Thiadiazoles as glutaminase 1 inhibitors

Abstract

The invention relates to compounds of formula (I) (Formula (I)) which are useful as glutaminase 1 inhibitors.

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 monocrotaline 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, WO’539 and WO’301 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] B is selected from the group consisting of; wherein R1is selected from the group consisting of H, halo, C1.4 alkyl, C1.4 haloalkyl, NR1aR1 b, COOR1cand 4-7 membered heterocyclyl-CH2C(=O)NH- wherein the 4-7 membered heterocyclyl is optionally substituted by C1.3 alkyl or C3-7 cycloalkyl;

[0016] R1aand R1 bare independently H or -C(O)C i-salkyl;

[0017] R1cis H or C1.3 alkyl;

[0018] R2is selected from the group consisting of H, C1.4 alkyl, C1.4 alkoxy, NR2aR2b, C3-7 cycloalkyl and 4-7 membered heterocyclyl wherein the 4-7 membered heterocyclyl is optionally substituted by one, two or three R2c;

[0019] R2Cis selected from the group consisting of C1.3 alkyl, C1.3 thioalkyl and C3-6 cycloalkyl;

[0020] R2aand R2bare independently C1.3 alkyl optionally substituted with OH;

[0021] R3is selected from the group consisting of halo, hydroxy, C1.4 alkyl, C1.4 alkoxy, C1.4 haloalkyl, C1.4 haloalkoxy and phenyl;

[0022] R4is H or halo;

[0023] R5is H or C1.3 alkyl;

[0024] A is selected from the group consisting of C5-10 cycloalkyl and Ce-12 spirocycloalkyl, wherein one CH2 group in the spirocycloalkyl group is optionally replaced by NH, and wherein the cycloalkyl group is optionally fused to phenyl wherein the phenyl is optionally substituted by halo; m is 0 or 1 ; and n is 0, 1 , 2, 3 or 4; or a salt and / or solvate thereof.

[0025] The present invention also provides a compound of formula (I’): wherein:

[0026] R1is selected from the group consisting of H, halo, C1.4 alkyl, C1.4 haloalkyl, NH2, and 4-7 membered heterocyclyl-CH2C(=O)NH- wherein the 4-7 membered heterocyclyl is optionally substituted by C1.3 alkyl or C3-7 cycloalkyl;

[0027] R2is selected from the group consisting of H, C1.4 alkyl, C1.4 alkoxy, NR2aR2b, C3-7 cycloalkyl and 4-7 membered heterocyclyl wherein the 4-7 membered heterocyclyl is optionally substituted by R2cwherein R2cis C1.3 alkyl or C3-6 cycloalkyl; wherein R2aand R2bare independently C1.3 alkyl optionally substituted with OH;

[0028] R3is selected from the group consisting of halo, hydroxy, C1.4 alkyl, C1.4 alkoxy, C1.4 haloalkyl, C1.4 haloalkoxy and phenyl;

[0029] R4is H or halo;

[0030] A is selected from the group consisting of C5-10 cycloalkyl and Ce-12 spirocycloalkyl, wherein one CH2 group in the spirocycloalkyl group is optionally replaced by NH, and wherein the cycloalkyl group is optionally fused to phenyl wherein the phenyl is optionally substituted by halo; m is 0 or 1 ; and n is 0, 1 , 2, 3 or 4; or a salt and / or solvate thereof.

[0031] Detailed description of the invention

[0032] Compounds of formula (I)

[0033] 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) apply equally to sub-formulae disclosed herein such as (I’), (IA), (IA’), (IB), (IB’), (IC), (IC’), (ID), (ID’), (IE), (IE’), (IF), (IF’), (lA’-a) and (lA’-b).

[0034] The term “alkyl”, such as “C1.4 alkyl or “C1.2 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” 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.

[0035] 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.

[0036] The term “halo” refers to fluoro, chloro, bromo or iodo. Particular examples of halo are fluoro and chloro, especially fluoro.

[0037] 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.

[0038] The term “thioalkyl”, such as “C1.3 thioalkyl” 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 sulphur atom. An example of thioalkyl is CH2CH2SCH3.

[0039] 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.

[0040] The term “hydroxy” (which may also be referred to as “hydroxyl”) refers to an -OH group.

[0041] The term “cycloalkyl”, such as “C5-10 cycloalkyl” or“C3-7 cycloalkyl”, 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 Jpentyl, 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. 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.

[0042] Certain compounds of formula (I) comprise a “spirocycloalkyl” group wherein one CH2 group in the spirocycloalkyl group is optionally replaced by NH. This means that any one of the CH2 groups present in the spirocycloalkyl group is replaced by an NH group, for example: wherein the circles represent the spirocycloalkyl group as defined above and / ' represents the point of connection to the remainder of the compound comprising the spirocycloalkyl group. The skilled person will appreciate that any one CH2 group present in the spirocycloalkyl group may be replaced by an NH group.

[0043] The term “heterocyclyl”, such as “4- to 7-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. Heterocyclic groups can typically be substituted by one or more (e.g. one or two) oxo groups. Suitably, thietanyl is substituted by one or two oxo groups.

[0044] In some suitable compounds of formula wherein / 'represents the point of connection to the remainder of the compound comprising the B group.

[0045] In other suitable compounds of formula wherein / 'represents the point of connection to the remainder of the compound comprising the B group.

[0046] N=N

[0047] In other suitable compounds of formula (I), B is N - ' wherein represents the point of connection to the remainder of the compound comprising the B group.

[0048] Most suitably, wherein 7 f - represents the point of connection to the remainder of the compound comprising the B group.

[0049] 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 NR1aR1 bwherein R1aand R1 bare independently H or -C(O)Ci-3 alkyl. In other suitable compounds of formula (I), R1is COOR1cwherein R1cis H or Ci.3 alkyl. In other suitable compounds of formula (I), R1is NH2. In other suitable compounds of formula (I), R1is 4-7 membered heterocyclyl-CH2C(=O)NH- wherein the 4-7 membered heterocyclyl is optionally substituted by C1.3 alkyl or C3-7 cycloalkyl.

[0050] In some suitable compounds of formula (I), the 4-7 membered heterocyclyl group of R1is not substituted. In other suitable compounds of formula (I), the 4-7 membered heterocyclyl group of R1is substituted by C1.3 alkyl or C3-7 cycloalkyl, such as is substituted by one or more (such as one) C1.3 alkyl or C3-7 cycloalkyl groups. In some such suitable compounds of formula (I), the 4-7 membered heterocyclyl group of R1is substituted by C1.3 alkyl. In other such suitable compounds of formula (I), the 4-7 membered heterocyclyl group of R1is substituted by C3-7 cycloalkyl.

[0051] The heterocyclyl group is suitably piperazinyl, which is optionally substituted by C1.3 alkyl or C3-7 cycloalkyl. Suitably, the heterocyclyl group is piperazinyl, which is substituted by methyl or C3 cycloalkyl.

[0052] Most suitably, R1is H, 4-7 membered heterocyclyl-CH2C(=O)NH- or halo.

[0053] 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 C1.4 alkoxy. In other suitable compounds of formula (I), R2is NR2aR2bwherein R2aand R2bare independently C1.3 alkyl optionally substituted with OH. In other suitable compounds of formula (I), R2is C3-7 cycloalkyl. In other suitable compounds of formula (I), R2is 4-7 membered heterocyclyl wherein the 4-7 membered heterocyclyl is optionally substituted by one, two or three (e.g. one) R2cwherein R2cis selected from the group consisting of C1.3 alkyl, C1.3 thioalkyl and C3-6 cycloalkyl.

[0054] In some suitable compounds, R2cis C1.3 alkyl. In other suitable compounds, R2cis C1.3 thioalkyl. In other suitable compounds, R2cis C3-6 cycloalkyl.

[0055] In some suitable compounds of formula (I), R2is selected from the group consisting of H, C1.4 alkyl, C3-7 cycloalkyl and 4-7 membered heterocyclyl wherein the 4-7 membered heterocyclyl is optionally substituted by one, two or three (e.g. one) R2cwherein R2cis selected from the group consisting of C1.3 alkyl, C1.3 thioalkyl and C3-6 cycloalkyl.

[0056] Most suitably, R2is H or 4-7 membered heterocyclyl wherein the 4-7 membered heterocyclyl is optionally substituted by one R2cwherein R2cis C1.3 alkyl or C3-6 cycloalkyl such as the 4-7 membered heterocyclyl is substituted by one R2cwherein R2cis C1.3 alkyl or C3-6 cycloalkyl.

[0057] The heterocyclyl group is suitably piperazinyl, which is optionally substituted by one, two or three (e.g. one) R2cwherein R2cis selected from the group consisting of C1.3 alkyl, C1.3 thioalkyl and C3- 7 cycloalkyl. Suitably, the heterocyclyl group is piperazinyl, which is substituted by one R2cwherein R2Cis methyl or C3 cycloalkyl.

[0058] R2Cmay be attached to any available ring atom of the heterocyclyl group. For example, R2cmay be attached to a carbon atom (i.e. replacing a hydrogen atom attached to a carbon atom to form a C-R2cbond) or attached to a nitrogen atom (i.e. replacing a hydrogen atom attached to a nitrogen atom to form a N-R2Cbond).

[0059] 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 t-butyl. 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. In other suitable compounds of formula (I), R3is phenyl.

[0060] In some suitable compounds of formula (I), R3is selected from the group consisting of halo, hydroxy, C1.4 alkyl, C1.4 alkoxy, C1.4 haloalkyl, C1.4 haloalkoxy. In some suitable compounds of formula (I), R4is H. In other suitable compounds of formula, R4is halo such as fluoro. It will be clear to the skilled person that R4may be attached to any carbon atom in the pyrrolidinyl ring.

[0061] Suitably, R4is attached to the carbon atom as shown below:

[0062] More suitably, the stereochemistry of the carbon atom to which R4is attached is:

[0063] In some suitable compounds of formula (I), R5is H. In other suitable compounds of formula (I), R5is C1.3 alkyl.

[0064] Suitably R5is H.

[0065] In some suitable compounds of formula (I), A is C5-10 cycloalkyl such as C7-10 cycloalkyl. In other suitable compounds of formula (I), A is Ce-12 spirocycloalkyl, wherein one CH2 group in the spirocycloalkyl group is optionally replaced by NH. In some suitable compounds, A is Ce-12 spirocycloalkyl. In other suitable compounds, A is Ce-12 spirocycloalkyl, wherein one CH2 group in the spirocycloalkyl group is replaced by NH.

[0066] The cycloalkyl group of A is optionally fused to phenyl wherein the phenyl is optionally substituted (e.g., is substituted) by halo such as fluoro.

[0067] Suitably the C5-10 cycloalkyl group is cyclohexyl, cycloheptyl or adamantyl e.g., adamantyl.

[0068] Suitably the Ce-12 spirocycloalkyl is spiro[3.5]nonyl or spiro[4.5]decyl: spiro[3.5]nonyl spiro[4.5]decyl

[0069] In some suitable compounds of formula (I), m is 0. In other suitable compounds of formula (I), m is 1.

[0070] Most suitably, m is 1.

[0071] 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 3. In other suitable compounds of formula (I), n is 4.

[0072] Most suitably, n is 0, 1 or 2.

[0073] When n is 2, 3 or 4, each R3may be the same or different.

[0074] When m is 0, R2is absent.

[0075] In some suitable compounds of formula (I), R5is H, m is 1 and n is 0, 1 or 2.

[0076] In some suitable compounds, the compound is a compound of formula (IA): wherein R2, R3, R4, R5, m, n, A and B are as defined elsewhere herein; or a salt and / or solvate thereof.

[0077] In other suitable compounds, the compound is a compound of formula (IA’): wherein R1, R2, R3, R4, m, n and A are as defined elsewhere herein; or a salt and / or solvate thereof.

[0078] In other suitable compounds, the compound is a compound of formula (IB): wherein R2, R3, R4, R5, m, n, A and B are as defined elsewhere herein; or a salt and / or solvate thereof.

[0079] In other suitable compounds, the compound is a compound of formula (IB’): wherein R1, R2, R3, R4, m, n and A are as defined elsewhere herein; or a salt and / or solvate thereof.

[0080] In other suitable compounds, the compound is a compound of formula (IC): wherein R2, R3, R4, R5, m, n, A and B are as defined elsewhere herein; or a salt and / or solvate thereof.

[0081] In other suitable compounds, the compound is a compound of formula (IC’): wherein R1, R2, R3, R4, m, n and A are as defined elsewhere herein; or a salt and / or solvate thereof. In other suitable compounds, the compound is a compound of formula (ID): wherein R2, R3, R4, R5, m, n, A and B are as defined elsewhere herein; or a salt and / or solvate thereof. In other suitable compounds, the compound is a compound of formula (ID’): wherein R1, R2, R3, R4, m, n, A and B are as defined elsewhere herein; or a salt and / or solvate thereof. In other suitable compounds, the compound is a compound of formula (IE): wherein R2, R3, R4, R5, m, n, A and B are as defined elsewhere herein; or a salt and / or solvate thereof. In other suitable compounds, the compound is a compound of formula (IE’): wherein R1, R2, R3, R4, m, n and A are as defined elsewhere herein; or a salt and / or solvate thereof.

[0082] In other suitable compounds, the compound is a compound of formula (IF): wherein R2, R3, R4, R5, m, n, A and B are as defined elsewhere herein; or a salt and / or solvate thereof.

[0083] In other suitable compounds, the compound is a compound of formula (IF’): wherein R1, R2, R3, R4, m, n and A are as defined elsewhere herein; or a salt and / or solvate thereof.

[0084] Most suitably, the compound is a compound of formula (IA) such as a compound of formula (ID) or (ID’).

[0085] As such, in some suitable compounds, the compound is a compound of formula (lA’-a): wherein R3, R2c, n and A are as defined elsewhere herein; or a salt and / or solvate thereof.

[0086] In other suitable compounds, the compound is a compound of formula (lA’-b): wherein R3, n and A are as defined elsewhere herein; or a salt and / or solvate thereof.

[0087] In one embodiment there is provided a compound of formula (I), which is selected from the list consisting of: 2-{3-azaspiro[5.5]undecan-9-yl}-A / -(5-{[(3 )-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4- thiadiazol-2-yl)acetamide;

[0088] A / -(5-{[(3 )-1-(6-aminopyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)-2- cycloheptylacetamide;

[0089] / V-{6-[(3 )-3-{[5-(2-cycloheptylacetamido)-1 ,3,4-thiadiazol-2-yl]amino}pyrrolidin-1-yl]pyridazin-3- yl}-2-(4-cyclopropylpiperazin-1-yl)acetamide;

[0090] 2-(4-methylpiperazin-1-yl)-A / -(5-{[(3 )-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2- yl)-2-{spiro[3.5]nonan-7-yl}acetamide;

[0091] ( )-2-(4-methylpiperazin-1-yl)-A / -(5-((( )-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol- 2-yl)-2-(spiro[3.5]nonan-7-yl)acetamide;

[0092] (S)-2-(4-methylpiperazin-1-yl)-A / -(5-((( )-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol- 2-yl)-2-(spiro[3.5]nonan-7-yl)acetamide;

[0093] 2-cyclopentyl-A / -(5-{[(3 )-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide; 2-{bicyclo[1 .1.1]pentan-1 -yl}- / V-(5-{[(3 )-1 -(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol- 2-yl)acetamide; 2-(3-hydroxyadamantan-1-yl)- / V-(5-{[(3 / ?)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4- thiadiazol-2-yl)acetamide;

[0094] 2-cyclopentyl-2-(4-methylpiperazin-1-yl)- / V-(5-{[(3 / ?)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}- 1 ,3,4-thiadiazol-2-yl)acetamide;

[0095] 2-cyclohexyl- / V-(5-{[(3 / ?)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;

[0096] 2-cycloheptyl- / V-(5-{[(3 / ?)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;

[0097] 2-cyclohexyl-2-(4-methylpiperazin-1-yl)- / V-(5-{[(3 / ?)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4- thiadiazol-2-yl)acetamide;

[0098] 2-(adamantan-1-yl)- / V-(5-{[(3 / ?)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2- yl)acetamide;

[0099] 2-(adamantan-2-yl)- / V-(5-{[(3 / ?)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2- yl)acetamide;

[0100] A / -(5-{[(3 / ?)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)bicyclo[4.1.0]heptane-7- carboxamide;

[0101] A / -(5-{[(3 / ?)-1 -(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)-2-(1 ,2,3,4- tetrahydronaphthalen-1-yl)acetamide;

[0102] 2-(4-phenylcyclohexyl)- / V-(5-{[(3 / ?)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2- yl)acetamide;

[0103] 2,2-dicyclohexyl- / V-(5-{[(3 / ?)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2- yl)acetamide;

[0104] A / -(5-{[(3 / ?)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)spiro[2.5]octane-1- carboxamide;

[0105] 2-(6-fluoro-1 ,2,3,4-tetrahydronaphthalen-2-yl)-A / -(5-{[(3 / ?)-1-(pyridazin-3-yl)pyrrolidin-3- yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;

[0106] 2-(1-methylcyclohexyl)- / V-(5-{[(3 / ?)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2- yl)acetamide;

[0107] (2S)- / V-(5-{[(3 / ?)-1-(6-chloropyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)-2- cyclohexyl-2-(dimethylamino)acetamide;

[0108] (2 / ?)- / V-(5-{[(3 / ?)-1-(6-chloropyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)-2- cyclohexyl-2-(dimethylamino)acetamide;

[0109] 2-[(1 S,2S,5S)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl]-A / -(5-{[(3 / ?)-1-(pyridazin-3-yl)pyrrolidin-3- yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;

[0110] A / -(5-{[(3 / ?)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)-2-[3-

[0111] (trifluoromethyl)adamantan-1-yl]acetamide;

[0112] 2-(4-ethylcyclohexyl)-2-(4-methylpiperazin-1-yl)-N-(5-((( / ?)-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0113] 2-(4-(ferf-butyl)cyclohexyl)-2-(4-methylpiperazin-1-yl)-N-(5-((( / ?)-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0114] 2-(4-methylpiperazin-1-yl)- / V-(5-((( / ?)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2- yl)-2-(3,3,5,5-tetramethylcyclohexyl)acetamide;

[0115] 2-((1 S,3S)-adamantan-1-yl)-A / -(5-((( / ?)-1-(6-(2-(4-cyclopropylpiperazin-1-yl)acetamido)pyridazin-

[0116] 3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0117] 2-((1 S,3S)-adamantan-1-yl)- / V-(5-((( / ?)-1-(6-(2-(4-methylpiperazin-1-yl)acetamido)pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0118] 2-((1 S,3S)-adamantan-1-yl)-2-(4-methylpiperazin-1-yl)-A / -(5-((( / ?)-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0119] (2 / ?)-2-((1 S,3S)-adamantan-1-yl)-2-(4-methylpiperazin-1-yl)-A / -(5-((( / ?)-1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0120] (2S)-2-((1 S,3 / ?)-adamantan-1-yl)-2-(4-methylpiperazin-1-yl)-A / -(5-((( / ?)-1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0121] 2-((1 S,3S)-adamantan-1-yl)-2-(4-cyclopropylpiperazin-1-yl)-A / -(5-((( / ?)-1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0122] (2 / ?)-2-((1 S,3S)-adamantan-1-yl)-2-(4-cyclopropylpiperazin-1-yl)-A / -(5-((( / ?)-1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0123] (2S)-2-((1 S,3 / ?)-adamantan-1-yl)-2-(4-cyclopropylpiperazin-1-yl)-A / -(5-((( / ?)-1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0124] 2-((1 S,3S)-adamantan-1-yl)-2-(4-ethylpiperazin-1-yl)-A / -(5-((( / ?)-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0125] (2 / ?)-2-((1 S,3S)-adamantan-1-yl)-2-(4-ethylpiperazin-1-yl)-A / -(5-((( / ?)-1-(pyridazin-3-yl)pyrrolidin-

[0126] 3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0127] (2S)-2-((1 S,3 / ?)-adamantan-1-yl)-2-(4-ethylpiperazin-1-yl)-A / -(5-((( / ?)-1-(pyridazin-3-yl)pyrrolidin-

[0128] 3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0129] 2-((1 S,3S)-adamantan-1-yl)-2-(4-isopropylpiperazin-1-yl)-A / -(5-((( / ?)-1-(pyridazin-3-yl)pyrrolidin-

[0130] 3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0131] (2 / ?)-2-((1 S,3S)-adamantan-1-yl)-2-(4-isopropylpiperazin-1-yl)-A / -(5-((( / ?)-1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0132] (2S)-2-((1 S,3 / ?)-adamantan-1-yl)-2-(4-isopropylpiperazin-1-yl)-A / -(5-((( / ?)-1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0133] 2-((1 / ?,3S)-3,5-dimethyladamantan-1-yl)-2-(4-methylpiperazin-1-yl)-A / -(5-((( / ?)-1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0134] (2S)-2-((1 / ?,3S)-3,5-dimethyladamantan-1-yl)-2-(4-methylpiperazin-1-yl)-A / -(5-((( / ?)-1-(pyridazin-

[0135] 3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0136] 2-(4-methylpiperazin-1-yl)- / V-(5-((( / ?)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2- yl)-2-(spiro[4.5]decan-8-yl)acetamide; ( / ?)-2-(4-methylpiperazin-1 -yl)- / V-(5-((( / ?)-1 -(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol- 2-yl)-2-(spiro[4.5]decan-8-yl)acetamide;

[0137] (S)-2-(4-methylpiperazin-1-yl)- / V-(5-((( / ?)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol- 2-yl)-2-(spiro[4.5]decan-8-yl)acetamide;

[0138] A / -(5-((( / ?)-1-(6-chloropyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-cyclohexyl-2- (4-methylpiperazin-1-yl)acetamide;

[0139] ( / ?)- / V-(5-((( / ?)-1-(6-chloropyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-cyclohexyl- 2-(4-methylpiperazin-1-yl)acetamide;

[0140] (S)- / V-(5-((( / ?)-1-(6-chloropyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-cyclohexyl- 2-(4-methylpiperazin-1-yl)acetamide;

[0141] A / -(5-((( / ?)-1-(6-chloropyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-(4,4- dimethylcyclohexyl)-2-(4-methylpiperazin-1-yl)acetamide;

[0142] ( / ?)- / V-(5-((( / ?)-1-(6-chloropyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-(4,4- dimethylcyclohexyl)-2-(4-methylpiperazin-1-yl)acetamide;

[0143] (S)- / V-(5-((( / ?)-1-(6-chloropyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-(4,4- dimethylcyclohexyl)-2-(4-methylpiperazin-1-yl)acetamide;

[0144] A / -(5-((( / ?)-1-(6-chloropyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-(4- methylpiperazin-1-yl)-2-(spiro[4.5]decan-8-yl)acetamide;

[0145] ( / ?)- / V-(5-((( / ?)-1-(6-chloropyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-(4- methylpiperazin-1-yl)-2-(spiro[4.5]decan-8-yl)acetamide;

[0146] (S)- / V-(5-((( / ?)-1-(6-chloropyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-(4- methylpiperazin-1-yl)-2-(spiro[4.5]decan-8-yl)acetamide;

[0147] 2-(4,4-dimethylcyclohexyl)-2-(4-methylpiperazin-1-yl)-N-(5-((( / ?)-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0148] ( / ?)-2-(4,4-dimethylcyclohexyl)-2-(4-methylpiperazin-1-yl)-A / -(5-((( / ?)-1-(pyridazin-3-yl)pyrrolidin-

[0149] 3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0150] (S)-2-(4,4-dimethylcyclohexyl)-2-(4-methylpiperazin-1-yl)-A / -(5-((( / ?)-1-(pyridazin-3-yl)pyrrolidin- 3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0151] 2-(4,4-dimethylcyclohexyl)-2-(4-isopropylpiperazin-1-yl)-A / -(5-((( / ?)-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0152] ( / ?)-2-(4,4-dimethylcyclohexyl)-2-(4-isopropylpiperazin-1-yl)-A / -(5-((( / ?)-1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0153] (S)-2-(4,4-dimethylcyclohexyl)-2-(4-isopropylpiperazin-1-yl)-A / -(5-((( / ?)-1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0154] 2-cyclooctyl-2-(4-ethylpiperazin-1-yl)- / V-(5-((( / ?)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4- thiadiazol-2-yl)acetamide;

[0155] ( / ?)-2-cyclooctyl-2-(4-ethylpiperazin-1-yl)- / V-(5-((( / ?)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)- 1 ,3,4-thiadiazol-2-yl)acetamide;

[0156] (S)-2-cyclooctyl-2-(4-ethylpiperazin-1-yl)- / V-(5-((( )-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-

[0157] 1.3.4-thiadiazol-2-yl)acetamide;

[0158] (2 )-2-((1 ,3S)-3,5-dimethyladamantan-1-yl)-2-(4-methylpiperazin-1-yl)-A / -(5-((( )-1-(pyridazin- 3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0159] A / -(5-{[(3S,4S)-4-fluoro-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)-2-(4- methylpiperazin-1-yl)-2-{spiro[3.5]nonan-7-yl}acetamide;

[0160] 2-(4,4-dimethylcyclohexyl)-N-(5-((( )-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2- yl)-2-((3R,5S)-3,4,5-trimethyl piperazin-1 -yl)acetamide;

