Pkmyt1 inhibitors and their use

Abstract

The present invention pertains generally to the field of therapeutic compounds. More specifically the present invention pertains to certain biarylamide compounds of formula (I) (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 PKMYT 1 kinase; to treat a proliferative disorder, cancer, etc.

Description

[0001] THERAPEUTIC COMPOUNDS AND THEIR USE

[0002] TECHNICAL FIELD

[0003] The present invention pertains generally to the field of therapeutic compounds.

[0004] 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 PKMYT1 kinase; to treat disorders (e.g., diseases) that are ameliorated by the inhibition of PKMYT 1 kinase; to treat a proliferative disorder, cancer, etc.

[0005] BACKGROUND

[0006] 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.

[0007] Throughout this specification, including the claims which follow, unless the context requires otherwise, the word “comprise,” and variations such as “comprises” and “comprising,” will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

[0008] It must be noted that, as used 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 pharmaceutical carrier” includes mixtures of two or more such carriers, and the like.

[0009] Ranges are often 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 that the particular value forms another embodiment.

[0010] 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. Protein kinase, membrane-associated

[0011] 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-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).

[0012] 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 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.

[0013] Drugs that inhibit the Cdk4 / 6-Cyclin D complexes are having a major therapeutic impact in hormone responsive HER2 negative breast cancer (HER2- ER+) and are being trialled in a variety of other cancers.

[0014] 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 normal cells.

[0015] 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 dependency on PKMYT1.

[0016] 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. CCNE1 amplification has been reported in several cancer types including endometrial, ovarian, 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, mesothelioma, lung adenocarcinoma, head & neck cancers, difuse 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.

[0017] CCNE1 amplification is observed in the more aggressive subtypes including uterine carcinosarcoma (UCS; -40%), uterine serous carcinoma (USC; - 25%), high-grade serous ovarian carcinoma (HGSOC; -20%), and triple-negative breast cancer (TNBC; -8%). CCNE1 overexpression 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.

[0018] Similarly, FBXW7 '\s 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.

[0019] 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, and in CDK4 / 6 inhibitor resistant TP53 mutant ER+ breast cancer (Chen et al, 2024).

[0020] A recently discovered inhibitor of PKMYT1, RP-6306 (Szychowski et al., 2022), has shown 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).

[0021] 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) (Yost et al., 2021). 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.

[0022] Replication stress induced by genetic alterations creates a synthetic lethal relationship between these specific alterations and PKMYT1 inhibition. RAS mutations, in particular in combination with TP53 mutations, are drivers of replication stress, and as such sensitises mutant RAS cancer cells to PKMYT1 inhibition. KRAS is mutated in about 11.6% of all cancers. KRAS mutations are most common in pancreatic ductal adenocarcinoma (PDAC) (-82% of patients), colorectal cancers (CRC) (-38%), non-small cells lung cancers (NSCLC) (-21%). In addition, KRAS mutations are found in choloangiocarcinoma, uterine endometrial carcinoma, testicular germ cell cancer and cervical squamous cell carcinoma, with a mutation frequency of about 12.7%, 14.1%, 11.7%, and 4.3%, respectively. NRAS is mutated in 5% of CRC, 15-20% of melanomas, and 15-20 of haematologic cancers such as acute myeloid leukemia (AML).

[0023] 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 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 greater demand upon the Cdk1-Cyclin B inhibitory activity of WEE1 and PKMYT1 such that PKMYT1 becomes essential. 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 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 demands upon the ability of WEE1 and PKMYT1 to restrain CDK1-Cyclin B activity to maintain cell viability.

[0024] PKMYT 1 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 generates a greater need for CDK1 cyclin B inhibition that PKMYTTs activities become essential.

[0025] 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 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).

[0026] 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 regulation make PKMYT1 is a highly attractive target for inhibition for patients whose tumours proliferate inappropriately because of enhanced Cdk2-Cyclin E activity. 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 Chromophobe cancer, renal papillary cell carcinoma, Head and Neck squamous cell carcinoma, colon adenocarcinoma, stomach adenocarcinoma, thyroid carcinoma, prostate adenocarcinoma. Elevated expression of PKMYT 1 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 adenocarcinoma, prostate adenocarcinoma, skin cutaneous melanoma, uveal melanoma (Shao et al., 2021), and breast cancer (Liu et al., 2020).

[0027] 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 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 multiple myeloma (Ghelli Luserna di Rora et al., 2020).

[0028] PKMYT1 can have application in addressing resistance to treatment or improving the efficacy of cancer treatment agents. PKMYT 1 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.

[0029] 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).

[0030] 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.

[0031] There is a clear need for PKMYT1 selective inhibitors with good pharmacokinetic properties, which are suitable for oral dosing with minimal or no toxicity.

[0032] This disclosure provides compounds and compositions that selectively inhibit PKMYT 1 to treat cancer. SUMMARY OF THE INVENTION

[0033] 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.

[0034] 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 carrier or diluent.

[0035] 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 carrier or diluent.

[0036] Another aspect of the present invention pertains to a method of inhibiting PKMYT 1 (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.

[0037] Another aspect of the present invention pertains to a method of inhibiting PKMYT 1 (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.

[0038] Another aspect of the present invention pertains to 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.

[0039] 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.

[0040] 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.

[0041] 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 subject in need of treatment a therapeutically-effective amount of a BAA compound, as described herein, preferably in the form of a pharmaceutical composition.

[0042] 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).

[0043] In one embodiment, the disorder is, for example, a proliferative condition, cancer, etc., as described herein.

[0044] Another aspect of the present invention pertains to a kit comprising (a) a BAA compound, as described herein, preferably 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 of treatment of a disorder (e.g., a disease) as described herein, for example, written instructions on how to administer the compound.

[0045] 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.

[0046] Another aspect of the present invention pertains to a BAA compound obtained by a method of synthesis as described herein, or a method comprising a method of synthesis as described herein.

[0047] 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.

[0048] Another aspect of the present invention pertains to the use of such novel intermediates, as described herein, in the methods of synthesis described herein.

[0049] Another aspect of the present invention pertains to A PKMYT 1 inhibitor for use in the treatment of cancer, wherein the PKMYT1 inhibitor is administered in combination with an antibody-drug conjugate.

[0050] 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 the invention.

[0051] BRIEF DESCRIPTION OF DRAWINGS

[0052] Figure 1 : PKMYT1 inhibitor Glso in a panel of cell lines with low, medium and high level of basal replication stress due to a range of genetic markers.

[0053] Figure 2: Selective yH2AX induction in multiple sensitive cancer lines.

[0054] Figure 3: Cellular biomarkers of PKMYT1 inhibitor BAA-065 in combination with topoisomerase 1 inhibitor SN38 in OVCAR3 cells.

[0055] Figure 4: Cellular biomarkers of PKMYT1 inhibitor BAA-065 in combination with other DNA- damaging agents: idarubicin and pidnarulex in OVCAR3 cells.

[0056] Figure 5: Time-course of PKMYT1 inhibitor impact on biomarkers of cell cycle progression in breast cancer cell line HCC1596.

[0057] Figure 6: In vivo efficacy of PKMYT1 inhibitors in OVCAR3 ovarian cancer xenografts in combination with antibody-drug conjugate with topoisomerase 1 inhibitor payload.

[0058] DETAILED DESCRIPTION

[0059] One aspect of the present invention is a compound of the following formula, or a pharmaceutically acceptable salt or solvate thereof, wherein Ring A, Ring B and R1are as defined herein (for convenience, collectively referred to herein as “biarylamide compounds” or “BAA compounds”):

[0060] Some embodiments include the following:

[0061] (1) A compound of the following formula: or a pharmaceutically acceptable salt or solvate thereof; wherein:

[0062] Y is =N- or =C(R1)-;

[0063] R1is H, F, Cl, or Me;

[0064] Ring A is: wherein indicates the point of attachment to formula (I);

[0065] R2is Br, Me, or i-Pr;

[0066] R3is F, or Me;

[0067] R4is H, Me, or Et;

[0068] Ring B is a nitrogen containing heterocyclyl; wherein Ring B may be optionally substituted on carbon by one or more R5; and wherein if said nitrogen containing heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R6;

[0069] R5is selected from one or more groups (i) to (xxi):

[0070] (i) halo;

[0071] (ii) hydroxy;

[0072] (iii) cyano;

[0073] (iv) amino;

[0074] (v) Ci-ealkyl; wherein said Ci-ealkyl may be optionally substituted by one or more halo, hydroxy, Ci-ealkoxy, N,N-(Ci-6alkyl)2amino, N-(Ci-6alkyl)aminocarbonyl, N,N-

[0075] (Ci-6alkyl)2aminocarbonyl optionally substituted by hydroxy, N-(Ci-ealkyl)-N- (cyclopropyl)aminocarbonyl, N-(Ci-6alkyl)-N-(cyclobutyl)aminocarbonyl, N- (Ci-6alkanoyl)-N-(Ci-6alkyl)amino, or heterocyclylcarbonyl;

[0076] (vi) Ci-ealkoxy; wherein said Ci-ealkoxy may be optionally substituted by one or more halo, cyclopropyl, cyclopentyl, phenyl optionally substituted by halo, or heterocyclyl;

[0077] (vii) Ci-ealkanoylamino; wherein said Ci-ealkanoylamino may be optionally substituted by one or more cyclopropyl;

[0078] (viii) Ci-ealkylsulphonylamino;

[0079] (ix) N-(Ci-6alkyl)amino; wherein said Ci-ealkylamino may be optionally substituted by one or more halo;

[0080] (x) N,N-(Ci-6alkyl)2amino;

[0081] (xi) N-(Ci-6alkyl)aminocarbonyl;

[0082] (xii) N,N-(Ci-6alkyl)2aminocarbonyl;

[0083] (xiii) N-(Ci-6alkyl)-N-(cyclopropyl)aminocarbonyl;

[0084] (xiv) Ci-6alkylS(O)awherein a is 0-2;

[0085] (xv) cyclopropylC(O)NH-; wherein said cyclopropyl may be optionally substituted by one or more halo;

[0086] (xvi) phenoxy; wherein said phenyl may be optionally substituted by one or more halo;

[0087] (xvii) phenyS(O)2NH-; wherein said phenyl may be optionally substituted by one or more methyl;

[0088] (xviii) heterocyclyl;

[0089] (xix) heterocyclylamino;

[0090] (xx) heterocyclyloxy;

[0091] (xxi) heterocyclylcarbonyl; wherein any heterocyclyl in R5may be optionally substituted on carbon by one or more halo, cyano, methyl, trifluoromethyl, or methoxymethyl; and wherein in R5, if any heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted on nitrogen by methyl, isopropyl, cyclopropyl, or hydroxyethyl;

[0092] R6is Ci-ealkyl or phenyl; wherein said Ci-ealkyl may be optionally substituted by one or more halo, hydroxy, methoxy, N-(Ci-6alkyl)-N-(cyclopropyl)aminocarbonyl, N-(Ci-ealkyl)-N- (cyclobutyl)aminocarbonyl, N,N-(Ci-6alkyl)2aminocarbonyl, or heterocyclylcarbonyl optionally substituted by isopropyl or CF3.

[0093] (2) A compound of the following formula: or a pharmaceutically acceptable salt or solvate thereof; wherein:

[0094] Y is =N- or =C(R1)-;

[0095] R1is H, F, Cl, or Me;

[0096] Ring A is: wherein indicates the point of attachment to formula (I);

[0097] R2is Br, Me, or i-Pr;

[0098] R3is F, or Me;

[0099] R4is H, Me, or Et;

[0100] Ring B is a nitrogen containing heterocyclyl; wherein Ring B may be optionally substituted on carbon by one or more R5; and wherein if said nitrogen containing heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R6;

[0101] R5is selected from one or more groups (i) to (xxv):

[0102] (i) halo;

[0103] (ii) hydroxy;

[0104] (iii) cyano;

[0105] (iv) amino;

[0106] (v) Ci-ealkyl; wherein said Ci-ealkyl may be optionally substituted by one or more halo, hydroxy, Ci-ealkoxy, N,N-(Ci-6alkyl)2amino, N-(Ci-6alkyl)aminocarbonyl, N,N- (Ci-6alkyl)2aminocarbonyl optionally substituted by hydroxy, N-(Ci-ealkyl)-N- (cyclopropyl)aminocarbonyl, N-(Ci-6alkyl)-N-(cyclobutyl)aminocarbonyl, N- (Ci-6alkanoyl)-N-(Ci-6alkyl)amino, or heterocyclylcarbonyl;

[0107] (vi) Ci-ealkoxy; wherein said Ci-ealkoxy may be optionally substituted by one or more halo, cyclopropyl, cyclopentyl, phenyl optionally substituted by halo, or heterocyclyl;

[0108] (vii) Ci-ealkanoylamino; wherein said Ci-ealkanoylamino may be optionally substituted by one or more cyclopropyl;

[0109] (viii) Ci-ealkylsulphonylamino;

[0110] (ix) N-(Ci-6alkyl)amino; wherein said Ci-ealkylamino may be optionally substituted by one or more halo or methoxy;

[0111] (x) N,N-(Ci-6alkyl)2amino;

[0112] (xi) N-(Ci-6alkyl)aminocarbonyl; wherein said N-(Ci-6alkyl)aminocarbonyl may be optionally substituted by one or more hydroxy or fluoro;

[0113] (xii) N,N-(Ci-6alkyl)2aminocarbonyl;

[0114] (xiii) N-(Ci-6alkyl)-N-(cyclopropyl)aminocarbonyl; (xiv) Ci-6alkylS(O)awherein a is 0-2;

[0115] (xv) cyclopropylC(O)NH-; wherein said cyclopropyl may be optionally substituted by one or more halo;

[0116] (xvi) cyclopentylaminocarbonyl;

[0117] (xvii) bicyclo[1 , 1 , 1]pentanylaminocarbonyl;

[0118] (xviii) cyclohexylamino;

[0119] (xix) phenoxy; wherein said phenyl may be optionally substituted by one or more halo;

[0120] (xx) phenyS(O)2NH-; wherein said phenyl may be optionally substituted by one or more methyl;

[0121] (xxi) heterocyclyl;

[0122] (xxii) heterocyclylamino;

[0123] (xxiii) heterocyclyloxy;

[0124] (xxiv) heterocyclylcarbonyl;

[0125] (xxv) heterocyclylaminocarbonyl; wherein any heterocyclyl in R5may be optionally substituted on carbon by one or more halo, cyano, methyl, trifluoromethyl, or methoxymethyl; and wherein in R5, if any heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted on nitrogen by methyl, isopropyl, cyclopropyl, or hydroxyethyl;

[0126] R6is Ci-ealkyl or phenyl; wherein said Ci-ealkyl may be optionally substituted by one or more halo, hydroxy, methoxy, N-(Ci-6alkyl)-N-(cyclopropyl)aminocarbonyl, N-(Ci-ealkyl)-N- (cyclobutyl)aminocarbonyl, N,N-(Ci-6alkyl)2aminocarbonyl, or heterocyclylcarbonyl optionally substituted by isopropyl or CF3.

[0127] A "heterocyclyl" is a saturated, partially saturated or unsaturated, mono or bicyclic ring containing 4-12 atoms of which at least one atom is chosen from nitrogen, sulphur or oxygen, which may, unless otherwise specified, be carbon or nitrogen linked, wherein a -CH2- group can optionally be replaced by a -C(=O)- or -C(=S)-, and a ring sulphur atom may be optionally oxidised to form the S-oxides. Unless otherwise specified, “heterocyclyl” includes monocyclic heterocyclyl, fused heterocyclyl, bridged heterocyclyl, and spiro heterocyclyl. Examples and suitable values of the term "heterocyclyl" are 2-oxa-5-azabicyclo[4.1.0]heptan-5-yl, morpholino, pyrazolyl, piperidinyl, piperazinyl, pyrrolidinyl, pyridyl, oxetan-3-yl, and tetrahydrofuranyl. A further example and suitable value of the term "heterocyclyl" is tetrahydropyranyl. Further examples and suitable values of the term "heterocyclyl" are 2-oxa-5-azabicyclo[4.1.0]heptan-5-yl, morpholino, pyrazolyl, piperidinyl, piperazinyl, pyrrolidinyl, pyridyl, oxetan-3-yl, tetrahydrofuranyl, and tetrahydropyranyl.

[0128] A “nitrogen containing heterocyclyl” is a saturated, partially saturated or unsaturated, mono or bicyclic ring containing 4-12 atoms of which at least one atom is nitrogen, which may, unless otherwise specified, be carbon or nitrogen linked, wherein a -CH2- group can optionally be replaced by a -C(=O)- or -C(=S)-, and a ring sulphur atom may be optionally oxidised to form the S-oxides. Unless otherwise specified, “nitrogen containing heterocyclyl” includes monocyclic heterocyclyl, fused heterocyclyl, bridged heterocyclyl, and spiro heterocyclyl. Examples and suitable values of the term "nitrogen containing heterocyclyl" are indazolyl, pyridyl, pyrimidinyl, pyrazolyl, pyrazolo[4,3-c]pyridinyl, 6,7-dihydro-5H-cyclopenta[b]pyridinyl, 5, 6,7,8- tetrahydroquinolinyl, and triazinyl. A particular example and suitable value of the term "nitrogen containing heterocyclyl" is pyridyl. A particular example and suitable value of the term "nitrogen containing heterocyclyl" is pyrazolyl.

[0129] The term "alkyl" includes both straight and branched chain alkyl groups. References to individual alkyl groups such as "propyl" are specific for the straight chain version only and references to individual branched chain alkyl groups such as 'isopropyl' are specific for the branched chain version only. For example, "Ci-ealkyl" includes Ci-4alkyl, Ci-3alkyl, methyl, ethyl, n- propyl, isopropyl and t-butyl. The term "halo" refers to fluoro, chloro, bromo and iodo.

[0130] Examples of "Ci-ealkoxy" include methoxy, ethoxy and propoxy. Examples of"Ci- ealkanoylamino" include formamido, acetamido and propionylamino. Examples of"Ci-6alkylS(O)awherein a is 0 to 2" include methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl and ethylsulphonyl. Examples of "N-(Ci-6alkyl)amino" include methylamino and ethylamino. Examples of "N,N-(Ci-6alkyl)2amino" include di-N-methylamino, di-(N-ethyl)amino and N-ethyl-N-methylamino. Examples of "N-(Ci-6alkyl)aminocarbonyl" are methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, isopropylaminocarbonyl, and i-butylaminocarbonyl. Examples of "N,N-(Ci-6alkyl)2aminocarbonyl" are dimethylaminocarbonyl and methylethylaminocarbonyl. Examples of "N-(Ci-6alkyl)-N-(cyclopropyl)aminocarbonyl” are N-(cyclopropyl)-N- (methyl)aminocarbonyl and N-(cyclopropyl)-N-(isopropyl)aminocarbonyl. Examples of "N- (Ci-6alkyl)-N-(cyclobutyl)aminocarbonyl" are N-(cyclobutyl)-N-(methyl)aminocarbonyl and N- (cyclobutyl)-N-(isopropyl)aminocarbonyl. Examples of "N-(Ci-6alkanoyl)-N-(Ci-6alkyl)amino" are N- (propionyl)-N-(methyl)amino and N-(acetyl)-N-(isopropyl)amino. Examples of "Ci- ealkylsulphonylamino" are mesylamino, ethylsulphonylamino and isopropylsulphonylamino.

[0131] The phrase “one or more groups” in the context of optional substituents (e.g., “one or more groups -R5”, 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., tetrazol- 1-yl) 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 more preferably is 1 , 2, or 3, yet more preferably 1 or 2, still more preferably 1 . Where optional substituents are chosen from "one or more" groups this definition includes all substituents being chosen from one of the specified groups or the substituents being chosen from two or more of the specified groups.

[0132] 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 indicated, where a compound has one chiral centre, each of the (F?) and

[0133] (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 of a pendant sec-butyl group, -CH(CH3)CH2CH3 is usually chiral, and so gives rise to stereoisomers, e.g., (F?) and (S) enantiomers if it is the only chiral centre, each of which is disclosed and encompassed.

[0134] The Group Y

[0135] (3) A compound according to (1) or (2), wherein:

[0136] Y is =N-.

[0137] (4) A compound according to (1) or (2), wherein:

[0138] Y is =C(R1)-;

[0139] The Group -R1

[0140] (5) A compound according to any one of (1) to (4), wherein: R1is H, F, or Me.

[0141] (6) A compound according to any one of (1) to (4), wherein: R1is H.

[0142] (7) A compound according to any one of (1) to (4), wherein: R1is F.

[0143] (8) A compound according to any one of (1) to (4), wherein: R1is Cl.

[0144] (9) A compound according to any one of (1) to (4), wherein: R1is Me.

[0145] The Group Ring A

[0146] (10) A compound according to any one of (1) to (9), wherein: Ring A is: wherein / indicates the point of attachment to formula (I).

[0147] (11) A compound according to any one of (1) to (9), wherein:

[0148] Ring A is: wherein indicates the point of attachment to formula (I).

[0149] The Group -R2

[0150] (12) A compound according to any one of (1) to (11), wherein:

[0151] R2is Br.

[0152] (13) A compound according to any one of (1) to (11), wherein: R2is Me.

[0153] (14) A compound according to any one of (1) to (11), wherein:

[0154] R2is i-Pr.

[0155] The Group -R3

[0156] (15) A compound according to any one of (1) to (14), wherein: R3is F.

[0157] (16) A compound according to any one of (1) to (14), wherein:

[0158] R3is Me.

[0159] The Group -R4

[0160] (17) A compound according to any one of (1) to (14), wherein:

[0161] R4is H.

[0162] (18) A compound according to any one of (1) to (16), wherein: R4is Me.

[0163] (19) A compound according to any one of (1) to (16), wherein:

[0164] R4is Et.

[0165] The Group Ring B

[0166] (20) A compound according to any one of (1) to (19), wherein:

[0167] Ring B is indazolyl; wherein said indazolyl may be optionally substituted on carbon by one or more R5; and wherein if said indazolyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R6.

[0168] (21) A compound according to any one of (1) to (19), wherein:

[0169] Ring B is pyridyl; wherein said pyridyl may be optionally substituted on carbon by one or more R5.

[0170] (22) A compound according to any one of (1) to (19), wherein:

[0171] Ring B is pyrimidinyl; wherein said pyrimidinyl may be optionally substituted on carbon by one or more R5.

[0172] (23) A compound according to any one of (1) to (19), wherein:

[0173] Ring B is pyrazolyl; wherein said pyrazolyl may be optionally substituted on carbon by one or more R5; and wherein if said pyrazolyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R6.

[0174] (24) A compound according to any one of (1) to (19), wherein: Ring B is pyrazolo[4,3-c]pyridinyl; wherein said pyrazolo[4,3-c]pyridinyl may be optionally substituted on carbon by one or more R5; and wherein if said pyrazolo[4,3-c]pyridinyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R6.

[0175] (25) A compound according to any one of (1) to (19), wherein:

[0176] Ring B is 6,7-dihydro-5H-cyclopenta[b]pyridinyl; wherein said

[0177] 6.7-dihydro-5H-cyclopenta[b]pyridinyl may be optionally substituted on carbon by one or more R5.

[0178] (26) A compound according to any one of (1) to (19), wherein:

[0179] Ring B is 5,6,7,8-tetrahydroquinolinyl; wherein said 5,6,7,8-tetrahydroquinolinyl may be optionally substituted on carbon by one or more R5.

[0180] (27) A compound according to any one of (1) to (19), wherein:

[0181] Ring B is triazinyl; wherein said triazinyl may be optionally substituted on carbon by one or more R5.

[0182] (27a) A compound according to any one of (1) to (19), wherein:

[0183] Ring B is pyridyl, pyrimidinyl, triazinyl, indazolyl, pyrazolyl, pyrazolo[4,3-c]pyridinyl,

[0184] 6.7-dihydro-5H-cyclopenta[b]pyridinyl, or 5,6,7,8-tetrahydroquinolinyl; wherein said ring may be optionally substituted on carbon by one or more R5; and wherein if said ring contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R6.

[0185] (27b) A compound according to any one of (1) to (19), wherein:

[0186] Ring B is pyridinyl, pyrazolyl, 6,7-dihydro-5H-cyclopenta[b]pyridinyl,

[0187] 5.6.7.8-tetrahydroquinolinyl; wherein said ring may be optionally substituted on carbon by one or more R5.

[0188] (27c) A compound according to any one of (1) to (19), wherein:

[0189] Ring B is pyridyl, pyrimidinyl, triazinyl, indazolyl, pyrazolyl, pyrazolo[4,3-c]pyridinyl,

[0190] 6,7-dihydro-5H-cyclopenta[b]pyridinyl, or 5,6,7,8-tetrahydroquinolinyl.

[0191] (27d) A compound according to any one of (1) to (19), wherein:

[0192] Ring B is pyridyl, pyrimidinyl, triazinyl, indazolyl, pyrazolyl, pyrazolo[4,3-c]pyridinyl,

[0193] 6,7-dihydro-5H-cyclopenta[b]pyridinyl, or 5,6,7,8-tetrahydroquinolinyl (27e) A compound according to any one of (1) to (19), wherein:

[0194] Ring B is pyridinyl, pyrazolyl, 6,7-dihydro-5H-cyclopenta[b]pyridinyl, or

[0195] 5.6.7.8-tetrahydroquinolinyl.

[0196] The Group -R5

[0197] (28) A compound according to any one of (1) to (27d), wherein:

[0198] R5is selected from one or more groups (i) to (viii):

[0199] (i) halo; (ii) Ci-ealkyl; wherein said Ci-ealkyl may be optionally substituted by one or more N-(Ci-6alkyl)-N-(cyclopropyl)aminocarbonyl;

[0200] (iii) Ci-ealkoxy; wherein said Ci-ealkoxy may be optionally substituted by one or more halo;

[0201] (iv) Ci-ealkylsulphonylamino;

[0202] (v) N-(Ci-6alkyl)aminocarbonyl;

[0203] (vi) N-(Ci-6alkyl)-N-(cyclopropyl)aminocarbonyl;

[0204] (vii) Ci-6alkylS(O)awherein a is 0; or

[0205] (viii) heterocyclylcarbonyl; wherein any heterocyclyl in R5may be optionally substituted on carbon by one or more trifluoromethyl; and wherein in R5, if any heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted on nitrogen by methyl, or isopropyl.

[0206] (29) A compound according to any one of (1) to (27d), wherein: R5is halo.

[0207] (30) A compound according to any one of (1) to (29), wherein: R5is Cl.

[0208] (31) A compound according to any one of (1) to (30), wherein: R5is Br.

[0209] (32) A compound according to any one of (1) to (31), wherein: R5is hydroxy.

[0210] (33) A compound according to any one of (1) to (32), wherein: R5is cyano.

[0211] (34) A compound according to any one of (1) to (33), wherein: R5is amino.

[0212] (35) A compound according to any one of (1) to (34), wherein:

[0213] R5is Ci-ealkyl; wherein said Ci-ealkyl may be optionally substituted by one or more halo, hydroxy, Ci-ealkoxy, N,N-(Ci-6alkyl)2amino, N-(Ci-6alkyl)aminocarbonyl, N,N-(Ci-6alkyl)2aminocarbonyl optionally substituted by hydroxy, N-(Ci-6alkyl)-N-(cyclopropyl)aminocarbonyl, N-(Ci-6alkyl)-N-(cyclobutyl)aminocarbonyl, N-(Ci-6alkanoyl)-N-(Ci-6alkyl)amino, or heterocyclylcarbonyl; wherein said heterocyclyl may be optionally substituted on carbon by one or more cyano, methyl, trifluoromethyl, or methoxymethyl.

[0214] (36) A compound according to any one of (1) to (35), wherein: R5is Ci-ealkyl.

[0215] (37) A compound according to any one of (1) to (36), wherein: R5is Me.

[0216] (38) A compound according to any one of (1) to (37), wherein: R5is Et.

[0217] (39) A compound according to any one of (1) to (38), wherein: R5is Ci-ealkyl substituted by one or more halo.

[0218] (40) A compound according to any one of (1) to (39), wherein: R5is CF3.

[0219] (41) A compound according to any one of (1) to (40), wherein:

[0220] R5is Ci-ealkyl substituted by one or more hydroxy.

[0221] (42) A compound according to any one of (1) to (41), wherein: R5is hydroxymethyl.

[0222] (43) A compound according to any one of (1) to (42), wherein:

[0223] R5is Ci-ealkyl substituted by one or more Ci-ealkoxy.

[0224] (44) A compound according to any one of (1) to (43), wherein: R5is methoxyethyl.

[0225] (45) A compound according to any one of (1) to (44), wherein: R5is 2-methoxyethyl.

[0226] (46) A compound according to any one of (1) to (45), wherein:

[0227] R5is Ci-ealkyl substituted by one or more N,N-(Ci-6alkyl)2amino.

[0228] (47) A compound according to any one of (1) to (46), wherein: R5is diethylaminomethyl.

[0229] (48) A compound according to any one of (1) to (47), wherein:

[0230] R5is Ci-ealkyl substituted by one or more N-(Ci-6alkyl)aminocarbonyl.

[0231] (49) A compound according to any one of (1) to (48), wherein:

[0232] R5is t-butylaminocarbonylmethyl.

[0233] (50) A compound according to any one of (1) to (49), wherein:

[0234] R5is Ci-ealkyl substituted by one or more N,N-(Ci-6alkyl)2aminocarbonyl.

[0235] (51) A compound according to any one of (1) to (50), wherein:

[0236] R5is N,N-diethylaminocarbonylmethyl.

[0237] (52) A compound according to any one of (1) to (51), wherein:

[0238] R5is N-isopropyl-N-methylaminocarbonylmethyl.

[0239] (53) A compound according to any one of (1) to (52), wherein:

[0240] R5is Ci-ealkyl substituted by one or more N,N-(Ci-6alkyl)2aminocarbonyl substituted by hydroxy.

[0241] (54) A compound according to any one of (1) to (53), wherein:

[0242] R5is N-(2-hydroxyethyl)-N-(methyl)aminocarbonylmethyl.

[0243] (55) A compound according to any one of (1) to (54), wherein:

[0244] R5is Ci-ealkyl substituted by one or more N-(Ci-6alkyl)-N-(cyclopropyl)aminocarbonyl.

[0245] (56) A compound according to any one of (1) to (55), wherein: R5is N-cyclopropyl-N-ethylaminocarbonylmethyl.

[0246] (57) A compound according to any one of (1) to (56), wherein:

[0247] R5is Ci-ealkyl substituted by one or more N-(Ci-6alkyl)-N-(cyclobutyl)aminocarbonyl.

[0248] (58) A compound according to any one of (1) to (57), wherein:

[0249] R5is N-(ethyl)-N-(cyclobutyl)aminocarbonylmethyl.

[0250] (59) A compound according to any one of (1) to (58), wherein:

[0251] R5is Ci-ealkyl substituted by one or more N-(Ci-6alkanoyl)-N-(Ci-6alkyl)amino.

[0252] (60) A compound according to any one of (1) to (59), wherein:

[0253] R5is N-(propionyl)-N-(ethyl)aminomethyl.

[0254] (61) A compound according to any one of (1) to (60), wherein:

[0255] R5is Ci-ealkyl substituted by one or more heterocyclylcarbonyl; wherein said heterocyclyl may be optionally substituted on carbon by one or more cyano, methyl, trifluoromethyl, or methoxymethyl.

[0256] (62) A compound according to any one of (1) to (61), wherein:

[0257] R5is Ci-ealkyl substituted by one or more pyrrolidine-1-ylcarbonyl or 2-oxa-5-azabicyclo[4.1.0]heptan-5-ylcarbonyl; wherein said pyrrolidinyl may be optionally substituted on carbon by one or more cyano, methyl, trifluoromethyl, or methoxymethyl.

[0258] (63) A compound according to any one of (1) to (62), wherein:

[0259] R5is Ci-ealkyl substituted by one or more 2-(trifluoromethyl)pyrrolidin-1-ylcarbonyl, 2-cyanopyrrolidin-1-ylcarbonyl, 2-methylpyrrolidin-1-ylcarbonyl, 2-(methoxymethyl)pyrrolidin-1-ylcarbonyl, or 2-oxa-5-azabicyclo[4.1.0]heptan-5-ylcarbonyl.

[0260] (64) A compound according to any one of (1) to (63), wherein:

[0261] R5is 2-(trifluoromethyl)pyrrolidin-1-ylcarbonylmethyl, 2-(trifluoromethyl)pyrrolidin-1-ylcarbonyleth-2-yl, 2-cyanopyrrolidin-1-ylcarbonylmethyl, 2-methylpyrrolidin-1-ylcarbonylmethyl, 2-(methoxymethyl)pyrrolidin-1-ylcarbonylmethyl, or 2-oxa-5-azabicyclo[4.1.0]heptan-5-ylcarbonylmethyl.

[0262] (65) A compound according to any one of (1) to (64), wherein:

[0263] R5is 2-(trifluoromethyl)pyrrolidin-1-ylcarbonylmethyl.

[0264] (66) A compound according to any one of (1) to (65), wherein:

[0265] R5is 2-(trifluoromethyl)pyrrolidin-1-ylcarbonyleth-2-yl.

[0266] (67) A compound according to any one of (1) to (66), wherein:

[0267] R5is 2-cyanopyrrolidin-1-ylcarbonylmethyl.

[0268] (68) A compound according to any one of (1) to (67), wherein:

[0269] R5is 2-methylpyrrolidin-1-ylcarbonylmethyl.

[0270] (69) A compound according to any one of (1) to (68), wherein:

[0271] R5is 2-(methoxymethyl)pyrrolidin-1-ylcarbonylmethyl.

[0272] (70) A compound according to any one of (1) to (69), wherein: R5is 2-oxa-5-azabicyclo[4.1.0]heptan-5-ylcarbonylmethyl.

[0273] (71) A compound according to any one of (1) to (70), wherein:

[0274] R5is Ci-ealkoxy; wherein said Ci-ealkoxy may be optionally substituted by one or more halo, cyclopropyl, cyclopentyl, phenyl optionally substituted by halo, or heterocyclyl; wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted on nitrogen by methyl, or isopropyl.

[0275] (72) A compound according to any one of (1) to (71), wherein:

[0276] R5is Ci-ealkoxy.

[0277] (73) A compound according to any one of (1) to (72), wherein:

[0278] R5is methoxy.

[0279] (74) A compound according to any one of (1) to (73), wherein:

[0280] R5is ethoxy.

[0281] (75) A compound according to any one of (1) to (74), wherein:

[0282] R5is isopropoxy.

[0283] (76) A compound according to any one of (1) to (75), wherein:

[0284] R5is 2-methylbutoxy.

[0285] (77) A compound according to any one of (1) to (76), wherein:

[0286] R5is sec-butoxy.

[0287] (78) A compound according to any one of (1) to (77), wherein:

[0288] R5is 3-methylbutoxy.

[0289] (79) A compound according to any one of (1) to (78), wherein:

[0290] R5is pentan-3-yloxy.

[0291] (80) A compound according to any one of (1) to (79), wherein:

[0292] R5is Ci-ealkoxy substituted by one or more halo.

[0293] (81) A compound according to any one of (1) to (80), wherein:

[0294] R5is 2,2,2-trifluoroethoxy.

[0295] (82) A compound according to any one of (1) to (81), wherein:

[0296] R5is 1 ,1 ,1-trifluoropropan-2-yloxy.

[0297] (83) A compound according to any one of (1) to (82), wherein:

[0298] R5is Ci-ealkoxy substituted by one or more cyclopropyl.

[0299] (84) A compound according to any one of (1) to (83), wherein:

[0300] R5is 1 -cyclopropylethoxy.

[0301] (85) A compound according to any one of (1) to (84), wherein:

[0302] R5is Ci-ealkoxy substituted by one or more cyclopentyl.

