Pharmaceutical combinations and uses thereof

Abstract

The present invention provides pharmaceutical combinations comprising a WRN inhibitor for the treatment of cancer, wherein the treatment further comprises administration of an ionising radiation-based therapy selected from external beam radiation, brachytherapy and a radiopharmaceutical, or further comprises a combination of carboplatin and paclitaxel.

Description

[0001] PAT059671 PHARMACEUTICAL COMBINATIONS AND USES THEREOF FIELD OF THE DISCLOSURE The present invention relates to a pharmaceutical combination comprising a WRN inhibitor in combination with at least one other therapeutic agent. In particular, the combination is a WRN inhibitor with an ionising radiation-based therapy, or with carboplatin and paclitaxel. The present invention further relates to methods of treating cancer, in particular microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) cancer, comprising administering said agents to a subject in need thereof. BACKGROUND The advent of targeted therapies for cancer has increased patient lifespan for various malignancies and helped to appreciate the complexity of tumors through the study of drug resistance mechanisms. The fact that clinical responses to targeted agents are generally incomplete and / or transient results from a multitude of factors that can be broadly put into two classes: toxicities that prevent optimal dosing of drugs and consequently limit target engagement (Brana and Siu 2012, Chapman, Solit et al.2014), and the ability of cancers to adapt and maintain their proliferative potential against perturbations (Druker 2008, Chandarlapaty 2012, Doebele, Pilling et al. 2012, Duncan, Whittle et al. 2012, Katayama, Shaw et al. 2012, Lito, Rosen et al. 2013, Sullivan and Flaherty 2013, Solit and Rosen 2014). Combinations of drugs can address both these factors by improving overall efficacies and at the same time targeting tumor robustness and complexity to counter resistance (Robert, Karaszewska et al.2015, Turner, Ro et al.2015). It is not yet clear how many drugs are required, and which processes need to be targeted in combination to overcome specific types of cancer. But it is almost certain that different pathways or drivers need to be inhibited, most likely requiring two or more drugs (Bozic, Reiter et al.2013). In spite of numerous treatment options for patients with specific types of cancer, there remains a need for effective and safe combination therapies that can be administered for the treatment of cancer. SUMMARY PAT059671 It is an object of the present invention to provide for a medicament to improve treatment of a cancer, in particular to improve treatment of cancer through inhibition of cell growth (proliferation) and / or induction of apoptosis (cell death). It is another object of the present invention to find novel combination therapies, for example those which selectively synergize the inhibition of proliferation and / or the induction of apoptosis. The present invention provides a WRN inhibitor for use in the treatment of cancer, in particular microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) cancer, wherein the treatment further comprises administration of: A. an ionising radiation-based therapy selected from: i) external beam radiation, ii) brachytherapy and iii) a radiopharmaceutical, or B. carboplatin and paclitaxel. The present invention also provides a method of treating cancer in a subject in need thereof, in particular microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) cancer, the method comprising administering to the subject a therapeutically effective amount of a WRN inhibitor in combination with a therapeutically effective amount of: A. an ionising radiation-based therapy selected from: i) external beam radiation, ii) brachytherapy and iii) a radiopharmaceutical, or B. carboplatin and paclitaxel. PAT059671 The present invention also provides a pharmaceutical combination comprising a WRN inhibitor and: A. an ionising radiation-based therapy selected from: i) external beam radiation, ii) brachytherapy and iii) a radiopharmaceutical, or B. carboplatin and paclitaxel. In particular, the present invention provides combination therapies comprising a WRN inhibitor compound of formula (1g), or a pharmaceutically acceptable salt thereof: and wherein R1is selected from:

[0002] PAT059671 R15is F; R16is R25(R24)N-; R17is F; R18is F; R19is F; R20is F; R21is CH3; R22is CF3, CHF2CH2, HOC(O)-CH2-, H3C-C(O)-, (H3C)3C-O-C(O)-; R23is CF3, CHF2CH2-, (H3C)3C-O-C(O)-; R24is CH3; and R25is CHF2CH2-; R2is the moiety: wherein R6is selected from H, halo, (C1-C4)alkyl unsubstituted or substituted by 1, 2 or 3 halo; R8 is selected from H, halo, (C1-C4)alkyl unsubstituted or substituted by 1, 2 or 3 halo; R9is selected from H, O-CH3, OH, CN, CH3and halo; PAT059671 R28is selected from SF5, halo, (C1-C4)alkyl unsubstituted or substituted by 1, 2 or 3 halo and - C(O)H; X is selected from C-R7and N; and R7is selected from H and halo; R3is (C1-C4)alkyl unsubstituted or substituted by 1, 2 or 3 substituents independently selected from halo and OH; x is 0 or 1; Y is N; y is 0, 1 or 2; R5is selected from CH3; or wherein in the moiety: two R5substituents on adjacent carbon atoms join to form ring C: -wherein ring C is a fused (C3-C6)cycloalkyl ring, in particular a fused cyclobutyl ring, and said fused (C3-C6)cycloalkyl ring is unsubstituted or substituted with 1 or 2 R40groups, wherein said R40is selected from: ^ (C1-C2)alkyl, wherein each (C1-C2)alkyl is independently unsubstituted or substituted by OH or 1, 2 or 3 halo, ^ halo, in particular F, PAT059671 ^ or wherein two R40substituents on the same ring carbon atom may join, together with the carbon atom to which they are attached, to form a (C3-C4)cycloalkyl spiro ring or a 3 or 4-membered heterocyclyl spiro ring, wherein said heterocyclyl spiro ring contains ring carbon ring atoms and one ring heteroatom selected from O, N and S; ^ or wherein two R40substituents on adjacent carbon atoms join together with the carbon atoms to which they are attached, to form a fused cyclopropyl ring; R4is selected from: wherein R10is selected from H, halo, (C1-C2)alkyl unsubstituted or substituted by 1, 2 or 3 halo substituents, -O-(C1-C2)alkyl unsubstituted or substituted by 1, 2 or 3 halo substituents; R11is selected from H, halo, (C1-C2)alkyl unsubstituted or substituted by 1, 2 or 3 halo substituents; R12is selected from H, halo, (C1-C2)alkyl unsubstituted or substituted by 1, 2 or 3 halo substituents; R13is selected from H, -S-CH3, halo, (C1-C2)alkyl unsubstituted or substituted by 1, 2 or 3 halo substituents; and R14is selected from H, halo, (C1-C2)alkyl unsubstituted or substituted by 1, 2 or 3 halo substituents, O-(C1-C2)alkyl unsubstituted or substituted by 1, 2 or 3 halo substituents, and cyclopropyl, or a WRN inhibitor compound C, or a pharmaceutically acceptable salt thereof: PAT059671 . Therefore, according to a first aspect of the invention, there is hereby provided a WRN inhibitor for use in the treatment of cancer, in particular microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) cancer, wherein the treatment further comprises administration of an ionising radiation-based therapy selected from: i) external beam radiation, ii) brachytherapy and iii) a radiopharmaceutical, in particular wherein the WRN inhibitor is a compound of formula (1g) as described herein, or a pharmaceutically acceptable salt thereof, or wherein the WRN inhibitor is compound C, or a pharmaceutically acceptable salt thereof: . Therefore, according to a second aspect of the invention, there is hereby provided a WRN inhibitor for use in the treatment of cancer, in particular microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) cancer, wherein the treatment further comprises administration of: i. carboplatin, and PAT059671 ii. paclitaxel, in particular wherein the WRN inhibitor is a compound of formula (1g) as described herein, or a pharmaceutically acceptable salt thereof, or wherein the WRN inhibitor is compound C, or a pharmaceutically acceptable salt thereof: . Therefore, according to a third aspect of the invention, there is hereby provided a method of treating cancer in a subject in need thereof, in particular microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) cancer, the method comprising administering to the subject a therapeutically effective amount of a WRN inhibitor in combination with a therapeutically effective amount of an ionising radiation-based therapy selected from: i) external beam radiation, ii) brachytherapy and iii) a radiopharmaceutical, in particular wherein the WRN inhibitor is a compound of formula (1g) as described herein, or a pharmaceutically acceptable salt thereof, or wherein the WRN inhibitor is compound C, or a pharmaceutically acceptable salt thereof:

[0003] PAT059671 Therefore, according to a fourth aspect of the invention, there is hereby provided a method of treating cancer in a subject in need thereof, in particular microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) cancer, the method comprising administering to the subject a therapeutically effective amount of a WRN inhibitor in combination with a therapeutically effective amount of: a. carboplatin, and b. paclitaxel, in particular wherein the WRN inhibitor is a compound of formula (1g) as described herein, or a pharmaceutically acceptable salt thereof, or wherein the WRN inhibitor is compound C, or a pharmaceutically acceptable salt thereof: . Therefore, according to a fifth aspect of the invention, there is hereby provided a pharmaceutical combination comprising a.) a WRN inhibitor, and b.) an ionising radiation-based therapy selected from i) external beam radiation, ii) brachytherapy and iii) a radiopharmaceutical, in particular wherein the WRN inhibitor is a compound of formula (1g) as described herein, or a pharmaceutically acceptable salt thereof, or wherein the WRN inhibitor is compound C, or a pharmaceutically acceptable salt thereof: PAT059671 . Therefore, according to a sixth aspect of the invention, there is hereby provided a pharmaceutical combination comprising a.) a WRN inhibitor, b.) carboplatin and c.) paclitaxel, in particular wherein the WRN inhibitor is a compound of formula (1g) as described herein, or a pharmaceutically acceptable salt thereof, or wherein the WRN inhibitor is compound C, or a pharmaceutically acceptable salt thereof: Therefore, according to a seventh aspect of the invention, there is hereby provided a WRN inhibitor for use in the treatment of cancer, in particular microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) cancer, wherein the treatment further comprises administration of administration of at least one therapeutically active agent selected from the group consisting of a chemotherapy agent, a Wee1 inhibitor, an ATR inhibitor, a DNA-PK inhibitor, a DNA polymerase alpha inhibitor, a MEK inhibitor, an MDM2 inhibitor, a G4- quadruplex stabilizer, an ATM inhibitor, a CHK1 or CHK2 inhibitor or dual CHK1 and CHK2 inhibitor, a topoisomerase inhibitor, a PARP inhibitor, PI3K-alpha inhibitor, a polymerase theta inhibitor, with IAP inhibitor, an SMAC mimetic, CTLA-4 inhibitor, a KRAS G12C inhibitor, a KRAS G12D inhibitor, a YAP / TEAD inhibitor, BCL2 inhibitor, or a BCL2 / BCLxl dual inhibitor, a MCL1 inhibitor, a CDK2 inhibitor, CDK4 or dual CDK 4 and 6 inhibitor, a HIF2alpha inhibitor, a PAT059671 PLK1 inhibitor, a SHP2 inhibitor, a PRMT5 inhibitor, a STING agonist, a TRAIL receptor agonist, a TAK1 inhibitor, a MK2 inhibitor, a HDAC inhibitor, an androgen biosynthesis inhibitor, and an androgen receptor modulator, and wherein the WRN inhibitor is a compound of formula (1g) as described herein, or a pharmaceutically acceptable salt thereof. Therefore, according to an eighth aspect of the invention, there is hereby provided a method of treating cancer in a subject in need thereof, in particular microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) cancer, the method comprising administering to the subject a therapeutically effective amount of a WRN inhibitor in combination with a therapeutically effective amount of at least one therapeutically active agent selected from the group consisting of a chemotherapy agent, a Wee1 inhibitor, an ATR inhibitor, a DNA-PK inhibitor, a DNA polymerase alpha inhibitor, a MEK inhibitor, an MDM2 inhibitor, a G4-quadruplex stabilizer, an ATM inhibitor, a CHK1 or CHK2 inhibitor or dual CHK1 and CHK2 inhibitor, a topoisomerase inhibitor, a PARP inhibitor, PI3K-alpha inhibitor, a polymerase theta inhibitor, with IAP inhibitor, an SMAC mimetic, CTLA-4 inhibitor, a KRAS G12C inhibitor, a KRAS G12D inhibitor, a YAP / TEAD inhibitor, BCL2 inhibitor, or a BCL2 / BCLxl dual inhibitor, a MCL1 inhibitor, a CDK2 inhibitor, CDK4 or dual CDK 4 and 6 inhibitor, a HIF2alpha inhibitor, a PLK1 inhibitor, a SHP2 inhibitor, a PRMT5 inhibitor, a STING agonist, a TRAIL receptor agonist, a TAK1 inhibitor, a MK2 inhibitor, a HDAC inhibitor, an androgen biosynthesis inhibitor, and an androgen receptor modulator, and wherein the WRN inhibitor is a compound of formula (1g) as described herein, or a pharmaceutically acceptable salt thereof. Therefore, according to a ninth aspect of the invention, there is hereby provided a pharmaceutical combination comprising a WRN inhibitor and at least one therapeutically active agent selected from the group consisting of a chemotherapy agent, a Wee1 inhibitor, an ATR inhibitor, a DNA- PK inhibitor, a DNA polymerase alpha inhibitor, a MEK inhibitor, an MDM2 inhibitor, a G4- quadruplex stabilizer, an ATM inhibitor, a CHK1 or CHK2 inhibitor or dual CHK1 and CHK2 inhibitor, a topoisomerase inhibitor, a PARP inhibitor, PI3K-alpha inhibitor, a polymerase theta inhibitor, with IAP inhibitor, an SMAC mimetic, CTLA-4 inhibitor, a KRAS G12C inhibitor, a KRAS G12D inhibitor, a YAP / TEAD inhibitor, BCL2 inhibitor, or a BCL2 / BCLxl dual inhibitor, a MCL1 inhibitor, a CDK2 inhibitor, CDK4 or dual CDK 4 and 6 inhibitor, a HIF2alpha inhibitor, a PLK1 inhibitor, a SHP2 inhibitor, a PRMT5 inhibitor, a STING agonist, a TRAIL receptor agonist, a TAK1 PAT059671 inhibitor, a MK2 inhibitor, a HDAC inhibitor, an androgen biosynthesis inhibitor, and an androgen receptor modulator, and wherein the WRN inhibitor is a compound of formula (1g) as described herein, or a pharmaceutically acceptable salt thereof. Therefore, according to a tenth aspect of the invention, there is provided a WRN inhibitor for use in the treatment of cancer, in particular microsatellite stable (MSS) cancer, wherein the treatment further comprises administration of at least one therapeutically active agent which can create or increase MSI-H status in cancer cells, and wherein the WRN inhibitor is a compound of formula (1g) as described herein, or a pharmaceutically acceptable salt thereof. Said treatment optionally further comprises administration of irinotecan. Therefore, according to an eleventh aspect of the invention, there is provided a method of treating cancer in a subject in need thereof, in particular microsatellite stable (MSS) cancer, the method comprising administering to the subject a therapeutically effective amount of a WRN inhibitor in combination with a therapeutically effective amount of at least one therapeutically active agent which can create or increase MSI-H status in cancer cells, and wherein the WRN inhibitor is a compound of formula (1g) as described herein, or a pharmaceutically acceptable salt thereof. Said treatment optionally further comprises administration of irinotecan. Therefore, according to a twelth aspect of the invention, there is hereby provided a pharmaceutical combination comprising a WRN inhibitor compound of formula (1g) as described herein, or a pharmaceutically acceptable salt thereof, and at least one therapeutically active agent which can create or increase MSI-H status in cancer cells, and optionally, irinotecan. Therefore, according to a thirteenth aspect of the invention, there is provided a WRN inhibitor, for example a WRN inhibitor compound of formula (1g) or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, in particular microsatellite stable (MSS cancer), wherein the treatment comprises: (a) administration of at least one therapeutically active agent which can create or increase MSI- H status in cancer cells, PAT059671 (b) identification of the presence of microsatellite instability (MSI-H) in a sample from a patient, and (c) administration of a WRN inhibitor, for example a WRN inhibitor compound of formula (1g), or a pharmaceutically acceptable salt thereof. BRIEF DESCRIPTION OF THE DRAWINGS FIG.1: Efficacy of Compound A in combination with carboplatin and paclitaxel against OVK18 ovarian xenografts in Crl:NU(NCr)-Foxn1numice FIG.2: Tolerability of Compound A in combination with carboplatin and paclitaxel against OVK18 ovarian xenografts in Crl:NU(NCr)-Foxn1numice. FIG.3: Efficacy of Compound A in combination with carboplatin and paclitaxel against JHUEM2 endometrial xenografts in CB17.Cg-PrkcscidLystbg-J / Crl mice. FIG. 4: Tolerability of Compound A in combination with carboplatin and paclitaxel against JHUEM2 endometrial xenografts in CB17.Cg-PrkcscidLystbg-J / Crl mice. FIG.5: Efficacy of Compound A in combination with EBRT against OVK18 ovarian xenografts in Crl:NU(NCr)-Foxn1numice. FIG.6: Tolerability of Compound A in combination with EBRT against OVK18 ovarian xenografts in in Crl:NU(NCr)-Foxn1numice. FIG. 7: Efficacy of Compound A in combination with EBRT against JHUEM2 endometrial xenografts in CB17.Cg-PrkcscidLystbg-J / Crl mice. FIG. 8: Tolerability of Compound A in combination with EBRT against JHUEM2 endometrial xenografts in CB17.Cg-PrkcscidLystbg-J / Crl mice. FIG.9: Efficacy of Compound A in combination with irinotecan against RKO colorectal xenografts in NOD-Rag2tm1-IL2rgtm1 / Rj mice. FIG. 10: Tolerability of Compound A in combination with irinotecan against RKO colorectal xenografts in NOD-Rag2tm1-IL2rgtm1 / Rj mice FIG 11: Efficacy of Compound A or Compound C in combination with carboplatin and paclitaxel against 4412-HX endometrial patient derived xenograft in Crl:NU(NCr)-Foxn1numice. PAT059671 FIG 12: Tolerability of Compound A or Compound C in combination with carboplatin and paclitaxel against 4412-HX endometrial patient derived xenograft in Crl:NU(NCr)-Foxn1numice. FIG 13: Efficacy of Compound A or Compound C in combination with carboplatin and paclitaxel against 3200-HX endometrial patient derived xenograft in Crl:NU(NCr)-Foxn1numice. FIG 14: Tolerability of Compound A or Compound C in combination with carboplatin and paclitaxel against 3200-HX endometrial patient derived xenograft in Crl:NU(NCr)-Foxn1numice. FIG 15: Efficacy of Compound A or Compound C in combination with carboplatin and paclitaxel against 2781-HX endometrial patient derived xenograft in Crl:NU(NCr)-Foxn1numice. FIG 16: Tolerability of Compound A or Compound C in combination with carboplatin and paclitaxel against 2781-HX endometrial patient derived xenograft in Crl:NU(NCr)-Foxn1numice. FIG 17: Efficacy of Compound A or Compound C in combination with carboplatin and paclitaxel against 20669-HX endometrial patient derived xenograft in Crl:NU(NCr)-Foxn1numice. FIG 18: Tolerability of Compound A or Compound C in combination with carboplatin and paclitaxel against 20669-HX endometrial patient derived xenograft in Crl:NU(NCr)-Foxn1numice. FIG 19: Efficacy of Compound A or Compound C in combination with EBRT against 4412-HX endometrial patient derived xenograft in Crl:NU(NCr)-Foxn1numice. FIG 20: Tolerability of Compound A or Compound C in combination with EBRT against 4412-HX endometrial patient derived xenograft in Crl:NU(NCr)-Foxn1numice. FIG 21: Efficacy of Compound A or Compound C in combination with EBRT against 3200-HX endometrial patient derived xenograft in Crl:NU(NCr)-Foxn1numice. FIG 22: Tolerability of Compound A or Compound C in combination with EBRT against 3200-HX endometrial patient derived xenograft in Crl:NU(NCr)-Foxn1numice. FIG 23: Efficacy of Compound C in combination with EBRT against 2781-HX endometrial patient derived xenograft in Crl:NU(NCr)-Foxn1numice. FIG 24: Tolerability of Compound C in combination with EBRT against 2781-HX endometrial patient derived xenograft in Crl:NU(NCr)-Foxn1numice. FIG 25: Efficacy of Compound A or Compound C in combination with EBRT against 20669-HX endometrial patient derived xenograft in Crl:NU(NCr)-Foxn1numice. PAT059671 FIG 26: Tolerability of Compound A or Compound C in combination with EBRT against 20669- HX endometrial patient derived xenograft in Crl:NU(NCr)-Foxn1numice. DETAILED DESCRIPTION As mentioned above, an object of the present invention is to find novel combination therapies for the treatment of cancer, in particular cancer characterized as microsatellite instability-high (MSI- H) or mismatch repair deficient (dMMR). In another object, the combination therapies synergize in inhibiting proliferation and / or in inducing apoptosis. Another object of the invention is to find novel combination therapies for the treatment of cancer, in particular cancer characterized as microsatellite stable (MSS). The combinations of the present invention in particular comprise a WRN inhibitor compound of Formula (1g), or a pharmaceutically acceptable salt thereof: and wherein R1is selected from:

[0004] PAT059671 R15is F; R16is R25(R24)N-; R17is F; R18is F; R19is F; R20is F; R21is CH3; R22is CF3, CHF2CH2, HOC(O)-CH2-, H3C-C(O)-, (H3C)3C-O-C(O)-; R23is CF3, CHF2CH2-, (H3C)3C-O-C(O)-; R24is CH3; and R25is CHF2CH2-; R2is the moiety: wherein R6is selected from H, halo, (C1-C4)alkyl unsubstituted or substituted by 1, 2 or 3 halo; R8 is selected from H, halo, (C1-C4)alkyl unsubstituted or substituted by 1, 2 or 3 halo; R9is selected from H, O-CH3, OH, CN, CH3and halo; PAT059671 R28is selected from SF5, halo, (C1-C4)alkyl unsubstituted or substituted by 1, 2 or 3 halo and - C(O)H; X is selected from C-R7and N; and R7is selected from H and halo; R3is (C1-C4)alkyl unsubstituted or substituted by 1, 2 or 3 substituents independently selected from halo and OH; x is 0 or 1; Y is N; y is 0, 1 or 2; R5is selected from CH3; or wherein in the moiety: two R5substituents on adjacent carbon atoms join to form ring C: -wherein ring C is a fused (C3-C6)cycloalkyl ring, in particular a fused cyclobutyl ring, and said fused (C3-C6)cycloalkyl ring is unsubstituted or substituted with 1 or 2 R40groups, wherein said R40is selected from: ^ (C1-C2)alkyl, wherein each (C1-C2)alkyl is independently unsubstituted or substituted by OH or 1, 2 or 3 halo, ^ halo, in particular F, PAT059671 ^ or wherein two R40substituents on the same ring carbon atom may join, together with the carbon atom to which they are attached, to form a (C3-C4)cycloalkyl spiro ring or a 3 or 4-membered heterocyclyl spiro ring, wherein said heterocyclyl spiro ring contains ring carbon ring atoms and one ring heteroatom selected from O, N and S; ^ or wherein two R40substituents on adjacent carbon atoms join together with the carbon atoms which they are attached, to form a fused cyclopropyl ring; R4is selected from: CH3, wherein R10is selected from H, halo, (C1-C2)alkyl unsubstituted or substituted by 1, 2 or 3 halo substituents, -O-(C1-C2)alkyl unsubstituted or substituted by 1, 2 or 3 halo substituents; R11is selected from H, halo, (C1-C2)alkyl unsubstituted or substituted by 1, 2 or 3 halo substituents; R12is selected from H, halo, (C1-C2)alkyl unsubstituted or substituted by 1, 2 or 3 halo substituents; R13is selected from H, -S-CH3, halo, (C1-C2)alkyl unsubstituted or substituted by 1, 2 or 3 halo substituents; and R14is selected from H, halo, (C1-C2)alkyl unsubstituted or substituted by 1, 2 or 3 halo substituents, O-(C1-C2)alkyl unsubstituted or substituted by 1, 2 or 3 halo substituents, and cyclopropyl or a WRN inhibitor compound C, or a pharmaceutically acceptable salt thereof: PAT059671 Therefore, according to a first aspect of the invention, there is provided a WRN inhibitor for use in the treatment of cancer, in particular microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) cancer, wherein the treatment further comprises administration of an ionising radiation-based therapy selected from: i) external beam radiation, ii) brachytherapy and iii) a radiopharmaceutical, and in particular wherein the WRN inhibitor is a compound of formula (1g) as described herein, or a pharmaceutically acceptable salt thereof, or wherein the WRN inhibitor is compound C as described herein, or a pharmaceutically acceptable salt thereof. According to a second aspect of the invention, there is provided a WRN inhibitor for use in the treatment of cancer, in particular microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) cancer, wherein the treatment further comprises administration of: i. carboplatin, and ii. paclitaxel, and in particular wherein the WRN inhibitor is a compound of formula (1g) as described herein, or a pharmaceutically acceptable salt thereof, or wherein the WRN inhibitor is compound C as described herein, or a pharmaceutically acceptable salt thereof. PAT059671 According to a third aspect of the invention, there is provided a method of treating cancer in a subject in need thereof, in particular microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) cancer, the method comprising administering to the subject a therapeutically effective amount of a WRN inhibitor in combination with a therapeutically effective amount of an ionising radiation-based therapy selected from: i) external beam radiation, ii) brachytherapy and iii) a radiopharmaceutical, in particular wherein the WRN inhibitor is a compound of formula (1g) as described herein, or a pharmaceutically acceptable salt thereof, or wherein the WRN inhibitor is compound C as described herein, or a pharmaceutically acceptable salt thereof. According to a fourth aspect of the invention, there is provided a method of treating cancer in a subject in need thereof, in particular microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) cancer, the method comprising administering to the subject a therapeutically effective amount of a WRN inhibitor in combination with a therapeutically effective amount of: a. carboplatin, and b. paclitaxel, in particular wherein the WRN inhibitor is a compound of formula (1g) as described herein, or a pharmaceutically acceptable salt thereof, or wherein the WRN inhibitor is compound C as described herein, or a pharmaceutically acceptable salt thereof. According to a fifth aspect of the invention, there is provided a pharmaceutical combination comprising a.) a WRN inhibitor, and b.) an ionising radiation-based therapy selected from i) external beam radiation, ii) brachytherapy and iii) a radiopharmaceutical, PAT059671 in particular wherein the WRN inhibitor is a compound of formula (1g) as described herein, or a pharmaceutically acceptable salt thereof, or wherein the WRN inhibitor is compound C as described herein, or a pharmaceutically acceptable salt thereof. According to a sixth aspect of the invention, there is provided a pharmaceutical combination comprising a.) a WRN inhibitor, b.) carboplatin and c.) paclitaxel, in particular wherein the WRN inhibitor is a compound of formula (1g) as described herein, or a pharmaceutically acceptable salt thereof, or wherein the WRN inhibitor is compound C as described herein, or a pharmaceutically acceptable salt thereof. According to a seventh aspect of the invention, there is hereby provided a WRN inhibitor for use in the treatment of cancer, in particular microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) cancer, wherein the treatment further comprises administration of administration of at least one therapeutically active agent selected from the group consisting of a chemotherapy agent, a Wee1 inhibitor, an ATR inhibitor, a DNA-PK inhibitor, a DNA polymerase alpha inhibitor, a MEK inhibitor, an MDM2 inhibitor, a G4-quadruplex stabilizer, an ATM inhibitor, a CHK1 or CHK2 inhibitor or dual CHK1 and CHK2 inhibitor, a topoisomerase inhibitor, a PARP inhibitor, PI3K-alpha inhibitor, a polymerase theta inhibitor, with IAP inhibitor, an SMAC mimetic, CTLA-4 inhibitor, a KRAS G12C inhibitor, a KRAS G12D inhibitor, a YAP / TEAD inhibitor, BCL2 inhibitor, or a BCL2 / BCLxl dual inhibitor, a MCL1 inhibitor, a CDK2 inhibitor, CDK4 or dual CDK 4 and 6 inhibitor, a HIF2alpha inhibitor, a PLK1 inhibitor, a SHP2 inhibitor, a PRMT5 inhibitor, a STING agonist, a TRAIL receptor agonist, a TAK1 inhibitor, a MK2 inhibitor, a HDAC inhibitor, an androgen biosynthesis inhibitor, and an androgen receptor modulator, and wherein the WRN inhibitor is a compound of formula (1g) as described herein, or a pharmaceutically acceptable salt thereof. According to an eighth aspect of the invention, there is hereby provided a method of treating cancer in a subject in need thereof, in particular microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) cancer, the method comprising administering to the subject a therapeutically effective amount of a WRN inhibitor in combination with a therapeutically effective amount of at least one therapeutically active agent selected from the group consisting PAT059671 of a chemotherapy agent, a Wee1 inhibitor, an ATR inhibitor, a DNA-PK inhibitor, a DNA polymerase alpha inhibitor, a MEK inhibitor, an MDM2 inhibitor, a G4-quadruplex stabilizer, an ATM inhibitor, a CHK1 or CHK2 inhibitor or dual CHK1 and CHK2 inhibitor, a topoisomerase inhibitor, a PARP inhibitor, PI3K-alpha inhibitor, a polymerase theta inhibitor, with IAP inhibitor, an SMAC mimetic, CTLA-4 inhibitor, a KRAS G12C inhibitor, a KRAS G12D inhibitor, a YAP / TEAD inhibitor, BCL2 inhibitor, or a BCL2 / BCLxl dual inhibitor, a MCL1 inhibitor, a CDK2 inhibitor, CDK4 or dual CDK 4 and 6 inhibitor, a HIF2alpha inhibitor, a PLK1 inhibitor, a SHP2 inhibitor, a PRMT5 inhibitor, a STING agonist, a TRAIL receptor agonist, a TAK1 inhibitor, a MK2 inhibitor, a HDAC inhibitor, an androgen biosynthesis inhibitor, and an androgen receptor modulator, and wherein the WRN inhibitor is a compound of formula (1g) as described herein, or a pharmaceutically acceptable salt thereof. According to a ninth aspect of the invention, there is hereby provided a pharmaceutical combination comprising a WRN inhibitor and at least one therapeutically active agent selected from the group consisting of a chemotherapy agent, a Wee1 inhibitor, an ATR inhibitor, a DNA- PK inhibitor, a DNA polymerase alpha inhibitor, a MEK inhibitor, an MDM2 inhibitor, a G4- quadruplex stabilizer, an ATM inhibitor, a CHK1 or CHK2 inhibitor or dual CHK1 and CHK2 inhibitor, a topoisomerase inhibitor, a PARP inhibitor, PI3K-alpha inhibitor, a polymerase theta inhibitor, with IAP inhibitor, an SMAC mimetic, CTLA-4 inhibitor, a KRAS G12C inhibitor, a KRAS G12D inhibitor, a YAP / TEAD inhibitor, BCL2 inhibitor, or a BCL2 / BCLxl dual inhibitor, a MCL1 inhibitor, a CDK2 inhibitor, CDK4 or dual CDK 4 and 6 inhibitor, a HIF2alpha inhibitor, a PLK1 inhibitor, a SHP2 inhibitor, a PRMT5 inhibitor, a STING agonist, a TRAIL receptor agonist, a TAK1 inhibitor, a MK2 inhibitor, a HDAC inhibitor, an androgen biosynthesis inhibitor, and an androgen receptor modulator, and wherein the WRN inhibitor is a compound of formula (1g) as described herein, or a pharmaceutically acceptable salt thereof. According to a tenth aspect of the invention, there is provided a WRN inhibitor for use in the treatment of cancer, in particular microsatellite stable (MSS) cancer, wherein the treatment further comprises administration of at least one therapeutically active agent which can create or increase MSI-H status in cancer cells, and wherein the WRN inhibitor is a compound of formula (1g) as described herein, or a pharmaceutically acceptable salt thereof. Said treatment optionally further comprises administration of irinotecan. PAT059671 According to an eleventh aspect of the invention, there is provided a method of treating cancer in a subject in need thereof, in particular microsatellite stable (MSS) cancer, the method comprising administering to the subject a therapeutically effective amount of a WRN inhibitor in combination with a therapeutically effective amount of at least one therapeutically active agent which can create or increase MSI-H status in cancer cells, and wherein the WRN inhibitor is a compound of formula (1g) as described herein, or a pharmaceutically acceptable salt thereof. Said treatment optionally further comprises administration of irinotecan. According to a twelth aspect of the invention, there is hereby provided a pharmaceutical combination comprising a WRN inhibitor compound of formula (1g) as described herein, or a pharmaceutically acceptable salt thereof, and at least one therapeutically active agent which can create or increase MSI-H status in cancer cells, and optionally, irinotecan. According to a thirteenth aspect of the invention, there is provided a WRN inhibitor, for example a WRN inhibitor compound of formula (1g) or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, in particular microsatellite stable (MSS cancer), wherein the treatment comprises: (a) administration of at least one therapeutically active agent which can create or increase MSI-H status in cancer cells, (b) identification of the presence of microsatellite instability (MSI-H) in a sample from a patient, and (c) administration of a WRN inhibitor, for example a WRN inhibitor compound of formula (1g), or a pharmaceutically acceptable salt thereof. In an embodiment of any of the first to sixth aspects of the invention, the cancer is microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), in particular microsatellite instability- high (MSI-H). PAT059671 In an embodiment of any of the first, third or fifth aspects of the invention, the ionising radiation is external beam radiation. In a particular embodiment, the cancer is selected from: ^ colorectal cancer (CRC), such as colon adenocarcinoma or rectal adenocarcinoma, ^ gastric cancer, such as stomach adenocarcinoma, ^ prostate cancer, ^ endometrial cancer, ^ adrenocortical cancer, such as adrenocortical carcinoma, ^ cervical cancer, such as cervical squamous cell carcinoma or endocervical adenocarcinoma, ^ uterine cancer, such as uterine corpus endometrial carcinoma and uterine carcinosarcoma, ^ esophageal ccancer, such as esophageal carcinoma, ^ breast cancer, such as breast carcinoma or triple negative breast cancer, ^ kidney cancer, such as kidney renal clear cell carcinoma, ^ ovarian cancer, such as ovarian serous cystadenocarcinoma, ^ glioma, ^ glioblastoma, ^ neuroendocrine tumors, ^ melanoma, ^ small cell lung cancer, and ^ sarcoma and in particular the cancer is colorectal cancer (CRC), ovarian cancer or endometrial cancer. In an embodiment of any of the first to thirteenth aspects of the invention, the WRN inhibitor is (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-6-((R)-4-(5- hydroxy-6-methylpyrimidine-4-carbonyl)-3-methylpiperazin-1-yl)-7-methyl-5-oxo-5,7,8,9- tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide, or a pharmaceutically acceptable salt thereof: PAT059671 . In another embodiment of any of the first to thirteenth aspects of the invention, the WRN inhibitor is (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-6- ((1S,6S)-5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-7- methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide, or a pharmaceutically acceptable salt thereof: . In an embodiment of any of the first to thirteenth aspects of the invention, the WRN inhibitor is compound C, or a pharmaceutically acceptable salt thereof:

[0005] PAT059671 In another embodiment of any of the first to thirteenth aspects of the invention, the WRN inhibitor is (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-6-((R)-4- (5-hydroxy-6-methylpyrimidine-4-carbonyl)-3-methylpiperazin-1-yl)-7-methyl-5-oxo-5,7,8,9- tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide: in non-zwitterionic form: or zwitterionic form: PAT059671 or a mixture of any two or three of said forms. In another embodiment of any of the first to thirteenth aspects of the invention, the WRN inhibitor is (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-6- ((1S,6S)-5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-7- methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide: in non-zwitterionic form or in zwitterionic form: PAT059671 or a mixture of any two or three of said forms. In an embodiment of any of the first to thirteenth aspects of the invention, the WRN inhibitor is compound C, in non-zwitterionic form: PAT059671 or zwitterionic form: or a mixture of any two or three of said forms. In another embodiment, there is provided a WRN inhibitor for use in the treatment of microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) cancer, in particular ovarian or endometrial cancer, wherein the treatment further comprises administration of an external beam radiation, and wherein the WRN inhibitor is compound A PAT059671 pharmaceutically acceptable salt thereof, or wherein the WRN inhibitor is compound C, or a pharmaceutically acceptable salt thereof: . In another embodiment, there is provided a WRN inhibitor for use in the treatment of microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) cancer, in particular ovarian or endometrial cancer, wherein the treatment further comprises administration of: i. carboplatin, and ii. paclitaxel, and the WRN inhibitor is:

[0006] PAT059671 or wherein the WRN inhibitor is compound C, or a pharmaceutically acceptable salt thereof: . In another embodiment, there is provided a WRN inhibitor for use in the treatment of microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) cancer, in particular colorectal cancer, wherein the treatment further comprises administration of irinotecan, and the WRN inhibitor is: pharmaceutically acceptable salt thereof, or wherein the WRN inhibitor is compound C, or a pharmaceutically acceptable salt thereof: . In an embodiment of the tenth aspect of the invention, there is provided a WRN inhibitor for use in the treatment of microsatellite stable (MSS) cancer, wherein the treatment further comprises PAT059671 administration of at least one therapeutically active agent which can create or increase MSI-H status in cancer cells, and wherein: i. the WRN inhibitor is a compound of formula (1g) as described herein, or a pharmaceutically acceptable salt thereof, and ii. the agent which can create or increase MSI-H status in cancer cells is temozolomide, cisplatin or 6-thioguanine, or is an ionising radiation-based therapy selected from i) external beam radiation, ii) brachytherapy and ii) a radiopharmaceutical, and optionally, iii. said treatment further comprises administration of irinotecan. In an embodiment of the eleventh aspect of the invention, there is provided a method of treating microsatellite stable (MSS) cancer, the method comprising administering to the subject a therapeutically effective amount of a WRN inhibitor in combination with a therapeutically effective amount of at least one therapeutically active agent which can create or increase MSI-H status in cancer cells, and wherein: i. the WRN inhibitor is a compound of formula (1g) as described herein, or a pharmaceutically acceptable salt thereof, and ii. the agent which can create or increase MSI-H status in cancer cells is temozolomide, cisplatin or 6-thioguanine, or is an ionising radiation-based therapy selected from i) external beam radiation, ii) brachytherapy and ii) a radiopharmaceutical, and optionally, iii. said treatment further comprises administration of irinotecan. The invention provides the following numbered embodiments: Embodiment 1. A WRN inhibitor for use in the treatment of cancer, in particular microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) cancer, wherein the treatment further comprises administration of an ionising radiation-based therapy selected from: i) external beam radiation, ii) brachytherapy and iii) a radiopharmaceutical, PAT059671 and wherein the WRN inhibitor is a compound of formula (1g), or a pharmaceutically acceptable salt thereof: and wherein R1is selected from: R16is R25(R24)N-; R17is F; R18is F; R19is F; R20is F; R21is CH3; PAT059671 R22is CF3, CHF2CH2, HOC(O)-CH2-, H3C-C(O)-, (H3C)3C-O-C(O)-; R23is CF3, CHF2CH2-, (H3C)3C-O-C(O)-; R24is CH3; and R25is CHF2CH2-; R2is the moiety: wherein R6is selected from H, halo, (C1-C4)alkyl unsubstituted or substituted by 1, 2 or 3 halo; R8is selected from H, halo, (C1-C4)alkyl unsubstituted or substituted by 1, 2 or 3 halo; R9is selected from H, O-CH3, OH, CN, CH3and halo; R28is selected from SF5, halo, (C1-C4)alkyl unsubstituted or substituted by 1, 2 or 3 halo and - C(O)H; X is selected from C-R7and N; and R7is selected from H and halo; R3is (C1-C4)alkyl unsubstituted or substituted by 1, 2 or 3 substituents independently selected from halo and OH; x is 0 or 1; Y is N; y is 0, 1 or 2; R5is selected from CH3; PAT059671 or wherein in the moiety: two R5substituents on adjacent carbon atoms join to form ring C: -wherein ring C is a fused (C3-C6)cycloalkyl ring, in particular a fused cyclobutyl ring, and said fused (C3-C6)cycloalkyl ring is unsubstituted or substituted with 1 or 2 R40groups, wherein said R40is selected from: ^ (C1-C2)alkyl, wherein each (C1-C2)alkyl is independently unsubstituted or substituted by OH or 1, 2 or 3 halo, ^ halo, in particular F, ^ or wherein two R40substituents on the same ring carbon atom may join, together with the carbon atom to which they are attached, to form a (C3-C4)cycloalkyl spiro ring or a 3 or 4- membered heterocyclyl spiro ring, wherein said heterocyclyl spiro ring contains ring carbon ring atoms and one ring heteroatom selected from O, N and S; ^ or wherein two R40substituents on adjacent carbon atoms join together with the carbon atoms to which they are attached, to form a fused cyclopropyl ring; R4is selected from: CH3, PAT059671 wherein R10is selected from H, halo, (C1-C2)alkyl unsubstituted or substituted by 1, 2 or 3 halo substituents, -O-(C1-C2)alkyl unsubstituted or substituted by 1, 2 or 3 halo substituents; R11is selected from H, halo, (C1-C2)alkyl unsubstituted or substituted by 1, 2 or 3 halo substituents; R12is selected from H, halo, (C1-C2)alkyl unsubstituted or substituted by 1, 2 or 3 halo substituents; R13is selected from H, -S-CH3, halo, (C1-C2)alkyl unsubstituted or substituted by 1, 2 or 3 halo substituents; and R14is selected from H, halo, (C1-C2)alkyl unsubstituted or substituted by 1, 2 or 3 halo substituents, O-(C1-C2)alkyl unsubstituted or substituted by 1, 2 or 3 halo substituents, and cyclopropyl, or wherein the WRN inhibitor is compound C, or a pharmaceutically acceptable salt thereof: . Embodiment 2. A WRN inhibitor for use in the treatment of cancer, in particular microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) cancer, wherein the treatment further comprises administration of: i. carboplatin, and PAT059671 ii. paclitaxel, and wherein the WRN inhibitor is a compound of formula (1g), or a pharmaceutically acceptable salt thereof, as described in embodiment 1, or wherein the WRN inhibitor is compound C as described in embodiment 1, or a pharmaceutically acceptable salt thereof. Embodiment 3. A method of treating cancer in a subject in need thereof, in particular microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) cancer, the method comprising administering to the subject a therapeutically effective amount of a WRN inhibitor in combination with a therapeutically effective amount of an ionising radiation-based therapy selected from: i) external beam radiation, ii) brachytherapy and iii) a radiopharmaceutical, wherein the WRN inhibitor is a compound of formula (1g), or a pharmaceutically acceptable salt thereof, as described in embodiment 1, or wherein the WRN inhibitor is compound C as described in embodiment 1, or a pharmaceutically acceptable salt thereof Embodiment 4. A method of treating cancer in a subject in need thereof, in particular microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) cancer, the method comprising administering to the subject a therapeutically effective amount of a WRN inhibitor in combination with a therapeutically effective amount of: a. carboplatin, and b. paclitaxel wherein the WRN inhibitor is a compound of formula (1g), or a pharmaceutically acceptable salt thereof, as described in embodiment 1, PAT059671 or wherein the WRN inhibitor is compound C as described in embodiment 1, or a pharmaceutically acceptable salt thereof. Embodiment 5. A combination comprising a.) a WRN inhibitor, and b.) an ionising radiation-based therapy selected from i) external beam radiation, ii) brachytherapy and iii) a radiopharmaceutical, wherein the WRN inhibitor is a compound of formula (1g), or a pharmaceutically acceptable salt thereof, as described in embodiment 1, or wherein the WRN inhibitor is compound C as described in embodiment 1, or a pharmaceutically acceptable salt thereof. Embodiment 6. A combination comprising a.) a WRN inhibitor, b.) carboplatin and c.) paclitaxel, wherein the WRN inhibitor is a compound of formula (1g), or a pharmaceutically acceptable salt thereof, as described in embodiment 1, or wherein the WRN inhibitor is compound C as described in embodiment 1, or a pharmaceutically acceptable salt thereof. Embodiment 7. The WRN inhibitor for use according to embodiment 1 or embodiment 2, or the method according to embodiment 3 or embodiment 4, or the combination according to embodiment 5 or embodiment 6, wherein the cancer is microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR). Embodiment 8. The WRN inhibitor for use according to any of embodiments 1 or 7, or the method according to any of embodiments 3 or 7, or the combination according to any of embodiment 5 or 7, wherein the ionising radiation is external beam radiation. PAT059671 Embodiment 9. The WRN inhibitor for use according to any of embodiments 1, 2, 7 or 8, or the method according to any of embodiments 3, 4, 7 or 8, or the combination according to any of embodiments 5, 6, 7 or 8, wherein the cancer is selected from: ^ colorectal cancer (CRC), such as colon adenocarcinoma or rectal adenocarcinoma, ^ gastric cancer, such as stomach adenocarcinoma, ^ prostate cancer, ^ endometrial cancer, ^ adrenocortical cancer, such as adrenocortical carcinoma, ^ cervical cancer, such as cervical squamous cell carcinoma or endocervical adenocarcinoma, ^ uterine cancer, such as uterine corpus endometrial carcinoma and uterine carcinosarcoma, ^ esophageal ccancer, such as esophageal carcinoma, ^ breast cancer, such as breast carcinoma or triple negative breast cancer, ^ kidney cancer, such as kidney renal clear cell carcinoma, ^ ovarian cancer, such as ovarian serous cystadenocarcinoma, ^ glioma, ^ glioblastoma, ^ neuroendocrine tumors, ^ melanoma, ^ small cell lung cancer, and ^ sarcoma. Embodiment 10. The WRN inhibitor for use according to embodiment 9, or the method according to embodiment 9, or the combination according to embodiment 9, wherein the cancer is colorectal cancer (CRC), ovarian cancer or endometrial cancer. Embodiment 11. The WRN inhibitor for use according to any of embodiments 1, 2 or 7 to 10, or the method according to any of embodiments 3, 4 or 7 to 10 , or the combination according to any of embodiments 5, 6 or 7 to 10, wherein the WRN inhibitor is (7R,9R)-N-(2-chloro-4- (trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-6-((R)-4-(5-hydroxy-6-methylpyrimidine-4- PAT059671 carbonyl)-3-methylpiperazin-1-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2- c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide, or a pharmaceutically acceptable salt thereof: . Embodiment 12. The WRN inhibitor for use according to any of embodiments 1, 2 or 7 to 10, or the method according to any of embodiments 3, 4 or 7 to 10, or the combination according to any of embodiments 5, 6 or 7 to 10, wherein the compound is (7R,9R)-N-(2-chloro-4- (trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-6-((1S,6S)-5-(5-hydroxy-6- methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-7-methyl-5-oxo-5,7,8,9- tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide, or a pharmaceutically acceptable salt thereof: . Embodiment 13. The WRN inhibitor for use according to any of embodiments 1, 2 or 7 to 10, or the method according to any of embodiments 3, 4 or 7 to 10, or the combination according to any of embodiments 5, 6 or 7 to 10, wherein the compound is (7R,9R)-N-(2-chloro-4- (trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-6-((R)-4-(5-hydroxy-6-methylpyrimidine-4- PAT059671 carbonyl)-3-methylpiperazin-1-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2- c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide: in non-zwitterionic form: or zwitterionic form:

[0007] PAT059671 or a mixture of any two or three of said forms, or wherein the compound is Compound C, in non-zwitterionic form: or zwitterionic form: PAT059671 or a mixture of any two or three of said forms. Embodiment 14. The WRN inhibitor for use according to any of embodiments 1, 2 or 7 to 10, or the method according to any of embodiments 3, 4 or 7 to 10, or the combination according to any of embodiments 5, 6 or 7 to 10, wherein the compound is (7R,9R)-N-(2-chloro-4- (trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-6-((1S,6S)-5-(5-hydroxy-6- methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-7-methyl-5-oxo-5,7,8,9- tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide: in non-zwitterionic form

[0008] PAT059671 or a mixture of any two or three of said forms. Embodiment 16. A WRN inhibitor for use in the treatment of microsatellite instability-high (MSI- H) or mismatch repair deficient (dMMR) cancer, in particular colorectal, ovarian or endometrial cancer, wherein the treatment further comprises administration of an external beam radiation, and wherein the WRN inhibitor is compound A PAT059671 pharmaceutically acceptable salt thereof, or wherein the WRN inhibitor is compound C, or a pharmaceutically acceptable salt thereof: . Embodiment 17. A WRN inhibitor for use in the treatment of microsatellite instability-high (MSI- H) or mismatch repair deficient (dMMR) cancer, in particular ovarian or endometrial cancer, wherein the treatment further comprises administration of: i. carboplatin, and ii. paclitaxel, and the WRN inhibitor is compound A:

[0009] PAT059671 wherein the WRN inhibitor is compound C, or a pharmaceutically acceptable salt thereof: Embodiment 18. A WRN inhibitor for use in the treatment of microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) cancer, in particular colorectal cancer, wherein the treatment further comprises administration of irinotecan, and the WRN inhibitor is compound A: pharmaceutically acceptable salt thereof, or wherein the WRN inhibitor is compound C, or a pharmaceutically acceptable salt thereof: , or wherein the WRN inhibitor is described in the art, in particular in any of the patent publications disclosing WRN inhibitors, as discussed herein. PAT059671 Embodiment 19. A WRN inhibitor for use in the treatment of cancer, in particular microsatellite stable (MSS) cancer, wherein the treatment further comprises administration of at least one therapeutically active agent which can create or increase MSI-H status in cancer cells, and wherein the WRN inhibitor is a compound of formula (1g) as described herein, or a pharmaceutically acceptable salt thereof, and said treatment optionally further comprises administration of irinotecan. Embodiment 20. A method of treating cancer in a subject in need thereof, in particular microsatellite stable (MSS) cancer, the method comprising administering to the subject a therapeutically effective amount of a WRN inhibitor in combination with a therapeutically effective amount of at least one therapeutically active agent which can create or increase MSI-H status in cancer cells, and wherein the WRN inhibitor is a compound of formula (1g) as described herein, or a pharmaceutically acceptable salt thereof, and said treatment optionally further comprises administration of irinotecan. Embodiment 21. A pharmaceutical combination comprising a WRN inhibitor compound of formula (1g) as described herein, or a pharmaceutically acceptable salt thereof, and at least one therapeutically active agent which can create or increase MSI-H status in cancer cells, and optionally, irinotecan. Embodiment 22. A WRN inhibitor, for example a WRN inhibitor compound of formula (1g) or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, in particular microsatellite stable (MSS cancer), wherein the treatment comprises: (a) administration of at least one therapeutically active agent which can create or increase MSI-H status in cancer cells, (b) identifying the presence of microsatellite instability (MSI-H) in a sample from a patient, and (c) administration of a WRN inhibitor, for example a WRN inhibitor compound of formula (1g), or a pharmaceutically acceptable salt thereof. PAT059671 Embodiment 23. A WRN inhibitor for use as described in embodiments 19 or 22, a method as described in embodiment 20, or a pharmaceutical combination as described in embodiment 21, wherein the compound of formula (1g) is compound A: or a pharmaceutically acceptable salt thereof. In another aspect of the invention, there is provided the WRN inhibitor for use according to any of embodiments 1, 2 or 7 to 17, or the method according to any of embodiments 3, 4 or 7 to 17, or the combination according to any of embodiments 5, 6 or 7 to 17, wherein the combination of the WRN inhibitor, carboplatin and paclitaxel, or the combination of the WRN inhibitor and ionising radiation-based therapy, is synergistic in the treatment of MSI-H cancer, in particular endometrial or ovarian cancer. In another aspect of the invention, there is provided the WRN inhibitor for use according to any of embodiments 1, 2 or 7 to 17, or the method according to any of embodiments 3, 4 or 7 to 17, or the combination according to any of embodiments 5, 6 or 7 to 17, wherein the combination partners the WRN inhibitor, carboplatin and paclitaxel, or the combination partners the WRN inhibitor and ionising radiation-based therapy, are provided in synergistically effective amounts for the treatment of MSI-H cancer, in particular for the treatment of endometrial or ovarian cancer. In another aspect of the invention, there is provided the WRN inhibitor for use according to any of embodiments 1, 2 or 7 to 17, or the method according to any of embodiments 3, 4 or 7 to 17, or PAT059671 the combination according to any of embodiments 5, 6 or 7 to 17, wherein the combination partners the WRN inhibitor, carboplatin and paclitaxel, or the combination partners the WRN inhibitor and ionising radiation-based therapy, are jointly therapeutically effective for the treatment of MSI-H cancer, in particular endometrial or ovarian cancer. In another aspect of the invention, there is provided a WRN inhibitor compound of formula (1g), or Compound C, as described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, in particular microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) cancer, wherein the treatment further comprises administration of at least one PD-1 inhibitor. In another aspect of the invention, there is provided a method of treating cancer in a subject in need thereof, in particular microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) cancer, the method comprising administering to the subject a therapeutically effective amount of a WRN inhibitor in combination with a therapeutically effective amount of at least one PD-1 inhibitor. In another aspect of the invention, there is provided a pharmaceutical combination comprising a.) a WRN inhibitor, and b.) at least one PD-1 inhibitor. In an embodiment, the PD-1 inhibitor is an anti-PD-1 antibody. In an embodiment, the PD-1 inhibitor is selected from PDR001 (Novartis), Nivolumab (Bristol-Myers Squibb), Pembrolizumab (Merck & Co), Pidilizumab (CureTech), MEDI0680 (Medimmune), Cemiplimab (REGN2810, Regeneron), Dostarlimab (TSR-042, Tesaro), PF-06801591 (Pfizer), Tislelizumab (BGB-A317, Beigene), BGB-108 (Beigene), INCSHR1210 (Incyte), Balstilimab (AGEN2035, Agenus), Sintilimab (InnoVent), Toripalimab (Shanghai Junshi Bioscience), Camrelizumab (Jiangsu Hengrui Medicine Co.), and AMP-224 (Amplimmune), in particular PDR001 or Tislelizumab. In an embodiment, the PD-1 inhibitor is tislelizumab or pembrolizumab, in particular pembrolizumab. Definitions The terms "a" and "an" and "the" and similar references in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Where the PAT059671 plural form is used for compounds, patients, cancers and the like, this is taken to mean also a single compound, patient, or the like. References in this specification to "the invention" are intended to reflect embodiments of the several inventions disclosed in this specification and should not be taken as unnecessarily limiting of the claimed subject matter. Compounds of Formula (1g) as described herein, including Compound A and Compound B, are described in PCT / IB2023 / 060166 (WO2024 / 079623) and US18 / 483651 (US2024-0245694), which are hereby incorporated by reference in their entirety. The terms “Compound A” or “compound A”, which are used interchangeably herein, refer to the compound of Example 21A of PCT / IB2023 / 060166 (WO2024 / 079623) and US18 / 483651 (US2024-0245694): Compound A (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-6-((1S,6S)-5-(5- hydroxy-6-methylpyrimidine-4-carbonyl)-2,5-diazabicyclo[4.2.0]octan-2-yl)-7-methyl-5-oxo- 5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide. Compound A is a preferred compound of formula (1g). The term “Compound B” refers to the compound of Example 18A of PCT / IB2023 / 060166 (WO 2024 / 079623). PAT059671 Compound B (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-6-((R)-4-(5- hydroxy-6-methylpyrimidine-4-carbonyl)-3-methylpiperazin-1-yl)-7-methyl-5-oxo-5,7,8,9- tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9-carboxamide. The terms “Compound C” or “compound C”, which are used interchangeably herein, refer to the compound of Ex 42 / Ex123 as described in PCT / IB2022 / 054850 (WO 2022 / 249060), or US 2023-0046859, which are hereby incorporated by reference in their entirety N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(2-(3,6-dihydro-2H-pyran-4-yl)-5-ethyl-6-(4-(5-hydroxy- 6-methylpyrimidine-4-carbonyl)piperazin-1-yl)-7-oxo-[1,2,4]triazolo[1,5-a]pyrimidin-4(7H)- yl)acetamide. “Combination” or “pharmaceutical combination” refers to either a fixed combination in one dosage unit form, or a kit of parts for the combined administration, or a combined administration, for example where a WRN inhibitor, such as a compound of formula (1g), or Compound C, or a pharmaceutically acceptable salt thereof, and a combination partner (e.g. another drug as explained herein, also referred to as “therapeutic agent” or “co-agent”) may be administered PAT059671 independently at the same time or separately within time intervals, especially where these time intervals allow that the combination partners show a cooperative, e.g. synergistic effect. The combination partner for the WRN inhibitor such as the compound of formula (1g), or Compound C, may also for example be an agent that is capable of sensitising or priming the cancer cells to treatment, for example for an improved response to treatment with a WRN inhibitor. The single components may be packaged in a kit or separately. One or both of the components (e.g., powders or liquids) may be reconstituted or diluted to a desired dose prior to administration. The terms “co-administration” or “combined administration” or the like as utilized herein are meant to encompass administration of the selected combination partner to a single subject in need thereof (e.g. a patient), and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time. The term “pharmaceutical combination” as used herein means a product that results from the mixing or combining of more than one therapeutic agent and includes both fixed and non-fixed combinations of the therapeutic agents. The term “fixed combination” means that the therapeutic agents, e.g. combination partners of the present invention, are both administered to a patient simultaneously in the form of a single entity or dosage. The term “non-fixed combination” means that the therapeutic agents, e.g. combination partners of the present invention, are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the two compounds in the body of the patient, or one agent provides a sensitizing or priming effect before or during treatment with a combination partner. This also applies to cocktail therapy, e.g. the administration of three or more therapeutic agents. In the combination therapies of the invention, the therapeutic agents may be manufactured and / or formulated by the same or different manufacturers. Moreover, the therapeutic agents may be brought together into a combination therapy: (i) prior to release of the combination product to physicians (e.g. in the case of a kit comprising the therapeutic agents); (ii) by the physician themselves (or under the guidance of the physician) shortly before administration; (iii) in the patient themselves, e.g. during sequential administration of the therapeutic agents. ‘Pre-treatment’ means administration separately and prior to administration of certain other active compounds, in particular the WRN inhibitor. For example, pre-treatment may sensitise or prime the cancer cells to be more responsive or sensitive to the active compound(s) subsequently administered. Pre-treatment may be used for example to increase MMR deficiency, or may be used to increase resistance of cancer cells to the the pre-treatment agent. Pre-treatment may be PAT059671 used to create or increase MSI-H status in cancer cells, create or increase MMR deficiency in cancer cells, or increase MMR heterogeneity of cancer cells. Temozolomide can be used herein as a pre-treatment agent to sensitise or prime the cancer cells to subsequent treatment, in particular to subsequent treatment with a WRN inhibitor. It is recognized that such effects may also occur when the agent such as temozolomide is used directly in combination with a WRN inhibitor, without pre-treatment administration in advance. The effects of such-pre-treatment may be determined according to tests taught in the art, or tests commercially available, or an FDA- approved test. The pre-treatment may be for example using an agent selected from temozolomide, cisplatin and 6-thioguanine, or the agent may be an ionising radiation based therapy selected from i) external beam radiation, ii) brachytherapy and ii) a radiopharmaceutical). The term "synergistic effect" as used herein refers to action of two or three therapeutic agents producing an effect, for example, slowing the progression of a proliferative disease, particularly cancer, or symptoms thereof, which is greater than the simple addition of the effects of each drug administered by themselves. A synergistic effect can be calculated, for example, using suitable methods such as the Sigmoid-Emax equation (Holford, N. H. G. and Scheiner, L. B., Clin. Pharmacokinet.6: 429-453 (1981)), the equation of Loewe additivity (Loewe, S. and Muischnek, H., Arch. Exp. Pathol Pharmacol.114: 313-326 (1926)) and the median effect equation (Chou, T. C. and Talalay, P., Adv. Enzyme Regul.22: 27-55 (1984)). Each equation referred to above can be applied to experimental data to generate a corresponding graph to aid in assessing the effects of a drug combination. The corresponding graphs associated with the equations referred to above are the concentration-effect curve, isobologram curve and combination index curve, respectively. The term “pharmaceutically acceptable salts” refers to salts that retain the biological effectiveness and properties of the compound and which typically are not biologically or otherwise undesirable. The compound may be capable of forming acid addition salts by virtue of the presence of an amino group. Unless otherwise specified, or clearly indicated by the text, reference to therapeutic agents useful in the pharmaceutical combination of the present invention includes both the free base of the compounds, and all pharmaceutically acceptable salts of the compounds. The term “combination” or “pharmaceutical combination” is defined herein to refer to either a fixed combination in one dosage unit form, a non-fixed combination or a kit of parts for the combined administration where the therapeutic agents may be administered together, independently at the same time or separately within time intervals, which preferably allows that the combination PAT059671 partners show a cooperative, e.g. synergistic effect. Thus, the single compounds of the pharmaceutical combination of the present invention could be administered simultaneously or sequentially. Furthermore, the pharmaceutical combination of the present invention may be in the form of a fixed combination or in the form of a non-fixed combination. The term “fixed combination” means that the therapeutic agents, e.g., the single compounds of the combination, are in the form of a single entity or dosage form. The term “non-fixed combination” means that the therapeutic agents, e.g., the single compounds of the combination, are administered to a patient as separate entities or dosage forms either simultaneously or sequentially with no specific time limits, wherein preferably such administration provides therapeutically effective levels of the two therapeutic agents in the body of the subject, e.g., a mammal or human in need thereof. The pharmaceutical combinations can further comprise at least one pharmaceutically acceptable carrier. Thus, the present invention relates to a pharmaceutical composition comprising the pharmaceutical combination of the present invention and at least one pharmaceutically acceptable carrier. As used herein, the term “carrier” or "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drug stabilizers, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, and the like and combinations thereof, as would be known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp.1289- 1329). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the therapeutic or pharmaceutical compositions is contemplated. The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. Generally, the term “pharmaceutical composition” is defined herein to refer to a mixture or solution containing at least one therapeutic agent to be administered to a subject, e.g., a mammal or human. The present pharmaceutical combinations can be formulated in a suitable pharmaceutical PAT059671 composition for enteral or parenteral administration are, for example, those in unit dosage forms, such as sugar-coated tablets, tablets, capsules or suppositories, or ampoules. If not indicated otherwise, these are prepared in a manner known per se, for example by means of various conventional mixing, comminution, direct compression, granulating, sugar-coating, dissolving, lyophilizing processes, or fabrication techniques readily apparent to those skilled in the art. It will be appreciated that the unit content of a combination partner contained in an individual dose of each dosage form need not in itself constitute an effective amount since the necessary effective amount may be reached by administration of a plurality of dosage units. The pharmaceutical composition may contain, from about 0.1 % to about 99.9%, preferably from about 1 % to about 60 %, of the therapeutic agent(s). One of ordinary skill in the art may select one or more of the aforementioned carriers with respect to the particular desired properties of the dosage form by routine experimentation and without any undue burden. The amount of each carriers used may vary within ranges conventional in the art. The following references disclose techniques and excipients used to formulate oral dosage forms. See The Handbook of Pharmaceutical Excipients, 4th edition, Rowe et al., Eds., American Pharmaceuticals Association (2003); and Remington: the Science and Practice of Pharmacy, 20th edition, Gennaro, Ed., Lippincott Williams & Wilkins (2003). These optional additional conventional carriers may be incorporated into the oral dosage form either by incorporating the one or more conventional carriers into the initial mixture before or during granulation or by combining the one or more conventional carriers with granules comprising the combination of agents or individual agents of the combination of agents in the oral dosage form. In the latter embodiment, the combined mixture may be further blended, e.g., through a V-blender, and subsequently compressed or molded into a tablet, for example a monolithic tablet, encapsulated by a capsule, or filled into a sachet. Clearly, the pharmaceutical combinations of the present invention can be used to manufacture a medicine. The present invention relates to such pharmaceutical combinations or pharmaceutical compositions that are particularly useful as a medicine. Specifically, the combinations or compositions of the present invention can be applied in the treatment of cancer. The present invention also relates to use of pharmaceutical combinations or pharmaceutical compositions of the present invention for the preparation of a medicament for the treatment of a cancer, and to a method for treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a pharmaceutical combination according to the present invention, or the pharmaceutical composition according to the present invention. PAT059671 The term “treatment” as used herein comprises a treatment relieving, reducing or alleviating at least one symptom in a subject, increasing progression-free survival, overall survival, extending duration of response or delaying progression of a disease. For example, treatment can be the diminishment of one or several symptoms of a disorder or complete eradication of a disorder, such as cancer. Within the meaning of the present invention, the term “treatment” also denotes to arrest, delay the onset (i.e., the period prior to clinical manifestation of a disease) and / or reduce the risk of developing or worsening a disease in a patient, e.g., a mammal, particularly the patient is a human. The term “treatment” as used herein comprises an inhibition of the growth of a tumor incorporating a direct inhibition of a primary tumor growth and / or the systemic inhibition of metastatic cancer cells. A "subject," "individual" or "patient" is used interchangeably herein, which refers to a vertebrate, preferably a mammal, more preferably a human. Mammals include, but are not limited to, mice, simians, humans, farm animals, sport animals, and pets. The term "a therapeutically effective amount" of a compound (e.g. chemical entity or biologic agent) of the present invention refers to an amount of the compound of the present invention that will elicit the biological or medical response of a subject, for example, reduction or inhibition of an enzyme or a protein activity, or ameliorate symptoms, alleviate conditions, slow or delay disease progression, or prevent a disease, etc. In one embodiment a therapeutically effective amount in vivo may range depending on the route of administration, between about 0.1-500 mg / kg, or between about 1-100 mg / kg. As used herein, the term “inhibit”, "inhibition" or “inhibiting” refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process. The term “therapeutically effective agent” or “therapeutic agent” as used herein is intended to be construed broadly and includes both drug molecules and ionising radiation based therapies. The ionizing radation based therapy may be provided in any suitable form known in the art, for example in the form of an external beam radiation therapy, brachytherapy or via a radiopharmaceutical (such as a radioligand agent). External beam radation therapy refers to wherein radiation is directed at the tumor from a source outside of the body. The term “brachytherapy” refers to a form of radiation therapy whereby a radiation source is positioned at the tumor site, enabling a high dose of localized radiation to be administration to that tumor site. Radiopharmaceuticals are discussed in more detail below. PAT059671 The optimal dosage of each combination partner for treatment of a cancer can be determined empirically for each individual using known methods and will depend upon a variety of factors, including, though not limited to, the degree of advancement of the disease; the age, body weight, general health, gender and diet of the individual; the time and route of administration; and other medications the individual is taking. Optimal dosages may be established using routine testing and procedures that are well known in the art. The amount of each combination partner that may be combined with the carrier materials to produce a single dosage form will vary depending upon the individual treated and the particular mode of administration. In some embodiments the unit dosage forms containing the combination of agents as described herein will contain the amounts of each agent of the combination that are typically administered when the agents are administered alone. Frequency of dosage may vary depending on the compound used and the particular condition to be treated or prevented. In general, the use of the minimum dosage that is sufficient to provide effective therapy is preferred. Patients may generally be monitored for therapeutic effectiveness using assays suitable for the condition being treated or prevented, which will be familiar to those of ordinary skill in the art. The combination of the present invention may, for example, be in unit dosage of about 1-1000 mg of each active ingredient for a subject of about 50-70 kg. ‘Zwitterion’ or ‘zwitterionic form’ means a compound containing both positive and negatively charged functional groups. For example, the compound of formula (1g) described herein can include the following forms, wherein R4is the zwitterionic form (c) or non-zwitterionic form (d), mixture thereof. The compound of formula (1g) or Compound C, described herein can also include the following forms, wherein R4is the zwitterionic form (a) or (b) or the non-zwitterionic form (e), PAT059671 or a mixture of two thereof, or a mixture of all three thereof. A ‘compound of formula (1g)’, or ‘Compound C’, includes zwitterionic and non-zwitterionic forms, and mixtures thereof. halo means fluoro, chloro or bromo, particularly fluoro or chloro. Alkyl, and alkoxy groups, containing the requisite number of carbon atoms, can be unbranched or branched. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n- butyl, i-butyl, sec-butyl and t-butyl. Examples of alkoxy include methoxy, ethoxy, n-propoxy, i- propoxy, n-butoxy, i-butoxy, sec-butoxy and t-butoxy. ‘=O’ means an oxo substituent. The term “cancer” refers to a disease characterized by the rapid and uncontrolled growth of aberrant cells. Cancer cells can spread locally or through the bloodstream and lymphatic system to other parts of the body. Examples of various cancers are described herein and include but are not limited to colorectal, gastric, endometrial, prostate, adrenocortical, uterine, cervical, esophageal, breast, kidney, ovarian cancer and the like. The terms “tumor” and “cancer” are used interchangeably, e.g., both terms encompass solid and liquid, e.g., diffuse or circulating, tumors. As used herein, the term “cancer” or “tumor” includes premalignant, as well as malignant cancers and tumors. ‘WRN inhibitor’ or ‘WRN helicase inhibitor’ as used herein means a compound or therapeutic agent that inhibits Werner Syndrome RecQ DNA helicase (WRN). The term "WRN" as used herein refers to the protein of Werner Syndrome RecQ DNA helicase. The term “WRN” includes mutants, fragments, variants, isoforms, and homologs of full-length wild-type WRN. In one embodiment, the protein is encoded by the WRN gene (Entrez gene ID 7486; Ensembl ID ENSG00000165392). Exemplary WRN sequences are available at the Uniprot database under accession number Q14191. PAT059671 WRN inhibitors are known in the art. The WRN inhibitor may be a compound of formula (I), (1a) or (1g) as described in WO2022 / 249060, for example as described in embodiment 1 or claim 1. The WRN inhibitor may alternatively be a compound of formula (I) or (1g) as described in WO2024 / 079623, for example as described in embodiment 1 or claim 1. These publications, including the WRN inhibitor compounds exemplified therein, are hereby incorporated by reference in their entirety. Other WRN inhibitors may be used in the inventions described herein. For example, the WRN inhibitors of WO24 / 120378, WO24 / 140597, WO24 / 140714, WO24 / 153155, WO24 / 153244, WO24 / 155884, CN24118459466, WO24187049, WO24 / 193683, WO24 / 193716, WO24 / 199109, WO24 / 199108, CN118684678, WO2024220887, WO24222842, WO24222866, WO24220887, WO24215923, CN118787645, WO2024222677, WO2024 / 230828, WO2024187049, WO24235292, CN119019407, CN118994204, WO2024254511, WO2024254602, WO24246862, WO25002413, CN119161363, US2025034136, WO24259048, WO24255765, CN119039190, CN119039203, CN119039191, CN119039303, CN119101045, WO24255790, WO2025021148, WO25014846 and WO25014877 may be used as the WRN inhibitor in the inventions disclosed herein. These publications and the WRN inhibitors described therein, including the compounds described in claim 1 and other claims, and the exemplified compounds, are hereby incorporated by reference in their entirety. ‘Disease or condition mediated by WRN’ includes a disease or condition, such as cancer, which is treated by WRN inhibition. In particular this can include cancers characterized as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR). ‘Microsatellite unstable cancer’, microsatellite instability-high cancer’, ‘microsatellite high cancer’ and ‘MSI-high cancer’ ‘MSIhi’ and ‘MSI-H’ when used herein, are used interchangeably, and describe cancers that have a high number of alterations in the length of simple repetitive genomic sequences within microsatellites. The determination of MSI-H or dMMR tumor status for patients can be performed using, e.g., polymerase chain reaction (PCR) tests for MSI-H status or immunohistochemistry (IHC) tests for dMMR. Methods for identification of MSI-H or dMMR tumor status are described, e.g., in Ryan et PAT059671 al. Crit Rev Oncol Hematol. 