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WO2025215188A1 - Composés thérapeutiques et leur utilisation en tant qu'inhibiteurs de pkmyt1 - Google Patents

Composés thérapeutiques et leur utilisation en tant qu'inhibiteurs de pkmyt1

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Publication number
WO2025215188A1
WO2025215188A1 PCT/EP2025/059968 EP2025059968W WO2025215188A1 WO 2025215188 A1 WO2025215188 A1 WO 2025215188A1 EP 2025059968 W EP2025059968 W EP 2025059968W WO 2025215188 A1 WO2025215188 A1 WO 2025215188A1
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WIPO (PCT)
Prior art keywords
optionally substituted
present
independently
branched saturated
compound according
Prior art date
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PCT/EP2025/059968
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English (en)
Inventor
Deborah SMITHEN
Michael Brown
Dan Niculescu-Duvaz
Richard Marais
Caroline Springer
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My T Bio Ltd
Cancer Research Technology Ltd
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My T Bio Ltd
Cancer Research Technology Ltd
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Publication of WO2025215188A1 publication Critical patent/WO2025215188A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention pertains generally to the field of therapeutic compounds. More specifically the present invention pertains to certain biarylamide compounds (also referred to herein as “BAA compounds”) which inhibit Protein Kinase, Membrane Associated Tyrosine/Threonine 1 (PKMYT1).
  • BAA compounds biarylamide compounds
  • the present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit 10 PKMYT1 kinase; to treat disorders (e.g., diseases) that are ameliorated by the inhibition of PKMYT1 kinase; to treat a proliferative disorder, cancer, etc.
  • BACKGROUND 15 [002] 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.
  • Ranges are inclusive of their endpoints, and may be expressed herein as from “about” one particular value, and/or to “about” another particular value. When such a range is expressed, another embodiment includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by the use of the antecedent “about,” it will be understood 30 that the particular value forms another embodiment. [006] 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.
  • PCMYT1 Protein kinase, membrane-associated tyrosine/threonine 1
  • a key hallmark of cancer is that cancer cells override the cell cycle controls that prevent commitment to division until the appropriate conditions have been fulfilled. Once the conditions are right, cells are pushed through a decision point called the “restriction point” into the cell division cycle by the activity of Cdk4/6-Cyclin D complexes. Once through this point of no return, cells activate Cdk2- P-000059-WO-PCT-MYT - 2 - Cyclin E in order to drive the duplication of the DNA that will be segregated into two daughter cells later in the cell cycle (by Cdk1-Cyclin B).
  • cancer cells In order to be able to proliferate illegitimately, cancer cells inappropriately boost the kinase activity of Cdk4/6-Cyclin D complexes or bypass the requirement for Cdk4/6-Cyclin D activation, by 5 activating the downstream Cdk2-Cyclin E complex, independently of any input from Cdk4/6-Cyclin D.
  • Implementation of either of these two approaches enable cancers to evade the normal controls that maintain balanced growth and homeostasis within the body. Consequently, cancer proliferation is unregulated.
  • CCNE1 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.
  • CCNE1 overproduction generates a 20 dependency on PKMYT1.
  • 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, 25 breast and gastric, ranging in frequency from 5-40%.
  • CCNE1 amplification and/or FBXW7 mutations occur in >60% of uterine carcinosarcomas, >20% of uterine cancers, ⁇ 20% of ovarian cancers, ⁇ 18% of stomach cancers, ⁇ 14% of colorectal cancer, ⁇ 12% of bladder cancers, 11.5% of oesophageal cancers, ⁇ 11% of cervical cancers, 7.5% of sarcomas and ⁇ 7% of lung squamous cancers (Durocher et al., 2021).
  • CCNE1 also occurs at lower levels in other cancers such as adenoid cystic carcinoma, pancreatic cancer, 30 mesothelioma, lung adenocarcinoma, head & neck cancers, diffuse large B-cells lymphoma, liver cancers and others (Gorski et al., 2020). Moreover, CCNE1 over expressing ovarian cancers are a subset of the 50% that are recombination proficient so do not benefit from PARP inhibitors (Gorski et al., 2020), highlighting the unmet need in these indications.
  • CCNE1 amplification is observed in the more aggressive subtypes including uterine 35 carcinosarcoma (UCS; ⁇ 40%), uterine serous carcinoma (USC; ⁇ 25%), high-grade serous ovarian carcinoma (HGSOC; ⁇ 20%), and triple-negative breast cancer (TNBC; ⁇ 8%).
  • CCNE1 over-expression in tumor biopsies is linked to lower overall survival compared to patients with normal Cyclin E1 levels. HGSOC patients with CCNE1 over-expression have a lower response rate to cisplatin, the current standard of care.
  • FBXW7 is frequently mutated in several cancer types including uterine carcinosarcoma, endometrial, colorectal, cervical, bladder, head & neck, gastric, cancers and lung squamous cells carcinoma ranging in frequency from 5-39%.
  • FBXW7 driver mutations are observed in the more aggressive subtypes of endometrial cancer including UCS and USC.
  • a recently discovered inhibitor of PKMYT1, RP-6306 (Szychowski et al., 2022), has shown 10 efficacy in vivo in models of breast and ovarian cancers overexpressing CCNE1, as well as in a pancreatic PDX model with increased expression of CCNE1, alone or in combination with Gemcitabine (Gallo et al., 2022).
  • PPP2R2A inactivation is present in 15% of prostate adenocarcinoma, and at >5% in ovarian serous cystadenocarcinoma, rectum adenocarcinoma, bladder urothelial carcinoma, colorectal adenocarcinoma, breast invasive carcinoma, uterine corpus endometrial carcinoma, uterine carcinosarcoma, liver hepatocellular carcinoma, lung squamous cell carcinoma, lung adenocarcinoma.
  • PPP2R1A is altered in 1.82% of all cancers with endometrial serous 20 adenocarcinoma, endometrial endometrioid adenocarcinoma, colon adenocarcinoma, breast invasive ductal carcinoma, and lung adenocarcinoma being the most prevalent.
  • PKMYT1 is a cell cycle regulating kinase, part of the WEE1 family of kinases that includes WEE1 and WEE2.
  • WEE2 is restricted to gonads as it regulates meiosis. In contrast both PKMYT1 and WEE1 are ubiquitously expressed.
  • PKMYT1 is localized predominantly in the endoplasmic reticulum and Golgi 25 complex, while WEE1 is predominantly a nuclear protein.
  • PKMYT1 is involved in the negative regulation of the CDK1-Cyclin B complex which promotes the progression of cells from G2-phase into the mitotic phase (M-phase) of the cell cycle.
  • M-phase mitotic phase
  • 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.
  • CCNE1 overproduction stimulates abnormally high levels of DNA replication that deplete the nucleotide pool and generate DNA damage (Jones et al., 2013).
  • the DNA damage generated by Cyclin E accumulation is not in itself lethal because cells have G2/M checkpoints that restrain 35 commitment to genome segregation in mitosis until all damage is repaired.
  • These checkpoint pathways boost the activity of the Wee1 family kinases WEE1 and PKMYT1, which restrain division by phosphorylating Cdk1 kinase to block Cdk1-Cyclin B activity.
  • WEE1 and PKMYT1 activities remain high and cells cannot divide.
  • WEE1 or PKMYT1 inhibition kills damaged cells by forcing them to divide when their DNA is still damaged and/or un-replicated. This places higher P-000059-WO-PCT-MYT - 4 - demands upon the ability of WEE1 and PKMYT1 to restrain CDK1-Cyclin B activity to maintain cell viability.
  • PKMYT1 can be removed from untransformed cells because the requirement for restraint of CDK1-CyclinB1 activity can be met by WEE1 alone.
  • PKMYT1 inhibition is unlikely to display similar S phase toxicity, because, unlike WEE1, it phosphorylates CDK1 (Booher et al., 1997; Liu et al., 1997). [023]
  • PKMYT1 phosphorylates CDK1
  • PKMYT1 has been observed in various cancers (compared to normal tissues), including lung squamous cell carcinoma, lung adenocarcinoma, uterine corpus endometrial carcinoma, breast invasive carcinoma, hepatocellular carcinoma, clear-cell renal-cell carcinoma, kidney 20 chromophobe cancer, renal papillary cell carcinoma, head and neck squamous cell carcinoma, colon adenocarcinoma, stomach adenocarcinoma, thyroid carcinoma, prostate adenocarcinoma.
  • lung squamous cell carcinoma including lung squamous cell carcinoma, lung adenocarcinoma, uterine corpus endometrial carcinoma, breast invasive carcinoma, hepatocellular carcinoma, clear-cell renal-cell carcinoma, kidney 20 chromophobe cancer, renal papillary cell carcinoma, head and neck squamous cell carcinoma, colon adenocarcinoma, stomach adenocarcinoma, thyroid carcinoma, prostate adenocarcinoma.
  • Elevated expression of PKMYT1 is associated with poor prognosis in adrenocortical carcinoma, kidney chromophobe, kidney renal clear cell carcinoma, kidney renal papillary cell carcinoma, lower grade glioma, liver hepatocellular carcinoma, lung adenocarcinoma, mesothelioma, pancreatic 25 adenocarcinoma, prostate adenocarcinoma, skin cutaneous melanoma, uveal melanoma (Shao et al., 2021), and breast cancer (Liu et al., 2020).
  • PKMYT1 is involved in the progression, invasion and/or metastasis of many solid tumours, for example non-small cell lung cancer (Zhang et al., 2022; He et al., 2021; Sun et al., 2019), osteosarcoma (Luo et al., 2022), clear cell renal cell carcinoma (Chen et al., 2020; Chen et al., 2021), oral squamous cell 30 carcinoma (Cai et al., 2022), gastric cancer (Hu et al., 2022; Zhang et al., 2020), prostate cancer (Wang et al., 2020), oesophageal squamous cell carcinoma (Zhang et al., 2019), colorectal cancer (Jeong et al., 2018), hepatocellular carcinoma (Liu et al., 2017), ovarian cancer (Xuan et al., 2020), neuroblastoma (in particular with M
  • PKMYT1 is essential for survival of some haematologic malignancies, such as acute lymphoblastic leukemia and 35 multiple myeloma (Ghelli Luserna di Rora et al., 2020). [026] PKMYT1 can have application in addressing resistance to treatment or improving the efficacy of cancer treatment agents. PKMYT1 elevation has been reported as a resistance mechanism to sustained WEE1 inhibition (Lewis et al., 2019). PKMYT1 inhibitors may also be a useful second line treatment to complement the emerging WEE1i based therapies.
  • KSHV Kaposi sarcoma herpesvirus
  • 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.
  • BAA compounds biarylamide compounds
  • PLMYT1 Protein Kinase, Membrane Associated Tyrosine/Threonine 1
  • Another aspect of the invention pertains to a composition (e.g., a pharmaceutical composition) comprising a BAA compound, as described herein, and a pharmaceutically acceptable excipient.
  • Another aspect of the present invention pertains to a method of inhibiting PKMYT1 (e.g., inhibiting or reducing or blocking the activity or function of PKMYT1), in vitro or in vivo, comprising 25 contacting the PKMYT1 with an effective amount of a BAA compound, as described herein.
  • Another aspect of the present invention pertains to a method of inhibiting PKMYT1 (e.g., inhibiting or reducing or blocking the activity or function of PKMYT1) in a cell, in vitro or in vivo, comprising contacting the cell with an effective amount of a BAA compound, as described herein.
  • Another aspect of the present invention pertains to a BAA compound as described herein for 30 use in a method of treatment of the human or animal body by therapy, for example, for use in a method of treatment of a disorder (e.g., a disease) as described herein.
  • 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.
  • 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.
  • Another aspect of the present invention pertains to a method of treatment, for example, a method of treatment of a disorder (e.g., a disease) as described herein, comprising administering to a P-000059-WO-PCT-MYT - 6 - subject in need of treatment a therapeutically effective amount of a BAA compound, as described herein, optionally in the form of a pharmaceutical composition.
  • 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).
  • the disorder is, for example, a proliferative condition, cancer, etc., as described herein.
  • kits comprising (a) a BAA compound, as described herein, optionally provided as a composition (e.g., a pharmaceutical composition) and in a suitable container and/or with suitable packaging; and (b) instructions for use, for example, in a method 10 of treatment of a disorder (e.g., a disease) as described herein, for example, written instructions on how to administer the compound.
  • a BAA compound obtainable by a method of synthesis as described herein, or a method comprising a method of synthesis as described herein.
  • Another aspect of the present invention pertains to a BAA compound obtained by a method of 15 synthesis as described herein, or a method comprising a method of synthesis as described herein.
  • 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.
  • Another aspect of the present invention pertains to the use of such novel intermediates, as described herein, in the methods of synthes is described herein. 20 [047]
  • features and preferred embodiments of one aspect of the invention will also pertain to other aspects of t he invention.
  • One aspect of the present invention is a compound of the following formula, or a pharmaceutically acceptable salt or co-crystal thereof, wherein Ring A and Ring B are as defined herein (for convenience, collectively referred to herein as “biarylamide compounds” or “BAA compounds”): 30 [049]
  • Some embodiments include the following: [050] (1) A compound of the following fo P-000059-WO-PCT-MYT - 7 - or a pharmaceut i c a l l y a c c e p t a b le s a l t o r c o -crystal thereof (e.g., or pharmaceutically acceptable salt thereof); wherein: Ring A is : wherein: Z 1 is N, CH, or CR Z1 ; and Z 2 is CH, CR Z2 , or N; wherein: each -R Z1 , and -R Z2 ,
  • pyridyl is an example of a C 6 heteroaryl group
  • piperidino is an example of a C6heterocyclyl group.
  • heteroaryl refers to a group that is attached to the rest of the molecule by an atom that is part of an aromatic ring, wherein the aromatic ring is part of an aromatic ring system, and the aromatic ring system has one or more heteroatoms (e.g., N, O, S, as the case may be).
  • heteroatoms e.g., N, O, S, as the case may be.
  • pyrazole is an example of a C5 heteroaryl group
  • pyridyl is an example of a C6heteroaryl group
  • quinolyl e.g., quinolin-2-yl, quinolin-7-yl, etc.
  • C10heteroaryl group is an example of a C10heteroaryl group.
  • the aromatic ring system may optionally be fused with one or more non-aromatic rings, which may contain one or more heteroatoms (e.g., N, O, S, as the case may be) or only carbon atoms.
  • one or more heteroatoms e.g., N, O, S, as the case may be
  • 4,5,6,7- tetrahydro-1H-indol-2-yl is an example of a C 9 heteroaryl group
  • 4,5,6,7-tetrahydro-1H-pyrrolo[2,3- b]pyridin-2-yl is an example of a C9heteroaryl group.
  • heterocyclyl refers to a group that is attached to the rest of the molecule by an atom that is part of a non-aromatic ring, and the non-aromatic ring has one or more heteroatoms (e.g., N, O, S, as the case may be).
  • heterocyclyl includes monocyclic heterocyclyl (e.g., piperidinyl, an example of a monocyclic C6heterocyclyl), fused heterocyclyl (e.g., 3-azabicyclo[3.1.0]hexyl, an example of a fused C6heterocyclyl; decahydroquinolinyl, an example of a fused C10heterocyclyl), bridged heterocyclyl (e.g., 6-azabicyclo[3.1.1]heptanyl and 2,5-diazabicyclo[2.2.1]heptane, examples of a bridged C7heterocyclyl; 3,8-diazabicyclo[3.2.1]octanyl, an example of a bridged C8heterocyclyl), and spiro heterocyclyl (2,6-diazaspiro[3.3]heptane, an example of a spiro C 7 heterocyclyl;
  • non-aromatic ring system may optionally be fused with one or more aromatic rings which may contain one or more heteroatoms (e.g., N, O, S, as the case may be) or only carbon atoms.
  • heteroatoms e.g., N, O, S, as the case may be
  • 4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridin-5-yl is an example of a C 9 heterocyclyl group
  • 1,2,3,4-tetrahydroisoquinolin-3-yl is an example of a C10heterocyclyl group.
  • a ”non-aromatic C 3-11 heterocyclyl having at least one N ring atom, and is attached via that N ring atom refers to a substituent comprising at least one non-aromatic ring system comprising at least one N ring atom, the non-aromatic ring system being attached to the rest of the molecule by that ring N atom, and optionally containing one or more additional heteroatoms (e.g., N, O, S, as the case may be). Furthermore, the non-aromatic ring system may optionally be fused with one or more aromatic rings which may contain one or more heteroatoms (e.g., N, O, S, as the case may be) or only carbon atoms.