[0161] 2-(4,4-dimethylcyclohexyl)-2-(1-isopropylpiperidin-4-yl)-A / -(5-((( )-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0162] (S)-2-(4,4-dimethylcyclohexyl)-2-(1-isopropylpiperidin-4-yl)-A / -(5-((( )-1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0163] (R)-2-(4,4-dimethylcyclohexyl)-2-(1-isopropylpiperidin-4-yl)-A / -(5-((( )-1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

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

[0165] 2-yl)-2-(spiro[3.5]nonan-7-yl)acetamide;

[0166] ( )-2-(4-isopropylpiperazin-1-yl)-A / -(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4- thiadiazol-2-yl)-2-(spiro[3.5]nonan-7-yl)acetamide;

[0167] (S)-2-(4-isopropylpiperazin-1-yl)-A / -(5-((( )-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4- thiadiazol-2-yl)-2-(spiro[3.5]nonan-7-yl)acetamide;

[0168] 2-(4,4-dimethylcyclohexyl)-2-(4-methylpiperazin-1-yl)-A / -(5-((( )-1-(6-methylpyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0169] (R)-2-(4,4-dimethylcyclohexyl)-2-(4-methylpiperazin-1-yl)-A / -(5-((( )-1-(6-methylpyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide

[0170] (S)-2-(4,4-dimethylcyclohexyl)-2-(4-methylpiperazin-1-yl)-A / -(5-((( )-1-(6-methylpyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide methyl 6-((3 )-3-((5-(2-(4,4-dimethylcyclohexyl)-2-(4-isopropylpiperazin-1-yl)acetamido)-1 ,3,4- thiadiazol-2-yl)amino)pyrrolidin-1-yl)pyridazine-4-carboxylate formate; methyl 6-(( )-3-((5-((R)-2-(4,4-dimethylcyclohexyl)-2-(4-isopropylpiperazin-1-yl)acetamido)-

[0171] 1.3.4-thiadiazol-2-yl)amino)pyrrolidin-1-yl)pyridazine-4-carboxylate; methyl 6-(( )-3-((5-((S)-2-(4,4-dimethylcyclohexyl)-2-(4-isopropylpiperazin-1-yl)acetamido)-

[0172] 1 ,3,4-thiadiazol-2-yl)amino)pyrrolidin-1-yl)pyridazine-4-carboxylate;

[0173] 6-((3 )-3-((5-(2-(4,4-dimethylcyclohexyl)-2-(4-isopropylpiperazin-1-yl)acetamido)-1 ,3,4- thiadiazol-2-yl)amino)pyrrolidin-1-yl)pyridazine-4-carboxylic acid;

[0174] 6-(( )-3-((5-(( )-2-(4,4-dimethylcyclohexyl)-2-(4-isopropylpiperazin-1-yl)acetamido)-1 ,3,4- thiadiazol-2-yl)amino)pyrrolidin-1-yl)pyridazine-4-carboxylic acid; 6-(( / ?)-3-((5-((S)-2-(4,4-dimethylcyclohexyl)-2-(4-isopropylpiperazin-1-yl)acetamido)-1 ,3,4- thiadiazol-2-yl)amino)pyrrolidin-1-yl)pyridazine-4-carboxylic acid;

[0175] A / -(5-((( / ?)-1-(6-acetamidopyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-(4,4- dimethylcyclohexyl)-2-(4-isopropylpiperazin-1-yl)acetamide;

[0176] (F?)- / V-(5-((( / ?)-1-(6-acetamidopyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-(4,4- dimethylcyclohexyl)-2-(4-isopropylpiperazin-1-yl)acetamide;

[0177] (S)- / V-(5-((( / ?)-1-(6-acetamidopyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-(4,4- dimethylcyclohexyl)-2-(4-isopropylpiperazin-1-yl)acetamide;

[0178] 2-(4,4-dimethylcyclohexyl)-2-(4-(2-(methylthio)ethyl)piperazin-1-yl)-A / -(5-((( / ?)-1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0179] 2-(4,4-dimethylcyclohexyl)-2-(4-methylpiperazin-1-yl)-A / -(5-((( / ?)-1-(5-methylpyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0180] (F?)-2-(4,4-dimethylcyclohexyl)-2-(4-methylpiperazin-1-yl)-A / -(5-(((F?)-1-(5-methylpyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0181] (S)-2-(4,4-dimethylcyclohexyl)-2-(4-methylpiperazin-1-yl)-A / -(5-((( / ?)-1-(5-methylpyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;

[0182] A / -(5-((( / ?)-1-(1 ,2,4-triazin-6-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-(4,4- dimethylcyclohexyl)-2-(4-isopropylpiperazin-1-yl)acetamide;

[0183] (F?)-A / -(5-(((F?)-1-(1 ,2,4-triazin-6-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-(4,4-dimethyl cyclohexyl)-2-(4-isopropyl piperazin-1 -yl)acetamide;

[0184] (S)-A / -(5-(((F?)-1-(1 ,2,4-triazin-6-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-(4,4- dimethylcyclohexyl)-2-(4-isopropylpiperazin-1-yl)acetamide;

[0185] A / -(5-((( / ?)-1-(1 ,2,4-triazin-6-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-(4-methylpiperazin-

[0186] 1-yl)-2-(spiro[4.5]decan-8-yl)acetamide;

[0187] (F?)-A / -(5-(((F?)-1-(1 ,2,4-triazin-6-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-(4- methylpiperazin-1-yl)-2-(spiro[4.5]decan-8-yl)acetamide;

[0188] (S)-A / -(5-(((F?)-1-(1 ,2,4-triazin-6-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-(4- methylpiperazin-1-yl)-2-(spiro[4.5]decan-8-yl)acetamide;

[0189] (S)-2-(4,4-dimethylcyclohexyl)-A / -(5-((( / ?)-1-(1-methyl-1 H-1 ,2,3-triazol-4-yl)pyrrolidin-3-yl)amino)-

[0190] 1 ,3,4-thiadiazol-2-yl)-2-(4-methylpiperazin-1-yl)acetamide; and

[0191] (2S)-2-(4,4-dimethylcyclohexyl)-A / -(5-{methyl[(3 / ?)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4- thiadiazol-2-yl)-2-(4-methylpiperazin-1-yl)acetamide; or a salt and / or solvate of any one thereof.

[0192] Compounds of formula (I) may be synthesised as shown in the schemes below and as shown in the Examples section. For each scheme, variables are as defined above unless otherwise stated. Scheme 1 : Synthesis of compounds of formula (I)

[0193] 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.

[0194] N-N

[0195] Scheme 2: Synthesis of compounds of formula (I) wherein B isR1 Z= / and R1is 4-7 membered heterocyclyl-CH2C(=O)NH- and wherein the 4-7 membered heterocyclyl is N-linked to the CH2carbon of CH2C(=O)NH-

[0196] X1is a leaving group such as halo e.g. bromo. X2is a leaving group such as halo e.g. chloro. PG is a nitrogen protecting group such a Boc. Other nitrogen protecting groups are as described herein. Y in formula (I) is N-linked 4-7 membered heterocyclyl.

[0197] Step 1 : Amines (X) are reacted with thiadiazoles (IX) under basic conditions (such as in the presence of K2COs) under a N2atmosphere to give compounds of formula (VII).

[0198] Step 2: Compounds of formula (VII) are reacted with carboxylic acids (VIII) using standard acid- activation conditions such as SOCh in an inert atmosphere, and then the protecting group PG is removed under conditions known to the skilled person to give amines (VI). When PG is Boc, for example HCI / 4 M dioxane is used to remove PG.

[0199] Step 3: Secondary amines (VI) are coupled with 6-halopyridazin-3-amine (suitable halo is iodo) in the presence of Cu(l) and amino acid (such as Cui and L-OH-Proline) to give primary amines (V).

[0200] Step 4: Primary amines (V) are reacted with a suitable acid chloride e.g. 2-chloroacetyl chloride under basic conditions (such as TEA) to give compounds of formula (IV).

[0201] Step 5: Compounds of formula (IV) are reacted with a 4-7 membered heterocycle (XV) comprising a NH group, under basic conditions (such as K2CO3) to provide compounds of formula (I).

[0202] Scheme 3: Synthesis of compounds of formula (III)

[0203] PG is a nitrogen protecting group such a Boc. Other nitrogen protecting groups are as described herein. X3is a leaving group such as halo e.g. chloro.

[0204] Step 1 : Compounds of formula (XIV) are reacted under basic conditions (such as in the presence of DI PEA) with pyridazines (XIII) to give compounds of formula (XII).

[0205] Step 2: PG is removed under conditions known to the skilled person to give amines (XI). For example, if PG is Boc, this protecting group can be removed using neat TFA.

[0206] Step 3: Amines (XI) 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).

[0207] Optionally, if R1is H in compounds of formula (III) and R1is halo e.g. chloro in compounds of formula (XIII), a reduction step using Pd / C and ammonium formate in ethanol can be included between step 1 and step 2 to give R1= H.

[0208] Compounds of formula (II) may be synthesised for example as set out in the Example section below.

[0209] 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, NR2aR2b, C3-7 cycloalkyl and 4-7 membered heterocyclyl such as NR2aR2band 4-7 membered heterocyclyl, wherein the 4-7 membered heterocyclyl is optionally substituted by R2cwherein R2a, R2b, R2care as defined elsewhere herein.

[0210] The invention also provides a compound of formula (III): or a salt, such as a pharmaceutically acceptable salt thereof.

[0211] The invention also provides a compound of formula (III’): or a salt, such as a pharmaceutically acceptable salt thereof.

[0212] The invention also provides a compound of formula (IV): or a salt, such as a pharmaceutically acceptable salt thereof.

[0213] The invention also provides a compound of formula (V): or a salt, such as a pharmaceutically acceptable salt thereof.

[0214] The invention also provides a compound of formula (VI): or a salt, such as a pharmaceutically acceptable salt thereof.

[0215] 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 R1, R2, R3, R4, m, n and A are as defined elsewhere herein.

[0216] 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 (IV): 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 and A are as defined elsewhere herein, X2is a leaving group such as halo e.g. chloro and Y is a 4-7 membered heterocycle.

[0217] 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.

[0218] 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.

[0219] 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.

[0220] 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.

[0221] 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. 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.

[0222] 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.

[0223] 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.

[0224] 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.

[0225] 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.

[0226] 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.

[0227] 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.

[0228] 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.

[0229] 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.

[0230] Therapeutic indications

[0231] 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 certain compounds of the invention do not epimerise unlike certain prior art compounds and thus have an advantage regarding drug candidate development. Biological Example 3 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 4 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.

[0232] 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.

[0233] 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. 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.

[0234] 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.

[0235] 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.

[0236] 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.

[0237] In a further aspect, the present invention provides a pharmaceutical composition as defined herein, for use in treating fibrotic and / or inflammatory diseases.

[0238] In a further aspect, the present invention provides a pharmaceutical composition as defined herein, for use in preventing fibrotic and / or inflammatory diseases.

[0239] 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.

[0240] 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.

[0241] 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.

[0242] 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. 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.

[0243] 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.

[0244] 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.

[0245] 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.

[0246] 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.

[0247] 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.

[0248] 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.

[0249] 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.

[0250] In any one of the above embodiments, suitably the fibrotic and / or inflammatory disease is a fibrotic and / or inflammatory disease of the lung.

[0251] 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.

[0252] 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.

[0253] 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.

[0254] In one embodiment, the fibrotic disease is fibrosis or non-alcoholic steatohepatitis.

[0255] 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.

[0256] 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.

[0257] 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.

[0258] Administration

[0259] 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) and one or more pharmaceutically acceptable diluents or carriers.

[0260] 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.

[0261] 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. 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.

[0262] 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.

[0263] 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.

[0264] 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.

[0265] 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.

[0266] 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. 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).

[0267] 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.

[0268] 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).

[0269] 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.

[0270] 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).

[0271] Preferably, for topical ocular administration, the compositions administered according to the present invention will be formulated as solutions, suspensions, emulsions and other dosage forms.

[0272] 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. 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.

[0273] 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.

[0274] 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.

[0275] 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. 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.

[0276] 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.

[0277] 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.

[0278] Compositions suitable for transdermal administration include ointments, gels and patches.

[0279] 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 0.05 mg to 1000 mg, 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 100 mg to 400 mg 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 mg to 1000 mg, more suitably 1.0 mg to 500 mg, 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.

[0280] 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.

[0281] 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.

[0282] 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).

[0283] Compounds of formula (I) may display, or may be expected to have, one or more of the following desirable properties:

[0284] • low IC50 in the cellular assay of Biological Example 1 ;

[0285] • low IC50 in the enzyme assay of Biological Example 1 ;

[0286] • no epimerisation as shown in Biological Example 2;

[0287] • improved duration of action in the lung as shown in Biological Example 3;

[0288] • higher lung concentrations as shown in Biological Example 3;

[0289] • improved solubility as shown in Biological Example 4.

[0290] Abbreviations

[0291] ACN acetonitrile aq. aqueous

[0292] BOC tert-Butyloxycarbonyl tBuOH tert-butanol

[0293] DCM dichloromethane d.e. diastereomeric excess

[0294] Dioxane 1 ,4-diethylene dioxide DIPEA N, N-diisopropylethylamine

[0295] DMF N, N-dimethylformamide

[0296] DMSO dimethyl sulfoxide

[0297] EDTA ethylenediaminetetraacetic acid

[0298] ESI Electrospray Ionisation

[0299] Et3N triethylamine

[0300] EtOAc ethyl acetate

[0301] EtOH ethanol

[0302] Et2<D Diethyl ether

[0303] FA Formic acid h hour / hours

[0304] HATLI 1-[bis(dimethylamino)methylene]-1 H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate

[0305] HPLC High Performance Liquid Chromatography

[0306] IN intranasal

[0307] LCMS Liquid Chromatography Mass Spectrometry

[0308] M Molar concentration

[0309] MeOH methanol min(s) minute(s)

[0310] NMR Nuclear Magnetic Resonance

[0311] Pd(dppf)Ch [1,T-Bis(diphenylphosphino)ferrocene]dichloropalladium(ll)

[0312] PE petroleum ether

[0313] PyBOP benzotriazol-1-yl-oxytripyrrolidino-phosphonium Hexafluorophosphate

[0314] RT retention time r.t. room temperature

[0315] SFC Supercritical Fluid Chromatography

[0316] T3P propylphosphonic anhydride solution

[0317] TEA triethylamine

[0318] TFA trifluoroacetic acid

[0319] THF tetra hydrofuran

[0320] TLC thin layer chromatography

[0321] UPLC Ultra Performance Liquid Chromatography EXAMPLES

[0322] Analytical Equipment

[0323] 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.).

[0324] 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.

[0325] HPLC was performed according to methods described below:

[0326] Method 1

[0327] Stationary phase: Kinetex EVO C18 2.1 x 30 mm, 5 pm

[0328] Mobile Phase A: 0.025% NH3 H2O in water(v / v)

[0329] Mobile Phase B: Acetonitrile

[0330] Flow rate: 1.5 mL / min

[0331] Gradient program: Time A% B%

[0332] 0.00 95.00 5.00

[0333] 0.80 5.00 95.00

[0334] 1.20 5.00 95.00

[0335] 1.21 95.00 5.00

[0336] 1.55 95.00 5.00

[0337] Method 2

[0338] Stationary phase: Kinetex EVO C18 2.1 x 30 mm, 5 pm

[0339] Mobile Phase A: 0.0375% TFA in water (v / v)

[0340] Mobile Phase B: 0.01875% TFA in acetonitrile (v / v)

[0341] Flow rate: 1.5 mL / min

[0342] Gradient program: Time A% B%

[0343] 0.00 95.00 5.00

[0344] 0.80 5.00 95.00

[0345] 1.20 5.00 95.00 1.21 95.00 5.00

[0346] 1.55 95.00 5.00

[0347] Method 3

[0348] Stationary phase: Kinetex EVO C18 2.1 x 30 mm, 5 pm

[0349] Mobile Phase A: 0.025% NH3 H2O in water(v / v)

[0350] Mobile Phase B: Acetonitrile

[0351] Flow rate: 1.5 mL / min

[0352] Gradient program: Time A% B%

[0353] 0.00 100.00 0.00

[0354] 0.80 40.00 60.00

[0355] 1.20 40.00 60.00

[0356] 1.21 100.00 0.00

[0357] 1.55 100.00 0.00

[0358] Method 4

[0359] Stationary phase: HALO C18 3.0 x 30 mm, 5 pm

[0360] Mobile Phase A: 0.0375% TFA in water (v / v)

[0361] Mobile Phase B: 0.01875% TFA in acetonitrile (v / v)

[0362] Flow rate: 1.5 mL / min

[0363] Gradient program: Time A% B%

[0364] 0.00 95.00 5.00

[0365] 0.50 5.00 95.00

[0366] 0.80 5.00 95.00

[0367] 0.81 95.00 5.00

[0368] 1.05 95.00 5.00

[0369] Method 5

[0370] Stationary phase: Agilent ZORBAX® 5pm SB-Aq, 2.1*50mm

[0371] Mobile Phase A: 0.0375% TFA in water (v / v)

[0372] Mobile Phase B: 0.01875% TFA in acetonitrile (v / v)

[0373] Gradient program: Time A% B% Flow (mL / min)

[0374] 0.00 99.00 1.00 0.8

[0375] 0.40 99.00 1.00 0.8

[0376] 3.40 10.00 90.00 0.8

[0377] 3.90 0.00 100.00 0.8

[0378] 3.91 99.00 1.00 0.8 4.00 99.00 1.00 1.0

[0379] 4.50 99.00 1.00 1.0

[0380] Method 6

[0381] Stationary phase: Acquity UPLC BEH - Waters, 1.7pm C18 (2.1 x 100 mm), 130A

[0382] Injection Volume 3.0 pL Flow Rate 0.5 mL / min Detection: MS-ESI+ m / z 100 to 1000

[0383] UV-DAD 200 - 800 nm (Measured at 220 and 254)

[0384] Mobile Phase A: 0.1 % v / v water solution of formic acid

[0385] Mobile Phase B: 0.1 % v / v acetonitrile solution of formic acid

[0386] Gradient program: Time A% B%

[0387] 0.10 80.00 20.00

[0388] 2.00 5.00 95.00

[0389] 2.70 5.00 95.00

[0390] 2.80 80.00 20.00

[0391] Method 7

[0392] Stationary phase: Waters X Bridge C18, 50 x 4.6 mm, 2.5 pM

[0393] Injection Volume 1.0 pL Flow Rate 2 mL / min Detection: MS-ESI+ m / z 80 to 1200

[0394] UV-DAD 190-400 nm

[0395] Mobile Phase A: 0.1% ammonia in H2O

[0396] Mobile Phase B: acetonitrile

[0397] Gradient program: 5% B hold for 0.6 min, increase to 95% B within 1.00 min,

[0398] Hold at 95% B for 0.9 min, back to 5% B within 0.01 min

[0399] Method 8

[0400] Stationary phase: Waters X Bridge C18, 50 x 4.6 mm, 3.5 pM

[0401] Injection Volume 6 pL Flow Rate 2 mL / min Detection: MS-ESI+ m / z 80 to 1200

[0402] UV-DAD 190-400 nm

[0403] Mobile Phase A: 10mmol / L NH4HCO3 in H2O

[0404] Mobile Phase B: acetonitrile

[0405] Gradient program: 5% B hold for 0.2 min, increase to 95% B within 1.40 min, Hold at 95% B for 0.9 min, back to 5% B within 0.01 min

[0406] Method 9

[0407] Stationary phase: Waters X Bridge C18, 50 x 4.6 mm, 5 pM

[0408] Injection Volume 5.0 pL Flow Rate 2 mL / min Detection: MS-ESI+ m / z 80 to 1200

[0409] UV-DAD 190-400 nm

[0410] Mobile Phase A: 0.1 % ammonia in H2O

[0411] Mobile Phase B: acetonitrile

[0412] Gradient program: 5% B hold for 0.2 min, increase to 95% B within 1.40 min,

[0413] Hold at 95% B for 0.9 min, back to 5% B within 0.01 min

[0414] Method 10

[0415] Stationary phase: Sunfire C18, 50 x 4.6 mm, 5 pM

[0416] Injection Volume 6.0 pL Flow Rate 2 mL / min Detection: MS-ESI+ m / z 80 to 1200

[0417] UV-DAD 190-400 nm

[0418] Mobile Phase A: 0.1 % FA in H2O

[0419] Mobile Phase B: 0.1 % FA in ACN

[0420] Gradient program: 10% B hold for 0.2 min, increase to 95% B within 1.40 min,

[0421] Hold at 95% B for 0.9 min, back to 10% B within 0.01 min

[0422] Method 11

[0423] Stationary phase: Gemini NX 3 pm C18 (4.6x150mm), 110A

[0424] Mobile Phase A: 0.1 % v / v water solution of formic acid

[0425] Mobile Phase B: 0.1 % v / v acetonitrile solution of formic acid

[0426] Flow rate: 1 mL / min

[0427] Gradient program: Time A% B%

[0428] 0.00 90.00 10.00

[0429] 7.50 50.00 50.00

[0430] 8.00 50.00 50.00

[0431] 8.50 5.00 95.00

[0432] 9.75 5.00 95.00

[0433] 10.25 90.00 10.00

[0434] 12.00 90.00 10.00 Method 12

[0435] Stationary phase: Gemini NX 3 pm C18 (4.6x150mm), 110A

[0436] Mobile Phase A: 0.1 % v / v water solution of formic acid

[0437] Mobile Phase B: 0.1 % v / v acetonitrile solution of formic acid

[0438] Flow rate: 1 mL / min

[0439] Gradient program: Time A% B%

[0440] 0.00 100.00 0.00

[0441] 7.50 70.00 30.00

[0442] 8.00 70.00 30.00

[0443] 8.50 5.00 95.00

[0444] 9.75 5.00 95.00

[0445] 10.25 100.00 0.00

[0446] 12.00 100.00 0.00

[0447] Method 13

[0448] Stationary phase: Gemini NX 3 pm C18 (4.6x150mm), 110A

[0449] Mobile Phase A: 0.1 % v / v water solution of formic acid

[0450] Mobile Phase B: 0.1 % v / v acetonitrile solution of formic acid

[0451] Flow rate: 1 mL / min

[0452] Gradient program: Time A% B%

[0453] 0.00 90.00 10.00

[0454] 7.50 60.00 40.00

[0455] 8.00 60.00 40.00

[0456] 8.50 5.00 95.00

[0457] 9.75 5.00 95.00

[0458] 10.25 90.00 10.00

[0459] 12.00 90.00 10.00

[0460] Method 14

[0461] Stationary phase: Kinetex ® 2.6 pm XB-C18 (4.6x50mm), 110A

[0462] Mobile Phase A: 0.1 % v / v water solution of formic acid

[0463] Mobile Phase B: 0.1 % v / v acetonitrile solution of formic acid

[0464] Flow rate: 1 mL / min

[0465] Gradient program: Time A% B%

[0466] 0.00 95.00 20.00

[0467] 1.00 95.00 80.00 4.75 20.00 80.00

[0468] 5.25 20.00 95.00

[0469] 6.00 95.00 95.00

[0470] 7.00 95.00 20.00

[0471] Method 15

[0472] Stationary phase: Kinetex ® 2.6 pm XB-C18 (4.6x50mm), 110A

[0473] Mobile Phase A: 0.1 % v / v water solution of formic acid

[0474] Mobile Phase B: 0.1 % v / v acetonitrile solution of formic acid

[0475] Flow rate: 1 mL / min

[0476] Gradient program: Time A% B%

[0477] 0.00 90.00 5.00

[0478] 3.35 30.00 70.00

[0479] 3.75 30.00 70.00

[0480] 3.90 5.00 95.00

[0481] 4.75 5.00 95.00

[0482] 5.00 90.00 5.00

[0483] 6.00 90.00 5.00

[0484] Method 16

[0485] Stationary phase: Kinetex ® 2.6 pm XB-C18 (4.6x50mm), 110A

[0486] Mobile Phase A: 0.1 % v / v water solution of formic acid

[0487] Mobile Phase B: 0.1 % v / v acetonitrile solution of formic acid

[0488] Flow rate: 1 mL / min

[0489] Gradient program: Time A% B%

[0490] 0.00 80.00 20.00

[0491] 3.35 20.00 80.00

[0492] 3.75 20.00 80.00

[0493] 3.90 5.00 95.00

[0494] 4.75 5.00 95.00

[0495] 5.00 80.00 20.00

[0496] 6.00 80.00 20.00

[0497] Method 17

[0498] Stationary phase: Gemini NX 3 pm C18 (4.6x150mm), 110A

[0499] Mobile Phase A: 0.1 % v / v water solution of formic acid

[0500] Mobile Phase B: 0.1 % v / v acetonitrile solution of formic acid Flow rate: 1 mL / min

