Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D498/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
• • 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
  • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

• the present invention relates to compounds of the general formula (1) as described and defined herein, methods for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds and the use of said compounds and pharmaceutical compositions for the treatment or prevention of diseases, in particular cancer or conditions with dysregulated immune functions, or other conditions associated with aberrant AhR signalling, as a sole agent or in combination with other active ingredients.
• Such compounds may also be of utility in the expansion of hematopoietic stem ceils (HSCs) and the use of HSCs in autologous or allogenic transplantation for the treatment of patients with inherited immunological and autoimmune diseases and diverse hematopoietic disorders, BACKGROUND
• the aryl hydrocarbon receptor is a ligand-activated factor that belongs to the family of the basic helix-loop-helix-Per/ARNT /Sim family. Following ligand binding in the cytoplasm, AhR dissociates from its complex with Hsp9Q and the AhR-interacting protein, XAP2, allowing ligated AhR to translocate to the nucleus. There, AhR dimerizes with the AhR nuclear translocator (ARNT), that then binds to xenobiotic response elements (XREs) promoting the up- or down-regulation of a multitude of target genes in many different tissues.
• ALTT AhR nuclear translocator
• XREs xenobiotic response elements
• AhR is best known for binding to environmental toxins and inducing various members of the cytochrome P450 family including CYR1A1, CYP1A2 and CYP1B1 required for their elimination.
• Activation of AhR by xenobiotics has demonstrated that this receptor plays a role in a range of physiological processes including embryogenesis, tumourigenesis and inflammation (Esser & Rannug, Pharmacol Rev, 2015, 67:259; Roman el: al, Pharmacol Ther, 2018, 185:50).
• AhR AhR is expressed in many immune cell types including dendritic cells, macrophages, T ceils, NK cells and B ceils and plays an important role in immunoregulation (Quintana & Sherr, Pharmacol Rev, 2013, 65:1148; Nguyen el: al., Front Immunol, 2014, 5:551).
• TCDD 2,3,7,8-Tetrachiorodibenzo-p-dioxin
• Physiological effects of AhR agonists on immune cells include promotion of regulatory T ceil (Treg) generation (Pot, Swiss Med Wkly, 2012, 142:wl3592), modulation of Thl7 cell differentiation and activation (Baricza et al., Cell Mol Life Sci, 2016, 73:95) and stimulation of interleukin-22 (IL-22) expression and/or release from human activated peripheral blood mononuclear cells and T ceils (Ramirez et al., Eur J Immunol, 2010, 40:2450; Effner etaL, Sci Rep, 2017, 7:44005).
• AhR also modulates the function of antigen presenting cells, such as dendritic cells and macrophages.
• AhR activation decreases the expression of class II major histocompatibility complex and co-stimuiatory molecules and also the production of Thl and Thl7 polarizing cytokines by dendritic cells (Mezrich et a/., J Immunol, 2010, 185:3190; Nguyen et al., Proc Natl Acad Sci USA, 2010, 107:19961; Quintana et al, 2010 Proc Natl Acad Sci USA, 107:20768). Indeed, AhR activation boosts the ability of DCs to promote the differentiation ofTregs (Jurado-Manzano etaL, 2017, Immunol Lett, 190:84).
• the AhR can also bind metabolic products of tryptophan degradation including kynurenine (KYN) and kynurenic acid (KYNA).
• KYN kynurenine
• KYNA kynurenic acid
• Indoleamine 2,3 dioxygenase 1 and 2 (IDO1/IDO2) and tryptophan 2,3-dioxygenase 2 (TDO2) catalyse the commitment step of the KYN metabolic pathway and are expressed in immune ceils (IDOl) and a range of cancer cells (IDO 1 and TD02)(PiIotte el: al., Proc Nat.
• TDO2 is predominately expressed in the liver but it is also constitutively expressed in some cancers, notably malignant glioma, hepatocellular carcinoma, melanoma, bladder, breast, lung and colorectal cancer (Opitz et al, Nature, 2011, 478:197; Pilotte et al, Proc Nat Acad Sci, 2012, 109:2497; D'Amato etc?/., Cancer Res, 2015, 75(21):4651; Hsu etal, Oncotarget. 2016, 7(19): 27584; Chen et al., Dis Markers, 2016, 2016:8169724).
• cancers notably malignant glioma, hepatocellular carcinoma, melanoma, bladder, breast, lung and colorectal cancer
• AhR antagonists may have broader efficacy than selective IDO-1 inhibitors, as they will attenuate endogenous AhR agonist signalling regardless of its source.
• IL4H Interleukin-4 induced 1
• Ectopic AhR expression in non-mallgnant human mammary epithelial cells Induces an epithelial-to-mesenchymal transition and a > 50% increase in cell growth rates (Brooks & Eltom, Curr Cancer Drug Targets, 2011, 11:654] and AhR knockdown induced gene changes in human breast, cancer cell lines consistent with a mesenchymal to epithelia] ceil reversion to a less aggressive phenotype (Narasimhan et al, lot J Mo] Sci, 2018, 19:1388).
• AliR antagonists or AhR knockdown has been shown to reduce proliferation, survival, invasiveness and migration of human breast cancer cells in culture (Parks et al, Mol Pharmacol, 2014, 86:593; D’Amato et at, Cancer Res, 2015, 75(21]:4651; Narasimhan etal., Int J Mol Sci, 2018, 19:1388) and to reduce survival of glioblastoma cells (Gramatzki et at, Oncogene, 2009, 28:2593; Opitz et al, Nature, 2011, 478:197; Guastella et al, ] Neuro-oncol, 2018, in press).
• AhR antagonists block the formation of turoourspheres (Stanford et: al, Mol Cancer Res, 2016, 14:696) which are formed by cancer stem ceils (CSCs), a subset of tumour cells that drive the initiation, progression and metastasis of tumours.
• CSCs cancer stem ceils
• AhR agonists reieased from immune ceils and from tumour ceils act in an autocrine and paracrine fashion to promote tumour growth
• Agents that reduce or block these effects may therefore find utility in the treatment of cancer and/or conditions with dysreguiated immune functions.
• agents may also have utility in a range of other diseases/conditions including but not limited to, obesity (Rojas st aL, Int J Obesity, 2020, 44:948) and various viral infections (Giovannoni et aL, NatNeurosci. 2020, 23:939; Giovannoni at aL. Res Sq. 2020, rs.3.rs-25639).
• WO2017/202816 relates to compounds and compositions for the treatment or prophylaxis of cancer or conditions with dysreguiated immune responses or other disorders associated with aberrant AhR signalling.
• WO2017/202816 W02018/146010 and W02019/101642 relate inter alia to heterocyclic compounds capable of inhibiting AhR function.
• WG2020/081840 relates to aryl hydrocarbon receptor antagonists, such as substituted imidazopyridines and imidazopyrazines, as well as methods of expanding hematopoietic stem cells by culturing hematopoietic stem or progenitor cells in the presence of these agents.
• W02020/039093 relates to compositions and methods for using tetrahydropyridopyrimidine derivatives as AhR modulators.
• WO2018/153893 relates to 6-amicic-lH-indoi-2-yi compounds which can act as aryl hydrocarbon receptor (AhR) modulators and, in particular, as AhR antagonists.
• the invention further relates to the use of the compounds for the treatment and/or prophylaxis of diseases and/or conditions through binding of said aryl hydrocarbon receptor by said compounds.
• W02020/021024 relates to bicyclic compounds which can act as aryl hydrocarbon receptor (AhR) modulators and, in particular, as AhR antagonists.
• the invention further relates to die use of the compounds for the treatment and/or prophylaxis of diseases and/or conditions through binding of said aryl hydrocarbon receptor by said compounds.
