WO2023033741A1 - Compounds useful in modulation of ahr signalling - Google Patents

Compounds useful in modulation of ahr signalling Download PDF

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WO2023033741A1
WO2023033741A1 PCT/SG2022/050634 SG2022050634W WO2023033741A1 WO 2023033741 A1 WO2023033741 A1 WO 2023033741A1 SG 2022050634 W SG2022050634 W SG 2022050634W WO 2023033741 A1 WO2023033741 A1 WO 2023033741A1
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inhibitor
compound according
alkyl
halogen
cancer
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PCT/SG2022/050634
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French (fr)
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Michael Stocks
Mark Graham
James HITCHIN
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Jaguahr Therapeutics Pte Ltd
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Publication of WO2023033741A1 publication Critical patent/WO2023033741A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to compounds of the general formula (1) and sub-formula's thereof 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.
  • diseases in particular cancer or conditions with dysregulated immune functions, or other conditions associated with aberrant AhR signalling
  • Such compounds may also be of utility in the expansion of hematopoietic stem cells (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.
  • HSCs hematopoietic stem cells
  • the m yi 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 Hsp90 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
  • the AhR is best known for binding to environmental toxins and inducing various members of the cytochrome P450 family including CYP1A1, 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 et al., Pharmacol Ther, 2018, 185:50).
  • AhR AhR is expressed in many immune cell types including dendritic cells, macrophages, T cells, NK cells and B cells and plays an important role in immunoregulation (Quintana &. Sherr, Pharmacol Rev, 2013, 65: 1148; Nguyen et a/., Front Immunol, 2014, 5:551).
  • TCDD 2,3,7,8-Tetrachlorodibenzo-p-dioxin
  • Physiological effects of AhR agonists on immune cells include promotion of regulatory T cell (Treg) generation (Pot, Swiss Med Wkly, 2012, 142:wl3592), modulation of Thl7 cell differentiation and activation (Baricza el: al., Cell Mol Eife Sei, 2016, 73:95) and stimulation of interleukin-22 (IL-22) expression and/or release from human activated peripheral blood mononuclear cells and T cells (Ramirez et al., Ear 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 al., J Immunol, 2010, 185:3190; Nguyen et at, 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 ofTre-gs (Jurado- Manzano et al, 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 (ID01/ID02) and tryptophan 2,3 -dioxygenase 2 (TDO2) catalyse the commitment step of the KYN metabolic pathway and are expressed in immune ceils (IDO1) and a range of cancer cells (IDO1 andTDO2) (Piiotte etal., Proc Nat Acad Sei, 2012, 109:2497).
  • IDO1 Inhibitors of IDO1 have attracted much interest as potential new' treatments to stimulate the immune system to recognize and eliminate cancer cells (Cheong & Sun, Trends Pharmacol Sci, 2018, 39:307).
  • the immunosuppressive effect of IDO1 has been attributed mainly to reduced levels of tryptophan, which activates the kinase GCN2 (general control non-derepressibie 2) and inhibits T cell proliferation/activation both in tumour draining lymph nodes lymph nodes and in the tumour micro-environment
  • GCN2 general control non-derepressibie 2
  • T cell proliferation/activation both in tumour draining lymph nodes lymph nodes lymph nodes and in the tumour micro-environment
  • 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 «/,, Nature, 2011, 478:197; Piiotte et al, Proc Nat Acad Sci, 2012, 109:2497; D'Amato etal., Cancer Res, 2015, 75(21):4651; Hsu etal, Oncotarget, 2016, 7(19): 27584; Chen et m.. Dis Markers, 2016, 2016:8169724).
  • cancers notably malignant glioma, hepatocellular carcinoma, melanoma, bladder, breast, lung and colorectal cancer
  • Ectopic AhR expression in non-malignant human mammary epithelial cells induces an epithelial-to-mesenchymal transition and a > 50% increase in cell growth rates (Brooks S Eltom, Curr Cancer Drug Targets, 2011, 11:654) and AhR knockdown induced gene changes in human breast cancer ceil lines consistent with a mesenchymal to epithelial ceil reversion to a less aggressive phenotype (Narasimhan et al., Int J Mol Sci, 2018, 19:1388).
  • AhR antagonists or AhR knockdowm 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 etal., Cancer Res, 2015, 75(21):4651; Narasimhan etal., Int J Mol Sci, 2018, 19:1388) and to reduce survival of glioblastoma cells (Gramatzki et al., Oncogene, 2009, 28:2593; Opitz et al, Nature, 2011, 478:197; Guastella et al., ] Neuro-oncol, 2018, in press).
  • tumourspheres (Stanford et al., Moi 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.
  • AhR agonists released from immune ceils and from tumour cells 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 dysregulated immune functions. Thus such agents may also have utility in a range of other diseases/ conditions including but not limited to, obesity (Rojas et al., Jnt J Obesity, 2020, 44:948) and various viral infections (Giovannoni er m’., NatNeurosci. 2020, 23:939; Giovannoni et 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 dysregulated immune responses or other disorders associated with aberrant. AhR signalling.
  • W02017/202816 W02018/146010 and W02019/101642 relate inter alia to heterocyclic compounds capable of inhibiting AhR function.
  • W0202Q/Q81840 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--amido-lH-indol-2tyl 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 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.
  • W02020/043880 relates to heterocyclic compounds which are ARH inhibitors, for prevention of diseases, in particular cancer or conditions with dysregulated 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.
  • W0202Q/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 ceils 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 in part, by AhR.
  • WO 2018/195397 relates to compositions and methods for indole AhR inhibitors.
  • WO 2018/146010 relates to the preparation of 2-heteroaryi-3-oxo-2,3-dmydropyridazine- 4-carboxamides for the treatmentor prophylaxis of diseases, in particular cancer or conditions with dysregulated immune responses, as a sole agent or in combination with other active ingredients.
  • W02010/059401 relates to compounds and compositions for expanding the number of CD34v 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.
  • W02012/015914 relates fotera/fo to heterocyclic compounds that modulate AhR activity for use in therapeutic compositions to inhibit cancer ceil proliferation and tumour cell invasion and metastasis.
  • W02020/0512Q7 relates to AhR antagonists as well as methods of modulating AhR activity and expanding hematopoietic stem cells by culturing hematopoietic stem or progenitor ceils in the presence of these agents. Additionally, 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, surprisingly the presently claimed compounds are potent inhibitors of AhR, in particular inhibitors, for example in an assay disclosed herein.
  • ⁇ is phenyl or a 3 to 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* is H or Ci-3 alkyl, C3.5 cycloalkyl, halogen and C1.3 alkyl optionally bearing one or more groups independently selected from OR Y , halogen -NR"R S - such as OR Y and halogen (e.g. F) in particular only one group;
  • R 2 is H, C : : alkyl or halogen; wherein R 1 & R 2 together can form an alkylene bridge -CH2CH2- or -CHz-between two carbons In the ring;
  • R 3 is H or C 1 3 alkyl:
  • R 4 is a 9 to 13 membered heterocycle with at least one heteroatom selected from N, 0 and S (for an aromatic or partially saturated), with substituents R 9 , R 9 ' and R 10 ;
  • R 5 is H, oxo, hydroxy, halogen (such as F, Cl), CN, C1-3 alkyl, C1.3 alkoxy (such as OMe), Ci-2 haloalkyl (i.e. alkyl bearing 1 to 6 halogen groups, such as CF3 J, C1 3 alkyl bearing one or more OH groups, -C(O](CH 2 )qNR 7 R 8 , -SO 2 Ci- 3 alkyl, -SO? NR 7 R 8 ,
  • R° is H, oxo, hydroxy, halogen (such as F, Cl), CN, Cs.3 alkyl, -C(O)(CH2)qNR 7 R 8 , -SO2C1.3 alky], ⁇ SO? NR 7 R 8 ,
  • R 7 is H, C1.3 alkyl, or -C(O)OR Y , for example H or C1.3 alkyl, such as -CH 3 ;
  • R* is H or C1-3 alkyl, such as -CH?,
  • R 9 is H, hydroxy, halogen (such as F, Cl), CN, C1.3 alkyl, C1 3 alkoxy (such as OMe), C1.3 alkyl bearing 1 to 6 halogen groups (such as CF?), C1.3 alkyl bearing one or more 0R Y groups, Cj-scydoalkyl, -(CHjlqOCr? alkyl substituted with 1 to 6 halogen groups (such as - (CH 2 )qOCF?,), -CO(CH?)q NR 7 R 8 , -SO2C1-3 alkyl, or -SO2 NR 7 R 8 ;
  • R 9 ' is H, OH, halogen (such as F, Cl), CN, C 1.3 alkyl, C 3-3 alkoxy (such as OMe), C1.3 alkyl bearing 1 to 6 halo groups (such as CF?,), C1-3 alkyl bearing one or more OH groups, -CO(CH?)q NR 7 R 8 , - SO2C1-?, alkyl, or -SO? NR 7 R 8 ;
  • R : o is H, hydroxy, halogen (such as F, Cl), CN, C1.3 alkyl, -C(O)(CH?)q NR 7 R 8 ; -SO2C1.3 alkyl, or -SO? NR 7 R 8 ;
  • R 11 is H or fo ; alkyl (such as -CH 3);
  • R" is H or Chalky! for example H or C1.3 alkyl (such as H, -CH? or - CH2CH3);
  • X is CH 2 , S, -S0 2 , NR n or 0; b is 0, 1 or 2; n is 1 or 2; m is 1 or 2; p is an integer 1, 2 or 3 (such as 1): q is 0, 1, 2 or 3 (such as 0 or 1), or a pharmaceutically acceptable salt thereof
  • Y is phenyl or a 3 to 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 ;
  • Rd is H or C1-3 alkyl, C? . cycloalkyl
  • R 2 is H or Ci.? alkyl; wherein R ! & R 2 together can form an alkylene bridge -CH2CH2- between two carbons in the ring;
  • R 3 is H or C1.3 alkyl
  • R 4 is a 9 to 13 membered heterocycle with at least one heteroatom selected from N, 0 and S (for an aromatic or partially saturated), with substituents R 9 , R 9 ' and R 10 :
  • R 5 is H, hydroxy, halogen (such as F, Cl), CN, C1.3 alkyl, C1.3 alkoxy (such as OMe),
  • C-...2 haloalkyl i.e. alkyl bearing 1 to 6 halogen groups, such as CF3
  • C1 3 alkyl bearing one or more OH groups -C(O)(CH 2 )qNR'R 8 , -SO2C1.3 alkyl, -SO 2 NR 7 R 8 ,
  • R 6 is I-I, hydroxy, halogen (such as F, CJ), CN, C1.3 alky], -C(O)(CH2)qNR 7 R* ⁇ SO2C1..3 alkyl, -SO 2 NR 7 R 8 ,
  • R 7 is H, C1.3 alkyl, such as -CH3;
  • R 8 is H or C 3-3 alkyl, such as -CH3;
  • R 9 is H, hydroxy, halogen (such as F, Cl), CN, C1.3 alkyl, C1.3 alkoxy (such as OMe), C 33 alkyl bearing 1 to 6 halogen groups (such as CF3), C1.3 alkyl bearing one or more OR y groups, Cs-scycloalkyl, -(CHzJqOCi-aalkyl substituted with 1 to 6 halogen groups (such as - (CH 2 )qOCF 3 ), -CO(CH 2 )q NR 7 R 3 , -SO2C1.3 alky], or -SO? 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 alkyl bearing 1 to 6 halo groups (such as CF3), C1.3 alkyl bearing one or more OH groups, -CO(CH 2 )q NR 7 R 8 , - SO2G.3 alkyl, or -SO2 NR 7 R 8 ;
  • R 19 is H, hydroxy, halogen (such as F, Cl), CN, C1.3 alkyl, -C(O)(CH 2 )q NR 7 R 8 ;
  • R 14 is H or C1-3 alkyl (such as -CH-,];
  • X is CI-1 2 , S, -SO 2 , NR 44 or 0; b is 0, 1 or 2: n is 1 or 2; m is 1 or 2; p is an integer 1, 2 or 3 (such as 1); q is 0, 1, 2 or 3 (such as 0 or 1 j, or a pharmaceutically acceptable salt thereof
  • a compound according to paragraph 8 wherein in R 1 is selected from methyl, ethyl, propyl and isopropyl, in particular isopropyl.
  • R 4 is a 9 or 13 membered heterocycle.
  • R 4 is a 13 membered heterocycle, for example a partially saturated heterocycle, such as tetrahydrocarbazole.
  • R 6 is H.
  • R 8 is H or methyl, eg H.
  • a pharmaceutical composition comprising a compound according to any one of paragraphs 1 to 35, and a pharmaceutically acceptable 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 compound according to any one of paragraphs 1 to 35 or a composition according to paragraph 36 for use in die manufacture of a medicament for 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.
  • a compound for use or a method according to any one of paragraphs 37 to 39 furdier comprising one or more checkpoint inhibitors, for example selected from the group comprising: PD-1 inhibitor, PD-L1 inhibitor, PD-1.2 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 ADP Ribose polymerase (PARP) inhibitor and Mytl inhibitor, in particular a PD-1 inhibitor, a PD-L1 inhibitor and/or a CTLA-4 inhibitor.
  • checkpoint inhibitors for example selected from the group comprising: PD-1 inhibitor, PD-L1 inhibitor, PD-1.2 inhibitor, CTLA-4 inhibitor, checkpoint kinase inhibitor 1 (CHE
  • 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], 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, in particular a PD-1 inhibitor, a PD-L1 inhibitor and/or a CTLA-4 inhibitor.
  • R ! is not H.
  • R 2 is not H. in one embodiment
  • R 3 is not H.
  • R ! and R 2 are not H. in one embodiment R ; and R 3 are not H.
  • R 2 and R 3 are not H.
  • R 1 , R 2 and R 3 are not H.
  • m is 1 and n Is 1 or 2
  • Y Is pyridine one or both of R 5 and R e are not H. in one embodiment when Y is pyridine one or both of R 3 and R & are not H.
  • R 3 is not II.
  • R 6 is not H. in one embodiment both R 3 and R 6 are notH.
  • R 9 is notH. In one embodiment R 9 ' is not H. In one embodiment R !0 is not H.
  • R 1 is independently selected from H, methyl, -CH2OCH3., -CH2OH, CF? note -CHzNfCHsja, such as H or methyl.
  • R 2 is methyl or H, such as H.
  • 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 3 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 5 and RY in particular a 5 or 6 membered ring, especially a nitrogen containing ring.
  • 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, tetrahydrocarbazole and tetrahydropyridoindole.
  • R 4 is a 9 membered heterocycle, for example a het.eroaromat.ic, such as tryptophan.
  • R 4 is a 13 membered heterocycle, for example a partially saturated heterocycle, such as tetrahydrocarbazole.
  • R 3 is independently selected from the group comprising oxo, methyl, ethyl, -CF3, -OCF3, -OCH3 and halogen, such as halogen, for example fluoro.
  • R 6 is independently selected from methyl, ethyl, -OCI-R, and H, such as H.
  • Y is aromatic. In one embodiment Y is partially saturated.