  • cycloalkyl refers to a ring system that contains at least one non-aromatic carbon ring, and contains only carbon atoms. Unless otherwise specified, “cycloalkyl” includes monocyclic cycloalkyl (e. g. cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl), bicyclic cycloalkyl (e.
  • cycloalkyl e.g. 7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene, P-000059-WO-PCT-MYT - 16 - core scaffold of estradiol
  • bridged cycloalkyl e. g.1,2,3,4-tetrahydro-1,4-methanonaphthalene
  • spiro cycloalkyl e. g.3',4'-dihydro-2'H-spiro[cyclopentane-1,1'-naphthalene]).
  • haloalkyl refers to an alkyl group substituted with one or more halo groups (e.g., -F, -Cl, -Br, -I).
  • fluoroalkyl refers to an alkyl group substituted with one or more -F groups.
  • -CF3 and -CHF2 are examples of a C1fluoroalkyl group
  • -CH2CF3 and -CH2CHF2 are examples of a C2fluoroalkyl group.
  • C1-4alkylene refers to an alkyl group with two points of attachment.
  • -CH2- is an example of a C1alkylene group
  • -CH2CH2- and -CH(CH3)- are examples of a C2alkylene group
  • -CH2CH2CH2- and -CH(CH3)2- are examples of a C3alkylene group.
  • Examples of C 1-7 alkyl, C 1-6 alkyl and C 1-4 alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, sec- butyl, iso-butyl and t-butyl.
  • Examples of C3-6cycloalk yl-C1-3alkyl include cyclopropylmethyl and cyclohexylethyl.
  • phenyl-C 1-3 alkyl examples include de benzyl and 2-phenylpropyl.
  • C 5- 6heteroaryl-C1-3alkyl examples include pyrimidin-2-ylmethyl, and t hiazol-4-ylethyl.
  • R-NH- where R comp a thiazole ring ] and a Q 1 , Q 2 , Q 3 , Q 4 or Q 5 group) at the indicated positions: [064]
  • the phrase “one or more groups” in the of optional substituents is necessarily constrained by the parent moiety and the number of positions on it that are suitable for substitution. In some parent moieties (e.g., tetrazolyl) there is only one position available for substitution. However, for other parent moieties, there may be several (e.g., phenyl has five).
  • the “one or more groups” may be, e.g., 1, 2, 3, 4, etc., though alternatively “one or more groups” may be 1, 2, or 3, optionally 1 or 2, or instead 1.
  • the phrase “substituent on carbon” is intended to refer to a substituent which is attached to a carbon ring atom.
  • the phrase “substituent on nitrogen” is intended to refer to a P-000059-WO-PCT-MYT - 17 - substituent which is attached to a nitrogen ring atom which, in the abs en ce of t he substituent, would be a secondary nitrogen ring atom (i.e., -NH-).
  • a pyridyl group may only have “substituents on carbon”, whereas 1H-pyrrole may have both “substituent s on ca rbo n” and a “substituent on secondary nitrogen”, as illustrated below. 5 [066] Similarly, a piperidino group may only have whereas piperazino may have both “substituents on carbon” and a “substituen o se ro a illustrated below. 10 [067] Certain group s despite having carbon ring ato h a c n ring atoms available for substitution.
  • a tetrazolyl group may only permit a “substituent on carbon” or may only permit a “substituent on secondary nitrogen”, as illustrated below. 15 [068] 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).
  • each of the (R) and (S) enantiomers are disclosed and encompassed, both individually (e.g., as isolated from the other enantiomer) and as a mixture (e.g., as equimolar or non-equimolar mixtures of the two enantiomers).
  • the initial carbon atom P-000059-WO-PCT-MYT - 18 - of a pendant sec-butyl group, -CH(CH 3 )CH 2 CH 3 is usually chiral, and so gives rise to stereoisomers, e.g., (R) and (S) enantiomers if it is the only chiral centre, each of which is disclosed and encompassed.
  • Ring A is: wherein: Z 1 is N, CH, or CR Z1 ; Z 2 is CH, CR Z2 , or N; and wherein: -R A2 is -R A222 , -F, -Cl, -Br, or -I; each -R A222 is independently linear or branched saturated C1-4alkyl; -R A3 is -H; -R A4 is -H; and: Ring B is selected from: wherein: Y 1 is S, Y 2 is CH and Y 3 is N, or Y 1 is S, Y 2 is N and Y 3 is CH; Y 4 is N, Y 5 is S, and Y 6 is CH; Y 7 is N, Y 8 is CH, and Y 9 is S; and wherein: -Q is -L Q1 -Q 1 , -L Q3 -Q 3 , or -L Q5 -Q 5 ; wherein: -Q is -L Q1 -Q
  • each -R Z1 , and -R Z2 are independently: -F, -Cl, -Br, -I, -R ZZ , -CF3, -OH, -OR ZZ , or -OCF3.
  • each -R Z1 , and -R Z2 if present, is independently: -F, -Cl, -Br, -I, -R ZZ , or -OH.
  • each -R Z1 , and -R Z2 if present, is independently: -F, -Cl, -R ZZ , or -OH.
  • each -R Z1 , and -R Z2 if present, is independently: -F, -Cl, or -R ZZ .
  • each -R Z2 if present is independently -Br.
  • each -R Z2 if present is independently -R ZZ .
  • the Group -R ZZ [091]
  • each -R ZZ , if present, is: -Me, -Et, -nPr, -iPr, -nBu, or -tBu.
  • each -R ZZ if present, is: -Me, -Et, -nPr, or -iPr.
  • each -R ZZ if present, is: -Me or -Et.
  • each -R ZZ if present, is: -Me.
  • the Group -R A2 [095] (28) A compound according to any one of (1) to (27), wherein: -R A2 is -R A222 , -F, -Cl, -Br, -I, -CF 3 , -CHF 2 , -OH, -OR A222 , -OCF 3 , or -CN. [096] (29) A compound according to any one of (1) to (27), wherein: -R A2 is -R A222 , -F, -Cl, -Br, -I, -CF 3 , -CHF 2 , -OH, -OR A222 , or -OCF 3 .
  • the Group -R A33 [114] (47) A compound according to any one of (1) to (46), wherein: -R A33 , if present, is: -R A333 , -F, -Cl, -Br, -I, -OH, or -OR A333 . [115] (48) A compound according to any one of (1) to (46), wherein: -R A33 , if present, is: -R A333 , -F, -Cl, -Br, -I, or -OH.
  • the Group -R A44 [126] (59) A compound according to any one of (1) to (58), wherein: -R A44 , if present, is: -R A444 , -F, -Cl, -Br, -I, -OH, or -OR A444 . [127] (60) A compound according to any one of (1) to (58), wherein: -R A44 , if present, is: -R A444 , -F, -Cl, -Br, -I, or -OH.
  • [139] (72) A compound according to any one of (1) to (68), wherein: P-000059-WO-PCT-MYT - 27 - Y 1 , if present, is S, O, or NH; Y 2 , if present, is CH or N; Y 3 , if present, is N or CH; Y 4 , if present, is N or CH; Y 5 , if present, is S, O, or NH; Y 6 , if present, is N or CH; Y 7 , if present, is N or CH; Y 8 , if present, is N or CH; and Y 9 , if present, is S, O, or NH.
  • Ring B is selected from: , , , , , , , P-000059-WO-PCT-MYT - 28 - , , , , , , .
  • Y 1 if present, is S
  • Y 2 if present, is CH, CR Y2 , or N
  • Y 3 if present, is N, CH, or CR Y3
  • Y 4 if present, is N, CH, or CR Y4
  • Y 5 if present, is S
  • Y 6 if present, is N, CH, or CR Y6
  • Y 7 if present, is N, CH, or CR Y7
  • Y 8 if present, is N, CH, or CR Y8
  • Y 9 if present, is S.
  • [142] (74) A compound according to any one of (1) to (68), wherein: Y 1 , if present, is S; Y 2 , if present, is CH or N; Y 3 , if present, is N or CH; Y 4 , if present, is N or CH; Y 5 , if present, is S; Y 6 , if present, is N or CH; P-000059-WO-PCT-MYT - 29 - Y 7 , if present, is N or CH; Y 8 , if present, is N or CH; and Y 9 , if present, is S.
  • Y 1 if present, is S
  • Y 2 if present, is CH, CR Y2 , or N
  • Y 3 if present, is N, CH, or CR Y3 ; wherein exactly one of Y 2 and Y 3 is N
  • Y 4 if present, is N, CH, or CR Y4
  • Y 5 if present, is S
  • Y 6 if present, is N, CH, or CR Y6
  • Y 9 if present, is S
  • Y 7 and Y 8 is N.
  • Y 1 if present, is S
  • Y 2 if present, is CH, CR Y2 , or N
  • Y 3 if present, is N, CH, or CR Y3 ; wherein exactly one of Y 2 and Y 3 is N
  • Y 4 if present, is N
  • Y 5 if present, is S
  • Y 6 if present, is CH or CR Y6
  • Y 7 if present, is N
  • Y 8 if present, is CH or CR Y8
  • Y 9 if present, is S.
  • each -R Y2 , -R Y3 , -R Y4 , -R Y6 , -R Y7 , and -R Y8 , if present, is independently: -F, -Cl, -Br, -I, or -R YY .
  • each -R Y2 , -R Y3 , -R Y4 , -R Y6 , -R Y7 , and -R Y8 , if present, is independently: -F, -Cl, -Br, or -I.
  • each -R Y2 , -R Y3 , -R Y4 , -R Y6 , -R Y7 , and -R Y8 , if present, is independently: -F, -Cl, or -R YY .
  • each -R Y2 , -R Y3 , -R Y4 , -R Y6 , -R Y7 , and -R Y8 , if present, is independently: -R YY .
  • each -R YY if present, is: -Me, -Et, -nPr, -iPr, -nBu, or -tBu.
  • P-000059-WO-PCT-MYT - 32 - each -R YY if present, is: -Me, -Et, -nPr, or -iPr.
  • each -R Y1 , -R Y5 , and -R Y9 is independently: The Group -R YYN [164]
  • each -R YYN is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, or phenyl, wherein each phenyl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, and -CF3.
  • each -R YYN is independently linear or branched saturated C 1-4 alkyl or phenyl.
  • each -R YYN is independently linear or branched saturated C 1-4 alkyl.
  • each -R YYN is independently linear or branched saturated C 1-4 alkyl.
  • each -R YYN is -Me.
  • the Group -Q [168] (100) A compound according to any one of (1) to (99), wherein: -Q is -L Q1 -Q 1 , [169] (101) A compound according to any one of (1) to (99), wherein: -Q is -L Q2 -Q 2 . [170] (102) A compound according to any one of (1) to (99), wherein: -Q is -L Q3 -Q 3 . [171] (103) A compound according to any one of (1) to (99), wherein: -Q is -L Q4 -Q 4 . [172] (104) A compound according to any one of (1) to (99), wherein: -Q is -L Q5 -Q 5 .
  • -Q 1 if present, is C 5-6 heteroaryl; and is: optionally substituted on carbon with one or more groups -R Q1C ; and optionally substituted on secondary nitrogen, if present, with a group -R Q1N .
  • [176] (108) A compound according to any one of (1) to (104), wherein: -Q 1 , if present, is pyrazolyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, or pyridyl; and is: optionally substituted on carbon with one or more groups -R Q1C ; and optionally substituted on secondary nitrogen, if present, with a group -R Q1N .
  • [178] (110) A compound according to any one of (1) to (104), wherein: -Q 1 , if present, is pyridyl, or pyrazolyl; and is: optionally substituted on carbon with one or more groups -R Q1C ; and optionally substituted on secondary nitrogen, if present, with a group -R Q1N .
  • (111) A compound according to any one of (1) to (104), wherein: -Q 1 , if present, is C 5 heteroaryl, and is: optionally substituted on carbon with one or more groups -R Q1C ; and optionally substituted on secondary nitrogen with a group -R Q1N .
  • -Q 1 if present, is pyrazolyl, pyrrolyl, imidazolyl, furanyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, or thiadiazolyl; and is: optionally substituted on carbon with one or more groups -R Q1C ; and optionally substituted on secondary nitrogen, if present, with a group -R Q1N .
  • [190] (122) A compound according to any one of (1) to (104), wherein: -Q 1 , if present, is pyrimidinyl, pyrazinyl, pyridazinyl, or pyridyl, and is: optionally substituted on carbon with one or more groups -R Q1C .
  • (123) A compound according to any one of (1) to (104), wherein: -Q 1 , if present, is pyridyl; and is: optionally substituted on carbon with one or more groups -R Q1C .
  • [192] (124) A compound according to any one of (1) to (104), wherein: -Q 1 , if present, is C9heteroaryl; and is: optionally substituted on carbon with one or more groups -R Q1C ; and optionally substituted on secondary nitrogen, if present, with a group -R Q1N .
  • [193] (125) A compound according to any one of (1) to (104), wherein: -Q 1 , if present, is C9heteroaryl; wherein, the C 9 heteroaryl is a 5:6-fused heteroaryl; and is: optionally substituted on carbon with one or more groups -R Q1C ; and optionally substituted on secondary nitrogen, if present, with a group -R Q1N .
  • [194] (126) A compound according to any one of (1) to (104), wherein: P-000059-WO-PCT-MYT - 36 - -Q 1 , if present, is indolyl, indazolyl, benzimidazolyl, benzoxazolyl, pyrazolo-pyridinyl, pyrazolo- pyrimidinyl, imidazo-pyridi n yl, or pyrrolo-pyridinyl; and is: optionally substituted on carbon with one or more groups -R Q1C ; and optionally substituted on secondary nitrogen, with a group -R Q1N .
  • (133) A comp ound according to any one of (1) to (104), wherein : -Q 1 , if present, is 1H-pyrazolo[3,4-b]pyridin-3-yl, 1H-pyrazolo -c] 3-yl, 1H- pyrazolo[4,3-c]pyridin-3-yl, or 1H-pyrazolo[4,3-b]pyridin-3-yl; and is: optionally substituted on car bon with one or more gro up s -R ; and optionally substituted on secondary nitrogen, with a group -R Q1N .
  • a compound according to any one of (1) to (148), wherein: -Q 2 , if present, is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azepanyl, or diazepanyl; and is: optionally substituted on sulfur, if present, with one or two groups O; optionally substituted on carbon with one or more groups -R Q2C ; and optionally substituted on secondary nitrogen, if present, with one or more groups -R Q2N .
  • a compound according to any one of (1) to (148), wherein: -Q 2 , if present, is pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl; and is: optionally substituted on sulfur, if present, with one or two groups O; optionally substituted on carbon with one or more groups -R Q2C ; and optionally substituted on secondary nitrogen, if present, with a group -R Q2N .
  • [220] (152) A compound according to any one of (1) to (148), wherein: -Q 2 , if present, is piperidinyl or piperazinyl; and is: optionally substituted on carbon with one or more groups -R Q2C ; and optionally substituted on secondary nitrogen, if pres Q2N en t, w ith a group -R .
  • [221] (153) A co mpound according to any one of (1) to (148 ), wherein: -Q 2 , if pres ent, is piperidinyl (e.g., piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl); and is: optionally substituted on carbon with one or more groups -R Q2C ; and optionally substituted on secondary nitrogen, if present, with a group -R Q2N .
  • piperidinyl e.g., piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl
  • a compou n d a c c o r d in g o n e o f ( 1 ) t o (148) -Q 2 , is piperidin-4-yl; and is: optionally stituted on carbon with one or more groups -R Q2C ; and optionally substituted on secondary nitrogen, with a group -R Q2N .
  • -Q 2 if present, is piperazin- -yl and is: optionally substituted on carbon one or more grou - Q2C ; and optionally substituted on seco n rogen with a gr -R Q2N .
  • a compound according to any one of (1) to (170), wherein: -L Q3 -, if present, is -C( S)NR LQ3A -.
  • the Group -Q 4 [249] (181) A compound according to any one of (1) to (180), wherein: -Q 4 , if present, is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; and is optionally substituted with one or more groups -R Q4C .
  • [252] (184) A compound according to any one of (1) to (180), wherein: -Q 4 , if present, is cyclobutyl; and is optionally substituted with one or more groups -R Q4C .
  • [253] (185) A compound according to any one of (1) to (180), wherein: -Q 4 , if present, is cyclopentyl; and is optionally substituted with one or more groups -R Q4C .
  • [254] (186) A compound according to any one of (1) to (180), wherein: -Q 4 , if present, is cyclohexyl; and is optionally substituted with one or more groups -R Q4C .
