Thiadiazole compound as CSF1r inhibitors

Abstract

The present invention relates to a thiadiazole compound or a salt thereof. The present invention also relates to a medicament having a thiadiazole compound or a salt thereof as an active ingredient and useful for treating, preventing and / or diagnosing diseases associated with colony-stimulating factor-1 receptor (CSF1R) as an inhibitor therefor.

Description

THIADIAZOLE COMPOUND AS CSF1R INHIBITORS

[0001] The present invention relates to a thiadiazole compound or a salt thereof. The present invention also relates to a medicament having a thiadiazole compound or a salt thereof as an active ingredient and useful for treating, preventing and / or diagnosing diseases associated with colony-stimulating factor-1 receptor (CSF1R) as an inhibitor therefor.

[0002] Macrophage colony-stimulating factor-1 receptor (CSF1R) is a member of class III receptor tyrosine kinase family, which also includes FMS-like tyrosine kinase 3 (FLT-3), tyrosine-protein kinase KIT (KIT), and platelet-derived growth factor receptor (PDGFR) α and β. CSF1R is primarily expressed in macrophage lineages including monocytes, tissue macrophages, dendritic cells, Kupffer cells, osteoclasts, and microglia. CSF1R binding CSF-1 or the more recently identified ligand, IL-34 activates signal transduction pathways, such as PI3K / AKT / NF-κB, PKC / NF-κB, and ROS / RAS / RAF / MAPK pathways, resulting in the differentiation, survival, proliferation, adhesion, and migration of monocyte / macrophage lineage cells.

[0003] The phenotype of mice lacking functionalCSF1R and ligands includes osteopetrosis, reduced numbers of macrophage and microglia and reduced inflammatory cytokine production, which indicates the diverse functions of CSF1R signaling.

[0004] CSF1R signaling may also lead to aberrant expression of proinflammatory cytokines, including tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), which are involved in the exacerbation of various types of cancer, bone disorders, and inflammatory diseases.

[0005] [NPL 1] Smith B.D et al. Vimseltinib: A Precision CSF1R Therapy for Tenosynovial Giant Cell Tumors and Diseases Promoted by Macrophages. Mol Cancer Ther 20(11):2098-2109 (2021).[NPL 2] Lv Qi et.al. Discovery of (Z)-1-(3-((1H-Pyrrol-2-yl)methylene)-2-oxoindolin-6-yl)-3-(isoxazol-3-yl)urea Derivatives as Novel and Orally Highly Effective CSF-1R Inhibitors for Potential Colorectal Cancer Immunotherapy. J Med Chem. 1c01184 (2021).[NPL 3] Branden A.S et.al. PLX3397 treatment inhibits constitutive CSF1R-induced oncogenic ERK signaling, reduces tumor growth, and metastatic burden in osteosarcoma. Bone.115353 (2020)[NPL 4] Debbie C S, Brian R, Yoko O, Mina J B, Lisa M C, Nancy P, Dylan D CSF1R inhibition delays cervical and mammary tumor growth in murine models by attenuating the turnover of tumor-associated macrophages and enhancing infiltration by CD8+ T cells Oncoimmunology, 2 26968 (2013)[NPL 5] Uesato N, et al. Pharmacological Properties of JTE-952, an Orally Available and Selective Colony Stimulating Factor 1 Receptor Kinase Inhibitor. Biological and Pharmaceutical Bulletin 43, 325-333 (2020)[NPL 6] Garcia S et al. Colony-stimulating factor (CSF) 1 receptor blockade reduces inflammation in human and murine models of rheumatoid arthritis. Arthritis Research & Therapy 18. 75 (2016)[NPL 7] Babaeijandaghi F. et al. Metabolic reprogramming of skeletal muscle by resident macrophages points to CSF1R inhibitors as muscular dystrophy therapeutics. Sci Transl Med 14(651) (2022).[NPL 8] Xiang C. et al. Interfering with alternatively activated macrophages by CSF-1R inhibition exerts therapeutic capacity on allergic airway inflammation. Biochem Pharmacol. 198:114952 (2022).[NPL 9] Moon H.G. et al. Colony-stimulating factor 1 and its receptor are new potential therapeutic targets for allergic asthma. Allergy 75(2):357-369 (2020).[NPL 10] Lodder C. et al. CSF1R inhibition rescues tau pathology and neurodegeneration in an A / T / N model with combined AD pathologies, while preserving plaque associated microglia. Acta Neuropathol Commun. 9(1):108 (2021).[NPL 11] Olmos-Alonso, A. et al. Pharmacological targeting of CSF1R inhibits microglial proliferation and prevents the progression of Alzheimer’s-like pathology. Brain 139, 891-907 (2016).[NPL 12] Dagher, N. N. et al. Colony-stimulating factor 1 receptor inhibition prevents microglial plaque association and improves cognition in 3xTg-AD mice. Journal of neuroinflammation 12, 139 (2015).[NPL 13] Spangenberg, E. E. et al. Eliminating microglia in Alzheimer's mice prevents neuronal loss without modulating amyloid-β pathology. Brain 139, 1265-1281 (2016).[NPL 14] Sosna, J. et al. Early long-term administration of the CSF1R inhibitor PLX3397 ablates microglia and reduces accumulation of intraneuronal amyloid, neuritic plaque deposition and pre-fibrillar oligomers in 5XFAD mouse model of Alzheimer's disease. Molecular neurodegeneration 13, 11 (2018).[NPL 15] Asai, H. et al. Depletion of microglia and inhibition of exosome synthesis halt tau propagation. Nature neuroscience 18, 1584 (2015).[NPL 16] Mancuso, R. et al. CSF1R inhibitor JNJ-40346527 attenuates microglial proliferation and neurodegeneration in P301S mice. Brain (2019).[NPL 17] Martinez-Muriana, A. et al. CSF1R blockade slows the progression of amyotrophic lateral sclerosis by reducing microgliosis and invasion of macrophages into peripheral nerves. Scientific reports 6, 25663 (2016).[NPL 18] Trias, E. et al. Post-paralysis tyrosine kinase inhibition with masitinib abrogates neuroinflammation and slows disease progression in inherited amyotrophic lateral sclerosis. Journal of neuroinflammation 13, 177 (2016).[NPL 19] Gowing, G., Lalancette-Hebert, M., Audet, J.-N., Dequen, F. & Julien, J.-P. Macrophage colony stimulating factor (M-CSF) exacerbates ALS disease in a mouse model through altered responses of microglia expressing mutant superoxide dismutase. Experimental neurology 220, 267-275 (2009).[NPL 20] Hagan N. et al. CSF1R signaling is a regulator of pathogenesis in progressive MS CSF1R signaling is a regulator of pathogenesis in progressive MS. Cell Death Dis. 11(10):904 (2020).[NPL 21] Wies Mancini V.S.B et al. Microglial modulation through colony-stimulating factor-1 receptor inhibition attenuates demyelination. Glia 67(2):291-308 (2019).[NPL 22] Borjini, N., Fernandez, M., Giardino, L. & Calza, L. Cytokine and chemokine alterations in tissue,CSF, and plasma in early presymptomatic phase of experimental allergic encephalomyelitis (EAE), in a rat model of multiple sclerosis. Journal of neuroinflammation 13, 291 (2016).[NPL 23] Beckmann, N. et al. Brain region-specific enhancement of remyelination and prevention of demyelination by the CSF1R kinase inhibitor BLZ945. Acta neuropathologica communications 6, 9 (2018).[NPL 24] Gerngross, L. & Fischer, T. Evidence for cFMS signaling in HIV production by brain macrophages and microglia. Journal of neurovirology 21, 249-256 (2015).[NPL 25] Gomez-Nicola D, Fransen NL, Suzzi S, Perry VH. Regulation of microglial proliferation during chronic neurodegeneration. Journal of Neuroscience 33. 2481-93 (2013)[NPL 26] Wang Y. et al. Early posttraumatic CSF1R inhibition via PLX3397 leads to time- and sex-dependent effects on inflammation and neuronal maintenance after traumatic brain injury in mice. Brain Behav Immun. S0889-1591(22)00338-5 (2022).[NPL 27] Rebecca J. H et al. Microglial depletion with CSF1R inhibitor during chronic phase of experimental traumatic brain injury reduces neurodegeneration and neurological deficits Journal of Neuroscience 10, 2402-19 (2020)[NPL 28] Oh S.J. et al. Evaluation of the Neuroprotective Effect of Microglial Depletion by CSF-1R Inhibition in a Parkinson's Animal Model. Mol Imaging Biol 22(4):1031-1042 (2020).[NPL 29] Neal ML et al. Pharmacological inhibition of CSF1R by GW2580 reduces microglial proliferation and is protective against neuroinflammation and dopaminergic neurodegeneration. The FASEB Journal. 34, 1679-1694 (2020).[NPL 30] Sawicki CM, et al Microglia Promote Increased Pain Behavior through Enhanced Inflammation in the Spinal Cord during Repeated Social Defeat Stress. Journal of Neuroscience 39, 1139-1149 (2019)[NPL 31] Yan X, Maixner DW, Li F3 Weng HR. Chronic pain and impaired glial glutamate transporter function in lupus-prone mice are ameliorated by blocking macrophage colony-stimulating factor-1 receptors. Journal f Neurochemistry 140, 963-976 (2017)[NPL 32] Poulen G. et al. Inhibiting microglia proliferation after spinal cord injury improves recovery in mice and nonhuman primates. Theranostics 11(18):8640-8659 (2021).[NPL 33] Gerber Y.N, et al .CSF1R inhibition reduces microglia proliferation, promotes tissue preservation and improves motor recovery after spinal cord injury .Frontiers in Cellular Neuroscience .12 368 (2018)[NPL 34] Zhou Y. et al. CSF1 / CSF1R-mediated Crosstalk Between Choroidal Vascular Endothelial Cells and Macrophages Promotes Choroidal Neovascularization. Invest Ophthalmol Vis Sci 62(3): 37 (2021)

[0006] It is an object of the present invention to provide a novel thiadiazole compound or a salt thereof useful for treating, preventing and / or diagnosing diseases associated with CSF1R as an inhibitor therefor.

[0007] It is another object of the present invention to provide a medicament having a wide treatment spectrum relating to CSF1R.

[0008] As a result of exhaustive research aimed at solving the aforementioned problems, the inventors succeeded in synthesizing a novel thiadiazole compound. The present invention has been perfected based on these findings.

[0009] This is, the present invention includes the following embodiments.(Item 1)A compound of formula [I], or a salt thereof: wherein:L1is L11, -L11-C(=O)-, or -C(=O)-L11-;L11is bond, -O-, or -N(L12)-; L12is H, C1-6alkyl, or C1-6alkyl-O-C1-6alkyl;R1is hydrogen, C1-6alkyl, C3-8cycloalkyl, C6-14aryl, cyano, or 4- to 15-membered heterocyclyl, wherein said alkyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more R11;each R11is independently halogen, cyano, C1-6alkyl, -O-C1-6alkyl, -OH, -NH2, NH(C1-6alkyl), N(C1-6alkyl)(C1-6alkyl), N(C1-6alkyl)(4 to 8-membered saturated heterocyclyl), oxo, -C(=O)-O-C1-6alkyl, -C(=O)-C1-6alkyl, C3-8cycloalkyl, or 4- to 15-membered heterocyclyl, wherein said alkyl, cycloalkyl, and heterocyclyl are optionally substituted with one or more R12;each R12is independently halogen, -OH, -O-C1-6alkyl, C1-6alkyl, -NH2, NH(C1-6alkyl), N(C1-6alkyl)(C1-6alkyl), or 4 to 8-membered saturated heterocyclyl containing at least one oxygen or nitrogen atom;R2is C1-6alkyl, C3-8cycloalkyl, C6-10aryl, 5- or 6-membered unsaturated heterocyclyl, 4- to 15-membered saturated or partially-unsaturated heterocyclyl, or C5-15bicyclic saturated or partially-unsaturated carbocyclyl, wherein R2is optionally substituted with one or more R21;each R21is independently halogen, cyano, -OH, C1-6alkyl, -O-C1-6alkyl, C1-6hydroxyalkyl, C1-6alkyl-O-C1-6alkyl, C3-8cycloalkyl, or oxo, wherein said alkyl and cycloalkyl are optionally substituted with one or more halogen atoms;each R4is independently hydrogen or C1-6alkyl;n is 0, 1, or 2;X1, X2, and X3are independently N or C-R3;each R3is independently hydrogen, halogen, cyano, or C1-6alkyl optionally substituted with one or more halogen atoms;provided the compound wherein n is 0 and R2is pyrimidinyl optionally substituted with R21is excluded.In addition, the above Item 1 also includes an embodiment in which 5-(5-(4-fluorophenoxy)-3-(3-(trifluoromethyl)phenyl)-1,2,4-triazin-6-yl)-1,2,4-thiadiazole and 5-(5-(4-fluorophenoxy)-3-(3-fluorophenyl)-1,2,4-triazin-6-yl)-1,2,4-thiadiazole are excluded.

[0010] (Item 2)The compound of Item 1, or a salt thereof, wherein R4is hydrogen or methyl.

[0011] (Item 3)The compound of Items 1 or 2, or a salt thereof, wherein n is 0 or 1.

[0012] (Item 4)The compound of any one of Item 1 to 3, or a salt thereof, when R2is C6-10aryl or 5- or 6-membered unsaturated heterocyclyl, then n is 1.

[0013] (Item 5)The compound of any one of Items 1 to 4, or a salt thereof, wherein formula [I] is the following formula [II].

[0014] (Item 6)The compound of any one of Items 1 to 5, or a salt thereof, wherein X1, X2, and X3are independently N or C-R3; and each R3independently represents hydrogen, halogen, or C1-6alkyl.

[0015] (Item 7)The compound of any one of Items 1 to 5, or a salt thereof, wherein X1and X3are independently N or C-R3and X2is C-R3.

[0016] (Item 8)The compound of any one of Items 1 to 5, or a salt thereof, wherein X1is N, CH, C(CH3) or CF, X2is CH or CF, and X3is N, CH or CF.

[0017] (Item 9)The compound of any one of Items 1 to 8, or a salt thereof, wherein L1is bond, -O-, -O-C(=O)-, -C(=O)-, -C(=O)-N(L12)-, or -N(L12)-.

[0018] (Item 10)The compound of any one of Items 1 to 9, or a salt thereof, wherein L12is H, methyl or -ethyl-O-methyl.

[0019] (Item 11)The compound of any one of Items 1 to 10, or a salt thereof, wherein the heterocyclyl as R1and / or R11contains at least one oxygen or nitrogen atom.

[0020] (Item 12)The compound of any one of Items 1 to 10, or a salt thereof, wherein R1is hydrogen; C1-6alkyl; C3-8cycloalkyl; 4- to 15-membered heterocyclyl, wherein said heterocyclyl is selected from the group consisting of 4- to 7-membered mono-cyclic saturated or partially-unsaturated heterocyclyl, or 6- to 15-membered bi-cyclic, bridged-cyclic, spiro-cyclic saturated or partially-unsaturated heterocyclyl, or 5- or 6-membered unsaturated heterocyclyl, wherein said alkyl, cycloalkyl, and heterocyclyl are optionally substituted with one or more R11.

[0021] (Item 13)The compound of any one of Items 1 to 10, or a salt thereof, wherein R1is 4- to 7-membered mono-cyclic saturated or partially-unsaturated heterocyclyl; or 6- to 15-membered bi-cyclic, bridged-cyclic, or spiro-cyclic saturated or partially-unsaturated heterocyclyl, wherein R1is optionally substituted with one or more R11.

[0022] (Item 14)The compound of any one of Items 1 to 10, or a salt thereof, wherein R1is a group containing a ring selected from the group consisting of piperazine; piperidine; morpholine; and bi-cyclic or bridged-cyclic heterocyclyl containing piperazine, piperidine, or morpholine ring, wherein R1is optionally substituted with one or more R11.

[0023] (Item 15)The compound of any one of Items 1 to 10, or a salt thereof, wherein R1is 7- to 11-membered spiro-cyclic heterocyclyl, wherein R1is optionally substituted with one or more R11.

[0024] (Item 16)The compound of any one of Items 1 to 10, or a salt thereof, wherein R1is methyl, and R1is substituted with C3-8cycloalkyl or 4- to 15-membered heterocyclyl, wherein the C3-8cycloalkyl or 4- to 15-membered heterocyclyl is optionally substituted with one or more R12.

[0025] (Item 17)The compound of any one of Items 1 to 10, or a salt thereof, wherein R1is methyl, ethyl, or a group containing a ring selected from the group consisting of cyclobutane, cyclopentane, piperazine, piperidine, morpholine, thiomorpholine, pyrazole, tetrahydropyridine, pyrrolidine, azetidine, oxetane, oxolane, oxane, 1,4-diazepane, 1,4-oxazepane, 2-oxa-5-azabicyclo[2.2.1]heptane, 2,5-diazabicyclo[2.2.1]heptane, 2,6-diazaspiro[3.3]heptane, 6-oxa-3-azabicyclo[3.1.1]heptane, 3-oxa-6-azabicyclo[3.1.1]heptane, 2-oxa-5-azabicyclo[4.1.0]heptane, 3,6-diazabicyclo[3.2.0]heptane, 3-azabicyclo[4.1.0]heptane, hexahydro-1H-pyrazino[2,1-c][1,4]oxazine, hexahydropyrrolo[3,4-b][1,4]oxazine, octahydropyrazino[2,1-c][1,4]oxazine, octahydropyrrolo[3,4-b][1,4]oxazine, octahydro-1H-pyrido[3,4-b][1,4]oxazine, hexahydropyrrolo[1,2-a]pyrazine, 6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazine, tetrahydro-1H-[1,3]oxazolo[3,4-a]pyrazine, 6,8-dihydro-5H-imidazo[1,2-a]pyrazine, 6,8-dihydro-5H-imidazo[1,5-a]pyrazine, octahydro-1H-[1,4]diazino[1,2-a]pyrazine, 5H,6H,7H,8H-imidazo[1,2-a]pyrazine, hexahydrofuro[3,4-c]pyrrole, hexahydrofuro[2,3-c]pyrrole, hexahydropyrrolo[2,3-c]pyrrole, hexahydropyrrolo[3,4-c]pyrrole, octahydropyrrolo[3,4-c]pyrrole, octahydropyrrolo[3,2-b]pyrrole, octahydropyrrolo[3,4-b]pyrrole, octahydropyrrolo[2,3-c]pyrrole, hexahydro-2H-furo[2,3-c]pyridine, 5,7-dihydropyrrolo[3,4-b]pyridine, 1H,4H,5H,6H,7H-pyrazolo[3,4-c]pyridine, 8-oxa-3-azabicyclo[3.2.1]octane, 6-oxa-2-azabicyclo[3.2.1]octane, 3-oxa-8-azabicyclo[3.2.1]octane, 4,7-diazaspiro[2.5]octane, 2-oxa-6-azaspiro[3.4]octane, 9-oxa-3,7-diazabicyclo[3.3.1]nonane, 3-oxa-7,9-diazabicyclo[3.3.1]nonane, azabicyclo[3.1.0]hexane, 3-oxabicyclo[3.1.0]hexane, 2-oxaspiro[3.3]heptane, 1-oxa-6-azaspiro[3.3]heptane, 2-oxa-6-azaspiro[3.3]heptane, 2-oxa-8-azaspiro[4.5]decane, 1-oxa-8-azaspiro[4.5]decane, 8-oxa-2-azaspiro[4.5]decane, 6-oxa-2,9-diazaspiro[4.5]decane, 1-oxa-9-azaspiro[5.5]undecane, 2-oxa-7-azaspiro[4.4]nonane, 5-oxa-2,8-diazaspiro[3.5]nonane, 2-oxa-5,8-diazaspiro[3.5]nonane, 2,5-dioxa-8-azaspiro[3.5]nonane, 2,6-diazaspiro[3.4]octane, 4-oxa-7-azaspiro[2.5]octane, and 3,6-diazabicyclo[3.1.1]heptane wherein R1is optionally substituted with one or more R11.

[0026] (Item 18)The compound of any one of Items 1 to 17, or a salt thereof, wherein each R11is independently halogen, cyano, C1-6alkyl, -O-C1-6alkyl, -OH, -NH2, NH(C1-6alkyl), N(C1-6alkyl)(C1-6alkyl), N(C1-6alkyl)(4 to 8-membered saturated heterocyclyl), oxo, -C(=O)-C1-6alkyl, C3-8cycloalkyl, oxetanyl, oxolanyl, oxanyl, morpholinyl, piperazinyl, pyridyl, or 2-oxa-5-azabicyclo[2.2.1]heptane, wherein said alkyl, cycloalkyl, oxetanyl, oxolanyl, oxanyl, morpholinyl, piperazinyl, pyridyl, and 2-oxa-5-azabicyclo[2.2.1]heptane are optionally substituted with one or more R12; and each R12is independently halogen, -OH, -O-C1-6alkyl, C1-6alkyl, -NH2, NH(C1-6alkyl), N(C1-6alkyl)(C1-6alkyl), morpholinyl, or oxetanyl.

[0027] (Item 19)The compound of any one of Items 1 to 17 or a salt thereof, wherein R11is fluoro, cyano, methyl, ethyl, -O-CH3, -OH, -NH2, NH(CH3), N(CH3)(CH3), N(CH3)(oxetanyl), oxo, -C(=O)-CH3, or a group containing a ring selected from the group consisting of cyclopropane, oxetane, oxolane, oxane, morpholine, piperadine, pyridine and 2-oxa-5-azabicyclo[2.2.1]heptane.

[0028] (Item 20)The compound of any one of Items 1 to 19, or a salt thereof, wherein R2is C1-6alkyl, C3-8cycloalkyl, phenyl, pyridyl, 4- to 15-membered saturated or partially unsaturated heterocyclyl, wherein said heterocyclyl is selected from the group consisting of 4- to 7-membered mono-cyclic saturated or partially-unsaturated heterocyclyl, or 6- to 15-membered bi-cyclic, bridged-cyclic, spiro-cyclic saturated or partially-unsaturated heterocyclyl, or C5-15bicyclic saturated or partially-unsaturated carbocyclyl, wherein R2is optionally substituted with one or more R21.

[0029] (Item 21)The compound of any one of Items 1 to 19, or a salt thereof, wherein R2is C1-6alkyl, C3-8cycloalkyl, or 4- to 7-membered oxygen-containing heterocyclyl, wherein R2is optionally substituted with one or more R21.

[0030] (Item 22)The compound of any one of Items 1 to 19, or a salt thereof, wherein R2is 2-methylpropyl, 2,2-dimethylpropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.2]octanyl, oxetanyl, oxolanyl, oxanyl, oxepanyl, azetidinyl, pyrrolidinyl, piperidinyl, thietanyl, 2-oxabicyclo[2.1.1]hexanyl, 3-oxabicyclo[3.1.0]hexanyl, 2-oxabicyclo[2.2.1]heptanyl, 3-oxabicyclo[4.1.0]heptanyl, 2-oxabicyclo[3.1.1]heptanyl, 2-oxaspiro[3.3]heptanyl, 5-oxaspiro[2.4]heptanyl, 8-oxaspiro[4.5]decanyl, 5-oxaspiro[2.3]hexanyl, or pyridyl, wherein R2is optionally substituted with one or more R21.

[0031] (Item 23)The compound of any one of Items 1 to 22, or a salt thereof, wherein each R21is independently halogen, -OH, C1-6alkyl, C1-6hydroxyalkyl, or C1-6alkyl substituted with one or more halogen atoms.

[0032] (Item 24)The compound of any one of Items 1 to 23, when R2is CH3optionally-substituted with one or more the same or different halogen (e.g. CH3, CH2F, CHF2, CF3), then n is 1.

[0033] (Item 25)The compound of Item 1, which is represented by formula [Ia]: whereinL1is bond or -N(L12)-; L12is H or C1-6alkyl;R1is 4- to 15-membered heterocyclyl which is optionally substituted with one or more R11;each R11is independently C1-6alkyl, C1-6alkyl substituted with -O-C1-6alkyl, or 4- to 15-membered heterocyclyl;R2is C3-8cycloalkyl or 4- to 15-membered saturated or partially-unsaturated heterocyclyl, wherein R2is optionally substituted with one or more R21;each R21is independently halogen, -OH, or C1-6alkyl which is optionally substituted with one or more halogen atoms;n is 0 or 1;X1, X2, and X3are independently N or C-R3; andeach R3is independently hydrogen or halogen;or a salt thereof.

[0034] (Item 26)The compound of Item 25 or a salt thereof, whereinX1and X2are C-R3, wherein R3is independently hydrogen or F; andX3is N or CH.

[0035] (Item 27)The compound of Item 25 or 26 or a salt thereof, wherein(1) L1is bond, and R1is any one of the following structures: (2) L1is -N(CH3)-, and R1is the following structure:

[0036] (Item 28)The compound of any one of Items 25 to 27 or a salt thereof, wherein(1) n is 0, and R2is any one of the following structures: (2) n is 1, and R2is any one of the following structures:

[0037] (Item 29)A compound selected from the group consisting of the following compounds, or a salt thereof.

[0038] (Item 30)A compound selected from the group consisting of the following compounds.

[0039] (Item 31)A pharmaceutical composition comprising the compound according to any one of Items 1 to 30 or a salt thereof as an active ingredient and a pharmaceutically acceptable carrier or excipient.

[0040] (Item 32)A therapeutic, preventative and / or diagnostic agent comprising the compound according to any one of Items 1 to 30 or a salt thereof as an active ingredient, for treating, preventing and / or diagnosing a disease selected from Alzheimer's disease (AD), tauopathies, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), HIV-associated neurocognitive disorders (HAND), prion disease, trauma brain injury (TBI), Parkinson's disease, pain, spinal cord injury, Crohn’s disease, radiation-induced lung fibrosis, glaucoma, infections, cardiovascular diseases such as inflammation post myocardial infarction, bone diseases, muscular dystrophy, or asthma.

[0041] (Item 33)A pharmaceutical composition comprising the compound according to any one of Items 1 to 30 or a salt thereof as an active ingredient, for treating, preventing and / or diagnosing a disease selected from Alzheimer's disease (AD), tauopathies, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), HIV-associated neurocognitive disorders (HAND), prion disease, trauma brain injury (TBI), Parkinson's disease, pain, spinal cord injury, Crohn’s disease, radiation-induced lung fibrosis, glaucoma, infections, cardiovascular diseases such as inflammation post myocardial infarction, bone diseases, muscular dystrophy, or asthma.

[0042] (Item 34)A method for treating, preventing and / or diagnosing a disease selected from Alzheimer's disease (AD), tauopathies, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), HIV-associated neurocognitive disorders (HAND), prion disease, trauma brain injury (TBI), Parkinson's disease, pain, spinal cord injury, Crohn’s disease, radiation-induced lung fibrosis, glaucoma, infections, cardiovascular diseases such as inflammation post myocardial infarction, bone diseases, muscular dystrophy, or asthma, comprising administering a therapeutically effective amount of the compound according to any one of Items 1 to 30 or a salt thereof to a human in need thereof.

[0043] (Item 35)The compound according to any one of Items 1 to 30 or a salt thereof for use in the treatment, prevention and / or diagnosis of a disease selected from Alzheimer's disease (AD), tauopathies, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), HIV-associated neurocognitive disorders (HAND), prion disease, trauma brain injury (TBI), Parkinson's disease, pain, spinal cord injury, Crohn’s disease, radiation-induced lung fibrosis, glaucoma, infections, cardiovascular diseases such as inflammation post myocardial infarction, bone diseases, muscular dystrophy, or asthma.

