[go: up one dir, main page]

WO2024115549A1 - Aryl- and heteroaryl-sulfonamide derivatives as ccr8 modulators - Google Patents

Aryl- and heteroaryl-sulfonamide derivatives as ccr8 modulators Download PDF

Info

Publication number
WO2024115549A1
WO2024115549A1 PCT/EP2023/083499 EP2023083499W WO2024115549A1 WO 2024115549 A1 WO2024115549 A1 WO 2024115549A1 EP 2023083499 W EP2023083499 W EP 2023083499W WO 2024115549 A1 WO2024115549 A1 WO 2024115549A1
Authority
WO
WIPO (PCT)
Prior art keywords
amino
cyclobutyl
pyrimidin
sulfonamide
isopropylamino
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2023/083499
Other languages
French (fr)
Inventor
Hamed Aissaoui
Olivier Corminboeuf
Stefan Diethelm
Lubos Remen
Sylvia Richard-Bildstein
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Idorsia Pharmaceuticals Ltd
Original Assignee
Idorsia Pharmaceuticals Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Idorsia Pharmaceuticals Ltd filed Critical Idorsia Pharmaceuticals Ltd
Publication of WO2024115549A1 publication Critical patent/WO2024115549A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/02—Local antiseptics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to novel compounds represented by Formula (I), or pharmaceutically acceptable salts thereof, and their use as active ingredients in medicine.
  • the invention further concerns a process for the preparation of said compounds, pharmaceutical compositions containing one or more of said compounds, and their use as C-C chemokine receptor 8 (CCR8) modulators, either alone or in combination with other active compounds or therapies, in the prevention or treatment of diseases or disorders such as cancer, fibrotic diseases, atopic diseases, and neuropathic pain.
  • the invention relates to certain isotopically labelled compounds, or pharmaceutically acceptable salts thereof, and their use in radiopharmaceutical therapy (RPT) or medical imaging such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT).
  • RPT radiopharmaceutical therapy
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • Chemokine receptors such as CCR8, are a group of G-protein coupled receptors (GPCRs) that recognize and bind to peptide chemokine ligands with high affinity.
  • GPCRs G-protein coupled receptors
  • the predominant functions of chemokine receptors and their ligands are to induce leukocyte trafficking to-and-from lymphoid organs and tissues in the steady state, as well as in the context of an infection or inflammation. Additionally, chemokine signaling events can induce the activation of integrin molecules on the surface of immune cells, allowing form adhesion to activated endothelium, facilitating migration from blood into inflamed tissue (Montresor A, Frontiers in Imm., 2012; Meissner A, Blood, 2003).
  • CCR8 (alias CKRL1 , CMKBR8, CMKBRL2, CC-CKR-8, CCR-8, CDw198, CKRL1, CMKBR8, CMKBRL2, CY6, GPRCY6, or TER1) has four known chemokine ligands: CCL1 (alias I-309 or SCYA1), CCL8 (alias MCP2, SCYA10, or SCYA8), CCL16 (alias ILINCK, NCC4, or SCYA16), and CCL18 (alias AMAC1 , DCCK1 , MIP4, PARC, or SCYA18).
  • CCL1 was first identified as a cytokine secreted by activated human T lymphocytes.
  • CCL1 Human CCL1 is the best- established natural ligand for CCR8, but other chemokine ligands such as CCL18 were reported to interact with hCCR8 as well.
  • CCR8 is the only known receptor for CCL1 , whereas the other CCR8 ligands bind several chemokine receptors, as well as decoy receptors.
  • CCR8 positive cells respond to CCL1 stimulation with increased intracellular calcium, chemotaxis and enhanced survival.
  • CCL1 is considered a Th2-related cytokine due to the expression of the CCR8 receptor on Th2 cells, but not on Th 1 cells, suggesting that CCL1 plays an important role in allergies and asthma.
  • the CCL1-CCR8 axis also plays a role in the homing of lymphocytes to the healthy skin and contributes to the immune protection of the skin (Schaerli P et al.; J. Exp. Med. 2004, 199, 1265-1275 and Ebert L et al.; J. Immunol. 2006, 176, 4331-4336).
  • Tumors are comprised of abnormally proliferating malignant cancer cells but also of a functionally supportive microenvironment.
  • This tumor microenvironment is comprised of a complex array of cells, extracellular matrix components, and signaling molecules, and is established by the altered communication between stromal and tumor cells.
  • CCL1 is such an immuno-modulatory factor produced in tumors.
  • High expression of CCL1 in a cancer cell occurs in leukemia caused by viruses such as human T cell leukemia virus type 1 (HTLV-1 ).
  • viruses such as human T cell leukemia virus type 1 (HTLV-1 ).
  • HTLV-1 human T cell leukemia virus type 1
  • vMIP- I viral macrophage inflammatory protein-l
  • Another example is Kaposi sarcoma-related human herpes virus-8 (Haque, NS et al; Blood. 2001 , 97, 39-45).
  • CCL1 In hepatocellular carcinomas, the expression of CCL1 is elevated in 12 of 34 tumor stroma and peritumoral tissues. The expression of CCL1 has also been demonstrated in breast cancer stem cells, bladder cancer tumors, and renal cell carcinomas. (Korbecki, J et al. Int. J. Mol. Sci. 2020, 21, 7619).
  • CCL1 is produced by Cancer Associated Fibroblasts, Tumor Associated Macrophages, CCR8-CD11 b+ myeloid cells, and Regulatory T-cells.
  • the secretion of CCL1 by myeloid cells is involved in Treg cell infiltration.
  • An increased expression of CCR8 is observed in Treg cells and NKT cells, particularly in cancer patients, and a low expression is observed in CD8+ T cells or Th 1 cells.
  • Interactions between CCL1 and CCR8 enhance the expression of FoxP3 and activated CCR8+ Treg cells strongly suppress antitumor immunity by promoting ATP-adenosine metabolism by CD39 and secretion of IL-10 and granzyme B. (Ohue.Y and Nishikawa, H, Cancer Sci, 2019, 110(7):2080-2089).
  • CCL1 is involved in the recruitment of CCR8+ CD 11 b+ myeloid cells (Eruslanov, E et al, Clin Cancer Res. 2013, 19, 1670-1680) as well as Regulatory T cells (Kuehnemuth, B et al, BMC Cancer 2018, 18, 1278) to the tumor site.
  • CCL1 can also participate in the conversion of CD4+ T cells into Treg (Hoelzinger, DB et al, J Immunol. 2010, 184, 6833-6842), in a process dependent on transforming growth factor-
  • CCL1 supports the immunosuppressive function of Treg in the tumor niche (Hoelzinger, DB et al, J Immunol. 2010, 184, 6833-6842), which is crucial for the interaction of cancer stem cells and CAF with the Tregs (Xu, Y et al, Stem cells 2017, 35, 2351-2365).
  • CCL1 increases the expression of interleukin 6 in MDSC, which acts as a proinflammatory in the tumor microenvironment (Eruslanov, E et al, Clin Cancer Res. 2013, 19, 1670-1680). It was also reported that CCL1 causes angiogenesis on vascular endothelial cells via CCR8 (Haque, NS, et al, Blood, 2001, 97, 39-45).
  • CCL1 has an antiapoptotic activity and induces chemoresistance to anticancer drugs due to the activation of the ERK MAPK cascade via CCR8 (Louahed, J et al, Eur J immunol. 2003, 33,494-501). CCL1 also stimulates proliferation (Cao, Q et al, Mol Med Rep. 2016, 13, 27-34) and causes the migration of bladder cancer cells (Yeh, CR, et al, Am J Cancer Res. 2018, 50, 894-907). At the same time, due to the expression of CCL1 in lymph nodes, this chemokine participates in metastasis to these peripheral lymphoid organs through the CCR8 receptor on cancer cells that have entered lymphatic vessels. This process is important in metastasis to lymph nodes in malignant melanoma, which often leads to increased CCR8 expression in the cancer cells of this tumor (Das, S et al, J Exp Med. 2013, 210, 1509-1528).
  • CCL18 is produced by dendritic cells, especially in germinal centers of regional lymph nodes. This chemokine then causes the chemoattraction of naive T cells. This leads to the initiation of an immunological response. CCL18 also acts as an anti-inflammatory chemokine, a marker for the macrophage M2 subset (Schraufstatter, III et al, Immunology, 2012, 135, 287-298). In a tumor, CCL18 is mainly produced by Tumor Associated Macrophages (Pettersen, JS et al; J. Investig. Dermatol.
  • CCL18 recruits immature dendritic cells to the tumor niche and participates in the differentiation of immature dendritic cells into tumor-associated dendritic cells (TADC) (Azzaoui, I et al; Blood, 2011 , 118, 3549-3558).
  • CCL18 binds to glycosaminoglycans on extracellular vesicles, which allows them to be retained on cells with an expression of CCR8.
  • CCL18 also increases the proliferation of cancer cells, but this depends on the tumor type. For example, CCL18 decreases the proliferation of acute lymphocytic leukemia B cells and cutaneous T-cell lymphoma (CTCL) (Catusse, J et al; J, Cell. Physiol. 2010, 225, 792-800; Gunther, C et al; Am J. Pathol. 2011, 179, 1434-1442).
  • CCL18 increases the proliferation of glioma and oral squamous cell carcinoma cells.
  • An increased expression of CCL18 in lesional skin and serum of patients with CTCL as well as in patients with diffuse large B cell lymphoma is associated with a worse prognosis.
  • CCR8 is a chemokine receptor preferentially, but not exclusively, expressed by FOXP3+ Tregs.
  • CCR8+ Tregs were recently identified as master drivers of the immune regulation. The relative number of CCR8+ Tregs which is very low in the periphery increases along with the development of experimental autoimmune encephalomyelitis (EAE), a T cell- mediated autoimmune disease of the central nervous system. It was also observed that within the central nervous system, CCR8+ Tregs are potentiated by CCL1 , possibly in an autocrine manner, which makes them “driver” regulatory cells that restrain the progression of the disease (Barsheshet, Y. et al; Proc. Natl. Acad. Sci. 2017, 114, 6086-6091).
  • CCL18 and CCR8 are elevated in idiopathic pulmonary fibrosis (Schman A. et al., medRxiv, 2023, doi: 10.1101/2023.04.29.23289296) and high serum CCL18 predicts poor patient outcome (Prasse A. et al., Am J Respir Crit Care Med, 2009 Apr 15;179(8):717-23). Furthermore, CCL1-CCR8 interaction is associated with more severe human lgG4-related sclerosing cholangitis (Yoh Zen et al., Journal of Hepatology, 59, 5, 2013, 1059-1064).
  • CCR8 is a part of a gene locus related to systemic sclerosis in a chicken model of scleroderma/systemic sclerosis has been disclosed by Weronica Ek. et. al., Developmental & Comparative Immunology, 38, 2, 2012, 352-359. Moreover, CCR8 mediates immune cell infiltration and resultant fibrosis in a murine model of allogeneic kidney transplant (Dangi A, et al., J Am Soc Nephrol. 2022 Oct;33(10): 1876- 1890).
  • CCR8 was determined to promote adhesion formation in part via an autocrine CCL1-CCR8 signaling loop in peritoneal macrophages that regulated their recruitment and aggregation (Akiyoshi Hoshino et al., J Immunol., 2007 Apr 15; 178(8):5296-304). CCR8 signaling in myeloid cells may sensitize individuals to bacterial infection.
  • CCL1-CCR8 signaling may play a deleterious role in chronic obstructive pulmonary disease (COPD) and allergic type exacerbations: CCR8 expression is pronounced in lung myeloid cells of patients with Global Initiative for Obstructive Lung Disease (GOLD) stage IV COPD (Martina Kvist Reimer et al. Clinical and Vaccine Immunology, 2011, 18, 12, doi: 10.1128/CVI.05275-11), and COPD exacerbation risk is associated with certain single nucleotide polymorphism profiles in the CCL1 gene (Takabatake N. et al., Am J Respir Crit Care Med. 2006 Oct 15; 174(8):875- 85, doi: 10.1164/rccm.200603-4430C).
  • CCL1/CCR8 neuronal signaling plays an important role in the development of neuropathic pain (Zychowska, M. et al.; International Immunopharmacology, 52, 2017, 261-271 ; and Akimoto, N., et al.; Cell Death Dis 4, e679 (2013)).
  • the interaction of CCL1 and CCR8 has been implicated in neuropathic pain exacerbation (Pawlik K., Molecules 2023, 28(15), 5766).
  • animal and ex vivo models suggest CCL1 enhances allodynia and neuropathy via CCR8 signaling in neurons, microglia, and astrocytes in the spinal cord (Akimoto N.
  • Healthy human skin was then reported as the primary residence site of CCR8+ cells with 50% of all skin a
  • CCR8 was also identified in CD16-expressing NK cells that reside mainly in human skin but not in peripheral blood (Ebert, L.M. et al; J. Immunol. 2006, 176, 4331-4336, Schaerli, P. et al; J. Exp. Med. 2004, 199, 1265— 1275).
  • CCR8 has been identified as a potential specific marker for tumor-infiltrating Tregs.
  • CCR8 expression is selectively upregulated in these Tregs in multiple cancers, including lung, colorectal, breast (Plitas, G et al.; Immunity 2016, 45, 1122-1134, De Simone, M. et al.; Immunity 2016, 45, 1135-1147, Wang, L. et al;. Nat. Immunol. 2019, 20, 1220-1230).
  • CCR8+ Tregs represent a highly suppressive subpopulation of Tregs and the high number of CCR8+ Tregs in the tumor microenvironment correlates with poor prognosis in various breast cancer types (Plitas, G et al.; Immunity 2016, 45, 1122-1134, De Simone, M. et al.; Immunity 2016, 45, 1135-1147, Zheng, C. et al.; Cell 2017, 169, 1342-1356, Magnuson, A.M.et al.; Proc. Natl. Acad. Sci. USA 2018, 115, E10672-E 10681).
  • CCR8 is rarely expressed on Tregs and Teffector cells in peripheral blood or healthy tissues, targeting CCR8+ tumor Tregs is expected to cause minimal toxicity risks making CCR8 a promising therapeutic target to inhibit the immunosuppressive functions of tumor-resident Tregs and increase the anti-tumor immune response.
  • CCR8 is a seven-transmembrane G-protein-coupled chemokine receptor (GPCR) expressed primarily on intratumoral FOXP3hi Tregs (Plitas, G et al.; Immunity 2016, 45, 1122-1134, De Simone, M. et al.; Immunity 2016, 45, 1135-1147, Wang, L. et al;. Nat. Immunol. 2019, 20, 1220-1230).
  • GPCR G-protein-coupled chemokine receptor
  • the CCL1-CCR8 axis also potentiates the immunosuppressive capacity of Tregs through upregulation of CCR8, FOXP3, IL-10 and other suppressive factors (Vila-Caballer M et al.; J Mol Cell Cardiol. 2019;132:154-1).
  • Small molecule CCR8 antagonists such as the compounds of the present invention, may be useful to inhibit the recruitment of CCR8+ Tregs to the tumor site and/or to decrease the suppressive functions of intratumoral CCR8+ Tregs resulting in a favorable environment for a positive response to immune-check point inhibitors or others current therapies.
  • the compounds of the present invention may be useful, alone, or in combination with one or more therapeutic agents or therapies, for the prevention / prophylaxis or treatment of cancer, especially cancer types infiltrated with intratumoral Tregs expressing CCR8.
  • cancer types are inter alia oral squamous cell carcinoma (Fraga M. et al.; Front. Immunol. 2021 , 12:643298), head and neck squamous cell carcinoma (Sun et al; Transl Cancer Res 2020; 9( 10) :5882- 5892, Meng et al; Front. Oncol. 2021, 11 :618187), liver cancer (Zheng, C.
  • cutaneous T cell lymphoma (Giustinani J. et al Blood Adv. 2022, 6(11):3507-3512), endometrial tumors (Campbell, J.R. et al.; Cancer Res. 2021 , 81 , 2983-2994, Nieto P. et al., Genome Res. 2021 ,10:1913-1926), Kaposi sarcoma (Haque, N.S. et al; Blood 2001, 97, 39-45), and basal cell carcinoma (Nieto P. et al., Genome Res. 2021,10: 1913- 1926).
  • OSCC oral squamous cell carcinoma
  • HNSCC head and neck squamous cell carcinoma
  • CCR8 in tumor associated Tregs in liver cancer has been described in the literature.
  • CCL1 expression was also reported in peripheral and extratumoral stromal compartment in hepatocellular carcinomas suggesting an involvement in the CCR8+ Tregs recruitment (Wiedemann G.M. et al; Pathology, 2019 51(6), 586-659).
  • De Simone et al. reported a transcriptional landscape of tumor-infiltrating Tregs from human colorectal tumor tissues and identified CCR8 as one of the top 5 genes overexpressed in tumor associated Tregs compared to peripheral blood Tregs. The specific expression of CCR8 in tumor-infiltrating Tregs was then confirmed at the protein level by FACS analysis (De Simone, M. et al.; Immunity 2016, 45, 1135-1147).
  • CCR8 in lung cancer was reported in several studies. De Simone et al. also did a similar transcriptional landscape of tumor-infiltrating Tregs from human non-small cell lung cancer (NSCLC) and CCR8 was highly expressed compared to peripheral blood Tregs. FACS analysis also confirmed the specific expression of CCR8 in tumor Tregs (De Simone, M. et al.; Immunity 2016, 45, 1135-1147). In lung adenocarcinoma, a high expression of CCR8 mRNA was found in various data sets (Liu F. et al; J Inflamm Res.
  • CCR8 a role of CCR8 has been described in bladder and kidney cancer.
  • Myeloid cells (CD33+ CD11b+) are CCR8+ in those indications and contribute to a strong immunosuppressive environment.
  • An elevated level of CCL1 was found in primary human urothelial and renal cancer tissues (Eruslanov, E et al.; Clin. Cancer Res. 2013, 19, 1670— 1680).
  • CCR8 blockade could destabilize intratumoral Tregs into a fragile phenotype accompanied with reactivation of antitumor immunity and augment of anti-PD-1 therapeutic benefits in muscle invasive bladder cancer (MIBC) patients.
  • MIBC muscle invasive bladder cancer
  • CCR8 was also described as strongly expressed in human malignant melanoma.
  • CCL1 was detected in lymph node lymphatic sinuses but not in the peripheral lymphatics. This study suggests that the CCL1/CCR8 axis is involved in the metastasis invasion process in melanoma patients (Das S. et al., J Exp Med. 2013, 210(8): 1509-1528).
  • Single cell RNA sequencing data analysis found in Nieto et al. or Sade Feldman et al. identified a specific expression of CCR8 in tumor infiltrated Tregs ((Nieto P. et al., Genome Res. 2021 ,10:1913-1926; Sade Feldman M. et al, Cell. 2018, 175(4): 998-1013).
  • CCR8 plays a role in breast cancer development.
  • Plitas et al. identified that tumor Tregs were CCR8+ whereas peripheral blood Tregs were not. They also reported a correlation between a high CCR8+ FoxP3+ Tregs content with a bad prognosis for the patients (Plitas, G et al.; Immunity 2016, 45, 1122— 1134).
  • Another study has shown that 50% of intratumoral Tregs are CCR8+ (Wang, L. et al;. Nat. Immunol. 2019, 20, 1220-1230).
  • CCR8+ Tregs have been found to migrate towards CCL1 and to be immunosuppressive (Kuehnemuth, B et al, BMC Cancer 2018, 18, 1278, Ding S. et al; Int Immunopharmacol. 2021 , 100:108122).
  • CCR8 has been proposed in lymphoma.
  • Overexpression of CCR8 has been reported in systemic ALK negative anaplastic large cell lymphomas (ALCL).
  • ALK negative anaplastic large cell lymphomas ALK negative anaplastic large cell lymphomas
  • Quantitative real-time PCR in frozen tissue and RNA in situ hybridization (ISH) in paraffin tissue showed higher CCR8 expression in ALCLs with DUSP22 rearrangements than in non-rearranged cases (Xing X. et al, Appl Immunohistochem Mol Morphol. 2015 (8):580-589).
  • CCR8 was also shown to play a role in T cell lymphoma and specifically cutaneous T cell lymphoma (CTCL).
  • CTCL cutaneous T cell lymphoma
  • the expression of CCR8 in lesional skin of CTCL patients is associated with high risks of disease progression.
  • CCR8 is expressed by peripheral blood Sezary cells and is reported expressed at cell surface of other T cell lymphoma (Giustinani J. et al Blood Adv. 2022, 6(11):3507-3512).
  • CCR8 was reported in Kaposi sarcoma. Immunohistochemical studies identified CCR8 and CCL-1 on the endothelium of human atherosclerotic plaques and in endothelial-derived spindle cells of Kaposi sarcoma. In addition, the viral monocyte inflammatory protein-l (vMIP-l), a human homologue of CCL1 is induced by the Kaposi sarcoma-related human herpesvirus-8 (Haque, N.S. et al; Blood 2001 , 97, 39-45).
  • vMIP-l viral monocyte inflammatory protein-l
  • Positron emission tomography (PET) and single-photon emission computed tomography (SPECT) are common imaging techniques in nuclear medicine.
  • the techniques use a radiopharmaceutical — a radioactive isotope attached to a ligand/drug, which is injected into the human body as a tracer.
  • a positron is emitted, and when the positron interacts with an ordinary electron in the human body, the two particles annihilate and gamma rays are emitted, which are then detected and form a three-dimensional image.
  • Radiopharmaceuticals are widely used e.g. in cardiology, neurology, and oncology.
  • radioactive tracers used in oncology imaging include glucose uptake tracer [ 18 F]fluorodeoxyglucose, tumor specific tracer [ 18 F]fluorothymidine, and [ 18 F]fluciclovine - a PET diagnostic agent in men with suspected prostate cancer recurrence.
  • Radiopharmaceuticals can also be used as therapeutic agents in radiopharmaceutical therapy (RPT).
  • RPT radiopharmaceutical therapy
  • a category of RPT involves the use of tumor-targeting agents that concentrate in tumors through natural physiological mechanisms occurring predominantly in neoplastic cells.
  • a widely implemented example of this category of RPT is the radioiodine therapy of thyroid cancer, where radioactive iodine is injected in the body and it is absorbed and concentrated in the thyroid gland.
  • the radiation can then destroy the gland and any other thyroid cells including cancer thyroid cells that take up iodine, with little effect on the rest of the body.
  • the compounds of Formula (I) comprising one or more radioactive isotopes of iodine may be used to associate with certain cells in the human/animal body and thereby destroy cancer cells by targeted delivery of radioactive iodine.
  • Certain small molecules targeting CCR8 have been disclosed in the art.
  • W02004032856, W02003037271, W02005040167, W02006107252, W02006107253, W02006107254, W02008099165, and W02007030061 relate to certain heterocyclic derivatives;
  • W02013131010 concerns a method of administration of diverse CCR8 antagonists on the surface of tumor cells; certain biphenyl ether derivatives are disclosed by Ghosh S et al. J. Med. Chem. 2006, 49, 9, 2669-2672; Jenkins TJ et al. J. Med. Chem. 2007, 50, 3, 566-584 teaches naphthalene-sulfonamide derivatives; Marro ML et al. Biochem. Biophys. Res. Commun.
  • RNA aptamers that block CCL1 chemokine function
  • Jin J et al. Bioorg. Med. Chem. Lett. 2007, 17, 6, 1722-1725 relates to certain aryl-oxazolidinones
  • Shamovsky I et al. J. Med. Chem. 2009, 52, 23, 7706-7723 discusses the metabolic stability and selectivity of a series of CCR8 related compounds
  • Biochemical Pharmacology 2012, 83, 778-787 disclose derivatives comprising a diazaspiroundecane scaffold; Yong Wu et al. J. Med. Chem. 2023, 66, 7, 4548-4564 and W02022000443 disclose IPG7236, a small molecule CCR8 antagonists in clinical stage of development (NCT05142592 and NCT05288543), and Petersen TP et al. Chem. Eur. J. 2013, 19, 9343 describes a multistep continuous-flow synthesis of certain biphenyl ethers.
  • W02004058736, W02004058709, W02004073619, and W02004074438 disclose certain aryl- and heteroaryl-sulfonamides.
  • the database CAS REGISTRY SM contains the structural formulas of certain aryl- and heteroaryl-sulfonamides (CAS RN 2068756-64-7, 2068741-89-7, 2068738-85-0, 2068733-03-7, 2068727-35-3, 2068732-71-6, 2068712-87-6, 2068699-30-7, 1783256- 82-5, 1783305-08-7, 1783155-99-6, 1783110-79-1, 1783211-08-4, 1783040-48-1, 1783125-47-2, and 1783136-48-0), however, neither a synthesis nor a medical use thereof is disclosed.
  • the present invention provides novel aryl- and heteroaryl-sulfonamides of Formula (I) which are modulators, especially antagonists of the CCR8 receptor.
  • 5-membered heteroaryl containing from one to three ring heteroatoms independently selected from nitrogen, sulfur, and oxygen is selected from thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl, and triazolyl; especially selected from thiophen-2-yl, thiophen-3- yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, [1,3,4]thiadiazol-2-yl, 1 H-pyrazol-3-yl, 1 H-pyrazol-4-yl, isothiazol-5-yl, isoxazol-4-y I , oxazol-5-yl, 1 H-[1 ,2,3]triazol-4-yl, and 2H-[1 ,2,3]triazol-4-yl; in particular selected from thiophen-
  • 6-membered heteroaryl containing from one to three ring nitrogen atoms is selected from pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; especially selected from pyridin- 2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl, pyrazin-2-yl, and pyridazin-3-yl; in particular selected from pyridin-3-yl); wherein said phenyl, 5-membered heteroaryl, or 6-membered heteroaryl, independently is unsubstituted, mono-, di-, or tri-substituted (notably unsubstituted, mono-, or di-substituted), wherein the substituent independently represents
  • halogen especially chlorine, fluorine, bromine, or iodine
  • R 1 represents
  • C1-5-alkyl notably Cu-alkyl; especially methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, or sec- butyl;
  • C1-4-fluoroalkyl especially 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-fluoro-1 -methyl-ethyl, 2- fluoro-1-fluoromethyl-ethyl, 2, 2-difluoro-1 -methyl-ethyl, 2,2,2-trifluoro-1, 1-dimethyl-ethyl, or 2,2,2-trifluoro-1- methyl-ethyl); or
  • > -L- represents a bond (i.e. Cy is directly attached to the nitrogen atom) or -CH2-;
  • Cy represents C3-6-cycloalkyl (especially cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl) optionally containing one oxygen ring atom, wherein said C3-6-cycloalkyl optionally containing one oxygen ring atom is unsubstituted or mono-substituted (especially at the point of attachment of said C3-6-cycloalkyl to the rest of the molecule), wherein the substituent represents fluorine
  • -L-Cy represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetan-3-yl, cyclopropyl- methyl, 1-fluoro-cyclopropylmethyl, or cyclobutyl-methyl];
  • R 2 represents hydrogen or fluorine (especially hydrogen).
  • halogen used alone or in combination, means fluorine, chlorine, bromine, or iodine; notably fluorine, chlorine, or bromine.
  • the halogen substituent(s) of Ar are stable, non-radioactive halogen isotopes; notably fluorine, chlorine, or iodine; most preferred is fluorine.
  • the halogen substituent(s) of Ar are unstable, radioactive halogen isotopes of fluorine and/or iodine; notably fluorine-18, iodine-123, iodine-124, iodine-125, and iodine-131 ; especially fluorine-18.
  • amino used alone or in combination, refers to the group -NH2.
  • alkyl refers to a saturated straight or branched hydrocarbon chain group containing one to six carbon atoms.
  • Cx-y-alkyl (x and y each being an integer), refers to an alkyl group as defined before, containing x to y carbon atoms.
  • the term means that said substituent is linked through a C x y -alkyl group to the rest of the molecule.
  • a C1-3-alkyl group contains from 1 to 3 carbon atoms.
  • C1-3-alkyl groups are methyl, ethyl, n- propyl, and isopropyl.
  • preferred examples of Cu-alkyl groups are methyl and ethyl, most preferred is methyl.
  • Examples of C1-5-alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methyl-butyl, 2-methyl-butyl, 3-methyl-butyl, 1,2-dimethyl-propyl, and 1 ,1-dimethyl-propyl.
  • C1-5-alkyl group is Cu-alkyl i.e., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl; more preferred is C2-4-alkyl i.e., ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl; most preferred are isopropyl and tert-butyl; particularly preferred is isopropyl.
  • hydroxyalkyl refers to an alkyl group as defined before, wherein one hydrogen atom has been replaced with a hydroxy group.
  • hydroxy-C x.y -alkyl (x and y each being an integer), used alone or in combination, refers to a hydroxyalkyl group as defined before wherein the alkyl group contains x to y carbon atoms.
  • a hydroxy-C2-4-alkyl group is a hydroxyalkyl group as defined before which contains from 2 to 4 carbon atoms.
  • hydroxy-C2-4-alkyl groups are 1 -hydroxyethyl, 2-hydroxyethyl, 1 -hydroxypropyl, 2- hydroxypropyl, 3-hydroxypropyl, 1 -hydroxy-1 -methyl-ethyl, 2-hydroxy-1 -methyl-ethyl, and 2-hydroxy-1 , 1 -dimethyl- ethyl.
  • substituent R 1 preferred examples are 2-hydroxy-1 -methyl-ethyl and 2-hydroxy-1 , 1 -dimethyl-ethyl.
  • fluoroalkyl refers to an alkyl group as defined before in which one or more (and possibly all) hydrogen atoms have been replaced by fluorine.
  • C x.y -fluoroalkyl (x and y each being an integer) refers to a fluoroalkyl group as defined before containing x to y carbon atoms.
  • a C1-2-fluoroalkyl group contains from 1 to 2 carbon atoms in which 1 to 5 hydrogen atoms have been replaced with fluorine.
  • C1-2-fluoroalkyl groups are fluoromethyl, difluoromethyl, trifluoromethyl, 1 -fluoroethyl, 1 ,1 -difluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, and 2,2,2-trifluoroethyl.
  • substituent(s) of Ar preferred examples of C1-2-fluoroalkyl groups are difluoromethyl, trifluoromethyl, or 1 ,1 -difluoroethyl; more preferred are C1-fluoroalkyl groups such as difluoromethyl and trifluoromethyl.
  • a C1-4-fluoroalkyl group contains from 1 to 4 carbon atoms in which 1 to 9 hydrogen atoms have been replaced with fluorine.
  • preferred examples of a C1-4-fluoroalkyl group are 2-fluoroethyl, 2,2- difluoroethyl, 2,2,2-trifluoroethyl, 1-methyl-2-fluoroethyl, 2-fluoro-1-fluoromethyl-ethyl, 1-methyl-2,2-difluoro-ethyl, 1- methyl-1-trifluoromethyl-ethyl, and 2,2,2-trifluoro-1-methyl-ethyl; preferred are 2,2,2-trifluoro-1-methyl-ethyl and 1- methyl-2,2-difluoro-ethyl.
  • cycloalkyl refers to a saturated monocyclic hydrocarbon ring containing three to seven carbon atoms (preferably three to six carbon atoms).
  • C x-y -cycloalkyl (x and y each being an integer), refers to a saturated monocyclic hydrocarbon ring containing x to y carbon atoms.
  • a C3-4-cycloal kyl group contains from 3 to 4 carbon atoms.
  • Examples of C3-4-cydoalkyl groups are cyclopropyl and cyclobutyl.
  • a preferred example of C3-4-cycloalkyl group is cyclopropyl.
  • a C3-6-cycloalkyl group contains from 3 to 6 carbon atoms.
  • Examples of a C3-6-cycloalkyl group are cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • For the substituent R 1 preferred examples of C3-6-cycloalkyl groups are cyclopropyl and cyclobutyl; most preferred is cyclopropyl.
  • the above-mentioned cycloalkyl groups are unsubstituted or substituted as explicitly defined.
  • C3-6-cycloalkyl optionally containing one oxygen ring atom refers to a C3-6- cycloal ky I group as defined before, wherein one carbon ring atom is optionally replaced with an oxygen atom.
  • C3-6-cycloalkyl optionally containing one oxygen ring atom examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl; preferred C3-6-cycloalkyl groups optionally containing one oxygen ring atom are cyclopropyl and cyclobutyl; particularly preferred is cyclopropyl.
  • the above-mentioned groups are unsubstituted or substituted as explicitly defined.
  • alkoxy refers to an alkyl group as defined before, wherein one hydrogen atom is replaced with an oxy group (-O-), i.e. the term refers to the group alkyl-O-.
  • C x-y -alkoxy (x and y each being an integer), used alone or in combination, refers to an alkoxy group as defined before, wherein the alkoxy group contains x to y carbon atoms.
  • a C1-2-alkoxy group is an alkoxy group as defined herein which contains 1 or 2 carbon atoms.
  • Examples of C1-2-alkoxy groups are methoxy and ethoxy.
  • a preferred example of a C1-2-alkoxy group is methoxy.
  • C1-2-alkoxy-C24-alkyl refers to an alkyl group as defined before, wherein one hydrogen atom is replaced by an alkoxy group, wherein said alkoxy group is as defined hereinabove.
  • C x 1- y 1- alkoxy-C X 2- y 2-alkyl (x1, y1 , x2, and y2, each being an integer), used alone or in combination, refers to an C X 2- y 2-alkyl group containing x2 to y2 carbon atoms, wherein one hydrogen atom is replaced with an C x 1- y 1-alkoxy group, said C x 1- y i-alkoxy group containing x1 to y1 carbon atoms.
  • C1-2-alkoxy-C24-alkyl refers to an C2-4-alkyl group containing 2 to 4 carbon atoms, wherein one hydrogen atom is replaced with an C1-2-alkoxy group containing 1 to 2 carbon atoms.
  • Examples of such C1-2-alkoxy-C2-4-alkyl are 2-methoxyethyl, 2-methoxy-1-methyl-ethyl, or 2-methoxy- 1 ,1-dimethyl-ethyl; preferred is 2-methoxy-1-methyl-ethyl.
  • fluoroalkoxy used alone or in combination, refers to an alkoxy group as defined before, wherein one or more (and possibly all) hydrogen atoms have been replaced with fluorine.
  • C x-y -fluoroalkoxy refers to a fluoroalkoxy group as defined before containing x to y carbon atoms.
  • a C 1-2- fluoroalkoxy group contains from 1 to 2 carbon atoms in which 1 to 5 hydrogen atoms have been replaced with fluorine.
  • Examples of C1-2-fluoroalkoxy groups are trifluoromethoxy, difluoromethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, and 2,2,2-trifluoroethoxy.
  • aryl used alone or in combination, means phenyl or naphthyl, preferably phenyl. The aryl groups are unsubstituted or substituted as explicitly defined.
  • heteroaryl used alone or in combination, means a 5- to 10-membered monocyclic or bicyclic aromatic ring containing one to a maximum of four heteroatoms (notably containing one to a maximum of three heteroatoms), each independently selected from oxygen, nitrogen and sulfur.
  • heteroaryl groups are furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, benzoxadiazolyl, benzothiadiazolyl, quinolinyl, isoquinolinyl, naphthyridinyl, cinnolinyl, quinazolin
  • 5-membered heteroaryl refers to a 5-membered monocyclic aromatic ring containing one to four ring heteroatoms (preferably one to three ring heteroatoms), each independently selected from oxygen, nitrogen, and sulfur.
  • 6-membered heteroaryl used alone or in combination, refers to a 6-membered monocyclic aromatic ring containing one to three ring nitrogen atoms.
  • 5-membered heteroaryl groups are furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, and tetrazolyl.
  • 5-membered heteroaryl groups are thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl, and triazolyl; more preferred are thiophen-2-yl, thiophen-3-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, [1,3,4]thiadiazol-2-yl, 1 H-pyrazol-3-yl, 1 H-pyrazol-4-yl, isothiazol-5-yl, isoxazol-4- yl, oxazol-5-yl, 1 H-[1 ,2,3]triazol-4-yl, or 2H-[1 ,2,3]triazol-4-yl; most preferred are thiophenyl such as thiophen-2-yl and thiophen-3-yl, thiazolyl such as
  • 6-membered heteroaryl groups are pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl; more preferred are pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl, pyrazine- yl, and pyridazin-3-yl; most preferred is pyridinyl such as pyridin-2-yl, pyridin-3-yl and pyridin-4-yl; particularly preferred is pyridin-3-yl.
  • the above-mentioned heteroaryl groups are unsubstituted or substituted as explicitly defined.
  • unsubstituted, mono-, di-, or tri-substituted refers to “unsubstituted, mono-substituted, di- substituted, or tri-substituted”.
  • unsubstituted, mono-, or di-substituted refers to “unsubstituted, mono-substituted, or di-substituted”.
  • a bond drawn as a dotted line shows the point of attachment of the radical drawn to the rest of the molecule.
  • the radical drawn below r represents phenyl or pyridin-3-yl.
  • halogen especially iodine, chlorine or fluorine
  • 5-membered heteroaryl containing from one to three ring heteroatoms independently selected from nitrogen, sulfur, and oxygen is selected from thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl, and triazolyl; especially selected from thiophen-2-yl, thiophen-3- yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, [1,3,4]thiadiazol-2-yl, 1 H-pyrazol-3-yl, 1 H-pyrazol-4-yl, isothiazol-5-yl, isoxazol-4-yl, oxazol-5-yl, 1 H-[1,2,3]triazol-4-yl, and 2H-[1 ,2,3]triazol-4-yl; in particular selected from thiophenyl such as
  • halogen especially chlorine, fluorine, or bromine
  • 6-membered heteroaryl containing from one to three ring nitrogen atoms is selected from pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl; especially selected from pyridine- yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl, pyrazin-2-yl, and pyridazin-3-yl; in particular selected from pyridin- 3-yl), wherein said 6-membered heteroaryl is unsubstituted, mono-, di-, or tri-substituted (notably unsubstituted, mono-, or di-substituted), wherein the substituent independently represents
  • halogen especially chlorine, fluorine, or bromine
  • Another embodiment relates to compounds according to embodiment 1) or 2), wherein Ar represents
  • halogen especially iodine, chlorine or fluorine
  • 5-membered heteroaryl containing from one to three ring heteroatoms independently selected from nitrogen, sulfur, and oxygen is selected from thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl, and triazolyl; especially selected from thiophen-2-yl, thiophen-3- yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, [1,3,4]thiadiazol-2-yl, 1 H-pyrazol-3-yl, 1 H-pyrazol-4-yl, isothiazol-5-yl, isoxazol-4-yl, oxazol-5-yl, 1 H-[1,2,3]triazol-4-yl, and 2H-[1 ,2,3]triazol-4-yl; in particular selected from thiophenyl such as
  • halogen especially chlorine, fluorine, or bromine
  • 6-membered heteroaryl containing from one to three ring nitrogen atoms is selected from pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; especially selected from pyridin- 2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl, pyrazin-2-yl, and pyridazin-3-yl; in particular selected from pyridin-3-yl), wherein said 6-membered heteroaryl is unsubstituted, mono-, di-, or tri-substituted (notably unsubstituted, mono-, or di-substituted), wherein the substituent independently represents
  • halogen especially chlorine, fluorine, or bromine
  • phenyl wherein said phenyl is unsubstituted, mono-, di-, or tri-substituted (notably unsubstituted, mono-, or di-substituted), wherein the substituent independently represents > halogen (especially iodine, chlorine, fluorine, or bromine);
  • Another embodiment relates to compounds according to embodiment 1) or 2), wherein Ar represents
  • phenyl wherein said phenyl is unsubstituted; mono-substituted in meta-position with regard to the point of attachment of the rest of the molecule; or di-substituted with one substituent in meta-position and another substituent in para- or ortho-position (any one of the ortho-positions), with regard to the point of attachment of the rest of the molecule; wherein the substituent independently represents
  • halogen especially iodine, chlorine, fluorine, or bromine; preferred is fluorine
  • Another embodiment relates to compounds according to any one of embodiments 1) to 3), wherein Ar represents
  • phenyl wherein said phenyl is unsubstituted; mono- substituted in meta-position with regard to the point of attachment of the rest of the molecule; or di-substituted with one substituent in meta-position and another substituent in para- or ortho-position (any one of the ortho-positions), with regard to the point of attachment of the rest of the molecule; wherein the substituent independently represents
  • halogen especially iodine, chlorine or fluorine
  • Another embodiment relates to compounds according to any one of embodiments 1) to 4), wherein Ar represents
  • phenyl wherein said phenyl is unsubstituted; mono- substituted in meta-position with regard to the point of attachment of the rest of the molecule; or di-substituted with one substituent in meta-position and another substituent in para-position, with regard to the point of attachment of the rest of the molecule; wherein the substituent independently represents
  • halogen especially iodine, chlorine or fluorine
  • C1-3-alkyl especially methyl
  • Another embodiment relates to compounds according to any one of embodiments 1) to 4), wherein Ar represents
  • phenyl wherein said phenyl is unsubstituted; mono- substituted in meta-position with regard to the point of attachment of the rest of the molecule; or di-substituted with one substituent in meta-position and another substituent in para-position, with regard to the point of attachment of the rest of the molecule; wherein the substituent independently represents chlorine, fluorine, or methoxy (notably iodine, chlorine or fluorine; especially fluorine).
  • 5-membered heteroaryl containing from one to three ring heteroatoms independently selected from nitrogen, sulfur, and oxygen is selected from thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl, and triazolyl; especially selected from thiophen-2-yl, thiophen-3- yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, [1,3,4]thiadiazol-2-yl, 1 H-pyrazol-3-yl, 1 H-pyrazol-4-yl, isothiazol-5-yl, isoxazol-4-y I , oxazol-5-yl, 1 H-[1 ,2,3]triazol-4-yl, and 2H-[1 ,2,3]triazol-4-yl; in particular selected from thiophen-
  • halogen especially chlorine, fluorine, or bromine
  • 5-membered heteroaryl containing at least one ring sulfur atom and optionally one or two ring nitrogen atoms
  • 5-membered heteroaryl is selected from thiophenyl, thiazolyl, isothiazolyl, and thiadiazolyl; especially selected from thiophen-2-yl, thiophen-3-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-5-yl, and [1 ,3,4]thiadiazol-2-yl; in particular selected from thiophenyl such as thiophen-2-yl and thiophen-3-yl); wherein said 5-membered heteroaryl is unsubstituted, mono-, or di-substituted (notably unsubstituted or mono- substituted; especially mono-substituted), wherein the substituent independently represents
  • halogen especially chlorine, fluorine, or bromine
  • 5-membered heteroaryl containing at least one ring sulfur atom and optionally one or two ring nitrogen atoms
  • 5-membered heteroaryl is selected from thiophenyl, thiazolyl, isothiazolyl, and thiadiazolyl; especially selected from thiophen-2-yl, thiophen-3-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-5-yl, and
  • [1.3.4]thiadiazol-2-yl in particular selected from thiophenyl such as thiophen-2-yl and thiophen-3-yl); wherein said 5-membered heteroaryl is unsubstituted, mono-, or di-substituted (notably unsubstituted or mono- substituted; especially mono-substituted), wherein the substituent independently represents
  • halogen especially chlorine, fluorine, or bromine
  • halogen especially chlorine, fluorine, or bromine
  • Another embodiment relates to compounds according to any one of embodiments 1) to 4), wherein Ar represents
  • 5-membered heteroaryl selected from thiophen-2-yl and thiophen-3-yl; wherein said 5-membered heteroaryl is mono-substituted (especially at position 3 with regard to the point of attachment of the rest of the molecule), wherein the substituent independently represents
  • halogen especially chlorine, fluorine, or bromine
  • Another embodiment relates to compounds according to embodiment 1) or 2), wherein Ar represents
  • 6-membered heteroaryl containing from one to three ring nitrogen atoms is selected from pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; especially selected from pyridin- 2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl, pyrazin-2-yl, and pyridazin-3-yl; in particular selected from pyridin-3-yl); wherein said 6-membered heteroaryl is unsubstituted, mono-, di-, or tri-substituted (notably unsubstituted, mono- , or di-substituted), wherein the substituent independently represents
  • halogen especially chlorine, fluorine, or bromine
  • 6-membered heteroaryl containing one or two ring nitrogen atoms, wherein at least one ring nitrogen atom is in position 3 with regard to the point of attachment of the rest of the molecule (notably such 6-membered heteroaryl is selected from pyridin-3-yl and pyrimidin-5-yl; especially selected from pyridin-3-yl), wherein said 6-membered heteroaryl is unsubstituted, mono-, di-, or tri-substituted (notably mono-, di- or tri-substituted; especially di- or tri-substituted; in particular di-substituted), wherein the substituent independently represents
  • halogen especially chlorine, fluorine, or bromine
  • 6-membered heteroaryl selected from pyridin-3-yl, wherein said 6-membered heteroaryl is unsubstituted, mono-, di-, or tri-substituted (notably mono-, di- or tri-substituted; especially di- or tri-substituted; in particular di-substituted), wherein the substituent independently represents
  • halogen especially chlorine, fluorine, or bromine
  • 6-membered heteroaryl selected from pyridin-3-yl, wherein said 6-membered heteroaryl is unsubstituted, mono-, di-, or tri-substituted (notably mono-, di- or tri-substituted; especially di- or tri-substituted; in particular di-substituted), wherein the substituent independently represents chlorine, fluorine, methyl, or methoxy (especially chlorine, fluorine, or methyl).
  • Another embodiment relates to compounds according to any one of embodiments 1) to 4), wherein Ar represents 6-membered heteroaryl selected from pyridin-3-yl, wherein said pyridin-3-yl is unsubstituted, mono-, di-, or tri- substituted (notably mono-, di- or tri-substituted; especially di- or tri-substituted; in particular di-substituted) in position(s) 2 and/or 5 and/or 6, with regard to the nitrogen atom of said pyridin-3-yl; wherein the substituent independently represents chlorine, fluorine, methyl, or methoxy (especially chlorine, fluorine, or methyl).
  • FIG. 20 Another embodiment relates to compounds according to any one of embodiments 1) to 4) and 15) to 18), wherein Ar represents 6-membered heteroaryl, wherein said 6-membered heteroaryl is selected from pyridin-3-yl, wherein said pyridin-3-yl is unsubstituted, mono-, di-, or tri-substituted (notably mono-, di- or tri-substituted; especially di- or tri- substituted; in particular di-substituted) in position(s) 2 and/or 5 and/or 6, with regard to the nitrogen atom of said pyridin-3-yl; wherein the substituents are as defined for the 6-membered heteroaryl in the corresponding embodiments 1) to 4) and 15) to 18).
  • Ar represents 6-membered heteroaryl, wherein said 6-membered heteroaryl is selected from pyridin-3-yl, wherein said pyridin-3-yl is unsubstituted, mono-, di-, or
  • FIG. 21 Another embodiment relates to compounds according to any one of embodiments 1) to 4), wherein Ar represents 6-membered heteroaryl, wherein said 6-membered heteroaryl is selected from pyridin-3-yl, wherein said pyridin-3-yl is unsubstituted, mono-, or di-substituted in position(s) 2 and/or 5 and/or 6, with regard to the nitrogen atom of said pyridin-3-yl; wherein the substituent(s), if present, independently represent methyl or fluorine.
  • Ar represents 6-membered heteroaryl, wherein said 6-membered heteroaryl is selected from pyridin-3-yl, wherein said pyridin-3-yl is unsubstituted, mono-, or di-substituted in position(s) 2 and/or 5 and/or 6, with regard to the nitrogen atom of said pyridin-3-yl; wherein the substituent(s), if present, independently represent methyl or fluorine.
  • C1-5-alkyl notably C1-4-alkyl; especially methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, or sec- butyl;
  • C1-4-fluoroalkyl especially 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-fluoro-1 -methyl-ethyl, 2- fluoro-1-fluoromethyl-ethyl, 2, 2-difluoro-1 -methyl-ethyl, 2,2,2-trifluoro-1, 1-dimethyl-ethyl, or 2,2,2-trifluoro-1- methyl-ethyl); or
  • > -L- represents a bond (i.e. Cy is directly attached to the nitrogen atom) or -CH2-;
  • Cy represents C3-6-cycloalkyl (especially cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl) optionally containing one oxygen ring atom, wherein said Ca-s-cycloalkyl optionally containing one oxygen ring atom is unsubstituted or mono-substituted (especially at the point of attachment of said C3-6-cycloalkyl to the rest of the molecule), wherein the substituent represents fluorine
  • -L-Cy represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetan-3-yl, cyclopropyl- methyl, 1-fluoro-cyclopropylmethyl, or cyclobutyl-methyl]
  • C1-5-alkyl notably Cu-alkyl; especially methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, or sec- butyl;
  • C1-4-fluoroalkyl especially 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 1-methyl-2-fluoroethyl, 2-fluoro- 1-fluoromethyl-ethyl, 1-methyl-2,2-difluoro-ethyl, 1-methyl-1-trifluoromethyl-ethyl, or 2, 2, 2-trifluoro-1 -methyl- ethyl); or
  • > -L- represents a bond (i.e. Cy is directly attached to the nitrogen atom) or -CH2-;
  • Cy represents C3-6-cycloalkyl, wherein said C3-6-cycloalkyl is unsubstituted or mono-substituted (especially at the point of attachment of said C3-6-cycloal kyl to the rest of the molecule), wherein the substituent represents fluorine (in particular -L-Cy represents cyclopropyl, cyclobutyl, cyclopropyl- methyl, (l-fluoro-cyclopropyl)-methyl, or cyclobutyl-methyl).
  • Another embodiment relates to compounds according to any one of embodiments 1) to 21), wherein R 1 represents
  • Another embodiment relates to compounds according to any one of embodiments 1) to 24), wherein R 2 represents hydrogen.
  • Ar represents a 6-membered heteroaryl, wherein said 6-membered heteroaryl is selected from pyridin-3-yl, wherein said pyridin-3-yl is unsubstituted, mono-, or di-substituted in position(s) 2 and/or 5 and/or 6, with regard to the nitrogen atom of said pyridin-3-yl; wherein the substituents independently represent methyl or fluorine;
  • R 1 represents C2-4-alkyl (notably ethyl, n-propyl, isopropyl, tert-butyl, or sec-butyl; especially isopropyl), cyclopropyl, or 2,2, 2-trifl uoro- 1 -methyl-ethyl; and
  • R 2 represents hydrogen
  • Another embodiment relates to compounds according to embodiment 1) or 2), wherein at least one, especially three of the following characteristics a) and/or b) and/or c) below are present: a) the radical represents: • phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 4-iodophenyl, 3-iodophenyl, 3-chlorophenyl, 3- cyanophenyl, 3-methylphenyl, 3-methoxyphenyl, 3-(trifluoromethoxy)-phenyl, 3,4-difluorophenyl, 2,3- difluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 3-fluoro-4-methoxyphenyl, 3- methyl-4-methoxyphenyl, 3-fluoro-4-methylphenyl, 2-methyl-5-fluorophenyl, 2-fluoro
  • thiophen-2-yl 4-methyl-thiophen-2-yl, 3-methyl-thiophen-2-yl, 5-methyl-thiophen-2-yl, 5-chloro-thiophen-2-yl, 5-fluoro-thiophen-2-yl, 5-bromo-thiophen-2-yl, 5-methoxy-thiophen-2-yl, 5-cyclopropyl-thiophene-2-yl, 5- methyl-thiophen-3-yl, 4-methyl-thiazol-2-yl, 2-methyl-thiazol-4-yl, 2-chloro-thiazol-4-yl, thiazol-4-yl, thiazol-5- yl, 2-ethyl-thiazol-5-yl, 2-methyl-thiazol-5-yl, 2-methoxy-thiazole-5-yl, 2-chloro-thiazol-5-yl, 2-cyclopropyl- thiazole-5-yl, 2-(1,1-difluoro-y
  • Another embodiment relates to compounds according to embodiment 1) or 2), wherein the radical represents pyridin-3-yl, 2-fluoro-pyridin-3-yl, 5-fluoro-pyridin-3-yl, 6-fluoro-pyridin-3-yl, 2-chloro-pyridin-3-yl, 5-chloro- pyridin-3-yl, 6-chloro-pyridin-3-yl, 2-bromo-pyridin-3-yl, 2-methyl-pyridin-3-yl, 5-methyl-pyridin-3-yl, 6-methyl- pyridin-3-yl, 5-ethyl-pyridin-3-yl, 6-ethyl-pyridin-3-yl, 5-cyclopropyl-pyridin-3-yl, 6-cyclopropyl-pyridin-3-yl, 2- difluoromethyl-pyridin-3-yl, 5,6-dimethyl-pyridin-3-yl, 2,6-dimethyl-pyridin-3-y
