 (s, 2H), 3.72-3.64 (m, 9H), 3.533.50 (m, 4H), 2.91 -2.89 (m, 2H). 3. 407.5 4. Example 2 16 ' Ya /~~ ^NH ? „<4-0 Υσ ⁰ ^ 1. 33% 2. Ή-NMR (400 MHz, DMSOί7 ₆ )δ = 7.53 (s, IH), 7.39 (d, J = 8.8 Hz, IH), 7.29 (d, J = 8.7 Hz, IH), 7.13 (d, J = 8.7 Hz, IH), 7.04 (d, J = 1.7 Hz, IH), 6.74 (d, J = 8 .8 Hz, IH), 4.34 (s, 2H), 3.78 (s, 3H), 3.74-3.73 (m, 4H), 3.67-3.65 (m, 2H) , 3.61 (s, 3H), 3.49-3.48 (m, 4H), 2.91-2.89 (m, 2H). 3. 435.6 4. Example 2 17 TjW\ 1. 18% 2. Ή-NMR (400 MHz, DMSO<7b) δ = 8.16 (s, IH), 7.82 (d, J= 8.5 Hz, IH), 7.52 (s, IH), 7 .40 (d, J = 8.8 Hz, IH), 7.12 (d, J = 8.7 Hz, IH), 4.36 (s, 2H), 3.783.74 (m, 7H), 3 .64-3.61 (m, 5H), 3.04-3.02 (m, 4H), 2.892.87 (m, 2H). 3. 424.5 4. Example 2

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18 Уа_λ~ ^νη Ts .AND) Z^VO ^'° H 1. 45% 2. ¹ H-NMR (400 MHz, DMSOd^ δ = 7.20-7.16 (m, ZN), 7.007.00 (m, IH), 6.97-6.94 (m, IH), 6.67-6.65 (m, IH), 4.31 (s, 2H), 3.76 (s, 3H), 3.73-3.70 (m, 4H), 3.61 (t, J = 11.2 Hz, 2H), 3.54-3.51 (m, 4H), 2.86-2.88 (m, 2H) 3. 405.5 4. Example 2 19 ' ΥΧ /ΝΗ Ts sXX^O ^' ^s H 1. 38% 2. ¹ H-NMR (400 MHz, DMSOd ₆ ) δ = 7.51 (s, IH), 7.38 (d, J = 8.80 Hz, IH), 7.17 (d, J = 8.80 Hz, IH), 7.11 (d, J = 8.00 Hz, IH), 6.99 (s, IH), 6.66 (d, J = 7.20 Hz, IH) , 4.33 (s, 2H), 3.733.77 (m, 7H), 3.62 (s, 2H), 3.48 (s, 4H), 2.88 (s, 2H). 3. 421.5 4. Example 2 20 ci ⁷ ^ Ά° 1. 13% 2. ¹ H-NMR (400 MHz, DMSOdd) δ = 7.28 (d, J = 8.80 Hz, IH), 7.17-7.21 (m, 2H), 7.03 (d, J = 2.40 Hz, IH), 6.94-6.97 (m, IH), 6.71-6.74 (m, IH), 4.32 (s, 2H), 3, 77 (s, 3H), 3.63-3.72 (m, 6H), 3.59 (s, 3H), 3.50-3.53 (m, 4H), 2.86-2.87 ( m, 2H). 3. 419.0 4. Example 2 21 'θΥΛ^ΝΗ O“L2 Ν ci ⁷ ^ 1. 15% 2. ¹ H-NMR (400 MHz, DMSOd ₆ ) δ = 7.24-7.29 (m, 2H), 7.04 (s, 2H), 6.71-6.79 (m , 2Н), 4.32 (bs, 2Н), 3.77 (s, ЗН), 3.71 (bs, 4Н), 3.64 (bs, 2Н), 3.59 (s, ЗН), 3 .55 (bs, 4H), 2.86 (bs, 2H). 3. 419.0 4. Example 2

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22 V /YrO C/ ^- N Xo'^^'O 1. 24% 2. ¹ H-NMR (400 MHz, DMSOd ₆ ) δ = 7.58 (d, J = 8.80 Hz, 1H), 7.32-7.41 (m, 2H), 7, 18 (d, J = 2.00 Hz, 1H), 6.90-6.96 (m, 2H), 4.39 (bs, 2H), 3.71-3.73 (m, 6H), 3 .63 (s, 3H), 3.49-3.51 (m, 4H), 2.87-2.89 (m, 2H). 3. 422.8 4. Example 2 23 Ър? Tos ^l-O 'Ър^“ Η 1. 13% 2. 'H-NMR (400 MHz, DMSOd ₆ ) δ = 10.65 (bs, 1H), 7.58 (d, J = 8.84 Hz, 1H), 7.17 (d, J = 8.68 Hz, 2H), 7.05 (s, 1H), 6.94 (d, J = 8.64 Hz, 1H), 6.66 (d, J = 8.76 Hz, 1H) , 4.37 (bs, 2H), 3.79 (s, 3H), 3.68-3.77 (m, 6H), 3.50 (bs, 4H), 2.86 (bs, 2H). 3. 420.8 4. Example 2 24 Ζν-Λ ^ΝΗ Is c±°op H 1. 16% 2. 'H-NMR (400 MHz, DMSOde) δ = 10.65 (bs, 1H), 7.26 (d, J = 8.80 Hz, 1H), 7.17 (d, J = 8.40 Hz, 1H), 7.00-7.04 (m, 2H), 6.79 (dd, J= 2.40, 8.80 Hz, 1H), 6.67 (d, 7=2.00 Hz , 1H), 4.31 (bs, 2H), 3.77 (s, 3H), 3.70-3.73 (m, 4H), 3.60-3.63 (m, 2H), 3, 55-3.57 (m, 4H), 2.84-2.86 (m, 2H). 3. 405.2 4. Example 2 25 R East 'ν F _Ν ΧΛ ^ύ 1 1. 42% 2. Ή-NMR (400 MHz, Chloroform-d) δ = 7.46 (d, J = 8.6 Hz, 1H), 7.29 (s, 1H), 7.20 (dd, J = 8, 8, 4.3 Hz, 1H), 7.15 (dd, J = 9.5, 2.5 Hz, 1H), 6.93 (ddd, J = 18.8, 8.9, 2.6 Hz , 2H), 5.10 (s, 1H), 4.46 (s, 2H), 3.97 (dd, J = 13.1, 6.6 Hz, 1H), 3.77 (t, J= 5.6 Hz, 2H), 3.65 (s, 3H), 2.94 (t, J= 5.5 Hz, 2H), 1.35 (d, J= 6.5 Hz, 6H). 4. Example 1

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26 Vvct 1 0-^° , £Y° 1. 13% 2. Ή-NMR (400 MHz, DMSOd ₆ ) δ = 8.16 (s, 1H), 7.86-7.89 (m, 1H), 7.58-7.60 (m, 1H), 7.19 (s, 1H), 6.94 (d, J = 8.80 Hz, 1H), 4.40 (bs, 2H), 3.683.76 (m, 9H), 3.50- 3.51 (m, 4H), 2.93-2.95 (m, 2H). 3. 424.0 4. Example 2 27 Br^ Y F Shae ? 1. 40% 2. Ή-NMR (400 MHz, Chloroform-7) δ = 7.48 (d, J = 8.6 Hz, 1H), 7.31 (d, J = 2.5 Hz, 1H), 7.21 (dd, J = 8.8, 4.3 Hz, 1H), 7.15 (dd, J = 9.5, 2.5 Hz, 1H), 6.99 - 6.90 (m, 2H), 5.22 (s, 1H), 4.47 (t, J= 1.6 Hz, 2H), 3.78 (t, J= 5.7 Hz, 2H), 3.66 (s, 3H), 3.13 (s, 3H), 2.95 (tt, J = 5.7, 1.8 Hz, 2H). 4. Example 1 28 b-σ V /1I / 1. 39% 2. Ή-NMR (400 MHz, DMSO7 ₆ ) δ = 7.52-7.55 (m, 1H), 7.387.41 (m, 1H), 7.32-7.35 (m, 1H), 7.15 (d, 7=2.04 Hz, 1H), 6.87-6.95 (m, 2H), 4.38 (bs, 2H), 3.72-3.73 (m , 2H), 3.64 (s, 3H), 3.11 (s, 6H), 2.89 (bs, 2H). 3. 381.2 4. Example 2 29 F. Yaz~nh jyy / 1. 17% 2. Ή-NMR (400 MHz, DMSO7 ₆ ) δ = 7.38-7.42 (m, 1H), 7.277.30 (m, 1H), 7.23 (d, 7 = 8, 80 Hz, 1H), 7.00 (d, J = 2.00 Hz, 1H), 6.91-6.95 (m, 1H), 6.726.74 (m, 1H), 4.31 (bs, 2H), 3.62-3.64 (m, 5H), 3.10 (s, 6H), 2.87-2.89 (m, 2H). 3. 365.0 4. Example 2

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thirty UA_Ζ ^νη Ts ClXX-N^ ^- ' Xcx^H 1. 15% 2. Ή-NMR (400 MHz, DMSOd^ δ = 10.65 (bs, 1H), 7.54 (d, 7 = 8.80 Hz, 1H), 7.15-7.18 (m, 2H) , 7.05 (s, 1H), 6.88 (dd, J = 2.00, 8.60 Hz, 1H), 6.66 (dd, J = 2.40, 8.60 Hz, 1H), 4.37 (bs, 2H), 3.77 (s, 3H), 3.66-3.69 (m, 2H), 3.11 (s, 6H), 2.84-2.86 (m, 2H). 3. 379.0 4. Example 2 31 CR da XO ⁰ ^' / 1. 27% 2. Ή-NMR (400 MHz, DMSO7 ₆ ) δ = 7.49 (d, J = 2.40 Hz, 1H), 7.34 (d, J = 8.80 Hz, 1H), 7.28 (d, J = 8.80 Hz, 1H), 7.08-7.10 (m, 1H), 7.03 (d, J = 2.40 Hz, 1H), 6.72-6 .74 (m, 1H), 4.32 (bs, 2H), 3.77 (s, 3H), 3.60-3.64 (m, 5H), 3.10 (s, 6H), 2, 87-2.90 (m, 2H). 3. 393.0 4. Example 2 32 ηχ _C| >^NX / 1. 21% 2. Ή-NMR (400 MHz, DMSO7 ₆ ) δ = 7.53 (d, J = 8.40 Hz, 1H), 7.28 (d, J = 8.80 Hz, 1H), 7.15 (s, 1H), 7.09 (s, 1H), 6.89 (d, J = 8.00 Hz, 1H), 6.72 (d, J = 8.80 Hz, 1H), 4.38 (bs, 2H), 3.78 (s, 3H), 3.69-3.71 (m, 2H), 3.59 (s, 3H), 3.11 (s, 6H), 2 .87 (bs, 2H). 3. 393.0 4. Example 2 33 yA_XNH 7 XXX 1. 28% 2. Ή-NMR (400 MHz, DMSOd ₆ ) δ = 7.28 (d, J = 8.80 Hz, 1H), 7.20 (d, 7 = 2.40 Hz, 1H), 7.127.14 (m, 1H), 7.04 (d, 7=2.40 Hz, 1H), 6.92 (dd, 7= 2.40, 8.60 Hz, 1H), 6.73 (dd , 7=2.80, 8.60 Hz, 1H), 4.31 (bs, 2H), 3.78 (s, 3H), 3.62-3.65 (m, 2H), 3.60 ( s, 3H), 3.08 (s, 6H), 2.86-2.89 (m, 2H). 3. 377.2 4. Example 2

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34 _C ,OC0 / 1. 16% 2. Ή-NMR (400 MHz, DMSO7 ₆ ) δ = 8.16 (s, 1H), 7.82 (dd, J = 2.60, 9.58 Hz, 1H), 7.48 (d, J = 2.08 Hz, 1H), 7.35 (d, J = 8.80 Hz, 1H), 7.09 (dd, J = 2.32, 8.82 Hz, 1H), 4 .34 (bs, 2H), 3.69 (s, 3H), 3.65-3.68 (m, 2H), 3.10 (s, 6H), 2.96 (bs, 2H). 3. 382.3 4. Example 2 35 R y-N Z-NH Ν' N _CAH bx?^ ^N'I 1. 27% 2. Ή-NMR (400 MHz, DMSO7b) δ = 8.16 (d, 7 = 1.72 Hz, 1H), 7.87 (dd, J = 2.52, 9.60 Hz, 1H), 7 ,54-7.56 (m, 1H), 7.16 (d, J = 1.96 Hz, 1H), 6.89 (dd, 7=1.96, 8.58 Hz, 1H), 4, 40 (bs, 2H), 3.75-3.76 (m, 2H), 3.70 (s, 3H), 3.12 (s, 6H), 2.94-2.96 (m, 2H) . 3. 382.0 4. Example 2 36 R Uu-GT ^N= N 1 „•Wo ^Q'XXnHD' 1. 13% 2. Ή-NMR (400 MHz, DMSO7 ₆ ) δ = 8.15-8.16 (m, 1H), 7.84 (dd, 7 = 2.72, 9.54 Hz, 1H) , 7.25-7.29 (m, 1H), 7.05 (d, 7 = 2.32 Hz, 1H), 6.79 (dd, 7 = 2.40, 8.76 Hz, 1H), 4.34 (bs, 2H), 3.67-3.73 (m, 9H), 3.55-3.57 (m, 4H), 2.94-2.97 (m, 2H). 3. 408.0 4. Example 2 37 ХХУ\ Gi^^O ⁴ 1. 22% 2. Ή-NMR (400 MHz, DMSO7 ₆ ) δ = 8.16 (bs, 1H), 7.82 (dd, 7 = 2.80, 9.40 Hz, 1H), 7.20 (d, 7= 2.00 Hz, 1H), 7.14 (d, 7 = 8.40 Hz, 1H), 6.92 (dd, 7 = 2.00, 8.60 Hz, 1H), 4 .33 (bs, 2H), 3.69 (s, 3H), 3.65-3.67 (m, 2H), 3.08 (s, 6H), 2.95-2.97 (m, 2H ). 3. 366.0 4. Example 2

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38 R ulm ^N= % _CI XXH 1. 19% 2. ¹ H-NMR (400 MHz, DMSOde) δ = 8.15-8.16 (m, 1H), 7.83 (dd, J = 2.80, 9.60 Hz, 1H) , 7.24 (d, J= 8.80 Hz, 1H), 7.00 (d, J = 2.40 Hz, 1H), 6.73 (dd, J = 2.80, 8.60 Hz, 1H), 4.33 (bs, 2H), 3.69 (s, 3H), 3.65-3.67 (m, 2H), 3.10 (s, 6H), 2.94-2.97 (m, 2H). 3. 366.0 4. Example 2 39 Ър ⁿ _cr mo / 1. 13% 2. ¹ H-NMR (400 MHz, DMSOJ ₆ ) δ = 8.15-8.16 (m, 1Η), 7.82 (dd, J = 2.40, 9.60 Hz, 1H ), 7.18-7.22 (m, 2H), 6.96 (dd, J= 2.00, 8.60 Hz, 1H), 4.34 (bs, 2H), 3.66-3, 73 (m, 9H), 3.513.54 (m, 4H), 2.95-2.97 (m, 2H). 3. 408.0 4. Example 2 40 ' Uuu~eun Ts 1. 12% 2. ¹ H-NMR (400 MHz, DMSOde) δ = 10.66 (bs, 1H), 7.12-7.20 (m, 3H), 7.00 (d, J = 2, 28 Hz, 1H), 6.92 (d, J = 8.48 Hz, 1H), 6.66 (dd, J = 2.40, 8.68 Hz, 1H), 4.30 (bs, 2H) , 3.77 (s, 3H), 3.59-3.61 (m, 2H), 3.09 (s, 6H), 2.86 (bs, 2H). 3. 363.2 4. Example 2 41 -O ₄ УХ_^NH N ^? _C. ^H / Ух /ΓΥν _z \=< X ) ^s n 1 1. 15% 2. 'H-NMR (400 MHz, Chloroform-<7) δ = 7.50 (d, J= 8.8 Hz, 1H), 7.32 (d, J= 2.5 Hz, 1H), 7 .21 (dd, J = 8.8, 0.6 Hz, 1H), 7.15 (dd, J = 8.8, 2.5 Hz, 1H), 6.98 (d, J = 2.4 Hz, 1H), 6.87 (dd, J = 8.8, 2.5 Hz, 1H), 5.21 (s, 1H), 4.44 (t, J = 1.6 Hz, 2H), 3.90 (s, 4H), 3.71 (t, J= 5.7 Hz, 2H), 3.64 (s, 4H), 2.93 (td, J = 5.6, 2.7 Hz , ZN). 4. Example 1

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42 F-OP _HAPPY BIRTHDAY 1. 11% 2. Ή-NMR (400 MHz, DMSOd ₆ ) δ = 7.46-7.50 (m, 1H), 7.217.30 (m, 2H), 7.00 (d, J = 2, 40 Hz, 1H), 6.83-6.89 (m, 1H), 6.73 (dd, J= 2.40, 8.60 Hz, 1H), 4.33 (bs, 2H), 3, 61-3.65 (m, 5H), 3.10 (s, 6H), 2.88-2.89 (m, 2H). 3. 365.2 4. Example 2 43 rDr ^NNS| T.S. ci-Q^nQ, 1. 14% 2. Ή-NMR (400 MHz, DMSOd ₆ ) δ = 10.96 (bs, 1H), 7.37-7.51 (m, ZN), 7.07-7.12 (m, 2H), 6.84-6.83 (m, 1H), 4.35 (bs, 2H), 3.73 (bs, 4H), 3.61 (bs, 2H), 3.48 (bs, 4H ), 2.89 (bs, 2H). 3. 409.0 4. Example 2 44. ts _a .O>o '^So-W'O 1. 19% 2. ¹ H-NMR (400 MHz, DMSOd ₆ ) δ = 10.95 (bs, 1H), 7.43-7.47 (m, 1H), 7.18-7.21 (m , 2H), 7.06-7.09 (m, 1H), 6.81-6.97 (m, 2H), 4.33 (bs, 2H), 3.713.73 (m, 4H), 3, 60-3.62 (m, 2H), 3.52-3.54 (m, 4H), 2.872.88 (m, 2H). 3. 393.2 4. Example 2 45 _F xsp ^HHCI Ts cX^^O 1. 15% 2. 'H-NMR (400 MHz, DMSOd ₆ ) δ = 10.94 (bs, 1H), 7.4-7.45 (m, 1H), 7.27 (d, J = 8 .80 Hz, 1H), 7.04-7.08 (m, 2H), 6.776.85 (m, 2H), 4.33 (bs, 2H), 3.72 (bs, 4H), 3.56 -3.61 (m, 6H), 2.86 (bs, 2H). 3. 393.2 4. Example 2 Example 45 can also be prepared according to the procedure described in Preparative Example 33 and Example 97.

