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WO2024184520A1 - Biarylamide derivatives and their use in the treatment of proliferative disorders - Google Patents

Biarylamide derivatives and their use in the treatment of proliferative disorders Download PDF

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Publication number
WO2024184520A1
WO2024184520A1 PCT/EP2024/056209 EP2024056209W WO2024184520A1 WO 2024184520 A1 WO2024184520 A1 WO 2024184520A1 EP 2024056209 W EP2024056209 W EP 2024056209W WO 2024184520 A1 WO2024184520 A1 WO 2024184520A1
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Prior art keywords
optionally substituted
alkyl
present
phenyl
independently
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PCT/EP2024/056209
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French (fr)
Inventor
Ali Raoof
Dan Niculescu-Duvaz
Michael Brown
Deborah SMITHEN
Christopher Fitzpatrick
Oleksandr GRYTSAI
Iain HAGAN
Richard Marais
Caroline Springer
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Cancer Research Technology Limited
My-T Bio Limited
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Publication of WO2024184520A1 publication Critical patent/WO2024184520A1/en

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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
    • C07D417/14—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
    • 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
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring

Definitions

  • the present invention pertains generally to the field of therapeutic compounds.
  • 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 Protein Kinase, Membrane Associated Tyrosine/Threonine 1
  • the present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit PKMYT1 kinase; to treat disorders (e.g., diseases) that are ameliorated by the inhibition of PKMYT 1 kinase; to treat a proliferative disorder, cancer, etc.
  • Ranges are often expressed herein as from “about” one particular value, and/or to “about” another particular value. When such a range is expressed, another embodiment includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by the use of the antecedent “about,” it will be understood that the particular value forms another embodiment.
  • PLMYT1 Protein kinase, membrane-associated tyrosine/threonine 1
  • cancer cells override the cell cycle controls that prevent commitment to division until the appropriate conditions have been fulfilled. Once the conditions are right, cells are pushed through a decision point called the “restriction point” into the cell division cycle by the activity of Cdk4/6-Cyclin D complexes. Once through this point of no return, cells activate Cdk2-Cyclin E in order to drive the duplication of the DNA that will be segregated into two daughter cells later in the cell cycle (by Cdk1-Cyclin B).
  • cancer cells In order to be able to proliferate illegitimately, cancer cells inappropriately boost t he kinase activity of Cdk4/6-Cyclin D complexes or bypass the requirement for Cdk4/6-Cyclin D activation, by activating the downstream Cdk2-Cyclin E complex, independently of any input from Cdk4/6-Cyclin D.
  • Implementation of either of these two approaches enable cancers to evade the normal controls that maintain balanced growth and homeostasis within the body. Consequently, cancer proliferation is unregulated.
  • Drugs that inhibit the Cdk4/6-Cyclin D complexes are having a major therapeutic impact in hormone responsive HER2 negative breast cancer (HER2- ER+) and are being trialled in a variety of other cancers.
  • 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 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, breast and gastric, ranging in frequency from 5-40%.
  • CCNE1 amplification and/or FBXW7 mutations occur in >60% of uterine carcinosarcomas, >20% of uterine cancers, ⁇ 20% of ovarian cancers, ⁇ 18% of stomach cancers, ⁇ 14% of colorectal cancer, ⁇ 12% of bladder cancers, 11.5% of oesophageal cancers, ⁇ 11% of cervical cancers, 7.5% of sarcomas and ⁇ 7% of lung squamous cancers (Durocher et al., 2021).
  • CCNE1 also occurs at lower levels in other cancers such as adenoid cystic carcinoma, pancreatic cancer, mesothelioma, lung adenocarcinoma, head & neck cancers, difuse large B-cells lymphoma, liver cancers and others (Gorski et al., 2020). Moreover, CCNE1 over expressing ovarian cancers are a subset of the 50% that are recombination proficient so do not benefit from PARP inhibitors (Gorski et al., 2020), highlighting the unmet need in these indications.
  • CCNE1 amplification is observed in the more aggressive subtypes including uterine carcinosarcoma (UCS; ⁇ 40%), uterine serous carcinoma (USC; ⁇ 25%), high-grade serous ovarian carcinoma (HGSOC; ⁇ 20%), and triple-negative breast cancer (TNBC; ⁇ 8%).
  • CCNE1 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.
  • Elevation of Cdk2-Cyclin E activity is also associated with resistance to Cdk4/6 inhibitors (Fassl et al., 2022); this suggests that PKMYT1 inhibition will also constitute a robust second line treatment in the cohort of HER2- ER+ breast cancer patients treated with Cdk4/6 inhibitors who generally develop resistance after around 2 years of therapy.
  • a recently discovered inhibitor of PKMYT1, RP-6306 (Szychowski et al., 2022), has shown efficacy in vivo in models of breast and ovarian cancers overexpressing CCNE1, as well as in a pancreatic PDX model with increased expression of CCNE1, alone or in combination with Gemcitabine (Gallo et al., 2022). It has been claimed that synthetic lethality occurs in cancer cells between PKMYT1 inhibition and deficiency in protein phosphatase 2 (PP2A), in particular, regulatory subunit B alpha (PPP2R2A) (Yost et al., 2021).
  • P2A protein phosphatase 2
  • PPP2R2A regulatory subunit B alpha
  • 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.
  • PKMYT1 is a cell cycle regulating kinase, part of the WEE1 family of kinases that includes WEE1 and WEE2.
  • WEE2 is restricted to gonads as it regulates meiosis. In contrast both PKMYT1 and WEE1 are ubiquitously expressed. PKMYT1 is localized predominantly in the endoplasmic reticulum and Golgi complex, while WEE1 is predominantly a nuclear protein. PKMYT1 is involved in the negative regulation of the CDK1-Cyclin B complex which promotes the progression of cells from G2-phase into the mitotic phase (M-phase) of the cell cycle. The biology of Cyclin E overproduction generates a need for the otherwise non-essential PKMYT1. Cyclin E accumulation boosts the transcription of cyclin B1; the potential to form active Cdk1-Cyclin B is greatly enhanced by CCNE1 overexpression.
  • 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 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. It is only when abnormally high levels of DNA damage generates a greater need for CDK1 cyclin B inhibition that PKMYT1’s activities become essential.
  • the WEE1 inhibitor adavosertib has progressed to clinical trials in a number of solid tumours (clinicaltrials.gov) but presented significant toxicity. WEE1 inhibition toxicity most likely arises from its ability to inhibit both CDK2 and CDK1 complexes.
  • CDK2-Cyclin E and CDK2-Cyclin A regulate the initiation and progression through DNA replication. Release of excessive levels of CDK2-Cyclin activities will generate DNA damage in a phenomenon known as oncogene induced replicative senescence.
  • PKMYT1 inhibition is unlikely to display similar S phase toxicity, because, unlike WEE1, it phosphorylates CDK1 (Booher et al., 1997; Liu et al., 1997).
  • PKMYT1 Overexpression of PKMYT1 has been observed in various cancers (compared to normal tissues), including Lung squamous cell carcinoma, lung adenocarcinoma, Uterine Corpus Endometrial Carcinoma, breast invasive carcinoma, hepatocellular carcinoma, clear-cell renal-cell carcinoma, Kidney Chromophobe cancer, renal papillary cell carcinoma, Head and Neck squamous cell carcinoma, colon adenocarcinoma, stomach adenocarcinoma, thyroid carcinoma, prostate adenocarcinoma.
  • Elevated expression of 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 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 carcinoma (Cai et al., 2022), gastric cancer (Hu et al., 2022; Zhang et al., 2020), prostate cancer (Wang et al., 2020), oesophageal squamous cell carcinoma (Zhang et al., 2019), colorectal cancer (Jeong et al., 2018), hepatocellular carcinoma (Liu et al., 2017), ovarian cancer (Xuan et al., 2020), neuroblastoma (in particular with MYCN a
  • PKMYT1 is essential for survival of some haematologic malignancies, such as acute lymphoblastic leukemia and multiple myeloma (Ghelli Luserna di Rora et al., 2020). 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.
  • Knockdown of PKMYT1 can eliminate the radiation-induced G2/M arrest, resulting in a lower survival rate for cells receiving radiation therapy and is therefore a promising target to improve the radiosensitivity of lung adenocarcinoma (Long et al., 2020). PKMYT1 could be also prove useful to enhance the efficacy of anti-microtubule cancer drugs (Visconti et al., 2017). PKMYT1 also plays a role in viral infection. Knockdown of PKMYT1 reduces the number of cells supporting Kaposi sarcoma herpesvirus (KSHV) lytic infection in S phase of the cell cycle (Bryan et al., 2006).
  • KSHV Kaposi sarcoma herpesvirus
  • KSHV is the cause of Kaposi’s sarcoma, primary effusion lymphoma (PEL) and the plasmablastic variant of multicentric Castleman’s disease.
  • PEL primary effusion lymphoma
  • PKMYT1 selective inhibitors with good pharmacokinetic properties, which are suitable for oral dosing with minimal or no toxicity.
  • BAA compounds certain biarylamide compounds which inhibit Protein Kinase, Membrane Associated Tyrosine/Threonine 1 (PKMYT1), as described herein.
  • compositions e.g., a pharmaceutical composition
  • a pharmaceutical composition comprising a BAA compound, as described herein, and a pharmaceutically acceptable carrier or diluent.
  • Another aspect of the invention pertains to a method of preparing a composition (e.g., a pharmaceutical composition) comprising the step of mixing a BAA compound, as described herein, and a pharmaceutically acceptable carrier or diluent.
  • 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 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 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 subject in need of treatment a therapeutically-effective amount of a BAA compound, as described herein, preferably 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, preferably provided as a composition (e.g., a pharmaceutical composition) and in a suitable container and/or with suitable packaging; and (b) instructions for use, for example, in a method of treatment of a disorder (e.g., a disease) as described herein, for example, written instructions on how to administer the compound.
  • 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 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 synthesis described herein.
  • features and preferred embodiments of one aspect of the invention will also pertain to other aspects of the invention.
  • One aspect of the present invention is a compound of the following formula, or a pharmaceutically acceptable salt or solvate thereof, wherein Ring A and Ring B are as defined herein (for convenience, collectively referred to herein as “biarylamide compounds” or “BAA compounds”): A B .
  • Some embodiments include the following: (1) A compound of the following formula: or a pharmaceutically acceptable salt or solvate thereof; wherein: wherein: Z 1 is N, CH, or CR Z1 ; Z 2 is CH, CR Z2 , or N; Z 3 is CH 2 , CHR Z3C1 , CR Z3C2 2, NH, NR Z3N , O, or S; Z 4 is CH 2 or CHR Z4 ; Z 5 is CH 2 or CHR Z5 ; Z 6 is N, CH, or CR Z6 ; Z 7 is N, CH, or CR Z7 ; Z 8 is N, CH, or CR Z8 ; Z 9 is N, CH, or CR Z9 ; either: Z 10 is CH 2 , CHR Z10C1 , CR Z10C2 2 , NH, NR Z10N , O, or S; and Z 11 is CH 2 , CHR Z11C1 , or CR Z11C2 2 ; or: Z 10 is CH 2
  • Z 1 is N, CH, or CR Z1 ;
  • Z 2 is CH, CR Z2 , or N;
  • Z 3 is CH 2 , CHR Z3C1 , CR Z3C2 2, NH, NR Z3N , O, or S;
  • Z 4 is CH 2 or CHR Z4 ;
  • Z 5 is CH 2 or CHR Z5 ;
  • Z 6 is N, CH, or CR Z6 ;
  • Z 7 is N, CH, or CR Z7 ;
  • Z 8 is N, CH, or CR Z8 ;
  • Z 9 is N, CH, or CR Z9 ; either:
  • Z 10 is CH 2 , CHR Z10C1 , CR Z10C2 2 , NH, NR Z10N , O, or S; and
  • Z 11 is CH 2 , CHR Z11C1 , or CR Z11C2 2 ; or:
  • Z 10 is CH 2 , CHR Z10C1 , or CR
  • C x-y in terms such as “C 9-10 heteroaryl”, “C 3-7 heterocyclyl”, and the like, refers to the number of ring atoms, which may be carbon atoms or heteroatoms (e.g., N, O, S, as the case may be).
  • pyridyl is an example of a C 6 heteroaryl group
  • piperidino is an example of a C 6 heterocyclyl 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). Unless otherwise stated, the heteroaryl may be attached via a ring carbon or a ring nitrogen atom.
  • pyridyl is an example of a C6heteroaryl group
  • quinolyl e.g., quinolin-2-yl, quinolin-7-yl, etc.
  • 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 C9heteroaryl 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 contains at least one non aromatic ring system comprising one or more heteroatoms (e.g., N, O, S, as the case may be) that is attached to the rest of the molecule by an atom that is part of a non aromatic ring system comprising one or more heteroatoms (e.g., N, O, S, as the case may be). Unless otherwise stated, the heterocyclyl may be attached via a ring carbon or a ring nitrogen atom.
  • 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, wherein the non-aromatic ring is part of a non-aromatic ring system, and the non-aromatic ring system 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 C7heterocyclyl), and spiro hetero
  • non-aromatic ring system may optionally be fused with one or more aromatic rings.
  • 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 Cwheterocyclyl group.
  • non-aromatic C 3- 11 heterocyclyl having at least one N ring atom, and is attached via that N ring atom refers to a heterocyclyl group that is attached via a N ring atom, but which may have additional N ring atoms. Examples include: aziridino, azetidino, pyrrolidino, piperidino, piperazino, morpholino, thiomorpholino, azepano, and diazepano.
  • 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.
  • -CF 3 and -CHF 2 are examples of a C 1 fluoroalkyl group
  • -CH 2 CF 3 and -CH 2 CHF 2 are examples of a C 2 fluoroalkyl group.
  • C 1-4 alkylene refers to an alkyl group with two points of attachment.
  • -CH 2 - is an example of a Cialkylene group
  • -CH 2 CH 2 - and -CH(CH 3 )- are examples of a C 2 alkylene group
  • -CH 2 CH 2 CH 2 - and -CH(CH 3 ) 2 - are examples of a C 3 alkylene group.
  • Examples of C 1-7 alkyl, C 1-6 alkyl and C 1-4 alkyl include methyl, ethyl, propyl, isopropyl and butyl.
  • Examples of C 3-6 cycloalkyl include cyclopropyl and cyclohexyl.
  • Examples of C 3-6 cycloalkyl-C 1-3 alkyl include cyclopropyl methyl and cyclohexylethyl.
  • Examples of phenyl-C 1-3 alkyl include benzyl and 2-phenylpropyl.
  • Examples of C 5-6 heteroaryl-C 1-3 alkyl include pyrimidin-2- ylmethyl and thiazol-4-ylethyl.
  • one or more groups in the context of optional substituents (e.g., “one or more groups -R AR1C ”, etc.) is necessarily constrained by the parent moiety and the number of positions on it that are suitable for substitution. In some parent moieties (e.g., tetrazolyl) there is only one position available for substitution. However, for other parent moieties, there may be several (e.g., phenyl has five). Except when constrained by the parent moiety, the “one or more groups” may be, e.g., 1 , 2, 3, 4, etc., though more preferably is 1 , 2, or 3, yet more preferably 1 or 2, still more preferably 1 .
  • substituted on carbon is intended to refer to a substituent which is attached to a carbon ring atom.
  • substituted on secondary nitrogen is intended to refer to a substituent which is attached to a nitrogen ring atom which, in the absence of the substituent, would be a secondary nitrogen ring atom (i.e. , -NH-). Consequently, a pyridyl group may only have “substituents on carbon”, whereas 1 H-pyrrole may have both “substituents on carbon” and a “substituent on secondary nitrogen”, as illustrated below.
  • a tetrazo aly slu gsrottuupen mt obon ring atoms available for subst any ca ornloyn permit a “substituent on carbon” or may only permit a “substituent on secondary nitrogen”, as illustrated below.
  • ea,r abolln 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 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.
  • Z 1 if present, is N or CH; Z 2 , if present, is CH or N; Z 3 , if present, is CH 2 , NH, O, or S; Z 4 , if present, is CH 2 ; Z 5 , if present, is CH 2 ; Z 6 , if present, is N or CH; Z 7 , if present, is N or CH; Z 8 , if present, is N or CH; Z 9 , if present, is N or CH; either: Z 10 , if present, is CH 2 , NH, O, or S; and Z 11 , if present, is CH 2 ; or: Z 10 , if present, is CH 2 ; and Z 11 , if present, is NH, O, or S; Z 12 , if present, is CH 2 ; Z 13 , if present, is CH 2 ; Z 14 , if present, is CH 2 , NH, O, or S;
  • each -R Z1 , -R Z2 , -R Z5 , -R Z6 , -R Z7 , -R Z8 , -R Z9 , and -R Z13 , if present, is independently: -F, -Cl, -Br, -I, -R ZZ , -CF 3 , -OH, -OR ZZ , or -OCF 3 .
  • each -R Z1 , -R Z2 , -R Z5 , -R Z6 , -R Z7 , -R Z8 , -R Z9 , and -R Z13 is independently: -F, -Cl, -Br, -I, -R ZZ , or -OH.
  • each -R Z1 , -R Z2 , -R Z5 , -R Z6 , -R Z7 , -R Z8 , -R Z9 , and -R Z13 is independently: -F, -Cl, -R ZZ , or -OH.
  • each -R Z1 , -R Z2 , -R Z5 , -R Z6 , -R Z7 , -R Z8 , -R Z9 , and -R Z13 , if present, is independently: -F, -Cl, or -R ZZ .
  • each -R Z1 , -R Z2 , -R Z5 , -R Z6 , -R Z7 , -R Z8 , -R Z9 , and -R Z13 if present, is independently: -F or -R ZZ .
  • each -R Z1 , -R Z2 , -R Z5 , -R Z6 , -R Z7 , -R Z8 , -R Z9 , and -R Z13 , if present, is: -R ZZ .
  • each -R Z2 if present is independently -Br, or -R ZZ .
  • each -R Z2 if present is independently -Br.
  • each -R Z2 if present is independently -R ZZ .
  • the Groups -R Z4 and -R Z12 (31) A compound according to any one of (1) to (30), wherein: each -R Z4 and -R Z12 , if present, is: -R ZZ .
  • each -R Z3C1 , -R Z10C1 , -R Z11C1 , and -R Z14C1 is independently: -F, -R ZZ , -CF 3 , -OH, -OR ZZ , or -OCF 3 .
  • each -R Z3C1 , -R Z10C1 , -R Z11C1 , and -R Z14C1 , if present, is independently: -F, -R ZZ , or -OH.
  • each -R Z3C1 , -R Z10C1 , -R Z11C1 , and -R Z14C1 , if present, is independently: -F or -R ZZ .
  • each -R Z3C2 , -R Z10C2 , -R Z11C2 , and -R Z14C2 A compound according to any one of (1) to (35), wherein: each -R Z3C2 , -R Z10C2 , -R Z11C2 , and -R Z14C2 , if present, is: -F.
  • 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.
  • each -R Z3N , -R Z10N , -R Z11N , and -R Z14N , if present, is independently: -R ZZN .
  • each -R ZZN is independently linear or branched saturated C 1-4 alkyl, C 3-6 cycloalkyl, 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, -CH 3 , -CF 3 , -OH, -OCH 3 , -NH 2 , -NH(CH 3 ), and -N(CH 3 ) 2 .
  • each -R ZZN is independently linear or branched saturated C 1-4 alkyl, phenyl, or phenyl-CH 2 -, wherein each phenyl is optionally substituted with one or more groups selected from: -F, -Cl, -CH 3 , -CF 3 , -OH, -OCH 3 , -NH 2 , -NH(CH 3 ), and -N(CH 3 ) 2 .
  • each -R ZZN is independently linear or branched saturated C 1-4 alkyl, phenyl, or benzyl.
  • each -R ZZN is independently linear or branched saturated C 1-4 alkyl.
  • each -R ZZN is -Me.
  • the Group -R A2 (49) A compound according to any one of (1) to (48), wherein: -R A2 is -R A222 , -F, -Cl, -Br, -I, -CF 3 , -CHF 2 , -OH, -OR A222 , -OCF 3 , or -CN. (50) A compound according to any one of (1) to (48), wherein: -R A2 is -R A222 , -F, -Cl, -Br, -I, -CF 3 , -CHF 2 , -OH, -OR A222 , or -OCF 3 .
  • each -R A222 if present, is -Me or -Et.
  • 63 A compound according to any one of (1) to (59), wherein: each -R A222 , if present, is -Me.
  • the Group -R A3 (64) A compound according to any one of (1) to (63), wherein: -R A3 , if present, is -H.
  • 65) A compound according to any one of (1) to (63), wherein: -R A3 , if present, is -R A33 .
  • the Group -R A33 (66) A compound according to any one of (1) to (65), wherein: -R A33 , if present, is: -R A333 , -F, -Cl, -Br, -I, -OH, or -OR A333 . (67) A compound according to any one of (1) to (65), wherein: -R A33 , if present, is: -R A333 , -F, -Cl, -Br, -I, or -OH. (68) A compound according to any one of (1) to (65), wherein: -R A33 , if present, is: -R A333 , -F, -Cl, or -OH.
  • each -R A333 if present, is -Me, -Et, -nPr, or -iPr.
  • each -R A333 if present, is -Me or -Et.
  • each -R A333 if present, is -Me or -Et.
  • the Group -R A4 76 A compound according to any one of (1) to (75), wherein: -R A4 , if present, is -H.
  • each -R A444 if present, is -Me, -Et, -nPr, -iPr, -nBu, or -tBu.
  • each -R A444 if present, is -Me, -Et, -nPr, or -iPr.
  • each -R A444 if present, is -Me or -Et.
  • 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
  • Y 9 if present, is S, O, or NH.
  • Ring B is selected from:
  • 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.
  • 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
  • Y 7 if present, is N or CH
  • Y 8 if present, is N or CH
  • 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
  • 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 is independently: -F, -Cl, -Br, -I, -R YY , -CF 3 , -OH, -OR YY , -OCF 3 , or -NH 2 .
  • each -R Y2 , -R Y3 , -R Y4 , -R Y6 , -R Y7 , and -R Y8 is independently: -F, -Cl, -Br, -I, -R YY , or -NH 2 .
  • each -R Y2 , -R Y3 , -R Y4 , -R Y6 , -R Y7 , and -R Y8 , if present, is independently: -F, -Cl, -R YY , or -NH 2 .
  • 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 YY if present, is: -Me, -Et, -nPr, -iPr, -nBu, or -tBu.
  • each -R YY if present, is: -Me, -Et, -nPr, or -iPr.
  • each -R YY if present, is: -Me or -Et.
  • each -R YY if present, is: -Me.
  • each -R Y1 , -R Y5 , and -R Y9 , if present, is independently: -R YYN .
  • the Group -R YYN (113) A compound according to any one of (1) to (112), wherein: each -R YYN , if present, is independently linear or branched saturated C 1-4 alkyl, C 3-6 cycloalkyl, 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, -CH 3 , -CF 3 , -OH, -OCH 3 , -NH 2 , -NH(CH 3 ), and -N(CH 3 ) 2 .
  • each -R YYN is independently linear or branched saturated C 1-4 alkyl, phenyl, or phenyl-CH 2 -, wherein each phenyl is optionally substituted with one or more groups selected from: -F, -Cl, -CH 3 , -CF 3 , -OH, -OCH 3 , -NH 2 , -NH(CH 3 ), and -N(CH 3 ) 2 .
  • (126) A compound according to any one of (1) to (117), wherein: -Q is -Q 3 .
  • (128) A compound according to any one of (1) to (117), wherein: -Q is -Q 4 , (129) A compound according to any one of (1) to (117), wherein: -Q is -L Q4 -Q 4 .
  • (130) A compound according to any one of (1) to (117), wherein: -Q is -Q 5 .
  • (131) A compound according to any one of (1) to (117), wherein: -Q is H.
  • the Group -Q 1 (132) A compound according to any one of (1) to (131), wherein: -Q 1 , if present, is C5-9heteroaryl; 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 .
  • -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 .
  • (136) A compound according to any one of (1) to (131), wherein: -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 .
  • (138) A compound according to any one of (1) to (131), wherein: -Q 1 , if present, is pyrazolyl (e.g., 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1H-pyrazol-5-yl, or pyrazol-1-yl); and is: optionally substituted on carbon with one or more groups -R Q1C ; and optionally substituted on secondary nitrogen, if present, with a group -R Q1N . (139) A compound according to any one of (1) to (131), wherein -Q 1 , if present, is pyrazol-1-yl; and is optionally substituted on carbon with one or more groups -R Q1C .
  • -Q 1 if present, is pyrazolyl (e.g., 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1H-pyrazol-5-yl, or pyrazol-1-yl); and
  • (140) A compound according to any one of (1) to (131), wherein -Q 1 , if present, is 1H-pyrazol-3-yl; and is: optionally substituted on carbon with one or more groups -R Q1C ; and optionally substituted on secondary nitrogen with a group -R Q1N .
  • (141) A compound according to any one of (1) to (131), wherein -Q 1 , if present, is 1H-pyrazol-4-yl; 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 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 .
  • -Q 1 is indolyl, indazolyl, benzimidazolyl, benzoxazolyl, pyrazolo-pyridinyl, pyrazolo-pyrimidinyl, imidazo-pyridinyl, 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 .
  • (146) A compound according to any one of (1) to (131), wherein: -Q 1 , if present, is indol-2-yl or indol-3-yl; and is: optionally substituted on carbon with one or more groups -R Q1C ; and optionally substituted on secondary nitrogen, with a group -R Q1N .
  • (148) A compound according to any one of (1) to (131), wherein: -Q 1 , if present, is benzimida tionally substituted on ca-rnzol-2-yl; and is: op boanzo w-ith-y one or more g-ronupaszo -R- Q - 1 y C l; and optionally substituted on secondary nitrogen, with a group -R Q1N .
  • (149) A compound according to any one of (1) to (131), wherein: -Q 1 , if present, is benzoxazol-2-yl; and is: optionally substituted on carbon wit-he onnzem or mazoor-e- gyroups -R Q1C .
  • razo (151) A compound accordloing to any one of (1) to (131), wherein: -Q 1 , if present, is 1H-p[1y,r5azolo[3,4-b]pyridin-3-yl, 1H-pyrazolo[3,4-c]pyridin-3-yl, 1H- pyrazolo[4,3-c]pyridin-3-yl, or 1H--ap]yrarizdoinlo-2[4-,3l-b]pyridin-3 rera-y gzl ro; and is: optionally substituted on carbon with one or mo oluop[1s,5 -R-a Q ] 1C ;ri adnind optionally substituted on secondary nitrogen, with a group -R Q1N .
  • a compound according to any one of (1) to (131)-,p wyrhroelroe[i3n,: -Q 1 is 1H-pyrrolo[3,2-c]pyridin-2-yl or 1H-pyrrolo2[-3b,]2py-cri]dpiyn-3r-i3-dy-ilynl-3-yl; 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 is pyrazolyl, pyrazolo[1,5-a]pyridinyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl; and is: optionally substituted on secondary nitrogen, if present, with one or more groups -R Q1N .
  • the Group -L Q1 - (159) A compound according to any one of (1) to (158), wherein: -L Q1 -, if present, is -CH 2 -, -C(CH 3 ) 2 -, -CH 2 CH 2 -, or -CH 2 CH 2 CH 2 -. (160) A compound according to any one of (1) to (158), wherein: -L Q1 -, if present, is -CH 2 -, -CH 2 CH 2 -, or -CH 2 CH 2 CH 2 -. (161) A compound according to any one of (1) to (158), wherein: -L Q1 -, if present, is -CH 2 -.
  • -Q 2 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 coimeprioduinn-e1d n- a s t,lccording to tituted on c is piperazii an arey broid o ninn w-e2it- of hl (1) to (163) one or mori, ee w grh rioderein: -Q 2 , if present, is piperid d ( iiin-4-yl; an s: optionaellryid sinuob) uinp-s3- -Rl tituted on c p Q2C ; and optionally substituted on secondary nitrogen, with a group -R Q2N .
  • n ieridin-4-l aiypl e.g., piperazin-1-yl, piperazin-2-yl
  • the Group -L Q2 - (171) A compound according to any one of (1) to (170), wherein: -L Q2 -, if present, is -CH 2 -, -C(CH 3 ) 2 -, -CH 2 CH 2 -, or -CH 2 CH 2 CH 2 -. (172) A compound according to any one of (1) to (170), wherein: -L Q2 -, if present, is -CH 2 -, -CH 2 CH 2 -, or -CH 2 CH 2 CH 2 -. (173) A compound according to any one of (1) to (170), wherein: -L Q2 -, if present, is -CH 2 -.
  • the Group -Q 3 (176) A compound according to any one of (1) to (175), wherein: -Q 3 , if present, is phenyl; and is optionally substituted with one or more groups -R Q3C .
  • the Group -L Q3 - (178) A compound according to any one of (1) to (177), wherein: -L Q3 -, if present, is -CH 2 -, -C(CH 3 ) 2 -, -CH 2 CH 2 -, or -CH 2 CH 2 CH 2 -. (179) A compound according to any one of (1) to (177), wherein: -L Q3 -, if present, is -CH 2 -, -CH 2 CH 2 -, or -CH 2 CH 2 CH 2 -. (180) A compound according to any one of (1) to (177), wherein: -L Q3 -, if present, is -CH 2 -.
  • the Group -L Q4 - (190) A compound according to any one of (1) to (189), wherein: -L Q4 -, if present, is -CH 2 -, -C(CH 3 ) 2 -, -CH 2 CH 2 -, or -CH 2 CH 2 CH 2 -. (191) A compound according to any one of (1) to (189), wherein: -L Q4 -, if present, is -CH 2 -, -CH 2 CH 2 -, or -CH 2 CH 2 CH 2 -. (192) A compound according to any one of (1) to (189), wherein: -L Q4 -, if present, is -CH 2 -.
  • the Group -Q 5 (195) A compound according to any one of (1) to (194), wherein: -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 linear or branched saturated C 1-4 alkyl; and is optionally substituted with one or more groups -R Q5C .
  • -Q 5 if present, is -Me, -Et, or -nPr; and is optionally substituted with one or more groups -R Q5C .
  • -Q 5 if present, is -CH 2 -R Q5C .
  • -Q 5 if present, is -CH 2 CH 2 -R Q5C .
  • each -R Q1C if present, is: -R Q1CC .
  • each -R Q1CC is independently linear or branched saturated C 1-4 alkyl, C 3-6 cycloalkyl, 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, -CH 3 , -CF 3 , -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, phenyl, or phenyl-CH 2 -, wherein each phenyl is optionally substituted with one or more groups selected from: -F, -Cl, -CH 3 , -CF 3 , -OH, -OCH 3 , -NH 2 , -NH(CH 3 ), and -N(CH 3 ) 2 .
  • each -R Q1CC is independently linear or branched saturated C 1-4 alkyl, phenyl, or benzyl.
  • each -R Q1CC is independently linear or branched saturated C 1-4 alkyl.
  • each -R Q1CC 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 -Et.
  • each -R Q1CC if present, is -Me.
  • each -R Q1CC is independently linear or branched saturated C 1-4 alkyl, C 3-6 cycloalkyl, C 3-7 heterocyclyl, phenyl, C 5-6 heteroaryl, or C 5-6 heteroaryl-C 1-3 alkyl, wherein C 1-4 alkyl is optionally substituted with -N(CH 3 ) 2 , or -C ⁇ N, and each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -CH 3 , and -CH 2 OCH 3 .
  • each -R Q1CC is independently linear or branched saturated -Me, -Et, i-Pr, -t-Bu, cyclopropyl, cyclobutyl, oxetanyl, phenyl, pyrazolyl, pyridyl, thiazolyl, or oxazolylmethyl, wherein -Me, -Et, i-Pr, or -t-Bu is optionally substituted with -N(CH 3 ) 2 , or -C ⁇ N, and each phenyl cyclopropyl, cyclobutyl, oxetanyl, phenyl, pyrazolyl, pyridyl, thiazolyl, and oxazolyl is optionally substituted with one or more groups selected from: -F, -CH 3 , and -CH 2 OCH 3
  • each -R Q1CC if present, is cyclopropyl or oxetanyl, wherein each cyclopropyl or oxetanyl is optionally substituted with one or more groups selected from: -F, -CH 3 , and -CH 2 OCH 3 .
  • n1 and “m1” in -(CH 2 ) n1 -O-(CH 2 ) m1 - (223) A compound according to any one of (1) to (222), wherein: n1, if present, is 0, 1, 2, or 3; m1, if present, is 0, 1, 2, or 3; with the proviso that m1+n1 is 2 or 3.
  • (225) A compound according to any one of (1) to (222), wherein: n1, if present, is 1 or 2; m1, if present, is 1 or 2; with the proviso that m1+n1 is 2 or 3.
  • the Index “p1” in -O-(CH 2 )p1-O- (226) A compound according to any one of (1) to (225), wherein: p1, if present, is 1.
  • (227) A compound according to any one of (1) to (225), wherein: p1, if present, is 2.
  • the Group -R Q1CX (228) A compound according to any one of (1) to (227), wherein: each -R Q1CX , if present, is independently linear or branched saturated C 1-4 fluoroalkyl.
  • each -R Q1CX is independently -CF 3 , -CHF2, -CH 2 CF 3 , or -CH 2 CHF2.
  • each -R Q1CX is -CF 3 .
  • each -R Q1CX is independently -CF 3 , or -CH 2 CHF2.
  • each -L Q1C - is independently -CH 2 -, -C(CH 3 ) 2 -, -CH 2 CH 2 -, or -CH 2 CH 2 CH 2 -.
  • each -L Q1C - is independently -CH 2 -, -CH 2 CH 2 -, or -CH 2 CH 2 CH 2 -.
  • each -L Q1C -, if present, is independently -CH 2 -, -CH 2 CH 2 -, or -CH 2 CH 2 CH 2 -.
  • each -L Q1C -, if present, is -CH 2 -.
  • each -L Q1C - is -CH 2 CH 2 -.
  • each -L Q1C - is -CH 2 CH 2 CH 2 -.
  • each -R Q1CM is independently non-aromatic C 3-11 heterocyclyl having at least one N ring atom, and is attached via that N ring atom; and is: optionally substituted on carbon with one or more groups -R Q1CMM ; optionally substituted on secondary nitrogen, if present, with a group selected from: -R Q1CMM .
  • each -R Q1CM is independently pyrrolidinyl, morpholinyl, azetidinyl, 1,1- dioxythiomorpholinyl, piperidinyl, 2-oxa-5-azabicyclo[4.1.0]heptanyl, 4,7-diazaspiro[2.5]octanyl, or piperazinyl, having at least one N ring atom, and is attached via that N ring atom; and is: optionally substituted on carbon with one or more groups -R Q1CMM ; optionally substituted on secondary nitrogen, if present, with a group selected from: -R Q1CMM .
  • each -R Q1CMM is independently linear or branched saturated C 1-4 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-3 alkyl, phenyl, or phenyl-C 1-3 alkyl, wherein C 1-4 alkyl is optionally substituted with -OH or -OCH 3 , and each cycloalkyl or phenyl is optionally substituted with one or more groups selected from: -F, -Cl, -CH 3 , -CF 3 , -OH, -OCH 3 , -NH 2 , -NH(CH 3 ), and -N(CH 3 ) 2 .
  • each -R Q1CMM if present, is independently linear or branched saturated C 1-4 alkyl, or phenyl-C 1-3 alkyl, wherein C 1-4 alkyl is optionally substituted with -OH or -OCH 3 , and each cycloalkyl and phenyl is optionally substituted with one or more groups selected from: -F, -Cl, -CH 3 , -CF 3 , -OH, -OCH 3 , -NH 2 , -NH(CH 3 ), and -N(CH 3 ) 2 ; (244) A compound according to any one of (1) to (241), wherein: each -R Q1CMM , if present, is independently linear or branched saturated C 1-4 alkyl, phenyl, or phenyl-CH 2 -, wherein C 1-4 alkyl is optionally substituted with -OH or -OCH 3
  • each -R Q1CMM if present, is independently linear or branched saturated C 1-4 alkyl, phenyl, or benzyl.
  • each -R Q1CMM if present, is independently linear or branched saturated C 1-4 alkyl, and is optionally substituted with -OH or -OCH 3 .
  • 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 Q1CMM if present, is independently -Me or -Et.
  • each -R Q1CMM if present, is -Me.
  • each -R Q1CMM if present, is independently -F, or linear or branched saturated C 1-4 alkyl.
  • each -R Q1CMM if present, is independently -F, or -Me.
  • each -R Q1N is independently: -R Q1Nhet or -L Q1N -R Q1Nhet .
  • each -R Q1N is: -R Q1Nhet .
  • each -R Q1N if present, is independently: -R Q1NC .
  • each -R Q1N if present, is independently: -L Q1N -OH or -L Q1N -OR Q1NC .
  • each -R Q1N is independently: -L Q1N -NH 2 , -L Q1N -NHR Q1NC , -L Q1N -NR Q1NC 2 , or -L Q1N -R Q1NM .
  • each -R Q1NC is independently linear or branched saturated C 1-4 alkyl, C 3-6 cycloalkyl, C 3-7 heterocyclyl, or C 5-6 heteroaryl, , wherein each C 1-4 alkyl is optionally substituted by MeS(O) 2 -, wherein each cycloalkyl, and heteroaryl is optionally substituted with one or more groups selected from: -CH 3 .
  • each -R Q1NC is independently -Me, Et, i-Pr, cyclopropyl, cyclohexyl, cyclobutyl, piperidinyl, tetrahydropyranyl, or pyrazolyl, wherein each -Me, Et or i-Pr is optionally substituted by MeS(O) 2 -, wherein each cyclopropyl, cyclohexyl, cyclobutyl, and pyrazolyl is optionally substituted with one or more groups selected from: -CH 3 .
  • each -R Q1NC if present, is independently linear or branched saturated C 1-4 alkyl, C 3-6 cycloalkyl, 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, -CH 3 , -CF 3 , -OH, -OCH 3 , -NH 2 , -NH(CH 3 ), and -N(CH 3 ) 2 .
  • each -R Q1NC if present, is independently linear or branched saturated C 1-4 alkyl, phenyl, or phenyl-CH 2 -, wherein each phenyl is optionally substituted with one or more groups selected from: -F, -Cl, -CH 3 , -CF 3 , -OH, -OCH 3 , -NH 2 , -NH(CH 3 ), and -N(CH 3 ) 2 .
  • each -R Q1NC if present, is independently linear or branched saturated C 1-4 alkyl, phenyl, or benzyl.
  • each -R Q1NC if present, is independently linear or branched saturated C 1-4 alkyl.
  • each -R Q1NC if present, 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 -Et.
  • each -R Q1NC if present, is -Me.
  • each -R Q1NX is independently linear or branched saturated C 1-4 fluoroalkyl.
  • each -R Q1NX if present, is independently -CF 3 , -CHF2, -CH 2 CF 3 , or -CH 2 CHF2.
  • each -R Q1NX if present, is independently -CH 2 CF 3 , or -CH 2 CH 2 F.
  • each -R Q1NX if present, is -CHF2.
  • the Group -L Q1N - (280) A compound according to any one of (1) to (279), wherein: each -L Q1N -, if present, is independently -CH 2 -, -CH 2 CH 2 -, -CH(CH 3 )-, -CH 2 C(CH 3 ) 2 -, or -CH 2 CH(CH 3 )-, optionally substituted by -F or -OCH 3 .
  • each -L Q1N -, if present, is independently -CH 2 -, -C(CH 3 ) 2 -, -CH 2 CH 2 -, or -CH 2 CH 2 CH 2 -.
  • each -L Q1N -, if present, is independently -CH 2 -, -CH 2 CH 2 -, or -CH 2 CH 2 CH 2 -.
  • each -L Q1N -, if present, is independently -CH 2 -, -CH 2 CH 2 -, or -CH 2 CH 2 CH 2 -.
  • each -L Q1N -, if present, is -CH 2 -.
  • each -L Q1N -, if present, is -CH 2 CH 2 -.
  • each -L Q1N -, if present, is -CH 2 CH 2 CH 2 -.
  • the Group -R Q1NM (286) A compound according to any one of (1) to (285), wherein: each -R Q1NM , if present, is independently non-aromatic C 3-7 heterocyclyl having at least one N ring atom, and is attached via that N ring atom.
  • each -R Q1NM is independently non-aromatic piperazinyl is attached via an N ring atom.
  • each -R Q1NMM is independently linear or branched saturated C 1-4 alkyl, C 3-6 cycloalkyl, 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, -CH 3 , -CF 3 , -OH, -OCH 3 , -NH 2 , -NH(CH 3 ), and -N(CH 3 ) 2 .
  • each -R Q1NMM if present, is independently linear or branched saturated C 1-4 alkyl, phenyl, or phenyl-CH 2 -, wherein each phenyl is optionally substituted with one or more groups selected from: -F, -Cl, -CH 3 , -CF 3 , -OH, -OCH 3 , -NH 2 , -NH(CH 3 ), and -N(CH 3 ) 2 .
  • each -R Q1NMM is independently linear or branched saturated C 1-4 alkyl, phenyl, or benzyl.
  • each -R Q1NMM is independently linear or branched saturated C 1-4 alkyl.
  • each -R Q1NHH is independently linear or branched saturated C 1-4 alkyl, C 3-6 cycloalkyl, 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, -CH 3 , -CF 3 , -OH, -OCH 3 , -NH 2 , -NH(CH 3 ), and -N(CH 3 ) 2 .
  • each -R Q1NHH is independently linear or branched saturated C 1-4 alkyl, phenyl, or phenyl-CH 2 -, wherein each phenyl is optionally substituted with one or more groups selected from: -F, -Cl, -CH 3 , -CF 3 , -OH, -OCH 3 , -NH 2 , -NH(CH 3 ), and -N(CH 3 ) 2 .
  • each -R Q1NHH is independently linear or branched saturated C 1-4 alkyl, phenyl, or benzyl.
  • each -R Q1NHH is independently linear or branched saturated C 1-4 alkyl.
  • each -R Q1NHH is independently -Me, -Et, -nPr, -iPr, -nBu, or -tBu.
  • each -R Q1NHH is independently -Me, -Et, -iPr, or -tBu.
  • each -R Q1NHH is independently -Me, -Et, -nPr, or -iPr.
  • each -R Q1NHH is independently -Me or -Et.
  • each -R Q1NHH is -Me.
  • the Group -R Q1NJJ (312) A compound according to any one of (1) to (311), wherein: -R Q1NJJ , if present, is -R J1 , -L J -R J2 , -L J -R J3 , -L J -R J4 , or -L J -R J5 . (313) A compound according to any one of (1) to (311), wherein: -R Q1NJJ , if present, is -R J1 , -L J -R J3 , -L J -R J4 , or -L J -R J5 .
  • 315 A compound according to any one of (1) to (311), wherein: -R Q1NJJ , if present, is -R J1 or -L J -R J4 .
  • -R Q1NJJ if present, is -L J -R J2 , -L J -R J3 , -L J -R J4 , or -L J -R J5 .
  • (320) A compound according to any one of (1) to (311), wherein: -R Q1NJJ , if present, is -R Q1NJJ is -R J1 .
  • -R J1 if present, is linear or branched saturated C 1-4 alkyl.
  • (330) A compound according to any one of (1) to (332014), wherein: -R J1 , if present, is -Me.
  • the Group -R J2 (331) A compound according to any one of (1) to (330), wherein: each -R J2 , if present, is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • (332) A compound according to any one of (1) to (330), wherein: each -R J2 , if present, is cyclopropyl.
  • (333) A compound according to any one of (1) to (330), wherein: each -R J2 , if present, is independently cyclobutyl.
  • each -R J2 if present, is independently cyclopentyl.
  • each -R J2 if present, is independently cyclohexyl.
  • each -R J4 if present, is phenyl; and is optionally substituted with one or more groups selected from: -F, -Cl, -R JJ , -OH, -NH 2 , -NHR JJ , and -NR JJ .
  • (341) A compound according to any one of (1) to (339), wherein: each -R J4 , if present, is phenyl.
  • each -R J5 if present, is independently thienyl, pyrazolyl, or pyridinyl.
  • the Group -L J - (346) A compound according to any one of (1) to (345), wherein: each -L J -, if present, is independently -CH 2 -, -CF 2 -, -C(CH 3 ) 2 -, -CH 2 CH 2 -, or -CH 2 CH 2 CH 2 -.
  • each -L J -, if present, is independently linear or branched saturated C 1-4 alkylene.
  • each -L J -, if present, is independently -CH 2 -, -C(CH 3 ) 2 -, -CH 2 CH 2 -, or -CH 2 CH 2 CH 2 -.
  • each -L J -, if present, is independently -CH 2 -, -CH 2 CH 2 -, or -CH 2 CH 2 CH 2 -.
  • each -L J -, if present, is independently -CH 2 -, -CH 2 CH 2 -, or -CH 2 CH 2 CH 2 -.
  • each -L J - is -CH 2 CH 2 -.
  • each -L J - is -CH 2 CH 2 CH 2 -.
  • the Group -R JJ (353) A compound according to any one of (1) to (352), wherein: each -R JJ , if present, is: -Me, -Et, -nPr, -iPr, -nBu, or -tBu.
  • each -R JJ if present, is: -Me, -Et, -nPr, or -iPr.
  • the Group -R Q1NK (357) A compound according to any one of (1) to (356), wherein: -R Q1NK , if present, is -R Q1NK is -R K1 , or -R K3 . (358) A compound according to any one of (1) to (356), wherein: -R Q1NK , if present, is -R K1 , -R K2 , -L K -R K2 , -R K3 , or -L K -R K3 ; (359) A compound according to any one of (1) to (356), wherein: -R Q1NK , if present, is -R K1 , -R K2 , -R K3 , or -L K -R K3 ; (360) A compound according to any one of (1) to (356), wherein: -R Q1NK , if present, is -R K1 .
  • -R K1 if present, is -Me, -Et, -nPr, -iPr, -nBu, or -tBu.
  • -R K1 if present, is -Me or -Et.
  • -R K1 if present, is -Me.
  • each -R K2 is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • each -R K2 is cyclopropyl.
  • each -R K2 is independently cyclobutyl.
  • each -R K2 is independently cyclopentyl.
  • each -R K2 if present, is independently cyclohexyl.
  • the Group -R K3 A compound according to any one of (1) to (378), wherein: each -R K3 , if present, is independently non-aromatic C 3-7 heterocyclyl.
  • each -R K3 if present, is tetrahydropyranyl.
  • each -R K4 if present, is phenyl; and is optionally substituted with one or more groups selected from: -F, -Cl, -R KK , -CF 3 , -OH, and -OR KK .
  • each -R K4 if present, is phenyl.
  • each -R K5 if present, is independently pyrrolyl, furanyl, thienyl, pyrazolyl, pyridinyl, pyrimidinyl, or pyridizinyl.
  • the Group -L K - (390) A compound according to any one of (1) to (389), wherein: each -L K -, if present, is independently linear or branched saturated C 1-4 alkylene.
  • each -L K -, if present, is independently -CH 2 -, -C(CH 3 ) 2 -, -CH 2 CH 2 -, or -CH 2 CH 2 CH 2 -.
  • each -L K -, if present, is independently -CH 2 -, -CH 2 CH 2 -, or -CH 2 CH 2 CH 2 -.
  • each -L K -, if present, is -CH 2 -.
  • each -L K -, if present is -CH 2 CH 2 -.
  • each -L K -, if present is -CH 2 CH 2 CH 2 -.
  • the Group -R KK (396) A compound according to any one of (1) to (395), wherein: each -R KK , if present, is: -Me, -Et, -nPr, -iPr, -nBu, or -tBu.
  • each -R KK if present, is: -Me, -Et, -nPr, or -iPr.
  • each -R KK if present, is: -Me or -Et.
  • each -R KK if present, is: -Me.
  • the Group -R Q1NP 400
  • -R Q1NP is independently: non-aromatic C 3-11 heterocyclyl having at least one N ring atom, and is attached via that N ring atom; and is: optionally substituted on carbon with one or more groups selected from -R Q1NPP , -F, -OH, -CF 3 , and -C(O)NH 2 ; and optionally substituted on secondary nitrogen, if present, with a group selected from: -R Q1NPP .
  • -R Q1NP is independently: morpholinyl, piperazinyl, pyrrolidinyl, 2,8-diazaspiro[4.5]decanyl, piperidinyl, azetidinyl, piperidinyl, 2-azaspiro[3.3]heptanyl, or 2-oxa-6-azaspiro[3.3]heptanyl, and is attached via an N ring atom; and is: optionally substituted on carbon with one or more groups selected from -R Q1NPP , -F, -OH, -CF 3 , and -C(O)NH 2 ; and optionally substituted on secondary nitrogen, if present, with a group selected from: -R Q1NPP .
  • (402) A compound according to any one of (1) to (399), wherein: -R Q1NP , if present, is independently: azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azepanyl, diazepanyl, 3-azabicyclo[3.1.0]hexanyl, 3,6-diazabicyclo[3.1.1]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-azabicyclo[2.2.1]heptanyl, 3,8-diazabicyclo[3.2.1]octanyl, 3-azabicyclo[3.2.1]octanyl, 2-azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 6-azaspiro[3.4]octanyl, 2-azaspiro[3.4]
  • a compound accord3in]hge piperid 2 t i 2n-poay-taaz a l,aznn pasey is o ppierniorre ao[3 o z[3.f i5n. ( y4]n12 l],oo),6 2nc to- -atd aan (i zn3aeae9za9s),p wir spiro[ 2ho 3,e[ .73r 3-e.
  • each -R Q1NPP is independently linear or branched saturated C 1-4 alkyl or phenyl, wherein C 1-4 alkyl is optionally substituted with -OH, -Cl or -OCH 3 .
  • each -R Q1NPP if present, is independently linear or branched saturated -Me, -iPr or phenyl, wherein -Me or -iPr is optionally substituted with -OH, -Cl or -OCH 3 .
  • each -R Q1NPP if present, is independently linear or branched saturated C 1-4 alkyl, phenyl, or phenyl-CH 2 -, wherein each phenyl is optionally substituted with one or more groups selected from: -F, -Cl, -CH 3 , -CF 3 , -OH, -OCH 3 , -NH 2 , -NH(CH 3 ), and -N(CH 3 ) 2 .
  • each -R Q1NPP is independently linear or branched saturated C 1-4 alkyl, phenyl, or phenyl-CH 2 -.
  • each -R Q1NPP is independently linear or branched saturated C 1-4 alkyl.
  • each -R Q1NPP is: -Me, -Et, -nPr, -iPr, -nBu, or -tBu.
  • each -R Q1NPP if present, is: -Me, -Et, -nPr, or -iPr.
  • each -R Q1NPP if present, is: -Me or -Et.
  • each -R Q1NPP if present, is: -Me or -Et.
  • each -R Q1NPP if present, is: -Me.
  • each -R Q1NPP if present, is: phenyl.
  • the Group -R Q1NPPX (415) A compound according to any one of (1) to (414), wherein: -R Q1NPPX , if present, is independently linear or branched saturated C 1-4 fluoroalkyl. (416) A compound according to any one of (1) to (414), wherein: -R Q1NPPX , if present, is independently -CF 3 , -CHF2, -CH 2 CF 3 , or -CH 2 CHF2. (417) A compound according to any one of (1) to (414), wherein: -R Q1NPPX , if present, is -CH 2 CF 3 .
  • each -R Q2C if present, is independently: -F, -R Q2CC , -R Q2CX , -OH, -OR Q2CC , -OR Q2CX , -NH 2 , -NHR Q2CC , -NR Q2CC 2 , or -R Q2CM .
  • each -R Q2C if present, is independently: -F, -R Q2CC , -R Q2CX , -OH, -OR Q2CC , or -OR Q2CX .
  • each -R Q2CC is independently linear or branched saturated C 1-4 alkyl, phenyl, or phenyl-CH 2 -, wherein each phenyl is optionally substituted with one or more groups selected from: -F, -Cl, -CH 3 , -CF 3 , -OH, -OCH 3 , -NH 2 , -NH(CH 3 ), and -N(CH 3 ) 2 .
  • each -R Q2CC if present, is independently linear or branched saturated C 1-4 alkyl, phenyl, or phenyl-CH 2 -.
  • each -R Q2CC if present, is independently linear or branched saturated C 1-4 alkyl.
  • each -R Q2CC if present, 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.
  • 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 -CF 3 .
  • each -R Q2CMM is independently linear or branched saturated C 1-4 alkyl, phenyl, or phenyl-CH 2 -, wherein each phenyl is optionally substituted with one or more groups selected from: -F, -Cl, -CH 3 , -CF 3 , -OH, -OCH 3 , -NH 2 , -NH(CH 3 ), and -N(CH 3 ) 2 .
  • each -R Q2CMM is independently linear or branched saturated C 1-4 alkyl, phenyl, or phenyl-CH 2 -.
  • each -R Q2CMM is independently linear or branched saturated C 1-4 alkyl.
  • each -R Q2CMM 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 Q2NC is independently linear or branched saturated C1-6alkyl, phenyl, phenyl-CH 2 -, pyridyl, or pyridyl-CH 2 -, wherein C1-6alkyl is optionally substituted with -OH or -OCH 3 , and each phenyl and pyridyl is optionally substituted with one or more groups selected from: -F, -Cl, -CH 3 , -CF 3 , -OH, -OCH 3 , -NH 2 , -NH(CH 3 ), and -N(CH 3 ) 2 ; (446) A compound according to any one of (1) to (444), wherein: each -R Q2NC , if present, is independently linear or branched saturated C 1-4 alkyl, phenyl, or phenyl-CH 2
  • each -R Q2NC if present, is independently linear or branched saturated C 1-4 alkyl, phenyl, or phenyl-CH 2 -.
  • each -R Q2NC if present, is independently linear or branched saturated C 1-4 alkyl.
  • 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 -L Q2N - is independently -CH 2 -, -C(CH 3 ) 2 -, -CH 2 CH 2 -, or -CH 2 CH 2 CH 2 -.
  • each -L Q2N - is independently -CH 2 -, -CH 2 CH 2 -, or -CH 2 CH 2 CH 2 -.
  • each -L Q2N -, if present, is independently -CH 2 -, -CH 2 CH 2 -, or -CH 2 CH 2 CH 2 -.
  • each -L Q2N -, if present, is -CH 2 -.
  • each -L Q2N - is -CH 2 CH 2 -.
  • each -L Q2N - is -CH 2 CH 2 CH 2 -.
  • each -R Q2NMM is independently linear or branched saturated C 1-4 alkyl, phenyl, or phenyl-CH 2 -, wherein each phenyl is optionally substituted with one or more groups selected from: -F, -Cl, -CH 3 , -CF 3 , -OH, -OCH 3 , -NH 2 , -NH(CH 3 ), and -N(CH 3 ) 2 .
  • each -R Q2NMM is independently linear or branched saturated C 1-4 alkyl, phenyl, or phenyl-CH 2 -.
  • each -R Q2NMM is independently linear or branched saturated C 1-4 alkyl.
  • each -R Q2NMM is: -Me, -Et, -nPr, -iPr, -nBu, or -tBu.
  • each -R Q2NMM if present, is: -Me, -Et, -nPr, or -iPr.
  • each -R Q2NMM if present, is: -Me or -Et.
  • each -R Q2NMM if present, is: -Me.
  • each -R Q3C is independently: -F, -Cl, -Br, -I, -R Q3CC , -R Q3CX , -OR Q3CX , -OH, -OR Q3CC , -NH 2 , -NHR Q3CC , -NR Q3CC 2, or -R Q3CM ; 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: -F, -Cl, -Br, -I, -R Q3CC , -R Q3CX , -OR Q3CX , -OH, or -OR Q3CC .
  • each -R Q3CC is independently linear or branched saturated C 1-4 alkyl, phenyl, or phenyl-CH 2 -, wherein each phenyl is optionally substituted with one or more groups selected from: -F, -Cl, -CH 3 , -CF 3 , -OH, -OCH 3 , -NH 2 , -NH(CH 3 ), and -N(CH 3 ) 2 .
  • each -R Q3CC if present, is independently linear or branched saturated C 1-4 alkyl, phenyl, or phenyl-CH 2 -.
  • 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 or -Et.
  • each -R Q3CC if present, is: -Me.
  • each -R Q3CX is independently linear or branched saturated C 1-4 fluoroalkyl.
  • each -R Q3CX if present, is independently -CF 3 , -CHF2, -CH 2 CF 3 , or -CH 2 CHF2.
  • each -R Q3CX if present, is -CF 3 .
  • each -L Q3C - is independently -CH 2 -, -C(CH 3 ) 2 -, -CH 2 CH 2 -, or -CH 2 CH 2 CH 2 -.
  • each -L Q3C - is independently -CH 2 -, -CH 2 CH 2 -, or -CH 2 CH 2 CH 2 -.
  • each -L Q3C -, if present, is independently -CH 2 -.
  • each -R Q3CM if present, is independently pyrrolidinyl and is attached via an N ring atom.
  • each -R Q3CMM is independently linear or branched saturated C 1-4 alkyl, phenyl, or phenyl-CH 2 -, wherein each phenyl is optionally substituted with one or more groups selected from: -F, -Cl, -CH 3 , -CF 3 , -OH, -OCH 3 , -NH 2 , -NH(CH 3 ), and -N(CH 3 ) 2 .
  • each -R Q3CMM is independently linear or branched saturated C 1-4 alkyl, phenyl, or phenyl-CH 2 -.
  • each -R Q3CMM is independently linear or branched saturated C 1-4 alkyl.
  • each -R Q3CMM 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.
  • (501) A compound according to any one of (1) to (498), 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-(CH 2 )p3-O- (502) A compound according to any one of (1) to (501), wherein: p3, if present, is 1.
  • (503) A compound according to any one of (1) to (501), wherein: p3, if present, is 2.
  • each -R Q4C is independently: -F, -R Q4CC , -R Q4CX , -OH, -OR Q4CC , -OR Q4CX , -NH 2 , -NHR Q4CC , -NR Q4CC 2, or -R Q4CM .
  • each -R Q4C if present, is independently: -R Q4CC , -R Q4CX , -OH, -OR Q4CC , or -OR Q4CX .
  • each -R Q4C if present, is independently: -R Q4CC , -OH, or -OR Q4CC .
  • the Group -R Q4CC (507) A compound according to any one of (1) to (506), wherein: each -R Q4CC is independently linear or branched saturated C 1-4 alkyl, phenyl, phenyl-C 1-3 alkyl, C 5-6 heteroaryl, or C 5-6 heteroaryl-C 1-3 alkyl, wherein each phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -CH 3 , -CF 3 , -OH, -OCH 3 , -NH 2 , -NH(CH 3 ), and -N(CH 3 ) 2 .
  • each -R Q4CC if present, is independently linear or branched saturated C 1-4 alkyl, phenyl, or phenyl-CH 2 -, wherein each phenyl is optionally substituted with one or more groups selected from: -F, -Cl, -CH 3 , -CF 3 , -OH, -OCH 3 , -NH 2 , -NH(CH 3 ), and -N(CH 3 ) 2 .
  • each -R Q4CC if present, is independently linear or branched saturated C 1-4 alkyl, phenyl, or phenyl-CH 2 -.
  • each -R Q4CC if present, is independently linear or branched saturated C 1-4 alkyl.
  • each -R Q4CC if present, is: -Me, -Et, -nPr, -iPr, -nBu, or -tBu.
  • each -R Q4CX is independently linear or branched saturated C 1-4 fluoroalkyl.
  • each -R Q4CX if present, is independently -CF 3 , -CHF2, -CH 2 CF 3 , or -CH 2 CHF2.
  • each -R Q4CX if present, is -CF 3 .
  • each -R Q4CMM is independently linear or branched saturated C 1-4 alkyl, phenyl, or phenyl-CH 2 -, wherein each phenyl is optionally substituted with one or more groups selected from: -F, -Cl, -CH 3 , -CF 3 , -OH, -OCH 3 , -NH 2 , -NH(CH 3 ), and -N(CH 3 ) 2 .
  • each -R Q4CMM is independently linear or branched saturated C 1-4 alkyl, phenyl, or phenyl-CH 2 -.
  • each -R Q4CMM is independently linear or branched saturated C 1-4 alkyl.
  • each -R Q4CMM is: -Me, -Et, -nPr, -iPr, -nBu, or -tBu.
  • each -R Q4CMM if present, is: -Me, -Et, -nPr, or -iPr.
  • each -R Q4CMM if present, is: -Me or -Et.
  • each -R Q4CMM if present, is: -Me.
  • each -R Q5CC is independently linear or branched saturated C 1-4 alkyl, phenyl, or phenyl-CH 2 -, wherein each phenyl is optionally substituted with one or more groups selected from: -F, -Cl, -CH 3 , -CF 3 , -OH, -OCH 3 , -NH 2 , -NH(CH 3 ), and -N(CH 3 ) 2 .
  • each -R Q5CC if present, is independently linear or branched saturated C 1-4 alkyl, phenyl, or phenyl-CH 2 -.
  • each -R Q5CC if present, is independently linear or branched saturated C 1-4 alkyl.
  • 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 Q5CC if present, is: -Me or -Et.
  • each -R Q5CC if present, is: -Me.
  • each -R Q5CMM is independently linear or branched saturated C 1-4 alkyl, phenyl, or phenyl-CH 2 -, wherein each phenyl is optionally substituted with one or more groups selected from: -F, -Cl, -CH 3 , -CF 3 , -OH, -OCH 3 , -NH 2 , -NH(CH 3 ), and -N(CH 3 ) 2 .
  • each -R Q5CMM is independently linear or branched saturated C 1-4 alkyl, phenyl, or phenyl-CH 2 -.
  • each -R Q5CMM is independently linear or branched saturated C 1-4 alkyl.
  • 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.
  • Certain Preferred Combinations (549) A compound according to any one of (1) to (548), as applicable, wherein: -R A3 is -H; and -R A4 is -H.
  • (550) A compound according to any one of (1) to (548), as applicable, wherein: Ring A is: ; and Ring B is: .
  • the compound is a compound of the following structural formula: . (551) A compound according to any one of (1) to (548), as applicable, wherein: Ring B is: . (552) A compound according to any one of (1) to (548), as applicable, wherein: Ring B is: ; -Q is -Q 1 ; and -Q 1 is pyrazolyl and is: optionally substituted on carbon with one or more groups -R Q1C ; and optionally substituted on secondary nitrogen, if present, with -R Q1N .
  • Ring A is: ; Ring B is: ; -Q is -Q 1 ; -Q 1 is 1H-pyrazol-3-yl and is: optionally substituted oHnN car Nbon w Oith one S or more groups -R Q1C ; and substituted on secondary nitrogen with -R Q1N .
  • the compound is a compound of the following structural formula: A NH NH .
  • the compound is a compound of the following structural formula: .
  • the compound is a compound of the following structural formula: .
  • the compound is a compound of the following structural formula: .
  • (559) A compound according to any one of (1) to (548), as applicable, wherein: Ring A is: Ring B is: ; -R A2 is -R A222 or -Cl; and -R A222 is -Me.
  • Ring A is: Ring B is: ; -Q is -Q 1 ; and -Q 1 is pyridyl and is: optionally substituted on carbon with one or more groups -R Q1C .
  • a compound according to (1) or (2) selected from compounds of the following formulae and pharmaceutically acceptable salts and solvates thereof (e.g., and pharmaceutically acceptable salts thereof): HN N O S H NN H O HN N NH O S HN N N N HN Nr H O HN N NH O S HN N N F N
  • N e Nmbo O NdHim Sen Nt N tHhe N B NAA O c OoH mpound is obtainable (or o .
  • the BAA compound is provided accordHb in Nta g Nined to a O) NnH by f y em Soll b Now o NdHing ime N th n a Ne methods described in the experimental section t described herein (for example, embodiment (1), (2) or (3); or claim 1) with the proviso th t a Ony O oHf the specific 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 are individually disclaimed.
  • the BAA compound is provided according to any embodiment described herein (for example, embodiment (1), (2) or (3); or claim 1) with the proviso that any other embodiment described herein is specifically disclaimed.
  • Substantially Purified Forms 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 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 stereoisomer. In one embodiment, the substantially purified form refers to a mixture of enantiomers. In one embodiment, the substantially purified form refers to an equimolar mixture of enantiomers (i.e., a racemic mixture, a racemate). In one embodiment, the substantially purified form refers to one enantiomer, e.g., optically pure enantiomer.
  • the contaminants represent no more than 50% by weight, e.g., no more than 40% by weight, e.g., no more than 30% by weight, e.g., no more than 20% by weight, e.g., no more than 10% by weight, e.g., no more than 5% by weight, e.g., no more than 3% by weight, e.g., no more than 2% by weight, e.g., no more than 1% by weight.
  • the contaminants refer to other compounds, that is, other than stereoisomers or enantiomers. In one embodiment, the contaminants refer to other compounds and other stereoisomers. In one embodiment, the contaminants refer to other compounds and the other enantiomer.
  • the substantially purified form is at least 60% optically pure (i.e., 60% of the compound, on a molar basis, is the desired stereoisomer or enantiomer, and 40% is the undesired stereoisomer or enantiomer), e.g., at least 70% optically pure, e.g., at least 80% optically pure, e.g., at least 90% optically pure, e.g., at least 95% optically pure, e.g., at least 97% optically pure, e.g., at least 98% optically pure, e.g., at least 99% optically pure.
  • 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
  • at least 70% optically pure e.g., at least 80% optically pure, e.g., at least 90% optically pure, e
  • Certain compounds may exist in one or more particular geometric, optical, enantiomeric, diastereoisomeric, epimeric, atropic, stereoisomeric, tautomeric, conformational, or anomeric forms, including but not limited to, cis- and trans-forms; E- and Z-forms; c-, t-, and r- forms; endo- and exo-forms; R-, S-, and meso-forms; D- and L-forms; d- and l-forms; (+) and (-) forms; keto-, enol-, and enolate-forms; syn- and anti-forms; synclinal- and anticlinal-forms; ⁇ - and ⁇ -forms; axial and equatorial forms; boat-, chair-, twist-, envelope-, and halfchair-forms; and combinations thereof, hereinafter collectively referred to as “isomers” (or “isomeric forms”).
  • 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, -OCH 3 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.
  • keto enol enolate For example, 1H-pyridin-2-one-5-yl and 2-hydroxyl-pyridin-5-yl (shown below) are tautomers of one another. A reference herein to one is intended to encompass both. 1 H-pyridin-2-one-5-yl 2-hydroxyl-pyridin-5-yl Note that specifically included in the term “isomer” are compounds with one or more isotopic substitutions.
  • 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.
  • 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 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., NH 4 + ).
  • 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 C 1-18 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-6 alkyl, and phenyl-C 1-6 alkyl, 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 C 1-18 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-6 alkyl, and phenyl-C 1-6 alkyl, 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., -NMe2 + ), or has a functional group, which upon protonation may become cationic (e.g., -NH 2 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.
  • Suitable organic anions include, but are not limited to, those derived from the following organic acids: 2-acetyloxybenzoic, acetic, trifluoroacetic, ascorbic, aspartic, benzoic, camphorsulfonic, cinnamic, citric, edetic, 1,2-ethanedisulfonic, ethanesulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, hydroxymaleic, hydroxynaphthalene carboxylic, isethionic, lactic, lactobionic, lauric, maleic, malic, methanesulfonic, mucic, oleic, oxalic, palmitic, pamoic, pantothenic, phenylacetic, phenylsulfonic, propionic, pyruvic, salicylic, stearic, succinic, sulfanilic, tartaric, toluenesulfonic, and va
  • 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 compounds (e.g., those with a -NMe2 + group) include 1-adamantanesulfonate, benzenesulfonate, bisulfate, bromide, chloride, iodide, methanesulfonate, methylsulfate, 1,5-napthalene-bis-sulfonate, 4-nitrobenzenesulfonate, formate, tartrate, tosylate, trifluoroacetate, trifluoromethylsulfonate, sulphate.
  • the compound also contains a group capable of forming an anion (e.g., -COOH), then an inner salt may be formed.
  • a reference to a particular compound also includes salt forms thereof.
  • 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).
  • Solvates and Hydrates It may be convenient or desirable to prepare, purify, and/or handle a corresponding solvate of the compound.
  • the term “solvate” is used herein in the conventional sense to refer to a complex of solute (e.g., compound, salt of compound) and solvent.
  • the solvate may be conveniently referred to as a hydrate, for example, a mono-hydrate, a di-hydrate, a tri-hydrate, etc. Unless otherwise specified, a reference to a particular compound also includes solvate and hydrate forms thereof.
  • the BAA compound is provided in the form of a solvate. In one embodiment, the BAA compound is provided in unsolvated form. In one embodiment, the BAA compound is provided in the form of a hydrate. Chemically Protected Forms It may be convenient or desirable to prepare, purify, and/or handle the compound in a chemically protected form.
  • 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).
  • specified conditions e.g., pH, temperature, radiation, solvent, reactive chemical reagents, and the like.
  • well-known chemical methods are employed to reversibly render unreactive a functional group, which otherwise would be reactive, under specified conditions.
  • 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 compound which has two non-equivalent reactive functional groups may be derivatized to render one of the functional groups “protected,” and therefore unreactive, under the specified conditions; so protected, the compound may be used as a reactant which has effectively only one reactive functional group.
  • the protected group may be “deprotected” to return it to its original functionality.
  • 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-CH 3 ); or as a carbamate (-NRCO-OR), for example: as a benzyloxy carbamate (-NHCO-OCH 2 C6H5, -NH-Cbz), as a t-butoxy carbamate (-NHCO-OC(CH 3 )3, -NH-Boc); as a 2-biphenyl-2-propoxy carbamate (-NHCO-OC(CH 3 ) 2 C 6 H 4 C 6 H 5 , -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 C1-7alkyl ester (e.g., a methyl ester; a t-butyl ester); a C1-7haloalkyl ester (e.g., a 2,2,2-trihaloethyl ester); a 2-tri(C1-7alkyl)silyl-ethyl ester; or a C5-20aryl-C1-7alkyl ester (e.g., a benzyl ester; a nitrobenzyl ester); or as an amide or hydrazide, for example, as acetamide or a N,N,N’-trimethylhydrazide.
  • an C1-7alkyl ester e.g., a methyl ester; a t-butyl ester
  • a C1-7haloalkyl ester e.g., a 2,2,2-trihaloethyl este
  • Prodrugs It may be convenient or desirable to prepare, purify, and/or handle the compound in the form of a prodrug.
  • the term “prodrug,” as used herein, pertains to a compound, which yields the desired active compound in vivo. Typically, the prodrug is inactive, or less active than the desired active compound, but may provide advantageous handling, administration, or metabolic properties.
  • compositions Also described herein is a composition (e.g., a pharmaceutical composition) comprising a BAA compound, as described herein, and a pharmaceutically acceptable carrier, diluent, or excipient.
  • a method of preparing a composition comprising mixing a BAA compound, as described herein, and a pharmaceutically acceptable carrier, diluent, or excipient.
  • the BAA compounds, as described herein inhibit PKMYT1 (e.g., inhibit or reduce or block the activity or function of PKMYT1).
  • the BAA compounds, as described herein 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).
  • a method of inhibiting PKMYT1 e.g., inhibiting or reducing or blocking the activity or function of PKMYT1, in vitro or in vivo, comprising contacting the PKMYT1 with an effective amount of a BAA compound, as described herein.
  • 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 morphological status of the cells (e.g., alive or dead, etc.) may be determined. Where the compound is found to exert an influence on the cells, this may be used as a prognostic or diagnostic marker of the efficacy of the compound in methods of treating a subject (e.g., patient) carrying cells of the same cellular type.
  • the direct interaction of the compound with the target in cells could be measured (e.g., “target engagement assay”) using, e.g., a colorimetric, fluorescent, or luminescent readout. 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 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 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 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 gastrointestinal (including, e.g., bowel, colon), breast (mammary), ovarian, prostate, liver (hepatic), kidney (renal), bladder, pancreas, brain, and skin cells.
  • gastrointestinal including, e.g., bowel, colon
  • breast mammary
  • ovarian ovarian
  • the BAA compounds described herein may inhibit cell migration and invasion, e.g., inhibit 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.
  • 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.
  • Use in Methods of Therapy Also described herein is a BAA compound, as described herein, for use in a method of treatment of the human or animal body by therapy, for example, for use in a method of treatment of a disorder (e.g., a disease) as described herein.
  • 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.
  • a disorder e.g., a disease
  • 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.
  • the medicament comprises the BAA compound.
  • Methods of Treatment 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, preferably in the form of a pharmaceutical composition.
  • a disorder e.g., a disease
  • a therapeutically-effective amount of a BAA compound as described herein, preferably 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 herein.
  • a disorder e.g., a disease
  • the disorder is: a proliferative disorder.
  • proliferative disorder 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, malignant, pre-metastatic, metastatic, or non-metastatic cellular proliferation, including for example: neoplasms, hyperplasias, tumours (e.g., histocytoma, glioma, astrocyoma, 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, astrocyoma, 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 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 further characterised by: inappropriate activity and/or expression of PKMYT1, CCNE1, FBXW7, or PPP2A or one of its subunits.
  • 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 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 or PPP2R2A.
  • 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.
  • the treatment is treatment of cancer.
  • Disorders Treated - Cancer In one embodiment (e.g., of use in methods of therapy, of use in the manufacture of medicaments, of methods of treatment), the treatment is treatment of cancer.
  • Carcinomas including tumours derived from stratified squamous epithelia (squamous cell carcinomas) and tumours arising within organs or glands (adenocarcinomas). Examples include breast, colon, lung, prostate, ovary.
  • Sarcomas including: osteosarcoma and osteogenic sarcoma (bone); chondrosarcoma (cartilage); leiomyosarcoma (smooth muscle); rhabdomyosarcoma (skeletal muscle); mesothelial sarcoma and mesothelioma (membranous lining of body cavities); fibrosarcoma (fibrous tissue); angiosarcoma and haemangioendothelioma (blood vessels); liposarcoma (adipose tissue); glioma and astrocytoma (neurogenic connective tissue found in the brain); myxosarcoma (primitive embryonic connective tissue); mesenchymous and mixed mesodermal tumour (mixed connective tissue types).
  • Haematopoietic tumours including: myelogenous and granulocytic leukaemia (malignancy of the myeloid and granulocytic white blood cell series), e.g., chronic myeloid leukemia (CML), acute myeloid leukemia (AML); lymphatic, lymphocytic, and lymphoblastic leukaemia (malignancy of the lymphoid and lymphocytic blood cell series), e.g., acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL); polycythaemia vera (malignancy of various blood cell products, but with red cells predominating).
  • 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 malignancy
  • Lymphomas including: Hodgkin and Non-Hodgkin lymphomas.
  • Mixed Types including, e.g., adenosquamous carcinoma; mixed mesodermal tumour; carcinosarcoma; teratocarcinoma.
  • the cancer is: a bone or muscle sarcoma, for example: bone cancer; bone sarcoma; chondrosarcoma; Ewing’s sarcoma; heart cancer; leiomyosarcoma; malignant fibrous histiocytoma of bone; osteosarcoma; or rhabdomyosarcoma; a brain and nervous system cancer, for example: astrocytoma; brain cancer; brainstem glioma; cerebellar astrocytoma; cerebral astrocytoma; ependymoma; glioblastoma; glioma; medulloblastoma; neuroblastoma; oligodendroglioma; pilocytic astrocytoma; pineal astrocytoma; pituitary adenoma; primitive neuroectodermal tumor; schwannoma; or visual pathway and hypothalamic glioma; a breast cancer,
  • 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.
  • the cancer is endometrial cancer.
  • the cancer is uterine cancer.
  • the cancer is ovarian cancer.
  • the cancer is breast cancer.
  • the cancer is gastric cancer.
  • the cancer is bladder cancer.
  • the cancer is pancreatic cancer.
  • the cancer is mesothelioma.
  • the cancer is kidney cancer. In one embodiment, the cancer is stomach cancer. In one embodiment, the cancer is esophageal cancer. In one embodiment, the cancer is colorectal cancer. In one embodiment, the cancer is glioblastoma. In one embodiment, the cancer is lung cancer. In one embodiment, the cancer is lung squamous cell carcinoma. In one embodiment, 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, 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: 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.
  • 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 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, 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).
  • 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, 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, 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.
  • 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. In one embodiment, the treatment resistant cancer is resistant to one or more of PARP inhibitors, cisplatin, WEE1 inhibitors and Cdk4/6 inhibitors. In one embodiment, the treatment resistant cancer is recombination proficient ovarian cancer. In one embodiment, the treatment resistant cancer is HER2- ER+ breast cancer with Cdk4/6 resistance. In one embodiment, the cancer (e.g., as above) 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 inhibition of cell cycle progression, the inhibition of angiogenesis (the formation of new blood vessels), the inhibition of metastasis (the spread of a tumour from its origin), the inhibition of cell migration (the spread of cancer cells to other parts of the body), the inhibition of invasion (the spread of tumour cells into neighbouring normal structures), the promotion of apoptosis (programmed cell death), death by necrosis, or induction of death by autophagy.
  • the compounds described herein may be used in the treatment of the cancers described herein, independent of the mechanisms discussed herein.
  • 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 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.
  • 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 BAA compounds described herein may also be used in combination therapies, e.g., in conjunction with other agents.
  • a BAA compound, as described herein in combination with one or more (e.g., 1, 2, 3, 4, etc.) additional therapeutic 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, where the BAA compound is administered in combination with one or more (e.g., 1, 2, 3, 4, etc.) additional therapeutic agents.
  • 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, where the BAA compound is administered in combination with one or more (e.g., 1, 2, 3, 4, etc.) additional therapeutic agents.
  • 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, where the BAA compound is administered in combination with one or more (e.g., 1, 2, 3, 4, etc.) additional therapeutic agents.
  • 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, where 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, where 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 particular combination would be at the discretion of the physician who would select dosages using their common general knowledge and dosing regimens known to a skilled practitioner.
  • 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 where required), the precise dosage regimen being commensurate with the properties of the therapeutic agent(s).
  • 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
  • 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 trastuzumab, bevacizumab, cetuximab, daratumumab, or naxitamab, necitumumab, obinutuzumab, ofatumumab, panitumumab, pertuzumab, ramucirumab, or rituximab), a bispecific antibody (for example blinatumomab), an immune checkpoint inhibitor (for example ipilimumab, nivolumab, pembrolizumab, cemiplimab, atezolizumab, durvalumab, avelumab, dostarlimab, or tremelimumab), an immunomodulator (for example imiquimod, thalidomide, lenalidomide, or ponalidomide),
  • the other agent is an antibody-drug conjugate (i.e. an “ADC”, for example brentuximab vedotin, inotuzumab ozogamicin, mirvetuximab soravtansine-gynx, fam- trastuzumab deruxtecan-nxki, ado-trastuzumab emtansine, gemtuzumab ozogamicin, enfortumab vedotin-ejfv, polatuzumab vedotin-piiq, tisotumab vedotin-tftv, sacituzumab govitecan-hziy, loncastuximab tesirine-lpyl, or distamab vedotin).
  • ADC antibody-drug conjugate
  • the other agent is a DNA-damaging agent, such as an alkylating agent (for example cis-platin, oxaliplatin, carboplatin, cyclophosphamide, melphalan, chlorambucil, bendamustine, temozolomide, trabectidin, mitomycin C, or dacarbazine); an antimetabolite (for example capecitabine, gemcitabine, 5-fluorouracil, fluoropyrimidine, trifluridine and tipiracil, cytarabine, or methotrexate); a DNA intercalator (for example an anthracycline like doxorubicin, epirubicin, or daunorubicin), an antibiotic (for example bleomycin, dactinomycin, or mithramycin); a topoisomerase 1 inhibitor (for example a camptothecin such as irinotecan, or topotecan), a topoisomerase
  • 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).
  • 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).
  • 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 (for example abemaciclib, acalabrutinib, afatinib, alectinib, avapritinib, axitinib, baricitinib, belumosudil, binimetinib, bosutinib, brigatinib, cabozantinib, capmatinib, ceritinib, cobimetinib, rizotinib, dabrafenib, dacomitinib, dasatinib, encorafenib, entrectinib, erdafitinib, erlotinib, everolimus, fedratinib, fostamatinib, gefitinib, gilteritinib, ibrutinib, imatinib, infigratinib, lapatinib,
  • 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 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 camonserti
  • 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 agent is a hormone therapy agent, such as an antiestrogen (for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene, or idoxifene), an antiandrogen (for example abiraterone, bicalutamide, enzalutamide, flutamide, nilutamide, or cyproterone acetate), an LHRH antagonist or LHRH agonist (for example goserelin, leuprorelin, or buserelin), a progestogen (for example megestrol acetate), an aromatase inhibitor (for example as anastrozole, letrozole, vorazole, or exemestane) an inhibitor of 5 ⁇ -reductase (for example finasteride) or an analogue of somatostatin (for example lanreotide).
  • an antiestrogen for example tamoxifen, fulvestrant,
  • the other agent is a proteasome inhibitor (for example bortezomib), a histone deacetylase inhibitor (for example vorinostat, romidepsin, panobinostat, or belinostat), or a DNA demethylating agent (for example azacitidine, or decitabine).
  • a proteasome inhibitor for example bortezomib
  • a 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 lutetium Lu 177inate, lutetium Lu 177 vipivotide tetraxetan, samarium Sm 153 lexidronam, radium Ra 223 dichloride, or Y-90 ibritumomab tiuxetan).
  • a radiotherapeutic drug for example lutetium Lu 177inate, lutetium Lu 177 vipivotide tetraxetan, samarium Sm 153 lexidronam, radium Ra 223 dichloride, or Y-90 ibritumomab tiuxetan.