  • R 1 represents ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, 1-fluoro-cyclopropylmethyl, 2,2-difluoro- ethyl, or 2,2,2-trifluoro-1-methyl-ethyl;
  • R 2 represents hydrogen
  • Another embodiment relates to compounds according to any one of embodiments 1) to 28), which are also compounds of Formula (II) (i.e. the compounds are in c/s-configuration with respect to the cyclobutan-1 ,3-diyl ring)
  • Another embodiment relates to compounds according to any one of embodiments 1) to 28), which are also compounds of Formula (III) (i.e. the compounds are in trans-configuration with respect to the cyclobutan-1 , 3-diyl ring)
  • Another embodiment relates to compounds according to embodiment 1), which are selected from the following compounds
  • Another embodiment relates to compounds according to embodiment 1), which are selected from the following compounds
  • N-(3-(2-amino-6-(methylamino)pyrimidin-4-yl)cyclobutyl)-2,4-difluorobenzenesulfonamide i.e. CAS RN 2068732-71- 6;
  • N-(3-(2-amino-6-(methylamino)pyrimidin-4-yl)cyclobutyl)-2,5-difluorobenzenesulfonamide i.e. CAS RN 2068712-87- 6;
  • Another embodiment relates to compounds according to embodiment 1), which are selected from the following compounds
  • a compound of Formula (I) according to any one of embodiments 1) to 25), which is a radiolabeled compound, wherein • Ar is as defined in embodiments 1) to 25), wherein Ar independently is mono-, di-, or tri-substituted (notably mono-, or di-substituted), wherein one substituent represents a radioactive isotope of fluorine (especially selected from a group consisting of fluorine-18), wherein the rest of the substituents of Ar, if any, independently is/are as defined in embodiments 1) to 25); R 1 is as defined in embodiments 1) to 25); and R 2 is as defined in any one of embodiments 1) to 25);
  • Ar is as defined in embodiments 1) to 25), wherein Ar independently is mono-, di-, or tri-substituted (notably mono-, or di-substituted), wherein one substituent represents a radioactive isotope of iodine (especially selected from iodine-123, iodine-124, iodine-125, or iodine-131), wherein the rest of the substituents of Ar, if any, independently is/are as defined in embodiments 1) to 25); R 1 is as defined in embodiments 1) to 25); and R 2 is as defined in any one of embodiments 1) to 25); or
  • Ar is as defined in embodiments 1) to 25), wherein Ar independently is unsubstituted, mono-, di-, or tri- substituted (notably unsubstituted, mono-, or di-substituted), wherein the substituent independently is/are as defined in embodiment 1) to 25); R 1 is as defined in embodiments 1) to 25); and R 2 represents a radioactive isotope of fluorine (especially selected from fluorine-18).
  • radioactive isotope also known as “radionuclide”, “radioisotope”, “radioactive label”, or “label”
  • RPT radiopharmaceutical therapy
  • SPECT single-photon emission computed tomography
  • a radiolabeled compound may represent a mixture of unmodified (non-radioactive or “cold”) compound and a compound comprising said radioactive isotope (modified or “hot” compound).
  • radiolabeled compounds when a substituent of the molecule is designated as representing a radioactive isotope, it is understood that the abundance of said radioactive isotope at that position is substantially greater than the natural abundance of the same radioactive isotope, that is this substituent is substantially enriched of said radioactive isotope allowing for sufficient therapeutic radiopharmaceutical activity or for a detectable signal in PET, SPECT, autoradiography, and the like.
  • One embodiment relates to a compound according to embodiment 34), which is a radiolabeled compound, wherein Ar represents a 6-membered heteroaryl, wherein said 6-membered heteroaryl is selected from pyridin-3-yl, wherein said pyridin-3-yl is mono-, or di-substituted in position(s) 2 and/or 5 and/or 6 with regard to the nitrogen atom of said pyridin-3-yl; wherein one substituent represents fluorine-18 and the other substituent, if present, represents methyl; R 1 represents C2-4-alkyl (notably ethyl, n-propyl, isopropyl, tert-butyl, or sec-butyl; notably isopropyl), cyclopropyl, or 2,2,2- trifluoro-1-methyl-ethyl [especially R 1 represents isopropyl or 2,2,2-trifluoro-1-methyl-ethyl]; and R 2 represents hydrogen.
  • Ar represents a
  • One embodiment relates to compounds of Formula (I) according to embodiment 34), which is a radiolabeled compound, wherein said compound is selected from N-(cis-3-(2-amino-6-(tert-butylamino)pyrimidin-4-yl)cyclobutyl)-2-(fluoro- 18 F)-6-methylpyridine-3-sulfonamide; N-(cis-3-(2-amino-6-(tert-butylamino)pyrimidin-4-yl)cyclobutyl)-2-(fluoro- 18 F)-pyridine-3-sulfonamide; N-(cis-3-(2-amino-6-(propylamino)pyrimidin-4-yl)cyclobutyl)-2-(fluoro- 18 F)-pyridine-3-sulfonamide;
  • One embodiment relates to compounds of Formula (I) according to embodiment 34), which is a radiolabeled compound, wherein said compound is selected from
  • Another aspect relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula (I) according to any one of embodiments 34) to 37), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
  • Another aspect relates to a compound of Formula (I) according to any one of embodiments 34) to 37), which is a radiolabeled compound, or a pharmaceutically acceptable salt thereof, for use as a medicament.
  • a compound of Formula (I) according to embodiment 34 which is a radiolabeled compound, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer by radiopharmaceutical therapy, wherein said compound, or a pharmaceutically acceptable salt thereof, comprise a radioactive isotope of iodine (especially iodine-125 or iodine-131).
  • Another aspect relates to a compound of Formula (I) according to any one of embodiments 34) to 37), which is a radiolabeled compound, or a pharmaceutically acceptable salt thereof, for use in the diagnosis of cancer (e.g. by medical imaging such as positron emission tomography (PET), single-photon emission computed tomography (SPECT), or autoradiography including drug or substrate tissue distribution assays).
  • medical imaging such as positron emission tomography (PET), single-photon emission computed tomography (SPECT), or autoradiography including drug or substrate tissue distribution assays.
  • Another aspect relates to a compound of Formula (I) according to any one of embodiments 34) to 37), which is a radiolabeled compound, or a pharmaceutically acceptable salt thereof, for use in diagnostic imaging of CCR8 receptors in humans, said method comprising:
  • a detectable quantity is a quantity of a compound which is required to render the compound detectable in the human body or in a sample as the case may be by the detection method chosen e.g. PET.
  • the amount of compound to be introduced into a patient/sample in order to provide for detection can be determined by those skilled in the art.
  • the present invention also includes 2 H (deuterium) labelled compounds of Formula (I), which compounds are identical to the compounds of Formula (I) except that one or more atoms have each been replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature.
  • 2 H (deuterium) labelled compounds of Formula (I) and salts thereof are within the scope of the present invention. Substitution of hydrogen with the heavier isotope 2 H (deuterium) may lead to greater metabolic stability, resulting e.g. in increased in-vivo half-life and/or reduced dosage requirements, and/or may lead to a modified metabolism pathway, resulting e.g. in an improved safety profile.
  • the compounds of Formula (I) are not isotopically labelled, or they are labelled only with one or more deuterium atoms. In a sub-embodiment, the compounds of formula (I) are not isotopically labelled at all. Isotopically labelled compounds of Formula (I) may be prepared in analogy to the methods described hereinafter but using the appropriate isotopic variation of suitable reagents or starting materials.
  • the invention relates to compounds of the Formula (I) as defined in embodiment 1), or to such compounds further limited by the characteristics of any one of embodiments 2) to 42), under consideration of their respective dependencies; to pharmaceutically acceptable salts thereof; and to the use of such compounds as medicaments especially in the treatment of diseases or disorders where CCR8 receptors are involved as described hereinbelow.
  • any reference to compounds of Formula (I) according to embodiments 1) to 42) is to be understood as referring also to the salts (and especially the pharmaceutically acceptable salts) of such compounds, as appropriate and expedient.
  • pharmaceutically acceptable salts refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects. Such salts include inorganic or organic acid and/or base addition salts depending on the presence of basic and/or acidic groups in the subject compound. For reference see for example “Handbook of Pharmaceutical Salts. Properties, Selection and Use.”, P. Heinrich Stahl, Camille G. Wermuth (Eds.), Wiley-VCH, 2008; and “Pharmaceutical Salts and Co-crystals”, Johan Wouters and Luc Quere (Eds.), RSC Publishing, 2012.
  • Definitions provided herein are intended to apply uniformly to the compounds of Formula (I), as defined in any one of embodiments 1 ) to 42), and, mutatis mutandis, throughout the description and the claims unless an otherwise expressly set out definition provides a broader or narrower definition. It is well understood that a definition or preferred definition of a term defines and may replace the respective term independently of (and in combination with) any definition or preferred definition of any or all other terms as defined herein.
  • the compounds of Formula (I) may encompass compounds with one or more asymmetric centers, such as one or more asymmetric carbon atoms, which may be present in (R)- as well as (S)-configuration.
  • the compounds of Formula (I) may further encompass compounds with one or more double bonds which are allowed to be present in Z- as well as E-configuration and/or compounds with substituents at a ring system which are allowed to be present, relative to each other, in cis- as well as trans-configuration.
  • the compounds of Formula (I) may thus be present as mixtures of stereoisomers or preferably in stereoisomerically enriched form, especially as essentially pure stereoisomers. Mixtures of stereoisomers may be separated in a manner known to a person skilled in the art.
  • essentially pure when used in the context of stereoisomers, is to be understood in the context of the present invention to mean that the respective stereoisomer is present in a purity of at least 95% by weight, especially of at least 99% by weight, with regard to the respective other stereoisomer / the entirety of the respective other stereoisomers.
  • the compounds of Formula (I) according to embodiments 1) to 37) and their pharmaceutically acceptable salts can be used as medicaments, e.g. in the form of pharmaceutical compositions for enteral (such especially oral) or parenteral administration (subcutaneous, intraperitoneal, intravenous, intradermal, intramuscular, topical, or inhalation).
  • compositions can be effected in a manner which will be familiar to any person skilled in the art (see for example Remington, The Science and Practice of Pharmacy, 21st Edition (2005), Part 5, “Pharmaceutical Manufacturing” [published by Lippincott Williams & Wilkins]) by bringing the described compounds of Formula (I), or their pharmaceutically acceptable salts, optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants.
  • One embodiment of the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula (I) according to any one of embodiments 1) to 37), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier/excipient.
  • the term “about’ (or alternatively the term “around”) placed before a numerical value “X” refers in the current application to an interval extending from X minus 10% of X to X plus 10% of X, and preferably to an interval extending from X minus 5% of X to X plus 5% of X.
  • the term “about” placed before a temperature “Y” refers in the current application to an interval extending from the temperature Y minus 10 °C to Y plus 10 °C, and preferably to an interval extending from Y minus 5 °C to Y plus 5 °C.
  • the compounds of Formula (I) of the present invention may be useful as single therapeutic agents or in combination with one or more therapeutic agents and/or therapies, for the prevention / prophylaxis or treatment of diseases or disorders relating to the CCR8 receptor or its ligands, which are diseases or disorders relating to a dysfunction of the CCR8 receptor, or dysfunction of ligands signaling through the CCR8 (i.e. CCL1, CCL8, CCL16, and/or CCL18, especially CCL1), or dysfunction of CCR8 ligands signaling through their other receptors (i.e. CCL8, CCL16, and/or CCL18).
  • diseases or disorders relating to the CCR8 receptor or its ligands which are diseases or disorders relating to a dysfunction of the CCR8 receptor, or dysfunction of ligands signaling through the CCR8 (i.e. CCL1, CCL8, CCL16, and/or CCL18, especially CCL1), or dysfunction of CCR8 ligands signaling through their other receptors (
  • the compounds of Formula (I) of the present invention may be useful as single therapeutic agents or in combination with one or more therapeutic agents and/or therapies, for the prevention / prophylaxis or treatment of diseases or disorders involving CCR8 and/or CCL1 and/or CCL18 mediated metastasis, chemotaxis, cell adhesion, trans- endothelial migration, cell proliferation and/or survival; especially in regulating the process of metastasis invasion e.g. in melanoma or bladder cancer patients.
  • the compounds of Formula (I) of the present invention may be useful as single therapeutic agents or in combination with one or more therapeutic agents and/or therapies, for the prevention / prophylaxis or treatment of diseases or disorders, where CCR8 receptors are involved i.e. diseases or disorders ameliorated by modulating, especially by antagonizing CCR8 receptors; wherein such diseases or disorders are defined as cancer.
  • cancer as used hereinabove and hereinbelow includes all sorts of cancers such as carcinomas; adenocarcinomas; leukemias; sarcomas; lymphomas; myelomas; metastatic cancers; brain tumors; neuroblastomas; pancreatic cancers; gastro-intestinal cancers; lung cancers; breast cancers; prostate cancers; endometrial cancers; skin cancers; bladder cancers; head and neck cancers; neuroendocrine tumors; ovarian cancers; cervical cancers; oral tumors; nasopharyngeal tumors; thoracic cancers; and virally induced tumors.
  • carcinomas such as carcinomas; adenocarcinomas; leukemias; sarcomas; lymphomas; myelomas; metastatic cancers; brain tumors; neuroblastomas; pancreatic cancers; gastro-intestinal cancers; lung cancers; breast cancers; prostate cancers; endometrial cancers; skin cancers; bladder cancers;
  • cancer as used hereinabove and hereinbelow notably refers to brain tumors including brain metastases, malignant gliomas, glioblastoma multiforme, medulloblastoma, meningiomas; neuroblastoma; pancreatic cancer including pancreatic adenocarcinoma/pancreatic ductal adenocarcinoma; gastro-intestinal cancers including colon carcinoma, colorectal adenoma, colorectal adenocarcinoma, metastatic colorectal cancer, familial adenomatous polyposis (FAP), gastric cancer, gallbladder cancer, cholangiocarcinoma, hepatocellular carcinoma; gastro- esophageal junction cancer; esophageal cancer; Kaposi sarcoma; leukemias including acute myeloid leukemia, chronic myeloid leukemia, adult T-cell leukemia, acute lymphoblastic leukemia, and chronic lymphocytic
  • cancer as used hereinabove and hereinbelow especially refers to oral squamous cell carcinoma; head and neck squamous cell carcinoma; liver cancer including hepatocellular carcinoma; cholangiosarcoma including extrahepatic cholangiosarcoma; gastrointestinal stromal tumors; colorectal cancer; lung cancer including non-small cell lung cancer; bladder cancer; kidney cancer; breast cancer; lymphoma including T cell lymphoma, cutaneous T cell lymphoma, and systemic ALK-negative anaplastic large cell lymphoma; endometrial tumors; Kaposi sarcoma; melanoma; and basal cell carcinoma.
  • cancer as used hereinabove and hereinbelow also refers to cancer types infiltrated with intratumoral regulatory T cells (Tregs) expressing CCR8.
  • Tregs intratumoral regulatory T cells
  • cancer as used hereinabove and hereinbelow particularly refers to gastrointestinal cancer, colorectal cancer, non-small cell lung cancer, lung squamous cell carcinoma, liver cancer, bladder cancer, kidney cancer, breast cancer, melanoma, oral squamous cell carcinoma, Kaposi sarcoma, head and neck squamous cell carcinoma, esophageal squamous cell carcinoma, and pancreatic ductal adenocarcinoma.
  • cancer as used hereinabove and hereinbelow also refers to solid tumors such as renal cancer, breast cancer including triple-negative breast cancer, stomach cancer, colorectal cancer, ovarian cancer, head and neck cancer, melanoma, and pancreatic cancer.
  • the compounds of Formula (I) of the present invention comprising a radioactive isotope may be useful in radiopharmaceutical therapy (RPT) of cancer, wherein cancer is as defined hereinabove.
  • RPT radiopharmaceutical therapy
  • the compounds of Formula (I) of the present invention comprising a radioactive isotope may be useful in the diagnosis e.g. in medical imaging such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) of cancer, wherein cancer is as defined hereinabove.
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • the compounds of Formula (I) of the present invention may be useful as single therapeutic agents or in combination with one or more further therapeutic agents and/or further therapies, for the prevention / prophylaxis or treatment of diseases or disorders, where CCR8 receptors are involved i.e.
  • diseases or disorders ameliorated by modulating, especially by antagonizing CCR8 receptors wherein such diseases or disorders are defined as atopic diseases; fibrotic diseases; neuropathic pain; sepsis; septic peritonitis; infections associated with immune suppression including infections resulting from burn injury; chronic obstructive pulmonary disease; organ transplantation including allogeneic kidney transplantation; peritoneal adhesions; pathological bondings of serosal membranes related to surgery or inflammation; and autoimmune encephalomyelitis.
  • atopic diseases; fibrotic diseases; and neuropathic pain Especially, fibrotic diseases including fibrosis.
  • atopic diseases includes all sorts of type 2 inflammatory diseases and immunoglobulin E (IgE) mediated diseases such as atopic dermatitis, allergic enteritis, allergic asthma (e.g. fungal-allergic asthma), allergic rhinitis, allergic conjunctivitis, IgE-mediated drug allergy, food allergy, insect bites, urticaria, angioedema, and anaphylactic shock.
  • IgE immunoglobulin E
  • fibrotic diseases includes all sorts of diseases defined by deleterious accumulation of extracellular matrix components such as collagen and fibronectin at sites of inflammation or tissue damage that can lead to permanent scarring and/or organ disfunction.
  • the term “fibrotic diseases” may be referred to “fibrosis”. Said term comprises, among others, liver fibrosis, pulmonary fibrosis, fibrosis associated with lgG4-related disease (e.g. salivary gland fibrosis and sclerosing cholangitis), systemic sclerosis, skin fibrosis including skin fibrosis associated with human chronic graft-versus-host disease, and fibrosis associated with organ transplantation including fibrosis associated with allogeneic kidney transplantation.
  • lgG4-related disease e.g. salivary gland fibrosis and sclerosing cholangitis
  • systemic sclerosis e.g. salivary gland fibrosis and sclerosing cholangitis
  • skin fibrosis including skin
  • pulmonary fibrosis includes all sorts of fibrotic disorders affecting the lungs, e.g. idiopathic pulmonary fibrosis and pulmonary fibrosis associated with human chronic graft-versus-host disease, and optionally non-idiopathic interstitial pulmonary fibrosis/interstitial lung disease.
  • liver fibrosis includes all sorts of fibrotic disorders affecting the liver, including those related to chronic viral liver infections such as Hepatitis C and Hepatitis B, chronic alcohol use, nonalcoholic steatohepatitis, chronic cholestatic disorders such as primary biliary cirrhosis and primary sclerosis cholangitis, and autoimmune hepatitis.
  • neuropathic pain refers to both central and peripheral neuropathic pain and includes all sorts of conditions affecting the somatosensory system that result in painful sensations such as dysesthesia and allodynia, including those caused by spinal cord injury, multiple sclerosis, all types of diabetes mellitus, cancer and cancer treatments as defined herein, metabolic disorders, herpes zoster infection, human immunodeficiency virus infection, nutritional deficiencies, exposure to toxins, autoimmune disorders, and physical trauma.
  • the compounds of Formula (I), or a pharmaceutically acceptable salt thereof may be useful for the treatment and/or prevention of neuropathic pain, wherein said compounds or a pharmaceutically acceptable salt thereof are used as a single therapeutic agent or in combination with one or more opioid and/or one or more non-opioid analgesics.
  • the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, may be useful for potentiating the analgesic effects of opioids such as methadone, oxycodone, hydrocodone, and the like.
  • the compounds of Formula (I), or a pharmaceutically acceptable salt thereof may be useful in the treatment and/or prevention of fibrotic diseases (especially liver fibrosis), wherein said compounds or a pharmaceutically acceptable salt thereof are used as a single therapeutic agent or in combination with one or more further treatment or therapy, wherein said further treatment or therapy is aimed at the treatment and/or prevention of the underlying cause of the fibrotic disease (especially liver fibrosis).
  • such use includes use of the present compounds as single therapeutic agents and their use in combination with one or more chemotherapy agents and / or radiotherapy and / or targeted therapy (especially in combination with targeted therapy).
  • radiotherapy or “radiation therapy” or “radiation oncology” refer to the medical use of ionizing radiation in the prevention (adjuvant therapy) and / or treatment of cancer, including external and internal radiotherapy.
  • targeted therapy refers to the prevention / prophylaxis (adjuvant therapy) and / or treatment of cancer with one or more anti-neoplastic agents such as small molecules or antibodies which act on specific types of cancer cells or stromal cells.
  • Some targeted therapies block the action of certain enzymes, proteins, or other molecules involved in the growth and spread of cancer cells.
  • Other types of targeted therapies help the immune system kill cancer cells (immunotherapies); or deliver toxic substances directly to cancer cells and kill them.
  • An example of a targeted therapy which is in particular suitable to be combined with the compounds of the present invention is immunotherapy, especially immunotherapy targeting the programmed cell death receptor 1 (PD-1 receptor) or its ligand PD-L1 (Feig C et al, PNAS 2013).
  • PD-1 receptor programmed cell death receptor 1
  • PD-L1 ligand PD-L1
  • Immunotherapy further refers to (i) an agonist of a stimulatory (including a co-stimulatory) receptor or (ii) an antagonist of an inhibitory (including a co- inhibitory) signal on T cells, both of which result in amplifying antigen-specific T cell responses (often referred to as immune checkpoint regulators).
  • a stimulatory and inhibitory molecules are members of the immunoglobulin super family (IgSF).
  • B7 family which includes B7-1 , B7-2, B7-HI (PD-LI), B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), and B7-H6.
  • TNF family of molecules that bind to cognate TNF receptor family members which includes CD40 and CD40L, OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-IBBL, CD137 (4-IBB), TRAIL/Apo2-L, TRAILR1/DR4, TRAILR2/DR5, TRAILR3, TRAILR4, OPG, RANK, RANKL, TWEAKR/Fnl4, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LTpR, LIGHT, DcR3, HVEM, VEGi/TLIA, TRAMP/DR3, EDAR, EDAI, XEDAR, EDA2, TNFRI, Lymphotoxin a/TNFp, TNFR2, TNFa, LTPR, Lymphotoxin a 1p2, FA
  • the term "targeted therapy” especially refers to agents such as: a) Epidermal growth factor receptor (EGFR) inhibitors or blocking antibodies (such as Gefitinib, Erlotinib, Afatinib, Icotinib, Lapatinib, Panitumumab, Neratinib, Osimertinib, Dacomitinib, Almonertinib, Tucatinib, Zalutumumab, Nimotuzumab, Matuzumab, Cetuximab), as well as trastuzumab (HERCEPTIN); b) RAS/RAF/MEK pathway inhibitors (such as Vemurafenib, Sorafenib, Dabrafenib,GDC-0879, PLX-4720, Encorafenib (LGX818), RG7304, Trametinib (GSK1120212), Cobimetinib (GDC-
  • EGFR Epidermal growth factor receptor
  • anti-OX40/CD134 Tumor necrosis factor receptor superfamily, member 4
  • antibodies including agonist antibodies
  • fusion proteins such as RG7888 (MOXR0916), 9B12, MEDI6469, GSK3174998, MEDI6383, MEDI0562), anti-OX40-Ligand/CD252; anti-glucocorticoid-induced TNFR family related gene (GITR) antibodies and fusion proteins (such as TRX518, MEDI1873, MK-4166, BMS-986156, BMS-986153); anti-CD40 (TNF receptor superfamily member 5) antibodies (such as Dacetuzumab (SGN-40), HCD122, CP-870,893, RG7876, ADC-1013, APX005M, SEA-CD40); anti-CD40- Ligand antibodies (such as BG9588); anti-CD27 antibodies (such as Varlilumab); anti-CD28 antibodies; anti--CD28 antibodies; anti-CD40- Liga
  • chemotherapy refers to the treatment of cancer with one or more cytotoxic anti-neoplastic agents ("cytotoxic chemotherapy agents"). Chemotherapy is often used in conjunction with other cancer treatments, such as radiation therapy or surgery. The term especially refers to conventional chemotherapeutic agents which act by killing cells that divide rapidly, one of the main properties of most cancer cells. Chemotherapy may use one drug at a time (single- agent chemotherapy) or several drugs at once (combination chemotherapy or polychemotherapy). Chemotherapy using drugs that convert to cytotoxic activity only upon light exposure is called photochemotherapy or photodynamic therapy.
  • cytotoxic chemotherapy agent refers to an active anti-neoplastic agent inducing apoptosis or necrotic cell death.
  • chemotherapy agent refers to an active anti-neoplastic agent inducing apoptosis or necrotic cell death.
  • conventional cytotoxic chemotherapy agents such as: a) alkylating agents (for example mechlorethamine, chlorambucil, cyclophosphamide, ifosfamide, streptozocin, carmustine, lomustine, melphalan, busulfan, dacarbazine, temozolomide, thiotepa or altretamine; in particular temozolomide); b) platinum drugs (for example cisplatin, carboplatin or oxaliplatin); c) antimetabolite drugs (for example 5-fluorouracil, capecitabine, 6-mercaptopurine, methotrexate, gemcitabine, cytarabine, fludarabine or
  • preferred cytotoxic chemotherapy agents are the above-mentioned alkylating agents (notably mechlorethamine, chlorambucil, cyclophosphamide, ifosfamide, streptozocin, carmustine, lomustine, melphalan, busulfan, dacarbazine, 3-methyl- (triazen-1-yl)imidazole-4-carboxamide (MTIC) and prodrugs thereof such as especially temozolomide, thiotepa, altretamine; or pharmaceutically acceptable salts of these compounds; in particular temozolomide); and mitotic inhibitors (notably paclitaxel, docetaxel, ixabepilone, vinblastine, vincristine, vinorelbine, vindesine, estramustine; or pharmaceutically acceptable salts of these compounds; in particular paclitaxel). Most preferred cytotoxic chemotherapy agents to be used in combination with the compounds of formula (I)
  • Chemotherapy may be given with a curative intent or it may aim to prolong life or to palliate symptoms.
  • Combined modality chemotherapy is the use of drugs with other cancer treatments, such as radiation therapy or surgery.
  • Induction chemotherapy is the first line treatment of cancer with a chemotherapeutic drug. This type of chemotherapy is used for curative intent.
  • Consolidation chemotherapy is the given after remission in order to prolong the overall disease-free time and improve overall survival. The drug that is administered is the same as the drug that achieved remission.
  • Intensification chemotherapy is identical to consolidation chemotherapy but a different drug than the induction chemotherapy is used.
  • Combination chemotherapy involves treating a patient with a number of different drugs simultaneously. The drugs differ in their mechanism and side effects.
  • Neoadjuvant chemotherapy is given prior to a local treatment such as surgery, and is designed to shrink the primary tumor. It is also given to cancers with a high risk of micro-metastatic disease.
  • Adjuvant chemotherapy is given after a local treatment (radiotherapy or surgery). It can be used when there is little evidence of cancer present, but there is risk of recurrence. It is also useful in killing any cancerous cells that have spread to other parts of the body. These micro-metastases can be treated with adjuvant chemotherapy and can reduce relapse rates caused by these disseminated cells.
  • h) Maintenance chemotherapy is a repeated low-dose treatment to prolong remission.
  • i) Salvage chemotherapy or palliative chemotherapy is given without curative intent, but simply to decrease tumor load and increase life expectancy. For these regimens, a better toxicity profile is generally expected.
  • preventive or curative forms of chemotherapy such as those listed under a), b) c), d), e), and especially g) and / or h) above are preferred.
  • chemotherapy, radiotherapy, EGFR inhibitors, aromatase inhibitors, and immunotherapy are preferred.
  • Immunotherapy such as especially those targeting the programmed cell death receptor 1 (PD-1 receptor) or its ligand PD-L1 i.e.
  • PD1 and/or PDL1 blockade are especially preferred.
  • Most preferred immunotherapy used in combination with the compounds of Formula (I) of the present invention is PD1 and/or PDL1 blockade.
  • compounds of the present invention are described as useful as single therapeutic agents or in combination with one or more therapeutic agents and/or therapies, for the prevention / prophylaxis or treatment of diseases or disorders, such compounds are likewise suitable for use in the preparation of a medicament for the prevention / prophylaxis or treatment of diseases or disorders.
  • the present invention also relates to a method for the prevention / prophylaxis or treatment of diseases or disorders mentioned hereinabove or hereinbelow, said method comprising administering to a subject in need of such prevention / prophylaxis or treatment a pharmaceutically active amount of a compound of Formula (I) of the present invention, either alone or in combination with other pharmacologically active compounds and/or therapies.
  • the administered amount is comprised between 1 mg and 1000 mg per day, particularly between 5 mg and 500 mg per day, more particularly between 25 mg and 400 mg per day, especially between 50 mg and 200 mg per day.
  • a further aspect of the invention is a process for the preparation of compounds of Formula (I) as defined in any one of embodiments 1 ) to 37).
  • Compounds of Formula (I) can be prepared from commercially available or well-known starting materials according to the methods described in the experimental part, by analogous methods; or according to the general sequence of reactions outlined below, wherein Ar, R 1 , and R 2 are as defined for Formula (I).
  • Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by a person skilled in the art by routine optimization procedures.
  • Other abbreviations used herein are explicitly defined or are as defined in the experimental section.
  • protecting groups (PG) may be required.
  • protecting groups are well known in the art (see for example “Protective Groups in Organic Synthesis", T.W. Greene, P.G.M. Wuts, Wiley-lnterscience, 1999) and for the purposes of this discussion, it will be assumed that such protecting groups as necessary are in place.
  • the compounds obtained may be converted into salts, especially pharmaceutically acceptable salts thereof in a manner known perse.
  • compounds of Formula (I) are obtained by reaction of an intermediate of Formula A with a sulfonylchloride of Formula B following a typical sulfonamide coupling reaction scheme in the presence of a base such as TEA or DIPEA in a solvent such as THF, DMF, DOM or a mixture at RT or at elevated temperature (Scheme 1).
  • a base such as TEA or DIPEA
  • a solvent such as THF, DMF, DOM or a mixture at RT or at elevated temperature
  • compounds of Formula (I) are obtained by reaction of an intermediate of Formula C with an amine following a typical SNAr coupling reaction scheme in the presence of a base such as TEA or DI PEA in a solvent such as THF, DMF, MeOH, EtOH or the like at RT or at elevated temperature (Scheme 2).
  • a base such as TEA or DI PEA
  • a solvent such as THF, DMF, MeOH, EtOH or the like
  • [ 18 F]-labelled compounds of Formula [ 18 F]-(I) are obtained by reaction of an intermediate of Formula G or an intermediate of Formula H with K[ 18 F]F in the presence of kryptofix 2.2.2, potassium oxalate and a base such as K2CO3 in a solvent such as DMF or DMSO at RT or at elevated temperature (Scheme 3).
  • [ 18 F]-labelled compounds of Formula [ 18 F]-(I) are obtained by standard methodologies known to a person skilled in the art (see for example Halder, R. et al. J. Org. Chem. 2021 , 86, 13873; or Liu, Z. et al. Frontiers in Chemistry 2022, 10, 883866).
  • compounds of Formula [ 18 F]-(I) are obtained by reaction of an intermediate of Formula
  • LG such as a boronic acid (-B(OH)2), boronic ester (-B(0R)2), phenol (-OH), iodonium salt (-l + R), sulfonium salt (-S + R2), stannane (-SnRj), halogen (-01, -Br, -I) or ammonium salt (-N+Rj) in intermediates of Formula J (Scheme 4).
  • LG such as a boronic acid (-B(OH)2), boronic ester (-B(0R)2), phenol (-OH), iodonium salt (-l + R), sulfonium salt (-S + R2), stannane (-SnRj), halogen (-01, -Br, -I) or ammonium salt (-N+Rj) in intermediates of Formula J (Scheme 4).
  • LG such as a boronic acid (-B(OH)2), boronic ester
  • [ 18 F]-labelled compounds of Formula [ 18 F]-(I) are obtained by reaction of an intermediate of Formula K with K[ 18 F]F under various conditions to displace a leaving group (LG) (Scheme 5).
  • radioiodine-labelled compounds of Formula [l*]-(l) may be obtained by standard methodologies known to a person skilled in the art (see for example Petrov, S. A. et al. Int. J. Mol. Sci. 2022, 23, 137896).
  • the symbol “I*” refers to any one of the radioactive isotopes of iodine suitable for the intended use (therapy or diagnostic).
  • compounds of Formula [l*]-(l) may be obtained by reaction of an intermediate of Formula L with radiolabeled [l*]-Nal under various conditions to displace a leaving group (LG) such as a boronic acid (-B(OH)2), boronic ester (-B(OR)2), silane (-SiRj), stannane (-SnRj), halogen (-CI, -Br) or diazonium salt (-IV) in intermediates of Formula L (Scheme 5i).
  • LG such as a boronic acid (-B(OH)2), boronic ester (-B(OR)2), silane (-SiRj), stannane (-SnRj), halogen (-CI, -Br) or diazonium salt (-IV) in intermediates of Formula L (Scheme 5i).
  • LG such as a boronic acid (-B(OH)2), boronic ester (-B(OR)2), silane
  • intermediates of Formula A are obtained by reaction of a chloropyrimidine of Formula D with an amine, followed by reaction of an intermediate of Formula Aa with an acid (Scheme 6).
  • intermediate D is stirred at RT or at elevated temperature with an appropriate amine in a solvent such as EtOH, MeOH or the like.
  • the resulting tert-butyl carbamate intermediate of Formula Aa is then treated at RT or at elevated temperature with an acid such as TFA, HOI, H2SO4, H3PO4 or the like in a solvent such as DOM, MeCN, THF, toluene or the like.
  • intermediates of Formula A are obtained by reaction of a pyrimidine p-toluenesulfonate of Formula E with an amine, followed by reaction of an intermediate of Formula Aa with an acid (Scheme 7).
  • intermediate E is stirred at RT or at elevated temperature with an appropriate amine in a solvent such as EtOH, MeOH or the like.
  • the resulting tert-butyl carbamate intermediate of Formula Aa is then treated at RT or at elevated temperature with an acid such as TFA, HCI, H2SO4, H3PO4 or the like in a solvent such as DCM, MeCN, THF, toluene or the like.
  • intermediates of Formula B are either commercially available or are obtained by reaction of an aryl bromide Ba with benzyl mercaptane followed by oxidation of the thioether intermediate of Formula Bb (Scheme 8).
  • an aryl bromide of Formula Ba is stirred at elevated temperature in a solvent such as dioxane or toluene or the like in the presence of benzyl mercaptane, a palladium catalyst such as Pd2(dba)3, a phosphine ligand such as XantPhos and a base such as DIPEA or the like.
  • the resulting intermediate Bb is stirred at RT or at elevated temperature in a solvent such as MeCN in the presence of an aqueous solution of HCI and an oxidant such as NCS or the like.
  • intermediates of Formula C are obtained by reaction of a chloropyrimidine of Formula D with an acid followed by reaction of an intermediate of Formula Ca with a sulfonylchloride of Formula B under typical sulfonamide coupling conditions (Scheme 9).
  • an intermediate of Formula D is treated at RT or at elevated temperature with an acid such as TFA, HCI, H2SO4, H3PO4 or the like in a solvent such as DCM, MeCN, THF, toluene or the like.
  • the resulting chloropyrimidine intermediate of Formula Ca is treated with a sulfonyl chloride of Formula B in the presence of a base such as TEA or DIPEA in a solvent such as THF, DMF, DCM or a mixture at RT or at elevated temperature.
  • a base such as TEA or DIPEA
  • a solvent such as THF, DMF, DCM or a mixture at RT or at elevated temperature.
  • intermediates of Formula D are obtained by reaction of intermediate F with a chlorinating reagent such as POCI3 in the presence of a base such as TEA, DIPEA or the like in solvent such as MeCN, toluene, DCM or the like at RT or at elevated temperature (Scheme 10).
  • a chlorinating reagent such as POCI3
  • a base such as TEA, DIPEA or the like
  • solvent such as MeCN, toluene, DCM or the like at RT or at elevated temperature
  • intermediates of Formula E are obtained by reaction of intermediate F with p-toluenesulfonyl chloride in the presence of a base such as TEA, DIPEA or the like in solvent such as MeCN, toluene, DCM or the like at RT or at elevated temperature (Scheme 11).
  • a base such as TEA, DIPEA or the like in solvent such as MeCN, toluene, DCM or the like at RT or at elevated temperature (Scheme 11).
  • intermediates of Formula F are obtained by reaction of commercially available acid Fa to produce intermediate ketoester Fb, followed by condensation with guanidine (Scheme 12).
  • a commercially available acid of Formula Fa is treated with 2, 2-dimethyl-1 ,3-dioxane-4, 6-dione or a 3-methoxy-3- oxopropanoic acid potassium salt of Formula Fc in the presence of an acid activating reagent such as EDC, GDI or the like and a base such as DMAP in a solvent such as DCM, followed by treatment with MeOH at RT or at elevated temperature.
  • ketoester intermediate of Formula Fb is treated with guanidine hydrochloride in the presence of a base such as NaOEt, KOtBu or the like in a solvent such as EtOH, MeOH or the like at RT or at elevated temperature.
  • a base such as NaOEt, KOtBu or the like
  • a solvent such as EtOH, MeOH or the like
  • the enantiomers can be separated using methods known to one skilled in the art: e.g. by formation and separation of diastereomeric salts or by HPLC or SFC over a chiral stationary phase such as a Regis Whelk-O1(R,R) (10 pirn) column, a Daicel ChiralCel OD-H (5-10 pirn) column, or a Daicel ChiralPak IA (10 jxm), IA, IB, IC, IE, or IF (5 pirn) or AD-H (5 pirn) column.
  • a chiral stationary phase such as a Regis Whelk-O1(R,R) (10 pirn) column, a Daicel ChiralCel OD-H (5-10 pirn) column, or a Daicel ChiralPak IA (10 jxm), IA, IB, IC, IE, or IF (5 pirn) or AD-H (5 pirn) column.
  • Typical conditions of chiral HPLC or SFC are an isocratic mixture of eluent A (EtOH, in presence or absence of an amine such as triethylamine or diethylamine) and eluent B (heptane or CO2), at a flow rate of 0.8 to 150 mL/min.
  • eluent A EtOH, in presence or absence of an amine such as triethylamine or diethylamine
  • eluent B heptane or CO2
  • HPLC pumps Gilson 333/334 or equivalent
  • Autosampler Gilson LH215 (with Gilson 845z injector) or equivalent
  • Degasser Dionex SRD-3200 or equivalent
  • Make-up pump Dionex ISO-3100A or equivalent
  • DAD detector Dionex DAD-3000 or equivalent
  • MS detector Single quadrupole mass analyzer Thermo Finnigan MSQ Plus or equivalent
  • MRA splitter MRA100-000 flow splitter or equivalent
  • ELS detector Polymer Laboratories PL-ELS1000 or equivalent.
  • Injection volume 100-2500 piL. Collection: UV / MS / ELSD if available, and all possible combinations; Make-up flow rate: 0.50 mL/min. Make-up eluent MS: acetonitrile/water/TFA 70:30:0.025 (V/V/V); MS ionization mode: ESI+.
  • DIPEA N, N-diisopropylethylamine Hunig’s base; CAS # 7087-68-5)
  • UV ultraviolet XantPhos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (CAS # 161265-03-8)INTERMEDIATES F Intermediate F1 : tert-butyl (c/s-3-(2-amino-6-hydroxypyrimidin-4-yl)cyclobutyl)carbamate
  • Step 1 methyl 3-(c/s-3-((tert-butoxycarbonyl)amino)cyclobutyl)-3-oxopropanoate Fb1 (CAS # 2407860-80-2)
  • Step 2 tert-butyl (c/s-3-(2-amino-6-hydroxypyrimidin-4-yl)cyclobutyl)carbamate F1
  • Step 1 methyl 3-(trans-3-((tert-butoxycarbonyl)amino)cyclobutyl)-3-oxopropanoate Fb2 (CAS # 2260789-10-2)
  • Intermediate F3 is made according to the procedure reported for intermediate F1 using c/s-3-(tert- butoxycarbonylamino)cyclobutanecarboxylic acid (CAS # 1008773-79-2) and intermediate F3c as starting materials.
  • intermediate F1 To a solution of intermediate F1 (5 g, 17.8 mmol) in DCM (110 mL) is added NEts (22.6 mL, 161 mmol) and p- toluenesulfonyl chloride (CAS # 98-59-9) (4.2 g, 21.4 mmol). The mixture is stirred for 18h at RT. The reaction is diluted with water (100 mL) and DCM (100 mL). The phases are separated, and the aq. phase is extracted with DCM (100 mL). The combined org. phases are washed with aq. NaHCOs (100 mL), dried (MgSO4), filtered and concentrated.
  • NEts 22.6 mL, 161 mmol
  • p- toluenesulfonyl chloride 4.2 g, 21.4 mmol
  • a vial is charged with a solution of intermediate D1 (500 mg, 1.7 mmol) in EtOH (7.5 mL), DIPEA (0.6 mL, 3.4 mmol) and methylamine (30wt% in EtOH, 0.3 mL, 2.5 mmol).
  • the vial is closed, and the mixture is heated to 90°C and stirred for 18h. More methylamine (30wt% in EtOH, 0.1 mL, 0.84 mmol) is added and the mixture is heated to 90°C and stirred for another 18h.
  • the mixture is diluted with aq. NaHCO 3 (100 mL) and EtOAc (100 mL). The phases are separated, and the aq. phase is extracted with EtOAc (100 mL).
  • Step 2 6-(c/s-3-aminocyclobutyl)-N 4 -methylpyrimidine-2,4-diamine hydrochloride A1
  • Step 2 6-(c/s-3-aminocyclobutyl)-N/ 4 -isopropylpyrimidine-2,4-diamine hydrochloride A3
  • Intermediate A3.1 is made according to the abovementioned procedure described for the synthesis of intermediate A1 using intermediate D2 and isopropylamine as starting materials.
  • the intermediates from Table 1 below are made according to the abovementioned procedures described for the synthesis of intermediates A1 or A3 using intermediates D1, D2 or E1 and the appropriate amine or amine hydrochloride as starting materials.
  • Example 1.1 The examples from Table 4 below are made according to the abovementioned procedure described for the synthesis of Example 1.1 using intermediate A1 and the appropriate sulfonylchloride B as starting materials. Reaction time goes up to 24h, at RT, with purification by prepHPLC (acidic or basic conditions).
  • Example 3.2 N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-2-fluoropyridine-3-sulfonamide
  • Example 3.2 is made according to the abovementioned procedure described for the synthesis of Example 3.1 using intermediate A3 and 2-fluoro-3-pyridinesulfonyl chloride (CAS # 1089330-70-0) as starting materials.
  • Example 3.3 is made according to the abovementioned procedure described for the synthesis of Example 3.1 using intermediate A3 and sulfonylchloride B1 as starting materials.
  • Example 3.1 The examples from Table 6 below are made according to the abovementioned procedure described for the synthesis of Example 3.1 using the appropriate intermediate A3 or A3.1 and the appropriate sulfonylchloride B as starting materials. Reaction time goes up to 24h, at RT, with purification by prepHPLC (acidic or basic conditions).
  • Table 6 The examples from Table 7 below are made according to the abovementioned procedure described for the synthesis of Example 3.1 using appropriate intermediate A and the appropriate sulfonylchloride B as starting materials. Reaction time goes up to 24h, at RT, with purification by prepHPLC (acidic or basic conditions). Table ?
  • Example 5.1 is made according to the abovementioned procedure described for the synthesis of Example 3.1 using intermediate A5 and 2-fluoro-3-pyridinesulfonyl chloride (CAS # 1089330-70-0) as starting materials.
  • Example 5.2 is made according to the abovementioned procedure described for the synthesis of Example 3.1 using intermediate A5 and sulfonylchloride B1 as starting materials.
  • Example 11.1 rac-N-(c/s-3-(2-amino-6-((1,1-difluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-3- fluorobenzenesulfonamide
  • Example 11.1 is made according to the abovementioned procedure described for the synthesis of Example 3.1 using the appropriate intermediate A11 and 3-fluorobenzenesulfonylchloride (CAS # 701-27-9) as starting materials.
  • Examples 11.2 and 11.3 N-(c/s-3-(2-amino-6-(((R)-1,1-difluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-3- fluorobenzenesulfonamide and N-(c/s-3-(2-amino-6-(((S)-1,1-difluoropropan-2-yl)amino)pyrimidin-4- yl)cyclobutyl)-3-fluorobenzenesulfonamide
  • Example 11.1 23 mg of Example 11.1 are separated on a chiral stationary phase using the method below to give 7 mg of each title compound.
  • Example 11.4 rac-N-(c/s-3-(2-amino-6-((1,1-difluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-5,6- dimethylpyridine-3-sulfonamide
  • Example 11.6 N-(c/s-3-(2-amino-6-(((R)-1,1-difluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-5,6- dimethylpyridine-3-sulfonamide and Example 11.5 N-(c/s-3-(2-amino-6-(((S)-1,1-difluoropropan-2- yl)amino)pyrimidin-4-yl)cyclobutyl)-5,6-dimethylpyridine-3-sulfonamide
  • Example 11.4 21 mg of Example 11.4 are separated on a chiral stationary phase using the method below to give 6 mg of each title compound.
  • Example 11 .5 can be prepared according to the abovementioned procedure described for the synthesis of Example 3.1 using intermediate A12 and the sulfonylchloride B1 as starting materials. Reaction time goes up to 24h, at RT, with purification by prepHPLC (acidic or basic conditions).
  • Example 11 .6 can be prepared according to the abovementioned procedure described for the synthesis of Example 3.1 using intermediate A13 and the sulfonylchloride B1 as starting materials. Reaction time goes up to 24h, at RT, with purification by prepHPLC (acidic or basic conditions).
  • Example 12.1 N/-(c/s-3-(2-amino-6-(oxetan-3-ylamino)pyrimidin-4-yl)cyclobutyl)-3-fluorobenzenesulfonamide
  • Step 1 4-(c/s-3-aminocyclobutyl)-6-chloropyrimidin-2-amine hydrochloride C1
  • To a solution of intermediate D1 (75 mg, 0.25 mmol) in dioxane (0.65 mL) is added a solution of HCI (4N in dioxane, 0.63 mL, 2.5 mmol). The reaction is stirred RT for 2h. The mixture is concentrated and the solid is dried under vacuum to give 68 mg of intermediate C1.
  • Step 2 N-(c/s-3-(2-amino-6-chloropyrimidin-4-yl)cyclobutyl)-3-fluorobenzenesulfonamide Ca1
  • [ 18 F]fluoride ions are produced by bombardment of 98% enriched 18 O-water via the 18 O(p,n) 18 F nuclear reaction.
  • the aqueous solution is transferred from the cyclotron to the hot-cell and trapped on a QMA cartridge (Waters SepPak Accel QMA cartridge carbonate).
  • a mixture of kryptofix 2.2.2 (CAS # 23978-09-8) (5 mg/mL), K2CO3 (1 mg/mL) in MeCN/H2O (4:1) is applied to elute the radioactivity to the reaction vial.
  • the collected fraction is diluted with 8 mL Milli-Q water and passed through a pre-conditioned C18 light cartridge (Waters, WAT023501). After washing with 5 mL Milli-Q water, the final radioligand is eluted with 1 mL EtOH and diluted with water for quality control.
  • the radiochemical yield of the radioligand is ranging between 2-5 GBq (collected activity) or 2-32 GBq/pimol (Molar activity), respectively.
  • the identity of the compounds was confirmed by identical retention time as compared to unlabeled Example 5.1.
  • HEK293.hCCR8 cells/well were seeded in 50pl of 90% DMEM, 10% none heat inactivated Foetal Bovine Serum, 1% Penicillin/Streptomycin, 800pg/ml G418, 200pg/ml hygromycin B into 384-well plate coated with Poly-L- Lysine. Cells were incubated at 37°C, 5% CO 2 for 24hours. Compounds to be tested were prepared by serial dilution from 10piM to 0.038nM.
  • FLIPR buffer containing HBSS/0.1%BSA/20mM Hepes/2.5mM probenecid was made and FLIPR staining solution was obtained by adding 15ml FLIPR buffer to 10ml calcium 6 for one plate. Medium was removed from cells. 50pl of the above staining solution was added. The plate was centrifugated briefly and incubated at 37°C, 5% CO 2 for 1 h30. 10pil of compounds diluted in FLIPR buffer were distributed and incubated for 30 minutes in the dark followed by the addition of 10pil of a 70nM hCCL1 stock solution. The signal is recorded immediately with the FLIPR device. Data were analyzed to generate IC50 values, and the results are summarized in Table 10.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Immunology (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to compounds of Formula (I), their synthesis and use as CCR8 receptor modulators in medicine.