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46 θ'^Ο 1. 23% 2. Ή-NMR (400 MHz, DMSOd ₆ ) δ = 7.53-7.57 (m, 2H), 7.337.43 (m, 2H), 7.06-7.14 (m, 2H), 4.32 (bs, 2H), 3.67-3.74 (m, 6H), 3.47-3.50 (m, 4H), 2.93-2.96 (m, 2H) . 3. 410.0 4. Example 2 47 St. <~~ ^ΝΗ TS _a J3X Cho^n 1. 15% 2. Ή-NMR (400 MHz, DMSOd ₆ ) δ = 10.64 (bs, 1H), 7.16-7.24 (m, 2H), 7.00 (s, 2H), 6 .66-6.74 (m, 2H), 4.31 (bs, 2H), 3.77 (s, 3H), 3.59-3.61 (m, 2H), 3.11 (s, 6H ), 2.84-2.86 (m, 2H). 3. 363.3 4. Example 2 48 yut ₀₁ £YG^ , £А° TV/^N 1. 12% 2. Ή-NMR (400 MHz, DMSOde) δ = 7.61 (d, J = 8.40 Hz, 1H), 7.54-7.57 (m, 1H), 7.46-7.49 ( m, 1H), 7.20-7.21 (m, 1H), 7.07-7.12 (m, 1H), 6.93-6.96 (m, 1H), 4.37 (bs, 2H), 3.723.76 (m, 6H), 3.50-3.52 (m, 4H), 2.91-2.93 (m, 2H). 3. 410.0 4. Example 2 49 ^F '^^_0Н _CI OM 1. 10% 2. Ή-NMR (400 MHz, DMSOd ₆ ) δ = 7.54-7.57 (m, 1H), 7.447.46 (m, 1H), 7.29 (d, J = 8, 80 Hz, 1H), 7.07-7.12 (m, 2H), 6.80 (d, J= 8.80 Hz, 1H), 4.31 (bs, 2H), 3.66-3, 73 (m, 6H), 3.56-3.58 (m, 4H), 2.91-2.93 (m, 2H). 3. 394.2 4. Example 2

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50 R Уу^ ^{мн i} “^2,NQ^ _N ; 1. 23% 2. Ή-NMR (400 MHz, DMSO7 ₆ ) δ = 7.54-7.58 (m, 2Η), 7.48 (dd, 7 = 2.40, 8.80 Hz, 1H) , 7.18 (d, J = 2.00 Hz, 1H), 7.09-7.10 (m, 1H), 6.89 (dd, J = 2.40, 9.00 Hz, 1H), 4.37 (bs, 2H), 3.733.75 (m, 2H), 3.12 (s, 6H), 2.932.95 (m, 2H). 3. 368.0 4. Example 2 51 F. У\ Z~~NH 1. 5% 2. Ή-NMR (400 MHz, DMSO7 ₆ ) δ = 7.54-7.57 (m, 1H), 7.50 (d, J = 2.40 Hz, 1H), 7.42 (dd, J = 2.80, 9.00 Hz, 1H), 7.36 (d, J = 8.80 Hz, 1H), 7.07-7.12 (m, 2H), 4.30 ( bs, 2H), 3.65-3.67 (m, 2H), 3.10 (s, 6H), 2.93-2.94 (m, 2H). 3. 368.0 4. Example 2 52 F wU Ν' Ts H 1. 14% 2. Ή-NMR (400 MHz, DMSO7 ₆ )δ = 11.19 (bs, 1H), 7.60 (d, 7 = 8.80 Hz, 1H), 7.13-7.14 (m, 2H), 6.98-7.00 (m, 1H), 6.92 (d, J= 8.80 Hz, 1H), 6.71-6.76 (m, 1H), 4, 50 (bs, 2H), 3.70-3.73 (m, 6H), 3.51-3.52 (m, 4H), 2.89-2.88 (m, 2H). 3. 409.0 4. Example 2 53 F QU N ts _S1 F> 1. 8% 2. Ή-NMR (400 MHz, DMSO7 ₆ ) δ = 11.17 (bs, 1H), 7.27 (d, J = 8.76 Hz, 1H), 7.13 (d, J = 8.00 Hz, 1H), 6.98-7.01 (m, 2H), 6.70-6.78 (m, 2H), 4.44 (bs, 2H), 3.70-3, 73 (m, 4H), 3.61-3.63 (m, 2H), 3.56-3.57 (m, 4H), 2.86-2.88 (m, 2H). 3. 393.0 4. Example 2

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54 ZhR ^NNS| Ts XX ₅ F CI^^ ^S 1. 23% 2. Ή-NMR (400 MHz, DMSOd ₆ ) δ = 10.96 (bs, 1H), 7.437.48 (m, 2H), 7.35 (d, J = 8.80 Hz, 1H ), 7.07-7.09 (m, 2H), 6.81-6.86 (m, 1H), 4.33 (bs, 2H), 3.59-3.60 (m, 2H), 3.10 (s, 6H), 2.87-2.89 (m, 2H). 3. 367.0 4. Example 2 55 G-SIT ⁰¹ Ν Ts XXY ci^^ ^{0 4} 1. 20% 2. Ή-NMR (400 MHz, DMSOd ₆ ) δ = 10.95 (s, 1H), 7.42-7.46 (m, 1H), 7.19 (d, 7 = 2, 40 Hz, 1H), 3.52 (d, 7= 8.40 Hz, 1H), 7.06 (d, 7 = 2.40 Hz, 1H), 6.856.86 (m, 1H), 6.80 -6.84 (m, 1H), 4.31 (s, 2H), 3.59 (t, 7 = 5.60 Hz, 2H), 3.09 (s, 6H), 2.86 (t, 7 =5.20 Hz, 2H). 3. 351.1 4. Example 2 56 FriT Ν Ts jfTW _C| >^N\ 1. 27% 2. Ή-NMR (400 MHz, DMSO7 ₆ ) δ = 10.95 (bs, 1H), 7.43-7.46 (m, 1H), 7.20 (s, 1H), 7 .09-7.14 (m, 1H), 7.06-7.09 (m, 1H), 6.86-6.93 (m, 1H), 6.81-6.85 (m, 1H) , 4.31 (bs, 2H), 3.59 (bs, 2H), 3.09 (s, 6H), 2.85-2.87 (m, 2H). 3. 351.0 4. Example 2 57 Ε eASO 1. 16% 2. Ή-NMR (400 MHz, DMSO7 ₆ ) δ = 10.95 (bs, 1H), 7.43-7.46 (m, 1H), 7.23 (d, 7 = 8, 40 Hz, 1H), 7.06-7.09 (m, 1H), 7.00 (s, 1H), 6.81-6.86 (m, 1H), 6.73 (d, 7= 8 .80 Hz, 1H), 4.32 (bs, 2H), 3.60 (bs, 2H), 3.10 (s, 6H), 2.85-2.87 (m, 2H). 3. 351.0 4. Example 2

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58 F, UA—z~ ^NH 'Ay' ⁷ A/K q^q 1. 7% 2. ¹ H-NMR (400 MHz, DMSOde) δ = 7.54-7.58 (m, IH), 7.43 (dd, J = 2.80, 8.80 Hz, IH) , 7.20-7.24 (m, 2H), 7.09-7.12 (m, IH), 6.96 (dd, J= 2.00, 8.60 Hz, IH), 4.31 (bs, 2H), 3.663.73 (m, 6H), 3.52-3.55 (m, 4H), 2.90-2.93 (m, 2H). 3. 394.0 4. Example 2 59 ^F ^_^H .ХХН F 1. 16% 2. 'H-NMR (400 MHz, DMSOd ₆ ) δ = 7.54-7.58 (m, IH), 7.43 (dd, J = 2.40, 8.80 Hz, IH ), 7.23 (d, J = 2.00 Hz, IH), 7.07-7.16 (m, 2H), 6.93 (dd, J = 2.00, 8.40 Hz, IH) , 4.29 (bs, 2H), 3.643.67 (m, 2H), 3.09 (s, 6H), 2.922.93 (m, 2H). 3. 352.0 4. Example 2 60 F Α/ΝΗ Q.U. Ν' Ts „.OO £c ^oi ^H 1. 16% 2. 'H-NMR (400 MHz, DMSOd ₆ ) δ = 7.54-7.57 (m, IH), 7.45 (d, J = 8.80 Hz, IH), 7, 25 (dd, J = 1.60, 8.60 Hz, IH), 7.02-7.12 (m, 2H), 6.73-6.75 (m, IH), 4.30 (bs, 2H), 3.65-3.68 (m, 2H), 3.11 (s, 6H), 2.92-2.93 (m, 2H). 3. 352.0 4. Example 2 61 F-Dr P>O U/—N Cl ⁷ 'Chsg ⁰ ^^ / 1. 16% 2. 'H-NMR (400 MHz, DMSOd ₆ ) δ = 10.96 (s, IH), 7.51 (d, J = 2.00 Hz, IH), 7.39 (d, J= 9.20 Hz, IH), 7.27-7.29 (m, 2H), 7.10-7.13 (m, IH), 6.83-6.88 (m, IH), 4 .33 (s, 2H), 3.73 (t, J = 5.20 Hz, 4H), 3.63 (t, J = 5.60 Hz, 2H), 3.48 (t, J = 4, 80 Hz, 4H), 2.90 (s, 2H). 3. 423.2 4. Example 2

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62 --Op g-\ f G 0 _C |X>0 - ^vO 1. 23% 2. ¹ H-NMR (400 MHz, DMSOd ₆ ) δ = 7.47-7.50 (m, IH), 7.277.30 (m, IH), 7.18-7.22 (m , 2H), 6.95-6.97 (m, IH), 6.846.89 (m, IH), 3.12 (s, 2H), 3.72 (t, J= 5.20 Hz, 4H) , 3.65 (t, J= 5.60 Hz, 2H), 3.62 (s, 3H), 3.52 (t, J= 4.40 Hz, 4H), 2.89 (t, J= 5.60 Hz, 2H). 3. 407.2 4. Example 2 63 Ts 0>° H 1. 35% 2. 'H-NMR (400 MHz, DMSOd ₆ ) δ = 10.95 (bs, IH), 7.58 (d, J = 8.80 Hz, IH), 7.47-7, 50 (m, IH), 7.17 (s, IH), 7.06-7.09 (m, IH), 6.93 (d, J= 8.80 Hz, IH), 6.81-6 .86 (m, IH), 4.39 (bs, 2H), 3.68-3.72 (m, 6H), 3.513.52 (m, 4H), 2.86 (bs, 2H). 3. 409.0 4. Example 2 64 blow Γ'ΪΓ^. /-, ci-AA _s % _N p _o 0_уО 1. 21% 2. Ή-NMR (400 MHz, DMSOd ₆ ) δ = 7.51 (d, 7 = 2.40 Hz, IH), 7.45-7.48 (m, IH), 7.37 (d, J = 8.40 Hz, IH), 7.26-7.29 (m, IH), 7.09-7.12 (m, IH), 6.836.69 (m, IH), 4, 35 (s, 2H), 3.72 (t, J = 5.20 Hz, 4H), 3.65 (t, J = 5.60 Hz, 2H), 3.61 (s, 3H), 3, 47 (t, J = 4.80 Hz, 4H), 2.90 (s, 2H). 3. 423.3 4. Example 2 65 -Op LC) 4p' 1. 40% 2. Ή-NMR (400 MHz, DMSOd ₆ ) δ = 7.47-7.51 (m, IH), 7.257.30 (m, 2H), 7.05 (s, IH), 6.846 .89 (m, IH), 6.79 (d, J= 8.40 Hz, IH), 4.34 (bs, 2H), 3.703.72 (m, 4H), 3.64-3.66 ( m, 2H), 3.61 (s, 3H), 3.56-3.57 (m, 4H), 2.80-2.88 (m, 2H). 3. 407.2 4. Example 2

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66 1. 24% 2. Ή-NMR (400 MHz, DMSO7 ₆ ) δ = 7.50-7.55 (m, 2H), 7.267.30 (m, 1H), 7.15 (d, J = 2, 40 Hz, 1H), 6.84-6.90 (m, 2H), 4.40 (bs, 2H), 3.71-3.72 (m, 2H), 3.61 (s, 3H), 3.11 (s, 6H), 2.88 (bs, 2H). 3. 381.2 4. Example 2 67 days 1. 23% 2. Ή-NMR (400 MHz, DMSOde) δ = 7.46-7.50 (m, 2H), 7.277.35 (m, 2H), 7.07-7.10 (m, 1H), 6, 85-6.89 (m, 1H), 4.34 (bs, 2H), 3.64-3.65 (m, 2H), 3.62 (s, 3H), 3.10 (s, 6H) , 2.882.91 (m, 2H). 3. 381.2 4. Example 2 68 '-ορ·· ΉΕ Αο-α?. 1. 34% 2. Ή-NMR (400 MHz, DMSO7 ₆ ) δ = 7.46-7.50 (m, 1H), 7.277.30 (m, 1H), 7.20 (d, J = 2, 16 Hz, 1H), 7.13 (d, J= 8.52 Hz, 1H), 6.84-6.93 (m, 2H), 4.33 (bs, 2H), 3.62-3, 64 (m, 5H), 3.09 (s, 6H), 2.88-2.90 (m, 2H). 3. 365.1 4. Example 2 69 Ts eAN ΆοΑ4 1. 10% 2. Ή-NMR (400 MHz, DMSO7 ₆ ) δ = 10.96 (bs, 1H), 7.47-7.55 (m, 2H), 7.15 (d, J = 1, 60 Hz, 1H), 7.06-7.09 (m, 1H), 6.846.89 (m, 2H), 4.38 (bs, 2H), 3.66-3.69 (m, 2H), 3.12 (s, 6H), 2.87 (bs, 2H). 3. 367.2 4. Example 2

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70 ACT +s f^N-N 1.15% 2. ¹ H-NMR (400 MHz, DMSOJ ₆ ) δ =11.02 (s, 1H), 8.38 (d, J = 7.56 Hz, 1H), 7.47-7, 51 (m, 1H), 7.07-7.10 (m, 1H), 6.806.90 (m, 3H), 4.52 (s, 2H), 3.80-3.82 (m, 2H) , 3.68-3.70 (m, 4H), 3.37-3.40 (m, 4H), 2.90 (t, J = 4.72 Hz, 2H). 3. 392.17 4. Example 2 71 E y=\ /~νη uu N Ts 0У° ci ⁷ ^ _a yO up H 1. 27% 2. 'H-NMR (400 MHz, DMSOd ₆ ) δ = 10.98 (s, 1H), 8.23 (d, 1H), 8.00 (d, 1H), 7.25 ( m, 2H), 6.86 (m, 1H), 4.37 (s, 2H), 3.74 (t, 4H), 3.67 (t, 2H), 3.55 (t, 4H), 2.91 (t, 2H). 3. 410.15. 72 T.S. cCr° oL Λ^νΟ _F >==N ^S 1. 34% 2. Ή-NMR (400 MHz, DMSOde) δ = 10.98 (s, 1H), 7.69 (d, 1H), 7.27 (dt, 2H), 6.98 (d, 1H), 6 .86 (td, 1H), 4.62 (s, 2H), 3.97 (t, 2H), 3.73 (t, 4H), 3.48 (t, 4H), 2.89 (t, 2H). 3. 410.16. 73 D£G Ts N^vO 0-s Br'^ £A° -40 H 1. 17% 2. Ή-NMR (400 MHz, DMSOd ₆ ) δ = 10.99 (bs, 1H), 8.23 (d, J = 2.68 Hz, 1H), 8.01 (d, J = 2.68 Hz, 1H), 7.43-7.44 (m, 1H), 7.07-7.08 (m, 1H), 6.826.82 (m, 1H), 4.39 (s, 2H), 3.733.74 (m, 4H), 3.64-3.66 (m, 2H), 3.54-3.55 (m, 4H), 2.90 (bs, 2H). 3. 410.1. 4. Example 2