[0044] (Item 36)Use of the compound according to any one of Items 1 to 30 or a salt thereof in the manufacture of a medicament for treating, preventing and / or diagnosing a disease selected from Alzheimer's disease (AD), tauopathies, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), HIV-associated neurocognitive disorders (HAND), prion disease, trauma brain injury (TBI), Parkinson's disease, pain, spinal cord injury, Crohn’s disease, radiation-induced lung fibrosis, glaucoma, infections, cardiovascular diseases such as inflammation post myocardial infarction, bone diseases, muscular dystrophy, or asthma.

[0045] (Item 37)A therapeutic, preventative and / or diagnostic agent comprising the compound according to any one of Items 1 to 30 or a salt thereof as an active ingredient, for treating, preventing and / or diagnosing cancers or autoimmune diseases such as rheumatoid arthritis.

[0046] (Item 38)A method for treating, preventing and / or diagnosing cancers or autoimmune diseases such as rheumatoid arthritis, comprising administering a therapeutically effective amount of the compound according to any one of Items 1 to 30 or a salt thereof to a human in need thereof.

[0047] (Item 39)The compound according to any one of Items 1 to 30 or a salt thereof for use in the treatment, prevention and / or diagnosis of cancers or autoimmune diseases such as rheumatoid arthritis.

[0048] (Item 40)Use of the compound according to any one of Items 1 to 30 or a salt thereof in the manufacture of a medicament for treating, preventing and / or diagnosing cancers or autoimmune diseases such as rheumatoid arthritis.

[0049] (Item 41)A process for preparing a compound of formula [I] according to any one of Items 1 to 30, or a salt thereof, as described herein.

[0050] (Item 42)An intermediate compound in the process for preparing a compound of formula [I], or a salt thereof, as described herein.

[0051] (Item 43)The compound of Item 1, or a salt thereof, wherein the compound is selected from Examples 1 to 695.

[0052] The phrases and terms used herein are explained in detail below.

[0053] In the present specification, the "C1-6alkyl" is a linear or branched alkyl having 1 to 6 carbon atoms (C1-6), and specific examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, 3-methylpentyl and the like.In addition, the "C1-6alkyl" includes C1-6alkyl in which 1 to 3 hydrogen atoms are substituted with deuterium atoms.

[0054] In the present specification, the "halogen" is fluorine, chlorine, bromine, or iodine. It is preferably fluorine, chlorine, or bromine, and more preferably fluorine or chlorine.

[0055] In the present specification, the "C3-8cycloalkyl" is saturated monocyclic hydrocarbon ring group having 3 to 8 carbon atoms (C3-8), which includes, for example, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, and cyclooctanyl.

[0056] In the present specification, the "C6-14aryl" is a mono-, bi-, or tri-cyclic aromatic hydrocarbon group having 6 to 14 carbon atoms, which includes phenyl, 1-naphthyl, 2-naphthyl, 1-anthracenyl, 2-anthracenyl, and 3-anthracenyl. The "C6-10aryl" is a mono-, or bi-cyclic aromatic hydrocarbon group having 6 to 10 carbon atoms, which includes phenyl, 1-naphthyl, and 2-naphthyl.

[0057] In the present specification, the "4- to 15-membered heterocyclyl" is a saturated, partially-unsaturated, or unsaturated, monocyclic or polycyclic heterocyclic ring group containing, as ring-constituting heteroatoms, 1 to 5 heteroatoms independently-selected from the group consisting of nitrogen, oxygen, and sulfur (preferably nitrogen and oxygen), which includes, for example,(a) a saturated, partially-unsaturated, or unsaturated 4- to 8-membered, preferably 4- to 7-membered, more preferably a saturated 5- or 6-membered mono-cyclic heterocyclic ring group containing 1 to 4 nitrogen atoms alone as ring-constituting heteroatoms; specifically including a group containing a ring selected from the group consisting of pyrrole, imidazole, pyrazole, pyridine, tetrahydropyridine, pyrimidine, pyrazine, pyridazine, triazole, tetrazole, dihydrotriazine, azetidine, pyrrolidine, imidazolidine, piperidine, pyrazolidine, piperazine, azepane and 1,4-diazepane, and oxides and dioxides thereof,(b) a saturated, partially-unsaturated, or unsaturated 6- to 15-membered, bi-cyclic, tri-cyclic, bridged-cyclic, or spiro-cyclic heterocyclic ring group containing 1 to 5 nitrogen atoms alone as ring-constituting atoms, preferably a saturated, partially-unsaturated, or unsaturated 6- to 12-membered bi-cyclic, tri-cyclic, bridged-cyclic, or spiro-cyclic heterocyclic ring containing 1 to 3 nitrogen atoms alone as ring-constituting heteroatoms; specifically including a group containing a ring selected from the group consisting of indole, indoline (dihydroindole), isoindole, isoindoline (dihydroisoindole), benzoimidazole, dihydrobenzoimidazole, indazole, indazoline (dihydroindazole), quinoline, dihydroquinoline, tetrahydroquinoline, decahydroquinoline, isoquinoline, dihydroisoquinoline, tetrahydroisoquinoline, benzotriazole, tetrazolopyridine, tetrazolopyridazine, dihydrotriazolopyridazine, imidazopyridine, naphthyridine, tetrahydronaphthyridine, hexahydronaphthyridine, cinnoline, quinoxaline, dihydroquinoxaline, tetrahydroquinoxaline, quinazoline, dihydroquinazoline, tetrahydroquinazoline, pentahydropyrazolo[3,4-c]pyridine, octahydro-2H-pyrazino[1,2-a]pyrazine, octahydropyrrolo[2,3-c]pyrrole, octahydropyrrolo[3,2-b]pyrrole, octahydropyrrolo[3,4-b]pyrrole, octahydropyrrolo[3,4-c]pyrrole, tetrahydropyridoindole, benzoazepine, tetrahydrobenzoazepine, carbazole, phenanthridine, dihydrophenanthridine, diazabicyclo[2.2.1]heptane, diazabicyclo[3.1.1]heptane, diazabicyclo[3.2.0]heptane, diazabicyclo[3.4]octane, diazaspiro[3.3]heptane, diazaspiro[2.5]octane, octahydro-1H-pyrido[3,4-b][1,4]oxazine, azabicyclo[3.1.0]hexane, hexahydropyrrolo[1,2-a]pyrazine, 2,5-diazabicyclo[2.2.1]heptane, and oxides and dioxides thereof,(c) a saturated, partially-unsaturated, or unsaturated 4- to 8-membered (preferably 5- or 6-membered) monocyclic heterocyclic ring containing 1 or 2 oxygen atoms alone as ring-constituting heteroatoms; specifically including a group containing a ring selected from the group consisting of oxetane, furan, tetrahydropyran, tetrahydrofuran and dioxane, oxepane, and oxides and dioxides thereof,(d) a saturated, partially-unsaturated, or unsaturated 6- to 15-membered bi-cyclic, tri-cyclic, bridged-cyclic, or spiro-cyclic heterocyclic ring group containing 1 to 3 oxygen atoms alone as ring-constituting heteroatoms; specifically including a group containing a ring selected from the group consisting of benzofuran, dihydrobenzofuran, chroman, benzodioxole, benzodioxane, 2-oxabicyclo[2.2.1]hexane, 3-oxabicyclo[3.1.0]hexane, 2-oxaspiro[3.3]heptane, 5-oxaspiro[2.4]heptane, 8-oxaspiro[4.5]decane, 2-oxabicyclo[2.2.1]heptane, 3-oxabicyclo[4.1.0]heptane, 2-oxabicyclo[3.1.1]heptane, 5-oxaspiro[2.3]hexaneand oxides and dioxides thereof,(e) a saturated, partially-unsaturated, or unsaturated 4- to 8-membered (preferably 5- or 6-membered) monocyclic heterocyclic ring containing, as ring-constituting heteroatoms, 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms; specifically including a group containing a ring selected from the group consisting of oxazole, isoxazole, oxadiazole and morpholine, and oxides and dioxides thereof,(f) a saturated, partially-unsaturated, bridged-cyclic, or unsaturated 6- to 15-membered bi-cyclic, tri-cyclic, bridged-cyclic, or spiro-cyclic heterocyclic ring containing, as ring-constituting heteroatoms, 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms; specifically including a group containing a ring selected from the group consisting of benzoxazole, dihydrobenzoxazole, benzoxadiazole, benzoisoxazole, benzoxazine, dihydrobenzoxazine, furopyridine, furopyrrole, benzoxazepine, tetrahydrobenzoxazepine, oxaazabicycloheptane,oxadiazabicyclononane, octahydropyrrolo[3,4-b][1.4]oxazine, octahydropyrazino[2,1-c][1.4]oxazine, pyridooxazine, 2-oxa-5-azabicyclo[4.1.0]heptane, 2-oxa-5-azabicyclo[2.2.1]heptane, 3-oxa-6-azabicyclo[3.1.1]heptane, 6-oxa-3-azabicyclo[3.1.1]heptane, 3-oxa-7,9-diazabicyclo[3.3.1]nonane, 9-oxa-3,7-diazabicyclo[3.3.1]nonane, hexahydrofuro[3,4-c]pyrrole, 1-oxa-6-azaspiro[3.3]heptane, 2-oxa-6-azaspiro[3.3]heptane, 2-oxa-6-azaspiro[3.4]octane, 2-oxa-5,8-diazaspiro[3.5]nonane, 5-oxa-2,8-diazaspiro[3.5]nonane, and oxides and dioxides thereof,(g) a saturated, partially-unsaturated, or unsaturated 4- to 8-membered mono-cyclic heterocyclic ring or a saturated, partially-unsaturated, bridged-cyclic, or unsaturated 6- to 15-membered bi-cyclic, tri-cyclic, bridged-cyclic, or spiro-cyclic heterocyclic ring containing, 1 or 2 sulfur atoms as ring-constituting heteroatoms; specifically including a group containing a ring selected from the group consisting of tetrahydrothiophene, tetrahydrothiopyran, thiepane, thiophen, thiopyran, benzothiophene, and oxides and dioxides thereof, and(h) a saturated, partially-unsaturated, or unsaturated 4- to 8-membered mono-cyclic heterocyclic ring or a saturated, partially-unsaturated, bridged-cyclic, or unsaturated 6- to 15-membered bi-cyclic, tri-cyclic, bridged-cyclic, or spiro-cyclic heterocyclic ring containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms as ring-constituting heteroatoms; specifically including a group containing a ring selected from the group consisting of thiazolidine, thiomorpholine, thiazole, thiadiazole, thiazine, and thiazepane, benzoisothiazole, benzothiazole, and oxides and dioxides thereof.

[0058] In the present specification, the "C5-15bicyclic saturated or partially-unsaturated carbocyclyl" is saturated or partially-unsaturated bi-cyclic hydrocarbon ring group having 5 to 15 carbon atoms (C5-15), which also includes bridged-cyclic and spiro-cyclic ring group. The "partially-unsaturated" ring group refers to a ring in which bonds between ring atoms are partially dehydrogenated. The ring atoms of the hydrocarbon ring may be substituted with oxo to form oxide or dioxide. Specific examples of the "C5-15bicyclic saturated or partially-unsaturated carbocyclyl" includes indene, dihydroindene, dihydronaphthalene, tetrahydronaphthalene, bicyclo[1.1.1]pentane, bicycle[2.2.1]heptane, bicyclo[3.2.0]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.1]octane, bicyclo[3.3.0]octane, bicyclo[3.2.2]nanone, bicyclo[3.3.1]nonane, spiro[2.4]heptane, spiro[3.3]heptane, spiro[2.5]octane, spiro[3.4]octane, spiro[2.6]nonane, spiro[3.5]nonanand oxides, and dioxides thereof.

[0059] In the present specification, the "C1-6hydroxyalkyl" is the above-defined "C1-6alkyl" which is substituted with one or more hydroxyl group, preferably 1 or 2 hydroxyl group, and specific examples thereof include hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, dihydroxymethyl, 2,2-dihydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, and the like.

[0060] In the present specification, the "5- or 6-membered unsaturated heterocyclyl" is mono-cyclic aromatic heterocyclyl containing 1 to 4 heteroatoms independently-selected from the group consisting of nitrogen, oxygen, and sulfur (preferably nitrogen and oxygen), which includes, for example, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiophenyl, and furanyl.

[0061] L1in the compound [I] of the present invention includes, for example, bond, -O-, -NH-, -N(C1-6alkyl)-, -N(C1-6alkyl-O-C1-6alkyl)-, -C(=O)-, and -C(=O)-NH-. Preferably, L1includes, for example, bond, -O-, -NH-, -N(CH3)-, -C(=O)-, and -C(=O)-NH-, more preferably, bond, -O-, -NH-, and -N(CH3)-.

[0062] X1, X2, are X3are independently N or C-R3, wherein R3includes, for example, hydrogen, halogen, cyano, and C1-6alkyl optionally substituted with one or more halogen atoms. Preferably, R3includes, for example, hydrogen, halogen and C1-6alkyl, more preferably hydrogen, fluoro and methyl. Preferably, X1, X2, are X3are CH; X2and X3are CH, and X1is C(CH3) or CF; or any one of X1are X3are N, and the other and X2are CH.

[0063] R1in the compound [I] of the present invention includes, for example, hydrogen; C1-6alkyl; C3-8cycloalkyl; phenyl; 4- to 7-membered mono-cyclic saturated or partially-unsaturated heterocyclyl; or 6- to 15-membered bi-cyclic, bridged-cyclic, or spiro-cyclic saturated or partially-unsaturated heterocyclyl, wherein said alkyl, cycloalkyl, phenyl, and heterocyclyl are optionally substituted with one or more R11.As an embodiment, R1in the compound [I] of the present invention includes, for example, 4- to 7-membered mono-cyclic saturated or partially-unsaturated heterocyclyl; or 6- to 15-membered bi-cyclic, bridged-cyclic, or spiro-cyclic saturated or partially-unsaturated heterocyclyl, wherein R1is optionally substituted with one or more R11.As an embodiment, R1in the compound [I] of the present invention includes, for example, R1is a group containing a ring selected from the group consisting of piperazine; piperidine; morpholine; and bi-cyclic or bridged-cyclic heterocyclyl containing piperazine, piperidine, or morpholine ring, wherein R1is optionally substituted with one or more R11.As an embodiment, R1in the compound [I] of the present invention includes, for example, 7- to 11-membered spiro-cyclic heterocyclyl, wherein R1is optionally substituted with one or more R11.As an embodiment, R1in the compound [I] of the present invention is, for example, methyl, and R1is substituted with C3-8cycloalkyl or 4- to 15-membered heterocyclyl, wherein the C3-8cycloalkyl or 4- to 15-membered heterocyclyl is optionally substituted with one or more R12.As an embodiment, R1in the compound [I] of the present invention includes, for example, a group containing a ring selected from the group consisting of cyclobutane, cyclopentane, piperazine, piperidine, morpholine, thiomorpholine, pyridine, pyrazole, tetrahydropyridine, pyrrolidine, azetidine, oxetane, oxolane, oxane, 1,4-diazepane, 1,4-oxazepane, 2-oxa-5-azabicyclo[2.2.1]heptane, 2,5-diazabicyclo[2.2.1]heptane, 2,6-diazaspiro[3.3]heptane, 6-oxa-3-azabicyclo[3.1.1]heptane, 3-oxa-6-azabicyclo[3.1.1]heptane, 2-oxa-5-azabicyclo[4.1.0]heptane, 3,6-diazabicyclo[3.2.0]heptane, 3-azabicyclo[4.1.0]heptane, hexahydro-1H-pyrazino[2,1-c][1,4]oxazine, hexahydropyrrolo[3,4-b][1,4]oxazine, octahydropyrazino[2,1-c][1,4]oxazine, octahydropyrrolo[3,4-b][1,4]oxazine, octahydro-1H-pyrido[3,4-b][1,4]oxazine, hexahydropyrrolo[1,2-a]pyrazine, 6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazine, tetrahydro-1H-[1,3]oxazolo[3,4-a]pyrazine, 6,8-dihydro-5H-imidazo[1,2-a]pyrazine, 6,8-dihydro-5H-imidazo[1,5-a]pyrazine, octahydro-1H-[1,4]diazino[1,2-a]pyrazine, 5H,6H,7H,8H-imidazo[1,2-a]pyrazine, hexahydrofuro[3,4-c]pyrrole, hexahydrofuro[2,3-c]pyrrole, hexahydropyrrolo[2,3-c]pyrrole, hexahydropyrrolo[3,4-c]pyrrole, octahydropyrrolo[3,4-c]pyrrole, octahydropyrrolo[3,2-b]pyrrole, octahydropyrrolo[3,4-b]pyrrole, octahydropyrrolo[2,3-c]pyrrole, hexahydro-2H-furo[2,3-c]pyridine, 5,7-dihydropyrrolo[3,4-b]pyridine, 1H,4H,5H,6H,7H-pyrazolo[3,4-c]pyridine, 8-oxa-3-azabicyclo[3.2.1]octane, 6-oxa-2-azabicyclo[3.2.1]octane, 3-oxa-8-azabicyclo[3.2.1]octane, 4,7-diazaspiro[2.5]octane, 2-oxa-6-azaspiro[3.4]octane, 9-oxa-3,7-diazabicyclo[3.3.1]nonane, 3-oxa-7,9-diazabicyclo[3.3.1]nonane, azabicyclo[3.1.0]hexane, 3-oxabicyclo[3.1.0]hexane, 2-oxaspiro[3.3]heptane, 1-oxa-6-azaspiro[3.3]heptane, 2-oxa-6-azaspiro[3.3]heptane, 2-oxa-8-azaspiro[4.5]decane, 1-oxa-8-azaspiro[4.5]decane, 8-oxa-2-azaspiro[4.5]decane, 6-oxa-2,9-diazaspiro[4.5]decane, 1-oxa-9-azaspiro[5.5]undecane, 2-oxa-7-azaspiro[4.4]nonane, 5-oxa-2,8-diazaspiro[3.5]nonane, 2-oxa-5,8-diazaspiro[3.5]nonane, 2,5-dioxa-8-azaspiro[3.5]nonane, 2,6-diazaspiro[3.4]octane, 4-oxa-7-azaspiro[2.5]octane, and 3,6-diazabicyclo[3.1.1]heptane wherein R1is optionally substituted with one or more R11.

[0064] R11in the compound [I] of the present invention includes, for example, halogen, cyano, C1-6alkyl, -O-C1-6alkyl, -OH, -NH2, N(C1-6alkyl)(C1-6alkyl), oxo, -C(=O)-C1-6alkyl, C3-8cycloalkyl, oxetanyl, oxolanyl, morpholinyl, pyridyl, or 2-oxa-5-azabicyclo[2.2.1]heptane, wherein said alkyl, cycloalkyl, oxetanyl, oxolanyl, morpholinyl, pyridyl, and 2-oxa-5-azabicyclo[2.2.1]heptane are optionally substituted with one or more R12; and each R12is independently halogen, -OH, -O-C1-6alkyl, C1-6alkyl, -NH2, NH(C1-6alkyl), N(C1-6alkyl)(C1-6alkyl), or oxetanyl.As an embodiment, R11in the compound [I] of the present invention is, for example, fluorine, -CH3, -CH2CH3, -CH2-OH, -CH2CH2-OH, -CH2CH2-O-CH3, -OH, -O-CH3, oxo, CHF2, CF3, cyclopropyl, -C(=O)-CH3, -N(CH3)2, -C(=O)-CH2-N(CH3)2, oxetanyl, oxolanyl, 2-oxa-5-azabicyclo[2.2.1]heptane, pyridyl, and morpholinyl.As an embodiment, R11in the compound [I] of the present invention includes, for example, a group containing a ring selected from the group consisting of cyclopropane, oxetane, oxolane, oxane, morpholine, and 2-oxa-5-azabicyclo[2.2.1]heptane.

[0065] R2in the compound [I] of the present invention includes, for example, 2-methylpropyl, 2,2-dimethylpropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.2]octanyl, oxetanyl, oxolanyl, oxanyl, oxepanyl, azetidinyl, pyrrolidinyl, piperidinyl, thietanyl, 2-oxabicyclo[2.1.1]hexanyl, 3-oxabicyclo[3.1.0]hexanyl, 2-oxabicyclo[2.2.1]heptanyl, 3-oxabicyclo[4.1.0]heptanyl, 2-oxabicyclo[3.1.1]heptanyl, 2-oxaspiro[3.3]heptanyl, 5-oxaspiro[2.4]heptanyl, 8-oxaspiro[4.5]decanyl, 5-oxaspiro[2.3]hexanyl, and pyridyl. Preferably, R2includes cyclopropyl, cyclopentyl, cyclohexyl, oxolanyl, oxanyl, 3-oxabicyclo[3.1.0]hexanyl, and 2-oxaspiro[3.3]heptanyl.

[0066] R21in the compound [I] of the present invention includes, for example, fluoride, -CH3, -CH2CH3, -CH2-OH, -CH2-O-CH3, -OH, -O-CH3, -CH2F, CHF2, -CF3, cyano, and cyclopropyl.

[0067] R3in the compound [I] of the present invention includes, for example, hydrogen, fluorine, chlorine, bromine, -CH3, -CF3and cyano. Preferably, R3is hydrogen, fluorine or -CH3.

[0068] R4in the compound [I] of the present invention includes, for example, hydrogen and CH3; and n in the compound [I] of the present invention includes, for example, 0 and 1. Preferably, n is 0; or n is 1 and R4is hydrogen.

[0069] Another preferred embodiment of the compound [I] of the present invention will be described below.A compound selected from the group consisting of the following compounds, or a salt thereof.

[0070] A further preferred embodiment of the compound [I] of the present invention will be described below: (1) R1in Formula [1] includes (2) R2in Formula [I] includes (3) X1, X2, and X3are C-R3; and each R3independently represents hydrogen or fluorine,(4) L1in Formula [I] includes bond and N-methylamine,(5) (CHR4)nin Formula [I] includes bond and methylene.

[0071] Another preferred embodiment of the compound [I] of the present invention will be described below:(1) the 4- to 15-membered heterocyclic ring formed in R1in Formula [1] is 4-methylpiperazine, 4-(oxetan-3-yl)piperazine, (S)-octahydropyrazino[2,1-c][1.4]oxazine, (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane, 6-methyl-2,6-diazaspiro[3.3]heptane, 6-methoxyethyl-2,6-diazaspiro[3.3]heptane, 6-(oxetan-3-yl)-2,6-diazaspiro[3.3]heptane, 2-oxa-6-azaspiro[3.3]heptane, or N-methylazetidine; (2) the carbocyclic ring or the heterocyclic ring formed in R2in Formula [I] is (1R)-2,2-difluoro-1-methylcyclopropane, (1R)-2,2-difluoro-1-fluoromethylcyclopropane, (1R,4R)-4-hydroxycyclohexane, 4,4-difluorocyclohexane, 4-methyltetrahydropyran, 4-fluoromethyltetrahydropyran, (1S,5R)-3-oxabicyclo[3.1.0]hexane, or (1S,5R)-6,6-difluoro-3-oxabicyclo[3.1.0]hexane; (3) X1, X2, and X3are C-R3; and each R3independently represents hydrogen or fluorine,(4) L1in Formula [I] includes bond and N-methylamine,(5) (CHR4)nin Formula [I] includes bond and methylene,(6) X1, X2, and X3are independently CH or N.

[0072] In this specification, the options and preferred embodiments for the different features of the compound, method and composition of the present invention as presented include all possible combinations of the options and preferred embodiments for these different features as long as they are consistent combinations.

[0073] Methods for manufacturing the compound [I] of the present invention are explained below. The compound [I] of the present invention can be manufactured based on the manufacturing methods described below for example. The manufacturing methods described below are examples, and the method for manufacturing the compound [I] is not limited thereto.

[0074] In the reaction formulae below, when performing an alkylation reaction, hydrolysis reaction, amination reaction, esterification reaction, amidation reaction, etherification reaction, nucleophilic substitution reaction, addition reaction, oxidation reaction, reduction reaction, or the like, these reactions are themselves performed by known methods. Examples of such methods include the methods described in Experimental Chemistry (Fifth Edition, edited by The Chemical Society of Japan, Maruzen Co., Ltd.); Organic Functional Group Preparations Second Edition, Academic Press, Inc., 1989; Comprehensive Organic Transformations, VCH Publishers, Inc., 1989; and P.G.M. Wuts and T.W. Greene, Greene's Protective Groups in Organic Synthesis (Fourth Edition, 2006), and the like.

[0075] General SynthesisIn general, the compounds of the invention and intermediates of use in the synthesis of such compounds may be made according to synthesis techniques known to those skilled in this field, as well as by the representative methods set forth below, those in the Examples and the Reference Examples, and any modifications thereof. In the following schemes, reactive groups can, as appropriate, be protected with protecting groups and deprotected according to established techniques well known to the skilled person. The processes of the invention include any individual step of a multi-step scheme.

[0076] General synthesis 1 Wherein X1, X2, and X3is as defined in Item 1, and Y2and Y3are leaving groups.Intermediate [IV] of compound [I] of the present invention can be manufactured by the reaction indicated by the synthetic pathway described above. Specifically, compound [IIIa] having a boronic acid is subjected to Suzuki Cross Coupling Reaction with compound [IV] in the presence of a palladium compound, (a phosphine ligand) and a base in an inert solvent in the reaction. Reaction temperature, reaction time, etc. can be appropriately determined based on the known Suzuki Cross Coupling Reaction.

[0077] Wherein X1, X2, and X3is as defined in Item 1, Y2and Y3are leaving groups, and (BPin)2means bis(pinacolato)diboron.The "boronic acid" or "boronic ester" to be used in the present reaction may be separately manufactured, and isolated and purified. For example, bispinacol diborane is subjected to reaction with a halogenated compound [IIIb] as a precursor in the presence of palladium compound, and the resulting product [IIIb'] is subjected to Suzuki Cross Coupling Reaction without isolation and purification.The leaving groups (Y1, Y2, Y3) include a group similar to the above-mentioned leaving group. Y1, Y2and Y3may be the same or different as long as the above-mentioned reaction proceeds.

[0078] General synthesis 2 Wherein X1, X2, X3, R2, R4and n are as defined in Item 1, and Y2and Y3are leaving groups.Intermediate [VI] of compound [I] of the present invention can be manufactured by the reaction indicated by the synthetic pathway described above. Specifically, compound [V] having a leaving group (Y2, Y3) is subjected to Nucleophilic Substitution Reaction with compound [VI] in the presence of a base in an inert solvent in the reaction. Reaction temperature, reaction time, etc. can be appropriately determined based on the known Nucleophilic Substitution Reaction.

[0079] General synthesis 3-1 Wherein X1, X2, X3, R1, R2, R4, n and L12are as defined in Item 1, and Y3is a leaving group.Compound [Ia] of the present invention can be manufactured by the reaction indicated by the synthetic pathway described above. Specifically, compound [VII] having a leaving group (Y3) is subjected to Buchwald-Hartwig Amination Cross Coupling Reaction with compound [VIII] in the presence of a palladium compound and a base in an inert solvent in the reaction. Reaction temperature, reaction time, etc. can be appropriately determined based on the known Buchwald-Hartwig Cross Coupling Reaction.

[0080] Wherein X1, X2, X3, R1, R2, R4and n and are as defined in Item 1, and Y3is a leaving group.Compound [Ib] of the present invention can be manufactured by the reaction indicated by the synthetic pathway described above. Specifically, compound [VII] having a leaving group (Y3) is subjected to Buchwald-Hartwig Amination Cross Coupling Reaction with primary or secondary amine compound [IX] in the presence of a palladium compound and a base in an inert solvent in the reaction. Reaction temperature, reaction time, etc. can be appropriately determined based on the known Buchwald-Hartwig Cross Coupling Reaction.