  • the Group -Q 5 [265] (197) A compound according to any one of (1) to (196), wherein: P-000059-WO-PCT-MYT - 44 - -Q 5 , if present, is -Me, -Et, -nPr, -iPr, -nBu, -iBu, -sBu, -tBu, n-pentyl, iso-pentyl, neo-pentyl, n-hexyl, iso-hexyl, or 3,3-dimethylbutyl; and is optionally substituted with one or more groups -R Q5C .
  • -Q 5 if present, is -Me, -Et, -iPr, -sBu, or -tBu; and is optionally substituted with one or more groups -R Q5C .
  • the Group -R LQ1A [286] (218) A compound according to any one of (1) to (217), wherein -R LQ1A , if present, is linear or branched saturated C1-4alkyl. [287] (219) A compound according to any one of (1) to (217), wherein -R LQ1A , if present, is -Me, -Et, -nPr, -iPr, -nBu, -iBu, -sBu, or -tBu. [288] (220) A compound according to any one of (1) to (217), wherein -R LQ1A , if present, is -Me.
  • each -R Q1C is independently: [295] (227) A compound according to any one of (1) to (221), wherein: each -R Q1C , if present, is: [296] (228) A compound according to any one of (1) to (221), wherein: each -R Q1C , if present, is: -F, -OH, -R Q1CC or -R Q1CX .
  • each -R Q1C if present, is: -F, -R Q1CC or -R Q1CX .
  • each -R Q1C if present, is: -F, -R Q1CC or -R Q1CX .
  • (230) A compound according to any one of (1) to (221), wherein: If -R Q1C is present, there is a single -R Q1C substituent selected from: -F, -OH, -R Q1CC and -R Q1CX .
  • each -R Q1C if present, is: -F, -OH, -tBu or -CF3.
  • the Group -R Q1CC [301] (233) A compound according to any one of (1) to (232), wherein: P-000059-WO-PCT-MYT - 47 - each -R Q1CC , if present, is independently linear or branched saturated C 1-4 alkyl, C 3-6 cycloalkyl, C3-6cycloalkyl-C1-3alkyl, phenyl, or phenyl-C1-3alkyl, wherein each phenyl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -CN, -OH, -O(CH3), -NH2, -NH(CH3), and -N(CH3)2.
  • each -R Q1CC if present, is independently linear or branched saturated C1-4alkyl, phenyl, or phenyl-CH2-, wherein each phenyl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -CN, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2.
  • each -R Q1CC if present, is independently linear or branched saturated C 1-4 alkyl or phenyl, wherein each phenyl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, - CN, -OH, -OCH 3 , -NH 2 , -NH(CH 3 ), and -N(CH 3 ) 2 .
  • each -R Q1CC if present, is independently linear or branched saturated C 1-4 alkyl or phenyl, wherein each phenyl is optionally substituted with one or more groups selected from: -CH3, and -OH.
  • each -R Q1CC if present, is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, phenyl, or benzyl.
  • each -R Q1CC is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, or phenyl.
  • each -R Q1CC is independently linear or branched saturated C 1-4 alkyl, or C 3-6 cycloalkyl.
  • each -R Q1CC if present, is independently linear or branched saturated C 1-4 alkyl, C 3-6 cycloalkyl, phenyl, or benzyl.
  • each -R Q1CC if present, is independently linear or branched saturated C1-4alkyl.
  • each -R Q1CC if present, is independently -Me, -Et, -nPr, -iPr, -nBu, or -tBu.
  • each -R Q1CC if present, is independently -Me, -Et, -nPr, or -iPr.
  • each -R Q1CC if present, is independently -Me or -tBu.
  • each -R Q1CC if present, is independently -Me or -Et.
  • each -R Q1CC if present, is -tBu.
  • P-000059-WO-PCT-MYT - 48 - each -R Q1CC if present, is -Me.
  • the Group -R Q1CCC [316] (248) A compound according to any one of (1) to (247), wherein: each -R Q1CCC , if present, is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, -sBu, or -tBu.
  • the Index “p1” in -O-(CH 2 ) p1 -O- [321] (253) A compound according to any one of (1) to (252), wherein: p1, if present, is 1.
  • each -R Q1CX is independently linear or branched saturated C1-4fluoroalkyl.
  • each -R Q1CX is independently -CF3, -CHF2, -CH2CF3, or -CH2CHF2.
  • each -R Q1CX if present, is -CF3.
  • each -R Q1CMM is independently linear or branched saturated C 1-4 alkyl, C 3-6 cycloalkyl, or C3-6cycloalkyl-C1-3alkyl, wherein C1-4alkyl and each cycloalkyl is optionally substituted with one or more groups selected from: -F, -OH, and -OCH 3 .
  • each -R Q1CMM if present, is independently linear or branched saturated C 1-4 alkyl, or C 3-6 cycloalkyl, wherein C1-4alkyl and each cycloalkyl is optionally substituted with one or more groups selected from: -F, -OH, and -OCH 3 .
  • each -R Q1CMM if present, is independently linear or branched saturated C1-4alkyl, wherein C1-4alkyl is optionally substituted with -OH, or -OCH3.
  • each -R Q1CMM if present, is independently linear or branched saturated C 1-4 alkyl.
  • each -R Q1CMM if present, is independently linear or branched saturated C 1-4 alkyl.
  • each -R Q1CMM if present, is independently -Me, -Et, -nPr, -iPr, -nBu, or -tBu.
  • each -R Q1CMM if present, is independently -Me, -Et, -nPr, or -iPr.
  • each -R Q1N is independently: [338]
  • each -R Q1N is independently: [339]
  • 271 A compound according to any one of (1) to (268), wherein: each -R Q1N , if present, is independently: -R Q1Nhet or -L Q1N -R Q1Nhet .
  • each -R Q1N if present, is: -R Q1Nhet .
  • each -R Q1N if present, is independently: [342]
  • each -R Q1N if present, is independently: -L Q1N -OH, or -L Q1N -OR Q1NC .
  • each -R Q1N is independently: -L Q1N -NH2, -L Q1N -NHR Q1NC , -L Q1N -NR Q1NC 2, or -L Q1N -R Q1NM .
  • each -R Q1NC is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C 3-6 cycloalkyl-C 1-3 alkyl, phenyl, phenyl-C 1-3 alkyl, wherein each phenyl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CN, -CF3, -OH, -OCH3, -NH2, -NHR Q1NCC , and -NR Q1NCC 2 .
  • each -R Q1NC is independently linear or branched saturated C1-4alkyl, phenyl, or benzyl.
  • each -R Q1NC is independently linear or branched saturated C1-4alkyl.
  • each -R Q1NC is independently -Me, -Et, -nPr, -iPr, -nBu, or -tBu.
  • each -R Q1NC if present, is independently -Me, -Et, -nPr, or -iPr.
  • each -R Q1NC if present, is independently -Me or -tBu.
  • each -R Q1NC if present, is independently -Me or -Et.
  • each -R Q1NC if present, is -Me.
  • each -R Q1NC if present, is -tBu.
  • the Group -R Q1NCC [354] (286 ) A compound according to any one of (1) to (285), wherein: each -R Q1NCC , if present, is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, -sBu, or -tBu.
  • each -R Q1NCC if present, is independently -Me.
  • the Group -R Q1NX [356]
  • each -R Q1NX if present, is independently linear or branched saturated C1-4fluoroalkyl.
  • each -R Q1NX if present, is independently -CF3, -CHF2, -CH2CF3, -CH2CHF2, or -CH2CH2F.
  • each -R Q1NX if present, is independently -CH2CF3, -CH2CHF2, or -CH2CH2F.
  • each -R Q1NX if present, is -CHF2.
  • the Group -L Q1N - [360] (292) A compound according to any one of (1) to (291), wherein: each -L Q1N -, if present, is independently -CH2-, -C(CH3)2-, -CH2CH2-, or -CH2CH2CH2-.
  • each -L Q1N -, if present, is independently -CH2-, -CH2CH2-, or -CH2CH2CH2-.
  • each -L Q1N -, if present, is -CH2-.
  • each -L Q1N -, if present, is -CH2CH2-.
  • each -L Q1N - is -CH2CH2CH2-.
  • each -R Q1NMM is independently linear or branched saturated C 1-4 alkyl, C 3-6 cycloalkyl, or C3-6cycloalkyl-C1-3alkyl.
  • each -R Q1NMM if present, is independently linear or branched saturated C1-4alkyl.
  • each -R Q1NMM is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, -sBu, or -tBu.
  • P-000059-WO-PCT-MYT - 53 - each -R Q1NMM if present, is -Me.
  • each -R Q1NHH is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, or C 3-6 cycloalkyl-C 1-3 alkyl; wherein C 1-4 alkyl and each cycloalkyl is optionally substituted with one or more groups selected from: -F, -OH, and -OCH3.
  • each -R Q1NHH is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, or C 3-6 cycloalkyl-C 1-3 alkyl.
  • each -R Q1NHH is independently linear or branched saturated C1-4alkyl.
  • each -R Q1NHH is independently -Me, -Et, -nPr, -iPr, -nBu, or -tBu.
  • each -R Q1NHH is independently -Me, -Et, -nPr, or -iPr.
  • each -R Q1NHH is independently -Me, -Et, -nPr, or -iPr.
  • each -R Q1NHH is independently -Me or -Et.
  • each -R Q2CC if present, is independently linear or branched saturated C 1-4 alkyl, phenyl, or phenyl-CH2-, wherein each phenyl is optionally substituted with one or more groups selected from: -F, -Cl, -CH 3 , -CF 3 , -CN, -OH, -O(CH 3 ), -NH 2 , -NH(CH 3 ), and -N(CH 3 ) 2 .
  • each -R Q2CC is independently linear or branched saturated C 1-4 alkyl, phenyl, or phenyl-CH2-.
  • each -R Q2CC is independently linear or branched saturated C1-4alkyl.
  • each -R Q2CC is: -Me, -Et, -nPr, -iPr, -nBu, or -tBu.
  • each -R Q2CC if present, is: -Me, -Et, -nPr, or -iPr.
  • each -R Q2CC if present, is: -Me or -Et.
  • each -R Q2CC if present, is: -Me or -Et.
  • P-000059-WO-PCT-MYT - 56 - each -R Q2CC if present, is: -Me.
  • each -R Q2CCC if present, is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, -sBu, or -tBu.
  • each -R Q2CCC if present, is independently -Me.
  • each -R Q2CX is independently linear or branched saturated C 1-4 fluoroalkyl.
  • each -R Q2CX if present, is independently -CF 3 , -CHF 2 , -CH 2 CF 3 , or -CH 2 CHF 2 .
  • each -R Q2CX if present, is -CF3.
  • the Group -R Q2CMM [409] (341) A compound according to any one of (1) to (340), wherein: P-000059-WO-PCT-MYT - 57 - each -R Q2CMM , if present, is independently linear or branched saturated C 1-4 alkyl [410] (342) A compound according to any one of (1) to (340), wherein: each -R Q2CMM , if present, is: -Me, -Et, -nPr, -iPr, -nBu, or -tBu.
  • each -R Q2CMM if present, is: -Me, -Et, -nPr, or -iPr.
  • each -R Q2CMM if present, is: -Me or -Et.
  • each -R Q2CMM if present, is: -Me.
  • each -R Q2N is independently: [415] (347)
  • each -R Q2NC is independently linear or branched saturated C 1-6 alkyl, phenyl, phenyl-CH2-, wherein C1-6alkyl is optionally substituted with one or more groups selected from: - F, -OH, or -OCH 3 , and each phenyl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -CN, -OH, -OCH3, -NH2, -NHR Q2NCC , and -NR Q2NCC 2; [419] (351) A compound according to any one of (1) to (349), wherein: P-000059-WO-PCT-MYT - 58 - Each -R Q2NC , if present, is independently linear or branched saturated C 1-4 alkyl, phenyl, or
  • each -R Q2NC if present, is independently linear or branched saturated C1-4alkyl, phenyl, or phenyl-CH2-.
  • each -R Q2NC if present, is independently linear or branched saturated C1-4alkyl.
  • each -R Q2NC if present, is: -Me, -Et, -nPr, -iPr, -nBu, or -tBu.
  • each -R Q2NC if present, is: -Me, -Et, -nPr, or -iPr.
  • each -R Q2NC if present, is: -Me or -Et.
  • each -R Q2NC if present, is: -Me.
  • each -R Q2NCC is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, -sBu, or -tBu.
  • each -R Q2NCC is independently -Me.
  • each -R Q3C if present, is independently: -CN, or -NO2; and two adjacent-R Q3C , if present, taken together may form -(CH 2 ) n3 -O-(CH 2 ) m3 - or -O-(CH 2 ) p3 -O.
  • each -R Q3C if present, is independently: and two adjacent-R Q3C , if present, taken together may form -(CH2)n3-O-(CH2)m3- or -O-(CH2)p3-O.
  • the Group -R Q3CC [442] (374) A compound according to any one of (1) to (373), wherein: P-000059-WO-PCT-MYT - 61 - each -R Q3CC , if present, is independently linear or branched saturated C 1-4 alkyl, C 3-6 cycloalkyl, phenyl, or phenyl-CH2-, wherein each cycloalkyl is optionally substituted with one or more groups selected from: -F, -OH, and -OCH3, and each phenyl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -CN, -OH, -O(CH3), -NH2, -NH(CH3), and -N(CH3)2.
  • each -R Q3CC is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, or phenyl, wherein each phenyl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -CN, -OH, -O(CH3), -NH2, -NH(CH3), and -N(CH3)2.
  • each -R Q3CC is independently linear or branched saturated C 1-4 alkyl, C 3-6 cycloalkyl, or phenyl, wherein each phenyl is optionally substituted with one or more -F groups.
  • each -R Q3CC if present, is independently -Me, -tBu, cyclopropyl or phenyl, wherein each phenyl is optionally substituted with one or more -F groups.
  • each -R Q3CC if present, is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, phenyl, or phenyl-CH2-.
  • each -R Q3CC if present, is independently linear or branched saturated C1-4alkyl, or C3-6cycloalkyl.
  • each -R Q3CC if present, is independently linear or branched saturated C 1-4 alkyl.
  • each -R Q3CC if present, is: -Me, -Et, -nPr, -iPr, -nBu, or -tBu.
  • each -R Q3CC if present, is: -Me, -Et, -nPr, or -iPr.
  • each -R Q3CC if present, is: -Me, -Et, -nPr, or -iPr.
  • each -R Q3CC if present, is: -Me or -tBu.
  • each -R Q3CC if present, is: -Me or -Et.
  • each -R Q3CC if present, is: -tBu.
  • each -R Q3CC if present, is: -Me.
  • each -R Q3CC if present, is C3-6cycloalkyl.
  • each -R Q3CC if present, is: cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • each -R Q3CC if present, is: cyclopropyl.
  • each -R Q3CC if present, is phenyl, wherein each phenyl is optionally substituted with one or more -F groups.
  • the Group -R Q3CCC [459] (391) A compound according to any one of (1) to (390), wherein: each -R Q3CCC , if present, is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, -sBu, or -tBu.
  • each -R Q3CCC if present, is independently -Me.
  • the Group -R Q3CX [461] (393) A compound according to any one of (1) to (392), wherein: each -R Q3CX , if present, is independently linear or branched saturated C 1-4 fluoroalkyl.
  • each -R Q3CX if present, is independently -CF 3 , -CHF 2 , -CH 2 CF 3 , or -CH 2 CHF 2 .
  • each -R Q3CX if present, is -CF 3 .
  • the Group -L Q3C - [464] (396) A compound according to any one wherein: each -L Q3C -, if present, is independently - -CH2CH2-, or -CH2CH2CH2-. [465] (397) A compound according to any one wherein: each -L Q3C -, if present, is independently - or -CH2CH2CH2-. [466] (398) A compound according to any one wherein: each -L Q3C -, if present, is -CH2-.
  • each -R Q3CMM is independently linear or branched saturated C1-4alkyl.
  • each -R Q3CMM if present, is: -Me, -Et, -nPr, -iPr, -nBu, or -tBu.
  • each -R Q3CMM if present, is: -Me, -Et, -nPr, or -iPr.
  • each -R Q3CMM if present, is: -Me or -Et.
  • each -R Q3CMM if present, is: -Me.
  • [479] (411) A compound according to any one of (1) to (408), wherein: n3, if present, is 1 or 2; m3, if present, is 1 or 2; with the proviso that m3+n3 is 2 or 3.
  • the Indices “p3” in -O-(CH2)p3-O- [480] (412) A compound according to any one of (1) to (411), wherein: p3, if present, is 1.
