Therapeutic compounds and their use as inhibitors of pkmyt1

Abstract

The present invention pertains generally to the field of therapeutic compounds. More specifically the present invention pertains to certain biarylamide compounds of the following formula (also referred to herein as "BAA compounds") which inhibit Protein Kinase, Membrane Associated Tyrosine / Threonine 1 (PKMYT1). The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit PKMYT1 kinase; to treat disorders (e.g., diseases) that are ameliorated by the inhibition of PKMYT1 kinase; to treat a proliferative disorder, cancer, etc.

Description

[0001] P-000059-WO-PCT-MYT - 1 - THERAPEUTIC COMPOUNDS AND THEIR USE TECHNICAL FIELD 5

[0001] The present invention pertains generally to the field of therapeutic compounds. More specifically the present invention pertains to certain biarylamide compounds (also referred to herein as “BAA compounds”) which inhibit Protein Kinase, Membrane Associated Tyrosine / Threonine 1 (PKMYT1). The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit 10 PKMYT1 kinase; to treat disorders (e.g., diseases) that are ameliorated by the inhibition of PKMYT1 kinase; to treat a proliferative disorder, cancer, etc. BACKGROUND 15

[0002] Publications are cited herein in order to more fully describe the state of the art to which the invention pertains. Each of these references is incorporated herein by reference in its entirety into the present disclosure, to the same extent as if each individual reference was specifically and individually indicated to be incorporated by reference.

[0003] Throughout this specification, including the claims which follow, unless the context requires 20 otherwise, the word “comprise,” and variations such as “comprises” and “comprising,” will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

[0004] In the specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a 25 pharmaceutical excipient” includes mixtures of two or more such excipients, and the like.

[0005] Ranges are inclusive of their endpoints, and may be expressed herein as from “about” one particular value, and / or to “about” another particular value. When such a range is expressed, another embodiment includes from the one particular value and / or to the other particular value. Similarly, when values are expressed as approximations, by the use of the antecedent “about,” it will be understood 30 that the particular value forms another embodiment.

[0006] This disclosure includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art. 35 Protein kinase, membrane-associated tyrosine / threonine 1 (PKMYT1)

[0007] A key hallmark of cancer is that cancer cells override the cell cycle controls that prevent commitment to division until the appropriate conditions have been fulfilled. Once the conditions are right, cells are pushed through a decision point called the “restriction point” into the cell division cycle by the activity of Cdk4 / 6-Cyclin D complexes. Once through this point of no return, cells activate Cdk2- P-000059-WO-PCT-MYT - 2 - Cyclin E in order to drive the duplication of the DNA that will be segregated into two daughter cells later in the cell cycle (by Cdk1-Cyclin B).

[0008] In order to be able to proliferate illegitimately, cancer cells inappropriately boost the kinase activity of Cdk4 / 6-Cyclin D complexes or bypass the requirement for Cdk4 / 6-Cyclin D activation, by 5 activating the downstream Cdk2-Cyclin E complex, independently of any input from Cdk4 / 6-Cyclin D. Implementation of either of these two approaches enable cancers to evade the normal controls that maintain balanced growth and homeostasis within the body. Consequently, cancer proliferation is unregulated.

[0009] Drugs that inhibit the Cdk4 / 6-Cyclin D complexes are having a major therapeutic impact in 10 hormone responsive HER2 negative breast cancer (HER2- ER+) and are being trialled in a variety of other cancers.

[0010] In contrast, counteracting Cdk2-Cyclin E hyperactivation was considered to be undruggable until a recent study reported that a WEE1 family kinase called PKMYT1 is only essential when Cyclin E levels are abnormally high (Gallo et al., 2022). Importantly, they found that PKMYT1 ablation does not kill 15 normal cells.

[0011] The same study showed that PKMYT1 ablation is synthetically lethal in the presence of Cyclin E (CCNE1) over-expression; CCNE1 overexpression drives the transcription of Cyclin B to elevate Cyclin B levels to generate so much Cdk1-Cyclin B that all the available Cdk1 inhibitory activity is required to restrain this Cdk1-CyclinB and prevent a catastrophic mitosis. Thus, CCNE1 overproduction generates a 20 dependency on PKMYT1.

[0012] FBXW7 is a gene which encodes an E3 ligase that degrades Cyclin E. FBXW7 loss has also been found to be synthetically lethal in the presence of PKMYT1 inhibition (Durocher et al., 2021), demonstrating that PKMYT1 drugs hold potential as first line therapy in several cancers.

[0013] CCNE1 amplification has been reported in several cancer types including endometrial, ovarian, 25 breast and gastric, ranging in frequency from 5-40%. CCNE1 amplification and / or FBXW7 mutations occur in >60% of uterine carcinosarcomas, >20% of uterine cancers, ~20% of ovarian cancers, ~18% of stomach cancers, ~14% of colorectal cancer, ~12% of bladder cancers, 11.5% of oesophageal cancers, ~11% of cervical cancers, 7.5% of sarcomas and ~7% of lung squamous cancers (Durocher et al., 2021). CCNE1 also occurs at lower levels in other cancers such as adenoid cystic carcinoma, pancreatic cancer, 30 mesothelioma, lung adenocarcinoma, head & neck cancers, diffuse large B-cells lymphoma, liver cancers and others (Gorski et al., 2020). Moreover, CCNE1 over expressing ovarian cancers are a subset of the 50% that are recombination proficient so do not benefit from PARP inhibitors (Gorski et al., 2020), highlighting the unmet need in these indications.

[0014] CCNE1 amplification is observed in the more aggressive subtypes including uterine 35 carcinosarcoma (UCS; ~40%), uterine serous carcinoma (USC; ~25%), high-grade serous ovarian carcinoma (HGSOC; ~20%), and triple-negative breast cancer (TNBC; ~8%). CCNE1 over-expression in tumor biopsies is linked to lower overall survival compared to patients with normal Cyclin E1 levels. HGSOC patients with CCNE1 over-expression have a lower response rate to cisplatin, the current standard of care. P-000059-WO-PCT-MYT - 3 -

[0015] Similarly, FBXW7 is frequently mutated in several cancer types including uterine carcinosarcoma, endometrial, colorectal, cervical, bladder, head & neck, gastric, cancers and lung squamous cells carcinoma ranging in frequency from 5-39%. Like CCNE1 overexpression, FBXW7 driver mutations are observed in the more aggressive subtypes of endometrial cancer including UCS and USC. 5

[0016] Elevation of Cdk2-Cyclin E activity, via a variety of means, is also associated with resistance to Cdk4 / 6 inhibitors (Fassl et al., 2022); this suggests that PKMYT1 inhibition will also constitute a robust second line treatment in the cohort of HER2- ER+ breast cancer patients treated with Cdk4 / 6 inhibitors who generally develop resistance after around 2 years of therapy.

[0017] A recently discovered inhibitor of PKMYT1, RP-6306 (Szychowski et al., 2022), has shown 10 efficacy in vivo in models of breast and ovarian cancers overexpressing CCNE1, as well as in a pancreatic PDX model with increased expression of CCNE1, alone or in combination with Gemcitabine (Gallo et al., 2022).

[0018] It has been claimed that synthetic lethality occurs in cancer cells between PKMYT1 inhibition and deficiency in protein phosphatase 2 (PP2A), in particular, regulatory subunit B alpha (PPP2R2A) 15 (Yost et al., 2021) or subunit PP2R1A (Yap et al, 2023). PPP2R2A inactivation is present in 15% of prostate adenocarcinoma, and at >5% in ovarian serous cystadenocarcinoma, rectum adenocarcinoma, bladder urothelial carcinoma, colorectal adenocarcinoma, breast invasive carcinoma, uterine corpus endometrial carcinoma, uterine carcinosarcoma, liver hepatocellular carcinoma, lung squamous cell carcinoma, lung adenocarcinoma. PPP2R1A is altered in 1.82% of all cancers with endometrial serous 20 adenocarcinoma, endometrial endometrioid adenocarcinoma, colon adenocarcinoma, breast invasive ductal carcinoma, and lung adenocarcinoma being the most prevalent.

[0019] PKMYT1 is a cell cycle regulating kinase, part of the WEE1 family of kinases that includes WEE1 and WEE2. WEE2 is restricted to gonads as it regulates meiosis. In contrast both PKMYT1 and WEE1 are ubiquitously expressed. PKMYT1 is localized predominantly in the endoplasmic reticulum and Golgi 25 complex, while WEE1 is predominantly a nuclear protein. PKMYT1 is involved in the negative regulation of the CDK1-Cyclin B complex which promotes the progression of cells from G2-phase into the mitotic phase (M-phase) of the cell cycle. The biology of Cyclin E overproduction generates a need for the otherwise non-essential PKMYT1. Cyclin E accumulation boosts the transcription of cyclin B1; the potential to form active Cdk1-Cyclin B is greatly enhanced by CCNE1 overexpression. This places a far 30 greater demand upon the Cdk1-Cyclin B inhibitory activity of WEE1 and PKMYT1 such that PKMYT1 becomes essential.

[0020] Furthermore, CCNE1 overproduction stimulates abnormally high levels of DNA replication that deplete the nucleotide pool and generate DNA damage (Jones et al., 2013). The DNA damage generated by Cyclin E accumulation is not in itself lethal because cells have G2 / M checkpoints that restrain 35 commitment to genome segregation in mitosis until all damage is repaired. These checkpoint pathways boost the activity of the Wee1 family kinases WEE1 and PKMYT1, which restrain division by phosphorylating Cdk1 kinase to block Cdk1-Cyclin B activity. While damage persists, WEE1 and PKMYT1 activities remain high and cells cannot divide. Thus, WEE1 or PKMYT1 inhibition kills damaged cells by forcing them to divide when their DNA is still damaged and / or un-replicated. This places higher P-000059-WO-PCT-MYT - 4 - demands upon the ability of WEE1 and PKMYT1 to restrain CDK1-Cyclin B activity to maintain cell viability.

[0021] PKMYT1 can be removed from untransformed cells because the requirement for restraint of CDK1-CyclinB1 activity can be met by WEE1 alone. It is only when abnormally high levels of DNA damage 5 generates a greater need for CDK1 cyclin B inhibition that PKMYT1’s activities become essential.

[0022] The WEE1 inhibitor adavosertib has progressed to clinical trials in a number of solid tumours (clinicaltrials.gov) but presented significant toxicity. WEE1 inhibition toxicity most likely arises from its ability to inhibit both CDK2 and CDK1 complexes. CDK2-Cyclin E and CDK2-Cyclin A regulate the initiation and progression through DNA replication. Release of excessive levels of CDK2-Cyclin activities will 10 generate DNA damage in a phenomenon known as oncogene induced replicative senescence. PKMYT1 inhibition is unlikely to display similar S phase toxicity, because, unlike WEE1, it phosphorylates CDK1 (Booher et al., 1997; Liu et al., 1997).

[0023] Collectively, the dependency on PKMYT1 that is generated by excessive Cdk2-Cyclin E activity in cancer cells and the markedly reduced toxicity in normal tissues arising from its restriction to CDK1 15 regulation make PKMYT1 is a highly attractive target for inhibition for patients whose tumours proliferate inappropriately because of enhanced Cdk2-Cyclin E activity.

[0024] Overexpression of PKMYT1 has been observed in various cancers (compared to normal tissues), including lung squamous cell carcinoma, lung adenocarcinoma, uterine corpus endometrial carcinoma, breast invasive carcinoma, hepatocellular carcinoma, clear-cell renal-cell carcinoma, kidney 20 chromophobe cancer, renal papillary cell carcinoma, head and neck squamous cell carcinoma, colon adenocarcinoma, stomach adenocarcinoma, thyroid carcinoma, prostate adenocarcinoma. Elevated expression of PKMYT1 is associated with poor prognosis in adrenocortical carcinoma, kidney chromophobe, kidney renal clear cell carcinoma, kidney renal papillary cell carcinoma, lower grade glioma, liver hepatocellular carcinoma, lung adenocarcinoma, mesothelioma, pancreatic 25 adenocarcinoma, prostate adenocarcinoma, skin cutaneous melanoma, uveal melanoma (Shao et al., 2021), and breast cancer (Liu et al., 2020).

[0025] PKMYT1 is involved in the progression, invasion and / or metastasis of many solid tumours, for example non-small cell lung cancer (Zhang et al., 2022; He et al., 2021; Sun et al., 2019), osteosarcoma (Luo et al., 2022), clear cell renal cell carcinoma (Chen et al., 2020; Chen et al., 2021), oral squamous cell 30 carcinoma (Cai et al., 2022), gastric cancer (Hu et al., 2022; Zhang et al., 2020), prostate cancer (Wang et al., 2020), oesophageal squamous cell carcinoma (Zhang et al., 2019), colorectal cancer (Jeong et al., 2018), hepatocellular carcinoma (Liu et al., 2017), ovarian cancer (Xuan et al., 2020), neuroblastoma (in particular with MYCN amplification) (Chayka et al., 2015), glioblastoma (Toledo et al., 2015). PKMYT1 is essential for survival of some haematologic malignancies, such as acute lymphoblastic leukemia and 35 multiple myeloma (Ghelli Luserna di Rora et al., 2020).

[0026] PKMYT1 can have application in addressing resistance to treatment or improving the efficacy of cancer treatment agents. PKMYT1 elevation has been reported as a resistance mechanism to sustained WEE1 inhibition (Lewis et al., 2019). PKMYT1 inhibitors may also be a useful second line treatment to complement the emerging WEE1i based therapies. P-000059-WO-PCT-MYT - 5 -

[0027] Knockdown of PKMYT1 can eliminate the radiation-induced G2 / M arrest, resulting in a lower survival rate for cells receiving radiation therapy and is therefore a promising target to improve the radiosensitivity of lung adenocarcinoma (Long et al., 2020). PKMYT1 could be also prove useful to enhance the efficacy of anti-microtubule cancer drugs (Visconti et al., 2017). 5

[0028] PKMYT1 also plays a role in viral infection. Knockdown of PKMYT1 reduces the number of cells supporting Kaposi sarcoma herpesvirus (KSHV) lytic infection in S phase of the cell cycle (Bryan et al., 2006). KSHV is the cause of Kaposi’s sarcoma, primary effusion lymphoma (PEL) and the plasmablastic variant of multicentric Castleman’s disease.

[0029] There is a clear need for PKMYT1 selective inhibitors with good pharmacokinetic properties, 10 which are suitable for oral dosing with minimal or no toxicity.

[0030] This disclosure provides compounds and compositions that selectively inhibit PKMYT1 to treat cancer. SUMMARY OF THE INVENTION 15

[0031] One aspect of the invention pertains to certain biarylamide compounds (also referred to herein as “BAA compounds”) which inhibit Protein Kinase, Membrane Associated Tyrosine / Threonine 1 (PKMYT1), as described herein.

[0032] Another aspect of the invention pertains to a composition (e.g., a pharmaceutical composition) comprising a BAA compound, as described herein, and a pharmaceutically acceptable excipient. 20

[0033] Another aspect of the invention pertains to a method of preparing a composition (e.g., a pharmaceutical composition) comprising the step of mixing a BAA compound, as described herein, and a pharmaceutically acceptable excipient.

[0034] Another aspect of the present invention pertains to a method of inhibiting PKMYT1 (e.g., inhibiting or reducing or blocking the activity or function of PKMYT1), in vitro or in vivo, comprising 25 contacting the PKMYT1 with an effective amount of a BAA compound, as described herein.

[0035] Another aspect of the present invention pertains to a method of inhibiting PKMYT1 (e.g., inhibiting or reducing or blocking the activity or function of PKMYT1) in a cell, in vitro or in vivo, comprising contacting the cell with an effective amount of a BAA compound, as described herein.

[0036] Another aspect of the present invention pertains to a BAA compound as described herein for 30 use in a method of treatment of the human or animal body by therapy, for example, for use in a method of treatment of a disorder (e.g., a disease) as described herein.

[0037] Another aspect of the present invention pertains to use of a BAA compound as described herein in a method of treatment of the human or animal body by therapy, for example, in a method of treatment of a disorder (e.g., a disease) as described herein. 35

[0038] Another aspect of the present invention pertains to use of a BAA compound, as described herein, in the manufacture of a medicament, for example, for use in a method of treatment, for example, for use in a method of treatment of a disorder (e.g., a disease) as described herein.

[0039] Another aspect of the present invention pertains to a method of treatment, for example, a method of treatment of a disorder (e.g., a disease) as described herein, comprising administering to a P-000059-WO-PCT-MYT - 6 - subject in need of treatment a therapeutically effective amount of a BAA compound, as described herein, optionally in the form of a pharmaceutical composition.

[0040] In one embodiment, the disorder is a disorder that is ameliorated by the inhibition of PKMYT1 (e.g., by the inhibition or reduction or blockage of the activity or function of PKMYT1). 5

[0041] In one embodiment, the disorder is, for example, a proliferative condition, cancer, etc., as described herein.

[0042] Another aspect of the present invention pertains to a kit comprising (a) a BAA compound, as described herein, optionally provided as a composition (e.g., a pharmaceutical composition) and in a suitable container and / or with suitable packaging; and (b) instructions for use, for example, in a method 10 of treatment of a disorder (e.g., a disease) as described herein, for example, written instructions on how to administer the compound.

[0043] Another aspect of the present invention pertains to a BAA compound obtainable by a method of synthesis as described herein, or a method comprising a method of synthesis as described herein.

[0044] Another aspect of the present invention pertains to a BAA compound obtained by a method of 15 synthesis as described herein, or a method comprising a method of synthesis as described herein.

[0045] Another aspect of the present invention pertains to novel intermediates, as described herein, which are suitable for use in the methods of synthesis described herein.

[0046] Another aspect of the present invention pertains to the use of such novel intermediates, as described herein, in the methods of synthes is described herein. 20

[0047] As will be appreciated by one of skill in the art, features and preferred embodiments of one aspect of the invention will also pertain to other aspects of t he invention. DETAILED DESCRIPTION 25 Compounds

[0048] One aspect of the present invention is a compound of the following formula, or a pharmaceutically acceptable salt or co-crystal thereof, wherein Ring A and Ring B are as defined herein (for convenience, collectively referred to herein as “biarylamide compounds” or “BAA compounds”): 30

[0049] Some embodiments include the following:

[0050] (1) A compound of the following fo P-000059-WO-PCT-MYT - 7 - or a pharmaceut i c a l l y a c c e p t a b le s a l t o r c o -crystal thereof (e.g., or pharmaceutically acceptable salt thereof); wherein: Ring A is : wherein: Z1is N, CH, or CRZ1; and Z2is CH, CRZ2, or N; wherein: each -RZ1, and -RZ2, is independently -F, -Cl, -Br, -I, -RZZ, -CF3, -OH, -ORZZ, -OCF3, -NH2, -NHRZZ, or -NRZZ2; each -RZZis independently linear or branched saturated C1-4alkyl; and wherein: each -RA222is independently linear or branched saturated C1-4alkyl; -RA3is -H or -RA33; -RA33is -RA333, -F, -Cl, -Br, -I, -CF3, -OH, -ORA333, or -OCF3; each -RA333is independently linear or branched saturated C1-4alkyl; -RA4is -H or -RA44; -RA44is -RA444, -F, -Cl, -Br, -I, -CF3, -OH, -ORA444, or -OCF3; each -RA444is independently linear or branched saturated C1-4alkyl; and: Ring B is selected from: P-000059-WO-PCT-MYT - 8 - wherein: Y1is S, O, NH, or NRY1; Y2is CH, CRY2, or N; Y3is N, CH, or CRY3; Y4is N, CH, or CRY4; Y5is S, O, NH, or NRY5; Y6is N, CH, or CRY6; Y7is N, CH, or CRY7; Y8is N, CH, or CRY8; Y9is S, O, NH, or NRY9; wherein: each -RY2, -RY3, -RY4, -RY6, -RY7, and -RY8is independently -H, -F, -Cl, -Br, -I, or -RYY; each -RYYis independently linear or branched saturated C1-4alkyl; and wherein: each -RY1, -RY5, and -RY9is independently -RYYN; each -RYYNis independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, phenyl, or C5-6heteroaryl, wherein C1-4alkyl and cycloalkyl are optionally substituted with one or more groups selected from: -F, -OH, and -OCH3, and phenyl and heteroaryl are optionally substituted with one or more groups selected from: -F, -Cl, -CH3, and -CF3; and wherein: -Q is -LQ1-Q1, -LQ2-Q2, -LQ3-Q3, -LQ4-Q4, or -LQ5-Q5; wherein: -LQ1- is -C(=O)-, -C(=YLQ1)NRLQ1A-, or -S(=O)2-; Q1is C5-10heteroaryl; and is: optionally substituted on carbon with one or more groups -RQ1C; and optionally substituted on secondary nitrogen, if present, with one or more groups -RQ1N; -LQ2- is -C(=O)-, -C(=YLQ2)NRLQ2A-, or -S(=O)2-; Q2is non-aromatic C3-7heterocyclyl; and is: optionally substituted on sulfur, if present, with one or two groups =O; optionally substituted on carbon with one or more groups -RQ2C; and optionally substituted on secondary nitrogen, if present, with one or more groups -RQ2N; -LQ3- is -C(=O)-, -C(=YLQ3)NRLQ3A-, or -S(=O)2-; Q3is phenyl or naphthyl; and is: optionally substituted with one or more groups -RQ3C; -LQ4- is -C(=O)-, -C(=YLQ4)NRLQ4A-, or -S(=O)2-; P-000059-WO-PCT-MYT - 9 - Q4is C3-7cycloalkyl; and is: optionally substituted with one or more groups -RQ4C; -LQ5- is -C(=O)-, -C(=YLQ5)NRLQ5A-, or -S(=O)2-; Q5is linear or branched saturated C1-6alkyl; and is: optionally substituted with one or more groups -RQ5C; and wherein: =YLQ1is: =O, or =S; and wherein: -RLQ1Ais: -H, or linear or branched saturated C1-4alkyl; and wherein: each -RQ1Cis independently: -CN, or -NO2; and two adjacent -RQ1C, if present, taken together may form -(CH2)n1-O-(CH2)m1- or -O-(CH2)p1-O-, wherein: n1 is 0, 1, 2, or 3; m1 is 0, 1, 2, or 3; and p1 is 1 or 2; with the proviso that m1+n1 is 2 or 3; wherein: each -RQ1CCis independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, C3-7heterocyclyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl and each cycloalkyl is optionally substituted with one or more groups selected from: -F, -OH, and -OCH3, and each phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -RQ1CCC, -CF3, -CN, -OH, -ORQ1CCC, -NH2, -NHRQ1CCC, and -NRQ1CCC2; and each -RQ1CCCis independently linear or branched saturated C1-4alkyl; each -RQ1CXis independently linear or branched saturated C1-4haloalkyl; each -RQ1CMis independently non-aromatic C3-11heterocyclyl having at least one N ring atom, and is attached via that N ring atom; and is: P-000059-WO-PCT-MYT - 10 - optionally substituted on carbon with one or more groups -RQ1CMM; optionally substituted on sulfur, if present, with one or two =O groups; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ1CMM, -C(=O)RQ1CMM, -C(=O)ORQ1CMM, and -S(=O)2RQ1CMM; and each -RQ1CMMis independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, or C3-6cycloalkyl-C1-3alkyl, wherein C1-4alkyl and each cycloalkyl is optionally substituted with one or more groups selected from: -F, -OH, and -OCH3; and wherein: each -RQ1Nis independently: wherein: each -RQ1NCis independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl and each cycloalkyl is optionally substituted with one or more groups selected from: -F, -OH, and -OCH3, and each phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -RQ1NCC, -CF3, -CN, -OH, -ORQ1NCC, -NH2, -NHRQ1NCC, and -NRQ1NCC2; and each -RQ1NCCis independently linear or branched saturated C1-4alkyl; each -RQ1NXis independently linear or branched saturated C1-4haloalkyl; each -LQ1N- is independently linear or branched saturated C1-4alkylene; each -RQ1NMis independently non-aromatic C3-7heterocyclyl having at least one N ring atom, and is attached via that N ring atom; and is: optionally substituted on carbon with one or more groups -RQ1NMM; optionally substituted on sulfur, if present, with one or two =O groups; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ1NMM, -C(=O)RQ1NMM, -C(=O)ORQ1NMM, and -S(=O)2RQ1NMM; and each -RQ1NMMis independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, or C3-6cycloalkyl-C1-3alkyl, wherein C1-4alkyl and each cycloalkyl is optionally substituted with one or more groups selected from: -F, -OH, and -OCH3; and wherein: each -RQ1Nhetis independently non-aromatic C3-7heterocyclyl; and is: optionally substituted on sulfur, if present, with one or two groups =O; optionally substituted on carbon with one or more groups -RQ1NHHor =O; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ1NHH, -C(=O)RQ1NHH, -C(=O)ORQ1NHH, and -S(=O)2RQ1NHH; P-000059-WO-PCT-MYT - 11 - wherein: each -RQ1NHHis independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, or C3-6cycloalkyl-C1-3alkyl, wherein C1-4alkyl and each cycloalkyl is optionally substituted with one or more groups selected from: -F, -OH, and -OCH3; and wherein: =YLQ2is: =O, or =S; and wherein: -RLQ2Ais: -H, or linear or branched saturated C1-4alkyl; and wherein: each -RQ2Cis independently: =O; wherein: each -RQ2CCis independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, phenyl, C3-7heterocyclyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl and each cycloalkyl is optionally substituted with one or more groups selected from: -F, -OH, and -OCH3, and each phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -RQ2CCC, -CF3, -CN, -OH, -ORQ2CCC, -NH2, -NHRQ2CCC, and -NRQ2CCC2; and each -RQ2CCCis independently linear or branched saturated C1-4alkyl; each -RQ2CXis independently linear or branched saturated C1-4haloalkyl; each -RQ2CMis independently non-aromatic C3-11heterocyclyl having at least one N ring atom, and is attached via that N ring atom; and is: optionally substituted on carbon with one or more groups -RQ2CMM; optionally substituted on sulfur, if present, with one or two =O groups; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ2CMM, -C(=O)RQ2CMM, -C(=O)ORQ2CMM, and -S(=O)2RQ2CMM; and each -RQ2CMMis independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, or C3-6cycloalkyl-C1-3alkyl, wherein C1-4alkyl and each cycloalkyl is optionally substituted with one or more groups selected from: -F, -OH, and -OCH3; and wherein: each -RQ2Nis independently: P-000059-WO-PCT-MYT - 12 - -C(=O)ORQ2NC, or -S(=O)2RQ2NC; wherein: each -RQ2NCis independently linear or branched saturated C1-6alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-6alkyl and each cycloalkyl is optionally substituted with one or more groups selected from: -F, -OH, and -OCH3, and each phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -RQ2NCC, -CF3, -CN, -OH, -ORQ2NCC, -NH2, -NHRQ2NCC, and -NRQ2NCC2; and each -RQ2NCCis independently linear or branched saturated C1-4alkyl; and wherein: =YLQ3is: =O, or =S; and wherein: -RLQ3Ais: -H, or linear or branched saturated C1-4alkyl; and wherein: each -RQ3Cis independently: -CN, or -NO2; and two adjacent-RQ3C, if present, taken together may form –(CH2)n3-O-(CH2)m3- or -O-(CH2)p3-O-, wherein: n3 is 0, 1, 2, or 3; m3 is 0, 1, 2, or 3; and p3 is 1 or 2; with the proviso that m3+n3 is 2 or 3; wherein: each -RQ3CCis independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, C3-7heterocyclyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl and each cycloalkyl is optionally substituted with one or more groups selected from: -F, -OH, and -OCH3, and each phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -RQ3CCC, -CF3, -CN, -OH, -ORQ3CCC, -NH2, -NHRQ3CCC, and -NRQ3CCC2; and each -RQ3CCCis independently linear or branched saturated C1-4alkyl; each -RQ3CXis independently linear or branched saturated C1-4haloalkyl; each -LQ3C- is independently linear or branched saturated C1-4alkylene; P-000059-WO-PCT-MYT - 13 - each -RQ3CMis independently non-aromatic C3-11heterocyclyl having at least one N ring atom, and is attached via that N ring atom; and is: optionally substituted on carbon with one or more groups -RQ3CMM; optionally substituted on sulfur, if present, with one or two =O groups; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ3CMM, -C(=O)RQ3CMM, -C(=O)ORQ3CMM, and -S(=O)2RQ3CMM; and each -RQ3CMMis independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, or C3-6cycloalkyl-C1-3alkyl, wherein C1-4alkyl and each cycloalkyl is optionally substituted with one or more groups selected from: -F, -OH, and -OCH3; and wherein: =YLQ4is: =O, or =S; and wherein: -RLQ4Ais: -H, or linear or branched saturated C1-4alkyl; and wherein: each -RQ4Cis independently: =O; wherein: each -RQ4CCis independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, C3-7heterocyclyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl and each cycloalkyl is optionally substituted with one or more groups selected from: -F, -OH, and -OCH3, and each phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -RQ4CCC, -CF3, -CN, -OH, -ORQ4CCC, -NH2, -NHRQ4CCC, and -NRQ4CCC2; and each -RQ4CCCis independently linear or branched saturated C1-4alkyl; each -RQ4CXis independently linear or branched saturated C1-4haloalkyl; each -RQ4CMis independently non-aromatic C3-11heterocyclyl having at least one N ring atom, and is attached via that N ring atom; and is: optionally substituted on carbon with one or more groups -RQ4CMM; optionally substituted on sulfur, if present, with one or two =O groups; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ4CMM, -C(=O)RQ4CMM, -C(=O)ORQ4CMM, and -S(=O)2RQ4CMM; P-000059-WO-PCT-MYT - 14 - each -RQ4CMMis independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, or C3-6cycloalkyl-C1-3alkyl, wherein C1-4alkyl and each cycloalkyl is optionally substituted with one or more groups selected from: -F, -OH, and -OCH3; and wherein: =YLQ5is: =O, or =S; and wherein: -RLQ5Ais: -H, or linear or branched saturated C1-4alkyl; and wherein: each -RQ5Cis independently: -RQ5CC, -F, -OH, -ORQ5CC, -OCF3, -NH2, -NHRQ5CC, -NRQ5CC2, -RQ5CM, or -C(=O)OH; wherein: each -RQ5CCis independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, C3-7heterocyclyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl and each cycloalkyl is optionally substituted with one or more groups selected from: -F, -OH, and -OCH3, and each phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -RQ5CCC, -CF3, -CN, -OH, -ORQ5CCC, -NH2, -NHRQ5CCC, and -NRQ5CCC2; and each -RQ5CCCis independently linear or branched saturated C1-4alkyl; each -RQ5CMis independently non-aromatic C3-11heterocyclyl having at least one N ring atom, and is attached via that N ring atom; and is: optionally substituted on carbon with one or more groups -RQ5CMM; optionally substituted on sulfur, if present, with one or two =O groups; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ5CMM, -C(=O)RQ5CMM, -C(=O)ORQ5CMM, and -S(=O)2RQ5CMM; each -RQ5CMMis independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, or C3-6cycloalkyl-C1-3alkyl, wherein C1-4alkyl and each cycloalkyl is optionally substituted with one or more groups selected from: -F, -OH, and -OCH3.

[0051] For the avoidance of doubt: - It is intended that the nitrogen atom of the central amide group, -NH-C(=O)-, linking Ring A and Ring B, is unsubstituted. - It is intended that the -NH- ring member in Ring A is unsubstituted. - It is intended that Ring B is not fused to any other ring.

[0052] “-“ Indicates a bond (for example, a covalent bond).

[0053] The index “Cx-y” in terms such as “C9-10heteroaryl”, “C3-7heterocyclyl”, and the like, refers to the number of ring atoms, which may be carbon atoms or heteroatoms (e.g., N, O, S, as the case may be). P-000059-WO-PCT-MYT - 15 - For example, pyridyl is an example of a C6heteroaryl group, and piperidino is an example of a C6heterocyclyl group.

[0054] The term “heteroaryl” refers to a group that is attached to the rest of the molecule by an atom that is part of an aromatic ring, wherein the aromatic ring is part of an aromatic ring system, and the aromatic ring system has one or more heteroatoms (e.g., N, O, S, as the case may be). For example, pyrazole is an example of a C5 heteroaryl group, pyridyl is an example of a C6heteroaryl group, and quinolyl (e.g., quinolin-2-yl, quinolin-7-yl, etc.) is an example of a C10heteroaryl group. Furthermore, the aromatic ring system may optionally be fused with one or more non-aromatic rings, which may contain one or more heteroatoms (e.g., N, O, S, as the case may be) or only carbon atoms. For example: 4,5,6,7- tetrahydro-1H-indol-2-yl is an example of a C9heteroaryl group; 4,5,6,7-tetrahydro-1H-pyrrolo[2,3- b]pyridin-2-yl is an example of a C9heteroaryl group.

[0055] The term “heterocyclyl” refers to a group that is attached to the rest of the molecule by an atom that is part of a non-aromatic ring, and the non-aromatic ring has one or more heteroatoms (e.g., N, O, S, as the case may be). Unless otherwise specified, a sulfur ring atom may be substituted with one or two oxo (=O) groups (for example, as in 1,1-dioxo-1,4-thiazinany-4-yl). Unless otherwise specified, “heterocyclyl” includes monocyclic heterocyclyl (e.g., piperidinyl, an example of a monocyclic C6heterocyclyl), fused heterocyclyl (e.g., 3-azabicyclo[3.1.0]hexyl, an example of a fused C6heterocyclyl; decahydroquinolinyl, an example of a fused C10heterocyclyl), bridged heterocyclyl (e.g., 6-azabicyclo[3.1.1]heptanyl and 2,5-diazabicyclo[2.2.1]heptane, examples of a bridged C7heterocyclyl; 3,8-diazabicyclo[3.2.1]octanyl, an example of a bridged C8heterocyclyl), and spiro heterocyclyl (2,6-diazaspiro[3.3]heptane, an example of a spiro C7heterocyclyl; 7-azaspiro[3.5]nonyl, an example of a spiro C9heterocyclyl; 2,8-diazaspiro[4.5]decane, an example of a spiro C10heterocyclyl). Furthermore, the non-aromatic ring system may optionally be fused with one or more aromatic rings which may contain one or more heteroatoms (e.g., N, O, S, as the case may be) or only carbon atoms. For example: 4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridin-5-yl is an example of a C9heterocyclyl group; 1,2,3,4-tetrahydroisoquinolin-3-yl is an example of a C10heterocyclyl group.

[0056] A ”non-aromatic C3-11heterocyclyl having at least one N ring atom, and is attached via that N ring atom” refers to a substituent comprising at least one non-aromatic ring system comprising at least one N ring atom, the non-aromatic ring system being attached to the rest of the molecule by that ring N atom, and optionally containing one or more additional heteroatoms (e.g., N, O, S, as the case may be). Furthermore, the non-aromatic ring system may optionally be fused with one or more aromatic rings which may contain one or more heteroatoms (e.g., N, O, S, as the case may be) or only carbon atoms. Examples include: aziridino, azetidino, pyrrolidino, piperidino, piperazino, morpholino, thiomorpholino, azepano, and diazepano.

[0057] The term “cycloalkyl” refers to a ring system that contains at least one non-aromatic carbon ring, and contains only carbon atoms. Unless otherwise specified, “cycloalkyl” includes monocyclic cycloalkyl (e. g. cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl), bicyclic cycloalkyl (e. g.2,3-dihydro- 1H-indene), fused cycloalkyl (eg 7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene, P-000059-WO-PCT-MYT - 16 - core scaffold of estradiol), bridged cycloalkyl (e. g.1,2,3,4-tetrahydro-1,4-methanonaphthalene), and spiro cycloalkyl (e. g.3',4'-dihydro-2'H-spiro[cyclopentane-1,1'-naphthalene]).

[0058] The term “haloalkyl” refers to an alkyl group substituted with one or more halo groups (e.g., -F, -Cl, -Br, -I). The term “fluoroalkyl” refers to an alkyl group substituted with one or more -F groups. For example, -CF3 and -CHF2 are examples of a C1fluoroalkyl group; -CH2CF3 and -CH2CHF2 are examples of a C2fluoroalkyl group.

[0059] The term “C1-4alkylene” refers to an alkyl group with two points of attachment. For example, -CH2- is an example of a C1alkylene group; -CH2CH2- and -CH(CH3)- are examples of a C2alkylene group; -CH2CH2CH2- and -CH(CH3)2- are examples of a C3alkylene group.

[0060] Examples of C1-7alkyl, C1-6alkyl and C1-4alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, sec- butyl, iso-butyl and t-butyl. Examples of C3-6cycloalk yl-C1-3alkyl include cyclopropylmethyl and cyclohexylethyl. Examples of phenyl-C1-3alkyl inclu de benzyl and 2-phenylpropyl. Examples of C5-6heteroaryl-C1-3alkyl include pyrimidin-2-ylmethyl, and t hiazol-4-ylethyl.

[0061] “-C(=O)-” groups have the following structure, link ing two other groups (for example a secondary amino group [e.g. “R-NH-”, where R comp rises a thiazole ring] and a Q1, Q2, Q3, Q4or Q5group) at the indicated positions:

[0062] “-C(=YLQn)NRLQzA-” groups (where “n” to the numerals used in the corresponding definitions herein, such as =YLQ1and -RLQ1A) have the following structure, linking two other groups (for example a secondary amino group [e.g. “R-NH-”, where R comprises a thiazole ring] at the left position and a Q1, Q2, Q3, Q4or Q5group) at the right position:

[0063] “-S(=O)2-” groups have the following struc linking two other groups (for example a secondary amino group [e.g. “R-NH-”, where R comp a thiazole ring ] and a Q1, Q2, Q3, Q4or Q5group) at the indicated positions:

[0064] The phrase “one or more groups” in the of optional substituents (e.g., “one or more groups -RAR1C”, etc.) is necessarily constrained by the parent moiety and the number of positions on it that are suitable for substitution. In some parent moieties (e.g., tetrazolyl) there is only one position available for substitution. However, for other parent moieties, there may be several (e.g., phenyl has five). Except when constrained by the parent moiety, the “one or more groups” may be, e.g., 1, 2, 3, 4, etc., though alternatively “one or more groups” may be 1, 2, or 3, optionally 1 or 2, or instead 1.