[0081] General synthesis 3-2 Wherein X1, X2, X3, R1, R2, R4and n are as defined in Item 1, and Y3is a leaving group.Compound [Ic] of the present invention can be manufactured by the reaction indicated by the synthetic pathway described above. Specifically, compound [VII] having a leaving group (Y3) is subjected to Buchwald-Hartwig C-O Cross Coupling Reaction with compound [X] in the presence of a palladium compound and a base in an inert solvent in the reaction. Reaction temperature, reaction time, etc. can be appropriately determined based on the known Buchwald-Hartwig Cross Coupling Reaction.

[0082] General synthesis 3-3 Wherein X1, X2, X3, R1, R2, R4and n are as defined in Item 1, and Y4is a leaving group.Compound [Ib’] of the present invention can be manufactured by the reaction indicated by the synthetic pathway described above. Specifically, compound [XI] having a boronic ester is subjected to Suzuki Cross Coupling Reaction with compound [XI’] having leaving group (Y4) bounded to carbon in the presence of a palladium compound and a base in an inert solvent in the reaction. Reaction temperature, reaction time, etc. can be appropriately determined based on the known Suzuki Cross Coupling Reaction.The "boronic acid" or "boronic ester" to be used in the present reaction may be separately manufactured, and isolated and purified. For example, bispinacol diborane is subjected to reaction with a halogenated compound as a precursor in the presence of palladium compound and a base, and the resulting product is subjected to Suzuki Cross Coupling Reaction without isolation and purification.

[0083] General synthesis 3-4 Wherein X1, X2, X3, R1, R2, R4and n are as defined in Item 1, and Y3is a leaving group.Compound [Ib’’] of the present invention can be manufactured by the reaction indicated by the synthetic pathway described above. Specifically, compound [VI] having a leaving group (Y3) is subjected to Suzuki Cross Coupling Reaction with compound [XII] in the presence of a palladium compound in an inert solvent in the reaction. Reaction temperature, reaction time, etc. can be appropriately determined based on the known Suzuki Cross Coupling Reaction.The "boronic acid" or "boronic ester" to be used in the present reaction may be separately manufactured, and isolated and purified. For example, bispinacol diborane is subjected to reaction with a halogenated compound as a precursor in the presence of palladium compound, and the resulting product is subjected to Suzuki Cross Coupling Reaction without isolation and purification.

[0084] General synthesis 3-5 Wherein X1, X2, X3, R1, R2, R4and n are as defined in Item 1.Compound [Id] of the present invention can be manufactured by the reaction indicated by the synthetic pathway described above. Specifically, carbonyl compound [XIII] is subjected to the reaction in the presence of the SnAP M Reagent in an inert solvent in the reaction. Reaction temperature, reaction time, etc. can be appropriately determined based on the known SnAP Reaction.

[0085] General synthesis 4-1 Wherein X1, X2, X3, R2, R4and n are as defined in Item 1, and each R is independently an alkyl.Compound [Ie] of the present invention can be manufactured by the reaction indicated by the synthetic pathway described above. Specifically, compound [XIV] having an amine is subjected to the reaction with a ketone compound in the presence of a reducution agent not particularly limited but including NaH(OAc)3in an inert solvent in the reaction. Reaction temperature, reaction time, etc. can be appropriately determined based on the known Borch Reductive Amination Reaction.

[0086] General synthesis 4-2 Wherein X1, X2, X3, R2, R4and n are as defined in Item 1, R is an alkyl, and Y5is a halogen atom.Compound [If] of the present invention can be manufactured by the reaction indicated by the synthetic pathway described above. Specifically, compound having amine [XV] is subjected to the alkylation with an alkyl halide in the presence of an amine and a ligand in an inert solvent in the reaction. Reaction temperature, reaction time, etc. can be appropriately determined based on the known Alkylation.

[0087] General synthesis 4-3 Wherein X1, X2, X3, R2, R4and n are as defined in Item 1, and R is an alkyl.Compound [Ig] of the present invention can be manufactured by the reaction indicated by the synthetic pathway described above. Specifically, compound having amine [XV] is subjected to the reaction with an acid halide in the presence of an amine and a ligand in an inert solvent in the reaction. Reaction temperature, reaction time, etc. can be appropriately determined based on the known Alkylation.

[0088] In the present specification, the term "palladium compound" is not particularly limited, and examples thereof include tetravalent palladium catalysts such as sodium hexachloropalladium (IV) acid tetrahydrate and potassium hexachloropalladium (IV) acid; divalent palladium catalysts such as [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (Pd(dppf)Cl2.DCM), (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (XPhos Pd G3), RockPhos Pd G3, DavePhos Pd G3, t-BuXPhos Pd G3, XantPhos Pd G4, palladium(II) chloride, palladium(II) bromide, palladium(II) acetate, palladium(II) acetylacetonate, dichlorobis(benzonitrile)palladium(II), dichlorobis(acetonitrile)palladium(II), dichlorobis(triphenylphosphine)palladium(II), dichlorotetraammine palladium(II), dichloro(cycloocta-1,5-diene)palladium(II), and palladium(II) trifluoroacetate; and zerovalent palladium catalysts such as tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3), tris(dibenzylideneacetone)dipalladium(0)-chloroform complex, and tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4). These palladium compounds are used alone or as a mixture of two or more of them. In addition, the term "palladium compound" may include combinations of the above-mentioned palladium compounds and one or more "phosphine ligand". The "phosphine ligand" is not particularly limited, and examples thereof include triphenylphosphiphospne, tri-t-butylphosphine, dppf, Xantphos, 2-dicyclohexylphosphino-2' 4' 6'-triisopropylbiphenyl (XPhos), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (SPhos), 2-(di-tert-butylphosphino)biphenyl (JohnPhos), 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)-biphenyl (DavePhos), 2-di(tert-butyl)phosphino-2’,4’,6’-triisopropyl-3-methoxy-6-methylbiphenyl (RockPhos) and Me4tButylXphos.

[0089] In the present specification, the term "base" is not particularly limited to examples used herein, but includes an inorganic base, an organic base, and the like. Examples of the "inorganic base" include an alkali metal hydroxide (e.g., sodium hydroxide and potassium hydroxide), an alkaline earth metal hydroxide (e.g., magnesium hydroxide and calcium hydroxide), an alkali metal carbonate (e.g., sodium carbonate and potassium carbonate), an alkaline earth metal carbonate (e.g., magnesium carbonate and calcium carbonate), an alkali metal hydrogen carbonate (e.g., sodium hydrogen carbonate and potassium hydrogen carbonate), an alkali metal phosphate (e.g., sodium phosphate and potassium phosphate), an alkaline earth metal phosphate (e.g., magnesium phosphate and calcium phosphate). Examples of the "organic bases" include trialkylamines (e.g., trimethylamine, triethylamine, and diisopropylethylamine), dialkylamines (e.g., diethylamine, diisopropylamine), picoline, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane, and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). These bases are used alone or as a mixture of two or more of them.

[0090] In the present specification, the term "inert solvent" is not particularly limited, and examples thereof include any solvent that is inactive in the reaction, and examples thereof include water, ethers (such as dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, diethylene glycol dimethyl ether, and ethylene glycol dimethyl ether), hydrocarbons (such as hexane), halohydrocarbons (such as methylene chloride, chloroform, 1,2-dichloroethane, and carbon tetrachloride), aromatic hydrocarbons (such as benzene, toluene, and xylene), lower alcohols (such as methanol, ethanol, and isopropanol), polar solvents (such as N,N-dimethylformamide (DMF), N-methylpyrrolidine (NMP), dimethyl sulfoxide (DMSO), hexamethylphosphoric acid triamide, and acetonitrile), ketones (such as acetone and methylethylketone), esters (such as methyl acetate and ethyl acetate). One of these solvents alone or a mixture of two or more kinds may be used.

[0091] As used herein, the term "leaving group" is not particularly limited to examples used herein, and examples thereof include halogen (e.g., fluorine, chlorine, bromine, and iodine), C1-18alkylsulfonyl, C1-18alkylsulfonyloxy (e.g., methylsulfonyloxy, ethylsulfonyloxy, and trifluoromethylsulfonyloxy), phenyloxy (e.g., 4-nitrophenyloxy), arylsulfonyloxy (e.g., benzenesulfonyloxy, p-toluenesulfonyloxy, 2,4,6-trimethylbenzenesulfonyloxy, 2-nitrobenzenesulfonyloxy, and 4-nitrobenzenesulfonyloxy), aralkylsulfonyloxy, perhaloalkanesulfonyloxy, sulfonio, toluenesulfoxy, nitrophenylcarbonate, imidazolecarbonate, and the like.

[0092] Examples of a condensation agent used herein include, but not limited to:T3P; PyBOP; DMT-MM; COMU; HBTU; HATU; DCC; N-cyclohexyl-N’-morpholinoethylcarbodiimide; N-cyclohexyl-N’-(4-diethylaminocyclohexyl)carbodiimide; N,N’-diethylcarbodiimide; N,N’-diisopropylcarbodiimide; N,N-diisopropylethylamine; WSC or a hydrochloride salt thereof; N,N’-carbonylbis(2-methylimidazole); pentamethyleneketene-N-cyclohexylimine; diphenylketene-N-cyclohexylimine; ethoxyacetylene, 1-alkoxy-1-chloroethylene; trialkyl phosphite; ethyl polyphosphate; isopropyl polyphosphate; phosphoryl chloride; phosphorus trichloride; diphenylphosphoryl azide; thionyl chloride; oxalyl chloride; alkyl haloformate such as ethyl chloroformate and isopropyl chloroformate; triphenylphosphine; 2-ethyl-7-hydroxybenzisoxazolium salt; 2-ethyl-5-(m-sulfophenyl)isoxazolium hydroxide inner salt; benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate; 1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole; and so-called Vilsmeier agents prepared by reactions of DMF with thionyl chloride, phosgene, trichloromethyl chloroformate, or phosphorus oxychloride.

[0093] In addition to a condensation agent, a condensation accelerator may be added. Examples of a condensation accelerator used herein include, but not limited to, 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu), 1-hydroxy-7-azabenzotriazole (HOAt), and hydroxy-3,4-dihydro-4-oxo-1,2,3-benzotriazine (HOOBt).

[0094] Examples of a reducing agent used to be used in reduction reations herein include, but not limited to, sodium borohydride, lithium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, sodium triethylborohydride, lithium triethylborohydride, lithium aluminum hydride, sodium dihydridobis(2-methoxyethoxy)aluminate, borane-tetrahydrofuran complex, diisobutylaluminium hydride, and hydrosilane such as triethylsilane and phenylsilane.

[0095] In the present specification, the term "reduction agent" for the reductive amination reaction is not particularly limited to examples used herein, but includes sodium cyanoboronhydride (NaBH3CN), sodium triacetoxyborohydride (NaBH(OAc)3), picolineborane, pyridineborane and the like.

[0096] Examples of a "catalyst for hydrogenation" to be used in hydrogenation reactions is not particularly limited to examples used herein, but examples thereof include palladium on carbon (Pd / C), platinum on carbon (Pt / C), platinum oxide (PtO2), Pd(OH)2and the like.

[0097] Examples of a "protecting group of hydroxy" used herein include, but not limited to, any protecting groups of hydroxy used in the field of synthetic organic chemistry, and include, for example, alkyl groups (e.g., methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, hydroxymethyl, 2-hydroxyethyl, acetylmethyl); alkenyl groups (e.g., ethenyl, 1-propenyl, 2-propenyl, 1-methyl-2-propenyl); alkynyl groups (e.g., ethynyl, 1-propynyl, 2-propynyl, 1-methyl-2-propynyl); formyl; alkyl (alkenyl) carbonyl groups (e.g., acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, acryloyl, propioloyl, methacryloyl, crotonoyl, isocrotonoyl, (E)-2-methyl-2-butenoyl); arylcarbonyl groups (e.g., benzoyl, α-naphthoyl, β-naphthoyl, 2-bromobenzoyl, 4-chlorobenzoyl, 2,4,6-trimethylbenzoyl, 4-toluoyl, 4-anisoyl, 4-nitrobenzoyl, 2-nitrobenzoyl, 2-(methoxycarbonyl)benzoyl, 4-phenylbenzoyl); alkoxycarbonyl groups (e.g., methoxycarbonyl, tert-butoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-trimethylsilylethoxycarbonyl, 9-fluorenylmethyloxycarbonyl); tetrahydro (thio) pyranyl (furanyl) groups (e.g., tetrahydropyran-2-yl, 3-bromotetrahydropyran-2-yl, 4-methoxytetrahydropyran-4-yl, tetrahydrothiopyran-2-yl, 4-methoxytetrahydrothiopyran-4-yl, tetrahydrofuran-2-yl, tetrahydrothiofuran-2-yl); silyl groups (e.g., trimethylsilyl, triethylsilyl, isopropyl dimethylsilyl, tert-butyldimethyl silyl, methyldiisopropyl silyl, methyl di-tert-butylsilyl, triisopropylsilyl, diphenylmethyl silyl, diphenylbutyl silyl, diphenylisopropyl silyl, phenyldiisopropyl silyl); alkoxymethyl groups (e.g., methoxymethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, tert-butoxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl); alkoxyethyl groups (e.g., 1-ethoxyethyl, 1-(isopropoxy)ethyl); halogenated ethyl groups (e.g., 2,2,2-trichloroethyl); aralkyl groups (e.g., benzyl, α-naphthylmethyl, β-naphthylmethyl, diphenylmethyl, triphenylmethyl, α-naphthyldiphenylmethyl, 9-anthrylmethyl, 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-cyanobenzyl); alkenyloxycarbonyl groups (e.g., vinyloxycarbonyl, allyloxycarbonyl); and aralkyloxycarbonyl groups (e.g., benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl).

[0098] Examples of a "protecting group of carboxy" used herein include, but not limited to, any protecting groups of carboxy used in the field of synthetic organic chemistry, and include, for example, the "alkyl groups", "alkenyl groups", "alkynyl groups", "aralkyl groups", and "silyl groups" as above listed in the examples of the "protecting group of hydroxy" and similar groups thereof.

[0099] Examples of a "protecting group of amino" used herein include, but not limited to, any protecting groups of amino used in the field of synthetic organic chemistry, and include, for example, the "alkyl (alkenyl) carbonyl groups", "arylcarbonyl groups", "alkoxycarbonyl groups", "silyl groups", "aralkyl groups", "alkenyloxycarbonyl groups", and "aralkyloxycarbonyl groups" as above listed in the "protecting group of hydroxy" and similar groups thereof.

[0100] The various substituents in the compound represented by General Formula [I] of the present invention (hereafter called "compound [I] of the present invention") are explained below.

[0101] In each of the reactions in the above reaction formulas, the reaction product can be used in the next reaction either as is in the form of the reaction solution or as a crude product, but it can also be isolated from the reaction mixture by ordinary methods and easily purified by ordinary separation techniques. Examples of ordinary separation techniques include recrystallization, distillation and chromatography.

[0102] The starting material compounds, intermediate compounds and object compounds in each of the above steps and the compound [I] of the present invention itself all include geometric isomers, stereoisomers, optical isomers and tautomers. The respective isomers can be separated by ordinary optical resolution methods. They can also be manufactured from starting material compounds having suitable optical activity.

[0103] The compound [I] of the present invention can be manufactured by the synthesis methods shown in the reaction formulae above, or by analogous methods.

[0104] Unless specific production methods are specified, the starting material compounds used in the manufacture of the compound [I] of the present invention may be commercial compounds, or may be produced by known methods or analogous methods.

[0105] The starting material compounds and object compounds in each step above may be used in the form of appropriate salts. Examples of such salts include salts similar to those given as examples of salts of compound [I] of the present invention below.

[0106] When the compounds obtained in each step or commercial products are salt-free compounds, they can be converted to the object salts by known methods. When the compounds obtained in each step or commercial products are salts, they can be converted to their free form or into other object salts by known methods.

[0107] The salt of the compound represented by formula [I] in the present invention means a pharmaceutically acceptable salt thereof. The pharmaceutically acceptable salt thereof may be an acid addition salt or a salt with a base depending on the kinds of substituents. Examples of the "acid" here include inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and phosphoric acid; and organic acids such as methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, citric acid, tartaric acid, maleic acid, fumaric acid, malic acid, lactic acid, and the like. Examples of the "base" include inorganic bases such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate; organic bases such as methylamine, diethylamine, trimethylamine, triethylamine, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, tris(hydroxymethyl)methylamine, dicyclohexylamine, N,N'-dibenzylethylenediamine, guanidine, pyridine, picoline, and choline; and ammonium salts and the like. The compound may also form a salt with an amino acid such as lysine, arginine, aspartic acid, glutamic acid, and the like.

[0108] The present invention also encompasses various hydrates, solvates and crystal polymorphisms of the compound [I] and salts thereof.

[0109] The compound [I] of the present invention also includes compounds in which one or more isotope atoms have been substituted for one or more atoms. Examples of isotope atoms include deuterium (2H or D), tritium (3H),11C,13C,14C,13N,15N,15O,17O,18O,32P,35S,36Cl,37Cl,18F,123I,125I, and the like.

[0110] The compound [I] of the present invention includes pharmaceutically acceptable prodrugs. The pharmaceutically acceptable prodrug form is converted in the body to a compound disclosed herein after the administration of the prodrug. In other embodiments, the prodrug is converted by an enzymatic activity of the host animal. Examples of substituents that can be modified to make prodrugs include reactive functional groups such as -OH, -COOH, amino, and the like. The modifying groups of these functional groups can be selected appropriately from the "substituents" in this specification.

[0111] The compound [I] or a salt thereof of the present invention may be in the form of a pharmaceutically acceptable co-crystal or co-crystal salts. A co-crystal or co-crystal salt here means a crystalline substance composed at room temperature of two or more independent solids each having different physical properties (such as structure, melting point, heat of fusion and the like). Co-crystals and co-crystal salts can be manufactured appropriately by well-known co-crystallization methods.

[0112] The compound [I] and a salt thereof of the present invention have an effect of inhibition of CSF1R which leads to reduction of macrophage, microglia and osteoclast. The compound [I] and a salt thereof of the present invention may preferably show highly selective CSF1R inhibitory activity compared to at least any one of other kinases adjacent to CSF1R such as FLT3, cKit, PDGFR including PDGFRα and PDGFRβ, and Trk including TrkC, so as to reduce any risks of undesired actions or side effects, including those caused by unexpected inhibition of tyrosine kinases in addition to CSF1R, upon administration of Compound [I], or a salt thereof. In certain embodiments, Compound [I], or a salt thereof, may prevent or reduce activation or proliferation of microglia (i.e., microgliosis) by inhibiting CSF1R particularly expressed in microglia, so that central immunomodulatory function can be reinforced. Compound [I], or a salt thereof, may be beneficial to treat cancers, autoimmune diseases such as rheumatoid arthritis, muscular dystrophy, and asthma. Compound [I], or a salt thereof, may also be beneficial to treat neurological diseases such as Alzheimer’s disease (AD), tauopathies, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), HIV-associated neurocognitive disorders (HAND), prion disease, traumatic brain injury (TBI), Parkinson’s disease, pain, spinal cord injury, Crohn’s disease, radiation-induced lung fibrosis, glaucoma, infections (such as viral, bacterial, and parasitic), cardiovascular diseases such as inflammation post myocardial infarction, and bone diseases.

[0113] The compound [I] or a salt thereof of the present invention is also effective in the treatment, prevention and / or diagnosis of multiple diseases described above.Moreover, the compound [I] and a salt thereof of the present invention have excellent features for use as active ingredients in pharmaceuticals, and for example have excellent features such as low side effects, tolerability, stability (storage stability, metabolic stability, etc.) and the like. These groups of compounds of the present invention also have effects as preventative and / or therapeutic agents as CSF1R inhibitor.In one embodiment, Compound [I], or a salt thereof, may be useful as a Positron Emission Topography (PET) tracer, preferably a PET imaging agent, that may be useful for in vitro, exo vivo, in vivo, or clinical trial tests and diagnostic imaging in humans and / or non-humans. Substitution with positron emitting isotopes, such as11C,18F,15O, and13N, can be useful in PET studies for examining target occupancy. For example, compounds labeled with11C or18F may be used for a PET tracer.

[0114] Next, a medical preparation (hereunder also called a "pharmaceutical composition") comprising a compound [I] or a salt thereof of the present invention as an active ingredient is explained.

[0115] The medical preparation is obtained by formulating a compound [I] or a salt thereof of the present invention in the form of an ordinary medical preparation, and is prepared using a compound [I] or a salt thereof of the present invention and a pharmaceutically acceptable carrier. Examples of the carrier include commonly-used diluents or excipients such as fillers, bulking agents, binders, humectants, disintegrants, surfactants, lubricants and the like.

[0116] Such a medical preparation can be selected from various forms according to the therapeutic objective, and examples thereof include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, injections (liquids, suspensions, etc.), and the like.

[0117] A wide range of known carriers may be used when molding the preparation in the form of a tablet, and examples thereof include excipients such as lactose; binders such as polyvinylpyrrolidone; disintegrants such as starch; absorption aids such as sodium lauryl sulfate; humectants such as glycerin and starch; absorbents such as colloidal silicic acid; and lubricants such as magnesium stearate, polyethylene glycol and the like.

[0118] Moreover, the tablet may as necessary be made into a tablet with an ordinary coating, such as a sugar-coated tablet, gelatin-coated tablet, enteric coated tablet, film-coated tablet, double tablet or multilayer tablet.

[0119] A wide range of known carriers may be used when molding the preparation in the form of a pill, and examples thereof include excipients such as glucose; binders such as gum arabic powder; and disintegrants such as laminaran and the like.

[0120] A wide range of known diluents may be used when forming the preparation as a liquid, emulsion or suspension, and examples thereof include water and the like. Ordinary solubilizing agents and buffers may also be included, as well as colorants, preservatives, aromatics, flavorings, sweeteners and other drugs and the like as necessary.

[0121] A wide range of known carriers may be used when forming the preparation as a suppository, and examples thereof include cocoa butter and the like.

[0122] When the preparation is an injection, the liquid, emulsion or suspension is preferably sterilized, and is also preferably isotonic with blood. An amount of sodium chloride sufficient to prepare an isotonic injection may be included in the injection, and another drug, soothing agent or the like may also be included.

[0123] The amount of the compound [I] or a salt thereof that is contained in the medical preparation is not particularly limited and may be selected appropriately from a wide range, but generally the compound [I] or a salt thereof of the present invention is preferably contained in the amount of 1% to 70% of the medical preparation.

[0124] The method for administering the medical preparation of the present invention is not particularly limited, and it can be administered by a method suited to the dosage form, the age and sex of the patient, the disease status and other conditions. For example, it can be administered orally if it is in the form of a tablet, pill, liquid, suspension, emulsion, granules or capsules. If it is an injection, it can be administered intravenously either alone or in a mixture with an ordinary replacement fluid such as glucose or amino acids, or else it can be administered by itself intramuscularly, intradermally, subcutaneously or intraperitoneally as necessary. In the case of a suppository, it can be administered in the rectum.

[0125] The dose of the medical preparation may be selected according to the administration method, the age and sex of the patient, the severity of the disease and other conditions, but generally 0.01 to 100 mg or preferably 0.1 to 50 mg per 1 kg of body weight can be administered per day in one or more administrations.

[0126] This dose is affected by various conditions, and in some cases a dose below the aforementioned range may be sufficient, while in others a dose above the aforementioned range may be necessary.

[0127] The compounds of formula [I] or a salt thereof according to the present invention possess excellent CSF1R inhibitory activity, that is, inhibitory activity of CSF1R, in mammals. The compounds of formula [I] or a salt thereof according to the present invention are also highly selective for CSF1R.

[0128] The compounds of formula [I] or a salt thereof in the present invention exhibit various pharmacological efficacies through their CSF1R inhibitory activity. Accordingly, a pharmaceutical composition comprising the compound of formula [I] or a pharmaceutically acceptable salt thereof as an active ingredient can be used to inhibit CSF1R activity.

[0129] A pharmaceutical composition comprising the compound [I] or a salt thereof of the present invention together with a pharmaceutically acceptable carrier and / or excipient is provided by one embodiment of the present invention.

[0130] Another embodiment provides a therapeutic, preventative and / or diagnostic agent for a disease caused by CSF1R which leads to reduction of macrophage, microglia and osteoclast, comprising the compound [I] or a salt thereof of the present invention together with a pharmaceutically acceptable carrier and / or excipient.

[0131] Yet another embodiment provides a therapeutic, preventative and / or diagnostic agent for a neurological disease such as Alzheimer's disease (AD), tauopathies, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), HIV-associated neurocognitive disorders (HAND), prion disease, trauma brain injury (TBI), Parkinson's disease, pain, spinal cord injury, Crohn’s disease, radiation-induced lung fibrosis, glaucoma, infections, cardiovascular diseases such as inflammation post myocardial infarction, bone diseases, muscular dystrophy, or asthma, comprising the compound [I] or a salt thereof of the present invention together with a pharmaceutically acceptable carrier and / or excipient.

[0132] Yet another embodiment provides a pharmaceutical composition for treating, preventing and / or diagnosing a disease caused by CSF1R which leads to reduction of macrophage, microglia and osteoclast, comprising the compound [I] or a salt thereof of the present invention together with a pharmaceutically acceptable carrier and / or excipient.

[0133] Yet another embodiment provides a pharmaceutical composition for treating, preventing and / or diagnosing a neurological disease such as Alzheimer's disease (AD), tauopathies, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), HIV-associated neurocognitive disorders (HAND), prion disease, trauma brain injury (TBI), Parkinson's disease, pain, spinal cord injury, Crohn’s disease, radiation-induced lung fibrosis, glaucoma, infections, cardiovascular diseases such as inflammation post myocardial infarction, bone diseases, muscular dystrophy, asthma, comprising the compound [I] or a salt thereof of the present invention together with a pharmaceutically acceptable carrier and / or excipient.

[0134] Yet another embodiment provides a method for treating, preventing and / or diagnosing of a disease caused by CSF1R which leads to reduction of macrophage, microglia and osteoclast, which comprises administering a therapeutically effective amount of the compound [I] or a salt thereof of the present invention to a human in need thereof.

[0135] Yet another embodiment provides a method for treating, preventing and / or diagnosing a neurological disease such as Alzheimer's disease (AD), tauopathies, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), HIV-associated neurocognitive disorders (HAND), prion disease, trauma brain injury (TBI), Parkinson's disease, pain, spinal cord injury, Crohn’s disease, radiation-induced lung fibrosis, glaucoma, infections, cardiovascular diseases such as inflammation post myocardial infarction, bone diseases, muscular dystrophy, asthma which comprises administering a therapeutically effective amount of the compound [I] or a salt thereof of the present invention to a human in need thereof.

[0136] Yet another embodiment provides the compound [I] or a salt thereof of the present invention for use in the treatment, prevention and / or diagnosis of a disease caused by CSF1R which leads to reduction of macrophage, microglia and osteoclast.

[0137] Yet another embodiment provides the compound [I] or a salt thereof of the present invention for use in the treatment, prevention and / or diagnosis of neurological disease such as Alzheimer's disease (AD), tauopathies, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), HIV-associated neurocognitive disorders (HAND), prion disease, trauma brain injury (TBI), Parkinson's disease, pain, spinal cord injury, Crohn’s disease, radiation-induced lung fibrosis, glaucoma, infections, cardiovascular diseases such as inflammation post myocardial infarction, bone diseases, muscular dystrophy, asthma.

[0138] Yet another embodiment provides use of the compound [I] or a salt thereof of the present invention in the manufacture of a medicament for treating, preventing and / or diagnosing inhibition of CSF1R leads to reduction of macrophage, microglia and osteoclast.

