Thiadiazoles as glutaminase 1 inhibitors

Abstract

The invention relates to compounds of formula (I) and their use in the treatment of fibrotic and / or inflammatory diseases.

Description

[0001] THIADIAZOLES AS GLUTAMINASE 1 INHIBITORS

[0002] Field of the invention

[0003] The present invention relates to compounds and their use in treating or preventing fibrotic and / or inflammatory diseases, particularly those of the lung, and to related compositions, methods and intermediate compounds.

[0004] Background of the invention

[0005] Glutaminase 1 (GLS1) is a metabolic enzyme which catalyses the conversion of glutamine to glutamate. Glutamate is a central metabolite in many pathways including synthesis of a- ketoglutarate, the TCA cycle, glutathione synthesis and protein synthesis.

[0006] Many tumour cells are reliant on glutamine for their growth and survival, and this has led to the discovery of allosteric inhibitors of GLS1 for the treatment of cancer (Zimmermann et. al. 2019). The first reported allosteric inhibitor was bis-2-[5-(phenyl-acetamido)-1 ,3,4-thiadiazol-2-yl]ethyl sulfide (BPTES) and following its discovery many inhibitors derived from BPTES have been identified including CB-839, which entered clinical trials in 2014. More recently the recognition of the role of GLS1 in fibrosis, in senescent cell survival and in TH 17 mediated inflammation has demonstrated a therapeutic potential for a GLS1 inhibitor in the treatment of chronic lung diseases. GLS1 has been shown to regulate the profibrotic activity of myofibroblasts (Ge et al. 2018). In particular, in idiopathic pulmonary fibrosis, the GLS1 inhibitor CB-839 has also shown efficacy in mouse models of pulmonary fibrosis induced by Bleomycin or TGF-pi (Cui et al. 2019). GLS1 has a role in TH 17 cell differentiation and function (Kono et al. 2018) and is elevated in TH 17 cells isolated from human and mice. Human senescent cells rely on glutaminase 1 for their survival and inhibition of glutaminase 1 has a senolytic effect (Johmura et al. 2021). A GLS1 inhibitor is a potential therapy for lung diseases where senescent cells and / or TH 17 mediated inflammation contribute to the pathology, such as in COPD (Cottage et al. 2019) or asthma (Contreras Healey et al. 2021).

[0007] GLS1 inhibitors may be useful for the treatment of other lung diseases such as pulmonary hypertension where increased GLS1 expression is observed in lungs of human pulmonary arterial hypertension (PAH) patients, and the GLS1 inhibitor CB-839 can decrease endothelial growth, vessel thickening and right ventricular pressure in monocrataline induced rat PAH models (Bertero et al. 2016). A GLS1 inhibitor also has a therapeutic potential in lung cancer, as GLS1 is the rate limiting enzyme for growth in cancer cell lines sensitive to glutamine (Enyu et al. 2022). GLS1 inhibitors could also augment radiation treatments to lung cancer patients by enhancement of radiation- induced cell death (Fujimoto et al. 2022).

[0008] GLS1 inhibitors may be useful as antiviral agents as glutamine metabolism has been demonstrated to be increased in virus-infected host cells with glutamine required for viral replication (Hirabara et al. 2021). Glutamine metabolism has been shown to be impacted in infections of respiratory viruses such as SARS-CoV-2 (Bharadwaj et al. 2021), influenza (Janke et al. 2011) and HRSV (Lu et al. 2023) demonstrating a relevance for a GLS1 inhibitor as an antiviral agent in the lung.

[0009] A GLS1 inhibitor may also provide a therapy in other diseases where fibrosis, inflammation or accumulation of senescent cells contribute to the pathology such as long covid, radiation induced fibrosis, non-alcoholic steatohepatitis diabetes, non-alcoholic fatty liver disease / Cirrhosis, chronic kidney disease, osteoporosis, osteoarthritis and obesity, asthma, psoriasis, psoriatic arthritis, hidradenitis suppurativa, rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease and retinal vasculopathies such as diabetic macular edema, diabetic retinopathy and dry and neovascular age-related macular degeneration (WO2022 / 251370, Unity Biotechnology, Inc.).

[0010] For diseases of the lung such as interstitial lung diseases including idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), lung cancer, radiation induced fibrosis, pulmonary hypertension, asthma, respiratory viral infection and long covid, an inhaled GLS1 inhibitor may be preferable to administer to the target organ while minimising systemic exposure. An ideal inhaled candidate will have high cellular potency, good retention of the compound in the respiratory tract and low oral bioavailability (Pasqua et al, 2022). Furthermore for nebulised delivery the compound must have high aqueous solubility, and high solution stability.

[0011] A number of GLS1 inhibitors are disclosed in Zhang et al. (2019), WO2015 / 181539 and W02017 / 093301 (both from AstraZeneca and Cancer Research Technology). In particular, WO2015 / 181539 and WO2017 / 093301 disclose compounds which are known to epimerise which is not desirable for drug development. In addition, the compounds disclosed in WO’539 and WO’301 do not exhibit retention in the lung.

[0012] Furthermore, WO2024 / 233839 (Leal Therapeutics, Inc.) discloses compounds which are said to be inhibitors of glutaminase (GLS1). There remains a need to identify and develop GLS1 inhibitors with acceptable or improved potency compared with known compounds, which do not epimerise, which have an improved duration in the lung and which have improved solubility compared to compounds known in the art.

[0013] Summary of the invention

[0014] The present invention provides a compound of formula (I): wherein:

[0015] D is selected from the group consisting of: wherein R1is selected from the group consisting of H, halo, C1.4 alkyl, C1.4 haloalkyl and NH2;

[0016] R2is selected from the group consisting of H, C1.4 alkyl, C1.4 alkoxy, NR2aR2band Co- salkyleneCs-ecycloalkyl; wherein: R2ais independently H or Ci-salkyl;

[0017] R2bis independently H or Ci-salkyl; each R3is independently selected from the group consisting of halo, hydroxy, C1.4 alkyl, C1-4 alkoxy, C1.4 haloalkyl and C1.4 haloalkoxy; each R4is independently selected from the group consisting of halo, hydroxy, C1.4 alkyl, C1-4 alkoxy, C1.4 haloalkyl, C1.4 haloalkoxy, CO2R4a, SCi-4alkyl, OCo-salkyleneCs-ecycloalkyl and Co-3alkyleneCs-6cycloalkyl wherein the Cs-ecycloalkyl is optionally substituted by one or two R4b, or when ring B is phenyl two R4groups which are attached to adjacent carbon atoms join to form a C4-7cycloalkyl ring; wherein: R4ais independently H or Ci-salkyl;

[0018] R4bis independently halo or Ci-salkyl;

[0019] R5is H or halo; A is selected from the group consisting of 4-10 membered heterocyclyl, 6-11 membered heterospirocycloalkyl and Cs-ecycloalkyl;

[0020] B is selected from the group consisting of phenyl, Cs- cycloalkyl, 4-7 membered heterocyclyl, 4-10 membered heteroaryl and Ce-n spirocycloalkyl;

[0021] X is either absent or is selected from the group consisting of O, S and NR6Ci-4alkylene; wherein R6is independently H or Ci-salkyl;

[0022] Y is either absent or is selected from the group consisting of O, S, Ci.4alkylene and NR7Ci.

[0023] 4alkylene, wherein the Ci.4alkylene group is optionally substituted by one or more R9; wherein R7is independently H or Ci-salkyl;

[0024] R8is independently H or Ci-salkyl;

[0025] R9is independently selected from the group consisting of halo, C1.4 alkyl, C1.4 alkoxy and NR2aR2b; m is 0, 1 or 2; n is 0, 1 or 2; and o is 0, 1 , 2, 3 or 4; wherein: when B is phenyl, o is 1 , 2, 3 or 4; or a salt and / or solvate thereof.

[0026] Detailed description of the invention

[0027] Compounds of formula (I)

[0028] Embodiments and preferences set out herein with respect to the compound of formula (I) apply equally to the pharmaceutical composition, compound or pharmaceutically acceptable salt and / or solvate thereof for use, pharmaceutical composition for use, use and method aspects of the invention, as well as intermediates used in the synthesis of the compounds of formula (I). Embodiments and preferences set out herein with respect to the compound of formula (I) also apply equally to the compounds of formulae (IA), (IB), (IC), (ID), (IE) and (IF).

[0029] The present invention also provides a compound of formula (IB): wherein:

[0030] D is selected from the group consisting of: wherein R1is selected from the group consisting of H, halo, C1.4 alkyl, C1.4 haloalkyl and NH2;

[0031] R2is selected from the group consisting of H, C1.4 alkyl, C1.4 alkoxy, NR2aR2band Co. salkyleneCs-ecycloalkyl; wherein: R2ais independently H or Ci-salkyl;

[0032] R2bis independently H or Ci-salkyl;

[0033] R3is selected from the group consisting of halo, hydroxy, C1.4 alkyl, C1.4 alkoxy, C1.4 haloalkyl and C1.4 haloalkoxy;

[0034] R4is selected from the group consisting of halo, hydroxy, C1.4 alkyl, C1.4 alkoxy, C1.4 haloalkyl, C1.4 haloalkoxy, CO2R4a, SCi-4alkyl, OCo-salkyleneCs-eCycloalkyl and Co-salkyleneCs- eCycloalkyl wherein the Cs-eCycloalkyl is optionally substituted by one or two R4b; wherein: R4ais independently H or Ci-salkyl;

[0035] R4bis independently halo or Ci-salkyl;

[0036] R5is H or halo;

[0037] A is selected from the group consisting of 4-10 membered heterocyclyl, 6-11 membered heterospirocycloalkyl and Cs-ecycloalkyl;

[0038] B is selected from the group consisting of phenyl, Cs- cycloalkyl, 4-7 membered heterocyclyl, 4-10 membered heteroaryl and Ce-n spirocycloalkyl;

[0039] X is either absent or is selected from the group consisting of O, S and NR6Ci-4alkylene; wherein R6is independently H or Ci-salkyl;

[0040] Y is either absent or is selected from the group consisting of O, S, Ci.4alkylene and NR7Ci. 4alkylene; wherein R7is independently H or Ci-salkyl;

[0041] R8is independently H or Ci-salkyl; m is 0, 1 or 2; n is 0, 1 or 2; and o is 0, 1 , 2, 3 or 4; or a salt and / or solvate thereof.

[0042] The term “alkyl”, such as “C1.4 alkyl or “C1.3 alkyl” refers to a straight or branched fully saturated hydrocarbon group having the specified number of carbon atoms. The term encompasses methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. The term “alkyl” also encompasses “alkylene”, such as Ci.4alkylene or Co-salkylene which is a bifunctional straight or branched fully saturated hydrocarbon group having a specified number of carbon atoms. Example “alkylene” groups include methylene, ethylene, n-propylene and n-butylene.

[0043] The term “alkoxy” refers to an alkyl group, such as “C1.4 alkyl” as defined above, singularly bonded via an oxygen atom. Examples of alkoxy groups include OCH3.

[0044] The term “halo” refers to fluoro, chloro, bromo or iodo. Particular examples of halo are fluoro and chloro, especially fluoro.

[0045] The term “haloalkyl”, such as “C1.3 haloalkyl” or “C1.2 haloalkyl” as used herein refers to a straight or a branched fully saturated hydrocarbon chain containing the specified number of carbon atoms and at least one halogen atom, such as fluoro or chloro, especially fluoro. An example of haloalkyl is CF3. Further examples of haloalkyl are CHF2 and CH2CF3.

[0046] The term “haloalkoxy” refers to a haloalkyl group, such as “C1.4 haloalkyl”, as defined above, singularly bonded via an oxygen atom. Examples of haloalkoxy groups include OCF3, OCHF2 and OCH2CF3.

[0047] The term “hydroxy” (which may also be referred to as “hydroxyl”) refers to an -OH group.

[0048] The term “cycloalkyl”, such as “C5-10 cycloalkyl”, “Cs-ecycloalkyl”, or “C4-7cycloalkyl”, refers to a fully saturated cyclic hydrocarbon group having the specified number of carbon atoms. The term encompasses cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl as well as bridged systems such as bicyclo[1 .1 .1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[4.1.0]heptyl bicyclo[3.1 .1]heptyl, bicyclo[2.2.2]octyl and adamantyl. Particularly preferred groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. In certain circumstances as defined herein, the cycloalkyl ring may be fused to a phenyl ring via two carbon atoms that are shared by the cycloalkyl and phenyl rings.

[0049] The term “spirocycloalkyl” such as Ce-12 spirocycloalkyl, refers to a bicyclic cycloalkyl group wherein the two rings are connected through just one atom. The rings can be different or identical in ring atom number. The term encompasses spiro[3.3]heptyl, spiro[2.5]octyl, spiro[3.5]nonyl, spiro[4.5]decyl, spiro[5.5]undecane. The term “heterocyclyl”, such as “4-7 membered heterocyclyl” or “4-10 membered heterocyclyl”, refers to a non-aromatic cyclic group having the specified number of ring atoms and wherein at least one of the ring atoms is a heteroatom selected from N, O, S and B. The term “heterocyclic ring” is interchangeable with “heterocyclyl”. The term encompasses oxetanyl, thietanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl.

[0050] The term "heterospirocycloalkyl" such as 6-11 membered heterospirocycloalkyl, means a bicyclic, saturated heterocycle with 6, 7, 8, 9, 10 or 11 ring atoms in total, in which the two rings share one common ring carbon atom, which "heterospirocycloalkyl" contains one or two identical or different ring heteroatoms from the series: N, O, S; it being possible for said heterospirocycloalkyl group to be attached to the rest of the compound via any one of the carbon atoms, except the spiro carbon atom. Said heterospirocycloalkyl group is, for example 8-azaspiro[4.5]decane or 2,6- diazaspiro[3.4]octane.

[0051] The term “heteroaryl” or “heteroaryl ring”, such as “4-10 membered heteroaryl” refers to a cyclic group with aromatic character having the specified number of ring atoms, at least one of which is a heteroatom independently selected from N, O and S. For example, “4-10 membered heteroaryl” has 4-10 ring atoms. The term encompasses pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, dioxazolyl, dithiazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, quinolinyl, isoquinolinyl, naphthyridinyl, quinolizinyl, quinoxalinyl, phthalazinyl, quinazolinyl and cinnolinyl as well as groups having a ring which is not aromatic in character, such as: wherein i indicates the bond via which the heteroaryl is attached to the rest of the molecule.

[0052] In some suitable compounds of formula wherein represents the point of connection to the remainder of the compound comprising the D group.

[0053] In other suitable compounds of formula wherein f represents the point of connection to the remainder of the compound comprising the D group.

[0054] In other suitable compounds of formula wherein represents the point of connection to the remainder of the compound comprising the D group.

[0055] In some suitable compounds of formula (I), R1is H. In other suitable compounds of formula (I), R1is halo such as chloro. In other suitable compounds of formula (I), R1is C1.4 alkyl. In other suitable compounds of formula (I), R1is C1.4 haloalkyl. In other suitable compounds of formula (I), R1is NH2.

[0056] In some suitable compounds of formula (I), R2is H. In other suitable compounds of formula (I), R2is C1.4 alkyl. In other suitable compounds of formula (I), R2is methyl or ethyl. In other suitable compounds of formula (I), R2is C1.4 alkoxy. In other suitable compounds of formula (I), R2is OCHs. In other suitable compounds of formula (I), R2is NR2aR2bwherein R2aand R2bare independently C1.3 alkyl or H. In other suitable compounds of formula (I), R2is N(CHs)2. In other suitable compounds of formula (I), R2is Co-s alkyleneCs-ecycloalkyl. In other suitable compounds of formula (I), R2is cyclopropyl or cyclobutyl.

[0057] In some suitable compounds of formula (I), R2ais H. In other suitable compounds of formula (I), R2ais Ci-salkyl. In some suitable compounds of formula (I), R2bis H. In other suitable compounds of formula (I), R2bis Ci-salkyl.

[0058] In some suitable compounds of formula (I) both R1and R2are H.

[0059] In some suitable compounds of formula (I), R2is H or C1.4 alkyl e.g. methyl.

[0060] In some suitable compounds of formula (I), R3is halo e.g., fluoro. In other suitable compounds of formula (I), R3is hydroxy. In other suitable compounds of formula (I), R3is C1.4 alkyl e.g., methyl, ethyl or isopropyl. In other suitable compounds of formula (I), R3is C1.4 alkoxy. In other suitable compounds of formula (I), R3is C1.4 haloalkyl e.g. CF3. In other suitable compounds of formula (I), R3is C1-4 haloalkoxy e.g. OCF3. In some suitable compounds of formula (I), R4is halo e.g. fluoro. In other suitable compounds of formula (I), R4is hydroxy. In other suitable compounds of formula (I), R4is C1.4 alkyl e.g. methyl, ethyl or isopropyl. In other suitable compounds of formula (I), R4is C1.4 alkoxy e.g. OCH(CHs)2. In other suitable compounds of formula (I), R4is C1.4 haloalkyl e.g. CF3. In other suitable compounds of formula (I), R4is C1.4 haloalkoxy e.g. OCF3. In other suitable compounds of formula (I), R4is CC>2R4a. In other suitable compounds of formula (I), R4is SCi-salkyl e.g. SCH(CH3)2. In other suitable compounds of formula (I), R4is OCo-salkyleneCs-ecycloalkyl e.g. Ocyclobutyl or Ocyclopentyl. In other suitable compounds of formula (I), R4is Co-salkyleneCs-ecycloalkyl. In some suitable compounds, such as when ring B is phenyl, two R4groups which are attached to adjacent carbon atoms join to form a C^cycloalkyl ring, such as a Cscycloalkyl ring. In such suitable compounds, for example compounds of formula (I) are formed: wherein s is 1 , 2, 3 or 4, such that a fused C4cycloalkyl, Cscycloalkyl, Cscycloalkyl or Cycycloalkyl ring forms respectively. Suitably s is 2. Ring B may be further substituted by other R4groups as defined herein e.g. Ring B may be substituted by one further R4group:

[0061] Alternatively, compounds of the formula (I) may form: wherein s is defined above.

[0062] In some suitable compounds of formula (I), R4ais H. In other suitable compounds of formula (I), R4ais Ci-salkyl e.g. methyl.

[0063] In some suitable compounds of formula (I), R4bis halo e.g. F. In other suitable compounds of formula (I), R4bis Ci-salkyl e.g. methyl. In some suitable compounds of formula (I), the C3- ecycloalkyl group of R4is not substituted. In other suitable compounds of formula (I), the C3- ecycloalkyl group of R4is substituted by one or two (e.g. two) R4b.

[0064] In some suitable compounds of formula (I), R4is selected from the group consisting of halo, C1.4 alkyl, C1-4 alkoxy, C1.4 haloalkyl and C1.4 haloalkoxy.

[0065] In some suitable compounds of formula (I), R5is H. In other suitable compounds of formula, R5is halo such as fluoro. It will be clear to the skilled person that R5may be attached to any carbon atom in the pyrrolidinyl ring.

[0066] Suitably, R5is attached to the carbon atom as shown below:

[0067] More suitably, the stereochemistry of the carbon atom to which R5is attached is:

[0068] In some suitable compounds of formula (I), both R1and R5are H.

[0069] In some suitable compounds of formula (I) R1, R2and R5are all H.

[0070] In some suitable compounds of formula (I), A is selected from 4-10 membered heterocyclyl, 6- 11 membered heterospirocycloalkyl and C^cycloalkyl.

[0071] In some suitable compounds of formula (I), A is selected from 4-10 membered heterocyclyl and 6-11 membered heterospirocycloalkyl.

[0072] In some suitable compounds of formula (I), A is 4-10 membered heterocyclyl.

[0073] In some suitable compounds of formula (I), A is a 4-10 membered heterocyclyl wherein the heterocyclyl ring is C, N linked e.g. as per (A1A) or N, N linked e.g. as per (A1 B) represents the point of connection to the remainder of the compound comprising the heterocyclyl group.

[0074] In other suitable compounds of formula (I), A is selected from the group consisting of:

[0075] wherein / ' represents the point of connection to the remainder of the compound comprising the heterocyclyl group.

[0076] Most suitably (A) is selected from the group consisting of wherein / ' represents the point of connection to the remainder of the compound comprising the heterocyclyl group.

[0077] In some suitable compounds of formula (I), A is 6-11 membered heterospirocycloalkyl.

[0078] In some suitable compounds of formula (I), A is a 6-11 membered heterospirocycloalkyl wherein both rings are either C, N linked e.g. as per (A2A) or N, N linked e.g. as per (A2B) represents the point of connection to the remainder of the compound comprising the heterospirocycloalkyl group.

[0079] In some suitable compounds of formula (I), A is selected from the group consisting of connection to the remainder of the compound comprising the heterospirocycloalkyl group. In some suitable compounds of formula (I), A is selected from the group consisting of wherein represents the point of connection to the remainder of the compound comprising the heterospirocycloalkyl group.

[0080] In some suitable compounds of formula (I), A is Cs-ecycloalkyl. In other suitable compounds of formula (I), A is cyclohexyl.

[0081] In other suitable compounds of formula (I), A is wherein represents the point of connection to the remainder of the compound comprising the cycloalkyl group.

[0082] In other suitable compounds of formula (I), A is Cs-ecycloalkyl which is directly bonded to the carbon backbone e.g. where X is absent and m is 1 such as: represents the point of connection to the remainder of the compound comprising the cycloalkyl group.

[0083] In some suitable compounds of formula (I) in group A, the points of connection to the remainder of the compound comprising A, are either in the meta e.g. as per (A4B) or para position e.g. as per (A4A) relative to each other. In other suitable compounds of formula (I), in group A, the points of connection to the remainder of the compound comprising A, are in the para position e.g. as per (A4A) relative to each other. wherein / ' represents the point of connection to the remainder of the compound comprising the heterocyclyl group.

[0084] In some suitable compounds of formula (I), B is selected from the group consisting of phenyl, Cs- cycloalkyl and 4-10 membered heteroaryl. The phenyl is substituted as defined elsewhere herein (i.e. o is 1 , 2, 3 or 4) and the Cs- cycloalkyl and 4-10 membered heteroaryl are optionally substituted as defined elsewhere herein (i.e. o is 0, 1 , 2, 3 or 4). In other suitable compounds of formula (I), B is phenyl or 4-10 membered heteroaryl. The phenyl is substituted as defined elsewhere herein (i.e. o is 1 , 2, 3 or 4) and the 4-10 membered heteroaryl is optionally substituted as defined elsewhere herein (i.e. o is 0, 1 , 2, 3 or 4). In other suitable compounds of formula (I), B is selected from the group consisting of phenyl, Cs-ecycloalkyl and 5-6 membered heteroaryl. The phenyl is substituted as defined elsewhere herein (i.e. o is 1 , 2, 3 or 4) and the Cs-ecycloalkyl and 5-6 membered heteroaryl are optionally substituted as defined elsewhere herein (i.e. o is 0, 1 , 2, 3 or 4). Most suitably B is selected from the group consisting of phenyl, cyclohexyl and pyridine. The phenyl is substituted as defined elsewhere herein (i.e. o is 1 , 2, 3 or 4) and the cyclohexyl and pyridine are optionally substituted as defined elsewhere herein (i.e. o is 0, 1 , 2, 3 or 4).

[0085] In some suitable compounds of formula (I), B is phenyl. In some suitable compounds of formula (I), B is phenyl which is substituted by one, two, three or four R4groups (i.e. o is 1 , 2, 3 or 4), such as one or two R4groups (i.e. o is 1 or 2). In other suitable compounds of formula (I), phenyl is substituted by one R4(i.e. o is 1). In other suitable compounds of formula (I), phenyl is substituted by two R4(i.e. o is 2). In other suitable compounds of formula (I), phenyl is substituted by three R4(i.e. o is 3). In other suitable compounds of formula (I), phenyl is substituted by four R4(i.e. o is 4). When B is phenyl, two R4groups which are attached to adjacent carbon atoms may join to form a C^cycloalkyl ring, as defined above.

[0086] In other suitable compounds of formula (I), B is Cs- cycloalkyl. In other suitable compounds of formula (I), B is Cs-ecycloalkyl. In other suitable compounds of formula (I), B is cyclopropyl or cyclohexyl. In other suitable compounds of formula (I), B is cyclohexyl.

[0087] In some suitable compounds of formula (I), Cs- cycloalkyl is not substituted (i.e. o is 0). In other suitable compounds of formula (I), Cs- cycloalkyl is substituted by one R4(i.e. o is 1). In other suitable compounds of formula (I), Cs- cycloalkyl is substituted by two R4(i.e. o is 2). In other suitable compounds of formula (I), Cs- cycloalkyl is substituted by three R4(i.e. o is 3). In other suitable compounds of formula (I), Cs- cycloalkyl is substituted by four R4(i.e. o is 4).

[0088] In other suitable compounds of formula (I), B is 4-7 membered heterocyclyl. In other suitable compounds of formula (I), B is a 6 membered heterocyclyl. In other suitable compounds of formula (I), B is piperidine.

[0089] In some suitable compounds of formula (I), 4-7 membered heterocyclyl is not substituted (i.e. o is 0). In other suitable compounds of formula (I), 4-7 membered heterocyclyl is substituted by one R4(i.e. o is 1). In other suitable compounds of formula (I), 4-7 membered heterocyclyl is substituted by two R4(i.e. o is 2). In other suitable compounds of formula (I), 4-7 membered heterocyclyl is substituted by three R4(i.e. o is 3). In other suitable compounds of formula (I), 4-7 membered heterocyclyl is substituted by four R4(i.e. o is 4).

[0090] In other suitable compounds of formula (I), B is 4-10 membered heteroaryl. In other suitable compounds of formula (I), B is a 5-6 membered heteroaryl. In other suitable compounds of formula (I), B is pyridine.

[0091] In some suitable compounds of formula (I), 4-10 membered heteroaryl is not substituted (i.e. o is 0). In other suitable compounds of formula (I), 4-10 membered heteroaryl is substituted by one R4(i.e. o is 1). In other suitable compounds of formula (I), 4-10 membered heteroaryl is substituted by two R4(i.e. o is 2). In other suitable compounds of formula (I), 4-10 membered heteroaryl is substituted by three R4(i.e. o is 3). In other suitable compounds of formula (I), 4-10 membered heteroaryl is substituted by four R4(i.e. o is 4).

[0092] In some suitable compounds of formula (I), B is C6-i2spirocycloalkyl. In other suitable compounds of formula (I), B is selected from the group consisting of:

[0093] e point of connection to the remainder of the compound comprising the spirocycloalkyl group.

[0094] In some suitable compounds of formula (I), C6-i2spirocycloalkyl is not substituted (i.e. o is 0). In other suitable compounds of formula (I), C6-i2spirocycloalkyl is substituted by one R4(i.e. o is 1). In other suitable compounds of formula (I), C6-i2spirocycloalkyl is substituted by two R4(i.e. o is 2). In other suitable compounds of formula (I), C6-i2spirocycloalkyl is substituted by three R4(i.e. o is 3). In other suitable compounds of formula (I), C6-i2spirocycloalkyl is substituted by four R4(i.e. o is 4).

[0095] In some suitable compounds of formula (I), X is absent. In other suitable compounds of formula (I), X is O. In other suitable compounds of formula (I), X is S. In other suitable compounds of formula (I), X is NR6Ci-4alkylene e.g. NR6Cialkylene.

[0096] In some suitable compounds of formula (I), R6is H. In other suitable compounds of formula (I), R6is Ci-salkyl. In other suitable compounds of formula (I), R6is methyl.

[0097] In some suitable compounds of formula (I) Y is absent. In some suitable compounds of formula (I), Y is O. In some suitable compounds of formula (I), Y is S. In some suitable compounds of formula (I), Y is Ci.4alkylene such as Cialkylene. In some suitable compounds of formula (I) Y is NR7Ci-4alkylene such as NR7Cialkylene.

[0098] In any of the above suitable compounds, the Ci^alkylene of Y (such as when Y is Ci^alkylene or NR7Ci-4alkylene) is optionally substituted by one or more such as one, two, three or four e.g. one R9. In some suitable compounds, the Ci^alkylene group is not substituted by R9. In other suitable compounds, the Ci^alkylene group is substituted by one or more such as one, two, three or four e.g. one R9. In some suitable compounds of formula (I), R7is H. In other suitable compounds of formula (I), R7is Ci-salkyl. In other suitable compounds of formula (I), R7is methyl.

[0099] In some suitable compounds of formula (I), X is absent and Y is Ci.4alkylene. In other suitable compounds of formula (I), X and Y are both absent.

[0100] Most suitably in compounds of formula (I), X is absent and Y is -CH2-.

[0101] In some suitable compounds of formula (I), R8is H. In other suitable compounds of formula (I), R8is C1.4 alkyl. In other suitable compounds of formula (I), R8is methyl.

[0102] In some suitable compounds of formula (I), R9is halo. In other suitable compounds of formula (I), R9is C1.4 alkyl e.g. methyl. In other suitable compounds of formula (I), R9is C1.4 alkoxy e.g. methoxy. In other suitable compounds of formula (I), R9is NR2aR2bwherein R2aand R2bare defined elsewhere herein.

[0103] Most suitably in compounds of formula (I), R1, R2, R5and R8are all H.

[0104] In some suitable compounds of formula (I), m is 0. In other suitable compounds of formula (I), m is 1. In other suitable compounds of formula (I), m is 2. Most suitably, m is 1.

[0105] When m is 0, R2is absent.

[0106] In some suitable compounds of formula (I), n is 0. In other suitable compounds of formula (I), n is 1. In other suitable compounds of formula (I), n is 2. In other suitable compounds of formula (I), n is 0 or 1 . Most suitably, n is 0.

[0107] In some suitable compounds of formula (I), o is 0. In other suitable compounds of formula (I), o is 1. In other suitable compounds of formula (I), o is 2. In other suitable compounds of formula (I), o is 3. In other suitable compounds of formula (I), o is 4. Most suitably, o is 1 or 2.

[0108] In some suitable compounds of formula (I), n is 0 and m is 0. In other suitable compounds of formula (I), n is 0 and m is 1.

[0109] Most suitably in compounds of formula (I), n is 0 and o is 1 or 2. Most suitably in compounds of formula (I), n is 0 and B is substituted by 1 or 2 R4groups. In some suitable compounds, the compound is a compound of formula (IA): wherein R2, R3, R4, R4, R5, R8, m, n, o, X, Y, A, B and D are as defined elsewhere herein; or a salt and / or solvate thereof.

[0110] In some suitable compounds there is provided a compound of formula (IC): wherein:

[0111] R4is selected from the group consisting of halo, hydroxy, C1.4 alkyl, C1.4 alkoxy, C1.4 haloalkyl, C1.4 haloalkoxy, CC>24a, SCi-4alkyl, OCo-salkyleneCs-ecycloalkyl and Co-salkyleneCs- ecycloalkyl wherein the Cs-ecycloalkyl is optionally substituted by one or two R4b; wherein: R4ais independently H or Ci-salkyl;

[0112] R4bis independently halo or Ci-salkyl;

[0113] A is selected from the group consisting of 4-10 membered heterocyclyl, 6-11 membered heterospirocycloalkyl and Cs-ecycloalkyl;

[0114] B is selected from the group consisting of phenyl, Cs- cycloalkyl, 4-7 membered heterocyclyl, 4-10 membered heteroaryl and Ce-n spirocycloalkyl;

[0115] Y is either absent or is selected from the group consisting of O, S, Ci.4alkylene and NR7Ci. 4alkylene; wherein R7is independently H or Ci-salkyl; and o is 0, 1 , 2, 3 or 4; wherein: when B is phenyl, o is 1 , , 3 or 4; or a salt and / or solvate thereof.

[0116] In some suitable compounds there is provided a compound of formula (ID): wherein:

[0117] R4is selected from the group consisting of halo, hydroxy, C1.4 alkyl, C1.4 alkoxy, C1.4 haloalkyl, C1.4 haloalkoxy, CC>24a, SCi-4alkyl, OCo-salkyleneCs-ecycloalkyl and Co-salkyleneCs- ecycloalkyl wherein the Cs-ecycloalkyl is optionally substituted by one or two R4b; wherein: R4ais independently H or Ci-salkyl;

[0118] R4bis independently halo or Ci-salkyl;

[0119] A is 4-10 membered heterocyclyl;

[0120] B is phenyl;

[0121] Y is Ci-4alkylene; and o is 1 , 2, 3 or 4; or a salt and / or solvate thereof.

[0122] In some suitable compounds there is provided a compound of formula (IE): wherein:

[0123] R4is selected from the group consisting of halo, hydroxy, C1.4 alkyl, C1.4 alkoxy, C1.4 haloalkyl and C1.4 haloalkoxy;

[0124] A is 4-10 membered heterocyclyl;

[0125] B is phenyl;

[0126] Y is Ci-4alkylene; and o is 1 or 2; or a salt and / or solvate thereof.

[0127] In some suitable compounds there is provided a compound of formula (IF): wherein:

[0128] A is 4-10 membered heterocyclyl, wherein A is attached via a carbon ring atom to the - C(H)CH2C(=O)NH- moiety; and

[0129] Y, B, R3, R4, n and o are as defined herein.

[0130] Suitably, in such suitable compounds, A is a 6 membered heterocyclyl.

[0131] In one embodiment there is provided a compound of formula (I), which is selected from any one of Examples 1 to 291 , or a salt and / or solvate thereof.

[0132] In one embodiment there is provided a compound of formula (I), which is selected from the list consisting of:

[0133] ( )-3-(4-((2-isopropoxyphenyl)thio)piperidin-1-yl)-A / -(5-((1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-

[0134] 1 ,3,4-thiadiazol-2-yl)propanamide;

[0135] ( )-2-(1-(methyl(3-(trifluoromethoxy)benzyl)amino)cyclobutyl)-A / -(5-((1-(pyridazin-3-yl)pyrrolidin- 3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0136] ( )-3-(4-((3,5-difluorophenyl)thio)piperidin-1-yl)-A / -(5-((1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-

[0137] 1.3.4-thiadiazol-2-yl)propanamide;

[0138] ( )-3-(4-(2-isopropoxyphenyl)piperidin-1-yl)- / V-(5-((1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4- thiadiazol-2-yl)propanamide;

[0139] (R)-2-(2-(2-(isopropylthio)benzyl)-2,6-diazaspiro[3.4]octan-6-yl)-A / -(5-((1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0140] 2-(1-(3-(difluoromethoxy)benzyl)-4-isopropylpiperazin-2-yl)-N-(5-(((R)-1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0141] 2-(4-(2-methylbenzyl)thiomorpholin-2-yl)-A / -(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-

[0142] 1.3.4-thiadiazol-2-yl)acetamide;

[0143] ( )-2-(2-(3,5-dimethylbenzyl)-2,6-diazaspiro[3.5]nonan-6-yl)-A / -(5-((1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0144] (R)-2-(2-(2-(isopropylthio)benzyl)-2,8-diazaspiro[4.5]decan-8-yl)-A / -(5-((1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0145] 1-{[4-(trifluoromethoxy)phenyl]methyl}piperidin-4-yl A / -(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3- yl]amino}-1 ,3,4-thiadiazol-2-yl)carbamate; 2-{1 -[(4-methoxy-3,5-dimethylphenyl)methyl]piperidin-4-yl}-A / -(5-{[(3 / ?)-1 -(pyridazin-3- yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;

[0146] A / -(5-{[(3 / ?)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)-2-(1-{[4-

[0147] (trifluoromethoxy)phenyl]methyl}piperidin-4-yl)acetamide;

[0148] A / -(5-{[(3 / ?)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)-2-(4-{[4-

[0149] (trifluoromethoxy)phenyl]methyl}piperazin-1-yl)acetamide;

[0150] A / -(5-{[(3 / ?)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)-2-(1-{[3-

[0151] (trifluoromethoxy)phenyl]methyl}piperidin-4-yl)acetamide;

[0152] (3 / ?)-A / -(5-{[(3 / ?)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)-1-{[4-

[0153] (trifluoromethoxy) phenyl]methyl}piperidine-3-carboxamide;

[0154] (3S)-A / -(5-{[(3 / ?)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)-1-{[4-

[0155] (trifluoromethoxy) phenyl]methyl}piperidine-3-carboxamide;

[0156] (3S)-N-(5-{[(3 / ?)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)-1-{[3-

[0157] (trifluoromethoxy) phenyl]methyl}piperidine-3-carboxamide;

[0158] (3 / ?)-N-(5-{[(3 / ?)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)-1-{[3-

[0159] (trifluoromethoxy) phenyl]methyl}piperidine-3-carboxamide;

[0160] A / -(5-{[(3 / ?)-1 -(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)-2-[(3S)-1 -{[3-

[0161] (trifluoromethoxy)phenyl] methyl}piperidin-3-yl]acetamide;

[0162] A / -(5-{[(3 / ?)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)-2-(1-{[4-

[0163] (trifluoromethoxy)phenyl]methyl}piperidin-4-yl)propanamide;

[0164] ( / ?)- / V-(5-((( / ?)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-(1-(4-

[0165] (trifluoromethoxy)benzyl)piperidin-4-yl)propanamide;

[0166] (S)- / V-(5-((( / ?)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-(1-(4-

[0167] (trifluoromethoxy)benzyl)piperidin-4-yl)propanamide;

[0168] A / -(5-{[(3 / ?)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)-2-[(3R)-1-{[4-

[0169] (trifluoromethoxy)phenyl] methyl}piperidin-3-yl]acetamide;

[0170] A / -(5-{[(3 )-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)-2-[(3 / ?)-1-{[3-

[0171] (trifluoromethoxy)phenyl]methyl}piperidin-3-yl]acetamide;

[0172] / V-(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)-2-[(3S)-1-{[4-

[0173] (trifluoromethoxy)phenyl]methyl}piperidin-3-yl]acetamide;

[0174] A / -(5-{[(3 )-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)-2-(1-{[5-

[0175] (trifluoromethyl)pyridin-3-yl]methyl}piperidin-4-yl)propanamide;

[0176] 2-(4-methyl-1-{[4-(trifluoromethoxy)phenyl]methyl}piperidin-4-yl)-A / -(5-{[(3 )-1-(pyridazin-3- yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;

[0177] N-(5-{[(3 )-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)-2-(4-{[4-

[0178] (trifluoromethoxy)phenyl]methyl}-1 ,4-diazepan-1-yl)acetamide 2-(4-{[4-(propan-2-ylsulfanyl)phenyl]methyl}piperazin-1 -yl)-N-(5-{[(3 / ?)-1 -(pyridazin-3- yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;

[0179] 2-{3-benzyl-3-azaspiro[5.5]undecan-9-yl}- / V-(5-{[(3 / ?)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}- 1 ,3,4-thiadiazol-2-yl)acetamide;

[0180] 2-(1-{[4-(propan-2-ylsulfanyl)phenyl]methyl}piperidin-4-yl)-A / -(5-{[(3 / ?)-1-(pyridazin-3- yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;

[0181] 2-(1-{[6-methyl-4-(trifluoromethyl)pyridin-2-yl]methyl}piperidin-4-yl)-N-(5-{[(3 / ?)-1-(pyridazin-3- yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;

[0182] 2-{1-[(3,5-dimethylphenyl)methyl]piperidin-4-yl}-N-(5-{[(3 / ?)-1-(pyridazin-3-yl)pyrrolidin-3- yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;

[0183] 2-[(3S)-1-[(3,5-difluorophenyl)methyl]piperidin-3-yl]-N-(5-{[(3 / ?)-1-(pyridazin-3-yl)pyrrolidin-3- yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;

[0184] 2-[(3S)-1-{[3-(difluoromethoxy)phenyl]methyl}piperidin-3-yl]- / V-(5-{[(3 / ?)-1-(pyridazin-3- yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;

[0185] 2-[(3 / ?,5S)-3,5-dimethyl-4-{[4-(trifluoromethoxy)phenyl]methyl}piperazin-1-yl]-N-(5-{[(3 / ?)-1- (pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;

[0186] 3-[(4-{[(5-{[(3 / ?)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2- yl)carbamoyl]methyl}piperidin-1-yl)methyl]benzoic acid;

[0187] 4-[(4-{[(5-{[(3 / ?)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2- yl)carbamoyl]methyl}piperidin-1-yl)methyl]benzoic acid;

[0188] 2-(1-{[2-(propan-2-yloxy)phenyl]methyl}piperidin-4-yl)-A / -(5-{[(3 / ?)-1-(pyridazin-3-yl)pyrrolidin-3- yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;

[0189] 2-(dimethylamino)- / V-(5-{[(3 / ?)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)-2-(1-

[0190] {[4-(trifluoromethoxy)phenyl]methyl}piperidin-4-yl)acetamide;

[0191] 2-(1-{[4-(difluoromethoxy)phenyl]methyl}piperidin-4-yl)- / V-(5-{[(3 / ?)-1-(pyridazin-3-yl)pyrrolidin-3- yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;

[0192] N-(5-{[(3 / ?)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)-2-[(3 / ?)-1-{[3-

[0193] (trifluoromethoxy)phenyl]methyl}pyrrolidin-3-yl]acetamide;

[0194] 2-[(3S)-1-[(4,4-dimethylcyclohexyl)methyl]piperidin-3-yl]-A / -(5-{[(3 / ?)-1-(pyridazin-3-yl)pyrrolidin-

[0195] 3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;

[0196] / V-(5-{[(3 / ?)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)-2-[(3S)-1-{[3-

[0197] (trifluoromethoxy)phenyl]methyl} pyrrolidin-3-yl]acetamide;

[0198] / V-(5-{[(3 / ?)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)-2-(5-{[5-

[0199] (trifluoromethyl)pyridin-3-yl]methyl}-5-azaspiro[2.5]octan-7-yl)acetamide;

[0200] 2-(5-{[5-methoxy-6-(trifluoromethyl)pyridin-2-yl]methyl}-5-azaspiro[2.5]octan-7-yl)-A / -(5-{[(3 / ?)-1-

[0201] (pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide; A / -(5-{[(3 / ?)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)-2-[(1-{[3-

[0202] (trifluoromethoxy)phenyl]methyl}piperidin-4-yl)sulfanyl]acetamide;

[0203] A / -(5-{[(3 / ?)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)-2-[(1-{[4-

[0204] (trifluoromethoxy)phenyl]methyl}piperidin-4-yl)sulfanyl]acetamide;

[0205] 2-[(3S)-1-[(3-chlorophenyl)methyl]piperidin-3-yl]- / V-(5-{[(3 / ?)-1-(pyridazin-3-yl)pyrrolidin-3- yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;

[0206] 2-(6-{[3-(difluoromethoxy)phenyl]methyl}-6-azaspiro[3.4]octan-2-yl)-A / -(5-{[(3 / ?)-1-(pyridazin-3- yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;

[0207] 2-{3-[(4,6-dimethylpyridin-2-yl)methyl]-3-azaspiro[5.5]undecan-9-yl}-N-(5-{[(3R)-1-(pyridazin-3- yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;

[0208] 2-{4-[(4,4-dimethylcyclohexyl)methyl]piperazin-1-yl}-A / -(5-{[(3 / ?)-1-(pyridazin-3-yl)pyrrolidin-3- yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;

[0209] A / -(5-{[(3 )-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)-2-{1-[(3,3,5,5- tetramethylcyclohexyl) methyl] piperidin-4-yl}acetamide;

[0210] 2-(2-{[3-(difluoromethoxy)phenyl]methyl}-2-azaspiro[3.3]heptan-6-yl)-A / -(5-{[(3 )-1-(pyridazin-3- yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;

[0211] 2-{1-[(4,4-dimethylcyclohexyl)methyl]piperidin-4-yl}-A / -(5-{[(3 / ?)-1-(pyridazin-3-yl)pyrrolidin-3- yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;

[0212] 3-(1-{[3-(difluoromethoxy)phenyl]methyl}piperidin-4-yl)-A / -(5-{[(3 / ?)-1-(pyridazin-3-yl)pyrrolidin-3- yl]amino}-1 ,3,4-thiadiazol-2-yl)propanamide;

[0213] A / -(5-{[(3 / ?)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)-8-{[3-

[0214] (trifluoromethoxy)phenyl]methyl}-2-oxa-8-azaspiro[4.5]decane-3-carboxamide;

[0215] A / -(5-{[(3 / ?)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)-2-{4-[(3,3,5,5- tetramethylcyclohexyl)methyl]piperazin-1-yl}acetamide;

[0216] 2-{1-[methyl({[3-(trifluoromethoxy)phenyl]methyl})amino]cyclopropyl}-A / -(5-{[(3 )-1-(pyridazin-3- yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;

[0217] 2-(1-{[4-hydroxy-3-(trifluoromethoxy)phenyl]methyl}piperidin-4-yl)-A / -(5-{[(3 / ?)-1-(pyridazin-3- yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;

[0218] 2-{1-[(2-chlorophenyl)methyl]piperidin-4-yl}- / V-(5-{[(3 / ?)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}- 1 ,3,4-thiadiazol-2-yl)acetamide;

[0219] 2-(4-methyl-1-{[3-(trifluoromethoxy)phenyl]methyl}piperazin-2-yl)-A / -(5-{[(3 )-1-(pyridazin-3- yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;

[0220] 2-((S)-4-methyl-1-(3-(trifluoromethoxy)benzyl)piperazin-2-yl)-A / -(5-((( / ?)-1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0221] 2-(( / ?)-4-methyl-1-(3-(trifluoromethoxy)benzyl)piperazin-2-yl)-A / -(5-((( / ?)-1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide; 2-methoxy-N-(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)-2-(1-{[4- (trifluoromethoxy)phenyl] methyl}piperidin-4-yl)acetamide;

[0222] (R)-2-methoxy- / V-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-(1-(4-

[0223] (trifluoromethoxy)benzyl)piperidin-4-yl)acetamide;

[0224] (S)-2-methoxy- / V-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-(1-(4-

[0225] (trifluoromethoxy)benzyl)piperidin-4-yl)acetamide;

[0226] 4-[(4,4-dimethylcyclohexyl)methyl]-A / -(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4- thiadiazol-2-yl)thiomorpholine-2-carboxamide;

[0227] 2-{4-[(4,4-dimethylcyclohexyl)methyl]morpholin-2-yl}- / V-(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3- yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;

[0228] 2-(( )-4-((4,4-dimethylcyclohexyl)methyl)morpholin-2-yl)-A / -(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-

[0229] 3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0230] 2-((S)-4-((4,4-dimethylcyclohexyl)methyl)morpholin-2-yl)-A / -(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-

[0231] 3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0232] 2-(1-{[3-(propan-2-yloxy)pyridin-2-yl]methyl}piperidin-4-yl)-A / -(5-{[(3R)-1-(pyridazin-3- yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;

[0233] A / -(5-{[(3 )-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)-2-(1-{[3-

[0234] (trifluoromethoxy)phenyl]methyl}azetidin-3-yl)acetamide;

[0235] 2-(1-{[2-(difluoromethoxy)phenyl]methyl}piperidin-4-yl)- / V-(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3- yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;

[0236] 2-(4-{[3-(propan-2-yloxy)pyridin-2-yl]methyl}-4-azaspiro[2.5]octan-7-yl)-A / -(5-{[(3 )-1-(pyridazin-

[0237] 3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;

[0238] 2-({1-[(3,5-dimethylphenyl)methyl]piperidin-4-yl}sulfanyl)- / V-(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-

[0239] 3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;

[0240] A / -(5-{[(3 )-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)-2-(2-{[3-

[0241] (trifluoromethoxy)phenyl]methyl}-6-oxa-2-azaspiro[3.4]octan-7-yl)acetamide;

[0242] A / -(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-((R)-2-(3-

[0243] (trifluoromethoxy)benzyl)-6-oxa-2-azaspiro[3.4]octan-7-yl)acetamide;

[0244] A / -(5-((( )-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-((S)-2-(3-

[0245] (trifluoromethoxy)benzyl)-6-oxa-2-azaspiro[3.4]octan-7-yl)acetamide;

[0246] 2-(2-{[3-(difluoromethoxy)phenyl]methyl}-6-oxa-2-azaspiro[3.4]octan-7-yl)-A / -(5-{[(3 )-1-

[0247] (pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;

[0248] 2-(2,2-dimethyl-1-{[3-(propan-2-yloxy)pyridin-2-yl]methyl}piperidin-4-yl)-A / -(5-{[(3R)-1-(pyridazin-

[0249] 3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;

[0250] 2-(2-{[2-(cyclopentyloxy)phenyl]methyl}-6-oxa-2-azaspiro[3.4]octan-7-yl)-A / -(5-{[(3 )-1- (pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide; 2-[(3S)-1-[(2-cyclobutoxyphenyl)methyl]piperidin-3-yl]- / V-(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3- yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;

[0251] 2-[(3S)-1-{[2-(cyclopentyloxy)phenyl] methyl}piperidin-3-yl]-A / -(5-{[(3 / ?)-1 -(pyridazin-3- yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;

[0252] 2-({1-[(2-cyclobutoxyphenyl)methyl]piperidin-4-yl}sulfanyl)-A / -(5-{[(3 / ?)-1-(pyridazin-3- yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;

[0253] 2-(4-cyclohexylmorpholin-2-yl)- / V-(5-{[(3 / ?)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4- thiadiazol-2-yl)acetamide;

[0254] 2-[(3S)-1-{[2-(3,3-difluorocyclobutoxy)phenyl]methyl}piperidin-3-yl]-A / -(5-{[(3 / ?)-1-(pyridazin-3- yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;

[0255] 2-(4-cyclopentylmorpholin-2-yl)- / V-(5-{[(3 / ?)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4- thiadiazol-2-yl)acetamide;

[0256] 2-(2-{[2-(propan-2-ylsulfanyl)phenyl]methyl}-6-oxa-2-azaspiro[3.4]octan-7-yl)-A / -(5-{[(3 / ?)-1-

[0257] (pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide

[0258] 2-(1-{[(4,4-dimethylcyclohexyl)methyl] (methyl)amino}cyclopropyl)-A / -(5-{[(3R)-1-(pyridazin-3- yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;

[0259] 2-(4-hydroxy-1-{[2-(propan-2-ylsulfanyl)phenyl]methyl}piperidin-4-yl)-A / -(5-{[(3 / ?)-1-(pyridazin-3- yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;

[0260] 2-{4-[(4,4-dimethylcyclohexyl)methyl]-1 ,4-diazepan-1-yl}-A / -(5-{[(3 / ?)-1-(pyridazin-3-yl)pyrrolidin-

[0261] 3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;

[0262] 2-({1-[(3-tert-butyl-1 ,2-oxazol-5-yl)methyl]piperidin-4-yl}sulfanyl)-A / -(5-{[(3 / ?)-1-(pyridazin-3- yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;

[0263] 2-{2-[(4,4-dimethylcyclohexyl)methyl]-6-oxa-2-azaspiro[3.4]octan-7-yl}-A / -(5-{[(3 / ?)-1-(pyridazin-

[0264] 3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;

[0265] 2-(( / ?)-2-((4,4-dimethylcyclohexyl)methyl)-6-oxa-2-azaspiro[3.4]octan-7-yl)-A / -(5-((( / ?)-1-

[0266] (pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0267] 2-((S)-2-((4,4-dimethylcyclohexyl)methyl)-6-oxa-2-azaspiro[3.4]octan-7-yl)-A / -(5-((( / ?)-1-

[0268] (pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0269] 2-[(1-{[2-(propan-2-yloxy)phenyl] methyl}piperidin-3-yl)sulfanyl]-A / -(5-{[(3 / ?)-1 -(pyridazin-3- yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;

[0270] 2-((( / ?)-1-(2-isopropoxybenzyl)piperidin-3-yl)thio)-A / -(5-((( / ?)-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0271] 2-(((S)-1-(2-isopropoxybenzyl)piperidin-3-yl)thio)-A / -(5-((( / ?)-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0272] 2-[(1-{[2-(methylsulfanyl)phenyl]methyl}piperidin-3-yl)oxy]- / V-(5-{[(3R)-1-(pyridazin-3- yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide; 2-((( )-1-(2-(methylthio)benzyl)piperidin-3-yl)oxy)- / V-(5-((( )-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0273] 2-(((S)-1-(2-(methylthio)benzyl)piperidin-3-yl)oxy)- / V-(5-((( / ?)-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0274] 2-[(1-{[2-(propan-2-ylsulfanyl)phenyl]methyl}piperidin-3-yl)oxy]-A / -(5-{[(3 / ?)-1-(pyridazin-3- yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;

[0275] 2-(((R)-1-(2-(isopropylthio)benzyl)piperidin-3-yl)oxy)-A / -(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0276] 2-(((S)-1-(2-(isopropylthio)benzyl)piperidin-3-yl)oxy)-A / -(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0277] 2-[4-(4,4-dimethylcyclohexyl)morpholin-2-yl]-A / -(5-{[(3 )-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-

[0278] 1 ,3,4-thiadiazol-2-yl)acetamide;

[0279] 2-((S)-4-(4,4-dimethylcyclohexyl)morpholin-2-yl)-A / -(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0280] 2-(( )-4-(4,4-dimethylcyclohexyl)morpholin-2-yl)-A / -(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0281] 2-[(2-{[2-(propan-2-yloxy)phenyl]methyl}-2-azaspiro[3.3]heptan-6-yl)sulfanyl]-A / -(5-{[(3 )-1- (pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;