[0501] Gradient program: Time A% B%

[0502] 0.00 95.00 5.00

[0503] 7.50 40.00 60.00

[0504] 8.00 40.00 60.00

[0505] 8.50 5.00 95.00

[0506] 9.75 5.00 95.00

[0507] 10.25 95.00 5.00

[0508] 12.00 95.00 5.00

[0509] Method 18

[0510] Stationary phase: Gemini NX 3 pm C18 (4.6x150mm), 110A

[0511] Mobile Phase A: 0.1 % v / v water solution of formic acid

[0512] Mobile Phase B: 0.1 % v / v acetonitrile solution of formic acid

[0513] Flow rate: 1 mL / min

[0514] Gradient program: Time A% B%

[0515] 0.00 80.00 20.00

[0516] 7.50 40.00 60.00

[0517] 8.00 40.00 60.00

[0518] 8.50 5.00 95.00

[0519] 9.75 5.00 95.00

[0520] 10.25 40.00 20.00

[0521] 12.00 40.00 20.00

[0522] Method 19

[0523] Stationary phase: ACQUITY UPLC BEH C8 1.7 pm (2.1x150mm), 130A

[0524] Mobile Phase A: 0.1 % v / v water solution of formic acid

[0525] Mobile Phase B: 0.1 % v / v acetonitrile solution of formic acid

[0526] Flow rate: 1 mL / min

[0527] Gradient program: Time A% B%

[0528] 0.00 95.00 5.00

[0529] 3.35 70.00 30.00

[0530] 3.75 70.00 30.00

[0531] 3.90 5.00 95.00

[0532] 4.75 5.00 95.00

[0533] 5.00 95.00 5.00

[0534] 6.00 95.00 5.00 Method 20

[0535] Stationary phase: Sunfire C18, 150 x 4.6 mm, 5 pm

[0536] Injection Volume 6.0 pL Flow Rate 1 mL / min Detection: MS-ESI+ m / z 80 to 1200

[0537] UV-DAD 190-400 nm

[0538] Mobile Phase A: 0.03% TFA in H20

[0539] Mobile Phase B: 0.03% TFA in ACN

[0540] Gradient program: 10% B hold for 1.8 min, increase to 95% B within 10.2 min,

[0541] Hold at 95% B for 3.0 min, back to 10% B within 0.01 min

[0542] Method 21

[0543] Stationary phase: Waters X Bridge C18, 50 x 4.6 mm, 5 pM

[0544] Injection Volume 5.0 pL Flow Rate 2 mL / min Detection: MS-ESI+ m / z 80 to 1200

[0545] UV-DAD 190-400 nm

[0546] Mobile Phase A: 10mmol / L NH4HCO3 in H2O

[0547] Mobile Phase B: acetonitrile

[0548] Gradient program: 5% B hold for 0.2 min, increase to 95% B within 1.40 min,

[0549] Hold at 95% B for 0.9 min, back to 5% B within 0.01 min

[0550] Method 22

[0551] Stationary phase: Waters SunFire C18, 50 x 4.6 mm, 5 pm

[0552] Mobile Phase A: 0.1 %FA in H2O (V / V)

[0553] Mobile Phase B: 0.1 %FA in ACN (v / v) Flow rate: 2.0 mL / min

[0554] Gradient program: 5% B hold for 0.2 min, increase to 95 % B within 1.40 min, hold at

[0555] 95 % B for 0.9 min, then back to 5% B within 0.01 min

[0556] Method 23

[0557] Stationary phase: ShimNex UP C18, 50 x 4.6 mm, 5pm

[0558] Mobile Phase A: 0.1 %FA in H2O (V / V)

[0559] Mobile Phase B: 0.1 %FA in ACN (v / v) Flow rate: 2.0 mL / min Gradient program: 5% B hold for 0.2 min, increase to 95 % B within 1.40 min, hold at

[0560] 95 % B for 0.9 min, then back to 5% B within 0.01 min

[0561] Method 24

[0562] Stationary phase: Agilent Pursuit XRs C18, 30 x 2.0 mm, 5 pm

[0563] Mobile Phase A: 0.1 %TFA in H2O (v / v)

[0564] Mobile Phase B: 0.1 %TFA in ACN (v / v) Flow rate: 1.2 mL / min

[0565] 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

[0566] Method 25

[0567] Stationary phase: Waters XBridge C18, 50 x 4.6 mm, 5 pm

[0568] Mobile Phase A: 0.1 % NH3.H2O in H2O (v / v)

[0569] Mobile Phase B: Acetonitrile Flow rate: 2.0 mL / min

[0570] Gradient program: 5% B hold for 0.2 min, increase to 95 % B within 1.40 min, hold at

[0571] 95 % B for 0.9 min, then back to 5% B within 0.01 min

[0572] Method 26

[0573] Stationary phase: Agilent Eclipse Plus C18, 4.6 x 100 mm, 3.5 pm Mobile Phase A: 0.1 %TFA in H2O (v / v)

[0574] Mobile Phase B: 0.1 %TFA in ACN (v / v) Flow rate: 1.5 mL / min

[0575] 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

[0576] Method 27

[0577] Stationary phase: Waters X Bridge C18, 50 x 4.6 mm, 5 pM

[0578] Injection Volume 5.0 pL Flow Rate 2 mL / min Detection: MS-ESI+ m / z 80 to 1200

[0579] UV-DAD 190-400 nm

[0580] Mobile Phase A: 10mmol / L NH4HCO3 in H2O

[0581] Mobile Phase B: acetonitrile

[0582] Gradient program: 10% B increase to 30% B within 0.40 min, increase to 95% B within 1.60min, Hold at 95% B for 0.9 min, back to 10% B within 0.01 min Method 28

[0583] Stationary phase: Waters SunFire C18, 50 x 4.6 mm, 5 .m

[0584] Mobile Phase A: 0.1 %FA in H2O (V / V)

[0585] Mobile Phase B: 0.1 %FA in ACN (v / v)

[0586] Flow rate: 2.0 mL / min

[0587] Gradient program: 10% B increase to 30% B within 0.40 min, increase to 95% B within

[0588] 1.60min, Hold at 95% B for 0.9 min, back to 10% B within 0.01 min

[0589] Method 29

[0590] Stationary phase: Waters SunFire C1 ,8 150 x 4.6 mm, 5 .m

[0591] Mobile Phase A: 0.03% TFA in H2O (v / v)

[0592] Mobile Phase B: 0.03% TFA in ACN(v / v)

[0593] Flow rate: 1.00 ml / min

[0594] 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

[0595] Commercial Materials

[0596] All starting materials are commercially available unless otherwise stated.

[0597] Synthesis of Intermediates

[0598] Intermediate compounds may have been prepared in a plurality of batches and the batch used in subsequent steps described herein may not be the same batch as that exemplified.

[0599] INTERMEDIATE 1 tert-butyl (R)-(1-(6-chloropyridazin-3-yl)pyrrolidin-3-yl)carbamate

[0600] Three reactions were run in parallel. To a solution of 3,6-dichloropyridazine (250 g, 1.68 mol, 1.0 eq.), terf-butyl ( ?)-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, 99.7% purity) 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 [MH]+, RT 0.866 minutes.

[0601] INTERMEDIATE 2 tert-.

[0602] Three reactions were run in parallel. To a solution of tert-butyl (R)-(1-(6-chloropyridazin-3- yl)pyrrolidin-3-yl)carbamate (prepared according to the procedure of Intermediate 1) (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, 99.3% purity) as a yellow solid without further purification.1H NMR (400 MHz, CDCh) 5 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.

[0603] INTERMEDIATE 3 (R)-1-t in-3-yl)pyrrolidin-3-amine

[0604] Two reactions were run in parallel. To a solution of tert-butyl (R)-(1-(pyridazin-3-yl)pyrrolidin-3- yl)carbamate (prepared according to the procedure of Intermediate 2) (400 g, 1.51 mol, 1.00 eq.) sin 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 Na2CC 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 (Method 3, ESI) 165.1 [MH]+, RT 0.654 minutes. INTERMEDIATE 4 (R)-N2-(1-(pyridazin-3-yl)pyrrolidin-3-yl)-1 ,3,4-thiadiazole-2,5-diamine

[0605] Three reactions were run in parallel. To a solution of (R)-1-(pyridazin-3-yl)pyrrolidin-3-amine (prepared according to the procedure of Intermediate 3) (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 RT and filtered. The filter cake was collected and dried in vacuo afford the title compound (252 g, 44.5% yield, 98.9% purity) 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.

[0606] INTERMEDIATE 5 (R)-1-(6-chloropyridazin-3-yl)pyrrolidin-3-amine, dihydrochloride

[0607] To a solution of tert-butyl (R)-(1-(6-chloropyridazin-3-yl)pyrrolidin-3-yl)carbamate (prepared according to the procedure of Intermediate 1) (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-de) 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 4, ESI) 199.1 [MH]+, RT 0.211 minutes.

[0608] To a solution of (R)-1-(6-chloropyridazin-3-yl)pyrrolidin-3-amine, dihydrochloride (prepared according to the procedure of Intermediate 5) (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-de) 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 5, ESI) 298.1 / 300.0 [MH]+, RT 1.123 minutes.

[0609] INTERMEDIATE 7 methyl 2-bromo-2-cvclopentylacetate

[0610] To a stirred solution of cyclopentylacetic acid (0.25 g, 8.97 mmol, 1 eq.) in chloro-benzene (12.5 mL, 0.15 M) was added phosphorus tribromide (1.11 mL, 11.70 mmol, 6 eq.) under argon atmosphere. The mixture was stirred for 2 h at r.t. and bromine (0.46 mL, 9.97 mmol, 4.6 eq.) was added. The reaction mixture was stirred at reflux for 7 h, then the mixture was cooled down to 0°C and MeOH (20 mL) was added dropwise. The mixture was warm to r.t. and stirred for 16 h. The solvent was evaporated in vacuo and the crude obtained was dissolved in EtOAc, washed with saturated aqueous sodium bicarbonate solution. Combined organic layers were dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The crude was purified by flash chromatography (silica, 10% DCM in hexane) to afford the title compound (0.11 g, 24%) as a yellow oil.1H NMR (300 MHz, CDCI3) 6 4.12 (d, = 9.6 Hz, 1 H), 3.80 (s, 3H), 2.65-2.44 (m, 1 H), 2.07-1.93 (m, 1 H), 1.91-1.74 (m, 1 H), 1.74-1.59 (m, 4H), 1.53-1.39 (m, 1 H), 1.37-1.13 (m, 1 H). INTERMEDIATE 8 methyl 2-cyclopentyl-2-(4-methylpiperazin-1-yl)acetate

[0611] To a solution of methyl 2-bromo-2-cyclopentylacetate (prepared according to the procedure of Intermediate 7) (0.11 g, 0.47 mmol, 1 eq.) and 1 -methylpiperazine (0.06 mL, 0.51 mmol, 1.1 eq.) in ACN (0.1 M) was added Et3N (0.20 mL, 1.40 mmol, 3 eq.). The mixture was stirred for 8 h at 90°C, then concentrated in vacuo. The crude was purified by flash chromatography (silica, 10% DCM in MeOH) to afford the title compound (0.05 g, 36%) as a colourless oil.1H NMR (300 MHz, CDCh) 6 3.68 (s, 3H), 2.89 (d, J = 11.0 Hz, 1 H), 2.81-2.67 (m, 2H), 2.67-2.40 (m, 6H), 2.35 (s, 3H), 2.34-2.20 (m, 1 H), 1.81-1.52 (m, 5H), 1.48-1.36 (m, 2H), 1.18-1.06 (m, 1 H).

[0612] INTERMEDIATE 9 2-cyclopentyl-2-(4-methylpiperazin-1-yl)acetic acid

[0613] A solution of methyl 2-cyclopentyl-2-(4-methylpiperazin-1-yl)acetate (prepared according to the procedure of Intermediate 8) (0.04 g, 0.17 mmol, 1 eq.) and lithium hydroxide monohydrate (0.01 g, 0.34 mmol, 2 eq.) in THF (0.1 M) was heated at 60°C for 72 h, then quenched with H2O. The mixture was washed with DCM and aqueous layer was neutralized and concentrated in vacuo. The white solid residue was washed with ACN and filtered off. The filtrate was concentrated in vacuo to afford the title compound (0.03 g, 79%) as a white solid without purification.1H NMR (300 MHz, MeOD-d4) 6 3.18-2.77 (m, 9H), 2.69 (s, 3H), 2.35-2.18 (m, 1 H), 1.86-1.39 (m, 7H), 1.38-1.16 (m, 1 H).

[0614] INTERMEDIATE 10 2-cyclohexyl-2-(4-methylpiperazin-1-yl)acetic acid

[0615] Intermediate 10 was prepared from cyclohexylacetic acid (1.00 g, 7.03 mmol, 1 eq.) following same procedure as for Intermediate 9 from cyclopentylacetic acid. The title compound (0.04 g, 66%) was used in the next step without any further purification. LIPLC (Method 6, ESI) 241 [MH]+, RT 1.32 minutes. INTERMEDIATE 11 2- / 3-[(tert-butoxy)carbonyll-3-azaspiro[5.51undecan-9-yl}acetic acid

[0616] To a solution of tert-butyl 9-(2-methoxy-2-oxoethyl)-3-azaspiro[5.5]undecane-3-carboxylate (0.08 g, 0.25 mmol, 1 eq.) in MeOH (1.23 mL) was added aqueous sodium hydroxide solution (1 M, 0.49 mL, 0.49 mmol, 2 eq.). The reaction mixture was stirred at r.t. for 16 h and the resulting mixture was concentrated in vacuo. The solution was then diluted with water and acidified with 10% aqueous potassium hydrogen sulphate solution to pH = 5. The precipitate was filtered off and washed with water. The solid was dried in vacuo to afford the title compound (0.08 g, 99%) as a white solid.1H NMR (300 MHz, DMSO-d6) 5 11.95 (s, 1 H), 3.28-3.21 (m, 4H), 2.11 (d, J = 6.9 Hz, 2H), 1.68-1.54 (m, 3H), 1.54-1.44 (m, 2H), 1.38 (s, 11 H), 1.24-1.16 (m, 2H), 1.15-0.99 (m, 4H). UPLC (Method 6, ESI) 312.0 [MH]+, RT 2.34 minutes.

[0617] INTERMEDIATE 12 tert-butyl 9- r(5- r(3R)-1-(pyridazin-3-yl)pyrrolidin-3-yllamino}-1,3,4- thiadiazol-2-yl)carbamoyl]methyl}-3-azaspiro[5.51undecane-3-carboxylate

[0618] 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 4) (0.07 g, 0.26 mmol, 1.2 eq.) and Intermediate 11 (0.07 g, 0.21 mmol, 1 eq.) in DMF (0.57 mL) under argon atmosphere were added DIPEA (0.26 mL, 1.46 mmol, 6.8 eq.) and 1-propylphosphonic acid cyclic anhydride in DMF (50+% soln., 0.57 mL, 0.98 mmol, 4.6 eq.). The reaction mixture was stirred at r.t. for 16 h before 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 twice with DCM. Combined organic phases were washed with water and brine, dried over sodium sulphate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica, 0-10% MeOH in DCM) to afford the title compound (0.17 g, 62%) as a yellowish solid.1H NMR (300 MHz, CDCh) 6 12.14 (s, 1 H), 8.53 (s, 1 H), 7.21-7.12 (m, 1 H), 6.62 (d, J = 9.2 Hz, 1 H), 5.99 (s, 1 H), 4.50 (s, 1 H), 3.96-3.86 (m, 1 H), 3.86-3.74 (m, 1 H), 3.76-3.57 (m, 2H), 3.46-3.13 (m, 4H), 2.54 (d, J = 5.6 Hz, 2H), 2.49-2.15 (m, 2H), 2.07-1.76 (m, 1 H), 1.64-1.59 (m, 2H), 1.54-1.37 (m, 11 H), 1.31-1.05 (m, 8H). UPLC (Method 6, ESI) 528.15 [MH]+, RT 2.08 minutes. INTERMEDIATE 13 (2S)-2-cyclohexyl-2

[0619] To a stirred solution of L-a-cyclohexylglycine (0.10 g, 0.64 mmol, 1 eq.) in MeOH (4.5 mL) were added paraformaldehyde (0.04 g, 1.34 mmol, 2.1 eq.) and acetic acid (0.02 mL, 0.64 mmol, 1 eq.) under argon atmosphere. The mixture was stirred for 18 h at40°C, then sodium cyanoborohydride (95 mg, 1.59 mmol, 2.5 eq.) was added. The reaction mixture was stirred for 18 h at 40°C, then diluted with saturated sodium bicarbonate solution and extracted with DCM (3 x 100 mL). Aqueous layer was acidified with 1 M aqueous HCI to pH = 6 and extracted with DCM. Water layer was concentrated in vacuo and MeOH (30 mL) was added to the solid residue. The suspension was filtrated, and the filtrate was concentrated in vacuo. The crude obtained was purified by reverse phase column chromatography (silica, 0-100% ACN in H2O) to afford the title compound (0.06 g, 49%) as an off-white solid.1H NMR (400 MHz, DMSO-d6) 5 2.69 (d, J = 9.4 Hz, 1 H), 2.26 (s, 6H), 1.86-1.79 (m, 1 H), 1.67-1.51 (m, 5H), 1.24-1.06 (m, 3H), 0.99-0.86 (m, 2H).

[0620] INTERMEDIATE 14 (2R)-2-cvclohexyl-2

[0621] To a stirred solution of D-a-cyclohexylglycine (0.50 g, 3.18 mmol, 1 eq.) in MeOH (22.7 mL) were added paraformaldehyde (0.20 g, 6.68 mmol, 2.1 eq.) and acetic acid (0.11 mL, 3.18 mmol, 1 eq.) under argon atmosphere. The mixture was stirred for 18 h at40°C, then sodium cyanoborohydride (0.48 g, 7.95 mmol, 2.5 eq.) was added. The reaction mixture was stirred at 40°C for 48 h, then concentrated in vacuo to afford the title compound (0.59 g, quantitative) as an off-white solid. The crude product was used in the next step without further purification. UPLC (Method 6, ESI) 186.10 [MH]+, RT 1.12 minutes.

[0622] INTERMEDIATE 15 tert-butyl N-r(3R)-1-(6-iodopyridazin-3-yl)pyrrolidin-3-yl]carbamate

[0623] The mixture of ( )-(+)-3-(Boc-amino)pyrrolidine (1.50 g, 8.05 mmol, 1 eq.), 3,6-diiodo-pyridazine (2.54 g, 7.65 mmol, 0.95 eq.) and potassium carbonate anhydrous (2.23 g, 16.11 mmol, 2 eq.) in DMF (20.13 mL) was heated to 80°C for 16 h. The solvent was evaporated in vacuo and the crude material was purified by flash column chromatography (silica, 0-10% MeOH in DCM) to afford the title compound (2.04 g, 65%) as a yellow solid.1H NMR (300 MHz, DMSO-cfe) 6 7.64 (d, J = 9.4 Hz, 1 H), 7.22 (d, J = 6.8 Hz, 1 H), 6.68 (d, J = 9.4 Hz, 1 H), 4.17-4.07 (m, 1 H), 3.65-3.38 (m, 3H), 3.28-3.20 (m, 1 H), 2.20-2.05 (m, 1 H), 1.96-1.82 (m, 1 H), 1.39 (s, 9H). UPLC (Method 6, ESI) 391.6 [MH]+, RT 1.56 minutes.

[0624] INTERMEDIATE 16 (3R)-1-(6-iodopyridazin-3-yl)pyrrolidin-3-amine, hydrochloride

[0625] Tert-butyl N-[(3R)-1-(6-iodopyridazin-3-yl)pyrrolidin-3-yl]carbamate (prepared according to the procedure of Intermediate 15) (2.04 g, 5.23 mmol, 1 eq.) was dissolved in DCM (52.28 mL), and HCI solution in 1 ,4-dioxane (4 M, 5.23 mL, 20.91 mmol, 4 eq.) was added. The reaction mixture was stirred at r.t. for 72 h, and then evaporated in vacuo to afford the title compound (1.97 g, 96%) as a beige solid.1H NMR (300 MHz, DMSO-cfe) 6 8.37 (s, 3H), 7.83 (d, = 9.4 Hz, 1 H), 6.97 (d, J = 9.4 Hz, 1 H), 4.03-3.92 (m, 1 H), 3.78-3.69 (m, 1 H), 3.68-3.49 (m, 3H), 2.38-2.25 (m, 1 H), 2.22-2.10 (m, 1 H). UPLC (Method 6, ESI) 291.0 [MH]+, RT 0.97 minutes.

[0626] INTERMEDIATE 17 N2-1(3R)-1-(6-iodopyridazin-3-yl)pyrrolidin-3-yl]- 3 -thiadiazole-2.5- diamine

[0627] A mixture of (3R)-1-(6-iodopyridazin-3-yl)pyrrolidin-3-amine, hydrochloride (prepared according to the procedure of Intermediate 76)(1.97 g, 4.99 mmol, 1 eq.), 2-amino-5-bromo-1 ,3,4- thiadiazole (0.94 g, 5.24 mmol, 1.05 eq.) and potassium carbonate anhydrous (3.45 g, 24.96 mmol, 5 eq.) in anhydrous DMF (49.93 mL) was heated at60°C for 16 h. 2-Amino-5-bromo-1 ,3,4- thiadiazole (0.94 g, 5.24 mmol, 1.05 eq.) was added and the reaction mixture was heated at 70°C for 4 h. The solvent was evaporated in vacuo and the crude material was purified by flash chromatography (silica, 0-10% 3M NHs / MeOH in DCM) to afford the title compound (1 .79 g, 88%) as a brown solid.1H NMR (300 MHz, DMSO-cfe) 6 7.64 (d, J = 9.4 Hz, 1 H), 7.07 (d, J = 5.9 Hz, 1 H), 6.71 (d, J = 9.4 Hz, 1 H), 6.29 (s, 2H), 4.31-4.20 (m, 1 H), 3.72-3.62 (m, 1 H), 3.56-3.46 (m, 2H), 3.46-3.36 (m, 1 H), 2.27-2.14 (m, 1 H), 2.10-1.94 (m, 1 H). UPLC (Method 6, ESI) 389.95 [MH]+, RT 1.25 minutes. INTERMEDIATE 18 2-cvcloheptyl-N-(5- / [(3R)-1-(6-iodopyndazin-3-yl)pyrrolidin-3-yllamino}-

[0628] 1 , 3, 4-thiadiazol-2-yl)acetamide

[0629] To a stirred solution of N2-[(3R)-1-(6-iodopyridazin-3-yl)pyrrolidin-3-yl]-1 ,3,4-thiadiazole-2,5- diamine (prepared according to the procedure of Intermediate 17) (0.20 g, 0.49 mmol, 1 eq.) and 2-cycloheptylacetic acid (0.08 g, 0.49 mmol, 1 eq.) in anhydrous DMF (0.57 mL) under argon atmosphere, DI PEA (0.26 mL, 1.46 mmol, 3 eq.) and 1-propylphosphonic acid cyclic anhydride in DMF (50+% soln., 0.57 mL, 0.98 mmol, 2 eq.) were added. The reaction mixture was stirred at r.t. for 16 h. The resulting 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 twice with DCM. Combined organic phases were washed with water and brine, dried over sodium sulphate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica, 0-10% MeOH in DCM) to afford the title compound (0.17 g, 62%) as a yellowish solid.1H NMR (300 MHz, DMSO-d6) 5 11.89 (s, 1 H), 7.66 (d, J = 9.4 Hz, 1 H), 7.60 (d, J = 6.0 Hz, 1 H), 6.73 (d, J =9.4 Hz, 1 H), 4.42-4.32 (m, 1 H), 3.72 (dd, J = 11.2, 5.8 Hz, 1 H), 3.59-3.42 (m, 3H), 2.33-2.24 (m, 3H), 2.12-2.02 (m, 1 H), 2.02-1.91 (m, 1 H), 1.63-1.34 (m, 9H), 1.25-1.11 (m, 3H). UPLC (Method 6, ESI) 528.15 [MH]+, RT 2.08 minutes.

[0630] INTERMEDIATE 19 Methyl 2-[spiro[3.

[0631] A mixture of spiro[3.5]nonan-7-one (0.60 g, 4.34 mmol, 1 eq.) and methyl(triphenyl- phosphoranylidene)acetate (3.05 g, 9.12 mmol, 2.1 eq.) in toluene (0.15 M) was refluxed for 10 h, then quenched with saturated aqueous ammonium chloride solution (30 mL) and extracted with EtOAc (2 x 40 mL). Combined organic layers were dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The crude residue was purified by flash chromatography (silica, 10% EtOAc in hexanes) to afford the title compound (0.58 g, 62%) as a yellow oil.1H NMR (300 MHz, CDCh) 6 5.60 (s, 1 H), 3.68 (s, 3H), 2.78 (t, J = 6.1 Hz, 2H), 2.29 (t, J = 6.7 Hz, 1 H), 2.14 (t, J = 6.3 Hz, 2H), 1.92-1.85 (m, 2H), 1.82-1.73 (m, 3H), 1.68-1.59 (m, 4H).

