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WO2025016906A1 - Nouveaux composés pour traiter le cancer et des maladies métaboliques - Google Patents

Nouveaux composés pour traiter le cancer et des maladies métaboliques Download PDF

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Publication number
WO2025016906A1
WO2025016906A1 PCT/EP2024/069828 EP2024069828W WO2025016906A1 WO 2025016906 A1 WO2025016906 A1 WO 2025016906A1 EP 2024069828 W EP2024069828 W EP 2024069828W WO 2025016906 A1 WO2025016906 A1 WO 2025016906A1
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Prior art keywords
alkyl
cycloalkyl
alkenyl
alkynyl
heterocycle
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PCT/EP2024/069828
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English (en)
Inventor
Sandro Boland
Egle KATKEVICIUTE
Amuri Kilonda
Dominique LAMBIN
Arnaud Marchand
Vincent PERICOLLE
Kalliopi PERVOLARAKI
Michael Scharl
Marianne SPALINGER
Jean-Christophe VANHERCK
Matthias Versele
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Katholieke Universiteit Leuven
University Of Zurich
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Publication of WO2025016906A1 publication Critical patent/WO2025016906A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/10—1,2,5-Thiadiazoles; Hydrogenated 1,2,5-thiadiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—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
    • C07D417/10—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 carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring

Definitions

  • the present invention relates to novel compounds.
  • the present invention also relates to said compounds for use as a medicine, more in particular for the prevention or treatment of diseases mediated by activity of PTPN2 and/or PTPN1, yet more in particular for the prevention or treatment of cancer.
  • the present invention also relates to a method for the prevention or treatment of said diseases comprising the use of the novel compounds.
  • the present invention furthermore relates to pharmaceutical compositions or combination preparations of the novel compounds as well as to said compositions or preparations for use as a medicine, more preferably for the prevention or treatment of diseases mediated by activity of PTPN2 and/or PTPN1, yet more in particular for the prevention or treatment of cancer.
  • the present invention also relates to processes for the preparation of said compounds.
  • the invention also relates to combinations of the novel compounds with other therapeutic agents.
  • PTPN2 Tyrosine-protein phosphatase non-receptor type 2
  • T-PTP T cell protein tyrosine phosphatase
  • receptor protein tyrosine kinases such as EGFR (epidermal growth factor receptor), CSF1R (Colony stimulating factor 1 receptor), PDGFR (Platelet-derived growth factor receptor), IR (insulin receptor) or non-receptor protein tyrosine kinases, such as JAK (janus family kinases), Src (src family kinases), or STAT (signal transducers and activators of transcription) family kinases, either in the cytoplasm or nucleus (J. Song et al, Int. J. Mol. Sci 2022, 23(17), 10025).
  • PTPN2 is associated with pathological processes, including inflammatory responses, immune disorders, and tumor development.
  • the anti-inflammatory cytosolic protein tyrosine phosphatase, PTPN2 was identified as a cancer immunotherapy target after a CRISPR–Cas9- mediated genome editing study showed that deletion of PTPN2 in murine tumor cells promotes susceptibility of the tumor to checkpoint inhibitor therapy by enhancing IFN ⁇ -mediated effects on antigen presentation and growth suppression.
  • Enhanced anti-PD-1 response was accompanied by the recruitment of cytotoxic CD8+ T cells, increased antigen presentation, as reflected by the increased expression of MHC-I on tumor cells, and the increased activation of recruited T-cells.
  • PTPN2-deficient tumor cells expressed higher levels of IFN- ⁇ /STAT1 target genes, including those encoding T cell chemo-attractants as well as components of the antigen-processing and presentation pathway (Manguso, R.T. et al. Nature 2017, 547, 413–418). More recently, PTPN2 deficiency has also been shown to enhance programmed T cell expansion and survival capacity of activated T cells (Flosbach, M. et al. Cell Rep.2020, 32, 107957). Hence, inhibitors of PTPN2 can be considered as a valuable approach as cancer immunotherapeutics.
  • Protein tyrosine phosphatase non-receptor type 1 (PTPN1), also known as protein tyrosine phosphatase-1B (PTP1B), has been shown to play a key role in insulin and leptin signaling and is a primary mechanism for down-regulating both the insulin and leptin receptor signaling pathways (Kenner K. A. et al., J Biol Chem 271: 19810-19816, 1996). Animals deficient in PTPN1 have improved glucose regulation and lipid profiles and are resistant to weight gain when treated with a high fat diet (Elchebly M. et al., Science 283: 1544-1548, 1999).
  • PTPN1 inhibitors are useful for the treatment of metabolic diseases such as type 2 diabetes, obesity, and metabolic syndrome.
  • Protein tyrosine phosphatases PTPs
  • PTPs Protein tyrosine phosphatases
  • Recent patent applications from Calico/Abbvie describe inhibitors of PTPN2 and/or PTPN1: WO/2020/186199A1 and WO/2021/127499A1 describe small molecule inhibitors and WO/2021/127586 proposed protein degradation via PROTACs targeting PTPN2.
  • the present invention provides a class of novel compounds which can be used as inhibitors of PTPN2 and/or PTPN1 in cancer (immuno)therapy and potentially other disease indications mediated by PTPN2 and/or PTPN1.
  • SUMMARY OF THE INVENTION The present invention is based on the unexpected finding that at least one of the above- mentioned problems can be solved by the below described compounds.
  • the present invention provides new compounds, especially a compound of formula (I), a stereo-isomeric form, a tautomer, a salt (in particular a pharmaceutically acceptable salt), solvate, hydrate, polymorph and/or prodrug thereof, wherein: - represents a double bond ( ) or a triple bond ( ); - R 1 is selected from alkyl; alkenyl; alkynyl; heteroalkyl; heteroalkenyl; heteroalkynyl; cycloalkyl; cycloalkenyl; cycloalkynyl; cycloalkylalkyl; cycloalkenylalkyl; cycloalkynylalkyl; cycloalkylheteroalkyl; cycloalkenylheteroalkyl; cycloalkynylheteroalkyl; aryl; heteroaryl; heterocycle; arylalkyl; heteroarylalkyl; heterocyclylalkyl
  • the present invention also encompasses preferably a compound of formula (I), and any subgroup thereof as described herein, a stereo-isomeric form, a tautomer, a salt (in particular a pharmaceutically acceptable salt), a solvate, a hydrate, a polymorph, an isotope, and/or a prodrug thereof, wherein: - represents a double bond ( ) or a triple bond ( ); - R 1 is selected from alkyl; alkenyl; alkynyl; heteroalkyl; heteroalkenyl; heteroalkynyl; cycloalkyl; cycloalkenyl; cycloalkynyl; cycloalkylalkyl; cycloalkenylalkyl; cycloalkynylalkyl; cycloalkylheteroalkyl; cycloalkenylheteroalkyl; cycloalkynylheteroalkyl; aryl; heteroary
  • the present invention also provides in a particular embodiment compounds of formula (III) and any subgroup thereof as described herein, a stereo-isomeric form, a tautomer, a salt (in particular a pharmaceutically acceptable salt), solvate, hydrate, polymorph, isotope, and/or prodrug thereof, wherein: - cycle B is selected from heterocycle; cycloalkyl; cycloalkenyl; and cycloalkynyl; - m is selected from 0; 1; 2; 3; 4; and 5.
  • the present invention provides new compounds which have been shown to possess inhibitory activity on PTPN2 and/or PTPN1.
  • the present invention furthermore demonstrates that these compounds efficiently inhibit the activity of PTPN2 and/or PTPN1. Therefore, these compounds constitute a useful class of new potent compounds that can be used in the treatment and/or prevention of PTPN2 and/or PTPN1 mediated disorders in animals, mammals and humans, more specifically for the treatment and/or prevention of (i) cancer, more specifically lung cancer, breast cancer, head and neck cancer, oesophageal cancer, kidney cancer, bladder cancer, colon cancer, ovarian cancer, cervical cancer, endometrial cancer, liver cancer, skin cancer, pancreatic cancer, gastric cancer, brain cancer and prostate cancer, yet more specifically colon cancer, kidney cancer, pancreatic cancer, breast cancer, melanoma, head and neck squamous cell carcinoma and non-small cell lung cancer and (ii) metabolic diseases.
  • cancer more specifically lung cancer, breast cancer, head and neck cancer, oesophageal
  • the present invention furthermore relates to the compounds of the invention for use as a medicine, to the use of such compounds as medicines and to their use for the manufacture of medicaments, more in particular for treating and/or preventing PTPN2 and/or PTPN1 mediated diseases, in particular (i) cancer and (ii) metabolic diseases in animals or mammals, more in particular in humans.
  • the invention also relates to pharmaceutical compositions comprising the compounds of the invention in an effective amount, to said pharmaceutical compositions for use as a medicine, more in particular for use as a medicine for the prevention or treatment of PTPN2 and/or PTPN1 mediated disorders and to the method of preparation of manufacturing of said pharmaceutical compositions.
  • the present invention also relates to a method of treatment or prevention of PTPN2 and/or PTPN1 mediated disorders in humans by the administration of one or more such compounds, optionally in combination with one or more other medicines, to a patient in need thereof.
  • a method of treating cancer in a patient in need thereof comprising administering to the patient an effective amount of a compound disclosed herein in combination with an additional therapeutic agent.
  • the additional medicine is an immunotherapeutic agent.
  • the immunotherapeutic agent is selected from the group consisting of an anti-PD-1 antibody, an anti- PD-L1 antibody and an anti- CTLA-4 antibody.
  • this in particular embodiment refers to (i) cancer, more in particular lung cancer, breast cancer, head and neck cancer, oesophageal cancer, kidney cancer, bladder cancer, colon cancer, ovarian cancer, cervical cancer, endometrial cancer, liver cancer, skin cancer, pancreatic cancer, gastric cancer, brain cancer and prostate cancer, yet more in particular colon cancer, kidney cancer, pancreatic cancer, breast cancer, melanoma, head and neck squamous cell carcinoma and non-small cell lung cancer and (ii) metabolic diseases, more specifically non- alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), liver fibrosis, obesity, type-2 diabetes, heart disease, atherosclerosis, arthritis, cystinosis, phenylketonuria, proliferative retinopathy, metabolic syndrome or Kearns-Sayre disease in animals or mammals, more in particular in humans.
  • NASH non-alcoholic steatohepatitis
  • NAFLD non-alcoholic fatty liver disease
  • the invention comprises administering to the patient an effective amount of a compound disclosed herein, also in combination with an additional therapeutic agent.
  • the additional therapeutic agent is an immunotherapeutic agent.
  • the immunotherapeutic agent is selected from the group consisting of an anti-PD-1 antibody, an anti- PD-L1 antibody and an anti-CTLA-4 antibody.
  • the treatment or prevention of metabolic diseases comprises the treatment or prevention of type-2 diabetes in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, or comprises treating and/or controlling obesity in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein.
  • FIGURES Figure 1 In vivo tumor growth inhibition with cpd008. Antitumor activity of cpd008 in the treatment of colon cancer in a syngeneic subcutaneous MC38 mouse tumor model performed in accordance with example 45. DETAILED DESCRIPTION OF THE INVENTION The present invention will be further described and in some instances with respect to particular embodiments, but the invention is not limited thereto.
  • PTPN2 and/or PTPN1 mediated diseases refers to diseases, disorders or conditions in which PTPN2 and/or PTPN1 signaling is active or activated and whereby PTPN2 and/or PTPN1 activity or activation is contributing, driving, sustaining, enabling or the like such disease.
  • PTPN2 and/or PTPN1 mediated diseases includes cancer, but also includes metabolic diseases or any other disease, disorder or ailment favorably responsive to PTPN2 or PTPN1 inhibitor treatment.
  • cancer refers to all types of animal, more specifically human cancers, neoplasm or (malignant) tumors including carcinomas, sarcomas, lymphomas, leukemias, germ cell tumors and blastomas and thus includes solid and lymphoid cancers.
  • Exemplary cancers that may be treated with a compound, pharmaceutical composition, or method provided herein include lymphoma, sarcoma, bladder cancer, bone cancer, brain tumor, cervical cancer, colon cancer, esophageal cancer, gastric cancer, head and neck cancer, kidney cancer, myeloma, thyroid cancer, leukemia, prostate cancer, breast cancer (e.g., ER positive, ER negative, chemotherapy resistant, herceptin resistant, HER2 positive, doxorubicin resistant, tamoxifen resistant, ductal carcinoma, lobular carcinoma, primary, metastatic), ovarian cancer, pancreatic cancer, liver cancer (e.g., hepatocellular carcinoma), lung cancer (e.g., non-small cell lung carcinoma, squamous cell lung carcinoma, adenocarcinoma, large cell lung carcinoma, small cell lung carcinoma, carcinoid, sarcoma), glioblastoma multiforme, glioma, or melanoma.
  • Additional examples include, cancer of the thyroid, endocrine system, brain, breast, cervix, colon, head & neck, liver, kidney, lung, non-small cell lung, melanoma, mesothelioma, ovary, sarcoma, stomach, uterus or Medulloblastoma, Hodgkin's Disease, Non-Hodgkin's Lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumors, cancer, malignant pancreatic insulanoma, malignant carcinoid, urinary bladder cancer, premalignant skin lesions, testicular cancer, lymphomas, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenal cortical cancer
  • carcinoma refers to a malignant new growth made up of epithelial cells tending to infiltrate the surrounding tissues and give rise to metastases.
  • exemplary carcinomas that may be treated with a compound, pharmaceutical composition, or method provided herein include, for example, medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, carcinoma adenomatosum, carcinoma of adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid carcinoma, basosquamous cell carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedo carcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum, cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma, ductal carcinoma, carcinoma durum, embryonal carcinoma
  • leukemia refers broadly to progressive, malignant diseases of the blood- forming organs and is generally characterized by a distorted proliferation and development of leukocytes and their precursors in the blood and bone marrow. Leukemia is generally clinically classified on the basis of (1) the duration and character of the disease-acute or chronic; (2) the type of cell involved; myeloid (myelogenous), lymphoid (lymphogenous), or monocytic; and (3) the increase or non-increase in the number abnormal cells in the blood-leukemic or aleukemic (subleukemic).
  • Exemplary leukemias that may be treated with a compound, pharmaceutical composition, or method provided herein include, for example, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, a leukocythemic leukemia, basophylic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilic leukemia, Gross' leukemia, hairy- cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous
  • sarcoma generally refers to a tumor which is made up of a substance like the embryonic connective tissue and is generally composed of closely packed cells embedded in a fibrillar or homogeneous substance.
  • Sarcomas that may be treated with a compound, pharmaceutical composition, or method provided herein include a chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, adipose sarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, chorio carcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sar
  • melanoma refers to a tumor arising from the melanocytic system of the skin and other organs.
  • Melanomas that may be treated with a compound, pharmaceutical composition, or method provided herein include, for example, acral-lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman's melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungal melanoma, or superficial spreading melanoma.
  • PTPN2 and/or PTPN1 mediated diseases also includes cancers that have developed resistance to prior treatments such has EGFR inhibitors, MEK inhibitors, AXL inhibitors, B-RAF inhibitors, RAS inhibitors, immunomodulatory agents and others.
  • the term “metabolic disease” as used herein refers to a disease or condition affecting a metabolic process in a subject and includes non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), liver fibrosis, obesity, heart disease, atherosclerosis, arthritis, cystinosis, diabetes (e.g., Type I diabetes, Type II diabetes, or gestational diabetes), metabolic syndrome, phenylketonuria, proliferative retinopathy, or Kearns- Sayre disease.
  • NASH non-alcoholic steatohepatitis
  • NAFLD non-alcoholic fatty liver disease
  • liver fibrosis obesity, heart disease, atherosclerosis, arthritis, cystinosis
  • diabetes e.g
  • the treatment or prevention of a metabolic disease comprises decreasing or eliminating a symptom of such metabolic disease comprising elevated blood pressure, elevated blood sugar level, weight gain, fatigue, blurred vision, abdominal pain, flatulence, constipation, diarrhea, jaundice, and the like.
  • a symptom of such metabolic disease comprising elevated blood pressure, elevated blood sugar level, weight gain, fatigue, blurred vision, abdominal pain, flatulence, constipation, diarrhea, jaundice, and the like.
  • the term “treat” or “treating” as used herein is intended to refer to administration of a compound or composition of the invention to a subject for the purpose of effecting a therapeutic benefit or prophylactic benefit, here in particular through inhibition of PTPN2 and/or PTPN1.
  • Treating includes reversing, ameliorating, alleviating, inhibiting the progress of, lessening the severity of, or preventing a disease, disorder, or condition, or one or more symptoms, complications or biochemical indicia of such disease, disorder or condition, here in particular mediated through PTPN2 and/or PTPN1.
  • therapeutic benefit is meant eradication, amelioration, reversing, alleviating, inhibiting the progress of or lessening the severity of the underlying disorder being treated.
  • a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient is afflicted with the underlying disorder in some embodiments.
  • the compositions are administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made.
  • certain methods herein treat cancer by decreasing or reducing or preventing the occurrence, growth, metastasis, or progression of cancer or decreasing a symptom of cancer.
  • subject refers to an animal, preferably a mammal, most preferably a human, a patient, who has been the object of treatment, observation or experiment or who is in need of such treatment.
  • composition means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation or partial alleviation of the symptoms of the disease or disorder being treated.
  • composition as used herein is intended to encompass a product comprising the specified ingredients in the therapeutically effective amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.
  • antagonist or “inhibitor” as used herein in reference to inhibitors of the PTPN2 and/or PTPN1 activity or activation, refers to a compound capable of producing, depending on the circumstance, a functional antagonism or inhibition of PTPN2 and/or PTPN1 activity or activation. It is to be noticed that the term “comprising”, used in the claims, should not be interpreted as being restricted to the means listed thereafter; it does not exclude other elements or steps. Reference throughout this specification to "one embodiment” or “an embodiment” means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention.
  • the number of carbon atoms represents the maximum number of carbon atoms generally optimally present in the substituent or linker; it is understood that where otherwise indicated in the present application, the number of carbon atoms represents the optimal maximum number of carbon atoms for that particular substituent or linker.
  • the term “leaving group” or “LG” as used herein means a chemical group which is susceptible to be displaced by a nucleophile or cleaved off or hydrolyzed in basic or acidic conditions.
  • a leaving group is selected from a halogen atom (e.g., Cl, Br, I) or a sulfonate (e.g., mesylate, tosylate, triflate).
  • protecting group refers to a moiety of a compound that masks or alters the properties of a functional group or the properties of the compound as a whole.
  • the chemical substructure of a protecting group varies widely.
  • One function of a protecting group is to serve as intermediates in the synthesis of the parental drug substance.
  • Chemical protecting groups and strategies for protection/deprotection are well known in the art. See: “Protective Groups in Organic Chemistry”, Theodora W.
  • Protecting groups are often utilized to mask the reactivity of certain functional groups, to assist in the efficiency of desired chemical reactions, e.g. making and breaking chemical bonds in an ordered and planned fashion. Protection of functional groups of a compound alters other physical properties besides the reactivity of the protected functional group, such as the polarity, lipophilicity (hydrophobicity), and other properties which can be measured by common analytical tools. Chemically protected intermediates may themselves be biologically active or inactive. Protected compounds may also exhibit altered, and in some cases, optimized properties in vitro and in vivo, such as passage through cellular membranes and resistance to enzymatic degradation or sequestration.
  • prodrugs In this role, protected compounds with intended therapeutic effects may be referred to as prodrugs.