[0282] 2-[(3S)-1-[(3,5-dimethylphenyl)methyl]piperidin-3-yl]- / V-(5-{[(3 / ?)-1-(pyridazin-3-yl)pyrrolidin-3- yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;

[0283] 2-[(1-{[2-(propan-2-yloxy)phenyl]methyl}piperidin-4-yl)sulfanyl]-A / -(5-{[(3 / ?)-1-(pyridazin-3- yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)butanamide;

[0284] / V-(5-{[(3 / ?)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)-2-{4-[(1s,4s)-4-tert- butylcyclohexyl]morpholin-2-yl}acetamide;

[0285] A / -(5-{[(3 )-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)-2-{4-[(1r,4r)-4-tert- butylcyclohexyl]morpholin-2-yl}acetamide;

[0286] 2-[(3S)-1-[(4-ethyl-2-fluorophenyl)methyl]piperidin-3-yl]- / V-(5-{[(3 / ?)-1-(pyridazin-3-yl)pyrrolidin-3- yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;

[0287] A / -(5-{[(3 )-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)-2-[4-(3,3,4,4- tetramethylcyclopentyl)morpholin-2-yl]acetamide;

[0288] 2-[(3R)-1-[(3,5-difluorophenyl)methyl]piperidin-3-yl]- / V-(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3- yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;

[0289] 2-[(3S)-1-[(4-fluoro-3,5-dimethylphenyl)methyl]piperidin-3-yl]-A / -(5-{[(3R)-1-(pyridazin-3- yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;

[0290] 2-[(3S)-1-[(3-fluoro-5-methylphenyl)methyl]piperidin-3-yl]- / V-(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-

[0291] 3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide; 2-[(3S)-1 -[(4-fluoro-3-methoxy-5-methylphenyl)methyl]piperidin-3-yl]-A / -(5-{[(3 )-1 -(pyridazin-3- yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;

[0292] 2-[(3S)-1-[(4-ethoxy-3,5-difluorophenyl)methyl]piperidin-3-yl]-A / -(5-{[(3 )-1-(pyridazin-3- yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;

[0293] 2-[(3S)-1-{[3-fluoro-5-(propan-2-yloxy)phenyl]methyl}piperidin-3-yl]-A / -(5-{[(3 / ?)-1-(pyridazin-3- yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;

[0294] 2-{3-[(5-ethyl-3-methyl-1 ,2-oxazol-4-yl)methyl]-3-azaspiro[5.5]undecan-9-yl}-A / -(5-{[(3 )-1-

[0295] (pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;

[0296] 2-[(3S)-1-{[3-methyl-5-(propan-2-yloxy)phenyl]methyl}piperidin-3-yl]-A / -(5-{[(3 / ?)-1-(pyridazin-3- yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;

[0297] 2-{4-[(1 S,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl]morpholin-2-yl}-A / -(5-{[(3 )-1-(pyridazin-3- yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;

[0298] 2-{(R)-4-[(1 S,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl]morpholin-2-yl}- / V-(5-{[(3R)-1-

[0299] (pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;

[0300] 2-{(S)-4-[(1 S,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl]morpholin-2-yl}- / V-(5-{[(3R)-1-

[0301] (pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;

[0302] 2-[(3S)-1-[(3-ethoxy-4,5-difluorophenyl)methyl]piperidin-3-yl]-A / -(5-{[(3R)-1-(pyridazin-3- yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;

[0303] 2-[(3S)-1-[(3-fluoro-5-methoxy-4-methylphenyl)methyl]piperidin-3-yl]-A / -(5-{[(3R)-1-(pyridazin-3- yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;

[0304] 2-[(3S)-1-{[3-(difluoromethoxy)-5-methylphenyl]methyl}piperidin-3-yl]-A / -(5-{[(3R)-1-(pyridazin-3- yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;

[0305] 2-[(3S)-1-[(2-ethyl-1-benzofuran-3-yl)methyl]piperidin-3-yl]-A / -(5-{[(3R)-1-(pyridazin-3- yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;

[0306] 2-[(3S)-1-[(3-fluoro-4,5-dimethylphenyl)methyl]piperidin-3-yl]- / \ / -(5-{[(3 9-1-(pyridazin-3- yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;

[0307] 2-[(3S)-1-[(2,5-dimethylthiophen-3-yl)methyl]piperidin-3-yl]-A / -(5-{[(3R)-1-(pyridazin-3- yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;

[0308] 2-({1-[(2,5-dimethylthiophen-3-yl)methyl]piperidin-4-yl}sulfanyl)-A / -(5-{[(3 )-1-(pyridazin-3- yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;

[0309] 2-[(3S)-1-[(3,5-difluorophenyl)methyl]piperidin-3-yl]- / V-(5-{methyl[(3R)-1-(pyridazin-3- yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;

[0310] 2-[4-(4,4-dimethylcyclohexyl)morpholin-2-yl]-A / -(5-{methyl[(3R)-1-(pyridazin-3-yl)pyrrolidin-3- yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;

[0311] 2-[4-(4,4-dimethylcyclohexyl)piperazin-1-yl]-A / -(5-{[(3 )-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-

[0312] 1 ,3,4-thiadiazol-2-yl)acetamide; 2-({1-[(1-tert-butyl-1 H-pyrrol-3-yl)methyl]piperidin-4-yl}sulfanyl)-A / -(5-{[(3 )-1-(pyridazin-3- yl)pyrrolidin-3-yl]amino}-1,3,4-thiadiazol-2-yl)acetamide;

[0313] 2-({1-[(1-tert-butyl-1 H-pyrazol-4-yl)methyl]piperidin-4-yl}sulfanyl)-A / -(5-{[(3 )-1-(pyridazin-3- yl)pyrrolidin-3-yl]amino}-1,3,4-thiadiazol-2-yl)acetamide;

[0314] N-(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)-2-[4-(3,3,5,5- tetramethylcyclohexyl)piperazin-1-yl]acetamide;

[0315] N-(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)-2-(4-{spiro[4.5]decan-8- yl}piperazin-1-yl)acetamide;

[0316] 2-(4,4-difluoro-1-{spiro[2.5]octan-6-yl}piperidin-3-yl)-N-(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3- yl]amino}-1,3,4-thiadiazol-2-yl)acetamide;

[0317] 2-(1-cyclohexyl-4,4-difluoropiperidin-3-yl)-N-(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-

[0318] 1 ,3,4-thiadiazol-2-yl)acetamide;

[0319] 2-[1-(4,4-dimethylcyclohexyl)-4,4-difluoropiperidin-3-yl]-N-(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3- yl]amino}-1,3,4-thiadiazol-2-yl)acetamide;

[0320] 2-[4-(4,4-diethylcyclohexyl)morpholin-2-yl]-N-(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-

[0321] 1 ,3,4-thiadiazol-2-yl)acetamide;

[0322] 2-((R)-4-(4,4-diethylcyclohexyl)morpholin-2-yl)-N-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0323] 2-((S)-4-(4,4-diethylcyclohexyl)morpholin-2-yl)-N-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0324] N-(5-(((R)-1-(1,2,4-triazin-6-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-(4-(4,4- dimethylcyclohexyl)morpholin-2-yl)acetamide;

[0325] N-(5-{[(3R)-1-(6-chloropyridazin-3-yl)pyrrolidin-3-yl]amino}-1,3,4-thiadiazol-2-yl)-2-[(3S)-1-[(3,5- difluorophenyl)methyl]piperidin-3-yl]acetamide;

[0326] 2-[4-(2-cyclohexylpropan-2-yl)morpholin-2-yl]-N-(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3- yl]amino}-1,3,4-thiadiazol-2-yl)acetamide;

[0327] 2-[(R)-4-(2-cyclohexylpropan-2-yl)morpholin-2-yl]- / V-(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3- yl]amino}-1,3,4-thiadiazol-2-yl)acetamide;

[0328] 2-[(S)-4-(2-cyclohexylpropan-2-yl)morpholin-2-yl]- / V-(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3- yl]amino}-1,3,4-thiadiazol-2-yl)acetamide;

[0329] 2-(1-cycloheptyl-4,4-difluoropiperidin-3-yl)-N-(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-

[0330] 1 ,3,4-thiadiazol-2-yl)acetamide; isopropyl (R)-4-((4-(2-oxo-2-((5-((1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1,3,4-thiadiazol-2- yl)amino)ethyl)piperidin-1-yl)methyl)benzoate; isopropyl (R)-3-((4-(2-oxo-2-((5-((1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1,3,4-thiadiazol-2- yl)amino)ethyl)piperidin-1-yl)methyl)benzoate; (R)-2-(1-(3-methyl-5-(trifluoromethoxy)benzyl)piperidin-4-yl)-N-(5-((1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0331] (R)-N-(5-((1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-(1-(2,4,6- trimethylbenzyl)piperidin-4-yl)acetamide;

[0332] (R)-2-(1-(2-methyl-4-(trifluoromethoxy)benzyl)piperidin-4-yl)-N-(5-((1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0333] (R)-2-(1-(3-methyl-4-(trifluoromethyl)benzyl)piperidin-4-yl)-N-(5-((1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0334] (R)-N-(5-((1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-(1-((5-

[0335] (trifluoromethyl)pyridin-3-yl)methyl)piperidin-4-yl)acetamide;

[0336] (R)-2-(1-((5-methoxy-6-(trifluoromethyl)pyridin-2-yl)methyl)piperidin-4-yl)-N-(5-((1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0337] 2-((S)-1-(3-methyl-5-(trifluoromethoxy)benzyl)piperidin-3-yl)-N-(5-(((R)-1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0338] (R)-2-(1-(3-(difluoromethoxy)-5-methylbenzyl)piperidin-4-yl)-N-(5-((1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide; isobutyl (R)-4-((4-(2-oxo-2-((5-((1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1,3,4-thiadiazol-2- yl)amino)ethyl)piperidin-1-yl)methyl)picolinate;

[0339] (R)-N-(5-((1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-(1-(2-

[0340] (trifluoromethoxy)benzyl)piperidin-4-yl)acetamide;

[0341] (R)-2-(1-(4-fluoro-2-(trifluoromethoxy)benzyl)piperidin-4-yl)-N-(5-((1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0342] (R)-2-(1-(2-(difluoromethoxy)-5-methylbenzyl)piperidin-4-yl)-N-(5-((1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0343] (R)-2-(1-(2-(isopropylthio)benzyl)piperidin-4-yl)-N-(5-((1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-

[0344] 1 ,3,4-thiadiazol-2-yl)acetamide;

[0345] (R)-2-((1-(2-isopropoxybenzyl)piperidin-4-yl)thio)-N-(5-((1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-

[0346] 1 ,3,4-thiadiazol-2-yl)acetamide;

[0347] (R)-2-(1-(3-isopropoxybenzyl)piperidin-4-yl)-N-(5-((1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4- thiadiazol-2-yl)acetamide;

[0348] (R)-2-(1-(2-cyclobutoxybenzyl)piperidin-4-yl)-N-(5-((1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-

[0349] 1 ,3,4-thiadiazol-2-yl)acetamide;

[0350] (R)-2-(1-(2-isopropoxy-4-methylbenzyl)piperidin-4-yl)-N-(5-((1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0351] (R)-2-(2-(3-(difluoromethoxy)benzyl)-2-azaspiro[3.5]nonan-7-yl)-N-(5-((1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide; (R)-N-(5-((1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-(2-(3-

[0352] (trifluoromethoxy)benzyl)-2-azaspiro[3.3]heptan-6-yl)acetamide;

[0353] 2-((S)-1-(2-isopropoxybenzyl)piperidin-3-yl)-N-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-

[0354] 1 ,3,4-thiadiazol-2-yl)acetamide;

[0355] 2-((R)-1-(2-isopropoxybenzyl)piperidin-3-yl)-N-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-

[0356] 1 ,3,4-thiadiazol-2-yl)acetamide;

[0357] 2-((S)-1-(2-isopropoxyphenethyl)piperidin-3-yl)-N-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0358] 2-((R)-1-(2-isopropoxyphenethyl)piperidin-3-yl)-N-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0359] 8-(3,5-dimethylbenzyl)-N-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2- oxa-8-azaspiro[4.5]decane-3-carboxamide;

[0360] 8-(2-isopropoxybenzyl)-N-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1,3,4-thiadiazol-2-yl)-

[0361] 2-oxa-8-azaspiro[4.5]decane-3-carboxamide;

[0362] (R)-2-(3-((6-(difluoromethyl)pyridin-3-yl)methyl)-3-azaspiro[5.5]undecan-9-yl)-N-(5-((1-

[0363] (pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0364] (R)-N-(5-((1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-(3-((5-

[0365] (trifluoromethyl)pyridin-2-yl)methyl)-3-azaspiro[5.5]undecan-9-yl)acetamide;

[0366] (R)-N-(5-((1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-(3-((2,4,6- trimethylpyridin-3-yl)methyl)-3-azaspiro[5.5]undecan-9-yl)acetamide;

[0367] (R)-2-(3-((5-chloropyridin-2-yl)methyl)-3-azaspiro[5.5]undecan-9-yl)-N-(5-((1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0368] (R)-2-(3-((5-bromopyridin-3-yl)methyl)-3-azaspiro[5.5]undecan-9-yl)-N-(5-((1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0369] (R)-N-(5-((1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-(6-(3-

[0370] (trifluoromethoxy)benzyl)-6-azaspiro[3.4]octan-2-yl)acetamide;

[0371] N-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-((2r,4R)-6-(3-

[0372] (trifluoromethoxy)benzyl)-6-azaspiro[3.4]octan-2-yl)acetamide;

[0373] N-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-((2s,4S)-6-(3-

[0374] (trifluoromethoxy)benzyl)-6-azaspiro[3.4]octan-2-yl)acetamide;

[0375] (R)-2-(6-(3-(difluoromethoxy)-5-methylbenzyl)-6-azaspiro[3.4]octan-2-yl)-N-(5-((1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0376] (R)-2-(6-(2-isopropoxy-4-methylbenzyl)-6-azaspiro[3.4]octan-2-yl)-N-(5-((1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0377] 2-((2r,4R)-6-(2-isopropoxy-4-methylbenzyl)-6-azaspiro[3.4]octan-2-yl)-N-(5-(((R)-1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide; 2-((2s,4S)-6-(2-isopropoxy-4-methylbenzyl)-6-azaspiro[3.4]octan-2-yl)-N-(5-(((R)-1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0378] 8-(3-(difluoromethoxy)benzyl)-N-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1,3,4-thiadiazol-

[0379] 2-yl)-2-oxa-8-azaspiro[4.5]decane-3-carboxamide;

[0380] (R)-8-(3-(difluoromethoxy)benzyl)- / V-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4- thiadiazol-2-yl)-2-oxa-8-azaspiro[4.5]decane-3-carboxamide;

[0381] (S)-8-(3-(difluoromethoxy)benzyl)- / V-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4- thiadiazol-2-yl)-2-oxa-8-azaspiro[4.5]decane-3-carboxamide;

[0382] (R)-2-(3-((3-cyclobutoxypyridin-2-yl)methyl)-3-azaspiro[5.5]undecan-9-yl)-N-(5-((1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0383] 2-(1-(3,5-dimethylbenzyl)piperidin-4-yl)-2-methoxy-N-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0384] 2-(1-(2-cyclobutoxybenzyl)piperidin-4-yl)-2-methoxy-N-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0385] 2-(1-(2-(isopropylthio)benzyl)piperidin-4-yl)-2-methoxy-N-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0386] (R)-2-(3-((5-chloropyridin-3-yl)methyl)-3-azaspiro[5.5]undecan-9-yl)-N-(5-((1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0387] (R)-2-(3-((4-bromopyridin-2-yl)methyl)-3-azaspiro[5.5]undecan-9-yl)-N-(5-((1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0388] (R)-2-(3-((5-bromopyridin-2-yl)methyl)-3-azaspiro[5.5]undecan-9-yl)-N-(5-((1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0389] 2-(4-ethyl-1-(3-(trifluoromethoxy)benzyl)piperazin-2-yl)-N-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0390] 2-(( )-4-ethyl-1-(3-(trifluoromethoxy)benzyl)piperazin-2-yl)-A / -(5-(((R)-1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0391] 2-((S)-4-ethyl-1-(3-(trifluoromethoxy)benzyl)piperazin-2-yl)-A / -(5-(((R)-1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0392] 2-(1-(2-isopropoxybenzyl)piperidin-4-yl)-N-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4- thiadiazol-2-yl)butanamide;

[0393] (R)-2-(1-(2-isopropoxybenzyl)piperidin-4-yl)- / V-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)- 1 ,3,4-thiadiazol-2-yl)butanamide;

[0394] (S)-2-(1-(2-isopropoxybenzyl)piperidin-4-yl)- / V-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-

[0395] 1 ,3,4-thiadiazol-2-yl)butanamide;

[0396] (R)-3-(1-(2-isopropoxybenzyl)piperidin-4-yl)-N-(5-((1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4- thiadiazol-2-yl)propanamide; (R)-2-((1-(2-(isopropylthio)benzyl)piperidin-4-yl)oxy)-N-(5-((1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0397] 8-(2-cyclobutoxybenzyl)-N-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-

[0398] 2-oxa-8-azaspiro[4.5]decane-3-carboxamide;

[0399] (R)-8-(2-cyclobutoxybenzyl)- / V-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2- yl)-2-oxa-8-azaspiro[4.5]decane-3-carboxamide;

[0400] (S)-8-(2-cyclobutoxybenzyl)- / V-(5-((( )-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2- yl)-2-oxa-8-azaspiro[4.5]decane-3-carboxamide;

[0401] 2-((R)-2-(2-(isopropylthio)benzyl)-6-oxa-2-azaspiro[3.4]octan-7-yl)-A / -(5-(((R)-1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0402] 2-((S)-2-(2-(isopropylthio)benzyl)-6-oxa-2-azaspiro[3.4]octan-7-yl)-A / -(5-((( )-1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0403] 2-cyclobutyl-2-(1-(2-methylbenzyl)piperidin-4-yl)-N-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0404] (R)-2-cyclobutyl-2-(1-(2-methylbenzyl)piperidin-4-yl)- / V-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0405] (S)-2-cyclobutyl-2-(1-(2-methylbenzyl)piperidin-4-yl)-A / -(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0406] 3-cyclopropyl-2-(1-(2-methylbenzyl)piperidin-4-yl)-N-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)propanamide;

[0407] ( )-3-cyclopropyl-2-(1-(2-methylbenzyl)piperidin-4-yl)-A / -(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)propanamide;

[0408] (S)-3-cyclopropyl-2-(1-(2-methylbenzyl)piperidin-4-yl)-A / -(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)propanamide;

[0409] 3-methyl-2-(1-(2-methylbenzyl)piperidin-4-yl)-N-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-

[0410] 1 ,3,4-thiadiazol-2-yl)butanamide;

[0411] (R)-3-methyl-2-(1-(2-methylbenzyl)piperidin-4-yl)- / V-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)butanamide;

[0412] (S)-3-methyl-2-(1-(2-methylbenzyl)piperidin-4-yl)- / V-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)butanamide;

[0413] 2-(4-cyclohexylmorpholin-3-yl)-N-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4- thiadiazol-2-yl)acetamide;

[0414] 2-(( )-4-cyclohexylmorpholin-3-yl)- / V-(5-((( )-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4- thiadiazol-2-yl)acetamide;

[0415] 2-((S)-4-cyclohexylmorpholin-3-yl)- / V-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4- thiadiazol-2-yl)acetamide; 2-[4-(4,4-dimethylcyclohexyl)-1,4-oxazepan-2-yl]-N-(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3- yl]amino}-1,3,4-thiadiazol-2-yl)acetamide;

[0416] (R)-2-(1-(4-(difluoromethoxy)benzyl)piperidin-4-yl)-2-ethoxy-N-(5-(((R)-1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0417] (S)-2-(1-(4-(difluoromethoxy)benzyl)piperidin-4-yl)-2-ethoxy-N-(5-(((R)-1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0418] 2-((1-(1-(2-isopropoxyphenyl)ethyl)piperidin-4-yl)thio)-N-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0419] 2-((1-(( )-1-(2-isopropoxyphenyl)ethyl)piperidin-4-yl)thio)-A / -(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-

[0420] 3-yl)amino)-1,3,4-thiadiazol-2-yl)acetamide;

[0421] 2-((1-((S)-1-(2-isopropoxyphenyl)ethyl)piperidin-4-yl)thio)-A / -(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-

[0422] 3-yl)amino)-1,3,4-thiadiazol-2-yl)acetamide;

[0423] 2-((S)-1-(3,5-difluoro-4-methylbenzyl)piperidin-3-yl)-N-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0424] 2-((S)-1-(3,5-difluoro-2-methylbenzyl)piperidin-3-yl)-N-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0425] 2-(1-(3,5-difluorobenzyl)azepan-3-yl)-N-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4- thiadiazol-2-yl)acetamide;

[0426] (R)-2-(methyl(2-(1-(3-(trifluoromethoxy)benzyl)piperidin-4-yl)propan-2-yl)amino)-N-(5-((1- (pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0427] 2-(4-((4,4-dimethylcyclohexyl)methyl)thiomorpholin-2-yl)-N-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0428] 2-((3S)-1-(1-(3,5-difluorophenyl)ethyl)piperidin-3-yl)-N-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0429] 2-((S)-1-((S)-1-(3,5-difluorophenyl)ethyl)piperidin-3-yl)-A / -(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0430] 2-((S)-1-(( )-1-(3,5-difluorophenyl)ethyl)piperidin-3-yl)- / V-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0431] 2-(4-(4-isopropylcyclohexyl)morpholin-2-yl)-N-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)- 1 ,3,4-thiadiazol-2-yl)acetamide;

[0432] 2-((S)-4-((1r,4S)-4-isopropylcyclohexyl)morpholin-2-yl)-A / -(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0433] 2-((R)-4-((1r,4R)-4-isopropylcyclohexyl)morpholin-2-yl)- / V-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0434] 2-((S)-4-((1s,4R)-4-isopropylcyclohexyl)morpholin-2-yl)-A / -(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide; 2-(( )-4-((1s,4S)-4-isopropylcyclohexyl)morpholin-2-yl)- / V-(5-((( )-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0435] (R)-2-(2-(3-fluoro-5-methylbenzyl)-2,6-diazaspiro[3.4]octan-6-yl)-N-(5-((1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0436] 2-((R)-1-(3-(difluoromethoxy)benzyl)-4-isopropylpiperazin-2-yl)-A / -(5-((( )-1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0437] 2-((S)-1-(3-(difluoromethoxy)benzyl)-4-isopropylpiperazin-2-yl)-A / -(5-((( )-1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0438] N-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-(4-(spiro[2.5]octan-6- yl)morpholin-2-yl)acetamide;

[0439] A / -(5-((( )-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-((S)-4-(spiro[2.5]octan-

[0440] 6-yl)morpholin-2-yl)acetamide;

[0441] A / -(5-((( )-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-((R)-4-(spiro[2.5]octan-

[0442] 6-yl)morpholin-2-yl)acetamide;

[0443] N-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-(4-(spiro[3.5]nonan-2- yl)morpholin-2-yl)acetamide;

[0444] A / -(5-((( )-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-((S)-4-

[0445] (spiro[3.5]nonan-2-yl)morpholin-2-yl)acetamide;

[0446] A / -(5-((( )-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-(( )-4-

[0447] (spiro[3.5]nonan-2-yl)morpholin-2-yl)acetamide;

[0448] (R)-2-(8-(2-(isopropylthio)benzyl)-2,8-diazaspiro[4.5]decan-2-yl)-N-(5-((1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0449] 2-((S)-1-(4-ethyl-3-fluorobenzyl)piperidin-3-yl)-N-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-

[0450] 1 ,3,4-thiadiazol-2-yl)acetamide;

[0451] 2-((3S)-1-(1-(3-fluoro-4-methylphenyl)ethyl)piperidin-3-yl)-N-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-

[0452] 3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0453] 2-((S)-1-((S)-1-(3-fluoro-4-methylphenyl)ethyl)piperidin-3-yl)-A / -(5-(((R)-1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0454] 2-((S)-1-(( )-1-(3-fluoro-4-methylphenyl)ethyl)piperidin-3-yl)-A / -(5-(((R)-1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0455] 2-((3S)-1-(1-(2-fluoro-4-methylphenyl)ethyl)piperidin-3-yl)-N-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-

[0456] 3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0457] 2-((S)-1-((S)-1-(2-fluoro-4-methylphenyl)ethyl)piperidin-3-yl)-A / -(5-(((R)-1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0458] 2-((S)-1-(( )-1-(2-fluoro-4-methylphenyl)ethyl)piperidin-3-yl)-A / -(5-(((R)-1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide; N-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-(4-(spiro[3.4]octan-2- yl)morpholin-2-yl)acetamide;

[0459] / V-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-((S)-4-(spiro[3.4]octan- 2-yl)morpholin-2-yl)acetamide;

[0460] / V-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-(( / ?)-4-(spiro[3.4]octan-

[0461] 2-yl)morpholin-2-yl)acetamide;

[0462] (R)-2-(2-(3-fluoro-5-methylbenzyl)-2,6-diazaspiro[3.5]nonan-6-yl)-N-(5-((1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0463] (R)-2-(2-(2-(methylthio)benzyl)-2,6-diazaspiro[3.5]nonan-6-yl)-N-(5-((1-(pyridazin-3-yl)pyrrolidin-

[0464] 3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0465] (R)-2-(2-(2-(isopropylthio)benzyl)-2,6-diazaspiro[3.5]nonan-6-yl)-N-(5-((1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0466] N-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-(4-(spiro[4.5]decan-8- yl)morpholin-2-yl)acetamide;

[0467] A / -(5-((( )-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-(( )-4-

[0468] (spiro[4.5]decan-8-yl)morpholin-2-yl)acetamide;

[0469] A / -(5-((( )-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-((S)-4-

[0470] (spiro[4.5]decan-8-yl)morpholin-2-yl)acetamide;

[0471] N-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-(4-(spiro[3.5]nonan-7- yl)morpholin-2-yl)acetamide;

[0472] N-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-((R)-4-

[0473] (spiro[3.5]nonan-7-yl)morpholin-2-yl)acetamide;

[0474] N-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-((S)-4-

[0475] (spiro[3.5]nonan-7-yl)morpholin-2-yl)acetamide; tert-butyl 4-(((S)-3-(2-((5-(((R)-1-(6-chloropyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2- yl)amino)-2-oxoethyl)piperidin-1-yl)methyl)piperidine-1 -carboxylate;

[0476] 2-(4-((4,4-dimethylcyclohexyl)methyl)-1-methylpiperazin-2-yl)-N-(5-(((R)-1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0477] 2-((R)-4-((4,4-dimethylcyclohexyl)methyl)-1-methylpiperazin-2-yl)-A / -(5-(((R)-1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0478] 2-((S)-4-((4,4-dimethylcyclohexyl)methyl)-1-methylpiperazin-2-yl)-A / -(5-(((R)-1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0479] 2-((R)-4-((4,4-dimethylcyclohexyl)methyl)-1-methylpiperazin-2-yl)N-(5-(((R)-1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0480] 2-((S)-4-((4,4-dimethylcyclohexyl)methyl)-1-methylpiperazin-2-yl)-N-(5-(((R)-1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide; N-(5-(((R)-1-(6-chloropyridazin-3-yl)pyrrolidin-3-yl)amino)-1,3,4-thiadiazol-2-yl)-2-(4-(4,4- dimethylcyclohexyl)morpholin-2-yl)acetamide;

[0481] N-(5-(((R)-1-(6-chloropyridazin-3-yl)pyrrolidin-3-yl)amino)-1,3,4-thiadiazol- 2-yl)-2-((S)-4-(4,4-dimethylcyclohexyl)morpholin-2-yl)acetamide;

[0482] N-(5-(((R)-1-(6-chloropyridazin-3-yl)pyrrolidin-3-yl)amino)-1,3,4-thiadiazol- 2-yl)-2-((R)-4-(4,4-dimethylcyclohexyl)morpholin-2-yl)acetamide;

[0483] 2-(4-(2,4-dimethylpentan-3-yl)morpholin-2-yl)-N-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)- 1 ,3,4-thiadiazol-2-yl)acetamide;

[0484] 2-((S)-1-(3,5-difluorobenzyl)piperidin-3-yl)-N-(5-(((3S,4S)-4-fluoro-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0485] 2-[4-(4,4-dimethylcyclohexyl)-1-methylpiperazin-2-yl]-N-(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3- yl]amino}-1,3,4-thiadiazol-2-yl)acetamide;

[0486] 2-[(R)-4-(4,4-dimethylcyclohexyl)-1-methylpiperazin-2-yl]-N-(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-

[0487] 3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;

[0488] 2-[(S)-4-(4,4-dimethylcyclohexyl)-1-methylpiperazin-2-yl]-N-(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-

[0489] 3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;

[0490] 2-[4-(4,4-dimethylcyclohexyl)thiomorpholin-2-yl]-N-(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3- yl]amino}-1,3,4-thiadiazol-2-yl)acetamide;

[0491] N-(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)-2-(4-{spiro[4.5]decan-8- yl}thiomorpholin-2-yl)acetamide; and 2-(4-{bicyclo[2.2.2]octan-1-yl}morpholin-2-yl)-N-(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}- 1 ,3,4-thiadiazol-2-yl)acetamide; or a salt and / or solvate of any one thereof such as a pharmaceutically acceptable salt and / or solvate thereof.

[0492] In one embodiment there is provided a compound of formula (I), which is selected from the list consisting of:

[0493] (R)-N-(5-((1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-(4-(3- (trifluoromethoxy)benzyl)piperazin-1-yl)acetamide;

[0494] (R)-N-(5-((1-(6-chloropyridazin-3-yl)pyrrolidin-3-yl)amino)-1,3,4-thiadiazol-2-yl)-2-(4-(4- (trifluoromethoxy)benzyl)piperazin-1-yl)acetamide;

[0495] (R)-2-(4-(2-chloro-4-(trifluoromethyl)benzyl)piperazin-1-yl)-N-(5-((1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0496] (R)-2-(4-(3-chloro-5-(trifluoromethyl)benzyl)piperazin-1-yl)-N-(5-((1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0497] (R)-N-(5-((1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-(4-(2- (trifluoromethoxy)benzyl)piperazin-1-yl)acetamide; (R)-2-(4-(3-fluoro-4-(trifluoromethyl)benzyl)piperazin-1-yl)-N-(5-((1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0498] (R)-2-(4-(3-bromo-5-fluorobenzyl)piperazin-1-yl)-N-(5-((1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)- 1 ,3,4-thiadiazol-2-yl)acetamide;

[0499] (R)-2-(4-(3-methoxy-4-(trifluoromethyl)benzyl)piperazin-1-yl)-N-(5-((1-(pyridazin-3-yl)pyrrolidin- 3-yl)amino)-1,3,4-thiadiazol-2-yl)acetamide;

[0500] (R)-2-(4-(4-chloro-3-fluorobenzyl)piperazin-1-yl)-N-(5-((1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)- 1 ,3,4-thiadiazol-2-yl)acetamide;

[0501] (R)-2-(4-(3-chloro-5-fluorobenzyl)piperazin-1-yl)-N-(5-((1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)- 1 ,3,4-thiadiazol-2-yl)acetamide;

[0502] (R)-2-(4-(3,4-difluorobenzyl)piperazin-1-yl)-N-(5-((1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1,3,4- thiadiazol-2-yl)acetamide;

[0503] (R)-2-(4-(3,5-difluorobenzyl)piperazin-1-yl)-N-(5-((1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1,3,4- thiadiazol-2-yl)acetamide;

[0504] (R)-2-(4-(3,5-difluoro-4-methoxybenzyl)piperazin-1-yl)-N-(5-((1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0505] N-(5-(((3S,4S)-4-fluoro-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1,3,4-thiadiazol-2-yl)-2-(4-(4-

[0506] (trifluoromethoxy)benzyl)piperazin-1-yl)acetamide;

[0507] (R)-2-(4-(2-chloro-5-(trifluoromethoxy)benzyl)piperazin-1-yl)-N-(5-((1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0508] (R)-2-(4-(3-chloro-4-(trifluoromethoxy)benzyl)piperazin-1-yl)-N-(5-((1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0509] (R)-2-(4-(3-(difluoromethoxy)-4-methylbenzyl)piperazin-1-yl)-N-(5-((1-(pyridazin-3-yl)pyrrolidin-

[0510] 3-yl)amino)-1,3,4-thiadiazol-2-yl)acetamide;

[0511] ((R)-2-(4-(3,5-dichloro-4-methylbenzyl)piperazin-1-yl)-N-(5-((1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0512] (R)-2-(4-(2,4-dichloro-6-fluorobenzyl)piperazin-1-yl)-N-(5-((1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0513] (R)-2-(4-(5-fluoro-2-(trifluoromethyl)benzyl)piperazin-1-yl)-N-(5-((1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0514] (R)-2-(4-(3-fluoro-5-(trifluoromethyl)benzyl)piperazin-1-yl)-N-(5-((1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0515] (R)-2-(4-((7-fluoro-2,3-dihydro-1 H-inden-5-yl)methyl)piperazin-1-yl)-N-(5-((1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0516] (R)-2-(4-(5-chloro-2-(difluoromethoxy)benzyl)piperazin-1-yl)-N-(5-((1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide; (R)-2-(4-(2,3-difluorobenzyl)piperazin-1-yl)-N-(5-((1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4- thiadiazol-2-yl)acetamide; and

[0517] (R)-2-(4-(3-difluoromethoxy)benzyl)piperazin-1-yl)-N-(5-((1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)- 1 ,3,4-thiadiazol-2-yl)acetamide; or a salt and / or solvate of any one thereof such as a pharmaceutically acceptable salt and / or solvate thereof.

[0518] Compounds of formula (I) may be synthesised as shown in the schemes below and as shown in the Examples section. Example compounds may be synthesized using one or more of the schemes below. For each scheme, variables are as defined above unless otherwise stated.

[0519] One skilled in the art will appreciate that the compounds of formula (I) may be synthesised by one or more of the following schemes.

[0520] Scheme 1 : Synthesis of compounds of formula (I)

[0521] Compounds of formula (I) may be prepared by coupling amine intermediate (III) with carboxylic acid (II) using a coupling agent such as T3P, HATLI or PyBOP in the presence of an organic base such as DIPEA in a solvent such as DMF. Scheme 2: Synthesis of compounds of formula (III), wherein D is pyridazine

[0522] PG is a nitrogen protecting group such as Boc. Other nitrogen protecting groups are as described herein. LG is a leaving group such as halo e.g. chloro. Step 1 : Compounds of formula (VII) are reacted in the presence of an organic base such as DI PEA with compounds of formula (VI) to give compounds of formula (V).

[0523] Step 2: PG is removed under conditions known to the skilled person to give amines (IV). For example, if PG is Boc, this protecting group can be removed using neat TFA.

[0524] Step 3: Amines (IV) are coupled with 5-halo-1 ,3,4-thiadiazol-2-amine (wherein halo is suitably bromo) under basic conditions (such as DIPEA) to give compounds of formula (III).

[0525] Scheme 3: Synthesis of compounds of formula (III), wherein D is 1 ,2,4-triazine

[0526] PG is a nitrogen protecting group such as Boc. Other nitrogen protecting groups are as described herein. LG is a leaving group such as halo e.g. chloro. Step 1 : Compounds of formula (X) are reacted with a reducing agent (such as tert-butyl nitrite) with dimethyldisulfane to give compounds of formula (IX).

[0527] Step 2: Compounds of formula (IX) are reacted in the presence of an organic base such as DI PEA with compounds of formula (V) to give compounds of formula (VIII).

[0528] Step 3: Compounds of formula (VIII) are reacted with a reducing agent (such as Raney-Nickel) to give compounds of formula (V).

[0529] Step 4: PG is removed under conditions known to the skilled person to give amines (IV). For example, if PG is Boc, this protecting group can be removed using neat TFA.

[0530] Step 5: Amines (IV) are coupled with 5-halo-1 ,3,4-thiadiazol-2-amine (wherein halo is suitably bromo) under basic conditions (such as DIPEA) to give compounds of formula (III). Scheme 4: Synthesis of compounds of formula (I) wherein A is a nitrogen containing heterocyclyl or heterospirocycloalkyl

[0531] PG is a nitrogen protecting group such as Boc. Other nitrogen protecting groups are as described herein. The skilled person will appreciate that when PG is attached to ring A, PG is attached to a nitrogen atom in ring A as shown in the following structure: indicates the connection to the remainder of the compound (e.g. any one of the compounds in Scheme 4). Furthermore, after Step 2 wherein PG is removed, the skilled person will appreciate that compounds of formula (XII) have the following structure:

[0532] (Xll-a)

[0533] Step 1 : Compounds of formula (XIV) are coupled with amine intermediate (III) using a coupling agent such as T3P, HATLI or PyBOP in the presence of an organic base such as DIPEA in a solvent such as DMF to give compounds of formula (XIII).

[0534] Step 2: PG is removed under conditions known to the skilled person to give intermediate (XII). For example, if PG is Boc, this protecting group can be removed using neat TFA.

[0535] Step 3: Compounds of formula (XII) are reacted with carbonyl intermediate (XI) using a reducing agent (such as STAB) to give compounds of formula (I). Scheme 5: Synthesis of compounds of formula (I) wherein A is a nitrogen containing heterocyclyl or heterospirocycloalkyl

[0536] PG is a nitrogen protecting group such as Boc. Other nitrogen protecting groups are as described herein. LG is a leaving group such as halo e.g. chloro. The comments regarding ring A under Scheme 4 apply egually to ring A in Scheme 5.

[0537] Step 1 : Compounds of formula (XIV) are coupled with amine intermediate (III) using a coupling agent such as T3P, HATLI or PyBOP in the presence of an organic base such as DIPEA in a solvent such as DMF to give compounds of formula (XIII). Step 2: PG is removed under conditions known to the skilled person to give intermediate (XII). For example, if PG is Boc, this protecting group can be removed using neat TFA.

[0538] Step 3: Compounds of formula (XII) are reacted with alkyl or benzyl halide intermediate (XV) in the presence of an organic base such as TEA to give compounds of formula (I).

[0539] of formula (I) wherein A is a nitrogen containing

[0540] PG is a nitrogen protecting group such as Boc and PG2is a carboxylic acid protecting group such as methyl or benzyl. Other nitrogen protecting groups are as described herein. LG is a leaving group such as halo e.g. chloro. The comments regarding ring A under Scheme 4 apply equally to ring A in Scheme 6, see removal of PG in Step 2 to form compounds of formula (XVII).

[0541] Step 1 : The carboxylic acid group in compounds of formula (XX) is protected with PG2under standard protection conditions known to the skilled person or as described in the Example section below.

[0542] Step 2: PG is removed under acidic conditions known to the skilled person to give intermediate (XVII). For example, if PG is Boc, this protecting group can be removed using HCI.

[0543] Step 3: Compounds of formula (XVII) are reacted with carbonyl intermediate (XI) using a reducing agent (such as STAB) to give compounds of formula (XVI).

[0544] Step 4: PG2is removed under conditions known to the skilled person to give intermediate (II). For example, if PG2is methyl, this protecting group can be removed using LiOH. Alternatively, if PG2is benzyl, this protecting group can be removed using Pd / C with hydrogen gas.

[0545] Step 5: Compounds of formula (II) are coupled with amine intermediate (III) to give compounds of formula (I) as described in Scheme 1. In instances wherein the compound of formula (XVIII) is a readily available starting material, Step 1 of Scheme 6 is omitted.

[0546] Scheme 7: Synthesis of compounds of formula (I) wherein A is a nitrogen containing heterocyclyl or heterospirocyclloalkyl

[0547] PG is a nitrogen protecting group such as Boc and PG2is a carboxylic acid protecting group such as methyl or benzyl. Other nitrogen protecting groups are as described herein. LG is a leaving group such as halo e.g. chloro. The comments regarding ring A under Scheme 4 apply egually to ring A in Scheme 7, see removal of PG in Step 1 to form compounds of formula (XVII). Step 1 : PG is removed under conditions known to the skilled person to give intermediate (XVII). For example, if PG is Boc, this protecting group can be removed using HCI.

[0548] Step 2: Compounds of formula (XVII) are reacted with the alkyl or benzyl halide intermediate (XV) in the presence of an organic base such as TEA to give compounds of formula (XVI). Step 3: PG2is removed under conditions known to the skilled person to give intermediate (II). For example, if PG2is methyl, this protecting group can be removed using LiOH.

[0549] Step 4: Compounds of formula (II) are coupled with amine intermediate (III) to give compounds of formula (I) as described in Scheme 1. Scheme 8: Synthesis of compounds of formula (I) wherein A is a nitrogen containing heterocyclyl or heterospirocyclloalkyl di) (i)

[0550] PG is a nitrogen protecting group such as Boc and PG2is a carboxylic acid protecting group such as methyl or benzyl. Other nitrogen protecting groups are as described herein. LG is a leaving group such as halo e.g. chloro. The comments regarding ring A under Scheme 4 apply egually to ring A in Scheme 8, see removal of PG in Step 2 to form compounds of formula (XXII). In addition, the skilled person will appreciate that ring A in compounds of formula (XXIV) must have an NH group present so that the compounds of formula (XXIV) can undergo reaction with aldehydes of formula (XI) in Step 1 . Thus, this scheme is particularly suitable for the synthesis of compounds where ring A contains two or more N ring atoms e.g. A is piperazinyl.

[0551] Step 1 : Compounds of formula (XXIV) are reacted with carbonyl intermediate (XI) using a reducing agent (such as STAB) to give compounds of formula (XXIII).

[0552] Step 2: Compounds of formula (XXIII) are reacted under acidic conditions (such as in the presence of TFA) to give compounds of formula (XXII).

[0553] Step 3: Compounds of formula (XXII) are reacted with compounds of formula (XXI) under SN2 reaction conditions to give compounds of formula (XVI).

[0554] Step 4: PG2is removed under conditions known to the skilled person to give compounds of formula (II). For example, if PG2is methyl, this protecting group can be removed using LiOH.

[0555] Step 5: Compounds of formula (II) are coupled with amine intermediate (III) to give compounds of formula (I) as described in Scheme 1. Compounds of formula (II) may be synthesised as set out in Schemes 6 to 8. Otherwise, compounds of formula (II) may be synthesised for example as set out in the Example section below. All variables are as defined herein unless otherwise specified.

[0556] The invention provides a compound of formula (II): or a salt, such as a pharmaceutically acceptable salt thereof. Suitably, R2is selected from the group consisting of C1.4 alkyl, C1.4 alkoxy, NR2aR2band Co-salkyleneCs-ecycloalkyl wherein R2aand R2bare as defined elsewhere herein.

[0557] The invention also provides a compound of formula (III): or a salt, such as a pharmaceutically acceptable salt thereof. Suitably, R5is H. Suitably R8is H. Most suitably, R5and R8are both independently H.

[0558] The invention also provides a compound of formula (XII): or a salt, such as a pharmaceutically acceptable salt thereof.

[0559] There is also provided a compound of formula (Xll-a):

[0560] (Xll-a) or a salt, such as a pharmaceutically acceptable salt thereof.

[0561] The invention also provides a compound of formula (XVI): or a salt, such as a pharmaceutically acceptable salt thereof, wherein PG2is a carboxylic acid protecting group such as methyl or benzyl.

[0562] There is also provided a process for the preparation of a compound of formula (I), or a salt such as a pharmaceutically acceptable salt thereof, which comprises reacting a compound of formula (HI): or a salt such as a pharmaceutically acceptable salt thereof; with a compound of formula (II): or a salt such as a pharmaceutically acceptable salt thereof; wherein R2, R3, R4, R5, R8, m, n, o, X, Y, A and B are as defined elsewhere herein.

[0563] There is also provided a process for the preparation of a compound of formula (I), or a salt such as a pharmaceutically acceptable salt thereof, which comprises reacting a compound of formula (XII): or a salt such as a pharmaceutically acceptable salt thereof; with a compound of formula (XI): or a salt such as a pharmaceutically acceptable salt thereof; wherein R2, R3, R4, R5, R8, m, n, o, X, Y, A and B are as defined elsewhere herein.

[0564] Suitably, the compound of formula (XII) is a compound of formula (Xll-a): or a salt such as a pharmaceutically acceptable salt thereof.

[0565] There is also provided a process for the preparation of a compound of formula (I), or a salt such as a pharmaceutically acceptable salt thereof, which comprises reacting a compound of formula (XII): or a salt such as a pharmaceutically acceptable salt thereof; with a compound of formula (XV): or a salt such as a pharmaceutically acceptable salt thereof; wherein R2, R3, R4, R5, R8, m, n, o, X, Y, A and B are as defined elsewhere herein. LG is a leaving group such as halo e.g. chloro.

[0566] Suitably, the compound of formula (XII) is a compound of formula (Xll-a):

[0567] (Xll-a) or a salt such as a pharmaceutically acceptable salt thereof.

[0568] There is also provided a process for the preparation of a compound of formula (XVI), or a salt such as a pharmaceutically acceptable salt thereof, which comprises reacting a compound of formula (XVII): or a salt such as a pharmaceutically acceptable salt thereof; with a compound of formula (XI): O<YYR4)O

[0569] O (XI) or a salt such as a pharmaceutically acceptable salt thereof; wherein R2, R3, R4, m, n, o, X, Y, A and B are as defined elsewhere herein, and PG2is a carboxylic acid protecting group such as methyl or benzyl.

[0570] Suitably, the compound of formula (XVII) is a compound of formula (XVII-a): (xvil-a) or a salt such as a pharmaceutically acceptable salt thereof.

[0571] There is also provided a process for the preparation of a compound of formula (XVI), or a salt such as a pharmaceutically acceptable salt thereof, which comprises reacting a compound of formula (XVII): or a salt such as a pharmaceutically acceptable salt thereof; with a compound of formula (XV): or a salt such as a pharmaceutically acceptable salt thereof; wherein R2, R3, R4, m, n, o, X, Y, A and B are as defined elsewhere herein, PG2is a carboxylic acid protecting group such as methyl or benzyl and LG is a leaving group such as halo e.g. chloro.

[0572] Suitably, the compound of formula (XVII) is a compound of formula (XVII-a): (xvi |-a) or a salt such as a pharmaceutically acceptable salt thereof.

[0573] There is also provided a process for the preparation of a compound of formula (XVI), or a salt such as a pharmaceutically acceptable salt thereof, which comprises reacting a compound of formula (XXI): or a salt such as a pharmaceutically acceptable salt thereof; with a compound of formula (XXII): or a salt such as a pharmaceutically acceptable salt thereof; wherein R2, R3, R4, m, n, o, X, Y, A and B are as defined elsewhere herein. PG2is a carboxylic acid protecting group such as methyl or benzyl. LG is a leaving group such as halo e.g. chloro.

[0574] Suitably, the compound of formula (XXII) is a compound of formula (XXII-a): or a salt such as a pharmaceutically acceptable salt thereof.

[0575] It will be appreciated that for use in therapy the salts of the compounds of formula (I) should be pharmaceutically acceptable. Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art. Pharmaceutically acceptable salts include acid addition salts, suitably salts of compounds of the invention comprising a basic group such as an amino group, formed with inorganic acids, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid. Also included are salts formed with organic acids, e.g., succinic acid, maleic acid, acetic acid, fumaric acid, citric acid, tartaric acid, benzoic acid, p-toluenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid and 1 ,5-naphthalenedisulfonic acid. Other salts, e.g., oxalates or formates, may be used, for example in the isolation of compounds of formula (I) and are included within the scope of this invention, as are basic addition salts such as sodium, potassium, calcium, aluminium, zinc, magnesium and other metal salts.

[0576] Pharmaceutically acceptable salts may also be formed with organic bases such as basic amines, e.g., with ammonia, meglumine, tromethamine, piperazine, arginine, choline, diethylamine, benzathine or lysine.

[0577] In one embodiment there is provided a compound of formula (I) in the form of a salt, such as a pharmaceutically acceptable salt. Alternatively, there is provided a compound of formula (I). When the compound contains a basic group as well as the free acid it may be zwitterionic. Suitably, the compound of formula (I) is not in the form of a salt, e.g., is not in the form of a pharmaceutically acceptable salt.

[0578] Suitably, where the compound of formula (I) is in the form of a salt, the pharmaceutically acceptable salt is a basic addition salt such as a carboxylate salt formed with a group 1 metal (e.g., a sodium or potassium salt), a group 2 metal (e.g., a magnesium or calcium salt) or an ammonium salt of a basic amine (e.g., an NH4+salt), such as a sodium salt.

[0579] The compounds of formula (I) may be prepared in crystalline or non-crystalline form and, if crystalline, may optionally be solvated, e.g., as the hydrate. This invention includes within its scope stoichiometric solvates (e.g., hydrates) as well as compounds containing variable amounts of solvent (e.g., water). Suitably, the compound of formula (I) is not in the form of a solvate. Suitably, the compound of formula (I) or salt and / or solvate thereof is a solvate of the compound of formula (I). Suitably the solvate of the compound of formula (I) is a pharmaceutically acceptable solvate.

[0580] The invention extends to a pharmaceutically acceptable derivative thereof, such as a pharmaceutically acceptable prodrug of compounds of formula (I). Typical prodrugs of compounds of formula (I) which comprise a carboxylic acid include ester (e.g. Ci-e alkyl e.g. C1.4 alkyl ester) derivatives thereof. Thus, in one embodiment, the compound of formula (I) is provided as a pharmaceutically acceptable prodrug. In another embodiment, the compound of formula (I) is not provided as a pharmaceutically acceptable prodrug.

[0581] It is to be understood that the present invention encompasses all isomers of compounds of formula (I) including all geometric, tautomeric and optical forms, and mixtures thereof (e.g. racemic mixtures). In particular, the invention extends to all tautomeric forms of the compounds of formula (I). Where additional chiral centres are present in compounds of formula (I), the present invention includes within its scope all possible diastereoisomers, including mixtures thereof. The different isomeric forms may be separated or resolved one from the other by conventional methods, or any given isomer may be obtained by conventional synthetic methods or by stereospecific or asymmetric syntheses.

[0582] It is also to be understood that when the stereochemistry is undefined in the name of a compound of formula (I), each stereoisomer and all possible mixtures of the stereoisomers (including racemic mixtures) at the stereocentre(s) are included within the scope of the invention. The present invention also includes all isotopic forms of the compounds provided herein, whether in a form (i) wherein all atoms of a given atomic number have a mass number (or mixture of mass numbers) which predominates in nature (referred to herein as the “natural isotopic form”) or (ii) wherein one or more atoms are replaced by atoms having the same atomic number, but a mass number different from the mass number of atoms which predominates in nature (referred to herein as an “unnatural variant isotopic form”). It is understood that an atom may naturally exists as a mixture of mass numbers. The term “unnatural variant isotopic form” also includes embodiments in which the proportion of an atom of given atomic number having a mass number found less commonly in nature (referred to herein as an “uncommon isotope”) has been increased relative to that which is naturally occurring e.g. to the level of >20%, >50%, >75%, >90%, >95% or> 99% by number of the atoms of that atomic number (the latter embodiment referred to as an "isotopically enriched variant form"). The term “unnatural variant isotopic form” also includes embodiments in which the proportion of an uncommon isotope has been reduced relative to that which is naturally occurring. Isotopic forms may include radioactive forms (i.e. they incorporate radioisotopes) and non-radioactive forms. Radioactive forms will typically be isotopically enriched variant forms.

[0583] An unnatural variant isotopic form of a compound may thus contain one or more artificial or uncommon isotopes such as deuterium (2H or D), carbon-11 (11C), carbon-13 (13C), carbon-14 (14C), nitrogen-13 (13N), nitrogen-15 (15N), oxygen-15 (15O), oxygen-17 (17O), oxygen-18 (18O), phosphorus-32 (32P), sulphur-35 (35S), chlorine-36 (36CI), chlorine-37 (37CI), fluorine-18 (18F) iodine-123 (123l), iodine-125 (125l) in one or more atoms or may contain an increased proportion of said isotopes as compared with the proportion that predominates in nature in one or more atoms.

[0584] Unnatural variant isotopic forms comprising radioisotopes may, for example, be used for drug and / or substrate tissue distribution studies. The radioactive isotopes tritium, i.e.3H, and carbon- 14, i.e.14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Unnatural variant isotopic forms which incorporate deuterium i.e.2H or D may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. Further, unnatural variant isotopic forms may be prepared which incorporate positron emitting isotopes, such as11C,18F,15O and13N, and would be useful in positron emission topography (PET) studies for examining substrate receptor occupancy.

[0585] In one embodiment, the compounds of formula (I) are provided in a natural isotopic form. In one embodiment, the compounds of formula (I) are provided in an unnatural variant isotopic form. In a specific embodiment, the unnatural variant isotopic form is a form in which deuterium (i.e.2H or D) is incorporated where hydrogen is specified in the chemical structure in one or more atoms of a compound of formula (I). In one embodiment, the atoms of the compounds of formula (I) are in an isotopic form which is not radioactive. In one embodiment, one or more atoms of the compounds of formula (I) are in an isotopic form which is radioactive. Suitably radioactive isotopes are stable isotopes. Suitably the unnatural variant isotopic form is a pharmaceutically acceptable form.

[0586] In one embodiment, a compound of formula (I) is provided whereby a single atom of the compound exists in an unnatural variant isotopic form. In another embodiment, a compound of formula (I) is provided whereby two or more atoms exist in an unnatural variant isotopic form.