[0632] INTERMEDIATE 20 Methyl 2-fspiro[3. To a solution of methyl 2-{spiro[3.5]nonan-7-ylidene}acetate (prepared according to the procedure of Intermediate 19) (0.58 g, 2.69 mmol, 1 eq.) in MeOH (0.15 M) under argon atmosphere was added palladium on carbon (10% wet., 0.086 g, 0.81 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 was filtered through a pad of celite and concentrated in vacuo. The crude product (0.55 g, 94%) was used without any further purification.1H NMR (300 MHz, CDCh) 6 3.68 (s, 3H), 2.19 (d, J = 7.1 Hz, 2H), 1.89-1.79 (m, 2H), 1.76-1.66 (m, 6H), 1.60- 1.50 (m, 3H), 1.28 (td, J = 12.9, 3.4 Hz, 2H), 1.10-0.93 (m, 2H).

[0633] INTERMEDIATE 21 2-[spiro[3.51nonan

[0634] To a stirred solution of methyl 2-{spiro[3.5]nonan-7-yl}acetate (prepared according to the procedure of Intermediate 20) (0.45 g, 2.06 mmol, 1 eq.) in MeOH (10.32 mL) was added aqueous sodium hydroxide solution (1 M, 4.10 mL, 4.13 mmol, 2 eq.) and the solution was stirred at 40°C for 16 h. The reaction mixture was concentrated in vacuo till complete removal of MeOH. The solution was then diluted with water and acidified with aqueous potassium hydrogen sulphate solution (10%) till pH = 5. The precipitate was filtered off, washed with excess of water and dried. The title compound (0.26 g, 70%) was obtained as a white solid.1H NMR (300 MHz, DMSO-cfe) 5 11.97 (s, 1 H), 2.05 (d, J = 6.7 Hz, 2H), 1.86-1.73 (m, 2H), 1.73-1.57 (m, 6H), 1.57-1.44 (m, 3H), 1.28-1.13 (m, 2H), 1.02-0.84 (m, 2H).

[0635] INTERMEDIATE 22 Methyl 2-bromo-2

[0636] 2-{spiro[3.5]nonan-7-yl}acetic acid (prepared according to the procedure of Intermediate 21) (0.26 g, 0.14 mmol, 1 eq.) was dissolved in SOCh (10.3 mL) and 1 drop of DMF was added. The mixture was stirred at 90°C for 5 h, then bromine (0.22 mL, 4.26 mmol, 3 eq.) was added slowly at 50°C and stirring was continued at 90°C for 16 h. The reaction mixture was cooled down to r.t. and MeOH was added. The mixture was stirred at r.t. for 30 min and the solvent was evaporated. The crude was dissolved in DCM and washed with saturated aqueous sodium bicarbonate solution. Combined organic layers were dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The title compound (0.39 g, quantitative) was used in the next step without any further purification.1H NMR (300 MHz, CDCh) 6 3.99 (d, J = 8.9 Hz, 1 H), 3.77 (s, 3H), 1.95-1.66 (m, 10H), 1.54-1.46 (m, 1 H), 1.33-1.19 (m, 2H), 1.17-0.98 (m, 2H). INTERMEDIATE 23 Methyl 2-(4-methy

[0637] To a stirred solution of methyl 2-bromo-2-{spiro[3.5]nonan-7-yl}acetate (prepared according to the procedure of Intermediate 22) (0.37 g, 1.34 mmol, 1 eq.) in ACN (6.5 mL), was added 1- methylpiperazine (0.18 mL, 1.61 mmol, 1.2 eq.) followed by Et3N (0.56 mL, 4.03 mmol, 3 eq.). The reaction mixture was then stirred at r.t. for 16 h. 1 -Methylpiperazine (0.18 mL, 1.61 mmol, 1.2 eq.) and Et3N (0.56 mL, 4.03 mmol, 3 eq.) were added and the reaction mixture was stirred at r.t. for 72 h. The resulting 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 twice with DCM. Combined organic phases were washed with water and brine, dried over sodium sulphate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica, 0-10% MeOH in DCM) to afford the title compound (0.09 g, 23%) as a yellow oil.1H NMR (300 MHz, DMSO-d6) 5 3.60 (s, 3H), 2.82 (d, J =10.5 Hz, 1 H), 2.48-2.35 (m, 4H), 2.27 (s, 4H), 2.11 (s, 3H), 1.82-1.59 (m, 10H), 1.22-1.11 (m, 3H), 0.99-0.81 (m, 2H). UPLC (Method 6, ESI) 295.5 [MH]+, RT 1.78 minutes.

[0638] INTERMEDIATE 24 2-(4-Methylpipera

[0639] To a solution of methyl 2-(4-methylpiperazin-1-yl)-2-{spiro[3.5]nonan-7-yl}acetate (prepared according to the procedure of Intermediate 23) (0.09 g, 0.31 mmol, 1 eq.) in MeOH (1.53 mL), aqueous sodium hydroxide solution (1 M, 0.025 g, 0.61 mmol, 2 eq.) was added. The reaction mixture was stirred at 80°C for 48 h. The mixture was concentrated in vacuo to afford the title compound (0.12 g, quantitative) without further purification.1H NMR (300 MHz, DMSO-cfe) 52.47- 2.39 (m, 4H), 2.30 (d, J = 10.1 Hz, 1 H), 2.27-2.11 (m, 4H), 2.08 (s, 3H), 1.83-1.71 (m, 2H), 1.72- 1.57 (m, 7H), 1.53-1.39 (m, 2H), 1.19-1.05 (m, 2H), 0.88-0.74 (m, 2H). UPLC (Method 6, ESI) 281.3 [MH]+, RT 1.75 minutes. INTERMEDIATE 25 tert-Butyl (R)-3-((5-amino-1, 3, 4-thiadiazol-2-yl)amino) pyrrolidine-1 - carboxylate

[0640] To a stirred solution of 5-bromo-1 ,3,4-thiadiazol-2-amine (4.00 g, 22.2 mmol, 1.0 eq.) in ACN (20 mL) was added terf-butyl (R)-3-aminopyrrolidine-1-carboxylate (4.95 g, 26.6 mmol, 1.2 eq.) and K2CO3 (9.19 g, 66.6 mmol, 3.0 eq.) under nitrogen atmosphere. The mixture was stirred for 6 h at 80°C before concentrated in vacuo. The crude residue was purified by flash chromatography (silica, 0-10% MeOH in DCM) to afford the title compound (5.0 g, 79%) as a yellow solid.1H NMR (400 MHz, DMSO-ds) 6 7.00 (t, J = 5.6 Hz, 1 H), 6.28 (s, 2H), 4.07-3.96 (m, 1 H), 3.49-3.44 (m, 1 H), 3.31-3.22 (m, 1 H), 3.20-3.15 (m, 1 H), 2.07-2.04 (m, 1 H), 1.85-1.81 (m, 1 H), 1.39 (s, 9 H). LCMS (Method 7, ESI) 286.1 [MH]+, RT 1.533 minutes.

[0641] INTERMEDIATE 26 tert-butyl (3R)-3-((5-(2-((1s,3S)-adamantan-1-yl)acetamido)-1,3,4- thiadiazol-2-yl)amino)pyrrolidine-1 -carboxylate

[0642] A mixture of 2-((1 S,3S)-adamantan-1-yl) acetic acid (100 mg, 0.52 mmol, 1.0 eq.) in SOCI2 (2.5 mL) was stirred at 85°C for 4 h under argon atmosphere. The reaction mixture was cooled to r.t. and concentrated in vacuo to remove SOCh and dry-DCM (10 mL x 2) was then added and evaporated in vacuo. Then a solution of tert-Butyl (R)-3-((5-amino-1 ,3,4-thiadiazol-2- yl)amino)pyrrolidine-1-carboxylate (prepared according to the procedure of Intermediate 25) (148 mg, 0.52 mmol, 1 .0 eq.) and TEA (158 mg, 1 ,56mmol, 3.0 eq.) in dry-DCM (3 mL) was added to the above residue in DCM (2 mL) dropwise at 0 °C, which was stirred at r.t. for 16 h. The reaction mixture was concentrated in vacuo and purified by flash chromatography (silica, 0-10% MeOH in DCM) to afford the title compound (200 mg, 83%) as a pale-yellow solid. LCMS (Method 8, ESI) 462.2 [MH]+, RT 2.039 minutes.

[0643] INTERMEDIATE 27 2-((1S,3S)-adamantan-1-yl)-N-(5-(((R)-pyrrolidin-3-yl)amino)-1 ,3,4- thiadiazol-2-yl)acetamide, hydrochloride A solution of tert-butyl (3R)-3-((5-(2-((1s,3S)-adamantan-1-yl)acetamido)-1 ,3,4-thiadiazol-2- yl)amino)pyrrolidine-1 -carboxylate (prepared according to the procedure of Intermediate 26) (200 mg, 0.43mmol, 1.0 eq.) in HCI (1.0 mL, 4 M in dioxane, 10.0 eq.) was stirred at r.t. for 4 h. This solution was concentrated in vacuo, and the residue was triturated with ethyl acetate (5 mL) to afford the title compound (173 mg, 100%) as a pale-yellow solid. LCMS (Method 9, ESI) 362.1 [MH]+, RT 1.796 minutes. pyridazin-S-vDpyrrolidin-

[0644] To a solution of 2-((1S,3S)-adamantan-1-yl)-N-(5-(((R)-pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2- yl)acetamide, hydrochloride (prepared according to the procedure of Intermediate 27) (173 mg, 0.43 mmol, 1.0 eq.) and 6-iodopyridazin-3-amine (95 mg, 0.43 mmol, 1.0 eq.) in dry-DMSO (4.0 mL) was added K3PO4 (365 mg, 1.72 mmol, 4.0 eq.), Cui (32 mg, 0.17 mmol, 0.4 eq.) and L-OH- Proline (34 mg, 0.26 mmol, 0.6 eq.) at r.t under argon atmosphere. The reaction mixture was heated at 50°C for 24 h. The reaction mixture was filtered, and the filtrate was purified by reverse phase column chromatography (C-120 g, ACN%=50%, +0.1 % NH3H2O) to afford the title compound (57 mg, 29%) as a yellow solid. LCMS (Method 9, ESI) 455.1 [MH]+, RT 1.599 minutes.

[0645] INTERMEDIATE 29 2-((1s,3S)-adamantan-1-yl)-N-(5-(((R)-1-(6-(2-chloroacetamido)pyridazin-3- yl)pyrrolidin-3-yl)amino)-1,3,4-thiadiazol-2-yl)acetamide

[0646] To a solution of 2-((1S,3S)-adamantan-1-yl)-N-(5-(((R)-1-(6-aminopyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide (prepared according to the procedure of Intermediate 28) (57 mg, 0.13 mmol, 1.0 eq.) in DCM (2.0 mL) was added 2-chloroacetyl chloride (19 mg, 0.16 mmol, 1 .2 eq.) and TEA (39 mg, 0.39 mmol, 3.0 eq.) at 0°C, and the solution was stirred at r.t. for 3 h. The solution was quenched with MeOH and concentrated in vacuo. The residue was purified by flash chromatography (silica, 0-10% MeOH in DCM) to afford the title compound (26 mg, 38%) as a white solid. LCMS (Method 10, ESI) 531.1 [MH]+, RT 1.693 minutes. INTERMEDIATE 30 tert-butyl N-[(3S,4S)-1-(6-chloropyridazin-3-yl)-4-fluoropyrrolidin-3- yllcarbamate

[0647] HN-Boc

[0648] To a stirred solution of terf-butyl A / -[(3S,4S)-4-fluoropyrrolidin-3-yl]carbamate (0.9 g, 4.40 mmol, 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%) as a white solid.1H NMR (300 MHz, CDCh) 6 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).

[0649] INTERMEDIATE 31 tert-butyl N-[(3S,4S)-4-fluoro-1-(pyridazin-3-yl)pyrrolidin-3-yllcarbamate

[0650] To a solution of tert-butyl N-[(3S,4S)-1-(6-chloropyridazin-3-yl)-4-fluoropyrrolidin-3-yl]carbamate (prepared according to the procedure of Intermediate 30) (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%) was used directly in the next step without any further purification.1H NMR (300 MHz, DMSO-cfe) 6 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 = 52.0 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 6, ESI) 283.15 [MH]+, RT 1.67 minutes.

[0651] INTERMEDIATE 32 (3S,4S)-4-fluoro-1-(pyridazin-3-yl)pyrrolidin-3-amine hydrochloride

[0652] To a solution of tert-butyl N-[(3S,4S)-4-fluoro-1-(pyridazin-3-yl)pyrrolidin-3-yl]carbamate (prepared according to the procedure of Intermediate 31) (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 evaporated in vacuo, crude was washed with Et2<D to afford the title compound (1 .97 g, 96%) 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, 1.0 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-

[0653] 3.51 (m, 1 H). UPLC (Method 6, ESI) 183.05 [MH]+, RT 0.47 minutes.

[0654] INTERMEDIATE 33 N2-r(3S,4S)-4-fluoro-1-(pyridazin-3-yl)pyrrolidin-3-yll-1 thiadiazole^S- diamine

[0655] A mixture of (3S,4S)-4-fluoro-1-(pyridazin-3-yl)pyrrolidin-3-amine hydrochloride (prepared according to the procedure of Intermediate 32) (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 evaporated, and the crude material was purified by flash chromatography (silica, 0-10% MeOH in DCM) to afford the title compound (0.11 g, 58%) 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 6, ESI) 282.05 [MH]+, RT 0.51 minutes.

[0656] INTERMEDIATE 34 2-(4,4-dimethylcvclohexyl)-2-(4-methylpiperazin-1-yl)acetic acid;

[0657] INTERMEDIATE 35 (R)-2-(4,4-dimethylcyclohexyl)-2-(4-methylpiperazin-1-yl)acetic acid; and

[0658] INTERMEDIATE 36 (S)-2-(4,4-dimethylcyclohexyl)-2-(4-methylpiperazin-1-yl)acetic acid

[0659] Stepl : benzyl 2-(4, 4-dimethylcyclohexylidene)acetate

[0660] To a mixture of benzyl 2-(dimethoxyphosphoryl)acetate (40 g, 155.04 mmol, 1.1 eq.) in dry-THF (400 mL) was added NaH (9.30 g, 155.04 mmol, 1.1 eq.) slowly portion-wise at O °C. The resulting mixture was stirred at 0 °C for 1 h under argon. The solution of 4,4-dimethylcyclohexan-1-one (17.76 g, 140.92 mmol, 1.0 eq.) in dry-THF (10 mL) was then added dropwise. The resulting mixture was stirred at r.t. for 3 h. The reaction mixture was then quenched with saturated aqueous ammonia chloride (100 mL), extracted with EtOAc (100 mL x 3). 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, 0-3% EtOAc in PE) to afford the title compound (31.12 g, 85.6%) as a colourless oil.1H NMR (400 MHz, DMSO-d6) 5 7.39-7.30 (m, 4H), 5.69 (s, 1 H), 5.10 (s, 2H), 2.81 (t, J = 5.6 Hz, 2 H), 2.22 (t, =6.4 Hz, 2 H), 1.40-1.34 (m, 4 H), 0.95 (s, 6 H).

[0661] Step 2: 2-(4, 4-dimethylcvclohexyl)acetic acid

[0662] To a solution of benzyl 2-(4,4-dimethylcyclohexylidene)acetate (31.32 g, 121.39 mmol) in EtOAc (400 mL) was added Pd / C (3.0 g, 10%). The resulting mixture was stirred at r.t. for 16 h under hydrogen (1 atm.). The reaction mixture was filtered and concentrated in vacuo to afford the title compound as a white solid.1H NMR (400 MHz, DMSO-d6) 6 11.96 (s, 1 H), 2.10 (d, = 6.8 Hz, 2 H), 1.63-1.51 (m, 3 H), 1.42-1.31 (m, 2H), 1.25-1.04 (m, 4 H), 0.88 (s, 3H), 0.85 (s, 3H).

[0663] Step 3: 2-bromo-2-(4, 4-dimethylcvclohexyl)acetyl chloride

[0664] A mixture of 2-(4,4-dimethylcyclohexyl)acetic acid (31.32 g, 184.24 mmol, 1.0 eq.) in SOCh (50 mL) was stirred at 85°C for 5 h under argon. The reaction mixture was cooled to r.t. , then aq. HBr (48% in H2O) (30 drops) was added followed by Br2 (88.45 g, 552.72 mmol, 3.0 eq.). The resulting mixture was stirred at 70°C for 3 h. The reaction mixture was cooled to r.t. and concentrated in vacuo to remove SOCI2 and Br2 to afford the title compound (50.38 g, quantitative) as a paleyellow oil, which was used in the next step without further purification.

[0665] Step 4: benzyl 2-bromo-2-(4, 4-dimethylcyclohexyl)acetate

[0666] To a stirred solution of 2-bromo-2-(4,4-dimethylcyclohexyl)acetyl chloride (50 g crude, 186.57 mmol, 1.0 eq.) in dry-DCM (500 mL) was added benzyl alcohol (28.21 g, 261.20 mmol, 1.4 eq.) slowly at 0°C under argon, followed by TEA (37.69 g, 373.14 mmol, 2.0 eq.). The resulting mixture was stirred at r.t. for 3 h. The reaction mixture was quenched with saturated aqueous ammonia chloride (100 mL) at 0°C, extracted with EtOAc (100 mL x 3). The combined organic phase was washed with brine (100 mL), dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica, 0-3% EtOAc in PE) to afford the title compound (25 g, 40.0% over 2 steps) as a yellow oil.1H NMR (400 MHz, DMSO-ds) 6 ppm 7.39-7.34 (m, 5 H), 5.20 (s, 2 H), 4.49 (d, J= 8.0 Hz, 1 H), 1.73-1.69 (m, 2 H), 1.38-1.12 (m, 7 H), 0.87 (s, 3 H), 0.83 (s, 3 H).

[0667] Step 5: benzyl 2-(4, 4-dimethylcyclohexyl)-2-(4-methylpiperazin- 1-yl) acetate

[0668] A mixture of benzyl 2-bromo-2-(4,4-dimethylcyclohexyl)acetate (25 g, 73.75 mmol, 1.0 eq.), 1- methylpiperazine (22.13 g, 221.25 mmol, 3.0 eq.) and TEA (22.35 g, 221.25 mmol, 3.0 eq.) in ACN (50 mL) in a sealed tube was stirred at 85 °C for 16 h. The reaction mixture was purified by reversed-phase column chromatography (C-120 g, ACN%=50% + 0.1% FA) to afford the title compound (16.34 g, 61.7%) as a colourless oil.1H NMR (400 MHz, DMSO-d6) 5 7.39-7.32 (m, 5 H), 5.12 (s, 2 H), 3.00 (d, J = 10.4 Hz, 1 H), 2.54-2.44 (m, 8 H), 2.23 (s, 3 H), 1.70-1.62 (m, 2 H), 1.34-1.23 (m, 3 H), 1.13-1.05 (m, 4 H), 0.86 (s, 3H), 0.83 (s, 3H). LCMS (Method 21 , ESI) 359.3 [MH]+, RT 2.213 minutes.

[0669] Step 6: 2-(4, 4-dimethylcyclohexyl)-2-(4-methylpiperazin- 1-yl) acetic acid

[0670] To a mixture of benzyl 2-(4,4-dimethylcyclohexyl)-2-(4-methylpiperazin-1-yl)acetate (7.2 g, 27.80 mmol, 1.0 eq.) in MeOH (160 mL) was added Pd / C (1.2 g, 10% on carbon, wetted with ca. 55% water) and the resulting mixture was stirred at r.t. for 16 h under hydrogen (1 atm.). The reaction mixture was filtered and the filtrate was concentrated in vacuo to afford the title compound (5.38 g, quantitative yield) as an off-white solid which was used without further purification. LCMS (Method 22, ESI): 269.2 [M+HJ+, RT 1.264 minutes.

[0671] Step 7: benzyl (S)-2-(4,4-dimethylcyclohexyl)-2-(4-methylpiperazin-1-yl)acetate & benzyl (R)-2- (4,4-dimethylcyclohexyl)-2-(4-methylpiperazin-1-yl)acetate

[0672] The compound benzyl 2-(4,4-dimethylcyclohexyl)-2-(4-methylpiperazin-1-yl)acetate (16 g, 44.57mmol,1.0 eq.) was separated by SFC to afford benzyl (S)-2-(4,4-dimethylcyclohexyl)-2-(4- methylpiperazin-1-yl)acetate (Peak 1, 7.2 g, 45% yield) as a yellow solid and benzyl ( )-2-(4,4- dimethylcyclohexyl)-2-(4-methylpiperazin-1-yl)acetate (Peak 2, 6.7 g, 41.9% yield). Chiral- Chromatography purification conditions: Column name: DAICELCHIRALCELOAD, Column Size: 250*50 mm 10 mm; Mobile Phase A: Supercritical CO2, Mobile Phase B: I PA (+0.1% 7.0mol / l Ammonia in MEOH), A:B(50:50); Flow: 140 ml / min.

[0673] Step 8: (R)-2-(4,4-dimethylcyclohexyl)-2-(4-methylpiperazin-1-yl)acetic acid (Intermediate 35) & (S)-2-(4,4-dimethylcyclohexyl)-2-(4-methylpiperazin-1-yl)acetic acid (Intermediate 36) ( )-2-(4,4-dimethylcyclohexyl)-2-(4-methylpiperazin-1-yl)acetic acid (Intermediate 35) and (S)- 2-(4,4-dimethylcyclohexyl)-2-(4-methylpiperazin-1-yl)acetic acid (Intermediate 36) were prepared using the same procedure as in Step 6 for the preparation of 2-(4,4-dimethylcyclohexyl)- 2-(4-methylpiperazin-1-yl)acetic acid (Intermediate 34).

[0674] INTERMEDIATE 37 2-(4,4-dimethylcvclohexyl)-2-(4-methylpiperazin-1-yl)acetic acid;

[0675] INTERMEDIATE 38 (R)-2-(4,4-dimethylcyclohexyl)-2-(4-methylpiperazin-1-yl)acetic acid; and

[0676] INTERMEDIATE 39 (S)-2-(4,4-dimethylcyclohexyl)-2-(4-methylpiperazin-1-yl)acetic acid

[0677] 2-(4,4-dimethylcyclohexyl)-2-(4-isopropylpiperazin-1-yl)acetic acid (Intermediate 37), (R)-2-(4,4- dimethylcyclohexyl)-2-(4-isopropylpiperazin-1-yl)acetic acid (Intermediate 38) and (S)-2-(4,4- dimethylcyclohexyl)-2-(4-isopropylpiperazin-1-yl)acetic acid (Intermediate 39) were prepared from benzyl 2-bromo-2-(4,4-dimethylcyclohexyl)acetate and 1 -isopropylpiperazine in accordance with the procedure for 2-(4,4-dimethylcyclohexyl)-2-(4-methylpiperazin-1-yl)acetic acid and corresponding enantiomers.1H NMR (400 MHz, CDCI3): 6 3.44-3.05 (m, 9 H), 1.72-1.67 (m, 2 H), 1.52-1.45 (m, 1 H), 1.37-1.35 (m, 8 H), 1.24-1.11 (m, 4 H), 0.89 (s, 3 H), 0.86 (s, 3 H). LCMS (Method 23, ESI): 297.2 [M+H]+, RT: 1.328 minutes.

[0678] Step 1 : methyl 2-bromo-2-(4, 4-dimethylcyclohexyl)acetate

[0679] To a solution of 2-bromo-2-(4,4-dimethylcyclohexyl)acetyl chloride (3.00 g, 11.28 mmol, 1.0 eq.) in DCM (45 mL) was added TEA (3.42 g, 33.84 mmol, 3.0 eq.) and MeOH (722 mg, 22.56 mmol, 2.0 eq.) at r.t. , and the mixture was stirred for 3 h before concentrated in vacuo. The residue was purified by flash chromatography (silica, EtOAc / PE=1 :9) to afford the title compound (2.30 g, 78% yield) as a yellow oil.

[0680] Step 2: methyl 2-(4, 4-dimethylcyclohexyl)-2-(piperazin- 1-yl) acetate

[0681] To a solution of methyl 2-bromo-2-(4,4-dimethylcyclohexyl)acetate (1.03 g, 3.94 mmol, 1.0 eq.) in MeCN (15 mL) was added piperazine (3.39 g, 39.40 mmol, 10.0 eq.) and TEA (1.20 g, 11.82 mmol, 3.0 eq.) at r.t., and the mixture was stirred at 80 °C for 48 h in a sealed tube (50 mL). The mixture was purified by reversed-phase chromatography (MeCN%=30% + 0.1 % FA) to afford the title compound (800 mg, 76 % yield) as a yellow oil. LCMS (Method 24, ESI): 269.3 [M+H]+, RT: 0.923 min. Step 3: methyl 2-(4, 4-dimethylcyclohexyl)-2-(4-(2-(methylthio)ethyl)piperazin- 1-yl) acetate

[0682] To a solution of methyl 2-(4,4-dimethylcyclohexyl)-2-(piperazin-1-yl)acetate (500 mg, 1.8 mmol, 1.0 eq.) in DCM (20 mL) was added 2-(methylthio)acetaldehyde (335 mg, 3.70 mmol, 2.0 eq.), NaBH(OAc)s (784 mg, 3.70 mmol, 2.0 eq.) and AcOH (15 mg). The mixture was stirred at r.t. for 16 h before quenched with water (5 mL). The aqueous solution was then extracted with DCM (3 x 20 mL), and the organic layer was separated and dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The residue was purified by reversed-phase column chromatography (MeCN%=50% +0.1% FA) to afford the title compound (130 mg, 30 % yield) as a colourless oil.1H NMR (400 MHz, DMSO-d6): 5 3.61 (s, 3 H), 2.93 (d, J = 12.0 Hz, 1 H), 2.48-2.21 (m, 12 H), 2.05 (s, 3 H), 1.41-1.04 (m, 9 H), 0.86 (d, J= 12.0 Hz, 6 H). LCMS (Method 25, ESI): 343.3 [M+H]+, RT: 2.167 min.