  • R 9 is independently selected from R 9 is H, methyl, OCF3. and - Cs-scycloalkyl, such asH, 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 40 is Independently selected from H, F and methyl such as H or r, in particular FI.
  • X is NR 11 .
  • Y is independently selected from pyrimidine, pyridine, pyridone, triazole and thiazole, in particular pyrimidine and or pyridine.
  • compounds of the disclosure have an activity of in an assay of human PBMC inhibition of CD3/CD28 induced IL-22 release.
  • the compounds of the disclosure have activity in an U937 assay, for exampie as disclosure herein.
  • the compounds of the present invention effectively inhibit AhR.
  • Said compounds are useful for the treatment or 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 contextof 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 nomsmah ceil and small ceil 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 a metastatic cancer.
  • 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.
  • Ci-3 alkyl 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 eaikylene refers to strait or branched chain alkyl of 1 to 6 carbons in length bearing terminal substituent, such as an alcohol, for example -CHzCHaCHz-substiiitesit is a straight chain alkylene.
  • a branch may terminate in an alkyl group to the satisfy the valency of the atoms, for example "CHzCHfCH ⁇ -substitnent is a C3 branched chain alkylene.
  • Ci-s alkoxy 7 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 -OCH3) 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 -ClfeF, -CHjCL, -CHF?, -CHCL2, -CF 3 , -CCL 2 , -CH2CF3, -CF 2 CF 3 , -CH 2 CHCL 2 , -CHCCU
  • C(O] represents carbonyl.
  • C'35 cydoalkyl 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.
  • 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, cyclobutane, cyclopentane, cyclohexane, azetidine, oxetane, thietane, tetrahydrofuran, tetrahydrothiophene, oxathiolane, 1,3 -dioxolane, pyrazoiidine, 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.
  • the ring is a saturated carbocyclic ring.
  • the ring in a saturated heterocyclic ring in one embodiment the ring in a saturated heterocyclic ring.
  • the ring is partially saturated or aromatic.
  • the ring is partially saturated or aromatic carbocycle.
  • the ring is partially saturated or aromatic heterocycle.
  • the ring is 5 membered, in one embodiment the 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.
  • 5 or 6 membered heteroaryi 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
  • 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, isoinclole, indolizine, indazole, benzimidazole, azainclole, pyrazolopyrimidine, purine, benzofuran, isobenzofuran, benzothiophene, benzoisooxazole, benzoisothiazole, benzoxazole, benzothiadiazole, adenine, guanine, tetrahydroquinoline, dihydroisoquinoline, quinoline, isoquinoiine, quinoilzine, quinoxaline, phthalazine, cinnoline, napthrhyridine, pyridopyrimidine
  • R 4 is a 9 or 10 membered heteroaryl.
  • 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, benzothiadlazoie, adenine, guanine, tetrahydroquinoiine, dihydroisoquinoline, quinoline, isoquinoline, quinolizine, quinoxaline, phthalazine, cinnoline, napthrhyridine, pyrido
  • the 9 or 10 membered heteroaryl is selected from indolylyl and benzimidazolyl, such as indol-3-yl or benzimidazole-2-yl.
  • the compounds of the present disclosure can be prepared by methods described herein.
  • reaction is a condensation reaction.
  • 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 VV, 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 ail pharmaceutically acceptable salts, such as, without limitation, acid addition salts of strong mineral acids such as HC1 and HBr salts and addition salts 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, intravaginal 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.
  • 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.
  • a compound of the present disclosure for use in the manufacture of a medicament for the treatment of cancer.
  • the 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.
  • the 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.
  • the 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.
  • the biliary duct cancer is in an intrahepatic bile duct. In one embodiment the 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 the biliary duct cancer is in a cystic duct. In one embodiment the biliary duct cancer is in a common bile duct. In one embodiment the 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.
  • the tumour is a solid tumour.
  • the cancer is a primary cancer, secondary cancer, metastasis or combination thereof.
  • the 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.
  • the treatment according to the present disclosure is suitable for the treatment of primary cancer, secondary cancer and metastases.
  • the treatment according to the present disclosure is suitable for the treatment of cancerous cells in a lymph node.
  • the liver cancer is primary liver cancer. In one embodiment the 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, II, HI 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 toierance/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.
  • 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 cells and tissues, for example alkylating agents, antimetabolites 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 :; depending on the exact cancer. Often the dose is in the range about 70 to about IQOmg/m 2 .
  • Nitrogen mustards include mechlorethamine, cyclophosphamide, melphalan, chlorambucil, rfosfamide and busulfan.
  • Nitrosoureas include N-Nitroso-N -methylurea (MNU), carmustine (BCNU), lomustine (CCNU) and semustine (MeCCNU), fotemustine and streptozotocm, Tetrazines include dacarbazine, mitozoiomide and temozolomide.
  • Aziridines include thiotepa, mytomycin and dlazlquone (AZQ).
  • antimetabolites examples include anti-folates (for example methotrexate and pemetrexed), purine analogues (for example thiopurines, such as azathiopurine, mercaptopurine, thiopurine, fluclarabine (including the phosphate form), pentostatin and cladribine), pyrimidine analogues (for example fluoropyrimidines, such as 5-fiuorouracil 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, fluclarabine (including the phosphate
  • anthracyclines examples include daunorubicin (Daunomycin), daunorubicin (liposomal), doxorubicin (Adriamycin), doxorubicin (liposomal), eplrubicin, idarubicin, valrubicin (currently used only to treat bladder cancer] and mitoxantrone an anthracycline analog, in particular 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 vinorelbine, vindesine, and vinfiunine
  • 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 formulations, 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 1 topoisomerase inhibitors, type 11 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 11 poisons include amsacrine, etoposide, etoposide phosphate, teniposide and doxorubicin and fluoroquinolones.
  • chemotherapeutic agents employed is, for example a platin and 5-Fli 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 (Xeiox).
  • 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-' IV over 90 minutes') concurrently with folinic acid (400 mg/nr : [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-Hydroxyphenyl)amino]-3-pyridinyl]-4- methoxybenzenesulfonamide (ABT-751), a taxol 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-Hydroxyphenyl)amino]-3-pyridinyl]-4- methoxybenzenesulfonamide (ABT-751), a taxol derived chemotherapeutic agent, for example paclitaxel, abraxane, or docetaxel or a combination thereof.
  • the chemotherapy combination comprises an antimetabolite such as capecitabine (xeloda), fludarabine phosphate, fludarabine (lludara), decitabine, raltitrexed (tomudex), gemcitabine hydrochloride and ciadribine.
  • an antimetabolite such as capecitabine (xeloda), fludarabine phosphate, fludarabine (lludara), decitabine, raltitrexed (tomudex), gemcitabine hydrochloride and ciadribine.
  • the anticancer therapy combination employs an mTor inhibitor.
  • mTor inhibitors include: everolimus (RAD001), WYE-354, KU-0063794, papamycin (Sirolimus), Temsirohmus, DeforoIlmus(MK-8669), AZD8055 and BEZ235(NVP-BEZ235).
  • the anticancer therapy combination employs a MEK inhibitor.
  • MEK inhibitors include: AS703026, CI-1040 (PD184352), AZD6244 (Selumetinib), PD318088, PD0325901, AZD8330, PD98059, U0126-ECOH, BIX 02189 or BIX 02188.
  • the chemotherapy combination employs an AKT inhibitor.
  • AKT 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, CCT129202 and Hesperadin.
  • the chemotherapy combination employs a p38 inhibitor, for example as disclosed in W02010/038086, such as JV-[4-( ⁇ 4-[3-(3-tert-Butyl-l-p-tolyl-l/7-pyrazol-5- ynureldo]naphthaiem l-yloxy ⁇ methyl)pyridim2-yi]-2-methoxyacetamlde.
  • a p38 inhibitor for example as disclosed in W02010/038086, such as JV-[4-( ⁇ 4-[3-(3-tert-Butyl-l-p-tolyl-l/7-pyrazol-5- ynureldo]naphthaiem l-yloxy ⁇ methyl)pyridim2-yi]-2-methoxyacetamlde.
  • the combination employs a BcI-2 inhibitor.
  • BcI-2 inhibitors include: obatociax mesylate, ABT-737, ABT-263fnavitodax) and T ’W- 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, Poly ADP Ribose polymerase (PARP) inhibitor and Mytl inhibitor.
  • PD-1 Inhibitor PD-L1/L2 inhibitor
  • CTLA-4 inhibitor CTLA-4 inhibitor
  • checkpoint kinase inhibitor 1 CHEK1/CHK1
  • checkpoint kinase inhibitor 2 CHEK2/ CHK2
  • ATR Ataxia telangiectasia and Rad3 related
  • ATM ataxia-telangiectasia mutated
  • 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-L1 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; nivoiumab (also known as OPDIVO®, 5C4, BMS- 936558, MDX-1106, and ONO-4538 ⁇ , pembrolizumab (Merck: also known as KEYTRUDA®, lambrollzumab, and MK-3475), PDR001 (Novartis; also known as spartalizumab), MEDI- 0680 (AstraZeneca; also known as AMP- 514), cemiplirnab (Regeneron; also known as REGN-2810), JS001 or "toripalimab” (TAIZHOU JUNSHI PHARMA), BGB-A317 ("Tislelizumab;” Beigene), 1NCSHR1210 (Jiangsu Hengrui Medicine; also known as “camrelizumab,”, SHR- 1210), TSR-042 or "dostarlimab” (Tesar
  • the checkpoint inhibitor is pembrolizumab. In one embodiment the checkpoint inhibitor is nivolumab. in one embodiment the checkpoint inhibitor is cemiplirnab. In one embodiment the checkpoint inhibitor is dostarlimab.
  • the checkpoint inhibitor is a PD-L1 inhibitor.
  • the PD- L1 inhibitor is selected from the group comprising: atezohzumab (Tecentriq), avelumab (Bavencio), durvalumab (Imfinzi), KN035, CK-301 (Checkpoint Therapeutics), AUNP12 (Aurigene), CA-170 (Aurigen/Curis) and BMS-986189 (BMS).
  • the checkpoint inhibitor is atezolizumab. 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 BGB-290 a PARP-1 and P ARP-2 inhibitor (structure not shown); MP-124 a PARP-1 inhibitor or a pharmaceutically acceptable salt or solvate of any one of the same.
  • 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-[(Aminocarbonyllamino]-3-(3-fiuorophenyi)-N-(3S)-3-piperidinyl-2- thiophenecarboxamide hydrochloride; [3R,4S)-4-[[2-(5-Fluoro-2-hydroxypbenyl)-6,7-dimethoxy-4-quinazohnyI]amino]- a,a-dimethyI-3-pyrrc4idinemethanoI dihydrochloride; 4,4'-diacetyIdiphenylurea bis(guanylhydrazone) ditosyl ate; 9-Hydroxy-4-phenyl-pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione; (R)-a-Amino-N-[5,6-dihydro-2-(l-methyl-l-
  • 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.
  • multiple cycles of treatment for example 2, 3, 4, 5, 6, 7 or 8.
  • the present compounds can be made by methods analogous to those described in W02020/039093 and PCT/SG2021/050095 both incorporated herein by reference.
  • the reaction mixture was evaporated to dryness and applied to a silica column as a slurry in DCM; or preabsorbed onto celite, which was loaded in to a dry load unit and placed in series with a silica cartridge.
  • the desired product was eluted with a gradient of ethyl acetate in hexane, sometimes more polar eluent of methanol (0-10%) in ethyl acetate may be required. Further chromatography on silica eluting with 7M ammonia in methanol (0-10%) in DCM may be required. Trituration with diethyl ether and subsequent filtration afforded the desired product.
  • Example 2 2"(5-flnoropyiidin-3-yI)"N-(2-(2"methyl-lH-indol-3-yI)ethyI)-:W"(oxetan-3- yl) ⁇ 6,7,8,9-tetrahydro ⁇ 5H-6,9-epiminocydohepta[d]pyrimidin ⁇ 4-amiiw Prepared accordingto an analogous procedure to that of JAG-557 using 4-(5-fluoro-3-pyridyl)-N-[2- (2-metbyl-lH-indol-3-yl)ethyl]-3,5,12-triazatrk ⁇ cIo[7.2,1.02,7]dodeca-2(7),3,5-trien-6-amine hydrochloride (85 mg, 0.17 mmol, 1.0 eq), triethyiamine (0.046 mL, 0.33 mmol, 2.0 eq), 3-oxetanone (0.053
  • Example 6 was made employing generic route 3.
  • the SCX cartridge so formed was washed through with a 1 : 1 (v/v) mixture of methanol an water (10 mb), then methanol (2 * 10 mL).
  • the product was eluted as the free base, eluting with 7M ammonia in methanol (20 mL).
  • the free based material was evaporated, then triturated with diethyl ether and filtered to afford the desired product as a brown solid (35 mg, 54%).
  • AhR antagonism was assessed in U937 cells (myeloid lineage cell line derived from a human histiocytic lymphoma).
  • Ligand binds the AhR in the cytoplasm, and the AhR-ligand complex translocates to the nucleus and forms a heterodimer with AhR nuclear translocator (Arnt).
  • This complex binds the xenobiot.ic response element (XRE) in the .T upstream region of the CYP1A1 promoter, enhancing CYP1A1 expression, CYP1A1 activity is subsequently determined by assessing the conversion of Luciferin-CEE to luciferin, which in turn reacts with luciferase to produce light. The amount of light produced is directly proportional to cytochrome P45Q activity.
  • U937 cells in Ultraculture serum free media were plated at 100,000 cells per well in a round bottom 96 well tissue culture plate. Seven concentrations of test compound (final [DMSO] 1%) were added and incubated for 10 minutes before the addition of 300pM KYNA. The plates were then placed in an incubator at 37°C, > 85% humidity, 5% COj for 24hrs. After aspiration of the supernatant the CYP1A1 substrate Luciferin-CEE ([Final] 83 pM) was added and incubated for 3 hrs before the reaction was stopped by adding iuciterin detection reagent and luminescence was read after 20 minutes.

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Abstract

Compounds of the general formula (I) 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.

Description

Compounds Useful in Modulation of AhR Signalling
The present invention relates to compounds of the general formula (1) and sub-formula's thereof 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 cells (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 m yi hydrocarbon receptor (AhR) 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 Hsp90 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. The AhR is best known for binding to environmental toxins and inducing various members of the cytochrome P450 family including CYP1A1, 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 et al., Pharmacol Ther, 2018, 185:50).
AhR is expressed in many immune cell types including dendritic cells, macrophages, T cells, NK cells and B cells and plays an important role in immunoregulation (Quintana &. Sherr, Pharmacol Rev, 2013, 65: 1148; Nguyen et a/., Front Immunol, 2014, 5:551). The toxic/adverse effects of classical exogenous AhR agonists, such as 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) are well known and include profound immunosuppression and initiation of malignancy (Esser el: al., Trends Immunol, 2009, 30:447; Feng et al., Biochimica et Biophysics Acta, 2013, 1836:197). Physiological effects of AhR agonists on immune cells include promotion of regulatory T cell (Treg) generation (Pot, Swiss Med Wkly, 2012, 142:wl3592), modulation of Thl7 cell differentiation and activation (Baricza el: al., Cell Mol Eife Sei, 2016, 73:95) and stimulation of interleukin-22 (IL-22) expression and/or release from human activated peripheral blood mononuclear cells and T cells (Ramirez et al., Ear 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 al., J Immunol, 2010, 185:3190; Nguyen et at, 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 ofTre-gs (Jurado- Manzano et al, 2017, Immunol Lett, 190:84).