  • Another function of a protecting group is to convert the parental drug into a prodrug, whereby the parental drug is released upon conversion of the prodrug in vivo. Because active prodrugs may be absorbed more effectively than the parental drug, prodrugs may possess greater potency in vivo than the parental drug.
  • Protecting groups are removed either in vitro, in the instance of chemical intermediates, or in vivo, in the case of prodrugs. With chemical intermediates, it is not particularly important that the resulting products after deprotection, e.g. alcohols, be physiologically acceptable, although in general it is more desirable if the products are pharmacologically innocuous.
  • alkyl or “C1-18alkyl” as used herein means C1-C18 normal, secondary, or tertiary, linear, branched or straight hydrocarbon with no site of unsaturation. Examples are methyl, ethyl, 1-propyl (n-propyl), 2-propyl (iPr), 1-butyl, 2-methyl-1-propyl(i-Bu), 2-butyl (s-Bu), 2-dimethyl-2- propyl (t-Bu), 1-pentyl (n-pentyl), 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl- 1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4- methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-but
  • alkyl refers to C1-12alkyl (C1-12 hydrocarbons), yet more in particular to C1-9alkyl (C1-9 hydrocarbons), yet more in particular to C 1-6 alkyl (C 1-6 hydrocarbons) as further defined herein above.
  • haloalkyl as a group or part of a group, refers to an alkyl group having the meaning as defined above wherein one, two, or three hydrogen atoms are each replaced with a halogen as defined herein.
  • Non-limiting examples of such haloalkyl groups include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1,1-trifluoroethyl and the like.
  • alkoxy or “alkyloxy”, as a group or part of a group, refers to a group having the formula –OR b wherein R b is C 1-6 alkyl as defined herein above.
  • suitable C 1-6 alkoxy include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert- butoxy, pentyloxy and hexyloxy.
  • haloalkoxy as a group or part of a group, refers to a group of formula -O-R c , wherein R c is haloalkyl as defined herein.
  • Non-limiting examples of suitable haloalkoxy include fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, 1,1,2,2-tetrafluoroethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2,2-difluoroethoxy, 2,2,2-trichloroethoxy, trichloromethoxy, 2- bromoethoxy, pentafluoroethyl, 3,3,3-trichloropropoxy, 4,4,4-trichlorobutoxy.
  • cycloalkyl or “C 3-18 cycloalkyl” as used herein and unless otherwise stated means a saturated hydrocarbon monovalent group having from 3 to 18 carbon atoms consisting of or comprising a C3-10 monocyclic or C7-18 polycyclic saturated hydrocarbon, such as for instance cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylethylene, methylcyclopropylene, cyclohexyl, cycloheptyl, cyclooctyl, cyclooctylmethylene, norbornyl, fenchyl, trimethyltricycloheptyl, decalinyl, adamantyl and the like.
  • cycloalkyl refers to C3-12cycloalkyl (saturated cyclic C3-12hydrocarbons), yet more in particular to C3-9cycloalkyl (saturated cyclic C3- 9 hydrocarbons), still more in particular to C 3-6 cycloalkyl (saturated cyclic C 3-6 hydrocarbons) as further defined herein above.
  • fused systems of a cycloalkyl ring with a heterocyclic ring are considered as heterocycle irrespective of the ring that is bound to the core structure.
  • Fused systems of a cycloalkyl ring with an aryl ring are considered as aryl irrespective of the ring that is bound to the core structure.
  • the double bond may be in the cis or trans configuration.
  • alkenyl refers to C2-12alkenyl (C2-12hydrocarbons), yet more in particular to C2-9 alkenyl (C2-9 hydrocarbons), still more in particular to C2-6 alkenyl (C2-6hydrocarbons) as further defined herein above with at least one site (usually 1 to 3, preferably 1) of unsaturation, namely a carbon-carbon, sp2 double bond.
  • site usually 1 to 3, preferably 1 of unsaturation, namely a carbon-carbon, sp2 double bond.
  • alkenyloxy refers to a group having the formula –OR d wherein R d is alkenyl as defined herein above.
  • cycloalkenyl refers to a non-aromatic hydrocarbon group having from 5 to 18 carbon atoms with at least one site (usually 1 to 3, preferably 1) of unsaturation, namely a carbon-carbon, sp2 double bond and consisting of or comprising a C5-10 monocyclic or C7-18 polycyclic hydrocarbon.
  • sites usually 1 to 3, preferably 1 of unsaturation, namely a carbon-carbon, sp2 double bond and consisting of or comprising a C5-10 monocyclic or C7-18 polycyclic hydrocarbon.
  • Examples include, but are not limited to: cyclopentenyl (-C5H7), cyclopentenylpropylene, methylcyclohexenylene and cyclohexenyl (-C 6 H 9 ).
  • the double bond may be in the cis or trans configuration.
  • cycloalkenyl refers to C 5- 12 cycloalkenyl (cyclic C 5-12 hydrocarbons), yet more in particular to C 5-9 cycloalkenyl (cyclic C 5-9 hydrocarbons), still more in particular to C 5-6 cycloalkenyl (cyclic C 5-6 hydrocarbons) as further defined herein above with at least one site of unsaturation, namely a carbon-carbon, sp2 double bond.
  • fused systems of a cycloalkenyl ring with a heterocyclic ring are considered as heterocycle irrespective of the ring that is bound to the core structure.
  • Fused systems of a cycloalkenyl ring with an aryl ring are considered as aryl irrespective of the ring that is bound to the core structure.
  • Fused systems of a cycloalkenyl ring with a heteroaryl ring are considered as heteroaryl irrespective of the ring that is bound to the core structure.
  • alkynyl or “C 2-18 alkynyl” as used herein refers to C 2 -C 18 normal, secondary, tertiary, linear, branched or straight hydrocarbon with at least one site (usually 1 to 3, preferably 1) of unsaturation, namely a carbon-carbon, sp triple bond.
  • alkynyl refers to C 2-12 alkynyl (C 2-12 hydrocarbons), yet more in particular to C 2-9 alkynyl (C 2-9 hydrocarbons) yet more in particular to C 2-6 alkynyl (C 2-6 hydrocarbons) as further defined herein above with at least one site (usually 1 to 3, preferably 1) of unsaturation, namely a carbon-carbon, sp triple bond.
  • alkynyloxy refers to a group having the formula –OR e wherein R e is alkynyl as defined herein above.
  • cycloalkynyl refers to a non-aromatic hydrocarbon group having from 5 to 18 carbon atoms with at least one site (usually 1 to 3, preferably 1) of unsaturation, namely a carbon-carbon, sp triple bond and consisting of or comprising a C5-10 monocyclic or C7- 18 polycyclic hydrocarbon.
  • Examples include, but are not limited to: cyclohept-1-yne, 3-ethyl- cyclohept-1-ynylene, 4-cyclohept-1-yn-methylene and ethylene-cyclohept-1-yne.
  • cycloalkynyl refers to C5-10 cycloalkynyl (cyclic C5-10 hydrocarbons), yet more in particular to C5-9 cycloalkynyl (cyclic C5-9 hydrocarbons), still more in particular to C5-6 cycloalkynyl (cyclic C5-6 hydrocarbons) as further defined herein above with at least one site (usually 1 to 3, preferably 1) of unsaturation, namely a carbon-carbon, sp triple bond.
  • site usually 1 to 3, preferably 1 of unsaturation
  • Fused systems of a cycloalkynyl ring with an aryl ring are considered as aryl irrespective of the ring that is bound to the core structure.
  • Fused systems of a cycloalkynyl ring with a heteroaryl ring are considered as heteroaryl irrespective of the ring that is bound to the core structure.
  • alkylene as used herein each refer to a saturated, branched or straight chain hydrocarbon group of 1-18 carbon atoms (more in particular C1-12, C1-9 or C1-6 carbon atoms), and having two monovalent group centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkane.
  • alkylene include, but are not limited to: methylene (-CH2-), 1,2-ethyl (-CH2CH2-), 1,3-propyl (-CH2CH2CH2-), 1,4-butyl (- CH2CH2CH2CH2-), and the like.
  • alkenylene as used herein each refer to a branched or straight chain hydrocarbon of 2-18 carbon atoms (more in particular C2-12, C2-9 or C2-6 carbon atoms) with at least one site (usually 1 to 3, preferably 1) of unsaturation, namely a carbon-carbon, sp2 double bond, and having two monovalent centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkene.
  • alkynylene each refer to a branched or straight chain hydrocarbon of 2-18 carbon atoms (more in particular C 2-12 , C 2-9 or C 2-6 carbon atoms) with at least one site (usually 1 to 3, preferably 1) of unsaturation, namely a carbon-carbon, sp triple bond, and having two monovalent centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkyne.
  • heteroalkyl refers to an alkyl wherein one or more carbon atoms are replaced by one or more atoms selected from the group comprising oxygen, nitrogen or sulphur atom.
  • heteroalkyl thus comprises –O-R b , -NR o -R b , -R a -O-R b , and –S-R b , wherein R a is alkylene, R b is alkyl, and R o is hydrogen or alky as defined herein.
  • R a is alkylene
  • R b is alkyl
  • R o is hydrogen or alky as defined herein.
  • the term refers to C1-12heteroalkyl, C1-9heteroalkyl or C1-6heteroalkyl.
  • heteroalkyl is selected from the group comprising alkyloxy, alkyl-oxy-alkyl, (mono or di)alkylamino, (mono or di-)alkyl-amino-alkyl, alkylthio, and alkyl-thio-alkyl.
  • heteroalkenyl refers to an acyclic alkenyl wherein one or more carbon atoms are replaced by one or more atoms selected from oxygen, nitrogen or sulphur atom.
  • heteroalkenyl thus comprises –O-R d , -NH-(R d ), -N(R d ))2, -N(R b )(R d ), and –S-R d wherein R b is alkyl and R d is alkenyl as defined herein.
  • the term refers to C2- 12heteroalkenyl, C2-9heteroalkenyl or C2-6heteroalkenyl.
  • heteroalkenyl is selected from the group comprising alkenyloxy, alkenyl-oxy-alkenyl, (mono or di-)alkenylamino, (mono or di-)alkenyl-amino-alkenyl, alkenylthio, and alkenyl-thio-alkenyl,
  • heteroalkynyl refers to an acyclic alkynyl wherein one or more carbon atoms are replaced by an oxygen, nitrogen or sulphur atom.
  • heteroalkynyl thus comprises but is not limited to -O-R d , -N(R d )2, NHR d , -N(R b )(R e ), -N(R d )(R e ), and -S-R d wherein R b is alkyl, R e is alkynyl and R d is alkenyl as defined herein.
  • the term refers to C 2-12 heteroalkynyl, C 2-9 heteroalkynyl or C 2-6 heteroalkynyl.
  • heteroalkynyl is selected from the group comprising alkynyloxy, alkynyl-oxy-alkynyl, (mono or di-)alkynylamino, (mono or di-)alkynyl-amino-alkynyl, alkynylthio, alkynyl-thio-alkynyl,
  • heteroalkylene refers to an alkylene wherein one or more carbon atoms are replaced by one or more oxygen, nitrogen or sulphur atoms.
  • heteroalkenylene refers to an alkenylene wherein one or more carbon atoms are replaced by one or more oxygen, nitrogen or sulphur atoms.
  • heteroalkynylene refers to an alkynylene wherein one or more carbon atoms are replaced by one or more oxygen, nitrogen or sulphur atom.
  • aryl as used herein means an aromatic hydrocarbon of 6-20 carbon atoms derived by the removal of hydrogen from a carbon atom of a parent aromatic ring system.
  • Typical aryl groups include, but are not limited to 1 ring, or 2 or 3 rings fused together, derived from benzene, naphthalene, anthracene, biphenyl, and the like.
  • the term aryl refers to a 6-14 carbon atoms membered aromatic cycle, yet more in particular refers to a 6- 10 carbon atoms membered aromatic cycle.
  • Fused systems of an aryl ring with a cycloalkyl ring, or a cycloalkenyl ring, or a cycloalkynyl ring are considered as aryl irrespective of the ring that is bound to the core structure.
  • Fused systems of an aryl ring with a heterocycle are considered as heterocycle irrespective of the ring that is bound to the core structure.
  • indoline, dihydrobenzofurane, dihydrobenzothiophene and the like are considered as heterocycle according to the invention.
  • Fused systems of an aryl ring with a heteroaryl ring are considered as heteroaryl irrespective of the ring that is bound to the core structure.
  • aryloxy refers to a group having the formula – OR g wherein R g is aryl as defined herein above.
  • arylalkyl or “arylalkyl-“ as used herein refers to an alkyl in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon atom, is replaced with an aryl.
  • Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, 2- phenylethen-1-yl, naphthylmethyl, 2-naphthylethyl, and the like.
  • the arylalkyl group comprises 6 to 20 carbon atoms, e.g.
  • arylalkyloxy refers to a group having the formula -O-R a -R g wherein R g is aryl, and R a is alkylene as defined herein above.
  • arylalkenyl or “arylalkenyl-“ as used herein refers to an alkenyl in which one of the hydrogen atoms bonded to a carbon atom, is replaced with an aryl.
  • the arylalkenyl group comprises 6 to 20 carbon atoms, e.g.
  • the alkenyl moiety of the arylalkenyl group is 1 to 6 carbon atoms and the aryl moiety is 6 to 14 carbon atoms.
  • arylalkynyl or “arylalkynyl-“ as used herein refers to an alkynyl in which one of the hydrogen atoms bonded to a carbon atom, is replaced with an aryl.
  • the arylalkynyl group comprises 6 to 20 carbon atoms, e.g. the alkynyl moiety of the arylalkynyl group is 1 to 6 carbon atoms and the aryl moiety is 6 to 14 carbon atoms.
  • arylheteroalkyl or “arylheteroalkyl-“ as used herein refers to a heteroalkyl in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon atom, is replaced with an aryl.
  • the arylheteroalkyl group comprises 6 to 20 carbon atoms, e.g. the heteroalkyl moiety of the arylheteroalkyl group is 1 to 6 carbon atoms and the aryl moiety is 6 to 14 carbon atoms.
  • arylheteroalkyl is selected from the group comprising aryl-O-alkyl, arylalkyl-O-alkyl, aryl-NH-alkyl, aryl-N(alkyl) 2 , arylalkyl-NH-alkyl, arylalkyl-N-(alkyl) 2 , aryl–S-alkyl, and arylalkyl-S-alkyl.
  • arylheteroalkenyl or “arylheteroalkenyl-“ as used herein refers to a heteroalkenyl in which one of the hydrogen atoms bonded to a carbon atom, is replaced with an aryl.
  • the arylheteroalkenyl group comprises 6 to 20 carbon atoms, e.g. the heteroalkenyl moiety of the arylheteroalkenyl group is 1 to 6 carbon atoms and the aryl moiety is 6 to 14 carbon atoms.
  • arylheteroalkenyl is selected from the group comprising aryl-O-alkenyl, arylalkenyl-O-alkenyl, aryl-NH-alkenyl, aryl-N(alkenyl) 2 , arylalkenyl-NH-alkenyl, arylalkenyl-N- (alkenyl) 2 , aryl–S-alkenyl, and arylalkenyl-S-alkenyl.
  • arylheteroalkynyl or “arylheteroalkynyl-“ as used herein refers to a heteroalkynyl in which one of the hydrogen atoms bonded to a carbon atom, is replaced with an aryl.
  • the arylheteroalkynyl group comprises 6 to 20 carbon atoms, e.g. the heteroalkynyl moiety of the arylheteroalkynyl group is 1 to 6 carbon atoms and the aryl moiety is 6 to 14 carbon atoms.
  • arylheteroalkynyl is selected from the group comprising aryl-O-alkynyl, arylalkynyl-O-alkynyl, aryl-NH-alkynyl, aryl-N(alkynyl)2, arylalkynyl-NH-alkynyl, arylalkynyl-N- (alkynyl) 2 , aryl–S-alkynyl, and arylalkynyl-S-alkynyl.
  • heterocycle or “heterocyclyl” as used herein refer to non-aromatic, fully saturated or partially unsaturated ring system of 3 to 18 atoms including at least one N, O, S, or P (for example, 3 to 7 member monocyclic, 7 to 11 member bicyclic, or comprising a total of 3 to 10 ring atoms).
  • the heterocycle may be attached at any heteroatom or carbon atom of the ring or ring system, where valence allows.
  • the rings of multi- ring heterocyclyls or heterocycles may be fused, bridged and/or joined through one or more spiro atoms.
  • Fused systems of a heterocycle or heterocyclyl with an aryl ring are considered as heterocycle or heterocyclyl irrespective of the ring that is bound to the core structure.
  • Fused systems of a heterocycle or heterocyclyl with a heteroaryl ring are considered as heteroaryl irrespective of the ring that is bound to the core structure.
  • Non limiting exemplary heterocycles or heterocyclic groups include piperidinyl, piperazinyl, homopiperazinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, 2-imidazolinyl, pyrazolidinyl imidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, succinimidyl, 3H-indolyl, indolinyl, isoindolinyl, chromanyl (also known as 3,4-dihydrobenzo[b]pyranyl), 2H-pyrrolyl, 1- pyrrolinyl, 2-pyrrolinyl
  • aziridinyl as used herein includes aziridin-1-yl and aziridin-2-yl.
  • oxyranyl as used herein includes oxyranyl-2-yl.
  • thiiranyl as used herein includes thiiran-2-yl.
  • azetidinyl as used herein includes azetidin-1-yl, azetidin-2-yl and azetidin-3-yl.
  • oxetanyl as used herein includes oxetan-2-yl and oxetan-3-yl.
  • thietanyl as used herein includes thietan-2-yl and thietan-3-yl.
  • pyrrolidinyl as used herein includes pyrrolidin-1-yl, pyrrolidin-2-yl and pyrrolidin-3-yl.
  • tetrahydrofuranyl as used herein includes tetrahydrofuran-2-yl and tetrahydrofuran-3-yl.
  • tetrahydrothiophenyl as used herein includes tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl.
  • succinimidyl as used herein includes succinimid-1-yl and succininmid-3-yl.
  • dihydropyrrolyl as used herein includes 2,3-dihydropyrrol-1-yl, 2,3-dihydro-1H-pyrrol-2-yl, 2,3-dihydro-1H-pyrrol-3-yl, 2,5- dihydropyrrol-1-yl, 2,5-dihydro-1H-pyrrol-3-yl and 2,5-dihydropyrrol-5-yl.
  • 2H-pyrrolyl as used herein includes 2H-pyrrol-2-yl, 2H-pyrrol-3-yl, 2H-pyrrol-4-yl and 2H-pyrrol-5-yl.
  • 3H-pyrrolyl as used herein includes 3H-pyrrol-2-yl, 3H-pyrrol-3-yl, 3H-pyrrol-4-yl and 3H-pyrrol- 5-yl.
  • dihydrofuranyl as used herein includes 2,3-dihydrofuran-2-yl, 2,3-dihydrofuran-3- yl, 2,3-dihydrofuran-4-yl, 2,3-dihydrofuran-5-yl, 2,5-dihydrofuran-2-yl, 2,5-dihydrofuran-3-yl, 2,5- dihydrofuran-4-yl and 2,5-dihydrofuran-5-yl.
  • dihydrothiophenyl as used herein includes 2,3-dihydrothiophen-2-yl, 2,3-dihydrothiophen-3-yl, 2,3-dihydrothiophen-4-yl, 2,3- dihydrothiophen-5-yl, 2,5-dihydrothiophen-2-yl, 2,5-dihydrothiophen-3-yl, 2,5-dihydrothiophen-4- yl and 2,5-dihydrothiophen-5-yl.