[0683] Step 4: 2-(4, 4-dimethylcyclohexyl)-2-(4-(2-(methylthio)ethyl)piperazin- 1-yl) acetic acid

[0684] To a solution of methyl 2-(4,4-dimethylcyclohexyl)-2-(4-(2-(methylthio)ethyl)piperazin-1-yl) acetate (130 mg, 0.38 mmol, 1.0 eq.) in MeOH (2 mL) / H2O (2 mL) was added NaOH (152 mg, 3.80 mmol, 10.0 eq.) at r.t., and the mixture was stirred at 50 °C for 48 hours. The mixture was purified by reversed-phase chromatography (MeCN%=50%, +0.1% FA) to afford the title compound (30 mg, 20 % yield) as a white solid. LCMS (Method 23, ESI): 329.1 [M+H]+, RT : 1 .288 min. Step 1 : benzyl 2-(4, 4-dimethylcvclohexylidene)acetate

[0685] To a solution of benzyl 2-(dimethoxyphosphoryl)acetate (6.60 g, 25.58 mmol, 1.2 eq.) in THF was added NaH (1.02 g, 25.58 mmol, 1.2 eq.) at 0 °C over 30 min followed by addition of 4,4- dimethylcyclohexan-1-one (2.60 g, 21.32 mmol, 1.0 eq.) in THF. The mixture was stirred at r.t. for 3 h under argon before quenched with saturated ammonium chloride solution. The mixture was extracted with EA (100 mL x 3). The organic layer was dried over sodium sulphate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica, PE / EA=20:1) to afford the title compound (7.0 g, crude) as a yellow oil.1H NMR (400 MHz, DMSO-de): 5 7.39- 7.31 (m, 5 H), 5.69 (s, 1 H), 2.02 (s, 2 H), 2.81 (t, J = 4.0 Hz, 2 H), 2.23 (t, J = 4.0 Hz, 2 H), 1 .41- 1.34 (m, 4 H), 0.95 (s, 6 H).

[0686] Step 2: benzyl 2-bromo-2-( 1-bromo-4,4-dimethylcyclohexyl)acetate

[0687] To a solution of benzyl 2-(4,4-dimethylcyclohexylidene)acetate (2.80 g, 10.85 mmol, 1.0 eq.) in DCM was added Br2 (1.74 g, 10.85 mmol, 1.0 eq.) at r.t., and the solution was stirred under argon for 6 h. The reaction mixture was then quenched with water and extrated with DCM (50 mL x 3). The organic layer was dried over sodium sulphate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica, PE / EtOAc =20:1) to afford the title compound (2.10 g, 46% ) as a yellow oil.1H NMR (400 MHz, DMSO-d6): 5 7.42-7.34 (m, 5 H), 5.23 (s, 1 H), 5.19 (s, 1 H), 2.29-1.75 (m, 4 H), 1.62-1.50 (m, 2 H), 1.36-1.33 (m, 2 H), 0.93 (s, 3 H), 0.84 (s, 3 H).

[0688] Step 3: benzyl 2-bromo-2-(4, 4-dimethylcyclohexylidene)acetate

[0689] To a solution of benzyl 2-bromo-2-(1-bromo-4,4-dimethylcyclohexyl)acetate (2.10 g, 5.02 mmol, 1 .0 eq.) in MeOH (30 mL) was added NaOMe (271 mg, 5.02 mmol, 1 .0 eq.) at r.t., and the mixture was stirred under argon for 3 h. The reaction mixture was quenched by saturated ammonium chloride solution followed by extracted with EA (500 mL x 3). The organic layer was dried over sodium sulphate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica, PE / EtOAc=20:1) to afford the title compound (1.59 g, 94 % yield) as a yellow oil.1H NMR (400 MHz, DMSO-d6): 5 7.40-7.33 (m, 5 H), 5.23 (s, 2 H), 2.51-2.44 (m, 4 H), 1.39-1.30 (m, 4 H), 0.94 (s, 6 H).

[0690] Step 4: tert-butyl 4-(2-(benzyloxy)- 1-(4, 4-dimethylcvclohexylidene)-2-oxoethyl)-3, 6- dihydropyridine-1(2H)-carboxylate

[0691] To a solution of benzyl 2-bromo-2-(4,4-dimethylcyclohexylidene)acetate (1.59 g, 4.72 mmol, 1.0 eq.) in 1 ,4-dioxane(40 mL) / H2O(4 mL) was added terf-butyl 4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.49 g, 4.72 mmol, 1.0 eq.), K2CO3 (1.30 g, 9.44 mmol, 2.0 eq.) and Pd(dppf)Cl2'DCM (381 mg, 0.47 mmol, 0.1 eq.) at r.t.. The solution was stirred at 65 °C for 16 h under argon. The mixture was diluted with water (100 mL), extracted with DCM (50 mL x 3). The organic layer was dried over sodium sulphate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica, PE / EA=20:1) to give the title compound (1.38 g, 67 % yield) as a yellow oil. 1 H NMR (400 MHz, DMSO-de): 5 7.38-7.31 (m, 5 H), 5.46 (s, 1 H), 5.12 (s, 2 H), 3.85 (s, 2 H), 3.37 (t, J = 4.0 Hz, 2 H), 2.42 (t, J = 4.0 Hz, 2 H), 2.19 (t, J = 4.0 Hz, 2 H), 2.03 (s, 1 H), 1.40 (s, 9 H), 1.35-1.31 (m, 4 H), 0.93 (s, 6 H). LCMS (Method 22, ESI): 340.3 [M-Boc]+, RT: 2.518 min.

[0692] Step 5: benzyl 2-(4,4-dimethylcyclohexylidene)-2-(1,2,3, 6-tetrahydropyridin-4-yl)acetate

[0693] To a solution of terf-butyl 4-(2-(benzyloxy)-1-(4,4-dimethylcyclohexylidene)-2-oxoethyl)-3,6- dihydropyridine-1(2H)-carboxylate (1.38 g, 3.14 mmol, 1.0 eq.) in DCM (15 mL) was added TFA (5 mL) at r.t. , and the solution was stirred for 2 h. The mixture was concentrated in vacuo afford the title compound (2.00 g, crude) as a paste. LCMS (Method 22, ESI): 340.3 [M]+, RT: 1.416 min.

[0694] Step 6: benzyl 2-(4,4-dimethylcyclohexylidene)-2-(1-isopropyl-1,2,3,6-tetrahydropyridin-4- yl) acetate

[0695] To a solution of compound benzyl 2-(4,4-dimethylcyclohexylidene)-2-(1 ,2,3,6-tetrahydropyridin- 4-yl)acetate (1.06 g, 3.14 mmol, 1.0 eq.) in DMF (10 mL) was added 2-iodopropane (2.14 g, 12.56 mmol, 4.0 eq.), K2CO3 (867 mg, 6.28 mmol, 2.0 eq.) and DIPEA (810 mg, 6.28 mmol, 2.0 eq.) at r.t.. The solution was then stirred at 45 °C for 16 h. The mixture was diluted with water (100 mL) and extracted with EA (50 mL x 3). The organic layer was dried over sodium sulphate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica, 5% MeOH in DCM) to give the title compound (1.10 g, 92 % yield) as a yellow oil.1H NMR (400 MHz, DMSO- de): 5 7.39-7.30 (m, 5 H), 5.43 (s, 1 H), 5.12 (s, 2 H), 3.03-3.02 (m, 2 H), 2.73 (s, 1 H), 2.52 (s, 2 H), 2.36 (t, J = 4.0 Hz, 2 H), 2.21 (t, J = 4.0 Hz, 2 H), 2.03 (s, 2 H), 1.34-1.31 (m, 4 H), 0.98 (d, J = 8.0 Hz, 6 H), 0.93 (s, 6 H). LCMS (Method 26, ESI) 382.2 [M+H]+, RT: 2.690 min.

[0696] Step 7: 2-(4, 4-dimethylcyclohexyl)-2-( 1-isopropylpiperidin-4-yl)acetic acid

[0697] To a solution of benzyl 2-(4,4-dimethylcyclohexylidene)-2-(1-isopropyl-1 ,2,3,6-tetrahydropyridin- 4-yl)acetate (200 mg, 0.52 mmol, 1.0 eq.) in MeOH (5 mL) was added Pd / C (200 mg, 10% on carbon, wetted with ca. 55% water) at r.t.. The solution was stirred at 50 °C for 16 h under hydrogen. The mixture was filtered through a pad of Celite and the filtrate was concentrated in vacuo to afford the title compound (120 mg, 60 % yield) as a white oil.1H NMR (400 MHz, DMSO- de): 5 3.44-3.33 (m, 3 H), 2.93-2.79 (m, 2 H), 2.09-1.81 (m, 6 H), 1.65-1.10 (m, 15 H), 0.89-0.88 (d, J = 4.0 Hz, 6 H). LCMS (Method 22, ESI) 296.4 [M+H]+, RT: 1.323 min.

[0698] Step 1 : tert-butyl (R)-(1-(6-methylpyridazin-3-yl)pyrrolidin-3-yl)carbamate

[0699] A solution of 3-chloro-6-methylpyridazine (7.00 g, 54.26 mmol, 1.0 eq.), terf-butyl ( )-pyrrolidin- 3-ylcarbamate (14.40 g, 54.26 mmol, 1.0 eq.) and DIPEA (30.00 g, 162.78 mmol, 3.0 eq.) in t- BuOH (120 mL) was stirred at 130 °C for 16 h under N2. The mixture was concentrated in vacuo, and the residue was purified by flash chromatography (silica, 5% MeOH in DCM) to afford the title compound (12.07 g, 80 % yield) as a yellow solid. LCMS (Method 25, ESI): 279.1 [M+H]+, RT 1.375 minutes.

[0700] Step 2: (R)-1-(6-methylpyridazin-3-yl)pyrrolidin-3-amine

[0701] To a solution of terf-butyl (R)-(1-(6-methylpyridazin-3-yl)pyrrolidin-3-yl)carbamate (4.00 g, 14.37 mmol, 1.0 eq.) in DCM (120 ml) was added TFA (24 mL) at 0 °C, and the mixture was stirred at r.t. for 16 h. The mixture was concentrated in vacuo, and the residue was purified by reversed- phase column chromatography (0.1% NH3H2O, MeCN% = 20%) to afford the title compound (2.90 g, crude) as a paste.1H NMR (400 MHz, DMSO-d6) 5 7.23 (d, J = 12.0 Hz, 1 H), 6.79 (d, J = 8.0 Hz, 1 H), 3.92 (s, 2 H), 3.72-3.68 (m, 1 H), 3.62-3.51 (m, 2 H), 3.45-3.39 (m, 1 H), 3.26-3.22 (m, 1 H), 2.41 (s, 3 H), 2.18-2.10 (m, 1 H), 1.87-1.80 (m, 1 H).

[0702] Step 3: (R)-N2-(1-(6-rnethylpyridazin-3-yl)pyrrolidin-3-yl)-1 ,3,4-thiadiazole-2,5-diamine

[0703] To a solution of (R)-1-(6-methylpyridazin-3-yl)pyrrolidin-3-amine (500 mg, 2.81 mmol, 1.0 eq.) and 5-bromo-1 ,3,4-thiadiazol-2-amine (506 mg, 2.81 mmol, 1.0 eq.) in MeCN (5 mL) was added K2CO3 (777 mg, 5.62 mmol, 2.0 eq.) at r.t., and the mixture was stirred at 80 °C for 2 h under nitrogen. The mixture was poured into water (100 mL) and extracted with EtOAc (100 mL x 2). The organic layer was separated and dried over anhydrous sodium sulphate, filtered and concentrated in vacuo to afford the title compound (1.42 g, crude) as a white solid. LCMS (Method 23, ESI): 278.0 [M+H]+, RT 0.395 minutes.

[0704] INTERMEDIATE 43 methyl (R)-6-(3-((5-amino-1,3,4-thiadiazol-2-yl)amino)pyrrolidin-1-

[0705] Step 1 : methyl (R)-6-(3-((tert-butoxycarbonyl)amino)pyrrolidin-1-yl)pyridazine-4-carboxylate

[0706] To a mixture of methyl 6-chloropyridazine-4-carboxylate (2.00 g, 11.6 mmol, 1.0 eq.) in t-BuOH (20.0 mL) was added DI PEA (3.70 g, 29.0 mmol, 2.5 eq.) and terf-butyl ( )-pyrrolidin-3- ylcarbamate (2.15 g, 11.6 mmol, 1.0 eq.) at r.t., and the mixture was stirred at 130 °C for 16 h. The reaction mixture was diluted with H2O (100 mL) and then extracted with EtOAc (30 mL x 3). The combined organic phase was washed with brine (100 mL x 2), dried over sodium sulphate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica, 5% MeOH in DCM) to afford the title compound (2.78 g, 74% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6): 5 8.80 (s, 1 H), 8.48 (d, J = 6.0 Hz, 1 H), 7.16 (s, 1 H), 4.18-4.17 (m, 1 H), 3.74- 3.50 (m, 3 H), 2.22-2.14 (m, 1 H), 1.98-1.90 (m, 1 H), 1.74-1.67 (m, 2 H), 1.46-1.37 (m, 11 H). LCMS (Method 25, ESI): 363.0 [M+41]+, RT 1.675 minutes.

[0707] Step 2: methyl (R)-6-(3-aminopyrrolidin-1-yl)pyridazine-4-carboxylate TFA salt

[0708] To a stirred solution of methyl ( )-6-(3-((tert-butoxycarbonyl)amino)pyrrolidin-1-yl)pyridazine-4- carboxylate (700 mg, 2.17 mmol, 1.0 eq.) in DCM (10.0 mL) was added TFA (3 mL) at r.t.. The mixture was stirred at r.t. for 16 h. The reaction mixture was concentrated in vacuo to afford the title compound (812 mg, crude) as a yellow oil. LCMS (Method 25, ESI): 223.0 [M+H]+, RT 1.032 minutes. Step 3: methyl (R)-6-(3-((5-amino-1,3,4-thiadiazol-2-yl)amino)pyrrolidin-1-yl)pyridazine-4-

[0709] To a mixture of crude methyl (R)-6-(3-aminopyrrolidin-1-yl)pyridazine-4-carboxylate TFA salt (346 mg, 0.92 mmol, 1.0 eq.) in DMF (3.0 mL) was added DIPEA (402 mg, 3.12 mmol, 3.4 eq.) and 5- bromo-1 ,3,4-thiadiazol-2-amine (281 mg, 1.56 mmol, 1.7 eq.) at r.t.. The mixture was stirred at 100°C for 3 h, and purified by reversed-phase column chromatography (20% MeCN / water, 0.1% FA) to afford the title compound (214 mg, 72.5% over two steps) as a yellow oil. LCMS (Method 23, ESI): 322.0 [M+H]+, RT 0.975 minutes.

[0710] INTERMEDIATE 44 (R)-N-(6-(3-((5-amino-1,3,4-thiadiazol-2-yl)amino)pyrrolidin-1-yl)pyridazin-

[0711] 3-yl) acetamide

[0712] Step 1 : tert-butyl (R)-(1-(6-aminopyridazin-3-yl)pyrrolidin-3-yl)carbamate

[0713] To a solution of 6-iodopyridazin-3-amine (4.75 g, 21.48 mmol, 2.0 eq.) in DMSO (20 mL) was added terf-butyl (R)-pyrrolidin-3-ylcarbamate (2.00 g, 10.74 mmol, 1.0 eq.), K3PO4 (6.84 g, 32.22 mmol, 3.0 eq.), Cui (614 mg, 3.22 mmol, 0.3 eq.) and L-OH-Proline (423 mg, 3.22 mmol, 0.3 eq.) at r.t.. The mixture was stirred at 80 °C for 48 h under N2 before purified by reversed-phase column chromatography (50% MeCN in water, 0.1 % NH3H2O) to afford the title compound (1.80 g, 30% yield) as a yellow solid. LCMS (Method 23, ESI): 280.1 [M+H]+, RT 1.130 minutes.

[0714] Step 2: tert-butyl (R)-(1-(6-acetamidopyridazin-3-yl)pyrrolidin-3-yl)carbamate

[0715] To a solution of terf-butyl ( )-(1-(6-aminopyridazin-3-yl)pyrrolidin-3-yl)carbamate (1.00 g, 3.58 mmol, 1.0 eq.) in DMF (5 mL) was added acetic acid (537 mg, 8.95 mmol, 2.5 eq.), HATU (2.04 g, 5.38 mmol, 1.5 eq.) and DIPEA (925 mg, 7.16 mmol, 2.0 eq.). The mixture was stirred at r.t. for 16 h under argon. The mixture was poured into water (200 mL) and extracted with EtOAc (100 mL x 2). The combined organic was dried over sodium sulphate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica, 8% MeOH in DCM) to afford the title compound (725 mg, 63% yield) LCMS (Method 24, ESI): 322.2 [M+H]+, RT 0.765 minutes. Step 3 : (R)-N-(6-(3-aminopyrrolidin-1-yl)pyridazin-3-yl)acetamide TFA salt

[0716] To a solution of terf-butyl ( )-(1-(6-acetamidopyridazin-3-yl)pyrrolidin-3-yl)carbamate (370 mg, 1.15 mmol, 1.0 eq.) in DCM (6 mL) was added TFA (2 mL) at r.t., and the mixture was stirred at r.t. for 2 h. The mixture was concentrated in vacuo to afford the title compound (300 mg, crude) as a yellow oil. LCMS (Method 23, ESI): 222.1 [M+H]+, RT 0.500 minutes.

[0717] Step 4: (R)-N-(6-(3-((5-amino-1,3,4-thiadiazol-2-yl)amino)pyrrolidin-1-yl)pyridazin-3- vDacetamide

[0718] To a solution of ( )-N-(6-(3-aminopyrrolidin-1-yl)pyridazin-3-yl)acetamide TFA salt (250 mg, 0.96 mmoL) in DMF (5 mL) was added 5-bromo-1 ,3,4-thiadiazol-2-amine (203 mg, 1.13 mmol, 1.2 eq.) and DI PEA (437 mg, 3.39 mmol, 3.5 eq.) at r.t., and the mixture was stirred at 80 °C for 2 h. The mixture was then poured into water (50 mL) and extrated with EtOAc (50 mL x 2). The combine organic layer was dried over sodium sulphate and concentrated in vacuo. The residue was purified by flash chromatography (silica, 8% MeOH in DCM) to afford the title compound (300 mg, 97.8% yield over two steps) as a yellow solid. LCMS (Method 25, ESI): 321.0 [M+H]+, RT 0.942 minutes.

[0719] Step 1 : tert-butyl (R)-(1-(5-methylpyridazin-3-yl)pyrrolidin-3-yl)carbamate

[0720] To a solution of 3-chloro-5-methylpyridazine (2.00 g, 15.50 mmol, 1.0 eq.), terf-butyl ( / ?)- pyrrolidin-3-ylcarbamate (2.90 g, 15.50 mmol, 1.0 eq.) in t-BuOH at r.t. was added DIPEA (6.00 g, 46.5 mmol, 3.0 eq.), and the mixture was stirred at 130 °C for 16 h under nitrogen. The mixture was concentrated in vacuo and purified by flash chromatography (silica, 9% MeOH in DCM) to afford the title compound (3.8 g, 83% ) as a brown solid. LCMS (Method 25, ESI): 279.3 [M+H]+, RT 1.400 minutes. Step 2: (R)-1-(5-methylpyridazin-3-yl)pyrrolidin-3-amine TFA salt

[0721] To a solution of terf-butyl ( )-(1-(5-methylpyridazin-3-yl)pyrrolidin-3-yl)carbamate (500 mg, 1.79 mmol, 1 .0 eq.) in DCM (3 mL) was added TFA (1 mL) at r.t., and the mixture was stirred at r.t. for 16 h. The mixture was concentrated in vacuo to afford the title compound (1.20 g, crude) as a brown oil. LCMS (Method 25, ESI): 179.0 [M+H]+, RT 1.392 minutes.

[0722] Step 3: (R)-N2-(1-(5-methylpyridazin-3-yl)pyrrolidin-3-yl)-1,3,4-thiadiazole-2,5-diamine

[0723] To a solution of (R)-1-(5-methylpyridazin-3-yl)pyrrolidin-3-amine TFA salt (320 mg, 0.477 mmol, 1.0 eq.), 5-bromo-1 ,3,4-thiadiazol-2-amine (322 mg, 1.79 mmol, 3.75 eq.) in DMF (8 mL) was added DI PEA (2.31 g, 17.90 mmol, 37.5 eq.) at r.t. , and the mixture was stirred at 80 °C for 2 h. The mixture was purified by reversed-phase column chromatography (30% MeCN in water, 0.1% NH3 H2O) to afford the title compound (300 mg, 57% yield) as a brown solid. LCMS (Method 25, ESI): 278.1 [M+H]+, RT 0.833 minutes.

[0724] INTERMEDIATE idin-3-yl)- 1,3, 4-thiadiazole-2, 5- diamine

[0725] Step 1 : 6-bromo-3-(methylthio)- 1 , 2, 4-triazine

[0726] To a mixture of 6-bromo-1 ,2,4-triazin-3-amine (15 g, 0.86 mol, 1.0 eq.) and 1 ,2-dimethyldisulfane (76 mL, 8.6 mmol, 10 eq.) in dry ACN (60 mL) was added terf-butyl nitrite (63 mL, 0.51 mol, 6 eq.) dropwise and the reaction mixture then 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% EtOAc / PE) to give the title compound (12.0 g, 42% yield) as a yellow oil. LCMS (Method 22, ESI):206.0 [M+H]+, RT 0.373 minutes.

[0727] Step 2: tert-butyl (R)-( 1-(3-(methylthio)- 1,2, 4-triazin-6-yl)pyrrolidin-3-yl)carbamate

[0728] To a stirred solution of 6-bromo-3-(methylthio)-1 ,2,4-triazine (12 g, 48.0 mmol, 1.0 eq.) in butan- l-ol (20 mL) were added terf-butyl (R)-pyrrolidin-3-ylcarbamate (9.82 g, 52.8 mmol, 1.1 eq.) and DI PEA (2.32 g, 134.0 mmol, 3.0 eq.). The resulting mixture was stirred at 80 °C for 16 h before concentrated in vacuo. The residue was purified by reverse column chromatography (0-90% ACN in H2O) followed by flash chromatography (silica, 20% EtOAc / PE) to afford the title compound (9.8 g, 65% yield) as a yellow solid. LCMS (Method 22, ESI): 312.1 [M+H]+, RT 1.583 minutes. 1 H MR (400 MHz, CDCI3) 1.46 (s, 9H), 5 1.96-2.09 (m, 1 H), 2.26-2.41 (m, 1 H), 2.63 (s, 3H), 3.43 (m, 1 H), 3.58-3.72 (m, 2H), 3.80 (m, 1 H), 4.39 (s, 1 H), 4.66 (s, 1 H), 7.91 (s, 1 H).

[0729] Step 3: tert-butyl (R)-( 1-(1,2,4-triazin-6-yl)pyrrolidin-3-yl)carbamate

[0730] 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. MnC>2 (5.5 g, 64 mmol, 20 eq.) was added to the filtrate, and 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 (Method 27, 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).

[0731] Step 4: (R)- 1-(1,2, 4-triazin-6-yl)pyrrolidin-3-amine

[0732] 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 Na2COs 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 crude contained inorganic salt) as a yellow solid. LCMS (Method 28, ESI): 166.3 [M+H]+, RT 0.243 minutes.

[0733] Step 5: (R)-N2-(1 -(1 ,2,4-triazin-6-yl)pyrrolidin-3-yl)-1 ,3,4-thiadiazole-2,5-diamine

[0734] 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% EtOAc / PE) to afford the title compound (150 mg, 0.56 mmol, 55% yield over two steps) as a yellow solid.1H NMR (400 MHz, DMSO-d6): 5 8.59 (s, 1 H), 8.27 (s, 1 H), 7.14 (d, J = 8.0 Hz, 2 H), 6.3 (s, 1 H), 4.31-4.26 (m, 1 H), 3.77-3.73 (m, 1 H), 3.62-3.59 (m, 2 H), 3.54-3.51 (m, 1 H), 2.29-2.21 (m, 1 H), 2.10-2.03 (m, 1 H). LCMS (Method 22, ESI): 265.1 [M+H]+, RT 1.318 minutes. INTERMEDIATE 47 (R)-N2-(1 -(1 -methyl-1 H-1 ,2, 3-triazol-4-yl)pyrrolidin-3-yl)-1 ,3, 4-thiadiazole-

[0735] 2,5-diamine

[0736] Stepl : tert-butyl (R)-( 1-( 1 -methyl- 1H-1,2, 3-triazol-4-yl)pyrrolidin-3-yl)carbamate

[0737] To a stirring solution of 4-bromo-1 -methyl-1 H-1 , 2, 3-triazole (5 g, 30.87 mmol, 1.0 eq.) and tertbutyl ( )-pyrrolidin-3-ylcarbamatein (5.8 g, 30.87 mmol, 1.0 eq.) in DMSO (250 mL) was added Cui (1.2 g, 6.17 mmol, 0.2 eq.), L-proline (0.71 g, 6.17 mmol, 0.2 eq.) and K2CO3 (13 g, 92.60 mmol, 3.0 eq.). Then the reaction mixture was stirred at 100 °C for 16 h under nitrogen. The reaction was diluted with EtOAc (300 mL) and H2O (300 mL). The organic layer was separated and extracted with EtOAc (3 x 300 mL). The organic layer was washed with brine (3 x 150 mL) and concentrated in vacuo. The residue was purified by flash chromatography (silica, 0-5% MeOH in DCM) to afford the title compound (1 .0 g, yield 12.1 %). LCMS (Method 20, ESI): 268.3 [M+H]+, RT 1.365 minutes.