In addition to xenobiotics, the AhR can also bind metabolic products of tryptophan degradation including kynurenine (KYN) and kynurenic acid (KYNA). Indoleamine 2,3 dioxygenase 1 and 2 (ID01/ID02) and tryptophan 2,3 -dioxygenase 2 (TDO2) catalyse the commitment step of the KYN metabolic pathway and are expressed in immune ceils (IDO1) and a range of cancer cells (IDO1 andTDO2) (Piiotte etal., Proc Nat Acad Sei, 2012, 109:2497). Inhibitors of IDO1 have attracted much interest as potential new' treatments to stimulate the immune system to recognize and eliminate cancer cells (Cheong & Sun, Trends Pharmacol Sci, 2018, 39:307). Traditionally the immunosuppressive effect of IDO1 has been attributed mainly to reduced levels of tryptophan, which activates the kinase GCN2 (general control non-derepressibie 2) and inhibits T cell proliferation/activation both in tumour draining lymph nodes lymph nodes and in the tumour micro-environment More recently ithas become apparent that some of the efficacy of IDO inhibitors may be the result of decreased production of AhR agonists. These endogenously generated AhR agonists have been shown to elicit a range of effects on immune ceils including upregulation of IDO1 in dendritic cells (Julliard e/;u/,, Front Immunol, 2014, 5:458), inhibition ofhuman T cell proliferation (Frumento et al., J Exp Med, 2002: 196:459; Terness et al, J Exp Med, 2002; 196: 447: Opitz et al, Nature, 2011, 478:197] and up-regulation of PD-1 expression in cytotoxic T lymphocytes (Liu etaL, Cancer Cell, 2018; 33:480). As highlighted above, IDO1 is not. the only source of endogenous AhR agonists. 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 «/,, Nature, 2011, 478:197; Piiotte et al, Proc Nat Acad Sci, 2012, 109:2497; D'Amato etal., Cancer Res, 2015, 75(21):4651; Hsu etal, Oncotarget, 2016, 7(19): 27584; Chen et m.. Dis Markers, 2016, 2016:8169724). Such data suggests that 7thR antagonists may have broader efficacy than selective IDO-1 inhibitors, as they will attenuate endogenous AhR agonist signalling regardless of its source. This assertion was given more weight by the recent discovery of another enzyme, Interleukin-4 induced 1 (IL4U), capable of generating endogenous AhR agonists (Sadik et al, Cell, 2020, 182:10).
In addition to their effects on immune cells, such endogenous agonists have also been implicated in cancer progression via direct effects on the tumour. For example, KYN increases human glioblastoma cell survival and migration (Opitz etal., Nature, 2011, 478:197). Several other studies also implicate the AhR in cancer progression in the absence of environmental ligands. The AhR-repressor (AHRR) protein acts as a tumour suppressor gene in several human cancers (Zudaire et a/., J Clin Invest, 2008, 118:640). AhR expression and "constitutive" (endogenous ligand-driven) activity' in breast cancer ceils correlate with tumour aggressiveness (Schlezinger et al., Biol Chem, 2006, 387:1175; Yang el: al., J Cell Biochem, 2008, 104:402] and control expression of genes associated with tumour invasion (Yang et al., Oncogene, 2005, 24:7869). Ectopic AhR expression in non-malignant human mammary epithelial cells induces an epithelial-to-mesenchymal transition and a > 50% increase in cell growth rates (Brooks S Eltom, Curr Cancer Drug Targets, 2011, 11:654) and AhR knockdown induced gene changes in human breast cancer ceil lines consistent with a mesenchymal to epithelial ceil reversion to a less aggressive phenotype (Narasimhan et al., Int J Mol Sci, 2018, 19:1388). AhR antagonists or AhR knockdowm 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 etal., Cancer Res, 2015, 75(21):4651; Narasimhan etal., Int J Mol Sci, 2018, 19:1388) and to reduce survival of glioblastoma cells (Gramatzki et al., Oncogene, 2009, 28:2593; Opitz et al, Nature, 2011, 478:197; Guastella et al., ] Neuro-oncol, 2018, in press). Finally, AhR antagonists block the formation of tumourspheres (Stanford et al., Moi 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.
Thus, AhR agonists released from immune ceils and from tumour cells 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 dysregulated immune functions. Thus such agents may also have utility in a range of other diseases/ conditions including but not limited to, obesity (Rojas et al., Jnt J Obesity, 2020, 44:948) and various viral infections (Giovannoni er m’., NatNeurosci. 2020, 23:939; Giovannoni et 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 dysregulated immune responses or other disorders associated with aberrant. AhR signalling. In particular, W02017/202816 W02018/146010 and W02019/101642 relate inter alia to heterocyclic compounds capable of inhibiting AhR function.
W0202Q/Q81840 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--amido-lH-indol-2tyl 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 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.
W02020/043880 relates to heterocyclic compounds which are ARH inhibitors, for prevention of diseases, in particular cancer or conditions with dysregulated 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.
W0202Q/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 ceils 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 in part, by AhR.
WO 2018/195397 relates to compositions and methods for indole AhR inhibitors. WO 2018/146010 relates to the preparation of 2-heteroaryi-3-oxo-2,3-dmydropyridazine- 4-carboxamides for the treatmentor prophylaxis of diseases, in particular cancer or conditions with dysregulated immune responses, as a sole agent or in combination with other active ingredients.
W02010/059401 relates to compounds and compositions for expanding the number of CD34v cells for transplantation. In particular, 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. In particular, W02012/015914 relates fotera/fo to heterocyclic compounds that modulate AhR activity for use in therapeutic compositions to inhibit cancer ceil proliferation and tumour cell invasion and metastasis.
W02020/0512Q7 relates to AhR antagonists as well as methods of modulating AhR activity and expanding hematopoietic stem cells by culturing hematopoietic stem or progenitor ceils in the presence of these agents. Additionally, 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, surprisingly the presently claimed compounds are potent inhibitors of AhR, in particular inhibitors, for example in an assay disclosed herein.
SUMMARY OF THE PRESENT DISCLOSURE
A compound of formula (I)
Figure imgf000005_0001
CI) wherein:
¥ is phenyl or a 3 to 6 membered ring optionally comprising 1, 2, or 3 heteroatoms selected from N, 0 and S, said phenyl or ring substituted with R5 and R6;
R* is H or Ci-3 alkyl, C3.5 cycloalkyl, halogen and C1.3 alkyl optionally bearing one or more groups independently selected from ORY, halogen -NR"RS- such as ORY and halogen (e.g. F) in particular only one group;
R2 is H, C : : alkyl or halogen; wherein R1 & R2 together can form an alkylene bridge -CH2CH2- or -CHz-between two carbons In the ring;
R3 is H or C 1 3 alkyl: R4 is a 9 to 13 membered heterocycle with at least one heteroatom selected from N, 0 and S (for an aromatic or partially saturated), with substituents R9, R9' and R10;
R5 is H, oxo, hydroxy, halogen (such as F, Cl), CN, C1-3 alkyl, C1.3 alkoxy (such as OMe), Ci-2 haloalkyl (i.e. alkyl bearing 1 to 6 halogen groups, such as CF3 J, C1 3 alkyl bearing one or more OH groups, -C(O](CH2)qNR7R8, -SO2Ci-3 alkyl, -SO? NR7R8,
R° is H, oxo, hydroxy, halogen (such as F, Cl), CN, Cs.3 alkyl, -C(O)(CH2)qNR7R8, -SO2C1.3 alky], ■SO? NR7R8,
R7 is H, C1.3 alkyl, or -C(O)ORY, for example H or C1.3 alkyl, such as -CH3;
R* is H or C1-3 alkyl, such as -CH?,;
R9 is H, hydroxy, halogen (such as F, Cl), CN, C1.3 alkyl, C1 3 alkoxy (such as OMe), C1.3 alkyl bearing 1 to 6 halogen groups (such as CF?), C1.3 alkyl bearing one or more 0RY groups, Cj-scydoalkyl, -(CHjlqOCr? alkyl substituted with 1 to 6 halogen groups (such as - (CH2)qOCF?,), -CO(CH?)q NR7R8, -SO2C1-3 alkyl, or -SO2 NR7R8;
R9' is H, OH, halogen (such as F, Cl), CN, C 1.3 alkyl, C 3-3 alkoxy (such as OMe), C1.3 alkyl bearing 1 to 6 halo groups (such as CF?,), C1-3 alkyl bearing one or more OH groups, -CO(CH?)q NR7R8, - SO2C1-?, alkyl, or -SO? NR7R8;
R: o is H, hydroxy, halogen (such as F, Cl), CN, C1.3 alkyl, -C(O)(CH?)q NR7R8; -SO2C1.3 alkyl, or -SO? NR7R8;
R11 is H or fo ; alkyl (such as -CH 3);
R" is H or Chalky! for example H or C1.3 alkyl (such as H, -CH? or - CH2CH3);
X is CH2, S, -S02, NRn or 0; b is 0, 1 or 2; n is 1 or 2; m is 1 or 2; p is an integer 1, 2 or 3 (such as 1): q is 0, 1, 2 or 3 (such as 0 or 1), or a pharmaceutically acceptable salt thereof
1. A compound of formula (I)
Figure imgf000006_0001
wherein:
Y is phenyl or a 3 to 6 membered ring optionally comprising 1, 2, or 3 heteroatoms selected from N, 0 and S, said phenyl or ring substituted with R5 and R6;
Rd is H or C1-3 alkyl, C? . cycloalkyl;
R2 is H or Ci.? alkyl; wherein R! & R2 together can form an alkylene bridge -CH2CH2- between two carbons in the ring;
R3 is H or C1.3 alkyl;
R4 is a 9 to 13 membered heterocycle with at least one heteroatom selected from N, 0 and S (for an aromatic or partially saturated), with substituents R9, R9' and R10:
R5 is H, hydroxy, halogen (such as F, Cl), CN, C1.3 alkyl, C1.3 alkoxy (such as OMe),
C-...2 haloalkyl (i.e. alkyl bearing 1 to 6 halogen groups, such as CF3), C1 3 alkyl bearing one or more OH groups, -C(O)(CH2)qNR'R8, -SO2C1.3 alkyl, -SO2 NR7R8,
R6 is I-I, hydroxy, halogen (such as F, CJ), CN, C1.3 alky], -C(O)(CH2)qNR7R* ■SO2C1..3 alkyl, -SO2 NR7R8,
R7 is H, C1.3 alkyl, such as -CH3;
R8 is H or C 3-3 alkyl, such as -CH3;
R9 is H, hydroxy, halogen (such as F, Cl), CN, C1.3 alkyl, C1.3 alkoxy (such as OMe), C 33 alkyl bearing 1 to 6 halogen groups (such as CF3), C1.3 alkyl bearing one or more ORy groups, Cs-scycloalkyl, -(CHzJqOCi-aalkyl substituted with 1 to 6 halogen groups (such as - (CH2)qOCF3), -CO(CH2)q NR7R3, -SO2C1.3 alky], or -SO? NR7R8;
R9 is H, OH, halogen (such as F, Cl), CN, C1.3 alkyl, C1.3 alkoxy (such as OMe), C1.3 alkyl bearing 1 to 6 halo groups (such as CF3), C1.3 alkyl bearing one or more OH groups, -CO(CH2)q NR7R8, - SO2G.3 alkyl, or -SO2 NR7R8;
R19 is H, hydroxy, halogen (such as F, Cl), CN, C1.3 alkyl, -C(O)(CH2)q NR7R8;
-SO2C1.3 alkyl, or -SO2 NR7R8;
R14 is H or C1-3 alkyl (such as -CH-,];
X is CI-12, S, -SO2, NR44 or 0; b is 0, 1 or 2: n is 1 or 2; m is 1 or 2; p is an integer 1, 2 or 3 (such as 1); q is 0, 1, 2 or 3 (such as 0 or 1 j, or a pharmaceutically acceptable salt thereof A compound according to paragraph 1, which has a formula (II):
Figure imgf000007_0001
wherein R4, R2, R3, R4, X, Y, b, n and m are defined above for compounds of formula (I) or a pharmaceutically acceptable salt thereof,
A compound according to paragraph 1 or 2 wherein Y is a 5 or 6 membered nitrogen containing ring. A compound according to paragraph 3, wherein the ring is aromatic, A compound according to paragraph 4, wherein the ring is pyrimidine or pyridine, A compound according to paragraph 5, which has a formula [111]:
Figure imgf000008_0001
wherein Ri, R2, R3, R4 R5, R6 X, b, n and m are defined above for compounds of formula (I) or a pharmaceutically acceptable salt thereof, A compound of formula [1] according to paragraph 5 or 6, wherein R5 is located at position 5 on the pyridine. A compound according to any one of paragraphs 1 to 7, wherein R ! is hydrogen or -C1..3 alkyl, in particular H. A compound according to paragraph 8, wherein in R1 is selected from methyl, ethyl, propyl and isopropyl, in particular isopropyl. A compound according to any one of paragraphs 1 to 9, wherein R2 is H or methyl, eg H, A compound according to any one of paragraphs 1 to 7, wherein R1 and R2 together represent -CH2CH2- or -NH- A compound according to any one of paragraphs 1 to 11, wherein R3 is H. A compound according to any one of paragraphs 1 to 12, wherein R4 is a 9 or 13 membered heterocycle. A compound according to paragraph 13, wherein R4 is a 9 membered heterocycle, for example a heteroaromat.ic, such as tryptophan. A compound according to paragraph 13, wherein R4 is a 13 membered heterocycle, for example a partially saturated heterocycle, such as tetrahydrocarbazole. A compound according to any one of paragraphs 1 to 15, wherein R3 is a halogen, for example fluoro, A compound according to any one of paragraphs 1 to 16, wherein R6 is H. A compound according to any one of paragraphs 1 to 17, wherein R7 is H or methyl, eg H, A compound according to any one of paragraphs 1 to 18, wherein R8 is H or methyl, eg H. A compound according to any one of paragraphs 1 to 19, wherein R9 is H, C1-3 alkyl (such a methyl) or C3.5 cycioalkyl (such as cyclopropyl], in particular H; A compound according to any one of paragraphs 1 to 20, wherein R9' is H or halo (such as fluoro), in particular H. A compound according to any one of paragraphs 1 to 21, wherein R1G is H or halo (such as fluoro], in particular H. A compound according to any one of paragraphs 1 to 22, wherein X is NR11. A compound according to any one of paragraphs 1 to 23, w’herein R! ! is H.
A compound according to any one of paragraphs 1 to 24, wherein m is 1.
A compound according to any one of paragraphs 1 to 24, wherein m is 2.
A compound according to any one of paragraphs 1 to 26, wherein n is 1.
A compound according to any one of paragraphs 1 to 26, wherein n is 2.