[0065] The phrase “substituent on carbon” is intended to refer to a substituent which is attached to a carbon ring atom. Similarly, the phrase “substituent on nitrogen” is intended to refer to a P-000059-WO-PCT-MYT - 17 - substituent which is attached to a nitrogen ring atom which, in the abs en ce of t he substituent, would be a secondary nitrogen ring atom (i.e., -NH-). Consequently, a pyridyl group may only have “substituents on carbon”, whereas 1H-pyrrole may have both “substituent s on ca rbo n” and a “substituent on secondary nitrogen”, as illustrated below. 5

[0066] Similarly, a piperidino group may only have whereas piperazino may have both “substituents on carbon” and a “substituen o se ro a illustrated below. 10

[0067] Certain group s despite having carbon ring ato h a c n ring atoms available for substitution. For example, a tetrazolyl group may only permit a “substituent on carbon” or may only permit a “substituent on secondary nitrogen”, as illustrated below. 15

[0068] Unless otherwise indicated, where a compound is shown or described which has one or more chiral centres, and two or more stereoisomers are possible, all such stereoisomers are disclosed and encompassed, both individually (e.g., as isolated from the other stereoisomer(s)) and as mixtures (e.g., as equimolar or non-equimolar mixtures of two or more stereoisomers). For example, unless otherwise 20 indicated, where a compound has one chiral centre, each of the (R) and (S) enantiomers are disclosed and encompassed, both individually (e.g., as isolated from the other enantiomer) and as a mixture (e.g., as equimolar or non-equimolar mixtures of the two enantiomers). For example, the initial carbon atom P-000059-WO-PCT-MYT - 18 - of a pendant sec-butyl group, -CH(CH3)CH2CH3is usually chiral, and so gives rise to stereoisomers, e.g., (R) and (S) enantiomers if it is the only chiral centre, each of which is disclosed and encompassed.

[0069] (2) A compound according to (1), wherein: Ring A is: wherein: Z1is N, CH, or CRZ1; Z2is CH, CRZ2, or N; and wherein: -RA2is -RA222, -F, -Cl, -Br, or -I; each -RA222is independently linear or branched saturated C1-4alkyl; -RA3is -H; -RA4is -H; and: Ring B is selected from: wherein: Y1is S, Y2is CH and Y3is N, or Y1is S, Y2is N and Y3is CH; Y4is N, Y5is S, and Y6is CH; Y7is N, Y8is CH, and Y9is S; and wherein: -Q is -LQ1-Q1, -LQ3-Q3, or -LQ5-Q5; wherein: -LQ1- is -C(=O)-, -C(=O)NRLQ1A-, or -S(=O)2-; Q1is C5-10heteroaryl; and is: optionally substituted on carbon with one or more groups -RQ1C; and optionally substituted on secondary nitrogen, if present, with one or more groups -RQ1N; P-000059-WO-PCT-MYT - 19 - -LQ3- is -C(=O)-, -C(=O)NRLQ3A-, or -S(=O)2-; Q3is phenyl or naphthyl; and is: optionally substituted with one or more groups -RQ3C; -LQ5- is -C(=O)-, -C(=O)NRLQ5A-, or -S(=O)2-; Q5is linear or branched saturated C1-6alkyl; and wherein: -RLQ1Ais: -H, or linear or branched saturated C1-4alkyl; each -RQ1Cis independently: wherein: each -RQ1CCis independently linear or branched saturated C1-4alkyl; each -RQ1CXis independently linear or branched saturated C1-4haloalkyl; and wherein: each -RQ1Nis independently: wherein: each -RQ1NCis independently linear or branched saturated C1-4alkyl; and wherein: -RLQ3Ais: -H, or linear or branched saturated C1-4alkyl; each -RQ3Cis independently: wherein: each -RQ3CCis independently linear or branched saturated C1-4alkyl; each -RQ3CXis independently linear or branched saturated C1-4haloalkyl; and wherein: -RLQ5Ais: -H, or linear or branched saturated C1-4alkyl. P-000059-WO-PCT-MYT - 20 -

[0070] (3) A compound according to (1) or (2), wherein: Ring A is: wherein: -RA2is -RA222, or -Cl; each -RA222is independently linear or branched saturated C1-4alkyl; and wherein: Ring B is: wherein: Y1is S, Y2is CH, and Y3is N; and wherein: -Q is -LQ1-Q1, -LQ3-Q3, or -LQ5-Q5; wherein: -LQ1- is -C(=O)-; Q1is C5-10heteroaryl; and is: optionally substituted on secondary nitrogen, if present, with one or more groups -RQ1N; -LQ3- is -C(=O)-; Q3is phenyl; and is: optionally substituted with one or more groups -RQ3C; -LQ5- is -C(=O)-; Q5is linear or branched saturated C1-6alkyl; and wherein: each -RQ1Nis independently: wherein: each -RQ1NCis independently linear or branched saturated C1-4alkyl; P-000059-WO-PCT-MYT - 21 - and wherein: each -RQ3Cis independently: wherein: each -RQ3CCis independently linear or branched saturated C1-4alkyl; and each -RQ3CXis independently linear or branched saturated C1-4haloalkyl. Ring A

[0071] (4) A compound according to any one of (1) to (3), wherein: Z1is N or CH; Z2is CH or N.

[0072] (5) A compound according to any one of (1) to (3), wherein: Z1is N; Z2is CH, CRZ2, or N.

[0073] (6) A compound according to any one of (1) to (3), wherein: Z1is N.

[0074] (7) A compound according to any one of (1) to (3), wherein: Z2is CH, CRZ2, or N.

[0075] (8) A compound according to any one of (1) to (3), wherein: Z2is CH.

[0076] (9) A compound according to any one of (1) to (3), wherein: Z2is CRZ2.

[0077] (10) A compound according to any one of (1) to (3), wherein: Z2is N.

[0078] (11) A compound according to any one of (1) to (3), wherein Ring A is selected from: .

[0079] (12) A compound according to any one of (1) to (3), wherein Ring A is: P-000059-WO-PCT-MYT - 22 - .

[0080] (13) A compound according to any one of (1) to (3), wherein Ring A is: .

[0081] (14) A compound according to any one of (1) to (3), wherein Ring A is: . The Groups -RZ1, -RZ2

[0082] (15) A compound according to any one of (1) to (14), wherein: each -RZ1, and -RZ2, if present, is independently: -F, -Cl, -Br, -I, -RZZ, -CF3, -OH, -ORZZ, or -OCF3.

[0083] (16) A compound according to any one of (1) to (14), wherein: each -RZ1, and -RZ2, if present, is independently: -F, -Cl, -Br, -I, -RZZ, or -OH.

[0084] (17) A compound according to any one of (1) to (14), wherein: each -RZ1, and -RZ2, if present, is independently: -F, -Cl, -RZZ, or -OH.

[0085] (18) A compound according to any one of (1) to (14), wherein: each -RZ1, and -RZ2, if present, is independently: -F, -Cl, or -RZZ.

[0086] (19) A compound according to any one of (1) to (14), wherein: P-000059-WO-PCT-MYT - 23 - each -RZ1, and -RZ2, if present, is independently: -F or -RZZ.

[0087] (20) A compound according to any one of (1) to (14), wherein: each -RZ1, and -RZ2, if present, is: -RZZ.

[0088] (21) A compound according to any one of (1) to (14), wherein: each -RZ2if present is independently -Br, or -RZZ.

[0089] (22) A compound according to any one of (1) to (14), wherein: each -RZ2if present is independently -Br.

[0090] (23) A compound according to any one of (1) to (14), wherein: each -RZ2if present is independently -RZZ. The Group -RZZ

[0091] (24) A compound according to any one of (1) to (23), wherein: each -RZZ, if present, is: -Me, -Et, -nPr, -iPr, -nBu, or -tBu.

[0092] (25) A compound according to any one of (1) to (23), wherein: each -RZZ, if present, is: -Me, -Et, -nPr, or -iPr.

[0093] (26) A compound according to any one of (1) to (23), wherein: each -RZZ, if present, is: -Me or -Et.

[0094] (27) A compound according to any one of (1) to (23), wherein: each -RZZ, if present, is: -Me. The Group -RA2

[0095] (28) A compound according to any one of (1) to (27), wherein: -RA2is -RA222, -F, -Cl, -Br, -I, -CF3, -CHF2, -OH, -ORA222, -OCF3, or -CN.

[0096] (29) A compound according to any one of (1) to (27), wherein: -RA2is -RA222, -F, -Cl, -Br, -I, -CF3, -CHF2, -OH, -ORA222, or -OCF3.

[0097] (30) A compound according to any one of (1) to (27), wherein: -RA2is -RA222, -F, -Cl, -Br, -I, -CF3, -OH, -ORA222, or -OCF3.

[0098] (31) A compound according to any one of (1) to (27), wherein: -RA2is -RA222, -F, -Cl, -Br, -I, -OH, or -ORA222.

[0099] (32) A compound according to any one of (1) to (27), wherein: -RA2is -RA222, -F, -Cl, -Br, -I, or -OH.

[0100] (33) A compound according to any one of (1) to (27), wherein: P-000059-WO-PCT-MYT - 24 - -RA2is -RA222, -F, -Cl, -Br, or -OH.

[0101] (34) A compound according to any one of (1) to (27), wherein: -RA2is -RA222, -F, -Cl, or -OH.

[0102] (35) A compound according to any one of (1) to (27), wherein: -RA2is -RA222, -F, or -Cl.

[0103] (36) A compound according to any one of (1) to (27), wherein: -RA2is -RA222.

[0104] (37) A compound according to any one of (1) to (27), wherein: -RA2is -F, -Cl, or -Br.

[0105] (38) A compound according to any one of (1) to (27), wherein: -RA2is -F.

[0106] (39) A compound according to any one of (1) to (27), wherein: -RA2is -Cl.

[0107] (40) A compound according to any one of (1) to (27), wherein: -RA2is -Br. The Group -RA222

[0108] (41) A compound according to any one of (1) to (40), wherein: each -RA222, if present, is -Me, -Et, -nPr, -iPr, -nBu, or -tBu.

[0109] (42) A compound according to any one of (1) to (40), wherein: each -RA222, if present, is -Me, -Et, -nPr, or -iPr.

[0110] (43) A compound according to any one of (1) to (40), wherein: each -RA222, if present, is -Me or -Et.

[0111] (44) A compound according to any one of (1) to (40), wherein: each -RA222, if present, is -Me. The Group -RA3

[0112] (45) A compound according to any one of (1) to (44), wherein: -RA3is -H.

[0113] (46) A compound according to any one of (1) to (44), wherein: -RA3is -RA33. The Group -RA33

[0114] (47) A compound according to any one of (1) to (46), wherein: -RA33, if present, is: -RA333, -F, -Cl, -Br, -I, -OH, or -ORA333.

[0115] (48) A compound according to any one of (1) to (46), wherein: -RA33, if present, is: -RA333, -F, -Cl, -Br, -I, or -OH. P-000059-WO-PCT-MYT - 25 -

[0116] (49) A compound according to any one of (1) to (46), wherein: -RA33, if present, is: -RA333, -F, -Cl, or -OH.

[0117] (50) A compound according to any one of (1) to (46), wherein: -RA33, if present, is: -RA333, -F, or -Cl.

[0118] (51) A compound according to any one of (1) to (46), wherein: -RA33, if present, is: -RA333.

[0119] (52) A compound according to any one of (1) to (46), wherein: -RA33, if present, is: -Cl. The Group -RA333

[0120] (53) A compound according to any one of (1) to (52), wherein: each -RA333, if present, is -Me, -Et, -nPr, -iPr, -nBu, or -tBu.

[0121] (54) A compound according to any one of (1) to (52), wherein: each -RA333, if present, is -Me, -Et, -nPr, or -iPr.

[0122] (55) A compound according to any one of (1) to (52), wherein: each -RA333, if present, is -Me or -Et.

[0123] (56) A compound according to any one of (1) to (52), wherein: each -RA333, if present, is -Me. The Group -RA4

[0124] (57) A compound according to any one of (1) to (56), wherein: -RA4is -H.

[0125] (58) A compound according to any one of (1) to (56), wherein: -RA4is -RA44. The Group -RA44

[0126] (59) A compound according to any one of (1) to (58), wherein: -RA44, if present, is: -RA444, -F, -Cl, -Br, -I, -OH, or -ORA444.

[0127] (60) A compound according to any one of (1) to (58), wherein: -RA44, if present, is: -RA444, -F, -Cl, -Br, -I, or -OH.

[0128] (61) A compound according to any one of (1) to (58), wherein: -RA44, if present, is: -RA444, -F, -Cl, or -OH. P-000059-WO-PCT-MYT - 26 -

[0129] (62) A compound according to any one of (1) to (58), wherein: -RA44, if present, is: -RA444, -F, or -Cl.

[0130] (63) A compound according to any one of (1) to (58), wherein: -RA44, if present, is: -RA444.

[0131] (64) A compound according to any one of (1) to (58), wherein: -RA44, if present, is: -Cl. The Group -RA444

[0132] (65) A compound according to any one of (1) to (64), wherein: each -RA444, if present, is -Me, -Et, -nPr, -iPr, -nBu, or -tBu.

[0133] (66) A compound according to any one of (1) to (64), wherein: each -RA444, if present, is -Me, -Et, -nPr, or -iPr.

[0134] (67) A compound according to any one of (1) to (64), wherein: each -RA444, if present, is -Me or -Et.

[0135] (68) A compound according to any one of (1) to (64), wherein: each -RA444, if present, is -Me. Ring B

[0136] (69) A compound according to any one of (1) to (68), wherein: Ring B is: .

[0137] (70) A compound according to any one of (1) to (68), wherein: Ring B is: .

[0138] (71) A compound according to any one of (1) to (68), wherein: Ring B is: .

[0139] (72) A compound according to any one of (1) to (68), wherein: P-000059-WO-PCT-MYT - 27 - Y1, if present, is S, O, or NH; Y2, if present, is CH or N; Y3, if present, is N or CH; Y4, if present, is N or CH; Y5, if present, is S, O, or NH; Y6, if present, is N or CH; Y7, if present, is N or CH; Y8, if present, is N or CH; and Y9, if present, is S, O, or NH.

[0140] For example, wherein Ring B is selected from: , , , , , , , P-000059-WO-PCT-MYT - 28 - , , , , , , .

[0141] (73) A compound according to any one of (1) to (68), wherein: Y1, if present, is S; Y2, if present, is CH, CRY2, or N; Y3, if present, is N, CH, or CRY3; Y4, if present, is N, CH, or CRY4; Y5, if present, is S; Y6, if present, is N, CH, or CRY6; Y7, if present, is N, CH, or CRY7; Y8, if present, is N, CH, or CRY8; and Y9, if present, is S.

[0142] (74) A compound according to any one of (1) to (68), wherein: Y1, if present, is S; Y2, if present, is CH or N; Y3, if present, is N or CH; Y4, if present, is N or CH; Y5, if present, is S; Y6, if present, is N or CH; P-000059-WO-PCT-MYT - 29 - Y7, if present, is N or CH; Y8, if present, is N or CH; and Y9, if present, is S.

[0143] (75) A compound according to any one of (1) to (68), wherein: Y1, if present, is S; Y2, if present, is CH, CRY2, or N; Y3, if present, is N, CH, or CRY3; wherein exactly one of Y2and Y3is N; Y4, if present, is N, CH, or CRY4; Y5, if present, is S; Y6, if present, is N, CH, or CRY6; wherein exactly one of Y4and Y6is N; Y7, if present, is N, CH, or CRY7; Y8, if present, is N, CH, or CRY8; Y9, if present, is S; and wherein exactly one of Y7and Y8is N.

[0144] (76) A compound according to any one of (1) to (68), wherein Ring B is: , .

[0146] (78) A compound according to any one of (1) to (68), wherein: P-000059-WO-PCT-MYT - 30 - Y1, if present, is S; Y2, if present, is N; and Y3, if present, is N.

[0147] (79) A compound according to any one of (1) to (68), wherein Ring B is: .

[0148] (80) A compound according to any one of (1) to (68), wherein Ring B is: , , , .

[0149] (81) A compound according to any one of (1) to (68), wherein: Y1, if present, is S; Y2, if present, is CH, CRY2, or N; Y3, if present, is N, CH, or CRY3; wherein exactly one of Y2and Y3is N; Y4, if present, is N; Y5, if present, is S; Y6, if present, is CH or CRY6; Y7, if present, is N; Y8, if present, is CH or CRY8; and Y9, if present, is S.

[0150] (82) A compound according to any one of (1) to (68), wherein Ring B is: , .

[0151] (83) A compound according to any one of (1) to (68), wherein: P-000059-WO-PCT-MYT - 31 - Y1, if present, is S; Y2, if present, is CH, CRY2, or N; Y3, if present, is N, CH, or CRY3; and wherein exactly one of Y2and Y3is N.

[0152] (84) A compound according to any one of (1) to (68), wherein Ring B is: .

[0153] (85) A compound according to any one of (1) to (68), wherein: Y1, if present, is S; Y2, if present, is CH or CRY2; and Y3, if present, is N.

[0154] (86) A compound according to any one of (1) to (68), wherein Ring B is: . The Groups -RY2, -RY3, etc.

[0155] (87) A compound according to any one of (1) to (86), wherein: each -RY2, -RY3, -RY4, -RY6, -RY7, and -RY8, if present, is independently: -F, -Cl, -Br, -I, or -RYY.

[0156] (88) A compound according to any one of (1) to (86), wherein: each -RY2, -RY3, -RY4, -RY6, -RY7, and -RY8, if present, is independently: -F, -Cl, -Br, or -I.

[0157] (89) A compound according to any one of (1) to (86), wherein: each -RY2, -RY3, -RY4, -RY6, -RY7, and -RY8, if present, is independently: -F, -Cl, or -RYY.

[0158] (90) A compound according to any one of (1) to (86), wherein: each -RY2, -RY3, -RY4, -RY6, -RY7, and -RY8, if present, is independently: -RYY. The Group -RYY

[0159] (91) A compound according to any one of (1) to (90), wherein: each -RYY, if present, is: -Me, -Et, -nPr, -iPr, -nBu, or -tBu.

[0160] (92) A compound according to any one of (1) to (90), wherein: P-000059-WO-PCT-MYT - 32 - each -RYY, if present, is: -Me, -Et, -nPr, or -iPr.

[0161] (93) A compound according to any one of (1) to (90), wherein: each -RYY, if present, is: -Me or -Et.

[0162] (94) A compound according to any one of (1) to (90), wherein: each -RYY, if present, is: -Me. The Groups -RY1, -RY5, and -RY9

[0163] (95) A compound according to any one of (1) to (94), wherein: each -RY1, -RY5, and -RY9, if present, is independently: The Group -RYYN

[0164] (96) A compound according to any one of (1) to (95), wherein: each -RYYN, if present, is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, or phenyl, wherein each phenyl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, and -CF3.

[0165] (97) A compound according to any one of (1) to (95), wherein: each -RYYN, if present, is independently linear or branched saturated C1-4alkyl or phenyl.

[0166] (98) A compound according to any one of (1) to (95), wherein: each -RYYN, if present, is independently linear or branched saturated C1-4alkyl.

[0167] (99) A compound according to any one of (1) to (95), wherein: each -RYYN, if present, is -Me. The Group -Q

[0168] (100) A compound according to any one of (1) to (99), wherein: -Q is -LQ1-Q1,

[0169] (101) A compound according to any one of (1) to (99), wherein: -Q is -LQ2-Q2.

[0170] (102) A compound according to any one of (1) to (99), wherein: -Q is -LQ3-Q3.

[0171] (103) A compound according to any one of (1) to (99), wherein: -Q is -LQ4-Q4.

[0172] (104) A compound according to any one of (1) to (99), wherein: -Q is -LQ5-Q5. P-000059-WO-PCT-MYT - 33 - The Group -Q1

[0173] (105) A compound according to any one of (1) to (104), wherein: -Q1, if present, is C5-10heteroaryl; and is: optionally substituted on carbon with one or more groups -RQ1C; and optionally substituted on secondary nitrogen, if present, with a group -RQ1N.

[0174] (106) A compound according to any one of (1) to (104), wherein: -Q1, if present, is C5-9heteroaryl; and is: optionally substituted on carbon with one or more groups -RQ1C; and optionally substituted on secondary nitrogen, if present, with a group -RQ1N.

[0175] (107) A compound according to any one of (1) to (104), wherein: -Q1, if present, is C5-6heteroaryl; and is: optionally substituted on carbon with one or more groups -RQ1C; and optionally substituted on secondary nitrogen, if present, with a group -RQ1N.

[0176] (108) A compound according to any one of (1) to (104), wherein: -Q1, if present, is pyrazolyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, or pyridyl; and is: optionally substituted on carbon with one or more groups -RQ1C; and optionally substituted on secondary nitrogen, if present, with a group -RQ1N.

[0177] (109) A compound according to any one of (1) to (104), wherein: -Q1, if present, is pyridyl, pyrazolyl, thienyl, or thiazolyl; and is: optionally substituted on carbon with one or more groups -RQ1C; and optionally substituted on secondary nitrogen, if present, with a group -RQ1N.

[0178] (110) A compound according to any one of (1) to (104), wherein: -Q1, if present, is pyridyl, or pyrazolyl; and is: optionally substituted on carbon with one or more groups -RQ1C; and optionally substituted on secondary nitrogen, if present, with a group -RQ1N.

[0179] (111) A compound according to any one of (1) to (104), wherein: -Q1, if present, is C5heteroaryl, and is: optionally substituted on carbon with one or more groups -RQ1C; and optionally substituted on secondary nitrogen with a group -RQ1N. P-000059-WO-PCT-MYT - 34 -

[0180] (112) A compound according to any one of (1) to (104), wherein: -Q1, if present, is pyrazolyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, or thiadiazolyl; and is: optionally substituted on carbon with one or more groups -RQ1C; and optionally substituted on secondary nitrogen, if present, with a group -RQ1N.

[0181] (113) A compound according to any one of (1) to (104), wherein: -Q1, if present, is pyrazolyl, pyrrolyl, imidazolyl, furanyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, or thiadiazolyl; and is: optionally substituted on carbon with one or more groups -RQ1C; and optionally substituted on secondary nitrogen, if present, with a group -RQ1N.

[0182] (114) A compound according to any one of (1) to (104), wherein: -Q1, if present, is pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, or thiadiazolyl; and is: optionally substituted on carbon with one or more groups -RQ1C; and optionally substituted on secondary nitrogen, if present, with a group -RQ1N.

[0183] (115) A compound according to any one of (1) to (104), wherein: -Q1, if present, is thienyl; and is: optionally substituted on carbon with one or more groups -RQ1C.

[0184] (116) A compound according to any one of (1) to (104), wherein: -Q1, if present, is pyrazolyl (e.g., 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1H-pyrazol-5-yl, or pyrazol-1-yl); and is: optionally substituted on carbon with one or more groups -RQ1C; and

[0185] (117) A compound according to any one of (1) to (104), wherein -Q1, if present, is pyrazol-1-yl; and is optionally substituted on carbon with one or more groups -RQ1C.

[0186] (118) A compound according to any one of (1) to (104), wherein P-000059-WO-PCT-MYT - 35 - -Q1, if present, is 1H-pyrazol-3-yl; and is: optionally substituted on carbon with one or more groups -RQ1C; and optionally substituted on secondary nitrogen with a group -RQ1N.

[0187] (119) A compound according to any one of (1) to (104), wherein -Q1, if present, is 1H-pyrazol-4-yl; and is: optionally substituted on carbon with one or more groups -RQ1C; and optionally substituted on secondary nitrogen with a group -RQ1N.

[0188] (120) A compound according to any one of (1) to (104), wherein -Q1, if present, is 1H-pyrazol-5-yl; and is: optionally substituted on carbon with one or more groups -RQ1C; and optionally substituted on secondary nitrogen with a group -RQ1N.

[0189] (121) A compound according to any one of (1) to (104), wherein: -Q1, if present, is C6heteroaryl, and is: optionally substituted on carbon with one or more groups -RQ1C.

[0190] (122) A compound according to any one of (1) to (104), wherein: -Q1, if present, is pyrimidinyl, pyrazinyl, pyridazinyl, or pyridyl, and is: optionally substituted on carbon with one or more groups -RQ1C.

[0191] (123) A compound according to any one of (1) to (104), wherein: -Q1, if present, is pyridyl; and is: optionally substituted on carbon with one or more groups -RQ1C.

[0192] (124) A compound according to any one of (1) to (104), wherein: -Q1, if present, is C9heteroaryl; and is: optionally substituted on carbon with one or more groups -RQ1C; and optionally substituted on secondary nitrogen, if present, with a group -RQ1N.

[0193] (125) A compound according to any one of (1) to (104), wherein: -Q1, if present, is C9heteroaryl; wherein, the C9heteroaryl is a 5:6-fused heteroaryl; and is: optionally substituted on carbon with one or more groups -RQ1C; and optionally substituted on secondary nitrogen, if present, with a group -RQ1N.

[0194] (126) A compound according to any one of (1) to (104), wherein: P-000059-WO-PCT-MYT - 36 - -Q1, if present, is indolyl, indazolyl, benzimidazolyl, benzoxazolyl, pyrazolo-pyridinyl, pyrazolo- pyrimidinyl, imidazo-pyridi n yl, or pyrrolo-pyridinyl; and is: optionally substituted on carbon with one or more groups -RQ1C; and optionally substituted on secondary nitrogen, with a group -RQ1N.

[0195] (127) A compound according to any one of (1) to (104), wherein: -Q1, if present, is indol-2-yl or indol-3-yl; and is: optionally substituted on carbon with one or more groups -RQ1C; and optionally substituted on secondary nitrogen, with a group -RQ1N.

[0196] (128) A compound according to a ny one of (1) to (104), whe rein: -Q1, if present, is 2H-indazol-3-yl or 1H-indazol-3-yl; and is: optionally substituted on c wi o or more groups -R and optionally substituted a group -RQ1N

[0197] (129) A c o m p o u n d a c c o r d in g t o a n y o n e of (1 ) t o (1 0 4 ) , w h : -Q1, if present, is benzimidazol-2-yl; and is: optionally substituted on carbon with one or more groups -RQ1C; and optionally substituted on secondary nitrogen, with a group -RQ1N.

[0198] (130) A compound according to any one of (1) to (104), wherein: P-000059-WO-PCT-MYT - 37 - -Q1, if present, is benzoxazol-2-yl; and is: optionally substituted on carbon with one or more groups -RQ1C.

[0199] (131) A compound according to any one of (1) to (104), wherein: -Q1, if present, is benzothiazol-2-yl; and is: optionally substituted on carbon with one or more groups -RQ1C.

[0200] (132) A compound according to any one of (1) to (104), wherein: -Q1, if present, is pyrazolo[1,5-a]pyridin-2-yl or pyrazolo[1,5-a]pyridin-3-yl; and is: optionally substituted on crbon one or more -RQ1C.

[0201] (133) A comp ound according to any one of (1) to (104), wherein : -Q1, if present, is 1H-pyrazolo[3,4-b]pyridin-3-yl, 1H-pyrazolo -c] 3-yl, 1H- pyrazolo[4,3-c]pyridin-3-yl, or 1H-pyrazolo[4,3-b]pyridin-3-yl; and is: optionally substituted on car bon with one or more gro up s -R ; and optionally substituted on secondary nitrogen, with a group -RQ1N.

[0202] (1 c o m d a c c o any f (1) t (1 P-000059-WO-PCT-MYT - 38 - -Q1, if present, is imidazo[1,2-a]pyridin-2-yl or imidazo[1,2-a]pyridin-3-yl; and is: optionally substituted on carbon with one or more groups -RQ1C.

[0203] (135) A compound according to any one of (1) to (104), wherei 1 n: -Q, if present, is 1H-pyrrolo[3,2-b]pyridin-2-yl or 1H-pyrrolo[3,2-b]pyridine-3-yl; and is: optionally substituted on carbon with one or more groups -RQ1C; and optionally substituted on secondary nitrogen, with a group -R .

[0204] (136) A c o m pound according to any one of (1) to (104), wherein: -Q1, if present, is 1H-pyrrolo[3,2-c]pyridin-2-yl or 1H-pyrrolo[3,2-c]pyridin-3-yl; and is: optionally substituted on carbon with one or more groups -RQ1C; and optionally substituted on secondary nitrogen, with a group -RQ1N.

[0205] (137) A compound according to any one of (1) to (104), wherein: -Q1, if present, is 1H-pyrrolo[2,3-c]pyridin -2-yl or 1H-pyrrolo[2,3-c]pyridin-3-yl; and is: optionally substituted on carbon with one or more groups -RQ1C; and optionally substituted on secondary nitrogen, with a group -RQ1N. P-000059-WO-PCT-MYT - 39 -

[0206] (138) A compound according to any one of (1) to (10 4), wherein: -Q1, if present, is -c] n-2-yl, p [1, c] 3-yl, pyrazolo[1,5- a]pyrimidin-2-yl, or pyrazolo[1,5-a]pyrimidin-3-yl; and is: optionally substituted on carbon with one or more groups -RQ1C. The Group -LQ1-

[0207] (139) A compound according to any one of (1) to (138), wherein: -LQ1-, if present, is -C(=O)-, -C(=YLQ1)NRLQ1A-, or -S(=O)2-;

[0208] (140) A compound according to any one of (1) to (138), wherein: -LQ1-, if present, is -C(=O)-, -C(=YLQ1)NH-, or -S(=O)2-;

[0209] (141) A compound according to any one of (1) to (138), wherein: -LQ1-, if present, is -C(=O)-, -C(=O)NH-, -C(=S)NH-, or -S(=O)2-.

[0210] (142) A compound according to any one of (1) to (138), wherein: -LQ1-, if present, is -C(=O)-, -C(=S)NRLQ1A-, or -C(=O)NRLQ1A-.

[0211] (143) A compound according to any one of (1) to (138), wherein: -LQ1-, if present, is -C(=O)-, or -S(=O)2-.

[0212] (144) A compound according to any one of (1) to (138), wherein: -LQ1-, if present, is -C(=O)NRLQ1A-, -C(=S)NRLQ1A-, or -S(=O)2-.

[0213] (145) A compound according to any one of (1) to (138), wherein: -LQ1-, if present, is -C(=O)-

[0214] (146) A compound according to any one of (1) to (138), wherein: -LQ1-, if present, is -C(=O)NRLQ1A-.

[0215] (147) A compound according to any one of (1) to (138), wherein: -LQ1-, if present, is -C(=S)NRLQ1A-.

[0216] (148) A compound according to any one of (1) to (138), wherein: -LQ1-, if present, is -S(=O)2-. P-000059-WO-PCT-MYT - 40 - The

[0217] (149) A compound according to any one of (1) to (148), wherein: -Q2, if present, is oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl; and is: optionally substituted on carbon with one or more groups -RQ2C.

[0218] (150) A compound according to any one of (1) to (148), wherein: -Q2, if present, is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azepanyl, or diazepanyl; and is: optionally substituted on sulfur, if present, with one or two groups =O; optionally substituted on carbon with one or more groups -RQ2C; and optionally substituted on secondary nitrogen, if present, with one or more groups -RQ2N.

[0219] (151) A compound according to any one of (1) to (148), wherein: -Q2, if present, is pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl; and is: optionally substituted on sulfur, if present, with one or two groups =O; optionally substituted on carbon with one or more groups -RQ2C; and optionally substituted on secondary nitrogen, if present, with a group -RQ2N.

[0220] (152) A compound according to any one of (1) to (148), wherein: -Q2, if present, is piperidinyl or piperazinyl; and is: optionally substituted on carbon with one or more groups -RQ2C; and optionally substituted on secondary nitrogen, if presQ2N en t, w ith a group -R .

[0221] (153) A co mpound according to any one of (1) to (148 ), wherein: -Q2, if pres ent, is piperidinyl (e.g., piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl); and is: optionally substituted on carbon with one or more groups -RQ2C; and optionally substituted on secondary nitrogen, if present, with a group -RQ2N.

[0222] (154) A compou n d a c c o r d in g o n e o f ( 1 ) t o (148) -Q2, , is piperidin-4-yl; and is: optionally stituted on carbon with one or more groups -RQ2C; and optionally substituted on secondary nitrogen, with a group -RQ2N.

[0223] (155) A compound according to any one of (1) to (148), wherein: P-000059-WO-PCT-MYT - 41 - -Q2, if present, is piperidin-1-yl; and is: optionally substituted on c arbon with one or more groups -RQ2C.

[0224] (156) A compound according to any one of (1) to (148), wherein: -Q2, if present, is piperidin-1-yl.

[0225] (157) A compound according to any one of (1) to (148), wherein: -Q2, if present, is piperazinyl (e.g., piperazin-1-yl, pipera zin -2 -yl); and is: optionally substituted on carbon with one or more groups -RQ2C; and optionally substituted on secondary nitrogen with a group -RQ2N.

[0226] (158) A compound according to any one of (1) to (148), wherein: -Q2, if present, is piperazin- -yl and is: optionally substituted on carbon one or more grou -Q2C; and optionally substituted on seco n rogen with a gr -RQ2N. The Group -LQ2-

[0227] (159) A compound according to any one of (1) to (158), wherein: -LQ2-, if present, is -C(=O)-, -C(=YLQ2)NRLQ2A-, or -S(=O)2-;

[0228] (160) A compound according to any one of (1) to (158), wherein: -LQ2-, if present, is -C(=O)-, -C(=YLQ2)NH-, or -S(=O)2-;

[0229] (161) A compound according to any one of (1) to (158), wherein: -LQ2-, if present, is -C(=O)-, -C(=O)NH-, -C(=S)NH-, or -S(=O)2-.

[0230] (162) A compound according to any one of (1) to (158), wherein: -LQ2-, if present, is -C(=O)-, -C(=S)NRLQ2A-, or -C(=O)NRLQ2A-.

[0231] (163) A compound according to any one of (1) to (158), wherein: -LQ2-, if present, is -C(=O)-, or -S(=O)2-.

[0232] (164) A compound according to any one of (1) to (158), wherein: -LQ2-, if present, is -C(=O)NRLQ2A-, -C(=S)NRLQ2A-, or -S(=O)2-.

[0233] (165) A compound according to any one of (1) to (158), wherein: -LQ2-, if present, is -C(=O)-

[0234] (166) A compound according to any one of (1) to (158), wherein: -LQ2-, if present, is -C(=O)NRLQ2A-.

[0235] (167) A compound according to any one of (1) to (158), wherein: P-000059-WO-PCT-MYT - 42 - -LQ2-, if present, is -C(=S)NRLQ2A-.

[0236] (168) A compound according to any one of (1) to (158), wherein: -LQ2-, if present, is -S(=O)2-. The Group -Q3

[0237] (169) A compound according to any one of (1) to (168), wherein: -Q3, if present, is phenyl; and is optionally substituted with one or more groups -RQ3C.

[0238] (170) A compound according to any one of (1) to (168), wherein: -Q3, if present, is naphthyl; and is optionally substituted with one or more groups -RQ3C. The Group -LQ3-

[0239] (171) A compound according to any one of (1) to (170), wherein: -LQ3-, if present, is -C(=O)-, -C(=YLQ3)NRLQ3A-, or -S(=O)2-;

[0240] (172) A compound according to any one of (1) to (170), wherein: -LQ3-, if present, is -C(=O)-, -C(=YLQ3)NH-, or -S(=O)2-;

[0241] (173) A compound according to any one of (1) to (170), wherein: -LQ3-, if present, is -C(=O)-, -C(=O)NH-, -C(=S)NH-, or -S(=O)2-.

[0242] (174) A compound according to any one of (1) to (170), wherein: -LQ3-, if present, is -C(=O)-, -C(=S)NRLQ3A-, or -C(=O)NRLQ3A-.

[0243] (175) A compound according to any one of (1) to (170), wherein: -LQ3-, if present, is -C(=O)-, or -S(=O)2-.

[0244] (176) A compound according to any one of (1) to (170), wherein: -LQ3-, if present, is -C(=O)NRLQ3A-, -C(=S)NRLQ3A-, or -S(=O)2-.

[0245] (177) A compound according to any one of (1) to (170), wherein: -LQ3-, if present, is -C(=O)-

[0246] (178) A compound according to any one of (1) to (170), wherein: -LQ3-, if present, is -C(=O)NRLQ3A-.

[0247] (179) A compound according to any one of (1) to (170), wherein: -LQ3-, if present, is -C(=S)NRLQ3A-.

[0248] (180) A compound according to any one of (1) to (170), wherein: -LQ3-, if present, is -S(=O)2-. The Group -Q4

[0249] (181) A compound according to any one of (1) to (180), wherein: -Q4, if present, is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; and is optionally substituted with one or more groups -RQ4C.

[0250] (182) A compound according to any one of (1) to (180), wherein: P-000059-WO-PCT-MYT - 43 - -Q4, if present, is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0251] (183) A compound according to any one of (1) to (180), wherein: -Q4, if present, is cyclopropyl; and is optionally substituted with one or more groups -RQ4C.

[0252] (184) A compound according to any one of (1) to (180), wherein: -Q4, if present, is cyclobutyl; and is optionally substituted with one or more groups -RQ4C.

[0253] (185) A compound according to any one of (1) to (180), wherein: -Q4, if present, is cyclopentyl; and is optionally substituted with one or more groups -RQ4C.

[0254] (186) A compound according to any one of (1) to (180), wherein: -Q4, if present, is cyclohexyl; and is optionally substituted with one or more groups -RQ4C. The Group -LQ4-

[0255] (187) A compound according to any one of (1) to (186), wherein: -LQ4-, if present, is -C(=O)-, -C(=YLQ4)NRLQ4A-, or -S(=O)2-;

[0256] (188) A compound according to any one of (1) to (186), wherein: -LQ4-, if present, is -C(=O)-, -C(=YLQ4)NH-, or -S(=O)2-;

[0257] (189) A compound according to any one of (1) to (186), wherein: -LQ4-, if present, is -C(=O)-, -C(=O)NH-, -C(=S)NH-, or -S(=O)2-.

[0258] (190) A compound according to any one of (1) to (186), wherein: -LQ4-, if present, is -C(=O)-, -C(=S)NRLQ4A-, or -C(=O)NRLQ4A-.

[0259] (191) A compound according to any one of (1) to (186), wherein: -LQ4-, if present, is -C(=O)-, or -S(=O)2-.

[0260] (192) A compound according to any one of (1) to (186), wherein: -LQ4-, if present, is -C(=O)NRLQ4A-, -C(=S)NRLQ4A-, or -S(=O)2-.

[0261] (193) A compound according to any one of (1) to (186), wherein: -LQ4-, if present, is -C(=O)-

[0262] (194) A compound according to any one of (1) to (186), wherein: -LQ4-, if present, is -C(=O)NRLQ4A-.

[0263] (195) A compound according to any one of (1) to (186), wherein: -LQ4-, if present, is -C(=S)NRLQ4A-.

[0264] (196) A compound according to any one of (1) to (186), wherein: -LQ4-, if present, is -S(=O)2-. The Group -Q5

[0265] (197) A compound according to any one of (1) to (196), wherein: P-000059-WO-PCT-MYT - 44 - -Q5, if present, is -Me, -Et, -nPr, -iPr, -nBu, -iBu, -sBu, -tBu, n-pentyl, iso-pentyl, neo-pentyl, n-hexyl, iso-hexyl, or 3,3-dimethylbutyl; and is optionally substituted with one or more groups -RQ5C.