[0738] Step 2: ( 1R)-3-( 1 -methyl- 1H-1,2, 3-triazol-4-yl)cyclopentan-1 -amine

[0739] To a solution of terf-butyl ( )-(1 -(1 -methyl-1 / 7-1 ,2,3-triazol-4-yl)pyrrolidin-3-yl) carbamate (500 mg, 1.87 mmol, 1.0 eq.) in DCM (6 mL) was added TFA (2 mL). The reaction mixture was stirred at r.t. for 2 h before concentrated in vacuo to afford the title compound (700 mg, crude), which was used without further purification. LCMS (Method 20, ESI): 168.1 [M+H]+, RT 0.188 minutes.

[0740] Step 3: (R)-N2-( 1-( 1 -methyl- 1H-1,2, 3-triazol-4-yl)pyrrolidin-3-yl)- 1,3, 4-thiadiazoie-2, 5-diamine To a stirring solution of (1 )-3-(1 -methyl-1 / 7-1 , 2, 3-triazol-4-yl)cyclopentan-1 -amine (250 mg, 1.50 mmol, 1.0 eq.) in DMF (20 mL) was added DIPEA (967 mg, 7.48 mmol, 5.0 eq.) and 5-bromo- 1 ,3,4-thiadiazol-2-amine (270 mg, 1.50 mmol, 1.0 eq.). Then the reaction mixture was stirred at 80 °C for 4 h before concentrated in vacuo. The residue was purified by reversed-phase chromatography (ACN / water + 0.01% TFA) to afford the title compound (120 mg, 30.1 % yield). LCMS (Method 20, ESI): 267.2 [M+H]+, RT 0.939 minutes. INTERMEDIATE 48 (R)-N2-methyl-N2-(1-(pyridazin-3-yl)pyrrolidin-3-yl)-1 ,3,4-thiadiazole-2,5-

[0741] Step 1 : tert-butyl N-r(3R)-1-(6-chloropyridazin-3-yl)pyrrolidin-3-yl]-N-methylcarbamate

[0742] 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 then concentrated 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 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 (Method 6, ESI) 312.95 [MH]+, RT 2.36 min.

[0743] Step 2: (3R)-N-methyl-1-(pyridazin-3-yl)pyrrolidin-3-amine hydrochloride

[0744] 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 evaporated 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 (Method 6, ESI) 178.90 [MH]+, RT 0.61 min.

[0745] Step 3: (R)-N2-methyl-N2-(1-(pyridazin-3-yl)pyrrolidin-3-yl)-1,3,4-thiadiazole-2,5-diamine

[0746] 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 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 evaporated. 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, = 4.5, 1.3 Hz, 1 H), 7.36 (dd, J = 9.1 , 4.4 Hz, 1 H), 6.92 (dd, = 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 (Method 6, ESI) 277.85 [MH]+, RT 0.61 min.

[0747] In the following general procedures, all variables are as defined herein.

[0748] General Procedure 1 amine intermediate carboxylic acid

[0749] To a suspension of the amine intermediate (1.0-1.1 eq.) in anhydrous DMF (0.1 M) was added the appropriate carboxylic acid (1 eq.) and DI PEA (3 eq.) at r.t. and the reaction mixture was purged with argon for 5 min. T3P in DMF (2 eq., 50% solution) was added at r.t. and purged with argon for 5 min. The reaction mixture was stirred at r.t. for 1-72 h. After completion, the reaction was quenched with aqueous sodium bicarbonate solution (0.05 M) and DCM. The phases were separated, the aqueous phase was washed with DCM. Combined organic fractions were dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The crude obtained was either purified by flash chromatography, or / and preparative TLC, or / and preparative HPLC (mobile phases: ACN, H2O + 0.05% NH3) followed by lyophilisation with ACN / H2O to afford the compound of formula (I).

[0750] General Procedure 2

[0751] To a suspension of the amine intermediate (1.0-1.1 eq.) in anhydrous DMF (0.1 M) was added the appropriate carboxylic acid (1 eq.) and DI PEA (3-5 eq.) at r.t. and the reaction mixture was purged with argon for 5 min. HATLI (1.1-2 eq.) was added at r.t. and purged with argon for 5 min. The reaction mixture was stirred at r.t. for 1-18 h. After completion, the reaction was quenched with aqueous sodium bicarbonate solution (0.05 M) and DCM. The phases were separated, the aqueous phase was washed with DCM. Combined organic fractions were dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The crude obtained was either purified by flash chromatography, or / and preparative TLC, or / and preparative HPLC (mobile phases: ACN, H2O + 0.05% NH3) followed by lyophilisation with ACN / H2O to afford the compound of formula (I).

[0752] General Procedure 3

[0753] Step 1: To a mixture of benzyl 2-(dimethoxyphosphoryl)acetate (1.1 eq.) in dry-THF was added NaH (1.1 eq.) at 0 °C. The resulting mixture was stirred at 0 °C for 1 h under argon atmosphere. Then the ketone (1.0 eq.) was added into above reaction mixture. The resulting mixture was stirred at r.t. for 1 h then quenched with saturated aqueous ammonia 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 enone. Step 2:

[0754] To a solution of the enone (1.0 eq.) in EtOAc was added Pd / C (10%, 0.5 eq.). The resulting mixture was stirred at r.t. for 16 h under hydrogen atmosphere. The reaction mixture was filtered and concentrated in vacuo to afford the carboxylic acid.

[0755] Step 3:

[0756] A mixture of the carboxylic acid (1.0 eq.) in SOCh was stirred at 85 °C for 5 h under argon atmosphere. The reaction mixture was cooled to r.t., then aq. HBr (48% in H2O) was added followed by Br2 (3.0 eq.). The resulting mixture was stirred at 60 °C for 1 h then 70 °C for 3 h. The reaction mixture was cooled to r.t. and concentrated in vacuo to remove SOCI2 and Br2 to afford the acyl chloride without purification.

[0757] Step 4:

[0758] To a stirred solution of the acyl chloride (1 .0 eq.) in dry-DCM was added benzyl alcohol (1 .4 eq.) slowly at 0°C under argon atmosphere, followed by TEA (2.0 eq.). The resulting mixture was stirred at r.t. for 3 h. The reaction mixture was quenched with saturated aqueous ammonia chloride at 0°C, 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 on silica gel to afford the bromo-benzyl ester.

[0759] Step 5:

[0760] A solution of the bromo-benzyl ester (1 .0 eq.), N-alkylated piperazine (10.0 eq.) and TEA (3.0 eq.) in ACN in a sealed tube was stirred at 85°C for 48 h. The reaction mixture was purified by reversed-phase column chromatography (C-120 g, ACN%=50%, +0.1% FA) to afford the N- alkylated piperazine benzyl ester.

[0761] Step 6:

[0762] To a solution of the N-alkylated piperazine benzyl ester in MeOH was added Pd / C (10%, 0.5 eq.) and HCI in MeOH (4M, 1 drop). The resulting mixture was stirred at r.t. for 16 h under hydrogen atmosphere. The reaction mixture was filtered and concentrated in vacuo to afford the carboxylic acid.

[0763] Step 7 :

[0764] A solution of the carboxylic acid intermediate (1 .0 eq.), amine intermediate (1.1 eq.) in anhydrous DMF was added T3P (50% in EtOAc, 2.0 eq.) and DIPEA (3.0 eq.). The resulting mixture was stirred at r.t. for 2 h. The reaction mixture was purified by reversed phase chromatography (ACN%=45%, +0.1% NH3H2O) and lyophilized with CH3CN / H2O to afford the final compound. Step 7B:

[0765] A solution of the carboxylic acid intermediate (1 .0 eq.), amine intermediate (1.1 eq.) in anhydrous DMF was added PyBOP (2.0 eq.) and DIPEA (3.0 eq.). The resulting mixture was stirred at r.t. for 2 h. The reaction mixture was purified by reversed phase chromatography (ACN%=30%, +0.1 % FA) to afford the crude product, which was further purified by reversed phase chromatography (ACN%=50%, +0.1% NH3H2O) and lyophilized with CH3CN / H2O to afford the compound of formula (I).

[0766] General Procedure 4

[0767] A solution of Intermediate 29 in DMF was added K2CO3 (3.0 eq.) and N-alkylated piperazine (2.0 eq.) at r.t. , the solution was stirred r.t. for 3h. The reaction mixture was purified by reversed phase column (ACN%=30%, +0.1% FA) to afford the crude product, which was further purified by reversed phase chromatography (ACN%=50%, +0.1% NH3H2O) and lyophilized with CH3CN / H2O to afford the compound of formula (I).

[0768] General Procedure 5

[0769] Chiral-Chromatography purification conditions: Column: DALCELCHIRALCEL®AS-M-D: 250*25 mm 10 pm; Mobile Phase A: Supercritical CO2; Mobile Phase B: MeOH (+0.1% 7.0 mol / L Ammonia in MeOH); Flow rate:80 ml / min.

[0770] General Procedure 6

[0771] To a suspension of the carboxylic acid intermediate (1.0 eq.), amine intermediate (1.1 eq.) in anhydrous DMF was added PyBOP (2.0 eq.) and DIPEA (3.0 eq.) at r.t. and the reaction mixture was stirred at r.t. for 2 h. After completion, the reaction was quenched with aqueous sodium bicarbonate solution (0.05 M) and DCM. The phases were separated, the aqueous phase was washed with DCM. Combined organic fractions were dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The crude obtained was either purified by flash chromatography, or / and preparative TLC, or / and preparative HPLC (mobile phases: ACN, H2O + 0.05% NH3) followed by lyophilisation with ACN / H2O to afford the compound of formula (I). Synthesis of Examples

[0772] Exam pie 1 2-{3-azaspiro[5.51undecan-9-yl}-N-(5- [ (3R)- 1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-

[0773] To a stirred solution of Intermediate 12 (20 mg, 0.03 mmol, 1 eq.) in DCM (0.7 mL) was added HCI in 1 ,4-dioxane (4 M, 90 pL, 035 mmol, 10 eq.) and the reaction mixture was stirred at r.t. for 16 h. The solvent was evaporated in vacuo and the crude material was purified by preparative HPLC (mobile phases: ACN, H2O + 0.05% NH3) to afford the title compound (3.7 mg, 43%) as a white solid.

[0774] Exam pie 2 (3R)- 1-(6-aminopyridazin-3-yl)pyrrolidin-3-yl]amino}- 1,3, 4-thiadiazol-2-yl)-2- cycloheptylacetamide

[0775] Intermediate 18 (170 mg, 0.30 mmol, 1 eq.), potassium phosphate (190 mg, 0.91 mmol, 3 eq.), trans-hydroxyproline (8 mg, 0.06 mmol, 0.2 eq.), copper(l) iodide (6 mg, 0.03 mmol, 0.1 eq.) were put into sealed tube under argon atmosphere. Anhydrous DMF (1.5 mL) was added, and the reaction mixture was bubbled with argon for 5 min. Ammonia (25% aqueous soln., 680 pL, 9.06 mmol, 30 eq.) was added and the reaction mixture was stirred at 65°C 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 twice with DCM (50 mL). Combined organic phases were washed with water and brine, dried over sodium sulphate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica, 0-10% 3M NHs / MeOH in DCM). The product was repurified by preparative HPLC (mobile phases: ACN, H2O + 0.1 % FA) to afford the title compound (10 mg, 9%) as a yellow solid. Exam pie 3 N- 6-[ (3R)-3- / [5-(2-cycloheptylacetamido)- 1,3, 4-thiadiazol-2-yllamino}pyrrolidin- 1- yl]pyridazin-3-yl}-2-(4-cvclopropylpiperazin-1-yl)acetamide

[0776] To a stirred solution of Example 2 (41 mg, 0.09 mmol, 1 eq.) and DIPEA (40 pL, 0.22 mmol, 2.2 eq.) in THF (4 mL) was added chloroacetyl chloride (10 pL, 0.09 mmol, 1 eq.). The mixture was stirred for 1 h at r.t., then was poured into saturated aqueous sodium bicarbonate solution and extracted with DCM (2 x 50 mL). Combined organic layers were dried over anhydrous sodium sulphate, filtered and evaporated in vacuo. The crude was dissolved in DCM (2 mL) and TEA (40 pL, 0.26 mmol, 2.9 eq.) and 1 -cyclopropylpiperazine (13 pL, 0.11 mmol, 1.2 eq.) were added to the stirred solution. The reaction mixture was stirred at r.t. for 16 h. The solvent was evaporated in vacuo and the crude residue was purified by flash chromatography (silica, 5% MeOH in DCM) to afford the title compound (6 mg, 12%) as an off-white solid.

[0777] Example 4 was prepared from Intermediate 4 and Intermediate 24 in accordance with General Procedure 2.

[0778] Example 5 and Example 6 were prepared from Example 4 in accordance with General Procedure 5.

[0779] Example 7 was prepared from Intermediate 4 and cyclopentylacetic acid in accordance with General Procedure 1.

[0780] Example 8 was prepared from Intermediate 4 and bicyclo[1.1.1]pentane-1 -acetic acid in accordance with General Procedure 1.

[0781] Example 9 was prepared from Intermediate 4 and (3-hydroxy-adamantan-1-yl)-acetic acid in accordance with General Procedure 1.

[0782] Example 10 was prepared from Intermediate 4 and Intermediate 9 in accordance with General Procedure 2.

[0783] Example 11 was prepared from Intermediate 4 and cyclohexylacetic acid in accordance with General Procedure 1.

[0784] Example 12 was prepared from Intermediate 4 and 2-cycloheptylacetic acid in accordance with General Procedure 1.

[0785] Example 13 was prepared from Intermediate 4 and Intermediate 10 in accordance with General Procedure 2.

[0786] Example 14 was prepared from Intermediate 4 and 1-adamantylacetic acid in accordance with General Procedure 1. Example 15 was prepared from Intermediate 4 and 2-(adamantan-2-yl)acetic acid in accordance with General Procedure 1.

[0787] Example 16 was prepared from Intermediate 4 and carboxybicyclo[4.1.0]heptane in accordance with General Procedure 1.

[0788] Example 17 was prepared from Intermediate 4 and 2-(1 ,2,3,4-tetrahydronaphthalen-1- yl)acetic acid in accordance with General Procedure 1.

[0789] Example 18 was prepared from Intermediate 4 and 2-(4-phenylcyclohexyl)acetic acid in accordance with General Procedure 1.

[0790] Example 19 was prepared from Intermediate 4 and 2,2-dicyclohexylacetic acid in accordance with General Procedure 2.

[0791] Example 20 was prepared from Intermediate 4 and spiro[2.5]octane-1 -carboxylic acid in accordance with General Procedure 1.

[0792] Example 21 was prepared from Intermediate 4 and (6-fluoro-1,2,3,4-tetrahydro- naphthalen-2-yl)-acetic acid in accordance with General Procedure 1.

[0793] Example 22 was prepared from Intermediate 4 and 2-(1 -methylcyclohexyl) acetic acid in accordance with General Procedure 1.

[0794] Example 23 was prepared from Intermediate 6 and Intermediate 13 in accordance with General Procedure 2.

[0795] Example 24 was prepared from Intermediate 6 and Intermediate 14 in accordance with General Procedure 2.

[0796] Example 25 was prepared from Intermediate 4 and 2-[(1 S,2S,5S)-6,6-dimethylbicyclo [3.1.1]heptan-2-yl]acetic acid in accordance with General Procedure 1.

[0797] Example 26 was prepared from Intermediate 4 and 2-[3-(trifluoromethyl) adamantan-1- yl]acetic acid in accordance with General Procedure 2.

[0798] Example 27 was prepared from Intermediate 4 and 2-(4-ethylcyclohexyl)-2-(4- methylpiperazin-1-yl)acetic acid in accordance with General Procedure 3 with Step 7 A.

[0799] Example 28 was prepared from Intermediate 4 and 2-(4-(terf-butyl)cyclohexyl)-2-(4- methylpiperazin-1-yl)acetic acid in accordance with General Procedure 3 with Step 7 A.

[0800] Example 29 was prepared from Intermediate 4 and 2-(4-methylpiperazin-1-yl)-2-(3, 3,5,5- tetramethylcyclohexyl)acetic acid with General Procedure 3 with Step 7 A.

[0801] Example 30 was prepared from Intermediate 29 and 1 -cyclopropylpiperazine in accordance with General Procedure 4.

[0802] Example 31 was prepared from Intermediate 29 and 1 -methylpiperazine in accordance with General Procedure 4.

[0803] Example 32 was prepared from Intermediate 4 and 2-((1 S,3S)-adamantan-1-yl)-2-(4- methylpiperazin-1-yl)acetic acid in accordance with General Procedure 3 with Step 7 A. Example 33 and Example 34 were prepared from Example 32 in accordance with General Procedure 5.

[0804] Example 35 was prepared from Intermediate 4 and 2-((1 S,3S)-adamantan-1-yl)-2-(4- cyclopropylpiperazin-1-yl)acetic acid in accordance with General Procedure 3 with Step 7 A.

[0805] Example 36 and Example 37 were prepared from Example 35 in accordance with General Procedure 5.

[0806] Example 38 was prepared from Intermediate 4 and 2-((1 S,3S)-adamantan-1-yl)-2-(4- ethylpiperazin-1-yl)acetic acid in accordance with General Procedure 3 with Step 7 A.

[0807] Example 39 and Example 40 were prepared from Example 38 in accordance with General Procedure 5.

[0808] Example 41 was prepared from Intermediate 4 and 2-((1 S,3S)-adamantan-1-yl)-2-(4- isopropylpiperazin-1-yl)acetic acid in accordance with General Procedure 3 with Step 7 A.

[0809] Example 42 and Example 43 were prepared from Example 41 in accordance with General Procedure 5.

[0810] Example 44 was prepared from Intermediate 4 and 2-((1 / ?,3S)-3,5-dimethyladamantan-1- yl)-2-(4-methylpiperazin-1-yl)acetic acid in accordance with General Procedure 3 with Step 7 A.

[0811] Example 45 and Example 67 was prepared from Example 44 in accordance with General Procedure 5.

[0812] Example 46 was prepared from Intermediate 4 and 2-(4-methylpiperazin-1-yl)-2- (spiro[4.5]decan-8-yl)acetic acid in accordance with General Procedure 3 with Step 7 A.

[0813] Example 47 and Example 48 were prepared from Example 46 in accordance with General Procedure 5.

[0814] Example 49 was prepared from Intermediate 6 and 2-cyclohexyl-2-(4-methylpiperazin-1- yl)acetic acid in accordance with General Procedure 3 with Step 7 A.

[0815] Example 50 and Example 51 were prepared from Example 49 in accordance with General Procedure 5.

[0816] Example 52 was prepared from Intermediate 6 and 2-(4,4-dimethylcyclohexyl)-2-(4- methylpiperazin-1-yl)acetic acid in accordance with General Procedure 3 with Step 7 A.

[0817] Example 53 and Example 54 were prepared from Example 52 in accordance with General Procedure 5.

[0818] Example 55 was prepared from Intermediate 6 and 2-(4-methylpiperazin-1-yl)-2- (spiro[4.5]decan-8-yl)acetic acid in accordance with General Procedure 3 with Step 7 A.

[0819] Example 56 and Example 57 were prepared from Example 55 in accordance with General Procedure 5.

[0820] Example 58 was prepared from Intermediate 4 and 2-(4,4-dimethylcyclohexyl)-2-(4- methylpiperazin-1-yl)acetic acid in accordance with General Procedure 3 with Step 7B. Example 59 and Example 60 were prepared from Example 58 in accordance with General Procedure 5.

[0821] Example 61 was prepared from Intermediate 4 and 2-(4,4-dimethylcyclohexyl)-2-(4- isopropylpiperazin-1-yl)acetic acid in accordance with General Procedure 3 with Step 7B.

[0822] Example 62 and Example 63 were prepared from Example 60 in accordance with General Procedure 5.

[0823] Example 64 was prepared from Intermediate 4 and 2-cyclooctyl-2-(4-ethylpiperazin-1- yl)acetic acid in accordance with General Procedure 3 with Step 7B.

[0824] Example 65 and Example 66 were prepared from Example 64 in accordance with General Procedure 5.

[0825] Example 68 was prepared from Intermediate 24 and Intermediate 33 in accordance with General Procedure 2.

[0826] Example 69 was prepared from Intermediate 4 and 2-(4,4-dimethylcyclohexyl)-2-((3S,5R)- 3,4,5-trimethylpiperazin-1-yl)acetic acid in accordance with General Procedure 3 with Step 7B.

[0827] Example 70 was prepared from Intermediate 4 and Intermediate 41 in accordance with General Procedure 6.

[0828] Example 71 and Example 72 were prepared from Example 70 in accordance with General Procedure 5.

[0829] Example 73 was prepared from Intermediate 4 and 2-(4-isopropylpiperazin-1-yl)-2- (spiro[3.5]nonan-7-yl)acetic acid in accordance with General Procedure 3 with Step 7B.

[0830] Example 74 and Example 75 were prepared from Example 73 in accordance with General Procedure 5.

[0831] Example 76 was prepared from Intermediate 42 and Intermediate 34 in accordance with General Procedure 6.

[0832] Example 77 was prepared from Intermediate 42 and Intermediate 35 in accordance with General Procedure 6.

[0833] Example 78 was prepared from Intermediate 42 and Intermediate 36 in accordance with General Procedure 6.

[0834] Example 79 was prepared from Intermediate 43 and Intermediate 37 in accordance with General Procedure 6.

[0835] Example 80 was prepared from Intermediate 43 and Intermediate 38 in accordance with General Procedure 6.

[0836] Example 81 was prepared from Intermediate 43 and Intermediate 39 in accordance with General Procedure 6.

[0837] Example 82 was prepared from purification of Example 79 using reverse phase flash chromatography (20% MeCN in water + 0.1% NH3 H2O). Example 83 was prepared by treating Example 80 with LiOH (4 eq.) in MeOH / H2O at r.t. for 2 h followed by Prep-HPLC (30% MeCN in water + 0.1% NH3H2O).

[0838] Example 84 was prepared by treating Example 81 with LiOH (4 eq.) in MeOH / H2O at r.t. for 2 h followed by Prep-HPLC (30% MeCN in water + 0.1% NH3H2O).

[0839] Example 85 was prepared from Intermediate 43 and Intermediate 34 in accordance with General Procedure 6.

[0840] Example 86 was prepared from Intermediate 43 and Intermediate 35 in accordance with General Procedure 6.

[0841] Example 87 was prepared from Intermediate 43 and Intermediate 36 in accordance with General Procedure 6.

[0842] Example 88 was prepared from Intermediate 4 and Intermediate 40 in accordance with General Procedure 6.

[0843] Example 89 was prepared from Intermediate 45 and Intermediate 34 in accordance with General Procedure 6.

[0844] Example 90 was prepared from Intermediate 45 and Intermediate 35 in accordance with General Procedure 6.

[0845] Example 91 was prepared from Intermediate 45 and Intermediate 36 in accordance with General Procedure 6.

[0846] Example 92 was prepared from Intermediate 46 and 2-(4-methylpiperazin-1-yl)-2- (spiro[4.5]decan-8-yl)acetic acid in accordance with General Procedure 3 with Step 7 A.

[0847] Example 93 and Example 94 were prepared from Example 92 in accordance with General Procedure 5.

[0848] Example 95 was prepared from Intermediate 45 and Intermediate 37 in accordance with Step 7B in General Procedure 6.

[0849] Example 96 was prepared from Intermediate 45 and Intermediate 38 in accordance with Step 7B in General Procedure 6.

[0850] Example 97 was prepared from Intermediate 45 and Intermediate 39 in accordance with Step 7B in General Procedure 6.

[0851] Example 98 was prepared from Intermediate 47 and Intermediate 35 in accordance with Step 7B in General Procedure 6.

[0852] Example 99 was prepared from Intermediate 48 and Intermediate 35 in accordance with

[0853] General Procedure 6.