[0587] Unnatural isotopic variant forms can generally be prepared by conventional techniques known to those skilled in the art or by processes described herein e.g. processes analogous to those described in the accompanying Examples for preparing natural isotopic forms. Thus, unnatural isotopic variant forms could be prepared by using appropriate isotopically variant (or labelled) reagents in place of the normal reagents employed in the Examples. Since the compounds of formula (I) are intended for use in pharmaceutical compositions it will readily be understood that they are each preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure and preferably at least 85%, especially at least 98% pure (% are on a weight for weight basis). Impure preparations of the compounds may be used for preparing the purer forms used in the pharmaceutical compositions.

[0588] Therapeutic indications

[0589] Compounds of formula (I) are of use in therapy, particularly for treating or preventing fibrotic and / or inflammatory diseases, such as fibrotic and / or inflammatory diseases of the lung. Biological Example 1 shows that the compounds of the invention are GLS1 inhibitors in both a cell and enzyme assay, and thus may be expected to have utility in the treatment of diseases associated with inhibition of GLS1 such as fibrotic and / or inflammatory diseases, in particular fibrotic and / or inflammatory diseases of the lung. Biological Example 2 shows that compounds of the invention are expected to have superior pharmacokinetic properties compared with prior art compounds, and are thus more suitable for drug candidate development. In particular, Example 60 was shown to have higher lung concentration compared with prior art compounds. Biological Example 3 shows that compounds of the invention are expected to have improved solubility compared with prior art compounds such as Reference Example 3, and thus have preferred drug properties compared with prior art compounds. Thus, in a further aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof as defined herein, for use as a medicament.

[0590] Also provided is a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof as defined herein. Thus, in a further aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof as defined herein, for use as a medicament.

[0591] In a further aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof as defined herein, for use in treating or preventing fibrotic and / or inflammatory diseases.

[0592] In a further aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof as defined herein, for use in treating fibrotic and / or inflammatory diseases.

[0593] In a further aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof as defined herein, for use in preventing fibrotic and / or inflammatory diseases.

[0594] In a further aspect, the present invention provides a pharmaceutical composition as defined herein, for use in treating or preventing fibrotic and / or inflammatory diseases.

[0595] In a further aspect, the present invention provides a pharmaceutical composition as defined herein, for use in treating fibrotic and / or inflammatory diseases.

[0596] In a further aspect, the present invention provides a pharmaceutical composition as defined herein, for use in preventing fibrotic and / or inflammatory diseases.

[0597] In a further aspect, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof as defined herein, in the manufacture of a medicament for treating or preventing fibrotic and / or inflammatory diseases.

[0598] In a further aspect, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof as defined herein, in the manufacture of a medicament for treating fibrotic and / or inflammatory diseases.

[0599] In a further aspect, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof as defined herein, in the manufacture of a medicament for preventing fibrotic and / or inflammatory diseases.

[0600] In a further aspect, the present invention provides the use of a pharmaceutical composition as defined herein, in the manufacture of a medicament for treating or preventing fibrotic and / or inflammatory diseases.

[0601] In a further aspect, the present invention provides the use of a pharmaceutical composition as defined herein, in the manufacture of a medicament for treating fibrotic and / or inflammatory diseases.

[0602] In a further aspect, the present invention provides the use of a pharmaceutical composition as defined herein, in the manufacture of a medicament for preventing fibrotic and / or inflammatory diseases.

[0603] In a further aspect, the present invention provides a method of treating or preventing fibrotic and / or inflammatory diseases which comprises administering a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof as defined herein.

[0604] In a further aspect, the present invention provides a method of treating fibrotic and / or inflammatory diseases which comprises administering a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof as defined herein.

[0605] In a further aspect, the present invention provides a method of preventing fibrotic and / or inflammatory diseases which comprises administering a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof as defined herein.

[0606] In a further aspect, the present invention provides a method of treating or preventing fibrotic and / or inflammatory diseases which comprises administering a pharmaceutical composition as defined herein.

[0607] In a further aspect, the present invention provides a method of treating fibrotic and / or inflammatory diseases which comprises administering a pharmaceutical composition as defined herein. In a further aspect, the present invention provides a method of preventing fibrotic and / or inflammatory diseases which comprises administering a pharmaceutical composition as defined herein.

[0608] In any one of the above embodiments, suitably the fibrotic and / or inflammatory disease is a fibrotic and / or inflammatory disease of the lung.

[0609] In any one of the above embodiments, the disease to be treated is a fibrotic disease of the lung. Alternatively, in any one of the above embodiments, the disease to be treated is an inflammatory disease of the lung. Alternatively, in any one of the above embodiments, the disease to be treated is a fibrotic and inflammatory disease of the lung.

[0610] In one embodiment, the fibrotic and / or inflammatory disease is an interstitial lung disease such as idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, lung cancer, radiation induced fibrosis, pulmonary hypertension, asthma, respiratory viral infection and long covid.

[0611] In one embodiment, the fibrotic and inflammatory disease is selected from the group consisting of diabetes, non-alcoholic fatty liver disease / cirrhosis, chronic kidney disease, osteoporosis, osteoarthritis and obesity.

[0612] In one embodiment, the fibrotic disease is fibrosis or non-alcoholic steatohepatitis.

[0613] In one embodiment, the inflammatory disease is selected from the group consisting of inflammation psoriasis, psoriatic arthritis, hidradenitis suppurativa, rheumatoid arthritis, ankylosing spondylitis and inflammatory bowel disease.

[0614] Suitably, the fibrotic and / or inflammatory disease is an interstitial lung disease such as idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, lung cancer, radiation induced fibrosis and pulmonary hypertension, asthma, respiratory viral infection and long covid.

[0615] For all aspects of the invention, suitably the compound is administered to a subject in need thereof, wherein the subject is suitably a human subject.

[0616] Administration

[0617] The compound of formula (I) is usually administered as a pharmaceutical composition. Thus, in one embodiment, is provided a pharmaceutical composition comprising a compound of formula (I) or pharmaceutically acceptable salt and / or solvate thereof and one or more pharmaceutically acceptable diluents or carriers.

[0618] The compound of formula (I) may be administered by any convenient method, e.g. by oral, parenteral, buccal, sublingual, nasal, rectal, intrathecal or transdermal administration, and the pharmaceutical compositions adapted accordingly.

[0619] The compound of formula (I) may be administered topically to the target organ e.g. topically to the eye, lung, nose or skin. Hence the invention provides a pharmaceutical composition comprising a compound of formula (I) optionally in combination with one or more topically acceptable diluents or carriers.

[0620] A compound of formula (I) which is active when given orally can be formulated as a liquid or solid, e.g. as a syrup, suspension, emulsion, tablet, capsule or lozenge.

[0621] A liquid formulation will generally consist of a suspension or solution of the compound of formula (I) in a suitable liquid carrier(s). Suitably the carrier is non-aqueous e.g. polyethylene glycol or an oil. The formulation may also contain a suspending agent, preservative, flavouring and / or colouring agent.

[0622] A composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations, such as magnesium stearate, starch, lactose, sucrose and cellulose.

[0623] A composition in the form of a capsule can be prepared using routine encapsulation procedures, e.g. pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatine capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), e.g. aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatine capsule.

[0624] Typical parenteral compositions consist of a solution or suspension of the compound of formula (I) in a sterile aqueous carrier or parenterally acceptable oil, e.g. polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil. Alternatively, the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration.

[0625] Compositions for nasal administration may conveniently be formulated as aerosols, drops, gels and powders. Aerosol formulations typically comprise a solution or fine suspension of the compound of formula (I) in a pharmaceutically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container which can take the form of a cartridge or refill for use with an atomising device. Alternatively, the sealed container may be a disposable dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve. Where the dosage form comprises an aerosol dispenser, it will contain a propellant which can be a compressed gas e.g. air, or an organic propellant such as a chlorofluorocarbon (CFC) or a hydrofluorocarbon (HFC). Aerosol dosage forms can also take the form of pump-atomisers.

[0626] Topical administration to the lung may be achieved by use of an aerosol formulation. Aerosol formulations typically comprise the active ingredient suspended or dissolved in a suitable aerosol propellant, such as a chlorofluorocarbon (CFC) or a hydrofluorocarbon (HFC).

[0627] Topical administration to the lung may also be achieved by use of a non-pressurised formulation such as an aqueous solution or suspension. These may be administered by means of a nebuliser e.g. one that can be hand-held and portable or for home or hospital use (i.e. non-portable). The formulation may comprise excipients such as water, buffers, tonicity adjusting agents, pH adjusting agents, surfactants and co-solvents.

[0628] Topical administration to the lung may also be achieved by use of a dry-powder formulation. The formulation will typically contain a topically acceptable diluent such as lactose, glucose or mannitol (preferably lactose).

[0629] The compound of the invention may also be administered rectally, for example in the form of suppositories or enemas, which include aqueous or oily solutions as well as suspensions and emulsions and foams. Such compositions are prepared following standard procedures, well known by those skilled in the art. For example, suppositories can be prepared by mixing the active ingredient with a conventional suppository base such as cocoa butter or other glycerides. In this case, the drug is mixed with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.

[0630] Generally, for compositions intended to be administered topically to the eye in the form of eye drops or eye ointments, the total amount of the compound of the present invention will be about 0.0001 to less than 4.0% (w / w). Preferably, for topical ocular administration, the compositions administered according to the present invention will be formulated as solutions, suspensions, emulsions and other dosage forms.

[0631] The compositions administered according to the present invention may also include various other ingredients, including, but not limited to, tonicity agents, buffers, surfactants, stabilizing polymer, preservatives, co-solvents and viscosity building agents. Suitable pharmaceutical compositions of the present invention include a compound of the invention formulated with a tonicity agent and a buffer. The pharmaceutical compositions of the present invention may further optionally include a surfactant and / or a palliative agent and / or a stabilizing polymer.

[0632] Various tonicity agents may be employed to adjust the tonicity of the composition, preferably to that of natural tears for ophthalmic compositions. For example, sodium chloride, potassium chloride, magnesium chloride, calcium chloride, simple sugars such as dextrose, fructose, galactose, and / or simply polyols such as the sugar alcohols mannitol, sorbitol, xylitol, lactitol, isomaltitol, maltitol, and hydrogenated starch hydrolysates may be added to the composition to approximate physiological tonicity. Such an amount of tonicity agent will vary, depending on the particular agent to be added. In general, however, the compositions will have a tonicity agent in an amount sufficient to cause the final composition to have an ophthalmically acceptable osmolality (generally about 150-450 mOsm, preferably 250-350 mOsm and most preferably at approximately 290 mOsm). In general, the tonicity agents of the invention will be present in the range of 2 to 4% w / w. Preferred tonicity agents of the invention include the simple sugars or the sugar alcohols, such as D-mannitol.

[0633] An appropriate buffer system (e.g. sodium phosphate, sodium acetate, sodium citrate, sodium borate or boric acid) may be added to the compositions to prevent pH drift under storage conditions. The particular concentration will vary, depending on the agent employed. Preferably however, the buffer will be chosen to maintain a target pH within the range of pH 5 to 8, and more preferably to a target pH of pH 5 to 7.

[0634] Surfactants may optionally be employed to deliver higher concentrations of compound of the present invention. The surfactants function to solubilise the compound and stabilise colloid dispersion, such as micellar solution, microemulsion, emulsion and suspension. Examples of surfactants which may optionally be used include polysorbate, poloxamer, polyosyl 40 stearate, polyoxyl castor oil, tyloxapol, Triton, and sorbitan monolaurate. Preferred surfactants to be employed in the invention have a hydrophile / lipophile / balance "HLB" in the range of 12.4 to 13.2 and are acceptable for ophthalmic use, such as Triton™ X-114 and tyloxapol. Additional agents that may be added to the ophthalmic compositions of compounds of the present invention are demulcents which function as a stabilising polymer. The stabilizing polymer should be an ionic / charged example with precedence for topical ocular use, more specifically, a polymer that carries negative charge on its surface that can exhibit a zeta-potential of (-)10-50 mV for physical stability and capable of making a dispersion in water (i.e. water soluble). A preferred stabilising polymer of the invention would be polyelectrolyte, or polyelectrolytes if more than one, from the family of cross-linked polyacrylates, such as carbomers and Pemulen®, specifically Carbomer 974p (polyacrylic acid), at 0.1-0.5% w / w.

[0635] Other compounds may also be added to the ophthalmic compositions of the compound of the present invention to increase the viscosity of the carrier. Examples of viscosity enhancing agents include, but are not limited to polysaccharides, such as hyaluronic acid and its salts, chondroitin sulfate and its salts, dextrans, various polymers of the cellulose family; vinyl polymers; and acrylic acid polymers.

[0636] Topical ophthalmic products are typically packaged in multidose form. Preservatives are thus required to prevent microbial contamination during use. Suitable preservatives include: benzalkonium chloride, chlorobutanol, benzododecinium bromide, methyl paraben, propyl paraben, phenylethyl alcohol, edentate disodium, sorbic acid, polyquaternium-1 , or other agents known to those skilled in the art. Such preservatives are typically employed at a level of from 0.001 to 1.0% w / v. Unit dose compositions of the present invention will be sterile, but typically unpreserved. Such compositions, therefore, generally will not contain preservatives.

[0637] Compositions suitable for buccal or sublingual administration include tablets, lozenges and pastilles where the compound of formula (I) is formulated with a carrier such as sugar and acacia, tragacanth, or gelatine and glycerine.

[0638] Compositions suitable for transdermal administration include ointments, gels and patches.

[0639] The composition may contain from 0.1 % to 100% by weight, for example from 10 to 60% by weight, of the compound of formula (I), depending on the method of administration. The composition may contain from 0% to 99% by weight, for example 40% to 90% by weight, of the carrier, depending on the method of administration. The composition may contain from 0.05mg to 1000mg, for example from 1.0 mg to 500 mg, such as from 1.0 mg to 50 mg, e.g. about 10 mg of the compound of formula (I), depending on the method of administration. The composition may contain from 50 mg to 1000 mg, for example from 100mg to 400mg of the carrier, depending on the method of administration. The dose of the compound used in the treatment of the aforementioned disorders will vary in the usual way with the seriousness of the disorders, the weight of the sufferer, and other similar factors. However, as a general guide, suitable unit doses may be 0.05 to 1000 mg, more suitably 1.0 to 500mg, such as from 1.0 mg to 50 mg, e.g. about 10 mg and such unit doses may be administered more than once a day, for example two or three times a day. Such therapy may extend for a number of weeks or months.

[0640] In one embodiment of the invention, the compound of formula (I) is used in combination with a further therapeutic agent or agents. When the compound of formula (I) is used in combination with other therapeutic agents, the compounds may be administered either sequentially or simultaneously by any convenient route. Alternatively, the compounds may be administered separately.

[0641] Therapeutic agents which may be used in combination with the present invention include: corticosteroids (glucocorticoids), retinoids (e.g. acitretin, isotretinoin, tazarotene), anthralin, vitamin D analogues (e.g. cacitriol, calcipotriol), calcineurin inhibitors (e.g. tacrolimus, pimecrolimus), phototherapy or photochemotherapy (e.g. psoralen ultraviolet irradiation, PLIVA) or other form of ultraviolet light irradiation therapy, ciclosporine, thiopurines (e.g. azathioprine, 6- mercaptopurine), methotrexate, anti-TNFa agents (e.g. infliximab, etanercept, adalimumab, certolizumab, golimumab and biosimilars), phosphodiesterase-4 (PDE4) inhibition (e.g. apremilast, crisaborole), anti-IL-17 agents (e.g. brodalumab, ixekizumab, secukinumab), anti- IL12 / IL-23 agents (e.g. ustekinumab, briakinumab), anti-IL-23 agents (e.g. guselkumab, tildrakizumab), JAK (Janus Kinase) inhibitors (e.g. tofacitinib, ruxolitinib, baricitinib, filgotinib, upadacitinib), plasma exchange, intravenous immune globulin (I VIG), cyclophosphamide, anti- CD20 B cell depleting agents (e.g. rituximab, ocrelizumab, ofatumumab, obinutuzumab), anthracycline analogues (e.g. mitoxantrone), cladribine, sphingosine 1 -phosphate receptor modulators or sphingosine analogues (e.g. fingolimod, siponimod, ozanimod, etrasimod), interferon beta preparations (including interferon beta 1 b / 1 a), glatiramer, anti-CD3 therapy (e.g. OKT3), anti-CD52 targeting agents (e.g. alemtuzumab), leflunomide, teriflunomide, gold compounds, laquinimod, potassium channel blockers (e.g. dalfampridine / 4-aminopyridine), mycophenolic acid, mycophenolate mofetil, purine analogues (e.g. pentostatin), mTOR (mechanistic target of rapamycin) pathway inhibitors (e.g. sirolimus, everolimus), anti-thymocyte globulin (ATG), IL-2 receptor (CD25) inhibitors (e.g. basiliximab, daclizumab), anti-IL-6 receptor or anti-IL-6 agents (e.g. tocilizumab, siltuximab), Bruton’s tyrosine kinase (BTK) inhibitors (e.g. ibrutinib), tyrosine kinase inhibitors (e.g. imatinib, nintedanib), ursodeoxycholic acid, hydroxychloroquine, chloroquine, B cell activating factor (BAFF, also known as BLyS, B lymphocyte stimulator) inhibitors (e.g. belimumab, blisibimod), other B cell targeted therapy including fusion proteins targeting both APRIL (A PRoliferation-lnducing Ligand) and BLyS (e.g. atacicept), PI3K inhibitors including pan-inhibitors or those targeting the p110b and / or p110y containing isoforms (e.g. idelalisib, copanlisib, duvelisib), interferon a receptor inhibitors (e.g. anifrolumab, sifalimumab), T cell co-stimulation blockers (e.g. abatacept, belatacept), thalidomide and its derivatives (e.g. lenalidomide), dapsone, clofazimine, leukotriene antagonists (e.g. montelukast), theophylline, anti-lgE therapy (e.g. omalizumab), anti-IL-5 agents (e.g. mepolizumab, reslizumab), long-acting muscarinic agents (e.g. tiotropium, aclidinium, umeclidinium), PDE4 inhibitors (e.g. roflumilast), riluzole, free radical scavengers (e.g. edaravone), proteasome inhibitors (e.g. bortezomib), complement cascade inhibitors including those directed against C5 (e.g. eculizumab), immunoadsor, antithymocyte globulin, 5- aminosalicylates and their derivatives (e.g. sulfasalazine, balsalazide, mesalamine), anti-integrin agents including those targeting a4pi and / or a4p7 integrins (e.g. natalizumab, vedolizumab), anti-CD11-a agents (e.g. efalizumab), non-steroidal anti-inflammatory drugs (NSAIDs) including the salicylates (e.g. aspirin), propionic acids (e.g. ibuprofen, naproxen), acetic acids (e.g. indomethacin, diclofenac, etodolac), oxicams (e.g. meloxicam) and fenamates (e.g. mefenamic acid), selective or relatively selective COX-2 inhibitors (e.g. celecoxib, etroxicoxib, valdecoxib and etodolac, meloxicam, nabumetone), colchicine, IL-4 receptor inhibitors (e.g. dupilumab), topical / contact immunotherapy (e.g. diphenylcyclopropenone, squaric acid dibutyl ester), anti-IL- 1 receptor therapy (e.g. anakinra), IL-i p inhibitor (e.g. canakinumab), IL-1 neutralising therapy (e.g. rilonacept), chlorambucil, specific antibiotics with immunomodulatory properties and / or ability to modulate NRF2 (e.g. tetracyclines including minocycline, clindamycin, macrolide antibiotics), anti-androgenic therapy (e.g. cyproterone, spironolactone, finasteride), pentoxifylline, ursodeoxycholic acid, obeticholic acid, fibrate, cystic fibrosis transmembrane conductance regulator (CFTR) modulators, VEGF (vascular endothelial growth factor) inhibitors (e.g. bevacizumab, ranibizumab, pegaptanib, aflibercept), pirfenidone, or mizoribine.

[0642] In one embodiment and suitably when the disease to be treated is lung cancer, the compounds of formula (I) may be administered as a combination therapy with radiation. It is understood that GLS1 inhibitors can augment radiation treatment (Fujimoto et al. 2022).

[0643] Compounds of formula (I) may display, or may be expected to have, one or more of the following desirable properties:

[0644] • low IC50 in the cellular assay of Biological Example 1 ;

[0645] • low IC50 in the enzyme assay of Biological Example 1 ;

[0646] • improved duration of action in the lung as shown in Biological Example 2;

[0647] • higher lung concentrations as shown in Biological Example 2;

[0648] • improved solubility as shown in Biological Example 3. Abbreviations

[0649] ACN Acetonitrile aq. Aqueous

[0650] BOC tert-Butyloxycarbonyl tBuOH tert-Butanol d day / days

[0651] DBU 1 ,8-Diazabicyclo(5.4.0)undec-7-ene

[0652] DCM Dichloromethane d.e. Diastereomeric excess

[0653] Dioxane 1 ,4-Diethylene dioxide

[0654] DIPEA N, N-Diisopropylethylamine

[0655] DMA Dimethylacetamide

[0656] DMF N, N-Dimethylformamide

[0657] DMSO Dimethyl sulfoxide

[0658] EDTA Ethylenediaminetetraacetic acid

[0659] ESI Electrospray Ionisation

[0660] Et3N Triethylamine

[0661] EtOAc Ethyl acetate

[0662] EtOH Ethanol

[0663] Et2<D Diethyl ether

[0664] FA Formic acid h Hour / hours

[0665] HATLI 1-[bis(dimethylamino)methylene]-1 H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate

[0666] HPLC High Performance Liquid Chromatography

[0667] I PA Isopropanol

[0668] IN Intranasal

[0669] LCMS Liquid Chromatography Mass Spectrometry

[0670] M Molar concentration

[0671] MeOH Methanol

[0672] MHz Megahertz min(s) Minute(s)

[0673] NMR Nuclear Magnetic Resonance

[0674] Pd(dppf)Ch [1,T-Bis(diphenylphosphino)ferrocene]dichloropalladium(ll)

[0675] PE Petroleum ether pH Potential of hydrogen (acidity / basicity) PyBOP Benzotriazol-1-yl-oxytripyrrolidino-phosphonium Hexafluorophosphate

[0676] RT Retention time r.t. Room temperature

[0677] SFC Supercritical Fluid Chromatography

[0678] STAB Sodium triacetoxyborohydride

[0679] T3P Propylphosphonic anhydride solution

[0680] TEA Triethylamine

[0681] TFA Trifluoroacetic acid

[0682] THF Tetrahydrofuran

[0683] Ti(O'Pr)4 Titanium(IV) isopropoxide

[0684] TLC Thin Layer Chromatography

[0685] UPLC Ultra Performance Liquid Chromatography

[0686] EXAMPLES

[0687] Analytical Equipment

[0688] Thin layer chromatography (TLC) was performed on silica gel plates (GF254, glass, silica gel size: 400-600 mesh). Spots were visualized by UV light (214 and 254 nm) or colour reagents (iodine, KMnC aq.).

[0689] Bruker 400 MHz Avance III™ spectrometer fitted with a BBFO 5 mm probe, or a Bruker 500 MHz Avance III™ HD spectrometer equipped with a Bruker 5 mm SmartProbe™.1H chemical shifts are reported in 5 values in ppm with the deuterated solvent as the internal standard. Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad, m = multiplet), coupling constant (Hz), integration.

[0690] HPLC was performed according to methods described below:

[0691] Analytical Conditions

[0692] Method 1

[0693] Stationary phase: Kinetex EVO C18 2.1 x 30 mm, 5 pm

[0694] Mobile Phase A: 0.025% NH3 H2O in water(v / v)

[0695] Mobile Phase B: Acetonitrile

[0696] Flow rate: 1.5 mL / min

[0697] Gradient program: Time A% B% 0.00 95.00 5.00

[0698] 0.80 5.00 95.00

[0699] 1.20 5.00 95.00

[0700] 1.21 95.00 5.00

[0701] 1.55 95.00 5.00

[0702] Method 2

[0703] Stationary phase: Kinetex EVO C182.1 x 30 mm, 5 pm

[0704] Mobile Phase A: 0.0375% TFA in water (v / v)

[0705] Mobile Phase B: 0.01875% TFA in acetonitrile (v / v)

[0706] Flow rate: 1.5 mL / min

[0707] Gradient program: Time A% B%

[0708] 0.00 95.00 5.00

[0709] 0.80 5.00 95.00

[0710] 1.20 5.00 95.00

[0711] 1.21 95.00 5.00

[0712] 1.55 95.00 5.00

[0713] Method 3

[0714] Stationary phase: HALO C18 3.0 x 30 mm, 5 pm

[0715] Mobile Phase A: 0.0375% TFA in water (v / v)

[0716] Mobile Phase B: 0.01875% TFA in acetonitrile (v / v)

[0717] Flow rate: 1.5 mL / min

[0718] Gradient program: Time A% B%

[0719] 0.00 95.00 5.00

[0720] 0.50 5.00 95.00

[0721] 0.80 5.00 95.00

[0722] 0.81 95.00 5.00

[0723] 1.05 95.00 5.00

[0724] Method 4

[0725] Stationary phase: Agilent ZORBAX 5pm SB-Aq, 2.1*50mm

[0726] Mobile Phase A: 0.0375% TFA in water (v / v)

[0727] Mobile Phase B: 0.01875% TFA in acetonitrile (v / v)

[0728] Gradient program: Time A% B% Flow (mL / min)

[0729] 0.00 99.00 1.00 0.8

[0730] 0.40 99.00 1.00 0.8 3.40 10.00 90.00 0.8

[0731] 3.90 0.00 100.00 0.8

[0732] 3.91 99.00 1.00 0.8

[0733] 4.00 99.00 1.00 1.0

[0734] 4.50 99.00 1.00 1.0

[0735] Method 5

[0736] Stationary phase: Acquity UPLC BEH - Waters, 1.7pm C18 (2.1 x 100 mm), 130A

[0737] Flow Rate 0.5 mL / min

[0738] Mobile Phase A: 0.1 % v / v water solution of formic acid

[0739] Mobile Phase B: 0.1 % v / v acetonitrile solution of formic acid

[0740] Gradient program: Time A% B%

[0741] 0.10 80.00 20.00

[0742] 2.00 5.00 95.00

[0743] 2.70 5.00 95.00

[0744] 2.80 80.00 20.00

[0745] Method 6

[0746] Stationary phase: Gemini NX 3 pm C18 (4.6x150mm), 110A

[0747] Mobile Phase A: 0.1 % v / v water solution of formic acid

[0748] Mobile Phase B: 0.1% v / v acetonitrile solution of formic acid

[0749] Flow rate: 1 mL / min

[0750] Gradient program: Time A% B%

[0751] 0.00 100.00 0.00

[0752] 7.50 70.00 30.00

[0753] 8.00 70.00 30.00

[0754] 8.50 5.00 95.00

[0755] 9.75 5.00 95.00

[0756] 10.25 100.00 0.00

[0757] 12.00 100.00 0.00

[0758] Method 7

[0759] Stationary phase: Kinetex ® 2.6 pm XB-C18 (4.6x50mm), 100A

[0760] Mobile Phase A: 0.1 % v / v water solution of formic acid

[0761] Mobile Phase B: 0.1% v / v acetonitrile solution of formic acid

[0762] Flow rate: 1 mL / min

[0763] Gradient program: Time A% B%

[0764] 0.00 100.00 0.00 1.00 95.00 5.00

[0765] 4.00 80 .00 20.00

[0766] 4.75 20 .00 80.00

[0767] 5.25 20 .00 80.00

[0768] 6.00 95 .00 5.00

[0769] 7.00 100 .00 0.00

[0770] Method 8

[0771] Stationary phase: ACQUITY UPLC BEH C8 1.7 pm (2.1x150mm), 130A

[0772] Mobile Phase A: 0.1 % v / v water solution of formic acid

[0773] Mobile Phase B: 0.1 % v / v acetonitrile solution of formic acid

[0774] Flow rate: 0.5 mL / min

[0775] Gradient program: Time A% B%

[0776] 0.00 100.00 0.00

[0777] 6.00 80.00 20.00

[0778] 6.80 80.00 20.00

[0779] 7.00 5.00 95.00

[0780] 8.10 5.00 95.00

[0781] 8.50 95.00 5.00

[0782] 10.00 95.00 5.00

[0783] Method 9

[0784] Stationary phase: Gemini NX 3 pm C18 (4.6x150mm), 110A

[0785] Mobile Phase A: 0.05% v / v water solution of ammonium hydroxide

[0786] Mobile Phase B: acetonitrile

[0787] Flow rate: 1 mL / min

[0788] Gradient program: Time A% B%

[0789] 0.00 80.00 20.00

[0790] 6.35 50.00 50.00

[0791] 6.75 50.00 50.00

[0792] 6.90 5.00 95.00

[0793] 7.75 5.00 95.00

[0794] 8.00 80.00 20.00

[0795] 9.00 80.00 20.00

[0796] Method 10

[0797] Stationary phase: Lux i-Amylose-3 (4.6x250mm), 5 pm Mobile Phase A: 60%, CO2

[0798] Mobile Phase B: 40%, 1% ammonium hydroxide in methanokacetonitrile (v / v, 1 :1)

[0799] Flow rate: 3 mL / min

[0800] Gradient program: Time A% B%

[0801] 0.00 60.00 40.00

[0802] 30.00 60.00 40.00

[0803] Method 11

[0804] Stationary phase: Lux Cellulose- 1 (4.6x250mm), 5 pm

[0805] Mobile Phase A: 60%, CO2

[0806] Mobile Phase B: 40%, 1% ammonium hydroxide in methanokacetonitrile (v / v, 1 :1)

[0807] Flow rate: 3 mL / min

[0808] Gradient program: Time A% B%

[0809] 0.00 60.00 40.00

[0810] 30.00 60.00 40.00

[0811] Method 12

[0812] Stationary phase: Chiralpak AD-H (4.6x250mm), 5 pm

[0813] Mobile Phase A: 0.1% v / v ethanol solution of triethylamine

[0814] Mobile Phase B: n-hexane

[0815] Flow rate: 1 mL / min

[0816] Gradient program: Time A% B%

[0817] 0.00 40.00 60.00

[0818] 20.00 40.00 60.00

[0819] Method 13

[0820] Stationary phase: Waters SunFire C18 150*4.6mm 5um

[0821] Mobile Phase A: 0.03% TFA in H2O (v / v)

[0822] Mobile Phase B: 0.03% TFA in ACN(v / v)

[0823] Flow rate: 1.00 ml / min

[0824] Gradient program: 10% B hold for 1.8 min, increase to 95 % B within 10.2 min, hold at 95 % B for 3.0 min, then back to 10% B within 0.01 min

[0825] Method 14

[0826] Stationary phase: Waters SunFire C18 5pm 50*4.6mm

[0827] Mobile Phase A: 0.03%FA in H2O (v / v)

[0828] Mobile Phase B: 0.03%FA in ACN (v / v)

[0829] Flow rate: 2.0 ml / min Gradient program: 5% B hold for 0.2min, increase to 95 % B within 1.40 min, hold at

[0830] 95 % B for 0.9 min, then back to 5% B within 0.01 min Method 15

[0831] Stationary phase: Waters SunFire C18 5 .m 50*4.6mm

[0832] Mobile Phase A: 0.1 %FA in H2O (V / V)

[0833] Mobile Phase B: 0.1 %FA in ACN (v / v)

[0834] Flow rate: 2.0 ml / min Gradient program: 5% B hold for 0.2min, increase to 95 % B within 1.40 min, hold at

[0835] 95 % B for 0.9 min, then back to 5% B within 0.01 min

[0836] Method 16

[0837] Stationary phase: Waters XBridge C18 50*4.6mm 5um Mobile Phase A: 0.1 % NH3.H2O in H2O (v / v)

[0838] Mobile Phase B: Acetonitrile

[0839] Flow rate: 2.0 ml / min

[0840] Gradient program: 5% B hold for 0.2min, increase to 95 % B within 1 .40 min, hold at 95

[0841] % B for 0.9 min, then back to 5% B within 0.01 min

[0842] Method 17

[0843] Stationary phase: Luna C18 30*2.0mm 3um

[0844] Mobile Phase A: 0.03%TFA in H2O (v / v)

[0845] Mobile Phase B: 0.03%TFA in ACN (v / v) Flow rate: 1.5 ml / min

[0846] Gradient program: 5% B increase to 95 % B within 0.7 min, hold at 95 % B for 0.4 min, back to 5% B within 0.01 min

[0847] Method 18 Stationary phase: Agilent Pursuit C18 20*2.0mm 5um

[0848] Mobile Phase A: 0.03%TFA in H2O (v / v)

[0849] Mobile Phase B: 0.03%TFA in ACN (v / v)

[0850] Flow rate: 1.5 mL / min

[0851] Gradient program: 5% B increase to 95 % B within 0.7 min, hold at 95 % B for 0.4 min, then back to 5% B within 0.01 min

[0852] Method 19 Stationary phase: ShimNex UP C18 50*4.6mm 5um

[0853] Mobile Phase A: 0.1 %FA in H2O (V / V)

[0854] Mobile Phase B: 0.1 %FA in ACN (v / v)

[0855] Flow rate: 2.0 mL / min Gradient program: 5% B hold for 0.2min, increase to 95 % B within 1.40 min, hold at

[0856] 95 % B for 0.9 min, then back to 5% B within 0.01 min

[0857] Method 20

[0858] Stationary phase: ShimNex UP C18 50*4.6mm 5um Mobile Phase A: 0.03%FA in H2O (v / v)

[0859] Mobile Phase B: 0.03%FA in ACN (v / v)

[0860] Flow rate: 2.0 mL / min

[0861] Gradient program: 5% B hold for 0.2min, increase to 95 % B within 1.40 min, hold at

[0862] 95 % B for 0.9 min, then back to 5% B within 0.01 min

[0863] Method 21

[0864] Stationary phase: Waters X Bridge C18, 50 x 4.6 mm, 5 pM

[0865] Flow Rate 2 mL / min

[0866] Mobile Phase A: 10mmol / L NH4HCO3 in H2O Mobile Phase B: acetonitrile

[0867] Gradient program: 5% B hold for 0.2 min, increase to 95% B within 1.40 min,

[0868] Hold at 95% B for 0.9 min, back to 5% B within 0.01 min

[0869] Method 22 Stationary phase: Agilent Pursuit XRs C18 30*2.0mm 5um

[0870] Mobile Phase A: 0.1 %TFA in H2O (v / v)

[0871] Mobile Phase B: 0.1 %TFA in ACN (v / v)

[0872] Flow rate: 1.2 mL / min

[0873] Gradient program: 5% B increase to 95 % B within 1.40 min, hold at 95 % B for 0.5 min, then back to 5% B within 0.01 min

[0874] Method 23

[0875] Stationary phase: Agilent Eclipse Plus C18 4.6*100mm 3.5um

[0876] Mobile Phase A: 0.1 %TFA in H2O (v / v) Mobile Phase B: 0.1 %TFA in ACN (v / v)

[0877] Flow rate: 1.5 mL / min Gradient program: 5% B increase to 95 % B within 1.40 min, hold at 95 % B for 0.5 min, then back to 5% B within 0.01 min

[0878] Method 24

[0879] Stationary phase: Lux Cellulose-1 (4.6x250mm), 5 pm

[0880] Mobile Phase A: 70%, CO2

[0881] Mobile Phase B: 30%, 1% ammonium hydroxide in methanokacetonitrile (v / v, 1 :1)

[0882] Flow rate: 3 mL / min

[0883] Gradient program: Time A% B%

[0884] 0.00 70.00 30.00

[0885] 10.00 70.00 30.00

[0886] Method 25

[0887] Stationary phase: Lux Cellulose-1 (4.6x250mm), 5 pm

[0888] Mobile Phase A: 65%, CO2

[0889] Mobile Phase B: 35%, 1% ammonium hydroxide in methanokacetonitrile (v / v, 1 :1)

[0890] Flow rate: 3 mL / min

[0891] Gradient program: Time A% B%

[0892] 0.00 65.00 35.00

[0893] 10.00 65.00 35.00

[0894] Commercial Materials

[0895] All starting materials are commercially available unless otherwise stated.

[0896] Synthesis of Intermediates

[0897] In the following general procedures, all variables are as defined herein.

[0898] INTERMEDIATE 1 : (R)-N2- in-3-vl)pyrrolidin-3-yl)-1,3,4-thiadiazole-2,5-diamine

[0899] Step 1 : tert-butyl (R)-(1-(6-chloropyridazin-3-yl)pyrrolidin-3-yl)carbamate

[0900] Three reactions were run in parallel. To a solution of 3,6-dichloropyridazine (250 g, 1.68 mol, 1.0 eq.), terf-butyl (R)-pyrrolidin-3-ylcarbamate (312 g, 1.68 mol, 1.0 eq.) in ACN (3.00 L) was added DIPEA (216 g, 1.68 mol, 292 mL, 1.0 eq.). The mixture was stirred at 80 °C for 16 h. Water (4.50 L) was added into the reaction mixture with stirring before filtering. The filter cake was washed in vacuo with water (1.50 L) followed by PE (1 .50 L). The filter cake was dried in vacuo to afford the title compound (1.16 kg, 76.8% yield) as a white solid without further purification.1H NMR (400 MHz, CDCh) 6 7.18 (d, J = 9.2 Hz, 1 H), 6.62 (d, J = 9.6 Hz, 1 H), 4.79 (br.s, 1 H), 4.38 (br.s, 1 H), 3.78 (dd, J = 11.2, 6.4 Hz, 1 H), 3.56-3.68 (m, 2H), 3.41 (dd, J = 10.8, 4.0 Hz, 1 H), 2.25-2.37 (m, 1 H), 1 .97-2.08 (m, 1 H), 1 .45 (s, 9H). LCMS (Method 1 , ESI) 299.0 [M H]+, RT 0.866 minutes.

[0901] Step 2: tert-butyl (R)-( 1-(pyridazin-3-yl)pyrrolidin-3-yl)carbamate

[0902] Three reactions were run in parallel. To a solution of terf-butyl (R)-(1-(6-chloropyridazin-3- yl)pyrrolidin-3-yl)carbamate (350 g, 1.17 mol, 1.00 eq.) in EtOH (3.00 L) was added Pd / C (30.0 g, 10.0% purity) and ammonium formate (738 g, 11.7 mol, 10.0 eq.). The mixture was stirred at 70°C for 50 mins before filtering through a pad of celite. The filtrate was concentrated in vacuo and then re-treated with DCM (3.00 L). The mixture was filtered, and the filtrate was concentrated in vacuo to give the title compound (800 g, 85.5% yield) as a yellow solid without further purification.1H NMR (400 MHz, CDCh) 6 8.52 (d, J = 3.6 Hz, 1 H), 7.17 (dd, J = 8.8, 4.4 Hz, 1 H), 6.60 (dd, J = 9.2, 1.2 Hz, 1 H), 4.92 (br.s, 1 H), 4.38 (br.s, 1 H), 3.77 (q, J = 6.0 Hz, 1 H), 3.56-3.69 (m, 2H), 3.42 (dd, J= 10.8, 4.4 Hz, 1 H), 2.23-2.35 (m, 1 H), 1.94-2.07 (m, 1 H), 1.44 (s, 9 H). LCMS (Method 2, ESI) 265.1 [MH]+, RT 0.343 minutes.

[0903] Step 3: (R)-1-(pyridazin-3-yl)pyrrolidin-3-amine

[0904] Two reactions were run in parallel. To a solution of terf-butyl (R)-(1-(pyridazin-3-yl)pyrrolidin-3- yl)carbamate (400 g, 1.51 mol, 1.00 eq.) in DCM (2.40 L) was added TFA (1.23 kg, 10.8 mol, 7.14 eq.). The mixture was stirred at 25°C for 3 h. The reaction mixture was adjusted to pH = 7 by addition of saturated aqueous Na2CO3 solution followed by concentrated in vacuo. The crude product was purified by reversed phase HPLC (0.1 % NH3*H2O condition) to afford the title compound (2.40 kg, 96.5% yield) as a yellow oil.1H NMR (400 MHz, DMSO-d6) 5 8.48 (br.s, 1 H), 7.32-7.35 (m, 1 H), 6.84 (d, J = 9.2 Hz, 1 H), 4.00-5.05 (br.s, 2H), 3.87 (br.s, 1 H), 3.67-3.72 (m, 1 H), 3.55-3.63 (m, 1 H), 3.44-3.52 (m, 2H), 2.20-2.31 (m, 1 H), 1.98-2.08 (m, 1 H). LCMS (An analogous method to Method 2, ESI) 165.1 [MH]+, RT 0.654 minutes.

[0905] Step 4: (R)-N2-(1-(pyridazin-3-yl)pyrrolidin-3-yl)-1 ,3,4-thiadiazole-2,5-diamine

[0906] Three reactions were run in parallel. To a solution of (R)-1-(pyridazin-3-yl)pyrrolidin-3-amine (581 g, 708 mmol, 20.0% purity, 1.00 eq.), 5-bromo-1 ,3,4-thiadiazol-2-amine (153 g, 849 mmol, 1.20 eq.) in MeOH (3.00 L) was added DI PEA (137 g, 1.06 mol, 1.50 eq.). The mixture was stirred at 45°C for 12 h before concentrated in vacuo to remove MeOH (ca. 2.0 L). The mixture was filtered and the filter cake was washed with MeOH (600 mL). The filter cake was then dried in vacuo. The crude product was triturated with water (750 mL x 2) and stirred at r.t. for 30 min. The mixture was filtered and the filter cake was triturated with MeOH (500 mL) at 40 °C for 30 min, then the mixture was cooled to r.t. and filtered. The filter cake was collected and dried in vacuo afford the title compound (252 g, 44.5% yield) as a grey solid.1H NMR (400 MHz, DMSO-d6) 5 8.47 (br.s, 1 H), 7.30-7.34 (m, 1 H), 7.08 (d, J = 5.2 Hz, 1 H), 6.85 (d, = 8.8 Hz, 1 H), 6.28 (br.s, 2H), 4.27 (br.d, J = 3.6 Hz, 1 H), 3.70-3.72 (m, 1 H), 3.53-3.54 (m, 2H), 3.44-3.47 (m, 1 H), 2.22-2.29 (m, 1 H), 1.99- 2.08 (m, 1 H). LCMS (Method 1 , ESI) 264.0 [MH]+, RT 0.725 minutes.

[0907] INTERMEDIATE 2: N2-r(3S,4S)-4-fluoro-1-(pyridazin-3-yl)pyrrolidin-3-yl]- diamine

[0908] Step 1 : tert-butyl N-r(3S,4S)-1-(6-chloropyridazin-3-yl)-4-fluoropyrrolidin-3-yl]carbamate

[0909] To a stirred solution of terf-butyl A / -[(3S,4S)-4-fluoropyrrolidin-3-yl]carbamate (0.9 g, 4.40 mmol,

[0910] 1 eq.) in ethanol (18 mL) was added 3,6-dichloropyridazine (0.656 g, 4.40 mmol, 1 eq.) followed by Et3N (0.89 mL, 6.61 mmol, 1.5 eq.). The reaction mixture was then stirred at reflux for 16 h. The resulting mixture was diluted with EtOAc, washed with 0.1M HCI and brine, dried over sodium sulphate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography (silica, 5-60% EtOAc in hexane) to afford the title compound (0.5 g, 34% yield) as a white solid.1H NMR (300 MHz, CDC ) 5 7.22 (d, J = 9.4 Hz, 1 H), 6.64 (d, J = 9.4 Hz, 1 H), 5.22 (d, J = 50.8 Hz, 1 H), 4.76 (s, 1 H), 4.45 (s, 1 H), 3.96-3.80 (m, 2H), 3.77 (s, 1 H), 3.64 (d, J = 11.4 Hz, 1 H), 1.44 (d, J = 7.9 Hz, 9H).

[0911] Step 2: tert-butyl N-[ (3S, 4S)-4-fluoro-1-(pyridazin-3-yl)pyrrolidin-3-yl]carbamate

[0912] To a solution of terf-butyl A / -[(3S,4S)-1-(6-chloropyridazin-3-yl)-4-fluoropyrrolidin-3-yl] carbamate (0.25 g, 0.74 mmol, 1 eq.) in THF (15 mL) were added Pd / C (0.02 g, 10.0% purity) and ammonium formate (0.46 g, 7.41 mmol, 10 eq.). The mixture was stirred at 50 °C for 16 h and the reaction was filtered through a pad of celite and concentrated in vacuo. The crude compound (0.20 g, 87% yield) was used directly in the next step without any further purification.1H NMR (300 MHz, DMSO-cfe) 5 8.52 (d, J = 4.3 Hz, 1 H), 7.37 (dd, J = 9.1 , 4.4 Hz, 2H), 6.90 (d, J = 9.5 Hz, 1 H), 5.16 (d, J = 52 hz, 1 H), 4.27-4.14 (m, 1 H), 3.87-3.67 (m, 3H), 3.51 (d, J = 11.2 Hz, 1 H), 1.39 (s, 9H). UPLC (Method 5, ESI) 283.15 [MH]+, RT 1.67 minutes.

[0913] Step 3: (3S, 4S)-4-fluoro-1-(pyridazin-3-yl)pyrrolidin-3-amine hydrochloride

[0914] To a solution of terf-butyl A / -[(3S,4S)-4-fluoro-1-(pyridazin-3-yl)pyrrolidin-3-yl]carbamate (0.20 g, 0.65 mmol, 1 eq.) in DCM (10 mL) was added HCI solution in 1 ,4-dioxane (4 M, 0.96 mL, 3.86 mmol, 5 eq.). The reaction mixture was stirred at 55 °C for 38 h. The solvent was removed in vacuo, crude was washed with Et20 to afford the title compound (1.97 g, 96% yield) as a white solid.1H NMR (300 MHz, D2O) 5 8.60 (d, J = 4.7 Hz, 1 H), 7.88 (dd, J = 9.5, 4.7 Hz, 1 H), 7.60 (dd, J = 9.5, 1 hz, 1 H), 5.67-5.44 (m, 1 H), 4.38 -4.27 (m, 1 H), 4.21-4.11 (m, 2H), 4.10-3.97 (m, 1 H), 3.89 (dd, J = 12.7, 2.5 Hz, 1 H), 3.59-3.51 (m, 1 H). UPLC (Method 5, ESI) 183.05 [MH]+, RT 0.47 minutes.

[0915] Step 4: N2-[ (3S, 4S)-4-fluoro- 1-(pyridazin-3-yl)pyrrolidin-3-yll- 1,3, 4-thiadiazoie-2, 5-diamine

[0916] A mixture of (3S,4S)-4-fluoro-1-(pyridazin-3-yl)pyrrolidin-3-amine hydrochloride (0.19 g, 0.61 mmol, 1 eq.), 2-amino-5-bromo-1 ,3,4-thiadiazole (0.33 g, 1.82 mmol, 3 eq.) and potassium carbonate anhydrous (0.42 g, 3.04 mmol, 5 eq.) in anhydrous DMF (7 mL) was heated at 60°C for 10 h. The solvent was removed in vacuo, and the crude material was purified by flash chromatography (silica, 0-10% MeOH in DCM) to afford the title compound (0.11 g, 58% yield) as a brown solid.1H NMR (300 MHz, DMSO-cfe) 5 8.54 (d, J = 4.1 Hz, 1 H), 7.39 (dd, J = 9.2, 4.5 Hz, 1 H), 7.22 (d, J = 5.4 Hz, 1 H), 6.95 (d, J = 9.1 Hz, 1 H), 6.42 (s, 2H), 5.36 (d, J = 51.4 Hz, 1 H), 4.43-4.30 (m, 1 H), 3.88-3.61 (m, 4H). UPLC (Method 5, ESI) 282.05 [MH]+, RT 0.51 minutes. INTERMEDIATE S: (R)-N2-(1-(6-chloropyndazin-3-yl)pyrrolidin-3-yl)-1 ,3,4-thiadiazole-2,5- diamine

[0917] Step 1 : (R)-1-(6-chloropyridazin-3-yl)pyrrolidin-3-amine, dihydrochloride

[0918] To a solution of terf-butyl ( )-(1-(6-chloropyridazin-3-yl)pyrrolidin-3-yl)carbamate (50.0 g, 167 mmol, 1.00 eq.) in EtOAc (400 mL) was added HCI / EtOAc (4 M, 227 mL, 5.43 eq.) at 0 °C. The mixture was stirred at r.t. for 4 h before filtering. The filter cake was dried in vacuo to afford the title compound (40.0 g, 147 mmol, 88.0% yield) as a white solid without further purification.1H NMR (400 MHz, DMSO-d6) 5 8.69 (s, 3H), 7.75-7.78 (m. 1 H), 7.41-7.44 (m, 1 H), 3.98-4.03 (m, 1 H), 3.76-3.84 (m, 3H), 3.63-3.73 (m, 1 H), 2.26-2.51 (m, 2H). LCMS (Method s, ESI) 199.1 [MH]+, RT 0.211 minutes.

[0919] Step 2: (R)-N2-(1-(6-chloropyridazin-3-yl)pyrrolidin-3-yl)-1 ,3,4-thiadiazole-2,5-diamine

[0920] To a solution of (R)-1-(6-chloropyridazin-3-yl)pyrrolidin-3-amine, dihydrochloride (8.00 g, 29.5 mmol, 1.00 eq.) in ACN (69.0 mL) was added 5-bromo-1 ,3,4-thiadiazol-2-amine (6.89 g, 38.3 mmol, 1.30 eq.) and DIPEA (15.2 g, 117 mmol, 20.5 mL, 4.00 eq.). The mixture was stirred at 45 °C for 12 h. The mixture was filtered, and the filter cake was dried in vacuo. The crude product was purified by normal phase chromatography (column: Welch Ultimate XB-CN 250*70*10 pm; mobile phase: [Hexane-EtOH (0.1% NH3.H2O)]; B%: 20%-60%,15 min). The solvent was removed in vacuo to afford the title compound (25.2 g,77.2 mmol, 38.3% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) 5 7.46 (d, J = 9.2 Hz, 1 H), 7.13 (d, J = 6 Hz, 1 H), 7.69 (d, J = 9.6 Hz, 1 H), 6.35 (s, 2H), 4.24-4.28 (m, 1 H), 3.67-3.71 (m, 1 H), 3.46-3.55 (m, 3H), 2.20-2.26 (m, 1 H), 2.00- 2.06 (m, 1 H). LCMS (Method 4, ESI) 298.1 / 300.0 [MH]+, RT 1.123 minutes. INTERMEDIATE 4: (R)-N2-(1-(1 ,2,4-triazin-6-yl)pyrroli p

[0921] Intermediate 4

[0922] Step 1 : 6-bromo-3-(methylthio)- 1 , 2, 4-triazine

[0923] To a mixture of 6-bromo-1 ,2,4-triazin-3-amine (15.0 g, 0.86 mol, 1.0 eq.) and 1 ,2- dimethyldisulfane (76 mL, 8.6 mmol, 10 eq.) in anhydrous ACN (60 mL) was added tert-butyl nitrite (63 mL, 0.51 mol, 6 eq.) dropwise and the reaction mixture was stirred at r.t. for 1 h. MeOH (6 mL) was added and the mixture was concentrated in vacuo. The residue was purified by flash chromatography (silica, 20% of EtOAc in PE) to afford the title compound (12.0 g, 42%) as a yellow oil. LCMS (Method 3, ESI):206.0 [M+H]+, RT 0.373 minutes.

[0924] Step 2: tert-butyl (R)-( 1-(3-(methylthio)- 1,2, 4-triazin-6-yl)pyrrolidin-3-yl)carbamate

[0925] To a stirred solution of 6-bromo-3-(methylthio)-1 , 2, 4-triazine (12.0 g, 48.0 mmol, 1.0 eq.) in butan- l-ol (20 mL) were added tert-butyl (R)-pyrrolidin-3-ylcarbamate (9.82 g, 52.8 mmol, 1.1 eq.) and DIPEA (2.32 g, 134.0 mmol, 3.0 eq.). The resulting mixture was stirred at 80 °C for 16 h. The reaction mixture was concentrated in vacuo. The residue was purified by reverse column chromatography (0-90% ACN in H2O) then by flash chromatography (silica, 20% of EtOAc in PE) to afford the title compound (9.8 g, 65% yield) as a yellow solid. LCMS (Method 15, ESI): 312.1 [M+H]+, RT 1.583 minutes. 1 H MR (400 MHz, CDCI3) 1.46 (9H, s), 5 1.96-2.09 (1 H, m), 2.26-2.41 (1 H, m), 2.63 (3H, s), 3.43 (1 H, m), 3.58-3.72 (2H, m), 3.80 (1 H, m), 4.39 (1 H, s), 4.66 (1 H, s), 7.91 (1 H, s).