[0266] (198) A compound according to any one of (1) to (196), wherein: -Q5, if present, is linear or branched saturated C1-4alkyl; and is optionally substituted with one or more groups -RQ5C.

[0267] (199) A compound according to any one of (1) to (196), wherein: -Q5, if present, is -Me, -Et, -iPr, -sBu, or -tBu; and is optionally substituted with one or more groups -RQ5C.

[0268] (200) A compound according to any one of (1) to (196), wherein: -Q5, if present, is -Me, -Et, -iPr, -sBu, or -tBu.

[0269] (201) A compound according to any one of (1) to (196), wherein: -Q5, if present, is -Me, -Et, or -nPr; and is optionally substituted with one or more groups -RQ5C.

[0270] (202) A compound according to any one of (1) to (196), wherein: -Q5, if present, is -CH2-RQ5C, -CH2CH2-RQ5C, or -CH2CH2CH2-RQ5C.

[0271] (203) A compound according to any one of (1) to (196), wherein: -Q5, if present, is -CH2-RQ5C.

[0272] (204) A compound according to any one of (1) to (196), wherein: -Q5, if present, is -CH2CH2-RQ5C.

[0273] (205) A compound according to any one of (1) to (196), wherein: -Q5, if present, is -CH2CH2CH2-RQ5C. The Group -LQ5-

[0274] (206) A compound according to any one of (1) to (205), wherein: -LQ5-, if present, is -C(=O)-, -C(=YLQ5)NRLQ5A-, or -S(=O)2-;

[0275] (207) A compound according to any one of (1) to (205), wherein: -LQ5-, if present, is -C(=O)-, -C(=YLQ5)NH-, or -S(=O)2-;

[0276] (208) A compound according to any one of (1) to (205), wherein: -LQ5-, if present, is -C(=O)-, -C(=O)NH-, -C(=S)NH-, or -S(=O)2-.

[0277] (209) A compound according to any one of (1) to (205), wherein: -LQ5-, if present, is -C(=O)-, -C(=S)NRLQ5A-, or -C(=O)NRLQ5A-.

[0278] (210) A compound according to any one of (1) to (205), wherein: -LQ5-, if present, is -C(=O)-, or -S(=O)2-.

[0279] (211) A compound according to any one of (1) to (205), wherein: -LQ5-, if present, is -C(=O)NRLQ5A-, -C(=S)NRLQ5A-, or -S(=O)2-.

[0280] (212) A compound according to any one of (1) to (205), wherein: -LQ5-, if present, is -C(=O)-

[0281] (213) A compound according to any one of (1) to (205), wherein: P-000059-WO-PCT-MYT - 45 - -LQ5-, if present, is -C(=O)NRLQ5A-.

[0282] (214) A compound according to any one of (1) to (205), wherein: -LQ5-, if present, is -C(=S)NRLQ5A-.

[0283] (215) A compound according to any one of (1) to (205), wherein: -LQ5-, if present, is -S(=O)2-. The Group =YLQ1

[0284] (216) A compound according to any one of (1) to (215), wherein =YLQ1, if present, is =O.

[0285] (217) A compound according to any one of (1) to (215), wherein =YLQ1, if present, is =S. The Group -RLQ1A

[0286] (218) A compound according to any one of (1) to (217), wherein -RLQ1A, if present, is linear or branched saturated C1-4alkyl.

[0287] (219) A compound according to any one of (1) to (217), wherein -RLQ1A, if present, is -Me, -Et, -nPr, -iPr, -nBu, -iBu, -sBu, or -tBu.

[0288] (220) A compound according to any one of (1) to (217), wherein -RLQ1A, if present, is -Me.

[0289] (221) A compound according to any one of (1) to (217), wherein -RLQ1A, if present, is -H. The Group -RQ1C

[0290] (222) A compound according to any one of (1) to (221), wherein: each -RQ1C, if present, is independently: -CN; and two adjacent -RQ1C, if present, taken together may form -(CH2)n1-O-(CH2)m1- or -O-(CH2)p1-O-.

[0291] (223) A compound according to any one of (1) to (221), wherein: each -RQ1C, if present, is independently: P-000059-WO-PCT-MYT - 46 - -C(=O)NH2, -C(=O)NHRQ1CC, -C(=O)NRQ1CC2, -C(=O)RQ1CM, or -C(=O)OH.

[0292] (224) A compound according to any one of (1) to (221), wherein: each -RQ1C, if present, is independently: -NH2, -NHRQ1CC, -NRQ1CC2, -RQ1CM, -C(=O)NH2, -C(=O)NHRQ1CC, -C(=O)NRQ1CC2, -C(=O)RQ1CM, or -C(=O)OH.

[0293] (225) A compound according to any one of (1) to (221), wherein: each -RQ1C, if present, is independently: -C(=O)NHRQ1CC.

[0294] (226) A compound according to any one of (1) to (221), wherein: each -RQ1C, if present, is independently:

[0295] (227) A compound according to any one of (1) to (221), wherein: each -RQ1C, if present, is:

[0296] (228) A compound according to any one of (1) to (221), wherein: each -RQ1C, if present, is: -F, -OH, -RQ1CCor -RQ1CX.

[0297] (229) A compound according to any one of (1) to (221), wherein: each -RQ1C, if present, is: -F, -RQ1CCor -RQ1CX.

[0298] (230) A compound according to any one of (1) to (221), wherein: If -RQ1Cis present, there is a single -RQ1Csubstituent selected from: -F, -OH, -RQ1CCand -RQ1CX.

[0299] (231) A compound according to any one of (1) to (221), wherein: each -RQ1C, if present, is: -F, -OH, -tBu or -CF3.

[0300] (232) A compound according to any one of (1) to (221), wherein: If -RQ1Cis present, there is a single -RQ1Csubstituent selected from: -F, -OH, -tBu and -CF3. The Group -RQ1CC

[0301] (233) A compound according to any one of (1) to (232), wherein: P-000059-WO-PCT-MYT - 47 - each -RQ1CC, if present, is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, phenyl, or phenyl-C1-3alkyl, wherein each phenyl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -CN, -OH, -O(CH3), -NH2, -NH(CH3), and -N(CH3)2.

[0302] (234) A compound according to any one of (1) to (232), wherein: each -RQ1CC, if present, is independently linear or branched saturated C1-4alkyl, phenyl, or phenyl-CH2-, wherein each phenyl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -CN, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2.

[0303] (235) A compound according to any one of (1) to (232), wherein: each -RQ1CC, if present, is independently linear or branched saturated C1-4alkyl or phenyl, wherein each phenyl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, - CN, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2.

[0304] (236) A compound according to any one of (1) to (232), wherein: each -RQ1CC, if present, is independently linear or branched saturated C1-4alkyl or phenyl, wherein each phenyl is optionally substituted with one or more groups selected from: -CH3, and -OH.

[0305] (237) A compound according to any one of (1) to (232), wherein: each -RQ1CC, if present, is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, phenyl, or benzyl.

[0306] (238) A compound according to any one of (1) to (232), wherein: each -RQ1CC, if present, is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, or phenyl.

[0307] (239) A compound according to any one of (1) to (232), wherein: each -RQ1CC, if present, is independently linear or branched saturated C1-4alkyl, or C3-6cycloalkyl.

[0308] (240) A compound according to any one of (1) to (232), wherein: each -RQ1CC, if present, is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, phenyl, or benzyl.

[0309] (241) A compound according to any one of (1) to (232), wherein: each -RQ1CC, if present, is independently linear or branched saturated C1-4alkyl.

[0310] (242) A compound according to any one of (1) to (232), wherein: each -RQ1CC, if present, is independently -Me, -Et, -nPr, -iPr, -nBu, or -tBu.

[0311] (243) A compound according to any one of (1) to (232), wherein: each -RQ1CC, if present, is independently -Me, -Et, -nPr, or -iPr.

[0312] (244) A compound according to any one of (1) to (232), wherein: each -RQ1CC, if present, is independently -Me or -tBu.

[0313] (245) A compound according to any one of (1) to (232), wherein: each -RQ1CC, if present, is independently -Me or -Et.

[0314] (246) A compound according to any one of (1) to (232), wherein: each -RQ1CC, if present, is -tBu.

[0315] (247) A compound according to any one of (1) to (232), wherein: P-000059-WO-PCT-MYT - 48 - each -RQ1CC, if present, is -Me. The Group -RQ1CCC

[0316] (248) A compound according to any one of (1) to (247), wherein: each -RQ1CCC, if present, is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, -sBu, or -tBu.

[0317] (249) A compound according to any one of (1) to (247), wherein: each -RQ1CCC, if present, is independently -Me. The Indices “n1” and “m1” in -(CH2)n1-O-(CH2)m1-

[0318] (250) A compound according to any one of (1) to (249), wherein: n1, if present, is 0, 1, 2, or 3; m1, if present, is 0, 1, 2, or 3; with the proviso that m1+n1 is 2 or 3.

[0319] (251) A compound according to any one of (1) to (249), wherein: n1, if present, is 0, 1, or 2; m1, if present, is 0, 1, or 2; with the proviso that m1+n1 is 2 or 3.

[0320] (252) A compound according to any one of (1) to (249), wherein: n1, if present, is 1 or 2; m1, if present, is 1 or 2; with the proviso that m1+n1 is 2 or 3. The Index “p1” in -O-(CH2)p1-O-

[0321] (253) A compound according to any one of (1) to (252), wherein: p1, if present, is 1.

[0322] (254) A compound according to any one of (1) to (252), wherein: p1, if present, is 2. The Group -RQ1CX

[0323] (255) A compound according to any one of (1) to (254), wherein: each -RQ1CX, if present, is independently linear or branched saturated C1-4fluoroalkyl.

[0324] (256) A compound according to any one of (1) to (254), wherein: each -RQ1CX, if present, is independently -CF3, -CHF2, -CH2CF3, or -CH2CHF2.

[0325] (257) A compound according to any one of (1) to (254), wherein: each -RQ1CX, if present, is -CF3. The Group -RQ1CM

[0326] (258) A compound according to any one of (1) to (257), wherein: P-000059-WO-PCT-MYT - 49 - each -RQ1CM, if present, is independently azetidino, pyrrolidino, piperidino, piperazino, morpholino, thiomorpholino, azepano, or diazepano, and is: optionally substituted on carbon with one or more groups -RQ1CMM; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ1CMM, -C(=O)RQ1CMM, -C(=O)ORQ1CMM, and -S(=O)2RQ1CMM.

[0327] (259) A compound according to any one of (1) to (257), wherein: each -RQ1CM, if present, is independently pyrrolidino, piperidino, piperazino, or morpholino, and is: optionally substituted on carbon with one or more groups -RQ1CMM; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ1CMM, -C(=O)RQ1CMM, -C(=O)ORQ1CMM, and -S(=O)2RQ1CMM.

[0328] (260) A compound according to any one of (1) to (257), wherein: each -RQ1CM, if present, is independently pyrrolidino, piperidino, piperazino, or morpholino, and is: optionally substituted on carbon with one or more groups -RQ1CMM; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ1CMM, -C(=O)RQ1CMM, and -C(=O)ORQ1CMM. The Group -RQ1CMM

[0329] (261) A compound according to any one of (1) to (260), wherein: each -RQ1CMM, if present, is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, or C3-6cycloalkyl-C1-3alkyl, wherein C1-4alkyl and each cycloalkyl is optionally substituted with one or more groups selected from: -F, -OH, and -OCH3.

[0330] (262) A compound according to any one of (1) to (260), wherein: each -RQ1CMM, if present, is independently linear or branched saturated C1-4alkyl, or C3-6cycloalkyl, wherein C1-4alkyl and each cycloalkyl is optionally substituted with one or more groups selected from: -F, -OH, and -OCH3.

[0331] (263) A compound according to any one of (1) to (260), wherein: each -RQ1CMM, if present, is independently linear or branched saturated C1-4alkyl, wherein C1-4alkyl is optionally substituted with -OH, or -OCH3.

[0332] (264) A compound according to any one of (1) to (260), wherein: each -RQ1CMM, if present, is independently linear or branched saturated C1-4alkyl.

[0333] (265) A compound according to any one of (1) to (260), wherein: each -RQ1CMM, if present, is independently -Me, -Et, -nPr, -iPr, -nBu, or -tBu.

[0334] (266) A compound according to any one of (1) to (260), wherein: each -RQ1CMM, if present, is independently -Me, -Et, -nPr, or -iPr.

[0335] (267) A compound according to any one of (1) to (260), wherein: each -RQ1CMM, if present, is independently -Me or -Et.

[0336] (268) A compound according to any one of (1) to (260), wherein: P-000059-WO-PCT-MYT - 50 - each -RQ1CMM, if present, is -Me. The Group -RQ1N

[0337] (269) A compound according to any one of (1) to (268), wherein: each -RQ1N, if present, is independently:

[0338] (270) A compound according to any one of (1) to (268), wherein: each -RQ1N, if present, is independently:

[0339] (271) A compound according to any one of (1) to (268), wherein: each -RQ1N, if present, is independently: -RQ1Nhetor -LQ1N-RQ1Nhet.

[0340] (272) A compound according to any one of (1) to (268), wherein: each -RQ1N, if present, is: -RQ1Nhet.

[0341] (273) A compound according to any one of (1) to (268), wherein: each -RQ1N, if present, is independently:

[0342] (274) A compound according to any one of (1) to (268), wherein: each -RQ1N, if present, is independently: -LQ1N-OH, or -LQ1N-ORQ1NC.

[0343] (275) A compound according to any one of (1) to (268), wherein: each -RQ1N, if present, is independently: -LQ1N-NH2, -LQ1N-NHRQ1NC, -LQ1N-NRQ1NC2, or -LQ1N-RQ1NM. The Group -RQ1NC

[0344] (276) A compound according to any one of (1) to (275), wherein: each -RQ1NC, if present, is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, phenyl, phenyl-C1-3alkyl, wherein each phenyl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CN, -CF3, -OH, -OCH3, -NH2, -NHRQ1NCC, and -NRQ1NCC2.

[0345] (277) A compound according to any one of (1) to (275), wherein: P-000059-WO-PCT-MYT - 51 - each -RQ1NC, if present, is independently linear or branched saturated C1-4alkyl, phenyl, or phenyl-CH2-, wherein each phenyl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -CN, -OH, -OCH3, -NH2, -NHRQ1NCC, and -NRQ1NCC2.

[0346] (278) A compound according to any one of (1) to (275), wherein: each -RQ1NC, if present, is independently linear or branched saturated C1-4alkyl, phenyl, or benzyl.

[0347] (279) A compound according to any one of (1) to (275), wherein: each -RQ1NC, if present, is independently linear or branched saturated C1-4alkyl.

[0348] (280) A compound according to any one of (1) to (275), wherein: each -RQ1NC, if present, is independently -Me, -Et, -nPr, -iPr, -nBu, or -tBu.

[0349] (281) A compound according to any one of (1) to (275), wherein: each -RQ1NC, if present, is independently -Me, -Et, -nPr, or -iPr.

[0350] (282) A compound according to any one of (1) to (275), wherein: each -RQ1NC, if present, is independently -Me or -tBu.

[0351] (283) A compound according to any one of (1) to (275), wherein: each -RQ1NC, if present, is independently -Me or -Et.

[0352] (284) A compound according to any one of (1) to (275), wherein: each -RQ1NC, if present, is -Me.

[0353] (285) A compound according to any one of (1) to (275), wherein: each -RQ1NC, if present, is -tBu. The Group -RQ1NCC

[0354] (286 ) A compound according to any one of (1) to (285), wherein: each -RQ1NCC, if present, is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, -sBu, or -tBu.

[0355] (287) A compound according to any one of (1) to (285), wherein: each -RQ1NCC, if present, is independently -Me. The Group -RQ1NX

[0356] (288) A compound according to any one of (1) to (287), wherein: each -RQ1NX, if present, is independently linear or branched saturated C1-4fluoroalkyl.

[0357] (289) A compound according to any one of (1) to (287), wherein: each -RQ1NX, if present, is independently -CF3, -CHF2, -CH2CF3, -CH2CHF2, or -CH2CH2F.

[0358] (290) A compound according to any one of (1) to (287), wherein: each -RQ1NX, if present, is independently -CH2CF3, -CH2CHF2, or -CH2CH2F.

[0359] (291) A compound according to any one of (1) to (287), wherein: each -RQ1NX, if present, is -CHF2. The Group -LQ1N-

[0360] (292) A compound according to any one of (1) to (291), wherein: each -LQ1N-, if present, is independently -CH2-, -C(CH3)2-, -CH2CH2-, or -CH2CH2CH2-. P-000059-WO-PCT-MYT - 52 -

[0361] (293) A compound according to any one of (1) to (291), wherein: each -LQ1N-, if present, is independently -CH2-, -CH2CH2-, or -CH2CH2CH2-.

[0362] (294) A compound according to any one of (1) to (291), wherein: each -LQ1N-, if present, is -CH2-.

[0363] (295) A compound according to any one of (1) to (291), wherein: each -LQ1N-, if present, is -CH2CH2-.

[0364] (296) A compound according to any one of (1) to (291), wherein: each -LQ1N-, if present, is -CH2CH2CH2-. The Group -RQ1NM

[0365] (297) A compound according to any one of (1) to (296), wherein: each -RQ1NM, if present, is independently azetidino, pyrrolidino, piperidino, piperazino, morpholino, thiomorpholino, azepano, or diazepano, and is: optionally substituted on carbon with one or more groups -RQ1NMM; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ1NMM, -C(=O)RQ1NMM, -C(=O)ORQ1NMM, and -S(=O)2RQ1NMM.

[0366] (298) A compound according to any one of (1) to (296), wherein: each -RQ1NM, if present, is independently pyrrolidino, piperidino, piperazino, or morpholino, and is: optionally substituted on carbon with one or more groups -RQ1NMM; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ1NMM, -C(=O)RQ1NMM, -C(=O)ORQ1NMM, and -S(=O)2RQ1NMM.

[0367] (299) A compound according to any one of (1) to (296), wherein: each -RQ1NM, if present, is independently pyrrolidino, piperidino, piperazino, or morpholino, and is: optionally substituted on carbon with one or more groups -RQ1CMM; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ1NMM, -C(=O)RQ1NMM, and -C(=O)ORQ1NMM. The Group -RQ1NMM

[0368] (300) A compound according to any one of (1) to (299), wherein: each -RQ1NMM, if present, is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, or C3-6cycloalkyl-C1-3alkyl.

[0369] (301) A compound according to any one of (1) to (299), wherein: each -RQ1NMM, if present, is independently linear or branched saturated C1-4alkyl.

[0370] (302) A compound according to any one of (1) to (299), wherein: each -RQ1NMM, if present, is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, -sBu, or -tBu.

[0371] (303) A compound according to any one of (1) to (299), wherein: P-000059-WO-PCT-MYT - 53 - each -RQ1NMM, if present, is -Me. The Group -RQ1Nhet

[0372] (304) A compound according to any one of (1) to (303), wherein: each -RQ1Nhet, if present, is independently azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, azepanyl, or diazepanyl; and is: optionally substituted on sulfur, if present, with one or two groups =O; optionally substituted on carbon with one or more groups -RQ1NHHor =O; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ1NHH, -C(=O)RQ1NHH, -C(=O)ORQ1NHH, and -S(=O)2RQ1NHH.

[0373] (305) A compound according to any one of (1) to (303), wherein: each -RQ1Nhet, if present, is independently oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, or morpholinyl; and is: optionally substituted on carbon with one or more groups -RQ1NHHor =O; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ1NHH, -C(=O)RQ1NHH, -C(=O)ORQ1NHH, and -S(=O)2RQ1NHH.

[0374] (306) A compound according to any one of (1) to (303), wherein: each -RQ1Nhet, if present, is independently oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl; and is: optionally substituted on carbon with one or more groups -RQ1NHHor =O.

[0375] (307) A compound according to any one of (1) to (303), wherein: each -RQ1Nhet, if present, is independently pyrrolidinyl, piperidinyl, or piperazinyl; and is: optionally substituted on carbon with one or more groups -RQ1NHHor =O; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ1NHH, -C(=O)RQ1NHH, -C(=O)ORQ1NHH, and -S(=O)2RQ1NHH.

[0376] (308) A compound according to any one of (1) to (303), wherein: each -RQ1Nhet, if present, is independently pyrrolidinyl or piperidinyl; and is: optionally substituted on carbon with one or more groups -RQ1NHHor =O; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ1NHH, -C(=O)RQ1NHH, -C(=O)ORQ1NHH, and -S(=O)2RQ1NHH.

[0377] (309) A compound according to any one of (1) to (303), wherein: P-000059-WO-PCT-MYT - 54 - each -RQ1Nhet, if present, is pyrrolidinyl; and is: optionally substituted on carbon with one or more groups -RQ1NHHor =O; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ1NHH, -C(=O)RQ1NHH, -C(=O)ORQ1NHH, and -S(=O)2RQ1NHH. The Group -RQ1NHH

[0378] (310) A compound according to any one of (1) to (309), wherein: each -RQ1NHH, if present, is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, or C3-6cycloalkyl-C1-3alkyl; wherein C1-4alkyl and each cycloalkyl is optionally substituted with one or more groups selected from: -F, -OH, and -OCH3.

[0379] (311) A compound according to any one of (1) to (309), wherein: each -RQ1NHH, if present, is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, or C3-6cycloalkyl-C1-3alkyl.

[0380] (312) A compound according to any one of (1) to (309), wherein: each -RQ1NHH, if present, is independently linear or branched saturated C1-4alkyl.

[0381] (313) A compound according to any one of (1) to (309), wherein: each -RQ1NHH, if present, is independently -Me, -Et, -nPr, -iPr, -nBu, or -tBu.

[0382] (314) A compound according to any one of (1) to (309), wherein: each -RQ1NHH, if present, is independently -Me, -Et, -nPr, or -iPr.

[0383] (315) A compound according to any one of (1) to (309), wherein: each -RQ1NHH, if present, is independently -Me or -Et.

[0384] (316) A compound according to any one of (1) to (309), wherein: each -RQ1NHH, if present, is -Me. The Group =YLQ2

[0385] (317) A compound according to any one of (1) to (316), wherein =YLQ2, if present, is =O.

[0386] (318) A compound according to any one of (1) to (316), wherein =YLQ2, if present, is =S. The Group -RLQ2A

[0387] (319) A compound according to any one of (1) to (318), wherein -RLQ2A, if present, is linear or branched saturated C1-4alkyl.

[0388] (320) A compound according to any one of (1) to (318), wherein -RLQ2A, if present, is -Me, -Et, -nPr, -iPr, -nBu, -iBu, -sBu, or -tBu.

[0389] (321) A compound according to any one of (1) to (318), wherein -RLQ2A, if present, is -Me.

[0390] (322) A compound according to any one of (1) to (318), wherein -RLQ2A, if present, is -H. The Group -RQ2C

[0391] (323) A compound according to any one of (1) to (322), wherein: P-000059-WO-PCT-MYT - 55 - each -RQ2C, if present, is independently: =O.

[0392] (324) A compound according to any one of (1) to (322), wherein: each -RQ2C, if present, is independently:

[0393] (325) A compound according to any one of (1) to (322), wherein: each -RQ2C, if present, is independently: or -ORQ2CX. The Group -RQ2CC

[0394] (326) A compound according to any one of (1) to (325), wherein: each -RQ2CC, if present, is independently linear or branched saturated C1-4alkyl, phenyl, or phenyl-CH2-, wherein each phenyl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -CN, -OH, -O(CH3), -NH2, -NH(CH3), and -N(CH3)2.

[0395] (327) A compound according to any one of (1) to (325), wherein: each -RQ2CC, if present, is independently linear or branched saturated C1-4alkyl, phenyl, or phenyl-CH2-.

[0396] (328) A compound according to any one of (1) to (325), wherein: each -RQ2CC, if present, is independently linear or branched saturated C1-4alkyl.

[0397] (329) A compound according to any one of (1) to (325), wherein: each -RQ2CC, if present, is: -Me, -Et, -nPr, -iPr, -nBu, or -tBu.

[0398] (330) A compound according to any one of (1) to (325), wherein: each -RQ2CC, if present, is: -Me, -Et, -nPr, or -iPr.

[0399] (331) A compound according to any one of (1) to (325), wherein: each -RQ2CC, if present, is: -Me or -Et.

[0400] (332) A compound according to any one of (1) to (325), wherein: P-000059-WO-PCT-MYT - 56 - each -RQ2CC, if present, is: -Me. The Group -RQ2CCC

[0401] (333) A compound according to any one of (1) to (332), wherein: each -RQ2CCC, if present, is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, -sBu, or -tBu.

[0402] (334) A compound according to any one of (1) to (332), wherein: each -RQ2CCC, if present, is independently -Me. The Group -RQ2CX

[0403] (335) A compound according to any one of (1) to (334), wherein: each -RQ2CX, if present, is independently linear or branched saturated C1-4fluoroalkyl.

[0404] (336) A compound according to any one of (1) to (334), wherein: each -RQ2CX, if present, is independently -CF3, -CHF2, -CH2CF3, or -CH2CHF2.

[0405] (337) A compound according to any one of (1) to (334), wherein: each -RQ2CX, if present, is -CF3. The Group -RQ2CM

[0406] (338) A compound according to any one of (1) to (337), wherein: each -RQ2CM, if present, is independently azetidino, pyrrolidino, piperidino, piperazino, morpholino, thiomorpholino, azepano, or diazepano, and is: optionally substituted on carbon with one or more groups -RQ2CMM; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ2CMM, -C(=O)RQ2CMM, -C(=O)ORQ2CMM, and -S(=O)2RQ2CMM.

[0407] (339) A compound according to any one of (1) to (337), wherein: each -RQ2CM, if present, is independently pyrrolidino, piperidino, piperazino, or morpholino, and is: optionally substituted on carbon with one or more groups -RQ2CMM; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ2CMM, -C(=O)RQ2CMM, -C(=O)ORQ2CMM, and -S(=O)2RQ2CMM.

[0408] (340) A compound according to any one of (1) to (337), wherein: each -RQ2CM, if present, is independently pyrrolidino, piperidino, piperazino, or morpholino, and is: optionally substituted on carbon with one or more groups -RQ2CMM; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ2CMM, -C(=O)RQ2CMM, and -C(=O)ORQ2CMM. The Group -RQ2CMM

[0409] (341) A compound according to any one of (1) to (340), wherein: P-000059-WO-PCT-MYT - 57 - each -RQ2CMM, if present, is independently linear or branched saturated C1-4alkyl

[0410] (342) A compound according to any one of (1) to (340), wherein: each -RQ2CMM, if present, is: -Me, -Et, -nPr, -iPr, -nBu, or -tBu.

[0411] (343) A compound according to any one of (1) to (340), wherein: each -RQ2CMM, if present, is: -Me, -Et, -nPr, or -iPr.

[0412] (344) A compound according to any one of (1) to (340), wherein: each -RQ2CMM, if present, is: -Me or -Et.

[0413] (345) A compound according to any one of (1) to (340), wherein: each -RQ2CMM, if present, is: -Me. The Group -RQ2N

[0414] (346) A compound according to any one of (1) to (345), wherein: each -RQ2N, if present, is independently:

[0415] (347) A compound according to any one of (1) to (345), wherein: each -RQ2N, if present, is independently: -RQ2NC, or -C(=O)RQ2NC.

[0416] (348) A compound according to any one of (1) to (345), wherein: each -RQ2N, if present, is independently:

[0417] (349) A compound according to any one of (1) to (345), wherein: each -RQ2N, if present, is: -C(=O)RQ2NC. The Group -RQ2NC

[0418] (350) A compound according to any one of (1) to (349), wherein: each -RQ2NC, if present, is independently linear or branched saturated C1-6alkyl, phenyl, phenyl-CH2-, wherein C1-6alkyl is optionally substituted with one or more groups selected from: - F, -OH, or -OCH3, and each phenyl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -CN, -OH, -OCH3, -NH2, -NHRQ2NCC, and -NRQ2NCC2;

[0419] (351) A compound according to any one of (1) to (349), wherein: P-000059-WO-PCT-MYT - 58 - Each -RQ2NC, if present, is independently linear or branched saturated C1-4alkyl, phenyl, or phenyl-CH2-, wherein each phenyl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -CN, -OH, -OCH3, -NH2, -NHRQ2NCC, and -NRQ2NCC2.

[0420] (352) A compound according to any one of (1) to (349), wherein: each -RQ2NC, if present, is independently linear or branched saturated C1-4alkyl, phenyl, or phenyl-CH2-.

[0421] (353) A compound according to any one of (1) to (349), wherein: each -RQ2NC, if present, is independently linear or branched saturated C1-4alkyl.

[0422] (354) A compound according to any one of (1) to (349), wherein: each -RQ2NC, if present, is: -Me, -Et, -nPr, -iPr, -nBu, or -tBu.

[0423] (355) A compound according to any one of (1) to (349), wherein: each -RQ2NC, if present, is: -Me, -Et, -nPr, or -iPr.

[0424] (356) A compound according to any one of (1) to (349), wherein: each -RQ2NC, if present, is: -Me or -Et.

[0425] (357) A compound according to any one of (1) to (349), wherein: each -RQ2NC, if present, is: -Me. The Group -RQ2NCC

[0426] (358) A compound according to any one of (1) to (357), wherein: each -RQ2NCC, if present, is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, -sBu, or -tBu.

[0427] (359) A compound according to any one of (1) to (357), wherein: each -RQ2NCC, if present, is independently -Me. The Group =YLQ3

[0428] (360) A compound according to any one of (1) to (359), wherein =YLQ3, if present, is =O.

[0429] (361) A compound according to any one of (1) to (359), wherein =YLQ3, if present, is =S. P-000059-WO-PCT-MYT - 59 - The Group -RLQ3A

[0430] (362) A compound according to any one of (1) to (361), wherein -RLQ3A, if present, is linear or branched saturated C1-4alkyl.

[0431] (363) A compound according to any one of (1) to (361), wherein -RLQ3A, if present, is -Me, -Et, -nPr, -iPr, -nBu, -iBu, -sBu, or -tBu.

[0432] (364) A compound according to any one of (1) to (361), wherein -RLQ3A, if present, is -Me.

[0433] (365) A compound according to any one of (1) to (361), wherein -RLQ3A, if present, is -H. The Group -RQ3C

[0434] (366) A compound according to any one of (1) to (365), wherein: each -RQ3C, if present, is independently: -CN, or -NO2; and two adjacent-RQ3C, if present, taken together may form -(CH2)n3-O-(CH2)m3- or -O-(CH2)p3-O.

[0435] (367) A compound according to any one of (1) to (365), wherein: each -RQ3C, if present, is independently: -CN, or -NO2; and two adjacent-RQ3C, if present, taken together may form -(CH2)n3-O-(CH2)m3- or -O-(CH2)p3-O.

[0436] (368) A compound according to any one of (1) to (365), wherein: each -RQ3C, if present, is independently: and two adjacent-RQ3C, if present, taken together may form -(CH2)n3-O-(CH2)m3- or -O-(CH2)p3-O.

[0437] (369) A compound according to any one of (1) to (365), wherein: P-000059-WO-PCT-MYT - 60 - each -RQ3C, if present, is independently:

[0438] (370) A compound according to any one of (1) to (365), wherein: each -RQ3C, if present, is independently: -F, -Cl, -Br, -I, -RQ3CC, -RQ3CX, -ORQ3CX, -OH, -ORQ3CC, or -NRQ3CC2.

[0439] (371) A compound according to any one of (1) to (365), wherein: - present, is independently: or

[0440] (372) A compound according to any one of (1) to (365), wherein: each -RQ3C, if present, is independently:

[0441] (373) A compound according to any one of (1) to (365), wherein: each -RQ3C, if present, is independently: -F, -Cl, -Me, -tBu, cyclopropyl, or phenyl, wherein each phenyl is optionally substituted with one or more groups selected from: -F (for example each -RQ3C, if present, is 4-fluorophenyl); -CF3, -OH, -OtBu, or -NMe2. The Group -RQ3CC

[0442] (374) A compound according to any one of (1) to (373), wherein: P-000059-WO-PCT-MYT - 61 - each -RQ3CC, if present, is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, phenyl, or phenyl-CH2-, wherein each cycloalkyl is optionally substituted with one or more groups selected from: -F, -OH, and -OCH3, and each phenyl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -CN, -OH, -O(CH3), -NH2, -NH(CH3), and -N(CH3)2.

[0443] (375) A compound according to any one of (1) to (373), wherein: each -RQ3CC, if present, is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, or phenyl, wherein each phenyl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -CN, -OH, -O(CH3), -NH2, -NH(CH3), and -N(CH3)2.

[0444] (376) A compound according to any one of (1) to (373), wherein: each -RQ3CC, if present, is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, or phenyl, wherein each phenyl is optionally substituted with one or more -F groups.

[0445] (377) A compound according to any one of (1) to (373), wherein: each -RQ3CC, if present, is independently -Me, -tBu, cyclopropyl or phenyl, wherein each phenyl is optionally substituted with one or more -F groups.

[0446] (378) A compound according to any one of (1) to (373), wherein: each -RQ3CC, if present, is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, phenyl, or phenyl-CH2-.

[0447] (379) A compound according to any one of (1) to (373), wherein: each -RQ3CC, if present, is independently linear or branched saturated C1-4alkyl, or C3-6cycloalkyl.

[0448] (380) A compound according to any one of (1) to (373), wherein: each -RQ3CC, if present, is independently linear or branched saturated C1-4alkyl.

[0449] (381) A compound according to any one of (1) to (373), wherein: each -RQ3CC, if present, is: -Me, -Et, -nPr, -iPr, -nBu, or -tBu.

[0450] (382) A compound according to any one of (1) to (373), wherein: each -RQ3CC, if present, is: -Me, -Et, -nPr, or -iPr.

[0451] (383) A compound according to any one of (1) to (373), wherein: each -RQ3CC, if present, is: -Me or -tBu.

[0452] (384) A compound according to any one of (1) to (373), wherein: each -RQ3CC, if present, is: -Me or -Et.

[0453] (385) A compound according to any one of (1) to (373), wherein: each -RQ3CC, if present, is: -tBu.

[0454] (386) A compound according to any one of (1) to (373), wherein: each -RQ3CC, if present, is: -Me. P-000059-WO-PCT-MYT - 62 -

[0455] (387) A compound according to any one of (1) to (373), wherein: each -RQ3CC, if present, is C3-6cycloalkyl.

[0456] (388) A compound according to any one of (1) to (373), wherein: each -RQ3CC, if present, is: cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0457] (389) A compound according to any one of (1) to (373), wherein: each -RQ3CC, if present, is: cyclopropyl.

[0458] (390) A compound according to any one of (1) to (373), wherein: each -RQ3CC, if present, is phenyl, wherein each phenyl is optionally substituted with one or more -F groups. The Group -RQ3CCC

[0459] (391) A compound according to any one of (1) to (390), wherein: each -RQ3CCC, if present, is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, -sBu, or -tBu.

[0460] (392) A compound according to any one of (1) to (390), wherein: each -RQ3CCC, if present, is independently -Me. The Group -RQ3CX

[0461] (393) A compound according to any one of (1) to (392), wherein: each -RQ3CX, if present, is independently linear or branched saturated C1-4fluoroalkyl.

[0462] (394) A compound according to any one of (1) to (392), wherein: each -RQ3CX, if present, is independently -CF3, -CHF2, -CH2CF3, or -CH2CHF2.

[0463] (395) A compound according to any one of (1) to (392), wherein: each -RQ3CX, if present, is -CF3. The Group -LQ3C-

[0464] (396) A compound according to any one wherein: each -LQ3C-, if present, is independently - -CH2CH2-, or -CH2CH2CH2-.

[0465] (397) A compound according to any one wherein: each -LQ3C-, if present, is independently - or -CH2CH2CH2-.

[0466] (398) A compound according to any one wherein: each -LQ3C-, if present, is -CH2-.

[0467] (399) A compound according to any one of (1) to (395), wherein: each -LQ3C-, if present, is -CH2CH2-.

[0468] (400) A compound according to any one of (1) to (395), wherein: each -LQ3C-, if present, is -CH2CH2CH2-. P-000059-WO-PCT-MYT - 63 - The Group -RQ3CM

[0469] (401) A compound according to any one of (1) to (400), wherein: each -RQ3CM, if present, is independently azetidino, pyrrolidino, piperidino, piperazino, morpholino, thiomorpholino, azepano, or diazepano, and is: optionally substituted on carbon with one or more groups -RQ3CMM; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ3CMM, -C(=O)RQ3CMM, -C(=O)ORQ3CMM, and -S(=O)2RQ3CMM.

[0470] (402) A compound according to any one of (1) to (400), wherein: each -RQ3CM, if present, is independently pyrrolidino, piperidino, piperazino, or morpholino, and is: optionally substituted on carbon with one or more groups -RQ3CMM; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ3CMM, -C(=O)RQ3CMM, -C(=O)ORQ3CMM, and -S(=O)2RQ3CMM.

[0471] (403) A compound according to any one of (1) to (400), wherein: each -RQ3CM, if present, is independently pyrrolidino, piperidino, piperazino, or morpholino, and is: optionally substituted on carbon with one or more groups -RQ3CMM; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ3CMM, -C(=O)RQ3CMM, and -C(=O)ORQ3CMM. The Group -RQ3CMM

[0472] (404) A compound according to any one of (1) to (403), wherein: each -RQ3CMM, if present, is independently linear or branched saturated C1-4alkyl.

[0473] (405) A compound according to any one of (1) to (403), wherein: each -RQ3CMM, if present, is: -Me, -Et, -nPr, -iPr, -nBu, or -tBu.

[0474] (406) A compound according to any one of (1) to (403), wherein: each -RQ3CMM, if present, is: -Me, -Et, -nPr, or -iPr.

[0475] (407) A compound according to any one of (1) to (403), wherein: each -RQ3CMM, if present, is: -Me or -Et.

[0476] (408) A compound according to any one of (1) to (403), wherein: each -RQ3CMM, if present, is: -Me. The Indices “n3” and “m3” –n -(CH2)n3-O-(CH2)m3-

[0477] (409) A compound according to any one of (1) to (408), wherein: P-000059-WO-PCT-MYT - 64 - n3, if present, is 0, 1, 2, or 3; m3, if present, is 0, 1, 2, or 3; with the proviso that m3+n3 is 2 or 3.

[0478] (410) A compound according to any one of (1) to (408), wherein: n3, if present, is 0, 1, or 2; m3, if present, is 0, 1, or 2; with the proviso that m3+n3 is 2 or 3.