• W02020/043880 relates to heterocyclic compounds which are ARH inhibitors, for prevention of diseases, in particular cancer or conditions with dysreguiated immune functions, or other conditions associated with aberrant AHR signalling, as a sole agent of in combination with other active ingredients.
• WO 2020/018848 relates to methods for expanding stem cells and/or lineage committed progenitor cells, such as hematopoietic stems cells and/or lineage committed progenitor cells, at least in part, by using compounds that antagonize AhR.
• W02020/050409 relates to novel heterocyclic compound having an aryl hydrocarbon receptor antagonist activity and useful for the promotion of platelet production
• WO 2019/236766 relates to methods for expanding stem cells and/or lineage committed progenitor cells, at. least, in part, by using lactam compounds that antagonize AhR.
• WO2019/018562 relates to compositions and methods of using heteroaryl amides as AhR modulator compounds, for the treatment of diseases modulated, as least hi part, by AhR.
• WO 2018/195397 relates to compositions and methods for indole AhR inhibitors.
• WO 2018/146010 relates to the preparation of 2'-heteroaryl-3-oxo-2,3“ dihydropyi'idazine-4-carboxamides for the treatment or prophylaxis of diseases, in particular cancer or conditions with dysreguiated immune responses, as a sole agent or in combination with other active ingredients.
• WO2010/059401 relates to compounds and compositions for expanding the number of CD34+ cells for transplantation.
• WO 2010/059401 relates inter alia to heterocyclic compounds capable of down regulating the activity and/or expression of AhR W02012/015914 relates to compositions and methods for modulating AhR activity.
• WO2012/015914 relates inter alia to heterocyclic compounds that modulate AhR activity for use in therapeutic compositions to inhibit cancer ceil proliferation and tumour ceil invasion and metastasis.
• W02020/051207 relates to AhR antagonists as well as methods of modulating AhR activity and expanding hematopoietic stem cells by culturing hematopoietic stem or progenitor cells in the presence of these agents.
• this disclosure provides methods of treating various pathologies, such as cancer, by administration of these AhR antagonists.
• US2018/327411 Al relates to compounds and compositions useful as inhibitors of AhR to treat a variety of diseases, disorders and conditions associated with AhR.
• US2019/389857 Al relates to compounds which can act as AhR modulators, and in particular, as AhR antagonists.
• W02020/039093 discloses certain AhR modulators,
• the presently disclosed compounds have one or more beneficial properties that render them particularly suitable for use as pharmaceuticals, for example high potency (for example a U937 and/or a IL-22 assay), adequate bioavailability, low cardiotoxicity (for example in a hERG assay), adequate cell permeability (for example in a Caco-2 assay), good solubility (for example kinetic solubility), a chromhogD value less than 5, and/or improved metabolic stability (such as improved CYP3A4 metabolism).
• a potency assay is, for example described below.
• the present inventors have generated lots of different templates and structure activity relationship data and it is not easy to design compounds with the level of activity and properties of those described herein.
• Y is phenyl or a 3 to 6 membered ring (such as a 5 or 6 membered ring) optionally comprising 1, 2, or 3 heteroatoms selected from N, 0 and S, said phenyl or ring substituted with R 5 and R 6 :
• R 1 is H, C1-3 alkyl, (-CH 2 )pCN, -COC1.3 alkyl, -CO(CH 2 )qNR 7 R 8 , -SO 2 Ci- 3 alkyl, -SO 2 NR 7 R 8 ,
• R 2 is H or Ci.?, alkyl, C3-5 cydoalkyl halogen and C1-3 alkyl optionally bearing one or more groups independently selected from OR Y , halogen -NR 7 R 8 , such as OR Y and halogen (e.g. F) in particular only one group;
• R 2 ’ is H, Ci-3 aikyl or halogen;
• R 3 is H or Ci-:; alkyl;
• R 4 is a 9 to 13 membered heterocycle with at least one heteroatom selected from N, 0 and S (for example an aromatic or partially saturated), with substituents R 9 , R 9 ' and R ! 0 ;
• R 5 is H, oxo, hydroxy, halogen (such as F, Cl], CN, CM alkyl, C3-5 cycloalkyl, -OC1-3 alkyl (such as -OCH3), -(0)o-iCi-3 alkyl bearing 1 to 6 halogen groups (such as CF3 or OCHF2), C1.3 alkyi bearing one or more 0R y groups, ⁇ C(O)C i.3 alkyiNR 7 R s , -SCRCi-s alkyi, -S0 2 NR 7 R S , or NR 7 R S (such as NH 2 )
• R 6 is H, oxo, hydroxy, halogen (such as F, Cl), CN, C1-3 alkyl, -C(O)C:i. 3 alkyiNR 7 R 0 , ⁇ S0 2 C-, 3 alkyl, or -S0 2 NR it;
• R 7 is H or C1.3 alkyl, or -C(0)0R Y , for example H or C1.3 alkyl, such as -CH 3 ;
• R 8 is H or C 3-3 alkyl, such as -CH3;
• R 5 is H, hydroxy, halogen (such as F, Cl), CN, Ci. 3 alkyl, Ci. 3 alkoxy (such as OMe), C i- 3 alkyl bearing 1 to 6 halogen groups (such as CF 3 ), C1.3 alkyl bearing one or more 0R y groups, -C3.5cycloaJkyl, -(CH 2 )qOC!. 3 aJkyl substituted with 1 to 6 halogen groups (such as - -C1.3 alky] OCF 3 ), -CO C1.3 alkylNR 7 R 8 , -SO2C1.3 alkyl, or -S0 2 NR 7 R 8 ;
• R 9 ’ is H, OH, halogen (such as F, Cl), CN, C1.3 alkyl, C1.3 alkoxy [such as OMe), C1.3 aikyl bearing 1 to 6 halo groups (such as CF3), C1.3 aikyl bearing one or more OH groups, -CO(CH 2 )q NR 7 R 8 , -SO 2 C V3 alkyl, or -SO2 NR"R 8 ;
• R 10 is H, hydroxy, halogen (such as F, Cl), CN, C1.3 aikyl, ⁇ C(0)Ci..3 aikyl NR 7 R 8 ;
• R 11 is H, Ci -?,aikyl (such as -CH3) or Cj-ehydroxyalkyl (such as -CH2CH2OH);
• R Y is I-I or C1.4 alkyl for example H or Chalky! (such as H, -CH3 or -CH2CH3);
• X is CH 2 , S, -S0 2 , NR 44 or 0:
• Z' is a 5 or 6 membered heteroaryl with at least one heteroatom selected from N, 0 and S, for example 1 or 2 nitrogens, wherein said heteroaryl optionally bears one, two or three substituents selected from hydroxy, halogen (such as F, Cl), CN, C1.3 alkyi;
• Z is a 3 to 6 membered ring optionally comprising 1, 2, or 3 heteroatoms selected from N, 0 and S (for example 1 or 2 nitrogens) bearing R 5 and R 6 (for example is a 5 or 6 membered cycloalkyl or heterocycle comprising at least heteroatom selected from N, 0 and S optionally bears one, two or three substituents selected from hydroxy, halogen (such as F, Cl), CN, C:-?, aikyl (such as bearing no substituents)), n is 0 or 1 (such as 0); n’ is O or l: m is 0, 1, 2 or 3 p is an integer 1, 2 or 3 (such as 1); p' is an integer 2 or 3 (such as 2); q is 0, 1, 2 or 3 (such as 0 or 1), or a pharmaceutically acceptable salt thereof.