Description

ARYL- AND HETEROARYL-SULFONAMIDE DERIVATIVES AS CCR8 MODULATORS
The present invention relates to novel compounds represented by Formula (I), or pharmaceutically acceptable salts thereof, and their use as active ingredients in medicine. The invention further concerns a process for the preparation of said compounds, pharmaceutical compositions containing one or more of said compounds, and their use as C-C chemokine receptor 8 (CCR8) modulators, either alone or in combination with other active compounds or therapies, in the prevention or treatment of diseases or disorders such as cancer, fibrotic diseases, atopic diseases, and neuropathic pain. Furthermore, the invention relates to certain isotopically labelled compounds, or pharmaceutically acceptable salts thereof, and their use in radiopharmaceutical therapy (RPT) or medical imaging such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT).
Chemokine receptors, such as CCR8, are a group of G-protein coupled receptors (GPCRs) that recognize and bind to peptide chemokine ligands with high affinity. The predominant functions of chemokine receptors and their ligands are to induce leukocyte trafficking to-and-from lymphoid organs and tissues in the steady state, as well as in the context of an infection or inflammation. Additionally, chemokine signaling events can induce the activation of integrin molecules on the surface of immune cells, allowing form adhesion to activated endothelium, facilitating migration from blood into inflamed tissue (Montresor A, Frontiers in Imm., 2012; Meissner A, Blood, 2003).
CCR8 (alias CKRL1 , CMKBR8, CMKBRL2, CC-CKR-8, CCR-8, CDw198, CKRL1, CMKBR8, CMKBRL2, CY6, GPRCY6, or TER1) has four known chemokine ligands: CCL1 (alias I-309 or SCYA1), CCL8 (alias MCP2, SCYA10, or SCYA8), CCL16 (alias ILINCK, NCC4, or SCYA16), and CCL18 (alias AMAC1 , DCCK1 , MIP4, PARC, or SCYA18). CCL1 was first identified as a cytokine secreted by activated human T lymphocytes. Human CCL1 is the best- established natural ligand for CCR8, but other chemokine ligands such as CCL18 were reported to interact with hCCR8 as well. CCR8 is the only known receptor for CCL1 , whereas the other CCR8 ligands bind several chemokine receptors, as well as decoy receptors. CCR8 positive cells respond to CCL1 stimulation with increased intracellular calcium, chemotaxis and enhanced survival. CCL1 is considered a Th2-related cytokine due to the expression of the CCR8 receptor on Th2 cells, but not on Th 1 cells, suggesting that CCL1 plays an important role in allergies and asthma. The CCL1-CCR8 axis also plays a role in the homing of lymphocytes to the healthy skin and contributes to the immune protection of the skin (Schaerli P et al.; J. Exp. Med. 2004, 199, 1265-1275 and Ebert L et al.; J. Immunol. 2006, 176, 4331-4336).
Tumors are comprised of abnormally proliferating malignant cancer cells but also of a functionally supportive microenvironment. This tumor microenvironment is comprised of a complex array of cells, extracellular matrix components, and signaling molecules, and is established by the altered communication between stromal and tumor cells. As tumors expand in size, they elicit the production of diverse factors that can help the tumor grow such as angiogenic factors (promoting ingrowth of blood vessels) or that can help evade the attack of the host immune response. CCL1 is such an immuno-modulatory factor produced in tumors.
High expression of CCL1 in a cancer cell occurs in leukemia caused by viruses such as human T cell leukemia virus type 1 (HTLV-1 ). Properties similar to the human CCL1 are shown by viral macrophage inflammatory protein-l (vMIP- I), a viral protein homologous to CCL1 expressed in tumor cells transformed by the herpes virus. Another example is Kaposi sarcoma-related human herpes virus-8 (Haque, NS et al; Blood. 2001 , 97, 39-45).
In hepatocellular carcinomas, the expression of CCL1 is elevated in 12 of 34 tumor stroma and peritumoral tissues. The expression of CCL1 has also been demonstrated in breast cancer stem cells, bladder cancer tumors, and renal cell carcinomas. (Korbecki, J et al. Int. J. Mol. Sci. 2020, 21, 7619).
In solid tumors, CCL1 is produced by Cancer Associated Fibroblasts, Tumor Associated Macrophages, CCR8-CD11 b+ myeloid cells, and Regulatory T-cells. The secretion of CCL1 by myeloid cells is involved in Treg cell infiltration. An increased expression of CCR8 is observed in Treg cells and NKT cells, particularly in cancer patients, and a low expression is observed in CD8+ T cells or Th 1 cells. Interactions between CCL1 and CCR8 enhance the expression of FoxP3 and activated CCR8+ Treg cells strongly suppress antitumor immunity by promoting ATP-adenosine metabolism by CD39 and secretion of IL-10 and granzyme B. (Ohue.Y and Nishikawa, H, Cancer Sci, 2019, 110(7):2080-2089).
In cancer, CCL1 is involved in the recruitment of CCR8+ CD 11 b+ myeloid cells (Eruslanov, E et al, Clin Cancer Res. 2013, 19, 1670-1680) as well as Regulatory T cells (Kuehnemuth, B et al, BMC Cancer 2018, 18, 1278) to the tumor site. CCL1 can also participate in the conversion of CD4+ T cells into Treg (Hoelzinger, DB et al, J Immunol. 2010, 184, 6833-6842), in a process dependent on transforming growth factor-|3, which increases the expression of CCL1 in CD4+ T cells. This is followed by an autocrine conversion of this cell to Treg, which also involves CCL1. In addition, CCL1 supports the immunosuppressive function of Treg in the tumor niche (Hoelzinger, DB et al, J Immunol. 2010, 184, 6833-6842), which is crucial for the interaction of cancer stem cells and CAF with the Tregs (Xu, Y et al, Stem cells 2017, 35, 2351-2365). CCL1 increases the expression of interleukin 6 in MDSC, which acts as a proinflammatory in the tumor microenvironment (Eruslanov, E et al, Clin Cancer Res. 2013, 19, 1670-1680). It was also reported that CCL1 causes angiogenesis on vascular endothelial cells via CCR8 (Haque, NS, et al, Blood, 2001, 97, 39-45).
In cancer, CCL1 has an antiapoptotic activity and induces chemoresistance to anticancer drugs due to the activation of the ERK MAPK cascade via CCR8 (Louahed, J et al, Eur J immunol. 2003, 33,494-501). CCL1 also stimulates proliferation (Cao, Q et al, Mol Med Rep. 2016, 13, 27-34) and causes the migration of bladder cancer cells (Yeh, CR, et al, Am J Cancer Res. 2018, 50, 894-907). At the same time, due to the expression of CCL1 in lymph nodes, this chemokine participates in metastasis to these peripheral lymphoid organs through the CCR8 receptor on cancer cells that have entered lymphatic vessels. This process is important in metastasis to lymph nodes in malignant melanoma, which often leads to increased CCR8 expression in the cancer cells of this tumor (Das, S et al, J Exp Med. 2013, 210, 1509-1528).
CCL18 is produced by dendritic cells, especially in germinal centers of regional lymph nodes. This chemokine then causes the chemoattraction of naive T cells. This leads to the initiation of an immunological response. CCL18 also acts as an anti-inflammatory chemokine, a marker for the macrophage M2 subset (Schraufstatter, III et al, Immunology, 2012, 135, 287-298). In a tumor, CCL18 is mainly produced by Tumor Associated Macrophages (Pettersen, JS et al; J. Investig. Dermatol. 2011 , 131 , 1322-1330) and causes cancer cell migration as well as Epithelial to Mesenchymal Transition by activating its receptors PITPNM3 and CCR8 (Hong, R et al; Asian Pac. J. Cancer Prev, 2012, 13, 1877- 1880; Islam, SA et al; J. Exp. Med. 2013, 210, 1889-1898). CCL18 recruits immature dendritic cells to the tumor niche and participates in the differentiation of immature dendritic cells into tumor-associated dendritic cells (TADC) (Azzaoui, I et al; Blood, 2011 , 118, 3549-3558). CCL18 binds to glycosaminoglycans on extracellular vesicles, which allows them to be retained on cells with an expression of CCR8. CCL18 also increases the proliferation of cancer cells, but this depends on the tumor type. For example, CCL18 decreases the proliferation of acute lymphocytic leukemia B cells and cutaneous T-cell lymphoma (CTCL) (Catusse, J et al; J, Cell. Physiol. 2010, 225, 792-800; Gunther, C et al; Am J. Pathol. 2011, 179, 1434-1442). In addition, CCL18 increases the proliferation of glioma and oral squamous cell carcinoma cells. An increased expression of CCL18 in lesional skin and serum of patients with CTCL as well as in patients with diffuse large B cell lymphoma is associated with a worse prognosis.
CCR8 is a chemokine receptor preferentially, but not exclusively, expressed by FOXP3+ Tregs. CCR8+ Tregs were recently identified as master drivers of the immune regulation. The relative number of CCR8+ Tregs which is very low in the periphery increases along with the development of experimental autoimmune encephalomyelitis (EAE), a T cell- mediated autoimmune disease of the central nervous system. It was also observed that within the central nervous system, CCR8+ Tregs are potentiated by CCL1 , possibly in an autocrine manner, which makes them “driver” regulatory cells that restrain the progression of the disease (Barsheshet, Y. et al; Proc. Natl. Acad. Sci. 2017, 114, 6086-6091).
Advances in staining reagents enabled to report CCR8 expression in human blood Th2 as well as Tregs (lellem, A et al.; J. Exp. Med. 2001 ,194, 847-853, Sebastiani, S. et al.; J. Immunol. 2001, 166, 996-1002). Along with this observation, in vivo studies revealed a clear role for CCR8 in type-2 inflammatory diseases including atopic dermatitis (Islam, S.A.et al; Nat. Immunol. 2011 , 12, 167-177, Gombert, M.et al; J. Immunol. 2005, 174, 5082-5091), allergic enteritis (Blanco-Perez, F. et al; Sci. Rep. 2019, 9, 9608), and allergic asthma (Nguyen KD. et al.; J Allergy Clin Immunol. 2009; 123(4):933-9.e10.) such as fungal-allergic asthma (Buckland KF. et al, J Allergy Clin Immunol. 2007 Apr;119(4):997-1004).
Owing to their chemotactic effects on inflammatory fibroblasts and various immune cells, such as monocytes and T cells, the interactions of CCR8 with its ligands CCL1, CCL8, and CCL18 have been implicated in exacerbating human fibrotic diseases and pathology in animal models of fibrotic disease (Liu, S. et al., Biomolecules 2023, 13, 333). Indeed, in murine models CCL1 interaction with CCR8 exacerbates bleomycin-driven lung fibrosis (Shan-shan Liu. et al., Immunity, 54, 9, 2021, 2042-2056. e8; and Suosi Liu., International Immunopharmacology, 120, 2023, 110343), carbon tetrachloride induced liver fibrosis (Heymann F. et al., Hepatology, 2012 Mar;55(3):898-909), salivary gland fibrosis modeling human immunoglobulin G4-related disease (Honda, F. et al., Arthritis Res Ther 23, 214, 2021), and skin and pulmonary fibrosis modeling human chronic graft-versus-host disease (Stem Cell Res Then, 2020 Jun 26; 11 (1):254. doi: 10.1186/s13287-020-01768-7). In patients, CCL18 and CCR8 are elevated in idiopathic pulmonary fibrosis (Unterman A. et al., medRxiv, 2023, doi: 10.1101/2023.04.29.23289296) and high serum CCL18 predicts poor patient outcome (Prasse A. et al., Am J Respir Crit Care Med, 2009 Apr 15;179(8):717-23). Furthermore, CCL1-CCR8 interaction is associated with more severe human lgG4-related sclerosing cholangitis (Yoh Zen et al., Journal of Hepatology, 59, 5, 2013, 1059-1064). An association of CCR8 being a part of a gene locus related to systemic sclerosis in a chicken model of scleroderma/systemic sclerosis has been disclosed by Weronica Ek. et. al., Developmental & Comparative Immunology, 38, 2, 2012, 352-359. Moreover, CCR8 mediates immune cell infiltration and resultant fibrosis in a murine model of allogeneic kidney transplant (Dangi A, et al., J Am Soc Nephrol. 2022 Oct;33(10): 1876- 1890). In animal models of postsurgical and post-inflammatory formation of peritoneal adhesions, CCR8 was determined to promote adhesion formation in part via an autocrine CCL1-CCR8 signaling loop in peritoneal macrophages that regulated their recruitment and aggregation (Akiyoshi Hoshino et al., J Immunol., 2007 Apr 15; 178(8):5296-304). CCR8 signaling in myeloid cells may sensitize individuals to bacterial infection. In a model of polymicrobial septic peritonitis, Matsukawa and colleagues observed that CCR8 skews macrophage polarization and limits clearance of microbes following cecal ligation and puncture in mice, ultimately increasing risk of death (Matsukawa, A., et al., 2006, FASEB J, 20: 302-304). Moreover, Asai and colleagues demonstrated that inhibition of CCL1 enhances resistance of mice to Staphylococcus aureus infection in a model of burn-related immune dysregulation (Akira Asai et al., Journal of Leukocyte Biology, 92, 4, 2012, 859-867, https://doi.org/10.1096/fj.04- 1728fje). CCL1-CCR8 signaling may play a deleterious role in chronic obstructive pulmonary disease (COPD) and allergic type exacerbations: CCR8 expression is pronounced in lung myeloid cells of patients with Global Initiative for Obstructive Lung Disease (GOLD) stage IV COPD (Martina Kvist Reimer et al. Clinical and Vaccine Immunology, 2011, 18, 12, doi: 10.1128/CVI.05275-11), and COPD exacerbation risk is associated with certain single nucleotide polymorphism profiles in the CCL1 gene (Takabatake N. et al., Am J Respir Crit Care Med. 2006 Oct 15; 174(8):875- 85, doi: 10.1164/rccm.200603-4430C).
CCL1/CCR8 neuronal signaling plays an important role in the development of neuropathic pain (Zychowska, M. et al.; International Immunopharmacology, 52, 2017, 261-271 ; and Akimoto, N., et al.; Cell Death Dis 4, e679 (2013)). The interaction of CCL1 and CCR8 has been implicated in neuropathic pain exacerbation (Pawlik K., Molecules 2023, 28(15), 5766). Specifically, animal and ex vivo models suggest CCL1 enhances allodynia and neuropathy via CCR8 signaling in neurons, microglia, and astrocytes in the spinal cord (Akimoto N. et al, Biochem Biophys Res Commun, 2013, Jul 5;436(3):455-61; Zychowska M. et al., Int Immunopharmacol. 2017 Nov:52:261-271; Noda M. et al., Neurochem Int., 2018 Oct: 119:184-189; Wang C. et al., Neurosci Res. 2020 May: 154:20-26; and Ruff M. et al., Life Sci. 2022 Oct 1 ; 306: 120788). Moreover, neutralization of CCL1 and CCR8 signaling ameliorates pain in animal models of diabetic neuropathy and potentiates the analgesic effects of opioids, representing a potential human therapeutic application (Zychowska M. et al., Int Immunopharmacol. 2017 Nov:52:261-271 ; and Ruff M. et al., Life Sci. 2022 Oct 1 ; 306: 120788).
Healthy human skin was then reported as the primary residence site of CCR8+ cells with 50% of all skin a|3 Tcells expressing CCR8 (Ebert, L.M. et al; J. Immunol. 2006, 176, 4331-4336, McCully, M.L et al.; Blood 2012, 120, 4591— 4598). Similarly, CCR8 was also identified in CD16-expressing NK cells that reside mainly in human skin but not in peripheral blood (Ebert, L.M. et al; J. Immunol. 2006, 176, 4331-4336, Schaerli, P. et al; J. Exp. Med. 2004, 199, 1265— 1275).
Recently, CCR8 has been identified as a potential specific marker for tumor-infiltrating Tregs. CCR8 expression is selectively upregulated in these Tregs in multiple cancers, including lung, colorectal, breast (Plitas, G et al.; Immunity 2016, 45, 1122-1134, De Simone, M. et al.; Immunity 2016, 45, 1135-1147, Wang, L. et al;. Nat. Immunol. 2019, 20, 1220-1230). These CCR8+ Tregs represent a highly suppressive subpopulation of Tregs and the high number of CCR8+ Tregs in the tumor microenvironment correlates with poor prognosis in various breast cancer types (Plitas, G et al.; Immunity 2016, 45, 1122-1134, De Simone, M. et al.; Immunity 2016, 45, 1135-1147, Zheng, C. et al.; Cell 2017, 169, 1342-1356, Magnuson, A.M.et al.; Proc. Natl. Acad. Sci. USA 2018, 115, E10672-E 10681). Because CCR8 is rarely expressed on Tregs and Teffector cells in peripheral blood or healthy tissues, targeting CCR8+ tumor Tregs is expected to cause minimal toxicity risks making CCR8 a promising therapeutic target to inhibit the immunosuppressive functions of tumor-resident Tregs and increase the anti-tumor immune response.
CCR8 is a seven-transmembrane G-protein-coupled chemokine receptor (GPCR) expressed primarily on intratumoral FOXP3hi Tregs (Plitas, G et al.; Immunity 2016, 45, 1122-1134, De Simone, M. et al.; Immunity 2016, 45, 1135-1147, Wang, L. et al;. Nat. Immunol. 2019, 20, 1220-1230). In addition to affecting the migration of Tregs to the Tumor microenvironment, the CCL1-CCR8 axis also potentiates the immunosuppressive capacity of Tregs through upregulation of CCR8, FOXP3, IL-10 and other suppressive factors (Vila-Caballer M et al.; J Mol Cell Cardiol. 2019;132:154-1).
Various groups have recently reported the generation of humanized anti-CCR8 antibodies for use in depleting tumor associated Tregs and treating cancer. Preclinical data indicates that treatment with mCCR8 depleting antibodies provides therapeutic benefit alone or in combination with immune checkpoint inhibitors such as anti-PD1 treatment in several mouse models including the colorectal cancer models CT26 and MC38, the melanoma model B16-F10, the bladder cancer model MB49, the breast cancer model 4T 1 and the lung cancer model LLC-OVA (Villarreal, D.O et al.; Cancer Res. 2018, 78, 5340-5348, Bhatt, D. et al.; J. Exp. Med. 2021 , 218, e20201329, Campbell, J.R. et al.; Cancer Res. 2021, 81 , 2983-2994, Van Damme, H. et al.; J. Immunother. Cancer 2021 , 9, e001749). In addition, neutralization of the CCR8 natural ligand CCL1 inhibits the Treg suppressive functions and enhances anti-tumor immunity (Hoelzinger D.B et al.; J. Immunol. 2010, 184:6833-6842).
One of the major reasons for which the success of immune checkpoint inhibitors can be limited is that therapy is given on cancer types that are designated as “cold tumors” either lacking infiltration of effector CD8+ T cells, or including massive accumulation of Tregs that suppress their activities. Targeting CCR8, mostly with depleting antibodies, are currently under preclinical development by several lead companies.
Small molecule CCR8 antagonists, such as the compounds of the present invention, may be useful to inhibit the recruitment of CCR8+ Tregs to the tumor site and/or to decrease the suppressive functions of intratumoral CCR8+ Tregs resulting in a favorable environment for a positive response to immune-check point inhibitors or others current therapies.
The compounds of the present invention may be useful, alone, or in combination with one or more therapeutic agents or therapies, for the prevention / prophylaxis or treatment of cancer, especially cancer types infiltrated with intratumoral Tregs expressing CCR8. Such cancer types are inter alia oral squamous cell carcinoma (Fraga M. et al.; Front. Immunol. 2021 , 12:643298), head and neck squamous cell carcinoma (Sun et al; Transl Cancer Res 2020; 9( 10) :5882- 5892, Meng et al; Front. Oncol. 2021, 11 :618187), liver cancer (Zheng, C. et al.; Cell 2017, 169, 1342-1356.e1316, Wiedemann G.M. et al; Pathology, 2019 51(6), 586-659), hepatocellular carcinoma (Nieto P. et al., Genome Res. 2021, 10:1913-1926), extrahepatic cholangiosarcoma (Xu L. et al, J Transl Med. 2022 20(1):210), gastrointestinal stromal tumors (Li HL.et al; World J Gastroenterol. 2020; 26(31):4656-4668. Fujimoto et al; J Immunol. 2018 ; 200(9):3291 -3303), colorectal cancer (De Simone, M. et al.; Immunity 2016, 45, 1135-1147, Nieto P. et al., Genome Res. 2021,10:1913-1926), lung cancer (Liu F. et al; J Inflamm Res. 2021 ; 14:267-285, Yu L. et al; Int Immunopharmacol. 2021 107734, Pastor M.D.et al; J Thorac Oncol. 2016 12:2183-2192, Campbell, J.R. et al.; Cancer Res. 2021, 81, 2983-2994), non- small cell lung cancer (De Simone, M. et al.; Immunity 2016, 45, 1135-1147, Van Damme, H. et al.; J. Immunother. Cancer 2021 , 9, e001749, Haruna M. et al; Sci Rep. 2022, 12(1 ):5377, Nieto P. et al., Genome Res. 2021,10:1913-1926), bladder cancer, kidney cancer (Eruslanov, E et al.; Clin. Cancer Res. 2013, 19, 1670-1680, Wang, T. et al.;Cancer Immunol. Immunother. 2020, 69, 1855-1867, Kidani Y. et al; Proc Natl Acad Sci U S A. 2022, 119(7):e2114282119, Campbell, J.R. et al.; Cancer Res. 2021 , 81, 2983-2994), melanoma (Das S. et al., J Exp Med. 2013, 210(8):1509-1528; Nieto P. et al., Genome Res. 2021 ,10:1913-1926; Sade Feldman M. et al, Cell. 2018, 175(4): 998-1013), breast cancer (Plitas, G et al.; Immunity 2016, 45, 1122-1134, Wang, L. et al;. Nat. Immunol. 2019, 20, 1220-1230, Kuehnemuth, B et al, BMC Cancer 2018, 18, 1278, Ding S. et al; Int Immunopharmacol. 2021, 100:108122), lymphoma (Xing X. et al, Appl Immunohistochem Mol Morphol. 2015 (8):580- 589) cutaneous T cell lymphoma (Giustinani J. et al Blood Adv. 2022, 6(11):3507-3512), endometrial tumors (Campbell, J.R. et al.; Cancer Res. 2021 , 81 , 2983-2994, Nieto P. et al., Genome Res. 2021 ,10:1913-1926), Kaposi sarcoma (Haque, N.S. et al; Blood 2001, 97, 39-45), and basal cell carcinoma (Nieto P. et al., Genome Res. 2021,10: 1913- 1926).
Specifically, the potential role of CCR8 in oral squamous cell carcinoma (OSCC) is known from the literature. Fraga et al. reported that 40% of the tumor infiltrated Tregs were CCR8 positive in OSCC and that CCL1 as well as CCL18 were involved in their recruitment. The OSCC secretome contributes to the upregulation of CCR8 expression on Tregs and Teff (Fraga M. et al.; Front. Immunol. 2021 , 12:643298).
Specifically, the role of CCR8 in head and neck squamous cell carcinoma (HNSCC) has been suggested in the literature using two independent data set analysis. A correlation has been established between the CCR8 high expression and a worse prognosis for patients with HNSCC (Sun et al; Transl Cancer Res 2020;9(10):5882-5892) while another study reported a significant higher level of CCR8 in tumor tissues than in normal tissues (Meng et al; Front. Oncol. 2021, 11 :618187).
A specific expression of CCR8 in tumor associated Tregs in liver cancer has been described in the literature. A landscape of infiltrating T cells in hepatocellular carcinoma revealed a particular gene signature among which CCR8 was reported to be specifically expressed in tumor Tregs but not in peripheral Tregs or in others T cells than Tregs Zheng, C. et al.; Cell 2017, 169, 1342-1356.e1316). In addition, CCL1 expression was also reported in peripheral and extratumoral stromal compartment in hepatocellular carcinomas suggesting an involvement in the CCR8+ Tregs recruitment (Wiedemann G.M. et al; Pathology, 2019 51(6), 586-659).
Furthermore, a specific expression of CCR8 in tumor associated Tregs in extrahepatic cholangiosarcoma was reported. Single-cell landscape of immunocytes in patients with extrahepatic cholangiosarcoma revealed that CCR8 was only expressed in tumor-infiltrating Tregs but not in peripheral Tregs or conventional T cells (Xu L. et al, J Transl Med. 2022 20(1):210).
Specifically, a role of CCR8 in gastrointestinal stromal tumors (GIST) has been reported in the literature. A correlation between CCR8 expression and a worse prognosis for patients with GIST was described (Li HL.et al; World J Gastroenterol. 2020; 26(31 ):4656-4668). Furthermore, a gene signature of colorectal adenocarcinoma-associated Tregs identified a specific CCR8 overexpression compared to normal intestinal samples (Fujimoto et al; J Immunol. 2018 ; 200(9):3291 -3303).
De Simone et al. reported a transcriptional landscape of tumor-infiltrating Tregs from human colorectal tumor tissues and identified CCR8 as one of the top 5 genes overexpressed in tumor associated Tregs compared to peripheral blood Tregs. The specific expression of CCR8 in tumor-infiltrating Tregs was then confirmed at the protein level by FACS analysis (De Simone, M. et al.; Immunity 2016, 45, 1135-1147).
In addition, a role of CCR8 in lung cancer was reported in several studies. De Simone et al. also did a similar transcriptional landscape of tumor-infiltrating Tregs from human non-small cell lung cancer (NSCLC) and CCR8 was highly expressed compared to peripheral blood Tregs. FACS analysis also confirmed the specific expression of CCR8 in tumor Tregs (De Simone, M. et al.; Immunity 2016, 45, 1135-1147). In lung adenocarcinoma, a high expression of CCR8 mRNA was found in various data sets (Liu F. et al; J Inflamm Res. 2021 ; 14:267-285) and CCL1 was particularly overexpressed in bronchoalveolar lavage fluid from patients with adenocarcinoma (Yu L. et al; Int Immunopharmacol. 2021 107734) suggesting CCL1 as an interesting biomarker in this indication (Pastor M.D.et al; J Thorac Oncol. 2016 12:2183-2192). Interestingly, it was also reported in NSCLC that intratumoral CCR8+ Tregs are more immunosuppressive than CCR8- Tregs in mouse and human tumor tissues. No major CCR8 positivity was found on peripheral Tregs (Van Damme, H. et al.; J. Immunother. Cancer 2021 , 9, e001749,). Another study was also able to show the impact of CCR8+ Tregs on the cytotoxic CD8+ Tcells in human lung cancer. The Cancer Genome Atlas analysis revealed that CD8 Tcell activities were suppressed in highly CCR8 expressing tumors. The depletion of CCR8+ cells in an ex vivo assay with lung tumor infiltrating cells, was able to enhance CD8+ Tcell function. Furthermore, CCR8+ Tregs but not CCR8- Tregs markedly prevent CD8+ T cells cytotoxic activity. The therapeutic effect of targeting CCR8 was ultimately demonstrated in a murine model of lung cancer (LLC mouse model) (Haruna M. et al; Sci Rep. 2022, 12(1):5377).
Specifically, a role of CCR8 has been described in bladder and kidney cancer. Myeloid cells (CD33+ CD11b+) are CCR8+ in those indications and contribute to a strong immunosuppressive environment. An elevated level of CCL1 was found in primary human urothelial and renal cancer tissues (Eruslanov, E et al.; Clin. Cancer Res. 2013, 19, 1670— 1680). Furthermore, it was also reported that CCR8 blockade could destabilize intratumoral Tregs into a fragile phenotype accompanied with reactivation of antitumor immunity and augment of anti-PD-1 therapeutic benefits in muscle invasive bladder cancer (MIBC) patients. It was also found that CCR8 expression by intratumoral Tregs maintains their stability and potentiated their suppressive function (Wang, T. et al.; Cancer Immunol. Immunother. 2020, 69, 1855-1867). Another study has shown that tumor infiltrating Tregs from human renal cancer tissue samples were 30 to 40% CCR8+ confirming the high specificity of CCR8 expression in human cancers (Kidani Y. et al; Proc Natl Acad Sci U S A. 2022, 119(7):e2114282119).
Specifically, the role of CCR8 was also described as strongly expressed in human malignant melanoma. CCL1 was detected in lymph node lymphatic sinuses but not in the peripheral lymphatics. This study suggests that the CCL1/CCR8 axis is involved in the metastasis invasion process in melanoma patients (Das S. et al., J Exp Med. 2013, 210(8): 1509-1528). Single cell RNA sequencing data analysis found in Nieto et al. or Sade Feldman et al. identified a specific expression of CCR8 in tumor infiltrated Tregs ((Nieto P. et al., Genome Res. 2021 ,10:1913-1926; Sade Feldman M. et al, Cell. 2018, 175(4): 998-1013).
Specifically, there is a body of evidence that CCR8 plays a role in breast cancer development. Plitas et al. identified that tumor Tregs were CCR8+ whereas peripheral blood Tregs were not. They also reported a correlation between a high CCR8+ FoxP3+ Tregs content with a bad prognosis for the patients (Plitas, G et al.; Immunity 2016, 45, 1122— 1134). Furthermore, another study has shown that 50% of intratumoral Tregs are CCR8+ (Wang, L. et al;. Nat. Immunol. 2019, 20, 1220-1230). CCR8+ Tregs have been found to migrate towards CCL1 and to be immunosuppressive (Kuehnemuth, B et al, BMC Cancer 2018, 18, 1278, Ding S. et al; Int Immunopharmacol. 2021 , 100:108122).
Furthermore, a role of CCR8 has been proposed in lymphoma. Overexpression of CCR8 has been reported in systemic ALK negative anaplastic large cell lymphomas (ALCL). Quantitative real-time PCR in frozen tissue and RNA in situ hybridization (ISH) in paraffin tissue showed higher CCR8 expression in ALCLs with DUSP22 rearrangements than in non-rearranged cases (Xing X. et al, Appl Immunohistochem Mol Morphol. 2015 (8):580-589).
Furthermore, CCR8 was also shown to play a role in T cell lymphoma and specifically cutaneous T cell lymphoma (CTCL). The expression of CCR8 in lesional skin of CTCL patients is associated with high risks of disease progression. CCR8 is expressed by peripheral blood Sezary cells and is reported expressed at cell surface of other T cell lymphoma (Giustinani J. et al Blood Adv. 2022, 6(11):3507-3512).
Specifically, the role of CCR8 was reported in Kaposi sarcoma. Immunohistochemical studies identified CCR8 and CCL-1 on the endothelium of human atherosclerotic plaques and in endothelial-derived spindle cells of Kaposi sarcoma. In addition, the viral monocyte inflammatory protein-l (vMIP-l), a human homologue of CCL1 is induced by the Kaposi sarcoma-related human herpesvirus-8 (Haque, N.S. et al; Blood 2001 , 97, 39-45).
Positron emission tomography (PET) and single-photon emission computed tomography (SPECT) are common imaging techniques in nuclear medicine. The techniques use a radiopharmaceutical — a radioactive isotope attached to a ligand/drug, which is injected into the human body as a tracer. When the radiopharmaceutical undergoes beta plus decay, a positron is emitted, and when the positron interacts with an ordinary electron in the human body, the two particles annihilate and gamma rays are emitted, which are then detected and form a three-dimensional image. Radiopharmaceuticals are widely used e.g. in cardiology, neurology, and oncology. Examples of radioactive tracers used in oncology imaging include glucose uptake tracer [18F]fluorodeoxyglucose, tumor specific tracer [18F]fluorothymidine, and [18F]fluciclovine - a PET diagnostic agent in men with suspected prostate cancer recurrence. Radiopharmaceuticals can also be used as therapeutic agents in radiopharmaceutical therapy (RPT). A category of RPT involves the use of tumor-targeting agents that concentrate in tumors through natural physiological mechanisms occurring predominantly in neoplastic cells. A widely implemented example of this category of RPT is the radioiodine therapy of thyroid cancer, where radioactive iodine is injected in the body and it is absorbed and concentrated in the thyroid gland. The radiation can then destroy the gland and any other thyroid cells including cancer thyroid cells that take up iodine, with little effect on the rest of the body. In the context of the present invention, the compounds of Formula (I) comprising one or more radioactive isotopes of iodine may be used to associate with certain cells in the human/animal body and thereby destroy cancer cells by targeted delivery of radioactive iodine. Certain small molecules targeting CCR8 have been disclosed in the art. For example, W02004032856, W02003037271, W02005040167, W02006107252, W02006107253, W02006107254, W02008099165, and W02007030061 relate to certain heterocyclic derivatives; W02013131010 concerns a method of administration of diverse CCR8 antagonists on the surface of tumor cells; certain biphenyl ether derivatives are disclosed by Ghosh S et al. J. Med. Chem. 2006, 49, 9, 2669-2672; Jenkins TJ et al. J. Med. Chem. 2007, 50, 3, 566-584 teaches naphthalene-sulfonamide derivatives; Marro ML et al. Biochem. Biophys. Res. Commun. 2006, 349, 270-276 discloses RNA aptamers that block CCL1 chemokine function; Jin J et al. Bioorg. Med. Chem. Lett. 2007, 17, 6, 1722-1725 relates to certain aryl-oxazolidinones; Shamovsky I et al. J. Med. Chem. 2009, 52, 23, 7706-7723 discusses the metabolic stability and selectivity of a series of CCR8 related compounds; Karlsson AKC et al. Biochem. Biophys. Res. Commun. 2011, 407, 4, 764-771 and Connolly S et al. Biochemical Pharmacology 2012, 83, 778-787 disclose derivatives comprising a diazaspiroundecane scaffold; Yong Wu et al. J. Med. Chem. 2023, 66, 7, 4548-4564 and W02022000443 disclose IPG7236, a small molecule CCR8 antagonists in clinical stage of development (NCT05142592 and NCT05288543), and Petersen TP et al. Chem. Eur. J. 2013, 19, 9343 describes a multistep continuous-flow synthesis of certain biphenyl ethers. Furthermore, W02004058736, W02004058709, W02004073619, and W02004074438 disclose certain aryl- and heteroaryl-sulfonamides. The database CAS REGISTRYSM contains the structural formulas of certain aryl- and heteroaryl-sulfonamides (CAS RN 2068756-64-7, 2068741-89-7, 2068738-85-0, 2068733-03-7, 2068727-35-3, 2068732-71-6, 2068712-87-6, 2068699-30-7, 1783256- 82-5, 1783305-08-7, 1783155-99-6, 1783110-79-1, 1783211-08-4, 1783040-48-1, 1783125-47-2, and 1783136-48-0), however, neither a synthesis nor a medical use thereof is disclosed.
The present invention provides novel aryl- and heteroaryl-sulfonamides of Formula (I) which are modulators, especially antagonists of the CCR8 receptor.
1) One aspect of the present invention relates to compounds of Formula (I)
Figure imgf000010_0001
wherein
Ar represents
• phenyl;
• 5-membered heteroaryl containing from one to three ring heteroatoms independently selected from nitrogen, sulfur, and oxygen (notably such 5-membered heteroaryl is selected from thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl, and triazolyl; especially selected from thiophen-2-yl, thiophen-3- yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, [1,3,4]thiadiazol-2-yl, 1 H-pyrazol-3-yl, 1 H-pyrazol-4-yl, isothiazol-5-yl, isoxazol-4-y I , oxazol-5-yl, 1 H-[1 ,2,3]triazol-4-yl, and 2H-[1 ,2,3]triazol-4-yl; in particular selected from thiophen- 2-yl and thiophen-3-yl); or
• 6-membered heteroaryl containing from one to three ring nitrogen atoms (notably such 6-membered heteroaryl is selected from pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; especially selected from pyridin- 2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl, pyrazin-2-yl, and pyridazin-3-yl; in particular selected from pyridin-3-yl); wherein said phenyl, 5-membered heteroaryl, or 6-membered heteroaryl, independently is unsubstituted, mono-, di-, or tri-substituted (notably unsubstituted, mono-, or di-substituted), wherein the substituent independently represents
> halogen (especially chlorine, fluorine, bromine, or iodine);
> cyano;
> C1-3-alkyl (especially methyl or ethyl);
> C1-2-fluoroalkyl (especially difluoromethyl, trifluoromethyl, or 1,1 -difluoroethyl);
> C1-2-alkoxy (especially methoxy);
> C3-4-cycloalkyl (especially cyclopropyl);
> C1-2-fluoroalkoxy (especially trifluoromethoxy); or
> amino optionally mono- or di-substituted with methyl or ethyl (especially methyl);
R1 represents
• C1-5-alkyl (notably Cu-alkyl; especially methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, or sec- butyl);
• hydroxy-C2-4-alkyl (especially 2-hydroxy-1 -methyl-ethyl or 2-hydroxy-1 , 1-dimethyl-ethyl);
• C1-2-alkoxy-C2-4-alkyl (especially 2-methoxyethyl, 2-methoxy-1 -methyl-ethyl, or 2-methoxy-1, 1 -dimethyl- ethyl);
• C1-4-fluoroalkyl (especially 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-fluoro-1 -methyl-ethyl, 2- fluoro-1-fluoromethyl-ethyl, 2, 2-difluoro-1 -methyl-ethyl, 2,2,2-trifluoro-1, 1-dimethyl-ethyl, or 2,2,2-trifluoro-1- methyl-ethyl); or
• -L-Cy, wherein
> -L- represents a bond (i.e. Cy is directly attached to the nitrogen atom) or -CH2-; and
> Cy represents C3-6-cycloalkyl (especially cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl) optionally containing one oxygen ring atom, wherein said C3-6-cycloalkyl optionally containing one oxygen ring atom is unsubstituted or mono-substituted (especially at the point of attachment of said C3-6-cycloalkyl to the rest of the molecule), wherein the substituent represents fluorine
[in particular -L-Cy represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetan-3-yl, cyclopropyl- methyl, 1-fluoro-cyclopropylmethyl, or cyclobutyl-methyl]; and
R2 represents hydrogen or fluorine (especially hydrogen). Definitions provided herein are intended to apply uniformly to the compounds of Formula (I) as defined in any one of embodiments 1 ) to 42), and, mutatis mutandis, throughout the description and the claims unless an otherwise expressly set out definition provides a broader or narrower definition. It is well understood that a definition or preferred definition of a term defines and may replace the respective term independently of (and in combination with) any definition or preferred definition of any or all other terms as defined herein. If not explicitly defined otherwise in the respective embodiment or claim, groups defined herein are unsubstituted.
The term “halogen”, used alone or in combination, means fluorine, chlorine, bromine, or iodine; notably fluorine, chlorine, or bromine.
In one embodiment, the halogen substituent(s) of Ar are stable, non-radioactive halogen isotopes; notably fluorine, chlorine, or iodine; most preferred is fluorine.
In another embodiment, the halogen substituent(s) of Ar are unstable, radioactive halogen isotopes of fluorine and/or iodine; notably fluorine-18, iodine-123, iodine-124, iodine-125, and iodine-131 ; especially fluorine-18.
It is understood that when a substituent is referred to as halogen, fluorine, chlorine, bromine, or iodine, said substituent represents halogen, fluorine, chlorine, bromine, or iodine, in its stable, non-radioactive isotope.
The term “amino”, used alone or in combination, refers to the group -NH2.
The term “alkyl”, used alone or in combination, refers to a saturated straight or branched hydrocarbon chain group containing one to six carbon atoms. The term “Cx-y-alkyl” (x and y each being an integer), refers to an alkyl group as defined before, containing x to y carbon atoms. In case a Cx y-alkyl group is used in combination with another substituent, the term means that said substituent is linked through a Cx y-alkyl group to the rest of the molecule. For example, a C1-3-alkyl group contains from 1 to 3 carbon atoms. Examples of C1-3-alkyl groups are methyl, ethyl, n- propyl, and isopropyl. For the substituent(s) of Ar preferred examples of Cu-alkyl groups are methyl and ethyl, most preferred is methyl. Examples of C1-5-alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methyl-butyl, 2-methyl-butyl, 3-methyl-butyl, 1,2-dimethyl-propyl, and 1 ,1-dimethyl-propyl. For the substituent R1 a preferred example of C1-5-alkyl group is Cu-alkyl i.e., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl; more preferred is C2-4-alkyl i.e., ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl; most preferred are isopropyl and tert-butyl; particularly preferred is isopropyl.
The term “hydroxyalkyl” , used alone or in combination, refers to an alkyl group as defined before, wherein one hydrogen atom has been replaced with a hydroxy group. The term “hydroxy-Cx.y-alkyl” (x and y each being an integer), used alone or in combination, refers to a hydroxyalkyl group as defined before wherein the alkyl group contains x to y carbon atoms. For example, a hydroxy-C2-4-alkyl group is a hydroxyalkyl group as defined before which contains from 2 to 4 carbon atoms. Examples of hydroxy-C2-4-alkyl groups are 1 -hydroxyethyl, 2-hydroxyethyl, 1 -hydroxypropyl, 2- hydroxypropyl, 3-hydroxypropyl, 1 -hydroxy-1 -methyl-ethyl, 2-hydroxy-1 -methyl-ethyl, and 2-hydroxy-1 , 1 -dimethyl- ethyl. For the substituent R1 preferred examples are 2-hydroxy-1 -methyl-ethyl and 2-hydroxy-1 , 1 -dimethyl-ethyl.