[0139] Yet another embodiment provides use of the compound [I] or a salt thereof of the present invention in the manufacture of a medicament for treating, preventing and / or diagnosing neurological disease such as Alzheimer's disease (AD), tauopathies, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), HIV-associated neurocognitive disorders (HAND), prion disease, trauma brain injury (TBI), Parkinson's disease, pain, spinal cord injury, Crohn’s disease, radiation-induced lung fibrosis, glaucoma, infections, cardiovascular diseases such as inflammation post myocardial infarction, bone diseases, muscular dystrophy, asthma.

[0140] Disclosures of all literature cited in the present description are incorporated by reference in the present description in their entireties.Example

[0141] The present invention is explained in further detail below through the following Test Examples, Reference Examples and Examples, but these do not limit the present invention, and these may be changed to the extent that they do not deviate from the scope of the present invention.The following abbreviations are used in this Description.

[0142]

[0143] In the examples below, "room temperature" generally indicates from about 10°C to about 35°C. The ratios indicated for mixed solvents are volume ratios unless otherwise specified.Percentages indicate weight% unless otherwise specified.The1H-NMR (proton nuclear magnetic resonance spectrum) was measured by Fourier-transform type NMR (either of Bruker AVANCE III 400 (400 MHz) and Bruker AVANCE III HD (500 MHz)).Mass spectrum (MS) was measured by LC / MS (either of ACQUITY UPLC H-Class, Agilent 1290 Infinity II / 6130 or Shimadzu Nexera / LCMS-2020). As an ionization method, ESI method was used. The data indicate actual measured values (found).Generally, molecular ion peaks ([M+H]+, [M-H]-, etc.) were observed. In the case of a salt, a molecular ion peak or fragment ion peak of free form was generally observed.In silica gel column chromatography, when denoted as basic, aminopropylsilane-bonded silica gel was used. Supercritical fluid chromatography (SFC) was used for chiral separation. Isomer 1 or peak 1 refers to the compound that was firstly eluted among the isomers, and isomer 2 or peak 2 refers to the compound that was eluted second in the SFC separation. The notation of racemate in STR refers to a mixture of the drawn absolute structure and its enantiomer. The absolute configuration of the compound was determined by known X-ray crystal structure analysis methods (for example, Shigeru Oba and Shigenobu Yano, "Basic Course for Chemists 12, X-ray Crystal Structure Analysis" (First Edition, 1999)), or estimated from empirical rules of Shi asymmetric epoxidation (Waldemar Adam, Rainer T. Fell, Chantu R. Saha-Moller and Cong-Gui Zhao : Tetrahedron: Asymmetry 1998, 9, 397-401. Yuanming Zhu, Yong Tu, Hongwu Yu, Yian Shi: Tetrahedron Lett. 1988, 29, 2437-2440).

[0144] Reference example 1: 5-[4-Chloro-2-[[(1S)-2,2-difluoro-1-methylcyclopropyl]methoxy]-5-fluorophenyl]-1,2,4-thiadiazoleNaH (60% dispersion, 103 mg) was added to a solution of (2,2-difluoro-1-methylcyclopropyl)methanol (289 mg) in DMF (10 mL) at 0°C under N2. After 10 min, 5-(4-chloro-2,5-difluorophenyl)-1,2,4-thiadiazole (500 mg) was added. The reaction was stirred for 2 hours and then water was added. The precipitate that formed was collected by filtration and purified by chiral SFC to give the desired product (80 mg).

[0145] Reference example 2: 5-(4-Chloro-2,5-difluorophenyl)-1,2,4-thiadiazolestep 1: (BPin)2(8.4 g) was added to a suspension of 1-bromo-4-chloro-2,5-difluorobenzene (5.0 g), PdCl2(dppf) DCM (0.8 g) and AcOK (4.3 g) in 1,4-dioxane (50 mL) and the reaction mixture was stirred at reflux for 2 h. The mixture was filtered, the filtrate was concentrated in vacuo and the crude material was columned on silica gel (petrol:AcOEt) to give the pinacol boronic acid ester intermediate (5.6 g).step 2:A mixture of the pinacol boronic acid ester intermediate (290 mg), 5-bromo-1,2,4-thiadiazole (158 mg),Pd(OAc)2(10.78 mg), Xantphos (27.8 mg) and K2CO3(265 mg) in dioxane / H2O (2 / 1, 6 ml) was heated at 100 °C under N2atmosphere for 2 h. Reaction was diluted by AcOEt and dried over Na2SO4, then inorganic salt was removed by filtration. Solvent was removed and residue was purified by silica gel column (AcOEt / hexane = 1 / 10) to give the desired product (145 mg).

[0146] Reference example 3: 5-(4-Chloro-2-fluorophenyl)-1,2,4-thiadiazoleA mixture of 5-bromo-1,2,4-thiadiazole (230 g), 4-chloro-2-fluorophenylboronic acid (267.3 g), Xantphos (8 g), K2CO3(385.2 g), Pd(OAc)2(1.5 g) in 1,4-dioxane (2.3 L) and water (1.15 L) was stirred at reflux for 4.5 h. The reaction was extracted with AcOEt and the organic phase concentrated. The residue was azeotroped with heptane and triturated in heptane. The solid was collected by filtration to give the desired product (270 g).

[0147] Reference example 4: 5-[4-Chloro-2-[(4-methyloxan-4-yl)methoxy]phenyl]-1,2,4-thiadiazoleNaH (60% dispersion, 85 mg) was added to a solution of (4-methyloxan-4-yl)methanol (273 mg) in DMF (2.8 mL) at 0°C under N2. After 10 min, 5-(4-chloro-2-fluorophenyl)-1,2,4-thiadiazole (300 mg) was added thereto. The reaction was stirred for 1.5 h and then water was added. The formed precipitate was collected by filtration to give the desired product (330 mg).

[0148] Reference example 5: 5-[4-Chloro-2-[[4-(fluoromethyl)oxan-4-yl]methoxy]phenyl]-1,2,4-thiadiazoleNaH (60% dispersion, 34.9 mg) was added to a solution of [4-(fluoromethyl)oxan-4-yl]methanol (129.3 mg) in DMF (4 mL) at 0°C under N2. After 10 min, 5-(4-chloro-2-fluorophenyl)-1,2,4-thiadiazole (125 mg) was added thereto. The reaction was stirred for 1 h and then water was added. The formed precipitate was collected by filtration to give the desired product (151 mg).

[0149] Reference example 6: 5-[4-chloro-2-[[(1S)-2,2-difluoro-1-methylcyclopropyl]methoxy]phenyl]-1,2,4-thiadiazoleNaH (60% dispersion, 99 mg) was added to a solution of (2,2-difluoro-1-methylcyclopropyl)methanol (303 mg) in DMF (3.3 mL) at 0°C under N2. After 15 min, 5-(4-chloro-2-fluorophenyl)-1,2,4-thiadiazole (400 mg) was added thereto. The reaction was stirred for 2 h and then water was added thereto. The formed precipitate was collected by filtration and purified by chiral SFC to give the desired product (182 mg).

[0150] Reference example 8: 5-[4-Chloro-2-(cyclopentylmethoxy)phenyl]-1,2,4-thiadiazoleTo a solution of cyclopentanemethanol (129 μl) in MeCN (2 ml) was added potassium tert-butoxide (133 mg) and the mixture was stirred at RT for 1 min. Then 5-(4-chloro-2-fluorophenyl)-1,2,4-thiadiazole (170 mg) in MeCN (1 ml) was added thereto and the mixture was stirred at RT for 5 h. It was quenched with water and sat. NH4Cl aq. and extracted with AcOEt. The organic layer was washed with brine, dried over Na2SO4and concentrated in vacuo. The residue was purified by column chromatography (hexane:AcOEt)to give the desired product (156 mg).

[0151] Reference example 13: 5-[4-Chloro-2-(4,4-difluorocyclohexyl)oxyphenyl]-1,2,4-thiadiazoleTo a solution of 4,4-difluorocyclohexanol (444 mg) in DMF (3 m) was added NaH (130 mg), and the mixture was stirred at RT for 10 min. Then a solution of 5-(4-chloro-2-fluorophenyl)-1,2,4-thiadiazole (350 mg) in DMF (3 ml) was added and the mixture was stirred at RT for 6 h. It was quenched with water and sat. NH4Cl aq and extracted with AcOEt. The organic layer was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by column chromatography (hexane:AcOEt = 90:10 to 70:30) to give the desired compound (181 mg).

[0152] Reference example 14: tert-Butyl 4-[3-cyclohexyloxy-4-(1,2,4-thiadiazol-5-yl)phenyl]-3,6-dihydro-2H-pyridine-1-carboxylateA mixture of 5-(4-chloro-2-cyclohexyloxyphenyl)-1,2,4-thiadiazole (342.9 mg), 3,6-dihydro-2H-pyridine-1-tert-butoxycarbonyl-4-boronic acid, pinacol ester (540 mg,), Pd2(dba)3chloroform adduct (60.2 mg,), K3PO4(494 mg,) and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (47.8 mg) in dioxane:H2O (10:1) (5.5 ml) was heated at 100°C for 3 h. After cooling to RT, it was quenched with water and extracted with AcOEt. The organic layer was washed with brine, dried over Na2SO4and concentrated in vacuo. The residue was purified by column chromatography (hexane:AcOEt) to give the desired product (372 mg).

[0153] Reference example 23: trans-4-(Methoxymethoxy)cyclohexan-1-olTo a solution of trans-1,4-cyclohexanediol (1 g) in THF (20 ml) was added sodium hydride (0.376 g) at 0°C and it was stirred at RT for 10 min. Then MOMCl (0.719 ml) was added at 0°C and the mixture was stirred at rt for 5 h. It was quenched with sat. NH4Cl aq and water and extracted with AcOEt. The organic layer was washed with water and brine, dried over Na2SO4and concentrated. The residue was purified by column chromatography (hexane:AcOEt) to give the desired compound (304 mg).

[0154] Reference example 24: 5-[4-Chloro-2-[trans-4-(methoxymethoxy)cyclohexyl]oxyphenyl]-1,2,4-thiadiazoleTo a solution of 5-(4-chloro-2-fluorophenyl)-1,2,4-thiadiazole (230 mg) and trans-4-(methoxymethoxy)cyclohexan-1-ol (309 mg) in THF (10 ml) was added 55% NaH (84 mg) at 0°C and the mixture was stirred at rt for 6 h. It was quenched with water and sat. NH4Cl aq and extracted with AcOEt. The organic layer was washed with brine, dried over Na2SO4and concentrated. The residue was purified by column chromatography (hexane:AcOEt) to give the desired compound (340 mg).

[0155] Reference example 25: 5-[2-[trans-4-(Methoxymethoxy)cyclohexyl]oxy-4-(4-methylpiperazin-1-yl)phenyl]-1,2,4-thiadiazoleA mixture of 5-[4-chloro-2-[trans-4-(methoxymethoxy)cyclohexyl]oxyphenyl]-1,2,4-thiadiazole (170 mg), 1-methyl piperazine (106 μl), DavePhos (18.85 mg), Pd2(dba)3(24.79 mg) and sodium tert-butoxide (71.4 mg) in toluene (3 ml) was heated at 90°C for 3 h. After cooling to RT, it was quenched with water and extracted with AcOEt. The organic layer was washed with brine, dried over Na2SO4and concentrated in vacuo. The residue was purified by column chromatography (NH-silica; hexane:AcOEt) to give the desired compound (174 mg).

[0156] Reference example 27: rac-cis-3-(Methoxymethoxy)cyclohexan-1-olTo a mixture of rac-trans-3-(methoxymethoxy)cyclohexan-1-ol (815 mg), 4-nitrobenzoic acid (2550 mg) and triphenylphosphine (4003 mg) in THF (15 ml) was added DEAD (6.94 ml). The mixture was stirred at RT for 16 h. It was quenched with water and extracted with AcOEt. The organic layer was washed with water and brine, dried over Na2SO4and concentrated in vacuo. The residue was purified by column chromatography ((NH-silica; hexane:AcOEt = 90:10 to 70:30). The product was dissolved to MeOH (3 ml) and 1M NaOH aq (1.5 ml) was added. It was stirred at RT for 1 h. It was quenched with 1 M HCl aq and extracted with AcOEt. The organic layer was washed with water and brine, dried over Na2SO4and concentrated in vacuo. The residue was purified by column chromatography (hexane:AcOEt) to give the desired product (165 mg).

[0157] Reference example 29: 3-[(4-Methyloxan-4-yl)methoxy]-4-(1,2,4-thiadiazol-5-yl)benzonitrileA mixture of Reference example 4 (50 mg, 0.154 mmol), Zn(CN)2(25.3 mg, 0.216 mmol), dppf (4.27 mg, 7.70 μmol) and Pd2dba3(3.52 mg, 3.85 μmol) in NMP (2 ml) was heated at 140°C for 16 h. It was quenched with water and extracted with AcOEt. The organic layer was washed with water and brine, dried over Na2SO4and concentrated in vacuo. The residue was purified by column chromatography (hexane:AcOEt) to give the desired product (17.8 mg).

[0158] Reference example 31: 3-[(4-Methyloxan-4-yl)methoxy]-4-(1,2,4-thiadiazol-5-yl)benzaldehydeTo a solution of 3-[(4-methyloxan-4-yl)methoxy]-4-(1,2,4-thiadiazol-5-yl)benzonitrile (90 mg) was added DIBAL (428 μl) at -78°C and it was stirred for 3 h. It was allowed to warm to 0°C slowly. It was quenched with sat. NH4Cl aq and extracted with DCM. The organic layer was concentrated in vacuo. The residue was purified by column chromatography (hexane:AcOEt) to give the desired product (22.3 mg).

[0159] Reference example 33: (1S,4S)-5-(Azetidin-3-yl)-2-oxa-5-azabicyclo[2.2.1]heptane; dihydrochlorideA mixture of 1-Boc-3-azetidinone (500 mg), (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptanehydrochloride (475 mg) and sodium triacetoxyborohydride (928 mg) in DCE (10 ml) was stirred at RT for 16 h. It was quenched with sat. NHCO3aq and extracted with DCM. It was concentrated in vacuo. The residue was purified by column chromatography (NH-silica; hexane:AcOEt). The product was dissolved to DCM (2 ml) and 4 M HCl-dioxane (4 ml) was added. The mixture was stirred at RT for 16 h. The product was collected by filtration and washed with DCM to give the desired product (130 mg).

[0160] Reference example 45: rac-cis-2-[[5-Chloro-2-(1,2,4-thiadiazol-5-yl)phenoxy]methyl]cyclopentan-1-olThe flask was charged with 5-(4-chloro-2-fluorophenyl)-1,2,4-thiadiazole (350 mg), rac-cis-2-(hydroxymethyl)cyclopentan-1-ol (341 mg), Cs2CO3(956 mg) and NMP (3 mL) under N2atmosphere. The reaction mixture was stirred at 80°C for 18 h. To the reaction mixture was added water at RT. The mixture was filtered. The residue was purified by silica gel column chromatography (AcOEt / hexane) to give the desired product (340 mg).

[0161] Reference example 56: Ethyl 5-fluoro-4-methyl-2,3-dihydropyran-4-carboxylateTo a solution of ethyl 3-oxotetrahydro-2H-pyran-4-carboxylate (800 mg) and K2CO3(771 mg) in DCM (3 ml) was added MeI (349 μl) at 0°C. The mixture was stirred at RT for 18 h. It was quenched with water, extracted with AcOEt. The organic layers were dried over Na2SO4and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt:hexane) to give ethyl 4-methyl-3-oxotetrahydro-2H-pyran-4-carboxylate (800 mg).To a solution of 4-methyl-3-oxotetrahydro-2H-pyran-4-carboxylate (600 mg) in DCM (15 ml) was added DAST (1277 μl) at 0°C and the mixture was stirred at RT for 18 h. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography (AcOEt:hexane) to give the desired product (53 mg).

[0162] Reference example 57: Methyl rac-trans-2-hydroxy-1,2-dimethylcyclopentane-1-carboxylateTo a solution of methyl 1-methyl-2-oxocyclopentane-1-carboxylate (200 mg) in ether (4 ml) was added 3 M methylmagnesium bromide in diethyl ether (512 μl) at 0°C and the mixture was stirred at 0°C for 10 min. The reaction mixture was quenched by water and extracted with AcOEt. The organic layers were dried over Na2SO4and concentrated under reduced pressure to give crude. The residue was purified by silica gel column chromatography (AcOEt:hexane) to give the desired product (200 mg).

[0163] Reference example 58: rac-trans-2-(Hydroxymethyl)-1,2-dimethylcyclopentan-1-olA 50 mL round-bottomed flask equipped with a magnetic stirring bar was charged with methyl rac-trans-2-hydroxy-1,2-dimethylcyclopentane-1-carboxylate (200 mg) and THF (20 ml). To the reaction was added LAH (132 mg) under N2atmosphere at 0°C. The reaction mixture was stirred at RT for 3 h. The reaction mixture was quenched with water (0.13 mL), 15% NaOH aq. (0.13 mL), and water (0.39 mL). The mixture was stirred for 30 min and filtrated. The filtrate was concentrated under reduced pressure to give the crude. The residue was purified by biotage column (AcOEt:hexane) to give the desired product (110 mg).

[0164] Reference example 60: 5-[2-[(4-Methyloxan-4-yl)methoxy]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,2,4-thiadiazoleThe MW tube was charged with Reference example 4 (100 mg), bis(pinacolato)diboron (78 mg), potassium acetate (91 mg) and DavePhos-Pd-G3 (13.06 mg) under N2atmosphere. To the mixture was added dioxane (2 ml) at RT. The reaction mixture was evacuated and backfilled with N2three times. The reaction mixture was stirred at 100°C for 2 h. It was diluted with AcOEt and filtered. The filtrate was concentrated under reduced pressure to give crude. The residue was purified by silica gel column chromatography (AcOEt:hexane) to give the desired product (110 mg).

[0165] Reference example 61: tert-Butyl 3-[3-[(4-methyloxan-4-yl)methoxy]-4-(1,2,4-thiadiazol-5-yl)phenyl]azetidine-1-carboxylateThe flask was charged with 5-[2-[(4-methyloxan-4-yl)methoxy]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,2,4-thiadiazole (100 mg), (1R,2R)-2-aminocyclohexanol hydrochloride (3.64 mg), nickel(II) iodide (1.287 μl) and IPA (1 ml) under N2. To the mixture was added NaHMDS (214 μl) at RT. To the reaction mixture was added 1-Boc-3-(iodo)azetidine (68.0 mg) in IPA (0.5 mL). The reaction mixture was evacuated and backfilled with N2three times. The reaction mixture was stirred at 100°C for 3 h under N2. To the reaction mixture was filtered and concentrated under reduced pressure to give crude. The crude was purified by silica gel column chromatography (AcOEt / hexane) to give the desired product (17 mg).

[0166] Reference example 62: (4-Methylideneoxolan-3-yl) benzoateThe flask was charged with tetrahydro-4-methylene-3-furanol (CAS: 390381-85-8, 1000 mg), TEA (2784 μl), DMAP (122 mg) and DCM (30 ml) under N2atmosphere. To the mixture was added benzoyl chloride (1391 μl) at 0°C. The reaction mixture was stirred at RT for 3 h. To the reaction mixture was diluted with water and DCM at RT. The organic layer was separated through a phase separator and concentrated under reduced pressure to give crude. The crude was purified by silica gel column chromatography (AcOEt / hexane) to give the desired product (1.1 g).

[0167] Reference example 63: [rac-trans-2,2-Difluoro-5-oxaspiro[2.4]heptan-7-yl] benzoateTo a solution of (4-methylideneoxolan-3-yl) benzoate (100 mg) and sodium iodide (36.7 mg) in THF (1 ml) was added (trifluoromethyl)trimethylsilane (182 μl) at RT and the mixture was stirred at reflux for 4 h. To the reaction mixture was added additional amount of (trifluoromethyl)trimethylsilane (182 μl) at RT. The mixture was stirred at reflux for 15 h. The reaction mixture was quenched with sat. NaHCO3aq. and extracted with AcOEt. The organic layers were washed with sat. Na2CO3aq., and brine and dried over Na2SO4and concentrated under reduced pressure to give crude. The crude was purified by silica gel column chromatography (hexane / AcOEt) to give the desired product (73 mg).

[0168] Reference example 64: 5-[4-(Azetidin-3-yl)-2-[(4-methyloxan-4-yl)methoxy]phenyl]-1,2,4-thiadiazoleThe flask was charged with tert-butyl 3-[3-[(4-methyloxan-4-yl)methoxy]-4-(1,2,4-thiadiazol-5-yl)phenyl]azetidine-1-carboxylate (110 mg), TFA (951 μl), and DCM (3 ml) under N2atmosphere at RT. The reaction mixture was stirred at RT for 3 h. The mixture was quenched with sat. NaHCO3aq. and extracted with DCM. The organic layer were dried over Na2SO4and concentrated under reduced pressure to give the desired product (87 mg).

[0169] Reference example 65: rac-trans-2,2-Difluoro-5-oxaspiro[2.4]heptan-7-olTo a solution of [rac-(3R,7S)-2,2-difluoro-5-oxaspiro[2.4]heptan-7-yl] benzoate (1000 mg) in MeOH (20 ml) was added 2 M NaOH aq. (3933 μl) at RT and the mixture was stirred at RT for 4 h. The mixture was concentrated under reduced pressure. The mixture was diluted with water and AcOEt and extracted with AcOEt. The organic layers were dried over Na2SO4and concentrated under reduced pressure to give crude. The residue was purified by silica gel column chromatography (hexane:AcOEt) to give the product (400 mg).

[0170] Reference example 67: tert-Butyl 6-[3-(4,4-dimethyloxolan-3-yl)oxy-4-(1,2,4-thiadiazol-5-yl)phenyl]-2,6-diazaspiro[3.3]heptane-2-carboxylateThe MW tube was charged 5-[4-chloro-2-(4,4-dimethyloxolan-3-yl)oxyphenyl]-1,2,4-thiadiazole (300 mg), tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (cas: 1041026-70-3, 191 mg), Cs2CO3(629 mg) and DavePhos-Pd-G3 (36.8 mg) under N2atmosphere. To the mixture was added dioxane (5 ml) at RT. The reaction mixture was evacuated and backfilled with N2three times. The reaction mixture was stirred at 100°C for 5 h. It was filtered. The filtrate was concentrated under reduced pressure to give crude. The residue was purified by biotage column (NH: AcOEt:hexane) to give the desired product (320 mg).

[0171] Reference example 68: 2,2-Difluoro-5-oxaspiro[2.4]heptan-7-oneThe flask was charged with rac-cis-2,2-difluoro-5-oxaspiro[2.4]heptan-7-ol (1.4 g) and DMSO:AcOEt = 1:1 (60 ml) under N2. To the mixture was added IBX (7.83 g) at RT. The reaction mixture was stirred at 85°C for 1 h. After the mixture was cooled, it was diluted by ether and water and filtered. The filtrate was washed with water and dried over Na2SO4to give crude. The residue was purified by silica gel column chromatography (DCM) to give the desired product (1.4 g).

[0172] Reference example 69: rac-cis-2,2-Difluoro-5-oxaspiro[2.4]heptan-7-ol2,2-Difluoro-5-oxaspiro[2.4]heptan-7-one (1.4g) was diluted with MeOH (30 ml). To the mixture was added NaBH4(0.715 g) at RT. The mixture was stirred for 0.5 h at RT. The mixture was quenched with water and extracted with DCM. The organic layers were dried over Na2SO4and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt:hexane) to give the title compound (300 mg).

[0173] Reference example 72: [rac-trans-3-Fluoro-4-methyloxan-4-yl]methanolThe mixture of (5-fluoro-4-methyl-2,3-dihydropyran-4-yl)methanol (1.3 g) and 5% Pd-C (wet) (0.947 gl) in EtOH (50 ml) was stirred at RT under H2for 5 h. The mixture was filtered through a pad of Celite and washed with AcOEt. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt / hexane) to give the desired product (300 mg).

[0174] Reference example 77: 5-[4-(Azetidin-3-yl)-2-[[4-(difluoromethyl)oxan-4-yl]methoxy]phenyl]-1,2,4-thiadiazoleTo a mixture of nickel(II) iodide (47.4 mg), (1R,2R)-2-aminocyclohexanol hydrochloride (23.0 mg) and 5-[2-[[4-(difluoromethyl)oxan-4-yl]methoxy]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,2,4-thiadiazole (686 mg) in IPA (7 ml) was added NaHMDS (3.03 ml) then 1-Boc-3-(iodo)azetidine (644 mg) at RT. Reaction was heated at 100°C for overnight under N2. Reaction was concentrated and residue was triturated by DCM. Insoluble material was filtered through a pad of Celite. Filtrate was concentrated and residue was purified by silica gel column (AcOEt / hexane = 1 / 9 to 1 / 1) to give the coupling product (<272 mg) including by-product. The coupling product was treated by TFA (2 ml) / DCM (2 ml). Reaction was concentrated and residue was purified by basic silica gel column (AcOEt / hexane then MeOH / AcOEt) to give the desired product (74 mg).

[0175] Reference example 80: [3-[[(1S)-2,2-Difluoro-1-methylcyclopropyl]methoxy]-4-(1,2,4-thiadiazol-5-yl)phenyl]boronic acidThe flask was charged with 5-[2-[[(1S)-2,2-difluoro-1-methylcyclopropyl]methoxy]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,2,4-thiadiazole (680 mg), dihydroxymethylborane (997 mg) and acetone:0.2 M HCl aq. = 1:1 (2 ml) under N2. The reaction mixture was stirred at RT for 18 h. The mixture was added to water and filtered to give the desired product (437 mg).

[0176] Reference example 87: tert-Butyl 2-[3-[[(1S)-2,2-difluoro-1-methylcyclopropyl]methoxy]-4-(1,2,4-thiadiazol-5-yl)phenyl]-6,8-dihydro-5H-imidazo[1,2-a]pyrazine-7-carboxylateThe MW tube was charged with 5-[2-[[(1S)-2,2-difluoro-1-methylcyclopropyl]methoxy]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,2,4-thiadiazole (165 mg), 2-bromo-5,6-dihydro-8H-imidazo[1,2-a]pyrazine-7-carboxylic acid tert-butyl ester (147 mg), K2CO3(168 mg) and DavePhos-Pd-G3 (15.42 mg) under N2atmosphere. To the mixture was added dioxane:H2O (3:1) (4 ml) at RT. The reaction mixture was evacuated and backfilled with N2three times. The reaction mixture was stirred at 100°C for 13 h under N2. The mixture was diluted with water and DCM at RT. The organic layer was separated through a phase separator and concentrated under reduced pressure to give crude. The crude was purified by silica gel column chromatography (AcOEt / hexane) to give the desired product (65 mg).

[0177] Reference example 89: tert-Butyl 4-[3-[[(1S)-2,2-difluoro-1-methylcyclopropyl]methoxy]-4-(1,2,4-thiadiazol-5-yl)phenyl]piperidine-1-carboxylateTo the flask were charged tert-butyl 4-[3-[[(1S)-2,2-difluoro-1-methylcyclopropyl]methoxy]-4-(1,2,4-thiadiazol-5-yl)phenyl]-3,6-dihydro-2H-pyridine-1-carboxylate (192 mg), 20% Pd(OH)2 / C (29.1 mg) and EtOH (6 ml) under N2atmosphere. The reaction mixture was stirred at RT for 2 h under H2atmosphere. The mixture was filtered and the filtrate was concentrated under reduced pressure to give the desired product (180 mg).