  • [481] (413) A compound according to any one of (1) to (411), wherein: p3, if present, is 2.
  • each -R Q4C is independently: [489] (421) A compound according to any one of (1) to (419), wherein: each -R Q4C , if present, is independently: P-000059-WO-PCT-MYT - 65 - -F, -R Q4CC , -R Q4CX , -OH, -OR Q4CC , or -OR Q4CX .
  • each -R Q4C if present, is independently: -F, -R Q4CC , -OH, or -OR Q4CC .
  • each -R Q4C if present, is independently: [492] (424)
  • each -R Q4C if present, is independently: -R Q4CC , -OH, or -OR Q4CC .
  • each -R Q4CC is independently linear or branched saturated C1-4alkyl, phenyl, phenyl-C 1-3 alkyl, wherein each phenyl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -CN, -OH, -O(CH3), -NH2, -NH(CH3), and -N(CH3)2.
  • each -R Q4CC if present, is independently linear or branched saturated C1-4alkyl, phenyl, or phenyl-CH 2 -, wherein each phenyl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -CN, -OH, -O(CH3), -NH2, -NH(CH3), and -N(CH3)2.
  • each -R Q4CC is independently linear or branched saturated C1-4alkyl, phenyl, or phenyl-CH2-.
  • each -R Q4CC is independently linear or branched saturated C1-4alkyl.
  • each -R Q4CC is: -Me, -Et, -nPr, -iPr, -nBu, or -tBu.
  • each -R Q4CC if present, is: -Me, -Et, -nPr, or -iPr.
  • [499] (431) A compound according to any one of (1) to (424), wherein: P-000059-WO-PCT-MYT - 66 - each -R Q4CC , if present, is: -Me or -Et.
  • [500] (432) A compound according to any one of (1) to (424), wherein: each -R Q4CC , if present, is: -Me.
  • each -R Q4CCC if present, is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, -sBu, or -tBu.
  • each -R Q4CCC if present, is independently -Me, -Et, or -nPr.
  • each -R Q4CCC if present, is independently -Me.
  • each -R Q4CX is independently linear or branched saturated C1-4fluoroalkyl.
  • each -R Q4CX is independently -CF3, -CHF2, -CH2CF3, or -CH2CHF2.
  • each -R Q4CX is -CF 3 .
  • each -R Q4CMM is independently linear or branched saturated C1-4alkyl [511] (443) A compound according to any one of (1) to (441), wherein: each -R Q4CMM , if present, is: -Me, -Et, -nPr, -iPr, -nBu, or -tBu. [512] (444) A compound according to any one of (1) to (441), wherein: each -R Q4CMM , if present, is: -Me, -Et, -nPr, or -iPr.
  • the Group -R LQ5A [517] (449) A compound according to any one of (1) to (448), wherein -R LQ5A , if present, is linear or branched saturated C1-4alkyl. [518] (450) A compound according to any one of (1) to (448), wherein -R LQ5A , if present, is -Me, -Et, -nPr, -iPr, -nBu, -iBu, -sBu, or -tBu. [519] (451) A compound according to any one of (1) to (448), wherein -R LQ5A , if present, is -Me.
  • [520] (452) A compound according to any one of (1) to (448), wherein -R LQ5A , if present, is -H.
  • the Group -R Q5C [521] (453) A compound according to any one of (1) to (452), wherein: each -R Q5C , if present, is independently: -R Q5CC , -F, -OH, -OR Q5CC , OCF 3 , or -NH 2 .
  • [522] (454) A compound according to any one of (1) to (452), wherein: P-000059-WO-PCT-MYT - 68 - each -R Q5C , if present, is independently: -R Q5CC , or -NH2.
  • each -R Q5C if present, is independently: phenyl, or -NH2.
  • each -R Q5C if present, is independently: -F, -OH, -OR Q5CC , or OCF3.
  • each -R Q5C if present, is independently: -OH, -OR Q5CC , -NH 2 , -NHR Q5CC , -NR Q5CC 2 , or -R Q5CM .
  • each -R Q5C if present, is independently: -NH2, -NHR Q5CC , -NR Q5CC 2, or -R Q5CM .
  • each -R Q5CC is independently linear or branched saturated C1-4alkyl, phenyl, or phenyl-CH 2 -, wherein each phenyl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -CN, -OH, -O(CH3), -NH2, -NH(CH3), and -N(CH3)2.
  • each -R Q5CC if present, is independently linear or branched saturated C1-4alkyl, phenyl, or phenyl-CH 2 -.
  • each -R Q5CC if present, is independently linear or branched saturated C1-4alkyl, or phenyl.
  • each -R Q5CC if present, is independently linear or branched saturated C1-4alkyl.
  • each -R Q5CC if present, is: -Me, -Et, -nPr, -iPr, -nBu, or -tBu.
  • each -R Q5CC if present, is: -Me, -Et, -nPr, or -iPr.
  • each -R Q5CCC is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, -sBu, or -tBu.
  • each -R Q5CCC is independently -Me.
  • each -R Q5CMM is independently linear or branched saturated C1-4alkyl.
  • P-000059-WO-PCT-MYT - 70 - each -R Q5CMM is: -Me, -Et, -nPr, -iPr, -nBu, or -tBu.
  • each -R Q5CMM if present, is: -Me, -Et, -nPr, or -iPr.
  • each -R Q5CMM if present, is: -Me or -Et.
  • each -R Q5CMM if present, is: -Me.
  • -Q 1 is C5-10heteroaryl; and is: optionally substituted on carbon with one or more groups -R Q1C ; and optionally substituted on secondary nitrogen, if present, with one or more groups -R Q1N .
  • -Q 1 is pyridyl (for example pyrid-2-yl, pyrid-3-yl, or pyrid-4-yl), or pyrazolyl (for example [1H- pyrazol-3-yl]) and is: optionally substituted on carbon with one or more groups -R Q1C ; and optionally substituted on secondary nitrogen, if present, with one or more groups -R Q1N .
  • -Q 1 is pyridyl (for example pyrid-2-yl, pyrid-3-yl, or pyrid-4-yl).
  • -Q 1 is pyrazolyl (for example [1H-pyrazol-3-yl]) and is: optionally substituted on carbon with one or more groups -R Q1C ; and optionally substituted on secondary nitrogen, if present, with one or more groups -R Q1N .
  • the compound is a compound of the following structural formula: .
  • Example Table 1 # Structure Name 2-benzamido-N-(5-methyl-1H- BAA-001 indazol-4-yl)thiazole-5- carboxamide P-000059-WO-PCT-MYT - 79 - # Structure Name N-(5-methyl-1H-indazol-4-yl)-2- BAA-002 (picolinamido) thiazole-5- carboxamide N-(5-methyl-1H-indazol-4-yl)-2- (3-(trifluoromethyl) BAA-003 benzamido)thiazole-5- carboxamide 2-(3,4-dimethylbenzamido)-N- BAA-004 (5-methyl-1H-indazol-4- yl)thi
  • the BAA compound is obtainable (or obtained) by following the methods described in the experimental section.
  • the BAA compound is provided according to any embodiment described herein (for example, embodiment (1), (2) or (3); or claim 1) with the proviso that any of the specific 10 Examples are individually disclaimed.
  • a further feature is any embodiment described herein (for example, embodiment (1), (2) or (3); or claim 1) with the proviso that any (for example any one, any two, or any three) of the compounds in the preceding table (for example BAA-015) are individually disclaimed.
  • the BAA compound is provided according to any embodiment described 15 herein (for example, embodiment (1), (2) or (3); or claim 1) with the proviso that any other embodiment described herein is specifically disclaimed.
  • Combinations [576] It is appreciated that certain features of the invention, which are, for clarity, described in the 20 context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination.
  • Substantially Purified Forms 5 [578]
  • 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.
  • the substantially purified form is at least 50% by weight, e.g., at least 60% by weight, e.g., at least 70% by weight, e.g., at least 80% by weight, e.g., at least 90% by weight, e.g., at least 95% by weight, e.g., at least 97% by weight, e.g., at least 98% by weight, e.g., at least 99% by 10 weight.
  • the substantially purified form refers to the compound in any stereoisomeric or enantiomeric form.
  • the substantially purified form refers to a mixture of stereoisomers, i.e., purified with respect to other compounds.
  • the substantially purified form refers to one stereoisomer, e.g., optically pure 15 stereoisomer.
  • the substantially purified form refers to a mixture of enantiomers.
  • the substantially purified form refers to an equimolar mixture of enantiomers (i.e., a racemic mixture, a racemate).
  • the substantially purified form refers to one enantiomer, e.g., optically pure enantiomer.
  • the contaminants represent no more than 50% by weight, e.g., no more 20 than 40% by weight, e.g., no more than 30% by weight, e.g., no more than 20% by weight, e.g., no more than 10% by weight, e.g., no more than 5% by weight, e.g., no more than 3% by weight, e.g., no more than 2% by weight, e.g., no more than 1% by weight.
  • the contaminants refer to other compounds, that is, other than stereoisomers or enantiomers. In one embodiment, the contaminants refer to other compounds and other 25 stereoisomers.
  • the contaminants refer to other compounds and the other enantiomer.
  • the substantially purified form is at least 60% optically pure (i.e., 60% of the compound, on a molar basis, is the desired stereoisomer or enantiomer, and 40% is the undesired stereoisomer or enantiomer), e.g., at least 70% optically pure, e.g., at least 80% optically pure, e.g., at 30 least 90% optically pure, e.g., at least 95% optically pure, e.g., at least 97% optically pure, e.g., at least 98% optically pure, e.g., at least 99% optically pure.
  • Certain compounds may exist in one or more particular geometric, optical, enantiomeric, 35 diastereoisomeric, epimeric, atropic, stereoisomeric, tautomeric, conformational, or anomeric forms, including but not limited to, cis- and trans-forms; E- and Z-forms; c-, t-, and r- forms; endo- and exo- forms; R-, S-, and meso-forms; D- and L-forms; d- and l-forms; (+) and (-) forms; keto-, enol-, and enolate-forms; syn- and anti-forms; synclinal- and anticlinal-forms; ⁇ - and ⁇ -forms; axial and equatorial P-000059-WO-PCT-MYT - 83 - forms; boat-, chair-, twist-, envelope-, and halfchair-forms; and combinations thereof, hereinafter collectively
  • a reference to a class of structures may well include structurally isomeric forms falling within that class (e.g., C1-6alkyl includes n-propyl and iso-propyl; butyl includes n-, iso-, sec-, and tert-butyl; methoxyphenyl includes ortho-, meta-, and para-methoxyphenyl).
  • C1-6alkyl includes n-propyl and iso-propyl
  • butyl includes n-, iso-, sec-, and tert-butyl
  • methoxyphenyl includes ortho-, meta-, and para-methoxyphenyl
  • 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.
  • a reference to a methoxy group, -OCH3 is not to be construed as a reference to its structural isomer, a hydroxymethyl group, -CH
  • a reference specifically to ortho-chlorophenyl is not to be construed as a reference to its structural isomer, meta-chlorophenyl.
  • 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.
  • H may be in any isotopic form, including 1 H, 2 H (D), and 3 H (T); C may be in any isotopic form, including 12 C, 13 C, and 14 C; O may be in any isotopic form, including 16 O and 18 O; and the like.
  • 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.
  • a reference to a particular compound includes all such isomeric forms, including mixtures (e.g., racemic mixtures) thereof.
  • Methods for the preparation (e.g., asymmetric synthesis) and separation (e.g., fractional crystallisation and chromatographic means) of such isomeric forms are either known in the art or are readily obtained by adapting the methods taught herein, or known methods, in a known manner.
  • P-000059-WO-PCT-MYT - 84 - Solid Forms [591] Compounds described in this specification may be conveniently prepared and handled in a range of solid forms.
  • Solid forms may comprise salts, co-crystals (for example solvates, such as hydrates) in various amorphous or crystalline forms. Solid forms may also include mixtures of such forms (for example a mixture of salt and co-crystal forms, a salt which is also a co-crystal (for example a solvate of a salt), and a mixture of amorphous and polymorphic forms of a given compound, salt or co-crystal. [592] Unless otherwise specified, a reference to a particular compound also includes all solid forms of that compound, including all salts, co-crystals, solvates and hydrates thereof.
  • Salts 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 Br ⁇ nsted acid or base), where there is complete transfer of a proton from one entity to another.
  • a first co-forming entity e.g. a compound such as a BAA compound
  • second co-forming entity e.g. a suitable Br ⁇ nsted acid or base
  • a salt may be formed with a suitable cation.
  • suitable inorganic cations include, but are not limited to, alkali metal ions such as Na + and K + , alkaline earth cations such as Ca 2+ and Mg 2+ , and other cations such as Al 3+ as well as the ammonium ion (i.e., NH4 + ).
  • Suitable organic cations include, but are not limited to substituted ammonium ions (e.g., NH 3 R + , NH 2 R 2 + , NHR 3 + , NR 4 + ), for example, where each R is independently linear or branched saturated C1-18alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-6alkyl, and phenyl-C1-6alkyl, wherein the phenyl group is optionally substituted.
  • substituted ammonium ions e.g., NH 3 R + , NH 2 R 2 + , NHR 3 + , NR 4 +
  • each R is independently linear or branched saturated C1-18alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-6alkyl, and phenyl-C1-6alkyl, wherein the phenyl group is optionally substituted.
  • Examples of some suitable substituted ammonium ions are those derived from: ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as amino acids, such as lysine and arginine.
  • An example of a common quaternary ammonium ion is N(CH 3 ) 4 + .
  • a salt may be formed with a suitable anion.
  • a parent structure contains a cationic group (e.g., -NMe3 + ), or has a functional group, which upon protonation may become cationic (e.g., -NH2 may become -NH3 + ), then a salt may be formed with a suitable anion.
  • a counter-anion is generally always present in order to balance the positive charge.
  • an inner salt also referred to as a zwitterion
  • 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.
  • organic anions include, but are not limited to, those derived from the following organic acids: 2-acetyloxybenzoic, acetic, trifluoroacetic, ascorbic, aspartic, benzoic, camphorsulfonic, cinnamic, citric, edetic, 1,2-ethanedisulfonic, ethanesulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, hydroxymaleic, hydroxynaphthalene carboxylic, isethionic, lactic, 5 lactobionic, lauric, maleic, malic, methanesulfonic, mucic, oleic, oxalic, palmitic, pamoic, pantothenic, phenylacetic, phenylsulfonic, propionic, pyruvic, salicylic, stearic, succinic,
  • suitable polymeric organic anions include, but are not limited to, those derived from the following polymeric acids: tannic acid, carboxymethyl cellulose.
  • suitable counter-ions which are especially suitable for quaternary ammonium 10 compounds (e.g., those with a -NMe 2 + group) include 1-adamantanesulfonate, benzenesulfonate, bisulfate, bromide, chloride, iodide, methanesulfonate, methylsulfate, 1,5-napthalene-bis-sulfonate, 4-nitrobenzenesulfonate, formate, tartrate, tosylate, trifluoroacetate, trifluoromethylsulfonate, sulphate.
  • the compound also contains a group capable of forming an anion (e.g., -COOH), then an inner salt may be formed.
  • an inner salt may be formed.
  • the BAA compound is provided in the form of a salt.
  • the BAA compound is provided in a neutral form (for example as a free acid, free base, or zwitterion).
  • 20 Co-crystals, Solvates and Hydrates [603] It may be convenient or desirable to prepare, purify, and/or handle a corresponding co-crystal of the compound.
  • co-crystal is used herein to refer to a solid complex comprising a first co- forming entity (e.g. a compound or salt of a compound, such as a BAA compound or a salt thereof) and a 25 second co-forming entity, where there is no complete transfer of a proton from one entity to another.
  • a first co-forming entity e.g. a compound or salt of a compound, such as a BAA compound or a salt thereof
  • solvate e.g. a compound or salt of a compound, such as a BAA compound or a salt thereof
  • the co-crystal may be referred to as a solvate.
  • the solvate may be conveniently referred to as a hydrate, for example, a mono-hydrate, a di-hydrate, a tri-hydrate, etc.
  • a reference to a particular compound also includes co-crystal, 30 solvate and hydrate forms thereof.
  • the BAA compound is provided in the form of a co-crystal (for example a solvate, such as a hydrate).
  • Chemically Protected Forms 35 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).
  • 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).
  • a protected or protecting 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.
  • the aldehyde or ketone group is readily regenerated, for example, by hydrolysis using water in the presence of acid.
