WRN inhibitory compounds

Abstract

The present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof. The present invention further relates to the compound of formula (I) of the present invention for use in therapy. Instant compounds are particularly useful as WRN inhibitors, and can be used in a method of treatment of cancer, in particular, the cancer is treatable by inhibition of WRN, and / or the cancer characterized by MSI-H and / or dMMR.

Description

[0001] WRN inhibitory compounds

[0002] Field of the invention

[0003] The present invention relates to a compound of formula (I): or a pharmaceutically acceptable salt thereof. The present invention further relates to the compound of formula (I) of the present invention for use in therapy. Instant compounds are particularly useful as WRN inhibitors, and can be used in a method of treatment of cancer, in particular, the cancer is treatable by inhibition of WRN, and / or the cancer characterized by MSI-H and / or dMMR.

[0004] Background of the invention

[0005] Cancer is a leading cause of death worldwide. A limitation of prevailing therapeutic approaches, e.g. chemotherapy is that their cytotoxic effects are not restricted to cancer cells and adverse side effects can occur within normal tissues. Consequently, novel strategies are needed to better target cancer cells.

[0006] Synthetic lethality (SL) arises when a combination of genetic deficiencies (e.g. gene mutations, silencing or global genomic lesions) and / or molecular perturbations (e.g. gene expression knockout / knockdown, pharmacological inhibition / activation) corresponding to two or more genes impaired cell wellbeing, whereas presence of single deficiency / perturbation does not (Dobzhansky, T., Genetics 1946; 31 , 269-290, Huang et al., Nature Reviews Drug Discovery 2020; volume 19, pages 23-38).

[0007] Microsatellite instability is a genomic lesion caused by defects in mismatch repair machinery (dMMR). MSI status is present in colorectal cancer, endometrial cancer, gastric cancer and other cancer types. Mutation or silencing of MMR genes, including MLH1 , MSH2, MSH6 and PMS2, abrogates cell’s ability to repair DNA mismatch mutations (Baudrin et al., Front. Oncol. 2018). As a consequence, tumor with MSI-H status carries higher mutation burden, disrupted microsatellite repeat sequences and extended TA dinucleotide repeat sequences across the genome (van Wietmarschen N. et al., Nature 2020; 586, pages 292-298). MSI status can be assessed by molecular testing of certain microsatellites, next-generation sequencing of patient genome or by immunohistochemical evaluation of expression of certain MMR proteins. Tumors can be categorized into MSI high (MSI-H), MSI low (MSI-L) and MSS depending on the number of tested microsatellite showing instability. Based on a consensus NCI- Reference Panel (Bethesda, 1998), MSI can be assessed by molecular testing of five microsatellites - including two mononucleotides (BAT25 and BAT26) and three dinucleotides (D2S123, D5S346, D17S250). Tumors are denoted as MSI-high (MSI-H) if two or more of the microsatellite markers show instability, MSI-low (MSI-L) if only one microsatellite marker shows instability, and MS-stable (MSS) if none of the five microsatellite markers show instability. In some instances, for example where molecular testing or immunohistochemical evaluation is not able to distinguish between MSI-L and general chromosomal instability, tumors can be classified as a MSS neoplasms.

[0008] WRN (WRN RecQ helicase) has been identified as a synthetic lethality vulnerability to cancer cells with high microsatellite instability status (MSI-H). WRN contains an exonuclease domain and an ATP - dependent helicase domain. It is localized to the nucleus and unwinds double strand DNA, particularly secondary structures (fork DNA, holliday junction, G4-quadruaplex, DNA hairpin and cruciform etc.) during DNA replication, damage and repair processes. Its helicase activity has been shown to be indispensable to the survival of MSI cell lines as helicase-deficient WRN mutant is insufficient to rescue impaired cell viability from WRN knockout or knockdown. The absence of either the WRN protein or inhibition of its helicase activity prevents normal DNA damage and repair processes, leading to increased DNA doublestrand breaks (DSB) and subsequent growth arrest and cell death.

[0009] Covalent inhibitors represent a class of small molecules which form covalent bonds with their biological targets to inhibit activities of these targets in physiological or pathological conditions. In general, covalent inhibitors engage with nucleophilic residues (e.g. Cysteine, Serine, Threonine, Histidine, Arginine, Tyrosine) lining specific binding pockets on target proteins, in a nucleophilic addition or substitution reaction, with their reactive electrophilic warhead. To date, a variety of reactive warheads have been identified, including epoxide, aziridine, ester, ketone, a, -unsaturated carbonyl, nitrile, etc. Covalent inhibitors have been discovered as medicines for more than a century, starting with Aspirin being manufactured and marketed as painkillers and anti-inflammatory drug, although its mechanism of action was not revealed until 1970s to be an irreversible inhibitor of cyclooxygenase- 1 (COX- 1 ). Other notable covalent inhibitors used as medicine include antibiotics Penicillin, proton pump inhibitor Omeprazole and Lansoprazole, anticoagulant Clopidogrel.

[0010] Document WO 2023 / 062575 discloses certain cyclic vinyl sulfone compounds as WRN inhibitors. Documents WO 2024 / 010782 and WO 2024 / 010784 disclose certain covalent WRN inhibitors. Further covalent inhibitors of WRN are disclosed in document WO 2024 / 028169.

[0011] Document WO 2022 / 249060 discloses certain compounds as WRN reversible inhibitors. Similar compounds are disclosed in WO 2024 / 079623.

[0012] Further reversible WRN inhibitors are disclosed in WO 2024 / 120378.

[0013] Summary of the invention

[0014] It was an objective technical problem of the present invention to provide compounds that are cell- permeable inhibitors of WRN. The technical problem of the present invention is solved by the embodiments described herein and as characterized by the claims.

[0015] Accordingly, the compounds of the present invention show improved PK / PD properties compared to previously known WRN inhibitors. Furthermore, the compounds of the present invention show improved selectivity as covalent inhibitors against WRN protein.

[0016] In a first embodiment, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0017] In a second embodiment, the present invention relates to a pharmaceutical composition comprising a compound of formula (I).

[0018] In a third embodiment, the present invention relates to a compound of formula (I) for use as a medicament.

[0019] In a fourth embodiment, the present invention relates to a compound of formula (I) for use in the treatment of cancer. It is preferred that the cancer is characterized by high microsatellite instability (MSI) and / or by defective DNA mismatch repair system (dMMR) in a patient.

[0020] In a fifth embodiment, the present invention relates to use of a compound of formula (I) in a manufacture of a medicament.

[0021] In a sixth embodiment, the present invention relates to use of a compound of formula (I) in a manufacture of a medicament for the treatment of cancer. It is preferred that the cancer is characterized by high microsatellite instability (MSI) and / or by defective DNA mismatch repair system (dMMR) in a patient.

[0022] In a seventh embodiment, the present invention relates to a method of treatment of cancer in a subject in need thereof, the method comprising the step of administering the compound of formula (I) to said subject. Typically, a therapeutically effective amount of the compound of formula (I) is administered. It is preferred that the cancer is characterized by high microsatellite instability (MSI) and / or by defective DNA mismatch repair system (dMMR) in a patient.

[0023] Definitions

[0024] The following definitions apply throughout the present specification and the claims, unless specifically indicated otherwise.

[0025] The term “hydrogen” is herein used to refer to protium, deuterium and / or tritium, preferably to protium. Accordingly, the term “non-hydrogen atom” refers to any atoms that is not hydrogen, i.e. that is not protium, deuterium or tritium. The term “hydrocarbon group” refers to a group consisting of carbon atoms and hydrogen atoms.

[0026] The term “alicyclic” is used in connection with cyclic groups and denotes that the corresponding cyclic group is non-aromatic.

[0027] As used herein, the term “alkyl” refers to a monovalent saturated acyclic (i.e., non-cyclic) hydrocarbon group which may be linear or branched. Accordingly, an “alkyl” group does not comprise any carbon-to-carbon double bond or any carbon-to-carbon triple bond. A “C1-5 alkyl” denotes an alkyl group having 1 to 5 carbon atoms. Preferred exemplary alkyl groups are methyl, ethyl, propyl (e.g., n-propyl or isopropyl), or butyl (e.g., n-butyl, isobutyl, sec-butyl, or tert-butyl). Unless defined otherwise, the term “alkyl” preferably refers to C1-4 alkyl, more preferably to methyl or ethyl, and even more preferably to methyl.

[0028] As used herein, the term “alkenyl” refers to a monovalent unsaturated acyclic hydrocarbon group which may be linear or branched and comprises one or more (e.g., one or two) carbon-to-carbon double bonds while it does not comprise any carbon-to-carbon triple bond. The term “C2-5 alkenyl” denotes an alkenyl group having 2 to 5 carbon atoms. Preferred exemplary alkenyl groups are ethenyl, propenyl (e.g., prop-1 -en-1-yl, prop-1 -en-2-yl, or prop-2-en-1-yl), butenyl, butadienyl (e.g., buta-1 ,3-dien-1-yl or buta-1 ,3- dien-2-yl), pentenyl, or pentadienyl (e.g., isoprenyl). Unless defined otherwise, the term “alkenyl” preferably refers to C2-4 alkenyl.

[0029] As used herein, the term “alkynyl” refers to a monovalent unsaturated acyclic hydrocarbon group which may be linear or branched and comprises one or more (e.g., one or two) carbon-to-carbon triple bonds and optionally one or more (e.g., one or two) carbon-to-carbon double bonds. The term “C2-5 alkynyl” denotes an alkynyl group having 2 to 5 carbon atoms. Preferred exemplary alkynyl groups are ethynyl, propynyl (e.g., propargyl), or butynyl. Unless defined otherwise, the term “alkynyl” preferably refers to C2-4 alkynyl.

[0030] As used herein, the term “alkylene” refers to an alkanediyl group, i.e. a divalent saturated acyclic hydrocarbon group which may be linear or branched. A “C1-5 alkylene” denotes an alkylene group having 1 to 5 carbon atoms, and the term “C0-3 alkylene” indicates that a covalent bond (corresponding to the option “Co alkylene”) or a C1-3 alkylene is present. Preferred exemplary alkylene groups are methylene (- CH2-), ethylene (e.g., -CH2-CH2- or -CH(-CH3)-), propylene (e.g., -CH2-CH2-CH2-, -CH(-CH2-CH3)-, -CH2- CH(-CH3)-, or -CH(-CH3)-CH2-), or butylene (e.g., -CH2-CH2-CH2-CH2-). Unless defined otherwise, the term “alkylene” preferably refers to C1-4 alkylene (including, in particular, linear C1-4 alkylene), more preferably to methylene or ethylene, and even more preferably to methylene.

[0031] As used herein, the term “alkenylene” refers to an alkenediyl group, i.e. a divalent unsaturated acyclic hydrocarbon group which may be linear or branched and comprises one or more (e.g., one or two) carbon-to-carbon double bonds while it does not comprise any carbon-to-carbon triple bond. A “C2- 5 alkenylene” denotes an alkenylene group having 2 to 5 carbon atoms. Unless defined otherwise, the term “alkenylene” preferably refers to C2-4 alkenylene (including, in particular, linear C2-4 alkenylene).

[0032] As used herein, the term “alkynylene” refers to an alkynediyl group, i.e. a divalent unsaturated acyclic hydrocarbon group which may be linear or branched and comprises one or more (e.g., one or two) carbon-to-carbon triple bonds and optionally one or more (e.g., one or two) carbon-to-carbon double bonds. A “C2-5 alkynylene” denotes an alkynylene group having 2 to 5 carbon atoms. Unless defined otherwise, the term “alkynylene” preferably refers to C24 alkynylene (including, in particular, linear C2-4 alkynylene).

[0033] As used herein, the term “carbocyclyl” refers to a hydrocarbon ring group, including monocyclic rings as well as bridged ring, spiro ring and / or fused ring systems (which may be composed, e.g., of two or three rings), wherein said ring group may be saturated, partially unsaturated (i.e., unsaturated but not aromatic) or aromatic. Unless defined otherwise, “carbocyclyl” preferably refers to aryl, cycloalkyl or cycloalkenyl.

[0034] As used herein, the term “heterocyclyl” refers to a ring group, including monocyclic rings as well as bridged ring, spiro ring and / or fused ring systems (which may be composed, e.g., of two or three rings), wherein said ring group comprises one or more (such as, e.g., one, two, three, or four) ring heteroatoms independently selected from 0, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) may optionally be oxidized, wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group), and further wherein said ring group may be saturated, partially unsaturated (i.e., unsaturated but not aromatic) or aromatic. For example, each heteroatom-containing ring comprised in said ring group may contain one or two 0 atoms and / or one or two S atoms (which may optionally be oxidized) and / or one, two, three or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that there is at least one carbon ring atom (which may optionally be oxidized) in the corresponding heteroatom-containing ring. Unless defined otherwise, “heterocyclyl” preferably refers to heteroaryl, heterocycloalkyl or heterocycloalkenyl.

[0035] As used herein, the term “aryl” refers to an aromatic hydrocarbon ring group, including monocyclic aromatic rings as well as bridged ring and / or fused ring systems containing at least one aromatic ring (e.g., ring systems composed of two or three fused rings, wherein at least one of these fused rings is aromatic; or bridged ring systems composed of two or three rings, wherein at least one of these bridged rings is aromatic). “Aryl” may, e.g., refer to phenyl, naphthyl, dialinyl (i.e., 1 ,2-dihydronaphthyl), tetralinyl (i.e., 1 ,2,3,4-tetrahydronaphthyl), indanyl, indenyl (e.g., 1 H-indenyl), anthracenyl, phenanthrenyl, 9H- fluorenyl, or azulenyl. Unless defined otherwise, an “aryl” preferably has 6 to 14 ring atoms, more preferably 6 to 10 ring atoms, even more preferably refers to phenyl or naphthyl, and most preferably refers to phenyl.

[0036] As used herein, the term “arylene” refers to an aryl group, as defined herein above, but having two points of attachment, i.e. a divalent aromatic hydrocarbon ring group, including monocyclic aromatic rings as well as bridged ring and / or fused ring systems containing at least one aromatic ring (e.g., ring systems composed of two or three fused rings, wherein at least one of these fused rings is aromatic; or bridged ring systems composed of two or three rings, wherein at least one of these bridged rings is aromatic). “Arylene” may, e.g., refer to phenylene (e.g., phen-1 ,2-diyl, phen-1 ,3-diyl, or phen-1 ,4-diyl), naphthylene (e.g., naphthalen-1 ,2-diyl, naphthalen-1 ,3-diyl, naphthalen-1 ,4-diyl, naphthalen-1 ,5-diyl, naphthalen-1 ,6- diyl, naphthalen-1 , 7-diyl, naphthalen-2,3-diyl, naphthalen-2,5-diyl, naphthalen-2,6-diyl, naphthalen-2,7- diyl, or naphthalen-2,8-diyl), 1 ,2-dihydronaphthylene, 1 ,2,3,4-tetrahydronaphthylene, indanylene, indenylene, anthracenylene, phenanthrenylene, 9H-fluorenylene, or azulenylene. Unless defined otherwise, an “arylene” preferably has 6 to 14 ring atoms, more preferably 6 to 10 ring atoms, even more preferably refers to phenylene or naphthylene, and most preferably refers to phenylene (particularly phen- 1 ,4-diyl).

[0037] As used herein, the term “heteroaryl” refers to an aromatic ring group, including monocyclic aromatic rings as well as bridged ring and / or fused ring systems containing at least one aromatic ring (e.g., ring systems composed of two or three fused rings, wherein at least one of these fused rings is aromatic; or bridged ring systems composed of two or three rings, wherein at least one of these bridged rings is aromatic), wherein said aromatic ring group comprises one or more (such as, e.g., one, two, three, or four) ring heteroatoms independently selected from 0, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) may optionally be oxidized, and further wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group). For example, each heteroatom-containing ring comprised in said aromatic ring group may contain one or two 0 atoms and / or one or two S atoms (which may optionally be oxidized) and / or one, two, three or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that there is at least one carbon ring atom (which may optionally be oxidized) in the corresponding heteroatom-containing ring. “Heteroaryl” may, e.g., refer to thienyl (i.e., thiophenyl), benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl (i.e., furanyl), benzofuranyl, isobenzofuranyl, chromanyl, chromenyl (e.g., 2H-1- benzopyranyl or 4H-1 -benzopyranyl), isochromenyl (e.g., 1 H-2-benzopyranyl), chromonyl, xanthenyl, phenoxathiinyl, pyrrolyl (e.g., 1 H-pyrrolyl), imidazolyl, pyrazolyl, pyridyl (i.e., pyridinyl; e.g., 2-pyridyl, 3- pyridyl, or 4-pyridyl), pyrazinyl, pyrimidinyl, pyridazinyl, indolyl (e.g., 3H-indolyl), isoindolyl, indazolyl, indolizinyl, purinyl, quinolyl, isoquinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, cinnolinyl, pteridinyl, carbazolyl, p-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl (e.g., [1 , 1 O]phenanthrolinyl, [1 ,7]phenanthrolinyl, or [4,7]phenanthrolinyl), phenazinyl, thiazolyl, isothiazolyl, phenothiazinyl, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1 ,2,4-oxadiazolyl, 1 ,2,5-oxadiazolyl (i.e., furazanyl), or 1 ,3,4-oxadiazolyl), thiadiazolyl (e.g., 1 ,2,4-thiadiazolyl, 1 ,2,5-thiadiazolyl, or 1 ,3,4-thiadiazolyl), phenoxazinyl, pyrazolo[1 ,5-a]pyrimidinyl (e.g., pyrazolo[1 ,5-a]pyrimidin-3-yl), 1 ,2-benzoisoxazol-3-yl, benzothiazolyl, benzothiadiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzo[b]thiophenyl (i.e., benzothienyl), triazolyl (e.g., 1 H-1 ,2,3-triazolyl, 2H-1 ,2,3-triazolyl, 1 H-1 ,2,4-triazolyl, or 4H-1 ,2,4-triazolyl), benzotriazolyl, 1 H-tetrazolyl, 2H-tetrazolyl, triazinyl (e.g., 1,2,3-triazinyl, 1 ,2,4-triazinyl, or 1 ,3,5-triazinyl), furo[2,3-c]pyridinyl, dihydrofuropyridinyl (e.g., 2,3-dihydrofuro[2,3-c]pyridinyl or 1 ,3-dihydrofuro[3,4- c]pyridinyl), imidazopyridinyl (e.g., imidazo[1 ,2-a]pyridinyl or imidazo[3,2-a]pyridinyl), quinazolinyl, thienopyridinyl, tetrahydrothienopyridinyl (e.g., 4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl), dibenzofuranyl, 1 ,3-benzodioxolyl, benzodioxanyl (e.g., 1 ,3-benzodioxanyl or 1 ,4-benzodioxanyl), or coumarinyl. Unless defined otherwise, the term “heteroaryl” preferably refers to a 5 to 14 membered (more preferably 5 to 10 membered) monocyclic ring or fused ring system comprising one or more (e.g., one, two, three or four) ring heteroatoms independently selected from 0, S and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized; even more preferably, a “heteroaryl” refers to a 5 or 6 membered monocyclic ring comprising one or more (e.g., one, two or three) ring heteroatoms independently selected from 0, S and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized.

[0038] As used herein, the term “heteroarylene” refers to a heteroaryl group, as defined herein above, but having two points of attachment, i.e. a divalent aromatic ring group, including monocyclic aromatic rings as well as bridged ring and / or fused ring systems containing at least one aromatic ring (e.g., ring systems composed of two or three fused rings, wherein at least one of these fused rings is aromatic; or bridged ring systems composed of two or three rings, wherein at least one of these bridged rings is aromatic), wherein said aromatic ring group comprises one or more (such as, e.g., one, two, three, or four) ring heteroatoms independently selected from 0, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) may optionally be oxidized, and further wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group). For example, each heteroatom-containing ring comprised in said aromatic ring group may contain one or two 0 atoms and / or one or two S atoms (which may optionally be oxidized) and / or one, two, three, or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that there is at least one carbon ring atom (which may optionally be oxidized) in the corresponding heteroatom-containing ring. “Heteroarylene” may, e.g., refer to thienylene (i.e., thiophenylene; e.g., thien-2,3-diyl, thien-2,4-diyl, or thien-2,5-diyl), benzo[b]thienylene, naphtho[2,3-b]thienylene, thianthrenylene, furylene (i.e., furanylene; e.g., furan-2,3-diyl, furan-2,4-diyl, or furan-2,5-diyl), benzofuranylene, isobenzofuranylene, chromanylene, chromenylene, isochromenylene, chromonylene, xanthenylene, phenoxathiinylene, pyrrolylene, imidazolylene, pyrazolylene, pyridylene (i.e., pyridinylene), pyrazinylene, pyrimidinylene, pyridazinylene, indolylene, isoindolylene, indazolylene, indolizinylene, purinylene, quinolylene, isoquinolylene, phthalazinylene, naphthyridinylene, quinoxalinylene, cinnolinylene, pteridinylene, carbazolylene, P-carbolinylene, phenanthridinylene, acridinylene, perimidinylene, phenanthrolinylene, phenazinylene, thiazolylene (e.g., thiazol-2,4-diyl, thiazol-2,5-diyl, or thiazol-4,5-diyl), isothiazolylene (e.g., isothiazol-3,4- diyl, isothiazol-3,5-diyl, or isothiazol-4,5-diyl), phenothiazinylene, oxazolylene (e.g., oxazol-2,4-diyl, oxazol-2,5-diyl, or oxazol-4,5-diyl), isoxazolylene (e.g., isoxazol-3,4-diyl, isoxazol-3,5-diyl, or isoxazol-4,5- diyl), oxadiazolylene (e.g., 1 ,2,4-oxadiazol-3,5-diyl, 1 ,2,5-oxadiazol-3,4-diyl, or 1 ,3,4-oxadiazol-2,5-diyl), thiadiazolylene (e.g., 1 ,2,4-thiadiazol-3,5-diyl, 1 ,2,5-thiadiazol-3,4-diyl, or 1 ,3,4-thiadiazol-2,5-diyl), phenoxazinylene, pyrazolo[1 ,5-a]pyrimidinylene, 1 ,2-benzoisoxazolylene, benzothiazolylene, benzothiadiazolylene, benzoxazolylene, benzisoxazolylene, benzimidazolylene, benzo[b]thiophenylene (i.e., benzothienylene), triazolylene (e.g., 1 H-1 ,2,3-triazolylene, 2H-1 ,2,3-triazolylene, I H-1 ,2,4- triazolylene, or 4H-1 ,2,4-triazolylene), benzotriazolylene, 1 H-tetrazolylene, 2H-tetrazolylene, triazinylene (e.g., 1 ,2,3-triazinylene, 1 ,2,4-triazinylene, or 1 ,3,5-triazinylene), furo[2,3-c]pyridinylene, dihydrofuropyridinylene (e.g., 2,3-dihydrofuro[2,3-c]pyridinylene or 1 ,3-dihydrofuro[3,4-c]pyridinylene), imidazopyridinylene (e.g., imidazo[1 ,2-a]pyridinylene or imidazo[3,2-a]pyridinylene), quinazolinylene, thienopyridinylene, tetrahydrothienopyridinylene (e.g., 4,5,6,7-tetrahydrothieno[3,2-c]pyridinylene), dibenzofuranylene, 1 ,3-benzodioxolylene, benzodioxanylene (e.g., 1 ,3-benzodioxanylene or 1 ,4-benzodioxanylene), or coumarinylene. Unless defined otherwise, the term “heteroarylene” preferably refers to a divalent 5 to 14 membered (more preferably 5 to 10 membered) monocyclic ring or fused ring system comprising one or more (e.g., one, two, three or four) ring heteroatoms independently selected from 0, S and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized; even more preferably, a “heteroarylene” refers to a divalent 5 or 6 membered monocyclic ring comprising one or more (e.g., one, two or three) ring heteroatoms independently selected from 0, S, and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized. A “heteroarylene”, including any of the specific heteroarylene groups described herein, may be attached through two carbon ring atoms, particularly through those two carbon ring atoms that have the greatest distance from one another (in terms of the number of ring atoms separating them by the shortest possible connection) within one single ring or within the entire ring system of the corresponding heteroarylene. As used herein, the term “cycloalkyl” refers to a saturated hydrocarbon ring group, including monocyclic rings as well as bridged ring, spiro ring and / or fused ring systems (which may be composed, e.g., of two or three rings; such as, e.g., a fused ring system composed of two or three fused rings). “Cycloalkyl” may, e.g., refer to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, decalinyl (i.e., decahydronaphthyl), or adamantyl. Unless defined otherwise, “cycloalkyl” preferably refers to a C3-11 cycloalkyl, and more preferably refers to a C3-7 cycloalkyl. A particularly preferred “cycloalkyl” is a monocyclic saturated hydrocarbon ring having 3 to 7 ring members (e.g., cyclopropyl or cyclohexyl).

[0039] As used herein, the term “cycloalkylene” refers to a cycloalkyl group, as defined herein above, but having two points of attachment, i.e. a divalent saturated hydrocarbon ring group, including monocyclic rings as well as bridged ring, spiro ring and / or fused ring systems (which may be composed, e.g., of two or three rings; such as, e.g., a fused ring system composed of two or three fused rings). “Cycloalkylene” may, e.g., refer to cyclopropylene (e.g., cyclopropan-1 , 1 -diyl or cyclopropan-1 ,2-diyl), cyclobutylene (e.g., cyclobutan-1 ,1-diyl, cyclobutan-1 ,2-diyl, or cyclobutan-1 ,3-diyl), cyclopentylene (e.g., cyclopentan-1,1 -diyl, cyclopentan-1 , 2-diyl, or cyclopentan-1 , 3-diyl), cyclohexylene (e.g., cyclohexan-1 , 1-diyl, cyclohexan-1, 2-diyl, cyclohexan-1, 3-diyl, or cyclohexan-1 ,4-diyl), cycloheptylene, decalinylene (i.e., decahydronaphthylene), or adamantylene. Unless defined otherwise, “cycloalkylene” preferably refers to a C3-11 cycloalkylene, and more preferably refers to a C3-7 cycloalkylene. A particularly preferred “cycloalkylene” is a divalent monocyclic saturated hydrocarbon ring having 3 to 7 ring members (e.g., cyclopropylene or cyclohexylene).

[0040] As used herein, the term “heterocycloalkyl” refers to a saturated ring group, including monocyclic rings as well as bridged ring, spiro ring and / or fused ring systems (which may be composed, e.g., of two or three rings; such as, e.g., a fused ring system composed of two or three fused rings), wherein said ring group contains one or more (such as, e.g., one, two, three, or four) ring heteroatoms independently selected from 0, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) may optionally be oxidized, and further wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group). For example, each heteroatom-containing ring comprised in said saturated ring group may contain one or two 0 atoms and / or one or two S atoms (which may optionally be oxidized) and / or one, two, three or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that there is at least one carbon ring atom (which may optionally be oxidized) in the corresponding heteroatom-containing ring. “Heterocycloalkyl” may, e.g., refer to aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, azepanyl, diazepanyl (e.g., 1 ,4-diazepanyl), oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, morpholinyl (e.g., morpholin-4-yl), thiomorpholinyl (e.g., thiomorpholin-4-yl), oxazepanyl, oxiranyl, oxetanyl, tetrahydrofuranyl, 1 ,3-dioxolanyl, tetrahydropyranyl, 1 ,4-dioxanyl, oxepanyl, thiiranyl, thietanyl, tetrahydrothiophenyl (i.e., thiolanyl), 1 ,3-dithiolanyl, thianyl, 1 ,1 -dioxothianyl, thiepanyl, decahydroquinolinyl, decahydroisoquinolinyl, or 2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl. Unless defined otherwise, “heterocycloalkyl” preferably refers to a 3 to 11 membered saturated ring group, which is a monocyclic ring or a fused ring system (e.g., a fused ring system composed of two fused rings), wherein said ring group contains one or more (e.g., one, two, three, or four) ring heteroatoms independently selected from 0, S and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized; more preferably, “heterocycloalkyl” refers to a 5 to 7 membered saturated monocyclic ring group containing one or more (e.g., one, two, or three) ring heteroatoms independently selected from 0, S and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized.

[0041] As used herein, the term “heterocycloalkylene” refers to a heterocycloalkyl group, as defined herein above, but having two points of attachment, i.e. a divalent saturated ring group, including monocyclic rings as well as bridged ring, spiro ring and / or fused ring systems (which may be composed, e.g., of two or three rings; such as, e.g., a fused ring system composed of two or three fused rings), wherein said ring group contains one or more (such as, e.g., one, two, three, or four) ring heteroatoms independently selected from 0, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) may optionally be oxidized, and further wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group). For example, each heteroatom-containing ring comprised in said saturated ring group may contain one or two 0 atoms and / or one or two S atoms (which may optionally be oxidized) and / or one, two, three or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that there is at least one carbon ring atom (which may optionally be oxidized) in the corresponding heteroatom-containing ring. “Heterocycloalkylene” may, e.g., refer to aziridinylene, azetidinylene, pyrrolidinylene, imidazolidinylene, pyrazolidinylene, piperidinylene, piperazinylene, azepanylene, diazepanylene (e.g., 1 ,4-diazepanylene), oxazolidinylene, isoxazolidinylene, thiazolidinylene, isothiazolidinylene, morpholinylene, thiomorpholinylene, oxazepanylene, oxiranylene, oxetanylene, tetrahydrofuranylene, 1 ,3-dioxolanylene, tetrahydropyranylene, 1 ,4-dioxanylene, oxepanylene, thiiranylene, thietanylene, tetrahydrothiophenylene (i.e., thiolanylene), 1 ,3-dithiolanylene, thianylene, 1 ,1 -dioxothianylene, thiepanylene, decahydroquinolinylene, decahydroisoquinolinylene, or 2-oxa-5-aza-bicyclo[2.2.1]hept-5-ylene. Unless defined otherwise, “heterocycloalkylene” preferably refers to a divalent 3 to 11 membered saturated ring group, which is a monocyclic ring or a fused ring system (e.g., a fused ring system composed of two fused rings), wherein said ring group contains one or more (e.g., one, two, three, or four) ring heteroatoms independently selected from 0, S and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized; more preferably, “heterocycloalkylene” refers to a divalent 5 to 7 membered saturated monocyclic ring group containing one or more (e.g., one, two, or three) ring heteroatoms independently selected from 0, S and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized.

[0042] As used herein, the term “W-heterocycloalkyl” refers to the heterocycloalkyl groups as defined hereinabove wherein said heterocycloalkyl includes at least one nitrogen atom which serves as an attachment point of said heterocycloalkyl.

[0043] As used herein, the term “cycloalkenyl” refers to an unsaturated alicyclic (non-aromatic) hydrocarbon ring group, including monocyclic rings as well as bridged ring, spiro ring and / or fused ring systems (which may be composed, e.g., of two or three rings; such as, e.g., a fused ring system composed of two or three fused rings), wherein said hydrocarbon ring group comprises one or more (e.g., one or two) carbon-to-carbon double bonds and does not comprise any carbon-to-carbon triple bond. “Cycloalkenyl” may, e.g., refer to cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, or cycloheptadienyl. Unless defined otherwise, “cycloalkenyl” preferably refers to a C3-11 cycloalkenyl, and more preferably refers to a C3-7 cycloalkenyl. A particularly preferred “cycloalkenyl” is a monocyclic unsaturated alicyclic hydrocarbon ring having 3 to 7 ring members and containing one or more (e.g., one or two; preferably one) carbon-to-carbon double bonds.

[0044] As used herein, the term “cycloalkenylene” refers to a cycloalkenyl group, as defined hereinabove, but having two points of attachment, i.e. a divalent unsaturated alicyclic (non-aromatic) hydrocarbon ring group, including monocyclic rings as well as bridged ring, spiro ring and / or fused ring systems (which may be composed, e.g., of two or three rings; such as, e.g., a fused ring system composed of two or three fused rings), wherein said hydrocarbon ring group comprises one or more (e.g., one or two) carbon-to- carbon double bonds and does not comprise any carbon-to-carbon triple bond.

[0045] As used herein, the term “heterocycloalkenyl” refers to an unsaturated alicyclic (non-aromatic) ring group, including monocyclic rings as well as bridged ring, spiro ring and / or fused ring systems (which may be composed, e.g., of two or three rings; such as, e.g., a fused ring system composed of two or three fused rings), wherein said ring group contains one or more (such as, e.g., one, two, three, or four) ring heteroatoms independently selected from 0, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) may optionally be oxidized, wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group), and further wherein said ring group comprises at least one double bond between adjacent ring atoms and does not comprise any triple bond between adjacent ring atoms. For example, each heteroatom-containing ring comprised in said unsaturated alicyclic ring group may contain one or two 0 atoms and / or one or two S atoms (which may optionally be oxidized) and / or one, two, three or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that there is at least one carbon ring atom (which may optionally be oxidized) in the corresponding heteroatom-containing ring. “Heterocycloalkenyl” may, e.g., refer to imidazolinyl (e.g., 2-imidazolinyl (i.e., 4,5-dihydro-1 H-imidazolyl), 3-imidazolinyl, or 4-imidazolinyl), tetrahydropyridinyl (e.g., 1 ,2,3,6-tetrahydropyridinyl), dihydropyridinyl (e.g., 1 ,2- dihydropyridinyl or 2,3-dihydropyridinyl), pyranyl (e.g., 2H-pyranyl or 4H-pyranyl), thiopyranyl (e.g., 2H-thiopyranyl or 4H-thiopyranyl), dihydropyranyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrazinyl, dihydroisoindolyl, octahydroquinolinyl (e.g., 1 ,2,3,4,4a,5,6,7-octahydroquinolinyl), or octahydroisoquinolinyl (e.g., 1 ,2,3,4,5,6,7,8-octahydroisoquinolinyl). Unless defined otherwise, “heterocycloalkenyl” preferably refers to a 3 to 11 membered unsaturated alicyclic ring group, which is a monocyclic ring or a fused ring system (e.g., a fused ring system composed of two fused rings), wherein said ring group contains one or more (e.g., one, two, three, or four) ring heteroatoms independently selected from 0, S and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, wherein one or more carbon ring atoms are optionally oxidized, and wherein said ring group comprises at least one double bond between adjacent ring atoms and does not comprise any triple bond between adjacent ring atoms; more preferably, “heterocycloalkenyl” refers to a 5 to 7 membered monocyclic unsaturated non-aromatic ring group containing one or more (e.g., one, two, or three) ring heteroatoms independently selected from 0, S and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, wherein one or more carbon ring atoms are optionally oxidized, and wherein said ring group comprises at least one double bond between adjacent ring atoms and does not comprise any triple bond between adjacent ring atoms.

[0046] As used herein, the term “heterocycloalkenylene” refers to a heterocycloalkenyl group, as defined hereinabove, as defined hereinabove, but having two points of attachment, i.e. a divalent unsaturated alicyclic (non-aromatic) ring group, including monocyclic rings as well as bridged ring, spiro ring and / or fused ring systems (which may be composed, e.g., of two or three rings; such as, e.g., a fused ring system composed of two or three fused rings), wherein said ring group contains one or more (such as, e.g., one, two, three, or four) ring heteroatoms independently selected from 0, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) may optionally be oxidized, wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group), and further wherein said ring group comprises at least one double bond between adjacent ring atoms and does not comprise any triple bond between adjacent ring atoms. For example, each heteroatom-containing ring comprised in said unsaturated alicyclic ring group may contain one or two 0 atoms and / or one or two S atoms (which may optionally be oxidized) and / or one, two, three or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that there is at least one carbon ring atom (which may optionally be oxidized) in the corresponding heteroatom-containing ring.

[0047] As used herein, the term “halogen” (or Hal) refers to fluoro (-F), chloro (-CI), bromo (-Br), or iodo (-I). Preferred halogen is fluoro.

[0048] As used herein, the term “haloalky I” refers to an alkyl group substituted with one or more (preferably 1 to 6, more preferably 1 to 3) halogen atoms which are selected independently from fluoro, chloro, bromo and iodo, and are preferably all fluoro atoms. It will be understood that the maximum number of halogen atoms is limited by the number of available attachment sites and, thus, depends on the number of carbon atoms comprised in the alkyl moiety of the haloalkyl group. “Haloalkyl” may, e.g., refer to -CF3, -CHF2, -CH2F, -CF2-CH3, -CH2-CF3, -CH2-CHF2, -CH2-CF2-CH3, -CH2-CF2-CF3, or -CH(CF3)2. A particularly preferred “haloalkyl” group is -CF3. In one embodiment, haloalkyl may also be a perhaloalkyl. The term “perhaloalkyl” refers to a haloalkyl wherein every -H atom has been substituted with a halo atom. Preferably, said perhaloalkyl is perfluoroalkyl.

[0049] The terms “bond” and “covalent bond” are used herein synonymously, unless explicitly indicated otherwise or contradicted by context.

[0050] As used herein, the terms “optional”, “optionally” and “may” denote that the indicated feature may be present but can also be absent. Whenever the term “optional”, “optionally” or “may” is used, the present invention specifically relates to both possibilities, i.e., that the corresponding feature is present or, alternatively, that the corresponding feature is absent. For example, the expression “X is optionally substituted with Y” (or “X may be substituted with Y”) means that X is either substituted with Y or is unsubstituted. Likewise, if a component of a composition is indicated to be “optional”, the invention specifically relates to both possibilities, i.e., that the corresponding component is present (contained in the composition) or that the corresponding component is absent from the composition.

[0051] Various groups are referred to as being “optionally substituted” in this specification. Generally, these groups may carry one or more substituents, such as, e.g., one, two, three or four substituents. It will be understood that the maximum number of substituents is limited by the number of attachment sites available on the substituted moiety. Unless defined otherwise, the “optionally substituted” groups referred to in this specification carry preferably not more than two substituents and may, in particular, carry only one substituent. Moreover, unless defined otherwise, it is preferred that the optional substituents are absent, i.e. that the corresponding groups are unsubstituted.

[0052] As understood herein, geminal groups or geminal substituents refer to two substituent groups attached to the same carbon atom in a molecule.

[0053] A skilled person will appreciate that the substituent groups comprised in the compounds of the present invention may be attached to the remainder of the respective compound via a number of different positions of the corresponding specific substituent group. Unless defined otherwise, the preferred attachment positions for the various specific substituent groups are as illustrated in the examples.

[0054] As used herein, unless explicitly indicated otherwise or contradicted by context, the terms “a”, “an” and “the” are used interchangeably with “one or more” and “at least one”. Thus, for example, a composition comprising “a” compound of formula (I) can be interpreted as referring to a composition comprising “one or more” compounds of formula (I).

[0055] It is to be understood that wherever numerical ranges are provided / disclosed herein, all values and subranges encompassed by the respective numerical range are meant to be encompassed within the scope of the invention. Accordingly, the present invention specifically and individually relates to each value that falls within a numerical range disclosed herein, as well as each subrange encompassed by a numerical range disclosed herein.

[0056] As used herein, the term “about” preferably refers to ±10% of the indicated numerical value, more preferably to ±5% of the indicated numerical value, and in particular to the exact numerical value indicated. If the term “about” is used in connection with the endpoints of a range, it preferably refers to the range from the lower endpoint -10% of its indicated numerical value to the upper endpoint +10% of its indicated numerical value, more preferably to the range from of the lower endpoint -5% to the upper endpoint +5%, and even more preferably to the range defined by the exact numerical values of the lower endpoint and the upper endpoint.

[0057] As used herein, the term “comprising” (or “comprise”, “comprises”, “contain”, “contains”, or “containing”), unless explicitly indicated otherwise or contradicted by context, has the meaning of “containing, inter alia”, i.e., “containing, among further optional elements, . . .”. In addition thereto, this term also includes the narrower meanings of “consisting essentially of’ and “consisting of’. For example, the term “A comprising B and C” has the meaning of “A containing, inter alia, B and C”, wherein A may contain further optional elements (e.g., “A containing B, C and D” would also be encompassed), but this term also includes the meaning of “A consisting essentially of B and C” and the meaning of “A consisting of B and C” (i.e., no other components than B and C are comprised in A).

[0058] Brief description of figures

[0059] The invention is illustrated using the following figures. These are not meant to be considered as limiting the scope of the claims in any way, and instead are intended to serve merely an illustrative purpose.

[0060] Figure 1 shows volcano plot illustrating exemplified Activity-based protein profiling (ABPP) experiments for compound 32d.

[0061] Detailed description of the invention

[0062] The invention is described in detail in the following. It is to be understood that the present invention specifically relates to each and every combination of features and embodiments described herein, including any combination of general and / or preferred features / embodiments.

[0063] In a first embodiment, the present invention relates to a compound of formula (I): or a pharmaceutically acceptable salt thereof.

[0064] In formula (I), A is selected from aryl, heteroaryl, heterocycloalkyl, heterocycloalkenyl, cycloalkyl, cycloalkenyl, C2 alkynyl, -N(CI-5 alkyl)(Ci-5 alkyl) (such as -N(CH3)(CH(CH3)2)), C2-haloalkyl (such as - CF2CH3) and — (C1-2 haloalkylene)-cycloalkyl (such as -CF2-cyclopropyl), wherein said aryl, said heteroaryl, said heterocycloalkyl, said heterocycloalkenyl, said cycloalkyl and said cycloalkenyl are each optionally substituted with one or more R1, and wherein said C2 alkynyl is optionally substituted with C1-6 alkyl, C1-6 haloalkyl, aryl (such as phenyl) or heteroaryl (such as thien-2-yl), preferably with C1-6 alkyl, C1- 6 haloalkyl, or aryl (such as phenyl), more preferably with C1-6 alkyl or C1-6 haloalkyl, such as C1-6 alkyl. It is to be understood that said cyclopropyl in -CF2-cyclopropyl is not substituted.

[0065] Preferably, A is selected from cycloalkyl, cycloalkenyl, -N(CI-5 alkyl)(Ci 5 alkyl) (such as - N(CH3)(CH(CH3)2)), C2-haloalkyl (such as -CF2CH3) and — (C1-2 haloalkylene)-cycloalkyl (such as -CF2- cyclopropyl), wherein said cycloalkyl and said cycloalkenyl are each optionally substituted with one or more R1.

[0066] More preferably, A is selected from -N(CI-5 alkyl)(Ci-5 alkyl) (such as -N(CH3)(CH(CH3)2)), C2- haloalkyl (such as -CF2CH3) and — (C1-2 haloalkylene)-cycloalkyl (such as -CF2-cyclopropyl). Accordingly, A in one embodiment may be -N(CI-5 alkyl)(Ci 5 alkyl). In this embodiment, A is preferably - N(CH3)(CH(CH3)2). In one embodiment, A may be C2-haloalkyl. In this embodiment, preferably A is - CF2CH3. In one embodiment, A is — (C1-2 haloalkylene)-cycloalkyl. In this embodiment, preferably A is - CF2-cyclopropyl . It is to be understood that said cyclopropyl in -CF2-cyclopropyl is not substituted.

[0067] Even more preferably, A is selected from C2-haloalkyl (such as -CF2CH3) and — (C1-2 haloalkylene)-cycloalkyl (such as -CF2-cyclopropyl).

[0068] Again more preferably, A is C2-haloalkyl (such as -CF2CH3).

[0069] However, alternatively, A may also be selected from aryl, heteroaryl, heterocycloalkyl, heterocycloalkenyl, cycloalkyl, cycloalkenyl, and C2 alkynyl, wherein said aryl, said heteroaryl, said heterocycloalkyl, said heterocycloalkenyl, said cycloalkyl and said cycloalkenyl are each optionally substituted with one or more R1, and wherein said C2 alkynyl is optionally substituted with C1-6 alkyl, C1-6 haloalkyl, aryl (such as phenyl) or heteroaryl (such as thien-2-yl), preferably with C1-6 alkyl, C1-6 haloalkyl, or aryl (such as phenyl), more preferably with C1-6 alkyl or C1-6 haloalkyl, such as C1-6 alkyl. Accordingly, in one embodiment, A is selected from aryl, heteroaryl, heterocycloalkyl, heterocycloalkenyl, cycloalkyl, cycloalkenyl and C2 alkynyl, wherein said aryl, said heteroaryl, said heterocycloalkyl, said heterocycloalkenyl, said cycloalkyl and said cycloalkenyl are each optionally substituted with one or more R1, and wherein said C2 alkynyl is optionally substituted with C1-6 alkyl or C1-6 haloalkyl, such as C1-6 alkyl.

[0070] Particularly suitable aryl, heteroaryl, heterocycloalkyl, heterocycloalkenyl, cycloalkyl and cycloalkenyl in A are each a single-ring system. Thus, A can be selected from a single ring aryl, a single ring heteroaryl, a single ring heterocycloalkyl, a single ring heterocycloalkenyl, a single ring cycloalkyl, a single ring cycloalkenyl and C2 alkynyl, wherein said aryl, said heteroaryl, said heterocycloalkyl, said heterocycloalkenyl, said cycloalkyl and said cycloalkenyl are each optionally substituted with one or more R1, and wherein said C2 alkynyl is optionally substituted with C1-6 alkyl or C1-6 haloalkyl.

[0071] If A is aryl, heteroaryl, heterocycloalkyl, heterocycloalkyl, cycloalkyl or cycloalkenyl that is optionally substituted with one or more R1, then said aryl, said heteroaryl, said heterocycloalkyl, said heterocycloalkenyl, said cycloalkyl or said cycloalkenyl may preferably be substituted with 0, 1 , 2, 3 or 4 groups R1. Preferably, said aryl, said heteroaryl, said heterocycloalkyl, said heterocycloalkenyl, said cycloalkyl or said cycloalkenyl is substituted with 0, 1 or 2 groups R1.

[0072] Thus, A may be selected from heterocycloalkyl, heterocycloalkenyl and C2 alkynyl, wherein said heterocycloalkyl and said heterocycloalkenyl are each optionally substituted with one or more R1, and wherein said C2 alkynyl is optionally substituted with C1-6 alkyl. More preferably, in this embodiment, A is heterocycloalkyl, or heterocycloalkenyl wherein said heterocycloalkyl and said heterocycloalkenyl are each optionally substituted with one or more R1. Even more preferably, in this embodiment, A is heterocycloalkyl optionally substituted with one or more R1.