  • imidazolidinyl as used herein includes imidazolidin-1- yl, imidazolidin-2-yl and imidazolidin-4-yl.
  • pyrazolidinyl as used herein includes pyrazolidin-1-yl, pyrazolidin-3-yl and pyrazolidin-4-yl.
  • imidazolinyl as used herein includes imidazolin-1-yl, imidazolin-2-yl, imidazolin-4-yl and imidazolin-5-yl.
  • pyrazolinyl as used herein includes 1-pyrazolin-3-yl, 1-pyrazolin-4-yl, 2-pyrazolin-1-yl, 2-pyrazolin-3-yl, 2- pyrazolin-4-yl, 2-pyrazolin-5-yl, 3-pyrazolin-1-yl, 3-pyrazolin-2-yl, 3-pyrazolin-3-yl, 3-pyrazolin-4- yl and 3-pyrazolin-5-yl.
  • dioxolanyl also known as “1,3-dioxolanyl” as used herein includes dioxolan-2-yl, dioxolan-4-yl and dioxolan-5-yl.
  • dioxolyl also known as “1,3- dioxolyl” as used herein includes dioxol-2-yl, dioxol-4-yl and dioxol-5-yl.
  • oxazolidinyl as used herein includes oxazolidin-2-yl, oxazolidin-3-yl, oxazolidin-4-yl and oxazolidin-5-yl.
  • isoxazolidinyl as used herein includes isoxazolidin-2-yl, isoxazolidin-3-yl, isoxazolidin-4-yl and isoxazolidin-5-yl.
  • oxazolinyl as used herein includes 2-oxazolinyl-2-yl, 2- oxazolinyl-4-yl, 2-oxazolinyl-5-yl, 3-oxazolinyl-2-yl, 3-oxazolinyl-4-yl, 3-oxazolinyl-5-yl, 4- oxazolinyl-2-yl, 4-oxazolinyl-3-yl, 4-oxazolinyl-4-yl and 4-oxazolinyl-5-yl.
  • isoxazolinyl as used herein includes 2-isoxazolinyl-3-yl, 2-isoxazolinyl-4-yl, 2-isoxazolinyl-5-yl, 3-isoxazolinyl- 3-yl, 3-isoxazolinyl-4-yl, 3-isoxazolinyl-5-yl, 4-isoxazolinyl-2-yl, 4-isoxazolinyl-3-yl, 4-isoxazolinyl- 4-yl and 4-isoxazolinyl-5-yl.
  • thiazolidinyl as used herein includes thiazolidin-2-yl, thiazolidin-3-yl, thiazolidin-4-yl and thiazolidin-5-yl.
  • isothiazolidinyl as used herein includes isothiazolidin-2-yl, isothiazolidin-3-yl, isothiazolidin-4-yl and isothiazolidin-5-yl.
  • thiazolinyl as used herein includes 2-thiazolinyl-2-yl, 2-thiazolinyl-4-yl, 2-thiazolinyl-5-yl, 3- thiazolinyl-2-yl, 3-thiazolinyl-4-yl, 3-thiazolinyl-5-yl, 4-thiazolinyl-2-yl, 4-thiazolinyl-3-yl, 4- thiazolinyl-4-yl and 4-thiazolinyl-5-yl.
  • isothiazolinyl as used herein includes 2- isothiazolinyl-3-yl, 2-isothiazolinyl-4-yl, 2-isothiazolinyl-5-yl, 3-isothiazolinyl-3-yl, 3-isothiazolinyl- 4-yl, 3-isothiazolinyl-5-yl, 4-isothiazolinyl-2-yl, 4-isothiazolinyl-3-yl, 4-isothiazolinyl-4-yl and 4- isothiazolinyl-5-yl.
  • piperidyl also known as “piperidinyl” as used herein includes piperid- 1-yl, piperid-2-yl, piperid-3-yl and piperid-4-yl.
  • dihydropyridinyl as used herein includes 1,2-dihydropyridin-1-yl, 1,2-dihydropyridin-2-yl, 1,2-dihydropyridin-3-yl, 1,2-dihydropyridin-4-yl, 1,2-dihydropyridin-5-yl, 1,2-dihydropyridin-6-yl, 1,4-dihydropyridin-1-yl, 1,4-dihydropyridin-2-yl, 1,4-dihydropyridin-3-yl, 1,4-dihydropyridin-4-yl, 2,3-dihydropyridin-2-yl, 2,3-dihydropyridin-3-yl, 2,3-dihydropyridin-4-yl, 2,3-
  • tetrahydropyridinyl as used herein includes 1,2,3,4- tetrahydropyridin-1-yl, 1,2,3,4-tetrahydropyridin-2-yl, 1,2,3,4-tetrahydropyridin-3-yl, 1,2,3,4- tetrahydropyridin-4-yl, 1,2,3,4-tetrahydropyridin-5-yl, 1,2,3,4-tetrahydropyridin-6-yl, 1,2,3,6- tetrahydropyridin-1-yl, 1,2,3,6-tetrahydropyridin-2-yl, 1,2,3,6-tetrahydropyridin-3-yl, 1,2,3,6- tetrahydropyridin-4-yl, 1,2,3,6-tetrahydropyridin-5-yl, 1,2,3,6-tetrahydropyridin-6-yl, 2,3,4,5- tetrahydropyridin-2-yl,
  • tetrahydropyranyl also known as “oxanyl” or “tetrahydro-2H-pyranyl”, as used herein includes tetrahydropyran-2-yl, tetrahydropyran-3-yl and tetrahydropyran-4-yl.
  • the term “2H-pyranyl” as used herein includes 2H-pyran-2-yl, 2H-pyran-3-yl, 2H-pyran-4-yl, 2H-pyran-5-yl and 2H-pyran- 6-yl.
  • the term “4H-pyranyl” as used herein includes 4H-pyran-2-yl, 4H-pyran-3-yl and 4H-pyran- 4-yl.
  • 3,4-dihydro-2H-pyranyl as used herein includes 3,4-dihydro-2H-pyran-2-yl, 3,4- dihydro-2H-pyran-3-yl, 3,4-dihydro-2H-pyran-4-yl, 3,4-dihydro-2H-pyran-5-yl and 3,4-dihydro-2H- pyran-6-yl.
  • 3,6-dihydro-2H-pyranyl as used herein includes 3,6-dihydro-2H-pyran-2-yl, 3,6-dihydro-2H-pyran-3-yl, 3,6-dihydro-2H-pyran-4-yl, 3,6-dihydro-2H-pyran-5-yl and 3,6- dihydro-2H-pyran-6-yl.
  • tetrahydrothiophenyl as used herein includes tetrahydrothiophen-2-yl, tetrahydrothiophenyl -3-yl and tetrahydrothiophenyl -4-yl.
  • 2H- thiopyranyl as used herein includes 2H-thiopyran-2-yl, 2H-thiopyran-3-yl, 2H-thiopyran-4-yl, 2H- thiopyran-5-yl and 2H-thiopyran-6-yl.
  • 4H-thiopyranyl as used herein includes 4H- thiopyran-2-yl, 4H-thiopyran-3-yl and 4H-thiopyran-4-yl.
  • 3,4-dihydro-2H-thiopyranyl as used herein includes 3,4-dihydro-2H-thiopyran-2-yl, 3,4-dihydro-2H-thiopyran-3-yl, 3,4-dihydro- 2H-thiopyran-4-yl, 3,4-dihydro-2H-thiopyran-5-yl and 3,4-dihydro-2H-thiopyran-6-yl.
  • 3-dihydro-2H-thiopyranyl as used herein includes 3,6-dihydro-2H-thiopyran-2-yl, 3,6-dihydro- 2H-thiopyran-3-yl, 3,6-dihydro-2H-thiopyran-4-yl, 3,6-dihydro-2H-thiopyran-5-yl and 3,6-dihydro- 2H-thiopyran-6-yl.
  • piperazinyl also known as “piperazidinyl” as used herein includes piperazin-1-yl and piperazin-2-yl.
  • morpholinyl as used herein includes morpholin-2-yl, morpholin-3-yl and morpholin-4-yl.
  • thiomorpholinyl as used herein includes thiomorpholin-2-yl, thiomorpholin-3-yl and thiomorpholin-4-yl.
  • dioxanyl as used herein includes 1,2-dioxan-3-yl, 1,2-dioxan-4-yl, 1,3-dioxan-2-yl, 1,3-dioxan-4-yl, 1,3-dioxan-5-yl and 1,4-dioxan-2-yl.
  • dithianyl as used herein includes 1,2-dithian-3-yl, 1,2-dithian-4-yl, 1,3- dithian-2-yl, 1,3-dithian-4-yl, 1,3-dithian-5-yl and 1,4-dithian-2-yl.
  • oxathianyl as used herein includes oxathian-2-yl and oxathian-3-yl.
  • trioxanyl as used herein includes 1,2,3-trioxan-4-yl, 1,2,3-trioxan-5-yl, 1,2,4-trioxan-3-yl, 1,2,4-trioxan-5-yl, 1,2,4-trioxan-6-yl and 1,3,4-trioxan-2-yl.
  • azepanyl as used herein includes azepan-1-yl, azepan-2-yl, azepan-3-yl and azepan-4-yl.
  • homoopiperazinyl as used herein includes homopiperazin-1-yl, homopiperazin-2-yl, homopiperazin-3-yl and homopiperazin-4-yl.
  • indolinyl as used herein includes indolin-1-yl, indolin-2-yl, indolin-3-yl, indolin-4-yl, indolin-5-yl, indolin-6-yl, and indolin-7-yl.
  • quinolizinyl as used herein includes quinolizidin-1-yl, quinolizidin-2-yl, quinolizidin-3-yl and quinolizidin-4-yl.
  • isoindolinyl as used herein includes isoindolin-1-yl, isoindolin-2-yl, isoindolin-3-yl, isoindolin-4-yl, isoindolin-5-yl, isoindolin-6- yl, and isoindolin-7-yl.
  • 3H-indolyl as used herein includes 3H-indol-2-yl, 3H-indol-3-yl, 3H-indol-4-yl, 3H-indol-5-yl, 3H-indol-6-yl, and 3H-indol-7-yl.
  • quinolizinyl as used herein includes quinolizidin-1-yl, quinolizidin-2-yl, quinolizidin-3-yl and quinolizidin-4-yl.
  • quinolizinyl as used herein includes quinolizidin-1-yl, quinolizidin-2-yl, quinolizidin-3-yl and quinolizidin-4-yl.
  • tetrahydroquinolinyl as used herein includes tetrahydroquinolin-1-yl, tetrahydroquinolin-2-yl, tetrahydroquinolin-3-yl, tetrahydroquinolin-4-yl, tetrahydroquinolin-5-yl, tetrahydroquinolin-6-yl, tetrahydroquinolin-7-yl and tetrahydroquinolin-8-yl.
  • tetrahydroisoquinolinyl as used herein includes tetrahydroisoquinolin-1-yl, tetrahydroisoquinolin-2-yl, tetrahydroisoquinolin-3-yl, tetrahydroisoquinolin-4-yl, tetrahydroisoquinolin-5-yl, tetrahydroisoquinolin-6-yl, tetrahydroisoquinolin-7-yl and tetrahydroisoquinolin-8-yl.
  • chromanyl as used herein includes chroman-2-yl, chroman- 3-yl, chroman-4-yl, chroman-5-yl, chroman-6-yl, chroman-7-yl and chroman-8-yl.
  • 1H- pyrrolizine as used herein includes 1H-pyrrolizin-1-yl, 1H-pyrrolizin-2-yl, 1H-pyrrolizin-3-yl, 1H- pyrrolizin-5-yl, 1H-pyrrolizin-6-yl and 1H-pyrrolizin-7-yl.
  • 3H-pyrrolizine as used herein includes 3H-pyrrolizin-1-yl, 3H-pyrrolizin-2-yl, 3H-pyrrolizin-3-yl, 3H-pyrrolizin-5-yl, 3H-pyrrolizin- 6-yl and 3H-pyrrolizin-7-yl.
  • Fused systems of a heteroaryl ring with a cycloalkyl ring, or a cycloalkenyl ring, or a cycloalkynyl ring are considered as heteroaryl irrespective of the ring that is bound to the core structure.
  • Fused systems of a heteroaryl ring with a heterocycle are considered as heteroaryl irrespective of the ring that is bound to the core structure.
  • Fused systems of a hetero aryl ring with an aryl ring are considered as heteroaryl irrespective of the ring that is bound to the core structure.
  • Non-limiting examples of such heteroaryl include: triazol-2-yl, pyridinyl, 1H-pyrazol-5-yl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, imidazo[2,1-b][1,3]thiazolyl, thieno[3,2-b]furanyl, thieno[3,2- b]thiophenyl, thieno[2,3-d][1,3]thiazolyl,
  • pyrrolyl (also called azolyl) as used herein includes pyrrol-1-yl, pyrrol-2-yl and pyrrol-3-yl.
  • furanyl (also called “furyl”) as used herein includes furan-2-yl and furan-3- yl (also called furan-2-yl and furan-3-yl).
  • thiophenyl (also called “thienyl”) as used herein includes thiophen-2-yl and thiophen-3-yl (also called thien-2-yl and thien-3-yl).
  • pyrazolyl (also called 1H-pyrazolyl and 1,2-diazolyl) as used herein includes pyrazol-1-yl, pyrazol-3-yl or 1H-pyrazol-5-yl, pyrazol-4-yl and pyrazol-5-yl.
  • imidazolyl as used herein includes imidazol-1-yl, imidazol-2-yl, imidazol-4-yl and imidazol-5-yl.
  • oxazolyl (also called 1,3-oxazolyl) as used herein includes oxazol-2-yl, oxazol-4-yl and oxazol-5-yl.
  • isoxazolyl (also called 1,2-oxazolyl), as used herein includes isoxazol-3-yl, isoxazol-4-yl, and isoxazol-5-yl.
  • thiazolyl also called 1,3-thiazolyl
  • thiazol-2-yl thiazol-4-yl
  • thiazol-5-yl also called 2-thiazolyl, 4-thiazolyl and 5-thiazolyl
  • isothiazolyl (also called 1,2-thiazolyl) as used herein includes isothiazol-3-yl, isothiazol-4-yl, and isothiazol-5-yl.
  • triazolyl as used herein includes triazol-2-yl, 1H-triazolyl and 4H-1,2,4- triazolyl
  • “1H-triazolyl” includes 1H-1,2,3-triazol-1-yl, 1H-1,2,3-triazol-4-yl, 1H-1,2,3-triazol-5-yl, 1H-1,2,4-triazol-1-yl, 1H-1,2,4-triazol-3-yl and 1H-1,2,4-triazol-5-yl.
  • “4H-1,2,4-triazolyl” includes 4H-1,2,4-triazol-4-yl, and 4H-1,2,4-triazol-3-yl.
  • oxadiazolyl as used herein includes 1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,5- oxadiazol-3-yl and 1,3,4-oxadiazol-2-yl.
  • thiadiazolyl as used herein includes 1,2,3- thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 1,2,5-thiadiazol-3- yl (also called furazan-3-yl) and 1,3,4-thiadiazol-2-yl.
  • tetrazolyl as used herein includes 1H-tetrazol-1-yl, 1H-tetrazol-5-yl, 2H-tetrazol-2-yl, and 2H-tetrazol-5-yl.
  • oxatriazolyl as used herein includes 1,2,3,4-oxatriazol-5-yl and 1,2,3,5-oxatriazol-4-yl.
  • thiatriazolyl as used herein includes 1,2,3,4-thiatriazol-5-yl and 1,2,3,5-thiatriazol-4-yl.
  • pyridinyl also called “pyridyl” as used herein includes pyridin-2-yl, pyridin-3-yl and pyridin-4-yl (also called 2- pyridyl, 3-pyridyl and 4-pyridyl).
  • pyrimidyl as used herein includes pyrimid-2-yl, pyrimid- 4-yl, pyrimid-5-yl and pyrimid-6-yl.
  • pyrazinyl as used herein includes pyrazin-2-yl and pyrazin-3-yl.
  • pyridazinyl as used herein includes pyridazin-3-yl and pyridazin-4-yl.
  • oxazinyl (also called "1,4-oxazinyl”) as used herein includes 1,4-oxazin-4-yl and 1,4- oxazin-5-yl.
  • dioxinyl also called “1,4-dioxinyl”
  • thiazinyl also called “1,4-thiazinyl”
  • 1,4-thiazinyl includes 1,4- thiazin-2-yl, 1,4-thiazin-3-yl, 1,4-thiazin-4-yl, 1,4-thiazin-5-yl and 1,4-thiazin-6-yl.
  • triazinyl as used herein includes 1,3,5-triazin-2-yl, 1,2,4-triazin-3-yl, 1,2,4-triazin-5-yl, 1,2,4- triazin-6-yl, 1,2,3-triazin-4-yl and 1,2,3-triazin-5-yl.
  • imidazo[2,1-b][1,3]thiazolyl includes imidazo[2,1-b][1,3]thiazoi-2-yl, imidazo[2,1-b][1,3]thiazol-3-yl, imidazo[2,1- b][1,3]thiazol-5-yl and imidazo[2,1-b][1,3]thiazol-6-yl.
  • thieno[3,2-b]furanyl as used herein includes thieno[3,2-b]furan-2-yl, thieno[3,2-b]furan-3-yl, thieno[3,2-b]furan-4-yl, and thieno[3,2-b]furan-5-yl.
  • thieno[3,2-b]thiophenyl as used herein includes thieno[3,2- b]thien-2-yl, thieno[3,2-b]thien-3-yl, thieno[3,2-b]thien-5-yl and thieno[3,2-b]thien-6-yl.
  • thieno[2,3-d][1,3]thiazolyl as used herein includes thieno[2,3-d][1,3]thiazol-2-yl, thieno[2,3- d][1,3]thiazol-5-yl and thieno[2,3-d][1,3]thiazol-6-yl.
  • thieno[2,3-d]imidazolyl as used herein includes thieno[2,3-d]imidazol-2-yl, thieno[2,3-d]imidazol-4-yl and thieno[2,3-d]imidazol-5- yl.
  • tetrazolo[1,5-a]pyridinyl as used herein includes tetrazolo[1,5-a]pyridine-5-yl, tetrazolo[1,5-a]pyridine-6-yl, tetrazolo[1,5-a]pyridine-7-yl, and tetrazolo[1,5-a]pyridine-8-yl.
  • indolyl as used herein includes indol-1-yl, indol-2-yl, indol-3-yl,-indol-4-yl, indol-5-yl, indol- 6-yl and indol-7-yl.
  • indolizinyl as used herein includes indolizin-1-yl, indolizin-2-yl, indolizin-3-yl, indolizin-5-yl, indolizin-6-yl, indolizin-7-yl, and indolizin-8-yl.
  • isoindolyl as used herein includes isoindol-1-yl, isoindol-2-yl, isoindol-3-yl, isoindol-4-yl, isoindol-5-yl, isoindol- 6-yl and isoindol-7-yl.
  • benzofuranyl (also called benzo[b]furanyl) as used herein includes benzofuran-2-yl, benzofuran-3-yl, benzofuran-4-yl, benzofuran-5-yl, benzofuran-6-yl and benzofuran-7-yl.
  • isobenzofuranyl (also called benzo[c]furanyl) as used herein includes isobenzofuran-1-yl, isobenzofuran-3-yl, isobenzofuran-4-yl, isobenzofuran-5-yl, isobenzofuran-6- yl and isobenzofuran-7-yl.