[0926] Step 3: tert-butyl (R)-( 1-(1,2,4-triazin-6-yl)pyrrolidin-3-yl)carbamate

[0927] To a stirred solution of tert-butyl ( )-(1-(3-(methylthio)-1 ,2,4-triazin-6-yl)pyrrolidin-3-yl)carbamate (1.0 g, 3.20 mmol, 1.0 eq.) in EtOH (15 mL) and water (5 mL) was added Raney-Nickel (5 g, wet) and the mixture was refluxed for 48 h. The reaction mixture was filtered and to the filtrate was added MnO2 (5.5 g, 64 mmol, 20 eq.). The resulting suspension was stirred at 25°C for 30 min. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by reverse column chromatography (0-90% ACN in H2O) to afford the title compound (280 mg, 32% yield) as a yellow solid. LCMS (An analogous method to Method 21 , ESI): 266.1 [M+H]+, RT 1.272 minutes.1H NMR (400 MHz, DMSO-cfe) 6 8.94 (s, 1 H), 8.24 (s, 1 H), 7.24 (d, J = 6.2 Hz, 1 H), 4.16 (d, J = 4.8 Hz, 1 H), 3.74-3.43 (m, 3H), 3.35 (dd, J = 11.1 , 4.4 Hz, 1 H), 2.15 (td, J = 13.2, 7.0 Hz, 1 H), 1.93 (td, J = 12.9, 5.7 Hz, 1 H), 1.39 (s, 9H).

[0928] Step 4: Preparation of (R)-1-(1 ,2,4-triazin-6-yl)pyrrolidin-3-amine

[0929] To a stirred solution of tert-butyl ( )-(1-(1 ,2,4-triazin-6-yl)pyrrolidin-3-yl)carbamate (280 mg, 1.02 mmol, 1.0 eq.) in DCM (5 mL) was added HCI / dioxane (5 mL, 4M) and the resulting mixture was stirred at 25°C for 2 h. The reaction mixture was concentrated in vacuo. The residue was basified with aqueous sodium carbonate solution (2N, 1.5 mL). the mixture was concentrated in vacuo and the residue was washed with MeOH (15 mL x 3). The organic layer was concentrated in vacuo to afford the title compound (260 mg as crude) as a yellow solid. LCMS (An analogous method to Method 15, ESI): 166.3 [M+H]+, RT 0.243 minutes.

[0930] Step 5: (R)-N2-(1 -(1 ,2,4-triazin-6-yl)pyrrolidin-3-yl)-1 ,3,4-thiadiazole-2,5-diamine

[0931] To a stirred solution of ( )-1-(1 ,2,4-triazin-6-yl)pyrrolidin-3-amine (260 mg crude, 1.02 mmol, 1.0 eq.) in DMF (5 mL) was added 5-bromo-1 ,3,4-thiadiazol-2-amine (456 mg, 2.55 mmol, 2.5 eq.) and NaHCOs (257 mg, 3.06 mmol, 3.0 eq.). The resulting mixture was stirred at 80°C for 4 h. The reaction mixture was concentrated in vacuo. The residue was purified by flash chromatography (silica, 10% of EtOAc in PE) to afford the title compound (150 mg, 0.56 mmol, 55% yield over two steps) as a yellow solid. LCMS (An analogous method to Method 21 , ESI): 265.0 [M+H]+, RT 0.532 minutes.

[0932] INTERMEDIATE 5: lithio 2-f1 -[(4-methoxy-3.5-dimethylphenyl)methyl]piperidin-4-yl}acetate

[0933] Step 1 : methyl 2-f1 -[(4-methoxy-3.5-dimethylphenyl)methyl]piperidin-4-yl}acetate

[0934] To a stirred solution of methyl (piperidin-4-yl)acetate hydrochloride (280 mg, 1.44 mmol, 0.95 eq.) in MeOH (25 mL) was added 3,5-dimethyl-4-methoxybenzaldehyde (250 mg, 1.52 mmol, 1.0 eq.) and the reaction mixture was stirred at r.t. under argon for 2 h. Sodium cyanoborohydride (136 mg, 2.28 mmol, 1.5 eq.) was added and the reaction mixture was stirred at r.t. for 16 h before the solvent was removed in vacuo. Crude mixture was re-dissolved in DCM and saturated aqueous sodium bicarbonate solution was added. Stirring was continued for 15 min and phases were separated. Aqueous phase was extracted with DCM (2x). Combined organic layers were dried over sodium sulphate, filtered and concentrated in vacuo to afford the title compound (210 mg, 40% yield) without further purification.1H NMR (300 MHz, CDC ) 6 7.56 (s, 2H), 3.83-3.76 (m, 3H), 3.76 - 3.68 (m, 3H), 3.38 - 3.29 (m, 1 H), 2.35 (s, 6H), 2.31 - 2.22 (m, 5H), 1.56 (s, 7H). UPLC (Method 20, ESI) 306.10 [MH]+, RT 2.10 min.

[0935] Step 2: lithio 2 -f 1 (4 -methoxy-3 5-dimethylphenyl)methyl]piperidin -4 -yljacetate

[0936] To a stirred solution of methyl 2-{1-[(4-methoxy-3,5-dimethylphenyl)methyl]piperidin-4-yl}acetate (210 mg, 0.63 mmol, 1 eq.) in a mixture of THF (4.6 mL) and water (3.2 mL) was added lithium hydroxide monohydrate (52 mg, 1.22 mmol, 2 eq.). The reaction mixture was stirred at r.t. for 16 h. After completion, solvent was removed in vacuo to afford the title compound (120 mg, 43% yield) without further purification. UPLC (An analogous method to Method 5, ESI) 292.10 [MH]+, RT 1.76 min.

[0937] INTERMEDIATE 6: lithio 2-(1 -f[4-(trifluoromethoxy)phenyl]methyl}piperidin-4-yl)acetate

[0938] Step 1 : methyl 2-(1-ff4-(trifluoromethoxy)phenyllmethyl}piperidin-4-yl)acetate

[0939] To a solution of methyl (piperidin-4-yl)acetate hydrochloride (170 mg, 0.88 mmol, 0.9 eq.) and anhydrous potassium carbonate (470 mg, 3.43 mmol, 3.5 eq.) in ACN (25 mL) was added 4-(trifluoromethoxy)benzyl bromide (0.16 mL, 0.98 mmol, 1.0 eq.). The reaction mixture was stirred at r.t. for 3 h before it was filtered and concentrated in vacuo to afford the title compound (450 mg, quantitative yield) without further purification. UPLC (An analogous method to Method 5, ESI) 332.25 [MH]+, RT 2.05 min.

[0940] Step 2: lithio 2-( 14T4-(trifluoromethoxy)phenyl]methyl}piperidin-4-yl)acetate

[0941] To a stirred solution of methyl 2-(1-{[4-(trifluoromethoxy)phenyl]methyl}piperidin-4-yl)acetate (450 mg, 0.95 mmol, 1 eq.) in MeOH (10 mL) was added lithium hydroxide monohydrate (790 mg, 1.9 mmol, 2 eq.). The reaction mixture was stirred at r.t. for 56 h and the solvent was removed in vacuo to afford the title compound (420 mg, 62% yield) without further purification. LIPLC (An analogous method to Method 5, ESI) 318.25 [MH]+, RT 1.88 min. Step 1 : ethyl 2-(4-ff4-(trifluoromethoxy)phenyllmethyl}piperazin-1-yl)acetate

[0942] To a stirred solution of 1-(ethoxycarbonylmethyl)piperazine (200 mg, 1.16 mmol, 1 eq.) in ACN (5.8 mL), was added Et3N (486 pL, 3.48 mmol, 3 eq.) followed by 4-(trifluoromethoxy)benzyl bromide (296 mg, 1.161 mmol, 1 eq.). The reaction mixture was stirred at r.t. for 16 h and the solvent was removed in vacuo. The crude material was re-dissolved in DCM and saturated aqueous sodium bicarbonate solution was added. The mixture was stirred for 15 min and phases were separated. Aqueous phase was extracted with DCM (2x). Combined organic phases were washed with water and brine, dried over sodium sulphate, filtered and concentrated in vacuo to afford the title compound (346 mg, 86% yield) as a yellow oil without further purification.1H NMR (300 MHz, CDCh) 6 7.39 - 7.30 (m, 2H), 7.15 (d, J = 8.1 Hz, 2H), 4.18 (q, J = 7.1 Hz, 2H), 3.51 (s, 2H), 3.20 (s, 2H), 2.68 - 2.57 (m, 4H), 2.57 - 2.45 (m, 4H), 1.27 (t, J = 7.2 Hz, 3H). UPLC (An analogous method to Method 5, ESI) 347.25 [MH]+, RT 1.64 min.

[0943] Step 2: sodium 2-(4- / [4-(trifluoromethoxy)phenyl]methyl}piperazin-1-yl)acetate

[0944] To a stirred solution of ethyl 2-(4-{[4-(trifluoromethoxy)phenyl]methyl}piperazin-1-yl)acetate (346 mg, 1.00 mmol, 1 eq.) in MeOH (5.0 mL) was added aqueous sodium hydroxide solution (1M, 2.0 mL, 2.00 mmol, 2 eq.). The reaction mixture was stirred at r.t. for 16 h. After completion, solvent was removed in vacuo to afford the title compound (400 mg, quantitative yield, 80% purity) as a yellow solid without further purification.1H NMR (300 MHz, DMSO-cfe) 5 7.45 - 7.37 (m, 2H), 7.29 (d, J = 8.2 Hz, 2H), 3.45 (s, 2H), 2.61 (s, 2H), 2.45 - 2.29 (m, 8H). UPLC (An analogous method to Method 5, ESI) 319.10 [MH]+, RT 1.55 min.

[0945] INTERMEDIATE 8: lithio 2-(1 -f[3-(trifluoromethoxy)phenyllmethyl}piperidin-4-yl)acetate

[0946] Step 1 : methyl 2-(1- / [3-(trifluoromethoxy)phenyl]methyl}piperidin-4-yl)acetate

[0947] To a stirred solution of 3-(trifluoromethoxy)benzaldehyde (154 pL, 1.05 mmol, 1.0 eq.) in MeOH (5.3 mL) was added methyl (piperidin-4-yl)acetate hydrochloride (224 mg, 1.16 mmol, 1.1 eq.). The reaction mixture was stirred at r.t. for 15 min and then sodium cyanoborohydride (94 mg, 1.58 mmol, 1.5 eq.) was added. The reaction mixture was stirred at r.t. for 16 h before concentrated in vacuo. Crude material was purified by flash chromatography (silica, 0-10% MeOH / DCM) to afford the title compound (175 mg, 40% yield).1H NMR (300 MHz, DMSO-cfe) 6 7.44 (t, J = 7.8 Hz, 1 H), 7.31 (d, J = 7.7 Hz, 1 H), 7.27 - 7.17 (m, 2H), 3.57 (s, 3H), 3.48 (s, 2H), 2.83 - 2.57 (m, 2H), 2.23 (d, J = 6.7 Hz, 2H), 1.93 (td, J = 12.1 , 2.3 Hz, 2H), 1.80 - 1.43 (m, 2H), 1.38 - 1.08 (m, 3H). UPLC (An analogous method to Method 5, ESI) 332.25 [MH]+, RT 1.98 min. Step 2: lithio 2-( 14T3-(trifluoromethoxy)phenyl]methyl}piperidin-4-yl)acetate

[0948] To a stirred solution of methyl 2-(1-{[3-(trifluoromethoxy)phenyl]methyl}piperidin-4-yl)acetate (165 mg, 0.39 mmol, 1 eq.) in MeOH (2.0 mL) was added aqueous sodium hydroxide solution (1M, 0.79 mL, 0.79 mmol, 2 eq.). The reaction mixture was stirred at r.t. for 16 h before removed in vacuo to afford the title compound (190 mg, quantitative yield) without further purification. UPLC (An analogous method to Method 5, ESI) 318.20 [MH]+, RT 1.76.

[0949] INTERMEDIATE S: 2-r(3S)-pipendin-3-yll-N-(5-m3R)-1-(pyridazin-3-yl)pyrrolidin-3-yllamino}-

[0950] 1 ,3,4-thiadiazol-2-yl)acetamide hydrochloride

[0951] Intermediate 9

[0952] Step 1 : tert-butyl (3S)-3-ff(5-ff(3R)-1-(pyridazin-3-yl)pyrrolidin-3-yllamino}-1 ,3,4-thiadiazol-2- yl)carbamoyl]methyl}piperidine-1 -carboxylate

[0953] To a stirred solution of (R)-N2-(1-(pyridazin-3-yl)pyrrolidin-3-yl)-1,3,4-thiadiazole-2,5-diamine (prepared according to the procedure of Intermediate 1) (250 mg, 0.94 mmol, 1.0 eq.) in anhydrous DMF (18.7 mL) was added 2-[(3S)-1-[(terf-butoxy)carbonyl]piperidin-3-yl]acetic acid (220 mg, 0.94 mmol, 1.0 eq.), DIPEA (0.82 mL, 4.67 mmol, 5.0 eq.) and 1-propylphosphonic acid cyclic anhydride (50+% soln, in DMF, 0.82 mL, 2.81 mmol, 3.0 eq.). The reaction mixture was stirred at r.t. for 16 h. The reaction mixture was diluted with DCM and saturated aqueous sodium bicarbonate solution was added. Stirring was continued for 15 min and phases were separated. Aqueous phase was extracted with DCM (2x). Combined organic phases were washed with water and brine, dried over sodium sulphate, filtered and concentrated in vacuo. Crude material was purified by flash chromatography (silica, 0-10% MeOH in DCM) to give the title compound (340 mg, 74% yield) as a yellow solid.1H NMR (300 MHz, DMSO-cfe) 5 11.95 (s, 1 H), 8.48 (dd, = 4.5, 1.3 Hz, 1 H), 7.62 (d, J = 6.1 Hz, 1 H), 7.33 (dd, J = 9.1 , 4.5 Hz, 1 H), 6.87 (dd, J = 9.2, 1.3 Hz, 1 H), 4.44 - 4.33 (m, 1 H), 3.75 (dd, J = 11.1 , 5.8 Hz, 1 H), 3.71 - 3.63 (m, 3H), 3.61 - 3.46 (m, 3H), 2.88 - 2.74 (m, 1 H), 2.33 - 2.23 (m, 3H), 2.13 - 2.01 (m, 1 H), 1.92 - 1.77 (m, 1 H), 1.76 - 1.65 (m, 1 H), 1 .63 - 1.52 (m, 1 H), 1.36 (s, 11 H). UPLC (An analogous method to Method 5, ESI) 489.3 [MH]+, RT 1.78 min. Step 2: 2-f (3S)-piperidin-3-yl]-N-(5- / T (3R)- 1-(pyridazin-3-yl)pyrrolidin-3-yllamino}- 1,3,4- thiadiazol-2-yl)acetamide hydrochloride

[0954] To a stirring solution of terf-butyl (3S)-3-{[(5-{[(3 )-1 -(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4- thiadiazol-2-yl)carbamoyl]methyl}piperidine-1 -carboxylate (340 mg, 0.69 mmol, 1 eq.) in anhydrous MeOH (7.0 mL) was added HCI in dioxane (4M, 1.74 mL, 6.96 mmol, 30 eq.) and the mixture was stirred at r.t. for 16 h. Solvent was removed in vacuo to give the title compound (350 mg, 99% yield, 75% purity) as a yellow solid. UPLC (An analogous method to Method 5, ESI) 388.95 [MH]+, RT 0.64 min.

[0955] INTERMEDIATE 10: 2-[1 -[(tert-butoxy)carbonyl -methylpiperidin-4-yl}acetic acid

[0956] To a stirred solution of terf-butyl 4-(2-ethoxy-2-oxo-ethyl)-4-methyl-piperidine-1-carboxylate (1.0 g, 3.50 mmol, 1 eq.) in MeOH (17.5 mL) was added aqueous sodium hydroxide solution (1M, 7.0 mL, 7.00 mmol, 2 eq.). The reaction mixture was stirred at r.t. for 16 h before concentrated in vacuo. Crude was dissolved in water and acidified with 10% aqueous potassium bisulphate solution till pH = 3. Aqueous phase was extracted with EtOAc (3x). Combined organic phases were washed with water and brine, dried over sodium sulphate, filtered and concentrated in vacuo to afford the title compound (1.0 g, quantitative yield, 90% purity) as a colourless oil without further purification.1H NMR (300 MHz, DMSO-cfe) 6 12.03 (s, 1H), 3.44 - 3.36 (m, 2H), 3.29 - 3.16 (m, 2H), 2.18 (s, 2H), 1.50 - 1.40 (m, 2H), 1.38 (s, 9H), 1.35 - 1.24 (m, 2H), 1.01 (s, 3H). UPLC (An analogous method to Method 5, ESI) 256.20 [MH]', RT 1.55 min.

[0957] INTERMEDIATE 11 : 2

[0958] Intermediate 11

[0959] Step 1 : ethyl 244-[(4-bromophenyl)methyl]piperazin-1 -yl acetate

[0960] To a mixture of 4-bromobenzyl bromide (500 mg, 2.00 mmol, 1 eq.) and anhydrous potassium carbonate (830 mg, 6.00 mmol, 3 eq.) in ACN (20.0 mL) at -10°C under argon was added dropwise a solution of ethyl 2-(piperazin-1-yl)acetate (370 pL, 2.20 mmol, 1.1 eq.) in ACN (1.0 mL). The reaction mixture was stirred at r.t. for 16 h. Then, it was filtered and concentrated in vacuo. The crude material was dissolved in DCM and saturated aqueous sodium bicarbonate solution was added. The mixture was stirred for 15 min and phases were separated. Aqueous phase was extracted with DCM (2x). Combined organic layers were dried over sodium sulphate, filtered and concentrated in vacuo to afford the title compound (680 mg, quantitative yield) without further purification.1H NMR (300 MHz, DMSO-cfe) 6 7.58 - 7.43 (m, 2H), 7.29 - 7.21 (m, 2H), 4.06 (q, J = 7.1 Hz, 2H), 3.41 (s, 2H), 3.18 (s, 2H), 2.49 - 2.43 (m, 4H), 2.42 - 2.23 (m, 4H), 1.17 (t, J = 7.1 Hz, 3H).

[0961] Step 2: ethyl 2 -(4 -([4 -(propan -2-ylsulfanyl)phenyllmethyl}piperazin-1 -yljacetate

[0962] A solution of ethyl 2-{4-[(4-bromophenyl)methyl]piperazin-1 -yljacetate (100 mg, 0.28 mmol, 1.0 eq.), propane-2-thiol (28 pL, 0.30 mmol, 1.1 eq.) in anhydrous dioxane (4.0 mL) was purged with argon for 10 min. Tris(dibenzylideneacetone)dipalladium(0) (25 mg, 0.03 mmol, 0.1 eq.) and XantPhos (16 mg, 0.03 mmol, 0.1 eq.) were then added and the mixture was purged with argon for 5 min. After that, DIPEA (150 pL, 0.83 mmol, 3.0 eq.) was added and the mixture was purged with argon for 5 min. The reaction mixture was heated at 100°C for 16 h. Then, it was filtered through a pad of Celite®, washed with MeOH and the organic layer was concentrated in vacuo. Crude material was purified by flash chromatography (silica, 0-5% MeOH in DCM) to afford the title compound (80 mg, 81 % yield).1H NMR (300 MHz, methanol-d4) 6 7.38 - 7.33 (m, 2H), 7.30 - 7.25 (m, 2H), 4.16 (q, J = 7.1 Hz, 2H), 3.52 (s, 2H), 3.46 - 3.34 (m, 1 H), 3.23 (s, 2H), 2.76 - 2.43 (m, 8H), 1.29 - 1.22 (m, 9H). UPLC (An analogous method to Method 5, ESI) 338.0 [MH]+, RT 1.73 min.

[0963] Step 3: 2 -(4 -([4 -(propan -2-ylsulfanyl)phenyl]methyl}piperazin-1 -vDacetic acid

[0964] To a stirred solution of ethyl 2-(4-{[4-(propan-2-ylsulfanyl)phenyl]methyl}piperazin-1-yl)acetate (260 mg, 0.73 mmol, 1 eq.) in MeOH (15.0 mL) was added lithium hydroxide monohydrate (160 mg, 6.60 mmol, 9 eq.). The reaction mixture was stirred at40°C for 48 h. After completion, solvent was removed in vacuo to afford the title compound (230 mg, quantitative yield) without further purification. LIPLC (An analogous method to Method 5, ESI) 307.8 [MH]', RT 1.32 min.

[0965] INTERMEDIATE 12: sodium 2-[3-benzyl-3-azaspiro[5.51undecan-9-yl}acetate

[0966] Step 1 : methyl 2 -(3 -benzyl -3 -azaspiro[5.5]undecan -9 -yl acetate To a stirred solution of methyl 2-{3-azaspiro[5.5]undecan-9-yl}acetate hydrochloride (730 mg, 2.79 mmol, 1.0 eq.) in ACN (13.9 mL) was added benzyl bromide (570 mg, 3.35 mmol, 1.2 eq.) followed by Et3N (1.13 g, 1.55 mL, 11.15 mmol, 4.0 eq.). The reaction mixture was stirred at r.t. for 16 h and the solvent was removed in vacuo. The crude material was purified by flash chromatography (silica, 0-10% MeOH in DCM) to afford the title compound (810 mg, 70% yield, 64% purity).1H NMR (300 MHz, CDCh) 6 7.56 - 7.46 (m, 2H), 7.43 - 7.32 (m, 3H), 3.91 (s, 2H), 3.65 (s, 3H), 2.93 - 2.60 (m, 4H), 2.20 (d, J = 7.0 Hz, 2H), 1.88 - 1.79 (m, 2H), 1.79 - 1.61 (m, 5H), 1.60 - 1.51 (m, 2H), 1.21 - 1.04 (m, 4H). UPLC (An analogous method to Method 5, ESI) 316.5 [MH]+, RT 1.62 min.

[0967] Step 2: sodium 243 -benzyl -3 -azaspiro[5.5]undecan -9 -yljacetate

[0968] To a stirred solution of methyl 2-{3-benzyl-3-azaspiro[5.5]undecan-9-yl}acetate (300 mg, 0.67 mmol, 1 eq.) in MeOH (3.3 mL), was added aqueous sodium hydroxide solution (1M, 1.33 mL, 1.33 mmol, 2 eq.). The reaction mixture was stirred at r.t. for 16 h and aqueous sodium hydroxide solution (1 M, 0.67 mL, 0.67 mmol, 1 eq.) was added. Stirring was continued at r.t. for an additional 16 h. After completion, solvent was concentrated in vacuo to afford the title compound (400 mg, quantitative yield) without further purification.1H NMR (300 MHz, DMSO-cfe) 5 7.36 - 7.16 (m, 5H), 3.42 (s, 2H), 2.34 - 2.22 (m, 4H), 1.77 - 1 .69 (m, 2H), 1 .60 - 1 .38 (m, 7H), 1.32 - 1 .20 (m, 2H), 1.07 - 0.90 (m, 4H). UPLC (An analogous method to Method 5, ESI) 302.35 [MH]+, RT 1.48 min.

[0969] IN

[0970] Intermediate 13

[0971] Step 1 : methyl 2-{ 1-[(4-bromophenyl)methyl]piperidin-4-yl}acetate

[0972] To a solution of 4-bromobenzyl bromide (500 mg, 2.0 mmol, 1.0 eq.) and anhydrous potassium carbonate (830 mg, 6.0 mmol, 3.0 eq.) in ACN (20.0 mL) at -10°C was added a solution of methyl (piperidin-4-yl)acetate hydrochloride (430 pL, 2.2 mmol, 1.1 eq.) in ACN (1.0 mL) dropwise under argon. The reaction mixture was stirred at r.t. for 16 h before filtered and concentrated in vacuo. Crude reaction was dissolved in DCM and saturated aqueous sodium bicarbonate solution was added. The mixture was stirred for 15 min and phases were separated. Aqueous phase was extracted with DCM (3x). Combined organic layers were washed with brine, dried over sodium sulphate, filtered and concentrated in vacuo. Crude material was purified by flash chromatography (silica, 5% MeOH in DCM) to afford the title compound (620 mg, 90% yield).1H NMR (300 MHz, CDC ) 6 7.44 - 7.40 (m, 2H), 7.22 - 7.15 (m, 2H), 3.66 (s, 3H), 3.42 (s, 2H), 2.87 - 2.77 (m, 2H), 2.23 (d, J = 7.0 Hz, 2H), 1.97 (td, J = 11.7, 2.3 Hz, 2H), 1 .85 - 1.72 (m, 1 H), 1.72 - 1.63 (m, 2H), 1.39 - 1.19 (m, 2H).

[0973] Step 2: methyl 2-(1- / [4-(propan-2-ylsulfanyl)phenyl]methyl}piperidin-4-yl)acetate

[0974] A solution of methyl 2-{1-[(4-bromophenyl)methyl]piperidin-4-yl}acetate (200 mg, 0.58 mmol, 1.0 eq.), propane-2-thiol (59 pL, 0.64 mmol, 1.1 eq.) in anhydrous dioxane (4.0 mL) was purged with argon for 10 min. Then, Tris(dibenzylideneacetone)dipalladium(0) (34 mg, 0.06 mmol, 0.1 eq.) and XantPhos (34m g, 0.06 mmol, 0.1 eq.) were added and mixture was purged with argon for 5 min. After that, DI PEA (304 pL, 1.74 mmol, 3.0 eq.) was added and the mixture was purged with argon for another 5 min. The reaction was heated at 120°C for 16 h. Then, it was filtered through a pad of Celite®, washed with MeOH and concentrated in vacuo. Crude material was purified by flash chromatography (silica, 0-5% MeOH in DCM) to afford the title compound (180 mg, 91% yield).1H NMR (300 MHz, methanol-d4) 6 7.42 - 7.37 (m, 2H), 7.36 - 7.30 (m, 2H), 3.80 (s, 2H), 3.65 (s, 3H), 3.45 (hept, J = 6.7 Hz, 1 H), 3.20 - 3.05 (m, 2H), 2.54 - 2.36 (m, 2H), 2.30 (d, J = 6.8 Hz, 2H), 1.97 - 1.75 (m, 3H), 1.49 - 1.33 (m, 2H), 1.28 (d, J = 6.7 Hz, 6H). UPLC (An analogous method to Method 5, ESI) 324.1 [MH]+, RT 1.83 min.

[0975] Step 3: lithio 2-( 1 -f[4-(propan-2-ylsulfanyl)phenyllmethyl}piperidin^4-yl)acetate

[0976] To a stirred solution of methyl 2-(1-{[4-(propan-2-ylsulfanyl)phenyl]methyl}piperidin-4-yl)acetate (260 mg, 0.77 mmol, 1 eq.) in MeOH (15.0 mL) was added lithium hydroxide monohydrate (160 mg, 6.60 mmol, 9 eq.). The reaction mixture was stirred at45°C for 48 h. After completion, solvent was removed in vacuo to afford the title compound (0.24 g, quantitative yield) without further purification. UPLC (An analogous method to Method 5, ESI) 308.9 [MH]', RT 1.33 min.

[0977] INTERMEDIATE 14: 4-nitrophenyl 1 -f[4-(trifluoromethoxy)phenyllmethyl}piperidin^4-yl

[0978] To a stirred solution of piperidin-4-ol (2.00 g, 19.77 mmol, 1 eq.) in ACN (60.0 mL) was added 4- (trifluoromethoxy)benzyl bromide (20.01 g, 19.77 mmol, 1 eq.) followed by Et3N (27.56 mL, 197.73 mmol, 10 eq.). The reaction mixture was stirred at r.t. for 16 h. Then, it was filtered and concentrated in vacuo. Crude material was purified by flash chromatography (silica, 0-5% MeOH in DCM) to afford the title compound (2.02 g, 27% yield, 74% purity).1H NMR (300 MHz, DMSO- d6) 6 7.49 - 7.39 (m, 2H), 7.37 - 7.27 (m, 2H), 4.60 (bs, 1 H), 3.58 - 3.39 (m, 3H), 2.81 - 2.58 (m, 2H), 2.23 - 1.85 (m, 2H), 1 .76 - 1.63 (m, 2H), 1 .49 - 1.31 (m, 2H). UPLC (An analogous method to Method 5, ESI) 276.0 [MH]+, RT 1.75 minutes.

[0979] Step 2: 4 -nitrophenyl 1 -fl4 -(trifluoromethoxy)phenyl]methyl}piperidin -4 -yl carbonate

[0980] To a stirred solution of 1-{[4-(trifluoromethoxy)phenyl]methyl}piperidin-4-ol (0.74 g, 2.69 mmol, 1 eq.) and DIPEA (0.94 mL, 5.38 mmol, 2.0 eq.) in anhydrous DMF (30.0 mL) under argon at 0°C, a solution of 4-nitrophenyl chloroformate (1.03 g, 5.11 mmol 1.9 eq.) in anhydrous DMF (30.0 mL) was added dropwise. The solution was stirred at 0°C for 1 h, warmed to r.t. and stirred for 16 h. The solvent was removed in vacuo and the crude residue was purified by flash chromatography (silica, 0-30% EtOAc in hexanes) to afford the title compound (106 mg, 7% yield, 73% purity). LIPLC (An analogous method to Method 5, ESI) 441.35 [MH]+, RT 2.51 min.

[0981] INTERMEDIATE 15: sodium 2- 3R.5S) -3.5 limethyl-4-[4- trifluoromethoxy)phenyllmethyl}piperazin-1 -yllacetate

[0982] Intermediate 15

[0983] Step 1 : tert-butyl (2R, 6S)-4-(2-ethoxy-2-oxoethyl) -2,6-dimethylpiperazine-1 -carboxylate

[0984] To a stirred solution of (2 ,6S)-terf-butyl 2,6-dimethylpiperazine-1-carboxylate (474 mg, 2.21 mmol, 1 eq.) in ACN (10.0 mL), was added ethyl bromoacetate (489 pL, 4.42 mmol, 2 eq.) followed by Et3N (1.23 mL, 8.84 mmol, 4 eq.). The reaction mixture was stirred at r.t. for 16 h. After completion, it was concentrated in vacuo. Crude material was purified by flash chromatography (silica, 0-5% MeOH in DCM) to afford the title compound (664 mg, 95% yield).1H NMR (300 MHz, DMSO-cfe) 6 4.09 (q, J = 7.1 Hz, 2H), 3.99 - 3.89 (m, 2H), 3.22 (s, 2H), 2.64 (d, J = 11.3 Hz, 2H), 2.23 (dd, J = 11.3, 4.5 Hz, 2H), 1.40 - 1.38 (m, 9H), 1.22 - 1.16 (m, 9H). UPLC (An analogous method to Method 5, ESI) 301.3 [MH]+, RT 2.76 min. Step 2: ethyl 2-[(3R,5S)-3,5-dimethylpiperazin-1 -yljacetate

[0985] To a stirred solution of terf-butyl (2 ,6S)-4-(2-ethoxy-2-oxoethyl)-2,6-dimethylpiperazine

[0986] -1 -carboxylate (664 mg, 2.10 mmol, 1 eq.) in DCM (10.0 mL) at 0°C was added HCI in dioxane (4M, 5.30 mL, 20.99 mmol, 10 eq.). The reaction mixture was stirred at r.t. for 16 h before concentrated in vacuo to afford the title compound (675 mg, quantitative yield, 90% purity).1H NMR (300 MHz, DMSO-cfe) 6 4.15 (q, J = 7.1 Hz, 2H), 3.56 (s, 2H), 3.50 - 3.38 (m, 3H), 3.29 - 3.20 (m, 2H), 2.82 - 2.68 (m, 2H), 1.27 - 1.19 (m, 9H).

[0987] Step 3: ethyl 2-[(3R,5S)-3,5-dimethyl-4 [4-(trifluoromethoxy)phenyl]methyl}piperazin

[0988] -1 -yl]acetate

[0989] To a stirred solution of ethyl 2-[(3R,5S)-3,5-dimethylpiperazin-1-yl]acetate (595 mg, 2.67 mmol, 1.0 eq.) in ACN (12.0 mL) was added 4-(trifluoromethoxy)benzyl bromide (642 pL, 4.01 mmol, 1.5 eq.) followed by Et3N (1.50 mL, 10.70 mmol, 10.0 eq.). The reaction mixture was stirred at r.t. for 16 h before concentrated in vacuo. Crude material was purified by flash chromatography (silica, 0-50% EtOAc in cyclohexane) to afford the title compound (54 mg, 5% yield).1H NMR (300 MHz, DMSO-cfe) 6 7.48 (d, J = 8.6 Hz, 2H), 7.28 (d, J = 8.6 Hz, 2H), 4.08 (q, J = 7.1 Hz, 2H), 3.73 (s, 2H), 3.14 (s, 2H), 2.76 - 2.66 (m, 2H), 2.58 (ddd, J = 9.3, 6.2, 2.9 Hz, 2H), 2.06 - 1 .93 (m, 2H), 1.19 (t, J = 7.1 Hz, 3H), 0.88 (d, J = 6.1 Hz, 6H).

[0990] Step 4: sodium 2- (3R, 5S) -3,5-dimethyl-44T4-(trifluoromethoxy)phenyllmethyl}piperazin-1 -

[0991] To a stirred solution of ethyl 2-[(3 ,5S)-3,5-dimethyl-4-{[4-(trifluoromethoxy)phenyl]methyl} piperazin- 1-yl]acetate (54 mg, 0.14 mmol, 1 eq.) in THF (0.8 mL), was added aqueous sodium hydroxide solution (0.9M, 300 pL, 0.27 mmol, 2 eq.) at r.t. and the reaction mixture was stirred at 60°C for 16 h. After completion, solvent was concentrated in vacuo to afford the title compound (59 mg, quantitative yield, 94% purity). UPLC (An analogous method to Method 5, ESI) 347.7 [MH]’, RT 1.35 min.

[0992] INTERMEDIATE 16: 1 -<

[0993] Intermediate 16

[0994] To a solution of [2-(propan-2-yloxy)phenyl]methanol (0.15 g, 0.90 mmol, 1.0 eq.) in anhydrous DCM (6.0 mL) under argon at 0°C, phosphorus tribromide (0.318 g, 1.17 mmol, 1.3 eq.) was added dropwise. The solution was stirred at 0°C for 5 h, warmed to r.t. and stirred for 16 h. The reaction mixture was neutralised to pH = 7 by addition of saturated aqueous sodium bicarbonate solution, diluted with water and extracted with DCM (3x). Combined organic layers were dried over sodium sulphate, filtered and concentrated in vacuo to give the title compound (150 mg, 67% yield) without any further purification.1H NMR (300 MHz, DMSO-cfe) 5 7.38 (dd, J = 7.5, 1.8 Hz, 1 H), 7.29 (ddd, J = 8.3, 7.4, 1.8 Hz, 1 H), 7.03 (dd, J = 8.4, 1.1 Hz, 1 H), 6.88 (td, J = 7.4, 1.1 Hz, 1 H), 4.69 (p, J = 6.1 Hz, 1 H), 4.62 (s, 2H), 1.30 (d, J = 6.0 Hz, 6H). UPLC (An analogous method to Method 5, ESI) 229.05 [MH]+, RT 1.87 min.

[0995] INTERMEDIATE 17 : 2-(dimethylamino) -2-( 1 -f[4-(trifluoromethoxy)phenyllmethyl}piperidin-4- yljacetic acid

[0996] Step 1 : methyl 2-f[(tert-butoxy)carbonyl]amino}-2-( 1 -f[4-(trifluoromethoxy)phenyl]methyl}- piperidin -4 -yljacetate

[0997] To a stirred solution of methyl 2-{[(terf-butoxy)carbonyl]amino}-2-(piperidin-4-yl)acetate (250 mg, 0.92 mmol, 1.0 eq.) and anhydrous potassium carbonate (380 mg, 2.75 mmol, 3.0 eq.) in ACN (10.0 mL) at -5°C under argon, a solution of 4-(trifluoromethoxy)benzyl bromide (260 pL, 1.01 mmol, 1.1 eq.) in ACN (1 .5 mL) was added dropwise. The reaction mixture was stirred at -5°C for 1 h, then warmed up to r.t. and stirred for 3 h. Then, it was filtered and the filtrate concentrated in vacuo. Crude material was purified by flash chromatography (silica, 3% MeOH in DCM) to afford the title compound (350 mg, 77% yield, 90% purity).1H NMR (300 MHz, CDCh) 6 7.39 - 7.28 (m, 2H), 7.20 - 7.12 (m, 2H), 5.16 - 4.95 (m, 1 H), 4.34 - 4.23 (m, 1 H), 3.74 (s, 4H), 3.57 - 3.38 (m, 2H), 3.01 - 2.77 (m, 2H), 2.07 - 1 .86 (m, 2H), 1.84 - 1 .70 (m, 1 H), 1 .65 - 1 .50 (m, 3H), 1 .43 (s, 9H). UPLC An analogous method to Method 5, ESI) 447.3 [MH]+, RT 4.27 min.

[0998] Step 2: methyl 2-amino-2-( 1 - / T4-(trifluoromethoxy)phenyl]methyl}piperidin-4-yl)acetate hydrochloride

[0999] To a stirred solution of methyl 2-{[(tert-butoxy)carbonyl]amino}-2-(1-{[4-(trifluoromethoxy) phenyl]methyl}-piperidin-4-yl)acetate (350 mg, 0.71 mmol, 1 eq.) in Et20 (14.0 mL) was added HCI solution in Et2<D (2M, 2.12 mL, 4.23 mmol, 6 eq.). The reaction mixture was stirred at r.t. for 16 h. HCI solution in Et2<D (2M, 2.12 mL, 4.23 mmol, 6 eq.) was added and the mixture was stirred at 45°C for 16 h. After completion, solvent was removed in vacuo to afford the title compound (270 mg, quantitative yield) without further purification.1H NMR (300 MHz, Deuterium Oxide) 5 7.61 - 7.53 (m, 2H), 7.47 - 7.38 (m, 2H), 4.34 (s, 2H), 4.13 (d, J = 5.4 Hz, 1 H), 3.86 (s, 3H), 3.68 - 3.50 (m, 2H), 3.16 - 2.96 (m, 2H), 2.43 - 2.25 (m, 1 H), 2.13 - 1.95 (m, 2H), 1.93 - 1.71 (m, 1 H), 1.71 - 1.50 (m, 1 H).

[1000] Step 3: methyl 2-(dimethylamino) -2-( 1 -f[4-(trifluoromethoxy)phenyl]methyl}piperidin-4-yl)acetate To a stirred solution of methyl 2-amino-2-(1-{[4-(trifluoromethoxy)phenyl]methyl}piperidin- 4-yl)acetate hydrochloride (270 mg, 0.70 mmol, 1 eq.) in MeOH (13.5 mL) was added formaldehyde solution (37 wt. % in H2O, contains 10-15% MeOH as stabilizer, 720 pL, 7.10 mmol, 10 eq.). The reaction mixture was stirred at r.t. for 1 h. Acetic acid (1 .0 mL) was then added and stirring was continued at 45°C for 3 h. Then, sodium cyanoborohydride (63 mg. 1.06 mmol, 1.5 eq.) was added. The reaction mixture was stirred at r.t. for 16 h before concentrated in vacuo. Crude material was washed with saturated aqueous sodium bicarbonate solution and extracted with DCM (3x). Combined organic layer were dried over sodium sulphate, filtered and concentrated in vacuo to give the tittle compound (264 mg, 92% yield) without further purification.1H NMR (300 MHz, CDCI3) 6 7.45 - 7.30 (m, 2H), 7.20 - 7.12 (m, 2H), 3.68 (s, 3H), 3.63 - 3.42 (m, 2H), 2.97 - 2.85 (m, 3H), 2.28 (s, 6H), 2.14 - 1 .84 (m, 3H), 1.84 - 1 .68 (m, 1 H), 1.54 - 1.45 (m, 1 H), 1.45 - 1.26 (m, 2H). UPLC (An analogous method to Method 5, ESI) 375.25 [MH]+, RT 1.18 min.

[1001] Step 4: 2-(dimethylamino) -2-( 144-(trifluoromethoxy)phenyl]methyl}piperidin-4-yl)acetic acid

[1002] To a solution of methyl 2-(dimethylamino)-2-(1-{[4-(trifluoromethoxy)phenyl]methyl} piperidin-4- yl)acetate (290 mg, 0.65 mmol, 1 eq.) in MeOH (17.0 mL) was added lithium hydroxide monohydrate (47 mg, 1.95 mmol, 3 eq.) and the reaction mixture was stirred at 60°C for 72 h and then at 80°C for another 72 h. After completion, solvent was removed in vacuo to afford the title compound (300 mg, quantitative yield) without further purification.1H NMR (300 MHz, Deuterium Oxide) 5 7.39 - 7.30 (m, 2H), 7.29 - 7.20 (m, 2H), 3.48 (s, 2H), 2.98 - 2.74 (m, 2H), 2.66 (d, J = 10.4 Hz, 1 H), 2.17 (s, 6H), 2.11 - 1.93 (m, 2H), 1.81 - 1.65 (m, 1 H), 1.66 - 1.53 (m, 1 H), 1.52 - 1.41 (m, 1 H), 1.29 - 1.01 (m, 2H). UPLC (An analogous method to Method 5, ESI) 361.20 [MH]+, RT 1.39 min. INTERMEDIATE 18: (

[1003] Step 1 : (4, 4-dimethylcyclohexyl) methanol

[1004] To a solution of 4,4-dimethylcyclohexane-1-carbaldehyde (150 mg, 1.07 mmol, 1 eq.) in MeOH (7.5 mL) at 0 °C was added sodium borohydride (120 mg, 3.21 mmol, 3 eq.). The reaction mixture was stirred at 0 °C for 10 min and concentrated in vacuo. Crude was re-dissolved in DCM and washed with brine. Combined organic layers were dried over sodium sulphate, filtered and concentrated in vacuo to give the title compound (120 mg, 75% yield) without any further purification.1H NMR (300 MHz, CDCh) 6 3.50 (d, J = 6.3 Hz, 2H), 1.64 - 1.58 (m, 2H), 1.47 - 1.39 (m, 3H), 1.31 - 1.07 (m, 4H), 0.93 (s, 3H), 0.90 (s, 3H).

[1005] Step 2: (4, 4-dimethylcyclohexyl) methyl 4-methylbenzene-1 -sulfonate

[1006] To a solution of p-toluenesulfonyl chloride (160 mg, 0.84 mmol, 1.05 eq.) in DCM (7.0 mL) was added a solution of (4,4-dimethylcyclohexyl)methanol (120 mg, 0.80 mmol, 1.0 eq.) and Et3N (340 pL, 2.40 mmol, 3.0 eq.) in DCM (5.0 mL). The reaction mixture was stirred at r.t. for 5 d with addition of p-toluenesulfonyl chloride (400 mg, 2.40 mmol, 3 eq.) and Et3N (1.02 mL, 7.20 mmol, 9 eq.). After completion, the reaction mixture was poured into H2O and extracted with DCM. Combined organic phases were washed with 1M aqueous HCI solution, saturated aqueous sodium bicarbonate solution, water and then dried over sodium sulphate, filtered and concentrated in vacuo to give the title compound (180 mg, 76% yield) without any further purification.1H NMR (300 MHz, CDCh) 6 7.85 - 7.72 (m, 2H), 7.42 - 7.30 (m, 2H), 3.84 (d, J = 6.2 Hz, 2H), 2.45 (s, 3H), 1.55 - 1 .47 (m, 3H), 1 .40 - 1 .31 (m, 2H), 1 .20 - 1 .00 (m, 4H), 0.88 (s, 3H), 0.82 (s, 3H). UPLC (An analogous method to Method 5, ESI) 293.20 [MH]', RT 4.59 min.

[1007] INTERM

[1008] Step 1 : tert-butyl (7E) -7 -[2 -(benzyloxy) -2-oxoethylidenel-5-azaspiro[2.51octane-5-carboxylate To a solution of benzyl 2-(dimethoxyphosphoryl)acetate (1.72 g, 6.66 mmol, 1.5 eq.) in anhydrous THF (6.0 mL) at 0°C sodium hydride (60 % dispersion in mineral oil, 0.16 g, 6.66 mmol, 1.5 eq.) was added. The resulting mixture was transferred at 0°C to a solution of terf-butyl 7-oxo-5- azaspiro[2.5]octane-5-carboxylate (1.00 g, 4.44 mmol, 1 eq.) in anhydrous THF (30.0 mL) and the solution was stirred at r.t. for 5 h. After completion, solvent was removed in vacuo and the crude mixture was re-dissolved in EtOAc. Saturated aqueous sodium bicarbonate solution was added, and the layers were separated. Aqueous phase was extracted with EtOAc (2x). Combined organic phases were dried over sodium sulphate, filtered and concentrated in vacuo. Crude material was purified by flash chromatography (silica, 5-10% EtOAc in cyclohexane) to afford the title compound (0.74 g, 44% yield, 85% purity).1H NMR (300 MHz, CDCh) 6 7.38 - 7.34 (m, 5H), 5.17 (s, 1 H), 5.13 (s, 2H), 4.03 (s, 2H), 3.27 (s, 2H), 2.80 (d, J = 1.6 Hz, 2H), 1.44 (s, 9H), 0.55 - 0.47 (m, 2H), 0.43 - 0.37 (m, 2H). UPLC (An analogous method to Method 5, ESI) 358.10 [MH]+, RT 4.35 min.

[1009] Step 2: 2 - / 5 -[ (tert -butoxy) carbonyl] -5 -azaspiro[2.5]octan -7 -yljacetic acid

[1010] To a solution of tert- butyl 7-[2-(benzyloxy)-2-oxoethylidene]-5-azaspiro[2.5]octane-5-carboxylate (800 mg, 2.11 mmol, 1 eq.) in MeOH (14.1 mL) under argon was added palladium on carbon (10% wet., 62 mg, 0.32 mmol, 15% w / w). The reaction was evacuated and backfilled with hydrogen 3 times before stirred at r.t. for 16 h under hydrogen atmosphere. The reaction mixture was then stirred at 40°C for 16 h under hydrogen atmosphere. The reaction mixture was filtered through a pad of Celite® and concentrated in vacuo to give (590 mg, 77% yield, 74% purity) without any further purification.1H NMR (300 MHz, CDCh) 6 3.96 - 3.74 (m, 1 H), 3.27 - 3.06 (m, 2H), 2.95 (dd, J = 13.2, 8.1 Hz, 1 H), 2.49 - 2.34 (m, 1 H), 2.34 - 2.10 (m, 2H), 1.45 (s, 11 H), 0.54 - 0.40 (m, 2H), 0.40 - 0.20 (m, 2H). UPLC (An analogous method to Method 5, ESI) 270.25 [MH]+, RT 4.47 min.

[1011] INTERMEDIATE 20: [5-m

[1012] Intermediate 20

[1013] Step 1 : [5-methoxy-6-(trifluoromethyl)pyridin-2-yl]methanol

[1014] To a solution of 5-methoxy-6-(trifluoromethyl)pyridine-2-carbaldehyde (250 mg., 1.22 mmol, 1 eq.) in MeOH (12.5 mL) was added sodium borohydride (140 mg, 3.66 mmol, 3 eq.) at 0°C. The reaction mixture was stirred at 0°C for 10 min and concentrated in vacuo. The obtained crude was dissolved in DCM and washed with brine. Combined organic layers were dried over sodium sulphate, filtered and concentrated in vacuo to give the title compound (250 mg, quantitative yield) without any further purification.1H NMR (300 MHz, CDCh) 6 7.51 - 7.36 (m, 2H), 4.75 (s, 2H), 3.94 (s, 3H). UPLC (An analogous method to Method 5, ESI) 208.60 [MH]+, RT 1.44 min.

[1015] Step 2: [5-methoxy-6-(trifluoromethyl)pyridin-2-yllmethyl methanesulfonate

[1016] To a stirred solution of [5-methoxy-6-(trifluoromethyl)pyridin-2-yl]methanol (240 mg, 1.16 mmol., 1.0 eq.) and Et3N (490 pL, 3.48 mmol, 3.0 eq.) in DCM (12.0 mL) at 0 °C under argon was slowly added methanesulfonyl chloride (140 pL, 1.74 mmol, 1.5 eq.). The reaction mixture was stirred at 0 °C for 30 min. Then, it was poured into saturated aqueous sodium bicarbonate solution. Aqueous layer was extracted with DCM (2x). Combined organic layers were dried over sodium sulphate, filtered and concentrated in vacuo to give the title compound (250 mg, quantitative yield, 90% purity) which was used in the next step without any further purification.1H NMR (300 MHz, CDCh) 6 7.67 (d, J = 8.6 Hz, 1 H), 7.46 (d, J = 8.7 Hz, 1 H), 3.99 (s, 3H), 3.17 (s, 2H), 3.15 (s, 3H). LIPLC (An analogous method to Method 5, ESI) 308.9 [MH+Na]+, RT 1.53 min.

[1017] INTERMEDIATE 21 : tert-butyl 4-[(2-ethoxy-2-oxoethyl)sulfanyllpiperidine-1 -carboxylate

[1018] To a mixture of terf-butyl 4-sulfanylpiperidine-1 -carboxylate (5.00 g, 23 mmol, 1 eq.) and anhydrous potassium carbonate (4.77 g, 34.5 mmol, 1.5 eq.) in ACN (250.0 mL) a solution of ethyl bromoacetate (2.67 mL, 24.16 mmol, 1.05 eq.) in ACN (10.0 mL) was added under argon. The reaction mixture was stirred at r.t. for 16 h. After completion, solvent was removed in vacuo and the crude mixture was re-dissolved in EtOAc and washed with saturated aqueous sodium bicarbonate solution. Aqueous layer was extracted with EtOAc (2x). Combined organic layers were dried over sodium sulphate, filtered and concentrated in vacuo to give the title compound (7.1 g, quantitative yield, 95% purity) without any further purification.1H NMR (400 MHz, Methanol-d4) 5 4.17 (q, J = 7.1 Hz, 2H), 3.99 - 3.88 (m, 2H), 3.32 (s, 2H), 3.06 - 2.88 (m, 3H), 2.01 - 1.90 (m, 2H), 1.45 (s, 9H), 1.43 - 1.36 (m, 2H), 1.27 (t, J = 7.1 Hz, 3H). UPLC (An analogous method to Method 5, ESI) 203.9 [MH - Boc]+, RT 2.5 min.

[1019] INTERMEDIATE 22: 2-( 1 -[(tert-butoxy)carbonyl]piperidin^-yl}sulfanyl)acetic acid To a stirred solution of tert-butyl 4-[(2-ethoxy-2-oxoethyl)sulfanyl]piperidine-1 -carboxylate Intermediate 21 (1.55 g, 4.85 mmol, 1 eq.) in MeOH (23.3 mL), at r.t. was added aqueous sodium hydroxide solution (1M, 24.3 mL, 24.27 mmol, 5 eq.). The resulting mixture was stirred at 45°C for 16 h before concentrated in vacuo. Crude product was then diluted with water and acidified with 1M aqueous HCI solution till pH = 5. The precipitate was filtered off, washed with excess of ACN and concentrated in vacuo to afford the title compound (1.7 g, 89% yield, 70% purity).1H NMR (300 MHz, DMSO-cfe) 6 3.82 - 3.75 (m, 2H), 2.95 (s, 2H), 2.93 - 2.76 (m, 3H), 1.91 - 1.81 (m, 2H), 1.38 (s, 9H), 1.34 - 1.15 (m, 2H). UPLC (An analogous method to Method 5, ESI) 273.9 [MH]; RT 2.06 min.

[1020] INTERMEDIATE 23: Sodium 2-((1 -[(tert-butoxy)carbonyl]piperidin-4-yl}sulfanyl)acetate

[1021] To a stirred solution of tert-butyl 4-[(2-ethoxy-2-oxoethyl)sulfanyl]piperidine-1 -carboxylate (prepared according to the procedure of Intermediate 21) (525 mg, 1.55 mmol, 1 eq.) in THF (8.0 mL) at r.t. was added aqueous sodium hydroxide solution (1.2M, 2.5 mL, 3.11 mmol, 2 eq.). The reaction mixture was stirred at 60°C for 16 h. After completion, solvent was removed in vacuo to afford the title compound (77Q mg, quantitative yield, 89% purity). LIPLC (An analogous method to Method 5, ESI) 274.7 [MH]', RT 1.28 min.

[1022] INTERMEDIATE 24: ethyl 2-(piperidin-4-ylsulfanyl)acetate hydrochloride

[1023] Intermediate 24

[1024] To a solution of tert-butyl 4-[(2 -ethoxy-2 -oxoethyl)sulfanyl]piperidine-1 -carboxylate (prepared according to the procedure of Intermediate 21) (2.45 g, 7.67 mmol, 1 eq.) in DCM (50.0 mL) was added a solution of HCI in dioxane (4M, 5.75 mL, 23.01 mmol, 3 eq.). The reaction mixture was stirred at40°C for 16 h. After completion, solvent was removed in vacuo to give the title compound (1.90 g, quantitative yield) without any further purification.1H NMR (400 MHz, DMSO-cfe) 5 8.96 - 8.57 (m, 2H), 4.10 (q, J = 7.1 Hz, 2H), 3.42 (s, 2H), 3.23 (dt, J = 12.9, 4.2 Hz, 2H), 3.14 - 2.99 (m, 1H), 2.98 - 2.80 (m, 2H), 2.15 - 1.94 (m, 2H), 1.76 - 1.49 (m, 2H), 1.20 (t, J = 7.1 Hz, 3H). UPLC (An analogous method to Method 5, ESI) 204.00 [MH]+, RT 1.04 min. INTERMEDIATE 25: sodium 2- 3-[(4,6-dimethylpyridin-2-yl)methyll-3-azaspiro[5.5lundecan-9- yljacetate

[1025] Step 1 : methyl 2- / 3-[ (4, 6-di methyl pyridin-2-yl) met hyl]-3-azaspiro['5.5]undecan-9-yl}acetate

[1026] To a solution of methyl 2-(3-azaspiro[5.5]undecan-9-yl)acetate hydrochloride (240 mg, 0.92 mmol, 1.0 eq.) in ACN (4.6 mL) was added Et3N (510 pL, 3.67 mmol, 4.0 eq.) and the resulting mixture was stirred for 5 min. 2-(bromomethyl)-4,6-dimethylpyridine (200 mg, 1.01 mmol, 1.1 eq.) was then added and the reaction stirred at r.t. for 16 h. After completion, it was concentrated in vacuo and the crude product was purified by flash chromatography (silica, 0-10% MeOH in DCM) to afford the title compound (309 mg, 97% yield). LIPLC (An analogous method to Method 5, ESI) 345.45 [MH]+, RT 1.91 min.