[0854] Stepl:

[0855] To a mixture of benzyl 2-(dimethoxyphosphoryl)acetate (40 g, 155.04 mmol, 1.1 eq.) in dry-THF (400 mL) was added NaH (9.30 g, 155.04 mmol, 1.1 eq.) slowly portion-wise at O °C. The resulting mixture was stirred at 0 °C for 1 h under argon atmosphere. Then the solution of 4,4- dimethylcyclohexan-1-one (17.76 g, 140.92 mmol, 1.0 eq.) in dry-THF (10 mL) was added dropwise. The resulting mixture was stirred at room temperature for 3 h. The reaction mixture was then quenched with saturated aqueous ammonia chloride (100 mL), extracted with EtOAc (100 mL x 3). 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, 0-3% EtOAc in PE) to afford benzyl 2-(4,4-dimethylcyclohexylidene) acetate (31.12 g, 85.6%) as a colourless oil.1H NMR (400 MHz, DMSO-d6) 5 7.39-7.30 (m, 4H), 5.69 (s, 1 H), 5.10 (s, 2H), 2.81 (t, J = 5.6 Hz, 2 H), 2.22 (t, =6.4 Hz, 2 H), 1.40-1.34 (m, 4 H), 0.95 (s, 6 H).

[0856] Step 2:

[0857] To a solution of benzyl 2-(4,4-dimethylcyclohexylidene)acetate (31.32 g, 121.39 mmol) in EtOAc (400 mL) was added Pd / C (3.0 g, 10%). The resulting mixture was stirred at r.t. for 16 h under hydrogen atmosphere (1 atm). The reaction mixture was filtered and concentrated in vacuo to afford 2-(4,4-dimethylcyclohexyl)acetic acid (19.74 g, 95.7%) as a white solid.1H NMR (400 MHz, DMSO-de) 5 11.96 (s, 1 H), 2.10 (d, J = 6.8 Hz, 2 H), 1.63-1.51 (m, 3 H), 1.42-1.31 (m, 2H), 1.25- 1.04 (m, 4 H), 0.88 (s, 3H), 0.85 (s, 3H). Step 3:

[0858] A mixture of 2-(4,4-dimethylcyclohexyl)acetic acid (31.32 g, 184.24 mmol, 1.0 eq.) in SOCh (50 mL) was stirred at 85 °C for 5 h under argon atmosphere. The reaction mixture was cooled to r.t. , then aq. HBr (48% in H2O) (30 drops) was added followed by Br2 (88.45 g, 552.72 mmol, 3.0 eq.). The resulting mixture was stirred at 70 °C for 3 h. The reaction mixture was cooled to r.t. and concentrated in vacuo to remove SOCI2 and Br2 to afford 2-bromo-2-(4,4-dimethyl cyclohexyl)acetyl chloride (50.38 g, quantitative) as a pale yellow oil, which was used in the next step without further purification.

[0859] Step 4:

[0860] To a stirred solution of 2-bromo-2-(4,4-dimethylcyclohexyl)acetyl chloride (50 g crude, 186.57 mmol, 1.0 eq.) in dry-DCM (500 mL) was added benzyl alcohol (28.21 g, 261.20 mmol, 1.4 eq.) slowly at 0°C under argon atmosphere, followed by TEA (37.69 g, 373.14 mmol, 2.0 eq.). The resulting mixture was stirred at r.t. for 3 h. The reaction mixture was quenched saturated aqueous ammonia chloride (100 mL) at 0°C, extracted with EtOAc (100 mL x 3). The combined organic phase was washed with brine (100 mL), dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica, 0-3% EtOAc in PE) to afford benzyl 2-bromo-2-(4,4-dimethylcyclohexyl)acetate (25 g, 40.0% over 2 steps) as a yellow oil.1H NMR (400 MHz, DMSO-d6) 5 ppm 7.39-7.34 (m, 5 H), 5.20 (s, 2 H), 4.49 (d, J= 8.0 Hz, 1 H), 1.73-1.69 (m, 2 H), 1.38-1.12 (m, 7 H), 0.87 (s, 3 H), 0.83 (s, 3 H).

[0861] Step 5:

[0862] A mixture of benzyl 2-bromo-2-(4,4-dimethylcyclohexyl)acetate (25 g, 73.75 mmol, 1.0 eq.), 1- methylpiperazine (22.13 g, 221.25 mmol, 3.0 eq.) and TEA (22.35 g, 221.25 mmol, 3.0 eq.) in ACN (50 mL) in a sealed tube was stirred at 85 °C for 16 h. The reaction mixture was purified by reversed-phase column chromatography (C-120 g, ACN%=50%, +0.1% FA) to afford benzyl 2- (4,4-dimethylcyclohexyl)-2-(4-methylpiperazin-1-yl)acetate (16.34 g, 61.7%) as a colourless oil.1H NMR (400 MHz, DMSO-d6) 5 7.39-7.32 (m, 5 H), 5.12 (s, 2 H), 3.00 (d, J = 10.4 Hz, 1 H), 2.54- 2.44 (m, 8 H), 2.23 (s, 3 H), 1.70-1.62 (m, 2 H), 1.34-1.23 (m, 3 H), 1.13-1.05 (m, 4 H), 0.86 (s, 3H), 0.83 (s, 3H). LCMS (Method 9, ESI) 359.3 [MH]+, RT 2.213 minutes.

[0863] Step 6:

[0864] Benzyl 2-(4,4-dimethylcyclohexyl)-2-(4-methylpiperazin-1-yl)acetate (16.0 g, 44.57 mmol) was separated by chiral-chromatography to afford benzyl ( )-2-(4,4-dimethylcyclohexyl)-2-(4- methylpiperazin-1-yl)acetate (6.7g, 41.9%) as a yellow solid (RT = 1.947 min, 100% ee.) and benzyl (S)-2-(4,4-dimethylcyclohexyl)-2-(4-methylpiperazin-1-yl)acetate (7.2 g, 45%) as a yellow solid (RT = 3.118 min, 99.38 % ee.).

[0865] Chiral-Chromatography purification conditions: Column: DALCELCHIRALCELOAD: 250*25 mm 10 pm; Mobile Phase A: Supercritical CO2; Mobile Phase B: MeOH (+0.1% 7.0 mol / L Ammonia in MeOH); Flow rate: 140 ml / min.

[0866] Step 7:

[0867] To a mixture of benzyl (S)-2-(4,4-dimethylcyclohexyl)-2-(4-methylpiperazin-1-yl)acetate (7.2 g, 27.80 mmol, 1.0 eq.) in MeOH (160 mL) was added Pd / C (1.2 g, 10%) and the resulting mixture was stirred at r.t. for 16 h under hydrogen atmosphere (1 atm). The reaction mixture was filtered and the filtrate was concentrated in vacuo to afford (S)-2-(4,4-dimethyl cyclohexyl)-2-(4- methylpiperazin-1-yl)acetic acid (5.38 g, quantitative) as an off-white solid which was used without further purification. LCMS (Method 9, ESI) 269.1 [MH]+, RT 1.039 minutes.

[0868] Step 8:

[0869] A mixture of (S)-2-(4,4-dimethylcyclohexyl)-2-(4-methylpiperazin-1-yl)acetic acid (5.2 g, 19.40 mmol, 1.0 eq.), ( )-N2-(1-(pyridazin-3-yl)pyrrolidin-3-yl)-1 ,3,4-thiadiazole-2,5-diamine (5.61 g, 21.34 mmol, 1.1 eq.) in dry-DMF (50 mL) was added PyBOP (15.13 g, 29.10 mmol, 1.5 eq.) and DI PEA (7.33 g, 58.20 mmol, 3.0 eq.). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (50 mL), extracted with EtOAc (3 x 50 mL). The combined organic layer was dried over anhydrous sodium sulphate to afford the crude product, which was purified by prep-HPLC (MeCN%=52%, +0.1% NH4HCO3) to afford the Example 60 (5.23 g, 52.5%) as a white solid.

[0870] Reference Examples

[0871] Reference Example 1 (RE1) corresponds to Compound 9a in WO2015 / 181539 (AstraZeneca AB and Cancer Research Technology Limited):

[0872] Reference Example 2 (RE2) corresponds to Compound 4a in WO2017 / 093301 (AstraZeneca AB and Cancer Research Technology Limited):

[0873] Reference Example 3 (RE3) corresponds to Compound 23 in Zhang et al., 2019:

[0874] Biological Example 1 - GLS1 inhibition in enzymatic and cellular assays

[0875] GLS1 Enzymatic assay

[0876] The inhibitory properties against GLS1 of the tested compounds were assessed by conducting a three-stage coupled endpoint enzymatic assay. Briefly, in the first stage, L-glutamine was converted to L-glutamate by the GLS1 enzyme. Then, L-glutamate was utilized by another enzyme used in the reaction, glutamate dehydrogenase (GDH), to form a-ketoglutarate, which is associated with the reduction of NAD to NADH. Finally, NADH was oxidized to NAD with concomitant reduction of resazurin to fluorescent resorufin. The resorufin level was measured with Ex554 / Em596. A decrease in signal intensity indicates GLS1 activity inhibition.

[0877] All reaction mixtures required for conducting the assay were prepared with use of 2x Assay Buffer pH=8.5 (100 mM phosphate buffer pH=8.5, 300 mM NaCI, 0.5 mM EDTA, 100 mM HEPES pH=8.5, 0.1% BSA). All compounds were tested in duplicates at a concentration range of 0.325 nM -5 pM (11 concentrations). DMSO (compounds solvent) and 5 pM reference compound CB- 839 were included on a plate as high control and low control, respectively. For running an assay run, reference compound CB-839 and test compounds were dispensed on a 384-well plate (with DMSO normalization to a final volume of 202 nL). Thereafter, 15 pL of 1.33x Enzyme Mix (2.67 mM NAD, 8 U / rnL GDH, 2 nM GLS1 in 1x Assay Buffer) was dispensed on a plate for compounds preincubation with the enzyme for 1h at 25 °C. Then, in order to start the enzymatic reaction, 5 pL of 4x Substrate Mix (40 mM L-glutamine, 1 mM ADP, 400 pM resazurin, 4 U / rnL diaphorase in 1x Assay Buffer) was dispensed on a plate with compounds and Enzyme Mix, followed by 1h incubation at 25 °C. The reaction was then stopped by adding 10 pL of 6% SDS solution and the fluorescence was measured with a microplate reader. Conducting the assay led to the determination of the potency of test compounds to inhibit GLS1 activity by generating concentration-response curves. Their specificity was additionally verified by running a counterscreen experiment, where test compounds were checked for the eventual inhibitory effect on the remaining enzymatic elements of the assay. For this purpose, 1 ,33x Enzyme Mix without GLS1 and 4x Substrate Mix containing 800 pM L-glutamate were used. For counterscreen experiments, the reference compound and test compounds were tested in a single concentration of 5 pM in duplicates.

[0878] GLS1 cell assay

[0879] The commercial Glutamine / Glutamate-Glo™ Assay kit provided by Promega was adjusted to measure changes in intracellular glutamate level in human lung carcinoma A549 cell line (ATCC No. CCL-185™) and in 384-well plate format after treatment with compounds of formula (I) and the reference examples.

[0880] A549 cells (ATCC No. CCL-185TM) were maintained in growth media consisting of DM EM high glucose (Gibco), 100 U / rnL Penicillin-Streptomycin, 1 mM Sodium Pyruvate, 10 % FBS. The cells were cultured at 37°C / 95% Air, 5% CO2 in a humidified incubator and passaged at 80-90% confluency.

[0881] A549 ceils were seeded into poly-D-lysine coated 384-well plates (Corning) at 10,000 cells / well density and in total volume of 40 pL / well. After overnight incubation at 37°C / 95% Air, 5% CO2 in a humidified incubator, the growth medium was removed and the cells were washed 2 x with 50 pL of warm assay medium composed of: DMEM no glucose, no glutamine, no phenol red (Gibco), 5 mM Glucose, 1 mM Sodium Pyruvate, 10% dialyzed FBS. Immediately after washing, warm assay medium was added in volume of 40 pL / well.

[0882] Compounds were dispensed into plate using D300e Digital Dispenser (Tecan) with a consistent concentration of 0.1% DMSO applied to all wells. After treatment cells were incubated for 2 hours at 37°C, 5% CO2 and then 10 pL of freshly prepared assay medium containing 5 x 1.25 mM L- Gln were added to each well. Afterwards, plates were incubated at 37°C / 95% Air, 5% CO2 in a humidified incubator for a further 24 hours.

[0883] The assay medium was removed completely and the cells were rinsed quickly 3 x with 60 pL of cold PBS. As instructed by the Glutamine / Glutamate-Glo™ Assay kit (Promega), 15 pL of cold PBS and 7.5 pL of Inactivation Solution I were added to each well and plates were mixed by shaking for 5 min. Afterwards, 7,5 pL of Tris Solution I were dispensed and plates were mixed again for 1 min. Lysates were frozen for about 24 hours at -20°C. Lysates were thawed at RT and diluted 2 x by adding lysis buffer composed of: 15 pL PBS, 7.5 pL Inactivation Solution I and 7.5 pL Tris Solution I. Glutamate Detection Reagent was prepared according to Glutamine / Glutamate-Glo™ Assay kit (Promega) protocol. After mixing, 12.5 pL of lysates were transferred to a new 384-well assay plate (Opti Plate-384, Perkin Elmer). As a positive control 12.5 pL of 50 pM glutamate (provided by Promega kit and prepared from 10 mM stock in lysis buffer) was used. A negative control was 12.5 pL of lysis buffer. 12.5 pL of Glutaminase Buffer (provided by Promega kit) were dispensed to all samples and plate was mixed by shaking for 1 min. Then, 25 pL of Glutamate Detection Reagent were added to each sample and mixed again for 1 min. A ratio of a Sample:Glutaminase Buffer: Glutamate Detection Reagent volume was established as 1 :1 :2. Plates were incubated for 60 min. at RT and protected from light. The final luminescence signal was recorded by using a plate reader.

[0884] To confirm that samples were within the linear range of the assay, a standard curve for glutamate was generated according to Glutamine / Glutamate-Glo™ Assay kit (Promega).

[0885] Dose response curves for tested compounds (representing % of inhibition) and pICso / ICso values were determined by using log(inhibitor) vs. response-variable slope (four parameters) model. Results were normalized to high control (VHL CTL - 0% of normalization) and to low control (POS CTL - 100% of normalization).

[0886] A number of example compounds were tested in this assay and the results are shown in Table 1 below. Reference Examples 1 , 2 and 3 were used as controls.

[0887] Table 1 - Cell and enzyme IC50 values (nM)

[0888] All compounds of formula (I) which were tested in this assay were active in the cell and / or enzyme assay as shown by the values in Table 1. Certain compounds of formula (I) that were tested in this assay were more potent than Reference Example 1 in the enzyme assay. Certain compounds of formula (I) that were tested in this assay were more potent than Reference Example 2 in the enzyme assay. Certain compounds of formula (I) that were tested in this assay were more potent than Reference Example 3 in the cell and / or enzyme assay.

[0889] Biological Example 2 - Epimerisation

[0890] Analytical Conditions

[0891] Method 1

[0892] Stationary phase: Gemini NX 3 pm C18 (4.6x150mm), 110A

[0893] Mobile Phase A: 0.1 % v / v water solution of formic acid

[0894] Mobile Phase B: 0.1 % v / v acetonitrile solution of formic acid

[0895] Flow rate: 1 mL / min

[0896] Gradient program: Time A% B%

[0897] 0.00 90.00 10.00

[0898] 7.50 60.00 40.00

[0899] 8.00 60.00 40.00

[0900] 8.50 5.00 95.00

[0901] 9.75 5.00 95.00

[0902] 10.25 90.00 10.00 12.00 90.00 10.00

[0903] Method 2

[0904] Stationary phase: Chiralpak AD-H (4.6x250 mm), 5 pm

[0905] Mobile Phase A: 0.1% v / v ethanol solution of triethylamine

[0906] Mobile Phase B: n-hexane

[0907] Flow rate: 1 mL / min

[0908] Gradient program: Time A% B%

[0909] 0.00 40.00 60.00

[0910] 25.00 40.00 60.00

[0911] Method 3

[0912] Stationary phase: Chiralpak IC (4.6x250 mm), 5 pm

[0913] Mobile Phase A: 0.1% v / v ethanol solution of triethylamine

[0914] Mobile Phase B: n-hexane

[0915] Flow rate: 1 mL / min

[0916] Gradient program: Time A% B%

[0917] 0.00 40.00 60.00

[0918] 20.00 40.00 60.00

[0919] General Procedure - Methanol

[0920] The title compound (2 mg) was dissolved in MeOH (1 mL) and a d.e. (%) (To) was determined by an HPLC analysis and calculated according to Equation 1 : . 100

[0921] The solution was maintained at Temperature for Duration summarized in Table 2. The solution was analysed by HPLC between 1 day and 29 days. Examples 34, 59 and 60 were tested. Reference Example 2 was used as a control.

[0922] Reference Example 2 was analysed by Method 1 after 7 days.

[0923] Example 34 was analysed by Method 2 after 1 , 2, 7, 14 and 29 days.

[0924] Example 59 was analysed by Method 3 after 1 , 2, 7 and 14 days.

[0925] Example 60 was analysed by Method 3 after 1 , 2, 7 and 14 days.

[0926] The results of these experiments are shown in Table 2 below. General Procedure - Citrate buffer

[0927] The title compound (2 mg) was dissolved in citrate buffer (pH 5.2) (1 mL) and a d.e. (%) (To) was determined by an HPLC analysis and calculated according to Equation 1 shown above. The solution was heated to 35 °C and maintain the same temperature for 28 days. An aliquot (150 pL) was evaporated, dissolved in MeOH, sonicated for 10 min, filtrated through syringe filter and submitted for HPLC analysis. The solution was analysed by HPLC between 1 day and 28 days.

[0928] Example 60 was analysed by Method 3 after 1 , 2, 7, 14 and 28 days.

[0929] Equation 2:

[0930] Change in d. e. (%) = d. e. (%)T— d. e. (° / o)Tx

[0931] The result of this experiment is shown in Table 2 below.

[0932] Table 2 - Epimerisation data

[0933] * calculated using Equation 2

[0934] The results shown in T able 2 show that the compounds of the invention, particularly those in T able 2 and certain other compounds of formula (I) wherein R2is other than H (in particular wherein R2is NR2aR2band 4-7 membered heterocyclyl wherein the 4-7 membered heterocyclyl is optionally substituted by R2cwherein R2a, R2b, R2care as defined herein) are expected to be stable to epimerisation compared with prior art compounds, for example Reference Example 2. The Example compounds tested were stable to epimerisation, unlike Reference Example 2, even under harsh conditions such as elevated temperatures and extended duration (up to 28 days). Therefore such compounds are superior for development as drug candidates, unlike compounds which epimerise particularly at room temperature (see Reference Example 2).

[0935] Biological Example 3 - PK data

[0936] PK experiments were performed according to the protocols described in Tables 3 and 4 below.

[0937] Table 3: PK protocol for RE1 and RE2

[0938] Table 4: PK protocol for Compounds of formula (I)

[0939] Table 6 - In-vivo pharmacokinetic assessment of compounds in lung, dosed intranasally in mouse

[0940] The results in Table 6 show that compounds of the invention are expected to have improved pharmacokinetic properties compared with compounds in the prior art, such as an improved duration in the lung. Example 60 was shown to have a higher lung concentrations and longer duration compared with both Reference Examples 1 and 2 as shown by the higher Cmax and higher AUCiast values. Biological Example 4 - Solubility Studies

[0941] Compounds tested in this assay were prepared as 10 mM stock solutions in DMSO. The assay was performed using Multiscreen Vacuum Manifold. PBS buffer, pH=7.4 was spiked with stock solution and incubated for 90 minutes at RT. After that time solution / suspension was filtrated. The concentration of each compound was determined on the base of prepared calibration curve using LIV-VIS (Biotec Synergy 2 (250 - 500 nm, interval range 10 nm) spectrophotometry method. The assay was made in triplicate.

[0942] Examples 60 and 66 were tested in this assay and the results are shown in Table 7 below. Reference Example 3 was used as a control.

[0943] Table 7 - Kinetic solubility data

[0944] The results in Table 7 show that compounds of the invention are expected to have improved solubility (for example, improved kinetic solubility) compared with compounds of the prior art. Examples 60 and 66 were shown to have improved kinetic solubility compared with Reference Example 3, and thus have preferred drug properties compared with Reference Example 3.

[0945] References

[0946] The following publication cited in this specification are herein incorporated by reference in their entirety.

[0947] Sarah C. Zimmermann, Bridget Duvall, and Takashi Tsukamoto. Recent Progress in the Discovery of Allosteric Inhibitors of Kidney-Type Glutaminase. J. Med. Chem. 2019, 62(1), 46- 59.

[0948] Ge J, Cui H, Xie N, Banerjee S, Guo S, Dubey S, Barnes S, Liu G. Glutaminolysis Promotes Collagen Translation and Stability via a-Ketoglutarate-mediated mTOR Activation and Proline Hydroxylation. Am. J. Respir. Cell. Mol. Biol. 2018, 58(3), 378-390.

[0949] Cui H, Xie N, Jiang D, Banerjee S, Ge J, Sanders YY, Liu G. Inhibition of Glutaminase 1 Attenuates Experimental Pulmonary Fibrosis. Am. J. Respir. Cell. Mol. Biol. 2019, 61 (4), 492- 500.

[0950] Kono M, Yoshida N, Maeda K, Tsokos GC. Transcriptional factor ICER promotes glutaminolysis and the generation of Th17 cells. Proc. Natl. Acad. Sci. USA. 2018, 115(10), 2478-2483. Johmura, Yoshikazu; Yamanaka, Takehiro; Omori, Satotaka; Wang, Teh-Wei; Sugiura, Yuki; Matsumoto, Masaki; Suzuki, Narumi; Kumamoto, Soichiro; Yamaguchi, Kiyoshi; Hatakeyama, Seira; Takami, Tomoyo; Yamaguchi, Rui; Shimizu, Eigo; Ikeda, Kazutaka; Okahashi, Nobuyuki; Mikawa, Ryuta; Suematsu, Makoto; Arita, Makoto; Sugimoto, Masataka; Nakayama, Keiichi I.; Furukawa, Yoichi; Imoto, Seiya; Nakanishi, Makoto. Senolysis by glutaminolysis inhibition ameliorates various age-associated disorders. Science 2021, 371 , 265-270.

[0951] Cottage, C.T., Peterson, N., Kearley, J. et al. Targeting p16-induced senescence prevents cigarette smoke-induced emphysema by promoting IGF1 / Akt1 signaling in mice. Commun. Biol. 2019, 2, 307

[0952] Tang Enyu, Liu Siyang, Zhang Zhiming, Zhang Rixin, Huang Dejing, Gao Tong, Zhang Tianze, Xu Guangquan, Therapeutic Potential of Glutamine Pathway in Lung Cancer. Front. One. 2022, 11 , 835141.

[0953] Masaki Fujimoto, Ritsuko Higashiyama, Hironobu Yasui, Koya Yamashita, Osamu Inanami, Preclinical studies for improving radiosensitivity of non-small cell lung cancer cell lines by combining glutaminase inhibition and senolysis, Translational Oncology 2022, 21, 101431. Thomas Bertero et al. Vascular stiffness mechanoactivates YAP / T AZ-dependent glutaminolysis to drive pulmonary hypertension. J. Clin. Invest. 2016, 126(9), 3313-3335.

[0954] Diana C. Contreras Healey et al. Targeting In Vivo Metabolic Vulnerabilities of Th2 and Th17 Cells Reduces Airway Inflammation. J. Immunol. 2021, 206(6), 1127-1139.

[0955] Zhang et al. Discovery of a thiadiazole-pyridizine-based allosteric glutaminase 1 inhibitor series that demonstrates oral bioavailability and activity in tumour zenograft models. J. Med. Chem. 2019, 62, 6540-6560.

[0956] Pasqua et al. Developing inhaled drugs for respiratory diseases: A medicinal chemistry perspective. Drug Discovery Today 2022, 27(1), 134-150.

[0957] Janke et al. Effect of influenza virus infection on key metabolic enzyme activities in MDCK cells. BMC Proceedings 2011, 5 (Suppl 8):P129.

[0958] Lu et al. Analysis of temporal metabolic rewiring for human respiratory syncytial virus infection by integrating metabolomics and proteomics. Metabolomics, 2023 19:30;

[0959] Hirabara et al. Host cell glutamine metabolism as a potential antiviral target. Clinical Science, 2021, 135, 305-325.

[0960] Bharadwaj et al. SARS-CoV-2 and Glutamine: SARS-CoV-2 Triggered Pathogenesis via Metabolic Reprogramming of Glutamine in Host Cells. Frontiers in Molecular Biosciences, 2021, 7, 627842.

[0961] Miscellaneous

[0962] All references referred to in this application, including patent and patent applications, are incorporated herein by reference to the fullest extent possible. Throughout the specification and the claims which follow, unless the context requires otherwise, the word ‘comprise’, and variations such as ‘comprises’ and ‘comprising’, will be understood to imply the inclusion of a stated integer, step, group of integers or group of steps but not to the exclusion of any other integer, step, group of integers or group of steps.

[0963] The application, of which this description and claims form part, may be used as a basis for priority in respect of any subsequent application. The claims of such subsequent application may be directed to any feature or combination of features described herein. They may take the form of product, composition, process, or use claims and may include, by way of example and without limitation, the following claims.