The term "fluoroalkyl”, used alone or in combination, refers to an alkyl group as defined before in which one or more (and possibly all) hydrogen atoms have been replaced by fluorine. The term “Cx.y-fluoroalkyl” (x and y each being an integer) refers to a fluoroalkyl group as defined before containing x to y carbon atoms. For example, a C1-2-fluoroalkyl group contains from 1 to 2 carbon atoms in which 1 to 5 hydrogen atoms have been replaced with fluorine. Examples of C1-2-fluoroalkyl groups are fluoromethyl, difluoromethyl, trifluoromethyl, 1 -fluoroethyl, 1 ,1 -difluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, and 2,2,2-trifluoroethyl. For the substituent(s) of Ar preferred examples of C1-2-fluoroalkyl groups are difluoromethyl, trifluoromethyl, or 1 ,1 -difluoroethyl; more preferred are C1-fluoroalkyl groups such as difluoromethyl and trifluoromethyl. A C1-4-fluoroalkyl group contains from 1 to 4 carbon atoms in which 1 to 9 hydrogen atoms have been replaced with fluorine. For the substituent R1 preferred examples of a C1-4-fluoroalkyl group are 2-fluoroethyl, 2,2- difluoroethyl, 2,2,2-trifluoroethyl, 1-methyl-2-fluoroethyl, 2-fluoro-1-fluoromethyl-ethyl, 1-methyl-2,2-difluoro-ethyl, 1- methyl-1-trifluoromethyl-ethyl, and 2,2,2-trifluoro-1-methyl-ethyl; preferred are 2,2,2-trifluoro-1-methyl-ethyl and 1- methyl-2,2-difluoro-ethyl.
The term "cycloalkyl", used alone or in combination, refers to a saturated monocyclic hydrocarbon ring containing three to seven carbon atoms (preferably three to six carbon atoms). The term "Cx-y-cycloalkyl" (x and y each being an integer), refers to a saturated monocyclic hydrocarbon ring containing x to y carbon atoms. For example, a C3-4-cycloal kyl group contains from 3 to 4 carbon atoms. Examples of C3-4-cydoalkyl groups are cyclopropyl and cyclobutyl. For the substituent(s) of Ar a preferred example of C3-4-cycloalkyl group is cyclopropyl. A C3-6-cycloalkyl group contains from 3 to 6 carbon atoms. Examples of a C3-6-cycloalkyl group are cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. For the substituent R1 preferred examples of C3-6-cycloalkyl groups are cyclopropyl and cyclobutyl; most preferred is cyclopropyl. The above-mentioned cycloalkyl groups are unsubstituted or substituted as explicitly defined.
The term “ C3-6-cycloalkyl optionally containing one oxygen ring atom”, used alone or in combination, refers to a C3-6- cycloal ky I group as defined before, wherein one carbon ring atom is optionally replaced with an oxygen atom. Examples of C3-6-cycloalkyl optionally containing one oxygen ring atom are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl; preferred C3-6-cycloalkyl groups optionally containing one oxygen ring atom are cyclopropyl and cyclobutyl; particularly preferred is cyclopropyl. The above-mentioned groups are unsubstituted or substituted as explicitly defined.
The term “alkoxy”, used alone or in combination, refers to an alkyl group as defined before, wherein one hydrogen atom is replaced with an oxy group (-O-), i.e. the term refers to the group alkyl-O-.The term “Cx-y-alkoxy” (x and y each being an integer), used alone or in combination, refers to an alkoxy group as defined before, wherein the alkoxy group contains x to y carbon atoms. For example, a C1-2-alkoxy group is an alkoxy group as defined herein which contains 1 or 2 carbon atoms. Examples of C1-2-alkoxy groups are methoxy and ethoxy. For the substituent(s) of Ar a preferred example of a C1-2-alkoxy group is methoxy.
The term “C1-2-alkoxy-C24-alkyl”, used alone or in combination, refers to an alkyl group as defined before, wherein one hydrogen atom is replaced by an alkoxy group, wherein said alkoxy group is as defined hereinabove. The term Cx1-y1- alkoxy-CX2-y2-alkyl (x1, y1 , x2, and y2, each being an integer), used alone or in combination, refers to an CX2-y2-alkyl group containing x2 to y2 carbon atoms, wherein one hydrogen atom is replaced with an Cx1-y1-alkoxy group, said Cx1- yi-alkoxy group containing x1 to y1 carbon atoms. Thus, the term “C1-2-alkoxy-C24-alkyl”, refers to an C2-4-alkyl group containing 2 to 4 carbon atoms, wherein one hydrogen atom is replaced with an C1-2-alkoxy group containing 1 to 2 carbon atoms. Examples of such C1-2-alkoxy-C2-4-alkyl are 2-methoxyethyl, 2-methoxy-1-methyl-ethyl, or 2-methoxy- 1 ,1-dimethyl-ethyl; preferred is 2-methoxy-1-methyl-ethyl. The term "fluoroalkoxy”, used alone or in combination, refers to an alkoxy group as defined before, wherein one or more (and possibly all) hydrogen atoms have been replaced with fluorine. The term “Cx-y-fluoroalkoxy” (x and y each being an integer) refers to a fluoroalkoxy group as defined before containing x to y carbon atoms. For example, a C 1-2- fluoroalkoxy group contains from 1 to 2 carbon atoms in which 1 to 5 hydrogen atoms have been replaced with fluorine. Examples of C1-2-fluoroalkoxy groups are trifluoromethoxy, difluoromethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, and 2,2,2-trifluoroethoxy. For the substituent(s) of Ar a preferred example of a C1-2-fluoroalkoxy group is trifluoromethoxy. The term "aryl", used alone or in combination, means phenyl or naphthyl, preferably phenyl. The aryl groups are unsubstituted or substituted as explicitly defined.
The term "heteroaryl", used alone or in combination, means a 5- to 10-membered monocyclic or bicyclic aromatic ring containing one to a maximum of four heteroatoms (notably containing one to a maximum of three heteroatoms), each independently selected from oxygen, nitrogen and sulfur. Examples of such heteroaryl groups are furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, benzoxadiazolyl, benzothiadiazolyl, quinolinyl, isoquinolinyl, naphthyridinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, pyrrolopyridinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrrolopyrazinyl, imidazopyridinyl, imidazopyridazinyl, and imidazothiazolyl.
The term "5-membered heteroaryl”, used alone or in combination, refers to a 5-membered monocyclic aromatic ring containing one to four ring heteroatoms (preferably one to three ring heteroatoms), each independently selected from oxygen, nitrogen, and sulfur. The term “6-membered heteroaryl", used alone or in combination, refers to a 6-membered monocyclic aromatic ring containing one to three ring nitrogen atoms. Examples of 5-membered heteroaryl groups are furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, and tetrazolyl. For Ar preferred examples of 5-membered heteroaryl groups are thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl, and triazolyl; more preferred are thiophen-2-yl, thiophen-3-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, [1,3,4]thiadiazol-2-yl, 1 H-pyrazol-3-yl, 1 H-pyrazol-4-yl, isothiazol-5-yl, isoxazol-4- yl, oxazol-5-yl, 1 H-[1 ,2,3]triazol-4-yl, or 2H-[1 ,2,3]triazol-4-yl; most preferred are thiophenyl such as thiophen-2-yl and thiophen-3-yl, thiazolyl such as thiazol-5-yl, and isothiazolyl such as isothiazol-5-yl; particularly preferred is thiophenyl such as thiophen-2-yl and thiophen-3-yl. For Ar preferred examples of 6-membered heteroaryl groups are pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl; more preferred are pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl, pyrazine- yl, and pyridazin-3-yl; most preferred is pyridinyl such as pyridin-2-yl, pyridin-3-yl and pyridin-4-yl; particularly preferred is pyridin-3-yl. The above-mentioned heteroaryl groups are unsubstituted or substituted as explicitly defined.
The term “unsubstituted, mono-, di-, or tri-substituted” as used herein refers to “unsubstituted, mono-substituted, di- substituted, or tri-substituted”. Likewise, the term “unsubstituted, mono-, or di-substituted” refers to “unsubstituted, mono-substituted, or di-substituted”.
In this patent application, a bond drawn as a dotted line shows the point of attachment of the radical drawn to the rest of the molecule. For example, the radical drawn below
Figure imgf000015_0001
r represents phenyl or pyridin-3-yl.
2) One embodiment relates to compounds according to embodiment 1), with the proviso that the following compounds and salts (especially pharmaceutically acceptable salts) thereof, are excluded:
N/-(3-(2-amino-6-(methylamino)pyrimidin-4-yl)cyclobutyl)-2,5-dimethylthiophene-3-sulfonamide (i.e. CAS RN 2068756- 64-7);
N/-(3-(2-amino-6-(methylamino)pyrimidin-4-yl)cyclobutyl)-5-chlorothiophene-2-sulfonamide (i.e. CAS RN 2068741-89- 7):
N/-(3-(2-amino-6-(methylamino)pyrimidin-4-yl)cyclobutyl)-2,4-dimethylbenzenesulfonamide (i.e. CAS RN 2068738-85- 0);
N/-(3-(2-amino-6-(methylamino)pyrimidin-4-yl)cyclobutyl)-3,5-dimethylisoxazole-4-sulfonamide (i.e. CAS RN 2068733- 03-7);
N/-(3-(2-amino-6-(methylamino)pyrimidin-4-yl)cyclobutyl)-2-methoxy-4-methylbenzenesulfonamide (i.e. CAS RN 2068727-35-3);
N/-(3-(2-amino-6-(methylamino)pyrimidin-4-yl)cyclobutyl)-2,4-difluorobenzenesulfonamide (i.e. CAS RN 2068732-71- 6);
N/-(3-(2-amino-6-(methylamino)pyrimidin-4-yl)cyclobutyl)-2,5-difluorobenzenesulfonamide (i.e. CAS RN 2068712-87- 6);
N/-(3-(2-amino-6-(methylamino)pyrimidin-4-yl)cyclobutyl)-4-methoxy-3-methylbenzenesulfonamide (i.e. CAS RN 2068699-30-7);
N/-(c/s-3-(2-amino-6-(methylamino)pyrimidin-4-yl)cyclobutyl)-2,5-dimethylthiophene-3-sulfonamide (i.e. CAS RN
1783256-82-5);
N/-(c/s-3-(2-amino-6-(methylamino)pyrimidin-4-yl)cyclobutyl)-5-chlorothiophene-2-sulfonamide (i.e. CAS RN 1783305- 08-7);
N/-(c/s-3-(2-amino-6-(methylamino)pyrimidin-4-yl)cyclobutyl)-2,4-dimethylbenzenesulfonamide (i.e. CAS RN 1783155- 99-6);
N/-(c/s-3-(2-amino-6-(methylamino)pyrimidin-4-yl)cyclobutyl)-3,5-dimethylisoxazole-4-sulfonamide (i.e. CAS RN 1783110-79-1);
N/-(c/s-3-(2-amino-6-(methylamino)pyrimidin-4-yl)cyclobutyl)-2-methoxy-4-methylbenzenesulfonamide (i.e. CAS RN 1783211-08-4);
N/-(c/s-3-(2-amino-6-(methylamino)pyrimidin-4-yl)cyclobutyl)-2,4-difluorobenzenesulfonamide (i.e. CAS RN 1783040- 48-1);
N/-(c/s-3-(2-amino-6-(methylamino)pyrimidin-4-yl)cyclobutyl)-2,5-difluorobenzenesulfonamide (i.e. CAS RN 1783125- 47-2); and
N/-(c/s-3-(2-amino-6-(methylamino)pyrimidin-4-yl)cyclobutyl)-4-methoxy-3-methylbenzenesulfonamide (i.e. CAS RN 1783136-48-0). It is understood that when a specific compound without “cis-" or “trans-" designation is referred to as excluded from the scope of embodiment 2), the c/s-isomer, the trans-isomer, and any mixture of cis- and trans-isomer, of said compound are also explicitly excluded from the scope of embodiment 2). For example, when the compound N/-(3-(2-amino-6- (methylamino)pyrimidin-4-yl)cyclobutyl)-2,5-dimethylthiophene-3-sulfonamide is referred to as excluded from the scope of embodiment 2), the isomers N-(c/s-3-(2-amino-6-(methylamino)pyrimidin-4-yl)cyclobutyl)-2,5- dimethylthiophene-3-sulfonamide, N-(trans-3-(2-amino-6-(methylamino)pyrimidin-4-yl)cyclobutyl)-2,5-dimethyl- thiophene-3-sulfonamide, and any mixture thereof, are also excluded from the scope of embodiment 2). For avoidance of doubt, salts (especially pharmaceutically acceptable salts) of the trans-isomers of the specific compounds listed in embodiment 2) are also excluded from the scope of embodiment 2).
3) Another embodiment relates to compounds according to embodiment 1) or 2), wherein Ar represents
• phenyl, wherein said phenyl is unsubstituted, mono-, or di-substituted, wherein the substituent independently represents
> halogen (especially iodine, chlorine or fluorine);
> cyano;
> C1-3-alkyl (especially methyl);
> C1-2-alkoxy (especially methoxy); or
> C1-2-fluoroalkoxy (especially trifluoromethoxy);
• 5-membered heteroaryl containing from one to three ring heteroatoms independently selected from nitrogen, sulfur, and oxygen (notably such 5-membered heteroaryl is selected from thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl, and triazolyl; especially selected from thiophen-2-yl, thiophen-3- yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, [1,3,4]thiadiazol-2-yl, 1 H-pyrazol-3-yl, 1 H-pyrazol-4-yl, isothiazol-5-yl, isoxazol-4-yl, oxazol-5-yl, 1 H-[1,2,3]triazol-4-yl, and 2H-[1 ,2,3]triazol-4-yl; in particular selected from thiophenyl such as thiophen-2-yl and thiophen-3-yl), wherein said 5-membered heteroaryl is unsubstituted, mono-, or di-substituted, wherein the substituent independently represents
> halogen (especially chlorine, fluorine, or bromine);
> cyano;
> C1-3-alkyl (especially methyl or ethyl);
> C1-2-fluoroalkyl (especially difluoromethyl or 1,1 -difluoroethyl);
> C1-2-alkoxy (especially methoxy); or
> C3-4-cycloalkyl (especially cyclopropyl);
• 6-membered heteroaryl containing from one to three ring nitrogen atoms (notably such 6-membered heteroaryl is selected from pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl; especially selected from pyridine- yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl, pyrazin-2-yl, and pyridazin-3-yl; in particular selected from pyridin- 3-yl), wherein said 6-membered heteroaryl is unsubstituted, mono-, di-, or tri-substituted (notably unsubstituted, mono-, or di-substituted), wherein the substituent independently represents
> halogen (especially chlorine, fluorine, or bromine);
> cyano; > C1-3-alkyl (especially methyl or ethyl);
> C1-2-fluoroalkyl (especially difluoromethyl or trifluoromethyl);
> C1-2-alkoxy (especially methoxy);
> C3-4-cycloalkyl (especially cyclopropyl); or
> amino optionally mono- or di-substituted with methyl or ethyl (especially methyl).
4) Another embodiment relates to compounds according to embodiment 1) or 2), wherein Ar represents
• phenyl, wherein said phenyl is unsubstituted, mono-, or di-substituted, wherein the substituent independently represents
> halogen (especially iodine, chlorine or fluorine);
> C1-3-alkyl (especially methyl); or
> C1-2-alkoxy (especially methoxy).
• 5-membered heteroaryl containing from one to three ring heteroatoms independently selected from nitrogen, sulfur, and oxygen (notably such 5-membered heteroaryl is selected from thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl, and triazolyl; especially selected from thiophen-2-yl, thiophen-3- yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, [1,3,4]thiadiazol-2-yl, 1 H-pyrazol-3-yl, 1 H-pyrazol-4-yl, isothiazol-5-yl, isoxazol-4-yl, oxazol-5-yl, 1 H-[1,2,3]triazol-4-yl, and 2H-[1 ,2,3]triazol-4-yl; in particular selected from thiophenyl such as thiophen-2-yl and thiophen-3-yl), wherein said 5-membered heteroaryl is unsubstituted, mono-, or di-substituted, wherein the substituent independently represents
> halogen (especially chlorine, fluorine, or bromine);
> C1-3-alkyl (especially methyl or ethyl);
> C1-2-fluoroalkyl (especially difluoromethyl or 1,1 -difluoroethyl);
> C1-2-alkoxy (especially methoxy); or
> C3-4-cycloalkyl (especially cyclopropyl);
• 6-membered heteroaryl containing from one to three ring nitrogen atoms (notably such 6-membered heteroaryl is selected from pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; especially selected from pyridin- 2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl, pyrazin-2-yl, and pyridazin-3-yl; in particular selected from pyridin-3-yl), wherein said 6-membered heteroaryl is unsubstituted, mono-, di-, or tri-substituted (notably unsubstituted, mono-, or di-substituted), wherein the substituent independently represents
> halogen (especially chlorine, fluorine, or bromine);
> cyano;
> C1-3-alkyl (especially methyl or ethyl);
> C1-2-fluoroalkyl (especially difluoromethyl or trifluoromethyl);
> C1-2-alkoxy (especially methoxy); or
> C3-4-cycloalkyl (especially cyclopropyl).
5) Another embodiment relates to compounds according to embodiment 1) or 2), wherein Ar represents
• phenyl, wherein said phenyl is unsubstituted, mono-, di-, or tri-substituted (notably unsubstituted, mono-, or di-substituted), wherein the substituent independently represents > halogen (especially iodine, chlorine, fluorine, or bromine);
> cyano;
> C1-3-alkyl (especially methyl or ethyl);
> C1-2-fluoroalkyl (especially difluoromethyl, trifluoromethyl, or 1,1 -difluoroethyl);
> C1-2-alkoxy (especially methoxy);
> C3-4-cycloalkyl (especially cyclopropyl);
> C1-2-fluoroalkoxy (especially trifluoromethoxy); or
> amino optionally mono- or di-substituted with methyl or ethyl (especially methyl). ) Another embodiment relates to compounds according to embodiment 1) or 2), wherein Ar represents
• phenyl, wherein said phenyl is unsubstituted; mono-substituted in meta-position with regard to the point of attachment of the rest of the molecule; or di-substituted with one substituent in meta-position and another substituent in para- or ortho-position (any one of the ortho-positions), with regard to the point of attachment of the rest of the molecule; wherein the substituent independently represents
> halogen (especially iodine, chlorine, fluorine, or bromine; preferred is fluorine);
> cyano;
> C1-3-alkyl (especially methyl or ethyl);
> C1-2-fluoroalkyl (especially difluoromethyl, trifluoromethyl, or 1,1 -difluoroethyl);
> C1-2-alkoxy (especially methoxy);
> C3-4-cycloalkyl (especially cyclopropyl);
> C1-2-fluoroalkoxy (especially trifluoromethoxy); or
> amino optionally mono- or di-substituted with methyl or ethyl (especially methyl). ) Another embodiment relates to compounds according to any one of embodiments 1) to 3), wherein Ar represents
• phenyl, wherein said phenyl is unsubstituted; mono- substituted in meta-position with regard to the point of attachment of the rest of the molecule; or di-substituted with one substituent in meta-position and another substituent in para- or ortho-position (any one of the ortho-positions), with regard to the point of attachment of the rest of the molecule; wherein the substituent independently represents
> halogen (especially iodine, chlorine or fluorine);
> cyano;
> C1-3-alkyl (especially methyl);
> C1-2-alkoxy (especially methoxy); or
> C1-2-fluoroalkoxy (especially trifluoromethoxy). ) Another embodiment relates to compounds according to any one of embodiments 1) to 4), wherein Ar represents
• phenyl, wherein said phenyl is unsubstituted; mono- substituted in meta-position with regard to the point of attachment of the rest of the molecule; or di-substituted with one substituent in meta-position and another substituent in para-position, with regard to the point of attachment of the rest of the molecule; wherein the substituent independently represents
> halogen (especially iodine, chlorine or fluorine); > C1-3-alkyl (especially methyl); or
> C1-2-alkoxy (especially methoxy).
9) Another embodiment relates to compounds according to any one of embodiments 1) to 4), wherein Ar represents
• phenyl, wherein said phenyl is unsubstituted; mono- substituted in meta-position with regard to the point of attachment of the rest of the molecule; or di-substituted with one substituent in meta-position and another substituent in para-position, with regard to the point of attachment of the rest of the molecule; wherein the substituent independently represents chlorine, fluorine, or methoxy (notably iodine, chlorine or fluorine; especially fluorine).
10) Another embodiment relates to compounds according to embodiment 1) or 2), wherein Ar represents
• 5-membered heteroaryl containing from one to three ring heteroatoms independently selected from nitrogen, sulfur, and oxygen (notably such 5-membered heteroaryl is selected from thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl, and triazolyl; especially selected from thiophen-2-yl, thiophen-3- yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, [1,3,4]thiadiazol-2-yl, 1 H-pyrazol-3-yl, 1 H-pyrazol-4-yl, isothiazol-5-yl, isoxazol-4-y I , oxazol-5-yl, 1 H-[1 ,2,3]triazol-4-yl, and 2H-[1 ,2,3]triazol-4-yl; in particular selected from thiophen- 2-yl and thiophen-3-yl), wherein said 5-membered heteroaryl is unsubstituted, mono-, di-, or tri-substituted (notably unsubstituted, mono-, or di-substituted), wherein the substituent independently represents
> halogen (especially chlorine, fluorine, or bromine);
> cyano;
> C1-3-alkyl (especially methyl or ethyl);
> C1-2-fluoroalkyl (especially difluoromethyl, trifluoromethyl, or 1,1 -difluoroethyl);
> C1-2-alkoxy (especially methoxy);
> C3-4-cycloalkyl (especially cyclopropyl);
> C1-2-fluoroalkoxy (especially trifluoromethoxy); or
> amino optionally mono- or di-substituted with methyl or ethyl (especially methyl).
11) Another embodiment relates to compounds according to embodiments 1) or 2), wherein Ar represents
• 5-membered heteroaryl containing at least one ring sulfur atom and optionally one or two ring nitrogen atoms (notably such 5-membered heteroaryl is selected from thiophenyl, thiazolyl, isothiazolyl, and thiadiazolyl; especially selected from thiophen-2-yl, thiophen-3-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-5-yl, and [1 ,3,4]thiadiazol-2-yl; in particular selected from thiophenyl such as thiophen-2-yl and thiophen-3-yl); wherein said 5-membered heteroaryl is unsubstituted, mono-, or di-substituted (notably unsubstituted or mono- substituted; especially mono-substituted), wherein the substituent independently represents
> halogen (especially chlorine, fluorine, or bromine);
> cyano;
> C1-3-alkyl (especially methyl or ethyl);
> C1-2-fluoroalkyl (especially difluoromethyl, trifluoromethyl, or 1,1 -difluoroethyl);
> C1-2-alkoxy (especially methoxy);
> C3-4-cycloalkyl (especially cyclopropyl); > C1-2-fluoroalkoxy (especially trifluoromethoxy); or
> amino optionally mono- or di-substituted with methyl or ethyl (especially methyl).
12) Another embodiment relates to compounds according to any one of embodiments 1) to 4), wherein Ar represents
• 5-membered heteroaryl containing at least one ring sulfur atom and optionally one or two ring nitrogen atoms (notably such 5-membered heteroaryl is selected from thiophenyl, thiazolyl, isothiazolyl, and thiadiazolyl; especially selected from thiophen-2-yl, thiophen-3-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-5-yl, and
[1.3.4]thiadiazol-2-yl; in particular selected from thiophenyl such as thiophen-2-yl and thiophen-3-yl); wherein said 5-membered heteroaryl is unsubstituted, mono-, or di-substituted (notably unsubstituted or mono- substituted; especially mono-substituted), wherein the substituent independently represents
> halogen (especially chlorine, fluorine, or bromine);
> C1-3-alkyl (especially methyl or ethyl);
> C1-2-fluoroalkyl (especially difluoromethyl);
> C1-2-alkoxy (especially methoxy); or
> C3-4-cycloalkyl (especially cyclopropyl).
13) Another embodiment relates to compounds according to any one of embodiments 1) to 4), wherein Ar represents
• 5-membered heteroaryl selected from thiophen-2-yl, thiophen-3-yl, isothiazol-5-yl, thiazol-5-yl, and
[1.3.4]thiadiazol-2-yl (especially thiophen-2-yl and thiophen-3-yl); wherein said 5-membered heteroaryl is mono-substituted (especially at position 3 with regard to the point of attachment of the rest of the molecule), wherein the substituent independently represents
> halogen (especially chlorine, fluorine, or bromine);
> C1-3-alkyl (especially methyl or ethyl);
> C1-2-fluoroalkyl (especially difluoromethyl);
> C1-2-alkoxy (especially methoxy); or
> C3-4-cycloalkyl (especially cyclopropyl).
14) Another embodiment relates to compounds according to any one of embodiments 1) to 4), wherein Ar represents
• 5-membered heteroaryl selected from thiophen-2-yl and thiophen-3-yl; wherein said 5-membered heteroaryl is mono-substituted (especially at position 3 with regard to the point of attachment of the rest of the molecule), wherein the substituent independently represents
> halogen (especially chlorine, fluorine, or bromine);
> C1-3-alkyl (especially methyl or ethyl); or
> C1-2-fluoroalkyl (especially difluoromethyl).
15) Another embodiment relates to compounds according to embodiment 1) or 2), wherein Ar represents
• 6-membered heteroaryl containing from one to three ring nitrogen atoms (notably such 6-membered heteroaryl is selected from pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; especially selected from pyridin- 2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl, pyrazin-2-yl, and pyridazin-3-yl; in particular selected from pyridin-3-yl); wherein said 6-membered heteroaryl is unsubstituted, mono-, di-, or tri-substituted (notably unsubstituted, mono- , or di-substituted), wherein the substituent independently represents
> halogen (especially chlorine, fluorine, or bromine);
> cyano;
> C1-3-alkyl (especially methyl or ethyl);
> C1-2-fluoroalkyl (especially difluoromethyl, trifluoromethyl, or 1,1 -difluoroethyl);
> C1-2-alkoxy (especially methoxy);
> C3-4-cycloalkyl (especially cyclopropyl);
> C1-2-fluoroalkoxy (especially trifluoromethoxy); or
> amino optionally mono- or di-substituted with methyl or ethyl (especially methyl).
16) Another embodiment relates to compounds according to embodiment 1) or 2), wherein Ar represents
• 6-membered heteroaryl containing one or two ring nitrogen atoms, wherein at least one ring nitrogen atom is in position 3 with regard to the point of attachment of the rest of the molecule (notably such 6-membered heteroaryl is selected from pyridin-3-yl and pyrimidin-5-yl; especially selected from pyridin-3-yl), wherein said 6-membered heteroaryl is unsubstituted, mono-, di-, or tri-substituted (notably mono-, di- or tri-substituted; especially di- or tri-substituted; in particular di-substituted), wherein the substituent independently represents
> halogen (especially chlorine, fluorine, or bromine);
> cyano;
> C1-3-alkyl (especially methyl or ethyl);
> C1-2-fluoroalkyl (especially difluoromethyl, trifluoromethyl, or 1,1 -difluoroethyl);
> C1-2-alkoxy (especially methoxy);
> C3-4-cycloalkyl (especially cyclopropyl);
> C1-2-fluoroalkoxy (especially trifluoromethoxy); or
> amino optionally mono- or di-substituted with methyl or ethyl (especially methyl).
17) Another embodiment relates to compounds according to any one of embodiments 1) to 4), wherein Ar represents
• 6-membered heteroaryl selected from pyridin-3-yl, wherein said 6-membered heteroaryl is unsubstituted, mono-, di-, or tri-substituted (notably mono-, di- or tri-substituted; especially di- or tri-substituted; in particular di-substituted), wherein the substituent independently represents
> halogen (especially chlorine, fluorine, or bromine);
> C1-3-alkyl (especially methyl or ethyl);
> C1-2-fluoroalkyl (especially difluoromethyl, trifluoromethyl, or 1,1 -difluoroethyl);
> C1-2-alkoxy (especially methoxy); or
> C3-4-cycloalkyl (especially cyclopropyl);
18) Another embodiment relates to compounds according to any one of embodiments 1) to 4), wherein Ar represents
• 6-membered heteroaryl selected from pyridin-3-yl, wherein said 6-membered heteroaryl is unsubstituted, mono-, di-, or tri-substituted (notably mono-, di- or tri-substituted; especially di- or tri-substituted; in particular di-substituted), wherein the substituent independently represents chlorine, fluorine, methyl, or methoxy (especially chlorine, fluorine, or methyl).
19) Another embodiment relates to compounds according to any one of embodiments 1) to 4), wherein Ar represents 6-membered heteroaryl selected from pyridin-3-yl, wherein said pyridin-3-yl is unsubstituted, mono-, di-, or tri- substituted (notably mono-, di- or tri-substituted; especially di- or tri-substituted; in particular di-substituted) in position(s) 2 and/or 5 and/or 6, with regard to the nitrogen atom of said pyridin-3-yl; wherein the substituent independently represents chlorine, fluorine, methyl, or methoxy (especially chlorine, fluorine, or methyl).
20) Another embodiment relates to compounds according to any one of embodiments 1) to 4) and 15) to 18), wherein Ar represents 6-membered heteroaryl, wherein said 6-membered heteroaryl is selected from pyridin-3-yl, wherein said pyridin-3-yl is unsubstituted, mono-, di-, or tri-substituted (notably mono-, di- or tri-substituted; especially di- or tri- substituted; in particular di-substituted) in position(s) 2 and/or 5 and/or 6, with regard to the nitrogen atom of said pyridin-3-yl; wherein the substituents are as defined for the 6-membered heteroaryl in the corresponding embodiments 1) to 4) and 15) to 18).
21) Another embodiment relates to compounds according to any one of embodiments 1) to 4), wherein Ar represents 6-membered heteroaryl, wherein said 6-membered heteroaryl is selected from pyridin-3-yl, wherein said pyridin-3-yl is unsubstituted, mono-, or di-substituted in position(s) 2 and/or 5 and/or 6, with regard to the nitrogen atom of said pyridin-3-yl; wherein the substituent(s), if present, independently represent methyl or fluorine.
For avoidance of doubt, the numbering of the pyridin-3-yl ring referred to in embodiments 19) and 21) is as follows:
Figure imgf000022_0001
22) Another embodiment relates to compounds according to any one of embodiments 1) to 21), wherein R1 represents
• C1-5-alkyl (notably C1-4-alkyl; especially methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, or sec- butyl);
• hydroxy-C2-4-alkyl (especially 2-hydroxy-1 -methyl-ethyl or 2-hydroxy-1 , 1-dimethyl-ethyl);
• C1-2-alkoxy-C2-4-alkyl (especially 2-methoxyethyl, 2-methoxy-1 -methyl-ethyl, or 2-methoxy-1, 1 -dimethyl- ethyl);
• C1-4-fluoroalkyl (especially 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-fluoro-1 -methyl-ethyl, 2- fluoro-1-fluoromethyl-ethyl, 2, 2-difluoro-1 -methyl-ethyl, 2,2,2-trifluoro-1, 1-dimethyl-ethyl, or 2,2,2-trifluoro-1- methyl-ethyl); or
• -L-Cy, wherein
> -L- represents a bond (i.e. Cy is directly attached to the nitrogen atom) or -CH2-; and
> Cy represents C3-6-cycloalkyl (especially cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl) optionally containing one oxygen ring atom, wherein said Ca-s-cycloalkyl optionally containing one oxygen ring atom is unsubstituted or mono-substituted (especially at the point of attachment of said C3-6-cycloalkyl to the rest of the molecule), wherein the substituent represents fluorine
[in particular -L-Cy represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetan-3-yl, cyclopropyl- methyl, 1-fluoro-cyclopropylmethyl, or cyclobutyl-methyl],
23) Another embodiment relates to compounds according to any one of embodiments 1) to 21), wherein R1 represents
• C1-5-alkyl (notably Cu-alkyl; especially methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, or sec- butyl);
• C1-4-fluoroalkyl (especially 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 1-methyl-2-fluoroethyl, 2-fluoro- 1-fluoromethyl-ethyl, 1-methyl-2,2-difluoro-ethyl, 1-methyl-1-trifluoromethyl-ethyl, or 2, 2, 2-trifluoro-1 -methyl- ethyl); or
• L-Cy, wherein
> -L- represents a bond (i.e. Cy is directly attached to the nitrogen atom) or -CH2-; and
> Cy represents C3-6-cycloalkyl, wherein said C3-6-cycloalkyl is unsubstituted or mono-substituted (especially at the point of attachment of said C3-6-cycloal kyl to the rest of the molecule), wherein the substituent represents fluorine (in particular -L-Cy represents cyclopropyl, cyclobutyl, cyclopropyl- methyl, (l-fluoro-cyclopropyl)-methyl, or cyclobutyl-methyl).
24) Another embodiment relates to compounds according to any one of embodiments 1) to 21), wherein R1 represents
• ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, or sec-butyl; especially isopropyl;
• 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 1-methyl-2-fluoroethyl, 2-fluoro-1-fluoromethyl-ethyl, 1- methyl-2,2-difluoro-ethyl, 1-methyl-1-trifluoromethyl-ethyl, or 2,2,2-trifluoro-1-methyl-ethyl; especially 1- methyl-1 -trifluoromethy l-ethy I ; or
• cyclopropyl, cyclopropyl-methyl, or (l-fluoro-cyclopropyl)-methyl; especially cyclopropyl.
25) Another embodiment relates to compounds according to any one of embodiments 1) to 24), wherein R2 represents hydrogen.
26) Another embodiment relates to compounds according to embodiment 1), wherein
Ar represents a 6-membered heteroaryl, wherein said 6-membered heteroaryl is selected from pyridin-3-yl, wherein said pyridin-3-yl is unsubstituted, mono-, or di-substituted in position(s) 2 and/or 5 and/or 6, with regard to the nitrogen atom of said pyridin-3-yl; wherein the substituents independently represent methyl or fluorine;
R1 represents C2-4-alkyl (notably ethyl, n-propyl, isopropyl, tert-butyl, or sec-butyl; especially isopropyl), cyclopropyl, or 2,2, 2-trifl uoro- 1 -methyl-ethyl; and
R2 represents hydrogen;
27) Another embodiment relates to compounds according to embodiment 1) or 2), wherein at least one, especially three of the following characteristics a) and/or b) and/or c) below are present: a) the radical
Figure imgf000023_0001
represents: • phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 4-iodophenyl, 3-iodophenyl, 3-chlorophenyl, 3- cyanophenyl, 3-methylphenyl, 3-methoxyphenyl, 3-(trifluoromethoxy)-phenyl, 3,4-difluorophenyl, 2,3- difluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 3-fluoro-4-methoxyphenyl, 3- methyl-4-methoxyphenyl, 3-fluoro-4-methylphenyl, 2-methyl-5-fluorophenyl, 2-fluoro-5-methylphenyl, 3,5,- dichlorophenyl, 2-fluoro-5-chlorophenyl, 3-chloro-4-iodophenyl, 3-fluoro-4-iodophenyl, 2-fluoro-4-iodophenyl,
3-cyano-4-iodophenyl, 3-methyl-4-iodophenyl, or 2-chloro-5-fluorophenyl; and/or
• thiophen-2-yl, 4-methyl-thiophen-2-yl, 3-methyl-thiophen-2-yl, 5-methyl-thiophen-2-yl, 5-chloro-thiophen-2-yl, 5-fluoro-thiophen-2-yl, 5-bromo-thiophen-2-yl, 5-methoxy-thiophen-2-yl, 5-cyclopropyl-thiophene-2-yl, 5- methyl-thiophen-3-yl, 4-methyl-thiazol-2-yl, 2-methyl-thiazol-4-yl, 2-chloro-thiazol-4-yl, thiazol-4-yl, thiazol-5- yl, 2-ethyl-thiazol-5-yl, 2-methyl-thiazol-5-yl, 2-methoxy-thiazole-5-yl, 2-chloro-thiazol-5-yl, 2-cyclopropyl- thiazole-5-yl, 2-(1,1-difluoro-ethyl)-thiazole-5-yl, 2,4-dimethyl-thiazol-5-yl, 2-bromo-4-methyl-thiazol-5-yl, 2- chloro-4-methyl-thiazol-5-yl, 3-methyl-isothiazol-5-yl, 5-methyl-[1,3,4]thiadiazol-2-yl, 1-methyl-1 H-pyrazole-4- yl, 3-methyl-isoxazol-4-yl, 2-methyl-oxazol-5-yl, 1 -methyl- 1 H-[1 ,2,3]triazol-4-yl, 2-methyl-2H-[1,2,3]triazol-4- yl, 1,5-dimethyl-1 H-pyrazol-3-yl, 3,5-dimethyl-isoxazole-4-yl, or 5-difluoromethyl-thiophen-3-yl; and/or
• pyridin-2-yl, pyridin-3-yl, 2-fluoro-pyridin-3-yl, 5-fluoro-pyridin-3-yl, 6-fluoro-pyridin-3-yl, 2-chloro-pyridin-3-yl,
4-chloro-pyridin-3-yl, 5-chloro-pyridin-3-yl, 6-chloro-pyridin-3-yl, 2-bromo-pyridin-3-yl, 2-methyl-pyridin-3-yl, 4- methyl-pyridin-3-yl, 5-methyl-pyridin-3-yl, 6-methyl-pyridin-3-yl, 5-ethyl-pyridin-3-yl, 6-ethyl-pyridin-3-yl, 5- cyclopropyl-pyridin-3-yl, 6-cyclopropyl-pyridin-3-yl, 5-cyano-pyridin-3-yl, 6-cyano-pyridin-3-yl, 6-methoxy- pyridin-3-yl, 6-methylamino-pyridin-3-yl, 2-difluoromethyl-pyridin-3-yl, 5-difluoromethyl-pyridin-3-yl, 6- difluoromethyl-pyridin-3-yl, 5,6-dimethyl-pyridin-3-yl, 2,6-dimethyl-pyridin-3-yl, 2,5-dimethyl-pyridin-3-yl, 4,6- dimethyl-pyridin-3-yl, 5-chloro-6-methyl-pyridin-3-yl, 6-chloro-5-methyl-pyridin-3-yl, 5-fluoro-6-methyl-pyridin- 3-yl, 2-fluoro-6-methyl-pyridin-3-yl, 6-fluoro-2-methyl-pyridin-3-yl, 6-fluoro-5-methyl-pyridin-3-yl, 2-chloro-6- methyl-pyridin-3-yl, 2,6-dichloro-pyridin-3-yl, 6-chloro-2-methyl-pyridin-3-yl, 2,6-difluoro-pyridin-3-yl, 6-chloro-
5-fluoro-pyridin-3-yl, 5,6-difluoro-pyridin-3-yl, 5,6-dichloro-pyridin-3-yl, 5-fluoro-2-methyl-pyridin-3-yl, 2-fluoro- 5-methyl-pyridin-3-yl, 5-chloro-2-methyl-pyridin-3-yl, 2-chloro-5-methyl-pyridin-3-yl, 6-chloro-4-methyl- pyridin-3-yl, 2-chloro-6-fluoro-pyridin-3-yl, 6-trifluoromethyl-pyridin-3-yl, 5-methyl-6-trifluoromethyl-pyridin-3- yl, 5-chloro-6-fluoro-pyridin-3-yl, 5-chloro-2-fluoro-pyridin-3-yl, 2-chloro-6-methoxy-pyridin-3-yl, 5-chloro-2- methoxy-pyridin-3-yl, 6-dimethylamino-pyridin-3-yl, 2-chloro-5,6-dimethyl-pyridin-3-yl, 2-fluoro-5,6-dimethyl- pyridin-3-yl, 2,5,6-trimethyl-pyridin-3-yl, pyridin-4-yl, pyridazin-2-yl, 6-methyl-pyridazin-2-yl, pyrimidin-5-yl, or 2-amino-pyrimidin-5-yl; b) R1 represents methyl, ethyl, cyclopropyl, 2-fluoroethyl, n-propyl, isopropyl, 2-hydroxyethyl, 2-fluoro-1 -methyl-ethyl, tert-butyl, sec-butyl, 2,2-difluoro-ethyl, 2-hydroxy-1 -methyl-ethyl, 2-methoxy-ethyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetan-3-yl, 1-fluoro-cyclopropylmethyl, cyclobutyl-methyl, 2,2,2-trifluoro-ethyl, 2, 2, 2-trifluoro-1 -methyl-ethyl, 2-fluoro-1-fluoromethyl-ethyl, 2, 2-difluoro-1 -methyl-ethyl, 2-hydroxy-1 ,1 -di methyl-ethyl, 2-methoxy-1 -methyl- ethyl, or 2-methoxy-1 , 1 -dimethyl-ethyl; c) R2 represents fluorine or hydrogen. 28) Another embodiment relates to compounds according to embodiment 1) or 2), wherein the radical
Figure imgf000025_0001
represents pyridin-3-yl, 2-fluoro-pyridin-3-yl, 5-fluoro-pyridin-3-yl, 6-fluoro-pyridin-3-yl, 2-chloro-pyridin-3-yl, 5-chloro- pyridin-3-yl, 6-chloro-pyridin-3-yl, 2-bromo-pyridin-3-yl, 2-methyl-pyridin-3-yl, 5-methyl-pyridin-3-yl, 6-methyl- pyridin-3-yl, 5-ethyl-pyridin-3-yl, 6-ethyl-pyridin-3-yl, 5-cyclopropyl-pyridin-3-yl, 6-cyclopropyl-pyridin-3-yl, 2- difluoromethyl-pyridin-3-yl, 5,6-dimethyl-pyridin-3-yl, 2,6-dimethyl-pyridin-3-yl, 2,5-dimethyl-pyridin-3-yl, 5- chloro-6-methyl-pyridin-3-yl, 6-chloro-5-methyl-pyridin-3-yl, 5-fluoro-6-methyl-pyridin-3-yl, 2-fluoro-6-methyl- pyridin-3-yl, 6-fluoro-2-methyl-pyridin-3-yl, 6-fluoro-5-methyl-pyridin-3-yl, 2-chloro-6-methyl-pyridin-3-yl, 2,6- dichloro-pyridin-3-yl, 6-chloro-2-methyl-pyridin-3-yl, 2,6-difluoro-pyridin-3-yl, 6-chloro-5-fluoro-pyridin-3-yl, 5,6-difluoro-pyridin-3-yl, 5,6-dichloro-pyridin-3-yl, 5-fluoro-2-methyl-pyridin-3-yl, 2-fluoro-5-methyl-pyridin-3- yl, 5-chloro-2-methyl-pyridin-3-yl, 2-chloro-5-methyl-pyridin-3-yl, 2-chloro-6-fluoro-pyridin-3-yl, 6- trifluoromethyl-pyridin-3-yl, 5-methyl-6-trifluoromethyl-pyridin-3-yl, 5-chloro-6-fluoro-pyridin-3-yl, 5-chloro-2- fluoro-pyridin-3-yl, 2-chloro-5,6-dimethyl-pyridin-3-yl, 2-fluoro-5,6-dimethyl-pyridin-3-yl, or 2,5,6-trimethyl- pyridin-3-yl;
R1 represents ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, 1-fluoro-cyclopropylmethyl, 2,2-difluoro- ethyl, or 2,2,2-trifluoro-1-methyl-ethyl; and
R2 represents hydrogen.
29) Another embodiment relates to compounds according to any one of embodiments 1) to 28), which are also compounds of Formula (II) (i.e. the compounds are in c/s-configuration with respect to the cyclobutan-1 ,3-diyl ring)
Figure imgf000025_0002
Formula (II).
30) Another embodiment relates to compounds according to any one of embodiments 1) to 28), which are also compounds of Formula (III) (i.e. the compounds are in trans-configuration with respect to the cyclobutan-1 , 3-diyl ring)
Figure imgf000026_0001
Formula (III).
31) Another embodiment relates to compounds according to embodiment 1), which are selected from the following compounds
N/-(c/s-3-(2-amino-6-(methylamino)pyrimidin-4-yl)cyclobutyl)-2-fluorobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-(methylamino)pyrimidin-4-yl)cyclobutyl)-3-fluorobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-(methylamino)pyrimidin-4-yl)cyclobutyl)-4-fluorobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-(methylamino)pyrimidin-4-yl)cyclobutyl)-3,4-difluorobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-(methylamino)pyrimidin-4-yl)cyclobutyl)-2,3-difluorobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-(methylamino)pyrimidin-4-yl)cyclobutyl)-2,6-difluorobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-(methylamino)pyrimidin-4-yl)cyclobutyl)-2-fluoro-5-methylbenzenesulfonamide;
N/-(c/s-3-(2-amino-6-(methylamino)pyrimidin-4-yl)cyclobutyl)-5-chloro-2-fluorobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-(methylamino)pyrimidin-4-yl)cyclobutyl)-2-chloro-5-fluorobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-(methylamino)pyrimidin-4-yl)cyclobutyl)-5-fluoro-2-methylbenzenesulfonamide;