[0073] In formula (I), each R1is independently selected from C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, -(C0-3 alkylene)-OH, -(C0-3 alkylene)-O(Ci-5 alkyl), -(C0-3 alkylene)-O(Ci-5 alkylene)-OH, -(C0-3 alkylene)-O(Ci-5 alkylene)-O(Ci-5 alkyl), -(C0-3 alkylene)-SH, -(C0-3 alkylene)-S(Ci-5 alkyl), -(C0-3 alkylene)-S(Ci-5 alkylene)-SH, -(C0-3 alkylene)-S(Ci-5 alkylene)-S(Ci-5 alkyl), -(C0-3 alkylene)-NH2, -(C0-3 alkylene)-NH(Ci-s alkyl), -(C0-3 alkylene)-N(Ci-5alkyl)(Ci-5 alkyl), -(C0-3 alkylene)-NH-OH, -(C0-3 alkylene)-N(Ci-5alkyl)-OH, -(C0-3 alkylene)-NH-O(Ci-5alkyl), -(C0-3 alkylene)-N(Ci-s alkyl)-O(Ci-5 alkyl), -(C0-3 alkylene)-halogen, -(C0-3 alkylene)-(Ci-5 haloalkyl), -(C0-3 alkylene)-O-(Ci-5 haloalkyl), -(C0-3 alkylene)-CN, -(C0-3 alkylene)-NC>2, -(C0-3 alkylene)-CHO, -(C0-3 alkylene)-CO-(Ci-5 alkyl), -(C0-3 alkylene)-COOH, -(C0-3 alkylene)-CO-O-(Ci-5 alkyl), -(C0-3 alkylene)-O-CO-(Ci-5 alkyl), -(C0-3 alkylene)-CO-NH2, -(C0-3 alkylene)-CO-NH(Ci-5alkyl), -(C0-3 alkylene)-CO-N(Ci-5alkyl)(Ci-5 alkyl), -(C0-3 alkylene)-NH-C0-(Ci-5 alkyl), -(Co-3 alkylene)-N(Ci-5alkyl)-C0-(Ci-5 alkyl), -(Co-3 alkylene)-NH-C0-0-(Ci-5alkyl), -(Co-3 alkylene)-N(Ci-5alkyl)-C0-0-(Ci-5alkyl), -(Co-3 alkylene)-0-C0-NH-(Ci-5alkyl), -(Co-3 alkylene)-0-C0-N(Ci-5alkyl)-(Ci-5alkyl), -(Co-3 alkylene)-SO2-NH2, -(Co-3 alkylene)-SO2-NH(Ci-5alkyl), -(Co-3 alkylene)-SO2-N(Ci-5 alkyl)(Ci-5 alkyl), -(Co-3 alkylene)-NH-SO2-(Ci-5 alkyl), -(Co-3 alkylene)-N(Ci-5 alkyl)-SO2-(Ci-5 alkyl), -(Co-3 alkylene)-SO2-(Ci-5 alkyl), -(Co-3 alkylene)-S0-(Ci-5 alkyl), -(Co-3 alkylene)-Si(Ci-5 alkyl)(Ci-5 alkyl)(Ci-5 alkyl), -(Co-3 alkylene)-SFs, -0-(Co-3 alkylene)-carbocyclyl, -0-(Co-3 alkylene)-heterocyclyl, -NH-(Co-3 alkylene)-carbocyclyl, -NH-(Co-3 alkylene)-heterocyclyl, -N(CI-5 alkyl)-(Co-3 alkylene)-carbocyclyl, -N(CI-5 alkyl)-(Co-3 alkylene)-heterocyclyl, -(Co-3 alkylene)-carbocyclyl, and -(Co-3 alkylene)-heterocyclyl, wherein the carbocyclyl moiety in said -0-(Co-3 alkylene)-carbocyclyl, the carbocyclyl moiety in said -NH-(Co-3 alkylene)-carbocyclyl, the carbocyclyl moiety in said -N(CI-5 alkyl)-(Co-3 alkylene)-carbocyclyl, the carbocyclyl moiety in said -(Co-3 alkylene)-carbocyclyl, the heterocyclyl moiety in said -0-(Co-3 alkylene)-heterocyclyl, the heterocyclyl moiety in said -NH-(Co-3 alkylene)-heterocyclyl, the heterocyclyl moiety in said -N(CI-5 alkyl)-(Co-3 alkylene)-heterocyclyl, and the heterocyclyl moiety in said -(Co-3 alkylene)-heterocyclyl are each optionally substituted with one or more groups independently selected from Ci-4 alkyl, halogen, -CN, -N02, -OH, -0-(Ci-4 alkyl), -SH, -S-(Ci-4 alkyl), -NH2, -NH(CI-4 alkyl), -N(Ci- 4 alkyl)(Ci-4 alkyl), -COOH, -COO(Ci-4 alkyl), -CONH2, -C0NH(CI-4 alkyl), -CON(CI-4 alkyl)(Ci-4 alkyl), - NHC0(CI-4 alkyl) and -N(CI-4 alkyl)-C0(Ci-4 alkyl).

[0074] Preferably, R1is independently selected from C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, -(C0-3 alkylene)-OH, -(C0-3 alkylene)-0(Ci-5 alkyl), -(C0-3 alkylene)-0(Ci-5 alkylene)-OH, -(C0-3 alkylene)-0(Ci-5 alkylene)-0(Ci-5 alkyl), -(C0-3 alkylene)-SH, -(C0-3 alkylene)-S(Ci-5 alkyl), -(C0-3 alkylene)-S(Ci-5 alkylene)-SH, -(C0-3 alkylene)-S(Ci-5 alkylene)-S(Ci-5 alkyl), -(C0-3 alkylene)-NH2, -(C0-3 alkylene)-NH(Ci-s alkyl), -(C0-3 alkylene)-N(Ci-5alkyl)(Ci-5alkyl), -(C0-3 alkylene)-NH-OH, -(C0-3 alkylene)-N(Ci-5alkyl)-OH, -(C0-3 alkylene)-NH-O(Ci-5alkyl), -(C0-3 alkylene)-N(Ci-5alkyl)-0(Ci-5 alkyl), -(C0-3 alkylene)-halogen, -(C0-3 alkylene)-(Ci-5 haloalkyl), -(C0-3 alkylene)-0-(Ci-5 haloalkyl), -(C0-3 alkylene)-CN, -(C0-3 alkylene)-NO2, -(C0-3 alkylene)-CHO, -(C0-3 alkylene)-C0-(Ci-5 alkyl), -(C0-3 alkylene)-COOH, -(C0-3 alkylene)-C0-0-(Ci-5 alkyl), -(C0-3 alkylene)-0-C0-(Ci-5 alkyl), -(C0-3 alkylene)-CO-NH2, -(C0-3 alkylene)-CO-NH(Ci-5alkyl), -(C0-3 alkylene)-CO-N(Ci-5alkyl)(Ci-5 alkyl), -(C0-3 alkylene)-NH-CO-(Ci-5alkyl), -(C0-3 alkylene)-N(Ci-5alkyl)-CO-(Ci-5alkyl), -(C0-3 alkylene)-NH-CO-O-(Ci-5alkyl), -(C0-3 alkylene)-N(Ci-5alkyl)-CO-O-(Ci-5alkyl), -(C0-3 alkylene)-O-CO-NH-(Ci-5alkyl), -(C0-3 alkylene)-O-CO-N(Ci-5alkyl)-(Ci-5alkyl), -(C0-3 alkylene)-SO2-NH2, -(C0-3 alkylene)-SO2-NH(Ci-5alkyl), -(C0-3 alkylene)-SO2-N(Ci-5 alkyl)(Ci-5 alkyl), -(C0-3 alkylene)-NH-SO2-(Ci-5 alkyl), -(C0-3 alkylene)-N(Ci-5 alkyl)-SO2-(Ci-5 alkyl), -(C0-3 alkylene)-SO2-(Ci-5 alkyl), -(C0-3 alkylene)-S0-(Ci-5 alkyl), -(C0-3 alkylene)-Si(Ci-5 alkyl)(Ci-5 alkyl)(Ci-5 alkyl), -(C0-3 alkylene)-SFs, -0-(Co-3 alkylene)-carbocyclyl, -0-(Co-3 alkylene)-heterocyclyl, -(Co-3 alkylene)-carbocyclyl, and -(Co-3 alkylene)-heterocyclyl, wherein the carbocyclyl moiety in said -0-(Co-3 alkylene)-carbocyclyl, the carbocyclyl moiety in said -(Co-3 alkylene)-carbocyclyl, the heterocyclyl moiety in said -0-(Co-3 alkylene)-heterocyclyl and the heterocyclyl moiety in said -(Co-3 alkylene)-heterocyclyl are each optionally substituted with one or more groups independently selected from Ci-4 alkyl, halogen, -CN, -NO2, -OH, -0- (C1-4 alkyl), -SH, -S-(Ci-4 alkyl), -NH2, -NH(CI-4 alkyl), -N(CI-4 alkyl)(Ci-4 alkyl), -COOH, -C00(Ci-4 alkyl), -CONH2, -C0NH(Ci-4 alkyl), -CON(CI-4 alkyl)(Ci-4 alkyl), -NHC0(Ci-4 alkyl) and -N(Ci-4 alkyl)-C0(Ci-4 alkyl).

[0075] More preferably, each R1is independently selected from C1-5 alkyl, C2-5 alkenyl, C2-5 alky nyl, -(C0-3 alkylene)-OH, -(C0-3 alkylene)-0(Ci-5 alkyl), -(C0-3 alkylene)-0(Ci-5 alkylene)-OH, -(C0-3 alkylene)-0(Ci-5 alkylene)-0(Ci-5 alkyl), -(C0-3 alkylene)-SH, -(C0-3 alkylene)-S(Ci-5 alkyl), -(C0-3 alkylene)-S(Ci-5 alkylene)-SH, -(C0-3 alkylene)-S(Ci-5 alkylene)-S(Ci-5 alkyl), -(C0-3 alkylene)-NH2, -(C0-3 alkylene)-NH(Ci-s alkyl), -(C0-3 alkylene)-N(Ci-5alkyl)(Ci-5 alkyl), -(C0-3 alkylene)-NH-OH, -(C0-3 alkylene)-N(Ci-5alkyl)-OH, -(C0-3 alkylene)-NH-O(Ci-5alkyl), -(C0-3 alkylene)-N(Ci-s alkyl)-O(Ci-5alkyl), -(C0-3 alkylene)-halogen, -(C0-3 alkylene)-(Ci-5 haloalkyl), -(C0-3 alkylene)-0-(Ci-5 haloalkyl), -(C0-3 alkylene)-CN, -(C0-3 alkylene)-N02, -(C0-3 alkylene)-CHO, -(C0-3 alkylene)-C0-(Ci-5 alkyl), -(C0-3 alkylene)-COOH, -(C0-3 alkylene)-C0-0-(Ci-5 alkyl), -(C0-3 alkylene)-0-C0-(Ci-5 alkyl), -(C0-3 alkylene)-CO-NH2, -(C0-3 alkylene)-CO-NH(Ci-5alkyl), -(C0-3 alkylene)-CO-N(Ci-5alkyl)(Ci-5alkyl), -(C0-3 alkylene)-NH-CO-(Ci-5alkyl), -(C0-3 alkylene)-N(Ci-5alkyl)-C0-(Ci-5 alkyl), -(C0-3 alkylene)-NH-CO-O-(Ci-5alkyl), -(C0-3 alkylene)-N(Ci-s alkyl)-C0-0-(Ci-5 alkyl), -(C0-3 alkylene)-O-CO-NH-(Ci-5alkyl), -(C0-3 alkylene)-0-C0-N(Ci-5 alkyl)-(Ci-5 alkyl), -(C0-3 alkylene)-SO2-NH2, -(C0-3 alkylene)-SO2-NH(Ci-5alkyl), -(C0-3 alkylene)-SO2-N(Ci-5 alkyl)(Ci-5 alkyl), -(C0-3 alkylene)-NH-SO2-(Ci-5 alkyl), -(C0-3 alkylene)-N(Ci-5 alkyl)-SO2-(Ci-5 alkyl), -(C0-3 alkylene)-SO2-(Ci-5 alkyl), and -(C0-3 alkylene)-S0-(Ci-5 alkyl).

[0076] Even more preferably, each R1is independently selected from C1-5 alkyl, C2-5 alkenyl, C2-5 alky nyl, -(C0-3 alkylene)-OH, -(C0-3 alkylene)-0(Ci-5 alkyl), -(C0-3 alkylene)-SH, -(C0-3 alkylene)-NH2, -(C0-3 alkylene)-NH(Ci-5alkyl), -(C0-3 alkylene)-N(Ci-5alkyl)(Ci-5alkyl), -(C0-3 alkylene)-NH-OH, -(C0-3 alkylene)-N(Ci-5alkyl)-OH, -(C0-3 alkylene)-NH-O(Ci-5alkyl), -(C0-3 alkylene)-N(Ci-s alkyl)-0(Ci-5 alkyl), -(C0-3 alkylene)-halogen, -(C0-3 alkylene)-(Ci-5 haloalkyl), and -(C0-3 alkylene)-0-(Ci-5 haloalkyl), preferably each R1is independently selected from C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, -(C0-3 alkylene)-OH, -(C0-3 alkylene)-0(Ci-5 alkyl), -(C0-3 alkylene)-SH, -(C0-3 alkylene)-NH2, -(C0-3 alkylene)-NH(Ci-5alkyl), -(C0-3 alkylene)-N(Ci-5alkyl)(Ci-5alkyl), -(C0-3 alkylene)-NH-OH, -(C0-3 alkylene)-N(Ci-5alkyl)-OH, -(C0-3 alkylene)-NH-O(Ci-5alkyl), -(C0-3 alkylene)-N(Ci-s alkyl)-0(Ci-5 alkyl), and -(C0-3 alkylene)-halogen. Even more preferably, each R1is independently selected from C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, -OH, -0(Ci-5 alkyl), -SH, -NH2, -NH(CI-5alkyl), -N(CI-5 alkyl)(Ci-5 alkyl), -NH-OH, -N(CI-5alkyl)-OH, -NH-0(CI-5 alkyl), -N(CI-5 alkyl)-O(Ci 5 alkyl), C1-5 haloalkyl and halogen, preferably each R1is independently selected from C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, -OH, -0(Ci-5 alkyl), -SH, -NH2, -NH(CI-5 alkyl), -N(CI-5 alkyl)(Ci-5 alkyl), -NH-OH, -N(CI-5alkyl)-OH, -NH-O(CI-5alkyl), -N(CI-5 alkyl)-0(Ci-5 alkyl), and halogen.

[0077] Even more preferably, each R1is independently selected from -OH and halogen.

[0078] In one embodiment, A is -CF2-cyclopropyl. In one embodiment, A is -CF2CH3.

[0079] In one embodiment, A is -N(CI-5 alkyl)(Ci-5 alkyl), preferably -N(CH3)(CH(CH3)2.

[0080] In formula (I), B is selected from arylene and heteroarylene, wherein said arylene and said heteroarylene are each optionally substituted with one or more R2.

[0081] Preferably, B is heteroarylene, optionally substituted with one or more R2.

[0082] Particularly preferred are 5 or 6-membered heteroarylene moieties, in particular 6-membered heteroarylene moieties. Thus, preferably, B is pyridinylene (such as 2,5-pyridinylene) or pyrimidinylene (such as 2, 5-pyrimidinylene), optionally substituted with one or more R2.

[0083] It is preferred that if B is 2,5-pyridinylene, B is (optionally) substituted with -0-(Co-3 alkylene)-carbocyclyl, or -0-(Co-3 alkylene)-heterocyclyl, preferably with -O-carbocyclyl, or - O-heterocyclyl, more preferably with -O-carbocyclyl, in particular -O-phenyl. Preferably, said substitution is at the carbon atom in the ring adjacent to the carbon atom connected to X.

[0084] It is further preferred that if B is 2, 5-pyrimidinylene, B (optionally) is substituted with -0-(Co-3 alkylene)-carbocyclyl, or -0-(Co-3 alkylene)-heterocyclyl, preferably with -O-carbocyclyl, or - O-heterocyclyl, more preferably with -O-carbocyclyl, in particular -O-phenyl. Preferably, said substitution is at the carbon atom in the ring adjacent to the carbon atom connected to X, or, in other words, at position 4 in the 2, 5-pyrimidinylene.

[0085] In formula (I), each R2is independently selected from C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, -(C0-3 alkylene)-OH, -(C0-3 alkylene)-0(Ci-5 alkyl), -(C0-3 alkylene)-0(Ci-5 alkylene)-OH, -(C0-3 alkylene)-0(Ci-5 alkylene)-0(Ci-5 alkyl), -(C0-3 alkylene)-SH, -(C0-3 alkylene)-S(Ci-5 alkyl), -(C0-3 alkylene)-S(Ci-5 alkylene)-SH, -(C0-3 alkylene)-S(Ci-5 alkylene)-S(Ci-5 alkyl), -(C0-3 alkylene)-NH2, -(C0-3 alkylene)-NH(Ci-s alkyl), -(C0-3 alkylene)-N(Ci-5alkyl)(Ci-5 alkyl), -(C0-3 alkylene)-NH-OH, -(C0-3 alkylene)-N(Ci-5alkyl)-OH, -(C0-3 alkylene)-NH-O(Ci-5alkyl), -(C0-3 alkylene)-N(Ci-5alkyl)-0(Ci-5 alkyl), -(C0-3 alkylene)-halogen, -(C0-3 alkylene)-(Ci-5 haloalkyl), -(C0-3 alkylene)-0-(Ci-5 haloalkyl), -(C0-3 alkylene)-CN, -(C0-3 alkylene)-N02, -(C0-3 alkylene)-CHO, -(C0-3 alkylene)-C0-(Ci-5 alkyl), -(C0-3 alkylene)-COOH, -(C0-3 alkylene)-C0-0-(Ci-5 alkyl), -(C0-3 alkylene)-0-C0-(Ci-5 alkyl), -(C0-3 alkylene)-CO-NH2, -(C0-3 alkylene)-CO-NH(Ci-5alkyl), -(C0-3 alkylene)-CO-N(Ci-5alkyl)(Ci-5 alkyl), -(C0-3 alkylene)-NH-C0-(Ci-5 alkyl), -(Co-3 alkylene)-N(Ci-5alkyl)-C0-(Ci-5 alkyl), -(Co-3 alkylene)-NH-C0-0-(Ci-5alkyl), -(Co-3 alkylene)-N(Ci-5alkyl)-C0-0-(Ci-5alkyl), -(Co-3 alkylene)-0-C0-NH-(Ci-5alkyl), -(Co-3 alkylene)-0-C0-N(Ci-5alkyl)-(Ci-5alkyl), -(Co-3 alkylene)-SO2-NH2, -(Co-3 alkylene)-SO2-NH(Ci-5alkyl), -(Co-3 alkylene)-SO2-N(Ci-5 alkyl)(Ci-5 alkyl), -(Co-3 alkylene)-NH-SO2-(Ci-5 alkyl), -(Co-3 alkylene)-N(Ci-5 alkyl)-SO2-(Ci-5 alkyl), -(Co-3 alkylene)-SO2-(Ci-5 alkyl), -(Co-3 alkylene)-S0-(Ci-5 alkyl), -(Co-3 alkylene)-Si(Ci-5 alkyl)(Ci-5 alkyl)(Ci-5 alkyl), -(Co-3 alkylene)-SFs, -0-(Co-3 alkylene)-carbocyclyl, -0-(Co-3 alkylene)-heterocyclyl -(Co-3 alkylene)-carbocyclyl, and -(Co-3 alkylene)-heterocyclyl, wherein the carbocyclyl moiety in said -0-(Co-3 alkylene)-carbocyclyl, the carbocyclyl moiety in said -(Co-3 alkylene)-carbocyclyl, the heterocyclyl moiety in said -0-(Co-3 alkylene)-heterocyclyl and the heterocyclyl moiety in said -(Co-3 alkylene)-heterocyclyl are each optionally substituted with one or more groups independently selected from Ci-4 alkyl, halogen, -CN, -N02, -OH, -0- (Ci-4 alkyl), -SH, -S-(Ci-4 alkyl), -NH2, -NH(CI-4 alkyl), -N(CI-4 alkyl)(Ci-4 alkyl), -COOH, -COO(Ci-4 alkyl), -CONH2, -C0NH(CI-4 alkyl), -CON(CI-4 alkyl)(Ci-4 alkyl), -NHC0(Ci-4 alkyl) and -N(Ci-4 alkyl)-C0(Ci-4 alkyl).

[0086] Preferably, each R2is independently selected from C1-5 alkyl, C2-5 alkenyl, C2-5 alky nyl, -(C0-3 alkylene)-OH, -(C0-3 alkylene)-0(Ci-5 alkyl), -(C0-3 alkylene)-0(Ci-5 alkylene)-OH, -(C0-3 alkylene)-0(Ci-5 alkylene)-0(Ci-5 alkyl), -(C0-3 alkylene)-SH, -(C0-3 alkylene)-S(Ci-5 alkyl), -(C0-3 alkylene)-S(Ci-5 alkylene)-SH, -(C0-3 alkylene)-S(Ci-5 alkylene)-S(Ci-5 alkyl), -(C0-3 alkylene)-NH2, -(C0-3 alkylene)-NH(Ci-s alkyl), -(C0-3 alkylene)-N(Ci-5alkyl)(Ci-5alkyl), -(C0-3 alkylene)-NH-OH, -(C0-3 alkylene)-N(Ci-5alkyl)-OH, -(C0-3 alkylene)-NH-O(Ci-5alkyl), -(C0-3 alkylene)-N(Ci-5alkyl)-0(Ci-5 alkyl), -(C0-3 alkylene)-halogen, -(C0-3 alkylene)-(Ci-5 haloalkyl), -(C0-3 alkylene)-0-(Ci-5 haloalkyl), -(C0-3 alkylene)-CN, -(C0-3 alkylene)-NO2, -(C0-3 alkylene)-CHO, -(C0-3 alkylene)-C0-(Ci-5 alkyl), -(C0-3 alkylene)-COOH, -(C0-3 alkylene)-C0-0-(Ci-5 alkyl), -(C0-3 alkylene)-0-C0-(Ci-5 alkyl), -(C0-3 alkylene)-CO-NH2, -(C0-3 alkylene)-CO-NH(Ci-5alkyl), -(C0-3 alkylene)-CO-N(Ci-5alkyl)(Ci-5 alkyl), -(C0-3 alkylene)-NH-CO-(Ci 5 alkyl), -(C0-3 alkylene)-N(Ci-5alkyl)-CO-(Ci-5alkyl), -(C0-3 alkylene)-NH-CO-O-(Ci-5alkyl), -(C0-3 alkylene)-N(Ci-5alkyl)-CO-O-(Ci-5alkyl), -(C0-3 alkylene)-O-CO-NH-(Ci-5alkyl), -(C0-3 alkylene)-O-CO-N(Ci-5alkyl)-(Ci-5alkyl), -(C0-3 alkylene)-SO2-NH2, -(C0-3 alkylene)-SO2-NH(Ci-5alkyl), -(C0-3 alkylene)-SO2-N(Ci-5 alkyl)(Ci-5 alkyl), -(C0-3 alkylene)-NH-SO2-(Ci-5 alkyl), -(C0-3 alkylene)-N(Ci-5 alkyl)-SO2-(Ci-5 alkyl), -(C0-3 alkylene)-SO2-(Ci-5 alkyl), and -(C0-3 alkylene)-S0-(Ci-5 alkyl).

[0087] More preferably, each R2is independently selected from C1-5 alkyl, C2-5 alkenyl, C2-5 alky nyl, -(C0-3 alkylene)-OH, -(C0-3 alkylene)-0(Ci-5 alkyl), -(C0-3 alkylene)-SH, -(C0-3 alkylene)-NH2, -(C0-3 alkylene)-NH(Ci-5alkyl), -(C0-3 alkylene)-N(Ci-5alkyl)(Ci-5 alkyl), -(C0-3 alkylene)-NH-OH, -(C0-3 alkylene)-N(Ci-5alkyl)-OH, -(Co-3 alkylene)-NH-O(Ci-5alkyl), -(Co-3 alkylene)-N(Ci-s alkyl)-O(Ci-5alkyl), and -(Co-3 alkylene)-halogen.

[0088] Even more preferably, each R2is independently selected from C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, -OH, -O(Ci-5 alkyl), -SH, -NH2, -NH(CI-5 alkyl), -N(CI-5 alkyl)(Ci-5 alkyl), -NH-OH, -N(CI-5 alkyl)-OH, -NH-O(CI-5 alkyl), -N(CI-5 alkyl)-O(Ci-5 alkyl), and halogen.

[0089] In one embodiment, R2is independently selected from -0-(Co-3 alkylene)-carbocyclyl, -0-(Co-3 alkylene)-heterocyclyl -(C0-3 alkylene)-carbocyclyl, and -(C0-3 alkylene)-heterocyclyl, wherein the carbocyclyl moiety in said -0-(Co-3 alkylene)-carbocyclyl, the carbocyclyl moiety in said -(C0-3 alkylene)-carbocyclyl, the heterocyclyl moiety in said -0-(Co-3 alkylene)-heterocyclyl and the heterocyclyl moiety in said -(C0-3 alkylene)-heterocyclyl are each optionally substituted with one or more groups independently selected from C1-4 alkyl, halogen, -CN, -NO2, -OH, -O-(Ci-4 alkyl), -SH, -S-(Ci-4 alkyl), -NH2, -NH(CI-4 alkyl), -N(Ci-4 alkyl)(Ci-4 alkyl), -COOH, -COO(Ci-4 alkyl), -CONH2, -CONH(Ci-4 alkyl), -CON(Ci- 4 alkyl)(Ci-4 alkyl), -NHCO(Ci-4 alkyl) and -N(Ci-4 alkyl)-CO(Ci-4 alkyl).

[0090] Alternatively, B may be as defined according to the following formula: wherein the left empty valence of B as shown in the structural formula, is connected to A, and the right empty valence of B is connected to X. Therein:

[0091] Xvis CRv2or N;

[0092] Yvis CRv4or N;

[0093] Zvis CRv5or N; or Yvand Zvtaken together form an optionally substituted five- to six-membered heteroaryl, or an optionally substituted five- to six-membered heterocyclyl; with the proviso that Xv, Yv, and Zvare not all simultaneously N;

[0094] Rv1is H, -O-(optionally substituted C3-C8 cycloalkyl), -O-(optionally substituted C1-C6 alkyl), -0- (optionally substituted C6-C10 aryl), -O-(optionally substituted five- to six-membered heteroaryl), -0- (optionally substituted five- to six-membered heterocycloalkyl), or optionally substituted C3-C8 cycloalkyl; or Rv1together with the carbon atoms to which it is shown attached and Xvform an optionally substituted five- to six-membered heterocyclyl;

[0095] Rv2is H, optionally substituted C1-C6 alkyl, or halo;

[0096] Rv4is H, C1-C6 alkyl, cyano, or halo; or Rv4together with the carbon atom to which it is shown attached and Zvform an optionally substituted five- to six-membered heteroaryl; Rv5is H, Ci-C6alkyl, -NR2Jor -N(R)-C(=0)-(CI-C6alkyl); each R independently is H, or optionally substituted Ci-Ce alkyl; and said optional substituents of alkyl, alkenyl, cycloalkenyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups in Rv1, Rv2, Rv4, and Rv5, are selected from the group consisting of halogen, -CN, - NO2, -N3, -SO2H, -SO3H, -OH, -0Raa, -N(Rbb)2, -N(0Rcc)Rbb, -SH, -SRaa, -C(=0)Raa, -CO2H, -CHO, - C02Raa, -0C(=0)Raa, -0C02Raa, -C(=0)N(Rbb)2, -0C(=0)N(Rbb)2, -NRbbC(=0)Raa, -NRbbC02Raa, - NRbbC(=0)N(Rbb)2, -C(=NRbb)Raa, -C(=NRbb)0Raa, -0C(=NRbb)Raa, -0C(=NRbb)0Raa, - C(=NRbb)N(Rbb)2, - 0C(=NRbb)N(Rbb)2, -NRbbC(=NRbb)N(Rbb)2, -C(=0)NRbbS02Raa, -NRbbS02Raa, - SO2N(Rbb)2, -SO2Raa, - S(=O)Raa, -OS(=O)Raa, -B(0Rcc)2, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3- 14 cycloalkyl, 3- to 14- membered heterocyclyl, Ce-14 aryl, and 5- to 14- membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1 , 2, 3, 4, or 5 Rddgroups, or two geminal hydrogens on a carbon atom are replaced with the group =0, wherein: each instance of Raais, independently, selected from the group consisting of C1-10 alkyl, Ci- 10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, C3-14 carbocyclyl, 3- to 14- membered heterocyclyl, Ce-14 aryl, and 5- to 14- membered heteroaryl, or two Raagroups are joined to form a 3- to 14- membered heterocyclyl or 5- to 14- membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1 , 2, 3, 4, or 5 Rddgroups; each instance of Rbbis, independently, selected from the group consisting of hydrogen, -OH, - ORaa, -N(RCC)2, -CN, -C(=0)Raa, -C(=O)N(RCC)2, -C02Raa, -SO2Raa, -SO2N(RCC)2, -SORaa, C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, C3-14 carbocyclyl, 3- to 14- membered heterocyclyl, Ce- 14 aryl, and 5- to 14- membered heteroaryl, or two Rbbgroups are joined to form a 3- to 14- membered heterocyclyl or 5- to 14- membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1 , 2, 3, 4, or 5 Rddgroups; each instance of Rccis, independently, selected from the group consisting of hydrogen, Ci- 10 alkyl, Ci— 10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, C3-14 carbocyclyl, 3- to 14- membered heterocyclyl, Ce-14 aryl, and 5- to 14- membered heteroaryl, or two Rccgroups are joined to form a 3- to 14- membered heterocyclyl or 5- to 14- membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1 , 2, 3, 4, or 5 Rddgroups; and each instance of Rddis, independently, selected from the group consisting of halogen, -CN, - NO2, -N3, -SO2H, -SO3H, -OH, -OC1-6 alkyl, -ON(CI-6 alkyl)2, -N(CI-6alkyl)2, -N(OCI-6alkyl)(Ci- 6 alkyl), - N(OH)(CI-6alkyl), -NH(OH), -SH, -SC1-6 alkyl, -C(=O)(Ci-6 alkyl), -CO2H, -CO2(Ci-6alkyl), - OC(=O)(Ci-6alkyl), -OCO2(Ci-6alkyl), -C(=O)NH2, -C(=O)N(CI-6alkyl)2, -OC(=O)NH(CI-6 alkyl), - NHC(=0)(CI-6 alkyl), -N(CI-6 alkyl)C(=O)( C1-6 alkyl), -NHCO2(CI-6alkyl), -NHC(=O)N(CI-6alkyl)2, - NHC(=0)NH(CI-6 alkyl), -NHC(=O)NH2, -C(=NH)0(CI-6 alkyl), -0C(=NH)(CI-6 alkyl), -OC(=NH)OCi- 6 alkyl, -C(=NH)N(CI-6alkyl)2, -C(=NH)NH(CI-6 alkyl), -C(=NH)NH2, -0C(=NH)N(CI-6 alkyl)2, - 0C(NH)NH(CI-6 alkyl), -OC(NH)NH2, -NHC(NH)N(CI-6 alkyl)2, -NHC(=NH)NH2, -NHSO2(CI-6 alkyl), - SO2N(CI-6 alkyl)2, -SO2NH(CI-6alkyl), -SO2NH2,-SO2CI-6alkyl, -B(OH)2, -B(0CI-6 alkyl)2,Ci-6 alkyl, Ci- 6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocyclyl, C6-10 aryl, 3- to 10- membered heterocyclyl, and 5- to 10- membered heteroaryl; or two geminal Rddsubstituents on a carbon atom may be joined to form =0.

[0097] Accordingly, Rv1together with the carbon atoms to which it is shown attached and Xvmay form an optionally substituted five- to six-membered heterocyclyl. Said heterocyclyl may for example be: wherein the double bond shown is between the carbo bearing the Rv1group and Xv.

[0098] Preferably however, Rv1is H, -O-(optionally substituted C3-C8 cycloalkyl), -O-(optionally substituted C1-C6 alkyl), -O-(optionally substituted C6-C10 aryl), -O-(optionally substituted five- to sixmembered heteroaryl), -0- (optionally substituted five- to six-membered heterocycloalkyl), or optionally substituted C3-C8 cycloalkyl. Suitable C3-C8 cycloalkyl include cyclobutyl, cyclopropyl, cyclohexyl, cyclopentyl. Suitable -O-(optionally substituted C1-C6 alkyl) include ethoxy, or isopropoxy.

[0099] More preferably, Rv1is -O-(optionally substituted C3-C8 cycloalkyl), -O-(optionally substituted C1- Ce alkyl), -O-(optionally substituted C6-C10 aryl), -O-(optionally substituted five- to six-membered heteroaryl), or -O-(optionally substituted five- to six-membered heterocycloalkyl).

[0100] Even more preferably, Rv1is -O-(optionally substituted C3-C8 cycloalkyl), -O-(optionally substituted C6-C10 aryl), -O-(optionally substituted five- to six-membered heteroaryl), or -O-(optionally substituted five- to six-membered heterocycloalkyl).

[0101] Again more preferably, Rv1is -O-(optionally substituted C6-C10 aryl), such as -O-(optionaly substituted phenyl), preferably -O-phenyl.

[0102] Preferably, Rv2is H, or optionally substituted C1-C6 alkyl.

[0103] More preferably, Rv2is H. As understood herein, Rv5is H, Ci-Ce alkyl, -NR2, (such as -NH2) or -N(R)-C(=0)-(Ci-Ce alkyl) (such as -NH-C(=0)-(CI-C6alkyl)).

[0104] Preferably, Rv4is H, C1-C6 alkyl, cyano, or halo.

[0105] More preferably, Rv4is H or C1-C6 alkyl.

[0106] Even more preferably, Rv4is H.

[0107] Preferably, Rv5is H, or C1-C6 alkyl.

[0108] More preferably, Rv5is H.

[0109] Accordingly, in one specific embodiment of the B group, as defined herein, the following applies:

[0110] Xvis N;

[0111] Yvis N; and

[0112] Zvis CRv5; or Yvand Zvtaken together form an optionally substituted five- to six-membered heteroaryl, or an optionally substituted five- to six-membered heterocyclyl.

[0113] In a further specific embodiment of the B group, as defined herein, the following applies:

[0114] Xvis CRv2;

[0115] Yvis CRv4;

[0116] Zvis CRv5; or Yvand Zvtaken together form an optionally substituted five- to six-membered heteroaryl, or an optionally substituted five- to six-membered heterocyclyl.

[0117] In a further specific embodiment of the B group, as defined herein, the following applies:

[0118] Xvis CRv2;

[0119] Yvis N;

[0120] Zvis CRv5; or Rv1together with the carbon atoms to which it is shown attached and Xvform an optionally substituted five- to six-membered heterocyclyl.

[0121] In a further specific embodiment of the B group, as defined herein, the following applies:

[0122] Xvis N;

[0123] Yvis CRv4;

[0124] Zvis CRv5.

[0125] In a further specific embodiment of the B group, as defined herein, the following applies:

[0126] Xvis N;

[0127] Yvis CRv4; and

[0128] Zvis N.

[0129] In a further specific embodiment of the B group, as defined herein, the following applies: Xvis CRv2;

[0130] Yvis CRv4; and

[0131] Zvis N.

[0132] In a further specific embodiment of the B group, as defined herein, the following applies:

[0133] Xvis N;

[0134] Yvis N; and

[0135] Zvis CRv5.

[0136] Particularly preferred B is according to formula: wherein the left empty valence of B as shown in the structural formula, is connected to A, and the right empty valence of B is connected to X.

[0137] In formula (I), X is selected from -CONH-, -CON(CI-6 alkyl)-, -CON(CI-6 haloalkyl)-, -SO2NH-, - SO2N(CI-6 alkyl)-, -SO2N(CI-6haloalkyl)-, -CH(CF3)NH-, -CH(CF3)N(CI-6alkyl)-, and -CH(CF3)N(CI-6haloalkyl)-.

[0138] Preferably, X is selected from -CONH-, and -CON(CI-6 alkyl)-. More preferably, X is -CONH-. It is to be understood that, preferably, the left side of the bivalent formula embodying X, as shown herein, is connected to B, and the right side of said bivalent formula embodying X is connected to Y.

[0139] Y is a moiety according to formula: wherein Ry1is selected from H, C1-6 alkyl (such as methyl), C3-s cycloalkyl (such as cyclopropyl), and 5 or 6-membered heterocyclyl, wherein said cycloalkyl and said heterocyclyl are each optionally substituted with one or more groups selected from Rs, Ry2is selected from -H, -F and -CN, Ry3is selected from C1-4 alkyl (such as methyl), C1-4 haloalkyl (such as trifluoromethyl), C3-s cycloalkyl (such as cyclopropyl), phenyl and 5 or 6-membered heterocyclyl, wherein said cycloalkyl, said phenyl and said heterocyclyl are each optionally substituted with one or more groups selected from Rs, Z is selected from =0 and =NRZ2, wherein each RZ1and Rz2are independently selected from hydrogen, -CN, C1-5 alkyl, C3- 8 cycloalkyl, heterocycloalkyl, phenyl, 5-6 membered heteroaryl, -CO-C1-5 alkyl, -COO-C1-5 alkyl, -SO2-C1- 5 alkyl, -CONH2, -C0NH(CI-5 alkyl), and -CON(Ci-s alkyl)(Ci 5 alkyl), wherein said alkyl is optionally substituted with one or more groups selected from Hal, -OH, -CN, -0-(Ci-5 alkyl), -NH2, -NH(CI-5 alkyl), - N(CI-5 alkyl)(Ci 5 alkyl), -CONH2, -C0NH(CI-5 alkyl) and -CO-N(Ci-s alkyl)(Ci 5 alkyl), wherein said cycloalkyl, said heterocycloalkyl, said phenyl and said heteroaryl are each independently optionally substituted with one or more groups selected from Rs(preferably are each independently substituted with one or more groups selected from Rs), wherein optionally RZ1and Ry3are joined to form, together with the N atom that otherwise carries RZ1and the sulfur atom that otherwise carries Ry3, 5 to 7 membered heterocyclic ring, which is optionally substituted with one or more groups selected from Rs. It is to be understood that the bonds drawn as indicate that both configurations of the double bond, Z and E, are possible.

[0140] As understood herein, RZ1and Rz1are used interchangeably, and likewise Rz2and Rz2are used interchangeably.

[0141] Preferably, Ry1is selected from H, C1-4 alkyl (such as methyl), and C3-8 cycloalkyl (such as cyclopropyl), wherein said cycloalkyl is optionally substituted with one or more groups selected from Rs. More preferably, Ry1is selected from C1-4 alkyl (such as methyl) and C3-8 cycloalkyl (such as cyclopropyl). Even more preferably, Ry1is selected from methyl and cyclopropyl.

[0142] Preferably Ry2is -H or F. More preferably Ry2is -H.

[0143] Preferably, Ry3is selected from C1-4 alkyl (such as methyl), C3-8 cycloalkyl (such as cyclopropyl), phenyl and 5 or 6-membered heterocyclyl, wherein said cycloalkyl, said phenyl and said heterocyclyl are each optionally substituted with one or more groups selected from Rs, More preferably, Ry3is selected from C1-4 alkyl (such as methyl), C3-8 cycloalkyl (such as cyclopropyl), and 5 or 6-membered heterocyclyl, wherein said cycloalkyl and said heterocyclyl are each optionally substituted with one or more groups selected from Rs. More preferably Ry3is C1-4 alkyl. Even more preferably Ry3is methyl.

[0144] Preferably, Z is =0.

[0145] Preferably, RZ1is selected from hydrogen, -CN, C1-5 alkyl, C3-8 cycloalkyl, heterocycloalkyl, phenyl, 5-6 membered heteroaryl, -CO-C1-5 alkyl, -COO-C1-5 alkyl, -SO2-C1-5 alkyl, -CONH2, -C0NH(CI-5 alkyl), and -C0N(CI-5 alkyl)(Ci-5 alkyl), wherein said alkyl is optionally substituted with one or more groups selected from Hal, -OH, -CN, -O-(Ci-5alkyl), -NH2, -NH(CI-5 alkyl), -N(CI-5alkyl)(Ci-5 alkyl), -CONH2, - C0NH(CI-5 alkyl) and -C0-N(CI-5 alkyl)(Ci-5 alkyl), wherein said cycloalkyl, said heterocycloalkyl, said phenyl and said heteroaryl are each independently optionally substituted with one or more groups selected from Rs(preferably are each independently substituted with one or more groups selected from Rs). More preferably, RZ1is selected from -CN, C2-5 alkyl, C3-8 cycloalkyl, heterocycloalkyl, phenyl, 5- 6 membered heteroaryl, -CO-C1-5 alkyl, -COO-C1-5 alkyl, -SO2-C1-5 alkyl, -CONH2, -CONH(Ci-s alkyl), and -C0N(CI-5 alkyl)(Ci-5 alkyl), wherein said alkyl is optionally substituted with one or more groups selected from Hal, -OH, -CN, -0-(Ci-5 alkyl), -NH2, -NH(CI-5 alkyl), -N(CI-5 alkyl)(Ci-5 alkyl), -CONH2, -CONH(CI-5alkyl) and -CO-N(Ci-s alkyl)(Ci 5 alkyl), wherein said cycloalkyl, said heterocycloalkyl, said phenyl and said heteroaryl are each optionally independently substituted with one or more groups selected from Rs(preferably are each independently substituted with one or more groups selected from Rs).

[0146] Even more preferably, RZ1is selected from -CN, cyclopropyl, cyclobutyl, oxetanyl, phenyl, pyridyl, -CO-CH3, -COO-CH3, -SO2-CH3, -CONH2, -CONH(CH3), and -CON(CH3)(CH3).

[0147] Even more preferably, RZ1is selected from -CN, cyclopropyl, oxetanyl, phenyl, pyridyl, -CO-CH3, -COO-CH3, -SO2-CH3, and -CONH(CH3).

[0148] Again more preferably, RZ1is selected from -CN, cyclopropyl, phenyl, pyridyl, -CO-CH3, -COO- CH3, -SO2-CH3, and -CONH(CH3).

[0149] In one particular embodiment, RZ1is -CO-C1-5 alkyl, wherein said alkyl is optionally substituted with one or more groups selected from Hal, -OH, -CN, -0-(Ci-5 alkyl), -NH2, -NH(CI-5 alkyl), -N(CI-5 alkyl)(Ci-5 alkyl), -CONH2, -CONH(CI-5alkyl) and -CO-N(CI-5alkyl)(Ci-5 alkyl). Preferably, in this embodiment, RZ1is -CO-C1-5 alkyl, such as -CO-CH3.

[0150] In one particular embodiment, RZ1is -C0NH(CI-5 alkyl), wherein said alkyl is optionally substituted with one or more groups selected from Hal, -OH, -CN, -0-(Ci-5 alkyl), -NH2, -NH(CI-5 alkyl), -N(CI-5 alkyl)(Ci-5 alkyl), -CONH2, -CONH(CI-5alkyl) and -CO-N(CI-5alkyl)(Ci-5 alkyl). Preferably, in this embodiment, RZ1is -C0NH(CI-5 alkyl), such as -CONHCH3.

[0151] In one particular embodiment, RZ1is phenyl, or 5-6 membered heteroaryl, wherein said phenyl and said heteroaryl are each optionally independently substituted with one or more groups selected from Rs(preferably are each independently substituted with one or more groups selected from Rs). Preferably, RZ1is phenyl.

[0152] In one particular embodiment, RZ1is -COO-C1-5 alkyl, wherein said alkyl is optionally substituted with one or more groups selected from Hal, -OH, -CN, -0-(Ci-5 alkyl), -NH2, -NH(CI-5 alkyl), -N(CI-5 alkyl)(Ci-5 alkyl), -CONH2, -CONH(CI-5alkyl) and -CO-N(CI-5alkyl)(Ci-5 alkyl). Preferably, in this embodiment, RZ1is -CO-C1-5 alkyl, such as -COO-CH3.

[0153] In one particular embodiment, RZ1is -SO2-C1-5 alkyl, wherein said alkyl is optionally substituted with one or more groups selected from Hal, -OH, -CN, -0-(Ci-5 alkyl), -NH2, -NH(CI-5 alkyl), -N(CI-5 alkyl)(Ci-5 alkyl), -CONH2, -CONH(CI-5alkyl) and -CO-N(CI-5alkyl)(Ci-5 alkyl). Preferably, in this embodiment, RZ1is -CO-C1-5 alkyl, such as - SO2-CH3.

[0154] In one particular embodiment, RZ1is tetrahydrofuranyl (preferably 3-tetrahydrofuranyl). In one particular embodiment, RZ1is hydrogen.

[0155] In one particular embodiment, RZ1is methyl.

[0156] In one particular embodiment, RZ1is selected from -CN, cyclopropyl, tetrahydrofuranyl (such as 3-tetrahydrofuranyl), phenyl, pyridyl, -CO-CH3, -COO-CH3, -SO2-CH3, and -C0NH(CH3).

[0157] In one particular embodiment, RZ1is C3-8 cycloalkyl, wherein said cycloalkyl is optionally substituted with one or more groups selected from Rs. Preferably, RZ1is cyclopropyl.

[0158] In one particular embodiment, RZ1is 5-6 membered heteroaryl, wherein said cycloalkyl, said heterocycloalkyl, wherein said heteroaryl is optionally substituted with one or more groups selected from Rs. Preferably, RZ1is pyridyl.

[0159] It is further preferred that RZ1and Ry3are not joined to form, together with an N atom that otherwise carries RZ1and sulfur atom that otherwise carriers Ry3, 5 to 7 membered heterocyclic ring, which is optionally substituted with one or more groups selected from Rs. Accordingly, RZ1and Ry3are as defined herein.

[0160] Z may also be =NRZ2. In such embodiments, Rz2is as defined herein.

[0161] Preferably, Rz2is selected from hydrogen, -CN, C1-5 alkyl, C3-8 cycloalkyl, heterocycloalkyl, phenyl, 5-6 membered heteroaryl, -CO-C1-5 alkyl, -COO-C1-5 alkyl, -SO2-C1-5 alkyl, -CONH2, -CONH(CI-5 alkyl), and -CON(CI-5 alkyl)(Ci-5 alkyl), wherein said alkyl is optionally substituted with one or more groups selected from Hal, -OH, -CN, -O-(Ci-5alkyl), -NH2, -NH(CI-5 alkyl), -N(Ci-5alkyl)(Ci-5 alkyl), -CONH2, - CONH(CI-5 alkyl) and -CO-N(CI-5 alkyl)(Ci-5 alkyl), wherein said cycloalkyl, said heterocycloalkyl, said phenyl and said heteroaryl are each optionally independently substituted with one or more groups selected from Rs(preferably are each independently substituted with one or more groups selected from Rs).

[0162] More preferably, Rz2is selected from hydrogen, -CN, methyl, cyclopropyl, cyclobutyl, oxetanyl, phenyl, -CO-CH3, -COO-CH3, -SO2-CH3, -CONH2, -CONH(CH3), and -CON(CH3)(CH3).

[0163] Even more preferably, Rz2is selected from hydrogen, -CN, methyl, cyclopropyl, oxetanyl, phenyl, -CO-CH3, -COO-CH3, -SO2-CH3, and -CONH(CH3).

[0164] It is particularly preferred that RZ1and Ry3are not joined to form, together with an N atom that otherwise carries RZ1and sulfur atom that otherwise carriers Ry3, 5 to 7 membered heterocyclic ring, which is optionally substituted with one or more groups selected from Rsand that Z is =0.

[0165] However, alternatively, in one preferred embodiment of the present invention, RZ1and Ry3are joined to form, together with the N atom that otherwise carries RZ1and the sulfur atom that otherwise carries Ry3, 5 to 7 membered heterocyclic ring, which is optionally substituted with one or more groups selected from Rsand that Z is =0.