  • a radiotherapeutic drug for example lutetium Lu 177inate, lutetium Lu 177 vipivotide tetraxetan, samarium Sm 153 lexidronam, radium Ra 2
  • 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 Also describes herein is a kit comprising (a) a BAA compound, as described herein, preferably provided as a composition (e.g., a pharmaceutical composition) and in a suitable container and/or with suitable packaging; and (b) instructions for use, for example, in a method of treatment of a disorder (e.g., a disease) as described herein, for example, written instructions on how to administer the compound.
  • the written instructions may also include a list of indications for which the BAA compound is a suitable treatment.
  • Routes of Administration 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; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular
  • 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 (e.g., a monkey or ape), a monkey (e.g., marmoset, baboon), an
  • the subject may be any of its forms of development, for example, a foetus.
  • the subject e.g., patient
  • a pharmaceutical formulation e.g., composition, preparation, medicament
  • a pharmaceutical formulation comprising at least one BAA compound, as described herein, together with one or more other pharmaceutically acceptable ingredients well known to those skilled in the art, including, for example, pharmaceutically acceptable carriers, diluents, excipients, 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 carriers e.g., diluents, excipients, adjuvants, fillers, buffers, preservatives, anti-oxidants, lubricants, stabilisers, solubilisers, surfactants (e.g., wetting agents), masking agents,
  • the formulation may further comprise other active agents, for example, other therapeutic or prophylactic agents.
  • 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., carriers, diluents, excipients, etc. If formulated as discrete units (e.g., tablets, etc.), each unit contains a predetermined amount (dosage) of the compound.
  • pharmaceutically acceptable 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 carrier, diluent, excipient, etc. must also be “acceptable” in the sense of being compatible with the other ingredients of the formulation. Suitable carriers, diluents, excipients, etc.
  • the formulations may be prepared by any methods well known in the art of pharmacy. Such methods include the step of bringing into association the compound with a carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the compound with carriers (e.g., liquid carriers, finely divided solid carrier, etc.), and then shaping the product, if necessary.
  • 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, losenges, pastilles, capsules (including, e.g., hard and soft gelatin capsules), cachets, pills, ampoules, boluses, suppositories, pessaries, tinctures, gels, pastes, ointments, creams, lotions, oils, foams, sprays, mists, or aerosols.
  • 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. 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., 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, losenges, pastilles, as well as patches, adhesive plasters, depots, and reservoirs. Losenges typically comprise the compound in a flavoured basis, usually sucrose and acacia or tragacanth.
  • Pastilles typically comprise the compound in an inert matrix, such as gelatin and glycerin, or sucrose and acacia.
  • Mouthwashes typically comprise the compound in a suitable liquid carrier.
  • Formulations suitable for sublingual administration include tablets, losenges, pastilles, capsules, and pills.
  • Formulations suitable for oral transmucosal administration include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), mouthwashes, losenges, pastilles, as well as patches, adhesive plasters, 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 machine the compound in a free-flowing form such as a powder or granules, optionally mixed with one or more binders (e.g., povidone, gelatin, acacia, sorbitol, tragacanth, hydroxypropylmethyl cellulose); fillers or diluents (e.g., lactose, microcrystalline cellulose, calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, silica); disintegrants (e.g., sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose); surface- active or dispersing or wetting agents (e.g., sodium lauryl sulfate); preservatives (e.g., methyl p-hydroxybenzoate, propyl
  • Emulsions are typically prepared from the compound and an oily phase, which may optionally comprise merely an emulsifier (otherwise known as an emulgent), or it may comprise a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil.
  • an emulsifier also 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.
  • the 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 should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers.
  • Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required.
  • Formulations suitable for intranasal administration, where the carrier is a liquid include, for example, nasal spray, nasal drops, or by aerosol administration by nebuliser, include aqueous or oily solutions of the compound.
  • Formulations suitable for intranasal administration, where the carrier is a solid include, for example, those presented as a coarse powder having a particle size, for example, in the range of about 20 to about 500 microns which is administered in the manner in which snuff is taken, i.e., by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
  • 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 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, 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 may additionally contain other pharmaceutically acceptable ingredients, such as anti-oxidants, 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 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. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets. Dosage It will be appreciated by one of skill in the art that appropriate dosages of the BAA compounds, and compositions comprising the BAA compounds, can vary from subject to subject (e.g., from patient to patient). Determining the optimal dosage will generally involve balancing the level of therapeutic benefit against any risk or deleterious side effects.
  • the selected dosage level will depend on a variety of factors including, for example: the activity of the particular BAA compound; the route of administration; the time of administration; the rate of excretion of the BAA compound; the duration of the treatment; other drugs, compounds, and/or materials used in combination; the severity of the disorder; and the species, sex, age, weight, condition, general health, and prior medical history of the subject (e.g., patient).
  • the amount of BAA compound and route of administration will ultimately be at the discretion of the physician, veterinarian, or clinician, although generally the dosage will be selected to achieve local concentrations at the site of action which achieve the desired effect without causing substantial harmful or deleterious side-effects.
  • Administration can be effected in one dose, continuously or intermittently (e.g., in divided doses at appropriate intervals) throughout the course of treatment. Methods of determining the most effective means and dosage of administration are well known to those of skill in the art and will vary with the formulation used for therapy, the purpose of the therapy, the target cell(s) being treated, and the subject being treated. Single or multiple administrations can be carried out with the dose level and pattern being selected by the treating physician, veterinarian, or clinician.
  • 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.
  • Thin layer chromatography was conducted with 5 ⁇ 10 cm plates coated with Merck Type 60 F254 silica gel to a thickness of 0.25 mm. All reagents obtained from commercial sources were used without further purification. Anhydrous solvents were obtained from the Sigma-Aldrich Chemical Company Ltd. or Fisher Chemicals Ltd., and used without further drying. HPLC grade solvents were obtained from Fisher Chemicals Ltd. All compounds were >90 % purity as determined by examination of both the LCMS and 1H NMR spectra unless otherwise indicated. Where Cl or Br were present, expected isotopic distribution patterns were observed.
  • NMR Proton ( 1 H) and carbon ( 13 C) and ( 19 F) NMR spectra were recorded on a 300 MHz Bruker or 400 MHz Jeol spectrometer. Solutions were typically prepared in either deuterated chloroform (Chloroform-d), deuterated methanol (Methanol-d4) or deuterated dimethylsulfoxide (DMSO-d6) with chemical shifts referenced to tetramethylsilane (TMS) or deuterated solvent as an internal standard.
  • Chloroform-d deuterated chloroform
  • Methanol-d4 deuterated methanol
  • DMSO-d6 deuterated dimethylsulfoxide
  • 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.
  • Analytical LCMS LCMS analyses were performed on a Waters Acquity UPLC using BEH C181.7 ⁇ M columns (2.1 ⁇ 50 mm) with a diode array detector coupled to a SQD mass spectrometer with optional ELS detection (Acquity UPLC ELS Detector) or, a Waters Acquity 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.
  • Acidic 6 min (“Acidic_Prep_Analysis”) 0.1% v/v formic acid in 10mM ammonium formate [Eluent A]; 0.1% v/v formic acid in MeCN [Eluent B]; flow rate 0.8mL/min; column oven 50 ⁇ C; sample manager 20 ⁇ C; injection volume 2 ⁇ L and 1.5 minutes equilibration time between samples on a Waters Acquity UPLC BEH C18 column (2.1 ⁇ 50 mm, 1.7 ⁇ m).
  • Basic 6 min (“Basic_Prep_Analysis”) 0.1% ammonia in water [Eluent A]; 0.1% ammonia in MeCN [Eluent B]; flow rate 0.8mL/min; column oven 50 ⁇ C; sample manager 20 ⁇ C; injection volume 2 ⁇ L and 1.5 minutes equilibration time between samples on a Waters Acquity UPLC BEH C18 column (2.1 ⁇ 50 mm, 1.7 ⁇ m).
  • Preparative HPLC-MS Some compounds were purified by preparative HPLC on a Waters FractionLynx MS autopurification system, with a Phenomonex Gemini NX 5 ⁇ m C18, 100 mm ⁇ 21.2 mm i.d.
  • Preparative HPLC purification was carried out either on a Teledyne ISCO ACCQPrep® HP150 system or on a Waters Mass-directed PrepLC system, with a C1 XBridge BEH C18 (dimensions: 19 mm x 150 mm 5 ⁇ m) or a C2 XBridge BEH C18 (dimensions: 19 mm x 150 mm 5 ⁇ m) column, running a flow rate of 20 mL/min. All masses were detected with electrospray ionisation (ESI). Purifications were performed using buffered acidic or basic solvent systems as appropriate.
  • ESI electrospray ionisation
  • Nitro pyrazole precursors 2-Methyl-1-(3-nitropyrazol-1-yl)propan-2-ol A suspension of 3-Nitro-1H-pyrazole (1000 mg, 8.84 mmol, 1.00 eq), Isobutylene oxide (1.6 mL, 18.0 mmol, 2.04 eq), and cesium carbonate (6500 mg, 19.9 mmol, 2.26 eq) was stirred overnight at 80°C.
  • Ethyl 2-(5-methyl-3-nitro-pyrazol-1-yl)acetate Prepared as described in Method A1: Ethyl bromoacetate (0.87 mL, 7.87 mmol) was added drop-wise to a suspension of 5-methyl-3-nitro-1H-pyrazole (1.0 g, 7.87 mmol) and potassium carbonate (1.65 g, 11.8 mmol) in anhydrous THF (20 mL), with stirring at room temperature under nitrogen. The reaction mixture was then heated to 75 °C with stirring for 4 hours, before cooling to room temperature and separating between ethyl acetate and water.
  • the mixture was stirred for 10 min then allowed to warm to rt and stirred for an additional 1 h.
  • the reaction mixture was diluted with DCM (50 mL) and was washed with NaHCO3 (3 x 30 mL), 0.5 M NaOH (30 mL), 0.5 M HCl (2 x 30 mL) and brine (30 mL).
  • the organic phase was dried over Na2SO4 and concentrated in vacuo to afford the 5-methyl-1-methylsulfonyl-3- nitro-pyrazole (1420 mg, 6.44 mmol, 81.80% yield) as a white solid.
  • Step 2 A solution of 1-propanephosphonic anhydride (1.62 eq, 1.7 mL, 2.94 mmol) [50% in EtOAc] was added to 2-(3-nitropyrazol-1-yl)propanoic acid (1 eq, 335 mg, 1.81 mmol) , pyrrolidine (2.02 eq, 0.30 mL, 3.65 mmol) , and triethylamine (3.97 eq, 1.0 mL, 7.17 mmol) in ethyl acetate (10 mL).
  • the reaction mixture was additionally stirred at 80 °C overnight.
  • the reaction mixture was recharged with 2- chloro-1-pyrrolidin-1-yl-ethanone (251 mg, 1.70 mmol) and the stirring continued at 80 °C for 2 h.
  • the reaction mixture was concentrated, preabsorbed on Celite and purified by column chromatography over silica (120 g cartridge) eluting with a gradient of MeOH (0% to 10%; v/v) in DCM (30 CV) to afford 2-(3-amino-4-chloro-pyrazol-1-yl)-1-pyrrolidin-1-yl-ethanone (854 mg, 3.59 mmol, 42.1% yield) as an off-white solid.
  • reaction mixture was stirred at 80 °C for 3 h and then at 50 °C for 16 h, then concentrated, preabsorbed on Celite and purified by column chromatography over silica (40 g cartridge) eluting with a gradient of MeOH (0% to 10%; v/v) in DCM (30 CV) to afford 2-(3-amino-5-chloro-pyrazol-1-yl)-1-pyrrolidin-1-yl-ethanone (40 mg, 0.135 mmol, 5.3% yield).
  • Step 1 Acrylonitrile (286 uL, 4.34 mmol) was added to a stirred mixture of 3-methyl-5-nitro- 1H-pyrazole (525 mg, 4.13 mmol) and N,N-diisopropylethylamine (DIPEA) (863 uL, 4.96 mmol) in DMSO (15 mL) at 25 °C and the resulting light yellow clear mixture was stirred for 30 h. The reaction mixture was poured in H2O (50 mL) and extracted with EtOAc (3 x 20 mL).
  • DIPEA N,N-diisopropylethylamine
  • Step 2 A stirred solution of 3-(5-methyl-3-nitro-pyrazol-1-yl)propanenitrile (570 mg, 3.16 mmol) in ethyl acetate (25 mL) / MeCN (25 mL) was evacuated and backfilled with nitrogen 3 times before a slurry of Palladium on activated Carbon (5%) (100 mg, 0.940 mmol) was added to the reactio On mixture. The flask was then placed under vacuum and refilled with nitrogen before fitting a hydrogen balloon and stirring at 25 °C for 18 h. The reaction mixture was refilled with nitrogen and filtered through Cellite and washed with MeCN.
  • Step 2 A stirred solution of 3-(4-methyl-3-nitro-pyrazol-1-yl)propanenitrile (560 mg, 3.01 mmol) in MeCN (50 mL) was evacuated and backfilled with nitrogen 3 times before slurry of Palladium on activated Carbon (5%) (160 mg, 1.50 mmol) in MeCN-H2O was added to the reaction mixture.
  • tert-Butyl 3-amino-4-methyl-1H-pyrazole-1-carboxylate 4-Dimethylaminopyridine (35 mg, 0.283 mmol) was added to a stirring solution of 4-methyl- 3-nitro-1H-pyrazole (360 mg, 2.83 mmol) , di-tert-butyl dicarbonate (742 mg, 3.40 mmol) and N,N- diisopropylethylamine (DIPEA) (1.2 mL, 7.1 mmol) in DCM (30 mL) . The solution was stirred at r.t. for 2 h. The reaction was quenched with sat. aq.
  • DIPEA N,N- diisopropylethylamine
  • the reaction mixture was cycled through N2/vacuum twice more before a balloon of molecular hydrogen was added.
  • the flask was cycled between H2/vacuum 3 times and the The reaction mixture was left under an atmosphere of H 2 for 72 h.
  • the reaction mixture was filtered through a Celite pad and the filter cake was washed with EtOAc (3 ⁇ 25 mL).
  • the filtrates were concentrated under reduced pressure to afford tert-butyl 3-amino-4-methyl- pyrazole-1-carboxylate (415 mg, 2.00 mmol, 96.63% yield) as a dark green viscous oil without further purification.
  • Diamino-aryl and diamino-heteroaryl precursors General Method B3: Buchwald coupling of Boc-amino-halo-aryl/heteroaryl with amines and subsequent deprotection Heteroaryl bromide (1 equiv.) and amine (1.5 equiv.) were dissolved in toluene:tert-butanol (5:1, [0.1 M]) and the solution was bubbled with nitrogen for 5 minutes. Pd2dba3 (15mol%), XantPhos (30mol%), and sodium tert-butoxide (1.5 equiv.) were then added with stirring and the mixture was bubbled with nitrogen for a further 5 minutes before heating to 85 °C with stirring overnight.
  • the vial was capped and heated to 60 °C with stirring overnight.
  • the reaction mixture was then diluted with ethyl acetate and filtered through a short pad of dicalite, washing with ethyl acetate.
  • the filtrate was then washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give the crude product, which was purified using flash column chromatography over silica, eluting with 0-80% ethyl acetate/petroleum ether, to give tert-butyl (6-(oxetan-3-yl)pyridin-2- yl)carbamate (73 mg, 40% yield) as a white solid.
  • tert-Butyl (6-amino-2-m ridin-3-yl) To a solution of 3,6-diamino-2-methylpyridine (200 mg, 1.62 mmol, 1.00 eq) in THF (10 mL) was added di-tert-butyl dicarbonate (354 mg, 1.62 mmol, 1.00 eq) and the reaction mixture was allowed to stir at ambient temperature for 1 hour. The product mixture was concentrated under reduced pressure before purification by reverse phase combiflash to furnish tert-butyl (6-amino-2- methylpyridin-3-yl)carbamate (268 mg, 1.20 mmol, 74%).
  • Bis-aryl/bis-heteroaryl amine precursor General Method B4: Suzuki coupling of Boc-amino-halo-aryl/heteroaryl with halo-aryl or halo-heteroaryl and subsequent deprotection Ayl/Heteroaryl bromide (1 equiv.) and boronic acid or ester (1.2 equiv.) were dissolved in 1,4-dioxane:water (5:1, [0.1 M]) and the solution was bubbled with nitrogen for 5 minutes.
  • Pd(PPh3)4 45 mg, 15mol%) and potassium carbonate (54 mg, 0.39 mmol) were then added with stirring and the mixture was bubbled with nitrogen for a further 5 minutes before heating to 90 °C with stirring overnight. After cooling to room temperature the reaction mixture was separated between ethyl acetate water.
  • Step 2 A mixture of tert-butyl 5-methyl-4-nitro-indazole-1-carboxylate (3.0 mg, 10.8 mmol, 1.0 eq) and Pd/C (10% w/w, 115 mg, 1.08 mmol, 0.1 eq in MeOH (150 mL) was placed under a hydrogen atmosphere and stirred at RT for 12 h. Reaction monitoring by consumption of starting material via UPLC.
  • Step 3 To a solution of 2-bromothiazole-5-carboxylic acid (1.8 mg, 8.65 mmol, 1.0 eq), tert- butyl 4-amino-5-methyl-indazole-1-carboxylate (2.57 mg, 10.4 mmol, 1.2 eq) and DIPEA (4.0 mL, 23.0 mmol, 2.65 eq) in THF (100 mL) was added T3P (50% in EtOAc, 4.0 mL, 13.6 mmol, 1.57 eq) and the mixture stirred for 16 h at 65°C. The mixture was poured into water and the aqueous phase extracted with EtOAc (4 x 50 mL).
  • N-Chlorosuccinimide was added in one portion and the reaction stirred at rt for 4 h then quenched by the addition of sat. NaHCO3 solution (5 mL). Ethyl acetate (15 mL) and water (15 mL) were added. The phases were separated and the aqueous phase extracted with ethyl acetate (2 x 20 mL). Combined organic phases were washed with NH4Cl (10 mL, 10% w/w aqueous solution), brine (20 mL), dried over MgSO4, filtered and concentrated in vacuo.
  • Step 2 To a mixture of tert-butyl 4-amino-5-chloro-indazole-1-carboxylate (446 mg, 1.67 mmol, 1.10 eq), 2-bromo-1,3-thiazole-5-carboxylic acid (315 mg, 1.51 mmol, 1.00 eq) and N,N- diisopropylethylamine (0.53 mL, 3.03 mmol, 2.00 eq) in THF (10.095 mL) was added 1- propanephosphonic anhydride 50% in Ethyl Acetate (1.3 mL, 2.27 mmol, 1.50 eq) and the reaction heated to 65 °C for 16 h.
  • the mixture was heated to 100 °C for 16 h. Reaction monitoring by consumption of starting material via UPLC. The mixture was cooled and concentrated in vacuo. The crude material was purified by either normal phase chromatography (SiO2) using a gradient of MeOH:DCM or reverse phase chromatography.
  • Step 2 A solution of 5-methyl-4-nitro-1-tetrahydropyran-2-yl-indazole (3.66 g, 14.0 mmol) in ethanol (120 mL) was bubbled with nitrogen for 5 minutes before adding 10% Palladium on Carbon (10 wt.%, 200 mg, 1.88 mmol) and bubbling for a further 5 minutes. The flask was then placed under vacuum and refilled with nitrogen before fitting a hydrogen balloon and stirring overnight at room temperature. The balloon was then removed and the reaction mixture bubbled with nitrogen for 5 minutes before filtering through dicalite, washing with ethanol.
  • Step 3 1-Propanephosphonic anhydride (50% in ethyl acetate, 3.82 mL, 6.49 mmol) was added drop-wise to a solution of 5-methyl-1-tetrahydropyran-2-yl-indazol-4-amine (1.0 g, 4.32 mmol) 2-bromo-1,3-thiazole-5-carboxylic acid (900 mg, 4.32 mmol), and DIPEA (1.51 mL, 8.65 mmol) in anhydrous THF (35 mL), with stirring at room temperature, and the reaction mixture was then heated to 70 °C, with stirring under nitrogen overnight.
  • 5-methyl-1-tetrahydropyran-2-yl-indazol-4-amine 1.0 g, 4.32 mmol
  • 2-bromo-1,3-thiazole-5-carboxylic acid 900 mg, 4.32 mmol
  • DIPEA 1.51 mL, 8.65 mmol
  • Step 2 To a solution of 5-bromo-4-nitro-1-tetrahydropyran-2-yl-indazole (1.10 g, 3.37 mmol) in DMF (33.7 mL) was added 4,4'-dipyridyl (53 mg, 0.337 mmol) followed by tetrahydroxy diboron (907 mg, 10.1 mmol) at 22 °C and stirred for 10 min.
  • the crude was treated with water (20 mL) and EtOAc (50 mL). The organic phase was separated, dried over Na2SO4 and concentrated under reduce pressure.
  • Step 3 To a solution of 2-bromothiazole-5-carboxylic acid (593 mg, 2.85 mmol) in MeCN (19 mL) was added 1-methylimidazole (530 uL, 6.65 mmol) and chloro-N,N,N',N'- tetramethylformamidinium hexafluorophosphate (1.60 g, 5.70 mmol). The reaction mixture was stirred at 22 °C for 5 min. To the reaction mixture was then added 5-bromo-1-tetrahydropyran-2-yl- indazol-4-amine (580 mg, 1.90 mmol) and stirred at 22 °C for 18 h.
  • Step 1 Caesium carbonate (1.70 eq, 25.00 g, 76.7 mmol) , tris(dibenzylideneacetone) dipalladium(0) (Pd2(dba)3) (0.0339 eq, 1.40 g, 1.53 mmol) and 4,5-bis(diphenylphosphino)-9,9- dimethylxanthene (Xantphos) (0.0750 eq, 1.95 g, 3.38 mmol) were added to a solution of 1-methyl- 1H-pyrazol-3-ylamine (1.28 eq, 5.0 mL, 57.7 mmol) and methyl 2-bromothiazole-5-carboxylate (1.00 eq, 10.00 g, 45.0 mmol)
  • Step 2 Lithium hydroxide (2.74 eq, 420 mg, 10.0 mmol) and water (10 mL) were added to a suspension of methyl 2-[(1-methylpyrazol-3-yl)amino]thiazole-5-carboxylate (1.00 eq, 870 mg, 3.65 mmol) in THF (10 mL) and stirred at 65 °C for 5h.
  • Step 3 To a solution of 2-[(1-methylpyrazol-3-yl)amino]thiazole-5-carboxylic acid (180 mg, 0.803 mmol), triethylamine (0.22 mL, 1.61 mmol) and a drop of N, N-dimethylformamide, (0.025 mL, 0.321 mmol) in DCM (2.68 mL) at rt was added thionyl chloride (0.23 mL, 3.21 mmol) . The mixture was stirred at rt for 2 h. The chloride acid (intermediate) was concentrated under reduce pressure.
  • Step 4 N-(3-bromo-5-methyl-1-tetrahydropyran-2-yl-indazol-4-yl)-2-[(1-methylpyrazol-3- yl)amino] thiazole-5-carboxamide (55 mg, 0.107 mmol) was suspended in 1,4-dioxane (0.9895 mL) and hydrogen chloride (7.5 mL, 29.8 mmol) was added at rt. Then, the mixture was stirred for 48h at rt, while adding an additional 1 mL of 4N HCl in dioxane. The crude was concentrated under reduce pressure. The solid was suspended in MeCN (3 mL) and it was sonicated for 5 min.
  • Step 2 3,4-Dihydro-2H-pyran (1.26 mL, 13.8 mmol) was added dropwise to a solution of 5- bromo-3-methyl-4-nitro-1H-indazole (1.18 g, 4.6 mmol) and p-Tosic acid monohydrate (88 mg, 0.46 mmol) in DCM (30 mL), with stirring at room temperature for 1 hour before quenching with saturated aqueous sodium bicarbonate solution.
  • reaction mixture was then concentrated and separated between ethyl acetate and water, and the organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give the crude product, which was purified using flash column chromatography over silica, eluting with 0-80% ethyl acetate/petroleum ether, to give 5-bromo-3-methyl-4-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H- indazole (1.404 g, 90% yield) as a yellow oil.
  • Step 3 To a solution of 5-bromo-3-methyl-4-nitro-1-tetrahydropyran-2-yl-indazole (400 mg, 1.18 mmol) in DMF (7.8 mL) was added 4,4'-dipyridyl (18 mg, 0.118 mmol) followed by tetrahydroxy diboron (316 mg, 3.53 mmol) at 22 °C. The reaction mixture was stirred for 18 h, then quenched upon the addition of water (50 mL) and the aqueous phase washed with EtOAc (3 x 50 mL). The organic phases were combined and concentrated at 40 °C under reduced presure affording a crude oil.
  • the crude was redissolved in EtOAc (50 mL) and the organic phase washed with 5% LiCl by weight (aq) (3 x 50 mL). The organic phase was then washed with brine (25 mL), dried over Na2SO4 and concentrated at 40 °C under reduced presure to afford a crude solid.
  • the crude material was purified by column chromatography over silica (12 g cartridge) eluting with a gradient of EtOAc (0% to 50%; v/v) in iso-hexane to afford the desired product 5-bromo-3-methyl- 1-tetrahydropyran-2-yl-indazol-4-amine (250 mg, 0.782 mmol, 66.48% yield) as a yellow solid.
  • Step 4 To a solution of 2-bromothiazole-5-carboxylic acid (146 mg, 0.704 mmol) in MeCN (3.13 mL) was added 1-methylimidazole (131 uL, 1.64 mmol) and chloro-N,N,N',N'- tetramethylformamidinium hexafluorophosphate (395 mg, 1.41 mmol) . The reaction mixture was stirred at 22 °C for 2 min.
  • Step 3 1-Propanephosphonic anhydride (50% in Ethyl Acetate, 0.72 mL, 1.22 mmol) was added drop-wise to a solution of 3,5-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-amine (200 mg, 0.82 mmol) 2-bromo-1,3-thiazole-5-carboxylic acid (187 mg, 0.9 mmol), and DIPEA (0.28 mL, 1.63 mmol) in anhydrous THF (8 mL), with stirring at room temperature, and the reaction mixture was then heated to 70 °C, with stirring under nitrogen overnight.
  • reaction mixture was stirred at 0 °C for 2 h 30 min To the reaction mixture was added dropwise a solution of stannous chloride (1.55 g, 8.16 mmol) in 37.5% hydrogen chloride solution (1.3 mL, 3.26 mmol) at 0 °C . The reaction mixture was stirred for 18 h. To the reaction mixture was added sat. Rochelles salt (aq) (2 mL) and the reaction mixture stirred for 15 min. The reaction mixture was quenched upon the addition of NaHCO3 ( ⁇ 50 mL) until the solution was mildly basic (pH ⁇ 8).
  • Step 2 To a solution of 5-fluoro-3-methyl-2H-indazole (417 mg, 2.78 mmol) in 95% sulfuric acid (23 mL, 410 mmol) at 0 °C was added 68% nitric acid (0.81 mL, 12.3 mmol) dropwise. The reaction mixture was allowed to warm to ⁇ 22 °C over the course of 30 min and stirred at 22 °C for 3 h. The reaction was quenched by pouring directly over ice.
  • Step 3 To a suspension of 5-fluoro-3-methyl-4-nitro-1H-indazole (212 mg, 0.923 mmol) in DCM (9.23 mL) was added 4-toluenesulfonic acid monohydrate (80 mg, 0.422 mmol) and 3,4- dihydro-2H-pyran (0.60 mL, 6.37 mmol) . The reaction mixture was stirred at 22 °C for 18 h, then quenched upon the addition of saturated NaHCO3 (10 mL). DCM (15 mL) and water (15 mL) were added and the organic phase separated. The aqueous phase was washed with DCM (2 x 25 mL).
  • Step 4 To a suspension of 5-fluoro-3-methyl-4-nitro-1-tetrahydropyran-2-yl-indazole (182 mg, 0.619 mmol) in Ethyl acetate (6.19 mL) was added Palladium on activated Carbon (320 mg, 0.0619 mmol) under N2. The N2 atmosphere was evacuated, the flask fitted with a balloon of H2 and the reaction mixture stirred for 2 h.
  • the crude TFA salt was purified by reverse phase chromatography to furnish the final compound.
  • the product mixture was treated with potassium carbonate followed by the addition of MeOH (1 mL) and allowed to stir for 30 minutes.
  • the suspension was filtered under reduced pressure and concentrated in vacuo to afford the free based product.
  • hydrogen chloride (2M in diethyl ether or 4M in dioxane) was added to a solution of THP-protected indazole in diethyl ether (2-5 mL) and the reaction stirred for 6 h at rt then concentrated in vacuo.
  • the vial was sealed and stirred at 80 °C for 3 h.
  • the reaction mixture was diluted with DCM (50 mL), filtered through Cellite, washed with 10% citric acid, brine, dried over Na2SO4 and concentrated to dryness to give a residue, which was purified by column chromatography over silica (40 g cartridge) eluting with a gradient of MeOH (0% to 10%; v/v) in DCM to afford the 22-[[1- (2-cyanoethyl)-5-methyl-pyrazol-3-yl]amino]-N-(5-methyl-1-tetrahydropyran-2-yl-indazol-4- yl)thiazole-5-carboxamide (50 mg, 0.0989 mmol, 36.58% yield) as an orange solid.
  • Step 2 Hydrogen chloride solution in dioxane (4M) (0.025 mL, 0.0989 mmol) was added to a stirred suspension of 2-[[1-(2-cyanoethyl)-5-methyl-pyrazol-3-yl]amino]-N-(5-methyl-1- tetrahydropyran-2-yl-indazol-4-yl)thiazole-5-carboxamide (50 mg, 0.0989 mmol) in 1,4-dioxane (4 mL) /DCM (4 mL) and stirred at 25 °C for 20 h.
  • the vial was sealed and stirred at 80 °C for 3 h.
  • the reaction mixture was diluted with DCM, filtered through Cellite, and concentrated to dryness to give a residue, which was purified by column chromatography over silica (40 g cartridge) eluting with a gradient of MeOH (0% to 10%; v/v) in DCM followed by washing collected fractions with with 5% citric acidic to afford the 2-[[1-(2-methoxyethyl)-4-methyl-pyrazol-3-yl]amino]-N-(5-methyl-1-tetrahydropyran-2-yl-indazol-4- yl)thiazole-5-carboxamide (64 mg, 0.116 mmol, 70.66% yield) as a beige sold.
  • Step 2 Boron tribromide (0.30 mL, 0.300 mmol) was added via syringe to a stirred homogeneous solution of 2-[[1-(2-methoxyethyl)-4-methyl-pyrazol-3-yl]amino]-N-(5-methyl-1- tetrahydropyran-2-yl-indazol-4-yl)thiazole-5-carboxamide (64 mg, 0.116 mmol) in DCM (5 mL) at 0 °C. The resulting yellow suspension was stirred at 0 °C for 10 min, then was allowed to slowly warmed to room temperature and the stirring was continued at 23 °C for 22 h.
  • reaction mixture was diluted with DCM (5 mL) , recharged with boron tribromide (0.23 mL, 0.232 mmol) and stirred for further 20 h.
  • the reaction was quenched with MeOH (1 mL), stirred for 5 min and then sat. NaHCO 3 solution was added (5 mL) followed by Et 2 O (10 mL). The resulting mixture was stirred for 30 min and the insoluble part was isolated and dissolved in MeOH.
  • the mixture was flushed with nitrogen before heating to 75 °C for 6 h.
  • the reaction mixture was recharged with palladium(II) acetate (5.0 mg, 0.0223 mmol) and 4,5- bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (26 mg, 0.0446 mmol) and the stirring continued at 75 °C overnight.
  • the reaction mixture was diluted with EtOAc, filtered through Cellite and washed with EtOAc (30 mL).
  • Step 2a Trifluoroacetic acid (3.0 mL, 39.2 mmol) was added to a stirred solution of 2-[[1- (cyanomethyl)-4-methyl-pyrazol-3-yl]amino]-N-(5-methyl-1-tetrahydropyran-2-yl-indazol-4- yl)thiazole-5-carboxamide (36 mg, 0.0680 mmol) in DCM (6 mL) at 23 °C for 3 h.
  • Step 2b 2-[[1-(2-Amino-2-oxo-ethyl)-4-methyl-pyrazol-3-yl]amino]-N-(5-methyl-1- tetrahydropyran-2-yl-indazol-4-yl)thiazole-5-carboxamide (14 mg, 0.0130 mmol) was stirred with hydrogen chloride solution in dioxane (4M) (5.0 mL, 20.0 mmol) at 23 °C overnight.
  • the reaction mixture was stirred at 80 °C for 18 h, cooled, diluted with DCM, filtered through a celite pad and evaporated.
  • the crude material was purified by column chromatography over silica (24 g cartridge) eluting with a gradient of EtOAc (10% to 100%; v/v) in isohexane then of MeOH (0% to 50%; v/v) in EtOAc to afford 4-methyl-N-(5-methyl-1-tetrahydropyran-2-yl-indazol-4-yl)-2-[[1-(2-oxo- 2-pyrrolidin-1-yl-ethyl)pyrazol-3-yl]amino]thiazole-5-carboxamide (40 mg, 0.0365 mmol, 14.3% yield).
  • N-(5-Methyl-1H-indazol-4-yl)-2-((4-methyl-1H-pyrazol-3-yl)amino)thiazole-5-carboxamide (BAA- 206) Prepared as described in Method C3 from 2-bromo-N-(5-methyl-1-tetrahydropyran-2-yl- indazol-4-yl)thiazole-5-carboxamide (100 mg, 0.24 mmol, 1.0 eq), tert-butyl 3-amino-4-methyl- pyrazole-1-carboxylate (94 mg, 0.453 mmol, 1.9 eq), potassium carbonate 325 mesh (93 mg, 0.673 mmol, 2.8 eq), palladium(II) acetate (7.9 mg, 0.0352 mmol, 0.15 eq) and 4,5- bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (41 mg,
  • the reaction mixture was stirred at 70 °C for 2.5 h under nitrogen atmosphere, cooled to rt, diluted with DCM and filtered through Celite.
  • the crude material was purified by column chromatography over silica (120 g cartridge) eluting with a gradient of MeOH (0% to 5%; v/v) in DCM (25 CV) to afford the desired product tert-butyl 2-[4- methyl-3-[[5-[(5-methyl-1-tetrahydropyran-2-yl-indazol-4-yl)carbamoyl]thiazol-2-yl]amino]pyrazol-1- yl]acetate (1.52 g, 2.62 mmol, 74.26% yield) as a brown solid.
  • Trifluoroacetic acid (5.0 mL, 65.3 mmol) was added to a stirred solution of the product from previous step (1.52 g, 2.62 mmol) in DCM (20 mL) at 23 °C. The reaction mixture was stirred at 23 °C for 18 h and concentrated to dryness. The brown solid residue was triturated with DCM/i- hexane mixture.
  • the rection mixture was stirred at 65 °C for 16 h under nitrogen, cooled to rt, diluted with DCM and filtered through Celite.
  • the crude material was purified by column chromatography over silica (80 g cartridge) eluting with a gradient of MeOH (0% to 5%; v/v) in DCM (25 CV) to afford tert-butyl 2-[4-methyl-3-[[5-[(5-methyl-1-tetrahydropyran-2-yl-indazol- 4-yl)carbamoyl]thiazol-2-yl]amino]pyrazol-1-yl]propanoate (457 mg, 0.711 mmol, 50.42% yield) as a brown solid.
  • Tris(dibenzylideneacetone)dipalladium(0) (182 mg, 0.199 mmol) was added and the reaction degassed again, then heated to 90 °C for 18 h. The reaction was partitioned between EtOAc and water. The aqueous phase was acidified to pH 4 with 2M aqueous HCl then extracted with ethyl acetate. The combined organic extracts were washed with brine, then concentrated in vacuo.
  • the mixture was degassed with N2 for 10 min before the addition of palladium(II) acetate (0.100 eq, 32 mg, 0.143 mmol) after which degassing was continued for another 5 min.
  • the reaction mixture was heated to 70 °C for 18 h.
  • the reaction mixture was cooled to r.t., filtered through a Celite pad, and the filter cake was washed with EtOAc (3 ⁇ 20 mL).
  • the filtrates were concentrated under reduced pressure and DCM (25 mL) was added.
  • Pd2dba3 (163 mg, 15mol%), XantPhos (206 mg, 30mol%), cesium carbonate (778 mg, 2.37 mmol) and lithium hydroxide monohydrate (51 mg, 1.19 mmol) were then added with stirring and the mixture was bubbled with nitrogen for a further 5 minutes before heating to 90 °C with stirring overnight. After cooling to room temperature the reaction mixture was separated between ethyl acetate and 0.5 M aqueous sodium hydroxide. The aqueous phase was acidified to pH 4 using 2 M aqueous HCl then extracted with ethyl acetate.
  • N-(5-Methyl-1-tetrahydropyran-2-yl-indazol-4-yl)-2-[[1-(2-morpholino-2-oxo-ethyl)pyrazol-3- yl]amino]thiazole-5-carboxamide (BAA-215) Prepared as described in Method D, from 2-[3-[[5-[(5-methyl-1-tetrahydropyran-2-yl- indazol-4-yl)carbamoyl]thiazol-2-yl]amino]pyrazol-1-yl]acetic acid (35 mg, 0.073 mmol), HATU (33 mg, 0.087 mmol), morpholine (8 uL, 0.087 mmol) and DIPEA (38 uL, 0.218 mmol) in anhydrous DMF (1 mL) to afford the THP-protected intermediate (30 mg, 75% yield) after normal phase chromatography (SiO2) e
  • TFA 50 equiv. was added to a solution of the THP protected compound (1 equiv.) in DCM ( ⁇ 0.07 M) with stirring under nitrogen for 3 hours before concentrating in vacuo. Methanol was added and the mixture concentrated again and the resulting precipitate was washed with diethyl ether to give the final compound.
  • TFA 50 equiv. was added to a solution of the THP protected compound (1 equiv.) in DCM ( ⁇ 0.07 M) with stirring under nitrogen for 3 hours before concentrating in vacuo. Methanol was added and the mixture concentrated again and the resulting precipitate was washed with diethyl ether to give the final compound.
  • Pd2dba3 (98 mg, 15mol%), XantPhos (124 mg, 30mol%), and cesium carbonate (467 mg, 1.42 mmol) were then added with stirring and the mixture was bubbled with nitrogen for a further 5 minutes before heating to 90 °C with stirring for 18 hours.
  • Step 2 TFA (0.20 mL, 2.62 mmol) was added to a solution of 2-[[1-[(3R)-1- (diethylcarbamoyl)pyrrolidin-3-yl]pyrazol-3-yl]amino]-N-(5-methyl-1-tetrahydropyran-2-yl-indazol-4- yl)thiazole-5-carboxamide (31 mg, 0.052 mmol) in DCM (0.5 mL), with stirring under nitrogen for 3 hours before concentrating in vacuo.
  • Lithium hydroxide monohydrate (259 mg, 6.0 mmol) was added to a solution of ethyl 2-(3- nitro-1H-pyrazol-1-yl)acetate (600 mg, 3.0 mmol) in methanol:THF:water (2:2:1, 25 mL) with stirring at 40 °C overnight.
  • the reaction mixture was then concentrated before separating between ethyl acetate and 1 M aqueous HCl.
  • the combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give 2-(3-nitro-1H-pyrazol-1- yl)acetic acid (498 mg, 97% yield) as a white solid that was used directly in the next step.
  • N-(5-Methyl-1H-indazol-4-yl)-5-((6-methylpyridin-2-yl)amino)-1,3,4-thiadiazole-2-carboxamide (BAA-332) 1-Propanephosphonic anhydride (50% in Ethyl Acetate, 0.27 mL, 0.45 mmol) was added drop-wise to a solution of 5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-amine (70 mg, 0.30 mmol), 5-((6-methylpyridin-2-yl)amino)-1,3,4-thiadiazole-2-carboxylic acid (75 mg, 0.32 mmol) and DIPEA (0.11 mL, 0.61 mmol) in anhydrous THF (4.5 mL), with stirring at room temperature, and the reaction mixture was then heated to 70 °C, with stirring under nitrogen overnight.
  • Lithium hydroxide monohydrate (125 mg, 2.9 mmol) was added to a solution of ethyl 2-((6- methylpyridin-2-yl)amino)oxazole-5-carboxylate (240 mg, 0.970 mmol) in methanol:THF:water (2:2:1, 15 mL) with stirring at 40 °C overnight.
  • the reaction mixture was then separated between ethyl acetate and 1 M aqueous sodium hydroxide.
  • the aqueous phase was acidified to pH 4 using 2 M aqueous HCl then extracted with 10% methanol/ethyl acetate.
  • N-(5-Methyl-1H-indazol-4-yl)-2-((6-methylpyridin-2-yl)amino)oxazole-5-carboxamide (BAA-333) 1-Propanephosphonic anhydride (50% in Ethyl Acetate, 0.38 mL, 0.65 mmol) was added drop-wise to a solution of 5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-amine (100 mg, 0.43 mmol), 2-((6-methylpyridin-2-yl)amino)oxazole-5-carboxylic acid (100 mg, 0.45 mmol), and DIPEA (0.23 mL, 1.3 mmol) in anhydrous THF (6 mL), with stirring at room temperature, and the reaction mixture was then heated to 70 °C, with stirring under nitrogen overnight.
  • PKMYT1 was further purified on a Superdex 20016/600 sizing column. The fractions containing PKMYT1 were pooled and concentrated using an ultrafiltration centrifugal protein concentrator. The purified protein was aliquoted, flash frozen in liquid nitrogen, and stored at ⁇ 80°C.
  • BIOLOGICAL EXAMPLE 2 ADP-Glo enzymatic assays
  • 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 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 MgCl 2 , 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.
  • 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 - 5000 fold; Z: >5000 fold.
  • 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 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.
  • BIOLOGICAL EXAMPLE 3 Nuclear count cell proliferation assay of isogenic h-TERT-RPE1 TP53 -/- parental and CCNE1 overexpressing cell lines h-TERT-RPE1 TP53 -/- and CCNE1 high expressing clones (clone cell lines 7 and 15) were treated with test compounds dissolved in DMSO at serially diluted concentrations alongside a DMSO only control for around 6 population doublings time. Cells were then fixed with 4% Paraformaldehyde and the cell nuclei were stained with DAPI (Sigma D9542). Images covering each well were acquired by an Opera Phenix® High-Content Screening System (PerkinElmer).
  • the RPE cell line GI50 values are banded as follows: A: ⁇ 0.5 ⁇ M; B: 0.5 ⁇ M - ⁇ 3 ⁇ M; C: 3 ⁇ M - 10 ⁇ M; D: >10 ⁇ M.
  • the RPE wild type (Wt) to clone cell line (CL15) GI50 selectivity ratio is banded by fold difference as follows: X: 3 - ⁇ 10 fold; Y: 10 - 30 fold; Z: >30 fold. Where either the RPE CL15 GI50 value was below the lowest concentration limit of the assay or the RPE Wt GI50 value was above the top concentration limit of the assay, the selectivty ratio wild type vs.
  • Biological Data Table 2 BIOLOGICAL EXAMPLE 4 Cancer Cell Lines Proliferation Assays Cancer cell lines with either normal (KYSE-30) or amplified CCNE1 expression (OVCAR3 – ovarian cancer) were evaluated for their sensitivity to PKMYT1 inhibitors in a nuclear count assay as described above for h-TERT-RPE1 TP53 -/- and a CCNE1 high expressing clones, taking into account the slower cell cycle division times of these lines. The following compounds in Biological Data Table 3 inhibit OVCAR3 cell proliferation with a GI50 ⁇ 5 ⁇ M.
  • 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: ⁇ 0.5 ⁇ M; B: 0.5 ⁇ M - ⁇ 3 ⁇ M; C: 3 ⁇ M - 10 ⁇ M; D: >10 ⁇ 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 - 30 fold; Z: >30 fold. Where either the OVCAR3 GI50 value was below the lowest concentration limit of the assay or the KYSE30 GI50 value was above the top concentration limit of the assay, the selectivity ratio KYSE30 GI50 vs. OVCAR3 GI50 is given as “>N”, where N is the selectivity band. The selectivity value for these compounds falls at least in this band but could be higher.
  • BIOLOGICAL EXAMPLE 5 Cancer Cell Lines Proliferation Assays – ATP-based cell viability endpoint Cancer cell lines with either normal (KYSE-30) or amplified CCNE1 expression (OVCAR 3 – ovarian cancer) were evaluated for their sensitivity to PKMYT1 inhibitors using Cell Titre Glow assay (Promega G7573) as endpoint to assess cell proliferation. The luminescence signal was read on a PHERAStar FS microplate reader (BMG Labtech). Data analysis was performed using Microsoft Excel® and GI 50 (concentration that achieves 50% cell growth proliferation inhibition) estimates generated with GraphPad Prism v9.
  • the following compounds in Biological Data Table 2 inhibit OVCAR 3 cell proliferation with a GI 50 ⁇ 0.5 ⁇ M.
  • selected compounds exhibit >3-fold selectivity for the CCNE1-amplified OVCAR 3 cells compared to KYSE30 cells expressing normal levels of CCNE1.
  • the cell line GI 50 values are banded as follows: A: ⁇ 0.5 ⁇ M; B: 0.5 ⁇ M - ⁇ 5 ⁇ M; C: >5 ⁇ M.
  • the normal CCNE1 expression cell line (KYSE-30) to CCNE1-amplified cell line (OVCAR 3) GI 50 selectivity ratio is banded by fold difference as follows: X: 3 - 20 fold; Y: >20 fold. Where either the OVCAR 3 GI 50 value was below the lowest concentration limit of the assay or the KYSE30 GI50 value was above the top concentration limit of the assay, the selectivity ratio KYSE30 GI50 vs. OVCAR 3 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.
  • Biological Data Table 4 ty ty 0 0 . 3 3 y ty 03 3
  • the cells 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.
  • the samples were analysed by immunoblot on a Jess Automated Western Blot System (BioTechne). The samples were separated using the 12-230 kDa Separation Module (BioTechne,) and blotted using an anti-CDK1 phospho T14 antibody (Abcam, #ab58509) and an anti-vinculin antibody (Abcam, #126002).
  • BIOLOGICAL EXAMPLE 7 Comparison Data 1 IC50 was measured for BAA-001, BAA-003, REF-001, and REF-002 as described for PKMYT1 biochemical ADP-Glo enzymatic assay in Biological Example 2. See Biological Data Table 4, below. As compared to REF-001, BAA-001 exhibits a 12.4-fold improvement in PKMYT1 IC 50 . As compared to REF-002, BAA-003 exhibits a 50-fold improvement in PKMYT1 IC 50 .
  • Protein kinase, membrane-associated tyrosine/threonine 1 is associated with the progression of colorectal cancer”, Oncology Reports, 39(6), 2829-2836. Jones et al., 2013, “Increased replication initiation and conflicts with transcription underlie Cyclin E- induced replication stress” Oncogene 32, 3744–3753. Lewis et al., 2019, “Upregulation of Myt1 Promotes Acquired Resistance of Cancer Cells to Wee1 Inhibition”, Cancer research, 79(23), 5971-5985.
  • PKMYT1 as a potential target to improve the radiosensitivity of lung adenocarcinoma”, Frontiers in Genetics, 11, 00376.
  • Luo et al., 2022 “c-Myb-mediated inhibition of miR-601 in facilitating malignance of osteosarcoma via augmentation of PKMYT1”, Scientific Reports, 12(1), 6692.
  • Shao et al., 2021 “The DNA damage repair-related gene PKMYT1 is a potential biomarker in various malignancies”, Translational Lung Cancer Research, 10(12), 4600-4616.
  • PLMYT1 is associated with prostate cancer malignancy and may serve as a therapeutic target”, Gene, 744, 144608.
  • Z 1 is N, CH, or CR Z1 ;
  • Z 2 is CH, CR Z2 , or N;
  • Z 3 is CH 2 , CHR Z3C1 , CR Z3C2 2, NH, NR Z3N , O, or S;
  • Z 4 is CH 2 or CHR Z4 ;
  • Z 5 is CH 2 or CHR Z5 ;
  • Z 6 is N, CH, or CR Z6 ;
  • Z 7 is N, CH, or CR Z7 ;
  • Z 8 is N, CH, or CR Z8 ;
  • Z 9 is N, CH, or CR Z9 ; either:
  • Z 10 is CH 2 , CHR Z10C1 , CR Z10C2 2, NH, NR Z10N , O, or S; and
  • Z 11 is CH 2 , CHR Z11C1 , or CR Z11C2 2; or:
  • Z 10 is CH 2 , CHR Z10C1 , or CR Z10C
  • a pharmaceutical composition comprising: a compound according to statement 1, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier or diluent.
  • a method of preparing a pharmaceutical composition comprising the step of: mixing a compound according to statement 1, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier or diluent.
  • Statement 4. A method of inhibiting PKMYT1 kinase, in vitro or in vivo, comprising contacting the kinase with an effective amount of a compound according to statement 1, or a pharmaceutically acceptable salt or solvate thereof.
  • a method of inhibiting PKMYT1 kinase function in a cell, in vitro or in vivo comprising contacting the cell with an effective amount of a compound according to statement 1, or a pharmaceutically acceptable salt or solvate thereof.
  • Statement 6. A compound according to statement 1, or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body by therapy.
  • Statement 7. A compound according to statement 1, or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of a disorder of the human or animal body that is ameliorated by the inhibition of PKMYT1 kinase.
  • a method of treatment of a disorder of the human or animal body that is ameliorated by the inhibition of PKMYT1 kinase comprising administering to a subject in need of treatment a therapeutically-effective amount of a compound according to statement 1, or a pharmaceutically acceptable salt or solvate thereof.
  • Statement 10. A compound according to statement 1, or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of a proliferative disorder.
  • a method of treatment of a proliferative disorder of the human or animal body comprising administering to a subject in need of treatment a therapeutically-effective amount of a compound according to statement 1, or a pharmaceutically acceptable salt or solvate thereof.
  • Statement 13 A compound, salt, or solvate for use according to statement 10, use according to statement 11, or a method according to statement 12, wherein the proliferative disorder is characterised by, or further characterised by: inappropriate activity and/or expression of PKMYT1, CCNE1, FBXW7, or PPP2A or one of its subunits.
  • Statement 15. A compound, salt, or solvate for use according to statement 10, use according to statement 11, or a method according to statement 12, wherein the proliferative disorder is: endometrial cancer, uterine cancer, ovarian cancer, breast cancer, gastric cancer, bladder cancer, pancreatic cancer, mesothelioma, kidney cancer, stomach cancer, esophageal cancer, colorectal cancer, glioblastoma, or lung cancer.

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Abstract

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

Description

BIARYLAMIDE DERIVATIVES AND THEIR USE IN THE TREATMENT OF PROLIFERATIVE DISORDERS
TECHNICAL FIELD
The present invention pertains generally to the field of therapeutic compounds.
More specifically the present invention pertains to certain biarylamide compounds (also referred to herein as “BAA compounds”) which inhibit Protein Kinase, Membrane Associated Tyrosine/Threonine 1 (PKMYT1). The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit PKMYT1 kinase; to treat disorders (e.g., diseases) that are ameliorated by the inhibition of PKMYT 1 kinase; to treat a proliferative disorder, cancer, etc.
BACKGROUND
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.
Throughout this specification, including the claims which follow, unless the context requires otherwise, the word “comprise,” and variations such as “comprises” and “comprising,” will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.
It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a pharmaceutical carrier” includes mixtures of two or more such carriers, and the like.
Ranges are often expressed herein as from “about” one particular value, and/or to “about” another particular value. When such a range is expressed, another embodiment includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by the use of the antecedent “about,” it will be understood that the particular value forms another embodiment.
This disclosure includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.
Protein kinase, membrane-associated tyrosine/threonine 1 (PKMYT1)
A key hallmark of cancer is that cancer cells override the cell cycle controls that prevent commitment to division until the appropriate conditions have been fulfilled. Once the conditions are right, cells are pushed through a decision point called the “restriction point” into the cell division cycle by the activity of Cdk4/6-Cyclin D complexes. Once through this point of no return, cells activate Cdk2-Cyclin E in order to drive the duplication of the DNA that will be segregated into two daughter cells later in the cell cycle (by Cdk1-Cyclin B). In order to be able to proliferate illegitimately, cancer cells inappropriately boost t he kinase activity of Cdk4/6-Cyclin D complexes or bypass the requirement for Cdk4/6-Cyclin D activation, by activating the downstream Cdk2-Cyclin E complex, independently of any input from Cdk4/6-Cyclin D. Implementation of either of these two approaches enable cancers to evade the normal controls that maintain balanced growth and homeostasis within the body. Consequently, cancer proliferation is unregulated. Drugs that inhibit the Cdk4/6-Cyclin D complexes are having a major therapeutic impact in hormone responsive HER2 negative breast cancer (HER2- ER+) and are being trialled in a variety of other cancers. In contrast, counteracting Cdk2-Cyclin E hyperactivation was considered to be undruggable until a recent study reported that a WEE1 family kinase called PKMYT1 is only essential when Cyclin E levels are abnormally high (Gallo et al., 2022). Importantly, they found that PKMYT1 ablation does not kill normal cells. The same study showed that PKMYT1 ablation is synthetically lethal in the presence of Cyclin E (CCNE1) over-expression; CCNE1 overexpression drives the transcription of Cyclin B to elevate Cyclin B levels to generate so much Cdk1-Cyclin B that all the available Cdk1 inhibitory activity is required to restrain this Cdk1-CyclinB and prevent a catastrophic mitosis. Thus, CCNE1 overproduction generates a dependency on PKMYT1. FBXW7 is a gene which encodes an E3 ligase that degrades Cyclin E. FBXW7 loss, has also been found to be synthetically lethal in the presence of PKMYT1 inhibition (Durocher et al., 2021), demonstrating that PKMYT1 drugs hold potential as first line therapy in several cancers. CCNE1 amplification has been reported in several cancer types including endometrial, ovarian, breast and gastric, ranging in frequency from 5-40%. CCNE1 amplification and/or FBXW7 mutations occur in >60% of uterine carcinosarcomas, >20% of uterine cancers, ~20% of ovarian cancers, ~18% of stomach cancers, ~14% of colorectal cancer, ~12% of bladder cancers, 11.5% of oesophageal cancers, ~11% of cervical cancers, 7.5% of sarcomas and ~7% of lung squamous cancers (Durocher et al., 2021). CCNE1 also occurs at lower levels in other cancers such as adenoid cystic carcinoma, pancreatic cancer, mesothelioma, lung adenocarcinoma, head & neck cancers, difuse large B-cells lymphoma, liver cancers and others (Gorski et al., 2020). Moreover, CCNE1 over expressing ovarian cancers are a subset of the 50% that are recombination proficient so do not benefit from PARP inhibitors (Gorski et al., 2020), highlighting the unmet need in these indications. CCNE1 amplification is observed in the more aggressive subtypes including uterine carcinosarcoma (UCS; ~40%), uterine serous carcinoma (USC; ~ 25%), high-grade serous ovarian carcinoma (HGSOC; ~20%), and triple-negative breast cancer (TNBC; ~8%). CCNE1 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. Similarly, FBXW7 is frequently mutated in several cancer types including uterine carcinosarcoma, endometrial, colorectal, cervical, bladder, head & neck, gastric, cancers and lung squamous cells carcinoma ranging in frequency from 5-39%. Like CCNE1 overexpression, FBXW7 driver mutations are observed in the more aggressive subtypes of endometrial cancer including UCS and USC. Elevation of Cdk2-Cyclin E activity, via a variety of means, is also associated with resistance to Cdk4/6 inhibitors (Fassl et al., 2022); this suggests that PKMYT1 inhibition will also constitute a robust second line treatment in the cohort of HER2- ER+ breast cancer patients treated with Cdk4/6 inhibitors who generally develop resistance after around 2 years of therapy. A recently discovered inhibitor of PKMYT1, RP-6306 (Szychowski et al., 2022), has shown efficacy in vivo in models of breast and ovarian cancers overexpressing CCNE1, as well as in a pancreatic PDX model with increased expression of CCNE1, alone or in combination with Gemcitabine (Gallo et al., 2022). It has been claimed that synthetic lethality occurs in cancer cells between PKMYT1 inhibition and deficiency in protein phosphatase 2 (PP2A), in particular, regulatory subunit B alpha (PPP2R2A) (Yost et al., 2021). PPP2R2A inactivation is present in 15% of prostate adenocarcinoma, and at >5% in Ovarian serous cystadenocarcinoma, rectum adenocarcinoma, Bladder Urothelial Carcinoma, colorectal adenocarcinoma, breast invasive carcinoma, Uterine Corpus Endometrial Carcinoma, Uterine Carcinosarcoma, Liver hepatocellular carcinoma, Lung squamous cell carcinoma, lung adenocarcinoma. PKMYT1 is a cell cycle regulating kinase, part of the WEE1 family of kinases that includes WEE1 and WEE2. WEE2 is restricted to gonads as it regulates meiosis. In contrast both PKMYT1 and WEE1 are ubiquitously expressed. PKMYT1 is localized predominantly in the endoplasmic reticulum and Golgi complex, while WEE1 is predominantly a nuclear protein. PKMYT1 is involved in the negative regulation of the CDK1-Cyclin B complex which promotes the progression of cells from G2-phase into the mitotic phase (M-phase) of the cell cycle. The biology of Cyclin E overproduction generates a need for the otherwise non-essential PKMYT1. Cyclin E accumulation boosts the transcription of cyclin B1; the potential to form active Cdk1-Cyclin B is greatly enhanced by CCNE1 overexpression. This places a far greater demand upon the Cdk1-Cyclin B inhibitory activity of WEE1 and PKMYT1 such that PKMYT1 becomes essential. Furthermore, CCNE1 overproduction stimulates abnormally high levels of DNA replication that deplete the nucleotide pool and generate DNA damage (Jones et al, 2013). The DNA damage generated by Cyclin E accumulation is not in itself lethal because cells have G2/M checkpoints that restrain commitment to genome segregation in mitosis until all damage is repaired. These checkpoint pathways boost the activity of the Wee1 family kinases WEE1 and PKMYT1, which restrain division by phosphorylating Cdk1 kinase to block Cdk1-Cyclin B activity. While damage persists, WEE1 and PKMYT1 activities remain high and cells cannot divide. Thus, WEE1 or PKMYT1 inhibition kills damaged cells by forcing them to divide when their DNA is still damaged and/or un-replicated. This places higher demands upon the ability of WEE1 and PKMYT1 to restrain CDK1-Cyclin B activity to maintain cell viability. PKMYT1 can be removed from untransformed cells because the requirement for restraint of CDK1-CyclinB1 activity can be met by WEE1 alone. It is only when abnormally high levels of DNA damage generates a greater need for CDK1 cyclin B inhibition that PKMYT1’s activities become essential. The WEE1 inhibitor adavosertib has progressed to clinical trials in a number of solid tumours (clinicaltrials.gov) but presented significant toxicity. WEE1 inhibition toxicity most likely arises from its ability to inhibit both CDK2 and CDK1 complexes. CDK2-Cyclin E and CDK2-Cyclin A regulate the initiation and progression through DNA replication. Release of excessive levels of CDK2-Cyclin activities will generate DNA damage in a phenomenon known as oncogene induced replicative senescence. PKMYT1 inhibition is unlikely to display similar S phase toxicity, because, unlike WEE1, it phosphorylates CDK1 (Booher et al., 1997; Liu et al., 1997). Collectively, the dependency on PKMYT1 that is generated by excessive Cdk2-Cyclin E activity in cancer cells and the markedly reduced toxicity in normal tissues arising from its restriction to CDK1 regulation make PKMYT1 is a highly attractive target for inhibition for patients whose tumours proliferate inappropriately because of enhanced Cdk2-Cyclin E activity. Overexpression of PKMYT1 has been observed in various cancers (compared to normal tissues), including Lung squamous cell carcinoma, lung adenocarcinoma, Uterine Corpus Endometrial Carcinoma, breast invasive carcinoma, hepatocellular carcinoma, clear-cell renal-cell carcinoma, Kidney Chromophobe cancer, renal papillary cell carcinoma, Head and Neck squamous cell carcinoma, colon adenocarcinoma, stomach adenocarcinoma, thyroid carcinoma, prostate adenocarcinoma. Elevated expression of 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 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 carcinoma (Cai et al., 2022), gastric cancer (Hu et al., 2022; Zhang et al., 2020), prostate cancer (Wang et al., 2020), oesophageal squamous cell carcinoma (Zhang et al., 2019), colorectal cancer (Jeong et al., 2018), hepatocellular carcinoma (Liu et al., 2017), ovarian cancer (Xuan et al., 2020), neuroblastoma (in particular with MYCN amplification) (Chayka et al., 2015), glioblastoma (Toledo et al., 2015). PKMYT1 is essential for survival of some haematologic malignancies, such as acute lymphoblastic leukemia and multiple myeloma (Ghelli Luserna di Rora et al., 2020). 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. Knockdown of PKMYT1 can eliminate the radiation-induced G2/M arrest, resulting in a lower survival rate for cells receiving radiation therapy and is therefore a promising target to improve the radiosensitivity of lung adenocarcinoma (Long et al., 2020). PKMYT1 could be also prove useful to enhance the efficacy of anti-microtubule cancer drugs (Visconti et al., 2017). PKMYT1 also plays a role in viral infection. Knockdown of PKMYT1 reduces the number of cells supporting Kaposi sarcoma herpesvirus (KSHV) lytic infection in S phase of the cell cycle (Bryan et al., 2006). KSHV is the cause of Kaposi’s sarcoma, primary effusion lymphoma (PEL) and the plasmablastic variant of multicentric Castleman’s disease. There is a clear need for PKMYT1 selective inhibitors with good pharmacokinetic properties, which are suitable for oral dosing with minimal or no toxicity. This disclosure provides compounds and compositions that selectively inhibit PKMYT1 to treat cancer. SUMMARY OF THE INVENTION 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. Another aspect of the invention pertains to a composition (e.g., a pharmaceutical composition) comprising a BAA compound, as described herein, and a pharmaceutically acceptable carrier or diluent. Another aspect of the invention pertains to a method of preparing a composition (e.g., a pharmaceutical composition) comprising the step of mixing a BAA compound, as described herein, and a pharmaceutically acceptable carrier or diluent. 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 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 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 subject in need of treatment a therapeutically-effective amount of a BAA compound, as described herein, preferably in the form of a pharmaceutical composition. In one embodiment, the disorder is a disorder that is ameliorated by the inhibition of PKMYT1 (e.g., by the inhibition or reduction or blockage of the activity or function of PKMYT1). In one embodiment, the disorder is, for example, a proliferative condition, cancer, etc., as described herein. Another aspect of the present invention pertains to a kit comprising (a) a BAA compound, as described herein, preferably provided as a composition (e.g., a pharmaceutical composition) and in a suitable container and/or with suitable packaging; and (b) instructions for use, for example, in a method of treatment of a disorder (e.g., a disease) as described herein, for example, written instructions on how to administer the compound. Another aspect of the present invention pertains to a BAA compound obtainable by a method of synthesis as described herein, or a method comprising a method of synthesis as described herein. Another aspect of the present invention pertains to a BAA compound obtained by a method of synthesis as described herein, or a method comprising a method of synthesis as described herein. 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 synthesis described herein. As will be appreciated by one of skill in the art, features and preferred embodiments of one aspect of the invention will also pertain to other aspects of the invention. DETAILED DESCRIPTION Compounds One aspect of the present invention is a compound of the following formula, or a pharmaceutically acceptable salt or solvate thereof, wherein Ring A and Ring B are as defined herein (for convenience, collectively referred to herein as “biarylamide compounds” or “BAA compounds”):
Figure imgf000008_0001
A B . Some embodiments include the following: (1) A compound of the following formula:
Figure imgf000008_0002
or a pharmaceutically acceptable salt or solvate thereof; wherein:
Figure imgf000008_0003
wherein: Z1 is N, CH, or CRZ1; Z2 is CH, CRZ2, or N; Z3 is CH2, CHRZ3C1, CRZ3C22, NH, NRZ3N, O, or S; Z4 is CH2 or CHRZ4; Z5 is CH2 or CHRZ5; Z6 is N, CH, or CRZ6; Z7 is N, CH, or CRZ7; Z8 is N, CH, or CRZ8; Z9 is N, CH, or CRZ9; either: Z10 is CH2, CHRZ10C1, CRZ10C2 2, NH, NRZ10N, O, or S; and Z11 is CH2, CHRZ11C1, or CRZ11C2 2; or: Z10 is CH2, CHRZ10C1, or CRZ10C2 2; and Z11 is NH, NRZ11N, O, or S; Z12 is CH2 or CHRZ12; Z13 is CH2 or CHRZ13; Z14 is CH2, CHRZ14C1, CRZ14C2 2, NH, NRZ14N, O, or S; wherein: each -RZ1, -RZ2, -RZ5, -RZ6, -RZ7, -RZ8, -RZ9, and -RZ13 is independently -F, -Cl, -Br, -I, -RZZ, -CF3, -OH, -ORZZ, -OCF3, -NH2, -NHRZZ, or -NRZZ2; each -RZ4 and -RZ12 is independently -RZZ or -CF3; each -RZ3C1, -RZ10C1, -RZ11C1, and -RZ14C1 is independently -F, -RZZ, -CF3, -OH, -ORZZ, -OCF3, -NH2, -NHRZZ, or -NRZZ2; each -RZ3C2, -RZ10C2, -RZ11C2, and -RZ14C2 is independently -F, or -RZZ; each -RZZ is independently linear or branched saturated C1-4alkyl; and wherein: each -RZ3N, -RZ10N, -RZ11N, and -RZ14N is independently -RZZN, -C(=O)RZZN, -C(=O)ORZZN, -C(=O)NH2, -C(=O)NHRZZN, -C(=O)NRZZN2, or -S(=O)2RZZN; each -RZZN is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, C3-7heterocyclyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl is optionally substituted with -OH or -OCH3, and each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2; and wherein: -RA2 is -RA222, -F, -Cl, -Br, -I, -CF3, -CHF2, -OH, -ORA222, -OCF3, -NH2, -NHRA222, -NRA2222, -CN, -CH2OH, -C(=O)RA222, -C(=O)OH, -C(=O)ORA222, -C(=O)NH2, -C(=O)NHRA222, -C(=O)NRA2222, or -S(=O)2RA222; each -RA222 is independently linear or branched saturated C1-4alkyl; -RA3 is -H or -RA33; -RA33 is -RA333, -F, -Cl, -Br, -I, -CF3, -OH, -ORA333, or -OCF3; each -RA333 is independently linear or branched saturated C1-4alkyl; -RA4 is -H or -RA44; -RA44 is -RA444, -F, -Cl, -Br, -I, -CF3, -OH, -ORA444, or -OCF3; each -RA444 is independently linear or branched saturated C1-4alkyl; and: Ring B is selected from:
Figure imgf000010_0001