N/-(c/s-3-(2-amino-6-(ethylamino)pyrimidin-4-yl)cyclobutyl)-3-fluorobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-(ethylamino)pyrimidin-4-yl)cyclobutyl)-2,3-difluorobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-(ethylamino)pyrimidin-4-yl)cyclobutyl)-2,5-difluorobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-3-fluorobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-2-fluoropyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-5,6-dimethylpyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)pyridine-2-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-3-cyanobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-3-fluoro-4-methylbenzenesulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-1 -methyl-1 H-pyrazole-4-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-3-methylbenzenesulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-3,5-dichlorobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)benzenesulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-5-fluoro-2-methylbenzenesulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-3-chlorobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-3-(trifluoromethoxy)benzenesulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-3-fluoro-4-methoxybenzenesulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-3-methoxybenzenesulfonamide; N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)pyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-2,3-difluorobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-2-chlorothiazole-5-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-3,4-difluorobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-6-methylpyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-2,6-difluoropyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-4,6-dimethylpyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-2-bromo-4-methylthiazole-5-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)thiazole-5-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-2-ethylthiazole-5-sulfonamide;
N-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-2-methylthiazole-5-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-2-cyclopropylthiazole-5-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-6-chloropyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)thiophene-2-sulfonamide;
N-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-3,5-dimethylisoxazole-4-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-6-chloro-2-methylpyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-6-fluoropyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-2-chloro-5-methylpyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-2-chloro-6-methoxypyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-6-chloro-4-methylpyridine-3-sulfonamide;
2-amino-N-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)pyrimidine-5-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-6-methoxypyridine-3-sulfonamide;
N/-(frans-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-2-chlorothiazole-5-sulfonamide;
N-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-2-methyloxazole-5-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)pyridine-4-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-2-chloropyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-5-methyl-1 ,3,4-thiadiazole-2-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-2-methylpyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-5-chloropyridine-3-sulfonamide;
N-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-5-chloro-2-methoxypyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-2-chloro-6-methylpyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-5-methyl-6-(trifluoromethyl)pyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-6-(dimethylamino)pyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-2-chloro-4-methylthiazole-5-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-6-(trifluoromethyl)pyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)thiazole-4-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-4-methylpyridine-3-sulfonamide;
N-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-2,5-difluorobenzenesulfonamide; N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-2-fluoro-5-methylpyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-2-methoxythiazole-5-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-4-chloropyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-4-methylthiazole-2-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-3-methylisoxazole-4-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-6-fluoro-5-methylpyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-2,4-dimethylthiazole-5-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)pyrazine-2-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-5-fluoropyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)pyrimidine-5-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-1-methyl-1 H-1 ,2,3-triazole-4-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-2-(1,1-difluoroethyl)thiazole-5-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-2-chlorothiazole-4-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-5-fluorothiophene-2-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-1 ,5-dimethyl-1 H-pyrazole-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-3-methylisothiazole-5-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-5-(difluoromethyl)thiophene-3-sulfonamide;
N-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-5-methylthiophene-2-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-2-methyl-2/-/-1 ,2,3-triazole-4-sulfonamide;
N-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-5-methoxythiophene-2-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-6-methylpyridazine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-4-methylthiophene-2-sulfonamide;
N-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-5-methylthiophene-3-sulfonamide;
N-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-5-chlorothiophene-2-sulfonamide;
N-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-5-cyclopropylthiophene-2-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-3-methylthiophene-2-sulfonamide;
N-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-5-bromothiophene-2-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-2,6-dichloropyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-6-chloro-5-methylpyridine-3-sulfonamide;
N-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-5-cyanopyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-6-cyanopyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-6-(difluoromethyl)pyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-6-chloro-5-fluoropyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-5-methylpyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-5-fluoro-6-methylpyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-5-chloro-6-fluoropyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-5,6-difluoropyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-2-fluoro-6-methylpyridine-3-sulfonamide; N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-6-fluoro-2-methylpyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-2-(difluoromethyl)pyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-5-chloro-6-methylpyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-6-ethylpyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-6-cyclopropylpyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-5-cyclopropylpyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-2-chloro-6-fluoropyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-2-chloro-5,6-dimethylpyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-5-(difluoromethyl)pyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-5-ethylpyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-2,6-dimethylpyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-5-chloro-2-methylpyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-5-chloro-2-fluoropyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-5-fluoro-2-methylpyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-2,5-dimethylpyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-2-fluoro-5,6-dimethylpyridine-3-sulfonamide;
N-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-5,6-dichloropyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-6-(methylamino)pyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-2-bromopyridine-3-sulfonamide;
N-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-2,5,6-trimethylpyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(cyclopropylamino)pyrimidin-4-yl)cyclobutyl)-3-fluorobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-(cyclopropylamino)pyrimidin-4-yl)cyclobutyl)-2-fluoropyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(cyclopropylamino)pyrimidin-4-yl)cyclobutyl)-2-methylthiazole-4-sulfonamide;
N/-(c/s-3-(2-amino-6-(cyclopropylamino)pyrimidin-4-yl)cyclobutyl)-2-methylthiazole-5-sulfonamide;
N/-(c/s-3-(2-amino-6-(cyclopropylamino)pyrimidin-4-yl)cyclobutyl)pyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(cyclopropylamino)pyrimidin-4-yl)cyclobutyl)-2-chloropyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(cyclopropylamino)pyrimidin-4-yl)cyclobutyl)-2-methylpyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(cyclopropylamino)pyrimidin-4-yl)cyclobutyl)-5-fluoropyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(cyclopropylamino)pyrimidin-4-yl)cyclobutyl)-5-chloropyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(cyclopropylamino)pyrimidin-4-yl)cyclobutyl)-6-fluoropyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(cyclopropylamino)pyrimidin-4-yl)cyclobutyl)-6-chloropyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(cyclopropylamino)pyrimidin-4-yl)cyclobutyl)-6-methylpyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(cyclopropylamino)pyrimidin-4-yl)cyclobutyl)-2-fluoro-6-methylpyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(cyclopropylamino)pyrimidin-4-yl)cyclobutyl)-2,6-dimethylpyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(cyclopropylamino)pyrimidin-4-yl)cyclobutyl)-5,6-dimethylpyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(((R)-1 , 1 , 1-trifluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-2-fluoropyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(((S)-1 , 1 , 1 -trif I uoropropan-2-y I) am i no) pyri mid i n-4-y l)cyclobu tyl)-2-f I uoropy ridi ne-3-su Ifon amide; N/-(c/s-3-(2-amino-6-(((R)-1,1 ,1-trifluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-5,6-dimethylpyridine-3- sulfonamide;
N/-(c/s-3-(2-amino-6-(((S)-1,1 ,1-trifluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-5,6-dimethylpyridine-3- sulfonamide;
N/-(c/s-3-(2-amino-6-(((R)-1,1 ,1-trifluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-3-fluorobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-(((S)-1,1 ,1-trifluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-3-fluorobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-(propylamino)pyrimidin-4-yl)cyclobutyl)-3-fluorobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-(propylamino)pyrimidin-4-yl)cyclobutyl)-2,3-difluorobenzenesulfonamide;
N-(c/s-3-(2-amino-6-(propylamino)pyrimidin-4-yl)cyclobutyl)-2,5-difluorobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-(tert-butylamino)pyrimidin-4-yl)cyclobutyl)-3-fluorobenzenesulfonamide;
N-(c/s-3-(2-amino-6-(tert-butylamino)pyrimidin-4-yl)cyclobutyl)-5,6-dimethylpyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(cyclobutylamino)pyrimidin-4-yl)cyclobutyl)-3-fluorobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-((cyclobutylmethyl)amino)pyrimidin-4-yl)cyclobutyl)-3-fluorobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-(cyclobutylamino)pyrimidin-4-yl)cyclobutyl)-2,3-difluorobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-((cyclobutylmethyl)amino)pyrimidin-4-yl)cyclobutyl)-2,3-difluorobenzenesulfonamide;
N-(c/s-3-(2-amino-6-(cyclobutylamino)pyrimidin-4-yl)cyclobutyl)-2,5-difluorobenzenesulfonamide;
N-(c/s-3-(2-amino-6-((cyclobutylmethyl)amino)pyrimidin-4-yl)cyclobutyl)-2,5-difluorobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-(((S)-1-hydroxypropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-3-fluorobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-((1-hydroxy-2-methylpropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-3-fluorobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-(sec-butylamino)pyrimidin-4-yl)cyclobutyl)-3-fluorobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-((2,2-difluoroethyl)amino)pyrimidin-4-yl)cyclobutyl)-3-fluorobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-((2,2,2-trifluoroethyl)amino)pyrimidin-4-yl)cyclobutyl)-3-fluorobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-((2-fluoroethyl)amino)pyrimidin-4-yl)cyclobutyl)-3-fluorobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-((1-fluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-3-fluorobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-((2-methoxyethyl)amino)pyrimidin-4-yl)cyclobutyl)-2-fluoropyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(((S)-1-hydroxypropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-2-fluoropyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(((S)-1-methoxypropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-2-fluoropyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-((1-methoxy-2-methylpropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-2-fluoropyridine-3- sulfonamide;
N/-(c/s-3-(2-amino-6-(((1-fluorocyclopropyl)methyl)amino)pyrimidin-4-yl)cyclobutyl)-3-fluorobenzenesulfonamide;
N-(c/s-3-(2-amino-6-(((1-fluorocyclopropyl)methyl)amino)pyrimidin-4-yl)cyclobutyl)-5,6-dimethylpyridine-3- sulfonamide;
N/-(c/s-3-(2-amino-6-((1,3-difluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-3-fluorobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-((1,1-difluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-3-fluorobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-(((R)-1,1-difluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-3-fluorobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-(((S)-1,1-difluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-3-fluorobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-((1 ,1-difluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-5,6-dimethylpyridine-3-sulfonamide; N/-(c/s-3-(2-amino-6-(((R)-1,1-difluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-5,6-dimethylpyridine-3- sulfonamide;
N/-(c/s-3-(2-amino-6-(((S)-1,1-difluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-5,6-dimethylpyridine-3- sulfonamide;
N/-(c/s-3-(2-amino-6-(oxetan-3-ylamino)pyrimidin-4-yl)cyclobutyl)-3-fluorobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-((1 ,1 ,1-trifluoro-2-methylpropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-2-fluoropyridine-3- sulfonamide;
N/-(c/s-3-(2-amino-6-(butylamino)pyrimidin-4-yl)cyclobutyl)-3-fluorobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-(isobutylamino)pyrimidin-4-yl)cyclobutyl)-3-fluorobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-(cyclopentylamino)pyrimidin-4-yl)cyclobutyl)-3-fluorobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-(cyclohexylamino)pyrimidin-4-yl)cyclobutyl)-3-fluorobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-((cyclopropylmethyl)amino)pyrimidin-4-yl)cyclobutyl)-3-fluorobenzenesulfonamide;
N-(c/s-3-(2-amino-6-(ethylamino)pyrimidin-4-yl)cyclobutyl)-5,6-dimethylpyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(ethylamino)pyrimidin-4-yl)cyclobutyl)-2-fluoropyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-4-iodobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-3-iodobenzenesulfonamide;
N-(frans-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-6-fluoro-2-methylpyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(((R)-1,1 ,1-trifluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)pyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(((R)-1,1 ,1-trifluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-6-fluoropyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(((R)-1,1 ,1-trifluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-6-methylpyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(((R)-1,1 ,1-trifluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-6-fluoro-5-methylpyridine-3- sulfonamide;
N/-(c/s-3-(2-amino-6-(((R)-1,1 ,1-trifluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-6-fluoro-2-methylpyridine-3- sulfonamide;
N/-(c/s-3-(2-amino-6-(((R)-1,1 ,1-trifluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-5-fluoro-2-methylpyridine-3- sulfonamide;
N/-(c/s-3-(2-amino-6-(((R)-1,1 ,1-trifluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-2-methylpyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(((R)-1,1 ,1-trifluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-2,6-dimethylpyridine-3- sulfonamide;
N/-(c/s-3-(2-amino-6-(((R)-1,1 ,1-trifluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-2-fluoro-6-methylpyridine-3- sulfonamide;
N/-(c/s-3-(2-amino-6-(((R)-1,1 ,1-trifluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-5-fluoro-6-methylpyridine-3- sulfonamide;
N/-(c/s-3-(2-amino-6-(((R)-1,1 ,1-trifluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-3-chloro-4- iodobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-(((R)-1,1 ,1-trifluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-3-fluoro-4- iodobenzenesulfonamide; N/-(c/s-3-(2-amino-6-(((R)-1,1 ,1-trifluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-2-fluoro-4- iodobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-(((R)-1,1 ,1-trifluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-4-iodobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-(((R)-1,1 ,1-trifluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-3-cyano-4- iodobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-(((R)-1,1 ,1-trifluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-4-iodo-3- methylbenzenesulfonamide;
N-(c/s-3-(2-amino-6-(propylamino)pyrimidin-4-yl)cyclobutyl)-5,6-dimethylpyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(propylamino)pyrimidin-4-yl)cyclobutyl)-2-fluoropyridine-3-sulfonamide;
N-(c/s-3-(2-amino-6-(fert-butylamino)pyrimidin-4-yl)cyclobutyl)-2-methylpyridine-3-sulfonamide;
N-(c/s-3-(2-amino-6-(fert-butylamino)pyrimidin-4-yl)cyclobutyl)-6-methylpyridine-3-sulfonamide;
N-(c/s-3-(2-amino-6-(fert-butylamino)pyrimidin-4-yl)cyclobutyl)-2-fluoropyridine-3-sulfonamide;
N-(c/s-3-(2-amino-6-(fert-butylamino)pyrimidin-4-yl)cyclobutyl)-2,6-dimethylpyridine-3-sulfonamide;
N-(c/s-3-(2-amino-6-(fert-butylamino)pyrimidin-4-yl)cyclobutyl)-2-fluoro-6-methylpyridine-3-sulfonamide;
N-(c/s-3-(2-amino-6-(((R)-sec-butyl)amino)pyrimidin-4-yl)cyclobutyl)-5,6-dimethylpyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(((R)-sec-butyl)amino)pyrimidin-4-yl)cyclobutyl)-2-fluoropyridine-3-sulfonamide;
N-(c/s-3-(2-amino-6-(((S)-sec-butyl)amino)pyrimidin-4-yl)cyclobutyl)-5,6-dimethylpyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(((S)-sec-butyl)amino)pyrimidin-4-yl)cyclobutyl)-2-fluoropyridine-3-sulfonamide; and
N-(c/s-3-(2-amino-6-(ethylamino)-5-fluoropyrimidin-4-yl)cyclobutyl)-3-fluorobenzenesulfonamide.
32) Another embodiment relates to compounds according to embodiment 1), which are selected from the following compounds
N-(3-(2-amino-6-(methylamino)pyrimidin-4-yl)cyclobutyl)-2,4-difluorobenzenesulfonamide (i.e. CAS RN 2068732-71- 6);
N-(3-(2-amino-6-(methylamino)pyrimidin-4-yl)cyclobutyl)-2,5-difluorobenzenesulfonamide (i.e. CAS RN 2068712-87- 6);
N-(3-(2-amino-6-(methylamino)pyrimidin-4-yl)cyclobutyl)-4-methoxy-3-methylbenzenesulfonamide (i.e. CAS RN 2068699-30-7);
N/-(c/s-3-(2-amino-6-(methylamino)pyrimidin-4-yl)cyclobutyl)-2,4-difluorobenzenesulfonamide (i.e. CAS RN 1783040- 48-1);
N-(c/s-3-(2-amino-6-(methylamino)pyrimidin-4-yl)cyclobutyl)-2,5-difluorobenzenesulfonamide (i.e. CAS RN 1783125-
47-2); and
N/-(c/s-3-(2-amino-6-(methylamino)pyrimidin-4-yl)cyclobutyl)-4-methoxy-3-methylbenzenesulfonamide (i.e. CAS RN 1783136-48-0).
33) Another embodiment relates to compounds according to embodiment 1), which are selected from the following compounds
N/-(c/s-3-(2-amino-6-(((R)-1,1 ,1-trifluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)pyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(((R)-1,1 ,1-trifluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-6-methylpyridine-3-sulfonamide; N/-(c/s-3-(2-amino-6-(((R)-1,1,1-trifluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-2-methylpyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-5,6-dimethylpyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(((R)-1,1,1-trifluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-2-fluoro-6-methylpyridine-3- sulfonamide; and
N/-(c/s-3-(2-amino-6-(((R)-1,1 ,1-trifluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-5-fluoro-6-methylpyridine-3- sulfonamide.
Based on the dependencies of the different embodiments 1) to 30) as disclosed hereinabove, the following embodiments are thus possible and intended, and herewith specifically disclosed in individualized form:
2+1, 3+1, 3+2+1, 4+1, 4+2+1, 15+1, 15+2+1, 16+1, 16+2+1, 17+1, 17+2+1, 17+3+1, 17+3+2+1, 17+4+1, 17+4+2+1, 18+1, 18+2+1, 18+3+1, 18+3+2+1, 18+4+1, 18+4+2+1, 19+1, 19+2+1, 19+3+1, 19+3+2+1, 19+4+1, 19+4+2+1, 20+1, 20+2+1, 20+3+1, 20+3+2+1, 20+4+1, 20+4+2+1, 20+15+1, 20+15+2+1, 20+16+1, 20+16+2+1, 20+17+1, 20+17+2+1, 20+17+3+1, 20+17+3+2+1, 20+17+4+1, 20+17+4+2+1, 20+18+1, 20+18+2+1, 20+18+3+1, 20+18+3+2+1, 20+18+4+1, 20+18+4+2+1, 21+1, 21+2+1, 21+3+1, 21+3+2+1, 21+4+1, 21+4+2+1, 22+15+1, 22+15+2+1, 22+16+1, 22+16+2+1, 22+17+1, 22+17+2+1, 22+17+3+1, 22+17+3+2+1, 22+17+4+1, 22+17+4+2+1, 22+18+1, 22+18+2+1, 22+18+3+1, 22+18+3+2+1, 22+18+4+1, 22+18+4+2+1, 22+19+1, 22+19+2+1, 22+19+3+1, 22+19+3+2+1, 22+19+4+1, 22+19+4+2+1, 22+20+1, 22+20+2+1, 22+20+3+1, 22+20+3+2+1, 22+20+4+1, 22+20+4+2+1, 22+20+15+1, 22+20+15+2+1, 22+20+16+1, 22+20+16+2+1, 22+20+17+1, 22+20+17+2+1, 22+20+17+3+1, 22+20+17+3+2+1, 22+20+17+4+1, 22+20+17+4+2+1, 22+20+18+1, 22+20+18+2+1, 22+20+18+3+1, 22+20+18+3+2+1, 22+20+18+4+1, 22+20+18+4+2+1, 22+21+1, 22+21+2+1, 22+21+3+1, 22+21+3+2+1, 22+21+4+1, 22+21+4+2+1, 23+15+1, 23+15+2+1, 23+16+1, 23+16+2+1, 23+17+1, 23+17+2+1, 23+17+3+1, 23+17+3+2+1, 23+17+4+1, 23+17+4+2+1, 23+18+1, 23+18+2+1, 23+18+3+1, 23+18+3+2+1, 23+18+4+1, 23+18+4+2+1, 23+19+1, 23+19+2+1, 23+19+3+1, 23+19+3+2+1, 23+19+4+1, 23+19+4+2+1, 23+20+1, 23+20+2+1, 23+20+3+1, 23+20+3+2+1, 23+20+4+1, 23+20+4+2+1, 23+20+15+1, 23+20+15+2+1, 23+20+16+1, 23+20+16+2+1, 23+20+17+1, 23+20+17+2+1, 23+20+17+3+1, 23+20+17+3+2+1, 23+20+17+4+1, 23+20+17+4+2+1, 23+20+18+1, 23+20+18+2+1, 23+20+18+3+1, 23+20+18+3+2+1, 23+20+18+4+1, 23+20+18+4+2+1, 23+21+1, 23+21+2+1, 23+21+3+1, 23+21+3+2+1, 23+21+4+1, 23+21+4+2+1, 24+15+1, 24+15+2+1, 24+16+1, 24+16+2+1, 24+17+1, 24+17+2+1, 24+17+3+1, 24+17+3+2+1, 24+17+4+1, 24+17+4+2+1, 24+18+1, 24+18+2+1, 24+18+3+1, 24+18+3+2+1, 24+18+4+1, 24+18+4+2+1, 24+19+1, 24+19+2+1, 24+19+3+1, 24+19+3+2+1, 24+19+4+1, 24+19+4+2+1, 24+20+1, 24+20+2+1, 24+20+3+1, 24+20+3+2+1, 24+20+4+1, 24+20+4+2+1, 24+20+15+1, 24+20+15+2+1, 24+20+16+1, 24+20+16+2+1, 24+20+17+1, 24+20+17+2+1, 24+20+17+3+1, 24+20+17+3+2+1, 24+20+17+4+1, 24+20+17+4+2+1, 24+20+18+1, 24+20+18+2+1, 24+20+18+3+1, 24+20+18+3+2+1, 24+20+18+4+1, 24+20+18+4+2+1, 24+21+1, 24+21+2+1, 24+21+3+1, 24+21+3+2+1, 24+21+4+1, or 24+21+4+2+1.
In the list above the numbers refer to the embodiments according to their numbering provided hereinabove whereas “+” indicates the dependency from another embodiment. The different individualized embodiments are separated by commas. In other words, “18+3+2+1,” for example refers to embodiment 18) depending on embodiments), depending on embodiment 2), depending on embodiment 1), i.e. embodiment “18+3+2+1” corresponds to the compounds of Formula (I) according to embodiment 1) further limited by all the features of the embodiments 2), 3), and 18).
34) Another aspect relates to a compound of Formula (I) according to any one of embodiments 1) to 25), which is a radiolabeled compound, wherein • Ar is as defined in embodiments 1) to 25), wherein Ar independently is mono-, di-, or tri-substituted (notably mono-, or di-substituted), wherein one substituent represents a radioactive isotope of fluorine (especially selected from a group consisting of fluorine-18), wherein the rest of the substituents of Ar, if any, independently is/are as defined in embodiments 1) to 25); R1 is as defined in embodiments 1) to 25); and R2 is as defined in any one of embodiments 1) to 25);
• Ar is as defined in embodiments 1) to 25), wherein Ar independently is mono-, di-, or tri-substituted (notably mono-, or di-substituted), wherein one substituent represents a radioactive isotope of iodine (especially selected from iodine-123, iodine-124, iodine-125, or iodine-131), wherein the rest of the substituents of Ar, if any, independently is/are as defined in embodiments 1) to 25); R1 is as defined in embodiments 1) to 25); and R2 is as defined in any one of embodiments 1) to 25); or
• Ar is as defined in embodiments 1) to 25), wherein Ar independently is unsubstituted, mono-, di-, or tri- substituted (notably unsubstituted, mono-, or di-substituted), wherein the substituent independently is/are as defined in embodiment 1) to 25); R1 is as defined in embodiments 1) to 25); and R2 represents a radioactive isotope of fluorine (especially selected from fluorine-18).
The term “radioactive isotope” (also known as “radionuclide”, “radioisotope”, “radioactive label”, or “label”), as used in the context of the present invention, is a radioactive nuclide useful in radiopharmaceutical therapy (RPT) or diagnosis such as medical imaging by positron emission tomography (PET), single-photon emission computed tomography (SPECT), autoradiography including drug or substrate tissue distribution assays, and the like. It is understood that a radiolabeled compound may represent a mixture of unmodified (non-radioactive or “cold”) compound and a compound comprising said radioactive isotope (modified or “hot” compound).
With regard to the radiolabeled compounds, when a substituent of the molecule is designated as representing a radioactive isotope, it is understood that the abundance of said radioactive isotope at that position is substantially greater than the natural abundance of the same radioactive isotope, that is this substituent is substantially enriched of said radioactive isotope allowing for sufficient therapeutic radiopharmaceutical activity or for a detectable signal in PET, SPECT, autoradiography, and the like.
35) One embodiment relates to a compound according to embodiment 34), which is a radiolabeled compound, wherein Ar represents a 6-membered heteroaryl, wherein said 6-membered heteroaryl is selected from pyridin-3-yl, wherein said pyridin-3-yl is mono-, or di-substituted in position(s) 2 and/or 5 and/or 6 with regard to the nitrogen atom of said pyridin-3-yl; wherein one substituent represents fluorine-18 and the other substituent, if present, represents methyl; R1 represents C2-4-alkyl (notably ethyl, n-propyl, isopropyl, tert-butyl, or sec-butyl; notably isopropyl), cyclopropyl, or 2,2,2- trifluoro-1-methyl-ethyl [especially R1 represents isopropyl or 2,2,2-trifluoro-1-methyl-ethyl]; and R2 represents hydrogen.
36) One embodiment relates to compounds of Formula (I) according to embodiment 34), which is a radiolabeled compound, wherein said compound is selected from N-(cis-3-(2-amino-6-(tert-butylamino)pyrimidin-4-yl)cyclobutyl)-2-(fluoro-18F)-6-methylpyridine-3-sulfonamide; N-(cis-3-(2-amino-6-(tert-butylamino)pyrimidin-4-yl)cyclobutyl)-2-(fluoro-18F)-pyridine-3-sulfonamide; N-(cis-3-(2-amino-6-(propylamino)pyrimidin-4-yl)cyclobutyl)-2-(fluoro-18F)-pyridine-3-sulfonamide;
N-(cis-3-(2-amino-6-(((S)-sec-butyl)amino)pyrimidin-4-yl)cyclobutyl)-2-(fluoro-18F)-pyridine-3-sulfonamide;
N-(cis-3-(2-amino-6-(((R)-sec-butyl)amino)pyrimidin-4-yl)cyclobutyl)-2-(fluoro-18F)-pyridine-3-sulfonamide;
N-(cis-3-(2-amino-6-(((R)-1 , 1 , 1-trifluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-2-(fluoro-18F)-6-methylpyridine-3- sulfonamide;
N-(cis-3-(2-amino-6-(((R)-1 , 1 , 1-trifluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-6-(fluoro-18F)-2-methylpyridine-3- sulfonamide;
N-(cis-3-(2-amino-6-(((R)-1 , 1 , 1-trifluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-6-(fluoro-18F)-5-methylpyridine-3- sulfonamide;
N-(cis-3-(2-amino-6-(((R)-1 , 1 , 1-trifluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-6-(fluoro-18F)-pyridine-3- sulfonamide;
N-(cis-3-(2-amino-6-(cyclopropylamino)pyrimidin-4-yl)cyclobutyl)-2-(fluoro-18F)-6-methylpyridine-3-sulfonamide;
N-(cis-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-2-(fluoro-18F)-5,6-dimethylpyridine-3-sulfonamide;
N-(cis-3-(2-amino-6-(((R)-1 , 1 , 1-trifluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-2-(fluoro-18F)-pyridine-3- sulfonamide;
N-(cis-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-6-(fluoro-18F)-2-methylpyridine-3-sulfonamide;
N-(cis-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-2-(fluoro-18F)-6-methylpyridine-3-sulfonamide;
N-(cis-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-6-(fluoro-18F)-5-methylpyridine-3-sulfonamide;
N-(cis-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-2-(fluoro-18F)-5-methylpyridine-3-sulfonamide;
N-(cis-3-(2-amino-6-(cyclopropylamino)pyrimidin-4-yl)cyclobutyl)-2-(fluoro-18F)-pyridine-3-sulfonamide;
N-(cis-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-6-(fluoro-18F)-pyridine-3-sulfonamide;
N-(cis-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-2-(fluoro-18F)-6-fluoropyridine-3-sulfonamide;
N-(cis-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-2-fluoro-6-(fluoro-18F)-pyridine-3-sulfonamide;
N-(cis-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-2-(fluoro-18F)-pyridine-3-sulfonamide;
N-(cis-3-(2-amino-6-(ethylamino)pyrimidin-4-yl)cyclobutyl)-3-(fluoro-18F)-benzenesulfonamide;
N-(cis-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-3-(fluoro-18F)-benzenesulfonamide;
N-(cis-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-3-(fluoro-18F)-4-methoxybenzenesulfonamide;
N-(cis-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-3-(fluoro-18F)-4-fluorobenzenesulfonamide;
N-(cis-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-3-fluoro-4-(fluoro-18F)-benzenesulfonamide;
N-(cis-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-2-(fluoro-18F)-5-fluorobenzenesulfonamide;
N-(cis-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-2-fluoro-5-(fluoro-18F)-benzenesulfonamide;
N-(cis-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-5-(fluoro-18F)-pyridine-3-sulfonamide;
N-(cis-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-5-(fluoro-18F)-thiophene-2-sulfonamide;
N-(cis-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-5-(fluoro-18F)-6-methylpyridine-3-sulfonamide;
N-(cis-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-5-(fluoro-18F)-2-methylpyridine-3-sulfonamide;
N-(cis-3-(2-amino-6-(cyclopropylamino)pyrimidin-4-yl)cyclobutyl)-3-(fluoro-18F)-benzenesulfonamide;
N-(cis-3-(2-amino-6-(cyclopropylamino)pyrimidin-4-yl)cyclobutyl)-5-(fluoro-18F)-pyridine-3-sulfonamide; N-(cis-3-(2-amino-6-(((R)-1 , 1 , 1-trifluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-3-(fluoro-18F)- benzenesulfonamide;
N-(cis-3-(2-amino-6-(((R)-1 , 1 , 1-trifluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-5-(fluoro-18F)-2-methylpyridine-3- sulfonamide;
N-(cis-3-(2-amino-6-(((R)-1 , 1 , 1-trifluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-5-(fluoro-18F)-6-methylpyridine-3- sulfonamide;
N-(cis-3-(2-amino-6-(((R)-1 , 1 , 1-trifluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-3-(fluoro-18F)-4- iodobenzenesulfonamide;
N-(cis-3-(2-amino-6-(((R)-1 , 1 , 1-trifluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-2-(fluoro-18F)-4- iodobenzenesulfonamide;
N-(cis-3-(2-amino-6-(propylamino)pyrimidin-4-yl)cyclobutyl)-3-(fluoro-18F)-benzenesulfonamide;
N-(cis-3-(2-amino-6-(tert-butylamino)pyrimidin-4-yl)cyclobutyl)-3-(fluoro-18F)-benzenesulfonamide;
N-(cis-3-(2-amino-6-(sec-butylamino)pyrimidin-4-yl)cyclobutyl)-3-(fluoro-18F)-benzenesulfonamide;
N-(cis-3-(2-amino-6-((1,1-difluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-3-(fluoro-18F)-benzenesulfonamide;
N-(cis-3-(2-amino-6-(((R)-1 ,1-difluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-3-(fluoro-18F)-benzenesulfonamide;
N-(cis-3-(2-amino-6-(ethylamino)-5-fluoropyrimidin-4-yl)cyclobutyl)-3-(fluoro-18F)-benzenesulfonamide;
N-(cis-3-(2-amino-6-(ethylamino)-5-(fluoro-18F)-pyrimidin-4-yl)cyclobutyl)-3- fluorobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-(((R)-1 , 1 , 1-trifluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-2-(fluoro-18F)-pyridine-3- sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-2-(fluoro-18F)-pyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-6-(fluoro-18F)-5-methylpyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-2-(fluoro-18F)-6-methylpyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-6-(fluoro-18F)-2-methylpyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(((R)-1 , 1 , 1-trifluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-6-(fluoro-18F)-pyridine-3- sulfonamide;
N/-(c/s-3-(2-amino-6-(((R)-1 , 1 , 1-trifluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-6-(fluoro-18F)-5-methylpyridine-3- sulfonamide;
N/-(c/s-3-(2-amino-6-(((R)-1 , 1 , 1-trifluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-6-(fluoro-18F)-2-methylpyridine-3- sulfonamide; and
N/-(c/s-3-(2-amino-6-(((R)-1 , 1 , 1-trifluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-2-(fluoro-18F)-6-methylpyridine-3- sulfonamide.
37) One embodiment relates to compounds of Formula (I) according to embodiment 34), which is a radiolabeled compound, wherein said compound is selected from
N/-(c/s-3-(2-amino-6-(((R)-1 , 1 , 1-trifluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-2-(fluoro-18F)-pyridine-3- sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-2-(fluoro-18F)-pyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-6-(fluoro-18F)-5-methylpyridine-3-sulfonamide; N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-2-(fluoro-18F)-6-methylpyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-6-(fluoro-18F)-2-methylpyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(((R)-1 , 1 , 1-trifluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-6-(fluoro-18F)-pyridine-3- sulfonamide;
N/-(c/s-3-(2-amino-6-(((R)-1 , 1 , 1-trifluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-6-(fluoro-18F)-5-methylpyridine-3- sulfonamide;
N/-(c/s-3-(2-amino-6-(((R)-1 , 1 , 1-trifluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-6-(fluoro-18F)-2-methylpyridine-3- sulfonamide; and
N/-(c/s-3-(2-amino-6-(((R)-1 , 1 , 1-trifluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-2-(fluoro-18F)-6-methylpyridine-3- sulfonamide;
38) Another aspect relates to a pharmaceutical composition comprising a compound of Formula (I) according to any one of embodiments 34) to 37), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
39) Another aspect relates to a compound of Formula (I) according to any one of embodiments 34) to 37), which is a radiolabeled compound, or a pharmaceutically acceptable salt thereof, for use as a medicament.
40) Another aspect relates to a compound of Formula (I) according to embodiment 34), which is a radiolabeled compound, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer by radiopharmaceutical therapy, wherein said compound, or a pharmaceutically acceptable salt thereof, comprise a radioactive isotope of iodine (especially iodine-125 or iodine-131).
41) Another aspect relates to a compound of Formula (I) according to any one of embodiments 34) to 37), which is a radiolabeled compound, or a pharmaceutically acceptable salt thereof, for use in the diagnosis of cancer (e.g. by medical imaging such as positron emission tomography (PET), single-photon emission computed tomography (SPECT), or autoradiography including drug or substrate tissue distribution assays).
42) Another aspect relates to a compound of Formula (I) according to any one of embodiments 34) to 37), which is a radiolabeled compound, or a pharmaceutically acceptable salt thereof, for use in diagnostic imaging of CCR8 receptors in humans, said method comprising:
(a) administering to the human a detectable quantity of a compound according to any one of embodiments 34) to 37), which is a radiolabeled compound, (especially wherein said compound comprises fluorine- 18), or of a pharmaceutically acceptable salt thereof; and
(b) detecting said compound when associated with CCR8 receptors.
A detectable quantity is a quantity of a compound which is required to render the compound detectable in the human body or in a sample as the case may be by the detection method chosen e.g. PET. The amount of compound to be introduced into a patient/sample in order to provide for detection can be determined by those skilled in the art.
The present invention also includes 2H (deuterium) labelled compounds of Formula (I), which compounds are identical to the compounds of Formula (I) except that one or more atoms have each been replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. 2H (deuterium) labelled compounds of Formula (I) and salts thereof are within the scope of the present invention. Substitution of hydrogen with the heavier isotope 2H (deuterium) may lead to greater metabolic stability, resulting e.g. in increased in-vivo half-life and/or reduced dosage requirements, and/or may lead to a modified metabolism pathway, resulting e.g. in an improved safety profile. In one embodiment of the invention, the compounds of Formula (I) are not isotopically labelled, or they are labelled only with one or more deuterium atoms. In a sub-embodiment, the compounds of formula (I) are not isotopically labelled at all. Isotopically labelled compounds of Formula (I) may be prepared in analogy to the methods described hereinafter but using the appropriate isotopic variation of suitable reagents or starting materials.
The invention relates to compounds of the Formula (I) as defined in embodiment 1), or to such compounds further limited by the characteristics of any one of embodiments 2) to 42), under consideration of their respective dependencies; to pharmaceutically acceptable salts thereof; and to the use of such compounds as medicaments especially in the treatment of diseases or disorders where CCR8 receptors are involved as described hereinbelow.
For avoidance of doubt, compounds designated as “cis“ are compounds that may be represented by any one of the following formulas:
Figure imgf000038_0001
Likewise, compounds designated as “trans “are compounds that may be represented by any one of the following formulas:
Figure imgf000038_0002
Where the plural form is used for compounds, salts, pharmaceutical compositions, diseases and the like, this is intended to mean also a single compound, salt, pharmaceutical composition, disease or the like.
Any reference to compounds of Formula (I) according to embodiments 1) to 42) is to be understood as referring also to the salts (and especially the pharmaceutically acceptable salts) of such compounds, as appropriate and expedient. The term "pharmaceutically acceptable salts" refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects. Such salts include inorganic or organic acid and/or base addition salts depending on the presence of basic and/or acidic groups in the subject compound. For reference see for example “Handbook of Pharmaceutical Salts. Properties, Selection and Use.”, P. Heinrich Stahl, Camille G. Wermuth (Eds.), Wiley-VCH, 2008; and “Pharmaceutical Salts and Co-crystals”, Johan Wouters and Luc Quere (Eds.), RSC Publishing, 2012.
Definitions provided herein are intended to apply uniformly to the compounds of Formula (I), as defined in any one of embodiments 1 ) to 42), and, mutatis mutandis, throughout the description and the claims unless an otherwise expressly set out definition provides a broader or narrower definition. It is well understood that a definition or preferred definition of a term defines and may replace the respective term independently of (and in combination with) any definition or preferred definition of any or all other terms as defined herein.