[0303] (86) A compound according to any one of (1) to (85), wherein:

[0304] R5is cyclopentylmethoxy.

[0305] (87) A compound according to any one of (1) to (86), wherein: R5is Ci-ealkoxy substituted by one or more phenyl substituted by halo.

[0306] (88) A compound according to any one of (1) to (87), wherein:

[0307] R5is 2-(3-fluorophenyl)ethoxy-2-yl.

[0308] (89) A compound according to any one of (1) to (88), wherein:

[0309] R5is Ci-ealkoxy substituted by one or more heterocyclyl; wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted on nitrogen by methyl, or isopropyl.

[0310] (90) A compound according to any one of (1) to (89), wherein:

[0311] R5is heterocyclylethoxy; wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted on nitrogen by methyl, or isopropyl.

[0312] (91) A compound according to any one of (1) to (90), wherein:

[0313] R5is heterocyclyl propoxy; wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted on nitrogen by methyl, or isopropyl.

[0314] (92) A compound according to any one of (1) to (91), wherein:

[0315] R5is Ci-ealkoxy substituted by piperazinyl, morpholino, or pyrrolidinyl; and wherein if said piperazinyl, morpholino, or pyrrolidinyl contains an -NH- moiety that nitrogen may be optionally substituted on nitrogen by methyl, or isopropyl.

[0316] (93) A compound according to any one of (1) to (92), wherein:

[0317] R5is Ci-ealkoxy substituted by 4-methylpiperazin-1-yl, 4-isopropylpiperazin-1-yl, morpholino, or pyrrolidine-1-yl.

[0318] (94) A compound according to any one of (1) to (93), wherein:

[0319] R5is 3-(4-methylpiperazin-1-yl)propoxy, 2-(4-methylpiperazin-1-yl)ethoxy,

[0320] 2-(pyrrolidin-1-yl)ethoxy, 2-morpholinoethoxy, or 2-(4-isopropylpiperazin-1-yl)ethoxy.

[0321] (95) A compound according to any one of (1) to (94), wherein:

[0322] R5is 3-(4-methylpiperazin-1-yl)propoxy.

[0323] (96) A compound according to any one of (1) to (95), wherein:

[0324] R5is 2-(4-methylpiperazin-1-yl)ethoxy.

[0325] (97) A compound according to any one of (1) to (96), wherein:

[0326] R5is 2-(pyrrolidin-1-yl)ethoxy.

[0327] (98) A compound according to any one of (1) to (97), wherein:

[0328] R5is 2-morpholinoethoxy.

[0329] (99) A compound according to any one of (1) to (98), wherein:

[0330] R5is 2-(4-isopropylpiperazin-1-yl)ethoxy.

[0331] (100) A compound according to any one of (1) to (99), wherein:

[0332] R5is Ci-ealkanoylamino; wherein said Ci-ealkanoylamino may be optionally substituted by one or more cyclopropyl.

[0333] (101) A compound according to any one of (1) to (100), wherein: R5is Ci-6alkanoylamino.

[0334] (102) A compound according to any one of (1) to (101), wherein: R5is acetylamino.

[0335] (103) A compound according to any one of (1) to (102), wherein: R5is t-butylcarbonylamino.

[0336] (104) A compound according to any one of (1) to (103), wherein: R5is Ci-ealkanoylamino substituted by cyclopropyl.

[0337] (105) A compound according to any one of (1) to (104), wherein: R5is 2-cyclopropylacetamido.

[0338] (106) A compound according to any one of (1) to (105), wherein: R5is Ci-ealkylsulphonylamino.

[0339] (107) A compound according to any one of (1) to (106), wherein: R5is propylsulphonylamino.

[0340] (108) A compound according to any one of (1) to (107), wherein: R5is isopropylsulphonylamino.

[0341] (109) A compound according to any one of (1) to (108), wherein: R5is N-(Ci-6alkyl)amino.

[0342] (110) A compound according to any one of (1) to (109), wherein:

[0343] R5is N-(Ci-6alkyl)amino optionally substituted by one or more halo or methoxy.

[0344] (111) A compound according to any one of (1) to (110), wherein:

[0345] R5is N-(Ci-6alkyl)amino substituted by one or more halo.

[0346] (112) A compound according to any one of (1) to (111), wherein:

[0347] R5is N-(Ci-6alkyl)amino substituted by one or more methoxy.

[0348] (113) A compound according to any one of (1) to (112), wherein: R5is isopropylamino.

[0349] (114) A compound according to any one of (1) to (113), wherein: R5is t-butylamino.

[0350] (115) A compound according to any one of (1) to (114), wherein: R5is 3-chloropropylamino.

[0351] (116) A compound according to any one of (1) to (115), wherein: R5is 1-methoxypropan-2-ylamino.

[0352] (117) A compound according to any one of (1) to (116), wherein: R5is N,N-(Ci-6alkyl)2amino.

[0353] (118) A compound according to any one of (1) to (117), wherein: R5is dimethylamino.

[0354] (119) A compound according to any one of (1) to (118), wherein: R5is diethylamino. (120) A compound according to any one of (1) to (119), wherein: R5is N-methyl isopropylamino.

[0355] (121) A compound according to any one of (1) to (120), wherein:

[0356] R5is N-(Ci-6alkyl)aminocarbonyl; wherein said N-(Ci-6alkyl)aminocarbonyl may be optionally substituted by one or more hydroxy or fluoro.

[0357] (122) A compound according to any one of (1) to (121), wherein: R5is N-(Ci-6alkyl)aminocarbonyl.

[0358] (123) A compound according to any one of (1) to (122), wherein: R5is methylaminocarbonyl.

[0359] (124) A compound according to any one of (1) to (123), wherein: R5is dimethylaminocarbonyl.

[0360] (125) A compound according to any one of (1) to (124), wherein: R5is dimethylaminocarbonyl.

[0361] (126) A compound according to any one of (1) to (125), wherein: R5is ethylaminocarbonyl.

[0362] (127) A compound according to any one of (1) to (126), wherein: R5is isopropylaminocarbonyl.

[0363] (128) A compound according to any one of (1) to (127), wherein: R5is 1-hydroxy-2-methylpropan-2-ylaminocarbonyl.

[0364] (129) A compound according to any one of (1) to (128), wherein: R5is 1 ,1 ,1-trifluoropropan-2-ylaminocarbonyl.

[0365] (130) A compound according to any one of (1) to (129), wherein: R5is (R)-1 ,1 ,1-trifluoropropan-2-ylaminocarbonyl.

[0366] (131) A compound according to any one of (1) to (130), wherein: R5is (S)-1,1 ,1-trifluoropropan-2-ylaminocarbonyl.

[0367] (132) A compound according to any one of (1) to (131), wherein: R5is t-butylaminocarbonyl.

[0368] (133) A compound according to any one of (1) to (132), wherein: R5is N,N-(Ci-6alkyl)2aminocarbonyl.

[0369] (134) A compound according to any one of (1) to (133), wherein: R5is N,N-diethylaminocarbonyl.

[0370] (135) A compound according to any one of (1) to (134), wherein: R5is N-f-butyl-N-methylaminocarbonyl.

[0371] (136) A compound according to any one of (1) to (135), wherein: R5is N-(Ci-6alkyl)-N-(cyclopropyl)aminocarbonyl.

[0372] (137) A compound according to any one of (1) to (136), wherein:

[0373] R5is N-(ethyl)-N-(cyclopropyl)aminocarbonyl. (138) A compound according to any one of (1) to (137), wherein: R5is N-(methyl)-N-(cyclopropyl)aminocarbonyl.

[0374] (139) A compound according to any one of (1) to (138), wherein: R5is Ci-6alkS(O)awherein a is 0-2.

[0375] (140) A compound according to any one of (1) to (139), wherein: R5is Ci-6alkS(O)awherein a is 0.

[0376] (141) A compound according to any one of (1) to (140), wherein: R5is Ci-6alkS(O)awherein a is 1.

[0377] (142) A compound according to any one of (1) to (141), wherein: R5is Ci-6alkS(O)awherein a is 2.

[0378] (143) A compound according to any one of (1) to (142), wherein:

[0379] R5is methylthio.

[0380] (144) A compound according to any one of (1) to (143), wherein: R5is methylsulphinyl.

[0381] (145) A compound according to any one of (1) to (144), wherein: R5is cyclopropylC(O)NH-.

[0382] (146) A compound according to any one of (1) to (145), wherein:

[0383] R5is cyclopropylC(O)NH-; wherein said cyclopropyl is substituted by one or more halo.

[0384] (147) A compound according to any one of (1) to (146), wherein: R5is cyclopropylcarbonylamino.

[0385] (148) A compound according to any one of (1) to (147), wherein:

[0386] R5is 1 -fluorocyclopropylcarbonylamino.

[0387] (149) A compound according to any one of (1) to (148), wherein: R5is cyclopentylaminocarbonyl.

[0388] (150) A compound according to any one of (1) to (149), wherein:

[0389] R5is bicyclo[1 ,1 ,1]pentanylaminocarbonyl.

[0390] (151) A compound according to any one of (1) to (150), wherein: R5is cyclohexylamino.

[0391] (152) A compound according to any one of (1) to (151), wherein:

[0392] R5is phenoxy; wherein said phenyl is substituted by one or more halo.

[0393] (153) A compound according to any one of (1) to (152), wherein:

[0394] R5is phenoxy; wherein said phenyl is substituted by one or more fluoro.

[0395] (154) A compound according to any one of (1) to (153), wherein: R5is 3,5-difluorophenoxy.

[0396] (155) A compound according to any one of (1) to (154), wherein: R5is phenyS(O)2NH-.

[0397] (156) A compound according to any one of (1) to (155), wherein: R5is phenyS(O)2NH-; wherein said phenyl is substituted by one or more methyl.

[0398] (157) A compound according to any one of (1) to (156), wherein:

[0399] R5is 4-methylphenylsulphonylamino.

[0400] (158) A compound according to any one of (1) to (157), wherein:

[0401] R5is heterocyclyl; wherein said heterocyclyl may be optionally substituted on carbon by one or more fluoro; and if any heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted on nitrogen by methyl, cyclopropyl, or hydroxyethyl.

[0402] (159) A compound according to any one of (1) to (158), wherein:

[0403] R5is piperazin-1-yl, oxetan-3-yl, or pyridyl; wherein said piperazin-1 -yl, oxetan-3-yl, or pyridyl, may be optionally substituted on carbon by one or more fluoro; and wherein an -NH- moiety of piperazin-1-yl may be optionally substituted on nitrogen by methyl, cyclopropyl, or hydroxyethyl.

[0404] (160) A compound according to any one of (1) to (159), wherein:

[0405] R5is pyrrolidin- 1 -yl, morpholino, piperazin-1-yl, oxetan-3-yl, or pyridyl; wherein said pyrrolidin- 1 -yl, piperazin- 1-yl, oxetan-3-yl, or pyridyl, may be optionally substituted on carbon by one or more fluoro; and wherein an -NH- moiety of piperazin-1-yl may be optionally substituted on nitrogen by methyl, cyclopropyl, or hydroxyethyl.

[0406] (161) A compound according to any one of (1) to (160), wherein:

[0407] R5is 4-(2-hydroxyethyl)piperazin-1-yl, 4-methylpiperazin-1-yl, 4-cyclopropylpiperazin-1-yl, 2-fluoropyridyl, or oxetan-3-yl.

[0408] (162) A compound according to any one of (1) to (161), wherein:

[0409] R5is pyrrolidin-1-yl, morpholino, 4-(2-hydroxyethyl)piperazin-1-yl, 4-methylpiperazin-1-yl, 4-cyclopropylpiperazin-1-yl, 2-fluoropyridyl, or oxetan-3-yl.

[0410] (163) A compound according to any one of (1) to (162), wherein:

[0411] R5is pyrrolidin-1-yl.

[0412] (164) A compound according to any one of (1) to (163), wherein: R5is morpholino.

[0413] (165) A compound according to any one of (1) to (164), wherein:

[0414] R5is 4-(2-hydroxyethyl)piperazin-1-yl.

[0415] (166) A compound according to any one of (1) to (165), wherein:

[0416] R5is 4-methylpiperazin-1-yl.

[0417] (167) A compound according to any one of (1) to (166), wherein:

[0418] R5is 4-cyclopropylpiperazin-1-yl.

[0419] (168) A compound according to any one of (1) to (167), wherein: R5is 2-fluoropyridyl.

[0420] (169) A compound according to any one of (1) to (168), wherein:

[0421] R5is oxetan-3-yl. (170) A compound according to any one of (1) to (169), wherein:

[0422] R5is heterocyclylamino wherein said heterocyclyl may be optionally substituted by one or more methyl.

[0423] (171) A compound according to any one of (1) to (170), wherein:

[0424] R5is heterocyclylamino.

[0425] (172) A compound according to any one of (1) to (171), wherein:

[0426] R5is (tetrahydro-2H-pyran-3-yl)amino.

[0427] (173) A compound according to any one of (1) to (172), wherein:

[0428] R5is (R)-(tetrahydro-2H-pyran-3-yl)amino.

[0429] (174) A compound according to any one of (1) to (173), wherein:

[0430] R5is (S)-(tetrahydro-2H-pyran-3-yl)amino.

[0431] (175) A compound according to any one of (1) to (174), wherein:

[0432] R5is (tetrahydro-2H-pyran-4-yl)amino.

[0433] (176) A compound according to any one of (1) to (175), wherein:

[0434] R5is (4-methyltetrahydro-2H-pyran-4-yl)amino.

[0435] (177) A compound according to any one of (1) to (176), wherein:

[0436] R5is (2,2-dimethyltetrahydro-2H-pyran-4-yl)amino.

[0437] (178) A compound according to any one of (1) to (177), wherein:

[0438] R5is (1-methylpiperidin-4-yl)amino.

[0439] (179) A compound according to any one of (1) to (178), wherein:

[0440] R5is heterocyclyloxy; wherein if any heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted on nitrogen by methyl.

[0441] (180) A compound according to any one of (1) to (179), wherein:

[0442] R5is tetrahydrofuran-3-yloxy, 1 H-pyrazol-4-yloxy, piperidin-4-yloxy, or pyridin-4-yloxy; wherein if any pyrazolyl or piperidyl contains an -NH- moiety that nitrogen may be optionally substituted on nitrogen by methyl.

[0443] (181) A compound according to any one of (1) to (180), wherein:

[0444] R5is 1-methyl-1 H-pyrazol-4-yloxy, 1-methylpiperidin-4-yloxy, pyridin-4-yloxy, or tetrahydrofuran-3-yloxy.

[0445] (182) A compound according to any one of (1) to (181), wherein:

[0446] R5is 1-methyl-1 H-pyrazol-4-yloxy.

[0447] (183) A compound according to any one of (1) to (182), wherein:

[0448] R5is 1-methylpiperidin-4-yloxy.

[0449] (184) A compound according to any one of (1) to (183), wherein:

[0450] R5is pyridin-4-yloxy.

[0451] (185) A compound according to any one of (1) to (184), wherein:

[0452] R5is tetrahydrofuran-3-yloxy. (186) A compound according to any one of (1) to (185), wherein:

[0453] R5is (R)-tetrahydrofuran-3-yloxy.

[0454] (187) A compound according to any one of (1) to (186), wherein: R5is (S)-tetrahydrofuran-3-yloxy.

[0455] (188) A compound according to any one of (1) to (187), wherein:

[0456] R5is heterocyclylcarbonyl, wherein said heterocyclyl may be optionally substituted on carbon by one or more trifluoromethyl.

[0457] (189) A compound according to any one of (1) to (188), wherein:

[0458] R5is pyrrolidine-1-carbonyl, wherein said pyrrolidinyl may be optionally substituted on carbon by one or more trifluoromethyl.

[0459] (190) A compound according to any one of (1) to (189), wherein: R5is 2-(trifluoromethyl)pyrrolidine-1-carbonyl.

[0460] (191) A compound according to any one of (1) to (190), wherein:

[0461] R5is (R)-2-(trifluoromethyl)pyrrolidine-1-carbonyl.

[0462] (192) A compound according to any one of (1) to (191), wherein:

[0463] R5is (S)-2-(trifluoromethyl)pyrrolidine-1-carbonyl.

[0464] (193) A compound according to any one of (1) to (192), wherein:

[0465] R5is heterocyclylaminocarbonyl.

[0466] (194) A compound according to any one of (1) to (193), wherein:

[0467] R5is (4-methyltetrahydro-2H-pyran-4-yl)aminocarbonyl.

[0468] The Group -R6

[0469] (195) A compound according to any one of (1) to (194), wherein:

[0470] R6is Ci-ealkyl; wherein said Ci-ealkyl may be optionally substituted by one or more N,N-(Ci-6alkyl)2aminocarbonyl, or heterocyclylcarbonyl optionally substituted by CF3.

[0471] (196) A compound according to any one of (1) to (194), wherein: R6is Ci-ealkyl.

[0472] (197) A compound according to any one of (1) to (194), wherein: R6is Me.

[0473] (198) A compound according to any one of (1) to (194), wherein: R6is Et.

[0474] (199) A compound according to any one of (1) to (194), wherein:

[0475] R6is Ci-ealkyl substituted by one or more halo, hydroxy, methoxy, N-(Ci-6alkyl)-N-(cyclopropyl)aminocarbonyl, N-(Ci-6alkyl)-N-(cyclobutyl)aminocarbonyl, N,N-(Ci-6alkyl)2aminocarbonyl, or heterocyclylcarbonyl optionally substituted by isopropyl or CF3.

[0476] (200) A compound according to any one of (1) to (194), wherein:

[0477] R6is Ci-ealkyl substituted by one or more halo. (201) A compound according to any one of (1) to (194), wherein: R6is 2-fluoroethyl.

[0478] (202) A compound according to any one of (1) to (194), wherein: R6is 2,2,2-trifluoroethyl.

[0479] (203) A compound according to any one of (1) to (194), wherein:

[0480] R6is Ci-ealkyl substituted by one or more N-(Ci-6alkyl)-N-(cyclopropyl)aminocarbonyl.

[0481] (204) A compound according to any one of (1) to (194), wherein: R6is N-(ethyl)-N-(cyclopropyl)aminocarbonylmethyl.

[0482] (205) A compound according to any one of (1) to (194), wherein:

[0483] R6is Ci-ealkyl substituted by one or more N-(Ci-6alkyl)-N-(cyclobutyl)aminocarbonyl.

[0484] (206) A compound according to any one of (1) to (194), wherein: R6is N-(methyl)-N-(cyclobutyl)aminocarbonylmethyl.

[0485] (207) A compound according to any one of (1) to (194), wherein:

[0486] R6is Ci-ealkyl substituted by one or more N,N-(Ci-6alkyl)2aminocarbonyl.

[0487] (208) A compound according to any one of (1) to (194), wherein: R6is diethylaminocarbonylmethyl.

[0488] (209) A compound according to any one of (1) to (194), wherein:

[0489] R6is Ci-ealkyl substituted by one or more heterocyclylcarbonyl.

[0490] (210) A compound according to any one of (1) to (194), wherein:

[0491] R6is Ci-ealkyl substituted by one or more pyrrolidin-1-ylcarbonyl.

[0492] (211) A compound according to any one of (1) to (194), wherein: R6is pyrrolidin-1-ylcarbonylmethyl.

[0493] (212) A compound according to any one of (1) to (194), wherein:

[0494] R6is Ci-ealkyl substituted by one or more heterocyclylcarbonyl substituted by isopropyl or CF3.

[0495] (213) A compound according to any one of (1) to (194), wherein:

[0496] R6is 2-heterocyclylcarbonyleth-2-yl; wherein said heterocyclyl may be optionally substituted by isopropyl or CF3.

[0497] (214) A compound according to any one of (1) to (194), wherein:

[0498] R6is Ci-ealkyl substituted by one or more 2-(isopropylmethyl)pyrrolidin-1-ylcarbonyl or 2-(trifluoromethyl)pyrrolidin-1-ylcarbonyl.

[0499] (215) A compound according to any one of (1) to (194), wherein: R6is 2-(trifluoromethyl)pyrrolidin-1-ylcarbonylmethyl.

[0500] (216) A compound according to any one of (1) to (194), wherein: R6is 2-(isopropyl)pyrrolidin-1-ylcarbonylmethyl.

[0501] (217) A compound according to any one of (1) to (194), wherein:

[0502] R6is 2-(trifluoromethyl)pyrrolidin-1-ylcarbonyleth-2-yl. (218) A compound according to any one of (1) to (194), wherein: R6is phenyl.

[0503] (219) A compound according to any one of (1) to (194), wherein:

[0504] R6is Ci-ealkyl substituted by one or more hydroxy and heterocyclylcarbonyl substituted by CF3.

[0505] (220) A compound according to any one of (1) to (194), wherein:

[0506] R6is Ci-ealkyl substituted by one or more hydroxy and

[0507] 2-(trifluoromethyl)pyrrolidin-1-ylcarbonyl substituted by CF3.

[0508] (221) A compound according to any one of (1) to (194), wherein:

[0509] R6is 1-hydroxy-2-(2-(trifluoromethyl)pyrrolidin-1-ylcarbonyl)eth-2-yl.

[0510] (222) A compound according to any one of (1) to (194), wherein:

[0511] R6is Ci-ealkyl substituted by one or more methoxy and heterocyclylcarbonyl substituted by CF3.

[0512] (223) A compound according to any one of (1) to (194), wherein:

[0513] R6is Ci-ealkyl substituted by one or more methoxy and

[0514] 2-(trifluoromethyl)pyrrolidin-1-ylcarbonyl substituted by CF3.

[0515] (224) A compound according to any one of (1) to (194), wherein:

[0516] R6is 1-methoxy-2-(2-(trifluoromethyl)pyrrolidin-1-ylcarbonyl)eth-2-yl.

[0517] Some Specific Formulae

[0518] (225) A compound according to any one of (1) to (224), of the following formula: wherein:

[0519] R1is H or Me;

[0520] R5’ is selected from the following groups of R5:

[0521] (i) halo;

[0522] (ii) amino;

[0523] (iii) Ci-ealkyl; wherein said Ci-ealkyl may be optionally substituted by one or more halo, hydroxy, Ci-ealkoxy, N,N-(Ci-6alkyl)2amino, N-(Ci-6alkyl)aminocarbonyl, N,N- (Ci-6alkyl)2aminocarbonyl optionally substituted by hydroxy, N-(Ci-ealkyl)-N- (cyclopropyl)aminocarbonyl, N-(Ci-6alkyl)-N-(cyclobutyl)aminocarbonyl, N- (Ci-6alkanoyl)-N-(Ci-6alkyl)amino, or heterocyclylcarbonyl;

[0524] (iv) Ci-ealkoxy; wherein said Ci-ealkoxy may be optionally substituted by one or more halo, cyclopropyl, cyclopentyl, phenyl optionally substituted by halo, or heterocyclyl; (v) N-(Ci-6alkyl)amino; wherein said Ci-ealkylamino may be optionally substituted by one or more halo or methoxy;

[0525] (vi) N,N-(Ci-6alkyl)2amino;

[0526] (vii) cyclohexylamino;

[0527] (viii) heterocyclyl;

[0528] (ix) heterocyclyloxy;

[0529] (x) heterocyclylamino;

[0530] R5” is selected from the following groups of R5:

[0531] (i) Ci-ealkoxy; wherein said Ci-ealkoxy may be optionally substituted by one or more halo, cyclopropyl, cyclopentyl, phenyl optionally substituted by halo, or heterocyclyl;

[0532] (ii) Ci-ealkanoylamino; wherein said Ci-ealkanoylamino may be optionally substituted by one or more cyclopropyl;

[0533] (iii) Ci-ealkylsulphonylamino;

[0534] (iv) N-(Ci-6alkyl)aminocarbonyl; wherein said N-(Ci-6alkyl)aminocarbonyl may be optionally substituted by one or more hydroxy or fluoro;

[0535] (v) N,N-(Ci-6alkyl)2aminocarbonyl;

[0536] (vi) N-(Ci-6alkyl)-N-(cyclopropyl)aminocarbonyl;

[0537] (vii) cyclopropylC(O)NH-; wherein said cyclopropyl may be optionally substituted by one or more halo;

[0538] (viii) cyclopentylaminocarbonyl;

[0539] (ix) bicyclo[1 , 1 , 1]pentanylaminocarbonyl;

[0540] (x) heterocyclyl;

[0541] (xi) heterocyclylcarbonyl;

[0542] (xii) heterocyclylaminocarbonyl; wherein any heterocyclyl in R5’ or R5” may be optionally substituted on carbon by one or more halo, cyano, methyl, trifluoromethyl, or methoxy methyl; and wherein in R5’ or R5”, if any heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted on nitrogen by methyl, isopropyl, cyclopropyl, or hydroxyethyl.

[0543] (225a) A compound according to any one of (1) to (224), of the following formula: wherein:

[0544] R1is H or Me;

[0545] R5’ is selected from the following groups of R5: (i) halo;

[0546] (ii) amino;

[0547] (iii) Ci-ealkyl; wherein said Ci-ealkyl may be optionally substituted by one or more halo, hydroxy, Ci-ealkoxy, N,N-(Ci-6alkyl)2amino, N-(Ci-6alkyl)aminocarbonyl, N,N- (Ci-6alkyl)2aminocarbonyl optionally substituted by hydroxy, N-(Ci-ealkyl)-N- (cyclopropyl)aminocarbonyl, N-(Ci-6alkyl)-N-(cyclobutyl)aminocarbonyl, N- (Ci-6alkanoyl)-N-(Ci-6alkyl)amino, or heterocyclylcarbonyl;

[0548] (iv) Ci-ealkoxy; wherein said Ci-ealkoxy may be optionally substituted by one or more halo, cyclopropyl, cyclopentyl, phenyl optionally substituted by halo, or heterocyclyl;

[0549] (v) N-(Ci-6alkyl)amino; wherein said Ci-ealkylamino may be optionally substituted by one or more halo or methoxy;

[0550] (vi) N,N-(Ci-6alkyl)2amino;

[0551] (vii) cyclohexylamino;

[0552] (viii) heterocyclylamino;

[0553] (ix) heterocyclyl;

[0554] (x) heterocyclyloxy;

[0555] R5” is selected from the following groups of R5:

[0556] (xiii) Ci-ealkoxy; wherein said Ci-ealkoxy may be optionally substituted by one or more halo, cyclopropyl, cyclopentyl, phenyl optionally substituted by halo, or heterocyclyl;

[0557] (xiv) Ci-ealkanoylamino; wherein said Ci-ealkanoylamino may be optionally substituted by one or more cyclopropyl;

[0558] (xv) Ci-ealkylsulphonylamino;

[0559] (xvi) N-(Ci-6alkyl)aminocarbonyl; wherein said N-(Ci-6alkyl)aminocarbonyl may be optionally substituted by one or more hydroxy or fluoro;

[0560] (xvii) N,N-(Ci-6alkyl)2aminocarbonyl;

[0561] (xviii) N-(Ci-6alkyl)-N-(cyclopropyl)aminocarbonyl;

[0562] (xix) cyclopropylC(O)NH-; wherein said cyclopropyl may be optionally substituted by one or more halo;

[0563] (xx) cyclopentylaminocarbonyl;

[0564] (xxi) bicyclo[1 , 1 , 1]pentanylaminocarbonyl;

[0565] (xxii) heterocyclylcarbonyl;

[0566] (xxiii) heterocyclylaminocarbonyl; wherein any heterocyclyl in R5’ or R5” may be optionally substituted on carbon by one or more halo, cyano, methyl, trifluoromethyl, or methoxy methyl; and wherein in R5’ or R5”, if any heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted on nitrogen by methyl, isopropyl, cyclopropyl, or hydroxyethyl

[0567] (226) A compound according to any one of (1) to (224), of the following formula: wherein:

[0568] R1is H or Me;

[0569] R5’ is selected from the following groups of R5:

[0570] (i) halo;

[0571] (ii) amino;

[0572] (iii) Ci-ealkyl; wherein said Ci-ealkyl may be optionally substituted by one or more halo, hydroxy, Ci-ealkoxy, N,N-(Ci-6alkyl)2amino, N-(Ci-6alkyl)aminocarbonyl, N,N- (Ci-6alkyl)2aminocarbonyl optionally substituted by hydroxy, N-(Ci-ealkyl)-N- (cyclopropyl)aminocarbonyl, N-(Ci-6alkyl)-N-(cyclobutyl)aminocarbonyl, N- (Ci-6alkanoyl)-N-(Ci-6alkyl)amino, or heterocyclylcarbonyl;

[0573] (iv) Ci-ealkoxy; wherein said Ci^alkoxy may be optionally substituted by one or more halo, cyclopropyl, cyclopentyl, phenyl optionally substituted by halo, or heterocyclyl;

[0574] (v) N-(Ci-6alkyl)amino; wherein said Ci-ealkylamino may be optionally substituted by one or more halo or methoxy;

[0575] (vi) N,N-(Ci-6alkyl)2amino;

[0576] (vii) cyclohexylamino;

[0577] (viii) heterocyclylamino;

[0578] (ix) heterocyclylcarbonylamino;

[0579] R5” is selected from the following groups of R5:

[0580] (i) Ci-ealkoxy; wherein said Ci-ealkoxy may be optionally substituted by one or more halo, cyclopropyl, cyclopentyl, phenyl optionally substituted by halo, or heterocyclyl;

[0581] (ii) Ci-ealkanoylamino; wherein said Ci-ealkanoylamino may be optionally substituted by one or more cyclopropyl;

[0582] (iii) Ci-ealkylsulphonylamino;

[0583] (iv) N-(Ci-6alkyl)aminocarbonyl; wherein said N-(Ci-6alkyl)aminocarbonyl may be optionally substituted by one or more hydroxy or fluoro;

[0584] (v) N,N-(Ci-6alkyl)2aminocarbonyl;

[0585] (vi) N-(Ci-6alkyl)-N-(cyclopropyl)aminocarbonyl;

[0586] (vii) cyclopropylC(O)NH-; wherein said cyclopropyl may be optionally substituted by one or more halo;

[0587] (viii) cyclopentylaminocarbonyl; (ix) bicyclo[1 , 1 , 1]pentanylaminocarbonyl;

[0588] (x) heterocyclylcarbonyl;

[0589] (xi) heterocyclylaminocarbonyl; wherein any heterocyclyl in R5’ or R5” may be optionally substituted on carbon by one or more halo, cyano, methyl, trifluoromethyl, or methoxy methyl; and wherein in R5’ or R5”, if any heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted on nitrogen by methyl, isopropyl, cyclopropyl, or hydroxyethyl.

[0590] (226a) A compound according to any one of (1) to (224), of the following formula: wherein:

[0591] R1is H or Me;

[0592] R5” is selected from the following groups of R5:

[0593] (i) N-(Ci-6alkyl)aminocarbonyl; wherein said N-(Ci-6alkyl)aminocarbonyl may be optionally substituted by one or more hydroxy or fluoro;

[0594] (ii) N,N-(Ci-6alkyl)2aminocarbonyl;

[0595] (iii) N-(Ci-6alkyl)-N-(cyclopropyl)aminocarbonyl;

[0596] (iv) cyclopentylaminocarbonyl;

[0597] (v) bicyclo[1 ,1 ,1]pentanylaminocarbonyl;

[0598] (vi) heterocyclylcarbonyl;

[0599] (vii) heterocyclylaminocarbonyl; wherein any heterocyclyl in R5’ or R5” may be optionally substituted on carbon by one or more halo, cyano, methyl, trifluoromethyl, or methoxymethyl; and wherein in R5’ or R5”, if any heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted on nitrogen by methyl, isopropyl, cyclopropyl, or hydroxyethyl.

[0600] (226b) A compound according to any one of (1) to (224), of the following formula: wherein:

[0601] R1is H or Me;

[0602] R5” is selected from the following groups of R5: (i) N-(Ci-6alkyl)aminocarbonyl; wherein said N-(Ci-6alkyl)aminocarbonyl may be optionally substituted by one or more hydroxy or fluoro;

[0603] (ii) N,N-(Ci-6alkyl)2aminocarbonyl;

[0604] (iii) N-(Ci-6alkyl)-N-(cyclopropyl)aminocarbonyl;

[0605] (iv) cyclopentylaminocarbonyl;

[0606] (v) bicyclo[1 ,1,1]pentanylaminocarbonyl;

[0607] (vi) heterocyclylcarbonyl;

[0608] (vii) heterocyclylaminocarbonyl; wherein any heterocyclyl in R5’ or R5” may be optionally substituted on carbon by one or more halo, cyano, methyl, trifluoromethyl, or methoxy methyl; and wherein in R5’ or R5”, if any heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted on nitrogen by methyl, isopropyl, cyclopropyl, or hydroxyethyl.

[0609] (227) A compound according to any one of (1) to (224), of the following formula: wherein:

[0610] R1is H or Me;

[0611] R5’ is selected from the following groups of R5:

[0612] (i) halo;

[0613] (ii) amino;

[0614] (iii) Ci-ealkyl; wherein said Ci-ealkyl may be optionally substituted by one or more halo, hydroxy, Ci-ealkoxy, N,N-(Ci-6alkyl)2amino, N-(Ci-6alkyl)aminocarbonyl, N,N- (Ci-6alkyl)2aminocarbonyl optionally substituted by hydroxy, N-(Ci-ealkyl)-N- (cyclopropyl)aminocarbonyl, N-(Ci-6alkyl)-N-(cyclobutyl)aminocarbonyl, N- (Ci-6alkanoyl)-N-(Ci-6alkyl)amino, or heterocyclylcarbonyl;

[0615] (iv) Ci-ealkoxy; wherein said Ci-ealkoxy may be optionally substituted by one or more halo, cyclopropyl, cyclopentyl, phenyl optionally substituted by halo, or heterocyclyl;

[0616] (v) N-(Ci-6alkyl)amino; wherein said Ci-ealkylamino may be optionally substituted by one or more halo or methoxy;

[0617] (vi) N,N-(Ci-6alkyl)2amino;

[0618] (vii) cyclohexylamino;

[0619] (viii) heterocyclylamino;

[0620] (ix) heterocyclylcarbonylamino; wherein any heterocyclyl in R5’ may be optionally substituted on carbon by one or more halo, cyano, methyl, trifluoromethyl, or methoxymethyl; and wherein if any heterocyclyl in R5’ contains an -NH- moiety that nitrogen may be optionally substituted on nitrogen by methyl, isopropyl, cyclopropyl, or hydroxyethyl;

[0621] R6is methyl; wherein said methyl may be optionally substituted by one or more N-(Ci-6alkyl)-N-(cyclopropyl)aminocarbonyl, N-(Ci-6alkyl)-N-(cyclobutyl)aminocarbonyl, N,N-(Ci-6alkyl)2aminocarbonyl, or heterocyclylcarbonyl optionally substituted by isopropyl or CF3, or ethyl; wherein said ethyl is substituted with halo.