[0166] In one embodiment, RZ1and Ry3are not joined to form, together with an N atom that otherwise carries RZ1and sulfur atom that otherwise carriers Ry3, 5 to 7 membered heterocyclic ring, which is optionally substituted with one or more groups selected from Rsand that Z is =NRZ2, wherein Rz2is as defined herein.

[0167] In one embodiment, RZ1and Ry3arejoined to form, together with the N atom that otherwise carries RZ1and the sulfur atom that otherwise carries Ry3, 5 to 7 membered heterocyclic ring, which is optionally substituted with one or more groups selected from Rsand that Z is =NRZ2, wherein Rz2is as defined herein.

[0168] In one embodiment of the present invention, Z is =0 and RZ1is hydrogen or methyl.

[0169] However, the present invention also encompasses embodiments wherein Y is not a moiety according to formula: or a moiety according to formula: including any specific configuration of the double bond, wherein Ry1is selected from H, C1-4 alkyl, C3-8 cycloalkyl, and 5 or 6-membered heterocyclyl, Ry2is selected from -H, -F and -CN, and Ry3is selected from Ci-4 alkyl, C3-8 cycloalkyl, and 5 or 6-membered heterocyclyl, and wherein the bonds drawn as indicate that both Z and E configurations of the double bond are possible.

[0170] As understood herein, preferably the moiety of formula moiety of formula It is further apparent to the skilled person that the moiety of formula may

[0171] In formula (I), each Rsis independently selected from C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, -(C0-3 alkylene)-OH, -(C0-3 alkylene)-0(Ci-5 alkyl), -(C0-3 alkylene)-0(Ci-5 alkylene)-OH, -(C0-3 alkylene)-0(Ci-5 alkylene)-0(Ci-5 alkyl), -(C0-3 alkylene)-SH, -(C0-3 alkylene)-S(Ci-5 alkyl), -(C0-3 alkylene)-S(Ci-5 alkylene)-SH, -(C0-3 alkylene)-S(Ci-5 alkylene)-S(Ci-5 alkyl), -(C0-3 alkylene)-NH2, -(C0-3 alkylene)-NH(Ci-s alkyl), -(C0-3 alkylene)-N(Ci-5alkyl)(Ci-5 alkyl), -(C0-3 alkylene)-NH-OH, -(C0-3 alkylene)-N(Ci-5alkyl)-OH, -(C0-3 alkylene)-NH-O(Ci-5alkyl), -(C0-3 alkylene)-N(Ci-s alkyl)-0(Ci-5 alkyl), -(C0-3 alkylene)-halogen, -(C0-3 alkylene)-(Ci-5 haloalkyl), -(C0-3 alkylene)-0-(Ci-5 haloalkyl), -(C0-3 alkylene)-CN, -(C0-3 alkylene)-NC>2, -(C0-3 alkylene)-CHO, -(C0-3 alkylene)-C0-(Ci-5 alkyl), -(C0-3 alkylene)-COOH, -(C0-3 alkylene)-C0-0-(Ci-5 alkyl), -(C0-3 alkylene)-0-C0-(Ci-5 alkyl), -(C0-3 alkylene)-CO-NH2, -(C0-3 alkylene)-CO-NH(Ci-5alkyl), -(C0-3 alkylene)-CO-N(Ci-5alkyl)(Ci-5 alkyl), -(C0-3 alkylene)-NH-C0-(Ci-5 alkyl), -(C0-3 alkylene)-N(Ci-5alkyl)-C0-(Ci-5 alkyl), -(C0-3 alkylene)-NH-CO-O-(Ci-5alkyl), -(C0-3 alkylene)-N(Ci-5alkyl)-CO-O-(Ci-5alkyl), -(C0-3 alkylene)-O-CO-NH-(Ci-5alkyl), -(C0-3 alkylene)-O-CO-N(Ci-5alkyl)-(Ci-5alkyl), -(C0-3 alkylene)-SO2-NH2, -(C0-3 alkylene)-SO2-NH(Ci-5alkyl), -(C0-3 alkylene)-SO2-N(Ci-5 alkyl)(Ci-5 alkyl), -(C0-3 alkylene)-NH-SO2-(Ci-5 alkyl), -(C0-3 alkylene)-N(Ci-5 alkyl)-SO2-(Ci-5 alkyl), -(C0-3 alkylene)-SO2-(Ci-5 alkyl), -(C0-3 alkylene)-S0-(Ci-5 alkyl), -(C0-3 alkylene)-Si(Ci-5 alkyl)(Ci-5 alkyl)(Ci-5 alkyl), -(C0-3 alkylene)-SFs, -0-(Co-3 alkylene)-carbocyclyl, -0-(Co-3 alkylene)-heterocyclyl, -NH-(Co-3 alkylene)-carbocyclyl, -NH-(Co-3 alkylene)-heterocyclyl, -N(Ci-s alkyl)-(Co-3 alkylene)-carbocyclyl, -N(Ci-s alkyl)-(Co-3 alkylene)-heterocyclyl, -(C0-3 alkylene)-carbocyclyl, and -(C0-3 alkylene)-heterocyclyl, wherein the carbocyclyl moiety in said -0-(Co-3 alkylene)-carbocyclyl, the carbocyclyl moiety in said -NH-(Co-3 alkylene)-carbocyclyl, the carbocyclyl moiety in said -N(CI-5 alkyl)-(Co-3 alkylene)-carbocyclyl, the carbocyclyl moiety in said -(Co-3 alkylene)-carbocyclyl, the heterocyclyl moiety in said -0-(Co-3 alkylene)-heterocyclyl, the heterocyclyl moiety in said -NH-(Co-3 alkylene)-heterocyclyl, the heterocyclyl moiety in said -N(CI-5 alkyl)-(Co-3 alkylene)-heterocyclyl, and the heterocyclyl moiety in said -(Co-3 alkylene)-heterocyclyl are each optionally substituted with one or more groups independently selected from Ci-4 alkyl, halogen, -CN, -N02, -OH, -0-(Ci-4 alkyl), -SH, -S-(Ci-4 alkyl), -NH2, -NH(CI-4 alkyl), -N(Ci- 4 alkyl)(Ci-4 alkyl), -COOH, -COO(Ci-4 alkyl), -CONH2, -C0NH(CI-4 alkyl), -CON(CI-4 alkyl)(Ci-4 alkyl), - NHC0(CI-4 alkyl) and -N(CI-4 alkyl)-C0(Ci-4 alkyl).

[0172] Preferably, Rsis independently selected from C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, -(C0-3 alkylene)-OH, -(C0-3 alkylene)-0(Ci-5 alkyl), -(C0-3 alkylene)-0(Ci-5 alkylene)-OH, -(C0-3 alkylene)-O(Ci-s alkylene)-0(Ci-5 alkyl), -(C0-3 alkylene)-SH, -(C0-3 alkylene)-S(Ci-5 alkyl), -(C0-3 alkylene)-S(Ci-5 alkylene)-SH, -(C0-3 alkylene)-S(Ci-5 alkylene)-S(Ci-5 alkyl), -(C0-3 alkylene)-NH2, -(C0-3 alkylene)-NH(Ci-s alkyl), -(C0-3 alkylene)-N(Ci-5alkyl)(Ci-5 alkyl), -(C0-3 alkylene)-NH-OH, -(C0-3 alkylene)-N(Ci-5alkyl)-OH, -(C0-3 alkylene)-NH-O(Ci-5alkyl), -(C0-3 alkylene)-N(Ci-s alkyl)-O(Ci-5alkyl), -(C0-3 alkylene)-halogen, -(C0-3 alkylene)-(Ci-5 haloalkyl), -(C0-3 alkylene)-0-(Ci-5 haloalkyl), -(C0-3 alkylene)-CN, -(C0-3 alkylene)-N02, -(C0-3 alkylene)-CHO, -(C0-3 alkylene)-CO-(Ci-s alkyl), -(C0-3 alkylene)-COOH, -(C0-3 alkylene)-C0-0-(Ci-5 alkyl), -(C0-3 alkylene)-0-C0-(Ci-5 alkyl), -(C0-3 alkylene)-CO-NH2, -(C0-3 alkylene)-CO-NH(Ci-5alkyl), -(C0-3 alkylene)-CO-N(Ci-5alkyl)(Ci-5alkyl), -(C0-3 alkylene)-NH-CO-(Ci-5alkyl), -(C0-3 alkylene)-N(Ci-5alkyl)-C0-(Ci-5 alkyl), -(C0-3 alkylene)-NH-CO-O-(Ci-5alkyl), -(C0-3 alkylene)-N(Ci-s alkyl)-C0-0-(Ci-5 alkyl), -(C0-3 alkylene)-O-CO-NH-(Ci-5alkyl), -(C0-3 alkylene)-0-C0-N(Ci-5 alkyl)-(Ci-5 alkyl), -(C0-3 alkylene)-SO2-NH2, -(C0-3 alkylene)-SO2-NH(Ci-5alkyl), -(C0-3 alkylene)-SO2-N(Ci-5 alkyl)(Ci-5 alkyl), -(C0-3 alkylene)-NH-SO2-(Ci-5 alkyl), -(C0-3 alkylene)-N(Ci-5 alkyl)-SO2-(Ci-5 alkyl), -(C0-3 alkylene)-SO2-(Ci-5 alkyl), -(C0-3 alkylene)-SO-(Ci-s alkyl), -(C0-3 alkylene)-Si(Ci-5 alkyl)(Ci-5 alkyl)(Ci-5 alkyl), -(C0-3 alkylene)-SFs, -0-(Co-3 alkylene)-carbocyclyl, -0-(Co-3 alkylene)-heterocyclyl, -(C0-3 alkylene)-carbocyclyl, and -(C0-3 alkylene)-heterocyclyl, wherein the carbocyclyl moiety in said -0-(Co-3 alkylene)-carbocyclyl, the carbocyclyl moiety in said -(C0-3 alkylene)-carbocyclyl, the heterocyclyl moiety in said -0-(Co-3 alkylene)-heterocyclyl and the heterocyclyl moiety in said -(C0-3 alkylene)-heterocyclyl are each optionally substituted with one or more groups independently selected from C1-4 alkyl, halogen, -CN, -NO2, -OH, -0- (C1-4 alkyl), -SH, -S-(Ci-4 alkyl), -NH2, -NH(CI-4 alkyl), -N(CI-4 alkyl)(Ci-4 alkyl), -COOH, -COO(Ci-4 alkyl), -CONH2, -C0NH(Ci-4 alkyl), -C0N(CI-4 alkyl)(Ci-4 alkyl), -NHC0(Ci-4 alkyl) and -N(Ci-4 alkyl)-C0(Ci-4 alkyl).

[0173] More preferably, each Rsis independently selected from C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, -(C0-3 alkylene)-OH, -(C0-3 alkylene)-0(Ci-5 alkyl), -(C0-3 alkylene)-0(Ci-5 alkylene)-OH, -(C0-3 alkylene)-O(Ci-s alkylene)-0(Ci-5 alkyl), -(Co-3 alkylene)-SH, -(Co-3 alkylene)-S(Ci-5 alkyl), -(Co-3 alkylene)-S(Ci-5 alkylene)-SH, -(Co-3 alkylene)-S(Ci-5 alkylene)-S(Ci-5 alkyl), -(Co-3 alkylene)-NH2, -(Co-3 alkylene)-NH(Ci-s alkyl), -(Co-3 alkylene)-N(Ci-s alkyl)(Ci-5alkyl), -(Co-3 alkylene)-NH-0H, -(Co-3 alkylene)-N(Ci-5alkyl)-0H, -(Co-3 alkylene)-NH-0(Ci-5 alkyl), -(Co-3 alkylene)-N(Ci-s alkyl)-0(Ci-5 alkyl), -(Co-3 alkylene)-halogen, -(Co-3 alkylene)-(Ci-5 haloalkyl), -(Co-3 alkylene)-O-(Ci-5 haloalkyl), -(Co-3 alkylene)-CN, -(Co-3 alkylene)-NC>2, -(Co-3 alkylene)-CHO, -(Co-3 alkylene)-C0-(Ci-5 alkyl), -(Co-3 alkylene)-COOH, -(Co-3 alkylene)-C0-0-(Ci-5 alkyl), -(Co-3 alkylene)-0-C0-(Ci-5 alkyl), -(Co-3 alkylene)-CO-NH2, -(Co-3 alkylene)-CO-NH(Ci-5alkyl), -(Co-3 alkylene)-CO-N(Ci-5alkyl)(Ci-5alkyl), -(Co-3 alkylene)-NH-CO-(Ci-5alkyl), -(Co-3 alkylene)-N(Ci-5alkyl)-CO-(Ci-5alkyl), -(Co-3 alkylene)-NH-CO-O-(Ci-5alkyl), -(Co-3 alkylene)-N(Ci-5alkyl)-CO-O-(Ci-5alkyl), -(Co-3 alkylene)-O-CO-NH-(Ci-5alkyl), -(Co-3 alkylene)-0-C0-N(Ci-5 alkyl)-(Ci-5alkyl), -(Co-3 alkylene)-SO2-NH2, -(Co-3 alkylene)-SO2-NH(Ci-5alkyl), -(Co-3 alkylene)-SO2-N(Ci-5 alkyl)(Ci-5 alkyl), -(Co-3 alkylene)-NH-SO2-(Ci-5 alkyl), -(Co-3 alkylene)-N(Ci-5 alkyl)-SO2-(Ci-5 alkyl), -(Co-3 alkylene)-SO2-(Ci-5 alkyl), and -(Co-3 alkylene)-S0-(Ci-5 alkyl).

[0174] Even more preferably, each Rsis independently selected from C1-5 alkyl, C2-5 alkenyl, C2-5 alky nyl, -(C0-3 alkylene)-OH, -(C0-3 alkylene)-0(Ci-5 alkyl), -(C0-3 alkylene)-SH, -(C0-3 alkylene)-NH2, -(C0-3 alkylene)-NH(Ci-5alkyl), -(C0-3 alkylene)-N(Ci-5alkyl)(Ci-5alkyl), -(C0-3 alkylene)-NH-OH, -(C0-3 alkylene)-N(Ci-5alkyl)-OH, -(C0-3 alkylene)-NH-O(Ci-5alkyl), -(C0-3 alkylene)-N(Ci-s alkyl)-O(Ci-5alkyl), -(C0-3 alkylene)-halogen, -(C0-3 alkylene)-(Ci-5 haloalkyl), and -(C0-3 alkylene)-0-(Ci-5 haloalkyl), preferably each R1is independently selected from C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, -(C0-3 alkylene)-OH, -(C0-3 alkylene)-0(Ci-5 alkyl), -(C0-3 alkylene)-SH, -(C0-3 alkylene)-NH2, -(C0-3 alkylene)-NH(Ci-5alkyl), -(C0-3 alkylene)-N(Ci-5alkyl)(Ci-5alkyl), -(C0-3 alkylene)-NH-OH, -(C0-3 alkylene)-N(Ci-5alkyl)-OH, -(C0-3 alkylene)-NH-O(Ci-5alkyl), -(C0-3 alkylene)-N(Ci-s alkyl)-O(Ci-5alkyl), and -(C0-3 alkylene)-halogen.

[0175] Even more preferably, each Rsis independently selected from C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, -OH, -0(Ci-5 alkyl), -SH, -NH2, -NH(CI-5 alkyl), -N(CI-5 alkyl)(Ci-5 alkyl), -NH-OH, -N(CI-5 alkyl)-OH, -NH-0(CI-5 alkyl), -N(CI-5 alkyl)-O(Ci 5 alkyl), C1-5 haloalkyl and halogen, preferably each R1is independently selected from C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, -OH, -0(Ci-5 alkyl), -SH, -NH2, -NH(CI-5 alkyl), -N(CI-5 alkyl)(Ci-5 alkyl), -NH-OH, -N(CI-5 alkyl)-OH, -NH-0(CI-5 alkyl), -N(CI-5 alkyl)-0(Ci-5 alkyl), and halogen.

[0176] Even more preferably, each Rsis independently selected from -OH and halogen.

[0177] The compound of formula (I) may be a compound according to any one of the following specific embodiments. In the following description of each embodiment, not every variable group of formula (I) is explicitly discussed. It is to be understood that all the remaining variable groups are as in the definition of the compound of formula (I), including any preferred definitions and embodiments. Accordingly, for example, while in a first specific embodiment of the compound of formula (I), as discussed hereinbelow, only A is discussed in detail, it is to be understood that in this first specific embodiment of the compound of formula (I) B, X and Y are as in formula (I), including any of provided preferred definitions as well as any of the specific embodiments of the compound pf formula (I).

[0178] In a first specific embodiment of the compound of formula (I), A is selected from aryl, heteroaryl, cycloalkyl, and cycloalkenyl wherein said aryl, said heteroaryl, said cycloalkyl and said cycloalkenyl are each optionally substituted with one or more R1. In this first specific embodiment, A is preferably selected from aryl and heteroaryl, wherein said aryl and said heteroaryl are each optionally substituted with one or more R1. More preferably, in this first specific embodiment of the compound of formula (I), A is aryl, optionally substituted with one or more R1. Particularly suitable aryl group is phenyl. Accordingly, even more preferably A is phenyl, optionally substituted with one or more R1(such as C1-6 alkyl and C1-6 haloalkyl).

[0179] In a second specific embodiment of the compound of formula (I), A is selected from heterocycloalkyl and heterocycloalkenyl, wherein said heterocycloalkyl and said heterocycloalkenyl are each optionally substituted with one or more R1. Particularly suitable heterocycloalkyl and heterocycloalkenyl are heterocycloalkyl and heterocycloalkenyl consisting of a single 5 or 6-membered ring (preferably 6-membered), and optionally substituted with one or more R1.

[0180] In a third specific embodiment of the compound of formula (I), A is C2 alkynyl, optionally substituted with C1-6 alkyl or C1-6 haloalkyl, such as C1-6 alkyl. Particularly suitable C1-6 alkyl are methyl and isopropyl.

[0181] In a fourth specific embodiment of the compound of formula (I), X is -CONH-, wherein the C atom is connected to B and the N atom is connected to Y.

[0182] In an fifth specific embodiment, Y is according to formula wherein Ry2and

[0183] RZ1are as defined herein, including any preferred embodiment and any preferred definition thereof. In a sixth specific embodiment, Y is according to formula wherein RZ1is as defined herein, including any preferred embodiment and any preferred definition thereof.

[0184] In a seventh specific embodiment, Y is according to formula wherein m is 1 , 2 or 3, preferably m is 1 or 2, more preferably m is 1 , wherein each Rsis as defined herein, and wherein n is 0, 1 or 2 (preferably 0 or 1 , more preferably 0), and wherein Ry2is as defined herein.

[0185] In an eighth specific embodiment, Y is according to formula wherein m is 1 , 2 or 3, preferably wherein m is 1 or 2, more preferably wherein m is 1 , wherein each Rsis as defined herein, and wherein n is 0, 1 or 2 (preferably 0 or 1 , more preferably 0).

[0186] In a ninth specific embodiment, Y is according to formula , wherein Ry2, RZ1and Rz2are as defined herein, including any preferred embodiment and any preferred definition thereof. In a tenth specific embodiment, Y is according to formula . wherein

[0187] RZ1and Rz2are as defined herein, including any preferred embodiment and any preferred definition thereof.

[0188] In an eleventh specific embodiment, Y is according to formula wherein m is 1 , 2 or 3, preferably m is 1 or 2, more preferably m is 1 , wherein each Rsis as defined herein, and wherein n is 0, 1 or 2 (preferably 0 or 1 , more preferably 0), and wherein Ry2and Rz2are as defined herein.

[0189] In a twelfth specific embodiment, Y is according to formula . wherein m is 1 , 2 or 3, preferably m is 1 or 2, more preferably m is 1 , wherein each Rsis as defined herein, and wherein n is 0, 1 or 2 (preferably 0 or 1 , more preferably 0), and wherein Rz2is as defined herein.

[0190] In a thirteenth specific embodiment of the compound of formula (I), Y is a moiety according to formula: wherein Ry1is selected from H, Ci-4 alkyl (such as methyl), C3-8 cycloalkyl (such as cyclopropyl), and 5 or 6-membered heterocyclyl, and Ry2is selected from -H, -F and -CN (preferably Ry2is -H), and Ry3is selected from C1-4 alkyl (such as methyl), C3-8 cycloalkyl (such as cyclopropyl), and 5 or 6-membered heterocyclyl, preferably wherein Ry3is C1-4 alkyl, preferably methyl, and wherein the bonds drawn as indicate that both Z and E configurations of the double bond are possible. In this thirteenth specific (selected from this thirteenth specific embodiment of the compound of formula (I), A is preferably -CF2CH3.

[0191] In an fourteenth specific embodiment of the compound of formula (I), Y is a moiety according to formula: wherein Ry1is selected from H, C1-4 alkyl (such as methyl), C3-8 cycloalkyl (such as cyclopropyl), and 5 or 6-membered heterocyclyl, and Ry2is selected from -H, -F and -CN (preferably Ry2is -H), and Ry3is selected from C1-4 alkyl (such as methyl), C3-8 cycloalkyl (such as cyclopropyl), and 5 or 6-membered heterocyclyl, preferably wherein Ry3is C1-4 alkyl, preferably methyl, and wherein the bonds drawn as - indicate that both Z and E configurations of the double bond are possible. In this fourteenth specific

[0192] )). In this fourteenth specific embodiment of the compound of formula (I), A is preferably -CF2CH3.

[0193] In a fifteenth specific embodiment of the compound of formula (I), B is 2,5-pyridinylene, optionally substituted with -0-(Co-3 alkylene)-carbocyclyl, or -0-(Co-3 alkylene)-heterocyclyl, preferably with - O-carbocyclyl, or -O-heterocyclyl, more preferably with -O-carbocyclyl, in particular -O-phenyl. Preferably, said substitution is at the carbon atom in the ring adjacent to the carbon atom connected to X.

[0194] In a sixteenth specific embodiment of the compound of formula (I), B is 2,5-pyrimidinylene, optionally substituted with -0-(Co-3 alkylenej-carbocyclyl, or -0-(Co-3 alkylenej-heterocyclyl, preferably with -O-carbocyclyl, or -O-heterocyclyl, more preferably with -O-carbocyclyl, in particular -O-phenyl. Preferably, said substitution is at the carbon atom in the ring adjacent to the carbon atom connected to X, or, in other words, at position 4 in the 2,5-pyrimidinylene. In a seventeenth specific embodiment of the compound of formula (I), A is -CF2CH3.

[0195] The present invention likewise relates to a compound of formula (II): or a pharmaceutically acceptable salt thereof.

[0196] In formula (II), Xvis CRv2or N;

[0197] Yvis CRv4or N;

[0198] Zvis CRv5or N; or Yvand Zvtaken together form an optionally substituted five- to six-membered heteroaryl, or an optionally substituted five- to six-membered heterocyclyl; with the proviso that Xv, Yv, and Zvare not all simultaneously N.

[0199] In formula (II), Rv1is H, -O-(optionally substituted C3-C8 cycloalkyl), -O-(optionally substituted C1- Ce alkyl), -0- (optionally substituted C6-C10 aryl), -O-(optionally substituted five- to six-membered heteroaryl), -0- (optionally substituted five- to six-membered heterocycloalkyl), or optionally substituted C3-C8 cycloalkyl; or Rv1together with the carbon atoms to which it is shown attached and Xvform an optionally substituted five- to six-membered heterocyclyl.

[0200] Accordingly, Rv1together with the carbon atoms to which it is shown attached and Xvmay form an optionally substituted five- to six-membered heterocyclyl. Said heterocyclyl may for example be: wherein the double bond shown is between the carbo bearing the Rv1group and Xv.

[0201] Preferably, Rv1is H, -O-(optionally substituted C3-C8 cycloalkyl), -O-(optionally substituted C1- Ce alkyl), -O-(optionally substituted C6-C10 aryl), -O-(optionally substituted five- to six-membered heteroaryl), -0- (optionally substituted five- to six-membered heterocycloalkyl), or optionally substituted C3-C8 cycloalkyl. Suitable C3-C8 cycloalkyl include cyclobutyl, cyclopropyl, cyclohexyl, cyclopentyl. Suitable -O-(optionally substituted C1-C6 alkyl) include ethoxy, or isopropoxy.

[0202] More preferably, Rv1is -O-(optionally substituted C3-C8 cycloalkyl), -O-(optionally substituted C1- Ce alkyl), -O-(optionally substituted C6-C10 aryl), -O-(optionally substituted five- to six-membered heteroaryl), or -O-(optionally substituted five- to six-membered heterocycloalkyl).

[0203] Even more preferably, Rv1is -O-(optionally substituted C3-C8 cycloalkyl), -O-(optionally substituted C6-C10 aryl), -O-(optionally substituted five- to six-membered heteroaryl), or -O-(optionally substituted five- to six-membered heterocycloalkyl).

[0204] Again more preferably, Rv1is -O-(optionally substituted C6-C10 aryl), such as -O-(optionaly substituted phenyl), preferably -O-phenyl.

[0205] In formula (II), Rv2is H, optionally substituted C1-C6 alkyl, or halo.

[0206] Preferably, Rv2is H, or optionally substituted C1-C6 alkyl.

[0207] More preferably, Rv2is H.

[0208] In formula (II), Rv3is optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 cycloalkenyl, optionally substituted C6-C10 aryl, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl (preferably C2-C6 alkenyl), -NR2, -NR(optionally substituted C4-C8 cycloalkyl), -S-(-optionally substituted C1-C6 alkyl), -O-(optionally substituted C1-C6 alkyl), -O-(optionally substituted C3-C8 cycloalkyl), optionally substituted four- to six-membered heterocycloalkyl or heterocycloalkenyl, optionally substituted five- to six-membered heteroaryl, or -O-(optionally substituted C3-C8 cycloalkyl); or Rv3taken together with the carbon atom to which it is shown attached and Yvform an optionally substituted C6-C10 aryl, an optionally substituted C3-C8 cycloalkyl or cycloalkenyl, or an optionally substituted five- to six-membered heterocyclyl or heterocycloalkenyl.

[0209] Accordingly, Rv3taken together with the carbon atom to which it is shown attached and Yvmay form an optionally substituted C6-C10 aryl, an optionally substituted C3-C8 cycloalkyl or cycloalkenyl, or an optionally substituted five- to six-membered heterocyclyl or heterocycloalkenyl, preferably Rv3taken together with the carbon atom to which it is shown attached and Yvmay form an optionally substituted Ce- C10 aryl, for example according to formula:

[0210] Rv3taken together with the carbon atom to which it is shown attached and Yvmay also form an optionally substituted five- to six-membered heterocyclyl or heterocycloalkenyl, such as: shown between the two carbons bearing the points of attachment is the carbon bearing the Rv3and Yv.

[0211] Rv3taken together with the carbon atom to which it is shown attached and Yvmay also form an optionally substituted C3-C8 cycloalkyl or cycloalkenyl, such as: wherein the carbon-carbon double bond shown is between the carbo bearing the Rv3group and Yv.

[0212] Preferably however, Rv3is optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 cycloalkenyl, optionally substituted C6-C10 aryl, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl (preferably C2-C6 alkenyl), -NR2, -NR(optionally substituted C4-C8 cycloalkyl), -S-(-optionally substituted C1-C6 alkyl), -O-(optionally substituted C1-C6 alkyl), -O-(optionally substituted C3-C8 cycloalkyl), optionally substituted four- to six-membered heterocycloalkyl or heterocycloalkenyl, optionally substituted five- to six-membered heteroaryl, or -O-(optionally substituted C3-C8 cycloalkyl).

[0213] More preferably, Rv3is optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 cycloalkenyl, optionally substituted C6-C10 aryl, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl (preferably C2-C6 alkenyl), -NR2, and -NR(optionally substituted C4-C8 cycloalkyl).

[0214] Even more preferably, Rv3is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl (preferably C2-C6 alkenyl), or -NR2.

[0215] Again more preferably, Rv3is optionally substituted C1-C6 alkyl, in particular C1-C6 haloalkyl, such as -CF2CH3

[0216] In formula (II), Rv4is H, C1-C6 alkyl, cyano, or halo; or Rv4together with the carbon atom to which it is shown attached and Zvform an optionally substituted five- to six-membered heteroaryl.

[0217] Preferably, Rv4is H, C1-C6 alkyl, cyano, or halo.

[0218] More preferably, Rv4is H or C1-C6 alkyl.

[0219] Even more preferably, Rv4is H.

[0220] In formula (II), Rv5is H, C1-C6 alkyl, -NR2, or -N(R)-C(=O)-(CI-C6alkyl). In formula (II), each R independently is H, or optionally substituted Ci-Ce alkyl.

[0221] Accordingly, Rv5is H, Ci-Ce alkyl, -NR2, (such as -NH2) or -N(R)-C(=O)-(Ci-Ce alkyl) (such as - NH-C(=0)-(CI-C6 alkyl)). Preferably, Rv5is H, or C1-C6 alkyl. More preferably, Rv5is H.

[0222] Said optional substituents of alkyl, alkenyl, cycloalkenyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups in Rv1, Rv2, Rv3, Rv4, and Rv5, are selected from the group consisting of halogen, -CN, - NO2, -N3, -SO2H, -SO3H, -OH, -0Raa, -N(Rbb)2, -N(0Rcc)Rbb, -SH, -SRaa, -C(=0)Raa, -CO2H, - CHO, - C02Raa, -0C(=0)Raa, -0C02Raa, -C(=0)N(Rbb)2, -0C(=0)N(Rbb)2, -NRbbC(=0)Raa, - NRbbC02Raa, - NRbbC(=0)N(Rbb)2, -C(=NRbb)Raa, -C(=NRbb)0Raa, -0C(=NRbb)Raa, -0C(=NRbb)0Raa, - C(=NRbb)N(Rbb)2, - 0C(=NRbb)N(Rbb)2, -NRbbC(=NRbb)N(Rbb)2, -C(=0)NRbbS02Raa, -NRbbS02Raa, - SO2N(Rbb)2, -SO2Raa, - S(=O)Raa, -OS(=O)Raa, -B(ORCC)2, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3- 14 cycloalkyl, 3- to 14- membered heterocyclyl, Ce-14 aryl, and 5- to 14- membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1 , 2, 3, 4, or 5 Rddgroups, or two geminal hydrogens on a carbon atom are replaced with the group =0;

[0223] As defined herein, each instance of Raais, independently, selected from the group consisting of C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, C3-14 carbocyclyl, 3- to 14- membered heterocyclyl, Ce-14 aryl, and 5- to 14- membered heteroaryl, or two Raagroups are joined to form a 3- to 14- membered heterocyclyl or 5- to 14- membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1 , 2, 3, 4, or 5 Rddgroups; each instance of Rbbis, independently, selected from the group consisting of hydrogen, -OH, - ORaa, -N(RCC)2, -CN, -C(=0)Raa, -C(=O)N(RCC)2, -C02Raa, -SO2Raa, -SO2N(RCC)2, -SORaa, C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, C3-14 carbocyclyl, 3- to 14- membered heterocyclyl, Ce- 14 aryl, and 5- to 14- membered heteroaryl, or two Rbbgroups are joined to form a 3- to 14- membered heterocyclyl or 5- to 14- membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1 , 2, 3, 4, or 5 Rddgroups; each instance of Rccis, independently, selected from the group consisting of hydrogen, Ci- 10 alkyl, Ci— 10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, C3-14 carbocyclyl, 3- to 14- membered heterocyclyl, Ce-14 aryl, and 5- to 14- membered heteroaryl, or two Rccgroups are joined to form a 3- to 14- membered heterocyclyl or 5- to 14- membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1 , 2, 3, 4, or 5 Rddgroups; and each instance of Rddis, independently, selected from the group consisting of halogen, -CN, - NO2, -N3, -SO2H, -SO3H, -OH, -OC1-6 alkyl, -ON(CI-6 alkyl)2, -N(CI-6alkyl)2, -N(OCI-6alkyl)(Ci- 6 alkyl), - N(OH)(CI-6alkyl), -NH(OH), -SH, -SC1-6 alkyl, -C(=O)(Ci-6 alkyl), -CO2H, -CO2(Ci-6alkyl), - 0C(=0)(Ci-6 alkyl), -OCO2(Ci-6alkyl), -C(=0)NH2, -C(=0)N(CI-6 alkyl)2, -0C(=0)NH(CI-6 alkyl), - NHC(=0)(CI-6alkyl), -N(CI-6alkyl)C(=0)( C1-6 alkyl), -NHCO2(CI-6alkyl), -NHC(=0)N(CI-6 alkyl)2, - NHC(=0)NH(CI-6 alkyl), -NHC(=0)NH2, -C(=NH)0(CI-6 alkyl), -0C(=NH)(CI-6 alkyl), -0C(=NH)0Ci- 6 alkyl, -C(=NH)N(CI-6alkyl)2, -C(=NH)NH(CI-6 alkyl), -C(=NH)NH2, -0C(=NH)N(CI-6 alkyl)2, - 0C(NH)NH(CI-6 alkyl), -0C(NH)NH2, -NHC(NH)N(CI-6 alkyl)2, -NHC(=NH)NH2, -NHSO2(CI-6 alkyl), - SO2N(CI-6 alkyl)2, -SO2NH(CI-6alkyl), -SO2NH2,-SO2CI-6alkyl, -B(0H)2, -B(0CI-6 alkyl)2,Ci-6 alkyl, Ci- 6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocyclyl, C6-10 aryl, 3- to 10- membered heterocyclyl, and 5- to 10- membered heteroaryl; or two geminal Rddsubstituents on a carbon atom may be joined to form =0.

[0224] Accordingly, in one specific embodiment of the compound of formula (II):

[0225] Xvis N;

[0226] Yvis N; and

[0227] Zvis CRv5; or Yvand Zvtaken together form an optionally substituted five- to six-membered heteroaryl, or an optionally substituted five- to six-membered heterocyclyl.

[0228] In a further specific embodiment of the compound of formula (II):

[0229] Xvis CRv2;

[0230] Yvis CRv4N;

[0231] Zvis CRv5N; or Yvand Zvtaken together form an optionally substituted five- to six-membered heteroaryl, or an optionally substituted five- to six-membered heterocyclyl, or Rv3taken together with the carbon atom to which it is shown attached and Yvform an optionally substituted C3-C8 cycloalkyl or cycloalkenyl.

[0232] In a further specific embodiment of the compound of formula (II):

[0233] Xvis CRv2;

[0234] Yvis N;

[0235] Zvis CRv5; or Rv1together with the carbon atoms to which it is shown attached and Xvform an optionally substituted five- to six-membered heterocyclyl.

[0236] In a further specific embodiment of the compound of formula (II):

[0237] Xvis N;

[0238] Yvis CRv4;

[0239] Zvis CRv5; or Rv3taken together with the carbon atom to which it is shown attached and Yvform an optionally substituted Ce-Cio aryl, an optionally substituted C3-C8 cycloalkyl or cycloalkenyl, or an optionally substituted five- to six-membered heterocyclyl or heterocycloalkenyl.

[0240] In a further specific embodiment of the compound of formula (II):

[0241] Xvis N;

[0242] Yvis CRv4; and

[0243] Zvis N.

[0244] In a further specific embodiment of the compound of formula (II):

[0245] Xvis CRv2;

[0246] Yvis CRv4; and

[0247] Zvis N.

[0248] In a further specific embodiment of the compound of formula (II):

[0249] Xvis N;

[0250] Yvis N; and

[0251] Zvis CRv5.

[0252] It is particularly preferred that Xvis N, Yvis N; Zvis CH, Rv1is -O-phenyl and Rv3is -CF2CH3.

[0253] In formula (II), X is as defined for formula (I). Preferably, X is selected from -CONH-, and -CON(Ci- 6 alkyl)-. Even more preferably, X is -CONH-. It is to be understood that, preferably, the right side of said bivalent formula embodying X is connected to Y.

[0254] In formula (II), Y is as defined for formula (I). In particular, in formula (II), Y is a moiety according to formula: wherein Ry1is selected from H, C1-6 alkyl (such as methyl), C3-8 cycloalkyl (such as cyclopropyl), and 5 or 6-membered heterocyclyl, wherein said cycloalkyl and said heterocyclyl are each optionally substituted with one or more groups selected from Rs, Ry2is selected from -H, -F and -CN, Ry3is selected from C1-4 alkyl (such as methyl), C1-4 haloalkyl (such as trifluoromethyl), C3-8 cycloalkyl (such as cyclopropyl), phenyl and 5 or 6-membered heterocyclyl, wherein said cycloalkyl, said phenyl and said heterocyclyl are each optionally substituted with one or more groups selected from Rs, Z is selected from =0 and =NRZ2, wherein each RZ1and Rz2are independently selected from hydrogen, -CN, C1-5 alkyl, C3- 8 cycloalkyl, heterocycloalkyl, phenyl, 5-6 membered heteroaryl, -CO-C1-5 alkyl, -COO-C1-5 alkyl, -SO2-C1- 5 alkyl, -CONH2, -C0NH(CI-5 alkyl), and -C0N(Ci-s alkyl)(Ci 5 alkyl), wherein said alkyl is optionally substituted with one or more groups selected from Hal, -OH, -ON, -0-(Ci-5 alkyl), -NH2, -NH(CI-5 alkyl), - N(CI-5 alkyl)(Ci 5 alkyl), -CONH2, -C0NH(CI-5 alkyl) and -C0-N(CI-5 alkyl)(Ci 5 alkyl), wherein said cycloalkyl, said heterocycloalkyl, said phenyl and said heteroaryl are each optionally independently substituted with one or more groups selected from Rs(preferably are each independently substituted with one or more groups selected from Rs), wherein optionally RZ1and Ry3are joined to form, together with the N atom that otherwise carries RZ1and the sulfur atom that otherwise carries Ry3, 5 to 7 membered heterocyclic ring, which is optionally substituted with one or more groups selected from Rs. It is to be understood that the bonds drawn as indicate that both configurations of the double bond, Z and E, are possible.

[0255] Preferably, Ry1is selected from H, C1-4 alkyl (such as methyl), and C3-8 cycloalkyl (such as cyclopropyl), wherein said cycloalkyl is optionally substituted with one or more groups selected from Rs. More preferably, Ry1is selected from C1-4 alkyl (such as methyl) and C3-8 cycloalkyl (such as cyclopropyl). Even more preferably, Ry1is selected from methyl and cyclopropyl.

[0256] Preferably Ry2is -H or F. More preferably Ry2is -H.

[0257] Preferably, Ry3is selected from C1-4 alkyl (such as methyl), C3-8 cycloalkyl (such as cyclopropyl), phenyl and 5 or 6-membered heterocyclyl, wherein said cycloalkyl, said phenyl and said heterocyclyl are each optionally substituted with one or more groups selected from Rs. More preferably, Ry3is selected from C1-4 alkyl (such as methyl), C3-8 cycloalkyl (such as cyclopropyl), and 5 or 6-membered heterocyclyl, wherein said cycloalkyl, and said heterocyclyl are each optionally substituted with one or more groups selected from Rs. More preferably, Ry3is C1-4 alkyl. Even more preferably Ry3is methyl.

[0258] Preferably, Z is =0.

[0259] Preferably, RZ1is selected from -CN, C2-5 alkyl, C3-8 cycloalkyl, heterocycloalkyl, phenyl, 5-6 membered heteroaryl, -CO-C1-5 alkyl, -COO-C1-5 alkyl, -SO2-C1-5 alkyl, -CONH2, -CONH(Ci-s alkyl), and - C0N(CI-5 alkyl)(Ci-5 alkyl), wherein said alkyl is optionally substituted with one or more groups selected from Hal, -OH, -CN, -0-(Ci-5 alkyl), -NH2, -NH(CI-5 alkyl), -N(CI-5 alkyl)(Ci-5 alkyl), -CONH2, -C0NH(CI-5alkyl) and -CO-N(Ci-s alkyl)(Ci 5 alkyl), wherein said cycloalkyl, said heterocycloalkyl, said phenyl and said heteroaryl are each independently optionally substituted with one or more groups selected from Rs(preferably are each independently substituted with one or more groups selected from Rs).

[0260] More preferably, RZ1is selected from -CN, cyclopropyl, cyclobutyl, oxetanyl, phenyl, pyridyl, -CO- CH3, -COO-CH3, -SO2-CH3, -CONH2, -C0NH(CH3), and -CON(CH3)(CH3).

[0261] Even more preferably, RZ1is selected from -CN, cyclopropyl, oxetanyl, phenyl, pyridyl, -CO-CH3, -COO-CH3, -SO2-CH3, and -C0NH(CH3). In one particular embodiment, RZ1is -CO-C1-5 alkyl, wherein said alkyl is optionally substituted with one or more groups selected from Hal, -OH, -ON, -0-(Ci-5 alkyl), -NH2, -NH(CI-5 alkyl), -N(CI-5 alkyl)(Ci-5 alkyl), -CONH2, -CONH(CI-5alkyl) and -C0-N(CI-5 alkyl)(Ci-5 alkyl). Preferably, in this embodiment, RZ1is -CO-C1-5 alkyl, such as -CO-CH3.

[0262] In one particular embodiment, RZ1is -CONH(Ci-s alkyl), wherein said alkyl is optionally substituted with one or more groups selected from Hal, -OH, -ON, -0-(Ci-5 alkyl), -NH2, -NH(CI-5 alkyl), -N(CI-5 alkyl)(Ci-5 alkyl), -CONH2, -CONH(CI-5alkyl) and -CO-N(CI-5alkyl)(Ci-5 alkyl). Preferably, in this embodiment, RZ1is -CONH(Ci-s alkyl), such as -CONHCH3.

[0263] In one particular embodiment, RZ1is phenyl, or 5-6 membered heteroaryl, wherein said phenyl and said heteroaryl are each independently optionally substituted with one or more groups selected from Rs(preferably are each independently substituted with one or more groups selected from Rs). Preferably, RZ1is phenyl.

[0264] In one particular embodiment, RZ1is -COO-C1-5 alkyl, wherein said alkyl is optionally substituted with one or more groups selected from Hal, -OH, -ON, -0-(Ci-5 alkyl), -NH2, -NH(CI-5 alkyl), -N(CI-5 alkyl)(Ci-5 alkyl), -CONH2, -CONH(CI-5alkyl) and -CO-N(CI-5alkyl)(Ci-5 alkyl). Preferably, in this embodiment, RZ1is -CO-C1-5 alkyl, such as -COO-CH3.

[0265] In one particular embodiment, RZ1is -SO2-C1-5 alkyl, wherein said alkyl is optionally substituted with one or more groups selected from Hal, -OH, -ON, -0-(Ci-5 alkyl), -NH2, -NH(CI-5 alkyl), -N(CI-5 alkyl)(Ci-5 alkyl), -CONH2, -CONH(CI-5alkyl) and -CO-N(CI-5alkyl)(Ci-5 alkyl). Preferably, in this embodiment, RZ1is -CO-C1-5 alkyl, such as - SO2-CH3.

[0266] In one particular embodiment, RZ1is tetrahydrofuranyl (preferably 3-tetrahydrofuranyl).

[0267] In one particular embodiment, RZ1is hydrogen.

[0268] In one particular embodiment, RZ1is methyl.

[0269] In one particular embodiment, RZ1is selected from -ON, cyclopropyl, tetrahydrofuranyl (such as 3-tetrahydrofuranyl), phenyl, pyridyl, -CO-CH3, -COO-CH3, -SO2-CH3, and -C0NH(CH3).

[0270] In one particular embodiment, RZ1is C3-8 cycloalkyl, wherein said cycloalkyl is optionally substituted with one or more groups selected from Rs. Preferably, RZ1is cyclopropyl.

[0271] In one particular embodiment, RZ1is 5-6 membered heteroaryl, wherein said cycloalkyl, said heterocycloalkyl, wherein said heteroaryl is optionally substituted with one or more groups selected from Rs. Preferably, RZ1is pyridyl.

[0272] It is further preferred that RZ1and Ry3are not joined to form, together with an N atom that otherwise carries RZ1and sulfur atom that otherwise carriers Ry3, 5 to 7 membered heterocyclic ring, which is optionally substituted with one or more groups selected from Rs. Accordingly, RZ1and Ry3are as defined herein. Z may also be =NRZ2. In such embodiments, Rz2is as defined herein.

[0273] Preferably, Rz2is selected from hydrogen, -CN, C1-5 alkyl, C3-8 cycloalkyl, heterocycloalkyl, phenyl, 5-6 membered heteroaryl, -CO-C1-5 alkyl, -COO-C1-5 alkyl, -SO2-C1-5 alkyl, -CONH2, -CONH(Ci-s alkyl), and -CON(CI-5 alkyl)(Ci-5 alkyl), wherein said alkyl is optionally substituted with one or more groups selected from Hal, -OH, -CN, -O-(Ci-5alkyl), -NH2, -NH(CI-5 alkyl), -N(Ci-5alkyl)(Ci-5 alkyl), -CONH2, - CONH(CI-5 alkyl) and -CO-N(CI-5 alkyl)(Ci-5 alkyl), wherein said cycloalkyl, said heterocycloalkyl, said phenyl and said heteroaryl are each optionally independently substituted with one or more groups selected from Rs(preferably are each independently substituted with one or more groups selected from Rs).

[0274] More preferably, Rz2is selected from hydrogen, -CN, methyl, cyclopropyl, cyclobutyl, oxetanyl, phenyl, -CO-CH3, -COO-CH3, -SO2-CH3, -CONH2, -CONH(CH3), and -CON(CH3)(CH3).

[0275] Even more preferably, Rz2is selected from hydrogen, -CN, methyl, cyclopropyl, oxetanyl, phenyl, -CO-CH3, -COO-CH3, -SO2-CH3, and -CONH(CH3).

[0276] It is particularly preferred that RZ1and Ry3are not joined to form, together with an N atom that otherwise carries RZ1and sulfur atom that otherwise carriers Ry3, 5 to 7 membered heterocyclic ring, which is optionally substituted with one or more groups selected from Rsand that Z is =0.

[0277] However, alternatively, in one preferred embodiment of the present invention, RZ1and Ry3are joined to form, together with the N atom that otherwise carries RZ1and the sulfur atom that otherwise carries Ry3, 5 to 7 membered heterocyclic ring, which is optionally substituted with one or more groups selected from Rsand that Z is =0.

[0278] In one embodiment, RZ1and Ry3are not joined to form, together with an N atom that otherwise carries RZ1and sulfur atom that otherwise carriers Ry3, 5 to 7 membered heterocyclic ring, which is optionally substituted with one or more groups selected from Rsand that Z is =NRZ2, wherein Rz2is as defined herein.

[0279] In one embodiment, RZ1and Ry3arejoined to form, together with the N atom that otherwise carries RZ1and the sulfur atom that otherwise carries Ry3, 5 to 7 membered heterocyclic ring, which is optionally substituted with one or more groups selected from Rsand that Z is =NRZ2, wherein Rz2is as defined herein.

[0280] In one embodiment of the present invention, Z is =0 and RZ1is hydrogen or methyl.