  • benzothiophenyl (also called benzo[b]thienyl) as used herein includes 2-benzo[b]thiophenyl, 3-benzo[b]thiophenyl, 4-benzo[b]thiophenyl, 5- benzo[b]thiophenyl, 6-benzo[b]thiophenyl and -7-benzo[b]thiophenyl (also called benzothien-2-yl, benzothien-3-yl, benzothien-4-yl, benzothien-5-yl, benzothien-6-yl and benzothien-7-yl).
  • isobenzothiophenyl also called benzo[c]thienyl
  • isobenzothien-1-yl isobenzothien-3-yl, isobenzothien-4-yl, isobenzothien-5-yl, isobenzothien-6-yl and isobenzothien- 7-yl.
  • indazolyl (also called 1H-indazolyl or 2-azaindolyl) as used herein includes 1H- indazol-1-yl, 1H-indazol-3-yl, 1H-indazol-4-yl, 1H-indazol-5-yl, 1H-indazol-6-yl, 1H-indazol-7-yl, 2H-indazol-2-yl, 2H-indazol-3-yl, 2H-indazol-4-yl, 2H-indazol-5-yl, 2H-indazol-6-yl, and 2H- indazol-7-yl.
  • benzimidazolyl as used herein includes benzimidazol-1-yl, benzimidazol- 2-yl, benzimidazol-4-yl, benzimidazol-5-yl, benzimidazol-6-yl and benzimidazol-7-yl.
  • 1,3-benzoxazolyl as used herein includes 1,3-benzoxazol-2-yl, 1,3-benzoxazol-4-yl, 1,3- benzoxazol-5-yl, 1,3-benzoxazol-6-yl and 1,3-benzoxazol-7-yl.
  • 1,2-benzisoxazolyl as used herein includes 1,2-benzisoxazol-3-yl, 1,2-benzisoxazol-4-yl, 1,2-benzisoxazol-5-yl, 1,2- benzisoxazol-6-yl and 1,2-benzisoxazol-7-yl.
  • 2,1-benzisoxazolyl as used herein includes 2,1-benzisoxazol-3-yl, 2,1-benzisoxazol-4-yl, 2,1-benzisoxazol-5-yl, 2,1-benzisoxazol-6- yl and 2,1-benzisoxazol-7-yl.
  • 1,3-benzothiazolyl as used herein includes 1,3- benzothiazol-2-yl, 1,3-benzothiazol-4-yl, 1,3-benzothiazol-5-yl, 1,3-benzothiazol-6-yl and 1,3- benzothiazol-7-yl.
  • 1,2-benzoisothiazolyl as used herein includes 1,2-benzisothiazol-3- yl, 1,2-benzisothiazol-4-yl, 1,2-benzisothiazol-5-yl, 1,2-benzisothiazol-6-yl and 1,2- benzisothiazol-7-yl.
  • 2,1-benzoisothiazolyl as used herein includes 2,1-benzisothiazol- 3-yl, 2,1-benzisothiazol-4-yl, 2,1-benzisothiazol-5-yl, 2,1-benzisothiazol-6-yl and 2,1- benzisothiazol-7-yl.
  • benzotriazolyl as used herein includes benzotriazol-1-yl, benzotriazol-4-yl, benzotriazol-5-yl, benzotriazol-6-yl and benzotriazol-7-yl.
  • 1,2,3- benzoxadiazolyl as used herein includes 1,2,3-benzoxadiazol-4-yl, 1,2,3-benzoxadiazol-5-yl, 1,2,3-benzoxadiazol-6-yl and 1,2,3-benzoxadiazol-7-yl.
  • 2,1,3-benzoxadiazolyl as used herein includes 2,1,3-benzoxadiazol-4-yl, 2,1,3-benzoxadiazol-5-yl, 2,1,3-benzoxadiazol-6-yl and 2,1,3-benzoxadiazol-7-yl.
  • 1,2,3-benzothiadiazolyl as used herein includes 1,2,3- benzothiadiazol-4-yl, 1,2,3-benzothiadiazol-5-yl, 1,2,3-benzothiadiazol-6-yl and 1,2,3- benzothiadiazol-7-yl.
  • 2,1,3-benzothiadiazolyl as used herein includes 2,1,3- benzothiadiazol-4-yl, 2,1,3-benzothiadiazol-5-yl, 2,1,3-benzothiadiazol-6-yl and 2,1,3- benzothiadiazol-7-yl.
  • thienopyridinyl as used herein includes thieno[2,3-b]pyridinyl, thieno[2,3-c]pyridinyl, thieno[3,2-c]pyridinyl and thieno[3,2-b]pyridinyl.
  • purinyl as used herein includes purin-2-yl, purin-6-yl, purin-7-yl and purin-8-yl.
  • imidazo[1,2-a]pyridinyl includes imidazo[1,2-a]pyridin-2-yl, imidazo[1,2-a]pyridin-3-yl, imidazo[1,2- a]pyridin-4-yl, imidazo[1,2-a]pyridin-5-yl, imidazo[1,2-a]pyridin-6-yl and imidazo[1,2-a]pyridin-7- yl.
  • 1,3-benzodioxolyl includes 1,3-benzodioxol-4-yl, 1,3-benzodioxol- 5-yl, 1,3-benzodioxol-6-yl, and 1,3-benzodioxol-7-yl.
  • quinolinyl as used herein includes quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl and quinolin-8- yl.
  • isoquinolinyl as used herein includes isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin- 4-yl, isoquinolin-5-yl, isoquinolin-6-yl, isoquinolin-7-yl and isoquinolin-8-yl.
  • cinnolinyl as used herein includes cinnolin-3-yl, cinnolin-4-yl, cinnolin-5-yl, cinnolin-6-yl, cinnolin-7-yl and cinnolin-8-yl.
  • quinazolinyl as used herein includes quinazolin-2-yl, quinazolin-4-yl, quinazolin-5-yl, quinazolin-6-yl, quinazolin-7-yl and quinazolin-8-yl.
  • quixalinyl as used herein includes quinoxalin-2-yl, quinoxalin-5-yl, and quinoxalin-6-yl.
  • Heteroaryl and heterocycle or heterocyclyl as used herein includes by way of example and not limitation these groups described in Paquette, Leo A. “Principles of Modern Heterocyclic Chemistry” (W.A.
  • heterocyclyloxy or “heterocycleoxy”, as a group or part of a group, refers to a group having the formula -O-R i wherein R i is heterocyclyl as defined herein above.
  • heterocyclylalkyloxy or “heterocycleoxy”, as a group or part of a group, refers to a group having the formula -O-R a -R i wherein R i is heterocyclyl, and R a is alkyl as defined herein above.
  • heteroaryloxy refers to a group having the formula -O-R k wherein R k is heteroaryl as defined herein above.
  • heteroarylalkyloxy refers to a group having the formula -O-R a -R i wherein R i is heteroaryl, and R a is alkyl as defined herein above.
  • heterocyclylalkyl or “heterocycle-alkyl” as a group or part of a group, refers to an alkyl in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon atom, is replaced with a heterocyclyl.
  • a non-limiting example of a heterocyclylalkyl or heterocycle-alkyl group is 2-piperidinyl-methylene.
  • the heterocyclylalkyl or heterocycle-alkyl group can comprise 6 to 20 atoms, e.g. the alkyl moiety is 1 to 6 carbon atoms and the heterocyclyl moiety is 3 to 14 atoms.
  • the term “heterocyclylalkenyl” or “heterocycle-alkenyl” as a group or part of a group refers to an alkenyl in which one of the hydrogen atoms bonded to a carbon atom, is replaced with an heterocyclyl.
  • the heterocyclylalkenyl or heterocycle-alkenyl group can comprise 6 to 20 atoms, e.g.
  • heterocyclylalkynyl or “heterocycle-alkynyl” as a group or part of a group refers to an alkynyl in which one of the hydrogen atoms bonded to a carbon atom, is replaced with a heterocyclyl.
  • the heterocyclylalkynyl or heterocycle-alkynyl group can comprise 6 to 20 atoms, e.g. the alkynyl moiety can comprise 2 to 6 carbon atoms and the heterocyclyl moiety can comprise 3 to 14 atoms.
  • heterocyclylheteroalkyl or “heterocycle-heteroalkyl” as a group or part of a group refers to a heteroalkyl in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon atom, is replaced with a heterocyclyl.
  • the heterocyclylheteroalkyl or heterocycle-heteroalkyl group can comprise 6 to 20 atoms, e.g. the heteroalkyl moiety can comprise 1 to 6 carbon atoms and the heterocyclyl moiety can comprise 3 to 14 atoms.
  • heterocyclylheteroalkyl or heterocycle-heteroalkyl is selected from the group comprising heterocyclyl-O-alkyl, heterocyclylalkyl-O-alkyl, heterocyclyl- NH-alkyl, heterocyclyl-N(alkyl)2, heterocyclylalkyl-NH-alkyl, heterocyclylalkyl-N-(alkyl)2, heterocyclyl–S-alkyl, and heterocyclylalkyl-S-alkyl.
  • heterocyclylheteroalkenyl or “heterocycle-heteroalkenyl” as a group or part of a group refers to a heteroalkenyl in which one of the hydrogen atoms bonded to a carbon atom, is replaced with a heterocyclyl.
  • the heterocyclylheteroalkenyl or heterocycle-heteroalkenyl group can comprise 6 to 20 atoms, e.g. the heteroalkenyl moiety can comprise 2 to 6 carbon atoms and the heterocyclyl moiety can comprise 3 to 14 atoms.
  • heterocyclyl- heteroalkenyl or heterocycle-heteroalkenyl is selected from the group comprising heterocyclyl-O- alkenyl, heterocyclylalkyl-O-alkenyl, heterocyclyl-NH-alkenyl, heterocyclyl-N(alkenyl)2, heterocyclylalkyl-NH-alkenyl, heterocyclylalkyl-N-(alkenyl)2, heterocyclyl–S-alkenyl, and heterocyclylalkenyl-S-alkenyl.
  • heterocyclylheteroalkynyl or “heterocycle-heteroalkynyl” as a group or part of a group refers to a heteroalkynyl in which one of the hydrogen atoms bonded to a carbon atom, is replaced with a heterocyclyl.
  • the heterocyclylheteroalkynyl or heterocycle-heteroalkynyl group can comprise 6 to 20 atoms, e.g. the heteroalkynyl moiety can comprise 2 to 6 carbon atoms and the heterocyclyl moiety can comprise 3 to 14 atoms.
  • heterocyclyl- heteroalkynyl is selected from the group comprising heterocyclyl-O-alkynyl, heterocyclylalkynyl- O-alkynyl, heterocyclyl-NH-alkynyl, heterocyclyl-N(alkynyl)2, heterocyclylalkynyl-NH-alkynyl, heterocyclylalkynyl-N-(alkynyl) 2 , heterocyclyl–S-alkynyl, and heterocyclylalkynyl-S-alkynyl.
  • heteroarylalkyl refers to an alkyl in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon atom, is replaced with a heteroaryl.
  • An example of a heteroarylalkyl group is 2-pyridyl-methylene.
  • the heteroarylalkyl group can comprise 6 to 20 atoms, e.g. the alkyl moiety of the heteroarylalkyl group can comprise 1 to 6 carbon atoms and the heteroaryl moiety can comprise 5 to 14 atoms.
  • heteroarylalkenyl refers to an alkenyl in which one of the hydrogen atoms bonded to a carbon atom, is replaced with an heteroaryl.
  • the heteroaryl-alkenyl group can comprise 6 to 20 atoms, e.g. the alkenyl moiety of the heteroaryl- alkenyl group can comprise 2 to 6 carbon atoms and the heteroaryl moiety can comprise 5 to 14 atoms.
  • heteroarylalkynyl as a group or part of a group as used herein refers to an alkynyl in which one of the hydrogen atoms bonded to a carbon atom, is replaced with a heteroaryl.
  • the heteroarylalkynyl group comprises 6 to 20 atoms, e.g. the alkynyl moiety of the heteroaryl-alkynyl group is 2 to 6 carbon atoms and the heteroaryl moiety is 5 to 14 atoms.
  • the term “heteroarylheteroalkyl” as a group or part of a group as used herein refers to a heteroalkyl in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon atom, is replaced with a heteroaryl.
  • the heteroarylheteroalkyl group comprises 7 to 20 atoms, e.g.
  • heteroaryl-heteroalkyl is selected from the group comprising heteroaryl-O-alkyl, heteroarylalkyl-O-alkyl, heteroaryl-NH- alkyl, heteroaryl-N(alkyl)2, heteroarylalkyl-NH-alkyl, heteroarylalkyl-N-(alkyl)2, heteroaryl–S-alkyl, and heteroarylalkyl-S-alkyl.
  • heteroarylheteroalkenyl refers to a heteroalkenyl in which one of the hydrogen atoms bonded to a carbon atom, is replaced with an heteroaryl.
  • the heteroarylheteroalkenyl group comprises 8 to 20 atoms, e.g. the heteroalkenyl moiety of the heteroarylheteroalkenyl group is 3 to 6 carbon atoms and the heteroaryl moiety is 5 to 14 atoms.
  • heteroarylheteroalkenyl is selected from the group comprising heteroaryl-O-alkenyl, heteroarylalkenyl-O-alkenyl, heteroaryl-NH-alkenyl, heteroaryl-N(alkenyl)2, heteroarylalkenyl-NH-alkenyl, heteroarylalkenyl-N-(alkenyl)2, heteroaryl–S-alkenyl, and heteroarylalkenyl-S-alkenyl.
  • heteroarylheteroalkynyl refers to a heteroalkynyl in which one of the hydrogen atoms bonded to a carbon atom, is replaced with a heteroaryl.
  • the heteroarylheteroalkynyl group comprises 8 to 20 atoms, e.g. the heteroalkynyl moiety of the heteroarylheteroalkynyl group is 2 to 6 carbon atoms and the heteroaryl moiety is 5 to 14 atoms.
  • heteroarylheteroalkynyl is selected from the group comprising heteroaryl-O-alkynyl, heteroarylalkynyl-O-alkynyl, heteroaryl-NH-alkynyl, heteroaryl-N(alkynyl)2, heteroarylalkynyl-NH-alkynyl, heteroarylalkynyl-N-(alkynyl) 2 , heteroaryl–S-alkynyl, and heteroarylalkynyl-S-alkynyl.
  • carbon bonded heteroaryl or heterocyclic rings can be bonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiophene, pyrrole or tetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of an aziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline.
  • carbon bonded heteroaryls and heterocyclyls include 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4- pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl.
  • nitrogen bonded heterocyclic rings are bonded at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3- imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole, position 2 of a isoindole, or isoindoline, position 4 of a morpholine, and position 9 of a carbazole, or ß-carboline.
  • nitrogen bonded heteroaryls or heterocyclyls include 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, and 1-piperidinyl.
  • the terms “alkoxy”, “cyclo-alkoxy”, “aryloxy”, “arylalkyloxy”, “heteroaryloxy” “heterocyclyloxy”, “alkylthio”, “cycloalkylthio”, “arylthio”, “arylalkylthio”, “heteroarylthio” and “heterocyclylthio” refer to substituents wherein an alkyl group, respectively a cycloalkyl, aryl, arylalkyl heteroaryl, or heterocyclyl (each of them such as defined herein), are attached to an oxygen atom or a sulfur atom through a single bond, such as but not limited to methoxy, ethoxy, propoxy,
  • alkylthio refers to a group having the formula – S-R b wherein R b is alkyl as defined herein above.
  • alkylthio groups include methylthio (-SCH3), ethylthio (-SCH2CH3), n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio and the like.
  • alkenylthio refers to a group having the formula –S-R d wherein R d is alkenyl as defined herein above.
  • alkynylthio refers to a group having the formula –S-R e wherein R e is alkynyl as defined herein above.
  • arylthio refers to a group having the formula – S-R g wherein R g is aryl as defined herein above.
  • arylalkylthio refers to a group having the formula -S-R a -R g wherein R a is alkylene and R g is aryl as defined herein above.
  • heterocyclylthio refers to a group having the formula –S-R i wherein R i is heterocyclyl as defined herein above.
  • heteroarylthio refers to a group having the formula –S-R k wherein R k is heteroaryl as defined herein above.
  • heterocyclylalkylthio refers to a group having the formula -S-R a -R i wherein R a is alkylene and R i is heterocyclyl as defined herein above.
  • heteroarylalkylthio refers to a group having the formula -S-R a -R k wherein R a is alkylene and R k is heteroaryl as defined herein above.
  • alkylamino refers to a group of formula -N(R o )(R b ) wherein R o is hydrogen, or alkyl, R b is alkyl.
  • alkylamino include mono- alkyl amino group (e.g. mono-alkylamino group such as methylamino and ethylamino), and di- alkylamino group (e.g. di-alkylamino group such as dimethylamino and diethylamino).
  • Non- limiting examples of suitable mono- or di-alkylamino groups include n-propylamino, isopropylamino, n-butylamino, i-butylamino, sec-butylamino, t-butylamino, pentylamino, n- hexylamino, di-n-propylamino, di-i-propylamino, ethylmethylamino, methyl-n-propylamino, methyl-i-propylamino, n-butylmethylamino, i-butylmethylamino, t-butylmethylamino, ethyl-n- propylamino, ethyl-i-propylamino, n-butylethylamino, i-butylethylamino, t-butylethylamino, di-n- butylamino, di-i-buty
  • halogen means any atom selected from the group consisting of fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).
  • heteroalkyl which optionally includes one or more heteroatoms, said heteroatoms being selected from the atoms consisting of O, S, and N
  • heteroalkyl refers to a group where one or more carbon atoms are replaced by an oxygen, nitrogen or sulphur atom and thus includes, depending on the group to which is referred, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloheteroalkyl, cycloheteroalkenyl, cycloheteroalkynyl, heteroaryl, arylheteroalkyl, heteroarylalkyl, heteroarylheteroalkyl, arylheteroalkenyl, heteroarylalkenyl, heteroarylheteroalkenyl, heteroarylheteroalkenyl, arylheteroalkenyl, arylheteroalkenyl, arylheteroalken
  • This term therefore comprises, depending on the group to which is referred, as an example alkoxy, alkenyloxy, alkynyloxy, alkyl-O-alkylene, alkenyl-O-alkylene, arylalkoxy, benzyloxy, heteroarylheteroalkyl, heterocyclylheteroalkyl, heteroaryl-alkoxy, heterocyclyl-alkoxy, among others.
  • alkyl which optionally includes one or more heteroatoms, said heteroatoms being selected from the atoms consisting of O, S, and N therefore refers to heteroalkyl, meaning an alkyl which comprises one or more heteroatoms in the hydrocarbon chain, whereas the heteroatoms may be positioned at the beginning of the hydrocarbon chain, in the hydrocarbon chain or at the end of the hydrocarbon chain.
  • heteroalkyl examples include methoxy, methylthio, ethoxy, propoxy, CH 3 -O-CH 2 -, CH 3 -S-CH 2 -, CH 3 -CH 2 -O-CH 2 -, CH 3 -NH-, (CH 3 ) 2 -N-, (CH 3 ) 2 -CH 2 -NH-CH 2 -CH 2 -, among many other examples.
  • arylalkylene which optionally includes one or more heteroatoms in the alkylene chain, said heteroatoms being selected from the atoms consisting of O, S, and N” therefore refers to arylheteroalkylene, meaning an arylalkylene which comprises one or more heteroatoms in the hydrocarbon chain, whereas the heteroatoms may be positioned at the beginning of the hydrocarbon chain, in the hydrocarbon chain or at the end of the hydrocarbon chain.