wherein: Y1 is S, O, NH, NRY1; Y2 is CH, CRY2, or N; Y3 is N, CH, or CRY3; Y4 is N, CH, or CRY4; Y5 is S, O, NH, NRY5; Y6 is N, CH, or CRY6; Y7 is N, CH, or CRY7; Y8 is N, CH, or CRY8; Y9 is S, O, NH, NRY9; wherein: each -RY2, -RY3, -RY4, -RY6, -RY7, and -RY8 is independently -H, -F, -Cl, -Br, -I, -RYY, -CF3, -OH, -ORYY, -OCF3, -NH2, -NHRYY, or -NRYY 2; each -RYY is independently linear or branched saturated C1-4alkyl; and wherein: each -RY1, -RY5, and -RY9 is independently -RYYN, -C(=O)RYYN, -C(=O)ORYYN, -C(=O)NH2, -C(=O)NHRYYN, -C(=O)NRYYN 2, or -S(=O)2RYYN; each -RYYN is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl is optionally substituted with -OH or -OCH3, and each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2; and wherein: -Q is -Q1, -LQ1-Q1, -Q2, -LQ2-Q2, -Q3, -LQ3-Q3, -Q4, -LQ4-Q4, -Q5, or -H; wherein: Q1 is C5-10heteroaryl; and is: optionally substituted on carbon with one or more groups -RQ1C; and optionally substituted on secondary nitrogen, if present, with one or more groups -RQ1N; -LQ1- is linear or branched saturated C1-4alkylene; Q2 is non-aromatic C3-7heterocyclyl; and is: optionally substituted on sulfur, if present, with one or two groups =O; optionally substituted on carbon with one or more groups -RQ2C; and optionally substituted on secondary nitrogen, if present, with one or more groups -RQ2N; -LQ2- is linear or branched saturated C1-4alkylene; Q3 is phenyl or naphthyl; and is optionally substituted with one or more groups -RQ3C; -LQ3- is linear or branched saturated C1-4alkylene; Q4 is C3-7cycloalkyl; and is optionally substituted with one or more groups -RQ4C; -LQ4- is linear or branched saturated C1-4alkylene; Q5 is linear or branched saturated C1-6alkyl; and is optionally substituted with one or more groups -RQ5C; and wherein: each -RQ1C is independently: -F, -Cl, -Br, -I, -RQ1CC, -RQ1CX, -ORQ1CX, -OH, -ORQ1CC, -LQ1C-OH, -LQ1C-ORQ1CC, -NH2, -NHRQ1CC, -NRQ1CC2, -RQ1CM, -LQ1C-NH2, -LQ1C-NHRQ1CC, -LQ1C-NRQ1CC2, -LQ1C-RQ1CM, -NHC(=O)RQ1CC, -NHC(=O)ORQ1CC, -LQ1C-NHC(=O)RQ1CC, -LQ1C-NHC(=O)ORQ1CC, -C(=O)NH2, -C(=O)NHRQ1CC, -C(=O)NRQ1CC2, -C(=O)RQ1CM, -LQ1C-C(=O)N(RQ1CC)ORQ1CC, -LQ1C-C(=O)NH2, -LQ1C-C(=O)NHRQ1CC, -LQ1C-C(=O)NRQ1CC2, -LQ1C-C(=O)RQ1CM, -C(=O)OH, -C(=O)ORQ1CC, -LQ1C-C(=O)ORQ1CC, -OC(=O)RQ1CC, -OC(=O)NH2, -OC(=O)NHRQ1CC, -OC(=O)NRQ1CC2, -OC(=O)RQ1CM, -S(=O)2RQ1CC, -S(=O)2NH2, -S(=O)2NHRQ1CC, -S(=O)2NRQ1CC2, -S(=O)2RQ1CM, -CN, or -NO2; and two adjacent -RQ1C, if present, taken together may form -(CH2)n1-O-(CH2)m1- or -O-(CH2)p1-O-, wherein: n1 is 0, 1, 2, or 3; m1 is 0, 1, 2, or 3; and p1 is 1 or 2; with the proviso that m1+n1 is 2 or 3; wherein: each -RQ1CC is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, C3-7heterocyclyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl is optionally substituted with -OH, -N(CH3)2, -C≡N, or -OCH3, and each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -CH2OCH3, -NH2, -NH(CH3), and -N(CH3)2; each -RQ1CX is independently linear or branched saturated C1-4haloalkyl; each -LQ1C- is independently linear or branched saturated C1-4alkylene; each -RQ1CM is independently non-aromatic C3-11heterocyclyl having at least one N ring atom, and is attached via that N ring atom; and is: optionally substituted on carbon with one or more groups -RQ1CMM; optionally substituted on sulfur, if present, with one or two =O groups; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ1CMM, -C(=O)RQ1CMM, -C(=O)ORQ1CMM, -C(=O)NH2, -C(=O)NHRQ1CMM, -C(=O)NRQ1CMM 2, and -S(=O)2RQ1CMM; and each -RQ1CMM is independently linear or branched saturated -F, C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl is optionally substituted with -OH or -OCH3, and each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2; and wherein: each -RQ1N is independently: -RQ1NC, -RQ1NX, -RQ1Nhet, -LQ1N-RQ1Nhet, -LQ1N-OH, -LQ1N-ORQ1NC, -LQ1N-C(=O)RQ1NC, -LQ1N-C(=O)OH, -LQ1N-C(=O)ORQ1NC, -LQ1N-C(=O)N(RQ1NC)ORQ1NC, -LQ1N-C(=O)NH2, -LQ1N-C(=O)NHRQ1NK, -LQ1N-C(=O)NRQ1NC2, -LQ1N-C(=O)RQ1NP, -LQ1N-NH2, -LQ1N-NHRQ1NC, -LQ1N-NRQ1NC2, -LQ1N-RQ1NM, -LQ1N-C≡N, -S(=O)2RQ1NC, -LQ1N-S(=O)2RQ1NC, or -LQ1N-NHC(=O)ORQ1NC; wherein: each -RQ1NC is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, phenyl, phenyl-C1-3alkyl, C3-7heterocyclyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein each C1-4alkyl is optionally substituted by MeS(O)2-,wherein each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2; each -RQ1NX is independently linear or branched saturated C1-4haloalkyl; each -LQ1N- is independently linear or branched saturated C1-4alkylene optionally substituted by -F or -OCH3; each -RQ1NM is independently non-aromatic C3-7heterocyclyl having at least one N ring atom, and is attached via that N ring atom; and is: optionally substituted on carbon with one or more groups -RQ1NMM; optionally substituted on sulfur, if present, with one or two =O groups; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ1NMM, -C(=O)RQ1NMM, -C(=O)ORQ1NMM, -C(=O)NH2, -C(=O)NHRQ1NMM, -C(=O)NRQ1NMM 2, and -S(=O)2RQ1NMM; and each -RQ1NMM is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl is optionally substituted with -OH or -OCH3, and each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2; and wherein: each -RQ1Nhet is independently non-aromatic C3-7heterocyclyl; and is: optionally substituted on sulfur, if present, with one or two groups =O; optionally substituted on carbon with one or more groups -RQ1NHH or =O; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ1NHH, -C(=O)RQ1NJJ, -C(=O)ORQ1NHH, -C(=O)NH2, -C(=O)NHRQ1NHH, -C(=O)NRQ1NHH2, and -S(=O)2RQ1NHH; wherein: each -RQ1NHH is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, C3-7heterocyclyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl is optionally substituted with -OH or -OCH3, and each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2; and wherein: -RQ1NJJ is -RJ1, -RJ2, -LJ-RJ2, -RJ3, -LJ-RJ3, -RJ4, -LJ-RJ4, -RJ5, or -LJ-RJ5; -RJ1 is linear or branched saturated C1-6alkyl; and is optionally substituted with one or more groups selected from: -F, -OH, -ORJJ, -O-phenyl, -C(=O)OH, -C(=O)ORJJ, -NH2, -NHRJJ, and -NRJJ2; each -RJ2 is independently C3-6cycloalkyl; and is optionally substituted with one or more groups selected from: -F, -RJJ, -CF3, -OH, -ORJJ, -NH2, -NHRJJ, and -NRJJ2; each -RJ3 is independently non-aromatic C3-7heterocyclyl; and is: optionally substituted on sulfur, if present, with one or two groups =O; optionally substituted on carbon with one or more groups selected from -F, -RJJ, -CF3, -OH, -ORJJ, -NH2, -NHRJJ, and -NRJJ2; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RJJ, -C(=O)RJJ, -C(=O)ORJJ, and -S(=O)2RJJ; each -RJ4 is phenyl; and is optionally substituted with one or more groups selected from: -F, -Cl, -RJJ, -CF3, -OH, -ORJJ, -NH2, -NHRJJ, and -NRJJ 2; each -RJ5 is independently C5-6heteroaryl; and is: optionally substituted on carbon with one or more groups selected from -F, -RJJ, -CF3, -OH, -ORJJ, -NH2, -NHRJJ, and -NRJJ 2; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RJJ, -C(=O) RJJ, -C(=O)ORJJ, and -S(=O)2RJJ; each -LJ- is independently linear or branched saturated C1-4alkylene, and is optionally substituted with one or more -F; each -RJJ is linear or branched saturated C1-4alkyl; and wherein: -RQ1NK is -RK1, -RK2, -LK-RK2, -RK3, -LK-RK3, -RK4, -LK-RK4, -RK5, or -LK-RK5; -RK1 is linear or branched saturated C1-7alkyl; and is optionally substituted with one or more groups selected from: -F, -OH, -ORKK, -OCH2CH2OCH3, -O-phenyl, -C(=O)OH, -C(=O)ORKK, -NH2, -NHRKK, and -NRKK2; each -RK2 is independently C3-6cycloalkyl; and is optionally substituted with one or more groups selected from: -F, -RKK, -CF3, -OH, -ORKK, -NH2, -NHRKK, and -NRKK2; each -RK3 is independently non-aromatic C3-7heterocyclyl; and is: optionally substituted on carbon with one or more groups selected from -F, -RKK, -CF3, -OH, -ORKK, -NH2, -NHRKK, and -NRKK2; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RKK, -C(=O)RKK, -C(=O)ORKK, and -S(=O)2RKK; each -RK4 is phenyl; and is optionally substituted with one or more groups selected from: -F, -Cl, -RKK, -CF3, -OH, -ORKK, -NH2, -NHRKK, and -NRKK2; each -RK5 is independently C5-6heteroaryl; and is: optionally substituted on carbon with one or more groups selected from -F, -RKK, -CF3, -OH, -ORKK, -NH2, -NHRKK, and -NRKK2; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RKK, -C(=O)RKK, -C(=O)ORKK, and -S(=O)2RKK; each -LK- is linear or branched saturated C1-4alkylene, and is optionally substituted with one or more -F; each -RKK is linear or branched saturated C1-4alkyl; and wherein: -RQ1NP is non-aromatic C3-11heterocyclyl having at least one N ring atom, and is attached via that N ring atom; and is: optionally substituted on sulfur, if present, with one or two =O groups; optionally substituted on carbon with one or more groups selected from -RQ1NPP, -F, -OH, -CF3, -ORQ1NPP, -C(O)NH2, and =O; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ1NPP, -RQ1NPPX, -C(=O)RQ1NPP, -C(=O)ORQ1NPP, -C(=O)NH2, -C(=O)NHRQ1NPP, -C(=O)NRQ1NPP 2, and -S(=O)2RQ1NPP; each -RQ1NPP is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl is optionally substituted with -OH, -Cl or -OCH3, and each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2; -RQ1NPPX is linear or branched saturated C1-4haloalkyl; and wherein: each -RQ2C is independently: -F, -RQ2CC, -RQ2CX, -OH, -ORQ2CC, -ORQ2CX, -NH2, -NHRQ2CC, -NRQ2CC2, -RQ2CM, -NHC(=O)RQ2CC, -NHC(=O)ORQ2CC, -C(=O)NH2, -C(=O)NHRQ2CC, -C(=O)NRQ2CC2, -C(=O)RQ2CM, -C(=O)OH, -C(=O)ORQ2CC, -OC(=O)RQ2CC, -OC(=O)NH2, -OC(=O)NHRQ2CC, -OC(=O)NRQ2CC2, -OC(=O)RQ2CM, or =O; wherein: each -RQ2CC is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, phenyl, C3-7heterocyclyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl is optionally substituted with -OH or -OCH3, and each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2; each -RQ2CX is independently linear or branched saturated C1-4haloalkyl; each -RQ2CM is independently non-aromatic C3-11heterocyclyl having at least one N ring atom, and is attached via that N ring atom; and is: optionally substituted on carbon with one or more groups -RQ2CMM; optionally substituted on sulfur, if present, with one or two =O groups; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ2CMM, -C(=O)RQ2CMM, -C(=O)ORQ2CMM, -C(=O)NH2, -C(=O)NHRQ2CMM, -C(=O)NRQ2CMM2, and -S(=O)2RQ2CMM; and each -RQ2CMM is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl is optionally substituted with -OH or -OCH3, and each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2; and wherein: each -RQ2N is independently: -RQ2NC, -C(=O)RQ2NC, -C(=O)-LQ2N-OH, -C(=O)-LQ2N-ORQ2NC, -C(=O)-LQ2N-NH2, -C(=O)-LQ2N-NHRQ2NC, -C(=O)-LQ2N-NRQ2NC2, -C(=O)-LQ2N-RQ2NM, -C(=O)ORQ2NC, -LQ2N-NH2, -LQ2N-NHRQ2NC, -LQ2N-NRQ2NC2, -LQ2N-RQ2NM, -C(=O)NH2, -C(=O)NHRQ2NC, -C(=O)NRQ2NC2, -C(=O)RQ2NM, -LQ2N-C(=O)NH2, -LQ2N-C(=O)NHRQ2NC, -LQ2N-C(=O)NRQ2NC2, -LQ2N-C(=O)RQ2NM, or -S(=O)2RQ2NC; wherein: each -RQ2NC is independently linear or branched saturated C1-6alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-6alkyl is optionally substituted with -OH or -OCH3, and each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2; each -LQ2N- is independently linear or branched saturated C1-4alkylene; each -RQ2NM is independently non-aromatic C3-11heterocyclyl having at least one N ring atom, and is attached via that N ring atom; and is: optionally substituted on carbon with one or more groups -RQ2NMM; optionally substituted on sulfur, if present, with one or two =O groups; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ2NMM, -C(=O)RQ2NMM, -C(=O)ORQ2NMM, -C(=O)NH2, -C(=O)NHRQ2NMM, -C(=O)NRQ2NMM2, and -S(=O)2RQ2NMM; and each -RQ2NMM is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl is optionally substituted with -OH or -OCH3, and each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2; and wherein: each -RQ3C is independently: -F, -Cl, -Br, -I, -RQ3CC, -RQ3CX, -ORQ3CX, -OH, -ORQ3CC, -LQ3C-OH, -LQ3C-ORQ3CC, -NH2, -NHRQ3CC, -NRQ3CC 2, -RQ3CM, -LQ3C-NH2, -LQ3C-NHRQ3CC, -LQ3C-NRQ3CC 2, -LQ3C-RQ3CM, -NHC(=O)RQ3CC, -NHC(=O)ORQ3CC, -LQ3C-NHC(=O)RQ3CC, -LQ3C-NHC(=O)ORQ3CC, -C(=O)NH2, -C(=O)NHRQ3CC, -C(=O)NRQ3CC2, -C(=O)RQ3CM, -LQ3C-C(=O)NH2, -LQ3C-C(=O)NHRQ3CC, -LQ3C-C(=O)NRQ3CC2, -LQ3C-C(=O)RQ3CM, -C(=O)OH, -C(=O)ORQ3CC, -LQ3C-C(=O)ORQ3CC, -OC(=O)RQ3CC, -OC(=O)NH2, -OC(=O)NHRQ3CC, -OC(=O)NRQ3CC2, -OC(=O)RQ3CM, -S(=O)2RQ3CC, -CN, or -NO2; and two adjacent-RQ3C, if present, taken together may form -(CH2)n3-O-(CH2)m3- or -O-(CH2)p3-O-, wherein: n3 is 0, 1, 2, or 3; m3 is 0, 1, 2, or 3; and p3 is 1 or 2; with the proviso that m3+n3 is 2 or 3; wherein: each -RQ3CC is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, C3-7heterocyclyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl is optionally substituted with -OH or -OCH3, and each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2; each -RQ3CX is independently linear or branched saturated C1-4haloalkyl; each -LQ3C- is independently linear or branched saturated C1-4alkylene; each -RQ3CM is independently non-aromatic C3-11heterocyclyl having at least one N ring atom, and is attached via that N ring atom; and is: optionally substituted on carbon with one or more groups -RQ3CMM; optionally substituted on sulfur, if present, with one or two =O groups; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ3CMM, -C(=O)RQ3CMM, -C(=O)ORQ3CMM, -C(=O)NH2, -C(=O)NHRQ3CMM, -C(=O)NRQ3CMM2, and -S(=O)2RQ3CMM; and each -RQ3CMM is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl is optionally substituted with -OH or -OCH3, and each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2; and wherein: each -RQ4C is independently: -F, -RQ4CC, -RQ4CX, -OH, -ORQ4CC, -ORQ4CX, -NH2, -NHRQ4CC, -NRQ4CC 2, -RQ4CM, -NHC(=O)RQ4CC, -NHC(=O)ORQ4CC, -C(=O)NH2, -C(=O)NHRQ4CC, -C(=O)NRQ4CC2, -C(=O)RQ4CM, -C(=O)OH, -C(=O)ORQ4CC, -OC(=O)RQ4CC, -OC(=O)NH2, -OC(=O)NHRQ4CC, -OC(=O)NRQ4CC2, -OC(=O)RQ4CM, or =O; wherein: each -RQ4CC is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, C3-7heterocyclyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl is optionally substituted with -OH or -OCH3, and each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2; each -RQ4CX is independently linear or branched saturated C1-4haloalkyl; each -RQ4CM is independently non-aromatic C3-11heterocyclyl having at least one N ring atom, and is attached via that N ring atom; and is: optionally substituted on carbon with one or more groups -RQ4CMM; optionally substituted on sulfur, if present, with one or two =O groups; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ4CMM, -C(=O)RQ4CMM, -C(=O)ORQ4CMM, -C(=O)NH2, -C(=O)NHRQ4CMM, -C(=O)NRQ4CMM2, and -S(=O)2RQ4CMM; each -RQ4CMM is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl is optionally substituted with -OH or -OCH3, and each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2; and wherein: each -RQ5C is independently: -F, -OH, -ORQ5CC, -OCF3, -NH2, -NHRQ5CC, -NRQ5CC 2, -RQ5CM, -NHC(=O)RQ5CC, -NHC(=O)ORQ5CC, -C(=O)NH2, -C(=O)NHRQ5CC, -C(=O)NRQ5CC 2, -C(=O)RQ5CM, -C(=O)OH, -C(=O)ORQ5CC, -OC(=O)RQ5CC, -OC(=O)NH2, -OC(=O)NHRQ5CC, -OC(=O)NRQ5CC 2, or -OC(=O)RQ5CM; wherein: each -RQ5CC is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, C3-7heterocyclyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl is optionally substituted with -OH or -OCH3, and each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2; each -RQ5CM is independently non-aromatic C3-11heterocyclyl having at least one N ring atom, and is attached via that N ring atom; and is: optionally substituted on carbon with one or more groups -RQ5CMM; optionally substituted on sulfur, if present, with one or two =O groups; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ5CMM, -C(=O)RQ5CMM, -C(=O)ORQ5CMM, -C(=O)NH2, -C(=O)NHRQ5CMM, -C(=O)NRQ5CMM2, and -S(=O)2RQ5CMM; each -RQ5CMM is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl is optionally substituted with -OH or -OCH3, and each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2. (2) A compound of the following formula:
Figure imgf000019_0001
or a pharmaceutically acceptable salt or s Aolvate thereof (e.g., or pharmaceutically acceptable salt thereof); wherein: Ring A is selected from: B
Figure imgf000020_0001
; wherein: Z1 is N, CH, or CRZ1; Z2 is CH, CRZ2, or N; Z3 is CH2, CHRZ3C1, CRZ3C22, NH, NRZ3N, O, or S; Z4 is CH2 or CHRZ4; Z5 is CH2 or CHRZ5; Z6 is N, CH, or CRZ6; Z7 is N, CH, or CRZ7; Z8 is N, CH, or CRZ8; Z9 is N, CH, or CRZ9; either: Z10 is CH2, CHRZ10C1, CRZ10C2 2, NH, NRZ10N, O, or S; and Z11 is CH2, CHRZ11C1, or CRZ11C2 2; or: Z10 is CH2, CHRZ10C1, or CRZ10C22; and Z11 is NH, NRZ11N, O, or S; Z12 is CH2 or CHRZ12; Z13 is CH2 or CHRZ13; Z14 is CH2, CHRZ14C1, CRZ14C22, NH, NRZ14N, O, or S; wherein: each -RZ1, -RZ2, -RZ5, -RZ6, -RZ7, -RZ8, -RZ9, and -RZ13 is independently -F, -Cl, -Br, -I, -RZZ, -CF3, -OH, -ORZZ, -OCF3, -NH2, -NHRZZ, or -NRZZ 2; each -RZ4 and -RZ12 is independently -RZZ or -CF3; each -RZ3C1, -RZ10C1, -RZ11C1, and -RZ14C1 is independently -F, -RZZ, -CF3, -OH, -ORZZ, -OCF3, -NH2, -NHRZZ, or -NRZZ 2; each -RZ3C2, -RZ10C2, -RZ11C2, and -RZ14C2 is independently -F, or -RZZ; each -RZZ is independently linear or branched saturated C1-4alkyl; and wherein: each -RZ3N, -RZ10N, -RZ11N, and -RZ14N is independently -RZZN, -C(=O)RZZN, -C(=O)ORZZN, -C(=O)NH2, -C(=O)NHRZZN, -C(=O)NRZZN2, or -S(=O)2RZZN; each -RZZN is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, C3-7heterocyclyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl is optionally substituted with -OH or -OCH3, and each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2; and wherein: -RA2 is -RA222, -F, -Cl, -Br, -I, -CF3, -CHF2, -OH, -ORA222, -OCF3, -NH2, -NHRA222, -NRA2222, -CN, -CH2OH, -C(=O)RA222, -C(=O)OH, -C(=O)ORA222, -C(=O)NH2, -C(=O)NHRA222, -C(=O)NRA2222, or -S(=O)2RA222; each -RA222 is independently linear or branched saturated C1-4alkyl; -RA3 is -H or -RA33; -RA33 is -RA333, -F, -Cl, -Br, -I, -CF3, -OH, -ORA333, or -OCF3; each -RA333 is independently linear or branched saturated C1-4alkyl; -RA4 is -H or -RA44; -RA44 is -RA444, -F, -Cl, -Br, -I, -CF3, -OH, -ORA444, or -OCF3; each -RA444 is independently linear or branched saturated C1-4alkyl; and: Ring B is selected from:
Figure imgf000021_0001
wherein: Y1 is S, O, NH, NRY1; Y2 is CH, CRY2, or N; Y3 is N, CH, or CRY3; Y4 is N, CH, or CRY4; Y5 is S, O, NH, NRY5; Y6 is N, CH, or CRY6; Y7 is N, CH, or CRY7; Y8 is N, CH, or CRY8; Y9 is S, O, NH, NRY9; wherein: each -RY2, -RY3, -RY4, -RY6, -RY7, and -RY8 is independently -H, -F, -Cl, -Br, -I, -RYY, -CF3, -OH, -ORYY, -OCF3, -NH2, -NHRYY, or -NRYY 2; each -RYY is independently linear or branched saturated C1-4alkyl; and wherein: each -RY1, -RY5, and -RY9 is independently -RYYN, -C(=O)RYYN, -C(=O)ORYYN, -C(=O)NH2, -C(=O)NHRYYN, -C(=O)NRYYN2, or -S(=O)2RYYN; each -RYYN is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl is optionally substituted with -OH or -OCH3, and each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2; and wherein: -Q is -Q1, -LQ1-Q1, -Q2, -LQ2-Q2, -Q3, -LQ3-Q3, -Q4, -LQ4-Q4, -Q5, or -H; wherein: Q1 is C5-10heteroaryl; and is: optionally substituted on carbon with one or more groups -RQ1C; and optionally substituted on secondary nitrogen, if present, with one or more groups -RQ1N; -LQ1- is linear or branched saturated C1-4alkylene; Q2 is non-aromatic C3-7heterocyclyl; and is: optionally substituted on sulfur, if present, with one or two groups =O; optionally substituted on carbon with one or more groups -RQ2C; and optionally substituted on secondary nitrogen, if present, with one or more groups -RQ2N; -LQ2- is linear or branched saturated C1-4alkylene; Q3 is phenyl or naphthyl; and is optionally substituted with one or more groups -RQ3C; -LQ3- is linear or branched saturated C1-4alkylene; Q4 is C3-7cycloalkyl; and is optionally substituted with one or more groups -RQ4C; -LQ4- is linear or branched saturated C1-4alkylene; Q5 is linear or branched saturated C1-6alkyl; and is optionally substituted with one or more groups -RQ5C; and wherein: each -RQ1C is independently: -F, -Cl, -Br, -I, -RQ1CC, -RQ1CX, -ORQ1CX, -OH, -ORQ1CC, -LQ1C-OH, -LQ1C-ORQ1CC, -NH2, -NHRQ1CC, -NRQ1CC 2, -RQ1CM, -LQ1C-NH2, -LQ1C-NHRQ1CC, -LQ1C-NRQ1CC 2, -LQ1C-RQ1CM, -NHC(=O)RQ1CC, -NHC(=O)ORQ1CC, -LQ1C-NHC(=O)RQ1CC, -LQ1C-NHC(=O)ORQ1CC, -C(=O)NH2, -C(=O)NHRQ1CC, -C(=O)NRQ1CC2, -C(=O)RQ1CM, -LQ1C-C(=O)NH2, -LQ1C-C(=O)NHRQ1CC, -LQ1C-C(=O)NRQ1CC 2, -LQ1C-C(=O)RQ1CM, -C(=O)OH, -C(=O)ORQ1CC, -OC(=O)RQ1CC, -OC(=O)NH2, -OC(=O)NHRQ1CC, -OC(=O)NRQ1CC2, -OC(=O)RQ1CM, -S(=O)2RQ1CC, -S(=O)2NH2, -S(=O)2NHRQ1CC, -S(=O)2NRQ1CC2, -S(=O)2NRQ1CM, -CN, or -NO2; and two adjacent -RQ1C, if present, taken together may form -(CH2)n1-O-(CH2)m1- or -O-(CH2)p1-O-, wherein: n1 is 0, 1, 2, or 3; m1 is 0, 1, 2, or 3; and p1 is 1 or 2; with the proviso that m1+n1 is 2 or 3; wherein: each -RQ1CC is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, C3-7heterocyclyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl is optionally substituted with -OH or -OCH3, and each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2; each -RQ1CX is independently linear or branched saturated C1-4haloalkyl; each -LQ1C- is independently linear or branched saturated C1-4alkylene; each -RQ1CM is independently non-aromatic C3-11heterocyclyl having at least one N ring atom, and is attached via that N ring atom; and is: optionally substituted on carbon with one or more groups -RQ1CMM; optionally substituted on sulfur, if present, with one or two =O groups; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ1CMM, -C(=O)RQ1CMM, -C(=O)ORQ1CMM, -C(=O)NH2, -C(=O)NHRQ1CMM, -C(=O)NRQ1CMM2, and -S(=O)2RQ1CMM; and each -RQ1CMM is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl is optionally substituted with -OH or -OCH3, and each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2; and wherein: each -RQ1N is independently: -RQ1NC, -RQ1NX, -RQ1Nhet, -LQ1N-RQ1Nhet, -LQ1N-OH, -LQ1N-ORQ1NC, -LQ1N-C(=O)RQ1NC, -LQ1N-C(=O)OH, -LQ1N-C(=O)ORQ1NC, -LQ1N-C(=O)NH2, -LQ1N-C(=O)NHRQ1NK, -LQ1N-C(=O)NRQ1NC2, -LQ1N-C(=O)RQ1NP, -LQ1N-NH2, -LQ1N-NHRQ1NC, -LQ1N-NRQ1NC2, -LQ1N-RQ1NM, or -LQ1N-NHC(=O)ORQ1NC; wherein: each -RQ1NC is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2; each -RQ1NX is independently linear or branched saturated C1-4haloalkyl; each -LQ1N- is independently linear or branched saturated C1-4alkylene; each -RQ1NM is independently non-aromatic C3-7heterocyclyl having at least one N ring atom, and is attached via that N ring atom; and is: optionally substituted on carbon with one or more groups -RQ1CMM; optionally substituted on sulfur, if present, with one or two =O groups; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ1NMM, -C(=O)RQ1NMM, -C(=O)ORQ1NMM, -C(=O)NH2, -C(=O)NHRQ1NMM, -C(=O)NRQ1NMM2, and -S(=O)2RQ1NMM; and each -RQ1NMM is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl is optionally substituted with -OH or -OCH3, and each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2; and wherein: each -RQ1Nhet is independently non-aromatic C3-7heterocyclyl; and is: optionally substituted on sulfur, if present, with one or two groups =O; optionally substituted on carbon with one or more groups -RQ1NHH or =O; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ1NHH, -C(=O)RQ1NJJ, -C(=O)ORQ1NHH, -C(=O)NH2, -C(=O)NHRQ1NHH, -C(=O)NRQ1NHH 2, and -S(=O)2RQ1NHH; wherein: each -RQ1NHH is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, C3-7heterocyclyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl is optionally substituted with -OH or -OCH3, and each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2; and wherein: -RQ1NJJ is -RJ1, -RJ2, -LJ-RJ2, -RJ3, -LJ-RJ3, -RJ4, -LJ-RJ4, -RJ5, or -LJ-RJ5; -RJ1 is linear or branched saturated C1-6alkyl; and is optionally substituted with one or more groups selected from: -F, -OH, -ORJJ, -O-phenyl, -C(=O)OH, -C(=O)ORJJ, -NH2, -NHRJJ, and -NRJJ2; each -RJ2 is independently C3-6cycloalkyl; and is optionally substituted with one or more groups selected from: -F, -RJJ, -CF3, -OH, -ORJJ, -NH2, -NHRJJ, and -NRJJ2; each -RJ3 is independently non-aromatic C3-7heterocyclyl; and is: optionally substituted on sulfur, if present, with one or two groups =O; optionally substituted on carbon with one or more groups selected from -F, -RJJ, -CF3, -OH, -ORJJ, -NH2, -NHRJJ, and -NRJJ2; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RJJ, -C(=O)RJJ, -C(=O)ORJJ, and -S(=O)2RJJ; each -RJ4 is phenyl; and is optionally substituted with one or more groups selected from: -F, -Cl, -RJJ, -CF3, -OH, -ORJJ, -NH2, -NHRJJ, and -NRJJ2; each -RJ5 is independently C5-6heteroaryl; and is: optionally substituted on carbon with one or more groups selected from -F, -RJJ, -CF3, -OH, -ORJJ, -NH2, -NHRJJ, and -NRJJ2; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RJJ, -C(=O) RJJ, -C(=O)ORJJ, and -S(=O)2RJJ; each -LJ- is independently linear or branched saturated C1-4alkylene, and is optionally substituted with one or more -F; each -RJJ is linear or branched saturated C1-4alkyl; and wherein: -RQ1NK is -RK1, -RK2, -LK-RK2, -RK3, -LK-RK3, -RK4, -LK-RK4, -RK5, or -LK-RK5; -RK1 is linear or branched saturated C1-7alkyl; and is optionally substituted with one or more groups selected from: -F, -OH, -ORKK, -OCH2CH2OCH3, -O-phenyl, -C(=O)OH, -C(=O)ORKK, -NH2, -NHRKK, and -NRKK2; each -RK2 is independently C3-6cycloalkyl; and is optionally substituted with one or more groups selected from: -F, -RKK, -CF3, -OH, -ORKK, -NH2, -NHRKK, and -NRKK 2; each -RK3 is independently non-aromatic C3-7heterocyclyl; and is: optionally substituted on carbon with one or more groups selected from -F, -RKK, -CF3, -OH, -ORKK, -NH2, -NHRKK, and -NRKK 2; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RKK, -C(=O)RKK, -C(=O)ORKK, and -S(=O)2RKK; each -RK4 is phenyl; and is optionally substituted with one or more groups selected from: -F, -Cl, -RKK, -CF3, -OH, -ORKK, -NH2, -NHRKK, and -NRKK 2; each -RK5 is independently C5-6heteroaryl; and is: optionally substituted on carbon with one or more groups selected from -F, -RKK, -CF3, -OH, -ORKK, -NH2, -NHRKK, and -NRKK2; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RKK, -C(=O)RKK, -C(=O)ORKK, and -S(=O)2RKK; each -LK- is linear or branched saturated C1-4alkylene, and is optionally substituted with one or more -F; each -RKK is linear or branched saturated C1-4alkyl; and wherein: -RQ1NP is non-aromatic C3-11heterocyclyl having at least one N ring atom, and is attached via that N ring atom; and is: optionally substituted on sulfur, if present, with one or two =O groups; optionally substituted on carbon with one or more groups selected from -RQ1NPP, -F, -OH, -ORQ1NPP, and =O; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ1NPP, -RQ1NPPX, -C(=O)RQ1NPP, -C(=O)ORQ1NPP, -C(=O)NH2, -C(=O)NHRQ1NPP, -C(=O)NRQ1NPP2, and -S(=O)2RQ1NPP; each -RQ1NPP is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl is optionally substituted with -OH or -OCH3, and each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2; -RQ1NPPX is linear or branched saturated C1-4haloalkyl; and wherein: each -RQ2C is independently: -F, -RQ2CC, -RQ2CX, -OH, -ORQ2CC, -ORQ2CX, -NH2, -NHRQ2CC, -NRQ2CC2, -RQ2CM, -NHC(=O)RQ2CC, -NHC(=O)ORQ2CC, -C(=O)NH2, -C(=O)NHRQ2CC, -C(=O)NRQ2CC2, -C(=O)RQ2CM, -C(=O)OH, -C(=O)ORQ2CC, -OC(=O)RQ2CC, -OC(=O)NH2, -OC(=O)NHRQ2CC, -OC(=O)NRQ2CC 2, -OC(=O)RQ2CM, or =O; wherein: each -RQ2CC is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, phenyl, C3-7heterocyclyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl is optionally substituted with -OH or -OCH3, and each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2; each -RQ2CX is independently linear or branched saturated C1-4haloalkyl; each -RQ2CM is independently non-aromatic C3-11heterocyclyl having at least one N ring atom, and is attached via that N ring atom; and is: optionally substituted on carbon with one or more groups -RQ2CMM; optionally substituted on sulfur, if present, with one or two =O groups; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ2CMM, -C(=O)RQ2CMM, -C(=O)ORQ2CMM, -C(=O)NH2, -C(=O)NHRQ2CMM, -C(=O)NRQ2CMM2, and -S(=O)2RQ2CMM; and each -RQ2CMM is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl is optionally substituted with -OH or -OCH3, and each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2; and wherein: each -RQ2N is independently: -RQ2NC, -C(=O)RQ2NC, -C(=O)-LQ2N-OH, -C(=O)-LQ2N-ORQ2NC, -C(=O)-LQ2N-NH2, -C(=O)-LQ2N-NHRQ2NC, -C(=O)-LQ2N-NRQ2NC2, -C(=O)-LQ2N-RQ2NM, -C(=O)ORQ2NC, -LQ2N-NH2, -LQ2N-NHRQ2NC, -LQ2N-NRQ2NC2, -LQ2N-RQ2NM, -C(=O)NH2, -C(=O)NHRQ2NC, -C(=O)NRQ2NC2, -C(=O)RQ2NM, -LQ2N-C(=O)NH2, -LQ2N-C(=O)NHRQ2NC, -LQ2N-C(=O)NRQ2NC2, -LQ2N-C(=O)RQ2NM, or -S(=O)2RQ2NC; wherein: each -RQ2NC is independently linear or branched saturated C1-6alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-6alkyl is optionally substituted with -OH or -OCH3, and each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2; each -LQ2N- is independently linear or branched saturated C1-4alkylene; each -RQ2NM is independently non-aromatic C3-11heterocyclyl having at least one N ring atom, and is attached via that N ring atom; and is: optionally substituted on carbon with one or more groups -RQ2NMM; optionally substituted on sulfur, if present, with one or two =O groups; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ2NMM, -C(=O)RQ2NMM, -C(=O)ORQ2NMM, -C(=O)NH2, -C(=O)NHRQ2NMM, -C(=O)NRQ2NMM 2, and -S(=O)2RQ2NMM; and each -RQ2NMM is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl is optionally substituted with -OH or -OCH3, and each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2; and wherein: each -RQ3C is independently: -F, -Cl, -Br, -I, -RQ3CC, -RQ3CX, -ORQ3CX, -OH, -ORQ3CC, -LQ3C-OH, -LQ3C-ORQ3CC, -NH2, -NHRQ3CC, -NRQ3CC2, -RQ3CM, -LQ3C-NH2, -LQ3C-NHRQ3CC, -LQ3C-NRQ3CC2, -LQ3C-RQ3CM, -NHC(=O)RQ3CC, -NHC(=O)ORQ3CC, -LQ3C-NHC(=O)RQ3CC, -LQ3C-NHC(=O)ORQ3CC, -C(=O)NH2, -C(=O)NHRQ3CC, -C(=O)NRQ3CC2, -C(=O)RQ3CM, -LQ3C-C(=O)NH2, -LQ3C-C(=O)NHRQ3CC, -LQ3C-C(=O)NRQ3CC2, -LQ3C-C(=O)RQ3CM, -C(=O)OH, -C(=O)ORQ3CC, -OC(=O)RQ3CC, -OC(=O)NH2, -OC(=O)NHRQ3CC, -OC(=O)NRQ3CC2, -OC(=O)RQ3CM, -CN, or -NO2; and two adjacent-RQ3C, if present, taken together may form -(CH2)n3-O-(CH2)m3- or -O-(CH2)p3-O-, wherein: n3 is 0, 1, 2, or 3; m3 is 0, 1, 2, or 3; and p3 is 1 or 2; with the proviso that m3+n3 is 2 or 3; wherein: each -RQ3CC is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, C3-7heterocyclyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl is optionally substituted with -OH or -OCH3, and each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2; each -RQ3CX is independently linear or branched saturated C1-4haloalkyl; each -LQ3C- is independently linear or branched saturated C1-4alkylene; each -RQ3CM is independently non-aromatic C3-11heterocyclyl having at least one N ring atom, and is attached via that N ring atom; and is: optionally substituted on carbon with one or more groups -RQ3CMM; optionally substituted on sulfur, if present, with one or two =O groups; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ3CMM, -C(=O)RQ3CMM, -C(=O)ORQ3CMM, -C(=O)NH2, -C(=O)NHRQ3CMM, -C(=O)NRQ3CMM2, and -S(=O)2RQ3CMM; and each -RQ3CMM is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl is optionally substituted with -OH or -OCH3, and each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2; and wherein: each -RQ4C is independently: -F, -RQ4CC, -RQ4CX, -OH, -ORQ4CC, -ORQ4CX, -NH2, -NHRQ4CC, -NRQ4CC2, -RQ4CM, -NHC(=O)RQ4CC, -NHC(=O)ORQ4CC, -C(=O)NH2, -C(=O)NHRQ4CC, -C(=O)NRQ4CC2, -C(=O)RQ4CM, -C(=O)OH, -C(=O)ORQ4CC, -OC(=O)RQ4CC, -OC(=O)NH2, -OC(=O)NHRQ4CC, -OC(=O)NRQ4CC2, -OC(=O)RQ4CM, or =O; wherein: each -RQ4CC is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, C3-7heterocyclyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl is optionally substituted with -OH or -OCH3, and each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2; each -RQ4CX is independently linear or branched saturated C1-4haloalkyl; each -RQ4CM is independently non-aromatic C3-11heterocyclyl having at least one N ring atom, and is attached via that N ring atom; and is: optionally substituted on carbon with one or more groups -RQ4CMM; optionally substituted on sulfur, if present, with one or two =O groups; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ4CMM, -C(=O)RQ4CMM, -C(=O)ORQ4CMM, -C(=O)NH2, -C(=O)NHRQ4CMM, -C(=O)NRQ4CMM 2, and -S(=O)2RQ4CMM; each -RQ4CMM is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl is optionally substituted with -OH or -OCH3, and each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2; and wherein: each -RQ5C is independently: -F, -OH, -ORQ5CC, -OCF3, -NH2, -NHRQ5CC, -NRQ5CC 2, -RQ5CM, -NHC(=O)RQ5CC, -NHC(=O)ORQ5CC, -C(=O)NH2, -C(=O)NHRQ5CC, -C(=O)NRQ5CC2, -C(=O)RQ5CM, -C(=O)OH, -C(=O)ORQ5CC, -OC(=O)RQ5CC, -OC(=O)NH2, -OC(=O)NHRQ5CC, -OC(=O)NRQ5CC2, or -OC(=O)RQ5CM; wherein: each -RQ5CC is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, C3-7heterocyclyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl is optionally substituted with -OH or -OCH3, and each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2; each -RQ5CM is independently non-aromatic C3-11heterocyclyl having at least one N ring atom, and is attached via that N ring atom; and is: optionally substituted on carbon with one or more groups -RQ5CMM; optionally substituted on sulfur, if present, with one or two =O groups; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ5CMM, -C(=O)RQ5CMM, -C(=O)ORQ5CMM, -C(=O)NH2, -C(=O)NHRQ5CMM, -C(=O)NRQ5CMM2, and -S(=O)2RQ5CMM; each -RQ5CMM is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl is optionally substituted with -OH or -OCH3, and each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2. For the avoidance of doubt: It is intended that the nitrogen atom of the central amide group, -NH-C(=O)-, linking Ring A and Ring B, is unsubstituted. It is intended that Ring B is not fused to any other ring. The index “Cx-y” in terms such as “C9-10heteroaryl”, “C3-7heterocyclyl”, and the like, refers to the number of ring atoms, which may be carbon atoms or heteroatoms (e.g., N, O, S, as the case may be). For example, pyridyl is an example of a C6heteroaryl group, and piperidino is an example of a C6heterocyclyl group. The term “heteroaryl” refers to a group that is attached to the rest of the molecule by an atom that is part of an aromatic ring, wherein the aromatic ring is part of an aromatic ring system, and the aromatic ring system has one or more heteroatoms (e.g., N, O, S, as the case may be). Unless otherwise stated, the heteroaryl may be attached via a ring carbon or a ring nitrogen atom. For example, pyridyl is an example of a C6heteroaryl group, and quinolyl (e.g., quinolin-2-yl, quinolin-7-yl, etc.) is an example of a C10heteroaryl group. Furthermore, the aromatic ring system may optionally be fused with one or more non-aromatic rings which may contain one or more heteroatoms (e.g., N, O, S, as the case may be) or only carbon atoms. For example: 4,5,6,7- tetrahydro-1H-indol-2-yl is an example of a C9heteroaryl group; 4,5,6,7-tetrahydro-1H-pyrrolo[2,3- b]pyridin-2-yl is an example of a C9heteroaryl group. The term “heterocyclyl” refers to a group that contains at least one non aromatic ring system comprising one or more heteroatoms (e.g., N, O, S, as the case may be) that is attached to the rest of the molecule by an atom that is part of a non aromatic ring system comprising one or more heteroatoms (e.g., N, O, S, as the case may be). Unless otherwise stated, the heterocyclyl may be attached via a ring carbon or a ring nitrogen atom. In one embodiment, the term “heterocyclyl” refers to a group that is attached to the rest of the molecule by an atom that is part of a non-aromatic ring, wherein the non-aromatic ring is part of a non-aromatic ring system, and the non-aromatic ring system has one or more heteroatoms (e.g., N, O, S, as the case may be). Unless otherwise specified, a sulfur ring atom may be substituted with one or two oxo (=O) groups (for example, as in 1,1-dioxo-1,4-thiazinany-4-yl). Unless otherwise specified, “heterocyclyl” includes monocyclic heterocyclyl (e.g., piperidinyl, an example of a monocyclic C6heterocyclyl), fused heterocyclyl (e.g., 3-azabicyclo[3.1.0]hexyl, an example of a fused C6heterocyclyl; decahydroquinolinyl, an example of a fused C10heterocyclyl), bridged heterocyclyl (e.g., 6-azabicyclo[3.1.1]heptanyl and 2,5-diazabicyclo[2.2.1]heptane, examples of a bridged C7heterocyclyl; 3,8-diazabicyclo[3.2.1]octanyl, an example of a bridged C8heterocyclyl), and spiro heterocyclyl (2,6-diazaspiro[3.3]heptane, an example of a spiro C7heterocyclyl; 7- azaspiro[3.5]nonyl, an example of a spiro C9heterocyclyl; 2,8-diazaspiro[4.5]decane, an example of a spiro C10heterocyclyl). Furthermore, the non-aromatic ring system may optionally be fused with one or more aromatic rings. For example: 4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridin-5-yl is an example of a C9heterocyclyl group; 1 ,2,3,4-tetrahydroisoquinolin-3-yl is an example of a Cwheterocyclyl group.
The term “non-aromatic C3- 11heterocyclyl having at least one N ring atom, and is attached via that N ring atom” refers to a heterocyclyl group that is attached via a N ring atom, but which may have additional N ring atoms. Examples include: aziridino, azetidino, pyrrolidino, piperidino, piperazino, morpholino, thiomorpholino, azepano, and diazepano.
The term “haloalkyl” refers to an alkyl group substituted with one or more halo groups (e.g., -F, -Cl, -Br, -I). The term “fluoroalkyl” refers to an alkyl group substituted with one or more -F groups. For example, -CF3 and -CHF2 are examples of a C1fluoroalkyl group; -CH2CF3 and -CH2CHF2 are examples of a C2fluoroalkyl group.
The term “C1-4alkylene” refers to an alkyl group with two points of attachment. For example, -CH2- is an example of a Cialkylene group; -CH2CH2- and -CH(CH3)- are examples of a C2alkylene group; -CH2CH2CH2- and -CH(CH3)2- are examples of a C3alkylene group.
Examples of C1-7alkyl, C1-6alkyl and C1-4alkyl include methyl, ethyl, propyl, isopropyl and butyl. Examples of C3-6cycloalkyl include cyclopropyl and cyclohexyl. Examples of C3-6cycloalkyl-C1-3alkyl include cyclopropyl methyl and cyclohexylethyl. Examples of phenyl-C1-3alkyl include benzyl and 2-phenylpropyl. Examples of C5-6heteroaryl-C1-3alkyl include pyrimidin-2- ylmethyl and thiazol-4-ylethyl.
The phrase “one or more groups” in the context of optional substituents (e.g., “one or more groups -RAR1C”, etc.) is necessarily constrained by the parent moiety and the number of positions on it that are suitable for substitution. In some parent moieties (e.g., tetrazolyl) there is only one position available for substitution. However, for other parent moieties, there may be several (e.g., phenyl has five). Except when constrained by the parent moiety, the “one or more groups” may be, e.g., 1 , 2, 3, 4, etc., though more preferably is 1 , 2, or 3, yet more preferably 1 or 2, still more preferably 1 .
The phrase “substituent on carbon” is intended to refer to a substituent which is attached to a carbon ring atom. Similarly, the phrase “substituent on secondary nitrogen” is intended to refer to a substituent which is attached to a nitrogen ring atom which, in the absence of the substituent, would be a secondary nitrogen ring atom (i.e. , -NH-). Consequently, a pyridyl group may only have “substituents on carbon”, whereas 1 H-pyrrole may have both “substituents on carbon” and a “substituent on secondary nitrogen”, as illustrated below. substituent on carbon
Figure imgf000032_0001
substituent on secondary nitrogen
Figure imgf000032_0002
a substituent on carbon Similarly, a piperidino group may only have “substituents on carbon”, whereas piperizino may have both “substituents on carbon” and a “substituent on secondary nitrogen”, as illustrated below.
Figure imgf000033_0001
Figure imgf000033_0002
Certain groups despite having carbon ring a s autbosmtitsue m anta s ouynb ns soteitctuoe hnnadtva oerny a c nanitrryboog cneanr itution. For example, a tetrazo aly slu gsrottuupen mt obon ring atoms available for subst any ca ornloyn permit a “substituent on carbon” or may only permit a “substituent on secondary nitrogen”, as illustrated below.
Figure imgf000033_0003
Unless otherwise indicated, where a comp aou sundst istue snhto ownn se ocro dndeasrcyr nibitreodge wnhich and two or more stereoisome ars su abrsetit puoensts oibnl c has one or more chiral centres, ea,r abolln such stereoisomers are disclosed and encompassed, both individually (e.g., as isolated from the other stereoisomer(s)) and as mixtures (e.g., as equimolar or non-equimolar mixtures of two or more stereoisomers). For example, unless otherwise indicated, where a compound has one chiral centre, each of the (R) and (S) enantiomers are disclosed and encompassed, both individually (e.g., as isolated from the other enantiomer) and as a mixture (e.g., as equimolar or non-equimolar mixtures of the two enantiomers). For example, the initial carbon atom of a pendant sec-butyl group, -CH(CH3)CH2CH3 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 (3) A compound according to (1) or (2), wherein: Z1, if present, is N or CH; Z2, if present, is CH or N; Z3, if present, is CH2, NH, O, or S; Z4, if present, is CH2; Z5, if present, is CH2; Z6, if present, is N or CH; Z7, if present, is N or CH; Z8, if present, is N or CH; Z9, if present, is N or CH; either: Z10, if present, is CH2, NH, O, or S; and Z11, if present, is CH2; or: Z10, if present, is CH2; and Z11, if present, is NH, O, or S; Z12, if present, is CH2; Z13, if present, is CH2; Z14, if present, is CH2, NH, O, or S; (4) A compound according to (1) or (2), wherein: Z1, if present, is N; Z2, if present, is CH, CRZ2, or N. (5) A compound according to (1) or (2), wherein: Z1, if present, is N. (6) A compound according to (1) or (2), wherein: Z2, if present, is CH, CRZ2, or N. (7) A compound according to (1) or (2), wherein: Z2, if present, is CH. (8) A compound according to (1) or (2), wherein: Z2, if present, is CRZ2. (9) A compound according to (1) or (2), wherein: Z2, if present, is N. (10) A compound according to (1) or (2), wherein Ring A is selected from:
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
, , , . (11) A compound according to (1) or (2), wherein Ring A is selected from:
Figure imgf000036_0002
. (12) A compound according to (1) or (2), wherein Ring A is:
Figure imgf000036_0003
. (13) A compound according to (1) or (2), wherein Ring A is selected from:
Figure imgf000036_0004
(14) A compound according to (1) or (2), wherein Ring A is:
Figure imgf000036_0005
. (15) A compound according to (1) or (2), wherein Ring A is:
Figure imgf000037_0001
. (16) A compound according to (1) or (2), wherein Ring A is:
Figure imgf000037_0002
. (17) A compound according to (1) or (2), wherein Ring A is:
Figure imgf000037_0003
. (18) A compound according to (1) or (2), wherein Ring A is:
Figure imgf000037_0004
. (19) A compound according to (1) or (2), wherein Ring A is selected from:
Figure imgf000038_0001
, . (20) A compound according to (1) or (2), wherein Ring A is:
Figure imgf000038_0002
. (21) A compound according to (1) or (2), wherein Ring A is:
Figure imgf000038_0003
. The Groups -RZ1, -RZ2, etc. (22) A compound according to any one of (1) to (21), wherein: each -RZ1, -RZ2, -RZ5, -RZ6, -RZ7, -RZ8, -RZ9, and -RZ13, if present, is independently: -F, -Cl, -Br, -I, -RZZ, -CF3, -OH, -ORZZ, or -OCF3. (23) A compound according to any one of (1) to (21), wherein: each -RZ1, -RZ2, -RZ5, -RZ6, -RZ7, -RZ8, -RZ9, and -RZ13, if present, is independently: -F, -Cl, -Br, -I, -RZZ, or -OH. (24) A compound according to any one of (1) to (21), wherein: each -RZ1, -RZ2, -RZ5, -RZ6, -RZ7, -RZ8, -RZ9, and -RZ13, if present, is independently: -F, -Cl, -RZZ, or -OH. (25) A compound according to any one of (1) to (21), wherein: each -RZ1, -RZ2, -RZ5, -RZ6, -RZ7, -RZ8, -RZ9, and -RZ13, if present, is independently: -F, -Cl, or -RZZ. (26) A compound according to any one of (1) to (21), wherein: each -RZ1, -RZ2, -RZ5, -RZ6, -RZ7, -RZ8, -RZ9, and -RZ13, if present, is independently: -F or -RZZ. (27) A compound according to any one of (1) to (21), wherein: each -RZ1, -RZ2, -RZ5, -RZ6, -RZ7, -RZ8, -RZ9, and -RZ13, if present, is: -RZZ. (28) A compound according to any one of (1) to (21), wherein: each -RZ2 if present is independently -Br, or -RZZ. (29) A compound according to any one of (1) to (21), wherein: each -RZ2 if present is independently -Br. (30) A compound according to any one of (1) to (21), wherein: each -RZ2 if present is independently -RZZ. The Groups -RZ4 and -RZ12 (31) A compound according to any one of (1) to (30), wherein: each -RZ4 and -RZ12, if present, is: -RZZ. (32) A compound according to any one of (1) to (30), wherein: each -RZ4 and -RZ12, if present, is: -CF3. The Groups -RZ3C1, -RZ10C1, -RZ11C1, and -RZ14C1 (33) A compound according to any one of (1) to (32), wherein: each -RZ3C1, -RZ10C1, -RZ11C1, and -RZ14C1, if present, is independently: -F, -RZZ, -CF3, -OH, -ORZZ, or -OCF3. (34) A compound according to any one of (1) to (32), wherein: each -RZ3C1, -RZ10C1, -RZ11C1, and -RZ14C1, if present, is independently: -F, -RZZ, or -OH. (35) A compound according to any one of (1) to (32), wherein: each -RZ3C1, -RZ10C1, -RZ11C1, and -RZ14C1, if present, is independently: -F or -RZZ. The Groups -RZ3C2, -RZ10C2, -RZ11C2, and -RZ14C2 (36) A compound according to any one of (1) to (35), wherein: each -RZ3C2, -RZ10C2, -RZ11C2, and -RZ14C2, if present, is: -F. (37) A compound according to any one of (1) to (35), wherein: each -RZ3C2, -RZ10C2, -RZ11C2, and -RZ14C2, if present, is: -RZZ. The Group -RZZ (38) A compound according to any one of (1) to (37), wherein: each -RZZ, if present, is: -Me, -Et, -nPr, -iPr, -nBu, or -tBu. (39) A compound according to any one of (1) to (37), wherein: each -RZZ, if present, is: -Me, -Et, -nPr, or -iPr. (40) A compound according to any one of (1) to (37), wherein: each -RZZ, if present, is: -Me or -Et. (41) A compound according to any one of (1) to (37), wherein: each -RZZ, if present, is: -Me. The Groups -RZ3N, -RZ10N, -RZ11N, and -RZ14N (42) A compound according to any one of (1) to (41), wherein: each -RZ3N, -RZ10N, -RZ11N, and -RZ14N, if present, is independently: -RZZN or -C(=O)RZZN. (43) A compound according to any one of (1) to (41), wherein: each -RZ3N, -RZ10N, -RZ11N, and -RZ14N, if present, is independently: -RZZN. The Group -RZZN (44) A compound according to any one of (1) to (43), wherein: each -RZZN, if present, is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, phenyl, phenyl-C1-3alkyl, wherein each phenyl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2. (45) A compound according to any one of (1) to (43), wherein: each -RZZN, 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, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2. (46) A compound according to any one of (1) to (43), wherein: each -RZZN, if present, is independently linear or branched saturated C1-4alkyl, phenyl, or benzyl. (47) A compound according to any one of (1) to (43), wherein: each -RZZN, if present, is independently linear or branched saturated C1-4alkyl. (48) A compound according to any one of (1) to (43), wherein: each -RZZN, if present, is -Me. The Group -RA2 (49) A compound according to any one of (1) to (48), wherein: -RA2 is -RA222, -F, -Cl, -Br, -I, -CF3, -CHF2, -OH, -ORA222, -OCF3, or -CN. (50) A compound according to any one of (1) to (48), wherein: -RA2 is -RA222, -F, -Cl, -Br, -I, -CF3, -CHF2, -OH, -ORA222, or -OCF3. (51) A compound according to any one of (1) to (48), wherein: -RA2 is -RA222, -F, -Cl, -Br, -I, -CF3, -OH, -ORA222, or -OCF3. (52) A compound according to any one of (1) to (48), wherein: -RA2 is -RA222, -F, -Cl, -Br, -I, -OH, or -ORA222. (53) A compound according to any one of (1) to (48), wherein: -RA2 is -RA222, -F, -Cl, -Br, -I, or -OH. (54) A compound according to any one of (1) to (48), wherein: -RA2 is -RA222, -F, -Cl, or -OH. (55) A compound according to any one of (1) to (48), wherein: -RA2 is -RA222, -F, or -Cl. (56) A compound according to any one of (1) to (48), wherein: -RA2 is -RA222. (57) A compound according to any one of (1) to (48), wherein: -RA2 is -Cl. (58) A compound according to any one of (1) to (48), wherein: -RA2 is -F. (59) A compound according to any one of (1) to (48), wherein: -RA2 is -RA222, -F, -Cl, or -Br. The Group -RA222 (60) A compound according to any one of (1) to (59), wherein: each -RA222, if present, is -Me, -Et, -nPr, -iPr, -nBu, or -tBu. (61) A compound according to any one of (1) to (59), wherein: each -RA222, if present, is -Me, -Et, -nPr, or -iPr. (62) A compound according to any one of (1) to (59), wherein: each -RA222, if present, is -Me or -Et. (63) A compound according to any one of (1) to (59), wherein: each -RA222, if present, is -Me. The Group -RA3 (64) A compound according to any one of (1) to (63), wherein: -RA3, if present, is -H. (65) A compound according to any one of (1) to (63), wherein: -RA3, if present, is -RA33. The Group -RA33 (66) A compound according to any one of (1) to (65), wherein: -RA33, if present, is: -RA333, -F, -Cl, -Br, -I, -OH, or -ORA333. (67) A compound according to any one of (1) to (65), wherein: -RA33, if present, is: -RA333, -F, -Cl, -Br, -I, or -OH. (68) A compound according to any one of (1) to (65), wherein: -RA33, if present, is: -RA333, -F, -Cl, or -OH. (69) A compound according to any one of (1) to (65), wherein: -RA33, if present, is: -RA333, -F, or -Cl. (70) A compound according to any one of (1) to (65), wherein: -RA33, if present, is: -RA333. (71) A compound according to any one of (1) to (64), wherein: -RA33, if present, is: -Cl. The Group -RA333 (72) A compound according to any one of (1) to (71), wherein: each -RA333, if present, is -Me, -Et, -nPr, -iPr, -nBu, or -tBu. (73) A compound according to any one of (1) to (71), wherein: each -RA333, if present, is -Me, -Et, -nPr, or -iPr. (74) A compound according to any one of (1) to (71), wherein: each -RA333, if present, is -Me or -Et. (75) A compound according to any one of (1) to (71), wherein: each -RA333, if present, is -Me. The Group -RA4 (76) A compound according to any one of (1) to (75), wherein: -RA4, if present, is -H. (77) A compound according to any one of (1) to (75), wherein: -RA4, if present, is -RA44. The Group -RA44 (78) A compound according to any one of (1) to (77), wherein: -RA44, if present, is: -RA444, -F, -Cl, -Br, -I, -OH, or -ORA444. (79) A compound according to any one of (1) to (77), wherein: -RA44, if present, is: -RA444, -F, -Cl, -Br, -I, or -OH. (80) A compound according to any one of (1) to (77), wherein: -RA44, if present, is: -RA444, -F, -Cl, or -OH. (81) A compound according to any one of (1) to (77), wherein: -RA44, if present, is: -RA444, -F, or -Cl. (82) A compound according to any one of (1) to (77), wherein: -RA44, if present, is: -RA444. (83) A compound according to any one of (1) to (77), wherein: -RA44, if present, is: -Cl. The Group -RA444 (84) A compound according to any one of (1) to (83), wherein: each -RA444, if present, is -Me, -Et, -nPr, -iPr, -nBu, or -tBu. (85) A compound according to any one of (1) to (83), wherein: each -RA444, if present, is -Me, -Et, -nPr, or -iPr. (86) A compound according to any one of (1) to (83), wherein: each -RA444, if present, is -Me or -Et. (87) A compound according to any one of (1) to (83), wherein: each -RA444, if present, is -Me. Ring B (88) A compound according to any one of (1) to (87), wherein: Ring B is:
Figure imgf000043_0001
. (89) A compound according to any one of (1) to (87), wherein: Ring B is:
Figure imgf000043_0002
. (90) A compound according to any one of (1) to (87), wherein: Ring B is:
Figure imgf000044_0001
. (91) A compound according to any one of (1) to (87), wherein: Y1, if present, is S, O, or NH; Y2, if present, is CH or N; Y3, if present, is N or CH; Y4, if present, is N or CH; Y5, if present, is S, O, or NH; Y6, if present, is N or CH; Y7, if present, is N or CH; Y8, if present, is N or CH; and Y9, if present, is S, O, or NH. For example, wherein Ring B is selected from:
Figure imgf000044_0002
Figure imgf000045_0001
. (92) A compound according to any one of (1) to (87), wherein: Y1, if present, is S; Y2, if present, is CH, CRY2, or N; Y3, if present, is N, CH, or CRY3; Y4, if present, is N, CH, or CRY4; Y5, if present, is S; Y6, if present, is N, CH, or CRY6; Y7, if present, is N, CH, or CRY7; Y8, if present, is N, CH, or CRY8; and Y9, if present, is S. (93) A compound according to any one of (1) to (87), wherein: Y1, if present, is S; Y2, if present, is CH or N; Y3, if present, is N or CH; Y4, if present, is N or CH; Y5, if present, is S; Y6, if present, is N or CH; Y7, if present, is N or CH; Y8, if present, is N or CH; and Y9, if present, is S. (94) A compound according to any one of (1) to (87), wherein: Y1, if present, is S; Y2, if present, is CH, CRY2, or N; Y3, if present, is N, CH, or CRY3; wherein exactly one of Y2 and Y3 is N; Y4, if present, is N, CH, or CRY4; Y5, if present, is S; Y6, if present, is N, CH, or CRY6; wherein exactly one of Y4 and Y6 is N; Y7, if present, is N, CH, or CRY7; Y8, if present, is N, CH, or CRY8; Y9, if present, is S; and wherein exactly one of Y7 and Y8 is N. (95) A compound according to any one of (1) to (87), wherein Ring B is: ,
Figure imgf000046_0001
. (96) A compound according to any one of (1) to (87), wherein: Y1, if present, is S; Y2, if present, is CH, CRY2, or N; Y3, if present, is N, CH, or CRY3; wherein exactly one of Y2 and Y3 is N; Y4, if present, is N; Y5, if present, is S; Y6, if present, is CH or CRY6; Y7, if present, is N; Y8, if present, is CH or CRY8; and Y9, if present, is S. (97) A compound according to any one of (1) to (87), wherein Ring B is: ,
Figure imgf000047_0001
, . (98) A compound according to any one of (1) to (87), wherein: Y1, if present, is S; Y2, if present, is CH, CRY2, or N; Y3, if present, is N, CH, or CRY3; and wherein exactly one of Y2 and Y3 is N. (99) A compound according to any one of (1) to (87), wherein Ring B is:
Figure imgf000047_0002
. (100) A compound according to any one of (1) to (87), wherein: Y1, if present, is S; Y2, if present, is CH or CRY2; Y3, if present, is N. (101) A compound according to any one of (1) to (87), wherein: Y1, if present, is S, or O; Y2, if present, is CH, or N; Y3, if present, is N. (102) A compound according to any one of (1) to (87), wherein Ring B is:
Figure imgf000047_0003
. The Groups -RY2, -RY3, etc. (103) A compound according to any one of (1) to (102), wherein: each -RY2, -RY3, -RY4, -RY6, -RY7, and -RY8, if present, is independently: -F, -Cl, -Br, -I, -RYY, -CF3, -OH, -ORYY, -OCF3, or -NH2. (104) A compound according to any one of (1) to (102), wherein: each -RY2, -RY3, -RY4, -RY6, -RY7, and -RY8, if present, is independently: -F, -Cl, -Br, -I, -RYY, or -NH2. (105) A compound according to any one of (1) to (102), wherein: each -RY2, -RY3, -RY4, -RY6, -RY7, and -RY8, if present, is independently: -F, -Cl, -RYY, or -NH2. (106) A compound according to any one of (1) to (102), wherein: each -RY2, -RY3, -RY4, -RY6, -RY7, and -RY8, if present, is independently: -F, -Cl, or -RYY. The Group -RYY (107) A compound according to any one of (1) to (106), wherein: each -RYY, if present, is: -Me, -Et, -nPr, -iPr, -nBu, or -tBu. (108) A compound according to any one of (1) to (106), wherein: each -RYY, if present, is: -Me, -Et, -nPr, or -iPr. (109) A compound according to any one of (1) to (106), wherein: each -RYY, if present, is: -Me or -Et. (110) A compound according to any one of (1) to (106), wherein: each -RYY, if present, is: -Me. The Groups -RY1, -RY5, and -RY9 (111) A compound according to any one of (1) to (110), wherein: each -RY1, -RY5, and -RY9, if present, is independently: -RYYN or -C(=O)RYYN. (112) A compound according to any one of (1) to (110), wherein: each -RY1, -RY5, and -RY9, if present, is independently: -RYYN. The Group -RYYN (113) A compound according to any one of (1) to (112), wherein: each -RYYN, if present, is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, phenyl, phenyl-C1-3alkyl, wherein each phenyl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2. (114) A compound according to any one of (1) to (112), wherein: each -RYYN, 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, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2. (115) A compound according to any one of (1) to (112), wherein: each -RYYN, if present, is independently linear or branched saturated C1-4alkyl, phenyl, or benzyl. (116) A compound according to any one of (1) to (112), wherein: each -RYYN, if present, is independently linear or branched saturated C1-4alkyl. (117) A compound according to any one of (1) to (98), wherein: each -RYYN, if present, is -Me. The Group -Q (118) A compound according to any one of (1) to (117), wherein: -Q is -Q1, -LQ1-Q1, -Q2, -LQ2-Q2, -Q3, -LQ3-Q3, -Q4, -LQ4-Q4, or -Q5 , (119) A compound according to any one of (1) to (116), wherein: -Q is -Q1, -Q3, -LQ3-Q3, -Q4, -Q5 , or -H. (120) A compound according to any one of (1) to (117), wherein: -Q is -Q1, -LQ1-Q1, -Q2, or -LQ2-Q2. (121) A compound according to any one of (1) to (117), wherein: -Q is -Q1 or -LQ2-Q2. (122) A compound according to any one of (1) to (117), wherein: -Q is -Q1. (123) A compound according to any one of (1) to (117), wherein: -Q is -LQ1-Q1. (124) A compound according to any one of (1) to (117), wherein: -Q is -Q2. (125) A compound according to any one of (1) to (117), wherein: -Q is -LQ2-Q2. (126) A compound according to any one of (1) to (117), wherein: -Q is -Q3. (127) A compound according to any one of (1) to (117), wherein: -Q is -LQ3-Q3. (128) A compound according to any one of (1) to (117), wherein: -Q is -Q4, (129) A compound according to any one of (1) to (117), wherein: -Q is -LQ4-Q4. (130) A compound according to any one of (1) to (117), wherein: -Q is -Q5. (131) A compound according to any one of (1) to (117), wherein: -Q is H. The Group -Q1 (132) A compound according to any one of (1) to (131), wherein: -Q1, if present, is C5-9heteroaryl; and is: optionally substituted on carbon with one or more groups -RQ1C; and optionally substituted on secondary nitrogen, if present, with a group -RQ1N. (133) A compound according to any one of (1) to (131), wherein: -Q1, if present, is C5-6heteroaryl; and is: optionally substituted on carbon with one or more groups -RQ1C; and optionally substituted on secondary nitrogen, if present, with a group -RQ1N. (134) A compound according to any one of (1) to (131), wherein: -Q1, if present, is C5heteroaryl, and is: optionally substituted on carbon with one or more groups -RQ1C; and optionally substituted on secondary nitrogen with a group -RQ1N. (135) A compound according to any one of (1) to (131), wherein: -Q1, if present, is pyrazolyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, or thiadiazolyl; and is: optionally substituted on carbon with one or more groups -RQ1C; and optionally substituted on secondary nitrogen, if present, with a group -RQ1N. (136) A compound according to any one of (1) to (131), wherein: -Q1, if present, is pyrazolyl, pyrrolyl, imidazolyl, furanyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, or thiadiazolyl; and is: optionally substituted on carbon with one or more groups -RQ1C; and optionally substituted on secondary nitrogen, if present, with a group -RQ1N. (137) A compound according to any one of (1) to (131), wherein: -Q1, if present, is pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, or thiadiazolyl; and is: optionally substituted on carbon with one or more groups -RQ1C; and optionally substituted on secondary nitrogen, if present, with a group -RQ1N. (138) A compound according to any one of (1) to (131), wherein: -Q1, if present, is pyrazolyl (e.g., 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1H-pyrazol-5-yl, or pyrazol-1-yl); and is: optionally substituted on carbon with one or more groups -RQ1C; and optionally substituted on secondary nitrogen, if present, with a group -RQ1N.
Figure imgf000050_0001
(139) A compound according to any one of (1) to (131), wherein -Q1, if present, is pyrazol-1-yl; and is optionally substituted on carbon with one or more groups -RQ1C. (140) A compound according to any one of (1) to (131), wherein -Q1, if present, is 1H-pyrazol-3-yl; and is: optionally substituted on carbon with one or more groups -RQ1C; and optionally substituted on secondary nitrogen with a group -RQ1N. (141) A compound according to any one of (1) to (131), wherein -Q1, if present, is 1H-pyrazol-4-yl; and is: optionally substituted on carbon with one or more groups -RQ1C; and optionally substituted on secondary nitrogen with a group -RQ1N. (142) A compound according to any one of (1) to (131), wherein -Q1, if present, is 1H-pyrazol-5-yl; and is: optionally substituted on carbon with one or more groups -RQ1C; and optionally substituted on secondary nitrogen with a group -RQ1N. (143) A compound according to any one of (1) to (131), wherein: -Q1, if present, is C9heteroaryl; and is: optionally substituted on carbon with one or more groups -RQ1C; and optionally substituted on secondary nitrogen, if present, with a group -RQ1N. (144) A compound according to any one of (1) to (131), wherein: -Q1, if present, is C9heteroaryl; wherein, the C9heteroaryl is a 5:6-fused heteroaryl; and is: optionally substituted on carbon with one or more groups -RQ1C; and optionally substituted on secondary nitrogen, if present, with a group -RQ1N. (145) A compound according to any one of (1) to (131), wherein: -Q1, if present, is indolyl, indazolyl, benzimidazolyl, benzoxazolyl, pyrazolo-pyridinyl, pyrazolo-pyrimidinyl, imidazo-pyridinyl, or pyrrolo-pyridinyl; and is: optionally substituted on carbon with one or more groups -RQ1C; and optionally substituted on secondary nitrogen, with a group -RQ1N. (146) A compound according to any one of (1) to (131), wherein: -Q1, if present, is indol-2-yl or indol-3-yl; and is: optionally substituted on carbon with one or more groups -RQ1C; and optionally substituted on secondary nitrogen, with a group -RQ1N.
Figure imgf000052_0001
(147) A compound according to tituted on s 1 any one of (1) to (131), wherein: -Q1, if present, is 2H-indazol-3-yl or 1H-indazol-3-yl; and is: optionally substituted on ca eHr c-b oino ndn do w al-r2it y-h nl one or mor itrogen, wit 1e hH g a-rino gdu roop uls-p3 --R -RlQ1C; and optionally subs Q1N.
Figure imgf000052_0002
(148) A compound according to any one of (1) to (131), wherein: -Q1, if present, is benzimida tionally substituted on ca-rnzol-2-yl; and is: op boanzo w-ith-y one or more g-ronupaszo -R-Q-1yCl; and optionally substituted on secondary nitrogen, with a group -RQ1N.
Figure imgf000052_0003
(149) A compound according to any one of (1) to (131), wherein: -Q1, if present, is benzoxazol-2-yl; and is: optionally substituted on carbon wit-he onnzem or mazoor-e- gyroups -RQ1C.
Figure imgf000052_0004
(150) A compound according to any one of (1) to (131), wherein: -Q1, if present, is pyrazolo[1,5-a]pyridin-2-yl o optionally substituted on carbon 1 w,ith- oennezo oxra mzr pyrazolo[1,5-a]pyridin-3-yl; and is: oo-re-y glroups -RQ1C. razo
Figure imgf000053_0001
(151) A compound accordloing to any one of (1) to (131), wherein: -Q1, if present, is 1H-p[1y,r5azolo[3,4-b]pyridin-3-yl, 1H-pyrazolo[3,4-c]pyridin-3-yl, 1H- pyrazolo[4,3-c]pyridin-3-yl, or 1H--ap]yrarizdoinlo-2[4-,3l-b]pyridin-3 rera-y gzl ro; and is: optionally substituted on carbon with one or mo oluop[1s,5 -R-aQ]1C;ri adnind optionally substituted on secondary nitrogen, with a group -RQ1N.
Figure imgf000053_0002
-3-l (152) 1 AH- cpoymrapzooulon[3d,4 a-cbc]ording 1H to any one of (1) to (131), wherein: -Q1 p,y irfid pirne-s3e-ynlt, is imidazo-[p p1yy,rr2aid-zaion]pl-o3y[-r3yi,dl4in-c-]2-yl o 1rH im- ppidyyarraizdzoion[1l-o3,[2-4y-,la3]-pcy]ridin- 13H-y-pl p; and is: optionally substituted on carbon with one or more groups -RQ1C.
Figure imgf000053_0003
(153) A compound according to any one of (1) to (131), wherein: -Q1, if presen y su yrraidzionl-o3[-4y,l3-b] 1bitHm, i s-tips idtuya 1rtrzH eoo- dl[op1y o[,3n2r,r-2o ca-l a]bop[ r]bpy3royi,dr2 niid-nb wi-n]2p i-t-2y hy-rlidin-2-yl o oylne or m 1oH ir rm 1 eidH ga-p rozuoy p[r1rolo[3,2-b]pyridin-3-yl; and is: optionally s,2 --RaQ]p1Cy;ri adnind optionally substituted on secondary nitrogen, with a group -RQ1N.
Figure imgf000053_0004
(154) A compound according to any one of (1) to (131)-,p wyrhroelroe[i3n,: -Q1, if present, is 1H-pyrrolo[3,2-c]pyridin-2-yl or 1H-pyrrolo2[-3b,]2py-cri]dpiyn-3r-i3-dy-ilynl-3-yl; and is: optionally substituted on carbon with one or more groups -RQ1C; and optionally substituted on secondary nitrogen, with a group -RQ1N.
Figure imgf000054_0001
(155) A compound ac-pcyorrrding to any one of (1) to (131), wherein: -Q1, if present, is 1H-pyrrolo[2,3-c]pyridin-2-yl or 1H-pyrrolo[2,3-c]pyridin-3-yl; and is: optionally substituteodo on, c-acrpbyorn wni-th-y one or more itrogen, with-p g ayrro grou roops up, -R -R-Qc1pC;y.
Figure imgf000054_0002
(156) A compound according to any one of (1) to (131), wherein: -Q1, if present, is pyrazolo[1,5-c]pyrimidin-2-yl, pyrazolor and optionally substituted on secondary n Q1Nn--y Q1 is C5-10het 1eHro-payrryrlo;lo[2,3-cp]ypryimrididinin-2-3-y[1,5-c]pyrimidin-3-yl, pyrazolo[1,5- a]pyrimidin-2-yl, or pyrazolo[1,5-a] -lyl; and is: optionally substituted on carbon with one or m 1oHr-ep gyrrrooulop[s2, -3R-cQ]1pCy.
Figure imgf000054_0003
(157) A compound according to any one of (1) to (131), wherein:ridin-3-yl and is: optionally substituted on secondary nitrogen, if present, with one or more groups -RQ1N. (158) A compound according to any one of (1) to (131), wherein: Q1 is pyrazolyl, pyrazolo[1,5-a]pyridinyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl; and is: optionally substituted on secondary nitrogen, if present, with one or more groups -RQ1N. The Group -LQ1- (159) A compound according to any one of (1) to (158), wherein: -LQ1-, if present, is -CH2-, -C(CH3)2-, -CH2CH2-, or -CH2CH2CH2-. (160) A compound according to any one of (1) to (158), wherein: -LQ1-, if present, is -CH2-, -CH2CH2-, or -CH2CH2CH2-. (161) A compound according to any one of (1) to (158), wherein: -LQ1-, if present, is -CH2-. (162) A compound according to any one of (1) to (158), wherein: -LQ1-, if present, is -CH2CH2-. (163) A compound according to any one of (1) to (158), wherein: -LQ1-, if present, is -CH2CH2CH2-. The Group -Q2 (164) A compound according to any one of (1) to (163), wherein: -Q2, if present, is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azepanyl, or diazepanyl; and is: optionally substituted on sulfur, if present, with one or two groups =O; optionally substituted on carbon with one or more groups -RQ2C; and optionally substituted on secondary nitrogen, if present, with one or more groups -RQ2N. (165) A compound according to any one of (1) to (163), wherein: -Q2, if present, is pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl; and is: optionally substituted on sulfur, if present, with one or two groups =O; optionally substituted on carbon with one or more groups -RQ2C; and optionally substituted on secondary nitrogen, if present, with a group -RQ2N. (166) A compound according to any one of (1) to (163), wherein: -Q2, if present, is piperidinyl or piperazinyl; and is: optionally substituted on carbon with one or more groups -RQ2C; and optionally substituted on secondary nitrogen, if present, with a group -RQ2N. (167) A compound according to any one of (1) to (163), wherein: -Q2, if present, is piperidinyl (e.g., piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl); and is: optionally substituted on carbon with one or more groups -RQ2C; and optionally substituted on secondary nitrogen, if present, with a group -RQ2N.
Figure imgf000056_0001
(168) A coimeprioduinn-e1d n- a s t,lccording to tituted on c is piperazii an arey broid o ninn w-e2it- of hl (1) to (163) one or mori, ee w grh rioderein: -Q2, if present, is piperid d ( iiin-4-yl; an s: optionaellryid sinuob) uinp-s3- -Rl tituted on c p Q2C; and optionally substituted on secondary nitrogen, with a group -RQ2N. (169) A compound according to any one of (1) to (163), wherein: -Q2, if pres n ieridin-4-l aiypl (e.g., piperazin-1-yl, piperazin-2-yl); and is: optionally substituted on carbon with one or more groups -RQ2C; and optionally substituted on secondary nitrogen with a group -RQ2N.