[1027] Step 2: ethyl 2 -(pi peridin -4-yl sulfanyl) acetate hydrochloride

[1028] To a stirred solution of ethyl sodium 2-{3-[(4,6-dimethylpyridin-2-yl)methyl]-3- azaspiro[5.5]undecan-9-yl}acetate (300 mg, 0.86 mmol, 1 eq.) in MeOH (18.0 mL) was added aqueous sodium hydroxide solution (1 M, 2.59 mL, 2.59 mmol, 3 eq.). The reaction mixture was stirred at 50°C for 5 h. After completion, solvent was removed in vacuo to afford the title compound (570 mg, 54% purity) without further purification. UPLC (An analogous method to Method 5, ESI) 331.40 [MH]+, RT 1.59 min.

[1029] INTERMEDIATE 26: sodium 2- 4-[(4,4-dimethylcvclohexyl)methyllpiperazin-1-yl}acetate

[1030] Step 1 : ethyl 2-{4-[ (4, 4-dimethylcyclohexyl)methyllpiperazin-1-yl}acetate

[1031] To a stirred solution of 1-(ethoxycarbonylmethyl)piperazine (100 mg, 0.58 mmol, 1 eq.) in ACN (2.9 mL) was added Et3N (243 pL, 1.74 mmol, 3 eq.) followed by 4-(bromomethyl)-1 ,1- dimethylcyclohexane (119 mg, 0.58 mmol, 1 eq.). The reaction mixture was stirred at r.t. for 16 h and then at 50°C for 16 h. The solvent was removed in vacuo and the crude was dissolved in DCM. Saturated aqueous sodium bicarbonate solution was added, mixture was stirred for 15 min and phases were separated. Aqueous phase was extracted with DCM (2x). Combined organic phases were washed with water and brine, dried over sodium sulphate, filtered and concentrated in vacuo to afford the title compound (74 mg, 41% yield) as a yellow oil without further purification.1H NMR (300 MHz, CDCh) 6 4.18 (q, = 7.1 Hz, 2H), 3.21 (s, 2H), 2.80 - 2.16 (m, 8H), 1.70 - 1.52 (m, 3H), 1.48 - 1.33 (m, 3H), 1.27 (t, J = 7.1 Hz, 3H), 1.33 - 1.22 (m, 1 H), 1.21 - 1.05 (m, 4H), 0.89 (s, 3H), 0.86 (s, 3H).

[1032] Step 2: sodium 2- / 4-[ (4, 4-dimethylcvclohexyl)methyl]piperazin- 1-yl}acetate

[1033] To a stirred solution of ethyl 2-{4-[(4,4-dimethylcyclohexyl)methyl]piperazin-1-yl}acetate (74 mg, 0.24 mmol, 1 eq.) in MeOH (1.2 mL) was added aqueous sodium hydroxide solution (1 M, 0.474 mL, 0.47 mmol, 2 eq.). The reaction mixture was stirred at r.t. for 16 h. After completion, solvent was removed in vacuo to afford the title compound (80 mg, quantitative yield, 80% purity) as a yellow solid without further purification.1H NMR (300 MHz, DMSO-cfe) 5 2.57 (s, 2H), 2.43 - 2.33 (m, 4H), 2.31 - 2.23 (m, 4H), 2.05 (d, J = 7.1 Hz, 2H), 1.58 - 1.47 (m, 2H), 1.37 - 1.27 (m, 3H), 1.18 - 1.03 (m, 3H), 1.02 - 0.95 (m, 1 H), 0.87 (s, 3H), 0.84 (s, 3H). UPLC (An analogous method to Method 5, ESI) 269.30 [MH]+, RT 1.50 min.

[1034] Step 1 : ethyl 2-{4-[ (3, 3, 5, 5-tetramethylcvclohexyl) methyllpiperazin-1 -yl acetate

[1035] To a stirred solution of 1-(ethoxycarbonylmethyl)piperazine (150 mg, 0.87 mmol, 1 eq.) in ACN (4.4 mL) was added Et3N (364 pL, 2.61 mmol, 3 eq.) followed by 5-(bromomethyl)-1 , 1 ,3,3- tetramethylcyclohexane (203 mg, 0.87 mmol, 1 eq.). The reaction mixture was stirred at 50°C for 16 h and the solvent was removed in vacuo. The crude was re-dissolved in DCM and saturated aqueous sodium bicarbonate solution was added. The mixture was stirred for 15 min and phases were separated. Aqueous phase was extracted with DCM (2x). Combined organic phases were washed with water and brine, dried over sodium sulphate, filtered and concentrated in vacuo. Crude material was purified by flash chromatography (silica, 0-2% MeOH in DCM) to afford the title compound (130 mg, 22% yield) as a yellow oil.1H NMR (300 MHz, CDCh) 6 4.19 (q, J = 7.1 Hz, 2H), 3.22 (s, 2H), 2.76 - 2.33 (m, 6H), 2.29 - 2.05 (m, 2H), 1.96 - 1.73 (m, 1 H), 1.62 - 1.44 (m, 3H), 1.27 (t, J = 7.1 Hz, 3H), 1.33 - 1.19 (m, 3H), 0.99 (s, 6H), 0.88 (s, 6H), 0.87 - 0.81 (m, 1 H), 0.72 - 0.65 (m, 1 H). UPLC (An analogous method to Method 5, ESI) 325.45 [MH]+, RT 1 .89 min.

[1036] Step 2: sodium 2-f4-[(3,3,5,5-tetramethylcyclohexyl)methyl]piperazin-1 -yl acetate

[1037] To a stirred solution of ethyl 2-{4-[(3,3,5,5-tetramethylcyclohexyl)methyl]piperazin-1-yl}acetate (130 mg, 0.38 mmol, 1 eq.) in MeOH (1.9 mL) was added aqueous sodium hydroxide solution (1 M, 750 pL, 0.75 mmol, 2 eq.). The reaction mixture was stirred at r.t. for 16 h. After completion, solvent was concentrated in vacuo to afford the title compound (120 mg, quantitative yield) as a yellow solid without further purification.1H NMR (300 MHz, DMSO-cfe) 5 2.59 (s, 2H), 2.46 - 2.34 (m, 4H), 2.33 - 2.20 (m, 4H), 2.01 (d, = 7.1 Hz, 2H), 1.88 - 1.74 (m, 1 H), 1.50 - 1.39 (m, 2H), 1.28 - 1.16 (m, 2H), 0.95 (s, 6H), 0.85 (s, 6H), 0.59 (t, J = 12.5 Hz, 2H). UPLC (An analogous method to Method 5, ESI) 297.30 [MH]+, RT 1.78 min.

[1038] INTERMEDIATE 28: 2-[1 -[methyl( [3-(trifluoromethoxy)phenyllmethyl})aminolcvclopropyl}acetic acid

[1039] Step 1 : ethyl 2-T1 -(ff3-(trifluoromethoxy)phenyllmethyl}amino)cyclopropyllacetate

[1040] To a solution of ethyl 2-(1-aminocyclopropyl)acetate hydrochloride (180 mg, 2.78 mmol, 1.0 eq.) in MeOH (12.5 mL) at 0°C under argon was added 3-(trifluoromethoxy)benzaldehyde (410 pL, 2.78 mmol, 1.0 eq.). Acetic acid were added dropwise until pH ~ 4.5. The reaction mixture was stirred for 30 min. at r.t. and sodium cyanoborohydride (250 mg, 4.18 mmol, 1.5 eq.) was added. The reaction mixture was stirred at 0°C for 1 h and then at r.t. for 16 h. Another portions of 3- (trifluoromethoxy)benzaldehyde (100 pL, 0.70 mmol, 0.25 eq.) and sodium cyanoborohydride (50 mg, 0.80 mmol, 0.3 eq.) were added and stirring was continued for 30 min. After completion, solvent was removed in vacuo. The residue was dissolved in EtOAc and washed with saturated sodium carbonate solution. Organic layer was separated, dried over sodium sulphate, filtered and concentrated in vacuo. Crude product was purified by flash chromatography (silica, 5-10% EtOAc in cyclohexane) to afford the title compound (590 mg, 63% yield).1H NMR (300 MHz, CDCh) 6 7.35 - 7.27 (m, 1 H), 7.26 - 7.22 (m, 1 H), 7.19 (s, 1 H), 7.12 - 7.05 (m, 1 H), 4.17 (q, = 7.1 Hz, 2H), 3.85 (s, 2H), 2.49 (s, 2H), 1.27 (t, J = 7.1 Hz, 3H), 0.83 - 0.73 (m, 2H), 0.58 - 0.47 (m, 2H). UPLC (An analogous method to Method 5, ESI) 318.30 [MH]+, RT 2.28 min.

[1041] Step 2: ethyl 2-{1 -{methyl({3-(trifluoromethoxy)phenyllmethyl})aminolcyclopropyl}acetate

[1042] To a solution of ethyl 2-[1-({[3-(trifluoromethoxy)phenyl]methyl}amino)cyclopropyl]acetate (570 mg, 1.71 mmol, 1 eq.) in MeOH (14.5 mL) were added paraformaldehyde (154 mg, 5.12 mmol, 2 eq.) and acetic acid (ca. 200 pL). The reaction mixture was stirred for 30 min, then sodium cyanoborohydride (200 mg, 3.41 mmol, 2 eq.) was added and the reaction mixture was heated up to 70°C for 16 h before concentrated in vacuo. The crude mixture was re-dissolved in DCM and washed with saturated aqueous sodium bicarbonate solution. Aqueous layer was extracted with DCM (2x). Combined organic layers were dried over sodium sulphate, filtered and concentrated in vacuo to give the title compound (550 mg, quantitative yield) without any further purification.1H NMR (300 MHz, methanol-d4) 6 7.40 - 7.33 (m, 1 H), 7.23 (d, J= 7.8 Hz, 1 H), 7.15 - 7.08 (m, 2H), 4.15 (q, J = 7.1 Hz, 2H), 3.77 (s, 2H), 2.58 (s, 2H), 2.22 (s, 3H), 1.28 (t, J = 7.1 Hz, 3H), 0.80 - 0.68 (m, 4H). UPLC (An analogous method to Method 5, ESI) 332.25 [MH]+, RT 2.87 min.

[1043] Step 3: 2 / 7 -[methyl( / [3-(trifluoromethoxy)phenyllmethyl})aminolcvclopropyl}acetic acid

[1044] To a solution of ethyl 2-{1-[methyl({[3-(trifluoromethoxy)phenyl]methyl})amino]- cyclopropyljacetate (550 mg, 1.58 mmol, 1 eq.) in MeOH (27.0 mL) was added aqueous sodium hydroxide solution (1M, 4.73 mL, 4.73 mmol, 3 eq.) and the reaction mixture was stirred at r.t. for 16 h. Aqueous sodium hydroxide solution (1M, 4.73 mL, 4.73 mmol, 3 eq.) was added to the reaction mixture which was stirred at 45°C for 3 h. After completion, solvent was removed in vacuo. Aqueous residue was neutralised by 1M aqueous HCI solution to pH~7 and concentrated in vacuo. Residual was then washed with ACN, filtered and concentrated in vacuo to give the title compound (490 mg, quantitative yield) without any further purification.1H NMR (300 MHz, methanol-d4) 67.41 (t, J= 7.8 Hz, 1H), 7.30 (d, J = 7.8 Hz, 1 H), 7.24 - 7.13 (m, 2H), 3.93 (s, 2H), 2.61 (s, 2H), 2.34 (s, 3H), 0.93 - 0.73 (m, 4H). UPLC (An analogous method to Method 5, ESI) 304.20 [MH]+, RT 1.64 min.

[1045] INTERMEDIATE 29: sodium 2-(1- [4-hvdroxy-3-(trifluoromethoxy)phenyl]methyl}piperidin-4- yl) acetate

[1046] Step 1 : methyl 2-(1- / [4-hvdroxy-3-(trifluoromethoxy)phenyl]methyl}piperidin-4-yl)acetate

[1047] To a stirred solution of methyl 2-(piperidin-4-yl)acetate (500 mg, 2.58 mmol, 1.0 eq.) and 4-hydroxy-3-(trifluoromethoxy)benzaldehyde (530 mg, 2.58 mmol, 1.0 eq.) in MeOH (12.9 mL) was added 10 drops of glacial acetic acid. The reaction mixture was stirred at r.t. for 30 min and then STAB (230 mg, 3.87 mmol, 1.5 eq.) was added. The reaction mixture was stirred at r.t. for 56 h. After completion, it was concentrated in vacuo. Crude material was purified by flash chromatography (silica, 0-5% MeOH in DCM) to afford the title compound (123 mg, 95% yield, 86% purity). UPLC (An analogous method to Method 5, ESI) 348.15 [MH]+, RT 1.77 min.

[1048] Step 2: sodium 2-(1- / [4-hvdroxy-3-(trifluoromethoxy)phenyl]methyl}piperidin-4-yl)acetate To a stirred solution of methyl 2-(1-{[4-hydroxy-3-(trifluoromethoxy)phenyl]methyl} piperidin-4- yl)acetate (120 mg, 0.33 mmol, 1 eq.) in MeOH (6.1 mL), was added aqueous sodium hydroxide solution (1 M, 660 pL, 0.66 mmol, 2 eq.). The reaction mixture was stirred at40°C for 16 h. Another portion of aqueous sodium hydroxide solution (1M, 660 pL, 0.66 mmol, 2 eq.) was added and stirring was continued at 40°C for 16 h. Another portion of aqueous sodium hydroxide solution (1 M, 660 pL, 0.66 mmol, 2 eq.) was added and stirring was continued at 40°C for 16 h. After completion, solvent was removed in vacuo to afford the title compound (160 mg, 75% purity) without further purification. UPLC (An analogous method to Method 5, ESI) 334.15 [MH]+, RT 1.38 min.

[1049] INTERMEDIATE 30: 2-(4-methyl-1 -ff3-(trifluoromethoxy)phenyllmethyl}piperazin-2-yl)acetic acid

[1050] Step 1 : tert-butyl 3-(2-methoxy-2-oxoethyl)-44T3-(trifluoromethoxy)phenyl]methyl} piperazine-1 - carboxylate

[1051] To a mixture of tert-butyl 3-(2-methoxy-2-oxoethyl)piperazine-1-carboxylate (380 mg, 1.47 mmol, 1 eq.) and 3-(trifluoromethoxy)benzaldehyde (240 pL, 1.62 mmol, 1.1 eq.) in MeOH (10.0 mL) under argon was added acetic acid (ca. 200 pL) to achieve pH~4. The reaction mixture was stirred at r.t. for 30 min. Sodium cyanoborohydride (170 mg, 2.94 mmol, 2 eq.) was added and the reaction mixture was stirred at r.t. for 2 h. Then, 3-(trifluoromethoxy) benzaldehyde (240 pL, 1.62 mmol, 1.1 eq.) and sodium cyanoborohydride (170 mg, 2.94 mmol, 2 eq.) were added and the mixture was stirred at 50°C for 5 h before concentrated in vacuo. The crude material was dissolved in EtOAc and washed with saturated aqueous sodium bicarbonate solution. Aqueous layer was washed with EtOAc (3x). Combined organic layers were dried over sodium sulphate, filtered and concentrated in vacuo. Crude product was purified by flash chromatography (silica, 100% DCM) to afford the title compound (420 mg, 63% yield).1H NMR (300 MHz, methanol-^) 5 7.44 - 7.36 (m, 1 H), 7.36 - 7.31 (m, 1 H), 7.28 (s, 1 H), 7.21 - 7.11 (m, 1 H), 3.88 - 3.75 (m, 1 H), 3.68 (s, 3H), 3.66 - 3.49 (m, 3H), 3.46 - 3.37 (m, 1 H), 3.26 - 3.13 (m, 1 H), 3.10 - 3.00 (m, 1 H), 2.72 - 2.46 (m, 3H), 2.41 - 2.26 (m, 1 H), 1.45 (s, 9H). UPLC (An analogous method to Method 5, ESI) 433.25 [MH]+, RT 3.66 min. Step 2: methyl 2-( 1 -iT3-(trifluoromethoxy)phenyllmethyl}piperazin-2-yl)acetate

[1052] To a solution of terf-butyl 3-(2-methoxy-2-oxoethyl)-4-{[3-(trifluoromethoxy)phenyl]methyl} piperazine- 1 -carboxylate (420 mg, 0.93 mmol, 1 eq.) in DCM (40.0 mL) was added HCI solution in dioxane (4M, 4.14 mL, 8.31 mmol, 9 eq.). The reaction mixture was refluxed for 80 h. After completion, solvent was removed in vacuo to give the title compound (360 mg, quantitative yield) without any further purification.1H N MR (300 MHz, Deuterium Oxide) 5 7.59 - 7.51 (m, 1H), 7.46 - 7.35 (m, 3H), 4.53 (d, J = 13.2 Hz, 1H), 3.95 (d, J = 13.2 Hz, 1H), 3.87 - 3.77 (m, 1 H), 3.76 (s, 3H), 3.73 - 3.62 (m, 1 H), 3.58 - 3.46 (m, 1 H), 3.44 - 3.23 (m, 3H), 3.18 - 2.96 (m, 3H). UPLC (An analogous method to Method 5, ESI) 333.10 [MH]+, RT 2.41 min.

[1053] Step 3: methyl 2-(4-methyl-1 -f[3-(trifluoromethoxy)phenyl]methyl}piperazin-2-yl)acetate

[1054] To a solution of methyl 2-(1-{[3-(trifluoromethoxy)phenyl]methyl}piperazin-2-yl)acetate hydrochloride (350 mg, 0.82 mmol, 1 eq.) in MeOH (9.0 mL) were added paraformaldehyde (74 mg, 2.46 mmol, 3 eq.) and acetic acid (ca. 200 pL). The reaction mixture was stirred for 10 min before the addition of sodium cyanoborohydride (98 mg, 1.64 mmol, 2 eq.). The reaction mixture was stirred at 50 °C for 1 h and concentrated in vacuo. After completion, solvent was removed in vacuo. Crude mixture was dissolved in DCM and washed with saturated aqueous sodium bicarbonate solution. Aqueous layer was washed with DCM (2x). Combined organic layers were dried over sodium sulphate, filtered and concentrated in vacuo to give the title compound (280 mg, quantitative yield, 98% purity) without any further purification.1H NMR (300 MHz, CDCI3) 5 7.32 (t, J = 7.8 Hz, 1 H), 7.24 - 7.16 (m, 2H), 7.13 - 7.06 (m, 1H), 4.01 - 3.81 (m, 1 H), 3.68 (s, 3H), 3.38 (d, J = 13.6 Hz, 1 H), 3.26 - 3.11 (m, 1 H), 2.82 - 2.24 (m, 11 H). UPLC (An analogous method to Method 5, ESI) 347.25 [MH]+, RT 1.81 min.

[1055] Step 4

[1056] 2-(4-methyl-1 -f[3-(trifluoromethoxy)phenyl]methyl}piperazin-2-yl)acetic acid

[1057] To a stirred solution of methyl 2-(4-methyl-1-{[3-(trifluoromethoxy)phenyl]methyl}piperazin- 2-yl)acetate (280 mg, 0.73 mmol, 1 eq.) in MeOH (14.0 mL) was added aqueous sodium hydroxide solution (1M, 2.18 mL, 2.18 mmol, 3 eq.) and the reaction mixture was stirred at 40°C for 16 h. After completion, solvent was concentrated in vacuo. Aqueous residue was neutralised with 1M aqueous HCI solution to pH~7 and concentrated in vacuo. Residual was washed with ACN, filtered and concentrated in vacuo to give the title compound (260 mg, quantitative yield, 98% purity) without any further purification.1H NMR (300 MHz, Methanol-^) 6 7.48 - 7.34 (m, 2H), 7.32 (s, 1H), 7.22 - 7.16 (m, 1H), 4.12 (d, J = 13.1 Hz, 1 H), 3.52 (d, J = 13.7 Hz, 1 H), 3.39 - 3.33 (m, 1 H), 3.24 - 2.85 (m, 5H), 2.77 (s, 3H), 2.67 (dd, J = 15.8, 4.4 Hz, 1H), 2.61 - 2.47 (m, 2H). UPLC (An analogous method to Method 5, ESI) 333.25 [MH]+, RT 1.64 min. INTERMEDIATE 31 : 2-methoxy-2-(1 -ff4-(trifluoromethoxy)phenyllmethyl}piperidin-4-yl)acetic acid

[1058] Step 1 tert-butyl 4-(1 -hydroxy -2-methoxy-2-oxoethyi)piperidine-1 -carboxylate

[1059] To a stirred solution of methyl 2-hydroxy-2-(piperidin-4-yl)acetate hydrochloride (400 mg, 1.91 mmol, 1 eq.) and di-terf-butyl dicarbonate (460 mg, 2.10 mmol, 1.1 eq.) in DCM (40.0 mL) was added Et3N (1.07 mL, 7.63 mmol, 4 eq.) under argon and the reaction mixture was stirred at r.t. for 16 h. Then, it was quenched with 0.01 M aqueous HCI solution and extracted with DCM (3x). Combined organic layers were dried over sodium sulphate, filtered and concentrated in vacuo. Crude product was purified by flash chromatography (silica, 50% cyclohexene in EtOAc) to afford the title compound (240 mg, 44% yield, 95% purity).1H NMR (300 MHz, DMSO-cfe) 6 5.40 (d, J = 6.0 Hz, 1 H), 4.00 - 3.92 (m, 2H), 3.88 (t, J = 5.7 Hz, 1 H), 3.63 (s, 3H), 2.72 - 2.55 (m, 2H), 1.83 - 1.67 (m, 1 H), 1.53 - 1.42 (m, 2H), 1.38 (s, 9H), 1.26 - 1.09 (m, 2H). UPLC (An analogous method to Method 5, ESI) 174.1 [MH-Boc]+, RT 0.54 min.

[1060] Step 2 tert -butyl 4 -(1,2 -di methoxy -2 -oxoethyl) pi peridi ne-1 -carboxylate

[1061] To a stirred solution of terf-butyl 4-(1-hydroxy-2-methoxy-2-oxoethyl)piperidine-1 -carboxylate (220 mg, 0.76 mmol, 1 eq.) in DMF (20.0 mL) at 0°C was added sodium hydride (60% dispersion in mineral oil, 34 mg, 0.84 mmol, 1.1 eq.). The reaction mixture was stirred for 10 min, then methyl iodide (52 pL, 0.84 mmol, 1.1 eq.) was added at the same temperature. The reaction mixture was stirred at r.t. for 30 min. Then, it was quenched with water and extracted with EtOAc. Combined organic layers were dried over sodium sulphate, filtered and concentrated in vacuo to give the title compound (220 mg, quantitative yield, 90% purity) without any further purification.1H NMR (300 MHz, CDCI3) 5 4.25 - 4.02 (m, 2H), 3.77 (s, 3H), 3.56 (d, J = 5.9 Hz, 1 H), 3.37 (s, 3H), 2.74 - 2.56 (m, 2H), 1.96 - 1 .79 (m, 1 H), 1.73 - 1 .60 (m, 1 H), 1 .56 - 1 .47 (m, 1 H), 1 .44 (s, 9H), 1 .40

[1062] - 1.27 (m, 2H). UPLC (An analogous method to Method 5, ESI) 188.1 [MH-Boc]+, RT 2.26 min.

[1063] Step 3 methyl 2 -methoxy-2 -(pi peridin -4-yl) acetate

[1064] To a stirred solution of terf-butyl 4-(1 ,2-dimethoxy-2-oxoethyl)piperidine-1 -carboxylate (220 mg, 0.69 mmol, 1 eq.) in DCM (20.0 mL) was added HCI solution in Et2<D (2M, 1.03 mL, 2.07 mmol, 3 eq.). The reaction mixture was stirred at r.t. for 16 h. Then, HCI solution in dioxane (4M, 3.00 mL, 12.0 mmol, 18 eq.) was added and reaction mixture was stirred at 60°Cfor 16 h. After completion, solvent was removed in vacuo to give the title compound (150 mg, quantitative yield, 95% purity) without any further purification.1H NMR (300 MHz, Deuterium Oxide) 5 3.92 (d, J = 5.0 Hz, 1 H), 3.80 (s, 3H), 3.49 - 3.40 (m, 2H), 3.38 (s, 3H), 3.06 - 2.89 (m, 2H), 2.21 - 2.05 (m, 1 H), 1.96 - 1.77 (m, 2H), 1.77 - 1.50 (m, 2H). UPLC (An analogous method to Method 5, ESI) 188.1 [MH]+, RT 0.80 min.

[1065] Step 4: methyl 2-methoxy-2-( 1 -f[4-(trifluoromethoxy)phenyl]methyl}piperidin-4-yl)acetate

[1066] To a solution of methyl 2-methoxy-2-(piperidin-4-yl)acetate hydrochloride (150 mg, 0.64 mmol, 1 eq.) and anhydrous potassium carbonate (310 mg, 2.23 mmol, 3.5 eq.) in ACN (15.0 mL) was added 4-(trifluoromethoxy)benzyl bromide (120 pL, 0.76 mmol, 1.2 eq.) under argon. The reaction mixture was stirred at r.t. for 4 h before filtered and the filtrate was concentrated in vacuo. Crude material was purified by flash chromatography (silica, 3% MeOH in DCM) to afford the title compound (190 mg, 78% yield).1H NMR (300 MHz, CDCh) 6 7.44 - 7.29 (m, 2H), 7.20 - 7.11 (m, 2H), 3.76 (s, 3H), 3.56 (d, J = 5.9 Hz, 1 H), 3.52 - 3.46 (m, 1 H), 3.36 (s, 3H), 3.06 - 2.71 (m, 2H), 2.14 - 1.85 (m, 2H), 1.82 - 1.67 (m, 2H), 1.63 - 1.43 (m, 4H). UPLC (An analogous method to Method 5, ESI) 362.25 [MH]+, RT 1.77 min.

[1067] Step 5: 2 -methoxy-2 -( 1 -f[4-(trifluoromethoxy)phenyl]methyl}piperidin-4-yl)acetic acid

[1068] To a stirred solution of methyl 2-methoxy-2-(1-{[4-(trifluoromethoxy)phenyl]methyl} piperidin-4- yl)acetate (190 mg, 0.5 mmol, 1 eq.) in MeOH (10 mL) was added aqueous sodium hydroxide solution (1M, 2.99 mL, 2.99 mmol, 6 eq.) and the reaction mixture was stirred at 45 °C for 16 h. After completion, solvent was concentrated in vacuo. Aqueous residue was neutralised with 1 M aqueous HCI solution to pH~7 and concentrated in vacuo. Residual was washed with ACN, filtered and concentrated in vacuo to give the title compound (180 mg, quantitative yield, 90% purity) without any further purification.1H NMR (300 MHz, CDCh) 6 7.55 (d, J = 7.8 Hz, 2H), 7.22 (d, J = 8.1 Hz, 2H), 4.08 - 4.02 (m, 1 H), 3.67 - 3.43 (m, 3H), 3.38 (s, 3H), 2.66 - 2.37 (m, 2H), 2.21 - 1.75 (m, 6H). UPLC (An analogous method to Method 5, ESI) 348.20 [MH]+, RT 1.60 min. I

[1069] Step 1 : ethyl 2-({1 -[(3,5 -di meth ylphen yl) methyllpiperidin -4 -yl}sulfan yl) acetate

[1070] To a solution of ethyl 2-(piperidin -ylsulfanyl)acetate hydrochloride (prepared according to the procedure of Intermediate 24) (58 mg, 0.20 mmol, 1 eq.) and anhydrous potassium carbonate (98 mg, 0.71 mmol, 3.5 eq.) in ACN (6.0 mL) was added 3,5-dimethylbenzyl bromide (49 pL, 0.24 mmol, 1.2 eq.) under argon. The reaction mixture was stirred at r.t. for 16 h before filtered and the filtrate was concentrated in vacuo. Crude material was purified by flash chromatography (silica, 3% MeOH in DCM) to afford the title compound (65 mg, 80% yield, 80% purity). LIPLC (An analogous method to Method 5, ESI) 322.55 [MH]+, RT 1.96 min.

[1071] Step 2: 2-( / 1-[(3,5 -di meth ylphen yl) meth yl]pi peridin -4 -vDsulfan yl) acetic acid

[1072] To a mixture of ethyl 2-({1-[(3,5-dimethylphenyl)methyl]piperidin-4-yl}sulfanyl)acetate (65 mg, 0.16 mmol, 1 eq.) in MeOH (7.0 mL) was added a solution of sodium hydroxide (1M, 490 pL, 0.49 mmol, 3 eq.), and the reaction mixture was stirred at 40 C° for 16 h. After completion, solvent was concentrated in vacuo. Aqueous residue was neutralised with 1M aqueous HCI solution and concentrated in vacuo. Residual was washed with ACN, filtered and concentrated in vacuo to give the title compound (55 mg, quantitative yield) without any further purification. LIPLC (An analogous method to Method 5, ESI) 294.5 [MH]+, RT 1.67 min.

[1073] INTERMEDIATE 33: 2-cycl

[1074] Intermediate 33

[1075] To a stirred solution of salicylaldehyde (2.00 g, 16.38 mmol, 1 eq.) in anhydrous DMF (40.0 mL) was added anhydrous potassium carbonate (4.53 g, 32.75 mmol, 2 eq.) followed by bromocyclobutane (4.42 g, 32.75 mmol, 2 eq.). The reaction mixture was stirred at 85°C for 16 h. The mixture was concentrated in vacuo and purified by flash chromatography (silica, 15% EtOAc in hexanes) to afford the title compound (2.88 g, 95% yield).1H NMR (400 MHz, CDCh) 6 10.53 - 10.48 (m, 1 H), 7.83 (dd, J = 7.7, 1.9 Hz, 1 H), 7.54 - 7.45 (m, 1 H), 7.04 - 6.96 (m, 1 H), 6.82 (d, = 8.4 Hz, 1 H), 4.75 (p, = 6.9 Hz, 1 H), 2.55 - 2.45 (m, 2H), 2.30 - 2.19 (m, 2H), 1.97 - 1.88 (m, 1 H), 1.80 - 1.69 (m, 1 H). UPLC (An analogous method to Method 5, ESI) 177.0 [MH]+, RT 2.48 min.

[1076] Step 1 : ethyl 2-( 1 -[(2-cvclobutoxyphenyl)methyl]piperidin-4-yl}sulfanyl)acetate

[1077] To a solution of ethyl 2-(piperidin -ylsulfanyl)acetate hydrochloride (prepared according to the procedure of Intermediate 24) (55 mg, 0.79 mmol, 1.0 eq.) and Et3N (190 pL, 1.43 mmol, 1.8 eq.) in DCE (10.0 mL) was added 2-cyclobutoxybenzaldehyde (prepared according to the procedure of Intermediate 33) (220 mg, 1.18 mmol, 1.5 eq.). The reaction mixture was stirred at r.t. for 40 min and sodium cyanoborohydride (140 mg, 2.38 mmol, 3.0 eq.) was added. After completion, solvent was removed in vacuo and the crude mixture was dissolved in DCM and washed with saturated aqueous sodium bicarbonate solution. Aqueous layer was extracted with DCM (2x). Combined organic layers were dried over sodium sulphate, filtered and concentrated in vacuo. Crude product was purified by flash chromatography (silica, 25% EtOAc in hexanes) to afford the title compound (200 mg, 35% yield, 50% purity).1H NMR (400 MHz, methanol-^) 6 7.28 (dd, J = 7.5, 1.6 Hz, 1 H), 7.20 (td, J = 8.1 , 1.7 Hz, 1 H), 6.89 (td, J = 7.5, 0.9 Hz, 1 H), 6.79 (d, J = 8.2 Hz, 1 H), 4.68 (p, J = 7.2 Hz, 1 H), 4.15 (q, J = 7.1 Hz, 2H), 3.60 (s, 2H), 3.28 (s, 2H), 2.98 - 2.87 (m, 2H), 2.85 - 2.75 (m, 1 H), 2.53 - 2.41 (m, 2H), 2.26 - 2.18 (m, 2H), 2.18 - 2.08 (m, 2H), 2.02 - 1.93 (m, 2H), 1.91 - 1.81 (m, 1 H), 1.81 - 1.69 (m, 1 H), 1.66 - 1.54 (m, 2H), 1.26 (t, J = 7.1 Hz, 3H). UPLC (An analogous method to Method 5, ESI) 364.6 [MH]+, RT 2.01 min.

[1078] Step 2: 2-((1 -[(2-cvclobutoxyphenyl)methyl]piperidin-4-yl}sulfanyl)acetic acid

[1079] To a solution of ethyl 2-({1-[(2-cyclobutoxyphenyl)methyl]piperidin-4-yl}sulfanyl)acetate (0.20 g, 0.28 mmol, 1 eq.) in MeOH (10.0 mL) was added aqueous sodium hydroxide solution (1M, 1 .65 mL, 1.65 mmol, 6 eq.) and the reaction mixture was stirred at 45°C for 1 h. After completion, solvent was concentrated in vacuo. Aqueous residue was neutralised with 1 M aqueous HCI solution and concentrated in vacuo. Residual was washed with ACN, filtered and concentrated in vacuo to give the title compound (100 mg, quantitative yield, 90% purity) without any further purification. LIPLC (An analogous method to Method 5, ESI) 336.6 [MH]+, RT 1.72 min. INTERMEDIATE 35: 2-(3,3-difluorocvclobutoxy)benzaldehyde

[1080] Intermediate 35

[1081] Step 1 : 3, 3 -difluorocyclobutyl 4 -meth y I benzene - 1 -sulfonate

[1082] To a solution of p-toluenesulfonyl chloride (880 mg, 4.63 mmol, 2 eq.) in anhydrous DCM (7.5 mL), a solution of 3,3-difluorocyclobutanol (250 mg, 2.31 mmol, 1 eq.) and Et3N (27.6 mL, 197.73 mmol, 10 eq.) in anhydrous DCM (7.5 mL) was added slowly at 0°C under argon. The resulting mixture was warmed to r.t. and stirred for 16 h. Then, it was then poured into water and extracted with DCM (3x). Combined organic layers were washed with 1 M aqueous HCI solution, saturated aqueous sodium bicarbonate solution and water. Combined organic layers were dried over sodium sulphate, filtered and concentrated in vacuo. Crude residue was purified by flash chromatography (silica, 10% EtOAc in hexanes) to afford the title compound (470 mg, 74% yield).1H NMR (400 MHz, DMSO-cfe) 6 7.85 - 7.78 (m, 2H), 7.53 - 7.46 (m, 2H), 4.87 - 4.77 (m, 1 H), 3.08 - 2.96 (m, 2H), 2.79 - 2.66 (m, 2H), 2.43 (s, 3H).

[1083] Step 2: 2-(3,3-difluorocyclobutoxy) benzaldehyde

[1084] To a stirred solution of salicylaldehyde (830 mg, 6.77 mmol, 1.1 eq.) in anhydrous DMF (51.0 mL) was added anhydrous potassium carbonate (2.55 g, 18.47 mmol, 3.0 eq.) followed by 3,3- difluorocyclobutyl 4-methylbenzene-1 -sulfonate (250 mg, 2.31 mmol, 1 eq.). The reaction mixture was stirred at 90°C for 16 h before concentrated in vacuo. Crude product was triturated with ACN and filtered. The filtrate was concentrated in vacuo and purified by flash chromatography (silica, 0-20% EtOAc in cyclohexane) to afford the title compound (220 mg, 15% yield, 87% purity).1H NMR (400 MHz, DMSO-cfe) 6 10.41 - 10.39 (m, 1 H), 7.72 (dd, J = 8.0, 1.8 Hz, 1 H), 7.68 - 7.62 (m, 1 H), 7.16 - 7.09 (m, 2H), 5.00 - 4.89 (m, 1 H), 3.31 - 3.20 (m, 2H), 2.91 - 2.77 (m, 2H).

[1085] INTERMEDIATE 36: 2-(propan-2-ylsulfanyl)benzaldehyde

[1086] Intermediate 36 To a stirred solution of 2-fluorobenzaldehyde (425 pL, 3.83 mmol, 1.0 eq.) in DMF (10.0 mL) was added propane-2-thiol (533 pL, 5.74 mmol, 1.5 eq.) followed by anhydrous potassium carbonate (800 mg, 5.74 mmol, 2.0 eq.). The reaction mixture was stirred at 80°C for 16 h. After completion, solvent was removed in vacuo and the crude mixture was dissolved in DCM. Water was added and the layers were separated. Aqueous layer was extracted with DCM (2x). Combined organic layers were dried over sodium sulphate, filtered and concentrated in vacuo to afford the title compound (572 mg, 82% yield).1H NMR (400 MHz, DMSO-cfe) 6 10.32 (s, 1 H), 7.86 (dd, J = 7.6, 1.5 Hz, 1 H), 7.68 - 7.57 (m, 2H), 7.46 - 7.39 (m, 1 H), 3.59 (hept, J = 6.7 Hz, 1 H), 1.28 (d, J = 6.7 Hz, 6H). UPLC (An analogous method to Method 5, ESI) 180.70 [MH]+, RT 3.56 min.

[1087] INTERMEDIATE 37: 2-(1- [(4,4-dimethylcvclohexyl)methyll(methyl)amino}cvclopropyl)acetic acid

[1088] Step 1 : ethyl 2-( 1-{ (4, 4-dimethylcvclohexyl)methyllamino}cvclopropyl)acetate

[1089] To a solution of ethyl 2-(1-aminocyclopropyl)acetate hydrochloride (200 mg, 1.11 mmol, 1.0 eq.) and anhydrous potassium carbonate (460 mg, 3.34 mmol, 3.0 eq.) in ACN (8.0 mL) was added 4-(bromomethyl)-1 ,1 -dimethylcyclohexane (240 pL, 0.67 mmol, 1.2 eq.) under argon. The reaction mixture was stirred at 75°C for 20 h. Then, it was filtered and the filtrate was concentrated in vacuo to give the title compound (210 mg, 45% purity) without any further purification. UPLC (An analogous method to Method 5, ESI) 268.25 [MH]+, RT 2.46 min.

[1090] Step 2: ethyl 2-( 1-{ (4, 4-dimethylcvclohexyl)methyll(methyl)amino}cvclopropyl)acetate

[1091] To a solution of ethyl 2-(1-{[(4,4-dimethylcyclohexyl)methyl]amino}cyclopropyl)acetate (210 mg, 0.35 mmol, 1 eq.) in DCE (5.0 mL) was added paraformaldehyde (104 mg, 3.45 mmol, 10 eq.). The reaction mixture was stirred for 10 min, then STAB (365 mg, 1.72 mmol, 5 eq.) was added and the reaction mixture was heated up to 80°C for 16 h. After completion, solvent was removed in vacuo and the crude mixture was dissolved in DCM and washed with saturated aqueous sodium bicarbonate solution. Aqueous layer was extracted with DCM (2x). Combined organic phases were dried over sodium sulphate, filtered and concentrated in vacuo. Crude product was purified by flash chromatography (silica, 10% EtOAc in cyclohexane) to afford the title compound (45 mg, 43% purity). LIPLC (An analogous method to Method 5, ESI) 282.15 [MH]+, RT 2.54 min.

[1092] Step 3: 2-(1- / T(4,4-dimethylcvclohexyl)methyl](methyl)amino}cvclopropyl)acetic acid

[1093] To a solution of ethyl 2-(1-{[(4,4-dimethylcyclohexyl)methyl](methyl)amino}cyclopropyl)-acetate (45 mg, 0.07 mmol, 1 eq.) in MeOH (5.0 mL) was added aqueous sodium hydroxide solution (1M, 340 pL, 0.34 mmol, 5 eq.). The reaction mixture was stirred at r.t. for 16 h and then at 50°C for 4 h. After completion, solvent was removed in vacuo. Aqueous residue was neutralised with 1 M aqueous HCI solution and concentrated in vacuo. Residual was washed with ACN, filtered and concentrated in vacuo to give the title compound (30 mg, quantitative yield) without any further purification. LIPLC (An analogous method to Method 5, ESI) 254.1 [MH]+, RT 1.79 min.

[1094] INTERMEDIATE 38: 2-[(1 - / 2-(propan-2-yloxy)phenyl]methyl}piperidin-3-yl)sulfanyl]acetic acid

[1095] Step 1 : tert-butyl 3-r(2-ethoxy-2-oxoethyl)sulfanyl]piperidine-1 -carboxylate

[1096] To a stirred solution of ethyl thioglycolate (1.25 mL, 11.36 mmol, 1.5 eq.) in DMF (40.0 mL), was added 1-Boc-3-bromopiperidine (2.00 g, 7.57 mmol, 1.0 eq.) followed by potassium carbonate (2.09 g, 15.14 mmol, 2.0 eq.). The reaction mixture was stirred at r.t. for 16 h. After completion, solvent was removed in vacuo and the crude mixture was re-dissolved in DCM. Water was added and the layers were separated. Aqueous phase was extracted with DCM (3x). Combined organic layers were dried over sodium sulphate, filtered and concentrated in vacuo. Crude product was purified by flash chromatography (silica, 0-30% EtOAc in cyclohexane) to afford the title compound (272 mg, 9% yield, 80% purity).1H NMR (400 MHz, DMSO-cfe) 5 4.14 - 4.05 (m, 2H), 3.93 - 3.80 (m, 1 H), 3.58 - 3.49 (m, 1 H), 3.32 (s, 2H), 3.05 - 2.94 (m, 1H), 2.91 - 2.81 (m, 1 H), 2.03 - 1.88 (m, 1 H), 1.71 - 1.60 (m, 1 H), 1.50 - 1.30 (m, 1 H), 1.39 (s, 9H), 1.30 - 1.14 (m, 5H). UPLC (An analogous method to Method 5, ESI) 325.90 [MNa]+, RT 3.69 min. Step 2: ethyl 2-(piperidin-3-ylsulfanyl)acetate

[1097] To a solution of terf-butyl 3-[(2-ethoxy-2-oxoethyl)sulfanyl]piperidine-1 -carboxylate (252 mg, 1.51 mmol, 1.0 eq.) in DCM (5.0 mL) at 0°C was added TFA (254 pL, 3.32 mmol, 5.0 eq.). The reaction mixture was stirred at r.t. for 16 h. After completion, solvent was concentrated in vacuo to afford the title compound (333 mg, 31% purity). LIPLC (An analogous method to Method 5, ESI) 204.10 [MH]+, RT 0.94 min.

[1098] Step 3: ethyl 2 (1 -ff2-(propan-2-yloxy)phenyl1methyl}piperidin-3-yl)sulfanyl1acetate

[1099] To a solution of ethyl 2-(piperidin-3-ylsulfanyl)acetate (293 mg, 0.45 mmol, 1.0 eq.) in DCE (3.0 mL) was added Et3N (249 pL, 1.79 mmol, 4.0 eq.). The resulting mixture was stirred for 5 min. After that 2-(propan-2-yloxy)benzaldehyde (110 mg, 0.67 mmol, 1.5 eq.) was added and the reaction mixture was stirred for 30 min. Then, STAB (284 mg, 1.34 mmol, 3.0 eq.) was added and the mixture was stirred at r.t. for 3 h before filtered and concentrated in vacuo. Crude product was purified by flash chromatography (silica, 0-80% EtOAc in cyclohexane) to afford the title compound (146 mg, 86% yield, 92% purity). LIPLC (An analogous method to Method 5, ESI) 352.55 [MH]+, RT 2.58 min.

[1100] Step 4: 2-[(1 ^2-(propan-2-yloxy)phenyl]methyl}piperidin-3-yl)sulfanyl]acetic acid

[1101] To a stirred solution of ethyl 2-[(1-{[2-(propan-2-yloxy)phenyl]methyl}piperidin-3-yl) sulfanyl]acetate (126 mg, 0.33 mmol, 1 eq.) in THF (1.9 mL) at r.t. was added aqueous sodium hydroxide solution (1.7 M, 630 pL, 0.99 mmol, 3 eq.). The resulting mixture was stirred at 60°C for 16 h before concentrated in vacuo. Crude product was then dissolved in water and acidified with 1M aqueous HCI solution till pH = 5. The precipitate was filtered off. The obtained solid was washed with excess of ACN and the filtrate concentrated in vacuo to afford the title compound (135 mg, 91% yield, 72% purity).1H NMR (400 MHz, DMSO-cfe) 6 7.49 - 7.39 (m, 1 H), 7.37 - 7.32 (m, 1 H), 7.10 - 7.05 (m, 1H), 7.00 - 6.91 (m, 1H), 4.74 - 4.60 (m, 1 H), 4.19 - 3.81 (m, 2H), 3.16 - 2.98 (m, 3H), 2.79 - 2.57 (m, 2H), 2.00 - 1.89 (m, 1H), 1.86 - 1.75 (m, 1H), 1.74 - 1.61 (m, 1 H), 1.39 - 1.32 (m, 1 H), 1.37 - 1.24 (m, 8H). UPLC (Method 21 , ESI) 324.45 [MH]+, RT 2.08 min.

[1102] INTERMEDIATE 39: 2 -(morpholin-2-yl) -N-(5-ff(3R) -1 -(pyridazin^3-yl)pyrrolidin^3-yllamino}-1,3,4

[1103] -thiadiazol-2-yl)acetamide hydrochloride

[1104] Intermediate 39 Step 1 : tert-butyl 2-fl'(5-fl'(3R) -1 -(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-

[1105] 2yl)carbamoyl]methyl}morpholine -4 -carboxylate

[1106] To a stirred solution of 2-{4-[(terf-butoxy)carbonyl]morpholin-2-yl}acetic acid (2.00 g, 8.15 mmol,

[1107] I .0 eq.) and DIPEA (4.26 mL, 3.16 g, 24.46 mmol, 3.0 eq.) in anhydrous DMF (40.0 mL) was added 1-propylphosphonic acid cyclic anhydride (50% sol. in DMF, 10.38 mL, 5.19 g, 16.31 mmol, 2.0 eq.) and the reaction mixture was stirred at r.t. for 15 min. (R)-N2-(1-(pyridazin-3-yl)pyrrolidin- 3-yl)-1 ,3,4-thiadiazole-2,5-diamine (prepared according to the procedure of Intermediate 1) (2.58 g, 16.31 mmol, 1 .2 eq.) was added and stirring was continued at r.t. for 16 h. The reaction mixture was concentrated in vacuo and purified by flash chromatography (silica, 0-15% MeOH in DCM) to afford the title compound (1 .04 g, 24% yield, 94% purity).1H NMR (300 MHz, DMSO-cfe) 6 12.01 (s, 1 H), 8.48 (d, J = 4.4 Hz, 1 H), 7.65 (d, J = 6.1 Hz, 1 H), 7.33 (dd, J = 9.2, 4.5 Hz, 1 H), 6.87 (dd, J = 9.1 , 1.3 Hz, 1 H), 4.43 - 4.33 (m, 1 H), 3.88 - 3.64 (m, 6H), 3.63 - 3.46 (m, 4H), 3.35 (td, J =

[1108] I I .5, 2.7 Hz, 1 H), 2.60 - 2.55 (m, 2H), 2.36 - 2.23 (m, 1 H), 2.14 - 2.01 (m, 1 H), 1.40 (s, 9H). LIPLC (An analogous method to Method 5, ESI) 491.55 [MH]+, RT 1.91 min.

[1109] Step 2: 2-(morpholin-2-yl) -N-(54T(3R) -1 -(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1,3,4- thiadiazol-2-yl)acetamide hydrochloride

[1110] To a stirring solution of terf-butyl 2-{[(5-{[(3 )-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4 -thiadiazol-2-yl)carbamoyl]methyl}morpholine-4-carboxylate (4.29 g, 8.66 mmol, 1 eq.) in MeOH (214.5 mL) was added HCI solution in dioxane (4M, 21.64 mL, 86.57 mmol, 10 eq.) at 0°C and the mixture was stirred at r.t. for 16 h. Crude material was purified by reverse phase flash chromatography (C-18 silica, 0-100% ACN in 0.1 % FA in H2O sol.). Obtained fraction was triturated with 1 :1 mixture of ACN and Et20 to afford the title compound (3.59 g, 93% yield, 88% purity). UPLC (An analogous method to Method 5, ESI) 390.90 [MH]+, RT 0.65 min.

[1111] INTERMEDIATE 40: 2-[(2-f[2-(propan-2-yloxy)phenyllmethyl}-2-azaspiro[3.31heptan-6-yl) sulfanyllacetic acid

[1112] Intermediate 40 Step 1 : tert -butyl 6 - (2 -ethoxy -2 -oxoethyl)sulfanyl]-2 -azaspiror3.3]heptane -2 -carboxylate

[1113] To a stirred solution of ethyl bromoacetate (362 pL, 3.27 mmol, 1.5 eq.) in DMF (10.0 mL), was added terf-butyl 6-sulfanyl-2-azaspiro[3.3]heptane-2-carboxylate (500 mg, 2.18 mmol, 1.0 eq.) followed by potassium carbonate (600 mg, 4.36 mmol, 2.0 eq.). The reaction mixture was then stirred at r.t. for 16 h. After completion, solvent was removed in vacuo and the crude mixture was re-dissolved in EtOAc, filtered and concentrated in vacuo. Crude product was purified by flash chromatography (silica, 0-35% EtOAc in cyclohexane) to afford the title compound (671 mg, 98% yield).1H NMR (400 MHz, DMSO-cfe) 6 4.08 (q, J = 7.1 Hz, 2H), 3.84 (s, 2H), 3.77 (s, 2H), 3.39 (p, J = 7.6 Hz, 1 H), 3.27 (s, 2H), 2.57 - 2.52 (m, 2H), 2.10 - 1.99 (m, 2H), 1.35 (s, 9H), 1.19 (t, J = 7.1 Hz, 3H). UPLC (An analogous method to Method 5, ESI) 315.85 [MH]+, RT 2.54 min.

[1114] Step 2: ethyl 2- / 2-azaspirol3.3]heptan-6-ylsulfanyl}acetate

[1115] To a solution of terf-butyl 3-[(2-ethoxy-2-oxoethyl)sulfanyl]piperidine-1 -carboxylate (350 mg, 1.11 mmol, 1 .0 eq.) in DCM (7.0 mL) was added TFA (425 pL, 5.55 mmol, 5.0 eq.) at 0°C. The reaction mixture was stirred at r.t. for 16 h. After completion, solvent was removed in vacuo to afford the title compound (796 mg, 53% purity). UPLC (An analogous method to Method 5, ESI) 216.10 [MH]+, RT 1.30 min.

[1116] Step 3: ethyl 2-[(2-f[2-(propan-2-yloxy)phenyllmethyl}-2-azaspiro[3.3]heptan-6-yl)sulfanyll acetate

[1117] To a solution of ethyl 2-{2-azaspiro[3.3]heptan-6-ylsulfanyl}acetate (756 mg, 0.95 mmol, 1.0 eq.) in DCE (7.6 mL) was added Et3N (529 pL, 3.79 mmol, 4.0 eq.). The resulting mixture was stirred for 5 min. 2-(propan-2-yloxy)benzaldehyde (234 mg, 1.42 mmol, 1.5 eq.) was added and the reaction was stirred for another 30 min. Then, STAB (603 mg, 2.84 mol, 3.0 eq.) was added and the mixture was stirred at r.t. for 2 h. After completion, it was filtered and concentrated in vacuo. Crude product was purified by flash chromatography (silica, 0-5% MeOH in DCM) to afford the title compound (226 mg, 47% yield, 72% purity).1H NMR (400 MHz, DMSO-cfe) 6 7.46 - 7.28 (m, 2H), 7.18 - 7.08 (m, 1 H), 7.01 - 6.93 (m, 1 H), 4.76 - 4.62 (m, 1 H), 4.28 - 4.16 (m, 2H), 4.08 (q, J = 7.1 Hz, 2H), 4.15 - 3.93 (m, 3H), 3.47 - 3.37 (m, 1 H), 3.29 (s, 2H), 2.63 - 2.55 (m, 2H), 2.20 - 2.07 (m, 2H), 1.32 (d, J = 6.0 Hz, 6H), 1.29 - 1.22 (m, 1 H), 1.19 (t, J = 7.1 Hz, 3H). UPLC (An analogous method to Method 5, ESI) 364.60 [MH]+, RT 2.65 min.