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74 r-NH.HCI ^f oP Ts y-O N-? cr 0 /X; H 1. 25% 2. ¹ H-NMR (400 MHz, DMSOde) δ = 1H NMR (400 MHz, DMSO-de) δ 10.95 (bs, 1H), 8.00-8.02 (m, 1H) , 7.43-7.45 (m, 1H), 7.20-7.28 (m, 2H), 6.79-6.87 (m, 2H), 4.24-4.26 (m, 2H), 3.69-3.71 (m, 4H), 3.52-3.54 (m, 2H), 3.29-3.36 (m, 4H), 2.50-2.52 ( m, 2H). 3. 353.0 4. Example 2 75 R y-y yNH if cr 0 nV w? V 1. 19% 2. 'H-NMR (400 MHz, DMSOd ₆ ) δ = 7.86-7.87 (m, 1H), 7.607.68 (m, 1H), 7.39-7.43 (m , 1H), 7.28 (dd, J = 2.40, 10.00 Hz, 1H), 6.91-6.99 (m, 2H), 4.31 (bs, 2H), 3.58- 3.73 (m, 9H), 3.36-3.43 (m, 4H), 2.90 (bs, 2H). 3. 367.0 4. Example 2 76 /—NH.HCI ^f yw ts W WK? N H 1. 11% 2. Ή-NMR (400 MHz, DMSOd ₆ ) δ = 10.95 (bs, 1H), 7.86-7.87 (m, 1H), 7.34 (d, J = 9, 08 Hz, 1H), 7.21-7.27 (m, 2H), 6.93 (d, J = 8.88 Hz, 1H), 6.82-6.89 (m, 1H), 4, 54 (bs, 2H), 3.86-3.89 (m, 2H), 3.73 (bs, 4H), 2.98 (bs, 4H), 2.85 (bs, 2H). 3. 353.0 4. Example 2 77 W O •W WK? 7 1. 12% 2. Ή-NMR (400 MHz, DMSOde) δ = 7.87 (d, J = 3.20 Hz, 1H), 7.38-7.41 (m, 1H), 7.32-7.35 ( m, 1H), 7.26-7.29 (m, 1H), 6.90-6.96 (m, 2H), 4.57 (bs, 2H), 3.91-3.94 (m, 2H), 3.713.74 (m, 4H), 3.63 (s, 3H), 2.962.98 (m, 4H), 2.87-2.89 (m, 2H). 3. 367.0 4. Example 2

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78 Ts ^MoBr 1. 29% 2. Ή-NMR (400 MHz, DMS07 ₆ ) δ =10.94 (s, 1H), 7.87 (d, J = 3.60 Hz, 1H), 7.43-7.46 (m, 1H), 7.32-7.36 (m, 1H), 7.047.08 (m, 1H), 3.12 (d, J= 12.40 Hz, 1H), 6.79-6, 85 (m, 1H), 4.56 (s, 2H), 3.89 (t, J = 7.60 Hz, 2H), 3.73 (t, J = 6.00 Hz, 4H), 2, 97 (t, 7= 6.00 Hz, 4H). 3. 353.2 4. Example 2 79 Ts ΒγΆ^Ν XΛθ M YWn hn-Vj 1. 25% 2. Ή-NMR (400 MHz, DMSO7 ₆ ) δ = 10.94 (s, 1H), 8.00 (d, J = 2.80 Hz, 1H), 7.40-7.46 (m, 2H), 7.05-7.08 (m, 1H), 6.796.85 (m, 2H), 3.12 (s, 2H), 3.69 (t, 7= 5.20 Hz, 4H), 3.51 (t, 7 = 5.20 Hz, 2H), 3.28 (t, 7 = 4.80 Hz, 4H), 2.84 (s, 2H). 3. 353.2 4. Example 2 80 .0° 0 0 V 1. 27% 2. Ή-NMR (400 MHz, DMSO7 ₆ ) δ = 7.87 (d, 7 = 2.64 Hz, 1H), 7.45-7.47 (m, 1H), 7.26 -7.27 (m, 2H), 6.95 (d, 7 = 9.08 Hz, 1H), 6.83-6.83 (m, 1H), 4.59 (s, 2H), 3, 90-3.91 (m, 2H), 3.713.73 (m, 4H), 3.62 (s, 3H), 2.962.97 (m, 4H), 2.86 (s, 2H), 1.081.10 (m, 2H). 3. 367.1 4. Example 2 81 F /M, /—NH U.M. N' Tos 0 0 Br~^ c° them NH 1. 23% 2. Ή-NMR (400 MHz, DMSO7 ₆ ) δ= 11.18 (bs, 1H), 7.99 (s, 1H), 7.43-7.43 (m, 1H), 7 .13 (d, 7= 8.08 Hz, 1H), 6.95-6.97 (m, 1H), 6.80-6.82 (m, 1H), 6.706.71 (m, 1H), 4.38 (s, 2H), 3.693.70 (m, 4H), 3.51-3.53 (m, 2H), 3.28-3.29 (m, 4H), 2.852.86 (m, 2H). 3. 353.2 4. Example 2

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82 F 0 Tos 'NH ,xy° Br N A 1. 27% 2. Ή-NMR (400 MHz, DMS07b) δ = 11.16 (bs, 1H), 7.88 (d, J = 2.68 Hz, 1H), 7.32-7.33 (m, 1H) , 7.12 (d, J= 7.92 Hz, 1H), 6.91-6.93 (m, 2H), 6.69-6.71 (m, 1H), 4.71 (s, 2H ), 3.88 (t, J = 5.12 Hz, 2H), 3.73-3.74 (m, 4H), 2.97-2.98 (m, 4H), 2.85 (bs, 2H). 3. 353.2 4. Example 2 83 F dr N 1 -NH 0 Br 0 G 0 dr* 'N' 1 1. 26% 2. Ή-NMR (400 MHz, DMSO7 ₆ ) δ = 7.99 (d, J = 2.80 Hz, 1H), 7.45 (dd, J = 2.96, 9.16 Hz , 1H), 7.26 (d, J= 8.24 Hz, 1H), 7.057.06 (m, 1H), 6.75-6.76 (m, 2H), 4.39 (s, 1H) , 3.69-3.70 (m, 4H), 3.65 (s, 3H), 3.56-3.57 (m, 2H), 3.28-3.29 (m, 4H), 2 .88 (bs, 2H). 3. 367.2 4. Example 2 84 (M ~NH 0 β 0 —z Ύ Q-Z z^^ 1. 23% 2. Ή-NMR (400 MHz, DMSO7 ₆ ) δ = 7.85 (d, J = 2.80 Hz, 1H), 7.47 (d, J = 8.00 Hz, 1H), 7.37 (d, J = 8.00 Hz, 1H), 7.30-7.31 (m, 1H), 7.06-7.06 (m, 1H), 6.93-6.95 ( m, 2H), 4.59 (s, 2H), 3.89-3.90 (m, 2H), 3.70-3.71 (m, 4H), 3.61 (s, 3H), 2 .94-2.95 (m, 4H), 2.85-2.86 (m, 2H). 3. 349.1 4. Example 2 85 Qi +os -NH DO Q O ^Z Q L ^ZI 0 1. 24% 2. Ή-NMR (400 MHz, DMSOd ₆ ) δ = 10.84 (s, 1H), 7.88 (d, J = 2.92 Hz, 1H), 7.45 (d, J = 7.68 Hz, 1H), 7.32-7.33 (m, 1H), 7.28 (d, J = 7.92 Hz, 1H), 6.936.95 (m, 3H), 3.91 (t, J= 5.56 Hz, 2H), 3.72-3.73 (m, 4H), 2.96-2.97 (m, 4H), 2.84-2.85 (m, 2H ). 3. 335.1 4. Example 2

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86 Qi N Tos N.H. 0 ^NBr 0 O QG ' _N - ' H 1. 53% 2. 'H-NMR (400 MHz, DMSOd ₆ ) δ = 10.85 (s, 1H), 8.02 (d, J = 2.72 Hz, 1H), 7.43-7, 45 (m, 2H), 7.28-7.30 (m, 1H), 6.956.97 (m, 2H), 6.80-6.81 (m, 1H), 4.28-0.00 ( m, 2H), 3.693.71 (m, 4H), 3.53-3.54 (m, 2H), 3.28-3.29 (m, 4H), 2.87 (bs, 2H). 3. 335.2 4. Example 2 87 lH/ ^NH ΒγΆ^Ν 1. 23% 2. 'H-NMR (400 MHz, DMSO7b): δ 8.01 (d, J = 2.40 Hz, 1H), 7.46-7.48 (m, 2H), 7.27-7.30 (m, 1H), 6.79-6.89 (m, 2H), 4.28 (s, 2H), 3.12 (t, J = 4.40 Hz, 4H), 3.61 (s, 3H), 3.56 (t, J = 5.60 Hz, 2H), 3.29 (t, J = 4.40 Hz, 4H), 2.87 (s, 2H). 3. 367.3 4. Example 2 88 F~f~v Xu ^NH XGAGo 1. 17% 2. 'H-NMR (400 MHz, DMSOd ₆ y. δ 11.00 (bs, 1H), 7.69 (d, J = 8.88 Hz, 1H), 7.47 (t, J= 5.88 Hz, 1H), 7.08 (d, J= 10.12 Hz, 1H), 6.99 (d, 7 =8.68 Hz, 1H), 6.84 (t, J = 8.52 Hz, 1H), 4.64 (s, 2H), 3.95-3.96 (m, 2H), 3.72 (d, 7 =4.08 Hz, 4H), 3.48 ( d, 7 = 3.96 Hz, 4H), 2.87 (bs, 2H). 3. 410.1 4. Example 2 89 ^F ~/~\ Xu ^NH WXo 1. 15% 2. Ή-NMR (400 MHz, DMSO7 ₆ ): δ 10.98 (bs, 1H), 8.35 (s, 1H), 7.42-7.43 (m, 2H), 7.067 .07 (m, 1H), 6.81-6.82 (m, 1H), 4.62 (s, 2H), 3.98 (bs, 2H), 3.71-3.73 (m, 4H ), 3.51 (bs, 4H), 2.87 (bs, 2H). 3. 410.1 4. Example 2

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90 EA ^NH TsNxL s'U^lo 1. 21% 2. 'H-NMR (400 MHz, DMSOd ₆ y δ 10.96 (s, IH), 8.34 (s, IH), 7.45 (s, IH), 7.19-7 .22 (m, 2H), 6.85 (s, IH), 4.60 (s, 2H), 3.98 (bs, 2H), 3.71 (bs, 4H), 3.50 (bs, 4H), 2.87 (bs, 2H). 3. 410.1 4. Example 2 91 λ//TsN-%> ? A 0w 1. 15% 2. 'H-NMR (400 MHz, DMSOd ₆ y δ 10.98 (s, IH), 7.87 (d, J= 8.96 Hz, IH), 7.51-7.52 (m, 2H), 7.20-7.21 (m, IH), 7.067.07 (m, IH), 7.00 (s, IH), 6.92 (d, J = 8.96 Hz, IH), 6.81-6.82 (m, IH), 4.49 (s, 2H), 3.77-3.79 (m, 2H), 3.70-3.71 (m, 4H) , 3.59-3.60 (m, 4H), 2.90 (bs, 2H) 3. 403.2 4. Example 2 92 7l NH TsN-AL axA 1. 16% 2. 'H-NMR (400 MHz, DMSOd ₆ y δ 10.99 (s, IH), 7.96 (d, J= 9.12 Hz, IH), 7.45-7.47 (m, 3H), 7.22 (s, IH), 7.17 (d, J = 9.12 Hz, IH), 7.08-7.08 (m, IH), 6.82-6, 83 (m, IH), 4.42 (s, 2H), 3.68-3.70 (m, 6H), 3.543.56 (m, 4H), 2.92 (bs, 2H). ,2 4. Example 2 93 E All NH nAJ / Br-^jC^r ^x 1. 78% 2. Ή NMR (400 MHz, DMSO-bA,) δ 8.48 (d, J= 9.6 Hz, IH), 8.42-8.33 (m, IH), 7.79 (d, 7 = 9.7 Hz, IH), 7.54 - 7.45 (m, 3H), 7.35 - 7.25 (m, IH), 7.07-6.95 (m, IH), 5, 14 (s, 2H), 4.50-4.30 (m, 2H), 3.89 (s, 3H), 3.70 (s, 3H), 3.24 - 3.07 (m, 2H) . 4. Example 1

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94 E fl N.H. N-K>/ ΒγΎν ΟΧνΎν 1. 47% 2. Ή NMR (400 MHz, Chloroform-d) δ 8.12 (d, J= 2.5 Hz, IH), 7.84 (d, 7=2.5 Hz, IH), 7.22 (dd , J = 8.8, 4.3 Hz, IH), 7.17 (dd, J = 9.5, 2.5 Hz, IH), 6.97 (td, J = 9.1, 2.5 Hz, IH), 6.84 (t, J = 2.4 Hz, IH), 4.47 (t, J = 1.6 Hz, 2H), 3.90 (s, 3H), 3.80( t, J= 5.7 Hz, 2H), 3.67 (s, 3H), 3.00 - 2.93 (m, 2H). 4. Example 1 95 E Λι Sfj N.H. N-\y/ BgC^ w 1. 58% 2. Ή NMR (400 MHz, DMSO-7 ₆ ) δ 8.04 - 7.85 (m, IH), 7.50 - 7.39 (m, IH), 7.31 (d, J= 9.8 Hz, IH), 7.12 - 7.01 (m, IH), 6.96 (t, J = 9.3 Hz, IH), 6.63 (s, IH), 4, 84 (s, 2H), 4.22 - 3.99 (m, 5H), 3.65 (s, 3H), 3.10 -2.97 (m, 2H). 4. Example 1 96 E fl__ 'F]/ NH / Вг'-''O at 1. 83% 2. IH NMR (400 MHz, DMSO-7b) δ 7.58 (d, 7=8.5 Hz, 2H), 7.57-7.52 (m, OH), 7.46 (dt, 7= 7.5, 3.2 Hz, IH), 7.30 (d, 7= 9.8 Hz, IH), 7.23 (d, 7= 8.6 Hz, 2H), 6.99 (t, 7 = 9.3 Hz, IH), 4.67 (s, 2H), 3.96 (t, 7 = 6.0 Hz, 2H), 3.80 (d, 7 = 5.6 Hz, 4H) , 3.66 (d,7 = 5.2 Hz, ZN), 3.27 (d, 7 = 5.6 Hz, 4H), 3.20 (s, 2H) 4. Example 1 96a HCl Cl n 1 '°£rO~ 1.15% 2. Ή-NMR (400 MHz, DMSOd ₆ ): δ 7.28 (d, 7= 8.80 Hz, IH), 7.22 (d, 7= 8.40 Hz, IH), 7.02 (dd, 7 = 2.40, 16.40 Hz, 2H), 6.71-6.71 (m, 2H), 4.31 (s, 2H), 3.77 (s, ZN) , 3.64 (t, 7 = 5.60 Hz, 2H), 3.59 (s, ZN), 3.10 (s, 6H), 2.85-2.85 (m, 2H). 3.377.1 4. Example 2

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96b ^HCI λ II NH ciX^nQ, 1. 22% 2. Ή-NMR (400 MHz, DMSOά>) δ 8.22-8.23 (m, 1H), 8.068.06 (m, 1H), 7.33-7.34 (m, 1H), 7. 29 (d, J = 8.72 Hz, 1H), 7.08 (d, 7 = 2.36 Hz, 1H), 6.80 (dd, 7 = 2.48, 8.74 Hz, 1H), 4.34 (s, 2H), 3.67-3.69 (m, 6H), 3.55-3.56 (m, 4H), 2.96 (bs, 2H). 3. 377.2 4. Example 2 96c HCl TsN-\^ /vO OO 1. 29% 2. Ή-NMR (400 MHz, DMSO7 ₆ ): δ 11.00 (bs, 1H), 9.11 (s, 1H), 7.78-7.79 (m, 1H), 7.457 .46 (m, 2H), 7.31 (d, 7= 2.80 Hz, 1H), 7.08-7.09 (m, 1H), 6.82-6.83 (m, 1H), 4.44 (s, 2H), 3.70-3.71 (m, 10H), 2.93-2.94 (m, 2H). 3. 404.0 4. Example 2 96d E nX/ / 3 F ₃ C / 1. 66% 2. 1H NMR (400 MHz, Chloroform-7) δ 8.60 (d, 7 = 2.9 Hz, 1H), 8.34 (s, 1H), 7.52 7.43 (m, 1H), 7.22 (ddd, 7 = 16,3,9,1,3,4 Hz, 2H), 6.99 (td, 7 = 9.1, 2.6 Hz, 2H), 4.54 (d, 7= 1.9 Hz, 2H), 3.87 (t, 7= 5.7 Hz, 2H), 3.69 (s, 3H), 3.00 (d, 7 = 5.6 Hz, 1H) . 4. Example 1 96e E N'V I rr ^F Br^N / 1. 62% 2. Ή NMR (400 MHz, DMSO7 ₆ ) δ 8.10 (d, 7 = 3.0 Hz, 1H), 7.61 (t, 7 = 8.9 Hz, 1H), 7, 38 (dd, 7 = 8.9, 4.4 Hz, 1H), 7.24 (dd, 7 = 9.8, 2.5 Hz, 1H), 7.10 (d, 7 = 9.4 Hz , 1H), 6.92 (td, 7= 9.2, 2.5 Hz, 1H), 4.63 (s, 2H), 3.97 (t, 7= 5.7 Hz, 2H), 3 .60 (s, ZN), 2.89 (t, 7= 5.6 Hz, 2H). 4. Example 1

Example 97.

The title compound of Preparative Example 33 (0.072 g, 0.142 mmol) and cesium carbonate (0.107 g, 0.328 mmol) were placed in a microwave tube, followed by MeOH (1.5 mL) and THF (3 mL). The reaction mixture was irradiated in a microwave oven to 110°C for 30 min and then allowed to cool to room temperature. Solvents were removed under reduced pressure and the residue was purified on a silica gel column using a Biotage Isolera One purification system with a nheptane/ethyl acetate gradient (80/20^0/100) to give the title compound as a yellow solid (0.027 g , 53%).