• R 5 and R 6 for example is a 5 or 6 membered cycloalkyl or heterocycle comprising at least heteroatom selected from N, 0 and
• a compound of formula (I) according to paragraph 1 wherein Y is a 3 to 6 membered ring optionally comprising 1, 2, or 3 heteroatoms selected from N, 0 and S, each substituted with R s and R 6 , for example a 5 to 6 membered ring comprising 1, 2, or 3 heteroatoms selected from N, 0 and S, each substituted with R 3 and R 6 .
• a compound of formula (I) according to paragraph 1 or 2 wherein Y is a 5 or 6 membered nitrogen containing ring.
• a compound of formula (I) according to paragraph 3 or 4 wherein the ring is independently selected from pyrimidine, pyridine, triazole and thiazole, in particular pyrimidine and or pyridine.
• a compound according to paragraph 1 of formula (U) wherein X, R 1 , R 2 , R 3 , R 4 and rn are defined above for compounds of formula (Il or a pharmaceutically acceptable salt thereof.
• R 1 is selected from methyl, ethyl, propyl and isopropyl, in particular isopropyl.
• R 2 is independently selected from H, methyl, -CH2OCH3, -CH2OH, CF3, -CH2N(CH?)2, such as H or methyl.
• R 4 is a 9 or 13 membered partially saturated or aromatic heterocycle (for example a 9 to 13 membered heteroaryi] for example selected from indole, tetrahydrobenzoindole, tetrahydrocarbazoie and tetrahydropyridoindole.
• R 4 is a 9 membered heterocycle, for example a heteroaromatic, such as tryptophan.
• R 4 is a 13 membered heterocycle, for example a partially saturated heterocycle, such as tetrahydrocarbazoie. 17.
• R 5 is independently selected from the group comprising oxo, methyl, ethyl, -CF3, -OCF3, -OCH3 and halogen, such as halogen, for example fluoro.
• R s is independently selected from methyl, ethyl, -OCH3, and H, such as H.
• R 9 is independently selected from R 9 is H, methyl, OCF3 and - Cs-scycloalkyl, such as H, methyl, or
• ⁇ Cs-scycloalkyl alternatively H, methyl or OCF3.
• R 9 ' is independently selected from H, F and methyl, such as H or F.
• R ;o is Independently selected from H, F and methyl such as H or F, in particular H.
• a pharmaceutical composition comprising a compound according to any one of paragraphs 1 to 35, and a pharmaceutically acceptable excipient, diluent or carrier.
• a compound according to any one of paragraphs 1 to 35 or a composition according to paragraph 36 for use in treatment, in particular the treatment of cancer.
• a method of treatment comprising administering a therapeutically effective amount of a compound according to any one of paragraphs 1 to 35 or a composition according to paragraph 36 to a patient in need thereof, for example for the treatment of cancer.
• checkpoint inhibitors for example selected from the group comprising: PD-1 inhibitor, PD-L1 inhibitor, PD-L2 inhibitor, CTLA-4 inhibitor, checkpoint kinase inhibitor 1 (CHEK1/CHK1), checkpoint kinase inhibitor 2 [CHEK2/ CHK2), Ataxia telangie
• a method according to paragraph 39 farther comprising administering one or more checkpoint inhibitors, for example selected from the group comprising: PD-1 inhibitor, PD- L1 inhibitor, PD-L2 inhibitor, CTLA-4 inhibitor, checkpoint kinase inhibitor 1 (CHEK1/CHK1), checkpoint kinase inhibitor 2 (CHEK2/ CHK2), Ataxia telangiectasia and Rad3 related (ATR) inhibitor, ataxia -telangiectasia mutated (ATM) inhibitor, Weel dual specificity protein kinase (Weel) inhibitor, Poly ADR Ribose polymerase (PAPP) inhibitor and Mytl inhibitor.
• one or more checkpoint inhibitors for example selected from the group comprising: PD-1 inhibitor, PD- L1 inhibitor, PD-L2 inhibitor, CTLA-4 inhibitor, checkpoint kinase inhibitor 1 (CHEK1/CHK1), checkpoint kinase inhibitor 2 (CHEK2/ CHK2), Ataxia telangiectasia and
• a combination therapy comprising a compound according to any one of paragraphs 1 to 35 or a composition according to paragraph 36, and one or more checkpoint inhibitors, for example selected from the group comprising: PD-1 inhibitor, PD-L1 inhibitor, PD-L2 inhibitor, CTLA-4 inhibitor, checkpoint kinase inhibitor 1 (CHEK1/CHK1), checkpoint kinase inhibitor 2 (CHEK2/ CHK2 J, Ataxia telangiectasia and Rad3 related (ATR) inhibitor, ataxia-telangiectasia mutated (ATM) inhibitor, Weel dual specificity protein kinase (Weel) inhibitor, Poly ADP Ribose polymerase (PARP) inhibitor and Mytl inhibitor.
• a method of preparing a compound according to any one of paragraphs 1 to 35 comprising the following steps:
• R2, R4 ; R7 and Y are as defined in paragraph 1. and B is boron.
• a method of preparing a compound according to any one of paragraphs 1 to 35 comprising the following steps: wherein R 1 . R2, R3, R4, R5, R7 and Y are as defined in paragraph 1, and B is boron.
• a method of preparing a compound according to any one of paragraphs 1 to 35 comprising the following steps:
• Rl, R2, R3. R4, R5 ; R7and ⁇ are as defined in paragraph 1, and B is boron.
• a method of preparing a compound according to any one of paragraphs 1 to 35.. comprising the following steps:
• Rl, R2, R3, R4, R5, R6 and Y are as defined in paragraph 1, and B is boron.
• a method of preparing a compound according to any one of paragraphs 1 to 35 comprising the following steps:
• a method of preparing a compound according to any one of paragraphs 1 to 35 comprising the following steps: wherein R1 , R2, R3, R4, R5, R7 and Y are as defined in paragraph 1, and B is boron.
• a method of preparing a compound according to any one of paragraphs 1 to 35 comprising the following steps: wherein R i , R2, i'3. R4, R5, R6 and Y are as defined in paragraph i ; and B is boron.
• R J is C(O)OR y .
• R Y is H. in one embodiment R Y is C : alkyl, such as CH;?, in one embodiment R 2 is not H. In one embodiment R 2 ' is not H In one embodiment k- is not H. In one embodiment R 2 and R 2 ' are not H. In one embodiment R 2 and R 3 are not H. In one embodiment R 2 ' and R 3 are not. H. In one embodiment when m is 1 and n is 1 or 2, and Y is pyridine one or both of R 5 and R 6 are not H. in one embodiment when Y is pyridine one or both of R 5 and R 6 are not H.
• R 4 is a 9 membered heterocycle, for example a 9 membered heterocycle with a N, in one embodiment R 4 is indole, in one embodiment k- is not. H. in one embodiment P. is hydroxy. In one embodiment R 5 is oxo. in one embodiment R 5 is OCHF?. In one embodiment R 5 is - OCi 3 alkyl (such as -OCHs). in one embodiment h is not H. In one embodiment R 9 is H. In one embodiment R 9 is not H, In one embodiment R 9 ' is not H.
• R 10 is not H.
• R 11 is Cz ⁇ hydroxyalkyi (such as - CH2CH2OH).
• X is 0.
• n is 0.
• m is 1.
• compounds of the disclosure have an activity' of lOnM or less (e.g. 5nM or less) in a U937 assay, such as 9, 8, 7, 6, 5, 4, 3, 2 or InM, in particular InM,
• compounds of the disclosure have an activity of 2 OnM or less (e.g, l OnM or less] in an IL-22 assay, such as 9, 8, 7, 6, 5, 4, 3, 2nM, in particular 2nM.