[0281] Encompassed by formula (II) are further the embodiments wherein Y is not a moiety according to formula: or a moiety according to formula: including any specific configuration of the double bond, wherein Ry1is selected from H, C1-4 alkyl, C3-8 cycloalkyl, and 5 or 6-membered heterocyclyl, Ry2is selected from -H, -F and -CN, and Ry3is selected from C1-4 alkyl, C3-8 cycloalkyl, and 5 or 6-membered heterocyclyl, and wherein the bonds drawn as indicate that both Z and E configurations of the double bond are possible.

[0282] In formula (II), Rsis defined as in formula (I). Accordingly, in formula (II), each Rsis independently selected from C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, -(C0-3 alkylene)-OH, -(C0-3 alkylene)-O(Ci-5 alkyl), -(C0-3 alkylene)-O(Ci-5 alkylene)-OH, -(C0-3 alkylene)-O(Ci-5 alkylene)-O(Ci-5 alkyl), -(C0-3 alkylene)-SH, -(C0-3 alkylene)-S(Ci-5 alkyl), -(C0-3 alkylene)-S(Ci-5 alkylene)-SH, -(C0-3 alkylene)-S(Ci-5 alkylene)-S(Ci-5 alkyl), -(C0-3 alkylene)-NH2, -(C0-3 alkylene)-NH(Ci-s alkyl), -(C0-3 alkylene)-N(Ci-s alkyl)(Ci-5 alkyl), -(C0-3 alkylene)-NH-OH, -(C0-3 alkylene)-N(Ci-5alkyl)-OH, -(C0-3 alkylene)-NH-O(Ci-5alkyl), -(C0-3 alkylene)-N(Ci-5 alkyl)-O(Ci-5 alkyl), -(C0-3 alkylene)-halogen, -(C0-3 alkylene)-(Ci-5 haloalkyl), -(C0-3 alkylene)-O-(Ci-5 haloalkyl), -(C0-3 alkylene)-CN, -(C0-3 alkylene)-NO2, -(C0-3 alkylene)-CHO, -(C0-3 alkylene)-CO-(Ci-5 alkyl), -(C0-3 alkylene)-COOH, -(C0-3 alkylene)-CO-O-(Ci-5 alkyl), -(C0-3 alkylene)-O-CO-(Ci-5 alkyl), -(C0-3 alkylene)-CO-NH2, -(C0-3 alkylene)-CO-NH(Ci-5 alkyl), -(C0-3 alkylene)-CO-N(Ci-5 alkyl)(Ci-5 alkyl), -(C0-3 alkylene)-NH-CO-(Ci-5 alkyl), -(C0-3 alkylene)-N(Ci-s alkyl)-CO-(Ci-5alkyl), -(C0-3 alkylene)-NH-CO-O-(Ci-5alkyl), -(C0-3 alkylene)-N(Ci-s alkyl)-CO-O-(Ci-5alkyl), -(C0-3 alkylene)-O-CO-NH-(Ci-5alkyl), -(C0-3 alkylene)-O-CO-N(Ci-5alkyl)-(Ci-5alkyl), -(C0-3 alkylene)-SO2-NH2, -(C0-3 alkylene)-SO2-NH(Ci-5 alkyl), -(C0-3 alkylene)-SO2-N(Ci-5 alkyl)(Ci-5 alkyl), -(C0-3 alkylene)-NH-SO2-(Ci-5 alkyl), -(C0-3 alkylene)-N(Ci-s alkyl)-SO2-(Ci-5 alkyl), -(C0-3 alkylene)-SO2-(Ci-5 alkyl), -(C0-3 alkylene)-SO-(Ci-5 alkyl), -(C0-3 alkylene)-Si(Ci-5 alkyl)(Ci-5 alkyl)(Ci-5 alkyl), -(C0-3 alkylene)-SFs, -0-(Co-3 alkylene)-carbocyclyl, -0-(Co-3 alkylene)-heterocyclyl, -NH-(Co-3 alkylene)-carbocyclyl, -NH-(Co-3 alkylene)-heterocyclyl, -N(CI-5 alkyl)-(Co-3 alkylene)-carbocyclyl, -N(CI-5 alkyl)-(Co-3 alkylene)-heterocyclyl, -(C0-3 alkylene)-carbocyclyl, and -(C0-3 alkylene)-heterocyclyl, wherein the carbocyclyl moiety in said -0-(Co-3 alkylene)-carbocyclyl, the carbocyclyl moiety in said -NH-(Co-3 alkylene)-carbocyclyl, the carbocyclyl moiety in said -N(CI-5 alkyl)-(Co-3 alkylene)-carbocyclyl, the carbocyclyl moiety in said -(C0-3 alkylene)-carbocyclyl, the heterocyclyl moiety in said -0-(Co-3 alkylene)-heterocyclyl, the heterocyclyl moiety in said -NH-(Co-3 alkylene)-heterocyclyl, the heterocyclyl moiety in said -N(CI-5 alkyl)-(Co-3 alkylene)-heterocyclyl, and the heterocyclyl moiety in said -(C0-3 alkylene)-heterocyclyl are each optionally substituted with one or more groups independently selected from Ci-4 alkyl, halogen, -CN, -NO2, -OH, -0-(Ci-4 alkyl), -SH, -S-(Ci-4 alkyl), -NH2, -NH(CI-4alkyl), -N(Ci- 4 alkyl)(Ci-4 alkyl), -COOH, -C00(Ci-4 alkyl), -CONH2, -C0NH(CI-4 alkyl), -C0N(CI-4 alkyl)(Ci-4 alkyl), - NHC0(CI-4 alkyl) and -N(CI-4 alkyl)-C0(Ci-4 alkyl).

[0283] Preferably, Rsis independently selected from C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, -(C0-3 alkylene)-OH, -(C0-3 alkylene)-0(Ci-5 alkyl), -(C0-3 alkylene)-0(Ci-5 alkylene)-OH, -(C0-3 alkylene)-0(Ci-5 alkylene)-0(Ci-5 alkyl), -(C0-3 alkylene)-SH, -(C0-3 alkylene)-S(Ci-5 alkyl), -(C0-3 alkylene)-S(Ci-5 alkylene)-SH, -(C0-3 alkylene)-S(Ci-5 alkylene)-S(Ci-5 alkyl), -(C0-3 alkylene)-NH2, -(C0-3 alkylene)-NH(Ci-s alkyl), -(C0-3 alkylene)-N(Ci-5alkyl)(Ci-5 alkyl), -(C0-3 alkylene)-NH-OH, -(C0-3 alkylene)-N(Ci-5alkyl)-OH, -(C0-3 alkylene)-NH-O(Ci-5alkyl), -(C0-3 alkylene)-N(Ci-s alkyl)-0(Ci-5 alkyl), -(C0-3 alkylene)-halogen, -(C0-3 alkylene)-(Ci-5 haloalkyl), -(C0-3 alkylene)-0-(Ci-5 haloalkyl), -(C0-3 alkylene)-CN, -(C0-3 alkylene)-N02, -(C0-3 alkylene)-CHO, -(C0-3 alkylene)-C0-(Ci-5 alkyl), -(C0-3 alkylene)-COOH, -(C0-3 alkylene)-C0-0-(Ci-5 alkyl), -(C0-3 alkylene)-0-C0-(Ci-5 alkyl), -(C0-3 alkylene)-CO-NH2, -(C0-3 alkylene)-CO-NH(Ci-5alkyl), -(C0-3 alkylene)-CO-N(Ci-5alkyl)(Ci-5 alkyl), -(C0-3 alkylene)-NH-CO-(Ci 5 alkyl), -(C0-3 alkylene)-N(Ci-5alkyl)-CO-(Ci-5alkyl), -(C0-3 alkylene)-NH-CO-O-(Ci-5alkyl), -(C0-3 alkylene)-N(Ci-5alkyl)-CO-O-(Ci-5alkyl), -(C0-3 alkylene)-O-CO-NH-(Ci-5alkyl), -(C0-3 alkylene)-O-CO-N(Ci-5alkyl)-(Ci-5alkyl), -(C0-3 alkylene)-SO2-NH2, -(C0-3 alkylene)-SO2-NH(Ci-5alkyl), -(C0-3 alkylene)-SO2-N(Ci-5 alkyl)(Ci-5 alkyl), -(C0-3 alkylene)-NH-SO2-(Ci-5 alkyl), -(C0-3 alkylene)-N(Ci-5 alkyl)-SO2-(Ci-5 alkyl), -(C0-3 alkylene)-SO2-(Ci-5 alkyl), -(C0-3 alkylene)-S0-(Ci-5 alkyl), -(C0-3 alkylene)-Si(Ci-5 alkyl)(Ci-5 alkyl)(Ci-5 alkyl), -(C0-3 alkylene)-SFs, -0-(Co-3 alkylene)-carbocyclyl, -0-(Co-3 alkylene)-heterocyclyl, -(C0-3 alkylene)-carbocyclyl, and -(C0-3 alkylene)-heterocyclyl, wherein the carbocyclyl moiety in said -0-(Co-3 alkylene)-carbocyclyl, the carbocyclyl moiety in said -(C0-3 alkylene)-carbocyclyl, the heterocyclyl moiety in said -0-(Co-3 alkylene)-heterocyclyl and the heterocyclyl moiety in said -(C0-3 alkylene)-heterocyclyl are each optionally substituted with one or more groups independently selected from C1-4 alkyl, halogen, -CN, -NO2, -OH, -0- (C1-4 alkyl), -SH, -S-(Ci-4 alkyl), -NH2, -NH(CI-4 alkyl), -N(CI-4 alkyl)(Ci-4 alkyl), -COOH, -C00(Ci-4 alkyl), -CONH2, -C0NH(CI-4 alkyl), -C0N(CI-4 alkyl)(Ci-4 alkyl), -NHC0(CI-4 alkyl) and -N(CI-4 alkyl)-C0(Ci-4 alkyl).

[0284] More preferably, each Rsis independently selected from C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, -(C0-3 alkylene)-OH, -(C0-3 alkylene)-0(Ci-5 alkyl), -(C0-3 alkylene)-0(Ci-5 alkylene)-OH, -(C0-3 alkylene)-0(Ci-5 alkylene)-0(Ci-5 alkyl), -(C0-3 alkylene)-SH, -(C0-3 alkylene)-S(Ci-5 alkyl), -(C0-3 alkylene)-S(Ci-5 alkylene)-SH, -(C0-3 alkylene)-S(Ci-5 alkylene)-S(Ci-5 alkyl), -(C0-3 alkylene)-NH2, -(C0-3 alkylene)-NH(Ci-s alkyl), -(C0-3 alkylene)-N(Ci-5alkyl)(Ci-5alkyl), -(C0-3 alkylene)-NH-OH, -(C0-3 alkylene)-N(Ci-5alkyl)-OH, -(C0-3 alkylene)-NH-O(Ci-5alkyl), -(C0-3 alkylene)-N(Ci-5alkyl)-O(Ci-5alkyl), -(C0-3 alkylene)-halogen, -(C0-3 alkylene)-(Ci-5 haloalkyl), -(C0-3 alkylene)-0-(Ci-5 haloalkyl), -(C0-3 alkylene)-CN, -(C0-3 alkylene)-NC>2, -(C0-3 alkylene)-CH0, -(C0-3 alkylene)-C0-(Ci-5 alkyl), -(C0-3 alkylene)-C00H, -(C0-3 alkylene)-C0-0-(Ci-5 alkyl), -(C0-3 alkylene)-0-C0-(Ci-5 alkyl), -(C0-3 alkylene)-C0-NH2, -(C0-3 alkylene)-CO-NH(Ci-5alkyl), -(C0-3 alkylene)-CO-N(Ci-5alkyl)(Ci-5 alkyl), -(C0-3 alkylene)-NH-C0-(Ci-5 alkyl), -(C0-3 alkylene)-N(Ci-s alkyl)-C0-(Ci-5 alkyl), -(C0-3 alkylene)-NH-C0-0-(Ci-5alkyl), -(C0-3 alkylene)-N(Ci-5alkyl)-C0-0-(Ci-5 alkyl), -(C0-3 alkylene)-0-C0-NH-(Ci-5alkyl), -(C0-3 alkylene)-0-C0-N(Ci-5 alkyl)-(Ci-5 alkyl), -(C0-3 alkylene)-SO2-NH2, -(C0-3 alkylene)-SO2-NH(Ci-5alkyl), -(C0-3 alkylene)-SO2-N(Ci-5 alkyl)(Ci-5 alkyl), -(C0-3 alkylene)-NH-SO2-(Ci-5 alkyl), -(C0-3 alkylene)-N(Ci-5 alkyl)-SO2-(Ci-5 alkyl), -(C0-3 alkylene)-SO2-(Ci-5 alkyl), and -(C0-3 alkylene)-S0-(Ci-5 alkyl).

[0285] Even more preferably, each Rsis independently selected from C1-5 alkyl, C2-5 alkenyl, C2-5 alky nyl, -(C0-3 alkylene)-OH, -(C0-3 alkylene)-0(Ci-5 alkyl), -(C0-3 alkylene)-SH, -(C0-3 alkylene)-NH2, -(C0-3 alkylene)-NH(Ci 5 alkyl), -(C0-3 alkylene)-N(Ci-5alkyl)(Ci-5 alkyl), -(C0-3 alkylene)-NH-OH, -(C0-3 alkylene)-N(Ci-5alkyl)-OH, -(C0-3 alkylene)-NH-O(Ci-5alkyl), -(C0-3 alkylene)-N(Ci-s alkyl)-0(Ci-5 alkyl), -(C0-3 alkylene)-halogen, -(C0-3 alkylene)-(Ci-5 haloalkyl), and -(C0-3 alkylene)-0-(Ci-5 haloalkyl), preferably each R1is independently selected from C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, -(C0-3 alkylene)-OH, -(C0-3 alkylene)-0(Ci-5 alkyl), -(C0-3 alkylene)-SH, -(C0-3 alkylene)-NH2, -(C0-3 alkylene)-NH(Ci 5 alkyl), -(C0-3 alkylene)-N(Ci-5alkyl)(Ci-5alkyl), -(C0-3 alkylene)-NH-OH, -(C0-3 alkylene)-N(Ci 5 alkyl)-OH, -(C0-3 alkylene)-NH-O(Ci-5alkyl), -(C0-3 alkylene)-N(Ci-s alkyl)-O(Ci-5alkyl), and -(C0-3 alkylene)-halogen.

[0286] Even more preferably, each Rsis independently selected from C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, -OH, -0(Ci-5 alkyl), -SH, -NH2, -NH(CI-5 alkyl), -N(CI-5 alkyl)(Ci-5 alkyl), -NH-OH, -N(CI-5 alkyl)-OH, -NH-0(CI-5 alkyl), -N(CI-5 alkyl)-O(Ci 5 alkyl), C1-5 haloalkyl and halogen, preferably each R1is independently selected from C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, -OH, -0(Ci-5 alkyl), -SH, -NH2, -NH(CI-5 alkyl), -N(CI-5 alkyl)(Ci-5 alkyl), -NH-OH, -N(CI-5 alkyl)-OH, -NH-0(CI-5 alkyl), -N(CI-5 alkyl)-0(Ci-5 alkyl), and halogen.

[0287] Even more preferably, each Rsis independently selected from -OH and halogen.

[0288] Particularly suitable compounds of formula (I) are selected from the following compounds, or their pharmaceutically acceptable salts:

[0289] In one embodiment, particularly suitable compound of formula (I) is

[0290] In one embodiment, particularly suitable compound of formula (I)

[0291] In one embodiment, particularly suitable compound of formula (I) is its pharmaceutically acceptable salt. In one embodiment, particularly suitable compound of formula (I) is In one embodiment, particularly suitable compound of formula (I) is

[0292] As further provided herein, particularly preferred is a compound selected from: N-((S,E)-1 -cyclopropyl-3-((R)-S-methylsulfonimidoyl)allyl)-2-(1 ,1 -difluoroethyl)-4- phenoxypyrimidine-5-carboxamide, N-((S,E)-1-cyclopropyl-3-((S)-S-methylsulfonimidoyl)allyl)-2-(1 ,1- difluoroethyl)-4-phenoxypyrimidine-5-carboxamide, N-((R,E)-1-cyclopropyl-3-((R)-S- methylsulfonimidoyl)allyl)-2-(1 ,1 -difluoroethyl)-4-phenoxypyrimidine-5-carboxamide, and N-((R,E)-1 - cyclopropyl-3-((S)-S-methylsulfonimidoyl)allyl)-2-(1 , 1 -difluoroethyl)-4-phenoxypyrimidine-5-carboxamide, characterized by the highest retention time of these compounds in an SFC experiment according to method 13 (SFC method 13), or a pharmaceutically acceptable salt thereof. Accordingly, particularly suitable is the compound described as compound 32d, i.e., the compound of formula: as defined in the foregoing.

[0293] As further provided herein, particularly preferred is a compound selected from:

[0294] N-((S,E)-1 -cyclopropyl-3-((R)-N,S-dimethylsulfonimidoyl)allyl)-2-(1 , 1-difluoroethyl)-4- phenoxypyrimidine-5-carboxamide, N-((S,E)-1-cyclopropyl-3-((S)-N,S-dimethylsulfonimidoyl)allyl)-2-(1 ,1- difluoroethyl)-4-phenoxypyrimidine-5-carboxamide, N-((R,E)-1-cyclopropyl-3-((R)-N,S- dimethylsulfonimidoyl)allyl)-2-(1 ,1 -difluoroethyl)-4-phenoxypyrimidine-5-carboxamide, and N-((R,E)-1- cyclopropyl-3-((S)-N,S-dimethylsulfonimidoyl)allyl)-2-(1 ,1 -difluoroethyl)-4-phenoxypyrimidine-5- carboxamide, characterized by the second highest retention time of these compounds in an SFC experiment according to method 14 (SFC method 14). Accordingly, particularly suitable is a compound described as 33c, i.e., the compound of formula: as defined in the foregoing.

[0295] Alternatively, particularly preferred is a compound selected from:

[0296] N-((S,E)-1 -cyclopropyl-3-((R)-N,S-dimethylsulfonimidoyl)allyl)-2-(1 , 1-difluoroethyl)-4- phenoxypyrimidine-5-carboxamide, N-((S,E)-1-cyclopropyl-3-((S)-N,S-dimethylsulfonimidoyl)allyl)-2-(1 ,1- difluoroethyl)-4-phenoxypyrimidine-5-carboxamide, N-((R,E)-1-cyclopropyl-3-((R)-N,S- dimethylsulfonimidoyl)allyl)-2-(1 ,1 -difluoroethyl)-4-phenoxypyrimidine-5-carboxamide, and N-((R,E)-1- cyclopropyl-3-((S)-N,S-dimethylsulfonimidoyl)allyl)-2-(1 ,1 -difluoroethyl)-4-phenoxypyrimidine-5- carboxamide, characterized by the highest retention time of these compounds in an SFC experiment according to method 14 (SFC method 14). Accordingly, particularly suitable is a compound described as 33d, i.e., the compound of formula: as defined in the foregoing.

[0297] Further preferred compounds according to the present invention are selected from the following compounds and their pharmaceutically acceptable salts:

[0298]

[0299] Further particularly preferred compounds according to the present invention are selected from the following compounds or their pharmaceutically acceptable salts: or a pharmaceutically acceptable salt thereof.

[0300] Further particular preferred compound is a compound of formula: or a pharmaceutically acceptable salt thereof. For a number of compounds disclosed herein, enantiomeric forms may exist. The present invention further refers to each and every enantiomeric form of such compound individually.

[0301] In the following, pharmaceutical formulations, medical uses and synthesis of the compounds of the invention are discussed. It is to be understood that any reference to a compound of formula (I), unless indicated explicitly to the contrary, also encompasses a direct and specific reference to a compound of formula (II).

[0302] The present invention also relates to each of the intermediates described further below in the examples section of this specification, including any one of these intermediates in non-salt form or in the form of a salt (e.g., a pharmaceutically acceptable salt) of the respective compound. Such intermediates can be used, in particular, in the synthesis of the compounds of formula (I).

[0303] The scope of the invention embraces all pharmaceutically acceptable salt forms of the compounds of formula (I) which may be formed, e.g., by protonation of an atom carrying an electron lone pair which is susceptible to protonation, such as an amino group, with an inorganic or organic acid, or as a salt of an acid group (such as a carboxylic acid group) with a physiologically acceptable cation. Exemplary base addition salts comprise, for example: alkali metal salts such as sodium or potassium salts; alkaline earth metal salts such as calcium or magnesium salts; zinc salts; ammonium salts; aliphatic amine salts such as trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, procaine salts, meglumine salts, ethylenediamine salts, or choline salts; aralkyl amine salts such as N,N- dibenzylethylenediamine salts, benzathine salts, benethamine salts; heterocyclic aromatic amine salts such as pyridine salts, picoline salts, quinoline salts or isoquinoline salts; quaternary ammonium salts such as tetramethylammonium salts, tetraethylammonium salts, benzyltrimethylammonium salts, benzyltriethylammonium salts, benzyltri butylammonium salts, methyltrioctylammonium salts or tetrabutylammonium salts; and basic amino acid salts such as arginine salts, lysine salts, or histidine salts. Exemplary acid addition salts comprise, for example: mineral acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate salts (such as, e.g., sulfate or hydrogensulfate salts), nitrate salts, phosphate salts (such as, e.g., phosphate, hydrogenphosphate, or dihydrogenphosphate salts), carbonate salts, hydrogencarbonate salts, perchlorate salts, borate salts, or thiocyanate salts; organic acid salts such as acetate, propionate, butyrate, pentanoate, hexanoate, heptanoate, octanoate, cyclopentanepropionate, decanoate, undecanoate, oleate, stearate, lactate, maleate, oxalate, fumarate, tartrate, malate, citrate, succinate, adipate, gluconate, glycolate, nicotinate, benzoate, salicylate, ascorbate, pamoate (embonate), camphorate, glucoheptanoate, or pivalate salts; sulfonate salts such as methanesulfonate (mesylate), ethanesulfonate (esylate), 2-hydroxyethanesulfonate (isethionate), benzenesulfonate (besylate), p-toluenesulfonate (tosylate), 2-naphthalenesulfonate (napsylate), 3-phenylsulfonate, or camphorsulfonate salts; glycerophosphate salts; and acidic amino acid salts such as aspartate or glutamate salts. Preferred pharmaceutically acceptable salts of the compounds of formula (I) include a hydrochloride salt, a hydrobromide salt, a mesylate salt, a sulfate salt, a tartrate salt, a fumarate salt, an acetate salt, a citrate salt, and a phosphate salt. A particularly preferred pharmaceutically acceptable salt of the compound of formula (I) is a hydrochloride salt. Accordingly, it is preferred that the compound of formula (I), including any one of the specific compounds of formula (I) described herein, is in the form of a hydrochloride salt, a hydrobromide salt, a mesylate salt, a sulfate salt, a tartrate salt, a fumarate salt, an acetate salt, a citrate salt, or a phosphate salt, and it is particularly preferred that the compound of formula (I) is in the form of a hydrochloride salt.

[0304] The present invention also specifically relates to the compound of formula (I), including any one of the specific compounds of formula (I) described herein, in non-salt form.

[0305] Moreover, the scope of the invention embraces the compounds of formula (I) in any solvated form, including, e.g., solvates with water (i.e., as a hydrate) or solvates with organic solvents such as, e.g., methanol, ethanol, isopropanol, acetic acid, ethyl acetate, ethanolamine, DMSO, or acetonitrile. All physical forms, including any amorphous or crystalline forms (i.e., polymorphs), of the compounds of formula (I) are also encompassed within the scope of the invention. It is to be understood that such solvates and physical forms of pharmaceutically acceptable salts of the compounds of the formula (I) are likewise embraced by the invention.

[0306] Furthermore, the compounds of formula (I) may exist in the form of different isomers, in particular stereoisomers (including, e.g., geometric isomers (or cis / trans isomers), enantiomers and diastereomers) or tautomers (including, in particular, prototropic tautomers, such as keto / enol tautomers or thione / thiol tautomers). All such isomers of the compounds of formula (I) are contemplated as being part of the present invention, either in admixture or in pure or substantially pure form. As for stereoisomers, the invention embraces the isolated optical isomers of the compounds according to the invention as well as any mixtures thereof (including, in particular, racemic mixtures / racemates). The racemates can be resolved by physical methods, such as, e.g., fractional crystallization, separation or crystallization of diastereomeric derivatives, or separation by chiral column chromatography. The individual optical isomers can also be obtained from the racemates via salt formation with an optically active acid followed by crystallization. The present invention further encompasses any tautomers of the compounds of formula (I). It will be understood that some compounds may exhibit tautomerism. In such cases, the formulae provided herein expressly depict only one of the possible tautomeric forms. The formulae and chemical names as provided herein are intended to encompass any tautomeric form of the corresponding compound and not to be limited merely to the specific tautomeric form depicted by the drawing or identified by the name of the compound.

[0307] The scope of the invention also embraces compounds of formula (I), in which one or more atoms are replaced by a specific isotope of the corresponding atom. For example, the invention encompasses compounds of formula (I), in which one or more hydrogen atoms (or, e.g., all hydrogen atoms) are replaced by deuterium atoms (i.e.,2H; also referred to as “D”). Accordingly, the invention also embraces compounds of formula (I) which are enriched in deuterium. Naturally occurring hydrogen is an isotopic mixture comprising about 99.98 mol-% hydrogen-1 (1H) and about 0.0156 mol-% deuterium (2H or D). The content of deuterium in one or more hydrogen positions in the compounds of formula (I) can be increased using deuteration techniques known in the art. For example, a compound of formula (I) or a reactant or precursor to be used in the synthesis of the compound of formula (I) can be subjected to an H / D exchange reaction using, e.g., heavy water (D2O). Further suitable deuteration techniques are described in: Atzrodt J et al., Bioorg Med Chem, 20(18), 5658-5667, 2012; William JS et al., Journal of Labelled Compounds and Radiopharmaceuticals, 53(11-12), 635-644, 2010; Modvig A et al., J Org Chem, 79, 5861-5868, 2014. The content of deuterium can be determined, e.g., using mass spectrometry or NMR spectroscopy. Unless specifically indicated otherwise, it is preferred that the compound of formula (I) is not enriched in deuterium. Accordingly, the presence of naturally occurring hydrogen atoms or1H hydrogen atoms in the compounds of formula (I) is preferred.

[0308] The present invention also embraces compounds of formula (I), in which one or more atoms are replaced by a positron-emitting isotope of the corresponding atom, such as, e.g.,18F,11C,13N,150,76Br,77Br,120l and / or124l. Such compounds can be used as tracers, trackers or imaging probes in positron emission tomography (PET). The invention thus includes (i) compounds of formula (I), in which one or more fluorine atoms (or, e.g., all fluorine atoms) are replaced by18F atoms, (ii) compounds of formula (I), in which one or more carbon atoms (or, e.g., all carbon atoms) are replaced by11C atoms, (iii) compounds of formula (I), in which one or more nitrogen atoms (or, e.g., all nitrogen atoms) are replaced by13N atoms, (iv) compounds of formula (I), in which one or more oxygen atoms (or, e.g., all oxygen atoms) are replaced by15O atoms, (v) compounds of formula (I), in which one or more bromine atoms (or, e.g., all bromine atoms) are replaced by76Br atoms, (vi) compounds of formula (I), in which one or more bromine atoms (or, e.g., all bromine atoms) are replaced by77Br atoms, (vii) compounds of formula (I), in which one or more iodine atoms (or, e.g., all iodine atoms) are replaced by120l atoms, and (viii) compounds of formula (I), in which one or more iodine atoms (or, e.g., all iodine atoms) are replaced by124l atoms. In general, it is preferred that none of the atoms in the compounds of formula (I) are replaced by specific isotopes.

[0309] The present invention further embraces the prodrugs of the compounds of formula (I). As preferably understood herein, the term “prodrug” of the compound of formula (I) refers to a derivative of the compounds of formula (I) that upon administration to a subject becomes metabolized to the said compound of formula (I). Said prodrugs of the compound of formula (I) may include modifications of -OH, -NH2, or -COOH group if present in the compound of formula (I), which preferably can be hydrolyzed to - OH, -NH2, or -COOH groups, respectively, e.g. upon administration to the subject. For example, as known to the skilled person, such prodrugs may preferably include for the compounds of formula (I) which comprise -OH moiety derivatives wherein said -OH moiety is turned into an -ORx moiety, wherein Rxpreferably comprises a moiety selected from -CO-, -CH2-O-CO, -CH2-O-CO-O-, and -CH(CH3)-O-COO-, more preferably wherein Rxis selected from -CO-Ry, -CH2-0-C0-Ry, -CH2-0-C0-0-Ry, and -CH(CH3)-0- COO-Ry, wherein Ryis preferably carbocyclyl, heterocyclyl, C1-5 alkyl, -NH-(CI-5 alkyl) or -S-(Ci-5 alkyl), wherein the said alkyl is optionally substituted with a group selected from halogen, -CN, -OH, C1-5 alkyl, C1-5 haloalkyl, -0(Ci-5 alkyl), -0(Ci-5 haloalkyl), -SH, -S(Ci-5 alkyl), -S(Ci-5 haloalkyl), -NH2, -NH(Ci-s alkyl), -NH(CI-5 haloalkyl), -N(CI-5 alkyl)(Ci-5 alkyl), -N(CI-5haloalkyl)(Ci-5 alkyl), -CONH2, -C0NH(CI-5alkyl), and -CON(Ci-s alkyl)(Ci 5 alkyl), and wherein the said carbocyclyl and heterocyclyl are each optionally substituted with a group selected from halogen, -CN, -OH, C1-5 alkyl, C1-5 haloalkyl, -0(Ci-5 alkyl), -0(Ci-5 haloalkyl), -SH, -S(Ci-5 alkyl), -S(Ci-5haloalkyl), -NH2, -NH(CI-5alkyl), -NH(CI-5 haloalkyl), -N(CI-5 alkyl)(Ci-5 alkyl), -N(CI-5 haloalkyl)(Ci-5 alkyl), -CONH2, -C0NH(CI-5alkyl), and -C0N(CI-5 alkyl)(Ci 5 alkyl). Furthermore, for example, as known to the skilled person, such prodrugs may preferably include for the compounds of formula (I) which comprise -NH2 moiety derivatives wherein said -NH2 moiety is turned into -NHC00-Rymoiety, wherein Ryis as defined hereinabove. Furthermore, for examples, as known to the skilled person, such prodrugs may preferably include for the compounds of formula (I) which comprise -C00H moiety derivatives wherein said -C00H group is turned into -C00Rymoiety, wherein Ryis as defined hereinabove. Further examples of groups that can be derivatized to yield prodrugs are known to the skilled person.

[0310] Pharmaceutical compositions

[0311] The compounds provided herein may be administered as compounds perse or may be formulated as medicaments. The medicaments / pharmaceutical compositions may optionally comprise one or more pharmaceutically acceptable excipients, such as carriers, diluents, fillers, disintegrants, lubricating agents, binders, colorants, pigments, stabilizers, preservatives, antioxidants, and / or solubility enhancers.

[0312] The pharmaceutical compositions may comprise one or more solubility enhancers, such as, e.g., polyfethylene glycol), including polyfethylene glycol) having a molecular weight in the range of about 200 to about 5,000 Da (e.g., PEG 200, PEG 300, PEG 400, or PEG 600), ethylene glycol, propylene glycol, glycerol, a non-ionic surfactant, tyloxapol, polysorbate 80, macrogol-15-hydroxystearate (e.g., Kolliphor® HS 15, CAS 70142-34-6), a phospholipid, lecithin, dimyristoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine, distearoyl phosphatidylcholine, a cyclodextrin, a-cyclodextrin, p-cyclodextrin, y- cyclodextrin, hydroxyethyl-p-cyclodextrin, hydroxypropyl-p-cyclodextrin, hydroxyethyl-y-cyclodextrin, hydroxypropyl-y-cyclodextrin, dihydroxypropyl-p-cyclodextrin, sulfobutylether-p-cyclodextrin, sulfobutylether-Y-cyclodextrin, glucosyl-a-cyclodextrin, glucosyl-p-cyclodextrin, diglucosyl-p-cyclodextrin, maltosyl-a-cyclodextrin, maltosyl-p-cyclodextrin, maltosyl-y-cyclodextrin, maltotriosyl-p-cyclodextrin, maltotriosyl-y-cyclodextrin, dimaltosyl-p-cyclodextrin, methyl-p-cyclodextrin, a carboxyalkyl thioether, hydroxypropyl methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, a vinyl acetate copolymer, vinyl pyrrolidone, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, or any combination thereof. The pharmaceutical compositions may also comprise one or more preservatives, particularly one or more antimicrobial preservatives, such as, e.g., benzyl alcohol, chlorobutanol, 2-ethoxyethanol, m-cresol, chlorocresol (e.g., 2-chloro-3-methyl-phenol or 4-chloro-3-methyl-phenol), benzalkonium chloride, benzethonium chloride, benzoic acid (or a pharmaceutically acceptable salt thereof), sorbic acid (or a pharmaceutically acceptable salt thereof), chlorhexidine, thimerosal, or any combination thereof.

[0313] The pharmaceutical compositions can be formulated by techniques known to the person skilled in the art, such as the techniques published in “Remington: The Science and Practice of Pharmacy”, Pharmaceutical Press, 22ndedition. The pharmaceutical compositions can be formulated as dosage forms for oral, parenteral, such as intramuscular, intravenous, subcutaneous, intradermal, intraarterial, intracardial, rectal, nasal, topical, aerosol or vaginal administration. Dosage forms for oral administration include coated and uncoated tablets, soft gelatin capsules, hard gelatin capsules, lozenges, troches, solutions, emulsions, suspensions, syrups, elixirs, powders and granules for reconstitution, dispersible powders and granules, medicated gums, chewing tablets and effervescent tablets. Dosage forms for parenteral administration include solutions, emulsions, suspensions, dispersions and powders and granules for reconstitution. Emulsions are a preferred dosage form for parenteral administration. Dosage forms for rectal and vaginal administration include suppositories and ovula. Dosage forms for nasal administration can be administered via inhalation and insufflation, for example by a metered inhaler. Dosage forms for topical administration include creams, gels, ointments, salves, patches and transdermal delivery systems.

[0314] The compounds of formula (I) or the above described pharmaceutical compositions comprising a compound of formula (I) may be administered to a subject by any convenient route of administration, whether systemically / peripherally or at the site of desired action, including but not limited to one or more of: oral (e.g., as a tablet, capsule, or as an ingestible solution), topical (e.g., transdermal, intranasal, ocular, buccal, and sublingual), parenteral (e.g., using injection techniques or infusion techniques, and including, for example, by injection, e.g., subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, or intrasternal by, e.g., implant of a depot, for example, subcutaneously or intramuscularly), pulmonary (e.g., by inhalation or insufflation therapy using, e.g., an aerosol, e.g., through mouth or nose), gastrointestinal, intrauterine, intraocular, subcutaneous, ophthalmic (including intravitreal or intracameral), rectal, or vaginal administration.

[0315] If said compounds or pharmaceutical compositions are administered parenterally, then examples of such administration include one or more of: intravenously, intraarterially, intraperitoneally, intrathecally, intraventricularly, intraurethrally, intrasternally, intracardially, intracranially, intramuscularly or subcutaneously administering the compounds or pharmaceutical compositions, and / or by using infusion techniques. For parenteral administration, the compounds are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood. The aqueous solutions should be suitably buffered (preferably to a pH of from 3 to 9), if necessary. The preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.

[0316] Said compounds or pharmaceutical compositions can also be administered orally in the form of tablets, capsules, ovules, elixirs, solutions or suspensions, which may contain flavoring or coloring agents, for immediate-, delayed-, modified-, sustained-, pulsed- or controlled-release applications.

[0317] The tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine, disintegrants such as starch (preferably corn, potato or tapioca starch), sodium starch glycolate, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included. Solid compositions of a similar type may also be employed as fillers in gelatin capsules. Preferred excipients in this regard include lactose, starch, a cellulose, or high molecular weight polyethylene glycols. For aqueous suspensions and / or elixirs, the agent may be combined with various sweetening or flavoring agents, coloring matter or dyes, with emulsifying and / or suspending agents and with diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof.

[0318] For oral administration, the compounds or pharmaceutical compositions are preferably administered by oral ingestion, particularly by swallowing. The compounds or pharmaceutical compositions can thus be administered to pass through the mouth into the gastrointestinal tract, which can also be referred to as “oral-gastrointestinal” administration.

[0319] Alternatively, said compounds or pharmaceutical compositions can be administered in the form of a suppository or pessary, or may be applied topically in the form of a gel, hydrogel, lotion, solution, cream, ointment or dusting powder. The compounds of the present invention may also be dermally or transdermally administered, for example, by the use of a skin patch.

[0320] Said compounds or pharmaceutical compositions may also be administered by sustained release systems. Suitable examples of sustained-release compositions include semi-permeable polymer matrices in the form of shaped articles, e.g., films, or microcapsules. Sustained-release matrices include, e.g., polylactides, copolymers of L-glutamic acid and gamma-ethyl-L-glutamate, poly(2-hydroxyethyl methacrylate), ethylene vinyl acetate, or poly-D-(— )-3-hydroxybutyric acid. Sustained-release pharmaceutical compositions also include liposomally entrapped compounds. The present invention thus also relates to liposomes containing a compound of the invention. Said compounds or pharmaceutical compositions may also be administered by the pulmonary route, rectal routes, or the ocular route. For ophthalmic use, they can be formulated as micronized suspensions in isotonic, pH adjusted, sterile saline, or, preferably, as solutions in isotonic, pH adjusted, sterile saline, optionally in combination with a preservative such as a benzalkonium chloride. Alternatively, they may be formulated in an ointment such as petrolatum.

[0321] It is also envisaged to prepare dry powder formulations of the compounds of formula (I) for pulmonary administration, particularly inhalation. Such dry powders may be prepared by spray drying under conditions which result in a substantially amorphous glassy or a substantially crystalline bioactive powder. Accordingly, dry powders of the compounds of the present invention can be made according to an emulsification / spray drying process.

[0322] For topical application to the skin, said compounds or pharmaceutical compositions can be formulated as a suitable ointment containing the active compound suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, emulsifying wax and water. Alternatively, they can be formulated as a suitable lotion or cream, suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, 2-octyldodecanol, benzyl alcohol and water.

[0323] The present invention thus relates to the compounds or the pharmaceutical compositions provided herein, wherein the corresponding compound or pharmaceutical composition is to be administered by any one of: an oral route; topical route, including by transdermal, intranasal, ocular, buccal, or sublingual route; parenteral route using injection techniques or infusion techniques, including by subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, intrasternal, intraventricular, intraurethral, or intracranial route; pulmonary route, including by inhalation or insufflation therapy; gastrointestinal route; intrauterine route; intraocular route; subcutaneous route; ophthalmic route, including by intravitreal, or intracameral route; rectal route; or vaginal route. Preferred routes of administration are oral administration or parenteral administration. For each of the compounds or pharmaceutical compositions provided herein, it is particularly preferred that the respective compound or pharmaceutical composition is to be administered orally (particularly by oral ingestion).

[0324] Typically, a physician will determine the actual dosage which will be most suitable for an individual subject. The specific dose level and frequency of dosage for any particular individual subject may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the individual subject undergoing therapy.

[0325] A proposed, yet non-limiting dose of the compounds according to the invention for oral administration to a human (of approximately 70 kg body weight) may be 0.05 to 2000 mg, preferably 0.1 mg to 1000 mg, of the active ingredient per unit dose. The unit dose may be administered, e.g., 1 to 3 times per day. The unit dose may also be administered 1 to 7 times per week, e.g., with not more than one administration per day. It will be appreciated that it may be necessary to make routine variations to the dosage depending on the age and weight of the patient / subject as well as the severity of the condition to be treated. The precise dose and also the route of administration will ultimately be at the discretion of the attendant physician or veterinarian.

[0326] Therapeutic use

[0327] In one embodiment, the present invention relates to the compound of formula (I), or a pharmaceutically acceptable salt, or a pharmaceutical composition as defined herein for use in therapy.

[0328] The present invention provides compounds that have activity of inhibitors of Werner syndrome ATP- dependent helicase (WRN). Thus, accordingly, the present invention provides a method of inhibiting WRN enzyme activity in vitro and in vivo, said method comprising contacting a cell with an effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein.

[0329] In one embodiment, the present invention provides a method for decreasing proliferation in a proliferative cell having a microsatellite instability (MSI), comprising decreasing the helicase activity of Werner syndrome ATP-dependent helicase (WRN) in the proliferative cell. In some embodiments, decreasing the helicase activity of Werner syndrome ATP-dependent helicase (WRN) in the proliferative cell is achieved by administering a compound of Formula of (I) (or any embodiment thereof disclosed herein) or a pharmaceutically acceptable salt thereof. In some embodiments, the proliferative cell is characterized as having MSI low (MSI-L). In some embodiments, the proliferative cell is characterized as having high MSI (MSI-H), used interchangeably with MSI-high. Cells can be characterized as MSI, including MSI-L or MSI- H, or as MSS (MS-stable), according to the method known in the art (see, for example, Dudley, Jonathan C., et al., Clinical Cancer Research, 22(4): 813-820, 2016.). MSI-H is used to classify tumors as having a high frequency of MSI. A tumor can be classified as MSI, including MSI-low or MSI-high, using polymerase chain reaction (PCR) and / or immunohistochemistry (IHC) assays. As stated in Dudley et al., a tumor is classified as MSI-H by PCR if (i) there is a shift (usually downward) in the size of at least two microsatellite loci from a reference panel of five microsatellite loci in tumor relative to normal, where the reference panel can be the “Bethesda Panel,” also referred to herein as the “NCI- Reference Panel (Bethesda, 1998)”, which includes two mononucleotide loci (BAT-25 and BAT-26) and three dinucleotide loci (D2S123, D5S346, and D17S250), or alternatively, the reference panel can be Promega Corporation’s MSI Analysis System, which includes five mononucleotide loci (BAT-25, BAT-26, NR-21 , NR-24, and MONO-27); or (ii) there is a shift in the size of 30% or more microsatellite loci from a reference panel of more than five microsatellite loci in tumor relative to normal. The MSI-H phenotype is associated with germline defects in the mismatch repair genes MLH1 , MSH2, MSH6, and PMS2, and is the primary phenotype observed in tumors from patients with HNPCC / Lynch syndrome. A tumor is classified as MSI-H in IHC test if it shows a loss of protein expression for at least 1 of the above 4 mismatch repair genes. Cells can be similarly classified as MSI-H using the tests described herein for tumors.

[0330] In some embodiments, a tumor or cell is classified as MSI-H using PCR to amplify the five microsatellite loci of the “Bethesda Panel” (BAT-25, BAT-26, D2S123, D5S346, and D17S250) from both tumor tissue or cells and normal tissue or cells, wherein the tumor or cell is classified as MSI-H if there is a shift in the size of at least two of the microsatellite loci from the tumor tissue or cells relative to the normal tissue or cells. In some embodiments, the shift in size of the microsatellite loci is a downward shift.

[0331] In some embodiments, a tumor or cell is classified as MSI-H using PCR to amplify the five microsatellite loci of Promega Corporation’s MSI Analysis System (BAT-25, BAT-26, NR- 21 , NR-24, and MONO-27) from both tumor tissue or cells and normal tissue or cells, wherein the tumor or cell is classified as MSI-H if there is a shift in the size of at least two of the microsatellite loci from the tumor tissue or cells relative to the normal tissue or cells. In some embodiments, the shift in size of the microsatellite loci is a downward shift.

[0332] In some embodiments, a tumor is classified as MSI-H using IHC to determine the expression level of the MMR proteins MLH1 , MSH2, MSH6, and / or PMS2 in both tumor tissue and normal tissue, wherein the tumor is classified as MSI-H if there is a loss of protein expression for at least one of the MMR proteins in the tumor tissue relative to the normal tissue. In some embodiments, the loss of protein expression is a decrease of at least 20% (such as a decrease of 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or more).

[0333] In contrast, a tumor is classified as MSI-L by PCR if (i) there is a shift in the size of one microsatellite locus from a reference panel of five microsatellite loci in tumor relative to normal, where the reference panel can be the “Bethesda Panel” or Promega Corporation’s MSI Analysis System; or (ii) there is a shift in the size of less than 30% microsatellite loci from a reference panel of more than five microsatellite loci in tumor relative to normal. MSI-L tumors are thought to represent a distinct mutator phenotype with potentially different molecular etiology than MSI-H tumors (Thibodeau, 1998; Wu et al., 1999, Am J Hum Genetics 65: 1291-1298). Cells can be similarly classified as MSI-L using the tests described herein for tumors.

[0334] Cancers classified as MSI-H include, but not limited to, uterine corpus endometrial carcinoma, colon adenocarcinoma, stomach adenocarcinoma, rectal adenocarcinoma, adenoid cystic carcinoma, uterine carcinosarcoma, cervical squamous cell carcinoma, and endocervical adenocarcinoma. In one embodiment, the present invention relates to a method for treating a cancer treatable by inhibition of WRN in a subject in need thereof, the method comprising the step of administering to the subject the compound of formula (I) or a pharmaceutically acceptable salt thereof. It is to be understood that, typically, a therapeutically effective amount is to be administered.

[0335] In one embodiment, the present invention relates to a method for treating a cancer characterized by MSI-H and / or dMMR in a subject in need thereof, the method comprising the step of administering to the subject the compound of formula (I) or a pharmaceutically acceptable salt thereof. It is to be understood that, typically, a therapeutically effective amount is to be administered.

[0336] In one embodiment, the present invention relates to use of a compound of formula (I) or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer. Preferably, the cancer is treatable by inhibition of WRN. In one embodiment, the cancer is characterized by MSI-H and / or dMMR.

[0337] In one embodiment, the present invention relates to the compound of formula (I) or a pharmaceutically acceptable salt thereof, for use in treating cancer. Preferably, the cancer is treatable by inhibition of WRN. In one embodiment, the cancer is characterized by MSI-H and / or dMMR.

[0338] The cancer to be treated in accordance with the present invention may be a solid cancer or a hematological cancer. Preferably, the cancer is selected from lung cancer (e.g., small cell lung cancer, non-small cell lung cancer, large cell lung carcinoma, lung adenocarcinoma, including also lung adenocarcinoma with EGFR mutation AE746-A750, or squamous cell carcinoma of the lung), renal cancer (or kidney cancer; e.g., renal carcinoma), gastrointestinal cancer, stomach cancer, colorectal cancer (e.g., colorectal carcinoma), colon cancer, anal cancer, genitourinary cancer, bladder cancer, liver cancer (e.g., hepatocellular carcinoma), pancreatic cancer (e.g., pancreatic adenocarcinoma or pancreatic ductal adenocarcinoma), cervical cancer, endometrial cancer, vaginal cancer, vulvar cancer, ovarian cancer (e.g., ovarian carcinoma), uterine cancer, prostate cancer (e.g., hormone-refractory prostate cancer), testicular cancer, biliary tract cancer, hepatobiliary cancer, neuroblastoma, brain cancer (e.g., glioblastoma), breast cancer (e.g., triple-negative breast cancer, breast cancer having a BRCA1 and / or BRCA2 gene mutation, or breast adenocarcinoma), head and / or neck cancer (e.g., head and neck squamous cell carcinoma), skin cancer, melanoma, Merkel-cell cancer (e.g., Merkel-cell carcinoma), epidermoid cancer, squamous cell cancer (or squamous cell carcinoma; including, e.g., oral squamous cell carcinoma / squamous-cell mouth carcinoma, squamous-cell skin cancer, squamous-cell lung carcinoma, squamous-cell thyroid carcinoma, squamous-cell esophageal carcinoma, or squamous-cell vaginal carcinoma), bone cancer (e.g., osteosarcoma or osteogenic sarcoma), fibrosarcoma, Ewing’s sarcoma, malignant mesothelioma, esophageal cancer, laryngeal cancer, mouth cancer, thymoma, neuroendocrine cancer (e.g., neuroendocrine carcinoma), goblet cell cancer (e.g., goblet cell carcinoid), hematological cancer, leukemia (e.g., acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, or chronic myeloid leukemia), lymphoma (e.g., Hodgkin lymphoma or non-Hodgkin lymphoma, such as, e.g., follicular lymphoma or diffuse large B-cell lymphoma), and multiple myeloma. Moreover, the cancer to be treated (including any one of the aforementioned specific types of cancer) may also be a chemoresistant and / or a metastatic cancer.