[1118] Step 4: 2-[(2-f[2-(propan-2-yloxy)phenyllmethyl}-2-azaspiro[3.3]heptan-6-yl)sulfanyllacetic acid To a stirred solution of ethyl 2-[(2-{[2-(propan-2-yloxy)phenyl]methyl}-2-azaspiro[3.3] heptan-6- yl)sulfanyl]acetate (206 mg, 0.41 mmol, 1 eq.) in THF (3.0 mL) at r.t. was added aqueous sodium hydroxide solution (1 ,2M, 1.0 mL, 1.22 mmol, 3 eq.). The resulting mixture was stirred at 60°C for 16 h. After completion, it was concentrated in vacuo. Crude product was then diluted with water and neutralised with 1 M aqueous HCI solution till pH = 5. The precipitate was filtered off, washed with excess of ACN and concentrated in vacuo to afford the title compound (198 mg, 74% purity). UPLC (An analogous method to Method 5, ESI) 336.45 [MH]+, RT 2.18 min.

[1119] INTERMEDIATE 41 : 2 (1 -f[2-(propan-2-yloxy)phenyllmethyl}piperidin^4-yl)sulfanyllbutanoic acid

[1120] Step 1 : tert-butyl 44(1 -ethoxy-1 -oxobutan-2-yl)sulfanyllpiperidine-1 -carboxylate

[1121] To a solution of terf-butyl 4-bromopiperidine-1 -carboxylate (500 mg, 1.89 mmol, 1 eq.) and anhydrous potassium carbonate (780 mg, 5.68 mmol, 3 eq.) in ACN (10.0 mL) was added ethyl 2-sulfanylbutanoate (550 pL, 3.79 mmol, 2 eq.) under argon. The reaction mixture was stirred at 70°C for 16 h before filtered and the filtrate was concentrated in vacuo. Crude material was purified by flash chromatography (silica, 1 % MeOH in DCM) to afford the title compound (210 mg, 32% yield).1H NMR (400 MHz, CDCh) 6 4.29 - 4.13 (m, 2H), 4.05 - 3.81 (m, 2H), 3.23 (dd, J = 8.3, 6.8 Hz, 1 H), 2.99 - 2.85 (m, 3H), 2.03 - 1.82 (m, 3H), 1.76 - 1.63 (m, 1 H), 1.53 - 1.46 (m, 2H), 1.45 (s, 9H), 1.29 (t, J = 7.1 Hz, 3H), 1.00 (t, J = 7.4 Hz, 3H). UPLC (An analogous method to Method 5, ESI) 231.85 [MH-Boc]+, RT 3.50 min.

[1122] Step 2: ethyl 2-(piperidin-4-ylsulfanyl)butanoate

[1123] To a solution of tert- butyl 4-[(1 -ethoxy-1 -oxobutan-2-yl)sulfanyl]piperidine-1 -carboxylate (210 mg, 0.6 mmol, 1 eq.) in DCM (7.0 mL) was added hydrogen chloride in dioxane (4M, 602 pL, 2.4 mmol, 4 eq.). The reaction mixture stirred at 50°C for 5 h. After completion, solvent was concentrated in vacuo to give the title compound (170 mg, quantitative yield, 95% purity), which was used in the next step without any further purification.1H NMR (400 MHz, CDCh) 6 4.27 - 4.13 (m, 2H), 3.51 - 3.27 (m, 2H), 3.21 - 2.99 (m, 4H), 2.38 - 2.19 (m, 2H), 2.06 - 1.83 (m, 3H), 1.74 - 1.69 (m, 1 H), 1.28 (t, J= 7.1 Hz, 3H), 1.00 (t, J= 7.3 Hz, 3H). UPLC (An analogous method to Method 5, ESI) 232.25 [MH]+, RT 1.74 min. Step 3: ethyl 2-[(14T2-(propan-2-yloxy)phenyllmethyl}piperidin-4-yl)sulfanyllbutanoate

[1124] To a stirred solution of ethyl 2-(piperidin-4-ylsulfanyl)butanoate hydrochloride (160 mg, 0.54 mmol, 1 eq.) in DCE (16.0 mL) under argon was added Et3N (220 pL, 1.62 mmol, 3 eq.). The mixture was stirred for 5 min, then 2-(propan-2-yloxy)benzaldehyde (150 pL, 0.97 mmol, 1.8 eq.) was added, followed by STAB (0.46 g, 2.15 mmol, 4 eq.). The reaction mixture was stirred at r.t. for 16 h. After completion, solvent was removed in vacuo and the crude mixture was dissolved in DCM and washed with saturated aqueous sodium bicarbonate solution. Aqueous layer was extracted with DCM (2x). Combined organic layers were dried over sodium sulphate, filtered and concentrated in vacuo. Crude was purified by flash chromatography (silica, 20-30% EtOAc in cyclohexane) to afford the title compound (200 mg, 93% yield).1H NMR (400 MHz, CDC ) 6 7.38 - 7.31 (m, 1 H), 7.21 - 7.15 (m, 1 H), 6.95 - 6.83 (m, 2H), 4.58 - 4.48 (m, 1 H), 4.27 - 4.12 (m, 2H), 3.54 (s, 2H), 3.22 (dd, J = 8.5, 6.7 Hz, 1 H), 2.94 - 2.82 (m, 2H), 2.82 - 2.71 (m, 1 H), 2.21 - 2.08 (m, 2H), 2.03 - 1 .96 (m, 1 H), 1.94 - 1 .82 (m, 2H), 1.75 - 1 .62 (m, 3H), 1 .32 (d, J = 6.0 Hz, 6H), 1.28 (t, J = 7.1 Hz, 3H), 0.99 (t, J = 7.4 Hz, 3H). UPLC (An analogous method to Method 5, ESI) 380.60 [MH]+, RT 2.01 min.

[1125] Step 4: 2-[(1 -f[2-(propan-2-yloxy)phenyllmethyl}piperidin^4-yl)sulfanyl]butanoic acid

[1126] To a solution of ethyl 2-[(1-{[2-(propan-2-yloxy)phenyl]methyl}piperidin-4-yl)sulfanyl] butanoate (200 mg, 0.5 mmol, 1 eq.) in MeOH (10.0 mL) was added aqueous sodium hydroxide solution (1M, 2.50 mL, 2.5 mmol, 5 eq.). The reaction mixture was stirred at 50°C for 4 h and then at r.t. for another 16 h. After completion, solvent was removed in vacuo. Aqueous residue was neutralised with 1 M aqueous HCI solution to pH~7 and concentrated in vacuo. Residual was washed with ACN, filtered and concentrated in vacuo to afford the title compound (175 mg, quantitative yield) without any further purification.1H NMR (300 MHz, DMSO-cfe) 5 12.48 (bs, 1 H), 7.40 - 7.30 (m, 1 H), 7.27 - 7.18 (m, 1 H), 6.99 (d, J = 8.2 Hz, 1 H), 6.89 (t, J = 7.3 Hz, 1 H), 4.67 - 4.52 (m, 1 H), 3.70 - 3.50 (m, 2H), 3.25 - 3.12 (m, 2H), 2.96 - 2.76 (m, 3H), 2.37 - 2.11 (m, 1 H), 2.04 - 1 .82 (m, 2H), 1.82 - 1 .66 (m, 1 H), 1 .64 - 1 .42 (m, 3H), 1 .26 (d, J = 6.0 Hz, 6H), 0.91 (t, J = 7.3 Hz, 3H). UPLC (An analogous method to Method 5, ESI) 352.55 [MH]+, RT 1.85 min.

[1127] INTERMEDIATE 42: 3-m

[1128] Intermediate 42

[1129] To a stirred suspension of 3-hydroxy-5-methylbenzaldehyde (1.00 g, 7.35 mmol, 1 eq.) in anhydrous DMF (18.4 mL) was added anhydrous potassium carbonate (3.05 g, 22.04 mmol, 2.0 eq.) followed by 2-bromopropane (1.36 g, 11.01 mmol, 1.5 eq.). The reaction mixture was stirred at 85°C for 16 h. An additional amount of 2-bromopropane (0.27 g, 2.20 mmol, 0.3 eq.) was added and the mixture was stirred at 90°C for 5 h. Another portion of 2-bromopropane (0.18 g, 1.47 mmol, 0.2 eq.) was added and the mixture was stirred at 90°C for another 16 h. The mixture was concentrated in vacuo. The residue was re-dissolved in DCM and washed with water. Combined organic layers were dried over sodium sulphate, filtered and concentrated in vacuo. Crude product was purified by flash chromatography (silica, 0-15% EtOAc in hexanes) to afford the title compound (0.95 g, 71 % yield).1H NMR (400 MHz, CDCh) 6 9.92 (s, 1 H), 7.24 (s, 1 H), 7.18 (s, 1 H), 6.97 (s, 1 H), 4.61 (hept, J = 6.0 Hz, 1 H), 2.39 (s, 3H), 1 .35 (d, J = 6.1 Hz, 6H). UPLC (An analogous method to Method 5, ESI) 178.9 [MH]+, RT 2.50 min.

[1130] INTERMEDIATE 43: (1 R,2S,5

[1131] Intermediate 43

[1132] To a solution of L-menthol (300 mg, 1.92 mmol, 1.0 eq.) in DCM (7.0 mL) was added Et3N (804 pL, 5.76 mol, 3.0 eq.) at 0°C. A solution of methanesulfonyl chloride (178 pL, 2.30 mmol, 1.2 eq.) in DCM (0.5 mL) was then added dropwise and the resulting mixture was stirred at r.t. for 16 h. After completion, saturated ammonium chloride solution was added and the layers were separated. Combined organic layers were washed with 1 M aqueous HCI solution, dried over sodium sulphate, filtered and concentrated in vacuo. Crude product was purified by flash chromatography (silica, 0-20% EtOAc in cyclohexane) to afford the title compound (350 mg, 74% yield).1H NMR (400 MHz, CDCh) 6 4.55 (td, J = 10.9, 4.6 Hz, 1 H), 3.00 (s, 3H), 2.31 - 2.20 (m, 1 H), 2.12 - 2.01 (m, 1 H), 1.76 - 1.64 (m, 2H), 1.54 - 1.37 (m, 2H), 1.33 - 1.21 (m, 1 H), 1.12 - 0.99 (m, 1 H), 0.94 (d, J = 6.5 Hz, 3H), 0.93 (d, J = 7.0 Hz, 3H), 0.90 - 0.84 (m, 1 H), 0.83 (d, J = 6.9 Hz, 3H).

[1133] INTERMEDIATE 44: (1 R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl 4-methylbenzene-1 - sulfonate

[1134] To a solution of L-menthol (300 mg, 1.92 mmol, 1.0 eq.) in DCM (7.0 mL) was added Et3N (804 pL, 5.76 mol, 3.0 eq.) at 0°C. A solution of p-toluenesulfonyl chloride (384 mg, 2.02 mmol, 1.1 eq.) in DCM (0.5 mL) was then added dropwise and the resulting mixture was stirred at r.t. for 16 h. After completion, it was washed with 1M aqueous HCI solution. Organic layer was dried over sodium sulphate, filtered and concentrated in vacuo. Crude product was purified by preparative TLC (silica, 20% EtOAc in cyclohexane) to afford the title compound (40 mg, 6% yield, 85% purity).1H NMR (400 MHz, CDCI3) 6 7.80 (d, J = 8.0 Hz, 2H), 7.32 (d, J = 7.8 Hz, 2H), 4.49 - 4.31 (m, 1 H), 2.44 (s, 3H), 2.19 - 2.08 (m, 1 H), 1.96 - 1.84 (m, 1 H), 1.70 - 1.60 (m, 2H), 1.48 - 1.31 (m, 2H), 1.25 - 1.10 (m, 1 H), 1.04 - 0.91 (m, 2H), 0.88 (d, = 6.6 Hz, 3H), 0.83 (d, = 7.1 Hz, 3H), 0.58 - 0.45 (m, 3H).

[1135] INTERMEDIATE 45: 3-(di

[1136] Intermediate 45

[1137] To a stirred solution of 3-hydroxy-5-methylbenzaldehyde (200 mg, 1.47 mmol, 1 eq.) and potassium hydroxide (1.65 g, 29.38 mmol, 20 eq.) in H2O (3.7 mL) and ACN (3.7 mL) at 0°C was added bromodifluoromethyl diethylphosphonate (784 mg, 2.94 mmol, 2 eq.). The reaction mixture was stirred at 0°C for 30 min, warmed up to r.t. and stirred for 16 h. The mixture was diluted with water and extracted with Et20 (3x). Combined organic phases were washed with water and brine, dried over sodium sulphate, filtered and concentrated in vacuo. Crude material was purified by flash chromatography (silica, 0-20% EtOAc in cyclohexane) to afford the title compound (100 mg, 35% yield) as a colourless oil.1H NMR (400 MHz, DMSO-cfe) 6 9.98 (s, 1 H), 7.63 (s, 1 H), 7.48 (s, 1 H), 7.37 (s, 1 H), 7.33 (t, J = 73.7 Hz, 1 H), 2.42 (s, 3H).

[1138] INTERMEDIATE 46: 3-fluoro-4,5-dimethylbenzaldehyde

[1139] Intermediate 46

[1140] A solution of 5-bromo-3-fluoro-4-methylbenzaldehyde (400 mg, 1.84 mmol, 1 eq.), potassium methyltrifluoroborate (450 mg, 3.69 mmol, 2.0 eq.), potassium carbonate (760 mg, 5.53 mmol, 3.0 eq.) in dioxane (16.0 mL) and water (2.0 mL) was purged with argon for 10 min. [1 ,T- bis(diphenylphosphino)ferrocene]dichloropalladium(ll), complex with dichloromethane (300 mg, 0.37 mmol, 0.2 eq.) was added and the reaction mixture was stirred at 100°C for 16 h. The reaction was diluted with MeOH and distilled. Crude product was collected as a solution of title compound (quantitative yield) in MeOH, water and dioxane without further purification.1H NMR (300 MHz, DMSO-cfe) 6 9.88 (d, J = 1 .8 Hz, 1 H), 7.57 (s, 1 H), 7.46 (d, J = 9.5 Hz, 1 H), 2.34 (s, 3H), 2.21 (d, J = 2.1 Hz, 3H). UPLC (An analogous method to Method 5, ESI) not found [MH]+,

[1141] RT 3.39 min.

[1142] INTERMEDIATE 47: 3-i ic acid

[1143] Intermediate 47

[1144] Step 1 : methyl 3-( 1, 1 -dimethyl -1 ,2,3, 4-tetrahvdroisoquinolin-2-yl)propanoate

[1145] To a stirred solution of 1 ,1-dimethyl-1 ,2,3,4-tetrahydroisoquinoline (30 mg, 1.86 mmol, 1.0 eq.) and potassium carbonate (770 mg, 5.58 mmol, 3.0 eq.) in DMF (12.0 mL) was added methyl 3- bromopropionate (490 mg, 2.79 mmol, 1.5 eq.). The reaction mixture was stirred at 100°C for 5 d. After completion, solvent was removed in vacuo and the crude mixture was dissolved in DCM. Water was added and the layers were separated. Aqueous phase was extracted with DCM (2x). Combined organic layers were dried over sodium sulphate, filtered and concentrated in vacuo. Crude material was purified by flash chromatography (silica, 0-9% MeOH in DCM) to afford the title compound (120 mg, 26% yield).1H NMR (400 MHz, DMSO-cfe) 5 7.14 - 6.96 (m, 4H), 3.56 (s, 3H), 2.78 - 2.65 (m, 6H), 2.49 - 2.46 (m, 2H), 1.28 (s, 6H). UPLC (An analogous method to Method 5, ESI) 248.1 [MH]+, RT 1.76 min.

[1146] Step 2: 3-( 1, 1 -dimethyl-1,2,3,4-tetrahydroisoquinolin-2-yl)propanoic acid

[1147] To a stirred solution of methyl 3-(1 ,1-dimethyl-1 ,2,3,4-tetrahydroisoquinolin-2-yl)propanoate (120 mg, 0.48 mmol, 1 eq.) in THF (1.9 mL) was added aqueous sodium hydroxide solution (0.15M, 620 pL, 2.40 mmol, 5 eq.) and the solution was stirred at r.t. for 16 h. The mixture was concentrated in vacuo to afford the title compound (400 mg, quantitative yield) without further purification. UPLC (An analogous method to Method 5, ESI) 234.15 [MH]+, RT 1.44 min.

[1148] INTERMEDIATE 48: N2-methyl-N2-[(3R)-1 -(pyridazin-3-yl)pyrrolidin-3-yll-1,3,4-thiadiazole-2,5- diamine

[1149] Intermediate 48

[1150] Step 1 : tert-butyl N-r(3R)-1-(6-chloropyridazin-3-yl)pyrrolidin-3-yll-N-methylcarbamate

[1151] To a stirred solution of 3,6-dichloropyridazine (0.74 g, 4.99 mmol, 1 eq.) and Et3N (2.09 mL, 14.98 mmol, 3 eq.) in ethanol (25.0 mL) was added terf-butyl / V-methyl- / V-[(3 )-pyrrolidin-3- yl]carbamate (1.00 g, 4.99 mmol, 1.0 eq.). The reaction mixture was stirred at 70°C for 16 h and the solvent was removed in vacuo. Crude mixture was re-dissolved in DCM and saturated aqueous sodium bicarbonate solution was added. The mixture was stirred for 15 min and phases were separated. Aqueous phase was extracted with DCM (2x). Combined organic phases were washed with water and brine, dried over sodium sulphate, filtered and concentrated in vacuo. Crude material was purified by flash chromatography (silica, 0-10% MeOH in DCM) to afford the title compound (0.91 g, 57% yield) as a yellow solid.1H NMR (300 MHz, CDCh) 6 7.22 (d, J = 9.4 Hz, 1 H), 6.68 (d, J = 9.4 Hz, 1 H), 4.99 - 4.80 (m, 1 H), 3.84 - 3.68 (m, 2H), 3.60 - 3.38 (m, 2H), 2.82 (s, 3H), 2.27 - 2.13 (m, 2H), 1.48 (s, 9H). UPLC (An analogous method to Method 5, ESI) 312.95 [MH]+, RT 2.36 min.

[1152] Step 2: (3R)-N-methyl-1-(pyridazin-3-yl)pyrrolidin-3-amine hydrochloride

[1153] To a stirred solution of terf-butyl A / -[(3R)-1-(6-chloropyridazin-3-yl)pyrrolidin-3-yl]-A / - methylcarbamate (890 mg, 2.79 mmol, 1.0 eq.) in MeOH (27.9 mL) was added palladium on carbon (10% wet. 89 mg, 0.84 mmol, 0.3 eq.). The system was evacuated and backfilled with hydrogen three times and stirred under hydrogen atmosphere at r.t. for 16 h. The suspension was filtered through a pad of Celite® and washed with MeOH (20.0 mL). 3M aqueous HCI solution in MeOH (8.36 mL, 25.10 mmol, 9.0 eq.) was added and the mixture was stirred at r.t. for 16 h. Solvent was removed in vacuo to afford the title compound (830 mg, 99% yield, 72% purity) as a yellow solid.1H NMR (400 MHz, DMSO-cfe) 6 9.88 (s, 1 H), 9.74 (s, 1 H), 8.68 (d, J = 4.3 Hz, 1 H), 7.97 (dd, J = 9.5, 4.4 Hz, 1 H), 7.77 (dd, J = 9.5, 1.2 Hz, 1 H), 4.00 - 3.95 (m, 1 H), 3.90 - 3.84 (m, 2H), 3.71 - 3.64 (m, 2H), 2.58 (t, J = 5.3 Hz, 3H), 2.45 - 2.37 (m, 2H). UPLC (An analogous method to Method 5, ESI) 178.90 [MH]+, RT 0.61 min.

[1154] Step

[1155] To a stirred solution of (3R)- / V-methyl-1-(pyridazin-3-yl)pyrrolidin-3-amine hydrochloride (810 mg, 2.70 mmol, 1 eq.) in DMF (13.5 mL) was added anhydrous DIPEA (1.88 mL, 10.81 mmol, 4 eq.) followed by 2-amino-5-bromo-1 ,3,4-thiadiazole (970 mg, 5.41 mmol, 2 eq.). The reaction mixture was stirred at 60°C for 12 h and the solvent was removed in vacuo. Crude mixture was dissolved in DCM and saturated aqueous sodium bicarbonate solution was added. The mixture was stirred for 15 min and phases were separated. Aqueous phase was extracted with CHC IPA (4:1 , 3 x 50mL). Combined organic phases were washed with water and brine, dried over sodium sulphate, filtered and concentrated in vacuo. Crude material was purified by flash chromatography (silica, 0-25% MeOH in DCM) to afford the title compound (540 mg, 70% yield) as a beige solid.1H NMR (400 MHz, DMSO-cfe) 6 8.50 (dd, J = 4.5, 1.3 Hz, 1 H), 7.36 (dd, J = 9.1 , 4.4 Hz, 1 H), 6.92 (dd, J = 9.1 , 1.4 Hz, 1 H), 6.46 (s, 2H), 4.53 (p, J = 7.2 Hz, 1 H), 3.76 - 3.64 (m, 2H), 3.54 - 3.42 (m, 2H), 2.86 (s, 3H), 2.27 - 2.15 (m, 2H). UPLC (An analogous method to Method 5, ESI) 277.85 [MH]+, RT 0.61 min.

[1156] INTERMEDIATE 49: sodium 2-r(3S)-1-r(3,5-difluorophenyl)methyl]piperidin-3-yl]acetate

[1157] Step 1 : tert-butyl (3S)-3-(2-ethoxy-2-oxoethyl)piperidine-1 -carboxylate

[1158] To a stirred solution of 2-[(3S)-1-[(terf-butoxy)carbonyl]piperidin-3-yl]acetic acid (0.90 g, 3.70 mmol, 1.0 eq.) and potassium carbonate (1.53 g, 11.10 mmol, 3.0 eq.) in anhydrous ACN (13.5 mL) under argon was added iodoethane (1.44 g, 9.25 mmol, 2.5 eq.). The reaction was stirred at 50°C for 10 h and at r.t. for 5 h. Then, it was filtered and the filtrate was concentrated in vacuo to afford the title compound (1.30 g, quantitative yield) without further purification.1H NMR (400 MHz, CDCh) 6 4.13 (q, J = 7.1 Hz, 2H), 4.00 - 3.65 (m, 1 H), 3.83 (dt, J = 13.1 , 4.0 Hz, 1 H), 2.91 - 2.75 (m, 1 H), 2.74 - 2.40 (m, 1 H), 2.25 (dd, J = 15.1 , 6.9 Hz, 1 H), 2.15 (dd, J = 15.1 , 7.2 Hz, 1 H), 2.03 - 1.90 (m, 1 H), 1.88 - 1.78 (m, 1 H), 1.67 - 1.57 (m, 1 H), 1.52 - 1.38 (m, 10H), 1.25 (t, J = 7.1 Hz, 3H), 1.23 - 1.10 (m, 1 H). UPLC (An analogous method to Method 5, ESI) 271.85 [MH]+, RT 2.53 min.

[1159] Step 2: ethyl 2-[(3S)-piperidin-3-yl]acetate hydrochloride

[1160] To a solution of terf-butyl (3S)-3-(2-ethoxy-2-oxoethyl)piperidine-1-carboxylate (1.30 g, 4.55 mmol, 1 eq.) in DCM (40.0 mL) was added HCI solution in dioxane (4M, 0.60 mL, 18.20 mmol, 4 eq.). The reaction mixture was stirred at 50°C for 16 h. After completion, solvent was concentrated in vacuo to give the title compound (0.99 g, quantitative yield) without any further purification.1H NMR (400 MHz, Deuterium Oxide) 5 4.17 (q, J = 7.1 Hz, 2H), 3.46 - 3.34 (m, 2H), 2.91 (td, J = 13.2, 3 hz, 1 H), 2.75 (t, J = 12.2 Hz, 1 H), 2.41 (d, J = 7.0 Hz, 2H), 2.30 - 2.14 (m, 1 H), 1.99 - 1.84 (m, 2H), 1.81 - 1.66 (m, 1 H), 1.44 - 1.28 (m, 1 H), 1.25 (t, J = 7.2 Hz, 3H). UPLC (An analogous method to Method 5, ESI) 172.00 [MH]+, RT 1.06 min.

[1161] Step 3: ethyl 2-[ (3S)- 1-[ (3, 5-difluorophenyl)methyl]piperidin-3-yllacetate

[1162] To a stirred solution of ethyl 2-[(3S)-piperidin-3-yl]acetate hydrochloride (500 mg, 2.29 mmol, 1.0 eq.) and DIPEA (1.59 mL, 9.15 mmol, 4.0 eq.) in ACN (22.9 mL) was added 3,5-difluorobenzyl bromide (520 mg, 2.52 mmol, 1.1 eq.). The resulting mixture was stirred at r.t. for 16 h and the solvent was removed in vacuo. Crude was re-dissolved in DCM and saturated aqueous sodium bicarbonate solution, and the mixture was stirred for 15 min before phases were separated. Aqueous phase was extracted with DCM (2x). Combined organic phases were washed with water and brine, dried over sodium sulphate, filtered and concentrated in vacuo. Crude material was purified by flash chromatography (silica, 0-3% MeOH in DCM) to afford the title compound (610 mg, 88% yield) as a yellow oil.1H NMR (300 MHz, CDCh) 6 7.10 - 6.85 (m, 2H), 6.81 - 6.64 (m, 1 H), 4.10 (q, J = 7.1 Hz, 2H), 3.76 - 3.41 (m, 2H), 3.03 - 2.69 (m, 2H), 2.34 - 2.09 (m, 4H), 1.86 - 1.66 (m, 3H), 1.28 (s, OH), 1.31 - 1.19 (m, 4H), 1.18 - 1.00 (m, 1 H). UPLC (An analogous method to Method 5, ESI) 298.05 [MH]+, RT 1.81 min.

[1163] Step 4: sodium 2-[ (3S)- 1-[ (3, 5-difluorophenyl)methyl]piperidin-3-yllacetate

[1164] To a stirred solution of ethyl 2-[(3S)-1-[(3,5-difluorophenyl)methyl]piperidin-3-yl]acetate (125 mg, 0.38 mmol, 1 eq.) in MeOH (1.9 mL) was added aqueous sodium hydroxide solution (1M, 750 pL, 0.75 mmol, 2 eq.). The reaction mixture was stirred at r.t. for 16 h. After completion, solvent was removed in vacuo to afford the title compound (124 mg, quantitative yield, 82% purity) as a yellow solid without further purification.1H NMR (400 MHz, Methanol-cL) <5 7.21 - 7.13 (m, 2H), 7.04 (tt, J = 9.1 , 2.3 Hz, 1 H), 4.13 (s, 2H), 3.36 - 3.32 (m, 1 H), 3.28 - 3.21 (m, 1 H), 2.72 (td, J = 12.1 , 2.9 Hz, 1 H), 2.54 (t, J = 11.1 Hz, 1 H), 2.32 - 2.17 (m, 3H), 1.94 - 1.85 (m, 2H), 1.84 - 1.71 (m, 1 H), 1.29 - 1.17 (m, 1 H). UPLC (An analogous method to Method 5, ESI) 270.10 [MH]+, RT 1.28 min.

[1165] I

[1166] Step 1teP 2 Intermediate 50

[1167] Step 1 : ethyl 2- 4-(4, 4-dimethylcyclohexyl) piperazin- 1-yllacetate

[1168] To a stirred solution of 1-(ethoxycarbonylmethyl)piperazine (100 mg, 0.58 mmol, 1 .0 eq.) and 4,4- dimethylcyclohexanone (81 mg, 0.64 mmol, 1.1 eq.) in DCM (5.8 mL) was added STAB (246 mg, 1.16 mmol, 2.0 eq.). The reaction mixture was stirred at r.t. for 16 h. MeOH was added to the reaction mixture and the solvents were removed in vacuo. Crude was dissolved in DCM and saturated aqueous sodium bicarbonate solution was added. The mixture was stirred for 15 min and phases were separated. Aqueous phase was extracted with DCM (2x). Combined organic phases were washed with water and brine, dried over sodium sulphate, filtered and concentrated in vacuo to afford the title compound (140 mg, 81% yield) as a yellow oil.1H NMR (400 MHz, CDCh) 6 4.19 (q, J = 7.1 Hz, 2H), 3.47 - 3.40 (m, 2H), 3.29 (s, 2H), 3.25 - 3.15 (m, 2H), 3.11 - 3.02 (m, 3H), 2.97 - 2.86 (m, 1 H), 2.12 - 2.04 (m, 2H), 1.86 - 1.72 (m, 2H), 1.61 - 1.57 (m, 4H), 1.28 (t, J = 7.1 Hz, 3H), 1.32 - 1.24 (m, 1 H), 0.95 (s, 3H), 0.94 (s, 3H). UPLC (An analogous method to Method 5, ESI) 283.30 [MH]+, RT 1.61 min.

[1169] Step 2: sodium 2-[4-(4, 4-dimethylcyclohexyl) piperazin- 1-yllacetate

[1170] To a stirred solution of ethyl 2-[4-(4,4-dimethylcyclohexyl)piperazin-1-yl]acetate (140 mg, 0.47 mmol, 1 eq.) in MeOH (2.4 mL), was added aqueous sodium hydroxide solution (1M, 940 pL, 0.94 mmol, 2 eq.). The reaction mixture was stirred at r.t. for 16 h. After completion, solvent was removed in vacuo to afford the title compound (170 mg, 70% purity) as a white solid without further purification.1H NMR (400 MHz, DMSO-cfe) 6 2.71 (s, 2H), 2.48 - 2.31 (m, 8H), 2.04 - 1.93 (m, 1 H), 1.62 - 1.53 (m, 2H), 1.35 - 1.28 (m, 2H), 1.28 - 1.17 (m, 2H), 1.13 - 1.02 (m, 2H), 0.80 (s, 3H), 0.79 (s, 3H). UPLC (An analogous method to Method 5, ESI) 255.10 [MH]+, RT 1.19 min. I

[1171] Intermediate 51

[1172] Step 1 : ethyl 2-(4-(3, 3, 5, 5-tetramethylcyclohexyl)piperazin- 1-yl) acetate

[1173] To a stirred solution of ethyl 2-(piperazin-1-yl)acetate (100 mg, 0.58 mmol, 1.0 eq.) and 3, 3,5,5- tetramethylcyclohexanone (100 mg, 0.64 mmol, 1.1 eq.) in DCM (11.6 mL) was added STAB (246 mg, 1.16 mmol, 2.0 eq.). The reaction mixture was stirred at r.t. for 64 h. The mixture was then diluted with DCM and saturated aqueous sodium bicarbonate solution was added. The mixture was stirred for 15 min and phases were separated. Aqueous phase was extracted with DCM (2x). Combined organic phases were washed with water and brine, dried over sodium sulphate, filtered and concentrated in vacuo to afford the title compound (100 mg, 53% yield) as a yellow oil. LIPLC (An analogous method to Method 5, ESI) 311.15 [MH]+, RT 1.94 min.

[1174] Step 2: sodium 2-(4-(3, 3, 5, 5-tetramethylcyclohexyl)piperazin- 1-yl) acetate T o a stirred solution of ethyl 2-{4-[(3,3,5,5-tetramethylcyclohexyl)methyl]piperazin-1-yl} acetate (100 mg, 0.31 mmol, 1 eq.) in MeOH (3.1 mL) was added aqueous sodium hydroxide solution (1 M, 610 pL, 0.61 mmol, 2 eq.). The reaction mixture was stirred at r.t. for 16 h. After completion, solvent was removed in vacuo to afford the title compound (90 mg, quantitative yield) as a yellow solid without further purification. UPLC (An analogous method to Method 5, ESI) 283.15 [MH]+, RT 1.55 min.

[1175] INTERMEDIATE 52: sodium 2-(4- spiro[4.5ldecan-8-yl}piperazin-1-yl)acetate

[1176] Intermediate 52

[1177] Step 1 : ethyl 2-(4-fspiro[4.5]decan-8-yl}piperazin-1-yl)acetate

[1178] To a stirred solution of ethyl 2-(piperazin-1-yl)acetate (500 mg, 2.90 mmol, 1.0 eq.) and spiro[4.5]decan-8-one (490 mg, 3.19 mmol, 1.1 eq.) in DCM (29.0 mL) was added STAB (1.23 g, 5.81 mmol, 2.0 eq.). The reaction mixture was stirred at r.t. for 64 h. It was then diluted with DCM and saturated aqueous sodium bicarbonate solution was added. The mixture was stirred for 15 min and phases were separated. Aqueous phase was extracted with DCM (2x). Combined organic phases were washed with water and brine, dried over sodium sulphate, filtered and concentrated in vacuo. Crude material was purified by flash chromatography (silica, 0-10% MeOH in DCM) to afford the title compound (690 mg, 76% yield) as a yellow oil.1H NMR (300 MHz, CDC ) 6 4.19 (q, J = 7.2 Hz, 2H), 3.25 (s, 2H), 2.96 (s, 8H), 2.07 - 1.98 (m, 1 H), 1.67 - 1.50 (m, 8H), 1.45 - 1.38 (m, 2H), 1 .38 - 1.30 (m, 4H), 1 .30 - 1.22 (m, 6H). UPLC (An analogous method to Method 5, ESI) 309.30 [MH]+, RT 1.82 min.

[1179] Step 2: sodium 2-(4-{spiror4.5]decan-8-yl}piperazin- 1-yl) acetate

[1180] To a stirred solution of ethyl 2-(4-{spiro[4.5]decan-8-yl}piperazin-1-yl)acetate (690 mg, 2.19 mmol, 1 eq.) in MeOH (21.9 mL) was added aqueous sodium hydroxide solution (1M, 4.38 mL, 4.38 mmol, 2 eq.). The reaction mixture was stirred at r.t. for 16 h. After completion, solvent was concentrated in vacuo to afford the title compound (780 mg, 80% purity) as a yellow solid without further purification.1H NMR (300 MHz, Deuterium Oxide) 52.99 (s, 2H), 2.85 - 2.36 (m, 8H), 2.26 - 2.14 (m, 1 H), 1.84 - 1.75 (m, 2H), 1.63 - 1.46 (m, 6H), 1.45 - 1.37 (m, 2H), 1.35 - 1.21 (m, 6H). UPLC (An analogous method to Method 5, ESI) 281.05 [MH]+, RT 1.59 min.

[1181] INT

[1182] Intermediate 53

[1183] Step 1 : (4-cvclohexanecarbonylmorpholin-2-yl) methanol

[1184] To a stirred solution of cyclohexanecarboxylic acid (3.28 g, 25.61 mmol, 1.0 eq.) in anhydrous DMF (90.0 mL) were added DIPEA (13.4 mL, 76.8 mmol, 3.0 eq.) and HATU (14.61 g, 38.41 mmol, 1.5 eq.). The reaction mixture was stirred for 15 min, (morpholin-2-yl)methanol (3.00 g, 25.61 mmol, 1.0 eq.) was then added before stirring at r.t. for 16 h. The reaction mixture was diluted with DCM and saturated aqueous sodium bicarbonate solution was added. Stirring was continued for 15 min and phases were separated. Aqueous phase was extracted with DCM (2x). Combined organic phases were washed with water and brine, dried over sodium sulphate, filtered and concentrated in vacuo. Crude material was purified by flash chromatography (silica, 0-10% MeOH in DCM) to give the title compound (15.91 g, quantitative yield, 37% purity). LIPLC (An analogous method to Method 5, ESI) 227.95 [MH]+, RT 1.88 min.

[1185] Step 2: 2-ff(tert-butyldimethylsilyl)oxylmethyl}-4-cyclohexanecarbonylmorpholine

[1186] To a stirred solution of (4-cyclohexanecarbonylmorpholin-2-yl)methanol (1.83 g, 8.03 mmol, 1 eq.) in anhydrous DMF (150.0 mL) was added imidazole (3.83 g, 56.20 mmol, 7 eq.) followed by terf-butyldimethylsi lyl chloride (3.63 g, 24.09 mmol, 3 eq.). The reaction mixture was stirred at r.t. for 16 h. The reaction mixture was diluted with DCM and water was added. The mixture was stirred for 15 min and phases were separated. Aqueous phase was extracted with DCM (3x). Combined organic phases were dried over sodium sulphate, filtered and concentrated in vacuo. Crude material was purified by flash chromatography (silica, 0-50% EtOAc in cyclohexane) to give the title compound (1.95 g, 71% yield).1H NMR (400 MHz, CDCh) 6 4.46 (dd, J = 57.3, 13.4 Hz, 1 H), 3.98 - 3.85 (m, 2H), 3.78 - 3.59 (m, 2H), 3.57 - 3.17 (m, 3H), 2.98 - 2.73 (m, 1 H), 2.56

[1187] - 2.39 (m, 1 H), 1.85 - 1.77 (m, 2H), 1.76 - 1.65 (m, 3H), 1.58 - 1.47 (m, 2H), 1.31 - 1.18 (m, 3H), 0.92 - 0.87 (m, 9H), 0.09 - 0.04 (m, 6H). UPLC (An analogous method to Method 5, ESI) 342.20 [MH]+, RT 4.63 min.

[1188] Step 3: 2- / [(tert-butyldimethylsilyl)oxylmethyl}-4-(2-cvclohexylpropan-2-yl)morpholine

[1189] To a stirred solution of 2-{[(terf-butyldimethylsilyl)oxy]methyl}-4-cyclohexanecarbonyl morpholine (920 mg, 2.69 mmol, 1.0 eq.) in anhydrous THF (46.0 mL) at -30°C was added ZnCk (840 mg, 3.04 mmol, 1.5 eq.). The reaction mixture was stirred at

[1190] -30°C for 30 min and methylmagnesium bromide in Et20 (3M, 8.98 mL, 26.93 mmol, 10.0 eq.) was added dropwise over 15 min. The reaction mixture was stirred at -30°C for 3 h, warmed up to r.t. and stirred for 16 h. It was then quenched with water and diluted with DCM. Phases were separated and the aqueous phase was extracted with DCM (3x). Combined organic phases were washed with water, dried over sodium sulphate, filtered and concentrated in vacuo. Crude material was purified by flash chromatography (silica, 0-50% EtOAc in cyclohexane) to give the title compound (550 mg, 57% yield).1H NMR (400 MHz, CDCh) 6 3.87 - 3.81 (m, 1 H), 3.71 - 3.64 (m, 1 H), 3.58 (td, J = 10.9, 2.5 Hz, 1 H), 3.54 - 3.45 (m, 2H), 2.93 - 2.87 (m, 1 H), 2.67 - 2.61 (m, 1 H), 2.33 - 2.25 (m, 1 H), 1.98 - 1.91 (m, 1 H), 1.85 - 1.73 (m, 4H), 1.69 - 1.62 (m, 1 H), 1.45

[1191] - 1.39 (m, 1 H), 1.35 - 1.24 (m, 1 H), 1.20 - 1.09 (m, 3H), 0.98 - 0.92 (m, 1 H), 0.90 - 0.86 (m, 15H), 0.06 (s, 6H). UPLC (An analogous method to Method 5, ESI) 356.50 [MH]+, RT 3.63 min.

[1192] Step 4: [4-(2-cvclohexylpropan-2-yl)morpholin-2-yl]methanol

[1193] To a stirred solution of 2-{[(terf-butyldimethylsilyl)oxy]methyl}-4-(2-cyclohexylpropan-2- yl)morpholine (550 mg, 1.55 mmol, 1.0 eq.) in anhydrous THF (16.5 mL) was added tetrabutylammonium fluoride in THF (1M, 1.85 mL, 1.86 mmol, 1.2 eq.). The reaction mixture was stirred at r.t. for 16 h before concentrated in vacuo. Crude material was purified by flash chromatography (silica, 0-50% EtOAc in cyclohexane) to give the title compound (360 mg, 97% yield).1H NMR (400 MHz, CDCh) 6 3.91 (dt, J = 10.9, 2.8 Hz, 1 H), 3.68 - 3.53 (m, 4H), 2.73 - 2.60 (m, 2H), 2.31 (td, J = 11.Of, 3.1 Hz, 1 H), 2.19 - 2.03 (m, 1 H), 1.82 - 1.73 (m, 4H), 1.70 - 1.62 (m, 1 H), 1 .45 - 1.36 (m, 1 H), 1 .21 - 1.09 (m, 3H), 0.98 - 0.89 (m, 2H), 0.87 (s, 3H), 0.86 (s, 3H). UPLC (An analogous method to Method 5, ESI) 242.20 [MH]+, RT 1.84 min. Step 5: [4-(2-cvclohexylpropan-2-yl)morpholin-2-yllmethyl 4-methylbenzene-1 -sulfonate

[1194] To a stirred solution of [4-(2-cyclohexylpropan-2-yl)morpholin-2-yl]methanol (360 mg, 1.50 mmol,

[1195] I .0 eq.) in anhydrous DCM (15.0 mL) were added Et3N (63 pL, 4.50 mmol, 3.0 eq.) and p- toluenesulfonyl chloride (370 mg, 1.95 mmol, 1.3 eq.). The reaction mixture was stirred at r.t. for 16 h before concentrated in vacuo. Crude material was purified by flash chromatography (silica, 0-20% EtOAc in cyclohexane) to give the title compound (530 mg, 89% yield).1H NMR (400 MHz, CDCh) 6 7.82 - 7.78 (m, 2H), 7.36 - 7.32 (m, 2H), 4.06 - 3.97 (m, 2H), 3.78 (dt, J = 10.9, 2.8 Hz, 1 H), 3.68 - 3.61 (m, 1 H), 3.50 (td, J = 10.8, 2.6 Hz, 1 H), 2.70 - 2.64 (m, 1 H), 2.62 - 2.56 (m, 1 H), 2.45 (s, 3H), 2.24 (td, = 11.0, 3.1 Hz, 1 H), 2.06 - 1.97 (m, 1 H), 1.79 - 1.70 (m, 4H), 1.69 - 1.63 (m, 1 H), 1.39 - 1.30 (m, 1 H), 1.20 - 1.09 (m, 3H), 0.95 - 0.85 (m, 2H), 0.82 (s, 3H), 0.82 (s, 3H). LIPLC (An analogous method to Method 5, ESI) 396.45 [MH]+, RT 2.75 min.

[1196] Step 6: 2-[4-(2-cyclohexylpropan-2-yl)morpholin-2-yl]acetonitrile

[1197] To a stirred solution of [4-(2-cyclohexylpropan-2-yl)morpholin-2-yl]methyl 4-methylbenzene-1- sulfonate (530 mg, 1.34 mmol, 1 eq.) in DMSO (26.4 mL) was added potassium cyanide (260 mg, 4.01 mmol, 3 eq.). The reaction mixture was stirred at 60°C for 16 h. Then, it was diluted with DCM and water was added. The mixture was stirred for 15 min and phases were separated. Aqueous phase was extracted with DCM (3x). Combined organic phases were dried over sodium sulphate, filtered and concentrated in vacuo. Crude material was purified by flash chromatography (silica, 0-50% EtOAc in cyclohexane) to give the title compound (330 mg, 90% purity) as a yellow oil.1H NMR (400 MHz, CDCh) 6 3.87 (dt, J = 11.0, 2.9 Hz, 1 H), 3.78 - 3.70 (m, 1 H), 3.60 (td, J = 10.7, 2.6 Hz, 1 H), 2.86 - 2.79 (m, 1 H), 2.69 - 2.62 (m, 1 H), 2.55 (d, J = 6.1 Hz, 2H), 2.33 (td, J =

[1198] I I .2, 3.1 Hz, 1 H), 2.18 - 2.11 (m, 1 H), 1.81 - 1.73 (m, 4H), 1.70 - 1.63 (m, 1 H), 1.27 - 1.09 (m, 4H), 0.99 - 0.90 (m, 2H), 0.87 (s, 6H). UPLC (An analogous method to Method 5, ESI) 251.15 [MH]+, RT 1.77 min.

[1199] Step 7: 2-[4-(2-cyclohexylpropan-2-yl)morpholin-2-yl]acetic acid

[1200] To a stirred solution of 2-[4-(2-cyclohexylpropan-2-yl)morpholin-2-yl]acetonitrile (330 mg, 1.34 mmol, 1 eq.) in mixture of ethanol and water (17.0 mL, 1 :1) was added potassium hydroxide (0.75 g, 13.363 mmol, 10 eq.). The reaction mixture was stirred at 90°C for 16 h. Then, itwas neutralised with 1 M aqueous HCI and concentrated in vacuo. Crude material was purified by flash chromatography (silica, 0-10% MeOH in DCM) to give the title compound (330 mg, 91% yield) as a yellow solid.1H NMR (400 MHz, CDCh) 6 4.86 - 4.77 (m, 1 H), 4.64 (t, J = 12.2 Hz, 1 H), 4.05 - 3.96 (m, 1 H), 3.64 (d, J = 11 .9 Hz, 1 H), 3.35 (d, J = 11.8 Hz, 1 H), 3.05 - 2.94 (m, 1 H), 2.82 (t, J = 11.2 Hz, 1 H), 2.61 (d, J= 6.1 Hz, 2H), 2.05 - 1.91 (m, 2H), 1.91 - 1.80 (m, 2H), 1.74 - 1.60 (m, 2H), 1.40 (s, 3H), 1.39 (s, 3H), 1.28 - 1.12 (m, 5H). UPLC (An analogous method to Method 5, ESI) 270.2 [MH]+, RT 1.69 min.

[1201] INTERMEDIATE 54: 2-(1-(tert-butoxycarbonyl)azepan-3-yl)acetic acid

[1202] Intermediate 54

[1203] Step 1 : tert-butyl (E)-3-(2-(benzyloxy)-2-oxoethylidene)azepane-1 -carboxylate

[1204] To a mixture of benzyl 2-(dimethoxyphosphoryl)acetate (1.16 g, 4.51 mmol, 1.2 eq.) in THF (10 mL) was added NaH (225 mg, 5.63 mmol, 1 .5 eq.) at 0°C. The mixture was stirred at 0°C for 30 min before addition of terf-butyl 3-oxoazepane-1 -carboxylate (800 mg, 3.76 mmol, 1.0 eq.). The reaction mixture was stirred at r.t. for 1 h, then quenched with H2O (3 mL) and extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine (20 mL x 3), dried over sodium sulphate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica, PE / EtOAc =10 / 1) to afford the title compound (650 mg, 50 % yield) as a white solid. LCMS (Method 16, ESI) 290.0 [M+H-56]+, RT 1.958 minutes.

[1205] Step 2: 2-( 1-(tert-butoxycarbonyl)azepan-3-yl)acetic acid

[1206] To a mixture of terf-butyl (E)-3-(2-(benzyloxy)-2-oxoethylidene)azepane-1 -carboxylate (2.60 mg, 0.75 mmol, 1.0 eq.) in MeOH (10 mL) was added Pd / C (250 mg, 10% on carbon with ca. 55% water). The reaction mixture was stirred at r.t. under H2 atmosphere for 1 h and filtered. The filtrate was concentrated in vacuo to afford the title compound (200 mg, 99.0% yield) as a yellow oil.1H NMR (400 MHz, CDCI3) 6 3.67-2.93 (m, 5 H), 2.43-2.23 (m, 3H), 1.81-1.69 (m, 3 H), 1.63-1.57 (m, 1 H), 1.48-1.41 (m, 9 H), 1.28-1.21 (m, 1 H). LCMS (Method 15, ESI) 258.1 [M+H]+, RT 1.614 minutes.

[1207] INTERMEDIATE 55: 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-3-methylbutanoic acid

[1208] Step 1 A: tert-butyl 4-(2-(benzyloxy)-2-oxoethylidene)piperidine-1 -carboxylate

[1209] To a mixture of benzyl 2-(dimethoxyphosphoryl)acetate (1.56 g, 6.03 mmol, 1.2 eq.) in THF (20 mL) was added NaH (181 mg, 7.54 mmol, 1 .5 eq.) at 0 °C. The mixture was stirred at 0 °C for 30 min before addition of terf-butyl 4-oxopiperidine-1-carboxylate (1.0 g, 5.03 mmol, 1.0 eq.). The reaction mixture was stirred at r.t. for 1 h, then quenched with H2O (10 mL) and extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine (20 mL x 3), dried over sodium sulphate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica, PE / EtOAc =10 / 1) to afford the title compound (1.53 g, 92.2% yield) as a white solid.1H NMR (400 MHz, DMSO-d6): 57.38-7.31 (m, 5 H), 5.83 (s, 2 H), 5.12 (s, 1 H), 3.42- 3.37 (m, 4 H), 2.85 (t, J = 6.0 Hz, 2 H), 2.27 (t, J = 6.0 Hz, 2H), 1.41 (s, 9 H).

[1210] Step 1 B: tert-butyl 4-(2-(benzyloxy)- 1-bromo-2-oxoethyl)-4-bromopiperidine- 1 -carboxylate

[1211] To a mixture of terf-butyl 4-(2-(benzyloxy)-2-oxoethylidene)piperidine-1 -carboxylate (2.5 g, 7.55 mmol, 1.0 eq.) in DCM (30 mL) was added bromine (0.5 mL, 9.75 mmol, 1.3 eq.) at 0 °C. The reaction mixture was stirred at r.t. for 3 h. Upon completion, the mixture was quenched with aqueous saturated Na2S20s solution and extracted with EtOAc (30 mLx3). The combined organic phase was washed with brine (50 mL), dried over sodium sulphate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica, PE / EtOAc =10 / 1) to afford the title compound (2.5 g 67.4 % yield) as a yellow oil.

[1212] Step 2: tert-butyl 4-(2-(benzyloxy)- 1-bromo-2-oxoethylidene)piperidine- 1 -carboxylate

[1213] To a mixture of terf-butyl 4-(2-(benzyloxy)-1-bromo-2-oxoethyl)-4-bromopiperidine-1-carboxylate (2.58 g, 5.25 mmol, 1.0 eq.), in DCM (30 mL) was added TEA (1.33 g, 13.13 mmol, 2.5 eq.) dropwise. The reaction mixture was stirred at r.t. for 1 h, concentrated in vacuo. The residue was purified by flash chromatography (silica, PE / EtOAc =10 / 1) to afford the title compound (1.9 g, yield 88.2%) as a white solid. LCMS (Method 14, ESI) 311.8 [M+H-100]+, RT 3.73 minutes.

[1214] Step 3: tert-butyl 4-( 1-(benzyloxy)-3-methyl- 1-oxobut-3-en-2-ylidene) piperidine- 1 -carboxylate

[1215] To a mixture of terf-butyl 4-(2-(benzyloxy)-1-bromo-2-oxoethylidene)piperidine-1 -carboxylate (800 mg, 1.95 mmol, 1.0 eq.), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1 ,3,2-dioxaborolane (983 mg, 5.85 mmol, 3.0 eq.), Pd(dppf)Ch (316 mg, 0.39 mmol, 0.2 eq.) in dioxane / H2O (15mL / 1.5mL) was added K2CO3 (538 mg, 3.90 mmol, 2.0 eq.). The resulting mixture was stirred at 95°C for 16 h in a sealed tube under argon. Upon completion, the reaction mixture was filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica, PE / EtOAc =10 / 1) to afford the title compound (510 mg, yield 70.4 %) as a yellow oil.1H NMR (400 MHz, DMSO-ds): 6 7.38-7.33 (m, 5H), 5.15 (s, 2H), 5.12-5.11 (m, 1 H), 4.76-4.75 (m, 1 H), 3.37-3.34 (m, 4H), 2.54-2.52 (m, 3H), 2.31 (t, J =5.6Hz, 2H), 1.78 (s, 2H), 1.40(s, 9H). LCMS (Method 14, ESI) 271.9 [M+H-100]+, RT 3.81 minutes.

[1216] Step 4: 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-3-methylbutanoic acid

[1217] To a mixture of terf-butyl 4-(1-(benzyloxy)-3-methyl-1-oxobut-3-en-2-ylidene)piperidine-1- carboxylate (460 mg, 1.24 mmol, 1.0 eq.) in MeOH (10 mL) was added Pd / C (500 mg, 10% on carbon with ca. 55% water). The reaction mixture was stirred at 50 °C under H2 atmosphere for 3 h, then filtered. The filtrate was concentrated in vacuo to afford the title compound (320 mg, yield 90.6%) as a colourless oil. LCMS (Method 16, ESI) 230.0 [M+H-56]+, RT 1.042 minutes.

[1218] INTERMEDIATE 56: 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-cvclobutylacetic acid

[1219] Intermediate 56

[1220] Step 1 : benzyl 2-cyclobutylideneacetate

[1221] To a mixture of benzyl 2-(dimethoxyphosphoryl)acetate (5.75 g, 22.26 mmol, 1.2 eq.) in THF (350.0 mL) was added NaH (4.11 g, 27.83 mmol, 1.5 eq.) at 0°C. The mixture was stirred at 0°C for 30 min. Cyclobutanone (5.75 g, 22.26 mmol, 1 .2 eq.) in THF (5.0 mL) was added at 0°C and the resulting mixture was stirred at r.t. for 1.5 h before quenched by saturated ammonium chloride solution (150 mL), extracted with EtOAc (200 mL x 3). The combined organic phase was washed with brine (200 mL), dried over sodium sulphate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica, PE / EtOAc = 30 / 1) to afford the title compound (3.0 g, yield 70%) as a colourless oil. LCMS (Method 15, ESI) 244.2 [M+41+H]+, RT 1.988 minutes.