• the compounds of the disclosure have a ratio of above 6.6/1.7 in Caco- 2 /efflux assay.
• this high potency based on the core allows the molecule to be optimised for other properties to fall within the candidate drug target profile, thereby balancing ail of the properties to ensure the molecule is “drug like”.
• the compounds of the present invention effectively inhibit AhR.
• Said compounds are useful for the treatmentor prophylaxis of conditions where exogenous and endogenous AhR ligands induce dysregulated immune responses, for example: uncontrolled cell growth, proliferation and/or survival of tumour cells, immunosuppression. This dysregulation may be observed in the context of cancer, inappropriate cellular immune responses, and inappropriate cellular inflammatory responses.
• the compounds of the present disclosure are useful in the treatment of cancer for example, liquid and/or solid tumours, and/or metastases thereof.
• cancers include head and neck cancer (such as brain tumours and brain metastases], cancer of the thorax including nomsmaii cell and small cell lung cancer, gastrointestinal cancer (including stomach, oesophageal, colon, and colorectal], biliary tract cancer, pancreatic cancer, liver cancer, endocrine cancer, breast cancer, ovarian cancer, bladder cancer, kidney cancer, prostate cancer, bone cancer and skin cancer.
• the cancer is an epithelial cancer. In one embodiment the cancer is a sarcoma. In one embodiment the cancer is metastatic.
• Y is independently selected from pyridine, pyrimidine, thiazole, triazole and pyridone.
• R 5 is independently oxo.
• substituents employed in molecules of the present disclosure will be suitable for use in therapeutic molecules.
• Reactive molecules such as epoxides etc will usually one be employed in intermediates.
• C’i 3 alky! as employed herein refers to straight or branched chain alkyl, for example methyl, ethyl, propyl or isopropyl. Where the alkyl is optionally substituted as defined herein will generally provide a straight or branched chain alkylene.
• Ci x alkylene refers to strait or branched chain alkyl of 1 to X carbons in length bearing terminal substituent, such as an alcohol, for example -CHsCHaCHz-substituent is a C?, straight chain alkylene.
• a branch may terminate in an alkyl group to the satisfy the valency of the atoms, for example -CHzCHfCHsJ-substituent is a C 3 branched chain alkylene.
• Ci-3 alkoxy refers to a branched or straight chain alkyl chain with an oxygen atom located in the chain, for example so the oxygen connects the alkoxy group to the remainder of the molecule (such as -OCHs) or a carbon links the alkoxy group to the rest of the molecule and the oxygen is located internally within the alkoxy chain (such as -CH2OCH3).
• Halogen as employed herein includes fluoro, chloro, bromo or iodo.
• alkyl bearing up to 6 halogen groups examples include -CH2F, -CH2CL, -CHF?, -CHCL 2 , -CFs, -CCI..2, -CH2CF3, -CF2CF3, -CH 2 CHCL 2 , -CHCCL3.
• C(O) represents carbonyl
• C35 cycloaikyl includes cyclopropyl, cyclobutyl and cyclopentyl.
• a 3 to 6 membered ring optionally comprising 1, 2 or 3 heteroatoms selected from nitrogen, oxygen and sulfur refers to a saturated, partially saturated or aromatic ring containing 3 or 6 atoms, for example as defined below.
• the 3 to 6 membered ring contains no heteroatoms, in one embodiment the 3 to 6 membered ring comprises 1, 2 or 3 heteroatoms selected from nitrogen, oxygen and sulfur.
• the ring is saturated.
• saturated rings include cyclopropane, cyclobutene, cyclopentane, cyclohexane, azetidine, oxetane, thietane, tetrahydrofuran, tetrahydrothiophene, oxathiolane, 1,3-dioxolane, pyrazolidine, pyrrolidine, thiolane, imidazoline, piperidine, tetrahydropyran, dioxane, morpholine, thiane, dithiane, piperazine and thiomorpholine.
• a 5 or 6 membered ring as optionally comprising 1, 2 or 3 heteroatoms selected from nitrogen, oxygen and sulfur, refers to a saturated, partially saturated or aromatic ring containing 5 or 6 atoms, including wherein all the atoms are carbon or where there are 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, for example including: cyclopentadiene, phenyl, thiophene, furan, pyrroline, pyrrole, pyrazoline, pyrazole, imidazoline, imidazole, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, thiadiazole, triazole, tetrazole, pyridine, pyrimidine, pyrazine, triazine, thiazine, oxazine, thiopyran, 2H pyran, 4H pyran, dioxine, 2H thiopyran,
• a 5 or 6 membered ring comprising 1, 2 or 3 heteroatoms selected from nitrogen, oxygen and sulfur
• the ring is saturated. In one embodiment the ring is a saturated carbocyclic ring. In one embodiment the ring in a saturated heterocyclic ring. In one embodiment the ring is partially saturated or aromatic. In one embodiment the ring is partially saturated or aromatic carbocycle, in one embodiment the ring is partially saturated or aromatic heterocycle. In one embodiment the ring is 5 membered. In one embodimentt.be ring is 6 membered. In one embodiment the 5 or 6 membered ring is unsaturated or aromatic. In one embodiment the 5 or 6 membered ring is selected from cyclopentadiene, phenyl, pyridine and pyrazine, such as phenyl and pyridine.
• Z' is a 5 or 6 membered heteroaryl with at least, one heteroatom selected from N, 0 and 3, for example 1 or 2 nitrogens, wherein said heteroaryl optionally bears one or two substituents selected from hydroxy, halogen (such as F, Ci], CN, Ci 3 alkyl.
• 5 or 6 membered heteroaryl as employed herein is a ring containing 5 or 6 atoms wherein at least one atom is a heteroatom, for example selected from nitrogen, oxygen or sulphur, such as pyrrole, pyrazole, imidazole, thiophene, oxazole, isothiazole, thiazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine, thiopyran, oxazine and thiazine, such as pyrrole, pyrazole and pyridine and pyrimidine.
• nitrogen, oxygen or sulphur such as pyrrole, pyrazole, imidazole, thiophene, oxazole, isothiazole, thiazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine, thiopyran, oxazine and thia
• 5 to 6 membered heterocycle as employed herein generally refers to a non-aromatic ring containing 5 or 6 atoms wherein at least one atom is a heteroatom (for example 1, 2, 3 or 4 heteroatoms independently selected from 0, N and S], for example pyrrolidine, imidazolidine, pyrazolidine, oxathiolane, tetrahydrofuran, morpholine, piperidine, piperazine, tetrahydropyran, thiane, dithiane, thiomorpholine and the like.
• a heteroatom for example 1, 2, 3 or 4 heteroatoms independently selected from 0, N and S
• pyrrolidine imidazolidine, pyrazolidine, oxathiolane, tetrahydrofuran, morpholine, piperidine, piperazine, tetrahydropyran, thiane, dithiane, thiomorpholine and the like.
• 9 to 13 membered heterocycle refers to a bicyclic or tricyclic system containing 9 to 13 atoms, for example containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, which is saturated, partially unsaturated or aromatic.
• 9 to 13 membered heteroaryl refers to a bicyclic or tricyclic system containing 9 to 13 atoms, wherein at least one ring is aromatic and at least, one ring contains a heteroatom, for example containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur such as indoline, indole, isoindole, indollzine, indazole, benzimidazole, azaindole, pyrazolopyrimidine, purine, benzofuran, isobenzofuran, benzothiophene, benzoisooxazole, benzoisothiazole, benzoxazole, benzothiadiazoie, adenine, guanine, tetrahydroquinohrie, dihydroisoquinoline, quinoline, isoquinoline, quinolizlne, quinoxaline, phthalazine, cinnollne, napthrhyridine
• R 4 is a 9 or 10 membered heteraryi.