Figure imgf000056_0002
(170) A compound according to an rbey ora o nzni wne-i1 o th-fy ( ol1) to (163), wherein: -Q2, if present, is piperazin- is: optionally subs (p1ip-yel; and razino)ne or mor peip gerorauzpisn- -2R-yQl2C; and optionally substituted on secondary nitrogen with a group -RQ2N. The Group -LQ2- (171) A compound according to any one of (1) to (170), wherein: -LQ2-, if present, is -CH2-, -C(CH3)2-, -CH2CH2-, or -CH2CH2CH2-. (172) A compound according to any one of (1) to (170), wherein: -LQ2-, if present, is -CH2-, -CH2CH2-, or -CH2CH2CH2-. (173) A compound according to any one of (1) to (170), wherein: -LQ2-, if present, is -CH2-. (174) A compound according to any one of (1) to (170), wherein: -LQ2-, if present, is -CH2CH2-. (175) A compound according to any one of (1) to (170), wherein: -LQ2-, if present, is -CH2CH2CH2-. The Group -Q3 (176) A compound according to any one of (1) to (175), wherein: -Q3, if present, is phenyl; and is optionally substituted with one or more groups -RQ3C. (177) A compound according to any one of (1) to (175), wherein: -Q3, if present, is naphthyl; and is optionally substituted with one or more groups -RQ3C. The Group -LQ3- (178) A compound according to any one of (1) to (177), wherein: -LQ3-, if present, is -CH2-, -C(CH3)2-, -CH2CH2-, or -CH2CH2CH2-. (179) A compound according to any one of (1) to (177), wherein: -LQ3-, if present, is -CH2-, -CH2CH2-, or -CH2CH2CH2-. (180) A compound according to any one of (1) to (177), wherein: -LQ3-, if present, is -CH2-. (181) A compound according to any one of (1) to (177), wherein: -LQ3-, if present, is -CH2CH2-. (182) A compound according to any one of (1) to (177), wherein: -LQ3-, if present, is -CH2CH2CH2-. The Group -Q4 (183) A compound according to any one of (1) to (182), wherein: -Q4, if present, is Q4 is C3-7cycloalkyl. (184) A compound according to any one of (1) to (182), wherein: -Q4, if present, is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; and is optionally substituted with one or more groups -RQ4C. (185) A compound according to any one of (1) to (182), wherein: -Q4, if present, is cyclopropyl; and is optionally substituted with one or more groups -RQ4C. (186) A compound according to any one of (1) to (182), wherein: -Q4, if present, is cyclopropyl. (187) A compound according to any one of (1) to (182), wherein: -Q4, if present, is cyclobutyl; and is optionally substituted with one or more groups -RQ4C. (188) A compound according to any one of (1) to (182), wherein: -Q4, if present, is cyclopentyl; and is optionally substituted with one or more groups -RQ4C. (189) A compound according to any one of (1) to (182), wherein: -Q4, if present, is cyclohexyl; and is optionally substituted with one or more groups -RQ4C. The Group -LQ4- (190) A compound according to any one of (1) to (189), wherein: -LQ4-, if present, is -CH2-, -C(CH3)2-, -CH2CH2-, or -CH2CH2CH2-. (191) A compound according to any one of (1) to (189), wherein: -LQ4-, if present, is -CH2-, -CH2CH2-, or -CH2CH2CH2-. (192) A compound according to any one of (1) to (189), wherein: -LQ4-, if present, is -CH2-. (193) A compound according to any one of (1) to (189), wherein: -LQ4-, if present, is -CH2CH2-. (194) A compound according to any one of (1) to (187189), wherein: -LQ4-, if present, is -CH2CH2CH2-. The Group -Q5 (195) A compound according to any one of (1) to (194), wherein: -Q5, if present, is -Me, -Et, -nPr, -iPr, -nBu, -iBu, -sBu, -tBu, n-pentyl, iso-pentyl, neo-pentyl, n-hexyl, iso-hexyl, or 3,3-dimethylbutyl; and is optionally substituted with one or more groups -RQ5C. (196) A compound according to any one of (1) to (194), wherein: -Q5, if present, is linear or branched saturated C1-4alkyl; and is optionally substituted with one or more groups -RQ5C. (197) A compound according to any one of (1) to (194), wherein: -Q5, if present, is -Me, -Et, or -nPr; and is optionally substituted with one or more groups -RQ5C. (198) A compound according to any one of (1) to (194), wherein: -Q5, if present, is -Me, or -Et. (199) A compound according to any one of (1) to (194), wherein: -Q5, if present, is -CH2-RQ5C, -CH2CH2-RQ5C, or -CH2CH2CH2-RQ5C. (200) A compound according to any one of (1) to (194), wherein: -Q5, if present, is -CH2-RQ5C. (201) A compound according to any one of (1) to (194), wherein: -Q5, if present, is -CH2CH2-RQ5C. (202) A compound according to any one of (1) to (194), wherein: -Q5, if present, is -CH2CH2CH2-RQ5C. The Group -RQ1C (203) A compound according to any one of (1) to (202), wherein: each -RQ1C, if present, is independently: -F, -Cl, -Br, -I, -RQ1CC, -RQ1CX, -ORQ1CX, -OH, -ORQ1CC, -LQ1C-OH, -LQ1C-ORQ1CC, -NH2, -NHRQ1CC, -NRQ1CC2, -RQ1CM, -LQ1C-NH2, -LQ1C-NHRQ1CC, -LQ1C-NRQ1CC2, -LQ1C-RQ1CM, -C(=O)NH2, -C(=O)NHRQ1CC, -C(=O)NRQ1CC2, -C(=O)RQ1CM, -C(=O)OH, or -C(=O)ORQ1CC, -S(=O)2RQ1CC, or -CN; and two adjacent -RQ1C, if present, taken together may form -(CH2)n1-O-(CH2)m1- or -O-(CH2)p1-O-. (204) A compound according to any one of (1) to (202), wherein: each -RQ1C, if present, is independently: -F, -Cl, -Br, -I, -RQ1CC, -RQ1CX, -ORQ1CX, -OH, -ORQ1CC, -NH2, -NHRQ1CC, -NRQ1CC 2, -RQ1CM, -C(=O)NH2, -C(=O)NHRQ1CC, -C(=O)NRQ1CC 2, -C(=O)RQ1CM, -C(=O)OH, or -C(=O)ORQ1CC. (205) A compound according to any one of (1) to (202), wherein: each -RQ1C, if present, is independently: -RQ1CC, -RQ1CX, -NH2, -NHRQ1CC, -NRQ1CC2, -RQ1CM, -C(=O)NH2, -C(=O)NHRQ1CC, -C(=O)NRQ1CC2, -C(=O)RQ1CM, -C(=O)OH, or -C(=O)ORQ1CC. (206) A compound according to any one of (1) to (202), wherein: each -RQ1C, if present, is independently: -RQ1CC, -RQ1CX, or -C(=O)ORQ1CC. (207) A compound according to any one of (1) to (202), wherein: each -RQ1C, if present, is: -RQ1CC. (208) A compound according to any one of (1) to (202), wherein: each -RQ1C, if present, is independently: -F, -Cl, -Br, -RQ1CC, -RQ1CX, -OH, -ORQ1CC, -NH2, -NRQ1CC2, -RQ1CM, -C(=O)RQ1CM, -LQ1C-C(=O)N(RQ1CC)ORQ1CC, -LQ1C-C(=O)NHRQ1CC, -LQ1C-C(=O)NRQ1CC2, -LQ1C-C(=O)RQ1CM, -C(=O)OH, -C(=O)ORQ1CC, -LQ1C-C(=O)ORQ1CC, -S(=O)2RQ1CC, -CN. (209) A compound according to any one of (1) to (202), wherein: each -RQ1C, if present, is independently: -LQ1C-C(=O)NRQ1CC 2, or -LQ1C-C(=O)RQ1CM. (210) A compound according to any one of (1) to (202), wherein: each -RQ1C, if present, is independently: -LQ1C-C(=O)NRQ1CC 2. (211) A compound according to any one of (1) to (202), wherein: each -RQ1C, if present, is independently: LQ1C-C(=O)RQ1CM. The Group -RQ1CC (212) A compound according to any one of (1) to (211), wherein: each -RQ1CC, if present, is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, phenyl, phenyl-C1-3alkyl, wherein each phenyl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2. (213) A compound according to any one of (1) to (211), wherein: each -RQ1CC, if present, is independently linear or branched saturated C1-4alkyl, phenyl, or phenyl-CH2-, wherein each phenyl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2. (214) A compound according to any one of (1) to (211), wherein: each -RQ1CC, if present, is independently linear or branched saturated C1-4alkyl, phenyl, or benzyl. (215) A compound according to any one of (1) to (211), wherein: each -RQ1CC, if present, is independently linear or branched saturated C1-4alkyl. (216) A compound according to any one of (1) to (211), wherein: each -RQ1CC, if present, is independently -Me, -Et, -nPr, -iPr, -nBu, or -tBu. (217) A compound according to any one of (1) to (211), wherein: each -RQ1CC, if present, is independently -Me, -Et, -nPr, or -iPr. (218) A compound according to any one of (1) to (211), wherein: each -RQ1CC, if present, is independently -Me or -Et. (219) A compound according to any one of (1) to (211), wherein: each -RQ1CC, if present, is -Me. (220) A compound according to any one of (1) to (211), wherein: each -RQ1CC, if present, is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-7heterocyclyl, phenyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl is optionally substituted with -N(CH3)2, or -C≡N, and each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -CH3, and -CH2OCH3. (221) A compound according to any one of (1) to (211), wherein: each -RQ1CC, if present, is independently linear or branched saturated -Me, -Et, i-Pr, -t-Bu, cyclopropyl, cyclobutyl, oxetanyl, phenyl, pyrazolyl, pyridyl, thiazolyl, or oxazolylmethyl, wherein -Me, -Et, i-Pr, or -t-Bu is optionally substituted with -N(CH3)2, or -C≡N, and each phenyl cyclopropyl, cyclobutyl, oxetanyl, phenyl, pyrazolyl, pyridyl, thiazolyl, and oxazolyl is optionally substituted with one or more groups selected from: -F, -CH3, and -CH2OCH3. (222) A compound according to any one of (1) to (211), wherein: each -RQ1CC, if present, is cyclopropyl or oxetanyl, wherein each cyclopropyl or oxetanyl is optionally substituted with one or more groups selected from: -F, -CH3, and -CH2OCH3. The Indices “n1” and “m1” in -(CH2)n1-O-(CH2)m1- (223) A compound according to any one of (1) to (222), wherein: n1, if present, is 0, 1, 2, or 3; m1, if present, is 0, 1, 2, or 3; with the proviso that m1+n1 is 2 or 3. (224) A compound according to any one of (1) to (222), wherein: n1, if present, is 0, 1, or 2; m1, if present, is 0, 1, or 2; with the proviso that m1+n1 is 2 or 3. (225) A compound according to any one of (1) to (222), wherein: n1, if present, is 1 or 2; m1, if present, is 1 or 2; with the proviso that m1+n1 is 2 or 3. The Index “p1” in -O-(CH2)p1-O- (226) A compound according to any one of (1) to (225), wherein: p1, if present, is 1. (227) A compound according to any one of (1) to (225), wherein: p1, if present, is 2. The Group -RQ1CX (228) A compound according to any one of (1) to (227), wherein: each -RQ1CX, if present, is independently linear or branched saturated C1-4fluoroalkyl. (229) A compound according to any one of (1) to (227), wherein: each -RQ1CX, if present, is independently -CF3, -CHF2, -CH2CF3, or -CH2CHF2. (230) A compound according to any one of (1) to (227), wherein: each -RQ1CX, if present, is -CF3. (231) A compound according to any one of (1) to (227), wherein: each -RQ1CX is independently -CF3, or -CH2CHF2. The Group -LQ1C- (232) A compound according to any one of (1) to (231), wherein: each -LQ1C-, if present, is independently -CH2-, -C(CH3)2-, -CH2CH2-, or -CH2CH2CH2-. (233) A compound according to any one of (1) to (231), wherein: each -LQ1C-, if present, is independently -CH2-, -CH2CH2-, or -CH2CH2CH2-. (234) A compound according to any one of (1) to (231), wherein: each -LQ1C-, if present, is -CH2-. (235) A compound according to any one of (1) to (231), wherein: each -LQ1C-, if present, is -CH2CH2-. (236) A compound according to any one of (1) to (231), wherein: each -LQ1C-, if present, is -CH2CH2CH2-. The Group -RQ1CM (237) A compound according to any one of (1) to (236), wherein: each -RQ1CM, if present, is independently non-aromatic C3-11heterocyclyl having at least one N ring atom, and is attached via that N ring atom; and is: optionally substituted on carbon with one or more groups -RQ1CMM; optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ1CMM. (238) A compound according to any one of (1) to (236), wherein: each -RQ1CM, if present, is independently pyrrolidinyl, morpholinyl, azetidinyl, 1,1- dioxythiomorpholinyl, piperidinyl, 2-oxa-5-azabicyclo[4.1.0]heptanyl, 4,7-diazaspiro[2.5]octanyl, or piperazinyl, having at least one N ring atom, and is attached via that N ring atom; and is: optionally substituted on carbon with one or more groups -RQ1CMM; optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ1CMM. (239) A compound according to any one of (1) to (236), wherein: each -RQ1CM, if present, is independently azetidino, pyrrolidino, piperidino, piperazino, morpholino, thiomorpholino, azepano, or diazepano, and is: optionally substituted on carbon with one or more groups -RQ1CMM; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ1CMM, -C(=O)RQ1CMM, -C(=O)ORQ1CMM, -C(=O)NH2, -C(=O)NHRQ1CMM, -C(=O)NRQ1CMM2, and -S(=O)2RQ1CMM. (240) A compound according to any one of (1) to (236), wherein: each -RQ1CM, if present, is independently pyrrolidino, piperidino, piperazino, or morpholino, and is: optionally substituted on carbon with one or more groups -RQ1CMM; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ1CMM, -C(=O)RQ1CMM, -C(=O)ORQ1CMM, -C(=O)NH2, -C(=O)NHRQ1CMM, -C(=O)NRQ1CMM2, and -S(=O)2RQ1CMM. (241) A compound according to any one of (1) to (236), wherein: each -RQ1CM, if present, is independently pyrrolidino, piperidino, piperazino, or morpholino, and is: optionally substituted on carbon with one or more groups -RQ1CMM; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ1CMM, -C(=O)RQ1CMM, and -C(=O)ORQ1CMM. The Group -RQ1CMM (242) A compound according to any one of (1) to (241), wherein: each -RQ1CMM, if present, is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, phenyl, or phenyl-C1-3alkyl, wherein C1-4alkyl is optionally substituted with -OH or -OCH3, and each cycloalkyl or phenyl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2. (243) A compound according to any one of (1) to (241), wherein: each -RQ1CMM, if present, is independently linear or branched saturated C1-4alkyl, or phenyl-C1-3alkyl, wherein C1-4alkyl is optionally substituted with -OH or -OCH3, and each cycloalkyl and phenyl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2; (244) A compound according to any one of (1) to (241), wherein: each -RQ1CMM, if present, is independently linear or branched saturated C1-4alkyl, phenyl, or phenyl-CH2-, wherein C1-4alkyl is optionally substituted with -OH or -OCH3. (245) A compound according to any one of (1) to (241), wherein: each -RQ1CMM, if present, is independently linear or branched saturated C1-4alkyl, phenyl, or benzyl. (246) A compound according to any one of (1) to (241), wherein: each -RQ1CMM, if present, is independently linear or branched saturated C1-4alkyl, and is optionally substituted with -OH or -OCH3. (247) A compound according to any one of (1) to (241), wherein: each -RQ1CMM, if present, is independently linear or branched saturated C1-4alkyl. (248) A compound according to any one of (1) to (241), wherein: each -RQ1CMM, if present, is independently -Me, -Et, -nPr, -iPr, -nBu, or -tBu. (249) A compound according to any one of (1) to (241), wherein: each -RQ1CMM, if present, is independently -Me, -Et, -nPr, or -iPr. (250) A compound according to any one of (1) to (241), wherein: each -RQ1CMM, if present, is independently -Me or -Et. (251) A compound according to any one of (1) to (235), wherein: each -RQ1CMM, if present, is -Me. (252) A compound according to any one of (1) to (241), wherein: each -RQ1CMM, if present, is independently -F, or linear or branched saturated C1-4alkyl. (253) A compound according to any one of (1) to (241), wherein: each -RQ1CMM, if present, is independently -F, or -Me. The Group -RQ1N (254) A compound according to any one of (1) to (253), wherein: each -RQ1N, if present, is independently: -RQ1NC, -RQ1NX, -RQ1Nhet, -LQ1N-RQ1Nhet, -LQ1N-OH, -LQ1N-ORQ1NC, -LQ1N-C(=O)OH, -LQ1N-C(=O)ORQ1NC, -LQ1N-C(=O)NH2, -LQ1N-C(=O)NHRQ1NK, -LQ1N-C(=O)NRQ1NC2, -LQ1N-C(=O)RQ1NP, -LQ1N-NH2, -LQ1N-NHRQ1NC, -LQ1N-NRQ1NC2, -LQ1N-RQ1NM, -LQ1N-NHC(=O)ORQ1NC. (255) A compound according to any one of (1) to (253), wherein: each -RQ1N, if present, is independently: -RQ1NC, -LQ1N-C(=O)NRQ1NC2, or -LQ1N-C(=O)RQ1NP. (256) A compound according to any one of (1) to (253), wherein: each -RQ1N, if present, is independently: -RQ1Nhet or -LQ1N-RQ1Nhet. (257) A compound according to any one of (1) to (253), wherein: each -RQ1N, if present, is: -RQ1Nhet. (258) A compound according to any one of (1) to (253), wherein: each -RQ1N, if present, is: -LQ1N-C(=O)NH2, -LQ1N-C(=O)NHRQ1NK, -LQ1N-C(=O)NRQ1NC2, or -LQ1N-C(=O)RQ1NP. (259) A compound according to any one of (1) to (253), wherein: each -RQ1N, if present, is: -LQ1N-C(=O)NHRQ1NK, -LQ1N-C(=O)NRQ1NC2, or -LQ1N-C(=O)RQ1NP. (260) A compound according to any one of (1) to (253), wherein: each -RQ1N, if present, is: -LQ1N-C(=O)NHRQ1NK. (261) A compound according to any one of (1) to (253), wherein: each -RQ1N, if present, is: -LQ1N-C(=O)RQ1NP. (262) A compound according to any one of (1) to (253), wherein: each -RQ1N, if present, is independently: -RQ1NC. (263) A compound according to any one of (1) to (253), wherein: each -RQ1N, if present, is independently: -LQ1N-OH or -LQ1N-ORQ1NC. (264) A compound according to any one of (1) to (253), wherein: each -RQ1N, if present, is independently: -LQ1N-NH2, -LQ1N-NHRQ1NC, -LQ1N-NRQ1NC 2, or -LQ1N-RQ1NM. (265) A compound according to any one of (1) to (253), wherein: each -RQ1N, if present, is independently: -RQ1NC, -RQ1NX, -RQ1Nhet, -LQ1N-OH, -LQ1N-ORQ1NC, -LQ1N-C(=O)RQ1NC, -LQ1N-C(=O)OH, -LQ1N-C(=O)N(RQ1NC)ORQ1NC, -LQ1N-C(=O)NH2, -LQ1N-C(=O)NHRQ1NK, -LQ1N-C(=O)NRQ1NC2, -LQ1N-C(=O)RQ1NP, -LQ1N-NRQ1NC2, -LQ1N-RQ1NM, -LQ1N-C≡N, or -S(=O)2RQ1NC, -LQ1N-S(=O)2RQ1NC. The Group -RQ1NC (266) A compound according to any one of (1) to (265), wherein: each -RQ1NC, if present, is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-7heterocyclyl, or C5-6heteroaryl, , wherein each C1-4alkyl is optionally substituted by MeS(O)2-, wherein each cycloalkyl, and heteroaryl is optionally substituted with one or more groups selected from: -CH3. (267) A compound according to any one of (1) to (265), wherein: each -RQ1NC, if present, is independently -Me, Et, i-Pr, cyclopropyl, cyclohexyl, cyclobutyl, piperidinyl, tetrahydropyranyl, or pyrazolyl, wherein each -Me, Et or i-Pr is optionally substituted by MeS(O)2-, wherein each cyclopropyl, cyclohexyl, cyclobutyl, and pyrazolyl is optionally substituted with one or more groups selected from: -CH3. (268) A compound according to any one of (1) to (265), wherein: each -RQ1NC, if present, is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, phenyl, phenyl-C1-3alkyl, wherein each phenyl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2. (269) A compound according to any one of (1) to (265), wherein: each -RQ1NC, if present, is independently linear or branched saturated C1-4alkyl, phenyl, or phenyl-CH2-, wherein each phenyl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2. (270) A compound according to any one of (1) to (265), wherein: each -RQ1NC, if present, is independently linear or branched saturated C1-4alkyl, phenyl, or benzyl. (271) A compound according to any one of (1) to (265), wherein: each -RQ1NC, if present, is independently linear or branched saturated C1-4alkyl. (272) A compound according to any one of (1) to (265), wherein: each -RQ1NC, if present, is independently -Me, -Et, -nPr, -iPr, -nBu, or -tBu. (273) A compound according to any one of (1) to (265), wherein: each -RQ1NC, if present, is independently -Me, -Et, -nPr, or -iPr. (274) A compound according to any one of (1) to (265), wherein: each -RQ1NC, if present, is independently -Me or -Et. (275) A compound according to any one of (1) to (265), wherein: each -RQ1NC, if present, is -Me. The Group -RQ1NX (276) A compound according to any one of (1) to (275), wherein: each -RQ1NX, if present, is independently linear or branched saturated C1-4fluoroalkyl. (277) A compound according to any one of (1) to (275), wherein: each -RQ1NX, if present, is independently -CF3, -CHF2, -CH2CF3, or -CH2CHF2. (278) A compound according to any one of (1) to (275), wherein: each -RQ1NX, if present, is independently -CH2CF3, or -CH2CH2F. (279) A compound according to any one of (1) to (275), wherein: each -RQ1NX, if present, is -CHF2. The Group -LQ1N- (280) A compound according to any one of (1) to (279), wherein: each -LQ1N-, if present, is independently -CH2-, -CH2CH2-, -CH(CH3)-, -CH2C(CH3)2-, or -CH2CH(CH3)-, optionally substituted by -F or -OCH3. (281) A compound according to any one of (1) to (279), wherein: each -LQ1N-, if present, is independently -CH2-, -C(CH3)2-, -CH2CH2-, or -CH2CH2CH2-. (282) A compound according to any one of (1) to (279), wherein: each -LQ1N-, if present, is independently -CH2-, -CH2CH2-, or -CH2CH2CH2-. (283) A compound according to any one of (1) to (279), wherein: each -LQ1N-, if present, is -CH2-. (284) A compound according to any one of (1) to (279), wherein: each -LQ1N-, if present, is -CH2CH2-. (285) A compound according to any one of (1) to (279), wherein: each -LQ1N-, if present, is -CH2CH2CH2-. The Group -RQ1NM (286) A compound according to any one of (1) to (285), wherein: each -RQ1NM, if present, is independently non-aromatic C3-7heterocyclyl having at least one N ring atom, and is attached via that N ring atom. (287) A compound according to any one of (1) to (285), wherein: each -RQ1NM, if present, is independently non-aromatic piperazinyl is attached via an N ring atom. (288) A compound according to any one of (1) to (285), wherein: each -RQ1NM, if present, is independently azetidino, pyrrolidino, piperidino, piperazino, morpholino, thiomorpholino, azepano, or diazepano, and is: optionally substituted on carbon with one or more groups -RQ1NMM; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ1NMM, -C(=O)RQ1NMM, -C(=O)ORQ1NMM, -C(=O)NH2, -C(=O)NHRQ1NMM, -C(=O)NRQ1NMM2, and -S(=O)2RQ1NMM. (289) A compound according to any one of (1) to (285), wherein: each -RQ1NM, if present, is independently pyrrolidino, piperidino, piperazino, or morpholino, and is: optionally substituted on carbon with one or more groups -RQ1NMM; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ1NMM, -C(=O)RQ1NMM, -C(=O)ORQ1NMM, -C(=O)NH2, -C(=O)NHRQ1NMM, -C(=O)NRQ1NMM2, and -S(=O)2RQ1NMM. (290) A compound according to any one of (1) to (285), wherein: each -RQ1NM, if present, is independently pyrrolidino, piperidino, piperazino, or morpholino, and is: optionally substituted on carbon with one or more groups -RQ1NMM; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ1NMM, -C(=O)RQ1NMM, and -C(=O)ORQ1NMM. The Group -RQ1NMM (291) A compound according to any one of (1) to (290), wherein: each -RQ1NMM, if present, is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, phenyl, phenyl-C1-3alkyl, wherein each phenyl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2. (292) A compound according to any one of (1) to (290), wherein: each -RQ1NMM, 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, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2. (293) A compound according to any one of (1) to (290), wherein: each -RQ1NMM, if present, is independently linear or branched saturated C1-4alkyl, phenyl, or benzyl. (294) A compound according to any one of (1) to (290), wherein: each -RQ1NMM, if present, is independently linear or branched saturated C1-4alkyl. (295) A compound according to any one of (1) to (290), wherein: each -RQ1NMM, if present, is -Me. The Group -RQ1Nhet (296) A compound according to any one of (1) to (295), wherein: each -RQ1Nhet, if present, is independently non-aromatic C3-7heterocyclyl; and is: optionally substituted on carbon with one or more groups =O; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ1NHH, -C(=O)RQ1NJJ, -C(=O)ORQ1NHH, -C(=O)NHRQ1NHH. (297) A compound according to any one of (1) to (295), wherein: each -RQ1Nhet, if present, is independently tetrahydropyranyl, pyrrolidinyl, or tetrahydrofuranyl; and is: optionally substituted on carbon with one or more groups =O; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ1NHH, -C(=O)RQ1NJJ, -C(=O)ORQ1NHH, -C(=O)NHRQ1NHH. (298) A compound according to any one of (1) to (295), wherein: each -RQ1Nhet, if present, is independently azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, azepanyl, or diazepanyl; and is: optionally substituted on sulfur, if present, with one or two groups =O; optionally substituted on carbon with one or more groups -RQ1NHH or =O; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ1NHH, -C(=O)RQ1NJJ, -C(=O)ORQ1NHH, -C(=O)NH2, -C(=O)NHRQ1NHH, -C(=O)NRQ1NHH2, and -S(=O)2RQ1NHH. (299) A compound according to any one of (1) to (295), wherein: each -RQ1Nhet, if present, is independently oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, or morpholinyl; and is: optionally substituted on carbon with one or more groups -RQ1NHH or =O; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ1NHH, -C(=O)RQ1NJJ, -C(=O)ORQ1NHH, -C(=O)NH2, -C(=O)NHRQ1NHH, -C(=O)NRQ1NHH2, and -S(=O)2RQ1NHH. (300) A compound according to any one of (1) to (295), wherein: each -RQ1Nhet, if present, is independently pyrrolidinyl, piperidinyl, or piperazinyl; and is: optionally substituted on carbon with one or more groups -RQ1NHH or =O; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ1NHH, -C(=O)RQ1NJJ, -C(=O)ORQ1NHH, -C(=O)NH2, -C(=O)NHRQ1NHH, -C(=O)NRQ1NHH 2, and -S(=O)2RQ1NHH. (301) A compound according to any one of (1) to (295), wherein: each -RQ1Nhet, if present, is independently pyrrolidinyl or piperidinyl; and is: optionally substituted on carbon with one or more groups -RQ1NHH or =O; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ1NHH, -C(=O)RQ1NJJ, -C(=O)ORQ1NHH, -C(=O)NH2, -C(=O)NHRQ1NHH, -C(=O)NRQ1NHH 2, and -S(=O)2RQ1NHH. (302) A compound according to any one of (1) to (295), wherein: each -RQ1Nhet, if present, is pyrrolidinyl; and is: optionally substituted on carbon with one or more groups -RQ1NHH or =O; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ1NHH, -C(=O)RQ1NJJ, -C(=O)ORQ1NHH, -C(=O)NH2, -C(=O)NHRQ1NHH, -C(=O)NRQ1NHH2, and -S(=O)2RQ1NHH. The Group -RQ1NHH (303) A compound according to any one of (1) to (302), wherein: each -RQ1NHH, if present, is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, phenyl, phenyl-C1-3alkyl, wherein each phenyl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2. (304) A compound according to any one of (1) to (302), wherein: each -RQ1NHH, 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, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2. (305) A compound according to any one of (1) to (302), wherein: each -RQ1NHH, if present, is independently linear or branched saturated C1-4alkyl, phenyl, or benzyl. (306) A compound according to any one of (1) to (302), wherein: each -RQ1NHH, if present, is independently linear or branched saturated C1-4alkyl. (307) A compound according to any one of (1) to (302), wherein: each -RQ1NHH, if present, is independently -Me, -Et, -nPr, -iPr, -nBu, or -tBu. (308) A compound according to any one of (1) to (302), wherein: each -RQ1NHH, if present, is independently -Me, -Et, -iPr, or -tBu. (309) A compound according to any one of (1) to (302), wherein: each -RQ1NHH, if present, is independently -Me, -Et, -nPr, or -iPr. (310) A compound according to any one of (1) to (302), wherein: each -RQ1NHH, if present, is independently -Me or -Et. (311) A compound according to any one of (1) to (302), wherein: each -RQ1NHH, if present, is -Me. The Group -RQ1NJJ (312) A compound according to any one of (1) to (311), wherein: -RQ1NJJ, if present, is -RJ1, -LJ-RJ2, -LJ-RJ3, -LJ-RJ4, or -LJ-RJ5. (313) A compound according to any one of (1) to (311), wherein: -RQ1NJJ, if present, is -RJ1, -LJ-RJ3, -LJ-RJ4, or -LJ-RJ5. (314) A compound according to any one of (1) to (311), wherein: -RQ1NJJ, if present, is -RJ1, -LJ-RJ4, or -LJ-RJ5. (315) A compound according to any one of (1) to (311), wherein: -RQ1NJJ, if present, is -RJ1 or -LJ-RJ4. (316) A compound according to any one of (1) to (311), wherein: -RQ1NJJ, if present, is -LJ-RJ2, -LJ-RJ3, -LJ-RJ4, or -LJ-RJ5. (317) A compound according to any one of (1) to (311), wherein: -RQ1NJJ, if present, is -LJ-RJ3, -LJ-RJ4, or -LJ-RJ5. (318) A compound according to any one of (1) to (311), wherein: -RQ1NJJ, if present, is -LJ-RJ4 or -LJ-RJ5. (319) A compound according to any one of (1) to (311), wherein: -RQ1NJJ, if present, is -LJ-RJ4. (320) A compound according to any one of (1) to (311), wherein: -RQ1NJJ, if present, is -RQ1NJJ is -RJ1. The Group -RJ1 (321) A compound according to any one of (1) to (320), wherein: -RJ1, if present, is linear or branched saturated C1-6alkyl; and is optionally substituted with one or more groups selected from: -F, -OH, -ORJJ, -O-phenyl, -C(=O)OH, -C(=O)ORJJ, -NH2, -NHRJJ, and -NRJJ2. (322) A compound according to any one of (1) to (320), wherein: -RJ1, if present, is linear or branched saturated C1-4alkyl; and is optionally substituted with one or more groups selected from: -F, -OH, -ORJJ, -O-phenyl, -C(=O)OH, -C(=O)ORJJ, -NH2, -NHRJJ, and -NRJJ2. (323) A compound according to any one of (1) to (320), wherein: -RJ1, if present, is linear or branched saturated C1-4alkyl; and is optionally substituted with one or more groups selected from: -F, -OH, or -ORJJ. (324) A compound according to any one of (1) to (320), wherein: -RJ1, if present, is linear or branched saturated C1-6alkyl. (325) A compound according to any one of (1) to (320), wherein: -RJ1, if present, is linear or branched saturated C1-4alkyl. (326) A compound according to any one of (1) to (320), wherein: -RJ1, if present, is -Me, -Et, -nPr, -iPr, -nBu, or -tBu. (327) A compound according to any one of (1) to (320), wherein: -RJ1, if present, is -Me, -Et, -nPr, or -iPr. (328) A compound according to any one of (1) to (320), wherein: -RJ1, if present, is -Me or -Et. (329) A compound according to any one of (1) to (320), wherein: -RJ1, if present, is -Et. (330) A compound according to any one of (1) to (332014), wherein: -RJ1, if present, is -Me. The Group -RJ2 (331) A compound according to any one of (1) to (330), wherein: each -RJ2, if present, is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. (332) A compound according to any one of (1) to (330), wherein: each -RJ2, if present, is cyclopropyl. (333) A compound according to any one of (1) to (330), wherein: each -RJ2, if present, is independently cyclobutyl. (334) A compound according to any one of (1) to (330), wherein: each -RJ2, if present, is independently cyclopentyl. (335) A compound according to any one of (1) to (330), wherein: each -RJ2, if present, is independently cyclohexyl. The Group -RJ3 (336) A compound according to any one of (1) to (335), wherein: each -RJ3, if present, is independently azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, azepanyl, or diazepanyl; and is: optionally substituted on sulfur, if present, with one or two groups =O; optionally substituted on carbon with one or more groups selected from -F, -RJJ, -CF3, -OH, -ORJJ, -NH2, -NHRJJ, and -NRJJ2; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RJJ, -C(=O)RJJ, -C(=O)ORJJ, and -S(=O)2RJJ. (337) A compound according to any one of (1) to (335), wherein: each -RJ3, if present, is independently pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, or morpholinyl; and is: optionally substituted on carbon with one or more groups selected from -F, -RJJ, -CF3, -OH, -ORJJ, -NH2, -NHRJJ, and -NRJJ2; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RJJ, -C(=O)RJJ, -C(=O)ORJJ, and -S(=O)2RJJ. (338) A compound according to any one of (1) to (335), wherein: each -RJ3, if present, is independently pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, or morpholinyl; and is: optionally substituted on carbon with one or more groups selected from -F and -RJJ; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RJJ, -C(=O)RJJ, -C(=O)ORJJ, and -S(=O)2RJJ. (339) A compound according to any one of (1) to (335), wherein: each -RJ3, if present, is independently pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, or morpholinyl; and is: optionally substituted on secondary nitrogen, if present, with a group selected from: -RJJ, -C(=O)RJJ, -C(=O)ORJJ, and -S(=O)2RJJ. The Group -RJ4 (340) A compound according to any one of (1) to (339), wherein: each -RJ4, if present, is phenyl; and is optionally substituted with one or more groups selected from: -F, -Cl, -RJJ, -OH, -NH2, -NHRJJ, and -NRJJ. (341) A compound according to any one of (1) to (339), wherein: each -RJ4, if present, is phenyl. The Group -RJ5 (342) A compound according to any one of (1) to (341), wherein: each -RJ5, if present, is independently pyrrolyl, furanyl, thienyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, or pyridizinyl; and is: optionally substituted on carbon with one or more groups selected from -F, -RJJ, -CF3, -OH, -ORJJ, -NH2, -NHRJJ, and -NRJJ2; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RJJ, -C(=O) RJJ, -C(=O)ORJJ, and -S(=O)2RJJ. (343) A compound according to any one of (1) to (341), wherein: each -RJ5, if present, is independently pyrrolyl, furanyl, thienyl, pyrazolyl, pyridinyl, pyrimidinyl, or pyridizinyl; and is: optionally substituted on carbon with one or more groups selected from -F, -RJJ, -CF3, -OH, -ORJJ, -NH2, -NHRJJ, and -NRJJ2; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RJJ, -C(=O) RJJ, -C(=O)ORJJ, and -S(=O)2RJJ. (344) A compound according to any one of (1) to (341), wherein: each -RJ5, if present, is independently thienyl, pyrazolyl, or pyridinyl; and is: optionally substituted on carbon with one or more groups selected from -F, -RJJ, -CF3, -OH, -ORJJ, -NH2, -NHRJJ, and -NRJJ2; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RJJ, -C(=O) RJJ, -C(=O)ORJJ, and -S(=O)2RJJ. (345) A compound according to any one of (1) to (341), wherein: each -RJ5, if present, is independently thienyl, pyrazolyl, or pyridinyl. The Group -LJ- (346) A compound according to any one of (1) to (345), wherein: each -LJ-, if present, is independently -CH2-, -CF2-, -C(CH3)2-, -CH2CH2-, or -CH2CH2CH2-. (347) A compound according to any one of (1) to (345), wherein: each -LJ-, if present, is independently linear or branched saturated C1-4alkylene. (348) A compound according to any one of (1) to (345), wherein: each -LJ-, if present, is independently -CH2-, -C(CH3)2-, -CH2CH2-, or -CH2CH2CH2-. (349) A compound according to any one of (1) to (345), wherein: each -LJ-, if present, is independently -CH2-, -CH2CH2-, or -CH2CH2CH2-. (350) A compound according to any one of (1) to (345), wherein: each -LJ-, if present, is -CH2-. (351) A compound according to any one of (1) to (345), wherein: each -LJ-, if present, is -CH2CH2-. (352) A compound according to any one of (1) to (345), wherein: each -LJ-, if present, is -CH2CH2CH2-. The Group -RJJ (353) A compound according to any one of (1) to (352), wherein: each -RJJ, if present, is: -Me, -Et, -nPr, -iPr, -nBu, or -tBu. (354) A compound according to any one of (1) to (352), wherein: each -RJJ, if present, is: -Me, -Et, -nPr, or -iPr. (355) A compound according to any one of (1) to (352), wherein: each -RJJ, if present, is: -Me or -Et. (356) A compound according to any one of (1) to (352), wherein: each -RJJ, if present, is: -Me. The Group -RQ1NK (357) A compound according to any one of (1) to (356), wherein: -RQ1NK, if present, is -RQ1NK is -RK1, or -RK3. (358) A compound according to any one of (1) to (356), wherein: -RQ1NK, if present, is -RK1, -RK2, -LK-RK2, -RK3, or -LK-RK3; (359) A compound according to any one of (1) to (356), wherein: -RQ1NK, if present, is -RK1, -RK2, -RK3, or -LK-RK3; (360) A compound according to any one of (1) to (356), wherein: -RQ1NK, if present, is -RK1. (361) A compound according to any one of (1) to (356), wherein: -RQ1NK, if present, is -RK2. (362) A compound according to any one of (1) to (356), wherein: -RQ1NK, if present, is -RK3. (363) A compound according to any one of (1) to (356), wherein: -RQ1NK, if present, is -LK-RK3. The Group -RK1 (364) A compound according to any one of (1) to (363), wherein: -RK1, if present, is linear or branched saturated C1-6alkyl; and is optionally substituted with one or more groups selected from: -F, -OH, -ORKK, -O-phenyl, -C(=O)OH, -C(=O)ORKK, -NH2, -NHRKK, and -NRKK2. (365) A compound according to any one of (1) to (363), wherein: -RK1, if present, is linear or branched saturated C1-4alkyl; and is optionally substituted with one or more groups selected from: -F, -OH, -ORKK, -O-phenyl, -C(=O)OH, -C(=O)ORKK, -NH2, -NHRKK, and -NRKK2. (366) A compound according to any one of (1) to (363), wherein: -RK1, if present, is linear or branched saturated C1-4alkyl; and is optionally substituted with one or more groups selected from: -F, -OH, or -ORKK. (367) A compound according to any one of (1) to (363), wherein: -RK1, if present, is linear or branched saturated C1-7alkyl; and is optionally substituted with one or more groups selected from: -OH. (368) A compound according to any one of (1) to (363), wherein: -RK1, if present, is linear or branched saturated -CHC(CH3)2-; and is optionally substituted with one or more groups selected from: -OH. (369) A compound according to any one of (1) to (363), wherein: -RK1, if present, is linear or branched saturated C1-4alkyl. (370) A compound according to any one of (1) to (363), wherein: -RK1, if present, is -Me, -Et, -nPr, -iPr, -nBu, or -tBu. (371) A compound according to any one of (1) to (363), wherein: -RK1, if present, is -Me, -Et, -nPr, or -iPr. (372) A compound according to any one of (1) to (363), wherein: -RK1, if present, is -Me or -Et. (373) A compound according to any one of (1) to (363), wherein: -RK1, if present, is -Me. The Group -RK2 (374) A compound according to any one of (1) to (373), wherein: each -RK2, if present, is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. (375) A compound according to any one of (1) to (373), wherein: each -RK2, if present, is cyclopropyl. (376) A compound according to any one of (1) to (373), wherein: each -RK2, if present, is independently cyclobutyl. (377) A compound according to any one of (1) to (373), wherein: each -RK2, if present, is independently cyclopentyl. (378) A compound according to any one of (1) to (373), wherein: each -RK2, if present, is independently cyclohexyl. The Group -RK3 (379) A compound according to any one of (1) to (378), wherein: each -RK3, if present, is independently non-aromatic C3-7heterocyclyl. (380) A compound according to any one of (1) to (378), wherein: each -RK3, if present, is tetrahydropyranyl. (381) A compound according to any one of (1) to (378), wherein: each -RK3, if present, is independently azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, azepanyl, or diazepanyl; and is: optionally substituted on sulfur, if present, with one or two groups =O; optionally substituted on carbon with one or more groups selected from -F, -RKK, -CF3, -OH, -ORKK, -NH2, -NHRKK, and -NRKK2; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RKK, -C(=O)RKK, -C(=O)ORKK, and -S(=O)2RKK. (382) A compound according to any one of (1) to (378), wherein: each -RK3, if present, is independently pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, or morpholinyl; and is: optionally substituted on carbon with one or more groups selected from -F, -RKK, -CF3, -OH, -ORKK, -NH2, -NHRKK, and -NRKK2; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RKK, -C(=O)RKK, -C(=O)ORKK, and -S(=O)2RKK. (383) A compound according to any one of (1) to (378), wherein: each -RK3, if present, is independently pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, or morpholinyl; and is: optionally substituted on carbon with one or more groups selected from -F and -RKK; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RKK, -C(=O)RKK, -C(=O)ORKK, and -S(=O)2RKK. (384) A compound according to any one of (1) to (378), wherein: each -RK3, if present, is independently pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, or morpholinyl; and is: optionally substituted on secondary nitrogen, if present, with a group selected from: -RKK, -C(=O)RKK, -C(=O)ORKK, and -S(=O)2RKK. The Group -RK4 (385) A compound according to any one of (1) to (384), wherein: each -RK4, if present, is phenyl; and is optionally substituted with one or more groups selected from: -F, -Cl, -RKK, -CF3, -OH, and -ORKK. (386) A compound according to any one of (1) to (384), wherein: each -RK4, if present, is phenyl. The Group -RK5 (387) A compound according to any one of (1) to (386), wherein: each -RK5, if present, is independently pyrrolyl, furanyl, thienyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, or pyridizinyl; and is: optionally substituted on carbon with one or more groups selected from -F, -RKK, -CF3, -OH, -ORKK, -NH2, -NHRKK, and -NRKK2; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RKK, -C(=O) RKK, -C(=O)ORKK, and -S(=O)2RKK. (388) A compound according to any one of (1) to (386), wherein: each -RK5, if present, is independently pyrrolyl, furanyl, thienyl, pyrazolyl, pyridinyl, pyrimidinyl, or pyridizinyl; and is: optionally substituted on carbon with one or more groups selected from -F, -RKK, -CF3, -OH, -ORKK, -NH2, -NHRKK, and -NRKK2; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RKK, -C(=O) RKK, -C(=O)ORKK, and -S(=O)2RKK. (389) A compound according to any one of (1) to (386), wherein: each -RK5, if present, is independently pyrrolyl, furanyl, thienyl, pyrazolyl, pyridinyl, pyrimidinyl, or pyridizinyl. The Group -LK- (390) A compound according to any one of (1) to (389), wherein: each -LK-, if present, is independently linear or branched saturated C1-4alkylene. (391) A compound according to any one of (1) to (389), wherein: each -LK-, if present, is independently -CH2-, -C(CH3)2-, -CH2CH2-, or -CH2CH2CH2-. (392) A compound according to any one of (1) to (389), wherein: each -LK-, if present, is independently -CH2-, -CH2CH2-, or -CH2CH2CH2-. (393) A compound according to any one of (1) to (389), wherein: each -LK-, if present, is -CH2-. (394) A compound according to any one of (1) to (389), wherein: each -LK-, if present, is -CH2CH2-. (395) A compound according to any one of (1) to (389), wherein: each -LK-, if present, is -CH2CH2CH2-. The Group -RKK (396) A compound according to any one of (1) to (395), wherein: each -RKK, if present, is: -Me, -Et, -nPr, -iPr, -nBu, or -tBu. (397) A compound according to any one of (1) to (395), wherein: each -RKK, if present, is: -Me, -Et, -nPr, or -iPr. (398) A compound according to any one of (1) to (395), wherein: each -RKK, if present, is: -Me or -Et. (399) A compound according to any one of (1) to (395), wherein: each -RKK, if present, is: -Me. The Group -RQ1NP (400) A compound according to any one of (1) to (399), wherein: -RQ1NP, if present, is independently: non-aromatic C3-11heterocyclyl having at least one N ring atom, and is attached via that N ring atom; and is: optionally substituted on carbon with one or more groups selected from -RQ1NPP, -F, -OH, -CF3, and -C(O)NH2; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ1NPP. (401) A compound according to any one of (1) to (399), wherein: -RQ1NP, if present, is independently: morpholinyl, piperazinyl, pyrrolidinyl, 2,8-diazaspiro[4.5]decanyl, piperidinyl, azetidinyl, piperidinyl, 2-azaspiro[3.3]heptanyl, or 2-oxa-6-azaspiro[3.3]heptanyl, and is attached via an N ring atom; and is: optionally substituted on carbon with one or more groups selected from -RQ1NPP, -F, -OH, -CF3, and -C(O)NH2; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ1NPP. (402) A compound according to any one of (1) to (399), wherein: -RQ1NP, if present, is independently: azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azepanyl, diazepanyl, 3-azabicyclo[3.1.0]hexanyl, 3,6-diazabicyclo[3.1.1]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-azabicyclo[2.2.1]heptanyl, 3,8-diazabicyclo[3.2.1]octanyl, 3-azabicyclo[3.2.1]octanyl, 2-azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 6-azaspiro[3.4]octanyl, 2-azaspiro[3.4]octanyl, 2,7-diazaspiro[3.4]octanyl, 7-azaspiro[3.5]nonanyl, 2-azaspiro[3.5]nonanyl, 2,7-diazaspiro[3.5]nonanyl, 2,7-diazaspiro[4.4]nonanyl, 2,8-diazaspiro[4.5]decanyl, or 3,9-diazaspiro[5.5]undecanyl; and is attached via an N ring atom; and is: optionally substituted on sulfur, if present, with one or two =O groups; optionally substituted on carbon with one or more groups selected from -RQ1NPP, -F, -OH, -ORQ1NPP, and =O; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ1NPP, -RQ1NPPX, -C(=O)RQ1NPP, -C(=O)ORQ1NPP, -C(=O)NH2, -C(=O)NHRQ1NPP, -C(=O a)zNetRiQ1NPP2, and -S(=O)2RQ1NPP.
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(403) (397) A compound accord3in]hge piperid 2 t i 2n-poay-taaz a l,aznn pasey is o ppierniorre ao[3 o z[3.f i5n. ( y4]n12 l],oo),6 2nc to- -atd aan (i zn3aeae9za9s),p wir spiro[ 2ho 3,e[ .73r 3-e. ]d 23i hi,n] ea7h: -aRsQp1iNrPo,[4 if.4 p]rneosneannte, is indep uted on s 2e e,8n c-d ode nian dztl aay rys:p niirtoro[4g.5e]nd,e icfa pnreesent, wit 3h,9 a-d gip raz-e td ozap a uaisnata pspyzn pila sire , eroso m[3 ptionally substituted on sulfur, if present, with one or two =O groups; optionally substituted on carbon with one or more groups selected from -RQ1NPP, -F, -OH, -ORQ1NPP, and =O; and ir.4o][o3c.5ta]nnoenane optionally substit le[5o c.r t5p e]h d from: -RQ1NPP, -RQ1NPPX, -C(=O)RQ1NPP, -C(=O)ORQ1NPP, -C(=O)NH2, -C(=O)NHRQ1NPPu, -C(=O)NRQ1NPP2, and -S(=O)2RQ1NPP. nodlinecyal, thiomorpholinyl, azepanyl, or diazepanyl; and is attached via an N ring atom; and is: o ne (404) (398) A compound according to any one of (1) to (399), wherein: -RQ1NP, if present, is independently: azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl; and is attached via an N ring atom; and is: optionally substituted on carbon with one or more groups selected from -RQ1NPP, -F, -OH, -ORQ1NPP, and =O; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ1NPP, -RQ1NPPX, -C(=O)RQ1NPP, -C(=O)ORQ1NPP, -C(=O)NH2, -C(=O)NHRQ1NPP, -C(=O)NRQ1NPP 2, and -S(=O)2RQ1NPP. The Group -RQ1NPP (405) A compound according to any one of (1) to (399), wherein: each -RQ1NPP, if present, is independently linear or branched saturated C1-4alkyl or phenyl, wherein C1-4alkyl is optionally substituted with -OH, -Cl or -OCH3. (406) A compound according to any one of (1) to (399), wherein: each -RQ1NPP, if present, is independently linear or branched saturated -Me, -iPr or phenyl, wherein -Me or -iPr is optionally substituted with -OH, -Cl or -OCH3. (407) A compound according to any one of (1) to (399), wherein: each -RQ1NPP, 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, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2. (408) A compound according to any one of (1) to (399), wherein: each -RQ1NPP, if present, is independently linear or branched saturated C1-4alkyl, phenyl, or phenyl-CH2-. (409) A compound according to any one of (1) to (399), wherein: each -RQ1NPP, if present, is independently linear or branched saturated C1-4alkyl. (410) A compound according to any one of (1) to (399), wherein: each -RQ1NPP, if present, is: -Me, -Et, -nPr, -iPr, -nBu, or -tBu. (411) A compound according to any one of (1) to (399), wherein: each -RQ1NPP, if present, is: -Me, -Et, -nPr, or -iPr. (412) A compound according to any one of (1) to (399), wherein: each -RQ1NPP, if present, is: -Me or -Et. (413) A compound according to any one of (1) to (399), wherein: each -RQ1NPP, if present, is: -Me. (414) A compound according to any one of (1) to (399), wherein: each -RQ1NPP, if present, is: phenyl. The Group -RQ1NPPX (415) A compound according to any one of (1) to (414), wherein: -RQ1NPPX, if present, is independently linear or branched saturated C1-4fluoroalkyl. (416) A compound according to any one of (1) to (414), wherein: -RQ1NPPX, if present, is independently -CF3, -CHF2, -CH2CF3, or -CH2CHF2. (417) A compound according to any one of (1) to (414), wherein: -RQ1NPPX, if present, is -CH2CF3. The Group -RQ2C (418) A compound according to any one of (1) to (417), wherein: each -RQ2C, if present, is independently: -F, -RQ2CC, -RQ2CX, -OH, -ORQ2CC, -ORQ2CX, -NH2, -NHRQ2CC, -NRQ2CC 2, -RQ2CM, -NHC(=O)RQ2CC, -NHC(=O)ORQ2CC, or =O. (419) A compound according to any one of (1) to (417), wherein: each -RQ2C, if present, is independently: -F, -RQ2CC, -RQ2CX, -OH, -ORQ2CC, -ORQ2CX, -NH2, -NHRQ2CC, -NRQ2CC 2, or -RQ2CM. (420) A compound according to any one of (1) to (417), wherein: each -RQ2C, if present, is independently: -F, -RQ2CC, -RQ2CX, -OH, -ORQ2CC, or -ORQ2CX. The Group -RQ2CC (421) A compound according to any one of (1) to (420), wherein: each -RQ2CC, if present, is independently linear or branched saturated C1-4alkyl, phenyl, or phenyl-CH2-, wherein each phenyl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2. (422) A compound according to any one of (1) to (420), wherein: each -RQ2CC, if present, is independently linear or branched saturated C1-4alkyl, phenyl, or phenyl-CH2-. (423) A compound according to any one of (1) to (420), wherein: each -RQ2CC, if present, is independently linear or branched saturated C1-4alkyl. (424) A compound according to any one of (1) to (420), wherein: each -RQ2CC, if present, is: -Me, -Et, -nPr, -iPr, -nBu, or -tBu. (425) A compound according to any one of (1) to (420), wherein: each -RQ2CC, if present, is: -Me, -Et, -nPr, or -iPr. (426) A compound according to any one of (1) to (420), wherein: each -RQ2CC, if present, is: -Me or -Et. (427) A compound according to any one of (1) to (420), wherein: each -RQ2CC, if present, is: -Me. The Group -RQ2CX (428) A compound according to any one of (1) to (427), wherein: each -RQ2CX, if present, is independently linear or branched saturated C1-4fluoroalkyl. (429) A compound according to any one of (1) to (427), wherein: each -RQ2CX, if present, is independently -CF3, -CHF2, -CH2CF3, or -CH2CHF2. (430) A compound according to any one of (1) to (427), wherein: each -RQ2CX, if present, is -CF3. The Group -RQ2CM (431) A compound according to any one of (1) to (430), wherein: each -RQ2CM, if present, is independently azetidino, pyrrolidino, piperidino, piperazino, morpholino, thiomorpholino, azepano, or diazepano, and is: optionally substituted on carbon with one or more groups -RQ2CMM; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ2CMM, -C(=O)RQ2CMM, -C(=O)ORQ2CMM, -C(=O)NH2, -C(=O)NHRQ2CMM, -C(=O)NRQ2CMM2, and -S(=O)2RQ2CMM. (432) A compound according to any one of (1) to (430), wherein: each -RQ2CM, if present, is independently pyrrolidino, piperidino, piperazino, or morpholino, and is: optionally substituted on carbon with one or more groups -RQ2CMM; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ2CMM, -C(=O)RQ2CMM, -C(=O)ORQ2CMM, -C(=O)NH2, -C(=O)NHRQ2CMM, -C(=O)NRQ2CMM2, and -S(=O)2RQ2CMM. (433) A compound according to any one of (1) to (430), wherein: each -RQ2CM, if present, is independently pyrrolidino, piperidino, piperazino, or morpholino, and is: optionally substituted on carbon with one or more groups -RQ2CMM; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ2CMM, -C(=O)RQ2CMM, and -C(=O)ORQ2CMM. The Group -RQ2CMM (434) A compound according to any one of (1) to (433), wherein: each -RQ2CMM, 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, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2. (435) A compound according to any one of (1) to (433), wherein: each -RQ2CMM, if present, is independently linear or branched saturated C1-4alkyl, phenyl, or phenyl-CH2-. (436) A compound according to any one of (1) to (433), wherein: each -RQ2CMM, if present, is independently linear or branched saturated C1-4alkyl. (437) A compound according to any one of (1) to (433), wherein: each -RQ2CMM, if present, is: -Me, -Et, -nPr, -iPr, -nBu, or -tBu. (438) A compound according to any one of (1) to (433), wherein: each -RQ2CMM, if present, is: -Me, -Et, -nPr, or -iPr. (439) A compound according to any one of (1) to (433), wherein: each -RQ2CMM, if present, is: -Me or -Et. (440) A compound according to any one of (1) to (433), wherein: each -RQ2CMM, if present, is: -Me. The Group -RQ2N (441) A compound according to any one of (1) to (440), wherein: each -RQ2N, if present, is independently: -RQ2NC, -C(=O)RQ2NC, -C(=O)-LQ2N-OH, -C(=O)-LQ2N-ORQ2NC, -C(=O)-LQ2N-NH2, -C(=O)-LQ2N-NHRQ2NC, -C(=O)-LQ2N-NRQ2NC2, -C(=O)-LQ2N-RQ2NM, -C(=O)ORQ2NC, -C(=O)NH2, -C(=O)NHRQ2NC, -C(=O)NRQ2NC2, -C(=O)RQ2NM, -LQ2N-C(=O)NH2, -LQ2N-C(=O)NHRQ2NC, -LQ2N-C(=O)NRQ2NC2, or -LQ2N-C(=O)RQ2NM. (442) A compound according to any one of (1) to (440), wherein: each -RQ2N, if present, is independently: -RQ2NC, -C(=O)RQ2NC, -C(=O)-LQ2N-OH, -C(=O)-LQ2N-ORQ2NC, -C(=O)-LQ2N-NH2, -C(=O)-LQ2N-NHRQ2NC, -C(=O)-LQ2N-NRQ2NC2, -C(=O)-LQ2N-RQ2NM, -C(=O)NH2, -C(=O)NHRQ2NC, -C(=O)NRQ2NC2, or -C(=O)RQ2NM. (443) A compound according to any one of (1) to (440), wherein: each -RQ2N, if present, is independently: -RQ2NC or -C(=O)RQ2NC. (444) A compound according to any one of (1) to (440), wherein: each -RQ2N, if present, is: -C(=O)RQ2NC. The Group -RQ2NC (445) A compound according to any one of (1) to (444), wherein: each -RQ2NC, if present, is independently linear or branched saturated C1-6alkyl, phenyl, phenyl-CH2-, pyridyl, or pyridyl-CH2-, wherein C1-6alkyl is optionally substituted with -OH or -OCH3, and each phenyl and pyridyl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2; (446) A compound according to any one of (1) to (444), wherein: each -RQ2NC, if present, is independently linear or branched saturated C1-4alkyl, phenyl, or phenyl-CH2-, wherein each phenyl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2. (447) A compound according to any one of (1) to (444), wherein: each -RQ2NC, if present, is independently linear or branched saturated C1-4alkyl, phenyl, or phenyl-CH2-. (448) A compound according to any one of (1) to (444), wherein: each -RQ2NC, if present, is independently linear or branched saturated C1-4alkyl. (449) A compound according to any one of (1) to (444), wherein: each -RQ2NC, if present, is: -Me, -Et, -nPr, -iPr, -nBu, or -tBu. (450) A compound according to any one of (1) to (444), wherein: each -RQ2NC, if present, is: -Me, -Et, -nPr, or -iPr. (451) A compound according to any one of (1) to (444), wherein: each -RQ2NC, if present, is: -Me or -Et. (452) A compound according to any one of (1) to (444), wherein: each -RQ2NC, if present, is: -Me. The Group -LQ2N- (453) A compound according to any one of (1) to (452), wherein: each -LQ2N-, if present, is independently -CH2-, -C(CH3)2-, -CH2CH2-, or -CH2CH2CH2-. (454) A compound according to any one of (1) to (452), wherein: each -LQ2N-, if present, is independently -CH2-, -CH2CH2-, or -CH2CH2CH2-. (455) A compound according to any one of (1) to (452), wherein: each -LQ2N-, if present, is -CH2-. (456) A compound according to any one of (1) to (452), wherein: each -LQ2N-, if present, is -CH2CH2-. (457) A compound according to any one of (1) to (452), wherein: each -LQ2N-, if present, is -CH2CH2CH2-. The Group -RQ2NM (458) A compound according to any one of (1) to (457), wherein: each -RQ2NM, if present, is independently azetidino, pyrrolidino, piperidino, piperazino, morpholino, thiomorpholino, azepano, or diazepano, and is: optionally substituted on carbon with one or more groups -RQ2NMM; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ2NMM, -C(=O)RQ2NMM, -C(=O)ORQ2NMM, -C(=O)NH2, -C(=O)NHRQ2NMM, -C(=O)NRQ2NMM2, and -S(=O)2RQ2NMM. (459) A compound according to any one of (1) to (457), wherein: each -RQ2NM, if present, is independently pyrrolidino, piperidino, piperazino, or morpholino, and is: optionally substituted on carbon with one or more groups -RQ2NMM; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ2NMM, -C(=O)RQ2NMM, -C(=O)ORQ2NMM, -C(=O)NH2, -C(=O)NHRQ2NMM, -C(=O)NRQ2NMM 2, and -S(=O)2RQ2NMM. (460) A compound according to any one of (1) to (457), wherein: each -RQ2NM, if present, is independently pyrrolidino, piperidino, piperazino, or morpholino, and is: optionally substituted on carbon with one or more groups -RQ2NMM; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ2NMM, -C(=O)RQ2NMM, and -C(=O)ORQ2NMM. The Group -RQ2NMM (461) A compound according to any one of (1) to (460), wherein: each -RQ2NMM, 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, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2. (462) A compound according to any one of (1) to (460), wherein: each -RQ2NMM, if present, is independently linear or branched saturated C1-4alkyl, phenyl, or phenyl-CH2-. (463) A compound according to any one of (1) to (460), wherein: each -RQ2NMM, if present, is independently linear or branched saturated C1-4alkyl. (464) A compound according to any one of (1) to (460), wherein: each -RQ2NMM, if present, is: -Me, -Et, -nPr, -iPr, -nBu, or -tBu. (465) A compound according to any one of (1) to (460), wherein: each -RQ2NMM, if present, is: -Me, -Et, -nPr, or -iPr. (466) A compound according to any one of (1) to (460), wherein: each -RQ2NMM, if present, is: -Me or -Et. (467) A compound according to any one of (1) to (460), wherein: each -RQ2NMM, if present, is: -Me. The Group -RQ3C (468) A compound according to any one of (1) to (467), wherein: each -RQ3C, if present, is independently: -F, -RQ3CC, -ORQ3CC, -C(=O)RQ3CM, -C(=O)ORQ3CC, -LQ3C-C(=O)ORQ3CC, or -S(=O)2RQ3CC. (469) A compound according to any one of (1) to (467), wherein: each -RQ3C, if present, is independently: -F, -Cl, -Br, -I, -RQ3CC, -RQ3CX, -ORQ3CX, -OH, -ORQ3CC, -NH2, -NHRQ3CC, -NRQ3CC 2, -RQ3CM, -NHC(=O)RQ3CC, -NHC(=O)ORQ3CC, -C(=O)NH2, -C(=O)NHRQ3CC, -C(=O)NRQ3CC2, -C(=O)RQ3CM, -C(=O)OH, -C(=O)ORQ3CC, -OC(=O)RQ3CC, -OC(=O)NH2, -OC(=O)NHRQ3CC, -OC(=O)NRQ3CC2, -OC(=O)RQ3CM, -CN, or -NO2; and two adjacent-RQ3C, if present, taken together may form -(CH2)n3-O-(CH2)m3- or -O-(CH2)p3-O. (470) A compound according to any one of (1) to (467), wherein: each -RQ3C, if present, is independently: -F, -Cl, -Br, -I, -RQ3CC, -RQ3CX, -ORQ3CX, -OH, -ORQ3CC, -NH2, -NHRQ3CC, -NRQ3CC2, or -RQ3CM; and two adjacent-RQ3C, if present, taken together may form -(CH2)n3-O-(CH2)m3- or -O-(CH2)p3-O. (471) A compound according to any one of (1) to (467), wherein: each -RQ3C, if present, is independently: -F, -Cl, -Br, -I, -RQ3CC, -RQ3CX, -ORQ3CX, -OH, or -ORQ3CC. The Group -RQ3CC (472) A compound according to any one of (1) to (471), wherein: each -RQ3CC, 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, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2. (473) A compound according to any one of (1) to (547104), wherein: each -RQ3CC, if present, is independently linear or branched saturated C1-4alkyl, phenyl, or phenyl-CH2-. (474) A compound according to any one of (1) to (547104), wherein: each -RQ3CC, if present, is independently linear or branched saturated C1-4alkyl. (475) A compound according to any one of (1) to (471), wherein: each -RQ3CC, if present, is: -Me, -Et, -nPr, -iPr, -nBu, or -tBu. (476) A compound according to any one of (1) to (471), wherein: each -RQ3CC, if present, is: -Me, -Et, -nPr, or -iPr. (477) A compound according to any one of (1) to (471), wherein: each -RQ3CC, if present, is: -Me or -Et. (478) A compound according to any one of (1) to (504471), wherein: each -RQ3CC, if present, is: -Me. The Group -RQ3CX (479) A compound according to any one of (1) to (478), wherein: each -RQ3CX, if present, is independently linear or branched saturated C1-4fluoroalkyl. (480) A compound according to any one of (1) to (478), wherein: each -RQ3CX, if present, is independently -CF3, -CHF2, -CH2CF3, or -CH2CHF2. (481) A compound according to any one of (1) to (478), wherein: each -RQ3CX, if present, is -CF3. The Group -LQ3C- (482) A compound according to any one of (1) to (481), wherein: each -LQ3C-, if present, is independently -CH2-, -C(CH3)2-, -CH2CH2-, or -CH2CH2CH2-. (483) A compound according to any one of (1) to (481), wherein: each -LQ3C-, if present, is independently -CH2-, -CH2CH2-, or -CH2CH2CH2-. (484) A compound according to any one of (1) to (481), wherein: each -LQ3C-, if present, is -CH2-. (485) A compound according to any one of (1) to (481), wherein: each -LQ3C-, if present, is -CH2CH2-. (486) A compound according to any one of (1) to (481), wherein: each -LQ3C-, if present, is -CH2CH2CH2-. The G -RQ3CM (487) A compound according to any one of (1) to (486), wherein: each -RQ3CM, if present, is independently non-aromatic C3-11heterocyclyl having at least one N ring atom, and is attached via that N ring atom. (488) A compound according to any one of (1) to (486), wherein: each -RQ3CM, if present, is independently pyrrolidinyl and is attached via an N ring atom. (489) A compound according to any one of (1) to (486), wherein: each -RQ3CM, if present, is independently azetidino, pyrrolidino, piperidino, piperazino, morpholino, thiomorpholino, azepano, or diazepano, and is: optionally substituted on carbon with one or more groups -RQ3CMM; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ3CMM, -C(=O)RQ3CMM, -C(=O)ORQ3CMM, -C(=O)NH2, -C(=O)NHRQ3CMM, -C(=O)NRQ3CMM2, and -S(=O)2RQ3CMM. (490) A compound according to any one of (1) to (486), wherein: each -RQ3CM, if present, is independently pyrrolidino, piperidino, piperazino, or morpholino, and is: optionally substituted on carbon with one or more groups -RQ3CMM; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ3CMM, -C(=O)RQ3CMM, -C(=O)ORQ3CMM, -C(=O)NH2, -C(=O)NHRQ3CMM, -C(=O)NRQ3CMM2, and -S(=O)2RQ3CMM. (491) A compound according to any one of (1) to (486), wherein: each -RQ3CM, if present, is independently pyrrolidino, piperidino, piperazino, or morpholino, and is: optionally substituted on carbon with one or more groups -RQ3CMM; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ3CMM, -C(=O)RQ3CMM, and -C(=O)ORQ3CMM. The Group -RQ3CMM (492) A compound according to any one of (1) to (491), wherein: each -RQ3CMM, 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, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2. (493) A compound according to any one of (1) to (491), wherein: each -RQ3CMM, if present, is independently linear or branched saturated C1-4alkyl, phenyl, or phenyl-CH2-. (494) A compound according to any one of (1) to (491), wherein: each -RQ3CMM, if present, is independently linear or branched saturated C1-4alkyl. (495) A compound according to any one of (1) to (491), wherein: each -RQ3CMM, if present, is: -Me, -Et, -nPr, -iPr, -nBu, or -tBu. (496) A compound according to any one of (1) to (491), wherein: each -RQ3CMM, if present, is: -Me, -Et, -nPr, or -iPr. (497) A compound according to any one of (1) to (491), wherein: each -RQ3CMM, if present, is: -Me or -Et. (498) A compound according to any one of (1) to (491), wherein: each -RQ3CMM, if present, is: -Me. The Indices “n3” and “m3” in -(CH2)n3-O-(CH2)m3- (499) A compound according to any one of (1) to (498), wherein: n3, if present, is 0, 1, 2, or 3; m3, if present, is 0, 1, 2, or 3; with the proviso that m3+n3 is 2 or 3. (500) A compound according to any one of (1) to (498), wherein: n3, if present, is 0, 1, or 2; m3, if present, is 0, 1, or 2; with the proviso that m3+n3 is 2 or 3. (501) A compound according to any one of (1) to (498), 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- (502) A compound according to any one of (1) to (501), wherein: p3, if present, is 1. (503) A compound according to any one of (1) to (501), wherein: p3, if present, is 2. The Group -RQ4C (504) A compound according to any one of (1) to (503), wherein: each -RQ4C, if present, is independently: -F, -RQ4CC, -RQ4CX, -OH, -ORQ4CC, -ORQ4CX, -NH2, -NHRQ4CC, -NRQ4CC2, or -RQ4CM. (505) A compound according to any one of (1) to (503), wherein: each -RQ4C, if present, is independently: -RQ4CC, -RQ4CX, -OH, -ORQ4CC, or -ORQ4CX. (506) A compound according to any one of (1) to (503), wherein: each -RQ4C, if present, is independently: -RQ4CC, -OH, or -ORQ4CC. The Group -RQ4CC (507) A compound according to any one of (1) to (506), wherein: each -RQ4CC is independently linear or branched saturated C1-4alkyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein each phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2. (508) A compound according to any one of (1) to (506), wherein: each -RQ4CC, if present, is independently linear or branched saturated C1-4alkyl, phenyl, or phenyl-CH2-, wherein each phenyl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2. (509) A compound according to any one of (1) to (506), wherein: each -RQ4CC, if present, is independently linear or branched saturated C1-4alkyl, phenyl, or phenyl-CH2-. (510) A compound according to any one of (1) to (506), wherein: each -RQ4CC, if present, is independently linear or branched saturated C1-4alkyl. (511) A compound according to any one of (1) to (506), wherein: each -RQ4CC, if present, is: -Me, -Et, -nPr, -iPr, -nBu, or -tBu. (512) A compound according to any one of (1) to (506), wherein: each -RQ4CC, if present, is: -Me, -Et, -nPr, or -iPr. (513) A compound according to any one of (1) to (506), wherein: each -RQ4CC, if present, is: -Me or -Et. (514) A compound according to any one of (1) to (506), wherein: each -RQ4CC, if present, is: -Me. The Group -RQ4CX (515) A compound according to any one of (1) to (514), wherein: each -RQ4CX, if present, is independently linear or branched saturated C1-4fluoroalkyl. (516) A compound according to any one of (1) to (514), wherein: each -RQ4CX, if present, is independently -CF3, -CHF2, -CH2CF3, or -CH2CHF2. (517) A compound according to any one of (1) to (514), wherein: each -RQ4CX, if present, is -CF3. The Group -RQ4CM (518) A compound according to any one of (1) to (517), wherein: each -RQ4CM, if present, is independently azetidino, pyrrolidino, piperidino, piperazino, morpholino, thiomorpholino, azepano, or diazepano, and is: optionally substituted on carbon with one or more groups -RQ4CMM; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ4CMM, -C(=O)RQ4CMM, -C(=O)ORQ4CMM, -C(=O)NH2, -C(=O)NHRQ4CMM, -C(=O)NRQ4CMM 2, and -S(=O)2RQ4CMM. (519) A compound according to any one of (1) to (517), wherein: each -RQ4CM, if present, is independently pyrrolidino, piperidino, piperazino, or morpholino, and is: optionally substituted on carbon with one or more groups -RQ4CMM; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ4CMM, -C(=O)RQ4CMM, -C(=O)ORQ4CMM, -C(=O)NH2, -C(=O)NHRQ4CMM, -C(=O)NRQ4CMM2, and -S(=O)2RQ4CMM. (520) A compound according to any one of (1) to (517), wherein: each -RQ4CM, if present, is independently pyrrolidino, piperidino, piperazino, or morpholino, and is: optionally substituted on carbon with one or more groups -RQ4CMM; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ4CMM, -C(=O)RQ4CMM, and -C(=O)ORQ4CMM. The Group -RQ4CMM (521) A compound according to any one of (1) to (520), wherein: each -RQ4CMM, 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, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2. (522) A compound according to any one of (1) to (520), wherein: each -RQ4CMM, if present, is independently linear or branched saturated C1-4alkyl, phenyl, or phenyl-CH2-. (523) A compound according to any one of (1) to (520), wherein: each -RQ4CMM, if present, is independently linear or branched saturated C1-4alkyl. (524) A compound according to any one of (1) to (520), wherein: each -RQ4CMM, if present, is: -Me, -Et, -nPr, -iPr, -nBu, or -tBu. (525) A compound according to any one of (1) to (520), wherein: each -RQ4CMM, if present, is: -Me, -Et, -nPr, or -iPr. (526) A compound according to any one of (1) to (520), wherein: each -RQ4CMM, if present, is: -Me or -Et. (527) A compound according to any one of (1) to (520), wherein: each -RQ4CMM, if present, is: -Me. The Group -RQ5C (528) A compound according to any one of (1) to (527), wherein: each -RQ5C, if present, is independently: -OH, -ORQ5CC, -NH2, -NHRQ5CC, -NRQ5CC 2, -RQ5CM, -NHC(=O)RQ5CC, -NHC(=O)ORQ5CC, -C(=O)NH2, -C(=O)NHRQ5CC, -C(=O)NRQ5CC 2, -C(=O)RQ5CM, -OC(=O)NH2, -OC(=O)NHRQ5CC, -OC(=O)NRQ5CC 2, or -OC(=O)RQ5CM. (529) A compound according to any one of (1) to (527), wherein: each -RQ5C, if present, is independently: -OH, -ORQ5CC, -NH2, -NHRQ5CC, -NRQ5CC 2, -RQ5CM, -NHC(=O)RQ5CC, or -NHC(=O)ORQ5CC. (530) A compound according to any one of (1) to (527), wherein: each -RQ5C, if present, is independently: -NH2, -NHRQ5CC, -NRQ5CC2, -RQ5CM, -NHC(=O)RQ5CC, or -NHC(=O)ORQ5CC. (531) A compound according to any one of (1) to (527), wherein: each -RQ5C, if present, is independently: -NHC(=O)RQ5CC or -NHC(=O)ORQ5CC. The Group -RQ5CC (532) A compound according to any one of (1) to (531), wherein: each -RQ5CC, if present, is independently linear or branched saturated C1-4alkyl, phenyl, or phenyl-CH2-, wherein each phenyl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2. (533) A compound according to any one of (1) to (531), wherein: each -RQ5CC, if present, is independently linear or branched saturated C1-4alkyl, phenyl, or phenyl-CH2-. (534) A compound according to any one of (1) to (531), wherein: each -RQ5CC, if present, is independently linear or branched saturated C1-4alkyl. (535) A compound according to any one of (1) to (531), wherein: each -RQ5CC, if present, is: -Me, -Et, -nPr, -iPr, -nBu, or -tBu. (536) A compound according to any one of (1) to (531), wherein: each -RQ5CC, if present, is: -Me, -Et, -nPr, or -iPr. (537) A compound according to any one of (1) to (531), wherein: each -RQ5CC, if present, is: -Me or -Et. (538) A compound according to any one of (1) to (531), wherein: each -RQ5CC, if present, is: -Me. The Group -RQ5CM (539) A compound according to any one of (1) to (538), wherein: each -RQ5CM, if present, is independently azetidino, pyrrolidino, piperidino, piperazino, morpholino, thiomorpholino, azepano, or diazepano, and is: optionally substituted on carbon with one or more groups -RQ5CMM; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ5CMM, -C(=O)RQ5CMM, -C(=O)ORQ5CMM, -C(=O)NH2, -C(=O)NHRQ5CMM, -C(=O)NRQ5CMM2, and -S(=O)2RQ5CMM. (540) A compound according to any one of (1) to (538), wherein: each -RQ5CM, if present, is independently pyrrolidino, piperidino, piperazino, or morpholino, and is: optionally substituted on carbon with one or more groups -RQ5CMM; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ5CMM, -C(=O)RQ5CMM, -C(=O)ORQ5CMM, -C(=O)NH2, -C(=O)NHRQ5CMM, -C(=O)NRQ5CMM2, and -S(=O)2RQ5CMM. (541) A compound according to any one of (1) to (538), wherein: each -RQ5CM, if present, is independently pyrrolidino, piperidino, piperazino, or morpholino, and is: optionally substituted on carbon with one or more groups -RQ5CMM; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ5CMM, -C(=O)RQ5CMM, and -C(=O)ORQ5CMM. The Group -RQ5CMM (542) A compound according to any one of (1) to (538), wherein: each -RQ5CMM, 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, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2. (543) A compound according to any one of (1) to (538), wherein: each -RQ5CMM, if present, is independently linear or branched saturated C1-4alkyl, phenyl, or phenyl-CH2-. (544) A compound according to any one of (1) to (538), wherein: each -RQ5CMM, if present, is independently linear or branched saturated C1-4alkyl. (545) A compound according to any one of (1) to (538), wherein: each -RQ5CMM, if present, is: -Me, -Et, -nPr, -iPr, -nBu, or -tBu. (546) A compound according to any one of (1) to (538), wherein: each -RQ5CMM, if present, is: -Me, -Et, -nPr, or -iPr. (547) A compound according to any one of (1) to (538), wherein: each -RQ5CMM, if present, is: -Me or -Et. (548) A compound according to any one of (1) to (538), wherein: each -RQ5CMM, if present, is: -Me. Certain Preferred Combinations (549) A compound according to any one of (1) to (548), as applicable, wherein: -RA3 is -H; and -RA4 is -H. (550) A compound according to any one of (1) to (548), as applicable, wherein: Ring A is:
Figure imgf000094_0002
; and Ring B is:
Figure imgf000094_0003
. For example, the compound is a compound of the following structural formula:
Figure imgf000094_0001
. (551) A compound according to any one of (1) to (548), as applicable, wherein:
Figure imgf000095_0001
Ring B is: . (552) A compound according to any one of (1) to (548), as applicable, wherein:
Figure imgf000095_0002
Ring B is: ; -Q is -Q1; and -Q1 is pyrazolyl and is: optionally substituted on carbon with one or more groups -RQ1C; and optionally substituted on secondary nitrogen, if present, with -RQ1N. (553) A compound according to any one of (1) to (548), as applicable, wherein: Ring A is:
Figure imgf000095_0003
; Ring B is:
Figure imgf000095_0004
; -Q is -Q1; -Q1 is 1H-pyrazol-3-yl and is: optionally substituted oHnN car Nbon w Oith one S or more groups -RQ1C; and substituted on secondary nitrogen with -RQ1N. For example, the compound is a compound of the following structural formula:
Figure imgf000096_0001
A NH NH . (554) A compound according to any one of (1) to (548), as applicable, wherein: Ring A is:
Figure imgf000096_0002
; Ring B is:
Figure imgf000096_0003
; -Q is -Q1; -Q1 is 1H-pyrazol-3-yl and is: optionally substituted on carbon with one or more groups -RQ1C; and substituted on secondary nitrogen with -RQ1N; wherein: -RQ1N is -LQ1N-C(=O)NHRQ1NK, -LQ1N-C(=O)NRQ1NC2, or -LQ1N-C(=O)RQ1NP. (555) A compound according to any one of (1) to (548), as applicable, wherein: Ring A is:
Figure imgf000096_0004
; Ring B is:
Figure imgf000097_0002
; -Q is -Q1; -Q1 is 1H-pyrazol-3-yl and is: optionally substituted on carbon with one or more groups -RQ1C; and substituted on secondary nitrogen with -RQ1N; wherein: -RQ1N is -LQ1N-C(=O)RQ1NP. For example, the compound is a compound of the following structural formula:
Figure imgf000097_0001
. (556) A compound according to any one of (1) to (548), as applicable, wherein: Ring A is:
Figure imgf000097_0003
; Ring B is:
Figure imgf000097_0004
; -Q is -Q1; -Q1 is 1H-pyrazol-3-yl and is: optionally substituted on carbon with one or more groups -RQ1C; and substituted on secondary nitrogen with -RQ1N; wherein: -RQ1C is -RQ1CC; -RQ1N is -LQ1N-C(=O)RQ1NP; and -LQ1N- is -CH2-. (557) A compound according to any one of (1) to (548), as applicable, wherein: Ring A is:
Figure imgf000098_0002
; Ring B is:
Figure imgf000098_0003
; -Q is -Q1; -Q1 is 1H-pyrazol-3-yl and is: optionally substituted on carbon with one or more groups -RQ1C; and substituted on secondary nitrogen with -RQ1N; wherein: -RQ1N is -LQ1N-C(=O)NRQ1NC 2; and -LQ1N- is -CH2-. For example, the compound is a compound of the following structural formula:
Figure imgf000098_0001
. (558) A compound according to any one of (1) to (548), as applicable, wherein: Ring A is:
Figure imgf000098_0004
; Ring B is:
Figure imgf000098_0005
; -Q is -Q1; -Q1 is 1H-pyrazol-3-yl and is: substituted on secondary nitrogen with -RQ1N; wherein: -RQ1N is -RQ1NC. For example, the compound is a compound of the following structural formula:
Figure imgf000099_0001
. (559) A compound according to any one of (1) to (548), as applicable, wherein: Ring A is:
Figure imgf000099_0002
Figure imgf000099_0003
Ring B is: ; -RA2 is -RA222 or -Cl; and -RA222 is -Me. (560) A compound according to any one of (1) to (548), as applicable, wherein: Ring A is:
Figure imgf000099_0004
Ring B is:
Figure imgf000099_0005
; -Q is -Q1; and -Q1 is pyridyl and is: optionally substituted on carbon with one or more groups -RQ1C. Some Specific Examples (561) A compound according to (1) or (2), selected from compounds of the following formulae and pharmaceutically acceptable salts and solvates thereof (e.g., and pharmaceutically acceptable salts thereof): HN N O S H NN
Figure imgf000100_0001
Figure imgf000100_0002
H
Figure imgf000101_0002
Figure imgf000101_0001
Figure imgf000102_0002
Figure imgf000102_0001
Figure imgf000103_0002
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000104_0002
O HN N NH O S HN N N N
Figure imgf000105_0001
Figure imgf000105_0002
Figure imgf000106_0001
Figure imgf000106_0002
Figure imgf000107_0002
Figure imgf000107_0001
Figure imgf000108_0002
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000109_0002
Figure imgf000110_0002
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000111_0002
Figure imgf000112_0002
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000113_0002
HN Nr H O
Figure imgf000114_0001
Figure imgf000114_0002
Figure imgf000115_0002
Figure imgf000115_0001
HN N NH O S HN N N F N
Figure imgf000116_0001
Figure imgf000116_0002
Figure imgf000117_0001
In oneH N e Nmbo O NdHim Sen Nt, N tHhe N B NAA O c OoH
Figure imgf000117_0002
mpound is obtainable (or o . In one embodiment, the BAA compound is provided accordHb in Nta g Nined to a O) NnH by f y em Soll b Now o NdHing ime N th n a Ne methods described in the experimental section t described herein (for example, embodiment (1), (2) or (3); or claim 1) with the proviso th t a Ony O oHf the specific Examples are individually disclaimed. For example, a further feature is any embodiment described herein (for example, embodiment (1), (2) or (3); or claim 1) with the proviso that any (for example any one, any two, or any three) of the compounds in the preceding table are individually disclaimed. In one embodiment, the BAA compound is provided according to any embodiment described herein (for example, embodiment (1), (2) or (3); or claim 1) with the proviso that any other embodiment described herein is specifically disclaimed. Combinations It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination. All combinations of the embodiments pertaining to the chemical groups represented by the variables (e.g., Ring A, Ring B, etc.) are specifically embraced by the present invention and are disclosed herein just as if each and every combination was individually and explicitly disclosed, to the extent that such combinations embrace compounds that are stable compounds (i.e., compounds that can be isolated, characterised, and tested for biological activity). In this context, the skilled person will readily appreciate that certain combinations of groups (e.g., substituents) may give rise to compounds which may not be readily synthesized and/or are chemically unstable. In addition, all sub-combinations of the chemical groups listed in the embodiments describing such variables are also specifically embraced by the present invention and are disclosed herein just as if each and every such sub-combination of chemical groups was individually and explicitly disclosed herein. Substantially Purified Forms 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. In one embodiment, the substantially purified form is at least 50% by weight, e.g., at least 60% by weight, e.g., at least 70% by weight, e.g., at least 80% by weight, e.g., at least 90% by weight, e.g., at least 95% by weight, e.g., at least 97% by weight, e.g., at least 98% by weight, e.g., at least 99% by weight. Unless otherwise specified, the substantially purified form refers to the compound in any stereoisomeric or enantiomeric form. For example, in one embodiment, the substantially purified form refers to a mixture of stereoisomers, i.e., purified with respect to other compounds. In one embodiment, the substantially purified form refers to one stereoisomer, e.g., optically pure stereoisomer. In one embodiment, the substantially purified form refers to a mixture of enantiomers. In one embodiment, the substantially purified form refers to an equimolar mixture of enantiomers (i.e., a racemic mixture, a racemate). In one embodiment, the substantially purified form refers to one enantiomer, e.g., optically pure enantiomer. In one embodiment, the contaminants represent no more than 50% by weight, e.g., no more than 40% by weight, e.g., no more than 30% by weight, e.g., no more than 20% by weight, e.g., no more than 10% by weight, e.g., no more than 5% by weight, e.g., no more than 3% by weight, e.g., no more than 2% by weight, e.g., no more than 1% by weight. Unless specified, the contaminants refer to other compounds, that is, other than stereoisomers or enantiomers. In one embodiment, the contaminants refer to other compounds and other stereoisomers. In one embodiment, the contaminants refer to other compounds and the other enantiomer. In one embodiment, the substantially purified form is at least 60% optically pure (i.e., 60% of the compound, on a molar basis, is the desired stereoisomer or enantiomer, and 40% is the undesired stereoisomer or enantiomer), e.g., at least 70% optically pure, e.g., at least 80% optically pure, e.g., at least 90% optically pure, e.g., at least 95% optically pure, e.g., at least 97% optically pure, e.g., at least 98% optically pure, e.g., at least 99% optically pure. Isomers Certain compounds may exist in one or more particular geometric, optical, enantiomeric, diastereoisomeric, epimeric, atropic, stereoisomeric, tautomeric, conformational, or anomeric forms, including but not limited to, cis- and trans-forms; E- and Z-forms; c-, t-, and r- forms; endo- and exo-forms; R-, S-, and meso-forms; D- and L-forms; d- and l-forms; (+) and (-) forms; keto-, enol-, and enolate-forms; syn- and anti-forms; synclinal- and anticlinal-forms; α- and β-forms; axial and equatorial forms; boat-, chair-, twist-, envelope-, and halfchair-forms; and combinations thereof, hereinafter collectively referred to as “isomers” (or “isomeric forms”). A reference to a class of structures may well include structurally isomeric forms falling within that class (e.g., C1-6alkyl includes n-propyl and iso-propyl; butyl includes n-, iso-, sec-, and tert-butyl; methoxyphenyl includes ortho-, meta-, and para-methoxyphenyl). However, reference to a specific group or substitution pattern is not intended to include other structural (or constitutional isomers) which differ with respect to the connections between atoms rather than by positions in space. For example, a reference to a methoxy group, -OCH3, is not to be construed as a reference to its structural isomer, a hydroxymethyl group, -CH2OH. Similarly, a reference specifically to ortho-chlorophenyl is not to be construed as a reference to its structural isomer, meta-chlorophenyl. 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.
Figure imgf000119_0001
keto enol enolate For example, 1H-pyridin-2-one-5-yl and 2-hydroxyl-pyridin-5-yl (shown below) are tautomers of one another. A reference herein to one is intended to encompass both.