[0622] (227a) A compound according to any one of (1) to (224), of the following formula: wherein:

[0623] R1is H or Me;

[0624] R5’ is selected from the following groups of R5:

[0625] (i) halo;

[0626] (ii) Ci-ealkyl; wherein said Ci-ealkyl may be optionally substituted by one or more halo, hydroxy, Ci-ealkoxy, N,N-(Ci-6alkyl)2amino, N-(Ci-6alkyl)aminocarbonyl, N,N- (Ci-6alkyl)2aminocarbonyl optionally substituted by hydroxy, N-(Ci-ealkyl)-N- (cyclopropyl)aminocarbonyl, N-(Ci-6alkyl)-N-(cyclobutyl)aminocarbonyl, N- (Ci-6alkanoyl)-N-(Ci-6alkyl)amino, or heterocyclylcarbonyl; wherein any heterocyclyl in R5’ may be optionally substituted on carbon by one or more halo, cyano, methyl, trifluoromethyl, or methoxymethyl; and wherein if any heterocyclyl in R5’ contains an -NH- moiety that nitrogen may be optionally substituted on nitrogen by methyl, isopropyl, cyclopropyl, or hydroxyethyl;

[0627] R6is Ci-ealkyl; wherein said Ci-ealkyl may be optionally substituted by one or more halo. (227b) A compound according to any one of (1) to (224), of the following formula: wherein:

[0628] R1is H or Me; R5’ is selected from the following groups of R5:

[0629] (i) halo;

[0630] (ii) Ci-ealkyl; wherein said Ci-ealkyl may be optionally substituted by one or more halo, hydroxy, Ci-ealkoxy, N,N-(Ci-6alkyl)2amino, N-(Ci-6alkyl)aminocarbonyl, N,N- (Ci-6alkyl)2aminocarbonyl optionally substituted by hydroxy, N-(Ci-ealkyl)-N- (cyclopropyl)aminocarbonyl, N-(Ci-6alkyl)-N-(cyclobutyl)aminocarbonyl, N- (Ci-6alkanoyl)-N-(Ci-6alkyl)amino, or heterocyclylcarbonyl; wherein any heterocyclyl in R5’ may be optionally substituted on carbon by one or more halo, cyano, methyl, trifluoromethyl, or methoxymethyl; and wherein if any heterocyclyl in R5’ contains an -NH- moiety that nitrogen may be optionally substituted on nitrogen by methyl, isopropyl, cyclopropyl, or hydroxyethyl;

[0631] R6is methyl; wherein said methyl may be optionally substituted by one or more N-(Ci-ealkyl)-N- (cyclopropyl)aminocarbonyl, N-(Ci-6alkyl)-N-(cyclobutyl)aminocarbonyl, N,N-(Ci-6alkyl)2aminocarbonyl, or heterocyclylcarbonyl optionally substituted by isopropyl or CF3.

[0632] (228) A compound according to any one of (225) to (227b) wherein:

[0633] R5’ is selected from the following groups of R5:

[0634] (i) N-(Ci-6alkyl)amino; wherein said Ci-ealkylamino may be optionally substituted by one or more halo or methoxy;

[0635] (ii) N,N-(Ci-6alkyl)2amino;

[0636] (iii) heterocyclylamino; wherein any heterocyclyl may be optionally substituted on carbon by one or more halo, cyano, methyl, trifluoromethyl, or methoxymethyl; and wherein in R5’ or R5”, if any heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted on nitrogen by methyl, isopropyl, cyclopropyl, or hydroxyethyl.

[0637] (229) A compound according to any one of (225) to (227) wherein:

[0638] R5’ is selected from the following groups of R5:

[0639] (i) halo;

[0640] (ii) Ci-ealkyl; wherein said Ci-ealkyl may be optionally substituted by one or more halo, hydroxy, Ci-ealkoxy, N,N-(Ci-6alkyl)2amino, N-(Ci-6alkyl)aminocarbonyl, N,N- (Ci-6alkyl)2aminocarbonyl optionally substituted by hydroxy, N-(Ci-ealkyl)-N- (cyclopropyl)aminocarbonyl, N-(Ci-6alkyl)-N-(cyclobutyl)aminocarbonyl, N- (Ci-6alkanoyl)-N-(Ci-6alkyl)amino, or heterocyclylcarbonyl; wherein any heterocyclyl in R5’ or R5” may be optionally substituted on carbon by one or more halo, cyano, methyl, trifluoromethyl, or methoxy methyl; and wherein in R5’ or R5”, if any heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted on nitrogen by methyl, isopropyl, cyclopropyl, or hydroxyethyl. (230) A compound according to any one of (225), (226) or (228) to (229) wherein:

[0641] R5” is selected from the following groups of R5:

[0642] (i) N-(Ci-6alkyl)aminocarbonyl; wherein said N-(Ci-6alkyl)aminocarbonyl may be optionally substituted by one or more hydroxy or fluoro;

[0643] (ii) N,N-(Ci-6alkyl)2aminocarbonyl;

[0644] (iii) heterocyclylcarbonyl;

[0645] (iv) heterocyclylaminocarbonyl; wherein any heterocyclyl may be optionally substituted on carbon by one or more halo, cyano, methyl, trifluoromethyl, or methoxymethyl; and wherein in R5’ or R5”, if any heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted on nitrogen by methyl, isopropyl, cyclopropyl, or hydroxyethyl.

[0646] (231) A compound according to any one of (225), (226) or (228) to (229) wherein:

[0647] R5” is selected from the following groups of R5:

[0648] (i) Ci-ealkoxy; wherein said Ci-ealkoxy may be optionally substituted by one or more halo, cyclopropyl, cyclopentyl, phenyl optionally substituted by halo, or heterocyclyl;

[0649] (ii) Ci-ealkanoylamino; wherein said Ci-ealkanoylamino may be optionally substituted by one or more cyclopropyl;

[0650] (iii) Ci-ealkylsulphonylamino;

[0651] (iv) heterocyclylcarbonyl;

[0652] (v) heterocyclylaminocarbonyl; wherein any heterocyclyl in R5’ or R5” may be optionally substituted on carbon by one or more halo, cyano, methyl, trifluoromethyl, or methoxy methyl; and wherein in R5’ or R5”, if any heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted on nitrogen by methyl, isopropyl, cyclopropyl, or hydroxyethyl.

[0653] (232) A compound according to any one of (1) to (231) or a pharmaceutically acceptable salt or solvate thereof.

[0654] Some

[0655] (233) A compound according to (1) or (2), selected from compounds of the following formulae and pharmaceutically acceptable salts and solvates thereof (e.g., and pharmaceutically acceptable salts thereof):

[0656] In one embodiment, the BAA compound is obtainable (or obtained) by following the methods described in the experimental section.

[0657] 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 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 are individually disclaimed.

[0658] 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 other embodiment described herein is specifically disclaimed.

[0659] 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 Examples from PCT / EP2024 / 056305 and PCT / EP2024 / 05620 are individually disclaimed.

[0660] 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 all of the specific Examples from PCT / EP2024 / 056305 and PCT / EP2024 / 05620 are individually disclaimed.

[0661] 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 Examples from PCT / EP2024 / 056305 are individually disclaimed.

[0662] 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 all of the specific Examples from PCT / EP2024 / 056305 are individually disclaimed.

[0663] 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 Examples from PCT / EP2024 / 05620 are individually disclaimed. 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 all of the specific Examples from PCT / EP2024 / 05620 are individually disclaimed.

[0664] Combinations

[0665] It is appreciated that certain features of the invention, which are, for clarity, described in the 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 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). 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 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 herein just as if each and every such sub-combination of chemical groups was individually and explicitly disclosed herein.

[0666] Substantially Purified Forms

[0667] 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.

[0668] 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 weight.

[0669] 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 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.

[0670] In one embodiment, the contaminants represent no more than 50% by weight, e.g., no more 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.

[0671] 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 stereoisomers. In one embodiment, the contaminants refer to other compounds and the other enantiomer.

[0672] 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 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.

[0673] Isomers

[0674] Certain compounds may exist in one or more particular geometric, optical, enantiomeric, 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; a- and p-forms; axial and equatorial forms; boat-, chair-, twist-, envelope-, and halfchair-forms; and combinations thereof, hereinafter collectively referred to as “isomers” (or “isomeric forms”).

[0675] A reference to a class of structures may well include structurally isomeric forms falling within that class (e.g., Ci-ealkyl 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.

[0676] 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 For example, 1 H-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.

[0677] 1 H-pyridin-2-one-5-yl 2-hydroxyl-pyridin-5-yl

[0678] 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.

[0679] 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.

[0680] 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.

[0681] Salts

[0682] 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 Bronsted 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.

[0683] 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., NF ). Examples of suitable organic cations include, but are not limited to substituted ammonium ions (e.g., NHsR+, NH2R2+, NHRs+, NR4+), for example, where each R is independently linear or branched saturated Ci-isalkyl , Cs-scycloalkyl, Cs-scycloalkyl-Ci-ealkyl, and phenyl-Ci-ealkyl, 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+.

[0684] 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.

[0685] For example, if a parent structure contains a cationic group (e.g., -NMe2+), 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., -NMe2+, -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.

[0686] 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.

[0687] 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, 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.

[0688] Examples of suitable counter-ions which are especially suitable for quaternary ammonium 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.

[0689] Unless otherwise specified, a reference to a particular compound also includes salt forms thereof.

[0690] In one embodiment, the BAA compound is provided in the form of a salt.

[0691] In one embodiment, the BAA compound is provided in a neutral form (for example as a free acid, free base, or zwitterion). Solvates and

[0692] It may be convenient or desirable to prepare, purify, and / or handle a corresponding solvate of the compound. The term “solvate” is used herein in the conventional sense to refer to a complex of solute (e.g., compound, salt of compound) and solvent. If the solvent is water, the solvate may be conveniently referred to as a hydrate, for example, a mono-hydrate, a di-hydrate, a tri-hydrate, etc.

[0693] Unless otherwise specified, a reference to a particular compound also includes solvate and hydrate forms thereof.

[0694] In one embodiment, the BAA compound is provided in the form of a solvate.

[0695] In one embodiment, the BAA compound is provided in the form of a hydrate.

[0696] In one embodiment, the BAA compound is provided in unsolvated form.

[0697] Chemically Protected Forms

[0698] 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 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).

[0699] 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.

[0700] 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). 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.

[0701] 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-OCH2C6Hs, -NH-Cbz), as a t-butoxy carbamate (-NHCO-OC(CH3)3, -NH-BOC); as a 2-biphenyl-2-propoxy carbamate (-NHCO-OC(CH3)2C6H4C6HS, -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).

[0702] For example, a carboxylic acid group may be protected as an ester for example, as: an Ci-?alkyl ester (e.g., a methyl ester; a t-butyl ester); a C haloalkyl ester (e.g., a 2,2,2-trihaloethyl ester); a 2-tri(Ci-7alkyl)silyl-ethyl ester; or a Cs-2oaryl-Ci-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.

[0703] 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).

[0704] Prodrugs

[0705] 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 compound, but may provide advantageous handling, administration, or metabolic properties.

[0706] For example, some prodrugs are esters of the active compound (e.g., a physiologically acceptable metabolically labile ester). During metabolism, the ester group (-C(=O)OR) is cleaved to yield the active drug. Such esters may be formed by esterification, for example, of any of the carboxylic acid groups (-C(=O)OH) in the parent compound, with, where appropriate, prior protection of any other reactive groups present in the parent compound, followed by deprotection if required.

[0707] Also, some prodrugs are activated enzymatically to yield the active compound, or a compound, which, upon further chemical reaction, yields the active compound (for example, as in antibody directed enzyme prodrug therapy (ADEPT), gene directed enzyme prodrug therapy (GDEPT), ligand-directed enzyme prodrug therapy (LIDEPT), etc.). For example, the prodrug may be a sugar derivative or other glycoside conjugate, or may be an amino acid ester derivative.

[0708] 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).

[0709] Also described herein is 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 (for example a carrier and / or diluent).

[0710] Uses

[0711] The BAA compounds, as described herein, inhibit PKMYT1 (e.g., inhibit or reduce or block the activity or function of PKMYT1).

[0712] 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).

[0713] Use in Methods of Inhibiting PKMYT1

[0714] 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 PKMYT 1 with an effective amount of a BAA compound, as described herein.

[0715] 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.

[0716] In one embodiment, the method is performed in vitro.

[0717] In one embodiment, the method is performed in vivo.

[0718] In one embodiment, the BAA compound is provided in the form of a pharmaceutically acceptable composition.

[0719] One of ordinary skill in the art is readily able to determine whether or not a candidate compound inhibits PKMYT 1 (e.g., inhibits or reduces or blocks the activity or function of PKMYT 1). For example, suitable assays are described herein and / or are known in the art.

[0720] 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 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 luminescent readout.

[0721] Use in Methods of Inhibiting Cell Proliferation, etc.

[0722] 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 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.

[0723] The BAA compounds described herein may e.g., (a) regulate (e.g., inhibit) cell proliferation;

[0724] (b) force cell cycle progression of cells with unrepaired DNA damage, resulting in cell death;

[0725] (c) promote apoptosis; (d) reduce clonogenicity; (e) reduce tumoursphere growth or self-renewal;

[0726] (f) enhance impact of DNA-damaging agents on cell killing; (g) prevent emergence of resistance to DNA damaging agents due to cell cycle progression block that allows for DNA repair, or (h) a combination of one or more of these.

[0727] 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 vitro or in vivo, comprising contacting a cell with an effective amount of a BAA compound, as described herein.

[0728] Also described herein is a method of regulating (e.g., inhibiting) cell proliferation (e.g., proliferation of a cell), forcing cell cycle progression of cells with unrepaired DNA damage, resulting in cell death, promoting apoptosis, reducing clonogenicity, reducing tumoursphere growth or self-renewal, preventing emergence of resistance, or a combination of one or more these, in vitro or in vivo, comprising contacting a cell with an effective amount of a BAA compound, as described herein. In one embodiment, the method is performed in vitro.

[0729] In one embodiment, the method is performed in vivo.

[0730] In one embodiment, the BAA compound is provided in the form of a pharmaceutically acceptable composition.

[0731] 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. 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.

[0732] The BAA compounds described herein may inhibit cell migration and invasion, e.g., inhibit metastasis.

[0733] The BAA compounds described herein may restore sensitivity to another agent in a resistant cell population.

[0734] The BAA compounds described herein may prevent emergence of resistance to another agent in a cell population.

[0735] 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, with BAA compounds synergising for example by forcing cell cycle progression of cells with unrepaired DNA damage, resulting in cell death.

[0736] Use in Methods of Therapy

[0737] 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.

[0738] 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.

[0739] Use in the Manufacture of Medicaments

[0740] 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.

[0741] In one embodiment, the medicament comprises the BAA compound.

[0742] Methods of Treatment

[0743] 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. Disorders Treated - Disorders Ameliorated by the Inhibition of PKMYT1

[0744] 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).

[0745] Disorders Treated

[0746] 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 herein.

[0747] Proliferative Disorders

[0748] In one embodiment, the disorder is: a proliferative disorder.

[0749] 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.

[0750] In one embodiment, the proliferative disorder is characterised by benign, pre-malignant, 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.

[0751] Disorders Treated - Proliferative Disorders

[0752] 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.

[0753] 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.

[0754] In one embodiment, the treatment is treatment of: a proliferative disorder characterised by benign, pre-malignant, or malignant cellular proliferation.

[0755] In one embodiment, the treatment is treatment of a proliferative disorder characterised by, or 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.

[0756] In one embodiment, the treatment is treatment of a proliferative disorder characterised by, or further characterised by: a dependency to PKMYT 1 due to high basal level of replication stress; inappropriate activity and / or expression of PKMYT1, CCNE1, FBXW7, PP2A or one of its subunits; mutation of KRAS or NRAS (for example concomitant mutation of p53 and KRAS or NRAS); or concomitant mutation of p53 and CDKN2A.

[0757] In one embodiment, the treatment is treatment of a proliferative disorder characterised by, or further characterised by: a dependency to PKMYT 1 due to high basal level of replication stress. In one embodiment, the treatment is treatment of a proliferative disorder characterised by, or further characterised by: mutation of KRAS or NRAS (for example concomitant mutation of p53 and KRAS or NRAS).

[0758] In one embodiment, the treatment is treatment of a proliferative disorder characterised by, or further characterised by: overexpression of PKMYT1 or CCNE1.

[0759] In one embodiment, the treatment is treatment of a proliferative disorder characterised by, or further characterised by overexpression of PKMYT1.

[0760] In one embodiment, the treatment is treatment of a proliferative disorder characterised by, or further characterised by overexpression of CCNE1.

[0761] 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 or PPP2R1A.

[0762] In one embodiment, the treatment is treatment of a proliferative disorder characterised by, or further characterised by inactivation of FBXW7.

[0763] 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. In one embodiment, the treatment is treatment of a proliferative disorder characterised by, or further characterised by mutation or deletion of CDKN2A (for example concomitant mutation of p53 and CDKN2A).

[0764] In one embodiment, the treatment is treatment of a proliferative disorder characterised by, or further characterised by concomitant mutation of p53 and CDKN2A.

[0765] In one embodiment, the treatment is treatment of cancer.

[0766] Disorders Treated - Cancer

[0767] 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:

[0768] (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.

[0769] (2) Sarcomas, including: osteosarcoma and osteogenic sarcoma (bone); chondrosarcoma (cartilage); leiomyosarcoma (smooth muscle); rhabdomyosarcoma (skeletal muscle); mesothelial 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).

[0770] (3) Myeloma.

[0771] (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 cells predominating).

[0772] (5) Lymphomas, including: Hodgkin and Non-Hodgkin lymphomas.

[0773] (6) Mixed Types, including, e.g., adenosquamous carcinoma; mixed mesodermal tumour; carcinosarcoma; teratocarcinoma.

[0774] In one embodiment, the cancer is: 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; 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 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; 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 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; 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 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; 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; 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 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; Sezary syndrome; or splenic marginal zone lymphoma; or a myelodysplastic syndrome; 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; 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 tumor; or liposarcoma. 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.

[0775] In one embodiment, the cancer is endometrial cancer.

[0776] In one embodiment, the cancer is uterine cancer.

[0777] In one embodiment, the cancer is ovarian cancer.

[0778] In one embodiment, the cancer is breast cancer.

[0779] In one embodiment, the cancer is gastric cancer.

[0780] In one embodiment, the cancer is bladder cancer.

[0781] In one embodiment, the cancer is pancreatic cancer.

[0782] In one embodiment, the cancer is mesothelioma.

[0783] In one embodiment, the cancer is kidney cancer.

[0784] In one embodiment, the cancer is stomach cancer.

[0785] In one embodiment, the cancer is esophageal cancer.

[0786] In one embodiment, the cancer is colorectal cancer.

[0787] In one embodiment, the cancer is glioblastoma.

[0788] In one embodiment, the cancer is lung cancer.

[0789] In one embodiment, the cancer is non-small cell lung cancer.

[0790] In one embodiment, the cancer is lung squamous cell carcinoma.

[0791] 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 renalcell carcinoma, kidney chromophobe cancer, renal papillary cell carcinoma, head and neck squamous cell carcinoma, colon adenocarcinoma, stomach adenocarcinoma, thyroid carcinoma, prostate adenocarcinoma, adrenocortical carcinoma, lower grade glioma, mesothelioma, pancreatic adenocarcinoma, skin cutaneous melanoma, uveal melanoma.

[0792] 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: 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. 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 squamous cancer, adenoid cystic carcinoma, pancreatic cancer, mesothelioma, lung adenocarcinoma, head & neck cancer, diffuse large B-cells lymphoma, or liver cancer.

[0793] 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, or lung squamous cancer.

[0794] In one embodiment, the cancer is uterine carcinosarcoma (UCS) or uterine serous carcinoma (USC).

[0795] In one embodiment, the cancer is high-grade serous ovarian carcinoma (HGSOC).

[0796] In one embodiment, the cancer is high-grade serous ovarian cancer with CCNE1 amplification.

[0797] In one embodiment, the cancer is triple-negative breast cancer (TNBC).

[0798] 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, stomach cancer, colorectal cancer, bladder cancer, oesophageal cancer, cervical cancer, sarcoma, lung squamous cancer, or head & neck cancer.

[0799] 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, head & neck cancer, gastric cancer, or lung squamous cells carcinoma.

[0800] In one embodiment, the cancer is uterine carcinosarcoma (UCS) or uterine serous carcinoma (USC).

[0801] 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 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.

[0802] In one embodiment, the cancer is characterised by, or further characterised by mutation (e.g., gain of function mutation) of KRAS. For example, in one embodiment, the cancer is: pancreatic ductal adenocarcinoma, colorectal cancer, non-small cell lung cancer, choloangiocarcinoma, uterine endometrial carcinoma, testicular germ cell cancer, or cervical squamous cell carcinoma.

[0803] In one embodiment, the cancer is characterised by, or further characterised by mutation (e.g., gain of function mutation) of NRAS. For example, in one embodiment, the cancer is: colorectal cancer, melanoma, or acute myeloid leukemia.

[0804] 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.

[0805] In one embodiment, the treatment resistant cancer is resistant to standard of care therapy.

[0806] In one embodiment, the treatment resistant cancer is resistant to one or more of PARP inhibitors, cisplatin, WEE1 inhibitors and Cdk4 / 6 inhibitors.

[0807] In one embodiment, the treatment resistant cancer is recombination proficient ovarian cancer. In one embodiment, the treatment resistant cancer is HER2- ER+ breast cancer with Cdk4 / 6 resistance.

[0808] In one embodiment, the treatment resistant cancer is CDK4 / 6 inhibitor resistant TP53 mutant ER+ breast cancer.

[0809] In one embodiment, the cancer (e.g., as above) is characterised, or further characterised, as metastatic cancer.

[0810] 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 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.

[0811] T reatment

[0812] 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 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.” 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.

[0813] 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.

[0814] Combination Therapies

[0815] 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.

[0816] 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).

[0817] It is to be understood when an additional therapeutic agent is described by its class (for example 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.

[0818] 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.

[0819] 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 PKMYT 1 inhibitor is administered in combination with one or more (e.g., 1, 2, 3, 4, etc.) additional therapeutic agents.

[0820] 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 PKMYT 1 inhibitor is administered in combination with one or more (e.g., 1, 2, 3, 4, etc.) additional therapeutic agents. 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 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.

[0821] 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 example, anti-cancer agents).

[0822] 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.

[0823] 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.

[0824] 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.

[0825] 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.

[0826] 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.

[0827] 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.

[0828] 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 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).

[0829] The agents (e.g., PKMYT1 inhibitors or the BAA compounds described here, plus one or more 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.

[0830] 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 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 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. 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, polatuzumab vedotin, tisotumab vedotin, sacituzumab govitecan, loncastuximab tesirine, cetuximab sarotalocan, belantamab mafodotin, moxetumomab pasudotox, telisotuzumab vedotin, or distamab vedotin).

[0831] 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, 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.

[0832] 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 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 a tumour-specific antigen such as HER2, TROP2, Claudin 18.2, B7-H3, 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, LIV-1 , Claudin 6, CDH17, CNTN4, PSMA, STEAP1 , STEAP2, uPARAP, ROR1, cMET, CDH3, FGFR2b, CLDN6 / 9, CADM1, SSTR2, integrin b4, integrin b6, IL-1 RAP, CD54, MUC17, GCC, ASCT2, ITGB6 / 8, GD2, ecDNA, LRCC15, Ly6E, or p-Cadherin.

[0833] 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 a tumour-specific antigen such as HER2, TROP2, Claudin 18.2, B7-H3, 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.

[0834] 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 a tumour-specific antigen such as HER2, TROP2, Claudin 18.2, B7-H3, 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, LIV-1, Claudin 6, CDH17, CNTN4, PSMA, STEAP1 , STEAP2, uPARAP, ROR1, cMET, CDH3, FGFR2b, CLDN6 / 9, CADM1 , SSTR2, integrin b4, integrin b6, IL-1 RAP, CD54, MUC17, GCC, ASCT2, ITGB6 / 8, GD2, ecDNA, LRCC15, Ly6E, or p-Cadherin.

[0835] 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), HER2, TROP2, mesothelin, NAPi2b, CDH6, B7-H4, B7-H3, 5T4, AXL, CD166, dipeptidase- 3, Lewis-Y, TIM1, or tissue factor (TF).

[0836] 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), CDH6, B7-H4, B7-H3, or CEACAM5.

[0837] 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) is bispecific, for example targeting both EGFR and c-MET, such as in AZD9592.

[0838] 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, STRG-002, MORAb-202, IMGN151 , PRO-1184, A166, SYD985, SGN-15, anetumab ravtansine, lifastuzumab vedotin, XMT-1536, XMT-1592, CDX-014, XB002, Dato-DXd, IMMU-132, SKB264, TORL-1-23, and AZD5335.

[0839] 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. 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 or topoisomerase 2 inhibitor. 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, MH 30010008, P1003, P1021, and ZD06519.

[0840] In one embodiment, the other agent is an antibody-drug conjugate, wherein the payload (i.e. the drug portion of the antibody-drug conjugate) comprises two or more active compounds, and at least one of the active compounds is a topoisomerase 1 inhibitor (for example KH815).

[0841] 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 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, 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 mirvetuximHR-A1904, SHR-A1921 , AZD-5335, MHB036C, CBX-12, DS-6000, TQB2102, DS- 6157a, BL-M11D1, Epratuzumab-SN38, 9MW-2921 , 7MW-3711 , or mirvetuximab exatecan). 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-B01 D1 , AZD-8205, DB-1303, DB-1305, ESG-401, FDA-022, IBI-354, MHB088C, PRO-1160, PRO-1184, SHR-A1904, SH R-A1921 , AZD-5335, MHB036C, CBX-12, DS-6000, TQB2102, DS-6157a, BL-M11 D1, Epratuzumab-SN38, 9MW-2921 , 7MW-3711, AZD9592, KH815, or mirvetuximab exatecan).

[0842] 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-B01 D1 , 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.

[0843] 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-B01 D1 , 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, AZD9592, KH815, and mirvetuximab exatecan.

[0844] 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), CDH6, B7-H4, B7-H3, or CEACAM5, and has a topoisomerase 1 inhibitor payload.

[0845] 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.

[0846] In one embodiment, the other agent is mirvetuximab exatecan.

[0847] In one embodiment, the cancer treated with the combination of PKMYT1 inhibitor and antibodydrug conjugate is characterised by, or further characterised by: a dependency to PKMYT 1 due to high basal level of replication stress.

[0848] In one embodiment, the cancer treated with the combination of PKMYT1 inhibitor and antibodydrug conjugate is characterised by, or further characterised by: amplification or overexpression of CCNE1.

[0849] In one embodiment, the cancer treated with the combination of PKMYT1 inhibitor and antibodydrug conjugate is characterised by, or further characterised by: inactivation, decreased activity, or decreased expression of FBXW7, PPP2R2A or PPP2R1A.

[0850] In one embodiment, the cancer treated with the combination of PKMYT1 inhibitor and antibodydrug conjugate is characterised by, or further characterised by: inactivation of FBXW7.

[0851] In one embodiment, the cancer treated with the combination of PKMYT1 inhibitor and antibodydrug conjugate is characterised by, or further characterised by: decreased activity or decreased expression of PPP2R2A or PPP2R1A.

[0852] In one embodiment, the cancer treated with the combination of PKMYT1 inhibitor and antibodydrug conjugate is characterised by, or further characterised by: mutation of KRAS or NRAS (for example concomitant mutation of p53 and KRAS or NRAS).

[0853] In one embodiment, the cancer treated with the combination of PKMYT1 inhibitor and antibodydrug conjugate is characterised by, or further characterised by: mutation or deletion of CDKN2A (for example concomitant mutation of p53 and CDKN2A).

[0854] In one embodiment, the cancer treated with the combination of PKMYT1 inhibitor and antibodydrug conjugate is characterised by, or further characterised by: concomitant mutation of p53 and CDKN2A.

[0855] 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. 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 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.

[0856] 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 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, telisotuzumab vedotin and distamab vedotin. 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, lifastuzumab vedotin, XMT-1536, XMT-1592, CDX-014, XB002, Dato-DXd, IMMU-132, SKB264, TORL-1-23, and AZD5335.

[0857] 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, a topoisomerase II inhibitor, or an anti metabolite.

[0858] 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 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.

[0859] 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), HER2, TROP2, mesothelin, NAPi2b, CDH6, B7-H4, B7-H3, 5T4, AXL, CD166, dipeptidase-3, Lewis-Y, TIM1 or tissue factor (TF).

[0860] 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 CEACAM5.

[0861] 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. the drug portion of the antibody-drug conjugate) is a DNA-damaging agent.

[0862] 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. the drug portion of the antibody-drug conjugate) is a topoisomerase 1 or topoisomerase 2 inhibitor.

[0863] 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. 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, MH 30010008, P1003, P1021, and ZD06519.

[0864] 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.

[0865] 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-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.

[0866] 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-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 , AZD9592, KH815, and mirvetuximab exatecan.

[0867] 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-drug conjugate is mirvetuximab exatecan.

[0868] 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 CEACAM5, and has a topoisomerase 1 inhibitor payload.

[0869] 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 a topoisomerase 1 inhibitor payload.

[0870] 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: a dependency to PKMYT 1 due to high basal level of replication stress.

[0871] 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: amplification, or overexpression, of CCNE1.

[0872] 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. 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: inactivation of FBXW7. 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 PPP2R2A or PPP2R1A.

[0873] 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: mutation of KRAS or NRAS (for example concomitant mutation of p53 and KRAS or NRAS).

[0874] 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: deletion or mutation of CDKN2A (for example concomitant mutation of p53 and CDKN2A).

[0875] 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: concomitant mutation of p53 and CDKN2A.

[0876] 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 cancer is characterised by, or further characterised by: deletion or mutation of CDKN2A (for example concomitant mutation of p53 and CDKN2A).

[0877] 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 cancer is characterised by, or further characterised by: concomitant mutation of p53 and CDKN2A.

[0878] 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 cancer is characterised by, or further characterised by: a dependency to PKMYT 1 due to high basal level of replication stress.

[0879] 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 cancer is characterised by, or further characterised by: amplification, or overexpression, of CCNE1.

[0880] 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 cancer is characterised by, or further characterised by: decreased activity, or decreased expression, of FBXW7, PPP2R2A or PPP2R1A.

[0881] 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 cancer is characterised by, or further characterised by: inactivation of FBXW7.

[0882] 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 cancer is characterised by, or further characterised by: decreased activity or decreased expression of PPP2R2A or PPP2R1A.

[0883] 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 cancer is characterised by, or further characterised by: mutation of KRAS or NRAS (for example concomitant mutation of p53 and KRAS or NRAS).

[0884] 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 cancer is characterised by, or further characterised by: deletion or mutation of CDKN2A (for example concomitant mutation of p53 and CDKN2A).

[0885] 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: concomitant mutation of p53 and CDKN2A.

[0886] 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 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 bleomycin, or mitomycin-C).

[0887] 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 DNA intercalator (for example an anthracycline like doxorubicin, epirubicin, idarubicin 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 bleomycin, mitomycin-C, or a Poll inhibitor and / or G-quadruplex targeting agent [for example pidnarulex]).

[0888] 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).

[0889] In one embodiment, the other agent is an alkylating agent (for example cis-platin).

[0890] In one embodiment, the other agent is an anthracycline (for example doxorubicin, or idarubicin). In one embodiment, the other agent is a topoisomerase I inhibitor (for example irinotecan, or topotecan).

[0891] In one embodiment, the other agent is a topoisomerase II inhibitor (for example etoposide).

[0892] In one embodiment, the other agent is an antimetabolite (for example gemcitabine).

[0893] In one embodiment, treatment with a combination of a PKMYT 1 inhibitor and a topoisomerase 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 deletion or mutation of CDKN2A (for example concomitant mutation of p53 and CDKN2A).

[0894] In one embodiment, treatment with a combination of a PKMYT 1 inhibitor and a topoisomerase 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.

[0895] In one embodiment, treatment with a combination of a PKMYT 1 inhibitor and a topoisomerase 1 inhibitor, a topoisomerase 2 inhibitor, or gemcitabine, induces selective DNA damage in cancers characterised by: a dependency to PKMYT 1 due to high basal level of replication stress; CCNE1 amplification or overexpression; inactivation, decreased activity, or decreased expression of FBXW7, PPP2R2A or PPP2R1A; mutation of KRAS or NRAS (for example concomitant mutation of p53 and KRAS or NRAS); or deletion or mutation of CDKN2A (for example concomitant mutation of p53 and CDKN2A).

[0896] In one embodiment, treatment with a combination of a PKMYT 1 inhibitor and a topoisomerase 1 inhibitor, a topoisomerase 2 inhibitor, or gemcitabine, induces selective DNA damage in cancers characterised by: a dependency to PKMYT 1 due to high basal level of replication stress; CCNE1 amplification or overexpression; inactivation, decreased activity, or decreased expression of FBXW7, PPP2R2A or PPP2R1A; mutation of KRAS or NRAS (for example concomitant mutation of p53 and KRAS or NRAS); or concomitant mutation of p53 and CDKN2A.

[0897] In one embodiment, treatment with a combination of a PKMYT 1 inhibitor and a topoisomerase 1 inhibitor, a topoisomerase 2 inhibitor, or gemcitabine, induces selective DNA damage in cancers characterised by: CCNE1 amplification or overexpression.

[0898] In one embodiment, treatment with a combination of a PKMYT 1 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 deletion or mutation of CDKN2A (for example concomitant mutation of p53 and CDKN2A).

[0899] In one embodiment, treatment with a combination of a PKMYT 1 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.

[0900] In one embodiment, treatment with a combination of a PKMYT 1 inhibitor and a topoisomerase 1 inhibitor, a topoisomerase 2 inhibitor, or gemcitabine, induces selective DNA damage in cancers characterised by: a dependency to PKMYT 1 due to high basal level of replication stress; inactivation, decreased activity, or decreased expression of FBXW7, PPP2R2A or PPP2R1A; mutation of KRAS or NRAS (for example concomitant mutation of p53 and KRAS or NRAS); or deletion or mutation of CDKN2A (for example concomitant mutation of p53 and CDKN2A).

[0901] In one embodiment, treatment with a combination of a PKMYT 1 inhibitor and a topoisomerase 1 inhibitor, a topoisomerase 2 inhibitor, or gemcitabine, induces selective DNA damage in cancers characterised by: a dependency to PKMYT 1 due to high basal level of replication stress; inactivation, decreased activity, or decreased expression of FBXW7, PPP2R2A or PPP2R1A; mutation of KRAS or NRAS (for example concomitant mutation of p53 and KRAS or NRAS); or concomitant mutation of p53 and CDKN2A.

[0902] In one embodiment, treatment with a combination of a PKMYT 1 inhibitor and a topoisomerase 1 inhibitor, a topoisomerase 2 inhibitor, or gemcitabine, induces selective DNA damage in cancers characterised by: a dependency to PKMYT 1 due to high basal level of replication stress. In one embodiment, treatment with a combination of a PKMYT 1 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.

[0903] In one embodiment, treatment with a combination of a PKMYT 1 inhibitor and a topoisomerase 1 inhibitor, a topoisomerase 2 inhibitor, or gemcitabine, induces selective DNA damage in cancers characterised by deletion or mutation of CDKN2A (for example concomitant mutation of p53 and CDKN2A).

[0904] In one embodiment, treatment with a combination of a PKMYT 1 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.

[0905] In one embodiment, treatment with a combination of a PKMYT 1 inhibitor and a topoisomerase 1 inhibitor, a topoisomerase 2 inhibitor, or gemcitabine, induces selective DNA damage in cancers characterised by mutation of KRAS or NRAS (for example concomitant mutation of p53 and KRAS or NRAS).

[0906] 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 yH2AX.

[0907] In one embodiment, treatment of cancer that exhibits CCNE1 amplification or overexpression; inactivation, decreased activity, or decreased expression of FBXW7, PPP2R2A or PPP2R1A; or deletion or mutation of CDKN2A (for example 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 yH2AX.

[0908] 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 induction of yH2AX.

[0909] In one embodiment, treatment of cancer that exhibits a dependency to PKMYT 1 due to high basal level of replication stress; CCNE1 amplification or overexpression; inactivation, decreased activity, or decreased expression of FBXW7, PPP2R2A or PPP2R1A; mutation of KRAS or NRAS (for example concomitant mutation of p53 and KRAS or NRAS); or deletion or mutation of CDKN2A (for example 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 yH2AX.