The compounds of Formula (I) may encompass compounds with one or more asymmetric centers, such as one or more asymmetric carbon atoms, which may be present in (R)- as well as (S)-configuration. The compounds of Formula (I) may further encompass compounds with one or more double bonds which are allowed to be present in Z- as well as E-configuration and/or compounds with substituents at a ring system which are allowed to be present, relative to each other, in cis- as well as trans-configuration. The compounds of Formula (I) may thus be present as mixtures of stereoisomers or preferably in stereoisomerically enriched form, especially as essentially pure stereoisomers. Mixtures of stereoisomers may be separated in a manner known to a person skilled in the art.
In case a particular compound (or generic structure) is designated as (R)- or (S)-enantiomer, such designation is to be understood as referring to the respective compound (or generic structure) in enriched, especially essentially pure, enantiomeric form. Likewise, in case a specific asymmetric center in a compound is designated as being in (R)- or (S)- configuration or as being in a certain relative configuration, such designation is to be understood as referring to the compound that is in enriched, especially essentially pure, form with regard to the respective configuration of said asymmetric center. In analogy, cis- or trans-designations are to be understood as referring to the respective stereoisomer in enriched, especially essentially pure, form. Likewise, in case a particular compound (or generic structure) is designated as Z- or E-stereoisomer (or in case a specific double bond in a compound is designated as being in Z- or E-configuration), such designation is to be understood as referring to the respective compound (or generic structure) in enriched, especially essentially pure, stereoisomeric form (or to the compound that is in enriched, especially essentially pure, form with regard to the respective configuration of the double bond).
The term "enriched", when used in the context of stereoisomers, is to be understood in the context of the present invention to mean that the respective stereoisomer is present in a ratio of at least 70:30, especially of at least 90:10 (i.e., in a purity of at least 70% by weight, especially of at least 90% by weight), with regard to the respective other stereoisomer / the entirety of the respective other stereoisomers.
The term “essentially pure”, when used in the context of stereoisomers, is to be understood in the context of the present invention to mean that the respective stereoisomer is present in a purity of at least 95% by weight, especially of at least 99% by weight, with regard to the respective other stereoisomer / the entirety of the respective other stereoisomers.
The compounds of Formula (I) according to embodiments 1) to 37) and their pharmaceutically acceptable salts can be used as medicaments, e.g. in the form of pharmaceutical compositions for enteral (such especially oral) or parenteral administration (subcutaneous, intraperitoneal, intravenous, intradermal, intramuscular, topical, or inhalation). The production of the pharmaceutical compositions can be effected in a manner which will be familiar to any person skilled in the art (see for example Remington, The Science and Practice of Pharmacy, 21st Edition (2005), Part 5, “Pharmaceutical Manufacturing” [published by Lippincott Williams & Wilkins]) by bringing the described compounds of Formula (I), or their pharmaceutically acceptable salts, optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants.
One embodiment of the present invention relates to a pharmaceutical composition comprising a compound of Formula (I) according to any one of embodiments 1) to 37), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier/excipient.
Whenever the word “between” is used to describe a numerical range, it is to be understood that the end points of the indicated range are explicitly included in the range. For example: if a temperature range is described to be between 40 °C and 80 °C, this means that the end points 40 °C and 80 °C are included in the range; or if a variable is defined as being an integer between 1 and 4, this means that the variable is the integer 1 , 2, 3, or 4.
Unless used regarding temperatures, the term “about’ (or alternatively the term “around”) placed before a numerical value “X” refers in the current application to an interval extending from X minus 10% of X to X plus 10% of X, and preferably to an interval extending from X minus 5% of X to X plus 5% of X. In the particular case of temperatures, the term “about” placed before a temperature “Y” refers in the current application to an interval extending from the temperature Y minus 10 °C to Y plus 10 °C, and preferably to an interval extending from Y minus 5 °C to Y plus 5 °C. The compounds of Formula (I) of the present invention may be useful as single therapeutic agents or in combination with one or more therapeutic agents and/or therapies, for the prevention / prophylaxis or treatment of diseases or disorders relating to the CCR8 receptor or its ligands, which are diseases or disorders relating to a dysfunction of the CCR8 receptor, or dysfunction of ligands signaling through the CCR8 (i.e. CCL1, CCL8, CCL16, and/or CCL18, especially CCL1), or dysfunction of CCR8 ligands signaling through their other receptors (i.e. CCL8, CCL16, and/or CCL18).
The compounds of Formula (I) of the present invention may be useful as single therapeutic agents or in combination with one or more therapeutic agents and/or therapies, for the prevention / prophylaxis or treatment of diseases or disorders involving CCR8 and/or CCL1 and/or CCL18 mediated metastasis, chemotaxis, cell adhesion, trans- endothelial migration, cell proliferation and/or survival; especially in regulating the process of metastasis invasion e.g. in melanoma or bladder cancer patients.
The compounds of Formula (I) of the present invention may be useful as single therapeutic agents or in combination with one or more therapeutic agents and/or therapies, for the prevention / prophylaxis or treatment of diseases or disorders, where CCR8 receptors are involved i.e. diseases or disorders ameliorated by modulating, especially by antagonizing CCR8 receptors; wherein such diseases or disorders are defined as cancer.
The term “cancer” as used hereinabove and hereinbelow includes all sorts of cancers such as carcinomas; adenocarcinomas; leukemias; sarcomas; lymphomas; myelomas; metastatic cancers; brain tumors; neuroblastomas; pancreatic cancers; gastro-intestinal cancers; lung cancers; breast cancers; prostate cancers; endometrial cancers; skin cancers; bladder cancers; head and neck cancers; neuroendocrine tumors; ovarian cancers; cervical cancers; oral tumors; nasopharyngeal tumors; thoracic cancers; and virally induced tumors.
The term “cancer” as used hereinabove and hereinbelow notably refers to brain tumors including brain metastases, malignant gliomas, glioblastoma multiforme, medulloblastoma, meningiomas; neuroblastoma; pancreatic cancer including pancreatic adenocarcinoma/pancreatic ductal adenocarcinoma; gastro-intestinal cancers including colon carcinoma, colorectal adenoma, colorectal adenocarcinoma, metastatic colorectal cancer, familial adenomatous polyposis (FAP), gastric cancer, gallbladder cancer, cholangiocarcinoma, hepatocellular carcinoma; gastro- esophageal junction cancer; esophageal cancer; Kaposi sarcoma; leukemias including acute myeloid leukemia, chronic myeloid leukemia, adult T-cell leukemia, acute lymphoblastic leukemia, and chronic lymphocytic leukemia; leukemic phase of lymphoma; lymphomas including Burkitt’s lymphoma, Hodgkin’s lymphoma, MALT lymphoma, and primary intra-ocular B-Cell lymphoma; lung cancer including non-small cell lung cancer; breast cancer including triple negative breast carcinoma; rhabdomyosarcoma; prostate cancer including castrate-resistant prostate cancer; esophageal squamous cancer; (oral) squamous cell carcinoma; endometrial cancer; thyroid carcinoma including papillary thyroid carcinoma; metastatic cancers; lung metastasis; skin cancer including melanoma and metastatic melanoma; bladder cancer including urinary bladder cancer, urothelial cell carcinoma; multiple myelomas; osteosarcoma; head and neck cancer; and renal carcinomas including renal cell carcinoma renal clear cell carcinoma, metastatic renal cell carcinoma, metastatic renal clear cell carcinoma; as well as neuroendocrine tumors; ovarian cancer; cervical cancer; oral tumors; nasopharyngeal tumors; thoracic cancer; choriocarcinoma; Ewing’s sarcoma; and virally induced tumors.
The term “cancer” as used hereinabove and hereinbelow especially refers to oral squamous cell carcinoma; head and neck squamous cell carcinoma; liver cancer including hepatocellular carcinoma; cholangiosarcoma including extrahepatic cholangiosarcoma; gastrointestinal stromal tumors; colorectal cancer; lung cancer including non-small cell lung cancer; bladder cancer; kidney cancer; breast cancer; lymphoma including T cell lymphoma, cutaneous T cell lymphoma, and systemic ALK-negative anaplastic large cell lymphoma; endometrial tumors; Kaposi sarcoma; melanoma; and basal cell carcinoma.
The term “cancer” as used hereinabove and hereinbelow also refers to cancer types infiltrated with intratumoral regulatory T cells (Tregs) expressing CCR8.
The term “cancer” as used hereinabove and hereinbelow particularly refers to gastrointestinal cancer, colorectal cancer, non-small cell lung cancer, lung squamous cell carcinoma, liver cancer, bladder cancer, kidney cancer, breast cancer, melanoma, oral squamous cell carcinoma, Kaposi sarcoma, head and neck squamous cell carcinoma, esophageal squamous cell carcinoma, and pancreatic ductal adenocarcinoma.
The term “cancer” as used hereinabove and hereinbelow also refers to solid tumors such as renal cancer, breast cancer including triple-negative breast cancer, stomach cancer, colorectal cancer, ovarian cancer, head and neck cancer, melanoma, and pancreatic cancer.
The compounds of Formula (I) of the present invention comprising a radioactive isotope may be useful in radiopharmaceutical therapy (RPT) of cancer, wherein cancer is as defined hereinabove. The compounds of Formula (I) of the present invention comprising a radioactive isotope may be useful in the diagnosis e.g. in medical imaging such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) of cancer, wherein cancer is as defined hereinabove.
The compounds of Formula (I) of the present invention may be useful as single therapeutic agents or in combination with one or more further therapeutic agents and/or further therapies, for the prevention / prophylaxis or treatment of diseases or disorders, where CCR8 receptors are involved i.e. diseases or disorders ameliorated by modulating, especially by antagonizing CCR8 receptors; wherein such diseases or disorders are defined as atopic diseases; fibrotic diseases; neuropathic pain; sepsis; septic peritonitis; infections associated with immune suppression including infections resulting from burn injury; chronic obstructive pulmonary disease; organ transplantation including allogeneic kidney transplantation; peritoneal adhesions; pathological bondings of serosal membranes related to surgery or inflammation; and autoimmune encephalomyelitis. Notably, atopic diseases; fibrotic diseases; and neuropathic pain. Especially, fibrotic diseases including fibrosis.
The term “atopic diseases”, as used herein, includes all sorts of type 2 inflammatory diseases and immunoglobulin E (IgE) mediated diseases such as atopic dermatitis, allergic enteritis, allergic asthma (e.g. fungal-allergic asthma), allergic rhinitis, allergic conjunctivitis, IgE-mediated drug allergy, food allergy, insect bites, urticaria, angioedema, and anaphylactic shock. Notably, the term refers to atopic dermatitis, allergic enteritis, allergic asthma and (e.g. fungal- allergic asthma).
The term “fibrotic diseases”, as used herein, includes all sorts of diseases defined by deleterious accumulation of extracellular matrix components such as collagen and fibronectin at sites of inflammation or tissue damage that can lead to permanent scarring and/or organ disfunction. The term “fibrotic diseases” may be referred to “fibrosis”. Said term comprises, among others, liver fibrosis, pulmonary fibrosis, fibrosis associated with lgG4-related disease (e.g. salivary gland fibrosis and sclerosing cholangitis), systemic sclerosis, skin fibrosis including skin fibrosis associated with human chronic graft-versus-host disease, and fibrosis associated with organ transplantation including fibrosis associated with allogeneic kidney transplantation.
The term “pulmonary fibrosis”, as used herein, includes all sorts of fibrotic disorders affecting the lungs, e.g. idiopathic pulmonary fibrosis and pulmonary fibrosis associated with human chronic graft-versus-host disease, and optionally non-idiopathic interstitial pulmonary fibrosis/interstitial lung disease.
The term “liver fibrosis”, as used herein, includes all sorts of fibrotic disorders affecting the liver, including those related to chronic viral liver infections such as Hepatitis C and Hepatitis B, chronic alcohol use, nonalcoholic steatohepatitis, chronic cholestatic disorders such as primary biliary cirrhosis and primary sclerosis cholangitis, and autoimmune hepatitis.
The term “neuropathic pain”, as used herein, refers to both central and peripheral neuropathic pain and includes all sorts of conditions affecting the somatosensory system that result in painful sensations such as dysesthesia and allodynia, including those caused by spinal cord injury, multiple sclerosis, all types of diabetes mellitus, cancer and cancer treatments as defined herein, metabolic disorders, herpes zoster infection, human immunodeficiency virus infection, nutritional deficiencies, exposure to toxins, autoimmune disorders, and physical trauma. The compounds of Formula (I), or a pharmaceutically acceptable salt thereof, may be useful for the treatment and/or prevention of neuropathic pain, wherein said compounds or a pharmaceutically acceptable salt thereof are used as a single therapeutic agent or in combination with one or more opioid and/or one or more non-opioid analgesics.
The compounds of Formula (I), or a pharmaceutically acceptable salt thereof, may be useful for potentiating the analgesic effects of opioids such as methadone, oxycodone, hydrocodone, and the like.
The compounds of Formula (I), or a pharmaceutically acceptable salt thereof, may be useful in the treatment and/or prevention of fibrotic diseases (especially liver fibrosis), wherein said compounds or a pharmaceutically acceptable salt thereof are used as a single therapeutic agent or in combination with one or more further treatment or therapy, wherein said further treatment or therapy is aimed at the treatment and/or prevention of the underlying cause of the fibrotic disease (especially liver fibrosis).
When used for the prevention / prophylaxis or treatment of a cancer, such use includes use of the present compounds as single therapeutic agents and their use in combination with one or more chemotherapy agents and / or radiotherapy and / or targeted therapy (especially in combination with targeted therapy).
The terms "radiotherapy" or "radiation therapy" or "radiation oncology", refer to the medical use of ionizing radiation in the prevention (adjuvant therapy) and / or treatment of cancer, including external and internal radiotherapy.
The term "targeted therapy" refers to the prevention / prophylaxis (adjuvant therapy) and / or treatment of cancer with one or more anti-neoplastic agents such as small molecules or antibodies which act on specific types of cancer cells or stromal cells. Some targeted therapies block the action of certain enzymes, proteins, or other molecules involved in the growth and spread of cancer cells. Other types of targeted therapies help the immune system kill cancer cells (immunotherapies); or deliver toxic substances directly to cancer cells and kill them. An example of a targeted therapy which is in particular suitable to be combined with the compounds of the present invention is immunotherapy, especially immunotherapy targeting the programmed cell death receptor 1 (PD-1 receptor) or its ligand PD-L1 (Feig C et al, PNAS 2013).
Immunotherapy further refers to (i) an agonist of a stimulatory (including a co-stimulatory) receptor or (ii) an antagonist of an inhibitory (including a co- inhibitory) signal on T cells, both of which result in amplifying antigen-specific T cell responses (often referred to as immune checkpoint regulators). Certain of the stimulatory and inhibitory molecules are members of the immunoglobulin super family (IgSF). One important family of membrane-bound ligands that bind to co-stimulatory or co-inhibitory receptors is the B7 family, which includes B7-1 , B7-2, B7-HI (PD-LI), B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), and B7-H6. Another family of membrane bound ligands that bind to co- stimulatory or co-inhibitory receptors is the TNF family of molecules that bind to cognate TNF receptor family members, which includes CD40 and CD40L, OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-IBBL, CD137 (4-IBB), TRAIL/Apo2-L, TRAILR1/DR4, TRAILR2/DR5, TRAILR3, TRAILR4, OPG, RANK, RANKL, TWEAKR/Fnl4, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LTpR, LIGHT, DcR3, HVEM, VEGi/TLIA, TRAMP/DR3, EDAR, EDAI, XEDAR, EDA2, TNFRI, Lymphotoxin a/TNFp, TNFR2, TNFa, LTPR, Lymphotoxin a 1p2, FAS, FASL, RELT, DR6, TROY, NGFR.
When used in combination with the compounds of Formula (I), the term "targeted therapy" especially refers to agents such as: a) Epidermal growth factor receptor (EGFR) inhibitors or blocking antibodies (such as Gefitinib, Erlotinib, Afatinib, Icotinib, Lapatinib, Panitumumab, Neratinib, Osimertinib, Dacomitinib, Almonertinib, Tucatinib, Zalutumumab, Nimotuzumab, Matuzumab, Cetuximab), as well as trastuzumab (HERCEPTIN); b) RAS/RAF/MEK pathway inhibitors (such as Vemurafenib, Sorafenib, Dabrafenib,GDC-0879, PLX-4720, Encorafenib (LGX818), RG7304, Trametinib (GSK1120212), Cobimetinib (GDC-0973/XL518), Binimetinib (MEK162, ARRY-162), Selumetinib (AZD6244), Sotorasib, Adagrasib, as well as various mutant KRAS- specific, pan RAS, SOS1, and SHP2 inhibitors (Punekar et al., Nature Rev Clin Oncology, 19(10):637-655)); c) Janus kinase (JAK) inhibitors (such as Ruxolitinib, Itacitinib, Momelotinib, Fedratinib); d) Aromatase inhibitors (such as Exemestane, Letrozole, Anastrozole, Vorozole, Formestane, Fadrozole); e) Signal transduction inhibitors (STI) that selectively inhibit one or more vital steps in signaling pathways in the normal function of cancer cells, thereby leading to apoptosis, especially (i) bcr/abl kinase inhibitors (such as STI 571 (GLEEVEC®), Dasatinib, Ponatinib, Imatinib, Nilotinib, Radotinib); (ii) inhibitors of Akt family kinases or the Akt pathway (such as Sirolimus, Everolimus, Temsirolimus); (iii) cell cycle kinase inhibitors (such as Palbociclib, Ribociclib, Abemaciclib); (iv) phosphatidyl inositol kinase inhibitors (such as Copanlisib, Duvelisib, Idelalisib, Leniolisib, Alpelisib, Umbralisib); (v) ALK inhibitors (such as Crizotinib, Ceritinib, Alectinib, Lorlatinib); (vi) BTK inhibitors (such as Ibrutinib, Acalabrutinib, Zanubrutinib); (vii) IDH inhibitors (such as Enasidenib, Ivosidenib); (viii) RET inhibitors (such as Selpercatinib); (ix) BCL-2 inhibitors (such as Venetoclax); or (x) c-MET inhibitors (such as Capmatinib, Tepotinib); f) Angiogenesis inhibitors, especially VEGF signalling inhibitors (such as Bevacuzimab (Avastin), Ramucirumab, Sorafenib, Axitinib); g) Poly-ADP-Ribose-Polymerase (PARP) inhibitors (such as Olaparib, Niraparib, Rucaparib, Talazoparib); h) Proteasome inhibitors (such as Bortezomib, Carfilzomib, Ixazomib); i) HDAC inhibitors (such as Vorinostat, Romidepsin, Belinostat, Panobinostat, Tucidinostat); j) EZH2 inhibitors (such as T azemetostat); k) Immune Checkpoint inhibitors (for example: anti-PD1 antibodies such as Pembrolizumab (Lambrolizumab, MK-3475), Nivolumab, Pidilizumab (CT-011), AMP-514/MED10680, PDR001, SHR-1210, REGN2810, BGBA317, PF-06801591, MGA-012, TSR042, JS-001 , BCD100, IBI-308, BI-754091, Toripalimab; fusion proteins targeting PD-1 such as AMP-224; small molecule anti-PD1 agents such as compounds disclosed in WO2015/033299, WO2015/044900 and WO2015/034820; anti-PD1 L antibodies, such as BMS-936559, Atezolizumab (MPDL3280A, RG7446), Avelumab (MSB0010718C), Durvalumab (MEDI4736); anti-PDL2 antibodies, such as AMP224; anti-CTLA-4 antibodies, such as Ipilimumab, Tremelmumab; anti-Lymphocyte- activation gene 3 (LAG-3) antibodies such as Relatlimab (BMS-986016), IMP701 , IMP731 , MK-4280, ImmuFact IMP321 ; anti-T cell immunoglobulin mucin-3 (TIM-3) antibodies, such as MBG453, TSR-022; anti- T cell immunoreceptor with Ig and ITIM domains (TIGIT) antibodies, such as RG6058 (anti-TIGIT, MTIG7192A); anti-Killer-cell immunoglobulin-like receptors (KIR) antibodies such as Lirilumab (I PH2102/BMS-986015); antagonists of Galectins (such as of Galectin-1, Galectin-9); anti-B and T lymphocyte attenuator (BTLA) antibodies such as JS004; l) Vaccination approaches (such as dendritic cell vaccination, DNA, RNA, peptide or protein vaccination (for example with gp100 peptide or MAGE-A3 peptide)); m) Re-introduction of patient derived or allogenic (non-self) cancer cells genetically modified to secrete immunomodulatory factors such as granulocyte monocyte colony stimulating factor (GMCSF), gene- transfected tumor cell vaccine (GVAX) or Fms-related tyrosine kinase 3 (Flt-3) ligand gene-transfected tumor cell vaccine (FVAX),or Toll like receptor enhanced GM-CSF tumor based vaccine (TEGVAX); n) T-cell based adoptive immunotherapies, including chimeric antigen receptor (CAR) engineered T-cells (such as CTLOW); o) Cytokine or immunocytokine based therapy (such as Interferon alpha, interferon beta, interferon gamma, interleukin 2, interleukin 6, interleukin 10, interleukin 15, TGF-£); p) Toll-like receptor (TLR) agonists (such as resiquimod, imiquimod, glucopyranosyl lipid A, CpG oligodesoxynucleotides); q) Thalidomide analogues (such as Lenalidomide, Pomalidomide); r) lndoleamin-2,3-Dioxgenase (IDO) and/or Tryptophane-2,3-Dioxygenase (TDO) inhibitors (such as RG6078 / NLG919 / GDC-0919; Indoximod / 1 MT (1 -methyltryptophan), INCB024360 / Epacadostat, PF-06840003 (EOS200271), F001287); s) Activators of T-cell co-stimulatory receptors (for example anti-CD 137/4-1 BB antibodies, such as BMS-663513 / Urelumab, Utomilumab (PF-05082566), and second generation 4-1 BB agonistic drugs (Claus et al., MABS 2023, VOL. 15(1), 2167189)); anti-OX40/CD134 (Tumor necrosis factor receptor superfamily, member 4) antibodies (including agonist antibodies) and fusion proteins, such as RG7888 (MOXR0916), 9B12, MEDI6469, GSK3174998, MEDI6383, MEDI0562), anti-OX40-Ligand/CD252; anti-glucocorticoid-induced TNFR family related gene (GITR) antibodies and fusion proteins (such as TRX518, MEDI1873, MK-4166, BMS-986156, BMS-986153); anti-CD40 (TNF receptor superfamily member 5) antibodies (such as Dacetuzumab (SGN-40), HCD122, CP-870,893, RG7876, ADC-1013, APX005M, SEA-CD40); anti-CD40- Ligand antibodies (such as BG9588); anti-CD27 antibodies (such as Varlilumab); anti-CD28 antibodies; anti- ICOS antibodies; t) Molecules binding a tumor specific antigen as well as a T-cell surface marker such as bispecific antibodies (for example RG7802 targeting CEA and CD3) or antibody fragments; antibody mimetic proteins such as designed ankyrin repeat proteins (DARPINS), bispecific T-cell engager (BITE, for example Blinatumomab, Amivantanab, Tebentafusp, and more in clinical development (Wei et al., Frontiers in Immunology, 2022,13:1035276)); u) Antibodies or small molecular weight inhibitors targeting colony-stimulating factor-1 receptor (CSF-1 R) (for example Emactuzumab (RG7155), Cabiralizumab (FPA-008), PLX3397); v) Agents targeting immune cell check points on natural killer cells such as antibodies against Killer-cell immunoglobulin-like receptors (KIR) for example Lirilumab (IPH2102/BMS-986015); w) Agents targeting the Adenosine receptors or the ectonucleases CD39 and CD73 that convert ATP to Adenosine, such as MEDI9447 (anti-CD73 antibody), PBF-509, CPI-444 (Adenosine A2a receptor antagonist); x) Antagonists of chemokine receptors including CCR2 or CCR4; y) Agents that deplete or inhibit T regulatory cells (for example anti-CD25 monoclonal antibodies (such as Daclizumab) or by ex vivo anti-CD25 bead depletion) or that reverse/prevent T cell anergy or exhaustion z) Antibody or biologic-based disease-modifying antirheumatic drugs (DMARDS) useful for the treatment of autoimmune diseases such as antibodies (including modified antibodies); biologies targeting CD20 (for example Rituximab), CD3 (for example Teplizumab), TNF alpha (for example Etanercept), IFN alpha (for example Anifrolumab), CD80 or CD86 (for example Abatacept) , VLA-4 (for example Natalizumab), IL-1 (for example Anakinra), IL-6 (for example Sarilumab), IL-17 (for example Secukinumab), IL-23 (for example Guselkumab), or IL12/23 (for example Ustekinumab); small molecule DMARDS such as methotrexate, leflunomide, hydroxychloroquine, sulfasalazine, or Janus kinase (JAK) inhibitors; bb) Glucocorticoids; cc) Antibody-drug conjugates, such as Mirvetuximab soravtansine, Tisotumab vedotin-tftv, Loncastuximab tesirine-lpyl, Belantamab mafodotin-blmf, Sacituzumab govitecan, Trastuzumab deruxtecan, Enfortumab vedotin, Polatuzumab vedotin-piiq, Moxetumomab pasudotox, Inotuzumab ozogamicin, Trastuzumab emtansine, Brentuximab vedotin, or Gemtuzumab ozogamicin; dd) Radioligand therapies such as 177Lu-Lutathera or 177Lu-PSMA-617.
The term "chemotherapy" refers to the treatment of cancer with one or more cytotoxic anti-neoplastic agents ("cytotoxic chemotherapy agents"). Chemotherapy is often used in conjunction with other cancer treatments, such as radiation therapy or surgery. The term especially refers to conventional chemotherapeutic agents which act by killing cells that divide rapidly, one of the main properties of most cancer cells. Chemotherapy may use one drug at a time (single- agent chemotherapy) or several drugs at once (combination chemotherapy or polychemotherapy). Chemotherapy using drugs that convert to cytotoxic activity only upon light exposure is called photochemotherapy or photodynamic therapy.
The term “cytotoxic chemotherapy agent” or “chemotherapy agent” as used herein refers to an active anti-neoplastic agent inducing apoptosis or necrotic cell death. When used in combination with the compounds of Formula (I), the term especially refers to conventional cytotoxic chemotherapy agents such as: a) alkylating agents (for example mechlorethamine, chlorambucil, cyclophosphamide, ifosfamide, streptozocin, carmustine, lomustine, melphalan, busulfan, dacarbazine, temozolomide, thiotepa or altretamine; in particular temozolomide); b) platinum drugs (for example cisplatin, carboplatin or oxaliplatin); c) antimetabolite drugs (for example 5-fluorouracil, capecitabine, 6-mercaptopurine, methotrexate, gemcitabine, cytarabine, fludarabine or pemetrexed); d) anti-tumor antibiotics (for example daunorubicin, doxorubicin, epirubicin, idarubicin, actinomycin-D, bleomycin, mitomycin-C or mitoxantrone); e) mitotic inhibitors (for example paclitaxel, docetaxel, ixabepilone, vinblastine, vincristine, vinorelbine, vindesine or estramustine); or f) topoisomerase inhibitors (for example etoposide, teniposide, topotecan, irinotecan, diflomotecan or elomotecan). When used in combination with the compounds of Formula (I) of the present invention, preferred cytotoxic chemotherapy agents are the above-mentioned alkylating agents (notably mechlorethamine, chlorambucil, cyclophosphamide, ifosfamide, streptozocin, carmustine, lomustine, melphalan, busulfan, dacarbazine, 3-methyl- (triazen-1-yl)imidazole-4-carboxamide (MTIC) and prodrugs thereof such as especially temozolomide, thiotepa, altretamine; or pharmaceutically acceptable salts of these compounds; in particular temozolomide); and mitotic inhibitors (notably paclitaxel, docetaxel, ixabepilone, vinblastine, vincristine, vinorelbine, vindesine, estramustine; or pharmaceutically acceptable salts of these compounds; in particular paclitaxel). Most preferred cytotoxic chemotherapy agents to be used in combination with the compounds of formula (I) are those routinely used in the treament of glioblastoma multiforme, in particular temozolomide. Equally preferred is radiotherapy.
Chemotherapy may be given with a curative intent or it may aim to prolong life or to palliate symptoms. a) Combined modality chemotherapy is the use of drugs with other cancer treatments, such as radiation therapy or surgery. b) Induction chemotherapy is the first line treatment of cancer with a chemotherapeutic drug. This type of chemotherapy is used for curative intent. c) Consolidation chemotherapy is the given after remission in order to prolong the overall disease-free time and improve overall survival. The drug that is administered is the same as the drug that achieved remission. d) Intensification chemotherapy is identical to consolidation chemotherapy but a different drug than the induction chemotherapy is used. e) Combination chemotherapy involves treating a patient with a number of different drugs simultaneously. The drugs differ in their mechanism and side effects. The biggest advantage is minimizing the chances of resistance developing to any one agent. Also, the drugs can often be used at lower doses, reducing toxicity. f) Neoadjuvant chemotherapy is given prior to a local treatment such as surgery, and is designed to shrink the primary tumor. It is also given to cancers with a high risk of micro-metastatic disease. g) Adjuvant chemotherapy is given after a local treatment (radiotherapy or surgery). It can be used when there is little evidence of cancer present, but there is risk of recurrence. It is also useful in killing any cancerous cells that have spread to other parts of the body. These micro-metastases can be treated with adjuvant chemotherapy and can reduce relapse rates caused by these disseminated cells. h) Maintenance chemotherapy is a repeated low-dose treatment to prolong remission. i) Salvage chemotherapy or palliative chemotherapy is given without curative intent, but simply to decrease tumor load and increase life expectancy. For these regimens, a better toxicity profile is generally expected.
When used in combination with the compounds of Formula (I) of the present invention, preventive or curative forms of chemotherapy (or mutatis mutandis', radiotherapy) such as those listed under a), b) c), d), e), and especially g) and / or h) above are preferred. When used in combination with the compounds of Formula (I) of the present invention, chemotherapy, radiotherapy, EGFR inhibitors, aromatase inhibitors, and immunotherapy are preferred. Immunotherapy such as especially those targeting the programmed cell death receptor 1 (PD-1 receptor) or its ligand PD-L1 i.e. PD1 and/or PDL1 blockade; and/or CTLA4 blockade; and/or TIGIT blockade and/or LAG3 blockade; or other targeted therapies are especially preferred. Most preferred immunotherapy used in combination with the compounds of Formula (I) of the present invention is PD1 and/or PDL1 blockade.
For avoidance of any doubt, if compounds of the present invention are described as useful as single therapeutic agents or in combination with one or more therapeutic agents and/or therapies, for the prevention / prophylaxis or treatment of diseases or disorders, such compounds are likewise suitable for use in the preparation of a medicament for the prevention / prophylaxis or treatment of diseases or disorders.
The present invention also relates to a method for the prevention / prophylaxis or treatment of diseases or disorders mentioned hereinabove or hereinbelow, said method comprising administering to a subject in need of such prevention / prophylaxis or treatment a pharmaceutically active amount of a compound of Formula (I) of the present invention, either alone or in combination with other pharmacologically active compounds and/or therapies.
In a preferred embodiment of the present invention, the administered amount is comprised between 1 mg and 1000 mg per day, particularly between 5 mg and 500 mg per day, more particularly between 25 mg and 400 mg per day, especially between 50 mg and 200 mg per day.
Synthesis of compounds of Formula (I)
A further aspect of the invention is a process for the preparation of compounds of Formula (I) as defined in any one of embodiments 1 ) to 37). Compounds of Formula (I) can be prepared from commercially available or well-known starting materials according to the methods described in the experimental part, by analogous methods; or according to the general sequence of reactions outlined below, wherein Ar, R1, and R2 are as defined for Formula (I). Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by a person skilled in the art by routine optimization procedures. Other abbreviations used herein are explicitly defined or are as defined in the experimental section. In some instances of the preparation described hereinbelow, protecting groups (PG) may be required. The use of protecting groups is well known in the art (see for example “Protective Groups in Organic Synthesis", T.W. Greene, P.G.M. Wuts, Wiley-lnterscience, 1999) and for the purposes of this discussion, it will be assumed that such protecting groups as necessary are in place. The compounds obtained may be converted into salts, especially pharmaceutically acceptable salts thereof in a manner known perse.
Generally, compounds of Formula (I) are obtained by reaction of an intermediate of Formula A with a sulfonylchloride of Formula B following a typical sulfonamide coupling reaction scheme in the presence of a base such as TEA or DIPEA in a solvent such as THF, DMF, DOM or a mixture at RT or at elevated temperature (Scheme 1).
Figure imgf000049_0001
Scheme 1
Alternatively, compounds of Formula (I) are obtained by reaction of an intermediate of Formula C with an amine following a typical SNAr coupling reaction scheme in the presence of a base such as TEA or DI PEA in a solvent such as THF, DMF, MeOH, EtOH or the like at RT or at elevated temperature (Scheme 2).
Figure imgf000049_0002
Scheme 2
[18F]-labelled compounds of Formula [18F]-(I) are obtained by reaction of an intermediate of Formula G or an intermediate of Formula H with K[18F]F in the presence of kryptofix 2.2.2, potassium oxalate and a base such as K2CO3 in a solvent such as DMF or DMSO at RT or at elevated temperature (Scheme 3).
Figure imgf000049_0003
Scheme 3
Generally, [18F]-labelled compounds of Formula [18F]-(I) are obtained by standard methodologies known to a person skilled in the art (see for example Halder, R. et al. J. Org. Chem. 2021 , 86, 13873; or Liu, Z. et al. Frontiers in Chemistry 2022, 10, 883866). For example, compounds of Formula [18F]-(I) are obtained by reaction of an intermediate of Formula
J with K[18F]F under various conditions to displace a leaving group (LG) such as a boronic acid (-B(OH)2), boronic ester (-B(0R)2), phenol (-OH), iodonium salt (-l+R), sulfonium salt (-S+R2), stannane (-SnRj), halogen (-01, -Br, -I) or ammonium salt (-N+Rj) in intermediates of Formula J (Scheme 4).
Figure imgf000050_0001
Scheme 4
Alternatively, [18F]-labelled compounds of Formula [18F]-(I) are obtained by reaction of an intermediate of Formula K with K[18F]F under various conditions to displace a leaving group (LG) (Scheme 5).
Figure imgf000050_0002
Scheme 5
Generally, radioiodine-labelled compounds of Formula [l*]-(l) may be obtained by standard methodologies known to a person skilled in the art (see for example Petrov, S. A. et al. Int. J. Mol. Sci. 2022, 23, 137896). The symbol “I*” refers to any one of the radioactive isotopes of iodine suitable for the intended use (therapy or diagnostic). For example, compounds of Formula [l*]-(l) may be obtained by reaction of an intermediate of Formula L with radiolabeled [l*]-Nal under various conditions to displace a leaving group (LG) such as a boronic acid (-B(OH)2), boronic ester (-B(OR)2), silane (-SiRj), stannane (-SnRj), halogen (-CI, -Br) or diazonium salt (-IV) in intermediates of Formula L (Scheme 5i).
Figure imgf000050_0003
Scheme 5i
Synthesis of intermediates of Formula A
Generally, intermediates of Formula A are obtained by reaction of a chloropyrimidine of Formula D with an amine, followed by reaction of an intermediate of Formula Aa with an acid (Scheme 6). In a typical experiment, intermediate D is stirred at RT or at elevated temperature with an appropriate amine in a solvent such as EtOH, MeOH or the like. The resulting tert-butyl carbamate intermediate of Formula Aa is then treated at RT or at elevated temperature with an acid such as TFA, HOI, H2SO4, H3PO4 or the like in a solvent such as DOM, MeCN, THF, toluene or the like.
Figure imgf000051_0001
Scheme 6
Alternatively, intermediates of Formula A are obtained by reaction of a pyrimidine p-toluenesulfonate of Formula E with an amine, followed by reaction of an intermediate of Formula Aa with an acid (Scheme 7). In a typical experiment, intermediate E is stirred at RT or at elevated temperature with an appropriate amine in a solvent such as EtOH, MeOH or the like. The resulting tert-butyl carbamate intermediate of Formula Aa is then treated at RT or at elevated temperature with an acid such as TFA, HCI, H2SO4, H3PO4 or the like in a solvent such as DCM, MeCN, THF, toluene or the like.
Figure imgf000051_0002
Scheme 7
Synthesis of intermediates of Formula B
Generally, intermediates of Formula B are either commercially available or are obtained by reaction of an aryl bromide Ba with benzyl mercaptane followed by oxidation of the thioether intermediate of Formula Bb (Scheme 8). In a typical experiment, an aryl bromide of Formula Ba is stirred at elevated temperature in a solvent such as dioxane or toluene or the like in the presence of benzyl mercaptane, a palladium catalyst such as Pd2(dba)3, a phosphine ligand such as XantPhos and a base such as DIPEA or the like. For a typical thioether oxidation, the resulting intermediate Bb is stirred at RT or at elevated temperature in a solvent such as MeCN in the presence of an aqueous solution of HCI and an oxidant such as NCS or the like.
Figure imgf000051_0003
Scheme 8
Synthesis of intermediates of Formula C
Generally, intermediates of Formula C are obtained by reaction of a chloropyrimidine of Formula D with an acid followed by reaction of an intermediate of Formula Ca with a sulfonylchloride of Formula B under typical sulfonamide coupling conditions (Scheme 9). In a typical experiment, an intermediate of Formula D is treated at RT or at elevated temperature with an acid such as TFA, HCI, H2SO4, H3PO4 or the like in a solvent such as DCM, MeCN, THF, toluene or the like. The resulting chloropyrimidine intermediate of Formula Ca is treated with a sulfonyl chloride of Formula B in the presence of a base such as TEA or DIPEA in a solvent such as THF, DMF, DCM or a mixture at RT or at elevated temperature.
Figure imgf000052_0001
is of intermediates of Formula D
Generally, intermediates of Formula D are obtained by reaction of intermediate F with a chlorinating reagent such as POCI3 in the presence of a base such as TEA, DIPEA or the like in solvent such as MeCN, toluene, DCM or the like at RT or at elevated temperature (Scheme 10).