  • 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-OCH 2 C 6 H 5 , -NH-Cbz), as a t-butoxy carbamate (-NHCO-OC(CH 3 ) 3 , -NH-Boc); as a 2- biphenyl-2-propoxy carbamate (-NHCO-OC(CH3)2C6H4C6H5, -NH-Bpoc), as a 9-fluorenylmethoxy carbamate (-NH-Fmoc), as a 6-nitroveratryloxy carbamate (-NH-Nvoc), as a 2-trimethylsilylethyloxy carbamate (-NH-Teoc), a 2,2,2-trichloroethyloxy carbamate (
  • a carboxylic acid group may be protected as an ester for example, as: an C 1-7 alkyl ester (e.g., a methyl ester; a t-butyl ester); a C1-7haloalkyl ester (e.g., a 2,2,2-trihaloethyl ester); a 2- tri(C 1-7 alkyl)silyl-ethyl ester; or a C 5-20 aryl-C 1-7 alkyl 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.
  • an C 1-7 alkyl ester e.g., a methyl ester; a t-butyl ester
  • a C1-7haloalkyl ester e.g., a 2,2,2-trihaloethyl
  • -SR thioether
  • P-000059-WO-PCT-MYT - 87 - It may be convenient or desirable to prepare, purify, and/or handle the compound in the form of a prodrug.
  • prodrug pertains to a compound, which yields the desired active compound in vivo. Typically, the prodrug is inactive, or less active than the desired active 5 compound, but may provide advantageous handling, administration, or metabolic properties.
  • prodrugs are metabolic precursors of the active compound, and are activated enzymatically to yield the active compound, or a compound, which, upon further chemical reaction, yields the active compound .
  • a composition e.g., a pharmaceutical composition
  • a pharmaceutically acceptable excipient for example a carrier and/or diluent
  • a method of preparing a composition comprising the step of mixing a BAA compound, as described herein, and a pharmaceutically acceptable excipient (for example a carrier and/or diluent).
  • 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).
  • PKMYT1 e.g., inhibiting or reducing or blocking the activity or function of PKMYT1
  • a method of inhibiting PKMYT1 e.g., inhibiting or reducing or blocking the activity or function of PKMYT1
  • 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.
  • the method is performed in vitro.
  • the method is performed in vivo.
  • the BAA compound is provided in the form of a pharmaceutically acceptable composition.
  • a candidate compound inhibits PKMYT1 (e.g., inhibits or reduces or blocks the activity or function of PKMYT1).
  • suitable assays are described herein and/or are known in the art.
  • a candidate compound inhibits PKMYT1 (e.g., inhibits or reduces or blocks or the activity or function of PKMYT1) in a cell.
  • 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.
  • effect the 5 morphological status of the cells (e.g., alive or dead, etc.) may be determined.
  • 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.
  • 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.
  • the direct interaction of the compound with the target in cells could be measured (e.g., “target engagement assay”) using, e.g., a colorimetric, fluorescent, or 10 luminescent readout. Use in Methods of Inhibiting Cell Proliferation, etc.
  • the BAA compounds described herein may e.g., (a) regulate (e.g., inhibit) cell proliferation; (b) inhibit cell cycle progression; (c) promote apoptosis; (d) reduce clonogenicity; (e) reduce 15 tumoursphere growth or self-renewal; (f) enhance impact of DNA-damaging agents on cell killing; or (g) a combination of one or more of these.
  • a method of regulating e.g., inhibiting cell proliferation (e.g., proliferation of a cell), inhibiting cell cycle progression, promoting apoptosis, reducing clonogenicity, reducing tumoursphere growth or self-renewal, or a combination of one or more these, in 20 vitro or in vivo, comprising contacting a cell with an effective amount of a BAA compound, as described herein.
  • the method is performed in vitro.
  • the method is performed in vivo.
  • the BAA compound is provided in the form of a pharmaceutically 25 acceptable composition.
  • 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.
  • blood including, e.g., neutrophils, eosinophils, basophils, lymphocytes, monocytes, erythrocytes, thrombocytes
  • lung including, e.g., bowel, colon
  • breast mammary
  • ovarian ovarian
  • prostate liver
  • liver hepatic
  • kidney renal
  • bladder pancreas
  • pancreas brain, and skin cells.
  • the BAA compounds described herein may inhibit cell migration and invasion, e.g., inhibit 35 metastasis.
  • the BAA compounds described herein may restore sensitivity to another agent in a resistant cell population.
  • the BAA compounds described herein may prevent emergence of resistance to another agent in a cell population. P-000059-WO-PCT-MYT - 89 -
  • 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.
  • a BAA compound 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.
  • a BAA compound for use in a method of treatment 10 of the human or animal body by therapy, for example, in a method of treatment of a disorder (e.g., a disease) as described herein.
  • a BAA compound as described herein, in the manufacture of a 15 medicament, for example, for use in a method of treatment, for example, for use in a method of treatment of a disorder (e.g., a disease) as described herein.
  • the medicament comprises the BAA compound.
  • Methods of Treatment 20 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.
  • 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).
  • a disorder e.g., a disease
  • PKMYT1 e.g., by the inhibition or reduction or blockage of the activity or function of PKMYT1
  • the treatment is treatment of a disorder (e.g., a disease), for example, a proliferative disorder, cancer, etc., as described 35 herein.
  • a disorder e.g., a disease
  • the disorder is: a proliferative disorder.
  • P-000059-WO-PCT-MYT - 90 - 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.
  • the proliferative disorder is characterised by benign, pre-malignant, 5 malignant, pre-metastatic, metastatic, or non-metastatic cellular proliferation, including for example: neoplasms, hyperplasias, tumours (e.g., histocytoma, glioma, astrocytoma, osteoma), cancers, psoriasis, bone diseases, fibroproliferative disorders (e.g., of connective tissues), pulmonary fibrosis, atherosclerosis, and smooth muscle cell proliferation in the blood vessels, such as stenosis or restenosis following angioplasty.
  • neoplasms e.g., hyperplasias, tumours (e.g., histocytoma, glioma, astrocytoma, osteoma), cancers, psoriasis, bone diseases, fibroproliferative disorders (e.g., of connective tissues), pulmonary fibrosis, atherosclerosis,
  • the treatment is treatment of a proliferative disorder.
  • proliferative disorder pertains to an unwanted or uncontrolled 15 cellular proliferation of excessive or abnormal cells which is undesired, such as neoplastic or hyperplastic growth.
  • the treatment is treatment of: a proliferative disorder characterised by benign, pre-malignant, or malignant cellular proliferation.
  • the treatment is treatment of a proliferative disorder characterised by, or 20 further characterised by: inappropriate activity and/or expression of PKMYT1, CCNE1, FBXW7, PP2A or one of its subunits, or concomitant mutation of p53 and CDKN2A.
  • the treatment is treatment of a proliferative disorder characterised by, or further characterised by: overexpression of PKMYT1 or CCNE1.
  • the treatment is treatment of a proliferative disorder characterised by, or 25 further characterised by overexpression of PKMYT1.
  • the treatment is treatment of a proliferative disorder characterised by, or further characterised by overexpression of CCNE1.
  • the treatment is treatment of a proliferative disorder characterised by, or further characterised by: inactivation, decreased activity, or decreased expression of FBXW7, PPP2R2A 30 or PPP2R1A.
  • the treatment is treatment of a proliferative disorder characterised by, or further characterised by inactivation of FBXW7.
  • the treatment is treatment of a proliferative disorder characterised by, or further characterised by decreased activity or decreased expression of PPP2R2A or PPP2R1A.
  • the treatment is treatment of a proliferative disorder characterised by, or further characterised by concomitant mutation of p53 and CDKN2A.
  • the treatment is treatment of cancer.
  • P-000059-WO-PCT-MYT - 91 - Disorders Treated - Cancer the treatment is treatment of cancer. Included among cancers are: 5 [660] (1) Carcinomas, including tumours derived from stratified squamous epithelia (squamous cell carcinomas) and tumours arising within organs or glands (adenocarcinomas).
  • Sarcomas including: osteosarcoma and osteogenic sarcoma (bone); chondrosarcoma (cartilage); leiomyosarcoma (smooth muscle); rhabdomyosarcoma (skeletal muscle); mesothelial 10 sarcoma and mesothelioma (membranous lining of body cavities); fibrosarcoma (fibrous tissue); angiosarcoma and haemangioendothelioma (blood vessels); liposarcoma (adipose tissue); glioma and astrocytoma (neurogenic connective tissue found in the brain); myxosarcoma (primitive embryonic connective tissue); mesenchymous and mixed mesodermal tumour (mixed connective tissue types).
  • Haematopoietic tumours including: myelogenous and granulocytic leukaemia (malignancy of the myeloid and granulocytic white blood cell series), e.g., chronic myeloid leukemia (CML), acute myeloid leukemia (AML); lymphatic, lymphocytic, and lymphoblastic leukaemia (malignancy of the lymphoid and lymphocytic blood cell series), e.g., acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL); polycythaemia vera (malignancy of various blood cell products, but with red 20 cells predominating).
  • myelogenous and granulocytic leukaemia malignancy of the myeloid and granulocytic white blood cell series
  • CML chronic myeloid leukemia
  • AML acute myeloid leukemia
  • lymphatic, lymphocytic, and lymphoblastic leukaemia malign
  • Lymphomas including: Hodgkin and Non-Hodgkin lymphomas.
  • Lymphomas including: Hodgkin and Non-Hodgkin lymphomas.
  • Mixed Types including, e.g., adenosquamous carcinoma; mixed mesodermal tumour; carcinosarcoma; teratocarcinoma.
  • the cancer is: 25 a bone or muscle sarcoma, for example: bone cancer; bone sarcoma; chondrosarcoma; Ewing’s sarcoma; heart cancer; leiomyosarcoma; malignant fibrous histiocytoma of bone; osteosarcoma; or rhabdomyosarcoma; a brain and nervous system cancer, for example: astrocytoma; brain cancer; brainstem glioma; cerebellar astrocytoma; cerebral astrocytoma; 30 ependymoma; glioblastoma; glioma; medulloblastoma; neuroblastoma; oligodendroglioma; pilocytic astrocytoma; pineal astrocytoma; pituitary adenoma; primitive neuroectodermal tumor; schwannoma; or visual pathway and hypothalamic glioma
  • the cancer is: endometrial cancer, uterine cancer, ovarian cancer, breast cancer, gastric cancer, bladder cancer, pancreatic cancer, mesothelioma, kidney cancer, stomach cancer, esophageal cancer, colorectal cancer, glioblastoma, lung cancer, or lung squamous cell carcinoma. 10 [668] In one embodiment, the cancer is endometrial cancer. [669] In one embodiment, the cancer is uterine cancer. [670] In one embodiment, the cancer is ovarian cancer. [671] In one embodiment, the cancer is breast cancer. [672] In one embodiment, the cancer is gastric cancer. 15 [673] In one embodiment, the cancer is bladder cancer.
  • the cancer is pancreatic cancer. [675] In one embodiment, the cancer is mesothelioma. [676] In one embodiment, the cancer is kidney cancer. [677] In one embodiment, the cancer is stomach cancer. 20 [678] In one embodiment, the cancer is esophageal cancer. [679] In one embodiment, the cancer is colorectal cancer. [680] In one embodiment, the cancer is glioblastoma. [681] In one embodiment, the cancer is lung cancer. [682] In one embodiment, the cancer is lung squamous cell carcinoma. 25 [683] In one embodiment, the cancer is characterised by, or further characterised by inappropriate activity (e.g., overexpression) of PKMYT1.
  • the cancer is characterised by, or further characterised by inappropriate activity (e.g., overexpression) of PKMYT1.
  • the cancer is: lung squamous cell carcinoma, lung adenocarcinoma, uterine corpus endometrial carcinoma, breast cancer, breast invasive carcinoma, hepatocellular carcinoma, clear-cell renal-cell carcinoma, kidney chromophobe cancer, renal papillary cell carcinoma, head and neck squamous cell carcinoma, 30 colon adenocarcinoma, stomach adenocarcinoma, thyroid carcinoma, prostate adenocarcinoma, adrenocortical carcinoma, lower grade glioma, mesothelioma, pancreatic adenocarcinoma, skin cutaneous melanoma, uveal melanoma.
  • the cancer is characterised by, or further characterised by involvement of PKMYT1 in progression, invasion and/or metastasis.
  • the cancer is: 35 non-small cell lung cancer, osteosarcoma, clear cell renal cell carcinoma, oral squamous cell carcinoma, gastric cancer, prostate cancer, oesophageal squamous cell carcinoma, colorectal cancer, hepatocellular carcinoma, ovarian cancer, neuroblastoma (in particular, with MYCN amplification), glioblastoma, acute lymphoblastic leukemia, multiple myeloma, Kaposi’s sarcoma, primary effusion lymphoma (PEL), or the plasmablastic variant of multicentric Castleman’s disease.
  • PEL primary effusion lymphoma
  • the cancer is characterised by, or further characterised by inappropriate activity (e.g., overexpression) of CCNE1.
  • the cancer is: uterine carcinosarcoma, uterine cancer, endometrial cancer, breast cancer, ovarian cancer, stomach cancer, colorectal cancer, bladder cancer, oesophageal cancer, cervical cancer, sarcoma, lung 5 squamous cancer, adenoid cystic carcinoma, pancreatic cancer, mesothelioma, lung adenocarcinoma, head & neck cancer, diffuse large B-cells lymphoma, or liver cancer.
  • the cancer is characterised by, or further characterised by inappropriate activity (e.g., overexpression) of CCNE1.
  • the cancer is: uterine carcinosarcoma, uterine cancer, endometrial cancer, breast cancer, ovarian cancer, 10 stomach cancer, colorectal cancer, bladder cancer, oesophageal cancer, cervical cancer, sarcoma, or lung squamous cancer.
  • the cancer is uterine carcinosarcoma (UCS) or uterine serous carcinoma (USC).
  • the cancer is high-grade serous ovarian carcinoma (HGSOC).
  • the cancer is high-grade serous ovarian cancer with CCNE1 amplification.
  • the cancer is triple-negative breast cancer (TNBC).
  • TNBC triple-negative breast cancer
  • the cancer is characterised by, or further characterised by inappropriate activity (e.g., inactivation) of FBXW7.
  • the cancer is: uterine carcinosarcoma, uterine cancer, endometrial cancer, breast cancer, ovarian cancer, 20 stomach cancer, colorectal cancer, bladder cancer, oesophageal cancer, cervical cancer, sarcoma, lung squamous cancer, or head & neck cancer.
  • the cancer is characterised by, or further characterised by inappropriate activity (e.g., inactivation) of FBXW7.
  • the cancer is: uterine carcinosarcoma, endometrial cancer, colorectal cancer, cervical cancer, bladder cancer, 25 head & neck cancer, gastric cancer, or lung squamous cells carcinoma.
  • the cancer is uterine carcinosarcoma (UCS) or uterine serous carcinoma (USC).
  • the cancer is characterised by, or further characterised by inappropriate activity (e.g., inactivation, decreased activity, decreased expression) of PPP2R2A or PPP2R1A.
  • 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.
  • the cancer e.g., as above
  • the treatment resistant cancer is resistant to standard of care therapy. P-000059-WO-PCT-MYT - 95 - [697] In one embodiment, the treatment resistant cancer is resistant to one or more of PARP inhibitors, cisplatin, WEE1 inhibitors and Cdk4/6 inhibitors. [698] In one embodiment, the treatment resistant cancer is recombination proficient ovarian cancer. [699] In one embodiment, the treatment resistant cancer is HER2- ER+ breast cancer with Cdk4/6 5 resistance. [700] In one embodiment, the treatment resistant cancer is CDK4/6 inhibitor resistant TP53 mutant ER+ breast cancer.
  • the cancer e.g., as above
  • the cancer is characterised, or further characterised, as metastatic cancer.
  • the anti-cancer effect may arise through one or more mechanisms, including but not limited to, the regulation of cell proliferation, the modulation of cell cycle progression, the inhibition of angiogenesis (the formation of new blood vessels), the inhibition of metastasis (the spread of a tumour from its origin), the inhibition of cell migration (the spread of cancer cells to other parts of the body), the inhibition of invasion (the spread of tumour cells into neighbouring normal structures), the 15 promotion of apoptosis (programmed cell death), death by necrosis, or induction of death by autophagy.
  • treatment refers generally to treatment of a human or an animal (e.g., in veterinary applications), in which some desired therapeutic effect is achieved, for example, the inhibition of the progress of the disorder (including, e.g., a reduction in the rate of progress, a halt in the rate of progress), alleviation of symptoms of the disorder, amelioration of the disorder, and cure of the disorder.