A compound according to any one of paragraphs 1 to 28, which iias a formula (IV):
Figure imgf000009_0001
iivj or a pharmaceutically acceptable salt thereof
A compound according any one of paragraphs 1 to 28, which has a formula (V):
Figure imgf000009_0002
(VI or a pharmaceutically acceptable salt thereof.
A compound according any one of paragraphs 1 to 28, which has a formula (VI):
Figure imgf000009_0003
or a pharmaceutically acceptable salt thereof.
A compound according any one of paragraphs 1 to 28, which has a formula (VII):
Figure imgf000010_0001
or a pharmaceutically acceptable salt thereof.
A compound according any one of paragraphs 1 to 28, which has a formula (VH1):
Figure imgf000010_0002
or a pharmaceutically acceptable salt thereof. A compound according any one of paragraphs 1 to 28, which has a formula (IX):
Figure imgf000010_0003
or a pharmaceutically acceptable salt thereof.
A compound according to paragraph 1, selected from:
Figure imgf000010_0004
Figure imgf000011_0001
Figure imgf000012_0001
a pharmaceutical acceptable salt of any one of the same, A pharmaceutical composition comprising a compound according to any one of paragraphs 1 to 35, and a pharmaceutically acceptable 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 compound according to any one of paragraphs 1 to 35 or a composition according to paragraph 36, for use in die manufacture of a medicament for 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. A compound for use or a method according to any one of paragraphs 37 to 39, furdier comprising one or more checkpoint inhibitors, for example selected from the group comprising: PD-1 inhibitor, PD-L1 inhibitor, PD-1.2 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 ADP Ribose polymerase (PARP) inhibitor and Mytl inhibitor, in particular a PD-1 inhibitor, a PD-L1 inhibitor and/or a CTLA-4 inhibitor. 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], 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, in particular a PD-1 inhibitor, a PD-L1 inhibitor and/or a CTLA-4 inhibitor. A process of preparing a compound of formula (I) according to any one of claims 1 to 35 by reacting a compound of formula (X):
Figure imgf000013_0001
(X) and Y’-R* wherein R1, RY R R4, X, m and n are defined for compounds of formula (I) and Y' is an activated derivative of Y also defined in formula (Il and Rx is the activating group.
In one embodiment R! is not H. In one embodiment R2 is not H. in one embodiment R3 is not H. In one embodiment. R! and R2 are not H. in one embodiment R; and R3 are not H. In one embodiment R2 and R3 are not H. In one embodiment R1, R2 and R3 are not H. In one embodiment when m is 1 and n Is 1 or 2, and Y Is pyridine one or both of R5 and Re are not H. in one embodiment when Y is pyridine one or both of R3 and R& are not H.
In one embodiment R3 is not II. In one embodiment R6 is not H. in one embodiment both R3 and R6 are notH. In one embodiment R9 is notH. In one embodiment R9' is not H. In one embodiment R!0 is not H.
R1 is independently selected from H, methyl, -CH2OCH3., -CH2OH, CF?„ -CHzNfCHsja, such as H or methyl.
R2 is methyl or H, such as H.
In one embodiment Y is a 3 to 6 membered ring optionally comprising 1, 2, or 3 heteroatoms selected from N, 0 and S, each substituted with R3 and R6, for example a 5 to 6 membered ring comprising 1, 2, or 3 heteroatoms selected from N, 0 and S, each substituted with R5 and RY in particular a 5 or 6 membered ring, especially a nitrogen containing ring.
In one embodiment R4 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, tetrahydrocarbazole and tetrahydropyridoindole.In one embodiment R4 is a 9 membered heterocycle, for example a het.eroaromat.ic, such as tryptophan.
In one embodiment R4 is a 13 membered heterocycle, for example a partially saturated heterocycle, such as tetrahydrocarbazole.
In one embodiment R3 is independently selected from the group comprising oxo, methyl, ethyl, -CF3, -OCF3, -OCH3 and halogen, such as halogen, for example fluoro.
R6 is independently selected from methyl, ethyl, -OCI-R, and H, such as H.
In one embodiment Y is aromatic. In one embodiment Y is partially saturated.
R9 is independently selected from R9 is H, methyl, OCF3. and - Cs-scycloalkyl, such asH, methyl, or ■ Cs-scycloalkyl, alternatively H, methyl or OCF3.
In one embodiment R9' is independently selected from H, F and methyl such as H or F.
In one embodiment R40 is Independently selected from H, F and methyl such as H or r, in particular FI. In one embodiment X is NR11.
In one embodiment Y is independently selected from pyrimidine, pyridine, pyridone, triazole and thiazole, in particular pyrimidine and or pyridine. in one embodiment compounds of the disclosure have an activity of in an assay of human PBMC inhibition of CD3/CD28 induced IL-22 release.
In one embodiment the compounds of the disclosure have activity in an U937 assay, for exampie as disclosure herein.
The compounds of the present invention effectively inhibit AhR. Said compounds are useful for the treatment or 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 contextof cancer, inappropriate cellular immune responses, and inappropriate cellular inflammatory responses.
In one embodiment the compounds of the present disclosure are useful in the treatment of cancer for example, liquid and/or solid tumours, and/or metastases thereof. Examples of cancers include head and neck cancer (such as brain tumours and brain metastases], cancer of the thorax including nomsmah ceil and small ceil 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.
In one embodiment the cancer is an epithelial cancer, in one embodiment the cancer is a sarcoma. In one embodiment the cancer is a metastatic cancer.
DETAILED DISCLOSURE
Generally, 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.
Ci-3 alkyl 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 eaikylene as employed herein refers to strait or branched chain alkyl of 1 to 6 carbons in length bearing terminal substituent, such as an alcohol, for example -CHzCHaCHz-substiiitesit is a straight chain alkylene. When the alkylene is branched then a branch may terminate in an alkyl group to the satisfy the valency of the atoms, for example "CHzCHfCH^-substitnent is a C3 branched chain alkylene.
Ci-s alkoxy7 as employed here 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 -OCH3) 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.
Examples of alkyl bearing up to 6 halogen groups include -ClfeF, -CHjCL, -CHF?, -CHCL2, -CF3, -CCL2, -CH2CF3, -CF2CF3, -CH2CHCL2, -CHCCU
C(O] represents carbonyl. C'35 cydoalkyl 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,
In one embodiment 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.
In one embodiment the ring is saturated. Examples of saturated rings include cyclopropane, cyclobutane, cyclopentane, cyclohexane, azetidine, oxetane, thietane, tetrahydrofuran, tetrahydrothiophene, oxathiolane, 1,3 -dioxolane, pyrazoiidine, pyrrolidine, thiolane, imidazoline, piperidine, tetrahydropyran, dioxane, morpholine, thiane, dithiane, piperazine and thiomorpholine.
In one embodiment there is provided 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, 4H thiopyran, 4H-l,2-oxazlne, 2H-l,2-oxazine, 6H-l,2-oxazine, 4H-1,3- oxazine, 6H-1, 3 -oxazine, 4H- l,4-oxazine, 4H-1, 4- thiazine, 2H- 1,2 -thiazine, 6H-1, 2- thiazine.
In one embodiment there is provided a 5 or 6 membered ring 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, where there are 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, for example as defined above, such as thiophene, furan, pyrroline, pyrrole, pyrazole, imidazole, oxazole, isoxazole, thiazole, isothiazole, triazole, pyridine, pyrimidine, pyrazine, triazine, thiazine, oxazine, pyrroline, 4-H pyran, thiopyran, .
In one embodiment 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 embodiment the 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.
5 or 6 membered heteroaryi 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. 9 to 13 membered heterocycle as employed herein 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 as employed herein 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, isoinclole, indolizine, indazole, benzimidazole, azainclole, pyrazolopyrimidine, purine, benzofuran, isobenzofuran, benzothiophene, benzoisooxazole, benzoisothiazole, benzoxazole, benzothiadiazole, adenine, guanine, tetrahydroquinoline, dihydroisoquinoline, quinoline, isoquinoiine, quinoilzine, quinoxaline, phthalazine, cinnoline, napthrhyridine, pyridopyrimidine, pyridopyrazine, pyridopyrazine, pteridine, chromene, isochromene, chromenone, benzoxazine, quinolinone, isoquinolinone, dibenzofuran, carbazole, acridine, phenothiazine, 2,3,4,9-tetrahydro-lH-carbazoie.
In one embodiment R4 is a 9 or 10 membered heteroaryl.
9 to 10 membered heteroaryl as employed herein 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, benzothiadlazoie, adenine, guanine, tetrahydroquinoiine, dihydroisoquinoline, quinoline, isoquinoline, quinolizine, quinoxaline, phthalazine, cinnoline, napthrhyridine, pyridopyrimidine, pyridopyrazine, pyridopyrazine, pteridine, chromene, isochromene, chromenone, benzoxazine, quinolinone, and isoquinolinone.
In one embodiment the 9 or 10 membered heteroaryl is selected from indolylyl and benzimidazolyl, such as indol-3-yl or benzimidazole-2-yl.
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 (X):
Figure imgf000016_0001
wherein R!, R2, R3, R4, X, m and n are defined for compounds of formula (I) and Y’ is an activated derivative of Y also defined in formula fi) and Rs is foe activating group.
In one embodiment the reaction is a condensation reaction. GENERIC ROUTE 1
Figure imgf000017_0001
aromatic substitution
Figure imgf000017_0002
Protecting
Figure imgf000017_0003
Reductive group amination
Figure imgf000017_0004
cieavage
Figure imgf000018_0001
Reduction oc- protec on Dieckmann condensation
Figure imgf000018_0002
Figure imgf000018_0003
Figure imgf000019_0001
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 VV, Greene and Peter G.M. Wuts, published by john Wiley & Sons Inc; 4th Rev Ed., 2006, ISBN- 10: 0471697540.
Examples of salts of compound of the present disclosure include ail pharmaceutically acceptable salts, such as, without limitation, acid addition salts of strong mineral acids such as HC1 and HBr salts and addition salts of strong organic acids, such as a methansulfonic acid salt.
The present disclosure extends to solvates of the compounds disclosed herein. Examples of 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.
Also provided herein a pharmaceutically composition comprising a compound according to the present disclosure and an excipient, diluent or carrier. A thorough discussion of pharmaceutically acceptable carriers is available in Remington's Pharmaceutical Sciences (Mack Publishing Company, NJ. 1991).
The pharmaceutical 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, intravaginal or rectal routes. Hyposprays may also be used to administer the pharmaceutical compositions of the invention. in one embodiment 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 (including lyophilised solids) may be selected from aqueous solutions, for example saline, dextrose or water for injection and the like. In one embodiment the reconstituted liquid formulation Is isotonic.
In one embodiment the pharmaceutical composition according to the present disclosure is provided as a tablet or a capsule for oral administration.
TREATMENT
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 die treatment of cancer.
In a further aspect there is provided a compound of the present disclosure (or a pharmaceutical composition comprising the same) for use in the manufacture of a medicament for the treatment of cancer. In one embodiment the 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.
In one embodiment the 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.
In one embodiment the 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.
In one embodiment the biliary duct cancer is in an intrahepatic bile duct. In one embodiment the 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 the biliary duct cancer is in a cystic duct. In one embodiment the biliary duct cancer is in a common bile duct. In one embodiment the biliary duct cancer is in an Ampulla of Vater. In one embodiment the epithelial cancer Is a carcinoma.
In one embodiment the treatment according to the disclosure is adjuvant therapy, for example after surgery.
In one embodiment the therapy according to the disclosure is neoadjuvant treatment, for example to shrink a tumour before surgery.
In one embodiment the tumour is a solid tumour. In one embodiment the cancer is a primary cancer, secondary cancer, metastasis or combination thereof In one embodiment the treatment according to the present disclosure is suitable for the treatment of secondary tumours. In one embodiment the cancer is metastatic cancer. In one embodiment the treatment according to the present disclosure is suitable for the treatment of primary cancer and metastases. In one embodiment 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 the treatment of primary cancer, secondary cancer and metastases.
In one embodiment the treatment according to the present disclosure is suitable for the treatment of cancerous cells in a lymph node.
In one embodiment the liver cancer is primary liver cancer. In one embodiment the liver cancer is secondary liver cancer. In one embodiment the liver cancer is stage 1, 2, 3A, 3B, 3C, 4A or 4B.
In one embodiment the gastric cancer is stage 0, 1, II, HI 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 toierance/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
In one embodiment the compound of the present disclosure is employed in combination therapy, for example wherein the further therapy is an anticancer therapy.
In one embodiment 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 cells and tissues, for example alkylating agents, antimetabolites 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.
Examples of 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 (also referred to as platins) 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:; depending on the exact cancer. Often the dose is in the range about 70 to about IQOmg/m2.
Nitrogen mustards include mechlorethamine, cyclophosphamide, melphalan, chlorambucil, rfosfamide and busulfan.
Nitrosoureas include N-Nitroso-N -methylurea (MNU), carmustine (BCNU), lomustine (CCNU) and semustine (MeCCNU), fotemustine and streptozotocm, Tetrazines include dacarbazine, mitozoiomide and temozolomide.
Aziridines include thiotepa, mytomycin and dlazlquone (AZQ).
Examples of antimetabolites, which may be employed in the method of the present disclosure, include anti-folates (for example methotrexate and pemetrexed), purine analogues (for example thiopurines, such as azathiopurine, mercaptopurine, thiopurine, fluclarabine (including the phosphate form), pentostatin and cladribine), pyrimidine analogues (for example fluoropyrimidines, such as 5-fiuorouracil and prodrugs thereof such as capecitabine [Xeloda®]), floxuridine, gemcitabine, cytarabine, decitabine, raltitrexed(tomudex) hydrochloride, cladribine and 6-azauracil.
Examples of anthracyclines, which may be employed in the method of the present disclosure, include daunorubicin (Daunomycin), daunorubicin (liposomal), doxorubicin (Adriamycin), doxorubicin (liposomal), eplrubicin, idarubicin, valrubicin (currently used only to treat bladder cancer] and mitoxantrone an anthracycline analog, in particular doxorubicin. Examples of anti- microtubule agents, which may be employed in the method of the present disclosure, include vinca alkaloids and taxanes.
Vinca alkaloids include completely natural chemicals, for example vincristine and vinblastine and also semi-synthetic vinca alkaloids, for example vinorelbine, vindesine, and vinfiunine
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 formulations, 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 1 topoisomerase inhibitors, type 11 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:
Figure imgf000023_0001
Type 11 poisons include amsacrine, etoposide, etoposide phosphate, teniposide and doxorubicin and fluoroquinolones.
In one embodiment a combination of chemotherapeutic agents employed is, for example a platin and 5-Fli or a prodrug thereof, for example cisplatin or oxaplatin and capecitabine or gemcitabine, such as FOLFOX,
In one embodiment the chemotherapy comprises a combination of chemotherapy agents, in particular cytotoxic chemotherapeutic agents,
In one embodiment the chemotherapy combination comprises a platin, such as cisplatin and fluorouracil or capecitabine.
In one embodiment the chemotherapy combination in capecitabine and oxaliplatin (Xeiox).
In one embodiment the chemotherapy is a combination of folinic acid and 5-FU, optionally in combination with oxaliplatin.