Figure imgf000052_0002
Scheme 10
Synthesis of intermediates of Formula E
Generally, intermediates of Formula E are obtained by reaction of intermediate F with p-toluenesulfonyl chloride in the presence of a base such as TEA, DIPEA or the like in solvent such as MeCN, toluene, DCM or the like at RT or at elevated temperature (Scheme 11).
Figure imgf000052_0003
Scheme 11
Synthesis of intermediates of Formula F
Generally, intermediates of Formula F are obtained by reaction of commercially available acid Fa to produce intermediate ketoester Fb, followed by condensation with guanidine (Scheme 12). In a typical experiment, a commercially available acid of Formula Fa is treated with 2, 2-dimethyl-1 ,3-dioxane-4, 6-dione or a 3-methoxy-3- oxopropanoic acid potassium salt of Formula Fc in the presence of an acid activating reagent such as EDC, GDI or the like and a base such as DMAP in a solvent such as DCM, followed by treatment with MeOH at RT or at elevated temperature. The resulting ketoester intermediate of Formula Fb is treated with guanidine hydrochloride in the presence of a base such as NaOEt, KOtBu or the like in a solvent such as EtOH, MeOH or the like at RT or at elevated temperature.
Figure imgf000053_0001
Scheme 12
Whenever the compounds of Formula (I) are obtained in the form of mixtures of enantiomers, the enantiomers can be separated using methods known to one skilled in the art: e.g. by formation and separation of diastereomeric salts or by HPLC or SFC over a chiral stationary phase such as a Regis Whelk-O1(R,R) (10 pirn) column, a Daicel ChiralCel OD-H (5-10 pirn) column, or a Daicel ChiralPak IA (10 jxm), IA, IB, IC, IE, or IF (5 pirn) or AD-H (5 pirn) column. Typical conditions of chiral HPLC or SFC are an isocratic mixture of eluent A (EtOH, in presence or absence of an amine such as triethylamine or diethylamine) and eluent B (heptane or CO2), at a flow rate of 0.8 to 150 mL/min.
The following examples are provided to illustrate the invention. These examples are illustrative only and should not be construed as limiting the invention in any way.
Experimental Part
Chemistry
All temperatures are stated in °C.
Preparative HPLC conditions:
The conditions for preparative HPLC purifications were chosen among the possibilities given below depending on the properties of the compounds to be purified. More than one option per problem can lead to a successful result. Equipment: HPLC pumps: Gilson 333/334 or equivalent; Autosampler: Gilson LH215 (with Gilson 845z injector) or equivalent; Degasser: Dionex SRD-3200 or equivalent; Make-up pump: Dionex ISO-3100A or equivalent; DAD detector: Dionex DAD-3000 or equivalent; MS detector: Single quadrupole mass analyzer Thermo Finnigan MSQ Plus or equivalent; MRA splitter: MRA100-000 flow splitter or equivalent; ELS detector: Polymer Laboratories PL-ELS1000 or equivalent. Method: Column: variable, Agilent Zorbax SB-Aq 30x75 mm 5 pirn (acidic conditions), Waters Xbridge C18, 30 x 75 mm 10 pirn (acidic/basic conditions), Waters Xbridge C18, 50 x 150 mm 10 pirn (acidic/basic conditions); Flow rate: variable 75 mL/min (for columns with dimension 30x75 mm), 150 ml/min (for columns with dimension 50x150 mm). Mobile phase: gradient mode, A1 : Water + 0.5% formic acid (acidic conditions), A2: Water + 0.5% ammonium hydroxide solution (25%) (basic conditions), B: Acetonitrile (acidic/basic conditions); Gradient: variable, e.g. for 75 mL/min: “extremely polar”: at 0.0 min 0%B, at 1 .0 min 0%B, at 3.5 min 20% B, at 4.0 min 95% B, at 6.0 min 95%B, at 6.2 min 0%B, at 6.6 min 0%B; “very polar”: at 0.0 min 5%B, at 0.1 min 5%B, at 3.0 min 50%B, at 4.0 min 95%B, at 6.0 min 95%B, at 6.2 min 5%B, at 6.6 min 5%B; “polar”: at 0.0 min 10%B, at 0.01 min 10%B, at 4.0 min 95%B, at 6.0 min 95% B, at 6.2 min 10%B, at 6.6 min 10%B; “normal”: at 0.0 min 20%B, at 0.01 min 20%B, at 4.0 min 95%B, at 6.0 min 95%B, at 6.2 min 20%B, at 6.6 min 20%B; “lypophilic”: at 0.0 min 30%B, at 0.01 min 30%B, at 3.5 min 95%B, at 6.0 min 95%B, at 6.2 min 30% B, at 6.6 min 30%B; “very lypophilic”: at 0.0 min 50% B, at 0.01 min 50% B, at 3.0 min 95% B, at 6.0 min 95%B, at 6.2 min 50%B, at 6.6 min 50%B. Injection volume: 100-2500 piL. Collection: UV / MS / ELSD if available, and all possible combinations; Make-up flow rate: 0.50 mL/min. Make-up eluent MS: acetonitrile/water/TFA 70:30:0.025 (V/V/V); MS ionization mode: ESI+.
LC-MS conditions:
Conditions A: Column: Waters BEH C18, 2.1x50 mm, 2.5 pirn; Temperature: 40°C; Injection volume: 0.15 jxL; Eluent A: water/NHa with cjNHa) = 13 mmol/L; Eluent B: Acetonitrile; Ionization: ESI+; Gradient: at 0.0 min = 5% B, 1.20 min = 95% B, at 1.90 min = 95% B, at 2.10 min = 5% B; Flow = 0.8 mL/min. Detection: UV 210 nm and MS.
Conditions B: Column: Zorbax RRHD SB-Aq, 2.1x50 mm, 1.8 pirn; Temperature: 40°C; Injection volume: 0.15 jxL; Eluent A: water 0.04% TFA; Eluent B: Acetonitrile; Ionization: ESI+; Gradient: at 0.0 min = 5% B, at 1 .20 min = 95% B, at 1.90 min = 95% B, at 2.10 min = 5% B; Flow = 0.8 mL/min. Detection: UV 210 nm and MS.
Conditions C: Column: Waters BEH C18, 2.1x50 mm, 1.7 pirn; Temperature: 40°C; Injection volume: 3.0 jxL; Eluent A: 95% water 7 mM CH3COONH4 / 5% acetonitrile; Eluent B: Acetonitrile; Ionization: ESI+; Gradient: at 0.0 min = 5% B, at 1.00 min = 95% B, at 2.6 min = 95% B, at 2.8 min = 5% B, at 3.30 min = 5% B; Flow = 0.5 mL/min. Detection: UV 210 nm and MS.
QC conditions'. Column: Waters Acquity UPLC CSH C18 2.1x50 mm, 1.7 pirn; Temperature: 60°C; Injection volume: 0.20 jxL; Eluent A1 : H2O + 0.05% v/v Formic Acid; Eluent B1 : Acetonitrile + 0.045% v/v Formic Acid; Ionization: ESI+; Gradient: at 0.0 min = 2% B, at 1 .50 min = 95% B, at 1 .90 min = 95% B, at 1.95 min = 2% B; Run time: 2.00 min; Flow = 1.0 mL/min. Detection: UV 214 nm and MS.
Chiral SFC conditions:
Chiral A conditions'. Column: Chiralcel OZ-H 4.6x250mm, 5 pirn; Temperature: 40°C; Injection volume: 10.0 jxL; Eluent A: CO2; Eluent B: EtOH 0.1 % diethylamine; Gradient: isocratic 30% B over 5 min.; Flow = 4.0 mL/min. Detection: UV 220 nm.
Chiral B conditions'. Column: Chiralcel OZ-H 4.6x250mm, 5 pirn; Temperature: 40°C; Injection volume: 10.0 jxL; Eluent A: CO2; Eluent B: EtOH 0.1 % diethylamine; Gradient: isocratic 35% B over 5 min.; Flow = 4.0 mL/min. Detection: UV 220 nm.
Abbreviations (as used hereinbefore or hereinafter):
Ac acetate
Aq. Aqueous
Boc tert-butyloxycarbonyl
BPR back pressure regulator
BSA bovine serum albumin
GDI 1,1 ’-carbonyldiimidazole (CAS # 530-62-1 )
DCM dichloromethane
DIPEA N, N-diisopropylethylamine (Hunig’s base; CAS # 7087-68-5)
DMAP 4-(dimethylamino)pyridine
DMEM Dulbecco's modified eagle medium
DMF dimethylformamide
DMSO dimethylsulfoxide EDC N/-(3-dimethylaminopropyl)-N/'-ethylcarbodiimide HCI (CAS # 25952-53-8)
ESI electrospray ionization
Et ethyl
EtOAc ethyl acetate
Et2O diethyl ether
EtOH ethanol
FC flash chromatography
FUPR fluorescent imaging plate reader h hour(s)
Hepes 2-[4-(2-Hydroxyethyl)piperazin-1-yl]ethane-1 -sulfonic acid
HBSS Hanks' Balanced Salt Solution
HPLC high pressure liquid chromatography
LC-MS liquid chromatography-mass spectrometry
Me methyl
MeCN acetonitrile
MeOH methanol min. minute(s)
MS mass spectrometry
NCS N-chlorosuccinimide (CAS # 128-09-6) n-Bu n-butyl
NEts triethylamine
NMR nuclear magnetic resonance spectrometry org. organic
Pd2(dba)3 tris(dibenzylideneacetone)dipalladium(0) (CAS # 51364-51-3)
POCI3 phosphorus(V) oxychloride prepHPLC preparative HPLC
RT room temperature sat. saturated
SFC supercritical fluid chromatography
SNAr nucleophilic aromatic substitution
TBME tert-butyl methyl ether t-Bu tert-butyl
TEA triethylamine
TFA trifluoroacetic acid
THF tetrahydrofuran tR retention time
Ts p-toluenesulfonate
UV ultraviolet XantPhos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (CAS # 161265-03-8)INTERMEDIATES F Intermediate F1 : tert-butyl (c/s-3-(2-amino-6-hydroxypyrimidin-4-yl)cyclobutyl)carbamate
Step 1 : methyl 3-(c/s-3-((tert-butoxycarbonyl)amino)cyclobutyl)-3-oxopropanoate Fb1 (CAS # 2407860-80-2)
To a suspension of c/s-3-(tert-butoxycarbonylamino)cyclobutanecarboxylic acid (CAS # 1008773-79-2) (15 g, 68.3 mmol) in DCM (400 mL) is added 2, 2-dimethyl-1,3-dioxane-4, 6-dione (12 g, 82 mmol), DMAP (12.6 g, 102 mmol) and EDC (15.7 g, 82 mmol). The mixture is stirred at RT for 1 ,5h. An aq. 0.5 M KHSO4 solution (500 mL) is added, and the mixture is stirred at RT for 5 min. The aq. phase is extracted with DCM (150 mL). The org. phase is washed with water (3x250 mL), dried (MgSO4), filtered and concentrated. The resulting solid is dissolved in MeOH (400 mL) and stirred at reflux for 3h. The mixture is concentrated and purified by FC (SiO2, EtOAc/heptane) to give 15 g of intermediate Fb1. LC-MS (conditions B): tR = 0.78 min; [M+H]+ = 272.24. 1H NMR (400 MHz, DMSO) 5: 7.13 (d, J = 8.0 Hz, 1 H), 3.87 (m, 1 H), 3.62 (s, 3 H), 3.56 (s, 2 H), 2.98 (m, 1 H), 2.31 (m, 2 H), 1.94-2.02 (m, 2 H), 1.36 (s, 9 H).
Step 2: tert-butyl (c/s-3-(2-amino-6-hydroxypyrimidin-4-yl)cyclobutyl)carbamate F1
To a solution of guanidine hydrochloride (CAS # 50-01-1) (16.4 g, 169 mmol) in EtOH (160 mL) is added a solution of NaOEt (21wt% in EtOH, 63 mL, 169 mmol) and the mixture is stirred at RT for 10 min. A solution of intermediate Fb1 (15.3 g, 56 mmol) in EtOH (160 mL) is added over 5 min. The suspension is heated to 80°C and stirred for 1 h. The reaction mixture is filtered and concentrated. The residue is taken up in water (50 mL) and the pH is adjusted to pH 5 by addition of an aq. 1 N HCI solution (100 mL). The resulting beige suspension is filtered and the collected solid is washed sequentially with water (50 mL), water/MeOH 1 :1 (50 mL) and Et20 (100 mL). The solid is dried by azeotropic distillation with toluene and then under vacuum for 1 h. The solid is taken up in MeOH (70 mL) and stirred at RT for 1 h. The suspension is filtered and the solid is collected and dried under high vacuum to give 11.8 g of intermediate F1. LC-MS (conditions B): tR = 0.54 min; [M+H]+ = 281.27. 1H NMR (400 MHz, DMSO) δ: 10.60 (d, J = 0.4 Hz, 1 H), 7.10 (d, J = 7.8 Hz, 1 H), 6.47 (d, J = 0.6 Hz, 2 H), 5.38 (s, 1 H), 3.85 (m, 1 H), 2.69-2.74 (m, 1 H), 2.37 (m, 2 H), 1 .93 (m, 2 H), 1.37 (s, 9 H).
Intermediate F2: tert-butyl (trans-3-(2-amino-6-hydroxypyrimidin-4-yl)cyclobutyl)carbamate
Step 1 : methyl 3-(trans-3-((tert-butoxycarbonyl)amino)cyclobutyl)-3-oxopropanoate Fb2 (CAS # 2260789-10-2)
To a suspension of trans-3-(tert-butoxycarbonylamino)cyclobutanecarboxylic acid (CAS # 939400-34-7) (1 g, 4.4 mmol) in DCM (40 mL) is added 2, 2-dimethyl-1 ,3-dioxane-4, 6-dione (780 mg, 5.3 mmol), DMAP (809 mg, 6.6 mmol) and EDC (1.02 g, 5.3 mmol). The mixture is stirred at RT for 18h. An aq. 0.5 M KHSO4 solution (100 mL) is added, and the mixture is stirred at RT for 5 min. The aq. phase is extracted with DCM (100 mL). The org. phase is washed with water (3x50 mL), dried (MgSO4), filtered and concentrated. The resulting solid is dissolved in MeOH (40 mL) and stirred at reflux for 3h. The mixture is concentrated and the solid is dried under vacuum to give 1.2 g of intermediate Fb2. LC- MS (conditions B): tR = 0.78 min; [M+H]+ = 216.23. 1H NMR (400 MHz, DMSO) δ: 7.11-7.27 (m, 1 H), 3.83-3.93 (m, 1
H), 3.54-3.66 (m, 5 H), 3.17-3.28 (m, 1 H), 2.26-2.40 (m, 2 H), 1.94-2.16 (m, 2 H), 1.33-1.41 (m, 9 H).
Step 2: tert-butyl (trans-3-(2-amino-6-hydroxypyrimidin-4-yl)cyclobutyl)carbamate F2
To a solution of intermediate Fb2 (1.2 g, 4.6 mmol) in MeOH (10 mL) is added guanidine hydrochloride (CAS # 50-01 -
I) (550 mg, 5.6 mmol) and KOtBu (2.9 g, 25 mmol). The reaction is heated to 60°C for 5 min and then stirred at RT for 18h. The mixture is filtered, and the filtrate is diluted with water (10 mL). The pH is adjusted to pH 5 by addition of 2 M aq. HCI. The resulting suspension is filtered and the solid is dried under vacuum to give 870 mg of intermediate F2. LC-MS (conditions B): tR = 0.54 min; [M+H]+ = 281.29. 1H NMR (400 MHz, DMSO) δ: 10.78-11.06 (m, 1 H), 7.10 (d, J = 8.0 Hz, 1 H), 6.65-6.66 (m, Ji = 1.1 Hz, J2 = 2.8 Hz, 2 H), 5.41 (s, 1 H), 3.83-3.90 (m, 1 H), 2.73 (m, 1 H), 2.35-2.41 (m, 2 H), 1.94 (m, 2 H), 1.37 (s, 9 H).
Intermediate F3: tert-butyl (c/s-3-(2-amino-5-fluoro-6-hydroxypyrimidin-4-yl)cyclobutyl)carbamate
Intermediate F3 is made according to the procedure reported for intermediate F1 using c/s-3-(tert- butoxycarbonylamino)cyclobutanecarboxylic acid (CAS # 1008773-79-2) and intermediate F3c as starting materials. LC-MS (conditions B): tR = 0.64 min; [M+H]+ = 299.21.
Intermediate F3c: 2-fluoro-3-methoxy-3-oxopropanoic acid, potassium salt
To a solution of dimethyl 2-fluoromalonate (CAS # 344-14-9) (500 mg, 3.3 mmol) in MeOH (10 mL) is added a solution of KOH (1 M in MeOH, 3 mL). The reaction is stirred at RT for 1.5h. The mixture is concentrated to give 500 mg of intermediate F3c.
INTERMEDIATES E
Intermediate E1 : 2-amino-6-(c/s-3-((tert-butoxycarbonyl)amino)cyclobutyl)pyrimidin-4-yl 4- methylbenzenesulfonate
To a solution of intermediate F1 (5 g, 17.8 mmol) in DCM (110 mL) is added NEts (22.6 mL, 161 mmol) and p- toluenesulfonyl chloride (CAS # 98-59-9) (4.2 g, 21.4 mmol). The mixture is stirred for 18h at RT. The reaction is diluted with water (100 mL) and DCM (100 mL). The phases are separated, and the aq. phase is extracted with DCM (100 mL). The combined org. phases are washed with aq. NaHCOs (100 mL), dried (MgSO4), filtered and concentrated. The residue is purified by FC (SiO2, EtOAc/heptane) to give 6.8 g of intermediate E1. LC-MS (conditions B): tR = 0.95 min; [M+H]+ = 435.67. 1H NMR (400 MHz, DMSO) δ: 7.97 (d, J = 8.3 Hz, 2 H), 7.48 (d, J = 8.3 Hz, 2 H), 7.14 (d, J = 8.1 Hz, 1 H), 6.97 (s, 2 H), 6.17 (s, 1 H), 3.91 (m, 1 H), 2.95 (m, 1 H), 2.43 (m, 5 H), 1.95-2.03 (m, 2 H), 1.37 (s, 9 H).
Intermediate E2: 2-amino-6-(c/s-3-((tert-butoxycarbonyl)amino)cyclobutyl)-5-fluoropyrimidin-4-yl 4- methylbenzenesulfonate
Intermediate E2 is made according to the abovementioned procedure described for the synthesis of intermediate E1 using intermediate F3 as starting material. LC-MS (conditions B): tR = 1.04 min; [M+H]+ = 453.18.
INTERMEDIATES D
Intermediate D1 : tert-butyl (c/s-3-(2-amino-6-chloropyrimidin-4-yl)cyclobutyl)carbamate
To a solution of intermediate F1 (2.7 g, 9.6 mmol) in MeCN (50 mL) is added DI PEA (5.1 mL, 30 mmol) and POCI3 (2.7 mL, 30 mmol). The mixture is stirred for 18h at RT. The reaction mixture is poured into aq. NaHCOs (250 mL). The aq. phase is extracted with DCM (2x250 mL). The combined org. phases are washed with water (250 mL), dried (MgSO4), filtered and concentrated to give 2.3 g of intermediate D1. LC-MS (conditions B): tR = 0.82 min; [M+H]+ = 299.11. 1H NMR (400 MHz, DMSO) δ: 7.13-7.15 (m, 1 H), 7.03 (s, 2 H), 6.59 (s, 1 H), 3.89-3.96 (m, 1 H), 2.92-2.99 (m, 1 H), 2.44- 2.46 (m, 2 H), 2.01-2.08 (m, 2 H), 1.38 (s, 9 H).
Intermediate D2: tert-butyl (trans-3-(2-amino-6-chloropyrimidin-4-yl)cyclobutyl)carbamate
Intermediate D2 is made according to the abovementioned procedure described for the synthesis of intermediate D1 using intermediate F2 as starting material. LC-MS (conditions B): tR = 0.82 min; [M+H]+ = 299.25. INTERMEDIATES A
Intermediate A1: 6-(c/s-3-aminocyclobutyl)-N4-methylpyrimidine-2,4-diamine hydrochloride Step 1 : tert-butyl (c/s-3-(2-amino-6-(methylamino)pyrimidin-4-yl)cyclobutyl)carbamate Aa1
A vial is charged with a solution of intermediate D1 (500 mg, 1.7 mmol) in EtOH (7.5 mL), DIPEA (0.6 mL, 3.4 mmol) and methylamine (30wt% in EtOH, 0.3 mL, 2.5 mmol). The vial is closed, and the mixture is heated to 90°C and stirred for 18h. More methylamine (30wt% in EtOH, 0.1 mL, 0.84 mmol) is added and the mixture is heated to 90°C and stirred for another 18h. The mixture is diluted with aq. NaHCO3 (100 mL) and EtOAc (100 mL). The phases are separated, and the aq. phase is extracted with EtOAc (100 mL). The combined org. phases are dried (MgSO4), filtered and concentrated. The residue is purified by FC (SiO2, MeOH/DCM) to give 495 mg of intermediate Aa1 . LC-MS (conditions B): tR = 0.59 min; [M+H]+ = 294.37. 1H NMR (500 MHz, DMSO) 5: 7.10 (d, J = 7.8 Hz, 1 H), 6.61-6.62 (m, 1 H), 5.79 (s, 2 H), 5.55 (s, 1 H), 3.83-3.88 (m, 1 H), 2.71-2.75 (m, 4 H), 2.37 (qd, Ji = 2.6 Hz, J2 = 7.7 Hz, 2 H), 1.96 (m, 2 H), 1.37 (s, 9 H).
Step 2: 6-(c/s-3-aminocyclobutyl)-N4-methylpyrimidine-2,4-diamine hydrochloride A1
To a solution of intermediate Aa1 (525 mg, 1.8 mmol) in dioxane (5.2 mL) is added a solution of HOI (4N in dioxane, 4.5 mL, 18 mmol) and MeOH (2.6 mL). The reaction is stirred at RT for 1 h. The mixture is concentrated and the solid is dried under vacuum to give 550 mg of intermediate A1. LC-MS (conditions A): tR = 0.42 min; [M+H]+ = 194.39. 1H NMR (400 MHz, DMSO) δ: 12.75 (s, 1 H), 8.96 (d, J = 4.8 Hz, 1 H), 8.42-8.50 (m, 2 H), 6.66-6.80 (m, 2 H), 3.70-3.76 (m, 1 H), 3.24 (m, 1 H), 2.86 (d, J = 4.7 Hz, 3 H), 2.56-2.63 (m, 2 H), 2.33-2.41 (m, 2 H).
Intermediate A2: 6-(c/s-3-aminocyclobutyl)-N/4-ethylpyrimidine-2,4-diamine hydrochloride
Intermediate A2 is prepared according to the procedure described for intermediate A1, using ethylamine and intermediate D1 as starting materials. LC-MS (conditions A): tR = 0.49 min; [M+H]+ = 208.34. 1H NMR (400 MHz, DMSO) δ: 12.72 (s, 1 H), 8.95 (t, J = 5.4 Hz, 1 H), 8.39-8.40 (m, 2 H), 6.18-6.31 (m, 2 H), 3.70-3.78 (m, 1 H), 3.33- 3.41 (m, 2 H), 3.21-3.28 (m, 1 H), 2.56-2.63 (m, 2 H), 2.33-2.40 (m, 2 H), 1.13 (t, J = 7.2 Hz, 3 H).
Intermediate A3: 6-(c/s-3-aminocyclobutyl)-N/4-isopropylpyrimidine-2,4-diamine hydrochloride Step 1 : tert-butyl (c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)carbamate Aa3
To a solution of intermediate E1 (1.5 g, 3.45 mmol) in EtOH (15 mL) is added isopropylamine (1.5 mL, 17.3 mmol). The reaction is heated to 80°C for 18h. The mixture is concentrated, and water (100 mL) is added. The aq. phase is extracted with DCM (2x100 mL). The combined org. phases are washed with aq. NaHCO3 (100 mL), dried (MgSO4), filtered and concentrated. The residue is purified by FC (SiO2, NH3 in MeOH/DCM) to give 630 mg of intermediate Aa3. LC-MS (conditions B): tR = 0.68 min; [M+H]+ = 321.94. 1H NMR (400 MHz, DMSO) δ: 7.11 (d, J = 7.6 Hz, 1 H), 6.57- 6.59 (m, 1 H), 5.78 (m, 2 H), 5.54 (s, 1 H), 4.03 (m, 1 H), 3.85 (m, 1 H), 2.68-2.74 (m, 1 H), 2.33-2.39 (m, 2 H), 1.95 (m, 2 H), 1 .37 (s, 9 H), 1.09 (d, J = 6.4 Hz, 6 H).
Step 2: 6-(c/s-3-aminocyclobutyl)-N/4-isopropylpyrimidine-2,4-diamine hydrochloride A3
To a solution of intermediate Aa3 (1.9 g, 5.9 mmol) in DCM (40 mL) is added HCI (4N in dioxane, 7.4 mL, 30 mmol). The reaction is stirred at RT for 3h. The mixture is concentrated and the solid is dried under vacuum to give 1 .7 g of intermediate A3. LC-MS (conditions B): tR = 0.37 min; [M+H]+ = 222.31 . 1H NMR (400 MHz, DMSO) δ: 12.71-12.80 (m, 1 H), 8.92 (d, J = 7.7 Hz, 1 H), 8.43-8.57 (m, 3 H), 5.93 (s, 1 H), 4.17 (m, 1 H), 3.70-3.76 (m, 1 H), 3.22 (m, 1 H), 2.53- 2.62 (m, 2 H), 2.33-2.40 (m, 2 H), 1 .16 (d, J = 6.6 Hz, 6 H).
Intermediate A3.1 : 6-(trans-3-aminocyclobutyl)-/\/4-isopropylpyrimidine-2,4-diamine hydrochloride
Intermediate A3.1 is made according to the abovementioned procedure described for the synthesis of intermediate A1 using intermediate D2 and isopropylamine as starting materials. LC-MS (conditions B): IR = 0.37 min; [M+H]+ = 222.20. The intermediates from Table 1 below are made according to the abovementioned procedures described for the synthesis of intermediates A1 or A3 using intermediates D1, D2 or E1 and the appropriate amine or amine hydrochloride as starting materials.
Table 1
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Intermediate A14: 6-(c/s-3-aminocyclobutyl)-N/4-ethyl-5-fluoropyrimidine-2,4-diamine hydrochloride
Intermediate A14 is made according to the abovementioned procedure described for the synthesis of intermediate A1 using intermediate E2 and ethylamine as starting materials. LC-MS (conditions B): IR = 0.32 min; [M+H]+ = 226.22. INTERMEDIATES B
Intermediate B1 : 5,6-dimethylpyridine-3-sulfonyl chloride (CAS # 1781875-71-5)
Step 1 : 5-(benzylthio)-2,3-dimethylpyridine B1a
A mixture of 5-bromo-2,3-dimethylpyridine (CAS # 27063-90-7) (500 mg, 2.58 mmol), Pd2(dba)s (122 mg, 0.13 mmol), XantPhos (152 mg, 0.26 mmol), benzylmercaptan (0.37 mL, 3.1 mmol) and dioxane (10 mL) is put under N2 and heated to 100°C for 18h. The mixture is diluted with water (50 mL) and the aq. phase is extracted with EtOAc (2x50 mL). The combined org. phases are washed with brine (50 mL), dried (MgSCU), filtered and concentrated. The residue is purified by FC (SiO2, EtOAc/heptane) to give 420 mg of intermediate B1a. LC-MS (conditions B): IR = 0.66 min; [M+H]+ = 230.16. 1H NMR (400 MHz, DMSO) δ: 8.15 (s, 1 H), 7.53 (s, 1 H), 7.22-7.30 (m, 5 H), 4.21 (s, 2 H), 2.36 (s, 3 H), 2.20 (s, 3 H).
Step 2: 5,6-dimethylpyridine-3-sulfonyl chloride B1
A solution of NCS (939 mg, 7.0 mmol) in MeCN (8 mL) is cooled to 0°C. 2M aq. HCI (1 mL, 1.9 mmol) is added, and the mixture is stirred at 0°C for 10 min. A solution of intermediate B1 a (420 mg, 1.8 mmol) in MeCN (4 mL) is added. The reaction is stirred at RT for 30 min. The mixture is diluted with water (50 mL) and the aq. phase is extracted with DCM (2x50 mL). The combined org. phases are dried (MgSO4), filtered and concentrated. The residue is purified by FC (SiO2, EtOAc/heptane) to give 138 mg of intermediate B1. LC-MS (conditions B): IR = 0.85 min; [M+H]+ = 206.11. 1H NMR (400 MHz, DMSO) δ: 8.66 (s, 1 H), 8.50 (s, 1 H), 2.66 (s, 3 H), 2.44 (s, 3 H).
The intermediates from Table 2 below are made according to the abovementioned procedure described for the synthesis of intermediate B1 using the appropriate arylbromide starting material. Reaction time goes up to 24h, with purification by FC or no purification.
Table 2
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
Intermediate B21 : 3-cyano-4-iodobenzenesulfonyl chloride
A solution of 5-amino-2-iodobenzonitrile (CAS # 1082454-14-5) (107 mg, 0.42 mmol) in cone. HCI (0.13 mL, 4.2 mmol) is cooled to 0°C. A solution of sodium nitrite (35 mg, 0.5 mmol) in water (80 pL, 4.6 mmol) is added slowly. The reaction is stirred at 0°C for 1 h. In a separate flask, a solution of thionyl chloride (90 pL, 1.25 mmol) in water (0.12 mL, 6.7 mmol) is cooled to 0°C and CuCI (4 mg, 0.042 mmol) is added. The two solutions are combined, and the reaction is stirred at RT for 20 min. The mixture is diluted with water (50 mL) and the aq. phase is extracted with TBME (2x50 mL). The combined org. phases are washed with brine (50 mL), dried (MgSCU), filtered and concentrated to give the crude product, which was directly used for the next step. LC-MS (conditions B): IR = 0.97 min; no ionization. INTERMEDIATES G and H
Intermediate G1 : N-(c/s-3-(2-amino-6-(((R)-1,1,1-trifluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-2- nitropyridine-3-sulfonamide
To a solution of intermediate A5 (415 mg, 1.33 mmol) in THF (10 mL) is added NEts (0.93 mL, 6.6 mmol) and sulfonyl chloride B22 (824 mg, 3.7 mmol). The reaction is stirred at RT for 30 min. Purification by prepH PLC (basic conditions) gives 260 mg of intermediate G1. LC-MS (QC conditions): IR = 0.601 min; [M+H]+ = 462.3. 1H NMR (500 MHz, DMSO) 6: 8.81 (dd, Ji = 1.5 Hz, J2 = 4.7 Hz, 1 H), 8.55 (dd, Ji = 1.5 Hz, J2 = 8.0 Hz, 1 H), 8.04 (dd, Ji = 4.7 Hz, J2 = 8.0 Hz, 1 H), 7.21-7.23 (m, 1 H), 5.99 (s, 2 H), 5.60 (s, 1 H), 4.92-4.98 (m, 1 H), 3.70-3.75 (m, 1 H), 2.75-2.82 (m, 1 H), 2.29 (qd, Ji = 3.7 Hz, J2 = 7.4 Hz, 2 H), 1 .96-2.03 (m, 2 H), 1 .25 (d, J = 7.0 Hz, 3 H). The intermediates from Table 3 below are made according to the abovementioned procedure described for the synthesis of intermediate G1 using the appropriate intermediate A and the appropriate sulfonyl chloride B. Reaction time goes up to 24h, with purification by prepHPLC (acidic or basic conditions).
Table 3
Figure imgf000065_0001
Figure imgf000066_0001
SYNTHESIS OF EXAMPLES
Example 1.1 : N-(c/s-3-(2-amino-6-(methylamino)pyrimidin-4-yl)cyclobutyl)-2,4-difluorobenzenesulfonamide
To a solution of intermediate A1 (15 mg, 0.05 mmol) in DCM (0.3 mL) is added NEts (0.03 mL, 0.25 mmol) and 2,4- difluorobenzenesulfonyl chloride (CAS # 13918-92-8) (11 mg, 0.05 mmol). The reaction is stirred at RT for 30 min. Purification by prepHPLC (basic conditions) gives 14 mg of Example 1.1. LC-MS (QC conditions): IR = 0.486 min; [M+H]+ = 370.2. 1H NMR (500 MHz, DMSO) δ: 8.35 (m, 1 H), 7.86 (m, 1 H), 7.53-7.58 (m, 1 H), 7.29 (td, Ji = 2.2 Hz, J2 = 8.4 Hz, 1 H), 6.61-6.63 (m, 1 H), 5.79 (s, 2 H), 5.47 (s, 1 H), 3.61-3.65 (m, 1 H), 2.69-2.73 (m, 4 H), 2.20 (qd, Ji = 2.7 Hz, J2 = 7.7 Hz, 2 H), 1.92-1 .98 (m, 2 H).
The examples from Table 4 below are made according to the abovementioned procedure described for the synthesis of Example 1.1 using intermediate A1 and the appropriate sulfonylchloride B as starting materials. Reaction time goes up to 24h, at RT, with purification by prepHPLC (acidic or basic conditions).
Table 4
Figure imgf000067_0001
Figure imgf000068_0001
Example 2.1: N-(c/s-3-(2-amino-6-(ethylamino)pyrimidin-4-yl)cyclobutyl)-3-fluorobenzenesulfonamide
To a solution of intermediate A2 (65 mg, 0.205 mmol) in DCM (3 mL) is added NEts (1.44 mL, 1.03 mmol) and 3- fluorobenzene-1 -sulfonyl chloride (CAS # 701-27-9) (42 mg, 0.205 mmol). The reaction is stirred at RT for 18h. Purification by prepHPLC (basic conditions) gives 71 mg of Example 2.1. LC-MS (QC conditions): IR = 0.541 min; [M+H]+ = 366.4. 1H NMR (500 MHz, DMSO) δ: 8.09 (d, J = 8.5 Hz, 1 H), 7.66-7.68 (m, 2 H), 7.58-7.61 (m, 1 H), 7.51- 7.55 (m, 1 H), 6.70-6.70 (m, 1 H), 5.80 (s, 2 H), 5.45 (s, 1 H), 3.63 (m, 1 H), 3.19 (m, 2 H), 2.70 (m, 1 H), 2.18 (qd, Ji = 2.7 Hz, J2 = 7.6 Hz, 2 H), 1 .82-1.88 (m, 2 H), 1 .06 (t, J = 7.2 Hz, 3 H).
The examples from Table 5 below are made according to the abovementioned procedure described for the synthesis of Example 2.1 using intermediate A2 and the appropriate sulfonylchloride B as starting materials. Reaction time goes up to 24h, at RT, with purification by prepHPLC (acidic or basic conditions).
Table 5
Figure imgf000068_0002
Figure imgf000069_0001
Example 3.1: N-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-3-fluorobenzenesulfonamide
To a solution of intermediate A3 (198 mg, 0.673 mmol) in DCM (10 mL) is added NEts (0.47 mL, 3.36 mmol) and 3- fluorobenzene-1 -sulfonyl chloride (CAS # 701-27-9) (138 mg, 0.673 mmol). The reaction is stirred at RT for 18h. Purification by prepHPLC (basic conditions) gives 142 mg of Example 3.1. LC-MS (QC conditions): tR = 0.574 min; [M+H]+ = 380.2. 1H NMR (500 MHz, DMSO) δ: 8.09 (s, 1 H), 7.66-7.68 (m, 2 H), 7.58-7.60 (m, 1 H), 7.52-7.53 (m, 1 H), 6.51 (d, J = 6.5 Hz, 1 H), 5.71 (s, 2 H), 5.42 (s, 1 H), 3.94-4.04 (m, 1 H), 3.60-3.64 (m, 1 H), 2.68 (m, 1 H), 2.17 (qd, Ji = 2.7 Hz, J2 = 7.6 Hz, 2 H), 1 .84 (m, 2 H), 1 .07 (d, J = 6.5 Hz, 6 H).
Example 3.2: N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-2-fluoropyridine-3-sulfonamide Example 3.2 is made according to the abovementioned procedure described for the synthesis of Example 3.1 using intermediate A3 and 2-fluoro-3-pyridinesulfonyl chloride (CAS # 1089330-70-0) as starting materials. LC-MS (QC conditions): tR = 0.491 min; [M+H]+ = 381.3. 1H NMR (500 MHz, DMSO) δ: 8.51-8.54 (m, 2 H), 8.34 (m, 1 H), 7.59 (ddd, Ji = 1.6 Hz, J2 = 4.9 Hz, J3 = 7.4 Hz, 1 H), 6.54-6.55 (m, 1 H), 5.74 (s, 2 H), 5.45 (s, 1 H), 3.99-4.04 (m, 1 H), 3.67 (m, 1 H), 2.66-2.73 (m, 1 H), 2.19 (m, 2 H), 1.94 (m, 2 H), 1.08 (d, J = 6.5 Hz, 6 H).
Example 3.3: N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-5,6-dimethylpyridine-3- sulfonamide
Example 3.3 is made according to the abovementioned procedure described for the synthesis of Example 3.1 using intermediate A3 and sulfonylchloride B1 as starting materials. LC-MS (QC conditions): tR = 0.516 min; [M+H]+ = 391.5. 1H NMR (500 MHz, DMSO) δ: 8.63 (d, J = 2.2 Hz, 1 H), 8.04 (d, J = 8.4 Hz, 1 H), 7.89 (d, J = 1.8 Hz, 1 H), 6.50 (d, J = 6.6 Hz, 1 H), 5.71 (s, 2 H), 5.44 (s, 1 H), 3.99-4.00 (m, 1 H), 3.62 (m, 1 H), 2.64-2.72 (m, 1 H), 2.51 (s, 3 H), 2.35 (s, 3 H), 2.18 (qd, Ji = 2.7 Hz, J2 = 7.6 Hz, 2 H), 1.81-1.87 (m, 2 H), 1.07 (d, J = 6.5 Hz, 6 H).
The examples from Table 6 below are made according to the abovementioned procedure described for the synthesis of Example 3.1 using the appropriate intermediate A3 or A3.1 and the appropriate sulfonylchloride B as starting materials. Reaction time goes up to 24h, at RT, with purification by prepHPLC (acidic or basic conditions).
Table 6
Figure imgf000069_0002
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
The examples from Table 7 below are made according to the abovementioned procedure described for the synthesis of Example 3.1 using appropriate intermediate A and the appropriate sulfonylchloride B as starting materials. Reaction time goes up to 24h, at RT, with purification by prepHPLC (acidic or basic conditions). Table ?
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Example 5.1 : N-(c/s-3-(2-amino-6-(((R)-1,1,1-trifluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-2- fluoropyridine-3-sulfonamide
Example 5.1 is made according to the abovementioned procedure described for the synthesis of Example 3.1 using intermediate A5 and 2-fluoro-3-pyridinesulfonyl chloride (CAS # 1089330-70-0) as starting materials. LC-MS (QC conditions): tR = 0.543 min; [M+H]+ = 435.4. 1H NMR (500 MHz, DMSO) δ: 8.51-8.53 (m, 2 H), 8.34 (m, 1 H), 7.60 (ddd, Ji = 1.7 Hz, J2 = 4.9 Hz, J3 = 7.5 Hz, 1 H), 7.20 (d, J = 9.0 Hz, 1 H), 5.98 (s, 2 H), 5.59 (s, 1 H), 4.93-4.97 (m, 1 H), 3.67-3.70 (m, 1 H), 2.75 (m, 1 H), 2.19-2.24 (m, 2 H), 1.93-1.99 (m, 2 H), 1.25 (d, J = 7.0 Hz, 3 H).
Example 5.2: N/-(c/s-3-(2-amino-6-(((R)-1,1,1-trifluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-5,6- dimethylpyridine-3-sulfonamide
Example 5.2 is made according to the abovementioned procedure described for the synthesis of Example 3.1 using intermediate A5 and sulfonylchloride B1 as starting materials. LC-MS (QC conditions): tR = 0.568 min; [M+H]+ = 445.4. 1H NMR (500 MHz, DMSO) δ: 8.63 (d, J = 2.1 Hz, 1 H), 8.04 (d, J = 8.4 Hz, 1 H), 7.89 (d, J = 1.8 Hz, 1 H), 7.19 (d, J = 9.0 Hz, 1 H), 5.97 (s, 2 H), 5.58 (s, 1 H), 4.94-4.95 (m, 1 H), 3.64 (m, 1 H), 2.74 (m, 1 H), 2.51 (s, 3 H), 2.35 (s, 3 H), 2.20 (qd, Ji = 3.7 Hz, J2 = 7.3 Hz, 2 H), 1.86 (m, 2 H), 1.24 (d, J = 7.0 Hz, 3 H).
The examples from Table 8 below are made according to the abovementioned procedure described for the synthesis of Example 3.1 using appropriate intermediate A and the appropriate sulfonylchloride B as starting materials. Reaction time goes up to 24h, at RT, with purification by prepHPLC (acidic or basic conditions).
Table 8
Figure imgf000086_0003
Figure imgf000086_0002
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
Example 11.1: rac-N-(c/s-3-(2-amino-6-((1,1-difluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-3- fluorobenzenesulfonamide
Example 11.1 is made according to the abovementioned procedure described for the synthesis of Example 3.1 using the appropriate intermediate A11 and 3-fluorobenzenesulfonylchloride (CAS # 701-27-9) as starting materials.
Purification by prepHPLC (basic conditions) gives the title compound. LC-MS (QC conditions): IR = 0.581 min; [M+H]+ = 416.4. 1H NMR (500 MHz, DMSO) 5: 8.09 (d, J = 8.5 Hz, 1 H), 7.66-7.68 (m, 2 H), 7.58-7.61 (m, 1 H), 7.51-7.55 (m, 1 H), 6.90 (d, J = 7.5 Hz, 1 H), 5.87-6.10 (m, 3 H), 5.55 (s, 1 H), 4.40-4.41 (m, 1 H), 3.63 (m, 1 H), 2.71 (m, 1 H), 2.16- 2.21 (m, 2 H), 1.82-1.88 (m, 2 H), 1.12 (d, J = 7.0 Hz, 3 H).
Examples 11.2 and 11.3: N-(c/s-3-(2-amino-6-(((R)-1,1-difluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-3- fluorobenzenesulfonamide and N-(c/s-3-(2-amino-6-(((S)-1,1-difluoropropan-2-yl)amino)pyrimidin-4- yl)cyclobutyl)-3-fluorobenzenesulfonamide
23 mg of Example 11.1 are separated on a chiral stationary phase using the method below to give 7 mg of each title compound. Example 11.2: SFC (chiral A): IR = 1.57 min. LC-MS (QC conditions): IR = 0.594; [M+H]+ = 416.3. Example 11.3: SFC (chiral A): IR = 2.55 min. LC-MS (QC conditions): IR = 0.596 min; [M+H]+ = 416.3.
Column: Chiralcel OZ-H 30x250mm, 5 pirn; Detector wavelength: 217 nm; Eluent: 70% CO2 and 30% (EtOH 0.1 % diethylamine); Flow: 160.00 mL/min; BPR: 100 bar; Temperature: 40°C. Injection volume: 1000 jxL.
Example 11.4: rac-N-(c/s-3-(2-amino-6-((1,1-difluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-5,6- dimethylpyridine-3-sulfonamide
Example 11 .4 is made according to the abovementioned procedure described for the synthesis of Example 3.1 using the appropriate intermediate A11 and sulfonylchloride B1 as starting materials. Purification by prepHPLC (basic conditions) gives the title compound. LC-MS (QC conditions): IR = 0.525 min; [M+H]+ = 427.5. 1H NMR (500 MHz, DMSO) 5: 8.63 (d, J = 2.2 Hz, 1 H), 8.05 (s, 1 H), 7.89 (d, J = 1.9 Hz, 1 H), 6.90 (d, J = 7.8 Hz, 1 H), 5.87-6.10 (m, 3 H), 5.56 (s, 1 H), 4.40-4.41 (m, 1 H), 3.61-3.65 (m, 1 H), 2.72 (m, 1 H), 2.51 (s, 3 H), 2.35 (s, 3 H), 2.17-2.22 (m, 2 H), 1.85 (m, 2 H), 1.12 (d, J = 7.0 Hz, 3 H).
Example 11.6: N-(c/s-3-(2-amino-6-(((R)-1,1-difluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-5,6- dimethylpyridine-3-sulfonamide and Example 11.5 N-(c/s-3-(2-amino-6-(((S)-1,1-difluoropropan-2- yl)amino)pyrimidin-4-yl)cyclobutyl)-5,6-dimethylpyridine-3-sulfonamide
21 mg of Example 11.4 are separated on a chiral stationary phase using the method below to give 6 mg of each title compound. Example 11.5: SFC (chiral B): IR = 2.17 min. LC-MS (QC conditions): IR = 0.536; [M+H]+ = 427.4. Example 11.6: SFC (chiral B): IR = 3.30 min. LC-MS (QC conditions): IR = 0.537 min; [M+H]+ = 427.4.
Column: Chiralcel OZ-H 30x250mm, 5 pirn; Detector wavelength: 214 nm; Eluent: 65% CO2 and 35% (EtOH 0.1 % diethylamine); Flow: 160.00 mL/min; BPR: 100 bar; Temperature: 40°C. Injection volume: 1000 jxL.
Alternatively, Example 11 .5 can be prepared according to the abovementioned procedure described for the synthesis of Example 3.1 using intermediate A12 and the sulfonylchloride B1 as starting materials. Reaction time goes up to 24h, at RT, with purification by prepHPLC (acidic or basic conditions).
Alternatively, Example 11 .6 can be prepared according to the abovementioned procedure described for the synthesis of Example 3.1 using intermediate A13 and the sulfonylchloride B1 as starting materials. Reaction time goes up to 24h, at RT, with purification by prepHPLC (acidic or basic conditions).
Example 12.1 : N/-(c/s-3-(2-amino-6-(oxetan-3-ylamino)pyrimidin-4-yl)cyclobutyl)-3-fluorobenzenesulfonamide Step 1 : 4-(c/s-3-aminocyclobutyl)-6-chloropyrimidin-2-amine hydrochloride C1 To a solution of intermediate D1 (75 mg, 0.25 mmol) in dioxane (0.65 mL) is added a solution of HCI (4N in dioxane, 0.63 mL, 2.5 mmol). The reaction is stirred RT for 2h. The mixture is concentrated and the solid is dried under vacuum to give 68 mg of intermediate C1. LC-MS (conditions A): tR = 0.51 min; [M+H]+ = 199.36.
Step 2: N-(c/s-3-(2-amino-6-chloropyrimidin-4-yl)cyclobutyl)-3-fluorobenzenesulfonamide Ca1
To a solution of intermediate C1 (68 mg, 0.25 mmol) in DCM (2 mL) is added 3-fluorobenzenesulfonyl chloride (CAS # 701-27-9) (51 mg, 0.25 mmol) and NEts (0.18 mL, 1.25 mmol). The reaction is stirred at RT for 16h. The mixture is diluted with water (50 mL) and the aq. phase is extracted with DCM (2x50 mL). The combined org. phases are washed with brine (50 mL), dried (MgSO4), filtered and concentrated to give 90 mg of intermediate Ca1 . LC-MS (conditions A): tR = 0.82 min; [M+H]+ = 357.42. 1H NMR (400 MHz, DMSO) δ: 8.13 (d, J = 8.7 Hz, 1 H), 7.66 (d, J = 3.2 Hz, 2 H), 7.59 (d, J = 8.8 Hz, 1 H), 7.52-7.56 (m, 1 H), 7.02 (s, 2 H), 6.48 (s, 1 H), 3.69 (m, 1 H), 2.94 (m, 1 H), 2.25-2.30 (m, 2 H), 1.90-1.97 (m, 2 H).
Step 3: N-(c/s-3-(2-amino-6-(oxetan-3-ylamino)pyrimidin-4-yl)cyclobutyl)-3-fluorobenzenesulfonamide Example 12.1
To a solution of intermediate Ca1 (70 mg, 0.2 mmol) in EtOH (0.9 mL) is added DIPEA (0.07 mL, 0.4 mmol) and oxetan- 3-amine (CAS # 21635-88-1) (30 mg, 0.4 mmol). The reaction is heated to 85°C for 16h. More oxetan-3-amine (CAS # 21635-88-1) (30 mg, 0.4 mmol) is added, and the mixture is stirred at 85°C for another 24h. Purification by prepHPLC (basic conditions) gives 2 mg of Example 12.1. LC-MS (QC conditions): tR = 0.476 min; [M+H]+ = 394.3. 1H NMR (500 MHz, DMSO) δ: 8.10 (d, J = 8.3 Hz, 1 H), 7.66-7.68 (m, 2 H), 7.58-7.60 (m, 1 H), 7.52-7.55 (m, 1 H), 6.67-6.69 (m, 1 H), 5.84 (s, 2 H), 5.46 (s, 1 H), 4.88-4.89 (m, 1 H), 4.73 (t, J = 6.5 Hz, 2 H), 4.39 (t, J = 6.4 Hz, 2 H), 3.60-3.65 (m, 1 H), 2.68-2.75 (m, 1 H), 2.18 (qd, Ji = 2.7 Hz, J2 = 7.7 Hz, 2 H), 1.85 (m, 2 H).
Example [18F]-5.1 : N/-(c/s-3-(2-amino-6-(((R)-1,1,1-trifluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-2- (fluoro-18F)-pyridine-3-sulfonamide
[18F]fluoride ions are produced by bombardment of 98% enriched 18O-water via the 18O(p,n)18F nuclear reaction. The aqueous solution is transferred from the cyclotron to the hot-cell and trapped on a QMA cartridge (Waters SepPak Accel QMA cartridge carbonate). A mixture of kryptofix 2.2.2 (CAS # 23978-09-8) (5 mg/mL), K2CO3 (1 mg/mL) in MeCN/H2O (4:1) is applied to elute the radioactivity to the reaction vial. After azeotropic drying with MeCN (3x0.8 mL), 2-3 mg of intermediate G1 dissolved in DMF or DMSO (0.3 mL) is added to the residue and the mixture is heated to 150°C for 10 min in a closed reaction vial. After cooling down the reaction and dilution with 2.7 mL water, the mixture is purified by semi-preparative HPLC (Column: Gemini 5pim C18, 250 x 10mm; Eluent A: 0.5% NH3 in water; Eluent B: MeCN; Gradient: isocratic with 23% A; Retention time: 770-970 seconds). The collected fraction is diluted with 8 mL Milli-Q water and passed through a pre-conditioned C18 light cartridge (Waters, WAT023501). After washing with 5 mL Milli-Q water, the final radioligand is eluted with 1 mL EtOH and diluted with water for quality control. The radiochemical yield of the radioligand is ranging between 2-5 GBq (collected activity) or 2-32 GBq/pimol (Molar activity), respectively. The identity of the compounds was confirmed by identical retention time as compared to unlabeled Example 5.1.
The examples from Table 9 below may be prepared in analogy to the procedure described for example [18F]-5.1 using the appropriate precursor G or H. Table 9
Figure imgf000097_0001
Figure imgf000098_0001
BIOLOGICAL TESTS
FLIPR hCCR8 assay
20’000 HEK293.hCCR8 cells/well were seeded in 50pl of 90% DMEM, 10% none heat inactivated Foetal Bovine Serum, 1% Penicillin/Streptomycin, 800pg/ml G418, 200pg/ml hygromycin B into 384-well plate coated with Poly-L- Lysine. Cells were incubated at 37°C, 5% CO2 for 24hours. Compounds to be tested were prepared by serial dilution from 10piM to 0.038nM. FLIPR buffer containing HBSS/0.1%BSA/20mM Hepes/2.5mM probenecid was made and FLIPR staining solution was obtained by adding 15ml FLIPR buffer to 10ml calcium 6 for one plate. Medium was removed from cells. 50pl of the above staining solution was added. The plate was centrifugated briefly and incubated at 37°C, 5% CO2 for 1 h30. 10pil of compounds diluted in FLIPR buffer were distributed and incubated for 30 minutes in the dark followed by the addition of 10pil of a 70nM hCCL1 stock solution. The signal is recorded immediately with the FLIPR device. Data were analyzed to generate IC50 values, and the results are summarized in Table 10.
Table 10
Figure imgf000098_0003
Figure imgf000098_0004
Figure imgf000098_0005
Figure imgf000098_0002
Figure imgf000099_0001
Figure imgf000099_0004
Figure imgf000099_0003
Figure imgf000099_0002
Figure imgf000100_0003
Figure imgf000100_0002
Figure imgf000100_0004
Figure imgf000100_0001