  • Treatment as a 25 prophylactic measure i.e., prophylaxis
  • prophylaxis is also included.
  • treatment includes reducing the progress of cancer, alleviating the symptoms of cancer, reducing the incidence of cancer, prophylaxis of cancer, etc. 30
  • therapeutically effective amount 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.
  • treatment includes combination treatments and therapies, in which two or more treatments or therapies are combined, for example, sequentially or simultaneously.
  • the PKMYT1 inhibitors and BAA compounds described herein may also be used in combination therapies, e.g., in conjunction with other agents.
  • P-000059-WO-PCT-MYT - 96 - is described herein.
  • a PKMYT1 inhibitor for example RP-6306, or a BAA compound as described herein
  • additional therapeutic agents for example, anti-cancer agents.
  • topoisomerase I inhibitor for example 5 as a “topoisomerase I inhibitor”, “topoisomerase II inhibitor”, “antimetabolite”, or other class of compound is mentioned herein in a general sense
  • this class includes all compounds demonstrating the required activity.
  • 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.
  • a PKMYT1 inhibitor for example RP-6306, or a BAA compound as described herein
  • 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.
  • a PKMYT1 inhibitor for example RP-6306, or a BAA compound as described herein
  • a method of treatment of the human or animal body by therapy for example, in a method of treatment of a disorder (e.g., a disease) as described herein, wherein the PKMYT1 inhibitor is administered in combination with one or more (e.g., 1, 2, 3, 4, etc.) additional therapeutic agents.
  • a PKMYT1 inhibitor for example RP-6306, or a BAA compound as 20 described herein
  • a method of treatment of the human or animal body by therapy for example, in a method of treatment of a disorder (e.g., a disease) as described herein, wherein the PKMYT1 inhibitor is administered in combination with one or more (e.g., 1, 2, 3, 4, etc.) additional therapeutic agents.
  • a method of treatment for example, a method of treatment of a disorder (e.g., a disease) as described herein, comprising administering to a subject in need of treatment 25 a therapeutically effective amount of a PKMYT1 inhibitor, for example as described herein, optionally in the form of a pharmaceutical composition, wherein the PKMYT1 inhibitor is administered in combination with one or more (e.g., 1, 2, 3, 4, etc.) additional therapeutic agents.
  • a BAA compound as described herein, wherein the BAA compound is administered in combination with one or more (e.g., 1, 2, 3, 4, etc.) additional therapeutic agents (for 30 example, anti-cancer agents).
  • a BAA compound 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.
  • a disorder e.g., a disease
  • additional therapeutic agents e.g., 1, 2, 3, 4, etc.
  • 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.
  • a disorder e.g., a disease
  • additional therapeutic agents e.g., 1, 2, 3, 4, etc.
  • 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.
  • a disorder e.g., a disease
  • additional therapeutic agents e.g., 1, 2, 3, 4, etc.
  • 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.
  • the medicament comprises the BAA compound.
  • 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.
  • a disorder e.g., a disease
  • additional therapeutic agents e.g., 1, 2, 3, 4, etc.
  • the agents may be administered simultaneously or sequentially, and may be administered in individually varying dose schedules and via different routes.
  • 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).
  • agents e.g., PKMYT1 inhibitors or the BAA compounds described here, plus one or more 25 other agents
  • the 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.
  • the other agent e.g., the additional therapeutic agent, for example the additional anti-cancer agent
  • an immunotherapy agent such as a monoclonal antibody (for example 30 trastuzumab, bevacizumab, cetuximab, daratumumab, or naxitamab, necitumumab, obinutuzumab, ofatumumab, panitumumab, pertuzumab, ramucirumab, or rituximab), a bispecific antibody (for example blinatumomab), an immune checkpoint inhibitor (for example ipilimumab, nivolumab, pembrolizumab, cemiplimab, atezolizumab, durvalumab, avelumab, dostarlimab, or tremelimumab), an immunomodulator (for example imiquimod, thalidomide, lenalidomide, or pon
  • the other agent is an antibody-drug conjugate (i.e. an “ADC”, for example brentuximab vedotin, inotuzumab ozogamicin, mirvetuximab exatecan, mirvetuximab soravtansine, trastuzumab deruxtecan, trastuzumab emtansine, gemtuzumab ozogamicin, enfortumab vedotin, P-000059-WO-PCT-MYT - 98 - polatuzumab vedotin, tisotumab vedotin, sacituzumab govitecan, loncastuximab tesirine, cetuximab sarotalocan, belantamab mafodotin, moxetumomab pasudotox or distamab vedotin).
  • ADC antibody-drug
  • the other agent is an antibody-drug conjugate, wherein the antibody-drug conjugate (or the antibody, or the antibody portion of the antibody-drug conjugate) targets HER2, 5 TROP2, Claudin 18.2, B7H3, EGFR, FOLR1 (FRa), CD22, MET, Nectin 4, CD19, B7-H4, CD276, CD33, CD70, CDH6, CEACAM5, GPR20, HER3, TACSTD2, CD79b, tissue factor (TF), CD19, BCMA, CD30, VTCN1, 5T4, AXL, CD166, dipeptidase-3, Lewis-Y, mesothelin, NAPi2b, TIM1, SEZ6, CD123, DLL3, PDL1, MUC1, PTK7, MUC18, or LIV-1.
  • the antibody-drug conjugate targets HER2, 5 TROP2, Claudin 18.2, B7H3, EGFR, FOLR1 (FRa), CD22, MET, Nectin 4, CD19, B7-
  • the other agent is an antibody-drug conjugate, wherein the antibody-drug 10 conjugate (or the antibody, or the antibody portion of the antibody-drug conjugate) targets FOLR1 (FRa), HER2, TROP2, mesothelin, NAPi2b, CDH6, B7-H4, B7-H3, 5T4, AXL, CD166, dipeptidase-3, Lewis-Y, TIM1, or tissue factor (TF).
  • the other agent is an antibody-drug conjugate, wherein the antibody-drug conjugate (or the antibody, or the antibody portion of the antibody-drug conjugate) targets FOLR1 (FRa), 15 CDH6, B7-H4, B7-H3, or CEACAM5.
  • the other agent is an antibody-drug conjugate useful in the treatment of ovarian cancer, for example an antibody-drug conjugate selected from mirvetuximab soravtansine, tisotumab vedotin, ASN004, enapotamab vedotin, vobramitamab duocarmazine, AZD8205, HKT228, CX- 2009, SC-003, STRO-002, MORAb-202, IMGN151, PRO-1184, A166, SYD985, SGN-15, anetumab 20 ravtansine, lifastuzumab vedotin, XMT-1536, XMT-1592, CDX-014, XB002, Dato-DXd, IMMU-132, SKB264, TORL-1–23, and AZD5335.
  • an antibody-drug conjugate selected from mirvetuximab soravtansine, tisotumab ved
  • 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.
  • the other agent is an antibody-drug conjugate, wherein the payload (i.e. 25 the drug portion of the antibody-drug conjugate) is a topoisomerase 1 or topoisomerase 2 inhibitor.
  • the other agent is an antibody-drug conjugate, wherein the payload (i.e.
  • the drug portion of the antibody-drug conjugate is a topoisomerase 1 inhibitor, for example a topoisomerase 1 inhibitor selected from exatecan, deruxtecan (Dxd), SN38, Ed-04, YL0014, SHR9265, AZ14170132, KL610023, HS-9265, A-1743332, MF-6, DDDXd, MH30010008, P1003, P1021, and ZD06519.
  • the other agent is an antibody-drug conjugate wherein the payload (i.e.
  • the drug portion of the antibody-drug conjugate is a topoisomerase 1 inhibitor (for example an antibody- drug conjugate such as trastuzumab deruxtecan, sacituzumab govitecan, datopotamab deruxtecan, patritumab deruxtecan, SHR-A1811, SKB-264, labetuzumab govitecan, Ifinatamab deruxtecan, BL- B01D1, AZD-8205, DB-1303, DB-1305, ESG-401, FDA-022, IBI-354, MHB088C, PRO-1160, PRO-1184, SHR- 35 A1904, SHR-A1921, AZD-5335, MHB036C, CBX-12, DS-6000, TQB2102, DS-6157a, BL-M11D1, Epratuzumab-SN38, 9MW-2921, 7MW-3711, or mirvetuximab exatecan).
  • the other agent is an antibody-drug conjugate selected from trastuzumab deruxtecan, sacituzumab govitecan, datopotamab deruxtecan, patritumab deruxtecan, SHR-A1811, SKB- 264, labetuzumab govitecan, Ifinatamab deruxtecan, BL-B01D1, AZD-8205, DB-1303, DB-1305, ESG-401, P-000059-WO-PCT-MYT - 99 - FDA-022, IBI-354, MHB088C, PRO-1160, PRO-1184, SHR-A1904, SHR-A1921, AZD-5335, MHB036C, CBX- 12, DS-6000, TQB2102, DS-6157a, BL-M11D1, Epratuzumab-SN38, 9MW-2921, 7MW-3711, and mirvetuximab exatecan.
  • the other agent is an antibody-drug conjugate, wherein the antibody-drug 5 conjugate (or the antibody, or the antibody portion of the antibody-drug conjugate) targets FOLR1 (FRa), CDH6, B7-H4, B7-H3, or CEACAM5, and has a topoisomerase 1 inhibitor payload.
  • 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.
  • the other agent is mirvetuximab exatecan.
  • the cancer treated with the combination of PKMYT1 inhibitor and antibody-drug conjugate is characterised by, or further characterised by: amplification or overexpression of CCNE1.
  • the cancer treated with the combination of PKMYT1 inhibitor and 15 antibody-drug conjugate is characterised by, or further characterised by: inactivation, decreased activity, or decreased expression of FBXW7, PPP2R2A or PPP2R1A.
  • the cancer treated with the combination of PKMYT1 inhibitor and antibody-drug conjugate is characterised by, or further characterised by: inactivation of FBXW7.
  • the cancer treated with the combination of PKMYT1 inhibitor and 20 antibody-drug conjugate is characterised by, or further characterised by: decreased activity or decreased expression of PPP2R2A or PPP2R1A.
  • the cancer treated with the combination of PKMYT1 inhibitor and antibody-drug conjugate is characterised by, or further characterised by: concomitant mutation of p53 and CDKN2A. 25 [741] 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.
  • a PKMYT1 inhibitor for example RP-6306, or a BAA compound as described herein
  • a PKMYT1 inhibitor for example RP-6306, or a BAA compound as described herein
  • the PKMYT1 inhibitor is administered in 30 combination with an antibody-drug conjugate selected from brentuximab vedotin, inotuzumab ozogamicin, mirvetuximab exatecan, mirvetuximab soravtansine, trastuzumab deruxtecan, trastuzumab emtansine, gemtuzumab ozogamicin, enfortumab vedotin, polatuzumab vedotin, tisotumab vedotin, sacituzumab govitecan, loncastuximab tesirine, cetuximab sarotalocan, belantamab mafodotin, moxetumomab
  • a PKMYT1 inhibitor for example RP-6306, or a BAA compound as described herein
  • the PKMYT1 inhibitor is administered in combination with an antibody-drug conjugate selected from mirvetuximab soravtansine, tisotumab vedotin, ASN004, Enapotamab vedotin, vobramitamab duocarmazine, AZD8205, HKT228, CX-2009, SC- 003, STRO-002, MORAb-202, IMGN151, PRO-1184, A166, SYD985, SGN-15, anetumab ravtansine, P-000059-WO-PCT-MYT - 100 - lifastuzumab vedotin, XMT-1536, XMT-1592, CDX-014, XB002, Dato-DXd, IMMU-132,
  • an antibody-drug conjugate selected from mirvetuximab so
  • a PKMYT1 inhibitor for example RP-6306, or a BAA compound as described herein
  • the PKMYT1 inhibitor is administered in 5 combination with an antibody-drug conjugate which is a topoisomerase I inhibitor, a topoisomerase II inhibitor, or an antimetabolite.
  • a PKMYT1 inhibitor for example RP-6306, or a BAA compound as described herein
  • the PKMYT1 inhibitor is administered in combination with an antibody-drug conjugate, and the antibody-drug conjugate (or the antibody, or 10 the antibody portion of the antibody-drug conjugate) targets HER2, TROP2, Claudin 18.2, B7H3, EGFR, FOLR1 (FRa), CD22, MET, Nectin 4, CD19, B7-H4, CD276, CD33, CD70, CDH6, CEACAM5, GPR20, HER3, TACSTD2, CD79b, tissue factor (TF), CD19, BCMA, CD30, VTCN1, 5T4, AXL, CD166, dipeptidase-3, Lewis-Y, mesothelin, NAPi2b, TIM1, SEZ6, CD123, DLL3, PDL1, MUC1, PTK7, MUC18 or LIV-1.
  • a PKMYT1 inhibitor for example RP-6306, or a BAA compound as 15 described herein
  • 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).
  • FOLR1 FRa
  • HER2 HER2, TROP2, mesothelin
  • NAPi2b CDH6, B7-H4, B7-H3, 5T4, AXL
  • CD166 dipeptidase-3
  • Lewis-Y TIM1 or tissue factor (TF).
  • a PKMYT1 inhibitor for example RP-6306, or a BAA compound as 20 described herein
  • 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.
  • a PKMYT1 inhibitor for example RP-6306, or a BAA compound as 25 described herein for use in the treatment of cancer, wherein the PKMYT1 inhibitor is administered in combination with an antibody-drug conjugate, and the payload of the antibody-drug conjugate (i.e. the drug portion of the antibody-drug conjugate) is a DNA-damaging agent.
  • a PKMYT1 inhibitor for example RP-6306, or a BAA compound as described herein
  • the PKMYT1 inhibitor is administered 30 in combination with an antibody-drug conjugate, and the payload of the antibody-drug conjugate (i.e.
  • the drug portion of the antibody-drug conjugate is a topoisomerase 1 or topoisomerase 2 inhibitor.
  • a PKMYT1 inhibitor for example RP-6306, or a BAA compound as described herein
  • the PKMYT1 inhibitor is administered in combination with an antibody-drug conjugate, and the payload of the antibody-drug conjugate (i.e.
  • 35 the drug portion of the antibody-drug conjugate is a topoisomerase 1 inhibitor selected from exatecan, deruxtecan (Dxd), SN38, Ed-04, YL0014, SHR9265, AZ14170132, KL610023, HS-9265, A-1743332, MF-6, DDDXd, MH30010008, P1003, P1021, and ZD06519.
  • a PKMYT1 inhibitor for example RP-6306, or a BAA compound as described herein
  • the PKMYT1 inhibitor is administered in combination with an antibody-drug conjugate which is a topoisomerase I inhibitor.
  • a PKMYT1 inhibitor for example RP-6306, or a BAA compound as 5 described herein
  • the PKMYT1 inhibitor is administered in combination with an antibody-drug conjugate which is a topoisomerase I inhibitor, and the antibody- drug conjugate is selected from trastuzumab deruxtecan, sacituzumab govitecan, datopotamab deruxtecan, patritumab deruxtecan, SHR-A1811, SKB-264, labetuzumab govitecan, Ifinatamab deruxtecan, BL-B01D1, AZD-8205, DB-1303, DB-1305, ESG-401, FDA-022, IBI-354, MHB088C, PRO-1160,10 PRO-1184, SHR-A1904, SHR-A1921, AZD-5335, MHB036C, CBX-12, DS-6000, TQB210
  • a PKMYT1 inhibitor for example RP-6306, or a BAA compound as described herein
  • the PKMYT1 inhibitor is administered in combination with an antibody-drug conjugate which is a topoisomerase I inhibitor, and the antibody- 15 drug conjugate is mirvetuximab exatecan.
  • a PKMYT1 inhibitor for example RP-6306, or a BAA compound as described herein
  • the PKMYT1 inhibitor is administered in combination with an antibody-drug conjugate, and the antibody-drug conjugate (or the antibody, or the antibody portion of the antibody-drug conjugate) targets FOLR1 (FRa), CDH6, B7-H4, B7-H3, or 20 CEACAM5, and has a topoisomerase 1 inhibitor payload.
  • a PKMYT1 inhibitor for example RP-6306, or a BAA compound as described herein
  • the PKMYT1 inhibitor is administered in combination with an antibody-drug conjugate, and the antibody-drug conjugate (or the antibody, or the antibody portion of the antibody-drug conjugate) targets folate receptor alpha (FOLR1, FRa), and has 25 a topoisomerase 1 inhibitor payload.