MS: 354.2 (M+H)+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ=10.96 (s, 1H), 7.39 (d, J=9.9 Hz, 1H), 7.28 (s, 1H), 7 .26 (t, J=4.4 Hz, 1H), 7.20 (dd, J=10.0, 2.6 Hz, 1H), 6.85 (td, J=9.2, 2.6 Hz, 1H), 4.62 (s, 2H), 3.91 (t, J=5.7 Hz, 2H), 3.79-3.67 (m, 4H), 3.37-3.32 (m, 4H), 2.88 (t, J=5.6 Hz, 2H).

Examples 98 to 105f.

Following the tosylate cleavage procedure as described in Example 97, except that the tosyl-substituted intermediates listed in the table below were used, the following compounds were obtained.

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Table 3

Example Tosyl-protected intermediate Product 1. Output 2. Ή-NMR Z. MN ⁺ (ESI) 98 ^t ' iz N Ts ,-oyNH \M“° Ν' H 1. 11% 2. Ή-NMR (400 MHz, Chloroformd) δ = 7.95 (s, 1H), 7.29 - 7.24 (m, 1H), 7.22 (dd, J = 8.8, 4.3 Hz, 1H), 7.12 (dd, J= 9.5, 2.5 Hz, 1H), 7.04 (d, J= 2.3 Hz, 1H), 6.96 (dd, J= 8 ,6, 2.3 Hz, 1H), 6.89 (td, J= 9.1, 2.5 Hz, 1H), 5.31 (s, 1H), 4.36 (s, 2H), 3 .64 (t, J = 5.6 Hz, 2H), 3.10 (s, 3H), 2.94 (td, J = 5.7, 4.9, 2.8 Hz, 2H). 3. 337.0 99 ABOUT E N Ts oD7 L ^ZI O LL 1.47% 2. Ή-NMR (400 MHz, DMSO-7 ₆ ) δ = 11.00 (s, 1H), 7.93 (d, 7 = 6.0 Hz, 1H), 7.35 - 7.18 (m, 2H), 6.86 (td, 7= 9.3, 2.6 Hz, 1H), 6.26 (d, 7= 6.0 Hz, 1H), 4.67 (s, 2H) , 4.00 (s, 2H), 3.64 (s, 8H), 2.84 (t, 7= 5.7 Hz, 2H). 3. 354.2 100 Ν _F Π y-Vv-* Coy Ν' Ts F Ssh N'H 1. 92% 2. Ή-NMR (400 MHz, DMSO-7 ₆ ) δ = 10.96 (s, 1H), 8.07 (d, 7 = 1.5 Hz, 1H), 7.92 (d , 7= 1.5 Hz, 1H), 7.26 (dd, 7 = 8.8, 4.6 Hz, 1H), 7.22 (dd, 7= 9.9, 2.6 Hz, 1H) , 6.85 (td, 7= 9.2, 2.6 Hz, 1H), 4.55 (s, 2H), 3.88 (t, 7= 5.7 Hz, 2H), 3.77 - 3.66 (m, 4H), 3.28 (q, 7= 4.9, 4.0 Hz, 4H), 2.87 (t, 7= 5.7 Hz, 2H). 3. 354.5 101 A'- _N'TS NH 1.22% 2. Ή-NMR (400 MHz, DMSO-7 ₆ ) δ = 10.98 (s, 1H), 7.46 - 7.36 (m, 2H), 7.26 (d, 7 = 9, 9 Hz, 1H), 7.07 (dd, 7 = 10.2, 2.4 Hz, 1H), 6.83 (ddd, 7 = 9.9, 8.6, 2.4 Hz, 1H), 4.64 (s, 2H), 3.89 (t, 7 = 5.6 Hz, 2H), 3.71 (t, 7 = 4.8 Hz, 4H), 3.38 - 3.32 (m , 4H), 2.86 (t, 7 = 5.7 Hz, 2H). 3. 354.5

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102 ,<Ή N Ts ..sh/ N H 1. 39% 2. Ή-NMR (400 MHz, DMSOM,) δ = 10.95 (s, 1H), 7.44 - 7.34 (m, 2H), 7.15 (d, J = 9.9 Hz, 1H ), 7.06 (dd, J= 10.1, 2.3 Hz, 1H), 6.82 (t, J= 9.2 Hz, 1H), 4.62 (s, 2H), 4.42 (s, 2H), 3.87 (t, J = 5.7 Hz, 2H), 3.68 (d, J = 11.8 Hz, 2H), 2.96 - 2.80 (m, 4H) , 1.91 - 1.73 (m, 4H). 3. 380.5 103 /-0 N-E .A f4==oU N Ts A -SH/ N H 1. 67% 2. Ή-NMR (400 MHz, DMSOM,) δ = 10.98 (s, 1H), 8.08 (d, J= 1.5 Hz, 1H), 7.91 (d, J= 1.5 Hz, 1H), 7.43 (dd, J= 8.6, 5.5 Hz, 1H), 7.07 (dd, J = 10.2, 2.4 Hz, 1H), 6.82 (ddd , J = 9.9, 8.6, 2.4 Hz, 1H), 4.57 (s, 2H), 3.87 (t, J = 5.7 Hz, 2H), 3.76 - 3, 66 (m, 4H), 3.30 - 3.24 (m, 4H), 2.85 (t, J = 5.7 Hz, 2H). 3. 354.5 104 N MJ at Ts N Ή> ъ A N H 1. 16% 2. Ή-NMR (400 MHz, DMSOM,) δ = 11.01 (s, 1H), 8.51 (s, 1H), 7.31 - 7.20 (m, 2H), 6.85 (td , J= 9.2, 2.6 Hz, 1H), 4.84 (s, 2H), 4.15 (t, J= 5.7 Hz, 2H), 3.76 - 3.66 (m, 4H), 3.52 (t, J = 4.9 Hz, 4H), 2.87 (s, 2H). 3. 354.5 105 F ^CHU-Αί 1. 48% 2. Ή-NMR (400 MHz, DMSO-Ή) δ = 10.98 (s, 1H), 8.04 (d, J= 1.5 Hz, 1H), 7.94 (d, J= 1, 5 Hz, 1H), 7.26 (dd, J= 8.8, 4.6 Hz, 1H), 7.21 (dd, J = 10.0, 2.6 Hz, 1H), 6.89 - 6.82 (m, 1H), 4.53 (s, 2H), 4.32 (s, 2H), 3.87 (t, J = 5.7 Hz, 2H), 3.67 (d, J = 10.7 Hz, 2H), 3.49 (dd, J = 10.8, 1.8 Hz, 2H), 2.87 (t, J = 5.7 Hz, 2H), 1.94 - 1 .86 (m, 2H), 1.83 - 1.73 (m, 2H). 3. 354.5

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105a Q.8 Ts 0 . 8 H 1. 18% 2. Ή-NMR (400 MHz, DMSO-7 ₆ ) δ = 10.99 (s, 1H), 7.81 (d, J = 9.2 Hz, 2H), 7.44 (d , 1H), 7.36 - 7.19 (m, 3H), 6.92 - 6.78 (m, 1H), 4.77 (s, 2H), 4.09 (t, 2H), 3, 73 (t, J = 4.7 Hz, 4H), 3.53 (t, J = 4.7 Hz, 4H), 2.92 (t, J = 5.8 Hz, 2H). 3.404.19 105b 0 8 ΆΌ is 0 8,008) H 18% 2. Ή-NMR (400 MHz, DMSO-7b) δ = 10.99 (s, 1H), 7.81 (d, J = 9.2 Hz, 2H), 7.44 (d, 1H), 7 .36 - 7.19 (m, 3H), 6.92 - 6.78 (m, 1H), 4.77 (s, 2H), 4.09 (t, 2H), 3.73 (t, J = 4.7 Hz, 4H), 3.53 (t, J = 4.7 Hz, 4H), 2.92 (t, J = 5.8 Hz, 2H). 3.404.19 105c 0 0 00 Y Ts 0 80 NH 1.4% 2. Ή-NMR (400 MHz, DMSO-7b) δ = 10.94 (s, 1H), 7.98 (d, 7 = 3.0 Hz, 1H), 7.46 - 7.36 (m, 2H), 7.06 (dd, J= 10.2, 2.4 Hz, 1H), 6.87 - 6.75 (m, 2H), 4.24 (s, 2H), 3.50 (t , J = 5.6 Hz, 2H), 3.37 - 3.32 (m, 4H), 2.89 - 2.79 (m, 2H), 2.39 (t, J = 5.1 Hz, 4H), 2.21 (s, 3H). 3. 366.19 105d (S)/^ kY< ⁵⁾ 0 TAD N Ts 00 o '80 NH 1. 52% 2. Ή-NMR (400 MHz, DMSO-7 ₆ ) δ = 10.94 (s, 1H), 7.93 (d, J = 2.9 Hz, 1H), 7.47 - 7 .35 (m, 2H), 7.07 (dd, J= 10.2, 2.4 Hz, 1H), 6.81 (s, 1H), 6.51 (d, J= 9.0 Hz, 1H), 4.70 (s, 1H), 4.59 (s, 1H), 4.21 (d, J= 1.6 Hz, 2H), 3.74 (dd, J= 7.3, 1 .5 Hz, 1H), 3.62 (d, J= 7.2 Hz, 1H), 3.46 (t, J= 5.7 Hz, 2H), 3.42 (dd, 7=9.8 , 1.5 Hz, 1H), 3.16 (d, 7 = 9.8 Hz, 1H), 2.93 - 2.78 (m, 2H), 1.88 (dd, 7 = 9.6, 2.2 Hz, 1H), 1.84 - 1.76 (m, 1H). 3. 365.15 105e "0" 0 80 N Ts Ά 0 Ά0 N ^Z ^ H 1. 37% 2. Ή-NMR (400 MHz, DMSO-7 ₆ ) δ = 10.94 (s, 1H), 7.93 (d, 7 = 2.9 Hz, 1H), 7.47 - 7 .31 (m, 2H), 7.06 (dd,7= 10.2, 2.4 Hz, 1H), 6.81 (ddd, 7= 10.0, 8.6, 2.4 Hz, 1H ), 6.51 (d, 7= 9.0 Hz, 1H), 4.70 (s, 1H), 4.59 (s, 1H), 4.21 (s, 2H), 3.74 (dd ,7=7.3, 1.5 Hz, 1H), 3.62 (d, 7 = 7.2 Hz, 1H), 3.46 (t, 7 = 5.7 Hz, 2H), 3.42 (dd, 7 = 9.8, 1.5 Hz, 1H), 3.16 (d, 7 = 9.8 Hz, 1H), 2.84 (t, 7 = 5.7 Hz, 2H), 1 .88 (dd, 7= 9.6, 2.2 Hz, 1H), 1.83 - 1.77 (m, 1H). 3. 365.14 105f ^vO Ai? ’ Ts _N 0 / ^N 0 ¢8 _<N JL^A-nh F 1.29% 2. Ή-NMR (400 MHz, DMSO-7b) δ = 8.54 (s, 1H), 7.82 (dd, 7= 9.3, 6.4 Hz, ZN), 7.65 (dd, 7 = 8.7, 5.4 Hz, 1H), 7.36 (d, 7= 8.1 Hz, 2H), 7.26 - 7.13 (m, 1H), 4.79 (s, 2H ), 4.15 (t, 7 = 5.6 Hz, 2H), 3.74 (t, 7 = 4.9 Hz, 4H), 3.55 (d, 7 = 4.9 Hz, 4H), 3.18 (s, 2H), 2.31 (s, 3H). 3. 565.21

- 139 043389

Example 106.

KOtBu, MeOH, dioxane with _thadium C

V

Stage A.

To a solution of the title compound of Preparation 7 (500 mg, 1.31 mmol) in DMF (5 ml) was added 2,5-dichlorobenzoxazole (327 mg, 1.74 mmol) and potassium carbonate (602 mg, 4.36 mmol) and heated to 100°C for 8 hours. After completion of the reaction, the reaction mixture was poured into ice water; the solid was filtered and dried to give the title compound. The product was taken as such to the next step without further purification (0.500 g, 77%).

MS: 496.1 (M+H)+.

Stage B.

Dry 1,4-dioxane (5 mL) was added to a 50 mL two-neck round bottom flask and degassed for 20 min. Palladium acetate (67 mg, 0.1008 mmol) and 2-dicyclohexylphosphino2',4',6'-triisopropylbiphenyl (144 mg, 0.302 mmol) were added to it. The resulting solution was orange in color and degassing was continued for another 10 minutes. The suspension was heated at 100°C in a preheated oil bath for several seconds (20-30 s). The color changed to dark green. The oil bath was removed and degassed for 5-10 minutes. Thereto were added the title compound from Step A above (500 mg, 1.008 mmol), morpholine (88 mg, 1.008 mmol) and cesium carbonate (0.98 g, 3.024 mmol), and the reaction mixture was heated to 100° C. for 3 hours After 3 hours, LCMS showed product as the main peak. The reaction mixture was filtered through a pad of celite and concentrated in vacuo to give the title compound. The product was taken as such to the next step without further purification (0.450 g, 82%).

MS: 547.3 (M+H)+.

Stage C.

To a solution of the title compound from Step B above (450 mg, 0.82 mmol) in 1,4dioxane:methanol (1:1; 5 ml), sodium tert-butoxide (230 mg, 2.4 mmol) was added and heated to 70°C for 16 hours. The reaction mixture was concentrated under vacuum. Purification was performed on a silica gel column using the Biotage Isolera One purification system using a petroleum ether/EtOAc gradient (0-100%) to obtain the title compound as a solid (0.270 g, 84%).

MS: 393.2 ((M+H)+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ=11.10 (s, 1H), 7.47-7.48 (m, 1H), 7.28 (d, J=8.72 Hz, 1H), 7.08-7.09 (m, 1H), 6.92 (d, J=2.20 Hz, 1H), 6.83-6.84 (m, 1H), 6.62-6 .63 (m, 1H), 4.81 (s, 2H), 3.98-4.00 (m, 2H), 3.73-3.74 (m, 4H), 3.04-3.05 (m, 4H), 2.94-2.95 (m, 2H).

Example 107.

Stage A.

To a solution of the title compound of Preparation 7 (500 mg, 1.318 mmol) in DMF (5 ml) was added 2,5-dichlorobenzothiazole (268 mg, 1.32 mmol) and potassium carbonate (545 mg, 3.95 mmol). and heated to 100°C for 8 hours. After completion of the reaction, the reaction mixture was poured into ice water, the solid was filtered and dried to obtain the title compound (500 mg, 74%). The product was taken as such for the next step without further purification.

MS: 513.1 (M+H)+.

Stage B.

To a stirred solution of the title compound from Step A above (200 mg, 0.39 mmol) in dry dioxane (5 ml) was added morpholine (51 mg, 0.58 mmol), sodium tert-butoxide (112 mg, 1.17 mmol) and degassed for 10 min under N ₂ atmosphere. To this reaction mixture was added

- 140 043389 tris(dibenzylideneacetone)dipalladium (0) (17.9 mg, 0.019 mmol) and 2-dicyclohexylphosphino-2',6'diisopropoxybiphenyl (18.2 mg, 0.039 mmol) and heated to 100°C until the reaction was complete. After completion of the reaction (monitored by LCMS), the reaction mixture was filtered through celite and washed with EtOAc. The filtrate was concentrated under reduced pressure to obtain the crude product. Purification was performed on a silica gel column using the Biotage Isolera One purification system using a petroleum ether/EtOAc gradient (0-100%) to obtain the title compound as a solid (50 mg, 33%).

MS: 409.1 (M+H)+.

Ή-NMR (400 MHz, DMSO-d6) δ=11.11 (s, 1H), 7.60 (d, J=8.68 Hz, 1H), 7.48-7.49 (m, 1H) , 7.07-7.08 (m, 2H), 6.86-6.88 (m, 2H), 4.77 (s, 2H), 3.97-3.98 (m, 2H), 3 .74-3.76 (m, 4H), 3.11-3.12 (m, 4H), 2.95-2.96 (m, 2H).

Example 108.

Stage A.

To a solution of the title compound of Preparation 7 (1 g, 2.63 mmol) in DMF (10 mL) was added 2,6-dichlorobenzothiazole (0.537 g, 2.63 mmol) and potassium carbonate (1.09 g, 7 .89 mmol) and heated to 100°C for 8 hours. After completion of the reaction, the reaction mixture was poured into ice water, the solid was filtered and dried to obtain the title compound (1.0 g, 74%). The product was taken as such for the next step without further purification.

MS: 513.2 (M+H) ⁺ .

Stage B.

To a stirred solution of the title compound from Step A above (150 mg, 0.293 mmol) in dry dioxane (5 ml) was added morpholine (39 mg, 0.44 mmol), sodium tert-butoxide (85 mg, 0.87 mmol) and degassed for 10 min under N2. Tris(dibenzylideneacetone)dipalladium (0) (13.4 mg, 0.0015 mmol) and 2-dicyclohexylphosphino-2',6'diisopropylbiphenyl (13.65 mg, 0.029 mmol) were added to this reaction mixture and heated to 100°C until the reaction is complete. Once the reaction was complete (monitored by LCMS), the reaction mixture was filtered through Celite and washed with EtOAc. The filtrate was concentrated under reduced pressure to obtain the crude product. Purification was performed on a silica gel column using the Biotage Isolera One purification system using a petroleum ether/EtOAc gradient (0-100%) to obtain the title compound as a solid (60 mg, 50%).

MS: 409.1 (M+H) ⁺ .