In one embodiment 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-' IV over 90 minutes') concurrently with folinic acid (400 mg/nr: [or 2 x 250 mg/m2] IV over 120 minutes): followed by fluorouracil (400-500 mg/m2 IV bolus] then fluorouracil (2400-3000 mg/m2 intravenous infusion over 46 hours). This cycle is typically repeated every two weeks. The dosages shown above may vary from cycle to cycle.
In one embodiment the chemotherapy combination employs a microtubule inhibitor, for example vincristine sulphate, epothilone A, N-[2-[(4-Hydroxyphenyl)amino]-3-pyridinyl]-4- methoxybenzenesulfonamide (ABT-751), a taxol derived chemotherapeutic agent, for example paclitaxel, abraxane, or docetaxel or a combination thereof. In one embodiment the chemotherapy combination comprises an antimetabolite such as capecitabine (xeloda), fludarabine phosphate, fludarabine (lludara), decitabine, raltitrexed (tomudex), gemcitabine hydrochloride and ciadribine. in one embodiment the anticancer therapy combination employs an mTor inhibitor. Examples of mTor inhibitors include: everolimus (RAD001), WYE-354, KU-0063794, papamycin (Sirolimus), Temsirohmus, DeforoIlmus(MK-8669), AZD8055 and BEZ235(NVP-BEZ235).
In one embodiment the anticancer therapy combination employs a MEK inhibitor. Examples of MEK inhibitors include: AS703026, CI-1040 (PD184352), AZD6244 (Selumetinib), PD318088, PD0325901, AZD8330, PD98059, U0126-ECOH, BIX 02189 or BIX 02188.
In one embodiment the chemotherapy combination employs an AKT inhibitor. Examples of AKT inhibitors include; MK-2206 and AT7867.
In one embodiment the anticancer therapy employs an aurora kinase inhibitor. Examples of aurora kinase inhibitors Include: Aurora A Inhibitor I, VX-680, AZD1152-HQPA (Barasertib), SNS- 314 Mesylate, PHA-680632, ZM-447439, CCT129202 and Hesperadin.
In one embodiment the chemotherapy combination employs a p38 inhibitor, for example as disclosed in W02010/038086, such as JV-[4-({4-[3-(3-tert-Butyl-l-p-tolyl-l/7-pyrazol-5- ynureldo]naphthaiem l-yloxy}methyl)pyridim2-yi]-2-methoxyacetamlde.
In one embodiment the combination employs a BcI-2 inhibitor. Examples of BcI-2 inhibitors include: obatociax mesylate, ABT-737, ABT-263fnavitodax) and T ’W- 37.
In one embodiment the chemotherapy combination comprises ganciclovir, which may assist in controlling immune responses and/or tumour vasculation.
In one embodiment the anticancer therapy includes a PARP inhibitor.
In one embodiment the anticancer therapy includes an Inhibitor of cancer metabolism with specific inhibition of the activity of the DHODH enzyme.
In one embodiment the compound of the present disclosure is employed in combination (for example in a combination therapy) with a checkpoint inhibitor. Thus, the present disclosure provides a combination therapy comprising a compound or pharmaceutical composition of the present disclosure, and a checkpoint inhibitor or a combination of checkpoint inhibitors.
In one embodiment 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, Poly ADP Ribose polymerase (PARP) inhibitor and Mytl inhibitor.
In one embodiment 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. In one embodiment a combination of a PD-1 inhibitor and a PD-L1 inhibitor is employed. In one embodiment a combination of a PD-1 and a CTA-4 inhibitor is employed. In one embodiment, a combination of a PD-L1 and CTA-4 inhibitor is employed. In one embodiment, a combination of a PD-1, PD-L1 and a CTA-4 inhibitor is employed. in one embodiment, the checkpoint inhibitor Is a PD-1 inhibitor. In one embodiment, the PD- 1 inhibitor is selected from the group comprising; nivoiumab (also known as OPDIVO®, 5C4, BMS- 936558, MDX-1106, and ONO-4538}, pembrolizumab (Merck: also known as KEYTRUDA®, lambrollzumab, and MK-3475), PDR001 (Novartis; also known as spartalizumab), MEDI- 0680 (AstraZeneca; also known as AMP- 514), cemiplirnab (Regeneron; also known as REGN-2810), JS001 or "toripalimab” (TAIZHOU JUNSHI PHARMA), BGB-A317 ("Tislelizumab;" Beigene), 1NCSHR1210 (Jiangsu Hengrui Medicine; also known as “camrelizumab,”, SHR- 1210), TSR-042 or "dostarlimab" (Tesaro Biopharmaceutical; also known as ANB011), GLS- 010 (VVuxi/Harbin Gloria Pharmaceuticals; also known as WBP3055), STI- 1110 (Sorrento Therapeutics), AGEN2034 or "balstilimab" (Agenus), MGA012 or "retifanlimab" (Macrogenics), IBI308 or “sinitllimab" (Innovent), BCD-100 or "bevacizamab" (Biocad), and JTX-4014 (Jounce Therapeutics).
In one embodiment, the checkpoint inhibitor is pembrolizumab. In one embodiment the checkpoint inhibitor is nivolumab. in one embodiment the checkpoint inhibitor is cemiplirnab. In one embodiment the checkpoint inhibitor is dostarlimab.
In one embodiment the checkpoint inhibitor is a PD-L1 inhibitor. In one embodiment the PD- L1 inhibitor is selected from the group comprising: atezohzumab (Tecentriq), avelumab (Bavencio), durvalumab (Imfinzi), KN035, CK-301 (Checkpoint Therapeutics), AUNP12 (Aurigene), CA-170 (Aurigen/Curis) and BMS-986189 (BMS).
In one embodiment, the checkpoint inhibitor is atezolizumab. In one embodiment, the checkpoint inhibitor is avelumab. In one embodiment, the checkpoint inhibitor is durvalumab.
In one embodiment, the checkpoint inhibitor is a CTLA-4- inhibitor. In one embodiment the CTLA-4 inhibitor is selected from the group comprising: ipilimumab (Yervoy), tremelimumab BGB-290 a PARP-1 and P ARP-2 inhibitor (structure not shown); MP-124 a PARP-1 inhibitor or a pharmaceutically acceptable salt or solvate of any one of the same.
In one embodiment 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.
In one embodiment the checkpoint kinase inhibitor is independently selected from: 3-[(Aminocarbonyllamino]-3-(3-fiuorophenyi)-N-(3S)-3-piperidinyl-2- thiophenecarboxamide hydrochloride; [3R,4S)-4-[[2-(5-Fluoro-2-hydroxypbenyl)-6,7-dimethoxy-4-quinazohnyI]amino]- a,a-dimethyI-3-pyrrc4idinemethanoI dihydrochloride; 4,4'-diacetyIdiphenylurea bis(guanylhydrazone) ditosyl ate; 9-Hydroxy-4-phenyl-pyrrolo[3,4-c]carbazole-l,3(2H,6H)-dione; (R)-a-Amino-N-[5,6-dihydro-2-(l-methyl-lH-pyrazol-4-yl)-6-oxo-lH-pyrrolo[4,3,2-ef|[2,3]benzo diazepin-8-yl] -cyclohexaneacetamide; 9,10,11,12-Tetrahydro- 9,12-epoxy- lH-diindolo[l,2,3- fg:3',2',l'-ki]pyrrolo[3,4-iJ| l,6]benzodiazocine-l,3(2H)-dione; 4’- [5- [[3- [(Cyclopropyl ammo)metbyl]phenyI]amino]-lH-pyrazo]-3-yl]-[l,l'-bipbenyl]-2,4-dioI; and (R)-5-((4-((Morpholin-2-yhnethyl)amino)-5-(trifluoromethyl)pyridin-2-yl)amino)pyrazine-2- carbonitrile (CCT245737).
In one embodiment 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.
In one embodiment, there is provided the use of multiple cycles of treatment, (such as chemotherapy) for example 2, 3, 4, 5, 6, 7 or 8.
Comprising” in the context of the present specification is intended to mean "including". Where technically appropriate, embodiments of the invention may be combined. Embodiments are described herein as comprising certain features/elements. The disclosure also extends to separate embodiments consisting or consisting essentially of said features/elements.
Technical references such as patents and applications are incorporated herein by reference. Any embodiments specifically and explicitly recited herein may form the basis of a disclaimer either alone or in combination with one or more further embodiments.
The invention will now be described with reference to the following examples, which are merely illustrative and should not be construed as limiting the scope of the present invention.
EXAMPLES
The present compounds can be made by methods analogous to those described in W02020/039093 and PCT/SG2021/050095 both incorporated herein by reference.
General method A (tryptamine)
A suitable round bottom flask or reactl-vial was charged with aryl halide (1 equiv.), tryptamine (1.1 equiv.), IPA (lOmL/mmol) and triethylamine (2 equiv.) and heated at 100°C for 3 h (reaction monitored by UPLC analysis). On cooling the reaction mixture was evaporated to dryness and the resultant residue partitioned between ethyl acetate and water. The organic phase was separated and sequentially washed with saturated bicarbonate solution, water, brine, then dried over sodium sulfate, filtered and evaporated. Purification, if required was performed by chromatography or trituration.
General method B (Suzuki)
A suitable round bottom flask or reacti-vial was charged with aryl halide (lequiv.), aryl boronic acid (1.5-2.0 equiv.), potassium carbonate (1, 5-2.0 equiv.), dioxane/vvater ([5:1] about 60 vol). Head space was flushed with nitrogen gas, then (l,l''-Bis(diphenyiphosphino) ferrocene]dichloropalladium(ll j dichloride (0.2-0.3 equiv.) was added. The reaction mixture was heated under nitrogen at 100°C for 2-24 h until complete as determined by UPLC analysis. The reaction mixture was evaporated to dryness and applied to a silica column as a slurry in DCM; or preabsorbed onto celite, which was loaded in to a dry load unit and placed in series with a silica cartridge. The desired product was eluted with a gradient of ethyl acetate in hexane, sometimes more polar eluent of methanol (0-10%) in ethyl acetate may be required. Further chromatography on silica eluting with 7M ammonia in methanol (0-10%) in DCM may be required. Trituration with diethyl ether and subsequent filtration afforded the desired product.
Examples 1 to 4 were made by generic route 2.
Example 1 ethyl (E)~5-(3~ethoxy-3-oxoprop-l-en~l-yI)-lH-pyrrole-2-€arboxylate
Figure imgf000026_0001
A cook'd suspension of sodium hydride (1.56 g, 38.9 mmol, 1.3 eq) in 1,4-dioxane (36 mL) was treated with ethyl 2-(diethoxyphosphoryl)acetate (8.3 mL, 41.9 mmol, 1.4 eq), and the resulting mixture was stirred at O °C for 3 h, Ethyl 5-forroyl-lH-pyrroIe-2-carboxylate (5.0 g. 29.9 mmol, 1.0 eq) was added, and the resulting mixture was stirred at ambient temperature for 18 h. The reaction mixture was quenched by the additional of a saturated solution of aqueous ammonium chloride (50 mL] and extracted into diethyl ether (5 * 50 mL). The combined organics were washed with brine
(50 mL), dried (NajSCU), filtered and concentrated under reduced pressure. The crude material was triturated in a 9:1 (v/v) mixture of n heptane and EtOAc [70 mL], filtered and dried under vacuum to afford the desired product as a solid (6.3 g, 26.4 mmol, 88.5%).
UPLC-MS (2 min basic): rtw 1.07 min (M-H- - 236.1). m NMR (400 MHz, DMSO) 6 12.31 (s, 1H), 7.51 (dd, J - 16.0, 1.6 Hz, 1H), 6.82 (dd, J - 4.0, 1.5 Hz, 1H), 6.74 (dd, J = 4.0, 1.6 Hz, 1H), 6.60 (dd, J = 16.0, 1.6 Hz, 1H), 4.27 (qd, J = 7.1, 1.6 Hz, 2H], 4.16 (qd, J = 7.2, 1.6 Hz, 2H), 1.34 ■■ 1.21 (m, 6H). ethyl 5"(3-ethoxy-3"Oxopropyl)pyrrofidine-2-carboxylate
Figure imgf000027_0001
A mixture of ethyl 54(lE)-3-etiwxy-3-oxoprop-l-en-l-yl]-lH-pyrrole-2-carboxylate (1.0 g, 4.22 mmol, 1.0 eq] and rhodium on alumina [(0.70 gj, corresponding to 0.34 mmol Rh (0.08 eq)], was suspended in acetic acid (4.0 mL] under nitrogen at ambient temperature. The flask was vacuum purged with hydrogen gas, and the resulting mixture was stirred at ambient temperature under hydrogen for 12 h. The crude reaction mixture was passed through a pad of Celite, washing with DCM (2 x 10 mL). The combined filtrate and washings were washed sequentially with a saturated solution of aqueous sodium bicarbonate (10 mb) and brine (10 mL), before being dried (NajSCH), filtered and concentrated under reduced pressure to afford the desired product as an oil (0.99 g, 4.09 mmol, 96.9%). The product was used without further purification.
H-l NMR (400 MHz, DMSO) 6 4.12 ■■ 4.00 (m, 4H), 3.64 (dd, J = 8.9, 5.4 Hz, 1H), 2.97 (p, J = 6.9 Hz, 1H), 2.85 (s, 1H], 2.42 -- 2.33 (m, 1H], 2.33 -- 2.24 (m, 1H), 2.00 - 1.86 (m, 1 H ), 1.85 - 1.71 (m, 2H), 1.62 (q, J - 7.4 Hz, 2H), 1.33 - 1.23 (m, 1H), 1.23 - 1.12 (m, 6H). l-(tert-butyl) 2-ethyl 5-(3"ethoxy-3"Oxopropyl)pyrroIidine-l,2-dicarbGxylate
Figure imgf000027_0002
A solution of ethyl 5-(3-ethoxy-3-oxopropyl)pyrrohdine-2-carboxylate (1.85 g, 7.60 mmol, 1.0 eq) and di-tert-butyl dicarbonate (1.83 g, 8.36 mmol, 1.10 eq) in dichloromethane (15.2 mL) was slowly charged with triethyiamine (2.1 mL, 15.21 mmol, 2.0 eq). The resulting reaction mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with DCM (TO mL) and washed with water, brine, dried over Na2SO4, filtered and concentrated to afford the desired product as an oil (2.72 g, 7.524 mmol, 99.0%).
UPLC-MS/ELSD (2 min basic): rt = 1.19 min (M+H+ = 344.2, M-Boc+H+ = 244.1).
LH NMR (400 MHz, DMSO) 5 4.25-3,98 (m,5H), 3.91 - 3.75 (m,l H), 2.42 -2.27 (m,2H), 2.25 - 2.13 (m,lH), 2.01 - 1.77 (m,3H), 1.75 - 1.59 (m,2H), 1.44 - 1.24 (m,9H), 1.25 - 1.14 (m,6H).