Claims

1. A compound of Formula (I)
Figure imgf000101_0001
Formula (I), wherein
Ar represents
• phenyl;
• 5-membered heteroaryl containing from one to three ring heteroatoms independently selected from nitrogen, sulfur, and oxygen; or
• 6-membered heteroaryl containing from one to three ring nitrogen atoms; wherein said phenyl, 5-membered heteroaryl, or 6-membered heteroaryl, independently is unsubstituted, mono-, di-, or tri-substituted, wherein the substituent independently represents
> halogen;
> cyano;
> C1-3-alkyl;
> C1-2-fluoroalkyl;
> C1-2-alkoxy;
> C3-4-cydoalkyl;
> C1-2-fluoroalkoxy; or
> amino optionally mono- or di-substituted with methyl or ethyl;
R1 represents
• C1-5-alkyl;
• hydroxy-C2-4-alkyl;
• C1-2-alkoxy-C2-4-alkyl;
• C1-4-fluoroalkyl; or
• -L-Cy, wherein
> -L- represents a bond or -CH2-; and > Cy represents C3-6-cycloalkyl optionally containing one oxygen ring atom, wherein said C3-6- cycloalkyl optionally containing one oxygen ring atom is unsubstituted or mono-substituted, wherein the substituent represents fluorine; and
R2 represents hydrogen or fluorine; or a pharmaceutically acceptable salt thereof; with the proviso that the following compounds and salts thereof are excluded:
N-(3-(2-amino-6-(methylamino)pyrimidin-4-yl)cyclobutyl)-2,5-dimethylthiophene-3-sulfonamide;
N-(3-(2-amino-6-(methylamino)pyrimidin-4-yl)cyclobutyl)-5-chlorothiophene-2-sulfonamide;
N-(3-(2-amino-6-(methylamino)pyrimidin-4-yl)cyclobutyl)-2,4-dimethylbenzenesulfonamide;
N-(3-(2-amino-6-(methylamino)pyrimidin-4-yl)cyclobutyl)-3,5-dimethylisoxazole-4-sulfonamide;
N-(3-(2-amino-6-(methylamino)pyrimidin-4-yl)cyclobutyl)-2-methoxy-4-methylbenzenesulfonamide;
N-(3-(2-amino-6-(methylamino)pyrimidin-4-yl)cyclobutyl)-2,4-difluorobenzenesulfonamide;
N-(3-(2-amino-6-(methylamino)pyrimidin-4-yl)cyclobutyl)-2,5-difluorobenzenesulfonamide;
N-(3-(2-amino-6-(methylamino)pyrimidin-4-yl)cyclobutyl)-4-methoxy-3-methylbenzenesulfonamide;
N-(c/s-3-(2-amino-6-(methylamino)pyrimidin-4-yl)cyclobutyl)-2,5-dimethylthiophene-3-sulfonamide;
N-(c/s-3-(2-amino-6-(methylamino)pyrimidin-4-yl)cyclobutyl)-5-chlorothiophene-2-sulfonamide;
N/-(c/s-3-(2-amino-6-(methylamino)pyrimidin-4-yl)cyclobutyl)-2,4-dimethylbenzenesulfonamide;
N-(c/s-3-(2-amino-6-(methylamino)pyrimidin-4-yl)cyclobutyl)-3,5-dimethylisoxazole-4-sulfonamide;
N/-(c/s-3-(2-amino-6-(methylamino)pyrimidin-4-yl)cyclobutyl)-2-methoxy-4-methylbenzenesulfonamide;
N/-(c/s-3-(2-amino-6-(methylamino)pyrimidin-4-yl)cyclobutyl)-2,4-difluorobenzenesulfonamide;
N-(c/s-3-(2-amino-6-(methylamino)pyrimidin-4-yl)cyclobutyl)-2,5-difluorobenzenesulfonamide; and
N/-(c/s-3-(2-amino-6-(methylamino)pyrimidin-4-yl)cyclobutyl)-4-methoxy-3-methylbenzenesulfonamide.
2. A compound according to claim 1, wherein Ar represents
• 6-membered heteroaryl containing from one to three ring nitrogen atoms, wherein said 6-membered heteroaryl is unsubstituted, mono-, di-, or tri-substituted, wherein the substituent independently represents
> halogen;
> cyano;
> C1-3-alkyl;
> C1-2-fluoroalkyl;
> C1-2-alkoxy;
> C3-4-cydoalkyl;
> C1-2-fluoroalkoxy; or
> amino optionally mono- or di-substituted with methyl or ethyl; or a pharmaceutically acceptable salt thereof.
3. A compound according to claim 1, wherein Ar represents
• 6-membered heteroaryl selected from pyridin-3-yl, wherein said 6-membered heteroaryl is unsubstituted, mono-, di-, or tri-substituted, wherein the substituent independently represents > halogen;
> C1-3-alkyl;
> C1-2-fluoroalkyl;
> C1-2-alkoxy; or
> C3-4-cycloalkyl; or a pharmaceutically acceptable salt thereof.
4. A compound according to any one of claims 1 to 3, wherein R1 represents
• C1-5-alkyl;
• hydroxy-C2-4-alkyl;
• C1-2-alkoxy-C2-4-alkyl;
• C1-4-fluoroalkyl; or
• -L-Cy, wherein
> -L- represents a bond or -CH2-; and
> Cy represents C3-6-cycloalkyl optionally containing one oxygen ring atom, wherein said C3-6- cycloalkyl optionally containing one oxygen ring atom is unsubstituted or mono-substituted, wherein the substituent represents fluorine; or a pharmaceutically acceptable salt thereof.
5. A compound according to any one of claims 1 to 3, wherein R1 represents
• ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, or sec-butyl;
• 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 1-methyl-2-fluoroethyl, 2-fluoro-1-fluoromethyl-ethyl, 1- methyl-2,2-difluoro-ethyl, 1-methyl-1-trifluoromethyl-ethyl, or 2,2,2-trifluoro-1-methyl-ethyl; especially 1- methyl-1 -trifluoromethy l-ethy I ; or
• cyclopropyl, cydopropyl-methyl, or (l-fluoro-cyclopropyl)-methyl; or a pharmaceutically acceptable salt thereof.
6. A compound according to any one of claims 1 to 5, wherein R2 represents hydrogen; or a pharmaceutically acceptable salt thereof.
7. A compound according to claim 1, wherein
Ar represents a 6-membered heteroaryl, wherein said 6-membered heteroaryl is selected from pyridin-3-yl, wherein said pyridin-3-yl is unsubstituted, mono-, or di-substituted in position(s) 2 and/or 5 and/or 6, with regard to the nitrogen atom of said pyridin-3-yl; wherein the substituent(s) independently represent methyl or fluorine;
R1 represents C2-4-alkyl, cyclopropyl, or 2,2,2-trifluoro-1-methyl-ethyl; and
R2 represents hydrogen; or a pharmaceutically acceptable salt thereof.
8. A compound according to any one of claims 1 to 6, which is a radiolabeled compound, wherein
• Ar is as defined in any one of claims 1 to 6, wherein Ar is mono-, di-, or tri-substituted, wherein one substituent represents a radioactive isotope of fluorine, wherein the rest of the substituents of Ar, if any, independently is/are as defined in any one of claims 1 to 6; R1 is as defined in any one of claims 1 to 6; and R2 is as defined in any one of claims 1 to 6; or
• Ar is as defined in any one of claims 1 to 6, wherein Ar is mono-, di-, or tri-substituted, wherein one substituent represents a radioactive isotope of iodine, wherein the rest of the substituents of Ar, if any, independently is/are as defined in any one of claims 1 to 6; R1 is as defined in any one of claims 1 to 6; and R2 is as defined in any one of claims 1 to 6; or
• Ar is as defined in any one of claims 1 to 6, wherein Ar is unsubstituted, mono-, di-, or tri-substituted, wherein the substituent, if any, independently is/are as defined in any one of claims 1 to 6; R1 is as defined in any one of claims 1 to 6; and R2 represents a radioactive isotope of fluorine; or a pharmaceutically acceptable salt thereof.
9. A compound according to claim 1, wherein the radical
Figure imgf000104_0001
represents:
• phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 4-iodophenyl, 3-iodophenyl, 3-chlorophenyl, 3- cyanophenyl, 3-methylphenyl, 3-methoxyphenyl, 3-(trifluoromethoxy)-phenyl, 3,4-difluorophenyl, 2,3- difluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 3-fluoro-4-methoxyphenyl, 3- methyl-4-methoxyphenyl, 3-fluoro-4-methylphenyl, 2-methyl-5-fluorophenyl, 2-fluoro-5-methylphenyl, 3,5,- dichlorophenyl, 2-fluoro-5-chlorophenyl, 3-chloro-4-iodophenyl, 3-fluoro-4-iodophenyl, 2-fluoro-4-iodophenyl,
3-cyano-4-iodophenyl, 3-methyl-4-iodophenyl, or 2-chloro-5-fluorophenyl; and/or
• thiophen-2-yl, 4-methyl-thiophen-2-yl, 3-methyl-thiophen-2-yl, 5-methyl-thiophen-2-yl, 5-chloro-thiophen-2-yl, 5-fluoro-thiophen-2-yl, 5-bromo-thiophen-2-yl, 5-methoxy-thiophen-2-yl, 5-cyclopropyl-thiophene-2-yl, 5- methyl-thiophen-3-yl, 4-methyl-thiazol-2-yl, 2-methyl-thiazol-4-yl, 2-chloro-thiazol-4-yl, thiazol-4-yl, thiazol-5- yl, 2-ethyl-thiazol-5-yl, 2-methyl-thiazol-5-yl, 2-methoxy-thiazole-5-yl, 2-chloro-thiazol-5-yl, 2-cyclopropyl- thiazole-5-yl, 2-(1,1-difluoro-ethyl)-thiazole-5-yl, 2,4-dimethyl-thiazol-5-yl, 2-bromo-4-methyl-thiazol-5-yl, 2- chloro-4-methyl-thiazol-5-yl, 3-methyl-isothiazol-5-yl, 5-methyl-[1,3,4]thiadiazol-2-yl, 1-methyl-1 H-pyrazole-4- yl, 3-methyl-isoxazol-4-yl, 2-methyl-oxazol-5-yl, 1 -methyl- 1 H-[1 ,2,3]triazol-4-yl, 2-methyl-2H-[1,2,3]triazol-4- yl, 1,5-dimethyl-1 H-pyrazol-3-yl, 3,5-dimethyl-isoxazole-4-yl, or 5-difluoromethyl-thiophen-3-yl; and/or
• pyridin-2-yl, pyridin-3-yl, 2-fluoro-pyridin-3-yl, 5-fluoro-pyridin-3-yl, 6-fluoro-pyridin-3-yl, 2-chloro-pyridin-3-yl,
4-chloro-pyridin-3-yl, 5-chloro-pyridin-3-yl, 6-chloro-pyridin-3-yl, 2-bromo-pyridin-3-yl, 2-methyl-pyridin-3-yl, 4- methyl-pyridin-3-yl, 5-methyl-pyridin-3-yl, 6-methyl-pyridin-3-yl, 5-ethyl-pyridin-3-yl, 6-ethyl-pyridin-3-yl, 5- cyclopropyl-pyridin-3-yl, 6-cyclopropyl-pyridin-3-yl, 5-cyano-pyridin-3-yl, 6-cyano-pyridin-3-yl, 6-methoxy- pyridin-3-yl, 6-methylamino-pyridin-3-yl, 2-difluoromethyl-pyridin-3-yl, 5-difluoromethyl-pyridin-3-yl, 6- difluoromethyl-pyridin-3-yl, 5,6-dimethyl-pyridin-3-yl, 2,6-dimethyl-pyridin-3-yl, 2,5-dimethyl-pyridin-3-yl, 4,6- dimethyl-pyridin-3-yl, 5-chloro-6-methyl-pyridin-3-yl, 6-chloro-5-methyl-pyridin-3-yl, 5-fluoro-6-methyl-pyridin- 3-yl, 2-fluoro-6-methyl-pyridin-3-yl, 6-fluoro-2-methyl-pyridin-3-yl, 6-fluoro-5-methyl-pyridin-3-yl, 2-chloro-6- methyl-pyridin-3-yl, 2,6-dichloro-pyridin-3-yl, 6-chloro-2-methyl-pyridin-3-yl, 2,6-difluoro-pyridin-3-yl, 6-chloro- 5-fluoro-pyridin-3-yl, 5,6-difluoro-pyridin-3-yl, 5,6-dichloro-pyridin-3-yl, 5-fluoro-2-methyl-pyridin-3-yl, 2-fluoro- 5-methyl-pyridin-3-yl, 5-chloro-2-methyl-pyridin-3-yl, 2-chloro-5-methyl-pyridin-3-yl, 6-chloro-4-methyl- pyridin-3-yl, 2-chloro-6-fluoro-pyridin-3-yl, 6-trifluoromethyl-pyridin-3-yl, 5-methyl-6-trifluoromethyl-pyridin-3- yl, 5-chloro-6-fluoro-pyridin-3-yl, 5-chloro-2-fluoro-pyridin-3-yl, 2-chloro-6-methoxy-pyridin-3-yl, 5-chloro-2- methoxy-pyridin-3-yl, 6-dimethylamino-pyridin-3-yl, 2-chloro-5,6-dimethyl-pyridin-3-yl, 2-fluoro-5,6-dimethyl- pyridin-3-yl, 2,5,6-trimethyl-pyridin-3-yl, pyridin-4-yl, pyridazin-2-yl, 6-methyl-pyridazin-2-yl, pyrimidin-5-yl, or 2-amino-pyrimidin-5-yl;
R1 represents: methyl, ethyl, cyclopropyl, 2-fluoroethyl, n-propyl, isopropyl, 2-hydroxyethyl, 2-fluoro-1 -methyl-ethyl, tert-butyl, sec-butyl, 2,2-difluoro-ethyl, 2-hydroxy-1 -methyl-ethyl, 2-methoxy-ethyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetan-3-yl, 1-fluoro-cyclopropylmethyl, cyclobutyl-methyl, 2,2,2-trifluoro-ethyl, 2, 2, 2-trifluoro-1 -methyl-ethyl, 2-fluoro-1-fluoromethyl-ethyl, 2, 2-difluoro-1 -methyl-ethyl, 2-hydroxy-1 ,1 -di methyl-ethyl, 2-methoxy-1 -methyl- ethyl, or 2-methoxy-1 ,1-dimethyl-ethyl; and
R2 represents fluorine or hydrogen; or a pharmaceutically acceptable salt thereof.
10. A compound according to any one of claims 1 to 9, which is also a compound of Formula (II)
Figure imgf000105_0001
Formula (II); or a pharmaceutically acceptable salt thereof.
11. A compound according to claim 1 which is
N/-(c/s-3-(2-amino-6-(methylamino)pyrimidin-4-yl)cyclobutyl)-2-fluorobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-(methylamino)pyrimidin-4-yl)cyclobutyl)-3-fluorobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-(methylamino)pyrimidin-4-yl)cyclobutyl)-4-fluorobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-(methylamino)pyrimidin-4-yl)cyclobutyl)-3,4-difluorobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-(methylamino)pyrimidin-4-yl)cyclobutyl)-2,3-difluorobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-(methylamino)pyrimidin-4-yl)cyclobutyl)-2,6-difluorobenzenesulfonamide;
N-(c/s-3-(2-amino-6-(methylamino)pyrimidin-4-yl)cyclobutyl)-2-fluoro-5-methylbenzenesulfonamide;
N-(c/s-3-(2-amino-6-(methylamino)pyrimidin-4-yl)cyclobutyl)-5-chloro-2-fluorobenzenesulfonamide;
N-(c/s-3-(2-amino-6-(methylamino)pyrimidin-4-yl)cyclobutyl)-2-chloro-5-fluorobenzenesulfonamide;
N-(c/s-3-(2-amino-6-(methylamino)pyrimidin-4-yl)cyclobutyl)-5-fluoro-2-methylbenzenesulfonamide;
N/-(c/s-3-(2-amino-6-(ethylamino)pyrimidin-4-yl)cyclobutyl)-3-fluorobenzenesulfonamide; N/-(c/s-3-(2-amino-6-(ethylamino)pyrimidin-4-yl)cyclobutyl)-2,3-difluorobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-(ethylamino)pyrimidin-4-yl)cyclobutyl)-2,5-difluorobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-3-fluorobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-2-fluoropyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-5,6-dimethylpyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)pyridine-2-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-3-cyanobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-3-fluoro-4-methylbenzenesulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-1-methyl-1 H-pyrazole-4-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-3-methylbenzenesulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-3,5-dichlorobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)benzenesulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-5-fluoro-2-methylbenzenesulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-3-chlorobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-3-(trifluoromethoxy)benzenesulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-3-fluoro-4-methoxybenzenesulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-3-methoxybenzenesulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)pyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-2,3-difluorobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-2-chlorothiazole-5-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-3,4-difluorobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-6-methylpyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-2,6-difluoropyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-4,6-dimethylpyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-2-bromo-4-methylthiazole-5-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)thiazole-5-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-2-ethylthiazole-5-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-2-methylthiazole-5-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-2-cyclopropylthiazole-5-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-6-chloropyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)thiophene-2-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-3,5-dimethylisoxazole-4-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-6-chloro-2-methylpyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-6-fluoropyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-2-chloro-5-methylpyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-2-chloro-6-methoxypyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-6-chloro-4-methylpyridine-3-sulfonamide;
2-amino-N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)pyrimidine-5-sulfonamide; N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-6-methoxypyridine-3-sulfonamide;
N/-(frans-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-2-chlorothiazole-5-sulfonamide;
N-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-2-methyloxazole-5-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)pyridine-4-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-2-chloropyridine-3-sulfonamide;
N/-(c/'s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-5-methyl-1 ,3,4-thiadiazole-2-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-2-methylpyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-5-chloropyridine-3-sulfonamide;
N-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-5-chloro-2-methoxypyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-2-chloro-6-methylpyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-5-methyl-6-(trifluoromethyl)pyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-6-(dimethylamino)pyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-2-chloro-4-methylthiazole-5-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-6-(trifluoromethyl)pyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)thiazole-4-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-4-methylpyridine-3-sulfonamide;
N-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-2,5-difluorobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-2-fluoro-5-methylpyridine-3-sulfonamide;
N-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-2-methoxythiazole-5-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-4-chloropyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-4-methylthiazole-2-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-3-methylisoxazole-4-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-6-fluoro-5-methylpyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-2,4-dimethylthiazole-5-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)pyrazine-2-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-5-fluoropyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)pyrimidine-5-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-1-methyl-1 H-1 ,2,3-triazole-4-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-2-(1,1-difluoroethyl)thiazole-5-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-2-chlorothiazole-4-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-5-fluorothiophene-2-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-1 ,5-dimethyl-1 H-pyrazole-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-3-methylisothiazole-5-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-5-(difluoromethyl)thiophene-3-sulfonamide;
N-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-5-methylthiophene-2-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-2-methyl-2/-/-1 ,2,3-triazole-4-sulfonamide;
N-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-5-methoxythiophene-2-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-6-methylpyridazine-3-sulfonamide; N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-4-methylthiophene-2-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-5-methylthiophene-3-sulfonamide;
N-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-5-chlorothiophene-2-sulfonamide;
N-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-5-cyclopropylthiophene-2-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-3-methylthiophene-2-sulfonamide;
N-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-5-bromothiophene-2-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-2,6-dichloropyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-6-chloro-5-methylpyridine-3-sulfonamide;
N-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-5-cyanopyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-6-cyanopyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-6-(difluoromethyl)pyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-6-chloro-5-fluoropyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-5-methylpyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-5-fluoro-6-methylpyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-5-chloro-6-fluoropyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-5,6-difluoropyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-2-fluoro-6-methylpyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-6-fluoro-2-methylpyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-2-(difluoromethyl)pyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-5-chloro-6-methylpyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-6-ethylpyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-6-cyclopropylpyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-5-cyclopropylpyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-2-chloro-6-fluoropyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-2-chloro-5,6-dimethylpyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-5-(difluoromethyl)pyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-5-ethylpyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-2,6-dimethylpyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-5-chloro-2-methylpyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-5-chloro-2-fluoropyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-5-fluoro-2-methylpyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-2,5-dimethylpyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-2-fluoro-5,6-dimethylpyridine-3-sulfonamide;
N-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-5,6-dichloropyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-6-(methylamino)pyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-2-bromopyridine-3-sulfonamide;
N-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-2,5,6-trimethylpyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(cyclopropylamino)pyrimidin-4-yl)cyclobutyl)-3-fluorobenzenesulfonamide; N/-(c/s-3-(2-amino-6-(cyclopropylamino)pyrimidin-4-yl)cyclobutyl)-2-fluoropyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(cyclopropylamino)pyrimidin-4-yl)cyclobutyl)-2-methylthiazole-4-sulfonamide;
N/-(c/s-3-(2-amino-6-(cyclopropylamino)pyrimidin-4-yl)cyclobutyl)-2-methylthiazole-5-sulfonamide;
N/-(c/s-3-(2-amino-6-(cyclopropylamino)pyrimidin-4-yl)cyclobutyl)pyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(cyclopropylamino)pyrimidin-4-yl)cyclobutyl)-2-chloropyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(cyclopropylamino)pyrimidin-4-yl)cyclobutyl)-2-methylpyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(cyclopropylamino)pyrimidin-4-yl)cyclobutyl)-5-fluoropyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(cyclopropylamino)pyrimidin-4-yl)cyclobutyl)-5-chloropyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(cyclopropylamino)pyrimidin-4-yl)cyclobutyl)-6-fluoropyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(cyclopropylamino)pyrimidin-4-yl)cyclobutyl)-6-chloropyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(cyclopropylamino)pyrimidin-4-yl)cyclobutyl)-6-methylpyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(cyclopropylamino)pyrimidin-4-yl)cyclobutyl)-2-fluoro-6-methylpyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(cyclopropylamino)pyrimidin-4-yl)cyclobutyl)-2,6-dimethylpyridine-3-sulfonamide;
N-(c/s-3-(2-amino-6-(cyclopropylamino)pyrimidin-4-yl)cyclobutyl)-5,6-dimethylpyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(((R)-1 , 1 , 1-trifluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-2-fluoropyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(((S)-1 , 1 , 1 -trif I uoropropan-2-y I) am i no) pyri mid i n-4-y l)cyclobu tyl)-2-f I uoropy ridi ne-3-su Ifon amide;
N/-(c/s-3-(2-amino-6-(((R)-1 , 1 , 1-trifluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-5,6-dimethylpyridine-3- sulfonamide;
N/-(c/s-3-(2-amino-6-(((S)-1,1 , 1-trifluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-5,6-dimethylpyridine-3- sulfonamide;
N/-(c/s-3-(2-amino-6-(((R)-1 , 1 , 1-trifluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-3-fluorobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-(((S)-1 , 1 , 1-trifluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-3-fluorobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-(propylamino)pyrimidin-4-yl)cyclobutyl)-3-fluorobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-(propylamino)pyrimidin-4-yl)cyclobutyl)-2,3-difluorobenzenesulfonamide;
N-(c/s-3-(2-amino-6-(propylamino)pyrimidin-4-yl)cyclobutyl)-2,5-difluorobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-(tert-butylamino)pyrimidin-4-yl)cyclobutyl)-3-fluorobenzenesulfonamide;
N-(c/s-3-(2-amino-6-(tert-butylamino)pyrimidin-4-yl)cyclobutyl)-5,6-dimethylpyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(cyclobutylamino)pyrimidin-4-yl)cyclobutyl)-3-fluorobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-((cyclobutylmethyl)amino)pyrimidin-4-yl)cyclobutyl)-3-fluorobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-(cyclobutylamino)pyrimidin-4-yl)cyclobutyl)-2,3-difluorobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-((cyclobutylmethyl)amino)pyrimidin-4-yl)cyclobutyl)-2,3-difluorobenzenesulfonamide;
N-(c/s-3-(2-amino-6-(cyclobutylamino)pyrimidin-4-yl)cyclobutyl)-2,5-difluorobenzenesulfonamide;
N-(c/s-3-(2-amino-6-((cyclobutylmethyl)amino)pyrimidin-4-yl)cyclobutyl)-2,5-difluorobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-(((S)-1-hydroxypropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-3-fluorobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-((1-hydroxy-2-methylpropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-3-fluorobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-(sec-butylamino)pyrimidin-4-yl)cyclobutyl)-3-fluorobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-((2,2-difluoroethyl)amino)pyrimidin-4-yl)cyclobutyl)-3-fluorobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-((2,2,2-trifluoroethyl)amino)pyrimidin-4-yl)cyclobutyl)-3-fluorobenzenesulfonamide; N/-(c/s-3-(2-amino-6-((2-fluoroethyl)amino)pyrimidin-4-yl)cyclobutyl)-3-fluorobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-((1-fluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-3-fluorobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-((2-methoxyethyl)amino)pyrimidin-4-yl)cyclobutyl)-2-fluoropyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(((S)-1-hydroxypropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-2-fluoropyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(((S)-1-methoxypropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-2-fluoropyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-((1-methoxy-2-methylpropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-2-fluoropyridine-3- sulfonamide;
N/-(c/s-3-(2-amino-6-(((1-fluorocyclopropyl)methyl)amino)pyrimidin-4-yl)cyclobutyl)-3-fluorobenzenesulfonamide;
N-(c/s-3-(2-amino-6-(((1-fluorocyclopropyl)methyl)amino)pyrimidin-4-yl)cyclobutyl)-5,6-dimethylpyridine-3- sulfonamide;
N/-(c/s-3-(2-amino-6-((1,3-difluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-3-fluorobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-((1,1-difluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-3-fluorobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-(((R)-1,1-difluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-3-fluorobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-(((S)-1,1-difluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-3-fluorobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-((1 ,1-difluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-5,6-dimethylpyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(((R)-1,1-difluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-5,6-dimethylpyridine-3- sulfonamide;
N/-(c/s-3-(2-amino-6-(((S)-1,1-difluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-5,6-dimethylpyridine-3- sulfonamide;
N/-(c/s-3-(2-amino-6-(oxetan-3-ylamino)pyrimidin-4-yl)cyclobutyl)-3-fluorobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-((1 ,1 ,1-trifluoro-2-methylpropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-2-fluoropyridine-3- sulfonamide;
N/-(c/s-3-(2-amino-6-(butylamino)pyrimidin-4-yl)cyclobutyl)-3-fluorobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-(isobutylamino)pyrimidin-4-yl)cyclobutyl)-3-fluorobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-(cyclopentylamino)pyrimidin-4-yl)cyclobutyl)-3-fluorobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-(cyclohexylamino)pyrimidin-4-yl)cyclobutyl)-3-fluorobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-((cyclopropylmethyl)amino)pyrimidin-4-yl)cyclobutyl)-3-fluorobenzenesulfonamide;
N-(c/s-3-(2-amino-6-(ethylamino)pyrimidin-4-yl)cyclobutyl)-5,6-dimethylpyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(ethylamino)pyrimidin-4-yl)cyclobutyl)-2-fluoropyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-4-iodobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-3-iodobenzenesulfonamide;
N-(frans-3-(2-amino-6-(isopropylamino)pyrimidin-4-yl)cyclobutyl)-6-fluoro-2-methylpyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(((R)-1,1 ,1-trifluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)pyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(((R)-1,1 ,1-trifluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-6-fluoropyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(((R)-1,1 ,1-trifluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-6-methylpyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(((R)-1,1 ,1-trifluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-6-fluoro-5-methylpyridine-3- sulfonamide; N/-(c/s-3-(2-amino-6-(((R)-1,1 ,1-trifluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-6-fluoro-2-methylpyridine-3- sulfonamide;
N/-(c/s-3-(2-amino-6-(((R)-1,1 ,1-trifluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-5-fluoro-2-methylpyridine-3- sulfonamide;
N/-(c/s-3-(2-amino-6-(((R)-1,1 ,1-trifluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-2-methylpyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(((R)-1,1 ,1-trifluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-2,6-dimethylpyridine-3- sulfonamide;
N/-(c/s-3-(2-amino-6-(((R)-1,1 ,1-trifluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-2-fluoro-6-methylpyridine-3- sulfonamide;
N/-(c/s-3-(2-amino-6-(((R)-1,1 ,1-trifluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-5-fluoro-6-methylpyridine-3- sulfonamide;
N/-(c/s-3-(2-amino-6-(((R)-1,1 ,1-trifluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-3-chloro-4- iodobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-(((R)-1,1 ,1-trifluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-3-fluoro-4- iodobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-(((R)-1,1 ,1-trifluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-2-fluoro-4- iodobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-(((R)-1,1 ,1-trifluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-4-iodobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-(((R)-1,1 ,1-trifluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-3-cyano-4- iodobenzenesulfonamide;
N/-(c/s-3-(2-amino-6-(((R)-1,1 ,1-trifluoropropan-2-yl)amino)pyrimidin-4-yl)cyclobutyl)-4-iodo-3- methylbenzenesulfonamide;
N-(c/s-3-(2-amino-6-(propylamino)pyrimidin-4-yl)cyclobutyl)-5,6-dimethylpyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(propylamino)pyrimidin-4-yl)cyclobutyl)-2-fluoropyridine-3-sulfonamide;
N-(c/s-3-(2-amino-6-(fert-butylamino)pyrimidin-4-yl)cyclobutyl)-2-methylpyridine-3-sulfonamide;
N-(c/s-3-(2-amino-6-(fert-butylamino)pyrimidin-4-yl)cyclobutyl)-6-methylpyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(fert-butylamino)pyrimidin-4-yl)cyclobutyl)-2-fluoropyridine-3-sulfonamide;
N-(c/s-3-(2-amino-6-(fert-butylamino)pyrimidin-4-yl)cyclobutyl)-2,6-dimethylpyridine-3-sulfonamide;
N-(c/s-3-(2-amino-6-(fert-butylamino)pyrimidin-4-yl)cyclobutyl)-2-fluoro-6-methylpyridine-3-sulfonamide;
N-(c/s-3-(2-amino-6-(((R)-sec-butyl)amino)pyrimidin-4-yl)cyclobutyl)-5,6-dimethylpyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(((R)-sec-butyl)amino)pyrimidin-4-yl)cyclobutyl)-2-fluoropyridine-3-sulfonamide;
N-(c/s-3-(2-amino-6-(((S)-sec-butyl)amino)pyrimidin-4-yl)cyclobutyl)-5,6-dimethylpyridine-3-sulfonamide;
N/-(c/s-3-(2-amino-6-(((S)-sec-butyl)amino)pyrimidin-4-yl)cyclobutyl)-2-fluoropyridine-3-sulfonamide; or
N-(c/s-3-(2-amino-6-(ethylamino)-5-fluoropyrimidin-4-yl)cyclobutyl)-3-fluorobenzenesulfonamide; or a pharmaceutically acceptable salt thereof.
12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
13. A compound of Formula (I)
Figure imgf000112_0001
Formula (I), wherein
Ar represents
• phenyl;
• 5-membered heteroaryl containing from one to three ring heteroatoms independently selected from nitrogen, sulfur, and oxygen; or
• 6-membered heteroaryl containing from one to three ring nitrogen atoms; wherein said phenyl, 5-membered heteroaryl, or 6-membered heteroaryl, independently is unsubstituted, mono-, di-, or tri-substituted, wherein the substituent independently represents
> halogen;
> cyano;
> C1-3-alkyl;
> C1-2-fluoroalkyl;
> C1-2-alkoxy;
> C3-4-cydoalkyl;
> C1-2-fluoroalkoxy; or
> amino optionally mono- or di-substituted with methyl or ethyl;
R1 represents
• C1-5-alkyl;
• hydroxy-C2-4-alkyl;
• C1-2-alkoxy-C2-4-alkyl;
• C1-4-fluoroalkyl; or
• -L-Cy, wherein
> -L- represents a bond or -CH2-; and
> Cy represents C3-6-cycloalkyl optionally containing one oxygen ring atom, wherein said C3-6- cycloalkyl optionally containing one oxygen ring atom is unsubstituted or mono-substituted, wherein the substituent represents fluorine;
R2 represents hydrogen or fluorine; or a pharmaceutically acceptable salt thereof; for use as a medicament.
14. A compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, for use as a medicament.
15. A compound according to any one of claims 1 to 11 , or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of
• a disease/disorder selected from a group consisting of cancer, wherein said compound, or a pharmaceutically acceptable salt thereof, is used as a single therapeutic agent or in combination with one or more chemotherapy agent and/or radiotherapy and/or targeted therapy; or • a disease/disorder selected from a group consisting of atopic diseases; fibrotic diseases; neuropathic pain; sepsis; septic peritonitis; infections associated with immune suppression; infections resulting from burn injury; chronic obstructive pulmonary disease; organ transplantation; allogeneic kidney transplantation; peritoneal adhesions; pathological bondings of serosal membranes related to surgery or inflammation; and autoimmune encephalomyelitis, wherein said compound, or a pharmaceutically acceptable salt thereof, is used as a single therapeutic agent or in combination with one or more further therapeutic agent or therapy.
PCT/EP2023/083499 2022-11-30 2023-11-29 Aryl- and heteroaryl-sulfonamide derivatives as ccr8 modulators Ceased WO2024115549A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EPPCT/EP2022/083811 2022-11-30
EP2022083811 2022-11-30

Publications (1)

Publication Number Publication Date
WO2024115549A1 true WO2024115549A1 (en) 2024-06-06

Family

ID=89076058

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2023/083499 Ceased WO2024115549A1 (en) 2022-11-30 2023-11-29 Aryl- and heteroaryl-sulfonamide derivatives as ccr8 modulators

Country Status (3)

Country Link
AR (1) AR131211A1 (en)
TW (1) TW202430180A (en)
WO (1) WO2024115549A1 (en)

Citations (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003037271A2 (en) 2001-10-30 2003-05-08 Millennium Pharmaceuticals,Inc. Compounds, pharmaceutical compositions and methods of use therefor
WO2004032856A2 (en) 2002-10-07 2004-04-22 Smithkline Beecham Corporation Compounds
WO2004058736A1 (en) 2002-12-23 2004-07-15 Millennium Pharmaceuticals, Inc. Ccr8 inhibitors
WO2004058709A1 (en) 2002-12-23 2004-07-15 Millennium Pharmaceuticals, Inc. Ccr8 inhibitors
WO2004073619A2 (en) 2003-02-14 2004-09-02 Smithkline Beecham Corporation Ccr8 antagonists
WO2004074438A2 (en) 2003-02-14 2004-09-02 Smithkline Beecham Corporation Ccr8 antagonists
WO2005040167A1 (en) 2003-10-23 2005-05-06 Astrazeneca Ab Novel diazaspiroalkanes and their use for treatment of ccr8 mediated diseases
WO2006107252A1 (en) 2005-04-04 2006-10-12 Astrazeneca Ab Novel diazaspiroalkanes and their use for treatment of ccr8 mediated diseases
WO2006107254A1 (en) 2005-04-04 2006-10-12 Astrazeneca Ab Novel diazaspiroalkanes and their use for treatment of ccr8 mediated diseases
WO2006107253A1 (en) 2005-04-04 2006-10-12 Astrazeneca Ab Novel diazaspiroalkanes and their use for treatment of ccr8 mediated diseases
WO2007030061A1 (en) 2005-09-06 2007-03-15 Astrazeneca Ab Novel diazaspiroalkanes and their use for treatment of ccr8 mediated diseases
WO2008099165A1 (en) 2007-02-15 2008-08-21 Astrazeneca Ab Piperidine derivatives and their use for treatment of ccr8 mediated diseases
WO2013131010A2 (en) 2012-03-02 2013-09-06 Icahn School Of Medicine At Mount Sinai Function of chemokine receptor ccr8 in melanoma metastasis
WO2015033299A1 (en) 2013-09-06 2015-03-12 Aurigene Discovery Technologies Limited 1,2,4-oxadiazole derivatives as immunomodulators
WO2015034820A1 (en) 2013-09-04 2015-03-12 Bristol-Myers Squibb Company Compounds useful as immunomodulators
WO2015044900A1 (en) 2013-09-27 2015-04-02 Aurigene Discovery Technologies Limited Therapeutic immunomodulating compounds
WO2022000443A1 (en) 2020-07-03 2022-01-06 Nanjing Immunophage Biotech Co., Ltd. Methods and compositions for targeting tregs using ccr8 inhibitors

Patent Citations (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003037271A2 (en) 2001-10-30 2003-05-08 Millennium Pharmaceuticals,Inc. Compounds, pharmaceutical compositions and methods of use therefor
WO2004032856A2 (en) 2002-10-07 2004-04-22 Smithkline Beecham Corporation Compounds
WO2004058736A1 (en) 2002-12-23 2004-07-15 Millennium Pharmaceuticals, Inc. Ccr8 inhibitors
WO2004058709A1 (en) 2002-12-23 2004-07-15 Millennium Pharmaceuticals, Inc. Ccr8 inhibitors
WO2004073619A2 (en) 2003-02-14 2004-09-02 Smithkline Beecham Corporation Ccr8 antagonists
WO2004074438A2 (en) 2003-02-14 2004-09-02 Smithkline Beecham Corporation Ccr8 antagonists
WO2005040167A1 (en) 2003-10-23 2005-05-06 Astrazeneca Ab Novel diazaspiroalkanes and their use for treatment of ccr8 mediated diseases
WO2006107254A1 (en) 2005-04-04 2006-10-12 Astrazeneca Ab Novel diazaspiroalkanes and their use for treatment of ccr8 mediated diseases
WO2006107252A1 (en) 2005-04-04 2006-10-12 Astrazeneca Ab Novel diazaspiroalkanes and their use for treatment of ccr8 mediated diseases
WO2006107253A1 (en) 2005-04-04 2006-10-12 Astrazeneca Ab Novel diazaspiroalkanes and their use for treatment of ccr8 mediated diseases
WO2007030061A1 (en) 2005-09-06 2007-03-15 Astrazeneca Ab Novel diazaspiroalkanes and their use for treatment of ccr8 mediated diseases
WO2008099165A1 (en) 2007-02-15 2008-08-21 Astrazeneca Ab Piperidine derivatives and their use for treatment of ccr8 mediated diseases
WO2013131010A2 (en) 2012-03-02 2013-09-06 Icahn School Of Medicine At Mount Sinai Function of chemokine receptor ccr8 in melanoma metastasis
WO2015034820A1 (en) 2013-09-04 2015-03-12 Bristol-Myers Squibb Company Compounds useful as immunomodulators
WO2015033299A1 (en) 2013-09-06 2015-03-12 Aurigene Discovery Technologies Limited 1,2,4-oxadiazole derivatives as immunomodulators
WO2015044900A1 (en) 2013-09-27 2015-04-02 Aurigene Discovery Technologies Limited Therapeutic immunomodulating compounds
WO2022000443A1 (en) 2020-07-03 2022-01-06 Nanjing Immunophage Biotech Co., Ltd. Methods and compositions for targeting tregs using ccr8 inhibitors

Non-Patent Citations (104)

* Cited by examiner, † Cited by third party
Title
"CAS", Database accession no. 178311 0-79-1
"Handbook of Pharmaceutical Salts. Properties, Selection and Use", 2008, WILEY-VCH
"Pharmaceutical Salts and Co-crystals", 2012, RSC PUBLISHING
AKIMOTO N. ET AL., BIOCHEM BIOPHYS RES COMMUN, vol. 436, no. 3, 5 July 2013 (2013-07-05), pages 455 - 61
AKIMOTO, N. ET AL., CELL DEATH DIS, vol. 4, 2013, pages e679
AKIRA ASAI ET AL., JOURNAL OF LEUKOCYTE BIOLOGY, vol. 92, no. 4, 2012, pages 859 - 867
AKIYOSHI HOSHINO ET AL., J IMMUNOL., vol. 178, no. 8, 15 April 2007 (2007-04-15), pages 5296 - 304
AZZAOUI, I ET AL., BLOOD, vol. 118, 2011, pages 3549 - 3558
BARSHESHET, Y. ET AL., PROC. NATL. ACAD. SCI., vol. 114, 2017, pages 6086 - 6091
BHATT, D. ET AL., J. EXP. MED., vol. 218, 2021, pages e20201329
BLANCO-PEREZ, F. ET AL., SCI. REP., vol. 9, 2019, pages 9608
BUCKLAND KF ET AL., J ALLERGY CLIN IMMUNOL., vol. 119, no. 4, April 2007 (2007-04-01), pages 997 - 1004
CAMPBELL, J.R. ET AL., CANCER RES., vol. 81, 2021, pages 2983 - 2994
CAO, Q ET AL., MOL MED REP., vol. 13, 2016, pages 27 - 34
CATUSSE, J ET AL., J,CELL.PHYSIOL., vol. 225, 2010, pages 792 - 800
CLAUS ET AL., MABS, vol. 15, no. 1, 2023, pages 2167189
CONNOLLY S ET AL., BIOCHEMICAL PHARMACOLOGY, vol. 83, 2012, pages 778 - 787
DANGI A ET AL., J AM SOC NEPHROL., vol. 33, no. 10, October 2022 (2022-10-01), pages 1876 - 1890
DAS S. ET AL., J EXP MED., vol. 210, no. 8, 2013, pages 1509 - 1528
DE SIMONE, M. ET AL., IMMUNITY, vol. 45, 2016, pages 1135 - 1147
DING S. ET AL., INT IMMUNOPHARMACOL., vol. 100, 2021, pages 108122
EBERT, L.M. ET AL., J. IMMUNOL., vol. 176, 2006, pages 4331 - 4336
ERUSLANOV, E ET AL., CLIN CANCER RES., vol. 19, 2013, pages 1670 - 1680
ERUSLANOV, E ET AL., CLIN. CANCER RES., vol. 19, 2013, pages 1670 - 1680
FEIG C ET AL., PNAS, 2013
FRAGA M. ET AL., FRONT. IMMUNOL., vol. 12, 2021, pages 643298
FUJIMOTO ET AL., J IMMUNOL., vol. 200, no. 9, 2018, pages 3291 - 3303
GHOSH S ET AL., J. MED. CHEM., vol. 49, no. 9, 2006, pages 2669 - 2672
GIUSTINANI J. ET AL., BLOOD ADV., vol. 6, no. 11, 2022, pages 3507 - 3512
GOMBERT, M. ET AL., J. IMMUNOL., vol. 174, 2005, pages 5082 - 5091
GUNTHER, C ET AL., AM J. PATHOL., vol. 179, 2011, pages 1434 - 1442
HALDER, R. ET AL., J. ORG. CHEM., vol. 86, 2021, pages 13873
HAQUE, N.S. ET AL., BLOOD, vol. 97, 2001, pages 39 - 45
HARUNA M. ET AL., SCI REP., vol. 12, no. 1, 2022, pages 5377
HEYMANN F. ET AL., HEPATOLOGY, vol. 55, no. 3, March 2012 (2012-03-01), pages 898 - 909
HOELZINGER D.B ET AL., J. IMMUNOL., vol. 184, 2010, pages 6833 - 6842
HOELZINGER, DB ET AL., J IMMUNOL., vol. 184, 2010, pages 6833 - 6842
HONDA, F. ET AL., ARTHRITIS RES THER, vol. 23, 2021, pages 214
HONG, R ET AL., ASIAN PAC. J. CANCER PREV, vol. 13, 2012, pages 1877 - 1880
ISLAM, S.A. ET AL., NAT. IMMUNOL., vol. 12, 2011, pages 167 - 177
ISLAM, SA ET AL., J. EXP. MED., vol. 210, 2013, pages 1889 - 1898
JENKINS TJ ET AL., J. MED. CHEM., vol. 50, no. 3, 2007, pages 566 - 584
JENKINS, T.J. ET AL.: "Design, Synthesis, and Evaluation of Naphthalene-Sulfonamide Antagonists of Human CCR8", JOURNAL OF MEDICINAL CHEMISTRY, vol. 50, no. 3, 2007, pages 566 - 584, XP055883728, ISSN: 0022-2623, Retrieved from the Internet <URL:https://pubs.acs.org/doi/pdf/10.1021/jm061118e> DOI: 10.1021/jm061118e *
JIN J ET AL., BIOORG. MED. CHEM. LETT., vol. 17, no. 6, 2007, pages 1722 - 1725
KARLSSON AKC ET AL., BIOCHEM. BIOPHYS. RES. COMMUN., vol. 407, no. 4, 2011, pages 764 - 771
KIDANI Y. ET AL., PROC NATL ACAD SCI USA, vol. 119, no. 7, 2022, pages e2114282119
KORBECKI, J ET AL., INT. J. MOL. SCI., vol. 21, 2020, pages 7619
KUEHNEMUTH, B ET AL., BMC CANCER, vol. 18, 2018, pages 1278
LELLEM, A ET AL., J. EXP. MED., vol. 194, 2001, pages 847 - 853
LI HL. ET AL., WORLD J GASTROENTEROL., vol. 26, no. 31, 2020, pages 4656 - 4668
LIU F. ET AL., J INFLAMM RES., vol. 14, 2021, pages 267 - 285
LIU, S. ET AL., BIOMOLECULES, vol. 13, 2023, pages 333
LIU, Z. ET AL., FRONTIERS IN CHEMISTRY, vol. 10, 2022, pages 883866
LOUAHED, J ET AL., EUR J IMMUNOL., vol. 33, 2003, pages 494 - 501
MAGNUSON, A.M. ET AL., PROC. NATL. ACAD. SCI. USA, vol. 115, 2018, pages E10672 - E10681
MARRO ML ET AL., BIOCHEM. BIOPHYS. RES. COMMUN., vol. 349, 2006, pages 270 - 276
MARTINA KVIST REIMER ET AL., CLINICAL AND VACCINE IMMUNOLOGY, vol. 18, no. 12, 2011
MATSUKAWA, A. ET AL., FASEB J, vol. 20, 2006, pages 302 - 304
MCCULLY, M.L ET AL., BLOOD, vol. 120, 2012, pages 4591 - 4598
MENG ET AL., FRONT. ONCOL., vol. 11, 2021, pages 618187
NGUYEN KD ET AL., J ALLERGY CLIN IMMUNOL., vol. 123, no. 4, 2009, pages 933 - 9
NIETO P. ET AL., GENOME RES., vol. 10, 2021, pages 1913 - 1926
NODA M. ET AL., NEUROCHEM INT., vol. 119, October 2018 (2018-10-01), pages 184 - 189
NORMAN, DR. P.: "CCR8 antagonists : Astrazeneca: WO2006107252, WO2006107253 and WO2006107254", EXPERT OPINION ON THERAPEUTIC PATENTS, vol. 17, no. 4, 2007, pages 465 - 469, XP093117065, ISSN: 1354-3776, Retrieved from the Internet <URL:https://dx.doi.org/10.1517/13543776.17.4.465> DOI: 10.1517/13543776.17.4.465 *
OHUE,YNISHIKAWA, H, CANCER SCI, vol. 110, no. 7, 2019, pages 2080 - 2089
PASTOR M.D. ET AL., J THORAC ONCOL., vol. 12, 2016, pages 2183 - 2192
PAWLIK K., MOLECULES, vol. 28, no. 15, 2023, pages 5766
PETERSEN TP ET AL., CHEM. EUR. J., vol. 19, 2013, pages 9343
PETROV, S. A. ET AL., INT. J. MOL. SCI., vol. 23, 2022, pages 137896
PETTERSEN, JS ET AL., J. INVESTIG. DERMATOL., vol. 131, 2011, pages 1322 - 1330
PRASSE A. ET AL., AM J RESPIR CRIT CARE MED, vol. 179, no. 8, 15 April 2009 (2009-04-15), pages 717 - 23
PUNEKAR ET AL., NATURE REV CLIN ONCOLOGY, vol. 19, no. 10, pages 637 - 655
REMINGTON: "The Science and Practice of Pharmacy", 2005, LIPPINCOTT WILLIAMS & WILKINS, article "Pharmaceutical Manufacturing"
RUFF M. ET AL., LIFE SCI., vol. 306, 1 October 2022 (2022-10-01), pages 120788
SADE FELDMAN M. ET AL., CELL, vol. 175, no. 4, 2018, pages 998 - 1013
SCHAERLI, P. ET AL., J. EXP. MED., vol. 199, 2004, pages 1265 - 1275
SCHRAUFSTATTER, IU ET AL., IMMUNOLOGY, vol. 135, 2012, pages 287 - 298
SEBASTIANI, S. ET AL., J. IMMUNOL., vol. 166, 2001, pages 996 - 1002
SHAMOVSKY I ET AL., J. MED. CHEM., vol. 52, no. 23, 2009, pages 7706 - 7723
SHAN-SHAN LIU ET AL., IMMUNITY, vol. 54, no. 9, 2021, pages 2042 - 2056
STEM CELL RES THER., vol. 11, no. 1, 26 June 2020 (2020-06-26), pages 254
SUN ET AL., TRANSL CANCER RES, vol. 9, no. 10, 2020, pages 5882 - 5892
SUOSI LIU, INTERNATIONAL IMMUNOPHARMACOLOGY, vol. 120, 2023, pages 110343
T.W. GREENEP.G.M. WUTS: "Protective Groups in Organic Synthesis", 1999, WILEY-INTERSCIENCE
TAKABATAKE N. ET AL., AM J RESPIR CRIT CARE MED., vol. 174, no. 8, 15 October 2006 (2006-10-15), pages 875 - 85
TREGS ZHENG, C. ET AL., CELL, vol. 169, 2017, pages 1342 - 1356
UNTERMAN A. ET AL., MEDRXIV, 2023
VAN DAMME, H. ET AL., J. IMMUNOTHER. CANCER, vol. 9, 2021, pages e001749
VILA-CABALLER M ET AL., J MOL CELL CARDIOL., vol. 132, 2019, pages 154 - 1
VILLARREAL, 0.0 ET AL., CANCER RES., vol. 78, 2018, pages 5340 - 5348
WANG C. ET AL., NEUROSCI RES., vol. 154, May 2020 (2020-05-01), pages 20 - 26
WANG, L. ET AL., NAT. IMMUNOL., vol. 20, 2019, pages 1220 - 1230
WANG, T. ET AL., CANCER IMMUNOL. IMMUNOTHER., vol. 69, 2020, pages 1855 - 1867
WEI ET AL., FRONTIERS IN IMMUNOLOGY, vol. 13, 2022, pages 1035276
WERONICA EK, DEVELOPMENTAL & COMPARATIVE IMMUNOLOGY, vol. 38, no. 2, 2012, pages 352 - 359
WIEDEMANN G.M. ET AL., PATHOLOGY, vol. 51, no. 6, 2019, pages 586 - 659
XING X. ET AL., APPL IMMUNOHISTOCHEM MOL MORPHOL., vol. 8, 2015, pages 580 - 589
XU L. ET AL., J TRANSL MED., vol. 20, no. 1, 2022, pages 210
XU, Y ET AL., STEM CELLS, vol. 35, 2017, pages 2351 - 2365
YEH, CR ET AL., AM J CANCER RES., vol. 50, 2018, pages 894 - 907
YOH ZEN ET AL., JOURNAL OF HEPATOLOGY, vol. 59, no. 5, 2013, pages 1059 - 1064
YONG WU ET AL., J. MED. CHEM., vol. 66, no. 7, 2023, pages 4548 - 4564
ZYCHOWSKA M. ET AL., INT IMMUNOPHARMACOL., vol. 52, November 2017 (2017-11-01), pages 261 - 271
ZYCHOWSKA, M. ET AL., INTERNATIONAL IMMUNOPHARMACOLOGY, vol. 52, 2017, pages 261 - 271

Also Published As

Publication number Publication date
AR131211A1 (en) 2025-02-26
TW202430180A (en) 2024-08-01

Similar Documents

Publication Publication Date Title
US11352360B2 (en) TGF-beta inhibitors
JP7273951B2 (en) Antiviral pyridopyrazinedione compounds
CN114222730B (en) Compounds for inhibiting α4β7 integrin
CN111164069A (en) N-(3-(2-(4-Chlorophenoxy)acetamido)bicyclo[1.1.1]pent-1-yl)-2-cyclobutane as an ATF4 inhibitor for the treatment of cancer and other diseases -1-Carboxamide derivatives and related compounds
TW201938542A (en) Aminopyrazine diol compounds as PI3K-[gamma] inhibitors
US20250002471A1 (en) 6-substituted indole compounds
AU2022204399A1 (en) Pyrrolo[1,2-B]pyridazine derivatives as IRAK4 inhibitors
WO2024115549A1 (en) Aryl- and heteroaryl-sulfonamide derivatives as ccr8 modulators
TW202325278A (en) Ccr6 receptor modulators
AU2022374959A1 (en) Ccr6 receptor modulators
US20250145590A1 (en) Ubiquitin specific processing protease 1 (usp1) compounds
US20250376445A1 (en) Compounds and methods for yap/tead modulation and indications therefor
JP2025541785A (en) Crystalline adipate salt forms of CCR6 antagonists
JP2026501039A (en) Substituted phenyloxazolone compounds
JP2024533374A (en) Thienopyrrole Compounds

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23817682

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 23817682

Country of ref document: EP

Kind code of ref document: A1