[0178] Reference example 90: 3-[[(1S)-2,2-Difluoro-1-methylcyclopropyl]methoxy]-4-(1,2,4-thiadiazol-5-yl)benzonitrileA mixture of 5-[4-chloro-2-[[(1S)-2,2-difluoro-1-methylcyclopropyl]methoxy]phenyl]-1,2,4-thiadiazole (325 mg, 1.026 mmol), Zn(CN)2(241 mg, 2.052 mmol), dppf (85 mg, 0.154 mmol) and Pd2(dba)3(94 mg, 0.103 mmol) in NMP (4 ml) was heated at 170°C for 2 h using MW. The mixture was diluted with AcOEt and filtered through a pad of Celite. The filtrate was diluted with H2O and the resulting precipitate was collected by filtration. To the solution of the residue in DCM was added Si-silica gel. The mixture was stirred at RT for 30 min, then filtered through a pad of Celite. The filtrate was concentrated to give the desired product (437 mg).

[0179] Reference example 92: tert-Butyl 3-[[3-[(4-methyloxan-4-yl)methoxy]-4-(1,2,4-thiadiazol-5-yl)benzoyl]amino]azetidine-1-carboxylateTo a solution of 3-[(4-methyloxan-4-yl)methoxy]-4-(1,2,4-thiadiazol-5-yl)benzonitrile (175 mg, 0.555 mmol) in EtOH (10 ml) was added 5 N NaOH aq. (1.5 ml) at RT. The mixture was stirred at 80°C for 3h. The mixture was acidified by addition of 5 N HCl aq. (2 ml) and concentrated to remove EtOH. The resulting precipitate was collected by filtration and dried in vacuo to give the carboxylic acid.To a solution of the carboxylic acid (90 mg) in DMF (3 ml) were added 3-amino-1-N-Boc-azetidine (50.6 μl), WSCDI (67.1 mg), HOBt (53.6 mg) and Et3N (75 μl) at RT. The mixture was stirred for 3h. The reaction mixture was diluted with H2O and the precipitate was collected by filtration. The residue was purified by column chromatography (Si, AcOEt / MeOH) to give the desired product (101mg).

[0180] Reference example 98: 5-[4-Chloro-2-[[4-(methoxymethyl)oxan-4-yl]methoxy]phenyl]-1,2,4-thiadiazoleTo a suspension of [4-[[5-chloro-2-(1,2,4-thiadiazol-5-yl)phenoxy]methyl]oxan-4-yl]methanol (100 mg) in THF (2 ml) was added NaH (55%, 38.4 mg) then MeI (55.0 μl). This was stirred at RT for overnight. Reaction was quenched by H2O and extracted by DCM. Organic phase was concentrated and residue was purified by silica gel column chromatography (AcOEt / hexane) to give the desired product (69 mg).

[0181] Reference example 102: tert-Butyl 4-[5-bromo-4-[(4-methyloxan-4-yl)methoxy]pyridin-2-yl]piperazine-1-carboxylateTo a solution of tert-butyl 4-[4-[(4-methyloxan-4-yl)methoxy]pyridin-2-yl]piperazine-1-carboxylate (1.48 g) in DCM (38 ml) was added NBS (673 mg) at 0°C and this was stirred at RT for overnight. Reaction was concentrated and purified by silica gel column chromatography (AcOEt / hexane) to give the desired product (1.36 g).

[0182] Reference example 104: 5-[4-[(4-Methyloxan-4-yl)methoxy]-6-piperazin-1-ylpyridin-3-yl]-1,2,4-thiadiazole; dihydrochlorideTo a solution of tert-butyl 4-[4-[(4-methyloxan-4-yl)methoxy]-5-(1,2,4-thiadiazol-5-yl)pyridin-2-yl]piperazine-1-carboxylate (262 mg) in AcOEt (6 ml) was added 4N HCl in AcOEt (6 ml) and reaction was stirred at RT for overnight. Precipitate was collected by filtration to give the desired product (238 mg).

[0183] Reference example 108: tert-Butyl 4-(4-chloro-3-fluorophenyl)-4-hydroxypiperidine-1-carboxylateMg (0.40 g) and I2(cat) in THF (30 ml) was heated to reflux. To this mixture was added 4-bromo-1-chloro-2-fluorobenzene (2.02 ml) dropwise. After the dropwise addition, heating was continued for 1 h. Resultant solution was cooled to 0°C and 1-methyl-4-piperidone (2.73 g) in THF (15ml) was added. This was stirred at RT for overnight. Reaction was quenched by the addition of citric acid aq. THF was removed and the residue was extracted with AcOEt. The organic phase was concentrated and the residue was purified by basic silica gel column chromatography (NH, AcOEt / hexane) to give the desired product (2.80 g).

[0184] Reference example 112: tert-Butyl 4-fluoro-4-[3-fluoro-4-(1,2,4-thiadiazol-5-yl)phenyl]piperidine-1-carboxylateTo a solution of tert-butyl 4-[3-fluoro-4-(1,2,4-thiadiazol-5-yl)phenyl]-4-hydroxypiperidine-1-carboxylate (100 mg) in DCM (3 ml) was added DAST (139 μl) at -78°C. Reaction was stirred for 2 h at this temperature then overnight at RT. Reaction was quenched by NaHCO3aq and the organic phase was concentrated. The residue was purified by silica gel column chromatography (AcOEt / hexane). To the residue was added tBuOH aq (1:1, 2 ml) then AD-mix (370 mg). This was stirred at RT for overnight. The reaction was quenched by Na2SO3and extracted with AcOEt. The organic phase was dried over Na2SO4and concentrated. The residue was purified by silica gel column chromatography (AcOEt / hexane) to give the desired product (81 mg).

[0185] Reference example 118: 5-(6-Chloro-2-fluoropyridin-3-yl)-1,2,4-thiadiazoleA mixture of 5-bromo-1,2,4-thiadiazole (1.0 g), (6-chloro-2-fluoropyridin-3-yl)boronic acid (1.2 g), Xantphos (400 mg), K2CO3(2.5 g), and Pd(OAc)2(70 mg,) in 1,4-dioxane (15 mL) and water (5 mL) was stirred at reflux for 3.5 h. The reaction was extracted with AcOEt and the organic phase concentrated. The residue was purified by column chromatography (KP-Sil, petrol:AcOEt) to give the desired product (1.05 g).

[0186] Reference example 145: 5-[4-Chloro-2-({3-oxabicyclo[3.1.0]hexan-1-yl}methoxy)phenyl]-1,2,4-thiadiazoleNaOtBu (10.9 g) was added to a solution of {3-oxabicyclo[3.1.0]hexan-1-yl}methanol (10.0 g) in DMF (200 mL) at 0°C under N2. After 15 min, a solution of 5-(4-chloro-2-fluorophenyl)-1,2,4-thiadiazole (18.0 g) in DMF (100 mL) was added thereto. The reaction was stirred for 2 h and then water was added to the reaction. The formed precipitate was collected by filtration to give the desired product (25.0 g).

[0187] Reference example 160: (6,6-Difluoro-3-oxabicyclo[3.1.0]hexan-1-yl)methanolLAH (1M, 4.0 mL) was added to a solution of 6,6-difluoro-3-oxabicyclo[3.1.0]hexane-1-carboxylic acid (300 mg) in THF (5.0 mL) at 0°C under N2. The reaction was then stirred at RT for 4 h. The reaction was quenched with water (6 mL) and 5N NaOH (3 mL) and filtered through Celite. The filtrate was carefully concentrated to give the desired product as a solution in THF which was used in the next step without further purification.

[0188] Reference example 162: 5-(4-Chloro-2-{[(1R,5S)-6,6-difluoro-3-oxabicyclo[3.1.0]hexan-1-yl]methoxy}phenyl)-1,2,4-thiadiazoleNaH (60% dispersion, 87.8 mg) was added to a solution of {6,6-difluoro-3-oxabicyclo[3.1.0]hexan-1-yl}methanol obtained from the previous step in DMF (3.7 mL) at 0°C under N2. After 10 min, 5-(4-chloro-2-fluorophenyl)-1,2,4-thiadiazole (353 mg) was added thereto. The reaction was stirred at RT overnight and then water was added to the reaction. The formed precipitate was collected by filtration to give the desired product (480mg). SFC chiral separation was carried out to give the desired isomer.

[0189] Reference example 173: 6-Chloro-2-[(2,2-difluoro-1-methylcyclopropyl)methoxy]-3-(1,2,4-thiadiazol-5-yl)pyridineNaOtBu (550 mg) was added to a solution of (2,2-difluoro-1-methylcyclopropyl)methanol (2.2 g) in THF (5 mL) at 0°C under N2. After 15 min, a solution of 6-chloro-2-fluoro-3-(1,2,4-thiadiazol-5-yl)pyridine (1.1 g) in THF (10 mL) was added thereto. The reaction was stirred for 1.5 h and then water was added to the reaction. The formed precipitate was collected by filtration to give the desired product (1.4 g).

[0190] Reference example 176: rac-trans-2-Methyl-2-[(triethylsilyl)oxy]cyclopentyl benzoateA stirred solution of rac-trans-2-hydroxy-2-methylcyclopentyl benzoate (602 mg) in DMF (6 mL) was treated with 1H-imidazole (447 mg) and TBSCl (494 mg) and stirred at 50°C for 2 h and then at 80°C for 2 h. A second aliquot of 1H-imidazole (447 mg) and TESCl (930 μL) was added and the reaction was stirred at 55°C for 2 h. The mixture was diluted with MTBE (75 mL) and washed successively with water (50 mL), 0.5 M HCl (50 mL) and Na2CO3(50 mL). The organics were concentrated and the crude material was purified by column chromatography (KP-Sil, isohexane: MTBE) to give the desired product (673 mg).

[0191] Reference example 177: rac-trans-2-Methyl-2-[(triethylsilyl)oxy]cyclopentan-1-olTo a stirred solution of rac-trans-2-methyl-2-((triethylsilyl)oxy)cyclopentyl benzoate (762 mg) in DCM (10 mL) at -78°C DIBAL (1 M in hexane, 4.78 mL) was added dropwise. After 2 h, the mixture was quenched with Rochelle's salt (5 g in 100 mL). The mixture was stirred for 2 h and the layers were separated. The organic phase was concentrated before purification by column chromatography (KP-Sil isohexane: AcOEt) to give the desired product (440 mg).

[0192] Reference example 185: rac-cis-4-(Difluoromethyl)oxolan-3-olTo a solution of rac-cis-4-(difluoromethyl)tetrahydrofuran-3-yl benzoate (96 mg) in THF (2 mL) were added LiOH (0.40 mL, 2 M in water) and MeOH (1 mL). The mixture was stirred at RT for four days. HCl (1 M, 25 ml) was added and the reaction was extracted with MTBE (2 x 50 ml). The organics were washed with Na2CO3(~50 ml) and concentrated to give the desired product (15 mg).

[0193] Reference example 190: [rac-trans-2-{[(tert-Butyldimethylsilyl)oxy]methyl}-2-methylcyclopropyl]methanol(E)-4-((tert-Butyldimethylsilyl)oxy)-3-methylbut-2-en-1-ol (0.72 g) was dissolved in DCM (11 mL) and cooled to 0°C. Zn(Et)2(6.62 ml, 1M) was added dropwise and the mixture was stirred for 10 min. Diiodomethane (1.1 ml) was added and the mixture was stirred at 0°C for 4 h. The reaction was quenched with NH4Cl aq. (10 mL) and extracted with AcOEt. The combined organic fractions were washed with brine and then concentrated. The crude product was purified by column chromatography (KP-Sil, isohexane: AcOEt) to afford the desired product (0.663 g).

[0194] Reference example 192: [rac-trans-2-(Methoxymethyl)-1-methylcyclopropyl]methanolTBAF (1 M in THF) (3.01 mL, 3.01 mmol) was added dropwise to tert-butyl((2-(methoxymethyl)-1-methylcyclopropyl)methoxy)dimethylsilane (0.614 g, 2.51 mmol) in THF (15 mL) at 0°C and the mixture was stirred for 30 min then allowed to warm to RT and stirred for 16 h. The solvent was removed under reduced pressure and the residue was dissolved in AcOEt (20 mL) and washed with NH4Cl aq. (20 mL). The organic phase was concentrated in vacuo and the crude product was purified by chromatography (SiO2, AcOEt / isohexane) to give the desired product (0.380 g).

[0195] Reference example 194: [rac-trans-2-{[(tert-Butyldimethylsilyl)oxy]methyl}-3,3-difluoro-2-methylcyclopropyl]methyl acetate(E)-4-((tert-Butyldimethylsilyl)oxy)-3-methylbut-2-en-1-yl acetate (CAS: 132032-95-2: 0.956 g) was dissolved in diglyme (1.9 mL) and heated to 150°C. Sodium 2-bromo-2,2-difluoroacetate (5.4 g) in diglyme (14 mL) was added dropwise and the mixture was stirred for 15 min. The reaction cooled to RT then poured onto ice and extracted with isohexane (3 x 50 mL). The combined organic fractions were washed with brine (200 mL) and concentrated. The residue was purified by column chromatography (KP-Sil, isohexane: AcOEt) to afford the desired product (0.742 g).

[0196] Reference example 195: [rac-trans-2-{[(tert-Butyldimethylsilyl)oxy]methyl}-3,3-difluoro-2-methylcyclopropyl]methanolNaOMe (0.96 mL, 0.50 M in MeOH) was added to a solution of [rac-trans-2-{[(tert-butyldimethylsilyl)oxy]methyl}-3,3-difluoro-2-methylcyclopropyl]methyl acetate (740 mg) in MeOH (11 mL) and the mixture was stirred for 16 h. The mixture was neutralized with HCl (1 M) and extracted with AcOEt (3 x 10 mL). The combined organic fractions were washed with brine (30 mL) and concentrated to afford the desired product (439 mg).

[0197] Reference example 210: 3-[5-Chloro-2-(1,2,4-thiadiazol-5-yl)phenoxy]-1,4,4-trimethylpiperidineNaH (60% dispersion, 168 mg) was added to a solution of 1-boc-3-hydroxy-4,4-dimethylpiperidine (500 mg, 3.8 mmol) in DMF (7 mL) at 0°C. After 30 min, 5-(4-chloro-2-fluorophenyl)-1,2,4-thiadiazole (750 mg, 3.5 mmol) was added thereto and the reaction was stirred at RT overnight. The reaction was quenched with water and extracted with AcOEt. The crude material was purified by column chromatography (SiO2, AcOEt / petrol) to give the desired product (1.2 g).A solution of tert-butyl 3-[5-chloro-2-(1,2,4-thiadiazol-5-yl)phenoxy]-4,4-dimethylpiperidine-1-carboxylate (1.2 g) in 4M HCl in dioxane (14.0 mL) and MeOH (0.5 mL) was stirred at RT for 1 h. The solvent was removed in vacuo and the crude material was used in the next step without further purification. AcOH (0.3 mL) and NaBH(OAc)3(0.7 g, 3.5 mmol) were added to a solution of the intermediate in DCM (5 mL) containing DIPEA (0.3 mL) and formaldehyde (51 mg). The reaction was stirred at RT overnight. The mixture was quenched with NaHCO3and extracted with DCM. The organic phase was concentrated and the crude material was purified by column chromatography (SiO2, AcOEt / petrol) to give the desired product (500 mg).

[0198] Reference example 215: 1-{[5-Chloro-2-(1,2,4-thiadiazol-5-yl)phenoxy]methyl}-2,2-difluorocyclopropyl)methanolNaH (60% dispersion, 75 mg) was added to a solution of [2,2-difluoro-1-(hydroxymethyl)cyclopropyl]methanol (257 mg) in DMF (10 mL) at 0°C under N2. After 15 min, 5-(4-chloro-2-fluorophenyl)-1,2,4-thiadiazole (200 mg) was added thereto and the reaction was stirred for 2 h. Water was added to the reaction and the formed precipitate was collected by filtration. The solid was purified by column chromatography (KP-Sil, petrol:AcOEt) to give the desired product (99 g).

[0199] Reference example 216: 5-(4-Chloro-2-{[2,2-difluoro-1-(fluoromethyl)cyclopropyl]methoxy}phenyl)-1,2,4-thiadiazoleDeoxo-Fluor (239 mg) was added dropwise to a solution of (1-{[5-chloro-2-(1,2,4-thiadiazol-5-yl)phenoxy]methyl}-2,2-difluorocyclopropyl)methanol (90 mg) in DCM (4 mL) at 0°C under N2. The reaction mixture was stirred at 0°C for 1 h, and then at RT overnight. The mixture was quenched with MeOH (1 mL) and NaHCO3aq. (3 mL). The organic phase was concentrated and the residue was purified by column chromatography (KP-Sil, petrol:AcOEt) to give the desired product (75 mg).

[0200] Reference example 223: 3-(5-Chloro-2-(1,2,4-thiadiazol-5-yl)phenoxy)-2-methylpropan-1-olBCl3(1.74 mL, 1 M) was added to 5-(2-(3-(benzyloxy)-2-methylpropoxy)-4-chlorophenyl)-1,2,4-thiadiazole (0.327 g) and pentamethylbenzene (388 mg) in DCM (2 mL) at -78°C and stirred for 4 h. The reaction was quenched with water (10 mL) and extracted with DCM. The combined organic fractions were washed with NaHCO3aq. and concentrated. The crude product was purified by column chromatography (KP-Sil isohexane: AcOEt) to afford the desired product (0.195 g).

[0201] Reference example 225: 5-(4-Chloro-2-(3,3-difluoro-2-methylpropoxy)phenyl)-1,2,4-thiadiazoleDAST (160 μL) was added to 3-(5-chloro-2-(1,2,4-thiadiazol-5-yl)phenoxy)-2-methylpropanal (0.114 g) in DCM (4 mL) at 0°C. The mixture was stirred for 1 hour at 0°C and then at RT for 1 hour. The mixture was cooled to 0°C and quenched with NaHCO3(20 mL) and extracted with DCM (3 x 20 mL). The organic phase was concentrated and the residue was purified by column chromatography (KP-Sil, isohexane: AcOEt) to afford the desired product (0.112 g).

[0202] Reference example 227: 5-(4-Chloro-2-((3,3-difluoro-1-methylpyrrolidin-2-yl)methoxy)phenyl)-1,2,4-thiadiazoleFormaldehyde (37 wt % solution in water) (180 μL) was added to a solution of 5-(4-chloro-2-((3,3-difluoropyrrolidin-2-yl)methoxy)phenyl)-1,2,4- thiadiazole (200 mg) in DCM (4 mL) and the mixture was stirred for 30 min. NaBH(OAc)3(383 mg) was added and the mixture was stirred for 16 h. H2O (10 mL) was added and the organic layer was separated. The aqueous was extracted with DCM (2 x 20 mL) and the combined organic fractions washed with brine (100 mL) then passed through a phase separator and the solvent removed under reduced pressure. The reaction was quenched with water and extracted with DCM. The crude material was purified by column chromatography (SiO2, AcOEt / isohexane) to give the desired product (194 mg).

[0203] Reference example 247: 4-{3-[(4-Methyloxan-4-yl)methoxy]-4-(1,2,4-thiadiazol-5-yl)phenyl}-1,2,3,6-tetrahydropyridine; hydrochlorideA solution of 5-{4-chloro-2-[(4-methyloxan-4-yl)methoxy]phenyl}-1,2,4-thiadiazole (314 mg, 0.96 mmol), (N-tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (200 mg), PdCl2dppf (32 mg) and K2CO3(365 mg, 2.6 mmol) in dioxane (30 mL and water (1 mL) was stirred in a sealed vial under N2at 80°C for 24 h. The reaction was quenched with water and extracted with AcOEt. The organic phase was concentrated in vacuo and the crude material was purified by column chromatography (SiO2, AcOEt). The product was suspended in HCl (4M in dioxane, 5 mL) and the mixture was stirred at RT for 1h. The solvent was removed in vacuo to give the desired product (200 mg).

[0204] Reference example 257: 4-[3-Fluoro-4-(1,2,4-thiadiazol-5-yl)benzoyl]morpholineHATU (0.285 g) and DIPEA (0.327 mL) were dissolved in DMF (1.0 mL). Then 3-fluoro-4-(1,2,4-thiadiazol-5-yl)benzoic acid (0.084 g) and morpholine (0.065 mL) were added and the mixture was stirred at 50°C for 2 h. The reaction was quenched with water (10 ml) and extracted with DCM (20 mL). The organic phase was concentrated and the crude product was purified by column chromatography (KP-Sil isohexane: AcOEt) to afford the product (85 mg).

[0205] Reference example 267: tert-Butyl 6-(3-{[(1S)-2,2-difluoro-1-methylcyclopropyl]methoxy}-4-(1,2,4-thiadiazol-5-yl)phenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylateA suspension of Reference example 6 (5.0 g), tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate hemioxylate (5.4 g), Pd2(dba)3(1.4 g), DavePhos (1.2 g), and NaOtBu (10.8 g) in toluene (100 mL) and water (0.5 mL) was refluxed under N2for 2 h. The reaction mixture was filtered through Celite and the filtrate was concentrated. The residue was purified by column chromatography (KP-NH, petrol:AcOEt) to give the desired product (2.7 g).

[0206] Reference example 268: 2-(3-{[(1S)-2,2-Difluoro-1-methylcyclopropyl]methoxy}-4-(1,2,4-thiadiazol-5-yl)phenyl)-2,6-diazaspiro[3.3]heptaneTo a solution of tert-butyl 6-(3-{[(1S)-2,2-difluoro-1-methylcyclopropyl]methoxy}-4-(1,2,4-thiadiazol-5-yl)phenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (1.0 g) in DCM (10 mL) was added TFA (2 mL). The reaction was stirred at RT for 30 min. The reaction was quenched with NaHCO3aq. and extracted with DCM. The organic phase was concentrated to give the desired product (800 mg).

[0207] Reference example 282: 5-[[(1S)-2,2-Difluoro-1-methylcyclopropyl]methoxy]-2-fluoro-4-(1,2,4-thiadiazol-5-yl)phenolTo a solution of (S)-5-(4-chloro-2-((2,2-difluoro-1-methylcyclopropyl)methoxy)-5-fluorophenyl)-1,2,4-thiadiazole (100 mg), Me4tButylXphos (7.18 mg), KOH (79 mg) in H2O-dioxane (4 ml) was added Pd2(dba)3(13.68 mg) under N2atmosphere at RT and the mixture was stirred at 100°C for 3 h (Microwave). It was quenched with water and extracted with DCM. The organic layer was concentrated in vacuo. The residue was purified by column chromatography (hexane:AcOEt = 20 to 33%) to give the desired compound (84.4 mg).

[0208] Reference example 284: tert-Butyl (2R)-2-[[3-[[(1S)-2,2-difluoro-1-methylcyclopropyl]methoxy]-4-(1,2,4-thiadiazol-5-yl)phenoxy]methyl]morpholine-4-carboxylateTo a solution of (S)-3-((2,2-difluoro-1-methylcyclopropyl)methoxy)-4-(1,2,4-thiadiazol-5-yl)phenol (50 mg), tert-butyl (R)-2-(hydroxymethyl)morpholine-4-carboxylate (146 mg) and triphenylphosphine (176 mg) in THF (1.5 ml) was added diisopropyl azodicarboxylate (132 μl) at rt under N2. The solution was stirred for 1h at 40°C. The solution was concentrated in vacuo. The residue was directly loaded onto a column chromatography and purified (hexane:EtOAc) to give the desired compound (104 mg).

[0209] Reference example 287: tert-Butyl 4-[3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]piperidine-1-carboxylateTo a solution of tert-butyl 4-(3,5-difluorophenoxy)piperidine-1-carboxylate (1561 mg) in dry THF (20 ml) under an atmosphere of N2at -78°C was added n-BuLi (4048 μl) slowly. The reaction was stirred for 0.45 hr at -78°C followed by the addition of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2134 μl). The reaction was allowed to warm to RT and stirred for 2 h. It was quenched with water and extracted with AcOEt. The organic layer was concentrated in vacuo. The residue was purified by column chromatography (hexane:AcOEt = 18 to 25%) to give the desired compound (1654 mg).

[0210] Reference example 289: tert-Butyl 4-[3-[[(1S)-2,2-difluoro-1-methylcyclopropyl]methoxy]-5-fluoro-4-(1,2,4-thiadiazol-5-yl)phenyl]piperazine-1-carboxylateTo a solution of (S)-2,2-difluoro-1-methylcyclopropane-1-carboxylic acid (CAS: 2199141-29-0, 231 mg) in Et2O (8 ml) was added LAH (107 mg) at RT. The mixture was stirred at RT for 3 h. It was quenched with 2N NaOH aq. (1 ml) at RT and stirred at RT for 0.5 h. Then Et2O and MgSO4were added. It was filtered with Celite and the filtrate was concentrated in vacuo to give colorless oil. The crude was dissolved to THF (10 ml) and tert-butyl 4-[3,5-difluoro-4-(1,2,4-thiadiazol-5-yl)phenyl]piperazine-1-carboxylate (540 mg) was added. Then NaH (55%, 246 mg) was added at RT. The mixture was stirred at RT for 2 h. It was quenched with NH4Cl aq. and water and extracted with DCM. The organic layer was concentrated in vacuo. The residue was purified by column chromatography (hexane:AcOEt) to give the desired compound (306 mg).

[0211] Reference example 290: tert-Butyl 4-[3,5-difluoro-4-(1,2,4-thiadiazol-5-yl)phenyl]piperazine-1-carboxylateA mixture of tert-butyl 4-[3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine-1-carboxylate (3000 mg), 5-bromo-1,2,4-thiadiazole (3500 mg), XantPhos Pd G4 (170 mgl) and K3PO4(3002 mg) in toluene / H2O (10 / 1) (15 ml) was stirred at 90°C for 0.5 h. After cooling to RT, it was quenched with NH4Cl aq. and extracted with AcOEt. The organic layer was washed with brine, dried over Na2SO4and concentrated in vacuo. The product was washed with IPE to give the desired compound (2080 mg).

[0212] Reference example 291: tert-Butyl 4-[3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine-1-carboxylateTo a solution of tert-butyl 4-(3,5-difluorophenyl)piperazine-1-carboxylate (4700 mg) in dry THF (30 ml) under an atmosphere of N2at -78°C was added BuLi (17 ml). The reaction was stirred for 0.5 h at -78°C followed by the addition of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (6.7 ml). The reaction was allowed to warm 0°C and stirred for 10 min. It was quenched with NH4Cl aq. and extracted with AcOEt. The organic layer was concentrated in vacuo. The residue was diluted with Hexane (50 ml), then white solid was appeared. It was filtered and washed with hexane to give the desired compound (3270 mg).

[0213] Reference example 292: tert-Butyl 4-(3,5-difluorophenyl)piperazine-1-carboxylateTo a solution of 1-bromo-3,5-difluorobenzene (2.98 ml), tert-butyl 1-piperazinecarboxylate (5.79 g), NaOtBu (4.98 g) and JohnPhos (0.773 g) was added Pd(OAc)2(0.291 g) at RT and stirred for 18 h at 100°C. It was quenched with H2O and extracted with AcOEt. The organic layer was concentrated in vacuo and purified with column (Hexane AcoEt) to give the desired compound (7.35 g)

[0214] Reference example 298: tert-Butyl (S)-3-(3-((2,2-difluoro-1-methylcyclopropyl)methoxy)-4-(1,2,4-thiadiazol-5-yl)phenoxy)azetidine-1-carboxylateThe tube was charged with (S)-5-(4-chloro-2-((2,2-difluoro-1-methylcyclopropyl)methoxy)phenyl)-1,2,4-thiadiazole (200 mg), N-Boc-3-hydroxyazetidine (328 mg), Cs2CO3(617 mg), RockPhos Pd G3 (26.5 mg) and toluene (4 ml) at RT under N2atmosphere. The reaction mixture was evacuated and backfilled with N2three times. The reaction mixture was stirred at 100°C for 3 h. To the reaction mixture was diluted with H2O and DCM at RT. The organic layer was separated through a phase separator and concentrated under reduced pressure. The crude was purified by silica gel column chromatography (AcOEt / hexane) to give the product (275 mg).