[0339] The antiproliferative treatment (i.e. the treatment of cancer) with the compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined hereinbefore, may be applied as a sole therapy or may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy. Such chemotherapy may include one or more of the following categories of anti-tumour agents:-

[0340] (i) other antiproliferative / antineoplastic drugs and combinations thereof, as used in medical oncology, such as alkylating agents (for example cis-platin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan, temozolamide and nitrosoureas); antimetabolites (for example gemcitabine and antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, and hydroxyurea); antitumour antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and taxoids like taxol and taxotere and polokinase inhibitors); and topoisomerase inhibitors (for example epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan and camptothecin);

[0341] (ii) cytostatic agents such as antioestrogens (for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestagens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5oc-reductase such as finasteride;

[0342] (iii) anti-invasion agents [for example c-Src kinase family inhibitors like 4-(6-chloro-2,3- methylenedioxyanilino)-7-[2-(4-methylpiperazin-1 -yl)ethoxy]-5-tetrahydropyran-4- yloxyquinazoline (AZD0530; International Patent Application WO 01 / 94341 ), N-(2-chloro-6- methylphenyl)-2-{6-[4-(2- hydroxyethyl)piperazin-1 -yl]-2-methylpyrimidin-4-ylamino}thiazole- 5-carboxamide (dasatinib, BMS- 354825; J. Med. Chem., 2004, 47, 6658-6661 ) and bosutinib (SKI-606), and metalloproteinase inhibitors like marimastat, inhibitors of urokinase plasminogen activator receptor function or antibodies to Heparanase];

[0343] (iv) inhibitors of growth factor function: for example such inhibitors include growth factor antibodies and growth factor receptor antibodies (for example the anti-erbB2 antibody trastuzumab [Herceptin™], the anti-EGFR antibody panitumumab, the anti-erbB1 antibody cetuximab [Erbitux, C225] and any growth factor or growth factor receptor antibodies disclosed by Stern et al. (Critical reviews in oncology / haematology, 2005, Vol. 54, pp1 1 -29); such inhibitors also include tyrosine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as N-(3-chloro- 4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib, ZD1839), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6- acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine (Cl 1033), erbB2 tyrosine kinase inhibitors such as lapatinib); inhibitors of the hepatocyte growth factor family; inhibitors of the insulin growth factor family; inhibitors of the platelet-derived growth factor family such as imatinib and / or nilotinib (AMN107); inhibitors of serine / threonine kinases (for example Ras / Raf signalling inhibitors such as farnesyl transferase inhibitors, for example sorafenib (BAY 43-9006), tipifarnib (R1 15777) and lonafarnib (SCH66336)), inhibitors of cell signalling through MEK and / or AKT kinases, c-kit inhibitors, abl kinase inhibitors, PI3 kinase inhibitors, Plt3 kinase inhibitors, CSF-1 R kinase inhibitors, IGF receptor (insulin-like growth factor) kinase inhibitors; aurora kinase inhibitors (for example AZD1 152, PH739358, VX-680, MLN8054, R763, MP235, MP529, VX-528 AND AX39459) and cyclin dependent kinase inhibitors such as CDK2 and / or CDK4 inhibitors;

[0344] (v) antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, [for example the anti-vascular endothelial cell growth factor antibody bevacizumab (Avastin™) and for example, a VEGF receptor tyrosine kinase inhibitor such as vandetanib (ZD6474), vatalanib (PTK787), sunitinib (SU1 1248), axitinib (AG-013736), pazopanib (GW 786034) and 4-(4-fluoro-2-methylindol-5- yloxy)-6-methoxy-7-(3-pyrrolidin-1 - ylpropoxy)quinazoline (AZD2171 ; Example 240 within WO 00 / 47212), compounds such as those disclosed in International Patent Applications W097 / 22596, WO 97 / 30035, WO 97 / 32856 and WO 98 / 13354 and compounds that work by other mechanisms (for example linomide, inhibitors of integrin av[33 function and angiostatin)];

[0345] (vi) vascular damaging agents such as Combretastatin A4 and compounds disclosed in International Patent Applications WO 99 / 02166, WO 00 / 40529, WO 00 / 41669, WO 01 Z92224, WO 02 / 04434 and WO 02 / 08213; (vii) an endothelin receptor antagonist, for example zibotentan (ZD4054) or atrasentan;

[0346] (viii) antisense therapies, for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense;

[0347] (ix) gene therapy approaches, including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi- drug resistance gene therapy; and

[0348] (x) immunotherapy approaches, including for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies.

[0349] In a particular embodiment, the antiproliferative treatment defined hereinbefore may involve, in addition to the compound of formula (I) of the invention, conventional surgery or radiotherapy or chemotherapy. Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment. Such combination products employ the compounds of this invention within the dosage range described hereinbefore and the other pharmaceutically-active agent within its approved dosage range.

[0350] According to this aspect the present invention further relates to the compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined herein, for use in the treatment of a cancer (for example a cancer involving a solid tumour) in combination with another anti-tumour agent. The antitumour agent is preferably selected from the anti-tumour agents as listed hereinabove.

[0351] As understood herein, the term "combination" refers to simultaneous, separate or sequential administration. In one aspect of the invention "combination" refers to simultaneous administration. In another aspect of the invention "combination" refers to separate administration. In a further aspect of the invention "combination" refers to sequential administration. Where the administration is sequential or separate, the delay in administering the second component should not be such as to lose the beneficial effect of the combination.

[0352] Examples

[0353] The following examples are merely illustrative of the present invention and should not be construed to limit the scope of the invention which is defined by the appended claims.

[0354] Synthesis of the compounds of formula (I)

[0355] The syntheses of the compounds of formula (I) according to the present invention are preferably carried out according to the general synthetic sequences as shown in Scheme 1 . In addition to said routes described below, also other routes may be used to synthesize the target compounds, in accordance with common general knowledge of a person skilled in the art of organic synthesis. The order of transformations exemplified in the following Schemes is therefore not intended to be limiting, and suitable synthesis steps from various schemes can be combined to form additional synthesis sequences. In addition, modification of any of the substituents can be achieved before and / or after the exemplified transformations. These modifications can be such as the introduction of protective groups, cleavage of protective groups, reduction or oxidation of functional groups, halogenation, metallation, metal-catalyzed coupling reactions, substitution or other reactions known to a person skilled in the art. These transformations include those which introduce a functionality allowing for further interconversion of substituents. Appropriate protective groups and their introduction and cleavage are well-known to a person skilled in the art (see for example: Greene's Protective Groups in Organic Synthesis; Editor: P.G.M. Wuts, 5th edition, Wiley 2014). Specific examples are described in the subsequent paragraphs. Further, it is possible that two or more successive steps may be performed without work-up being performed between said steps, e.g. a “one-pot” reaction, as it is well-known to a person skilled in the art. It is further understood to the skilled person that a reaction can lead to side product(s) which, when appropriate, can be used forthe preparation of compounds of formula (I) using similar procedures as reported in the general schemes hereinbelow.

[0356] Scheme 1

[0357] Y

[0358] 4

[0359] A + B-X - *- A-B-X - ► A-B-X-Y

[0360] 1 2 3 (I)

[0361] Scheme 1 illustrates a preferred synthetic approach to compounds of the general formula (I).

[0362] In the first step, compound 3 is prepared via cross-coupling reactions of suitably functionalized building blocks 1 and 2. Formation of a C-C bond between A (1) and B-X (2) can be e.g. achieved by the cross-coupling of an aryl, heteroaryl, alkyl, or vinyl boronic acid, borate ester, or borane 1 with an aryl or heteroaryl halide or tritiate 2 using a variety of palladium catalysts (Suzuki reaction; see e.g. B. S. Kadu, Catal. Sci. Technol., 2021 ,11 , 1186-1221). The formation of a carbon-carbon bond between a terminal alkyne 1 and an aryl or heteroaryl halide 2 can be achieved employing palladium catalysts as well as copper co-catalysts (Sonogashira coupling, see e.g. I. Kanwal et al, Catalysts 2020, 10(4), 443). Moreover, formation of a C-N can be achieved via the palladium-catalyzed coupling reactions of amines 1 with aryl and heteroaryl halides 2 (Buchwald-Hartwig coupling, see e.g. R. Dorel et al, Angew. Chem. Int. Ed. 2019, 58, 171 18).

[0363] In the second step, cross-coupling of A-B-X (3) and Y (4) can be achieved by various methods known of a person skilled in the art of organic synthesis, including e.g. a) coupling of carboxylic acids (3) and amines (4) (amide bond formation; see e.g. E. Massolo et al, Eur. J. Org. Chem. 2020, 4641), b) coupling of sulfonyl chlorides (3) and amines (4) (sulfonamide bond formation: see e.g. A. Kolaczek et al, CHEMIK 2014, 68, 620) or c) coupling of amines (3) and halides (4) (amine alkylation: see e.g. R. N Salvatoreet al, Tetrahedron 2001 , 7785).

[0364] Preparative examples

[0365] General considerations

[0366] Abbreviations used in the descriptions that follow are: AcOH (acetic acid); aq. (aqueous); Ar (argon); Atm (atmosphere); BH3.THF (boran tetrahydrofuran complex); br (broad,1H NMR signal); BOC2O (di-tert- butyldicarbonate); BuLi (Butyl Lithium), Cataxium APdGs (mesylate[(di(1 -adamantyl)-n-butylphosphine)- 2-(2'-amino-1 ,1'-biphenyl)]palladium(ll)); CDCh (deuterated chloroform); cHex (cyclohexane); CMPB (cyanomethylene trimethylphosphorane); CS2CO3 (cesium carbonate); Cu(OAc)2 (copper acetate); Cui (copper iodide); CuSC (cupric sulfate), DABCO (1 ,4-diazabicyclo[2.2.2]octane); DAST (diethylaminosulfur trifluoride); DBU (1 ,8-diazabicyclo(5.4.0)undec-7-ene); DCE (dichloroethane); d (doublet,1H NMR signal); DCM (dichloromethane); DEA (diethylamine); DIBAL-H (diisobutyl aluminium hydride); DIPEA or DIEA (di- / so-propylethylamine); DMA (dimethylacetamide); (DMAP (4- N-N- dimethylaminopyridine), DME (1,2-dimethoxyethane), DMEDA (dimethylethylenediamine ); DMF (N-N- dimethylformamide); DMSO (dimethyl sulfoxide); DPPA (diphenylphosphoride azide); dtbbpy (bis(1 ,1- dimethylethyl)-2,2'-bipyridine); ee (enantiomeric excess); ES (electrospray); EtOAc or EA (ethyl acetate); EtOH (ethanol); h (hour(s)); FA (formic acid); MgO (magnesium oxide); HATU (1- [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate); HBr (hydrobromic acid); HFIP ( hexafluoroisopropanol); HI (hydrogen iodide);1H NMR (proton nuclear magnetic resonance spectroscopy); HPLC (high performance liquid chromatography); iPrMgBr (isopropylmagnesium bromide); iPrOH ( / so-propanol); K2CO3 (potassium carbonate); K3PO4 (tripotassium phosphate); lr[dF(CF3)(dtbbpy)PFe ((4,4'-di-t-butyl-2,2'-bipyridine)bis[3,5-difluoro-2-[5- trifluoromethyl-2-pyridinyl-kN)phenyl-kC]iridium(lll) hexafluorophosphate); KHMDS (potassium bis(trimethylsilyl)amide); LiOH (lithium hydroxide); m (multiplet,1H NMR signal); mCPBA (mefa- chloroperoxybenzoic acid), MeCN (acetonitrile), MeOH (methanol); MeOK (potassium methanolate); min (minute(s)); MnO2 (manganese (IV) oxide); MS (mass spectrometry); MTBE (methyl ferf-butyl ether); NaBH4 (sodium borohydride); NaHCOs (sodium hydrogenocarbonate); Nal (sodium iodide); NaIC (sodium periodate); Na2COs (sodium carbonate); Na2SOs (sodium sulfite); Na2S20s (sodium thiosulfate); Na2SO4 (sodium sulfate); NCS (N-chlorosuccinimide); NH3 (ammonia); NH4CI (ammonium chloride); NiCb (nickel dichloride); NIS (N-iodosuccinimide); NMP (N-methylpyrrolidone); NMR (nuclear magnetic resonance); Pd / C (palladium on charcoal); Pd2dbas (tris(di benzylide neacetone)dipalladi um); Pd(dppf)Cl2 (1 , 1 -bis (di p henylp hosp hi no)ferroce ne dichloropalladium); Pd(PPhs)4 (tetrakis(triphenylphosphine) palladium (0)); Pd(PPh3)2Cl2 (bis(triphenylphosphine)palladium(l I) dichloride ); PE (petroleum ether); Pd- PEPPSI-IPentCI o-picoline ([1 ,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-imidazol-2-ylidene]- dichloro-(2-methylpyridin-1 -ium-1 -yl)palladium; Pd(0H)2 (palladium hydroxide); Pd(PPh3)4 (palladium- tetrakis(triphenylphosphine)); Phl(0Ac)2 ((diacetoxyiodo)benzene)); P(tBu)3 (tri-tert-butylphosphine ); Py (pyridine); q (quartet, 1 H NMR signal); quin (quintet, 1 H NMR signal); rac (racemic); RT (retention time); s (singlet,1H NMR signal); sat. (saturated); t (triplet,1H NMR signal); SFC (supercritical fluid chromatography); TBAF (tetrabutylammonium fluoride); ferf-BuBrettPhos-Pd-G3 ([(2-di-ferf- butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1 ,1 '-biphenyl)-2-(2'-amino-1 ,1 '-biphenyl)]palladium(ll) methanesulfonate); tBuXPhos Pd G3 (methanesulfonato(2-di-t-butylphosphino-2',4',6'-tri-i-propyl-1 ,1 biphenyl)(2'-amino-1 ,1'-biphenyl-2-yl)palladium(ll)); TBDMSCI orTBSCI (tert-butyldimethylsilyl chloride); tBuOH (tert-butanol); TEA (triethylamine); TFA (trifluoroacetic acid); TFAA (trifluoroacetic anhydride); THF (tetrahydrofuran); TLC (thin layer chromatography); TMSCHN2 (trimethylsilyldiazomethane); TMSCN (trimethylsilyl cyanide); TMSI (trimethylsilyl iodide); TMSOTf (trimethylsilyl trifluoromethanesulfonate); TTMSS (trimethylsilane); TsOH (p-Toluenesulfonic acid); T4P (2,4,6-tri butyl- 1 ,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide); UPLC (ultra-high performance liquid chromatography), UV (ultraviolet), wt-% (percent by weight); Xantphos (4,5-bis(diphenylphosphino)-9,9- dimethylxanthene); Xantphos Pd G4 (methanesulfonato[9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene](2'-methylamino-1 ,1'-biphenyl-2-yl)palladium(ll)), Xphos (2- Dicyclohexylphosphin-2',4',6'-triisopropylbiphenyl).

[0367] General Procedure: All starting materials and solvents were obtained either from commercial sources or prepared according to literature references. Commercially available reagents and anhydrous solvents were used as supplied, without further purification. Unless otherwise stated all reactions were stirred. Organic solutions were routinely dried over anhydrous sodium sulfate. Column chromatography was performed on pre-packed silica (100-1000 mesh, 40-63 pm) cartridges using the amount indicated. All air- and moisture-sensitive reactions were carried out in oven-dried (at 120 °C) glassware under an inert atmosphere of nitrogen or argon. Compound names were generated using ChemDraw Professional (Perkin Elmer, Version 16.0.1.4 (77)) or BIOVIA draw (version 17.2 SP1.NET). In some cases generally accepted names of commercially available reagents were used in place of ChemDraw generated names.

[0368] Methods for Reversed Phase HPLC conditions for LCMS Analysis of compounds:

[0369] Method 1 : SHIMADZU LCMS-2020 Kinetex EVO C18 2.1X30mm, 5pm at 50°C; Mobile Phase: A: 0.0375% TFA in water (v / v); B: 0.01875% TFA in MeCN (v / v); flow rate held at 1.5 mL / min; eluted with the mobile phase over 1 .55 min employing UV detection at 220 nm and 254 nm. Gradient information: 0- 0.80 min, ramped from 95% A-5% B to 5% A-95% B; 0.80-1 .20 min, held at 5% A-95% B; 1 .20-1 .21 min, returned to 95% A-5% B, 1.21-1 .55 min, held at 95% A-5% B. Method 2: SHIMADZU LCMS-2020 Kinetex EVO C18 2.1X30mm, 5pm at 40°C ; Mobile Phase : A: 0.025% NHs- W in water (v / v); B: MeCN; flow rate held at 1 .5 mL / min; eluted with the mobile phase over 1 .55 min employing UV detection at 220 nm and 254 nm. Gradient information: 0-0.80 min, ramped from 95% A-5% B to 5% A-95% B; 0.80-1 .20 min, held at 5% A-95% B; 1 .20-1.21 min, returned to 95% A-5% B, 1 .21-1 .55 min, held at 95% A-5% B.

[0370] Method 3: SHIMADZU LCMS-2020 Kinetex EVO C18 2.1X30mm,5pm at 50°C; Mobile Phase: A: 0.0375% TFA in water (v / v); B: 0.01875% TFA in MeCN (v / v); flow rate held at 2.0 mL / min; eluted with the mobile phase over 0.80 min employing UV detection at 220 nm and 254 nm. Gradient information: 0- 0.80 min, ramped from 95% A-5% B to 5% A-95% B; 0.80-1 .20 min, held at 5% A-95% B; 1 .20-1 .21 min, returned to 95% A-5% B, 1.21-1 .55 min, held at 95% A-5% B.

[0371] Method 4: SHIMADZU LCMS-2020 Kinetex® EVO C18 2.1X20 mm 2.6 pm at 50°C; Mobile Phase: A: 0.0375% TFA in water (v / v); B: 0.01875% TFA in MeCN (v / v); flow rate held at 2.0 mL / min; eluted with the mobile phase over 1.00 min employing UV detection at 220 nm and 254 nm. Gradient information: 0.01-0.60 min, ramped from 95% A-5% B to 5% A-95% B; 0.61-0.78 min, held at 5% A-95% B; 0.78-0.79 min, returned to 95% A-5% B, 0.79-0.80 min, held at 95% A-5% B.

[0372] Method 5: SHIMADZU LCMS-2020 Kinetex® EVO C18 2.1X30 mm 5 pm at 50°C Mobile Phase: A: 0.0375% TFA in water (v / v); B: 0.01875% TFA in MeCN (v / v); flow rate held at 1 .5 mL / min; eluted with the mobile phase over 1.00 min employing UV detection at 220 nm and 254 nm. Gradient information: 0.01-0.80 min, ramped from 95% A-5% B to 5% A-95% B; 0.80-0.95 min, held at 5% A-95% B; 0.95-0.96 min, returned to 95% A-5% B, 0.96-1.00 min, held at 95% A-5% B.

[0373] Method 6: SHIMADZU LCMS-2020 Kinetex® HALO C18 3.0X30mm, 5 pm at 50°C; Mobile Phase: A: 0.0375% TFA in water (v / v); B: 0.01875% TFA in MeCN (v / v); flow rate held at 1 .5 mL / min; eluted with the mobile phase over 1 .05 min employing UV detection at 220 nm and 254 nm. Gradient information: 0- 0.80 min, ramped from 50% A-50% B to 0% A-100% B; 0.80-1 .05 min, held at 50% A-50% B.

[0374] Method 7: SHIMADZU LCMS-2020 HALO C18 3.0X30 mm, 5 pm at 50 °C, Mobile Phase: A: 0.0375% TFA in water (v / v); B: 0.01875% TFA in Acetonitrile (v / v); flow rate held at 1.5 mL / min; eluted with the mobile phase over 1 .05 min employing UV detection at 220 nm and 254 nm. Gradient information: 0-0.50 min, ramped from 95% A-5% B to 5% A-95% B; 0.50-0.80 min, held at 5% A-95% B; 0.80-0.81 min, returned to 95% A-5% B, 0.81-1.05 min, held at 95% A-5% B.

[0375] Method 8: SHIMADZU LCMS-2020 HALO C183.0X30mm, 5pm at 50 °C; Mobile Phase: A:

[0376] 0.0375% TFA in water (v / v); B: 0.01875% TFA in MeCN (v / v); flow rate held at 1.5 mL / min; eluted with the mobile phase over 0.80 min employing UV detection at 220 nm and 254 nm. Gradient information: 0- 0.45 min, ramped from 95% A-5% B to 5% A-95% B; 0.45-0.70 min, held at 5% A-95% B; 0.70-0.71 min, returned to 95% A-5% B, 0.71-0.80 min, held at 95% A-5% B.

[0377] Method 9: SHIMADZU LCMS-2020 Kinetex® EVO C18 2.1X30 mm, 5 pm at 40°CMobile Phase: A: water; B: MeCN; flow rate held at 1.5 mL / min; eluted with the mobile phase over 1.55 min employing UV detection at 220 nm and 254 nm. Gradient information: 0-0.80 min, ramped from 95% A-5% B to 5% A-95% B; 0.80-1.20 min, held at 5% A-95% B; 1.20-1.21 min, returned to 95% A-5% B, 1.21-1.55 min, held at 95% A-5% B.

[0378] Method 10: SHIMADZU LCMS-2020 Waters Xselect HSS T3, 3.5 pm, 4.6*50mm at 40°C; Mobile Phase: A: 0.0375% TFA in water (v / v); B: 0.01875% TFA in MeCN (v / v); flow rate held at 1.5 mL / min; eluted with the mobile phase over 5.20 min employing UV detection at 220 nm and 254 nm. Gradient information: 0-3.50 min, ramped from 95% A-5% B to 5% A-95% B; 3.50-4.80 min, held at 5% A-95% B; 4.80-4.81 min, returned to 95% A-5% B; 4.81-5.20 min, held at 95% A-5% B

[0379] Method 11 : SHIMADZU LCMS-2020 HALO C18 3.0X30mm,5pm at 50 °C; Mobile Phase: A: 0.0375% TFA in water (v / v); B: 0.01875% TFA in MeCN (v / v); flow rate held at 1.5 mL / min; eluted with the mobile phase over 3.00 min employing UV detection at 220 nm and 254 nm. Gradient information: 0- 2.10 min, ramped from 95% A-5% B to 5% A-95% B; 2. 10-2.80 min, held at 5% A-95% B; 2.80-2.81 min, returned to 95% A-5% B, 2.81-3.00 min, held at 95% A-5% B.

[0380] Method 12: SHIMADZU LCMS-2020 HALO C18 3.0X30 mm, 5 pm at 50 °C, Mobile Phase: A: 0.0375% TFA in water (v / v); B: 0.01875% TFA in Acetonitrile (v / v); flow rate held at 2 mL / min; eluted with the mobile phase over 1 .05 min employing UV detection at 220 nm and 254 nm. Gradient information: 0- 0.40 min, ramped from 95% A-5% B to 5% A-95% B; 0.40-0.75 min, held at 5% A-95% B; 0.75-0.76 min, returned to 95% A-5% B, 0.76-1 .05 min, held at 95% A-5% B.

[0381] Method 13: SHIMADZU LCMS-2020 HALO C18 3.0X30 mm, 5 pm at 50°C Mobile Phase: A: 0.04% TFA in water (v / v); B: 0.02% TFA in MeCN (v / v); flow rate held at 1 .5 mL / min; eluted with the mobile phase over 1 .00 min employing UV detection at 220 nm and 254 nm. Gradient information: 0.01-0.50 min, ramped from 95% A-5% B to 5% A-95% B; 0.50-0.80 min, held at 5% A-95% B; 0.80-0.81 min, returned to 95% A-5% B, 0.81-1 .00 min, held at 95% A-5% B.

[0382] Method 14: SHIMADZU LCMS-2020 HALO C18 3.0X30 mm, 5 pm at 50°C Mobile Phase: A: 10mmol / L NH4HCO3 in water; B: MeCN; flow rate held at 1.5 mL / min; eluted with the mobile phase over 2.20 min employing UV detection at 220 nm and 254 nm. Gradient information: 0-1.50 min, ramped from 95% A-5% B to 5% A-95% B; 1 .50-1 .90 min, held at 5% A-95% B; 1 .90-1 .91 min, returned to 95% A-5% B, 1.91-2.20 min, held at 95% A-5% B. Method 15: SHIMADZU LCMS 2020 XBridge C18 2.1X50 mm, 5 m at 50 °C; Mobile Phase: A: 10mmol / L NH4HCO3 in water (v / v); B: MeCN; flow rate held at 1.5 mL / min; eluted with the mobile phase over 2.2 min employing UV detection at 220 nm and 254 nm. Gradient information: 0-0.1.5 min, ramped from 95 A-5% B to 5% A-95% B; 1 .50-1 .90 min, held at 5% A-95% B; 1 .900-1 .91 min, returned to 95% A- 5% B, 1.91-2.2 min, held at 95% A-5% B

[0383] Method 16: SHIMADZU LCMS 2020 XBridge C18 2.1X50 mm, 5 pm at 50 °C; Mobile Phase: A: 10mmol / L NH4HCO3 in water (v / v); B: MeCN; flow rate held at 0.8 mL / min; eluted with the mobile phase over 4 min employing UV detection at 220 nm and 254 nm. Gradient information: 0-2.60 min, ramped from 95 A-5% B to 5% A-95% B; 2.60-3.60 min, held at 5% A-95% B; 3.60-3.61 min, returned to 95% A-5% B, 3.61-4.00 min, held at 95% A-5% B

[0384] Methods for MS Analysis of compounds:

[0385] Method 1 : SHIMADZU LCMS-2020 Kinetex® EVO C18 2.1X30 mm, 5 pm at 40 °C Mobile

[0386] Phase: A: 0.025% NH3-H2O in water (v / v); B: MeCN; flow rate held at 1.5 mL / min; eluted with the mobile phase over 0.40 min employing UV detection at 220 nm. Gradient information: 0-0.40 min, ramped from 10% A-90% B to 10% A-90% B;

[0387] Method 21 : SHIMADZU LCMS-2020 HALO C18 3.0X30mm, 5 pm at 50 °C Mobile Phase: Mobile Phase: A: 0.0375% TFA in water (v / v); B: 0.01875% TFA in MeCN (v / v); flow rate held at 1 .5 mL / min; eluted with the mobile phase over 0.35 min employing UV detection at 220 nm. Gradient information: 0- 0.35 min, ramped from 10% A-90% B to 10% A-90% B;

[0388] Methods for SFC analysis of compounds:

[0389] SFC Method 1 : Column: Chiralcel OX-3 50*4.6 mm I.D., 3 pm; Mobile phase: Phase A for CO2, Phase B for MeOH+ACN with 0.05% DEA additive; Gradient elution: 50% B in CO2, Flow rate: 3 mL / min; Detector: PDA; Column Temp: 35 °C; Back Pressure: 100Bar.

[0390] SFC Method 2: ColummChiralpak AD-3 50*4.6 mm I.D., 3 pm Mobile phase: Phase A for CO2, Phase B for EtOH+ACN with 0.05% DEA additive; Gradient elution: 60% B in CO2 , Flow rate: 3 mL / min; Detector: PDA; Column Temp: 35 °C; Back Pressure: 100Bar.

[0391] SFC Method 3: ColummChiralpak I G-3 50*4.6 mm I.D., 3pm; Mobile phase: Phase A for CO2, and Phase B for MeOH+ACN with 0.05% DEA additive; Gradient elution: 60% B in CO2, Flow rate: 3 mL / min; Detector: PDA; Column Temp: 35 °C; Back Pressure: 100Bar. SFC Method 4: ColummChiralcel OJ-3 50*4.6mm I. D. ,3pm; Mobile phase: Phase A for CO2,and Phase B for MeOH(0.05% DEA); Gradient elution: MeOH(0.05% DEA) in CO2 from 5% to 40%, Flow rate:3 mL / min; Detector: PDA; Column Temp: 35C; Back Pressure: 100Bar.

[0392] SFC Method 5: ColummChiralpak IG-3 50*4.6mm I.D.,3pm; Mobile phase: Phase A for CO2, and Phase B for IPA+ACN(0.05% DEA); Gradient elution: IPA+ACN(0.05% DEA) from 20% to 60% in CO2; Flow rate:3 mL / min; Detector :PDA; Column Temp: 35C; Back Pressure: 100Bar.

[0393] SFC Method 6: Column: Chiralcel OJ-3 50*4.6mm I.D.,3 pm; Mobile phase: Phase A for CO2, and Phase B for I PA(0.05% DEA); Gradient elution: I PA(0.05% DEA) in CO2 from 5% to 40%, Flow rate: 3 mL / min; Detector: PDA; Column Temp: 35C; Back Pressure: 100Bar.

[0394] SFC Method 7: Column:Chiralcel OJ-3 50*4.6 mm I.D., 3 pm; Mobile phase:Phase A for CO2, and Phase B for EtOH(0.05% DEA); Gradient elution: EtOH(0.05% DEA) in CO2 from 5% to 40%, Flow rate: 3 mL / min; Detector: PDA; Column Temp: 35C; Back Pressure: 100Bar.

[0395] SFC Method 8: Column: Chiralpak IC-3 50*4.6mm I.D., 3pm Mobile phase: Phase A for CO2 and Phase B for EtOH(0.05%DEA); Gradient elution: 60% EtOH(0.05%DEA) in CO2 .Flow rate:3mL / min; DetectorPDA; Column Temp:35C; Back Pressure: 100Bar"

[0396] SFC Method 9: Column: Chiralpak IC-3 50*4.6mm I.D., 3pm Mobile phase: Phase A for CO2and Phase B for IPA+ACN(0.05%DEA); Gradient elution: IPA+ACN(0.05%DEA) in CO2 from 20% to 60%, Flow rate:3mL / min; DetectorPDA; Column Temp:35C; Back Pressure: 100Bar".

[0397] SFC Method 10: Column: Chiralpak AD-3 50*4.6mm I.D.,3 pm Mobile phase: Phase A for CO2,and Phase B for IPA+ACN(0.05%DEA); Gradient elution: IPA+ACN(0.05%DEA) in CO2 from 20% to 60%, Flow rate:3mL / min; DetectorPDA; Column Temp:35C;Back Pressure: 100Bar

[0398] SFC Method 11 : Column: (S,S)Whelk-O1 50*4.6mm I.D., 3.5 pm; Mobile phase:Phase A for CO2,and Phase B for IPA(0.05%DEA); Gradient elution: IPA (0.05% DEA) in CO2 from 5% to 40%, Flow rate: 3 mL / min; Detector: PDA; Column Temp: 35°C; Back Pressure: 100 Bar.

[0399] SFC Method 12: Column: Chiralpak AD-3 50*4.6mm I.D., 3 pm; Mobile phase: Phase A for CO2, and Phase B for MeCH(0.05%DEA); Gradient elution: MeOH (0.05% DEA) in CO2 from 5% to 40%, Flow rate: 3 mL / min; Detector: PDA; Column Temp: 35°C; Back Pressure: 100 Bar.

[0400] SFC Method 13: Column: Chiralpak AD-3 50*4.6mm I.D., 3 pm Mobile phase: Phase A for CO2, and Phase B for IPA (0.05%DEA); Gradient elution: IPA (0.05% DEA) in CO2 from 5% to 40%, Flow rate: 3 mL / min; Detector: PDA; Column Temp: 35°C; Back Pressure: 100 Bar.

[0401] SFC Method 14: Column: Chiralpak IG-3 50*4.6 mm I.D., 3 pm; Mobile phase: Phase A for CO2, and Phase B for EtOH (0.05% DEA); Gradient elution: EtOH (0.05% DEA) from 20% to 60% in CO2; Flow rate: 3 mL / min; Detector: PDA; Column Temp: 35 °C; Back Pressure: 100 Bar. SFC Method 15: Column: Chiralcel OX-3 50*4.6 mm I.D., 3 pm; Mobile phase: Phase A for CO2, Phase B for MeOH (0.05% DEA), Gradient elution: MeOH (0.05% DEA) from 10% to 60% in CO2, Flow rate: 3 mL / min; Detector: PDA; Column Temp: 35 °C; Back Pressure: 100Bar.

[0402] SFC Method 16: Column: Chiralcel OD-3 50*4.6 mm I.D., 3 pm; Mobile phase: Phase A for CO2, Phase B for EtOH (0.05% DEA), Gradient elution: EtOH (0.05% DEA) from 5% to 40% in CO2, Flow rate: 3 mL / min; Detector: PDA; Column Temp: 35 °C; Back Pressure: 100Bar.

[0403] SFC Method 17: Column: Chiralpak IG-3 50*4.6 mm I.D., 3 pm; Mobile phase: Phase A for CO2, Phase B for EtOH+ACN (0.05% DEA); Gradient elution: 60% B in CO2, Flow rate: 3 mL / min; Detector: PDA; Column Temp: 35 °C; Back Pressure: 100Bar.

[0404] SFC Method 18: Column: Chiralpak IG-3 50*4.6 mm I.D., 3 pm; Mobile phase: Phase A for CO2, Phase B for IPA (0.05% DEA); Gradient elution: 40% B in CO2, Flow rate: 3 mL / min; Detector: PDA; Column Temp: 35 °C; Back Pressure: 100Bar.

[0405] SFC Method 19: Column: Chiralcel OZ -3 50*4.6 mm I.D., 3 pm; Mobile phase: Phase A for CO2, Phase B for EtOH+ACN (0.05% DEA); Gradient elution: 60% B in CO2, Flow rate: 3 mL / min; Detector: PDA; Column Temp: 35 °C; Back Pressure: 100Bar.

[0406] SFC Method 20: Column: Chiralpak AD-3 50*4.6 mm I.D., 3 pm; Mobile phase: Phase A for CO2, Phase B for IPA (0.05% DEA); Gradient elution: IPA (0.05% DEA) in CO2 from 20% to 60%, Flow rate: 3 mL / min; Detector: PDA; Column Temp: 35 °C; Back Pressure: 100 Bar

[0407] SFC Method 21 : Col umn : Chi ralcel OJ-3 50*4.6 mm I.D., 3 pm; Mobile phase: Phase A for CO2, Phase B for IPA+ACN (0.05% DEA); Gradient elution: IPA+ACN (0.05% DEA) in CO2 from 5% to 40%, Flow rate: 3 mL / min; Detector: PDA; Column Temp: 35 °C; Back Pressure: 100Bar.

[0408] SFC Method 22: Column: Chiralpak AD-3 50*4.6 mm I.D., 3 pm; Mobile phase: Phase A for CO2, Phase B for EtOH (0.05% DEA); Gradient elution: 60% EtOH (0.05% DEA) in CO2, Flow rate: 3 mL / min; Detector: PDA; Column Temp: 35 °C; Back Pressure: 100 Bar.

[0409] SFC Method 23: Column: Lux 3um Cellulose-2 50*4.6 mm I.D., 3 pm; Mobile phase: Phase A for CO2, Phase B for MeOH (0.05% DEA); Gradient elution: 60% MeOH (0.05% DEA) in CO2, Flow rate: 3mL / min; Detector: PDA; Column Temp: 35 °C; Back Pressure: 100Bar.

[0410] SFC Method 24: Column: Chiralpak AD-3 50*4.6 mm I.D., 3 pm; Mobile phase: Phase A for CO2, Phase B for EtOH (0.05% DEA); Gradient elution: EtOH (0.05% DEA) in CO2 from 5% to 40%, Flow rate: 3 mL / min; Detector: PDA; Column Temp: 35 °C; Back Pressure: 100 Bar.

[0411] SFC Method 25: Column: Chiralpak AD-3 50*4.6 mm I.D., 3 pm; Mobile phase: Phase A for CO2, Phase B for EtOH (0.05% DEA); Gradient elution: 40% EtOH (0.05% DEA) in CO2, Flow rate: 3 mL / min; Detector: PDA; Column Temp: 35 °C; Back Pressure: 100 Bar. SFC Method 26: Column: Chiralpak AD-3 50*4.6 mm I.D., 3 pm; Mobile phase: Phase A for CO2, Phase B for EtOH (0.05% DEA); Gradient elution: EtOH (0.05% DEA) from 20% to 60% in CO2; Flow rate: 3 mL / min; Detector: PDA; Column Temp: 35 °C; Back Pressure: 100 Bar.

[0412] SFC Method 27: Column: Chiralpak IG-3 50*4.6 mm I.D., 3 pm; Mobile phase: Phase A for CO2, Phase B for MeOH (0.05% DEA); Gradient elution: 40% MeOH (0.05% DEA) in CO2; Flow rate: 3 mL / min; Detector: PDA; Column Temp: 35 °C; Back Pressure: 100 Bar.

[0413] SFC Method 28: Column: Chiralpak AD-3 50*4.6 mm I.D., 3 pm; Mobile phase: Phase A for CO2, Phase B for IPA+ACN (0.05% DEA); Gradient elution: 40% IPA+ACN in CO2, Flow rate: 3mL / min; Detector: PDA; Column Temp: 35 °C; Back Pressure: 100Bar

[0414] SFC Method 29: Column: Chiralpak ID-3 50*4.6 mm I.D., 3 pm; Mobile phase: Phase A for CO2, Phase B for IPA+ACN (0.05% DEA); Gradient elution: 60% IPA+ACN (0.05% DEA) in CO2, Flow rate: 3mL / min; Detector: PDA; Column Temp: 35 °C; Back Pressure: 100Bar.

[0415] SFC Method 30: Column: Chiralpak IC-3 50*4.6 mm I.D., 3 pm; Mobile phase: Phase A for CO2, Phase B for EtOH (0.05% DEA); Gradient elution: EtOH (0.05% DEA) in CO2 from 10% to 60%, Flow rate: 3mL / min; Detector: PDA; Column Temp: 35 °C; Back Pressure: 100Bar.

[0416] SFC Method 31 : Column: Chiralcel OJ-3 50*4.6mm I.D., 3 pm; Mobile phase: Phase A for CO2, Phase B for EtOH+ACN (0.05% DEA); Gradient elution: from 20% to 60% of EtOH+ACN (0.05% DEA) in CO2, Flow rate: 3mL / min; Detector: PDA; Column Temp: 35 °C; Back Pressure: 100Bar

[0417] SFC Method 32: Column: Chiralpak IE-3 100*4.6mm I.D., 3 pm; Mobile phase: Phase A for Water with 0.0375%TFA, Phase B for ACN (0.01875% TFA); Gradient elution: 80% B in A; Flow rate: 1 mL / min; Detector: PDA; Column Temp: 35 °C; Back Pressure: 100Bar

[0418] SFC Method 33: Column: Chiralpak IK-3 50*4.6 mm I.D., 3 pm; Mobile phase: Phase A for CO2, Phase B for IPA+ACN (0.05% DEA); Gradient elution: 50% IPA+ACN (0.05% DEA) in CO2, Flow rate: 3mL / min; Detector: PDA; Column Temp: 35 °C; Back Pressure: 100Bar

[0419] SFC Method 34: Column: Chiralpak IG-3 50*4.6 mm I.D., 3 pm; Mobile phase: Phase A for CO2, Phase B for EtOH (0.05% DEA); Gradient elution: EtOH (0.05% DEA) from 20% to 40% in CO2; Flow rate: 3 mL / min; Detector: PDA; Column Temp: 35 °C; Back Pressure: 100 Bar.

[0420] SFC Method 35: Column: Chiralpak IH-3 50*4.6 mm I.D., 3 pm; Mobile phase: Phase A for CO2, Phase B for EtOH (0.05% DEA); Gradient elution: EtOH (0.05% DEA) from 5% to 40% in CO2; Flow rate: 3 mL / min; Detector: PDA; Column Temp: 35 °C; Back Pressure: 100 Bar.

[0421] SFC Method 36: Column: Chiralpak AS-3 50*4.6 mm I.D., 3 pm; Mobile phase: Phase A for CO2, Phase B for EtOH (0.05% DEA); Gradient elution: EtOH (0.05% DEA) from 5% to 40% in CO2; Flow rate: 3 mL / min; Detector: PDA; Column Temp: 35 °C; Back Pressure: 100 Bar SFC Method 37: Column: Chiralpak IG-3 50*4.6 mm I.D., 3 pm; Mobile phase: Phase A for CO2, Phase B for MeOH (0.05% DEA); Gradient elution: 60% MeOH (0.05% DEA) in CO2; Flow rate: 3 mL / min; Detector: PDA; Column Temp: 35 °C; Back Pressure: 100 Bar.

[0422] SFC Method 38: Column: Chiralcel Cellulose-2 50*4.6 mm I.D., 3 pm; Mobile phase: Phase A for CO2, Phase B for EtOH (0.05% DEA); Gradient elution: EtOH (0.05% DEA) from 20% to 60% in CO2; Flow rate: 3 mL / min; Detector: PDA; Column Temp: 35 °C; Back Pressure: 100 Bar.

[0423] SFC Method 39: Column: Chiralpak AY-3 50*4.6mm I.D., 3 pm; Mobile phase: Phase A for CO2, Phase B for EtOH (0.05% DEA); Gradient elution: 40% EtOH (0.05%DEA) in CO2; Flow rate: 3 mL / min; Detector: PDA; Column Temp: 35 °C; Back Pressure: 100 Bar.

[0424] SFC Method 40: Column: Chiralpak IG-3 50*4.6 mm I.D., 3 pm; Mobile phase: Phase A for CO2, Phase B for EtOH (0.05% DEA); Gradient elution: EtOH (0.05% DEA) from 5% to 40% in CO2; Flow rate: 3 mL / min; Detector: PDA; Column Temp: 35 °C; Back Pressure: 100 Bar.

[0425] SFC Method 41 : Column: Chiralpak AS-3 50*4.6mm I.D., 3 pm; Mobile phase: Phase A for CO2, Phase B for MeOH (0.05% DEA); Gradient elution: MeOH (0.05% DEA) in CO2 from 5% to 40%, Flow rate: 3 mL / min; Detector: PDA; Column Temp: 35 °C; Back Pressure: 100 Bar.

[0426] SFC Method 42: Column: Lux 3um Cellulose-4 50*4.6mm I.D, 3 pm; Mobile phase: Phase A for CO2, Phase B for IPA+ACN (0.05% DEA); Gradient elution: IPA+ACN (0.05% DEA) from 20% to 60% in CO2, Flow rate: 3mL / min; Detector: PDA; Column Temp: 35 °C; Back Pressure: 100Bar

[0427] SFC Method 43: Column: Chiralcel OX-3 50*4.6 mm I.D., 3 pm; Mobile phase: Phase A for CO2, and Phase B for IPA (0.05% DEA); Gradient elution: IPA (0.05 % DEA) in CO2 from 5% to 40%, Flow rate: 3 mL / min; Detector: PDA; Column Temp: 35°C; Back Pressure: 100Bar.

[0428] SFC Method 44: Column: Chiralpak I C-3 50*4.6mm I.D. ,3 pm Mobile phase: Phase A for CO2 and Phase B for EtOH (0.05%DEA); Gradient elution: EtOH(0.05%DEA) in CO2 from 5% to 40%, Flow rate:3mL / min; Detector: PDA; Column Temp:35 °C; Back Pressure: 100Bar

[0429] SFC Method 47: Column: Chiralpak IF- 3-3 50*4.6mm I.D., 3um; Mobile phase: Phase A for CO2, and Phase B for EtOH (0.05%DEA); Gradient elution: B in CO2 from 5% to 40%, Flow rate: 3 mL / min; Detector: PDA; Column Temp: 35°C; Back Pressure: 100 Bar.

[0430] SFC Method 48: Column: Chiralcel OX-3 50*4.6 mm I.D., 3 pm; Mobile phase: Phase A for CO2, Phase B for EtOH (0.05% DEA), Gradient elution: B from 10% to 60% in CO2, Flow rate: 3 mL / min; Detector: PDA; Column Temp: 35 °C; Back Pressure: 100Bar.

[0431] SFC Method 49: Column: Chiralcel OD-3 50*4.6 mm I.D., 3 pm; Mobile phase: Phase A for CO2, Phase B for IPA (0.05% DEA), Gradient elution: B from 10% to 60% in CO2, Flow rate: 4 mL / min; Detector: PDA; Column Temp: 35 °C; Back Pressure: 100Bar. SFC Method 50: Column: Chiralpak AD-3 50x4.6mm I.D., 3um Mobile phase: Phase A for CO2, and Phase B for EtOH(0.05%DEA); Gradient elution: B in CO2 from 10% to 60%; Flow rate: 4mL / min; Detector: PDA; Column Temp: 35C;Back Pressure: 100Bar.

[0432] 1H NMR Spectroscopy:

[0433] 1H NMR spectra were acquired on a Bruker Avance IH spectrometer at 400 MHz using residual undeuterated solvent as reference.1H NMR signals are specified with their multiplicity / combined multiplicities as apparent from the spectrum; possible higher-order effects are not considered. Chemical shifts of the signals (5) are specified as ppm (parts per million).

[0434] Salt stoichiometry:

[0435] In the present text, in particular in the experimental section, for the synthesis of intermediates and of examples of the present invention, when a compound is mentioned as a salt form with the corresponding base or acid, the exact stoichiometric composition of said salt form, as obtained by the respective preparation and / or purification process, is, in most cases, unknown. Unless specified otherwise, suffixes to chemical names or structural formulae such as "hydrochloride", "trifluoroacetate", "sodium salt", or "x HO", "x CF3COOH", "x Na+", for example, are to be understood as not a stoichiometric specification, but solely as a salt form. This applies analogously to cases in which synthesis intermediates or example compounds or salts thereof have been obtained, by the preparation and / or purification processes described, as solvates, such as hydrates with (if defined) unknown stoichiometric composition.

[0436] General procedure 1 (Suzuki coupling): To a solution of the bromide compound (1 eq), the borate ester or borate acid substrate (1 to 2 eq) and Na2COs or K2CO3 (2 to 3 eq) in dioxane (20 to 100 mg / mL) and H2O (1 / 10 to 1 / 5 of the dioxane volume) was added Pd(dppf)Cl2 or Pd(PPh3)4 (0.05 to 0.1 eq). The reaction mixture was degassed and purged with N2 (3x), stirred at 80 to 100 °C for 2 to16 h and concentrated under reduced pressure. The resulting residue was purified by preparative-HPLC or phase chromatographic column to give the corresponding product.