[0479] (411) A compound according to any one of (1) to (408), wherein: n3, if present, is 1 or 2; m3, if present, is 1 or 2; with the proviso that m3+n3 is 2 or 3. The Indices “p3” in -O-(CH2)p3-O-

[0480] (412) A compound according to any one of (1) to (411), wherein: p3, if present, is 1.

[0481] (413) A compound according to any one of (1) to (411), wherein: p3, if present, is 2. The Group =YLQ4

[0482] (414) A compound according to any one of (1) to (413), wherein =YLQ4, if present, is =O.

[0483] (415) A compound according to any one of (1) to (413), wherein =YLQ4, if present, is =S. The Group -RLQ4A

[0484] (416) A compound according to any one of (1) to (415), wherein -RLQ4A, if present, is linear or branched saturated C1-4alkyl.

[0485] (417) A compound according to any one of (1) to (415), wherein -RLQ4A, if present, is -Me, -Et, -nPr, -iPr, -nBu, -iBu, -sBu, or -tBu.

[0486] (418) A compound according to any one of (1) to (415), wherein -RLQ4A, if present, is -Me.

[0487] (419) A compound according to any one of (1) to (415), wherein -RLQ4A, if present, is -H. The Group -RQ4C

[0488] (420) A compound according to any one of (1) to (419), wherein: each -RQ4C, if present, is independently:

[0489] (421) A compound according to any one of (1) to (419), wherein: each -RQ4C, if present, is independently: P-000059-WO-PCT-MYT - 65 - -F, -RQ4CC, -RQ4CX, -OH, -ORQ4CC, or -ORQ4CX.

[0490] (422) A compound according to any one of (1) to (419), wherein: each -RQ4C, if present, is independently: -F, -RQ4CC, -OH, or -ORQ4CC.

[0491] (423) A compound according to any one of (1) to (419), wherein: each -RQ4C, if present, is independently:

[0492] (424) A compound according to any one of (1) to (419), wherein: each -RQ4C, if present, is independently: -RQ4CC, -OH, or -ORQ4CC. The Group -RQ4CC

[0493] (425) A compound according to any one of (1) to (424), wherein: each -RQ4CC, if present, is independently linear or branched saturated C1-4alkyl, phenyl, phenyl-C1-3alkyl, wherein each phenyl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -CN, -OH, -O(CH3), -NH2, -NH(CH3), and -N(CH3)2.

[0494] (426) A compound according to any one of (1) to (424), wherein: each -RQ4CC, if present, is independently linear or branched saturated C1-4alkyl, phenyl, or phenyl-CH2-, wherein each phenyl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -CN, -OH, -O(CH3), -NH2, -NH(CH3), and -N(CH3)2.

[0495] (427) A compound according to any one of (1) to (424), wherein: each -RQ4CC, if present, is independently linear or branched saturated C1-4alkyl, phenyl, or phenyl-CH2-.

[0496] (428) A compound according to any one of (1) to (424), wherein: each -RQ4CC, if present, is independently linear or branched saturated C1-4alkyl.

[0497] (429) A compound according to any one of (1) to (424), wherein: each -RQ4CC, if present, is: -Me, -Et, -nPr, -iPr, -nBu, or -tBu.

[0498] (430) A compound according to any one of (1) to (424), wherein: each -RQ4CC, if present, is: -Me, -Et, -nPr, or -iPr.

[0499] (431) A compound according to any one of (1) to (424), wherein: P-000059-WO-PCT-MYT - 66 - each -RQ4CC, if present, is: -Me or -Et.

[0500] (432) A compound according to any one of (1) to (424), wherein: each -RQ4CC, if present, is: -Me. The Group -RQ4CCC

[0501] (433) A compound according to any one of (1) to (432), wherein: each -RQ4CCC, if present, is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, -sBu, or -tBu.

[0502] (434) A compound according to any one of (1) to (432), wherein: each -RQ4CCC, if present, is independently -Me, -Et, or -nPr.

[0503] (435) A compound according to any one of (1) to (432), wherein: each -RQ4CCC, if present, is independently -Me. The Group -RQ4CX

[0504] (436) A compound according to any one of (1) to (435), wherein: each -RQ4CX, if present, is independently linear or branched saturated C1-4fluoroalkyl.

[0505] (437) A compound according to any one of (1) to (435), wherein: each -RQ4CX, if present, is independently -CF3, -CHF2, -CH2CF3, or -CH2CHF2.

[0506] (438) A compound according to any one of (1) to (435), wherein: each -RQ4CX, if present, is -CF3. The Group -RQ4CM

[0507] (439) A compound according to any one of (1) to (438), wherein: each -RQ4CM, if present, is independently azetidino, pyrrolidino, piperidino, piperazino, morpholino, thiomorpholino, azepano, or diazepano, and is: optionally substituted on carbon with one or more groups -RQ4CMM; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ4CMM, -C(=O)RQ4CMM, -C(=O)ORQ4CMM, and -S(=O)2RQ4CMM.

[0508] (440) A compound according to any one of (1) to (438), wherein: each -RQ4CM, if present, is independently pyrrolidino, piperidino, piperazino, or morpholino, and is: optionally substituted on carbon with one or more groups -RQ4CMM; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ4CMM, -C(=O)RQ4CMM, -C(=O)ORQ4CMM, and -S(=O)2RQ4CMM.

[0509] (441) A compound according to any one of (1) to (438), wherein: P-000059-WO-PCT-MYT - 67 - each -RQ4CM, if present, is independently pyrrolidino, piperidino, piperazino, or morpholino, and is: optionally substituted on carbon with one or more groups -RQ4CMM; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ4CMM, -C(=O)RQ4CMM, and -C(=O)ORQ4CMM. The Group -RQ4CMM

[0510] (442) A compound according to any one of (1) to (441), wherein: each -RQ4CMM, if present, is independently linear or branched saturated C1-4alkyl

[0511] (443) A compound according to any one of (1) to (441), wherein: each -RQ4CMM, if present, is: -Me, -Et, -nPr, -iPr, -nBu, or -tBu.

[0512] (444) A compound according to any one of (1) to (441), wherein: each -RQ4CMM, if present, is: -Me, -Et, -nPr, or -iPr.

[0513] (445) A compound according to any one of (1) to (441), wherein: each -RQ4CMM, if present, is: -Me or -Et.

[0514] (446) A compound according to any one of (1) to (441), wherein: each -RQ4CMM, if present, is: -Me. The Group =YLQ5

[0515] (447) A compound according to any one of (1) to (446), wherein =YLQ5, if present, is =O.

[0516] (448) A compound according to any one of (1) to (446), wherein =YLQ5, if present, is =S. The Group -RLQ5A

[0517] (449) A compound according to any one of (1) to (448), wherein -RLQ5A, if present, is linear or branched saturated C1-4alkyl.

[0518] (450) A compound according to any one of (1) to (448), wherein -RLQ5A, if present, is -Me, -Et, -nPr, -iPr, -nBu, -iBu, -sBu, or -tBu.

[0519] (451) A compound according to any one of (1) to (448), wherein -RLQ5A, if present, is -Me.

[0520] (452) A compound according to any one of (1) to (448), wherein -RLQ5A, if present, is -H. The Group -RQ5C

[0521] (453) A compound according to any one of (1) to (452), wherein: each -RQ5C, if present, is independently: -RQ5CC, -F, -OH, -ORQ5CC, OCF3, or -NH2.

[0522] (454) A compound according to any one of (1) to (452), wherein: P-000059-WO-PCT-MYT - 68 - each -RQ5C, if present, is independently: -RQ5CC, or -NH2.

[0523] (455) A compound according to any one of (1) to (452), wherein: each -RQ5C, if present, is independently: phenyl, or -NH2.

[0524] (456) A compound according to any one of (1) to (452), wherein: each -RQ5C, if present, is independently: -F, -OH, -ORQ5CC, or OCF3.

[0525] (457) A compound according to any one of (1) to (452), wherein: each -RQ5C, if present, is independently: -OH, -ORQ5CC, -NH2, -NHRQ5CC, -NRQ5CC2, or -RQ5CM.

[0526] (458) A compound according to any one of (1) to (452), wherein: each -RQ5C, if present, is independently: -NH2, -NHRQ5CC, -NRQ5CC2, or -RQ5CM.

[0527] (459) A compound according to any one of (1) to (452), wherein: each -RQ5C, if present, is independently: -C(=O)OH. The Group -RQ5CC

[0528] (460) A compound according to any one of (1) to (459), wherein: each -RQ5CC, if present, is independently linear or branched saturated C1-4alkyl, phenyl, or phenyl-CH2-, wherein each phenyl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -CN, -OH, -O(CH3), -NH2, -NH(CH3), and -N(CH3)2.

[0529] (461) A compound according to any one of (1) to (459), wherein: each -RQ5CC, if present, is independently linear or branched saturated C1-4alkyl, phenyl, or phenyl-CH2-.

[0530] (462) A compound according to any one of (1) to (459), wherein: each -RQ5CC, if present, is independently linear or branched saturated C1-4alkyl, or phenyl.

[0531] (463) A compound according to any one of (1) to (459), wherein: each -RQ5CC, if present, is independently linear or branched saturated C1-4alkyl.

[0532] (464) A compound according to any one of (1) to (459), wherein: each -RQ5CC, if present, is: -Me, -Et, -nPr, -iPr, -nBu, or -tBu.

[0533] (465) A compound according to any one of (1) to (459), wherein: each -RQ5CC, if present, is: -Me, -Et, -nPr, or -iPr.

[0534] (466) A compound according to any one of (1) to (459), wherein: P-000059-WO-PCT-MYT - 69 - each -RQ5CC, if present, is: -Me or -Et.

[0535] (467) A compound according to any one of (1) to (459), wherein: each -RQ5CC, if present, is: -Me.

[0536] (468) A compound according to any one of (1) to (459), wherein: each -RQ5CC, if present, is independently phenyl. The Group -RQ5CCC

[0537] (469) A compound according to any one of (1) to (468), wherein: each -RQ5CCC, if present, is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, -sBu, or -tBu.

[0538] (470) A compound according to any one of (1) to (468), wherein: each -RQ5CCC, if present, is independently -Me. The Group -RQ5CM

[0539] (471) A compound according to any one of (1) to (470), wherein: each -RQ5CM, if present, is independently azetidino, pyrrolidino, piperidino, piperazino, morpholino, thiomorpholino, azepano, or diazepano, and is: optionally substituted on carbon with one or more groups -RQ5CMM; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ5CMM, -C(=O)RQ5CMM, -C(=O)ORQ5CMM, and -S(=O)2RQ5CMM.

[0540] (472) A compound according to any one of (1) to (470), wherein: each -RQ5CM, if present, is independently pyrrolidino, piperidino, piperazino, or morpholino, and is: optionally substituted on carbon with one or more groups -RQ5CMM; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ5CMM, -C(=O)RQ5CMM, -C(=O)ORQ5CMM, and -S(=O)2RQ5CMM.

[0541] (473) A compound according to any one of (1) to (470), wherein: each -RQ5CM, if present, is independently pyrrolidino, piperidino, piperazino, or morpholino, and is: optionally substituted on carbon with one or more groups -RQ5CMM; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ5CMM, -C(=O)RQ5CMM, and -C(=O)ORQ5CMM. The Group -RQ5CMM

[0542] (474) A compound according to any one of (1) to (473), wherein: each -RQ5CMM, if present, is independently linear or branched saturated C1-4alkyl.

[0543] (475) A compound according to any one of (1) to (473), wherein: P-000059-WO-PCT-MYT - 70 - each -RQ5CMM, if present, is: -Me, -Et, -nPr, -iPr, -nBu, or -tBu.

[0544] (476) A compound according to any one of (1) to (473), wherein: each -RQ5CMM, if present, is: -Me, -Et, -nPr, or -iPr.

[0545] (477) A compound according to any one of (1) to (473), wherein: each -RQ5CMM, if present, is: -Me or -Et.

[0546] (478) A compound according to any one of (1) to (473), wherein: each -RQ5CMM, if present, is: -Me. Certain Preferred Combinations

[0547] (479) A compound according to any one of (1) to (478), as applicable, wherein: -RA3is -H; and -RA4is -H.

[0548] (480) A compound according to any one of (1) to (478), as applicable, wherein: .

[0549] For example, the compound is a compound of the following structural formula: .

[0550] (481) A compound according to any one of (1) to (478), as applicable, wherein: P-000059-WO-PCT-MYT - 71 - 5

[0551] (482) A compound according to any one of (1) to (478), as applicable, wherein: ; 10

[0552] (483) A compound according to any one of (1) to (478), as applicable, wherein: ; and P-000059-WO-PCT-MYT - 72 - -Q is -LQ1-Q1.

[0553] For example, the compound is a compound of the following structural formula: .

[0554] (484) A compound according to any one of (1) to (478), as applicable, wherein: -Q1is C5-10heteroaryl; and is: optionally substituted on carbon with one or more groups -RQ1C; and optionally substituted on secondary nitrogen, if present, with one or more groups -RQ1N.

[0555] (485) A compound according to any one of (1) to (478), as applicable, wherein: ; -Q is -LQ1-Q1; P-000059-WO-PCT-MYT - 73 - -LQ1- is -C(=O)-; and -Q1is C5-10heteroaryl; and is: optionally substituted on secondary nitrogen, if present, with one or more groups -RQ1N.

[0556] (486) A compound according to any one of (1) to (478), as applicable, wherein: -Q1is pyridyl (for example pyrid-2-yl, pyrid-3-yl, or pyrid-4-yl), or pyrazolyl (for example [1H- pyrazol-3-yl]) and is: optionally substituted on carbon with one or more groups -RQ1C; and optionally substituted on secondary nitrogen, if present, with one or more groups -RQ1N.

[0557] (487) A compound according to any one of (1) to (478), as applicable, wherein: -Q1is pyridyl (for example pyrid-2-yl, pyrid-3-yl, or pyrid-4-yl) and is: optionally substituted on carbon with one or more groups -RQ1C.

[0558] (488) A compound according to any one of (1) to (478), as applicable, wherein: P-000059-WO-PCT-MYT - 74 - -Q1is pyridyl (for example pyrid-2-yl, pyrid-3-yl, or pyrid-4-yl).

[0559] (489) A compound according to any one of (1) to (478), as applicable, wherein: -Q1is pyrazolyl (for example [1H-pyrazol-3-yl]) and is: optionally substituted on carbon with one or more groups -RQ1C; and optionally substituted on secondary nitrogen, if present, with one or more groups -RQ1N.

[0560] For example, the compound is a compound of the following structural formula: . P-000059-WO-PCT-MYT - 75 -

[0561] (490) A compound according to any one of (1) to (478), as applicable, wherein: -Q1is 1H-pyrazol-3-yl and is: substituted on secondary nitrogen with -RQ1N; wherein: -RQ1Nis -RQ1NC.

[0562] For example, the compound is a compound of the following structural formula:

[0563] (491) A compound according to any one of (1) to (478), as applicable, wherein: ; and P-000059-WO-PCT-MYT - 76 - -Q is -LQ3-Q3.

[0564] For example, the compound is a compound of the following structural formula:

[0565] (492) A compound according to any one of (1) to (478), as applicable, wherein: ; -Q is -LQ3-Q3; -LQ3- is -C(=O); and -Q3is phenyl; and is: optionally substituted with one or more groups -RQ3C.

[0566] For example, the compound is a compound having the following structural formula:

[0567] (493) A compound according to any one of (1) to (478), as applicable, wherein: P-000059-WO-PCT-MYT - 77 - ; -Q is -LQ3-Q3; -LQ3- is -C(=O); -Q3is phenyl; and is: optionally substituted with one or more groups -RQ3C; and each -RQ3Cis independently:

[0568] (494) A compound according to any one of (1) to (478), as applicable, wherein:

[0569] For example, the compound is a compound of the following structural formula: P-000059-WO-PCT-MYT - 78 -

[0570] (495) A compound according to any one of (1) to (478), as applicable, wherein: ; -Q is -LQ5-Q5; -LQ5- is -C(=O); and -Q5is linear or branched saturated C1-6alkyl. Some Specific Examples

[0571] (496) A BAA compound according to any one of (1) to (495), as applicable, selected from compounds of the following formulae and pharmaceutically acceptable salts and co-crystals thereof (e.g., and pharmaceutically acceptable salts thereof): Example Table 1 # Structure Name 2-benzamido-N-(5-methyl-1H- BAA-001 indazol-4-yl)thiazole-5- carboxamide P-000059-WO-PCT-MYT - 79 - # Structure Name N-(5-methyl-1H-indazol-4-yl)-2- BAA-002 (picolinamido) thiazole-5- carboxamide N-(5-methyl-1H-indazol-4-yl)-2- (3-(trifluoromethyl) BAA-003 benzamido)thiazole-5- carboxamide 2-(3,4-dimethylbenzamido)-N- BAA-004 (5-methyl-1H-indazol-4- yl)thiazole-5-carboxamide N-(5-methyl-1H-indazol-4-yl)-2- (3-methylbutanamido) thiazole- BAA-005 5-carboxamide 2-(4-(tert-butyl)benzamido)-N- (5-methyl-1H-indazol-4- BAA-006 yl)thiazole-5-carboxamide 2-(3-(tert-butyl)benzamido)-N- (5-methyl-1H-indazol-4- BAA-007 yl)thiazole-5-carboxamide P-000059-WO-PCT-MYT - 80 - # Structure Name 2-(3-methoxybenzamido)-N-(5- methyl-1H-indazol-4-yl)thiazole- BAA-008 5-carboxamide 2-(4-methoxybenzamido)-N-(5- methyl-1H-indazol-4-yl)thiazole- BAA-009 5-carboxamide 2-(1-(tert-butyl)-1H-pyrazole-3- carboxamido)-N-(5-methyl-1H- BAA-010 indazol-4-yl)thiazole-5- carboxamide 2-(3-(2- (cyclopropyl(methyl)amino)-2- BAA-011 oxoethyl)benzamido) -N-(5- methyl-1H-indazol-4-yl)thiazole- 5-carboxamide 2-(4-(tert-butyl)benzamido)-N- BAA-012 (5-chloro-1H-indazol-4- yl)thiazole-5-carboxamide 2-(2,4-dimethylbenzamido)-N- BAA-013 (5-methyl-1H-indazol-4- yl)thiazole-5-carboxamide 2-(4-(dimethylamino) benzamido)-N-(5-methyl-1H- BAA-014 indazol-4-yl)thiazole-5- carboxamide P-000059-WO-PCT-MYT - 81 - # Structure Name 2-(3-(tert-butyl)-1-methyl-1H- pyrazole-5-carboxamido)-N-(5- BAA-015 methyl-1H-indazol-4-yl)thiazole- 5-carboxamide

[0572] (497) A BAA compound according to any one of (1) to (496), as applicable, selected from BAA- 001, BAA-002, BAA-003, BAA-004, BAA-005, BAA-006, BAA-007, BAA-008, BAA-009, BAA-010, BAA-011, BAA-012, BAA-013, BAA-014, and pharmaceutically acceptable salts and co-crystals thereof (e.g., and 5 pharmaceutically acceptable salts thereof).

[0573] In one embodiment, the BAA compound is obtainable (or obtained) by following the methods described in the experimental section.

[0574] In one embodiment, the BAA compound is provided according to any embodiment described herein (for example, embodiment (1), (2) or (3); or claim 1) with the proviso that any of the specific 10 Examples are individually disclaimed. For example, a further feature is any embodiment described herein (for example, embodiment (1), (2) or (3); or claim 1) with the proviso that any (for example any one, any two, or any three) of the compounds in the preceding table (for example BAA-015) are individually disclaimed.

[0575] In one embodiment, the BAA compound is provided according to any embodiment described 15 herein (for example, embodiment (1), (2) or (3); or claim 1) with the proviso that any other embodiment described herein is specifically disclaimed. Combinations

[0576] It is appreciated that certain features of the invention, which are, for clarity, described in the 20 context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination. All combinations of the embodiments pertaining to the chemical groups represented by the variables (e.g., Ring A, Ring B, etc.) are specifically embraced by the present invention and are disclosed herein just as if each and 25 every combination was individually and explicitly disclosed, to the extent that such combinations embrace compounds that are stable compounds (i.e., compounds that can be isolated, characterised, and tested for biological activity).

[0577] In this context, the skilled person will readily appreciate that certain combinations of groups (e.g., substituents) may give rise to compounds which may not be readily synthesized and / or are 30 chemically unstable. In addition, all sub-combinations of the chemical groups listed in the embodiments describing such variables are also specifically embraced by the present invention and are disclosed P-000059-WO-PCT-MYT - 82 - herein just as if each and every such sub-combination of chemical groups was individually and explicitly disclosed herein. Substantially Purified Forms 5

[0578] One aspect of the present invention pertains to BAA compounds, as described herein, in substantially purified form and / or in a form substantially free from contaminants.

[0579] In one embodiment, the substantially purified form is at least 50% by weight, e.g., at least 60% by weight, e.g., at least 70% by weight, e.g., at least 80% by weight, e.g., at least 90% by weight, e.g., at least 95% by weight, e.g., at least 97% by weight, e.g., at least 98% by weight, e.g., at least 99% by 10 weight.

[0580] Unless otherwise specified, the substantially purified form refers to the compound in any stereoisomeric or enantiomeric form. For example, in one embodiment, the substantially purified form refers to a mixture of stereoisomers, i.e., purified with respect to other compounds. In one embodiment, the substantially purified form refers to one stereoisomer, e.g., optically pure 15 stereoisomer. In one embodiment, the substantially purified form refers to a mixture of enantiomers. In one embodiment, the substantially purified form refers to an equimolar mixture of enantiomers (i.e., a racemic mixture, a racemate). In one embodiment, the substantially purified form refers to one enantiomer, e.g., optically pure enantiomer.

[0581] In one embodiment, the contaminants represent no more than 50% by weight, e.g., no more 20 than 40% by weight, e.g., no more than 30% by weight, e.g., no more than 20% by weight, e.g., no more than 10% by weight, e.g., no more than 5% by weight, e.g., no more than 3% by weight, e.g., no more than 2% by weight, e.g., no more than 1% by weight.

[0582] Unless specified, the contaminants refer to other compounds, that is, other than stereoisomers or enantiomers. In one embodiment, the contaminants refer to other compounds and other 25 stereoisomers. In one embodiment, the contaminants refer to other compounds and the other enantiomer.

[0583] In one embodiment, the substantially purified form is at least 60% optically pure (i.e., 60% of the compound, on a molar basis, is the desired stereoisomer or enantiomer, and 40% is the undesired stereoisomer or enantiomer), e.g., at least 70% optically pure, e.g., at least 80% optically pure, e.g., at 30 least 90% optically pure, e.g., at least 95% optically pure, e.g., at least 97% optically pure, e.g., at least 98% optically pure, e.g., at least 99% optically pure. Isomers

[0584] Certain compounds may exist in one or more particular geometric, optical, enantiomeric, 35 diastereoisomeric, epimeric, atropic, stereoisomeric, tautomeric, conformational, or anomeric forms, including but not limited to, cis- and trans-forms; E- and Z-forms; c-, t-, and r- forms; endo- and exo- forms; R-, S-, and meso-forms; D- and L-forms; d- and l-forms; (+) and (-) forms; keto-, enol-, and enolate-forms; syn- and anti-forms; synclinal- and anticlinal-forms; α- and β-forms; axial and equatorial P-000059-WO-PCT-MYT - 83 - forms; boat-, chair-, twist-, envelope-, and halfchair-forms; and combinations thereof, hereinafter collectively referred to as “isomers” (or “isomeric forms”).

[0585] A reference to a class of structures may well include structurally isomeric forms falling within that class (e.g., C1-6alkyl includes n-propyl and iso-propyl; butyl includes n-, iso-, sec-, and tert-butyl; methoxyphenyl includes ortho-, meta-, and para-methoxyphenyl). However, reference to a specific group or substitution pattern is not intended to include other structural (or constitutional isomers) which differ with respect to the connections between atoms rather than by positions in space. For example, a reference to a methoxy group, -OCH3, is not to be construed as a reference to its structural isomer, a hydroxymethyl group, -CH2OH. Similarly, a reference specifically to ortho-chlorophenyl is not to be construed as a reference to its structural isomer, meta-chlorophenyl.

[0586] The above exclusion does not pertain to tautomeric forms, for example, keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto / enol (illustrated below), imine / enamine, amide / imino alcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, N-nitroso / hydroxyazo, and nitro / aci-nitro. A reference herein to one tautomer is intended to encompass both tautomers. keto enol enolate

[0587] For example, 1H-pyridin-2-one-5-yl and 2-hydroxyl-pyridin-5-yl (shown below) are tautomers of one another. A reference herein to one is intended to encompass both. 1H-pyridin-2-one-5-yl2-hydroxyl-pyridin-5-yl

[0588] Note that specifically included in the term “isomer” are compounds with one or more isotopic substitutions. For example, H may be in any isotopic form, including1H,2H (D), and3H (T); C may be in any isotopic form, including12C,13C, and14C; O may be in any isotopic form, including16O and18O; and the like.

[0589] Unless otherwise specified, a reference to a particular compound includes all such isomeric forms, including mixtures (e.g., racemic mixtures) thereof. Methods for the preparation (e.g., asymmetric synthesis) and separation (e.g., fractional crystallisation and chromatographic means) of such isomeric forms are either known in the art or are readily obtained by adapting the methods taught herein, or known methods, in a known manner.

[0590] Unless otherwise specified, a reference to a particular compound includes all such isomeric forms, including mixtures (e.g., racemic mixtures) thereof. Methods for the preparation (e.g., asymmetric synthesis) and separation (e.g., fractional crystallisation and chromatographic means) of such isomeric forms are either known in the art or are readily obtained by adapting the methods taught herein, or known methods, in a known manner. P-000059-WO-PCT-MYT - 84 - Solid Forms

[0591] Compounds described in this specification may be conveniently prepared and handled in a range of solid forms. Solid forms may comprise salts, co-crystals (for example solvates, such as hydrates) in various amorphous or crystalline forms. Solid forms may also include mixtures of such forms (for example a mixture of salt and co-crystal forms, a salt which is also a co-crystal (for example a solvate of a salt), and a mixture of amorphous and polymorphic forms of a given compound, salt or co-crystal.

[0592] Unless otherwise specified, a reference to a particular compound also includes all solid forms of that compound, including all salts, co-crystals, solvates and hydrates thereof. Salts

[0593] It may be convenient or desirable to prepare, purify, and / or handle a corresponding salt of the compound, for example, a pharmaceutically acceptable salt. The term “salt” is used herein to refer to a solid complex comprising a first co-forming entity (e.g. a compound such as a BAA compound) and a second co-forming entity (e.g. a suitable Brønsted acid or base), where there is complete transfer of a proton from one entity to another. Examples of pharmaceutically acceptable salts are discussed in Berge et al., 1977, “Pharmaceutically Acceptable Salts,” J. Pharm. Sci., Vol.66, pp.1-19.

[0594] For example, if the compound is anionic, or has a functional group, which may be anionic (e.g., -COOH may be -COO-), then a salt may be formed with a suitable cation. Examples of suitable inorganic cations include, but are not limited to, alkali metal ions such as Na+and K+, alkaline earth cations such as Ca2+and Mg2+, and other cations such as Al3+as well as the ammonium ion (i.e., NH4+). Examples of suitable organic cations include, but are not limited to substituted ammonium ions (e.g., NH3R+, NH2R2+, NHR3+, NR4+), for example, where each R is independently linear or branched saturated C1-18alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-6alkyl, and phenyl-C1-6alkyl, wherein the phenyl group is optionally substituted. Examples of some suitable substituted ammonium ions are those derived from: ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as amino acids, such as lysine and arginine. An example of a common quaternary ammonium ion is N(CH3)4+.

[0595] If the compound is cationic, or has a functional group, which upon protonation may become cationic (e.g., -NH2 may become -NH3+), then a salt may be formed with a suitable anion.

[0596] For example, if a parent structure contains a cationic group (e.g., -NMe3+), or has a functional group, which upon protonation may become cationic (e.g., -NH2 may become -NH3+), then a salt may be formed with a suitable anion. In the case of a quaternary ammonium compound a counter-anion is generally always present in order to balance the positive charge. If, in addition to a cationic group (e.g., -NMe3+, -NH3+), the compound also contains a group capable of forming an anion (e.g., -COOH), then an inner salt (also referred to as a zwitterion) may be formed.

[0597] Examples of suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, nitric, nitrous, phosphoric, and phosphorous. P-000059-WO-PCT-MYT - 85 -

[0598] Examples of suitable organic anions include, but are not limited to, those derived from the following organic acids: 2-acetyloxybenzoic, acetic, trifluoroacetic, ascorbic, aspartic, benzoic, camphorsulfonic, cinnamic, citric, edetic, 1,2-ethanedisulfonic, ethanesulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, hydroxymaleic, hydroxynaphthalene carboxylic, isethionic, lactic, 5 lactobionic, lauric, maleic, malic, methanesulfonic, mucic, oleic, oxalic, palmitic, pamoic, pantothenic, phenylacetic, phenylsulfonic, propionic, pyruvic, salicylic, stearic, succinic, sulfanilic, tartaric, toluenesulfonic, and valeric. Examples of suitable polymeric organic anions include, but are not limited to, those derived from the following polymeric acids: tannic acid, carboxymethyl cellulose.

[0599] Examples of suitable counter-ions which are especially suitable for quaternary ammonium 10 compounds (e.g., those with a -NMe2+group) include 1-adamantanesulfonate, benzenesulfonate, bisulfate, bromide, chloride, iodide, methanesulfonate, methylsulfate, 1,5-napthalene-bis-sulfonate, 4-nitrobenzenesulfonate, formate, tartrate, tosylate, trifluoroacetate, trifluoromethylsulfonate, sulphate. Again, if the compound also contains a group capable of forming an anion (e.g., -COOH), then an inner salt may be formed. 15

[0600] Unless otherwise specified, a reference to a particular compound also includes salt forms thereof.

[0601] In one embodiment, the BAA compound is provided in the form of a salt.

[0602] In one embodiment, the BAA compound is provided in a neutral form (for example as a free acid, free base, or zwitterion). 20 Co-crystals, Solvates and Hydrates

[0603] It may be convenient or desirable to prepare, purify, and / or handle a corresponding co-crystal of the compound. The term “co-crystal” is used herein to refer to a solid complex comprising a first co- forming entity (e.g. a compound or salt of a compound, such as a BAA compound or a salt thereof) and a 25 second co-forming entity, where there is no complete transfer of a proton from one entity to another. If at least one co-forming entity is a liquid under standard conditions (e.g. under ambient conditions), the co-crystal may be referred to as a solvate. If at least one co-forming entity is water, the solvate may be conveniently referred to as a hydrate, for example, a mono-hydrate, a di-hydrate, a tri-hydrate, etc.

[0604] Unless otherwise specified, a reference to a particular compound also includes co-crystal, 30 solvate and hydrate forms thereof.

[0605] In one embodiment, the BAA compound is provided in the form of a co-crystal (for example a solvate, such as a hydrate). Chemically Protected Forms 35

[0606] It may be convenient or desirable to prepare, purify, and / or handle the compound in a chemically protected form. The term “chemically protected form” is used herein in the conventional chemical sense and pertains to a compound in which one or more reactive functional groups are protected from undesirable chemical reactions under specified conditions (e.g., pH, temperature, radiation, solvent, reactive chemical reagents, and the like). In practice, well-known chemical methods P-000059-WO-PCT-MYT - 86 - are employed to reversibly render unreactive a functional group, which otherwise would be reactive, under specified conditions. In a chemically protected form, one or more reactive functional groups are in the form of a protected or protecting group (alternatively as a masked or masking group or a blocked or blocking group). By protecting a reactive functional group, reactions involving other unprotected reactive functional groups can be performed, without affecting the protected group; the protecting group may be removed or the masking group transformed, usually in a subsequent step, without substantially affecting the remainder of the molecule. See, for example, Protective Groups in Organic Synthesis (T. Green and P. Wuts; 4th Edition; John Wiley and Sons, 2006).

[0607] A wide variety of such “protecting,” “blocking,” or “masking” methods are widely used and well known in organic synthesis. For example, a compound which has two non-equivalent reactive functional groups, both of which would be reactive under specified conditions, may be derivatized to render one of the functional groups “protected,” and therefore unreactive, under the specified conditions; so protected, the compound may be used as a reactant which has effectively only one reactive functional group. After the desired reaction (involving the other functional group) is complete, the protected group may be “deprotected” to return it to its original functionality.

[0608] For example, a hydroxy group may be protected as an ether (-OR) or an ester (-OC(=O)R), for example, as: a t-butyl ether; a benzyl, benzhydryl (diphenylmethyl), or trityl (triphenylmethyl) ether; a trimethylsilyl or t-butyldimethylsilyl ether; or an acetyl ester (-OC(=O)CH3, -OAc).

[0609] For example, an aldehyde or ketone group may be protected as an acetal (R-CH(OR)2) or ketal (R2C(OR)2), respectively, in which the carbonyl group (>C=O) is converted to a 1,1-diether (>C(OR)2), by reaction with, for example, a primary alcohol in the presence of an acid. The aldehyde or ketone group is readily regenerated, for example, by hydrolysis using water in the presence of acid.

[0610] For example, an amine group may be protected, for example, as an amide (-NRCO-R), for example: as an acetamide (-NHCO-CH3); or as a carbamate (-NRCO-OR), for example: as a benzyloxy carbamate (-NHCO-OCH2C6H5, -NH-Cbz), as a t-butoxy carbamate (-NHCO-OC(CH3)3, -NH-Boc); as a 2- biphenyl-2-propoxy carbamate (-NHCO-OC(CH3)2C6H4C6H5, -NH-Bpoc), as a 9-fluorenylmethoxy carbamate (-NH-Fmoc), as a 6-nitroveratryloxy carbamate (-NH-Nvoc), as a 2-trimethylsilylethyloxy carbamate (-NH-Teoc), a 2,2,2-trichloroethyloxy carbamate (-NH-Troc), as an allyloxy amide (-NH-Alloc), or as a 2(-phenylsulfonyl)ethyloxy carbamate (-NH-Psec); or, in suitable cases (e.g., cyclic amines), as a nitroxide radical (>N-O●); or, in suitable cases (e.g., heterocyclic nitrogens), as a 2- trimethylsilylethoxymethyl (N-SEM).

[0611] For example, a carboxylic acid group may be protected as an ester for example, as: an C1-7alkyl ester (e.g., a methyl ester; a t-butyl ester); a C1-7haloalkyl ester (e.g., a 2,2,2-trihaloethyl ester); a 2- tri(C1-7alkyl)silyl-ethyl ester; or a C5-20aryl-C1-7alkyl ester (e.g., a benzyl ester; a nitrobenzyl ester); or as an amide or hydrazide, for example, as acetamide or a N,N,N’-trimethylhydrazide.

[0612] For example, a thiol group may be protected as a thioether (-SR), for example, as: a benzyl thioether; an acetamidomethyl ether (-S-CH2NHC(=O)CH3). P-000059-WO-PCT-MYT - 87 -

[0613] It may be convenient or desirable to prepare, purify, and / or handle the compound in the form of a prodrug. The term “prodrug,” as used herein, pertains to a compound, which yields the desired active compound in vivo. Typically, the prodrug is inactive, or less active than the desired active 5 compound, but may provide advantageous handling, administration, or metabolic properties.

[0614] Generally prodrugs are metabolic precursors of the active compound, and are activated enzymatically to yield the active compound, or a compound, which, upon further chemical reaction, yields the active compound . 10

[0615] Also described herein is a composition (e.g., a pharmaceutical composition) comprising a BAA compound, as described herein, and a pharmaceutically acceptable excipient (for example a carrier and / or diluent).

[0616] Also described herein is a method of preparing a composition (e.g., a pharmaceutical 15 composition) comprising the step of mixing a BAA compound, as described herein, and a pharmaceutically acceptable excipient (for example a carrier and / or diluent). Uses

[0617] The BAA compounds, as described herein, inhibit PKMYT1 (e.g., inhibit or reduce or block the 20 activity or function of PKMYT1).

[0618] Accordingly, the BAA compounds, as described herein, as well as compositions (e.g., pharmaceutical compositions) comprising them, are useful, for example, in the treatment of disorders (e.g., diseases) that are ameliorated by the inhibition of PKMYT1 (e.g., by the inhibition or reduction or blockage of the activity or function of PKMYT1). 25 Use in Methods of Inhibiting PKMYT1

[0619] Also described herein is a method of inhibiting PKMYT1 (e.g., inhibiting or reducing or blocking the activity or function of PKMYT1), in vitro or in vivo, comprising contacting the PKMYT1 with an effective amount of a BAA compound, as described herein. 30

[0620] Also described herein is a method of inhibiting PKMYT1 (e.g., inhibiting or reducing or blocking the activity or function of PKMYT1) in a cell, in vitro or in vivo, comprising contacting the cell with an effective amount of a BAA compound, as described herein.

[0621] In one embodiment, the method is performed in vitro.

[0622] In one embodiment, the method is performed in vivo. 35

[0623] In one embodiment, the BAA compound is provided in the form of a pharmaceutically acceptable composition.

[0624] One of ordinary skill in the art is readily able to determine whether or not a candidate compound inhibits PKMYT1 (e.g., inhibits or reduces or blocks the activity or function of PKMYT1). For example, suitable assays are described herein and / or are known in the art. P-000059-WO-PCT-MYT - 88 -

[0625] One of ordinary skill in the art is readily able to determine whether or not a candidate compound inhibits PKMYT1 (e.g., inhibits or reduces or blocks or the activity or function of PKMYT1) in a cell. For example, a sample of cells may be grown in vitro and a compound brought into contact with said cells, and the effect of the compound on those cells observed. As an example of “effect,” the 5 morphological status of the cells (e.g., alive or dead, etc.) may be determined. Where the compound is found to exert an influence on the cells, this may be used as a prognostic or diagnostic marker of the efficacy of the compound in methods of treating a subject (e.g., patient) carrying cells of the same cellular type. As another example of “effect,” the direct interaction of the compound with the target in cells could be measured (e.g., “target engagement assay”) using, e.g., a colorimetric, fluorescent, or 10 luminescent readout. Use in Methods of Inhibiting Cell Proliferation, etc.

[0626] The BAA compounds described herein may e.g., (a) regulate (e.g., inhibit) cell proliferation; (b) inhibit cell cycle progression; (c) promote apoptosis; (d) reduce clonogenicity; (e) reduce 15 tumoursphere growth or self-renewal; (f) enhance impact of DNA-damaging agents on cell killing; or (g) a combination of one or more of these.

[0627] Accordingly, also described herein is a method of regulating (e.g., inhibiting) cell proliferation (e.g., proliferation of a cell), inhibiting cell cycle progression, promoting apoptosis, reducing clonogenicity, reducing tumoursphere growth or self-renewal, or a combination of one or more these, in 20 vitro or in vivo, comprising contacting a cell with an effective amount of a BAA compound, as described herein.