Figure imgf000119_0002
1H-pyridin-2-one-5-yl 2-hydroxyl-pyridin-5-yl Note that specifically included in the term “isomer” are compounds with one or more isotopic substitutions. For example, H may be in any isotopic form, including 1H, 2H (D), and 3H (T); C may be in any isotopic form, including 12C, 13C, and 14C; O may be in any isotopic form, including 16O and 18O; and the like. Unless otherwise specified, a reference to a particular compound includes all such isomeric forms, including mixtures (e.g., racemic mixtures) thereof. Methods for the preparation (e.g., asymmetric synthesis) and separation (e.g., fractional crystallisation and chromatographic means) of such isomeric forms are either known in the art or are readily obtained by adapting the methods taught herein, or known methods, in a known manner. Unless otherwise specified, a reference to a particular compound includes all such isomeric forms, including mixtures (e.g., racemic mixtures) thereof. Methods for the preparation (e.g., asymmetric synthesis) and separation (e.g., fractional crystallisation and chromatographic means) of such isomeric forms are either known in the art or are readily obtained by adapting the methods taught herein, or known methods, in a known manner. 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 Brønsted acid or base), where there is complete transfer of a proton from one entity to another. Examples of pharmaceutically acceptable salts are discussed in Berge et al., 1977, “Pharmaceutically Acceptable Salts,” J. Pharm. Sci., Vol. 66, pp.1-19. For example, if the compound is anionic, or has a functional group, which may be anionic (e.g., -COOH may be -COO-), then a salt may be formed with a suitable cation. Examples of suitable inorganic cations include, but are not limited to, alkali metal ions such as Na+ and K+, alkaline earth cations such as Ca2+ and Mg2+, and other cations such as Al3+ as well as the ammonium ion (i.e., NH4 +). Examples of suitable organic cations include, but are not limited to substituted ammonium ions (e.g., NH3R+, NH2R2 +, NHR3 +, NR4 +), for example, where each R is independently linear or branched saturated C1-18alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-6alkyl, and phenyl-C1-6alkyl, wherein the phenyl group is optionally substituted. Examples of some suitable substituted ammonium ions are those derived from: ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as amino acids, such as lysine and arginine. An example of a common quaternary ammonium ion is N(CH3)4+. If the compound is cationic, or has a functional group, which upon protonation may become cationic (e.g., -NH2 may become -NH3 +), then a salt may be formed with a suitable anion. For example, if a parent structure contains a cationic group (e.g., -NMe2+), or has a functional group, which upon protonation may become cationic (e.g., -NH2 may become -NH3+), then a salt may be formed with a suitable anion. In the case of a quaternary ammonium compound a counter-anion is generally always present in order to balance the positive charge. If, in addition to a cationic group (e.g., -NMe2+, -NH3+), the compound also contains a group capable of forming an anion (e.g., -COOH), then an inner salt (also referred to as a zwitterion) may be formed. Examples of suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, nitric, nitrous, phosphoric, and phosphorous. Examples of suitable organic anions include, but are not limited to, those derived from the following organic acids: 2-acetyloxybenzoic, acetic, trifluoroacetic, ascorbic, aspartic, benzoic, camphorsulfonic, cinnamic, citric, edetic, 1,2-ethanedisulfonic, ethanesulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, hydroxymaleic, hydroxynaphthalene carboxylic, isethionic, lactic, lactobionic, lauric, maleic, malic, methanesulfonic, mucic, oleic, oxalic, palmitic, pamoic, pantothenic, phenylacetic, phenylsulfonic, propionic, pyruvic, salicylic, stearic, succinic, sulfanilic, tartaric, toluenesulfonic, and valeric. Examples of suitable polymeric organic anions include, but are not limited to, those derived from the following polymeric acids: tannic acid, carboxymethyl cellulose. Examples of suitable counter-ions which are especially suitable for quaternary ammonium compounds (e.g., those with a -NMe2+ group) include 1-adamantanesulfonate, benzenesulfonate, bisulfate, bromide, chloride, iodide, methanesulfonate, methylsulfate, 1,5-napthalene-bis-sulfonate, 4-nitrobenzenesulfonate, formate, tartrate, tosylate, trifluoroacetate, trifluoromethylsulfonate, sulphate. Again, if the compound also contains a group capable of forming an anion (e.g., -COOH), then an inner salt may be formed. Unless otherwise specified, a reference to a particular compound also includes salt forms thereof. In one embodiment, the BAA compound is provided in the form of a salt. In one embodiment, the BAA compound is provided in a neutral form (for example as a free acid, free base, or zwitterion). Solvates and Hydrates It may be convenient or desirable to prepare, purify, and/or handle a corresponding solvate of the compound. The term “solvate” is used herein in the conventional sense to refer to a complex of solute (e.g., compound, salt of compound) and solvent. If the solvent is water, the solvate may be conveniently referred to as a hydrate, for example, a mono-hydrate, a di-hydrate, a tri-hydrate, etc. Unless otherwise specified, a reference to a particular compound also includes solvate and hydrate forms thereof. In one embodiment, the BAA compound is provided in the form of a solvate. In one embodiment, the BAA compound is provided in unsolvated form. In one embodiment, the BAA compound is provided in the form of a hydrate. Chemically Protected Forms It may be convenient or desirable to prepare, purify, and/or handle the compound in a chemically protected form. The term “chemically protected form” is used herein in the conventional chemical sense and pertains to a compound in which one or more reactive functional groups are protected from undesirable chemical reactions under specified conditions (e.g., pH, temperature, radiation, solvent, reactive chemical reagents, and the like). In practice, well-known chemical methods are employed to reversibly render unreactive a functional group, which otherwise would be reactive, under specified conditions. In a chemically protected form, one or more reactive functional groups are in the form of a protected or protecting group (alternatively as a masked or masking group or a blocked or blocking group). By protecting a reactive functional group, reactions involving other unprotected reactive functional groups can be performed, without affecting the protected group; the protecting group may be removed or the masking group transformed, usually in a subsequent step, without substantially affecting the remainder of the molecule. See, for example, Protective Groups in Organic Synthesis (T. Green and P. Wuts; 4th Edition; John Wiley and Sons, 2006). A wide variety of such “protecting,” “blocking,” or “masking” methods are widely used and well known in organic synthesis. For example, a compound which has two non-equivalent reactive functional groups, both of which would be reactive under specified conditions, may be derivatized to render one of the functional groups “protected,” and therefore unreactive, under the specified conditions; so protected, the compound may be used as a reactant which has effectively only one reactive functional group. After the desired reaction (involving the other functional group) is complete, the protected group may be “deprotected” to return it to its original functionality. For example, a hydroxy group may be protected as an ether (-OR) or an ester (-OC(=O)R), for example, as: a t-butyl ether; a benzyl, benzhydryl (diphenylmethyl), or trityl (triphenylmethyl) ether; a trimethylsilyl or t-butyldimethylsilyl ether; or an acetyl ester (-OC(=O)CH3, -OAc). For example, an aldehyde or ketone group may be protected as an acetal (R-CH(OR)2) or ketal (R2C(OR)2), respectively, in which the carbonyl group (>C=O) is converted to a 1,1-diether (>C(OR)2), by reaction with, for example, a primary alcohol in the presence of an acid. The aldehyde or ketone group is readily regenerated, for example, by hydrolysis using water in the presence of acid. For example, an amine group may be protected, for example, as an amide (-NRCO-R), for example: as an acetamide (-NHCO-CH3); or as a carbamate (-NRCO-OR), for example: as a benzyloxy carbamate (-NHCO-OCH2C6H5, -NH-Cbz), as a t-butoxy carbamate (-NHCO-OC(CH3)3, -NH-Boc); as a 2-biphenyl-2-propoxy carbamate (-NHCO-OC(CH3)2C6H4C6H5, -NH-Bpoc), as a 9-fluorenylmethoxy carbamate (-NH-Fmoc), as a 6- nitroveratryloxy carbamate (-NH-Nvoc), as a 2-trimethylsilylethyloxy carbamate (-NH-Teoc), a 2,2,2-trichloroethyloxy carbamate (-NH-Troc), as an allyloxy amide (-NH-Alloc), or as a 2(- phenylsulfonyl)ethyloxy carbamate (-NH-Psec); or, in suitable cases (e.g., cyclic amines), as a nitroxide radical (>N-O●); or, in suitable cases (e.g., heterocyclic nitrogens), as a 2- trimethylsilylethoxymethyl (N-SEM). For example, a carboxylic acid group may be protected as an ester for example, as: an C1-7alkyl ester (e.g., a methyl ester; a t-butyl ester); a C1-7haloalkyl ester (e.g., a 2,2,2-trihaloethyl ester); a 2-tri(C1-7alkyl)silyl-ethyl ester; or a C5-20aryl-C1-7alkyl ester (e.g., a benzyl ester; a nitrobenzyl ester); or as an amide or hydrazide, for example, as acetamide or a N,N,N’-trimethylhydrazide. For example, a thiol group may be protected as a thioether (-SR), for example, as: a benzyl thioether; an acetamidomethyl ether (-S-CH2NHC(=O)CH3). Prodrugs It may be convenient or desirable to prepare, purify, and/or handle the compound in the form of a prodrug. The term “prodrug,” as used herein, pertains to a compound, which yields the desired active compound in vivo. Typically, the prodrug is inactive, or less active than the desired active compound, but may provide advantageous handling, administration, or metabolic properties. For example, some prodrugs are esters of the active compound (e.g., a physiologically acceptable metabolically labile ester). During metabolism, the ester group (-C(=O)OR) is cleaved to yield the active drug. Such esters may be formed by esterification, for example, of any of the carboxylic acid groups (-C(=O)OH) in the parent compound, with, where appropriate, prior protection of any other reactive groups present in the parent compound, followed by deprotection if required. Also, some prodrugs are activated enzymatically to yield the active compound, or a compound, which, upon further chemical reaction, yields the active compound (for example, as in antibody directed enzyme prodrug therapy (ADEPT), gene directed enzyme prodrug therapy (GDEPT), ligand-directed enzyme prodrug therapy (LIDEPT), etc.). For example, the prodrug may be a sugar derivative or other glycoside conjugate, or may be an amino acid ester derivative. Compositions Also described herein is a composition (e.g., a pharmaceutical composition) comprising a BAA compound, as described herein, and a pharmaceutically acceptable carrier, diluent, or excipient. Also described herein is a method of preparing a composition (e.g., a pharmaceutical composition) comprising mixing a BAA compound, as described herein, and a pharmaceutically acceptable carrier, diluent, or excipient. Uses The BAA compounds, as described herein, inhibit PKMYT1 (e.g., inhibit or reduce or block the activity or function of PKMYT1). Accordingly, the BAA compounds, as described herein, 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). Use in Methods of Inhibiting PKMYT1 Also described herein is a method of inhibiting PKMYT1 (e.g., inhibiting or reducing or blocking the activity or function of PKMYT1), in vitro or in vivo, comprising contacting the PKMYT1 with an effective amount of a BAA compound, as described herein. Also described herein is a method of inhibiting PKMYT1 (e.g., inhibiting or reducing or blocking the activity or function of PKMYT1) in a cell, in vitro or in vivo, comprising contacting the cell with an effective amount of a BAA compound, as described herein. In one embodiment, the method is performed in vitro. In one embodiment, the method is performed in vivo. In one embodiment, the BAA compound is provided in the form of a pharmaceutically acceptable composition. One of ordinary skill in the art is readily able to determine whether or not a candidate compound inhibits PKMYT1 (e.g., inhibits or reduces or blocks the activity or function of PKMYT1). For example, suitable assays are described herein and/or are known in the art. One of ordinary skill in the art is readily able to determine whether or not a candidate compound inhibits PKMYT1 (e.g., inhibits or reduces or blocks or the activity or function of PKMYT1) in a cell. For example, a sample of cells may be grown in vitro and a compound brought into contact with said cells, and the effect of the compound on those cells observed. As an example of “effect,” the morphological status of the cells (e.g., alive or dead, etc.) may be determined. Where the compound is found to exert an influence on the cells, this may be used as a prognostic or diagnostic marker of the efficacy of the compound in methods of treating a subject (e.g., patient) carrying cells of the same cellular type. As another example of “effect,” the direct interaction of the compound with the target in cells could be measured (e.g., “target engagement assay”) using, e.g., a colorimetric, fluorescent, or luminescent readout. 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 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. Accordingly, also described herein is a method of regulating (e.g., inhibiting) cell proliferation (e.g., proliferation of a cell), inhibiting cell cycle progression, promoting apoptosis, reducing clonogenicity, reducing tumoursphere growth or self-renewal, or a combination of one or more these, in vitro or in vivo, comprising contacting a cell with an effective amount of a BAA compound, as described herein. In one embodiment, the method is performed in vitro. In one embodiment, the method is performed in vivo. In one embodiment, the BAA compound is provided in the form of a pharmaceutically 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. One of ordinary skill in the art is readily able to determine whether or not a candidate compound regulates (e.g., inhibits) cell proliferation, etc. For example, assays which may conveniently be used to assess the activity offered by a particular compound are described herein and/or are known in the art. The BAA compounds described herein may inhibit cell migration and invasion, e.g., inhibit 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. 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. Use in Methods of Therapy Also described herein is a BAA compound, as described herein, for use in a method of treatment of the human or animal body by therapy, for example, for use in a method of treatment of a disorder (e.g., a disease) as described herein. Also described herein is use of a BAA compound, as described herein, in a method of treatment of the human or animal body by therapy, for example, in a method of treatment of a disorder (e.g., a disease) as described herein. Use in the Manufacture of Medicaments Also described herein is use of a BAA compound, as described herein, in the manufacture of a medicament, for example, for use in a method of treatment, for example, for use in a method of treatment of a disorder (e.g., a disease) as described herein. In one embodiment, the medicament comprises the BAA compound. Methods of Treatment 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, preferably in the form of a pharmaceutical composition. Disorders Treated - Disorders Ameliorated by the Inhibition of PKMYT1 In one embodiment (e.g., of compounds for use in methods of therapy, of use in methods of therapy, of use in the manufacture of medicaments, of methods of treatment), the treatment is treatment of a disorder (e.g., a disease) that is ameliorated by the inhibition of PKMYT1 (e.g., by the inhibition or reduction or blockage of the activity or function of PKMYT1). Disorders Treated In one embodiment (e.g., of compounds for use in methods of therapy, of use in methods of therapy, of use in the manufacture of medicaments, of methods of treatment), the treatment is treatment of a disorder (e.g., a disease), for example, a proliferative disorder, cancer, etc., as described herein. Proliferative Disorders In one embodiment, the disorder is: a proliferative disorder. 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. In one embodiment, the proliferative disorder is characterised by benign, pre-malignant, malignant, pre-metastatic, metastatic, or non-metastatic cellular proliferation, including for example: neoplasms, hyperplasias, tumours (e.g., histocytoma, glioma, astrocyoma, 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. Disorders Treated - Proliferative Disorders In one embodiment (e.g., for use in methods of therapy, of use in the manufacture of medicaments, of methods of treatment), the treatment is treatment of a proliferative disorder. 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. In one embodiment, the treatment is treatment of: a proliferative disorder characterised by benign, pre-malignant, or malignant cellular proliferation. In one embodiment, the treatment is treatment of a proliferative disorder characterised by, or further characterised by: inappropriate activity and/or expression of PKMYT1, CCNE1, FBXW7, or PPP2A or one of its subunits. In one embodiment, the treatment is treatment of a proliferative disorder characterised by, or further characterised by: overexpression of PKMYT1 or CCNE1. In one embodiment, the treatment is treatment of a proliferative disorder characterised by, or further characterised by overexpression of PKMYT1. In one embodiment, the treatment is treatment of a proliferative disorder characterised by, or further characterised by overexpression of CCNE1. In one embodiment, the treatment is treatment of a proliferative disorder characterised by, or further characterised by: inactivation, decreased activity, or decreased expression of FBXW7 or PPP2R2A. In one embodiment, the treatment is treatment of a proliferative disorder characterised by, or further characterised by inactivation of FBXW7. In one embodiment, the treatment is treatment of a proliferative disorder characterised by, or further characterised by decreased activity or decreased expression of PPP2R2A. In one embodiment, the treatment is treatment of cancer. Disorders Treated - Cancer In one embodiment (e.g., of use in methods of therapy, of use in the manufacture of medicaments, of methods of treatment), the treatment is treatment of cancer. Included among cancers are: (1) Carcinomas, including tumours derived from stratified squamous epithelia (squamous cell carcinomas) and tumours arising within organs or glands (adenocarcinomas). Examples include breast, colon, lung, prostate, ovary. (2) Sarcomas, including: osteosarcoma and osteogenic sarcoma (bone); chondrosarcoma (cartilage); leiomyosarcoma (smooth muscle); rhabdomyosarcoma (skeletal muscle); mesothelial sarcoma and mesothelioma (membranous lining of body cavities); fibrosarcoma (fibrous tissue); angiosarcoma and haemangioendothelioma (blood vessels); liposarcoma (adipose tissue); glioma and astrocytoma (neurogenic connective tissue found in the brain); myxosarcoma (primitive embryonic connective tissue); mesenchymous and mixed mesodermal tumour (mixed connective tissue types). (3) Myeloma. (4) Haematopoietic tumours, including: myelogenous and granulocytic leukaemia (malignancy of the myeloid and granulocytic white blood cell series), e.g., chronic myeloid leukemia (CML), acute myeloid leukemia (AML); lymphatic, lymphocytic, and lymphoblastic leukaemia (malignancy of the lymphoid and lymphocytic blood cell series), e.g., acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL); polycythaemia vera (malignancy of various blood cell products, but with red cells predominating). (5) Lymphomas, including: Hodgkin and Non-Hodgkin lymphomas. (6) Mixed Types, including, e.g., adenosquamous carcinoma; mixed mesodermal tumour; carcinosarcoma; teratocarcinoma. In one embodiment, the cancer is: a bone or muscle sarcoma, for example: bone cancer; bone sarcoma; chondrosarcoma; Ewing’s sarcoma; heart cancer; leiomyosarcoma; malignant fibrous histiocytoma of bone; osteosarcoma; or rhabdomyosarcoma; a brain and nervous system cancer, for example: astrocytoma; brain cancer; brainstem glioma; cerebellar astrocytoma; cerebral astrocytoma; ependymoma; glioblastoma; glioma; medulloblastoma; neuroblastoma; oligodendroglioma; pilocytic astrocytoma; pineal astrocytoma; pituitary adenoma; primitive neuroectodermal tumor; schwannoma; or visual pathway and hypothalamic glioma; a breast cancer, for example: breast cancer; invasive cribriform carcinoma; inflammatory breast cancer; invasive lobular carcinoma; medullary carcinoma; male breast cancer; phyllodes tumor; or tubular carcinoma; an endocrine system cancer, for example: adrenal gland cancer; adrenocortical carcinoma; papillary thyroid cancer; follicular thyroid cancer; islet cell carcinoma; multiple endocrine neoplasia syndrome; parathyroid cancer; pheochromocytoma; thyroid cancer; or thyroid gland cancer; an eye cancer, for example: retinoblastoma; or uveal melanoma; a gastrointestinal cancer, for example: anal cancer; appendix cancer; biliary tract cancer; bowel cancer; cholangiocarcinoma; colon adenocarcinoma; colon adenoma; colon cancer; exocrine pancreatic carcinoma; extrahepatic bile duct cancer; gallbladder cancer; gastric (stomach) cancer; gastrointestinal cancer; gastrointestinal carcinoid tumor; gastrointestinal carcinoid tumor; gastrointestinal stromal tumor (GIST); hepatocellular cancer; hepatoblastoma; kidney cancer; large bowel cancer; liver cancer; ocolorectal cancer; pancreatic cancer; rectal cancer; or small bowel cancer; a genitourinary or gynecologic cancer, for example: bladder cancer; cervical cancer; endometrial cancer; extragonadal germ cell tumor; genito-urinary cancer; gestational trophoblastic tumor; gynaecological cancer; ovarian cancer; ovarian epithelial cancer; ovarian germ cell tumor; penile cancer; prostate cancer; renal cell carcinoma; renal pelvis and ureter, transitional cell cancer; seminoma; teratocarcinoma; testicular cancer; transitional cell cancer of the ureter and renal pelvis; urethral cancer; uterine sarcoma; vaginal cancer; vulvar cancer; or Wilms tumor; a cancer of the head or neck, for example: esophageal cancer; head and neck cancer; head and neck squamous cell carcinoma; hypopharyngeal cancer; nasopharyngeal cancer; nasopharyngeal carcinoma; oral cancer; oropharyngeal cancer; paranasal sinus and nasal cavity cancer; pharyngeal cancer; or salivary gland cancer; a hematopoietic cancer, for example: a plasma cell neoplasm, for example, plasmacytoma or multiple myeloma; a leukemia, for example: acute biphenotypic leukemia; acute eosinophilic leukemia; acute lymphoblastic leukemia; acute myeloid dendritic cell leukemia; acute myeloid leukemia; acute promyelocytic leukemia; B-cell prolymphocytic leukemia; chronic lymphocytic leukemia; chronic myelogenous leukemia; hairy cell leukemia; large granular lymphocytic leukemia; mast cell leukemia; precursor B lymphoblastic leukemia; T-cell prolymphocytic leukemia; a lymphoma, for example: AIDS-related lymphoma; anaplastic large cell lymphoma; angioimmunoblastic T-cell lymphoma; Burkitt's lymphoma; cutaneous T-cell lymphoma; diffuse large B-cell lymphoma; follicular lymphoma; hepatosplenic T-cell lymphoma; Hodgkin's lymphoma; intravascular large B-cell lymphoma; lymphomatoid granulomatosis; lymphoplasmacytic lymphoma; mantle cell lymphoma; marginal zone B-cell lymphoma; mediastinal large B cell lymphoma; mucosa-associated lymphoid tissue lymphoma; mycosis fungoides; nodal marginal zone B cell lymphoma; non-Hodgkin lymphoma; plasmablastic lymphoma; primary central nervous system lymphoma; primary cutaneous follicular lymphoma; primary cutaneous immunocytoma; primary effusion lymphoma; Sézary syndrome; or splenic marginal zone lymphoma; or a myelodysplastic syndrome; a skin cancer, for example: basal cell carcinoma; dermatofibrosarcoma protuberans; fibrosarcoma; keratoacanthoma; malignant melanoma; melanoma; Merkel cell carcinoma; sebaceous carcinoma; or squamous cell carcinoma; a thoracic and respiratory cancer, for example: adenocarcinoma; bronchial adenoma; bronchial carcinoid; laryngeal cancer; lung cancer; mediastinum cancer; mesothelioma; non-small cell lung cancer; peritoneal cancer; pleuropulmonary blastoma; small cell lung cancer; thymic carcinoma; or thymoma carcinoma; an HIV/AIDS related cancer, for example, Kaposi sarcoma; or other cancer, for example, epithelioid hemangioendothelioma; desmoplastic small round cell tumor; or liposarcoma. In one embodiment, the cancer is: endometrial cancer, uterine cancer, ovarian cancer, breast cancer, gastric cancer, bladder cancer, pancreatic cancer, mesothelioma, kidney cancer, stomach cancer, esophageal cancer, colorectal cancer, glioblastoma, lung cancer, or lung squamous cell carcinoma. In one embodiment, the cancer is endometrial cancer. In one embodiment, the cancer is uterine cancer. In one embodiment, the cancer is ovarian cancer. In one embodiment, the cancer is breast cancer. In one embodiment, the cancer is gastric cancer. In one embodiment, the cancer is bladder cancer. In one embodiment, the cancer is pancreatic cancer. In one embodiment, the cancer is mesothelioma. In one embodiment, the cancer is kidney cancer. In one embodiment, the cancer is stomach cancer. In one embodiment, the cancer is esophageal cancer. In one embodiment, the cancer is colorectal cancer. In one embodiment, the cancer is glioblastoma. In one embodiment, the cancer is lung cancer. In one embodiment, the cancer is lung squamous cell carcinoma. In one embodiment, the cancer is characterised by, or further characterised by inappropriate activity (e.g., overexpression) of PKMYT1. For example, in one embodiment, the cancer is: lung squamous cell carcinoma, lung adenocarcinoma, uterine corpus endometrial carcinoma, breast cancer, breast invasive carcinoma, hepatocellular carcinoma, clear-cell renal- cell carcinoma, kidney chromophobe cancer, renal papillary cell carcinoma, head and neck squamous cell carcinoma, colon adenocarcinoma, stomach adenocarcinoma, thyroid carcinoma, prostate adenocarcinoma, adrenocortical carcinoma, lower grade glioma, mesothelioma, pancreatic adenocarcinoma, skin cutaneous melanoma, uveal melanoma. In one embodiment, the cancer is characterised by, or further characterised by involvement of PKMYT1 in progression, invasion and/or metastasis. For example, in one embodiment, the cancer is: non-small cell lung cancer, osteosarcoma, clear cell renal cell carcinoma, oral squamous cell carcinoma, gastric cancer, prostate cancer, oesophageal squamous cell carcinoma, colorectal cancer, hepatocellular carcinoma, ovarian cancer, neuroblastoma (in particular, with MYCN amplification), glioblastoma, acute lymphoblastic leukemia, multiple myeloma, Kaposi’s sarcoma, primary effusion lymphoma (PEL), or the plasmablastic variant of multicentric Castleman’s disease. In one embodiment, the cancer is characterised by, or further characterised by inappropriate activity (e.g., overexpression) of CCNE1. For example, in one embodiment, the cancer is: uterine carcinosarcoma, uterine cancer, endometrial cancer, breast cancer, ovarian cancer, stomach cancer, colorectal cancer, bladder cancer, oesophageal cancer, cervical cancer, sarcoma, lung squamous cancer, adenoid cystic carcinoma, pancreatic cancer, mesothelioma, lung adenocarcinoma, head & neck cancer, diffuse large B-cells lymphoma, or liver cancer. In one embodiment, the cancer is characterised by, or further characterised by inappropriate activity (e.g., overexpression) of CCNE1. For example, in one embodiment, the cancer is: uterine carcinosarcoma, uterine cancer, endometrial cancer, breast cancer, ovarian cancer, stomach cancer, colorectal cancer, bladder cancer, oesophageal cancer, cervical cancer, sarcoma, or lung squamous cancer. In one embodiment, the cancer is uterine carcinosarcoma (UCS) or uterine serous carcinoma (USC). In one embodiment, the cancer is high-grade serous ovarian carcinoma (HGSOC). In one embodiment, the cancer is high-grade serous ovarian cancer with CCNE1 amplification. In one embodiment, the cancer is triple-negative breast cancer (TNBC). In one embodiment, the cancer is characterised by, or further characterised by inappropriate activity (e.g., inactivation) of FBXW7. For example, in one embodiment, the cancer is: uterine carcinosarcoma, uterine cancer, endometrial cancer, breast cancer, ovarian cancer, stomach cancer, colorectal cancer, bladder cancer, oesophageal cancer, cervical cancer, sarcoma, lung squamous cancer, or head & neck cancer. In one embodiment, the cancer is characterised by, or further characterised by inappropriate activity (e.g., inactivation) of FBXW7. For example, in one embodiment, the cancer is: uterine carcinosarcoma, endometrial cancer, colorectal cancer, cervical cancer, bladder cancer, head & neck cancer, gastric cancer, or lung squamous cells carcinoma. In one embodiment, the cancer is uterine carcinosarcoma (UCS) or uterine serous carcinoma (USC). In one embodiment, the cancer is characterised by, or further characterised by inappropriate activity (e.g., inactivation, decreased activity, decreased expression) of PPP2R2A. For example, in one embodiment, the cancer is: prostate adenocarcinoma, ovarian serous cystadenocarcinoma, rectum adenocarcinoma, bladder urothelial carcinoma, colorectal adenocarcinoma, breast invasive carcinoma, uterine corpus endometrial carcinoma, uterine carcinosarcoma, liver hepatocellular carcinoma, lung squamous cell carcinoma, or lung adenocarcinoma. In one embodiment, the cancer (e.g., as above) is characterised, or further characterised, as treatment resistant cancer, e.g., chemotherapy-resistant cancer, radiotherapy-resistant cancer, and/or immunotherapy-resistant cancer. In one embodiment, the treatment resistant cancer is resistant to standard of care therapy. In one embodiment, the treatment resistant cancer is resistant to one or more of PARP inhibitors, cisplatin, WEE1 inhibitors and Cdk4/6 inhibitors. In one embodiment, the treatment resistant cancer is recombination proficient ovarian cancer. In one embodiment, the treatment resistant cancer is HER2- ER+ breast cancer with Cdk4/6 resistance. In one embodiment, the cancer (e.g., as above) 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 inhibition of cell cycle progression, the inhibition of angiogenesis (the formation of new blood vessels), the inhibition of metastasis (the spread of a tumour from its origin), the inhibition of cell migration (the spread of cancer cells to other parts of the body), the inhibition of invasion (the spread of tumour cells into neighbouring normal structures), the promotion of apoptosis (programmed cell death), death by necrosis, or induction of death by autophagy. The compounds described herein may be used in the treatment of the cancers described herein, independent of the mechanisms discussed herein. Treatment The term “treatment,” as used herein in the context of treating a disorder (e.g., disease), pertains generally to treatment of a human or an animal (e.g., in veterinary applications), in which some desired therapeutic effect is achieved, for example, the inhibition of the progress of the disorder (including, e.g., a reduction in the rate of progress, a halt in the rate of progress), alleviation of symptoms of the disorder, amelioration of the disorder, and cure of the disorder. Treatment as a prophylactic measure (i.e., prophylaxis) is also included. For example, use with subjects (e.g., patients) who have not yet developed the disorder, but who are at risk of developing the disorder, is encompassed by the term “treatment.” For example, treatment of cancer includes reducing the progress of cancer, alleviating the symptoms of cancer, reducing the incidence of cancer, prophylaxis of cancer, etc. The term “therapeutically-effective amount,” as used herein, pertains to that amount of a compound, or a material, composition, or dosage form comprising a compound, which is effective for producing some desired therapeutic effect, commensurate with a reasonable benefit/risk ratio, when administered in accordance with a desired treatment regimen. Combination Therapies The term “treatment” as used herein includes combination treatments and therapies, in which two or more treatments or therapies are combined, for example, sequentially or simultaneously. For example, the BAA compounds described herein may also be used in combination therapies, e.g., in conjunction with other agents. Accordingly, also described herein is a BAA compound, as described herein, in combination with one or more (e.g., 1, 2, 3, 4, etc.) additional therapeutic agents. For example, also described herein is a BAA compound, as described herein, for use in a method of treatment of the human or animal body by therapy, for example, for use in a method of treatment of a disorder (e.g., a disease) as described herein, where the BAA compound is administered in combination with one or more (e.g., 1, 2, 3, 4, etc.) additional therapeutic agents. Also described herein is use of a BAA compound, as described herein, in a method of treatment of the human or animal body by therapy, for example, in a method of treatment of a disorder (e.g., a disease) as described herein, where the BAA compound is administered in combination with one or more (e.g., 1, 2, 3, 4, etc.) additional therapeutic agents. Also described herein is use of a BAA compound, as described herein, in a method of treatment of the human or animal body by therapy, for example, in a method of treatment of a disorder (e.g., a disease) as described herein, where the BAA compound is administered in combination with one or more (e.g., 1, 2, 3, 4, etc.) additional therapeutic agents. Also described herein is use of a BAA compound, as described herein, in the manufacture of a medicament, for example, for use in a method of treatment, for example, for use in a method of treatment of a disorder (e.g., a disease) as described herein, where the BAA compound is administered in combination with one or more (e.g., 1, 2, 3, 4, etc.) additional therapeutic agents. In one embodiment, the medicament comprises the BAA compound. 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, where the BAA compound is administered in combination with one or more (e.g., 1, 2, 3, 4, etc.) additional therapeutic agents. The particular combination would be at the discretion of the physician who would select dosages using their common general knowledge and dosing regimens known to a skilled practitioner. The agents (e.g., the BAA compound as described herein, plus one or more other agents) may be administered simultaneously or sequentially, and may be administered in individually varying dose schedules and via different routes. For example, when administered sequentially, the agents can be administered at closely spaced intervals (e.g., over a period of 5-10 minutes) or at longer intervals (e.g., 1, 2, 3, 4 or more hours apart, or even longer periods apart where required), the precise dosage regimen being commensurate with the properties of the therapeutic agent(s). The agents (e.g., the BAA compound described here, plus one or more other agents) may be formulated together in a single dosage form, or alternatively, the individual agents may be formulated separately, and optionally may be presented together in the form of a kit, optionally with instructions for their use. In one embodiment, the other agent (e.g., the additional therapeutic agent) is an immunotherapeutic agent, for example, an immune checkpoint inhibitor. In one embodiment, the other agent (e.g., the additional therapeutic agent, for example the additional anti-cancer agent) is an immunotherapy agent, such as a monoclonal antibody (for example trastuzumab, bevacizumab, cetuximab, daratumumab, or naxitamab, necitumumab, obinutuzumab, ofatumumab, panitumumab, pertuzumab, ramucirumab, or rituximab), a bispecific antibody (for example blinatumomab), an immune checkpoint inhibitor (for example ipilimumab, nivolumab, pembrolizumab, cemiplimab, atezolizumab, durvalumab, avelumab, dostarlimab, or tremelimumab), an immunomodulator (for example imiquimod, thalidomide, lenalidomide, or ponalidomide), a cytokine such as an interleukin (for example IL-2 aldesleukin), an interferon (for example IFNa), an oncolytic virus (for example talimogene laherparepvec), or a T-cell therapy. In one embodiment, the other agent is an antibody-drug conjugate (i.e. an “ADC”, for example brentuximab vedotin, inotuzumab ozogamicin, mirvetuximab soravtansine-gynx, fam- trastuzumab deruxtecan-nxki, ado-trastuzumab emtansine, gemtuzumab ozogamicin, enfortumab vedotin-ejfv, polatuzumab vedotin-piiq, tisotumab vedotin-tftv, sacituzumab govitecan-hziy, loncastuximab tesirine-lpyl, or distamab vedotin). In one embodiment, the other agent is a DNA-damaging agent, such as an alkylating agent (for example cis-platin, oxaliplatin, carboplatin, cyclophosphamide, melphalan, chlorambucil, bendamustine, temozolomide, trabectidin, mitomycin C, or dacarbazine); an antimetabolite (for example capecitabine, gemcitabine, 5-fluorouracil, fluoropyrimidine, trifluridine and tipiracil, cytarabine, or methotrexate); a DNA intercalator (for example an anthracycline like doxorubicin, epirubicin, or daunorubicin), an antibiotic (for example bleomycin, dactinomycin, or mithramycin); a topoisomerase 1 inhibitor (for example a camptothecin such as irinotecan, or topotecan), a topoisomerase 2 inhibitor (for example etoposide), a microtubule-targeting agent (for example a taxane such as paclitaxel; or a vinca alkaloid such as vincristine, vinblastine, vindesine, vinorelbine, or eribulin); or an antibiotic (for example bleomycin, or mitomycin-C). In one embodiment, the other agent is a topoisomerase I inhibitor (for example irinotecan or topotecan), a topoisomerase II inhibitor (for example etoposide), or an antimetabolite (for example gemcitabine). In one embodiment, the other agent is an alkylating agent (for example cis-platin). In one embodiment, the other agent is a topoisomerase I inhibitor (for example irinotecan or topotecan). In one embodiment, the other agent is a topoisomerase II inhibitor (for example etoposide). In one embodiment, the other agent is an antimetabolite (for example gemcitabine). In one embodiment, the other agent is a DNA-damage repair inhibitor (for example a PARP inhibitor such as olaparib, rucaparib, niraparib, or talazoparib; or a PARG inhibitor; or a USP1 inhibitor). In one embodiment, the other agent is double strand-break repair inhibitor (for example a Pol ^ inhibitor, or a RAD51 inhibitor). In one embodiment, the other agent is a signalling pathway inhibitor, such as a kinase inhibitor (for example abemaciclib, acalabrutinib, afatinib, alectinib, avapritinib, axitinib, baricitinib, belumosudil, binimetinib, bosutinib, brigatinib, cabozantinib, capmatinib, ceritinib, cobimetinib, rizotinib, dabrafenib, dacomitinib, dasatinib, encorafenib, entrectinib, erdafitinib, erlotinib, everolimus, fedratinib, fostamatinib, gefitinib, gilteritinib, ibrutinib, imatinib, infigratinib, lapatinib, larotrectinib, lenvatinib, lorlatinib, midostaurin, mobocertinib, neratinib, netarsudil, nilotinib, nintedanib, osimertinib, palbociclib, pazopanib, pemigatinib, pexidartinib, ponatinib, pralsetinib, regorafenib, ribociclib, ripretinib, ruxolitinib, selpercatinib, selumetinib, sirolimus, sorafenib, sunitinib, temsirolimus, tepotinib, tivozanib, tofacitinib, trametinib, trilaciclib, tucatinib, upadacitinib, vandetanib, vemurafenib, or zanubrutinib). In one embodiment, the other agent is a cell cycle targeting inhibitor, such as a CDK4/6 inhibitor (for example palbociclib, abemaciclib, or ribociclib). In one embodiment, the other agent is an agent targeting DNA damage checkpoints, such as an ATR inhibitor (for example ceralasertib, gartisertib, tuvusertib, elimusertib, or camonsertib), an ATM inhibitor (for example AZD0156), a CHK1 inhibitor (for example prexasertib), a CHK2 inhibitor, a WEE1 inhibitor (for example adavosertib, or azenosertib), a PLK1 inhibitor (for example onvansertib), or an AUR-A inhibitor (for example JAB-2485). In one embodiment, the other agent is an ATR inhibitor (for example ceralasertib, gartisertib, tuvusertib, elimusertib, or camonsertib), a CHK1 inhibitor (for example prexasertib), or a WEE1 inhibitor (for example adavosertib, or azenosertib). In one embodiment, the other agent is an ATR inhibitor (for example ceralasertib, gartisertib, tuvusertib or camonsertib), or a WEE1 inhibitor (for example azenosertib). In one embodiment, the other agent is a CHK1 inhibitor (for example prexasertib). In one embodiment, the other agent is an ATR inhibitor (for example ceralasertib, gartisertib, tuvusertib, elimusertib, or camonsertib). In one embodiment, the other agent is a WEE1 inhibitor (for example adavosertib, or azenosertib). In one embodiment, the agent is a hormone therapy agent, such as an antiestrogen (for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene, or idoxifene), an antiandrogen (for example abiraterone, bicalutamide, enzalutamide, flutamide, nilutamide, or cyproterone acetate), an LHRH antagonist or LHRH agonist (for example goserelin, leuprorelin, or buserelin), a progestogen (for example megestrol acetate), an aromatase inhibitor (for example as anastrozole, letrozole, vorazole, or exemestane) an inhibitor of 5α-reductase (for example finasteride) or an analogue of somatostatin (for example lanreotide). In one embodiment, the other agent is a proteasome inhibitor (for example bortezomib), a histone deacetylase inhibitor (for example vorinostat, romidepsin, panobinostat, or belinostat), or a DNA demethylating agent (for example azacitidine, or decitabine). In one embodiment, the other agent is radiotherapy, such as radiotherapy comprising treatment with a radiotherapeutic drug (for example lutetium Lu 177 dotatate, lutetium Lu 177 vipivotide tetraxetan, samarium Sm 153 lexidronam, radium Ra 223 dichloride, or Y-90 ibritumomab tiuxetan). Other Uses 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 sactivity 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 Also describes herein is a kit comprising (a) a BAA compound, as described herein, preferably provided as a composition (e.g., a pharmaceutical composition) and in a suitable container and/or with suitable packaging; and (b) instructions for use, for example, in a method of treatment of a disorder (e.g., a disease) as described herein, for example, written instructions on how to administer the compound. The written instructions may also include a list of indications for which the BAA compound is a suitable treatment. Routes of Administration 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; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; by implant of a depot or reservoir, for example, subcutaneously or intramuscularly. The Subject The subject (e.g., patient) may be a chordate, a vertebrate, a mammal, a placental mammal, a marsupial (e.g., kangaroo, wombat), a rodent (e.g., a guinea pig, a hamster, a rat, a mouse), murine (e.g., a mouse), a lagomorph (e.g., a rabbit), avian (e.g., a bird), canine (e.g., a dog), feline (e.g., a cat), equine (e.g., a horse), porcine (e.g., a pig), ovine (e.g., a sheep), bovine (e.g., a cow), a primate, simian (e.g., a monkey or ape), a monkey (e.g., marmoset, baboon), an ape (e.g., gorilla, chimpanzee, orangutan, gibbon), or a human. Furthermore, the subject (e.g., patient) may be any of its forms of development, for example, a foetus. In one preferred embodiment, the subject (e.g., patient) is a human. Formulations While it is possible for a BAA compound to be administered alone, it is preferable to present it as a pharmaceutical formulation (e.g., composition, preparation, medicament) comprising at least one BAA compound, as described herein, together with one or more other pharmaceutically acceptable ingredients well known to those skilled in the art, including, for example, pharmaceutically acceptable carriers, diluents, excipients, adjuvants, fillers, buffers, preservatives, anti-oxidants, lubricants, stabilisers, solubilisers, surfactants (e.g., wetting agents), masking agents, colouring agents, flavouring agents, and sweetening agents. The formulation may further comprise other active agents, for example, other therapeutic or prophylactic agents. Thus, also described herein are pharmaceutical compositions, as defined above, and methods of making a pharmaceutical composition comprising mixing at least one BAA compound, as described herein, together with one or more other pharmaceutically acceptable ingredients well known to those skilled in the art, e.g., carriers, diluents, excipients, 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 carrier, diluent, excipient, etc. must also be “acceptable” in the sense of being compatible with the other ingredients of the formulation. Suitable carriers, diluents, excipients, etc. can be found in standard pharmaceutical texts, for example, Remington: The Science and Practice of Pharmacy, 21st edition, Lippinott Williams and Wilkins, 2005; Remington: The Science and Practice of Pharmacy, 22nd edition, Pharmaceutical Press, 2012; and Handbook of Pharmaceutical Excipients, 7th edition, Pharmaceutical Press, 2012. The formulations may be prepared by any methods well known in the art of pharmacy. Such methods include the step of bringing into association the compound with a carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the compound with carriers (e.g., liquid carriers, finely divided solid carrier, etc.), and then shaping the product, if necessary. 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, losenges, pastilles, capsules (including, e.g., hard and soft gelatin capsules), cachets, pills, ampoules, boluses, suppositories, pessaries, tinctures, gels, pastes, ointments, creams, lotions, oils, foams, sprays, mists, or aerosols. 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. 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 (e.g., by ingestion) include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in- water, water-in-oil), elixirs, syrups, electuaries, tablets, granules, powders, capsules, cachets, pills, ampoules, boluses. Formulations suitable for buccal administration include mouthwashes, losenges, pastilles, as well as patches, adhesive plasters, depots, and reservoirs. Losenges typically comprise the compound in a flavoured basis, usually sucrose and acacia or tragacanth. Pastilles typically comprise the compound in an inert matrix, such as gelatin and glycerin, or sucrose and acacia. Mouthwashes typically comprise the compound in a suitable liquid carrier. Formulations suitable for sublingual administration include tablets, losenges, pastilles, capsules, and pills. Formulations suitable for oral transmucosal administration include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), mouthwashes, losenges, 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, 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 machine the compound in a free-flowing form such as a powder or granules, optionally mixed with one or more binders (e.g., povidone, gelatin, acacia, sorbitol, tragacanth, hydroxypropylmethyl cellulose); fillers or diluents (e.g., lactose, microcrystalline cellulose, calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, silica); disintegrants (e.g., sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose); surface- active or dispersing or wetting agents (e.g., sodium lauryl sulfate); preservatives (e.g., methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, sorbic acid); flavours, flavour enhancing agents, and sweeteners. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled 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 ointment base. Creams are typically prepared from the compound and an oil-in-water cream base. If desired, the aqueous phase of the cream base may include, for example, at least about 30% w/w of a polyhydric alcohol, i.e., an alcohol having two or more hydroxyl groups such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol and mixtures thereof. The topical formulations may desirably include a compound which enhances absorption or penetration of the compound through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogues. Emulsions are typically prepared from the compound and an oily phase, which may optionally comprise merely an emulsifier (otherwise known as an emulgent), or it may comprise a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabiliser. It is also preferred to include both an oil and a fat. Together, the emulsifier(s) with or without stabiliser(s) make up the so-called emulsifying wax, and the wax together with the oil and/or fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations. Suitable emulgents and emulsion stabilisers include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulfate. The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the compound in most oils likely to be used in pharmaceutical emulsion formulations may be very low. Thus the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers. Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used. Formulations suitable for intranasal administration, where the carrier is a liquid, include, for example, nasal spray, nasal drops, or by aerosol administration by nebuliser, include aqueous or oily solutions of the compound. Formulations suitable for intranasal administration, where the carrier is a solid, include, for example, those presented as a coarse powder having a particle size, for example, in the range of about 20 to about 500 microns which is administered in the manner in which snuff is taken, i.e., by rapid inhalation through the nasal passage from a container of the powder held close up to the nose. Formulations suitable for pulmonary administration (e.g., by inhalation or insufflation therapy) include those presented as an aerosol spray from a pressurised pack, with the use of a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichorotetrafluoroethane, carbon dioxide, or other suitable gases. Formulations suitable for ocular administration include eye drops wherein the compound is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the compound. 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, 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 (e.g., by injection), include aqueous or non-aqueous, isotonic, pyrogen-free, sterile liquids (e.g., solutions, suspensions), in which the compound is dissolved, suspended, or otherwise provided (e.g., in a liposome or other microparticulate). Such liquids may additionally contain other pharmaceutically acceptable ingredients, such as anti-oxidants, buffers, preservatives, stabilisers, bacteriostats, suspending agents, thickening agents, and solutes which render the formulation isotonic with the blood (or other relevant bodily fluid) of the intended recipient. Examples of excipients include, for example, water, alcohols, polyols, glycerol, vegetable oils, and the like. Examples of suitable isotonic carriers for use in such formulations include Sodium Chloride Injection, Ringer's Solution, or Lactated Ringer's Injection. Typically, the concentration of the compound in the liquid is from about 1 ng/mL to about 10 μg/mL, for example from about 10 ng/mL to about 1 μg/mL. The formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets. Dosage It will be appreciated by one of skill in the art that appropriate dosages of the BAA compounds, and compositions comprising the BAA compounds, can vary from subject to subject (e.g., from patient to patient). Determining the optimal dosage will generally involve balancing the level of therapeutic benefit against any risk or deleterious side effects. The selected dosage level will depend on a variety of factors including, for example: the activity of the particular BAA compound; the route of administration; the time of administration; the rate of excretion of the BAA compound; the duration of the treatment; other drugs, compounds, and/or materials used in combination; the severity of the disorder; and the species, sex, age, weight, condition, general health, and prior medical history of the subject (e.g., patient). The amount of BAA compound and route of administration will ultimately be at the discretion of the physician, veterinarian, or clinician, although generally the dosage will be selected to achieve local concentrations at the site of action which achieve the desired effect without causing substantial harmful or deleterious side-effects. Administration can be effected in one dose, continuously or intermittently (e.g., in divided doses at appropriate intervals) throughout the course of treatment. Methods of determining the most effective means and dosage of administration are well known to those of skill in the art and will vary with the formulation used for therapy, the purpose of the therapy, the target cell(s) being treated, and the subject being treated. Single or multiple administrations can be carried out with the dose level and pattern being selected by the treating physician, veterinarian, or clinician. In general, a suitable dose of the BAA compound is in the range of about 0.01 mg to about 5000 mg (more typically about 0.1 mg to about 1000 mg, e.g., about 0.1 mg to about 300 mg) per day. Where the compound is a salt, a solvate, an ester, an amide, a prodrug, or the like, the amount administered is calculated on the basis of the parent compound and so the actual weight to be used is increased proportionately. EXAMPLES Chemical Synthesis Abbreviations DCM Dichloromethane (methylene chloride) DIPEA N,N-diisopropylethylamine-- DMSO Dimethylsulfoxide ES Electrospray ionisation EtOAc Ethyl acetate EtOH Ethanol (ethyl alcohol) MeOH Methanol (methyl alcohol) Pd/C Palladium on carbon Pd2dba3 tris(dibenzylideneacetone)dipalladium(0) PE Petroleum ether RT Room temperature T3P 1-Propanephosphonic anhydride THF Tetrahydrofuran UPLC Ultra Performance Liquid Chromatography XantPhos 4,5-bis(diphenylphospheno)-9,9-dimethylxanthene Methods General Experimental Flash chromatography was performed using pre-packed silica gel cartridges (RediSep Rf, Isco). Thin layer chromatography was conducted with 5 × 10 cm plates coated with Merck Type 60 F254 silica gel to a thickness of 0.25 mm. All reagents obtained from commercial sources were used without further purification. Anhydrous solvents were obtained from the Sigma-Aldrich Chemical Company Ltd. or Fisher Chemicals Ltd., and used without further drying. HPLC grade solvents were obtained from Fisher Chemicals Ltd. All compounds were >90 % purity as determined by examination of both the LCMS and 1H NMR spectra unless otherwise indicated. Where Cl or Br were present, expected isotopic distribution patterns were observed. NMR Proton (1H) and carbon (13C) and (19F) NMR spectra were recorded on a 300 MHz Bruker or 400 MHz Jeol spectrometer. Solutions were typically prepared in either deuterated chloroform (Chloroform-d), deuterated methanol (Methanol-d4) or deuterated dimethylsulfoxide (DMSO-d6) with chemical shifts referenced to tetramethylsilane (TMS) or deuterated solvent as an internal standard.1H NMR data are reported indicating the chemical shift (δ), the integration (e.g., 1H), the multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad; dd, doublet of doublets) and the coupling constant (J) in Hz. Deuterated solvents were purchased from the Sigma-Aldrich Chemical Company, Goss or Fluorochem. Analytical LCMS LCMS analyses were performed on a Waters Acquity UPLC using BEH C181.7 µM columns (2.1 × 50 mm) with a diode array detector coupled to a SQD mass spectrometer with optional ELS detection (Acquity UPLC ELS Detector) or, a Waters Acquity I-Class UPLC using BEH C181.7 µM columns (2.1 × 50 mm) with a diode array detector coupled to a QDa mass spectrometer. Analyses were performed with either buffered acidic or basic solvents using gradients as detailed below: Low pH: Solvent A – Water + 10 mM ammonium hydrogen carbonate + 0.1 % formic acid Solvent B – MeCN + 5 % water + 0.1 % formic acid High pH: Solvent A – Water + 10 mM ammonium hydrogen carbonate + 0.1 % ammonia solution Solvent B – MeCN + 5 % water + 0.1 % ammonia solution Gradient:
Figure imgf000142_0001
For some compounds, the following gradients were used: Acidic 2 min 0.1% v/v Formic acid in 10mM ammonium formate [Eluent A]; 0.1% v/v Formic acid in MeCN [Eluent B]; flow rate 0.8mL/min; column oven 50˚C; sample manager 20˚C; injection volume 2 ^L and 1.5 minutes equilibration time between samples, on a Waters Acquity UPLC BEH C18 column (2.1 × 50 mm, 1.7 ^m). Gradient:
Figure imgf000142_0002
Figure imgf000143_0001
Acidic 4 min 0.1% v/v formic acid in 10mM ammonium formate [Eluent A]; 0.1% v/v formic acid in MeCN [Eluent B]; flow rate 0.8mL/min; column oven 50˚C; sample manager 20˚C; injection volume 2 ^L and 1.5 minutes equilibration time between samples on a Waters Acquity UPLC BEH C18 column (2.1 × 50 mm, 1.7 ^m).
Figure imgf000143_0002
Acidic 6 min (“Acidic_Prep_Analysis”) 0.1% v/v formic acid in 10mM ammonium formate [Eluent A]; 0.1% v/v formic acid in MeCN [Eluent B]; flow rate 0.8mL/min; column oven 50˚C; sample manager 20˚C; injection volume 2 ^L and 1.5 minutes equilibration time between samples on a Waters Acquity UPLC BEH C18 column (2.1 × 50 mm, 1.7 ^m).
Figure imgf000143_0003
Basic 2 min 0.1% ammonia in water [Eluent A]; 0.1% ammonia in MeCN [Eluent B]; flow rate 0.8mL/min; column oven 50˚C; sample manager 20˚C; injection volume 2 ^L and 1.5 minutes equilibration time between samples on a Waters Acquity UPLC BEH C18 column (2.1 × 50 mm, 1.7 ^m).
Figure imgf000144_0001
Basic 4 min 0.1% ammonia in water [Eluent A]; 0.1% ammonia in MeCN [Eluent B]; flow rate 0.8mL/min; column oven 50˚C; sample manager 20˚C; injection volume 2 ^L and 1.5 minutes equilibration time between samples on a Waters Acquity UPLC BEH C18 column (2.1 × 50 mm, 1.7 ^m).
Figure imgf000144_0002
Basic 6 min (“Basic_Prep_Analysis”) 0.1% ammonia in water [Eluent A]; 0.1% ammonia in MeCN [Eluent B]; flow rate 0.8mL/min; column oven 50˚C; sample manager 20˚C; injection volume 2 ^L and 1.5 minutes equilibration time between samples on a Waters Acquity UPLC BEH C18 column (2.1 × 50 mm, 1.7 ^m).
Figure imgf000144_0003
Preparative HPLC-MS Some compounds were purified by preparative HPLC on a Waters FractionLynx MS autopurification system, with a Phenomonex Gemini NX 5 µm C18, 100 mm × 21.2 mm i.d. column (for low pH runs) or a Waters XBridge 5 µm C18, 100 mm × 19 mm i.d. column (for high pH runs), running at a flow rate of 20 mL/min with UV diode array detection (210–400 nm) and mass-directed collection using both positive and negative mass ion detection. Alternatively, Preparative HPLC purification was carried out either on a Teledyne ISCO ACCQPrep® HP150 system or on a Waters Mass-directed PrepLC system, with a C1 XBridge BEH C18 (dimensions: 19 mm x 150 mm 5 μm) or a C2 XBridge BEH C18 (dimensions: 19 mm x 150 mm 5 μm) column, running a flow rate of 20 mL/min. All masses were detected with electrospray ionisation (ESI). Purifications were performed using buffered acidic or basic solvent systems as appropriate. Compound retention times on the system were routinely assessed using a 30 - 50 µL test injection and a standard gradient, then purified using an appropriately chosen focussed gradient as detailed below, based upon observed retention time. Low pH: Solvent A – Water + 10 mM ammonium formate + 0.1 % formic acid Solvent B – MeCN + 5 % water +0.1 % formic acid High pH: Solvent A – Water + 10 mM ammonium formate + 0.1 % ammonia solution Solvent B – MeCN + 5 % water + 0.1 % ammonia solution or MeCN + 0.1 % ammonia solution Standard Gradient:
Figure imgf000145_0001
Focused Gradients:
Figure imgf000145_0002
Figure imgf000146_0004
Synthetic Methods Several methods for the chemical synthesis of the compounds of the present invention are described herein. These and/or other well-known methods may be modified and/or adapted in known ways in order to facilitate the synthesis of additional compounds within the scope of the present invention.
Figure imgf000146_0001
Nitro pyrazole precursors 2-Methyl-1-(3-nitropyrazol-1-yl)propan-2-ol
Figure imgf000146_0002
A suspension of 3-Nitro-1H-pyrazole (1000 mg, 8.84 mmol, 1.00 eq), Isobutylene oxide (1.6 mL, 18.0 mmol, 2.04 eq), and cesium carbonate (6500 mg, 19.9 mmol, 2.26 eq) was stirred overnight at 80°C. Upon completion, the reaction mixture was poured into water (200 mL) and the aqueous phase was extracted with EtOAc (5 x 50 mL). The combined organic phase was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EtOAc 0 to 100%) to afford 2-methyl-1-(3-nitropyrazol-1-yl)propan-2-ol (1000 mg, 5.40 mmol, 61%) as a yellowish solid. MS (ES+): m/z 186.3 (M+H). Used in the next step without further purification. Synthesis of alkyl halides 2-Chloro-1-[2-(trifluoromethyl)pyrrolidin-1-yl]ethanone
Figure imgf000146_0003
Chloroacetyl chloride (1.09 eq, 0.30 mL, 3.77 mmol) was added dropwise to a cooled solution of (±)-2-(trifluoromethyl)pyrrolidine (1 eq, 480 mg, 3.45 mmol) and triethylamine (2.08 eq, 1.0 mL, 7.17 mmol) in DCM (10 mL) at 0 °C. After 1h, the reaction mixture was diluted with DCM (50mL) and washed with water (2x 50mL), dried over sodium sulfate, filtered and evaporated to afford 2-chloro-1-[2-(trifluoromethyl)pyrrolidin-1-yl]ethanone (0.71 g, 3.29 mmol, 95.45% yield) as a brown oil.1H NMR (400 MHz, CDCl3) δ 4.87 – 4.45 (m, 1H), 4.26 – 3.99 (m, 2H), 3.84 – 3.45 (m, 2H), 2.31 – 1.92 (m, 4H).19F NMR (376 MHz, CDCl3, decoupled) δ -73.94, -74.07. General Method A1: Alkylation of 3-nitro-1H-pyrazoles
Figure imgf000147_0001
Alkyl halide (1 eq) is added dropwise to a suspension of unsubstituted or substituted nitropyrazole (1 eq) and potassium carbonate (1.5 eq) in anhydrous THF, with stirring at room temperature under nitrogen. The reaction mixture is then heated to 65-75 °C with stirring for 4 hours, before cooling to room temperature and separating between ethyl acetate and water. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give the product. Ethyl 2-(5-methyl-3-nitro-pyrazol-1-yl)acetate
Figure imgf000147_0002
Prepared as described in Method A1: Ethyl bromoacetate (0.87 mL, 7.87 mmol) was added drop-wise to a suspension of 5-methyl-3-nitro-1H-pyrazole (1.0 g, 7.87 mmol) and potassium carbonate (1.65 g, 11.8 mmol) in anhydrous THF (20 mL), with stirring at room temperature under nitrogen. The reaction mixture was then heated to 75 °C with stirring for 4 hours, before cooling to room temperature and separating between ethyl acetate and water. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give the product (1.63 g, 97% yield) as a white solid that did not need further purification. MS (ES+) m/z 214.2 (M+H).1H NMR (DMSO-d6, 300 MHz) δ 6.91 (s, 1H), 5.24 (s, 2H), 4.19 (q, 2H, J = 7.1 Hz), 2.29 (s, 3H), 1.22 (t, 3H, J = 7.1 Hz). The following examples were prepared in a similar manner from the appropriate nitro- pyrazole:
Figure imgf000147_0003
Figure imgf000148_0003
From Mitsunobu reaction with 3-nitro-1H-pyrazole
Figure imgf000148_0001
General Method A2: Mitsunobu reaction with 3-nitro-1H-pyrazole DIAD (1.1 - 1.6 eq) was added dropwise to a solution of alcohol (1.0 eq), 3-nitro-1H- pyrazole (1.0 eq) and PPh3 (1.1 - 1.5 eq) in anhydrous THF (0.2 – 0.4 M) with stirring, under nitrogen. The mixture was stirred overnight at RT before concentrating to dryness to give the crude product, which was chromatographed (SiO2) eluting with 0 -50% EtOAc:PE. tert-Butyl (3R)-3-(3-nitropyrazol-1-yl)pyrrolidine-1-carboxylate
Figure imgf000148_0002
Prepared as described in Method A2 from 3-nitro-1H-pyrazole (1.2 g, 12.7 mmol, 1.0 eq), (S)-1-N-boc-3-hydroxy-pyrrolidine (2.0 g, 10.7 mmol, 1.0 eq), PPh3 (3.36 g, 12.82 mmol, 1.2 eq) and DIAD (2.52 mL, 12.82 mmol, 1.2 eq) in anhydrous THF (50 mL) to afford the title compound (1.81 g, 6.41 mmol, 60%) as a clear colourless oil after normal phase chromatography (SiO2) eluting with 0 -50% EtOAc:PE. MS (ES+) m/z 227.2 (M-tBu+H).1H NMR (Chloroform-d, 300 MHz) δ 7.51O (sN, 1H), 7.07 (d, 1H, J = 2.1 Hz), 5.73-5.64 (m, 1H), 3.87-3.50 (m, 4H), 2.55-2.45 (m, 1H), 2.43-2.30 (m, 1H), 1.43 (s, 9H) ppm The following examples were prepared in a similar manner from the appropriate alcohol:
Figure imgf000148_0004
2N N O
Figure imgf000149_0004
5-Methyl-1-methylsulfonyl-3-nitro-pyrazole
Figure imgf000149_0001
To a stirred solution of methyl 5-methyl-3-nitro-1H-pyrazole (1000 mg, 7.87 mmol) in DCM (40 mL) at 0 °C was added triethylamine (1.5 mL, 10.5 mmol) followed by methanesulfonyl chloride (661 uL, 8.53 mmol) . The mixture was stirred for 10 min then allowed to warm to rt and stirred for an additional 1 h. The reaction mixture was diluted with DCM (50 mL) and was washed with NaHCO3 (3 x 30 mL), 0.5 M NaOH (30 mL), 0.5 M HCl (2 x 30 mL) and brine (30 mL). The organic phase was dried over Na2SO4 and concentrated in vacuo to afford the 5-methyl-1-methylsulfonyl-3- nitro-pyrazole (1420 mg, 6.44 mmol, 81.80% yield) as a white solid.1H NMR (400 MHz, DMSO- D6) δ 7.15 (q, J = 0.9 Hz, 1H), 3.76 (s, 3H), 2.57 (d, J = 0.9 Hz, 3H). 4-Methyl-1-methylsulfonyl-3-nitro-pyrazole
Figure imgf000149_0002
To a stirred solution of 4-methyl-3-nitro-1H-pyrazole (500 mg, 3.93 mmol) in DCM (20 mL) at 0 °C was added triethylamine (734 uL, 5.27 mmol) followed by methanesulfonyl chloride (330 uL, 4.27 mmol) . The mixture was stirred for 30 min then allowed to warm to rt and stirred for an additional 1 h. The reaction mixture was diluted with DCM (50 mL) and was washed with 0.5 M NaOH (30 mL), 0.5 M HCl (1 x 30 mL) and brine (30 mL). The organic phase was dried over Na2SO4 and concentrated in vacuo to afford 4-methyl-1-methylsulfonyl-3-nitro-pyrazole (692 mg, 3.24 mmol, 82.3% yield) as a white solid.1H NMR (400 MHz, DMSO-D6) δ 8.47 (q, J = 1.0 Hz, 1H), 3.75 (s, 3H), 2.29 (d, J = 1.0 Hz, 3H). 2-(3-Nitro-1H-pyrazol-1-yl)-1-(pyrrolidin-1-yl)propan-1-one
Figure imgf000149_0003
Step 1: 2-Bromopropionic acid (1.07 eq, 0.68 mL, 7.56 mmol) was added to a mixture of 5- nitro-1H-pyrazole (1 eq, 800 mg, 7.07 mmol) and potassium carbonate 325 mesh (2.05 eq, 2.00 g, 14.5 mmol) in MeCN (15 mL). The reaction mixture was heated at 80 °C for 2h then cooled to rt, acidified with HBr, diluted with water and extracted into EtOAc (x2). The combined organic phases were dried over sodium sulfate, filtered and evaporated, to afford 2-(3-nitropyrazol-1-yl)propanoic acid (1.30 g, 7.02 mmol, 99.25% yield) as a colourless oil.MS (EH-) m/z = 184.1 [M-H]-, 1H NMR (400 MHz, DMSO-D6) δ 13.39 (s, 1H), 8.10 (d, J = 2.7 Hz, 1H), 7.05 (d, J = 2.6 Hz, 1H), 5.33 (q, J = 7.3 Hz, 1H), 1.67 (d, J = 7.3 Hz, 3H). Step 2: A solution of 1-propanephosphonic anhydride (1.62 eq, 1.7 mL, 2.94 mmol) [50% in EtOAc] was added to 2-(3-nitropyrazol-1-yl)propanoic acid (1 eq, 335 mg, 1.81 mmol) , pyrrolidine (2.02 eq, 0.30 mL, 3.65 mmol) , and triethylamine (3.97 eq, 1.0 mL, 7.17 mmol) in ethyl acetate (10 mL). The reaction mixture was stirred at room temperature for 3 h, then diluted with EtOAc and washed with water, 1M HCl aq, then brine, dried over sodium sulfate, filtered and evaporated to afford2-(3-nitropyrazol-1-yl)-1-pyrrolidin-1-yl-propan-1-one (280 mg, 1.02 mmol, 56.51% yield) as a colourless oil.MS (ES+) m/z = 239.2 [M+H]+.1H NMR (400 MHz, CHLOROFORM-D) δ 7.82 (d, J = 2.6 Hz, 1H), 6.92 (d, J = 2.6 Hz, 1H), 5.37 (q, J = 7.1 Hz, 1H), 3.69 – 3.36 (m, 4H), 2.09 – 1.95 (m, 2H), 1.95 – 1.79 (m, 2H), 1.72 (d, J = 7.1 Hz, 3H). 3-Methoxy-2-(4-methyl-3-nitro-1H-pyrazol-1-yl)-1-((S)-2-(trifluoromethyl)pyrrolidin-1-yl)propan-1- one
Figure imgf000150_0001
Methyl 2-bromo-3-methoxypropanoate (1.9 mL, 14.5 mmol) was added to a stirring solution of 4-methyl-3-nitro-1H-pyrazole (1.50 g, 11.8 mmol) and potassium carbonate 325 mesh (4.90 g, 35.5 mmol) in MeCN (100 mL) . The reaction mixture was heated to 50 °C and stirred for 3h, quenched with water (100 mL) and extracted with EtOAc (2x150 mL). The combined organics were washed with brine (100 mL), then dried over Na2SO4 and concentrated in vacuo. The crude material was purified by column chromatography over silica (120 g cartridge) eluting with a gradient of EtOAc (0% to 50%; v/v) in iso-Hexane to afford methyl 3-methoxy-2-(4-methyl-3-nitro- pyrazol-1-yl)propanoate (1.86 g, 7.63 mmol, 64.62% yield) as an off-white solid.MS (ES+) m/z = 244.1 [M+H]+.1H NMR (400 MHz, CDCl3) δ 7.63 (d, J = 0.9 Hz, 1H), 5.22 (dd, J = 5.4, 3.0 Hz, 1H), 4.13 (dd, J = 10.3, 5.4 Hz, 1H), 3.90 (dd, J = 10.3, 3.1 Hz, 1H), 3.80 (s, 3H), 3.39 (s, 3H), 2.36 (d, J = 0.9 Hz, 3H). A solution of caesium carbonate (7.50 g, 23.0 mmol) in water (10 mL) was added to methyl 3-methoxy-2-(4-methyl-3-nitro-pyrazol-1-yl)propanoate (1.86 g, 7.63 mmol) in 1,4-dioxane (40 mL). The reaction mixture was heated to 60 °C and stirred overnight, then it was concentrated in vacuo. The residue was treated with MeCN (100 mL), sonicated to a fine suspension, then filtered on paper, washing with MeCN. The filtered solution was concentrated in vacuo, affording cesium 3- methoxy-2-(4-methyl-3-nitro-pyrazol-1-yl)propanoate (2474 mg, 5.62 mmol, 73.66% yield) as a yellow glass. MS (ES+) m/z = 230.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 7.77 (d, J = 0.9 Hz, 1H), 4.67 (dd, J = 9.8, 3.7 Hz, 1H), 3.98 – 3.81 (m, 2H), 3.17 (s, 3H), 2.24 (d, J = 0.8 Hz, 3H). To a solution of cesium 3-methoxy-2-(4-methyl-3-nitro-pyrazol-1-yl)propanoate (1.20 g, 3.32 mmol), DIPEA (1.8 mL, 10.0 mmol) and HATU (1.50 g, 3.94 mmol) in DMF (20 mL) was added (S)-(+)-2-(Trifluoromethyl)pyrrolidine (650 mg, 4.67 mmol). The reaction misture was stirred at rt overnight. then diluted with EtOAc (100 mL) and washed with aq. LiCl 1M (150 mL). The aqueous solution was extracted with EtOAc (150 mL), then the combined organics were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by column chromatography over silica (120 g cartridge) eluting with a gradient of ethyl acetate (5% to 80%; v/v) in iso-hexane to afford the desired product 3-methoxy-2-(4-methyl-3-nitro-pyrazol-1-yl)-1-[(2S)-2- (trifluoromethyl)pyrrolidin-1-yl]propan-1-one (256 mg, 0.665 mmol, 20 % yield) as a yellow oil. MS (ES+) m/z = 351.1 [M+H]+.1H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 1.0 Hz, 1H), 5.63 – 5.43 (m, 1H), 4.89 – 4.68 (m, 1H), 4.03 – 3.69 (m, 4H), 3.39 (s, 3H), 2.35 (d, J = 0.9 Hz, 3H), 2.28 – 1.95 (m, 4H).19F NMR (376 MHz, CDCl3) δ -73.97 (d, J = 7.6 Hz), -74.45 (d, J = 7.6 Hz). The product is present as an approx.6:1 mixture of diastereoisomers. Synthesis of amino-aryl or amino-heteroaryl intermediates Amino pyrazole precursors General Method B: Hydrogenation of N-substituted nitro-pyrazoles