• 9 to 10 membered heteroaryl refers to a bicyclic ring system containing 9 or 10 atoms, wherein at least one ring is aromatic and at least one ring contains a heteroatom, for example containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, such as indoline, indole, isoindole, indolizine, indazole, benzimidazole, azaindole, pyrazolopyrimidine, purine, benzofuran, isobenzofuran, benzothiophene, benzoisooxazole, benzoisothiazole, benzoxazole, benzothiadiazoie, adenine, guanine, tetrahydroquinoline, dihydroisoquinoline, quinoline, isoquinoline, quinolizlne, quinoxaline, phthalazine, cinnollne, napthrhyridine, pyri
• the 9 or 10 membered heteroaryi is selected from indolylyl and benzimldazolyi, such as mdoI-3-yI or benzimidazoIe-2-yl.
• Ph as employed herein refers to phenyl.
• R 1 is oxetanyl.
• n' is 0.
• n' is 1.
• the compounds of the present disclosure can be prepared by methods described herein. In one embodiment there is provided a process of preparing a compound of formula (I) by reaction a compound of formula (III): wherein R 1 , R 2 , R 2 ’, R 3 , R 4 , X, m and n are defined for compounds of formula (I) and Y’ is an activated derivative of Y also defined in formula (1) and R x Is the activating group.
• the reaction is a condensation reaction.
• GENERIC ROUTES 1 to 8 can be employed to make certain compounds of the present disclosure:
• any one of generic routes 1 to 8 is empioyed. In one embodiment, any one of generic routes 1 to 4 is employed. In one embodiment, any one of generic routes 5 to 8 is employed. In one embodiment, any one of generic routes 1, 2 or 5 to 8 is employed. In one embodiment, generic route 1 is employed. In one embodiment, generic route 2 is employed. In one embodiment, generic route 3 is employed, in one embodiment, generic route 4 is employed. In one embodiment, generic route 5 is employed, in one embodiment, generic route 6 is employed. In one embodiment, generic route 7 is employed. In one embodiment, generic route 8 is employed.
• Protecting groups may be required to protect chemically sensitive groups during one or more of the reactions described above, to ensure that the process is efficient. Thus, if desired or necessary, intermediate compounds may be protected by the use of conventional protecting groups. Protecting groups and means for their removal are described in “Protective Groups in Organic Synthesis”, by Theodora W, Greene and Peter G.M. Wuts, published by john Wiley & Sons Inc; 4 th Rev Ed., 2006, ISBN- 10: 0471697540.
• salts of compound of the present disclosure include all pharmaceutically acceptable salts, such as, without limitation, acid addition salts of strong mineral acids such as HC1 and I IB: salts and addition salt;? of strong organic acids, such as a methansulfonic acid salt.
• solvates of the compounds disclosed herein.
• solvates include hydrates.
• Novel intermediates are an aspect of the invention.
• a further aspect of the present disclosure is methods of making the compounds disclosed herein.
• compositions comprising a compound according to the present disclosure and an excipient, diluent or carrier.
• excipient diluent or carrier.
• compositions of this disclosure may be administered by any number of routes including, but not limited to, oral, Intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, intraventricular, transdermal, transcutaneous (for example, see WO98/20734), subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual, intravagina] or rectal routes. Hyposprays may also be used to administer the pharmaceutical compositions of the invention.
• the therapeutic compositions may be prepared as injectables, either as liquid solutions or suspensions.
• Solid forms suitable for solution in, or suspension in, liquid vehicles prior to injection may also be prepared.
• Suitable liquids for reconstitution of such solid forms may be selected from aqueous solutions, for example saline, dextrose or water for injection and the like.
• the reconstituted liquid formulation is isotonic.
• the pharmaceutical composition according to the present disclosure is provided as a tablet or a capsule for oral administration.
• the present disclosure also extends to methods of treating a patient comprising administering a therapeutically effective amount of a compound of the present disclosure (or a pharmaceutical composition comprising the same), for example for the treatment of cancer. Also provide is a compound according to the present disclosure (or a pharmaceutical composition comprising the same) for use in treatment, for example for use in foe treatment of cancer.
• a compound of the present disclosure (or a pharmaceutical composition comprising foe same] for use in the manufacture of a medicament for foe treatment of cancer.
• foe cancer is an epithelial cancer, for example selected from example is selected from liver cancer (such as hepatocellular carcinoma), biliary tract cancer, breast cancer (such as none ER+ breast cancer), prostate cancer, colorectal cancer, ovarian cancer, cervical cancer, lung cancer, gastric cancer, pancreatic, bone cancer, bladder cancer, head and neck cancer, thyroid cancer, skin cancer, renal cancer, and oesophagus cancer, for example gastric cancer.
• liver cancer such as hepatocellular carcinoma
• breast cancer such as none ER+ breast cancer
• prostate cancer colorectal cancer
• ovarian cancer cervical cancer
• lung cancer gastric cancer
• pancreatic bone cancer
• bladder cancer head and neck cancer
• thyroid cancer skin cancer
• renal cancer renal cancer
• oesophagus cancer for example gastric cancer.
• foe cancer is selected from selected from the group comprising hepatocellular carcinoma, cholangiocarcinoma, breast cancer, prostate cancer, colorecetal cancer, ovarian cancer, lung cancer, gastric cancer, pancreatic and oesophagus cancer.
• foe biliary duct cancer is in a location selected from intrahepatic bile ducts, left hepatic duct, right hepatic duct, common hepatic duct, cystic duct, common bile duct, Ampulla of Vater and combinations thereof.
• foe biliary duct cancer is in an intrahepatic bile duct. In one embodiment foe biliary duct cancer is in a left hepatic duct In one embodiment the biliary duct cancer is in a right hepatic duct. In one embodiment the biliary duct cancer is in a common hepatic duct. In one embodiment foe biliary duct cancer is in a cystic duct. In one embodiment the biliary duct cancer is in a common bile duct. In one embodiment foe biliary duct cancer is in an Ampulla of Vater, In one embodiment the epithelial cancer is a carcinoma.
• the treatment according to the disclosure is adjuvant therapy, for example after surgery.
• the therapy according to the disclosure is neoadjuvant treatment, for example to shrink a tumour before surgery,
• tumour is a solid tumour.
• the cancer is a primary cancer, secondary cancer, metastasis or combination thereof.
• foe treatment according to the present disclosure is suitable for the treatment of secondary tumours.
• the cancer is metastatic cancer.
• the treatment according to the present disclosure is suitable for the treatment of primary cancer and metastases.
• the treatment according to the present disclosure is suitable for the treatment of secondary cancer and metastases, in one embodiment the treatment according to the present disclosure is suitable for foe treatment of primary cancer, secondary cancer and metastases.
• the treatment according to foe present disclosure is suitable for the treatment of cancerous cells in a lymph node.
• foe liver cancer is primary liver cancer. In one embodiment foe liver cancer is secondary liver cancer. In one embodiment the liver cancer is stage 1, 2, 3A, 3B, 3C, 4A or 4B.
• the gastric cancer is stage 0, 1, If, ill or IV.
• the precise therapeutically effective amount for a human subject will depend upon the severity of the disease state, the general health of the subject, the age, weight and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities and tolerance/response to therapy. This amount can be determined by routine experimentation and is within the judgement of the clinician. Generally, a therapeutically effective amount will be from 0,01 mg/kg to 1000 mg/kg, for example 0.1 mg/kg to 500 mg/kg. Pharmaceutical compositions may be conveniently presented in unit dose forms containing a predetermined amount of an active agent of the invention per dose. Combination Therapy
• the compound of the present disclosure is employed in combination therapy, for example wherein the further therapy is an anticancer therapy,
• the anticancer therapy is a chemotherapy.