Ή-NMR (400 MHz, DMSO-d ₆ ) δ=11.10 (s, 1H), 7.48-7.50 (m, 1H), 7.36-7.38 (m, 2H), 7 .08-7.09 (m, 1H), 6.96-6.97 (m, 1H), 6.85-6.86 (m, 1H), 4.74 (s, 2H), 3.94 -3.95 (m, 2H), 3.74-3.75 (m, 4H), 3.06-3.07 (m, 4H), 2.94-2.95 (m, 2H).

Example 109.

Stage A.

To a solution of the title compound of Preparation 7 (250 mg, 0.725 mmol) in DMF (5 ml) was added 2,6-dichlorobenzoxazole (166 mg, 0.88 mmol) and potassium carbonate (326 mg, 2.36 mmol) and heated to 100°C for 8 hours. After completion of the reaction, the reaction mixture was poured into ice water, the solid was filtered and dried to obtain the title compound (250 mg, 70%). The product was taken as such for the next step without further purification.

MS: 496.1 (M+H) ⁺ .

Stage B.

To a stirred solution of the title compound from Step A above (250 mg, 0.505 mmol) in dry dioxane (5 ml) was added morpholine (53 mg, 0.60 mmol), sodium tert-butoxide (145 mg, 1.52 mmol) and degassed for 10 min under N2. Tris(dibenzylideneacetone)dipalladium (0) (23.1 mg, 0.0252 mmol) and 2-dicyclohexylphosphino-2',6'diisopropoxybiphenyl (23.53 mg, 0.051 mmol) were added to this reaction mixture and heated to 100°C until the reaction is complete. Once the reaction was complete (monitored by LCMS), the reaction mixture was filtered through Celite and washed with EtOAc. The filtrate was concentrated under reduced pressure to obtain the crude

- 141 043389 product. Purification was performed on a silica gel column using the Biotage Isolera One purification system using a petroleum ether/EtOAc gradient (0-100%) to obtain the title compound as a solid (50 mg, 25%).

MS: 393.2 (M+H)+.

¹ H-NMR (400 MHz, DMSO-06) δ=11.09 (s, 1H), 7.45-7.46 (m, 1H), 7.17 (d, J=8.56 Hz, 1H ), 7.08-7.09 (m, 2H), 6.87-6.79 (m, 2H), 4.77 (s, 2H), 3.95-3.96 (m, 2H), 3.72-3.74 (m, 4H), 3.03-3.04 (m, 4H), 2.91-2.93 (m, 2H).

Example 110.

Stage A.

To a stirred solution of the title compound of Preparation 1 (0.15 g, 0.43 mmol) in dry 1,4-dioxane (5 ml) was added the title compound of Preparation 50 (0.17 g, 0. 43 mmol) and Cs ₂ CO ₃ (0.420 g, 1.29 mmol). The reaction mixture was degassed for 10 min under N2 atmosphere. Then Pd(OAc) ₂ was added; (0.009 g, 0.043 mmol) and 2dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.062 g, 0.129 mmol), and the reaction mixture was heated to 100°C until the reaction was complete. After completion of the reaction (monitored by LCMS), the reaction mixture was filtered through celite and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude material was purified by flash column chromatography or preparative HPLC to give the tosyl-protected compound. To a solution of the tosyl compound (1.0 eq.) in a mixture of dioxane:MeOH (1:1, 10 vol.) was added NaOtBu (3 eq.) and heated to 70°C for 6 hours. The reaction mixture was concentrated in vacuum, and the crude product was purified on a column to obtain the desired product. The crude material was purified by flash column chromatography or preparative HPLC to give the title compound (0.042 g, 24%).

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.00 (bs, 1H), 8.70 (s, 1H), 7.96 (d, J=9.60 Hz, 1H), 7 .45-7.46 (m, 1H), 7.39 (d, J=9.20 Hz, 1H), 7.07-7.08 (m, 2H), 6.82-6.83 (m , 1H), 4.64 (s, 2H), 4.02-4.04 (m, 2H), 3.73 (d, J=4.80 Hz, 4H), 3.59 (d, J= 4.40 Hz, 4H), 2.90 (bs, 2H). MS: 404.2 (M+H)+.

Examples lll and 112.

Following the palladium cross-coupling followed by deprotection procedure as described in Examples 110, the following compounds were prepared.

Table 4

Example Tricyclic amino derivative Bromine or chlorine derivative, aqueous Product 1. Exit 2. Ή-NMR 3. ΜΉ (IER) 111 /L ^F TsN-ΑΉ HCl 4 ³ 1. 29% 2. Ή-NMR (400 MHz, DMSO7 ₆ ): δ 11.29 (s, 1H), 7.25-7.27 (m, 2H), 7.04 (d, J = 2, 40 Hz, 1H), 6.77-6.94 (m, 3H), 4.34 (s, 2H), 3.70-3.71 (m, 4H), 3.613.62 (m, 2H), 3.54-3.55 (m, 4H), 2.87-2.89 (m, 2H). 3. 393.2 112 NH TsN^ _hc| jYvO 1. 51% 2. Ή-NMR (400 MHz, DMSO7 ₆ ): δ 11.01 (s, 1H), 8.81 (s, 1H), 8.07 (d, 7 =9.04 Hz, 1H ), 7.88 (s, 1H), 7.44-7.46 (m, 1H), 7.35 (d, 7= 8.68 Hz, 1H), 7.077.08 (m, 1H), 6 .85-6.87 (m, 1H), 4.48 (s, 2H), 3.70-3.72 (m, 10H), 2.94-2.95 (m, 2H). 3. 404.2

- 142 043389

Example 113.

Stage A.

Palladium(II) acetate (0.013 g, 0.058 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (XANTPHOS) (0.101 g, 0.174 mmol) were placed in the reaction vessel and degassed. 1,4dioxane (6 ml) was added. The resulting solution was quickly degassed. The suspension was heated at 100°C (on a preheated heating block) for less than 1 min until the color of the solution changed from orange to dark pink. The vessel was then removed from the heating block and the title compound of Preparation 52 (148 mg, 0.581 mmol), the title compound of Preparation 1 (0.200 g, 0.581 mmol) and cesium carbonate (0.662 g, 2.033 mmol) were added. . The reaction vessel was filled with argon before being sealed. The reaction mixture was heated at 100°C for 18 hours. The reaction mixture was diluted with ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate two more times. The combined organic layers were dried over Na ₂ SO ₄ , filtered and the solvents were evaporated under reduced pressure. The crude product was purified on a silica gel column using the Biotage Isolera One purification system using a ngeptane/ethyl acetate gradient (100/00^50/50). The resulting crude reaction mixture (0.261 g, 0.469 mmol) and cesium carbonate (0.214 g, 0.658 mmol) were placed in a microwave tube, followed by the addition of MeOH (4 mL) and THF (8 mL). The reaction mixture was irradiated in a microwave oven to 110°C for 30 min and then allowed to cool to room temperature. Solvents were removed under reduced pressure and the residue was purified on a silica gel column using a Biotage Isolera purification system

One with a dichloromethane/methanol gradient (100/00^95/05) to give the title compound as a yellow solid (0.020 g, 9%).

1H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 7.95 (d, 1H), 7.54 (d, 2H), 7.33 - 7.10 (m, 4H) , 6.86 (td, 1H), 4.41 (s, 2H), 3.72 (dt, 6H), 3.55 (t, 4H), 2.95 (d, 2H). MS: 403.19 (M+H)+.

Example 114.

Stage A.

Palladium(II) acetate (0.013 g, 0.058 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (XANTPHOS) (0.101 g, 0.174 mmol) were placed in the reaction vessel and degassed. 1,4dioxane (6 ml) was added. The resulting solution was quickly degassed. The suspension was heated at 100°C (on a preheated heating block) for less than 1 min until the color of the solution changed from orange to dark pink. The vessel was then removed from the heating block and the title compound from Preparation 51 (144 mg, 0.581 mmol), the title compound from Preparation 1 (0.200 g, 0.581 mmol) and cesium carbonate (0.662 g, 2.033 mmol) were added. . The reaction vessel was filled with argon before being sealed. The reaction mixture was heated at 100°C for 18 hours. The reaction mixture was diluted with ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted two more times with ethyl acetate. The combined organic layers were dried over Na ₂ SO ₄ , filtered, and the solvents were evaporated under reduced pressure. The crude product was purified on a silica gel column using the Biotage Isolera One purification system using an n-heptane/ethyl acetate gradient (100/00^50/50). The resulting crude reaction mixture (0.122 g, 0.219 mmol) and cesium carbonate (0.214 g, 0.658 mmol) were placed in a microwave tube, followed by the addition of MeOH (4 mL) and THF (8 mL). The reaction mixture was irradiated in a microwave oven to 110°C for 30 min and then allowed to cool to room temperature. Solvents were removed under reduced pressure and the residue was purified on a silica gel column using a Biotage Isolera One purification system with a dichloromethane/methanol gradient (100/00^95/05) to give the title compound as a yellow solid (0.081 g , 35%).

1H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 7.88 (d, 1H), 7.56 (d, 1H), 7.40 - 7.13 (m, 3H) , 7.02 (d, 1H), 6.97 - 6.79 (m, 2H), 4.49 (s, 2H), 3.80 (t, 2H), 3.72 (t, 4H), 3.60 (t, 4H), 2.93 (d, 2H). MS: 403.20 (M+H)+.

- 143 043389

Example 115.

Stage A.

Pd(OAc)2 (16 mg, 0.072 mmol) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos; 103 mg, 0.2177 mmol) were added to the reaction vessel, and degassed dioxane (5 mL) was added ). The vessel was filled with argon gas and hermetically sealed. The suspension was heated at 100°C for 1 min, then 8-fluoro-5-tosyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (Preparative Example 1) (250 mg , 0.725 mmol), 4-(4-bromophenyl)morpholine (210 mg, 0.87 mmol) and Cs ₂ CO ₃ (707 mg, 2.177 mmol), and the solution was heated at 100°C for 18 hours. The reaction mixture was diluted ethyl acetate (30 ml) and water (30 ml). The organic phase was separated and the aqueous phase was extracted with ethyl acetate two more times. The combined organic phase was dried over Na ₂ SO ₄ , filtered and the solvents were evaporated under reduced pressure. The crude material was purified on an HP-Sil column (Biotage) using a DCM/MeOH gradient (100/0^95/05) to give 4-(4-(8-fluoro-5-tosyl-1,3,4,5- tetrahydro-2H-pyrudo[4,3-b]indol-2yl)phenyl)morpholine (235 mg, 64%) as a yellow solid.

To a solution of 4-(4-(8-fluoro-5-tosyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)phenyl)morpholine (0.235 mg, 0.465 mmol) in a mixture of dioxane:MeOH (1:1.5 vol.), NaOtBu (133 mg, 1.39 mmol) was added and heated to 70°C for 6 hours. The reaction mixture was concentrated in vacuo and the crude product was purified by column on an HP-Sil column (Biotage) using a DCM/MeOH gradient (100/0^95/05) to give the title compound as a white metallic solid (57 mg, 35%).

MS: 352.0 (M+H)+.

¹ H-NMR (400 MHz, DMSO-d6) δ 10.93 (bs, 1H), 7.21-7.24 (m, 2H), 6.99-7.01 (m, 2H), 6, 85-6.86 (m, 3H), 4.24 (s, 2H), 3.73 (bs, 4H), 3.52-3.53 (m, 2H), 2.98 (bs, 4H) , 2.86 (bs, 2H).

Example 116.

Ruphos G ₄ Pd

NaOtBu, Dioxane

HCl

Stage A

To a stirred solution of 7-fluoro-5-tosyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (Preparative Example 7) (250 mg, 0.7267 mmol) in dry dioxane ( 5 ml) added 5-chloro-N-(2-methoxyethyl)N-methylbenzo[d]oxazol-2-amine (preparation example 60) (190 mg, 0.7994 mmol), sodium tert-butoxide (202 mg, 2.180 mmol) and degassed for 10 min under N2. Ruphos G4 Pd (60 mg, 0.0726 mmol) was added to this reaction mixture and heated to 100°C until the reaction was complete. After completion of the reaction, the reaction mixture was filtered through a pad of celite and washed with EtOAc. The filtrate was concentrated and the crude product was purified by HP-Sil column chromatography (Biotage) using a DCM/MeOH gradient (100/0^95/05) to give the title compound (37 mg, 13%).

MS: 395.0 (M+H) ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ 10.94 (bs, 1H), 7.43-7.44 (m, 1H), 7.23 (d, J=8.80 Hz, 1H) , 7.06-7.06 (m, 1H), 6.99 (d, J=2.40 Hz, 1H), 6.80-6.81 (m, 1H), 6.71-6.72 (m, 1H), 4.32 (s, 2H), 3.64-3.65 (m, 2H), 3.563.58 (m, 4H), 3.27 (s, 3H), 3.13 ( s, 3H), 2.86 (t, J=5.20 Hz, 2H).

Examples 117 to 145.

Following the procedures described in Example 115 and Example 116, the following compounds were prepared.

- 144 043389

Table 5

Example Tricyclic amino derivative Bromine or chlorine derivative Product 1. Yield 2. Ή-NMR of Z. MN ⁺ (ESI) 4. Synthesis procedure 117 —\II J on Ts^ nO GT γθ f-/~v^ _n XT 1 7 ΝΆ^ n 1. 55% 2. Ή-NMR (400 MHz, DMSOd ₆ ): δ 10.93 (bs, 1H), 7.40-7.41 (m, 1H), 6.98-7.00 (m, 3H), 6.81-6.83 (m, 3H), 4.24 (s, 2H), 3.70-3.72 (m, 4H), 3.503.51 (m, 2H), 2.95 -2.97 (m, 4H), 2.84 (bs, 2H). 3.352.3 4. Example 115 118 F-YA /χ YYYnh nAY HCl Ts aХ ¹ ^ ⁰ - Ύο^^ ⁰ ' n 1. 10% 2. Ή-NMR (400 MHz, DMSOd ₆ ): δ 10.94 (bs, 1H), 7.87 (t, J = 5.56 Hz, 1H), 7.43-7.44 (m, 1H), 7.17-7.19 (m, 1H), 7.067.07 (m, 1H), 6.98-6.99 (m, 1H), 6.80-6.81 (m , 1H), 6.646.66 (m, 1H), 4.31 (s, 2H), 3.59 (t, J= 5.60 Hz, 2H), 3.50 (t, J= 5.32 Hz , 2H), 3.44 (t,J = 5.52 Hz, 2H), 3.28 (s, 3H), 2.86 (bs, 2H). 3. 381.1 4. Example 116 119 TsaA nh ^NS| / Br^ ^N about Οχ? ⁰ Ν'Χα / 1. 22% 2. Ή-NMR (400 MHz, DMSOd ₆ ): δ 8.01 (d, J= 2.92 Hz, 1H), 7.45-7.46 (m, 2H), 7.39 (d, J = 8.12 Hz, 1H), 7.10 (t, 7 = 7.92 Hz, 1H), 7.01 (t, J = 7.36 Hz, 1H), 6.80 (d , 7= 9.08 Hz, 1H), 4.30 (s, 2H), 3.69-3.70 (m, 4H), 3.64 (s, 3H), 3.56-3.58 ( m, 2H), 3.27-3.29 (m, 4H), 2.88-2.89 (m, 2H). 3. 349.2 4. Example 115 120 γ/Ήΐ nh F NAY HCl / _C ,ХХ> fO^xto / 1. 28% 2. Ή-NMR (400 MHz, DMSOd ₆ ): δ 7.31 (d, 7= 7.60 Hz, 1H), 7.25 (d, 7= 8.80 Hz, 1H), 7.04 (d, J = 2.00 Hz, 1H), 6.86-6.88 (m, 2H), 6.77-6.78 (m, 1H), 4.33 (s, 2H) , 3.80 (s, 3H), 3.643.65 (m, 6H), 3.54-3.56 (m, 4H), 2.88 (bs, 2H). 3. 407.2 4. Example 115 121 _F YYNH \=< ft ) HCl Ts .CN bXn ,ΤΝ GU γγγ ^Ν Η 1. 6% 2. Ή-NMR (400 MHz, DMSOd ₆ ): δ 11.05 (bs, 1H), 8.54 (s, 1H), 7.90 (d, 7= 8.00 Hz, 1H ), 7.46 (s, 1H), 7.09 (d, 7= 8.08 Hz, 2H), 6.85 (t, J = 6.88 Hz, 1H), 4.82 (s, 2H ), 4.12 (bs, 2H), 2.88 (bs, 2H). 3. 292.9 4. Example 115

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122 ^F Y1 x/Anh TsN-VJ HCl aO c.Tr N T.A. 1. 23% 2. Ή-NMR (400 MHz, DMSOde): δ 10.99 (bs, 1H), 8.85 (s, 1H), 7.63 (s, 2H), 7.46-7.47 (m, 1H), 7.32 (s, 1H), 7.077.08 (m, 1H), 6.82-6.83 (m, 2H), 4.44 (s, 2H), 3.70-3.71 (m, 6H), 3.39-3.40 (m, 4H), 2.91-2.93 (m, 2H). 3. 403.2 4. Example 115 123 Λ/ΓΉη TsN—HCl 00z _.cn ^g ТУтЧ \=\ VJ H 1. 10% 2. Ή-NMR (400 MHz, DMSOde): δ 11.05 (bs, 1H), 8.57 (d, J = 2.80 Hz, 1H), 7.78 (d, J = 9.20 Hz , 1H), 7.46-7.47 (m, 2H), 7.09 (dd, 7=2.40, 10.20 Hz, 1H), 6.85-6.86 (m, 1H), 4.62 (s, 2H), 3.90 (t, J = 5.60 Hz, 2H), 2.91 (t, J = 5.20 Hz, 2H). 3. 293.1 4. Example 115 124 _F HCl Ts ΓΓα _ν α Гч ^N \о ci — 0 T LL 1. 39% 2. Ή-NMR (400 MHz, DMSOde): 400 MHz, DMSODb: δ 10.96 (bs, 1H), 7.23-7.26 (m, 1H), 7.20-7.20 (m, 1H), 6.926.94 (m, 2H), 6.83-6.84 (m, 1H), 6.73-6.74 (m, 1H), 4.51 (s, 2H), 3.98 (t, J = 5.44 Hz, 2H), 3.73-3.74 (m, 4H), 3.583.59 (m, 4H), 2.89 (bs, 2H). 3. 393.1 4. Example 115 125 ^F A ^< A ^hci S; ^NH TsN-LL ciAI^nQ, oh 1. 32% 2. Ή-NMR (400 MHz, DMSOde): δ 10.95 (bs, 1H), 7.43-7.44 (m, 1H), 7.26 (d, J = 8.72 Hz, 1H) , 7.02-7.03 (m, 2H), 6.776.79 (m, 2H), 4.33 (s, 2H), 3.50-3.51 (m, 9H), 2.86 (bs , 2H), 1.97-1.99 (m, 4H), 1.681.71 (m, 2H). 3,433.1 4. Example 115