Figure imgf000151_0001
A mixture of N-substituted nitro-pyrazoles (1.0 eq) and Pd/C (10% w/w, 0.05 eq) in MeOH (0.01 – 0.26 M) or THF was placed under a hydrogen atmosphere and stirred at RT for 12 – 72 h. Reaction was monitrored by consumption of starting material via UPLC. The mixture was filtered through a pad of dicalite and concentrated in vacuo to afford the amine product. Ethyl 2-(3-amino-5-methyl-pyrazol-1-yl)acetate
Figure imgf000151_0002
Prepared as described in Method B from ethyl 2-(5-methyl-3-nitro-pyrazol-1-yl)acetate (500 mg, 2.35 mmol) and Pd/C (10% w/w, 50 mg) in THF (25 mL) after 16 h to afford the title compound (417 mg, 97% yield) as a clear colourless oil. MS (ES+) m/z 184.2 (M+H).1H NMR (CDCl3, 300 MHz) δ 5.42 (d, 1H, J = 0.7 Hz), 4.58 (s, 2H), 4.18 (q, 2H, J = 7.1 Hz), 3.53 (br s, 2H), 2.12 (d, 3H, J = 0.7 Hz), 1.24 (t, 3H, J = 7.1 Hz) The following N-substituted amino-pyrazoleswere obtained in a similar manner:
Figure imgf000152_0001
Figure imgf000153_0002
General Procedure B2: Synthesis of aminopyrazole intermediates by alkylation of nitro- pyrazoles and hydrogenation
Figure imgf000153_0001
Potassium carbonate (1.5 equiv.) was added to a solution of alkyl halide (1 equiv.) and nitropyrazole (1 equiv.) in anhydrous THF (10 mL) with stirring at room temperature under nitrogen. The reaction mixture was then heated to 75 °C with stirring for 4 hours, before cooling to room temperature and separating between ethyl acetate and water. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give the crude product, which was purified using flash column chromatography over silica. A solution of alkylated nitropyrazole (1 equiv.) in ethanol (0.1 M) was bubbled with nitrogen for 10 minutes before adding 10% Palladium on Carbon (10 mol%). The flask was then placed under vacuum and filled with nitrogen (x 2) before fitting a hydrogen balloon and stirring overnight at room temperature. The balloon was then removed and the reaction mixture bubbled with nitrogen for 5 minutes before filtering through dicalite, washing with ethyl acetate. The filtrate was concentrated to give the desired alkylated aminopyrazole. The following heteroaromatic amines were obtained using general Method B2:
Figure imgf000154_0001
Figure imgf000155_0001
Figure imgf000156_0001
Figure imgf000157_0001
Figure imgf000158_0002
1-(3,3,3-Trifluoro-2-propoxypropyl)-1H-pyrazol-3-amine
Figure imgf000158_0001
Potassium tert-butoxide (120 mg, 1.07 mmol) was added to a solution of 1,1,1-trifluoro-3-(3- nitro-1H-pyrazol-1-yl)propan-2-ol (200 mg, 0.89 mmol) and 1-bromopropane (90 uL, 0.98 mmol) in anhydrous THF (9 mL), with stirring at room temperature under nitrogen. The reaction mixture was then heated to 60 °C with stirring overnight, before cooling to room temperature and separating between ethyl acetate and water. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give the crude product, which was purified using flash column chromatography over silica, eluting with 0-50% ethyl acetate/petroleum ether to give 3-nitro-1-(3,3,3-trifluoro-2-propoxypropyl)-1H-pyrazole (98 mg, 41% yield) as a clear yellow oil. MS (ES+) 268.1 (M+H); 1H NMR (DMSO-d6, 300 MHz) δ 7.55 (d, 1H, J = 2.5 Hz), 6.90 (d, 1H, J = 2.5 Hz), 4.58-4.47 (m, 1H), 4.27-4.12 (m, 2H), 3.69-3.62 (m, 1H), 3.23-3.16 (m, 1H), 1.41 (h, 2H, J = 7.3 Hz), 0.76 (t, 3H, J = 7.4 Hz) ppm; 19F NMR (DMSO-d6, 282 MHz) δ −76.21 (d, J = 5.9 Hz) ppm. A solution of 3-nitro-1-(3,3,3-trifluoro-2-propoxypropyl)-1H-pyrazole (98 mg, 0.37 mmol) in THF (8 mL) was bubbled with nitrogen for 10 minutes before adding 10% Palladium on Carbon (10 mg). The flask was then placed under vacuum and filled with nitrogen (x 2) before fitting a hydrogen balloon and stirring overnight at room temperature. The balloon was then removed and the reaction mixture bubbled with nitrogen for 5 minutes before filtering through dicalite, washing with ethyl acetate. The filtrate was concentrated to give the desired product (84 mg, 97% yield) as a brown oil that did not require further purification. MS (ES+) 238.2 (M+H); 1H NMR (CDCl3, 300 MHz) δ 7.17 (d, 1H, J = 2.3 Hz), 5.57 (d, 1H, J = 2.3 Hz), 4.22 (dd, 1H, J = 13.8, 2.5 Hz), 4.09-3.98 (m, 1H), 3.90 (dd, 1H, J = 13.8, 9.4 Hz), 3.67 (br s, 2H), 3.54 (dt, 1H, J = 8.9, 6.5 Hz), 3.16 (dt, 1H, J = 9.0, 6.6 Hz), 1.43 (h, 2H, J = 7.3 Hz), 0.79 (t, 3H, J = 7.4 Hz) ppm; 19F NMR (CDCl3, 282 MHz) δ −76.57 (d, J = 6.5 Hz) ppm. tert-Butyl 4-(2-(3-amino-1H-pyrazol-1-yl)ethyl)piperazine-1-carboxylate
Figure imgf000159_0001
Potassium carbonate (465 mg, 3.32 mmol) was added to a solution of 3-nitro-1H-pyrazole (250 mg, 2.21 mmol) in anhydrous THF (10 mL) with stirring for 10 minutes, before adding 1,2- dibromoethane (0.29 mL, 3.32 mmol) and warming to 80 °C, with stirring for 3 hours. N-Boc- piperazine (618 mg, 3.32 mmol) was then added, with continued stirring at 80 °C overnight, before cooling to room temperature and separating between ethyl acetate and water. The organic phase was washed with water and 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 0-100% ethyl acetate/petroleum, to give tert-butyl 4-(2-(3-nitro-1H-pyrazol- 1-yl)ethyl)piperazine-1-carboxylate (77 mg, 11% yield) as a yellow oil.1H NMR (CDCl3, 300 MHz) δ 7.50 (d, 1H, J = 2.2 Hz), 6.99 (d, 1H, J = 2.2 Hz), 4.71 (t, 2H, J = 6.2 Hz), 3.31 (t, 4H, J = 5.1 Hz), 2.71 (t, 2H, J = 6.2 Hz), 2.37 (t, 4H, J = 5.0 Hz), 1.43 (s, 9H) ppm. A solution of tert-butyl 4-(2-(3-nitro-1H-pyrazol-1-yl)ethyl)piperazine-1-carboxylate (90 mg, 0.28 mmol) in ethanol (6 mL) was bubbled with nitrogen for 5 minutes before adding 10% Palladium on Carbon (10 wt.%, 29 mg, 0.028 mmol) and bubbling for a further 5 minutes. The flask was then placed under vacuum and refilled with nitrogen before fitting a hydrogen balloon and stirring overnight at room temperature. The balloon was then removed and the reaction mixture bubbled with nitrogen for 5 minutes before filtering through dicalite, washing with ethyl acetate. The filtrate was concentrated to give the product (82 mg, 100% yield) as a yellow oil that was used directly in the next step. MS (ES+) 296.3 (M+H). 2-(3-Amino-4-chloro-pyrazol-1-yl)-1-pyrrolidin-1-yl-ethanone
Figure imgf000160_0001
A solution of 2-chloro-1-pyrrolidin-1-yl-ethanone (1.30 g, 8.81 mmol) in MeCN (150 mL) was slowly added to a stirred suspension of 4-chloro-1H-pyrazol-3-amine (1.00 g, 8.51 mmol) and potassium carbonate 325 mesh (1.29 g, 9.36 mmol) in MeCN (100 mL) at 80 °C . The reaction mixture was additionally stirred at 80 °C overnight. The reaction mixture was recharged with 2- chloro-1-pyrrolidin-1-yl-ethanone (251 mg, 1.70 mmol) and the stirring continued at 80 °C for 2 h. The reaction mixture was concentrated, preabsorbed on Celite and purified by column chromatography over silica (120 g cartridge) eluting with a gradient of MeOH (0% to 10%; v/v) in DCM (30 CV) to afford 2-(3-amino-4-chloro-pyrazol-1-yl)-1-pyrrolidin-1-yl-ethanone (854 mg, 3.59 mmol, 42.1% yield) as an off-white solid. MS (ES+) m/z = 229.1, 230.9 [M+H]+, (mono Cl pattern). 1H NMR (400 MHz, DMSO-D6) δ 7.52 (s, 1H), 4.73 (s, 2H), 4.67 (s, 2H), 3.42 (t, J = 6.8 Hz, 2H), 3.28 (t, J = 6.9 Hz, 2H), 1.94 – 1.83 (m, 2H), 1.82 – 1.70 (m, 2H). 2-(3-Amino-5-chloro-pyrazol-1-yl)-1-pyrrolidin-1-yl-ethanone
Figure imgf000160_0002
A solution of 3-chloro-1H-pyrazol-5-amine (300 mg, 2.55 mmol) in MeCN (15 mL) was added to a stirred suspension of 3-chloro-1H-pyrazol-5-amine (300 mg, 2.55 mmol) and potassium carbonate 325 mesh (423 mg, 3.06 mmol) in MeCN (20 mL) at 80 °C. The reaction mixture was stirred at 80 °C for 3 h and then at 50 °C for 16 h, then concentrated, preabsorbed on Celite and purified by column chromatography over silica (40 g cartridge) eluting with a gradient of MeOH (0% to 10%; v/v) in DCM (30 CV) to afford 2-(3-amino-5-chloro-pyrazol-1-yl)-1-pyrrolidin-1-yl-ethanone (40 mg, 0.135 mmol, 5.3% yield). MS (ES+) m/z = 229.1, 231.1 [M+H]+ (mono Cl pattern).1H NMR (400 MHz, CHLOROFORM-D) δ 5.65 (s, 1H), 4.68 (s, 3H), 3.50 (t, J = 6.9 Hz, 2H), 3.42 (t, J = 6.9 Hz, 2H), 2.02 – 1.91 (m, 2H), 1.90 - 1.77 (m, 2H). 3-(3-Amino-5-methyl-pyrazol-1-yl)propanenitrile
Figure imgf000161_0001
Step 1: Acrylonitrile (286 uL, 4.34 mmol) was added to a stirred mixture of 3-methyl-5-nitro- 1H-pyrazole (525 mg, 4.13 mmol) and N,N-diisopropylethylamine (DIPEA) (863 uL, 4.96 mmol) in DMSO (15 mL) at 25 °C and the resulting light yellow clear mixture was stirred for 30 h. The reaction mixture was poured in H2O (50 mL) and extracted with EtOAc (3 x 20 mL). The organic solution was washed sequentially with 0.5 M NaOH (2 × 20mL) and saturated brine solution (20 mL), dried (Na2SO4) and concentrated to dryness to give 3-(5-methyl-3-nitro-pyrazol-1- yl)propanenitrile (580 mg, 3.22 mmol, 77.93% yield) as a white solid.1H NMR (400 MHz, CHLOROFORM-D) δ 6.70 (d, J = 0.9 Hz, 1H), 4.40 (t, J = 6.5 Hz, 2H), 3.03 (t, J = 6.5 Hz, 2H), 2.46 (s, 3H). Step 2: A stirred solution of 3-(5-methyl-3-nitro-pyrazol-1-yl)propanenitrile (570 mg, 3.16 mmol) in ethyl acetate (25 mL) / MeCN (25 mL) was evacuated and backfilled with nitrogen 3 times before a slurry of Palladium on activated Carbon (5%) (100 mg, 0.940 mmol) was added to the reactio On mixture. The flask was then placed under vacuum and refilled with nitrogen before fitting a hydrogen balloon and stirring at 25 °C for 18 h. The reaction mixture was refilled with nitrogen and filtered through Cellite and washed with MeCN. The filtrate was concentrated and dried at 40 °C/10 mbar to give 3-(3-amino-5-methyl-pyrazol-1-yl)propanenitrile (470 mg, 2.97 mmol, 94% yield) as a brown oil. MS (ES+) m/z = 151.2 [M+H]+.1H NMR (400 MHz, DMSO-D6) δ 5.23 (q, J = 0.7 Hz, 1H), 4.52 (s, 2H), 4.01 (t, J = 6.4 Hz, 2H), 2.86 (t, J = 6.4 Hz, 2H), 2.14 (d, J = 0.7 Hz, 3H). 3-(3-Amino-4-methyl-pyr S2Ntep 1: Nazol-1-yl) Acrylonitrile (275 u2propan L, 4.17 Nenitrile
Figure imgf000161_0002
ON mmol) was added to a stirred m Hix2tNure o Nf 4-methyl-3- yrazole (50 N5 mg, 3.97 mmol) and N,N N-diisopropylethylamine (DIPEA) (830 uL Nnitro- 1H-pH CN , 4.77 m CmNol) in DMSO (15 mL). The reaction mixture was stirred at 25 °C for 48 h, recharged with acrylonitrile (131 uL, 1.99 mmol) and stirred at 25 °C forfurther 2 h before it was diluted with water (50 mL). The product was extracted with EtOAc (3 x 20 mL). The organic fraction was washed sequentially with water (2 × 20mL) and saturated brine solution (20 mL), dried (Na2SO4) and concentrated to dryness to give the 3-(4-methyl-3-nitro-pyrazol-1-yl)propanenitrile (586 mg, 3.15 mmol, 79.40% yield) as a white solid.1H NMR (400 MHz, CHLOROFORM-D) δ 7.44 (q, J = 0.8 Hz, 1H), 4.42 (t, J = 6.4 Hz, 2H), 3.02 (t, J = 6.4 Hz, 2H), 2.36 (d, J = 0.8 Hz, 3H). Step 2: A stirred solution of 3-(4-methyl-3-nitro-pyrazol-1-yl)propanenitrile (560 mg, 3.01 mmol) in MeCN (50 mL) was evacuated and backfilled with nitrogen 3 times before slurry of Palladium on activated Carbon (5%) (160 mg, 1.50 mmol) in MeCN-H2O was added to the reaction mixture. The flask was then placed under vacuum and refilled with nitrogen before fitting a hydrogen balloon and stirring at 25 °C for 20 h. The reaction mixture was filtered through Cellite and washed with MeCN. The filtrate was concentrated to dryness to give 3-(3-amino-4-methyl- pyrazol-1-yl)propanenitrile (472 mg, 2.83 mmol, 93.82% yield) as a white solid.MS (ES+) m/z = 151.1 [M+H]+.1H NMR (400 MHz, DMSO-D6) δ 7.18 (d, J = 1.0 Hz, 1H), 4.46 (s, 2H), 4.02 (t, J = 6.3 Hz, 2H), 2.88 (t, J = 6.3 Hz, 2H), 1.80 (d, J = 0.8 Hz, 3H). 2-(3-Amino-4-methyl-1H-pyrazol-1-yl)acetonitrile
Figure imgf000162_0001
Tetrahydroxy diboron (547 mg, 6.10 mmol) was added to a stirring solution of 2-(4-methyl- 3-nitro-pyrazol-1-yl)acetonitrile (340 mg, 2.05 mmol) and 4,4'-dipyridyl (16 mg, 0.100 mmol) in DMF (20 mL). The reaction was stirred at rt for 10 minutes, quenched with sat. aq. NaHCO3 (20 mL) and water (20 mL) and extracted with EtOAc (3x30 mL). The combined organics were washed with 5% aq. LiCl (30 mL), then dried over Na2SO4 and concentrated. The crude material was purified by column chromatography over C18 (45 g cartridge) eluting with a gradient of MeCN (0.1% NH3) (2% to 20%; v/v) in water (0.1% NH3). The combined fractions containing the product were concentrated in vacuo. The residue was dissolved in MeOH and loaded onto an SCX-2 cartridge (10 g). The cartridge was washed with MeOH (15 mL), then the compound was eluted with 3 M ammonia in MeOH (10 mL). The eluent was concentrated to dryness under reduced pressure to afford the desired product 2-(3-amino-4-methyl-pyrazol-1-yl)acetonitrile (280 mg, 1.95 mmol, 95.5% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 7.20 (d, J = 0.9 Hz, 1H), 5.05 (s, 2H), 4.69 (s, 2H), 1.80 (d, J = 1.0 Hz, 3H). tert-Butyl 3-amino-4-methyl-1H-pyrazole-1-carboxylate
Figure imgf000162_0002
4-Dimethylaminopyridine (35 mg, 0.283 mmol) was added to a stirring solution of 4-methyl- 3-nitro-1H-pyrazole (360 mg, 2.83 mmol) , di-tert-butyl dicarbonate (742 mg, 3.40 mmol) and N,N- diisopropylethylamine (DIPEA) (1.2 mL, 7.1 mmol) in DCM (30 mL) . The solution was stirred at r.t. for 2 h. The reaction was quenched with sat. aq. NH4Cl (50 mL) and organic phase was washed NH4Cl (2 × 50 mL), dried over Na2SO4, filtered and the filtrates concentrated under reduced pressure. The crude material was purified by column chromatography over silica (40 g cartridge) eluting with a gradient of EtOAc (0% to 30%; v/v) in iso-Hexane to afford the desired product tert- butyl 4-methyl-3-nitro-pyrazole-1-carboxylate (490 mg, 2.16 mmol, 76.1% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.97 (q, J = 1.0 Hz, 1H), 2.35 (d, J = 1.0 Hz, 3H), 1.66 (s, 9H). tert-Butyl 4-methyl-3-nitro-pyrazole-1-carboxylate (1.00 eq, 470 mg, 2.07 mmol) was dissolved in EtOAc:EtOH (3:1, 20 mL) at r.t., and the flask was cycled through N2/vacuum 3 times before the slurry loading of palladium on activated carbon, Type 39 paste (0.0500 eq, 220 mg, 0.103 mmol) in minimal EtOAc. The reaction mixture was cycled through N2/vacuum twice more before a balloon of molecular hydrogen was added. The flask was cycled between H2/vacuum 3 times and the The reaction mixture was left under an atmosphere of H2 for 72 h. The reaction mixture was filtered through a Celite pad and the filter cake was washed with EtOAc (3 × 25 mL). The filtrates were concentrated under reduced pressure to afford tert-butyl 3-amino-4-methyl- pyrazole-1-carboxylate (415 mg, 2.00 mmol, 96.63% yield) as a dark green viscous oil without further purification.1H NMR (400 MHz, CDCl3) δ 7.59 (s, 1H), 4.24 (br s, 2H), 1.93 (d, J = 1.1 Hz, 3H), 1.59 (s, 9H). tert-Butyl 3-amino-4-chloro-1H-pyrazole-1-carboxylate
Figure imgf000163_0001
4-Dimethylaminopyridine (30 mg, 0.242 mmol) was added to a stirring solution of 4-chloro- 1H-pyrazol-3-amine (300 mg, 2.42 mmol) , di-tert-butyl dicarbonate (635 mg, 2.91 mmol) and N,N- Diisopropylethylamine (DIPEA) (1.1 mL, 6.06 mmol) in DCM (30 mL) at 23 °C . The solution was stirred at rt for 2h, quenched with sat. aq. NH4Cl (50 mL) and the organic phase was washed NH4Cl (2 X 50 mL), water (50 mL), NaCl (50 mL) and dried over Na2SO4. All volatiles were evaporated and the residue was dried and purified by column chromatography over silica (24 g cartridge) eluting with a gradient of MeOH (0% to 4%; v/v) in DCM (20 CV) to afford the tert-butyl 3-amino-4-chloro-pyrazole-1-carboxylate (340 mg, 1.53 mmol, 63.14% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-D6) δ 8.16 (s, 1H), 5.72 (s, 2H), 1.52 (s, 9H). tert-Butyl 3-amino-4-bromo-1H-pyrazole-1-carboxylate
Figure imgf000163_0002
4-Dimethylaminopyridine (23 mg, 0.185 mmol) was added to a stirring solutin of 5-amino-4- bromo-1H-pyrazole (300 mg, 1.85 mmol) , di-tert-butyl dicarbonate (485 mg, 2.22 mmol) and N,N- diisopropylethylamine (DIPEA) (0.81 mL, 4.63 mmol) in DCM (30 mL) at 0 °C under N2. The solution was stirred at rt for 2h, the reaction was quenched with sat. aq. NH4Cl (50 mL) and the organic phase was washed with NH4Cl (2 X 50 mL), water (50 mL), NaCl (50 mL) and dried over Na2SO4. All volatiles were evaporated to afford the desire product (453 mg) as a mixture of regioisomers tert-butyl 3-amino-4-bromo-pyrazole-1-carboxylate (358 mg, 1.37 mmol, 73.7% yield) / tert-butyl 5-amino-4-bromo-pyrazole-1-carboxylate (95 mg, 0.362 mmol, 19.6% yield) as an off- white solid, which was used in sthe subsequent step without separation.1H NMR (400 MHz, DMSO-D6) δ 8.16 (s, 1H), 5.64 (br s, 2H), 1.52 (s, 9H) - major isomer. 3-(3-Amino-1H-pyrazol-1-yl)-1-methylpyrrolidin-2-one
Figure imgf000164_0001
Potassium carbonate 325 mesh (3.49 eq, 1.30 g, 9.41 mmol) was added to a mixture of 3- bromo-1H-pyrazole (1.62 eq, 640 mg, 4.35 mmol) and 3-bromo-1-methylpyrrolidin-2-one (1.00 eq, 480 mg, 2.70 mmol) in MeCN (20 mL). The reaction mixture was heated at 60 °C for 18 h, cooled, filtered and evaporated. The crude material was purified by column chromatography over silica (24 g cartridge) eluting with isocratic EtOAc (5 vol) then a gradient of MeOH (0% to 20%; v/v) in EtOAc to afford 3-(3-bromopyrazol-1-yl)-1-methyl-pyrrolidin-2-one (520 mg, 2.11 mmol, 78.22% yield) as an off-white solid.MS (ES+) m/z = 244.0/246.0 mono Br pattern.1H NMR analysis (sample reference: PT-0472-199-S2) 1H NMR (400 MHz, CHLOROFORM-D) δ 7.50 (t, J = 2.4 Hz, 1H), 6.35 – 6.27 (m, 1H), 4.83 (t, J = 8.5 Hz, 1H), 3.60 (ddt, J = 9.8, 8.7, 3.1 Hz, 1H), 3.51 – 3.39 (m, 1H), 2.93 (t, J = 1.3 Hz, 3H), 2.76 – 2.53 (m, 2H). 3-(3-Bromopyrazol-1-yl)-1-methyl-pyrrolidin-2-one (520 mg, 2.13 mmol) and 4,5- bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (280 mg, 0.484 mmol) were dissolved in 1,4-dioxane (10 mL). Benzophenoneimine (0.60 mL, 3.58 mmol), caesium carbonate (2.00 g, 6.14 mmol) and palladium(II) acetate (0.314 eq, 150 mg, 0.668 mmol) were then added, under nitrogen. The reaction mixture was stirred at 110 °C for 18h, then cooled, filtered through a short pad of celite and rinsed with DCM. The filtrate was concentrated. The crude material was purified by column chromatography over silica (24 g cartridge) eluting with a gradient of EtOAc (5% to 100%; v/v) in isohexane [note 3] to afford the 3-[3-(benzhydrylidene amino)pyrazol-1-yl]-1-methyl- pyrrolidin-2-one (550 mg, 1.44 mmol, 67.46% yield) as a yellow solid.MS (ES+) m/z = 345.2 [M+H]+.1H NMR (400 MHz, CHLOROFORM-D) δ 7.84 – 7.78 (m, 2H), 7.41 (dd, J = 5.2, 2.0 Hz, 4H), 7.39 – 7.32 (m, 2H), 7.27 (s, 1H), 7.25 – 7.19 (m, 2H), 5.02 (d, J = 2.5 Hz, 1H), 4.78 – 4.68 (m, 1H), 3.58 (td, J = 9.3, 4.0 Hz, 1H), 3.39 (ddd, J = 9.7, 8.0, 6.4 Hz, 1H), 2.90 (s, 3H), 2.73 (ddt, J = 13.5, 8.9, 6.8 Hz, 1H), 2.62 – 2.49 (m, 1H). A slurry of palladium on activated carbon (100 mg, 0.0470 mmol) [type 39 paste] in EtOAc/EtOH [3:1](5mL) was added under nitrogen to 3-[3-(benzhydrylideneamino)pyrazol-1-yl]-1- methyl-pyrrolidin-2-one (1.00 eq, 550 mg, 1.44 mmol) in Ethanol (5 mL) and Ethyl acetate (15 mL) . The reaction mixture head space was flushed with hydrogen gas. The reaction mixture was stirred under hydrogen atmosphere for 3 days, purged with nitrogen, the catalyst was filtered off through a celite pad and washed copiously with MeCN. The filtrate was evaporated. The residue was dissolved in fresh ethanol (25 mL). Under nitrogen, a slurry of palladium hydroxide on carbon (Pd(OH)2/C, 20% wt) (0.0991 eq, 100 mg, 0.142 mmol) in ethanol (2x 5mL) was added. The reaction mixture was stirred under hydrogen atmosphere for 7 days.The catalyst was filtered off through a celite pad and washed with EtOH. The filtrate was evaporated re-dissolved in MeOH and loaded onto an SCX-2 cartridge (5 g). The cartridge was washed with MeCN/MeOH 1:1 (25 mL), then the compound was eluted with 7 M ammonia in MeOH (25 mL). The eluent was concentrated to dryness under reduced pressure to afford 3-(3-aminopyrazol-1-yl)-1-methyl-pyrrolidin-2-one (340 mg, 1.51 mmol, 100% yield) as a brown oil.1H NMR (400 MHz, METHANOL-D4) δ 7.36 (d, J = 2.4 Hz, 1H), 5.60 (d, J = 2.4 Hz, 1H), 4.88 – 4.76 (m, 1H), 3.63 – 3.34 (m, 2H), 2.93 – 2.83 (m, 3H), 2.65 – 2.20 (m, 2H). Diamino-aryl and diamino-heteroaryl precursors General Method B3: Buchwald coupling of Boc-amino-halo-aryl/heteroaryl with amines and subsequent deprotection
Figure imgf000165_0001
Heteroaryl bromide (1 equiv.) and amine (1.5 equiv.) were dissolved in toluene:tert-butanol (5:1, [0.1 M]) and the solution was bubbled with nitrogen for 5 minutes. Pd2dba3 (15mol%), XantPhos (30mol%), and sodium tert-butoxide (1.5 equiv.) were then added with stirring and the mixture was bubbled with nitrogen for a further 5 minutes before heating to 85 °C with stirring overnight. After cooling to room temperature, the reaction mixture was separated between ethyl acetate water. The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give the crude product, which was purified using flash column chromatography. TFA (25 equiv.) was added to a solution of the Boc protected compound (1 equiv.) in DCM (~0.07 M) with stirring under nitrogen for 3 hours before concentrating in vacuo. DCM was added and the mixture concentrated again and the resulting precipitate was washed with diethyl ether to give the final compound. N2-(2-(Dimethylamino)ethyl)-N2-methylpyridine-2,6-diamine
Figure imgf000165_0002
BocHN tert-B Nutyl 6 B-rbromopyridin-2 B-oyclcHaNrbam Nate ( N200 mg, 0.73 mmol) and H N2N1,N1, NN2- trimethylethane-1,2-diamine (0.14 mL, 1.1 mmol) were d Nissolved in toluene:tert-butano Nl (5:1, 9 N mL) and the solution was bubbled with nitrogen for 5 minutes. Pd2dba3 (101 mg, 15mol%), XantPhos (127 mg, 30mol%), and sodium tert-butoxide (106 mg, 1.1 mmol) were then added with stirring and the mixture was bubbled with nitrogen for a further 5 minutes before heating to 85 °C with stirring overnight. After cooling to room temperature the reaction mixture was separated between ethyl acetate water. The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give the crude product, which was purified using flash column chromatography over basic alumina, eluting with 0-10% methanol/dichloromethane, to give tert-butyl (6-((2-(dimethylamino)ethyl)(methyl)amino)pyridin-2-yl)carbamate (120 mg, 56% yield) as a yellow oil. MS (ES+) 295.3 (M+H); 1H NMR (CDCl3, 300 MHz) δ 7.40 (t, 1H, J = 8.1 Hz), 7.09 (d, 1H, J = 7.3 Hz), 6.94 (br, 1H), 6.13 (dd, 1H, J = 8.3, 0.7 Hz), 3.61-3.56 (m, 2H), 2.97 (s, 3H), 2.46-2.41 (m, 2H), 2.27 (s, 6H), 1.50 (s, 9H) ppm. TFA (0.94 mL, 12.2 mmol) was added to a solution of tert-butyl (6-((2- (dimethylamino)ethyl)(methyl)amino)pyridin-2-yl)carbamate (120 mg, 0.4 mmol) in DCM (3 mL), with stirring under nitrogen for 3 hours before concentrating in vacuo. DCM was added and the mixture concentrated again and the resulting precipitate was washed with diethyl ether to give the title compound (175 mg, 100% yield) as a brown solid that was used directly in the next step. MS (ES+) 195.1 (M+H). The following diaminopyridines were obtained using general Method B3:
Figure imgf000166_0002
6-(Oxetan-3-yl)pyridin-2-amine
Figure imgf000166_0001
To a 35 mL capacity reaction vial were added, in the following order, anhydrous DMA (4 mL), pyridine-2,6-bis(carboximidamide) (ligand, 17 mg, 0.073 mmol, 10 mol%), NiCl2(DME) (16 mg, 10 mol%), sodium iodide (27 mg, 0.18 mmol, 25 mol%), tert-butyl 6-bromopyridin-2- ylcarbamate (200 mg, 0.73 mmol), 3-bromooxetane (0.12 mL, 1.46 mmol, 2 equiv.), zinc metal powder (96 mg, 1.46 mmol, 2 equiv.) and TFA (6 uL, 0.073 mmol, 10 mol%). The vial was capped and heated to 60 °C with stirring overnight. The reaction mixture was then diluted with ethyl acetate and filtered through a short pad of dicalite, washing with ethyl acetate. The filtrate was then washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give the crude product, which was purified using flash column chromatography over silica, eluting with 0-80% ethyl acetate/petroleum ether, to give tert-butyl (6-(oxetan-3-yl)pyridin-2- yl)carbamate (73 mg, 40% yield) as a white solid. MS (ES+) 251.3 (M+H); 1H NMR (CDCl3, 300 MHz) δ 7.80 (d, 1H, J = 8.3 Hz), 7.60 (t 1H, J = 8.2 Hz), 7.31 (br s, 1H), 6.84 (d, 1H, J = 7.3 Hz), 4.99 (dd, 2H, J = 8.5, 5.7 Hz), 4.90 (dd, 2H, J = 6.7, 5.7 Hz), 4.29-4.19 (m, 1H), 1.52 (s, 9H) ppm. TFA (0.6 mL, 7.29 mmol) was added to a solution of tert-butyl (6-(oxetan-3-yl)pyridin-2- yl)carbamate (73 mg, 0.291 mmol) in DCM (1.8 mL), with stirring under nitrogen for 3 hours before concentrating in vacuo. DCM was added and the mixture concentrated again and the resulting precipitate was washed with diethyl ether to give the title compound (65 mg, 84% yield) as an off- white solid. MS (ES+) 151.2 (M+H). tert-Butyl (6-amino-2-m
Figure imgf000167_0001
ridin-3-yl
Figure imgf000167_0002
Figure imgf000167_0003
To a solution of 3,6-diamino-2-methylpyridine (200 mg, 1.62 mmol, 1.00 eq) in THF (10 mL) was added di-tert-butyl dicarbonate (354 mg, 1.62 mmol, 1.00 eq) and the reaction mixture was allowed to stir at ambient temperature for 1 hour. The product mixture was concentrated under reduced pressure before purification by reverse phase combiflash to furnish tert-butyl (6-amino-2- methylpyridin-3-yl)carbamate (268 mg, 1.20 mmol, 74%). 1H NMR (300 MHz, DMSO-d6) δ 8.27 (s, 1H), 7.13 (d, J = 8.5 Hz, 1H), 6.24 (d, J = 8.5 Hz, 1H), 5.72 (s, 2H), 2.14 (s, 3H), 1.44 (s, 9H). MS (ES+) m/z 224.3 (M+H)+. Bis-aryl/bis-heteroaryl amine precursor General Method B4: Suzuki coupling of Boc-amino-halo-aryl/heteroaryl with halo-aryl or halo-heteroaryl and subsequent deprotection
Figure imgf000167_0004
Ayl/Heteroaryl bromide (1 equiv.) and boronic acid or ester (1.2 equiv.) were dissolved in 1,4-dioxane:water (5:1, [0.1 M]) and the solution was bubbled with nitrogen for 5 minutes. Pd(PPh3)4 (15mol%) and potassium carbonate (1.5 equiv.) or cesium carbonate (2 eq) were then added with stirring and the mixture was bubbled with nitrogen for a further 5 minutes before heating to 90 °C with stirring overnight. After cooling to room temperature, the reaction mixture was separated between ethyl acetate water. The combined organic extracts were 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. TFA (25 equiv.) was added to a solution of the Boc protected compound (1 equiv.) in DCM (~0.07 M) with stirring under nitrogen for 3 hours before concentrating in vacuo. DCM was added and the mixture concentrated again and the resulting precipitate was washed with diethyl ether to give the final compound. 3-Meth l-6- hen l ridin-2-amine
Figure imgf000168_0001
Boc anhydride (1.4 g, 6.46 mmol) was added to a solution of 6-bromo-3-methylpyridin-2- amine (575 mg, 3.07 mmol), DMAP (75 mg, 0.61 mmol) and triethylamine (1.1 mL, 7.69 mmol) in dichloromethane (30 mL), with stirring at 35 °C overnight. After cooling to room temperature, the reaction mixture was separated between dichloromethane and water. The organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product, which was purified using flash column chromatography over silica, eluting with 0- 70% ethyl acetate/petroleum ether to give di-tert-butyl (6-bromo-3-methylpyridin-2- yl)iminodicarbonate (1.0 g, 84% yield) as a white solid. MS (ES+) 389.2 (M+H)+; 1H NMR (CDCl3, 300 MHz) δ 7.44 (dd, 1H, J = 7.9, 0.7 Hz), 7.36 (d, 1H, J = 7.9 Hz), 2.19 (s, 3H), 1.41 (s, 18H) ppm di-tert-Butyl (6-bromo-3-methylpyridin-2-yl)iminodicarbonate (100 mg, 0.26 mmol) and phenylboronic acid (38 mg, 0.31 mmol) were dissolved in 1,4-dioxane:water (5:1, 2.4 mL) and the solution was bubbled with nitrogen for 5 minutes. Pd(PPh3)4 (45 mg, 15mol%) and potassium carbonate (54 mg, 0.39 mmol) were then added with stirring and the mixture was bubbled with nitrogen for a further 5 minutes before heating to 90 °C with stirring overnight. After cooling to room temperature the reaction mixture was separated between ethyl acetate water. The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give the crude product, which was purified using flash column chromatography over silica, eluting with 0-80% ethyl acetate/petroleum ether, to give di-tert-butyl (3-methyl-6- phenylpyridin-2-yl)iminodicarbonate (90 mg, 91% yield) as a white solid. MS (ES+) 385.4 (M+H)+; 1H NMR (CDCl3, 300 MHz) δ 7.99-7.96 (m, 2H), 7.61 (s, 2H), 7.48-7.36 (m, 3H), 2.26 (s, 3H), 1.41 (s, 18H) ppm. TFA (0.5 mL, 7.0 mmol) was added to a solution of di-tert-butyl (3-methyl-6-phenylpyridin-2- yl)iminodicarbonate (90 mg, 0.23 mmol) in DCM (1.5 mL), with stirring under nitrogen for 3 hours before concentrating in vacuo. DCM was added and the mixture concentrated again and the resulting precipitate was purified using flash column chromatography over silica, eluting with 0-20% methanol/dichloromethane to give the title compound (44 mg, 100% yield) as an off-white solid. MS (ES+) 185.2 (M+H)+. The following bis-aryl amines were obtained using general Method B4:
Figure imgf000169_0001
Figure imgf000170_0001
1',4-Dimethyl-1'H-[1,4'-bipyrazol]-3-amine
Figure imgf000171_0001
Copper iodide (30 mg, 0.16 mmol) was added to a solution of 4-methyl-3-nitro-1H-pyrazole (100 mg, 0.79 mmol), 4-bromo-1-methyl-1H-pyrazole (0.1 mL, 1.02 mmol) and anhydrous potassium phosphate tribasic (334 mg, 1.57 mmol) in anhydrous DMF (3 mL) and the mixture was bubbled with nitrogen for 5 minutes, before heating to 120 °C with stirring for 3 days. After cooling to room temperature, the reaction mixture was separated between ethyl acetate water and water, and the combined organic extracts were washed with water and 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 40-100% ethyl acetate/petroleum ether, to give 1',4-dimethyl-3-nitro-1'H-1,4'-bipyrazole (28 mg, 17% yield) as a yellow solid. MS (ES+) 208.6 (M+H)+; 1H NMR (DMSO-d6, 300 MHz) δ 8.33 (d, 1H, J = 0.8 Hz), 8.30 (q, 1H, J = 0.8 Hz), 7.93 (d, 1H, J = 0.8 Hz), 3.89 (s, 3H), 2.31 (d, 3H, J = 0.8 Hz) ppm. A solution of 1',4-dimethyl-3-nitro-1'H-1,4'-bipyrazole (70 mg, 0.34 mmol) in ethanol (12 mL) was bubbled with nitrogen for 5 minutes before adding 10% Palladium on Carbon (10 wt.%, 36 mg, 0.034 mmol) and bubbling for a further 5 minutes. The flask was then placed under vacuum and refilled with nitrogen before fitting a hydrogen balloon and stirring overnight at room temperature. The balloon was then removed and the reaction mixture bubbled with nitrogen for 5 minutes before filtering through dicalite, washing with ethyl acetate. The filtrate was concentrated to give the product (60 mg, 100% yield) as an off-white solid that was used directly in the next step. MS (ES+) 178.2 (M+H)+. Pd coupling of N-protected 4-[(2-bromothiazole-5-carbonyl)amino]-5-substituted-indazoles with substituted amino pyrazoles
Figure imgf000171_0002
Synthesis of tert-butyl 4-[(2-bromothiazole-5-carbonyl)amino]-5-methyl-indazole-1-carboxylate
Figure imgf000171_0003
Step 1: To a solution of 5-methyl-4-nitro-1H-indazole (850 mg, 4.80 mmol, 1.0 eq), prepared as described in WO2014/3483, in DCM (100 mL) was added NEt3 (0.80 mL, 5.76 mmol, 1.2 eq) followed by di-tert-butyl dicarbonate (1.15 g, 5.28 mmol, 1.1 eq). The mixture was stirred overnight at RT. Water added and the phases separated. The aqueous layer was extracted with DCM (3 x 50 mL), the combined organic phases dried (MgSO4), filtered and concentrated in vacuo. The crude product was chromatographed (SiO2) eluting with 5 % EtOAc:PE to afford tert-butyl 5- methyl-4-nitro-indazole-1-carboxylate (3.0 g, 10.8 mmol, 38%) as red solid. The material was used directly in the next step.1H NMR (300 MHz, DMSO-d6) δ 8.53 (s, 1H), 8.30 (d, J = 9.0 Hz, 1H), 7.70 (d, J = 9.1 Hz, 1H), 2.65 (s, 3H), 1.66 (s, 9H). Step 2: A mixture of tert-butyl 5-methyl-4-nitro-indazole-1-carboxylate (3.0 mg, 10.8 mmol, 1.0 eq) and Pd/C (10% w/w, 115 mg, 1.08 mmol, 0.1 eq in MeOH (150 mL) was placed under a hydrogen atmosphere and stirred at RT for 12 h. Reaction monitoring by consumption of starting material via UPLC. The mixture was filtered through a pad of dicalite and concentrated in vacuo to afford tert-butyl 4-amino-5-methyl-indazole-1-carboxylate (2.3 g, 9.30 mmol, 86%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.47 (s, 1H), 7.15 – 7.08 (m, 2H), 5.82 (s, 2H), 2.13 (s, 3H), 1.61 (s, 9H). Step 3: To a solution of 2-bromothiazole-5-carboxylic acid (1.8 mg, 8.65 mmol, 1.0 eq), tert- butyl 4-amino-5-methyl-indazole-1-carboxylate (2.57 mg, 10.4 mmol, 1.2 eq) and DIPEA (4.0 mL, 23.0 mmol, 2.65 eq) in THF (100 mL) was added T3P (50% in EtOAc, 4.0 mL, 13.6 mmol, 1.57 eq) and the mixture stirred for 16 h at 65°C. The mixture was poured into water and the aqueous phase extracted with EtOAc (4 x 50 mL). The combined organic phase was dried (MgSO4) and concentrated in vacuo. The residue was chromatographed (SiO2) eluting with 0 – 100% EtOAc:PE to afford the title compound (2.0 g, 4.57 mmol, 53%) as a brown solid. MS (ES-) m/z 435.1/437.1 (M-H), Br isotope pattern, 72% purity. Synthesis of tert-butyl 4-[(2-bromothiazole-5-carbonyl)amino]-5-chloro-indazole-1-carboxylate
Figure imgf000172_0001
Step 1: To tert-butyl 4-aminoindazole-1-carboxylate (80%, 1105 mg, 3.79 mmol, 1.00 eq) in THF (20 mL) at -78 °C was added dropwise a solution of N-Chlorosuccinimide (557 mg, 4.17 mmol, 1.10 eq) in THF (6 mL) at -78 °C. The reaction was stirred at this temperature for 1h then allowed to warm to rt and stirred for 16 h. A further 0.75 eq N-Chlorosuccinimide was added in one portion and the reaction stirred at rt for 4 h then quenched by the addition of sat. NaHCO3 solution (5 mL). Ethyl acetate (15 mL) and water (15 mL) were added. The phases were separated and the aqueous phase extracted with ethyl acetate (2 x 20 mL). Combined organic phases were washed with NH4Cl (10 mL, 10% w/w aqueous solution), brine (20 mL), dried over MgSO4, filtered and concentrated in vacuo. Column chromatography (petrol:ethyl acetate) gave tert-butyl 4-amino-5- chloro-indazole-1-carboxylate (660 mg, 2.47 mmol, 65%).1H NMR (300 MHz, Methanol-d4) δ 8.35 (s, 1H), 7.39 – 7.17 (m, 2H), 1.68 (s, 9H). MS (ES-) m/z = 266, 268 ([M-H]-, 100) Step 2: To a mixture of tert-butyl 4-amino-5-chloro-indazole-1-carboxylate (446 mg, 1.67 mmol, 1.10 eq), 2-bromo-1,3-thiazole-5-carboxylic acid (315 mg, 1.51 mmol, 1.00 eq) and N,N- diisopropylethylamine (0.53 mL, 3.03 mmol, 2.00 eq) in THF (10.095 mL) was added 1- propanephosphonic anhydride 50% in Ethyl Acetate (1.3 mL, 2.27 mmol, 1.50 eq) and the reaction heated to 65 °C for 16 h. Ethyl acetate (15 mL) and water (15 mL) were added. The phases were separated and the aqueous phase extracted with ethyl acetate (2 x 20 mL). Combined organic phases were washed with NH4Cl (10 mL, 10% w/w aqueous solution), brine (20 mL), dried over MgSO4, filtered and concentrated in vacuo. Column chromatography (petrol:ethyl acetate) gave the title compound (505 mg, 0.552 mmol, 36%). This material was used directly in the next step without further purification. General Method C1: Palladium catalysed coupling of Boc N-protected, 5-substituted indazole with substituted amino pyrazoles A mixture of tert-butyl 4-[(2-bromothiazole-5-carbonyl)amino]-5-substituted-indazole-1- carboxylate (1 eq), substituted amino pyrazole (1.5 – 2 eq) and sodium tert-butoxide (2.5 – 4 eq) in 1,4-dioxane (0.01 - 0.04 M) or cesium carbonate (1.5 eq) in 1,4-dioxane:water 4:1 was flushed with nitrogen before the addition of Pd2dba3 (0.1 eq) and XantPhos (0.1 eq). The mixture was heated to 100 °C for 16 h. Reaction monitoring by consumption of starting material via UPLC. The mixture was cooled and concentrated in vacuo. The crude material was purified by either normal phase chromatography (SiO2) using a gradient of MeOH:DCM or reverse phase chromatography. N-(5-methyl-1H-indazol-4-yl)-2-[(1-methylpyrazol-3-yl)amino]thiazole-5-carboxamide (BAA-001)
Figure imgf000173_0001
Prepared as described in Method C1 from tert-butyl 4-[(2-bromothiazole-5- carbonyl)amino]-5-methyl-indazole-1-carboxylate (400 mg, 0.915 mmol, 1.0 eq), 1-methyl-1H- pyrazol-3-ylamine (133 mg, 1.37 mmol, 1.5 eq), sodium tert-butoxide (220 mg, 2.29 mmol, 2.5 eq) Pd2dba3 (84 mg, 0.0915 mmol, 0.1 eq) and XantPhos (53 mg, 0.0915 mmol, 0.1 eq) in 1,4-dioxane (25 mL) for 16 h at 100°C to afford the title compound (12 mg, 0.0340 mmol, 3.7%) as a beige solid after normal phase chromatography (SiO2) eluting with 0 – 30% MeOH:DCM. MS (ES+) m/z 354.3 (M+H)+.1H NMR (300 MHz, Methanol-d4) δ 8.11 (s, 1H), 7.92 (d, J = 0.9 Hz, 1H), 7.49 (d, J = 2.3 Hz, 1H), 7.44 – 7.39 (m, 1H), 7.33 (d, J = 8.7 Hz, 1H), 6.03 (d, J = 2.3 Hz, 1H), 3.84 (s, 3H), 2.38 (s, 3H). The following example compounds were prepared similarly using Method C1 using the appropriately substituted amine:
Figure imgf000174_0001
Figure imgf000175_0001
Figure imgf000176_0002
(R)-N-(5-chloro-1H-indazol-4-yl)-2-((1-(1-isobutyrylpyrrolidin-3-yl)-1H-pyrazol-3-yl)amino)thiazole- 5-carboxamide (BAA-010)
Figure imgf000176_0001
Step 1. tert-butyl (R)-3-(3-((5-((5-chloro-1H-indazol-4-yl)carbamoyl)thiazol-2-yl)amino)-1H- pyrazol-1-yl)pyrrolidine-1-carboxylate (BAA-007) (18 mg, 0.0340 mmol, 1.00 eq) was stirred in HCl (4M in dioxane) for 16 h then concentrated in vacuo to give (R)-N-(5-chloro-1H-indazol-4-yl)-2-((1- (pyrrolidin-3-yl)-1H-pyrazol-3-yl)amino)thiazole-5-carboxamide hydrochloride (15 mg, 0.0322 mmol, 95%) which was used in the next step without further purification. Step 2. To (R)-N-(5-chloro-1H-indazol-4-yl)-2-((1-(pyrrolidin-3-yl)-1H-pyrazol-3- yl)amino)thiazole-5-carboxamide hydrochloride (25 mg, 0.0537 mmol, 1.00 eq) and N,N- diisopropylethylamine (0.023 mL, 0.134 mmol, 2.50 eq) in DCM (3 mL) at 0 °C was added dropwise isobutyryl chloride (0.0056 mL, 0.0537 mmol, 1.00 eq) and the reaction stirred for 4 h at rt. The reaction was concentrated in vacuo and column chromatography directly on the crude material (petrol:ethyl acetate) followed by trituration with CH2Cl2 gave the title compound (9.0 mg, 0.0180 mmol, 34%).1H NMR (300 MHz, DMSO-d6) δ 8.07 (d, J = 1.8 Hz, 1H), 7.95 (s, 1H), 7.56 – 7.51 (m, 1H), 7.48 (d, J = 1.1 Hz, 2H), 6.32 (s, 1H), 5.14 (s, 1H), 4.07 – 3.67 (m, 4H), 3.62 – 3.39 (m, 2H), 2.78 (dp, J = 27.5, 6.7 Hz, 1H), 2.53 – 2.26 (m, 2H), 1.32 (d, J = 6.5 Hz, 6H), 0.95 – 0.78 (m, 1H). MS (ES+) m/z 499 (M+H)+ Synthesis of indazole building blocks and corresponding brom-thiazolecarboxamide intermediates Synthesis of 2-bromo-N-(5-methyl-1-tetrahydropyran-2-yl-indazol-4-yl)thiazole-5-carboxamide
Figure imgf000177_0001
Step 1: To a suspension of 5-methyl-4-nitro-1H-indazole (5.10 g, 28.8 mmol, 1.00 eq) in DCM (170 mL) was added p-toluenesulfonic acid monohydrate (548 mg, 2.88 mmol, 0.100 eq) followed by 3,4-dihydro-2H-pyran (7.8 mL, 86.4 mmol, 3.00 eq). The resulting suspension slowly dissolved upon stirring. The mixture was stirred for 1 h, quenched with sat. aq. NaHCO3 (150 mL), the phases separated, the aqueous phase washed with DCM (2 x 50 mL) and the combined extracts filtered throug a hydrophobic frit and concentrated in vacuo. The resulting residue was chromatographed (SiO2) using 0 - 25 % EtOAc:PE as eluent to afford 5-methyl-4-nitro-1- tetrahydropyran-2-yl-indazole (6.74 g, 25.8 mmol, 90 %) as an orange powder.1H NMR (300 MHz, Chloroform-d) δ 8.40 (d, J = 0.9 Hz, 1H), 7.79 (dd, J = 8.5, 0.9 Hz, 1H), 7.33 (dd, J = 8.6, 0.6 Hz, 1H), 5.77 (dd, J = 8.8, 2.7 Hz, 1H), 3.98 (dtd, J = 11.4, 3.8, 1.4 Hz, 1H), 3.74 (dddd, J = 9.7, 8.0, 4.5, 2.5 Hz, 1H), 2.74 (s, 3H), 2.63 – 2.43 (m, 1H), 2.25 – 1.99 (m, 2H), 1.87 – 1.62 (m, 3H). Step 2: A solution of 5-methyl-4-nitro-1-tetrahydropyran-2-yl-indazole (3.66 g, 14.0 mmol) in ethanol (120 mL) was bubbled with nitrogen for 5 minutes before adding 10% Palladium on Carbon (10 wt.%, 200 mg, 1.88 mmol) and bubbling for a further 5 minutes. The flask was then placed under vacuum and refilled with nitrogen before fitting a hydrogen balloon and stirring overnight at room temperature. The balloon was then removed and the reaction mixture bubbled with nitrogen for 5 minutes before filtering through dicalite, washing with ethanol. The filtrate was concentrated to give 5-methyl-1-tetrahydropyran-2-yl-indazol-4-amine (2.811 g, 87% yield) as an orange oil that solidified on standing.1H NMR (DMSO-d6), 300 MHz) δ 8.14 (s, 1H), 6.97 (d, 1H, J = 8.5 Hz), 6.70 (d, 1H, J = 8.8 Hz), 5.61 (dd, 1H, J = 9.8, 2.5 Hz), 5.50 (s, 2H), 3.90-3.83 (m, 1H), 3.71-3.63 (m, 1H), 2.44-2.31 (m, 1H), 2.12 (s, 3H), 2.05-1.98 (m, 1H), 1.92-1.84 (m, 1H), 1.79-1.65 (m, 1H), 1.59- 1.50 (m, 2H). MS (ES+) m/z 233.1 (M+H)+. Step 3: 1-Propanephosphonic anhydride (50% in ethyl acetate, 3.82 mL, 6.49 mmol) was added drop-wise to a solution of 5-methyl-1-tetrahydropyran-2-yl-indazol-4-amine (1.0 g, 4.32 mmol) 2-bromo-1,3-thiazole-5-carboxylic acid (900 mg, 4.32 mmol), and DIPEA (1.51 mL, 8.65 mmol) in anhydrous THF (35 mL), with stirring at room temperature, and the reaction mixture was then heated to 70 °C, with stirring under nitrogen overnight. After cooling to room temperature, the reaction was quenched with water and extracted with diethyl ether, and the organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give the crude product, which was purified using flash column chromatography over silica, eluting with 0- 90% ethyl acetate/petroleum ether to give the title compound (1.542 g, 85% yield) as a yellow solid.1H NMR (DMSO-d6, 300 MHz) δ 10.55 (s, 1H), 8.52 (s, 1H), 7.93 (s, 1H), 7.60 (d, 1H, J = 8.5 Hz), 7.34 (d, 1H, J = 8.7 Hz), 5.83 (dd, 1H, J = 9.7, 2.3 Hz), 3.92-3.86 (m, 1H), 3.78-3.70 (m, 1H), 2.46-2.34 (m, 1H), 2.29 (s, 3H), 2.05-1.93 (m, 2H), 1.82-1.69 (m, 1H), 1.62-1.55 (m, 2H). MS (ES+) m/z 422.9 (M+H)+ 2-Amino-N-(5-methyl-1H-indazol-4-yl)thiazole-5-carboxamide (BAA-011
Figure imgf000178_0001
Figure imgf000178_0002
1-Propanephosphonic anhydride (50% in Ethyl Acetate, 0.76 mL, 1.3 mmol) was added drop-wise to a solution of 5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-amine (200 mg, 0.86 mmol) 2-((tert-butoxycarbonyl)amino)thiazole-5-carboxylic acid (222 mg, 0.91 mmol), and DIPEA (0.3 mL, 1.7 mmol) in anhydrous THF (10 mL), with stirring at room temperature, and the reaction mixture was then heated to 70 °C, with stirring under nitrogen overnight. After cooling to room temperature, the reaction was quenched with water and extracted with diethyl ether, and the organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered through a short pad of silica and concentrated to give the crude product, which was purified using flash column chromatography over silica, eluting with 25-100% ethyl acetate/petroleum, to give tert-butyl (5-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)carbamoyl) thiazol-2-yl)carbamate (179 mg, 45% yield) as a white solid. MS (ES+) 458.3 (M+H)+; 1H NMR (DMSO-d6, 300 MHz) δ 11.81 (s, 1H), 10.17 (s, 1H), 8.26 (s, 1H), 7.88 (s, 1H), 7.56 (d, 1H, J = 8.6 Hz), 7.32 (d, 1H, J = 9.0 Hz), 5.82 (dd, 1H, J = 9.8, 2.5 Hz), 3.91-3.87 (m, 1H), 3.78-3.70 (m, 1H), 2.45-2.34 (m, 1H), 2.28 (s, 3H), 2.05-1.93 (m, 2H), 1.78-1.72 (m, 1H), 1.64-1.57 (m, 2H), 1.51 (s, 9H) ppm 4 M HCl/dioxane (2 mL, 8.2 mmol) was added to a suspension of tert-butyl (5-((5-methyl-1- (tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)carbamoyl)thiazol-2-yl)carbamate (150 mg, 0.33 mmol) in DCM (2 mL) with stirring under nitrogen for 3 hours before concentrating in vacuo. DCM was added and the mixture concentrated again and the resulting precipitate was purified using flash column chromatography over silica, eluting with 0-35% methanol/dichloromethane to give the title compound (67 mg, 75% yield) as a white solid. MS (ES+) 274.4 (M+H)+; 1H NMR (DMSO-d6, 300 MHz) δ 10.42 (s, 1H), 9.29 (br, 2H), 8.30 (s, 1H), 7.85 (s, 1H), 7.38 (d, 1H, J = 8.4 Hz), 7.25 (d, 1H, J = 8.6 Hz), 2.27 (s, 3H) ppm. 2-Bromo-N-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)thiazole-5-carboxamide
Figure imgf000178_0003
Step 1: To a suspension of 5-bromo-4-nitro-1H-indazole (1.18 g, 4.88 mmol) in DCM (48.8 mL) were added p-toluenesulfonic acid, polymer bound (84 mg, 0.488 mmol) and 3,4-dihydro-2H- pyran (1.4 mL, 14.6 mmol) . The mixture was stirred for 1h at rt, then quenched with sat. Aq. NaHCO3 (50 mL), brine (30 mL) and DCM (50 mL). The organic phases were separated, dried over Na2SO4 and concentrated under reduce pressure. The crude material was purified by column chromatography over silica (20 g cartridge) eluting with a gradient of EtOAc (0% to 25%; v/v) in iso-hexane to afford the desired product 5-bromo-4-nitro-1-tetrahydropyran-2-yl-indazole (1.60 g, 4.71 mmol, 96.60% yield) as a yellow solid.1H NMR (400 MHz, DMSO-D6) δ 8.28 (d, J = 0.9 Hz, 1H), 8.05 (dd, J = 8.9, 1.0 Hz, 1H), 7.83 (d, J = 8.9 Hz, 1H), 5.96 (dd, J = 9.4, 2.5 Hz, 1H), 3.86 – 3.80 (m, 1H), 3.77 – 3.69 (m, 1H), 2.38 – 2.26 (m, 1H), 2.03 – 1.96 (m, 2H), 1.77 – 1.64 (m,1H), 1.55 (tq, J = 8.2, 3.9 Hz, 2H). Step 2: To a solution of 5-bromo-4-nitro-1-tetrahydropyran-2-yl-indazole (1.10 g, 3.37 mmol) in DMF (33.7 mL) was added 4,4'-dipyridyl (53 mg, 0.337 mmol) followed by tetrahydroxy diboron (907 mg, 10.1 mmol) at 22 °C and stirred for 10 min. The crude was treated with water (20 mL) and EtOAc (50 mL). The organic phase was separated, dried over Na2SO4 and concentrated under reduce pressure. The crude was purified by column chromatography over silica (4 g cartridge) eluting with a gradient of EtOAc (0% to 30%; v/v) in iso-hexane to afford 5-bromo-1- tetrahydropyran-2-yl-indazol-4-amine (580 mg, 1.66 mmol, 49.35% yield) as a pale yellow solid. MS (ES+), m/z = 295.9/297.9 [M+H]+.1H NMR (400 MHz, DMSO-D6) δ 8.24 (d, J = 0.9 Hz, 1H), 7.27 (d, J = 8.7 Hz, 1H), 6.79 (dd, J = 8.8, 0.9 Hz, 1H), 6.03 (s, 2H), 5.67 (dd, J = 9.7, 2.6 Hz, 1H), 3.86 (dtd, J = 11.4, 3.8, 1.7 Hz, 1H), 3.76 – 3.58 (m, 1H), 2.42 – 2.27 (m, 1H), 2.05 – 1.98 (m, 1H), 1.90 (dq, J = 13.1, 3.6 Hz, 1H), 1.71 (dtd, J = 19.4, 13.2, 3.9 Hz, 1H), 1.55 (tq, J = 8.1, 3.9 Hz, 2H). Step 3: To a solution of 2-bromothiazole-5-carboxylic acid (593 mg, 2.85 mmol) in MeCN (19 mL) was added 1-methylimidazole (530 uL, 6.65 mmol) and chloro-N,N,N',N'- tetramethylformamidinium hexafluorophosphate (1.60 g, 5.70 mmol). The reaction mixture was stirred at 22 °C for 5 min. To the reaction mixture was then added 5-bromo-1-tetrahydropyran-2-yl- indazol-4-amine (580 mg, 1.90 mmol) and stirred at 22 °C for 18 h. The reaction mixture was treated with NaHCO3 (30 mL), water (20 mL), brine (20 mL) and EtOAc (40 ml). The organic phase was separated, dried over Na2SO4 and concentrated under reduce pressure. The crude material was purified by column chromatography over silica (24 g cartridge) eluting with a gradient of EtOAc (0% to 40%; v/v) in iso-hexane to afford the desired product 2-bromo-N-(5-bromo-1- tetrahydropyran-2-yl-indazol-4-yl)thiazole-5-carboxamide (930 mg, 1.86 mmol, 97.7% yield) as a orange solid. MS (ES+) m/z = 484.9/486.8/489.9 [M+H]+, 97% purity.1H NMR (400 MHz, CHLOROFORM-D) δ 8.17 (d, J = 2.7 Hz, 1H), 8.08 – 8.02 (m, 2H), 7.53 (d, J = 8.9 Hz, 1H), 7.40 (dd, J = 8.9, 1.0 Hz, 1H), 5.71 (dd, J = 9.1, 2.8 Hz, 1H), 4.06 – 3.97 (m, 1H), 3.75 (ddd, J = 11.5, 9.9, 3.2 Hz, 1H), 2.60 – 2.46 (m, 1H), 2.22 – 2.05 (m, 2H), 1.85 – 1.60 (m, 3H). 3-Bromo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-amine
Figure imgf000180_0001
N-Bromosuccinimide (1.2 g, 6.74 mmol) was added to a solution of 5-methyl-4-nitro-1H- indazole (1.00 g, 5.64 mmol) in MeCN (56.4 mL) . The mixture was stirred at 90 °C for 14 h. The solvent was removed in vacuo, and the residue was taken up in 20 mL of EtOAc, washed with water (2 x 10 ml), sat. aq. Na2S2O3 (10 mL) and brine (5 ml). The crude was dried under reduce pressure to afford the desired product 3-bromo-5-methyl-4-nitro-1H-indazole (1.15 g, 4.45 mmol, 78.77% yield) as yellow solid. MS (ES-) m/z = 254.0/256.0 [M-H]-.1H NMR (400 MHz, DMSO-D6) δ 7.79 (d, J = 8.6 Hz, 1H), 7.49 (dd, J = 8.6, 0.5 Hz, 1H), 2.38 (s, 3H). To a solution of 3-bromo-5-methyl-4-nitro-1H-indazole (1.10 g, 4.30 mmol) in DCM (43 mL) was added 3,4-dihydro-2H-pyran (1.2 mL, 12.9 mmol) followed by p-toluenesulfonic acid, polymer bound (74 mg, 0.430 mmol) at 22 °C and stirred for 10 min. The crude was treated with NaHCO3 (20 ML), water (20 mL) and EtOAc (50 mL). The organic phase was separated, dried over Na2SO4 and concentrated under reduce pressure. The crude material was purified by column chromatography over silica (4 g cartridge) eluting with a gradient of EtOAc (0% to 30%; v/v) in iso- hexane to afford 3-bromo-5-methyl-4-nitro-1-tetrahydropyran-2-yl-indazole (1.21 g, 3.49 mmol, 81.14% yield) as a pale yellow solid.1H NMR (400 MHz, DMSO-D6) δ 8.00 (d, J = 8.8 Hz, 1H), 7.55 (d, J = 8.8 Hz, 1H), 5.92 (dd, J = 9.5, 2.4 Hz, 1H), 3.83 (ddt, J = 11.8, 4.7, 2.3 Hz, 1H), 3.71 (ddd, J = 11.3, 7.9, 5.7 Hz, 1H), 2.35 (s, 3H), 2.35 - 2.26 (m, 1H), 2.01 – 1.96 (m, 1H), 1.75 – 1.62 (m, 1H), 1.57 – 1.51 (m, 2H), 1.43 (tdd, J = 11.0, 6.1, 2.4 Hz, 1H). To a solution of 3-bromo-5-methyl-4-nitro-1-tetrahydropyran-2-yl-indazole (1.20 g, 3.46 mmol) in DMF (34.6 mL) was added 4,4'-dipyridyl (54 mg, 0.346 mmol) followed by tetrahydroxy diboron (930 mg, 10.4 mmol) at 22 °C and stirred for 10 min. The crude was treated with water (20 mL) and EtOAc (50 mL). The organic phase was separated, dried over Na2SO4 and concentrated under reduce pressure. The crude material was purified by column chromatography over silica (24 g cartridge) eluting with a gradient of EtOAc (0% to 35%; v/v) in iso-hexane to afford 3-bromo-5- methyl-1-tetrahydropyran-2-yl-indazol-4-amine (795 mg, 2.36 mmol, 68.20% yield) as a pink solid. MS (ES+) m/z = 309.9/311.9 [M+H]+.1H NMR (400 MHz, DMSO-D6) δ 7.08 (d, J = 8.4 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H), 5.64 (dd, J = 9.7, 2.5 Hz, 1H), 5.32 (s, 2H), 3.85 (d, J = 11.5 Hz, 1H), 3.73 – 3.62 (m, 1H), 2.36 – 2.22 (m, 1H), 2.12 (s, 3H), 2.03 – 1.96 (m, 1H), 1.89 (dd, J = 13.1, 3.2 Hz, 1H), 1.77 – 1.61 (m, 1H), 1.58 – 1.50 (m, 2H). N-(3-Bromo-5-methyl-1H-indazol-4-yl)-2-[(1-methylpyrazol-3-yl)amino]thiazole-5-carboxamide (BAA-012)
Figure imgf000181_0001
Step 1: Caesium carbonate (1.70 eq, 25.00 g, 76.7 mmol) , tris(dibenzylideneacetone) dipalladium(0) (Pd2(dba)3) (0.0339 eq, 1.40 g, 1.53 mmol) and 4,5-bis(diphenylphosphino)-9,9- dimethylxanthene (Xantphos) (0.0750 eq, 1.95 g, 3.38 mmol) were added to a solution of 1-methyl- 1H-pyrazol-3-ylamine (1.28 eq, 5.0 mL, 57.7 mmol) and methyl 2-bromothiazole-5-carboxylate (1.00 eq, 10.00 g, 45.0 mmol) in 1,4-Dioxane (100 mL) , under nitrogen. The reaction mixture was heated at 80 °C for 18h, cooled, poured onto water (200mL). The solid was recovered by filtration, washed with water several times; the solid wastriturated in DCM and filtered again, washed with DCM several times, dried in vacuo at 40C on the sinter to afford methyl 2-[(1-methylpyrazol-3- yl)amino]thiazole-5-carboxylate (8.30 g, 33.1 mmol, 73.49% yield) as a green/brown solid. MS (ES+) m/z = 239.0 [M+H]+.1H NMR (400 MHz, DMSO-D6) δ 11.33 (s, 1H), 7.94 (s, 1H), 7.62 (d, J = 2.3 Hz, 1H), 5.92 (d, J = 2.3 Hz, 1H), 3.80 (s, 3H), 3.76 (s, 3H). Step 2: Lithium hydroxide (2.74 eq, 420 mg, 10.0 mmol) and water (10 mL) were added to a suspension of methyl 2-[(1-methylpyrazol-3-yl)amino]thiazole-5-carboxylate (1.00 eq, 870 mg, 3.65 mmol) in THF (10 mL) and stirred at 65 °C for 5h. The reaction mixture was cooled and acidified with hydrogen chloride (4.54 eq, 1.4 mL, 16.6 mmol); a solid precipitates. The solid was collected by filtration, washed with water, dried in vacuo at 40C to afford 2-[(1-methylpyrazol-3- yl)amino]thiazole-5-carboxylic acid;hydrochloride (670 mg, 2.13 mmol, 58.42% yield) as a yellow solid. MS (ES+) m/z = 225 [M+H]+.1H NMR (400 MHz, DMSO-D6) δ 12.64 (s, 1H), 11.21 (s, 1H), 7.85 (d, J = 0.6 Hz, 1H), 7.62 (d, J = 2.2 Hz, 1H), 5.93 (d, J = 2.3 Hz, 1H), 3.79 (s, 3H). Step 3: To a solution of 2-[(1-methylpyrazol-3-yl)amino]thiazole-5-carboxylic acid (180 mg, 0.803 mmol), triethylamine (0.22 mL, 1.61 mmol) and a drop of N, N-dimethylformamide, (0.025 mL, 0.321 mmol) in DCM (2.68 mL) at rt was added thionyl chloride (0.23 mL, 3.21 mmol) . The mixture was stirred at rt for 2 h. The chloride acid (intermediate) was concentrated under reduce pressure. In a flask was dissolved 3-bromo-5-methyl-1-tetrahydropyran-2-yl-indazol-4-amine (299 mg, 0.963 mmol) and triethylamine (0.22 mL, 1.61 mmol) in 1 mL of MeCN at rt, then the chloride acid dissolved in 2 mL of MeCN was added dropwise at rt. The mixture was stirred at rt overnight. The mixture was filtrated through a pad of celite and rinsed with EtOAc (5 mL). The solution was concentrated. The crude material was purified by column chromatography over C18 (12 g cartridge) eluting with a gradient of MeCN (0.1% NH3) (0% to 45%; v/v) in water (0.1% NH3) to afford the desired product N-(3-bromo-5-methyl-1-tetrahydropyran-2-yl-indazol-4-yl)-2-[(1- methylpyrazol-3-yl)amino]thiazole-5-carboxamide (70 mg, 0.136 mmol, 16.89% yield) as a yellow solid. MS (ES+) m/z = 516.0/517.9 [M+H]+.1H NMR (400 MHz, DMSO-D6) δ 11.05 (s, 1H), 9.92 (s, 1H), 8.15 (s, 1H), 7.67 (d, J = 8.7 Hz, 1H), 7.61 (d, J = 2.3 Hz, 1H), 7.43 (d, J = 8.7 Hz, 1H), 5.95 (d, J = 2.3 Hz, 1H), 5.84 (dd, J = 9.7, 2.4 Hz, 1H), 3.89 (d, J = 11.5 Hz, 1H), 3.79 (s, 3H), 3.77 – 3.70 (m, 1H), 2.38 – 2.28 (m, 1H), 2.27 (s, 3H), 2.05 – 1.91 (m, 2H), 1.81 – 1.68 (m, 1H), 1.57 (t, J = 7.2 Hz, 2H). Step 4: N-(3-bromo-5-methyl-1-tetrahydropyran-2-yl-indazol-4-yl)-2-[(1-methylpyrazol-3- yl)amino] thiazole-5-carboxamide (55 mg, 0.107 mmol) was suspended in 1,4-dioxane (0.9895 mL) and hydrogen chloride (7.5 mL, 29.8 mmol) was added at rt. Then, the mixture was stirred for 48h at rt, while adding an additional 1 mL of 4N HCl in dioxane. The crude was concentrated under reduce pressure. The solid was suspended in MeCN (3 mL) and it was sonicated for 5 min. The solid was filtrated and rinsed with diethyl ether to afford the desired product N-(3-bromo-5-methyl- 1H-indazol-4-yl)-2-[(1-methylpyrazol-3-yl)amino]thiazole-5-carboxamide (49 mg, 0.105 mmol, 99.02% yield) as a beige solid. MS (ES+) m/z = 432.2/434.2 [M+H]+.1H NMR (400 MHz, DMSO- D6) δ 13.43 (s, 1H), 10.02 (s, 1H), 8.22 (s, 1H), 7.65 (d, J = 2.3 Hz, 1H), 7.45 (d, J = 8.5 Hz, 1H), 7.35 (d, J = 8.6 Hz, 1H), 5.99 (d, J = 2.3 Hz, 1H), 3.80 (s, 3H), 2.26 (s, 3H). 2-Bromo-N-(5-bromo-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)thiazole-5- carboxamide
Figure imgf000182_0001
Step 1: Nitric acid (70% in water, 1 mL, 15.8 mmol) was added carefully drop-wise to a solution of 5-bromo-3-methyl-1H-indazole (1.0 g, 4.74 mmol) in sulfuric acid (20 mL) at 0 °C, with stirring at 0 °C for 1 hour. The reaction mixture was then poured into ice-cold water (100 ml) and the precipitate formed was collected using filtration, washing with water. The precipitate was then dissolved in 20% methanol/dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated and dried in a vacuum oven to give 5-bromo-3-methyl-4-nitro-1H-indazole (1.187 g, 98% yield) as an orange solid that did not require further purification. MS (ES-) 253.9 (M-H); 1H NMR (DMSO-d6, 300 MHz) δ 13.56 (br, 1H), 7.73 (d, 1H, J = 8.9 Hz), 7.67 (d, 1H, J = 8.9 Hz), 2.32 (s, 3H) ppm. Step 2: 3,4-Dihydro-2H-pyran (1.26 mL, 13.8 mmol) was added dropwise to a solution of 5- bromo-3-methyl-4-nitro-1H-indazole (1.18 g, 4.6 mmol) and p-Tosic acid monohydrate (88 mg, 0.46 mmol) in DCM (30 mL), with stirring at room temperature for 1 hour before quenching with saturated aqueous sodium bicarbonate solution. The reaction mixture was then concentrated and separated between ethyl acetate and water, and the organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give the crude product, which was purified using flash column chromatography over silica, eluting with 0-80% ethyl acetate/petroleum ether, to give 5-bromo-3-methyl-4-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H- indazole (1.404 g, 90% yield) as a yellow oil. MS (ES+) 342.2 (M+H)+; 1H NMR (DMSO-d6, 300 MHz) δ 7.95 (d, 1H, J = 8.9 Hz), 7.77 (d, 1H, J = 8.9 Hz), 5.88 (dd, 1H, J = 9.7, 2.5 Hz), 3.89-3.83 (m, 1H), 3.78-3.69 (m, 1H), 2.38-2.27 (m, 4H), 2.05-1.92 (m, 2H), 1.79-1.66 (m, 1H), 1.60-1.55 (m, 2H) ppm. Step 3: To a solution of 5-bromo-3-methyl-4-nitro-1-tetrahydropyran-2-yl-indazole (400 mg, 1.18 mmol) in DMF (7.8 mL) was added 4,4'-dipyridyl (18 mg, 0.118 mmol) followed by tetrahydroxy diboron (316 mg, 3.53 mmol) at 22 °C. The reaction mixture was stirred for 18 h, then quenched upon the addition of water (50 mL) and the aqueous phase washed with EtOAc (3 x 50 mL). The organic phases were combined and concentrated at 40 °C under reduced presure affording a crude oil. The crude was redissolved in EtOAc (50 mL) and the organic phase washed with 5% LiCl by weight (aq) (3 x 50 mL). The organic phase was then washed with brine (25 mL), dried over Na2SO4 and concentrated at 40 °C under reduced presure to afford a crude solid. The crude material was purified by column chromatography over silica (12 g cartridge) eluting with a gradient of EtOAc (0% to 50%; v/v) in iso-hexane to afford the desired product 5-bromo-3-methyl- 1-tetrahydropyran-2-yl-indazol-4-amine (250 mg, 0.782 mmol, 66.48% yield) as a yellow solid. MS (ES+) m/z = 309.9 [M+H]+.1H NMR (400 MHz, DMSO-D6) δ 7.27 (d, J = 8.8 Hz, 1H), 6.79 (d, J = 8.8 Hz, 1H), 5.58 (dd, J = 9.9, 2.5 Hz, 1H), 5.38 (s, 2H), 3.89 – 3.81 (m, 1H), 3.72 – 3.61 (m, 1H), 2.60 (s, 3H), 2.39 – 2.25 (m, 1H), 2.03 – 1.95 (m, 1H), 1.90 – 1.82 (m, 1H), 1.77 – 1.62 (m, 1H), 1.57 – 1.48 (m, 2H). Step 4: To a solution of 2-bromothiazole-5-carboxylic acid (146 mg, 0.704 mmol) in MeCN (3.13 mL) was added 1-methylimidazole (131 uL, 1.64 mmol) and chloro-N,N,N',N'- tetramethylformamidinium hexafluorophosphate (395 mg, 1.41 mmol) . The reaction mixture was stirred at 22 °C for 2 min. To the reaction mixture was then added 5-bromo-3-methyl-1- tetrahydropyran-2-yl-indazol-4-amine (150 mg, 0.469 mmol) and the reaction mixture was stirred at 22 °C for 18 h then quenched by the addition of sat NaHCO3 (aq) (2 mL) and partially concentrated under reduced presure at 40 °C. The wet crude was suspended in NaHCO3 (aq) (8 mL), filtered under reduced presure, washed with NaHCO3 (aq) (10 mL) and water (10 mL) to afford the product 2-bromo-N-(5-bromo-3-methyl-1-tetrahydropyran-2-yl-indazol-4-yl)thiazole-5-carboxamide (169 mg, 0.257 mmol, 54.74% yield) as an off-white solid. MS (ES+) m/z = 500.9, 502.9 [M+H]+.1H NMR (400 MHz, DMSO-D6) δ 10.83 (s, 1H), 8.53 (s, 1H), 7.67 (s, 2H), 5.80 (d, J = 9.8 Hz, 1H), 3.92 – 3.84 (m, 1H), 3.79 – 3.68 (m, 1H), 2.40 (s, 3H), 2.38 – 2.31 (m, 1H), 2.09 – 1.91 (m, 2H), 1.76 – 1.71 (m, 1H), 1.59 – 1.54 (m, 2H). 2-Bromo B-N-(3,5-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)thiazole-5-c
Figure imgf000184_0001
r NO NN 1. T P Drdiiom(xPaePnthhey,)lb H,o CrOosxinCeO,, NH NN H DOIPE T O3P S B Nr OnNe: Nar wat Oboxamide Step 1: 5-Bromo-3 l) and trimethylb Oorox 2- in.m He e,t ( Ph 0dy .5/Cl-4-nitro-1-(tetrahydro-2H-pyra 9 mL, 4.2 mmol) were OAn,- T2H-Fyl)-1H-indazole N (1.3 g, dissolved in 1,4-dioxa er (10 3 4 , 15mol% B N 3.8 mmo H S:r1, 44 mL) and the solution was bubbled with nitrogen for 5 minutes. Pd(PPh) (662 mg ) and cesium carbonate (3.76 g, 11.5 mmol) were then added with stirring and the mixture was bubbled with nitrogen for a further 5 minutes before heating to 90 °C with stirring overnight. After cooling to room temperature, the reaction mixture was separated between ethyl acetate water. The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give the crude product, which was purified using flash column chromatography over silica, eluting with 0-80% ethyl acetate/petroleum ether, to give 3,5-dimethyl-4-nitro-1- (tetrahydro-2H-pyran-2-yl)-1H-indazole (787 g, 75% yield) as a yellow solid. MS (ES+) 276.3 (M+H)+; 1H NMR (DMSO-d6, 300 MHz) δ 7.91 (d, 1H, J = 8.6 Hz), 7.45 (d, 1H, J = 8.7 Hz), 5.84 (dd, 1H, J = 9.7, 2.5 Hz), 3.91-3.84 (m, 1H), 3.77-3.69 (m, 1H), 2.41-2.30 (m, 7H), 2.05-1.92 (m, 2H), 1.75-1.69 (m, 1H), 1.61-1.53 (m, 2H) ppm Step 2: A solution of 3,5-dimethyl-4-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (740 mg, 2.69 mmol) in ethanol (30 mL) was bubbled with nitrogen for 5 minutes before adding 10% Palladium on Carbon (10 wt.%, 286 mg, 0.27 mmol) and bubbling for a further 5 minutes. The flask was then placed under vacuum and refilled with nitrogen before fitting a hydrogen balloon and stirring overnight at room temperature. The balloon was then removed and the reaction mixture bubbled with nitrogen for 5 minutes before filtering through dicalite, washing with ethyl acetate. The filtrate was concentrated to give 3,5-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-amine (630 mg, 96% yield) as a beige solid that was used directly in the next step. MS (ES+) 246.3 (M+H)+; 1H NMR (DMSO-d6, 300 MHz) δ 6.94 (d, 1H, J = 8.8 Hz), 6.67 (d, 1H, J = 8.4 Hz), 5.51 (dd, 1H, J = 9.9, 2.5 Hz), 4.99 (s, 2H), 3.88-3.82 (m, 1H), 3.68-3.60 (m, 1H), 2.61 (s, 3H), 2.41-2.28 (m, 1H), 2.12 (s, 3H), 2.01-1.95 (m, 1H), 1.87-1.80 (m, 1H), 1.72-1.66 (m, 1H), 1.56-1.48 (m, 2H) ppm. Step 3: 1-Propanephosphonic anhydride (50% in Ethyl Acetate, 0.72 mL, 1.22 mmol) was added drop-wise to a solution of 3,5-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-amine (200 mg, 0.82 mmol) 2-bromo-1,3-thiazole-5-carboxylic acid (187 mg, 0.9 mmol), and DIPEA (0.28 mL, 1.63 mmol) in anhydrous THF (8 mL), with stirring at room temperature, and the reaction mixture was then heated to 70 °C, with stirring under nitrogen overnight. After cooling to room temperature, the reaction was quenched with water and extracted with ethyl acetate, and the organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give the crude product, which was purified using flash column chromatography over silica, eluting with 0-100% ethyl acetate/petroleum ether to give the title compound (302 mg, 85% yield) as a white solid. MS (ES+) 437.2 (M+H)+; 1H NMR (DMSO-d6, 300 MHz) δ 10.53 (s, 1H), 8.49 (s, 1H), 7.56 (d, 1H, J = 8.6 Hz), 7.33 (d, 1H, J = 8.9 Hz), 5.73 (dd, 1H, J = 9.9, 2.5 Hz), 3.90-3.86 (m, 1H), 3.75-3.67 (m, 1H), 2.44-2.31 (m, 4H), 2.26 (s, 3H), 2.04-1.89 (m, 2H), 1.77-1.69 (m, 1H), 1.59-1.53 (m, 2H) ppm. 5-Fluoro-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-amine
Figure imgf000185_0001
Step 1: To a solution of 1-(2-amino-5-fluorophenyl)ethanone (500 mg, 3.26 mmol) in 37.5% hydrogen chloride solution (2.5 mL, 3.26 mmol) was added dropwise a solution of sodium nitrite (248 mg, 3.59 mmol) in water (1.24 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 2 h 30 min To the reaction mixture was added dropwise a solution of stannous chloride (1.55 g, 8.16 mmol) in 37.5% hydrogen chloride solution (1.3 mL, 3.26 mmol) at 0 °C . The reaction mixture was stirred for 18 h. To the reaction mixture was added sat. Rochelles salt (aq) (2 mL) and the reaction mixture stirred for 15 min. The reaction mixture was quenched upon the addition of NaHCO3 (~50 mL) until the solution was mildly basic (pH ~8). The aqueous phase was extracted with DCM (3 x 50 mL), the combined organic phases dried over Na2SO3 and concentrated under reduced presure at 40 °C to afford a yellow solid (786 mg, 160% yield). The crude solid was dissolved in the minimum amount of EtOAc and filtered through a short plug of silica, eluting with an isocratic gradient of 100% EtOAc (10 CV) to afford the desired product 5-fluoro-3-methyl-1H-indazole (417 mg, 2.78 mmol, 85.07% yield) as a yellow solid. MS (ES+) m/z = 151.1 [M+H]+.1H NMR (400 MHz, DMSO-D6) δ 12.72 (s, 1H), 7.52 – 7.43 (m, 2H), 7.20 (td, J = 9.1, 2.5 Hz, 1H), 2.45 (s, 3H). Step 2: To a solution of 5-fluoro-3-methyl-2H-indazole (417 mg, 2.78 mmol) in 95% sulfuric acid (23 mL, 410 mmol) at 0 °C was added 68% nitric acid (0.81 mL, 12.3 mmol) dropwise. The reaction mixture was allowed to warm to ~22 °C over the course of 30 min and stirred at 22 °C for 3 h. The reaction was quenched by pouring directly over ice. The solution was neutralised to pH ~8 upon the addition of solid Na2CO3 (~20 g) under strong stirring (700-800 rpm). The aqueous phase (400 mL) was extracted with 3:1 CHCl3:iPrOH (3 x 250 mL). The combined organic phases were dried over Na2SO4 and concentrated at 40 °C under reduced pressure to afford the desired product 5-fluoro-3-methyl-4-nitro-1H-indazole (212 mg, 0.989 mmol, 35.60% yield) as a beige solid. The product was used directly in the next reaction without further purification. MS (ES+) m/z = 196.2 [M+H]+.1H NMR (400 MHz, DMSO-D6) δ 13.54 (s, 1H), 7.89 (dd, J = 9.1, 3.9 Hz, 1H), 7.54 (dd, J = 10.7, 9.1 Hz, 1H), 2.42 (s, 3H).19F NMR (376 MHz, DMSO-D6) δ -132.18 (dd, J = 10.8, 3.9 Hz). Step 3: To a suspension of 5-fluoro-3-methyl-4-nitro-1H-indazole (212 mg, 0.923 mmol) in DCM (9.23 mL) was added 4-toluenesulfonic acid monohydrate (80 mg, 0.422 mmol) and 3,4- dihydro-2H-pyran (0.60 mL, 6.37 mmol) . The reaction mixture was stirred at 22 °C for 18 h, then quenched upon the addition of saturated NaHCO3 (10 mL). DCM (15 mL) and water (15 mL) were added and the organic phase separated. The aqueous phase was washed with DCM (2 x 25 mL). The combined organic phases were dried over brine (10 mL), Na2SO4 and concentrated under reduced presure at 40 °C to afford a crude brown oil. The crude material was purified by column chromatography over silica (12 g cartridge) eluting with a gradient of EtOAc (0% to 50%; 10 CV) in iso-hexane to afford the desired product 5-fluoro-3-methyl-4-nitro-1-tetrahydropyran-2-yl-indazole (182 mg, 0.619 mmol, 67.05% yield) as an orange amorphous solid.MS (ES+) m/z = 280.2 [M+H]+. 1H NMR (400 MHz, DMSO-D6) δ 8.14 (dd, J = 9.3, 3.9 Hz, 1H), 7.66 (dd, J = 10.6, 9.3 Hz, 1H), 5.91 (dd, J = 9.7, 2.4 Hz, 1H), 3.92 – 3.84 (m, 1H), 3.80 – 3.70 (m, 1H), 2.41 (s, 3H), 2.38 – 2.29 (m, 1H), 2.08 – 1.93 (m, 2H), 1.80 – 1.68 (m, 1H), 1.62 – 1.54 (m, 2H).19F NMR (376 MHz, DMSO- D6) δ -131.08 (dd, J = 10.6, 3.9 Hz). Step 4: To a suspension of 5-fluoro-3-methyl-4-nitro-1-tetrahydropyran-2-yl-indazole (182 mg, 0.619 mmol) in Ethyl acetate (6.19 mL) was added Palladium on activated Carbon (320 mg, 0.0619 mmol) under N2. The N2 atmosphere was evacuated, the flask fitted with a balloon of H2 and the reaction mixture stirred for 2 h. The reaction mixture was filtered through celite, washed with EtOAc (~75 mL) and the filtrate concentrated under vacuum at 40 °C to afford the desired product 5-fluoro-3-methyl-1-tetrahydropyran-2-yl-indazol-4-amine (167 mg, 0.616 mmol, 99.5% yield) as a purple gum. MS (ES+) m/z = 250.2 [M+H]+.1H NMR (400 MHz, DMSO-D6) δ 7.08 (dd, J = 11.5, 8.8 Hz, 1H), 6.71 (dd, J = 8.9, 3.2 Hz, 1H), 5.55 (dd, J = 9.9, 2.5 Hz, 1H), 5.26 (s, 2H), 3.84 (dq, J = 11.4, 2.8 Hz, 1H), 3.73 – 3.61 (m, 1H), 2.59 (s, 3H), 2.40 – 2.27 (m, 1H), 2.05 – 1.93 (m, 1H), 1.90 – 1.83 (m, 1H), 1.77 – 1.61 (m, 1H), 1.58 – 1.48 (m, 2H).19F NMR (376 MHz, DMSO- D6) δ -149.28 (dd, J = 11.5, 3.2 Hz, 1H). 2-Bromo-N-(5-fluoro-3-methyl-1-tetrahydropyran-2-yl-indazol-4-yl)thiazole-5-carboxamide
Figure imgf000186_0001
1-Propanephosphonic anhydride (50% in ethyl acetate, 1.06 mL, 1.81 mmol) was added drop-wise to a solution of 5-fluoro-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-amine (300 mg, 1.20 mmol) 2-bromo-1,3-thiazole-5-carboxylic acid (275 mg, 1.32 mmol), and DIPEA (0.42 mL, 2.41 mmol) in anhydrous THF (12 mL), with stirring at room temperature, and the reaction mixture was then heated to 70 °C, with stirring under nitrogen overnight. After cooling to room temperature, the reaction was quenched with water and extracted with ethyl acetate, and the organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give the crude product, which was purified using flash column chromatography over silica, eluting with 0- 100% ethyl acetate/petroleum ether to give the title compound (359 mg, 68% yield) as a brown solid. MS (ES+) 441.2 (M+H)+; 1H NMR (CDCl3, 300 MHz) δ 8.11-8.01 (br, 2H), 7.30 (dd, 1H, J = 9.1, 3.6 Hz), 7.03 (t, 1H, J = 9.3 Hz), 5.56 (dd, 1H, J = 10.0, 2.6 Hz), 4.07-4.02 (m, 1H), 3.79-3.70 (m, 1H), 2.61-2.47 (m, 1H), 2.40 (s, 3H), 2.18-2.09 (m, 1H), 2.05-1.99 (m, 1H), 1.78-1.64 (m, 3H) ppm; 19F NMR (CDCl3, 282 MHz) δ -132.43 ppm. General Method C2: Palladium catalysed coupling of THP N-protected, 5-substituted indazole with substituted heteroaryl amines such as amino pyrazoles, amino-oxazoles, amino-pyridines and deprotection of THP group. Step 1. A mixture of 2-bromo-N-(5-substituted-1-tetrahydropyran-2-yl-indazol-4-yl)thiazole- 5-carboxamide (1 eq), substituted amino pyrazole (3 eq) and cesium carbonate (1.5-3 eq) or potassium carbonate (4 eq) in 1,4-dioxane:water 4-5:1 was flushed with nitrogen before the addition of Pd2dba3 (0.15 eq) or Pd(OAc)2 (0.1 eq) and XantPhos (0.3 eq). The mixture was flushed with nitrogen for a further 5 minutes before heating to 95 °C with stirring for 18 hours. After cooling to room temperature the reaction mixture was separated between ethyl acetate water. The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give the crude product, which was purified by either normal phase chromatography (SiO2) using a gradient of MeOH:DCM. Step 2. TFA (30-50 eq) was added to a solution of THP-protected indazole (1 eq) in DCM (TFA to DCM ratio ~1:2-1:4 v:V), with stirring under nitrogen for 1-20 hours before concentrating in vacuo. DCM was added and the mixture concentrated again and the resulting precipitate was washed with diethyl ether to give the final product as a TFA salt. The crude TFA salt was purified by reverse phase chromatography to furnish the final compound. Optionally, the product mixture was treated with potassium carbonate followed by the addition of MeOH (1 mL) and allowed to stir for 30 minutes. The suspension was filtered under reduced pressure and concentrated in vacuo to afford the free based product. Purification by reverse phase chromatography, optionally followed by high pH preparative HPLC, furnished the final compound. Alternatively, hydrogen chloride (2M in diethyl ether or 4M in dioxane) was added to a solution of THP-protected indazole in diethyl ether (2-5 mL) and the reaction stirred for 6 h at rt then concentrated in vacuo. Trituration with diethyl ether, followed by neutralisation with triethylamine (5 eq) and reverse phase chromatography (water:acetonitrile) or preparative HPLC (water:acetonitrile) gave the final product as the free base. 2-(Isoxazol-3-ylamino)-N-(5-methyl-1H-indazol-4-yl)thiazole-5-carboxamide (BAA-013)
Figure imgf000188_0001
Prepared as described in Method C2 from 2-bromo-N-(5-methyl-1-tetrahydropyran-2-yl- indazol-4-yl)thiazole-5-carboxamide (100 mg, 0.24 mmol, 1.0 eq), isoxazol-3-amine (60 mg, 0.72 mmol, 3 eq), Pd2dba3 (33 mg, 15mol%), XantPhos (41 mg, 30mol%), and cesium carbonate (156 mg, 0.47 mmol) in dioxane:water (4:1, 5 mL) followed by deprotection with in TFA/DCM to afford the title compound (32 mg, 75% yield) as a trifluoroacetate salt. MS (ES+) m/z 341.0 (M+H)+.1H NMR (DMSO-d6, 300 MHz) δ 13.24-10.98 (br, 3H), 10.13 (s, 1H), 8.79 (d, 1H, J= 1.8 Hz), 8.26 (s, 1H), 7.86 (d, 1H, J= 0.8 Hz), 7.38 (d, 1H, J= 8.5 Hz), 7.26 (d, 1H, J= 8.5 Hz), 6.44 (d, 1H, J= 1.8 Hz), 2.28 (s, 3H).19F NMR (DMSO-d6, 282 MHz) δ -75.02
Figure imgf000188_0002
The fo HlN ppm. The following example compound was prepared similarly using Method C2 using the appropriately substituted amin low Ne: i NHng O add S Nition N NaHl O example compounds were prepared similarly using Method C2 using the appropriately substituted amine.