[0215] Reference example 304: tert-Butyl 3-(4-chloro-3-fluorophenyl)-3-hydroxyazetidine-1-carboxylateThe flask was charged with 4-bromo-1-chloro-2-fluorobenzene (1.754 ml) and THF (40 ml). To the mixture was added isopropylmagnesium chloride lithium chloride complex (19.83 ml) at RT. The reaction mixture was stirred at RT for 0.5 h. To the mixture was added 1-Boc-3-azetidinone (4.90 g) at RT. The reaction mixture was stirred at RT for 18 h. To the mixture was added H2O and the reaction mixture was filtered. The solid was dissolved by AcOEt and washed with brine. The organic layer was dried over Na2SO4and concentrated under reduced pressure. The crude was purified by silica gel column chromatography (AcOEt / hexane) to give tert-butyl 3-(4-chloro-3-fluorophenyl)-3-hydroxyazetidine-1-carboxylate (3.3 g).

[0216] Reference example 307: 2-Chloro-4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridineA flask was charged with Di-mu-methoxobis(1,5-cyclooctadiene)diiridium (I) (0.066 g), 4,4'-di-tert-butyl-2,2'-dipyridyl (0.054 g), (Bpin)2(1.270 g) and 2-chloro-4-fluoropyridine (0.903 ml). To the mixture was added THF (15 ml) and the mixture was stirred at 80°C for 18 h under N2. The solvent was evaporated. The mixture was concentrated and purified by silica gel column chromatography (AcOEt / hexane) to give 2-chloro-4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.5 g).

[0217] Reference example 310: 2-(3-((4-Methyltetrahydro-2H-pyran-4-yl)methoxy)-4-(1,2,4-thiadiazol-5-yl)phenyl)ethan-1-olTo a solution of 5-(2-((4-methyltetrahydro-2H-pyran-4-yl)methoxy)-4-vinylphenyl)-1,2,4-thiadiazole was added 1 M borane-tetrahydrofuran complex in THF (636 μl) at 0°C and the mixture was stirred at RT for 15 h. It was cooled to 0°C and 1 M NaOH aq. (289 μl) and hydrogen peroxide (30% in water) (118 μl) were added. The mixture was stirred at RT for 5 h. It was quenched with water and extracted with AcOEt. The organic layer was washed with brine, dried over Na2SO4and concentrated in vacuo. The residue was purified by column chromatography (hexane:AcOEt = 70:30 to 50:50) to give the desired compound (25.6 mg).

[0218] Reference example 322: 2,6-Dichloro-3-fluoro-5-(1,2,4-thiadiazol-5-yl)pyridineTo a solution of 3-bromo-2,6-dichloro-5-fluoropyridine (CAS: 152840-66-9, 4.5 g, 18.5 mmol) in THF (20 mL) at -78°C under N2was added isopropylmagnesium bromide, lithium chloride complex (1.3 M in THF, 14.9 mL) and the reaction was stirred at the same temperature for 1 h. The reaction was allowed to warm up to -20°C and ZnCl2(0.7 M in THF, 26.4 mL) was added thereto. After 20 min, 5-bromo-1,2,4-thiadiazole (6.1 g, 36.9 mmol) and Pd(PPh3)4(1.1 g) were added. The reaction was then stirred at 50°C overnight. The reaction was quenched with NH4Cl aq. and extracted with DCM. The organic phase was concentrated in vacuo and the crude was purified by column chromatography (SiO2, AcOEt / isohexane) to give the desired product (3.1g).

[0219] Reference example 323: 1-[6-Chloro-3-fluoro-5-(1,2,4-thiadiazol-5-yl)pyridin-2-yl]-4-(oxetan-3-yl)piperazineDIPEA (5.4 mL, 31.1 mmol) was added to a solution of 1-(oxetan-3-yl)piperazine (4.9 g, 34.8 mmol) and 2,6-dichloro-3-fluoro-5-(1,2,4-thiadiazol-5-yl)pyridine (4.6 g) in NMP (29.0 mL) and the reaction was stirred at RT for 1.5 h. Water (10 mL) was added and the reaction mixture was stirred for 30 min. The resulting precipitate was collected by filtration, washed with water and dried in vacuo to give the desired product (5.9 g).

[0220] Reference example 326: (2,2-Difluoro-1-(fluoromethyl)cyclopropyl)methanolA mixture of KF (36.0 g) and 2,2'-((oxybis(ethane-2,1-diyl))bis(oxy))bis(ethan-1-ol) (1.0 L) was stirred at 60°C for 1 h. 1,1-Difluoro-5,7-dioxa-6-thiaspiro[2.5]octane 6,6-dioxide (109 g) was added to the mixture and stirring was continued for 5 h. Water (30.0 mL) and silicon dioxide (50 g) were added followed by sulfuric acid (55.2 g). The mixture was stirred at RT for 1 h. The mixture was diluted with water (1.5 L) then basified with K2CO3(150.0 g). The mixture was filtered and extracted with TBME. The organic phase was concentrated in vacuo and the residue was purified by chromatography (SiO2, AcOEt / pentane) to give the desired product (53.7 g).

[0221] Reference example 329: tert-Butyl 4-(5-((6,6-difluoro-3-oxabicyclo[3.1.0]hexan-1-yl)methoxy)-2-fluoro-4-(1,2,4-thiadiazol-5-yl)phenoxy)piperidine-1-carboxylateA solution of 5-((6,6-difluoro-3-oxabicyclo[3.1.0]hexan-1-yl)methoxy)-2-fluoro-4-(1,2,4-thiadiazol-5-yl)phenol (601 mg), tert-butyl 4-iodopiperidine-1-carboxylate (2.53 g) and K2CO3(1.19 g, 8.61 mmol) in DMF (20.0 mL) was stirred at 80°C for 3 days. The reaction was quenched with water and extracted with AcOEt. The organic phase was concentrated in vacuo and the residue was purified by column chromatography (SiO2, AcOEt / iso-hexane) to give the desired product (569 mg).

[0222] Reference example 330: tert-Butyl (R)-8-methyl-6,9-dioxooctahydro-2H-pyrazino[1,2-a]pyrazine-2-carboxylate2-Chloroacetyl chloride (1.79 mL, 22.6 mmol) was added to a suspension of 1-(tert-butyl) 3-methyl (R)-piperazine-1,3-dicarboxylate (5.2 g) and NaHCO3(2.59 g) in DCM (25 mL) under N2at 0°C and the mixture was stirred for 3 h. The reaction was quenched with water and extracted with DCM. The organic layer was washed with NaHCO3aq. and water and concentrated in vacuo to give the desired product which was used in the next step without further purification. A solution of 1-(tert-butyl) 3-methyl (R)-4-(2-chloroacetyl)piperazine-1,3-dicarboxylate (3.5 g) in methylamine (33% Wt, 45.0 mL) was stirred at RT for 3 h. Volatiles were removed in vacuo and the residue redissolved in CHCl3(90 mL). The salts were removed by filtration and the filtrate was concentrated in vacuo. The crude product was purified by chromatography (SiO2, 0.7 M ammonia / MeOH) / DCM) to afford the desired product (3.6 g).

[0223] The other compounds of Reference Examples were manufactured in the same manner as in any of the above Reference Examples. The structural formulae and physicochemical data of the compounds of Reference Examples 1 to 335 are shown in the following table. The conditions of the SFC separation are also shown there.

[0224]

[0225] Example 10: 5-[2-(4,4-Difluorocyclohexyl)oxy-4-(4-methylpiperazin-1-yl)phenyl]-1,2,4-thiadiazole; hydrochlorideA mixture of Reference example 13 (90 mg), 1-methyl piperazine (60.4 μl), DavePhos (10.71 mg), Pd2(dba)3(14.08 mg), NaOtBu (40.5 mg) and toluene (3 ml) was heated at 80°C for 2 h. The reaction mixture was quenched with water and extracted with AcOEt. The organic phase was concentrated, and the residue was then purified by column chromatography (NH-silica; hexane:AcOEt). The resulted solid was dissolved to EtOH / AcOEt (1:1) (2 ml) and 1 M HCl-EtOH (233 μl) was added to the solution, and stirred at RT for 10 min. The reaction mixture was concentrated to give the desired product (57.4 mg).

[0226] Example 13: 5-(2-Cyclohexyloxy-4-piperidin-4-ylphenyl)-1,2,4-thiadiazole; hydrochlorideA solution of Reference example 15 (280 mg) in AcOEt (2 ml) was added 4 M HCl-AcOEt (2 ml) and the mixture was stirred at RT for 30 min (1400). It was concentrated in vacuo. The product was washed with AcOEt to give the desired product (72.5 mg).

[0227] Example 14: 5-[2-Cyclohexyloxy-4-(1-methylpiperidin-4-yl)phenyl]-1,2,4-thiadiazole; hydrochlorideTo a suspension of Example 13 (104 mg) were added Et3N (46 μL) and formaldehyde (67.6 μL). It was stirred at RT for 10 min then NaBH(OAc)3(104 mg) was added. The mixture was stirred at RT for 15 h. It was quenched with sat. NHCO3aq and extracted with DCM. The organic layer was concentrated in vacuo. The residue was purified by column chromatography (NH; hexane:AcOEt). The product was dissolved to EtOH (2 ml) and 1 M HCL-EtOH (116 μL) was added. The mixture was stirred at RT for 30 min. It was concentrated in vacuo. The product was washed with EtOH to give the desired product (23.2 mg).

[0228] Example 21: 5-[2-(4,4-Difluorocyclohexyl)oxy-4-piperidin-4-ylphenyl]-1,2,4-thiadiazole; hydrochlorideReference example 19 (1.84 g, 3.85 mmol) was dissolved to EtOH (45 ml) and Pd(OH)2 / C (360 mg) was added. H2gas was charged and the mixture was heated at 50°C for 1 h. After cooling to RT, it was filtered by Celite. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (hexane:AcOEt). The product was dissolved to AcOEt (10 ml) was added 4 M HCl-AcOEt (10 ml) and the mixture was stirred at RT for 30 min. It was concentrated in vacuo. The product was washed with AcOEt to give the desired compound (294 mg).

[0229] Example 23: 1-[4-[3-(4,4-Difluorocyclohexyl)oxy-4-(1,2,4-thiadiazol-5-yl)phenyl]piperidin-1-yl]ethanoneTo a solution of Example 21 (90 mg) and TEA (129 μl) in DCM (2ml) was added AcCl (25.3 μl). It was stirred at RT for 1 h. It was quenched with water and extracted with AcOEt. The organic layer was washed with brine, dried over Na2SO4and concentrated in vacuo. The residue was purified by column chromatography (NH-silica; hexane:AcOEt) to give the desired compound (36.0 mg).

[0230] Example 24: rac-trans-3-[5-(4-Methylpiperazin-1-yl)-2-(1,2,4-thiadiazol-5-yl)phenoxy]cyclohexan-1-ol; hydrochlorideA mixture of Reference example 20 (306 mg), 1-methyl piperazine (191 μl), DavePhos, Pd2dba3(44.6 mg, 0.043 mmol) and NaOtBu (128 mg) in toluene (3 ml) was heated at 80°C for 3 h. After cooling to RT, it was quenched with water and extracted with AcOEt. The organic layer was washed with brine, dried over Na2SO4and concentrated in vacuo. The residue was purified by column chromatography (NH-silica; hexane:AcOEt = 70:30 to 50:50). The product was dissolved to MeOH (3 ml) and 5 M HCl aq. (1.5 ml) was added. The mixture was heated at 50°C for 20 min. After cooling to RT, it was quenched with 5 M NaOH aq. and water and extracted with AcOEt. The organic layer was washed with brine, dried over Na2SO4and concentrated in vacuo. The residue was purified by column chromatography (NH-silica; AcOEt:MeOH). The product was dissolved to EtOH (2 ml) and 1 M HCl-EtOH (0.5 ml) was added to the solution. It was stirred at RT for 20 min and concentrated in vacuo. It was washed with AcOEt to give the desired compound (182 mg).

[0231] Example 25: 1-[4-[3-(4,4-Difluorocyclohexyl)oxy-4-(1,2,4-thiadiazol-5-yl)phenyl]piperidin-1-yl]-2-(dimethylamino)ethanoneTo a suspension of Example 21 (100 mg) in DCM (5 ml) were added N,N-dimethylglycine (82 mg), TEA (223 μl) and HATU (150 mg). The reaction mixture was stirred at RT for 20 h. Sat. NaHCO3aq was added to the reaction mixture. It was extracted with DCM. The organic layer was dried over Na2SO4and concentrated in vacuo. The residue was purified by column chromatography (NH-silica; hexane:AcOEt) to give the desired product (65.0 mg).

[0232] Example 27: rac-trans-3-[5-Morpholin-4-yl-2-(1,2,4-thiadiazol-5-yl)phenoxy]cyclohexan-1-olA mixture of Reference example 20 (288 mg,), morpholine (142 μl), 2-DavePhos (31.9 mg), Pd2dba3(42.0 mg) and NaOtBu (121 mg) in toluene (3 ml) was heated at 80°C for 3 h. After cooling to RT, it was quenched with water and extracted with AcOEt. The organic layer was washed with brine, dried over Na2SO4and concentrated in vacuo. The residue was purified by column chromatography (NH-silica; hexane:AcOEt). The product was dissolved to MeOH (3 ml) and 5 M HCl aq. (1.5 ml) was added. The mixture was heated at 50°C for 20 min. After cooling to RT, it was quenched with 5 M NaOH aq. and water and extracted with AcOEt. The organic layer was washed with brine, dried over Na2SO4and concentrated in vacuo. The residue was purified by column chromatography (NH-silica; hexane:AcOEt) to give the desired compound (144 mg).

[0233] Example 28: 4-[3-[rac-trans-3-Methoxycyclohexyl]oxy-4-(1,2,4-thiadiazol-5-yl)phenyl]morpholineExample 27 (100 mg) in THF (4 ml) was added 55% NaH (18.11 mg) at 0°C. It was stirred at RT for 10 min. Then it was cooled to 0°C. MeI (34.8 μl) was added to the mixture at 0°C and it was stirred at RT for 16 h. It was quenched with water and sat. NH4Cl aq. and extracted with AcOEt. The organic layer was washed with brine, dried over Na2SO4and concentrated in vacuo. The residue was purified by column chromatography (NH-silica; hexane:AcOEt = 90:10 to 70:30) to give the desired compound (46.8 mg).

[0234] Example 29: trans-4-[5-(4-Methylpiperazin-1-yl)-2-(1,2,4-thiadiazol-5-yl)phenoxy]cyclohexan-1-olA mixture of Reference example 25 (173.5 mg) and 5 M HCl aq. (1 ml) in MeOH (3 ml) was heated at 50°C for 30 min. After cooling to RT, it was quenched with 5 M NaOH aq. and water and extracted with AcOEt. The organic layer was washed with brine, dried over Na2SO4and concentrated in vacuo. The residue was purified by column chromatography (NH-silica; AcOEt:MeOH). The resulting solid was washed with AcOEt to give the desired compound (76.9 mg).

[0235] Example 32: 5-[2-(4,4-Difluorocyclohexyl)oxy-4-[1-(2-methoxyethyl)piperidin-4-yl]phenyl]-1,2,4-thiadiazole; hydrochlorideA mixture of Example 21 (100 mg), 2-Bromoethyl methyl ether (27.2 μl), K2CO3(89 mg) and KI (48.1 mg) in MeCN (10 ml) was heated at 80°C overnight. After cooling to RT, it was quenched with water and extracted with AcOEt. The organic layer was washed with brine, dried over Na2SO4and concentrated in vacuo. The residue was purified by column chromatography (NH-silica; hexane:AcOEt = 70:30 to 50:50). The product was dissolved to EtOH (3 ml) and 1 M HCl-EtOH (0.264 ml) was added. The mixture was stirred at RT for 10 min. It was concentrated in vacuo. The product was washed with AcOEt to give the desired compound (80.2 mg).

[0236] Example 36: 5-[2-(4,4-Difluorocyclohexyl)oxy-4-(oxetan-3-yloxy)phenyl]-1,2,4-thiadiazoleThe MW tube was charged with Reference example 13 (100 mg), 3-hydroxyoxetane (67.2 mg), RockPhos Pd G3 (12.67 mg) Cs2CO3(296 mg) and toluene (2 ml) at RT. The reaction mixture was stirred at 100°C under MW irradiation for 3 h. To the reaction mixture was diluted with water and DCM at RT. The organic layer was separated through a phase separator and concentrated under reduced pressure to give crude. The residue was purified by silica gel column chromatography (AcOEt / hexane) to give the product (65 mg).

[0237] Example 59: (9aS)-8-[3-[(4-Methyloxan-4-yl)methoxy]-4-(1,2,4-thiadiazol-5-yl)phenyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazineThe MW tube was charged with Reference example 4 (75 mg), (S)-octahydropyrazino[2,1-c][1,4]oxazine dihydrochloride (74.5 mg), DavePhos (9.09 mg), NaOtBu (101 mg) and Pd2(dba)3(10.57 mg) under N2atmosphere. To the mixture was added toluene (2 ml) at RT. The reaction mixture was evacuated and backfilled with N2three times. The reaction mixture was stirred at 100°C for 3 h. To the reaction mixture was diluted with water and DCM at RT. The organic layer was separated through a phase separator and concentrated under reduced pressure to give crude. The residue was purified by silica gel column chromatography (AcOEt / hexane then add MeOH 0 to 10%) to give the product (71 mg).

[0238] Example 64: 6-[3-[(4-Methyloxan-4-yl)methoxy]-4-(1,2,4-thiadiazol-5-yl)phenyl]-2-oxa-6-azaspiro[3.3]heptaneA mixture of Reference example 4 (80 mg), 2-oxa-6-azaspiro[3.3]heptane (44.4 μl), DavePhos (9.69 mg), Pd2(dba)3(11.3 mg), NaOtBu (39.1 mg) and toluene (3 ml) was heated at 90°C for 5 h. The reaction mixture was quenched with water and extracted with AcOEt. The organic phase was concentrated, and the residue was then purified by column chromatography (NH-silica;hexane:AcOEt). The resulted solid was recrystallized from AcOEt to give the desired compound (50.2 mg).

[0239] Example 114: 5-[2-[(4-Methyloxan-4-yl)methoxy]-4-(4-methylpiperazin-1-yl)phenyl]-1,2,4-thiadiazole; hydrochlorideA mixture of Reference example 4 (50 mg), 1-methylpiperazine (25.6 μl), Pd2(dba)3(7.05 mg), DavePhos (6.06 mg) and NaOtBu (44.4 mg) in toluene (2 ml) was degassed and backfilled with N2. The reaction was heated at 100°C for 3 h. The reaction mixture was charged to silica gel column and eluted by (AcOEt then MeOH / AcOEt = 1 / 4). The residue was dissolved into AcOEt and treated by 4M HCl in AcOEt (38.5 μl). The precipitate was collected by filtration. (58 mg).

[0240] Example 125: 5-[5-Methyl-2-[(4-methyloxan-4-yl)methoxy]phenyl]-1,2,4-thiadiazoleA mixture of Reference example 107 (80 mg), trimethylboroxine (155 mg), K2CO3(102 mg) and PEPPSI-iPr (33.6 mg) in dioxane (2 ml) was heated at 80°C overnight under N2. The reaction was charged to silica gel column and eluted by (AcOEt / hexane = 1 / 10 to 1 / 2). The fraction without starting material was concentrated (17 mg).

[0241] Example 146: 3-[3-[(4-Methyloxan-4-yl)methoxy]-4-(1,2,4-thiadiazol-5-yl)phenyl]morpholine; oxalateA mixture of Reference example 31 (100 mg), SnAP M Reagent (100 μl) and MS 4A (100 mg) in DCM (4 ml) was stirred at RT for 2.5 h. It was filtered and the filtrate was concentrated in vacuo. To another flask were added Cu(OTf)2(114 mg), 2,6-lutidine (36.6 μl) and HFIP (1 ml). The mixture was stirred at RT for 1 h. To the mixture was added a solution of the resulting imine in DCM (4 ml). The combined mixture was stirred at RT overnight. It was quenched with NH3(MeOH solution) and H2O and extracted with DCM. The organic layer was concentrated in vacuo. The residue was purified by column chromatography (NH-silica; hexane:AcOEt = 70:30 to 50:50 then AcOEt). The product was dissolved to EtOH (2 ml) and oxalic acid (10.75 mg) was added thereto. The mixture was stirred at RT for 5 min. It was concentrated in vacuo. The product was washed with EtOH to give the desired product (30.8 mg).

[0242] Example 152: 5-[5-Fluoro-2-[(4-methyloxan-4-yl)methoxy]-4-(4-methylpiperazin-1-yl)phenyl]-1,2,4-thiadiazoleA mixture of Reference example 99 (70 mg), 1-methylpiperazine (40.9 mg), Pd2dba3(9.35 mg), DavePhos (8.04 mg) and NaOtBu (49.1 mg) in toluene (2 ml) was heated at 100°C for 2 h under N2. The reaction was charged to silica gel column and eluted by (AcOEt then MeOH / AcOEt = 1 / 9 to 1 / 3). The residue was triturated with hexane to give the desired product (49 mg).

[0243] Example 171: 5-[2-[(4-Methyloxan-4-yl)methoxy]-4-[2-(oxetan-3-yl)-2,7-diazaspiro[3.4]octan-7-yl]phenyl]-1,2,4-thiadiazoleA mixture of Reference example 4 (160 mg), tert-butyl 2,6-diazaspiro[3.4]octane-2-carboxylate (130 mg), DavePhos (19 mg), Pd2dba3(23 mg) and NaOtBu (70 mg) in toluene (4 ml) was heated at 90°C. After cooling to RT, it was quenched with water and extracted with DCM. The organic layer was concentrated in vacuo. The residue was purified by column chromatography (NH-silica; hexane:AcOEt = 70:30 to 50:50 then AcOEt). The product ( was dissolved to DCM (4 ml) and TFA (2 ml) was added. The mixture was stirred at RT. It was concentrated with toluene. It was neutralized with 5 M NaOH aq. It was extracted with CHCl3. The organic layer was concentrated in vacuo. To the product were added 3-oxetanone (41.6 μl) NaBH(OAc)3(138 mg) and DCE (3 ml). The mixture was stirred at RT. It was quenched with sat. NaHCO3aq. and extracted with DCM. It was concentrated in vacuo. The residue was purified by column chromatography (NH-silica; hexane:AcOEt = 50:50 then AcOEt) to give the desired product (78.8 mg).

[0244] Example 186: 5-[4-(2,6-Diazaspiro[3.3]heptan-2-yl)-2-[[1-(difluoromethyl)cyclopropyl]methoxy]phenyl]-1,2,4-thiadiazoleTo a solution of Reference example 37 (250 mg) in DCM (4 ml) was added TFA and the mixture was stirred at RT for 30 min. It was concentrated with toluene in vacuo. To the residue was added sat. NaHCO3aq and the precipitate was collected by filtration. It was washed with Et2O to give the desired product (161 mg).

[0245] Example 189: 5-[4-[4-(Oxetan-3-yl)piperazin-1-yl]-2-[[rac-cis-2,2-difluoro-5-oxaspiro[2.4]heptan-7-yl]oxy]phenyl]-1,2,4-thiadiazoleThe MW tube was charged with Reference example 70 (120 mg), 1-(oxetan-3-yl)piperazine oxalate (60.1 μl), DavePhos-Pd-G3 (13.28 mg) and 2 N NaOH (313 μl) under N2atmosphere. To the mixture was added tBuOH (1.2 ml) at RT. The reaction mixture was evacuated and backfilled with N2three times. The reaction mixture was stirred at 100°C for 1 h. The mixture was diluted with water and DCM at RT. The organic layer was separated through a phase separator and concentrated under reduced pressure to give crude. The residue was purified by NH silica gel column chromatography (AcOEt / hexane = 0% to 100) to give the desired product (55 mg).

[0246] Example 196: 5-[4-(2,6-Diazaspiro[3.3]heptan-2-yl)-2-[[4-(difluoromethyl)oxan-4-yl]methoxy]phenyl]-1,2,4-thiadiazoleA mixture of Reference example 116 (250 mg), tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (CAS:1041026-70-3, 192 mg), Pd2(dba)3(31.7 mg), DavePhos (27.3 mg) and NaOtBu (133 mg) in toluene (6 ml) was heated at 100°C for 2 h under N2. The insoluble material was filtered through a pad of Celite and washed with AcOEt. The filtrate was concentrated and the residue was purified by silica gel column chromatography (AcOEt / hexane = 1 / 3 to 1 / 1). (0.27g as pale yellow powder). To a solution of the pale yellow powder (0.27 g) in DCM (5 ml) was added TFA (5 ml) and this was stirred at RT for 1h. The reaction was concentrated and the residue was purified by short-pass basic silica gel column chromatography (MeOH / AcOEt as an eluent). The filtrate was concentrated to give the desired product (194 mg).

[0247] Example 201: 5-[2-[(4-Methyloxan-4-yl)methoxy]-4-(1-methylpyrazol-3-yl)phenyl]-1,2,4-thiadiazoleThe MW tube was charged with 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (77 mg), Reference example 4 (100 mg), K2CO3(128 mg) and DavePhos-Pd-G3 (11.75 mg) under N2atmosphere. To the mixture was added dioxane:H2O (3:1) (2 ml) at RT. The reaction mixture was evacuated and backfilled with N2three times. The reaction mixture was stirred at 100°C for 3 h. The mixture was diluted with water and DCM at RT. The organic layer was separated through a phase separator and concentrated under reduced pressure to give crude. The residue was purified by silica gel column chromatography (AcOEt / hexane = 50% to 100) to give the product (87 mg).

[0248] Example 226: N-(1-Methylazetidin-3-yl)-3-[(4-methyloxan-4-yl)methoxy]-4-(1,2,4-thiadiazol-5-yl)benzamideTo a solution of Reference example 92 (101 mg, 0.207 mmol) in DCM (3 ml) was added TFA (0.5 ml, 6.49 mmol) at 0°C. The mixture was stirred for 5h. The mixture was concentrated, diluted with sat. NaHCO3aq. and extracted with DCM. The organic layer was dried over Na2SO4and concentrated. The residue was purified by column chromatography (NH, AcOEt / MeOH=8 / 2) to give the amine compound as white powder.To a solution of the amine compound (33 mg, 0.085 mmol) in DCM (3 ml) were added formaldehyde (10 μl, 0.127 mmol), AcOH (19.45 μl, 0.340 mmol) and sodium triacetoxyborohydride (36.0 mg, 0.170 mmol) at RT. The mixture was stirred for 30 min. The reaction mixture was diluted with sat. NaHCO3aq. and extracted with DCM. The organic layer was concentrated. The residue was purified by column chromatography (NH, AcOEt / MeOH=100 / 0-95 / 5) to give the desired product(23 mg).

[0249] Example 230: 3-[[(1S)-2,2-Difluoro-1-methylcyclopropyl]methoxy]-N-(1-methylazetidin-3-yl)-4-(1,2,4-thiadiazol-5-yl)benzamideTo a solution of Reference example 93 (146 mg, 0.304 mmol) in DCM (10 ml) was added TFA (1 ml) at RT. The mixture was stirred for 5 h. The mixture was concentrated and co-evaporated with toluene. The residue was purified by column chromatography (NH, AcOEt / MeOH=8 / 2) to give the amine compound as white powder.To a solution of the amine compound (48 mg) in DCM (3 ml) were added formaldehyde (14.90 μl), AcOH (28.9 μl) and sodium triacetoxyborohydride (53.5 mg) at RT. The mixture was stirred for 30 min. The reaction mixture was diluted with sat. NaHCO3aq. and extracted with DCM. The organic layer was concentrated. The residue was purified by column chromatography (NH, AcOEt / MeOH=100 / 0-95 / 5) to give the desired product (39 mg).