[0437] Alternatively, after stirring at 80 to 100 °C for 2 to 16 h, the reaction mixture was cooled to room temperature, diluted with H2O and extracted with EtOAc or DCM (3x). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by preparative-HPLC or phase chromatographic column to give the corresponding product.

[0438] General procedure 2 (oxidation, via m-CPBA) : To a solution of the compound (1.0 eq) in DCM (50 to 100 mg / mL) was added m-CPBA (2.0 to 3.0 eq). The reaction mixture was stirred at 25 °C for 2 to 12 h. The mixture was poured into saturated sodium sulfite aqueous solution. The aqueous layer was extracted with EtOAc or DCM (2x or 3x). The combined organic layer was washed with brine, dried over anhydrous Na2SC , filtered and concentrated under reduced pressure. The resulting residue was purified by preparative-HPLC or chromatographic column to give the corresponding product.

[0439] General procedure 3 (Saponification): To the mixture of the ester substrate (1 eq) in MeOH or THF (50 to 100 mg / mL) and H2O (1 / 2 to 1 / 1 of the MeOH or THF volume) was added LiOH or LiOH H2O (3.0 to 5.0 eq). The mixture was stirred at 20 °C for 1 to 2 h. The pH of the reaction mixture was adjusted to a value ranged between 1 to 6 by addition of an aqueous solution of hydrochloric acid (1 N). Work up procedure 1 : The resulting precipitate was filtered, collected and dried under reduced pressure to give the desired product. Work up procedure 2: The aqueous layer was extracted with EtOAc or DCM (2x or 3x). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure give the desired product.

[0440] General procedure 4 (amidation): To a solution of the carboxylic acid compound (1 .0 eq), the amino compound (1.3 to 2.0 eq), DIEA (3.0 to 4.0 eq,) in DMF or DCM (15 to 70 mg of carboxylic acid compound / mL) was added T4P in EtOAc (1.3 to 2.5 eq, 50% in EtOAc) or HATU (1.3 to 2.5 eq). The mixture was stirred at 25 °C for 1 to 2 h. Work up procedure 1 : The resulting mixture was diluted with H2O, followed by extraction with EtOAc (3x). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by preparative-HPLC to give the corresponding product. Work up 2: The resulting mixture was directly purified by preparative-HPLC or Reversed-phase flash purification to give the corresponding product.

[0441] General procedure 5 (Boc cleavage): To a solution of the Boc-protected compound in DCM (0.1 g / mL) was added TFA (1 / 5 to1 / 3 of the DCM volume) at 25 °C. The mixture was stirred at 25 °C for 1 to 2 h and, then, concentrated under reduce pressure. The resulting residue was purified by preparative- HPLC or reversed-phase flash purification to give the corresponding product.

[0442] Preparation of Intermediate 32.1

[0443] Diethyl ((methylsulfinyl)methyl)phosphonate

[0444] Eto ACN, H2O, 0 C, 3 hEto

[0445] To a solution of diethyl ((methylthio)methyl)phosphonate (2000 mg, 10.1 mmol) in MeCN (20 mL) was added dropwise a solution of NalO4 (4337 mg, 20.2 mmol) in water (16 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 3 h, then diluted with water (20 mL) and extracted with ethyl acetate (30 mL; 3x). The combined organic layer was washed with aq. solution of Na2SO3 (sat., 30 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (ISCO; 12 g SepaFlash Silica Flash Column, Eluent DCM / MeOH gradient from 100 / 0 to ~90 / ~10 @ 60 mL / min) to give the product diethyl ((methylsulfi nyl)methyl)phosphonate (870 mg, 4.06 mmol, 40.25 % yield) as colorless oil.

[0446] MS: (method 1); m / z 215.1 (M+H)+(ESI+).1H NMR (CDCh, 400 MHz): 4.26-4.14 (m, 4H), 3.42-3.19

[0447] (m, 2H), 2.86 (s, 3H), 1.37 (t, J= 7.2 Hz, 6H)

[0448] Preparation of Intermediate 32.2

[0449] Tert-butyl (((diethoxyphosphoryl)methyl)(methyl)(oxo)- / '.6-sulfaneylidene)carbamate

[0450] BOCNH2, MgO, Phl(OAc)2Rhodium(ll) acetate dimer DCM, 50 °C, 3 h Eto NBOC

[0451] To a solution of diethyl ((methylsulfinyl)methyl)phosphonate (840 mg, 3.92 mmol) in DCM (15 mL) was added tert-butyl carbamate (919 mg, 7.84 mmol), rhodium(ll) acetate dimer powder (52 mg, 0.118 mmol) and MgO (627 mg, 15.7 mmol). The mixture was stirred at 20 °C under N2 for 20 min and Phl(OAc)2 (1895 mg, 5.88 mmol) was added. The mixture was stirred at 50 °C for 3 h under N2, then cooled to room temperature and filtered. The filtrate was purified by column chromatography (ISCO; 12 g SepaFlash Silica Flash Column, Eluent Petroleum ether / Ethyl acetate gradient from 60 / 40 to 0 / 100 @ 40 mL / min) to give the product tert-butyl(((diethoxyphosphoryl)methyl)(methyl)(oxo)- X6-sulfaneylidene)carbamate (1000 mg, 3.04 mmol, 77.43 % yield) as yellow oil.

[0452] MS: (method 1); m / z 230.2(M+H-Boc)+(ESI+);1H NMR (CDCh, 400 MHz): 4.36 (t, J= 15.6 Hz, 1 H), 4.31-4.19 (m, 4H), 3.95 (t, J = 15.6 Hz, 1 H), 3.41 (s, 3H), 1.50 (s, 9H), 1.38 (t, J= 7.2 Hz, 6H) Preparation of Intermediate 32.3

[0453] Tert-butyl (E)-(3-(N-(tert-butoxycarbonyl)-S-methylsulfonimidoyl)-1-cyclopropylallyl)carbamate (mixture of four stereoisomers)

[0454] To a solution of tert-butyl (((diethoxyphosphoryl)methyl)(methyl)(oxo)-X6-sulfaneylidene)carbamate (400 mg, 1.21 mmol) in THF (8 mL) was added tert-butyl (S)-(1-cyclopropyl-2-oxoethyl)carbamate (290 mg, 1.46 mmol) and K2CO3 (420 mg, 3.04 mmol). The reaction mixture was stirred at 80 °C for 1 h, then cooled to room temperature, diluted with water (20 mL) and extracted with ethyl acetate (30 mL; 3x). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (ISCO; 12 g SepaFlash Silica Flash Column, Eluent Petroleum ether / Ethylacetate / gradient from 90 / 10 to 70 / 30 @ 100 mL / min) to give the product tert-butyl (E)-(3-(N- (tert-butoxycarbonyl)-S-methylsulfonimidoyl)-1 -cyclopropylallyl)carbamate (130 mg, 0.347 mmol, 28.58 % yield) as a yellow oil. It is noted that the starting material has likely racemized in the course of the reaction, as the product appears to be a mixture of four stereoisomers (as indicated by SFC).

[0455] RT 0. 601 min (LCMS: method 2; m / z 375.1 (M+H)+(ESI*); RT 0.654 min, 0.747 min, 0.825 min, 1.021 min (SFC: Method 12 showed 4 peaks);1H NMR (CDCI3, 400 MHz): 7.12-6.90 (m, 1 H), 6.63-6.50 (m, 1 H), 4.87-4.58 (m, 1 H), 3.84-3.63 (m, 1 H), 3.25 (m, 3H), 1.49 (s, 9H), 1.46 (m, 9H), 0.98-0.87 (m, 1 H), 0.71-0.58 (m, 2H), 0.51-0.34 (m, 2H)

[0456] Preparation of Intermediate 32.4

[0457] (E)-(3-amino-3-cyclopropylprop-1-en-1-yl)(imino)(methyl)-6-sulfanone (mixture of four stereoisomers)

[0458] A solution of tert-butyl (E)-(3-(N-(tert-butoxycarbonyl)-S-methylsulfonimidoyl)-1 - cyclopropylallyl)carbamate (55 mg, 0.147 mmol) in HCI / EtOAc (2 M, 1.5 mL) was stirred at 25 °C for 2 h. The resulting mixture was concentrated under vacuum (30°C). The crude product was triturated with petroleum ether (2 mL) at 20 °C for 10 min. Then, the mixture was filtered and the precipitate was dried under vacuum(30°C) to give the product (E)-(3-amino-3-cyclopropylprop-1-en-1 -yl)(imino)(methyl)- 6- sulfanone (35 mg, crude) as a yellow solid which was used directly in the next step without any further purification.

[0459] MS: method 1; m / z 175.2 (M+H)+(ESI*);

[0460] Preparation of Example 32

[0461] (E)-N-(1-cyclopropyl-3-(S-methylsulfonimidoyl)allyl)-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5- carboxamide (mixture of four stereoisomers)

[0462] To a solution of (E)-(3-amino-3-cyclopropylprop-1 -en-1-yl)(imino)(methyl)- 6-sulfanone hydrochloride (25 mg, 0.119 mmol), 2-(1 ,1 -difluoroethyl)-4-phenoxypyrimidine-5-carboxylic acid (25 mg, 0.0892 mmol) and DIEA (95 u, 0.535 mmol) in DMF (1 mL) was added T4P / ethyl acetate (84 mg, 0.116 mmol, wt%: 50%) at 0 °C under N2. The mixture was stirred at 20 °C for 12 h, then diluted with water (3 mL) and extracted with ethyl acetate (5 mL, 3x). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by Preparative TLC (ethyl acetate: 100%), further purified by preparative HPLC (column: Unisil 3-100 C18 Ultra 150*50 mm*10 pm; mobile phase: A: 0.225% formic acid in water, B: MeCN; B%: 55%-85%, 10 min) and lyophilized directly to give the product (E)-N-(1-cyclopropyl-3-(S-methylsulfonimidoyl)allyl)-2-(1 ,1-difluoroethyl)-4- phenoxypyrimidine-5-carboxamide (6.0 mg, 0.0136 mmol, 15.27 % yield) as an off-white solid. The product is obtained as a mixture of four stereoisomers, as indicated by SFC.

[0463] RT 0.540 min (LCMS: method 8); m / z 437.2 (M +H)+(ESI+). RT 1 .333 min, 1 .416 min, 1 .529 min, 1.635 min (SFC: SFC Method 13 showed 4 peaks);1H NMR (CDCh, 400 MHz): 9.48 (s, 1 H), 7.78 (d, J= 6.8 Hz, 1 H), 7.56-7.48 (m, 2H), 7.42-7.35 (m, 1 H), 7.26-7.22 (m, 2H), 7.00-6.92 (m, 1 H), 6.75-6.65 (m, 1 H), 4.31-4.22 (m, 1 H), 3.03 (s, 3H), 2.76-2.51 (brs, 1 H), 1.86 (t, J = 18.4 Hz, 3H), 1.14-1.03 (m, 1 H), 0.79-0.71 (m, 1 H), 0.71-0.62 (m, 1 H), 0.55-0.44 (m, 2H).19F NMR (CDCh, 400 MHz): -93.84 (s, 2F)

[0464] Each Example 32a, 32b, 32c and 32d are single stereoisomers, as outlined in the following.

[0465] Preparation of: Example 32a

[0466] N-((S or R, E)-1-cyclopropyl-3-((R or S)-S-methylsulfonimidoyl)allyl)-2-(1 ,1 -difluoroethyl)-4- phenoxypyrimidine-5-carboxamide

[0467] Example 32b

[0468] N-((S or R, E)-1-cyclopropyl-3-((S or R)-S-methylsulfonimidoyl)allyl)-2-(1 ,1 -difluoroethyl)-4- phenoxypyrimidine-5-carboxamide

[0469] Example 32c N-((R or S, E)-1-cyclopropyl-3-((R or S)-S-methylsulfonimidoyl)allyl)-2-(1 ,1 -difluoroethyl)-4- phenoxypyrimidine-5-carboxamide

[0470] Example 32d

[0471] N-((R or S, E)-1-cyclopropyl-3-((S or R)-S-methylsulfonimidoyl)allyl)-2-(1 ,1 -difluoroethyl)-4- phenoxypyrimidine-5-carboxamide

[0472] (E)-N-(1-cyclopropyl-3-(S-methylsulfonimidoyl)allyl)-2-(1,1 -difluoroethyl)-4-phenoxypyrimidine-5- carboxamide (350 mg, 0.802 mmol) was purified by preparative SFC (column: DAICEL CHIRALPAK IC(250mm*30 mm, 10 pm); mobile phase: A for CO2, B for / -PrOH + ACN; Gradient elution:40% B in CO2, 4 mins)(SFC Method 6) to give two product solutions corresponding to peak 1 and peak 2. The solution containing peak 1 was concentrated under vacuum (30 °C) to give fraction A (SFC: RT: 1 .323 min, 1 .402 min (SFC Method 13)). The solution containing peak 2 was concentrated under vacuum (30 °C) to give fraction B (SFC: RT: 1.528 min, 1.646 (SFC Method 13)).

[0473] Fraction A (140 mg, 0.321 mmol) was further purified by preparative SFC (column: DAICEL CHIRALPAK IC(250 mm*30 mm, 10 pm); mobile phase: A for CO2, B for / -PrOH / ACN(2:1); Gradient elution: 40% B in CO2, 4 mins) to afford 2 solutions which were concentrated separately under vacuum (30 °C) to give the respective products (it is noted that the stereochemistry has been assigned arbitrarily):

[0474] Example 32a: N-((S or R,E)-1-cyclopropyl-3-((R or S)-S-methylsulfonimidoyl)allyl)-2-(1 ,1- difluoroethyl)-4-phenoxypyrimidine-5-carboxamide (60 mg, 0.137 mmol, 99.39% purity,) as colorless gum. LCMS: RT 0.451 min (method 6); m / z 437.0 (M+H)+(ESI+); SFC: RT: 1.325 min (SFC Method 13); 100% ee ;1H NMR (CDCh, 400 MHz): 9.47 (s, 1 H), 7.79 (d, J = 7.2 Hz, 1 H), 7.58-7.47 (m, 2H), 7.44-7.34 (m, 1 H), 7.26-7.23 (m, 2H), 6.97 (dd, J = 4.8, 15.2 Hz, 1 H), 6.70 (dd, J = 1 .6, 15.2 Hz, 1 H), 4.37-4.14 (m, 1 H), 3.04 (s, 3H), 1.86 (t, J = 18.4 Hz, 3H), 1.15-1.05 (m, 1 H), 0.80-0.64 (m, 2H), 0.57-0.44 (m, 2H);19F NMR (CDCh, 400 MHz): -93.83 (s, 2F).

[0475] Example 32b: N-((S or R,E)-1-cyclopropyl-3-((S or R)-S-methylsulfonimidoyl)allyl)-2-(1 ,1 - difluoroethyl)-4-phenoxypyrimidine-5-carboxamide (51 mg, 0.115 mmol, 99.07% purity,) as colorless gum. LCMS: RT 0.452 min (method 6); m / z 437.1 (M+H)+(ESI ): SFC: RT: 1.405 min (SFC Method 13); 94.96% ee;1H NMR (CDCh, 400 MHz): 9.49 (s, 1 H), 7.79 (d, J = 7.2 Hz, 1 H), 7.57-7.48 (m, 2H), 7.46- 7.35 (m, 1 H), 7.28-7.23 (m, 2H), 6.97 (dd, J = 4.8, 15.2 Hz, 1 H), 6.74 (dd, J = 1 .6, 15.2 Hz, 1 H), 4.37-4.14 (m, 1 H), 3.04 (s, 3H), 1.87 (t, J = 18.4 Hz, 3H), 1.16-1.04 (m, 1 H), 0.81-0.65 (m, 2H), 0.59-0.45 (m, 2H);19F NMR (CDCh, 400 MHz): 93.83 (s, 2F)

[0476] Fraction B (140 mg, 0.321 mmol) was further purified by preparative SFC (column: DAICEL CHIRALPAK AD(250mm*30mm,10 pm; mobile phase: A for CO2, B for / -PrOH; Gradient elution: 30% B in CO2, 2.6 mins) to afford 2 solutions which were concentrated separately under vacuum (30 °C) to give the respective products:

[0477] Example 32c: N-((R or S,E)-1 -cyclopropyl-3-((R or S)-S-methylsulfonimidoyl)allyl)-2-(1 ,1- difl uoroethyl)-4-p henoxypyrimidi ne-5-carboxamide (56 mg, 0.124 mmol, 97.57% purity,) as colorless gum. LCMS: RT 0.451 min (method 6); m / z 437.1 (M+H)+(ESP); SFC : RT 1.533 min (SFC Method 13); 96.16% ee;1H NMR (CDCh, 400 MHz): 9.47 (s, 1 H), 7.78 (d, J = 7.2 Hz, 1 H), 7.56-7.47 (m, 2H), 7.42- 7.35 (m, 1 H), 7.26-7.22 (m, 2H), 6.95 (dd, J = 4.8, 15.2 Hz, 1 H), 6.72 (dd, J = 1 .6, 15.2 Hz, 1 H), 4.36-4.13 (m, 1 H), 3.02 (s, 3H), 1.86 (t, J = 18.4 Hz, 3H), 1.15-1.02 (m, 1 H), 0.79-0.64 (m, 2H), 0.56-0.44 (m, 2H);19F NMR (CDCh, 400 MHz): -93.83 (s, 2F)

[0478] Example 32d: N-((R or S,E)-1-cyclopropyl-3-((S or R)-S-methylsulfonimidoyl)allyl)-2-(1 , 1- difluoroethyl)-4-phenoxypyrimidine-5-carboxamide (59 mg, 0.133 mmol, 98.74% purity,) as colorless gum. LCMS: RT 0.457 min (method 6); m / z 437.1 (M+H)+(ESI+); SFC: RT: 1.646 min (Method 13); 97.49% ee;1H NMR (CDCh, 400 MHz): 9.49 (s, 1 H), 7.81 (d, J = 7.2 Hz, 1 H), 7.57-7.48 (m, 2H), 7.44-7.37 (m, 1 H), 7.26-7.22 (m, 2H), 6.99 (dd, J = 4.8, 15.2 Hz, 1 H), 6.72 (dd, J = 1 .6, 15.2 Hz, 1 H), 4.32-4.23 (m, 1 H), 3.06 (s, 3H), 1 .87 (t, J = 18.4 Hz, 3H), 1 .15 - 1 .05 (m, 1 H), 0.82 - 0.65 (m, 2H), 0.58 - 0.46 (m, 2H)

[0479] Preparation of Example 33

[0480] (E)-N-( 1-cyclopropyl-3-(N, S-dimethylsulfonimidoyl)allyl)-2-(1, 1-difluoroethyl)-4- To a solution of (E)-N-(1 -cyclopropyl-3-(S-methylsulfonimidoyl)allyl)-2-(1 ,1 -difluoroethyl)-4- phenoxypyrimidine-5-carboxamide (10 mg, 0.0229 mmol) in DCM (0.30 mL) was added trimethyloxonium tetrafluoroborate (3.7 mg, 0.0252 mmol) in MeCN (0.04 mL). The resulting mixture was stirred at 25 °C for 3 h and quenched with aqueous NaHCOs (sat. 3 mL). The aqueous layer was extracted with DCM (3 mL; 3x). The combined organic layer was dried over Na2SO4, filtered and the filtrate was concentrated under vacuum (30 °C). The residue was purified by preparative HPLC (column: Waters xbridge 150*25mm 10 pm; mobile phase: A: 10 mmol / L NH4HCO3 in water, B: MeCN; B%: 30%-60%, 9 min) and lyophilized directly to give the product (E)-N-(1-cyclopropyl-3-(N,S-dimethylsulfonimidoyl)allyl)-2-(1 ,1 -difluoroethyl)- 4-phenoxypyrimidine-5-carboxamide (1.5 mg, 0.00335 mmol, 14.63 % yield) as a white solid.

[0481] RT 0.563 min (LCMS: method 9); m / z 451. (M +H)+(ESI+). RT 0.796 min, 0.975 min, 1.133 min, 1 .356 min (SFC: SFC Method 14 showed 4 peaks);1H NMR (CDCh, 400 MHz): 9.48 (s, 1 H), 7.78 (br d, J= 7.2 Hz, 1 H), 7.57-7.44 (m, 2H), 7.42-7.36 (m, 1 H), 7.28-7.22 (m, 2H), 6.97-6.82 (m, 1 H), 6.40 (dd, J= 15.2, 1.6 Hz„ 1 H), 4.38-4.22 (m, 1 H), 2.99 (s1 , , 1.7H, s2, 1.3 H), 2.72 (s1 , 1.3H, s2, 1.7H), 1.86 (t, J = 18.4 Hz, 3H), 1.14-1 .03 (m, 1 H), 0.81-0.64 (m, 2H), 0.56-0.43 (m, 2H).19F NMR (CDCh, 400 MHz): -93.84 (s, 2F)

[0482] Preparation of (single stereoisomers):

[0483] Example 33a

[0484] N-((S or R, E)-1-cyclopropyl-3-((R or S)-N,S-dimethylsulfonimidoyl)allyl)-2-(1 ,1 -difluoroethyl)-4- phenoxypyrimidine-5-carboxamide

[0485] Example 33b

[0486] N-((S or R, E)-1-cyclopropyl-3-((S or R)-N,S-dimethylsulfonimidoyl)allyl)-2-(1 ,1 -difluoroethyl)-4- phenoxypyrimidine-5-carboxamide

[0487] Example 33c

[0488] N-((R or S, E)-1-cyclopropyl-3-((R or S)-N,S-dimethylsulfonimidoyl)allyl)-2-(1 ,1 -difluoroethyl)-4- phenoxypyrimidine-5-carboxamide

[0489] Example 33d

[0490] N-((R or S, E)-1-cyclopropyl-3-((S or R)-N,S-dimethylsulfonimidoyl)allyl)-2-(1 ,1 -difluoroethyl)-4- phenoxypyrimidine-5-carboxamide

[0491] (E)-N - (1 -cyclopropy I-3- (N, S-di methyls u Ifo n imi doy l)al lyl) -2- ( 1 , 1 -d ifl uoroethy l)-4-p he noxypyri mi di ne- 5-carboxamide (400 mg, 0.888 mmol) was purified by preparative SFC (column: DAICEL CHIRALCEL OX(250mm*30mm, 10 pm); mobile phase: A for CO2, B for / -PrOH; Gradient elution: 30% B in CO2, 10 mins) (SFC Method 43) to give three product solutions The solution from peak 1 was concentrated under vacuum (30 °C) to give Fraction A (SFC: RT 2.170 min, 2.368 min (SFC Method 11)) containing 2 products.

[0492] The solution from peak 2 was concentrated under vacuum (30 °C) to give Example 33a: N-((S or R,E)-1-cyclopropyl-3-((R or S)-N,S-dimethylsulfonimidoyl)allyl)-2-(1 ,1 -difluoroethyl)-4- phenoxypyrimidine-5-carboxamide (85 mg, 0.184 mmol, 96.89% purity,) as colorless gum.

[0493] LCMS: RT 0.570 min (method 10); m / z 451.1 (M+H)+(ESI+); SFC: RT: 0.798 min (SFC Method 14); 98.97% ee,1H NMR (CDCh, 400 MHz): 9.47 (s, 1 H), 7.78 (d, J = 7.2 Hz, 1 H), 7.57-7.49 (m, 2H), 7.41 -7.36 (m, 1 H), 7.26-7.22 (m, 2H), 6.93 (dd, J = 4.8, 15.2 Hz, 1 H), 6.42 (dd, J = 1 .6, 15.2 Hz, 1 H), 4.38- 4.25 (m, 1 H), 3.00 (s, 3H), 2.71 (s, 3H), 1 .86 (t, J = 18.4 Hz, 3H), 1 .16 - 1 .05 (m, 1 H), 0.78 - 0.64 (m, 2H), 0.56 - 0.45 (m, 2H);19F NMR (CDCh, 400 MHz): -93.83 (s, 2F)

[0494] The solution from peak 3 was concentrated under vacuum (30 °C) to give Example 33b: N-((S or R,E)-1-cyclopropyl-3-((S or R)-N,S-dimethylsulfonimidoyl)allyl)-2-(1 ,1 -difluoroethyl)-4- phenoxypyrimidine-5-carboxamide (71 mg, 0.155 mmol, 98.73% purity) as a white solid.

[0495] LCMS: RT 0.570 min (method 10); m / z 451.1 (M+H)+(ESI+); SFC: RT: 0.975 min (SFC Method 14); 96.25% ee;1H NMR (CDCh, 400 MHz): 9.48 (s, 1 H), 7.79 (d, J = 7.2 Hz, 1 H), 7.54-7.48 (m, 2H), 7.42-7.36 (m, 1 H), 7.26-7.22 (m, 2H), 6.88 (dd, J = 5.2, 15.2 Hz, 1 H), 6.41 (dd, J = 1 .2, 15.2 Hz, 1 H), 4.33- 4.24 (m, 1 H), 3.00 (s, 3H), 2.73 (s, 3H), 1 .86 (t, J = 18.4 Hz, 3H), 1 .18 - 1 .06 (m, 1 H), 0.78 - 0.64 (m, 2H), 0.58 - 0.43 (m, 2H);19F NMR (CDCh, 400 MHz): -93.83 (s, 2F)

[0496] Fraction A (SFC: RT 2.170 min, 2.368 min (SFC Method 11)) (150 mg, 0.333 mmol) was further purified by preparative SFC (column: REGIS (s,s) WHELK-01 (250mm*30mm,10 pm); mobile phase: A for CO2, B for / -PrOH; Gradient elution: 35% B in CO2, 3.70 mins) to afford 2 solutions which were concentrated separately under vacuum (30 °C) to give: Example 33c: (SFC,) N-((R or S,E)-1-cyclopropyl-3-((R or S)-N,S-dimethylsulfonimidoyl)allyl)-2- (1 , 1 -difluoroethyl)-4-phenoxypyrimidine-5-carboxamide (58 mg, 0.129 mmol, 100% purity,) as a white solid.)

[0497] LCMS: RT 0.567 min (method 10); m / z 451.1 (M+H)+(ESI ): SFC: RT: 1.127 min (SFC Method 14); 94.68% ee;1H NMR (CDCh, 400 MHz): 9.48 (s, 1 H), 7.79 (d, J = 7.2 Hz, 1 H), 7.56-7.48 (m, 2H), 7.42- 7.35 (m, 1 H), 7.26-7.23 (m, 2H), 6.88 (dd, J = 5.2, 15.2 Hz, 1 H), 6.41 (d, J = 15.2 Hz, 1 H), 4.34-4.23 (m, 1 H), 2.99 (s, 3H), 2.73 (s, 3H), 1.86 (t, J = 18.4 Hz, 3H), 1.17 - 1.05 (m, 1 H), 0.78 - 0.65 (m, 2H), 0.57 - 0.44 (m, 2H);19F NMR (CDCh, 400 MHz): -93.83 (s, 2F)

[0498] Example 33d: N-((R or S,E)-1-cyclopropyl-3-((S or R)-N,S-dimethylsulfonimidoyl)allyl)-2-(1 ,1- difluoroethyl)-4-phenoxypyrimidine-5-carboxamide (65 mg, 0.141 mmol, 98.53% purity) as a white solid.

[0499] LCMS: RT 0.556 min (method 10); m / z 451.1 (M+H)+(ESI*); SFC: RT: 1.334 min (SFC Method 14), 97.42% ee;1H NMR (CDCh, 400 MHz): 9.47 (s, 1 H), 7.79 (d, J = 7.2 Hz, 1 H), 7.56-7.48 (m, 2H), 7.42-7.35 (m, 1 H), 7.26-7.21 (m, 2H), 6.93 (dd, J = 4.8, 15.2 Hz, 1 H), 6.41 (d, J = 15.2 Hz, 1 H), 4.36-4.27 (m, 1 H), 3.00 (s, 3H), 2.73 (s, 3H), 1 .86 (t, J = 18.4 Hz, 3H), 1 .17 - 1 .04 (m, 1 H), 0.80 - 0.63 (m, 2H), 0.57 - 0.45 (m, 2H);19F NMR (CDCh, 400 MHz): -93.84 (s, 2F)

[0500] Preparation of Intermediate 1.1

[0501] Tert-butyl (((diethoxyphosphoryl)fluoromethyl)(methyl)(oxo)- -sulfaneylidene)-4- azanecarboxylate (mixture of four stereoisomers)

[0502] To a solution of tert-butyl (((diethoxyphosphoryl)methyl)(methyl)(oxo)-6- sulfaneylidene)carbamate ( 2100 mg, 6.38 mmol) in THF (21 mL) was added KHMDS in THF (1 M, 8.0 mL, 7.97 mmol) dropwise at -78 °C. The mixture was stirred at -78 °C for 45 min before Selectfluor (3.39 g, 9.56 mmol) was added in batches at -78 °C. The mixture was stirred at -78 °C for 5 min and then, DMF (14 mL) was added. The reaction mixture was warmed to 0 °C, stirred for 3 h under N2, then diluted with EtOAc (30 mL) and quenched with NH4CI (aq., sat., 30 mL) at 0 °C. The mixture was slowly warmed to 20 °C while stirring. The aqueous layer was extracted with EtOAc (50 mL; 3x). The combined organic layer was washed with brine (50 mL; 3x), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by column chromatography (ISCO; 40 g SepaFlash Silica Flash Column, Eluent: 20-60% Ethyl acetate / Petroleum ether @ 100 mL / min) to give the product tert-butyl (((diethoxyphosphoryl)fluoromethyl)(methyl)(oxo)-6-sulfaneylidene)-4-azanecarboxylate (1 g, 2.88 mmol, 45.15 % yield) as a yellow solid.

[0503] MS: (Method 2); m / z 247.9(M-Boc+H)+(ESI+);1H NMR (CDCh, 400 MHz): 6.62-5.90 (m, 1 H), 4.44-4.24 (m, 4H), 3.50-3.29 (m, 3H), 1.53-1.46 (m, 9H), 1.44-1.36 (m, 6H);

[0504] Preparation of Intermediate 1.2, Intermediate 1.3, and Intermediate 1.4

[0505] Tert-butyl (E)-(3-(N-(tert-butoxycarbonyl)-S-methylsulfonimidoyl)-1-cyclopropyl-3- fluoroallyl)carbamate (mixture of four stereoisomers)

[0506] Tert-butyl ((S orR, Z)-3-((S or R)-N-(tert-butoxycarbonyl)-S-methylsulfonimidoyl)-1 - cyclopropyl-3-fluoroallyl)carbamate (mixture of two stereoisomers)

[0507] Tert-butyl ((S orR, Z)-3-((R or S)-N- (tert-butoxycarbonyl)- S-methylsulf onimidoy I) -1- cyclopropyl-3-fluoroallyl)carbamate (mixture of two stereoisomers)

[0508] Intermediate 1.2 Intermediate 1.3 Intermediate 1.4

[0509] To a solution of tert-butyl (((diethoxyphosphoryl)fluoromethyl)(methyl)(oxo)-6-sulfaneylidene)-4- azanecarboxylate (300 mg, 0.864 mmol) in THF (6 mL) were added tert-butyl (1-cyclopropyl-2- oxoethyl)carbamate (207 mg, 1.04 mmol) and K2CO3 (298 mg, 2.16 mmol). The reaction mixture was stirred at 80 °C for 3 h under N2. The resulting mixture was filtered and concentrated under vacuum at 30 °C. The residue was purified by column chromatography (ISCO; 20 g SepaFlash Silica Flash Column, Eluent of 5%~20% Ethyl acetate / Petroleum ether @ 80 mL / min) to give the product tert-butyl (E)-(3-(N- (tert-butoxycarbonyl)-S-methylsulfonimidoyl)-1-cyclopropyl-3-fluoroallyl)carbamate (150 mg, 0.382 mmol, 44.25 % yield, mixture of four compounds) as yellow oil, the product tert-butyl ((S or R, Z)-3-((S or R)-N- (tert-butoxycarbonyl)-S-methylsulfonimidoyl)-1-cyclopropyl-3-fluoroallyl)carbamate (45 mg, mixture of two compounds, crude) as colorless oil and the product tert-butyl ((S or R, Z)-3-((R or S)-N-(tert- butoxycarbonyl)-S-methylsulfonimidoyl)-1 -cyclopropyl-3-fluoroallyl)carbamate (26 mg, mixture of two compounds, crude) as white solid. Intermediate 1.2: RT 0.592 min (LCMS: Method 13); m / z 393.1 (M+H)+(ESI*);1H NMR (CDCh, 400 MHz): 6.22 (dd, J= 8.0, 32.4 Hz, 1 H), 4.92-4.74 (m, 1 H), 4.06-3.91 (m, 1 H), 3.21-3.19 (m, 3H), 1.48 (s, 9H), 1.45 (s, 9H), 1.09-0.97 (m, 1 H), 0.64-0.55 (m, 2H), 0.51-0.32 (m, 2H).

[0510] Intermediate 1.3:1H NMR (CDCh, 400 MHz): 6.34 (dd, J= 10.4, 21.2 Hz, 1 H), 5.26-4.96 (m, 1 H), 4.26-4.06 (m, 1 H), 3.29 (s, 3H), 1 .48 (s, 9H), 1 .44 (s, 9H), 1 .37-1 .25 (m, 1 H), 0.65 - 0.51 (m, 2H), 0.47- 0.38 (m, 2H).

[0511] Intermediate 1.4:1H NMR (CDCh, 400 MHz): 5.96 (dd, J = 10.4, 19.6 Hz, 1 H), 4.87-4.76 (m, 1 H), 4.47-4.34 (m, 1 H), 3.40 (s, 3H), 1.49 (s, 9H), 1.43 (s, 9H), 1.00-1.85 (m, 1 H), 0.71-0.57 (m, 3H), 0.52-0.45 (m, 1 H).

[0512] Preparation of Intermediate 1 .5

[0513] (E)-(3-amino-3-cyclopropyl-1-fluoroprop-1-en-1-yl)(imino)(methyl)-6-sulfanone hydrochloride

[0514] (mixture of four stereoisomers)

[0515] A solution of tert-butyl (E)-(3-( / V-(tert-butoxycarbonyl)-S-methylsulfonimidoyl)-1 -cyclopropyl-3- fluoroallyl)carbamate (30 mg, 0.0764 mmol) in HCI ethyl acetate solution (1.5 mL, 2 M) was stirred at 25 °C for 1 h. The resulting mixture was concentrated under reduced pressure to give the product (E)-(3- amino-3-cyclopropyl-1 -fluoroprop-1 -en-1-yl)(imino)(methyl)- X6-sulfanone hydrochloride (20 mg, crude) as a white solid.

[0516] 1H NMR (DMSO-ofe, 400 MHz): 8.45 (br, 3H), 6.21-6.10 (m, 1 H), 3.56-3.45 (m, 1 H), 3.05 (s, 3H), 1.19-1.14 (m, 1 H), 0.68-0.46 (m, 3H), 0.40-0.27 (m, 1 H).

[0517] Preparation of Example 1

[0518] (E)-N-(1-cyclopropyl-3-fluoro-3-(S-methylsulfonimidoyl)allyl)-2-(1,1-difluoroethyl)-4- phenoxypyrimidine-5-carboxamide (mixture of four stereoisomers)

[0519] To a solution of (E)-(3-amino-3-cyclopropyl-1-fluoroprop-1-en-1-yl)(imino)(methyl)- X6-sulfanone hydrochloride (19 mg, 0.0714 mmol), DIEA (102 uL, 0.571 mmol), 2-(1 ,1 -difluoroethyl)-4- phenoxypyrimidine-5-carboxylic acid (20 mg, 0.0714 mmol) in DMF (1 mL) was added a solution of T4P in ethyl acetate (67 mg, 0.0928 mmol, 50 wt%). The mixture was stirred at 0 °C for 2 h and filtered. The filtrate was directly purified by preparative HPLC (column: Waters xbridge 150*25 mm 10 m; mobile phase: A: 10mM NH4HCO3 in water; B: ACN; B%: 35%-65%, 9.00 min; flow rate: 25.00 mL / min) and lyophilized to give the product (E)-N-(1 -cyclopropyl-3-fluoro-3-(S-methylsulfonimidoyl)allyl)-2-(1 , 1 - difluoroethyl)-4-phenoxypyrimidine-5-carboxamide (11 mg, 0.0234 mmol, 32.80 % yield) as an off-white solid.

[0520] RT 1 .091 min (LCMS: Method 14); m / z 455.3 (M +H)+(ESI+); RT 1 .724 min, 1 .864 min, 1 .972 min, 2.062 min (SFC Method 43));1H NMR (DMSO-de, 400 MHz): 8.99 (s, 1 H), 8.97-8.88 (m, 1 H), 7.55-7.45 (m, 2H), 7.37-7.29 (m, 3H), 6.29-6.12 (m, 1 H), 4.75-4.67 (m, 1 H), 4.57-4.46 (m, 1 H), 3.01 (s, 3H), 1.86 (t, J = 19.2 Hz, 3H), 1.28-1.14 (m, 1 H), 0.56-0.46 (m, 2H), 0.45-0.33 (m, 2H).

[0521] Preparation of:

[0522] Example 1 a

[0523] N-((S or R, E)-1-cyclopropyl-3-fluoro-3-((S or R)-S-methylsulfonimidoyl)allyl)-2-(1,1- difluoroethyl)-4-phenoxypyrimidine-5-carboxamide (single stereoisomer)

[0524] Example 1 b

[0525] N-((S or R, E)-1-cyclopropyl-3-fluoro-3-((R or S)-S-methylsulfonimidoyl)allyl)-2-(1,1- difluoroethyl)-4-phenoxypyrimidine-5-carboxamide (single stereoisomer)

[0526] Example 1c

[0527] N-((R or S, E)-1-cyclopropyl-3-fluoro-3-((R or S)-S-methylsulfonimidoyl)allyl)-2-(1,1- difluoroethyl)-4-phenoxypyrimidine-5-carboxamide (single stereoisomer)

[0528] Example 1 d N-((R or S, E)-1-cyclopropyl-3-fluoro-3-((S or R)-S-methylsulfonimidoyl)allyl)-2-(1,1- difluoroethyl)-4-phenoxypyrimidine-5-carboxamide (single stereoisomer)

[0529] (E)-N-(1-cyclopropyl-3-fluoro-3-(S-methylsulfonimidoyl)allyl)-2-(1 ,1 -difluoroethyl)-4- phenoxypyrimidine-5-carboxamide (200 mg, 0.440 mmol) (SFC Method 43, RT: 1.687 min, 1.831 min, 1.937 min, 2.014 min, respectively) was purified by preparative-SFC (column: DAICEL CHIRALPAK IG (250 mm*30 mm, 10 pm); mobile phase: A for CO2; B for I PA; Gradient elution: 40% B in CO2, 2.40 mins) to give two product solutions, one containing peak 1 and one containing peak 2. The solution containing peak 1 was concentrated under vacuum (30 °C) to give peak A. The solution containing peak 2 was concentrated under vacuum (30 °C) to give peak B.

[0530] Peak B (90 mg, 0.198 mmol) was further purified by preparative SFC (column: DAICEL CHIRALCEL OX (250 mm*30 mm, 10 pm); mobile phase: A for CO2; A for IPA; Gradient elution: 20% B in CO2, 3.80 mins) to afford 2 solutions which were concentrated separately under vacuum (30 °C) to give the corresponding products:

[0531] Example 1 a: N-((S or R,E)-1-cyclopropyl-3-fluoro-3-((S or R)-S-methylsulfonimidoyl)allyl)-2-(1 ,1 - difluoroethyl)-4-phenoxypyrimidine-5-carboxamide (14 mg, 0.0312 mmol, 100% purity) as an off-white solid. RT 1.100 min (LCMS Method 14); m / z 455.1 (M+H)+(ESI+); RT: 1.696 min (SFC Method 43), 96.52% ee;1H NMR (DMSO-de, 400 MHz): 8.99 (s, 1 H), 8.90 (d, J = 8.4 Hz, 1 H), 7.54-7.45 (m, 2H), 7.36- 7.28 (m, 3H), 6.192 (dd, J = 9.2, 33.6 Hz, 1 H), 4.68 (s, 1 H), 4.53-4.47 (m, 1 H), 3.01 (s, 3H), 1.85 (t, J = 19.2 Hz, 3H), 1.25-1.17 (m, 1 H), 0.56-0.47 (m, 2H), 0.46-0.32 (m, 2H);

[0532] Example 1 b: N-((S or R,E)-1-cyclopropyl-3-fluoro-3-((R or S)-S-methylsulfonimidoyl)allyl)-2-(1 ,1- difluoroethyl)-4-phenoxypyrimidine-5-carboxamide (42 mg, 0.0915 mmol, 100% purity,) as a white solid. RT 1.100 min (LCMS Method 14); m / z 455.1 (M+H)+(ESI+); RT: 1.831 min ( SFC Method 43), 99.62% ee;1H NMR (DMSO-de, 400 MHz): 8.99 (s, 1 H), 8.92 (d, J = 8.4 Hz, 1 H), 7.55-7.46 (m, 2H), 7.37-7.27 (m, 3H), 6.21 (dd, J = 9.2, 33.2 Hz , 1 H), 4.72 (s, 1 H), 4.54-4.48 (m, 1 H), 3.01 (s, 3H), 1.85 (t, J = 19.2 Hz, 3H), 1.25-1.15 (m, 1 H), 0.56-0.46 (m, 2H), 0.46-0.32 (m, 2H);

[0533] Peak A (90 mg, 0.198 mmol) was further purified by preparative SFC (column: DAICEL CHIRALCEL OJ(250 mm*30 mm, 10 pm);mobile phase: A for CO2; B for IPA; Gradient elution: 30% B in CO2, 4.60 mins) to give the corresponding products:

[0534] Example 1c N-((R or S,E)-1-cyclopropyl-3-fluoro-3-(( R or S)-S-methylsulfonimidoyl)allyl)-2-(1 ,1- difluoroethyl)-4-phenoxypyrimidine-5-carboxamide (15 mg, 0.0334 mmol, 100% purity) as a yellow solid. RT 1.099 min (LCMS Method 14); m / z 455.1 (M+H)* (ESI*); RT: 1.936 min ( SFC Method 43), 97.33% ee;1H NMR (DMSO-de, 400 MHz): 8.99 (s, 1 H), 8.90 (d, J = 8.4 Hz, 1 H), 7.55-7.45 (m, 2H), 7.37-7.28 (m, 3H), 6.19 (dd, J= 8.8, 33.6 Hz Hz, 1 H), 4.68 (s, 1 H), 4.53-4.47 (m, 1 H), 3.01 (s, 3H), 1.86 (t, J = 19.2 Hz, 3H), 1.23- .17 (m, 1 H), 0.56-0.47 (m, 2H), 0.46-0.32 (m, 2H);

[0535] Example 1 d: N-((R or S,E)-1-cyclopropyl-3-fluoro-3-(( S or R)-S-methylsulfonimidoyl)allyl)-2-(1 ,1- difluoroethyl)-4-phenoxypyrimidine-5-carboxamide (50 mg, 0.109 mmol, 100% purity) as a white solid. RT 1.104 min (LCMS Method 14); m / z 455.1 (M+H)+(ESI*); RT: 2.027 min ( SFC Method 43), 99.53% ee;1H NMR (DMSO-de, 400 MHz): 8.99 (s, 1 H), 8.92 (d, J = 8.0 Hz, 1 H), 7.55-7.43 (m, 2H), 7.39-7.26 (m, 3H), 6.21 (dd, J = 8.8, 33.6 Hz, 1 H), 4.72 (s, 1 H), 4.54-4.48 (m, 1 H), 3.01 (s, 3H), 1.85 (t, J = 19.2 Hz, 3H), 1.29-1.13 (m, 1 H), 0.56-0.47 (m, 2H), 0.46-0.32 (m, 2H);

[0536] Preparation of Example 3 phenoxypyrimidine-5-carboxamide (mixture of four stereoisomers)

[0537] To a mixture of (E)-N-(1-cyclopropyl-3-(S-methylsulfonimidoyl)allyl)-2-(1 ,1 -difluoroethyl)-4- phenoxypyrimidine-5-carboxamide (10 mg, 0.0229 mmol) and DIEA (0.0076 mL, 0.0458 mmol) in DCM (0.5 mL) was added acetyl chloride (2.2 mg, 0.0275 mmol) at 0°C. The mixture was stirred at 0°C for 1 h and concentrated under vacuum. The residue was purified by preparative HPLC (column: Waters xbridge 150*25mm 10um; mobile phase: A: 10 mmol / L NH4HCO3 in water; B: MeCN; B%: 42.00%-62.00%, 8.00 min, flow rate: 25 mL / min) to give the product (E)-N-(3-(N-acetyl-S-methylsulfonimidoyl)-1- cyclopropylallyl)-2-(1 ,1 -difluoroethyl)-4-phenoxypyrimidine-5-carboxamide (6.7 mg, 0.0136 mmol, 59.33% yield) as a yellow gum.

[0538] RT 1.043 min (LCMS: method 15); m / z 479.2 (M +H)+(ESI*). RT 1.319 min, 1.351 min, 1.442 min, 1 .541 min (SFC: Method 47);1H NMR (CDCh, 400 MHz): 9.47 (s, 1 H), 7.80 (d, J = 7.2 Hz, 1 H), 7.55-7.47 (m, 2H), 7.41-7.35 (m, 1 H), 7.25 (d, J= 4.4 Hz, 2H), 7.20-7.03 (m, 1 H), 6.88-6.75 (m, 1 H), 4.34-4.25 (m, 1 H), 3.28 (s, 3H), 2.11-2.07 (m, 3H), 1.86 (t, J = 18.4 Hz, 3H), 1.19-1.05 (m, 1 H), 0.82- 0.73 (m, 1 H), 0.72-0.65 (m, 1 H), 0.59 - 0.44 (m, 2H)

[0539] Preparation of Example 6

[0540] (E)-N-(1-cyclopropyl-3-(S-methyl-N-(methylsulfonyl)sulfonimidoyl)allyl)-2-(1,1-difluoroethyl)-4- phenoxypyrimidine-5-carboxamide (mixture of four stereoisomers)

[0541] To a mixture of (E)-N-(1-cyclopropyl-3-(S-methylsulfonimidoyl)allyl)-2-(1 ,1 -difluoroethyl)-4- phenoxypyrimidine-5-carboxamide (20 mg, 0.0458 mmol) and DIEA (0.023 mL, 0.137 mmol) in DCM (1 mL) was added methanesulfonic anhydride (16 mg, 0.0916 mmol) at O°C. The mixture was stirred at 20°C for 4 h and concentrated under vacuum. The resulting residue was purified by preparative HPLC (column: Waters xbridge 150*25mm 10pm; mobile phase: A: 10 mmol / L NH4HCO3 in water; B: MeCN; B%: 38.00%- 58.00%, 10.00 min, flow rate: 25 mL / min) to give the product (E)-N-(1-cyclopropyl-3-(S-methyl-N- (methylsulfonyl)sulfonimidoyl)allyl)-2-(1 ,1 -difluoroethyl)-4-phenoxypyrimidine-5-carboxamide (5.6 mg, 0.0107 mmol, 23.45% yield) as a yellow solid.