Figure imgf000189_0001
Figure imgf000190_0001
Figure imgf000191_0001
Figure imgf000192_0001
Figure imgf000193_0001
Figure imgf000194_0001
Figure imgf000195_0001
HN N NH O S HN N N F
Figure imgf000196_0001
Figure imgf000197_0001
Figure imgf000198_0001
Figure imgf000199_0001
Figure imgf000200_0001
Figure imgf000201_0001
Figure imgf000202_0001
Figure imgf000203_0001
Figure imgf000204_0001
Figure imgf000205_0001
Figure imgf000206_0001
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O
Figure imgf000224_0001
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Figure imgf000232_0002
2-((1-(3-Amino-3-oxopropyl)-5-methyl-1H-pyrazol-3-yl)amino)-N-(5-methyl-1H-indazol-4-yl)thiazole- 5
Figure imgf000232_0001
Step 1: A mixture of 2-bromo-N-(5-methyl-1-tetrahydropyran-2-yl-indazol-4-yl)thiazole-5- carboxamide (115 mg, 0.270 mmol) , 3-(3-amino-5-methyl-pyrazol-1-yl)propanenitrile (120 mg, 0.757 mmol) and potassium carbonate 325 mesh (105 mg, 0.757 mmol) in 1,4-dioxane (4 mL) was bubbled with N2 flow for 10 min before palladium(II) acetate (9.1 mg, 0.0405 mmol) and 4,5- bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (47 mg, 0.0811 mmol) were added to the reaction vial. The vial was sealed and stirred at 80 °C for 3 h. The reaction mixture was diluted with DCM (50 mL), filtered through Cellite, washed with 10% citric acid, brine, dried over Na2SO4 and concentrated to dryness to give a residue, which was purified by column chromatography over silica (40 g cartridge) eluting with a gradient of MeOH (0% to 10%; v/v) in DCM to afford the 22-[[1- (2-cyanoethyl)-5-methyl-pyrazol-3-yl]amino]-N-(5-methyl-1-tetrahydropyran-2-yl-indazol-4- yl)thiazole-5-carboxamide (50 mg, 0.0989 mmol, 36.58% yield) as an orange solid. MS (ES+) m/z = 491.1 [M+H]+.1H NMR (400 MHz, DMSO-D6) δ 11.05 (s, 1H), 9.96 (s, 1H), 8.16 (s, 1H), 7.84 (d, J = 0.9 Hz, 1H), 7.51 (d, J = 8.3 Hz, 1H), 7.28 (d, J = 8.7 Hz, 1H), 5.80 (d, J = 0.9 Hz, 1H), 5.79 – 5.76 (m, 1H), 4.22 (t, J = 6.3 Hz, 2H), 3.85 (d, J = 11.5 Hz, 1H), 3.76 – 3.65 (m, 1H), 2.97 (t, J = 6.3 Hz, 2H), 2.26 (d, J = 0.8 Hz, 3H), 2.25 (s, 3H), 2.05 - 1.95 (m, 1H), 1.96 – 1.85 (m, 1H), 1.80- 1.65 (m, 1H), 1.62 - 1.48 (m, 3H). Step 2: Hydrogen chloride solution in dioxane (4M) (0.025 mL, 0.0989 mmol) was added to a stirred suspension of 2-[[1-(2-cyanoethyl)-5-methyl-pyrazol-3-yl]amino]-N-(5-methyl-1- tetrahydropyran-2-yl-indazol-4-yl)thiazole-5-carboxamide (50 mg, 0.0989 mmol) in 1,4-dioxane (4 mL) /DCM (4 mL) and stirred at 25 °C for 20 h. The reaction was concentrated to dryness to give a residue, which was purified by Prep HPLC under basic conditions to afford the 2-[[1-(3-amino-3- oxo-propyl)-5-methyl-pyrazol-3-yl]amino]-N-(5-methyl-1H-indazol-4-yl)thiazole-5-carboxamide (9.7 mg, 0.0229 mmol, 23.11% yield) as a white solid. MS (ES+) m/z = 425.4 [M+H]+.1H NMR (400 MHz, DMSO-D6) δ 12.98 (s, 1H), 10.99 (s, 1H), 9.95 (s, 1H), 8.18 (s, 1H), 7.85 (s, 1H), 7.42 (s, 1H), 7.36 (d, J = 8.5 Hz, 1H), 7.25 (d, J = 8.5 Hz, 1H), 6.87 (s, 1H), 5.75 (d, J = 0.8 Hz, 1H), 4.12 (t, J = 6.8 Hz, 2H), 2.62 (t, J = 6.9 Hz, 2H), 2.28 (s, 3H), 2.26 (d, J = 0.7 Hz, 3H). 2-[[1-(2-Hydroxyethyl)-4-m
Figure imgf000233_0001
ol-3-yl]amino]-N-(5-methyl-1H-indazol-4-yl)thiazole-5- carboxamide (BAA-202)
Figure imgf000233_0002
Step 1: A mixture of 2-bromo-N-(5-methyl-1-tetrahydropyran-2-yl-indazol-4-yl)thiazole-5- carboxamide (70 mg, 0.164 mmol) , 1-(2-methoxyethyl)-4-methyl-pyrazol-3-amine (59 mg, 0.329 mmol) and potassium carbonate 325 mesh (64 mg, 0.461 mmol) in 1,4-dioxane (3 mL) was bubbled with N2 flow for 10 min before palladium(II) acetate (5.5 mg, 0.0247 mmol) and 4,5- bis(diphenyl phosphino)-9,9-dimethylxanthene (Xantphos) (29 mg, 0.0493 mmol) were added to the reaction vial. The vial was sealed and stirred at 80 °C for 3 h. The reaction mixture was diluted with DCM, filtered through Cellite, and concentrated to dryness to give a residue, which was purified by column chromatography over silica (40 g cartridge) eluting with a gradient of MeOH (0% to 10%; v/v) in DCM followed by washing collected fractions with with 5% citric acidic to afford the 2-[[1-(2-methoxyethyl)-4-methyl-pyrazol-3-yl]amino]-N-(5-methyl-1-tetrahydropyran-2-yl-indazol-4- yl)thiazole-5-carboxamide (64 mg, 0.116 mmol, 70.66% yield) as a beige sold. MS (ES+) m/z = 496.1 [M+H]+.1H NMR (400 MHz, DMSO-D6) δ 10.75 (s, 1H), 9.97 (s, 1H), 8.21 (s, 1H), 7.88 (s, 1H), 7.54 (d, J = 8.5 Hz, 1H), 7.45 (s, 1H), 7.32 (d, J = 8.6 Hz, 1H), 5.82 (dd, J = 9.8, 2.6 Hz, 1H), 4.14 (t, J = 5.2 Hz, 2H), 3.93 – 3.85 (m, 1H), 3.79 – 3.70 (m, 1H), 3.68 (t, J = 5.2 Hz, 2H), 3.22 (s, 3H), 2.47 – 2.34 (m, 1H), 2.29 (s, 3H), 2.07 – 1.91 (m, 5H) , 1.83 – 1.66 (m, 1H), 1.62 – 1.56 (m, 2H). Step 2: Boron tribromide (0.30 mL, 0.300 mmol) was added via syringe to a stirred homogeneous solution of 2-[[1-(2-methoxyethyl)-4-methyl-pyrazol-3-yl]amino]-N-(5-methyl-1- tetrahydropyran-2-yl-indazol-4-yl)thiazole-5-carboxamide (64 mg, 0.116 mmol) in DCM (5 mL) at 0 °C. The resulting yellow suspension was stirred at 0 °C for 10 min, then was allowed to slowly warmed to room temperature and the stirring was continued at 23 °C for 22 h. The reaction mixture was diluted with DCM (5 mL) , recharged with boron tribromide (0.23 mL, 0.232 mmol) and stirred for further 20 h. The reaction was quenched with MeOH (1 mL), stirred for 5 min and then sat. NaHCO3 solution was added (5 mL) followed by Et2O (10 mL). The resulting mixture was stirred for 30 min and the insoluble part was isolated and dissolved in MeOH. The residue obtained after MeOH evaporation was purified by column chromatography over C18 (12 g cartridge) eluting with a gradient of MeCN (0.1% NH3) (5% to 50%; v/v) in water (0.1% NH3) to afford 2-[[1-(2- hydroxyethyl)-4-methyl-pyrazol-3-yl]amino]-N-(5-methyl-1H-indazol-4-yl)thiazole-5-carboxamide (15 mg, 0.0375 mmol, 32.26% yield) as a white solid. MS (ES+) m/z = 398.3 [M+H]+.1H NMR (400 MHz, DMSO-D6) δ 12.98 (s, 1H), 10.73 (s, 1H), 9.92 (s, 1H), 8.19 (s, 1H), 7.85 (d, J = 1.0 Hz, 1H), 7.44 (d, J = 0.9 Hz, 1H), 7.35 (d, J = 8.5 Hz, 1H), 7.25 (d, J = 8.5 Hz, 1H), 4.86 (t, J = 5.3 Hz, 1H), 4.02 (t, J = 5.7 Hz, 2H), 3.73 (q, J = 5.4 Hz, 2H), 2.28 (s, 3H), 2.00 (d, J = 0.8 Hz, 3H). Synthesis of 2-((1-(cyanomethyl)-4-methyl-1H-pyrazol-3-yl)amino)-N-(5-methyl-1H-indazol-4- yl)thiazole-5-carboxamide (BAA-203) and 2-((1-(2-amino-2-oxoethyl)-4-methyl-1H-pyrazol-3- yl)amino)-N-(5-methyl-1H-indazol-4-yl)thiazole-5-carboxamide (BAA-204)
Figure imgf000234_0001
Step 1: A mixture of 2-bromo-N-(5-methyl-1-tetrahydropyran-2-yl-indazol-4-yl)thiazole-5- carboxamide (95 mg, 0.223 mmol) , 2-(3-amino-4-methyl-pyrazol-1-yl)acetonitrile (64 mg, 0.447 mmol) and Potassium carbonate 325 mesh (77 mg, 0.558 mmol) in 1,4-Dioxane (2.5 mL) /Water (0.5 mL) was evacuated and filled with nitrogen before the addition of palladium(II) acetate (5.0 mg, 0.0223 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (26 mg, 0.0446 mmol) . The mixture was flushed with nitrogen before heating to 75 °C for 6 h. The reaction mixture was recharged with palladium(II) acetate (5.0 mg, 0.0223 mmol) and 4,5- bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (26 mg, 0.0446 mmol) and the stirring continued at 75 °C overnight. The reaction mixture was diluted with EtOAc, filtered through Cellite and washed with EtOAc (30 mL). The resulting EtOAc solution was concentrated to dryness to give the crude material which was further purified by column chromatography over silica (40 g cartridge) eluting with a gradient of MeOH (0% to 10%; v/v) in DCM to afford the following products: 2-[[1-(cyanomethyl)-4-methyl-pyrazol-3-yl]amino]-N-(5-methyl-1-tetrahydropyran-2-yl-indazol-4- yl)thiazole-5-carboxamide (40 mg, 0.0755 mmol, 33.8% yield) as a yellow solid. MS (ES+) m/z = 477.1 [M+H]+.1H NMR (400 MHz, DMSO-D6) δ 10.96 (s, 1H), 10.03 (s, 1H), 8.24 (s, 1H), 7.89 (d, J = 0.8 Hz, 1H), 7.59 (d, J = 1.0 Hz, 1H), 7.55 (d, J = 8.5 Hz, 1H), 7.32 (d, J = 8.6 Hz, 1H), 5.82 (dd, J = 9.7, 2.5 Hz, 1H), 5.37 (s, 2H), 3.93 – 3.85 (m, 1H), 3.74 (ddd, J = 11.5, 8.0, 5.9 Hz, 1H), 2.47 – 2.34 (m, 1H), 2.30 (s, 3H), 2.09 – 1.92 (m, 5H), 1.84 – 1.67 (m, 1H), 1.59 (m,2H). 2-[[1-(2-Amino-2-oxo-ethyl)-4-methyl-pyrazol-3-yl]amino]-N-(5-methyl-1-tetrahydropyran-2- yl-indazol-4-yl)thiazole-5-carboxamide (14 mg, 0.0130 mmol, 5.8% yield) as a brown solid. MS (ES+) m/z = 495.3 [M+H]+. Step 2a: Trifluoroacetic acid (3.0 mL, 39.2 mmol) was added to a stirred solution of 2-[[1- (cyanomethyl)-4-methyl-pyrazol-3-yl]amino]-N-(5-methyl-1-tetrahydropyran-2-yl-indazol-4- yl)thiazole-5-carboxamide (36 mg, 0.0680 mmol) in DCM (6 mL) at 23 °C for 3 h. The crude reaction mixture was diluted with DCM (10 mL), evaporated to dryness and purified by column chromatography over C18 (12 g cartridge) eluting with a gradient of MeCN (0.1% NH3) (5% to 80%; v/v) in water (0.1% NH3) to afford the white solid which after washing with aq. NaHCO3 and drying afforded 2-[[1-(cyanomethyl)-4-methyl-pyrazol-3-yl]amino]-N-(5-methyl-1H-indazol-4- yl)thiazole-5-carboxamide (4.8 mg, 0.0115 mmol, 16.91% yield) as a white solid. MS (ES+) m/z = 393.3 [M+H]+, 98% purity.1H NMR (400 MHz, DMSO-D6) δ 12.96 (s, 1H), 10.86 (s, 1H), 9.79 (s, 1H), 8.17 (s, 1H), 7.85 (d, J = 1.0 Hz, 1H), 7.52 (s, 1H), 7.34 (d, J = 8.4 Hz, 1H), 7.24 (d, J = 8.5 Hz, 1H), 5.32 (s, 2H), 2.28 (s, 3H), 2.00 (s, 3H). Step 2b: 2-[[1-(2-Amino-2-oxo-ethyl)-4-methyl-pyrazol-3-yl]amino]-N-(5-methyl-1- tetrahydropyran-2-yl-indazol-4-yl)thiazole-5-carboxamide (14 mg, 0.0130 mmol) was stirred with hydrogen chloride solution in dioxane (4M) (5.0 mL, 20.0 mmol) at 23 °C overnight. The reaction mixture was diluted with Et2O (30 mL) and stirred for 30 min; the solid product obtained was filtered, washed with Et2O (3 X 20 mL) and purified by prep-HPLC to afford 2-[[1-(2-amino-2-oxo- ethyl)-4-methyl-pyrazol-3-yl]amino]-N-(5-methyl-1H-indazol-4-yl)thiazole-5-carboxamide (1.8 mg, 0.004 mmol, 30.6% yield) as a white solid. MS (ES+) m/z = 411.4 [M+H]+.1H NMR (400 MHz, DMSO-D6) δ 12.97 (s, 1H), 10.75 (s, 1H), 9.89 (s, 1H), 8.18 (s, 1H), 7.85 (d, J = 1.0 Hz, 1H), 7.44 (s, 1H), 7.40 (s, 1H), 7.35 (d, J = 8.5 Hz, 1H), 7.25 (s,1 H), 7.24 (d, J = 8.5 Hz, 1H), 4.62 (s, 2H), 2.27 (s, 3H), 2.01 (s, 3H). 4-Methyl-N-(5-methyl-1H-indazol-4-yl)-2-((1-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-1H-pyrazol-3- yl)amino)thiazole-5-carboxamide (BAA-205)
Figure imgf000236_0001
Chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (1.85 eq, 540 mg, 1.92 mmol) was added to a stirred solution of 5-methyl-1-tetrahydropyran-2-yl-indazol-4-amine (240 mg, 1.04 mmol) , 2-chloro-4-methylthiazole-5-carboxylic acid (200 mg, 1.13 mmol) and 1- methylimidazole (0.20 mL, 2.51 mmol) in MeCN (10 mL) at room temperature. The reaction mixture was stirred for 4 h, evaporated, and the crude material was purified by column chromatography over silica (24 g cartridge) eluting with a gradient of EtOAc (10% to 100%; v/v) in isohexane to afford 2-chloro-4-methyl-N-(5-methyl-1-tetrahydropyran-2-yl-indazol-4-yl)thiazole-5- carboxamide (290 mg, 0.727 mmol, 70.07% yield) as a brown solid.MS (ES+) m/z = 391.1/393.1 [M+H]+ mono Cl pattern.1H NMR (400 MHz, CHLOROFORM-D) δ 7.91 (d, J = 1.0 Hz, 1H), 7.48 (d, J = 8.5 Hz, 1H), 7.32 (s, 1H), 7.30 – 7.26 (m, 1H), 5.71 (dd, J = 9.2, 2.8 Hz, 1H), 4.06 – 3.97 (m, 1H), 3.79 – 3.68 (m, 1H), 2.76 (s, 3H), 2.57 (d, J = 26.5 Hz, 1H), 2.38 (s, 3H), 2.15 (dd, J = 8.9, 5.0 Hz, 1H), 2.06 (d, J = 12.9 Hz, 1H), 1.83 – 1.65 (m, 3H). A mixture of 2-chloro-4-methyl-N-(5-methyl-1-tetrahydropyran-2-yl-indazol-4-yl)thiazole-5- carboxamide (100 mg, 0.256 mmol) , 2-(3-aminopyrazol-1-yl)-1-pyrrolidin-1-yl-ethanone (65 mg, 0.335 mmol) and potassium carbonate 325 mesh (90 mg, 0.651 mmol) in 1,4-dioxane (5 mL) was combined under nitrogen, before palladium(II) acetate (20 mg, 0.0891 mmol) and 4,5- bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (40 mg, 0.0691 mmol) were added. The reaction mixture was stirred at 80 °C for 18 h, cooled, diluted with DCM, filtered through a celite pad and evaporated. The crude material was purified by column chromatography over silica (24 g cartridge) eluting with a gradient of EtOAc (10% to 100%; v/v) in isohexane then of MeOH (0% to 50%; v/v) in EtOAc to afford 4-methyl-N-(5-methyl-1-tetrahydropyran-2-yl-indazol-4-yl)-2-[[1-(2-oxo- 2-pyrrolidin-1-yl-ethyl)pyrazol-3-yl]amino]thiazole-5-carboxamide (40 mg, 0.0365 mmol, 14.3% yield). MS (ES+) m/z = 549.3 [M+H]+. The product from the previous step was dissolved in DCM (2 mL), trifluoroacetic acid (358 eq, 1.0 mL, 13.1 mmol) was added and the reaction mixture was stirred for 4 hours. MeOH (2mL) was added and and the volatiles evaporated. The crude solid was purified by preparative HPLC, to afford 4-methyl-N-(5-methyl-1H-indazol-4-yl)-2-[[1-(2-oxo-2-pyrrolidin-1-yl-ethyl)pyrazol-3- yl]amino]thiazole-5-carboxamide (11 mg, 0.0230 mmol, 63% yield) as a white solid. MS (ES+) m/z = 465.2 [M+H]+.1H NMR (400 MHz, DMSO-D6) δ 12.96 (s, 1H), 10.97 (s, 1H), 9.54 (s, 1H), 7.86 (d, J = 1.5 Hz, 1H), 7.59 (d, J = 2.4 Hz, 1H), 7.34 (d, J = 8.5 Hz, 1H), 7.23 (d, J = 8.5 Hz, 1H), 5.98 (d, J = 2.4 Hz, 1H), 4.92 (s, 2H), 3.50 (t, J = 6.8 Hz, 2H), 3.30 (t, J = 6.8 Hz, 2H), 2.52 (s, 3H), 2.25 (s, 3H), 1.89 (p, J = 6.8 Hz, 2H), 1.82 – 1.70 (m, 2H). General Method C3: Synthesis of indazole with distal group NH-unsubstituted pyrazoles via palladium-catalysed coupling of Boc-protected aminopyrazoles
Figure imgf000237_0001
Step 1. A mixture of 2-bromo-N-(5-substituted-1-tetrahydropyran-2-yl-indazol-4-yl)thiazole- 5-carboxamide (1 eq), substituted amino pyrazole (1.8-3 eq) and potassium carbonate (1.5-3 eq) or potassium carbonate (4 eq) in 1,4-dioxane was flushed with nitrogen before the addition of Pd(OAc)2 (0.15 eq) and XantPhos (0.3 eq). The mixture was flushed with nitrogen for a further 5 minutes before heating to 80 °C with stirring for 2 hours. After cooling to room temperature and filtration through Celite, the reaction mixture was concentrated to give the crude product, which was purified by either normal phase chromatography (SiO2) using a gradient of MeOH:DCM. Step 2. TFA (30-50 eq) was added to a solution of THP-protected indazole (1 eq) in DCM (TFA to DCM ratio ~1:2-1:4 v:V), with stirring 1-20 hours before concentrating in vacuo. DCM was added and the mixture concentrated again and the resulting crude TFA salt was purified by reverse phase chromatography to furnish the final compound. N-(5-Methyl-1H-indazol-4-yl)-2-((4-methyl-1H-pyrazol-3-yl)amino)thiazole-5-carboxamide (BAA- 206)
Figure imgf000237_0002
Prepared as described in Method C3 from 2-bromo-N-(5-methyl-1-tetrahydropyran-2-yl- indazol-4-yl)thiazole-5-carboxamide (100 mg, 0.24 mmol, 1.0 eq), tert-butyl 3-amino-4-methyl- pyrazole-1-carboxylate (94 mg, 0.453 mmol, 1.9 eq), potassium carbonate 325 mesh (93 mg, 0.673 mmol, 2.8 eq), palladium(II) acetate (7.9 mg, 0.0352 mmol, 0.15 eq) and 4,5- bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (41 mg, 0.0705 mmol, 0.3 eq) in 1,4- dioxane (4 mL) followed by deprotection in TFA/DCM to afford the title compound (10 mg, 14% yield) as a trifluoroacetate salt. MS (ES+) m/z = 354.2 [M+H]+.1H NMR (400 MHz, DMSO-D6) δ 12.97 (s, 1H), 12.20 (s, 1H), 10.69 (s, 1H), 9.93 (s, 1H), 8.18 (s, 1H), 7.84 (t, J = 1.2 Hz, 1H), 7.49 (t, J = 1.2 Hz, 1H), 7.35 (d, J = 8.5 Hz, 1H), 7.24 (d, J = 8.5 Hz, 1H), 2.27 (s, 3H), 2.02 (d, J = 0.8 Hz, 3H).19F NMR (376 MHz, DMSO-D6) δ -73.30.. The following example compounds were prepared similarly using Method C3 using the appropriately Boc-protected aminopyrazoles:
Figure imgf000238_0001
Synthesis of carboxylic acid intermediates 2-[3-[[5-[(5-Methyl-1-tetrahydropyran-2-yl-indazol-4-yl)carbamoyl]thiazol-2-yl]amino]pyrazol-1- yl]acetic acid
Figure imgf000239_0001
2-Bromo-N-(5-methyl-1-tetrahydropyran-2-yl-indazol-4-yl)thiazole-5-carboxamide (300 mg, 0.71 mmol) and ethyl 2-(3-aminopyrazol-1-yl)acetate (361 mg, 2.14 mmol) were dissolved in Dioxane:Water (5:1, 12 mL) and the solution was bubbled with nitrogen for 5 minutes. Pd2dba3 (98 mg, 15mol%), XantPhos (124 mg, 30mol%), and cesium carbonate (700 mg, 2.14 mmol) were then added with stirring and the mixture was bubbled with nitrogen for a further 5 minutes before heating to 95 °C with stirring for 18 hours. After cooling to room temperature the reaction mixture was separated between ethyl acetate and 0.5 M aqueous sodium hydroxide. The aqueous phase was acidified to pH 4 using 2 M aqueous HCl then extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give the title compound (296 mg, 86% yield) as a yellow solid that did not need further purification. MS (ES+) m/z 482.3 (M+H)+. 1H NMR (DMSO-d6, 300 MHz) δ 12.99 (br s, 1H), 11.12 (br s, 1H), 10.00 (s, 1H), 8.19 (s, 1H), 7.88 (s, 1H), 7.67 (d, 1H, J= 2.4 Hz), 7.55 (d, 1H, J= 8.6 Hz), 7.32 (d, 1H, J = 8.7 Hz), 6.02 (d, 1H, J = 2.4 Hz), 5.82 (dd, 1H, J= 9.7, 2.3 Hz), 4.89 (s, 2H), 3.91-3.87 (m, 1H), 3.78-3.70 (m, 1H), 2.47-2.34 (m, 1H), 2.29 (s, 3H), 2.06-1.93 (m, 2H), 1.83- 1.69 (m, 1H), 1.62-1.56 (m, 2H). 2-[3-[[5-[(5-Methyl-1H-indazol-4-yl)carbamoyl]thiazol-2-yl]amino]pyrazol-1-yl]acetic acid (BAA-211)
Figure imgf000239_0002
TFA (0.16 mL, 2.077 mmol) was added to a solution of 2-[3-[[5-[(5-methyl-1- tetrahydropyran-2-yl-indazol-4-yl)carbamoyl]thiazol-2-yl]amino]pyrazol-1-yl]acetic acid (20 mg, 0.042 mmol) in DCM (0.32 mL), with stirring under nitrogen for 3 hours before concentrating in vacuo. DCM was added and the mixture concentrated again and the resulting precipitate was washed with diethyl ether to give the title compound (19 mg, 89% yield; trifluoroacetate salt) as a beige solid. MS (ES+) m/z 398.0 (M+H)+.1H NMR (DMSO-d6, 300 MHz) δ 12.88-11.13 (br, 3H), 9.99 (s, 1H), 8.19 (s, 1H), 7.85 (d, 1H, J = 0.9 Hz), 7.67 (d, 1H, J = 2.4 Hz), 7.36 (d, 1H, J = 8.6 Hz), 7.25 (d, 1H, J = 8.6 Hz), 6.03 (d, 1H, J = 2.4 Hz), 4.89 (s, 2H), 2.28 (s, 3H).19F NMR (DMSO- d6, 282 MHz) δ -74.76 2-[5-Methyl-3-[[5-[(5-methyl-1-tetrahydropyran-2-yl-indazol-4-yl)carbamoyl]thiazol-2- yl]amino]pyrazol-1-yl]acetic acid
Figure imgf000240_0001
2-Bromo-N-(5-methyl-1-tetrahydropyran-2-yl-indazol-4-yl)thiazole-5-carboxamide (200 mg, 0.47 mmol) and ethyl 2-(3-amino-5-methyl-pyrazol-1-yl)acetate (261 mg, 1.42 mmol) were dissolved in Dioxane:Water (5:1, 9 mL) and the solution was bubbled with nitrogen for 5 minutes. Pd2dba3 (65 mg, 15mol%), XantPhos (82 mg, 30mol%), and cesium carbonate (467 mg, 1.42 mmol) were then added with stirring and the mixture was bubbled with nitrogen for a further 5 minutes before heating to 95 °C with stirring for 18 hours. After cooling to room temperature the reaction mixture was separated between ethyl acetate and 0.5 M aqueous sodium hydroxide. The aqueous phase was acidified to pH 4 using 2 M aqueous HCl then extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give the title compound (208 mg, 88% yield) as a yellow solid that did not need further purification. MS (ES+) m/z 496.1 (M+H)+.1H NMR (DMSO-d6, 300 MHz) δ 12.34 (br s, 1H), 11.21 (br s, 1H), 9.99 (s, 1H), 8.18 (s, 1H), 7.88 (s, 1H), 7.54 (d, 1H, J= 8.6 Hz), 7.32 (d, 1H, J= 8.7 Hz), 5.86 (s, 1H), 5.81 (dd, 1H, J= 9.7, 2.2 Hz), 4.82 (s, 2H), 3.91-3.87 (m, 1H), 3.78- 3.70 (m, 1H), 2.46-2.35 (m, 1H), 2.29 (s, 3H), 2.20 (s, 3H), 2.06-1.93 (m, 2H), 1.78-1.72 (m, 1H), 1.62-1.55 (m, 2H). 2-(4-Methyl-3-((5-((5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)carbamoyl)thiazol-2- yl)amino)-1H-pyrazol-1-yl)acetic acid
Figure imgf000240_0002
2-Bromo-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)thiazole-5-carbox-amide (150 mg, 0.36 mmol) and ethyl 2-(3-amino-4-methyl-1H-pyrazol-1-yl)acetate (200 mg, 1.07 mmol) were dissolved in 1,4-dioxane:water (5:1, 6 mL) and the solution was bubbled with nitrogen for 5 minutes. Pd2dba3 (49 mg, 15mol%), XantPhos (62 mg, 30mol%), and cesium carbonate (350 mg, 1.07 mmol) were then added with stirring and the mixture was bubbled with nitrogen for a further 5 minutes before heating to 95 °C with stirring for 18 hours. After cooling to room temperature the reaction mixture was separated between ethyl acetate and 0.5 M aqueous sodium hydroxide. The aqueous phase was acidified to pH ~2 using 2 M aqueous HCl then extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give the title compound (144 mg, 82% yield) as a yellow solid that did not need further purification. MS (ES+) 496.1 (M+H)+; 1H NMR (DMSO-d6, 300 MHz) δ 12.45-11.11 (br, 2H), 9.98 (s, 1H), 8.21 (s, 1H), 7.88 (s, 1H), 7.54 (d, 1H, J = 8.5 Hz), 7.48 (d, 1H, J = 0.8 Hz), 7.32 (d, 1H, J = 8.7 Hz), 5.81 (dd, 1H, J = 9.7, 2.2 Hz), 4.83 (s, 2H), 3.91-3.87 (m, 1H), 3.78-3.70 (m, 1H), 2.47-2.34 (m, 1H), 2.29 (s, 3H), 2.02 (s, 3H), 2.07-1.93 (m, 2H), 1.82-1.69 (m, 1H), 1.62- 1.55 (m, 2H) ppm 2-(4-Methyl-3-((5-((5-methyl-1H-indazol-4-yl)carbamoyl)thiazol-2-yl)amino)-1H-pyrazol-1-yl)acetic acid (BAA-212)
Figure imgf000241_0001
A mixture of 2-bromo-N-(5-methyl-1-tetrahydropyran-2-yl-indazol-4-yl)thiazole-5- carboxamide (1.50 g, 3.52 mmol) , tert-butyl 2-(3-amino-4-methyl-pyrazol-1-yl)acetate (2.00 g, 8.14 mmol) in 1,4-dioxane (45 mL) was bubbled with N2 flow for 10 min before 4,5- bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (612 mg, 1.06 mmol) and palladium(II) acetate (119 mg, 0.529 mmol) were added. The reaction mixture was stirred at 70 °C for 2.5 h under nitrogen atmosphere, cooled to rt, diluted with DCM and filtered through Celite. The crude material was purified by column chromatography over silica (120 g cartridge) eluting with a gradient of MeOH (0% to 5%; v/v) in DCM (25 CV) to afford the desired product tert-butyl 2-[4- methyl-3-[[5-[(5-methyl-1-tetrahydropyran-2-yl-indazol-4-yl)carbamoyl]thiazol-2-yl]amino]pyrazol-1- yl]acetate (1.52 g, 2.62 mmol, 74.26% yield) as a brown solid. MS (ES+) m/z =552.2 [M+H]+.1H NMR (400 MHz, DMSO-D6) δ 10.78 (s, 1H), 9.99 (s, 1H), 8.21 (s, 1H), 7.88 (d, J = 0.8 Hz, 1H), 7.54 (d, J = 8.5 Hz, 1H), 7.48 (d, J = 1.0 Hz, 1H), 7.32 (d, J = 8.7 Hz, 1H), 5.82 (dd, J = 9.7, 2.6 Hz, 1H), 4.81 (s, 2H), 3.89 (d, J = 11.6 Hz, 1H), 3.79 – 3.69 (m, 1H), 2.44 – 2.27 (m, 1H), 2.29 (s, 3H), 2.10 – 2.04 (m, 1H), 2.01 (d, J = 0.8 Hz, 3H), 1.99 – 1.90 (m, 1H), 1.81 – 1.68 (m, 1H), 1.58 (q, J = 6.1 Hz, 2H), 1.42 (s, 9H). Trifluoroacetic acid (5.0 mL, 65.3 mmol) was added to a stirred solution of the product from previous step (1.52 g, 2.62 mmol) in DCM (20 mL) at 23 °C. The reaction mixture was stirred at 23 °C for 18 h and concentrated to dryness. The brown solid residue was triturated with DCM/i- hexane mixture. The solid precipitate was filtered, washed with DCM, i-hexane and dried at 45 °C/100 mbar to afford 2-[4-methyl-3-[[5-[(5-methyl-1H-indazol-4-yl)carbamoyl]thiazol-2- yl]amino]pyrazol-1-yl]acetic acid (1.70 g, 2.50 mmol, 95.5% yield; TFA salt) as a beige solid.MS (ES+) m/z = 412.2 [M+H]+, 1H NMR (400 MHz, DMSO-D6) δ 12.97 (s, 1H), 10.80 (s, 1H), 9.97 (s, 1H), 8.20 (s, 1H), 7.85 (d, J = 1.0 Hz, 1H), 7.48 (d, J = 1.1 Hz, 1H), 7.36 (d, J = 8.8 Hz, 1H), 7.25 (d, J = 8.5 Hz, 1H), 4.83 (s, 2H), 2.27 (s, 3H), 2.02 (s, 3H). 2-(4-Methyl-3-((5-((5-methyl-1H-indazol-4-yl)carbamoyl)thiazol-2-yl)amino)-1H-pyrazol-1- yl)propanoic acid (BAA-213)
Figure imgf000242_0001
A mixture of 2-bromo-N-(5-methyl-1-tetrahydropyran-2-yl-indazol-4-yl)thiazole-5- carboxamide (600 mg, 1.41 mmol) , tert-butyl 2-(3-amino-4-methyl-pyrazol-1-yl)propanoate (850 mg, 3.24 mmol) in1,4-Dioxane (15 mL) was bubbled with N2 flow for 10 min before palladium(II) acetate (47 mg, 0.211 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (245 mg, 0.423 mmol) were added. The rection mixture was stirred at 65 °C for 16 h under nitrogen, cooled to rt, diluted with DCM and filtered through Celite. The crude material was purified by column chromatography over silica (80 g cartridge) eluting with a gradient of MeOH (0% to 5%; v/v) in DCM (25 CV) to afford tert-butyl 2-[4-methyl-3-[[5-[(5-methyl-1-tetrahydropyran-2-yl-indazol- 4-yl)carbamoyl]thiazol-2-yl]amino]pyrazol-1-yl]propanoate (457 mg, 0.711 mmol, 50.42% yield) as a brown solid. MS (ES+) m/z = 566.2 [M+H]+.1H NMR (400 MHz, DMSO-D6) δ 10.80 (s, 1H), 9.98 (s, 1H), 8.21 (s, 1H), 7.88 (d, J = 0.8 Hz, 1H), 7.56 (s, 1H), 7.54 (d, J = 8.8 Hz, 1H), 7.32 (d, J = 8.6 Hz, 1H), 5.82 (dd, J = 9.8, 2.6 Hz, 1H), 4.93 (q, J = 7.2 Hz, 1H), 3.89 (d, J = 11.5 Hz, 1H), 3.74 (dt, J = 11.6, 6.6 Hz, 1H), 2.44 – 2.36 (m, 1H), 2.29 (s, 3H), 2.09 – 2.03 (m, 1H), 2.02 (s, 3H), 1.99 – 1.92 (m, 1H), 1.78 – 1.73 (m, 1H), 1.62 (d, J = 7.2 Hz, 3H), 1.60 – 1.53 (m, 1H), 1.37 (s, 9H). To a stirred solution of product from the previous step (457 mg, 0.711 mmol) in 1,4-dioxane (4 mL) was added hydrogen chloride solution in dioxane (4M) (6.0 mL, 24.0 mmol). The reaction mixture was stirred at 23 °C for 16 h. The reaction mixture (yellow suspension) was diluted with TBME and the precipitate was filtered, washed with TBME and dried to afford 2-[4-methyl-3-[[5-[(5-methyl-1H- indazol-4-yl)carbamoyl]thiazol-2-yl]amino]pyrazol-1-yl]propanoic acid;dihydrochloride (415 mg, 0.766 mmol, 107.76% yield) as a yellow solid. MS (ES+) m/z =462.2 [M+H]+.1H NMR (400 MHz, DMSO-D6) δ 10.17 (s, 1H), 8.33 (s, 1H), 7.86 (d, J = 0.9 Hz, 1H), 7.63 – 7.58 (m, 2H), 7.37 (d, J = 8.6 Hz, 1H), 7.25 (d, J = 8.6 Hz, 1H), 5.02 (q, J = 7.2 Hz, 1H), 2.28 (s, 3H), 2.04 (s, 2H), 1.65 (d, J = 7.3 Hz, 3H). 2-(3-((5-((5-Chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)carbamoyl)thiazol-2-yl)amino)-1H- pyrazol-1-yl)acetic acid
Figure imgf000243_0001
2-Bromo-N-(5-chloro-1-tetrahydropyran-2-yl-indazol-4-yl)thiazole-5-carboxamide (876 mg, 1.98 mmol) , ethyl 2-(3-aminopyrazol-1-yl)acetate (781 mg, 4.62 mmol), 4,5- bis(diphenylphospheno)-9,9-dimethylxanthene (229 mg, 0.396 mmol) and cesium carbonate (1939 mg, 5.91 mmol) in 1,4-dioxane (20 mL) and water (5 mL) was degassed under nitrogen. Tris(dibenzylideneacetone)dipalladium(0) (182 mg, 0.199 mmol) was added and the reaction degassed again, then heated to 90 °C for 18 h. The reaction was partitioned between EtOAc and water. The aqueous phase was acidified to pH 4 with 2M aqueous HCl then extracted with ethyl acetate. The combined organic extracts were washed with brine, then concentrated in vacuo. Reverse phase column chromatography (water:acetonitrile) gave impure 2-[3-[[5-[(5-chloro-1- tetrahydropyran-2-yl-indazol-4-yl)carbamoyl]thiazol-2-yl]amino] pyrazol-1-yl]acetic acid (302 mg, 30%) which was used directly in the next step. MS (ES+) m/z 502, 504 (M+H)+. 2-(3-((5-((5-Bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)carbamoyl)thiazol-2-yl)amino)-1H- pyrazol-1-yl)acetic acid
Figure imgf000243_0002
2-Bromo-N-(5-bromo-1-tetrahydropyran-2-yl-indazol-4-yl)thiazole-5-carboxamide (1.00 eq, 770 mg, 1.43 mmol) was dissolved in anhydrous 1,4-dioxane (15 mL) at r.t., to which ethyl 2-(3- aminopyrazol-1-yl)acetate (2.77 eq, 0.67 g, 3.94 mmol), 4,5-bis(diphenylphosphino)-9,9- dimethylxanthene (Xantphos) (0.200 eq, 165 mg, 0.285 mmol) and potassium carbonate 325 mesh (3.00 eq, 591 mg, 4.28 mmol) were added. The mixture was degassed with N2 for 10 min before the addition of palladium(II) acetate (0.100 eq, 32 mg, 0.143 mmol) after which degassing was continued for another 5 min. The reaction mixture was heated to 70 °C for 18 h. The reaction mixture was cooled to r.t., filtered through a Celite pad, and the filter cake was washed with EtOAc (3 × 20 mL). The filtrates were concentrated under reduced pressure and DCM (25 mL) was added. The resultant precipitate was filtered off and dried to afford ethyl 2-[3-[[5-[(5-bromo-1- tetrahydropyran-2-yl-indazol-4-yl)carbamoyl]thiazol-2-yl]amino]pyrazol-1-yl]acetate (570 mg, 0.903 mmol, 63.35% yield) as a pale-pink solid without further purification. This solid was dissolved in a mixture of 1,4-dioxane (10 mL) and H2O (1.0 mL), and caesium carbonate (1.26 eq, 300 mg, 0.921 mmol) was added. The resulting mixture was heated to 100 °C and left to stir for 18 h. The reaction mixture was concentrated under reduced pressure and dried in a vaccuum oven at 40 °C to afford caesium 2-[3-[[5-[(5-bromo-1-tetrahydropyran-2-yl-indazol-4-yl)carbamoyl]thiazol-2- yl]amino]pyrazol-1-yl]acetate (778 mg, 0.746 mmol, 101.97% yield) as a brown solid without further purification. MS (ES+) m/z = 546.0/548.0, [M+H]+, mono-Br splitting pattern.1H NMR (400 MHz, DMSO-d6) δ 10.98 (br s, 1H), 10.13 (br s, 1H), 8.17 (br s, 1H), 7.95 (s, 1H), 7.63 (br s, 2H), 7.50 (d, J = 2.3 Hz, 1H), 5.91 (d, J = 2.2 Hz, 1H), 5.86 (br d, J = 9.6 Hz, 2H), 4.26 (s, 2H), 3.93 – 3.86 (m, 2H), 3.79 – 3.70 (m, 1H), 2.44 – 2.30 (m, 1H), 2.07 – 1.93 (m, 2H), 1.82 – 1.68 (m, 1H), 1.64 – 1.51 (m, 2H). 2-(3-((5-((5-Bromo-1H-indazol-4-yl)carbamoyl)thiazol-2-yl)amino)-4-methyl-1H-pyrazol-1-yl)acetic acid (BAA-
Figure imgf000244_0001
2-B 0. O214) rom 648 No m N-N-(5 m Borl O N-brom So N-1 HN-tetr Nah Nydropy Oran-2-yl-indazol H-4N-y Nl)thia O NzHole- S5- Nca HNrbox Na Nmid Oe (1 O.H00 eq, 350 mg, )H was dissolved in a Onhydrous 1,4-dioxane (4. B0r mL) at r.t., to which tert-butyl 2- (3-amino-4-methyl-pyrazol-1-yl)acetate (2.5 eq, 342 mg, 1.62 mmol) , 4,5-bis(diphenyl phosphino)- 9,9-dimethylxanthene (Xantphos) (0.2 eq, 75 mg, 0.130 mmol) and potassium carbonate 325 mesh (3 eq, 269 mg, 1.94 mmol) were added. The mixture was degassed with N2 for 10 min before the addition of palladium(II) acetate (0.1 eq, 15 mg, 0.0648 mmol), after which degassing was continued for another 5 min. The reaction mixture was heated to 70 °C for 18 h, then it was cooled to r.t., filtered through a Celite pad, and the filter cake was washed with EtOAc (3 × 5 mL). The filtrates were concentrated under reduced pressure and the crude material was purified by column chromatography over silica (40 g cartridge) eluting with a gradient of EtOAc (0% to 100%; v/v) in iso-Hexane [Note 3] to afford the desired product tert-butyl 2-[3-[[5-[(5-bromo-1-tetrahydropyran-2- yl-indazol-4-yl)carbamoyl]thiazol-2-yl]amino]-4-methyl-pyrazol-1-yl]acetate (291 mg, 0.448 mmol,69.21% yield) as an orange solid. MS (ES+) m/z = 616.1/618.0, [M+H]+.1H NMR (400 MHz, CDCl3) δ 8.49 (br s, 1H), 8.15 (d, J = 0.9 Hz, 1H), 8.03 – 7.94 (m, 2H), 7.51 (dd, J = 8.8, 0.7 Hz, 1H), 7.34 (dt, J = 8.9, 0.8 Hz, 1H), 7.28 – 7.16 (m, 2H), 5.70 (dd, J = 9.1, 2.8 Hz, 1H), 4.72 (s, 2H), 4.05 – 3.96 (m, 1H), 3.73 (ddd, J = 11.4, 9.7, 3.2 Hz, 1H), 2.59 – 2.45 (m, 1H), 2.20 – 2.11 (m, 1H), 2.11 – 2.07 (m, 1H), 2.06 (d, J = 0.8 Hz, 3H), 1.81 – 1.68 (m, 3H), 1.49 (s, 9H). The product from previous step (1.00 eq, 290 mg, 0.470 mmol) was dissolved in DCM (5.0 mL) at r.t., to which trifluoroacetic acid (5.00 eq, 180 uL, 2.35 mmol) was added. The reaction mixture was stirred at r.t. for 96 h. A precipitate formed that was collected via suction filtration and washed with DCM (3 × 10 mL) and concentrated under reduced presssure to afford 2-[3-[[5-[(5-bromo-1H- indazol-1-ium-4-yl)carbamoyl]thiazol-2-yl]amino]-4-methyl-pyrazol-1-yl]acetic acid;2,2,2- trifluoroacetate (147 mg, 0.249 mmol, 52.9% yield) as an off-white solid. MS (ES+) m/z = 476.1/478.1, [M+H]+, mono-Br splitting pattern.1H NMR (400 MHz, DMSO-d6) δ 13.05 (br s, 1H), 10.80 (br s, 1H), 10.08 (s, 1H), 8.20 (s, 1H), 7.88 (d, J = 1.0 Hz, 1H), 7.54 (d, J = 8.8 Hz, 1H), 7.47 – 7.43 (m, 1H), 7.43 – 7.37 (m, 1H), 5.29 (br s, 2H), 4.79 (s, 2H), 1.98 (s, 3H).19F NMR (376 MHz, DMSO-d6) δ -74.81. 2-(6-((5-((5-Methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)carbamoyl)thiazol-2- yl)amino)pyridin-2-yl)acetic acid
Figure imgf000245_0001
2-Bromo-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)thiazole-5-carbox-amide (500 mg, 1.19 mmol) and ethyl 2-(6-aminopyridin-2-yl)acetate (257 mg, 1.42 mmol) were dissolved in 1,4-dioxane:water (5:1, 12 mL) and the solution was bubbled with nitrogen for 5 minutes. Pd2dba3 (163 mg, 15mol%), XantPhos (206 mg, 30mol%), cesium carbonate (778 mg, 2.37 mmol) and lithium hydroxide monohydrate (51 mg, 1.19 mmol) were then added with stirring and the mixture was bubbled with nitrogen for a further 5 minutes before heating to 90 °C with stirring overnight. After cooling to room temperature the reaction mixture was separated between ethyl acetate and 0.5 M aqueous sodium hydroxide. The aqueous phase was acidified to pH 4 using 2 M aqueous HCl then extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give the product (567 mg, 97% yield) as a yellow solid, which did not require further purification. MS (ES+) 493.3 (M+H)+; 1H NMR (DMSO-d6, 300 MHz) δ 11.77 (br, 1H), 10.21 (s, 1H), 8.43 (s, 1H), 7.90 (s, 1H), 7.72 (dd, 1H, J = 8.3, 7.3 Hz), 7.55 (d, 1H, J = 7.9 Hz), 7.32 (d, 1H, J = 8.8 Hz), 7.05 (d, 1H, J = 7.5 Hz), 6.96 (d, 1H, J = 7.0 Hz), 5.82 (dd, 1H, J = 9.7, 2.5 Hz), 3.91-3.84 (m, 1H), 3.74-3.70 (m, 1H), 3.56 (s, 2H), 2.42-2.35 (m, 1H), 2.31 (s, 3H), 2.05-1.93 (m, 2H), 1.83-1.71 (m, 1H), 1.62-1.55 (m, 2H) ppm. 3-((5-((5-Methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)carbamoyl)thiazol-2-yl)amino)benzoic acid
Figure imgf000246_0001
2-Bromo-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)thiazole-5-carbox-amide (80 mg, 0.19 mmol) and 3-aminobenzoic acid (78 mg, 0.57 mmol) were dissolved in 1,4- dioxane:water (5:1, 3.0 mL) and the solution was bubbled with nitrogen for 5 minutes. Pd2dba3 (26 mg, 15mol%), XantPhos (33 mg, 30mol%), and cesium carbonate (125 mg, 0.38 mmol) were then added with stirring and the mixture was bubbled with nitrogen for a further 5 minutes before heating to 90 °C with stirring overnight. After cooling to room temperature, the reaction mixture was separated between ethyl acetate and 1 M aqueous sodium hydroxide. The aqueous phase was acidified to pH 4 using 2 M aqueous HCl then extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give the title compound (90 mg, 99% yield) as a yellow solid that did not need further purification. MS (ES+) 478.3 (M+H)+; 1H NMR (DMSO-d6, 300 MHz) δ 10.88 (br, 1H), 10.18 (s, 1H), 8.32-8.31 (m, 1H), 8.24 (s, 1H), 7.91-7.87 (m, 2H), 7.60-7.55 (m, 2H), 7.47 (t, 1H, J = 7.9 Hz), 7.33 (d, 1H, J = 8.8 Hz), 5.82 (dd, 1H, J = 9.7, 2.4 Hz), 3.91-3.87 (m, 1H), 3.78-3.70 (m, 1H), 2.46-2.34 (m, 1H), 2.30 (s, 3H), 2.06-1.93 (m, 2H), 1.78-1.69 (m, 1H), 1.61-1.55 (m, 2H) ppm. 6-((5-((5-Methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)carbamoyl)thiazol-2- yl)amino)nicotinic acid
Figure imgf000246_0002
2-Bromo-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)thiazole-5-carbox-amide (65 mg, 0.15 mmol) and 6-aminonicotinic acid (64 mg, 0.46 mmol) were dissolved in 1,4- dioxane:water (5:1, 3.6 mL) and the solution was bubbled with nitrogen for 5 minutes. Pd2dba3 (21 mg, 15mol%), XantPhos (27 mg, 30mol%), and cesium carbonate (126 mg, 0.39 mmol) were then added with stirring and the mixture was bubbled with nitrogen for a further 5 minutes before heating to 90 °C with stirring overnight. After cooling to room temperature, the reaction mixture was separated between ethyl acetate and 1 M aqueous sodium hydroxide. The aqueous phase was acidified to pH 4 using 2 M aqueous HCl then extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give the title compound (73 mg, 99% yield) as a yellow solid that did not need further purification. MS (ES+) 479.3 (M+H)+; 1H NMR (DMSO-d6, 300 MHz) δ 12.18 (br, 2H), 10.16 (s, 1H), 8.89 (dd, 1H, J = 2.3, 0.8 Hz), 8.38 (s, 1H), 8.20 (dd, 1H, J = 8.8, 2.3 Hz), 7.90 (s, 1H), 7.56 (d, 1H, J = 9.0 Hz), 7.33 (d, 1H, J = 8.9 Hz), 7.19 (d, 1H, J = 8.8 Hz), 5.82 (dd, 1H, J = 9.8, 2.4 Hz), 3.92-3.88 (m, 1H), 3.79-3.70 (m, 1H), 2.46-2.34 (m, 1H), 2.31 (s, 3H), 2.06-1.94 (m, 2H), 1.83- 1.69 (m, 1H), 1.62-1.52 (m, 2H) ppm. 6-((5-((5-Methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)carbamoyl)thiazol-2- yl)amino)picolinic acid
Figure imgf000247_0001
2-Bromo-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)thiazole-5-carbox-amide (250 mg, 0.59 mmol) and 6-amino-pyridine-2-carboxylic acid (164 mg, 1.19 mmol) were dissolved in 1,4-dioxane:water (5:1, 12 mL) and the solution was bubbled with nitrogen for 5 minutes. Pd2dba3 (82 mg, 15mol%), XantPhos (103 mg, 30mol%), and cesium carbonate (389 mg, 1.19 mmol) were then added with stirring and the mixture was bubbled with nitrogen for a further 5 minutes before heating to 90 °C with stirring overnight. After cooling to room temperature the reaction mixture was separated between ethyl acetate and 0.5 M aqueous sodium hydroxide. The aqueous phase was acidified to pH 4 using 2 M aqueous HCl then extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated to give the product (237 mg, 83% yield) as an off-white solid, which was used without further purification. MS (ES+) 479.6 (M+H)+; 1H NMR (DMSO-d6, 300 MHz) δ 12.82 (br, 1H), 10.63 (br s, 1H), 8.25 (br s, 1H), 8.01 (t, 1H, J = 7.7 Hz), 7.91 (s, 1H), 7.74 (d, 1H, J = 7.5 Hz), 7.59 (d, 1H, J = 8.5 Hz), 7.35 (d, 2H, J = 8.8 Hz), 5.83 (dd, 1H, J = 9.7, 2.4 Hz), 3.91-3.87 (m, 1H), 3.79- 3.70 (m, 1H), 2.45-2.35 (m, 1H), 2.31 (s, 3H), 2.06-1.93 (m, 2H), 1.79-1.72 (m, 1H), 1.62-1.54 (m, 2H) ppm. 2-((5-((5-Methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)carbamoyl)thiazol-2- yl)amino)isonicotinic acid
Figure imgf000248_0001
2-Bromo-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)thiazole-5-carbox-amide (200 mg, 0.47 mmol) and 2-aminoisonicotinic acid (164 mg, 1.19 mmol) were dissolved in 1,4- dioxane:water (5:1, 12 mL) and the solution was bubbled with nitrogen for 5 minutes. Pd2dba3 (65 mg, 15mol%), XantPhos (82 mg, 30mol%), and cesium carbonate (467 mg, 1.42 mmol) were then added with stirring and the mixture was bubbled with nitrogen for a further 5 minutes before heating to 90 °C with stirring overnight. After cooling to room temperature the reaction mixture was separated between ethyl acetate and 0.5 M aqueous sodium hydroxide. The aqueous phase was acidified to pH 4 using 2 M aqueous HCl then extracted with ethyl acetate. The combined organic extracts were 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 0-50% methanol/dichloromethane, to give the title compound (155 mg, 68% yield) as an off-white solid. MS (ES+) 479.7 (M+H)+; 1H NMR (DMSO-d6, 300 MHz) δ 11.92 (s, 1H), 10.21 (s, 1H), 8.50 (d, 1H, J = 5.2 Hz), 8.42 (s, 1H), 7.91 (s, 1H), 7.65 (s, 1H), 7.57 (d, 1H, J = 8.6 Hz), 7.40 (dd, 1H, J = 5.2, 1.5 Hz), 7.34 (d, 1H, J = 8.6 Hz), 5.84 (dd, 1H, J = 9.7, 2.5 Hz), 3.93- 3.89 (m, 1H), 3.80-3.72 (m, 1H), 2.48-2.36 (m, 1H), 2.32 (s, 3H), 2.08-1.95 (m, 2H), 1.80-1.71 (m, 1H), 1.63-1.57 (m, 2H) ppm. Coupling of THP-protected indazoles-pyrazole acetic acid with amines to generate amides and subsequent deprotection
Figure imgf000248_0002
General Method D: Amide formation between 2-[(Substituted)-3-[[5-[(5-substituted-1- tetrahydropyran-2-yl-indazol-4-yl)carbamoyl]thiazol-2-yl]amino]pyrazol-1-yl]acetic acid and amines Step 1. (Amide formation) HATU (1.2 eq) was added to a solution of 2-[(substituted)-3-[[5- [(5-substituted-1-tetrahydropyran-2-yl-indazol-4-yl)carbamoyl]thiazol-2-yl]amino]pyrazol-1-yl]acetic acid (1 eq), amine (1.2 eq) and DIPEA (2-4 eq) in anhydrous DMF with stirring at room temperature for 12-18 hrs. The reaction mixture was separated between ethyl acetate and water, and the organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give the crude product, which was purified using flash column chromatography over silica, eluting with a methanol/dichloromethane gradient to give the THP-protected amide intermediate. Step 2. (THP deprotection) TFA (50 eq) was added to a solution of THP-protected indazole (1 eq) in DCM (TFA to DCM ratio ~1:2-1:4 v:V), with stirring under nitrogen for 3 hrs hours before concentrating in vacuo. DCM was added and the mixture concentrated again and the resulting precipitate was washed with diethyl ether to provide the final product as a TFA salt. Alternatively, hydrogen chloride (2M in diethyl ether or 4M in dioxane) was added to a solution of THP-protected indazole in diethyl ether (2-5 mL) and the reaction stirred for 6 h at rt then concentrated in vacuo. Trituration with diethyl ether, followed by neutralisation with triethylamine (5 eq) and reverse phase chromatography (water:acetonitrile) or preparative HPLC (water:acetonitrile) gave the final product as the free base. N-(5-Methyl-1-tetrahydropyran-2-yl-indazol-4-yl)-2-[[1-(2-morpholino-2-oxo-ethyl)pyrazol-3- yl]amino]thiazole-5-carboxamide (BAA-215)
Figure imgf000249_0001
Prepared as described in Method D, from 2-[3-[[5-[(5-methyl-1-tetrahydropyran-2-yl- indazol-4-yl)carbamoyl]thiazol-2-yl]amino]pyrazol-1-yl]acetic acid (35 mg, 0.073 mmol), HATU (33 mg, 0.087 mmol), morpholine (8 uL, 0.087 mmol) and DIPEA (38 uL, 0.218 mmol) in anhydrous DMF (1 mL) to afford the THP-protected intermediate (30 mg, 75% yield) after normal phase chromatography (SiO2) eluting with 0 – 20% gradient of MeOH:DCM (Step 1), followed by deprotection with in TFA (0.18 mL)/DCM (0.5 mL) to afford the title compound (23 mg, 84% yield; trifluoroacetate salt) as an off-white solid. MS (ES+) m/z 467.1 (M+H)+.1H NMR (DMSO-d6, 300 MHz) δ 12.92 (br s, 1H), 11.10 (br s, 1H), 9.99 (s, 1H), 8.20 (s, 1H), 7.85 (d, 1H, J = 0.9 Hz), 7.60 (d, 1H, J = 2.4 Hz), 7.36 (d, 1H, J = 8.4 Hz), 7.25 (d, 1H, J = 8.6 Hz), 6.00 (d, 1H, J = 2.4 Hz), 5.08 (s, 2H), 3.62-3.44 (m, 8H), 2.28 (s, 3H).19F NMR (DMSO-d6, 282 MHz) δ -74.89. The following example compounds were prepared similarly using Method D using appropriately substituted amine:
Figure imgf000250_0001
Figure imgf000251_0001
Figure imgf000252_0001
Figure imgf000253_0001
Figure imgf000254_0001
Figure imgf000255_0001
The following additional compounds were synthesised using the same Method D:
Figure imgf000255_0002
Figure imgf000256_0001
Figure imgf000257_0001
Figure imgf000258_0001
Figure imgf000259_0001
Nr O SN N N
Figure imgf000260_0001
General method D2: Coupling of THP-protected aromatic carboxylic acid with amines to generate amides and subsequent deprotection
Figure imgf000261_0001
HATU (1.2 equiv.) was added to a solution of aromatic carboxylic acid (1 equiv.), amine (1.2 equiv.) and DIPEA (4 equiv.) in anhydrous DMF (0.12 M), with stirring at room temperature overnight. The reaction mixture was separated between ethyl acetate and water, and the organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give the crude product, which was purified using flash column chromatography over silica. TFA (50 equiv.) was added to a solution of the THP protected compound (1 equiv.) in DCM (~0.07 M) with stirring under nitrogen for 3 hours before concentrating in vacuo. Methanol was added and the mixture concentrated again and the resulting precipitate was washed with diethyl ether to give the final compound. N-(5-Methyl-1H-indazol-4-yl)-2-((3-(pyrrolidine-1-carbonyl)phenyl)amino)thiazole-5- carboxamide.TFA salt (BAA-253)
Figure imgf000261_0002
HATU (48 mg, 0.13 mmol) was added to a solution of 3-((5-((5-methyl-1-(tetrahydro-2H- pyran-2-yl)-1H-indazol-4-yl)carbamoyl)thiazol-2-yl)amino)benzoic acid (50 mg, 0.10 mmol), pyrrolidine (11 uL, 0.13 mmol and DIPEA (55 uL, 0.31 mmol) in anhydrous DMF (1.5 mL), with stirring at room temperature overnight. The reaction mixture was separated between ethyl acetate and water, and the organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give the crude product, which was purified using flash column chromatography over silica, eluting with 0-25% methanol/dichloromethane to give N-(5-methyl-1- (tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-2-((3-(pyrrolidine-1-carbonyl)phenyl)amino)thiazole-5- carboxamide (30 mg, 54% yield) as an off-white solid. MS (ES+) 531.3 (M+H)+; 1H NMR (MeOD-d4, 300 MHz) δ 8.10 (s, 1H), 7.93-7.90 (m, 2H), 7.64 (ddd, 1H, J = 8.2, 2.4, 1.0 Hz), 7.54 (d, 1H, J = 8.6 Hz), 7.42 (t, 1H, J = 8.1 Hz), 7.35 (d, 1H, J = 9.1 Hz), 7.20-7.17 (m, 1H), 5.78 (dd, 1H, J = 9.8, 2.6 Hz), 4.03-3.96 (m, 1H), 3.84-3.76 (m, 1H), 3.61 (t, 2H, J = 6.9 Hz), 3.50 (t, 2H, J = 6.5 Hz), 2.55-2.42 (m, 1H), 2.37 (s, 3H), 2.15-2.08 (m, 1H), 2.05-1.63 (m, 8H) ppm. TFA (0.22 mL, 2.83 mmol) was added to a solution of N-(5-methyl-1-(tetrahydro-2H-pyran- 2-yl)-1H-indazol-4-yl)-2-((3-(pyrrolidine-1-carbonyl)phenyl)amino)thiazole-5-carboxamide (30 mg, 0.057 mmol) in DCM (0.7 mL), with stirring under nitrogen for 3 hours before concentrating in vacuo. Methanol was added and the mixture concentrated again and the resulting precipitate was washed with diethyl ether to give the title compound (25 mg, 79% yield) as an off-white solid. MS (ES+) 447.3 (M+H)+; 1H NMR (DMSO-d6, 300 MHz) δ 12.99 (br, 1H), 10.74 (s, 1H), 10.11 (s, 1H), 8.20 (s, 1H), 7.90 (t, 1H, J = 1.9 Hz), 7.86 (d, 1H, J = 1.0 Hz), 7.66-7.63 (m, 1H), 7.43-7.36 (m, 2H), 7.26 (d, 1H, J = 8.8 Hz), 7.15 (d, 1H, J = 8.1 Hz), 3.44 (dt, 4H, J = 22.0, 6.8 Hz), 2.28 (s, 3H), 1.91-1.80 (m, 4H) ppm; 19F NMR (DMSO-d6, 282 MHz) δ -74.70 ppm. The following were obtained by the same General Method D2 from the corresponding acid and amine:
Figure imgf000262_0001
Figure imgf000263_0002
General method D3: Coupling of THP-protected aryl/heteroaryl acetic acid with amines to generate amides and subsequent deprotection
Figure imgf000263_0001
HATU (1.2 equiv.) was added to a solution of aryl/heteroaryl acetic acid (1 equiv.), amine (1.2 equiv.) and DIPEA (4 equiv.) in anhydrous DMF (0.12 M), with stirring at room temperature overnight. The reaction mixture was separated between ethyl acetate and water, and the organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give the crude product, which was purified using flash column chromatography over silica. TFA (50 equiv.) was added to a solution of the THP protected compound (1 equiv.) in DCM (~0.07 M) with stirring under nitrogen for 3 hours before concentrating in vacuo. Methanol was added and the mixture concentrated again and the resulting precipitate was washed with diethyl ether to give the final compound. N-(5-Methyl-1H-indazol-4-yl)-2-((6-(2-oxo-2-(pyrrolidin-1-yl)ethyl)pyridin-2-yl)amino)thiazole-5- carboxamide.TFA salt (BAA-259)
Figure imgf000264_0001
Figure imgf000264_0002
HATU (60 mg, 0.16 mmol) was added to a solution of 2-(6-((5-((5-methyl-1-(tetrahydro-2H- pyran-2-yl)-1H-indazol-4-yl)carbamoyl)thiazol-2-yl)amino)pyridin-2-yl)acetic acid (65 mg, 0.13 mmol), pyrrolidine (13 uL, 0.16 mmol) and DIPEA (80 uL, 0.46 mmol) in anhydrous DMF (1.5 mL), with stirring at room temperature overnight. The reaction mixture was separated between ethyl acetate and water, and the organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give the crude product, which was purified using flash column chromatography over silica, eluting with 0-20% methanol/dichloromethane to give N- (5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-2-((6-(2-oxo-2-(pyrrolidin-1-yl)ethyl)pyridin- 2-yl)amino)thiazole-5-carboxamide (18 mg, 25% yield) as a beige solid. MS (ES+) 546.3 (M+H)+; 1H NMR (MeOD-d4, 300 MHz) δ 8.21 (s, 1H), 7.93 (d, 1H, J = 0.9 Hz), 7.68 (dd, 1H, J = 8.3, 7.3 Hz), 7.55 (d, 1H, J = 8.6 Hz), 7.36 (d, 1H, J = 8.6 Hz), 6.94 (ddd, 2H, J = 8.3, 5.9, 0.8 Hz), 5.78 (dd, 1H, J = 9.8, 2.6 Hz), 4.02-3.98 (m, 1H), 3.92 (s, 2H), 3.85-3.75 (m, 1H), 3.69 (t, 2H, J = 6.7 Hz), 3.55 (t, 2H, J = 6.8 Hz), 2.55-2.42 (m, 1H), 2.38 (s, 3H), 2.17-2.10 (m, 1H), 2.04-1.66 (m, 8H) ppm TFA (0.13 mL, 1.65 mmol) was added to a solution of N-(5-methyl-1-(tetrahydro-2H-pyran- 2-yl)-1H-indazol-4-yl)-2-((6-(2-oxo-2-(pyrrolidin-1-yl)ethyl)pyridin-2-yl)amino)thiazole-5- carboxamide (18 mg, 0.033 mmol) in DCM (0.5 mL), with stirring under nitrogen for 3 hours before concentrating in vacuo. Methanol was added and the mixture concentrated again and the resulting precipitate was washed with diethyl ether to give the title compound (13 mg, 77% yield) as an off- white solid. MS (ES+) 462.3 (M+H)+; 1H NMR (DMSO-d6, 300 MHz) δ 12.99 (br, 1H), 11.63 (br, 1H), 10.01 (s, 1H), 8.31 (s, 1H), 7.86 (d, 1H, J = 1.1 Hz), 7.69 (dd, 1H, J = 8.3, 7.3 Hz), 7.37 (d, 1H, J = 8.5 Hz), 7.26 (d, 1H, J = 8.6 Hz), 6.97 (d, 1H, J = 7.6 Hz), 6.90 (d, 1H, J = 7.2 Hz), 3.80 (s, 2H), 3.59 (t, 2H, J = 6.8 Hz), 3.37 (t, 2H, J = 6.8 Hz), 2.29 (s, 3H), 1.94-1.85 (m, 2H), 1.81-1.72 (m, 2H) ppm; 19F NMR (DMSO-d6, 282 MHz) δ -74.70 ppm The following were obtained by the same General Method D3 from the corresponding acid and amine , , , 5 3
Figure imgf000265_0001
Figure imgf000266_0001
, , , , ,
Figure imgf000267_0001
, ,
Figure imgf000268_0001
,
Figure imgf000269_0001
Figure imgf000270_0001
, ;
Figure imgf000271_0002
General method D4: Coupling of unprotected indazole carboxylic acids with amines to generate amides
Figure imgf000271_0001
1-Propanephosphonic anhydride (2-5 eq) [50% in EtOAc] or HATU ( eq) was added to a mixture of amine (4-6 eq,), carboxylic acid (1.00 eq) and triethylamine (9-10 eq) or diisopropylethylamine (10-15 eq) in MeCN or DMF. The reaction mixture was stirred at room temperature for 1-3 h then evaporated. The crude material was purified by reverse phase chromatography to provide the product. N-(5-Bromo-1H-indazol-4-yl)-2-[[4-methyl-1-[2-(4-methylpiperazin-1-yl)-2-oxo-ethyl]pyrazol-3- yl]amino]thiazole-5-carboxamide (BAA-281)
Figure imgf000272_0001
Prepared as described in Method D4, from 2-(3-((5-((5-bromo-1H-indazol-4- yl)carbamoyl)thiazol-2-yl)amino)-4-methyl-1H-pyrazol-1-yl)acetic acid (1.00 eq, 130 mg, 0.220 mmol), 1-propane phosphonic anhydride (2.35 eq, 0.30 mL, 0.519 mmol) [50% in EtOAc], 1- methylpiperazine (6.12 eq, 0.15 mL, 1.35 mmol), triethylamine (9.77 eq, 0.30 mL, 2.15 mmol) in MeCN to afford the title compound (62 mg, 0.108 mmol, 48.90% yield) after purification over C18 (45 g cartridge) eluting with a gradient of MeCN (0.1% NH3) (5% to 95%; v/v) in water (0.1% NH3). MS (ES+) m/z = 558.2/560.2 [M+H]+ mono Br pattern.1H NMR (400 MHz, DMSO-D6) δ 13.25 (s, 1H), 10.77 (s, 1H), 10.08 (s, 1H), 8.20 (s, 1H), 7.87 (s, 1H), 7.54 (d, J = 8.8 Hz, 1H), 7.40 (dd, J = 8.8, 1.0 Hz, 1H), 7.37 (d, J = 1.0 Hz, 1H), 4.96 (s, 2H), 3.46 (d, J = 5.2 Hz, 2H), 3.40 (s, 2H), 2.31 (s, 2H), 2.24 (s, 2H), 2.14 (s, 3H), 1.98 (d, J = 0.8 Hz, 3H). The following example compounds were prepared similarly using Method D4 with appropriate carboxylic acids and amines:
Figure imgf000272_0002
Figure imgf000273_0001
Figure imgf000274_0001
, ,
Figure imgf000275_0001
Figure imgf000276_0001
Figure imgf000277_0001
Figure imgf000278_0001
Figure imgf000279_0001
Figure imgf000280_0001
Figure imgf000281_0001
Figure imgf000282_0002
Pyrrolidinyl-pyrazole analogues N-(5-Methyl-1-tetrahydropyran-2-yl-indazol-4-yl)-2-[[1-[(3R)-pyrrolidin-3-yl]pyrazol-3- yl]amino]thiazole-5-carboxamide
Figure imgf000282_0001
Step 1.2-Bromo-N-(5-methyl-1-tetrahydropyran-2-yl-indazol-4-yl)thiazole-5-carboxamide (300 mg, 0.71 mmol) and tert-butyl (3R)-3-(3-aminopyrazol-1-yl)pyrrolidine-1-carboxylate (450 mg, 1.78 mmol) were dissolved in Dioxane:Water (5:1, 12 mL) and the solution was bubbled with nitrogen for 5 minutes. Pd2dba3 (98 mg, 15mol%), XantPhos (124 mg, 30mol%), and cesium carbonate (467 mg, 1.42 mmol) were then added with stirring and the mixture was bubbled with nitrogen for a further 5 minutes before heating to 90 °C with stirring for 18 hours. After cooling to room temperature the reaction mixture was separated between ethyl acetate and water, and the organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give the crude product, which was purified using flash column chromatography over silica, eluting with 20-100% ethyl acetate/petroleum ether followed by 0-10% methanol/ethyl acetate, then a second column eluting with 0-15% methanol/dichloromethane to give tert-butyl (3R)-3-[3-[[5-[(5-methyl-1-tetrahydropyran-2-yl-indazol-4-yl)carbamoyl]thiazol-2-yl]amino]pyrazol-1- yl]pyrrolidine-1-carboxylate (219 mg, 52% yield) as a yellow solid. MS (ES+) m/z 593.3 (M+H)+.1H NMR (DMSO-d6, 300 MHz) δ 10.54 (br s, 1H), 10.06 (s, 1H), 8.14 (s, 1H), 7.87 (s, 1H), 7.55 (d, 1H, J = 8.5 Hz), 7.48 (d, 1H, J = 1.8 Hz), 7.32 (d, 1H, J = 8.7 Hz), 6.30 (br s, 1H), 5.82 (dd, 1H, J = 9.7, 2.3 Hz), 5.06-5.00 (m, 1H), 3.91-3.87 (m, 1H), 3.78-3.65 (m, 2H), 3.59-3.35 (m, 3H), 2.46-2.19 (m, 6H), 2.05-1.93 (m, 2H), 1.78-1.72 (m, 1H), 1.61-1.55 (m, 2H), 1.40 (d, 9H, J = 5.7 Hz) Step 2. HCl (4 M in dioxane, 0.63 mL, 2.53 mmol) was added to a solution of tert-butyl (3R)-3-[3-[[5-[(5-methyl-1-tetrahydropyran-2-yl-indazol-4-yl)carbamoyl]thiazol-2-yl]amino]pyrazol-1- yl]pyrrolidine-1-carboxylate (100 mg, 0.169 mmol) in DCM (1.0 mL) at 0 °C, with stirring under nitrogen for 3 hours before concentrating in vacuo to give the crude product, which was purified using flash column chromatography over silica, eluting with 0-50% methanol/dichloromethane to give the title product (68 mg, 82% yield) as a pale yellow solid. MS (ES+) m/z 493.7 (M+H)+.1H NMR (MeOD-d4, 300 MHz) δ 8.03 (s, 1H), 7.90 (s, 1H), 7.57-7.54 (m, 2H), 7.35 (d, 1H, J = 8.8 Hz), 6.27 (d, 1H, J = 2.0 Hz), 5.78 (dd, 1H, J = 9.8, 2.5 Hz), 5.35 (tt, 1H, J = 6.4, 2.8 Hz), 4.02-3.98 (m, 1H), 3.84-3.76 (m, 1H), 3.72-3.59 (m, 3H), 3.51-3.42 (m, 1H), 2.56-2.41 (m, 2H), 2.35 (s, 3H), 2.33-2.24 (m, 1H), 2.14-2.09 (m, 1H), 2.03-1.98 (m, 1H), 1.90-1.64 (m, 3H). Synthesis of 2-[[1-[(3R)-1-(diethylcarbamoyl)pyrrolidin-3-yl]pyrazol-3-yl]amino]-N-(5-methyl-1H- indazol-4-yl)thiazole-5-carboxamide (BAA-320)
Figure imgf000283_0001
Step 1. Diethylcarbamoyl chloride (10 μL, 0.078 mmol) was added to a solution of N-(5- methyl-1-tetrahydropyran-2-yl-indazol-4-yl)-2-[[1-[(3R)-pyrrolidin-3-yl]pyrazol-3-yl]amino]thiazole-5- carboxamide (35 mg, 0.071 mmol) and DIPEA (37 μL, 0.213 mmol) in anhydrous DMF (1.0 mL) with stirring at room temperature overnight. The reaction mixture was then separated between ethyl acetate and water, and the organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give the crude product, which was using flash column chromatography over silica, eluting with 0-25% methanol/dichloromethane to give 2-[[1- [(3R)-1-(diethylcarbamoyl)pyrrolidin-3-yl]pyrazol-3-yl]amino]-N-(5-methyl-1-tetrahydropyran-2-yl- indazol-4-yl)thiazole-5-carboxamide (31 mg, 74% yield) as an off-white solid. MS (ES+) m/z 592.1 (M+H)+.1H NMR (MeOD-d4, 300 MHz) δ 8.03 (br s, 1H), 7.92 (d, 1H, J = 0.6 Hz), 7.58-7.54 (m, 2H), 7.37 (d, 1H, J = 8.7 Hz), 6.34 (d, 1H, J = 2.0 Hz), 5.80 (dd, 1H, J = 9.8, 2.5 Hz), 5.07 (p, 1H, J = 6.6 Hz), 4.05-3.99 (m, 1H), 3.86-3.78 (m, 2H), 3.74-3.65 (m, 2H), 3.60-3.52 (m, 1H), 3.27 (q, 4H, J = 7.2 Hz), 2.55-2.39 (m, 2H), 2.37 (s, 3H), 2.35-2.26 (m, 1H), 2.17-2.00 (m, 2H), 1.90-1.64 (m, 3H), 1.16 (t, 6H, J = 7.1 Hz). Step 2. TFA (0.20 mL, 2.62 mmol) was added to a solution of 2-[[1-[(3R)-1- (diethylcarbamoyl)pyrrolidin-3-yl]pyrazol-3-yl]amino]-N-(5-methyl-1-tetrahydropyran-2-yl-indazol-4- yl)thiazole-5-carboxamide (31 mg, 0.052 mmol) in DCM (0.5 mL), with stirring under nitrogen for 3 hours before concentrating in vacuo. DCM was added and the mixture concentrated again and the resulting precipitate was washed with diethyl ether to give the title compound (24 mg, 74% yield; TFA salt) as an off-white solid. MS (ES+) m/z 508.3 (M+H)+.1H NMR (DMSO-d6, 300 MHz) δ 13.01 (br s, 1H), 10.04 (s, 1H), 8.14 (s, 1H), 7.84 (s, 1H), 7.48 (d, 1H, J = 2.0 Hz), 7.37 (d, 1H, J = 8.4 Hz), 7.25 (d, 1H, J = 8.6 Hz), 6.29 (br s, 1H), 5.03-4.94 (m, 1H), 3.70 (dd, 1H, J = 10.5, 7.0 Hz), 3.57-3.39 (m, 3H), 3.12 (q, 4H, J = 7.0 Hz), 2.26 (s, 3H), 2.24-2.20 (m, 2H), 1.05 (t, 6H, J = 7.0 Hz). Synthesis of N-(5-methyl-1H-indazol-4-yl)-2-[[1-[(3R)-1-propanoylpyrrolidin-3-yl]pyrazol-3- yl]amino]thiazole-5-carboxamide (BAA-321)
Figure imgf000284_0001
Step 1. Propionyl chloride (7 μL, 0.080 mmol) was added to a solution of N-(5-methyl-1- tetrahydropyran-2-yl-indazol-4-yl)-2-[[1-[(3R)-pyrrolidin-3-yl]pyrazol-3-yl]amino]thiazole-5- carboxamide (33 mg, 0.067 mmol) and DIPEA (35 μL, 0.20 mmol) in anhydrous DMF (1.0 mL) with stirring at room temperature overnight. The reaction mixture was then separated between ethyl acetate and water, and the organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give the crude product, which was using flash column chromatography over silica, eluting with 0-25% methanol/dichloromethane to give N-(5- methyl-1-tetrahydropyran-2-yl-indazol-4-yl)-2-[[1-[(3R)-1-propanoylpyrrolidin-3-yl]pyrazol-3- yl]amino]thiazole-5-carboxamide (11 mg, 30% yield) as an off-white solid. MS (ES+) m/z 549.1 (M+H)+.1H NMR (MeOD-I, 300 MHz) δ 8.01 (s, 1H), 7.90 (s, 1H), 7.57-7.51 (m, 2H), 7.35 (d, 1H, J = 8.6 Hz), 6.30 (s, 1H), 5.78 (dd, 1H, J = 9.8, 2.5 Hz), 5.16 (dp, 1H, J = 18.1, 6.2 Hz), 4.02-3.51 (m, 6H), 2.53-2.31 (m, 8H), 2.15-1.98 (m, 2H), 1.90-1.63 (m, 3H), 1.13 (td, 3H, J = 7.5, 6.0 Hz). Step 2. TFA (0.08 mL, 1.00 mmol) was added to a solution of N-(5-methyl-1- tetrahydropyran-2-yl-indazol-4-yl)-2-[[1-[(3R)-1-propanoylpyrrolidin-3-yl]pyrazol-3-yl]amino]thiazole- 5-carboxamide (11 mg, 0.020 mmol) in DCM (0.25 mL), with stirring under nitrogen for 3 hours before concentrating in vacuo. DCM was added and the mixture concentrated again and the resulting precipitate was washed with diethyl ether to give the title compound (10 mg, 86% yield; TFA salt) as an off-white solid. MS (ES+) m/z 465.3 (M+H)+.1H NMR (MeOD-d4, 300 MHz) δ 8.02 (s, 1H), 7.90 (s, 1H), 7.53 (t, 1H, J = 2.2 Hz), 7.42 (d, 1H, J = 8.6 Hz), 7.33 (d, 1H, J = 8.6 Hz), 6.32 (d, 1H, J = 1.7 Hz), 5.16 (dq, 1H, J = 18.1, 6.0 Hz), 3.99-3.65 (m, 4H), 2.48-2.31 (m, 7H), 1.13 (td, 3H, J = 7.5, 5.7 Hz). General Method E: Nucleophilic substitution of tert-butyl 4-[(2-bromothiazole-5- carbonyl)amino]-5-methyl-indazole-1-carboxylate with amines
Figure imgf000285_0001
To a solution of tert-butyl 4-[(2-bromothiazole-5-carbonyl)amino]-5-methyl-indazole-1- carboxylate (1 eq) in THF was added amine (5-100 eq) in THF. The mixture was stirred for 2 days at 20-50oC, concentrated in vacuo and chromatographed (SiO2) eluting with a MeOH:DCM gradient or on reverse phase preparative HPLC eluting with a water:MeCN gradient to afford the final product. 2-(Methylamino)-N-(5-methyl-1H-indazol-4-yl)thiazole-5-carboxamide (BAA-322)
Figure imgf000285_0002
Prepared as described in Method E, from tert-butyl 4-[(2-bromothiazole-5-carbonyl)amino]- 5-methyl-indazole-1-carboxylate (300 mg, 0.686 mmol, 1.0 eq) in THF (50 mL) and methylamine (2M in THF, 3.0 mL, 6.00 mmol, 8.8 eq). to afford the title compound (20 mg, 10%) as a white powder after normal phase chromatography (SiO2) eluting with 0 – 20% gradient of MeOH:DCM. MS (ES+) m/z 288.3 (M+H)+.1H NMR (300 MHz, Methanol-d4) δ 7.93 (d, J = 21.6 Hz, 2H), 7.49 – 7.23 (m, 2H), 2.98 (s, 3H), 2.36 (s, 3H). The following example compounds were prepared similarly using Method E using appropriately substituted indazoles and amines:
Figure imgf000286_0002
2-(Ethylamino)-N-(5-methyl-1H-indazol-4-yl)thiazole-5-carboxamide (BAA-327)
Figure imgf000286_0001
2-Bromo-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)thiazole-5-carbox-amide (50 mg, 0.12 mmol) and ethylamine solution (0.59 mL, 1.19 mmol) were dissolved in 1,4- dioxane:water (4:1, 2.5 mL) and the solution was bubbled with nitrogen for 5 minutes. Pd2dba3 (16 mg, 15mol%), XantPhos (21 mg, 30mol%), and cesium carbonate (78 mg, 0.24 mmol) were then added with stirring and the mixture was bubbled with nitrogen for a further 5 minutes before heating to 85 °C with stirring for 16 hours. After cooling to room temperature the reaction mixture was separated between ethyl acetate water. The combined organic extracts were 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 0-10% methanol/dichloromethane, to give 2-(ethylamino)-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H- indazol-4-yl)thiazole-5-carboxamide (12 mg, 22% yield) as an off-white solid. MS (ES+) 386.1 (M+H)+; 1H NMR (MeOD-d4, 300 MHz) δ 7.94 (s, 1H), 7.89 (s, 1H), 7.53 (d, 1H, J = 9.0 Hz), 7.34 (d, 1H, J = 8.9 Hz), 5.78 (dd, 1H, J = 9.8, 2.5 Hz), 4.03-3.97 (m, 1H), 3.84-3.76 (m, 1H), 3.37 (q, 2H, J = 7.2 Hz), 2.55-2.42 (m, 1H), 2.35 (s, 3H), 2.15-2.08 (m, 1H), 2.03-1.98 (m, 1H), 1.85-1.64 (m, 3H), 1.28 (t, 3H, J = 7.2 Hz) ppm. TFA (0.12 mL, 1.56 mmol) was added to a solution of 2-(ethylamino)-N-(5-methyl-1- (tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)thiazole-5-carboxamide (12 mg, 0.031 mmol) in DCM (0.35 mL), with stirring under nitrogen for 3 hours before concentrating in vacuo. DCM was added and the mixture concentrated again and the resulting precipitate was purified using flash column chromatography over silica, eluting with 0-20% methanol/dichloromethane, to give the title compound (4 mg, 43% yield) as an off-white solid. MS (ES+) 302.1 (M+H)+; 1H NMR (MeOD-d4, 300 MHz) δ 7.94 (s, 1H), 7.89 (d, 1H, J = 0.8 Hz), 7.40 (d, 1H, J = 8.5 Hz), 7.31 (d, 1H, J = 8.6 Hz), 3.38 (q, 2H, J = 7.2 Hz), 2.36 (s, 3H), 1.28 (t, 3H, J = 7.2 Hz) ppm. General Method E2: Nucleophilic substitution of THP-protected 2-bromo-N-(5-substituted- 1H-indazol-4-yl)thiazole-5-carboxamide with amines
Figure imgf000287_0001
2-Bromo-N-(5-substituted-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)thiazole-5-carbox- amide (1 equiv.) and amine (2 equiv.) were dissolved in dioxane (0.1 M) and the solution was heated to 90 °C with stirring overnight, before cooling to room temperature and concentrating to give the crude product, which was purified using flash column chromatography over silica. TFA (50 equiv.) was added to a solution of the THP protected compound (1 equiv.) in DCM (~0.07 M) with stirring under nitrogen for 3 hours before concentrating in vacuo. Methanol was added and the mixture concentrated again and the resulting precipitate was washed with diethyl ether to give the final compound. The following were obtained by the same General Method E2 from the corresponding benzylamine
Figure imgf000288_0002
Synthesis of benzotriazole tert-Butyl 4-amino-5-methyl-1H-benzo[d][1,2,3]triazole-1-carboxylate
Figure imgf000288_0001
Boc anhydride (147 mg, 0.67 mmol) was added slowly to a solution of 5-methyl-1H-1,2,3- benzotriazol-4-amine (100 mg, 0.67 mmol) in pyridine (3 mL), with stirring at room temperature under nitrogen overnight, before diluting with water and extracting with ethyl acetate. The organic extracts were 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 0-100% ethyl acetate/petroleum ether, to give the title compound (120 mg, 72% yield) as a yellow solid. MS (ES+) 249.5 (M+H)+; 1H NMR (DMSO-d6, 300 MHz) δ 7.27 (d, 1H, J = 8.1 Hz), 6.96 (d, 1H, J = 8.1 Hz), 6.09 (s, 2H), 2.19 (s, 3H), 1.67 (s, 9H) ppm. tert-Butyl 4-(2-bromothiazole-5-carboxamido)-5-methyl-1H-benzo[d][1,2,3]triazole-1-carboxylate
Figure imgf000289_0001
1-Propanephosphonic anhydride (50% in Ethyl Acetate, 2.71 mL, 4.6 mmol) was added drop-wise to a solution of tert-butyl 4-amino-5-methyl-1H-benzo[d][1,2,3]triazole-1-carboxylate (760 mg, 3.06 mmol), 2-bromo-1,3-thiazole-5-carboxylic acid (764 mg, 3.67 mmol) and DIPEA (1.07 mL, 6.12 mmol) in anhydrous THF (25 mL), with stirring at room temperature, and the reaction mixture was then heated to 70 °C, with stirring under nitrogen overnight. After cooling to room temperature, the reaction was quenched with water and extracted with diethyl ether, and the organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give the product, which was purified using flash column chromatography over silica, eluting with 0-70% ethyl acetate/petroleum ether, to give the title compound (561 mg, 42% yield) as a yellow solid. MS (ES-) 438.0 (M-H); 1H NMR (DMSO-d6, 300 MHz) δ 11.02 (s, 1H), 8.57 (s, 1H), 7.87 (d, 1H, J = 8.5 Hz), 7.70 (d, 1H, J = 8.5 Hz), 2.35 (s, 3H), 1.70 (s, 9H) ppm. 2-(3-Amino-1H-pyrazol-1-yl)-N-cyclopropyl-N-methylacetamide
Figure imgf000289_0002
Ethyl bromoacetate was added drop-wise to a suspension of 3-nitro-1H-pyrazole and potassium carbonate in anhydrous THF (50 mL), with stirring at room temperature under nitrogen. The reaction mixture was then heated to 70 °C with stirring for 2 hours, before cooling to room temperature and separating between ethyl acetate and water. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give ethyl 2-(3-nitro- 1H-pyrazol-1-yl)acetate (5.22 g, 99% yield) as a white solid that did not need further purification. MS (ES+) 199.9 (M+H)+; 1H NMR (DMSO-d6, 300 MHz) δ 8.05 (d, 1H, J = 2.6 Hz), 7.09 (d, 1H, J = 2.6 Hz), 5.28 (s, 2H), 4.18 (q, 2H, J = 7.1 Hz), 1.22 (t, 3H, J = 7.1 Hz) ppm. Lithium hydroxide monohydrate (259 mg, 6.0 mmol) was added to a solution of ethyl 2-(3- nitro-1H-pyrazol-1-yl)acetate (600 mg, 3.0 mmol) in methanol:THF:water (2:2:1, 25 mL) with stirring at 40 °C overnight. The reaction mixture was then concentrated before separating between ethyl acetate and 1 M aqueous HCl. The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give 2-(3-nitro-1H-pyrazol-1- yl)acetic acid (498 mg, 97% yield) as a white solid that was used directly in the next step. MS (ES- ) 170.5 (M-H); 1H NMR (DMSO-d6, 300 MHz) δ 13.43 (br, 1H), 8.03 (d, 1H, J = 2.5 Hz), 7.07 (d, 1H, J = 2.5 Hz), 5.15 (s, 2H) ppm. HATU (1.33 g, 3.51 mmol) was added to a solution of 2-(3-nitro-1H-pyrazol-1-yl)acetic acid (500 mg, 2.92 mmol), N-methylcyclopropanamine hydrochloride (377 mg, 3.51 mmol) and DIPEA (2.54 mL, 14.6 mmol) in anhydrous DMF (14 mL), with stirring at room temperature overnight. The reaction mixture was separated between ethyl acetate and water, and the organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give the crude product, which was purified using flash column chromatography over silica, eluting with 0- 10% methanol/dichloromethane, to give N-cyclopropyl-N-methyl-2-(3-nitro-1H-pyrazol-1- yl)acetamide (700 mg, 96% yield) as a beige solid. MS (ES+) 225.2 (M+H)+; 1H NMR (DMSO-d6, 300 MHz) δ 7.95 (br s, 1H), 7.07 (d, 1H, J = 2.5 Hz), 5.42 (s, 2H), 2.88-2.83 (m, 1H), 2.83 (s, 3H), 0.89-0.85 (m, 4H) ppm. A solution of N-cyclopropyl-N-methyl-2-(3-nitro-1H-pyrazol-1-yl)acetamide (650 mg, 2.6 mmol) in ethanol (40 mL) was bubbled with nitrogen for 5 minutes before adding 10% Palladium on Carbon (10 wt.%, 278 mg, 0.26 mmol) and bubbling for a further 5 minutes. The flask was then placed under vacuum and refilled with nitrogen before fitting a hydrogen balloon and stirring overnight at room temperature. The balloon was then removed and the reaction mixture bubbled with nitrogen for 5 minutes before filtering through dicalite, washing with ethyl acetate. The filtrate was concentrated to give 2-(3-amino-1H-pyrazol-1-yl)-N-cyclopropyl-N-methylacetamide (510 mg, 100% yield) as a beige solid that was used directly in the next step. MS (ES+) 195.3 (M+H)+; 1H NMR (DMSO-d6, 300 MHz) δ 7.26 (d, 1H, J = 2.3 Hz), 5.39 (d, 1H, J = 2.3 Hz), 4.88 (s, 2H), 4.56 (br, 2H), 2.79 (s, 3H), 2.78-2.74 (m, 1H), 0.86-0.81 (m, 4H) ppm. 2-((1-(2-(Cyclopropyl(methyl)amino)-2-oxoethyl)-1H-pyrazol-3-yl)amino)-N-(5-methyl-1H- benzo[d][1,2,3]triazol-4-yl)thiazole-5-carboxamide (BAA-331)
Figure imgf000290_0001
tert-Butyl 4-(2-bromothiazole-5-carboxamido)-5-methyl-1H-benzo[d][1,2,3]triazole-1- carboxylate (280 mg, 0.64 mmol) and 2-(3-amino-1H-pyrazol-1-yl)-N-cyclopropyl-N- methylacetamide (174 mg, 0.89 mmol) were dissolved in 1,4-dioxane:water (4:1, 9.6 mL) and the solution was bubbled with nitrogen for 5 minutes. Pd2dba3 (88 mg, 15mol%), XantPhos (111 mg, 30mol%), and cesium carbonate (293 mg, 0.89 mmol) were then added with stirring and the mixture was bubbled with nitrogen for a further 5 minutes before heating to 90 °C with stirring overnight. After cooling to room temperature the reaction mixture was diluted with 30% methanol/dichloromethane (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product, which was purified using flash column chromatography over silica, eluting with 0-30% methanol/dichloromethane, to give the title compound (14 mg, 5% yield) as an off-white solid. MS (ES+) 452.3 (M+H)+; 1H NMR (CDCl3 containing ~20% MeOD-d4, 300 MHz) δ 7.89 (s, 1H), 7.59 (br, 1H), 7.32 (d, 1H, J = 2.4 Hz), 7.16 (d, 1H, J = 8.5 Hz), 5.93 (d, 1H, J = 2.4 Hz), 4.99 (s, 2H), 2.79 (s, 3H), 2.72-2.67 (m, 1H), 2.31 (s, 3H), 0.90-0.75 (m, 4H) ppm. Synthesis of thiadiazole core analogue 5-((6-Methylpyridin-2-yl)amino)-1,3,4-thiadiazole-2-carboxylic acid
Figure imgf000291_0001
Ethyl 5-bromo-1,3,4-thiadiazole-2-carboxylate (500 mg, 2.1 mmol) and 2-amino-6- methylpyridine (274 mg, 2.53 mmol) were dissolved in Dioxane:Water (5:1, 24 mL) and the solution was bubbled with nitrogen for 5 minutes. Pd2dba3 (290 mg, 15mol%), XantPhos (366 mg, 30mol%), and cesium carbonate (830 mg, 2.53 mmol) were then added with stirring and the mixture was bubbled with nitrogen for a further 5 minutes before heating to 90 °C with stirring overnight. After cooling to room temperature the reaction mixture was separated between ethyl acetate water. The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give the crude product, which was purified using flash column chromatography over basic alumina, eluting with 0-15% methanol/dichloromethane, then again eluting with 50-100% ethyl acetate/petroleum ether followed by 0-30% methanol/ethyl acetate, to give ethyl 5-((6-methylpyridin-2-yl)amino)-1,3,4-thiadiazole-2-carboxylate (119 mg, 21% yield) as a yellow solid. MS (ES+) 265.2 (M+H)+. Lithium hydroxide monohydrate (29 mg, 0.68 mmol) was added to a solution of ELN453- 006 (119 mg, 0.45 mmol) in methanol:water (2:1, 6 mL) with stirring at 40 °C overnight. The reaction mixture was then concentrated and acidified to pH ~2 using 2 M aq. HCl. The precipitate was collected and washed with ice cold water, and dried in a vacuum oven overnight to give the title compound (85 mg, 57% purity, 46% yield) as a beige solid that was used directly in the next step. MS (ES+) 237.5 (M+H)+. N-(5-Methyl-1H-indazol-4-yl)-5-((6-methylpyridin-2-yl)amino)-1,3,4-thiadiazole-2-carboxamide (BAA-332)
Figure imgf000292_0001
1-Propanephosphonic anhydride (50% in Ethyl Acetate, 0.27 mL, 0.45 mmol) was added drop-wise to a solution of 5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-amine (70 mg, 0.30 mmol), 5-((6-methylpyridin-2-yl)amino)-1,3,4-thiadiazole-2-carboxylic acid (75 mg, 0.32 mmol) and DIPEA (0.11 mL, 0.61 mmol) in anhydrous THF (4.5 mL), with stirring at room temperature, and the reaction mixture was then heated to 70 °C, with stirring under nitrogen overnight. After cooling to room temperature, the reaction was quenched with water and extracted with ethyl acetate, and the organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give the product, which was purified using flash column chromatography over basic alumina, eluting with 0-10% methanol/dichloromethane, to give N-(5-methyl-1-(tetrahydro- 2H-pyran-2-yl)-1H-indazol-4-yl)-5-((6-methylpyridin-2-yl)amino)-1,3,4-thiadiazole-2-carboxamide (11 mg, 8% yield) as a yellow solid. MS (ES+) 450.3 (M+H)+. TFA (0.1 mL, 1.22 mmol) was added to a solution of N-(5-methyl-1-(tetrahydro-2H-pyran-2- yl)-1H-indazol-4-yl)-5-((6-methylpyridin-2-yl)amino)-1,3,4-thiadiazole-2-carboxamide (11 mg, 0.025 mmol) in DCM (0.3 mL), with stirring under nitrogen for 3 hours before concentrating in vacuo. DCM was added and the mixture concentrated again and the resulting precipitate was purified using flash column chromatography over basic alumina, eluting with 0-40% methanol/dichloromethane to give the title compound (4 mg, 45% yield) as a white solid. MS (ES+) 366.3 (M+H)+; 1H NMR (DMSO-d6, 300 MHz) δ 13.01 (s, 1H), 12.16 (s, 1H), 10.77 (s, 1H), 7.86 (s, 1H), 7.71 (dd, 1H, J = 8.2, 7.3 Hz), 7.40 (d, 1H, J = 8.3 Hz), 7.27 (d, 1H, J = 8.7 Hz), 6.97- 6.92 (m, 2H), 2.49 (s, 3H), 2.31 (s, 3H) ppm. Synthesis of oxazole core analogue 2-((6-Methylpyridin-2-yl)amino)oxazole-5-carboxylic acid