2017; 116:38-57; Dietmaier and Hofstadter. Lab Invest 2001, 81:1453-1456; and Kawakami et al. Curr Treat Options Oncol.2015; 16(7): 30). “pMMR” means proficient mismatch repair. “pMMR / MSS” means “MSS cancer” or “pMMR cancer”. MSS cancer cells are proficient for MMR (pMMR), thus the terms “MSS cancer” or “pMMR cancer” can be used separately and interchangeably. Microsatellite instability is present in various cancers, including but not limited to colorectal cancer, gastric cancer and endometrial cancer in particular, but also in adrenocortical, uterine, cervical, esophageal, breast, kidney, prostate and ovarian cancers. Examples of microsatellite high cancers include uterine corpus endometrial carcinoma, colon adenocarcinoma, stomach adenocarcinoma, rectal adenocarcinoma, adrenocortical carcinoma, uterine carcinosarcoma, cervical squamous cell carcinoma, endocervical adenocarcinoma, esophageal carcinoma, breast carcinoma, kidney renal clear cell carcinoma and ovarian serous cystadenocarcinoma. A cancer that has “defective mismatch repair” (dMMR) or “dMMR character” includes cancer types associated with documented MLH1, PMS2, MSH2, MSH3, MSH6, MLH3, and PMS1 mutations or epigenetic silencing, microsatellite fragile sites, or other gene inactivation mechanisms, including but not limited to cancers of the lung, breast, kidney, large intestine, ovary, prostate, upper aerodigestive tract, stomach, endometrium, liver, pancreas, haematopoietic and lymphoid tissue, skin, thyroid, pleura, autonomic ganglia, central nervous system, soft tissue, pediatric rhabdoid sarcomas, melanomas and other cancers. A cell or cancer with “defective” mismatch repair has a significantly reduced (e.g., at least about 25%, 30%, 40%, 50%, 60%, 70%, 80% or 90% decrease) amount of mismatch repair. In some cases, a cell or cancer which is defective in mismatch repair will perform no mismatch repair. The invention herein provides combinations comprising a WRN inhibitor compound of Formula (1g) or Compound C, in particular Compound A or Compound C, or a pharmaceutically acceptable salt thereof, or Compound B or a pharmaceutically acceptable salt thereof, with another therapeutically active agent. Examples of therapeutically active agents as combinations partners for the WRN inhibitor compound of Formula (1g) or Compound C are provided below. Such PAT059671 combination partners may be used as a single combination partner with the WRN inhibitor, or with more than one combination partner as described herein, with the WRN inhibitor. In an embodiment of the invention, the therapeutically active agent is a chemotherapy agent. In an embodiment, the chemotherapy agent is selected from anastrozole (Arimidex®), vinblastine, vindesine, vinorelbine, vincristine, bicalutamide (Casodex®), bleomycin (e.g. bleomycin sulfate) (Blenoxane®), busulfan (Myleran®), busulfan injection (Busulfex®), calactin, capecitabine (Xeloda®), N4-pentoxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin (Paraplatin®), carmustine (BiCNU®), lomustine (CCNU®), chlorambucil (Leukeran®), bendamustine (Treanda®), cisplatin (Platinol®), cladribine (Leustatin®), cyclophosphamide (Cytoxan® or Neosar®), cytarabine, cytosine arabinoside (Cytosar-U®), cytarabine liposome injection (DepoCyt®), dacarbazine (DTIC-Dome®), dactinomycin (Actinomycin D, Cosmegan), daunorubicin hydrochloride (Cerubidine®), daunorubicin citrate liposome injection (DaunoXome®), dexamethasone, docetaxel (Taxotere®), doxorubicin (e.g. doxorubicin hydrochloride) (Adriamycin®, Rubex®), etoposide (Vepesid®), fludarabine phosphate (Fludara®), 5-fluorouracil (Adrucil®, Efudex®), flutamide (Eulexin®), tezacitibine, gemcitabine (difluorodeoxycitidine), hydroxyurea (Hydrea®), Idarubicin (Idamycin®), ifosfamide (IFEX®), irinotecan (Camptosar®), L-asparaginase (ELSPAR®), leucovorin calcium, melphalan (Alkeran®), 6-mercaptopurine (Purinethol®), methotrexate (Folex®), a mitomycin (e.g. mitomycin A, mitomcyin B or mitomycin C, particularly mitomycin C), mitoxantrone (Novantrone®), mylotarg, paclitaxel (Taxol®), phoenix (Yttrium90 / MX-DTPA), pentostatin, polifeprosan 20 with carmustine implant (Gliadel®), tamoxifen citrate (Nolvadex®), camptothecin, teniposide (Vumon®), 6-thioguanine, thiotepa, tirapazamine (Tirazone®), topotecan hydrochloride for injection (Hycamptin®), vinblastine (Velban®), vincristine (Oncovin®), oxaliplatin (Eloxatin®), epirubicin (Ellence®, Pharmorubicin®) temozolomide (Temodar®), tegafur, and vinorelbine (Navelbine®), in particular irinotecan. In an embodiment, the chemotherapy agent is selected from gemcitabine, camptothecin, irinotecan (Camptosar®), docetaxel (Taxotere®), doxorubicin (e.g. doxorubicin hydrochloride) (Adriamycin®, Rubex®), 5-fluorouracil (Adrucil®, Efudex®), capecitabine (Xeloda®), etoposide (Vepesid®), epirubicin (Ellence®, Pharmorubicin®), oxaliplatin (Eloxatin®), mitomycin (e.g. mitomycin A, mitomcyin B or mitomycin C, particularly mitomycin C), cisplatin (Platinol®), carboplatin (Paraplatin®) and paclitaxel (Taxol®). In particular, the chemotherapy agent is selected from 5-fluorouracil, cisplatin, bleomycin, docetaxel, epirubicin, etoposide, camptothecin, mitomycin, oxaliplatin, mitomycin (e.g. mitomycin C) and gemcitabine. PAT059671 In an embodiment of the invention, the therapeutically active agent is a WEE1 inhibitor. In an embodiment, the WEE1 inhibitor is selected from Adavosertib (also known as AZD1775 and MK- 1775) and PDO166285. In an embodiment, the WEE1 inhibitor is Adavosertib (also known as AZD1775 and MK-1775). In an embodiment of the invention, the therapeutically active agent is an ATR inhibitor. In an embodiment, the ATR inhibitor is selected from RP-3500, ceralasertib (also known as AZD6738), berzosertib, ART-0380, gartisertib (also known as M4344), and elimusertib (also known as BAY- 1895344). In an embodiment, the ATR inhibitor is elimusertib (BAY-1895344). In an embodiment of the invention, the therapeutically active agent is a DNA-PK inhibitor. In an embodiment, the DNA-PK inhibitor is selected from AZD-7648, NU7441 (also known as KU- 57788), Omipalisib, BAY8400 and M3814. In an embodiment, the DNA-PK inhibitor is AZD-7648 or NU7441 (KU-57788), particularly AZD-7648. In an embodiment of the invention, the therapeutically active agent is a ionising radiation based therapy selected from i) external beam radiation, ii) brachytherapy and iii) a radiopharmaceutical. In an embodiment, the ionising radiation is external beam radiation. In an embodiment, the ionising radiation is a radiopharmaceutical. In an embodiment, the radiopharmaceutical is a radioligand agent. In an embodiment, the radioligand agent is selected from177Lu-PSMA-617,177Lu-PSMA-R2,177Lu-NeoB, and177Lu-FAP-2286. In an embodiment of the invention, the therapeutically active agent is a MEK inhibitor. In an embodiment, the MEK inhibitor is selected from the group consisting of refametinib, pimasertib, selumetinib, trametinib, binimetinib and cobimetinib, or a pharmaceutically acceptable salt thereof. In an embodiment, the MEK inhibitor is trametinib. In an embodiment of the invention, the therapeutically active agent is an MDM2 inhibitor. In an embodiment, the MDM2 inhibitor is selected from the group consisting of nutlin-3a, idasanutlin (also known as RG7388), RG7112, KRT-232 (also known as AMG-232), APG-115, RAIN-32 (also known as DS-3032 and milademetan), BI-907828 and HDM201 (also known as siremadlin), or a pharmaceutically acceptable salt thereof. In an embodiment, the MDM2 inhibitor is HDM201. In an embodiment of the invention, the therapeutically active agent is a G4-quadruplex stabilizer. In an embodiment, the G4-quadruplex stabilizer is pyridostatin. PAT059671 In an embodiment of the invention, the therapeutically active agent is an ATM inhibitor. In an embodiment, the ATM inhibitor is selected from KU-55933, KU-60019, KU-59403, M3541, CP- 466722, AZ31, AZ32, AZD0156 and AZD1390. In an embodiment, the ATM inhibitor is KU-60019. In an embodiment of the invention, the therapeutically active agent is a PARP inhibitor. In an embodiment, the PARP inhibitor is selected from olaparib, NMS293, niraparib, prexasertib, veliparib, rucaparib, talazoparib, AZD-5305 and KU0058948. In an embodiment, the PARP inhibitor is olaparib. In an embodiment of the invention, the therapeutically active agent is a chemotherapy agent, and the chemotherapy agent is a topoisomerase inhibitor. In an embodiment, the topoisomerase inhibitor is selected from QAP1, irinotecan, topotecan, camptothecin and etoposide. In an embodiment, the topoisomerase inhibitor is selected from QAP1, etoposide and irinotecan. In an embodiment of the invention, the therapeutically active agent is a CHK1 or CHK2 inhibitor. In an embodiment, the CHK1 or CHK2 inhibitor is selected from GDC-0575, Prexasertib (also known as LY2606368), SCH900776 (also known as MK-8776), SRA737, PF477736, LY2606368 and AZD7762. In an embodiment of the invention, the therapeutically active agent is a DNA polymerase alpha inhibitor, for example aphidicolin. In an embodiment of the invention, the therapeutically active agent is a PI3K inhibitor, e.g. a PI3K- alpha inhibitor. In an embodiment, the PI3K inhibitor is selected from AMG511, buparlisib, Idelalisib, Copanlisib, Duvelisib, Alpelisib, and Umbralisib. In an embodiment, the PI3K inhibitor is Alpelisib. In an embodiment, the PI3K inhibitor is a PI3K-alpha inhibitor selected from RLY- 2608, BPI-21668, PF-06843195, LX-086, HS-10352, HH-CYH33, JS-105, MEN-1611, LOX- 22783, TOS-358, STX-478, Alpelisib, Serabelisib and Inavolisib. In an embodiment, the PI3K- alpha inhibitor is selected from Alpelisib, Serabelisib and Inavolisib. In an embodiment of the invention, the therapeutically active agent is a polymerase theta inhibitor, for example RP-2119 or Pol Theta Helicase Inhibitor (Ideaya / GSK). In an embodiment of the invention, the therapeutically active agent is an IAP inhibitor or an SMAC mimetic. In an embodiment, the IAP inhibitor is selected from LCL161, Bininapant and Xevinapant. In an embodiment of the invention, the therapeutically active agent is a CTLA-4 inhibitor, for example ipilimumab. PAT059671 In an embodiment of the invention, the therapeutically active agent is a KRAS G12C inhibitor, for example a compound selected from sotorasib, adagrasib, GDC6036, D-1553, and in particular, JDQ443. JDQ443 is described in Example 1 of PCT application WO2021 / 124222, published 24 June 2021. WO2021 / 124222 is hereby incorporated by reference in its entirety. In an embodiment of the invention, the therapeutically active agent is a KRAS G12D inhibitor, for example siG12D LODER, HRS-4642 and ASP-3082. In an embodiment of the invention, the therapeutically active agent is a YAP / TEAD inhibitor. Examples of YAP / TEAD inhibitors include IAG933 (Novartis), NSC-682769 (University of California), MSC-4106 (Merck), GNE-7883 (Genentech), TED-347 (Indiana University), K-975 (Kyowa Kirin) and the compounds in WO 2021 / 186324, WO2022 / 087008; WO2021 / 102204; WO2020 / 214734; WO2020 / 097389; WO2019 / 222431; WO2019 / 113236; WO2019 / 040380; WO2018 / 204532; WO2017 / 058716; WO2022 / 159986; WO2022 / 120354; WO2022 / 120355; WO2022 / 120353; WO2020 / 243423 or WO2020 / 243415. In an embodiment of the invention, the therapeutically active agent is a BCL2 inhibitor, or a BCL2 / BCLxl dual inhibitor. Examples include venetoclax, APG-2575 (lisaftoclax), obatoclax meylate, BGB-11417 (Beigene), pelcitoclax, Zn-d5 (Zentalis), AZD-0466 (Astra Zeneca), ABBV- 453, ABBV-167 (AbbVie), LP-118, LP-108, (Guangzhou Lupeng), FCN-338 (Fochon Pharmaceuticals) and navitoclax. In an embodiment of the invention, the therapeutically active agent is a MCL1 inhibitor. Examples of MCL1 inhibitors useful in combinations and methods of the present invention include AMG176 (tapotoclax), GS-9716, ABBV-467, Murizatoclax, AZD-5991, JNJ-1245, JNJ-4355, and PRT-1419 (Prelude Therapeutics). In an embodiment of the invention, the therapeutically active agent is a CDK2 inhibitor, for example BLU222 (Blueprint Medicines), PF-07104091 (Pfizer) and INCB-0123667 (Incyte). In an embodiment of the invention, the therapeutically active agent is a CDK2 / CDK9 or CDK2 / CDK9 / CDK7 inhibitor, for example fadraciclib and seliciclib. In an embodiment of the invention, the therapeutically active agent is a CDK4 or CDK4 / 6 inhibitor. Examples include ribociclib, palbociclib, trilaciclib, birociclib and lerociclib. In an embodiment of the invention, the therapeutically active agent is a HIF2 alpha inhibitor. Examples include belzutifan, MK-6482, PT2385 and DFF332. PAT059671 In an embodiment of the invention, the therapeutically active agent is a PLK1 inhibitor, such as volasertib. In an embodiment of the invention, the therapeutically active agent is a SHP2 inhibitor, for TNO155, JAB3312 or JAB-3068 (Jacobio), RLY1971 (Roche), SAR442720 / RMC-4630 (Sanofi / Revolution Medicines), RMC4450 (Revolution Medicines), BBP398 (Navire), BR790 (Shanghai Blueray), SH3809 (Nanjing Sanhome), PF0724982 (Pfizer), ERAS601 (Erasca), RX- SHP2 (Redx Pharma), ICP189 (InnoCare), HBI2376 (HUYA Bioscience), ETS001 (Shanghai ETERN Biopharma), HS-10381 (Hansoh Pharma / Jiangsu Hansoh), BPI-442096 (Betta Pharmaceuticals), I-0436650 (IRBM), PCC-0208023 (Binzhou Medical University), IACS-15414 (Navire) and X-37-SHP2 (X-37). A particularly preferred SHP2 inhibitor for use according to the invention is (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2- oxa-8-azaspiro[4.5]decan-4-amine (TNO155), or a pharmaceutically acceptable salt thereof. TNO155 is synthesized according to example 69 of WO2015 / 107495, which is hereby incorporated by reference in its entirety. A preferred salt of TNO155 is the succinate salt. In an embodiment of the invention, the therapeutically active agent is a PRMT5 inhibitor, such as SCR-6277, AMG-193, SKL-27969, MRTX-1719, onametostat / JNJ-64619178, TNG-90 and PF- 0693999. In an embodiment of the invention, the therapeutically active agent is a STING agonist, such as CDK-002, TAK-500, ONO-7914, VB-85247, KL-340399, TAK-676, SNX-281, SB-11285 and IMSA-101. In an embodiment of the invention, the therapeutically active agent is a TRAIL receptor agonist, such as drozitumab, PRO-95780, CS-1008, IGM-8444, and lexatumumab. In an embodiment of the invention, the therapeutically active agent is a TAK1 inhibitor, such as takinib. In an embodiment of the invention, the therapeutically active agent is a MK2 inhibitor, such as CC-99677. In an embodiment of the invention, the therapeutically active agent is a HDAC inhibitor such as panobinostat, vorinostat, romidepsin, or belinostat. In an embodiment of the invention, the therapeutically active agent is an androgen biosynthesis inhibitor, such as abiraterone, or an androgen receptor modulator, such as enzalutamide. PAT059671 Therapeutically active agents which can create or increase MSI-H status in cancer cells, are known in the art. The agent can for example be an agent such as temozolomide, cisplatin, 6- thioguanine, or an ionising radiation-based therapy selected from i) external beam radiation, ii) brachytherapy and ii) a radiopharmaceutical. Said agent may be adminsistered at the same time as the WRN inhibitor, or before the WRN inhibitor administration, as a pre-treatment. MSI-H status can be determined by tests known in the art, including commercially available or FDA-approved tests. Therefore, ‘a therapeutically active agent which can create or increase MSI-H status in cancer cells’, includes an agent that is shown to create or increase MSI-H status in cells, using a test known in the art. The combination partner for the WRN inhibitor compound of formula (1g), or Compound C, may include, for example, an agent that is capable of sensitising or priming the cancer cells to treatment. The combination partner may therefore be used, for example, to: ^ sensitise the cancer cells, for example for an improved response to treatment with a WRN inhibitor, ^ prime the cancer cells, for example, such priming may include triggering hypermutation status in cancer cells, ^ create or increase MMR deficiency in cancer cells, ^ create or increase MSI-H status in cancer cells, ^ increase MMR heterogeneity of cancer cells, and / or ^ create or increase resistance in cancer cells to temolozolomide. These effects may be determined according to tests taught in the art, or tests commercially available, or tests approved by the FDA. Such therapeutic agents are known in the art. Said therapeutic agent may be an alkylating agent, for example temozolomide. Said therapeutic agent may also be cisplatin or 6-thioguanine. Said therapeutic agent may also be an ionising radiation based therapy selected from i) external beam radiation, ii) brachytherapy and ii) a radiopharmaceutical, for example as described herein. PAT059671 Priming, or pre-treatment, with temozolomide may be performed in patients with MSS cancer, or in patients with MGMT-defective, or MGMT-deficient, or MGMT-silenced tumors. Such priming may take place in patients with pMMR / MSS MGMT-defective, or pMMR / MSS MGMT-deficient, or pMMR / MSS MGMT-silenced.tumors. In one example, the tumor is MGMT-defective, or MGMT- deficient, or MGMT-silenced CRC. In particular, the tumor is pMMR / MSS and MGMT-silenced mCRC. In another aspect, the tumor is MGMT-methylated glioblastoma. “MGMT” means O6-methylguanine DNA methyltransferase. “MGMT” refers to the gene encoding MGMT. The MGMT gene encodes a repair protein (MGMT; formerly also termed alkyl guanine alkyltransferase) that removes DNA alkylation modifications from DNA. Alkylating chemotherapeutic agents such as TMZ (temozolomide) induce cytotoxic cell death in tumor cells by alkylating DNA at multiple sites. Repair of the most toxic event, alkylation of the O6group of guanine, is dependent on MGMT. Assessment of MGMT tumor status can be for example by protein expression promoter methylation, as described in the references below which are hereby incorporated by reference in their entirety, or also by MGMT gene mutations. Methods to evaluate MGMT status are summarized in this reference: Mansouri A, Hachem LD, Mansouri S, et al. MGMT promoter methylation status testing to guide therapy for glioblastoma: refining the approach based on emerging evidence and current challenges. Neuro Oncol. 2019;21(2):167-178. doi:10.1093 / neuonc / noy132. References: Cell 177, 821-836, May 2, 2019, Journal of Clinical Oncology 40, no.14 (May 10, 2022) 1562-1573 DOI: 10.1200 / JCO.21.02583, Biochemical Pharmacology, Vol 54, pp.419-424, 1997, Nat Genet.2021 July ; 53(7): 1088–1096. doi:10.1038 / s41588-021-00874-3. Germano, G., Lamba, S., Rospo, G. et al. Inactivation of DNA repair triggers neoantigen generation and impairs tumour growth. Nature 552, 116–120 (2017). PAT059671 Cancer Discov 2022;12:1656–75 doi: 10.1158 / 2159-8290.CD-21-1434 Amodio et al., 2023, Cancer Cell 41, 196–209, https: / / doi.org / 10.1016 / j.ccell.2022.12.003, 118 Nature Vol 5527 Dec 2017. Radiopharmaceutical The term “Radiopharmaceutical” as used herein refers to a pharmaceutical drug comprising one or more radioactive isotopes configured such that the radioactive isotopes are preferentially delivered to the tumor site. In some cases, the radiopharmaceutical can simply be a radioactive isotope or a pharmaceutically acceptable salt thereof. For example,223Ra-Radium Dichloride (BAY88-8223, Xofigo® previously known as223Ra-Alpharadin) (available from Bayer Pharma) is an approved medication for the treatment of cancer types that commonly metastasize to the bone. The radium is preferentially delivered to the bone as a result of its chemical similarity to calcium. Other examples are iodine salts based on131I (usually in the form of Sodium Iodide), and32P- Sodium Phosphate used in the palliation of bone pain,153Sm-Lexidronam pentasodium (153Sm- Samarium Ethylene Diamine Tetramethylene Phosphoric Acid,153Sm-Samarium EDTMP, Quadramet®) used for the relief of bone pain in patients with multiple osteoblastic skeletal metastases,153Sm-DOTMP (CycloSAM™),153Sm-Oxabiphor (153Sm-Samarium oxa- bis(ethylenedithio) tetramethylphosphonium acid,153Sm-OXB,153Sm-Oxabifor,153Sm-ETMP) used for the relief of bone pain in patients with multiple osteoblastic skeletal metastases,166Ho- Phytate used for the potential treatment of chronic synovitis,177Lu-ST2210 (IART -177Lu-DOTA- Biotin) (available from Sigma-Tau),186Re-Rhenium Etidronate (186Re-HEDP, hydroxyethylidene diphosphonate) used in relieving the pain associated with metastatic bone cancer,186Re-Rhenium Sulfide used for isotopic radiation synovectomy of medium size joints,188Re-Rhenium Etidronate (HEDP) is indicated for bone pain palliation in cancer metastases (prostate, breast). In other embodiments, the radioactive isotope is combined with a targeting vector intended to drive the radionuclide to the target. The combination of such a radioactive isotope and a targeting vector is referred to herein as a "radioligand agent”. The radionuclide is selected on the basis of the application of the drug (diagnostic or therapeutic agent), of the type of radiation and of its energy. The targeting vector is intended to drive the radionuclide preferentially to the target tissue, target organ or target cell and can be chemical molecules, peptides, polypeptide, proteins (such as antibodies, antigen binding fragments, Bispecific Antibodies, affibodies, or Fibronectin type III PAT059671 domains), peptidomimetics, fusion proteins / polypeptides, Aptamers, Antisense oligonucleotides, siRNA, microparticles or nanoparticles. In order to link the radionuclide to the vector, chemists may have to develop special chemical structures called linkers. The linkers may be inert moieties used to increase the distance of binding moieties from chelators in order to prevent steric influence and loss of activity on the cell receptors upon functionalization. The length and composition of the linker may influence the binding affinity of the radiopharmaceutical to the receptor, the accumulation of radionuclides in tumor cells and the pharmacokinetic. Direct binding through so-called ‘covalent’ bonds is possible, e.g. with radionuclides such as the radiohalogens131I or211At. Radiometals may need a so-called ‘chelator’, or “chelating agent”, a molecule moiety in form of a cage that can trap the radiometal. Examples of chelating agents include but not limited to DOTA, DTPA, AAZTA, TCMC, DAT, DFO, DOTAGA, DOTAM, EDTA, HBED / HBED-CC, HYNIC, NODAGA, NODA, NODASA, NOPO, NOTA and PCTA and their derivates. In one embodiment the radionuclides can be administrated in gel, micelle, sphere, particle, microparticle or nanoparticle forms and including therapeutics such as:166Ho-Chitosan used for hepatocellular carcinoma treatment (available from Dong Wha.), 90Y-SIR-Spheres a resin-based microspheres used for hepatocellular carcinoma treatment(available from Sirtex), 90Y- TheraSpheres a suspension of insoluble glass microspheres used for transarterial radioembolization in hepatic neoplasia including hepatocellular carcinoma(available from BTG / Boston Scientific), 90Y-RadioGel a hydrogel liquid made of water-based biodegradable polymer that delivers 90Y microspheres directly into tumor tissues (Vivos Inc.),131I-SapC-DOPS (131I-Saposin;131I-BXD-350) a nanovesicle composed of Saposin C (SapC) coupled to dioleoylphosphatidylserine (DOPS) (Molecular Targeting Technologies Inc.),131I-Lipiodol (131I- Ethiodized Oil,131I-IOM-40) a mixture of iodinated ethyl esters of fatty acids of poppy seed oil used for the treatment of hepatocarcinoma (HCC),166Ho-QuiremSpheres a poly-L-lactic acid (PLLA) based particles (available from Quirem Medical BV / Terumo Corp.),166Ho-TheraneaM an holmium based microparticles (Novartis),177Lu-DOTA-αMSH-PEG-C’ dots a dual modality product (Therapy / fluorescence) developed on the basis of ultrasmall fluorescent (Cy5) silica nanoparticles (C′ dots), conjugated with MC1-R targeting alpha melanocyte stimulating hormone (αMSH) peptides on the polyethylene glycol (PEG) coated surface (Elucida Oncology Inc.),188Re- ImDendrim a delivery system made from dendrimer (G5) diffusible probes for targeting hypoxic tumoral cells combined with the beta emitter Rhenium-188 (Nano Gun Technology),224Ra- PAT059671 RadSpherin a calcium carbonate microspheres based for the treatment of ovarian cancer (Oncoinvent),225Ac-Au@TADOTAGA (225AC-Au-2,2′,2”-(10-(4-((2-(5-(1,2-dithiolan-3- yl)pentanamido)ethyl) amino)-1-carboxy-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7- triyl)triacetic acid) a gold nanoparticle as an injectable radiopharmaceutical form of brachytherapy for local radiation treatment of cancer (NCSR Demokritos). In one embodiment the radionuclides can be conjugated with small molecules (with molecular weight from a hundred to several thousand daltons). These molecules are generally but not limited designed on the basis of natural ligands that have a specific affinity for some receptors that are expressed on the surface of tumors. Natural molecules already used as drugs are often starting points for the development of such tracers and drugs. As a consequence, small molecules have the highest potential to cover all types of indications and including therapeutics such as: 47Sc- cm10 (47Sc-DOTA-Folate,47Sc-Folate) a folate analogue cm-10 is a combination of three entities: the folic acid, a DOTA-chelator and an albumin binding. Mechanism of action: Folate (Paul Scherrer Institute),90Y / 177Lu-FAPI-04 and90Y / 177Lu-FAPI-46 a DOTA-coupled quinolone analogue based on a Fibroblast Activation Protein (FAP)-specific enzyme inhibitor (FAPI). Mechanism of action: Fibroblasts (Novartis),90Y / 177Lu-NM600 (DOTA-18-(p- aminophenyl)octadecyl phosphocholine) a tumor-targeting alkylphosphocholine. Mechanism of action: Alkyl PhosphoCholine (University of Wisconsin-Madison),117mSn-RAGE a targeting agent to the receptor against glycation end-products (RAGE) for the treatment of Alzheimer’s disease. Mechanism of action: Receptor Against Glycation End-products (NeuroSn, Inc.),131I-CLR-131 (131I-CLR-1404,131I-NM404,131I-18-p-iodophenyl-octadecyl phosphorcholine) an alkyl phosphocholine (APC) from the family of phospholipid ether (PLE) analogs. Mechanism of action: (PI3K) / Akt (Cellectar Biosciences),149Tb-DOTA-Folate a folate derivate. Mechanism of action: Folate receptor (Paul Scherrer Institute),131I-IITM (131I-Iodo-N-[4-(6-(isopropylamino)pyridine-4- yl)-1,3-thiazol-2-yl]-N-methyl benzamide) a benzamide targeting