• Chemotherapeutic agent and chemotherapy or cytotoxic agent are employed interchangeably herein unless the context indicates otherwise.
• Chemotherapy as employed herein is intended to refer to specific antineoplastic chemical agents or drugs that are "selectively” destructive to malignant cehs and tissues, for example alkylating agents, antirnetaboiites including thymidylate synthase inhibitors, anthracyclines, antimicrotubule agents including plant alkaloids, topoisomerase inhibitors, parp inhibitors and other antitumour agents. Selectively in this context is used loosely because of course many of these agents have serious side effects.
• the preferred dose may be chosen by the practitioner, based on the nature of the cancer being treated.
• alkylating agents which may be employed in the method of the present disclosure include an alkylating agent selected from nitrogen mustards, nitrosoureas, tetrazines, aziridines, platins and derivatives, and non-classical alkylating agents.
• Platinum containing chemotherapeutic agent includes, for example cisplatin, carboplatin, oxaliplatin, satraplatin, picoplatin, nedaplatin, triplatin and lipoplatin (a liposomal version of cisplatin), in particular cisplatin, carboplatin and oxaliplatin.
• the dose for cisplatin ranges from about 20 to about 270 mg/m 2 depending on the exact cancer. Often the dose is in the range about 70 to about 100mg/m 2 .
• Nitrogen mustards include mechlorethamine, cyclophosphamide, melphalan, chlorambucil, ifosfamide and busulfan.
• Nitrosoureas include N-Nitroso-N-methylurea (MNU), carmustine (BCNU), lomustine (CCNU) and semustine (MeCCNU), fotemustine and streptozotocin.
• Tetrazines include dacarbazine, mitozolomide and temozolomide.
• Aziridines include thiotepa, mytomycin and diaziquone (AZQ).
• antirnetaboiites examples include anti-folates (for example methotrexate and pemetrexed), purine analogues (for example thiopurines, such as azathiopurine, mercaptopurine, thiopurine, fludarabine (including the phosphate form), pentostatin and ciadribine), pyrimidine analogues (for example fluoropyrimidines, such as 5-fluorouracil and prodrugs thereof such as capecitabine (Xeloda®]), floxuridine, gemcitabine, cytarabine, decitabine, raltitrexed(tomudex) hydrochloride, cladribine and 6-azauracil.
• anti-folates for example methotrexate and pemetrexed
• purine analogues for example thiopurines, such as azathiopurine, mercaptopurine, thiopurine, fludarabine (including the phosphat
• anthracyclines examples include daunorubicin (Daunomycin), daunorubicin (liposomal], doxorubicin (Adriamycin], doxorubicin (liposomal), epirubicin, idarubicin, valrubicin (currently used only to treat bladder cancer) and mitoxantrone an anthracycline analog, in particulm' doxorubicin.
• anti-microtubule agents examples include vinca alkaloids and taxanes.
• Vinca alkaloids include completely natural chemicals, for example vincristine and vinblastine and also semi -synthetic vinca alkaloids, for example vinoreibine, vindesine, and vinflunine
• Taxanes include paclitaxel, docetaxel, abraxane, carbazitaxel and derivatives of thereof.
• Derivatives of taxanes as employed herein includes reformulations of taxanes like taxol, for example in a micellar formulation, derivatives also include chemical derivatives wherein synthetic chemistry is employed to modify a starting material which is a taxane.
• Topoisomerase inhibitors which may be employed in a method of the present disclosure include type I topoisomerase inhibitors, type II topoisomerase inhibitors and type II topoisomerase poisons.
• Type I inhibitors include topotecan, irinotecan, indotecan and indimitecan.
• Type 11 inhibitors include genistein and ICRF 193 which has the following structure:
• Type II poisons include amsacrine, etoposide, etoposide phosphate, teniposide and doxorubicin and fluoroquinolones.
• chemotherapeutic agents employed is, for example a platin and 5-FU or a prodrug thereof, for example cisplatin or oxaplatin and capecitabine or gemcitabine, such as FOLFOX.
• the chemotherapy comprises a combination of chemotherapy agents, in particular cytotoxic chemotherapeutic agents.
• the chemotherapy combination comprises a platin, such as cisplatin and fluorouracil or capecitabine.
• the chemotherapy combination in capecitabine and oxaliplatin in capecitabine and oxaliplatin (Xelox).
• the chemotherapy is a combination of folinic acid and 5-FU, optionally in combination with oxaliplatin.
• the chemotherapy is a combination of folinic acid, 5-FU and irinotecan (FOLFIR1), optionally in combination with oxaliplatin (FOLFIRINOX).
• the regimen consists of: irinotecan (180 mg/m 2 IV over 90 minutes] concurrently with folinic acid (400 mg/m 2 [or 2 x 250 mg/m 2 ] IV over 120 minutes]: followed by fluorouracil (400-500 mg/m 2 IV bolus) then fluorouracil (2400-3000 mg/m 2 intravenous infusion over 46) hours). This cycle is typically repeated every two weeks.
• the dosages shown above may vary from cycle to cycle.
• the chemotherapy combination employs a microtubule inhibitor, for example vincristine sulphate, epothilone A, N-[2-[(4-HydroxyphenyJ)amino]-3-pyridinyJ]-4- methoxybenzenesulfonamide (ABT- 751), a taxoi derived chemotherapeutic agent, for example paclitaxel, abraxane, or docetaxel or a combination thereof.
• a microtubule inhibitor for example vincristine sulphate, epothilone A, N-[2-[(4-HydroxyphenyJ)amino]-3-pyridinyJ]-4- methoxybenzenesulfonamide (ABT- 751)
• ABT- 751 N-[2-[(4-HydroxyphenyJ)amino]-3-pyridinyJ]-4- methoxybenzenesulfonamide
• the chemotherapy combination comprises an anti metabolite such as capecitabine (xeioda), fludarabine phosphate, fludarabine (fludara), decitabine, raititrexed (tomudex), gemcitabine hydrochloride and cladribine.
• an anti metabolite such as capecitabine (xeioda), fludarabine phosphate, fludarabine (fludara), decitabine, raititrexed (tomudex), gemcitabine hydrochloride and cladribine.
• the anticancer therapy combination employs an mTor inhibitor.
• mTor inhibitors include: everolimus (RAD001), WYE-354, KU-0063794, papamycin (Siroiimus), Temsirolimus, DeforoIlmus(MK-8669), AZD8055 and BEZ235(NVP-BEZ235).
• the anticancer therapy combination employs a MEK inhibitor.
• MEK inhibitors include: AS703026, Cl-1040 (PD184352), AZD6244 (Sehimetinib), PD318088, PD0325901, AZD8330, PD98059, U0126-EtOH, BIX 02189 or BIX 02188.
• the chemotherapy combination employs an ART inhibitor.
• ART inhibitors include: MK-2206 and AT7867.
• the anticancer therapy employs an aurora kinase inhibitor.
• aurora kinase inhibitors include: Aurora A inhibitor I, VX-680, AZD1152-HQPA (Barasertib), SNS- 314 Mesylate, PHA-680632, ZM-447439, CCT 129202 and Hesperadin.
• the chemotherapy combination employs a p38 inhibitor, for example as disclosed in W02010/038086, such as /V-[4"( ⁇ 4-[3-(3-tert-Butyl-l-p-tnlyl-l//--pyrazol-5- yI)ureido]naphthaIen-l-yioxy ⁇ methyl]pyridin-2-yI]-2-methoxyacetamide.