8- (tert- butyl) 3-ethyl 2-oxo-8-azabicydu[3.2.1]octane-3,8-dicarboxyIate
Figure imgf000028_0001
A stirring solution of l-(tert-butyl) 2 --ethyl 5-(3-ethoxy-3-oxopropy])pyrrolidine-l,2-dicarboxylate ( 1.00 eq, 1.35 g, 3.73 mmol) In THE (30 mL) and Potassium tert-butoxide (1.20 eq, 0.50 g, 4.48 mmol) was heated at 60° C for 2h.
The reaction was cooled and concentrated under reduced pressure. The residue was resuspended in DCM (20 ml q and washed with sat. NH4C1. The aqueous layer was re-extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine, dried (NazSOa), filtered and concentrated under reduced pressure to afford the desired product as an oil (0.99 g, 3,16 mmol, 84.7%). UPLC -MS (2 min acidic): rt = 1.26 min (M-Boc%l+ = 198.1). HI NMR (400 MHz, DMSO) 5 11.78 (s, 1H), 4.25 (s, 2H), 4.20 - 4.01 (m, 6H], 3.87 (dd, J = 11.1, 7.8 Hz, 1H), 2.64 (s, 1H), 2.22 - 2.02 in:, 4H), 2.02 - 1.82 ( m, 4H), 1.70 - 1.55 (m, 2H), 1.38 (s, 18H), 1.25 - 1.15 (m, 6H). tert-butyl 2-(5-fluoropyridin-3-yl)-4-hydroxy-6,7,8,9-tetrahydro-5H-6,9 epiminocydohepta(d]pyrtmidme-10-carboxylate
Figure imgf000028_0002
A stirred solution of 8- (tert-butyl) 3-ethyl 2-oxo-8-azabicyclo[3,2.1]octane-3,8-dicarboxylate (0.99 g, 3,16 mmol, 1.0 eq) in ethanol (25 mL) was treated with 5-tluoropyridine-3-carboxamidine hydrochloride (555 mg, 3.16 mmol, 1.0 eq) and potassium tert-butoxide (1.06 g, 9.49 mmol, 3.0 eq), and the resulting mixture was stirred at ambient temperature for 18 h. The reaction mixture was evaporated under reduced pressure. Water (20 mb) was added to the residue to obtain a solution which was acidified with citric acid added portion wise to pH --3. The resulting suspension was filtered. The solid precipitate was washed with the minimum amount of water and vacuum dried at 45 °C to afford the desired product as a solid (0.77 g, 1.84 mmol, 58.2%).
UPLC-MS (2 min acidic): rt - 1.00 mins (M-f-H-s- - 373.2, M-H- - 371.2) lH NMR (400 MHz, DMSO) 89.14 (s, 1H), 8.74 (d, J - 2.8 Hz, 1H), 8.36 - 8.26 (m, 1 H), 4.63 (cl, J = 5.5 Hz, 1H), 4.42 (s, 1H), 2.84 (dd, J = 17.7, 4.8 Hz, 1H), 2.39 - 2.09 (m, 3H), 2.00 - 1.87 (m, 1H), 1.62 (s,
Figure imgf000028_0003
-127.02. tert-butyl 4-chIoro-2-(5-fluoropyridin-3-yI)-6,7,8,9-tetrahydro-5H-6(9- epiminocyclohepta [d] pyrimidine- 1 O-carboxylate
Figure imgf000028_0004
A suspension of tert-butyl 2-(5-fluoropyridin-3-yl)-4-hydroxy-6,7,8,9-tetrahydro-5H-6,9 epiminocyclohepta[d]pyrimidine-10-carboxylate (0.72 g, 1.72 mmol, 1.0 eq] and triphenylphosphine (1.35 g, 5.16 mmol, 3.0 eq] in 1,2-dichloroethane (17mL) was treated with carbon tetrachloride (0.66 mL, 6.88 mmol, 4.0 eq), and the resulting mixture was stirred at 70 °C for 1 h. The solvent was evaporated to afford a residue, which was purified by automated column chromatography (24 g column), eluting with 25% EtOAc in iso-hexane to afford the desired product as a solid (0.57 g, 1.44 mmol, 83.9%). UPLC-MS (2 min basic): rt- 1.32 mins (M+H+ - 391.3/393,3) 1H NMR (400 MHz, DMSO) S 9.31 (t, J = 1.7 Hz, 1H), 8.79 (d, J - 2.8 Hz, 1 H), 8.50 - 8.31 (m, 1H), 4.94 (cl, J = 6.4 Hz, 1H], 4.56 (s, 1H), 3.14 (dd, J = 17.8, 5.1 Hz, 1H), 2.69 (d, J = 17.6 Hz, 1H), 2.33 - 2.13 Im, 2H), 2.02 - 1.91 (m, 1H), 1.83 - 1.69 (m, 1H), 1.27 (s, 9H).
19F NMR (376 MHz, DMSO) 6 -126.66. tert-butyl 4~((2~(lH-indol-3-yl)ethyI)amino)-2~(5-fluoropyridm-3-yI)-6,7,8(9-tetrahydro- 5H-6,9-epiminocydohepta[d]pyrimidine-10-carboxyIate
Figure imgf000029_0001
Prepared according to general method A, using tert- butyl 4-chloro-2-(5-fluoropyridin-3-yl)-6, 7,8,9- tetrahydro-5H-6,9-epiminocyclohepta[d]pyrimidine-10-carboxylate (0.18 g, 0.46 mmol, 1.0 eq], 2- (lH-indoh3-yl)ethan-l-amine (97 mg, 0.61 mmol, 1.32 eq] and triethylamine (0.13 mL, 0.92 mmol, 2.0 eq). The crude product was thoroughly washed with water followed by a 5:1 (v/v) mixture of iso-hexane and diethyl ether ( 1 mL), before being dried under vacuum to afford the desired product as a solid (0.21 g, 0.41 mmol, 88.6%).
UPLC-MS (2 mm basic): rt = 1.27 mins (M+H+ = 515.3, M-H- = 513.3]
! H NMR (400 MHz, DMSO) 8 10.83 is, 1H), 9.33 (t, j = 1.7 Hz, 1H), 8.68 (d, J = 2.9 Hz, 1H), 8.40 - 8.29 (m, 1H), 7.58 (d, J = 7.9 Hz, 1H), 7.37 - 7.30 (ro, 1H), 7.20 (d, ] = 2.3 Hz, 1H], 7.15 (t, J = 5.7 Hz, 1H), 7.10 - 7.04 (ro, 1H), 7.00 - 6.94 (ro, 1H), 4.68 (d, J = 5.9 Hz, 1 H), 4.49 (s, 1H), 3.85 - 3.68 (m, 2H), 3.03 (t, J = 7.5 Hz, 2H], 2.88 (d, j = 15.6 Hz, 1H], 2.30 - 2.04 (m, 3H], 1.94 - 1.84 (m, 1H], 1.70 - 1.58 (m, 1 H), 1.36 (
Figure imgf000029_0002
127.65.
N-(2-(lH"indol-3"yl)ethyI)-2"(5-fluoropyridin-3-yl)"6,7,8,9-tetrahydro"5H-6,9- epiminocydohepta[d]pyrimidin-4~amine hydrochloride
Figure imgf000029_0003
A 4M solution of hydrogen chloride (2.0 mb, 7.97 mmol, 20.0 eq) in 1,4-dioxane was added to a suspension of tert- butyl 4-{[2-(2-ethyl-lH-indoI-3-yl)ethyI]arnino}-2-(5-fluoropyridin-3-yl)- 5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate) (0.21 g, 0.398 mmol, 1,0 eq) in dichloromethane (2.4 mL], The reaction mixture was stirred at ambient temperature for 1 h. The reaction mixture was evaporated to dryness to obtain an orange residue which was triturated with 9:1 (v/v) mixture of diethyl ether and MeOH (10 mb), filtered, washed with diethyl ether (10 mi,) and dried under vacuum at 45 CC to afford the desired product as a solid (0,18 g 0,39 mmol, 100%), UPLC-MS (4 min basic): rt = 1,66 mins (M+H+ = 415,3, M-H- = 413.3) iH NMR (400 MHz, DMSO) 6 10.87 (s, 1H), 9.72 (s, 1H), 9.48 (d, J = 10.1 Hz, 1H), 9.34 (t, J = 1.7 Hz, 1H), 8.73 (d, J - 2,9 Hz, 1H), 8.42 - 8.34 (m, 1H), 7.67 - 7.51 (m, 2H), 7.39 - 7.30 (m, 1H), 7.23 (d, J - 2.2 Hz, 1H), 7.13 - 7.04 (m, 1H), 7.03 - 6.95 (m, 1H), 4.64 (d, J = 5,2 Hz, 1H), 4.46 (s, 1 H), 3.89 - 3.76 (m, 2H), 3.09 ■■ 2.94 (m, 3H), 2.44 (d, J = 17.3 Hz, 1H), 2.37 ■■ 2.22 (m, 2H), 2.16 (t, J = 10.4 Hz, 1H), 1.86 - 1.74 (m, 1H) W NMR (376 MHz, DMSO) 6 -127.32.
N"(2-(lH-iiidoI"3-yI)ethyl)"2-(5"f5uoropyridin"3"yl)-10"(oxetaii"3-yl)-6,7,B79"tetrahydro-5H" 6,9-epiminocyclohepta[d]pyrimidm-4"amine
Figure imgf000030_0001
A mixture of N-(2-(lH-mdol-3-yl)ethyl)-2-(5-fluoropyridfn-3-yl)-6,7,8,9-tetrahydro-5H-6,9- epiminocyclohepta[d]pyrimidin-4-amine hydrochloride (60 mg, 0.13 mmol, 1.0 eq), triethylamine (0.037 mL, 0.266 mmol, 2.0 eq), oxetan-3-one (0.043 mb, 0.67 mmol, 5.0 eq') and sodium triacetoxyborohydride (85 mg. 0.39 mmol, 3,0 eq) in 1,2-dichloroethane (1.3 mb) was stirred at 70 °C for 2 h. The mixture was cooled to ambient temperature and partitioned between dichloromethane (10 mb) and a saturated aqueous solution of sodium bicarbonate (10 mb). The organic phase was collected and the aqueous phase was extracted with dichloromethane (3 * 10 mb). The combined organic phases were dried (NasSO^J, filtered and evaporated to dryness to give the crude product as a residue. Purification by automated column chromatography over silica (12 g cartridge), eluting with a gradient of MeOH in dichloromethane (0-10%), gave the desired product as a solid (37 mg, 0.079 mmol, 59.1%). UPLC-MS (4 min basic): rt - 1,72 min (M+H+ - 471.4) Hl NMR (400 MHz, DMSO) 8 10.83 (s, 1H), 9.32 (t, J = 1.7 Hz, 1H), 8.66 (d, J = 2.9 Hz, 1H), 8.38 - 8.27 (m, 1H), 7.58 (dd, J = 7.9, 1.1 Hz, 1H), 7.38 - 7.31 (m, 1H), 7.21 (d, J = 2.1 Hz, 1H), 7.12 - 7.05 (m, 1 H), 7.03 (t, J = 5,8 Hz, 1H), 7.00 - 6.93 (m, 1H), 4.64 (t. .] - 6.3 Hz, 1 H), 4,54 (t, J = 6.2 Hz, 1H), 4.49 - 4.35 (m, 2H), 3.82 - 3.73 (m, 3H), 3.73 - 3.67 (m, 1H), 3.58 ft, J - 5.9 Hz, 1H), 3,04 (t, J = 7.5 Hz, 2H), 2.60 ■■ 2.53 (m, 1 H ), 2.24 ■■ 2.06 (m, 2H), 2.03 (d, J = 16.9 Hz, 1 H ), 1.86 ■■ 1.72 (m, 1 H ), 1.55 - 1.41 (m, 1H). iSF NMR (376 MHz, DMSO) 6 -127.77.
Example 2 2"(5-flnoropyiidin-3-yI)"N-(2-(2"methyl-lH-indol-3-yI)ethyI)-:W"(oxetan-3- yl)~6,7,8,9-tetrahydro~5H-6,9-epiminocydohepta[d]pyrimidin~4-amiiw
Figure imgf000030_0002
Prepared accordingto an analogous procedure to that of JAG-557 using 4-(5-fluoro-3-pyridyl)-N-[2- (2-metbyl-lH-indol-3-yl)ethyl]-3,5,12-triazatrk^cIo[7.2,1.02,7]dodeca-2(7),3,5-trien-6-amine hydrochloride (85 mg, 0.17 mmol, 1.0 eq), triethyiamine (0.046 mL, 0.33 mmol, 2.0 eq), 3-oxetanone (0.053 mL, 0.82 mmol, 5.0 eq) and sodium cyanoborohydride (31 mg, 0.49 mmol, 3.0 eq) in 1,2- dicbloroetbane (2 mb) at. 70 °C. Purification by automated column chromatography over silica (12 g column), eluting with a gradient of MeOH in EtOAc (0- 10%), gave the desired product as solid (42 mg, 0.087 mmol, 52.7%). UPLC-MS (4 min basic): rt = 1.80 min (M+H+ = 485.3)
!H NMR (400 MHz, DMSO) 5 10.69 (s, 1H), 9.31 (t, j = 1.7 Hz, 1H), 8.65 (d, J = 2.9 Hz, 1H), 8.34 - 8.22 (m, 1H), 7.51 - 7.41 (m, 1H), 7.21 (dt, J - 8.0, 1.0 Hz, 1H), 7.03 (t, J - 5.9 Hz, 1H), 7.01 - 6.86
(m, 2H), 4.62 (t, J = 6.3 Hz, 1 H), 4.53 (t, J = 6.1 Hz, 1 H ), 4.49 - 4.35 (m, 2H), 3.84 - 3.51 (m, 5H), 2.95 (dd, J = 8.6, 6.5 Hz, 2H), 2.53 (d, J = 4.8 Hz, 1H), 2.33 (s, 3H), 2.22 - 2.07 (m, 2H), 1.99 (d, J = 17.0 Hz, 1H), 1.85 - 1.73 (m, 1H), 1.56 - 1.42 (m, 1H). NMR (376 MHz, DMSO) 5 -127.87
Example 3 N-(2-(7-fluoro-2-methyl-lH-indol-3-yI)ethyl)-2-(5-fluoropyridin"3-yI)-10- (oxetan-3~yl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[d]pyrimidin-4-amine
Figure imgf000031_0001
Prepared according to an analogous procedure to that of JAG-557 using N-J2-(7-fluorc-2-methyl- lH-indoi-3-yI)ethyi]-4-(5-fluoro-3-pyridyI)-3,5,12-triazatricyclo[7.2.1.02,7]dodeca-2(7),3,5-trien- 6-amine hydrochloride (203 mg, 0.32 mmol, 1.0 eq), triethyiamine (0,089 mb, 0.64 mmol, 2,0 eq), 3-oxetanone (0.10 mb, 1,60 mmo], 5.0 eq) and sodium cyanoborohydride (60 mg, 0.96 mmol, 3.0 eq) in 1,2-dichloroethane (3 mb) at 70 °C. Purification by automated column chromatography over silica (24 g column), eluting with a gradient, of MeOH in EtOAc (0-10%), followed by trituration of the resulting solid in diethyl ether (10 mb) afforded the desired product as a solid (40 mg, 0.077 mmol, 24%). UPLCMS (basic, 4 min): RT= 1.85 min, m/z = 503.3 [M+H+]
*H NMR (400 MHz, DMSO) 8 11.14 (s, 1H), 9.28 (t, J = 1.7 Hz, 1H), 8.66 (d, ] = 2.9 Hz, 1H), 8.25 (ddd, J - 10.1, 2.9, 1.6 Hz, 1 H), 7.28 (d, J - 7,7 Hz, 1H), 7.03 (t, J - 5.9 Hz, 1H), 6.94 - 6.87 (m, 1H), 6.80 ( del, J = 11.6, 7.8 Hz, 1H), 4.63 (t, J = 6.3 Hz, 1H), 4.53 (t, J = 6.1 Hz, 1 H ), 4.44 (t, J = 5.8 Hz, 1H), 4.39 (t, ] = 5.6 Hz, 1H), 3.73 (d, J = 5.7 Hz, 1H), 3.67 (p, J = 7.3, 6.7 Hz, 3H), 3.58 (s, 1H), 3.00 - 2.92 (m, 2H), 2.34 (s, 3H), 2.15 (dd, J - 12.1, 6.3 Hz, 2H), 2.09 (d, J - 4.9 Hz, 1H), 1.98 (d, J - 16.9 Hz, 1H), 1.79 (t, J - 9.5 Hz, 1H), 1.47 (t, J = 8.6 Hz, 1H). NMR (376 MHz, DMSO) 6 -127.86, - 134.39.