[0910] In one embodiment, treatment of cancer that exhibits a dependency to PKMYT 1 due to high basal level of replication stress; CCNE1 amplification or overexpression; inactivation, decreased activity, or decreased expression of FBXW7, PPP2R2A or PPP2R1A; mutation of KRAS or NRAS (for example concomitant mutation of p53 and KRAS or NRAS); or deletion or mutation of CDKN2A (for example 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 yH2AX.

[0911] In one embodiment, treatment of cancer that exhibits a dependency to PKMYT 1 due to high basal level of replication stress; CCNE1 amplification or overexpression; inactivation, decreased activity, or decreased expression of FBXW7, PPP2R2A or PPP2R1A; mutation of KRAS or NRAS (for example concomitant mutation of p53 and KRAS or NRAS); or deletion or mutation of CDKN2A (for esample 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 yH2AX.

[0912] In one embodiment, treatment of cancer that exhibits a dependency to PKMYT 1 due to high basal level of replication stress; CCNE1 amplification or overexpression; inactivation, decreased activity, or decreased expression of FBXW7, PPP2R2A or PPP2R1A; mutation of KRAS or NRAS (for example concomitant mutation of p53 and KRAS or NRAS); 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 yH2AX.

[0913] 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 yH2AX.

[0914] In one embodiment, treatment of cancer that exhibits inactivation, decreased activity, or decreased expression of FBXW7, PPP2R2A or PPP2R1A; or deletion or mutation of CDKN2A (for example concomitant mutation of p53 and CDKN2A) with a combination of a PKMYT 1 inhibitor and a topoisomerase 1 inhibitor, a topoisomerase 2 inhibitor, or gemcitabine, is characterised by synergistic induction of yH2AX.

[0915] In one embodiment, treatment of cancer that exhibits 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 induction of yH2AX.

[0916] In one embodiment, treatment of cancer that exhibits a dependency to PKMYT 1 due to high basal level of replication stress; inactivation, decreased activity, or decreased expression of FBXW7, PPP2R2A or PPP2R1A; mutation of KRAS or NRAS (for example concomitant mutation of p53 and KRAS or NRAS); or deletion or mutation of CDKN2A (for example 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 yH2AX. In one embodiment, treatment of cancer that exhibits a dependency to PKMYT 1 due to high basal level of replication stress; inactivation, decreased activity, or decreased expression of FBXW7, PPP2R2A or PPP2R1A; mutation of KRAS or NRAS (for example concomitant mutation of p53 and KRAS or NRAS); or concomitant mutation of p53 and CDKN2A with a combination of a PKMYT 1 inhibitor and a topoisomerase 1 inhibitor, a topoisomerase 2 inhibitor, or gemcitabine, is characterised by synergistic induction of yH2AX.

[0917] In one embodiment, treatment of cancer that exhibits a dependency to PKMYT 1 due to high basal level of replication stress with a combination of a PKMYT1 inhibitor and a topoisomerase 1 inhibitor, a topoisomerase 2 inhibitor, or gemcitabine, is characterised by synergistic induction of yH2AX.

[0918] In one embodiment, treatment of cancer that exhibits inactivation, decreased activity, or decreased expression of FBXW7, PPP2R2A or PPP2R1A, with a combination of a PKMYT 1 inhibitor and a topoisomerase 1 inhibitor, a topoisomerase 2 inhibitor, or gemcitabine, is characterised by synergistic induction of yH2AX.

[0919] In one embodiment, treatment of cancer that exhibits mutation of KRAS or NRAS (for example concomitant mutation of p53 and KRAS or NRAS), with a combination of a PKMYT1 inhibitor and a topoisomerase 1 inhibitor, a topoisomerase 2 inhibitor, or gemcitabine, is characterised by synergistic induction of yH2AX.

[0920] In one embodiment, treatment of cancer that exhibits deletion or mutation of CDKN2A (for example concomitant mutation of p53 and CDKN2A) with a combination of a PKMYT 1 inhibitor and a topoisomerase 1 inhibitor, a topoisomerase 2 inhibitor, or gemcitabine, is characterised by synergistic induction of yH2AX.

[0921] In one embodiment, treatment of cancer that exhibits 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 yH2AX.

[0922] 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 LISP1 inhibitor).

[0923] In one embodiment, the other agent is double strand-break repair inhibitor (for example a Pol0 inhibitor, or a RAD51 inhibitor).

[0924] In one embodiment, the other agent is a signalling pathway inhibitor, such as a kinase inhibitor (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, 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).

[0925] In one embodiment, the other agent is a cell cycle targeting inhibitor, such as a CDK4 / 6 inhibitor (for example palbociclib, abemaciclib, or ribociclib).

[0926] 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 inhibitor (for example adavosertib, or azenosertib), a PLK1 inhibitor (for example onvansertib), or an ALIR-A inhibitor (for example JAB-2485).

[0927] 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).

[0928] In one embodiment, the other agent is an ATR inhibitor (for example ceralasertib, gartisertib, tuvusertib or camonsertib), or a WEE1 inhibitor (for example azenosertib).

[0929] In one embodiment, the other agent is a CHK1 inhibitor (for example prexasertib).

[0930] In one embodiment, the other agent is an ATR inhibitor (for example ceralasertib, gartisertib, tuvusertib, elimusertib, or camonsertib).

[0931] In one embodiment, the other agent is a WEE1 inhibitor (for example adavosertib, or azenosertib).

[0932] 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 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 5a-reductase (for example finasteride) or an analogue of somatostatin (for example lanreotide).

[0933] In one embodiment, the other agent is a proteasome inhibitor (for example bortezomib), a histone deacetylase inhibitor (for example vorinostat, romidepsin, panobinostat, or belinostat), or a DNA demethylating agent (for example azacitidine, or decitabine).

[0934] 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 dichloride, Ac-225 prostate-specific membrane antigen (PSMA) radioligand or other Ac-225 targeted radiotherapeutic, or Y-90 ibritumomab tiuxetan). Certain Combined Therapies

[0935] 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 DNA damaging agent, and the cancer is characterised by, or further characterised by: a dependency to PKMYT 1 due to high basal level of replication stress; CCNE1 amplification or overexpression; inactivation, decreased activity, or decreased expression of FBXW7, PPP2R2A or PPP2R1A; mutation of KRAS or NRAS (for example concomitant mutation of p53 and KRAS or NRAS); or deletion or mutation of CDKN2A (for example concomitant mutation of p53 and CDKN2A).

[0936] 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 cancer is characterised by, or further characterised by: CCNE1 amplification or overexpression; inactivation, decreased activity, or decreased expression of FBXW7, PPP2R2A or PPP2R1A; or mutation or deletion of CDKN2A (for example concomitant mutation of p53 and CDKN2A).

[0937] 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 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.

[0938] 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 cancer is characterised by, or further characterised by: CCNE1 amplification or overexpression; inactivation, decreased activity, or decreased expression of FBXW7, PPP2R2A or PPP2R1A; mutation of KRAS or NRAS (for example concomitant mutation of p53 and KRAS or NRAS); or mutation or deletion of CDKN2A (for example concomitant mutation of p53 and CDKN2A).

[0939] 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 cancer is characterised by, or further characterised by: a dependency to PKMYT 1 due to high basal level of replication stress.

[0940] 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 cancer is characterised by, or further characterised by: a dependency to PKMYT 1 due to high basal level of replication stress; CCNE1 amplification or overexpression; inactivation, decreased activity, or decreased expression of FBXW7, PPP2R2A or PPP2R1A; mutation of KRAS or NRAS (for example concomitant mutation of p53 and KRAS or NRAS); or deletion or mutation of CDKN2A (for example concomitant mutation of p53 and CDKN2A).

[0941] 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, a DNA intercalator (for example an anthracycline, such as doxorubicin or idarubicin), 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; mutation of KRAS or NRAS (for example concomitant mutation of p53 and KRAS or NRAS); or mutation or deletion of CDKN2A (for example concomitant mutation of p53 and CDKN2A).

[0942] 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, a DNA intercalator (for example an anthracycline, such as doxorubicin or idarubicin), or gemcitabine, and the cancer is characterised by, or further characterised by: a dependency to PKMYT 1 due to high basal level of replication stress.

[0943] 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, a DNA intercalator (for example an anthracycline, such as doxorubicin or idarubicin), or gemcitabine, and the cancer is characterised by, or further characterised by: a dependency to PKMYT 1 due to high basal level of replication stress; CCNE1 amplification or overexpression; inactivation, decreased activity, or decreased expression of FBXW7, PPP2R2A or PPP2R1A; mutation of KRAS or NRAS (for example concomitant mutation of p53 and KRAS or NRAS); or deletion or mutation of CDKN2A (for example concomitant mutation of p53 and CDKN2A).

[0944] 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 cancer is characterised by, or further characterised by: CCNE1 amplification or overexpression; inactivation, decreased activity, or decreased expression of FBXW7, PPP2R2A or PPP2R1A; mutation of KRAS or NRAS (for example concomitant mutation of p53 and KRAS or NRAS); or concomitant mutation of p53 and CDKN2A.

[0945] 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 PKMYT 1 inhibitor, wherein the PKMYT 1 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 PPP2R1A; or deletion or mutation of CDKN2A (for example concomitant mutation of p53 and CDKN2A).

[0946] 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 PKMYT 1 inhibitor, wherein the PKMYT 1 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 PPP2R1A; or concomitant mutation of p53 and CDKN2A.

[0947] 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 PKMYT 1 inhibitor, wherein the PKMYT 1 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 PPP2R1A; mutation of KRAS or NRAS (for example concomitant mutation of p53 and KRAS or NRAS); or mutation or deletion of CDKN2A (for example concomitant mutation of p53 and CDKN2A).

[0948] 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 PKMYT 1 inhibitor, wherein the PKMYT 1 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 PPP2R1A; mutation of KRAS or NRAS (for example concomitant mutation of p53 and KRAS or NRAS); or concomitant mutation of p53 and CDKN2A.

[0949] 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 subpopulation whose cancer is characterised by, or further characterised by: CCNE1 amplification or overexpression; inactivation, decreased activity, or decreased expression of FBXW7, PPP2R2A or PPP2R1A; or mutation or deletion of CDKN2A (for example concomitant mutation of p53 and CDKN2A).

[0950] 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 subpopulation whose 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.

[0951] 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 subpopulation whose cancer is characterised by, or further characterised by: CCNE1 amplification or overexpression; inactivation, decreased activity, or decreased expression of FBXW7, PPP2R2A or PPP2R1A; mutation of KRAS or NRAS (for example concomitant mutation of p53 and KRAS or NRAS); or mutation or deletion of CDKN2A (for example concomitant mutation of p53 and CDKN2A).

[0952] 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 subpopulation whose cancer is characterised by, or further characterised by: CCNE1 amplification or overexpression; inactivation, decreased activity, or decreased expression of FBXW7, PPP2R2A or PPP2R1A; mutation of KRAS or NRAS (for example concomitant mutation of p53 and KRAS or NRAS); or concomitant mutation of p53 and CDKN2A.

[0953] 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 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 deletion or mutation of CDKN2A (for example 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.

[0954] 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 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.

[0955] 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 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; mutation of KRAS or NRAS (for example concomitant mutation of p53 and KRAS or NRAS); or deletion or mutation of CDKN2A (for example 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.

[0956] 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 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; mutation of KRAS or NRAS (for example concomitant mutation of p53 and KRAS or NRAS); 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.

[0957] 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.

[0958] Also disclosed herein is a method of determining a treatment regimen for a subject with cancer, comprising:

[0959] Determining the level of expression of CCNE1, or the mutation status of FBXW7, PP2A or its subunits, or p53 and CDKN2A, in a biological sample of the subject (for example a biological sample of the subject’s cancer); and

[0960] Selecting the subject as suitable for receiving a treatment regimen comprising a therapeutically effective amount of a combination of a PKMYT 1 inhibitor and 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 CDKN2A together, are mutated.

[0961] Also disclosed herein is a method of treatment of cancer in a subject in need of such treatment, comprising:

[0962] Determining the level of expression of CCNE1, or the mutation status of FBXW7, PP2A or its subunits, or p53 and CDKN2A in a biological sample of the subject (for example a biological sample of the subject’s cancer); and Administering a treatment regimen comprising a therapeutically effective amount of a 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 CDKN2A together, are mutated.

[0963] Also disclosed herein is a method of determining a treatment regimen for a subject with cancer, comprising:

[0964] Determining the level of expression of CCNE1, or the mutation status of FBXW7, PP2A or its subunits, NRAS, KRAS, p53, and / or CDKN2A, and / or p53 and CDKN2A, and / or p53 and KRAS or NRAS, in a biological sample of the subject (for example a biological sample of the subject’s cancer); and

[0965] Selecting the subject as suitable for receiving a treatment regimen comprising a therapeutically effective amount of a combination of a PKMYT 1 inhibitor and 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 CDKN2A together, are mutated.

[0966] Also disclosed herein is a method of treatment of cancer in a subject in need of such treatment, comprising:

[0967] Determining the level of expression of CCNE1, or the mutation status of FBXW7, PP2A or its subunits, NRAS, KRAS, p53, and / or CDKN2A, and / or p53 and CDKN2A, and / or p53 and KRAS or NRAS, in a biological sample of the subject (for example a biological sample of the subject’s cancer); and

[0968] Administering a treatment regimen comprising a therapeutically effective amount of a 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 CDKN2A together, are mutated.

[0969] Other Uses

[0970] The BAA compounds described herein may also be used as cell culture additives to inhibit PKMYT 1 (e.g., to inhibit or reduce or block the activity or function of PKMYT1).

[0971] 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.

[0972] 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 PKMYT 1 inhibitors, etc.

[0973] Kits

[0974] 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 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.

[0975] The written instructions may also include a list of indications for which the BAA compound is a suitable treatment.

[0976] Routes of Administration

[0977] 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).

[0978] Routes of administration include, for example: oral (e.g., by ingestion); buccal; sublingual; 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, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; by implant of a depot or reservoir, for example, subcutaneously or intramuscularly.

[0979] The Subject

[0980] 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 (e.g., a monkey or ape), a monkey (e.g., marmoset, baboon), an ape (e.g., gorilla, chimpanzee, orangutan, gibbon), or a human.

[0981] Furthermore, the subject (e.g., patient) may be any of its forms of development, for example, a foetus.

[0982] In one preferred embodiment, the subject (e.g., patient) is a human.

[0983] Formulations

[0984] 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 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.

[0985] 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.

[0986] 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 the sense of being compatible with the other ingredients of the formulation.

[0987] 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 Press, 2012.

[0988] 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 intimately bringing into association the compound with carriers (e.g., liquid carriers, finely divided solid carrier, etc.), and then shaping the product, if necessary.

[0989] The formulation may be prepared to provide for rapid or slow release; immediate, delayed, timed, or sustained release; or a combination thereof.

[0990] 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 aerosols.

[0991] 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.

[0992] 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 micro particulate which is designed to target the compound, for example, to blood components or one or more organs.

[0993] Formulations suitable for oral administration (e.g., by ingestion) include 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, tablets, granules, powders, capsules, cachets, pills, ampoules, boluses.

[0994] 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 an inert matrix, such as gelatin and glycerin, or sucrose and acacia. Mouthwashes typically comprise the compound in a suitable liquid carrier.

[0995] Formulations suitable for sublingual administration include tablets, lozenges, pastilles, capsules, and pills.

[0996] Formulations suitable for 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), mouthwashes, lozenges, pastilles, as well as patches, adhesive plasters, depots, and reservoirs.

[0997] 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, adhesive plasters, depots, and reservoirs.

[0998] Formulations suitable for transdermal administration include gels, pastes, ointments, creams, lotions, and oils, as well as patches, adhesive plasters, bandages, dressings, depots, and reservoirs.

[0999] 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 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, cross-linked sodium carboxymethyl cellulose); surfaceactive 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 release of the compound therein using, for example, hydroxypropyl methyl 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.

[1000] Ointments are typically prepared from the compound and a paraffinic or a water-miscible ointment base.

[1001] 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 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.

[1002] 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 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.

[1003] 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 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 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. 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 solutions of the compound.

[1004] 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.

[1005] 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.

[1006] Formulations suitable for ocular administration include eye drops wherein the compound is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the compound.

[1007] 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.

[1008] Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the compound, such carriers as are known in the art to be appropriate.

[1009] 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 micro particulate). Such liquids 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 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 pg / mL, for example from about 10 ng / mL to about 1 pg / 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. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets. Dosage

[1010] 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 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; 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 or deleterious side-effects.

[1011] 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 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.

[1012] 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.

[1013] Where the compound is a pharmaceutically acceptable salt or solvate thereof, the amount administered is calculated on the basis of the parent compound and so the actual weight to be used is increased proportionately.

[1014] EXAMPLES

[1015] Chemical Synthesis

[1016] Abbreviations

[1017] {1 H} Proton decoupling aq. Aqueous

[1018] Bl NAP 2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl

[1019] DBU 1 ,8-diazabicyclo[5.4.0]undec-7-ene

[1020] DCM Dichloromethane (methylene chloride)

[1021] DIAD diisopropyl azodicarboxylate DI PEA / V, / V-diisopropylethylamine

[1022] DMA Dimethylacetamide

[1023] DME ethylene glycol dimethyl ether

[1024] DMF Dimethylformamide

[1025] DMSO Dimethylsulfoxide

[1026] ES Electrospray ionisation

[1027] Et20 Ether (diethyl ether)

[1028] EtOAc Ethyl acetate

[1029] EtOH Ethanol (ethyl alcohol)

[1030] HATLI 2-(7-aza-1 / 7-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate

[1031] HFIP Hexafluoroisopropanol

[1032] I PA isopropyl alcohol

[1033] MeCN Acetonitrile

[1034] MeOH Methanol (methyl alcohol)

[1035] Pd / C Palladium on carbon

[1036] PE Petroleum ether

[1037] Pd2dba3 tris(dibenzylideneacetone)dipalladium(0)

[1038] RT Room temperature

[1039] Sat. aq. Saturated aqueous

[1040] STAB Sodium triacetoxyborohydride

[1041] T3P 1-Propanephosphonic anhydride

[1042] TBDMS tert-Butyldimethylsilyl

[1043] TFA Trifluroacetic acid

[1044] THF Tetrahydrofuran

[1045] LIPLC Ultra Performance Liquid Chromatography

[1046] XantPhos 4,5-bis(diphenylphospheno)-9,9-dimethylxanthene

[1047] Flash chromatography was performed using pre-packed silica gel cartridges (RediSep Rf, Isco). Thin layer chromatography was conducted with 5 x 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. All compounds were >90 % purity as determined by examination of both the LCMS and 1 H NMR spectra unless otherwise indicated. Where Cl or Br were present, expected isotopic distribution patterns were observed.

[1048] NMR

[1049] Proton (1H) and carbon (13C) and (19F) NMR spectra were recorded on a 300 MHz Bruker or 400 MHz Jeol spectrometer. Solutions were typically prepared in either deuterated chloroform (Chloroform-d), deuterated methanol (Methanol-d4) or deuterated dimethylsulfoxide (DMSO-cfe) with chemical shifts referenced to tetramethylsilane (TMS) or deuterated solvent as an internal standard.1H NMR data are reported indicating the chemical shift (5), 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.

[1050] Analytical LCMS

[1051] LCMS analyses were performed on a Waters Acquity UPLC using BEH Cis 1.7 pM columns (2.1 x 50 mm) with a diode array detector coupled to a SQD mass spectrometer with optional ELS detection (Acquity UPLC ELS Detector) or, a Waters Acquity l-Class UPLC using BEH Cis 1.7 pM columns (2.1 x 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:

[1052] Low pH:

[1053] Solvent A - Water + 10 mM ammonium hydrogen carbonate + 0.1 % formic acid

[1054] Solvent B - MeCN + 5 % water + 0.1 % formic acid

[1055] High pH:

[1056] Solvent A - Water + 10 mM ammonium hydrogen carbonate + 0.1 % ammonia solution Solvent B - MeCN + 5 % water + 0.1 % ammonia solution

[1057] Gradient:

[1058] For some compounds, the following gradients were used:

[1059] Acidic 2 min

[1060] 0.1% v / v Formic acid in 10mM ammonium formate [Eluent A]; 0.1% v / v Formic acid in MeCN [Eluent B]; flow rate 0.8mL / min; column oven 50°C; sample manager 20°C; injection volume 2pL and 1.5 minutes equilibration time between samples, on a Waters Acquity LIPLC BEH C18 column (2.1 x 50 mm, 1.7 pm).

[1061] Gradient:

[1062] Acidic 4 min

[1063] 0.1% v / v formic acid in 10mM ammonium formate [Eluent A]; 0.1% v / v formic acid in MeCN [Eluent B]; flow rate 0.8mL / min; column oven 50°C; sample manager 20°C; injection volume 2pL and 1.5 minutes equilibration time between samples on a Waters Acquity LIPLC BEH C18 column (2.1 x 50 mm, 1.7 pm).

[1064] Acidic 6 min (“Acidic Prep Analysis”)

[1065] 0.1% v / v formic acid in 10mM ammonium formate [Eluent A]; 0.1% v / v formic acid in MeCN [Eluent B]; flow rate 0.8mL / min; column oven 50°C; sample manager 20°C; injection volume 2pL and 1.5 minutes equilibration time between samples on a Waters Acquity LIPLC BEH C18 column (2.1 x 50 mm, 1.7 pm).

[1066] Basic 2 min

[1067] 0.1% ammonia in water [Eluent A]; 0.1% ammonia in MeCN [Eluent B]; flow rate 0.8mL / min; column oven 50°C; sample manager 20°C; injection volume 2D L and 1.5 minutes equilibration time between samples on a Waters Acquity LIPLC BEH C18 column (2.1 x 50 mm, 1.7 pm).

[1068] Basic 4 min

[1069] 0.1% ammonia in water [Eluent A]; 0.1% ammonia in MeCN [Eluent B]; flow rate 0.8mL / min; column oven 50°C; sample manager 20°C; injection volume 2pL and 1.5 minutes equilibration time between samples on a Waters Acquity LIPLC BEH C18 column (2.1 x 50 mm, 1.7 pm). Basic 6 min (“Basic Prep Analysis’”)

[1070] 0.1% ammonia in water [Eluent A]; 0.1% ammonia in MeCN [Eluent B]; flow rate 0.8mL / min; column oven 50°C; sample manager 20°C; injection volume 2pL and 1.5 minutes equilibration time between samples on a Waters Acquity LIPLC BEH C18 column (2.1 x 50 mm, 1.7 pm).

[1071] Preparative HPLC-MS

[1072] Some compounds were purified by preparative HPLC on a Waters FractionLynx MS autopurification system, with a Phenomenex Gemini NX 5 pm Cis, 100 mm x 21.2 mm i.d. column (for low pH runs) or a Waters XBridge 5 pm Cis, 100 mm x 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.

[1073] Alternatively, Preparative HPLC purification was carried out either on a Teledyne ISCO ACCQPrep® HP150 system or on a Waters Mass-directed PrepLC system, with a C1 XBridge BEH C18 (dimensions: 19 mm x 150 mm 5 pm) or a C2 XBridge BEH C18 (dimensions: 19 mm x 150 mm 5 pm) column, running a flow rate of 20 mL / min. All masses were detected with electrospray ionisation (ESI).

[1074] Purifications were performed using buffered acidic or basic solvent systems as appropriate. Compound retention times on the system were routinely assessed using a 30 - 50 pL test injection and a standard gradient, then purified using an appropriately chosen focussed gradient as detailed below, based upon observed retention time.

[1075] Low pH:

[1076] Solvent A - Water + 10 mM ammonium formate + 0.1 % formic acid

[1077] Solvent B - MeCN + 5 % water +0.1 % formic acid

[1078] High pH:

[1079] Solvent A - Water + 10 mM ammonium formate + 0.1 % ammonia solution

[1080] Solvent B - MeCN + 5 % water + 0.1 % ammonia solution or MeCN + 0.1 % ammonia solution

[1081] Standard Gradient:

[1082] Focused Gradients:

[1083] Synthetic Methods

[1084] 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.

[1085] 1. Heteroarylamine precursors

[1086] 2-Chloro-1-f2-(trifluoromethyl)pyrrolidin-1-yl1 ethanone

[1087] Chloroacetyl chloride (1.09 eq, 0.30 mL, 3.77 mmol) was added dropwise to a cooled solution of (±)-2-(trifluoromethyl)pyrrolidine (1.00 eq, 480 mg, 3.45 mmol) and triethylamine (2.08 eq, 1.0 mL, 7.17 mmol) in DCM (10 mL) at 0 °C. After stirring for 1 h, the reaction mixture was diluted with DCM (50mL) and washed with water (2x 50mL), dried over sodium sulfate , filtered and evaporated to afford the title product (0.71 g, 3.29 mmol, 95.45% yield) as a brown oil.1H NMR (400 MHz, CDCh) 6 4.87 - 4.45 (m, 1 H), 4.26 - 3.99 (m, 2H), 3.84 - 3.45 (m, 2H), 2.31 - 1 .92 (m, 4H).19F NMR (376 MHz, CDCh) 6 -73.94 (d, J = 7.7 Hz), -74.00 - -74.15 (m).

[1088] 1.1 Nitro pyrazoles

[1089] General method A. Alkylation of 3-nitro-1 H-pyrazoles

[1090] X = Br,CI, I

[1091] Alkyl halide (1 eq) is added dropwise to a suspension of unsubstituted or substituted nitropyrazole (1 eq) and potassium carbonate (1.5 eq) or caesium carbonate (1-1.5 eq) in anhydrous THF or MeCN, or NaH (1.2 eq) in DMF, with stirring at room temperature under nitrogen. The reaction mixture was then stirred at rt or heated to 65-75 °C with stirring for 4 hours, before cooling to room temperature and separating between ethyl acetate and water. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give the product.

[1092] Potassium carbonate (1.63 eq, 0.45 g, 3.26 mmol) was added to a mixture of 2-chloro-1-[2- (trifluoromethyl)pyrrolidin-1-yl]ethanone (1.00 eq, 0.43 g, 1.99 mmol) and 4-methyl-3-nitro-1 H- pyrazole (1.07 eq, 0.27 g, 2.12 mmol) in MeCN (10 mL). The reaction mixture was heated at 80 °C for 5 hours, then diluted with MeCN (50mL) and inorganics filtered off. The filtrate was evaporated and the crude material was purified by column chromatography over silica (12 g cartridge) eluting with a gradient of EtOAc (2% to 100%; v / v) in isohexane to afford the title product (620 mg, 2.02 mmol, 101.51% yield) as a brown gum.1H NMR (400 MHz, CDCh) 6 7.52 - 7.40 (m, 1 H), 5.26 - 4.47 (m, 3H), 3.65 (s, 2H), 2.40 - 2.33 (m, 3H), 2.32 - 1.92 (m, 4H).19F NMR (376 MHz, CDCh) 6 - 73.77 (d, J = 7.6 Hz), -73.96 (d, J = 7.4 Hz). MS (ES+) m / z 307.0 (M+H)+.

[1093] The following examples were prepared in a similar manner using method A with the appropriate nitro-pyrazole and alkyl halide: Cesium 3- '-2- l-3-nitro-i 1-1-

[1094] A solution of caesium carbonate (9.00 g, 27.6 mmol) in water (15 mL) was added to a solution of methyl 3-methoxy-2-(4-methyl-3-nitro-pyrazol-1-yl)propanoate (2.24 g, 9.21 mmol) in 1 ,4-Dioxane (50 mL) . The reaction mixture was heated to 60 °C for 16h, cooled to rt and concentrated in vacuo. MeCN (100 mL) was added and the mixture was sonicated to a fine suspension, then filtered on paper, washing with MeCN. The filtered solution was concentrated in vacuo, affording cesium 3-methoxy-2-(4-methyl-3-nitro-pyrazol-1-yl)propanoate (3143 mg, 7.14 mmol, 77.50% yield) as an orange gum. 1 H NMR (400 MHz, DMSO-d6) 5 7.77 (d, J = 1.0 Hz, 1 H), 4.69 (dd, J = 9.7, 3.7 Hz, 1 H), 3.99 - 3.81 (m, 2H), 3.17 (s, 3H), 2.24 (d, J = 0.8 Hz, 3H). MS (ES+) m / z = 230.1 , [M+H]+

[1095] 3-Methoxy-2-(4-methyl-3-nitro-pyrazol-1-yl)-1-[(2R)-2-(trifluoromethyl)pyrrolidin-1-yllpropan-1-one

[1096] To a solution of cesium 3-methoxy-2-(4-methyl-3-nitro-pyrazol-1-yl)propanoate (1.20 g, 3.32 mmol), DIPEA (1.8 mL, 10.0 mmol) and HATU (1.50 g, 3.94 mmol) in DMF (20 mL) was added (2R)-2-(trifluoromethyl)pyrrolidine (650 mg, 4.67 mmol) . The reaction was stirred at rt overnight, then it was diluted with EtOAc (100 mL) and washed with aq. LiCI 1M (150 mL). The aqueous solution was extracted with EtOAc (150 mL), then the combined organics were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by column chromatography over silica (120 g cartridge) eluting with a gradient of ethyl acetate (5% to 80%; v / v) in iso-hexane to afford the title compound (280 mg, 0.767 mmol, 23.07% yield) as a yellow oil. MS (ES+) m / z = 351.1 [M+H]+.1H NMR (400 MHz, CDCI3) 6 7.71 (d, J = 1.0 Hz, 1 H), 5.64 - 5.43 (m, 1 H), 4.93 - 4.63 (m, 1 H), 4.00 - 3.68 (m, 4H), 3.38 (s, 3H), 2.35 (d, J = 0.9 Hz, 3H), 2.27 - 1.97 (m, 4H).

[1097] 3-Methoxy-2-(4-methyl-3-nitro-pyrazol-1-yl)-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yllpropan-1-one To a solution of cesium 3-methoxy-2-(4-methyl-3-nitro-pyrazol-1-yl)propanoate (1.20 g, 3.32 mmol), DIPEA (1.8 mL, 10.0 mmol) and HATU (1.50 g, 3.94 mmol) in DMF (20 mL) was added (2S)-2-(trifluoromethyl)pyrrolidine (650 mg, 4.67 mmol) . The reaction was stirred at rt overnight, then it was diluted with EtOAc (100 mL) and washed with aq. LiCI 1M (150 mL). The aqueous solution was extracted with EtOAc (150 mL), then the combined organics were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by column chromatography over silica (120 g cartridge) eluting with a gradient of ethyl acetate (5% to 80%; v / v) in iso-hexane to afford the title compound (280 mg, 0.767 mmol, 23.07% yield) as a yellow oil. MS (ES+) m / z = 351.1 [M+H]+.1H NMR (400 MHz, CDCI3) 6 7.71 (d, J = 1.0 Hz, 1H), 5.63 - 5.43 (m, 1 H), 4.89 - 4.68 (m, 1H), 4.03 - 3.69 (m, 4H), 3.39 (s, 3H), 2.35 (d, J = 0.9 Hz, 3H), 2.28 - 1.95 (m, 4H).

[1098] 1.2. Amino-pyrazoles

[1099] General Method B: Hydrogenation of nitro-pyrazoles

[1100] A mixture of 3-nitro-1-alkylpyrazoles (1.0 eq) and Pd / C (10% w / w, 0.05 - 0.15 eq) in methanol, ethanol, MeCN, EtOAc or THF (0.01 - 0.5 M) was placed under a hydrogen atmosphere and stirred at RT for 12 - 72 h. The reaction was monitored by consumption of starting material via UPLC. The mixture was filtered through a pad of dicalite and concentrated in vacuo to afford the amine product. tert- 2-(3-amino-4-

[1101] A stirred solution of tert-butyl 2-(4-methyl-3-nitro-pyrazol-1-yl)acetate (5.30 g, 21.1 mmol) in ethanol (200 mL) was evacuated and backfilled with nitrogen 3 times before slurry of Palladium on activated Carbon (0.40 g, 3.76 mmol) in EtOH (10mL) was added to the reaction mixture. The flask was then placed under vacuum and refilled with nitrogen before fitting a hydrogen balloon and vigorously stirring at 23 °C for 20 h. The reaction mixture was refilled with nitrogen, filtered through Cellite and washed with Ethanol. The filtrate was concentrated and dried under vacuum to give the title product (4.61 g, 18.8 mmol, 88.92% yield) as a light brown oil which was crystallized to off- white solid. 1H NMR (400 MHz, DMSO-D6) 5 7.14 - 7.08 (m, 1 H), 4.70 (br s, 2H), 4.52 (s, 2H), 1.80 (t, J = 0.7 Hz, 3H), 1.40 (s, 9H).

[1102] The following heteroaromatic amines were obtained using general Method B:

[1103] 2-(3-Amino-4-chloro-pyrazol-1-yl)-N,N-diethyl-acetamide

[1104] A mixture of 2-chloro-N,N-diethyl-acetamide (1.06 eq, 0.77 g, 5.15 mmol) , 4-chloro-1 H- pyrazol-3-amine (1 eq, 0.57 g, 4.85 mmol) and potassium carbonate 325 mesh (1.24 eq, 0.83 g, 6.01 mmol) in MeCN (10 mL) were heated at 80 °C for 4 h, then cooled, filtered and evaporated. The crude was purified by column chromatography over silica (40 g cartridge) eluting with a gradient of DCM-MeOH [9: 1](0% to 80%; v / v) in DCM to afford the title compound (410 mg, 1.71 mmol, 35.18% yield) as an orange solid.1H NMR (400 MHz, CDCI3) 6 7.32 (s, 1 H), 4.69 (s, 2H), 3.43 - 3.29 (m, 4H), 1.20 (t, J = 7.2 Hz, 3H), 1.12 (t, J = 7.1 Hz, 3H). MS (ES+) m / z = 231.1 / 232.9 [M+H]+ mono Cl pattern.

[1105] 1.3. Fused bicyclic aminopyrazoles

[1106] General Method C1 : Synthesis of 3-amino-indazoles from substituted cyano-fluoroaryl and hydrazines

[1107] A mixture of cyano-fluoroaryl (1 eq.) and substituted hydrazine (3 eq.) were heated in ethanol (0.2- 0.6M) at 90 °C for 16h, then allowed to cool at room temperature. The precipitated product is recovered by filtration; alternatively the solvent is evaporated and the residue purified by column chromatography on silica to afford the product.

[1108] 1-Methyl-4-(trifluoromethyl)indazol-3-amine

[1109] 2-Fluoro-6-(trifluoromethyl)benzonitrile (1.00 g, 5.29 mmol, 1.00 eq) was taken up in ethanol (24 mL), methylhydrazine (0.84 mL, 15.9 mmol, 3.00 eq) was added, the reaction mixture was heated at 90 °C overnight then allowed to cool to RT. The solvent was evaporated and the residue purified by column cheomatography on silica, eluting with EtOAc:PE (0-100%), to afford the product (0.9 g, 79%) as a light yellow solid.1H NMR (300 MHz, CDCI3) 5 7.43 - 7.30 (m, 3H), 3.89 (s, 3H).19F NMR (282 MHz, CDCI3) 5 -58.70. MS (ES+) m / z 216.2 (M+H)+.

[1110] The following example compounds were prepared similarly using Method C1 with the appropriately substituted cyano- fluoroaryls and hydrazines.

[1111] Method C2: Synthesis of substituted bicyclic pyrazoles by N-alkylation

[1112] Z=CR, N

[1113] X= Cl, Br, I, sulfonate, triflate The alkylating agent (1.3 eq) is added to a mixture of caesium carbonate (2 eq) in DMF (0.5-1M), followed by 3-aminoindazole or 3-amino-pyrazolopyridine (1 eq). The reaction mixture is stirred at 65 °C for 24h, extracted between EtOAc and water, the organic layer separated, washed with water and brine, dried over MgSO4, filtered and concentrated. The residue is purified by silica column chromatography to afford the product.