  • Arylheteroalkylene thus includes aryloxy, arylalkoxy, aryl-alkyl-NH- and the like and examples are phenyloxy, benzyloxy, aryl-CH2-S-CH2-, aryl-CH2-O-CH2-, aryl-NH-CH2- among many other examples.
  • single bond refers to a molecule wherein the linking group is not present and therefore refers to compounds with a direct linkage via a single bond between the two moieties being linked by the linking group.
  • substituted such as in “substituted alkyl”, “substituted alkenyl”, substituted alkynyl”, “substituted aryl”, “substituted heteroaryl”, “substituted heterocyclyl”, “substituted arylalkyl”, “substituted heteroaryl-alkyl”, “substituted heterocyclylalkyl” and the like refer to the chemical structures defined herein, and wherein the said alkyl, alkenyl, alkynyl, group and/or the said aryl, heteroaryl, or heterocyclyl may be optionally substituted with one or more substituents (preferable 1, 2, 3, 4, 5 or 6), meaning that one or more hydrogen atoms are each independently replaced with at least one substituent.
  • substituents preferable 1, 2, 3, 4, 5 or 6
  • Typical substituents include, but are not limited to and in a particular embodiment said substituents are being independently selected from the group consisting of halogen, amino, hydroxyl, sulfhydryl, alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, alkynyloxy, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heteroarylalkyl, heterocyclylalkyl, heteroarylalkenyl, heterocyclylalkenyl and heteroarylalkynyl, heterocyclylalkynyl, -X, -Z,
  • Alkyl(ene), alkenyl(ene), and alkynyl(ene) groups may also be similarly substituted. Any substituent designation that is found in more than one site in a compound of this invention shall be independently selected. Substituents optionally are designated with or without bonds. Regardless of bond indications, if a substituent is polyvalent (based on its position in the structure referred to), then any and all possible orientations of the substituent are intended. As used herein and unless otherwise stated, the term “solvate” includes any combination which may be formed by a derivative of this invention with a suitable inorganic solvent (e.g.
  • heteroatom(s) means an atom selected from nitrogen, which can be quaternized; oxygen; and sulfur, including sulfoxide and sulfone.
  • hydroxy as used herein means -OH.
  • carbonyl as used herein means carbon atom bonded to oxygen with a double bond, i.e., C ⁇ O.
  • amino as used herein means the -NH2 group.
  • these compounds constitute a useful class of new potent compounds that can be used in the treatment and/or prevention of PTPN2 and/or PTPN1 mediated diseases in subjects, more specifically for the treatment and/or prevention of cancer and metabolic diseases, among other diseases.
  • the present invention furthermore relates to the compounds for use as medicines and to their use for the manufacture of medicaments for treating and/or preventing cancer or metabolic diseases.
  • the present invention relates to the compounds for use as medicines for treating and/or preventing PTPN2 and/or PTPN1 mediated diseases such as cancer or metabolic diseases in animals, mammals, more in particular in humans.
  • the invention also relates to methods for the preparation of all such compounds and to pharmaceutical compositions comprising them in an effective amount.
  • the present invention also relates to a method of treatment or prevention of cancer or metabolic diseases in humans by the administration of one or more such compounds, optionally in combination with one or more other medicines, to a patient in need thereof.
  • the present invention also relates to the compounds for veterinary use and to their use as medicines for the prevention or treatment of diseases in a non-human mammal, such as cancer and metabolic diseases in non-human mammals.
  • the compounds of the invention are compounds of formula (I) and any subgroup thereof as described herein, a stereo-isomeric form, a tautomer, a salt (in particular a pharmaceutically acceptable salt), solvate, polymorph and/or prodrug thereof, wherein: - represents a double bond ) or a triple bond ( ); - R is 1 selected from alkyl; heteroalkyl; heteroalkenyl; heteroalkynyl; cycloalkyl; cycloalkenyl; cycloalkynyl; cycloalkylalkyl; cycloalkenylalkyl; cycloalkynylalkyl; cycloalkylheteroalkyl; cycloalkenylheteroalkyl; cycloalkynylheteroalkyl; aryl; heteroaryl; heterocycle; arylalkyl; heteroarylalkyl; heterocyclylalkyl; heterocyclylalkyl;
  • R 1 can be unsubstituted or substituted with one or more R 4 and that in formula (I) and other relevant formulas and embodiments herein when is a double bond, R 2 is selected from hydrogen; alkyl and halogen, or R 2 can be taken together with R 1 to form a 3- , 4-, 5-, 6-, or 7-membered cycloalkyl; a 3-, 4-, 5-, 6-, or 7-membered cycloalkenyl; a 3-, 4-, 5-, 6- , or 7-membered cycloalkynyl; or a 4-, 5-, 6-, or 7-membered heterocycle; wherein said 3-, 4-, 5-, 6-, or 7-membered cycloalkyl, 3-, 4-, 5-, 6-, or 7-membered cycloalkenyl, 3-, 4-, 5-, 6-, or 7-membered cycloalkyny
  • - cycle A is selected from cycloalkyl; cycloalkenyl; cycloalkynyl; aryl; heteroaryl; and heterocycle; preferably cycle A is selected from C3-9cycloalkyl; C5-10cycloalkenyl; C7-10cycloalkynyl; C6-10aryl; heteroaryl; and heterocycle; and - n is selected from 0; 1; 2; 3; 4; and 5.
  • n is selected from 1; 2; 3 and 4.
  • said compound has a structure of formula (Ib) wherein: - R 1 is selected from alkyl; alkenyl; alkynyl; heteroalkyl; heteroalkenyl; heteroalkynyl; cycloalkyl; cycloalkenyl; cycloalkynyl; cycloalkylalkyl; cycloalkenylalkyl; cycloalkynylalkyl; cycloalkylheteroalkyl; cycloalkenylheteroalkyl; cycloalkynylheteroalkyl; aryl; heteroaryl; heterocycle; arylalkyl; heteroarylalkyl; heterocyclylalkyl; arylheteroalkyl; heteroarylheteroalkyl; and heterocyclylheteroalkyl; preferably R 1 is selected from C1-9alkyl; C2-9
  • said compound has a structure of formula (IIa): cycle A is selected from cycloalkyl; cycloalkenyl; cycloalkynyl; aryl; heteroaryl; and heterocycle; and R 3 , n, each R 4 , have the same meaning as that defined in any one of statements A1-A3, A5-A7; preferably cycle A is selected from C3-9cycloalkyl; C5-10cycloalkenyl; C7-10cycloalkynyl; C6-10aryl; heteroaryl; and heterocycle; and R 3 , n, each R 4 , have the same meaning as that defined in any one of statements A1-A3, A5-A7.
  • R 1 or cycle A is selected from the group comprising wherein each cycle A1 and cycle A2 is independently selected from 5-, 6-, or 7--membered heterocycle; 5-, 6-, or 7-membered cycloalkyl; and n, each R 4 , have the same meaning as that defined in any one of statements A1-A8. A10. In some embodiments of the compound according to any one of statements A1-A9, R 1 or cycle A is selected from the group comprising
  • R 1 or cycle A is selected from the group comprising .
  • A12 In some embodiments of the compound according to any one of statements A1-A9, R 1 or cycle A is selected from the group comprising . A13.
  • R 3 is hydrogen.
  • R 3 In some embodiments of the compound according to any one of statements A1 to A12, R 3 is alkyl, preferably R 3 is C1-6alkyl, A15.
  • said compound is selected from the group comprising Cpd001, Cpd002, Cpd003, Cpd004, Cpd005, Cpd006, Cpd007, Cpd008, Cpd009, Cpd010, Cpd011, Cpd012, Cpd013, Cpd014, Cpd015, Cpd016, Cpd017, Cpd018, Cpd019, Cpd020, Cpd021, Cpd022, Cpd023, Cpd024, Cpd025, Cpd026, Cpd027, Cpd028, Cpd029, Cpd030, Cpd031, Cpd032, Cpd033, Cpd034, Cpd035, Cpd036, Cpd040, Cpd041, Cpd042, Cpd043, Cpd044, Cpd045, Cpd001, Cpd002, Cpd003, Cpd004, Cpd00
  • a method for the preparation of compounds according to any one of statements A1-A20 comprising the steps of: - coupling a halogen-containing compound of formula (A1) with an alkyne derivative and further removing PG (if different than H) thereby obtaining a compound of formula (A2), wherein R 1 and R 3 have the same meaning as defined in any one of statements A1-A20, PG is a protecting group or a hydrogen and X is a halogen; or - a a ; in a next step, performing concomitant in situ silyl deprotection with a fluoride source and coupling with a R 1 -X halogen derivative, and further removing PG, if different than H, thereby obtaining a compound of formula (A2), wherein R 1 and R 3 have the same meaning as defined in any one of statements A1-A20, PG is a protecting group or a hydrogen and X is a halogen; or - a an and further removing
  • cycle B is selected from 4-, 5-, 6-, 7-, 8-, 9-, 10-, or 11-membered heterocycle; 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, or 11-membered cycloalkyl; 4-, 5-, 6-, 7-, 8-, 9-, 10-, or 11-membered cycloalkenyl; and 7-, 8-, 9-, 10-, or 11-membered cycloalkynyl.
  • cycle B is selected from 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered heterocycle; 3-, 4-, 5-, 6-, or 7-, 8-, 9-, or 10-membered cycloalkyl; 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered cycloalkenyl; and 7-, 8-, 9-, or 10-membered cycloalkynyl.
  • cycle B is selected from the group comprising 4-, 5-, 6-, or 7-membered heterocycle; 3-, 4-, 5-, 6-, or 7- membered cycloalkyl; 5-, 6-, or 7-membered cycloalkenyl; and 7-membered cycloalkynyl.
  • R 3 is alkyl, for example R 3 is C1-6alkyl.
  • each R 4 is independently selected from alkyl; cycloalkyl; halogen; hydroxyl; sulfhydryl; -CF3; -OCF3; -CHF2; -OCHF2; cyano; -OZ 1 ; -C(O)Z 2 ; -C(O)OZ 1 ; -C(O)NZ 3 Z 4 ; -NZ 3 Z 4 ; -NZ 3 S(O)2Z 1 ; - NZ 3 S(O)2NZ 3 Z 4 ; -NZ 3 C(O)OZ 1 ; -NZ 3 C(O)Z 1 ; -NZ 3 C(O)Z 1 ; -NZ 3 C(O)NZ 3 Z 4 ; and aryl; preferably each R 4 is independently selected from C1-9alkyl; C3-9cycloalkyl; halogen; hydroxyl; -CF3; -OCF3; -CHF2;
  • cycle B is selected from 4-, 5-, or 6-, or 7-membered heterocycle, preferably cycle B is selected from the group comprising pyrrolidinyl; azetidinyl; oxetanyl; tetrahydrofuranyl; piperidinyl; tetrahydro-2H-pyranyl; and azepanyl; preferably cycle B is selected from the group comprising pyrrolidinyl; azetidinyl; and piperidinyl.
  • B15 is selected from the group comprising pyrrolidinyl; azetidinyl; and piperidinyl.
  • cycle B is selected 3-, 4-, 5-, 6-, or 7-membered cycloalkyl, preferably cycle B is selected from the group comprising cyclobutyl; cyclopentyl; cyclohexyl; and cycloheptyl.
  • said compound is a compound of formula (IIIa), (IIIb) or (IIIc) m same as any one B1- B14. B17.
  • said compound is selected from the group comprising Cpd037, Cpd038, Cpd039, Cpd046, Cpd047, Cpd048, Cpd095, Cpd096, Cpd114, Cpd115, Cpd130, Cpd131, Cpd132, Cpd133, Cpd139, Cpd143, Cpd144, Cpd145, Cpd146, Cpd147, Cpd156, Cpd156-en1, Cpd156-en2, Cpd157, Cpd158, Cpd158-en1, Cpd158-en2, Cpd159, Cpd160, Cpd162, Cpd163, Cpd164, Cpd165, Cpd167 and Cpd168.
  • the present invention also encompasses a pharmaceutical composition comprising a pharmaceutically acceptable carrier, and as active ingredient, an effective amount of a compound according to any one of statements A1 to A20, B1 to B17. B19.
  • the present invention also encompasses a compound according to any one of statements A1 to A20, B1 to B17, or a pharmaceutical composition according to statement B18, for use as a medicine.
  • the present invention also encompasses a compound according to any one of statements A1 to A20, B1 to B17, or a pharmaceutical composition according to statement B18, for use in the prevention or treatment of a PTPN2 and/or PTPN1 mediated disorder in an animal, mammal or human. B21.
  • the PTPN2 and/or PTPN1 mediated disorders is selected from the group comprising cancer and metabolic diseases.
  • the PTPN2 and/or PTPN1 mediated disorders is selected from lung cancer, breast cancer, head and neck cancer, oesophageal cancer, kidney cancer, bladder cancer, colon cancer, ovarian cancer, cervical cancer, endometrial cancer, liver cancer, skin cancer, pancreatic cancer, gastric cancer, brain cancer and prostate cancer.
  • the present invention also encompasses a method for the prevention or treatment of a PTPN2 and/or PTPN1 activation mediated disorders in an animal, mammal or human comprising administering to said animal, mammal or human in need for such prevention or treatment an effective dose of at least one compound according to any one of statements A1 to A20, B1 to B17. B24.
  • a method for the prevention or treatment of a PTPN2 and/or PTPN1 activation mediated disorders in an animal, mammal or human comprising administering to said animal, mammal or human in need for such prevention or treatment an effective dose of at least one compound according to any one of statements A1 to A20, B1 to B17, in combination with one or more other anti- cancer agents, more specifically immunotherapeutic agents.
  • R 2 when is a double bond, R 2 is selected from hydrogen; alkyl and halogen, or R 2 can be taken together with R 1 to form a 3-, 4-, 5-, 6-, or 7-membered cycloalkyl; a 3-, 4-, 5-, 6-, or 7-membered cycloalkenyl; a 3-, 4-, 5-, 6-, or 7-membered cycloalkynyl; or a 4-, 5-, 6-, or 7-membered heterocycle; wherein said 3-, 4-, 5-, 6-, or 7-membered cycloalkyl, 3-, 4-, 5-, 6-, or 7-membered cycloalkenyl, 3-, 4-, 5-, 6-, or 7-membered cycloalkynyl, or a 4-, 5-, 6-, or 7-membered heterocycle is unsubstituted or substituted with one or more R 4 .
  • R 2 when is a double bond, R 2 is selected from hydrogen; alkyl and halogen, or R 2 can be taken together with R 1 to form a 3-, 4-, 5-, 6-, or 7-membered cycloalkyl; or a 4-, 5-, 6-, or 7-membered heterocycle; wherein said 3-, 4-, 5-, 6-, or 7-membered cycloalkyl, or 4-, 5-, 6-, or 7-membered heterocycle is unsubstituted or substituted with one or more R 4 .
  • the compounds have a structure according to formula I described herein, more in particular according to the formulas, statements, embodiments and aspects described herein, yet more in particular according to any one of statements A1, A2, 1, and 2 herein, whereby represents a double bond ( ).
  • the compounds have a structure according to formula I described herein, more in particular according to the formulas, statements, embodiments and aspects described herein, yet more in particular according to any one of statements A1, A2, 1, and 2 herein, whereby represents a triple bond ( ).
  • R 2 is selected from hydrogen; alkyl and halogen, or R 2 can be taken together with R 1 to form a 3-, 4-, 5-, 6-, or 7-membered cycloalkyl; a 3-, 4-, 5-, 6-, or 7-membered cycloalkenyl; a 3-, 4-, 5-, 6-, or 7-membered cycloalkynyl; or a 4-, 5- , 6-, or 7-membered heterocycle; wherein said 3-, 4-, 5-, 6-, or 7-membered cycloalkyl, 3-, 4-, 5-, 6-, or 7-membered cycloalkenyl, 3-, 4-, 5-, 6-, or 7-membered cycloalkynyl, or 4-, 5-, 6-, or 7-membered heterocycle is unsubstituted or substituted with one or more R 4 .
  • the compounds have a structure according to formula (I), (Ia), (Ib), (II), (IIa), (III), (IIIa), (IIIb) and (IIIc), described herein, more in particular according to the other formulas, statements, embodiments and aspects described herein, yet more in particular according to statements A1-A20, B1-B17, 1, 2, 3, 4, 5, 6, and 7 herein, whereby: - each alkyl is C1-C18 membered alkyl, more in particular is a C1-C12 membered alkyl; yet more in particular is a C1-C9 membered alkyl; still more in particular is a C1-C6 membered alkyl; including when such alkyl is linked for example to aryl, heteroaryl or heterocycle as for example in arylalkyl, heteroarylalkyl and heterocycle-alkyl; - each alkenyl is C2-C18 membered alkenyl, more in
  • the compounds have a structure according to formula (I), (Ia), (Ib), (II), (IIa), (III), (IIIa), (IIIb) and (IIIc), described herein, more in particular according to the other formulas, statements, embodiments and aspects described herein, yet more in particular according to statements A1-A20, B1-B17, 1, 2, 3, 4, 5, 6 and 7 herein, whereby: - each cycloalkyl is C 3 -C 18 membered cycloalkyl, more in particular is a C 3 -C 12 membered cycloalkyl; yet more in particular is a C 3 -C 9 membered cycloalkyl; still more in particular is a C 3 - C6 membered cycloalkyl; - each cycloalkenyl is C5-C18 membered cycloalkenyl, more in particular is a C5-C12 membered cycloalkenyl; yet
  • the compounds have a structure according to formula (I), (Ia) and (Ib) described herein, more in particular according to the formulas, statements, embodiments and aspects described herein, yet more in particular according to statements A1, A6, A7, 1, 2, 3 and 4 herein, whereby - R 1 is selected from alkyl; alkenyl; alkynyl; heteroalkyl; heteroalkenyl; heteroalkynyl; cycloalkyl; cycloalkenyl; cycloalkynyl; aryl; heteroaryl; and heterocycle; whereby each of said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and heterocycle is unsubstituted or is substituted with one or more R 4 ; or - R 1 is selected from alkyl
  • the compounds have a structure according to formula (I), (Ia) and (Ib) described herein, more in particular according to the formulas, statements, embodiments and aspects described herein, yet more in particular according to statements A1, A6, A7, 1, 2, 3 and 4 herein, whereby: - R 1 is selected from C1-C6 alkyl; yet more specifically whereby R 1 is selected from methyl, ethyl, propyl; butyl; pentyl and hexyl; or - R 1 is selected from C1-C6 heteroalkyl; or - R 1 is selected from C3-C6 cycloalkyl; yet more specifically whereby R 1 is selected from cyclopropyl; cyclobutyl; cyclopentyl and cyclohexyl; or - R1 is selected from C1-C6 alkyl; and C3-C6 cycloalkyl; yet more specifically whereby R 1 is selected from methyl,
  • the compounds have a structure according to formula (I), (Ia) and (Ib) described herein, more in particular according to the formulas, statements, embodiments and aspects described herein, yet more in particular according to statements A1, A6, A7, 1, 2, 3 and 4 herein, whereby - R 1 is selected from C 1 -C 6 alkyl; yet more specifically whereby R 1 is selected from methyl, ethyl, propyl; butyl; pentyl and hexyl; and is unsubstituted or substituted with one or more R 4 ; or - R 1 is selected from C 1 -C 6 heteroalkyl and is unsubstituted or is substituted with one or more R 4 ; or - R 1 is selected from C 3 -C 4 cycloalkyl; yet more specifically whereby R 1 is selected from cyclopropyl and cyclobutyl; or R 1 is selected from C cycloalkyl; yet more specifically w 1 3
  • the compounds have a structure according to formula (I) and (Ia) described herein, more in particular according to the formulas, statements, embodiments and aspects described herein, yet more in particular according to statements 1, 2 and 3 herein, whereby - R 2 is selected from hydrogen; and alkyl; yet more in particular R 2 is hydrogen; still more in particular R 2 is alkyl; or - R 2 is taken together with R 1 to form a 3-, 4-, 5-, 6-, or 7-membered cycloalkyl; a 3-, 4-, 5-, 6-, or 7-membered cycloalkenyl; or a 4-, 5-, 6-, or 7-membered heterocycle; - yet more in particular R 2 is taken together with R 1 to form a 4-, 5-, 6-, or 7-membered cycloalkyl; or a 4-, 5-, 6-, or 7-membered heterocycle.