Example 4 N-(2~(5,7-difIuoro-2~methyI-lH-indol-3-yl)ethyI)-2-(5-fIuoropyridiu-3-yI)-10- (oxetan-3-yl)-6,7,8,9-tetrahydro-5H-6,9-epiminocy/dohepta[d]pyrimidin-4-amine
Figure imgf000031_0002
Prepared accordingto an analogous procedure to that of jAG-557 using 4-(5-fluoro-3-pyridyi)-N-[2- (2-metbyl-lH-indo]-3-yl)ethyl]-3,5,12-triazatrkycIo[7.2,1.02,7]dodeca-2(7),3,5-trien-6-amme hydrochloride (85 mg, 0.17 mmol, 1.0 eq), triethyiamine (0.046 mL, 0.33 mmol, 2.0 eq), 3-oxetanone (0.053 mL, 0.82 mmol, 5.0 eq) and sodium cyanoborohydride (31 mg, 0.49 mmol, 3.0 eq) in 1,2- dicbloroetbane (2 mL) at 70 °C. Purification by automated column chromatography over silica (12 g column), eluting with a gradient of MeOH in EtOAc (0-10%) afforded the desired product as a solid (42 mg, 0.0867 mmol, 52.68% yield) as an off-white solid.
UPLC-MS (4 min basic): rt- 1.80 mins (M+H+ - 485.3, M-H- - 483.3), 100% iH NMR (400 MHz, DMSO) 8 10.69 (s, 1H), 9.31 (t, J - 1.7 Hz, 1H), 8.65 (d, J = 2.9 Hz, 1H), 8.34 - 8.22 (m, 1H), 7.51 - 7.41 (m, 1H), 7.21 (dt, J = 8.0, 1.0 Hz, 1H), 7.03 (t, J = 5.9 Hz, 1H), 7.01 - 6.86 (m, 2H), 4.62 (t, J = 6.3 Hz, 1 Hl, 4.53 (t, J = 6.1 Hz, 1H), 4.49 - 4.35 (m, 2H), 3.84 - 3.51 (m, 5H), 2.95 (dd, J - 8.6, 6.5 Hz, 2H), 2.53 (d, J = 4.8 Hz, 1H), 2.33 (s, 3H), 2.22 - 2.07 (m, 2H), 1.99 (d, J - 17.0 Hz, 1H), 1.85 - 1.73 (m, 1H), 1.56 - 1.42 (m, 1H). WF NMR (376 MHz, DMSO) 8 -127.87 Example 5 was made by generic route 3
Example 5 tert-butyl 4-((2-(lH-indol-3-yl)ethyl)amino)-2-ebloro-5)6,8,9"tetrahydro-7H"
Figure imgf000032_0001
Prepared according to general method A, using tert-butyl 2,4-dichloro-5H,6H,7H,8H,9H- pyrimido[4,5-d]azepine-7-carboxylate (1.0 g, 3.14 mmol, 1.0 eq), (lH-indol-3-yi)ethan-l-amine (0.55 g, 3.46) mmol, 1.1 eq) and triethylamine (0,87 mL, 6.29 mmol, 2.0 eq). Purification by automated column chromatography over silica (40 g cartridge), eluting with a gradient of EtOAc in iso-hexane (0-100%) afforded the desired product as a solid (0.80 g, 1.34 mmol, 42.6%).
UPLC-MS (2 min basic): rt~ 1.19 min (M+H-f- ~ 442,3/444.4) Cl isotope pattern observed
1H NMR (400 MHz, DMSO) 8 10.85 - 10.77 (m, 1H), 7.65 (t, J = 9.2 Hz, 1H), 7.48 (t, J - 5.5 Hz, 1H), 7.40 - 7.29 (m, 1H), 7.18 (d, J = 2.4 Hz, 1H), 7.07 (ddd, J = 8.1, 6.9, 1.3 Hz, 1H), 6.99 (ddd, J = 8.0, 6.9, 1.1 Hz, i Hl, 3.62 - 3.53 (m, 2H), 3.53 - 3.45 (m, 4H), 3.00 - 2.89 (m, 2H), 2.88 (d, J = 5.9 Hz, 2H), 2.64 (i. J - .5.4 Hz, 2H), 1.39 (s, 9H). tert-butyl 4-((2"(lH-indol-3-yl)ethyl)amino)-2-(5-fluoropyridin"3-yI)-5,6,8,9"tetrahydro- carboxylate
Figure imgf000032_0002
Prepared according to general method B, using tert-butyl 2-chloro-4-{[2-(lH-indol-3- yl)elhyI]amino}-.5H,6H,7H,8H,9H-pyrimido[4,.5-d]azep!ne-7-carboxj,]ate (220 mg, 0,37 mmol, 1.0 eq) and (5-fluoropyridin-3-yi)boronic acid (104 mg, 0.74 mmol, 2.0 eq). Purification by automated column chromatography over silica (40 g cartridge), eluting with a gradient of EtOAc in dichloromethane (20-40%) to afford the desired product as a solid (6)4 mg, 0.13 mmol, 34.1%).
UPLCMS (2 min, basic): rt~ 1.27 min, m/z-503.4 (M+H+)
!H NMR (400 MHz, DMSO) 5 10.83 (s, 1H), 9.34 (t, J = 1.7 Hz, 1H), 8.67 (d, J = 2.9 Hz, 1H), 8.34 (cldd, J - 10.1, 2.9, 1.6 Hz, 1H), 7.59 (d, J - 7.8 Hz, TH), 7,35 (dt, J - 8.0, 1.0 Hz, 1H), 7.28 ft. J - 5.5 Hz, TH), 7.21 (d, J - 2.3 Hz, 1H), 7.07 (ddd, J - 8.1, 6.9, 1.2 Hz, 1H), 6.97 (ddd, J - 8.0, 6.9, 1.0 Hz, 1H), 3.77 (q, j = 6.8 Hz, 2H), 3.56 (t, J = 5.4 Hz, 4H), 3.03 (t, J = 7.6 Hz, 4H), 2.73 (s, 2 H), 1.40 (s, 9H).
19F NMR (376 MHz, DMSO) 8 -127.72
N-(2“(lH-mdob3-yi)ethyl)-2-(5-Huoropyridm-3-yI)-6,7,8,9-tetrahydTO-5H-pyrimido[4,5- dJazepin-4-amine hydrochloride
Figure imgf000033_0001
A stirred solution of tert -butyl 4-((2-(lH-fndo]-3-yl)ethyl)amino)-2-(5-tluoropyridin-3-yI)-5,6,8,9- tetrahydrO“7H-pyrimido[4,5“d]azepine-7-carboxyiate (64 mg, 0.12 mmol, 1.0 eq) in dichioromethane (0.41 mL) was treated with a 4 N solution of hydrogen chloride in 1,4-dioxane (0.62 mL, 2.49 mmol, 20 eq), and the resulting mixture was stirred for 1 h at ambient temperature. The resulting suspension was filtered to give the crude product as a solid, which was washed dichioromethane (5 mL) and diethyl ether (10 mL), before being dried under vacuum to afford the desired product as a solid (51 mg, 0.11 mmol, 87.9%).
UPLCMS (4mln, basic, +): RT-1.00 (94%), m/z- 403.3 (M-CI-)
H-l NMR (400 MHz, DMSO) S 10.92 - 10.84 (m, 1H), 9.54 (s, 2H), 9.30 (t, J - 1.7 Hz, 1H), 8.85 - 8.77 (m, 1H), 8.47 (d, J = 9.8 Hz, 1H), 7.57 (d, J = 7.9 Hz, 1H), 7.33 (dt, J = 8.2, 1.0 Hz, 1H), 7.23 (cl, J = 2.2 Hz, TH), 7.06 (ddd, J - 8.2, 7.0, 1.2 Hz, TH), 6.96 (ddd, J - 7.9, 6.9, 1.1 Hz, 1 H), 3.84 (d, J - 8.4 Hz, 2H), 3.41 (s, 2H), 3.34 (s, 2H), 3.24 (s, 3H), 3.17 - 3.00 (m, 3H). Purity not calculated.
Figure imgf000033_0002
A mixture of N-(2-(lH-indol-3-yI)ethyl)-2-(5-fluoropyridin-3-yl)-6,7,8,9-tetrahydro-5H- pyrimido[4,5-d]azepin-4-amine hydrochloride (51 mg, 0.11 mmol, 1.0 eq), triethylamine (0.030 mb, 0.22 mmol, 2.0 eq), oxetan-3-one (0.035 mb, 0.55 mmol, 5.0 eq) and sodium triacetoxyborohydride (69 mg, 0.33 mmol, 3.0 eq) in 1,2-dichIoroethane (1.1 mb) was stirred at 70 °C for 3 h. The mixture was cooled to ambient, temperature and partitioned between dichloromethane (10 mL) and a saturated aqueous solution of sodium bicarbonate (10 mb). The organic phase was collected and the aqueous phase was extracted with dichloromethane (3 x 10 mL). The combined organic phases were dried (NaaSCR), filtered and evaporated to dryness to give the crude product as a residue. Purification by automated column chromatography over silica (12 g cartridge), eluting with a gradient of MeOH in EtOAc (0 -20%) gave the desired product as a solid (29 mg, 0.06 mmol, 58.1%) UPbCMS (4 min, basic): rt = 1.72 min, m/z = 459.3 (M+H+)
’H NMR (400 MHz, DMSO) S 10.83 (s, 1H), 9.34 (t, J = 1.7 Hz, 1H), 8.66 (d, J = 2.9 Hz, 1H), 8.34 (ddd, J = 10.1, 2.9, 1.6 Hz, III), 7.58 (d, J = 7.8 Hz, 1H), 7.34 (dt. J = 8.1, 0.9 Hz, 1H), 7.31 (t, J = 5.6 Hz, 1H), 7.20 (d, J = 2.3 Hz, 1HJ, 7.07 (ddd, J = 8.2, 7.0, 1.2 Hz, 1H), 6.97 (ddd, ] = 7.9, 7.0, 1.0 Hz, 1H), 4.55 (t, J = 6.4 Hz, 2H), 4.48 (t, J = 6.2 Hz, 2H), 3.76 (q, J = 6.6 Hz, 2H), 3.57 (p, J = 6.5 Hz, 1 H), 3.07 - 3.00 (m, 2H), 3.00 - 2.95 (m, 2H), 2.80 - 2.73 (in, 2H), 2.46 - 2.38 (m, 2H), 2.31 (t, J = 5.0 Hz, 2H).
Purity=100%. 19F NMR (376 MHz, DMSO) 5 - 127.77
Example 6 was made employing generic route 3.
Example 6 t- Butyl 4"((2"(lH-indol-3-yI)ethyl)amino)-2-chloro-5,8-dihydropyHdo[3,4- d j pyrimidine-7 (6H)~carboxylate
Figure imgf000034_0001
Prepared according to genera] method A, using t-butyl 2,4-dichloro-5,8-dihydropyrido[3,4- d]pyrimidine-7(6H)- carboxylate (470 mg') and purification by trituration with DCM, to give the desired product as a beige solid (370 mg, 55%),
UPLC-MS (acidic Method, 2 min): rt l.22 min, m/z 428.2/430,2 [M+H]*
1H NMR (400 MHz, DMSO-d6) 5 ppm 10.82 (br s, 1H), 7.65 (d, )=7.8 Hz, 1 H), 7.54 (br s, 1H), 7.34 (d, J =8.0 Hz, H i ), 7.19 (d, (=2.3 Hz, 1H), 7.07 (td, j=7.5, 1.0 Hz, 1 H ), 6.98 (td, J=7.5, 1.0 Hz, 1H), 4.27
(br s, 2H), 3.49-3.70 (m, 4H), 2.95 (t, J= 13.8 Hz, 2H], 2.36 (br t, J=5.8 Hz, 2H), 1.39-1.49 (m, 9H). tert-butyl 4-((2"(lH-indol-3-yl)ethyl)amino)-2-(5-fluoropyridin"3-yI)-5,8- dihydropyrido[3,4d]pyrimidine-7(6H)-carboxylate
Figure imgf000035_0001
Prepared according to general method B, using t-butyl 4-((2-(lH-indol-3-yl)ethyl)araino)-2-chloro- 5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate (160 mg) and 5-fluoropyridine- 3-boronic acid (90 mg) to give the desired product as a residue (85 mg, 46%),
UPLC-MS (acidic Method, 4 min): rt 2.16 min, m/z 489.2 [M-rHj-r lH NMR (400 MHz, DMSO-d6) 6 ppm 10.83 (s, 1 H), 9.33 (t, (=1.5 Hz, 1H), 8.68 (d, (-2.8 Hz, 1 H), 8.24-8.38 (m, 1H), 7.60 i d, J=7.8 Hz, 1H), 7.34 (d, J=8.0 Hz, 1 H ), 7.30 (br s, 1 H i, 7.21 (cl, J=2.3 Hz, 1H), 7.07 (td, (=7.5, 1.0 Hz, 1H), 6.92-7.00 (m, 1H), 4.41 (s, 2H), 3,74-3.87 (m, 2H), 3.65 (br t, (=5.4 Hz, 2H), 3.04 (t, J=7.5 Hz, 2H), 2.45 (br t, J=5.5 Hz, 2H), 1.35-1.54 (m, 9H).