[1114] 1-(2,2,2-Trifluoroethyl)pyrazolo(4,3-clpyridin-3-amine

[1115] Cesium carbonate (4561 mg, 14.0 mmol) was taken up in DMF (10 ml), 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.4 ml, 10.0 mmol) was added and the mixture was stirred for 2 mins. 1H-pyrazolo[4,3-c]pyridin-3-amine (1000 mg, 7.45 mmol) was added, the reaction mixture was stirred at 65 °C for 1 day then cooled at RT. Water and EtOAc were added, the layers were separated, the aq. layer was extracted with EtOAc, and the combined organic layers were washed with water and brine (1x each). The organic extract was dried (MgSO4), filtered and concentrated to yield a brown oil, which was purified on silica, eluting with EtOAc:PE (0-100%), to yield the title product (900 mg, 4.2 mmol, 55.9%) as a light brown solid.1H NMR (300 Mhz, MeOD) 5 8.96 (d, H = 1.1 Hz, 1 H), 8.30 (d, J = 6.1 Hz, 1 H), 7.43 (d, J = 7.3 Hz, 1 H), 4.93 (q, J = 8.8 Hz, 2H).19F NMR (282 Mhz, MeOD) 5 -72.66. MS (ES+) m / z 216.2 [M+ H]+.

[1116] The following example compounds were prepared similarly using Method C2 with the appropriately substituted 3-aminoindazoles and 2,2,2-trifluoroethyl tritiates.

[1117] 1.4 Amino-pyridine ethers

[1118] General method D: Amino-pyridine ethers by SNAr of 2-amino-6-bromopyridines with alcohols

[1119] The 2-amino-6-bromopyridine (1 eq.), NaOH (2-3 eq) and the aliphatic or aromatic alcohol (1-3 eq), neat or dissolved in propanol or DMSO, were heated at 140-180 °C for 2-4h, then the mixture was purified by reverse phase chromatography to afford the desired ether.

[1120] 3-Methyl-6-(3-(4-methylpiperazin-1-yl)propoxy)pyridin-2-amine

[1121] Sodium hydroxide (107 mg, 2.67 mmol, 2.50 eq) was added to 6-bromo-3-methylpyridin-2-amine (200 mg, 1.07 mmol, 1.00 eq) and 1-(3-hydroxypropyl)-4-methylpiperazine (423 mg, 2.67 mmol, 2.50 eq) in 1-propanol (1 mL) and the mixture heated at 160 °C for 4h under microwave irradiation.

[1122] After allowing to cool, the mixture was disolved in DMSO (2 ml) and subject to reverse phase column chromatography (water: acetonitrile) to give the title product (147 mg, 0.556 mmol, 52%).1H NMR (300 MHz, MeOD) 67.19 (dd, J= 7.9, 0.8 Hz, 1H), 5.96 (d, J= 7.9 Hz, 1H), 4.13 (t, J =

[1123] 6.3 Hz, 2H), 2.86-2.36 (m, 10H), 2.27 (s, 3H), 2.02 (d, J= 0.8 Hz, 3H), 1.99- 1.86 (m, 2H). MS (ES+) m / z = 265 [M+HJ+, The following examples were prepared in a similar manner using method D with the appropriate nitro-pyrazole and alkyl halide:

[1124] 3-Methyl-4-(3-(4-methylpiperazin-1-yl)propoxy)pyridin-2-amine

[1125] Sodium hydroxide (66 mg, 1.66 mmol, 1.00 eq) was added to 4-fluoro-3-methyl-pyridin-2-amine (209 mg, 1.66 mmol, 1.00 eq) and 1-(3-hydroxypropyl)-4-methylpiperazine (551 mg, 3.48 mmol,

[1126] 2.10 eq) and the mixture heated at 180 °C for 1.5h under microwave irradiation. After allowing to cool, the mixture was disolved in DMSO (2 ml) and subject to reverse phase column chromatography (water: aceto nitrile gradient) to give the title product (72 mg, 0.272 mmol, 16%).1H NMR (300 MHz, MeOD) 5 7.72 (dd, J = 6.0, 0.7 Hz, 1 H), 6.41 (d, J = 6.0 Hz, 1 H), 4.10 (t, J = 6.1 Hz, 2H), 2.89 - 2.39 (m, 10H), 2.31 (s, 3H), 2.09 - 1.95 (m, 5H).

[1127] MS (ES+) m / z = 265 [M+H]+. 1.5. Diamino-pyridines

[1128] 2-(4-(6-Amino-5-methylpyridin-2-yl)piperazin-1-yl)ethan-1-ol

[1129] 1-(2-hydroxyethyl)piperazine (0.12 ml, 1.01 mmol, 1.10 eq) was added to 6-bromo-3-methylpyridin-

[1130] 2-amine (200 mg, 1.07 mmol, 1.00 eq) and the mixture was heated at 115 °C for 2h. After allowing to cool, the mixture was disolved in DMSO (2 ml) and subject directly to reverse phase column chromatography (water: aceto nitrile) to give the title compound (54 mg, 0.229 mmol, 21%).1H NMR (300 MHz, MeOD) 5 7.15 (dd, J = 8.0, 0.8 Hz, 1 H), 6.02 (d, J = 8.0 Hz, 1 H), 3.74 (t, J = 6.0 Hz, 2H), 3.46 - 3.36 (m, 4H), 2.67 - 2.62 (m, 4H), 2.59 (t, J = 6.0 Hz, 2H), 2.03 (d, J = 0.8 Hz, 3H). MS (ES+) m / z = 237.1 [M+H]+.

[1131] 3-Chloro-6-(4-cyclopropylpiperazin-1-yl)pyridin-2-amine

[1132] 1-cyclopropylpiperazine (134 mg, 1.06 mmol, 1.10 eq) was added to 6-bromo-3-chloropyridin-2- amine (100 mg, 0.482 mmol, 1.00 eq) and the mixture was heated at 160 °C for 6h. After allowing to cool, the mixture was dissolved in DMSO (2 ml) and purified by reverse phase column chromatography (water: aceto nitrile) to give the title product (98 mg, 0.388 mmol, 80%).1H NMR (300 MHz, MeOD) 5 7.27 (d, J = 8.6 Hz, 1 H), 6.03 (d, J = 8.6 Hz, 1 H), 3.47 - 3.37 (m, 4H), 2.75 - 2.65 (m, 4H), 1.69 (tt, J = 6.6, 3.9 Hz, 1 H), 0.58 - 0.38 (m, 4H). MS (ES+) m / z = 253.3 / 255.3 [M+H]+, Cl pattern.

[1133] 2-Amino-6-(dimethylamino)pyridine-3,5-dicarbonitrile

[1134] To 2-amino-6-chloro-pyridine-3,5-dicarbonitrile (100 mg, 0.560 mmol, 1.00 eq) in ethanol (5 mL) was added dimethylamine hydrochloride (100 mg, 1.23 mmol, 2.20 eq) followed by triethylamine (0.34 mL, 2.46 mmol, 4.40 eq) and the reaction mixture was stirred at reflux for 1 hour. The reaction mixture was allowed to cool to ambient temperature, concentrated under reduced pressure, redissolved in DMSO (3 mL) and purified by reverse phase chromatography (MeCN:H2O eluent) to furnish the title product (66 mg, 0.353 mmol, 63%) as a beige solid.1H NMR (300 MHz, DMSO) 5 8.09 (s, 1 H), 7.32 (s, 2H), 3.22 (s, 6H). MS (ES+) m / z = 186.1 [M+HJ+. tert-Butyl (6-amino-5-methylpyridin-2-yl)carbamate

[1135] To a solution of 3-methylpyridine-2,6-diamine (150 mg, 1.22 mmol) in THF (10 mL) was added di- tert-butyl dicarbonate (0.27 g, 1.22 mmol, 1.00 eq) and the reaction mixture was allowed to stir at ambient temperature for 140h. The reaction mixture was concentrated under reduced pressure and the residue purified by reverse phase chromatography (MeCN:H2O eluent) to furnish the title compound (185 mg, 0.829 mmol, 68%) as a red oil.1H NMR (300 MHz, CDCI3) 6 7.39 (dq, J = 8.2, 0.8 Hz, 1H), 7.27 (d, J = 8.1 Hz, 1H), 5.33 (s, 1 H), 4.91 (s, 2H), 2.15 - 2.03 (m, 3H), 1.54 (s, 9H). MS (ES+) m / z = 224.3 [M+HJ+.

[1136] 1.6. Other aminopyridine building blocks

[1137] 3-Chloro-6-(2-methoxyethyl)pyridin-2-amine

[1138] Step 1: BOC anhydride (526 mg, 2.4 mmol) was added to a solution of 6-bromo-3-chloropyridin-2- amine (250 mg, 1.2 mmol), DMAP (15 mg, 0.12 mmol) and triethylamine (0.34 ml, 2.4 mmol) in DCM (12 ml), with stirring at 35 °C overnight. After cooling to room temperature, the reaction mixture was separated between DCM and water. The organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product, which was purified using column chromatography over silica, eluting with 0-60% ethyl acetate / petroleum ether to give tert-butyl N-(6-bromo-3-chloro-2-pyridyl)-N-tert-butoxycarbonyl-carbamate (391 mg, 80% yield) as a white solid.1H NMR (300 MHz, CDCI3) 6 7.63 (d, 1H, J = 8.3 Hz), 7.42 (d, 1 H, J = 8.3 Hz), 1.41 (s, 18H).

[1139] Step 2: A mixture of tert-butyl N-(6-bromo-3-chloro-2-pyridyl)-N-tert-butoxycarbonyl-carbamate (300 mg, 0.74 mmol), anhydrous DMA (5 ml), pyridine-2,6-dicarboxamidine dihydrochloride (17 mg, 0.074 mmol), NiCh.DME (16 mg, 0.074 mmol), sodium iodide (27 mg, 0.18 mmol), 2- bromoethyl methyl ether (0.14 ml, 1.47 mmol, 2 equiv.), zinc metal powder (96 mg, 1.47 mmol, 2 equiv.) and TFA (6 ul, 10 mol%) was sealed in a flask and heated to 60 °C with stirring overnight. The reaction mixture was diluted with EtOAc, filtered through a short pad of dicalite, washed with EtOAc. The filtrate was washed with water and brine, dried (MgSO4), filtered and concentrated to give the crude product, which was purified using column chromatography over silica, eluting with 0- 80% EtOAc / PE, to give tert-butyl N-tert-butoxycarbonyl-N-[3-chloro-6-(2-methoxyethyl)-2- pyridyl]carbamate (233 mg, 82% yield) as a white solid.1H NMR (300 MHz, CDCI3) 6 7.67 (d, 1 H, J = 8.1 Hz), 7.15 (d 1 H, J = 8.1 Hz), 3.71 (t, 2H, J = 6.5 Hz), 3.31 (s, 3H), 3.02 (t, 2H, J = 6.5 Hz), 1.39 (s, 18H). MS (ES+) m / z = 387.2 [M+HJ+.

[1140] Step 3: TFA (1.1 ml, 14.0 mmol) was added to a solution of tert-butyl N-tert-butoxycarbonyl-N-[3- chloro-6-(2-methoxyethyl)-2-pyridyl]carbamate (216 mg, 0.56 mmol) in DCM (4.0 ml), with stirring under nitrogen for 3 hours before concentrating in vacuo. The residue was separated between EtOAc and aqueous NaHCCh solution, and the combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated to give the title product (108 mg, 100% yield) as a clear beige oil.1H NMR (300 MHz, CDCI3) 6 7.38 (d, 1 H, J = 7.9 Hz), 6.52 (d, 1H, J = 7.8 Hz), 4.90 (br, 2H), 3.68 (t, 2H, J = 6.7 Hz), 3.33 (s, 3H), 2.84 (t, 2H, J = 6.7 Hz). MS (ES+) m / z = 189.0 [M+HJ+.

[1141] 6- i-2-amine

[1142] Step 1 : A mixture of terf-butyl 6-bromopyridin-2-ylcarbamate (300 mg, 1.1 mmol), anhydrous DMA (5 ml), pyridine-2,6-dicarboxamidine dihydrochloride (26 mg, 0.11 mmol), NiCI2.DME (24 mg, 0.11 mmol), sodium iodide (41 mg, 0.27 mmol, 25 mol%), 2-bromoethyl methyl ether (0.21 ml, 2.2 mmol, 2 equiv.), zinc metal powder (144 mg, 2.2 mmol, 2 equiv.) and TFA (8 ul, 0.11 mmol, 10 mol%) was sealed in a flask and heated to 60 °C with stirring overnight. The reaction mixture was diluted with EtOAc, filtered through a short pad of dicalite, washed with EtOAc. The filtrate was washed with water and brine, dried (MgSO4), filtered and concentrated to give the crude product, which was purified using column chromatography over silica, eluting with 0-70% EtOAc / PE ether, to give tert-butyl N-[6-(2-methoxyethyl)-2-pyridyl]carbamate (101 mg, 36% yield) as a clear colourless oil.

[1143] Step 2: TFA (0.76 ml, 9.91 mmol) was added to a solution of tert-butyl N-[6-(2-methoxyethyl)-2- pyridyl]carbamate (100 mg, 0.40 mmol) in DCM (3.0 ml), with stirring under nitrogen for 3 hours before concentrating in vacuo. The residue was separated between EtOAc and aqueous NaHCOs solution, and the combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated to give the title product (62 mg, 100% yield) as a clear colourless oil. 1 H NMR (300 MHz, CDCI3) 6 7.34 (dd, 1 H, J = 8.2, 7.3 Hz), 6.55 (d, 1 H, J = 7.3 Hz), 6.33 (d, 1 H, J = 8.2 Hz), 4.47 (br, 2H), 3.70 (t, 2H, J = 6.8 Hz), 3.34 (s, 3H), 2.87 (t, 2H, J = 6.8 Hz). MS (ES+) m / z = 153.1 [M+HJ+.

[1144] 6- in-2-amine Step 1: A mixture of terf-butyl 6-bromopyridin-2-ylcarbamate (200 mg, 0.73 mmol), 3- bromooxetane (0.12 ml, 1.46 mmol), pyridine-2,6-dicarboxamidine dihydrochloride (17 mg, 0.073 mmol), NiCI2.DME (16 mg, 0.073 mmol), sodium iodide (27 mg, 0.18 mmol), zinc metal powder (96 mg, 1.46 mmol) and TFA (6 ul, 0.073 mmol) in anhydrous DMA (4 ml) was sealed and heated to 60 °C with stirring overnight. The reaction mixture was diluted with EtOAc, filtered through a short pad of dicalite, washed with EtOAc. The filtrate was washed with water and brine, dried (MgSO4), filtered and concentrated to give the crude product, which was purified using column chromatography over silica, eluting with 0-80% EtOAc / PE, to give tert-butyl N-[6-(oxetan-3-yl)-2- pyridyl]carbamate (73 mg, 40% yield) as a white solid. 1H NMR (300 MHz, CDCh) 6 7.80 (d, 1H, J = 8.3 Hz), 7.60 (t 1H, J = 8.2 Hz), 7.31 (br s, 1H), 6.84 (d, 1H, J = 7.3 Hz), 4.99 (dd, 2H, J = 8.5, 5.7 Hz), 4.90 (dd, 2H, J = 6.7, 5.7 Hz), 4.29-4.19 (m, 1H), 1.52 (s, 9H). MS (ES+) m / z = 251.3 [M+HJ+.

[1145] Step 2: TFA (0.6 ml, 7.29 mmol) was added to a solution of tert-butyl N-[6-(oxetan-3-yl)-2- pyridyl]carbamate (73 mg, 0.291 mmol) in DCM (1.8 ml), with stirring under nitrogen for 3 hours before concentrating in vacuo. DCM was added and the mixture concentrated again and the resulting precipitate was washed with diethyl ether to give the title compound (65 mg, 84% yield) as an off-white solid. MS (ES+) m / z = 151.2 [M+H]+.

[1146] 3-Chloro-6-(oxetan-3-yl)pyridin-2-amine

[1147] Step 1: A mixture of tert-butyl N-(6-bromo-3-chloro-2-pyridyl)-N-tert-butoxycarbonyl-carbamate (200 mg, 0.49 mmol), 3-bromooxetane (0.08 ml, 0.98 mmol), pyridine-2,6-dicarboxamidine dihydrochloride (12 mg, 0.049 mmol), NiCI2.DME (11 mg, 0.049 mmol), sodium iodide (18 mg, 0.12 mmol), zinc metal powder (64 mg, 0.98 mmol) and TFA (4 ul, 0.049 mmol) in anhydrous DMA (3 ml) was sealed and heated to 60 °C with stirring overnight. The reaction mixture was diluted with EtOAc, filtered through a short pad of dicalite, washed with EtOAc. The filtrate was washed with water and brine, dried (MgSO4), filtered and concentrated to give the crude product, which was purified using column chromatography over silica, eluting with 0-80% EtOAc / PE, to give tert-butyl N-tert-butoxycarbonyl-N-[3-chloro-6-(oxetan-3-yl)-2-pyridyl]carbamate (127 mg, 67% yield) as a clear yellow oil.1H NMR (300 MHz, CDCI3) 5 7.74 (d, 1H, J = 8.1 Hz), 7.20 (d 1H, J = 8.1 Hz), 5.02 (dd, 2H, J = 8.5, 5.9 Hz), 4.87 (dd, 2H, J = 6.7, 5.9 Hz), 4.42-4.32 (m, 1H), 1.40 (s, 18H). MS (ES+) m / z = 385.3 [M+HJ+.

[1148] Step 2: TFA (0.63 ml, 8.18 mmol) was added to a solution of tert-butyl N-tert-butoxycarbonyl-N-[3- chloro-6-(oxetan-3-yl)-2-pyridyl]carbamate (126 mg, 0.33 mmol) in DCM (2.4 ml), with stirring under nitrogen for 3 hours before concentrating in vacuo. The residue was then separated between EtOAc and aqueous NaHCO3 solution, and the combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated to give the product (61 mg, 100% yield) as a beige solid. MS (ES+) m / z = 185.0 [M+HJ+.

[1149] Step 1: 6-((tert-Butoxycarbonyl)amino)picolinic acid (50 mg, 0.210 mmol) was dissolved in MeCN (5 mL) and DIPEA (0.11 mL, 0.630 mmol) was added followed by 2-trifluoromethylpyrrolidine (29 mg, 0.210 mmol) and 1-propanephosphonic anhydride 50% in EtOAc (0.062 mL, 0.210 mmol). The reaction mixture was stirred at ambient temperature for 16 hours, then diluted with EtOAc (10 ml) and washed with water (5 ml). The organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure to give the crude product, which was purified by reverse phase chromatography (MeCN: H2O eluent) to furnish tert-butyl N-[6-[2-(trifluoromethyl)pyrrolidine- 1-carbonyl]-2-pyridyl]carbamate (49 mg, 0.136 mmol, 65%) as a peach solid. MS (ES+) m / z = 292.3 [M+HJ+.

[1150] Step 2: Trifluoroacetic acid (0.050 mL, 0.649 mmol) was added to a solution of tert-butyl N-[6-[2- (trifluoromethyl)pyrrolidine-1-carbonyl]-2-pyridyl]carbamate (46 mg, 0.128 mmol) in DCM (5 mL) and the reaction mixture was stirred at ambient temperature for 16 hours, then concentrated under reduced pressure, diluted with DCM (10 mL) and washed with saturated NaHCO3 (aq) (5 ml). The organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure to give the title product (31 mg, 0.120 mmol, 94%) as a pale yellow oil.1H NMR (300 MHz, CDCI3) 5 7.63 (dd, J = 8.6, 7.3 Hz, 1H), 7.08 (d, J = 6.9 Hz, 1H), 6.98 (s, 1H), 6.80 (s, 1H), 5.14 (s, 1H), 3.81 (s, 3H), 2.18 (s, 4H). MS (ES+) m / z = 260.2 [M+HJ+.

[1151] 2'-Fluoro-5-methyl-[2,3'-bipyridinl-6-amine

[1152] Step 1: Boc anhydride (1.4 g, 6.46 mmol) was added to a solution of 6-bromo-3-methylpyridin-2- amine (575 mg, 3.07 mmol), DMAP (75 mg, 0.61 mmol) and triethylamine (1.1 ml, 7.69 mmol) in DCM (30 ml), with stirring at 35 °C overnight. The reaction mixture was separated between DCM and water, the organic extracts washed with brine, dried (Na2SO4), filtered and concentrated. The crude product was purified by column chromatography over silica, eluting with 0-70% EtOAc / PE to give tert-butyl N-(6-bromo-3-methyl-2-pyridyl)-N-tert-butoxycarbonyl-carbamate (1.0 g, 84% yield) as a white solid. 1H NMR (300 MHz, CDCI3) 6 7.44 (dd, 1 H, J = 7.9, 0.7 Hz), 7.36 (d, 1H, J = 7.9 Hz), 2.19 (s, 3H), 1.41 (s, 18H). MS (ES+) m / z = 389.2 [M+HJ+.

[1153] Step 2: tert-Butyl N-(6-bromo-3-methyl-2-pyridyl)-N-tert-butoxycarbonyl-carbamate (150 mg, 0.39 mmol) and 2-fluoro-3-pyridineboronic acid (65 mg, 0.46 mmol) were dissolved in 1,4-dioxane:water (5:1 , 6 ml), the solution was flushed with nitrogen for 5 minutes, Pd(PPh3)4 (67 mg, 15mol%) and potassium carbonate (65 mg, 0.46 mmol) were added, the mixture was flushed with nitrogen for a further 5 minutes then heated to 90 °C with stirring overnight. The reaction mixture was separated between EtOAc and water, the organic extracts washed with brine, dried (MgSO4), filtered and concentrated. The crude product was dissolved in DCM (4 ml) and TFA (0.75 ml, 9.68 mmol) was added, with stirring for 3 hours before concentrating in vacuo. Methanol was added and the mixture concentrated again. The resulting precipitate was purified using column chromatography over silica, eluting with 0-15% methanol / DCM, then again with 20-100% EtOAc / PE, to give the title compound (61 mg, 77% yield) as an off-white solid. 1 H NMR (300 MHz, DMSO-cftS) 5 8.43 (ddd, 1H, J = 10.3, 7.5, 2.0 Hz), 8.21 (ddd, 1H, J = 4.8, 2.1, 1.4 Hz), 7.48-7.43 (m, 1H), 7.36 (dd, 1 H, J = 7.4, 0.9 Hz), 6.98 (dd, 1H, J = 7.4, 2.5 Hz), 5.93 (s, 2H), 2.09 (s, 3H).19F NMR (282 MHz, DMSO- d6) 6 -69.52. MS (ES-) m / z = 202.1 [M-H]-.

[1154] 5-Chloro-2'-fluoro-[2,3'-bipyridin1-6-amine tert-butyl N-(6-bromo-3-chloro-2-pyridyl)-N-tert-butoxycarbonyl-carbamate (150 mg, 0.37 mmol) and 2-fluoro-3-pyridineboronic acid (62 mg, 0.44 mmol) were dissolved in 1,4-dioxane:water (5:1, 6 ml), the solution was flushed with nitrogen for 5 minutes, Pd(PPh3)4 (64 mg, 15mol%) and potassium carbonate (62 mg, 0.44 mmol) were added, the mixture was flushed with nitrogen for a further 5 minutes then heated to 90 °C with stirring overnight. The reaction mixture was separated between EtOAc and water, the organic extracts washed with brine, dried (MgSO4), filtered and concentrated. The crude product was dissolved in DCM (4 ml) and TFA (0.71 ml, 9.2 mmol) was added, with stirring for 3 hours before concentrating in vacuo. Methanol was added and the mixture concentrated again. The resulting precipitate was purified using column chromatography over silica, eluting with 0-100% EtOAc / PE, to give the title compound (82 mg, 100% yield) as an off- white solid. 1H NMR (300 MHz, DMSO-d6) 5 8.41 (ddd, 1H, J = 10.3, 7.5, 2.0 Hz), 8.27 (ddd, 1H, J = 4.8, 2.1 , 1.3 Hz), 7.71 (d, 1H, J = 8.0 Hz), 7.49 (ddd, 1H, J = 7.5, 4.8, 2.1 Hz), 7.04 (dd, 1 H, J = 8.0, 2.3 Hz), 6.53 (br s, 2H).19F NMR (DMSO-d6, 282 MHz) 5 -69.25. MS (ES-) m / z = 222.0 [M-H]-. Methyl 2-amino-6,7-dihvdro-5H-cvclopentafblpyridine-7-carboxylate

[1155] Step 1: Methyl 2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridine-7-carboxylate (70 mg, 0.33 mmol) and t-butyl carbamate (97 mg, 0.83 mmol) were dissolved in 1,4-dioxane:water (10:1, 3.3 ml), the solution was bubbled with nitrogen for 5 minutes, then Pd2dba3 (45 mg, 15mol%), Xantphos (47 mg, 30mol%), and cesium carbonate (130 mg, 0.40 mmol) were added. The reaction mixture was bubbled with nitrogen for further 5 minutes, heated to 90 °C with stirring overnight, cooled, separated between EtOAc and water, the organic extracts washed with brine, dried (MgSO4), filtered and concentrated. The crude product was purified by column chromatography over silica, eluting with 0-50% EtOAc / PE, to give methyl 2-(tert-butoxycarbonylamino)-6,7-dihydro-5H- cyclopenta[b]pyridine-7-carboxylate (64 mg, 66% yield) as a clear colourless oil.1H NMR (300 MHz, CDCI3) 5 7.76 (d, 1H, J = 8.4 Hz), 7.51 (d, 1H, J = 8.4 Hz), 7.29 (s, 1H), 3.99 (dd, 1H, J = 8.7, 6.0 Hz), 3.73 (s, 3H), 3.10-2.99 (m, 1H), 2.90-2.80 (m, 1 H), 2.49-2.31 (m, 2H), 1.49 (s, 9H). MS (ES+) m / z = 293.3 [M+HJ+.

[1156] Step 2: TFA (0.38 ml, 4.96 mmol) was added to a solution of product from step 1 (58 mg, 0.20 mmol) in DCM (1.6 ml), with stirring under nitrogen for 4 hours before concentrating in vacuo. DCM was added, the mixture concentrated again and the resulting crude product was purified using flash column chromatography over silica, eluting with 0-25% methanol / DCM to give the title compound (36 mg, 94% yield) as a white solid.1H NMR (300 MHz, DMSO-cftS) 5 7.78 (d, 1H, J = 8.9 Hz), 7.64 (br, 2H), 6.79 (d, 1H, J = 8.8 Hz), 4.22 (dd, 1H, J = 9.5, 5.7 Hz), 3.67 (s, 3H), 2.89-2.70 (m, 2H), 2.54-2.51 (m, 1H), 2.28-2.16 (m, 1 H). MS (ES+) m / z = 193.2 [M+HJ+.

[1157] Methyl 2-amino-5,6,7,8-tetrahvdroquinoline-8-carboxylate

[1158] Methyl 2-chloro-5,6,7,8-tetrahydroquinoline-8-carboxylate (490 mg, 2.17 mmol), t-butyl carbamate (636 mg, 5.43 mmol), Pd2dba3 (298 mg, 15mol%), Xantphos (311 mg, 30mol%), and cesium carbonate (1.068 g, 3.26 mmol) were dissolved in 1 ,4-dioxane:water (5:1, 24 ml) solution bubbled with nitrogen. The reaction mixture was heated at 90 °C overnight, then separated between EtOAc and water, the organic extracts washed with brine, dried (MgSO4), filtered and concentrated. The crude product was partially purified by column chromatography over silica, eluting with 0-50% EtOAc / PE. The resulting material was dissolved in DCM (20 ml) and TFA (4.2 ml, 54.3 mmol) was added with stirring for 3 hours. The reaction mixture was concentrated, separated between EtOAc and aqueous NaHCO3, the organic extracts washed with brine, dried MgSO4), filtered and concentrated. The crude product was purified by column chromatography over silica, eluting with 0-20% EtOAc / PE, to give the title compound (126 mg, 28% yield) as a yellow solid.1H NMR (300 MHz, CDCI3) 5 7.15 (d, 1 H, J = 8.3 Hz), 6.35 (d, 1 H, J = 8.3 Hz), 4.33 (br, 2H), 3.76 (t, 1 H, J = 6.8 Hz), 3.72 (s, 3H), 2.73-2.54 (m, 2H), 2.17-2.00 (m, 2H), 1.97-1.84 (m, 1 H), 1.77-1.64 (m, 1 H). MS (ES+) m / z = 207.2 [M+HJ+.

[1159] 2. Halo-heteroaryl precursors

[1160] 2.1. 6-Halo-pyridyl-2-carboxamides

[1161] General Method E: Amide formation from 6-halopyridine-2-carboxylic acid

[1162] A mixture of amine (1.0-3.0 eq), pyridyl 2-carboxylic acid (1.0 eq), DI PEA (0-5.0 eq) and HATLI (1.2 eq.) in solvent (e.g. MeCN, DCM) was stirred at rt or heated at 50-70 °C for 1-16 h before it was diluted with H2O and extracted with EtOAc (3 x). The combined organic phases was dried over MgSC>4 and filtered. The solvent was removed under reduced pressure. The crude can be purified by chromatography if necessary.

[1163] 6-Bromo- / V-(tert-butyl)-5-methylnicotinamide

[1164] A mixture of 6-bromo-5-methylpyridine-3-carboxylic acid (250 mg, 1.16 mmol, 1.00 eq), tert- butylamine (0.36 mL, 3.47 mmol, 3.00 eq), HATLI (528 mg, 1.39 mmol, 1.20 eq) and acetonitrile (6 mL) was stirred at rt for 16 h before it was diluted with EtOAc (40 mL) and washed with sat. NaHCOs (3 x 30 mL), dried over MgSO4 and filtered. The solvent was removed under reduced pressure and the crude was purified by chromatography (EtOAc / PE 0>60%) to afford 6-bromo- / V- terf-butyl-5-methyl-pyridine-3-carboxamide (234 mg, 0.863 mmol, 75%) as white crystals.1H NMR (300 MHz, CDCh) 6 8.32 (dd, J = 2.4, 0.7 Hz, 1 H), 7.73 (dd, J = 2.4, 0.9 Hz, 1 H), 6.51 (s, 1 H), 2.26 (s, 3H), 1.37 (s, 9H). MS (ES+) m / z 271 .2 / 273.2 (M+H)+.

[1165] The following examples were prepared in a similar manner using method E with the appropriate carboxylic acid and amine:

[1166] General Method F: Nucleophilic aromatic substitution of fluoropyridine carboxamide A mixture of fluoropyridine carboxamide (1.0 eq), potassium carbonate (1.0-4 eq) in alcohol ( 0.2- 0.3 M) or nucleophile (thiolate, amine, alcohol, phenol) (1.0-2 eq) in DMF or DMSO was stirred at 80-120 °C for 3-24 h. After cooling to rt, the reaction mixture was concentrated under reduced pressure or extracted between EtOAc and water, the organic layer dried (MgSO4) and evaporated and the crude was purified by silica or RP chromatography to afford the desired product.

[1167] 6-Bromo- / V-(tert-butyl)-5-(methylthio)picolinamide

[1168] A mixture of 6-bromo- / V-tert-bL / ty / -5-fluoro-pyridine-2-carboxamide (150 mg, 0.545 mmol, 1.00 eq), sodium thiomethoxide (46 mg, 0.654 mmol, 1.20 eq) and DMF (2.5 mL) was stirred at 80 °C for 16 h. After cooling to rt, the crude was purified by RP chromatography (MeCN / H2O 5 >95%) to afford 6-bromo- / V-terf-butyl-5-methylsulfanyl-pyridine-2-carboxamide (60 mg, 0.198 mmol, 36%) as white solids.1H NMR (300 MHz, CDCI3) 5 8.12 - 8.02 (m, 1 H), 7.61 (s, 1 H), 7.44 (d, J = 8.1 Hz, 1 H), 2.49 (s, 3H), 1.47 (s, 9H). MS (ES+) m / z 303.0 / 305.0 (M+H)+. The following examples were prepared in a similar manner using method F with the appropriate nucleophile:

[1169] / V-(tert-Butyl)-6-chloro-5-methylpicolinamide

[1170] A mixture of 6-chloro-5-methylpyridine-2-carboxylic acid (200 mg, 1.17 mmol, 1.00 eq) and thionyl chloride (2.5 mL) was stirred at 80 °C for 2 h before the solvent was removed under reduced pressure. DCM (5 mL) was added followed by tert- butyl amine (0.13 mL, 1.28 mmol, 1.10 eq) and pyridine (0.14 mL, 1.75 mmol, 1.50 eq). The mixture was stirred at rt for 3 h before it was diluted with DCM (10 mL), washed with 0.5 M HCI (15 mL), sat. NaHCCh (15 mL), dried over MgSC>4 and filtered. The solvent was removed under reduced pressure and the crude was purified by RP chromatography (MeCN / hLO 5>95%) to afford / V-tert-butyl-6-chloro-5-methyl-pyridine-2- carboxamide (173 mg, 0.763 mmol, 65%) as white solids.1H NMR (300 MHz, CDCh) 6 7.89 (d, J = 7.6 Hz, 1 H), 7.64 - 7.54 (m, 2H), 2.31 (s, 3H), 1 .39 (s, 9H). MS (ES+) m / z 227.0 / 229.0 [M+H]+. 6-Bromo-N-(tert-butyl)-5-(pentan-3-yloxy)picolinamide

[1171] Potassium tert-butoxide (51 mg, 0.45 mmol) was added to a solution of 3-pentanol (0.047 ml, 0.44 mmol) in anhydrous THF (3.5 ml), with stirring at room temperature for 30 minutes. 6-bromo-N-tert- butyl-5-fluoro-pyridine-2-carboxamide (100 mg, 0.36 mmol) and the reaction mixture heated to 60°C stirring overnight, cooled to room temperature, separated between EtOAc and water, the organic phase washed with brine, dried (MgSO4), filtered and concentrated. The crude product was purified using flash column chromatography over silica, eluting with 0-40% EtOAc / PE, to give the title compound (116 mg, 93% yield) as a white solid.1H NMR (CDCI3, 300 MHz) 5 8.05 (d, 1H, J = 8.5 Hz), 7.57 (br, 1 H), 7.17 (d, 1H, J = 8.5 Hz), 4.23 (p, 1H, J = 5.8 Hz), 1.79-1.68 (m, 4H), 1.47 (s, 9H), 0.98 (t, 6H, J = 7.4 Hz). MS (ES+) m / z 345.4 [M+H]+.

[1172] 6-Bromo-N-(tert-butyl)-5-(1-cvclopropylethoxy)picolinamide

[1173] Potassium tert-butoxide (69 mg, 0.61 mmol) was added to a solution of 1-cyclopropylethan-1-ol (0.055 ml, 0.57 mmol) in anhydrous THF (4.0 ml), with stirring at room temperature for 20 minutes. 6-bromo-N-tert-butyl-5-fluoro-pyridine-2-carboxamide (120 mg, 0.44 mmol) was then added, and the reaction mixture heated to 65°C stirring overnight, cooled to room temperature, separated between EtOAc and water, the organic phase washed with brine, dried (MgSO4), filtered and concentrated. The crude product was purified using flash column chromatography over silica, eluting with 0-60% EtOAc / PE, to give the title compound (117 mg, 79% yield) as a white solid.1H NMR (CDCI3, 300 MHz) 5 8.05 (d, 1 H, J = 8.4 Hz), 7.57 (br, 1 H), 7.21 (d, 1 H, J = 8.4 Hz), 4.05- 3.97 (m, 1H), 1.47 (s, 9H), 1.44 (d, 3H, J = 6.2 Hz), 1.23-1.12 (m, 1H), 0.64-0.52 (m, 2H), 0.44- 0.27 (m, 2H). MS (ES+) m / z 343.2 [M+H]+.