[0250] Example 242: 1-[4-[3-[[(1S)-2,2-Difluoro-1-methylcyclopropyl]methoxy]-4-(1,2,4-thiadiazol-5-yl)phenyl]piperidin-1-yl]ethanoneThe flask was charged with Reference example 89 (180 mg), TFA (1489 μl), and DCM (2 ml) under N2atmosphere at RT. The reaction mixture was stirred at RT for 0.5 h. The mixture was concentrated under reduced pressure to give the crude. It was treated with DCM (2 ml), TEA (216 μl) and AcCl (41.2 μl) at RT for 1 h. The mixture was quenched with water. The mixture was extracted with DCM and the organic layers were dried over Na2SO4and concentrated under reduced pressure to give crude. The residue was purified by amino silica gel column chromatography (AcOEt / hexane = 50-100% then add 5% of MeOH) to give the desired product (108 mg).

[0251] Example 249: 1-[6-(Cyclohexylmethoxy)-5-(1,2,4-thiadiazol-5-yl)pyridin-2-yl]-4-methylpiperazineA solution of KOtBu (0.017 g) and cyclohexanemethanol (0.019 mL) in MeCN (1.0 mL) was stirred at RT for 15 min before addition of 6-chloro-2-fluoro-3-(1,2,4-thiadiazol-5-yl)pyridine (0.03 g). After 5 min Cs2CO3(0.18 g), N-methylpiperazine (0.05 mL) and MeCN (1 mL) were added and the reaction was stirred at 80°C for 2 h. The solvent was removed and DMF (1 mL) was added and heated at 100°C overnight. The reaction was concentrated and the residue purified by column chromatography (KP-NH-Sil, petrol:AcOEt) to give the desired product (0.02 g).

[0252] Example 290: 5-[2-(2-Methylpropoxy)-4-(oxan-4-yloxy)phenyl]-1,2,4-thiadiazoleTo a solution of Reference example 236 (0.05 g), 4-hydroxytetrahydropyran (0.023 mL) and TPP (0.055 g) in THF (0.7 mL) was added DIAD (0.041 mL) dropwise. The reaction was stirred at RT for 2 h. The reaction was concentrated and the residue purified by column chromatography (KP-Sil, petrol:AcOEt) and preparative HPLC to give the desired product (0.007 g).

[0253] Example 304: 2,2-Dimethyl-3-{5-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-2-(1,2,4-thiadiazol-5-yl)phenoxy}propan-1-olA mixture of Reference example 133 (185 mg), (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane (85 mg), Pd2dba3(26 mg), DavePhos (22 mg) and NaOtBu (82 mg) in toluene (2 mL) was stirred at 90°C under N2in a sealed vial for 3 h. The reaction was partitioned between water and AcOEt. The aqueous phase was acidified to pH 3 with 1M HCl and was extracted with AcOEt. The organic phase was concentrated in vacuo. The crude material was dissolved in THF (2 mL) and LAH (1M in THF, 1.2 mL) was added at -78°C. The reaction was stirred at the same temperature for 1.5 h. The reaction was quenched with water and extracted with DCM. The crude material was purified by silica gel column chromatography (AcOEt / petrol) to give the desired product (12 mg).

[0254] Example 305: (1S,4S)-5-{3-[(4-Methyloxan-4-yl)methoxy]-4-(1,2,4-thiadiazol-5-yl)phenyl}-2-oxa-5-azabicyclo[2.2.1]heptaneA suspension of Reference example 4 (100 mg), (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (46 mg), Pd2(dba)3(14 mg), DavePhos (12 mg), NaOtBu (44 mg) in toluene (10 mL) and water (0.5 mL) and refluxed under N2for 3 h. The reaction was quenched with water and extracted with AcOEt. The filtrate was concentrated and the residue purified by column chromatography (KP-Sil, petrol:AcOEt) to give the desired product (87 mg).

[0255] Example 322: 1-{3-[(4-Methyloxan-4-yl)methoxy]-4-(1,2,4-thiadiazol-5-yl)phenyl}-4-(oxetan-3-yl)piperazineA suspension of Reference example 4 (200 mg), 1-(oxetan-3-yl)piperazine (96 mg), Pd2(dba)3(28 mg), DavePhos (24 mg), NaOtBu (92 mg) in toluene (5 mL) and water (1 drop) was refluxed under N2for 1 h. The reaction was filtered through Celite and the filtrate was concentrated. The residue was purified by column chromatography (KP-NH, petrol:AcOEt). The product was then triturated in MeOH / water to give the desired product (181 mg).

[0256] Example 344: 1-(3-{[4-(Fluoromethyl)oxan-4-yl]methoxy}-4-(1,2,4-thiadiazol-5-yl)phenyl)-4-(oxetan-3-yl)piperazine; hydrochloridestep 1:A mixture of Reference example 5 (4.53 g), 1-(oxetan-3-yl)piperazine oxalate (2.349 g), Pd2(dba)3(0.484 g) and DavePhos (0.416 g) in tBuOH (45 ml) was heated at 100°C for 3 h under N2. The reaction was extracted with DCM and dried over Na2SO4. The inorganic salt was removed and the filtrate was concentrated. The residue was purified by silica gel column chromatography (AcOEt to MeOH / AcOEt = 1 / 20: basic silica gel as inject column). The fractions were concentrated and the residue was crystalized from 20v of EtOH. The precipitate was collected and washed with cooled EtOH. The residue was purified by silica gel column chromatography (AcOEt to MeOH / AcOEt = 1 / 20: basic silica gel as inject column). The fractions were concentrated and the residue was crystalized from 20v of EtOH. The precipitate was collected and washed with cooled EtOH. 3.98 g was obtained as a pale yellow solid (free form).step 2:To a suspension of the free form (19.3 g) in IPA / H2O (600 ml / 100 ml) was added 5N HCl aq. (9.47 ml). The resultant solution was stirred overnight. IPA was removed (~600 ml) and diluted with H2O (100ml), then the reaction was cooled in ice bath. The precipitate was collected and washed with cooled water (100 ml). (28.38g wet). This was dried under reduced pressure at 35°C overnight to obtain the desired product (20.23 g).

[0257] Example 348: 2-[(1S,4S)-5-{3-[(4-Methyloxan-4-yl)methoxy]-4-(1,2,4-thiadiazol-5-yl)phenyl}-2,5-diazabicyclo[2.2.1]heptan-2-yl]ethan-1-olA solution of Reference example 245 (680 mg) in 4M HCl (dioxane, 7 mL) and MeOH (0.5 mL) was stirred at RT for 1 h. The solvent was removed in vacuo and the residue was used in the next step without further purification. AcOH (0.1 ml) and NaBH(OAc)3(377 mg) were added to a solution of intermediate in DCM (2 mL) containing DIPEA (0.12 mL) and ethyl glyoxylate (0.1 mL). The mixture was tired at RT overnight. The reaction was quenched with NaHCO3and extracted with DCM. The crude material was purified by column chromatography (SiO2, AcOEt / petrol). The product was suspended in THF (3 mL) at 0°C and LAH (1 M in THF, 2.3 mL) was added. The mixture was stirred at RT for 1 h. The reaction was quenched with water and extracted with DCM. The crude material was purified by column chromatography (SiO2, AcOEt / MeOH) to give the desired product (85 mg).

[0258] Example 351: 2-(Dimethylamino)-1-(4-{3-[(4-methyloxan-4-yl)methoxy]-4-(1,2,4-thiadiazol-5-yl)phenyl}piperidin-1-yl)ethan-1-one; fromic acidReference example 248 (120 mg) and 10% Pd / C (60 mg) were mixed in EtOH under N2. The mixture was then shaken at RT under H2for 30 min. The reaction was filtered and concentrated. The residue was purified by preparative HPLC to afford the desired product (70 mg).

[0259] Example 357: 2-[(1S,4S)-5-[3-(2-Methylpropoxy)-4-(1,2,4-thiadiazol-5-yl)phenyl]-2,5-diazabicyclo[2.2.1]heptan-2-yl]ethan-1-olA solution of Reference example 250 (100 mg), 2-[(tert-butyldimethylsilyl)oxy]acetaldehyde (79 mg) and NaBH(OAc)3(160 mg) in DCM (2 mL) was stirred at RT for 1 h. The reaction was quenched with HCl (4M in dioxane) and extracted with AcOEt. The organic phase was concentrated in vacuo and the crude material was purified by column chromatography (SiO2, AcOEt / MeOH) to give the desired product (13 mg).

[0260] Example 369: N,1-Dimethyl-N-{3-[(4-methyloxan-4-yl)methoxy]-4-(1,2,4-thiadiazol-5-yl)phenyl}azetidin-3-amineA suspension of Reference example 4 (100 mg), N,1-dimethylazetidin-3-amine (37 mg), Pd2(dba)3(14 mg), DavePhos (12 mg), NaOtBu (44 mg) in toluene (5 mL) and water (1 drop) and refluxed under N2for 1 h. The reaction was filtered through Celite and the filtrate was concentrated. The residue was purified by preparative HPLC to give the desired product (81 mg).

[0261] Example 376: 4-{3-[(4-Methyloxan-4-yl)methoxy]-4-(1,2,4-thiadiazol-5-yl)phenyl}-1-(oxetan-3-yl)piperidineAcOH (0.05 mL) and NaBH(OAc)3(130 mg) were added to a solution of Reference example 247 (100 mg), 3-oxetanone (0.02 mL) and DIPEA (0.04 mL) in DCM (2 mL). The reaction was stirred at RT overnight. The reaction was quenched with water and extracted with AcOEt. The organic phase was concentrated in vacuo and the crude material was used in the next step without further purification. The residue was stirred under H2with Pd / C (10% w / w, 50 mg) in EtOH (6 mL) at RT for 30 min. The reaction was filtered through Celite and the filtrate was concentrated in vacuo to give the desired product (32 mg).

[0262] Example 391: 1-(3-{[(1S)-2,2-Difluoro-1-methylcyclopropyl]methoxy}-4-(1,2,4-thiadiazol-5-yl)phenyl)-4-(oxetan-3-yl)piperazineA suspension of Reference example 6 (500 mg), 1-(oxetan-3-yl)piperazine (247 mg), Pd2(dba)3(72 mg), DavePhos (62 mg), NaOtBu (228 mg) in toluene (10 mL) and water (0.5 mL) and refluxed under N2for 2 h. The reaction mixture was filtered through Celite and the filtrate concentrated. The residue was purified by reverse phase chromatography (MeCN:H2O:0.1 formic acid) followed by trituration in MeOH to give the desired product (357 mg).

[0263] Example 402: (1S,2R)-2-Methyl-2-({5-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-2-(1,2,4-thiadiazol-5-yl)phenoxy}methyl)cyclopentan-1-olTo a solution of Reference example 254 (200 mg) in THF (3 mL) was added TBAF (1.6 mL, 1 M in THF solution). The reaction was heated at 50°C for 30 min. The reaction was quenched with NaHCO3aq. (10 mL) and extracted with AcOEt. The combined organic layers were concentrated and the residue was purified by column chromatography (KP-Sil, isohexane:AcOEt) to afford the racemic product which was then separated by chiral SFC to give the two isomers.

[0264] Example 406: 1-Methyl-4-[methyl({3-[(4-methyloxan-4-yl)methoxy]-4-(1,2,4-thiadiazol-5-yl)phenyl})amino]pyrrolidin-2-oneTo a solution of Reference example 256 (0.13 g) in DMF (2 mL) NaH (0.012 g, 60% weight) was added at 0°C and the mixture stirred under N2at RT for 5 min. Then MeI (0.061 ml) was added and the reaction mixture was stirred at RT for 1 hour. The reaction mixture was quenched with water and extracted with AcOEt. The organic layer was washed with brine and concentrated. The crude product was purified by column chromatography (KP-Sil, (0.7 M Ammonia / MeOH) / DCM) to afford the desired product (100 mg).

[0265] Example 410: 1-(3-{[(1S,5S)-3-Oxabicyclo[3.1.0]hexan-1-yl]methoxy}-4-(1,2,4-thiadiazol-5-yl)phenyl)-4-(oxetan-3-yl)piperazineA suspension of Reference example 145 (19.0 g), 1-(oxetan-3-yl)piperazine (9.6 g), Pd2(dba)3(2.8 g), DavePhos (2.4 g), NaOtBu (8.9 g) in toluene (200 mL) and water (1.7 mL) and refluxed under N2for 1 h. DCM (150 mL) and saturated NaHCO3aq. (50 mL) were added to the reaction mixture, and the organic phase was concentrated. The residue was triturated in MeOH and the solid collected by filtration. Obtained 3.5 g of desired product.

[0266] Example 419: N,N-Dimethyl-(2-{3-[(4-methyloxan-4-yl)methoxy]-4-(1,2,4-thiadiazol-5-yl)phenoxy}ethyl)amineCs2CO3(0.301 g), Reference example 4 (0.100 g), 2-(dimethylamino)ethanol (0.031 mL) and 1,4-dioxane (5 mL) were added to a vial and evacuated then backfilled with N2. The mixture was sparged for 10 minutes with nitrogen then t-BuXPhos Pd G3 (0.024 g) was added. The mixture was sparged with N2for a further 5 min then heated to 90°C and stirred for 40 h. The mixture was cooled to RT and filtered through celite. The filtrate was concentrated and the residue was purified by column chromatography (KP-Sil, DCM: MeOH). The residual oil was triturated with tert-butyl methyl ether, and the solids collected to afford the product (20 mg).

[0267] Example 447: 2-(3-{[(1S)-2,2-Difluoro-1-methylcyclopropyl]methoxy}-4-(1,2,4-thiadiazol-5-yl)phenyl)-6-(oxetan-3-yl)-2,6-diazaspiro[3.3]heptanestep 1: BuchwaldA suspension of Reference example 6 (5.0 g), tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate hemioxylate (5.4 g), Pd2(dba)3(1.4 g), DavePhos (1.2 g), NaOtBu (10.8 g) in toluene (100 mL) and water (0.5 mL) and refluxed under N2for 2 h. The reaction mixture was filtered through Celite and the filtrate concentrated. The residue was purified by column chromatography (KP-NH, petrol:AcOEt) to give the desired product (2.7 g).step 2: Boc_deprotectionTo a solution of tert-butyl 6-(3-{[(1S)-2,2-difluoro-1-methylcyclopropyl]methoxy}-4-(1,2,4-thiadiazol-5-yl)phenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (1.0 g) in DCM (10 mL) was added TFA (2 mL). The reaction was stirred at RT for 30 min. The reaction was quenched with NaHCO3aq. and extracted with DCM. The organic phase was concentrated to give the desired product (800 mg).step 3: Reductive aminationNaBH(OAc)3(20 g) was added to a solution of 2-(3-{[(1S)-2,2-difluoro-1-methylcyclopropyl]methoxy}-4-(1,2,4-thiadiazol-5-yl)phenyl)-2,6-diazaspiro[3.3]heptane (14.3 g), oxetan-3-one (4.1 g) in DCM (140 mL) and MeCN (35 mL). After 1 hour at RT another portion of NaBH(OAc)3(10 g) was added and the reaction was stirred at RT overnight. The reaction was quenched with sat. NaHCO3aq. and extracted with DCM. The organic phase was concentrated and the crude material was purified by column chromatography (KP-Sil, MaOH:DCM:0.2M NH3) followed by recrystallisation in acetone to give the desired product (9.2 g).

[0268] Example 464: (1S,2R)-2-Methyl-2-({5-[4-(oxetan-3-yl)piperazin-1-yl]-2-(1,2,4-thiadiazol-5-yl)phenoxy}methyl)cyclopentan-1-olTo a suspension of Reference example 219 (251 mg), Pd2(dba)3(26.2 mg), DavePhos (22.50 mg) and NaOtBu (165 mg) in toluene (1.1 mL) under N2were added 1-(oxetan-3-yl)piperazine (98 mg) and water (0.1 mL). The mixture was degassed with N2and stirred at 90°C overnight. The mixture was filtered through Celite and concentrated in vacuo. TBAF (1M in THF, 2.0 mL) was added to a solution of the crude material in THF (4 mL) and the solution of was stirred at 50°C for 30 min. The reaction was quenched with NaHCO3aq. and extracted with AcOEt. The organic layer were concentrated in vacuo and the residue was purified by column chromatography (SiO2, AcOEt / MeOH / NH3) to give the desired product (158 mg) which was separated by chiral SFC.

[0269] Example 477: 2-(3-{[(1S)-2,2-Difluoro-1-methylcyclopropyl]methoxy}-4-(1,2,4-thiadiazol-5-yl)phenyl)-6-methyl-2,6-diazaspiro[3.3]heptanestep 1: BuchwaldA suspension of Reference example 6 (5.0 g), tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate hemioxylate (5.4 g), Pd2(dba)3(1.4 g), DavePhos (1.2 g), NaOtBu (10.8 g) in toluene (100 mL) and water (0.5 mL) and refluxed under N2for 2 h. The reaction mixture was filtered through Celite and the filtrate concentrated. The residue was purified by column chromatography (KP-NH, petrol:AcOEt) to give the desired product (2.7 g).step 2: Boc_deprotectionTo a solution of tert-butyl 6-(3-{[(1S)-2,2-difluoro-1-methylcyclopropyl]methoxy}-4-(1,2,4-thiadiazol-5-yl)phenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (1.0 g) in DCM (10 mL) was added TFA (2 mL). The reaction was stirred at RT for 30 min. The reaction was quenched with NaHCO3aq. and extracted with DCM. The organic phase was concentrated to give the desired product (800 mg).step 3: Red AmineNaBH(OAc)3(1.1 g) was added to a solution of 2-(3-{[(1S)-2,2-difluoro-1-methylcyclopropyl]methoxy}-4-(1,2,4-thiadiazol-5-yl)phenyl)-2,6-diazaspiro[3.3]heptane (800 mg), formaldehyde (37% in water, 257 mg) in DCM (10mL). After 30 min at RT the reaction was quenched with sat. NaHCO3aq. and extracted with DCM. The organic phase was concentrated and the crude material was purified by column chromatography (KP-Sil, MeOH:DCM:0.2 M NH3) to give the desired product (230 mg).

[0270] Example 504: 1-(3-{[(1S)-2,2-Difluoro-1-(fluoromethyl)cyclopropyl]methoxy}-4-(1,2,4-thiadiazol-5-yl)phenyl)-4-(oxetan-3-yl)piperazineA suspension of Reference example 216 (75 mg), 1-(oxetan-3-yl)piperazine (35 mg), Pd2(dba)3(10 mg), DavePhos (9 mg), NaOtBu (33 mg) in toluene (5 mL) and water (1 drop) and refluxed under N2for 2 h. The reaction was filtered through Celite and the filtrate was concentrated. The residue purified by column chromatography (KP-Sil, AcOEt:MeOH) followed by chiral SFC purification to give the desired compound (16 mg).

[0271] Example 522: 1-(3-{[(1R,5S)-6,6-Difluoro-3-oxabicyclo[3.1.0]hexan-1-yl]methoxy}-4-(1,2,4-thiadiazol-5-yl)phenyl)-4-(oxetan-3-yl)piperazineA suspension of Reference example 162 (200 mg), 1-(oxetan-3-yl)piperazine (91 mg), Pd2(dba)3(27 mg), DavePhos (23 mg), NaOtBu (86 mg) in toluene (5 mL) and water (1 drop) and refluxed under N2for 1 h. The reaction was filtered through Celite and the filtrate was concentrated. The residue purified by column chromatography (KP-Sil, AcOEt:MeOH) followed by chiral SFC purification to give the desired compound (70 mg).

[0272] Example 527: 1-(5-{[(1S)-2,2-Difluoro-1-methylcyclopropyl]methoxy}-2-fluoro-4-(1,2,4-thiadiazol-5-yl)phenyl)-4-(oxetan-3-yl)piperazineA suspension of Reference example 1 (80 mg), 1-(oxetan-3-yl)piperazine (37 mg), Pd2(dba)3(11 mg), DavePhos (10 mg), NaOtBu (35 mg) in toluene (5 mL) and water (1 drop) and refluxed under N2for 1 h. The reaction was filtered through Celite and the filtrate was concentrated. The residue purified by reverse phase column chromatography (MeCN:H2O:0.1% formic acid) to give the desired compound (8 mg).

[0273] Example 540: trans-1-Methyl-3-[methyl({3-[(4-methyloxan-4-yl)methoxy]-4-(1,2,4-thiadiazol-5-yl)phenyl})amino]cyclobutan-1-olTo a solution of Reference example 265 (129.3 mg) in DMF (0.8 mL) was added NaH (60% Wt 13.09 mg). The mixture was stirred at RT for 10 min and then MeI (20.4 μL) was added. The reaction was stirred for 4 h. The reaction was quenched with water and extracted with AcOEt. The solvent was removed in vacuo and the residue was dissolved in THF (2 mL) and 1.0 M solution of TBAF (763.6 μL) was added. The mixture was stirred at 50°C for 30 min. The mixture was quenched with NaHCO3aq. and extracted with AcOEt. The organic layer was concentrated in vacuo and the crude product was purified by chromatography (SiO2, AcOEt / isohexane) followed by reverse phase chromatography (C18, water / MeCN) to afford the desired product (20 mg).

[0274] Example 551: 2-(3-{[(1S)-2,2-Difluoro-1-(fluoromethyl)cyclopropyl]methoxy}-4-(1,2,4-thiadiazol-5-yl)phenyl)-6-(oxetan-3-yl)-2,6-diazaspiro[3.3]heptaneA suspension of Reference example 216 (170 mg), tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate hemioxylate (148 mg), Pd2(dba)3(23 mg), DavePhos (20 mg), NaOtBu (146 mg) in toluene (10 mL) and water (1 drop) and refluxed under N2for 2 h. The reaction mixture was filtered through Celite and the filtrate concentrated. The residue was purified by column chromatography (KP-Sil, petrol:AcOEt). The product was dissolved in DCM (4 mL) and TFA (1 mL) was added. The reaction was stirred at RT for 1 h and the solvent was concentrated. The residue was dissolved in DCM (4 mL) and AcOH (17 μL), NaBH(OAc)3(86 mg) and oxetan-3-one (54 μL) were added. The reaction was stirred at RT for 2 h. The reaction was quenched with NaHCO3aq. and extracted with DCM. The solvent was concentrated and the crude material was purified by column chromatography (KP-Sil, AcOEt:MeOH) followed by chiral SFC chiral separation to give the desired product (16 mg).

[0275] Example 586: 2-(3-{[(1S)-2,2-Difluoro-1-methylcyclopropyl]methoxy}-4-(1,2,4-thiadiazol-5-yl)phenyl)-6-(2-methoxyethyl)-2,6-diazaspiro[3.3]heptane1-Bromo-2-methoxyethane (148 μL) and K2CO3(607 mg) were added to a solution of Reference example 268 (349 mg) in MeCN (20 mL). The reaction was stirred at 80°C for 2 h. 1-Bromo-2-methoxyethane (148 μL) was added and stirring was maintained for 2 h. The reaction mixture was filtered and the filtrated was concentrated. The residue was purified by column chromatography (KP-Sil, petrol:AcOEt) to give the desired product (40 mg).

[0276] Example 597: 2-(5-{[(1S)-2,2-Difluoro-1-methylcyclopropyl]methoxy}-2-fluoro-4-(1,2,4-thiadiazol-5-yl)phenyl)-6-(oxetan-3-yl)-2,6-diazaspiro[3.3]heptaneStep 1.A suspension of Reference example 171 (4.8 g), 2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester hemioxylate (4.9 g), Pd2(dba)3(1.3 g), DavePhos (564 mg), NaOtBu (5.5 g) in toluene (50 mL) and water (0.5 mL) and refluxed under N2for 2 h. The reaction mixture was quenched with H2O and extracted with DCM. The organic phase was concentrated and the residue was purified by column chromatography (KP-Sil, petrol:AcOEt) to give the desired product (3.5 g).Step 2.tert-Butyl 6-{5-[(2,2-difluoro-1-methylcyclopropyl)methoxy]-2-fluoro-4-(1,2,4-thiadiazol-5-yl)phenyl}-2,6-diazaspiro[3.3]heptane-2-carboxylate (3.5 g) was dissolved in DCM (30 mL) and TFA (5 mL) was added. The reaction was stirred for 2 h at RT. The solvent was concentrated and the crude material was used in the next step without further purifications.Step 3.NaBH(OAc)3(2.37 g) was added to a solution of 2-{5-[(2,2-difluoro-1-methylcyclopropyl)methoxy]-2-fluoro-4-(1,2,4-thiadiazol-5-yl)phenyl}-2,6-diazaspiro[3.3]heptane TFA salt crude form from previous step (2.8 g), oxetan-3-one (806 mg) and AcOH (210 μL) in DCM (50 mL). After 1 h at RT another portion of NaBH(OAc)3(2.4 g) and oxetan-3-one (806 mg) were added and the reaction was stirred at RT for 2 h. The reaction was quenched with sat. NaHCO3aq. and extracted with DCM. The organic phase was concentrated and the crude material was purified by column chromatography (KP-Sil, AcOEt:MeOH) followed by chiral SCF separation to give the desired product (650 mg).

[0277] Example 612: 1-(6-{[(1S)-2,2-Difluoro-1-methylcyclopropyl]methoxy}-5-(1,2,4-thiadiazol-5-yl)pyridin-2-yl)-4-(oxetan-3-yl)piperazineA suspension of Reference example 173 (100 mg), 1-(oxetan-3-yl)piperazine (55 mg) and Cs2CO3(200 mg) in DMF (1.5 mL) was stirred at 100°C for 15 min. Water was added and the solid that formed was collected by filtration. The crude material was purified by column chromatography (KP-Sil, DCM:MeOH:0.7M NH3) followed by chiral SFC separation to give the desired compound (18 mg) . SFC chiral separation. Peak 1

[0278] Example 623: 2-(3-{[(1R,5S)-6,6-Difluoro-3-oxabicyclo[3.1.0]hexan-1-yl]methoxy}-4-(1,2,4-thiadiazol-5-yl)phenyl)-6-(2-methoxyethyl)-2,6-diazaspiro[3.3]heptaneA solution of Reference example 162 (300 mg), 2,6-diazaspiro[3,3]heptane-2-carboxylic acid tert-butyl ester hemioxylate (233 mg), DavePhos (34.2 mg) Pd2dba3(40 mg) and NaOtBu (251 mg, 2.6 mmol) in toluene (3 mL) containing 3 drops of water was stirred in a sealed tube under N2at 95°C for 1 h. The reaction was concentrated in vacuo and the residue was purified by column chromatography (SiO2, AcOEt / petrol). The product was dissolved in DCM (4 mL) and TFA (1 mL) was added. The solution was stirred at RT for 6 h. The reaction was concentrated in vacuo. The residue was dissolved in MeCN (17 mL) and K2CO3(600 mg) and 2-bromoethyl methyl ether (0.1 mL) were added. The reaction was stirred at 80°C for 2 h. The reaction was concentrated in vacuo and the residue was purified by column chromatography (KP-NH, AcOEt / petrol) to give the desired product (77 mg).