• a p38 inhibitor for example as disclosed in W02010/038086, such as /V-[4"( ⁇ 4-[3-(3-tert-Butyl-l-p-tnlyl-l//--pyrazol-5- yI)ureido]naphthaIen-l-yioxy ⁇ methyl]pyridin-2-yI]-2-methoxyacetamide.
• the combination employs a Bci-2 inhibitor.
• Bcl-2 inhibitors include: obatoclax mesylate, ABT-737, ABT-263(navitoclax) and TW-37,
• the chemotherapy combination comprises ganciclovir, which may assist in controlling immune responses and/or tumour vasculation.
• the anticancer therapy includes a PARP inhibitor.
• the anticancer therapy includes an inhibitor of cancer metabolism with specific inhibition of the activity of the DHODH enzyme.
• the compound of the present disclosure is employed in combination (for example in a combination therapy) with a checkpoint Inhibitor.
• a combination therapy comprising a compound or pharmaceutical composition of the present disclosure, and a checkpoint inhibitor or a combination of checkpoint inhibitors.
• the checkpoint inhibitor is selected from the group comprising; PD-1 inhibitor, PD-L1/L2 inhibitor, CTLA-4 inhibitor, checkpoint kinase inhibitor 1 (CHEK1/CHK1), checkpoint kinase inhibitor 2 (CHEK2/ CHK2), Ataxia telangiectasia and Rad3 related (ATR) inhibitor, ataxia-telangiectasia mutated (ATM) inhibitor, Weel dual specificity protein kinase (Weel) inhibitor, Poiy ADP Ribose polymerase (PARP) inhibitor and Mytl inhibitor.
• the checkpoint inhibitor is selected from the group comprising: a PD-1 inhibitor, a PD-L1/L2 inhibitor, a CTLA-4 inhibitor; and a combination thereof.
• a combination of a PD- 1 inhibitor and a PD-L1 inhibitor is employed.
• a combination of a PD-1 and a CTA-4 inhibitor is employed.
• a combination of a PD-L'l and CTA-4 inhibitor is employed.
• a combination of a PD-1, PD-L1 and a CTA-4 inhibitor is employed.
• the checkpoint inhibitor is a PD-1 inhibitor.
• the PD- 1 inhibitor is selected from the group comprising: nivolumab (also known as OPDIVO®, 5C4, BMS- 936558, MDX-1106, and ONO-4538], pembrolizumab (Merck; also known as KEYTRUDA®, larnbrolizuraab, and MK-3475), PDR001 (Novartis; also known as spartalizumab), MEDI- 0680 (AstraZeneca; also known as AMP-514), cemlplirnab (Regeneron; also known as REGN-2810), JS001 or "toripalimab” (TAIZHOU JUNSHI PHARMA), BGB-A317 ("Tisleiizumab;” Beigene), INCSHR1210 (Jiangsu Hengrul Medicine; also known as "camrelizumab,”, SHR- 1210), TSR-04
• the checkpoint inhibitor is pembrolizumab. In one embodiment the checkpoint, inhibitor is nivolumab. In one embodiment, the checkpoint inhibitor is cemiplimab. In one embodiment the checkpoint inhibitor is dostarlimab.
• the checkpoint inhibitor is a PD-L1 inhibitor.
• the PD- LI inhibitor is selected from the group comprising: atezoiizumab (Tecentriq), avelumab (Bavencio), durvalumab (Imfinzi), KN035, CK-301 (Checkpoint Therapeutics), AUNP12 (Aurigene), CA-170 (Aurigen/Curis) and BMS-986189 (BMS).
• the checkpoint inhibitor is atezoiizumab. In one embodiment, the checkpoint inhibitor is avelumab. In one embodiment, the checkpoint inhibitor is durvalumab.
• the checkpoint inhibitor is a CTLA-4 inhibitor.
• the CTLA-4- inhibitor is selected from the group comprising: ipilimumab (Yervoy), tremelimumab
• the checkpoint, inhibitor is an antibody or binding fragment specific to a checkpoint protein, in particular one disclosed herein, such as PD-1, PD-L1 or CTLA-4.
• the checkpoint kinase inhibitor is independently selected from: 3-((Aminocarbonyi)ammo]-5-(3-fIuorophenyl)-N-(3S)-3-piperidinyl-2-thiophenecarboxamide hydrochloride; (3R,4S)-4-[[2-(5-Fhmro-2-hydroxyphenyl)-6,7-dimethoxy-4-qumazolrnyI]ammo]- a,a-dirnethyi-3-pyrroIidinemethanoi dihydrochloride; 4,4'-diacetyldiphenylurea bis(guanylhydrazone) ditosylate; 9-Hydroxy-4-phenyi-pyrrolo[3,4-c]carbazoIe-l,3(2H,6H)-dione; (R)-a-Amino-N-[.5,6-dihydro-2-(l-methyl- lH-
• one or more therapies employed in the method herein are metronomic, that is a continuous or frequent treatment with low doses of anticancer drugs, often given concomitant with other methods of therapy.
• Embodiments are described herein as comprising certain features/elements. The disclosure also extends to separate embodiments consisting or consisting essentially of said features/elements.
• present compounds can be made by methods analogous to those described in WO2020/039093 and PCT/SG2021/050095 both incorporated herein by reference.
• Example 5 (51 mg, 0.125 mmol) was submitted to chiral separation to provide two enantiomers
• Example 14 title compound (125 mg, 0.309 mmol) was submitted to chirai separation to provide two enantiomers Example 61 and Example 62.
• Example 17 is subject to keto- enol tautomerism. It may also exist in the following form: 3-(4-((2-(lH-indol-3-yi)ethyl)amino]-7,8- dihydro-6H-pyrimido[5,4-b][l,4]oxazin-2-yl)pyridin-2-ol observed.
• Example 21 3-[4-[2-(6"nuoro"lH4ndol“3-yl)ethylammo]-7,8-dihydro-6H-pyrimido[5,4- b][l,4]oxazin"2-yl]"lH-pyridin"2-one - dihydro-6H-pyrimido[5,4-b][l,4]oxazin-2-yl]-lH-pyridin-2-one [5.0 mg,0.0122 mmol, 2.64% yield) as a beige solid.
• Example 21 is subject to keto-enol tautomerism.
• Example 25 3-(4-(2-(lH-iudol ⁇ 3-yl)ethoxy)-7,8-dihydro-6H ⁇ pyrimido(5,4-b]
• Example 25 is subject, to keto-enol tautomerism. It may also exist in the following form: 3-(4-(2-(lH-indol-3-yl)ethoxy)-7,8-dihydro-6H-pyrimido[5,4-b][l,4]oxazm-2-yl)pyridin-2-ol
• Example 26 is subject to keto-enol tautomerism.
• Example 27 is subject to keto-enol tautomerism, it may also exist in the following form; (R)-3-(4-((2-(lH-mdoI-3-yl)ethyI]amino)-7-(hydroxymethyl]-7,8- dihydro-6H-pyr!mido[5,4-b][l,4]oxazin-2-yl)pyridin-2-ol
• Example 28 (7S)"2-(541wm>3 ⁇ pyndyl)"N42“(lH4adoK%yl)ethyI]-7 ⁇ (methoxymethyl) ⁇ 7 J 8-dihydro-6H-pyrimido[S J 4-b][l,4]oxazin-4-ainine eluting with a gradient of 30 to 70% fv/v) EtOAc in iso-Hexane to afford (7S)-2-(5-fluoro-3- pyridyl)-N-[2-(lH-indol-3-yl)et.hyl]-7-fmethoxymethyl)-7,8-dihydro-6H-pyrlmido[.5,4-b][l,4] oxazin-4-amine (60 mg, 0.138 mmol, 15.64% yield) as a brown solid.