[0542] RT 1.072 min (LCMS: method 15); m / z 515.1 (M +H)+(ESP). RT 1.267 min, 1.417 min, 1.679 min, 1.955 min (SFC: Method 48);1H NMR (CDCI3, 400 MHz): 9.45 (s, 1 H), 7.94-7.81 (m, 1 H), 7.55-7.48 (m, 2H), 7.42-7.35 (m, 1 H), 7.27-7.23 (m, 2H), 7.21-7.08 (m, 1 H), 6.77-6.64 (m, 1 H), 4.35-4.19 (m, 1 H), 3.35- 3.32 (m, 3H), 3.10 (s, 3H), 1.86 (t, J = 18.4 Hz, 3H), 1.21-1.08 (m, 1 H), 0.85-0.67 (m, 2H), 0.58-0.45 (m, 2H)

[0543] Preparation of Example 5a

[0544] N-((R or S, E)-1-cyclopropyl-3-((S or R)-methyl-N-(methylcarbamoyl)sulfonimidoyl)allyl)-2-( 1, 1- difluoroethyl)-4-phenoxypyrimidine-5-carboxamide (single stereoisomer)

[0545] To a mixture of N-((R or S, E)- 1 -cyclop ropyl-3-(S or R-methyls ulfonimidoyl) allyl)-2-(1 ,1 -difl uoroethyl)- 4-phenoxypyrimidine-5-carboxamide (single stereoisomer - compound 32d, 15 mg, 0.0344 mmol) and DIEA (0.023 mL, 0.137 mmol) in DCM (1 mL) was added methylcarbamic chloride (6.4 mg, 0.0687 mmol) at 0°C. The mixture was stirred at 20°C for 12 h and concentrated under vacuum. The resulting residue was purified by preparative HPLC (column: Waters xbridge 150*25mm 10pm;mobile phase A: 10 mmol / L NH4HCO3 in water; B: MeCN; B%: 38%-58%, 15 min, flow rate: 25 mL / min) to give the product N-((R or S, E)-1-cyclopropyl-3-((S or R)-methyl-N-(methylcarbamoyl)sulfonimidoyl)allyl)-2-(1 ,1 -difluoroethyl)-4- phenoxypyrimidine-5-carboxamide (3.1 mg, 0.00629 mmol, 18.32 % yield, purity: 98%) as an orange solid.

[0546] RT 1.035 min (LCMS: method 15); m / z 494.1 (M +H)+(ESP). RT 0.765 min, ee:97.69% (SFC: Method 49);1H NMR (CDCI3, 400 MHz): 9.45 (s, 1 H), 7.86 (d, J= 7.6 Hz, 1 H), 7.57-7.46 (m, 2H), 7.44- 7.32 (m, 1 H), 7.27-7.25 (m, 2H), 7.11 (dd, J= 4.0, 15.2 Hz, 1 H), 6.75 (d, J = 15.2 Hz, 1 H), 4.5-4.859 (m, 1 H), 4.35-4.24 (m, 1 H), 3.27 (s, 3H), 2.74 (d, J= 4.8 Hz, 3H), 1.86 (t, J = 18.4 Hz, 3H), 1.19-1.07 (m, 1 H), 0.81-0.72 (m, 1 H), 0.71-0.64 (m, 1 H), 0.57-0.48 (m, 2H)

[0547] Preparation of Example 9a

[0548] N-(R or S, E)-1-cyclopropyl-3-((S or R)-methyl-N-phenylsulfonimidoyl)allyl)-2-(1, 1 -di fluoroethyl) -4- phenoxypyrimidine-5-carboxamide (single stereoisomer)

[0549] To a solution of N-((R or S, E)-1-cyclopropyl-3-((S or R)-S-methylsulfonimidoyl)allyl)-2-(1 ,1- difluoroethyl)-4-phenoxypyrimidine-5-carboxamide (single stereoisomer - 32d,15 mg, 0.0344 mmol) in methanol (0.5 mL) were added phenylboronic acid (9.6 mg, 0.0790 mmol) and Cu(OAc)2 (0.62 mg, 0.00344 mmol). The mixture was stirred at 20 °C for 4 h under O2 and concentrated under vacuum. The residue was purified by preparative HPLC (column: Waters xbridge 150*25mm 10|jm;mobile phase: A: 10 mmol / L NH4HCO3 in water; B: MeCN; B%: 48.00%-78.00%, 9.00 min, flow rate: 25 mL / min) to give the product N-((R or S, E)-1 -cyclopropyl-3-((S or R)-methyl-N-phenylsulfonimidoyl)allyl)-2-(1 , 1 -difluoroethyl)- 4-phenoxypyrimidine-5-carboxamide (4.0 mg, 0.00776 mmol, 22.59 % yield, purity: 100%) as a yellow solid.

[0550] RT 1.311 min (LCMS: method 15); m / z 513.1 (M +H)+(ESI*). RT 1.197 min, ee: 98.32% (SFC: Method 50);1H NMR (CDCh, 400 MHz): 9.45 (s, 1 H), 7.68 (d, J = 7.6 Hz, 1 H), 7.55-7.47 (m, 2H), 7.43- 7.34 (m, 1 H), 7.19 (d, J= 7.6 Hz, 2H), 7.16-7.10 (m, 2H), 7.07-6.98 (m, 3H), 6.92-6.86 (m, 1 H), 6.51 (dd, J = 1.2, 15.2 Hz, 1 H), 4.40-4.28 (m, 1 H), 3.14 (s, 3H), 1.86 (t, J = 18.4 Hz, 3H), 1.08-0.95 (m, 1 H), 0.74- 0.57 (m, 2H), 0.51-0.34 (m, 2H)

[0551] Preparation of Example 2

[0552] (E)-N-(3-(N-cyano-S-methylsulfonimidoyl)-1-cyclopropylallyl)-2-(1,1-difluoroethyl)-4- phenoxypyrimidine-5-carboxamide (mixture of four stereoisomers)

[0553] To a solution of (E)-N-(1 -cyclopropyl-3-(S-methylsulfonimidoyl)allyl)-2-(1 ,1 -difluoroethyl)-4- phenoxypyrimidine-5-carboxamide (50 mg, 0.115 mmol) and Na2COs (24 mg, 0.229 mmol) in MeCN (2 mL) was added cyanic bromide (24 mg, 0.229 mmol) at 0 °C under N2. The mixture was stirred at 25°C for 12 h under N2. Additional Na2COs (24 mg, 0.229 mmol) and cyanic bromide (24 mg, 0.229 mmol) were added. The mixture was stirred at 25°C for another 12 h under N2, quenched with water (2 mL) and extracted with EtOAc (3 mL; 3x). The combined organic layer was washed with brine (3 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by preparative HPLC (column: Waters xbridge 150*25mm 10pm; mobile phase A: 10 mmol / L NH4HCO3 in water; B: MeCN; B%: 25.00%-55.00%, 15.00 min, flow rate: 25 mL / min) and lyophilized to give the product (E)-N- (3-(N-cyano-S-methylsulfonimidoyl)-1-cyclopropylallyl)-2-(1 , 1 -difluoroethyl)-4-phenoxypyrimidine-5- carboxamide (8.0 mg, 0.0151 mmol, 13.17 % yield, purity: 87.06%) as a light yellow solid.

[0554] RT 1.921 min (LCMS: method 16); m / z 462.1.1 (M +H)+(ESI*);1H NMR (CDCh, 400 MHz): 9.47 (s, 1 H), 7.94-7.92 (m, 1 H), 7.57-7.50 (m, 2H), 7.44-7.37 (m, 1 H), 7.33-7.29 (m, 1 H), 7.28-7.17 (m, 2H), 6.71-6.56 (m, 1 H), 4.32-4.20 (m, 1 H), 3.28-3.25 (m, 3H), 1.87 (t, J = 18.4 Hz, 3H), 1.25-1.14 (m, 1 H),

[0555] 0.88-0.72 (m, 2H), 0.60-0.53 (m, 2H)

[0556] Preparation of Example 4

[0557] Methyl (E)-((3-cyclopropy l-3-(2-(1,1 -di fluoroethyl) -4-phenoxypyrimidine-5-carboxamido) prop-1 - en-1-yl)(methyl)(oxo)- -sulfaneylidene)carbamate (mixture of four stereoisomers)

[0558] To a mixture of (E)-N-(1-cyclopropyl-3-(S-methylsulfonimidoyl)allyl)-2-(1 ,1 -difluoroethyl)-4- phenoxypyrimidine-5-carboxamide (50 mg, 0.115 mmol) and DIEA (151 uL, 0.916 mmol) in DCM (2 mL) was added methyl carbonochloridate (270 uL, 3.49 mmol) dropwise under N2 at 0°C. The mixture was stirred at 0°C for 1 h under N2, quenched with NaHCOs (aq., sat., 2 mL) and extracted with EtOAc (3 mL; 3x). The combined organic layer was washed with brine (3 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by preparative HPLC (column: Waters xbridge 150*25mm 10|jm;mobile phase: A: 10 mmol / L NH4HCO3 in water; B: MeCN; B%: 38.00%-58.00%, 10.00 min, flow rate: 25 mL / min) and lyophilized to give the product methyl (E)-((3-cyclopropyl-3-(2-(1 ,1- d ifl uoroethy l)-4-p henoxypyri mid i ne-5-carboxami do)prop- 1 -en-1 -yl) (methyl) (oxo)-6- sulfaneylidene)carbamate (24 mg, 0.0478 mmol, 41 .70% yield, purity: 97.6%) as a yellow solid.

[0559] RT 1.913 min (LCMS: method 16); m / z 495.1 (M +H)+(ESP);1H NMR (CDCh, 400 MHz): 9.46 (s, 1 H), 7.91-7.76 (m, 1 H), 7.56-7.47 (m, 2H), 7.43-7.34 (m, 1 H), 7.27-7.22 (m, 2H), 7.21-7.05 (m, 1 H), 6.74-6.60 (m, 1 H), 4.34-4.23 (m, 1 H), 3.70-3.66 (m, 3H), 3.28 (s, 3H), 1.86 (t, J = 18.4 Hz, 3H), 1.13- 1.12 (m, 1 H), 0.81-0.65 (m, 2H), 0.57-0.46 (m, 2H)

[0560] Preparation of Example 22

[0561] N-((R or S, E)-1-cyclopropyl-3((S or R)-(S-methyl-N-(pyridin-3-yl)sulfonimidoyl)allyl)-2-( 1, 1- difluoroethyl)-4-phenoxypyrimidine-5-carboxamide (single stereoisomer)

[0562] To a solution of N-((R or S, E)-1-cyclopropyl-3-((S or R)-methylsulfonimidoyl)allyl)-2-(1 , 1- difluoroethyl)-4-phenoxypyrimidine-5-carboxamide (single stereoisomer 32d, 20 mg, 0.0458 mmol) in MeOH (1 mL) were added pyridin-3-ylboronic acid (13 mg, 0.105 mmol) and Cu(OAc)2 (0.83 mg, 0.00458 mmol). The mixture was stirred at 20°C for 4 h under an O2 atmosphere (1 bar) and concentrated under vacuum. The residue was purified by preparative HPLC (column: Waters xbridge 150*25mm 10pm; mobile phase: A: 10 mmol / L NH4HCO3 in water; B: MeCN; B%: 30.00%-60.00%, 15.00 min, flow rate: 25 mL / min) and lyophilized directly to give the product N-((R or S, E)-1-cyclopropyl-3((S or R)-methyl-N- (py ridi n-3-yl)sulfo ni mi doy l)al I y l)-2- (1 , 1 -d ifl uoroethyl)-4-p henoxy pyri mid i ne-5-carboxami de (7.2 mg, 0.0135 mmol, 29.52 % yield, purity: 96.5%) as a light yellow solid.

[0563] RT 1.093 min (LCMS: method 15); m / z 514.2 (M+H)+(ESI*). RT 1.311 min, ee:97.96% (SFC: Method 50);1H NMR (ACN-ob, 400 MHz): 9.13 (s, 1 H), 8.22-8.09 (br s, 1 H), 8.09 - 7.95 (br s, 1 H), 7.71 (d, J= 7.6 Hz, 1 H), 7.54-7.48 (m, 2H), 7.39-7.34 (m, 1 H), 7.30-7.25 (m, 2H), 7.25-7.19 (m, 1 H), 7.09-7.03 (m, 1 H), 6.99 (dd, J = 4.8, 15.2 Hz, 1 H), 6.62 (dd, J= 1.6, 15.2 Hz, 1 H), 4.30-4.23 (m, 1H), 3.11 (s, 3H), 1.86 (t, J = 18.8 Hz, 3H), 1.15-1.05 (m, 1 H), 0.63-0.49 (m, 2H), 0.42-0.34 (m, 2H)

[0564] N-((R or S, E)-1-cyclopropyl-3((S orR)-(N-cyclopropyl-S-methylsulfonimidoyl)allyl)-2-(1,1- difluoroethyl)-4-phenoxypyrimidine-5-carboxamide (single stereoisomer) To a solution of N-((R or S, E)-1-cyclopropyl-3-((S or R)-S-methylsulfonimidoyl)allyl)-2-(1 ,1- difluoroethyl)-4-phenoxypyrimidine-5-carboxamide (single stereoisomer 32d, 25 mg, 0.0573 mmol), CU(OAC)2 (1.0 mg, 0.00573 mmol), TEA (17 mg, 0.172 mmol) and 2,2'-bipyridine (0.89 mg, 0.00573 mmol) in DCE (1 mL) was added cyclopropylboronic acid (9.8 mg, 0.115 mmol). The reaction mixture was stirred at 20°C for 16 h under an O2 atmosphere (1 bar) and concentrated under vacuum. The residue was purified by preparative HPLC (column: Waters xbridge 150*25mm 10|jm;mobile phase: A: 10 mmol / L NH4HCO3 in water; B: MeCN; B%: 30.00%-60.00%, 9.00 min, flow rate: 25 mL / min) and lyophilized directly to give the product N-((R or S, E)-1-cyclopropyl-3 ((S or R)-(N-cyclopropyl-S- methylsulfonimidoyl)allyl)-2-(1 ,1 -difluoroethyl)-4-phenoxypyrimidine-5-carboxamide (2.5 mg,0 .00520 mmol, 9.09 % yield) as a light yellow gum.

[0565] RT 1.106 min (LCMS: method 15); m / z 477.2 (M +H)+(ESI+). RT 0.804 min, ee:97.96% (SFC: Method 50);1H NMR (CDCh, 400 MHz): 9.47 (s, 1 H), 7.79 (d, J = 7.2 Hz, 1 H), 7.57-7.47 (m, 2H), 7.43- 7.34 (m, 1 H), 7.24 (d, J = 7.6 Hz, 2H), 7.00 (dd, J = 4.8, 15.2 Hz, 1 H), 6.48 (dd, J = 1.6, 15.2 Hz, 1 H), 4.36-4.26 (m, 1 H), 3.01 (s, 3H), 2.54-2.44 (m, 1 H), 1.86 (t, J = 18.4 Hz, 3H), 1.16-1.01 (m, 1 H), 0.79-0.63 (m, 2H), 0.56-0.45 (m, 5H), 0.43-0.36 (m, 1 H)

[0566] The following Table 1 provides an overview on the compounds described in the example section:

[0567] Table 1

[0568] Further exemplary compounds of the invention which are all mixture of 4 stereoisomers and which can be prepared with the methods disclosed herein or analogous to the methods disclosed herein, or using the methods known to the skilled person, are listed below.

[0569] Preparation of reference example 1

[0570] In the following, preparation of reference example 1 is described. This example is identical to example 87 reported in WO 2024 / 010782.

[0571] Preparation of reference Intermediate 1.1

[0572] Ethyl 2-(1-ethoxyvinyl)-4-phenoxypyrimidine-5-carboxylate To a solution of ethyl 2-chloro-4-phenoxypyrimidine-5-carboxylate (3.00 g, 10.8 mmol) in DMF (30 mL) was added Pd(PPh3)2Cl2 (756 mg, 1.08 mmol) and tributyl(1-ethoxyvinyl)stannane (5.83 g, 16.1 mmol) under N2, and then stirred at 80°C for 12 h under N2. The resulting mixture was poured into KF (aq., sat., 40 mL) and stirred for 30 min. The resulting mixture was filtered and the filtrate was extracted with EtOAc (40 mL; 2x). The combined organic layers were washed with brine (40 mL; 2x), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO; 40 g SepaFlash Silica Flash Column, Eluent of 0%-20% ethyl acetate / petroleum ether; gradient @ 80 mL / min) and concentrated under vacuum to give the product ethyl 2-(1- ethoxyvinyl)-4-phenoxypyrimidine-5-carboxylate (2.70 g, 8.59 mmol, 79.79 % yield) as a brown oil.

[0573] LCMS: RT 0. 558 min (method 7); m / z 315.1 (M+H)+(ESI+);1H NMR (CDCh, 400 MHz): 9.17 (s, 1 H), 7.48-7.38 (m, 2H), 7.29-7.25 (m, 1 H), 7.22-7.18 (m, 2H), 5.37 (d, J= 2.0 Hz, 1 H), 4.53 (d, J= 2.0 Hz, 1 H), 4.44 (q, J = 8.0 Hz, 2H), 3.94 (q, J = 8.0 Hz, 2H), 1 .45-1 .40 (m, 6H) Preparation of reference Intermediate 1.2

[0574] Ethyl 2-acetyl-4-phenoxypyrimidine-5-carboxylate

[0575] To a solution of ethyl 2-(1 -ethoxyvinyl)-4-phenoxypyrimidine-5-carboxylate (2.7 g, 8.59 mmol) in DCM (50 mL) was added CF3COOH (2.0 mL, 35.4 mmol), and the mixture was stirred at 20°C for 20 h. The mixture was diluted with DCM (100 mL) and washed with NaHCOs (aq., sat, 50 mL; 2x). The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum to give the crude product ethyl 2-acetyl-4-phenoxypyrimidine-5-carboxylate (1600 mg, 5.59 mmol, 65.07 % yield) as a brown solid. The crude product was used directly without further purification.

[0576] LCMS: RT 0. 515 min (method 7); m / z 287.0 (M+H)+(ESI+);1H NMR (CDCh, 400 MHz): 9.25 (s, 1 H), 7.50-7.42 (m, 2H), 7.35-7.28 (m, 1 H), 7.25 - 7.18 (m, 2H), 4.48 (q, J= 8.0 Hz, 2H), 2.47 (s, 3H), 1.44 (t, J = 8.0 Hz, 3H)

[0577] Preparation of reference Intermediate 1.3

[0578] Ethyl 2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxylate

[0579] A solution of ethyl 2-acetyl-4-phenoxypyrimidine-5-carboxylate (800 mg, 2.79 mmol) in DAST (4.0 mL, 56.2 mmol) was stirred at 20 °C for 1 h. The resulting mixture was diluted with DCM (30 mL) and slowly poured into ice water (30 mL) over 5 min. The organic layer was washed with water (20 mL; 2x), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by column chromatography (ISCO; 20 g SepaFlash Silica Flash Column, Eluent of 5%~20% ethyl acetate / petroleum ether @ 40 mL / min) to give the product ethyl 2-(1 ,1 -difluoroethyl)-4- phenoxypyrimidine-5-carboxylate (680 mg, 2.21 mmol, 78.94 % yield) as a brown solid.

[0580] LCMS: RT 0. 560 min (method 7); m / z 309.0 (M+H)+(ESI*);1H NMR (CDCh, 400 MHz): 9.19 (s, 1 H), 7.48-7.40 (m, 2H), 7.33-7.27 (m, 1 H), 7.23-7.18 (m, 2H), 4.47 (q, J = 8.0 Hz, 2H), 1.84 (t, J = 18.4 Hz, 3H), 1.44 (t, J= 8.0 Hz, 3H);19F NMR (CDCh, 400 MHz): -93.95 (s, 2F)

[0581] Preparation of reference Intermediate 1.4

[0582] 2-( 1, 1-difluoroethyl)-4-phenoxypyrimidine-5-carboxylic acid

[0583] To a solution of ethyl 2-(1 ,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxylate (580 mg, 1.88 mmol) in THF (6 mL) and water (3 mL) at 0°C was added LiOH H2O (158 mg, 3.76 mmol), and the mixture was stirred at 0°C for 1 h. The mixture was diluted with EtOAc (30 mL). The pH was adjusted to pH to 2-3 with HCI (aq., 1 M) and the mixture was washed with water (20 mL; 2x). The combined organics layers were dried over anhydrous Na2SO4, filtered and concentrated under vacuum to give the product 2-(1 ,1- difluoroethyl)-4-phenoxypyrimidine-5-carboxylic acid (410 mg, 1 .46 mmol, 77.77 % yield) as a brown solid. It was used directly in the next step without any further purification.

[0584] LCMS: RT 0.476min (method 7); m / z 281.0 (M +H)+(ESI+).;1H NMR (CDCh, 400 MHz): 9.18 (s, 1 H), 7.34-7.28 (m, 2H), 7.23-7.16 (m, 1 H), 7.15-7.05 (m, 2H), 1.74 (t, J = 18.4 Hz, 3H);19F NMR (CDCh, 400 MHz): -93.86 (s, 2F)

[0585] Preparation of reference Intermediate 1.5

[0586] Tert-butyl (S, E)-( 1-cyclopropyl-3-(methylsulfonyl)allyl)carbamate

[0587] To a solution of diethyl ((methylsulfonyl)methyl)phosphonate (381 mg, 1.66 mmol) in THF (6 mL) was added NaH (66 mg, purity: 60%, 1 .66 mmol,) at 0°C and the mixture was stirred for 1 h. After 1 h, tertbutyl N-[(1 S)-1-cyclopropyl-2-oxo-ethyl]carbamate (300 mg, 1.51 mmol) was added and the mixture was stirred at 0 °C for 1 .5 h. In parallel, another reaction was conducted with the same protocol but on different scale of diethyl ((methylsulfonyl)methyl)phosphonate (165 mg, 0.652 mmol). The combined resulting Ill mixture was poured into NH4CI (aq., sat., 15 mL) and extracted with ethyl acetate (20 ml; 3x). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by flash silica gel chromatography (ISCO; 20 g SepaFlash Silica Flash Column, Eluent of 0 to -15% ethyl acetate / petroleum ether gradient @ 60 mL / min) to give the product tert-butyl (S,E)-(1-cyclopropyl-3-(methylsulfonyl)allyl)carbamate (250 mg, 0.908 mmol, 42.07 % yield) as a white solid.

[0588] LCMS: RT 0.452 min (method 7); m / z 298.1 (M+Na)+(ESI+); SFC: RT 1.067 min (Method 44), ee:99.79%;1H NMR (CDCh, 400 MHz): 6.94 (dd, J = 4.8, 15.2 Hz, 1 H), 6.53 (d, J =15.2 Hz, 1 H), 4.77- 4.70 (m, 1 H), 3.72 (br s, 1 H), 2.96 (s, 3H), 1.46 (s, 9H), 0.96-0.84 (m, 1 H), 0.73-0.56 (m, 2H), 0.51-0.42 (m, 1 H), 0.40-0.31 (m, 1 H)

[0589] Preparation of reference Intermediate 1.6

[0590] (S,E)-1-cyclopropyl-3-(methylsulfonyl)prop-2-en-1 -amine

[0591] A solution of tert-butyl (S,E)-(1 -cyclopropyl-3-(methylsulfonyl)allyl)carbamate (230 mg, 0.835 mmol) in a solution of HCI in EtOAc (4.6 mL, 2M) was stirred at 20 °C for 2 h. The resulting mixture was concentrated under vacuum to give the crude product (S, E)-1 -cyclopropyl-3-(methylsulfonyl)prop-2-en-1 - amine hydrochloride (170 mg, 0.803 mmol, 96.14 % yield, HCI salt) as a white solid. The crude product was used directly in the next step without any further purification.

[0592] 1H NMR (400 MHz, MeOD): 7.05-6.98 (m, 1 H), 6.93-6.83 (m, 1 H), 3.37-3.32 (m, 1 H), 3.05 (s, 3H), 1.18-1.07 (m, 1 H), 0.85-0.78 (m, 2H), 0.66-0.47 (m, 2H) Preparation of reference example 1

[0593] (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5- carboxamide

[0594] To a solution of (S,E)-1 -cyclopropyl-3-(methylsulfonyl)prop-2-en-1 -amine hydrochloride (68 mg, 0.321 mmol) and 2-(1 ,1 -difluoroethyl)-4-phenoxypyrimidine-5-carboxylic acid (90 mg, 0.321 mmol) in DMF (2 mL) at 0°C was added DIEA (0.18 mL, 0.963 mmol) and T4P in EtOAc (694 mg, 50% purity, 0.963 mmol), and the mixture was stirred at 0 °C for 1 h. The resulting mixture was poured into ice-water (20 mL) and extracted with EtOAc (20 mL; 2x). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by preparative HPLC (column: Unisil 3-100 C18 Ultra 150*50mm*3 pm;mobile phase: A: 0.225% FA in water, B: MeCN; B%: 38%-68%, 10 min) and lyophilized directly to give the product (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-2-(1 ,1- difl uoroethyl)-4-p henoxypyrimidi ne-5-carboxamide (86.25 mg, 0.197 mmol, 61 .39 % yield) as a white solid.

[0595] LCMS: RT 0.504min (method 7); m / z 438.1 (M +H)+(ESI+). SFC: RT 1.270 min: (Method 13, 97.51 % ee);1H NMR (CDCh, 400 MHz): 9.47 (s, 1 H), 7.78 (d, J = 8.0 Hz, 1 H), 7.58-7.47 (m, 2H), 7.43- 7.35 (m, 1 H), 7.27-7.20 (m, 2H), 7.03 (dd, J = 4.8, 15.2 Hz, 1 H), 6.61 (d, J =15.2 Hz, 1 H), 4.33-4.19 (m, 1 H), 2.97 (s, 3H), 1.86 (t, J = 18.4 Hz, 3H), 1.16-1.03 (m, 1 H), 0.81-0.63 (m, 2H), 0.58 - 0.44 (m, 2H);19F NMR (CDCh, 400 MHz): -93.83 (s, 2F)

[0596] Biological evaluation of the exemplary compounds

[0597] Exemplary compounds of formula (I) were tested in selected biological and / or physicochemical assays one or more times. When tested more than once, data are reported as either average values or as median values, wherein the average value, also referred to as the arithmetic mean value, represents the sum of the values obtained divided by the number of times tested, and the median value represents the middle number of the group of values when ranked in ascending or descending order. If the number of values in the data set is odd, the median value is the middle value. If the number of values in the data set is even, the median is the arithmetic mean of the two middle values. The in vitro pharmacological, pharmacokinetic and physicochemical properties of the compounds can be determined according to the following assays and methods.

[0598] WRN Protein Expression and Purification

[0599] WRN (amino acid 517-1093, L1074F isoform) was purchased from CRELUX GmbH, Planegg, Germany. WRN was produced in a Sf21 expression system, purified, and stored and frozen in 50 mM HEPES / NaOH, 500 mM NaCI, 5% Glycerol and 0.5 mM TCEP, pH 7.5.

[0600] Forked DNA Preparation

[0601] The forked DNA was prepared by mixing the two DNA strands in a 1 :1.8 ratio of OLIGOB-FLU (FAM(fluorescein)-GAACGA ACA CAT CGG GTA CGT TTT TTT TTT TTT TTT TTT TTT TTT TTT TT) (SEQ ID NO.: 1) to OLIGOA-BHQ1 (TTT TTT TTT TTT TTT TTT TTT TTT TTT TTT CGT ACC CGA TGT GTT CGT TC-BHQ1 ) (SEQ ID NO.: 2) in DNA-annealing buffer (10 mM Tris / HCI pH 7.5, 50 mM NaCI & 1 mM EDTA, pH 8.0). The mixture is heated to 95 °C and cooled down to 35 °C at a rate of 5°C per minute in a Roche LightCycler® 96 System.

[0602] In vitro WRN Helicase assay

[0603] A continuous, fluorescence-based helicase assay was set up to measure ATP-coupled unwinding of a forked DNA substrate by WRN (517-1093, L1074F isoform). Fluorescently labelled forked DNA was used as a DNA substrate, the DNA sequences were described by Sommers et al. 2019 (doi: 10.1371 / journal. pone.0210525), with different fluorescent dyes. WRN mediated separation of the forked DNA leads to an increase in fluorescence. ssDNA complementary to the quenching strand, oligo-block (GAA CGA ACA CAT CGG GTA CG) (SEQ ID NO.: 3), is included in 10-fold excess to prevent reannealing of the forked DNA. Labelled DNA was purchased from IDT (Integrated DNA Technologies, Inc.) and ssDNA oligo-block from Microsynth AG.

[0604] Reaction

[0605] A typical reaction consists of 30 pL of 1 nM WRN in 25 mM Tris / HCI pH 7.5, 100 mM NaCI, 1 mM DTT, 0.01 % TWEEN-20, 0.025 mg / mL BSA, 0.1 mM forked DNA substrate, 1 mM Oligo-BLOCK and 0.5 mM Mg-ATP in a 384 well black plate (Thermo Scientific). To assess inhibition, IC50s were determined by pre-incubating compounds (10 mM DMSO stock solutions) with WRN in a 12-point custom dilution series to a final DMSO concentration of 1 %. DMSO only controls were included to represent no inhibition (high control) Compounds and WRN were pre-incubated for 2 or 6 hours at room temperature, before the addition of forked DNA, ssDNA oligo-block, and Mg-ATP to initiate the reaction. Fluorescence (Ex: 485 nm, Em: 535 nm, gain 66, 5 flashes per measurement) was measured on a Tecan Spark plate reader for 45 minutes, in 60 seconds intervals at 27.5°C. All points were measured in triplicate.

[0606] Data Analysis

[0607] Data analysis was performed using dotmatics (www.dotmatics.com). Enzymatic activity was assessed by the rates of DNA unwinding, measured by the rate of increase in fluorescence. The initial slopes were normalized to % activity, as follows: percentage of activity (Normalized) = (Sample Value / High Control Value (Average of DMSO only wells)) * 100%. The resulting dose response was fitted with the following equation: Y=Bottom + (Top-Bottom) / (1 +(IC50 / X)AHillSlope), where X values are concentrations and Y is the response (decreasing as X increases). The curve fitting was performed using the least squares regression method. Reported values are the mean of at least 2 independent replicates. The Absorbance ICso value of compounds of Formula (I) in Examples 1 to 189 are provided in Table 3 below. In case there is a blank cell in the Table, this means that no data have been generated. Cellular Viability Assay

[0608] The colon carcinoma cell lines HCT116 and SW48 (both microsatellite instability- high and WRN- inhibition sensitive cell lines) and SW620 (microsatellite stable and WRN-inhibition insensitive cell line) were obtained from ATCC.

[0609] HCT116 were cultured in growth medium composed of McCoy's 5A (Modified) Medium (ThermoFisher Scientific Cat# 16600082), 1x Penicillin-Streptomycin (ThermoFisher Scientific Cat# 15140163), and 10% fetal bovine serum (ThermoFisher Scientific Cat#A5256801). SW48 and SW620 were cultured in growth medium composed of Leibovitz's L-15 Medium (ThermoFisher Scientific Cat#11415056), 1x Penicillin-Streptomycin and 10% fetal bovine serum.

[0610] HCT 116, SW48 and SW620 were plated at 1500 cells / well, 2000 cel Is / well and 2000 cells / well, respectively, in 96-well black plates with clear flat bottom (Huberlab #.655 983), in a volume of 200 pL per well. The outer wells of the plate were filled with DPBS (ThermoFisher Scientific Cat#14190250) to compensate evaporation mediated effects in the plate periphery. After 24 hours, the compounds were dispensed with the Tecan digital dispenser (D300e), starting at 20 pM for a 8-point dose curve at 1 :4 dilution, in duplicates. The final concentration of DMSO was normalized to the highest compound concentration and a maximum of 0.1 %.. After 4d of incubation, 145 pl of the growth medium were removed and 50 pL of Cell Titer-Gio (Promega Cat#G9243) were added per well. Plates were shaken for 2 minutes and after an incubation of 10 minutes, luminescence was read using a plate reader (Tecan Spark).

[0611] For data analysis, the assay background signal which was determined in wells that contained medium only was subtracted from all the data points. Averaged values of the samples were normalized to DMSO treated control samples. The fitting of the logistic curve were performed using the following equation: Y=Bottom + (Top-Bottom) / (1 +(IC50 / X)AHillSlope), where X values are concentrations and Y is the response (decreasing as X increases). The curve fitting was performed using the least squares regression method.

[0612] The ICso value of compounds of Formula (I) in Examples are provided in Table 3 below. In case there is a blank cell in the Table, this means that no data have been generated.

[0613] Table 3

[0614] (T) Example number

[0615] @ IC50 in pM determined in WRN helicase assay described under In vitro WRN Helicase assay following 6 hours incubation. The readout of this assay is not reflecting the full potential of compounds relying on an ATP-cooperative mode of action, since ATP is added after 6 hours of incubation with the compound.

[0616] (3) IC50 in pM determined in WRN helicase assay described under In vitro WRN Helicase assay following 2 hours incubation. The readout of this assay is not reflecting the full potential of compounds relying on an ATP-cooperative mode of action, since ATP is added after 2 hours of incubation with the compound.

[0617] @ IC50 in pM determined in SW48 assay described under Cellular viability assay

[0618] (5) IC50 in pM determined in HCT116 assay described under Cellular viability assay

[0619] ® IC50 in pM determined in SW620 assay described under Cellular viability assay

[0620] In case of (T) and (2) the readout is limited by the ATP-cooperative binding mode of the compounds of the invention, and thus this readout may be less suitable for analysing the compounds of the invention than cell-based assays. Further assays

[0621] Human plasma stability

[0622] 1 . Materials

[0623] 1.1. Plasma Animal or human plasma were purchased from BiolVT or other qualified suppliers.

[0624] 1.2. Control compounds:

[0625] Propantheline is used as control compound in CD-1 mouse and human plasma. Enalapril, bisacodyl, and procaine are used as control compounds in SD rat, beagle dog, and cynomolgus monkey plasma, respectively.

[0626] 2. Preparation of Working Solution

[0627] Stock solution: 10 mM test compound and control compound (except propantheline) in DMSO; 10 mM propantheline in H2O.

[0628] Working solution: 100 pM test compound and control compound (except propantheline) in 100% DMSO; 100 pM propantheline in H2O.

[0629] 3. Assay Procedure

[0630] 3.1. Plasma Preparation

[0631] Frozen plasma was thawed under cold water for 10 to 20 minutes, and then centrifuged at 3220*g for 5 minutes.

[0632] 3.2. Incubation

[0633] Aliquots of 2.00 pL test compound or control compounds working solutions were mixed with 98.0 pL of blank plasma from animal and human in corresponding time points TO, T 10, T30, T60, and T120 in duplicate, respectively. Incubate all sample plates in a water bath at 37.0°C. The final concentration of test compound and control compounds was 2.00 pM in the incubation system.

[0634] 3.3. Sample Processing and Extraction Procedure

[0635] At each corresponding time point, all samples were extracted with a protein precipitation method by adding 500 pL of stop solution. All sample collection plates were then sealed and shaken for 10 minutes prior to centrifugation at 4000 rpm and 4°C for 20 minutes. And 150 pL / well of the resulting supernatant were transferred to corresponding bioanalysis plate prior to LC-MS / MS analysis.

[0636] 4. Bioanalytical Analysis

[0637] Concentrations of test compounds and positive controls in the samples are determined by using a liquid chromatography-tandem mass spectrometry (LC-MS / MS) method.

[0638] 5. Data Calculation

[0639] In the determination of the in vitro elimination constant, ke, of test compound and control compounds, the peak area ratios (PAR) of analyte / internal standard were used to calculate the percentage of remaining (%Remaining) with the following equation:

[0640] Re r ininc - PAR of anahte to mternal standard at each x ie point > .....

[0641] “ PAR of anahie to internal standard at T = C

[0642] When the %Remaining value at the maximal incubation time, which was 120 min in this study, was higher than 75%, it is considered to be within the acceptable experimental variation, i.e., CV =25%. Therefore, a corresponding T1 / 2 value of >289.1 min is reported.

[0643] 6. Reference

[0644] [1] Li Di, Edward H. Kerns, Yan Hong, Hong Chen, International Journal of Pharmaceutics. Development and application of high throughput plasma stability assay for drug discovery 297 (2005) 110- 119.

[0645] The T1 / 2 value is reported in table 4 for selected examples. As evidenced by the data in Table 4, Examples 32, 32d, 33 and 33d show an improved in vitro stability in human plasma in comparison to Reference Example 1

[0646] Table 4 The T1 / 2 value is reported for selected example compounds.

[0647] Kinetic solubility assay

[0648] The Kinetic solubility assay employs the shake flask method followed by HPLC-UV analysis. For exemplary compounds, the kinetic solubility was measured according to the following protocol:

[0649] 1 . Samples were weighed and dissolved in 100% DMSO to make a stock solution of 10 mM. About 100 pL of stock solution is needed to cover this assay.

[0650] 2. Test compounds and controls (10 mM in DMSO, 10 pL / tube) were added into the buffer (490 pL / well) which were placed in a Mini-UniPrep filter. The buffer was prepared as the customer’s requirement.

[0651] 3. The kinetic solubility samples were vortexed for 2 minutes.

[0652] 4. The solubility solutions were shaken in an orbital shaker for 24 hr at room temperature .

[0653] 5. 200 pL of each solubility solution were transferred into a 96-deep well for analysis when the samples were directly filtered by the syringeless filter device.

[0654] 6. The test compound concentration of the filtrate were determined using HPLC-UV.

[0655] 7. Three UV standard solutions were injected into HPLC from low to high concentrations, followed by testing of the K.S. supernatant. Testing samples were injected in duplicate.

[0656] Bidirectional permeability in Caco2

[0657] The bidirectional permeability in Caco-2 cells assay was performed for the exemplary compounds of formula (I) according to the following protocol:

[0658] 1. Caco-2 cells purchased from ATCC were seeded onto polyethylene membranes (PET) in 96- well BD insert plates at 1 x 105 cells / cm2, and refreshed medium every 4~5 days until to the 21stto 28thday for confluent cell monolayer formation.

[0659] 2. The integrity of the monolayer was verified by performing Lucifer yellow rejection assay.

[0660] 3. The quality of the monolayer was verified by measuring the unidirectional (A— >B) permeability of fenoterol / nadolol (low permeability marker), propranolol / metopronolol (high permeability marker) and bi-directional permeability of digoxin (a P-glycoprotein substrate marker) in duplicate wells.

[0661] 4. Standard assay conditions for test compounds:

[0662] -test concentration: 2 pM (DMSO<1 %);

[0663] -replicates: n=2;

[0664] -directions: bi-directional transport including A^B and B^A;

[0665] -incubation time: single time point, 2hours;

[0666] -transport buffer: HBSS containing 10 mM HEPES, pH7.40±0.05;

[0667] -incubation condition: 37±1 °C, 5% CO2, relatively saturated humidity.

[0668] 5. Dosing solution were spiked and mixed with transport buffer and stop solution (containing an appropriate internal standard (IS)) as TO sample.

[0669] 6. At the end of incubation, sample solutions from both donor and receiver wells were mixed with stop solution immediately.

[0670] 7. All samples including TO samples, donor samples and receiver samples were analyzed using LC / MS / MS. Concentrations of test compound were expressed as peak area ratio of analytes versus IS without a standard curve. Liver Microsomes Stability Assay

[0671] 1 . Materials

[0672] 1.1 Liver microsomes

[0673] Animal or human liver microsomes were purchased from Xenotech or Corning and stored in a freezer (lower than -60°C) before use.

[0674] 1 .2 p-nicotinamide adenine dinucleotide phosphate reduced form, tetrasodium salt, Vendor: Chem-lmpex International, Cat.No. 00616

[0675] 1 .3 Control compounds: Testosterone, diclofenac and propafenone.

[0676] 2. Preparation of Working Solution

[0677] Stock Solution: 10 mM test compound in DMSO.

[0678] Working solution: 100 pM test or control compounds in 100% acetonitrile (concentration of organic solvent: 1 % (v / v) DMSO and 99% (v / v) acetonitrile)

[0679] 3. Assay Procedure

[0680] A total of two sample plates with 96-well format were prepared for incubation, labeled as 'Incubation' T60 and 'Incubation' NCF60. Empty 'Incubation' T60 and NCF60 plates were pre-warmed for 10 min minutes. Liver microsomes were diluted to 0.56 mg / mL in 100 mM phosphate buffer. Microsome working solutions (0.56 mg / mL) were transferred (445 uL) into pre-warmed 'Incubation' T60 and NCF60 plates, followed by incubation for 10 min at 37°C with constant shaking.

[0681] Liver microsomes (54 pL) were transferred to a Blank60 plate, followed by the addition of 6 pL NAPDH cofactor and 180 pL stop solution (acetonitrile containing internal standards) into each well.

[0682] An aliquot (5 pL) of compound working solution (100 pM) was added into the 'incubation' plates (T60 and NCF60) containing microsomes and mixed 3 times thoroughly.

[0683] For the 'Incubation' NCF60 plate, 50 uL of buffer was added and mixed 3 times thoroughly. The plates were incubated at 37°C for 60 min while shaking, samples were mixed once and 60 pL was transferred from the NCF60 incubation plate to the stop plate containing stop solution after the 60- min incubation.

[0684] Stop solution (180 pL) and NAPDH cofactor (6 pL) were added to 'Quenching' plate TO. Plates were chilled to prevent evaporation.

[0685] For the 'Incubation' T60 plate: mixed 3 times thoroughly, and immediately removed 54 pL mixture for the 0-min time point to stop plate ('Quenching' plate TO). NAPDH cofactor (44 pL) was added to the 'Incubation' T60 plate. The plate was incubated at 37°C for 60 min while shaking. At 5, 15, 30, 45, and 60 min, 180 pL stop solution was added to the 'Quenching' plates, samples were mixed once, and 60 pL was serially transferred from 'Incubation' T60 plate per time point. Consequently, for the wells containing the test or control compounds, the final concentration was 1 pM for test compounds, testosterone, diclofenac and propafenone, 0.5 mg / mL for animal or human liver microsomes, 0.01 % (v / v) for DMSO and 0.99% (v / v) for acetonitrile.

[0686] All sampling plates were shaken for 10 min, then centrifuged at 3220 xg for 20 minutes at 4°C. Supernatant (80 pL) was transferred into 240 pL HPLC water, and mixed by plate shaker for 10 min. Each bioanalysis plate was sealed and shaken for 10 minutes prior to LC-MS / MS analysis.

[0687] 4. Bioanalytical Analysis

[0688] Concentrations of test con pounds and positive controls, testosterone, diclofenac and propafenone in the samples were determined by using a liquid chromatography-tandem mass spectrometry (LC- MS / MS) method.

[0689] 5. Data Calculation

[0690] In the determination of the in vitro elimination constant, ke, of test compound and control compounds, the peak area ratios (PAR) of analyte / internal standard were used to calculate the percentage of remaining (%Remaining) with the following equation: point

[0691] CLmt(mic) = 0.693 / T1 / 2 / mg microsome protein per mL

[0692] CLint(liver) = CLmt(rnic) x mg microsomal protein / g liver weight x g liver weight / kg body weight

[0693] According to the well-stirred model, hepatic intrinsic clearance and hepatic clearance can be calculated by the following formula.

[0694] CL(liver) = (CLint(liver) x fu x Qh) / (CLint(liver) x fu + Qh)

[0695] The default value of fu (the fraction unbound in blood) is assumed as 1.

[0696] The parameters in equations are listed in following table.

[0697] Liver Weight Hepatic Blood Flow (Qh) Microsomal Protein

[0698] Species

[0699] (g / kg Body Weight) I1 2i (mL / min / kg) n2i (mg / g liver weight) Mouse 88 90.0

[0700] Rat 40 55.2

[0701] Dog 32 30.9 45

[0702] Monkey 30 43.6

[0703] Human 20 20.7

[0704] When the %Remaining value at the maximal incubation time, which was 60 min in this study, was higher than 75%, it is considered to be within the acceptable experimental variation, i.e., CV =25%. Therefore, a corresponding T1 / 2 value of >145 min is reported. Consequently, the corresponding CLint(mic)value is reported as <9.6 pL / min / mg protein.

[0705] 6. References

[0706] [1] Brian Davies and Tim Morris, Physiological Parameters in Laboratory Animals and Human. Pharmaceutical Research, Vol. 10 No.7, 1993

[0707] [2] Journal of Pharmacology and Experimental Therapeutics, 1997, 283(1): 46-58

[0708] Hepatocyte Metabolic Stability

[0709] 1 . Materials

[0710] 1.1 Hepatocyte

[0711] Animal or human hepatocytes were purchased from BioreclamationIVT or RILD.

[0712] 1 .2 Control compounds: 7-Ethoxycoumarin and 7-Hydroxycoumarin

[0713] 2. Preparation of Working Solution

[0714] Stock Solution: 10 mM test compound and 30 mM control compound in DMSO.

[0715] Working solution: 100 pM test compound or 300 pM control compounds in 100% acetonitrile (Concentration of organic solvent: 1 % (v / v) DMSO and 99% (v / v) acetonitrile)

[0716] 3. Assay Procedure

[0717] Cryopreserved hepatocytes were thawed, isolated, and suspended in Williams’ Medium E, then diluted with pre-incubated Williams’ Medium E to a final concentration of 0.510x106 cells / mL.

[0718] One hundred and ninety-eight (198) pL of cells suspension (0.510x106 cells / mL) were added into appropriate wells. The incubation plate was pre-incubated in a 37.0°C incubator for about 10 minutes. Then 2 pL of test compound and positive controls were added into plate except for the blank plate. Incubate all plates at 37.0°C in a 95.0% humidified incubator at 5.0% CO2 to start the reactions with constant shaking.

[0719] For the TO plate, a corresponding quenching plate was prepared by adding 125 pL / well of acetonitrile containing 200 ng / mL tolbutamide and 200 ng / mL labetalol as internal standards (stop solution), and 25 pL / well of the incubation sample were transferred to this plate after shaking for 1 minute to ensure homogeneity.

[0720] At each time-point, the corresponding plate was removed from the incubator, and 25 pL / well of the corresponding sample was transferred to its corresponding quenching plate containing 125 pL / well of stop solution. Medium control (MC) plates (TO-MC and T90-MC) were prepared by adding everything except for Williams’ Medium E at the corresponding time-points.

[0721] The plates were then sealed and shaken for 10 minutes prior to centrifugation at 4000 rpm and 4°C for 20 minutes. 80 pL / well of the resulting supernatant were diluted with 240 pL / well of pure water and sealed and shaken for 10 minutes prior to LC-MS / MS analysis.

[0722] 4. Bioanalytical Analysis

[0723] Concentrations of test compounds and positive controls, 7-Ethoxycoumarin and 7- Hydroxycoumarin in the samples were determined by using a liquid chromatography-tandem mass spectrometry (LC-MS / MS) method.