  • the compounds have a structure according to formula (I) and (Ia) described herein, more in particular according to the formulas, statements, embodiments and aspects described herein, yet more in particular according to statements 1, 2 and 3 herein, whereby - R 2 is selected from hydrogen; and alkyl; yet more in particular R 2 is hydrogen; still more in particular R 2 is alkyl; or - R 2 is taken together with R 1 to form a 3-, 4-, 5-, 6-, or 7-membered cycloalkyl; a 5-, 6-, or 7- membered cycloalkenyl; or a 4-, 5-, 6-, or 7-membered heterocycle; wherein said 3-, 4-, 5-, 6-, or 7-membered cycloalkyl, 5-, 6-, or 7- membered cycloalkenyl, or 4-, 5-, 6-, or 7-membered heterocycle is unsubstituted or substituted with one or more R 4 ; - yet more in particular R
  • the compounds have a structure according to formula (I) and (Ia) described herein, more in particular according to the formulas, statements, embodiments and aspects described herein, yet more in particular according to statements 1, 2 and 3 herein, whereby: - R 2 is selected from C 1 -C 6 alkyl; yet more specifically whereby R 2 is selected from methyl; ethyl; propyl; butyl; pentyl and hexyl; or - R 2 is taken together with R 1 to form a 4-, 5-, 6-, or 7-membered cycloalkyl; yet more in particular to form cyclobutyl; cyclopentyl; cyclohexyl; or cycloheptyl; or - R 2 is taken together with R 1 to form a 4-, 5-, 6-, or 7-membered heterocycle; yet more in particular to form azetidinyl; oxetanyl; pyrrolidinyl;
  • the compounds have a structure according to formula (I) and (Ia) described herein, more in particular according to the formulas, statements, embodiments and aspects described herein, yet more in particular according to statements 1, 2 and 3 herein, whereby: - R 2 is selected from C1-C6 alkyl; yet more specifically whereby R 2 is selected from methyl; ethyl; propyl; butyl; pentyl and hexyl; or - R 2 is taken together with R 1 to form a 4-, 5-, 6-, or 7-membered cycloalkyl unsubstituted or substituted with one or more R 4 ; yet more in particular to form cyclobutyl; cyclopentyl; cyclohexyl; or cycloheptyl; wherein said cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl is unsubstituted or substituted with one or
  • the compounds have a structure according to formula (I), (Ia) and (Ib) described herein, more in particular according to the formulas, statements, embodiments and aspects described herein, yet more in particular according to any one of statements A1-A20, B1-B17, 1, 2, 3 and 4 herein, whereby - R 3 is hydrogen; or - R 3 is C 1 -C 6 alkyl; yet more specifically R 3 is selected from methyl; ethyl; propyl; butyl; pentyl and hexyl; still more in particular R 3 is selected from methyl, ethyl, and propyl; 5.
  • the compounds have a structure according to formula (IIa) described herein, more in particular according to the statements, embodiments and aspects described herein: Z 3 and each Z 4 are independently according to the formulas, statements, aspects and embodiments described herein, such as for formula (II).
  • the compounds have a structure according to formulas, statements, embodiments and aspects described herein whereby: R 1 is cycle A selected from cycloalkyl; cycloalkenyl; cycloalkynyl; aryl; heteroaryl; and heterocycle; - at least one R 4 substituent is present on cycle A, more in particular such substituent is positioned in the meta-position.
  • the compounds have a structure according to formulas, statements, embodiments and aspects described herein whereby R 1 or cycle A is unsubstituted or substituted with one or more R 4 , and is selected from the following structures:
  • the compounds have a structure according to formulas, statements, embodiments and aspects described herein whereby R 1 or cycle A unsubstituted or substituted with one or more R 4 and is selected from the following structures: .
  • the compounds have a structure according to formulas, statements, embodiments and aspects described herein whereby R 1 or cycle A unsubstituted or substituted with one or more R 4 and is selected from the following structures: . 6.
  • the compounds have a structure according to formula (I), (Ia), (Ib), (II), (IIa), (III), (IIIa), (IIIb) and (IIIc) described herein, more in particular according to the formulas, statements, embodiments and aspects described herein, yet more in particular according to statements A1, A3-A7, 1, 2, 3, 4, 5, 6 and 7 herein, whereby R 1 is substituted with 1, 2, 3, 4, 5 or 6 R 4 ; or more specifically, R 1 is substituted with 1, 2, 3, 4 or 5 R 4 ; or more specifically, R 1 is substituted with 1, 2, 3 or 4 R 4 ; or more specifically, R 1 is substituted with 1, 2, 3 or 4 R 4 ; still more in particular, R 1 is substituted with 1, 2 or 3 R 4 ; yet more in particular, R 1 is substituted with 1 or 2 R 4 ; still more in particular, R 1 is substituted with 1 R 4 ; or in another embodiment, R 1 is unsubstituted.
  • the compounds have a structure according to formula (I), (Ia), (Ib), (II), (IIa), (III), (IIIa), (IIIb) and (IIIc) described herein, more in particular according to the formulas, statements, embodiments and aspects described herein, yet more in particular according to statements 1, 2, 3, 4, 5, 6 and 7 herein, whereby R 1 taken together with R 2 is substituted with 1, 2, 3, 4, 5 or 6 R 4 ; or more specifically, R 1 taken together with R 2 is substituted with 1, 2, 3, 4 or 5 R 4 ; or more specifically, R 1 taken together with R 2 is substituted with 1, 2, 3 or 4 R 4 ; still more in particular, R 1 taken together with R 2 is substituted with 1, 2 or 3 R 4 ; yet more in particular, R 1 taken together with R 2 is substituted with 1 or 2 R 4 ; still more in particular, R 1 taken together with R 2 is substituted with 1 R 4 ; or in another embodiment, R 1 taken together with R 2 is unsubstituted
  • the compounds are according to any one of statements A2, A8- A12, 5, wherein n is selected from 1, 2, 3, 4, 5 and 6. In another embodiment, the compounds are according to any one of statements A2, A8-A12, 5, wherein n is selected from 1, 2, 3, 4 and 5. In another embodiment, the compounds are according to any one of statements A2, A8-A12, 5, wherein n is selected from 1, 2, 3 and 4. In another embodiment, the compounds are according to any one of statements A2, A8-A12, 5, wherein n is selected from 1, 2 and 3. In another embodiment, the compounds are according to any one of statements A2, A8-A12, 5, wherein n is selected from 1 and 2.
  • the compounds are according to any one of statements A2, A8-A12, 5, wherein n is not 0.
  • the compounds are according to any one of statements B1- B17, 6, wherein m is selected from 1, 2, 3, 4, 5 and 6.
  • the compounds are according to any one of statements B1-B17, 6, wherein m is selected from 1, 2, 3, 4 and 5.
  • the compounds are according to any one of statements B1-B17, 6, wherein m is selected from 1, 2, 3 and 4.
  • the compounds are according to any one of statements B1-B17, 6 and 7, wherein m is selected from 1, 2 and 3.
  • the compounds have a structure according to formula (I), (Ia), (Ib), (II), (IIa), (III), (IIIa), (IIIb) and (IIIc) described herein, more in particular according to the formulas, statements, embodiments and aspects described herein, yet more in particular according to any one of statements A1-A20, B1-B17, 1, 2, 3, 4, 5 and 6 and 7 herein, whereby: - each Z 1 is independently selected from alkyl; alkenyl; alkynyl; cycloalkyl; cycloalkenyl; cycloalkynyl; heteroalkyl; heteroalkenyl; and heteroalkynyl; wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl is unsubstituted or is substituted with one or
  • the compounds of the invention are selected from the compounds listed in Table 1 and as described with their chemical name below.
  • Cpd001 5-(3-(cyclopentylethynyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1- dioxide
  • Cpd002 5-(3-(3,3-dimethylbut-1-yn-1-yl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide
  • Cpd003 5-(3-((3-chlorophenyl)ethynyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide
  • Cpd004 5-(2-fluoro-3-((3-fluorophenyl)ethynyl)-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1
  • Cpd142-en1 rel-5-(3-(((1R,6R,7R)-3-azabicyclo[4.1.0]heptan-7-yl)ethynyl)-2-fluoro-6- hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide
  • Cpd142-en2 rel-5-(3-(((1R,6R,7R)-3-azabicyclo[4.1.0]heptan-7-yl)ethynyl)-2-fluoro-6- hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide
  • Cpd143 (S,Z)-5-(2-fluoro-6-hydroxy-3-((4-(hydroxymethyl)pyrrolidin-3-ylidene)methyl)phenyl)- 1,2,5-thiadiazolidin-3-one 1,1-dioxide
  • Cpd144 (S,E)-5-(2-fluoro
  • the compounds have a structure according to the formulas provided herein selected from (I), (Ia), (Ib), (II), (IIa), (III), (IIIa), (IIIb) and (IIIc) or other formulas, aspects, statements or embodiments described herein provided that R 3 is not hydrogen.
  • the compounds have a structure according to the formulas provided herein selected from (I), (Ia), (Ib), (II), (IIa), (III), (IIIa), (IIIb) and (IIIc) or other formulas, aspects, statements or embodiments described herein provided that n is not 0; or n is not 1; or n is not 2; or n is not 1 and 2; or n is not 0 and 2.
  • the compounds have a structure according to the formulas provided herein selected from (I), (Ia), (Ib), (II), (IIa), (III), (IIIa), (IIIb) and (IIIc) or other formulas, aspects, statements or embodiments described herein provided that m is not 0; or m is not 1; or m is not 2; or m is not 1 and 2; or m is not 0 and 2.
  • said compound is not a compound listed below: , , , , ,
  • the present compounds used in the current invention may also exist in their stereochemically isomeric form, defining all possible compounds made up of the same atoms bonded by the same sequence of bonds but having different three-dimensional structures, which are not interchangeable. Unless otherwise mentioned or indicated, the chemical designation of compounds encompasses the mixture of all possible stereochemically isomeric forms, which said compounds might possess. Said mixture may contain all diastereomers and/or enantiomers of the basic molecular structure of said compound.
  • the invention relates to the compounds of the formulae described herein and embodiments, statements and aspects thereof being useful as agents having biological activity or as diagnostic agents. Any of the uses mentioned with respect to the present invention may be restricted to a non-medical use, a non-therapeutic use, a non-diagnostic use, or exclusively an in vitro use, or a use related to cells remote from an animal.
  • Compounds of the present disclosure are small molecule PTPN2 and/or PTPN1 inhibitors.
  • Small molecule PTPN2 and/or PTPN1 inhibitors are useful, e.g., for the treatment of cancer, including with no limitations, lung cancer, breast cancer, head and neck cancer, oesophageal cancer, kidney cancer, bladder cancer, colon cancer, ovarian cancer, cervical cancer, endometrial cancer, liver cancer, skin cancer, pancreatic cancer, gastric cancer, brain cancer and prostate cancer, mesotheliomas, and/or sarcomas.
  • small molecule PTPN2 and/or PTPN1 inhibitors are useful for the treatment of cancers selected from colon cancer, kidney cancer, pancreatic cancer, breast cancer, multiple myeloma or cancers of secretory cells.
  • the compounds of the invention are useful for the treatment of cancers selected from colon cancer, kidney cancer, pancreatic cancer, breast cancer, melanoma, head and neck squamous cell carcinoma and non-small cell lung cancer. Still in more particular embodiments, the compounds of the invention are useful for the treatment of colon cancer, melanoma and lung cancer.
  • solid cancers are characterized by the overexpression of PTPN2 and/or PTPN1. Small molecule PTPN2 and/or PTPN1 inhibitors may also be useful to treat cancers that have developed resistance to prior treatments. This may include, for instance, the treatment of cancers that have developed resistance to chemotherapy, or to targeted therapy or to immunotherapy.
  • Small molecule PTPN2 and/or PTPN1 inhibitors may also be useful to treat a metastasized cancer.
  • the metastasized cancer is selected from metastasized uveal melanoma, esophageal cancer, liver cancer, breast cancer, hepatocellular carcinoma, lung adenocarcinoma, glioma, colon cancer, gastric cancer, medulloblastoma, ovarian cancer, esophageal squamous cell carcinoma, sarcoma, Ewing sarcoma, head and neck cancer, prostate cancer and meningioma.
  • small molecule PTPN2 and/or PTPN1 inhibitors are useful, e.g., for the treatment of metabolic disorders, such as non-alcoholic steatohepatitis (NASH), non- alcoholic fatty liver disease (NAFLD), liver fibrosis, obesity, heart disease, atherosclerosis, arthritis, cystinosis, diabetes (e.g., Type I diabetes, Type II diabetes, or gestational diabetes) and metabolic syndrome.
  • metabolic disorders such as non-alcoholic steatohepatitis (NASH), non- alcoholic fatty liver disease (NAFLD), liver fibrosis, obesity, heart disease, atherosclerosis, arthritis, cystinosis, diabetes (e.g., Type I diabetes, Type II diabetes, or gestational diabetes) and metabolic syndrome.
  • the treatment or prevention of a metabolic disease comprises decreasing or eliminating a symptom of such metabolic disease comprising elevated blood pressure, elevated blood sugar level, weight gain, fatigue, blurred vision, abdominal pain, flatulence, constipation, diarrhea, jaundice, and the
  • Small molecule PTPN2 and/or PTPN1 inhibitors and pharmaceutical compositions comprising them may also be useful when combined, upon simultaneous administration, or subsequent administration, with other agents used for the treatment of diseases such as cancer and metabolic diseases.
  • Co-administration includes administering two active agents simultaneously, approximately simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order. In some embodiments, co-administration can be accomplished by co-formulation, i.e., preparing a single pharmaceutical composition including both active agents. In other embodiments, the active agents can be formulated separately. In another embodiment, the active and/or adjunctive agents may be linked or conjugated to one another. In certain embodiments, the second agent is an anti-cancer agent.
  • the second agent is a chemotherapeutic.
  • the second agent is a (cancer) immunotherapy or (cancer) immunotherapeutic agent.
  • the second agent is an agent for treating a metabolic disease.
  • the second agent is an anti-diabetic agent.
  • the second agent is an anti-obesity agent.
  • Anti-cancer agent refers to a composition (e.g. compound, drug, antagonist, inhibitor, modulator, vaccine, cells) having antineoplastic properties or the ability to inhibit the growth or proliferation of cells or in general an agent having utility in treating or preventing cancer and comprises chemotherapeutic agents, immunotherapeutic agents, radiotherapeutic agents, cancer vaccines and the like.
  • an anticancer agent is an agent approved by the FDA or EMA or similar regulatory agency of a country other than the USA or Europe, for treating cancer.
  • Cancer immunotherapy refers to the use of the immune system to treat cancer. Types of immunotherapy used to treat cancer include compound-base, cell-based, antibody-based, and cytokine therapies.
  • Exemplary immunotherapies or immunotherapeutic agent that may be useful when combined with the compounds of the invention include, but are not limited a compounds (e.g., a ligand, an antibody) that inhibits the immune checkpoint blockade pathway.
  • the immunotherapeutic agent is a compound that inhibits the indoleamine 2,3- dioxygenase (IDO) pathway.
  • the immunotherapeutic agent is a compound that agonizes the STING pathway.
  • Cancer immunotherapy e.g., anti-tumor immunotherapy or anti-tumor immunotherapeutics
  • Cell-based therapies e.g., cancer vaccines
  • Immune cells specific for the tumor will be activated, grown, and returned to a subject suffering from cancer where the immune cells provide an immune response against the cancer.
  • Cell types that can be used in this way are e.g., natural killer cells, lymphokine- activated killer cells, cytotoxic T-cells, dendritic cells, CAR-T therapies (e.g., chimeric antigen receptor T-cells which are T-cells engineered to target specific antigens), TIL therapy (e.g., administration of tumor-infiltrating lymphocytes), TCR gene therapy, protein vaccines, and nucleic acid vaccines.
  • An exemplary cell-based therapy is Provenge.
  • the cell- based therapy is a CAR-T therapy.
  • Interleukin-2 and interferon-alpha are examples of cytokines, proteins that regulate and coordinate the behavior of the immune system.
  • Cancer vaccines with neoantigens might also be combined with the compounds of the invention.
  • Neoantigens are antigens encoded by tumor-specific mutated genes.
  • the invention described herein comprises, in some embodiments, administering in combination with a compound of the invention a cancer immunotherapy.
  • the immunotherapeutic agent is a compound (e.g., an inhibitor or antibody) that inhibits the immune checkpoint blockade pathway.
  • Immune checkpoint proteins under normal physiological conditions, maintain self-tolerance (e.g., prevent autoimmunity) and protect tissues from damage when the immune system is responding to e.g., pathogenic infection.
  • Immune checkpoint proteins can be dysregulated by tumors as an important immune resistance mechanism (Pardoll, Nature Rev. Cancer, 2012, 12, 252-264). Agonists of co- stimulatory receptors or antagonists of inhibitory signals (e.g., immune checkpoint proteins), provide an amplification of antigen-specific T-cell responses. Antibodies that block immune checkpoints do not target tumor cells directly but typically target lymphocyte receptors or their ligands to enhance endogenous antitumor activity. [00241] Exemplary checkpoint blocking antibodies include but are not limited to, anti-CTLA-4, anti-PD-1, anti-LAG3 (e.g., antibodies against lymphocyte activation gene 3), and anti-TIM3 (e.g., antibodies against T-cell membrane protein 3).
  • Exemplary anti-CTLA-4 antibodies include but are not limited to, ipilimumab and tremelimumab.
  • Exemplary anti-PD-1 ligands include but are not limited to, PD-L1 (e.g., B7-H1 and CD274) and PD-L2 (e.g., B7-DC and CD273).
  • Exemplary anti- PD-1 antibodies include but are not limited to, nivolumab (e.g., MDX- 1106, BMS-936558, or ONO-4538)), CT-011, AMP-224, pembrolizumab (trade name Keytruda), and MK-3475.
  • Exemplary PD-L1-specific antibodies include but are not limited to,BMS936559 (e.g., MDX-1105), MEDI4736 and MPDL-3280A.
  • Exemplary checkpoint blocking antibodies also include but are not limited to, IMP321 and MGA271.
  • T-regulatory cells e.g., CD4+, CD25+, or T-reg
  • self and non-self antigens are also involved in policing the distinction between self and non-self (e.g., foreign) antigens, and may represent an important mechanism in suppression of immune response in many cancers.
  • T-reg cells can either emerge from the thymus (e.g., “natural T-reg”) or can differentiate from mature T- cells under circumstances of peripheral tolerance induction (e.g., “induced T-reg”). Strategies that minimize the action of T-reg cells would therefore be expected to facilitate the immune response to tumors.
  • IDO pathway inhibitors The IDO pathway regulates immune response by suppressing T cell function and enabling local tumor immune escape. IDO expression by antigen-presenting cells (APCs) can lead to tryptophan depletion, and resulting antigen-specific T cell energy and regulatory T cell recruitment. Some tumors even express IDO to shield themselves from the immune system.