  • FOLR1, FRa folate receptor alpha
  • a PKMYT1 inhibitor for example RP-6306, or a BAA compound as described herein
  • the PKMYT1 inhibitor is administered in combination with an antibody-drug conjugate, and the cancer is characterised by, or further characterised by: by amplification, or overexpression, of CCNE1.
  • a PKMYT1 inhibitor for example RP-6306, or a BAA compound as described herein
  • 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.
  • a PKMYT1 inhibitor for example RP-6306, or a BAA compound as 35 described herein
  • 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.
  • a PKMYT1 inhibitor for example RP-6306, or a BAA compound as described herein
  • the PKMYT1 inhibitor is administered P-000059-WO-PCT-MYT - 102 - in combination with an antibody-drug conjugate, and the cancer is characterised by, or further characterised by: decreased activity or decreased expression of PPP2R2A or PPP2R1A.
  • a PKMYT1 inhibitor for example RP-6306, or a BAA compound as described herein
  • the PKMYT1 inhibitor is administered 5 in combination with an antibody-drug conjugate, and the cancer is characterised by, or further characterised by: concomitant mutation of p53 and CDKN2A.
  • a PKMYT1 inhibitor for example RP-6306, or a BAA compound as described herein
  • the PKMYT1 inhibitor is administered in combination with a topoisomerase 1 inhibitor, a topoisomerase 2 inhibitor, or gemcitabine, and the 10 cancer is characterised by, or further characterised by: concomitant mutation of p53 and CDKN2A.
  • the other agent is a DNA-damaging agent, such as an alkylating agent (for example cis-platin, oxaliplatin, carboplatin, cyclophosphamide, melphalan, chlorambucil, bendamustine, temozolomide, trabectidin, mitomycin C, or dacarbazine); an antimetabolite (for example capecitabine, gemcitabine, 5-fluorouracil, fluoropyrimidine, trifluridine and tipiracil, cytarabine, or methotrexate); a 15 DNA intercalator (for example an anthracycline like doxorubicin, epirubicin, or daunorubicin), an antibiotic (for example bleomycin, dactinomycin, or mithramycin); a topoisomerase 1 inhibitor (for example a camptothecin such as irinotecan, or topotecan), a
  • 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).
  • the other agent is an alkylating agent (for example cis-platin).
  • the other agent is a topoisomerase I inhibitor (for example irinotecan, or topotecan).
  • the other agent is a topoisomerase II inhibitor (for example etoposide).
  • the other agent is an antimetabolite (for example gemcitabine).
  • treatment with a combination of a PKMYT1 inhibitor and a topoisomerase 30 1 inhibitor, a topoisomerase 2 inhibitor, or gemcitabine induces selective DNA damage in cancers characterised by: CCNE1 amplification or overexpression; inactivation, decreased activity, or decreased expression of FBXW7, PPP2R2A or PPP2R1A; or concomitant mutation of p53 and CDKN2A.
  • treatment with a combination of a PKMYT1 inhibitor and a topoisomerase 1 inhibitor, a topoisomerase 2 inhibitor, or gemcitabine induces selective DNA damage in cancers 35 characterised by: CCNE1 amplification or overexpression.
  • treatment with a combination of a PKMYT1 inhibitor and a topoisomerase 1 inhibitor, a topoisomerase 2 inhibitor, or gemcitabine induces selective DNA damage in cancers characterised by: inactivation, decreased activity, or decreased expression of FBXW7, PPP2R2A or PPP2R1A; or concomitant mutation of p53 and CDKN2A.
  • treatment with a combination of a PKMYT1 inhibitor and a topoisomerase 1 inhibitor, a topoisomerase 2 inhibitor, or gemcitabine induces selective DNA damage in cancers characterised by: inactivation, decreased activity, or decreased expression of FBXW7, PPP2R2A or PPP2R1A.
  • treatment with a combination of a PKMYT1 inhibitor and a topoisomerase 1 inhibitor, a topoisomerase 2 inhibitor, or gemcitabine induces selective DNA damage in cancers characterised by concomitant mutation of p53 and CDKN2A.
  • DNA damage induced by a combination of a PKMYT1 inhibitor and a topoisomerase 1 inhibitor, a topoisomerase 2 inhibitor, or gemcitabine is characterised by induction of 10 ⁇ H2AX.
  • treatment of cancer that exhibits CCNE1 amplification or overexpression; inactivation, decreased activity, or decreased expression of FBXW7, PPP2R2A or PPP2R1A; or concomitant mutation of p53 and CDKN2A; with a combination of a PKMYT1 inhibitor and a topoisomerase 1 inhibitor, a topoisomerase 2 inhibitor, or gemcitabine, is characterised by synergistic 15 induction of ⁇ H2AX.
  • 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 ⁇ H2AX.
  • treatment of cancer that exhibits inactivation, decreased activity, or 20 decreased expression of FBXW7, PPP2R2A or PPP2R1A; or concomitant mutation of p53 and CDKN2A with a combination of a PKMYT1 inhibitor and a topoisomerase 1 inhibitor, a topoisomerase 2 inhibitor, or gemcitabine, is characterised by synergistic induction of ⁇ H2AX.
  • treatment of cancer that exhibits inactivation, decreased activity, or decreased expression of FBXW7, PPP2R2A or PPP2R1A, with a combination of a PKMYT1 inhibitor and a 25 topoisomerase 1 inhibitor, a topoisomerase 2 inhibitor, or gemcitabine is characterised by synergistic induction of ⁇ H2AX.
  • treatment of cancer that exhibit concomitant mutation of p53 and CDKN2A with a combination of a PKMYT1 inhibitor and a topoisomerase 1 inhibitor, a topoisomerase 2 inhibitor, or gemcitabine is characterised by synergistic induction of ⁇ H2AX.
  • the other agent is a DNA-damage repair inhibitor (for example a PARP inhibitor such as olaparib, rucaparib, niraparib, or talazoparib; or a PARG inhibitor; or a USP1 inhibitor).
  • a PARP inhibitor such as olaparib, rucaparib, niraparib, or talazoparib
  • a PARG inhibitor such as a PACAP1 inhibitor
  • USP1 inhibitor a DNA-damage repair inhibitor
  • the other agent is double strand-break repair inhibitor (for example a Pol ⁇ inhibitor, or a RAD51 inhibitor).
  • the other agent is a signalling pathway inhibitor, such as a kinase inhibitor 35 (for example abemaciclib, acalabrutinib, afatinib, alectinib, avapritinib, axitinib, baricitinib, belumosudil, binimetinib, bosutinib, brigatinib, cabozantinib, capmatinib, ceritinib, cobimetinib, rizotinib, dabrafenib, dacomitinib, dasatinib, encorafenib, entrectinib, erdafitinib, erlotinib, everolimus, fedratinib, fostamatinib, gefitinib, gilteritinib, ibrutinib, imatinib, infigratinib, la
  • the other agent is a cell cycle targeting inhibitor, such as a CDK4/6 inhibitor (for example palbociclib, abemaciclib, or ribociclib).
  • the other agent is an agent targeting DNA damage checkpoints, such as an ATR inhibitor (for example ceralasertib, gartisertib, tuvusertib, elimusertib, or camonsertib), an ATM inhibitor (for example AZD0156), a CHK1 inhibitor (for example prexasertib), a CHK2 inhibitor, a WEE1 10 inhibitor (for example adavosertib, or azenosertib), a PLK1 inhibitor (for example onvansertib), or an AUR-A inhibitor (for example JAB-2485).
  • ATR inhibitor for example ceralasertib, gartisertib, tuvusertib, elimusertib, or camonsert
  • 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).
  • the other agent is an ATR inhibitor (for example ceralasertib, gartisertib, tuvusertib or camonsertib), or a WEE1 inhibitor (for example azenosertib).
  • the other agent is a CHK1 inhibitor (for example prexasertib).
  • the other agent is an ATR inhibitor (for example ceralasertib, gartisertib, tuvusertib, elimusertib, or camonsertib).
  • the other agent is a WEE1 inhibitor (for example adavosertib, or azenosertib).
  • the other agent is a hormone therapy agent, such as an antiestrogen (for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene, or idoxifene), an antiandrogen (for example abiraterone, bicalutamide, enzalutamide, flutamide, nilutamide, or cyproterone acetate), an 25 LHRH antagonist or LHRH agonist (for example goserelin, leuprorelin, or buserelin), a progestogen (for example megestrol acetate), an aromatase inhibitor (for example as anastrozole, letrozole, vorazole, or exemestane) an inhibitor of 5 ⁇ -reductase (for example finasteride) or an analogue of somatostatin (for example lanreotide).
  • an antiestrogen for example tamoxifen, fulvest
  • the other agent is a proteasome inhibitor (for example bortezomib), a 30 histone deacetylase inhibitor (for example vorinostat, romidepsin, panobinostat, or belinostat), or a DNA demethylating agent (for example azacitidine, or decitabine).
  • a proteasome inhibitor for example bortezomib
  • a 30 histone deacetylase inhibitor for example vorinostat, romidepsin, panobinostat, or belinostat
  • a DNA demethylating agent for example azacitidine, or decitabine
  • the other agent is radiotherapy, such as radiotherapy comprising treatment with a radiotherapeutic drug (for example a targeted radionuclide, or for example lutetium Lu 177inate, lutetium Lu 177 vipivotide tetraxetan, samarium Sm 153 lexidronam, radium Ra 223 35 dichloride, Ac-225 prostate-specific membrane antigen (PSMA) radioligand or other Ac-225 targeted radiotherapeutic, or Y-90 ibritumomab tiuxetan).
  • a radiotherapeutic drug for example a targeted radionuclide, or for example lutetium Lu 177inate, lutetium Lu 177 vipivotide tetraxetan, samarium Sm 153 lexidronam, radium Ra 223 35 dichloride, Ac-225 prostate-specific membrane antigen (PSMA) radioligand or other Ac-225 targeted radiotherapeutic, or Y-90
  • a PKMYT1 inhibitor for example RP-6306, or a BAA compound as described herein
  • the PKMYT1 inhibitor is administered in P-000059-WO-PCT-MYT - 105 - combination with a topoisomerase 1 inhibitor, a topoisomerase 2 inhibitor, or gemcitabine, and the cancer is characterised by, or further characterised by: CCNE1 amplification or overexpression; inactivation, decreased activity, or decreased expression of FBXW7, PPP2R2A or PPP2R1A; or concomitant mutation of p53 and CDKN2A.
  • Also described herein is a method of treatment of cancer, comprising administering to a subject in need of treatment a therapeutically effective amount of a PKMYT1 inhibitor, wherein the PKMYT1 inhibitor is administered in combination with a topoisomerase 1 inhibitor, a topoisomerase 2 inhibitor, or gemcitabine, and the cancer is characterised by, or further characterised by: CCNE1 amplification or overexpression; inactivation, decreased activity, or decreased expression of FBXW7, PPP2R2A or 10 PPP2R1A; or concomitant mutation of p53 and CDKN2A.
  • a method of increasing the sensitivity rate i.e.
  • a therapeutic combination comprising a PKMYT1 inhibitor and a topoisomerase 1 inhibitor, a topoisomerase 2 inhibitor, or gemcitabine; where the method comprises selecting a patient sub- population whose cancer is characterised by, or further characterised by: CCNE1 amplification or 15 overexpression; inactivation, decreased activity, or decreased expression of FBXW7, PPP2R2A or PPP2R1A; or concomitant mutation of p53 and CDKN2A.
  • Also disclosed herein is a method of identifying a subject having increased likelihood of responsiveness or sensitivity to a therapeutic combination comprising a PKMYT1 inhibitor and a topoisomerase 1 inhibitor, a topoisomerase 2 inhibitor, or gemcitabine; comprising determining the 20 level of expression of CCNE1, or the mutation status of FBXW7, PP2A or its subunits, p53 and CDKN2A in a biological sample of the subject (for example a biological sample of the subject’s cancer), wherein increased levels of CCNE1, mutations of FBXW7, PPP2R2A, PPP2R1A, or concomitant mutation of p53 and CDKN2A, when compared to a reference sample, identifies the subject as having increased likelihood of responsiveness or sensitivity to the indicated combinations.
  • a method of determining a treatment regimen for a subject with cancer comprising: a) Determining the level of expression of CCNE1, or the mutation status of FBXW7, PP2A or its 30 subunits, or p53 and CDKNA2, in a biological sample of the subject (for example a biological sample of the subject’s cancer); and b) Selecting the subject as suitable for receiving a treatment regimen comprising a therapeutically effective amount of a combination of a PKMYT1 inhibitor and a topoisomerase 1 inhibitor, a topoisomerase 2 inhibitor, or gemcitabine, when CCNE1 is amplified or overexpressed, and/or 35 one or more of FBXW7, PP2A or its subunits, or p53 and CDKNA2 together, are mut
  • Also disclosed herein is a method of treatment of cancer in a subject in need of such treatment, comprising: P-000059-WO-PCT-MYT - 106 - a) Determining the level of expression of CCNE1, or the mutation status of FBXW7, PP2A or its subunits, or p53 and CDKNA2 in a biological sample of the subject (for example a biological sample of the subject’s cancer); and b) Administering a treatment regimen comprising a therapeutically effective amount of a 5 combination of a PKMYT1 inhibitor with a topoisomerase 1 inhibitor, a topoisomerase 2 inhibitor, or gemcitabine, when CCNE1 is amplified or overexpressed, and/or one or more of FBXW7, PP2A or its subunits, or p53 and CDKNA2 together, are mutated.
  • the BAA compounds described herein may also be used as cell culture additives to inhibit PKMYT1 (e.g., to inhibit or reduce or block the activity or function of PKMYT1).
  • 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.
  • the BAA compounds described herein may also be used as a standard, for example, in an assay, in order to identify other active compounds, other PKMYT1 inhibitors, etc.
  • Kits [802] Also describes herein is a kit comprising (a) a BAA compound, as described herein, optionally provided as a composition (e.g., a pharmaceutical composition) and in a suitable container and/or with 20 suitable packaging; and (b) instructions for use, for example, in a method of treatment of a disorder (e.g., a disease) as described herein, for example, written instructions on how to administer the compound.
  • the written instructions may also include a list of indications for which the BAA compound is a suitable treatment.
  • 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).
  • Routes of administration include, for example: oral (e.g., by ingestion); buccal; sublingual; 30 transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including sub
  • the subject may be a chordate, a vertebrate, a mammal, a placental mammal, a marsupial (e.g., kangaroo, wombat), a rodent (e.g., a guinea pig, a hamster, a rat, a mouse), murine (e.g., a mouse), a lagomorph (e.g., a rabbit), avian (e.g., a bird), canine (e.g., a dog), feline (e.g., a cat), equine (e.g., a horse), porcine (e.g., a pig), ovine (e.g., a sheep), bovine (e.g., a cow), a primate, simian 5 (e.g., a monkey or
  • the subject may be any of its forms of development, for example, a foetus.
  • the subject e.g., patient
  • the subject is a human.
  • 10 Formulations [809] While it is possible for a BAA compound to be administered alone, may also be presented as a pharmaceutical formulation (e.g., composition, preparation, medicament) comprising at least one BAA compound, as described herein, together with one or more other pharmaceutically acceptable 15 ingredients well known to those skilled in the art, including, for example, pharmaceutically acceptable excipients, such as carriers, diluents, adjuvants, fillers, buffers, preservatives, anti-oxidants, lubricants, stabilisers, solubilisers, surfactants (e.g., wetting agents), masking agents, colouring agents, flavouring agents, and sweetening agents.
  • pharmaceutically acceptable excipients such as carriers, diluents, adjuvants, fillers, buffers, preservatives, anti-oxidants, lub
  • the formulation may further comprise other active agents, for example, other therapeutic or prophylactic agents.
  • other active agents for example, other therapeutic or prophylactic agents.
  • 20 [810] 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.
  • 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
  • Suitable excipients for example a carrier and/or diluent
  • the formulations may be prepared by any methods well known in the art of pharmacy. Such methods include the step of bringing into association the compound with a carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and P-000059-WO-PCT-MYT - 108 - intimately bringing into association the compound with carriers (e.g., liquid carriers, finely divided solid carrier, etc.), and then shaping the product, if necessary.
  • carriers e.g., liquid carriers, finely divided solid carrier, etc.
  • the formulation may be prepared to provide for rapid or slow release; immediate, delayed, timed, or sustained release; or a combination thereof.
  • Formulations may suitably be in the form of liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), elixirs, syrups, electuaries, mouthwashes, drops, tablets (including, e.g., coated tablets), granules, powders, lozenges, pastilles, capsules (including, e.g., hard and soft gelatin capsules), cachets, pills, ampoules, boluses, suppositories, pessaries, tinctures, gels, pastes, ointments, creams, lotions, oils, foams, sprays, mists, or 10 aerosols.