[0628] In one embodiment, the method is performed in vitro.

[0629] In one embodiment, the method is performed in vivo.

[0630] In one embodiment, the BAA compound is provided in the form of a pharmaceutically 25 acceptable composition.

[0631] Any type of cell may be treated or targeted, including for example blood (including, e.g., neutrophils, eosinophils, basophils, lymphocytes, monocytes, erythrocytes, thrombocytes), lung, gastrointestinal (including, e.g., bowel, colon), breast (mammary), ovarian, prostate, liver (hepatic), kidney (renal), bladder, pancreas, brain, and skin cells. 30

[0632] One of ordinary skill in the art is readily able to determine whether or not a candidate compound regulates (e.g., inhibits) cell proliferation, etc. For example, assays which may conveniently be used to assess the activity offered by a particular compound are described herein and / or are known in the art.

[0633] The BAA compounds described herein may inhibit cell migration and invasion, e.g., inhibit 35 metastasis.

[0634] The BAA compounds described herein may restore sensitivity to another agent in a resistant cell population.

[0635] The BAA compounds described herein may prevent emergence of resistance to another agent in a cell population. P-000059-WO-PCT-MYT - 89 -

[0636] The BAA compounds described herein may enhance the impact of other agents on DNA damage and subsequent cell killing. Such agents can be therapeutic compounds generating DNA damage or interfering with DNA damage response. 5 Use in Methods of Therapy

[0637] Also described herein is a BAA compound, as described herein, for use in a method of treatment of the human or animal body by therapy, for example, for use in a method of treatment of a disorder (e.g., a disease) as described herein.

[0638] Also described herein is use of a BAA compound, as described herein, in a method of treatment 10 of the human or animal body by therapy, for example, in a method of treatment of a disorder (e.g., a disease) as described herein. Use in the Manufacture of Medicaments

[0639] Also described herein is use of a BAA compound, as described herein, in the manufacture of a 15 medicament, for example, for use in a method of treatment, for example, for use in a method of treatment of a disorder (e.g., a disease) as described herein.

[0640] In one embodiment, the medicament comprises the BAA compound. Methods of Treatment 20

[0641] Also described herein is a method of treatment, for example, a method of treatment of a disorder (e.g., a disease) as described herein, comprising administering to a subject in need of treatment a therapeutically effective amount of a BAA compound, as described herein, optionally in the form of a pharmaceutical composition. 25 Disorders Treated - Disorders Ameliorated by the Inhibition of PKMYT1

[0642] In one embodiment (e.g., of compounds for use in methods of therapy, of use in methods of therapy, of use in the manufacture of medicaments, of methods of treatment), the treatment is treatment of a disorder (e.g., a disease) that is ameliorated by the inhibition of PKMYT1 (e.g., by the inhibition or reduction or blockage of the activity or function of PKMYT1). 30 Disorders Treated

[0643] In one embodiment (e.g., of compounds for use in methods of therapy, of use in methods of therapy, of use in the manufacture of medicaments, of methods of treatment), the treatment is treatment of a disorder (e.g., a disease), for example, a proliferative disorder, cancer, etc., as described 35 herein. Proliferative Disorders

[0644] In one embodiment, the disorder is: a proliferative disorder. P-000059-WO-PCT-MYT - 90 -

[0645] The term “proliferative disorder,” as used herein, pertains to an unwanted or uncontrolled cellular proliferation of excessive or abnormal cells which is undesired, such as neoplastic or hyperplastic growth.

[0646] In one embodiment, the proliferative disorder is characterised by benign, pre-malignant, 5 malignant, pre-metastatic, metastatic, or non-metastatic cellular proliferation, including for example: neoplasms, hyperplasias, tumours (e.g., histocytoma, glioma, astrocytoma, osteoma), cancers, psoriasis, bone diseases, fibroproliferative disorders (e.g., of connective tissues), pulmonary fibrosis, atherosclerosis, and smooth muscle cell proliferation in the blood vessels, such as stenosis or restenosis following angioplasty. 10 Disorders Treated - Proliferative Disorders

[0647] In one embodiment (e.g., for use in methods of therapy, of use in the manufacture of medicaments, of methods of treatment), the treatment is treatment of a proliferative disorder.

[0648] The term “proliferative disorder,” as used herein, pertains to an unwanted or uncontrolled 15 cellular proliferation of excessive or abnormal cells which is undesired, such as neoplastic or hyperplastic growth.

[0649] In one embodiment, the treatment is treatment of: a proliferative disorder characterised by benign, pre-malignant, or malignant cellular proliferation.

[0650] In one embodiment, the treatment is treatment of a proliferative disorder characterised by, or 20 further characterised by: inappropriate activity and / or expression of PKMYT1, CCNE1, FBXW7, PP2A or one of its subunits, or concomitant mutation of p53 and CDKN2A.

[0651] In one embodiment, the treatment is treatment of a proliferative disorder characterised by, or further characterised by: overexpression of PKMYT1 or CCNE1.

[0652] In one embodiment, the treatment is treatment of a proliferative disorder characterised by, or 25 further characterised by overexpression of PKMYT1.

[0653] In one embodiment, the treatment is treatment of a proliferative disorder characterised by, or further characterised by overexpression of CCNE1.

[0654] In one embodiment, the treatment is treatment of a proliferative disorder characterised by, or further characterised by: inactivation, decreased activity, or decreased expression of FBXW7, PPP2R2A 30 or PPP2R1A.

[0655] In one embodiment, the treatment is treatment of a proliferative disorder characterised by, or further characterised by inactivation of FBXW7.

[0656] In one embodiment, the treatment is treatment of a proliferative disorder characterised by, or further characterised by decreased activity or decreased expression of PPP2R2A or PPP2R1A. 35

[0657] In one embodiment, the treatment is treatment of a proliferative disorder characterised by, or further characterised by concomitant mutation of p53 and CDKN2A.

[0658] In one embodiment, the treatment is treatment of cancer. P-000059-WO-PCT-MYT - 91 - Disorders Treated - Cancer

[0659] In one embodiment (e.g., of use in methods of therapy, of use in the manufacture of medicaments, of methods of treatment), the treatment is treatment of cancer. Included among cancers are: 5

[0660] (1) Carcinomas, including tumours derived from stratified squamous epithelia (squamous cell carcinomas) and tumours arising within organs or glands (adenocarcinomas). Examples include breast, colon, lung, prostate, ovary.

[0661] (2) Sarcomas, including: osteosarcoma and osteogenic sarcoma (bone); chondrosarcoma (cartilage); leiomyosarcoma (smooth muscle); rhabdomyosarcoma (skeletal muscle); mesothelial 10 sarcoma and mesothelioma (membranous lining of body cavities); fibrosarcoma (fibrous tissue); angiosarcoma and haemangioendothelioma (blood vessels); liposarcoma (adipose tissue); glioma and astrocytoma (neurogenic connective tissue found in the brain); myxosarcoma (primitive embryonic connective tissue); mesenchymous and mixed mesodermal tumour (mixed connective tissue types).

[0662] (3) Myeloma. 15

[0663] (4) Haematopoietic tumours, including: myelogenous and granulocytic leukaemia (malignancy of the myeloid and granulocytic white blood cell series), e.g., chronic myeloid leukemia (CML), acute myeloid leukemia (AML); lymphatic, lymphocytic, and lymphoblastic leukaemia (malignancy of the lymphoid and lymphocytic blood cell series), e.g., acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL); polycythaemia vera (malignancy of various blood cell products, but with red 20 cells predominating).

[0664] (5) Lymphomas, including: Hodgkin and Non-Hodgkin lymphomas.

[0665] (6) Mixed Types, including, e.g., adenosquamous carcinoma; mixed mesodermal tumour; carcinosarcoma; teratocarcinoma.

[0666] In one embodiment, the cancer is: 25 a bone or muscle sarcoma, for example: bone cancer; bone sarcoma; chondrosarcoma; Ewing’s sarcoma; heart cancer; leiomyosarcoma; malignant fibrous histiocytoma of bone; osteosarcoma; or rhabdomyosarcoma; a brain and nervous system cancer, for example: astrocytoma; brain cancer; brainstem glioma; cerebellar astrocytoma; cerebral astrocytoma; 30 ependymoma; glioblastoma; glioma; medulloblastoma; neuroblastoma; oligodendroglioma; pilocytic astrocytoma; pineal astrocytoma; pituitary adenoma; primitive neuroectodermal tumor; schwannoma; or visual pathway and hypothalamic glioma; a breast cancer, for example: breast cancer; invasive cribriform carcinoma; inflammatory breast cancer; invasive lobular carcinoma; medullary carcinoma; male breast cancer; phyllodes tumor; or 35 tubular carcinoma; an endocrine system cancer, for example: adrenal gland cancer; adrenocortical carcinoma; papillary thyroid cancer; follicular thyroid cancer; islet cell carcinoma; multiple endocrine neoplasia syndrome; parathyroid cancer; pheochromocytoma; thyroid cancer; or thyroid gland cancer; an eye cancer, for example: retinoblastoma; or uveal melanoma; P-000059-WO-PCT-MYT - 92 - a gastrointestinal cancer, for example: anal cancer; appendix cancer; biliary tract cancer; bowel cancer; cholangiocarcinoma; colon adenocarcinoma; colon adenoma; colon cancer; exocrine pancreatic carcinoma; extrahepatic bile duct cancer; gallbladder cancer; gastric (stomach) cancer; gastrointestinal cancer; gastrointestinal carcinoid 5 tumor; gastrointestinal carcinoid tumor; gastrointestinal stromal tumor (GIST); hepatocellular cancer; hepatoblastoma; kidney cancer; large bowel cancer; liver cancer; colorectal cancer; pancreatic cancer; rectal cancer; or small bowel cancer; a genitourinary or gynecologic cancer, for example: bladder cancer; cervical cancer; endometrial cancer; extragonadal germ cell tumor; genito-urinary cancer; gestational trophoblastic tumor; 10 gynaecological cancer; ovarian cancer; ovarian epithelial cancer; ovarian germ cell tumor; penile cancer; prostate cancer; renal cell carcinoma; renal pelvis and ureter, transitional cell cancer; seminoma; teratocarcinoma; testicular cancer; transitional cell cancer of the ureter and renal pelvis; urethral cancer; uterine sarcoma; vaginal cancer; vulvar cancer; or Wilms tumor; a cancer of the head or neck, for example: esophageal cancer; head and neck cancer; head and 15 neck squamous cell carcinoma; hypopharyngeal cancer; nasopharyngeal cancer; nasopharyngeal carcinoma; oral cancer; oropharyngeal cancer; paranasal sinus and nasal cavity cancer; pharyngeal cancer; or salivary gland cancer; a hematopoietic cancer, for example: a plasma cell neoplasm, for example, plasmacytoma or multiple myeloma; 20 a leukemia, for example: acute biphenotypic leukemia; acute eosinophilic leukemia; acute lymphoblastic leukemia; acute myeloid dendritic cell leukemia; acute myeloid leukemia; acute promyelocytic leukemia; B-cell prolymphocytic leukemia; chronic lymphocytic leukemia; chronic myelogenous leukemia; hairy cell leukemia; large granular lymphocytic leukemia; mast cell leukemia; precursor B lymphoblastic leukemia; T-cell prolymphocytic leukemia; 25 a lymphoma, for example: AIDS-related lymphoma; anaplastic large cell lymphoma; angioimmunoblastic T-cell lymphoma; Burkitt's lymphoma; cutaneous T-cell lymphoma; diffuse large B- cell lymphoma; follicular lymphoma; hepatosplenic T-cell lymphoma; Hodgkin's lymphoma; intravascular large B-cell lymphoma; lymphomatoid granulomatosis; lymphoplasmacytic lymphoma; mantle cell lymphoma; marginal zone B-cell lymphoma; mediastinal large B cell lymphoma; mucosa-associated 30 lymphoid tissue lymphoma; mycosis fungoides; nodal marginal zone B cell lymphoma; non-Hodgkin lymphoma; plasmablastic lymphoma; primary central nervous system lymphoma; primary cutaneous follicular lymphoma; primary cutaneous immunocytoma; primary effusion lymphoma; Sézary syndrome; or splenic marginal zone lymphoma; or a myelodysplastic syndrome; 35 a skin cancer, for example: basal cell carcinoma; dermatofibrosarcoma protuberans; fibrosarcoma; keratoacanthoma; malignant melanoma; melanoma; Merkel cell carcinoma; sebaceous carcinoma; or squamous cell carcinoma; a thoracic and respiratory cancer, for example: adenocarcinoma; bronchial adenoma; bronchial carcinoid; laryngeal cancer; lung cancer; mediastinum cancer; mesothelioma; non-small cell lung cancer; P-000059-WO-PCT-MYT - 93 - peritoneal cancer; pleuropulmonary blastoma; small cell lung cancer; thymic carcinoma; or thymoma carcinoma; an HIV / AIDS related cancer, for example, Kaposi sarcoma; or other cancer, for example, epithelioid hemangioendothelioma; desmoplastic small round cell 5 tumor; or liposarcoma.

[0667] In one embodiment, the cancer is: endometrial cancer, uterine cancer, ovarian cancer, breast cancer, gastric cancer, bladder cancer, pancreatic cancer, mesothelioma, kidney cancer, stomach cancer, esophageal cancer, colorectal cancer, glioblastoma, lung cancer, or lung squamous cell carcinoma. 10

[0668] In one embodiment, the cancer is endometrial cancer.

[0669] In one embodiment, the cancer is uterine cancer.

[0670] In one embodiment, the cancer is ovarian cancer.

[0671] In one embodiment, the cancer is breast cancer.

[0672] In one embodiment, the cancer is gastric cancer. 15

[0673] In one embodiment, the cancer is bladder cancer.

[0674] In one embodiment, the cancer is pancreatic cancer.

[0675] In one embodiment, the cancer is mesothelioma.

[0676] In one embodiment, the cancer is kidney cancer.

[0677] In one embodiment, the cancer is stomach cancer. 20

[0678] In one embodiment, the cancer is esophageal cancer.

[0679] In one embodiment, the cancer is colorectal cancer.

[0680] In one embodiment, the cancer is glioblastoma.

[0681] In one embodiment, the cancer is lung cancer.

[0682] In one embodiment, the cancer is lung squamous cell carcinoma. 25

[0683] In one embodiment, the cancer is characterised by, or further characterised by inappropriate activity (e.g., overexpression) of PKMYT1. For example, in one embodiment, the cancer is: lung squamous cell carcinoma, lung adenocarcinoma, uterine corpus endometrial carcinoma, breast cancer, breast invasive carcinoma, hepatocellular carcinoma, clear-cell renal-cell carcinoma, kidney chromophobe cancer, renal papillary cell carcinoma, head and neck squamous cell carcinoma, 30 colon adenocarcinoma, stomach adenocarcinoma, thyroid carcinoma, prostate adenocarcinoma, adrenocortical carcinoma, lower grade glioma, mesothelioma, pancreatic adenocarcinoma, skin cutaneous melanoma, uveal melanoma.

[0684] In one embodiment, the cancer is characterised by, or further characterised by involvement of PKMYT1 in progression, invasion and / or metastasis. For example, in one embodiment, the cancer is: 35 non-small cell lung cancer, osteosarcoma, clear cell renal cell carcinoma, oral squamous cell carcinoma, gastric cancer, prostate cancer, oesophageal squamous cell carcinoma, colorectal cancer, hepatocellular carcinoma, ovarian cancer, neuroblastoma (in particular, with MYCN amplification), glioblastoma, acute lymphoblastic leukemia, multiple myeloma, Kaposi’s sarcoma, primary effusion lymphoma (PEL), or the plasmablastic variant of multicentric Castleman’s disease. P-000059-WO-PCT-MYT - 94 -

[0685] In one embodiment, the cancer is characterised by, or further characterised by inappropriate activity (e.g., overexpression) of CCNE1. For example, in one embodiment, the cancer is: uterine carcinosarcoma, uterine cancer, endometrial cancer, breast cancer, ovarian cancer, stomach cancer, colorectal cancer, bladder cancer, oesophageal cancer, cervical cancer, sarcoma, lung 5 squamous cancer, adenoid cystic carcinoma, pancreatic cancer, mesothelioma, lung adenocarcinoma, head & neck cancer, diffuse large B-cells lymphoma, or liver cancer.

[0686] In one embodiment, the cancer is characterised by, or further characterised by inappropriate activity (e.g., overexpression) of CCNE1. For example, in one embodiment, the cancer is: uterine carcinosarcoma, uterine cancer, endometrial cancer, breast cancer, ovarian cancer, 10 stomach cancer, colorectal cancer, bladder cancer, oesophageal cancer, cervical cancer, sarcoma, or lung squamous cancer.

[0687] In one embodiment, the cancer is uterine carcinosarcoma (UCS) or uterine serous carcinoma (USC).

[0688] In one embodiment, the cancer is high-grade serous ovarian carcinoma (HGSOC). 15

[0689] In one embodiment, the cancer is high-grade serous ovarian cancer with CCNE1 amplification.

[0690] In one embodiment, the cancer is triple-negative breast cancer (TNBC).

[0691] In one embodiment, the cancer is characterised by, or further characterised by inappropriate activity (e.g., inactivation) of FBXW7. For example, in one embodiment, the cancer is: uterine carcinosarcoma, uterine cancer, endometrial cancer, breast cancer, ovarian cancer, 20 stomach cancer, colorectal cancer, bladder cancer, oesophageal cancer, cervical cancer, sarcoma, lung squamous cancer, or head & neck cancer.

[0692] In one embodiment, the cancer is characterised by, or further characterised by inappropriate activity (e.g., inactivation) of FBXW7. For example, in one embodiment, the cancer is: uterine carcinosarcoma, endometrial cancer, colorectal cancer, cervical cancer, bladder cancer, 25 head & neck cancer, gastric cancer, or lung squamous cells carcinoma.

[0693] In one embodiment, the cancer is uterine carcinosarcoma (UCS) or uterine serous carcinoma (USC).

[0694] In one embodiment, the cancer is characterised by, or further characterised by inappropriate activity (e.g., inactivation, decreased activity, decreased expression) of PPP2R2A or PPP2R1A. For 30 example, in one embodiment, the cancer is: prostate adenocarcinoma, ovarian serous cystadenocarcinoma, rectum adenocarcinoma, bladder urothelial carcinoma, colorectal adenocarcinoma, breast invasive carcinoma, uterine corpus endometrial carcinoma, uterine carcinosarcoma, liver hepatocellular carcinoma, lung squamous cell carcinoma, or lung adenocarcinoma. 35

[0695] In one embodiment, the cancer (e.g., as above) is characterised, or further characterised, as treatment resistant cancer, e.g., chemotherapy-resistant cancer, radiotherapy-resistant cancer, and / or immunotherapy-resistant cancer.

[0696] In one embodiment, the treatment resistant cancer is resistant to standard of care therapy. P-000059-WO-PCT-MYT - 95 -

[0697] In one embodiment, the treatment resistant cancer is resistant to one or more of PARP inhibitors, cisplatin, WEE1 inhibitors and Cdk4 / 6 inhibitors.

[0698] In one embodiment, the treatment resistant cancer is recombination proficient ovarian cancer.

[0699] In one embodiment, the treatment resistant cancer is HER2- ER+ breast cancer with Cdk4 / 6 5 resistance.

[0700] In one embodiment, the treatment resistant cancer is CDK4 / 6 inhibitor resistant TP53 mutant ER+ breast cancer.

[0701] In one embodiment, the cancer (e.g., as above) is characterised, or further characterised, as metastatic cancer. 10

[0702] The anti-cancer effect may arise through one or more mechanisms, including but not limited to, the regulation of cell proliferation, the modulation of cell cycle progression, the inhibition of angiogenesis (the formation of new blood vessels), the inhibition of metastasis (the spread of a tumour from its origin), the inhibition of cell migration (the spread of cancer cells to other parts of the body), the inhibition of invasion (the spread of tumour cells into neighbouring normal structures), the 15 promotion of apoptosis (programmed cell death), death by necrosis, or induction of death by autophagy. The compounds described herein may be used in the treatment of the cancers described herein, independent of the mechanisms discussed herein. Treatment 20

[0703] The term “treatment,” as used herein in the context of treating a disorder (e.g., disease), pertains generally to treatment of a human or an animal (e.g., in veterinary applications), in which some desired therapeutic effect is achieved, for example, the inhibition of the progress of the disorder (including, e.g., a reduction in the rate of progress, a halt in the rate of progress), alleviation of symptoms of the disorder, amelioration of the disorder, and cure of the disorder. Treatment as a 25 prophylactic measure (i.e., prophylaxis) is also included. For example, use with subjects (e.g., patients) who have not yet developed the disorder, but who are at risk of developing the disorder, is encompassed by the term “treatment.”

[0704] For example, treatment of cancer includes reducing the progress of cancer, alleviating the symptoms of cancer, reducing the incidence of cancer, prophylaxis of cancer, etc. 30

[0705] The term “therapeutically effective amount,” as used herein, pertains to that amount of a compound, or a material, composition, or dosage form comprising a compound, which is effective for producing some desired therapeutic effect, commensurate with a reasonable benefit / risk ratio, when administered in accordance with a desired treatment regimen. 35 Combination Therapies

[0706] The term “treatment” as used herein includes combination treatments and therapies, in which two or more treatments or therapies are combined, for example, sequentially or simultaneously. For example, the PKMYT1 inhibitors and BAA compounds described herein may also be used in combination therapies, e.g., in conjunction with other agents. P-000059-WO-PCT-MYT - 96 -

[0707] Accordingly, described herein is a PKMYT1 inhibitor (for example RP-6306, or a BAA compound as described herein), wherein the PKMYT1 inhibitor is administered in combination with one or more (e.g., 1, 2, 3, 4, etc.) additional therapeutic agents (for example, anti-cancer agents).

[0708] It is to be understood when an additional therapeutic agent is described by its class (for example 5 as a “topoisomerase I inhibitor”, “topoisomerase II inhibitor”, “antimetabolite”, or other class of compound is mentioned herein in a general sense), this class includes all compounds demonstrating the required activity. For example, any mention of “topoisomerase I inhibitor”, “topoisomerase II inhibitor”, or “antimetabolite” includes for example small molecule or biologic compounds possessing the required activities, including antibody-drug conjugates. 10

[0709] For example, also described herein is a PKMYT1 inhibitor (for example RP-6306, or a BAA compound as described herein), for use in a method of treatment of the human or animal body by therapy, for example, for use in a method of treatment of a disorder (e.g., a disease) as described herein, wherein the PKMYT1 inhibitor is administered in combination with one or more (e.g., 1, 2, 3, 4, etc.) additional therapeutic agents. 15

[0710] Also described herein is use of a PKMYT1 inhibitor (for example RP-6306, or a BAA compound as described herein), in a method of treatment of the human or animal body by therapy, for example, in a method of treatment of a disorder (e.g., a disease) as described herein, wherein the PKMYT1 inhibitor is administered in combination with one or more (e.g., 1, 2, 3, 4, etc.) additional therapeutic agents.

[0711] Also described herein is use of a PKMYT1 inhibitor (for example RP-6306, or a BAA compound as 20 described herein), in a method of treatment of the human or animal body by therapy, for example, in a method of treatment of a disorder (e.g., a disease) as described herein, wherein the PKMYT1 inhibitor is administered in combination with one or more (e.g., 1, 2, 3, 4, etc.) additional therapeutic agents.

[0712] Also described herein is a method of treatment, for example, a method of treatment of a disorder (e.g., a disease) as described herein, comprising administering to a subject in need of treatment 25 a therapeutically effective amount of a PKMYT1 inhibitor, for example as described herein, optionally in the form of a pharmaceutical composition, wherein the PKMYT1 inhibitor is administered in combination with one or more (e.g., 1, 2, 3, 4, etc.) additional therapeutic agents.

[0713] Also described herein is a BAA compound, as described herein, wherein the BAA compound is administered in combination with one or more (e.g., 1, 2, 3, 4, etc.) additional therapeutic agents (for 30 example, anti-cancer agents).

[0714] For example, also described herein is a BAA compound, as described herein, for use in a method of treatment of the human or animal body by therapy, for example, for use in a method of treatment of a disorder (e.g., a disease) as described herein, wherein the BAA compound is administered in combination with one or more (e.g., 1, 2, 3, 4, etc.) additional therapeutic agents. 35

[0715] Also described herein is use of a BAA compound, as described herein, in a method of treatment of the human or animal body by therapy, for example, in a method of treatment of a disorder (e.g., a disease) as described herein, wherein the BAA compound is administered in combination with one or more (e.g., 1, 2, 3, 4, etc.) additional therapeutic agents. P-000059-WO-PCT-MYT - 97 -

[0716] Also described herein is use of a BAA compound, as described herein, in a method of treatment of the human or animal body by therapy, for example, in a method of treatment of a disorder (e.g., a disease) as described herein, wherein the BAA compound is administered in combination with one or more (e.g., 1, 2, 3, 4, etc.) additional therapeutic agents. 5

[0717] Also described herein is use of a BAA compound, as described herein, in the manufacture of a medicament, for example, for use in a method of treatment, for example, for use in a method of treatment of a disorder (e.g., a disease) as described herein, wherein the BAA compound is administered in combination with one or more (e.g., 1, 2, 3, 4, etc.) additional therapeutic agents. In one embodiment, the medicament comprises the BAA compound. 10

[0718] Also described herein is a method of treatment, for example, a method of treatment of a disorder (e.g., a disease) as described herein, comprising administering to a subject in need of treatment a therapeutically effective amount of a BAA compound, as described herein, optionally in the form of a pharmaceutical composition, wherein the BAA compound is administered in combination with one or more (e.g., 1, 2, 3, 4, etc.) additional therapeutic agents. 15

[0719] The particular combination would be at the discretion of the physician who would select dosages using their common general knowledge and dosing regimens known to a skilled practitioner.

[0720] The agents (e.g., the PKMYT1 inhibitors or BAA compounds as described herein, plus one or more other agents) may be administered simultaneously or sequentially, and may be administered in individually varying dose schedules and via different routes. For example, when administered 20 sequentially, the agents can be administered at closely spaced intervals (e.g., over a period of 5-10 minutes) or at longer intervals (e.g., 1, 2, 3, 4 or more hours apart, or even longer periods apart wherein required), the precise dosage regimen being commensurate with the properties of the therapeutic agent(s).

[0721] The agents (e.g., PKMYT1 inhibitors or the BAA compounds described here, plus one or more 25 other agents) may be formulated together in a single dosage form, or alternatively, the individual agents may be formulated separately, and optionally may be presented together in the form of a kit, optionally with instructions for their use.

[0722] In one embodiment, the other agent (e.g., the additional therapeutic agent, for example the additional anti-cancer agent) is an immunotherapy agent, such as a monoclonal antibody (for example 30 trastuzumab, bevacizumab, cetuximab, daratumumab, or naxitamab, necitumumab, obinutuzumab, ofatumumab, panitumumab, pertuzumab, ramucirumab, or rituximab), a bispecific antibody (for example blinatumomab), an immune checkpoint inhibitor (for example ipilimumab, nivolumab, pembrolizumab, cemiplimab, atezolizumab, durvalumab, avelumab, dostarlimab, or tremelimumab), an immunomodulator (for example imiquimod, thalidomide, lenalidomide, or ponalidomide), a cytokine 35 such as an interleukin (for example IL-2 aldesleukin), an interferon (for example IFNa), an oncolytic virus (for example talimogene laherparepvec), or a T-cell therapy.

[0723] In one embodiment, the other agent is an antibody-drug conjugate (i.e. an “ADC”, for example brentuximab vedotin, inotuzumab ozogamicin, mirvetuximab exatecan, mirvetuximab soravtansine, trastuzumab deruxtecan, trastuzumab emtansine, gemtuzumab ozogamicin, enfortumab vedotin, P-000059-WO-PCT-MYT - 98 - polatuzumab vedotin, tisotumab vedotin, sacituzumab govitecan, loncastuximab tesirine, cetuximab sarotalocan, belantamab mafodotin, moxetumomab pasudotox or distamab vedotin).

[0724] In one embodiment, the other agent is an antibody-drug conjugate, wherein the antibody-drug conjugate (or the antibody, or the antibody portion of the antibody-drug conjugate) targets HER2, 5 TROP2, Claudin 18.2, B7H3, EGFR, FOLR1 (FRa), CD22, MET, Nectin 4, CD19, B7-H4, CD276, CD33, CD70, CDH6, CEACAM5, GPR20, HER3, TACSTD2, CD79b, tissue factor (TF), CD19, BCMA, CD30, VTCN1, 5T4, AXL, CD166, dipeptidase-3, Lewis-Y, mesothelin, NAPi2b, TIM1, SEZ6, CD123, DLL3, PDL1, MUC1, PTK7, MUC18, or LIV-1.

[0725] In one embodiment, the other agent is an antibody-drug conjugate, wherein the antibody-drug 10 conjugate (or the antibody, or the antibody portion of the antibody-drug conjugate) targets FOLR1 (FRa), HER2, TROP2, mesothelin, NAPi2b, CDH6, B7-H4, B7-H3, 5T4, AXL, CD166, dipeptidase-3, Lewis-Y, TIM1, or tissue factor (TF).

[0726] In one embodiment, the other agent is an antibody-drug conjugate, wherein the antibody-drug conjugate (or the antibody, or the antibody portion of the antibody-drug conjugate) targets FOLR1 (FRa), 15 CDH6, B7-H4, B7-H3, or CEACAM5.

[0727] In one embodiment, the other agent is an antibody-drug conjugate useful in the treatment of ovarian cancer, for example an antibody-drug conjugate selected from mirvetuximab soravtansine, tisotumab vedotin, ASN004, enapotamab vedotin, vobramitamab duocarmazine, AZD8205, HKT228, CX- 2009, SC-003, STRO-002, MORAb-202, IMGN151, PRO-1184, A166, SYD985, SGN-15, anetumab 20 ravtansine, lifastuzumab vedotin, XMT-1536, XMT-1592, CDX-014, XB002, Dato-DXd, IMMU-132, SKB264, TORL-1–23, and AZD5335.

[0728] In one embodiment, the other agent is an antibody-drug conjugate wherein the payload (i.e. the drug portion of the antibody-drug conjugate) is a DNA-damaging agent.

[0729] In one embodiment, the other agent is an antibody-drug conjugate, wherein the payload (i.e. 25 the drug portion of the antibody-drug conjugate) is a topoisomerase 1 or topoisomerase 2 inhibitor.

[0730] In one embodiment, the other agent is an antibody-drug conjugate, wherein the payload (i.e. the drug portion of the antibody-drug conjugate) is a topoisomerase 1 inhibitor, for example a topoisomerase 1 inhibitor selected from exatecan, deruxtecan (Dxd), SN38, Ed-04, YL0014, SHR9265, AZ14170132, KL610023, HS-9265, A-1743332, MF-6, DDDXd, MH30010008, P1003, P1021, and ZD06519. 30

[0731] In one embodiment, the other agent is an antibody-drug conjugate wherein the payload (i.e. the drug portion of the antibody-drug conjugate) is a topoisomerase 1 inhibitor (for example an antibody- drug conjugate such as trastuzumab deruxtecan, sacituzumab govitecan, datopotamab deruxtecan, patritumab deruxtecan, SHR-A1811, SKB-264, labetuzumab govitecan, Ifinatamab deruxtecan, BL- B01D1, AZD-8205, DB-1303, DB-1305, ESG-401, FDA-022, IBI-354, MHB088C, PRO-1160, PRO-1184, SHR- 35 A1904, SHR-A1921, AZD-5335, MHB036C, CBX-12, DS-6000, TQB2102, DS-6157a, BL-M11D1, Epratuzumab-SN38, 9MW-2921, 7MW-3711, or mirvetuximab exatecan).

[0732] In one embodiment, the other agent is an antibody-drug conjugate selected from trastuzumab deruxtecan, sacituzumab govitecan, datopotamab deruxtecan, patritumab deruxtecan, SHR-A1811, SKB- 264, labetuzumab govitecan, Ifinatamab deruxtecan, BL-B01D1, AZD-8205, DB-1303, DB-1305, ESG-401, P-000059-WO-PCT-MYT - 99 - FDA-022, IBI-354, MHB088C, PRO-1160, PRO-1184, SHR-A1904, SHR-A1921, AZD-5335, MHB036C, CBX- 12, DS-6000, TQB2102, DS-6157a, BL-M11D1, Epratuzumab-SN38, 9MW-2921, 7MW-3711, and mirvetuximab exatecan.

[0733] In one embodiment, the other agent is an antibody-drug conjugate, wherein the antibody-drug 5 conjugate (or the antibody, or the antibody portion of the antibody-drug conjugate) targets FOLR1 (FRa), CDH6, B7-H4, B7-H3, or CEACAM5, and has a topoisomerase 1 inhibitor payload.

[0734] In one embodiment, the other agent is an antibody-drug conjugate, wherein the antibody-drug conjugate (or the antibody, or the antibody portion of the antibody-drug conjugate) targets folate receptor alpha (FOLR1, FRa), and has a topoisomerase 1 inhibitor payload. 10

[0735] In one embodiment, the other agent is mirvetuximab exatecan.

[0736] In one embodiment, the cancer treated with the combination of PKMYT1 inhibitor and antibody-drug conjugate is characterised by, or further characterised by: amplification or overexpression of CCNE1.

[0737] In one embodiment, the cancer treated with the combination of PKMYT1 inhibitor and 15 antibody-drug conjugate is characterised by, or further characterised by: inactivation, decreased activity, or decreased expression of FBXW7, PPP2R2A or PPP2R1A.

[0738] In one embodiment, the cancer treated with the combination of PKMYT1 inhibitor and antibody-drug conjugate is characterised by, or further characterised by: inactivation of FBXW7.

[0739] In one embodiment, the cancer treated with the combination of PKMYT1 inhibitor and 20 antibody-drug conjugate is characterised by, or further characterised by: decreased activity or decreased expression of PPP2R2A or PPP2R1A.

[0740] In one embodiment, the cancer treated with the combination of PKMYT1 inhibitor and antibody-drug conjugate is characterised by, or further characterised by: concomitant mutation of p53 and CDKN2A. 25

[0741] Accordingly, also described herein is a PKMYT1 inhibitor (for example RP-6306, or a BAA compound as described herein) for use in the treatment of cancer, wherein the PKMYT1 inhibitor is administered in combination with an antibody-drug conjugate.

[0742] Also described herein is a PKMYT1 inhibitor (for example RP-6306, or a BAA compound as described herein) for use in the treatment of cancer, wherein the PKMYT1 inhibitor is administered in 30 combination with an antibody-drug conjugate selected from brentuximab vedotin, inotuzumab ozogamicin, mirvetuximab exatecan, mirvetuximab soravtansine, trastuzumab deruxtecan, trastuzumab emtansine, gemtuzumab ozogamicin, enfortumab vedotin, polatuzumab vedotin, tisotumab vedotin, sacituzumab govitecan, loncastuximab tesirine, cetuximab sarotalocan, belantamab mafodotin, moxetumomab pasudotox, and distamab vedotin. 35

[0743] Also described herein is a PKMYT1 inhibitor (for example RP-6306, or a BAA compound as described herein) for use in the treatment of cancer, wherein the PKMYT1 inhibitor is administered in combination with an antibody-drug conjugate selected from mirvetuximab soravtansine, tisotumab vedotin, ASN004, Enapotamab vedotin, vobramitamab duocarmazine, AZD8205, HKT228, CX-2009, SC- 003, STRO-002, MORAb-202, IMGN151, PRO-1184, A166, SYD985, SGN-15, anetumab ravtansine, P-000059-WO-PCT-MYT - 100 - lifastuzumab vedotin, XMT-1536, XMT-1592, CDX-014, XB002, Dato-DXd, IMMU-132, SKB264, TORL-1– 23, and AZD5335.

[0744] Also described herein is a PKMYT1 inhibitor (for example RP-6306, or a BAA compound as described herein) for use in the treatment of cancer, wherein the PKMYT1 inhibitor is administered in 5 combination with an antibody-drug conjugate which is a topoisomerase I inhibitor, a topoisomerase II inhibitor, or an antimetabolite.

[0745] Also described herein is a PKMYT1 inhibitor (for example RP-6306, or a BAA compound as described herein) for use in the treatment of cancer, wherein the PKMYT1 inhibitor is administered in combination with an antibody-drug conjugate, and the antibody-drug conjugate (or the antibody, or 10 the antibody portion of the antibody-drug conjugate) targets HER2, TROP2, Claudin 18.2, B7H3, EGFR, FOLR1 (FRa), CD22, MET, Nectin 4, CD19, B7-H4, CD276, CD33, CD70, CDH6, CEACAM5, GPR20, HER3, TACSTD2, CD79b, tissue factor (TF), CD19, BCMA, CD30, VTCN1, 5T4, AXL, CD166, dipeptidase-3, Lewis-Y, mesothelin, NAPi2b, TIM1, SEZ6, CD123, DLL3, PDL1, MUC1, PTK7, MUC18 or LIV-1.

[0746] Also described herein is a PKMYT1 inhibitor (for example RP-6306, or a BAA compound as 15 described herein) for use in the treatment of cancer, wherein the PKMYT1 inhibitor is administered in combination with an antibody-drug conjugate, and the antibody-drug conjugate (or the antibody, or the antibody portion of the antibody-drug conjugate) targets FOLR1 (FRa), HER2, TROP2, mesothelin, NAPi2b, CDH6, B7-H4, B7-H3, 5T4, AXL, CD166, dipeptidase-3, Lewis-Y, TIM1 or tissue factor (TF).

[0747] Also described herein is a PKMYT1 inhibitor (for example RP-6306, or a BAA compound as 20 described herein), for use in the treatment of cancer, wherein the PKMYT1 inhibitor is administered in combination with an antibody-drug conjugate, and the antibody-drug conjugate (or the antibody, or the antibody portion of the antibody-drug conjugate) targets FOLR1 (FRa), CDH6, B7-H4, B7-H3, or CEACAM5.

[0748] Also described herein is a PKMYT1 inhibitor (for example RP-6306, or a BAA compound as 25 described herein) for use in the treatment of cancer, wherein the PKMYT1 inhibitor is administered in combination with an antibody-drug conjugate, and the payload of the antibody-drug conjugate (i.e. the drug portion of the antibody-drug conjugate) is a DNA-damaging agent.

[0749] Also described herein is a PKMYT1 inhibitor (for example RP-6306, or a BAA compound as described herein), for use in the treatment of cancer, wherein the PKMYT1 inhibitor is administered 30 in combination with an antibody-drug conjugate, and the payload of the antibody-drug conjugate (i.e. the drug portion of the antibody-drug conjugate) is a topoisomerase 1 or topoisomerase 2 inhibitor.