Figure imgf000292_0002
Ethyl 2-bromooxazole-5-carboxylate (300 mg, 1.36 mmol) and 2-amino-6-methylpyridine (221 mg, 2.05 mmol) were dissolved in 1,4-dioxane:water (5:1, 18 mL) and the solution was bubbled with nitrogen for 5 minutes. Pd2dba3 (187 mg, 15mol%), XantPhos (237 mg, 30mol%), and cesium carbonate (894 mg, 2.73 mmol) were then added with stirring and the mixture was bubbled with nitrogen for a further 5 minutes before heating to 90 °C with stirring overnight. After cooling to room temperature the reaction mixture was separated between ethyl acetate water. The combined organic extracts were 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 0-15% methanol/dichloromethane, to give ethyl 2-((6-methylpyridin-2- yl)amino)oxazole-5-carboxylate (240 mg, 71% yield) as a yellow solid. MS (ES+) 248.6 (M+H)+; 1H NMR (DMSO-d6, 300 MHz) δ 11.24 (br, 1H), 7.85 (d, 1H, J = 8.3 Hz), 7.83 (s, 1H), 7.69 (dd, 1H, J = 8.4, 7.3 Hz), 6.91 (d, 1H, J = 7.3 Hz), 4.28 (q, 2H, J = 7.1 Hz), 2.40 (s, 3H), 1.28 (t, 3H, J = 7.1 Hz) ppm. Lithium hydroxide monohydrate (125 mg, 2.9 mmol) was added to a solution of ethyl 2-((6- methylpyridin-2-yl)amino)oxazole-5-carboxylate (240 mg, 0.970 mmol) in methanol:THF:water (2:2:1, 15 mL) with stirring at 40 °C overnight. The reaction mixture was then separated between ethyl acetate and 1 M aqueous sodium hydroxide. The aqueous phase was acidified to pH 4 using 2 M aqueous HCl then extracted with 10% methanol/ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give 2-((6-methylpyridin-2-yl)amino)oxazole-5-carboxylic acid as a beige solid that was used directly in the next step. MS (ES+) 220.6 (M+H)+; 1H NMR (DMSO-d6, 300 MHz) δ 7.85-7.72 (m, 3H), 6.94 (d, 1H, J = 7.7 Hz), 2.42 (s, 3H) ppm. N-(5-Methyl-1H-indazol-4-yl)-2-((6-methylpyridin-2-yl)amino)oxazole-5-carboxamide (BAA-333)
Figure imgf000293_0001
1-Propanephosphonic anhydride (50% in Ethyl Acetate, 0.38 mL, 0.65 mmol) was added drop-wise to a solution of 5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-amine (100 mg, 0.43 mmol), 2-((6-methylpyridin-2-yl)amino)oxazole-5-carboxylic acid (100 mg, 0.45 mmol), and DIPEA (0.23 mL, 1.3 mmol) in anhydrous THF (6 mL), with stirring at room temperature, and the reaction mixture was then heated to 70 °C, with stirring under nitrogen overnight. After cooling to room temperature, the reaction was quenched with water and extracted with diethyl ether, and the organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered through a short pad of silica and concentrated to give the crude product, which was purified using flash column chromatography over silica, eluting with 0-10% methanol/dichloromethane, to give N-(5- methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-2-((6-methylpyridin-2-yl)amino)oxazole-5- carboxamide (24 mg, 13% yield) as an off-white solid. MS (ES+) 433.6 (M+H)+; 1H NMR (MeOD-d4, 300 MHz) δ 7.94 (d, 1H, J = 0.9 Hz), 7.78 (br, 1H), 7.69 (t, 1H, J = 7.9 Hz), 7.58 (d, 1H, J = 8.5 Hz), 7.38 (d, 1H, J = 9.1 Hz), 6.88 (br, 1H), 5.80 (dd, 1H, J = 9.8, 2.6 Hz), 4.03-3.97 (m, 1H), 3.85- 3.77 (m, 1H), 2.56-2.43 (m, 4H), 2.39 (s, 3H), 2.16-1.99 (m, 2H), 1.89-1.63 (m, 3H) ppm TFA (0.21 mL, 2.77 mmol) was added to a solution of N-(5-methyl-1-(tetrahydro-2H-pyran- 2-yl)-1H-indazol-4-yl)-2-((6-methylpyridin-2-yl)amino)oxazole-5-carboxamide (24 mg, 0.056 mmol) in DCM (0.6 mL), with stirring under nitrogen for 3 hours before concentrating in vacuo. DCM was added and the mixture concentrated again and the resulting precipitate was washed with diethyl ether to give the title compound (17 mg, 66% yield) as an off-white solid. MS (ES+) 349.3 (M+H)+; 1H NMR (DMSO-d6, 300 MHz) δ 13.00 (br, 1H), 11.04 (br, 1H), 10.04 (s, 1H), 7.96 (s, 1H), 7.90- 7.86 (m, 2H), 7.73 (t, 1H, J = 7.9 Hz), 7.38 (d, 1H, J = 8.4 Hz), 7.26 (d, 1H, J = 8.7 Hz), 6.92 (d, 1H, J = 7.4 Hz), 2.43 (s, 3H), 2.28 (s, 3H) ppm; 19F NMR (DMSO-d6, 282 MHz) δ -74.63 ppm. Synthesis of reference compounds:
Figure imgf000294_0001
tert-Butyl 4-[(2-bromothiazole-5-carbonyl)amino]indazole-1-carboxylate To a mixture of tert-butyl 4-aminoindazole-1-carboxylate (1.08 g, 4.61 mmol, 1.20 eq), 2- bromo-1,3-thiazole-5-carboxylic acid (800 mg, 3.85 mmol, 1.00 eq) and N,N-diisopropyl ethylamine (1.7 mL, 9.61 mmol, 2.50 eq) in THF (15 mL) was added dropwise 1-propane phosphonic anhydride 50% in Ethyl Acetate (3.2 mL, 5.38 mmol, 1.40 eq) and the reaction heated to 50 °C for 16 h. A further 1 ml T3P was added and the reaction stirred for a further 4 h. The reaction was quenched by the addition of saturated NaHCO3 solution (4 mL). Dietheyl ether (15 mL) and water (15 mL) were added. The phases were separated and the aqueous phase extracted with ether (2 x 20 mL). Combined organic phases were washed with brine (20 mL), dried over MgSO4, filtered and concentrated in vacuo. Column chromatography (petrol:ethyl acetate) gave the title compound (966 mg, 59%) which was used directly in the next step. MS (ES+) m/z 421 (M+H)+. 1H NMR (300 MHz, Chloroform-d) δ 8.86 (s, 1H), 8.31 – 8.09 (m, 2H), 7.90 (d, J = 8.3 Hz, 1H), 7.55 (d, J = 7.7 Hz, 1H), 7.42 (t, J = 8.1 Hz, 1H), 1.69 (s, 9H). Synthesis of N-(1H-indazol-4-yl)-2-[(1-methylpyrazol-3-yl)amino]thiazole-5-carboxamide (REF-001)
Figure imgf000294_0002
A mixture of tert-butyl 4-[(2-bromothiazole-5-carbonyl)amino]indazole-1-carboxylate (125 mg, 0.295 mmol, 1.00 eq), 1-methyl-1H-pyrazol-3-ylamine (57 mg, 0.591 mmol, 2.00 eq), sodium tert-butoxide (114 mg, 1.18 mmol, 4.00 eq) and 4,5-bis(diphenylphospheno)-9,9-dimethylxanthene (17 mg, 0.0295 mmol, 0.100 eq) in 1,4-dioxane (4 mL) was degassed thoroughly by bubbling nitrogen through the mixture. tris(dibenzylideneacetone) dipalladium(0) (27 mg, 0.0295 mmol, 0.100 eq) was added and the reaction heated to 85 °C for 16 h. The reaction was filtered through celite (ethyl acetate). The filtrate was discarded. The residue washed with hot isopropanol and the filtrate concentrated in vacuo to give the crude product. Preparative HPLC (water:acetonitrile) gave the title compound (1.6 mg, 1.6%). MS (ES+) m/z 340 (M+H)+.1H NMR (300 MHz, Methanol-d4) δ 8.53 (s, 1H), 8.17 (d, J = 0.7 Hz, 1H), 8.14 (s, 1H), 7.50 (d, J = 2.3 Hz, 1H), 7.44 – 7.29 (m, 3H), 6.03 (d, J = 2.3 Hz, 1H), 3.86 (s, 3H). Synthesis of 2-[[1-(2-hydroxy-2-methyl-propyl)pyrazol-3-yl]amino]-N-(1H-indazol-4-yl)thiazole-5- carboxamide (REF-002)
Figure imgf000295_0001
A mixture of tert-butyl 4-[(2-bromothiazole-5-carbonyl)amino]indazole-1-carboxylate (125 mg, 0.295 mmol, 1.00 eq), 1-(3-aminopyrazol-1-yl)-2-methyl-propan-2-ol (92 mg, 0.591 mmol, 2.00 eq), sodium tert-butoxide (114 mg, 1.18 mmol, 4.00 eq) and 4,5-bis(diphenyl phospheno)-9,9- dimethylxanthene (17 mg, 0.0295 mmol, 0.100 eq) in 1,4-dioxane (4 mL) was degassed thoroughly by bubbling nitrogen through the mixture. Tris(dibenzylidene acetone)dipalladium(0) (27 mg, 0.0295 mmol, 0.100 eq) was added and the reaction heated to 85 °C for 16 h. The reaction was concentrated in vacuo. Column chromatography (DCM:methanol) followed by preparative HPLC (water:acetonitrile) gave the title compound (1.0 mg, 0.85%). MS (ES+) m/z 398 (M+H)+.1H NMR (300 MHz, Methanol-d4) δ 8.24 – 8.10 (m, 2H), 7.56 (d, J = 2.4 Hz, 1H), 7.43 – 7.31 (m, 3H), 6.05 (d, J = 2.4 Hz, 1H), 4.07 (s, 2H), 1.24 (d, J = 5.4 Hz, 7H). Biological Methods and Data BIOLOGICAL EXAMPLE 1: PKMYT1 protein production Human PKMYT175-362 was cloned as a TEV cleavable 6xHis fusion in bacterial cells. After purification on a Ni++ HiTrap Chelating HP column, the His-tag was cleaved using TEV protease. Cleaved PKMYT1 was further purified on a Superdex 20016/600 sizing column. The fractions containing PKMYT1 were pooled and concentrated using an ultrafiltration centrifugal protein concentrator. The purified protein was aliquoted, flash frozen in liquid nitrogen, and stored at −80°C. BIOLOGICAL EXAMPLE 2: ADP-Glo enzymatic assays PKMYT1 biochemical assay: Inhibition of PKMYT1 was assessed using the ADP-GloTM 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 according to the following protocol. Compounds were dosed into Corning white low volume 384 well assay plates using an Echo acoustic dispenser to generate 10- point curves spanning a 3-fold dilution series. DMSO (no inhibitor) control wells were prepared to benchmark the maximum and minimum signals in the presence and absence of PKMYT1, respectively. The PKMYT1 kinase domain was purified in-house, as described above, and added to the wells at a final concentration of 15 nM in a buffer of 50 mM HEPES (pH 7.5), 10 mM MgCl2, 1 mM EGTA, 0.01 % Brij-35, 1 % DMSO. 500 μM ATP was added to start the reaction with the final assay volume being 4 μl. The plate was then incubated for 60 minutes at 26oC before the addition of 4 μl of ADP-Glo Reagent to stop the reaction and deplete the unconsumed ATP. Following a further 60 minute incubation the assay signal was developed by the addition of 8 μl ADP-Glo Max Detection Reagent. After 60 minutes the luminescence signal was read on a PHERAStar FS microplate reader (BMG Labtech). Selectivity versus WEE1 assay: Selectivity was established using the same format as outlined for PKMYT1. After dosing of compounds via the Echo acoustic dispenser - as described above - WEE1 (Thermo Fisher PR7373A) was added to each well at a final concentration of 15 nM in a buffer of 50 mM HEPES (pH 7.5), 10 mM MgCl2, 1 mM EGTA, 0.01 % Brij-35, 1 % DMSO. 30 μM ATP was added to start the reaction with the final assay volume being 4 μl. The plate was then incubated for 60 minutes at 26 oC before the addition of 4 μl of ADP-Glo Reagent. Following a further 60 minute incubation the assay signal was developed by the addition of 8 μl ADP-Glo Detection Reagent. After 60 minutes the luminescence signal was read on a PHERAStar FS microplate reader (BMG Labtech). Data analysis: Data was captured and analysed within the Dotmatics Studies software module where dose response curves were generated and IC50 values determined. Acceptance and verification of data followed strict in-house business rules which are summarised as follows. All assay plates should demonstrate Z’ values >0.5 and reference compounds run on each plate should fall within 2-fold of the geometric mean of historical IC50 values. Technical and biological replicates of each compound are routinely tested and replicate IC50 values must fall within 3-fold of each other with dose response curves showing ‘goodness of fit’ r2 values >0.9. Failure to meet any of these defined criteria result in rejection of data. The data for the primary biochemical assay (PKMYT1 IC50) and selectivity assay (WEE1 IC50) are summarised in the following Biological Data Table 1. The PKMYT1 IC50 and WEE1 IC50 values are banded as follows: A: <50 nM; B: 50 nM - <1 μM; C: 1 μM - 11 μM; D: >11 μM. 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 - 5000 fold; Z: >5000 fold. 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 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. Biological Data Table 1
Figure imgf000297_0001
Figure imgf000297_0002
Figure imgf000298_0001
Figure imgf000298_0002
Figure imgf000299_0001
Figure imgf000299_0002
Figure imgf000300_0001
Figure imgf000300_0002
Figure imgf000301_0001
Figure imgf000301_0002
Figure imgf000302_0001
Figure imgf000302_0002
BIOLOGICAL EXAMPLE 3: Nuclear count cell proliferation assay of isogenic h-TERT-RPE1 TP53 -/- parental and CCNE1 overexpressing cell lines h-TERT-RPE1 TP53 -/- and CCNE1 high expressing clones (clone cell lines 7 and 15) were treated with test compounds dissolved in DMSO at serially diluted concentrations alongside a DMSO only control for around 6 population doublings time. Cells were then fixed with 4% Paraformaldehyde and the cell nuclei were stained with DAPI (Sigma D9542). Images covering each well were acquired by an Opera Phenix® High-Content Screening System (PerkinElmer). Image analysis was performed using Harmony ® high-content analysis software (PerkinElmer). Data analysis was performed using Microsoft Excel® and GI50 estimates generated with GraphPad Prism v9. Percent nuclear count was compared to vehicle control wells and used to measure inhibition of proliferation. The compound in Biological Data Table 2 shows an increase in cell proliferation inhibition of at least 3-fold in a CCNE1 overexpressing clone compared to parent cell line expressing endogenous CCNE1 levels. These PKMYT1 inhibitors show CCNE1 amplification dependent increased activity in isogenic cell line pairs. The RPE cell line GI50 values are banded as follows: A: <0.5 μM; B: 0.5 μM - <3 μM; C: 3 μM - 10 μM; D: >10 μM. The RPE wild type (Wt) to clone cell line (CL15) GI50 selectivity ratio is banded by fold difference as follows: X: 3 - <10 fold; Y: 10 - 30 fold; Z: >30 fold. Where either the RPE CL15 GI50 value was below the lowest concentration limit of the assay or the RPE Wt GI50 value was above the top concentration limit of the assay, the selectivty ratio wild type vs. CL15 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. Biological Data Table 2
Figure imgf000303_0001
BIOLOGICAL EXAMPLE 4: Cancer Cell Lines Proliferation Assays Cancer cell lines with either normal (KYSE-30) or amplified CCNE1 expression (OVCAR3 – ovarian cancer) were evaluated for their sensitivity to PKMYT1 inhibitors in a nuclear count assay as described above for h-TERT-RPE1 TP53 -/- and a CCNE1 high expressing clones, taking into account the slower cell cycle division times of these lines. The following compounds in Biological Data Table 3 inhibit OVCAR3 cell proliferation with a GI50 <5 μM. In addition, selected compounds exhibit >3-fold selectivity for the CCNE1-amplified OVCAR3 cells compared to KYSE30 cells expressing normal levels of CCNE1. (Cell proliferation inhibition in cancer cell lines: OVCAR3 expresses high level of CCNE1; control cell line KYSE30 expresses normal levels of CCNE1.) The cell line GI50 values are banded as follows: A: <0.5 μM; B: 0.5 μM - <3 μM; C: 3 μM - 10 μM; D: >10 μM. 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 - 30 fold; Z: >30 fold. Where either the OVCAR3 GI50 value was below the lowest concentration limit of the assay or the KYSE30 GI50 value was above the top concentration limit of the assay, the selectivity ratio KYSE30 GI50 vs. OVCAR3 GI50 is given as “>N”, where N is the selectivity band. The selectivity value for these compounds falls at least in this band but could be higher. Biological Data Table 3
Figure imgf000304_0001
BIOLOGICAL EXAMPLE 5: Cancer Cell Lines Proliferation Assays – ATP-based cell viability endpoint Cancer cell lines with either normal (KYSE-30) or amplified CCNE1 expression (OVCAR 3 – ovarian cancer) were evaluated for their sensitivity to PKMYT1 inhibitors using Cell Titre Glow assay (Promega G7573) as endpoint to assess cell proliferation. The luminescence signal was read on a PHERAStar FS microplate reader (BMG Labtech). Data analysis was performed using Microsoft Excel® and GI50 (concentration that achieves 50% cell growth proliferation inhibition) estimates generated with GraphPad Prism v9. The following compounds in Biological Data Table 2 inhibit OVCAR 3 cell proliferation with a GI50 <0.5 μM. In addition, selected compounds exhibit >3-fold selectivity for the CCNE1-amplified OVCAR 3 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: <0.5 μM; B: 0.5 μM - <5 μM; C: >5 μM. The normal CCNE1 expression cell line (KYSE-30) to CCNE1-amplified cell line (OVCAR 3) GI50 selectivity ratio is banded by fold difference as follows: X: 3 - 20 fold; Y: >20 fold. Where either the OVCAR 3 GI50 value was below the lowest concentration limit of the assay or the KYSE30 GI50 value was above the top concentration limit of the assay, the selectivity ratio KYSE30 GI50 vs. OVCAR 3 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. Biological Data Table 4 ty ty 0 0 . 3 3
Figure imgf000305_0001
Figure imgf000305_0002
y ty 03 3
Figure imgf000306_0002
Figure imgf000306_0001
Figure imgf000307_0001
Figure imgf000307_0002
Figure imgf000308_0001
Figure imgf000308_0002
BIOLOGICAL EXAMPLE 6: Inhibition of cellular PKMYT1 biomarker CDK1 pT14 To determine compound PKMYT1 IC50 in a cellular assay, OVCAR 3 cells were incubated at 37°C in 5% CO2 atmosphere. The cells were maintained in RPMI medium supplemented with 20% foetal bovine serum, 1X non essential amino acids, 1mM sodium pyruvate, Glutamax and insulin. Cells were seeded into 12-well plates at low density (50,000-200,000 cells per well), grown to confluence (~350-400,000 cells per well) and then treated with a range of concentrations of PKMYT1 inhibitors. The cells 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. The samples were analysed by immunoblot on a Jess Automated Western Blot System (BioTechne). The samples were separated using the 12-230 kDa Separation Module (BioTechne,) and blotted using an anti-CDK1 phospho T14 antibody (Abcam, #ab58509) and an anti-vinculin antibody (Abcam, #126002). Specific binding was detected by fluorescence using the Anti-Rabbit Detection Module (BioTechne, #DM-001), quantified using Compass for Simple Western software, and IC50 values were calculated by regression analysis in GraphPad Prism. The following compounds in Biological Data Table 5 inhibit CDK1 pT14 in OVCAR 3 cells with an IC50 <1 μM. The CDK1 pT14 IC50 values are banded as follows: A: <100 nM; B: 100 nM - 1 μM;
Figure imgf000308_0003
Figure imgf000308_0004
Figure imgf000309_0001
Figure imgf000309_0002
Figure imgf000310_0001
Figure imgf000310_0002
BIOLOGICAL EXAMPLE 7: Comparison Data 1 IC50 was measured for BAA-001, BAA-003, REF-001, and REF-002 as described for PKMYT1 biochemical ADP-Glo enzymatic assay in Biological Example 2. See Biological Data Table 4, below. As compared to REF-001, BAA-001 exhibits a 12.4-fold improvement in PKMYT1 IC50. As compared to REF-002, BAA-003 exhibits a 50-fold improvement in PKMYT1 IC50. The enhancement in activity seen when the indazole ring is substituted at the position ortho- to the amide group indicates that this ortho-substituted pattern confers surprising and unexpected improvements in PKMYT1 potency as compared to compounds lacking a substituent at the corresponding position. Biological Data Table 4
Figure imgf000311_0001
* * * The foregoing has described the principles, preferred embodiments, and modes of operation of the present invention. However, the invention should not be construed as limited to the particular embodiments discussed. Instead, the above-described embodiments should be regarded as illustrative rather than restrictive. It should be appreciated that variations may be made in those embodiments by workers skilled in the art without departing from the scope of the present invention. REFERENCES Publications are cited herein in order to more fully describe the state of the art to which the invention pertains. Full citations for these references are provided below. Each of these publications 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. Booher et al., 1997, ‘Human Myt1 Is a Cell Cycle-regulated Kinase That Inhibits Cdc2 but Not Cdk2 Activity’, J Biol Chem. 29;272(35):22300-6. Bryan et al., 2006, “304. Identifying cellular genes crucial for the reactivation of Kaposi's sarcoma- associated herpesvirus latency”, Journal of General Virology, 87(3), 519-529. Cai et al., 2022, “PKMYT1 regulates the proliferation and epithelial-mesenchymal transition of oral squamous cell carcinoma cells by targeting CCNA2”, Oncology Letters (2022), 23(2), 63. Chayka et al., 2015, “Identification and Pharmacological Inactivation of the MYCN Gene Network as a Therapeutic Strategy for Neuroblastic Tumor Cells”, Journal of Biological Chemistry, 290(4), 2198-2212. Chen et al., 2020, “Overexpression of PKMYT1 facilitates tumor development and is correlated with poor prognosis in clear cell renal cell carcinoma” Medical Science Monitor, 26, e926755. Chen et al., 2021, “PKMYT1, exacerbating the progression of clear cell renal cell carcinoma, is implied as a biomarker for the diagnosis and prognosis”, Aging, 13(24), 25778-25798. Durocher et al., 2021, “Methods of Using Myt1 Inhibitors”, International (PCT) Patent Application Publication No. WO 2021/195782 A1. Fassl et al., 2022, ‘CDK4 and CDK6 kinases: From basic science to cancer therapy.’ Science. 375(6577):eabc1495. Gallo et al., 2022, “CCNE1 amplification is synthetic lethal with PKMYT1 kinase inhibition”, Nature, 604(7907), 749-756. Ghelli Luserna di Rora et al., 2020, “A WEE1 family business: regulation of mitosis, cancer progression, and therapeutic target”, Journal of Hematology & Oncology, 13(1):126. Gorski et al., 2020, ‘CCNE1 Amplification as a Predictive Biomarker of Chemotherapy Resistance in Epithelial Ovarian Cancer.’ Diagnostics (Basel). 5;10(5):279. He et al., 2021, “LncRNA PKMYT1AR promotes cancer stem cell maintenance in non-small cell lung cancer via activating Wnt signaling pathway”, Molecular Cancer, 20(1), 156. Hu et al., 2022, “. Demethylase ALKBH5 suppresses invasion of gastric cancer via PKMYT1 m6A modification”, Molecular Cancer, 21(1), 34. Jeong et al., 2018, “109. Protein kinase, membrane-associated tyrosine/threonine 1 is associated with the progression of colorectal cancer”, Oncology Reports, 39(6), 2829-2836. Jones et al., 2013, “Increased replication initiation and conflicts with transcription underlie Cyclin E- induced replication stress” Oncogene 32, 3744–3753. Lewis et al., 2019, “Upregulation of Myt1 Promotes Acquired Resistance of Cancer Cells to Wee1 Inhibition”, Cancer research, 79(23), 5971-5985. Liu et al., 1997, ‘The human Myt1 kinase preferentially phosphorylates Cdc2 on threonine 14 and localizes to the endoplasmic reticulum and Golgi complex’, Mol Cell Biol. 17(2):571-83. Liu et al., 2017, “PKMYT1 promoted the growth and motility of hepatocellular carcinoma cells by activating beta-catenin/TCF signaling”, Experimental Cell Research, 358(2), 209-216. Liu et al., 2020, “Systematic expression analysis of WEE family kinases reveals the importance of PKMYT1 in breast carcinogenesis”, Cell proliferation, 53(2), e12741. Long et al., 2020, “84. PKMYT1 as a potential target to improve the radiosensitivity of lung adenocarcinoma”, Frontiers in Genetics, 11, 00376. Luo et al., 2022, “c-Myb-mediated inhibition of miR-601 in facilitating malignance of osteosarcoma via augmentation of PKMYT1”, Scientific Reports, 12(1), 6692. Shao et al., 2021, “The DNA damage repair-related gene PKMYT1 is a potential biomarker in various malignancies”, Translational Lung Cancer Research, 10(12), 4600-4616. Sun et al., 2019, “Overexpression of PKMYT1 indicates the poor prognosis and enhances proliferation and tumorigenesis in non-small cell lung cancer via activation of Notch signal pathway”, European review for medical and pharmacological sciences, 23(10), 4210-4219. Szychowski et al., 2022, “Discovery of an Orally Bioavailable and Selective PKMYT1 Inhibitor, RP- 6306”, Journal of Medicinal Chemistry, 65(15), 10251-10284 Toledo et al., 2015, “Genome-wide CRISPR-Cas9 Screens Reveal Loss of Redundancy between PKMYT1 and WEE1 in Glioblastoma Stem-like Cells”, Cell Reports, 13(11), 2425-2439. Visconti et al., 2017, “Fighting tubulin-targeting anticancer drug toxicity and resistance”, Endocrine- Related Cancer, 24(9), T107-T117. Wang et al., 2020, “PKMYT1 is associated with prostate cancer malignancy and may serve as a therapeutic target”, Gene, 744, 144608. Xuan et al., 2020, “PKMYT1 aggravates the progression of ovarian cancer by targeting SIRT3”, European review for medical and pharmacological sciences, 24(10), 5259-5266. Yost et al., 2021, “Methods and compositions for treating cancer”, PCT Int. Appl. (2021), WO 2021202780. Zhang et al., 2019, “Overexpressed PKMYT1 promotes tumor progression and associates with poor survival in esophageal squamous cell carcinoma”, Cancer Management and Research, 11, 7813-7824. Zhang et al., 2020, “PKMYT1 promotes gastric cancer cell proliferation and apoptosis resistance”, OncoTargets and Therapy, 13, 7747-7757. Zhang et al., 2022, “KDM2B mediates the Wnt/β-catenin pathway through transcriptional activation of PKMYT1 via microRNA-let-7b-5p/EZH2 to affect the development of non-small cell lung cancer”, Experimental Cell Research, 417(2), 113208. Statements Statement 1. A compound of the following formula:
Figure imgf000314_0001
or a pharmaceutically acceptable salt or solvate thereof; wherein: Ring A is selected from:
Figure imgf000314_0002
and
Figure imgf000315_0001
wherein: Z1 is N, CH, or CRZ1; Z2 is CH, CRZ2, or N; Z3 is CH2, CHRZ3C1, CRZ3C22, NH, NRZ3N, O, or S; Z4 is CH2 or CHRZ4; Z5 is CH2 or CHRZ5; Z6 is N, CH, or CRZ6; Z7 is N, CH, or CRZ7; Z8 is N, CH, or CRZ8; Z9 is N, CH, or CRZ9; either: Z10 is CH2, CHRZ10C1, CRZ10C22, NH, NRZ10N, O, or S; and Z11 is CH2, CHRZ11C1, or CRZ11C22; or: Z10 is CH2, CHRZ10C1, or CRZ10C2 2; and Z11 is NH, NRZ11N, O, or S; Z12 is CH2 or CHRZ12; Z13 is CH2 or CHRZ13; Z14 is CH2, CHRZ14C1, CRZ14C2 2, NH, NRZ14N, O, or S; wherein: each -RZ1, -RZ2, -RZ5, -RZ6, -RZ7, -RZ8, -RZ9, and -RZ13 is independently -F, -Cl, -Br, -I, -RZZ, -CF3, -OH, -ORZZ, -OCF3, -NH2, -NHRZZ, or -NRZZ 2; each -RZ4 and -RZ12 is independently -RZZ or -CF3; each -RZ3C1, -RZ10C1, -RZ11C1, and -RZ14C1 is independently -F, -RZZ, -CF3, -OH, -ORZZ, -OCF3, -NH2, -NHRZZ, or -NRZZ2; each -RZ3C2, -RZ10C2, -RZ11C2, and -RZ14C2 is independently -F, or -RZZ; each -RZZ is independently linear or branched saturated C1-4alkyl; and wherein: each -RZ3N, -RZ10N, -RZ11N, and -RZ14N is independently -RZZN, -C(=O)RZZN, -C(=O)ORZZN, -C(=O)NH2, -C(=O)NHRZZN, -C(=O)NRZZN 2, or -S(=O)2RZZN; each -RZZN is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, C3-7heterocyclyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl is optionally substituted with -OH or -OCH3, and each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2; and wherein: -RA2 is -RA222, -F, -Cl, -Br, -I, -CF3, -CHF2, -OH, -ORA222, -OCF3, -NH2, -NHRA222, -NRA222 2, -CN, -CH2OH, -C(=O)RA222, -C(=O)OH, -C(=O)ORA222, -C(=O)NH2, -C(=O)NHRA222, -C(=O)NRA2222, or -S(=O)2RA222; each -RA222 is independently linear or branched saturated C1-4alkyl; -RA3 is -H or -RA33; -RA33 is -RA333, -F, -Cl, -Br, -I, -CF3, -OH, -ORA333, or -OCF3; each -RA333 is independently linear or branched saturated C1-4alkyl; -RA4 is -H or -RA44; -RA44 is -RA444, -F, -Cl, -Br, -I, -CF3, -OH, -ORA444, or -OCF3; each -RA444 is independently linear or branched saturated C1-4alkyl; and: Ring B is selected from:
Figure imgf000316_0001
wherein: Y1 is S, O, NH, NRY1; Y2 is CH, CRY2, or N; Y3 is N, CH, or CRY3; Y4 is N, CH, or CRY4; Y5 is S, O, NH, NRY5; Y6 is N, CH, or CRY6; Y7 is N, CH, or CRY7; Y8 is N, CH, or CRY8; Y9 is S, O, NH, NRY9; wherein: each -RY2, -RY3, -RY4, -RY6, -RY7, and -RY8 is independently -H, -F, -Cl, -Br, -I, -RYY, -CF3, -OH, -ORYY, -OCF3, -NH2, -NHRYY, or -NRYY 2; each -RYY is independently linear or branched saturated C1-4alkyl; and wherein: each -RY1, -RY5, and -RY9 is independently -RYYN, -C(=O)RYYN, -C(=O)ORYYN, -C(=O)NH2, -C(=O)NHRYYN, -C(=O)NRYYN 2, or -S(=O)2RYYN; each -RYYN is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl is optionally substituted with -OH or -OCH3, and each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2; and wherein: -Q is -Q1, -LQ1-Q1, -Q2, -LQ2-Q2, -Q3, -LQ3-Q3, -Q4, -LQ4-Q4, -Q5 , or -H; wherein: Q1 is C5-10heteroaryl; and is: optionally substituted on carbon with one or more groups -RQ1C; and optionally substituted on secondary nitrogen, if present, with one or more groups -RQ1N; -LQ1- is linear or branched saturated C1-4alkylene; Q2 is non-aromatic C3-7heterocyclyl; and is: optionally substituted on sulfur, if present, with one or two groups =O; optionally substituted on carbon with one or more groups -RQ2C; and optionally substituted on secondary nitrogen, if present, with one or more groups -RQ2N; -LQ2- is linear or branched saturated C1-4alkylene; Q3 is phenyl or naphthyl; and is optionally substituted with one or more groups -RQ3C; -LQ3- is linear or branched saturated C1-4alkylene; Q4 is C3-7cycloalkyl; and is optionally substituted with one or more groups -RQ4C; -LQ4- is linear or branched saturated C1-4alkylene; Q5 is linear or branched saturated C1-6alkyl; and is optionally substituted with one or more groups -RQ5C; and wherein: each -RQ1C is independently: -F, -Cl, -Br, -I, -RQ1CC, -RQ1CX, -ORQ1CX, -OH, -ORQ1CC, -LQ1C-OH, -LQ1C-ORQ1CC, -NH2, -NHRQ1CC, -NRQ1CC 2, -RQ1CM, -LQ1C-NH2, -LQ1C-NHRQ1CC, -LQ1C-NRQ1CC 2, -LQ1C-RQ1CM, -NHC(=O)RQ1CC, -NHC(=O)ORQ1CC, -LQ1C-NHC(=O)RQ1CC, -LQ1C-NHC(=O)ORQ1CC, -C(=O)NH2, -C(=O)NHRQ1CC, -C(=O)NRQ1CC 2, -C(=O)RQ1CM, -LQ1C-C(=O)NH2, -LQ1C-C(=O)NHRQ1CC, -LQ1C-C(=O)NRQ1CC 2, -LQ1C-C(=O)RQ1CM, -C(=O)OH, -C(=O)ORQ1CC, -OC(=O)RQ1CC, -OC(=O)NH2, -OC(=O)NHRQ1CC, -OC(=O)NRQ1CC 2, -OC(=O)RQ1CM, -S(=O)2RQ1CC, -S(=O)2NH2, -S(=O)2NHRQ1CC, -S(=O)2NRQ1CC2, -S(=O)2NRQ1CM, -CN, or -NO2; and two adjacent -RQ1C, if present, taken together may form -(CH2)n1-O-(CH2)m1- or -O-(CH2)p1-O-, wherein: n1 is 0, 1, 2, or 3; m1 is 0, 1, 2, or 3; and p1 is 1 or 2; with the proviso that m1+n1 is 2 or 3; wherein: each -RQ1CC is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, C3-7heterocyclyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl is optionally substituted with -OH or -OCH3, and each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2; each -RQ1CX is independently linear or branched saturated C1-4haloalkyl; each -LQ1C- is independently linear or branched saturated C1-4alkylene; each -RQ1CM is independently non-aromatic C3-11heterocyclyl having at least one N ring atom, and is attached via that N ring atom; and is: optionally substituted on carbon with one or more groups -RQ1CMM; optionally substituted on sulfur, if present, with one or two =O groups; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ1CMM, -C(=O)RQ1CMM, -C(=O)ORQ1CMM, -C(=O)NH2, -C(=O)NHRQ1CMM, -C(=O)NRQ1CMM2, and -S(=O)2RQ1CMM; and each -RQ1CMM is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl is optionally substituted with -OH or -OCH3, and each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2; and wherein: each -RQ1N is independently: -RQ1NC, -RQ1NX, -RQ1Nhet, -LQ1N-RQ1Nhet, -LQ1N-OH, -LQ1N-ORQ1NC, -LQ1N-C(=O)RQ1NC, -LQ1N-C(=O)OH, -LQ1N-C(=O)ORQ1NC, -LQ1N-C(=O)NH2, -LQ1N-C(=O)NHRQ1NK, -LQ1N-C(=O)NRQ1NC 2, -LQ1N-C(=O)RQ1NP, -LQ1N-NH2, -LQ1N-NHRQ1NC, -LQ1N-NRQ1NC 2, -LQ1N-RQ1NM, or -LQ1N-NHC(=O)ORQ1NC; wherein: each -RQ1NC is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2; each -RQ1NX is independently linear or branched saturated C1-4haloalkyl; each -LQ1N- is independently linear or branched saturated C1-4alkylene; each -RQ1NM is independently non-aromatic C3-7heterocyclyl having at least one N ring atom, and is attached via that N ring atom; and is: optionally substituted on carbon with one or more groups -RQ1CMM; optionally substituted on sulfur, if present, with one or two =O groups; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ1NMM, -C(=O)RQ1NMM, -C(=O)ORQ1NMM, -C(=O)NH2, -C(=O)NHRQ1NMM, -C(=O)NRQ1NMM2, and -S(=O)2RQ1NMM; and each -RQ1NMM is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl is optionally substituted with -OH or -OCH3, and each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2; and wherein: each -RQ1Nhet is independently non-aromatic C3-7heterocyclyl; and is: optionally substituted on sulfur, if present, with one or two groups =O; optionally substituted on carbon with one or more groups -RQ1NHH or =O; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ1NHH, -C(=O)RQ1NJJ, -C(=O)ORQ1NHH, -C(=O)NH2, -C(=O)NHRQ1NHH, -C(=O)NRQ1NHH2, and -S(=O)2RQ1NHH; wherein: each -RQ1NHH is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, C3-7heterocyclyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl is optionally substituted with -OH or -OCH3, and each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2; and wherein: -RQ1NJJ is -RJ1, -RJ2, -LJ-RJ2, -RJ3, -LJ-RJ3, -RJ4, -LJ-RJ4, -RJ5, or -LJ-RJ5; -RJ1 is linear or branched saturated C1-6alkyl; and is optionally substituted with one or more groups selected from: -F, -OH, -ORJJ, -O-phenyl, -C(=O)OH, -C(=O)ORJJ, -NH2, -NHRJJ, and -NRJJ2; each -RJ2 is independently C3-6cycloalkyl; and is optionally substituted with one or more groups selected from: -F, -RJJ, -CF3, -OH, -ORJJ, -NH2, -NHRJJ, and -NRJJ 2; each -RJ3 is independently non-aromatic C3-7heterocyclyl; and is: optionally substituted on sulfur, if present, with one or two groups =O; optionally substituted on carbon with one or more groups selected from -F, -RJJ, -CF3, -OH, -ORJJ, -NH2, -NHRJJ, and -NRJJ2; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RJJ, -C(=O)RJJ, -C(=O)ORJJ, and -S(=O)2RJJ; each -RJ4 is phenyl; and is optionally substituted with one or more groups selected from: -F, -Cl, -RJJ, -CF3, -OH, -ORJJ, -NH2, -NHRJJ, and -NRJJ2; each -RJ5 is independently C5-6heteroaryl; and is: optionally substituted on carbon with one or more groups selected from -F, -RJJ, -CF3, -OH, -ORJJ, -NH2, -NHRJJ, and -NRJJ2; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RJJ, -C(=O) RJJ, -C(=O)ORJJ, and -S(=O)2RJJ; each -LJ- is independently linear or branched saturated C1-4alkylene, and is optionally substituted with one or more -F; each -RJJ is linear or branched saturated C1-4alkyl; and wherein: -RQ1NK is -RK1, -RK2, -LK-RK2, -RK3, -LK-RK3, -RK4, -LK-RK4, -RK5, or -LK-RK5; -RK1 is linear or branched saturated C1-7alkyl; and is optionally substituted with one or more groups selected from: -F, -OH, -ORKK, -OCH2CH2OCH3, -O-phenyl, -C(=O)OH, -C(=O)ORKK, -NH2, -NHRKK, and -NRKK2; each -RK2 is independently C3-6cycloalkyl; and is optionally substituted with one or more groups selected from: -F, -RKK, -CF3, -OH, -ORKK, -NH2, -NHRKK, and -NRKK2; each -RK3 is independently non-aromatic C3-7heterocyclyl; and is: optionally substituted on carbon with one or more groups selected from -F, -RKK, -CF3, -OH, -ORKK, -NH2, -NHRKK, and -NRKK2; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RKK, -C(=O)RKK, -C(=O)ORKK, and -S(=O)2RKK; each -RK4 is phenyl; and is optionally substituted with one or more groups selected from: -F, -Cl, -RKK, -CF3, -OH, -ORKK, -NH2, -NHRKK, and -NRKK 2; each -RK5 is independently C5-6heteroaryl; and is: optionally substituted on carbon with one or more groups selected from -F, -RKK, -CF3, -OH, -ORKK, -NH2, -NHRKK, and -NRKK 2; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RKK, -C(=O)RKK, -C(=O)ORKK, and -S(=O)2RKK; each -LK- is linear or branched saturated C1-4alkylene, and is optionally substituted with one or more -F; each -RKK is linear or branched saturated C1-4alkyl; and wherein: -RQ1NP is non-aromatic C3-11heterocyclyl having at least one N ring atom, and is attached via that N ring atom; and is: optionally substituted on sulfur, if present, with one or two =O groups; optionally substituted on carbon with one or more groups selected from -RQ1NPP, -F, -OH, -ORQ1NPP, and =O; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ1NPP, -RQ1NPPX, -C(=O)RQ1NPP, -C(=O)ORQ1NPP, -C(=O)NH2, -C(=O)NHRQ1NPP, -C(=O)NRQ1NPP2, and -S(=O)2RQ1NPP; each -RQ1NPP is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl is optionally substituted with -OH or -OCH3, and each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2; -RQ1NPPX is linear or branched saturated C1-4haloalkyl; and wherein: each -RQ2C is independently: -F, -RQ2CC, -RQ2CX, -OH, -ORQ2CC, -ORQ2CX, -NH2, -NHRQ2CC, -NRQ2CC2, -RQ2CM, -NHC(=O)RQ2CC, -NHC(=O)ORQ2CC, -C(=O)NH2, -C(=O)NHRQ2CC, -C(=O)NRQ2CC2, -C(=O)RQ2CM, -C(=O)OH, -C(=O)ORQ2CC, -OC(=O)RQ2CC, -OC(=O)NH2, -OC(=O)NHRQ2CC, -OC(=O)NRQ2CC2, -OC(=O)RQ2CM, or =O; wherein: each -RQ2CC is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, phenyl, C3-7heterocyclyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl is optionally substituted with -OH or -OCH3, and each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2; each -RQ2CX is independently linear or branched saturated C1-4haloalkyl; each -RQ2CM is independently non-aromatic C3-11heterocyclyl having at least one N ring atom, and is attached via that N ring atom; and is: optionally substituted on carbon with one or more groups -RQ2CMM; optionally substituted on sulfur, if present, with one or two =O groups; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ2CMM, -C(=O)RQ2CMM, -C(=O)ORQ2CMM, -C(=O)NH2, -C(=O)NHRQ2CMM, -C(=O)NRQ2CMM2, and -S(=O)2RQ2CMM; and each -RQ2CMM is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl is optionally substituted with -OH or -OCH3, and each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2; and wherein: each -RQ2N is independently: -RQ2NC, -C(=O)RQ2NC, -C(=O)-LQ2N-OH, -C(=O)-LQ2N-ORQ2NC, -C(=O)-LQ2N-NH2, -C(=O)-LQ2N-NHRQ2NC, -C(=O)-LQ2N-NRQ2NC2, -C(=O)-LQ2N-RQ2NM, -C(=O)ORQ2NC, -LQ2N-NH2, -LQ2N-NHRQ2NC, -LQ2N-NRQ2NC2, -LQ2N-RQ2NM, -C(=O)NH2, -C(=O)NHRQ2NC, -C(=O)NRQ2NC2, -C(=O)RQ2NM, -LQ2N-C(=O)NH2, -LQ2N-C(=O)NHRQ2NC, -LQ2N-C(=O)NRQ2NC2, -LQ2N-C(=O)RQ2NM, or -S(=O)2RQ2NC; wherein: each -RQ2NC is independently linear or branched saturated C1-6alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-6alkyl is optionally substituted with -OH or -OCH3, and each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2; each -LQ2N- is independently linear or branched saturated C1-4alkylene; each -RQ2NM is independently non-aromatic C3-11heterocyclyl having at least one N ring atom, and is attached via that N ring atom; and is: optionally substituted on carbon with one or more groups -RQ2NMM; optionally substituted on sulfur, if present, with one or two =O groups; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ2NMM, -C(=O)RQ2NMM, -C(=O)ORQ2NMM, -C(=O)NH2, -C(=O)NHRQ2NMM, -C(=O)NRQ2NMM 2, and -S(=O)2RQ2NMM; and each -RQ2NMM is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl is optionally substituted with -OH or -OCH3, and each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2; and wherein: each -RQ3C is independently: -F, -Cl, -Br, -I, -RQ3CC, -RQ3CX, -ORQ3CX, -OH, -ORQ3CC, -LQ3C-OH, -LQ3C-ORQ3CC, -NH2, -NHRQ3CC, -NRQ3CC2, -RQ3CM, -LQ3C-NH2, -LQ3C-NHRQ3CC, -LQ3C-NRQ3CC2, -LQ3C-RQ3CM, -NHC(=O)RQ3CC, -NHC(=O)ORQ3CC, -LQ3C-NHC(=O)RQ3CC, -LQ3C-NHC(=O)ORQ3CC, -C(=O)NH2, -C(=O)NHRQ3CC, -C(=O)NRQ3CC2, -C(=O)RQ3CM, -LQ3C-C(=O)NH2, -LQ3C-C(=O)NHRQ3CC, -LQ3C-C(=O)NRQ3CC2, -LQ3C-C(=O)RQ3CM, -C(=O)OH, -C(=O)ORQ3CC, -OC(=O)RQ3CC, -OC(=O)NH2, -OC(=O)NHRQ3CC, -OC(=O)NRQ3CC2, -OC(=O)RQ3CM, -CN, or -NO2; and two adjacent-RQ3C, if present, taken together may form -(CH2)n3-O-(CH2)m3- or -O-(CH2)p3-O-, wherein: n3 is 0, 1, 2, or 3; m3 is 0, 1, 2, or 3; and p3 is 1 or 2; with the proviso that m3+n3 is 2 or 3; wherein: each -RQ3CC is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, C3-7heterocyclyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl is optionally substituted with -OH or -OCH3, and each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2; each -RQ3CX is independently linear or branched saturated C1-4haloalkyl; each -LQ3C- is independently linear or branched saturated C1-4alkylene; each -RQ3CM is independently non-aromatic C3-11heterocyclyl having at least one N ring atom, and is attached via that N ring atom; and is: optionally substituted on carbon with one or more groups -RQ3CMM; optionally substituted on sulfur, if present, with one or two =O groups; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ3CMM, -C(=O)RQ3CMM, -C(=O)ORQ3CMM, -C(=O)NH2, -C(=O)NHRQ3CMM, -C(=O)NRQ3CMM2, and -S(=O)2RQ3CMM; and each -RQ3CMM is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl is optionally substituted with -OH or -OCH3, and each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2; and wherein: each -RQ4C is independently: -F, -RQ4CC, -RQ4CX, -OH, -ORQ4CC, -ORQ4CX, -NH2, -NHRQ4CC, -NRQ4CC2, -RQ4CM, -NHC(=O)RQ4CC, -NHC(=O)ORQ4CC, -C(=O)NH2, -C(=O)NHRQ4CC, -C(=O)NRQ4CC2, -C(=O)RQ4CM, -C(=O)OH, -C(=O)ORQ4CC, -OC(=O)RQ4CC, -OC(=O)NH2, -OC(=O)NHRQ4CC, -OC(=O)NRQ4CC2, -OC(=O)RQ4CM, or =O; wherein: each -RQ4CC is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, C3-7heterocyclyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl is optionally substituted with -OH or -OCH3, and each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2; each -RQ4CX is independently linear or branched saturated C1-4haloalkyl; each -RQ4CM is independently non-aromatic C3-11heterocyclyl having at least one N ring atom, and is attached via that N ring atom; and is: optionally substituted on carbon with one or more groups -RQ4CMM; optionally substituted on sulfur, if present, with one or two =O groups; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ4CMM, -C(=O)RQ4CMM, -C(=O)ORQ4CMM, -C(=O)NH2, -C(=O)NHRQ4CMM, -C(=O)NRQ4CMM 2, and -S(=O)2RQ4CMM; each -RQ4CMM is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl is optionally substituted with -OH or -OCH3, and each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2; and wherein: each -RQ5C is independently: -F, -OH, -ORQ5CC, -OCF3, -NH2, -NHRQ5CC, -NRQ5CC2, -RQ5CM, -NHC(=O)RQ5CC, -NHC(=O)ORQ5CC, -C(=O)NH2, -C(=O)NHRQ5CC, -C(=O)NRQ5CC2, -C(=O)RQ5CM, -C(=O)OH, -C(=O)ORQ5CC, -OC(=O)RQ5CC, -OC(=O)NH2, -OC(=O)NHRQ5CC, -OC(=O)NRQ5CC2, or -OC(=O)RQ5CM; wherein: each -RQ5CC is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, C3-7heterocyclyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl is optionally substituted with -OH or -OCH3, and each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2; each -RQ5CM is independently non-aromatic C3-11heterocyclyl having at least one N ring atom, and is attached via that N ring atom; and is: optionally substituted on carbon with one or more groups -RQ5CMM; optionally substituted on sulfur, if present, with one or two =O groups; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ5CMM, -C(=O)RQ5CMM, -C(=O)ORQ5CMM, -C(=O)NH2, -C(=O)NHRQ5CMM, -C(=O)NRQ5CMM2, and -S(=O)2RQ5CMM; each -RQ5CMM is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl is optionally substituted with -OH or -OCH3, and each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2. Statement 2. A pharmaceutical composition comprising: a compound according to statement 1, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier or diluent. Statement 3. A method of preparing a pharmaceutical composition comprising the step of: mixing a compound according to statement 1, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier or diluent. Statement 4. A method of inhibiting PKMYT1 kinase, in vitro or in vivo, comprising contacting the kinase with an effective amount of a compound according to statement 1, or a pharmaceutically acceptable salt or solvate thereof. Statement 5. A method of inhibiting PKMYT1 kinase function in a cell, in vitro or in vivo, comprising contacting the cell with an effective amount of a compound according to statement 1, or a pharmaceutically acceptable salt or solvate thereof. Statement 6. A compound according to statement 1, or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body by therapy. Statement 7. A compound according to statement 1, or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of a disorder of the human or animal body that is ameliorated by the inhibition of PKMYT1 kinase. Statement 8. Use of a compound according to statement 1, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of a disorder of the human or animal body that is ameliorated by the inhibition of PKMYT1 kinase. Statement 9. A method of treatment of a disorder of the human or animal body that is ameliorated by the inhibition of PKMYT1 kinase, comprising administering to a subject in need of treatment a therapeutically-effective amount of a compound according to statement 1, or a pharmaceutically acceptable salt or solvate thereof. Statement 10. A compound according to statement 1, or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of a proliferative disorder. Statement 11. Use of a compound according to statement 1, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of a proliferative disorder. Statement 12. A method of treatment of a proliferative disorder of the human or animal body, comprising administering to a subject in need of treatment a therapeutically-effective amount of a compound according to statement 1, or a pharmaceutically acceptable salt or solvate thereof. Statement 13. A compound, salt, or solvate for use according to statement 10, use according to statement 11, or a method according to statement 12, wherein the proliferative disorder is characterised by, or further characterised by: inappropriate activity and/or expression of PKMYT1, CCNE1, FBXW7, or PPP2A or one of its subunits. Statement 14. A compound, salt, or solvate for use according to statement 10, use according to statement 11, or a method according to statement 12, wherein the proliferative disorder is cancer. Statement 15. A compound, salt, or solvate for use according to statement 10, use according to statement 11, or a method according to statement 12, wherein the proliferative disorder is: endometrial cancer, uterine cancer, ovarian cancer, breast cancer, gastric cancer, bladder cancer, pancreatic cancer, mesothelioma, kidney cancer, stomach cancer, esophageal cancer, colorectal cancer, glioblastoma, or lung cancer.

Claims

CLAIMS 1. A compound of the following formula:
Figure imgf000328_0001
or a pharmaceutically acceptable s Aalt or solvate th Bereof; wherein: Ring A is selected from: and
Figure imgf000328_0002
wherein: Z1 is N, CH, or CRZ1; Z2 is CH, CRZ2, or N; Z3 is CH2, CHRZ3C1, CRZ3C22, NH, NRZ3N, O, or S; Z4 is CH2 or CHRZ4; Z5 is CH2 or CHRZ5; Z6 is N, CH, or CRZ6; Z7 is N, CH, or CRZ7; Z8 is N, CH, or CRZ8; Z9 is N, CH, or CRZ9; either: Z10 is CH2, CHRZ10C1, CRZ10C2 2, NH, NRZ10N, O, or S; and Z11 is CH2, CHRZ11C1, or CRZ11C2 2; or: Z10 is CH2, CHRZ10C1, or CRZ10C2 2; and Z11 is NH, NRZ11N, O, or S; Z12 is CH2 or CHRZ12; Z13 is CH2 or CHRZ13; Z14 is CH2, CHRZ14C1, CRZ14C2 2, NH, NRZ14N, O, or S; wherein: each -RZ1, -RZ2, -RZ5, -RZ6, -RZ7, -RZ8, -RZ9, and -RZ13 is independently -F, -Cl, -Br, -I, -RZZ, -CF3, -OH, -ORZZ, -OCF3, -NH2, -NHRZZ, or -NRZZ2; each -RZ4 and -RZ12 is independently -RZZ or -CF3; each -RZ3C1, -RZ10C1, -RZ11C1, and -RZ14C1 is independently -F, -RZZ, -CF3, -OH, -ORZZ, -OCF3, -NH2, -NHRZZ, or -NRZZ2; each -RZ3C2, -RZ10C2, -RZ11C2, and -RZ14C2 is independently -F, or -RZZ; each -RZZ is independently linear or branched saturated C1-4alkyl; and wherein: each -RZ3N, -RZ10N, -RZ11N, and -RZ14N is independently -RZZN, -C(=O)RZZN, -C(=O)ORZZN, -C(=O)NH2, -C(=O)NHRZZN, -C(=O)NRZZN2, or -S(=O)2RZZN; each -RZZN is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, C3-7heterocyclyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl is optionally substituted with -OH or -OCH3, and each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2; and wherein: -RA2 is -RA222, -F, -Cl, -Br, -I, -CF3, -CHF2, -OH, -ORA222, -OCF3, -NH2, -NHRA222, -NRA2222, -CN, -CH2OH, -C(=O)RA222, -C(=O)OH, -C(=O)ORA222, -C(=O)NH2, -C(=O)NHRA222, -C(=O)NRA222 2, or -S(=O)2RA222; each -RA222 is independently linear or branched saturated C1-4alkyl; -RA3 is -H or -RA33; -RA33 is -RA333, -F, -Cl, -Br, -I, -CF3, -OH, -ORA333, or -OCF3; each -RA333 is independently linear or branched saturated C1-4alkyl; -RA4 is -H or -RA44; -RA44 is -RA444, -F, -Cl, -Br, -I, -CF3, -OH, -ORA444, or -OCF3; each -RA444 is independently linear or branched saturated C1-4alkyl; and: Ring B is selected from:
Figure imgf000330_0001
wherein: Y1 is S, O, NH, NRY1; Y2 is CH, CRY2, or N; Y3 is N, CH, or CRY3; Y4 is N, CH, or CRY4; Y5 is S, O, NH, NRY5; Y6 is N, CH, or CRY6; Y7 is N, CH, or CRY7; Y8 is N, CH, or CRY8; Y9 is S, O, NH, NRY9; wherein: each -RY2, -RY3, -RY4, -RY6, -RY7, and -RY8 is independently -H, -F, -Cl, -Br, -I, -RYY, -CF3, -OH, -ORYY, -OCF3, -NH2, -NHRYY, or -NRYY2; each -RYY is independently linear or branched saturated C1-4alkyl; and wherein: each -RY1, -RY5, and -RY9 is independently -RYYN, -C(=O)RYYN, -C(=O)ORYYN, -C(=O)NH2, -C(=O)NHRYYN, -C(=O)NRYYN 2, or -S(=O)2RYYN; each -RYYN is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl is optionally substituted with -OH or -OCH3, and each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2; and wherein: -Q is -Q1, -LQ1-Q1, -Q2, -LQ2-Q2, -Q3, -LQ3-Q3, -Q4, -LQ4-Q4, -Q5, or -H; wherein: Q1 is C5-10heteroaryl; and is: optionally substituted on carbon with one or more groups -RQ1C; and optionally substituted on secondary nitrogen, if present, with one or more groups -RQ1N; -LQ1- is linear or branched saturated C1-4alkylene; Q2 is non-aromatic C3-7heterocyclyl; and is: optionally substituted on sulfur, if present, with one or two groups =O; optionally substituted on carbon with one or more groups -RQ2C; and optionally substituted on secondary nitrogen, if present, with one or more groups -RQ2N; -LQ2- is linear or branched saturated C1-4alkylene; Q3 is phenyl or naphthyl; and is optionally substituted with one or more groups -RQ3C; -LQ3- is linear or branched saturated C1-4alkylene; Q4 is C3-7cycloalkyl; and is optionally substituted with one or more groups -RQ4C; -LQ4- is linear or branched saturated C1-4alkylene; Q5 is linear or branched saturated C1-6alkyl; and is optionally substituted with one or more groups -RQ5C; and wherein: each -RQ1C is independently: -F, -Cl, -Br, -I, -RQ1CC, -RQ1CX, -ORQ1CX, -OH, -ORQ1CC, -LQ1C-OH, -LQ1C-ORQ1CC, -NH2, -NHRQ1CC, -NRQ1CC2, -RQ1CM, -LQ1C-NH2, -LQ1C-NHRQ1CC, -LQ1C-NRQ1CC 2, -LQ1C-RQ1CM, -NHC(=O)RQ1CC, -NHC(=O)ORQ1CC, -LQ1C-NHC(=O)RQ1CC, -LQ1C-NHC(=O)ORQ1CC, -C(=O)NH2, -C(=O)NHRQ1CC, -C(=O)NRQ1CC2, -C(=O)RQ1CM, -LQ1C-C(=O)N(RQ1CC)ORQ1CC, -LQ1C-C(=O)NH2, -LQ1C-C(=O)NHRQ1CC, -LQ1C-C(=O)NRQ1CC2, -LQ1C-C(=O)RQ1CM, -C(=O)OH, -C(=O)ORQ1CC, -LQ1C-C(=O)ORQ1CC, -OC(=O)RQ1CC, -OC(=O)NH2, -OC(=O)NHRQ1CC, -OC(=O)NRQ1CC2, -OC(=O)RQ1CM, -S(=O)2RQ1CC, -S(=O)2NH2, -S(=O)2NHRQ1CC, -S(=O)2NRQ1CC2, -S(=O)2RQ1CM, -CN, or -NO2; and two adjacent -RQ1C, if present, taken together may form -(CH2)n1-O-(CH2)m1- or -O-(CH2)p1-O-, wherein: n1 is 0, 1, 2, or 3; m1 is 0, 1, 2, or 3; and p1 is 1 or 2; with the proviso that m1+n1 is 2 or 3; wherein: each -RQ1CC is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, C3-7heterocyclyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl is optionally substituted with -OH, -N(CH3)2, -C≡N, or -OCH3, and each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -CH2OCH3, -NH2, -NH(CH3), and -N(CH3)2; each -RQ1CX is independently linear or branched saturated C1-4haloalkyl; each -LQ1C- is independently linear or branched saturated C1-4alkylene; each -RQ1CM is independently non-aromatic C3-11heterocyclyl having at least one N ring atom, and is attached via that N ring atom; and is: optionally substituted on carbon with one or more groups -RQ1CMM; optionally substituted on sulfur, if present, with one or two =O groups; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ1CMM, -C(=O)RQ1CMM, -C(=O)ORQ1CMM, -C(=O)NH2, -C(=O)NHRQ1CMM, -C(=O)NRQ1CMM 2, and -S(=O)2RQ1CMM; and each -RQ1CMM is independently linear or branched saturated -F, C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl is optionally substituted with -OH or -OCH3, and each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2; and wherein: each -RQ1N is independently: -RQ1NC, -RQ1NX, -RQ1Nhet, -LQ1N-RQ1Nhet, -LQ1N-OH, -LQ1N-ORQ1NC, -LQ1N-C(=O)RQ1NC, -LQ1N-C(=O)OH, -LQ1N-C(=O)ORQ1NC, -LQ1N-C(=O)N(RQ1NC)ORQ1NC, -LQ1N-C(=O)NH2, -LQ1N-C(=O)NHRQ1NK, -LQ1N-C(=O)NRQ1NC2, -LQ1N-C(=O)RQ1NP, -LQ1N-NH2, -LQ1N-NHRQ1NC, -LQ1N-NRQ1NC2, -LQ1N-RQ1NM, -LQ1N-C≡N, -S(=O)2RQ1NC, -LQ1N-S(=O)2RQ1NC, or -LQ1N-NHC(=O)ORQ1NC; wherein: each -RQ1NC is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, phenyl, phenyl-C1-3alkyl, C3-7heterocyclyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein each C1-4alkyl is optionally substituted by MeS(O)2-,wherein each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2; each -RQ1NX is independently linear or branched saturated C1-4haloalkyl; each -LQ1N- is independently linear or branched saturated C1-4alkylene optionally substituted by -F or -OCH3; each -RQ1NM is independently non-aromatic C3-7heterocyclyl having at least one N ring atom, and is attached via that N ring atom; and is: optionally substituted on carbon with one or more groups -RQ1NMM; optionally substituted on sulfur, if present, with one or two =O groups; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ1NMM, -C(=O)RQ1NMM, -C(=O)ORQ1NMM, -C(=O)NH2, -C(=O)NHRQ1NMM, -C(=O)NRQ1NMM 2, and -S(=O)2RQ1NMM; and each -RQ1NMM is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl is optionally substituted with -OH or -OCH3, and each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2; and wherein: each -RQ1Nhet is independently non-aromatic C3-7heterocyclyl; and is: optionally substituted on sulfur, if present, with one or two groups =O; optionally substituted on carbon with one or more groups -RQ1NHH or =O; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ1NHH, -C(=O)RQ1NJJ, -C(=O)ORQ1NHH, -C(=O)NH2, -C(=O)NHRQ1NHH, -C(=O)NRQ1NHH2, and -S(=O)2RQ1NHH; wherein: each -RQ1NHH is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, C3-7heterocyclyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl is optionally substituted with -OH or -OCH3, and each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2; and wherein: -RQ1NJJ is -RJ1, -RJ2, -LJ-RJ2, -RJ3, -LJ-RJ3, -RJ4, -LJ-RJ4, -RJ5, or -LJ-RJ5; -RJ1 is linear or branched saturated C1-6alkyl; and is optionally substituted with one or more groups selected from: -F, -OH, -ORJJ, -O-phenyl, -C(=O)OH, -C(=O)ORJJ, -NH2, -NHRJJ, and -NRJJ2; each -RJ2 is independently C3-6cycloalkyl; and is optionally substituted with one or more groups selected from: -F, -RJJ, -CF3, -OH, -ORJJ, -NH2, -NHRJJ, and -NRJJ 2; each -RJ3 is independently non-aromatic C3-7heterocyclyl; and is: optionally substituted on sulfur, if present, with one or two groups =O; optionally substituted on carbon with one or more groups selected from -F, -RJJ, -CF3, -OH, -ORJJ, -NH2, -NHRJJ, and -NRJJ 2; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RJJ, -C(=O)RJJ, -C(=O)ORJJ, and -S(=O)2RJJ; each -RJ4 is phenyl; and is optionally substituted with one or more groups selected from: -F, -Cl, -RJJ, -CF3, -OH, -ORJJ, -NH2, -NHRJJ, and -NRJJ 2; each -RJ5 is independently C5-6heteroaryl; and is: optionally substituted on carbon with one or more groups selected from -F, -RJJ, -CF3, -OH, -ORJJ, -NH2, -NHRJJ, and -NRJJ 2; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RJJ, -C(=O) RJJ, -C(=O)ORJJ, and -S(=O)2RJJ; each -LJ- is independently linear or branched saturated C1-4alkylene, and is optionally substituted with one or more -F; each -RJJ is linear or branched saturated C1-4alkyl; and wherein: -RQ1NK is -RK1, -RK2, -LK-RK2, -RK3, -LK-RK3, -RK4, -LK-RK4, -RK5, or -LK-RK5; -RK1 is linear or branched saturated C1-7alkyl; and is optionally substituted with one or more groups selected from: -F, -OH, -ORKK, -OCH2CH2OCH3, -O-phenyl, -C(=O)OH, -C(=O)ORKK, -NH2, -NHRKK, and -NRKK2; each -RK2 is independently C3-6cycloalkyl; and is optionally substituted with one or more groups selected from: -F, -RKK, -CF3, -OH, -ORKK, -NH2, -NHRKK, and -NRKK2; each -RK3 is independently non-aromatic C3-7heterocyclyl; and is: optionally substituted on carbon with one or more groups selected from -F, -RKK, -CF3, -OH, -ORKK, -NH2, -NHRKK, and -NRKK2; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RKK, -C(=O)RKK, -C(=O)ORKK, and -S(=O)2RKK; each -RK4 is phenyl; and is optionally substituted with one or more groups selected from: -F, -Cl, -RKK, -CF3, -OH, -ORKK, -NH2, -NHRKK, and -NRKK2; each -RK5 is independently C5-6heteroaryl; and is: optionally substituted on carbon with one or more groups selected from -F, -RKK, -CF3, -OH, -ORKK, -NH2, -NHRKK, and -NRKK2; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RKK, -C(=O)RKK, -C(=O)ORKK, and -S(=O)2RKK; each -LK- is linear or branched saturated C1-4alkylene, and is optionally substituted with one or more -F; each -RKK is linear or branched saturated C1-4alkyl; and wherein: -RQ1NP is non-aromatic C3-11heterocyclyl having at least one N ring atom, and is attached via that N ring atom; and is: optionally substituted on sulfur, if present, with one or two =O groups; optionally substituted on carbon with one or more groups selected from -RQ1NPP, -F, -OH, -CF3, -ORQ1NPP, -C(O)NH2, and =O; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ1NPP, -RQ1NPPX, -C(=O)RQ1NPP, -C(=O)ORQ1NPP, -C(=O)NH2, -C(=O)NHRQ1NPP, -C(=O)NRQ1NPP2, and -S(=O)2RQ1NPP; each -RQ1NPP is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl is optionally substituted with -OH, -Cl or -OCH3, and each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2; -RQ1NPPX is linear or branched saturated C1-4haloalkyl; and wherein: each -RQ2C is independently: -F, -RQ2CC, -RQ2CX, -OH, -ORQ2CC, -ORQ2CX, -NH2, -NHRQ2CC, -NRQ2CC2, -RQ2CM, -NHC(=O)RQ2CC, -NHC(=O)ORQ2CC, -C(=O)NH2, -C(=O)NHRQ2CC, -C(=O)NRQ2CC2, -C(=O)RQ2CM, -C(=O)OH, -C(=O)ORQ2CC, -OC(=O)RQ2CC, -OC(=O)NH2, -OC(=O)NHRQ2CC, -OC(=O)NRQ2CC2, -OC(=O)RQ2CM, or =O; wherein: each -RQ2CC is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, phenyl, C3-7heterocyclyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl is optionally substituted with -OH or -OCH3, and each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2; each -RQ2CX is independently linear or branched saturated C1-4haloalkyl; each -RQ2CM is independently non-aromatic C3-11heterocyclyl having at least one N ring atom, and is attached via that N ring atom; and is: optionally substituted on carbon with one or more groups -RQ2CMM; optionally substituted on sulfur, if present, with one or two =O groups; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ2CMM, -C(=O)RQ2CMM, -C(=O)ORQ2CMM, -C(=O)NH2, -C(=O)NHRQ2CMM, -C(=O)NRQ2CMM 2, and -S(=O)2RQ2CMM; and each -RQ2CMM is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl is optionally substituted with -OH or -OCH3, and each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2; and wherein: each -RQ2N is independently: -RQ2NC, -C(=O)RQ2NC, -C(=O)-LQ2N-OH, -C(=O)-LQ2N-ORQ2NC, -C(=O)-LQ2N-NH2, -C(=O)-LQ2N-NHRQ2NC, -C(=O)-LQ2N-NRQ2NC2, -C(=O)-LQ2N-RQ2NM, -C(=O)ORQ2NC, -LQ2N-NH2, -LQ2N-NHRQ2NC, -LQ2N-NRQ2NC2, -LQ2N-RQ2NM, -C(=O)NH2, -C(=O)NHRQ2NC, -C(=O)NRQ2NC2, -C(=O)RQ2NM, -LQ2N-C(=O)NH2, -LQ2N-C(=O)NHRQ2NC, -LQ2N-C(=O)NRQ2NC2, -LQ2N-C(=O)RQ2NM, or -S(=O)2RQ2NC; wherein: each -RQ2NC is independently linear or branched saturated C1-6alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-6alkyl is optionally substituted with -OH or -OCH3, and each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2; each -LQ2N- is independently linear or branched saturated C1-4alkylene; each -RQ2NM is independently non-aromatic C3-11heterocyclyl having at least one N ring atom, and is attached via that N ring atom; and is: optionally substituted on carbon with one or more groups -RQ2NMM; optionally substituted on sulfur, if present, with one or two =O groups; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ2NMM, -C(=O)RQ2NMM, -C(=O)ORQ2NMM, -C(=O)NH2, -C(=O)NHRQ2NMM, -C(=O)NRQ2NMM2, and -S(=O)2RQ2NMM; and each -RQ2NMM is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl is optionally substituted with -OH or -OCH3, and each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2; and wherein: each -RQ3C is independently: -F, -Cl, -Br, -I, -RQ3CC, -RQ3CX, -ORQ3CX, -OH, -ORQ3CC, -LQ3C-OH, -LQ3C-ORQ3CC, -NH2, -NHRQ3CC, -NRQ3CC2, -RQ3CM, -LQ3C-NH2, -LQ3C-NHRQ3CC, -LQ3C-NRQ3CC2, -LQ3C-RQ3CM, -NHC(=O)RQ3CC, -NHC(=O)ORQ3CC, -LQ3C-NHC(=O)RQ3CC, -LQ3C-NHC(=O)ORQ3CC, -C(=O)NH2, -C(=O)NHRQ3CC, -C(=O)NRQ3CC2, -C(=O)RQ3CM, -LQ3C-C(=O)NH2, -LQ3C-C(=O)NHRQ3CC, -LQ3C-C(=O)NRQ3CC2, -LQ3C-C(=O)RQ3CM, -C(=O)OH, -C(=O)ORQ3CC, -LQ3C-C(=O)ORQ3CC, -OC(=O)RQ3CC, -OC(=O)NH2, -OC(=O)NHRQ3CC, -OC(=O)NRQ3CC2, -OC(=O)RQ3CM, -S(=O)2RQ3CC, -CN, or -NO2; and two adjacent-RQ3C, if present, taken together may form -(CH2)n3-O-(CH2)m3- or -O-(CH2)p3-O-, wherein: n3 is 0, 1, 2, or 3; m3 is 0, 1, 2, or 3; and p3 is 1 or 2; with the proviso that m3+n3 is 2 or 3; wherein: each -RQ3CC is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, C3-7heterocyclyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl is optionally substituted with -OH or -OCH3, and each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2; each -RQ3CX is independently linear or branched saturated C1-4haloalkyl; each -LQ3C- is independently linear or branched saturated C1-4alkylene; each -RQ3CM is independently non-aromatic C3-11heterocyclyl having at least one N ring atom, and is attached via that N ring atom; and is: optionally substituted on carbon with one or more groups -RQ3CMM; optionally substituted on sulfur, if present, with one or two =O groups; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ3CMM, -C(=O)RQ3CMM, -C(=O)ORQ3CMM, -C(=O)NH2, -C(=O)NHRQ3CMM, -C(=O)NRQ3CMM2, and -S(=O)2RQ3CMM; and each -RQ3CMM is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl is optionally substituted with -OH or -OCH3, and each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2; and wherein: each -RQ4C is independently: -F, -RQ4CC, -RQ4CX, -OH, -ORQ4CC, -ORQ4CX, -NH2, -NHRQ4CC, -NRQ4CC2, -RQ4CM, -NHC(=O)RQ4CC, -NHC(=O)ORQ4CC, -C(=O)NH2, -C(=O)NHRQ4CC, -C(=O)NRQ4CC2, -C(=O)RQ4CM, -C(=O)OH, -C(=O)ORQ4CC, -OC(=O)RQ4CC, -OC(=O)NH2, -OC(=O)NHRQ4CC, -OC(=O)NRQ4CC2, -OC(=O)RQ4CM, or =O; wherein: each -RQ4CC is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, C3-7heterocyclyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl is optionally substituted with -OH or -OCH3, and each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2; each -RQ4CX is independently linear or branched saturated C1-4haloalkyl; each -RQ4CM is independently non-aromatic C3-11heterocyclyl having at least one N ring atom, and is attached via that N ring atom; and is: optionally substituted on carbon with one or more groups -RQ4CMM; optionally substituted on sulfur, if present, with one or two =O groups; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ4CMM, -C(=O)RQ4CMM, -C(=O)ORQ4CMM, -C(=O)NH2, -C(=O)NHRQ4CMM, -C(=O)NRQ4CMM2, and -S(=O)2RQ4CMM; each -RQ4CMM is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl is optionally substituted with -OH or -OCH3, and each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2; and wherein: each -RQ5C is independently: -F, -OH, -ORQ5CC, -OCF3, -NH2, -NHRQ5CC, -NRQ5CC2, -RQ5CM, -NHC(=O)RQ5CC, -NHC(=O)ORQ5CC, -C(=O)NH2, -C(=O)NHRQ5CC, -C(=O)NRQ5CC2, -C(=O)RQ5CM, -C(=O)OH, -C(=O)ORQ5CC, -OC(=O)RQ5CC, -OC(=O)NH2, -OC(=O)NHRQ5CC, -OC(=O)NRQ5CC2, or -OC(=O)RQ5CM; wherein: each -RQ5CC is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, C3-7heterocyclyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl is optionally substituted with -OH or -OCH3, and each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2; each -RQ5CM is independently non-aromatic C3-11heterocyclyl having at least one N ring atom, and is attached via that N ring atom; and is: optionally substituted on carbon with one or more groups -RQ5CMM; optionally substituted on sulfur, if present, with one or two =O groups; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ5CMM, -C(=O)RQ5CMM, -C(=O)ORQ5CMM, -C(=O)NH2, -C(=O)NHRQ5CMM, -C(=O)NRQ5CMM2, and -S(=O)2RQ5CMM; each -RQ5CMM is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-3alkyl, phenyl, phenyl-C1-3alkyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl is optionally substituted with -OH or -OCH3, and each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -Cl, -CH3, -CF3, -OH, -OCH3, -NH2, -NH(CH3), and -N(CH3)2.
2. A compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof; wherein Ring A is selected from:
Figure imgf000341_0001
wherein: Z1 is N; and Z2 is CH, CRZ2, or N; each -RZ2 is independently -Br, or -RZZ; and each -RZZ is independently linear or branched saturated C1-4alkyl.
3. A compound according to any one of the preceeding claims or a pharmaceutically acceptable salt or solvate thereof; wherein: -RA2 is -RA222, -F, -Cl, or -Br; each -RA222 is independently linear or branched saturated C1-4alkyl.
4. A compound according to any one of the preceeding claims or a pharmaceutically acceptable salt or solvate thereof; wherein -RA3 is -H.
5. A compound according to any one of the preceeding claims or a pharmaceutically acceptable salt or solvate thereof; wherein -RA4 is -H.
6. A compound according to any one of the preceeding claims or a pharmaceutically acceptable salt or solvate thereof; wherein Ring B is selected from:
Figure imgf000342_0001
wherein: Y1 is S, or O; Y2 is CH or N; Y3 is N.
7. A compound according to any one of the preceeding claims or a pharmaceutically acceptable salt or solvate thereof; wherein -Q is -Q1. wherein: Q1 is C5-10heteroaryl; and is: optionally substituted on carbon with one or more groups -RQ1C; and optionally substituted on secondary nitrogen, if present, with one or more groups -RQ1N; each -RQ1C is independently: -F, -Cl, -Br, -RQ1CC, -RQ1CX, -OH, -ORQ1CC, -NH2, -NRQ1CC2, -RQ1CM, -C(=O)RQ1CM, -LQ1C-C(=O)N(RQ1CC)ORQ1CC, -LQ1C-C(=O)NHRQ1CC, -LQ1C-C(=O)NRQ1CC2, -LQ1C-C(=O)RQ1CM, -C(=O)OH, -C(=O)ORQ1CC, -LQ1C-C(=O)ORQ1CC, -S(=O)2RQ1CC, or -CN; wherein: each -RQ1CC is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-7heterocyclyl, phenyl, C5-6heteroaryl, or C5-6heteroaryl-C1-3alkyl, wherein C1-4alkyl is optionally substituted with -N(CH3)2, or -C≡N, and each cycloalkyl, phenyl and heteroaryl is optionally substituted with one or more groups selected from: -F, -CH3, or -CH2OCH3; each -RQ1CX is independently linear or branched saturated C1-4haloalkyl; each -LQ1C- is independently linear or branched saturated C1-4alkylene; each -RQ1CM is independently non-aromatic C3-11heterocyclyl having at least one N ring atom, and is attached via that N ring atom; and is: optionally substituted on carbon with one or more groups -RQ1CMM; optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ1CMM; and each -RQ1CMM is independently -F, linear or branched saturated C1-4alkyl; and wherein: each -RQ1N is independently: -RQ1NC, -RQ1NX, -RQ1Nhet, -LQ1N-OH, -LQ1N-ORQ1NC, -LQ1N-C(=O)RQ1NC, -LQ1N-C(=O)OH, -LQ1N-C(=O)N(RQ1NC)ORQ1NC, -LQ1N-C(=O)NH2, -LQ1N-C(=O)NHRQ1NK, -LQ1N-C(=O)NRQ1NC2, -LQ1N-C(=O)RQ1NP, -LQ1N-NRQ1NC2, -LQ1N-RQ1NM, -LQ1N-C≡N, or -S(=O)2RQ1NC, -LQ1N-S(=O)2RQ1NC, wherein: each -RQ1NC is independently linear or branched saturated C1-4alkyl, C3-6cycloalkyl, C3-7heterocyclyl, or C5-6heteroaryl, wherein each C1-4alkyl is optionally substituted by MeS(O)2-, wherein each cycloalkyl, heteroaryl is optionally substituted with one or more groups selected from: -CH3; each -RQ1NX is independently linear or branched saturated C1-4haloalkyl; each -LQ1N- is independently linear or branched saturated C1-4alkylene optionally substituted by -F or -OCH3; each -RQ1NM is independently non-aromatic C3-7heterocyclyl having at least one N ring atom, and is attached via that N ring atom; and is: and wherein: each -RQ1Nhet is independently non-aromatic C3-7heterocyclyl; and is: optionally substituted on carbon with one or more groups =O; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ1NHH, -C(=O)RQ1NJJ, -C(=O)ORQ1NHH, -C(=O)NHRQ1NHH; wherein: each -RQ1NHH is independently linear or branched saturated C1-4alkyl; and wherein: -RQ1NJJ is -RJ1; -RJ1 is linear or branched saturated C1-6alkyl; and wherein: -RQ1NK is -RK1, or -RK3; -RK1 is linear or branched saturated C1-7alkyl; and is optionally substituted with one or more groups selected from: -OH; each -RK3 is independently non-aromatic C3-7heterocyclyl; and is: and wherein: -RQ1NP is non-aromatic C3-11heterocyclyl having at least one N ring atom, and is attached via that N ring atom; and is: optionally substituted on carbon with one or more groups selected from -RQ1NPP, -F, -OH, -CF3, and -C(O)NH2; and optionally substituted on secondary nitrogen, if present, with a group selected from: -RQ1NPP; each -RQ1NPP is independently linear or branched saturated C1-4alkyl or phenyl, wherein C1-4alkyl is optionally substituted with -OH or -OCH3.
8. A compound according to any one of the preceeding claims or a pharmaceutically acceptable salt or solvate thereof; wherein -Q is -Q1. wherein: Q1 is pyrazolyl, pyrazolo[1,5-a]pyridinyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, 1,3,5- triazinyl.
9. A pharmaceutical composition comprising: a compound according any one of the preceeding claims, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier or diluent.
10. A compound according any one of claims 1-8, or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body by therapy.
11. Use of a compound according to any one of claims 1-8, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of a proliferative disorder.
12. A method of treatment of a proliferative disorder of the human or animal body, comprising administering to a subject in need of treatment a therapeutically-effective amount of a compound according to any one of claims 1-8, or a pharmaceutically acceptable salt or solvate thereof.
13. A compound, salt, or solvate for use according to claim 11, or a method according to claim 12, wherein the proliferative disorder is cancer.
14. A compound, salt, or solvate for use according to claim 11, or a method according to claim 12, wherein the proliferative disorder is: endometrial cancer, uterine cancer, ovarian cancer, breast cancer, gastric cancer, bladder cancer, pancreatic cancer, mesothelioma, kidney cancer, stomach cancer, esophageal cancer, colorectal cancer, glioblastoma, or lung cancer.
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