• Tri-o-tolylphosphin 0.0800 eq, .5.0 mg, 0.0166 mmol
• Trisfdibenzyl ideneacetone)dipaliadium(O) Pd2(dba)3
• Pd2(dba)3 Trisfdibenzyl ideneacetone
• Example 36 [(7R)-8-[2-(dimethylammo)ethyI]-2-(2-methyithiazol ⁇ 5-yI)-4-[[(3R)-2,3,4,9- tetrahydro-lH-carba2ob3-yl]amino]“6,7-dibydropyrimido[5,4"b][l,4]oxazin"7-yI]methanol . , . temperature for 18 h. Further addition of boron tribromide solution and stirring, were needed to take the reaction to completion as shown by UPLC analysis. The reaction mixture was carefully quenched with MeOH (1 mid anti then with water. Layers were separated and aqueous was extracted twice with DCM.
• the reaction was quenched by the addition of water (25 mb) and extracted with dichloromethane (2 x 60 mL). The resulting solution was washed sequentially with saturated brine solution (25 mb). The organic phase was then separated and dried (Na2SO4), before being concentration to dryness.
• Methanesuifonyl chloride (1.10 eq, 0.052 mb, 0.677 mmol) was added dropwise atat O °C and the reaction mixture was left warmed up to room temperature over 3h.
• the reaction mixture was diluted with DCM (30 mb) then the organic phase was washed with 1 N HCI (3 x 15 mb), dried over Na2SO4, filtered and concentrated to dryness.
• Xantplios 4,5-Bis(diphenylphosphino)-9,9-dimethy]xanthene (Xantplios) (14 mg, 0.0244 mmol) were added. The mixture was stirred at 100°C tor 24h. The reaction mixture was diluted with EtOAc and filtered through celite then the filtrate was evaporated to dryness.
• Example 39 8"metbyIsulfonyl-2"(2-methylthiazoI"5-yI)-N-[(3R)-2,3,4,9-tetrahydro-lH” carbazol- 3 -yl
• F tytyty Prepared according to general method 2a, using tert-butyl in 20:1 MeCN:MeOH, filtered, washed with diethyl ether to afford tert-butyl N-[2-[2,4-dichtoro-6- [2-(7-iluoro-2-methyl-lH-indol-3-yl)ethylamino]pyrimidin-5-yl]oxyethyl]carbamate (500 mg, 1.00 mmol, 85.93% yield) as a brown solid.
• Example 42 3"[4-[2"(5,7"diRuoro-2"methyI-lH-indoI-3-yI)ethyIainino]"7,8"dihydrO"6H- pyrimido [ 5,4-b Hl, 4] oxazin-2 ⁇ yi] - 1 H-pyridi n-2 -one b][l,4]oxazin-2-yl]-lH-pyridin-2-one (40 mg, 0.0912 mmol, 45.29% yield) as a yellow solid.
• Example 43 is subject to keto-enol tautomerism. It may also exist, in the following form:
• Example 44 is subject to keto-enol tautomerism. It may also exist in the following form: 3-(4-((2-(lH-indol-3-yl)ethyi)amino)-8- metiiyl-7,8-dihydro-6H-pyrimido[5,4-b] [l,4]oxazin-2-yl]pyridin-2-oi
• 6H-pyrimido[5,4-b][l,4]oxazin-2-yl)pyridln-2(lH)-one Prepared according to general method 5b, using (7S)-2-chloro-N- [2-(lH-indol-3-yl]e&yl]-7-(methoxymethyl]-7,8-dlhydro-6H- pyrimido[5,4-b][1.4]oxazin-4-amine (150 mg. 0.401 mmol] and (2- hvdroxy-3-pyridyl)boromc acid (84 mg, 0.602 mmol). The crude was purified by Reversed Phase column chromatography (23 g cartridge] eluting with MeCN in water gradient (5% to 95% acidic buffer] to afford
• Example 45 is subject, to keto-enol tautomerism. It may also exist in the following form:
• Example 47 is subject to keto-enol tautomerism. It may also exist in the following form: hexane:EtOAc to afford tert-butyl N-[(lR]-l-[(2,4-dichloro-6-[2-(lH-indol-3-yI)ethoxy]pyrimidin- 5-yI]oxymethyl]-2-methoxy-ethyl]carbamate (350 mg, 0.684 mmol, 44.85% yield) as a while solid.
• Example 48 3-[(7R)-4-[2-(lH-mdob3-yJ)etboxy]-7“(methoxymethyl)“7,8-dihydro-6H- pynmido[5,4-b][l,4]oxazin-2-yl]-4H"pyridin-2-one eluting with a gradient of EtOAc (0-100%; v/v) in iso-Hex then MeOH (0-10%; v/v) in EtOAc followed by Reversed Phase column chromatography (12 g cartridge) eluting with a gradient of
• Example 48 is subject to keto-enol tautomerism. It may also exist in the following form: (R)-3-(4-(2-(lH-indoi-3-yI)ethoxy)-7-
• Example 56 (7R)-2-(4-iluorophenyl)"N-[2-(lH”indol-3"yl)etbyl]-7-(metboxymetbyl)"7,8" dihydro-6H-pyrimido[5,4 ⁇ b] ( l,4]oxazin-4-amiiie Hexane:EtOAc to afford (7R)-2-(4-fluorophenyl)-N-
• Example 59 (7R)-N-[2 ⁇ (lH-indoI-3-yl)ethyl]-7-(methaxymethyI)-2 ⁇ (2-methylthiazol-5-yl)- under vacuum.
• the crude was purified column chromatography eluting with 3:1 and 1:1 hexane:EtOAc to afford (7R]-N-[2-(lH-indo]-3--yl)ethyl]“7“(methoxy methyl)-2-(2-methyithiazol-5-yi]-7,8-dihydro-6H-pyrlrnido[5,4-b][l,4]oxazin-4-amine [157 mg, 0.360 mmol, 48.19% yield] as a white solid.
• Example 60 [(7R)-4-[2-(lH-indol-3-yI)ethyIamiiio) ⁇ 2-(2 ⁇ methyIthiazol-5-yI) ⁇ 7,8 ⁇ dihydro- mixture was carefully quenched with MeOH(l mb] and water (4 mb] then extracted with DCM twice and the organics were dried over Na2SO4, filtered and concentrated to dryness.
• Example 66 is subject to keto-enol tautomerism.
• Example 68 is subject to keto-enol tautomerism. It may also exist in the following form:
• Example 69 is subject to keto-enol tautomerism, It may also exist in the following form:
• Example 70 5-fiuoro-3-(4-((2-(6 ⁇ fluoro-lH-indoI-3-yI)ethyl)amino)-7,8-dihydro-6H- pyrimido[5,4 ⁇ b][l,4]oxazin"2-yI)pyridm ⁇ 2(lH)-one .
• Example 70 is subject to keto-enol tautomerism. It may also exist in the following form: 5-fluoro-3-(4-((2-(6-fhioro-lH-mdol-3 y])ethyl)amfno)-7,8-dihydro-6H-pyrimido[5,4-b] [l,4]oxazin-2-yi)pyridin-2-o] 2H), 3.51 - 3.42 (m, 2H), 3,02- 2.92 (m, 2H). 1H not observed.
• Example 71 is subject to keto-enoi tautomerism.
• Example 72 is subject to keto-enoi tautomerism, it may also exist in the following form: 3-(4-((2-(lH-indoI-3-yl)ethyi)amino)-7,8-dihydro-6H-pyrimido[5,4-b][l,4]oxazin-2-yl)-5- chloropyridin-2-ol

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