the ectopic metabotropic glutamate receptor 1 (mGluR1) used in melanomas. Mechanism of action: mGluR1 (NIQRST),131I-BA52 (131I-benzo(1,3)dioxolo-5-carboxylic acid (4-(2-diethylamino-ethylcarbamoyl)-2-iodo-5- methoxy-phenyl)-amide) a melanin-binding benzamide for the therapy of malignant melanomas. Mechanism of action: Melamine (Bayer Pharmaceuticals),131I-Iobenguane (131I- Metaiodobenzylguanidine,131I-MIBG,123I-Azedra) a small molecule similar to norepinephrine used in the detection and therapy of primary or metastatic pheochromocytoma and paraganglioma (Progenics-Lantheus),177Lu-DOTAZOL (177Lu-DOTAZOL,177Lu-Zoledronic acid,177Lu-DOTA-ZOL,177Lu-DOTA-Zoledronate,177Lu-Zoledronate,177Lu-DOTA-BP DOTAZOL, PAT059671177Lu-ZLD,177Lu-DOTAMZOL,177Lu-DP-4411) a zoledronic acid derivative (177Lu-(2,2',2''-(10-(2- (2-(1-(2-hydroxy-2,2-diphosphonoethyl) -1H-imidazol -4-yl) ethylamino)-2-oxoethyl) -1,4,7,10- tetraazacyclo dodecane-1,4,7-triyl)triacetic acid) used for the therapy metastasized prostate cancer. Mechanism of action: bisphosphonate (Mainz University / ITM),177Lu-FF-10158 an antagonist targeting integrin αvβ3 and αvβ5 receptors. Mechanism of action: Integrin (AAA / Novartis / FUJIFILM),90Y-DOTA-EB-MCG a MCG ((I-1-carboxy-2- mcercaptoethyl)carbamoyl)- L-glutamic acid) conjugated with the albumin-binding Evans Blue (EB) derivative and of a DOTA group. Mechanism of action: GRPR (Johns Hopkins Medical Institutions / NIH),177Lu-DO3A-VS- Cys40-Exendin-4 (177Lu-Exendin-4;177Lu-DO3A-Exendin-4) a molecule targeting the Glucagon- like peptide-1. Mechanism of action: GLP-1 (Sanofi),177Lu-DOTA-LLP2A (177Lu-LLP2A;177Lu- DOTA-PEG4-LLP2A) a molecule with high affinity for VLA-4. Mechanism of action: VLA-4 (University of Pittsburgh),177Lu-EBRGD (177Lu-EB-RGD;177Lu-DOTA-EBRGD) a molecule conjugated with Evans Blue (EB) structure to bind albumin, targeting integrin αvβ3 receptor. Mechanism of action: Integrin (Molecular Targeting Technologies Inc.),177Lu-NM600 (177Lu- DOTA-18-(p-aminophenyl)octadecyl phosphocholine) a tumor-targeting alkylphosphocholine. Mechanism of action: alkylphosphocholine (APC). (University of Wisconsin-Madison),177Lu- CTT1403 a phosphoramide based molecule for the therapy of prostate cancer developed by Mechanism of action: PSMA (Cancer Targeted Technology ),211At-AITM (211At-Astatino-N-[4- (6-(isopropylamino)pyridine-4-yl)-1,3-thiazol-2-yl]-N-methyl benzamide) a benzamide targeting the ectopic metabotropic glutamate receptor 1 (mGluR1) used in melanomas Mechanism of action: mGluR1 (NIQRST),177Lu-CTT1403 a phosphoramidate-based molecule (Cancer Targeted Technology),225Ac-DOTA-MC1RL a melanocortin 1 receptor ligand. Mechanism of action: MCR1 (Moffit Cancer Center and Research Institute),225Ac-DOTAZOL (225Ac-DOTAZOL,225Ac-DOTA-ZOL,225Ac-DOTA-Zoledronate) a Zoledronic acid derivative. Mechanism of action: bisphosphonate (University of Mainz). In one embodiment the radionuclides can be conjugated with proteins (such as antibodies, antigen binding fragments, Bispecific Antibodies, affibodies, or Fibronectin type III domains) including therapeutics such as :67Cu-CTPA-mAB35 an anti CEA monoclonal antibody, 67Ga- THP-Trastuzumab a mAb targeting HER2 (St. Thomas’ Hospital, London),90Y-DOTA-FF-21101 (90Y-FF-21101, FF-21101) a chimeric monoclonal anti-P-Cadherin (CDH3) mAb (FUJIFILM Pharmaceuticals),90Y-OTSA101-DTPA (90Y-OTSA101,90Y-Tabituximab barzuxetan, TT641 pAb, FZD10 mAb) an anti-FZD10 (Frizzled Homolog 10) antibody (OncoTherapy Science Inc.),90Y- Clivatuzumab tetraxetan (hPAM4-Cide™) a fully human IgG1 monoclonal antibody directed PAT059671 against the human insulin-like growth factor (Immunomedics Inc.),225Ac-Codrituzumab a full length humanized monoclonal antibody directed at Glypican 3 (NIH / MSKCC),90Y-Daclizumab a humanized murine monoclonal antibody that binds to CD25 (Interleukin-2),90Y-Epratuzumab tetraxetan (IMMU-102,90Y-Lymphocide,90Y-DOTA-hLL2) a humanized IgG1 antibody targeting CD22 for treatment of non-Hodgkin's lymphoma (NHL) and diffuse large B-cell lymphoma (DLBCL) (Immunomedics Inc.),90Y-Ibritumomab tiuxetan (Zevalin®) an IgG1 kappa-monoclonal murine antibody directed against the CD20 antigen. (available from Biogen Idec, Acrotech Biopharma),90Y-Ferritarg a rabbit polyclonal antibody which targets Ferritin (Alissa Pharma),90Y- IDEC-159 a monoclonal antibody which targets TAG-72 (Biogen-IDEC),90Y-IDEC-159 a monoclonal antibody reactive to tumor-associated glycoprotein (TAG-72). (Biogen Idec), 117mSn-DOTA-Annexin-V a natural protein that can be used to both image and treat vulnerable plaque, cancers or rheumatoid arthritis (Serene LLC),131I-Tenatumomab a Tenascin-C targeting monoclonal antibody (ST2146) (Sigma-tau),131I-chTNT (131I-chTNT-1 / B;131I-TNT, Cotara®, Vivatuxin®,131I-derlotuximab biotin) a DNA / histone-targeting monoclonal antibody used to treat brain cancer through in situ infusion directly into the tumor. (Avid Bioservices, Shanghai Medipharm Biotech),131I-Metuximab an antibody fragment targeting the hepatocellular cancer (HCC)-associated antigen HAb18G / CD147. (Chengdu Taihe Health Technology),131I- Tositumomab (Bexxar®) an anti-CD20 antibody (GlaxoSmithKline),131I-Weimeisheng a chimeric antibody (CIRC - Shanghai Meien Biotechnology),131I-CAM-H2 (131I-SGMIB anti-HER2-VHH1;131I-SGMIB) a single domain antibody fragment (sdAb) targeting HER2. (Camel-IDS),131I-CR3022 an antibody targeting specifically the SARS-CoV-2 RBD (host cell receptor binding domain). (MSKCC),131I-81C6 (131I-Monoclonal Antibody 81C6,131I-MoAB 81C6, Neuradiab™) a murine IgG2 anti-tenascin monoclonal antibody (Bradmer Pharmaceuticals),131I-Naxitamab (131I-3F8,131I-MoAb-3F8) a murine IgG3 monoclonal antibody which binds to the cell-surface GD2, a disialoganglioside antigen (Y-Mabs Therapeutics),131I-Omburtamab (131I-Burtomab,131I-8H9;131I- 8H9 (B7-H3),131I-MoAb-8H9) a murine monoclonal antibody IgG1 recognizing cell surface antigen 4Ig-B7H3, (Y-Mabs Therapeutics),131I-chTNT (Tumor Necrosis Therapy-1,131I-chTNT-1 / B;131I- TNT, Cotara®, Vivatuxin®,131I-derlotuximab biotin) a DNA / histone-targeting monoclonal antibody (Avid Bioservices / Shanghai MediPharm Biotech),131I-81C6 mAb (131I-Monoclonal Antibody81C6,131I-MoAB 81C6, Neuradiab™) a murine IgG2 anti-tenascin monoclonal antibody (Bradmer Pharmaceuticals),131I-BC8 (Iomab-B™,131I-apamistamab) a murine monoclonal antibody that targets CD45. (Actinium Pharmaceuticals),131I Radretumab (131I-L19-SIP,131I-L19SIP) a human recombinant antibody fragment consisting of the variable regions of the L19 mAb directed against the extra-domain B (ED-B) of fibronectin that is overexpressed in tumoral vasculature. (Philogen), PAT059671177Lu-Lilotomab (Betalutin®) an anti-CD37 antibody (Nordic Nanovector),177Lu-Lilotomab satetraxetan (BetalutinTM) an anti-CD37 antibody (Nordic Nanovector),177Lu-MVT-1075 (177Lu- DFO-HuMab-5B1) an antibody binds to the carbohydrate antigen sialyl-Lewis a (sLea) (CA19-9) (BioNTech SE),177Lu / 227Th APOMAB a murine monoclonal antibody DAB4, (AusHealth Corp Pty Ltd),177Lu-IMP-288 a Dock-and-Lock bispecific antibody anti-CEA (Nantes University – Radboud University),177Lu-TLX591 (177Lu-Rosapatumab,177Lu-MLN591,177Lu-huJ591,177Lu- J591,177Lu-ATL-101,177Lu-TLX591t) an anti-PSMA (prostate-specific membrane antigen) antibody with high specificity for prostate tumor cells. (Telix Pharmaceuticals Ltd),177Lu-DTPA- TRC105 an anti-CD105 antibody (Tracon Pharmaceuticals),177Lu-225Ac-hu11B6 (177Lu-DTPA- hu11B6;177Lu-h11B6) a PSMA targeting antibody (Lund University),177Lu-Humalutin (177Lu- NNV003) an anti-CD37 antibody (Nordic Nanovector),177Lu / 225Ac-Rosapatumab (J591, TLX591) an anti-PSMA (prostate-specific membrane antigen) an antibody with high specificity for prostate tumor cells (Telix Pharmaceuticals),177Lu-TLX250 (177Lu-cG250, TLX250,177Lu- TLX250t,177Lu-Lutarex®,177Lu-DOTA-Girentuximab,177Lu-Girentuximab) a chimeric murine human monoclonal antibody which targets the Carbonic Anhydrase IX (CA-IX) molecule / G250 antigen. (Telix Pharmaceuticals),188Re / 213Bi-8C3 a murine antibody to melanin of the IgG isotype (Radimmune Inc.),211At-81C6 a chimeric monoclonal antibody anti tenascin (Duke University),211At-MX35-F(ab’)2 (211At-labeled-MX35),211At-MX35, anti-human SLC34A2) anti body fragment of the murine IgG1-class monoclonal antibody directed toward a cell-surface glycoprotein of 95 kDa on OVCAR-3 cells (MSKCC),212Pb-TCMC-Trastuzumab a Tetrakis Carbamoyl Methyl tetraza Cyclododecane (TCMC) conjugated with a monoclonal antibody interfering with the HER2 / neu receptor (an epidermal growth factor receptor EGFR) (Orano Med),212Pb-Daratumumab (212Pb-anti-CD38,212Pb-Dara,212Pb-TCMC-Daratumumab) a human immunoglobulin G1 kappa (IgG1k) monoclonal antibody directed against the cell surface glycoprotein CD38 which is expressed on various hematopoietic cells and is overexpressed on multiple myeloma (MM) cells (Orano Med),212Pb-376.96 (212Pb-TCMC-376.96) a monoclonal antibody which recognizes a B7-H3 (CD276) epitope expressed on ovarian cancer cells, pancreas tumor cells and cancer initiating cells (CICs) (University of Alabama),212Pb-NNV003 an anti-CD37 humanized antibody (Orano Med / Nordic Nanovector), 213Bi-DTPA-PAN-622 (213Bi-PAN-622) a radiolabeled fully human monoclonal antibody (PAN-622) to human aspartyl (asparaginyl)- hydroxylase (HAAH) (Sensei Biotherapeutics Inc.),213Bi-Lintuzumab (213Bi-Bismab-A™, 213Bi- DTPA-Lintuzumab,213Bi-CHX-A’’-DTPA-huM195) an anti-CD33 humanized antibody huM195 (Actinium Pharmaceuticals),225Ac-Cixutumumab (225Ac-IMC-A12,225Ac-DOTA-Cixutumumab) a fully human IgG1 monoclonal antibody directed against the human insulin-like growth factor-1 PAT059671 receptor (IGF-1R). (University of Saskatchewan),225Ac-Girentuximab (TLX251) a chimeric murine human monoclonal antibody which targets the Carbonic Anhydrase IX (CA-IX) molecule / G250 antigen, expressed on over 90% of clear cell renal cell carcinomas. (Telix Pharmaceuticals),225Ac-J591 (225Ac-ATL-101,225Ac-TLX591) an anti-PSMA (prostate-specific membrane antigen) antibody with high specificity for prostate tumor cells (Telix Pharmaceuticals),225Ac-TLX251 (225Ac-cG250,225Ac-DOTA-Girentuximab,225Ac-Girentuximab) a chimeric murine human monoclonal antibody which targets the Carbonic Anhydrase IX (CA-IX) molecule / G250 antigen, expressed on over 90% of clear cell renal cell carcinomas. (Telix Pharmaceuticals),225Ac-TLX591 (225Ac-J591) anti-PSMA (prostate-specific membrane antigen) antibody with high specificity for prostate tumor cells (Telix Pharma / Weill Medical College of Cornell University),225Ac-TLX592 (225Ac-J591, improved225Ac-TLX591 ) a re-engineered antibody hu591 targeting PSMA (Telix Pharma),225Ac-FPI-1434 an humanized monoclonal antibody which targets the insulin-like growth factor-1 receptor (IGF-1R) (Fusion Pharmaceuticals),225Ac-Lintuzumab (225Ac-Actimab-A™,225Ac-DOTA-huM195,225Ac-DOTA-Lintuzumab,225Ac-CHX-A’’-DOTA-huM195, Lin-Ac225,225Ac- huM195) an anti-CD33 humanized antibody huM195 (Actinium Pharmaceuticals),225Ac Daratumumab (225Ac-anti-CD38,225Ac-Dara,225Ac-DOTA-Daratumumab) a human immunoglobulin G1 kappa (IgG1k) monoclonal antibody directed against the cell surface glycoprotein CD38 which is expressed on various hematopoietic cells and is overexpressed on multiple myeloma (MM) cells (Actinium Pharmaceuticals),227Th-Anetumab (227Th-BAY2287411; BAY2287411; BAY 2287411) a human immunoglobulin G1 (IgG1) monoclonal antibody which targets mesothelin (Bayer Pharma),227Th-Epratuzumab a humanized IgG1 antibody targeting CD22 (Bayer),227Th-Trastuzumab a humanized HER2 monoclonal antibody (Bayer Pharma),227Th-CD33-TTC (227Th-Lintuzumab;227Th-Anti-CD33-Conjugate) a monoclonal antibody which binds to the sialoadhesin receptor CD33 (Siglec-3), a 67-kDa protein, expressed on leukemic blasts of AML patients (Bayer Pharma),227Th-CD70-TTC (227Th-CD70-Thorium Targeted Conjugate) a CD70 targeting antibody (IgG1) (Bayer Pharma). In one embodiment the radionuclides can be conjugated with a peptide or polypeptide including therapeutics such as: somatostatin analogues targeting somatostatin (SST) receptors with for e.g.90Y-DOTATATE (90Y-DOTA0- Phe1-Tyr3-octreotate,90Y-Octreotate, and90Y-DOTA-Octreotate), Lutetium (177Lu)Oxodotreotide [INN] (Lutathera®,177Lu-DOTATATE,177Lu-DOTA0-Tyr3-octreotate,177Lu- Octreotate,177Lu-Lutate,177Lu-Edotreotate officially USAN: lutetium Lu-177 dotatate and INN: lutetium (177Lu) oxodotreotide) (AAA / Novartis),213Bi-DOTATATE (213Bi-[DOTA0,Tyr3]-octreotate), PAT059671225Ac-DOTATATE (225Ac-[DOTA0,Tyr3]octreotate) (Bad Berka),67Cu-SARTATE (67Cu- MeCOSAR-Octreotate;67Cu-SAR-[Tyr3]-Octreotate) (Clarity Pharmaceuticals),177Lu-DOTA-EB- TATE (177Lu-DOTA-EBTATE; EBTATE; lutetium-177-1,4,7,10-tetra-azacyclododecane-1,4,7,10- tetraacetic acid-Evans blue-Tyr3-octreotate) a molecule based on octreotate that uses an Evans blue structure to bind albumin (Molecular Targeting Technologies, Inc.),177Lu-HA-DOTATATE (177Lu-high affinity-DOTATATE,177Lu-DOTA-3-iodo-Tyr3-octreotate) (Scintomics), 90Y- DOTATOC (90Y-DOTATOC,90Y-SMT487,90Y-Onalta®,90Y-OctreoTher®,90Y-DOTA0-Phe1-Tyr3- Octreotide),177Lu-Edotreotide (177Lu-DOTA0-Phe1-Tyr3-Octreotide,177Lu-Octreotide,177Lu-SMT- 487,177Lu-DOTATOC,177Lu-Solucin®,177Lu-Edo,177Lu-Edotreotide PRRT) a somatostatin analogue (ITM Solucin GmbH),149Tb-DOTANOC (Paul Scherrer Institute),152Tb-DOTATOC (Paul Scherrer Institute),213Bi-DOTATOC,225Ac-DOTATOC (LANL),177Lu-DOTANOC (177Lu-DOTA-1- Nal3-octreotide),177Lu-IPN-01072 (177Lu-OPS201,177Lu-DOTA-JR11637,177Lu-OPSC001,177Lu- Satoreotide tetraxetan) a somatostatin analogue binding sst2 receptor (Octreopharm / Ipsen Pharma),212Pb-DOTAMTATE (212Pb-AR-RMX;212Pb-AlphaMedix™, ORM2110) (Orano Med),90Y-OPS201 (90Y-DOTA-JR11,90Y-SOMTher®)90Y-DOTALAN (90Y-DOTA-Lanreotide,90Y- Lanreotide, or90Y-Somatulin),177Lu-DOTA-LM3 (177Lu-1,4,7,10-tetraazacyclododecane, 1,4,7- triacetic acid, 10- acetamide N-p-Cl-Phe-cyclo(d-Cys-Tyr-d-4-amino-Phe(carbamoyl)-Lys-Thr- Cys)-d-Tyr- NH2) (Zentralklinik Bad Berka), Peptides targeting Prostate-specific membrane antigen (PSMA) with for e.g.44Sc-PSMA-617,90Y-PSMA-617 (Paul Scherrer Institute),152Tb-PSMA-617 (Paul Scherrer Institute – Bad Berka Hospital),177Lu-PSMA-617 (177Lu-DKFZ-PSMA-617,177Lu-PSMA617, lutetium (177Lu)vipivotide tetraxetan [INN]) (Novartis),225Ac-PSMA-617 (Novartis),161Tb-PSMA- 617 (Paul Scherrer Institute / ETH / ILL),213Bi-PSMA-617 (213Bi-Vipivotide tetraxetan) (University Hospital of Heidelberg),177Lu-EB-PSMA-617 a PSMA-617 analogue conjugated with a truncated Evans Blue (Peking Union Medical College),177Lu-FC705 (FutureChem),203Pb-CA012 (University Hospital of Heidelberg),177Lu-PSMA-I&T (177Lu-PSMAI&T,177Lu-PSMA-TUM1,177Lu-DOTAGA- (l-y)fk(Sub-KuE) (University of Munich – Scintomics),177Lu-PSMA-R2 ((Nε-[177Lu-(4,7,10- Tricarboxymethyl-1,4,7,10-tetrazacyclododec-1-yl)acetyl]-6-aminohexanoic)—(Nε’-4- bromobenzyl) lysine-CO-glutamic-acid) (Novartis) ( ),177Lu-PSMA-CC-34 (177Lu-NODAGA- PSMA-CC-34; 177Lu-PSMA-CC34),177Lu-L1 (177Lu-DOTAMA-L1) (Johns Hopkins University),177Lu-PSMA-ALB-56 (177Lu-DOTA-PSMA-ALB-56) a PSMA ligand combining with an albumin binder based on the p-(tolyl)-moiety (ETH Zurich / PSI),177Lu-RPS-063 a molecule with a high- affinity PSMA-binding domain, linked to an albumin-binding group (ABG) (Weill Cornell Medicine),177Lu-iPSMA (177Lu-DOTA-HYNIC-Lys(NaI)-Urea-Glu) (ININ),212Pb-NG001 (212Pb-p-SCN-Bn- PAT059671 TCMC-PSMA;212Pb-TCMC-PSMA) (Nucligen AS),131I-RPS-027 molecule with a high-affinity PSMA-binding domain, linked to an albumin-binding group (ABG) (Weill Cornell Medicine),225Ac- RPS-074 (Weill Cornell Medical),188Re-P2045 (BAY 86-5284, Tozaride®) a 11-amino acid somatostatin peptide (Andarix Pharmaceuticals),131I-RPS-001 (131I-MIP-1095;131I-(S)-2-(3-((S)- 1-carboxy- 5-(3-(4-iodophenyl) ureido) pentyl) ureido) pentanedioic acid) a glutamate-urea-lysine analogue for therapeutic application in prostate cancer (Progenics / Lantheus), 177Lu-DOTA- Peptide-2 (177Lu-DOTA-p-Cl-Phe-Cyclo(d-Cys-l-BzThi-d-Aph-Lys-Thr-Cys)-d- Tyr-NH2;177Lu-[(1, 4, 7, 10-Tricarboxymethyl-1, 4, 7, 10-tetrazacyclododec-1-yl) acetyl]-(L) pChlorophenylalanyl-(D) Cysteinyl-(L)-3-BenzoThienylalanyl (L-BzThi)-(D)-4-Amino carbamoyl phenylalanyl(D-Aph)- (L)- Lysyl-(L)-Threoninyl- (L)-Cysteinyl-(D)-Tyrosine-NH2- cyclic disulfide) (Tehran Faculty of Pharmacy). In another embodiment, the radioligand agent is selected from any of the agents disclosed in 1) Theranostics 2016; 7(7): 1928-1939, 2) The Journal of Nuclear Medicine, Vol.60, No.7, 910-916, 3) Mol Imaging Biol 2020 April ; 22(2): 274-284, and related electronic supplementary material, all of which are hereby incorporated by reference. In a specific embodiment, the radioligand agent is selected from177Lu-CTT1401,177Lu-CTT1403, CTT1057 (which incorporates 18F) and177Lu- CTT1751. Bombesin analogues targeting Gastrin Releasing Peptide Receptor (GRPR) with for e.g. 177Lu-NeoB (177Lu-NeoBomb1,177Lu-DOTA-(p-aminobenzylamine-diglycolic acid)-[D-Phe6- His- NHCH-[(CH2CH(CH3)2]212-des-Leu13-des-Met14] BBN) (Novartis), 177Lu-ProBOMB1 (68Ga- DOTA-pABzA-DIG-d-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-ψ(CH2N)- Pro-NH2) (University of British Columbia), 212Pb-RM2 (212Pb-DOTA-4-amino-1-carboxymethyl-piperidine-D-Phe-Gln-Trp-Ala- Val-Gly-His-Sta-Leu-NH2) (US Department of Veterans Affairs),177Lu-RM2 (177Lu-DOTA-4- amino-1-carboxymethyl-piperidine-D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2,177Lu-BAY- 1017858) (Rostock University), Fibroplast Activation Proteins (FAP) Inhibitor targeting FAP with for e.g177Lu-FAP-2286 (177Lu-3BP-3554,177Lu-3B-201) (3B Pharma), Peptides targeting L-Amino Acid Transporter-1 (LAT-1) with for e.g131I-TLX101 (4-[131I]-4-L-iodophenylalanine,131I-IPA,131I-TLX101t, TLX101, previously developed under the name131I-ACD-101) (Telix Pharmaxceutical),211At-TLX102 (4-[211At]- astatinophenylalanine) an analogue of IPA (iodophenylalanine) (Telix Pharmaceuticals Ltd), Minigastrin analogues targeting Cholecystokinin-2 (CCK-2) receptors with for e.g177Lu-DOTA-MGS5 (177Lu-MGS5;177Lu-DOTA-D-Glu-Ala-Tyr-Gly-Trp-(N-Me)Nle-Asp-1- Nal- NH2) (Innsbruck University),177Lu-Debio 1124 (177Lu-DOTA-(DGlu)6-Ala-Tyr-Gly-Trp-Nle-Asp- PAT059671 Phe-NH2, Debio 1124,177Lu-PSIG-2,177Lu-PP-F11N) (Debiopharm International SA / PSI / University Hospital of Basel), Modified substance P targeting GPCR neurokinin type 1 receptor (NK-1R) with for e.g213Bi-DOTA-SP (213Bi-Substance-P,213Bi-DOTA-Substance P,213Bi-[Thi8,Met(O2)11]-substance- P) (Novacurie),225Ac-DOTA-SP (225Ac-Substance-P,225Ac-DOTA-Substance P) (Novacurie), Peptide targeting CXCR4 receptor with for e.g177Lu-Pentixather (3-iodo-D-Tyr1-pentixafor; cyclo(D-3-iodo-Tyr1-[NMe]-D-Orn2(AMBS-DOTA)- Arg3-2-Nal4-Gly5) (Scintomics GmbH), 177Lu-BL01 (177Lu-cyclo[Phe-Tyr-Lys(iPr)-d-Arg-2-Nal- Gly-d-Glu]-Lys(iPr)-NH2), (University of British Columbia),212Pb-DOTA-VMT-MCR1 a peptides that bind with high affinity and specificity to melanocortin receptor subtype I (MCR1) (Viewpoint Molecular Targeting LLC / RadioMedix),177Lu-IPN-01087 (177Lu-3BP-227) a neurotensin antagonist peptide targeting NTR-1 (or NTSR1 - neurotensin receptor-1) (3B Pharmaceuticals / Ipsen Pharma), 177Lu-DOTA-Exendin-4 (177Lu-Exendin-4;177Lu-DOTA-Ahx-Lys40-Exendin-4) a peptide targeting the Glucagon-like peptide-1 receptor (GLP-1) (Bhabha Atomic Research Center). Integrin Radioligands68Ga-FF58 (68Ga-2,2’,2’’-(10-(2-(((R)-1-((2-(4-(4-(N-((S)-1-carboxy-2-(5-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)pentanamide)ethyl)sulfamoyl)-3,5-diemthylphenoxy)butanamide)ethyl)amino)- 1-oxo-3-sulfopropan-2-yl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid) and 177Lu-FF58 (177Lu-2,2’,2’’-(10-(2-(((R)-1-((2-(4-(4-(N-((S)-1-carboxy-2-(5-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)pentanamide)ethyl)sulfamoyl)-3,5- diemthylphenoxy)butanamide)ethyl)amino)-1-oxo-3-sulfopropan-2-yl)amino)-2-oxoethyl)- 1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid). Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g. "such as”) provided herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. PAT059671 Isomeric forms Any asymmetric atom (e.g., carbon or the like) of the compound(s) that can be used in the present invention can be present in racemic or enantiomerically enriched, for example the (R)-, (S)- or (R,S)- configuration. In certain embodiments, each asymmetric atom has at least 50 % enantiomeric excess, at least 60 % enantiomeric excess, at least 70 % enantiomeric excess, at least 80 % enantiomeric excess, at least 90 % enantiomeric excess, at least 95 % enantiomeric excess, or at least 99 % enantiomeric excess in the (R)- or (S)- configuration. Substituents at atoms with unsaturated double bonds may, if possible, be present in cis- (Z)- or trans- (E)- form. Accordingly, as used herein a compound that can be used in the present invention can be in the form of one of the possible stereoisomers, rotamers, atropisomers, tautomers or mixtures thereof, for example, as substantially pure geometric (cis or trans) stereoisomers, diastereomers, optical isomers (antipodes), racemates or mixtures thereof. Any resulting mixtures of stereoisomers can be separated on the basis of the physicochemical differences of the constituents, into the pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and / or fractional crystallization. Any resulting racemates of compounds that can be used in the present invention or of intermediates can be resolved into the optical antipodes by known methods, e.g., by separation of the diastereomeric salts thereof, obtained with an optically active acid or base, and liberating the optically active acidic or basic compound. In particular, a basic moiety may thus be employed to resolve the compounds that can be used in the present invention into their optical antipodes, e.g., by fractional crystallization of a salt formed with an optically active acid, e.g., tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, di-O,O'-p-toluoyl tartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid. Racemic compounds that can be used in the present or racemic intermediates can also be resolved by chiral chromatography, e.g., high pressure liquid chromatography (HPLC) using a chiral adsorbent. Compounds that can be used in the present, i.e. compounds of formula (I) that contain groups capable of acting as donors and / or acceptors for hydrogen bonds may be capable of forming co- crystals with suitable co-crystal formers. These co-crystals may be prepared from compounds of formula (I) by known co-crystal forming procedures. Such procedures include grinding, heating, co-subliming, co-melting, or contacting in solution compounds of formula (I) with the co-crystal PAT059671 former under crystallization conditions and isolating co-crystals thereby formed. Suitable co- crystal formers include those described in WO 2004 / 078163. Furthermore, the compounds that can be used in the present invention, including their salts, can also be obtained in the form of their hydrates, or include other solvents used for their crystallization. The compounds of the present invention may inherently or by design form solvates with pharmaceutically acceptable solvents (including water). The term "solvate" refers to a molecular complex of a compound (including pharmaceutically acceptable salts thereof) with one or more solvent molecules. Such solvent molecules are those commonly used in the pharmaceutical art, which are known to be innocuous to the recipient, e.g., water, ethanol, and the like. The term "hydrate" refers to the complex where the solvent molecule is water. Compounds of Formula (1g), or Compound C, as described herein may also be used to form bifunctional degrader compounds, using the methods described herein and known synthetic routes. In an embodiment, the WRN bifunctional degrader molecule is a compound of Formula Ia: or a pharmaceutically acceptable salt thereof, wherein: the Targeting Ligand is a group that is capable of binding to Werner Syndrome RecQ DNA helicase (WRN), such as a compound of Formula 1g, or Compound A, Compound C, or Compound B herein; the Linker is a group that covalently links the Targeting Ligand to the Targeting Ligase Binder; and the Targeting Ligase Binder is a group that is capable of binding to a ligase (e.g., VHL, IAP or Cereblon E3 Ubiquitin ligase. In another aspect of the invention there is provided an antibody-drug conjugate comprising a WRN inhibitor compound as described herein. Antibodies and linker components can be selected according to those known in the art. PAT059671 Methods (Examples 1 to 3, Figs 1 to 10) Experiments were performed in female Crl:NU(NCr)-Foxn1nu-homozygous nude mice (Charles River) or NOD-Rag2tm1-IL2rgtm1 / Rj (NRG) mice (Janvier) or CB17.Cg-PrkcscidLystbg-J / Crl SCID beige (Charles River). Animals were housed under Optimized Hygienic Conditions in Allentown XJ cages (IVC, max. 6 mice per cage) with food and water at libitum and a 12h:12h light: dark cycle. Animals were allowed to acclimatize for at least 1 week before being enrolled in the experimental design. The study described here was performed according to license 1975 approved by the Basel Cantonal Veterinary Office. The JHUEM-2 cells were cultured in DMEM Ham’s F12 (BioConcept #1-26F08-0I) supplemented with 10% FBS (Corning #35-015-CV), 4mM L-Glutamine (BioConcept # 5-10K50-H) and 1mM Sodium Pyruvate (BioConcept # 5-60F00-H) at 37^C in an atmosphere of 5%CO2. Both RKO and OVK-18 were cultured in MEM Eagle (BioConcept #1-31S01-I) supplemented with 10% FBS (Corning #35-015-CV), 2mM L-Glutamine (BioConcept # 5-10K50-H) and 1mM Sodium Pyruvate (BioConcept # 5-60F00-H) at 37^C in an atmosphere of 5%CO2. To establish xenografts, cells were harvested and re-suspended in half HBSS (Sigma, #H6648) and half Matrigel (Corning #354234) before injecting subcutaneously 200 µL containing 5 million cells in the right flank of animals which were anaesthetized with isoflurane. Tumor size, in mm3, was calculated following the formula: (L x W2 x π / 6); where W = width and L = length of the tumor. As a measure of efficacy the %T / C value is calculated at the end of the experiment according to: (Δtumor volumetreated / Δtumor volumecontrol)*100 Tumor regression was calculated according to: -(Δtumor volumetreated / tumor volumetreated at start)*100 PAT059671 Where Δtumor volumes represent the mean tumor volume on the evaluation day minus the mean tumor volume at the start of the experiment. Regression was evaluated after at least seven days of treatment. Amorphous sodium salt of test compound (corrected by salt factor) was dissolved in an aqueous 20% w / v solution of 2-hydroxypropyl-beta-cyclodextrin (HPBCD). A range of concentrations was prepared by serial dilution starting from the solution at highest concentration for the highest dose in the study. Example 1: Combination of Compound A with carboplatin and paclitaxel Treatment was initiated about one (OVK18) or two weeks (JHUEM2) post tumor cell inoculation, when the xenografts reached a mean volume of approximately 200 mm3. The tumor bearing animals were randomized based on tumor volumes into experimental groups with 6 animals per group and treatment was initiated. Compound A was dosed orally (p.o.) once per day (qd) at 10 mg / kg; carboplatin was dosed intraperitoneally (i.p) once per week either at 25 mg / kg (JHUEM2) or at 50 mg / kg (OVK18); paclitaxel was dosed intravenously (i.v.) once per week at 12.5 mg / kg in both studies. In addition, a control group treated once per day orally (p.o.) with vehicle (20% 2-hydroxypropyl-^-cyclodextrin) was included in each study. Tumor volumes and body weights were measured two times per week until the study termination. In the study assessing an efficacy of Compound A in combination with carboplatin and paclitaxel in OVK18 model the tumors in the vehicle treated group grew approximately linearly from about 200 to 1.000 mm3(Figure 1). Throughout the treatment duration the vehicle treated animals gained up to 11% of body weight at the treatment start (Figure 2). Animals treated with Compound A only experienced body weight loss not greater than 13% for individual mice. Animals from the group treated with carboplatin and paclitaxel and from the group treated with Compound A on top of carboplatin and paclitaxel suffered from body weight loss reaching up to 19% among individual mice (Figure 2). Groups treated with Compound A as standalone and with combined carboplatin and paclitaxel displayed minor tumor growth delay compared to vehicle control (eight day of the treatment to reach 550mm3 on average for both groups against fifth day for a vehicle control). Group treated with Compound A on top of carboplatin and paclitaxel maintained stable disease throughout the treatment phase, with maximum regression of 10% reached after ten days of treatment (Figure 1). PAT059671 In the study assessing an efficacy of Compound A in combination with carboplatin and paclitaxel in JHUEM2 model the tumors in the vehicle treated group grew approximately linearly from about 200 to 1.000 mm3(Figure 3). Throughout the treatment duration the vehicle treated animals gained up to 11% of body weight at the treatment start (Figure 4). Animals treated with Compound A standalone experienced body weight loss not greater than 8% for individual mice. Animals from the group treated with carboplatin and paclitaxel and from the group treated with Compound A on top of carboplatin and paclitaxel suffered from body weight loss reaching up to 5 or 11% among individual mice, respectively (Figure 4). Overall gain in body weight was observed toward the end of the study. Groups treated with Compound A as standalone and with combined carboplatin and paclitaxel displayed minor tumor growth delay compared to vehicle control (twentieth day of the treatment to reach 550mm3 on average for both groups against sixth day for a vehicle control). Group treated with Compound A on top of carboplatin and paclitaxel maintained stable disease throughout the treatment phase, with maximum regression of 65% reached after nineteen days of treatment (Figure 3). Example 2: Combination of Compound A with External Beam Radiotherapy (EBRT) Treatment was initiated about one week post tumor cell inoculation, when the xenografts reached a mean volume of approximately 190 mm3(OVK18). The tumor bearing animals were randomized based on tumor volumes into experimental groups with 6 animals per group and treatment was initiated. Compound A was dosed orally (p.o.) once per day (qd) at 10 mg / kg; external beam radiotherapy (EBRT) was applied at 5Gy once per week or at 7.5Gy every other week (OVK18) or at 2.5Gy once per week or at 5Gy every other week (JHUEM2). In addition, a control group treated once per day orally (p.o.) with vehicle (20% 2-hydroxypropyl-^- cyclodextrin) was included in each study. Tumor volumes and body weights were measured two times per week until the study termination. In the study assessing an efficacy of Compound A in combination with EBRT in OVK18 model the tumors in the vehicle treated group grew approximately linearly from about 190 to 800 mm3(Figure 5). Throughout the treatment duration the vehicle treated animals gained up to 8% of body weight at the treatment start (Figure 6). Animals treated with Compound A only experienced body weight loss not greater than 13% among individual mice. Animals from the group treated with EBRT at 5Gy once a week and 7.5Gy once in two weeks suffered from body weight loss reaching up to 9 and 6% among individual mice, respectively (Figure 6). Individual PAT059671 animals treated with combination of EBRT and Compound A suffered from body weight loss of up to 7% for both doses of irradiation, however overall gain in body weight was observed over the duration of the study. Group treated with Compound A standalone displayed a progressive disease with only minor tumor growth delay compared to the vehicle control (twelve days of treatment against six to reach 550mm3, respectively). Groups treated with both doses of EBRT as standalone reached stable disease followed by progression. Group treated with Compound A on top of either 5Gy once per week of EBRT or 7.5Gy once per two weeks reached maximum regression of 52 and 58%, respectively. The tumors from combo group dosed with 7.5Gy once per two weeks started progressing after around three weeks of treatment. The tumors from the combo group treated at 5Gy once per week did not progress over the course of the treatment. For this group the treatment was discontinued after approximately one hundred days and animals were observed for another ninety days for a disease progression. Two tumors out of six did not progress until the study termination (Figure 5). In the study assessing an efficacy of Compound A in combination with external beam radiotherapy (EBRT) in JHUEM2 model the tumors in the vehicle treated group grew approximately linearly from about 200 to 1.200 mm3(Figure 7). Animals treated with Compound A only experienced body weight loss not greater than 5% among individual mice. Animals from the group treated with EBRT at 2.5Gy once a week and 5Gy once in two weeks suffered from body weight loss reaching up to 12 and 19% among individual mice, respectively (Figure 8). Individual animals treated with combination of Compound A with EBRT either at 2.5Gy once per week or 5Gy once per two weeks suffered from body weight loss of up to 12 and 17%, respectively (Figure 8). Groups treated with Compound A or EBRT at 2.5Gy once per week or 5Gy once per two weeks as standalone displayed a stable disease for seventeen, seventeen or twenty-one days, respectively, followed by a progressive disease in all three cases. Group treated with Compound A on top of either 2.5Gy once per week of EBRT or 5Gy once per two weeks reached maximum regression of 60 and 64%, respectively. The tumors from both combo groups did not progress over the course of the four-week treatment phase. After the treatment discontinuation, tumors relapsed within approximately additional two weeks (Figure 7). Example 3: Combination of Compound A with irinotecan Treatment was initiated about one week post tumor cell inoculation, when the xenografts reached a mean volume of approximately 200 mm3. The tumor bearing animals were PAT059671 randomized based on tumor volumes into experimental groups with 6 animals per group and treatment was initiated. Compound A was dosed orally (p.o.) once per day (qd) at 3 or 10 mg / kg; irinotecan was dosed intravenously (i.v.) once per week at 15 mg / kg. In addition, a control group treated once per day orally (p.o.) with vehicle (20% 2-hydroxypropyl-^- cyclodextrin) was included in each study. Tumor volumes and body weights were measured two times per week until the study termination. In the study assessing an efficacy of Compound A in combination with irinotecan in RKO model the tumors in the vehicle treated group grew approximately linearly from about 200 to 900 mm3(Figure 9). Throughout the treatment duration the vehicle treated animals gained up to 22% of body weight at the treatment start (Figure 10). Animals treated with Compound A standalone experienced body weight loss not greater than 12% (when dosed at 3 mg / kg) or up to 5% (when dosed at 10 mg / kg) among individual mice. Animals from the group treated with irinotecan standalone suffered from body weight loss of up to 4%. Animals treated with combination of irinotecan and Compound A either at 3 or at 10 mg / kg suffered from body weight loss up to 14 and 20%, respectively (Figure 10). Groups treated with irinotecan standalone displayed minor tumor growth delay compared to vehicle control (twelfth day of the treatment to reach 550mm3 against nineth day for a vehicle control). Group treated with Compound A at 3 mg / kg (standalone) reached stable disease but started relapsing after three weeks of treatment. Group treated with combination of Compound A at 3 mg / kg and irinotecan reached regressions of 64% on day twenty first of the treatment. Groups treated with Compound A at 10 mg / kg standalone or in combination with irinotecan reached regression of 55 (day twenty-one) or 80% (day thirty four), respectively. Group treated with Compound A at 10 mg / kg started progressing after thirty days of treatment (Figure 9). Efficacy of WRN inhibitors against subcutaneous MSI endometrial patient derived xenografts Methods (Examples 4 and 5, Figs 11 to 26) Experiments were performed in female Crl:NU(NCr)-Foxn1nu-homozygous nude mice (Charles River). Animals were housed under Optimized Hygienic Conditions in Allentown XJ cages (IVC, max. 6 mice per cage) with food and water at libitum and a 12h:12h light: dark cycle. Animals were allowed to acclimatize for at least 1 week before being enrolled in the experimental PAT059671 design. The study described here was performed according to license 1975 approved by the Basel Cantonal Veterinary Office. Four endometrial PDX models were tested: 3200HX (OD33776), 4412HX (OD37223), 20669HX (ND01590), 2781HX (OD32866). The source vendor of the models is the National Disease Research Interchange (NDRI). To establish xenografts, tumor piece of around 3x3mm was put in half DMEM medium (BioConcept #1-26F03-I) and half Matrigel (Corning #354234) for at least 10min and then implanted s.c in the right flank of animals which were anaesthetized with isoflurane. Tumor size, in mm3, was calculated following the formula: (L x W2 x π / 6); where W = width and L = length of the tumor. As a measure of efficacy the %T / C value is calculated at the end of the experiment according to: (Δtumor volumetreated / Δtumor volumecontrol)*100 Tumor regression was calculated according to: -(tumor volumetreated / tumor volumetreated at start)*100 Where Δtumor volumes represent the mean tumor volume on the evaluation day minus the mean tumor volume at the start of the experiment. Regression was evaluated after at least seven days of treatment. Amorphous sodium salt of test Compound A or Compound C (corrected by salt factor) was dissolved in an aqueous 20% w / v solution of 2-hydroxypropyl-beta-cyclodextrin (HPBCD). Paclitaxel (Sandoz, Pharmacode #4896111) was diluted with 5% glucose solution. Carboplatin (Sandoz, Pharmacode #7209565) was diluted with 0.9% sodium chloride solution. Example 4: Combination of WRN inhibitor Compound A or C, with carboplatin and paclitaxel Treatment was initiated when the xenografts reached a mean volume of approximately 160-180 mm3. The tumor bearing animals were randomized based on tumor volumes into experimental groups with 5 or 6 animals per group at start. In all studies Compound A was dosed orally (p.o.) once per day (qd) at 3 mg / kg; Compound C was dosed orally (p.o.) once per day (qd) at 120 PAT059671 mg / kg; carboplatin was dosed intraperitoneally (i.p) once per week at 25 mg / kg in four cycles; paclitaxel was dosed intravenously (i.v.) once per week at 12.5 mg / kg in four cycles. In addition, a control group treated once per day orally (p.o.) with vehicle (20% 2-hydroxypropyl-^- cyclodextrin) and once per week intravenously (i.v.) with 5% glucose solution was included in each study. Tumor volumes and body weights were measured two times per week until the study termination. In the study assessing an efficacy of Compound A or Compound C in combination with carboplatin and paclitaxel in 4412-HX (n=5) model the tumors in the vehicle treated group grew approximately linearly from about 160 to 1.000 mm3(Figure 11). Drop in the tumor growth curves for any of the groups (Figure 11) indicate the need for termination of individual animals due to a tumor mass. Throughout the treatment duration the individual vehicle treated animals gained up to 9% of body weight at the treatment start (Figure 12). Animals treated only with Compound A or Compound C experienced body weight loss not greater than 6% or 5%, respectively, for individual mice, followed by body weight gain. Animals from the group treated with carboplatin and paclitaxel lost up to 16% of the body weight at baseline. Animals treated with either Compound A or Compound C on top of carboplatin and paclitaxel suffered from body weight loss reaching up to 9% or 11%, respectively, among individual mice (Figure 12). Groups treated with Compound A or Compound C as standalone or with combined carboplatin and paclitaxel displayed tumor growth delay compared to a vehicle control (sixty first or twenty first or fourteenth day of the treatment, respectively, to reach 450mm3on average against seventh day for a vehicle control). Group treated with Compound A on top of carboplatin and paclitaxel maintained regression from the second week of the treatment phase, with maximum regression of 97% reached after thirty-seven days of treatment (Figure 11). Group treated with Compound C on top of carboplatin and paclitaxel maintained stable disease throughout the treatment phase, with maximum regression of 40% reached after twenty-eight days of treatment (Figure 11). After 70 days the treatment with either Compound A or Compound C was discontinued. At this point one tumor out of four or one out of two remaining on the study and treated with either Compound A or Compound C, respectively, on top of carboplatin and paclitaxel was palpable and relapsed after treatment discontinuation. In the study assessing an efficacy of Compound A or Compound C in combination with carboplatin and paclitaxel in 3200-HX (n=6) model the tumors in the vehicle treated group grew approximately linearly from about 180 to 1.500 mm3(Figure 13). Drop in the tumor growth curves for any of the groups (Figure 13) indicate the need for termination of individual animals due to a tumor mass. Throughout the treatment duration the individual vehicle treated animals gained up to 5% of body PAT059671 weight at the treatment start (Figure 14). Animals treated only with Compound A or Compound C experienced body weight loss not greater than 16% or 5%, respectively, for individual mice on individual occasion. Animals from the group treated with carboplatin and paclitaxel lost up to 15% of the body weight at baseline. Animals treated with either Compound A or Compound C on top of carboplatin and paclitaxel suffered from body weight loss reaching up to 14% or 22%, respectively, among individual mice on individual occasion (Figure 14). Groups treated with Compound A or Compound C as standalone did not benefit from the treatment and had no tumor growth delay compared to a vehicle control (seventh or fifth day of the treatment, respectively, to reach 450mm3on average against sixth day for a vehicle control). Group treated with combined carboplatin and paclitaxel displayed tumor growth delay compared to a vehicle control (thirty- fourth day of the treatment to reach 450mm3on average against sixth day for a vehicle control). Group treated with Compound A on top of carboplatin and paclitaxel maintained regression from the second week of the treatment phase, with maximum regression of 68% reached after thirty- eight days of treatment (Figure 13). Group treated with Compound C on top of carboplatin and paclitaxel maintained stable disease throughout the treatment phase, with maximum regression of 83% reached after thirty-three days of treatment (Figure 13). Remaining animals in both combination groups relapsed toward the end of the study. In the study assessing an efficacy of Compound A or Compound C in combination with carboplatin and paclitaxel in 2781-HX (n=5-6) model the tumors in the vehicle treated group grew approximately linearly from about 170 to 1.000 mm3(Figure 15). Drop in the tumor growth curves for any of the groups (Figure 15) indicate the need for termination of individual animals due to a tumor mass. Throughout the treatment duration the individual vehicle treated animals gained up to 10% of body weight at the treatment start (Figure 16). Animals treated only with Compound A or Compound C experienced body weight loss not greater than 5% or 8%, respectively, for individual mice on individual occasion. Animals from the group treated with carboplatin and paclitaxel lost up to 15% of the body weight at baseline. Animals treated with either Compound A or Compound C on top of carboplatin and paclitaxel suffered from body weight loss reaching up to 8% or 5%, respectively, among individual mice on individual occasion (Figure 16). Groups treated with Compound A or Compound C as standalone or with combined carboplatin and paclitaxel displayed tumor growth delay compared to a vehicle control (twenty eighth or fourteenth or seventeenth day of the treatment, respectively, to reach 450mm3on average against eighth day for a vehicle control). Group treated with Compound A or Compound C on top of carboplatin and paclitaxel maintained stable disease throughout the treatment phase, with maximum PAT059671 regression of 54% reached after sixty-five days of treatment or 46% reached after forty-eight days of treatment, respectively (Figure 15). In the study assessing an efficacy of Compound A or Compound C in combination with carboplatin and paclitaxel in 20669-HX (n=5-6) model the tumors in the vehicle treated group grew approximately linearly from about 180 to 700 mm3(Figure 17). Drops in the tumor growth curves for any of the groups (Figure 17) indicate the need for termination of individual animals due to a tumor mass. Throughout the treatment duration the individual vehicle treated animals gained up to 12% of body weight at the treatment start (Figure 18). Animals treated only with Compound A or Compound C experienced body weight loss not greater than 1% or 3%, respectively, for individual mice on individual occasion. Animals from the group treated with carboplatin and paclitaxel lost up to 20% of the body weight at baseline. Animals treated with either Compound A or Compound C on top of carboplatin and paclitaxel suffered from body weight loss reaching up to 13% or 20%, respectively, among individual mice on individual occasion (Figure 18). Groups treated with Compound A or Compound C as standalone or with combined carboplatin and paclitaxel displayed tumor growth delay compared to a vehicle control (nineteenth or fifteenth or fouty-third day of the treatment, respectively, to reach 450mm3on average against twelfth day for a vehicle control). Group treated with Compound A or Compound C on top of carboplatin and paclitaxel maintained regression from the second week of the treatment phase, with maximum regression of 80% reached after twenty-eight days of treatment or 87% reached after fourty-five days of treatment, respectively (Figure 17). Example 5: Combination with EBRT Treatment was initiated when the xenografts reached a mean volume of approximately 140-230 mm3. The tumor bearing animals were randomized based on tumor volumes into experimental groups with 5-6 animals per group at start. In all studies Compound A was dosed orally (p.o.) once per day (qd) at 3 mg / kg; Compound C was dosed orally (p.o.) once per day (qd) at 120 mg / kg; EBRT was applied at 2.5 or 5Gy once per week in four cycles. In addition, a control group treated once per day orally (p.o.) with vehicle (20% 2-hydroxypropyl-^-cyclodextrin) was included in each study. Tumor volumes and body weights were measured two times per week until the study termination. PAT059671 In the study assessing an efficacy of Compound A or Compound C in combination with EBRT (at 5Gy) in 4412-HX (n=5) model the tumors in the vehicle treated group grew approximately linearly from about 160 to 1.000 mm3(Figure 19). Drop in the tumor growth curves for any of the groups (Figure 9) indicate the need for termination of individual animals due to a tumor mass. Throughout the treatment duration the individual vehicle treated animals gained up to 9% of body weight at the treatment start (Figure 20). Animals treated only with Compound A or Compound C experienced body weight loss not greater than 6% or 5%, respectively, for individual mice, followed by body weight gain. Animals from the group treated with EBRT only lost up to 18% of the body weight at baseline, for individual animals on individual occasion. Animals treated with either Compound A or Compound C on top of EBRT suffered from body weight loss reaching up to 12% or 10%, respectively, among individual mice (Figure 20), however overall gain in body weight was observed over the duration of the study. Groups treated with Compound A or Compound C or EBRT as standalone displayed tumor growth delay compared to a vehicle control (sixty first or twenty first or fourty-eighth day of the treatment, respectively, to reach 450mm3on average against seventh day for a vehicle control). Group treated either with Compound A or Compound C on top of EBRT maintained regression from the second week of the treatment phase, with maximum regression of 98% reached after sixty-three days of treatment or of 94% reached after fourty-two days of treatment, respectively (Figure 19). After 70 days the treatment with either Compound A or Compound C was discontinued. At this point one tumor out of five or two out of five remaining on the study and treated with either Compound A or Compound C on top of EBRT, respectively, relapsed after treatment discontinuation. In the study assessing an efficacy of Compound A or Compound C in combination with EBRT (at 5Gy) in 3200-HX (n=6) model the tumors in the vehicle treated group grew approximately linearly from about 220 to 1.000 mm3(Figure 21). Drop in the tumor growth curves for any of the groups (Figure 11) indicate the need for termination of individual animals due to a tumor mass. Throughout the treatment duration the individual vehicle treated animals lost up to 13% of body weight at the treatment start (Figure 22). Animals treated only with Compound A or Compound C experienced body weight loss not greater than 15% for individual mice in both groups. Animals from the group treated with EBRT only lost up to 15% of the body weight at baseline, for individual animals on individual occasion. Animals treated with either Compound A or Compound C on top of EBRT suffered from body weight loss reaching up to 21% or 19%, respectively, among individual mice (Figure 22). Groups treated with Compound A or Compound C as standalone did PAT059671 not benefit from the treatment and had no tumor growth delay compared to a vehicle control (seventh or fifth day of the treatment, respectively, to reach 450mm3on average against sixth day for a vehicle control). Group treated with EBRT only maintained regression from the second week of the treatment phase, with maximum regression of 76% reached after fifty-five days of treatment (Figure 21). Groups treated with either Compound A or Compound C on top of EBRT maintained regression from the second week of the treatment phase, with maximum regression of 55% reached after thirty-one days of treatment or of 70% reached after fifty-eight days of treatment, respectively (Figure 21). In the study assessing an efficacy of Compound C in combination with EBRT (at 2.5Gy) in 2781- HX (n=5) model the tumors in the vehicle treated group grew approximately linearly from about 230 to 1.000 mm3(Figure 23). Throughout the treatment duration the individual vehicle treated animals gained up to 8% of body weight at the treatment start (Figure 24). Animals treated only with Compound C experienced body weight loss not greater than 5%, for individual mouse on individual occasion. Animals from the group treated with EBRT only lost up to 7% of the body weight at baseline, for individual mouse on individual occasion. Animals treated with Compound C on top of EBRT suffered from body weight loss reaching up to 11%, for individual mouse on individual occasion (Figure 24). Group treated with Compound C as standalone showed only minor growth delay compared to vehicle control (eighth day of treatment to reach 450mm3on average against fourth day for a vehicle). Group treated with EBRT as standalone displayed strong tumor growth delay compared to a vehicle control (sixteenth day of treatment to reach 450mm3on average against fourth day for a vehicle control). Group treated with Compound C on top of EBRT maintained stable disease throughout the treatment phase, with T / C oscillating between 4 and 16% within first 13 days (when control group was available) and reaching 2% regression after twenty-three days of treatment (Figure 23). In the study assessing an efficacy of Compound A or Compound C in combination with EBRT (at 2.5Gy) in 20669-HX (n=5-6) model the tumors in the vehicle treated group grew approximately linearly from about 140 to 800 mm3(Figure 25). Drop in the tumor growth curves for any of the groups (Figure 25) indicate the need for termination of individual animals due to a tumor mass. Throughout the treatment duration the individual vehicle treated animals gained up to 11% of body weight at the treatment start (Figure 26). Animals treated only with Compound A or Compound C experienced body weight loss not greater than 6% or 5%, respectively, for individual mice, followed by body weight gain. Animals from the group treated with EBRT only lost up to 18% of the body weight at baseline, for individual mouse on individual occasion. Animals treated PAT059671 with either Compound A or Compound C on top of EBRT suffered from body weight loss reaching up to 15% or 4%, respectively, among individual mice (Figure 26). Groups treated with Compound A or Compound C as standalone did not benefit from the treatment and had no tumor growth delay compared to a vehicle control (nineteenth or twenty-fifth day of the treatment, respectively, to reach 450mm3on average against twenty-first day for a vehicle control) (Figure 25). Group treated with EBRT only maintained stable disease until thirty-nineth day of the study and progressing only toward the end (Figure 25). Group treated either with Compound A or Compound C on top of EBRT maintained stable disease throughout the treatment phase, with T / C oscillating between 2 and 47% or 12 and 66%, respectively (Figure 25). Synthesis of WRN Inhibitors and Assays thereof The synthesis of WRN inhibitors of Formula (1g), biological assays and data, according to specific embodiments of the present invention, are described in PCT / IB2023 / 060166 (WO 2024 / 079623) and US 18 / 483651 which are hereby incorporated by reference in their entirety. The synthesis of Compound C, biological assays and data, according to specific embodiments of the present invention, is described in Ex 42 / Ex123 of PCT / IB2022 / 054850 (WO 2022 / 249060), or US 2023-0046859, which are hereby incorporated by reference in their entirety.