[1174] 6-Bromo-N-(tert-butyl)-5-(cvclopentylmethoxy)picolinamide

[1175] A mixture of 6-bromo-N-tert-butyl-5-fluoro-pyridine-2-carboxamide (150 mg, 0.545 mmol), cyclopentylmethanol (66 mg, 0.654 mmol) and potassium tert-butoxide (73 mg, 0.654 mmol) in THF (1 mL) was heated to 90°C for 16 h. After allowing to cool, the mixture was directly subject to reverse phase column chromatography (wateracetonitrile) to afford the title compound (120 mg, 0.338 mmol, 62%). MS (ES+) m / z = 355, 357 ([M+H]+. (R)-6-Bromo-5-(sec-butoxy)-N-(tert-butyl)picolinamide

[1176] A mixture of 6-bromo-N-tert-butyl-5-fluoro-pyridine-2-carboxamide (137 mg, 0.498 mmol) ,(2R)- butan-2-ol (48 mg, 0.647 mmol) and potassium tert-butoxide (67 mg, 0.598 mmol) in THF (1 mL) was heated to 90°C for 16 h. After allowing to cool, the mixture was directly subject to reverse phase column chromatography (wateracetonitrile) to afford the title compound (148 mg, 0.450 mmol, 90%). MS (ES+) m / z = 329, 331 ([M+H]+.

[1177] 2.2. Amides of 6-halo-2-amino-pyridines

[1178] General Method G: Amide formation with carboxylic acid

[1179] A mixture of 6-halo-2-aminopyridine (1.0-3.0 eq), carboxylic acid (1.0-3.0 eq), DIPEA (0-3.0 eq) and HATU (1.2 eq.) in solvent (e.g. MeCN) was stirred at rt or heated at 50-70 °C for 1-16 h before it was diluted with H2O and extracted with EtOAc (3 x). The combined organic phases was dried over MgSO4 and filtered. The solvent was removed under reduced pressure. The crude can be purified by chromatography if necessary.

[1180] / V-(6-Bromo-5-methylpyridin-2-yl)-1-fluorocyclopropane-1 -carboxamide

[1181] A mixture of 6-bromo-5-methylpyridin-2-amine (200 mg, 1.07 mmol), 1-fluorocyclopropane-1- carboxylic acid (278 mg, 2.67 mmol), HATLI (1220 mg, 3.21 mmol), DIPEA (0.56 mL, 3.21 mmol) and acetonitrile (5.2 mL) was stirred at 70 °C for 5 h. The reaction mixture was then diluted with EtOAc (20 mL), washed with sat. NaHCO3 (2 x 10 mL), dried over MgSO4 and filtered. The solvent was removed under reduced pressure and the crude was purified by reverse phase chromatography (MeCN / H2O 5 >95%) to afford the title product (222 mg, 0.813 mmol, 76%) as beige crystals.1H NMR (300 MHz, CDCI3) 6 8.73 (s, 1 H), 8.05 - 7.93 (m, 1H), 7.51 - 7.39 (m, 1 H), 2.31 - 2.22 (m, 3H), 1.49 - 1.24 (m, 4H). MS (ES+) m / z 273.0 / 275.0 [M + H]+. The following examples were prepared in a similar manner using method G with the appropriate carboxylic acid:

[1182] 2.3. Sulfonamides of 6-halo-2-amino-pyridines

[1183] General Method H: Sulfonamide formation from amines and sulfonyl chlorides

[1184] A mixture of amine (1.00 eq), sulfonyl chloride (1.0-3.0 eq), pyridine (1 .0-3.0 eq) and DCM (0.2

[1185] M) was stirred at rt for 1-16h before it was diluted with 0.5 M HCI or sat. NaHCOs and extracted with EtOAc (3 x). The combined organic phases was dried over MgSC>4 and filtered. The solvent was removed under reduced pressure to afford the desired sulfonamide which could be purified by chromatography if required.

[1186] / V-(6-Bromo-5-methylpyridin-2-yl)-4-methylbenzenesulfonamide

[1187] A mixture of 6-bromo-5-methylpyridin-2-amine (200 mg, 1.07 mmol, 1.00 eq), p-toluenesulfonyl chloride (224 mg, 1.18 mmol, 1.10 eq), pyridine (0.10 mL, 1.28 mmol, 1.20 eq) and DCM (5.2 mL) was stirred at rt for 2 h before it was diluted with 0.5 M HCI (15 mL) and extracted with EtOAc (3 x 10 mL). The combined organic phases was dried over MgSO4 and filtered. The solvent was removed under reduced pressure to afford / V-(6-bromo-5-methyl-2-pyridyl)-4-methyl- benzenesulfonamide (355 mg, 1.04 mmol, 97%) as pink solids.1H NMR (300 MHz, CDCh) 6 7.85 - 7.78 (m, 2H), 7.60 - 7.31 (m, 2H), 7.28 - 7.18 (m, 3H), 2.37 (s, 3H), 2.25 (s, 3H). MS (ES+) m / z 341.1 / 343.1 (M+H)+.

[1188] The following examples were prepared in a similar manner using method H with the appropriate sulfonyl chloride:

[1189] 2.4. Other halopyridine intermediates

[1190] (6-Bromo-5-methylpyridin-2-yl)methanol

[1191] Borane tetra hydrofuran complex solution (1M in THF, 6.1 mL, 6.12 mmol, 1.50 eq) was carefully added to a mixture of 6-chloro-5-methylpyridine-2-carboxylic acid (700 mg, 4.08 mmol, 1.00 eq) in THF (6 mL) and the mixture was stirred at rt for 5 h before it was carefully quenched with MeOH and EtsN. The mixture was diluted with EtOAc (50 mL), washed with sat. NaHCCh (2 x 10 mL), dried over MgSC>4 and filtered. The solvent was removed under reduced pressure and the crude was purified by chromatography (EtOAc / pet ether 0>80%) to afford (6-chloro-5-methyl-2- pyridyl)methanol (307 mg, 1.95 mmol, 48%) as a colourless oil. MS (ES+) m / z 158.2 (M+H)+. 6-((Diethylamino)methyl)pyridin-2-amine

[1192] Diethylamine (0.25 ml, 2.39 mmol) was added to a solution of 2-bromo-6-(bromomethyl) pyridine (400 mg, 1.59 mmol) and potassium carbonate (447 mg, 3.19 mmol) in acetonitrile (12 ml), and the reaction mixture was warmed to 50 °C with stirring overnight. The reaction mixture was separated between EtOAc and water, the organic extracts were washed with brine, dried (MgSO4), filtered and concentrated to give the product (395 mg, 100% yield) as a yellow oil.1H NMR (300 MHz, CDCI3) 5 7.52-7.46 (m, 2H), 7.34-7.28 (m, 1H), 3.70 (s, 2H), 2.57 (q, 4H, J = 7.2 Hz), 1.03 (t, 6H, J = 7.2 Hz). MS (ES+) m / z = 244.7 [M+HJ+.

[1193] N-((6-Bromopyridin-2-yl)methyl)-N-ethylpropionamide

[1194] Step 1: Ethylamine (2 M in THF, 2.39 ml, 4.78 mmol) was added to a solution of 2-bromo-6- (bromomethyl)pyridine (600 mg, 2.39 mmol) and potassium carbonate (671 mg, 4.78 mmol) in acetonitrile (18 ml). The reaction mixture was stirred at 40 °C overnight, then partitioned between EtOAc and water, the organic extracts washed with brine, dried (MgSO4), filtered and concentrated to give N-[(6-bromo-2-pyridyl)methyl]ethanamine (461 mg, 80% pure, 72% yield) as a yellow oil.1H NMR (300 MHz, CDCI3) 6 7.52-7.48 (m, 1 H), 7.35 (d, 1H, J = 7.3 Hz), 7.29 (d, 1 H, J = 7.4 Hz), 3.87 (s, 2H), 2.69 (q, 2H, J = 7.1 Hz), 1.14 (t, 3H, J = 7.1 Hz). MS (ES+) m / z = 217.1 [M+HJ+. Step 2: Propionyl chloride (0.089 ml, 1.02 mmol) was added drop-wise to a solution of N-[(6- bromo-2-pyridyl)methyl]ethanamine (200 mg, 0.93 mmol) and triethylamine (0.39 ml, 2.79 mmol) in DCM (9 ml), with stirring at room temperature for 4 hours. The reaction mixture was partitioned between DCM and water, the organic phase washed with brine, dried (Na2SO4), filtered and concentrated. The crude product was purified by column chromatography over silica, eluting with 20-100% EtOAc / PE ether to give the title compound (341 mg, 81% yield) as a clear colourless oil.1H NMR (300 MHz, CDCI3) 6 7.47 (t, 1H, J = 7.7 Hz), 7.33 (d, 1H, J = 7.8 Hz), 7.21 (d, 1 H, J = 7.6 Hz), 4.61 (s, 2H), 3.40 (q, 2H, J = 7.1 Hz), 2.41 (q, 2H, J = 7.5 Hz), 1.19-1.13 (m, 3H), 1.10 (t, 3H, J = 7.5 Hz). MS (ES+) m / z = 273.1 [M+HJ+.

[1195] Methyl 2-chloro-6,7-dihvdro-5H-cvclopentafblpyridine-7-carboxylate

[1196] A solution of 2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridine (1.0 g, 6.51 mmol) and diisopropyl amine (0.96 ml, 6.84 mmol) in anhydrous diethyl ether (100 ml) was cooled to -30 °C (dry- ice / acetonitrile, temperature monitored and mixture adjusted as necessary). nBuLi (2.5 m in hexanes, 5.5 ml, 13.7 mmol) was added drop-wise, with stirring at -30 °C under nitrogen for 1 hour, followed by dimethyl carbonate (0.60 ml, 7.16 mmol) with continued stirring at -30 °C for 1 hour before leaving to stir overnight slowly warming to RT. The reaction mixture was quenched with saturated aqueous NH4CI, extracted with EtOAc, the organic extracts washed with brine, dried (MgSO4), filtered and concentrated. The crude product was purified by column chromatography over silica, eluting with 0-80% AcOEt / PE, to give the title compound (973 mg, 71% yield) as a yellow oil.1H NMR (300 MHz, CDCI3) 6 7.49 (d, 1H, J = 8.0 Hz), 7.13 (d, 1H, J = 8.0 Hz), 4.09-4.04 (m, 1H), 3.73 (s, 3H), 3.13-3.03 (m, 1 H), 2.94-2.83 (m, 1H), 2.47-2.39 (m, 2H). MS (ES+) m / z 214.0 [M+H]+.

[1197] Methyl 2-chloro-5,6,7,8-tetrahydroquinoline-8-carboxylate

[1198] A solution of 2-chloro-5,6,7,8-tetrahydroquinoline (1.0 g, 5.97 mmol) and diisopropylamine (0.88 ml, 6.26 mmol) in anhydrous diethyl ether (100 ml) was cooled to -30 °C , nBuLi (2.5 M in hexanes, 5.0 ml, 12.5 mmol) was added drop-wise at -30 °C under nitrogen for 1 hour, followed by dimethyl carbonate (0.55 ml, 6.56 mmol) with continued stirring at -30 °C for 1 hour before leaving to stir overnight slowly warming to RT. The reaction mixture was quenched with saturated aqueous NH4CI, extracted with EtOAC, the organic extracts washed with brine, dried (MgSO4), filtered and concentrated. The crude product was purified by column chromatography over silica, eluting with 0-80% EtOAc / PE, to give the title compound (1.118 g, 83% yield) as a yellow oil.1H NMR (300 MHz, CDCI3) 6 7.36 (d, 1H, J = 8.0 Hz), 7.11 (d, 1H, J = 8.1 Hz), 3.93 (t, 1H, J = 5.9 Hz), 3.71 (s, 3H), 2.86-2.66 (m, 2H), 2.25-2.01 (m, 2H), 1.96-1.72 (m, 2H). MS (ES+) m / z 228.0 [M+H]+.

[1199] General method I: 2-Halopyridyl fused cycloalkylamides by ester deprotection and amide coupling

[1200] R=Me, Et

[1201] Step 1: Lithium hydroxide monohydrate (2-3 eq.) was added to a solution of ester (1 eq) in methanokwater (1:1) with stirring at 45 °C for 3 hours. The reaction mixture was concentrated, acidified to pH ~2 using 2 M aq. HCI, extracted with EtOAc, the organic extracts washed with brine, dried (MgSO4), filtered and concentrated to give the carboxylic acid used in the next step without further purification. Step 2: HATLI (1.2 eq) was added to a solution of carboxylic acid (1 eq.), amine (1.2 eq) and DIPEA (4 eq.) in anhydrous DMF, with stirring at room temperature for 12-18h. The reaction mixture was separated between EtOAc and water, the organic phase washed with brine, dried (MgSO4), filtered and concentrated. The crude product can be purified using flash column chromatography over silica.

[1202] (2-Chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl)((S)-2-(trifluoromethyl)pyrrolidin-1-yl) methanone

[1203] Step 1: Lithium hydroxide monohydrate (181 mg, 4.2 mmol) was added to a solution of methyl 2- chloro-6,7-dihydro-5H-cyclopenta[b]pyridine-7-carboxylate (356 mg, 1.68 mmol) in methanokwater (1:1 , 16 ml) with stirring at 45 °C for 3 hours. The reaction mixture was concentrated, acidified to pH ~2 using 2 M aq. HCI, extracted with EtOAc, the organic extracts washed with brine, dried (MgSO4), filtered and concentrated to give 2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridine-7- carboxylic acid (314 mg, 94% yield) as a white solid.1H NMR (300 MHz, DMSO-d6) 5 12.58 (s, 1H), 7.74 (d, 1 H, J = 8.0 Hz), 7.31 (d, 1 H, J = 8.0 Hz), 3.95 (dd, 1H, J = 8.9, 6.2 Hz), 3.03-2.82 (m, 2H), 2.45-2.20 (m, 2H). MS (ES+) m / z 198.0 [M+H]+.

[1204] Step 2: HATLI (277 mg, 0.73 mmol) was added to a solution of 2-chloro-6,7-dihydro-5H- cyclopenta[b]pyridine-7-carboxylic acid (120 mg, 0.61 mmol), 2(S)-2-trifluoromethyl pyrrolidine (101 mg, 0.73 mmol) and DIPEA (0.42 ml, 2.43 mmol) in anhydrous DMF (3.0 ml), with stirring at room temperature overnight. The reaction mixture was separated between EtOAc and water, the organic phase washed with brine, dried (MgSO4), filtered and concentrated. The crude product was purified by column chromatography over silica, eluting with 5-60% EtOAc / PE, to give the title compound as the major product (131 mg, 68% yield); white solid, enantiomer 1, single stereoisomer on D-Carbon, of unknown absolute stereochemistry.1H NMR (300 MHz, CDCI3) 5 7.48 (d, 1H, J = 8.0 Hz), 7.11 (d, 1 H, J = 8.0 Hz), 4.90-4.78 (m, 1 H), 4.49-4.41 (m, 1H), 4.30 (dd, 1H, J = 8.7, 5.6 Hz), 3.68-3.61 (m, 1H), 3.22-3.11 (m, 1H), 2.94-2.83 (m, 1H), 2.69-2.57 (m, 1H), 2.43-2.31 (m, 1 H), 2.20-2.10 (m, 4H).19F NMR (CDCI3, 282 MHz) 5 -74.11 (d, J = 7.7 Hz). MS (ES+) m / z 319.2 [M+H]+.

[1205] The following examples were prepared in a similar manner using method I with the appropriate carboxylic acid and amine:

[1206] 3. Phenol 2-halo-thiazole 5-carboxamide intermediates

[1207] 3.1 Unprotected phenol 2-halo-thiazole 5-carboxamide

[1208] 2-Bromo-N-(3-hydroxy-2,6-dimethyl-phenyl)thiazole-5-carboxamide

[1209] To a stirring solution of 2-bromo-1 ,3-thiazole-5-carboxylic acid (300 mg, 1.44 mmol, 1.0 eq) and 3- amino-2,4-dimethyl-phenol (237 mg, 1.73 mmol, 1.2 eq) in THF (10 mL) was added DIPEA (0.50 mL, 2.88 mmol, 2.0 eq) and T3P (50% in EtOAc, 1.3 mL, 2.16 mmol, 1.5 eq). The reaction mixture was heated to 65°C and left to stir overnight. The mixture was allowed to cool to RT, water and EtOAc added, and the layers separated. The aqueous layer was extracted further with EtOAc, organics collected, passed through a phase separator and the solvents removed in vacuo. The crude material was chromatographed (SiO2) eluting with 0 - 100% EtOAc:PE to afford the title compound (288 mg, 0.880 mmol, 61 %) as a thick colourless oil. MS (ES+) m / z 327.1 / 329.1 (M+H), Br isotope pattern.1H NMR, (300 MHz, DMSO-cfe) 6 10.04 (s, 1 H), 9.25 (s, 1 H), 8.42 (s, 1 H), 6.91 (d, J = 8.2 Hz, 1 H), 6.72 (d, J = 8.2 Hz, 1 H), 2.06 (s, 3H), 1.98 (s, 3H).

[1210] 3.2. Methyl ether-protected phenol 2-halo-thiazole 5-carboxamide

[1211] 2-Bromo-N-(3-methoxv-2,6- >- 5-carboxamide

[1212] To a mixture of 2-bromo-1 ,3-thiazole-5-carboxylic acid (1.0 g, 4.81 mmol, 1.0 eq) and 3-methoxy- 2,6-dimethyl-aniline (800 mg, 5.29 mmol, 1.1 eq), (prepared as reported in Can. J. Chem. 90: 75- 84 (2012) in THF (40 mL) under nitrogen, was added DIPEA (1.7 mL, 9.61 mmol, 2.0 eq) and T3P (50% in EtOAc, 4.2 mL, 7.21 mmol, 1.5 eq) and the reaction was heated at 70°C for 18 h. Then, the crude was concentrated and partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc (x 2) and the combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. The crude material was chromatographed (SiO2) eluting with 0 - 100% EtOAc:PE to afford the title compound (1.45 g, 4.25 mmol, 88%) as a white solid. MS (ES-) m / z 339.0 / 341.0 (M-H), Br-isotope pattern.1H NMR (300 MHz, DMSO-cfe) 6 10.15 (s, 1 H), 8.44 (s, 1 H), 7.10 (d, J = 8.4 Hz, 1 H), 6.88 (d, J = 8.4 Hz, 1 H), 3.79 (s, 3H), 2.11 (s, 3H), 2.01 (s, 3H).

[1213] Step 1 : To a solution of 4-methyl-3-nitrophenol (9.80 g, 64.0 mmol) in Chloroform (200 mL) was added bromine (8.5 mL, 166 mmol) and the reaction heated at 35 °C for 20h, then quenched with slow addition to sodium metabisulfite (3.00 eq, 36.50 g, 192 mmol) in water (500mL), with rapid stirring for 30 min. The phases were separated and the aq extracted with chloroform (200mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 2-bromo-4-methyl-3-nitro-phenol (15.10 g, 53.4 mmol, 83.39% yield) as the major isomer. 1 H NMR (400 MHz, CHLOROFORM-D) 5 7.16 (dq, J = 8.5, 0.7 Hz, 1 H), 7.05 (d, J = 8.5 Hz, 1 H), 5.64 (d, J = 1.4 Hz, 1 H), 2.28 (dd, J = 2.5, 0.7 Hz, 3H). MS (ES-) 230.0 / 231.9 [M- H]-. The product contains other bromo isomers as impurities and was used in the next step without further purification.

[1214] Step 2: lodomethane (1.11 eq, 1.4 mL, 22.5 mmol) was added to a mixture of 2-bromo-4-methyl-3- nitro-phenol (1.00 eq, 4.70 g, 20.3 mmol) from step 1 and potassium carbonate 325 mesh (1.57 eq, 4.40 g, 31.8 mmol) in MeCN (20 mL) . After 1.5 h, further Mel (0.5mL) was added and the stirring was continued for 72h. The inorganics were filtered off and the filtrate evaporated. The crude material was purified by column chromatography over silica (80 g cartridge) eluting with a gradient of DCM (0% to 100%; v / v) in isohexane to afford 2-bromo-1-methoxy-4-methyl-3-nitrobenzene (3.4g). 1H NMR (400 MHz, CDCI3) 5 7.20 (ddd, J = 9.3, 1.5, 0.8 Hz, 1H), 6.90 (d, J = 8.6 Hz, 1 H), 3.92 (s, 3H), 2.27 (d, J = 0.9 Hz, 3H). The product contains other bromo isomers as impurities and was used in the next step without further purification.

[1215] Step 3: Potassium carbonate 325 mesh (2.00 g, 14.5 mmol) was added to a solution of 2-bromo-1- methoxy-4-methyl-3-nitro-benzene (1.90 g, 7.72 mmol) from step 2 in MeCN (20 mL) and water (5 mL), followed by potassium trifluoro(prop-1-en-2-yl)borate (1.90 g, 12.8 mmol) and 1,1'- Bis(diphenylphosphino)ferrocenepalladium (II) dichloride (650 mg, 0.888 mmol). The head space was flushed with nitrogen and the reaction mixture was heat at 80 °C for 24h. The reaction mixture was evaporated, the residue partitioned between EtOAc and water, filtered, the phases separated. The organic phase was dried over sodium sulfate, filtered and evaporated. Fresh MeCN (20 mL) and water (5 mL) were added followed by potassium carbonate 325 mesh (1.87 eq, 2.00 g, 14.5 mmol), potassium trifl uoro(prop-1-en-2-yl) borate (1.66 eq, 1.90 g, 12.8 mmol), and 1,1'- bis(diphenylphosphino)ferrocenepalladium (II) dichloride (500 mg). The head space was flushed with nitrogen, the reaction mixture heated at 80 °C for further 24h, evaporated, the residue partitioned between EtOAc and water, filtered, the phases separated. The organic phase was dried over sodium sulfate, filtered and evaporated. The crude material was purified by column chromatography over silica (40 g cartridge) eluting with a gradient of DCM (0% to 100%; v / v) in isohexane to afford 2-isopropenyl-1-methoxy-4-methyl-3-nitro-benzene (1.03 g, 4.97 mmol, 64.37% yield) as a yellow oil. The product contains 1-isopropenyl-2-methoxy-5-methyl-4-nitro- benzene isomer as an impurity and was used in the next step as a mixture.

[1216] Step 4: A slurry of Palladium on activated Carbon [type487 paste] (130 mg, 1.22 mmol) in EtOAc:EtOH 3:1 (2mL) was added under nitrogen to a solution of 2-isopropenyl-1-methoxy-4- methyl-3-nitro-benzene and 1-isopropenyl-2-methoxy-5-methyl-4-nitro-benzene mixture (1.00 eq, 1.01 g, 4.87 mmol) from step 3 in EtOAc (15 mL) and Ethanol (5 mL). The reaction mixture was stirred for 72h under hydrogen atmosphere. The catalyst was filtered off, washed with EtOAc: EtOH 3:1 (30mL), and the filtrate evaporated. The residue was redissolved in EtOAc:EtOH 3:1 (20mL), a slurry of Palladium on activated Carbon [type 39 paste] (150 mg, 1.41 mmol) in EtOAc: EtOH 3:1 (2mL) was added under nitrogen, and the reaction mixture was stirred under hydrogen atmosphere for further 72h. The catalyst was filtered off, washed with EtOAc: EtOH 3:1 (30mL) and the filtrate evaporated. The residue was dissolved in MeOH and loaded onto an SCX-2 cartridge (10 g). The cartridge was washed with MeOH (50 mL) . The wash fraction was concentrated to dryness under reduced pressure to afford purified 2-isopropenyl-1-methoxy-4-methyl-3-nitro-benzene (510 mg, 2.21 mmol, 45.45% yield) as a black oil. 1 H NMR (400 MHz, METHANOL-D4) 5 7.21 (dp, J = 8.6, 0.7 Hz, 1H), 7.03 (d, J = 8.5 Hz, 1H), 5.10 (p, J = 1.6 Hz, 1H), 4.75 (dq, J = 1.9, 1.0 Hz, 1H), 3.81 (s, 3H), 2.17 (d, J = 0.9 Hz, 3H), 1.99 (dd, J = 1.5, 1.0 Hz, 3H). The cartridge was eluted with 7M ammonia in MeOH (40 mL). The eluent was concentrated to dryness under reduced pressure to afford reduced impurity 4-isopropyl-5-methoxy-2-methyl-aniline (350 mg, 1.27 mmol, 26.04% yield) as a purple oil. 1H NMR (400 MHz, METHANOL-D4) 56.75 (s, 1H), 6.34 (s, 1H), 3.71 (s, 3H), 3.12 (dq, J = 13.8, 7.0 Hz, 1H), 2.12 - 2.00 (m, 3H), 1.17 - 1.06 (m, 6H).

[1217] Step 5: A slurry of Palladium on activated Carbon (140 mg, 1.32 mmol) in EtOAc:EtOH 3:1 (5mL) was added under nitrogen to a solution of 2-isopropenyl-1-methoxy-4-methyl-3-nitro-benzene (1.00 eq, 0.50 g, 2.41 mmol) in EtOAc (15 mL) and Ethanol (5 mL). The reaction mixture was stirred under an atmosphere of hydrogen for 80h, then the catalyst was filtered off through a celite pad, washed through with copious EtOAc: EtOH 3:1. The filtrate was evaporated to afford 440mg of a 2:1 mixture of 2-isopropenyl-1-methoxy-4-methyl-3-nitro-benzene (1.00 eq, 440 mg, 2.12 mmol) and 2-isopropyl-1-methoxy-4-methyl-3-nitro-benzene.

[1218] Step 6: Zinc (500 mg, 7.65 mmol) was added to the mixture from step 5 (440 mg) 2 in Methanol (10 mL) and Acetic acid (2 mL) . The reaction mixture was stirred at ambient temperature for 3h, then it was diluted with EtOAc (20mL), filtered, washed with EtOAc and the filtrate evaporated to afford 580mg of a 2:1 mixture of 2-isopropenyl-3-methoxy-6-methyl-aniline, MS (ES+) m / z = 178.1 [M+H]+ and 2-isopropyl-3-methoxy-6-methyl-aniline, MS (ES+) m / z = 180.2 [M+H]+.

[1219] Step 7: A slurry of Palladium on activated Carbon [type 39 paste] (0.387 eq, 130 mg, 1.22 mmol) in EtOAc / EtOH 3:1 (4 mL) was added under nitrogen to the mixture of 2-isopropenyl-3-methoxy-6- methyl-aniline and 2-isopropyl-3-methoxy-6-methyl-from Step 6 (560 mg) in Ethanol (5 mL) and Ethyl acetate (15 mL). The reaction mixture was stirred under a hydrogen atmosphere for 80 h, then the catalyst was filtered off through a celite pad, wash through with EtOAc / EtOH 3:1, and the iltrate evaporated to afford 2-isopropyl-3-methoxy-6-methyl-aniline (940 mg, 100% yield) as a dark brown residue.1H NMR (400 MHz, CD3OD) 56.93 (d, J = 8.3 Hz, 1H), 6.56 (d, J = 8.4 Hz, 1 H), 3.74 (s, 3H), 3.24 - 3.15 (m, 1H), 2.18 (s, 3H), 1.31 (d, J = 7.0 Hz, 6H). MS (ES+), m / z = 180.2 [M+HJ+.

[1220] 2-Bromo-N-(3-hydroxy-2-isopropyl-6-methylphenyl)thiazole-5-carboxamide

[1221] Thionyl chloride (3.40 eq, 1.3 mL, 17.8 mmol) was added to a mixture of 2-bromothiazole-5- carboxylic acid (0.917 eq, 1.00 g, 4.81 mmol) in DCM (25 mL) and DMF (0.1 mL). The reaction mixture was stirred at room temperature for 1 hour, evaporated to dryness and the residue (acid chloride) was slurried in 1 ,4-dioxane (5 mL) and MeCN (5 mL) and added to the mixture of Caesium carbonate (3.04 eq, 5.20 g, 16.0 mmol) and 2-isopropyl-3-methoxy-6-methyl-aniline (1.00 eq, 940 mg, 5.24 mmol) in 1 ,4-Dioxane (10 mL) and MeCN (10 mL) heated at 90 °C. The reaction mixture was stirred at 90 °C for 16h, cooled, quenched with water, diluted with EtOAc and washed with water (x2) and brine. The organic phase was dried over sodium sulfate, filtered and evaporated. The crude material was purified by column chromatography over silica (24 g cartridge) eluting with a gradient of EtOAc: isohexane (5% to 100%; v / v) to afford 2-chloro-N-(2-isopropyl-3- methoxy-6-methyl-phenyl)thiazole-5-carboxamide (120 mg, 0.369 mmol, 7% yield).1H NMR (400 MHz, CDCI3) 6 7.78 (d, J = 205.3 Hz, 1 H), 7.14 - 6.76 (m, 2H), 3.82 (d, J = 17.4 Hz, 3H), 3.34 (dp, J = 42.6, 7.1 Hz, 1 H), 2.22 - 2.05 (m, 3H), 1.32 - 1.10 (m, 6H). MS (ES-) m / z = 323 / 325 [M-H]-.

[1222] 3.3. TBDMS-protected phenol 2-halo-thiazole 5-carboxamide

[1223] 3-ftert-Butyl(dimethyl)silyl1oxy-2,6-dimethyl-aniline tert-Butyldimethylchlorosilane (2.00 eq, 17.32 g, 115 mmol) was added to a mixture of 3-amino- 2,4-dimethyl-phenol (1.00 eq, 7.88 g, 57.4 mmol) and Imidazole (4.03 eq, 15.75 g, 231 mmol) in anhydrous THF (200 mL) at r.t. The reaction mixture was stirred at r.t. for 3.5 h. The reaction mixture was concentrated under reduced pressure and the residue taken up in a mixture of EtOAc (250 mL) and H2O (250 mL). The layers were separated and the organic layer was washed with H2O (2 x 200mL) and brine (200 mL), before being dried over Na2SO4, filtered and the filtrates concentrated under reduced pressure to afford a brown oil which was purified by column chromatography over silica (330 g cartridge) eluting with a gradient of EtOAc (0% to 20%; v / v) in iso-Hexane [Note 4] to afford the desired product 3-[tert-butyl(dimethyl)silyl]oxy-2,6-dimethyl- aniline (15.80 g, 41.5 mmol, 72.20% yield) as a yellow oil. MS (ES+) m / z = 252.3 [M+HJ+. 1 H NMR (400 MHz, CDCI3) 5 6.77 (dt, J = 8.0, 0.8 Hz, 1 H), 6.24 (d, J = 8.1 Hz, 1 H), 3.57 (br s, 2H), 2.12 (d, J = 0.8 Hz, 3H), 2.06 (s, 3H), 1.02 (s, 9H), 0.20 (s, 6H).

[1224] General Method J: Synthesis of 2-halo-N-(3-((tert-butyldimethylsilyl)oxy)-2,6-disubstituted phenyl)thiazole-5-carboxamide via amide coupling

[1225] 3-[tert-Butyl(dimethyl)silyl]oxy-2,6-disubstituted-aniline (1 eq) was dissolved in MeCN or THF, 2- halothiazole-5-carboxylic acid (1-2 eq), DIPEA (2-3 eq) and 1-propanephosphonic anhydride, 50 wt% in EtOAc (1.5-4 eq) were added and the reaction mixture was stirred for 2-18h at 18-65 °C, then the reaction mixture was extracted between EtOAc and water, the organic layer dried over Na2SC>4, filtered and evaporated. The residue is used as such or purified by silica column cheomatography to afford the product.

[1226] 2-Bromo-N-f3-rtert-butyl(dimethyl)silyl1oxy-2,6-dimethyl-phenyl1thiazole-5-carboxamide

[1227] 3-[tert-Butyl(dimethyl)silyl]oxy-2,6-dimethyl-aniline (1.00 eq, 15.80 g, 41.5 mmol) was partially dissolved in MeCN (250 mL) at r.t. , to which 2-bromothiazole-5-carboxylic acid (1.50 eq, 12.94 g, 62.2 mmol), DIPEA (2.00 eq, 14 mL, 82.9 mmol) and 1-propanephosphonic anhydride, 50 wt% in EtOAc (1.50 eq, 37 mL, 62.2 mmol) were added sequentially. The reaction mixture was heated at r.t for 3.5 h. Additional DIPEA (1.02 eq, 7.3 mL, 42.1 mmol) and 1-propanephosphonic anhydride (0.306 eq, 7.3 mL, 12.7 mmol) were added and the reaction mixture was heated to 65 °C for 18 h. The reaction mixture was diluted with H2O (200 mL) and the volatiles removed under reduced pressure before being poured into a mixture of EtOAc (300 mL) and H2O (150 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with H2O (200 mL) and brine (200 mL), before being dried over Na2SO4, filtered and the filtrates concentrated under reduced pressure. The crude material was purified by column chromatography over silica (330 g cartridge) eluting with a gradient of EtOAc (0% to 20%; v / v) in iso-Hexane, to afford the title compound (13.48 g, 30.5 mmol, 73.63% yield) as a pale-yellow foamy solid. ES (MS+) m / z = 443.0 / 441.0 [M+H]+ and 441.1 / 439.1 [M-H]- , mono-Br splitting pattern.1H NMR (400 MHz, CDCI3) 5 8.05 (s, 1H), 7.23 (br s, 1 H), 6.96 (d, J = 8.3 Hz, 1H), 6.72 (d, J = 8.3 Hz, 1H), 2.18 (s, 3H), 2.12 (s, 3H), 1.01 (s, 9H), 0.20 (s, 6H).

[1228] The following example compounds were prepared similarly using Method J with the appropriately substituted thiazole carboxylic acid

[1229] 4. Phenol 2-amino-thiazole 5-carboxamide intermediates

[1230] 2-Amino-N-(3-hydroxy-2,6-dimethylphenyl)thiazole-5-carboxamide

[1231] Step 1: To a solution of 2-N-Boc-Amino-thiazole-5-carboxylic acid (23.10 g, 94.6 mmol) in THF (300 mL) was added 3-methoxy-2,6-dimethylaniline (13.00 g, 86.0 mmol), DIPEA (37 mL, 215 mmol) then 1-Propanephosphonic anhydride (102 mL, 172 mmol). The reaction mixture was stirred at 60°C overnight, then concentrated under reduced pressure, and redissolved in 2-MeTHF (450 mL) and 1,4-dioxane (50 mL). The organics were washed with water (500 mL) and brine (500 mL), separated, dried (Na2SO4), filtered and concentrated under reduced pressure to give a beige solid. The solid was suspended in 1,4-dioxane (150 mL), cone. HCI (150 mL) was added and the reaction mixture stirred overnight at room temperature. The reaction mixture was adjusted to pH 8 with 1M NaOH solution and solid NaOH pellets. The solution was filtered and the solids collected and dried in a vacuum oven overnight.to provide 2-amino-N-(3-methoxy-2,6-dimethyl- phenyl)thiazole-5-carboxamide (16.27 g, 58.6 mmol, 68.22% yield) as a beige solid.1H NMR (400 MHz, DMSO-d6) 5H 9.39 (s, 1H), 7.83 (s, 1 H), 7.55 (d, J = 2.6 Hz, 2H), 7.04 (d, J = 8.3 Hz, 1 H), 6.82 (d, J = 8.4 Hz, 1H), 3.77 (s, 3H), 2.09 (s, 3H), 1.99 (s, 3H). MS (ES+) m / z = 278.0 [M+H+], Step 2: Boron tribromide (1.0 mL, 10.8 mmol, 3.00 eq) was carefully added to a mixture of 2- amino-N-(3-methoxy-2,6-dimethyl-phenyl)thiazole-5-carboxamide (1.00 g, 3.61 mmol, 1.00 eq) and DCM (35 mL) at 0 °C. The mixture was stirred at 40 °C for 2 h before it was poor into cold water (50 mL) and basified with 2 M NaOH. The aqueous phase (containing the product) was washed with DCM (2 x 100 mL). The pH of the aqueous phase was adjusted to ~8 by careful addition of cone. HCI followed by sat. NaHCO3 and then extracted with EtOAc (3 * 100 mL). The combined organic phases were dried over MgSO4, filtered and the solvent was removed under reduced pressure to afford 2-amino-N-(3-hydroxy-2,6-dimethyl-phenyl)thiazole-5-carboxamide (911 mg, 3.46 mmol, 96%) as a beige solid.1H NMR (300 MHz, DMSO-d6) 5 9.32 (s, 1 H), 9.13 (s, 1H), 7.83 (s, 1 H), 7.53 (br s, 2H), 6.87 (d, J = 8.2 Hz, 1 H), 6.67 (d, J = 8.2 Hz, 1 H), 2.05 (s, 3H), 1.97 (s, 3H).