Claims

CLAIMS1 . A compound of formula (I):wherein:B is selected from the group consisting of;R1is selected from the group consisting of H, halo, C1.4 alkyl, C1.4 haloalkyl, NR1aR1 b, COOR1cand 4-7 membered heterocyclyl-CH2C(=O)NH- wherein the 4-7 membered heterocyclyl is optionally substituted by C1.3 alkyl or C3-7 cycloalkyl;R1aand R1 bare independently H or -C(O)C i-salkyl;R1cis H or C1.3 alkyl;R2is selected from the group consisting of H, C1.4 alkyl, C1.4 alkoxy, NR2aR2b, C3-7 cycloalkyl and 4-7 membered heterocyclyl wherein the 4-7 membered heterocyclyl is optionally substituted by one, two or three R2c;R2Cis selected from the group consisting of C1.3 alkyl, C1.3 thioalkyl and C3-6 cycloalkyl;R2aand R2bare independently C1.3 alkyl optionally substituted with OH;R3is selected from the group consisting of halo, hydroxy, C1.4 alkyl, C1.4 alkoxy, C1.4 haloalkyl, C1.4 haloalkoxy and phenyl;R4is H or halo;R5is H or C1.3 alkyl;A is selected from the group consisting of C5-10 cycloalkyl and Ce-12 spirocycloalkyl, wherein one CH2 group in the spirocycloalkyl group is optionally replaced by NH, and wherein the cycloalkyl group is optionally fused to phenyl wherein the phenyl is optionally substituted by halo; m is 0 or 1 ; and n is 0, 1 , 2, 3 or 4; or a salt and / or solvate thereof.

2. A compound according to claim 1 which is a compound of formula (I’):wherein:R1is selected from the group consisting of H, halo, C1.4 alkyl, C1.4 haloalkyl, NH2, and 4-7 membered heterocyclyl-CH2C(=O)NH- wherein the 4-7 membered heterocyclyl is optionally substituted by C1.3 alkyl or C3-7 cycloalkyl;R2is selected from the group consisting of H, C1.4 alkyl, C1.4 alkoxy, NR2aR2b, C3-7 cycloalkyl and 4-7 membered heterocyclyl wherein the 4-7 membered heterocyclyl is optionally substituted by R2cwherein R2cis C1.3 alkyl or C3-6 cycloalkyl; wherein R2aand R2bare independently C1.3 alkyl optionally substituted with OH;R3is selected from the group consisting of halo, hydroxy, C1.4 alkyl, C1.4 alkoxy, C1.4 haloalkyl, C1.4 haloalkoxy and phenyl;R4is H or halo;A is selected from the group consisting of C5-10 cycloalkyl and Ce-12 spirocycloalkyl, wherein one CH2 group in the spirocycloalkyl group is optionally replaced by NH, and wherein the cycloalkyl group is optionally fused to phenyl wherein the phenyl is optionally substituted by halo; m is 0 or 1 ; and n is 0, 1 , 2, 3 or 4; or a salt and / or solvate thereof.

3. The compound or a salt and / or solvate according to claim 1 which is a pharmaceutically acceptable salt and / or solvate of the compound of formula (I).

4. The compound or a salt and / or solvate thereof according to claim 1 which is a compound of formula (I).

5. The compound or a salt and / or solvate thereof according to any one of claims 1 to 4 wherein R1is H, 4-7 membered heterocyclyl-CH2C(=O)NH- or halo.

6. The compound or a salt and / or solvate thereof according to any one of claims 1 to 4 wherein R1is H.

7. The compound or a salt and / or solvate thereof according to any one of claims 1 to 6wherein R2is H or 4-7 membered heterocyclyl wherein the 4-7 membered heterocyclyl is optionally substituted by one R2cwherein R2cis C1.3 alkyl or C3-6 cycloalkyl.

8. The compound or a salt and / or solvate thereof according to claim 7 wherein R2is H.

9. The compound or a salt and / or solvate thereof according claim 7 wherein R2is 4-7 membered heterocyclyl wherein the 4-7 membered heterocyclyl is optionally substituted by one R2Cwherein R2cis C1.3 alkyl or C3-6 cycloalkyl.

10. The compound or a salt and / or solvate thereof according claim 7 wherein the 4-7 membered heterocyclyl is piperazinyl substituted by one R2cwherein R2cis C1.3 alkyl or C3-6 cycloalkyl.

11. The compound or a salt and / or solvate thereof according to any one of claims 1 to 10 wherein R3is halo e.g., fluoro, C1.4 alkyl e.g., methyl, or C1.4 haloalkyl e.g., CF3.

12. The compound or a salt and / or solvate thereof according to any one of claims 1 to 11 wherein the A is selected from the group consisting of cyclohexyl, cycloheptyl, adamantyl, and the Ce-12 spirocycloalkyl is spiro[3.5]nonyl or spiro[4.5]decyl.

13. The compound or a salt and / or solvate thereof according to any one of claims 1 to 12 wherein14. The compound or a salt and / or solvate thereof according to any one of claims 1 to 13 wherein m is 1.

15. The compound or a salt and / or solvate thereof according to any one of claims 1 to 14 wherein n is 0.

16. The compound or a salt and / or solvate thereof according to any one of claims 1 to 14 wherein n is 1.

17. The compound or a salt and / or solvate thereof according to any one of claims 1 to 14 wherein n is 2.

18. The compound or a salt and / or solvate thereof according to any one of claims 1 to 17 wherein R5is H, m is 1 and n is 0, 1 or 2.

19. The compound or a salt and / or solvate thereof according to any one of claims 1 to 18 which is a compound of formula (IA):wherein R2, R3, R4, R5, m, n, A and B are as defined in any one of claims 1 to 18; or a salt and / or solvate thereof.

20. The compound or a salt and / or solvate thereof according to any one of claims 1 to 18 which is a compound of formula (lA’-a):wherein R3, R2c, n and A are as defined in any one of claims 1 to 18; or a salt and / or solvate thereof.

21. The compound or a salt and / or solvate thereof according to any one of claims 1 to 19 which is a compound of formula (lA’-b):wherein R3, n and A are as defined in any one of claims 1 to 18; or a salt and / or solvate thereof.

22. The compound or a salt and / or solvate thereof according to any one of claims 1 to 19 which is a compound of formula (ID):wherein R2, R3, R4, R5, m, n, A and B are as defined in any one of claims 1 to 18; or a salt and / or solvate thereof.

23. A compound according to claim 1 which is selected from the list consisting of: 2-{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;A / -(5-{[(3 )-1-(6-aminopyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)-2- cycloheptylacetamide; / V-{6-[(3 )-3-{[5-(2-cycloheptylacetamido)-1 ,3,4-thiadiazol-2-yl]amino}pyrrolidin-1-yl]pyridazin-3- yl}-2-(4-cyclopropylpiperazin-1-yl)acetamide;2-(4-methylpiperazin-1-yl)-N-(5-{[(3R)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2- yl)-2-{spiro[3.5]nonan-7-yl}acetamide;(R)-2-(4-methylpiperazin-1-yl)-N-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol- 2-yl)-2-(spiro[3.5]nonan-7-yl)acetamide;(S)-2-(4-methylpiperazin-1-yl)-N-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol- 2-yl)-2-(spiro[3.5]nonan-7-yl)acetamide;2-cyclopentyl-A / -(5-{[(3 )-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;2-{bicyclo[1.1.1]pentan-1-yl}-A / -(5-{[(3 )-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol- 2-yl)acetamide;2-(3-hydroxyadamantan-1-yl)-A / -(5-{[(3 )-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4- thiadiazol-2-yl)acetamide;2-cyclopentyl-2-(4-methylpiperazin-1-yl)-A / -(5-{[(3 )-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}- 1 ,3,4-thiadiazol-2-yl)acetamide;2-cyclohexyl-A / -(5-{[(3 )-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide; 2-cycloheptyl-A / -(5-{[(3 )-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;2-cyclohexyl-2-(4-methylpiperazin-1-yl)-A / -(5-{[(3 )-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4- thiadiazol-2-yl)acetamide;2-(adamantan-1-yl)-A / -(5-{[(3 )-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;2-(adamantan-2-yl)- / V-(5-{[(3 / ?)-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)bicyclo[4.1.0]heptane-7- carboxamide;A / -(5-{[(3 / ?)-1 -(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)-2-(1 ,2,3,4- tetrahydronaphthalen-1-yl)acetamide;2-(4-phenylcyclohexyl)- / V-(5-{[(3 / ?)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2- yl)acetamide;2,2-dicyclohexyl- / V-(5-{[(3 / ?)-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)spiro[2.5]octane-1- carboxamide;2-(6-fluoro-1 ,2,3,4-tetrahydronaphthalen-2-yl)-A / -(5-{[(3 / ?)-1-(pyridazin-3-yl)pyrrolidin-3- yl]amino}-1 ,3,4-thiadiazol-2-yl)acetamide;2-(1-methylcyclohexyl)- / V-(5-{[(3 / ?)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2- yl)acetamide;(2S)- / V-(5-{[(3 / ?)-1-(6-chloropyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)-2- cyclohexyl-2-(dimethylamino)acetamide;(2 / ?)- / V-(5-{[(3 / ?)-1-(6-chloropyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)-2- cyclohexyl-2-(dimethylamino)acetamide;2-[(1 S,2S,5S)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl]-A / -(5-{[(3 / ?)-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-[3-(trifluoromethyl)adamantan-1-yl]acetamide;2-(4-ethylcyclohexyl)-2-(4-methylpiperazin-1-yl)-N-(5-((( / ?)-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;2-(4-(ferf-butyl)cyclohexyl)-2-(4-methylpiperazin-1-yl)-N-(5-((( / ?)-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;2-(4-methylpiperazin-1-yl)- / V-(5-((( / ?)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2- yl)-2-(3,3,5,5-tetramethylcyclohexyl)acetamide;2-((1 S,3S)-adamantan-1-yl)-A / -(5-((( / ?)-1-(6-(2-(4-cyclopropylpiperazin-1-yl)acetamido)pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;2-((1 S,3S)-adamantan-1-yl)-A / -(5-((( / ?)-1-(6-(2-(4-methylpiperazin-1-yl)acetamido)pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;2-((1 S,3S)-adamantan-1-yl)-2-(4-methylpiperazin-1-yl)-A / -(5-((( / ?)-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;(2 / ?)-2-((1 S,3S)-adamantan-1-yl)-2-(4-methylpiperazin-1-yl)-A / -(5-((( / ?)-1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;(2S)-2-((1 S,3 / ?)-adamantan-1-yl)-2-(4-methylpiperazin-1-yl)-A / -(5-((( / ?)-1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;2-((1 S,3S)-adamantan-1-yl)-2-(4-cyclopropylpiperazin-1-yl)-A / -(5-((( / ?)-1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;(2 / ?)-2-((1 S,3S)-adamantan-1-yl)-2-(4-cyclopropylpiperazin-1-yl)-A / -(5-((( / ?)-1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;(2S)-2-((1 S,3 / ?)-adamantan-1-yl)-2-(4-cyclopropylpiperazin-1-yl)-A / -(5-((( / ?)-1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;2-((1 S,3S)-adamantan-1-yl)-2-(4-ethylpiperazin-1-yl)-A / -(5-((( / ?)-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;(2 / ?)-2-((1 S,3S)-adamantan-1-yl)-2-(4-ethylpiperazin-1-yl)-A / -(5-((( / ?)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;(2S)-2-((1 S,3 / ?)-adamantan-1-yl)-2-(4-ethylpiperazin-1-yl)-A / -(5-((( / ?)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;2-((1 S,3S)-adamantan-1-yl)-2-(4-isopropylpiperazin-1-yl)-A / -(5-((( / ?)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;(2 / ?)-2-((1 S,3S)-adamantan-1-yl)-2-(4-isopropylpiperazin-1-yl)-A / -(5-((( / ?)-1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;(2S)-2-((1 S,3 / ?)-adamantan-1-yl)-2-(4-isopropylpiperazin-1-yl)-A / -(5-((( / ?)-1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;2-((1 / ?,3S)-3,5-dimethyladamantan-1-yl)-2-(4-methylpiperazin-1-yl)-A / -(5-((( / ?)-1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;(2S)-2-((1 / ?,3S)-3,5-dimethyladamantan-1-yl)-2-(4-methylpiperazin-1-yl)-A / -(5-((( / ?)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;2-(4-methylpiperazin-1-yl)- / V-(5-((( / ?)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2- yl)-2-(spiro[4.5]decan-8-yl)acetamide;( / ?)-2-(4-methylpiperazin-1-yl)- / V-(5-((( / ?)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-(spiro[4.5]decan-8-yl)acetamide;(S)-2-(4-methylpiperazin-1-yl)- / V-(5-((( / ?)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-(spiro[4.5]decan-8-yl)acetamide;A / -(5-((( / ?)-1-(6-chloropyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-cyclohexyl-2-(4-methylpiperazin-1-yl)acetamide;( / ?)- / V-(5-((( / ?)-1-(6-chloropyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-cyclohexyl- 2-(4-methylpiperazin-1-yl)acetamide;(S)- / V-(5-((( / ?)-1-(6-chloropyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-cyclohexyl-2-(4-methylpiperazin-1-yl)acetamide;A / -(5-((( / ?)-1-(6-chloropyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-(4,4- dimethylcyclohexyl)-2-(4-methylpiperazin-1-yl)acetamide;( / ?)- / V-(5-((( / ?)-1-(6-chloropyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-(4,4- dimethylcyclohexyl)-2-(4-methylpiperazin-1-yl)acetamide;(S)- / V-(5-((( / ?)-1-(6-chloropyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-(4,4- dimethylcyclohexyl)-2-(4-methylpiperazin-1-yl)acetamide;A / -(5-((( / ?)-1-(6-chloropyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-(4- methylpiperazin-1-yl)-2-(spiro[4.5]decan-8-yl)acetamide;( / ?)- / V-(5-((( / ?)-1-(6-chloropyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-(4- methylpiperazin-1-yl)-2-(spiro[4.5]decan-8-yl)acetamide;(S)- / V-(5-((( / ?)-1-(6-chloropyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-(4- methylpiperazin-1-yl)-2-(spiro[4.5]decan-8-yl)acetamide;2-(4,4-dimethylcyclohexyl)-2-(4-methylpiperazin-1-yl)-N-(5-((( / ?)-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;( / ?)-2-(4,4-dimethylcyclohexyl)-2-(4-methylpiperazin-1-yl)-A / -(5-((( / ?)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;(S)-2-(4,4-dimethylcyclohexyl)-2-(4-methylpiperazin-1-yl)-A / -(5-((( / ?)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;2-(4,4-dimethylcyclohexyl)-2-(4-isopropylpiperazin-1-yl)-A / -(5-((( / ?)-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;( / ?)-2-(4,4-dimethylcyclohexyl)-2-(4-isopropylpiperazin-1-yl)-A / -(5-((( / ?)-1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;(S)-2-(4,4-dimethylcyclohexyl)-2-(4-isopropylpiperazin-1-yl)-A / -(5-((( / ?)-1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;2-cyclooctyl-2-(4-ethylpiperazin-1-yl)- / V-(5-((( / ?)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4- thiadiazol-2-yl)acetamide;( / ?)-2-cyclooctyl-2-(4-ethylpiperazin-1-yl)- / V-(5-((( / ?)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)- 1 ,3,4-thiadiazol-2-yl)acetamide;(S)-2-cyclooctyl-2-(4-ethylpiperazin-1-yl)- / V-(5-((( / ?)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)- 1 ,3,4-thiadiazol-2-yl)acetamide;(2 / ?)-2-((1 / ?,3S)-3,5-dimethyladamantan-1-yl)-2-(4-methylpiperazin-1-yl)-A / -(5-((( / ?)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;A / -(5-{[(3S,4S)-4-fluoro-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4-thiadiazol-2-yl)-2-(4- methylpiperazin-1-yl)-2-{spiro[3.5]nonan-7-yl}acetamide;2-(4,4-dimethylcyclohexyl)-N-(5-((( / ?)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2- yl)-2-((3 / ?,5S)-3,4,5-trimethyl piperazin-1 -yl)acetamide;2-(4,4-dimethylcyclohexyl)-2-(1-isopropylpiperidin-4-yl)-A / -(5-((( )-1-(pyridazin-3-yl)pyrrolidin-3- yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;(S)-2-(4,4-dimethylcyclohexyl)-2-(1-isopropylpiperidin-4-yl)-A / -(5-((( )-1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;(R)-2-(4,4-dimethylcyclohexyl)-2-(1-isopropylpiperidin-4-yl)-A / -(5-((( )-1-(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;2-(4-isopropylpiperazin-1-yl)- / V-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-(spiro[3.5]nonan-7-yl)acetamide;( )-2-(4-isopropylpiperazin-1-yl)- / V-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4- thiadiazol-2-yl)-2-(spiro[3.5]nonan-7-yl)acetamide;(S)-2-(4-isopropylpiperazin-1-yl)- / V-(5-(((R)-1-(pyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4- thiadiazol-2-yl)-2-(spiro[3.5]nonan-7-yl)acetamide;2-(4,4-dimethylcyclohexyl)-2-(4-methylpiperazin-1-yl)-A / -(5-((( )-1-(6-methylpyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;(R)-2-(4,4-dimethylcyclohexyl)-2-(4-methylpiperazin-1-yl)-A / -(5-((( )-1-(6-methylpyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;(S)-2-(4,4-dimethylcyclohexyl)-2-(4-methylpiperazin-1-yl)-A / -(5-((( )-1-(6-methylpyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide; methyl 6-((3 )-3-((5-(2-(4,4-dimethylcyclohexyl)-2-(4-isopropylpiperazin-1-yl)acetamido)-1 ,3,4- thiadiazol-2-yl)amino)pyrrolidin-1-yl)pyridazine-4-carboxylate formate; methyl 6-(( )-3-((5-((R)-2-(4,4-dimethylcyclohexyl)-2-(4-isopropylpiperazin-1-yl)acetamido)-1 ,3,4-thiadiazol-2-yl)amino)pyrrolidin-1-yl)pyridazine-4-carboxylate; methyl 6-(( )-3-((5-((S)-2-(4,4-dimethylcyclohexyl)-2-(4-isopropylpiperazin-1-yl)acetamido)- 1 ,3,4-thiadiazol-2-yl)amino)pyrrolidin-1-yl)pyridazine-4-carboxylate;6-((3 )-3-((5-(2-(4,4-dimethylcyclohexyl)-2-(4-isopropylpiperazin-1-yl)acetamido)-1 ,3,4- thiadiazol-2-yl)amino)pyrrolidin-1-yl)pyridazine-4-carboxylic acid;6-(( )-3-((5-(( )-2-(4,4-dimethylcyclohexyl)-2-(4-isopropylpiperazin-1-yl)acetamido)-1 ,3,4- thiadiazol-2-yl)amino)pyrrolidin-1-yl)pyridazine-4-carboxylic acid;6-(( )-3-((5-((S)-2-(4,4-dimethylcyclohexyl)-2-(4-isopropylpiperazin-1-yl)acetamido)-1 ,3,4- thiadiazol-2-yl)amino)pyrrolidin-1-yl)pyridazine-4-carboxylic acid;A / -(5-((( )-1-(6-acetamidopyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-(4,4- dimethylcyclohexyl)-2-(4-isopropylpiperazin-1-yl)acetamide;(R)- / V-(5-(((R)-1-(6-acetamidopyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-(4,4- dimethylcyclohexyl)-2-(4-isopropylpiperazin-1-yl)acetamide;(S)- / V-(5-(((R)-1-(6-acetamidopyridazin-3-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-(4,4- dimethylcyclohexyl)-2-(4-isopropylpiperazin-1-yl)acetamide;2-(4,4-dimethylcyclohexyl)-2-(4-(2-(methylthio)ethyl)piperazin-1 -yl)- / V-(5-((( / ?)-1 -(pyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;2-(4,4-dimethylcyclohexyl)-2-(4-methylpiperazin-1-yl)-A / -(5-((( / ?)-1-(5-methylpyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;( / ?)-2-(4,4-dimethylcyclohexyl)-2-(4-methylpiperazin-1-yl)-A / -(5-((( / ?)-1-(5-methylpyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;(S)-2-(4,4-dimethylcyclohexyl)-2-(4-methylpiperazin-1-yl)-A / -(5-((( / ?)-1-(5-methylpyridazin-3- yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)acetamide;A / -(5-((( / ?)-1-(1 ,2,4-triazin-6-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-(4,4- dimethylcyclohexyl)-2-(4-isopropylpiperazin-1-yl)acetamide;( / ?)-A / -(5-((( / ?)-1-(1 ,2,4-triazin-6-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-(4,4-dimethyl cyclohexyl)-2-(4-isopropyl piperazin-1 -yl)acetamide;(S)-A / -(5-((( / ?)-1-(1 ,2,4-triazin-6-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-(4,4- dimethylcyclohexyl)-2-(4-isopropylpiperazin-1-yl)acetamide;A / -(5-((( / ?)-1-(1 ,2,4-triazin-6-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-(4-methylpiperazin- 1-yl)-2-(spiro[4.5]decan-8-yl)acetamide;( / ?)-A / -(5-((( / ?)-1-(1 ,2,4-triazin-6-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-(4- methylpiperazin-1-yl)-2-(spiro[4.5]decan-8-yl)acetamide;(S)-A / -(5-((( / ?)-1-(1 ,2,4-triazin-6-yl)pyrrolidin-3-yl)amino)-1 ,3,4-thiadiazol-2-yl)-2-(4- methylpiperazin-1-yl)-2-(spiro[4.5]decan-8-yl)acetamide;(S)-2-(4,4-dimethylcyclohexyl)-A / -(5-((( / ?)-1-(1-methyl-1 H-1 ,2,3-triazol-4-yl)pyrrolidin-3-yl)amino)- 1 ,3,4-thiadiazol-2-yl)-2-(4-methylpiperazin-1-yl)acetamide; and(2S)-2-(4,4-dimethylcyclohexyl)-A / -(5-{methyl[(3 / ?)-1-(pyridazin-3-yl)pyrrolidin-3-yl]amino}-1 ,3,4- thiadiazol-2-yl)-2-(4-methylpiperazin-1-yl)acetamide; or pharmaceutically acceptable salts and / or solvates of any one thereof.

24. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt and / or solvate thereof according to any one of claims 3 to 23 and one or more pharmaceutically acceptable diluents or carriers.

25. A compound or pharmaceutically acceptable salt and / or solvate thereof according to any one of claims 3 to 23 or a pharmaceutical composition according to claim 24 for use as a medicament.

26. A compound or a pharmaceutically acceptable salt and / or solvate thereof according to any one of claims 3 to 23 or a pharmaceutical composition according to claim 24 for use in treating or preventing fibrotic and / or inflammatory diseases.

27. Use of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof according to any one of claims 3 to 23 or a pharmaceutical composition according to claim 24 in the manufacture of a medicament for treating or preventing fibrotic and / or inflammatory diseases.

28. 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 3 to 23, or a pharmaceutical composition according to claim 24.

29. The compound or pharmaceutically acceptable salt and / or solvate thereof for use according to claim 26, the pharmaceutical composition for use according to claim 26, use according to claim 27 or the method according to claim 28, wherein the fibrotic and / or inflammatory disease is a fibrotic and / or inflammatory disease of the lung.

30. The compound or pharmaceutically acceptable salt and / or solvate thereof for use according to claim 26, the pharmaceutical composition for use according to claim 26, use according to claim 27 or the method according to claim 28, wherein the fibrotic and / or inflammatory disease is an interstitial lung disease.

31. The compound or pharmaceutically acceptable salt and / or solvate thereof for use, pharmaceutical composition for use, use or method according to claim 30, 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.

32. The compound or pharmaceutically acceptable salt and / or solvate thereof for use according to claim 26, the pharmaceutical composition for use according to claim 26, use according to claim 27 or the method according to claim 28, 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.

33. The compound or pharmaceutically acceptable salt and / or solvate thereof for use according to claim 26, the pharmaceutical composition for use according to claim 26, use according to claim 27 or the method according to claim 28, wherein the fibrotic disease is fibrosis or non-alcoholic steatohepatitis.STX-P3675PCT Application as filed14334. The compound or pharmaceutically acceptable salt and / or solvate thereof for use according to claim 26, the pharmaceutical composition for use according to claim 26, use according to claim 27 or the method according to claim 28, 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.

35. A process for the preparation of a compound of formula (I):or a salt and / or solvate such as a pharmaceutically acceptable salt and / or solvate 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; or(b) reacting a compound of formula (IV):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 R1, R2, R3, R4, m, n and A are as in any one of claims 1 to 23, X2is a leaving group such as halo e.g. chloro and Y is a 4-7 membered heterocycle.

36. A compound selected from the group consisting of:- a compound of formula (IV):or a salt, such as a pharmaceutically acceptable salt thereof; wherein R2, R3, R4, m, n and A are as in any one of claims 1 to 23 and X2is a leaving group such as halo e.g. chloro;- a compound of formula (V):or a salt, such as a pharmaceutically acceptable salt thereof; wherein R2, R3, R4, m, n and A are as in any one of claims 1 to 23; and- a compound of formula (VI):or a salt, such as a pharmaceutically acceptable salt thereof; wherein R2, R3, R4, m, n and A are as in any one of claims 1 to 23.

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