[1222] Step 2: benzyl 2-bromo-2-( 1-bromocvclobutyl)acetate

[1223] To a mixture of benzyl 2-cyclobutylideneacetate (2.68 g, 13.27 mmol, 1.0 eq.) in anhydrous DCM (20.0 mL) was added Br2 (2.54 g, 15.92 mmol, 1 .2 eq.) dropwise at 0°C. The mixture was stirred at r.t. for 40 min before quenched with saturated NaS2Os solution (20 mL) and extracted with DCM (30 mL x 3). The combined organic phase was washed with brine (30 mL), dried over sodium sulphate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica, PE / EtOAc = 97 / 3) to afford the title compound (4.5 g, yield 84%) as a colourless oil.

[1224] Step 3: benzyl 2-bromo-2-cyclobutylideneacetate

[1225] To a mixture of benzyl 2-bromo-2-(1-bromocyclobutyl)acetate (4.2 g, 11.67 mmol, 1.0 eq.) in DCM (40.0 mL) was added TEA (3.53 g, 34.00 mmol, 3.0 eq.) at r.t. , and the mixture was stirred at r.t. for 1 h. The reaction mixture was concentrated in vacuo and purified by flash chromatography (silica, PE / EtOAc = 95 / 5) to afford the title compound (3.0 g, yield 86%) as a colourless oil.1H NMR (400 MHz, CDCh) 6 7.4-7.28 (m, 5 H), 5.22 (s, 2 H), 3.1-3.01 (m, 2 H), 2.84-2.76 (m, 2 H), 2.09-1.95 (m, 2 H).

[1226] Step 4: tert-butyl 4-(2-(benzyloxy)- 1-cyclobutylidene-2-oxoethyl)-3, 6-dihydropyridine- 1 (2H)- carboxylate

[1227] A mixture of benzyl 2-bromo-2-cyclobutylideneacetate (2.7 g, 9.64 mmol, 1.0 eq.), terf-butyl 4- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1 (2H)-carboxylate (2.98 g, 9.64 mmol, 1.0 eq.), Pd(dppf)Ch DCM (704.68 mg, 0.96 mmol, 0.1 eq.) and K2CO3 (3.99 g, 28.92 mmol, 3.0 eq.) in dioxane (50.0 mL) and H2O (5.0 mL) was stirred at 90°C for 3 h under N2. The reaction mixture was diluted with H2O (60 mL), extracted with EtOAc (50 mL x 3). The combined organic phase was washed with brine (50 mL x 2), dried over sodium sulphate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica, PE / EtOAc = 95 / 5) to afford the title compound (1.56 g, yield 42%) as a yellow oil. LCMS (Method 22, ESI) 284.2 [M-100+H]+, RT 1.663 minutes.1H NMR (400 MHz, CDCh) 6 7.32 (m, 5 H), 5.46 (s, 1 H), 5.15 (s, 2 H), 3.95-3.93 (m, 2 H), 3.56-3.44 (m, 2 H), 3.10 (t, J = 7.6 Hz, 2 H), 2.81 (t, J = 8.0 Hz, 2 H), 2.20 (d, J = 1 .6 Hz, 2 H), 2.06 - 1 .94 (m, 2 H), 1 .47-1.46 (m, 9 H).

[1228] Step 5: 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-cyclobutylacetic acid

[1229] To a mixture of terf-butyl 4-(2-(benzyloxy)-1-cyclobutylidene-2-oxoethyl)-3,6-dihydro pyridine- 1 (2H)-carboxylate (300 mg, 0.78 mmol, 1.0 eq.) in MeOH (4.0 mL) was added Pd (300 mg, 10% on carbon with ca. 55% water) at r.t.. The mixture was stirred at r.t. for 1 h under H2 (1 atm). The reaction mixture was then filtered and the filtrate was concentrated in vacuo to afford the title compound (330 mg, crude) as a yellow oil which was used directly without further purification.1H NMR (400 MHz, CDCh) 6 4.10 (s, 1 H), 2.95-2.98 (m, 1 H), 2.70-2.54 (m, 2H), 2.30-2.20 (m, 1 H), 2.12-1.54 (m, 7H), 1.44 (s, 9H), 1.28-1.23 (m, 5H). LCMS (Method 15, ESI) 198.3 [M-100+H]+, RT 1.824 minutes.

[1230] INTERMEDIATE 57: tert-butyl 6-(2-methoxy-2-oxoethyl)-2-azaspiro[3.31heptane-2-carboxylate

[1231] Intermediate 57

[1232] Step 1 : tert-butyl 6-(2-methoxy-2-oxoethylidene)-2-azaspiro[3.3]heptane-2-carboxylate

[1233] To a mixture of methyl 2-(dimethoxyphosphoryl)acetate (1.55 g, 8.53 mmol, 1.2 eq.) in THF (30.0 mL) was added NaH (426.00 mg, 10.65 mmol, 1.5 eq.) at 0°C, and the mixture was stirred at 0°C for 30 min. terf-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (1.5 g, 7.10 mmol, 1.0 eq.) in THF (10.0 mL) was added at 0°C. The resulting mixture was stirred at r.t. for 30 min before quenched by saturated ammonium chloride solution (40 mL), extracted with EtOAc (40 mL x 3). The combined organic phase was washed with brine (40 mL), dried over sodium sulphate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica, PE / EtOAc = 3 / 1) to afford the title compound (1.8 g, yield 95%) as a colourless oil.1H NMR (400 MHz, CDCh) 6 5.67 (s, 1 H), 4.06 - 3.86 (m, 4 H), 3.69 (s, 3 H), 3.29 (s, 2 H), 3.01 (s, 2 H), 1.44 (s, 9 H).

[1234] Step 2: tert-butyl 6-(2-methoxy-2-oxoethyl)-2-azaspiro[3.3]heptane-2-carboxylate

[1235] To a mixture of terf-butyl 6-(2-methoxy-2-oxoethylidene)-2-azaspiro[3.3]heptane-2-carboxylate (1.8 g, 6.69 mmol, 1.0 eq.) in MeOH (20.0 mL) was added Pd (200 mg, 10% on carbon with ca. 55% water) at r.t.. The mixture was stirred at r.t. for 1 h under H2. The reaction mixture was filtered and concentrated in vacuo to afford the title compound (1.71 g, yield 94.5%) as a colourless oil.1H NMR (400 MHz, CDCh) 5 3.93 (s, 2 H), 3.80 (s, 2 H), 3.65 (s, 3 H), 2.56-2.47 (m, 1 H), 2.42- 2.27 (m, 4 H), 1.90-1.77 (m, 2 H), 1.43 (s, 9 H).

[1236] INTERMEDIATE 58:

[1237] Intermediate 58

[1238] To a mixture of terf-butyl 4-(1-hydroxy-2-methoxy-2-oxoethyl)piperidine-1 -carboxylate (400 mg, 1.47 mmol, 1.0 eq.), methyl iodide (416 mg, 2.93 mmol, 2.0 eq.) in THF (10 mL) was added t- BuOK (2.2 mL, 2.21 mmol, 1.5 eq.). The resulting mixture was stirred at r.t. for 2 h, then quenched with saturated ammonium chloride solution (10 mL) and extracted with EtOA (20 mLx3 ). The combined organic phase was washed with brine (30 mL), dried over sodium sulphate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica, PE / EtOAc = 3 / 1) to afford the title compound (330 mg, 78.6 % yield) as a colourless oil. LCMS (Method 23, ESI)188.1 [M+H-100]+, RT 0.73 minutes.1H NMR (400 MHz, CDCI3) 6 4.14-4.11 (m, 2H), 3.77 (s,

[1239] 3H), 4.47 (d, J=6.0Hz, 1 H), 3.35 (s, 3H), 2.70-2.61 (m, 2H), 1.90-1.82 (m, 1 H), 1.71-1.67 (m, 1 H),

[1240] 1.60-1.54 (m, 1 H), 1.45 (s, 9H), 1.39-1.26 (m, 2H).

[1241] INTERMEDIATE 59: tert-butyl 4-(1,

[1242] Intermediate 59

[1243] Step 1 : ethyl 2-(diethoxyphosphoryl)-2-ethoxyacetate

[1244] A mixture of ethyl 2-chloro-2-ethoxyacetate (1 .0 g, 6.02 mmol, 1 .0 eq.) and triethyl phosphite (1.10 g, 6.62 mmol, 1.1 eq.) was stirred at 130°C for 5 h under argon. The reaction mixture was concentrated in vacuo to afford the title compound (1 .5 g, crude, 92.9 % yield) as a colourless oil. LCMS (Method 15, ESI) 269.1 [M+H]+, RT 1.457 minutes.

[1245] Step 2: tert-butyl 4-( 1 ,2-diethoxy-2-oxoethylidene)piperidine-1 -carboxylate

[1246] To a mixture of ethyl 2-(diethoxyphosphoryl)-2-ethoxyacetate (1.40 g, 5.26 mmol, 1.2 eq.) in THF (20 mL) was added NaH (263 mg, 6.57 mmol, 1.5 eq.) at 0°C. The mixture was stirred at 0°C for 0.5 h, added with tert-butyl 4-oxopiperidine-1 -carboxylate (872 mg, 4.38 mmol, 1 .0 eq.) and stirred at r.t. for 2 h under argon. The reaction mixture was quenched with NH4CI (5mL) and extracted with EtOA (20 ml_x3). The combined organic phase was washed with brine (30 mL), dried over sodium sulphate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica, PE / EtOAc = 10 / 1) to afford the title compound (470 mg, yield 34.3%) as a colourless oil. LCMS (Method 16, ESI) 214.2 [M+H-100]+, RT 1.948 minutes.1H NMR (400 MHz, DMSO-d6) 5 4.19-4.14 (m, 2H), 3.68-3.63 (m, 2H), 3.37-3.32 (m, 4H), 2.61 (t, J = 5.6Hz, 2H), 2.37 (t, J = 5.6Hz, 2H), 1.40 (s, 9H), 1.24 (t, J =7.2Hz, 3H), 1.17 (t, J = 6.8Hz, 3H).

[1247] Step 3: tert-butyl 4-( 1 ,2-diethoxy-2-oxoethyl)piperidine-1 -carboxylate

[1248] To a mixture of tert-butyl 4-(1 ,2-diethoxy-2-oxoethylidene)piperidine-1 -carboxylate (420 mg, 1.34 mmol, 1.0 eq.) in MeOH (10 mL) with added Pd / C (300 mg, 10% on carbon with ca. 55% water), and it was stirred at r.t. under H2 atmosphere for 2 h. The reaction mixture was then filtered and the filtrate was concentrated in vacuo to afford the title compound (402 mg, yield 95.0 %) as a colourless oil. LCMS (Method 15, ESI) 216.2 [M+H-100]+, RT 1.037 minutes.

[1249] INTERMEDIATE 60: tert-butyl 4-(1

[1250] Intermediate 60

[1251] Step 1 : tert-butyl 4-( 1 -ethoxy- 1-oxobutan-2-ylidene)piperidine- 1 -carboxylate

[1252] To a mixture of ethyl 2-(diethoxyphosphoryl)butanoate (1.0 g, 6.03 mmol, 1.2 eq.) in THF (20.0 mL) was added NaH (119 mg, 4.95 mmol, 1.5 eq.) at 0°C, and the mixture was stirred at 0°C for 30 min. terf-butyl 4-oxopiperidine-1 -carboxylate (657 mg, 3.3 mmol, 1.0 eq.) in THF (5.0 mL) was added at 0°C. The resulting mixture was stirred at r.t. for 1 .5 h before quenched by saturated ammonium chloride solution (20 mL), extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine (20 mL), dried over sodium sulphate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (PE / EtOAc =94% / 6%) to afford the title compound (630 mg, yield 64%) as a colourless oil. LCMS (Method 19, ESI) 198.2 [M+H-100]+, RT 2.036 minutes.1H NMR (400 MHz, CDCh) 6 4.21 (q, J = 7.2 Hz, 2 H), 3.54-3.36 (m, 4 H), 2.54 (t, J = 5.6 Hz, 2 H), 2.35-2.29 (m, 4 H), 1.47 (s, 9 H), 1.30 (t, J = 7.2 Hz, 3 H), 1.01 (t, J = 7.6 Hz, 3 H).

[1253] Step 2: tert-butyl 4-( 1 -ethoxy- 1 -oxobutan-2-yl)piperidine-1 -carboxylate

[1254] To a mixture of terf-butyl 4-(1 -ethoxy-1 -oxobutan-2-ylidene)piperidine-1 -carboxylate (530 mg, 1.78 mmol, 1.0 eq.) in MeOH (10.0 mL) was added Pd / C (350 mg, 10% on carbon with ca. 55% water) at r.t., and the mixture was stirred for 1 h under H2. The reaction mixture was then filtered and the filtrate was concentrated in vacuo to afford the title compound (510 mg, yield 96%) as a colourless oil.1H NMR (400 MHz, CDCh) 6 4.18-4.06 (m, 4 H), 2.65 (t, J = 12.8 Hz, 2 H), 2.12- 2.06 (m, 1 H), 1.74-1.53 (m, 6 H), 1.52 (s, 9 H), 1.27 (t, J = 7.6 Hz, 3 H), 1.28-1.23 (m, 1 H), 0.88 (t, J = 7.6 Hz, 3 H). INTERMEDIATE 61 : tert-butyl 4-(3-cyclopropyl-1 -ethoxy-1 -oxopropan-2-yl)piperidine-1- carboxylate

[1255] Intermediate 61

[1256] Step 1 : ethyl 3-cyclopropyl-2-(diethoxyphosphoryl)propanoate

[1257] To a mixture of ethyl 2-(diethoxyphosphoryl)acetate (800 mg, 3.57 mmol, 1.0 eq.) in DMSO (10.0 mL) was added t-BuOK (1M, 4.64 mL, 1.3 eq.) at 0°C, and the mixture was stirred at r.t. for 15 min. Then (iodomethyl)cyclopropane (974.99 mg, 5.36 mmol, 1.5 eq.) was added at r.t., and the resulting mixture was stirred at 60°C for 3 h. The reaction mixture was diluted with H2O (40 mL), extracted with EtOAc (30 mL x 3). The combined organic phase was washed with brine (30 mL x 2), dried over sodium sulphate, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography (silica, PE / EA = 1 / 1) to afford the title compound (880 mg, yield 89%) as a colourless oil.1H NMR (400 MHz, CDCh) 6 4.36-4.01 (m, 6 H), 3.11-3.02 (m, 1 H), 2.06-1.91 (m, 1 H), 1.72-1.63 (m, 1 H), 1.37-1.28 (m, 9 H), 0.80-0.69 (m, 1 H), 0.51-0.38 (m, 2 H), 0.18-0.01 (m, 2 H).

[1258] Step 2: tert-butyl 4-(3-cyclopropyl- 1 -ethoxy-1 -oxopropan-2-ylidene) piperidine- 1 -carboxylate

[1259] To a mixture of ethyl 3-cyclopropyl-2-(diethoxyphosphoryl)propanoate (386.55 mg, 1.94 mmol, 1.2 eq.) in THF (10.0 mL) was added NaH (58.32 mg, 2.43 mmol, 1.5 eq.) at 0 °C. The mixture was stirred at 0 °C for 30 min. terf-butyl 4-oxopiperidine-1 -carboxylate (450 mg, 1.62 mmol, 1.0 eq.) in THF (2.0 mL) was added at 0 °C. The resulting mixture was stirred at r.t. for 1.5 h before quenched by saturated ammonium chloride solution (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine (20 mL), dried over sodium sulphate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica, PE / EtOAc = 92 / 8) to afford the title compound (140 mg, yield 27%) as a colourless oil.1H NMR (400 MHz, CDCh) 6 4.23 (q, J = 7.2 Hz, 2 H), 3.50-3.45 (m, 4 H), 2.55-2.52 (m, 2 H), 2.38-2.35 (m, 2 H), 2.28 (d, J = 6.8 Hz, 2 H), 1.48 (s, 9 H), 1.33 (t, J = 7.2 Hz, 3 H), 0.79-0.72 (m, 1 H), 0.47-0.42 (m, 2 H), 0.13-0.10 (m, 2 H). LCMS (Method 15, ESI) 224.2 [M+H-100]+, RT 2.116 minutes.

[1260] Step 3: tert-butyl 4-(3-cyclopropyl- 1 -ethoxy-1 -oxopropan-2-yl)piperidine- 1 -carboxylate

[1261] To a mixture of terf-butyl 4-(3-cyclopropyl-1 -ethoxy-1 -oxopropan-2-ylidene)piperidine-1- carboxylate (220 mg, 0.62 mmol, 1.0 eq.) in MeOH (5.0 mL) was added Pd / C (100 mg, 10% on carbon with ca. 55% water) at r.t. The mixture was stirred at r.t. for 1 h under H2. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to afford the title compound (190 mg, crude) as a colourless oil. LCMS (Method 15, ESI) 270.2 [M+H-56]+, RT 2.128 minutes.

[1262] INTERMEDIATE 62: 2-(2-isopropoxyphe

[1263] Intermediate 62

[1264] Step 1 : (E)-1-isopropoxy-2-(2-methoxyvinyl) benzene

[1265] To a mixture of (methoxymethyl)triphenylphosphonium chloride (13.92 g, 42.87 mmol, 2.0 eq.) in THF (160.0 mL) was added LiHMDS (1 M, 42.87 mL, 2.0 eq.) at -70 °C. The mixture was warmed slowly to 0 °C and stirred for 2 h. Then the mixture was cooled to -70 °C and 2- isopropoxybenzaldehyde (3.52 g, 21.44 mmol, 1.0 eq.) was added. The resulting mixture was stirred at r.t. for 2 h. The reaction mixture was quenched by saturated ammonium chloride solution (300 mL), extracted with EtOAc (300 mL x 3). The combined organic phase was washed with brine (300 mL), dried over sodium sulphate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (PE / EtOAc = 97 / 3) to afford the title compound (2.16 g, yield 52%) as a yellow oil.1H NMR (400 MHz, DMSO) 5 7.31-7.18 (m, 1 H), 7.13-7.02 (m, 1 H), 7.00- 6.89 (m, 1 H), 6.83 (m, 1 H), 6.33-5.41 (m, 2 H), 4.59-4.52 (m, 1 H), 3.67 (s, 3 H), 1.28-1.23 (m, 6 H). LCMS (Method 22, ESI) 193.2 [M+H]+, RT 1.448 minutes.

[1266] Step 2: 2-(2-isopropoxyphenyl)acetaldehyde

[1267] A mixture of (E)-1-isopropoxy-2-(2-methoxyvinyl)benzene (2.16 g, 11.25 mmol, 1.0 eq.) in formic acid (25.0 mL) was stirred at r.t. for 2 h. The reaction mixture was then concentrated in vacuo and the residue purified by flash chromatography (PE / EtOAc = 30 / 1) to afford the title compound (720 mg, yield 36%) as a yellow oil.1H NMR (400 MHz, DMSO) 5 9.59 (s, 1 H), 7.33-7.12 (m, 2 H), 7.02 (d, J = 8.4 Hz, 1 H), 6.89 (t, J = 7.6 Hz, 1 H), 4.64-4.58 (m, 1 H), 3.59 (s, 2 H), 1 .22 (d, J = 6.0 Hz, 6 H). INTERMEDIATE 63: 2-(4-(tert-butoxycarbonyl)thiomorpholin-2-yl)acetic acid

[1268] Intermediate 63

[1269] Step 1 : tert-butyl 2-(hydroxymethyl)thiomorpholine-4-carboxylate

[1270] To a solution of 4-(tert-butoxycarbonyl)thiomorpholine-2-carboxylic acid (1 g, 4.05 mmol, 1.0 eq.) in anhydrous THF (20 mL) was added a solution of BH3 in THF (1 M, 16.2 mL, 4.0 eq.) slowly at 0° C. The reaction mixture was stirred at r.t. for 16 h then quenched with saturated aqueous sodium carbonate solution (50 mL). The aqueous layer was extracted with EtOAc (2x50 mL). The combined organic layers were washed with brine, dried over sodium sulphate, filtered and concentrated in vacuo to afford the title compound (1 .06 g, crude) as a colourless oil, which was used without further purification. LCMS (Method 15, ESI): 256.4 [M+Na]+, RT 1.633 minutes.

[1271] Step 2: tert-butyl 2-(((methylsulfonyl)oxy)methyl)thiomorpholine-4-carboxylate

[1272] To a solution of tert-butyl 2-(hydroxymethyl)thiomorpholine-4-carboxylate (1.06 g, 4.55 mmol, 1.0 eq.) and methanesulfonyl chloride (1.04 g, 9.1 mmol, 2.0 eq.) in DCM (10 mL) was added TEA (1.38 g, 13.65 mmol, 3.0 eq.) slowly. After stirring for 3 h at 0 °C the mixture was diluted with water (100 mL), the organic phase separated was dried over sodium sulfate and concentrated in vacuo to afford the title compound (825 mg, yield 58.93%). No mass signal was detected by LCMS.

[1273] Step 3: tert-butyl 2-(cyanomethyl)thiomorpholine-4-carboxylate

[1274] A mixture of the tert-butyl 2-(((methylsulfonyl)oxy)methyl)thiomorpholine-4-carboxylate (825 mg, 2.65 mmol, 1.0 eq.) in DMSO(10 ml) was added KCN (516.75 mg, 7.95 mmol, 3.0 eq.). The resulting mixture was stirred at 80 °C for 2 h under argon. The reaction mixture was quenched with saturated aqueous ammonium chloride, extracted with EtOAc (x3). The combined organic phase was washed with brine, dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica, 0-5% MeOH in DCM) to afford the title compound (243 mg, yield 37.91 %). No mass signal was detected by LCMS. Step 4: 2-(4-(tert-butoxycarbonyl)thiomorpholin-2-yl)acetic acid

[1275] To a stirred solution of the terf-butyl 2-(cyanomethyl)thiomorpholine-4-carboxylate (243 mg, 1.0 mmol, 1.0 eq.) in EtOH / Water (1 / 1) was added KOH (112.46 mg, 2.01 mmol, 2.0 eq.). The resulting mixture was stirred at 100 °C for 16 h. The reaction mixture was concentrated in vacuo to afford the title compound (275 mg, crude) without further purification.1H NMR (400 MHz, DMSO) 54.23 - 3.66 (m, 2H), 3.28 - 3.09 (m, 1 H), 3.06 - 2.85 (m, 2H), 2.84 - 2.55 (m, 2H), 2.47 - 2.04 (m, 1 H), 1.96 - 1.79 (m, 1 H), 1.39 (d, J = 1.4 Hz, 9H). LCMS (Method 15, ESI): 261.9 [M+H]+, RT 1.438 minutes.

[1276] INTERMEDIATE 64: Preparation of 2-(2-(tert-butoxycarbonyl)-2,6-diazaspiro[3.4]octan-6- vDacetic acid

[1277] Intermediate 64

[1278] Step 1 : tert-butyl 6-(2-methoxy-2-oxoethyl)-2, 6-diazaspiro[3.4]octane-2-carboxylate

[1279] To a mixture of terf-butyl 2,6-diazaspiro[3.4]octane-2-carboxylate (1 g, 4.72 mmol, 1.0 eq.) in ACN (10 mL) were added methyl 2-bromoacetate (1.08 g, 7.08 mmol, 1.5 eq.) and DIPEA (1.22 g, 9.44 mmol, 2.0 eq.) The resulting mixture was stirred at 40°C for 2 h, then quenched with saturated aqueous ammonium chloride, extracted with EtOAc. The combined organic phase was washed with brine, dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel to afford the title compound (630 mg, yield 47.01%) as a yellow oil.1H NMR (400 MHz, DMSO-d6) 53.76 (d, = 21.8 Hz, 4H), 3.60 (s, 3H), 3.31 (s, 2H), 2.76 (s, 2H), 2.61 (t, J = 7.0 Hz, 2H), 1.99 - 1.92 (m, 2H), 1.37 (s, 9H).

[1280] Step 2: Preparation of 2-(2-(tert-butoxycarbonyl)-2, 6-diazaspiro[3.4]octan-6-yl)acetic acid

[1281] To a stirred solution of the terf-butyl 6-(2-methoxy-2-oxoethyl)-2,6-diazaspiro[3.4]octane-2- carboxylate (630 mg, 2.22 mmol, 1.0 eq.) in MeOH / THF / Water (1 / 1 / 1) was added LiOH (186.48 mg, 4.44 mmol, 2.0 eq.). The resulting mixture was stirred at r.t. for 2 h and concentrated in vacuo to afford the title compound (530 mg, yield 88.5%) without purification. No mass signal was detected by LCMS. INTERMEDIATE 65: 2-(4-(2,4-dimethylpentan-3-yl)morpholin-2-yl)acetic acid

[1282] Step 1 : 2-((2,4-dimethylpentan-3-yl)amino)ethan-1-ol

[1283] To a mixture of 2,4-dimethylpentan-3-one (2 g, 17.51 mmol, 1.0 eq.) in MeOH (20 mL) were added 2-aminoethan-1-ol (5.35 g, 87.57 mmol, 5.0 eq.) and Ti(Oi-Pr)4 (14.93 g, 52.54 mmol, 3.0 eq.) . The resulting mixture was heated in a microwave reactor at 100°C for 2 h. Then NaBHsCN (3.3 g, 52.54 mmol, 3.0 eq.) was added, and the reaction mixture was heated in a microwave reactor at 100°C for another 2 h. The reaction mixture was concentrated in vacuo. The residue was purified by flash chromatography (silica, DCM / MeOH = 20 / 1) to afford the title compound (2.1 g, 75.3% yield) as a yellow oil. LCMS (Method 21 , ESI): 160.1[M+H]+, RT 1.178 minutes.

[1284] Step 2: ethyl (E)-4-((2,4-dimethylpentan-3-yl)(2-hvdroxyethyl)amino)but-2-enoate

[1285] To a stirred solution of 2-((2,4-dimethylpentan-3-yl)amino)ethan-1-ol (2.1 g, 13.18 mmol, 1.0 eq.) in THF (20 mL) was added ethyl (E)-4-bromobut-2-enoate (3.82 g, 19.78 mmol, 1.5 eq.) and K2CO3 (5.47 g, 39.55 mmol, 3.0 eq.). The resulting mixture was stirred at 25°C for 16 h before the reaction mixture was concentrated in vacuo. The residue was purified by reverse flash chromatography (0-90% ACN in H2O) to afford the title compound (186 mg, 7.5% yield) as a yellow oil. LC MS (Method 21 , ESI): 272.1 [M+H]+, RT 2.021 minutes.

[1286] Step 3: ethyl 2-(4-(2, 4-dimethylpentan-3-yl)morpholin-2-yl)acetate

[1287] To a stirred solution of ethyl (E)-4-((2,4-dimethylpentan-3-yl)(2-hydroxyethyl)amino)but-2-enoate (263 mg, 0.969 mmol, 1.0 eq.) in toluene (2 mL) was added DBU (148 mg, 0.969 mmol, 1.0 eq.). The resulting mixture was stirred at 100°C for 16 h before concentrated in vacuo. The residue was purified by Prep-TLC (DCM / MeOH = 20 / 1) to afford the title compound (186 mg, 70.7% yield). LCMS (An analogous method to Method 15, ESI): 272.3[M+H]+, RT 0.983 minutes. Step 4: 2-(4-(2, 4-dimethylpentan-3-yl)morpholin-2-yl)acetic acid

[1288] To a stirred solution of ethyl 2-(4-(2,4-dimethylpentan-3-yl)morpholin-2-yl)acetate (186 mg, 0.685 mmol, 1.0 eq.) in THF / Water (5 mL / 1 mL) was added LiOH (25 mg, 1.03 mmol, 1.5 eq.). The resulting mixture was stirred at 60°C for 16 h. The reaction mixture was concentrated in vacuo to afford the title compound (210 mg crude, 50% purity) without further purification. LCMS (Method 18, ESI): 244.2 [M+H]+, RT 1.051 minutes.

[1289] INTERMEDIATE 66: 2-(4-(tert-butoxycarbonyl)-1-methylpiperazin-2-yl)acetic acid

[1290] Step 1 : tert-butyl 3-(2-methoxy-2-oxoethyl)-4-methylpiperazine-1 -carboxylate

[1291] To a mixture of tert-butyl 3-(2-methoxy-2-oxoethyl)piperazine-1-carboxylate (1 g, 3.87 mmol, 1.0 eq.) in ACN (10 mL) were added methyl iodide (0.24 mL, 3.87 mmol, 1.0 eq.) and potassium carbonate (1.61 g, 11.61 mmol, 3.0 eq.). The resulting mixture was stirred at 80 °C for 16 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (silica, MeOH: DCM= 0 - 5%) to afford the title compound (953 mg, yield: 91.4%) as a yellow oil. LCMS (Method 15, ESI): 273.3 [M+H]+, RT 0.373 minutes.

[1292] Step 2: 2-(4-(tert-butoxycarbonyl)-1-methylpiperazin-2-yl)acetic acid

[1293] To a stirred mixture of tert-butyl 3-(2-methoxy-2-oxoethyl)-4-methylpiperazine-1-carboxylate (853 mg, 3.13 mmol, 1.0 eq.) in THF / Water (10 mL / 2 mL) was added LiOH (113 mg, 4.70 mmol, 2.0 eq.). The resulting mixture was stirred at 60 °C. for 2 h. The reaction mixture was concentrated in vacuo to afford the title compound (960 mg, crude) without further purification. LCMS (Method 15, ESI): 259.2 [M+H]+, RT 1.095 minutes.

[1294] INTERMEDIATE 67: 2- / 4-[(tert-butoxy)carbonyl]-1 ,4-oxazepan-2-yl}acetic acid

[1295] Intermediate 67

[1296] Step 1 : tert-butyl 2-(hydroxymethyl)- 1 ,4-oxazepane-4-carboxylate

[1297] To a stirred solution of 4-[(terf-butoxy)carbonyl]-1 ,4-oxazepane-2-carboxylic acid (1.25 g, 5.10 mmol, 1 eq.) in anhydrous THF (25.5 ml) under argon at 0°C was added a solution of borane tetrahydrofuran complex (1M, 10.20 mL, 10.20 mmol, 2 eq.) dropwise over 30 min. The reaction mixture was stirred at r.t. for 16 h. Crude material was quenched with saturated aqueous sodium bicarbonate solution and extracted with EtOAc (2x). Combined organic phases were washed with water and brine, dried over sodium sulphate, filtered and concentrated in vacuo. Crude material was purified by flash chromatography (silica, 0-50% EtOAc in cyclohexane) to afford the title compound (900 mg, 73% yield) as an yellow oil. LIPLC (An analogous method to Method 5, ESI) 231.95 [MH]+, RT 2.20 min.

[1298] Step 2: tert-butyl 2- / T(4-methylbenzenesulfonyl)oxy]methyl}-1 ,4-oxazepane-4-carboxylate

[1299] To a stirred solution of terf-butyl 2-(hydroxymethyl)-1 ,4-oxazepane-4-carboxylate (0.88 g, 3.61 mmol, 1.0 eq.) and triethylamine (1.51 ml, 10.84 mmol, 3.0 eq.) in anhydrous DCM (36.1 ml) under argon was added p-toluenesulfonyl chloride (0.90 g, 4.70 mmol, 1.3 eq.) and the reaction mixture was stirred at r.t. for 16 h. The reaction mixture was concentrated in vacuo and the crude was purified by flash chromatography (silica, 0-20% EtOAc in cyclohexane) to afford the title compound (1.38 g, 88% yield, 89% purity).1H NMR (400 MHz, Chloroform-d) 5 7.79 (d, J = 8.1 Hz, 2H), 7.34 (d, J = 7.9 Hz, 2H), 4.05 - 3.92 (m, 3H), 3.84 - 3.57 (m, 3H), 3.46 - 3.34 (m, 1 H), 3.33 - 3.18 (m, 1 H), 3.10 - 2.92 (m, 1 H), 2.45 (s, 3H), 1.92 - 1.78 (m, 2H), 1.44 (s, 9H).

[1300] Step 3: tert-butyl 2-(cyanomethyl)- 1 ,4-oxazepane-4-carboxylate

[1301] To a stirred solution of terf-butyl 2-{[(4-methylbenzenesulfonyl)oxy]methyl}-1 ,4-oxazepane-4- carboxylate (1.33 g, 3.07 mmol, 1 eq.) in DMSO (40.0 mL) was added potassium cyanide (0.60 g, 9.21 mmol, 3 eq.). The reaction mixture was stirred at 55°C for 5 h before diluted with DCM and water was added. The mixture was stirred for 15 min and phases were separated. Aqueous phase was extracted with DCM (3x). Combined organic phases were dried over sodium sulphate, filtered and concentrated in vacuo. Crude material was purified by flash chromatography (silica, 0-50% EtOAc in cyclohexane). Obtained fraction was lyophilised twice with water to afford the title compound (668 mg, 86% yield) as a white solid.1H NMR (400 MHz, DMSO-cfe) 5 4.03 - 3.89 (m, 1 H), 3.81 - 3.63 (m, 2H), 3.58 - 3.49 (m, 1 H), 3.49 - 3.38 (m, 1 H), 3.29 - 3.19 (m, 1 H), 3.15 - 2.97 (m, 1 H), 2.82 - 2.72 (m, 1 H), 2.72 - 2.63 (m, 1 H), 1.84 - 1.70 (m, 2H), 1.41 (s, 9H).

[1302] Step 4: 2- / 4-[(tert-butoxy)carbonyl]-1,4-oxazepan-2-yl}acetic acid

[1303] To a stirred solution of terf-butyl 2-(cyanomethyl)-1 ,4-oxazepane-4-carboxylate (638 mg, 2.52 mmol, 1 eq.) in a mixture of ethanol and water (32.0 mL, 1 :1) was added potassium hydroxide (1.42 g, 25.23 mmol, 10 eq.). The reaction mixture was stirred at 85°C for 16 h before it was neutralized with 1 M aqueous HCI. Crude material was extracted with DCM (5x). Combined organic phases were dried over sodium sulphate, filtered and concentrated in vacuo to afford the title compound (238 mg, 20% yield, 55% purity) as an yellow oil.1H NMR (400 MHz, Chloroformed) 6 4.13 - 4.02 (m, 1 H), 3.99 - 3.91 (m, 1 H), 3.84 - 3.61 (m, 2H), 3.56 - 3.49 (m, 1 H), 3.33 - 3.22 (m, 1 H), 3.07 - 2.93 (m, 1 H), 2.56 - 2.47 (m, 2H), 1.98 - 1.84 (m, 2H), 1.47 (s, 9H). UPLC (An analogous method to Method 5, ESI) 159.95 [MH-Boc]+, RT 2.67 min

[1304] INTERMEDIATE 68: sodium 2-(4- bicvclo[2.2.2]octan-1-yl}morpholin-2-yl)acetate

[1305] Intermediate 68

[1306] Step 1 : N-(2-((tert-butyldimethylsilyl) oxy) ethyl) bicyclol2.2.2]octan- 1 -amine

[1307] To a mixture of bicyclo[2.2.2]octan-1-amine hydrochloride (644 mg, 4.0 mmol, 1.0 eq.) in MeOH (20 mL) was added 2-((terf-butyldimethylsilyl)oxy)acetaldehyde (696 mg, 4 mmol, 1.0 eq.), KOAc (491 mg, 5.0 mmol, 1.25 eq.) and NaBHsCN at 25 °C. The reaction mixture was stirred at 25 °C for 16 h before quenched with water and extracted with EtOAc (50 mL x 3). The combined organic phase was washed with brine (50 mL), dried over sodium sulphate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica, PE / EtOAc =2 / 1) to afford the title compound (603 mg, 53.2% yield) as a colourless oil. LCMS (Method 21 , ESI) 284.1 [M+H]+, RT 1.774 minutes.1H NMR (400 MHz, CDCh) 6 3.78 (t, J = 5.2 Hz, 2 H), 2.69 (t, J = 6.8 Hz, 2 H), 1.96 (s, 8 H), 1.65-1.61 (m, 6 H), 0.89 (s, 9 H), 0.065 (s, 6 H).

[1308] Step 2: ethyl (E)-4-(bicvclor2.2.2loctan-1-yl(2-((tert-butyldimethylsilyl)oxy)ethyl)amino)but-2- enoate

[1309] To a mixture of A / -(2-((tert-butyldimethylsilyl)oxy)ethyl)bicyclo[2.2.2]octan-1-amine (603 mg, 2.13 mmol, 1.0 eq.) in THF (20 mL) was added ethyl (E)-4-bromobut-2-enoate (1.23 g, 6.39 mmol, 3.0 eq.) and K2CO3 (588 mg, 4.26 mmol, 2.0 eq.). The reaction was stirred at 65 °C for 16 h under nitrogen. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (silica, PE / EtOAc = 50 / 1) to afford the title compound (409 mg, yield 48.6%) as a colourless oil. LCMS (Method 15, ESI) 396.2 [M+H]+, RT 0.930 minutes.

[1310] Step 3: ethyl (E)-4-(bicvclo[2.2.2loctan-1-yl(2-hvdroxyethyl)amino)but-2-enoate

[1311] To a solution of ethyl (E)-4-(bicyclo[2.2.2]octan-1-yl(2-((tert-butyldimethylsilyl)oxy) ethyl)amino)but-2-enoate (409 mg, 1.03 mmol, 1.0 eq.) in DCM (10 mL) was added TFA (10 mL), and the resulting mixture was stirred at 40 °C for 16 h under argon. Upon completion, the reaction mixture was concentrated in vacuo. The residue was purified by flash chromatography (silica, PE / EtOAc = 50 / 1) to afford the title compound (280 mg, 96.2% yield) as a colourless oil. LCMS (Method 15, ESI) 282.1[M+H]+, RT 0.814 minutes.

[1312] Step 4: ethyl 2-(4-(bicyclo[2.2.2loctan-1-yl)morpholin-2-yl)acetate

[1313] To a mixture of ethyl (E)-4-(bicyclo[2.2.2]octan-1-yl(2-hydroxyethyl)amino)but-2-enoate (280 mg, 1 .00 mmol, 1 .0 eq.) in toluene (30 mL) was added DBU (609 mg, 4.00 mmol, 4.0 eq.). The reaction mixture was stirred at 110 °C for 16 h then concentrated in vacuo. The residue was purified by Prep HPLC to afford the title compound (203 mg, 72.5% yield) as a white solid. LCMS (Method 15, ESI) 282.1 [M+H]+, RT 0.803 minutes.1H NMR (400 MHz, CDCh) 6 4.18-4.05 (m, 3 H), 4.00- 3.86 (m, 2H), 3.49-3.35 (m, 2 H), 2.81-2.70 (m, 2 H), 2.48-2.47 (m, 2 H), 1.77-1.76 (m, 6 H), 1.68- 1.65 (m, 7 H), 1.18 (t, J = 6.8 Hz, 3 H).

[1314] Step 5: sodium 2-(4- / bicyclo[2.2.2]octan-1-yl}morpholin-2-yl)acetate

[1315] To a stirred solution of ethyl 2-(4-{bicyclo[2.2.2]octan-1-yl}morpholin-2-yl)acetate (200 mg, 0.74 mmol, 1.0 eq.) in MeOH (7.4 mL) was added aqueous sodium hydroxide solution (1 M, 1.50 mL, 1.50 mmol, 2 eq.). The reaction mixture was stirred at r.t. for 16 h. After completion, solvent was evaporated in vacuo to afford the title compound (200 mg, quantitative yield, 95% purity) without further purification. UPLC (Method 5, ESI) 253.9 [MH]+, RT 1.56 min. In the following general procedures, all variables are as defined herein and PG / PG2are respectively suitable nitrogen / carboxylic acid protecting groups as understood by one skilled in the art, and more specifically, as defined above.

[1316] One skilled in the art will appreciate that the compounds of formula (I) may be synthesised by one or more of the following general procedures. The comments regarding ring A above in the Process and Intermediate sections are equally applicable here i.e. in any one of the following General Procedures, where PG is attached to ring A, PG is attached to a nitrogen ring atom of ring A.

[1317] INTERMEDIATE 69: 3-(

[1318] Intermediate 69

[1319] Potassium hydroxide (4.94 g, 88.1 mmol) was suspended in a solution of acetonitrile (10 mL) and water (10 mL) and cooled to -20 °C. 3-hydroxy-4-methylbenzaldehyde (600.0 mg, 4.4 mmol) was dissolved in acetonitrile (10 mL) and was added dropwise, followed by bromodifluoromethyl diethylphosphonate (2.35 g, 8.81 mmol) over 15 min. Then the mixture was allowed to warm to r.t. over 1 h. The mixture was extracted with EtOAc (3 x 30 mL), the combined organic layers were washed with brine (2 x 30 mL) and dried over sodium sulphate, filtered, and the filtrate was concentrated in vacuo. Crude material was purified by flash chromatography (silica, 0-20% EtOAc in PE) to afford the title compound (402.3 g, 49% yield) as a clear oil.1H NMR (400 MHz, DMSO- cfe), d 9.97 (s, 1 H), 7.74 (dd, J = 8.0, 1.6 Hz, 1 H), 7.64 (s, 1 H), 7.57 (d, J = 7.6 Hz, 1 H), 7.34 (t, J = 73.8 Hz, 1 H), 2.32 (s, 3H).

[1320] INTERMEDIATE 70: 3,5-dichloro-4-methylbenzaldehyde

[1321] Intermediate 70

[1322] Step 1 : (3, 5-dichloro-4-methylphenyl) methanol

[1323] To a stirring solution of methyl 3,5-dichloro-4-methylbenzoate (500.0 mg, 2.28 mmol) in THF (20 mL) was added lithium aluminum hydride (2.5 M in THF, 1.8 mL, 4.5 mmol). Then the reaction mixture was stirred at r.t. for 16 h. The reaction mixture was quenched with methanol and concentrated in vacuo to give the residue, which was purified by flash chromatography (silica, 0- 50% EtOAc in PE) to afford the title compound (300.0 mg, 68.8% yield) as a colourless oil.

[1324] Step 2: 3, 5-dichloro-4-meth ylbenzaldeh yde

[1325] To a stirring solution of (3,5-dichloro-4-methylphenyl)methanol (300.0 mg, 1.57 mmol) in DCM (15 mL) was added DMP (1.33 g, 3.14 mmol). Then the reaction mixture was stirred at r.t. for 16 h. The reaction mixture was concentrated in vacuo and re-dissolved in DCM and washed with H2O. The mixture was extracted with DCM (20 mL) three times. The combined organic phases were washed with H2O and brine, dried over anhydrous sodium sulphate, filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (silica, 0-50% EtOAc in PE) to give the title compound (150.1 mg, 30.3% yield) as a white solid.1H NMR (400 MHz, DMSO-cfe) 6 9.87 (s, 1 H), 7.87 (s, 2H), 2.55 (s, 3H).

[1326] INTERMEDIATE 71 : 7-fluoro-2,3-dihvdro-1H-indene-5-carbaldehyde

[1327] Intermediate 71

[1328] Step 1 : 6-bromo-4-fluoro-2, 3-dihydro- 1H-indene

[1329] A solution of 5-bromo-7-fluoro-2,3-dihydro-1 H-inden-1-one (500.0 mg, 2.18 mmol), triethylsilane (5 mL) and trifluoroacetic acid (10 mL) was stirred at 50° C for 16 h before concentrated in vacuo. The residue was extracted with EtOAc (50 mL), washed with water, dried over Na2SO4, filtered and concentrated in vacuo. Crude material was purified by flash chromatography (silica, 0-5% EtOAc in PE) to afford the title compound (350.0 mg, 75.6% yield) as a colourless oil.

[1330] Step 2: 7-fluoro-2, 3-dihydro- 1 H-indene-5-carbaldehyde

[1331] To a solution of 6-bromo-4-fluoro-2,3-dihydro-1 H-indene (350 mg, 1.63 mmol) in THF (10 mL) was added n-butyl lithium (2.5 M in hexane, 1.3 mL, 3.25 mmol) dropwise slowly at -78°C under nitrogen. After the addition, the mixture was stirred for 1 h, and N, / V-dimethyl formamide (1 mL) was added dropwise. The mixture was stirred at -78°C for 1 h. The reaction solution was then quenched with water, extracted with EtOAc (30 mL x 3), and the combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. Crude material was purified by flash chromatography (silica, 0-20% EtOAc in PE) to afford the title compound (180.5 mg, 67.4% yield) as a white solid.1H NMR (400 MHz, DMSO-cfe) 6 9.89 (d, J = 1.6 Hz, 1 H), 7.59 (s, 1 H), 7.37 (d, J = 8.8 Hz, 1 H), 3.05-2.97 (m, 4H), 2.22-2.15 (m, 2H). General Procedure 1

[1332] (III) amine intermediate (II) carboxylic acid

[1333] To a stirring solution of the acid intermediate (1.0 eq.) and DIPEA (3.0 eq.) in DMF was added the amine intermediate (1.2 eq.) and the coupling reagent (HATLI, T3P or PyBOP, 1.5 eq.). The reaction mixture was stirred at r.t. for 16 h. The reaction mixture was diluted with DCM and saturated aqueous sodium bicarbonate solution was added. The mixture was stirred for 15 min and phases were separated. Aqueous phase was extracted with DCM (2x). Combined organic phases were washed with water and brine, dried over sodium sulphate, fil...

Claims

CLAIMS1 . A compound of formula (I):wherein R1is selected from the group consisting of H, halo, C1-4 alkyl, C1-4 haloalkyl and NH2;R2is selected from the group consisting of H, C1-4 alkyl, C1-4 alkoxy, NR2aR2band Co- salkyleneCs-ecycloalkyl; wherein: R2ais independently H or Ci-3alkyl;R2bis independently H or Ci-3alkyl; each R3is independently selected from the group consisting of halo, hydroxy, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl and C1-4 haloalkoxy; each R4is independently selected from the group consisting of halo, hydroxy, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, CO2R4a, SCi-4alkyl, OCo-salkyleneCs-ecycloalkyl and Co-salkyleneCs-ecycloalkyl wherein the Cs-ecycloalkyl is optionally substituted by one or two R4b; or when ring B is phenyl two R4groups which are attached to adjacent carbon atoms join to form a C4-7cycloalkyl ring; wherein: R4ais independently H or Ci-3alkyl;R4bis independently halo or Ci-3alkyl;R5is H or halo;A is selected from the group consisting of 4-10 membered heterocyclyl, 6-11 membered heterospirocycloalkyl and Cs-ecycloalkyl;B is selected from the group consisting of phenyl, Cs- cycloalkyl, 4-7 membered heterocyclyl, 4-10 membered heteroaryl and Ce-n spirocycloalkyl;X is either absent or is selected from the group consisting of O, S and NR6Ci-4alkylene;wherein R6is independently H or Ci-3alkyl;Y is either absent or is selected from the group consisting of O, S, Ci-4alkylene and NR7Ci- 4alkylene, wherein the Ci-4alkylene group is optionally substituted by one or more R9; wherein R7is independently H or Ci-3alkyl;R8is independently H or Ci-3alkyl;R9is independently selected from the group consisting of halo, C1-4 alkyl, C1-4 alkoxy and NR2aR2b; m is 0, 1 or 2; n is 0, 1 or 2; and o is 0, 1 , 2, 3 or 4; wherein: when B is phenyl, o is 1 , 2, 3 or 4; or a salt and / or solvate thereof.

2. A compound or a salt and / or solvate thereof which is a compound of formula (IB):wherein:D is selected from the group consisting of:wherein R1is selected from the group consisting of H, halo, C1-4 alkyl, C1-4 haloalkyl and NH2;R2is selected from the group consisting of H, C1-4 alkyl, C1-4 alkoxy, NR2aR2band Co- salkyleneCs-ecycloalkyl; wherein: R2ais independently H or Ci-3alkyl;R2bis independently H or Ci-3alkyl;R3is selected from the group consisting of halo, hydroxy, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl and C1-4 haloalkoxy;R4is selected from the group consisting of halo, hydroxy, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, CCLR43, SCi-4alkyl, OCo-salkyleneCs-eCycloalkyl and Co-salkyleneCs- eCycloalkyl wherein the Cs-eCycloalkyl is optionally substituted by one or two R4b; wherein: R4ais independently H or Ci-3alkyl;R4bis independently halo or Ci-3alkyl;R5is H or halo;A is selected from the group consisting of 4-10 membered heterocyclyl, 6-11 membered heterospirocycloalkyl and Cs-ecycloalkyl;B is selected from the group consisting of phenyl, Cs- cycloalkyl, 4-7 membered heterocyclyl, 4-10 membered heteroaryl and Ce-n spirocycloalkyl;X is either absent or is selected from the group consisting of O, S and NR6Ci-4alkylene; wherein R6is independently H or Ci-3alkyl;Y is either absent or is selected from the group consisting of O, S, Ci-4alkylene and NR7Ci- 4alkylene; wherein R7is independently H or Ci-3alkyl;R8is independently H or Ci-3alkyl; m is 0, 1 or 2; n is 0, 1 or 2; and o is 0, 1 , 2, 3 or 4; or a salt and / or solvate thereof.

3. The compound or a salt and / or solvate of a compound of formula (I) according to claim 14. The compound or a salt and / or solvate thereof according to any one of claims 1 to 3 wherein R1is H.

5. The compound or a salt and / or solvate thereof according to any one of claims 1 to 3 wherein R1is Cl.

6. The compound or a salt and / or solvate thereof according to any one of claims 1 to 5 wherein R2is H.

7. The compound or a salt and / or solvate thereof according to any one of claims 1 to 5 wherein R2is C1-4 alkyl, e.g. methyl.

8. The compound or a salt and / or solvate thereof according to any one of claims 1 to 5 wherein R2is CM alkoxy.

9. The compound or a salt and / or solvate thereof according to any one of claims 1 to 5 wherein R2is NR2aR2b.

10. The compound or a salt and / or solvate thereof according to claim 9 wherein R2aand R2bare both methyl.

11. The compound or a salt and / or solvate thereof according to any one of claims 1 to 5 wherein R2is Co-salkyleneCs-ecycloalkyl.

12. The compound or a salt and / or solvate thereof according to claim 11 wherein R2is selected from the group consisting of cyclopropyl, CH2-cyclopropyl and cyclobutyl.

13. The compound or a salt and / or solvate thereof according to any one of claims 1 to 12 wherein R3is halo.

14. The compound or a salt and / or solvate thereof according to any one of claims 1 to 12 wherein R3is hydroxy.

15. The compound or a salt and / or solvate thereof according to any one of claims 1 to 12 wherein R3is CM alkyl e.g., methyl, ethyl or isopropyl.

16. The compound or a salt and / or solvate thereof according to any one of claims 1 to 12 wherein R3is CM haloalkoxy.

17. The compound or a salt and / or solvate thereof according to any one of claims 1 to 16 wherein R4is halo.

18. The compound or a salt and / or solvate thereof according to any one of claims 1 to 16 wherein R4is hydroxy.

19. The compound or a salt and / or solvate thereof according to any one of claims 1 to 16 wherein R4is CM alkyl.

20. The compound or a salt and / or solvate thereof according to any one of claims 1 to 16 wherein R4is C1-4 alkoxy.

21. The compound or a salt and / or solvate thereof according to any one of claims 1 to 16 wherein R4is C1-4 haloalkyl.

22. The compound or a salt and / or solvate thereof according to any one of claims 1 to 16 wherein R4is C1-4 haloalkoxy.

23. The compound or a salt and / or solvate thereof according to any one of claims 1 to 16 wherein R4is CCLR43.

24. The compound or a salt and / or solvate thereof according to any one of claims 1 to 16 wherein R4is SCi-4alkyl.

25. The compound or a salt and / or solvate thereof according to any one of claims 1 to 16 wherein R4is OCs-ecycloalkyl.

26. The compound or a salt and / or solvate thereof according to any one of claims 1 to 16 wherein R4is selected from the group consisting of halo, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl and C1-4 haloalkoxy.

27. The compound or a salt and / or solvate thereof according to any one of claims 1 to 26 wherein R5is H.

28. The compound or a salt and / or solvate thereof according to any one of claims 1 to 27 wherein A is a 4-10 membered heterocyclyl.

29. The compound or a salt and / or solvate thereof according to any one of claims 1 to 28 wherein B is phenyl.

30. The compound or a salt and / or solvate thereof according to claim 29, wherein two R4groups which are attached to adjacent carbon atoms join to form a C4-7cycloalkyl ring.

31. The compound or a salt and / or solvate thereof according to any one of claims 1 to 28 wherein B is 4-10 membered heteroaryl.

32. The compound or a salt and / or solvate thereof according to any one of claims 1 to 31 wherein X is absent.

33. The compound or a salt and / or solvate thereof according to any one of claims 1 to 32 wherein Y is Ci-4alkylene e.g. CH2.

34. The compound or a salt and / or solvate thereof according to any one of claims 1 to 33 wherein R8is H.

35. The compound or a salt and / or solvate thereof according to any one of claims 1 to 34 wherein n is 0 and m is 1 .

36. The compound or a salt and / or solvate thereof according to any one of claims 1 to 35 wherein o is 1.

37. The compound or a salt and / or solvate thereof according to any one of claims 1 to 35 wherein o is 2.

38. The compound or a salt and / or solvate of a compound of formula (I) according to any one of claims 1 to 37 which is a compound of formula (IA):wherein each of R2, R3, R4, R4, R5, R8, m, n, o, X, Y, A, B and D is as defined in any one of claims1 to 37; or a salt and / or solvate thereof.