[0724] 5. Data Calculation

[0725] In the determination of the in vitro elimination constant, ke, of test compound and control compounds, the peak area ratios (PAR) of analyte / internal standard were used to calculate the percentage of remaining (%Remaining) with the following equation: PAR of anal te re internal standard ar each tirnepcint i

[0726] CLmt (hep) = k / million cells per mL

[0727] CLmt (liver) = CLmt (hep) x liver weight (g / kg body weight) x hepatocellularity

[0728] According to the well-stirred model, hepatic intrinsic clearance and hepatic clearance can be calculated by the following formula.

[0729] CL(liver) - (CLint(liver)xfuX Qh) / (CLint(liver)xfu+ Qh)

[0730] The default value of fu (the fraction unbound in blood) is assumed as 1.

[0731] The parameters in equations are listed in following table. Liver Weight (g / kg Body Liver Blood Flow Hepatocell ularity peCieSWeight) R-3) (Qh) (mL / min / kg) [2-3]

[0732] Mouse 88 90.0 135*106

[0733] Rat 40 55.2 117x10®

[0734] Dog 32 30.9 215x10®

[0735] Monkey 30 43.6 120x10®

[0736] Human 20 20.7 139x10®

[0737] When the %Remaining value at the maximal incubation time, which was 90 min in this study, was higher than 75%, it is considered to be within the acceptable experimental variation, i.e., CV =25%.

[0738] Therefore, a corresponding T1 / 2 value of >216.8 min is reported. Consequently, the corresponding CLint(hep) ( L / min / 106 cells) is reported as <7.5.

[0739] 6. References

[0740] [1] Anna-Karin Sohlenius-Sternbeck. Determination of the hepatocell ularity number for human, dog, rabbit, rat and mouse livers from protein concentration measurements. Toxicology in Vitro, Vol. 20 No.8, 2006

[0741] [2] Brian Davies and Tim Morris, Physiological Parameters in Laboratory Animals and Human. Pharmaceutical Research, Vol. 10 No.7, 1993

[0742] [3] Obach R S, Baxter J G, Liston T E, et al. The prediction of human pharmacokinetic parameters from preclinical and in vitro metabolism data [J]. Journal of Pharmacology and Experimental Therapeutics, 1997, 283(1): 46

[0743] Mouse PK

[0744] Group Test Article No. of Sex Dose Dose Cone Dose Vehicle

[0745] No. animals Route (mg / kg) (mg / mL) Volume

[0746] 01Ex^Ple3 Female IV bolus 1 0.2 5 10%NMP+90% water

[0747] 32d

[0748] 10%NMP+15%Kolliph n_ Example0_ .nr>or EL

[0749] 02 3 Female PC 10 1

[0750] +1 %Tween20+74%

[0751] (20%HP-p-CD) Reference 0.2 5 10%NMP+90% water

[0752] Example 1

[0753] 10%NMP+15%Kolliph

[0754] Reference or EL

[0755] Example 1 +1 %Tween20+74% (20%HP-p-CD)

[0756] SAMPLE COLLECTION

[0757] ANIMAL SPECIFICATIONS

[0758] Strain: BALB / c nude

[0759] Species: Mouse

[0760] Vender: LC or other qualified vendors

[0761] Gender: Female

[0762] Age: 6-9 W

[0763] Total Number of Animals: 6

[0764] Overnight Fast of Animals: True

[0765] Comments: Fast for PO, fed for IV

[0766] Food Returned: 4 hours post dose. Only for PO.

[0767] Euthanasia: CO2 euthanasia Animal No. of Non-surgery: 6

[0768] Species Abbr: M

[0769] Table 5. Mouse PK parameters reported for selected examples

[0770] As evidenced by the data in Table 5 example 32d shows a longer half-life (T1 / 2) and a reduced plasma clearance (CL) after iv application as well as improved exposure (AUG) and bioavailability after oral application in comparison to reference example 1.

[0771] Activity-based protein profiling (ABPP)

[0772] Activity-based protein profiling (ABPP) is a chemical proteomic method for functional interrogation of enzymes within complex proteomes.

[0773] Assay Procedure:

[0774] 1 . Compound treatment of HCT 116 cells: 10uM compound or DMSO for 2 hours at 37°C with an N=3 for each group.

[0775] 2. Protein extraction and total protein quantitation

[0776] 3. Biotin-PEO-IAA (BPI) incubation with cell lysate

[0777] 4. DTT reduction and IAA alkylation, followed by acetone precipitation

[0778] 5. Trypsin digestion and biotin-peptides enrichment

[0779] 6. MS analysis with DIA method

[0780] 7. Data analysis with DIANN

[0781] Accordingly, in the present experiment HCT 116 cells were treated with either DMSO or compound 32d (1 pM) for 2 hours, followed by treatment with a cysteine reactive, isotopically labeled probe. Samples (quadruplicates) were merged, trypsinized and enriched for proteomic analysis. The isotopically labelled probe allows quantification of specific cysteine engagement in the compound treated samples (measured as decreased enrichment over the DMSO sample).

[0782] In the experiment performed with compound 32d, 33,665 cysteine residues were identified within the cell. Among those, WRN C727 is the top target. Furthermore, only 13 other cysteines have been seen as being significantly enriched (p<0.01 , engagement >75%) in this data set. This is immediately apparent from the data shown in Figure 1 . This allows concluding that compound 32d is highly selective across the proteome, In other words, the compound of the present invention is a highly selective, clean covalent inhibitor of WRN.

Claims

Claims1. A compound of formulaor a pharmaceutically acceptable salt thereof, wherein:A is selected from aryl, heteroaryl, heterocycloalkyl, heterocycloalkenyl, cycloalkyl, cycloalkenyl, C2 alky nyl, -N(CI-5 alkyl)(Ci 5 alkyl), C2-haloalkyl and — (C1-2 haloalkylene)-cycloalkyl, wherein said aryl, said heteroaryl, said heterocycloalkyl, said heterocycloalkenyl, said cycloalkyl and said cycloalkenyl are each optionally substituted with one or more R1, and wherein said C2 alkynyl is optionally substituted with C1-6 alkyl, C1-6 haloalkyl, aryl (such as phenyl) or heteroaryl (such as thien-2-yl);B is selected from arylene and heteroarylene, wherein said arylene and said heteroarylene are each optionally substituted with one or more R2;X is selected from -CONH-, -CON(CI-6 alkyl)-, -CON(CI-6 haloalkyl)-, -SO2NH-, -SO2N(CI-6alkyl)- , -SO2N(CI-6 haloalkyl)-, -CH(CF3)NH-, -CH(CF3)N(CI-6alkyl)-, and -CH(CF3)N(CI-6haloalkyl)-;Y is a moiety according to formula:wherein Ry1is selected from H, C1-6 alkyl, C3-s cycloalkyl, and 5 or 6-membered heterocyclyl, wherein said cycloalkyl and said heterocyclyl are each optionally substituted with one or more groups selected from Rs, Ry2is selected from -H, -F and -CN, Ry3is selected from C1-4 alkyl, C3- 8 cycloalkyl, phenyl and 5 or 6-membered heterocyclyl, wherein said cycloalkyl, said phenyl and said heterocyclyl are each optionally substituted with one or more groups selected from Rs, Z is selected from =0 and =NRZ2, wherein each RZ1and Rz2are independently selected from hydrogen, -CN, C1-5 alkyl, C3-8 cycloalkyl, heterocycloalkyl, phenyl, 5-6 membered heteroaryl, -C0-C1-5 alkyl, -COO-C1-5 alkyl, -SO2-C1-5 alkyl, -CONH2, -C0NH(Ci-5alkyl), and -C0N(CI-5 alkyl)(Ci-5 alkyl), wherein said alkyl is optionally substituted with one or more groups selected from Hal, -OH, -ON, -0-(Ci-5 alkyl), -NH2, -NH(CI-5 alkyl), -N(CI-5 alkyl)(Ci-5 alkyl), -CONH2, - C0NH(CI-5 alkyl) and -CO-N(Ci-s alkyl)(Ci 5 alkyl), wherein said cycloalkyl, said heterocycloalkyl, said phenyl and said heteroaryl are each independently optionally substituted with one or more groups selected from Rs(preferably are each independently substituted with one or more groups selected from Rs), wherein optionally RZ1and Ry3are joined to form, together with the N atom that otherwise carries RZ1and the sulfur atom that otherwise carries Ry3, a 5 to 7 membered heterocyclic ring, which is optionally substituted with one or more groups selected from Rs; each R1is independently selected from C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, -(C0-3 alkylene)-OH, -(C0-3 alkylene)-0(Ci-5 alkyl), -(C0-3 alkylene)-0(Ci-5 alkylene)-OH, -(C0-3 alkylene)-0(Ci-5 alkylene)-0(Ci-5 alkyl), -(C0-3 alkylene)-SH, -(C0-3 alkylene)-S(Ci-5 alkyl), -(C0-3 alkylene)-S(Ci-5 alkylene)-SH, -(C0-3 alkylene)-S(Ci-5 alkylene)-S(Ci-5 alkyl), -(C0-3 alkylene)-NH2, -(C0-3 alkylene)-NH(Ci-s alkyl), -(C0-3 alkylene)-N(Ci-s alkyl)(Ci-5 alkyl), -(C0-3 alkylene)-NH-OH, -(C0-3 alkylene)-N(Ci-s alkyl)-OH, -(C0-3 alkylene)-NH-O(Ci-s alkyl), -(C0-3 alkylene)-N(Ci-5 alkyl)-0(Ci-5 alkyl), -(C0-3 alkylene)-halogen, -(C0-3 alkylene)-(Ci-5 haloalkyl), -(C0-3 alkylene)-0-(Ci-5 haloalkyl), -(C0-3 alkylene)-CN, -(C0-3 alkylene)-NC>2, -(C0-3 alkylene)-CHO, -(C0-3 alkylene)-C0-(Ci-5 alkyl), -(C0-3 alkylene)-COOH, -(C0-3 alkylene)-C0-0-(Ci-5 alkyl), -(C0-3 alkylene)-0-C0-(Ci-5 alkyl), -(C0-3 alkylene)-C0-NH2, -(C0-3 alkylene)-CO-NH(Ci-5alkyl), -(C0-3 alkylene)-CO-N(Ci-5alkyl)(Ci-5 alkyl), -(C0-3 alkylene)-NH-CO-(Ci-5alkyl), -(C0-3 alkylene)-N(Ci-s alkyl)-C0-(Ci-5 alkyl), -(C0-3 alkylene)-NH-C0-0-(Ci-5 alkyl), -(C0-3 alkylene)-N(Ci-s alkyl)-C0-0-(Ci-5 alkyl), -(C0-3 alkylene)-0-C0-NH-(Ci-5 alkyl), -(C0-3 alkylene)-O-CO-N(Ci-5alkyl)-(Ci-5 alkyl), -(C0-3 alkylene)-SO2-NH2, -(C0-3 alkylene)-SO2-NH(Ci-5 alkyl), -(C0-3 alkylene)-SO2-N(Ci-5 alkyl)(Ci-5 alkyl), -(C0-3 alkylene)-NH-SO2-(Ci-5 alkyl), -(C0-3 alkylene)-N(Ci-s alkyl)-SO2-(Ci-5 alkyl), -(C0-3 alkylene)-SC>2-(Ci-5 alkyl), -(C0-3 alkylene)-S0-(Ci-5 alkyl), -(C0-3 alkylene)-Si(Ci-5 alkyl)(Ci-5 alkyl)(Ci-5 alkyl), -(C0-3 alkylenej-SFs, -0-(Co-3 alkylene)-carbocyclyl, -0-(Co-3 alkylene)-heterocyclyl, -NH-(Co-3 alkylene)-carbocyclyl, -NH-(Co-3 alkylene)-heterocyclyl, -N(CI-5 alkyl)-(Co-3 alkylene)-carbocyclyl, -N(CI-5 alkyl)-(Co-3 alkylene)-heterocyclyl, -(C0-3 alkylene)-carbocyclyl, and -(C0-3 alkylene)-heterocyclyl, wherein the carbocyclyl moiety in said - 0-(Co-3 alkylene)-carbocyclyl, the carbocyclyl moiety in said -NH-(Co-3 alkylene)-carbocyclyl, the carbocyclyl moiety in said -N(CI-5 alkyl)-(Co-3 alkylene)-carbocyclyl, the carbocyclyl moiety in said -(C0-3 alkylene)-carbocyclyl, the heterocyclyl moiety in said -0-(Co-3 alkylene)-heterocyclyl, the heterocyclyl moiety in said -NH-(Co-3 alkylene)-heterocyclyl, the heterocyclyl moiety in said -N(CI-5 alkyl)-(Co-3 alkylene)-heterocyclyl, and the heterocyclyl moiety in said -(Co-3 alkylene)-heterocyclyl are each optionally substituted with one or more groups independently selected from Ci-4 alkyl, halogen, -CN, -NO2, -OH, -0-(Ci-4 alkyl), -SH, -S-(Ci-4 alkyl), -NH2, - NH(CI-4 alkyl), -N(CI-4 alkyl)(Ci-4 alkyl), -COOH, -COO(Ci-4 alkyl), -CONH2, -C0NH(CI-4 alkyl), -CON(CI-4 alkyl)(Ci-4 alkyl), -NHC0(Ci-4 alkyl) and -N(CI-4 alkyl)-C0(Ci-4 alkyl);R2is independently selected from C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, -(C0-3 alkylene)-OH, -(C0-3 alkylene)-0(Ci-5 alkyl), -(C0-3 alkylene)-O(Ci-s alkylene)-OH, -(C0-3 alkylene)-O(Ci-s alkylene)-0(Ci-5 alkyl), -(C0-3 alkylene)-SH, -(C0-3 alkylene)-S(Ci-5 alkyl), -(C0-3 alkylene)-S(Ci-s alkylene)-SH, -(C0-3 alkylene)-S(Ci-5 alkylene)-S(Ci-5 alkyl), -(C0-3 alkylene)-NH2, -(C0-3 alkylene)-NH(Ci-5alkyl), -(C0-3 alkylene)-N(Ci-s alkyl)(Ci-5 alkyl), -(C0-3 alkylene)-NH-OH, -(C0-3 alkylene)-N(Ci-5alkyl)-OH, -(C0-3 alkylene)-NH-O(Ci-5alkyl), -(C0-3 alkylene)-N(Ci-s alkyl)-0(Ci-5 alkyl), -(C0-3 alkylene)-halogen, -(C0-3 alkylene)-(Ci-5 haloalkyl), -(C0-3 alkylene)-0-(Ci-5 haloalkyl), -(C0-3 alkylene)-CN, -(C0-3 alkylene)-N02, -(C0-3 alkylene)-CHO, -(C0-3 alkylene)-C0-(Ci-5 alkyl), -(C0-3 alkylene)-COOH, -(C0-3 alkylene)-C0-0-(Ci-5 alkyl), -(C0-3 alkylene)-0-C0-(Ci-5 alkyl), -(C0-3 alkylene)-C0-NH2, -(C0-3 alkylene)-C0-NH(Ci-5 alkyl), -(C0-3 alkylene)-C0-N(Ci-5 alkyl)(Ci-5 alkyl), -(C0-3 alkylene)-NH-C0-(Ci-5 alkyl), -(C0-3 alkylene)-N(Ci-s alkyl)-CO-(Ci-5alkyl), -(C0-3 alkylene)-NH-CO-O-(Ci-5alkyl), -(C0-3 alkylene)-N(Ci-s alkyl)-CO- O-(Ci-5alkyl), -(C0-3 alkylene)-O-CO-NH-(Ci-5alkyl), -(C0-3 alkylene)-O-CO-N(Ci-5alkyl)-(Ci-5 alkyl), -(C0-3 alkylene)-SO2-NH2, -(C0-3 alkylene)-SO2-NH(Ci-5 alkyl), -(C0-3 alkylene)-SO2-N(Ci-5 alkyl)(Ci-5 alkyl), -(C0-3 alkylene)-NH-SO2-(Ci-5 alkyl), -(C0-3 alkylene)-N(Ci-s alkyl)-SO2-(Ci-5 alkyl), -(C0-3 alkylene)-SO2-(Ci-5 alkyl), -(C0-3 alkylene)-S0-(Ci-5 alkyl), -(C0-3 alkylene)-Si(Ci-5 alkyl)(Ci-5 alkyl)(Ci-5 alkyl), -(C0-3 alkylene)-SFs, -0-(Co-3 alkylene)-carbocyclyl, -0-(Co-3 alkylene)-heterocyclyl -(C0-3 alkylene)-carbocyclyl, and -(C0-3 alkylene)-heterocyclyl, wherein the carbocyclyl moiety in said -0-(Co-3 alkylene)-carbocyclyl, the carbocyclyl moiety in said -(C0-3 alkylene)-carbocyclyl, the heterocyclyl moiety in said -0-(Co-3 alkylene)-heterocyclyl and the heterocyclyl moiety in said -(C0-3 alkylene)-heterocyclyl are each optionally substituted with one or more groups independently selected from C1-4 alkyl, halogen, -CN, -NO2, -OH, -0-(Ci-4 alkyl), -SH, -S-(Ci-4 alkyl), -NH2, -NH(CI-4 alkyl), -N(CI-4 alkyl)(Ci-4 alkyl), -COOH, -COO(Ci-4 alkyl), - CONH2, -CONH(Ci-4 alkyl), -CON(CI-4 alkyl)(Ci-4 alkyl), -NHCO(Ci-4 alkyl) and -N(CI-4 alkyl)- CO(Ci-4 alkyl); and each Rsis independently selected from C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, -(C0-3 alkylene)-OH, -(C0-3 alkylene)-0(Ci-5 alkyl), -(C0-3 alkylene)-O(Ci-s alkylene)-OH, -(C0-3 alkylene)-0(Ci-5 alkylene)-0(Ci-5 alkyl), -(C0-3 alkylene)-SH, -(C0-3 alkylene)-S(Ci-5 alkyl), -(C0-3 alkylene)-S(Ci-5 alkylene)-SH, -(C0-3 alkylene)-S(Ci-5 alkylene)-S(Ci-5 alkyl), -(C0-3alkylene)-NH2, -(Co-3 alkylene)-NH(Ci-s alkyl), -(Co-3 alkylene)-N(Ci-s alkyl)(Ci-5 alkyl), -(Co-3 alkylene)-NH-OH, -(Co-3 alkylene)-N(Ci-5alkyl)-OH, -(Co-3 alkylene)-NH-O(Ci-s alkyl), -(Co-3 alkylene)-N(Ci-5 alkyl)-0(Ci-5 alkyl), -(Co-3 alkylene)-halogen, -(Co-3 alkylene)-(Ci-5 haloalkyl), -(Co-3 alkylene)-O-(Ci-5 haloalkyl), -(C0-3 alkylene)-CN, -(C0-3 alkylene)-NC>2, -(C0-3 alkylene)-CHO, -(C0-3 alkylene)-CO-(Ci-5 alkyl), -(C0-3 alkylene)-COOH, -(C0-3 alkylene)-CO-O-(Ci-5 alkyl), -(C0-3 alkylene)-O-CO-(Ci-5 alkyl), -(C0-3 alkylene)-CO-NH2, -(C0-3 alkylene)-CO-NH(Ci-5 alkyl), -(C0-3 alkylene)-CO-N(Ci-5alkyl)(Ci-5alkyl), -(C0-3 alkylene)-NH-CO-(Ci-5alkyl), -(C0-3 alkylene)-N(Ci-5alkyl)-CO-(Ci-5alkyl), -(C0-3 alkylene)-NH-CO-O-(Ci-5 alkyl), -(C0-3 alkylene)-N(Ci-5alkyl)-CO-O-(Ci-5alkyl), -(C0-3 alkylene)-O-CO-NH-(Ci-5 alkyl), -(C0-3 alkylene)-O-CO-N(Ci-5alkyl)-(Ci-5alkyl), -(C0-3 alkylene)-SO2-NH2, -(C0-3 alkylene)-SO2-NH(Ci-5 alkyl), -(C0-3 alkylene)-SO2-N(Ci-5 alkyl)(Ci-5 alkyl), -(C0-3 alkylene)-NH-SO2-(Ci-5 alkyl), -(C0-3 alkylene)-N(Ci-s alkyl)-SO2-(Ci-5 alkyl), -(C0-3 alkylene)-SO2-(Ci-5 alkyl), -(C0-3 alkylene)-SO-(Ci-5 alkyl), -(C0-3 alkylene)-Si(Ci-5 alkyl)(Ci-5 alkyl)(Ci-5 alkyl), -(C0-3 alkylene)-SFs, -0-(Co-3 alkylene)-carbocyclyl, -0-(Co-3 alkylene)-heterocyclyl, -NH-(Co-3 alkylene)-carbocyclyl, -NH-(Co-3 alkylene)-heterocyclyl, -N(CI-5 alkyl)-(Co-3 alkylene)-carbocyclyl, -N(CI-5 alkyl)-(Co-3 alkylene)-heterocyclyl, -(C0-3 alkylene)-carbocyclyl, and -(C0-3 alkylene)-heterocyclyl, wherein the carbocyclyl moiety in said - 0-(Co-3 alkylene)-carbocyclyl, the carbocyclyl moiety in said -NH-(Co-3 alkylene)-carbocyclyl, the carbocyclyl moiety in said -N(CI-5 alkyl)-(Co-3 alkylene)-carbocyclyl, the carbocyclyl moiety in said -(C0-3 alkylene)-carbocyclyl, the heterocyclyl moiety in said -0-(Co-3 alkylene)-heterocyclyl, the heterocyclyl moiety in said -NH-(Co-3 alkylene)-heterocyclyl, the heterocyclyl moiety in said - N(CI-5 alkyl)-(Co-3 alkylene)-heterocyclyl, and the heterocyclyl moiety in said -(C0-3 alkylene)-heterocyclyl are each optionally substituted with one or more groups independently selected from C1-4 alkyl, halogen, -CN, -NO2, -OH, -O-(Ci-4 alkyl), -SH, -S-(Ci-4 alkyl), -NH2, - NH(CI-4 alkyl), -N(Ci-4 alkyl)(Ci-4 alkyl), -COOH, -COO(Ci-4 alkyl), -CONH2, -CONH(Ci-4 alkyl), -CON(CI-4 alkyl)(Ci-4 alkyl), -NHCO(Ci-4 alkyl) and -N(Ci-4 alkyl)-CO(Ci-4 alkyl).

2. The compound of claim 1 , wherein Y is a moiety according to formula:wherein Ry1is selected from H, Ci-4 alkyl, C3-8 cycloalkyl, and 5 or 6-membered heterocyclyl, wherein said cycloalkyl and said heterocyclyl are each optionally substituted with one or more groups selected from Rs, Ry2is selected from -H, -F and -CN, Ry3is selected from C1-4 alkyl, C3-8 cycloalkyl, phenyl and 5 or 6-membered heterocyclyl, wherein said cycloalkyl, said phenyl and said heterocyclyl are each optionally substituted with one or more groups selected from Rs, Z is selected from =0 and =NRZ2, wherein each RZ1and Rz2are independently selected from hydrogen, -CN, C1-5 alkyl, C3-8 cycloalkyl, heterocycloalkyl, phenyl, 5-6 membered heteroaryl, - CO-C1-5 alkyl, -COO-C1-5 alkyl, -SO2-C1-5 alkyl, -CONH2, -CONH(CI-5alkyl), and -C0N(CI-5 alkyl)(Ci-5 alkyl), wherein said alkyl is optionally substituted with one or more groups selected from Hal, -OH, -CN, -O-(Ci-5alkyl), -NH2, -NH(CI-5 alkyl), -N(Ci-5alkyl)(Ci-5 alkyl), -CONH2, - C0NH(CI-5 alkyl) and -CO-N(Ci-s alkyl)(Ci 5 alkyl), wherein said cycloalkyl, said heterocycloalkyl, said phenyl and said heteroaryl are each optionally independently substituted with one or more groups selected from Rs(preferably are each independently substituted with one or more groups selected from Rs).

3. The compound of claim 1 or 2, wherein the following provisions apply to formula (I):Y is not a moiety according to formula:or a moiety according to formula:wherein Ry1is selected from H, C1-4 alkyl, C3-8 cycloalkyl, and 5 or 6-membered heterocyclyl, Ry2is selected from -H, -F and -CN, and Ry3is selected from C1-4 alkyl, C3-8 cycloalkyl, and 5 or 6- membered heterocyclyl, and wherein the bonds drawn asindicate that both Z and E configurations of the double bond are possible.

4. The compound of any one of claims 1 to 3, wherein A is -CF2-cyclopropyl or -CF2CH3, preferably wherein A is -CF2CH3.5 The compound of any one of claims 1 to 4, wherein B is heteroarylene, optionally substituted with one or more R2.

6. The compound of claim 5, wherein B is 2,5-pyridinylene, optionally substituted with -0-(Co-3 alkylenej-carbocyclyl, or -0-(Co-3 alkylene)-heterocyclyl, preferably with -O-carbocyclyl, or - O-heterocyclyl, more preferably with -O-carbocyclyl, in particular -O-phenyl, or wherein B is 2,5-pyrimidinylene, optionally substituted with -0-(Co-3 alkylene)-carbocyclyl, or - 0-(Co-3 alkylene)-heterocyclyl, preferably with -O-carbocyclyl, or -O-heterocyclyl, more preferably with -O-carbocyclyl, in particular -O-phenyl.

7. The compound of claim 6, wherein B is according to formula:wherein the left empty valence of B as shown in the structural formula, is connected to A, and the right empty valence of B is connected to X.

8. The compound of any one of claims 1 to 4, wherein B is arylene, optionally substituted with one or more R2.

9. The compound of claim 8, wherein B is 1 ,4-phenylene optionally substituted with one or more - 0-(Co-3 alkylenej-carbocyclyl, or -0-(Co-3 alkylenej-heterocyclyl, preferably with -O-carbocyclyl, or -O-heterocyclyl, more preferably with -O-carbocyclyl, even more preferably -O-phenyl, preferably at the carbon atom in the ring adjacent to the carbon atom connected to X.

10. The compound of any one of claims 1 to 9, wherein X is -CONH-.11 . The compound of any one of claims 1 to 10, wherein Ry1is selected from methyl and cyclopropyl.

12. The compound of any one of claims 1 to 11 , wherein Ry2is -H or F, preferably wherein Ry2is -H.

13. The compound of any one of claims 1 to 12, wherein Ry3is methyl.

14. The compound of any one of claims 1 to 13, wherein Z is =0.

15. The compound of any one of claims 1 to 14, wherein RZ1is selected from -CN, cyclopropyl, cyclobutyl, oxetanyl, phenyl, pyridyl, -CO-CH3, -COO-CH3, -SO2-CH3, -CONH2, -C0NH(CH3), and -CON(CH3)(CH3), preferably wherein RZ1is selected from -CN, cyclopropyl, oxetanyl, phenyl, pyridyl, -CO-CH3, -COO-CH3, -SO2-CH3, and -C0NH(CH3), or wherein RZ1is selected from -CN, cyclopropyl, tetrahydrofuranyl (such as 3-tetrahydrofuranyl), phenyl, pyridyl, -CO-CH3, -COO- CH3, -SO2-CH3, and -CONH(CH3)..

16. The compound of any one of claims 1 to 9, wherein Y is selected from:1 , and wherein n is 0, 1 or 2, preferably n is 0 or 1, more preferably n is 0.

17. The compound of claim 1 , wherein A and B are as defined in any one of claims 1 to 16, wherein X is -CONH-, wherein X is connected to B through its carbon atom, and wherein Y is a moiety according to formula:or a moiety according to formula:wherein Ry1is selected from H, Ci-4 alkyl, C3-8 cycloalkyl, and 5 or 6-membered heterocyclyl, Ry2is selected from -H, -F and -CN, and Ry3is selected from C1-4 alkyl, C3-8 cycloalkyl, and 5 or 6- membered heterocyclyl, and wherein the bonds drawn asindicate that both Z and E configurations of the double bond are possible.

18. The compound of claim 1 , selected frompharmaceutically acceptable salt of these, preferably a compound selected from N-((S,E)-1 -cyclopropyl-3-((R)-S-methylsulfonimidoyl)allyl)- 2-(1 ,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide, N-((S,E)-1-cyclopropyl-3-((S)-S- methylsulfonimidoyl)allyl)-2-(1 ,1 -difluoroethyl)-4-phenoxypyrimidine-5-carboxamide, N-((R,E)-1- cyclopropyl-3-((R)-S-methylsulfonimidoyl)allyl)-2-(1 ,1 -difluoroethyl)-4-phenoxypyrimidine-5- carboxamide, and N-((R,E)-1 -cyclop ropyl-3-((S)-S-methyls ulfoni midoyl) al lyl) -2- ( 1 , 1 - difluoroethyl)-4-phenoxypyrimidine-5-carboxamide, characterized by the highest retention time of these compounds in an SFC experiment according to method 13 (SFC method 13), or a pharmaceutically acceptable salt thereof, or a compound selected from N-((S, E)-1 -cyclopropyl-3- ((R)-N,S-dimethylsulfonimidoyl)allyl)-2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxamide, N-((S,E)-1 -cyclopropyl-3- ((S)- N, S-di methylsulfoni midoy l)al lyl) -2- (1 , 1 -d ifl uoroethyl)-4- phenoxypyrimidine-5-carboxamide, N-((R,E)-1-cyclopropyl-3-((R)-N,S- dimethylsulfonimidoyl)allyl)-2-(1 ,1 -difluoroethyl)-4-phenoxypyrimidine-5-carboxamide, and N-((R,E)-1 -cyclopropyl -3-((S)-N, S-d imethylsulfoni midoy l)al lyl) -2- (1 , 1 -d ifl uoroethyl)-4- phenoxypyrimidine-5-carboxamide, characterized by the second highest retention time of thesecompounds in an SFC experiment according to method 14 (SFC method 14) , or a pharmaceutically acceptable salt thereof, or a compound selected from N-((S, E)-1 -cyclopropyl-3- ((R)-N,S-dimethylsulfonimidoyl)allyl)-2-(1 , 1 -difluoroethyl)-4-phenoxypyrimidine-5-carboxamide, N-((S,E)-1 -cyclopropyl-3- ((S)- N, S-di methylsulfoni midoy l)al lyl) -2- (1 , 1 -d ifl uoroethyl)-4- phenoxypyrimidine-5-carboxamide, N-((R,E)-1-cyclopropyl-3-((R)-N,S- dimethylsulfonimidoyl)allyl)-2-(1 ,1 -difluoroethyl)-4-phenoxypyrimidine-5-carboxamide, and N- ((R , E)-1 -cyclopropyl -3-((S)-N, S-d imethylsulfoni midoy l)al lyl) -2- (1 , 1 -d ifl uoroethyl)-4- phenoxypyrimidine-5-carboxamide, characterized by the highest retention time of these compounds in an SFC experiment according to method 14 (SFC method 14), or a pharmaceutically acceptable salt thereof.The compound of claim 1, selected from:, or its pharmaceutically acceptable salt.

20. The compound of claim 1 , wherein the compoundor its pharmaceutically acceptable salt.

21. A compound of formula (II)or a pharmaceutically acceptable salt thereof, whereinXvis CRv2or N;Yvis CRv4or N;Zvis CRv5or N; or Yvand Zvtaken together form an optionally substituted five- to six-membered heteroaryl, or an optionally substituted five- to six-membered heterocyclyl; with the proviso that Xv, Yv, and Zvare not all simultaneously N;Rv1is H, -O-(optionally substituted Cs-Cs cycloalkyl), -O-(optionally substituted Ci-Ce alkyl), -0- (optionally substituted Ce-Cio aryl), -O-(optionally substituted five- to six-membered heteroaryl), - 0- (optionally substituted five- to six-membered heterocycloalkyl), or optionally substituted C3- Cs cycloalkyl; or Rv1together with the carbon atoms to which it is shown attached and Xvform an optionally substituted five- to six-membered heterocyclyl;Rv2is H, optionally substituted Ci-Ce alkyl, or halo;Rv3is optionally substituted Cs-Cs cycloalkyl, optionally substituted Cs-Cs cycloalkenyl, optionally substituted Ce-Cio aryl, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkenyl (preferably C2-C6 alkenyl), -NR2, -NR(optionally substituted C4-C8 cycloalkyl), -S-(-optionally substituted C1-C6 alkyl), -O-(optionally substituted Ci-Ce alkyl), -O-(optionally substituted C3-C8 cycloalkyl), optionally substituted four- to six-membered heterocycloalkyl or heterocycloalkenyl, optionally substituted five- to six-membered heteroaryl, or -O-(optionally substituted C3-C8 cycloalkyl); or Rv3taken together with the carbon atom to which it is shown attached and Yvform an optionally substituted C6-C10 aryl, an optionally substituted C3-C8 cycloalkyl or cycloalkenyl, or an optionally substituted five- to six-membered heterocyclyl or heterocycloalkenyl;Rv4is H, Ci-Ce alkyl, cyano, or halo; or Rv4together with the carbon atom to which it is shown attached and Zvform an optionally substituted five- to six-membered heteroaryl;Rv5is H, C1-C6 alkyl, -NR2, or -N(R)-C(=0)-(CI-C6alkyl); each R independently is H, or optionally substituted Ci-Ce alkyl; and said optional substituents of alkyl, alkenyl, cycloalkenyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups in Rv1, Rv2, Rv4, and Rv5, are selected from the group consisting of halogen, - CN, - NO2, -N3, -SO2H, -SO3H, -OH, -0Raa, -N(Rbb)2, -N(0Rcc)Rbb, -SH, -SRaa, -C(=0)Raa, -CO2H, -CHO, -C02Raa, -0C(=0)Raa, -0C02Raa, -C(=0)N(Rbb)2, -0C(=0)N(Rbb)2, - NRbbC(=0)Raa, -NRbbC02Raa, - NRbbC(=0)N(Rbb)2, -C(=NRbb)Raa, -C(=NRbb)0Raa, - 0C(=NRbb)Raa, -0C(=NRbb)0Raa, -C(=NRbb)N(Rbb)2, - 0C(=NRbb)N(Rbb)2, - NRbbC(=NRbb)N(Rbb)2, -C(=0)NRbbS02Raa, -NRbbS02Raa, -SO2N(Rbb)2, -S02Raa, - S(=0)Raa, - 0S(=0)Raa, -B(0RCC)2, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-14 cycloalkyl, 3- to 14- membered heterocyclyl, Ce-14 aryl, and 5- to 14- membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1 , 2, 3, 4, or 5 Rddgroups, or two geminal hydrogens on a carbon atom are replaced with the group =0, wherein: each instance of Raais, independently, selected from the group consisting of C1-10 alkyl, Ci- 10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, C3-14 carbocyclyl, 3- to 14- membered heterocyclyl, C6-14 aryl, and 5- to 14- membered heteroaryl, or two Raagroups are joined to form a 3- to 14- membered heterocyclyl or 5- to 14- membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1 , 2, 3, 4, or 5 Rddgroups; each instance of Rbbis, independently, selected from the group consisting of hydrogen, -OH, - ORaa, -N(RCC)2, -CN, -C(=0)Raa, -C(=O)N(RCC)2, -C02Raa, -SO2Raa, -SO2N(RCC)2, -SORaa, Ci-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, C3-14 carbocyclyl, 3- to 14- membered heterocyclyl, Ce-14 aryl, and 5- to 14- membered heteroaryl, or two Rbbgroups are joined to form a 3- to 14- membered heterocyclyl or 5- to 14- membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; each instance of Rccis, independently, selected from the group consisting of hydrogen, Ci- 10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, C3-14 carbocyclyl, 3- to 14- membered heterocyclyl, Ce-14 aryl, and 5- to 14- membered heteroaryl, or two Rccgroups are joined to form a 3- to 14- membered heterocyclyl or 5- to 14- membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; and each instance of Rddis, independently, selected from the group consisting of halogen, -CN, - NO2, -N3, -SO2H, -SO3H, -OH, -OC1-6 alkyl, -ON(CI-6alkyl)2, -N(CI-6 alkyl)2, -N(OCi- 6 alkyl)(Ci-6alkyl), - N(OH)(CI-6alkyl), -NH(OH), -SH, -SC1-6 alkyl, -C(=O)(Ci-6alkyl), -CO2H, -CO2(Ci-6alkyl), - OC(=O)(Ci-6 alkyl), -OCO2(Ci-6alkyl), -C(=O)NH2, -C(=O)N(CI-6 alkyl)2, - OC(=O)NH(CI-6alkyl), -NHC(=O)(CI-6 alkyl), -N(CI-6 alkyl)C(=O)(Ci-6 alkyl), -NHCO2(CI- 6 alkyl), -NHC(=O)N(CI-6alkyl)2, - NHC(=O)NH(CI-6alkyl), -NHC(=O)NH2, -C(=NH)O(Ci- 6 alkyl), -OC(=NH)(CI-6alkyl), -OC(=NH)OCI-6alkyl, -C(=NH)N(CI-6 alkyl)2, -C(=NH)NH(Ci- 6 alkyl), -C(=NH)NH2, -OC(=NH)N(CI-6 alkyl)2, -OC(NH)NH(CI-6alkyl), -OC(NH)NH2, - NHC(NH)N(CI-6alkyl)2, -NHC(=NH)NH2, -NHSO2(CI-6alkyl), -SO2N(Ci-6alkyl)2, -SO2NH(Ci- 6 alkyl), -SO2NH2, -SO2C1-6 alkyl, — B(OH)2, — B(OCI-6 alkyl)2Ci-6 alkyl, C1-6 perhaloalkyl, C2- 6 alkenyl, C2-6 alkynyl, C3-10 carbocyclyl, C6-10 aryl, 3- to 10- membered heterocyclyl, and 5- to 10- membered heteroaryl; or two geminal Rddsubstituents on a carbon atom may be joined to form =0; and wherein X and Y are as defined in any one of claims 1 to 17.

22. A compound of formulaor a pharmaceutically acceptable salt thereof, wherein:A is -CF2CH3;B is 2,5-pyridinylene, optionally substituted with -0-(Co-3 alkylene)-carbocyclyl, or -0-(Co-3 alkylene)-heterocyclyl, preferably with -O-carbocyclyl, or -O-heterocyclyl, more preferably with -O-carbocyclyl, in particular -O-phenyl, or B is 2,5-pyrimidinylene, optionally substituted with - 0-(Co-3 alkylene)-carbocyclyl, or -0-(Co-3 alkylene)-heterocyclyl, preferably with -O-carbocyclyl, or -O-heterocyclyl, more preferably with -O-carbocyclyl, in particular -O-phenyl;X is -CONH-;Y is a moiety according to formula:wherein Ry1is selected from H, C1-6 alkyl, C3-8 cycloalkyl, and 5 or 6-membered heterocyclyl, wherein said cycloalkyl and said heterocyclyl are each optionally substituted with one or more groups selected from Rs, Ry2is selected from -H, -F and -ON, Ry3is selected from C1-4 alkyl, C3- 8 cycloalkyl, phenyl and 5 or 6-membered heterocyclyl, wherein said cycloalkyl, said phenyl and said heterocyclyl are each optionally substituted with one or more groups selected from Rs, Z is selected from =0 and =NRZ2, wherein each RZ1and Rz2are independently selected from hydrogen, -CN, C1-5 alkyl, C3-8 cycloalkyl, heterocycloalkyl, phenyl, 5-6 membered heteroaryl, - CO-C1-5 alkyl, -COO-C1-5 alkyl, -SO2-C1-5 alkyl, -CONH2, -CONH(CI-5alkyl), and -CON(CI-5alkyl)(Ci-5 alkyl), wherein said alkyl is optionally substituted with one or more groups selected from Hal, -OH, -CN, -O-(Ci-5alkyl), -NH2, -NH(CI-5 alkyl), -N(CI-5 alkyl)(Ci-5 alkyl), -CONH2, - C0NH(CI-5 alkyl) and -CO-N(Ci-s alkyl)(Ci 5 alkyl), wherein said cycloalkyl, said heterocycloalkyl, said phenyl and said heteroaryl are each optionally independently substituted with one or more groups selected from Rs(preferably are each independently substituted with one or more groups selected from Rs), wherein optionally RZ1and Ry3are joined to form, together with the N atom that otherwise carries RZ1and the sulfur atom that otherwise carries Ry3, a 5 to 7 membered heterocyclic ring, which is optionally substituted with one or more groups selected from Rs; and each Rsis independently selected from C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, -(C0-3 alkylene)-OH, -(C0-3 alkylene)-0(Ci-5 alkyl), -(C0-3 alkylene)-0(Ci-5 alkylene)-OH, -(C0-3 alkylene)-0(Ci-5 alkylene)-0(Ci-5 alkyl), -(C0-3 alkylene)-SH, -(C0-3 alkylene)-S(Ci-5 alkyl), -(C0-3 alkylene)-S(Ci-5 alkylene)-SH, -(C0-3 alkylene)-S(Ci-5 alkylene)-S(Ci-5 alkyl), -(C0-3 alkylene)-NH2, -(C0-3 alkylene)-NH(Ci-s alkyl), -(C0-3 alkylene)-N(Ci-s alkyl)(Ci-5 alkyl), -(C0-3 alkylene)-NH-OH, -(C0-3 alkylene)-N(Ci-s alkyl)-OH, -(C0-3 alkylene)-NH-O(Ci-s alkyl), -(C0-3 alkylene)-N(Ci-5 alkyl)-0(Ci-5 alkyl), -(C0-3 alkylene)-halogen, -(C0-3 alkylene)-(Ci-5 haloalkyl), -(C0-3 alkylene)-0-(Ci-5 haloalkyl), -(C0-3 alkylene)-CN, -(C0-3 alkylene)-NC>2, -(C0-3 alkylene)-CHO, -(C0-3 alkylene)-C0-(Ci-5 alkyl), -(C0-3 alkylene)-COOH, -(C0-3alkylene)-C0-0-(Ci-5 alkyl), -(Co-3 alkylene)-0-C0-(Ci-5 alkyl), -(Co-3 alkylene)-C0-NH2, -(Co-3 alkylene)-C0-NH(Ci-5 alkyl), -(Co-3 alkylene)-CO-N(Ci-5alkyl)(Ci-5alkyl), -(Co-3 alkylene)-NH-CO-(Ci-5alkyl), -(Co-3 alkylene)-N(Ci-5alkyl)-C0-(Ci-5 alkyl), -(Co-3 alkylene)-NH-C0-0-(Ci-5 alkyl), -(Co-3 alkylene)-N(Ci-5alkyl)-C0-0-(Ci-5 alkyl), -(Co-3 alkylene)-0-C0-NH-(Ci-5 alkyl), -(Co-3 alkylene)-0-C0-N(Ci-5alkyl)-(Ci-5alkyl), -(Co-3 alkylene)-SO2-NH2, -(Co-3 alkylene)-SO2-NH(Ci-5 alkyl), -(Co-3 alkylene)-SO2-N(Ci-5 alkyl)(Ci-5 alkyl), -(Co-3 alkylene)-NH-SO2-(Ci-5 alkyl), -(Co-3 alkylene)-N(Ci-s alkyl)-SO2-(Ci-5 alkyl), -(Co-3 alkylene)-SO2-(Ci-5 alkyl), -(Co-3 alkylene)-S0-(Ci-5 alkyl), -(Co-3 alkylene)-Si(Ci-5 alkyl)(Ci-5 alkyl)(Ci-5 alkyl), -(Co-3 alkylene)-SFs, -0-(Co-3 alkylene)-carbocyclyl, -0-(Co-3 alkylene)-heterocyclyl, -NH-(Co-3 alkylene)-carbocyclyl, -NH-(Co-3 alkylene)-heterocyclyl, -N(CI-5 alkyl)-(Co-3 alkylene)-carbocyclyl, -N(CI-5 alkyl)-(Co-3 alkylene)-heterocyclyl, -(Co-3 alkylene)-carbocyclyl, and -(Co-3 alkylene)-heterocyclyl, wherein the carbocyclyl moiety in said - 0-(Co-3 alkylene)-carbocyclyl, the carbocyclyl moiety in said -NH-(Co-3 alkylene)-carbocyclyl, the carbocyclyl moiety in said -N(CI-5 alkyl)-(Co-3 alkylene)-carbocyclyl, the carbocyclyl moiety in said -(Co-3 alkylene)-carbocyclyl, the heterocyclyl moiety in said -0-(Co-3 alkylene)-heterocyclyl, the heterocyclyl moiety in said -NH-(Co-3 alkylene)-heterocyclyl, the heterocyclyl moiety in said - N(CI-5 alkyl)-(Co-3 alkylene)-heterocyclyl, and the heterocyclyl moiety in said -(Co-3 alkylene)-heterocyclyl are each optionally substituted with one or more groups independently selected from Ci-4 alkyl, halogen, -CN, -NO2, -OH, -0-(Ci-4 alkyl), -SH, -S-(Ci-4 alkyl), -NH2, - NH(CI-4 alkyl), -N(Ci-4 alkyl)(Ci-4 alkyl), -COOH, -COO(Ci-4 alkyl), -CONH2, -CONH(Ci-4 alkyl), -CON(CI-4 alkyl)(Ci-4 alkyl), -NHCO(Ci-4 alkyl) and -N(Ci-4 alkyl)-C0(Ci-4 alkyl).

23. The compound of claim 22, wherein:Ry1is selected from methyl and cyclopropyl;Ry2is -H or F, preferably Ry2is -H;Ry3is methyl; wherein Z is =0, and / orRZ1is selected from -CN, cyclopropyl, cyclobutyl, oxetanyl, phenyl, pyridyl, -CO-CH3, -COO-CH3, -SO2-CH3, -CONH2, -CONH(CH3), and -CON(CH3)(CH3), preferably RZ1is selected from -CN, cyclopropyl, oxetanyl, phenyl, pyridyl, -CO-CH3, -COO-CH3, -SO2-CH3, and -C0NH(CH3), more preferably RZ1is selected from -CN, cyclopropyl, phenyl, pyridyl, -CO-CH3, -COO-CH3, -SO2-CH3, and -CONH(CH3).

24. A pharmaceutical composition comprising the compound of any one of claims 1 to 23, and a pharmaceutically acceptable excipient.

25. The compound of any one of claims 1 to 23 or the pharmaceutical composition of claim 24 for use as a medicament.

26. The compound of any one of claims 1 to 23 or the pharmaceutical composition of claim 24 for use in the treatment of cancer.

27. The compound for use or the pharmaceutical composition for use of claim 26, wherein the cancer is treatable by inhibition of WRN and / or the cancer is characterized by MSI-H and / or dMMR.

28. Use of the compound of any one of claims 1 to 23 in the manufacture of a medicament for treating cancer, preferably wherein the cancer is treatable by inhibition of WRN and / or the cancer is characterized by MSI-H and / or dMMR.

29. A method for treating a cancer in a subject in need thereof, the method comprising the step of administering to the subject the therapeutically effective amount of the compound of any one of claims 1 to 23, preferably wherein the cancer is treatable by inhibition of WRN and / or the cancer is characterized by MSI-H and / or dMMR.

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