[0750] Also described herein is a PKMYT1 inhibitor (for example RP-6306, or a BAA compound as described herein) for use in the treatment of cancer, wherein the PKMYT1 inhibitor is administered in combination with an antibody-drug conjugate, and the payload of the antibody-drug conjugate (i.e. 35 the drug portion of the antibody-drug conjugate) is a topoisomerase 1 inhibitor selected from exatecan, deruxtecan (Dxd), SN38, Ed-04, YL0014, SHR9265, AZ14170132, KL610023, HS-9265, A-1743332, MF-6, DDDXd, MH30010008, P1003, P1021, and ZD06519. P-000059-WO-PCT-MYT - 101 -

[0751] Also described herein is a PKMYT1 inhibitor (for example RP-6306, or a BAA compound as described herein) for use in the treatment of cancer, wherein the PKMYT1 inhibitor is administered in combination with an antibody-drug conjugate which is a topoisomerase I inhibitor.

[0752] Also described herein is a PKMYT1 inhibitor (for example RP-6306, or a BAA compound as 5 described herein) for use in the treatment of cancer, wherein the PKMYT1 inhibitor is administered in combination with an antibody-drug conjugate which is a topoisomerase I inhibitor, and the antibody- drug conjugate is selected from trastuzumab deruxtecan, sacituzumab govitecan, datopotamab deruxtecan, patritumab deruxtecan, SHR-A1811, SKB-264, labetuzumab govitecan, Ifinatamab deruxtecan, BL-B01D1, AZD-8205, DB-1303, DB-1305, ESG-401, FDA-022, IBI-354, MHB088C, PRO-1160,10 PRO-1184, SHR-A1904, SHR-A1921, AZD-5335, MHB036C, CBX-12, DS-6000, TQB2102, DS-6157a, BL- M11D1, Epratuzumab-SN38, 9MW-2921, 7MW-3711, and mirvetuximab exatecan.

[0753] Also described herein is a PKMYT1 inhibitor (for example RP-6306, or a BAA compound as described herein), for use in the treatment of cancer, wherein the PKMYT1 inhibitor is administered in combination with an antibody-drug conjugate which is a topoisomerase I inhibitor, and the antibody- 15 drug conjugate is mirvetuximab exatecan.

[0754] Also described herein is a PKMYT1 inhibitor (for example RP-6306, or a BAA compound as described herein) for use in the treatment of cancer, wherein the PKMYT1 inhibitor is administered in combination with an antibody-drug conjugate, and the antibody-drug conjugate (or the antibody, or the antibody portion of the antibody-drug conjugate) targets FOLR1 (FRa), CDH6, B7-H4, B7-H3, or 20 CEACAM5, and has a topoisomerase 1 inhibitor payload.

[0755] Also described herein is a PKMYT1 inhibitor (for example RP-6306, or a BAA compound as described herein) for use in the treatment of cancer, wherein the PKMYT1 inhibitor is administered in combination with an antibody-drug conjugate, and the antibody-drug conjugate (or the antibody, or the antibody portion of the antibody-drug conjugate) targets folate receptor alpha (FOLR1, FRa), and has 25 a topoisomerase 1 inhibitor payload.

[0756] Also described herein is a PKMYT1 inhibitor (for example RP-6306, or a BAA compound as described herein) for use in the treatment of cancer, wherein the PKMYT1 inhibitor is administered in combination with an antibody-drug conjugate, and the cancer is characterised by, or further characterised by: by amplification, or overexpression, of CCNE1. 30

[0757] Also described herein is a PKMYT1 inhibitor (for example RP-6306, or a BAA compound as described herein) for use in the treatment of cancer, wherein the PKMYT1 inhibitor is administered in combination with an antibody-drug conjugate, and the cancer is characterised by, or further characterised by: decreased activity, or decreased expression, of FBXW7, PPP2R2A or PPP2R1A.

[0758] Also described herein is a PKMYT1 inhibitor (for example RP-6306, or a BAA compound as 35 described herein) for use in the treatment of cancer, wherein the PKMYT1 inhibitor is administered in combination with an antibody-drug conjugate, and the cancer is characterised by, or further characterised by: inactivation of FBXW7.

[0759] Also described herein is a PKMYT1 inhibitor (for example RP-6306, or a BAA compound as described herein) for use in the treatment of cancer, wherein the PKMYT1 inhibitor is administered P-000059-WO-PCT-MYT - 102 - in combination with an antibody-drug conjugate, and the cancer is characterised by, or further characterised by: decreased activity or decreased expression of PPP2R2A or PPP2R1A.

[0760] Also described herein is a PKMYT1 inhibitor (for example RP-6306, or a BAA compound as described herein) for use in the treatment of cancer, wherein the PKMYT1 inhibitor is administered 5 in combination with an antibody-drug conjugate, and the cancer is characterised by, or further characterised by: concomitant mutation of p53 and CDKN2A.

[0761] Also described herein is a PKMYT1 inhibitor (for example RP-6306, or a BAA compound as described herein) for use in the treatment of cancer, wherein the PKMYT1 inhibitor is administered in combination with a topoisomerase 1 inhibitor, a topoisomerase 2 inhibitor, or gemcitabine, and the 10 cancer is characterised by, or further characterised by: concomitant mutation of p53 and CDKN2A.

[0762] In one embodiment, the other agent is a DNA-damaging agent, such as an alkylating agent (for example cis-platin, oxaliplatin, carboplatin, cyclophosphamide, melphalan, chlorambucil, bendamustine, temozolomide, trabectidin, mitomycin C, or dacarbazine); an antimetabolite (for example capecitabine, gemcitabine, 5-fluorouracil, fluoropyrimidine, trifluridine and tipiracil, cytarabine, or methotrexate); a 15 DNA intercalator (for example an anthracycline like doxorubicin, epirubicin, or daunorubicin), an antibiotic (for example bleomycin, dactinomycin, or mithramycin); a topoisomerase 1 inhibitor (for example a camptothecin such as irinotecan, or topotecan), a topoisomerase 2 inhibitor (for example etoposide), a microtubule-targeting agent (for example a taxane such as paclitaxel; or a vinca alkaloid such as vincristine, vinblastine, vindesine, vinorelbine, or eribulin); or an antibiotic (for example 20 bleomycin, or mitomycin-C).

[0763] In one embodiment, the other agent is a topoisomerase I inhibitor (for example irinotecan or topotecan), a topoisomerase II inhibitor (for example etoposide), or an antimetabolite (for example gemcitabine).

[0764] In one embodiment, the other agent is an alkylating agent (for example cis-platin). 25

[0765] In one embodiment, the other agent is a topoisomerase I inhibitor (for example irinotecan, or topotecan).

[0766] In one embodiment, the other agent is a topoisomerase II inhibitor (for example etoposide).

[0767] In one embodiment, the other agent is an antimetabolite (for example gemcitabine).

[0768] In one embodiment, treatment with a combination of a PKMYT1 inhibitor and a topoisomerase 30 1 inhibitor, a topoisomerase 2 inhibitor, or gemcitabine, induces selective DNA damage in cancers characterised by: CCNE1 amplification or overexpression; inactivation, decreased activity, or decreased expression of FBXW7, PPP2R2A or PPP2R1A; or concomitant mutation of p53 and CDKN2A.

[0769] In one embodiment, treatment with a combination of a PKMYT1 inhibitor and a topoisomerase 1 inhibitor, a topoisomerase 2 inhibitor, or gemcitabine, induces selective DNA damage in cancers 35 characterised by: CCNE1 amplification or overexpression.

[0770] In one embodiment, treatment with a combination of a PKMYT1 inhibitor and a topoisomerase 1 inhibitor, a topoisomerase 2 inhibitor, or gemcitabine, induces selective DNA damage in cancers characterised by: inactivation, decreased activity, or decreased expression of FBXW7, PPP2R2A or PPP2R1A; or concomitant mutation of p53 and CDKN2A. P-000059-WO-PCT-MYT - 103 -

[0771] In one embodiment, treatment with a combination of a PKMYT1 inhibitor and a topoisomerase 1 inhibitor, a topoisomerase 2 inhibitor, or gemcitabine, induces selective DNA damage in cancers characterised by: inactivation, decreased activity, or decreased expression of FBXW7, PPP2R2A or PPP2R1A. 5

[0772] In one embodiment, treatment with a combination of a PKMYT1 inhibitor and a topoisomerase 1 inhibitor, a topoisomerase 2 inhibitor, or gemcitabine, induces selective DNA damage in cancers characterised by concomitant mutation of p53 and CDKN2A.

[0773] In one embodiment, DNA damage induced by a combination of a PKMYT1 inhibitor and a topoisomerase 1 inhibitor, a topoisomerase 2 inhibitor, or gemcitabine, is characterised by induction of 10 γH2AX.

[0774] In one embodiment, treatment of cancer that exhibits CCNE1 amplification or overexpression; inactivation, decreased activity, or decreased expression of FBXW7, PPP2R2A or PPP2R1A; or concomitant mutation of p53 and CDKN2A; with a combination of a PKMYT1 inhibitor and a topoisomerase 1 inhibitor, a topoisomerase 2 inhibitor, or gemcitabine, is characterised by synergistic 15 induction of γH2AX.

[0775] In one embodiment, treatment of cancer that exhibits CCNE1 amplification or overexpression with a combination of a PKMYT1 inhibitor and a topoisomerase 1 inhibitor, a topoisomerase 2 inhibitor, or gemcitabine, is characterised by synergistic induction of γH2AX.

[0776] In one embodiment, treatment of cancer that exhibits inactivation, decreased activity, or 20 decreased expression of FBXW7, PPP2R2A or PPP2R1A; or concomitant mutation of p53 and CDKN2A with a combination of a PKMYT1 inhibitor and a topoisomerase 1 inhibitor, a topoisomerase 2 inhibitor, or gemcitabine, is characterised by synergistic induction of γH2AX.

[0777] In one embodiment, treatment of cancer that exhibits inactivation, decreased activity, or decreased expression of FBXW7, PPP2R2A or PPP2R1A, with a combination of a PKMYT1 inhibitor and a 25 topoisomerase 1 inhibitor, a topoisomerase 2 inhibitor, or gemcitabine, is characterised by synergistic induction of γH2AX.

[0778] In one embodiment, treatment of cancer that exhibit concomitant mutation of p53 and CDKN2A with a combination of a PKMYT1 inhibitor and a topoisomerase 1 inhibitor, a topoisomerase 2 inhibitor, or gemcitabine, is characterised by synergistic induction of γH2AX. 30

[0779] In one embodiment, the other agent is a DNA-damage repair inhibitor (for example a PARP inhibitor such as olaparib, rucaparib, niraparib, or talazoparib; or a PARG inhibitor; or a USP1 inhibitor).

[0780] In one embodiment, the other agent is double strand-break repair inhibitor (for example a Pol^ inhibitor, or a RAD51 inhibitor).

[0781] In one embodiment, the other agent is a signalling pathway inhibitor, such as a kinase inhibitor 35 (for example abemaciclib, acalabrutinib, afatinib, alectinib, avapritinib, axitinib, baricitinib, belumosudil, binimetinib, bosutinib, brigatinib, cabozantinib, capmatinib, ceritinib, cobimetinib, rizotinib, dabrafenib, dacomitinib, dasatinib, encorafenib, entrectinib, erdafitinib, erlotinib, everolimus, fedratinib, fostamatinib, gefitinib, gilteritinib, ibrutinib, imatinib, infigratinib, lapatinib, larotrectinib, lenvatinib, lorlatinib, midostaurin, mobocertinib, neratinib, netarsudil, nilotinib, nintedanib, osimertinib, P-000059-WO-PCT-MYT - 104 - palbociclib, pazopanib, pemigatinib, pexidartinib, ponatinib, pralsetinib, regorafenib, ribociclib, ripretinib, ruxolitinib, selpercatinib, selumetinib, sirolimus, sorafenib, sunitinib, temsirolimus, tepotinib, tivozanib, tofacitinib, trametinib, trilaciclib, tucatinib, upadacitinib, vandetanib, vemurafenib, or zanubrutinib). 5

[0782] In one embodiment, the other agent is a cell cycle targeting inhibitor, such as a CDK4 / 6 inhibitor (for example palbociclib, abemaciclib, or ribociclib).

[0783] In one embodiment, the other agent is an agent targeting DNA damage checkpoints, such as an ATR inhibitor (for example ceralasertib, gartisertib, tuvusertib, elimusertib, or camonsertib), an ATM inhibitor (for example AZD0156), a CHK1 inhibitor (for example prexasertib), a CHK2 inhibitor, a WEE1 10 inhibitor (for example adavosertib, or azenosertib), a PLK1 inhibitor (for example onvansertib), or an AUR-A inhibitor (for example JAB-2485).

[0784] In one embodiment, the other agent is an ATR inhibitor (for example ceralasertib, gartisertib, tuvusertib, elimusertib, or camonsertib), a CHK1 inhibitor (for example prexasertib), or a WEE1 inhibitor (for example adavosertib, or azenosertib). 15

[0785] In one embodiment, the other agent is an ATR inhibitor (for example ceralasertib, gartisertib, tuvusertib or camonsertib), or a WEE1 inhibitor (for example azenosertib).

[0786] In one embodiment, the other agent is a CHK1 inhibitor (for example prexasertib).

[0787] In one embodiment, the other agent is an ATR inhibitor (for example ceralasertib, gartisertib, tuvusertib, elimusertib, or camonsertib). 20

[0788] In one embodiment, the other agent is a WEE1 inhibitor (for example adavosertib, or azenosertib).

[0789] In one embodiment, the other agent is a hormone therapy agent, such as an antiestrogen (for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene, or idoxifene), an antiandrogen (for example abiraterone, bicalutamide, enzalutamide, flutamide, nilutamide, or cyproterone acetate), an 25 LHRH antagonist or LHRH agonist (for example goserelin, leuprorelin, or buserelin), a progestogen (for example megestrol acetate), an aromatase inhibitor (for example as anastrozole, letrozole, vorazole, or exemestane) an inhibitor of 5α-reductase (for example finasteride) or an analogue of somatostatin (for example lanreotide).

[0790] In one embodiment, the other agent is a proteasome inhibitor (for example bortezomib), a 30 histone deacetylase inhibitor (for example vorinostat, romidepsin, panobinostat, or belinostat), or a DNA demethylating agent (for example azacitidine, or decitabine).

[0791] In one embodiment, the other agent is radiotherapy, such as radiotherapy comprising treatment with a radiotherapeutic drug (for example a targeted radionuclide, or for example lutetium Lu 177 dotatate, lutetium Lu 177 vipivotide tetraxetan, samarium Sm 153 lexidronam, radium Ra 223 35 dichloride, Ac-225 prostate-specific membrane antigen (PSMA) radioligand or other Ac-225 targeted radiotherapeutic, or Y-90 ibritumomab tiuxetan). Certain Combined Therapies

[0792] Also described herein is a PKMYT1 inhibitor (for example RP-6306, or a BAA compound as described herein) for use in the treatment of cancer, wherein the PKMYT1 inhibitor is administered in P-000059-WO-PCT-MYT - 105 - combination with a topoisomerase 1 inhibitor, a topoisomerase 2 inhibitor, or gemcitabine, and the cancer is characterised by, or further characterised by: CCNE1 amplification or overexpression; inactivation, decreased activity, or decreased expression of FBXW7, PPP2R2A or PPP2R1A; or concomitant mutation of p53 and CDKN2A. 5

[0793] Also described herein is a method of treatment of cancer, comprising administering to a subject in need of treatment a therapeutically effective amount of a PKMYT1 inhibitor, wherein the PKMYT1 inhibitor is administered in combination with a topoisomerase 1 inhibitor, a topoisomerase 2 inhibitor, or gemcitabine, and the cancer is characterised by, or further characterised by: CCNE1 amplification or overexpression; inactivation, decreased activity, or decreased expression of FBXW7, PPP2R2A or 10 PPP2R1A; or concomitant mutation of p53 and CDKN2A.

[0794] Also disclosed herein is a method of increasing the sensitivity rate (i.e. efficacy rate) of a therapeutic combination comprising a PKMYT1 inhibitor and a topoisomerase 1 inhibitor, a topoisomerase 2 inhibitor, or gemcitabine; where the method comprises selecting a patient sub- population whose cancer is characterised by, or further characterised by: CCNE1 amplification or 15 overexpression; inactivation, decreased activity, or decreased expression of FBXW7, PPP2R2A or PPP2R1A; or concomitant mutation of p53 and CDKN2A.

[0795] Also disclosed herein is a method of identifying a subject having increased likelihood of responsiveness or sensitivity to a therapeutic combination comprising a PKMYT1 inhibitor and a topoisomerase 1 inhibitor, a topoisomerase 2 inhibitor, or gemcitabine; comprising determining the 20 level of expression of CCNE1, or the mutation status of FBXW7, PP2A or its subunits, p53 and CDKN2A in a biological sample of the subject (for example a biological sample of the subject’s cancer), wherein increased levels of CCNE1, mutations of FBXW7, PPP2R2A, PPP2R1A, or concomitant mutation of p53 and CDKN2A, when compared to a reference sample, identifies the subject as having increased likelihood of responsiveness or sensitivity to the indicated combinations. 25

[0796] Testing and comparison of patient samples with references samples from e.g. healthy subjects is known in the art and can be practiced by a suitably skilled physician or team thereof.

[0797] Also disclosed herein is a method of determining a treatment regimen for a subject with cancer, comprising: a) Determining the level of expression of CCNE1, or the mutation status of FBXW7, PP2A or its 30 subunits, or p53 and CDKNA2, in a biological sample of the subject (for example a biological sample of the subject’s cancer); and b) Selecting the subject as suitable for receiving a treatment regimen comprising a therapeutically effective amount of a combination of a PKMYT1 inhibitor and a topoisomerase 1 inhibitor, a topoisomerase 2 inhibitor, or gemcitabine, when CCNE1 is amplified or overexpressed, and / or 35 one or more of FBXW7, PP2A or its subunits, or p53 and CDKNA2 together, are mutated.

[0798] Also disclosed herein is a method of treatment of cancer in a subject in need of such treatment, comprising: P-000059-WO-PCT-MYT - 106 - a) Determining the level of expression of CCNE1, or the mutation status of FBXW7, PP2A or its subunits, or p53 and CDKNA2 in a biological sample of the subject (for example a biological sample of the subject’s cancer); and b) Administering a treatment regimen comprising a therapeutically effective amount of a 5 combination of a PKMYT1 inhibitor with a topoisomerase 1 inhibitor, a topoisomerase 2 inhibitor, or gemcitabine, when CCNE1 is amplified or overexpressed, and / or one or more of FBXW7, PP2A or its subunits, or p53 and CDKNA2 together, are mutated. Other Uses 10

[0799] The BAA compounds described herein may also be used as cell culture additives to inhibit PKMYT1 (e.g., to inhibit or reduce or block the activity or function of PKMYT1).

[0800] The BAA compounds described herein may also be used as part of an in vitro assay, for example, in order to determine whether a candidate host is likely to benefit from treatment with the compound in question. 15

[0801] The BAA compounds described herein may also be used as a standard, for example, in an assay, in order to identify other active compounds, other PKMYT1 inhibitors, etc. Kits

[0802] Also describes herein is a kit comprising (a) a BAA compound, as described herein, optionally provided as a composition (e.g., a pharmaceutical composition) and in a suitable container and / or with 20 suitable packaging; and (b) instructions for use, for example, in a method of treatment of a disorder (e.g., a disease) as described herein, for example, written instructions on how to administer the compound.

[0803] The written instructions may also include a list of indications for which the BAA compound is a suitable treatment. 25 Routes of Administration

[0804] The BAA compound or pharmaceutical composition comprising the BAA compound may be administered to a subject by any convenient route of administration, whether systemically / peripherally or topically (i.e., at the site of desired action).

[0805] Routes of administration include, for example: oral (e.g., by ingestion); buccal; sublingual; 30 transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, 35 intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; by implant of a depot or reservoir, for example, subcutaneously or intramuscularly. The Subject P-000059-WO-PCT-MYT - 107 -

[0806] The subject (e.g., patient) may be a chordate, a vertebrate, a mammal, a placental mammal, a marsupial (e.g., kangaroo, wombat), a rodent (e.g., a guinea pig, a hamster, a rat, a mouse), murine (e.g., a mouse), a lagomorph (e.g., a rabbit), avian (e.g., a bird), canine (e.g., a dog), feline (e.g., a cat), equine (e.g., a horse), porcine (e.g., a pig), ovine (e.g., a sheep), bovine (e.g., a cow), a primate, simian 5 (e.g., a monkey or ape), a monkey (e.g., marmoset, baboon), an ape (e.g., gorilla, chimpanzee, orangutan, gibbon), or a human.

[0807] Furthermore, the subject (e.g., patient) may be any of its forms of development, for example, a foetus.

[0808] In one preferred embodiment, the subject (e.g., patient) is a human. 10 Formulations

[0809] While it is possible for a BAA compound to be administered alone, may also be presented as a pharmaceutical formulation (e.g., composition, preparation, medicament) comprising at least one BAA compound, as described herein, together with one or more other pharmaceutically acceptable 15 ingredients well known to those skilled in the art, including, for example, pharmaceutically acceptable excipients, such as carriers, diluents, adjuvants, fillers, buffers, preservatives, anti-oxidants, lubricants, stabilisers, solubilisers, surfactants (e.g., wetting agents), masking agents, colouring agents, flavouring agents, and sweetening agents. The formulation may further comprise other active agents, for example, other therapeutic or prophylactic agents. 20

[0810] Thus, also described herein are pharmaceutical compositions, as defined above, and methods of making a pharmaceutical composition comprising mixing at least one BAA compound, as described herein, together with one or more other pharmaceutically acceptable ingredients well known to those skilled in the art, e.g., excipients (for example a carrier and / or diluent), etc. If formulated as discrete units (e.g., tablets, etc.), each unit contains a predetermined amount (dosage) of the compound. 25

[0811] The term “pharmaceutically acceptable,” as used herein, pertains to compounds, ingredients, materials, compositions, dosage forms, etc., which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of the subject in question (e.g., human) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. Each excipient (for example a carrier and / or diluent), etc. must also be “acceptable” in 30 the sense of being compatible with the other ingredients of the formulation.

[0812] Suitable excipients (for example a carrier and / or diluent), etc. can be found in standard pharmaceutical texts, for example, Remington: The Science and Practice of Pharmacy, 21stedition, Lippinott Williams and Wilkins, 2005; Remington: The Science and Practice of Pharmacy, 22nd edition, Pharmaceutical Press, 2012; and Handbook of Pharmaceutical Excipients, 7th edition, Pharmaceutical 35 Press, 2012.

[0813] The formulations may be prepared by any methods well known in the art of pharmacy. Such methods include the step of bringing into association the compound with a carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and P-000059-WO-PCT-MYT - 108 - intimately bringing into association the compound with carriers (e.g., liquid carriers, finely divided solid carrier, etc.), and then shaping the product, if necessary.

[0814] The formulation may be prepared to provide for rapid or slow release; immediate, delayed, timed, or sustained release; or a combination thereof. 5

[0815] Formulations may suitably be in the form of liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), elixirs, syrups, electuaries, mouthwashes, drops, tablets (including, e.g., coated tablets), granules, powders, lozenges, pastilles, capsules (including, e.g., hard and soft gelatin capsules), cachets, pills, ampoules, boluses, suppositories, pessaries, tinctures, gels, pastes, ointments, creams, lotions, oils, foams, sprays, mists, or 10 aerosols.

[0816] Formulations may suitably be provided as a patch, adhesive plaster, bandage, dressing, or the like which is impregnated with one or more compounds and optionally one or more other pharmaceutically acceptable ingredients, including, for example, penetration, permeation, and absorption enhancers. Formulations may also suitably be provided in the form of a depot or reservoir. 15

[0817] The compound may be dissolved in, suspended in, or mixed with one or more other pharmaceutically acceptable ingredients. The compound may be presented in a liposome or other microparticulate which is designed to target the compound, for example, to blood components or one or more organs.

[0818] Formulations suitable for oral administration (e.g., by ingestion) include liquids, solutions (e.g.,20 aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water- in-oil), elixirs, syrups, electuaries, tablets, granules, powders, capsules, cachets, pills, ampoules, boluses.

[0819] Formulations suitable for buccal administration include mouthwashes, lozenges, pastilles, as well as patches, adhesive plasters, depots, and reservoirs. Lozenges typically comprise the compound in a flavoured basis, usually sucrose and acacia or tragacanth. Pastilles typically comprise the compound in 25 an inert matrix, such as gelatin and glycerin, or sucrose and acacia. Mouthwashes typically comprise the compound in a suitable liquid carrier.

[0820] Formulations suitable for sublingual administration include tablets, lozenges, pastilles, capsules, and pills.

[0821] Formulations suitable for oral transmucosal administration include liquids, solutions (e.g.,30 aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water- in-oil), mouthwashes, lozenges, pastilles, as well as patches, adhesive plasters, depots, and reservoirs.

[0822] Formulations suitable for non-oral transmucosal administration include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water- in-oil), suppositories, pessaries, gels, pastes, ointments, creams, lotions, oils, as well as patches, 35 adhesive plasters, depots, and reservoirs.

[0823] Formulations suitable for transdermal administration include gels, pastes, ointments, creams, lotions, and oils, as well as patches, adhesive plasters, bandages, dressings, depots, and reservoirs.

[0824] Tablets may be made by conventional means, e.g., compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable P-000059-WO-PCT-MYT - 109 - machine the compound in a free-flowing form such as a powder or granules, optionally mixed with one or more binders (e.g., povidone, gelatin, acacia, sorbitol, tragacanth, hydroxypropylmethyl cellulose); fillers or diluents (e.g., lactose, microcrystalline cellulose, calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, silica); disintegrants (e.g., sodium starch glycolate, cross-linked povidone, 5 cross-linked sodium carboxymethyl cellulose); surface-active or dispersing or wetting agents (e.g., sodium lauryl sulfate); preservatives (e.g., methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, sorbic acid); flavours, flavour enhancing agents, and sweeteners. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled 10 release of the compound therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with a coating, for example, to affect release, for example an enteric coating, to provide release in parts of the gut other than the stomach.

[0825] Ointments are typically prepared from the compound and a paraffinic or a water-miscible 15 ointment base.

[0826] Creams are typically prepared from the compound and an oil-in-water cream base. If desired, the aqueous phase of the cream base may include, for example, at least about 30% w / w of a polyhydric alcohol, i.e., an alcohol having two or more hydroxyl groups such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol and mixtures thereof. The topical formulations may 20 desirably include a compound which enhances absorption or penetration of the compound through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogues.

[0827] Emulsions are typically prepared from the compound and an oily phase, which may optionally comprise merely an emulsifier (otherwise known as an emulgent), or it may comprise a mixture of at 25 least one emulsifier with a fat or an oil or with both a fat and an oil. Optionally, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabiliser. It is also preferred to include both an oil and a fat. Together, the emulsifier(s) with or without stabiliser(s) make up the so-called emulsifying wax, and the wax together with the oil and / or fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations. 30

[0828] Suitable emulgents and emulsion stabilisers include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulfate. The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the compound in most oils likely to be used in pharmaceutical emulsion formulations may be very low. Thus the cream may be a non-greasy, non-staining and washable product with suitable consistency to avoid 35 leakage from tubes or other containers. Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used P-000059-WO-PCT-MYT - 110 - alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and / or liquid paraffin or other mineral oils can be used.

[0829] Formulations suitable for intranasal administration, where the carrier is a liquid, include, for example, nasal spray, nasal drops, or by aerosol administration by nebuliser, include aqueous or oily 5 solutions of the compound.

[0830] Formulations suitable for intranasal administration, where the carrier is a solid, include, for example, those presented as a coarse powder having a particle size, for example, in the range of about 20 to about 500 microns which is administered in the manner in which snuff is taken, i.e., by rapid inhalation through the nasal passage from a container of the powder held close up to the nose. 10

[0831] Formulations suitable for pulmonary administration (e.g., by inhalation or insufflation therapy) include those presented as an aerosol spray from a pressurised pack, with the use of a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichorotetrafluoroethane, carbon dioxide, or other suitable gases.

[0832] Formulations suitable for ocular administration include eye drops wherein the compound is 15 dissolved or suspended in a suitable carrier, especially an aqueous solvent for the compound.

[0833] Formulations suitable for rectal administration may be presented as a suppository with a suitable base comprising, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols, for example, cocoa butter or a salicylate; or as a solution or suspension for treatment by enema.

[0834] Formulations suitable for vaginal administration may be presented as pessaries, tampons, 20 creams, gels, pastes, foams or spray formulations containing in addition to the compound, such carriers as are known in the art to be appropriate.

[0835] Formulations suitable for parenteral administration (e.g., by injection), include aqueous or non- aqueous, isotonic, pyrogen-free, sterile liquids (e.g., solutions, suspensions), in which the compound is dissolved, suspended, or otherwise provided (e.g., in a liposome or other microparticulate). Such liquids 25 may additionally contain other pharmaceutically acceptable ingredients, such as antioxidants, buffers, preservatives, stabilisers, bacteriostats, suspending agents, thickening agents, and solutes which render the formulation isotonic with the blood (or other relevant bodily fluid) of the intended recipient. Examples of excipients include, for example, water, alcohols, polyols, glycerol, vegetable oils, and the like. Examples of suitable isotonic carriers for use in such formulations include Sodium Chloride 30 Injection, Ringer's Solution, or Lactated Ringer's Injection. Typically, the concentration of the compound in the liquid is from about 1 ng / mL to about 10 μg / mL, for example from about 10 ng / mL to about 1 μg / mL. The formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. 35 Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets.

[0836] It will be appreciated by one of skill in the art that appropriate dosages of the BAA compounds, and compositions comprising the BAA compounds, can vary from subject to subject (e.g., from patient P-000059-WO-PCT-MYT - 111 - to patient). Determining the optimal dosage will generally involve balancing the level of therapeutic benefit against any risk or deleterious side effects. The selected dosage level will depend on a variety of factors including, for example: the activity of the particular BAA compound; the route of administration; the time of administration; the rate of excretion of the BAA compound; the duration of the treatment; 5 other drugs, compounds, and / or materials used in combination; the severity of the disorder; and the species, sex, age, weight, condition, general health, and prior medical history of the subject (e.g., patient). The amount of BAA compound and route of administration will ultimately be at the discretion of the physician, veterinarian, or clinician, although generally the dosage will be selected to achieve local concentrations at the site of action which achieve the desired effect without causing substantial harmful 10 or deleterious side-effects.

[0837] Administration can be effected in one dose, continuously or intermittently (e.g., in divided doses at appropriate intervals) throughout the course of treatment. Methods of determining the most effective means and dosage of administration are well known to those of skill in the art and will vary with the formulation used for therapy, the purpose of the therapy, the target cell(s) being treated, and 15 the subject being treated. Single or multiple administrations can be carried out with the dose level and pattern being selected by the treating physician, veterinarian, or clinician.

[0838] In general, a suitable dose of the BAA compound is in the range of about 0.01 mg to about 5000 mg (more typically about 0.1 mg to about 1000 mg, e.g., about 0.1 mg to about 300 mg) per day.

[0839] Where the compound is a salt, a co-crystal, an ester, a prodrug, or the like, the amount 20 administered is calculated on the basis of the parent compound and so the actual weight to be used is increased proportionately. EXAMPLES 25 Chemical Synthesis Abbreviations DCM Dichloromethane (methylene chloride) DIPEA N,N-diisopropylethylamine DMSO Dimethylsulfoxide 30 ES Electrospray ionisation EtOAc Ethyl acetate EtOH Ethanol (ethyl alcohol) MeOH Methanol (methyl alcohol) Pd / C Palladium on carbon 35 Pd2dba3 tris(dibenzylideneacetone)dipalladium(0) PE Petroleum ether RT Room temperature T3P 1-Propanephosphonic anhydride THF Tetrahydrofuran P-000059-WO-PCT-MYT - 112 - UPLC Ultra Performance Liquid Chromatography XantPhos 4,5-bis(diphenylphospheno)-9,9-dimethylxanthene Methods General Experimental

[0840] Flash chromatography was performed using pre-packed silica gel cartridges (RediSep Rf, Isco). Thin layer chromatography was conducted with 5 × 10 cm plates coated with Merck Type 60 F254 silica gel to a thickness of 0.25 mm. All reagents obtained from commercial sources were used without further purification. Anhydrous solvents were obtained from the Sigma-Aldrich Chemical Company Ltd. or Fisher Chemicals Ltd., and used without further drying. HPLC grade solvents were obtained from Fisher Chemicals Ltd.

[0841] All compounds were >90 % purity as determined by examination of both the LCMS and 1H NMR spectra unless otherwise indicated. Where Cl or Br were present, expected isotopic distribution patterns were observed. NMR

[0842] Proton (1H) and carbon (13C) NMR spectra were recorded on a 300 MHz Bruker spectrometer. Solutions were typically prepared in either deuterated chloroform (Chloroform-d), deuterated methanol (Methanol-d4) or deuterated dimethylsulfoxide (DMSO-d6) with chemical shifts referenced to tetramethylsilane (TMS) or deuterated solvent as an internal standard.1H NMR data are reported indicating the chemical shift (δ), the integration (e.g.1H), the multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad; dd, doublet of doublets) and the coupling constant (J) in Hz. Deuterated solvents were purchased from the Sigma-Aldrich Chemical Company, Goss or Fluorochem. Analytical LCMS

[0843] LCMS analyses were performed on a Waters Acquity UPLC using BEH C181.7 µM columns (2.1 × 50 mm) with a diode array detector coupled to a SQD mass spectrometer or, a Waters Acquity I-Class UPLC using BEH C181.7 µM columns (2.1 × 50 mm) with a diode array detector coupled to a QDa mass spectrometer. Analyses were performed with either buffered acidic or basic solvents using gradients as detailed below: Low pH: Solvent A – Water + 10 mM ammonium hydrogen carbonate + 0.1 % formic acid Solvent B – MeCN + 5 % water + 0.1 % formic acid P-000059-WO-PCT-MYT - 113 - High pH: Solvent A – Water + 10 mM ammonium hydrogen carbonate + 0.1 % ammonia solution Solvent B – MeCN + 5 % water + 0.1 % ammonia solution 5 Gradient: Flow rate Time (mL / min) % Solvent A % Solvent B 0 0.6 95 5 1.2 0.6 5 95 1.7 0.6 5 95 1.8 0.6 95 5 Preparative HPLC-MS

[0844] Some compounds were purified by preparative HPLC on a Waters FractionLynx MS 10 autopurification system, with a Phenomonex Gemini NX 5 µm C18, 100 mm × 21.2 mm i.d. column (for low pH runs) or a Waters XBridge 5 µm C18, 100 mm × 19 mm i.d. column (for high pH runs), running at a flow rate of 20 mL / min with UV diode array detection (210–400 nm) and mass-directed collection using both positive and negative mass ion detection.

[0845] Purifications were performed using buffered acidic or basic solvent systems as appropriate. 15 Compound retention times on the system were routinely assessed using a 30 - 50 µL test injection and a standard gradient, then purified using an appropriately chosen focussed gradient as detailed below, based upon observed retention time.

[0002] P-000059-WO-PCT-MYT - 114 - Low pH: Solvent A – Water + 10 mM ammonium formate + 0.1 % formic acid Solvent B – MeCN + 5 % water +0.1 % formic acid 5 High pH: Solvent A – Water + 10 mM ammonium formate + 0.1 % ammonia solution Solvent B – MeCN + 5 % water + 0.1 % ammonia solution Standard Gradient: 10 Flow rate Time (mL / min) % Solvent A % Solvent B 0 20 90 10 0.3 20 90 10 8.5 20 2 98 12 20 2 98 12.5 0 2 98 Focused Gradients: % Solvent B Retention time on standard gradient (min.) Time Flow rate 0 - 5.2 4.9 - 6.6 6.3 - 7.5 7.3 - 9.5 9.3 - 12 (mL / min) 0 20 10 10 10 10 10 0.25 20 10 10 10 10 10 0.35 20 10 20 35 45 60 10 20 45 55 65 75 98 12 20 98 98 98 98 98 12.5 0 98 98 98 98 98 15 Synthetic Methods

[0846] Several methods for the chemical synthesis of the compounds of the present invention are described herein. These and / or other well-known methods may be modified and / or adapted in known ways in order to facilitate the synthesis of additional compounds within the scope of the present invention. 20 P-000059-WO-PCT-MYT - 115 - General Synthetic Route

[0847] Synthesis of 5-methyl-4-nitro-1H-indazole. Method 1: Formic acid (1.65 ml, 42.8 mmol) was added dropwise to a suspension of 2,4-dinitro-m-xylene (2.0 g, 10.2 mmol) and Palladium on carbon (10% loading, 200 mg, 0.18 mmol) in triethylamine (6.4 mL, 45.9 mmol), and the resulting mixture was heated to 80 °C, with stirring for 30 mins. The reaction mixture was then cooled and separated between ethyl acetate and aqueous sodium bicarbonate and the organic extracts were then washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give the crude product, which was purified using flash column chromatography over silica, eluting with 0-80% ethyl acetate / petroleum ether to give 2,4-dimethyl-3-nitroaniline (947 mg, 56% yield) as a yellow solid. MS (ES+) 166.9 (M+H);1H NMR (CDCl3, 300 MHz) δ 6.92 (d, 1H, J = 8.2 Hz), 6.67 (d, 1H, J = 8.2 Hz), 3.70 (br s, 2H), 2.18 (s, 3H), 2.04 (s, 3H) ppm.

[0848] tButyl nitrite (0.81 mL, 6.82 mmol) was added dropwise to a solution of 2,4-dimethyl-3- nitroaniline (945 mg, 5.69 mmol) in acetic acid (45 mL), with stirring at 10-15 °C overnight, warming to room temperature. The reaction mixture was then diluted with ethyl acetate and carefully washed with a saturated aqueous sodium bicarbonate solution. The organic extracts were then washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give the crude product, which was purified using flash column chromatography over silica, eluting with 0-20% methanol / dichloromethane, to give 5-methyl-4-nitro-1H-indazole (539 mg, 54% yield) as an orange solid. MS (ES-) 175.9 (M-H);1H NMR (DMSO-d6, 300 MHz) δ 13.70 (br s, 1H), 8.29 (s, 1H), 7.88 (d, 1H, J = 8.5 Hz), 7.47 (d, 1H, J = 8.5 Hz), 2.67 (s, 3H) ppm.