  • APCs antigen-presenting cells
  • a compound that inhibits IDO or the IDO pathway activates the immune system to attack the cancer (e.g., tumor in a subject).
  • IDO pathway inhibitors include indoximod, epacadostat and EOS200271.
  • STING pathway agonists Stimulator of interferon genes (STING) is an adaptor protein that plays an important role in the activation of type I interferons in response to cytosolic nucleic acid ligands. Evidence indicates involvement of the STING pathway in the induction of antitumor immune response. For example, activation of the STING-dependent pathway in cancer cells can result in tumor infiltration with immune cells and modulation of the anticancer immune response.
  • STING agonists are being developed as a class of cancer therapeutics.
  • Exemplary STING agonists include MK-1454 and ADU-S100.
  • the immunotherapeutic agent is a co-stimulatory inhibitor or antibody, e.g. by depleting or activating anti-4-1BB, anti-OX40, anti-GITR, anti-CD27 and anti- CD40, and variants thereof.
  • immunostimulants e.g., Bacillus Calmette- Guerin (BCG), levamisole, interleukin-2, alpha-interferon, etc.
  • BCG Bacillus Calmette- Guerin
  • levamisole levamisole
  • interleukin-2 alpha-interferon, etc.
  • anti-cancer agents include, but are not limited to MEK inhibitors, EGFR inhibitors, RAS inhibitors, inhibitors of B-RAF, alkylating agents, nitrogen mustards, ethylenimine and methylmelamines, alkyl sulfonates, nitrosoureas, triazenes, anti-metabolites, pyrimidine analogs, purine analogs, plant alkaloids, topoisomerase inhibitors, antitumor antibiotics, platinum- based compounds, anthracenedione, substituted urea, methyl hydrazine derivative, adrenocortical suppressant, epipodophyllotoxins, inhibitors of mitogen-activated protein kinase signaling, mTOR inhibitors, agents that arrest cells in the G2-M phases and/or modulate the formation or stability of microtubules, antiestrogen, antiandrogen, monoclonal antibodies (e.g., anti-CD20, anti-HER2, anti-CD52, anti-
  • Radiotherapeutic refers to a chemical composition or compound having antineoplastic properties or the ability to inhibit the growth or proliferation of cells.
  • the compounds described herein can be co-administered with conventional radiotherapeutic agents including, but not limited to, radionuclides such as 47 Sc, 64 Cu, 67 Cu, 89 Sr, 86 Y, 87 Y, 90 Y, 105 Rh, m Ag, m In, 117m Sn, 149 Pm, 153 Sm, 166 Ho, 177 Lu, 186 Re, 1 88 Re, 211 At, and 212 Bi, optionally conjugated to antibodies directed against tumor antigens.
  • radionuclides such as 47 Sc, 64 Cu, 67 Cu, 89 Sr, 86 Y, 87 Y, 90 Y, 105 Rh, m Ag, m In, 117m Sn, 149 Pm, 153 Sm, 166 Ho, 177 Lu, 186 Re, 1 88 Re, 211 At, and 212 Bi,
  • the compounds of the invention can inhibit PTPN2 and/or PTPN1 activity.
  • the compounds have been shown to inhibit PTPN2 and/or PTPN1 activity in cellular models and in an animal model.
  • the compounds have also been shown to have an inhibitory effect on cancer cell lines and on the growth of cancer in an animal cancer model.
  • the compounds of the invention can optionally be bound covalently to an insoluble matrix and used for affinity chromatography (separations, depending on the nature of the groups of the compounds, for example compounds with pendant aryl are useful in hydrophobic affinity separations).
  • the active ingredients of the compound(s) may be administered to the animal or mammal (including a human) to be treated by any means well known in the art, i.e. orally, intranasally, subcutaneously, intramuscularly, intradermally, intravenously, intra-arterially, parenterally or by catheterization.
  • the therapeutically effective amount of the preparation of the compound(s), especially for the treatment of diseases mediated by activity of PTPN2 and/or PTPN1 in humans and other mammals preferably is a PTPN2 and/or PTPN1 inhibiting amount of the compounds of the formulae, statements, aspects and embodiments as defined herein and corresponds to an amount which ensures a plasma level that is able to inhibit the PTPN2 and/or PTPN1 activity and is in a particular embodiment between 1ng/ml and 100 mg/ml, more in particular between 1ng/ml and 1mg/ml, still more in particular between 1ng/ml and 1 ⁇ g/ml.
  • Suitable dosages of the compounds or compositions of the invention should be used to treat or prevent the targeted diseases in a subject.
  • the said effective amount may be divided into several sub- units per day or may be administered at more than one day intervals.
  • the compounds of the invention may be employed in combination with other therapeutic agents for the treatment or prophylaxis of diseases mediated by activity of PTPN2 and/or PTPN1 in humans and other mammals (such as cancer and metabolic disorders).
  • the invention therefore relates to the use of a composition
  • a composition comprising: (a) one or more compounds of the formulae and aspects, statements and embodiments herein, and (b) one or more further therapeutic or preventive agents that are used for the prevention or treatment of cancer or metabolic diseases as biologically active agents in the form of a combined preparation for simultaneous, separate or sequential use.
  • the compound or composition can be administered concurrently with, prior to, or subsequent to the one or more additional therapeutic agents, which are different from the compound described herein and may be useful as, e.g., combination therapies. Examples of such further therapeutic agents for use in combinations include anti-cancer agents as described herein.
  • the pharmaceutical composition or combined preparation according to this invention may contain the compounds of the present invention over a broad content range depending on the contemplated use and the expected effect of the preparation.
  • the content of the derivatives of the present invention of the combined preparation is within the range of 0.1 to 99.9% by weight, preferably from 1 to 99% by weight, more preferably from 5 to 95% by weight.
  • the compounds of the invention may exist in many different protonation states, depending on, among other things, the pH of their environment. While the structural formulae provided herein depict the compounds in only one of several possible protonation states, it will be understood that these structures are illustrative only, and that the invention is not limited to any particular protonation state - any and all protonated forms of the compounds are intended to fall within the scope of the invention.
  • the term "pharmaceutically acceptable salts" as used herein means the therapeutically active non-toxic salt forms which the compounds of formulae herein are able to form. Therefore, the compounds of this invention optionally comprise salts of the compounds herein, especially pharmaceutically acceptable non-toxic salts containing, for example, Na + , Li + , K + , Ca 2+ and Mg 2+ .
  • Such salts may include those derived by combination of appropriate cations such as alkali and alkaline earth metal ions or ammonium and quaternary amino ions with an acid anion moiety, typically a carboxylic acid.
  • the compounds of the invention may bear multiple positive or negative charges. The net charge of the compounds of the invention may be either positive or negative.
  • any associated counter ions are typically dictated by the synthesis and/or isolation methods by which the compounds are obtained.
  • Typical counter ions include, but are not limited to ammonium, sodium, potassium, lithium, halides, acetate, trifluoroacetate, etc., and mixtures thereof. It will be understood that the identity of any associated counter ion is not a critical feature of the invention, and that the invention encompasses the compounds in association with any type of counter ion.
  • the invention is intended to encompass not only forms of the compounds that are in association with counter ions (e.g., dry salts), but also forms that are not in association with counter ions (e.g., aqueous or organic solutions).
  • Metal salts typically are prepared by reacting the metal hydroxide with a compound of this invention.
  • metal salts which are prepared in this way are salts containing Li + , Na + , and K + .
  • a less soluble metal salt can be precipitated from the solution of a more soluble salt by addition of the suitable metal compound.
  • salts may be formed from acid addition of certain organic and inorganic acids to basic centers, typically amines, or to acidic groups. Examples of such appropriate acids include, for instance, inorganic acids such as hydrohalogen acids, e.g.
  • hydrochloric or hydrobromic acid sulfuric acid, nitric acid, phosphoric acid and the like; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, 2- hydroxypropanoic, 2-oxopropanoic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclohexanesulfamic, salicylic (i.e.
  • compositions herein comprise compounds of the invention in their unionized, as well as zwitterionic form, and combinations with stoichiometric amounts of water as in hydrates. Also included within the scope of this invention are the salts of the parental compounds with one or more amino acids, especially the naturally-occurring amino acids found as protein components.
  • the amino acid typically is one bearing a side chain with a basic or acidic group, e.g., lysine, arginine or glutamic acid, or a neutral group such as glycine, serine, threonine, alanine, isoleucine, or leucine.
  • the compounds of the invention also include physiologically acceptable salts thereof.
  • physiologically acceptable salts of the compounds of the invention include salts derived from an appropriate base, such as an alkali metal (for example, sodium), an alkaline earth (for example, magnesium), ammonium and NX4 + (wherein X is C1-C4 alkyl).
  • Physiologically acceptable salts of an hydrogen atom or an amino group include salts of organic carboxylic acids such as acetic, benzoic, lactic, fumaric, tartaric, maleic, malonic, malic, isethionic, lactobionic and succinic acids; organic sulfonic acids, such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids; and inorganic acids, such as hydrochloric, sulfuric, phosphoric and sulfamic acids.
  • organic carboxylic acids such as acetic, benzoic, lactic, fumaric, tartaric, maleic, malonic, malic, isethionic, lactobionic and succinic acids
  • organic sulfonic acids such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids
  • Physiologically acceptable salts of a compound containing a hydroxy group include the anion of said compound in combination with a suitable cation such as Na + and NX4 + (wherein X typically is independently selected from H or a C1-C4 alkyl group).
  • a suitable cation such as Na + and NX4 + (wherein X typically is independently selected from H or a C1-C4 alkyl group).
  • salts of acids or bases which are not physiologically acceptable may also find use, for example, in the preparation or purification of a physiologically acceptable compound. All salts, whether or not derived form a physiologically acceptable acid or base, are within the scope of the present invention.
  • the term ‘’enantiomer‘’ means each individual optically active form of a compound of the invention, having an optical purity or enantiomeric excess (as determined by methods standard in the art) of at least 80% (e.g. at least 90% of one enantiomer and at most 10% of the other enantiomer), preferably at least 90% and more preferably at least 98%.
  • isomers as used herein means all possible isomeric forms, including tautomeric and stereochemical forms, which the compounds of formulae herein may possess, but not including position isomers. Typically, the structures shown herein exemplify only one tautomeric or resonance form of the compounds, but the corresponding alternative configurations are contemplated as well.
  • the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers (since the compounds of formulae herein may have at least one chiral center) of the basic molecular structure, as well as the stereochemically pure or enriched compounds. More particularly, stereogenic centers may have either the R- or S-configuration, and multiple bonds may have either cis- or trans-configuration. Pure isomeric forms of the said compounds are defined as isomers substantially free of other enantiomeric or diastereomeric forms of the same basic molecular structure.
  • stereoisomerically pure or “chirally pure” relates to compounds having a stereoisomeric excess of at least about 80% (e.g. at least 90% of one isomer and at most 10% of the other possible isomers), preferably at least 90%, more preferably at least 94% and most preferably at least 97%.
  • enantiomerically pure and diastereomerically pure should be understood in a similar way, having regard to the enantiomeric excess, respectively the diastereomeric excess, of the mixture in question. Separation of stereoisomers is accomplished by standard methods known to those in the art.
  • One enantiomer of a compound of the invention can be separated substantially free of its opposing enantiomer by a method such as formation of diastereomers using optically active resolving agents ("Stereochemistry of Carbon Compounds,” (1962) by E. L. Eliel, McGraw Hill; Lochmuller, C. H., (1975) J. Chromatogr., 113:(3) 283-302).
  • Separation of isomers in a mixture can be accomplished by any suitable method, including: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure enantiomers, or (3) enantiomers can be separated directly under chiral conditions.
  • diastereomeric salts can be formed by reaction of enantiomerically pure chiral bases such as brucine, quinine, ephedrine, strychnine, a-methyl- b-phenylethylamine (amphetamine), and the like with asymmetric compounds bearing acidic functionality, such as carboxylic acid and sulfonic acid.
  • the diastereomeric salts may be induced to separate by fractional crystallization or ionic chromatography.
  • addition of chiral carboxylic or sulfonic acids such as camphorsulfonic acid, tartaric acid, mandelic acid, or lactic acid can result in formation of the diastereomeric salts.
  • the substrate to be resolved may be reacted with one enantiomer of a chiral compound to form a diastereomeric pair
  • a diastereomeric pair Eliel, E. and Wilen, S. (1994) Stereochemistry of Organic Compounds, John Wiley & Sons, Inc., p.322).
  • Diastereomeric compounds can be formed by reacting asymmetric compounds with enantiomerically pure chiral derivatizing reagents, such as menthyl derivatives, followed by separation of the diastereomers and hydrolysis to yield the free, enantiomerically enriched compound.
  • a method of determining optical purity involves making chiral esters, such as a menthyl ester or Mosher ester, a-methoxy- a-(trifluoromethyl)phenyl acetate (Jacob III. (1982) J. Org. Chem. 47:4165), of the racemic mixture, and analyzing the NMR spectrum for the presence of the two atropisomeric diastereomers.
  • chiral esters such as a menthyl ester or Mosher ester, a-methoxy- a-(trifluoromethyl)phenyl acetate (Jacob III. (1982) J. Org. Chem. 47:4165)
  • Stable diastereomers can be separated and isolated by normal- and reverse- phase chromatography following methods for separation of atropisomeric naphthyl-isoquinolines (Hoye, T., WO 96/15111).
  • a racemic mixture of two asymmetric enantiomers is separated by chromatography using a chiral stationary phase.
  • Suitable chiral stationary phases are, for example, polysaccharides, in particular cellulose or amylose derivatives.
  • Commercially available polysaccharide based chiral stationary phases are ChiralCeI TM CA, OA, OB5, OC5, OD, OF, OG, OJ and OK, and Chiralpak TM AD, AS, OP(+) and OT(+).
  • eluents or mobile phases for use in combination with said polysaccharide chiral stationary phases are hexane and the like, modified with an alcohol such as ethanol, isopropanol and the like.
  • the terms cis and trans are used herein in accordance with Chemical Abstracts nomenclature and include reference to the position of the substituents on a ring moiety.
  • the absolute stereochemical configuration of the compounds of the formulae described herein may easily be determined by those skilled in the art while using well-known methods such as, for example, X-ray diffraction.
  • the present invention also includes isotopically labelled compounds, which are identical to those recited in the formulas recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes examples include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine and chlorine, such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 CI, respectively.
  • Compounds of the present invention and pharmaceutically acceptable salts of said compounds or which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention.
  • Certain isotopically labeled compounds of the present invention for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays.
  • Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances.
  • lsotopically labelled compounds of the formulas of this invention may generally be prepared by carrying out the procedures disclosed in the examples and preparations described herein, by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent.
  • the PROTAC technology designs a bifunctional small molecule, one end of which is a compound of the general formula (I) or other formulas, embodiments, aspects or parts thereof or metabolites thereof, and the other end of which is connected with a ligand of E3 ubiquitin ligase through a connecting chain, to form a target-induced protein degradation complex. Because this degradation has a catalytic effect, a lower dosage can achieve efficient degradation.
  • the compound of the general formula (I) or other formulas, embodiments, aspects or parts thereof or metabolites thereof can be connected via a linker arm (e.g. long-chain ethylene glycol with the length of 2-10, long-chain propylene glycol with the length of 2-10 and long-chain fatty alkane with the length of 2-10) to a ligand of E3 ubiquitin ligase such as e.g. thalidomide analogs.
  • the compounds of the invention may be formulated with conventional carriers and excipients, which will be selected in accord with ordinary practice. Tablets will contain excipients, glidants, fillers, binders and the like.
  • Aqueous formulations are prepared in sterile form, and when intended for delivery by other than oral administration generally will be isotonic.
  • Formulations optionally contain excipients such as those set forth in the "Handbook of Pharmaceutical Excipients" (1986) and include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid and the like.
  • the term "pharmaceutically acceptable carrier” as used herein means any material or substance with which the active ingredient is formulated in order to facilitate its application or dissemination to the locus to be treated, for instance by dissolving, dispersing or diffusing the said composition, and/or to facilitate its storage, transport or handling without impairing its effectiveness.
  • the pharmaceutically acceptable carrier may be a solid or a liquid or a gas which has been compressed to form a liquid, e.g. the compositions of this invention can suitably be used as concentrates, emulsions, solutions, granulates, dusts, sprays, aerosols, suspensions, ointments, creams, tablets, pellets or powders.
  • Suitable pharmaceutical carriers for use in the said pharmaceutical compositions and their formulation are well known to those skilled in the art, and there is no particular restriction to their selection within the present invention. They may also include additives such as wetting agents, dispersing agents, stickers, adhesives, emulsifying agents, solvents, coatings, antibacterial and antifungal agents (for example phenol, sorbic acid, chlorobutanol), isotonic agents (such as sugars or sodium chloride) and the like, provided the same are consistent with pharmaceutical practice, e.g. carriers and additives which do not create permanent damage to mammals.
  • additives such as wetting agents, dispersing agents, stickers, adhesives, emulsifying agents, solvents, coatings, antibacterial and antifungal agents (for example phenol, sorbic acid, chlorobutanol), isotonic agents (such as sugars or sodium chloride) and the like, provided the same are consistent with pharmaceutical practice, e.g. carriers and additives which do not create permanent damage to mammals.
  • compositions of the present invention may be prepared in any known manner, for instance by homogeneously mixing, coating and/or grinding the active ingredients, in a one-step or multi-steps procedure, with the selected carrier material and, where appropriate, the other additives such as surface-active agents. may also be prepared by micronisation, for instance in view to obtain them in the form of microspheres usually having a diameter of about 1 to 10 gm, namely for the manufacture of microcapsules for controlled or sustained release of the active ingredients.
  • Suitable surface-active agents, also known as emulgent or emulsifier, to be used in the pharmaceutical compositions of the present invention are non-ionic, cationic and/or anionic materials having good emulsifying, dispersing and/or wetting properties.
  • Suitable anionic surfactants include both water-soluble soaps and water-soluble synthetic surface-active agents.
  • Suitable soaps are alkaline or alkaline-earth metal salts, unsubstituted or substituted ammonium salts of higher fatty acids (C10-C22), e.g. the sodium or potassium salts of oleic or stearic acid, or of natural fatty acid mixtures obtainable from coconut oil or tallow oil.
  • Synthetic surfactants include sodium or calcium salts of polyacrylic acids; fatty sulphonates and sulphates; sulphonated benzimidazole derivatives and alkylarylsulphonates.
  • Fatty sulphonates or sulphates are usually in the form of alkaline or alkaline-earth metal salts, unsubstituted ammonium salts or ammonium salts substituted with an alkyl or acyl group having from 8 to 22 carbon atoms, e.g. the sodium or calcium salt of lignosulphonic acid or dodecylsulphonic acid or a mixture of fatty alcohol sulphates obtained from natural fatty acids, alkaline or alkaline-earth metal salts of sulphuric or sulphonic acid esters (such as sodium lauryl sulphate) and sulphonic acids of fatty alcohol/ethylene oxide adducts.
  • alkaline or alkaline-earth metal salts unsubstituted ammonium salts or ammonium salts substituted with an alkyl or acyl group having from 8 to 22 carbon atoms, e.g. the sodium or calcium salt of lignosulphonic acid or dodecylsulph
  • Suitable sulphonated benzimidazole derivatives preferably contain 8 to 22 carbon atoms.
  • alkylarylsulphonates are the sodium, calcium or alcoholamine salts of dodecylbenzene sulphonic acid or dibutyl-naphthalenesulphonic acid or a naphthalene-sulphonic acid/formaldehyde condensation product.