39. A compound according to claim 1 which is selected from the list consisting of: (R)-3-(4-((2-isopropoxyphenyl)thio)piperidin-1-yl)- / \ / -(5-((1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)- 1 ,3,4-thiadiazol-2-yl)propanamide;(R)-2-(1-(methyl(3-(trifluoromethoxy)benzyl)amino)cyclobutyl)- / \ / -(5-((1-(pyridazin-3-yl)pyrrolidin- 3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;(R)-3-(4-((3,5-difluorophenyl)thio)piperidin-1-yl)- / \ / -(5-((1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)- 1 ,3,4-thiadiazol-2-yl)propanamide;(R)-3-(4-(2-isopropoxyphenyl)piperidin-1-yl)- / V-(5-((1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4- thiadiazol-2-yl)propanamide;(R)-2-(2-(2-(isopropylthio)benzyl)-2,6-diazaspiro[3.4]octan-6-yl)- / \ / -(5-((1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1,3,4-thiadiazol-2-yl)acetamide;2-(1-(3-(difluoromethoxy)benzyl)-4-isopropylpiperazin-2-yl)-N-(5-(((R)-1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1,3,4-thiadiazol-2-yl)acetamide;2-(4-(2-methylbenzyl)thiomorpholin-2-yl)- / V-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1,3,4-thiadiazol-2-yl)acetamide;(R)-2-(2-(3,5-dimethylbenzyl)-2,6-diazaspiro[3 ]nonan-6-yl)- / \ / -(5-((1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1,3,4-thiadiazol-2-yl)acetamide;(R)-2-(2-(2-(isopropylthio)benzyl)-2,8-diazaspiro[4.5]decan-8-yl)- / \ / -(5-((1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1,3,4-thiadiazol-2-yl)acetamide;1-{[4-(trifluoromethoxy)phenyl]methyl}piperidin-4-yl / V-(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3- yl]amino}-1,3,4-thiadiazol-2-yl)carbamate;2-{1-[(4-methoxy-3,5-dimethylphenyl)methyl]piperidin-4-yl}- / \ / -(5-{[(3R)-1-(pyridazin-3- yl)pyrrolidin-3-yl]amino}-1,3,4-thiadiazol-2-yl)acetamide; / V-(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)-2-(1-{[4-(trifluoromethoxy)phenyl]methyl}piperidin-4-yl)acetamide;A / -(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)-2-(4-{[4-(trifluoromethoxy)phenyl]methyl}piperazin-1-yl)acetamide; / V-(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)-2-(1-{[3-(trifluoromethoxy)phenyl]methyl}piperidin-4-yl)acetamide;(3R)- / V-(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)-1-{[4-(trifluoromethoxy) phenyl]methyl}piperidine-3-carboxamide;(3S)- / V-(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)-1-{[4-(trifluoromethoxy) phenyl]methyl}piperidine-3-carboxamide;(3S)-N-(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)-1-{[3-(trifluoromethoxy) phenyl]methyl}piperidine-3-carboxamide;(3R)-N-(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)-1-{[3-(trifluoromethoxy) phenyl]methyl}piperidine-3-carboxamide; / V-(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)-2-[(3S)-1-{[3-(trifluoromethoxy)phenyl] methyl}piperidin-3-yl]acetamide; / V-(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)-2-(1-{[4-(trifluoromethoxy)phenyl]methyl}piperidin-4-yl)propanamide;(R)- / V-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)propanamide;(S)- / V-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)propanamide; / V-(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)-2-[(3R)-1-{[4-(trifluoromethoxy)phenyl] methyl}piperidin-3-yl]acetamide; / V-(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)-2-[(3 / ?)-1-{[3-(trifluoromethoxy)phenyl]methyl}piperidin-3-yl]acetamide; / V-(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)-2-[(3S)-1-{[4-(trifluoromethoxy)phenyl]methyl}piperidin-3-yl]acetamide; / V-(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)-2-(1-{[5-(trifluoromethyl)pyridin-3-yl]methyl}piperidin-4-yl)propanamide;2-(4-methyl-1-{[4-(trifluoromethoxy)phenyl]methyl}piperidin-4-yl)- / \ / -(5-{[(3R)-1-(pyridazin-3- yl)pyrrolidin-3-yl]amino}-1,3,4-thiadiazol-2-yl)acetamide;N-(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)-2-(4-{[4-(trifluoromethoxy)phenyl]methyl}-1,4-diazepan-1-yl)acetamide2-(4-{[4-(propan-2-ylsulfanyl)phenyl]methyl}piperazin-1-yl)-N-(5-{[(3R)-1-(pyridazin-3- yl)pyrrolidin-3-yl]amino}-1,3,4-thiadiazol-2-yl)acetamide;2-{3-benzyl-3-azaspiro[5.5]undecan-9-yl}- / V-(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1,3,4-thiadiazol-2-yl)acetamide;2-(1-{[4-(propan-2-ylsulfanyl)phenyl]methyl}piperidin-4-yl)-A / -(5-{[(3R)-1-(pyridazin-3- yl)pyrrolidin-3-yl]amino}-1,3,4-thiadiazol-2-yl)acetamide;2-(1-{[6-methyl-4-(trifluoromethyl)pyridin-2-yl]methyl}piperidin-4-yl)-N-(5-{[(3R)-1-(pyridazin-3- yl)pyrrolidin-3-yl]amino}-1,3,4-thiadiazol-2-yl)acetamide;2-{1-[(3,5-dimethylphenyl)methyl]piperidin-4-yl}-N-(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3- yl]amino}-1,3,4-thiadiazol-2-yl)acetamide;2-[(3S)-1-[(3,5-difluorophenyl)methyl]piperidin-3-yl]-N-(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3- yl]amino}-1,3,4-thiadiazol-2-yl)acetamide;2-[(3S)-1-{[3-(difluoromethoxy)phenyl]methyl}piperidin-3-yl]- / V-(5-{[(3R)-1-(pyridazin-3- yl)pyrrolidin-3-yl]amino}-1,3,4-thiadiazol-2-yl)acetamide;2-[(3R,5S)-3,5-dimethyl-4-{[4-(trifluoromethoxy)phenyl]methyl}piperazin-1-yl]-N-(5-{[(3R)-1- (pyridazin-3-yl)pyrrolidin-3-yl]amino}-1,3,4-thiadiazol-2-yl)acetamide;3-[(4-{[(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1,3,4-thiadiazol-2- yl)carbamoyl]methyl}piperidin-1-yl)methyl]benzoic acid;4-[(4-{[(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2- yl)carbamoyl]methyl}piperidin-1-yl)methyl]benzoic acid;2-(1-{[2-(pr°pan-2-yloxy)phenyl]methyl}piperidin-4-yl)- / \ / -(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3- yl]amino}-1,3,4-thiadiazol-2-yl)acetamide;2-(dimethylamino)- / V-(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)-2-(1- {[4-(trifluoromethoxy)phenyl]methyl}piperidin-4-yl)acetamide;2-(1-{[4-(difluoromethoxy)phenyl]methyl}piperidin-4-yl)- / V-(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3- yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;N-(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)-2-[(3 / ?)-1-{[3-(trifluoromethoxy)phenyl]methyl}pyrrolidin-3-yl]acetamide;2-[(3S)-1-[(4,4-dimethylcyclohexyl)methyl]piperidin-3-yl]- / \ / -(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide; / V-(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)-2-[(3S)-1-{[3-(trifluoromethoxy)phenyl]methyl} pyrrolidin-3-yl]acetamide;A / -(5-{[(3 / )-1 -(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)-2-(5-{[5-(trifluoromethyl)pyridin-3-yl]methyl}-5-azaspiro[2.5]octan-7-yl)acetamide;2-(5-{[5-methoxy-6-(trifluoromethyl)pyridin-2-yl]methyl}-5-azaspiro[2.5]octan-7-yl)- / \ / -(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;A / -(5-{[(3 / )-1 -(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)-2-[(1 -{[3-(trifluoromethoxy)phenyl]methyl}piperidin-4-yl)sulfanyl]acetamide;A / -(5-{[(3 / )-1 -(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)-2-[(1 -{[4-(trifluoromethoxy)phenyl]methyl}piperidin-4-yl)sulfanyl]acetamide;2-[(3S)-1-[(3-chlorophenyl)methyl]piperidin-3-yl]- / V-(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3- yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;2-(6-{[3-(difluoromethoxy)phenyl]methyl}-6-azaspiro[3.4]octan-2-yl)- / \ / -(5-{[(3R)-1-(pyridazin-3- yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;2-{3-[(4,6-dimethylpyridin-2-yl)methyl]-3-azaspiro[5.5]undecan-9-yl}-N-(5-{[(3R)-1-(pyridazin-3- yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;2-{4-[(4,4-dimethylcyclohexyl)methyl]piperazin-1-yl}- / V-(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3- yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide; / V-(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)-2-{1-[(3,3,5,5- tetramethylcyclohexyl)methyl] piperidin-4-yl}acetamide;2-(2-{[3-(difluoromethoxy)phenyl]methyl}-2-azaspiro[3.3]heptan-6-yl)- / \ / -(5-{[(3R)-1-(pyridazin-3- yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;2-{1-[(4,4-dimethylcyclohexyl)methyl]piperidin-4-yl}- / \ / -(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3- yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;3-(1-{[3-(difluoromethoxy)phenyl]methyl}piperidin-4-yl)- / V-(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3- yl]amino}-1 ,3,4-thiadiazol-2-yl)propanamide;A / -(5-{[(3 / )-1 -(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)-8-{[3-(trifluoromethoxy)phenyl]methyl}-2-oxa-8-azaspiro[4.5]decane-3-carboxamide; / V-(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)-2-{4-[(3,3,5,5- tetramethyl cyclohexyl)methyl]piperazin-1-yl}acetamide;2-{1-[methyl({[3-(trifluoromethoxy)phenyl]methyl})amino]cyclopropyl}- / \ / -(5-{[(3R)-1-(pyridazin-3- yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;2-(1-{[4-hydroxy-3-(trifluoromethoxy)phenyl]methyl}piperidin-4-yl)- / \ / -(5-{[(3 / ?)-1-(pyridazin-3- yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;2-{1 -[(2-chlorophenyl)methyl]piperidin-4-yl}-A / -(5-{[(3 ?)-1 -(pyridazin-3-yl)pyrrolidin-3-yl]amino}- 1 ,3,4-thiadiazol-2-yl)acetamide;2-(4-methyl-1-{[3-(trifluoromethoxy)phenyl]methyl}piperazin-2-yl)- / \ / -(5-{[(3R)-1-(pyridazin-3- yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;2-((S)-4-methyl-1-(3-(trifluoromethoxy)benzyl)piperazin-2-yl)- / \ / -(5-(((R)-1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;2-((R)-4-methyl-1-(3-(trifluoromethoxy)benzyl)piperazin-2-yl)- / \ / -(5-(((R)-1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;2-methoxy-N-(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)-2-(1-{[4-(trifluoromethoxy)phenyl] methyl}piperidin-4-yl)acetamide;(R)-2-methoxy- / V-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)acetamide;(S)-2-methoxy-A / -(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)acetamide;4-[(4,4-dimethylcyclohexyl)methyl]- / \ / -(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4- thiadiazol-2-yl)thiomorpholine-2-carboxamide;2-{4-[(4,4-dimethylcyclohexyl)methyl]morpholin-2-yl}- / \ / -(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3- yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;2-((R)-4-((4,4-dimethylcyclohexyl)methyl)morpholin-2-yl)- / \ / -(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;2-((S)-4-((4,4-dimethylcyclohexyl)methyl)morpholin-2-yl)- / \ / -(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;2-(1-{[3-(pr°pan-2-yloxy)pyridin-2-yl]methyl}piperidin-4-yl)- / V-(5-{[(3 / ?)-1-(pyridazin-3- yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide; / V-(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)-2-(1-{[3-(trifluoromethoxy)phenyl]methyl}azetidin-3-yl)acetamide;2-(1-{[2-(difluoromethoxy)phenyl]methyl}piperidin-4-yl)- / \ / -(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3- yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;2-(4-{[3-(propan-2-yloxy)pyridin-2-yl]methyl}-4-azaspiro[2.5]octan-7-yl)- / \ / -(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;2-({1-[(3,5-dimethylphenyl)methyl]piperidin-4-yl}sulfanyl)- / V-(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;A / -(5-{[(3 / )-1 -(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)-2-(2-{[3-(trifluoromethoxy)phenyl]methyl}-6-oxa-2-azaspiro[3.4]octan-7-yl)acetamide; / V-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-((R)-2-(3-(trifluoromethoxy)benzyl)-6-oxa-2-azaspiro[3.4]octan-7-yl)acetamide; / V-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-((S)-2-(3-(trifluoromethoxy)benzyl)-6-oxa-2-azaspiro[3.4]octan-7-yl)acetamide;2-(2-{[3-(difluoromethoxy)phenyl]methyl}-6-oxa-2-azaspiro[3.4]octan-7-yl)- / \ / -(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;2-(2,2-dimethyl-1-{[3-(propan-2-yloxy)pyridin-2-yl]methyl}piperidin-4-yl)- / \ / -(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;2-(2-{[2-(cyclopentyloxy)phenyl]methyl}-6-oxa-2-azaspiro[3.4]octan-7-yl)- / \ / -(5-{[(3R)-1- (pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;2-[(3S)-1-[(2-cyclobutoxyphenyl)methyl]piperidin-3-yl]- / \ / -(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3- yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;2-[(3S)-1-{[2-(cyclopentyloxy)phenyl] methyl}piperidin-3-yl]- / V-(5-{[(3R)-1-(pyridazin-3- yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;2-({1-[(2-cyclobutoxyphenyl)methyl]piperidin-4-yl}sulfanyl)-A / -(5-{[(3R)-1-(pyridazin-3- yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;2-(4-cyclohexylmorpholin-2-yl)- / V-(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4- thiadiazol-2-yl)acetamide;2-[(3S)-1-{[2-(3,3-difluorocyclobutoxy)phenyl]methyl}piperidin-3-yl]- / \ / -(5-{[(3R)-1-(pyridazin-3- yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;2-(4-cyclopentylmorpholin-2-yl)- / V-(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4- thiadiazol-2-yl)acetamide;2-(2-{[2-(propan-2-ylsulfanyl)phenyl]methyl}-6-oxa-2-azaspiro[3.4]octan-7-yl)- / \ / -(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide2-(1-{[(4,4-dimethylcyclohexyl)methyl] (methyl)amino}cyclopropyl)- / \ / -(5-{[(3R)-1-(pyridazin-3- yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;2-(4-hydroxy-1-{[2-(propan-2-ylsulfanyl)phenyl]methyl}piperidin-4-yl)- / \ / -(5-{[(3R)-1-(pyridazin-3- yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;2-{4-[(4,4-dimethylcyclohexyl)methyl]-1,4-diazepan-1-yl}- / V-(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;2-({1-[(3-tert-butyl-1 ,2-oxazol-5-yl)methyl]piperidin-4-yl}sulfanyl)- / \ / -(5-{[(3R)-1-(pyridazin-3- yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;2-{2-[(4,4-dimethylcyclohexyl)methyl]-6-oxa-2-azaspiro[3.4]octan-7-yl}- / \ / -(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;2-((R)-2-((4,4-dimethylcyclohexyl)methyl)-6-oxa-2-azaspiro[3.4]octan-7-yl)- / \ / -(5-(((R)-1- (pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;2-((S)-2-((4,4-dimethylcyclohexyl)methyl)-6-oxa-2-azaspiro[3.4]octan-7-yl)- / \ / -(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;2-[(1-{[2-(propan-2-yloxy)phenyl] methyl}piperidin-3-yl)sulfanyl]-A / -(5-{[(3 ?)-1 -(pyridazin-3- yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;2-(((R)-1-(2-isopropoxybenzyl)piperidin-3-yl)thio)- / \ / -(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;2-(((S)-1-(2-isopropoxybenzyl)piperidin-3-yl)thio)- / \ / -(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;2-[(1-{[2-(methylsulfanyl)phenyl]methyl}piperidin-3-yl)oxy]- / \ / -(5-{[(3R)-1-(pyridazin-3- yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;2-(((R)-1-(2-(methylthi°)benzyl)piperidin-3-yl)oxy)- / V-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;2-(((S)-1-(2-(methylthio)benzyl)piperidin-3-yl)oxy)- / V-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;2-[(1-{[2-(propan-2-ylsulfanyl)phenyl]methyl}piperidin-3-yl)oxy]-A / -(5-{[(3R)-1-(pyridazin-3- yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;2-(((R)-1-(2-(isopr°pylthio)benzyl)piperidin-3-yl)oxy)- / \ / -(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;2-(((S)-1-(2-(isopropylthio)benzyl)piperidin-3-yl)oxy)- / \ / -(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;2-[4-(4,4-dimethylcyclohexyl)morpholin-2-yl]- / V-(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;2-((S)-4-(4,4-dimethylcyclohexyl)morpholin-2-yl)- / \ / -(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;2-((R)-4-(4,4-dimethylcyclohexyl)morpholin-2-yl)- / V-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;2-[(2-{[2-(propan-2-yloxy)phenyl]methyl}-2-azaspiro[3.3]heptan-6-yl)sulfanyl]- / \ / -(5-{[(3R)-1- (pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;2-[(3S)-1-[(3,5-dimethylphenyl)methyl]piperidin-3-yl]- / V-(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3- yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;2-[(1-{[2-(propan-2-yloxy)phenyl]methyl}piperidin-4-yl)sulfanyl]- / \ / -(5-{[(3R)-1-(pyridazin-3- yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)butanamide; / V-(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)-2-{4-[(1s,4s)-4-tert- butylcyclohexyl]morpholin-2-yl}acetamide; / V-(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)-2-{4-[(1 r,4r)-4-tert- butylcyclohexyl]morpholin-2-yl}acetamide;2-[(3S)-1-[(4-ethyl-2-fluorophenyl)methyl]piperidin-3-yl]- / V-(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3- yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide; / V-(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)-2-[4-(3,3,4,4- tetramethylcyclopentyl)morpholin-2-yl]acetamide;2-[(3R)-1-[(3,5-difluorophenyl)methyl]piperidin-3-yl]- / V-(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3- yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;2-[(3S)-1-[(4-fluoro-3,5-dimethylphenyl)methyl]piperidin-3-yl]- / \ / -(5-{[(3R)-1-(pyridazin-3- yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;2-[(3S)-1-[(3-fluoro-5-methylphenyl)methyl]piperidin-3-yl]- / V-(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;2-[(3S)-1-[(4-fluoro-3-methoxy-5-methylphenyl)methyl]piperidin-3-yl]- / \ / -(5-{[(3R)-1-(pyridazin-3- yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;2-[(3S)-1-[(4-ethoxy-3,5-difluorophenyl)methyl]piperidin-3-yl]- / \ / -(5-{[(3R)-1-(pyridazin-3- yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;2-[(3S)-1-{[3-fluoro-5-(propan-2-yloxy)phenyl]methyl}piperidin-3-yl]-A / -(5-{[(3R)-1-(pyridazin-3- yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;2-{3-[(5-ethyl-3-methyl-1 ,2-oxazol-4-yl)methyl]-3-azaspiro[5.5]undecan-9-yl}-A / -(5-{[(3R)-1- (pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;2-[(3S)-1-{[3-methyl-5-(propan-2-yloxy)phenyl]methyl}piperidin-3-yl]- / \ / -(5-{[(3R)-1-(pyridazin-3- yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;2-{4-[(1 S,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl]morpholin-2-yl}- / \ / -(5-{[(3R)-1-(pyridazin-3- yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;2-{(R)-4-[(1 S,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl]morpholin-2-yl}- / V-(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;2-{(S)-4-[(1 S,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl]morpholin-2-yl}- / V-(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;2-[(3S)-1-[(3-ethoxy-4,5-difluorophenyl)methyl]piperidin-3-yl]- / \ / -(5-{[(3R)-1-(pyridazin-3- yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;2-[(3S)-1-[(3-fluoro-5-methoxy-4-methylphenyl)methyl]piperidin-3-yl]- / \ / -(5-{[(3R)-1-(pyridazin-3- yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;2-[(3S)-1-{[3-(difluoromethoxy)-5-methylphenyl]methyl}piperidin-3-yl]- / \ / -(5-{[(3R)-1-(pyridazin-3- yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;2-[(3S)-1-[(2-ethyl-1-benzofuran-3-yl)methyl]piperidin-3-yl]- / V-(5-{[(3R)-1-(pyridazin-3- yl)pyrrolidin-3-yl]amino}-1,3,4-thiadiazol-2-yl)acetamide;2-[(3S)-1-[(3-fluoro-4,5-dimethylphenyl)methyl]piperidin-3-yl]- / V-(5-{[(3R)-1-(pyridazin-3- yl)pyrrolidin-3-yl]amino}-1,3,4-thiadiazol-2-yl)acetamide;2-[(3S)-1-[(2,5-dimethylthiophen-3-yl)methyl]piperidin-3-yl]- / \ / -(5-{[(3R)-1-(pyridazin-3- yl)pyrrolidin-3-yl]amino}-1,3,4-thiadiazol-2-yl)acetamide;2-({1-[(2,5-dimethylthiophen-3-yl)methyl]piperidin-4-yl}sulfanyl)- / \ / -(5-{[(3R)-1-(pyridazin-3- yl)pyrrolidin-3-yl]amino}-1,3,4-thiadiazol-2-yl)acetamide;2-[(3S)-1-[(3,5-difluorophenyl)methyl]piperidin-3-yl]- / V-(5-{methyl[(3R)-1-(pyridazin-3- yl)pyrrolidin-3-yl]amino}-1,3,4-thiadiazol-2-yl)acetamide;2-[4-(4,4-dimethylcyclohexyl)morpholin-2-yl]- / V-(5-{methyl[(3R)-1-(pyridazin-3-yl)pyrrolidin-3- yl]amino}-1,3,4-thiadiazol-2-yl)acetamide;2-[4-(4,4-dimethylcyclohexyl)piperazin-1-yl]- / V-(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1,3,4-thiadiazol-2-yl)acetamide;2-({1-[(1-tert-butyl-1 H-pyrrol-3-yl)methyl]piperidin-4-yl}sulfanyl)- / V-(5-{[(3R)-1-(pyridazin-3- yl)pyrrolidin-3-yl]amino}-1,3,4-thiadiazol-2-yl)acetamide;2-({1-[(1-tert-butyl-1H-pyrazol-4-yl)methyl]piperidin-4-yl}sulfanyl)- / \ / -(5-{[(3 / ?)-1-(pyridazin-3- yl)pyrrolidin-3-yl]amino}-1,3,4-thiadiazol-2-yl)acetamide;N-(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)-2-[4-(3,3,5,5- tetramethylcyclohexyl)piperazin-1-yl]acetamide;N-(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)-2-(4-{spiro[4.5]decan-8- yl}piperazin-1-yl)acetamide;2-(4,4-difluoro-1-{spiro[2.5]octan-6-yl}piperidin-3-yl)-N-(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3- yl]amino}-1,3,4-thiadiazol-2-yl)acetamide;2-(Tcyclohexyl-4,4-difluoropiperidin-3-yl)-N-(5-{[(3R)-T(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;2-[1-(4,4-dimethylcyclohexyl)-4,4-difluoropiperidin-3-yl]-N-(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3- yl]amino}-1,3,4-thiadiazol-2-yl)acetamide;2-[4-(4,4-diethylcyclohexyl)morpholin-2-yl]-N-(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1,3,4-thiadiazol-2-yl)acetamide;2-((R)-4-(4,4-diethylcyclohexyl)morpholin-2-yl)-N-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1,3,4-thiadiazol-2-yl)acetamide;2-((S)-4-(4,4-diethylcyclohexyl)morpholin-2-yl)-N-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1,3,4-thiadiazol-2-yl)acetamide;N-(5-(((R)-1-(1 ,2,4-triazin-6-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-(4-(4,4- dimethylcyclohexyl)morpholin-2-yl)acetamide;N-(5-{[(3R)-1-(6-chloropyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)-2-[(3S)-1-[(3,5- difluorophenyl)methyl]piperidin-3-yl]acetamide;2-[4-(2-cyclohexylpropan-2-yl)morpholin-2-yl]-N-(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3- yl]amino}-1,3,4-thiadiazol-2-yl)acetamide;2-[(R)-4-(2-cyclohexylpropan-2-yl)morpholin-2-yl]- / V-(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3- yl]amino}-1,3,4-thiadiazol-2-yl)acetamide;2-[(S)-4-(2-cyclohexylpropan-2-yl)morpholin-2-yl]- / V-(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3- yl]amino}-1,3,4-thiadiazol-2-yl)acetamide;2-(Tcycloheptyl-4,4-difluoropiperidin-3-yl)-N-(5-{[(3R)-T(pyridazin-3-yl)pyrrolidin-3-yl]amino}- 1,3,4-thiadiazol-2-yl)acetamide; isopropyl (R)-4-((4-(2-oxo-2-((5-((1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2- yl)amino)ethyl)piperidin-1-yl)methyl)benzoate; isopropyl (R)-3-((4-(2-oxo-2-((5-((1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2- yl)amino)ethyl)piperidin-1-yl)methyl)benzoate;(R)-2-(1-(3-methyl-5-(trifluoromethoxy)benzyl)piperidin-4-yl)-N-(5-((1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1,3,4-thiadiazol-2-yl)acetamide;(R)-N-(5-((1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-(1-(2,4,6- trimethylbenzyl)piperidin-4-yl)acetamide;(R)-2-(1-(2-methyl-4-(trifluoromethoxy)benzyl)piperidin-4-yl)-N-(5-((1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1,3,4-thiadiazol-2-yl)acetamide;(R)-2-(1-(3-methyl-4-(trifluoromethyl)benzyl)piperidin-4-yl)-N-(5-((1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1,3,4-thiadiazol-2-yl)acetamide;(R)-N-(5-((1-(Pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-(T((5-(trifluoromethyl)pyridin-3-yl)methyl)piperidin-4-yl)acetamide;(R)-2-(1-((5-methoxy-6-(trifluoromethyl)pyridin-2-yl)methyl)piperidin-4-yl)-N-(5-((1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1,3,4-thiadiazol-2-yl)acetamide;2-((S)-1-(3-methyl-5-(trifluoromethoxy)benzyl)piperidin-3-yl)-N-(5-(((R)-1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1,3,4-thiadiazol-2-yl)acetamide;(R)-2-(1-(3-(difluoromethoxy)-5-methylbenzyl)piperidin-4-yl)-N-(5-((1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1,3,4-thiadiazol-2-yl)acetamide; isobutyl (R)-4-((4-(2-oxo-2-((5-((1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2- yl)amino)ethyl)piperidin-1-yl)methyl)picolinate;(R)-N-(5-((1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-(1-(2-(trifluoromethoxy)benzyl)piperidin-4-yl)acetamide;(R)-2-(1-(4-fluoro-2-(trifluoromethoxy)benzyl)piperidin-4-yl)-N-(5-((1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1,3,4-thiadiazol-2-yl)acetamide;(R)-2-(1-(2-(difluoromethoxy)-5-methylbenzyl)piperidin-4-yl)-N-(5-((1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1,3,4-thiadiazol-2-yl)acetamide;(R)-2-(1-(2-(isopropylthio)benzyl)piperidin-4-yl)-N-(5-((1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1,3,4-thiadiazol-2-yl)acetamide;(R)-2-((1-(2-isopropoxybenzyl)piperidin-4-yl)thio)-N-(5-((1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1,3,4-thiadiazol-2-yl)acetamide;(R)-2-(1-(3-isopropoxybenzyl)piperidin-4-yl)-N-(5-((1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4- thiadiazol-2-yl)acetamide;(R)-2-(1-(2-cyclobutoxybenzyl)piperidin-4-yl)-N-(5-((1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1,3,4-thiadiazol-2-yl)acetamide;(R)-2-(1-(2-isopropoxy-4-methylbenzyl)piperidin-4-yl)-N-(5-((1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1,3,4-thiadiazol-2-yl)acetamide;(R)-2-(2-(3-(difluoromethoxy)benzyl)-2-azaspiro[3.5]nonan-7-yl)-N-(5-((1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1,3,4-thiadiazol-2-yl)acetamide;(R)-N-(5-((1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-(2-(3-(trifluoromethoxy)benzyl)-2-azaspiro[3.3]heptan-6-yl)acetamide;2-((S)-1-(2-isopropoxybenzyl)piperidin-3-yl)-N-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1,3,4-thiadiazol-2-yl)acetamide;2-((R)-1-(2-isopropoxybenzyl)piperidin-3-yl)-N-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1,3,4-thiadiazol-2-yl)acetamide;2-((S)-1-(2-isopropoxyphenethyl)piperidin-3-yl)-N-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1,3,4-thiadiazol-2-yl)acetamide;2-((R)-1-(2-isopropoxyphenethyl)piperidin-3-yl)-N-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1,3,4-thiadiazol-2-yl)acetamide;8-(3,5-dimethylbenzyl)-N-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2- oxa-8-azaspiro[4.5]decane-3-carboxamide;8-(2-isopropoxybenzyl)-N-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-oxa-8-azaspiro[4.5]decane-3-carboxamide;(R)-2-(3-((6-(difluoromethyl)pyridin-3-yl)methyl)-3-azaspiro[5.5]undecan-9-yl)-N-(5-((1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1,3,4-thiadiazol-2-yl)acetamide;(R)-N-(5-((1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-(3-((5-(trifluoromethyl)pyridin-2-yl)methyl)-3-azaspiro[5.5]undecan-9-yl)acetamide;(R)-N-(5-((1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-(3-((2,4,6- trimethylpyridin-3-yl)methyl)-3-azaspiro[5.5]undecan-9-yl)acetamide;(R)-2-(3-((5-chloropyridin-2-yl)methyl)-3-azaspiro[5.5]undecan-9-yl)-N-(5-((1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1,3,4-thiadiazol-2-yl)acetamide;(R)-2-(3-((5-bromopyridin-3-yl)methyl)-3-azaspiro[5.5]undecan-9-yl)-N-(5-((1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1,3,4-thiadiazol-2-yl)acetamide;(R)-N-(5-((1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-(6-(3-(trifluoromethoxy)benzyl)-6-azaspiro[3.4]octan-2-yl)acetamide;N-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-((2r,4R)-6-(3-(trifluoromethoxy)benzyl)-6-azaspiro[3.4]octan-2-yl)acetamide;N-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-((2s,4S)-6-(3-(trifluoromethoxy)benzyl)-6-azaspiro[3.4]octan-2-yl)acetamide;(R)-2-(6-(3-(difluoromethoxy)-5-methylbenzyl)-6-azaspiro[3.4]octan-2-yl)-N-(5-((1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1,3,4-thiadiazol-2-yl)acetamide;(R)-2-(6-(2-isopropoxy-4-methylbenzyl)-6-azaspiro[3.4]octan-2-yl)-N-(5-((1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1,3,4-thiadiazol-2-yl)acetamide;2-((2r,4R)-6-(2-isopropoxy-4-methylbenzyl)-6-azaspiro[3.4]octan-2-yl)-N-(5-(((R)-1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1,3,4-thiadiazol-2-yl)acetamide;2-((2s,4S)-6-(2-isopropoxy-4-methylbenzyl)-6-azaspiro[3.4]octan-2-yl)-N-(5-(((R)-1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1,3,4-thiadiazol-2-yl)acetamide;8-(3-(difluoromethoxy)benzyl)-N-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol- 2-yl)-2-oxa-8-azaspiro[4.5]decane-3-carboxamide;(R)-8-(3-(difluoromethoxy)benzyl)- / V-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4- thiadiazol-2-yl)-2-oxa-8-azaspiro[4.5]decane-3-carboxamide;(S)-8-(3-(difluoromethoxy)benzyl)- / V-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4- thiadiazol-2-yl)-2-oxa-8-azaspiro[4.5]decane-3-carboxamide;(R)-2-(3-((3-cyclobutoxypyridin-2-yl)methyl)-3-azaspiro[5.5]undecan-9-yl)-N-(5-((1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1,3,4-thiadiazol-2-yl)acetamide;2-(1-(3,5-dimethylbenzyl)piperidin-4-yl)-2-methoxy-N-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1,3,4-thiadiazol-2-yl)acetamide;2-(1-(2-cyclobutoxybenzyl)piperidin-4-yl)-2-methoxy-N-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1,3,4-thiadiazol-2-yl)acetamide;2-(1-(2-(isopr°pylthio)benzyl)piperidin-4-yl)-2-methoxy-N-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1,3,4-thiadiazol-2-yl)acetamide;(R)-2-(3-((5-chloropyridin-3-yl)methyl)-3-azaspiro[5.5]undecan-9-yl)-N-(5-((1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1,3,4-thiadiazol-2-yl)acetamide;(R)-2-(3-((4-bromopyridin-2-yl)methyl)-3-azaspiro[5.5]undecan-9-yl)-N-(5-((1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1,3,4-thiadiazol-2-yl)acetamide;(R)-2-(3-((5-bromopyridin-2-yl)methyl)-3-azaspiro[5.5]undecan-9-yl)-N-(5-((1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1,3,4-thiadiazol-2-yl)acetamide;2-(4-ethyl-1-(3-(trifluoromethoxy)benzyl)piperazin-2-yl)-N-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;2-((R)-4-ethyl-1-(3-(trifluoromethoxy)benzyl)piperazin-2-yl)- / \ / -(5-(((R)-1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;2-((S)-4-ethyl-1-(3-(trifluoromethoxy)benzyl)piperazin-2-yl)- / \ / -(5-(((R)-1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;2-(1-(2-isopropoxybenzyl)piperidin-4-yl)-N-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4- thiadiazol-2-yl)butanamide;(R)-2-(1-(2-isopropoxybenzyl)piperidin-4-yl)- / V-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)butanamide;(S)-2-(1-(2-isopropoxybenzyl)piperidin-4-yl)- / V-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)butanamide;(R)-3-(1-(2-isopropoxybenzyl)piperidin-4-yl)-N-(5-((1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4- thiadiazol-2-yl)propanamide;(R)-2-((1-(2-(isopropylthi°)benzyl)piperidin-4-yl)oxy)-N-(5-((1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;8-(2-cyclobutoxybenzyl)-N-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-oxa-8-azaspiro[4.5]decane-3-carboxamide;(R)-8-(2-cyclobutoxybenzyl)-A / -(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2- yl)-2-oxa-8-azaspiro[4.5]decane-3-carboxamide;(S)-8-(2-cyclobutoxybenzyl)- / V-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2- yl)-2-oxa-8-azaspiro[4.5]decane-3-carboxamide;2-((R)-2-(2-(isopropylthio)benzyl)-6-oxa-2-azaspiro[3.4]octan-7-yl)- / \ / -(5-(((R)-1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;2-((S)-2-(2-(isopropylthio)benzyl)-6-oxa-2-azaspiro[3.4]octan-7-yl)- / \ / -(5-(((R)-1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;2-cyclobutyl-2-(1-(2-methylbenzyl)piperidin-4-yl)-N-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;(R)-2-cyclobutyl-2-(1-(2-methylbenzyl)piperidin-4-yl)- / V-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;(S)-2-cyclobutyl-2-(1-(2-methylbenzyl)piperidin-4-yl)- / \ / -(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;3-cyclopropyl-2-(1-(2-methylbenzyl)piperidin-4-yl)-N-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)propanamide;(R)-3-cyclopropyl-2-(1-(2-methylbenzyl)piperidin-4-yl)- / \ / -(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)propanamide;(S)-3-cyclopropyl-2-(1-(2-methylbenzyl)piperidin-4-yl)- / V-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)propanamide;3-methyl-2-(1-(2-methylbenzyl)piperidin-4-yl)-N-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)butanamide;(R)-3-methyl-2-(1-(2-methylbenzyl)piperidin-4-yl)- / V-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)butanamide;(S)-3-methyl-2-(1-(2-methylbenzyl)piperidin-4-yl)- / \ / -(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)butanamide;2-(4-cyclohexylmorpholin-3-yl)-N-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4- thiadiazol-2-yl)acetamide;2-((R)-4-cyclohexylmorpholin-3-yl)- / V-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4- thiadiazol-2-yl)acetamide;2-((S)-4-cyclohexylmorpholin-3-yl)- / V-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4- thiadiazol-2-yl)acetamide;2-[4-(4,4-dimethylcyclohexyl)-1 ,4-oxazepan-2-yl]-N-(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3- yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;(R)-2-(1-(4-(difluoromethoxy)benzyl)piperidin-4-yl)-2-ethoxy-N-(5-(((R)-1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;(S)-2-(1-(4-(difluoromethoxy)benzyl)piperidin-4-yl)-2-ethoxy-N-(5-(((R)-1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;2-((1-(1-(2-isopropoxyphenyl)ethyl)piperidin-4-yl)thio)-N-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;2-((1-((R)-1T2-isopropoxyphenyl)ethyl)piperidin-4-yl)thio)- / \ / -(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;2-((1-((S)-1-(2-isopropoxyphenyl)ethyl)piperidin-4-yl)thio)- / \ / -(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;2-((S)-1-(3,5-difluoro-4-methylbenzyl)piperidin-3-yl)-N-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;2-((S)-1-(3,5-difluoro-2-methylbenzyl)piperidin-3-yl)-N-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;2-(1-(3,5-difluorobenzyl)azepan-3-yl)-N-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4- thiadiazol-2-yl)acetamide;(R)-2-(methyl(2-(1-(3-(trifluorometh°xy)benzyl)piperidin-4-yl)propan-2-yl)amino)-N-(5-((1- (pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;2-(4-((4,4-dimethylcyclohexyl)methyl)thiomorpholin-2-yl)-N-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;2-((3S)-1-(1-(3,5-difluorophenyl)ethyl)piperidin-3-yl)-N-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;2-((S)-1-((S)-1-(3,5-difluorophenyl)ethyl)piperidin-3-yl)- / V-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;2-((S)-1-((R)-1-(3,5-difluorophenyl)ethyl)piperidin-3-yl)- / V-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;2-(4-(4-isopropylcyclohexyl)morpholin-2-yl)-N-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;2-((S)-4-((1r,4S)-4-isopropylcyclohexyl)morpholin-2-yl)- / \ / -(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;2-((R)-4-((1r,4R)-4-isopropylcyclohexyl)morpholin-2-yl)- / \ / -(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;2-((S)-4-((1s,4R)-4-isopropylcyclohexyl)morpholin-2-yl)- / \ / -(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;2-((R)-4-((1s,4S)-4-isopropylcyclohexyl)morpholin-2-yl)- / \ / -(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;(R)-2-(2-(3-fluoro-5-methylbenzyl)-2,6-diazaspiro[3.4]octan-6-yl)-N-(5-((1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;2-((R)-1-(3-(difluoromethoxy)benzyl)-4-isopropylpiperazin-2-yl)-A / -(5-(((R)-1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;2-((S)-1-(3-(difluoromethoxy)benzyl)-4-isopropylpiperazin-2-yl)- / \ / -(5-(((R)-1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;N-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-(4-(spiro[2.5]octan-6- yl)morpholin-2-yl)acetamide; / V-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-((S)-4-(spiro[2.5]octan-6-yl)morpholin-2-yl)acetamide; / V-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-((R)-4-(spiro[2.5]octan-6-yl)morpholin-2-yl)acetamide;N-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-(4-(spiro[3.5]nonan-2- yl)morpholin-2-yl)acetamide; / V-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-((S)-4-(spiro[3.5]nonan-2-yl)morpholin-2-yl)acetamide; / V-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-((R)-4-(spiro[3.5]nonan-2-yl)morpholin-2-yl)acetamide;(R)-2-(8-(2-(isopropylthio)benzyl)-2,8-diazaspiro[4.5]decan-2-yl)-N-(5-((1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;2-((S)-1-(4-ethyl-3-fluorobenzyl)piperidin-3-yl)-N-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)- 1 ,3,4-thiadiazol-2-yl)acetamide;2-((3S)-1-(1T3-fluoro-4-methylphenyl)ethyl)piperidin-3-yl)-N-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;2-((S)-1-((S)-1-(3-fluoro-4-methylphenyl)ethyl)piperidin-3-yl)- / \ / -(5-(((R)-1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;2-((S)-1-((R)-1T3Tlu°r°-4-methylphenyl)ethyl)piperidin-3-yl)- / \ / -(5-(((R)-1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;2-((3S)-1-(1T2-fluoro-4-methylphenyl)ethyl)piperidin-3-yl)-N-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;2-((S)-1-((S)-1-(2-fluoro-4-methylphenyl)ethyl)piperidin-3-yl)- / \ / -(5-(((R)-1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;2-((S)-1-((R)-1T2-fluoro-4-methylphenyl)ethyl)piperidin-3-yl)- / V-(5-(((R)-1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;N-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-(4-(spiro[3.4]octan-2- yl)morpholin-2-yl)acetamide; / V-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-((S)-4-(spiro[3.4]octan-2-yl)morpholin-2-yl)acetamide;A / -(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-((R)-4-(spiro[3.4]octan-2-yl)morpholin-2-yl)acetamide;(R)-2-(2-(3-fluoro-5-methylbenzyl)-2,6-diazaspiro[3.5]nonan-6-yl)-N-(5-((1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;(R)-2-(2-(2-(methylthio)benzyl)-2,6-diazaspiro[3.5]nonan-6-yl)-N-(5-((1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;(R)-2-(2-(2-(isopropylthio)benzyl)-2,6-diazaspiro[3.5]nonan-6-yl)-N-(5-((1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;N-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-(4-(spiro[4.5]decan-8- yl)morpholin-2-yl)acetamide; / V-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-((R)-4-(spiro[4.5]decan-8-yl)morpholin-2-yl)acetamide; / V-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-((S)-4-(spiro[4.5]decan-8-yl)morpholin-2-yl)acetamide;N-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-(4-(spiro[3.5]nonan-7- yl)morpholin-2-yl)acetamide;N-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-((R)-4-(spiro[3.5]nonan-7-yl)morpholin-2-yl)acetamide;N-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-((S)-4- (spiro[3.5]nonan-7-yl)morpholin-2-yl)acetamide; tert-butyl 4-(((S)-3-(2-((5-(((R)-1-(6-chloropyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2- yl)amino)-2-oxoethyl)piperidin-1-yl)methyl)piperidine-1 -carboxylate;2-(4-((4,4-dimethylcyclohexyl)methyl)-1-methylpiperazin-2-yl)-N-(5-(((R)-1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;2-((R)-4-((4,4-dimethylcyclohexyl)methyl)-1-methylpiperazin-2-yl)- / \ / -(5-(((R)-1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;2-((S)-4-((4,4-dimethylcyclohexyl)methyl)-1-methylpiperazin-2-yl)- / \ / -(5-(((R)-1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;2-((R)-4-((4,4-dimethylcyclohexyl)methyl)-1-methylpiperazin-2-yl)N-(5-(((R)-1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;2-((S)-4-((4,4-dimethylcyclohexyl)methyl)-1-methylpiperazin-2-yl)-N-(5-(((R)-1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;N-(5-(((R)-1-(6-chloropyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-(4-(4,4- dimethylcyclohexyl)morpholin-2-yl)acetamide;N-(5-(((R)-1-(6-chloropyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-((S)-4-(4,4-dimethylcyclohexyl)morpholin-2-yl)acetamide;N-(5-(((R)-1-(6-chloropyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-((R)-4-(4,4-dimethylcyclohexyl)morpholin-2-yl)acetamide;2-(4-(2,4-dimethylpentan-3-yl)morpholin-2-yl)-N-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)- 1 ,3,4-thiadiazol-2-yl)acetamide;2-((S)-1-(3,5-difluorobenzyl)piperidin-3-yl)-N-(5-(((3S,4S)-4-fluoro-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;2-[4-(4,4-dimethylcyclohexyl)-1-methylpiperazin-2-yl]-N-(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3- yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;2-[(R)-4-(4,4-dimethylcyclohexyl)-1-methylpiperazin-2-yl]-N-(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;2-[(S)-4-(4,4-dimethylcyclohexyl)-1-methylpiperazin-2-yl]-N-(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;2-[4-(4,4-dimethylcyclohexyl)thiomorpholin-2-yl]-N-(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3- yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;N-(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)-2-(4-{spiro[4.5]decan-8- yl}thiomorpholin-2-yl)acetamide;2-(4-{bicyclo[2.2.2]octan-1-yl}morpholin-2-yl)-N-(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}- 1 ,3,4-thiadiazol-2-yl)acetamide;(R)-N-(5-((1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-(4-(3-(trifluoromethoxy)benzyl)piperazin-1-yl)acetamide;(R)-N-(5-((1-(6-chloropyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-(4-(4-(trifluoromethoxy)benzyl)piperazin-1-yl)acetamide;(R)-2-(4-(2-chloro-4-(trifluoromethyl)benzyl)piperazin-1-yl)-N-(5-((1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1,3,4-thiadiazol-2-yl)acetamide;(R)-2-(4-(3-chloro-5-(trifluoromethyl)benzyl)piperazin-1-yl)-N-(5-((1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1,3,4-thiadiazol-2-yl)acetamide;(R)-N-(5-((1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-(4-(2-(trifluoromethoxy)benzyl)piperazin-1-yl)acetamide;(R)-2-(4-(3-fluoro-4-(trifluoromethyl)benzyl)piperazin-1-yl)-N-(5-((1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1,3,4-thiadiazol-2-yl)acetamide;(R)-2-(4-(3-bromo-5-fluorobenzyl)piperazin-1-yl)-N-(5-((1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1,3,4-thiadiazol-2-yl)acetamide;(R)-2-(4-(3-methoxy-4-(trifluoromethyl)benzyl)piperazin-1-yl)-N-(5-((1-(pyridazin-3-yl)pyrrolidin- 3-yl)amino)-1,3,4-thiadiazol-2-yl)acetamide;(R)-2-(4-(4-chloro-3-fluorobenzyl)piperazin-1-yl)-N-(5-((1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1,3,4-thiadiazol-2-yl)acetamide;(R)-2-(4-(3-chloro-5-fluorobenzyl)piperazin-1-yl)-N-(5-((1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1,3,4-thiadiazol-2-yl)acetamide;(R)-2-(4-(3,4-difluorobenzyl)piperazin-1-yl)-N-(5-((1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1,3,4- thiadiazol-2-yl)acetamide;(R)-2-(4-(3,5-difluorobenzyl)piperazin-1-yl)-N-(5-((1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1,3,4- thiadiazol-2-yl)acetamide;(R)-2-(4-(3,5-difluoro-4-methoxybenzyl)piperazin-1-yl)-N-(5-((1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1,3,4-thiadiazol-2-yl)acetamide;N-(5-(((3S,4S)-4-fluoro-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-(4-(4-(trifluoromethoxy)benzyl)piperazin-1-yl)acetamide;(R)-2-(4-(2-chloro-5-(trifluoromethoxy)benzyl)piperazin-1-yl)-N-(5-((1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1,3,4-thiadiazol-2-yl)acetamide;(R)-2-(4-(3-chloro-4-(trifluoromethoxy)benzyl)piperazin-1-yl)-N-(5-((1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1,3,4-thiadiazol-2-yl)acetamide;(R)-2-(4-(3-(difluoromethoxy)-4-methylbenzyl)piperazin-1-yl)-N-(5-((1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1,3,4-thiadiazol-2-yl)acetamide;((R)-2-(4-(3,5-dichloro-4-methylbenzyl)piperazin-1-yl)-N-(5-((1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1,3,4-thiadiazol-2-yl)acetamide;(R)-2-(4-(2,4-dichloro-6-fluorobenzyl)piperazin-1-yl)-N-(5-((1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1,3,4-thiadiazol-2-yl)acetamide;(R)-2-(4-(5-fluoro-2-(trifluoromethyl)benzyl)piperazin-1-yl)-N-(5-((1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1,3,4-thiadiazol-2-yl)acetamide;(R)-2-(4-(3-fluoro-5-(trifluoromethyl)benzyl)piperazin-1-yl)-N-(5-((1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1,3,4-thiadiazol-2-yl)acetamide;(R)-2-(4-((7-fluoro-2,3-dihydro-1 H-inden-5-yl)methyl)piperazin-1-yl)-N-(5-((1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1,3,4-thiadiazol-2-yl)acetamide;(R)-2-(4-(5-chloro-2-(difluoromethoxy)benzyl)piperazin-1-yl)-N-(5-((1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1,3,4-thiadiazol-2-yl)acetamide;(R)-2-(4-(2,3-difluorobenzyl)piperazin-1-yl)-N-(5-((1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1,3,4- thiadiazol-2-yl)acetamide; and(R)-2-(4-(3-difluoromethoxy)benzyl)piperazin-1-yl)-N-(5-((1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)- 1,3,4-thiadiazol-2-yl)acetamide; or a salt and / or solvate of any one thereof such as a pharmaceutically acceptable salt and / or solvate thereof.

40. The compound or a salt and / or solvate thereof according to any one of claims 1 to 39 which is a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof.

41. The pharmaceutically acceptable salt and solvate according to claim 40.

42. The pharmaceutically acceptable salt according to claim 40.

43. The pharmaceutically acceptable solvate according to claim 40.

44. The compound according to any one of claims 1 to 39.

45. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt and / or solvate thereof according to any one of claims 40 to 44 and one or more pharmaceutically acceptable diluents or carriers.

46. A compound or pharmaceutically acceptable salt and / or solvate thereof according to any one of claims 40 to 44 or a pharmaceutical composition according to claim 45 for use as a medicament.

47. A compound or a pharmaceutically acceptable salt and / or solvate thereof according to anyone of claims 40 to 44 or a pharmaceutical composition according to claim 45 for use in treating or preventing fibrotic and / or inflammatory diseases.

48. Use of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof according to any one of claims 40 to 44 or a pharmaceutical composition according to claim 45 in the manufacture of a medicament for treating or preventing fibrotic and / or inflammatory diseases.

49. A method of treating or preventing fibrotic and / or inflammatory diseases which comprises administering of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof according to any one of claims 40 to 44, or a pharmaceutical composition according to claim 45.

50. The compound or pharmaceutically acceptable salt and / or solvate thereof for use according to claim 47, the pharmaceutical composition for use according to claim 47, use according to claim 48 or the method according to claim 49, wherein the fibrotic and / or inflammatory disease is a fibrotic and / or inflammatory disease of the lung.

51. The compound or pharmaceutically acceptable salt and / or solvate thereof for use according to claim 47, the pharmaceutical composition for use according to claim 47, use according to claim 48 or the method according to claim 49, wherein the fibrotic and / or inflammatory disease is an interstitial lung disease.

52. The compound or pharmaceutically acceptable salt and / or solvate thereof for use, pharmaceutical composition for use, use or method according to claim 51 , wherein the interstitial lung disease is selected from the group consisting of idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, lung cancer, radiation induced fibrosis, pulmonary hypertension, asthma, respiratory viral infection and long covid.

53. The compound or pharmaceutically acceptable salt and / or solvate thereof for use according to claim 47, the pharmaceutical composition for use according to claim 47, use according to claim 48 or the method according to claim 49, wherein the fibrotic and inflammatory disease is selected from the group consisting of diabetes, non-alcoholic fatty liver disease / cirrhosis, chronic kidney disease, osteoporosis, osteoarthritis and obesity.

54. The compound or pharmaceutically acceptable salt and / or solvate thereof for use according to claim 47, the pharmaceutical composition for use according to claim 47, useaccording to claim 48 or the method according to claim 49, wherein the fibrotic disease is fibrosis or non-alcoholic steatohepatitis.

55. The compound or pharmaceutically acceptable salt and / or solvate thereof for use according to claim 47, the pharmaceutical composition for use according to claim 47, use according to claim 48 or the method according to claim 49, wherein the inflammatory disease is selected from the group consisting of inflammation psoriasis, psoriatic arthritis, hidradenitis suppurativa, rheumatoid arthritis, ankylosing spondylitis and inflammatory bowel disease.

56. A compound selected from the group consisting of: a compound of formula (XII):wherein R2, R3, R5, R8, m, n, X, A and D are as in any one of claims 1 to 39 and; a compound of formula (XVI):wherein R2, R3, R4, m, n, o, X, Y, A and B are as in any one of claims 1 to 39, and PG2is a carboxylic acid protecting group such as methyl or benzyl; or a salt, such as a pharmaceutically acceptable salt thereof of any one thereof.

57. A process for the preparation of a compound of formula (I), or a salt such as a pharmaceutically acceptable salt thereof, which comprises:(a) reacting a compound of formula (III):or a salt such as a pharmaceutically acceptable salt thereof; with a compound of formula (II):or a salt such as a pharmaceutically acceptable salt thereof; wherein R2, R3, R4, R5, R8, m, n, o, X, Y, A and B are as defined in any one of claims 1 to 39;(b) reacting a compound of formula (XII):or a salt such as a pharmaceutically acceptable salt thereof; with a compound of formula (XI):or a salt such as a pharmaceutically acceptable salt thereof; wherein R2, R3, R4, R5, R8, m, n, o, X, Y, A and B are as defined in any one of claims 1 to 39; or(c) reacting a compound of formula (XII):or a salt such as a pharmaceutically acceptable salt thereof; with a compound of formula (XI):or a salt such as a pharmaceutically acceptable salt thereof; wherein R2, R3, R4, R5, R8, m, n, o, X, Y, A and B are as defined in any one of claims 1 to 39 and LG is a leaving group such as halo e.g. chloro.

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