[0849] Synthesis of 5-methyl-4-nitro-1H-indazole. Method 2: 68% Nitric acid (6.6 mL, 101 mmol) was placed in dropping funnel and slowly added (~20 min) to a stirred and precooled to -10 °C solution of 5- Methyl-1H-indazole (3.00 g, 22.7 mmol) in Sulfuric acid (95 mL, 1691 mmol) [Note 1]. Clear reaction P-000059-WO-PCT-MYT - 116 - mixture was stirred at 0 °C for 1h. Light brown reaction mixture was poured into a stirred ice-water mixture (500 mL) and resulting off-white suspension was stirred for 10 minutes. Precipitated solid was filtered, washed with water (500 mL) and dried (45°C / 10 mbar) to afford 5-methyl-4-nitro-1H-indazole (2.93 g, 16.5 mmol, 72.86% yield) as a beige solid.1H NMR (400 MHz, CDCl3) δ 8.50 (s, 1H), 7.69 (d, J = 7.4 Hz, 1H), 7.38 (d, J = 8.5 Hz, 1H), 2.76 (s, 3H). MS (ES) 176.1 [M-H]-.

[0850] 3,4-Dihydro-2H-pyran (0.83 mL, 9.13 mmol) was added dropwise to a solution of 5-methyl-4- nitro-1H-indazole (539 mg, 3.04 mmol) and p-Tosic acid monohydrate (58 mg, 0.3 mmol) in DCM (20 mL), with stirring at room temperature for 1 hour before quenching with saturated aqueous sodium bicarbonate solution. The reaction mixture was then separated between DCM and water, and the organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product, which was purified using flash column chromatography over silica, eluting with 0-70% ethyl acetate / petroleum ether, to give 5-methyl-4-nitro-1-(tetrahydro-2H- pyran-2-yl)-1H-indazole (718 mg, 90% yield) as an orange solid. MS (ES+) 262.2 (M+H);1H NMR (DMSO- d6, 300 MHz) δ 8.32 (s, 1H), 8.09 (d, 1H, J = 8.7 Hz), 7.54 (d, 1H, J = 8.7 Hz), 5.96 (dd, 1H, J = 9.5, 2.5 Hz), 3.91-3.84 (m, 1H), 3.80-3.72 (m, 1H), 2.67 (s, 3H), 2.46-2.32 (m, 1H), 2.08-1.96 (m, 2H), 1.82-1.67 (m, 1H), 1.63-1.56 (m, 2H) ppm.

[0851] A solution of 5-methyl-4-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole d(2.0 g, 7.65 mmol) in ethanol (70 mL) was bubbled with nitrogen for 5 minutes before adding 10% Palladium on Carbon (10 wt.%, 407 mg, 0.38 mmol) and bubbling for a further 5 minutes. The flask was then placed under vacuum and refilled with nitrogen before fitting a hydrogen balloon and stirring overnight at room temperature. The balloon was then removed and the reaction mixture bubbled with nitrogen for 5 minutes before filtering through dicalite, washing with ethyl acetate. The filtrate was concentrated to give 5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-amine (1.788 g, 100% yield) as a beige solid that did not require further purification. MS (ES+) 232.0 (M+H);1H NMR (DMSO-d6, 300 MHz) δ 8.14 (s, 1H), 6.97 (d, 1H, J = 8.5 Hz), 6.70 (d, 1H, J = 8.8 Hz), 5.61 (dd, 1H, J = 9.8, 2.5 Hz), 5.50 (s, 2H), 3.90-3.83 (m, 1H), 3.71-3.63 (m, 1H), 2.44-2.31 (m, 1H), 2.12 (s, 3H), 2.05-1.98 (m, 1H), 1.92-1.84 (m, 1H), 1.79- 1.65 (m, 1H), 1.59-1.50 (m, 2H) ppm.

[0852] To tert-butyl 4-aminoindazole-1-carboxylate (80%, 1105 mg, 3.79 mmol, 1.00 eq) in THF (20 mL) at -78 °C was added dropwise a solution of N-Chlorosuccinimide (557 mg, 4.17 mmol, 1.10 eq) in THF (6 mL) at -78 °C. The reaction was stirred at this temperature for 1h then allowed to warm to rt and stirred for 16 h. A further 0.75 eq N-Chlorosuccinimide was added in one portion and the reaction stirred at rt for 4 h then quenched by the addition of sat. NaHCO3 solution (5 mL). Ethyl acetate (15 mL) and water P-000059-WO-PCT-MYT - 117 - (15 mL) were added. The phases were separated and the aqueous phase extracted with ethyl acetate (2 x 20 mL). Combined organic phases were washed with NH4Cl (10 mL, 10% w / w aqueous solution), brine (20 mL), dried over MgSO4, filtered and concentrated in vacuo. Column chromatography (petrol:ethyl acetate) gave tert-butyl 4-amino-5-chloro-indazole-1-carboxylate (660 mg, 2.47 mmol, 65%).1H NMR (300 MHz, Methanol-d4) δ 8.35 (s, 1H), 7.39 – 7.17 (m, 2H), 1.68 (s, 9H). MS (ES-) m / z = 266, 268 ([M-H]-, 100) Synthesis of carboxylic acid reactants 3-(2-(cyclopropyl(methyl)amino)-2-oxoethyl)benzoic acid

[0853] HATU (587 mg, 1.54 mmol) was added to a solution of methyl 3-(2-(cyclopropyl(methyl)amino)- 2-oxoethyl)benzoate (250 mg, 1.29 mmol), N-methylcyclopropanamine hydrochloride (208 mg, 1.93 mmol and DIPEA (1.12 mL, 6.4 mmol) in anhydrous DMF (6 mL), with stirring at room temperature overnight. The reaction mixture was separated between ethyl acetate and water, and the organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give the crude product, which was purified using flash column chromatography over silica, eluting with 20-100% ethyl acetate / petroleum ether, to give methyl 3-(2-(cyclopropyl(methyl)amino)-2-oxoethyl)benzoate (280 mg, 88% yield) as clear colourless oil. MS (ES+) 248.3 (M+H);1H NMR (DMSO-d6, 300 MHz) δ 7.92- 7.88 (m, 2H), 7.49 (d, 1H, J = 7.9 Hz), 7.37 (t, 1H, J = 7.5 Hz), 3.92 (s, 2H), 3.88 (s, 3H), 2.92 (s, 3H), 2.68- 2.60 (m, 1H), 0.94-0.87 (m, 2H), 0.79-0.74 (m, 2H) ppm.

[0854] Lithium hydroxide monohydrate (73 mg, 1.70 mmol) was added to a solution of methyl 3-(2- (cyclopropyl(methyl)amino)-2-oxoethyl)benzoate (280 mg, 1.13 mmol) in methanol:water (2:1, 18 mL) with stirring at 40 °C overnight. The reaction mixture was then concentrated and separated between ethyl acetate and water. The aqueous phase was acidified to pH ~2 using 2 M aq. HCl and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered, concentrated and dried in a vacuum oven to give 3-(2-(cyclopropyl(methyl)amino)-2- oxoethyl)benzoic acid (265 mg, 100% yield) as an off-white semi-solid that was used directly in the next step. MS (ES+) 234.3 (M+H). acid intermediate P-000059-WO-PCT-MYT - 118 - General Procedure A1

[0855] HATU (1.2 equiv.) was added to a solution of methyl 2-amino-1,3-thiazole-5-carboxylate (1 equiv.), carboxylic acid (1.2 equiv.) and DIPEA (3 equiv.) in anhydrous DMF (0.2 M), with stirring at room temperature overnight. The reaction mixture was separated between ethyl acetate (containing 5% ethanol as necessary) and water, and the organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give the intermediate ester as a crude product, which was purified using flash column chromatography over silica or used directly, as required. Lithium hydroxide monohydrate (2.5 equiv.) was added to a solution of the methyl ester (1 equiv.) in methanol:water (2:1, 0.07 M) with stirring at 45 °C overnight. The reaction mixture was then concentrated and separated between ethyl acetate and 0.5 M aqueous sodium hydroxide. The aqueous phase was acidified to pH ~2 using 2 M aq. HCl and the product was either collected via filtration or extracted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The carboxylic acid was dried in a vacuum oven before further use. 2-benzamidothiazole-5-carboxylic acid

[0856] Prepared as described in method A1 from HATU (865 mg, 2.28 mmol), methyl 2-amino-1,3- thiazole-5-carboxylate (300 mg, 1.9 mmol), benzoic acid (278 mg, 2.26 mmol) and DIPEA (1.0 mL, 5.69 mmol) in anhydrous DMF (6 mL) and purification using flash column chromatography over silica, eluting with 0-10% methanol / dichloromethane to afford methyl 2-benzamidothiazole-5-carboxylate (185 mg, 37% yield), followed by hydrolysis with lithium hydroxide monohydrate (88 mg, 2.06 mmol) in methanol:THF:water (2:2:1, 5 mL) to give the title product (182 mg, 100% yield) as an off-white solid. MS (ES+) 249.4 (M+H);1H NMR (DMSO-d6, 300 MHz) δ 13.06 (br, 2H), 8.15 (s, 1H), 8.11 (d, 2H, J = 8.3 Hz), 7.66 (t, 1H, J = 7.3 Hz), 7.56 (t, 2H, J = 7.4 Hz) ppm

[0857] The following were obtained by the same General Method A1 # Compound Chemical Name Characterisation 1H NMR (DMSO-d6, 300 MHz) δ 13.10 (br, 1H), 12.52 (br, 1H), 8.79 2-(picolinamido) (ddd, 1H, J = 4.8, 1.7, 0.9 Hz), 8.21 thiazole-5-carboxylic (dt, 1H, J = 7.8, 1.2 Hz), 8.15 (s, 1H), acid 8.12 (td, 1H, J = 7.6, 1.7 Hz), 7.75 (ddd, 1H, J = 7.5, 4.7, 1.3 Hz) ppm; MS (ES+) 250.1 (M+H) P-000059-WO-PCT-MYT - 119 - General Procedure A2

[0858] Acid chloride (1.1 equiv.) was added drop-wise to a solution of methyl 2-amino-1,3-thiazole-5- carboxylate (1 equiv.) and pyridine (5 equiv.) in DCM (0.1 M), with stirring at room temperature overnight. The reaction mixture was then concentrated and separated between ethyl acetate (containing 5% ethanol as necessary) and water, and the organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give the intermediate ester as a crude product, which was purified using flash column chromatography over silica or used directly, as required.

[0859] The intermediate ester was hydrolysed with lithium hydroxide using the same conditions described in Method A1 to afford the corresponding carboxylic acid. 2-(3-(trifluoromethyl)benzamido)thiazole-5-carboxylic acid

[0860] Prepared as described in method A2 from 3-(trifluoromethyl)benzoyl chloride (0.31 mL, 2.09 mmol), methyl 2-amino-1,3-thiazole-5-carboxylate (300 mg, 1.9 mmol) and pyridine (0.77 mL, 9.48 mmol) in DCM (20 mL), and purification using flash column chromatography over silica, eluting with 10- 100% ethyl acetate / petroleum ether, to give methyl 2-(3-(trifluoromethyl)benzamido)thiazole-5- carboxylate (498 mg, 80% yield), followed by hydrolysis withlithium hydroxide monohydrate (186 mg, 4.3 mmol) in methanol:THF:water (2:2:1, 20 mL) to give the title product (392 mg, 86% yield) as a pale pink solid. MS (ES-) 315.0 (M-H);1H NMR (DMSO-d6, 300 MHz) δ 13.27 (br, 2H), 8.49 (s, 1H), 8.39 (d, 1H, J = 7.8 Hz), 8.15 (s, 1H), 8.02 (d, 1H, J = 7.8 Hz), 7.81 (t, 1H, J = 7.8 Hz) ppm;19F NMR (DMSO-d6, 282 MHz) δ -61.20 ppm.

[0861] The following were obtained by the same General Method A2 # Compound Chemical Name Characterisation 1H NMR (DMSO-d6, 300 MHz) δ 2-(3,4- 12.95 (br, 2H), 8.13 (s, 1H), 7.93 (d, dimethylbenzamido) 1H, J = 2.4 Hz), 7.85 (dd, 1H, J = 7.8, thiazole-5-carboxylic 2.2 Hz), 7.31 (d, 1H, J = 7.6 Hz), acid 2.30 (s, 6H) ppm; MS (ES+) 277.2 (M+H) 1 2-(3- H NMR (DMSO-d6, 300 MHz) δ methylbutanamido) 13.05 (br, 1H), 12.47 (s, 1H), 8.04 (s, 1H), 2.35 (d, 2H, J = 7.2 Hz), thiazole-5-carboxylic 2.15-2.02 (m, 1H), 0.91 (d, 6H, J = acid 6.6 Hz) ppm; MS (ES+) 229.2 (M+H) P-000059-WO-PCT-MYT - 120 - 2-(4-(tert-1H NMR (DMSO-d6, 300 MHz) δ butyl)benzamido) 13.01 (br, 2H), 8.14 (s, 1H), 8.06 (d, thiazole-5-carboxylic 2H, J = 8.8 Hz), 7.58 (d, 2H, J = 8.8 acid Hz), 1.32 (s, 9H) ppm 1 2-(3-(tert- H NMR (DMSO-d6, 300 MHz) δ 13.06 (br, 2H), 8.19-8.14 (m, 2H), butyl)benzamido) 7.93-7.90 (m, 1H), 7.70-7.64 (m, thiazole-5-carboxylic acid 1H), 7.48 (t, 1H, J = 7.8 Hz), 1.34 (s, 9H) ppm; MS (ES+) 305.3 (M+H) 1 2-(3- H NMR (DMSO-d6, 300 MHz) δ methoxybenzamido) 13.01 (br, 2H), 8.15 (s, 1H), 7.71- 7.68 (m, 2H), 7.47 (t, 1H, J = 8.2 thiazole-5-carboxylic acid Hz), 7.23-7.19 (m, 1H), 3.85 (s, 3H) ppm; MS (ES+) 279.0 (M+H) 2-(4-1H NMR (DMSO-d6, 300 MHz) δ methoxybenzamido) 12.73 (br, 2H), 8.15-8.10 (m, 3H), thiazole-5-carboxylic 7.08 (d, 2H, J = 9.0 Hz), 3.85 (s, 3H) acid ppm; MS (ES+) 279.2 (M+H) General Procedure A3

[0862] Oxalyl chloride (1.5 equiv.) was added drop-wise to a solution of carboxylic acid (1 equiv.) in DCM (0.1 M) and DMF (10 uL), with stirring at room temperature for 3 hours before concentrating to dryness. The residue was re-suspended in DCM (0.1 M) and methyl 2-amino-1,3-thiazole-5-carboxylate (1 equiv.) and pyridine (5 equiv.) were added, with stirring at room temperature overnight. The reaction mixture was then concentrated and separated between ethyl acetate (containing 5% ethanol as necessary) and water, and the organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give the intermediate ester as a crude product, which was purified using flash column chromatography over silica or used directly, as required. The intermediate ester was hydrolysed with lithium hydroxide using the same conditions described in Method A1 to afford the corresponding carboxylic acid. 2-(1-(tert-butyl)-1H-pyrazole-3-carboxamido)thiazole-5-carboxylic acid P-000059-WO-PCT-MYT - 121 -

[0863] Prepared as described in Method A3 fro l (0.19 mL, 2.2 8 mmol) and 1-(tert- butyl)-1H-pyrazole-3-carboxylic acid (255 mg, 1.52 mmol) in DCM (15 mL) and DMF (10 uL), and purified using flash column chromatography over silica, eluting with 20-100% ethyl acetate / petroleum ether to 5 give methyl 2-(1-(tert-butyl)-1H-pyrazole-3-carboxamido)thiazole-5-carboxylate (388 mg, 83% yield), followed by hydrolysis with lithium hydroxide monohydrat (80 mg, 1.87 mmol) in methanol:water (2:1, 18 mL) to give the title compound (332 mg, 90% yield) as an off-white solid. MS (ES+) 295.2 (M+H);1H NMR (DMSO-d6, 300 MHz) δ 12.55 (br, 2H), 8.13 (s, 1H), 8.03 (d, 1H, J = 2.4 Hz), 7.02 (d, 1H, J = 2.4 Hz), 1.58 (s, 9H) ppm 10

[0864] The following were obtained by the same General Method A3 # Compound Chemical Name Characterisation 2-(3-(2- MS (ES+) 360.0 (M+H) (cyclopropyl(methyl) amino)-2-oxoethyl) benzamido)thiazole-5- carboxylic acid 2-(4-(dimethyl MS (ES-) m / z 290.1 (M-H)- amino)benzamido) thiazole-5-carboxylic acid 2-(3-(tert-butyl)-1- 1H NMR (DMSO-d6, 300 MHz) δ methyl-1H-pyrazole-5- 13.07 (br, 2H), 8.13 (s, 1H), 7.30 (s, carboxamido)thiazole-5- 1H), 4.07 (s, 3H), 1.26 (s, 9H) ppm. carboxylic acid MS (ES+) m / z 309.1 (M+H)+. Synthesis of THP-Protected Amide Analogues 15 P-000059-WO-PCT-MYT - 122 - General Procedure D:

[0865] 1-Propanephosphonic anhydride (50% in ethyl acetate, 1.5 equiv.) was added drop-wise to a solution of amine (1 equiv.), thiazole-5-carboxylic acid (1.1 equiv.), and DIPEA (2 equiv.) in anhydrous THF (0.07 M), with stirring at room temperature, and the reaction mixture was then heated to 70 °C, with stirring under nitrogen overnight. After cooling to room temperature, the reaction was quenched with water and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give the crude product, which was purified using flash column chromatography over silica. 2-benzamido-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)thiazole-5-carboxamide

[0866] 1-Propanephosphonic anhydride (50% in Ethyl Acetate, 0.19 mL, 0.32 mmol) was added drop- wise to a solution of 5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-amine (50 mg, 0.22 mmol), 2- benzamidothiazole-5-carboxylic acid (59 mg, 0.24 mmol), and DIPEA (0.075 mL, 0.43 mmol) in anhydrous THF (3 mL), with stirring at room temperature, and the reaction mixture was then heated to 70 °C, with stirring under nitrogen overnight. After cooling to room temperature, the reaction was quenched with water and extracted with ethyl acetate, and the organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give the crude product, which was purified using flash column chromatography over silica, eluting with 50-100% ethyl acetate / petroleum, to give the title compound (28 mg, 28% yield) as an off-white solid. MS (ES+) 462.3 (M+H);1H NMR (MeOD-d4, 300 MHz) δ 8.34 (s, 1H), 8.07-7.94 (m, 3H), 7.65-7.37 (m, 5H), 5.82-5.78 (m, 1H), 4.06-3.92 (m, 1H), 3.89-3.74 (m, 1H), 2.56-2.32 (m, 4H), 2.11-2.02 (m, 2H), 1.89-1.61 (m, 3H) ppm

[0867] The following were obtained by the same General Method D from the corresponding carboxylic acids: # Compound Chemical Name Characterisation 1H NMR (DMSO-d6, 300 MHz) δ 12.39 (s, N-(5-methyl-1- 1H), 10.33 (s, 1H), 8.80 (ddd, 1H, J = 4.8, (tetrahydro-2H- 1.7, 0.9 Hz), 8.46 (s, 1H), 8.22 (dt, 1H, J = 7.9, 1.2 Hz), 8.12 (td, 1H, J = 7.7, 1.7 Hz), pyran-2-yl)-1H- 7.92 (d, 1H, J = 0.9 Hz), 7.75 (ddd, 1H, J = indazol-4-yl)-2- (picolinamido) 7.6, 4.8, 1.3 Hz), 7.58 (d, 1H, J = 8.5 Hz), thiazole-5- 7.35 (d, 1H, J = 8.9 Hz), 5.83 (dd, 1H, J = 9.7, 2.5 Hz), 3.92-3.88 (m, 1H), 3.79-3.70 carboxamide (m, 1H), 2.46-2.35 (m, 1H), 2.31 (s, 3H), 2.06-1.94 (m, 2H), 1.79-1.72 (m, 1H), P-000059-WO-PCT-MYT - 123 - 1.60-1.56 (m, 2H) ppm; MS (ES+) 463.5 (M+H) 1H NMR (DMSO-d6, 300 MHz) δ 13.26 (s, 1H), 10.30 (s, 1H), 8.50 (d, 2H, J = 14.7 N-(5-methyl-1- (tetrahydro-2H- Hz), 8.41 (d, 1H, J = 8.1 Hz), 8.04 (d, 1H, J pyran-2-yl)-1H- = 7.8 Hz), 7.92 (s, 1H), 7.83 (t, 1H, J = 7.7 indazol-4-yl)-2-(3- Hz), 7.58 (d, 1H, J = 8.3 Hz), 7.35 (d, 1H, J = 8.7 Hz), 5.83 (dd, 1H, J = 9.7, 2.6 Hz), (trifluoromethyl) benzamido) 3.92-3.88 (m, 1H), 3.79-3.70 (m, 1H), thiazole-5- 2.46-2.35 (m, 1H), 2.31 (s, 3H), 2.06-1.94 (m, 2H), 1.79-1.72 (m, 1H), 1.60-1.54 (m, carboxamide 2H) ppm;19F NMR (DMSO-d6, 282 MHz) δ -61.18 ppm; MS (ES+) 530.3 (M+H) 1H NMR (DMSO-d6, 300 MHz) δ 12.81 (s, 2-(3,4- 1H), 10.25 (s, 1H), 8.44 (s, 1H), 7.96 (d, dimethylbenzamido) 1H, J = 2.2 Hz), 7.92 (s, 1H), 7.88 (dd, 1H, J -N-(5-methyl-1- = 7.8, 2.1 Hz), 7.58 (d, 1H, J = 8.6 Hz), (tetrahydro-2H- 7.36-7.32 (m, 2H), 5.83 (dd, 1H, J = 9.7, pyran-2-yl)-1H- 2.5 Hz), 3.92-3.88 (m, 1H), 3.79-3.70 (m, indazol-4-yl)thiazole- 1H), 2.46-2.36 (m, 1H), 2.32 (s, 9H), 2.06- 5-carboxamide 1.94 (m, 2H), 1.79-1.70 (m, 1H), 1.62-1.55 (m, 2H) ppm; MS (ES+) 490.3 (M+H) 1H NMR (DMSO-d6, 300 MHz) δ 12.41 (s, N-(5-methyl-1- 1H), 10.22 (s, 1H), 8.35 (s, 1H), 7.89 (s, (tetrahydro-2H- 1H), 7.57 (d, 1H, J = 8.6 Hz), 7.33 (d, 1H, J pyran-2-yl)-1H- = 8.8 Hz), 5.82 (dd, 1H, J = 9.7, 2.6 Hz), indazol-4-yl)-2-(3- 3.91-3.87 (m, 1H), 3.78-3.70 (m, 1H), methylbutanamido) 2.45-2.34 (m, 3H), 2.29 (s, 3H), 2.17-1.19 thiazole-5- (m, 3H), 1.78-1.72 (m, 1H), 1.62-1.54 (m, carboxamide 2H), 0.93 (d, 6H, J = 6.7 Hz) ppm; MS (ES+) 442.3 (M+H) 2-(4-(tert-1H NMR (DMSO-d6, 300 MHz) δ 12.91 (s, butyl)benzamido)-N- 1H), 10.28 (s, 1H), 8.46 (s, 1H), 8.09 (d, (5-methyl-1- 2H, J = 8.8 Hz), 7.93 (d, 1H, J = 0.8 Hz), (tetrahydro-2H- 7.60-7.57 (m, 3H), 7.34 (d, 1H, J = 8.9 Hz), pyran-2-yl)-1H- 5.83 (dd, 1H, J = 9.7, 2.5 Hz), 3.92-3.88 indazol-4-yl)thiazole- (m, 1H), 3.79-3.70 (m, 1H), 2.46-2.34 (m, 5-carboxamide 1H), 2.31 (s, 3H), 2.06-1.94 (m, 2H), 1.79- P-000059-WO-PCT-MYT - 124 - 1.53 (m, 3H), 1.33 (s, 9H) ppm; MS (ES+) 518.4 (M+H) 1H NMR (DMSO-d6, 300 MHz) δ 13.04 (s, 1H), 10.28 (s, 1H), 8.47 (s, 1H), 8.18 (t, 1H, 2-(3-(tert- butyl)benzamido)-N- J = 1.9 Hz), 7.96-7.92 (m, 2H), 7.70 (d, 1H, (5-methyl-1- J = 7.9 Hz), 7.58 (d, 1H, J = 8.7 Hz), 7.50 (t, (tetrahydro-2H- 1H, J = 7.8 Hz), 7.34 (d, 1H, J = 8.9 Hz), 5.83 (dd, 1H, J = 9.7, 2.4 Hz), 3.92-3.88 pyran-2-yl)-1H- indazol-4-yl)thiazole- (m, 1H), 3.79-3.70 (m, 1H), 2.46-2.35 (m, 5-carboxamide 1H), 2.31 (s, 3H), 2.06-1.94 (m, 2H), 1.79- 1.72 (m, 1H), 1.62-1.54 (m, 2H), 1.36 (s, 9H) ppm; MS (ES+) 518.4 (M+H) 1H NMR (DMSO-d6, 300 MHz) δ 13.02 (br, 2-(3- 1H), 10.30 (s, 1H), 8.47 (s, 1H), 7.92 (d, 1H, J = 0.9 Hz), 7.74-7.68 (m, 2H), 7.58 (d, methoxybenzamido)- 1H, J = 8.6 Hz), 7.48 (t, 1H, J = 8.2 Hz), N-(5-methyl-1- (tetrahydro-2H- 7.34 (d, 1H, J = 8.9 Hz), 7.25-7.21 (m, 1H), pyran-2-yl)-1H- 5.83 (dd, 1H, J = 9.7, 2.5 Hz), 3.92-3.87 (m, 1H), 3.86 (s, 3H), 3.79-3.70 (m, 1H), indazol-4-yl)thiazole- 2.46-2.36 (m, 1H), 2.31 (s, 3H), 2.06-1.94 5-carboxamide (m, 2H), 1.78-1.72 (m, 1H), 1.62-1.54 (m, 2H) ppm; MS (ES+) 492.3 (M+H) 1H NMR (DMSO-d6, 300 MHz) δ 12.82 (s, 1H), 10.27 (s, 1H), 8.45 (s, 1H), 8.15 (d, 2-(4- methoxybenzamido)- 2H, J = 9.0 Hz), 7.92 (d, 1H, J = 0.9 Hz), N-(5-methyl-1- 7.58 (d, 1H, J = 8.6 Hz), 7.34 (d, 1H, J = 8.9 Hz), 7.10 (d, 2H, J = 9.1 Hz), 5.83 (dd, 1H, J (tetrahydro-2H- pyran-2-yl)-1H- = 9.8, 2.5 Hz), 3.92-3.87 (m, 1H), 3.86 (s, indazol-4-yl)thiazole- 3H), 3.79-3.70 (m, 1H), 2.46-2.34 (m, 1H), 5-carboxamide 2.31 (s, 3H), 2.06-1.94 (m, 2H), 1.78-1.72 (m, 1H), 1.62-1.54 (m, 2H) ppm; MS (ES+) 492.4 (M+H) P-000059-WO-PCT-MYT - 125 - 1H NMR (DMSO-d6, 300 MHz) δ 12.44 (s, 2-(1-(tert-butyl)-1H- 1H), 10.28 (s, 1H), 8.44 (s, 1H), 8.05 (d, pyrazole-3- 1H, J = 2.5 Hz), 7.92 (d, 1H, J = 0.9 Hz), carboxamido)-N-(5- 7.58 (d, 1H, J = 8.5 Hz), 7.34 (d, 1H, J = 8.9 methyl-1- Hz), 7.03 (d, 1H, J = 2.4 Hz), 5.83 (dd, 1H, J (tetrahydro-2H- = 9.7, 2.4 Hz), 3.91-3.88 (m, 1H), 3.79- pyran-2-yl)-1H- 3.70 (m, 1H), 2.46-2.34 (m, 1H), 2.31 (s, indazol-4-yl)thiazole- 3H), 2.06-1.93 (m, 2H), 1.81-1.72 (m, 1H), 5-carboxamide 1.62-1.54 (m, 11H) ppm; MS (ES+) 508.4 (M+H) 1H NMR (CDCl3 containing 10% MeOD, 2-(3-(2- 300 MHz) δ 7.99 (br, 1H), 7.85 (s, 1H), (cyclopropyl(methyl) 7.81 (dt, 1H, J = 6.6, 2.1 Hz), 7.75 (s, 1H), amino)-2- 7.44-7.34 (m, 3H), 7.21 (d, 1H, J = 8.7 Hz), oxoethyl)benzamido) 5.60 (dd, 1H, J = 9.7, 2.6 Hz), 3.98-3.94 -N-(5-methyl-1- (m, 1H), 3.91 (s, 2H), 3.71-3.66 (m, 1H), (tetrahydro-2H- 2.81 (s, 3H), 2.72-2.65 (m, 1H), 2.46-2.35 pyran-2-yl)-1H- (m, 1H), 2.28 (s, 3H), 2.04-1.93 (m, 2H), indazol-4-yl)thiazole- 1.70-1.58 (m, 3H), 0.94-0.87 (m, 2H), 5-carboxamide 0.77-0.72 (m, 2H) ppm; MS (ES+) 573.4 (M+H) 1H NMR (CDCL3, 300 MHz) δ 12.47 (br, 2-(2,4- 1H), 7.88 (d, 1H, J = 0.9 Hz), 7.52 (s, 1H), dimethylbenzamido) 7.48 (d, 1H, J = 7.5 Hz), 7.41 (d, 1H, J = 8.6 -N-(5-methyl-1- Hz), 7.22 (d, 1H, J = 8.9 Hz), 7.19 (s, 1H), (tetrahydro-2H- 7.14-7.10 (m, 2H), 5.68 (dd, 1H, J = 9.3, pyran-2-yl)-1H- 2.7 Hz), 4.04-4.00 (m, 1H), 3.78-3.70 (m, indazol-4-yl)thiazole- 1H), 2.58-2.50 (m, 1H), 2.48 (s, 3H), 2.34 5-carboxamide (s, 6H), 2.17-2.03 (m, 2H), 1.79-1.65 (m, 3H) ppm; MS (ES+) m / z 490.4 (M+H)+. 2-(4-(dimethyl amino)benzamido)- N-(5-methyl-1- (tetrahydro-2H- MS (ES+) m / z 505.2 (M+H)+ pyran-2-yl)-1H- indazol-4-yl)thiazole- 5-carboxamide P-000059-WO-PCT-MYT - 126 - 2-(3-(tert-butyl)-1- 1H NMR (DMSO-d6, 300 MHz) δ 12.89 methyl-1H-pyrazole- (br, 1H), 10.28 (s, 1H), 8.44 (s, 1H), 7.91 5-carboxamido)-N- (s, 1H), 7.58 (d, 1H, J = 8.6 Hz), 7.35- 7.32 (m, 2H), 5.83 (dd, 1H, J = 9.7, 2.5 Hz), (5-methyl-1- (tetrahydro-2H- 4.09 (s, 3H), 3.91-3.88 (m, 1H), 3.79-3.70 pyran-2-yl)-1H- (m, 1H), 2.46-2.36 (m, 1H), 2.31 (s, 3H), 2.06-1.94 (m, 2H), 1.79-1.72 (m, 1H), indazol-4-yl)thiazole- 1.62-1.55 (m, 2H), 1.28 (s, 9H) ppm. MS 5-carboxamide (ES+) m / z 522.5 (M+H)+. tert-butyl 4-[[2-[(4-tert-butylbenzoyl)amino]thiazole-5-carbonyl]amino]-5-chloro-indazole-1-carboxylate

[0868] Phosphorus(v) oxychloride (0.017 ml, 0.181 mmol, 1.10 eq) was added dropwise to a mixture 5 of 2-[(4-tert-butylbenzoyl)amino]thiazole-5-carboxylic acid (80%, 63 mg, 0.166 mmol, 1.01 eq), tert- butyl 4-amino-5-chloro-indazole-1-carboxylate (44 mg, 0.164 mmol, 1.00 eq) and pyridine (0.040 ml, 0.493 mmol, 3.00 eq) in acetonitrile (10 ml) at 0°c. The reaction was stirred at 0 °c for 30 min, allowed to warm to rt then stirred for 52 h. The reaction was quenched by the addition of sat. aq. NaHCO3 solution (1 ml) then concentrated in vacuo. Column chromatography (dichloromethane:methanol) gave the title 10 product (10 mg, 0.0180 mmol, 11%).1H NMR (300 MHz, MeOD) δ 8.39 (s, 1H), 8.23 (d, J = 0.8 Hz, 1H), 8.10 (dd, J = 9.0, 0.9 Hz, 1H), 8.04 – 7.98 (m, 2H), 7.71 (d, J = 9.0 Hz, 1H), 7.65 – 7.58 (m, 2H), 1.73 (s, 9H), 1.38 (s, 9H). MS (ES-) m / z = 552, 554 ([M-H]-, 100). 15 General Procedure E:

[0869] TFA (50 equiv.) was added to a solution of the THP protected compound (1 equiv.) in DCM (~0.07 M) with stirring under nitrogen for 3 hours before concentrating in vacuo. Methanol was added and the mixture concentrated again and the resulting precipitate was washed with diethyl ether to give 20 the final compound. P-000059-WO-PCT-MYT - 127 - 2-benzamido-N-(5-methyl-1H-indazol-4-yl)thiazole-5-carboxamide.TFA salt (BAA-001)

[0870] TFA (0.23 mL, 3.03 mmol) was added to a solution of 2-benzamido-N-(5-methyl-1-(tetrahydro- 2H-pyran-2-yl)-1H-indazol-4-yl)thiazole-5-carboxamide (28 mg, 0.061 mmol) in DCM (0.75 mL), with stirring under nitrogen for 3 hours before concentrating in vacuo. Methanol was added and the mixture concentrated again and the resulting precipitate was washed with diethyl ether to give the title compound (24 mg, 80% yield) as an off-white solid. MS (ES+) 378.4 (M+H);1H NMR (DMSO-d6, 300 MHz) δ 12.96 (br, 2H), 10.24 (s, 1H), 8.45 (s, 1H), 8.15-8.12 (m, 2H), 7.88 (d, 1H, J = 1.0 Hz), 7.67 (t, 1H, J = 7.3 Hz), 7.57 (t, 2H, J = 7.4 Hz), 7.39 (d, 1H, J = 8.5 Hz), 7.27 (d, 1H, J = 8.8 Hz), 2.30 (s, 3H) ppm;19F NMR (DMSO-d6, 282 MHz) δ -74.83 ppm