[1232] MS (ES+) m / z 264 [M+HJ+.

[1233] 2-Amino-N-(3-hvdroxy-2,6-dimethylphenyl)-4-methylthiazole-5-carboxamide

[1234] Step 1: 1-Propanephosphonic anhydride (50% in EtOAc, 1.75 ml, 2.98 mmol) was added dropwise to a solution of 3-methoxy-2,6-dimethylaniline (300 mg, 1.98 mmol), N-Boc-amino-4- methylthiazole-5-carboxylic acid (564 mg, 2.18 mmol), and DI PEA (0.76 ml, 4.36 mmol) in anhydrous THF (20 ml). The reaction mixture was stirred at 70 °C under nitrogen overnight, quenched with water, extracted with EtOAc, the organic phase washed with 0.5 M aq sodium hydroxide then brine, dried (MgSO4), filtered and concentrated. The crude product was purified using column chromatography over silica, eluting with 10-100% EtOAc / PE, to give tert-butyl N-[5- [(3-methoxy-2,6-dimethyl-phenyl)carbamoyl]-4-methyl-thiazol-2-yl]carbamate (391 mg, 50% yield) as an off-white solid.1H NMR (300 MHz, DMSO-d6) 5 11.71 (s, 1H), 9.27 (s, 1H), 7.05 (d, 1H, J = 8.4 Hz), 6.83 (d, 1 H, J = 8.4 Hz), 3.77 (s, 3H), 2.48 (s, 3H), 2.10 (s, 3H), 2.01 (s, 3H), 1.49 (s, 9H). MS (ES+) m / z 392.3 [M+HJ+.

[1235] Step 2: Boron tribromide solution (1 M in DCM, 2.87 ml, 2.87 mmol) was added drop-wise to a solution of tert-butyl N-[5-[(3-methoxy-2,6-dimethyl-phenyl)carbamoyl]-4-methyl-thiazol-2- yl]carbamate (375 mg, 0.96 mmol) in anhydrous DCM (10 ml) at 0 °C under nitrogen, with stirring for 4h at room temperature. The reaction mixture was then cooled to 0 °C, quenched with 1:1 triethylamine:ethanol (10 equiv., 2.6 ml), partitioned between DCM and water, the organic extracts washed with brine, dried (Na2SO4), filtered and concentrated. The crude product was purified by column chromatography over silica, eluting with 0-20% methanol / DCM, to give the title compound (193 mg, 73% yield) as an off-white solid.1H NMR (300 MHz, DMSO-d6) 5 9.12 (s, 1H), 8.70 (s, 1H), 7.40 (s, 2H), 6.85 (d, 1 H, J = 8.1 Hz), 6.66 (d, 1H, J = 8.1 Hz), 2.37 (s, 3H), 2.03 (s, 3H), 1.96 (s, 3H). MS (ES+) m / z 278.1 [M+HJ+.

[1236] 2-Amino-4-chloro-N-(3-hvdroxy-2,6-dimethylphenyl)thiazole-5-carboxamide

[1237] Step 1: T3P (50% in ethyl acetate, 1.11 ml, 1.88 mmol) was added drop-wise to a solution of 3- methoxy-2,6-dimethylaniline (190 mg, 1.26 mmol), 2-(tert-butoxycarbonylamino)-4-chloro-thiazole- 5-carboxyhc acid (420 mg, 1.50 mmol), and DIPEA (0.48 ml, 2.76 mmol) in anhydrous THF (18 ml). The reaction mixture was heated to 70 °C, with stirring under nitrogen overnight, then quenched with water and extracted with diethyl ether, and the organic phase was washed with brine, dried (MgSO4), filtered through a short pad of silica and concentrated. The crude product was purified by column chromatography over silica, eluting with 5-80% EtOAc / PE, to give tert-butyl N-[4-chloro-5- [(3-methoxy-2,6-dimethyl-phenyl)carbamoyl]thiazol-2-yl]carbamate (331 mg, 64% yield) as a white solid.1H NMR (300 MHz, DMSO-d6) 5 9.03 (br, 1 H), 8.04 (s, 1 H), 7.06 (d, 1 H, J = 8.4 Hz), 6.76 (d, 1 H, J = 8.4 Hz), 3.81 (s, 3H), 2.23 (s, 3H), 2.16 (s, 3H), 1.56 (s, 9H). MS (ES+) m / z 412.2 [M+HJ+. Step 2: Boron tribromide solution (1 M in DCM, 2.33 ml, 2.33 mmol) was added drop-wise to a solution of product from step (320 mg, 0.78 mmol) in anhydrous DCM (7 ml) at 0 °C under nitrogen, with stirring for 4h at room temperature. The reaction mixture was cooled to 0 °C, quenched with 1:1 triethylamine:ethanol (2 ml), separated between DCM and water, the organic extracts washed with brine, dried Na2SO4), filtered and concentrated. The crude product was purified by column chromatography over silica, eluting with 0-15% methanol / DCM, to give the title compound (114 mg, 49% yield) as an off-white solid.1H NMR (300 MHz, DMSO-d6) 5 9.17 (s, 1 H), 8.90 (s, 1 H), 7.91 (s, 2H), 6.86 (d, 1 H, J = 8.2 Hz), 6.67 (d, 1 H, J = 8.2 Hz), 2.05 (s, 3H), 1.97 (s, 3H). MS (ES+) m / z 298.1 [M+HJ+.

[1238] 2-Amino-4-fluoro-N-(3-hvdroxy-2,6-dimethylphenyl)thiazole-5-carboxamide

[1239] Step 1 : CsF (17.3 g, 114.2 mmol) was added to a solution of tert-butyl N-(4-chloro-5-formyl-thiazol- 2-yl)carbamate (3.0 g, 11.4 mmol) in DMSO (35 ml). The reaction mixture was stirred at 132 °C for 2 days, then diluted with EtOAc, filtered through a short pad of dicalite, partitioned between EtOAc and aqueous NaHCOs, the organic extracts washed with brine, dried (MgSO4), filtered and concentrated. The crude product was purified using reverse-phase column chromatography over C-18 silica, eluting with 5-95% MeCN / water, to give tert-butyl N-(4-fluoro-5-formyl-thiazol-2- yl)carbamate (400 mg, 14% yield) as an off-white solid.1H NMR (300 MHz, DMSO-cftS) 5 12.58 (s, 1 H), 9.83 (s, 1 H), 1.50 (s, 9H).19F NMR (282 MHz, DMSO-d6) 5 -97.69. MS (ES-) m / z 245.0 [M- H]-.

[1240] Step 2: 2-Methyl-2-butene (0.69 ml, 6.5 mmol) and sodium phosphate monobasic dihydrate (507 mg, 3.25 mmol) were added to a solution of tert-butyl N-(4-fluoro-5-formyl-thiazol-2-yl)carbamate (200 mg, 0.81 mmol) in THF:tert-butanol:water (5:5:2, 12 ml) with stirring at RT for 30 minutes. Sodium chlorite (25% in water, 0.49 ml, 1.62 mmol) was added with stirring for 3 hours, followed by additional sodium chlorite (25% in water, 0.12 ml, 0.41 mmol) with continued stirring overnight The reaction was quenched with saturated aqueous NH4CI, extracted with EtOAc, the organic extracts washed with brine, dried (MgSOt), filtered and concentrated to give 2-(tert-butoxycarbonylamino)- 4-fluoro-thiazole-5-carboxylic acid (220 mg, 100% yield) as a white solid.1H NMR (300 MHz, DMSO-d6) 5 13.07 (br, 1H), 12.25 (s, 1 H), 1.49 (s, 9H).19F NMR (282 MHz, DMSO-d6) 5 -95.22. MS (ES-) m / z 261.0 [M-H]-.

[1241] Step 4: 1-Propanephosphonic anhydride (50% in ethyl acetate, 1.23 ml, 2.08 mmol) was added drop-wise at RT to a solution of 3-methoxy-2,6-dimethylaniline (210 mg, 1.39 mmol), 2-(tert- butoxycarbonylamino)-4-fluoro-thiazole-5-carboxylic acid (401 mg, 1.53 mmol), and DIPEA (0.53 ml, 3.06 mmol) in anhydrous THF (15 ml). The reaction mixture was stirred at 70 °C under nitrogen overnight, then quenched with water, extracted with EtOAc, the organic phase washed with 0.5 M aq NaOH then brine, dried (MgSO4), filtered and concentrated. The crude product was purified by column chromatography over silica, eluting with 10-60% EtOAc / PE, to give tert-butyl N-[4-fluoro-5- [(3-methoxy-2,6-dimethyl-phenyl) carbamoyl]thiazol-2-yl]carbamate (229 mg, 42% yield) as an off- white solid.1H NMR (300 MHz, DMSO-d6) 5 12.15 (s, 1H), 9.16 (s, 1H), 7.05 (d, 1 H, J = 8.4 Hz), 6.84 (d, 1H, J = 8.4 Hz), 3.77 (s, 3H), 2.10 (s, 3H), 2.00 (s, 3H), 1.49 (s, 9H).19F NMR (282 MHz, DMSO-d6) 5 -98.24. MS (ES+) m / z 396.2 [M+HJ+.

[1242] Step 3: Boron tribromide solution (1 M in DCM, 1.7 ml, 1.7 mmol) was added drop-wise to a solution of tert-butyl N-[4-fluoro-5-[(3-methoxy-2,6-dimethyl-phenyl) carbamoyl]thiazol-2- yl]carbamate (220 mg, 0.56 mmol) in anhydrous DCM (6 ml) at 0 °C under nitrogen, with stirring for 4h at room temperature. The reaction mixture was then cooled to 0 °C, quenched with 1 :1 triethylamine:ethanol (10 equiv., 1.6 ml), partitioned between DCM and water, the organic extracts washed with brine, dried (Na2SO4), filtered and concentrated. The crude product was purified by column chromatography over silica, eluting with 0-15% methanol / DCM, to give the title compound (92 mg, 59% yield) as a white solid.1H NMR (300 MHz, DMSO-d6) 5 9.12 (s, 1 H), 8.71 (d, 1H, J = 2.9 Hz), 8.05 (s, 2H), 6.85 (d, 1 H, J = 8.2 Hz), 6.66 (d, 1H, J = 8.1 Hz), 2.03 (s, 3H), 1.95 (s, 3H).19F NMR (282 MHz, DMSO-d6) 5 -95.35. MS (ES+) m / z 282.1 [M+HJ+.

[1243] 5. Syntheses from phenol 2-halo-thiazole 5-carboxamide and heteroaryl amines

[1244] 5.1. Buchwald coupling using unprotected phenol 2-halo-thiazole 5-carboxamide

[1245] General Method K: Palladium catalysed coupling of 2-bromo- / V-(3-hydroxy-2,6-dimethyl- phenyl)thiazole-5-carboxamide with heteroaryl amines To a mixture of 2-bromo- / V-(3-hydroxy-2,6-dimethyl-phenyl)thiazole-5-carboxamide (1 eq), substituted heteroaryl amine (1 - 3 eq), XantPhos (0.2-0.3 eq) and CS2CO3 (1-5 eq) in 1 ,4- dioxane:H2O (4-10:1) or in dioxane / water / MeCN or sodium tert-butoxide (3 eq.) in dioxane was flushed with nitrogen before the addition of Pd2dba3 ( 0.1 -0.2 eq). The mixture was heated to 90- 100°C for 16-18 h. The reaction mixture was then cooled, optionally filtered through a pad of dicalite or extracted between EtOAc and water, and the organic fraction concentrated. The crude material was purified by either normal phase chromatography (SiC>2) using a gradient of EtOAc: PE and / or MeOH:DCM and / or MeOH:EtOAc, reverse phase chromatography (Cis) using a gradient of MeCN:H2O and / or by preparative HPLC-MS using a gradient of high or low pH aq. MeCN. Optionally, the product was treated with HOI (4M in dioxane) to afford the HOI salt.

[1246] 2-((4-Chloro-1-ethyl-1 H-indazol-3-yl)amino)-N-(3-hydroxy-2,6-dimethylphenyl)thiazole-5- carboxamide

[1247] 2-Bromo-N-(3-hydroxy-2,6-dimethyl-phenyl)thiazole-5-carboxamide (150 mg, 0.458 mmol, 1.00 eq) was taken up in dioxane (2.5 ml) and water (0.5 ml) was added. The mixture was purged with nitrogen for 5 minutes, during which time 4-chloro-1-ethyl-1 H-indazol-3-amine (268 mg, 1.37 mmol, 3.00 eq), cesium carbonate (449 mg, 1.37 mmol, 3.00 eq) and XantPhos (52 mg, 0.0900 mmol, 0.200 eq) were added. After further 5 minutes stirring Pd2dba3 (41 mg, 0.0450 mmol, 0.100 eq) was added. The reaction mixture was heated to 100 °C and stirred under a positive flow of nitrogen for 16 hours, then allowed to cool to RT and filtered through celite. The filtrate was adsorbed onto isolute NH and purified on silica, eluting with MeOH:DCM (0-15%), which yielded a brown oil. This was dissolved in DMSO and purified by reverse phase chromatography (13 g C18 cartridge) and then by preparative HPLC (0-100% H2O:CH3CN) which yielded the title product (4.9 mg, 2.4%) as a pale yellow powder.1H NMR (300 MHz, MeOD) 5 8.14 (s, 1 H), 7.53 - 7.49 (m, 1 H), 7.41 (dd, J = 8.6, 7.3 Hz, 2H), 7.16 (dd, J = 7.3, 0.8 Hz, 1 H), 6.95 (d, J = 8.2 Hz, 1 H), 6.72 (d, J = 8.2 Hz, 1 H), 4.44 (q, J = 7.2 Hz, 2H), 1.55 (t, J = 7.2 Hz, 3H). MS (ES+) m / z 442.3 / 444.3, Cl isotope pattern (M+H)+.

[1248] The following example compounds were prepared similarly using Method K with appropriately substituted heteroaromatic amines.

[1249] N-(3-Hydroxy-2,6-dimethylphenyl)-2-((6-hydroxy-3-methylpyridin-2-yl)amino)thiazole-5- carboxamide (BAA-023)

[1250] 2-bromo-N-(3-hydroxy-2,6-dimethyl-phenyl)thiazole-5-carboxamide (80 mg, 0.244 mmol, 1.00 eq), tris(dibenzylideneacetone)dipalladium(0) (34 mg, 0.0367 mmol, 0.150 eq), cesium carbonate (168 mg, 0.513 mmol, 2.10 eq) and a solution of 6-(1-cyclopropylethoxy)-3-methyl-pyridin-2-amine (0.049 mL, 0.293 mmol, 1.20 eq) in water and acetonitrile (10 mL), and 1 ,4-dioxane (8 mL) was degassed under nitrogen. Xantphos (35 mg, 0.0611 mmol, 0.250 eq) was added and the reaction degassed again, then heated to 90 °C for 18 h. The reaction was partitioned between EtOAc and water. The organic phase was concentrated in vacuo. Column chromatography (DCM:methanol) followed by reverse phase column chromatography (wateracetonitrile) gave a mixture of 2-[[6-(1- cyclopropylethoxy)-3-methyl-2-pyridyl]amino]-N-(3-hydroxy-2,6-dimethyl-phenyl)thiazole-5- carboxamide and N-(3-hydroxy-2,6-dimethyl-phenyl)-2-[(6-hydroxy-3-methyl-2- pyridyl)amino]thiazole-5-carboxamide. HCI in dioxane was added to the mixture, heated to remove dioxane, to afford N-(3-hydroxy-2,6-dimethyl-phenyl)-2-[(6-hydroxy-3-methyl-2- pyridyl)amino]thiazole-5-carboxamide;hydrochloride (14 mg, 0.0337 mmol, 14%).1H NMR (300 MHz, MeOD) 5 8.36 (s, 1 H), 7.73 (d, J = 8.2 Hz, 1 H), 6.94 (d, J = 8.3 Hz, 1 H), 6.71 (d, J = 8.2 Hz, 1 H), 6.53 (d, J = 8.2 Hz, 1 H), 2.35 (s, 3H), 2.17 (s, 3H), 2.12 (s, 3H). MS (ES+) m / z = 371 [M+HJ+.

[1251] 2-((6-(1-Cvclopropylethoxy)pyridin-2-yl)amino)-N-(3-hvdroxy-2,6-dimethylphenyl)thiazole-5- carboxamide (BAA-021)

[1252] 2-Bromo-N-(3-hydroxy-2,6-dimethyl-phenyl)thiazole-5-carboxamide (90 mg, 0.275 mmol, 1.00 eq) Pd2dba3 (38 mg, 0.0413 mmol, 0.150 eq), cesium carbonate (189 mg, 0.578 mmol, 2.10 eq) and a solution of 6-(1-cyclopropylethoxy)pyridin-2-amine (0.051 mL, 0.330 mmol, 1.20 eq) in water and acetonitrile (2:1; 10 mL) and 1,4-dioxane (8 mL) was degassed under nitrogen. Xantphos (40 mg, 0.0688 mmol, 0.250 eq) was added and the reaction degassed again, then heated to 90 °C for 18 h. The reaction was partitioned between EtOAc and water, the organic phase was concentrated in vacuo. Column chromatography (CH2CI2: methanol) followed by reverse phase column chromatography (water: aceto nitrile) gave the title compound (5.4 mg, 0.0127 mmol, 4.6%).1H NMR (300 MHz, MeOD) 5 8.13 (s, 1H), 7.59 (t, J = 7.9 Hz, 1H), 6.97 - 6.88 (m, 1H), 6.69 (d, J = 8.2 Hz, 1H), 6.55 (dd, J = 7.8, 0.7 Hz, 1H), 6.33 (dd, J = 8.0, 0.7 Hz, 1 H), 5.03 (dq, J = 8.0, 6.1 Hz, 1H), 2.18 (s, 3H), 2.13 (s, 3H), 1.44 (d, J = Q.2 Hz, 3H), 1.20 - 1.04 (m, 1H), 0.61 - 0.37 (m, 4H). MS (ES+) m / z = 425 [M+HJ+.

[1253] N-(3-Hydroxy-2,6-dimethylphenyl)-2-((6-hydroxypyridin-2-yl)amino)thiazole-5-carboxamide (BAA-

[1254] 2-[[6-(1-Cyclopropylethoxy)-2-pyridyl]amino]-N-(3-hydroxy-2,6-dimethyl-phenyl)thiazole-5- carboxamide was treated with HCI in dioxane, then the reaction mixture was heated under a stream of nitrogen to remove dioxane, to afford the title compound (HCI salt; 18.6 mg, 0.052 mmol, 92%).1H NMR (300 MHz, MeOD) 5 8.33 (d, J = 0.8 Hz, 1H), 7.82 (t, J = 8.0 Hz, 1 H), 6.94 (d, J = 8.2 Hz, 1H), 6.72 (dd, J = 8.1 , 3.2 Hz, 2H), 6.54 (d, J = 8.1 Hz, 1 H), 2.17 (s, 3H), 2.12 (s, 3H)...

Claims

CLAIMS1. A compound of the following formula:or a pharmaceutically acceptable salt or solvate thereof; wherein:Y is =N- or =C(R1)-;R1is H, F, Cl, or Me;Ring A is:wherein / indicates the point of attachment to formula (I);R2is Br, Me, or i-Pr;R3is F, or Me;R4is H, Me, or Et;Ring B is a nitrogen containing heterocyclyl; wherein Ring B may be optionally substituted on carbon by one or more R5; and wherein if said nitrogen containing heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R6;R5is selected from one or more groups (i) to (xxv):(i) halo;(ii) hydroxy;(iii) cyano;(iv) amino;(v) Ci-ealkyl; wherein said Ci-ealkyl may be optionally substituted by one or more halo, hydroxy, Ci-ealkoxy, N,N-(Ci-6alkyl)2amino, N-(Ci-6alkyl)aminocarbonyl, N,N-(Ci-6alkyl)2aminocarbonyl optionally substituted by hydroxy, N-(Ci-6alkyl)-N-(cyclopropyl)aminocarbonyl, N-(Ci-6alkyl)-N-(cyclobutyl)aminocarbonyl, N-(Ci-6alkanoyl)-N-(Ci-6alkyl)amino, or heterocyclylcarbonyl;(vi) Ci-ealkoxy; wherein said Ci^alkoxy may be optionally substituted by one or more halo, cyclopropyl, cyclopentyl, phenyl optionally substituted by halo, or heterocyclyl;(vii) Ci-ealkanoylamino; wherein said Ci-ealkanoylamino may be optionally substituted by one or more cyclopropyl;(viii) Ci-ealkylsulphonylamino;(ix) N-(Ci-6alkyl)amino; wherein said Ci-ealkylamino may be optionally substituted by one or more halo or methoxy;(x) N,N-(Ci-6alkyl)2amino;(xi) N-(Ci-6alkyl)aminocarbonyl; wherein said N-(Ci-6alkyl)aminocarbonyl may be optionally substituted by one or more hydroxy or fluoro;(xii) N,N-(Ci-6alkyl)2aminocarbonyl;(xiii) N-(Ci-6alkyl)-N-(cyclopropyl)aminocarbonyl;(xiv) Ci-6alkylS(O)awherein a is 0-2;(xv) cyclopropylC(O)NH-; wherein said cyclopropyl may be optionally substituted by one or more halo;(xvi) cyclopentylaminocarbonyl;(xvii) bicyclo[1 , 1 , 1]pentanylaminocarbonyl;(xviii) cyclohexylamino;(xix) phenoxy; wherein said phenyl may be optionally substituted by one or more halo;(xx) phenyS(O)2NH-; wherein said phenyl may be optionally substituted by one or more methyl;(xxi) heterocyclyl;(xxii) heterocyclylamino;(xxiii) heterocyclyloxy;(xxiv) heterocyclylcarbonyl;(xxv) heterocyclylaminocarbonyl; wherein any heterocyclyl in R5may be optionally substituted on carbon by one or more halo, cyano, methyl, trifluoromethyl, or methoxymethyl; and wherein in R5, if any heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted on nitrogen by methyl, isopropyl, cyclopropyl, or hydroxyethyl;R6is Ci-ealkyl or phenyl; wherein said Ci-ealkyl may be optionally substituted by one or more halo, hydroxy, methoxy, N-(Ci-6alkyl)-N-(cyclopropyl)aminocarbonyl, N-(Ci-6alkyl)-N-(cyclobutyl)aminocarbonyl, N,N-(Ci-6alkyl)2aminocarbonyl, or heterocyclylcarbonyl optionally substituted by isopropyl or CF3.

2. A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as claimed in claim 1 with the proviso that the disclosed compounds in PCT / EP2024 / 056305 and PCT / EP2024 / 05620 are individually disclaimed.

3. A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as claimed in claim 1 or 2 wherein Y is =C(R1)-.

4. A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as claimed in claim 1 or 2 wherein Y is =N-.

5. A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as claimed in any one of claims 1-3 wherein R1is H, F, or Me.

6. A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as claimed in any one of claims 1-5 wherein Ring A is:wherein / indicates the point of attachment to formula (I).

7. A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as claimed in claim 6 wherein R2is Me.

8. A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as claimed in any one of claims 1-10 wherein Ring B is pyrazolyl; wherein said pyrazolyl may be optionally substituted on carbon by one or more R5; and wherein if said pyrazolyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R6.

9. A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as claimed in any one of claims 1-10 wherein Ring B is pyridyl; wherein said pyridyl may be optionally substituted on carbon by one or more R5.

10. A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as claimed in any one of claims 1-10 wherein Ring B is pyridyl, pyrimidinyl, triazinyl, indazolyl, pyrazolyl, pyrazolo[4,3-c]pyridinyl, 6,7-dihydro-5H-cyclopenta[b]pyridinyl, or 5,6,7,8-tetrahydroquinolinyl; wherein said ring may be optionally substituted on carbon by one or more R5; and wherein if said ring contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R6.

11. A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as claimed in any one of claims 1-10 wherein R5is selected from one or more groups (i) to (ix):(i) halo;(ii) amino;(iii) Ci-ealkyl; wherein said Ci-ealkyl may be optionally substituted by one or more halo, hydroxy, Ci-ealkoxy, N,N-(Ci-6alkyl)2amino, N-(Ci-6alkyl)aminocarbonyl, N,N- (Ci-6alkyl)2aminocarbonyl optionally substituted by hydroxy, N-(Ci-ealkyl)-N- (cyclopropyl)aminocarbonyl, N-(Ci-6alkyl)-N-(cyclobutyl)aminocarbonyl, N- (Ci-6alkanoyl)-N-(Ci-6alkyl)amino, or heterocyclylcarbonyl;(iv) Ci-ealkoxy; wherein said Ci-ealkoxy may be optionally substituted by one or more halo, cyclopropyl, cyclopentyl, phenyl optionally substituted by halo, or heterocyclyl;(v) N-(Ci-6alkyl)amino; wherein said Ci-ealkylamino may be optionally substituted by one or more halo or methoxy;(vi) N,N-(Ci-6alkyl)2amino;(vii) heterocyclyl;(viii) heterocyclyloxy;(ix) cyclohexylamino;(x) heterocyclylamino; wherein any heterocyclyl in R5may be optionally substituted on carbon by one or more halo, cyano, methyl, trifluoromethyl, or methoxymethyl; and wherein in R5, if any heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted on nitrogen by methyl, isopropyl, cyclopropyl, or hydroxyethyl.

12. A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as claimed in any one of claims 1-11 wherein R5is selected from one or more groups (i) to (xi):(i) Ci-ealkoxy; wherein said Ci-ealkoxy may be optionally substituted by one or more halo, cyclopropyl, cyclopentyl, phenyl optionally substituted by halo, or heterocyclyl;(ii) Ci-ealkanoylamino; wherein said Ci-ealkanoylamino may be optionally substituted by one or more cyclopropyl;(iii) Ci-ealkylsulphonylamino;(iv) N-(Ci-6alkyl)aminocarbonyl; wherein said N-(Ci-6alkyl)aminocarbonyl may be optionally substituted by one or more hydroxy or fluoro;(v) N,N-(Ci-6alkyl)2aminocarbonyl;(vi) N-(Ci-6alkyl)-N-(cyclopropyl)aminocarbonyl;(vii) cyclopropylC(O)NH-; wherein said cyclopropyl may be optionally substituted by one or more halo;(viii) cyclopentylaminocarbonyl;(ix) bicyclo[1 , 1 , 1]pentanylaminocarbonyl;(x) heterocyclylcarbonyl;(xi) heterocyclylaminocarbonyl;wherein any heterocyclyl in R5may be optionally substituted on carbon by one or more halo, cyano, methyl, trifluoromethyl, or methoxymethyl; and wherein in R5, if any heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted on nitrogen by methyl, isopropyl, cyclopropyl, or hydroxyethyl.

13. A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as claimed in any one of claims 1-8 wherein R6is Ci-ealkyl; wherein said Ci-ealkyl may be optionally substituted by one or more N,N-(Ci-6alkyl)2aminocarbonyl, or heterocyclylcarbonyl optionally substituted by CF3.

14. A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as claimed in claim 1 which is a compound of formula (IA):wherein:R1is H or Me;R5’ is selected from the following groups of R5:(i) halo;(ii) amino;(iii) Ci-ealkyl; wherein said Ci-ealkyl may be optionally substituted by one or more halo, hydroxy, Ci-ealkoxy, N,N-(Ci-6alkyl)2amino, N-(Ci-6alkyl)aminocarbonyl, N,N- (Ci-6alkyl)2aminocarbonyl optionally substituted by hydroxy, N-(Ci-ealkyl)-N- (cyclopropyl)aminocarbonyl, N-(Ci-6alkyl)-N-(cyclobutyl)aminocarbonyl, N- (Ci-6alkanoyl)-N-(Ci-6alkyl)amino, or heterocyclylcarbonyl;(iv) Ci-ealkoxy; wherein said Ci-ealkoxy may be optionally substituted by one or more halo, cyclopropyl, cyclopentyl, phenyl optionally substituted by halo, or heterocyclyl;(v) N-(Ci-6alkyl)amino; wherein said Ci-ealkylamino may be optionally substituted by one or more halo or methoxy;(vi) N,N-(Ci-6alkyl)2amino;(vii) cyclohexylamino;(viii) heterocyclyl;(ix) heterocyclyloxy;(x) heterocyclylamino;R5” is selected from the following groups of R5:(i) Ci-ealkoxy; wherein said Ci-ealkoxy may be optionally substituted by one or more halo, cyclopropyl, cyclopentyl, phenyl optionally substituted by halo, or heterocyclyl;(ii) Ci-ealkanoylamino; wherein said Ci-ealkanoylamino may be optionally substituted by one or more cyclopropyl;(iii) Ci-ealkylsulphonylamino;(iv) N-(Ci-6alkyl)aminocarbonyl; wherein said N-(Ci-6alkyl)aminocarbonyl may be optionally substituted by one or more hydroxy or fluoro;(v) N,N-(Ci-6alkyl)2aminocarbonyl;(vi) N-(Ci-6alkyl)-N-(cyclopropyl)aminocarbonyl;(vii) cyclopropylC(O)NH-; wherein said cyclopropyl may be optionally substituted by one or more halo;(viii) cyclopentylaminocarbonyl;(ix) bicyclo[1 , 1 , 1]pentanylaminocarbonyl;(x) heterocyclyl;(xi) heterocyclylcarbonyl;(xii) heterocyclylaminocarbonyl; wherein any heterocyclyl in R5’ or R5” may be optionally substituted on carbon by one or more halo, cyano, methyl, trifluoromethyl, or methoxy methyl; and wherein in R5’ or R5”, if any heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted on nitrogen by methyl, isopropyl, cyclopropyl, or hydroxyethyl.

15. A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as claimed in claim 1 which is a compound of formula (IB):wherein:R1is H or Me;R5” is selected from the following groups of R5:(i) N-(Ci-6alkyl)aminocarbonyl; wherein said N-(Ci-6alkyl)aminocarbonyl may be optionally substituted by one or more hydroxy or fluoro;(ii) N,N-(Ci-6alkyl)2aminocarbonyl;(iii) N-(Ci-6alkyl)-N-(cyclopropyl)aminocarbonyl;(iv) cyclopentylaminocarbonyl;bicyclo[1 ,1 ,1]pentanylaminocarbonyl; heterocyclylcarbonyl; heterocyclylaminocarbonyl; wherein any heterocyclyl in R5’ or R5” may be optionally substituted on carbon by one or more halo, cyano, methyl, trifluoromethyl, or methoxy methyl; and wherein in R5’ or R5”, if any heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted on nitrogen by methyl, isopropyl, cyclopropyl, or hydroxyethyl.

16. A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as claimed in claim 1 which is a compound of formula:wherein:R1is H or Me;R5” is selected from the following groups of R5:N-(Ci-6alkyl)aminocarbonyl; wherein said N-(Ci-6alkyl)aminocarbonyl may be optionally substituted by one or more hydroxy or fluoro;N,N-(Ci-6alkyl)2aminocarbonyl;N-(Ci-6alkyl)-N-(cyclopropyl)aminocarbonyl;(iv) cyclopentylaminocarbonyl;(v) bicyclo[1 ,1 ,1]pentanylaminocarbonyl;(vi) heterocyclylcarbonyl;(vii) heterocyclylaminocarbonyl; wherein any heterocyclyl in R5’ or R5” may be optionally substituted on carbon by one or more halo, cyano, methyl, trifluoromethyl, or methoxy methyl; and wherein in R5’ or R5”, if any heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted on nitrogen by methyl, isopropyl, cyclopropyl, or hydroxyethyl.

17. A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as claimed in claim 1 which is a compound of formula (IC):(IC) wherein:R1is H or Me;R5’ is selected from the following groups of R5:(i) halo;(ii) Ci-ealkyl; wherein said Ci-ealkyl may be optionally substituted by one or more halo, hydroxy, Ci-ealkoxy, N,N-(Ci-6alkyl)2amino, N-(Ci-6alkyl)aminocarbonyl, N,N- (Ci-6alkyl)2aminocarbonyl optionally substituted by hydroxy, N-(Ci-ealkyl)-N- (cyclopropyl)aminocarbonyl, N-(Ci-6alkyl)-N-(cyclobutyl)aminocarbonyl, N- (Ci-6alkanoyl)-N-(Ci-6alkyl)amino, or heterocyclylcarbonyl; wherein any heterocyclyl in R5’ may be optionally substituted on carbon by one or more halo, cyano, methyl, trifluoromethyl, or methoxymethyl; and wherein if any heterocyclyl in R5’ contains an -NH- moiety that nitrogen may be optionally substituted on nitrogen by methyl, isopropyl, cyclopropyl, or hydroxyethyl;R6is methyl; wherein said methyl may be optionally substituted by one or more N-(Ci-6alkyl)-N-(cyclopropyl)aminocarbonyl, N-(Ci-6alkyl)-N-(cyclobutyl)aminocarbonyl, N,N-(Ci-6alkyl)2aminocarbonyl, or heterocyclylcarbonyl optionally substituted by isopropyl or CF3.