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126 HCl λ/Υ'νη TsN-%J ^c| 41i _n +-nQ ₀ 1.47% 2. Ή-NMR (400 MHz, DMSOd ₆ ): 400 MHz, DMSOdb: δ 10.95 (bs, 1H), 7.43-7.44 (m, 1H), 7.26 (d , 7=8.68 Hz, 1H), 7.03-7.04 (m, 2H), 6.78-6.79 (m, 2H), 4.32 (s, 2H), 4.044.14 ( m, 1H), 3.90-3.90 (m, 1H), 3.59-3.61 (m, 6H), 3.503.53 (m, 1H), 2.86 (bs, 2H), 1 .28 (d, 7= 6.72 Hz, ZN). 3.406.9 4. Example 115 127 ^with Oio 1. 5% 2. Ή-NMR (400 MHz, DMSOd ₆ ): δ 10.90 (bs, 1H), 7.26 (d,7 = 8.80 Hz, 1H), 7.05 (d, 7 = 2.40 Hz, 2H), 6.90 (t, 7= 7.60 Hz, 1H), 6.76-6.77 (m, 1H), 6.63 (d, 7= 7.60 Hz , 1H), 4.31 (s, 2H), 3.90 (s, 3H), 3.60-3.62 (m, 4H), 3.54-3.56 (m, 6H), 2, 83-2.85 (m, 2H). 3.405.1 4. Example 116 128 ^F ~\'\HCl TJ NH TsN-<CJ ^ciA1 n^O 1. 33% 2. Ή-NMR (400 MHz, DMSOd ₆ ): δ 10.95 (bs, 1H), 7.43-7.44 (m, 1H), 7.26 (d, 7 = 8, 76 Hz, 1H), 7.02-7.03 (m, 2H), 6.816.83 (m, 2H), 4.32 (s, 2H), 3.87-3.89 (m, 3H), 3.58-3.59 (m, 4H), 3.13-3.14 (m, 1H), 2.82-2.85 (m, 3H), 1.15 (d, 7 = 6.20 Hz, ZN). 3.407.3 4. Example 115

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129 hci Λ/Γ^ΝΗ TsNA^> “'<70 1.28% 2. Ή-NMR (400 MHz, DMSOde): 510.95 (bs, 1H), 7.43-7.44 (m, 1H), 7.26 (d, J = 8.68 Hz, 1H), 7.03-7.04 (m, 2H), 6.806.81 (m, 2H), 4.33 (s, 2H), 4.14-4.16 (m, 1H), 3.89-3, 90 (m, 1H), 3.66-3.68 (m, 6H), 3.50-3.52 (m, 1H), 2.86 (sb, 2H), 1.28 (d, 7= 6.72 Hz, 3H). 3,407.1 4. Example 115 130 HCl XO ^H ci-OT _n %n^ 1. 42% 2. Ή-NMR (400 MHz, DMSOde): 510.94 (bs, 1H), 7.42-7.43 (m, 1H), 7.24 (d, J = 8.80 Hz, 1H), 7.01-7.02 (m, 2H), 6.776.78 (m, 2H), 4.31 (s, 2H), 3.86-3.88 (m, 3H), 3.55-3, 58 (m, 4H), 3.15-3.18 (m, 1H), 2.80-2.84 (m, 3H), 1.13-1.14 (m, 3H). 3,407.1 4. Example 115 131 \/4 ^{nh TsN} O hci 1. 48% 2. Ή-NMR (400 MHz, DMSO-7 ₆ ) δ 10.67 (bs, 1H), 7.25-7.27 (m, 2H), 7.17 (d, J = 8 ,16 Hz, 1H), 7.02 (s, 1H), 6.85 (d, 7= 8.16 Hz, 1H), 6.77 (d, 7 = 8.24 Hz, 1H), 4, 31 (s, 2H), 3.70-3.71 (m, 4H), 3.60-3.62 (m, 2H), 3.56-3.57 (m, 4H), 2.85 ( bs, 2H), 2.37 (s, 3H). 3. 389.2 4. Example 115 132 -op" Ts h Br fAaM N H 1. 19% 2. Ή-NMR (400 MHz, DMSO-7 ₆ ) δ 11.01 (bs, 1H), 7.82 (d, 7= 6.12 Hz, 1H), 7.467.47 (m, 1H), 7.06-7.07 (m, 1H), 6.81-6.82 (m, 1H), 6.706.70 (m, 1H), 6.27 (d, 7= 2.20 Hz , 1H), 4.49 (s, 2H), 3.753.77 (m, 5H), 2.84-2.86 (m, 2H). 3. 298.2 4. Example 115

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133 TsN'W HCl 1. 23% 2. Ή-NMR (400 MHz, DMSOh/b) δ 10.63 (bs, 1H), 7.32 (d, J= 8.40 Hz, 1H), 7.25 (d, J = 8.40 Hz, 1H), 7.01 (d, J = 2.40 Hz, 1H), 6.75-6.76 (m, 2H), 6.62 (dd, J = 2.40, 8.60 Hz , 1H), 4.28 (s, 2H), 3.693.70 (m, 7H), 3.53-3.54 (m, 6H), 2.82-2.83 (m, 2H). 3. 405.1 4. Example 115 134 Cl λ/Χνη TSN-Хд HCl 16% 2. Ή-NMR (400 MHz, DMSOh/b) δ 11.06 (s, 1H), 7.54 (s, 1H), 7.25-7.27 (m, 2H), 7.01-7 .03 (m, 2H), 6.78 (d, J = 8.56 Hz, 1H), 4.33 (s, 2H), 3.70-3.71 (m, 4H), 3.613.62 ( m, 2H), 3.55-3.56 (m, 4H), 2.88 (s, 2H). 3. 409.1 4. Example 115 135 F ^HCI λ/Χνη tsn-Xj ^N CI'^cAnQ, F ί'ΎΝ UOCD) 16% 2. Ή-NMR (400 MHz, DMSOh/b) δ 10.96 (bs, 1H), 8.15 (s, 1H), 7.21-7.22 (m, 1H), 7.13 (s , 1H), 6.82-6.83 (m, 1H), 4.60 (s, 2H), 3.98 (bs, 2H), 3.71-3.72 (m, 4H), 3.543, 55 (m, 4H), 2.87 (bs, 2H). 3. 394.1 4. Example 116 136 TsN-O 77° z~, ^c| -VA _n X-nQo 1. 41% 2. Ή-NMR (400 MHz, DMSOh/b) δ 10.63 (bs, 1H), 7.26 (d, J =8.72 Hz, 1H), 7.15 (d, J = 8.68 Hz, 1H), 6.98-6.99 (m, 2H), 6.76-6.77 (m, 1H), 6.64-6.65 (m, 1H), 4.30 (s, 2H), 4.02 (q, J= 6.92 Hz, 2H), 3.70-3.71 (m, 4H), 3.56-3.57 (m, 6H), 2.85 (bs , 2H), 1.34 (t, J =6.92 Hz, ZN). 3. 419.2 4. Example 115

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137 fl ΆΑιΑ in hn-\l 4 _Ν Υ _Ο ΥοΎ^ο 16% 2. 'H-NMR (400 MHz, DMSO-7b) δ 10.74 (bs, IH), 7.25-7.27 (m, 2H), 7.03 (d, J = 2.28 Hz, IH), 6.77-6.78 (m, 3H), 4.33 (s, 2H), 3.70-3.71 (m, 4H), 3.63 (t, J = 5.52 Hz , 2H), 3.54-3.55 (m, 4H), 2.902.91 (m, 2H), 2.43 (s, 3H). 3. 389.1 4. Example 116 138 - Vs b Br o ^z n4 /=\ F-xrtj NH 1. 44% 2. 'H-NMR (400 MHz, DMSO-7b) δ 10.99 (bs, IH), 7.43-7.45 (m, 2H), 7.08 (dd, J = 2.20, 10 ,18 Hz, IH), 6.816.82 (m, IH), 6.46 (d, J= 8.08 Hz, IH), 6.03 (d, J = 7.76 Hz, IH), 4, 63 (s, 2H), 4.00 (t, J = 5.56 Hz, 2H), 3.82 (s, 3H), 2.86 (t, J = 5.24 Hz, 2H). 3. 298.2 4. Example 115 139 ^F A\ ^HCI Λ/Γ^ΝΗ TsN-V-/ 0 Br r=\/~-N fAaIJ N H 1. 12% 2. Ή-NMR (400 MHz, DMSO-7b) δ 10.99 (bs, IH), 7.79 (d, J= 6.00 Hz, IH), 7.477.48 (m, IH), 7, 08 (dd, J = 2.40, 10.20 Hz, IH), 6.84 (t, J = 2.40 Hz, IH), 6.65-6.65 (m, IH), 6.20 (d, J = 2.40 Hz, IH), 5.20 (t, J = 6.00 Hz, IH), 4.48 (s, 2H), 3.76 (t, J = 5.60 Hz , 2H), 2.85 (t, J = 5.60 Hz, 2H), 1.24 (d, 7 = 6.40 Hz, 6H). 3. 326.1 4. Example 115 140 F^f%HCl Λ/Γ^ΝΗ TsN-K^ X o ^z b fAaIj NH 1. 38% 2. Ή-NMR (400 MHz, DMSO-7b) δ 10.98 (s, IH), 7.96 (d, 7= 5.68 Hz, IH), 7.457.46 (m, IH), 7, 08 (d, 7= 10.32 Hz, IH), 6.84 (t, 7 = 8.48 Hz, IH), 6.43 (s, IH), 6.29 (d, 7 = 5.08 Hz, IH), 4.65 (s, 2H), 3.99 (t, 7 = 5.16 Hz, 2H), 3.81 (s, 3H), 2.84 (bs, 2H). 3. 298.1 4. Example 115 141 F^^HCl TpNH TsN-\> A fAXM N H 1. 33% 2. Ή-NMR (400 MHz, DMSO-7 ₆ ) δ 10.96 (bs, IH), 7.91 (d, 7= 2.92 Hz, IH), 7.427.43 (m, IH), 7.28-7.29 (m, IH), 7.07 (dd, 7=2.32, 10.20 Hz, IH), 6.95-6.97 (m, IH), 6 .84-6.85 (m, IH), 6.79-6.80 (m, IH), 4.56 (s, 2H), 3.873.88 (m, 2H), 3.73 (s, 3H ), 2.84 (bs, 2H). 3. 298.1 4. Example 115 142 F-^>HCl Λ/Γ^ΝΗ Yr o\ U 1.22% 2. Ή-NMR (400 MHz, DMSO-7 ₆ ) δ 10.95 (bs, IH), 7.43-7.44 ( _m , 1H), 7.25 (d,7 = 8 .80 Hz, IH), 7.06-7.06 (m, IH), 7.01-7.02 (m, IH), 6.816.83 (m, 2H), 4.32 (s, 2H) , 3.95 (d, 7 = 12.80 Hz, 2H), 3.643.65 (m, 4H), 2.86 (bs, 2H), 2.68-2.73 (m, 2H), 1, 15 (d, 7 = 6.00 Hz, 6H). 3. 421.1 4. Example 115

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143 HCl oW Η 1. 5% 2. 'H-NMR (400 MHz, DMSO-7 ₆ ): δ 10.93 (bs, IH), 7.56 (s, IH), 7.42-7.44 (m, IH ), 7.15 (d, 7=8.80 Hz, IH), 7.01-7.02 (m, 2H), 6.81-6.82 (m, IH), 6.69-6, 70 (m, IH), 4.30 (s, 2H), 3.58 (t, J = 5.60 Hz, 2H), 2.85 (t, J = 4.80 Hz, 2H), 1, 39 (s, 9H). 3. 379.0 4. Example 115 144 AV/. ^HCI νΆ/ ! Vko· / 1. 38% 2. 'H-NMR (400 MHz, DMSO-7 ₆ ): δ 7.50 (d, J = 7.60 Hz, IH), 7.39 (d, J = 8.40 Hz, IH), 7.26 (d, J= 8.80 Hz, IH), 7.08-7.10 (m, IH), 7.01-7.03 (m, 2H), 6.79 (dd , J = 2.40, 8.80 Hz, IH), 4.35 (s, 2H), 3.64-3.65 (m, 9H), 3.54-3.55 (m, 4H), 2.90 (t, J = 5.20 Hz, 2H). 3. 389.0 4. Example 115 145 GGU Z^NH f-AW Tos ι%°ηΑ- OK- H G 62% 2. 1H-NMR (400 MHz, DMSO-7th): δ 10.95 (bs, IH), 7.43-7.44 ( _m , 1H), 7.24 (d, J = 8, 68 Hz, IH), 7.06-7.07 (m, IH), 7.01-7.02 (m, IH), 6.816.83 (m, 2H), 4.32 (s, 2H), 3.56-3.57 (m, 6H), 2.86 (bs, 2H), 2.40-2.41 (m, 4H), 2.22 (s, 3H). 3. 406.1 4. Example 115

Example 146.

Stage A.

To a suspension of sodium hydride (0.0293 g, 0.764 mmol) in DMF (3 ml) was added dropwise 5-(7fluoro-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)- 2-morpholino-1,3-benzoxazole (Example 45) (0.100 g, 0.255 mmol) (dissolved in 3 ml DMF) at 0°C, then stirred at room temperature for 60 minutes. Iodoethane (0.0596 g, 0.382 mmol) was then added dropwise at 0°C (dissolved in 2 ml DMF) and then stirred at room temperature for 3 hours. After completion of the reaction by TLC, the reaction mixture was quenched with ice water and followed by extraction using ethyl acetate (20 ml). The organic layer was separated, dried over sodium sulfate, filtered and then concentrated to give the crude product and then purified on a silica gel column (Biotage) using 40-50% ethyl acetate in petroleum ether to give 5-(5-ethyl-7 -fluoro-3,4dihydro-1H-pyrido[4,3-b]indol-2-yl)-2-morpholino-1,3-benzoxazole in the form of a white solid with a metallic tint. (15 mg, 14%)

MS: 421.2 (M+H)+.

1H-NMR (400 MHz, DMSO-d6) δ 7.47-7.48 (m, 1H), 7.26-7.28 (m, 2H), 7.06 (d, J=2.40 Hz , 1H), 6.84-6.85 (m, 1H), 6.78-6.79 (m, 1H), 4.33 (s, 2H), 4.10 (q, J=7.20 Hz, 2H), 3.55-3.57 (m, 10H), 2.90 (t, J=4.80 Hz, 2H), 1.22 (t, J=7.20 Hz, 3H).

Examples 147 to 153.

Following the palladium cross-coupling procedures as described in Examples 1, 2 and 115, except using the tricyclic amino and bromo/chloro derivatives listed in the table below, the following compounds were prepared.