  • Formulations may suitably be provided as a patch, adhesive plaster, bandage, dressing, or the like which is impregnated with one or more compounds and optionally one or more other pharmaceutically acceptable ingredients, including, for example, penetration, permeation, and absorption enhancers. Formulations may also suitably be provided in the form of a depot or reservoir. 15 [817] The compound may be dissolved in, suspended in, or mixed with one or more other pharmaceutically acceptable ingredients. The compound may be presented in a liposome or other microparticulate which is designed to target the compound, for example, to blood components or one or more organs.
  • Formulations suitable for oral administration include liquids, solutions (e.g.,20 aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water- in-oil), elixirs, syrups, electuaries, tablets, granules, powders, capsules, cachets, pills, ampoules, boluses.
  • Formulations suitable for buccal administration include mouthwashes, lozenges, pastilles, as well as patches, adhesive plasters, depots, and reservoirs.
  • Lozenges typically comprise the compound in a flavoured basis, usually sucrose and acacia or tragacanth.
  • Pastilles typically comprise the compound in 25 an inert matrix, such as gelatin and glycerin, or sucrose and acacia.
  • Mouthwashes typically comprise the compound in a suitable liquid carrier.
  • Formulations suitable for sublingual administration include tablets, lozenges, pastilles, capsules, and pills.
  • Formulations suitable for oral transmucosal administration include liquids, solutions (e.g.,30 aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water- in-oil), mouthwashes, lozenges, pastilles, as well as patches, adhesive plasters, depots, and reservoirs.
  • solutions e.g.,30 aqueous, non-aqueous
  • suspensions e.g., aqueous, non-aqueous
  • emulsions e.g., oil-in-water, water- in-oil
  • mouthwashes e.g., lozenges, pastilles, as well as patches, adhesive plasters, depots, and reservoirs.
  • Formulations suitable for non-oral transmucosal administration include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water- in-oil), suppositories, pessaries, gels, pastes, ointments, creams, lotions, oils, as well as patches, 35 adhesive plasters, depots, and reservoirs.
  • Formulations suitable for transdermal administration include gels, pastes, ointments, creams, lotions, and oils, as well as patches, adhesive plasters, bandages, dressings, depots, and reservoirs.
  • Tablets may be made by conventional means, e.g., compression or moulding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable P-000059-WO-PCT-MYT - 109 - machine the compound in a free-flowing form such as a powder or granules, optionally mixed with one or more binders (e.g., povidone, gelatin, acacia, sorbitol, tragacanth, hydroxypropylmethyl cellulose); fillers or diluents (e.g., lactose, microcrystalline cellulose, calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, silica); disintegrants (e.g., sodium starch glycolate, cross-linked povidone, 5 cross-linked sodium carboxymethyl cellulose); surface-active or dispersing or wetting agents (e.g., sodium lauryl sulfate); preservative
  • Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled 10 release of the compound therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile.
  • Tablets may optionally be provided with a coating, for example, to affect release, for example an enteric coating, to provide release in parts of the gut other than the stomach.
  • Ointments are typically prepared from the compound and a paraffinic or a water-miscible 15 ointment base.
  • Creams are typically prepared from the compound and an oil-in-water cream base.
  • the aqueous phase of the cream base may include, for example, at least about 30% w/w of a polyhydric alcohol, i.e., an alcohol having two or more hydroxyl groups such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol and mixtures thereof.
  • the topical formulations may 20 desirably include a compound which enhances absorption or penetration of the compound through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogues.
  • Emulsions are typically prepared from the compound and an oily phase, which may optionally comprise merely an emulsifier (otherwise known as an emulgent), or it may comprise a mixture of at 25 least one emulsifier with a fat or an oil or with both a fat and an oil.
  • an emulsifier otherwise known as an emulgent
  • 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.
  • emulsifier(s) with or without stabiliser(s) make up the so-called emulsifying wax
  • 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.
  • Suitable emulgents and emulsion stabilisers include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulfate.
  • 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.
  • the cream may be a non-greasy, non-staining and washable product with suitable consistency to avoid 35 leakage from tubes or other containers.
  • Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters.
  • Formulations suitable for intranasal administration, where the carrier is a liquid include, for example, nasal spray, nasal drops, or by aerosol administration by nebuliser, include aqueous or oily 5 solutions of the compound.
  • Formulations suitable for intranasal administration 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.
  • Formulations suitable for pulmonary administration 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.
  • a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichorotetrafluoroethane, carbon dioxide, or other suitable gases.
  • Formulations suitable for ocular administration include eye drops wherein the compound is 15 dissolved or suspended in a suitable carrier, especially an aqueous solvent for the compound.
  • 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.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, 20 creams, gels, pastes, foams or spray formulations containing in addition to the compound, such carriers as are known in the art to be appropriate.
  • Formulations suitable for parenteral administration include aqueous or non- aqueous, isotonic, pyrogen-free, sterile liquids (e.g., solutions, suspensions), in which the compound is dissolved, suspended, or otherwise provided (e.g., in a liposome or other microparticulate).
  • Such liquids 25 may additionally contain other pharmaceutically acceptable ingredients, such as antioxidants, buffers, preservatives, stabilisers, bacteriostats, suspending agents, thickening agents, and solutes which render the formulation isotonic with the blood (or other relevant bodily fluid) of the intended recipient.
  • excipients include, for example, water, alcohols, polyols, glycerol, vegetable oils, and the like.
  • suitable isotonic carriers for use in such formulations include Sodium Chloride 30 Injection, Ringer's Solution, or Lactated Ringer's Injection.
  • concentration of the compound in the liquid is from about 1 ng/mL to about 10 ⁇ g/mL, for example from about 10 ng/mL to about 1 ⁇ g/mL.
  • the formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. 35 Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets. [836] It will be appreciated by one of skill in the art that appropriate dosages of the BAA compounds, and compositions comprising the BAA compounds, can vary from subject to subject (e.g., from patient P-000059-WO-PCT-MYT - 111 - to patient).
  • Determining the optimal dosage will generally involve balancing the level of therapeutic benefit against any risk or deleterious side effects.
  • the selected dosage level will depend on a variety of factors including, for example: the activity of the particular BAA compound; the route of administration; the time of administration; the rate of excretion of the BAA compound; the duration of the treatment; 5 other drugs, compounds, and/or materials used in combination; the severity of the disorder; and the species, sex, age, weight, condition, general health, and prior medical history of the subject (e.g., patient).
  • BAA compound and route of administration will ultimately be at the discretion of the physician, veterinarian, or clinician, although generally the dosage will be selected to achieve local concentrations at the site of action which achieve the desired effect without causing substantial harmful 10 or deleterious side-effects.
  • Administration can be effected in one dose, continuously or intermittently (e.g., in divided doses at appropriate intervals) throughout the course of treatment. Methods of determining the most effective means and dosage of administration are well known to those of skill in the art and will vary with the formulation used for therapy, the purpose of the therapy, the target cell(s) being treated, and 15 the subject being treated. Single or multiple administrations can be carried out with the dose level and pattern being selected by the treating physician, veterinarian, or clinician.
  • 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.
  • the amount 20 administered is calculated on the basis of the parent compound and so the actual weight to be used is increased proportionately.
  • Solutions were typically prepared in either deuterated chloroform (Chloroform-d), deuterated methanol (Methanol-d4) or deuterated dimethylsulfoxide (DMSO-d6) with chemical shifts referenced to tetramethylsilane (TMS) or deuterated solvent as an internal standard.
  • TMS tetramethylsilane
  • 1 H NMR data are reported indicating the chemical shift ( ⁇ ), the integration (e.g. 1 H), 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.
  • LCMS analyses were performed on a Waters Acquity UPLC using BEH C 18 1.7 ⁇ M columns (2.1 ⁇ 50 mm) with a diode array detector coupled to a SQD mass spectrometer or, a Waters Acquity I-Class UPLC using BEH C 18 1.7 ⁇ M columns (2.1 ⁇ 50 mm) with a diode array detector coupled to a QDa mass spectrometer.
  • reaction mixture was then diluted with ethyl acetate and carefully washed with a saturated aqueous sodium bicarbonate solution.
  • organic extracts were then washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give the crude product, which was purified using flash column chromatography over silica, eluting with 0-20% methanol/dichloromethane, to give 5-methyl-4-nitro-1H-indazole (539 mg, 54% yield) as an orange solid.
  • reaction mixture was then separated between DCM and water, and the organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product, which was purified using flash column chromatography over silica, eluting with 0-70% ethyl acetate/petroleum ether, to give 5-methyl-4-nitro-1-(tetrahydro-2H- pyran-2-yl)-1H-indazole (718 mg, 90% yield) as an orange solid.
  • the reaction mixture was separated between ethyl acetate (containing 5% ethanol as necessary) and water, and the organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give the intermediate ester as a crude product, which was purified using flash column chromatography over silica or used directly, as required.
  • Lithium hydroxide monohydrate (2.5 equiv.) was added to a solution of the methyl ester (1 equiv.) in methanol:water (2:1, 0.07 M) with stirring at 45 °C overnight.
  • the reaction mixture was then concentrated and separated between ethyl acetate and 0.5 M aqueous sodium hydroxide.
  • the aqueous phase was acidified to pH ⁇ 2 using 2 M aq. HCl and the product was either collected via filtration or extracted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated.
  • the carboxylic acid was dried in a vacuum oven before further use.
  • 2-benzamidothiazole-5-carboxylic acid [856] Prepared as described in method A1 from HATU (865 mg, 2.28 mmol), methyl 2-amino-1,3- thiazole-5-carboxylate (300 mg, 1.9 mmol), benzoic acid (278 mg, 2.26 mmol) and DIPEA (1.0 mL, 5.69 mmol) in anhydrous DMF (6 mL) and purification using flash column chromatography over silica, eluting with 0-10% methanol/dichloromethane to afford methyl 2-benzamidothiazole-5-carboxylate (185 mg, 37% yield), followed by hydrolysis with lithium hydroxide monohydrate (88 mg, 2.06 mmol) in methanol:THF:water (2:2:1, 5 mL) to give the title product (182 mg, 100% yield) as an off-white solid.
  • the reaction mixture was then concentrated and separated between ethyl acetate (containing 5% ethanol as necessary) and water, and the organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give the intermediate ester as a crude product, which was purified using flash column chromatography over silica or used directly, as required.
  • the intermediate ester was hydrolysed with lithium hydroxide using the same conditions described in Method A1 to afford the corresponding carboxylic acid.
  • BIOLOGICAL EXAMPLE 2 ADP-Glo enzymatic assays
  • PKMYT1 biochemical assay Inhibition of PKMYT1 was assessed using the ADP-Glo TM Max Detection System from Promega. This assay detects the production of ADP from ATP by PKMYT1 via a two-step process ultimately involving the conversion of ADP to ATP with the latter converted to light in a coupled reaction with luciferase/luciferin. Inhibition of PKMYT1 by small molecule inhibitors results in a retardation of luminescence above background.
  • the intrinsic ATPase activity of PKMYT1 was assessed P-000059-WO-PCT-MYT - 131 - according to the following protocol.
  • Compounds were dosed into Corning white low volume 384 well assay plates using an Echo acoustic dispenser to generate 10-point curves spanning a 3-fold dilution series.
  • DMSO (no inhibitor) control wells were prepared to benchmark the maximum and minimum signals in the presence and absence of PKMYT1, respectively.
  • the PKMYT1 kinase domain was purified in-house, as described above, and added to the wells at a final concentration of 15 nM in a buffer of 50 mM HEPES (pH 7.5), 10 mM MgCl2, 1 mM EGTA, 0.01 % Brij-35, 1 % DMSO.500 ⁇ M ATP was added to start the reaction with the final assay volume being 4 ⁇ l. The plate was then incubated for 60 minutes at 26 o C before the addition of 4 ⁇ l of ADP-Glo Reagent to stop the reaction and deplete the unconsumed ATP.
  • WEE1 (Thermo Fisher PR7373A) was added to each well at a final concentration of 15 nM in a buffer of 50 mM HEPES (pH 7.5), 10 mM MgCl2, 1 mM EGTA, 0.01 % Brij-35, 1 % DMSO.30 ⁇ M ATP was added to start the reaction with the final assay volume being 4 ⁇ l. The plate was then incubated for 60 minutes at 26 o C before the addition of 4 ⁇ l of ADP-Glo Reagent.
  • PKMYT1 IC50 primary biochemical assay
  • WEE1 IC50 selectivity assay
  • the PKMYT1 vs WEE1 selectivity is banded by fold difference in selectivity for PKMYT1 over WEE1 as follows: V: 3 - ⁇ 10 fold; W: 10 - ⁇ 100 fold; X: 100 - ⁇ 1000 fold; Y: >1000 fold. [880] Where either the PKMYT1 IC50 value was below the lowest concentration limit of the assay or the WEE1 IC50 value was above the top concentration limit of the assay, the PKMYT1 vs WEE1 selectivity value for these compounds falls at least in the band assigned but could be higher.
  • the luminescence signal was read on a PHERAStar FS microplate reader (BMG Labtech). Data analysis was performed using Microsoft Excel® and GI50 (concentration that achieves 50% cell growth proliferation inhibition) estimates generated with 10 GraphPad Prism v9. [882] The following compounds in Biological Data Table 2 inhibit OVCAR3 cell proliferation with a GI50 ⁇ 5 ⁇ M. In addition, selected compounds exhibit >3-fold selectivity for the CCNE1-amplified OVCAR3 cells compared to KYSE30 cells expressing normal levels of CCNE1.
  • Cell proliferation inhibition in cancer cell lines OVCAR3 expresses high level of CCNE1; control cell line KYSE30 expresses normal levels of CCNE1.
  • the cell line GI50 values are banded as follows: A: ⁇ 1 ⁇ M; B: 1 ⁇ M - ⁇ 5 ⁇ M; C: >5 ⁇ M.
  • the normal CCNE1 expression cell line (KYSE-30) to CCNE1-amplified cell line (OVCAR3) GI50 selectivity ratio is banded by fold difference as follows: X: 3 - ⁇ 10 fold; Y: >10 fold.
  • the selectivity ratio KYSE30 GI50 vs. OVCAR3 GI50 is given as “>N”, where N is the selectivity band. The selectivity value for these compounds falls at least in this band but could be higher. 5 Biological Data Table 2 Selectivity ratio # OVCAR3 KYSE30 GI50 ( ⁇ M) GI50 ( ⁇ M) KYSE30 GI50 vs.
  • the cells were maintained in RPMI medium supplemented with 20% foetal bovine serum, 1X non essential amino acids, 1mM sodium pyruvate, Glutamax and insulin.
  • Cells were seeded into 12-well plates at low density (50,000-200,000 cells per well), grown to confluence ( ⁇ 350- 400,000 cells per well) and then treated with a range of concentrations of PKMYT1 inhibitors.
  • the cells15 were incubated 20 hours and then harvested into 1X Laemmli Sample Buffer (BIORAD) without 2- mercaptoethanol, heated to 95°C for 5 min, centrifuged and sonicated using a microprobe for 15 sec, 21W to shear the DNA.

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Abstract

La présente invention relève d'une manière générale du domaine des composés thérapeutiques. Plus particulièrement, la présente invention concerne certains composés de biarylamide de formule suivante (également appelés "composés BAA") qui inhibent la protéine kinase, la tyrosine/thréonine 1 associée à la membrane (PKMYT1). La présente invention concerne également des compositions pharmaceutiques comprenant de tels composés, et l'utilisation de tels composés et de telles compositions, à la fois in vitro et in vivo, pour inhiber la PKMYT1 kinase; pour traiter des troubles (par exemple, des maladies) qui sont soulagés par l'inhibition de la PKMYT1 kinase; pour traiter un trouble prolifératif, un cancer, etc.
PCT/EP2025/059968 2024-04-11 2025-04-10 Composés thérapeutiques et leur utilisation en tant qu'inhibiteurs de pkmyt1 Pending WO2025215188A1 (fr)

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WO2008098096A1 (fr) * 2007-02-08 2008-08-14 Boehringer Ingelheim International Gmbh Composés hétérocycliques anti-cytokine
WO2021195782A1 (fr) 2020-04-01 2021-10-07 Repare Therapeutics Inc. Procédés d'utilisation d'inhibiteurs de myt1
WO2021202780A2 (fr) 2020-04-01 2021-10-07 Engine Biosciences Pte. Ltd. Méthodes et compositions pour le traitement du cancer
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