[0279] Example 667: (S)-5-(2-((2,2-Difluoro-1-methylcyclopropyl)methoxy)-4-(4-fluoro-1-methylpiperidin-4-yl)phenyl)-1,2,4-thiadiazole; hydrochlorideReference example 311 (100mg) was treated with TFA / DCM (1 / 1 ml) for 2 h and the volatiles were removed under reduced pressure. To the residue was added DCE (1 ml), TEA (1 ml) and 37% formaldehyde (0.077 ml) then NaBH(OAc)3(219 mg). The reaction was stirred at RT for overnight. Reaction was quenched by Na2CO3aq and extracted by DCM. The organic phase was dried over Na2SO4and concentrated. The residue was purified by basic silica gel column chromatography (AcOEt to MeOH / AcOEt = 1 / 9). The fraction was concentrated and the residue was treated with 4M HCl / AcOEt (0.044 ml). Precipitate was collected by filtration to provide the desired product (50 mg).

[0280] Example 673: (S)-5-(2-((2,2-Difluoro-1-methylcyclopropyl)methoxy)-4-((4-(oxetan-3-yl)piperazin-1-yl)methyl)phenyl)-1,2,4-thiadiazoleTo a solution of Reference example 314 (70 mg, 0.226 mmol) in DCM (5 ml) were added 1-(oxetan-3-yl)piperazine oxalate (38.5 mg) and NaBH(OAc)3(62.2 mg) at RT. The mixture was stirred overnight. The reaction mixture was diluted with sat. NaHCO3aq., H2O and extracted with DCM. The organic layer was concentrated. The residue was purified by column chromatography (NH, Hex / AcOEt=7 / 3-5 / 5) to give the desired product (59 mg).

[0281] Example 678: 5-[2-[[(1S)-2,2-Difluoro-1-methylcyclopropyl]methoxy]-6-fluoro-4-[4-(oxetan-3-yl)piperazin-1-yl]phenyl]-1,2,4-thiadiazoleTo a solution of Reference example 289 (300 mg) in DCM (5 ml) was added TFA (3 ml) at RT and stirred for 1 h. It was quenched with 2N NaOH aq. and extracted with DCM. The organic layer was concentrated in vacuo to give the amine compound (241 mg). To a solution of the amine compound (241 mg) in DCE (6.0 ml) was added 3-oxetanone (0.119 ml), NaBH(OAc)3(394 mg) and AcOH (0.106 ml) at RT and stirred for 3 h. The solution was evaporated and directly located onto silica column chromatography and purified (AcOEt : MeOH = 0 to 15%) to give product. It was re-crystalized with EtOH to give the desired compound (190 mg).

[0282] Example 680: (S)-5-(4-((2,2-Difluoro-1-methylcyclopropyl)methoxy)-6-((1-methylpiperidin-4-yl)oxy)pyridin-3-yl)-1,2,4-thiadiazoleTo a solution of 4-hydroxy-N-methylpiperidine (37.7 mg) and Reference example 305 (80 mg) in THF (1 ml) was added NaH (21.97 mg) at RT. The mixture was stirred at RT for 18 h. It was quenched with H2O and extracted with DCM. The organic layers were dried over Na2SO4and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (AcOEt / hexane) to give the desired product (80 mg).

[0283] Example 681: 5-(2-((4-Methyltetrahydro-2H-pyran-4-yl)methoxy)-4-(2-(4-(oxetan-3-yl)piperazin-1-yl)ethyl)phenyl)-1,2,4-thiadiazoleTo a solution of Reference example 310 (106.7 ml) in DCM (5 ml) was added DMP (149 mg). The mixture was stirred at RT for 2 h. It was quenched with sat. NaHCO3aq and sat. Na2S2O3aq. and extracted with DCM. The organic layer was concentrated in vacuo. To the residue were added DCE (4 ml) and 1-(oxetan-3-yl)piperazine (61.9 μl). The mixture was stirred at RT for 10 min. Then NaBH(OAc)3(203 mg) was added and the mixture was stirred at RT for 48 h. It was quenched with water and extracted with DCM. The organic layer was concentrated in vacuo. The residue was purified by column chromatography (hexane:AcOEt = 70:30 to 50:50 then AcOEt). The product was recrystallized from EtOH-hexane (10:1), collected by filtration and dried in vacuo to give the desired compound (43.4 mg).

[0284] Example 682: 1-(6-{[(1R,5S)-6,6-Difluoro-3-oxabicyclo[3.1.0]hexan-1-yl]methoxy}-3-fluoro-5-(1,2,4-thiadiazol-5-yl)pyridin-2-yl)-4-(oxetan-3-yl)piperazineNaH (60% Wt, 0.8 g, 20 mmol) was added to a solution of (6,6-difluoro-3-oxabicyclo[3.1.0]hexan-1-yl)methanol (4.5 g, 22.0 mmol) in DMF (50.0 mL) at 0°C. After 10 min a solution of Reference example 323 (5.9 g, 17.0 mmol) in THF (64.0 mL) was added and the reaction mixture was stirred at room temperature overnight. The reaction was quenched with water and extracted with AcOEt. The organic phase was dried in vacuo and the crude material was filtered through an SCX column (eluted with 0.7M ammonia in MeOH). The residue was triturated in MeOH and dried in vacuo to give the desired product (1.9 g).The mixture of enantiomers was separated by chiral SFC to give the desired product (isomer 1).

[0285] Example 692: (S)-5-(2-((2,2-Difluoro-1-methylcyclopropyl)methoxy)-4-(2-(4-(oxetan-3-yl)piperazin-1-yl)ethyl)phenyl)-1,2,4-thiadiazoleTo a mixture of Reference example 308 (520 mg) in THF (6 ml) was added 5 M HCl aq. (1180 μl) at RT. The mixture was stirred at RT for 18 h and stirred at 40°C for 4 h. To the mixture was added H2O and it was extracted with DCM. The organic layers were concentrated under reduced pressure to give crude. To the crude in DCM (5 ml) was added 1-(oxetan-3-yl)piperazine oxalate (315 mg), sodium triacetoxyborohydride (938 mg) and AcOH (253 μl) at RT and stirred for 3 h. To the mixture was added NaHCO3aq. and Na2SO4and filtered. The solution was evaporated. The crude was purified by NH silica column chromatography (AcOEt / hexane) and silica column chromatography (AcOEt / hexane / MeOH) to give (S)-5-(2-((2,2-difluoro-1-methylcyclopropyl)methoxy)-4-(2-(4-(oxetan-3-yl)piperazin-1-yl)ethyl)phenyl)-1,2,4-thiadiazole (387 mg).

[0286] The compounds of Examples were manufactured in the same manner as in any of the above Examples. Structural formulae and physicochemical data of the compounds of Examples 1 to 695 are shown in the following table. The conditions of the SFC separation are also shown there.

[0287]

[0288] Biological ActivityTest Example 1: CSF1R kinase assayExample Compounds were serially diluted (half log scale; 10 concentrations) in DMSO. Serially diluted compounds were prepared with the assay buffer (0.25 M EPPS pH7.5, 50 mM MgCl2, 2.5 mM EGTA, 0.05% Briji-35) to reach 4 times concentration in 4% (v / v) DMSO. Each compound concentration was added at 5 μL / well in a 384-wells plate. The ATP / peptide solution (0.372 mM ATP, 0.4 μM Fluorescein-polyGT (PV3610, Life Technologies)) was added at 5 μL in all wells. The CSF1R (PV3249, Life Technologies) diluted solution (0.28 nM) was added at 10 μL in wells of each compound concentration and compound free control designated as 0% inhibition. On the other hand, assay buffer without enzyme was added at 10 μL in wells of 0% response control designated as 100% inhibition. The plates were incubated for 80 min at room temperature with orbital shaker at 750 rpm. The stop solution (20 mM EDTA, 2 nM Tb-PY20 (PV3528, Life Technologies) antibody diluted with TR-FRET dilution buffer (PV3574, Life Technologies)) was added at 20 μL in all wells. The plates were incubated for 30 min at room temperature with orbital shaker at 750 rpm. The plates were read using LanthaScreenTM Assay Mode of Infinite M1000 (Tecan). The value of signal is calculated with the ratio of 520 nm / 490 nm emission using an excitation light at 337 nm. The IC50 value was calculated by plotting the percentage of inhibition against the concentration of compound in curve fitting of a non-linear regression using GraphPad Prism 7 software.

[0289] Results are shown in the following table.

[0290] Test Example 2: CSF1R phosphorylation assay in human CSF1R overexpressing cell.Example Compounds were tested in H4 cells stably transfected with human CSF1R (H4 / hCSF1R). H4 / hCSF1R cells were cultured in DMEM medium supplemented with 10%FBS, 0.5 mg / mL Geneticin (G418), 100 units / mL penicillin and 100 μg / mL streptomycin in T150 flask and split twice a week. For the experiment, the cells were trypsinized, counted and diluted with culture medium to 1.11 x 105 cell / mL. The cells were seeded into 96-well culture plate with 180 μL for each well (20,000 cells / well). Compounds were serially diluted with DMSO to make an 8-point half-log fold concentration series, and then diluted with culture medium to 10 fold of final concentration. Each compound concentration was added to cells at 20 μl / well. The plates were mixed briefly using an orbital shake and incubated for 1 hour at 37°C, 5% CO2, and 95% humidified atmosphere. And then 22 μl of hCSF1 (300 ng / mL, #300-25, Peprotech) were added to each well. On every plate, 100% response control, treated with hCSF1 without compounds, and 0% response control, no hCSF1 treatment, were prepared to calculate percent inhibition of test compounds and Z prime value. The plates were mixed briefly again and incubated for 15 min at 37°C, 5% CO2, and 95% humidified atmosphere. CSF1R phosphorylation was detected by ELISA kit (PathScan(R) Phospho-CSF1R / M-CSF-R (panTyr) Sandwich ELISA Kit, 13491C, CST) following the instruction. Medium in each well was aspirated off and cell were washed with 200 μl of ice-cold PBS. After adding 50 μl of lysis buffer with phosphatase and protease inhibitors, the plates were incubated for 20 minutes at 4°C. One hundred μL of sample diluent was added and mixed by an orbital shaker. 80 μL of cell lysate was transferred to ELISA plate. The plates were sealed and stored overnight at 4°C sealed. The next day lysates were removed and plates were washed with 200 μl of wash buffer 4 times. The remaining wash buffer was tapped out before 100 μl of detection antibody solution was added and plates were incubated for one hour at 37°C. The antibody solution was removed and plates were washed with 200 μl of wash buffer 4 times. One hundred μL of HRP linked secondary antibody solution was added and plates were incubated for 30 minutes at 37°C. The antibody solution was removed and plates were washed with 200 μl of wash buffer 4 times. One hundred μL / well of TMB substrate was added and plates were incubated for 10 minutes at room temperature. One hundred μL of stop solution was added to the plates and the absorbance at 450 nm was measured by Infinite M1000 (Tecan). The average background was subtracted and result normalized to 100% response control. The IC50 value was calculated by plotting the percentage of inhibition for CSF1R phosphorylation against the concentration of a compound in curve fitting of a non-linear regression using GraphPad Prism 7 software.

[0291] Representative Results are shown in the following table.

[0292] Test Example 3. Kinase assay for selectivity within receptor type tyrosine kinases (RTKs)Five kinds of commercially available RTKs (as shown in the following table) were subjected to the tests using a LabChip EZReader II and ProfilerPro kinase selectivity assay kits (PerkinElmer). Compounds were serially diluted (half log scale; 10 concentrations) in DMSO. Two hundred nL of serially diluted compounds were mixed with 10 μL of kinase buffer (50 mM HEPES pH7.5, 10 mM MgCl2, 1 mM EGTA, 0.01% Briji-35) containing substrate (10 μM) and ATP (198 μM (CSF1R), 86 μM (FLT3, cKit, PDGFRβ, or TrkC)) to reach 2 times concentration. The fluorescently-labelled peptide substrates were shown in the following table. Each enzyme diluted solution (200 ng / mL) was added at 10 μL in all wells. 0% inhibition controls contained no inhibitor and 100% inhibition controls contained no ATP. The plates were mixed on a plate shaker for a few seconds and incubated for 60 min at room temperature. The termination buffer (100 mM HEPES pH7.5, 40 mM EDTA, 1 mM DTT, 0.015% Briji-35, 0.13% LabChip Sipper Chip Coating Reagent 3 (760050, PerkinElmer)) was added at 60 μL in all wells. Phosphorylated and unphosphorylated peptides were separated by electrophoresis and detected by those fluorescence. Percent conversion from substrate to product was determined using the peak heights. The IsC50 value was calculated by plotting the percentage of inhibition against the concentration of compound in curve fitting of a non-linear regression using GraphPad Prism 7 software. Compounds were confirmed to show selective inhibitory activity against CSF1R compared to at least one of the tested kinases.

[0293]

[0294] Test Example 4. Pharmacokinetics / PharmacodynamicsMale Mice (C57BL / 6J, The Jackson Laboratory Japan, eight weeks old) were orally administered with test compounds in 5% gum arabic in water as vehicle. Mice administered with vehicle only were used as a negative control. In each study, one control group and one or more test compound administered group(s) were prepared, but each group was only administered with one test compound at one concentration. Blood was collected via retro orbital puncture into heparin capillary at 30 minutes, 1 hour, 2 hours and 6 hours after dosing. After anesthetization, blood was collected through posterior vena cava into heparin tubes and brain was harvested at 24 hours after dosing. The blood was centrifuged at 1,710 g for 10 minutes at 4°C to obtain plasma. The half hemisphere of the brain was homogenized in 3-fold weight of saline by PHYSCOTRON homogenizer (NS-360D, Microtec) and subjected to pharmacokinetic study. The other half hemisphere was soaked in RNAlater (AM7021, Life Technologies) for gene expression assay.

[0295] Determination of Compound in Mouse Plasma and Brain HomogenatesThe compound in mouse plasma and brain homogenates was quantified with the high-performance liquid chromatographic-electrospray ionization tandem mass spectrometry method. The compound was dissolved in DMSO and was diluted with methanol to prepare the standard solutions. The concentrations of calibration curve samples were 0.01 to 10 μg / mL, and those of quality control samples were 0.03, 5, and 8 μg / mL. To each sample, the internal standard solution (spiperone: 500 ng / mL) and methanol were added and mixed. The mixture was centrifuged at 6130 g for 10 minutes at 10°C or below to obtain the supernatant. The supernatant was mixed with water / acetonitrile (1:1, v / v). Liquid chromatography and tandem mass spectrometry analysis were carried out with the Prominence UFLC system (Shimadzu Corp.) and the switching valve (Valco Instruments Co. Inc.). Chromatographic separation was achieved on an XBridge C18 (3.5 μm, 2.1 mmID x 50 mm, Waters Corp.). A binary gradient was formed with 10 mmol / L ammonium acetate aqueous solution and acetonitrile at a flow rate of 0.55 mL / min. The ionization method was electrospray ionization with a positive mode. Multiple reaction monitoring mode utilizing the precursor and product ions of the analyte and internal standard was employed. The peak-area ratios of the analyte to the IS in the calibration curve samples were obtained. The quadratic regression equation (Y = aX2 + bX + c, weight: 1 / X2) was calculated by the least square method using the peak-area ratios (Y) and the spiked concentrations (X). The concentrations of the analyte in the samples were determined by substituting the obtained peak-area ratios into the above equations. Analyst version 1.5.1 (AB Sciex Pte. Ltd.) was used for the construction of the calibration curve, and the determination of peak areas and concentrations. The mean of concentration at each time point, and the concentration ratio of brain to plasma (Kp) were calculated with Microsoft Excel 2013 (Microsoft Corp). Brain concentrations were corrected with dilution factor (4-time dilution) of brain homogenates. The pharmacokinetic parameters, including Cmax. tmax, t1 / 2 and AUC, were calculated with the aid of non-compartmental model, Phoenix(R) WinNonlin(R) 8.0 (Certara LP).

[0296] Quantification of microglia related gene expressionRNA was extracted from each brain using Maxwell(R) RSC simplyRNA Tissue Kit (AS1340, Promega), RNAdvance Tissue kit (A32646, Beckman Coulter), or RNeasy Mini Kit (74106, Qiagen). RNA concentration and purity was assessed using spectrophotometer (DropSense96, Trinean or Nanodrop, Thermo Scientific). Equal amount of RNA was reverse transcribed to cDNA using High-Capacity RNA-to-cDNA Kit (4388950, Life Technologies) or High-Capacity cDNA Reverse Transcription Kit (4368813, Life Technologies). Quantitative PCR was performed on LightCycler 480 (Roche) or ViiA7 (Thermo Scientific) using a TaqMan Fast Universal PCR Master Mix (#4352042, Life Technologies) or TaqMan Fast Advanced Master Mix (4444964, Life Technologies). Data was analyzed using ΔΔCt method or fold change which was relatively calculated by standard curve that was made from 5-points 1:2 dilution of vehicle treated animals. GAPDH gene was used as an internal control for normalization. Percentage inhibition of CD11b gene was calculated by taking the rate of decrease in the absence of drug as 0%. The primers used in this study were the followings: GAPDH gene (Mm99999915_g1, Life Technologies), CD11b gene (Mm00434455_m1, Life Technologies). All calculation were performed with Microsoft Excel 2013 (Microsoft Corp).

[0297] Representative Results of administration of the 30 mg / kg dose of test compounds are shown in the following table, unless otherwise noted.

[0298] A compound of Formula [I], or a salt thereof, may have CSF1R inhibitory activity and is expected to be useful for treating, preventing, and / or diagnosing diseases associated with CSF1R.

Claims

1.A compound of formula [I], or a salt thereof: wherein:L1is L11, -L11-C(=O)-, or -C(=O)-L11-;L11is bond, -O-, or -N(L12)-; L12is H, C1-6alkyl, or C1-6alkyl-O-C1-6alkyl;R1is hydrogen, C1-6alkyl, C3-8cycloalkyl, C6-14aryl, cyano, or 4- to 15-membered heterocyclyl, wherein said alkyl, cycloalkyl, aryl, and heterocyclyl are optionally substituted with one or more R11;each R11is independently halogen, cyano, C1-6alkyl, -O-C1-6alkyl, -OH, -NH2, NH(C1-6alkyl), N(C1-6alkyl)(C1-6alkyl), N(C1-6alkyl)(4 to 8-membered saturated heterocyclyl), oxo, -C(=O)-O-C1-6alkyl, -C(=O)-C1-6alkyl, C3-8cycloalkyl, or 4- to 15-membered heterocyclyl, wherein said alkyl, cycloalkyl, and heterocyclyl are optionally substituted with one or more R12;each R12is independently halogen, -OH, -O-C1-6alkyl, C1-6alkyl, -NH2, NH(C1-6alkyl), N(C1-6alkyl)(C1-6alkyl), or 4 to 8-membered saturated heterocyclyl containing at least one oxygen or nitrogen atom;R2is C1-6alkyl, C3-8cycloalkyl, C6-10aryl, 5- or 6-membered unsaturated heterocyclyl, 4- to 15-membered saturated or partially-unsaturated heterocyclyl, or C5-15bicyclic saturated or partially-unsaturated carbocyclyl, wherein R2is optionally substituted with one or more R21;each R21is independently halogen, cyano, -OH, C1-6alkyl, -O-C1-6alkyl, C1-6hydroxyalkyl, C1-6alkyl-O-C1-6alkyl, C3-8cycloalkyl, or oxo, wherein said alkyl and cycloalkyl are optionally substituted with one or more halogen atoms;each R4is independently hydrogen or C1-6alkyl;n is 0, 1, or 2;X1, X2, and X3are independently N or C-R3;each R3is independently hydrogen, halogen, cyano, or C1-6alkyl optionally substituted with one or more halogen atoms;provided the compound wherein n is 0 and R2is pyrimidinyl optionally substituted with R21is excluded.2.The compound of claim 1, or a salt thereof, wherein R4is hydrogen or methyl, and n is 0 or 1.3.The compound of claim 1 or 2, or a salt thereof, when R2is C6-10aryl or 5- or 6-membered unsaturated heterocyclyl, then n is 1.4.The compound of any one of claims 1 to 3, or a salt thereof, wherein formula [I] is the following formula [II]. 5.The compound of any one of claims 1 to 4, or a salt thereof, wherein X1, X2, and X3are independently N or C-R3; and each R3independently represents hydrogen, halogen, or C1-6alkyl.6.The compound of any one of claims 1 to 5, or a salt thereof, wherein L1is bond, -O-, -O-C(=O)-, -C(=O)-, -C(=O)-N(L12)-, or -N(L12)-.7.The compound of any one of claims 1 to 6, or a salt thereof, wherein R1is hydrogen; C1-6alkyl; C3-8cycloalkyl; 4- to 15-membered heterocyclyl, wherein said heterocyclyl is selected from the group consistaing of 4- to 7-membered mono-cyclic saturated or partially-unsaturated heterocyclyl, or 6- to 15-membered bi-cyclic, bridged-cyclic, or spiro-cyclic saturated or partially-unsaturated heterocyclyl; or 5- or 6- membered unsaturated heterocyclyl, wherein said alkyl, cycloalkyl, and heterocyclyl are optionally substituted with one or more R11.8.The compound of any one of claims 1 to 7, or a salt thereof, wherein each R11is independently halogen, cyano, C1-6alkyl, -O-C1-6alkyl, -OH, -NH2, NH(C1-6alkyl), N(C1-6alkyl)(C1-6alkyl), N(C1-6alkyl)(4 to 8-membered saturated heterocyclyl), oxo, -C(=O)-C1-6alkyl, C3-8cycloalkyl, oxetanyl, oxolanyl, oxanyl, morpholinyl, piperazinyl, pyridyl, or 2-oxa-5-azabicyclo[2.2.1]heptane, wherein said alkyl, cycloalkyl, oxetanyl, oxolanyl, oxanyl, morpholinyl, piperazinyl, pyridyl, and 2-oxa-5-azabicyclo[2.2.1]heptane are optionally substituted with one or more R12; and each R12is independently halogen, -OH, -O-C1-6alkyl, C1-6alkyl, -NH2, NH(C1-6alkyl), N(C1-6alkyl)(C1-6alkyl), morpholinyl, or oxetanyl.9.The compound of any one of Claims 1 to 8, or a salt thereof, wherein R2is C1-6alkyl, C3-8cycloalkyl, phenyl, pyridyl, 4- to 15-membered saturated or partially unsaturated heterocyclyl, wherein said heterocyclyl is selected from the group consisting of 4- to 7-membered mono-cyclic saturated or partially-unsaturated heterocyclyl, or 6- to 15-membered bi-cyclic, bridged-cyclic, spiro-cyclic saturated or partially-unsaturated heterocyclyl, or C5-15bicyclic saturated or partially-unsaturated carbocyclyl, wherein R2is optionally substituted with one or more R21.10.The compound of any one of claims 1 to 9, or a salt thereof, wherein each R21is independently halogen, -OH, C1-6alkyl, C1-6hydroxyalkyl, or C1-6alkyl substituted with one or more halogen atoms.11.The compound of claim 1, which is represented by formula [Ia]: whereinL1is bond or -N(L12)-; L12is H or C1-6alkyl;R1is 4- to 15-membered heterocyclyl which is optionally substituted with one or more R11;each R11is independently C1-6alkyl, C1-6alkyl substituted with -O-C1-6alkyl, or 4- to 15-membered heterocyclyl;R2is C3-8cycloalkyl or 4- to 15-membered saturated or partially-unsaturated heterocyclyl, wherein R2is optionally substituted with one or more R21;each R21is independently halogen, -OH, or C1-6alkyl which is optionally substituted with one or more halogen atoms;n is 0 or 1;X1, X2, and X3are independently N or C-R3; andeach R3is independently hydrogen or halogen;or a salt thereof.12.The compound of claim 11 or a salt thereof, whereinX1and X2are C-R3, wherein R3is independently hydrogen or F; andX3is N or CH.13.The compound of claim 11 or 12 or a salt thereof, wherein(1) L1is bond, and R1is any one of the following structures: (2) L1is -N(CH3)-, and R1is the following structure: 14.The compound of any one of claims 11 to 13 or a salt thereof, wherein(1) n is 0, and R2is any one of the following structures: (2) n is 1, and R2is any one of the following structures: 15.A compound selected from the group consisting of the following compounds, or a salt thereof. 16.A compound selected from the group consisting of the following compounds. 17.A pharmaceutical composition comprising the compound according to any one of claims 1 to 16 or a salt thereof as an active ingredient and a pharmaceutically acceptable carrier or excipient.18.A therapeutic, preventative and / or diagnostic agent comprising the compound according to any one of claims 1 to 16 or a salt thereof as an active ingredient, for treating, preventing and / or diagnosing a disease selected from Alzheimer's disease (AD), tauopathies, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), HIV-associated neurocognitive disorders (HAND), prion disease, trauma brain injury (TBI), Parkinson's disease, pain, spinal cord injury, Crohn’s disease, radiation-induced lung fibrosis, glaucoma, infections, cardiovascular diseases such as inflammation post myocardial infarction, bone diseases, muscular dystrophy, or asthma.19.A pharmaceutical composition comprising the compound according to any one of claims 1 to 16 or a salt thereof as an active ingredient, for treating, preventing and / or diagnosing a disease selected from Alzheimer's disease (AD), tauopathies, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), HIV-associated neurocognitive disorders (HAND), prion disease, trauma brain injury (TBI), Parkinson's disease, pain, spinal cord injury, Crohn’s disease, radiation-induced lung fibrosis, glaucoma, infections, cardiovascular diseases such as inflammation post myocardial infarction, bone diseases, muscular dystrophy, or asthma.20.A method for treating, preventing and / or diagnosing a disease selected from Alzheimer's disease (AD), tauopathies, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), HIV-associated neurocognitive disorders (HAND), prion disease, trauma brain injury (TBI), Parkinson's disease, pain, spinal cord injury, Crohn’s disease, radiation-induced lung fibrosis, glaucoma, infections, cardiovascular diseases such as inflammation post myocardial infarction, bone diseases, muscular dystrophy, or asthma, comprising administering a therapeutically effective amount of the compound according to any one of claims 1 to 16 or a salt thereof to a human in need thereof.21.The compound according to any one of claims 1 to 16 or a salt thereof for use in the treatment, prevention and / or diagnosis of a disease selected from Alzheimer's disease (AD), tauopathies, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), HIV-associated neurocognitive disorders (HAND), prion disease, trauma brain injury (TBI), Parkinson's disease, pain, spinal cord injury, Crohn’s disease, radiation-induced lung fibrosis, glaucoma, infections, cardiovascular diseases such as inflammation post myocardial infarction, bone diseases, muscular dystrophy, or asthma.22.Use of the compound according to any one of claims 1 to 16 or a salt thereof in the manufacture of a medicament for treating, preventing and / or diagnosing a disease selected from Alzheimer's disease (AD), tauopathies, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), HIV-associated neurocognitive disorders (HAND), prion disease, trauma brain injury (TBI), Parkinson's disease, pain, spinal cord injury, Crohn’s disease, radiation-induced lung fibrosis, glaucoma, infections, cardiovascular diseases such as inflammation post myocardial infarction, bone diseases, muscular dystrophy, or asthma.23.A therapeutic, preventative and / or diagnostic agent comprising the compound according to any one of claims 1 to 16 or a salt thereof as an active ingredient, for treating, preventing and / or diagnosing cancers or autoimmune diseases such as rheumatoid arthritis.24.A method for treating, preventing and / or diagnosing cancers or autoimmune diseases such as rheumatoid arthritis, comprising administering a therapeutically effective amount of the compound according to any one of claims 1 to 16 or a salt thereof to a human in need thereof.25.The compound according to any one of claims 1 to 16 or a salt thereof for use in the treatment, prevention and / or diagnosis of cancers or autoimmune diseases such as rheumatoid arthritis.26.Use of the compound according to any one of claims 1 to 16 or a salt thereof in the manufacture of a medicament for treating, preventing and / or diagnosing cancers or autoimmune diseases such as rheumatoid arthritis.

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