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Table 5 a

Example Tricyclic amino derivative Bromine or chlorine derivative, aqueous Product 1. Output 2. ¹ H-NMR 3. ΜΗ ⁺ (ESI) 4. Synthesis procedure 147 ΛΓ / 2. 1H NMR (400 MHz, DMSO76) δ 7.52 - 7.43 (m, 1H), 7.30 (d, J = 9.8 Hz, 1H), 7.22 (d, J = 5, 8 Hz, 1H), 7.08 (s, 1H), 7.06 6.93 (m, 2H), 4.66 (s, 2H), 3.94 (s, 2H), 3.68 (d , J= 2.3 Hz, 3H), 3.20 (t, J= 5.7 Hz, 2H), 2.12 (s, 3H). 4. Example 1 148. E A ^nh / M XX / 1. 91% 2. 1H NMR (400 MHz, DMSO76) δ 7.68 (d, J = 8.4 Hz, 2H), 7.51 - 7.40 (m, 1H), 7.30 (d, J = 9, 7 Hz, 1H), 7.11 (d, 7=8.4 Hz, 2H), 7.01 (t, 7 = 9.2 Hz, 1H), 4.71 (s, 2H), 4.13 - 3.87 (m, 2H), 3.79 (d, 7 = 2.3 Hz, 3H), 3.69 (s, 3H), 3.25 (t, 7 = 5.5 Hz, 2H) 4. Example 1 149 F A I // NH N-V> / \^γ°^ΌΗ QjTj / 1. 48.9% 2. 1H NMR (400 MHz, DMSO76) δ 7.48 - 7.42 (m, 1H), 7.32 - 7.23 (m, 1H), 7.20 - 7.15 (m, 1H), 7.12 - 7.06 (m, 1H), 7.02 6.94 (m, 2H), 4.62 (s, 2H), 4.25 (s, 3H), 3.94 - 3.87 (m, 2H), 3.66 (s, 3H), 3.54 (s, 3H), 3.22 -3.11 (m, 2H). 4. Example 1 150 F Ж// ^NH NVj / G T J Χτθ-ΟΧ / 1. 76% 2. 1H NMR (400 MHz, DMSO76) δ 8.51 - 8.36 (m, 1H), 8.15 - 8.05 (m, 1H), 7.80 - 7.64 (m, 1H), 7.55 - 7.42 (m, 1H), 7.40 7.33 (m, 1H), 7.32 - 7.21 (m, 2H), 7.06 - 6.94 (m, 1H) , 5.08 (s, 2H), 4.33 (t, J= 5.8 Hz, 2H), 3.70 (s, 3H), 3.13 (t, 7= 5.8 Hz, 2H) . 4. Example 1 151 F A ΉΜνη OH EAR ⁷ in/ OH F 0Ό ^Ζ рр 1.99% 2. 1H NMR (400 MHz, DMSO76) δ 7.47 (dd, 7=8.9, 4.4 Hz, 1H), 7.30 (dd, 7= 9.8, 2.6 Hz, 1H) , 6.99 (td, 7 = 9.3, 2.6 Hz, 2H), 6.86 (s, 1H), 4.72 - 4.46 (m, 2H), 3.80 (s, 3H ), 3.69 (s, 3H), 3.45-3.35 (m, 5H). 4. Example 1 152 ^F XCp ^NH Ts /G n 1. 33% 2. Ή-NMR (400 MHz, DMSOd6): δ 10.95 (bs, 1H), 7.43 (t, J = 6.00 Hz, 1H), 6.97-7.00 (m, 3H) , 6.80 (d, 7 = 9.20 Hz, 2H), 4.28 (s, 2H), 3.75 (s, 3H), 3.553.56 (m, 2H), 2.84 (bs, 2H). 3. 315.1 4. Example 115 153 CoTs PS Br-^^^O N-^ Ж Η 3. 315.1 4. Example 2

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HCl salt of the compounds of the present invention. Example 89 HCl.

Stage A.

To a solution of 4-(6-(7-fluoro-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)thiazolo[4,5-c]pyridin-2yl) morpholine (example 89) (0.1 g, 0.244 mmol) in dry DCM (5 ml), cooled to 0°C, added 4M HCl in dioxane (0.2 ml) and stirred for 1 hour. The reaction mixture was concentrated in vacuum and triturated with diethyl ether to give the title compound (0.09 g, 83%) as a brown solid.

MS: 410.2 (M+H)+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 11.14 (bs, 1H), 8.28 (s, 1H), 7.98 (s, 1H), 7.38-7.40 (m , 1H), 7.11-7.12 (m, 1H), 6.85-6.86 (m, 1H), 4.75 (s, 2H), 4.02 (t, J=5.64 Hz, 2H), 3.73-3.75 (m, 8H), 2.97 (s, 2H).

Examples.

Following the procedure for preparing the hydrochloride salt as described in Example 89 HCl, the following compounds were prepared.

Table 6

Example Original free base Product 1. Ή-NMR 2. ΜΗ ⁺ (ESI) 110 NS1 0 y u. 1. Ή-NMR (400 MHz, DMSO7 ₆ ) δ 11.04 (bs, 1H), 9.03 (s, 1H), 8.20 (d, 7= 9.80 Hz, 1H), 7.67 (d, J = 9.76 Hz, 1H), 7.437.45 (m, 1H), 7.34 (s, 1H), 7.087.09 (m, 1H), 6.83-6.84 (m, 1H), 4.72 (s, 2H), 4.07 (t, J = 5.52 Hz, 2H), 3.79-3.80 (m, 8H), 2.92 (s, 2H). 2. 404.2 87 NS1 Ν-Υ 0 f-СУ ^HCI Ν 1 1. Ή-NMR (400 MHz, DMSO7 ₆ ) δ 8.16-8.17 (m, 1H), 7.65 (bs, 1H), 7.49-7.50 (m, 1H), 7, 30-7.31 (m, 2H), 6.86-6.87 (m, 1H), 4.44 (s, 2H), 3.73-3.74 (m, 6H), 3.73- 3.74 (m, 7H), 2.96 (bs, 2H). 2. 367.2 76 NS1 ΥΓ Η Ο Ър Η 1. Ή-NMR (400 MHz, DMSOί/b) δ δ 11.18 (bs, 1H), 8.07 (d, J = 7.48 Hz, 1H), 7.54 (d, J = 9, 84 Hz, 1H), 7.41 (s, 1H), 7.30-7.32 (m, 1H), 7.16-7.17 (m, 1H), 6.89-6.90 (m , 1H), 4.80 (s, 2H), 4.07-4.08 (m, 2H), 3.76-3.77 (m, 4H), 3.10 (bs, 4H), 2.993, 00 (m, 2H), . 2. 353.3

Radioligand synthesis of the compounds of the present invention. Example ³ N-12.

n

The catalyst was added to the reaction vessel with tritium, followed by the addition of a solution of the starting material of Example 12 (1.0 mg, 0.003 mmol) in dichloromethane. The vessel was connected to the tritium line and was pressurized with tritium gas at -200°C. The solution was stirred for 8 hours, cooled to -200°C and excess gas was removed. The reaction flask was washed with 4x1 ml methanol, transferring each content to a 100 ml distillate flask. The combined organic phase was evaporated in vacuo (crude yield: 124 mCi). The crude material was purified by HPLC, mobile

- 153 043389 the phase was evaporated in vacuo and the product was redissolved in absolute ethanol (yield: 17 mCi, purity > 97%). The specific activity was determined to be 80.6 Ci/mmol using mass spectrometry.

Example ³ N-45.

The catalyst was added to the reaction vessel with tritium, followed by the addition of a solution of Example 45 starting material (1.0 mg, 0.003 mmol) in dichloromethane. The vessel was connected to the tritium line and was pressurized with tritium gas at -200°C. The solution was stirred for 8 hours, cooled to -200°C and excess gas was removed. The reaction flask was washed with 4x 1 ml methanol, transferring each content to a 100 ml distillate flask. The combined organic phase was evaporated in vacuo (crude yield: 124 mCi). The crude material was purified by HPLC, the mobile phase was evaporated in vacuo and the product was redissolved in absolute ethanol (yield: 17 mCi, >99% purity). The specific activity was determined to be 96.8 Ci/mmol using mass spectrometry.

Description of biological analysis

Thioflavin T (ThT) disaggregation assay of full-length tau (flTau).

The longest isoform of human tau (2N4R; 441 amino acids) was expressed in bacteria and purified. To analyze the disaggregation of tau by ThT, 35 μM recombinant full-length (fl) tau in PBS was aggregated for 24 h at 37°C in the presence of 50 μM heparin (Sigma-Aldrich) and 10 mMDTT (Sigma-Aldrich) with shaking at 750 rpm . Compounds were dissolved in anhydrous dimethyl sulfoxide (DMSO, Sigma-Aldrich) to achieve a concentration of 10 mM. flTau aggregates and serial dilutions of compounds were mixed together in PBS (50 μL volume) to a final concentration of 2 μM flTau aggregates and 160 to 0.04 μM compounds. The mixture was incubated for 30 min at room temperature (RT), then 40 μl of this mixture was transferred to a black 384-well assay plate (PerkinElmer) and mixed with 10 μl of 100 μM ThT in 250 mM glycine (both from Sigma-Aldrich) on PBS. Fluorescence (relative fluorescence units; RFU) was measured once or in duplicate on a Tecan reader (excitation: 440 nm; emission: 485 nm). The percentage of flTau disaggregation and the half maximum effective concentration (EC ₅₀ ) were then calculated. determined using GraphPad Prism version 5 (GraphPad Software), assuming a single-binding site selection model.

Analysis of Tau K18 disaggregation by ThT.

The Tau K18 fragment, comprising amino acids 244 to 372 of the longest isoform (2N4R) of human Tai441, was expressed in bacteria and purified or purchased from SignalChem. To assay K18 disaggregation by ThT, 35 μM recombinant K18 in PBS was aggregated for 24 h at 37°C in the presence of 50 μM heparin (Sigma-Aldrich) and 10 mM DTT (Sigma-Aldrich) with shaking at 750 rpm. Compounds were dissolved in anhydrous dimethyl sulfoxide (DMSO, Sigma-Aldrich) to achieve a concentration of 10 mM. K18 aggregates and serial dilutions of compounds were mixed together in PBS (50 μL volume) to a final concentration of 2 μM K18 aggregates and 160 to 0.04 μM compounds. The mixture was incubated for 30 min at room temperature (RT), then 40 μl of this mixture was transferred to a black 384-well assay plate (Perkin-Elmer) and mixed with 10 μl of 100 μM ThT in 250 mM glycine (both from Sigma-Aldrich) in PBS. Fluorescence (relative fluorescence units; RFU) was measured once or in duplicate on a Tecan reader (excitation: 440 nm; emission: 485 nm). The percentage of K18 disaggregation was then calculated and the half maximum effective concentration (EC ₅₀ ) was determined using GraphPad Prism version 5 (GraphPad Software), assuming a single-binding site selection model.

The following examples of compounds were measured.

- 154 043389

Table 7

- 155 043389

52 +++ 53 +++ 54 +++ 55 +++ 56 +++ 60 +++ 61 +++ 62 +++ 63 +++ 64 +++ 65 +++ 67 +++ 69 +++ 70 +++ 71 +++ 72 +++ 73 +++ 74 + 75 ++ 76 +++ 77 +++ 78 +++ 79 +++ 80 +++ 81 ++ 82 ++ 83 +++ 84 +++ 85 +++ 86 ++ 87 +++ 88 +++ 89 +++ 90 +++ 91 ++ 92 +++ 93 +++ 94 +++ 95 +++ 96 +++ 97 +++ 98 +++ 99 + 100 +

- 156043389

101 +++ 102 + 103 +++ 104 +++ 105 +++ 106 +++ 107 +++ 108 +++ 109 +++ BY +++ 111 +++ 112 +++ 113 +++ 114 ++ 115 +++ 117 +++ 116 +++ 118 ++ 119 +++ 120 +++ 121 +++ 122 +++ 123 +++ 124 +++ 125 +++ 126 +++ 127 +++ 128 +++ 96a ++ 129 +++ 130 +++ 131 +++ 132 +++

- 157043389

+++ EC50 < 10 µM;

++ EC ₅₀ 10 <x<25 µM;

+ EC ₅₀ 25 <x <50 µM.

Reduced intracellular tau aggregation.

A human neuroblastoma cell line overexpressing full-length human tau carrying the P301L mutation was cultured in complete medium [DMEM-F12 4.5 g/L Glutamax (Invitrogen), 15% FBS (Biochrom), 1% penicillin/streptomycin (Invitrogen)] with the addition of 2.5 μg/ml selective antibiotic G418 (Sigma-Aldrich)]. The day before the experiment, 5x105 cells/well were seeded in a 6-well plate in 3 ml of complete medium. The next day, cells were incubated with DMSO or a compound of the present invention at 5 μM for an additional 24 hours at 37°C. After incubation, the cells were trypsinized and re-added into 100 μl of homogenization buffer. [25 mM Tris-HCl, pH 7.4, 150 mM NaCl, 1 mM EDTA, 1 mM EGTA-containing phosphatase inhibitors (30 mM NaF, 0.2 mM Na VO Na ₃ VO ₄ , 1 nM okadaic acid, 1 mM PMSF, 5 mM Na ₄ P ₂ O ₇ ) and protease inhibitor cocktail (Complete™, Roche)] and then physically lysed using three rapid freeze-thaw cycles. The samples were then directly tested in the AlphaLISA assay.

AlphaLisa quantified phosphorylated, aggregated, and total tau using the following antibody pairs:

HT7-acceptor granules + biotin (BT)-tau13-donor granules: total tau;

HT7 acceptor beads + biotin (BT)-HT7 donor beads: aggregated human tau;

Tau 13 (Abcam) was biotinylated using the EZ-Link® NHS-PEO Solid Phase Biotinylation Kit (Thermo Scientific), while HT7-biotin was purchased from a commercial source (Thermo Scientific).

For each pair of antibodies, the concentration of acceptor beads and biotinylated antibodies was optimized. All samples were first tested in a series of dilutions in PBS to determine the linear range and optimal dilution for each sample and assay. For the final protocol, the following reagents were added to a 384-well white OptiPlate (PerkinElmer):

µl of diluted sample 20 µl of a mixture of biotin-mAb acceptor beads at the following final concentrations:

- 158 043389

HT7-BT at a concentration of 1.25 nM in combination with HT7-Act granules at a concentration of 10 μg/ml.

Tau13-BT at a concentration of 5 nM in combination with HT7-Act granules at a concentration of 2.5 μg/ml.

After incubating this mixture at room temperature for 1 h in the dark, 25 μl of streptavidin donor beads (Perkin Elmer) at a concentration of 25 μg/ml was added. Plates were analyzed after 30 min of incubation using the EnSpire Alpha instrument and EnSpire workstation version 3.00. Data for aggregated tau were normalized to total tau and then expressed as a percentage of DMSO-treated cells.

The following examples of compounds were measured.

+++ %>50;

++ % 50<x<25;

+%25<x<10.

In vivo effectiveness of the compounds of the present invention.

In vivo study design for testing Example 12 and Example 45.

Double transgenic rTg4510 mice express full-length human tau carrying the P301L mutation (Tau4R0N-P301L) under the control of the tet-inducible CaMKP promoter (Ramsden et al., J. Neurosci., 2005, 25 (46): 10637-10647). Single transgenic mice expressing only the tetracycline-controlled transactivator (tTA) were used as genotype controls. The study included 4 treatment groups (n=15 female mice/group for tTa and n=11 female mice/group for treatment) with the following group distribution (see Table 9). Compounds or vehicle control were administered once daily or twice daily by gavage for 1 month starting at 5 months of age. All mice received 200 ppm. doxycycline in the diet for 3 weeks plus a loading dose in drinking water for the first two days at a concentration of 1.5 mg/ml in 4% sucrose. Doxycycline dosing began at week 2 and continued throughout the dosing period. Cerebrospinal fluid (CSF) analysis was performed on all animals, while misfolded tau (MC1), total microglia (Iba1), and phagocytic microglia (CD68) histology was performed on 10 animals/group.

Table 9

In Vivo Study Design for Testing Example 12 and Example 45

Genotype Number of mice Treatment/dose tTA 15 Carrier medium ^(s) rTg4510 AND Carrier medium ^(s) rTg4510 AND Example 12 (30 mg/kg twice daily) rTg4510 AND Example 45 (30 mg/kg twice daily)

^(a) carrier medium: 0.5 w/v% hydroxypropyl methylcellulose 4000 cps; 0.5 w/v% Tween 80.

Collection and analysis of cerebrospinal fluid (CSF).

Mice were deeply anesthetized using standard injectable anesthesia and transcardially perfused with cold PBS. Fur and skin from the neck were removed with surgical scissors (the mouse was not decapitated). The tissue surrounding the base of the skull and brain stem was carefully removed by blunt dissection with minimal bleeding. After the meninges were exposed at the base of the skull, in the region of the foramen magnum, a 27-ga butterfly needle was held perpendicular to the skull and inserted laterally into the cerebrospinal fluid (CSF) space. Samples were quickly immersed in liquid nitrogen and stored at -80°C until biochemical analysis using AlphaLISA. Human total tau in CSF tau was quantified using the following pairs

- 159 043389 antibodies: HT7-acceptor granules + biotin (BT)-tau13-donor granules. Tau 13 antibody (Abeam) was biotinylated using the EZ-Link® NHS-PEO Solid Phase Biotinylation Kit (Thermo Scientific). For the final protocol, the following reagents were added to a 384-well white OptiPlate (PerkinElmer):

µl of diluted sample;

µl of a mixture of biotin-mAb acceptor beads at final concentrations: tau13-BT at a concentration of 0.6 nM in combination with HT7-Ac beads at a concentration of 2.5 µg/ml.

After incubating this mixture at room temperature for 1 h in the dark, 25 μl of streptavidin donor beads (Perkin Elmer) at a concentration of 25 μg/ml was added. Plates were analyzed after a 30-minute incubation using the EnSpire Alpha instrument and EnSpire workstation version 3.00. Data were analyzed using one-way ANOVA followed by post hoc comparisons, and statistics reported refer to differences compared to vehicle-fed rTg4510 mice.

As illustrated in FIG. 1, both Example 12 and Example 45 reduced CSF tau levels.

Histological evaluation of rTg4510 mice treated with the compound of Example 12 and Example 45.