N-(2~(lI-I-ind01-3-yl)ethyI)-2-(5-fluoropyridin-3-yl)-5,6,7,8-tetrahydropyrido(3,4- d( pyrimidin-4-amine
Figure imgf000035_0002
A S N solution of hydrogen chloride in iso-propan-2-ol (5 mL) was added to a solution of t-butyl 4- ((2-(lH-mdol-3-yl)ethyIjamino)-2-(5-fluoropyridin-3-yI)-5,8-dihydropyrido[3,4-d]pyrimidine- 7(6H)-carboxylate (80 mg) in methanol (5 mb). The reaction mixture darkened in colour. After 18h the reaction mixture was evaporated. Loose SCX resin (1 g) was added followed by water (5 mL) and methanol (5 mL). Spin to mix for about 10 min, then load into a fritted tube and allow to drain. The SCX cartridge so formed was washed through with a 1 : 1 (v/v) mixture of methanol an water (10 mb), then methanol (2 * 10 mL). The product was eluted as the free base, eluting with 7M ammonia in methanol (20 mL). The free based material was evaporated, then triturated with diethyl ether and filtered to afford the desired product as a brown solid (35 mg, 54%).
UPLC-MS (Basic Method, 4 min): rt 1.61 mln, m/z 389.2 [M+H] +
H-l NMR (400 MHz, DMSO-d6) 6 ppm 10.86 (s, 1 H ), 9.32 (t, (=1.5 Hz, 1H), 8.67 (cl, (=3.0 Hz, 1H), 8.26-8.39 (m, 1H), 7.62 (d, J=8.0 Hz, 1H), 7.35 (d, J=8.0 Hz, 1H), 7.22 (d, J-2.0 Hz, 1H), 7.15 (br t, (=5.6 Hz, 1H), 7.05-7.10 (m, 1H), 6.91-7.01 (m, 1H), 3.74-3.85 (m, 2H), 3.72 (s, 2H), 2.90-3.09 (m, 4H), 2.75-2.85 (m, 1H), 2.33 (br t, (=5.5 Hz, 2H).
! 9F NMR (400 MHz, DMSO-d6) 6 ppm -127.75 proton decoupled
N"(2-(lH-indoI"3-yI)ethyl)-2-(5"fluoropyridin-3-yl)-7-(oxetan-3"yl)-.5,6,7,8- tetrahydropyrido[3,4-d]pyrimidin-4"amine (JAG-00547)
Figure imgf000036_0001
To a solution of N-(2-(lH-indol-3-y])ethyl)-2-(5-fIuoropyridin-3-yI)-5,6,7,8-tetrahydropyrido[3,4- d]pyrimidin-4-amine hydrochloride (50 mg, 0.11 mol, 1.0 eq) in dichloromethane (0.681 mL) was treated sequentially with triethylamine (0.030 mL, 0.21 mol, 2.0 eq), oxetan-3-one (0.021 mL, 0.32 mmol, 3.0 eq] and acetic acid (0.018 mL, 0.32 mmol, 3.0 eq), and the resulting mixture was stirred for 15 min. Sodium triacetoxyborofiydride (36.3 mg, 0.17 mmol, 1.6 eq) was added, and the resulting mixture was stirred for 12 h. The mixture was cooled to ambient temperature and partitioned between dichloromethane (10 mb] and a saturated aqueous solution of sodium bicarbonate (10 mL). The organic phase was collected and the aqueous phase was extracted with dichloromethane (3 x 10 rnL], The combined organic phases were dried (Na^SCD), filtered and evaporated to dryness to give the crude product as a residue. Purification by automated column chromatography over silica (4 g cartridge), eluting with a gradient of MeOH in dichloromethane (0-10%) gave the desired product as a solid (41.9 mg, 0.091 mmol, 85.4%).
UPLCMS (4min, basic, +): RT=1.68 (97%), m/z=445.3 (M+H-J-)
’H NMR (400 MHz, DMSO) S 10.83 (s, 1H], 9.31 (t, J = 1.7 Hz, 1H), 8.66 (d, J - 2.9 Hz, 1H], 8.31 (ddd, J - 10.0, 2.9, 1.6 Hz, III), 7.61 (d, J - 7.8 Hz, III], 7.36 - 7.31 (m, 1 H], 7.26 - 7.18 (m, 2H), 7.07 (ddd, J = 8.1, 7.0, 1.2 Hz, 1 H ), 6.98 (ddd, J = 7.9, 7.0, 1.1 Hz, 1 H ), 4.64 (t, J = 6.6 Hz, 2H), 4.56 (t, J = 6.2 Hz, 2H), 3.80 (q, J - 6.9 Hz, 2H), 3.66 (p, J = 6.4 Hz, 1H), 3.40 (s, 2H), 3.04 (t, f - 7.6 Hz, 2H], 2.63 (t. J - 5.8 Hz, 2H), 2.47 (s, 2H). Purity~97% (contains DCM<3%].
Figure imgf000036_0002
127.74.
Examples 7 to 11 were prepared using methods analogous to those described above, see the table below.
Figure imgf000036_0003
Figure imgf000037_0001
AhR antagonism was assessed in U937 cells (myeloid lineage cell line derived from a human histiocytic lymphoma). Ligand binds the AhR in the cytoplasm, and the AhR-ligand complex translocates to the nucleus and forms a heterodimer with AhR nuclear translocator (Arnt). This complex binds the xenobiot.ic response element (XRE) in the .T upstream region of the CYP1A1 promoter, enhancing CYP1A1 expression, CYP1A1 activity is subsequently determined by assessing the conversion of Luciferin-CEE to luciferin, which in turn reacts with luciferase to produce light. The amount of light produced is directly proportional to cytochrome P45Q activity.
U937 cells in Ultraculture serum free media (Lonza) were plated at 100,000 cells per well in a round bottom 96 well tissue culture plate. Seven concentrations of test compound (final [DMSO] 1%) were added and incubated for 10 minutes before the addition of 300pM KYNA. The plates were then placed in an incubator at 37°C, > 85% humidity, 5% COj for 24hrs. After aspiration of the supernatant the CYP1A1 substrate Luciferin-CEE ([Final] 83 pM) was added and incubated for 3 hrs before the reaction was stopped by adding iuciterin detection reagent and luminescence was read after 20 minutes.
Figure imgf000038_0001

Claims

1. A compound of formula (I)
Figure imgf000039_0001
wherein:
Y is phenyl or a 3 to 6 membered ring optionally comprising 1, 2, or 3 heteroatoms selected from N, 0 and S, said phenyl or ring substituted with Rs and R6;
R1 is H or C I ?, alky I, C3.5 cycloalkyl, halogen and C1-3 alkyl optionally bearing one or more groups independently selected from ORY, halogen -NR7Ra such as ORY and halogen (e.g. F) in particular only one group;
R2 is H, Cv?, alkyl or halogen; wherein R1 & R2 together can form an alkylene bridge -CH2CH2- or -CH2- between two carbons in the ring or R1 & R2 together can form a nitrogen bridge -NRS- between two carbons in the ring (such as -NH-);
R3 is H or Cr?, alkyl;
R4 is a 9 to 13 membered heterocycle with at least one heteroatom selected from N, 0 and S (for an aromatic or partially saturated], with substituents R9, R9' and R!0;
Rs is FI, oxo, hydroxy, halogen (such as F, Cl], CN, C1-3 alkyl, C1.3 alkoxy (such as OMe),
Ci-2 haloalkyl (i.e. alkyl bearing 1 to 6 halogen groups, such as CF3), -C(O](CH2)qNR7Rs, -SO2C1..3 alkyl, -SO3 NR7R8, C1..3 alkyl bearing one or more OH groups, ,
R6 is H, oxo, hydroxy, halogen (such as F, Cl], CN, C,.?, alkyl, -C(O)(CH2)qNR7R3, •SO2C1.3 alkyl, -SO? NR'R3,
R7 is H, Ci 3 alkyl or -C(O]ORy,, such as -CH3;
R8 is H or C1-3 alkyl, such as -CH?,;
R9 is FI, hydroxy, halogen (such as F, Cl), CN, C1-3 alkyl, C 3 -3 alkoxy (such as OMe], Ca-scycloalkyl, Ci.? alkyl bearing 1 to 6 halogen groups (such as CF O, C1.3 alkyl bearing one or more ORY groups; -(CH2 JqOCi-saikyl substituted with 1 to 6 halogen groups (such as -(CHzJqOCFs) J;
-LOfLFIzjq NR'R*, -SO2L1.3, alkyl, or -SO2 NR/R8;
R9’ is H, OH, halogen (such as F, Cl), CN, C 1 3 alkyl,
Figure imgf000039_0002
alkoxy (such as OMe], C1.3 alkyl bearing 1 to 6 halo groups (such as CF3), C1..3 alkyl bearing one or more OH groups, -CO(CH2)q NR7R8, -SO2C1.3 alkyl, or -SO2 NR7R3;
R10 is FI, hydroxy, halogen (such as F, Cl), CN, C1.3 alkyl, “C(O](CH?]q NR7R8;
-SO2C:..3 alkyl, or -SO2 NR7R8;
R; 1 (such as -CH?];
R" (such as H, -CH?, or -CH2CFI?,];
X
Figure imgf000039_0003
Rn or 0; b is 0, 1 or 2; n is 1 or 2: m is 1 or 2: p is an integer 1, 2 or 3 (such as 1); q is 0, 1, 2 or 3 (such as 0 or 1), or a pharmaceutically acceptable salt thereof . A compound according to claim 1, which has a formula (II):
Figure imgf000040_0001
wherein Ri, R2, R3, R4, X, Y. b, n and m are defined above for compounds of formula (1 j or a pharmaceutically acceptable salt thereof. . A compound according to claim 1 or 2 wherein Y is a 5 or 6 membered nitrogen containing ring. . A compound according to claim 3, wherein the ring is aromatic. . A compound according to claim 4, wherein the ring is pyrimidine or pyridine. . A compound according to claim 5, which has a formula (III):
Figure imgf000040_0002
wherein Ri, R2, R3, R4, R5, Rs X, b, n and m are defined above for compounds of formula (I) or a pharmaceutically acceptable salt thereof. . A compound of formula (I) according to claim 5 or 6, wherein Rs is located at position 5 on the pyridine. . A compound according to any one of claims 1 to 7, wherein R> is hydrogen or -C1.3 alkyl, in particular H. . A compound according to claim 8, wherein in R; is selected from methyl, ethyl, propyl and isopropyl, in particular isopropyl. 0. A compound according to any one of claims 1 to 9, wherein R2 is H or methyl, such as H.1. A compound according to any one of claims 1 to 7, wherein R1 and R2 together represent
■ CH - .
12. A compound according to any one of claims 1 to 11, wherein R3 is H.
13. A compound according to any one of claims 1 to 12, wherein R : is a 9 or 13 membered heterocycle.
14. A compound according to claim 13, wherein R4 is a 9 membered heterocycle, for exampie a heteroaromatic, such as tryptophan.
15. A compound according to ciaim 13, wherein R4 is a 13 membered heterocycle, for example a partially saturated heterocycle, such as tetrahydrocarbazole.
16. A compound according to any one of claims 1 to 15, wherein R3 is a halogen, for example fluoro.
17. A compound according to any one of claims 1 to 16, wherein R6 is H.
18. A compound according to any one of claims 1 to 17, wherein R? is H or methyl, such as H.
19. A compound according to any one of claims 1 to 18, wherein R3 is H or methyl, such as H,
20. A compound according to any one of claims 1 to 19, wherein R9 is H, C alkyl ('such a methyl) or C3.5 cycloalkyl (such as cyclopropyl], in particular H;
21. A compound according to any one of claims 1 to 20, wherein R9' is H or halo (such as fluoro), in particular H.
22. A compound according to any one of claims 1 to 21, wherein R! 0 is H or halo ( such as fluoro), in particular H.
23. A compound according to any one of claims 1 to 22, wherein X is NR11.
24. A compound according to any one of claims 1 to 23, wherein R11 is H.
25. A compound according to any one of claims 1 to 24, wherein m is 1.
26. A compound according to any one of claims 1 to 24, wherein m is 2.
27 A compound according to any one of claims 1 to 26, wherein n is 1.
28. A compound according to any one of claims 1 to 26, wherein n is 2.
29, A compound according to any one of claims 1 to 28, which has a formula: a) (IV):
Figure imgf000041_0001
or a pharmaceutically acceptable salt thereof; b) (V):
40
Figure imgf000042_0001
or a pharmaceutically acceptable salt thereof; c) (VI);
Figure imgf000042_0002
or a pharmaceutically acceptable salt thereof; d) (VII):
Figure imgf000042_0003
or a pharmaceutically acceptable salt thereof; e) (VIII):
Figure imgf000042_0004
or a pharmaceutically acceptable salt thereof; fj (IX):
Figure imgf000043_0001
or a pharmaceutically acceptable salt thereof.
30. A compound according to claim 1, selected from:
Figure imgf000043_0002
Figure imgf000044_0001
a pharmaceutical acceptable salt of any one of the same. A pharmaceutical composition comprising a compound according to any one of claims 1 to 30, and a pharmaceutically acceptable diluent or carrier. A compound according to any one of claims 1 to 30 or a composition according to claim 31, for use in treatment, in particular the treatment of cancer. A compound according to any one of claims 1 to 30 or a composition according to claim 31, for use in the manufacture of a medicament for the treatment of cancer. A method of treatment comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 30 or a composition according to claim 36 to a patient in need thereof, for example for the treatment of cancer. A compound for use or a method according to any one of claims 32 to 34, further comprising 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, Wee 1 dual specificity protein kinase (Weel) inhibitor, Poly ADP Ribose polymerase (PARP) inhibitor and Mytl inhibitor, in particular a PD-1 inhibitor, a PD-L1 inhibitor and/or a CTLA-4 inhibitor,
A combination therapy comprising a compound according to any one of claims 1 to 35 or a composition according to claim 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), Ataxia telangiectasia and Rad3 related (ATR) inhibitor, ataxiatelangiectasia mutated (ATM) inhibitor, Weel dual specificity protein kinase (Weel) inhibitor, Poly ADP Ribose polymerase (PART) inhibitor and Mytl inhibitor, in particular a PD-1 inhibitor, a PD-L1 inhibitor and/or a CTLA-4 inhibitor,
A process of preparing a compound of formula (I) according to any one of claims 1 to 35 by reacting a compound of formula (X):
Figure imgf000045_0001
wherein R!, R2, R3, R4, X, m and n are defined for compounds of formula (I) and Y’ is an activated derivative of Y also defined in formula (I) and Rx is the activating group,
PCT/SG2022/050634 2021-09-02 2022-08-31 Compounds useful in modulation of ahr signalling WO2023033741A1 (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018195397A2 (en) * 2017-04-21 2018-10-25 Kyn Therapeutics Indole ahr inhibitors and uses thereof
WO2020039093A1 (en) * 2018-08-24 2020-02-27 Jaguahr Therapeutics Pte Ltd Tetrahydropyridopyrimidine derivatives as ahr modulators
WO2020050409A1 (en) * 2018-09-07 2020-03-12 Otsuka Pharmaceutical Co., Ltd. Heterocyclic compound

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018195397A2 (en) * 2017-04-21 2018-10-25 Kyn Therapeutics Indole ahr inhibitors and uses thereof
WO2020039093A1 (en) * 2018-08-24 2020-02-27 Jaguahr Therapeutics Pte Ltd Tetrahydropyridopyrimidine derivatives as ahr modulators
WO2020050409A1 (en) * 2018-09-07 2020-03-12 Otsuka Pharmaceutical Co., Ltd. Heterocyclic compound

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