[0871] The following were obtained by the same General Method E from the corresponding THP- protected amide analogues # Compound Chemical Name Characterisation 1H NMR (DMSO-d6, 300 MHz) δ 12.98 (br, N-(5-methyl-1H- 1H), 12.37 (br, 1H), 10.29 (s, 1H), 8.80 (d, indazol-4-yl)-2- 1H, J = 4.7 Hz), 8.46 (s, 1H), 8.23 (d, 1H, J = 7.8 Hz), 8.12 (td, 1H, J = 7.7, 1.7 Hz), BAA- (picolinamido 002 )thiazole-5- 7.89 (d, 1H, J = 1.1 Hz), 7.75 (ddd, 1H, J = carboxamide.TFA 7.6, 4.8, 1.4 Hz), 7.40 (d, 1H, J = 8.5 Hz), salt 7.27 (d, 1H, J = 8.5 Hz), 2.30 (s, 3H) ppm; 19F NMR (DMSO-d6, 282 MHz) δ -74.66 ppm; MS (ES+) 379.3 (M+H) 1 N-(5-methyl-1H- H NMR (DMSO-d6, 300 MHz) δ 13.23- indazol-4-yl)-2-(3- 13.02 (br, 2H), 10.27 (s, 1H), 8.52 (s, 1H), 8.47 (s, 1H), 8.41 (d, 1H, J = 7.8 Hz), 8.04 BAA- (trifluoromethyl) benzamido) (d, 1H, J = 7.8 Hz), 7.89 (d, 1H, J = 1.0 Hz), 003 thiazole-5- 7.82 (t, 1H, J = 7.9 Hz), 7.40 (d, 1H, J = 8.4 Hz), 7.27 (d, 1H, J = 8.7 Hz), 2.30 (s, 3H) carboxamide.TFA ppm;19F NMR (DMSO-d6, 282 MHz) δ - salt 61.18, -74.30 ppm; MS (ES+) 446.2 (M+H) P-000059-WO-PCT-MYT - 128 - 2-(3,4-1H NMR (DMSO-d6, 300 MHz) δ 12.79 (br, dimethylbenzami 2H), 10.23 (s, 1H), 8.44 (s, 1H), 7.96 (d, BAA- do)-N-(5-methyl- 1H, J = 2.2 Hz), 7.90-7.86 (m, 2H), 7.39 (d, 1H-indazol-4- 1H, J = 8.4 Hz), 7.33 (d, 1H, J = 7.8 Hz), 004 yl)thiazole-5- 7.27 (d, 1H, J = 8.6 Hz), 2.32 (s, 6H), 2.30 carboxamide.TFA (s, 3H) ppm;19F NMR (DMSO-d6, 282 salt MHz) δ -75.00 ppm; MS (ES+) 406.7 (M+H) 1H NMR (DMSO-d6, 300 MHz) δ 12.93 (br, N-(5-methyl-1H- indazol-4-yl)-2-(3- 1H), 12.41 (s, 1H), 10.20 (s, 1H), 8.34 (s, methy 1H), 7.85 (d, 1H, J = 1.0 Hz), 7.38 (d, 1H, J BAA- l = 8.4 Hz), 7.26 (d, 1H, J = 8.8 Hz), 2.37 (d, 005 butanamido 2H, J = 7.1 Hz), 2.27 (s, 3H), 2.11 (dt, 1H, J )thiazole-5- carboxamide.TFA = 14.1, 7.1 Hz), 0.93 (d, 6H, J = 6.6 Hz) salt ppm;19F NMR (DMSO-d6, 282 MHz) δ - 74.95 ppm; MS (ES+) 358.3 (M+H) 1H NMR (DMSO-d6, 300 MHz) δ 13.02 (br, 2-(4-(tert- butyl)benzamido) 1H), 12.89 (br, 1H), 10.24 (s, 1H), 8.45 (s, -N-(5-methyl-1H 1H), 8.09 (d, 2H, J = 8.8 Hz), 7.88 (d, 1H, J BAA- - = 1.0 Hz), 7.59 (d, 2H, J = 8.9 Hz), 7.39 (d, 006 indazol-4- 1H, J = 8.4 Hz), 7.27 (d, 1H, J = 8.9 Hz), yl)thiazole-5- xamide.TFA 2.30 (s,19carbo 3H), 1.33 (s, 9H) ppm; F NMR salt (DMSO-d6, 282 MHz) δ -74.38 ppm; MS (ES+) 434.3 (M+H) 1H NMR (DMSO-d6, 300 MHz) δ 13.04 (br, 2-(3-(tert- butyl)benzamido) 2H), 10.25 (s, 1H), 8.46 (s, 1H), 8.18 (t, 1H, - J = 1.9 Hz), 7.94 (d, 1H, J = 8.4 Hz), 7.89 BAA- N-(5-methyl-1H- (d, 1H, J = 1.0 Hz), 7.70 (d, 1H, J = 7.9 Hz), 007 indazol-4- yl)thiazole-5- 7.50 (t, 1H, J = 7.8 Hz), 7.39 (d, 1H, J = 8.4 carboxamide.TFA Hz), 7.27 (d, 1H, J = 8.7 Hz), 2.30 (s, 3H), salt 1.36 (s, 9H) ppm;19F NMR (DMSO-d6, 282 MHz) δ -74.48 ppm; MS (ES+) 434.4 (M+H) 1 2-(3- H NMR (DMSO-d6, 300 MHz) δ 12.99 (br, methoxybenzami 2H), 10.26 (s, 1H), 8.46 (s, 1H), 7.89 (d, do)-N-(5-m 1H, J = 1.0 Hz), 7.73-7.68 (m, 2H), 7.48 (t, BAA- ethyl- 1H, J = 8.2 Hz), 7.40 (d, 1H, J = 8.5 Hz), 008 1H-indazol-4- yl)thiazole-5- 7.27 (d, 1H, J = 8.8 Hz), 7.24-7.20 (m, 1H), de.TFA 3.86 (s, 3H),19carboxami 2.30 (s, 3H) ppm; F NMR salt (DMSO-d6, 282 MHz) δ -74.98 ppm; MS (ES+) 408.3 (M+H) P-000059-WO-PCT-MYT - 129 - 2-(4-1methoxybenzami H NMR (DMSO-d6, 300 MHz) δ 12.80 (br, do)-N-(5 2H), 10.24 (s, 1H), 8.44 (s, 1H), 8.15 (d, BAA- -methyl- 2H, J = 9.0 Hz), 7.88 (d, 1H, J = 1.0 Hz), 009 1H-indazol-4- yl)thiazole-5- 7.39 (d, 1H, J = 8.5 Hz), 7.27 (d, 1H, J = 8.7 carboxamide.TFA Hz), 7.10 (d, 2H, J = 9.0 Hz), 3.86 (s, 3H), 2.29 (s, 3H) ppm;19F NMR (DMSO-d, 282 salt 6 MHz) δ -74.93 ppm; MS (ES+) 408.3 (M+H) 2-(1-(tert-butyl)-1H NMR (DMSO-d6, 300 MHz) δ 13.03 (br, 1H-pyrazole-3- 1H), 12.42 (s, 1H), 10.25 (s, 1H), 8.44 (s, carboxamido)-N- 1H), 8.05 (d, 1H, J = 2.4 Hz), 7.89 (d, 1H, J BAA- (5-methyl-1H- = 1.0 Hz), 7.39 (d, 1H, J = 8.5 Hz), 7.27 (d, 010 indazol-4- 1H, J = 8.7 Hz), 7.03 (d, 1H, J = 2.5 Hz), yl)thiazole-5- 2.29 (s, 3H), 1.60 (s, 9H) ppm;19F NMR carboxamide.TFA (DMSO-d6, 282 MHz) δ -74.00 ppm; MS salt (ES+) 424.3 (M+H) 2-(3-(2-(cyclo1H NMR (DMSO-d, 300 MHz) δ 12.94 (br, propyl(methyl) 6 amino)-2-oxo 2H), 10.25 (s, 1H), 8.45 (s, 1H), 8.02-7.96 ethyl)benzamido) (m, 2H), 7.88 (d, 1H, J = 1.0 Hz), 7.54-7.46 BAA- -N-(5-me (m, 2H), 7.39 (d, 1H, J = 8.4 Hz), 7.27 (d, 011 thyl-1H- 1H, J = 8.7 Hz), 3.97 (s, 2H), 2.85-2.78 (m, indazol-4-yl) thiazole-5- 4H), 2.30 (s, 3H), 0.94-0.80 (m, 4H) ppm; 19carboxamide.TFA F NMR (DMSO-d6, 282 MHz) δ -74.62 ppm; MS (ES+) 489.4 (M+H) salt 2-(2,4-dimethyl 1H NMR (DMSO-d6, 300 MHz) δ 12.99 (br, 1H), 12.76 (br, 1H), 10.24 (s, 1H), 8.41 benzamido)-N-(5- BAA- methyl-1H- (s, 1H), 7.87 (d, 1H, J = 1.0 Hz), 7.52 (d, 013 indazol-4-yl) 1H, J = 7.7 Hz), 7.39 (d, 1H, J = 8.4 thiazole-5- Hz), 7.27 (d, 1H, J = 8.6 Hz), 7.17-7.13 (m, 2H), 2.40 (s, 3H), 2.34 (s, 3H), 2.29 (s, carboxamide 3H) ppm;MS (ES+) m / z 406.3 (M+H)+. 1 2-(4-(dimethyl H NMR (DMSO-d6, 300 MHz) δ 12.52 (br, amino)benzamido 2H), 10.19 (s, 1H), 8.41 (s, 1H), 8.04 (d, 2H, J = 9.1 Hz), 7.88 (d, 1H, J = 1.0 Hz), BAA- )-N-(5-methyl-1H- 014 indazol-4-yl) 7.39 (d, 1H, J = 8.5 Hz), 7.26 (d, 1H, J = 8.6 thiazole-5- Hz), 6.77 (d, 2H, J = 9.2 Hz), 3.03 (s, 6H), carboxamide 2.29 (s, 3H) ppm. MS (ES+) m / z 421.1 (M+H)+. P-000059-WO-PCT-MYT - 130 - 2-(3-(tert-butyl)-1H NMR (DMSO-d6, 300 MHz) δ 2.86 (br, 1-methyl-1H- 2H), 10.25 (s, 1H), 8.44 (s, 1H), 7.88 (d, pyrazole-5- carboxamido)-N- 1H, J= 1.0 Hz), 7.39 (d, 1H, J = 8.4 Hz), BAA- (5-methyl-1H- 7.33 (s, 1H), 7.27 (d, 1H, J = 8.6 Hz), 4.09 015 (s, 3H), 2.29 (s, 3H), 1.28 (s, 9H) ppm.19F indazol-4- yl)thiazole-5- NMR (DMSO-d6, 282 MHz) δ -74.71 ppm carboxamide.TFA MS (ES+) m / z 438.2 (M+H)+. salt 2-[(4-tert-butylbenzoyl)amino]-N-(5-chloro-1H-indazol-4-yl)thiazole-5-carboxamide (TFA salt) (BAA-012)

[0872] tert-butyl 4-[[2-[(4-tert-butylbenzoyl)amino]thiazole-5-carbonyl]amino]-5-chloro-indazole-1- carboxylate (11 mg, 0.0199 mmol, 1.00 eq) was stirred in DCM (3 mL) and trifluoroacetic acid (3.0 mL, 38.9 mmol, 1961 eq) for 1 h at rt then concentrated in vacuo. Trituration with ether gave 2-[(4-tert- butylbenzoyl)amino]-N-(5-chloro-1H-indazol-4-yl)thiazole-5-carboxamide (2,2,2-trifluoroacetic acid salt; 7.0 mg, 0.0123 mmol, 62%) .1H NMR (300 MHz, MeOD) δ 8.39 (s, 1H), 8.02 (d, J = 7.2 Hz, 3H), 7.63 (d, J = 8.2 Hz, 2H), 7.50 (s, 2H), 1.40 (d, J = 2.2 Hz, 9H).19F NMR (282 MHz, MeOD) δ -77.49. MS (ES+) m / z = 454, 456 ([M+H]+, 100). Biological Methods and Data BIOLOGICAL EXAMPLE 1: PKMYT1 protein production

[0873] Human PKMYT175-362 was cloned as a TEV cleavable 6xHis fusion in bacterial cells. After purification on a Ni++ HiTrap Chelating HP column, the His-tag was cleaved using TEV protease. Cleaved PKMYT1 was further purified on a Superdex 20016 / 600 sizing column. The fractions containing PKMYT1 were pooled and concentrated using an ultrafiltration centrifugal protein concentrator. The purified protein was aliquoted, flash frozen in liquid nitrogen, and stored at −80°C. BIOLOGICAL EXAMPLE 2: ADP-Glo enzymatic assays

[0874] PKMYT1 biochemical assay: Inhibition of PKMYT1 was assessed using the ADP-GloTMMax Detection System from Promega. This assay detects the production of ADP from ATP by PKMYT1 via a two-step process ultimately involving the conversion of ADP to ATP with the latter converted to light in a coupled reaction with luciferase / luciferin. Inhibition of PKMYT1 by small molecule inhibitors results in a retardation of luminescence above background. The intrinsic ATPase activity of PKMYT1 was assessed P-000059-WO-PCT-MYT - 131 - according to the following protocol. Compounds were dosed into Corning white low volume 384 well assay plates using an Echo acoustic dispenser to generate 10-point curves spanning a 3-fold dilution series. DMSO (no inhibitor) control wells were prepared to benchmark the maximum and minimum signals in the presence and absence of PKMYT1, respectively. The PKMYT1 kinase domain was purified in-house, as described above, and added to the wells at a final concentration of 15 nM in a buffer of 50 mM HEPES (pH 7.5), 10 mM MgCl2, 1 mM EGTA, 0.01 % Brij-35, 1 % DMSO.500 μM ATP was added to start the reaction with the final assay volume being 4 μl. The plate was then incubated for 60 minutes at 26oC before the addition of 4 μl of ADP-Glo Reagent to stop the reaction and deplete the unconsumed ATP. Following a further 60 minute incubation the assay signal was developed by the addition of 8 μl ADP-Glo Max Detection Reagent. After 60 minutes the luminescence signal was read on a PHERAStar FS microplate reader (BMG Labtech).

[0875] Selectivity versus WEE1 assay: Selectivity was established using the same format as outlined for PKMYT1. After dosing of compounds via the Echo acoustic dispenser – as described above – WEE1 (Thermo Fisher PR7373A) was added to each well at a final concentration of 15 nM in a buffer of 50 mM HEPES (pH 7.5), 10 mM MgCl2, 1 mM EGTA, 0.01 % Brij-35, 1 % DMSO.30 μM ATP was added to start the reaction with the final assay volume being 4 μl. The plate was then incubated for 60 minutes at 26oC before the addition of 4 μl of ADP-Glo Reagent. Following a further 60 minute incubation the assay signal was developed by the addition of 8 μl ADP-Glo Detection Reagent. After 60 minutes the luminescence signal was read on a PHERAStar FS microplate reader (BMG Labtech).

[0876] Data analysis: Data was captured and analysed within the Dotmatics Studies software module where dose response curves were generated and IC50 values determined. Acceptance and verification of data followed strict in-house business rules which are summarised as follows. All assay plates should demonstrate Z’ values >0.5 and reference compounds run on each plate should fall within 2-fold of the geometric mean of historical IC50 values. Technical and biological replicates of each compound are routinely tested and replicate IC50 values must fall within 3-fold of each other with dose response curves showing ‘goodness of fit’ r2 values >0.9. Failure to meet any of these defined criteria result in rejection of data.

[0877] The data for the primary biochemical assay (PKMYT1 IC50) and selectivity assay (WEE1 IC50) are summarised in the following Biological Data Table 1.

[0878] The PKMYT1 IC50 and WEE1 IC50 values are banded as follows: A: <50 nM; B: 50 nM - <1 μM; C: 1 μM – 11 μM; D: >11 μM.

[0879] The PKMYT1 vs WEE1 selectivity is banded by fold difference in selectivity for PKMYT1 over WEE1 as follows: V: 3 - <10 fold; W: 10 - <100 fold; X: 100 - <1000 fold; Y: >1000 fold.

[0880] Where either the PKMYT1 IC50 value was below the lowest concentration limit of the assay or the WEE1 IC50 value was above the top concentration limit of the assay, the PKMYT1 vs WEE1 selectivity value for these compounds falls at least in the band assigned but could be higher. P-000059-WO-PCT-MYT - 132 - Biological Data Table 1 PKMYT1 # PKMYT1 WEE1 IC50 vs. WEE1 IC50 (µM) (µM) selectivity (fold) BAA-001 A D Y BAA-002 A D Y BAA-003 B D X BAA-004 B D Y BAA-005 C BAA-006 B D X BAA-007 B D X BAA-008 B D Y BAA-009 A D Y BAA-010 A D Y BAA-011 A D Y BAA-012 B D X BAA-013 B D X BAA-014 A D Y BAA-015 A D Y BIOLOGICAL EXAMPLE 3: Cancer Cell Lines Proliferation Assays 5

[0881] Cancer cell lines with either normal (KYSE-30) or amplified CCNE1 expression (OVCAR3 – ovarian cancer) were evaluated for their sensitivity to PKMYT1 inhibitors using Cell Titre Glow assay (Promega G7573) as endpoint to assess cell proliferation. The luminescence signal was read on a PHERAStar FS microplate reader (BMG Labtech). Data analysis was performed using Microsoft Excel® and GI50 (concentration that achieves 50% cell growth proliferation inhibition) estimates generated with 10 GraphPad Prism v9.

[0882] The following compounds in Biological Data Table 2 inhibit OVCAR3 cell proliferation with a GI50 <5 μM. In addition, selected compounds exhibit >3-fold selectivity for the CCNE1-amplified OVCAR3 cells compared to KYSE30 cells expressing normal levels of CCNE1. (Cell proliferation inhibition in cancer cell lines: OVCAR3 expresses high level of CCNE1; control cell line KYSE30 expresses normal levels of CCNE1.) 15

[0883] The cell line GI50 values are banded as follows: A: <1 μM; B: 1 μM - <5 μM; C: >5 μM.

[0884] The normal CCNE1 expression cell line (KYSE-30) to CCNE1-amplified cell line (OVCAR3) GI50 selectivity ratio is banded by fold difference as follows: X: 3 - <10 fold; Y: >10 fold. P-000059-WO-PCT-MYT - 133 -

[0885] Where either the OVCAR3 GI50 value was below the lowest concentration limit of the assay or the KYSE30 GI50 value was above the top concentration limit of the assay, the selectivity ratio KYSE30 GI50 vs. OVCAR3 GI50 is given as “>N”, where N is the selectivity band. The selectivity value for these compounds falls at least in this band but could be higher. 5 Biological Data Table 2 Selectivity ratio # OVCAR3 KYSE30 GI50 (μM) GI50 (μM) KYSE30 GI50 vs. OVCAR3 GI50 BAA-001 B C X BAA-004 A C Y BAA-005 B C X BAA-006 A B Y BAA-007 B C X BAA-008 A C Y BAA-009 A C Y BAA-010 A C Y BAA-011 B C X BAA-013 B C X BIOLOGICAL EXAMPLE 4: Inhibition of cellular PKMYT1 biomarker CDK1 pT14 10

[0886] To determine compound PKMYT1 IC50in a cellular assay, OVCAR 3 cells were incubated at 37°C in 5% CO2 atmosphere. The cells were maintained in RPMI medium supplemented with 20% foetal bovine serum, 1X non essential amino acids, 1mM sodium pyruvate, Glutamax and insulin. Cells were seeded into 12-well plates at low density (50,000-200,000 cells per well), grown to confluence (~350- 400,000 cells per well) and then treated with a range of concentrations of PKMYT1 inhibitors. The cells15 were incubated 20 hours and then harvested into 1X Laemmli Sample Buffer (BIORAD) without 2- mercaptoethanol, heated to 95°C for 5 min, centrifuged and sonicated using a microprobe for 15 sec, 21W to shear the DNA.

[0887] The samples were analysed by immunoblot on a Jess Automated Western Blot System (BioTechne). The samples were separated using the 12-230 kDa Separation Module (BioTechne,) and 20 blotted using an anti-CDK1 phospho T14 antibody (Abcam, #ab58509) and an anti-vinculin antibody (Abcam, #126002). Specific binding was detected by fluorescence using the Anti-Rabbit Detection Module (BioTechne, #DM-001), quantified using Compass for Simple Western software, and IC50 values were calculated by regression analysis in GraphPad Prism.

[0888] The following compounds in Biological Data Table 3 inhibit CDK1 pT14 in OVCAR 3 cells with an 25 IC50<1 μM. The CDK1 pT14 IC50values are banded as follows: A: <100 nM; B: 100 nM - 1 μM; P-000059-WO-PCT-MYT - 134 - # CDK1 pT14 IC50(μM) BAA-004 A BAA-006 A BAA-007 A BAA-010 A BAA-011 A * * *

[0889] The foregoing has described the principles, preferred embodiments, and modes of operation of 5 the present invention. However, the invention should not be construed as limited to the particular embodiments discussed. Instead, the above-described embodiments should be regarded as illustrative rather than restrictive. It should be appreciated that variations may be made in those embodiments by workers skilled in the art without departing from the scope of the present invention.

[0003] P-000059-WO-PCT-MYT - 135 - REFERENCES

[0890] Publications are cited herein in order to more fully describe the state of the art to which the invention pertains. Full citations for these references are provided below.

[0891] Each of these publications is incorporated herein by reference in its entirety into the present 5 disclosure, to the same extent as if each individual reference was specifically and individually indicated to be incorporated by reference.

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[0908] Liu et al., 1997, ‘The human Myt1 kinase preferentially phosphorylates Cdc2 on threonine 14 and localizes to the endoplasmic reticulum and Golgi complex’, Mol Cell Biol.17(2):571-83.

[0909] Liu et al., 2017, “PKMYT1 promoted the growth and motility of hepatocellular carcinoma cells by activating beta-catenin / TCF signaling”, Experimental Cell Research, 358(2), 209-216. 5

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Claims

P-000059-WO-PCT-MYT - 137 - CLAIMS 1. A compound of the following formula:or a pharmaceutically acceptable sa or co-crystal thereof; wherein:Ring A is:wherein: Z1is N, CH, or CRZ1; and Z2is CH, CRZ2, or N; wherein: each -RZ1, and -RZ2, is independently -F, -Cl, -Br, -I, -RZZ, -CF3, -OH, -ORZZ, -OCF3, -NH2, -NHRZZ, or -NRZZ2; each -RZZis independently linear or branched saturated C1-4alkyl; and wherein:each -RA222is independently linear or branched saturated C1-4alkyl; -RA3is -H or -RA33; -RA33is -RA333, -F, -Cl, -Br, -I, -CF3, -OH, -ORA333, or -OCF3; each -RA333is independently linear or branched saturated C1-4alkyl; -RA4is -H or -RA44; -RA44is -RA444, -F, -Cl, -Br, -I, -CF3, -OH, -ORA444, or -OCF3; each -RA444is independently linear or branched saturated C1-4alkyl; and:P-000059-WO-PCT-MYT - 138 - Ring B is selected from:wherein: each -RY2, -RY3, -RY4, -RY6, -RY7, and -RY8is independently -H, -F, -Cl, -Br, -I, or -RYY; each -RYYis independently linear or branched saturated C1-4alkyl; and wherein: each -RY1, -RY5, and -RY9is independently -RYYN; each -RYYNis independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, phenyl, or C5-6heteroaryl, wherein C1-4alkyl and cycloalkyl are optionally substituted with one or more groups selected from: -F, -OH, and -OCH3, and phenyl and heteroaryl are optionally substituted with one or more groups selected from: -F, -Cl, -CH3, and -CF3; and wherein: -Q is -LQ1-Q1, -LQ2-Q2, -LQ3-Q3, -LQ4-Q4, or -LQ5-Q5; wherein: -LQ1- is -C(=O)-, -C(=YLQ1)NRLQ1A-, or -S(=O)2-; Q1is C5-10heteroaryl; and is: optionally substituted on carbon with one or more groups -RQ1C; and optionally substituted on secondary nitrogen, if present, with one or more groups -RQ1N; -LQ2- is -C(=O)-, -C(=YLQ2)NRLQ2A-, or -S(=O)2-; Q2is non-aromatic C3-7heterocyclyl; and is: optionally substituted on sulfur, if present, with one or two groups =O; optionally substituted on carbon with one or more groups -RQ2C; and optionally substituted on secondary nitrogen, if present, with one or more groups -RQ2N; -LQ3- is -C(=O)-, -C(=YLQ3)NRLQ3A-, or -S(=O)2-;P-000059-WO-PCT-MYT - 139 - Q3is phenyl or naphthyl; and is: optionally substituted with one or more groups -RQ3C; -LQ4- is -C(=O)-, -C(=YLQ4)NRLQ4A-, or -S(=O)2-; Q4is C3-7cycloalkyl; and is: optionally substituted with one or more groups -RQ4C; -LQ5- is -C(=O)-, -C(=YLQ5)NRLQ5A-, or -S(=O)2-; Q5is linear or branched saturated C1-6alkyl; and is: optionally substituted with one or more groups -RQ5C; and wherein: =YLQ1is: =O, or =S; and wherein: -RLQ1Ais: -H, or linear or branched saturated C1-4alkyl; and wherein: each -RQ1Cis independently:-CN, or -NO2; and two adjacent -RQ1C, if present, taken together may form -(CH2)n1-O-(CH2)m1- or -O-(CH2)p1-O-, wherein: n1 is 0, 1, 2, or 3; m1 is 0, 1, 2, or 3; and p1 is 1 or 2; with the proviso that m1+n1 is 2 or 3; wherein: each -RQ1CCis independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, C3-7heterocyclyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl and each cycloalkyl is optionally substituted with one or more groups selected from: -F, -OH, and -OCH3, and each phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -RQ1CCC, -CF3, -P-000059-WO-PCT-MYT - 140 - CN, -OH, -ORQ1CCC, -NH2, -NHRQ1CCC, and -NRQ1CCC2; and each -RQ1CCCis independently linear or branched saturated C1-4alkyl; each -RQ1CXis independently linear or branched saturated C1-4haloalkyl; each -RQ1CMis independently non-aromatic C3-11heterocyclyl having at least one N ring atom, and is attached via that N ring atom; and is: optionally substituted on carbon with one or more groups -RQ1CMM; optionally substituted on sulfur, if present, with one or two =O groups; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ1CMM, -C(=O)RQ1CMM, -C(=O)ORQ1CMM, and -S(=O)2RQ1CMM; and each -RQ1CMMis independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, or C3-6cycloalkyl-C1-3alkyl, wherein C1-4alkyl and each cycloalkyl is optionally substituted with one or more groups selected from: -F, -OH, and -OCH3; and wherein: each -RQ1Nis independently:wherein: each -RQ1NCis independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl and each cycloalkyl is optionally substituted with one or more groups selected from: -F, -OH, and -OCH3, and each phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -RQ1NCC, -CF3, -CN, -OH, -ORQ1NCC, -NH2, -NHRQ1NCC, and -NRQ1NCC2; and each -RQ1NCCis independently linear or branched saturated C1-4alkyl; each -RQ1NXis independently linear or branched saturated C1-4haloalkyl; each -LQ1N- is independently linear or branched saturated C1-4alkylene; each -RQ1NMis independently non-aromatic C3-7heterocyclyl having at least one N ring atom, and is attached via that N ring atom; and is: optionally substituted on carbon with one or more groups -RQ1NMM; optionally substituted on sulfur, if present, with one or two =O groups; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ1NMM, -C(=O)RQ1NMM, -C(=O)ORQ1NMM, and -S(=O)2RQ1NMM; and each -RQ1NMMis independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, or C3-6cycloalkyl-C1-3alkyl, wherein C1-4alkyl and each cycloalkyl is optionally substituted with one or more groups selected from: -F, -OH, and -OCH3;P-000059-WO-PCT-MYT - 141 - and wherein: each -RQ1Nhetis independently non-aromatic C3-7heterocyclyl; and is: optionally substituted on sulfur, if present, with one or two groups =O; optionally substituted on carbon with one or more groups -RQ1NHHor =O; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ1NHH, -C(=O)RQ1NHH, -C(=O)ORQ1NHH, and -S(=O)2RQ1NHH; wherein: each -RQ1NHHis independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, or C3-6cycloalkyl-C1-3alkyl, wherein C1-4alkyl and each cycloalkyl is optionally substituted with one or more groups selected from: -F, -OH, and -OCH3; and wherein: =YLQ2is: =O, or =S; and wherein: -RLQ2Ais: -H, or linear or branched saturated C1-4alkyl; and wherein: each -RQ2Cis independently:=O; wherein: each -RQ2CCis independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, phenyl, C3-7heterocyclyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl and each cycloalkyl is optionally substituted with one or more groups selected from: -F, -OH, and -OCH3, and each phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -RQ2CCC, -CF3, - CN, -OH, -ORQ2CCC, -NH2, -NHRQ2CCC, and -NRQ2CCC2; and each -RQ2CCCis independently linear or branched saturated C1-4alkyl; each -RQ2CXis independently linear or branched saturated C1-4haloalkyl; each -RQ2CMis independently non-aromatic C3-11heterocyclyl having at least one N ring atom, and is attached via that N ring atom; and is: optionally substituted on carbon with one or more groups -RQ2CMM; optionally substituted on sulfur, if present, with one or two =O groups; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ2CMM, -C(=O)RQ2CMM, -C(=O)ORQ2CMM, and -S(=O)2RQ2CMM; andP-000059-WO-PCT-MYT - 142 - each -RQ2CMMis independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, or C3-6cycloalkyl-C1-3alkyl, wherein C1-4alkyl and each cycloalkyl is optionally substituted with one or more groups selected from: -F, -OH, and -OCH3; and wherein: each -RQ2Nis independently:wherein: each -RQ2NCis independently linear or branched saturated C1-6alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-6alkyl and each cycloalkyl is optionally substituted with one or more groups selected from: -F, -OH, and -OCH3, and each phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -RQ2NCC, -CF3, -CN, -OH, -ORQ2NCC, -NH2, -NHRQ2NCC, and -NRQ2NCC2; and each -RQ2NCCis independently linear or branched saturated C1-4alkyl; and wherein: =YLQ3is: =O, or =S; and wherein: -RLQ3Ais: -H, or linear or branched saturated C1-4alkyl; and wherein: each -RQ3Cis independently:-CN, or -NO2; and two adjacent-RQ3C, if present, taken together may form -(CH2)n3-O-(CH2)m3- or -O-(CH2)p3-O-, wherein: n3 is 0, 1, 2, or 3; m3 is 0, 1, 2, or 3; and p3 is 1 or 2; with the proviso that m3+n3 is 2 or 3; wherein: each -RQ3CCis independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, C3-7heterocyclyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, orP-000059-WO-PCT-MYT - 143 - C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl and each cycloalkyl is optionally substituted with one or more groups selected from: -F, -OH, and -OCH3, and each phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -RQ3CCC, -CF3, - CN, -OH, -ORQ3CCC, -NH2, -NHRQ3CCC, and -NRQ3CCC2; and each -RQ3CCCis independently linear or branched saturated C1-4alkyl; each -RQ3CXis independently linear or branched saturated C1-4haloalkyl; each -LQ3C- is independently linear or branched saturated C1-4alkylene; each -RQ3CMis independently non-aromatic C3-11heterocyclyl having at least one N ring atom, and is attached via that N ring atom; and is: optionally substituted on carbon with one or more groups -RQ3CMM; optionally substituted on sulfur, if present, with one or two =O groups; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ3CMM, -C(=O)RQ3CMM, -C(=O)ORQ3CMM, and -S(=O)2RQ3CMM; and each -RQ3CMMis independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, or C3-6cycloalkyl-C1-3alkyl, wherein C1-4alkyl and each cycloalkyl is optionally substituted with one or more groups selected from: -F, -OH, and -OCH3; and wherein: =YLQ4is: =O, or =S; and wherein: -RLQ4Ais: -H, or linear or branched saturated C1-4alkyl; and wherein: each -RQ4Cis independently:=O; wherein: each -RQ4CCis independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, C3-7heterocyclyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl and each cycloalkyl is optionally substituted with one or more groups selected from: -F, -OH, and -OCH3, and each phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -RQ4CCC, -CF3, - CN, -OH, -ORQ4CCC, -NH2, -NHRQ4CCC, and -NRQ4CCC2; and each -RQ4CCCis independently linear or branched saturated C1-4alkyl; each -RQ4CXis independently linear or branched saturated C1-4haloalkyl;P-000059-WO-PCT-MYT - 144 - each -RQ4CMis independently non-aromatic C3-11heterocyclyl having at least one N ring atom, and is attached via that N ring atom; and is: optionally substituted on carbon with one or more groups -RQ4CMM; optionally substituted on sulfur, if present, with one or two =O groups; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ4CMM, -C(=O)RQ4CMM, -C(=O)ORQ4CMM, and -S(=O)2RQ4CMM; each -RQ4CMMis independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, or C3-6cycloalkyl-C1-3alkyl, wherein C1-4alkyl and each cycloalkyl is optionally substituted with one or more groups selected from: -F, -OH, and -OCH3; and wherein: =YLQ5is: =O, or =S; and wherein: -RLQ5Ais: -H, or linear or branched saturated C1-4alkyl; and wherein: each -RQ5Cis independently: -RQ5CC, -F, -OH, -ORQ5CC, -OCF3, -NH2, -NHRQ5CC, -NRQ5CC2, -RQ5CM, or -C(=O)OH; wherein: each -RQ5CCis independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, C3-7heterocyclyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl and each cycloalkyl is optionally substituted with one or more groups selected from: -F, -OH, and -OCH3, and each phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -RQ5CCC, -CF3, - CN, -OH, -ORQ5CCC, -NH2, -NHRQ5CCC, and -NRQ5CCC2; and each -RQ5CCCis independently linear or branched saturated C1-4alkyl; each -RQ5CMis independently non-aromatic C3-11heterocyclyl having at least one N ring atom, and is attached via that N ring atom; and is: optionally substituted on carbon with one or more groups -RQ5CMM; optionally substituted on sulfur, if present, with one or two =O groups; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ5CMM, -C(=O)RQ5CMM, -C(=O)ORQ5CMM, and -S(=O)2RQ5CMM;P-000059-WO-PCT-MYT - 145 - each -RQ5CMMis independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, or C3-6cycloalkyl-C1-3alkyl, wherein C1-4alkyl and each cycloalkyl is optionally substituted with one or more groups selected from: -F, -OH, and -OCH3.

2. A compound, salt or co-crystal according to claim 1, wherein Ring A is:.

3. A compound, salt or co-crystal according to claim 1 or claim 2, wherein Ring B is selected from: , , , , ,,P-000059-WO-PCT-MYT - 146 -4. A compound, salt or co-crystal according to claim 3, wherein Ring B is: ,P-000059-WO-PCT-MYT - 147 - 5. A compound, salt or co-crystal according to claim 4, wherein Ring B is:.

6. A compound, salt or co-crystal according to any one of claims 1 to 5, wherein: -Q is -LQ1-Q1, or -LQ3-Q3.

7. A compound, salt or co-crystal according to claim 6, wherein: -Q is -LQ1-Q1.

8. A compound, salt or co-crystal according to claim 6, wherein: -Q is -LQ3-Q3.

9. A compound, salt or co-crystal according to claim 1, wherein: Ring A is:wherein: Z1is N, CH, or CRZ1; Z2is CH, CRZ2, or N; and wherein: -RA2is -RA222, -F, -Cl, -Br, or -I; each -RA222is independently linear or branched saturated C1-4alkyl; -RA3is -H; -RA4is -H; and: Ring B is selected from:P-000059-WO-PCT-MYT - 148 - wherein: Y1is S, Y2is CH and Y3is N, or Y1is S, Y2is N and Y3is CH; Y4is N, Y5is S, and Y6is CH; Y7is N, Y8is CH, and Y9is S; and wherein: -Q is -LQ1-Q1, -LQ3-Q3, or -LQ5-Q5; wherein: -LQ1- is -C(=O)-, -C(=O)NRLQ1A-, or -S(=O)2-; Q1is C5-10heteroaryl; and is: optionally substituted on carbon with one or more groups -RQ1C; and optionally substituted on secondary nitrogen, if present, with one or more groups -RQ1N; -LQ3- is -C(=O)-, -C(=O)NRLQ3A-, or -S(=O)2-; Q3is phenyl or naphthyl; and is: optionally substituted with one or more groups -RQ3C; -LQ5- is -C(=O)-, -C(=O)NRLQ5A-, or -S(=O)2-; Q5is linear or branched saturated C1-6alkyl; and wherein: -RLQ1Ais: -H, or linear or branched saturated C1-4alkyl; each -RQ1Cis independently:wherein: each -RQ1CCis independently linear or branched saturated C1-4alkyl; each -RQ1CXis independently linear or branched saturated C1-4haloalkyl; and wherein: each -RQ1Nis independently: wherein: each -RQ1NCis independently linear or branched saturated C1-4alkyl;P-000059-WO-PCT-MYT - 149 - and wherein: RLQ3Ais: -H, or linear or branched saturated C1-4alkyl; each -RQ3Cis independently:wherein: each -RQ3CCis independently linear or branched saturated C1-4alkyl, or C3-6cycloalkyl; each -RQ3CXis independently linear or branched saturated C1-4haloalkyl; and wherein: RLQ5Ais: -H, or linear or branched saturated C1-4alkyl.

10. A compound, salt or co-crystal according to claim 9 wherein: Ring A is:each -RA222is independently linear or branched saturated C1-4alkyl; and wherein: Ring B is:; wherein: Y1is S, Y2is CH, and Y3is N; and wherein: -Q is -LQ1-Q1, -LQ3-Q3, or -LQ5-Q5;P-000059-WO-PCT-MYT - 150 - wherein: -LQ1- is -C(=O)-; Q1is C5-10heteroaryl; and is: optionally substituted on secondary nitrogen, if present, with one or more groups -RQ1N; -LQ3- is -C(=O)-; Q3is phenyl; and is: optionally substituted with one or more groups -RQ3C; -LQ5- is -C(=O)-; Q5is linear or branched saturated C1-6alkyl; and wherein: each -RQ1Nis independently: wherein: each -RQ1NCis independently linear or branched saturated C1-4alkyl; and wherein: each -RQ3Cis independently:wherein: each -RQ3CCis independently linear or branched saturated C1-4alkyl, or C3-6cycloalkyl; and each -RQ3CXis independently linear or branched saturated C1-4haloalkyl.P-000059-WO-PCT-MYT - 151 - 11.or a pharmaceutically acceptable salt or co-crystal thereof.

12. A pharmaceutical composition comprising: a compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt or co-crystal thereof, and a pharmaceutically acceptable excipient.

13. A method of preparing a pharmaceutical composition comprising the step of:P-000059-WO-PCT-MYT - 152 - mixing a compound according to any of claims 1 to 11, or a pharmaceutically acceptable salt or co-crystal thereof, and a pharmaceutically acceptable excipient. 5 14. A method of inhibiting PKMYT1 kinase, in vitro or in vivo, comprising contacting the kinase with an effective amount of a compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt or co-crystal thereof, or a pharmaceutical composition according to claim 12.

15. A method of inhibiting PKMYT1 kinase function in a cell, in vitro or in vivo, comprising contacting the cell with an effective amount of a compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt or co-crystal thereof, or a pharmaceutical composition according to claim 12.

16. A compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt or co- crystal thereof, or a pharmaceutical composition according to claim 12, for use in a method of treatment of the human or animal body by therapy.

17. A compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt or co- crystal thereof, or a pharmaceutical composition according to claim 12, for use in a method of treatment of a disorder of the human or animal body that is ameliorated by the inhibition of PKMYT1 kinase.

18. Use of a compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt or co-crystal thereof, or a pharmaceutical composition according to claim 12, in the manufacture of a medicament for the treatment of a disorder of the human or animal body that is ameliorated by the inhibition of PKMYT1 kinase.

19. A method of treatment of a disorder of the human or animal body that is ameliorated by the inhibition of PKMYT1 kinase, comprising administering to a subject in need of treatment a therapeutically effective amount of a compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt or co-crystal thereof, or a pharmaceutical composition according to claim 12.P-000059-WO-PCT-MYT - 153 - 20. A compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt or co- crystal thereof, or a pharmaceutical composition according to claim 12, for use in a method of treatment of a proliferative disorder. 5 21. Use of a compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt or co-crystal thereof, or a pharmaceutical composition according to claim 12, in the manufacture of a medicament for the treatment of a proliferative disorder.

22. A method of treatment of a proliferative disorder of the human or animal body, comprising administering to a subject in need of treatment a therapeutically effective amount of a compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt or co- crystal thereof, or a pharmaceutical composition according to claim 12.

23. A compound, salt, co-crystal, or pharmaceutical composition for use according to claim 20, use according to claim 21, or a method according to claim 22, wherein the proliferative disorder is characterised by, or further characterised by: inappropriate activity and / or expression of PKMYT1, CCNE1, FBXW7, or PP2A or one of its subunits.

24. A compound, salt, co-crystal, or pharmaceutical composition for use according to claim 20, use according to claim 21, or a method according to claim 22, wherein the proliferative disorder is cancer.

25. A compound, salt, co-crystal, or pharmaceutical composition for use according to claim 20, use according to claim 21, or a method according to claim 22, wherein the proliferative disorder is: endometrial cancer, uterine cancer, ovarian cancer, breast cancer, gastric cancer, bladder cancer, pancreatic cancer, mesothelioma, kidney cancer, stomach cancer, esophageal cancer, colorectal cancer, glioblastoma, or lung cancer.

26. A compound, salt, co-crystal, or pharmaceutical composition for use according to claim 20, use according to claim 21, or a method according to claim 22, wherein the compound, salt, co-crystal, or pharmaceutical composition is administered in combination with an antibody-drug conjugate.P-000059-WO-PCT-MYT - 154 - 27. A compound, salt, co-crystal, or pharmaceutical composition for use according to claim 26, use according to claim 26, or a method according to claim 26, wherein the compound, salt, co-crystal, or pharmaceutical composition is administered 5 in combination with an antibody-drug conjugate, wherein the antibody-drug conjugate is a topoisomerase I inhibitor, a topoisomerase II inhibitor, or an antimetabolite.

28. A compound, salt, co-crystal, or pharmaceutical composition for use according to claim 27, use according to claim 27, or a method according to claim 27, wherein the antibody-drug conjugate is selected from trastuzumab deruxtecan, sacituzumab govitecan, datopotamab deruxtecan, patritumab deruxtecan, SHR-A1811, SKB-264, labetuzumab govitecan, Ifinatamab deruxtecan, BL-B01D1, AZD-8205, DB-1303, DB-1305, ESG- 401, FDA-022, IBI-354, MHB088C, PRO-1160, PRO-1184, SHR-A1904, SHR-A1921, AZD-5335, MHB036C, CBX-12, DS-6000, TQB2102, DS-6157a, BL-M11D1, epratuzumab-SN38, 9MW-2921, 7MW-3711, and mirvetuximab exatecan.

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