18. A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as claimed in claim 1 selected from:N-(3-hydroxy-2,6-dimethylphenyl)-2-((1-methyl-4-(trifluoromethyl)-1 H-indazol-3-yl)amino)thiazole- 5-carboxamide;N-(3-hydroxy-2,6-dimethylphenyl)-2-((6-(4-(2-hydroxyethyl)piperazin-1-yl)-3-methylpyridin-2- yl)amino)thiazole-5-carboxamide;2-((6-acetamidopyrimidin-4-yl)amino)-N-(3-hydroxy-2,6-dimethylphenyl)thiazole-5-carboxamide; N-(3-hydroxy-2,6-dimethylphenyl)-5-((4-methyl-1-(2-oxo-2-(2-(trifluoromethyl)pyrrolidin-1-yl)ethyl)- 1 H-pyrazol-3-yl)amino)-1,3,4-thiadiazole-2-carboxamide;N-(3-hydroxy-2,6-dimethylphenyl)-2-((3-methyl-1-phenyl-1 H-pyrazol-5-yl)amino)thiazole-5- carboxamide;2-((4-cyano-1-methyl-1 H-indazol-3-yl)amino)-N-(3-hydroxy-2,6-dimethylphenyl)thiazole-5- carboxamide;(S)-N-(3-hydroxy-2,6-dimethylphenyl)-2-((3-methyl-6-((tetrahydrofuran-3-yl)oxy)pyridin-2- yl)amino)thiazole-5-carboxamide;N-(3-hydroxy-2,6-dimethylphenyl)-2-((3-methyl-6-(3-(4-methylpiperazin-1-yl)propoxy)pyridin-2- yl)amino)thiazole-5-carboxamide;2-((4-chloro-1-ethyl-1 H-indazol-3-yl)amino)-N-(3-hydroxy-2,6-dimethylphenyl)thiazole-5- carboxamide;2-((4-bromo-1-methyl-1H-indazol-3-yl)amino)-N-(3-hydroxy-2,6-dimethylphenyl)thiazole-5- carboxamide;5-((4-chloro-1-(2-(diethylamino)-2-oxoethyl)-1H-pyrazol-3-yl)amino)-N-(3-hydroxy-2,6- dimethylphenyl)-1,3,4-thiadiazole-2-carboxamide;(S)-N-(3-hydroxy-2,6-dimethylphenyl)-2-((4-methyl-1-(2-oxo-2-(2-(trifluoromethyl)pyrrolidin-1- yl)ethyl)-1H-pyrazol-3-yl)amino)thiazole-5-carboxamide;(R)-N-(3- hydroxy-2, 6-dimethylphenyl)-2-((4-methyl-1-(2-oxo-2-(2-(trifluoromethyl)pyrrolidin-1- yl)ethyl)-1H-pyrazol-3-yl)amino)thiazole-5-carboxamide;2-((3-chloro-6-isopropoxypyridin-2-yl)amino)-N-(3-hydroxy-2,6-dimethylphenyl)thiazole-5- carboxamide;2-((6-(tert-butylcarbamoyl)-3-methylpyridin-2-yl)amino)-N-(3-hydroxy-2,6-dimethylphenyl)thiazole-5-carboxamide;N-(3-hydroxy-2,6-dimethylphenyl)-2-((3-methyl-6-((4-methylphenyl)sulfonamido)pyridin-2- yl)amino)thiazole-5-carboxamide;2-((1-ethyl-4-(trifluoromethyl)-1H-indazol-3-yl)amino)-N-(3-hydroxy-2,6-dimethylphenyl)thiazole-5- carboxamide;N-(3-hydroxy-2,6-dimethylphenyl)-2-((6-isopropoxy-3-methylpyridin-2-yl)amino)thiazole-5- carboxamide;N-(3-hydroxy-2,6-dimethylphenyl)-2-((3-methyl-6-(2-methylbutoxy)pyridin-2-yl)amino)thiazole-5- carboxamide;N-(3-hydroxy-2,6-dimethylphenyl)-2-((3-methyl-4-(3-(4-methylpiperazin-1-yl)propoxy)pyridin-2- yl)amino)thiazole-5-carboxamide;2-((6-(1-cyclopropylethoxy)pyridin-2-yl)amino)-N-(3-hydroxy-2,6-dimethylphenyl)thiazole-5- carboxamide;N-(3-hydroxy-2,6-dimethylphenyl)-2-((6-hydroxypyridin-2-yl)amino)thiazole- 5-carboxamide;N-(3-hydroxy-2,6-dimethylphenyl)-2-((6-hydroxy-3-methylpyridin-2-yl)amino)thiazole-5- carboxamide;N-(3-hydroxy-2,6-dimethylphenyl)-2-((6-((1-methyl-1 H-pyrazol-4-yl)oxy)pyridin-2-yl)amino)thiazole-5-carboxamide;N-(3-hydroxy-2,6-dimethylphenyl)-2-((3-methyl-6-(2-(4-methylpiperazin-1-yl)ethoxy)pyridin-2- yl)amino)thiazole-5-carboxamide;2-((1-((R)-3-hydroxy-1-oxo-1-((S)-2-(trifluoromethyl)pyrrolidin-1-yl)propan-2-yl)-4-methyl-1H- pyrazol-3-yl)amino)-N-(3-hydroxy-2,6-dimethylphenyl)thiazole- 5-carboxamide;2-((1-((S)-3-hydroxy-1-oxo-1-((S)-2-(trifluoromethyl)pyrrolidin-1-yl)propan-2-yl)-4-methyl-1H- pyrazol-3-yl)amino)-N-(3-hydroxy-2,6-dimethylphenyl)thiazole- 5-carboxamide;N-(3-hydroxy-2,6-dimethylphenyl)-2-((1-((R)-3-methoxy-1-oxo-1-((S)-2-(trifluoromethyl)pyrrolidin-1- yl)propan-2-yl)-4-methyl-1 H-pyrazol-3-yl)amino)thiazole- 5-carboxamide;N-(3-hydroxy-2,6-dimethylphenyl)-2-((1-((S)-3-methoxy-1-oxo-1-((S)-2-(trifluoromethyl)pyrrolidin-1- yl)propan-2-yl)-4-methyl-1 H-pyrazol-3-yl)amino)thiazole-5-carboxamide;N-(3-hydroxy-2,6-dimethylphenyl)-2-((1-((R)-3-methoxy-1-oxo-1-((R)-2-(trifluoromethyl)pyrrolidin-1- yl)propan-2-yl)-4-methyl-1 H-pyrazol-3-yl)amino)thiazole-5-carboxamide;N-(3-hydroxy-2,6-dimethylphenyl)-2-((1-((S)-3-methoxy-1-oxo-1-((R)-2-(trifluoromethyl)pyrrolidin-1- yl)propan-2-yl)-4-methyl-1 H-pyrazol-3-yl)amino)thiazole-5-carboxamide;4-chloro-N-(3-hydroxy-2,6-dimethylphenyl)-2-((1-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-1 H-pyrazol-3- yl)amino)thiazole-5-carboxamide;N-(3-hydroxy-2,6-dimethylphenyl)-4-methyl-2-((1-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-1 H-pyrazol-3- yl)amino)thiazole-5-carboxamide;2-((5-(tert-butylcarbamoyl)-3-methylpyridin-2-yl)amino)-N-(3-hydroxy-2,6-dimethylphenyl)thiazole-5-carboxamide;2-((6-(1-fluorocyclopropane-1-carboxamido)-3-methylpyridin-2-yl)amino)-N-(3-hydroxy-2,6- dimethylphenyl)thiazole- 5-carboxamide;N-(3-hydroxy-2,6-dimethylphenyl)-2-((6-(hydroxymethyl)-3-methylpyridin-2-yl)amino)thiazole-5- carboxamide;2-((6-(2-cyclopropylacetamido)-3-methylpyridin-2-yl)amino)-N-(3-hydroxy-2,6- dimethylphenyl)thiazole- 5-carboxamide;2-((6-(cyclopropanecarboxamido)-3-methylpyridin-2-yl)amino)-N-(3-hydroxy-2,6- dimethylphenyl)thiazole- 5-carboxamide;N-(3-hydroxy-2,6-dimethylphenyl)-2-((6-((1,1,1-trifluoropropan-2-yl)oxy)pyridin-2-yl)amino)thiazole-5-carboxamide;2-((6-(1-(3-fluorophenyl)ethoxy) pyridin-2-yl)amino)-N-(3-hydroxy-2,6-dimethylphenyl)thiazole-5- carboxamide;2-((6-ethoxypyridin-2-yl)amino)-N-(3-hydroxy-2,6-dimethylphenyl)thiazole- 5-carboxamide;N-(3-hydroxy-2,6-dimethylphenyl)-2-((4-methoxy-1-methyl-1 H-indazol-3-yl)amino)thiazole-5- carboxamide;2-((6-(tert-butylcarbamoyl)-3-(methylthio)pyridin-2-yl)amino)-N-(3-hydroxy-2,6- dimethylphenyl)thiazole- 5-carboxamide;2-((6-(tert-butylcarbamoyl)-3-((3-chloropropyl)amino)pyridin-2-yl)amino)-N-(3-hydroxy-2,6- dimethylphenyl)thiazole- 5-carboxamide;N-(3-hydroxy-2,6-dimethylphenyl)-2-((6-((1-methylpiperidin-4-yl)oxy) pyridin-2-yl)amino)thiazole-5- carboxamide;2-((3-chloro-6-(4-cyclopropylpiperazin-1-yl)pyridin-2-yl)amino)-N-(3-hydroxy-2,6- dimethylphenyl)thiazole- 5-carboxamide;N-(3-hydroxy-2,6-dimethylphenyl)-2-((1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridin-3- yl)amino)thiazole-5-carboxamide;2-((6-((diethylamino)methyl)pyridin-2-yl)amino)-N-(3-hydroxy-2,6-dimethylphenyl)thiazole-5- carboxamide;N-(3-hydroxy-2,6-dimethylphenyl)-2-((6-(oxetan-3-yl)pyridin-2-yl)amino)thiazole-5-carboxamide;2-((3-chloro-6-(oxetan-3-yl)pyridin-2-yl)amino)-N-(3-hydroxy-2,6-dimethylphenyl)thiazole-5- carboxamide;N-(3-hydroxy-2,6-dimethylphenyl)-2-((3-methyl-6-((1-methyl-1H-pyrazol-4-yl)oxy)pyridin-2- yl)amino)thiazole-5-carboxamide;2-((1-(2-fluoroethyl)-4-methyl-1H-pyrazol-3-yl)amino)-N-(3-hydroxy-2,6-dimethylphenyl)-4- methylthiazole-5-carboxamide;4-chloro-2-((1-(2-fluoroethyl)-4-methyl-1H-pyrazol-3-yl)amino)-N-(3-hydroxy-2,6- dimethylphenyl)thiazole-5-carboxamide;N-(3-hydroxy-2,6-dimethylphenyl)-4-methyl-2-((4-methyl-1-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-1 H- pyrazol-3-yl)amino)thiazole-5-carboxamide;4-chloro-N-(3-hydroxy-2,6-dimethylphenyl)-2-((4-methyl-1-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-1H- pyrazol-3-yl)amino)thiazole-5-carboxamide;N-(3-hydroxy-2,6-dimethylphenyl)-2-((1-(2,2,2-trifluoroethyl)-5-(trifluoromethyl)-1H-indazol-3- yl)amino)thiazole-5-carboxamide;2-((6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)amino)-N-(3-hydroxy-2,6-dimethylphenyl)thiazole-5- carboxamide;2-((4-chloro-1-(2,2,2-trifluoroethyl)-1 H-indazol-3-yl)amino)-N-(3-hydroxy-2,6- dimethylphenyl)thiazole-5-carboxamide;N-(3-hydroxy-2,6-dimethylphenyl)-2-((3-methyl-6-(2-(pyrrolidin-1-yl)ethoxy)pyridin-2- yl)amino)thiazole-5-carboxamide;2-((6-(diethylcarbamoyl)pyridin-2-yl)amino)-N-(3-hydroxy-2,6-dimethylphenyl)thiazole-5- carboxamide;2-((6-(2-(diethylamino)-2-oxoethyl)pyridin-2-yl)amino)-N-(3-hydroxy-2,6-dimethylphenyl)thiazole-5- carboxamide;2-((6-(2-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)-2-oxoethyl)pyridin-2-yl)amino)-N-(3-hydroxy-2,6- dimethylphenyl)thiazole-5-carboxamide;2-((6-(2-(cyclobutyl(ethyl)amino)-2-oxoethyl)pyridin-2-yl)amino)-N-(3-hydroxy-2,6- dimethylphenyl)thiazole-5-carboxamide;2-((6-((N-ethylpropionamido)methyl)pyridin-2-yl)amino)-N-(3-hydroxy-2,6-dimethylphenyl)thiazole-5-carboxamide;N-(3-hydroxy-2,6-dimethylphenyl)-2-((3-methyl-6-(2-morpholinoethoxy)pyridin-2-yl)amino)thiazole-5-carboxamide;N-(3-hydroxy-2,6-dimethylphenyl)-2-((3-methyl-6-(pyridin-4-yloxy)pyridin-2-yl)amino)thiazole-5- carboxamide;2-((6-(tert-butylcarbamoyl)-3-isopropoxypyridin-2-yl)amino)-N-(3-hydroxy-2,6- dimethylphenyl)thiazole-5-carboxamide;2-((6-(tert-butylcarbamoyl)-3-ethoxypyridin-2-yl)amino)-N-(3-hydroxy-2,6-dimethylphenyl)thiazole-5-carboxamide;2-((6-(tert-butylcarbamoyl)-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)amino)-N-(3-hydroxy-2,6- dimethylphenyl)thiazole- 5-carboxamide;N-(3-hydroxy-2,6-dimethylphenyl)-2-((4-methyl-1-((R)-1-oxo-1-((S)-2-(trifluoromethyl)pyrrolidin-1- yl)propan-2-yl)-1 H-pyrazol-3-yl)amino)thiazole- 5-carboxamide;N-(3-hydroxy-2,6-dimethylphenyl)-2-((4-methyl-1-((S)-1-oxo-1-((S)-2-(trifluoromethyl)pyrrolidin-1- yl)propan-2-yl)-1 H-pyrazol-3-yl)amino)thiazole- 5-carboxamide;N-(3-hydroxy-2,6-dimethylphenyl)-2-((4-methyl-1-((R)-1-oxo-1-((R)-2-(trifluoromethyl)pyrrolidin-1- yl)propan-2-yl)-1 H-pyrazol-3-yl)amino)thiazole- 5-carboxamide;N-(3-hydroxy-2,6-dimethylphenyl)-2-((4-methyl-1-((S)-1-oxo-1-((R)-2-(trifluoromethyl)pyrrolidin-1- yl)propan-2-yl)-1 H-pyrazol-3-yl)amino)thiazole- 5-carboxamide;N-(2-bromo-3-hydroxy-6-methylphenyl)-2-((1-(2-(cyclopropyl(ethyl)amino)-2-oxoethyl)-4-methyl-1H-pyrazol-3-yl)amino)thiazole- 5-carboxamide;N-(2-bromo-3-hydroxy-6-methylphenyl)-2-((4-methyl-1-(2-oxo-2-(2-(trifluoromethyl)pyrrolidin-1- yl)ethyl)-1H-pyrazol-3-yl)amino)thiazole- 5-carboxamide;2-((6-(tert-butylcarbamoyl)-3-(methylsulfinyl)pyridin-2-yl)amino)-N-(3-hydroxy-2,6- dimethylphenyl)thiazole- 5-carboxamide;N-(3-hydroxy-2,6-dimethylphenyl)-2-((6-(2-(isopropyl(methyl)amino)-2-oxoethyl)pyridin-2- yl)amino)thiazole-5-carboxamide;N-(3-hydroxy-2,6-dimethylphenyl)-2-((3-methyl-6-(propylsulfonamido)pyridin-2-yl)amino)thiazole-5- carboxamide;N-(3-hydroxy-2,6-dimethylphenyl)-2-((3-methyl-6-((1-methylethyl)sulfonamido)pyridin-2- yl)amino)thiazole-5-carboxamide;2-((8-(cyclopropyl(ethyl)carbamoyl)-5,6,7,8-tetrahydroquinolin-2-yl)amino)-N-(3-hydroxy-2,6- dimethylphenyl)thiazole- 5-carboxamide;4-chloro-2-((6-(2-(cyclopropyl(ethyl)amino)-2-oxoethyl)pyridin-2-yl)amino)-N-(3-hydroxy-2,6- dimethylphenyl)thiazole- 5-carboxamide;N-(3-hydroxy-2,6-dimethylphenyl)-2-(((R)-8-((R)-2-(trifluoromethyl)pyrrolidine-1-carbonyl)-5,6,7,8- tetrahydroquinolin-2-yl)amino)thiazole- 5-carboxamide;N-(3-hydroxy-2,6-dimethylphenyl)-2-(((S)-8-((R)-2-(trifluoromethyl)pyrrolidine-1-carbonyl)-5,6,7,8- tetrahydroquinolin-2-yl)amino)thiazole- 5-carboxamide;N-(3-hydroxy-2,6-dimethylphenyl)-2-(((R)-8-((S)-2-(trifluoromethyl)pyrrolidine-1-carbonyl)-5,6,7,8- tetrahydroquinolin-2-yl)amino)thiazole- 5-carboxamide;N-(3-hydroxy-2,6-dimethylphenyl)-2-(((S)-8-((S)-2-(trifluoromethyl)pyrrolidine-1-carbonyl)-5,6,7,8- tetrahydroquinolin-2-yl)amino)thiazole-5-carboxamide;2-((3-chloro-6-(2-(4-methylpiperazin-1-yl)ethoxy)pyridin-2-yl)amino)-N-(3-hydroxy-2,6- dimethylphenyl)thiazole-5-carboxamide;N-(3-hydroxy-2,6-dimethylphenyl)-2-((6-(2-(4-isopropylpiperazin-1-yl)ethoxy)-3-methylpyridin-2- yl)amino)thiazole-5-carboxamide;N-(3-hydroxy-2-isopropyl-6-methylphenyl)-2-((4-methyl-1-(2-oxo-2-(2-(trifluoromethyl)pyrrolidin-1- yl)ethyl)-1H-pyrazol-3-yl)amino)thiazole-5-carboxamide;(S)-N-(3-hydroxy-2,6-dimethylphenyl)-2-((6-(2-oxo-2-(2-(trifluoromethyl)pyrrolidin-1-yl)ethyl)pyridin-2-yl)amino)thiazole-5-carboxamide;N-(3-hydroxy-2,6-dimethylphenyl)-2-((6-(2-methoxyethyl)pyridin-2-yl)amino)thiazole-5- carboxamide;2-((3-chloro-6-(2-methoxyethyl)pyridin-2-yl)amino)-N-(3-hydroxy-2,6-dimethylphenyl)thiazole-5- carboxamide;N-(3-hydroxy-2,6-dimethylphenyl)-2-(((R)-7-((S)-2-(trifluoromethyl)pyrrolidine-1-carbonyl)-6,7- dihydro-5H-cyclopenta[b]pyridin-2-yl)amino)thiazole-5-carboxamide;N-(3-hydroxy-2,6-dimethylphenyl)-2-(((S)-7-((S)-2-(trifluoromethyl)pyrrolidine-1-carbonyl)-6,7- dihydro-5H-cyclopenta[b]pyridin-2-yl)amino)thiazole-5-carboxamide;(S)-2-((6-(2-(2-cyanopyrrolidin-1-yl)-2-oxoethyl)pyridin-2-yl)amino)-N-(3-hydroxy-2,6- dimethylphenyl)thiazole-5-carboxamide;(R)-N-(3- hydroxy-2, 6-dimethylphenyl)-2-((6-(2-(2-methylpyrrolidin-1-yl)-2-oxoethyl)pyridin-2- yl)amino)thiazole-5-carboxamide;(S)-N-(3-hydroxy-2,6-dimethylphenyl)-2-((6-(2-(2-(methoxymethyl)pyrrolidin-1-yl)-2- oxoethyl)pyridin-2-yl)amino)thiazole-5-carboxamide;N-(3-hydroxy-2,6-dimethylphenyl)-2-((6-isopropoxy-3-methylpyridin-2-yl)amino)-4-methylthiazole-5- carboxamide;2-((6-(2-(cyclopropyl(ethyl)amino)-2-oxoethyl)pyridin-2-yl)amino)-N-(3- hydroxy-2, 6- dimethylphenyl)-4-methylthiazole-5-carboxamide;2-((3,5-dicyano-6-(dimethylamino)pyridin-2-yl)amino)-N-(3-hydroxy-2,6-dimethylphenyl)thiazole-5- carboxamide;2-((6-(2-(cyclopropyl(ethyl)amino)-2-oxoethyl)pyridin-2-yl)amino)-4-fluoro-N-(3-hydroxy-2,6- dimethylphenyl)thiazole-5-carboxamide;(S)-N-(3-hydroxy-2,6-dimethylphenyl)-4-methyl-2-((6-(2-oxo-2-(2-(trifluoromethyl)pyrrolidin-1- yl)ethyl)pyridin-2-yl)amino)thiazole-5-carboxamide;(S)-4-fluoro-N-(3-hydroxy-2,6-dimethylphenyl)-2-((6-(2-oxo-2-(2-(trifluoromethyl)pyrrolidin-1- yl)ethyl)pyridin-2-yl)amino)thiazole-5-carboxamide;2-((6-(2-(tert-butylamino)-2-oxoethyl)pyridin-2-yl)amino)-N-(3-hydroxy-2,6-dimethylphenyl)thiazole- 5-carboxamide;2-((6-(tert-butylcarbamoyl)-3-(2-methylbutoxy)pyridin-2-yl)amino)-N-(3-hydroxy-2,6- dimethylphenyl)thiazole- 5-carboxamide;2-((6-(tert-butylcarbamoyl)-3-(3,5-difluorophenoxy)pyridin-2-yl)amino)-N-(3-hydroxy-2,6- dimethylphenyl)thiazole- 5-carboxamide;2-((6-(tert-butylcarbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino) pyridin-2-yl)amino)-N-(3-hydroxy- 2, 6-dimethylphenyl)thiazole- 5-carboxamide;2-((6-(tert-butylcarbamoyl)-3-(pentan-3-yloxy)pyridin-2-yl)amino)-N-(3-hydroxy-2,6- dimethylphenyl)thiazole- 5-carboxamide;2-((6-(tert-butylcarbamoyl)-3-(1-cyclopropylethoxy)pyridin-2-yl)amino)-N-(3-hydroxy-2,6- dimethylphenyl)thiazole- 5-carboxamide;2-((6-(tert-butylcarbamoyl)-3-(cyclopentylmethoxy)pyridin-2-yl)amino)-N-(3-hydroxy-2,6- dimethylphenyl)thiazole- 5-carboxamide;(S)-2-((6-(tert-butylcarbamoyl)-3-((tetrahydrofuran-3-yl)oxy)pyridin-2-yl)amino)-N-(3-hydroxy-2,6- dimethylphenyl)thiazole- 5-carboxamide;(R)-2-((3-(sec-butoxy)-6-(tert-butylcarbamoyl)pyridin-2-yl)amino)-N-(3- hydroxy-2, 6- dimethylphenyl)thiazole- 5-carboxamide;N-(5-methyl-1 H-indazol-4-yl)-2-((6-(2-(trifluoromethyl)pyrrolidine-1-carbonyl)pyridin-2- yl)amino)thiazole-5-carboxamide;(S)-N-(5-fluoro-3-methyl-1 H-indazol-4-yl)-2-((4-methyl-1-(2-oxo-2-(2-(trifluoromethyl)pyrrolidin-1- yl)ethyl)-1 H-pyrazol-3-yl)amino)thiazole- 5-carboxamide;(R)-N-(5-fluoro-3-methyl-1 H-indazol-4-yl)-2-((4-methyl-1-(2-oxo-2-(2-(trifluoromethyl)pyrrolidin-1- yl)ethyl)-1 H-pyrazol-3-yl)amino)thiazole- 5-carboxamide;2-((1-(2-(cyclopropyl(ethyl)amino)-2-oxoethyl)-4-methyl-1 H-pyrazol-3-yl)amino)-N-(5-fluoro-3- methyl-1 H-indazol-4-yl)thiazole- 5-carboxamide;2-((1-(2-(diethylamino)-2-oxoethyl)-4-methyl-1 H-pyrazol-3-yl)amino)-N-(5- fluoro- 3-methyl-1 H- indazol-4-yl)thiazole- 5-carboxamide;2-((1-(2-(cyclobutyl(methyl)amino)-2-oxoethyl)-4-methyl-1 H-pyrazol-3-yl)amino)-N-(5-fluoro-3- methyl-1 H-indazol-4-yl)thiazole- 5-carboxamide;(S)-N-(5-fluoro-3-methyl-1 H-indazol-4-yl)-2-((1-(2-(2-isopropylpyrrolidin-1-yl)-2-oxoethyl)-4-methyl-1 H-pyrazol-3-yl)amino)thiazole- 5-carboxamide;2-((7-(diethylcarbamoyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)amino)-N-(5-methyl-1 H-indazol- 4-yl)thiazole- 5-carboxamide;2-((3-ethyl-6-methylpyridin-2-yl)amino)-N-(5-methyl-1 H-indazol-4-yl) thiazole- 5-carboxamide;2-((6-(diethylamino)pyrimidin-4-yl)amino)-N-(5-fluoro-3-methyl-1 H-indazol-4-yl)thiazole-5- carboxamide;N-(5-fluoro-3-methyl-1 H-indazol-4-yl)-2-((1-methyl-1 H-pyrazol-5-yl)amino)thiazole-5-carboxamide;2-((3, 6-dimethylpyridin-2-yl)amino)-N-(5- fluoro- 3-methyl-1 H-indazol-4-yl)thiazole-5-carboxamide; 2-((4,6-dimethyl-1 ,3,5-triazin-2-yl)amino)-N-(5-methyl-1 H-indazol-4-yl)thiazole-5-carboxamide; N-(3,5-dimethyl-1 H-indazol-4-yl)-2-((3,6-dimethylpyridin-2-yl)amino)thiazole-5-carboxamide;2-((5-chloro-2'-fluoro-[2,3'-bipyridin]-6-yl)amino)-N-(5-methyl-1 H-indazol-4-yl)thiazole-5- carboxamide;2-((6-isopropoxypyridin-2-yl)amino)-N-(5-methyl-1 H-indazol-4-yl)thiazole-5-carboxamide;2-((2'-fluoro-5-methyl-[2,3'-bipyridin]-6-yl)amino)-N-(5-methyl-1 H-indazol-4-yl)thiazole-5- carboxamide;2-((6-(dimethylcarbamoyl)pyridin-2-yl)amino)-N-(5-methyl-1 H-indazol-4-yl)thiazole-5-carboxamide;2-((6-(2-((2-hydroxyethyl)(methyl)amino)-2-oxoethyl)pyridin-2-yl)amino)-N-(5-methyl-1 H-indazol-4- yl)thiazole-5-carboxamide;2-((3-chloro-6-isopropoxypyridin-2-yl)amino)-N-(5-methyl-1 H-indazol-4-yl)thiazole-5-carboxamide;2-((6-amino-3-methylpyridin-2-yl)amino)-N-(5-methyl-1 H-indazol-4-yl)thiazole-5-carboxamide;N-(5-fluoro-3-methyl-1 H-indazol-4-yl)-2-((6-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)thiazole-5- carboxamide;2-((7-(cyclopropyl(methyl)carbamoyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)amino)-N-(5-methyl- 1 H-indazol-4-yl)thiazole-5-carboxamide;N-(5-methyl-1 H-indazol-4-yl)-2-((5,6,7,8-tetrahydroquinolin-2-yl)amino)thiazole-5-carboxamide;2-((1-((R)-3-methoxy-1-oxo-1-((R)-2-(trifluoromethyl)pyrrolidin-1-yl)propan-2-yl)-4-methyl-1 H- pyrazol-3-yl)amino)-N-(5-methyl-1 H-indazol-4-yl)thiazole-5-carboxamide;2-((1-((S)-3-methoxy-1-oxo-1-((S)-2-(trifluoromethyl)pyrrolidin-1-yl)propan-2-yl)-4-methyl-1 H- pyrazol-3-yl)amino)-N-(5-methyl-1 H-indazol-4-yl)thiazole-5-carboxamide;2-((8-(diethylcarbamoyl)-5,6,7,8-tetrahydroquinolin-2-yl)amino)-N-(5-methyl-1 H-indazol-4- yl)thiazole-5-carboxamide;2-((8-(cyclopropyl(methyl)carbamoyl)-5,6,7,8-tetrahydroquinolin-2-yl)amino)-N-(5-methyl-1 H- indazol-4-yl)thiazole-5-carboxamide;N-(5-methyl-1 H-indazol-4-yl)-2-((3-methyl-6-pivalamidopyridin-2-yl)amino)thiazole-5-carboxamide;N-(3-ethyl-5-fluoro-1 H-indazol-4-yl)-2-((4-methyl-1-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-1 H-pyrazol-3- yl)amino)thiazole-5-carboxamide;2-((6-(tert-butylcarbamoyl)-3-isopropoxypyridin-2-yl)amino)-N-(3-hydroxy-2,6-dimethylphenyl)-4- methylthiazole- 5-carboxamide;2-((6-(tert-butylcarbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)pyridin-2-yl)amino)-N-(3-hydroxy- 2, 6-dimethylphenyl)-4-methylthiazole- 5-carboxamide;(S)-2-((6-(tert-butylcarbamoyl)-3-((tetrahydrofuran-3-yl)oxy)pyridin-2-yl)amino)-N-(3-hydroxy-2,6- dimethylphenyl)-4-methylthiazole- 5-carboxamide;2-((6-(tert-butylcarbamoyl)-3-(pyrrolidin-1-yl)pyridin-2-yl)amino)-N-(3-hydroxy-2,6- dimethylphenyl)thiazole-5-carboxamide;2-((6-(tert-butylcarbamoyl)-3-morpholinopyridin-2-yl)amino)-N-(3-hydroxy-2,6-dimethylphenyl) thiazole- 5-carboxamide;(R)-2-((6-(tert-butylcarbamoyl)-3-((1-methoxypropan-2-yl)amino) pyridin-2-yl)amino)-N-(3-hydroxy-2.6-dimethylphenyl)thiazole- 5-carboxamide;2-((6-(tert-butylcarbamoyl)-3-(isopropyl(methyl)amino)pyridin-2-yl)amino)-N-(3-hydroxy-2,6- dimethylphenyl)thiazole- 5-carboxamide;2-((6-(tert-butylcarbamoyl)-3-(isopropylamino)pyridin-2-yl)amino)-N-(3-hydroxy-2,6- dimethylphenyl)-4-methylthiazole- 5-carboxamide;2-((6-(tert-butylcarbamoyl)-3-(cyclohexylamino)pyridin-2-yl)amino)-N-(3-hydroxy-2,6- dimethylphenyl)-4-methylthiazole- 5-carboxamide;2-((6-(cyclopentylcarbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)pyridin-2-yl)amino)-N-(3-hydroxy-2.6-dimethylphenyl)-4-methylthiazole- 5-carboxamide;2-((6-(diethylcarbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)pyridin-2-yl)amino)-N-(3-hydroxy-2,6- dimethylphenyl)-4-methylthiazole- 5-carboxamide;2-((6-(tert-butylcarbamoyl)-3-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyridin-2-yl)amino)-N- (3-hydroxy-2,6-dimethylphenyl)-4-methylthiazole- 5-carboxamide;N-(3-hydroxy-2,6-dimethylphenyl)-4-methyl-2-((6-(pyrrolidine-1-carbonyl)-3-((tetrahydro-2H-pyran- 4-yl)amino)pyridin-2-yl)amino)thiazole- 5-carboxamide;2-((6-(tert-butyl(methyl)carbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)pyridin-2-yl)amino)-N-(3- hydroxy-2, 6-dimethylphenyl)-4-methylthiazole- 5-carboxamide;(R)-2-((6-(tert-butylcarbamoyl)-3-((tetrahydro-2H-pyran-3-yl)amino)pyridin-2-yl)amino)-N-(3- hydroxy-2, 6-dimethylphenyl)-4-methylthiazole- 5-carboxamide;(S)-2-((6-(tert-butylcarbamoyl)-3-((tetrahydro-2H-pyran-3-yl)amino)pyridin-2-yl)amino)-N-(3- hydroxy-2, 6-dimethylphenyl)-4-methylthiazole- 5-carboxamide;2-((6-(tert-butylcarbamoyl)-3-((1-methylpiperidin-4-yl)amino)pyridin-2-yl)amino)-N-(3-hydroxy-2,6- dimethylphenyl)-4-methylthiazole- 5-carboxamide;2-((3-(tert-butylamino)-6-(tert-butylcarbamoyl)pyridin-2-yl)amino)-N-(3- hydroxy-2, 6- dimethylphenyl)-4-methylthiazole- 5-carboxamide;(S)-N-(3-hydroxy-2,6-dimethylphenyl)-4-methyl-2-((3-((tetrahydro-2H-pyran-4-yl)amino)-6-(2-(trifluoromethyl)pyrrolidine-1-carbonyl)pyridin-2-yl)amino)thiazole-5-carboxamide;2-((6-(tert-butylcarbamoyl)-3-((4-methyltetrahydro-2H-pyran-4-yl)amino)pyridin-2-yl)amino)-N-(3- hydroxy-2, 6-dimethylphenyl)-4-methylthiazole- 5-carboxamide;2-((6-(tert-butylcarbamoyl)-3-(dimethylamino)pyridin-2-yl)amino)-N-(3- hydroxy-2, 6-dimethylphenyl)- 4-methylthiazole- 5-carboxamide;2-((6-(bicyclo[1.1.1]pentan-1-ylcarbamoyl)-3-((tetrahydro-2H-pyran-4-yl)amino)pyridin-2-yl)amino)- N-(3-hydroxy-2,6-dimethylphenyl)-4-methylthiazole-5-carboxamide;N-(3-hydroxy-2,6-dimethylphenyl)-4-methyl-2-((3-(((R)-tetrahydro-2H-pyran-3-yl)amino)-6-((S)-2- (trifluoromethyl)pyrrolidine-1-carbonyl)pyridin-2-yl)amino) thiazole- 5-carboxamide;N-(3-hydroxy-2,6-dimethylphenyl)-4-methyl-2-((6-((4-methyltetrahydro-2H-pyran-4-yl)carbamoyl)-3- ((tetrahydro-2H-pyran-4-yl)amino)pyridin-2-yl)amino)thiazole-5-carboxamide;N-(3-hydroxy-2,6-dimethylphenyl)-2-((6-((1-hydroxy-2-methylpropan-2-yl)carbamoyl)-3- ((tetrahydro-2H-pyran-4-yl)amino)pyridin-2-yl)amino)-4-methylthiazole- 5-carboxamide;(S)-N-(3-hydroxy-2,6-dimethylphenyl)-4-methyl-2-((3-((tetrahydro-2H-pyran-4-yl)amino)-6-((1,1,1- trifluoropropan-2-yl)carbamoyl)pyridin-2-yl)amino)thiazole- 5-carboxamide; or N-(3-hydroxy-2,6-dimethylphenyl)-2-((6-(isopropylcarbamoyl)-3-((tetrahydro-2H-pyran-4- yl)amino)pyridin-2-yl)amino)-4-methylthiazole- 5-carboxamide.

19. A pharmaceutical composition comprising a compound according to any one of claims 1- 18, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier or diluent.

20. 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 18, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 19.

21. A method of inhibiting PKMYT 1 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 18, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 19.

22. A compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 19, for use in a method of treatment of the human or animal body by therapy.

23. A compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 19, 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.

24. Use of a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 19, 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.

25. 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 18, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 19.

26. A compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 19, for use in a method of treatment of a proliferative disorder.

27. Use of a compound according to any one of claim 1 to 18, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 19, in the manufacture of a medicament for the treatment of a proliferative disorder.

28. 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 18, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 19.

29. A compound, salt, solvate, or pharmaceutical composition for use according to claim 26, use according to claim 27, or a method according to claim 28, wherein the proliferative disorder is characterised by, or further characterised by: inappropriate activity and / or expression of PKMYT1, CCNE1, FBXW7, PP2A or one of its subunits, mutation of KRAS or NRAS (for example concomitant mutation of p53 and KRAS or NRAS), or mutation or deletion of CDKN2A (for example concomitant mutation of p53 and CDKN2A).

30. A compound, salt, solvate, or pharmaceutical composition for use according to claim 26, use according to claim 27, or a method according to claim 28, wherein the proliferative disorder is characterised by, or further characterised by: a dependency to PKMYT 1 due to high basal level of replication stress.

31. A compound, salt, solvate, or pharmaceutical composition for use according to claim 26, use according to claim 27, or a method according to claim 28, wherein the proliferative disorder is cancer.

32. A compound, salt, solvate, or pharmaceutical composition for use according to claim 26, use according to claim 27, or a method according to claim 28, 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.

33. A PKMYT 1 inhibitor for use in the treatment of cancer, wherein the PKMYT 1 inhibitor is administered in combination with an antibody-drug conjugate.

34. A PKMYT 1 inhibitor for use according to claim 33, wherein the PKMYT 1 inhibitor is a compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 18.

35. A PKMYT 1 inhibitor for use according to claim 34, wherein the PKMYT 1 inhibitor is RP- 6306, or a pharmaceutically acceptable salt or solvate thereof.

36. A PKMYT 1 inhibitor for use according to any one of claims 31 to 35, wherein the antibodydrug conjugate is a topoisomerase I inhibitor, a topoisomerase II inhibitor, a DNA intercalator, or an antimetabolite.

37. A PKMYT 1 inhibitor for use according to claim 36, 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- B01 D1 , 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 , AZD9592, KH815, and mirvetuximab exatecan.

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