Claims

PAT059671 CLAIMS 1. A WRN inhibitor for use in the treatment of cancer, in particular microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) cancer, wherein the treatment further comprises administration of: A. an ionising radiation-based therapy selected from: i) external beam radiation, ii) brachytherapy and iii) a radiopharmaceutical, or B. carboplatin and paclitaxel.

2. A WRN inhibitor for use in the treatment of cancer, according to claim 1, in particular microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) cancer, wherein the treatment further comprises administration of an ionising radiation-based therapy selected from: i) external beam radiation, ii) brachytherapy and iii) a radiopharmaceutical, and wherein the WRN inhibitor is a compound of formula (1g), or a pharmaceutically acceptable salt thereof:and wherein R1is selected from:PAT059671R15is F; R16is R25(R24)N-; R17is F; R18is F; R19is F; R20is F; R21is CH3; R22is CF3, CHF2CH2, HOC(O)-CH2-, H3C-C(O)-, (H3C)3C-O-C(O)-; R23is CF3, CHF2CH2-, (H3C)3C-O-C(O)-; R24is CH3; and R25is CHF2CH2-; R2is the moiety:PAT059671wherein R6 is selected from H, halo, (C1-C4)alkyl unsubstituted or substituted by 1, 2 or 3 halo; R8is selected from H, halo, (C1-C4)alkyl unsubstituted or substituted by 1, 2 or 3 halo; R9is selected from H, O-CH3, OH, CN, CH3and halo; R28is selected from SF5, halo, (C1-C4)alkyl unsubstituted or substituted by 1, 2 or 3 halo and - C(O)H; X is selected from C-R7and N; and R7is selected from H and halo; R3is (C1-C4)alkyl unsubstituted or substituted by 1, 2 or 3 substituents independently selected from halo and OH; x is 0 or 1; Y is N; y is 0, 1 or 2; R5is selected from CH3; or wherein in the moiety:two R5substituents on adjacent carbon atoms join to form ring C:PAT059671-wherein ring C is a fused (C3-C6)cycloalkyl ring, in particular a fused cyclobutyl ring, and said fused (C3-C6)cycloalkyl ring is unsubstituted or substituted with 1 or 2 R40groups, wherein said R40is selected from: ^ (C1-C2)alkyl, wherein each (C1-C2)alkyl is independently unsubstituted or substituted by OH or 1, 2 or 3 halo, ^ halo, in particular F, ^ or wherein two R40substituents on the same ring carbon atom may join, together with the carbon atom to which they are attached, to form a (C3-C4)cycloalkyl spiro ring or a 3 or 4- membered heterocyclyl spiro ring, wherein said heterocyclyl spiro ring contains ring carbon ring atoms and one ring heteroatom selected from O, N and S; ^ or wherein two R40substituents on adjacent carbon atoms join together with the carbon atoms to which they are attached, to form a fused cyclopropyl ring; R4is selected from: CH3,wherein R10is selected from H, halo, (C1-C2)alkyl unsubstituted or substituted by 1, 2 or 3 halo substituents, -O-(C1-C2)alkyl unsubstituted or substituted by 1, 2 or 3 halo substituents;PAT059671 R11is selected from H, halo, (C1-C2)alkyl unsubstituted or substituted by 1, 2 or 3 halo substituents; R12is selected from H, halo, (C1-C2)alkyl unsubstituted or substituted by 1, 2 or 3 halo substituents; R13is selected from H, -S-CH3, halo, (C1-C2)alkyl unsubstituted or substituted by 1, 2 or 3 halo substituents; and R14is selected from H, halo, (C1-C2)alkyl unsubstituted or substituted by 1, 2 or 3 halo substituents, O-(C1-C2)alkyl unsubstituted or substituted by 1, 2 or 3 halo substituents, and cyclopropyl, or wherein the WRN inhibitor is compound C, or a pharmaceutically acceptable salt thereof:.

3. A WRN inhibitor for use in the treatment of cancer, according to claim 1, in particular microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) cancer, wherein the treatment further comprises administration of: i. carboplatin, and ii. paclitaxel, and wherein the WRN inhibitor is a compound of formula (1g) or a pharmaceutically acceptable salt thereof, as described in claim 2, or is compound C or a pharmaceutically acceptable salt thereof, as described in claim 2.

4. A method of treating cancer in a subject in need thereof, in particular microsatellite instability- high (MSI-H) or mismatch repair deficient (dMMR) cancer, the method comprising administeringPAT059671 to the subject a therapeutically effective amount of a WRN inhibitor in combination with a therapeutically effective amount of an ionising radiation-based therapy selected from: i) external beam radiation, ii) brachytherapy and iii) a radiopharmaceutical, wherein the WRN inhibitor is a compound of formula (1g) or a pharmaceutically acceptable salt thereof, as described in claim 2, or is compound C or a pharmaceutically acceptable salt thereof, as described in claim 2.

5. A method of treating cancer in a subject in need thereof, in particular microsatellite instability- high (MSI-H) or mismatch repair deficient (dMMR) cancer, the method comprising administering to the subject a therapeutically effective amount of a WRN inhibitor in combination with a therapeutically effective amount of: a. carboplatin, and b. paclitaxel wherein the WRN inhibitor is a compound of formula (1g) or a pharmaceutically acceptable salt thereof, as described in claim 2, or is compound C or a pharmaceutically acceptable salt thereof, as described in claim 2.

6. A pharmaceutical combination comprising a.) a WRN inhibitor, and b.) an ionising radiation- based therapy selected from i) external beam radiation, ii) brachytherapy and iii) a radiopharmaceutical, wherein the WRN inhibitor is a compound of formula (1g) or a pharmaceutically acceptable salt thereof, as described in claim 2, or is compound C or a pharmaceutically acceptable salt thereof, as described in claim 2.PAT059671 7. A pharmaceutical combination comprising a.) a WRN inhibitor, b.) carboplatin and c.) paclitaxel, wherein the WRN inhibitor is compound of formula (1g) or a pharmaceutically acceptable salt thereof, as described in claim 2, or is compound C or a pharmaceutically acceptable salt thereof, as described in claim 2.

8. The WRN inhibitor of claims 1 or 2, for use according to any of claims 1, 2 3, or the method according to claim 4 or claim 5, or the combination according to claim 6 or claim 7, wherein the cancer is microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR).

9. The WRN inhibitor of claims 1 or 2, for use according to any of claims 1, 2 or 8, or the method according to any of claims 4 or 8, or the combination according to any of claims 6 or 8, wherein the ionising radiation is external beam radiation.

10. The WRN inhibitor of claims 1 or 2, for use according to any of claims 1, 2, 3 or 8, or the method according to any of claims, 4, 5 or 8, or the combination according to any of claims 6, 7 or 8, wherein the cancer is selected from: ^ colorectal cancer (CRC), such as colon adenocarcinoma or rectal adenocarcinoma, ^ gastric cancer, such as stomach adenocarcinoma, ^ prostate cancer, ^ endometrial cancer, ^ adrenocortical cancer, such as adrenocortical carcinoma, ^ cervical cancer, such as cervical squamous cell carcinoma or endocervical adenocarcinoma, ^ uterine cancer, such as uterine corpus endometrial carcinoma and uterine carcinosarcoma, ^ esophageal ccancer, such as esophageal carcinoma, ^ breast cancer, such as breast carcinoma or triple negative breast cancer, ^ kidney cancer, such as kidney renal clear cell carcinoma, ^ ovarian cancer, such as ovarian serous cystadenocarcinoma, ^ glioma, ^ glioblastoma,PAT059671 ^ neuroendocrine tumors, ^ melanoma, ^ small cell lung cancer, and ^ sarcoma.

11. The WRN inhibitor of claim 1 or 2, for use according claim 10, or the method according to claim 10, or the combination according to claim 10, wherein the cancer is colorectal cancer (CRC), ovarian cancer or endometrial cancer.

12. The WRN inhibitor of claim 1 or 2, for use according to any of claims 1, 2, 3 or 8 to 11, or the method according to any of claims 4, 5or 8 to 11, or the combination according to any of claims 6, 8, or 8 to 11, wherein the WRN inhibitor is (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2- (3,6-dihydro-2H-pyran-4-yl)-6-((R)-4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-3- methylpiperazin-1-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5- a]pyrimidine-9-carboxamide, or a pharmaceutically acceptable salt thereof:or wherein the WRN inhibitor is compound C, or a pharmaceutically acceptable salt thereof:PAT059671 13. The WRN inhibitor of claim 1 or claim 2, for use according to any of claims 1, 2, 3 or 8 to 11, or the method according to any of claims 4, 5 or 8 to 11, or the combination according to any of claims 6, 7 or 8 to 11, wherein the compound is (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)- 2-(3,6-dihydro-2H-pyran-4-yl)-6-((1S,6S)-5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,5- diazabicyclo[4.2.0]octan-2-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5- a]pyrimidine-9-carboxamide, or a pharmaceutically acceptable salt thereof:.

14. The WRN inhibitor of claim 1 or 2, for use according to any of claims 1, 2, 3 or 8 to 11, or the method according to any of claims 4, 5 or 8 to 11, or the combination according to any of claims 6, 7 or 8 to 11, wherein the compound is (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(3,6- dihydro-2H-pyran-4-yl)-6-((R)-4-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-3-methylpiperazin-1- yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidine-9- carboxamide: in non-zwitterionic form:PAT059671 or zwitterionic form:or a mixture of any two or three of said forms, or wherein the compound is Compound C, in non-zwitterionic form:PAT059671 or zwitterionic form:or a mixture of any two or three of said forms.

15. The WRN inhibitor of claim 1 or 2, for use according to any of claims 1, 2, 3 or 8 to 11, or the method according to any of claims 4, 5 or 8 to 11, or the combination according to any of claims 6, 7, or 8 to 11, wherein the compound is (7R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(3,6- dihydro-2H-pyran-4-yl)-6-((1S,6S)-5-(5-hydroxy-6-methylpyrimidine-4-carbonyl)-2,5- diazabicyclo[4.2.0]octan-2-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5- a]pyrimidine-9-carboxamide: in non-zwitterionic formPAT059671 5PAT059671 or a mixture of any two or three of said forms.

16. A WRN inhibitor of claims 1 or 2, for use according to any of claims 1, 2 or 8 to 11, in the treatment of microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) cancer, in particular colorectal, ovarian or endometrial cancer, wherein the treatment further comprises administration of an external beam radiation, and wherein the WRN inhibitor ispharmaceutically acceptable salt thereof, or wherein the WRN inhibitor is compound C, or a pharmaceutically acceptable salt thereof:.

17. A WRN inhibitor of claims 1 or 2, for use according to any of claims 1, 3 or 8 to 11, in the treatment of microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) cancer, in particular colorectal, ovarian or endometrial cancer, wherein the treatment further comprises administration of: i. carboplatin, and ii. paclitaxel, and the WRN inhibitor is:PAT059671pharmaceutically acceptable salt thereof, or wherein the WRN inhibitor is compound C, or a pharmaceutically acceptable salt thereof:.

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