After perfusion, the brain was removed and divided hemisagittally. The right hemispheres were fixed in 4% paraformaldehyde in PBS for 3 h at room temperature, cryopreserved by immersion in 15% sucrose at 4°C for three days, and prepared for cryosection. The fixed hemispheres were then cryo-frozen in dry ice in OCT medium and subjected to sagittal cryosectioning (10 μm thickness) using a Leica CM3050 cryotome. Sections from 10 mice per group were collected at approximately 12 mediolateral levels. A systematic random set of sections from seven sagittal levels per animal was used to quantify Iba1 and CD68 immunoreactivity, while 1 section/animal from mediolateral level 4 was used to assess tau misfolding (monoclonal antibody MC1). Cryosections were removed at −20°C and air dried for 25 min at room temperature. Brain tissue was swathed in liquid pap blocker and washed once for 5 min and once for 10 min in PBS at room temperature. Blocking and permeabilization were performed for 2 h at room temperature with 10% normal goat serum (NGS) and 0.25% Triton X-100 in PBS. The paper sections were then blotted and incubated with mouse monoclonal antibody MC1 diluted 1:1000 in PBS containing 5% NGS and 0.25% Triton X-100 overnight at 4°C in a humidified chamber. Sections were washed three times for 10 min in PBS at room temperature and incubated with Cy3-labeled anti-mouse IgG (H+L) secondary antibody (Jackson) diluted 1:1000 in PBS for 30 min at room temperature, protected from light. After washing three times for 10 min in PBS, sections were incubated with a solution of 0.1% Sudan black (Sigma) in 70% ethanol for 30 s at room temperature to reduce tissue autofluorescence. Sections were washed three times for 10 min in PBS, mounted using ProLong Gold Antifade with DAPI (Molecular Probes), and coverslipped. Sections were acquired using a digital slide scanner (Panoramic 250 Flash, 3D Histech Ltd.) and quantified using Visiopharm imaging software. MC1 staining was analyzed in the frontal cortex in the upper cortical layers. A single region of interest (ROI) was drawn around the frontal cortex, corresponding to the visual field at 20× magnification. This ROI was analyzed in Visiopharm using a predefined threshold for MS1 staining with a pixel intensity threshold greater than 30 (8-bit images) and excluding all detected objects smaller than 20 μm ² . Data were analyzed using one-way ANOVA followed by post hoc test.

As shown in FIG. 2, both example 12 and example 45 reduced the region positive for MS1. These data show that treatment of both example 12 and example 45 in rTg4510 reduces levels of misfolded tau in this aggressive transgenic model of tau.

To assess whether the above-described effect of the test compounds also affected markers of neuroinflammation, sections were labeled with rat anti-mouse CD68 clone FA-11 (BD Biosciences), goat polyclonal anti-Iba1 antibody (Abcam), and counterstained with DAPI. Antibody binding was visualized using highly cross-absorbed fluorescently labeled secondary antibodies (Thermo Fisher). The antibody was diluted in antibody diluent (Dako), and nonspecific endogenous IgG binding was blocked with MOM serum (Vector) before primary incubation. The mounted sections were imaged as a whole on an Axio Scan Z1 slide scanner controlled by ZEN software at 20× magnification (apochromatic lens plan), using LED (Colibri2) illumination and a sensitive Orca Flash 4.0 monochrome camera. Data were analyzed using one-way ANOVA followed by comparison analysis, and statistics reported refer to differences compared to vehicle-fed rTg4510 mice.

As shown in FIG. 3A, both example 12 and example 45 reduced microgliosis measured as Iba1 immunoreactive area. Moreover, both Example 12 and 45 reduced the number of highly activated phagocytic migratory cells that are positive for CD68 (Fig.

- 160 -

Claims (33)

3B). Taken together, these data indicate that treatment of both example 12 and example 45 in rTg4510 reduces levels of neuroinflammation in this aggressive transgenic model of tau. Reduction of tau misfolding in neurofibrillary tangles (NFTs) from human AD and PSP brain slices. Fresh frozen tissue sections from one AD case and two PSP cases were obtained from a commercial distributor (Tissue Solutions, UK). Tissue sections were incubated with the compound from Example 45 at a concentration of 100 μM or DMSO at room temperature for about 60 hours in a humidified chamber. After incubation, sections were washed three times in PBS, fixed for 10 min at 4°C with paraformaldehyde (PFA; Sigma), and then washed again three times in PBS. Sections were then permeabilized with blocking buffer (PBS, 10% goat serum (NGS), 0.25% Triton X) for 1 h at room temperature. After blocking, sections were incubated overnight at 4°C with conformational tau antibody (monoclonal antibody MC1) in blocking buffer (5% NGS, 0.25% Triton X). The next day, sections were washed three times for 5 min in PBS and incubated with Cy3-conjugated AffiniPure goat anti-mouse antibody (Jackson laboratories) for 1 h at room temperature. Excess antibodies were washed three times for five minutes in PBS. To reduce autofluorescence, sections were incubated with 0.1% Sudan black dissolved in 70% ethanol (Sigma) for 8 min at room temperature. Finally, sections were washed five times for 5 min in PBS and mounted under coverslips using ProLong Gold Antifade reagent with DAPI (Invitrogen). Sections were then dried at room temperature for 24 h and then imaged using a digital slide scanner (Pannoramic P250 Flash III, 3D Histech Ltd.), and tau misfolding in NFTs was quantified using Visiopharm software. As shown in FIG. 4, example 45 reduced tau misfolding in NFTs by about 30% with similar effectiveness in AD and PSP human brain samples. High-resolution ex-vivo autoradiography of ^3H -example 45 in human AD brain sections. Fresh frozen tissue sections from one AD case were obtained from a commercial distributor (Tissue Solutions, UK). For autoradiography, brain sections were fixed for 15 min at 4°C with 4% PFA (Sigma). Sections were incubated with [ ^3H ]-example 45 at 20 nM and either alone or together with 5 µM non-radioactive example 45) for 1 hour at room temperature. Sections were then washed as follows: first in ice-cold buffer for 1 min, then in ice-cold 70% ethanol twice for 1 min, in ice-cold buffer for 1 min, and finally rinsed quickly in ice-cold distilled water. Sections were then air-dried for 1 h and then exposed to Ilford Nuclear Emulsion Type K5 (Agar Scientific) for 5 days at 4°C in a light-tight slide storage box. Exposure to the emulsion was always carried out in a dark room illuminated with a safe light, and the emulsion clumps were melted in an equal volume of water preheated to 40°C according to the manufacturer's instructions. After 5 days, sections were developed according to the manufacturer's instructions. Sections were mounted using ProLong Gold Antifade reagent (Invitrogen) and visualized with a digital slide scanner (Pannoramic P250 Flash III, 3D Histech Ltd.) As shown in FIG. 5, Example 45 illustrates a specific target enhancement on tau NFT in human AD brain samples. CLAIM 1. Compound of formula (I) or a pharmaceutically acceptable salt thereof; i%n С ji ιΓ®ϊ%ι h У kg hg Ά V_Z \—/ where a is selected from the group consisting of ''''' ^{where N f} ' and can be attached to Q in any available position , where ^N N. Ίν ’ and also is substituted with one or more substituents R ^j , and if A is , R ^j is not -CN, -halogen or -CF ₃ , when- than if A represents or ' R ^j is not -halogen; and where may be optionally substituted with one or more R substituents; B is selected from the group consisting of O and NR ^a ; E and V are independently selected from the group consisting of N, O and S; G is selected from the group consisting of a benzene ring and a pyridine ring; J is selected from the group consisting of O and NR ¹ ; Q represents N; Y is selected from the group consisting of CZ and N, with the proviso that when Y is N, B is N-alkyl or O; Y ¹ represents CZ; Y ² represents CZ; Y ³ represents CZ; Z is independently selected from the group consisting of H, halogen, O-alkyl and alkyl; Rj (R ² )n а-Ц —N j с cl R is independently selected from the group consisting of R ^a is selected from the group consisting of H and alkyl; R ^b , R ^c , R ^d , R ^e , R ^f and R ^g represent H; and -NR ³ R ⁴ ; independently selected from the group consisting of -halogen, -O-alkyl, -CF ₃ , -CN, -NR ³ R ⁴ and wherein a bridge containing a C1.2 carbon atom may be present between carbon atom and carbon atom c or d, or a bridge containing a C _1-2 carbon atom may be present between carbon atom b and carbon atom c or d; R ¹ is selected from the group consisting of H and alkyl; R ² represents alkyl, and if two R ² are geminal, they can be connected to form a 3-6 membered ring; R ³ and R ⁴ are independently selected from the group consisting of H and alkyl, where alkyl may be optionally substituted with -O-alkyl; n is 0, 1, 2, 3 or 4, and where alkyl has 1 to 6 carbon atoms. 2. The connection according to claim 1, in which ^v represents 3. A compound according to claim 1, which is a compound of formula (Ia) where A, B, R ^b , R ^c , R ^d , R ^e , R ^f , R ^g , Y and Z have the meanings defined in paragraph 1. 4. A compound according to claim 1, which is a compound of formula (Ib) - 162 043389 (lb) where A, B, R ^b , R ^c , R ^d , R ^e , R ^f , R ^g and Z have the meanings defined in paragraph 1. 5. The compound according to any one of claims 1 to 4, where A represents ’ in which CcO CxXx may be attached to Q at any available position, and may optionally be substituted by one or more substituents R, where G, E, V and R are as defined in claim 1. 6. A compound according to any one of claims 1 to 5, which is a compound of formula (Ic) (Ic) where E, R, V and Z have the meanings defined in paragraph 1. 7. A connection selected from the group consisting of - 163 043389 - 164 043389 - 165 043389 - 166 043389 - 167 043389 - 168 043389 - 169 043389 - 170 043389 - 171 043389 - 172 043389 - 173 043389 - 174 043389 8. A pharmaceutical composition containing a compound according to any one of claims 1 to 7 and optionally a pharmaceutically acceptable carrier or excipient. 9. Use of the compound of formula (I) where A is selected from the group consisting of where or a pharmaceutically acceptable salt thereof; for the treatment, relief or prevention of a disorder or abnormality associated with tau protein aggregates, may be attached to Q in any additionally substituted with one or more substituents R ^j , an obtuse position, where R ^j is not -CN, -halogen or -CF3, and where and, if A is ^v may optionally be substituted with one or more R substituents; B is selected from the group consisting of O and NR ^a ; E and V are independently selected from the group consisting of N, O and S; - 175 043389 G is selected from the group consisting of a benzene ring and a pyridine ring; J is selected from the group consisting of O and NR ¹ ; Q represents N; Y is selected from the group consisting of CZ and N, with the proviso that when Y is N, B is N-alkyl or O; Y ¹ represents CZ; Y ² represents CZ; Y ³ represents CZ; Z is independently selected from the group consisting of H, halogen, O-alkyl and alkyl; (R ² )n—NJ R is independently selected from the group consisting of ³ R ⁴ ; R ^a is selected from the group consisting of H and alkyl; R ^b , R ^c , R ^d , R ^e , R ^f and R ^g represent H; R ^j is independently selected from the group consisting of -halogen, -O-alkyl, -CF3, -CN, -NR ³ R ⁴ , as well as (R ² )n -N j cd ~ „ ' where the bridge containing the C1 carbon atom . ₂ may be present between carbon atom and carbon atom c or d, or a bridge containing a carbon atom C _1-2 may be present between carbon atom b and carbon atom c or d; R ¹ is selected from the group consisting of H and alkyl; R ² represents alkyl, and if two R ² are geminal, they can be connected to form a 3-6 membered ring; R ³ and R ⁴ are independently selected from the group consisting of H and alkyl, where alkyl may be optionally substituted with -O-alkyl; n is 0, 1, 2, 3 or 4; and where alkyl has from 1 to 6 carbon atoms. 10. Application according to claim 9, in which represents 11. Use according to claim 9, wherein the compound is a compound of formula (Ia) z Z (1a) where A, B, R ^b , R ^c , R ^d , R ^e , R ^f , R ^g , Y and Z have the meanings defined in clause 9. 12. Use according to claim 9, wherein the compound is a compound of formula (Ib) Z (lb) where A, B, R ^b , R ^c , R ^d , R ^e , R ^f , R ^g and Z have the meanings defined in clause 9. 13. Use according to any one of claims 9 to 12, where A is can be attached to Q in any available position, and moreover ’ in which there may be - 176 043389 is optionally substituted with one or more R substituents, where G, E, V and R have the meanings defined in claim 9. 14. Use according to any one of formula (Ic) claims 9 to 13, where the compound is a compound where E, R, V and Z have the meanings defined in paragraph 9. 15. The use of a compound or a pharmaceutically acceptable salt thereof for the treatment, amelioration or prevention of a disorder or abnormality associated with tau protein aggregates, wherein the compound is selected from the group consisting of - 177 043389 - 178 043389 - 179 043389 - 180 043389 - 181 043389 - 182 043389 - 183 043389 - 184 043389 - 185 043389 - 186 043389 - 187 043389 16. A method of treating, preventing, or alleviating a disorder or abnormality associated with tau protein aggregates, comprising administering an effective amount of a compound according to any one of claims 17 to a subject in need thereof. 17. The method according to claim 16, characterized in that the disorder is selected from Alzheimer's disease (AD), familial AD, primary age-related tauopathy (PART), Creutzfeldt-Jakob disease, Boxer dementia, Down syndrome, Gerstmann-Straussler-Scheinker disease (GSS ), inclusion body myositis, cerebral prion protein-induced amyloid angiopathy, traumatic brain injury (TBI), amyotrophic lateral sclerosis (ALS), Guam parkinsonism-dementia complex, non-Guam motor neuron disease with neurofibrillary tangles, disease characterized by the appearance of argyrophilic grains , corticobasal degeneration (CBD), diffuse neurofibrillary tangles with calcification, frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), Hallerwarden-Spatz disease, multiple system atrophy (MSA), Niemann-Pick disease type C, pallido -ponto-nigral degeneration, Pick's disease (PiD), progressive subcortical gliosis, progressive supranuclear palsy (PSP), subacute sclerosing panencephalitis, tangle-predominant dementia, postencephalitic parkinsonism, myotonic dystrophy, subacute sclerosing panencephalitis, mutations in LRRK2, chronic traumatic encephalopathy ( CTE), familial British dementia, familial Danish dementia, other frontotemporal lobar degenerations, Guadalupean parkinsonism, neurodegeneration with brain iron accumulation, SLC9A6-related mental retardation, white matter tauopathy with globular glial inclusions, epilepsy, dementia with Lewy bodies ( LBD), mild cognitive impairment (MCI), multiple sclerosis, Parkinson's disease, HIV-associated dementia, adult-onset diabetes, frailty-related cardiac amyloidosis, glaucoma, ischemic stroke, psychosis - 188 043389 for AD and Huntington's disease, preferably Alzheimer's disease (AD), corticobasal degeneration (CBD), Pick's disease (PiD) and progressive supranuclear palsy (PSP). 18. Use of a compound as defined in any one of claims 1 to 7 in the manufacture of a medicament for the treatment, prevention or amelioration of a disorder or abnormality associated with tau protein aggregates. 19. The use of claim 9 or the use of claim 18, characterized in that the disorder is selected from Alzheimer's disease (AD), familial AD, primary age-related tauopathy (PART), Creutzfeldt-Jakob disease, Boxer's dementia, Down syndrome, Gerstmann's disease -Straussler-Scheinker (GSS), inclusion body myositis, cerebral prion protein-induced amyloid angiopathy, traumatic brain injury (TBI), amyotrophic lateral sclerosis (ALS), Guam parkinsonism-dementia complex, non-Guam motor neuron disease with neurofibrillary tangles, disease characterized by the appearance of argyrophilic granules, corticobasal degeneration (CBD), diffuse neurofibrillary tangles with calcification, frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), Hallervorden-Spatz disease, multiple system atrophy (MSA), Niemann disease -Pica type C, pallidoponto-nigral degeneration, Pick's disease (PiD), progressive subcortical gliosis, progressive supranuclear palsy (PSP), subacute sclerosing panencephalitis, tangle-predominant dementia, postencephalitic parkinsonism, myotonic dystrophy, subacute sclerosing panencephalitis, mutations in LRRK2, chronic traumatic encephalopathy (CTE), familial British dementia, familial Danish dementia, other frontotemporal lobar degenerations, Guadalupean parkinsonism, neurodegeneration with brain iron accumulation, SLC9A6-related mental retardation, white matter tauopathy with globular glial inclusion bodies, epilepsy , Lewy body dementia (LBD), mild cognitive impairment (MCI), multiple sclerosis, Parkinson's disease, HIV-associated dementia, adult-onset diabetes, senile cardiac amyloidosis, glaucoma, ischemic stroke, AD psychosis and Huntington's disease, preferably Alzheimer's disease (AD) ), corticobasal degeneration (CBD), Pick's disease (PiD) and progressive supranuclear palsy (PSP). 20. Use of a compound according to any one of claims 1 to 7 to reduce tau aggregation. 21. Use of a compound according to any one of claims 1 to 7 for preventing the formation of tau aggregates and/or for inhibiting tau aggregation. 22. Use of a compound according to any one of claims 1 to 7 for intracellular interaction with tau aggregates. 23. Use of a compound according to any one of claims 1 to 7 for reducing tau misfolding and hyperphosphorylation in vivo. 24. A method of reducing tau aggregation, comprising administering an effective amount of a compound according to any one of claims 1 to 7 to a subject in need thereof. 25. A method of preventing the formation of tau aggregates and/or inhibiting tau aggregation, comprising administering an effective amount of a compound according to any one of claims 1 to 7 to a subject in need thereof. 26. A method of intracellular interaction with tau aggregates, comprising administering an effective amount of a compound according to any one of claims 1 to 7 to a subject in need thereof. 27. A method of reducing tau misfolding and hyperphosphorylation in vivo, comprising administering an effective amount of a compound according to any one of claims 1 to 7 to a subject in need thereof. 28. Use of a compound according to any one of claims 1 to 7 in the manufacture of a medicament for reducing tau aggregation. 29. Use of a compound according to any one of claims 1 to 7 in the manufacture of a medicinal product for preventing the formation of tau aggregates and/or for inhibiting tau aggregation. 30. Use of a compound according to any one of claims 1 to 7 in the manufacture of a medicinal product for intracellular interaction with tau aggregates. 31. Use of a compound according to any one of claims 1 to 7 in the manufacture of a medicament for reducing tau misfolding and hyperphosphorylation in vivo. 32. Use of a compound as defined in any one of claims 1 to 7 for characterizing tissue with tau pathology. 33. Use of a compound as defined in any one of claims 1 to 7 for testing compounds targeting tau pathology in tissue with tau pathology. - 189 -