  • corresponding phosphates e.g. salts of phosphoric acid ester and an adduct of p-nonylphenol with ethylene and/or propylene oxide, or phospholipids.
  • Suitable phospholipids for this purpose are the natural (originating from animal or plant cells) or synthetic phospholipids of the cephalin or lecithin type such as e.g. phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerine, lysolecithin, cardiolipin, dioctanylphosphatidyl-choline, dipalmitoylphoshatidyl -choline and their mixtures.
  • cephalin or lecithin type such as e.g. phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerine, lysolecithin, cardiolipin, dioctanylphosphatidyl-choline, dipalmitoylphoshatidyl -choline and their mixtures.
  • Suitable non-ionic surfactants include polyethoxylated and polypropoxylated derivatives of alkylphenols, fatty alcohols, fatty acids, aliphatic amines or amides containing at least 12 carbon atoms in the molecule, alkylarenesulphonates and dialkylsulphosuccinates, such as polyglycol ether derivatives of aliphatic and cycloaliphatic alcohols, saturated and unsaturated fatty acids and alkylphenols, said derivatives preferably containing 3 to 10 glycol ether groups and 8 to 20 carbon atoms in the (aliphatic) hydrocarbon moiety and 6 to 18 carbon atoms in the alkyl moiety of the alkylphenol.
  • non-ionic surfactants are water-soluble adducts of polyethylene oxide with poylypropylene glycol, ethylenediaminopolypropylene glycol containing 1 to 10 carbon atoms in the alkyl chain, which adducts contain 20 to 250 ethyleneglycol ether groups and/or 10 to 100 propyleneglycol ether groups.
  • Such compounds usually contain from 1 to 5 ethyleneglycol units per propyleneglycol unit.
  • non-ionic surfactants are nonylphenol -polyethoxyethanol, castor oil polyglycolic ethers, polypropylene/polyethylene oxide adducts, tributylphenoxypolyethoxyethanol, polyethyleneglycol and octylphenoxypolyethoxyethanol.
  • Fatty acid esters of polyethylene sorbitan such as polyoxyethylene sorbitan trioleate
  • glycerol glycerol
  • sorbitan sucrose and pentaerythritol are also suitable non-ionic surfactants.
  • Suitable cationic surfactants include quaternary ammonium salts, particularly halides, having 4 hydrocarbon groups optionally substituted with halo, phenyl, substituted phenyl or hydroxy; for instance quaternary ammonium salts containing as N-substituent at least one C8- 22alkyl (e.g. cetyl, lauryl, palmityl, myristyl, oleyl and the like) and, as further substituents, unsubstituted or halogenated lower alkyl, benzyl and/or hydroxy-lower alkyl.
  • quaternary ammonium salts particularly halides, having 4 hydrocarbon groups optionally substituted with halo, phenyl, substituted phenyl or hydroxy
  • quaternary ammonium salts containing as N-substituent at least one C8- 22alkyl (e.g. cetyl, lauryl, palmityl, myristyl,
  • compositions of the invention and their pharmaceutically acceptable salts may be administered by any route appropriate to the condition to be treated, suitable routes including oral, rectal, nasal, topical (including ocular, buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural).
  • suitable routes including oral, rectal, nasal, topical (including ocular, buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural).
  • the preferred route of administration may vary with for example the condition of the recipient.
  • the active ingredients While it is possible for the active ingredients to be administered alone it is preferable to present them as pharmaceutical formulations.
  • the formulations, both for veterinary and for human use, of the present invention comprise at least one active ingredient, as above described, together with one or more pharmaceutically acceptable carriers therefore and optionally other therapeutic ingredients.
  • the carrier(s) optimally are "acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the formulations include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural) administration.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein. For infections of the eye or other external tissues e.g.
  • the formulations are optionally applied as a topical ointment or cream containing the active ingredient(s) in an amount of, for example, 0.075 to 20% w/w (including active ingredient(s) in a range between 0.1% and 20% in increments of 0.1% w/w such as 0.6% w/w, 0.7% w/w, etc.), preferably 0.2 to 15% w/w and most preferably 0.5 to 10% w/w.
  • the active ingredients may be employed with either a paraffinic or a water-miscible ointment base.
  • the active ingredients may be formulated in a cream with an oil-in-water cream base.
  • the aqueous phase of the cream base may include, for example, at least 30% w/w of a polyhydric alcohol, e.g. an alcohol having two or more hydroxyl groups such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG400) and mixtures thereof.
  • the topical formulations may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogs.
  • the oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner.
  • the phase may comprise merely an emulsifier (otherwise known as an emulgent), it desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil.
  • a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat.
  • the emulsifier(s) with or without stabilizer(s) make up the so-called emulsifying wax, and the wax together with the oil and fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations.
  • oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the active compound in most oils likely to be used in pharmaceutical emulsion formulations is very low.
  • the cream should optionally be a non- greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers.
  • Straight or branched chain, mono- or dibasic alkyl esters such as di- isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.
  • Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient.
  • the active ingredient is optionally present in such formulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10% particularly about 1.5% w/w.
  • Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.
  • Formulations suitable for nasal administration wherein the carrier is a solid include a coarse powder having a particle size for example in the range 20 to 500 microns (including particle sizes in a range between 20 and 500 microns in increments of 5 microns such as 30 microns, 35 microns, etc.), which is administered in the manner in which snuff is taken, e.g. by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
  • Suitable formulations wherein the carrier is a liquid, for administration as for example a nasal spray or as nasal drops include aqueous or oily solutions of the active ingredient.
  • Formulations suitable for aerosol administration may be prepared according to conventional methods and may be delivered with other therapeutic agents.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • sterile liquid carrier for example water for injections
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • Preferred unit dosage formulations are those containing a daily dose or unit daily sub- dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient.
  • the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
  • Controlled release formulations adapted for oral administration in which discrete units comprising one or more compounds of the invention can be prepared according to conventional methods. Additional ingredients may be included in order to control the duration of action of the active ingredient in the composition.
  • Control release compositions may thus be achieved by selecting appropriate polymer carriers such as for example polyesters, polyamino acids, polyvinyl pyrrolidone, ethylene-vinyl acetate copolymers, methylcellulose, carboxymethylcellulose, protamine sulfate and the like.
  • the rate of drug release and duration of action may also be controlled by incorporating the active ingredient into particles, e.g. microcapsules, of a polymeric substance such as hydrogels, polylactic acid, hydroxymethylcellulose, polymethyl methacrylate and the other above-described polymers.
  • Such methods include colloid drug delivery systems like liposomes, microspheres, microemulsions, nanoparticles, nanocapsules and so on.
  • the pharmaceutical composition may require protective coatings.
  • Pharmaceutical forms suitable for injectionable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation thereof.
  • Typical carriers for this purpose therefore include biocompatible aqueous buffers, ethanol, glycerol, propylene glycol, polyethylene glycol and the like and mixtures thereof.
  • the corresponding composition may also be in the form of a medical kit or package containing the two ingredients in separate but adjacent repositories or compartments.
  • each active ingredient may therefore be formulated in a way suitable for an administration route different from that of the other ingredient, e.g. one of them may be in the form of an oral or parenteral formulation whereas the other is in the form of an ampoule for intravenous injection or an aerosol.
  • Another embodiment of this invention relates to various precursor or “pro-drug” forms of the compounds of the present invention.
  • the compounds of the present invention may be desirable to formulate the compounds of the present invention in the form of a chemical species which itself is not significantly biologically- active, but which when delivered to the animal, mammal or human will undergo a chemical reaction catalyzed by the normal function of the body of the fish, inter alia, enzymes present in the stomach or in blood serum, said chemical reaction having the effect of releasing a compound as defined herein.
  • the term “pro-drug” thus relates to these species which are converted in vivo into the active pharmaceutical ingredient.
  • the pro-drugs of the compounds of the present invention can have any form suitable to the formulator, for example, esters are non-limiting common pro-drug forms.
  • the pro-drug may necessarily exist in a form wherein a covalent bond is cleaved by the action of an enzyme present at the target locus.
  • a C-C covalent bond may be selectively cleaved by one or more enzymes at said target locus and, therefore, a pro-drug in a form other than an easily hydrolysable precursor, inter alia an ester, an amide, and the like, may be used.
  • the counterpart of the active pharmaceutical ingredient in the pro-drug can have different structures such as an amino acid or peptide structure, alkyl chains, sugar moieties and others as known in the art.
  • the term “therapeutically suitable pro-drug” is defined herein as “a compound modified in such a way as to be transformed in vivo to the therapeutically active form, whether by way of a single or by multiple biological transformations, when in contact with the tissues of the animal, mammal or human to which the pro-drug has been administered, and without undue toxicity, irritation, or allergic response, and achieving the intended therapeutic outcome ”. More specifically the term “prodrug”, as used herein, relates to an inactive or significantly less active derivative of a compound such as represented by the structural formulae herein described, which undergoes spontaneous or enzymatic transformation within the body in order to release the pharmacologically active form of the compound.
  • the present invention relates to methods for the preparation of the compounds, comprising the steps of: - coupling a halogen-containing compound of formula (A1) with an alkyne derivative and further removing PG (if different than H) thereby obtaining a compound of formula (A2), wherein R 1 and R 3 have the meaning according to any one of the formula or embodiments presented herein, PG is a protecting group or a hydrogen and X is a halogen; or - a a ; in a next step, performing concomitant in situ silyl deprotection with a fluoride source and coupling with a R1-X halogen derivative, and further removing PG (if different than H) thereby obtaining a compound of formula (A2), wherein R1 and R3 have the meaning according to any one of the formula or embodiments presented herein, PG is a protecting group or a hydrogen and X is a halogen; or - a a and further removing PG (if different than H)
  • the alkenyl boronic derivative can be replaced by a terminal alkene, an alkenyl zinc reagent or an alkenyl stannane reagent .
  • the compounds of the present invention may be prepared according to the general procedures outlined in below Schemes.
  • Scheme A all R3 (different than H) are as described for the compounds of the present invention and its embodiments and formulae.
  • X1, X2 are halogen (Br, I, Cl).
  • PG is protecting group.
  • LG is leaving group.
  • Y is an ester protecting group (like methyl, ethyl, t-Bu and the like).
  • 2,6-difluoronitrobenzene 1 may be reacted with a primary alcohol of general formula PG1OH (like benzylalcohol, MeOH, 4-methoxybenzylalcohol and the like) in the presence of a base (like NaH, K2CO3, Cs2CO3, DBU and the like) in a suitable solvent (e.g., DCM, THF, toluene and the like) at a temperature ranging from -78°C to 100°C to provide intermediates of formula 2.
  • a suitable solvent e.g., DCM, THF, toluene and the like
  • Intermediates of formula 2 may be halogenated with a suitable halogenating agent (e.g.
  • Anilines of formula 4 may be reacted with ester derivatives having a leaving group LG (like Br, Cl, OMs and the like) and where Y is an ester protecting group (like methyl, ethyl, t-Bu and the like) in the presence of a base (e.g. DIPEA, K2CO3, Cs2CO3, DBU and the like) in a polar aprotic solvent (e.g., CH3CN, THF, DCM and the like) at a temperature ranging from 0°C to 100°C to provide intermediates of formula 5.
  • Anilines of formula 5 may be halogenated with a suitable halogenating agent (e.g.
  • Anilines of formula 7 may react with chlorosulfonyl isocyanate in the presence of a suitable alcohol derivative (tBuOH, benzylalcohol and the like) to provide sulfonylureas of formula 8.
  • a suitable alcohol derivative tBuOH, benzylalcohol and the like
  • Y is an ester protecting group (like methyl, ethyl, t-Bu and the like).
  • 2,6-difluoronitrobenzene 1 may be reacted with a primary alcohol of general formula PG1OH (like benzylalcohol, MeOH, 4-methoxybenzylalcohol and the like) in the presence of a base (like NaH, K 2 CO 3 , Cs 2 CO 3 , DBU and the like) in a suitable solvent (e.g., DCM, THF, toluene and the like) at a temperature ranging from -78°C to 100°C to provide intermediates of formula 2.
  • Intermediates of formula 2 may be halogenated with a suitable halogenating agent (e.g.
  • Anilines of formula 4 may be reacted with ester derivatives having a leaving group LG (like Br, Cl, OMs and the like) and where Y is an ester protecting group (like methyl, ethyl, t-Bu and the like) in the presence of a base (e.g. DIPEA, K2CO3, Cs2CO3, DBU and the like) in a polar aprotic solvent (e.g., CH3CN, THF, DCM and the like) at a temperature ranging from 0°C to 100°C to provide intermediates of formula 5.
  • a base e.g. DIPEA, K2CO3, Cs2CO3, DBU and the like
  • a polar aprotic solvent e.g., CH3CN, THF, DCM and the like
  • Anilines of formula 5 may react with chlorosulfonyl isocyanate in the presence of a suitable alcohol derivative (tBuOH, benzylalcohol and the like) to provide sulfonylureas of formula 8.
  • a suitable alcohol derivative tBuOH, benzylalcohol and the like
  • Intermediates of formula 9 can themselves undergo an intermolecular cyclisation in the presence of a base (like NaOMe, NaOEt, NaH and the like) in a aprotic or protic polar solvent (e.g. THF, MeOH, EtOH and the like) at a temperature ranging from -78°C to 100°C to provide intermediates of formula 10.
  • a base like NaOMe, NaOEt, NaH and the like
  • a aprotic or protic polar solvent e.g. THF, MeOH, EtOH and the like
  • compounds of the present invention may also be synthesized according to the general procedure outlined in Scheme C.
  • a polar aprotic solvent e.g. CH3CN, DMF, DMSO and the like
  • Alkyne derivatives of formula 12 may themselves undergo functional group manipulation (using a series of chemical reactions well known to those skilled in the art or as set forth in the examples below) to provide alkyne intermediates of formula 11 which are converted in compounds of formula 13 after removal of the O-protecting group following procedures known to the skilled in the art (e.g. treatment with BBr3 or BCl3, hydrogenation with H2 in the presence of Pd/C and the like) as described in Scheme C.
  • compounds of the present invention may also be synthesized according to the general procedure outlined in Scheme D.
  • Scheme D all R1, R3, are as described for the compounds of the present invention and its embodiments, statements and formulae.
  • Phenols derivatives of formula 14 may be obtained by removal of the O-protecting group from intermediates of general 10 following procedures known to the skilled in the art (e.g. treatment with BBr3 or BCl3, hydrogenation with H2 in the presence of Pd/C and the like).
  • Alkynes compounds of formula 13 may be obtained by reaction of an halogenated compound of formula 14 and a suitable terminal alkyne (either commercially available or synthesized by procedures known to the skilled in the art or as set forth in the examples below or also generated in situ from an appropriated terminally silylated alkyne in the presence of a fluoride source in the reaction medium (CsF, TBAF and the like)) in the presence of a Pd catalyst (e.g.
  • a polar aprotic solvent e.g. CH3CN, DMF, DMSO and the like
  • compounds of the present invention may also be synthesized according to the general procedure outlined in Scheme E.
  • Alkenes derivatives of formula 16 may themselves undergo functional group transformation (using a series of chemical reactions well known to those skilled in the art or as set forth in the examples) to deliver alkenes derivatives of formula 15.
  • Compounds of interest having a formula 17 may be obtained after removal of the O-protecting group following procedures known to the skilled in the art (e.g. treatment with BBr3 or BCl3, hydrogenation with H2 in the presence of Pd/C and the like) as described in Scheme E.
  • Table 1 Structures of example compounds of the invention and their respective codes Structure and Structure and Structure and Structure and Compound Code Compound Code Compound Code Compound Code Compound Code C pd001 Cpd002 Cpd003 Cpd004 Cpd005 Cpd006 Cpd007 Cpd008 Cpd009 Cpd010 Cpd011 Cpd012 Cpd013 Cpd014 Cpd015 Cpd016 C pd017 Cpd018 Cpd019 Cpd020 C pd021 Cpd022 Cpd023 Cpd024 Cpd025 Cpd026 Cpd027 Cpd028 Cpd029 Cpd030 Cpd031 Cpd032 Cpd033 Cpd034 Cpd035 Cpd036 C pd037 Cpd038 Cpd039 Cpd040 Cpd041 Cpd042 Cpd0
  • the compounds can be either racemic, a mixture of diastereomers, a pure diastereomer of unknown stereochemistry, or a pure enantiomer of unknown stereochemistry.
  • Part A represent the preparation of the compounds of the invention whereas Part B represents the pharmacological examples.
  • Part A Experimental chemistry procedures The compounds of the invention can be prepared while using a series of chemical reactions well known to those skilled in the art, altogether making up the process for preparing said compounds and exemplified further. The processes described further are only meant as examples and by no means are meant to limit the scope of the present invention.
  • NMR data were recorded using Bruker Advance 400MHz or 600MHz NMR spectrometers (TopSpin-softwares). 1 H data were calibrated using tetramethylsilane as an internal calibration reference. The chemical shifts ⁇ - values are expressed in parts per million (ppm). The following acronyms were used: s (singlet), d (doublet), t (triplet), q (quartet), quint (quintet), m (multiplet), brs (broadened singulet).
  • SFC-Method A The SFC method used in the preparation and analysis of compounds of the invention referred to as “SFC-Method A”) is as following: Column: CHIRALCEL OX-H (4.6*250 mm, 5 ⁇ m), Co-Solvent: 0.5% diethylamine in MeOH, Total Flow: 3mL/min, % of CO2: 65; % of Co-Solvent: 35, ABPR: 1500 psi, Column Temp: 30 °C.
  • SFC-Method B The SFC method used in the preparation and analysis of compounds of the invention referred to as “SFC-Method B” is as following: Column: CHIRALPAK IK (4.6*250 mm, 5 ⁇ m), 0.5% isopropylamine in IPA:CH3CN (1:1), Total Flow: 4 mL/min, % of CO2: 60; % of Co-Solvent: 40, ABPR: 1500 psi, Column Temp: 30 °C. Examples of intermediates for the synthesis of the compounds of the invention and their preparation.
  • Step-2 To a stirred solution of 1-(benzyloxy)-3-fluoro-2-nitrobenzene (25 g, 101 mmol) in AcOH (600 mL) and DCM (600 mL), was added Br 2 (104.3 mL, 2.02 mol) at -10 °C. The reaction mixture was slowly allowed to reach RT.
  • Step-3 To a stirred solution of 1-(benzyloxy)-4-bromo-3-fluoro-2-nitrobenzene (25 g, 76.7 mmol) in ethanol (250 mL) and H2O (100 mL), were added iron powder (12.8 g, 229.9 mmol) and NH4Cl (42 g, 383.3 mmol) at RT. The resulting reaction mixture was heated at 90°C. After completion of the reaction (TLC monitoring), the reaction mixture was filtered through a celite bed and the bed was washed thoroughly with EtOH.
  • Step-4 To a stirred solution of 6-(benzyloxy)-3-bromo-2-fluoroaniline (40 g, 135.1 mmol), in acetonitrile (400 mL), were added DIPEA (95.6 mL, 540 mmol) followed by ethyl 2-bromoacetate (29.8 mL, 270 mmol) at RT. The reaction mixture was then stirred at 80°C. After completion of the reaction (TLC monitoring), the reaction mixture was quenched with a saturated NaHCO3 solution at 0°C and then concentrated under reduced pressure.
  • the obtained crude product was diluted with water (150 mL) and extracted with EtOAc (2x300 mL). The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by column chromatography on silica gel eluting with a gradient of EtOAc in PE (0-5%). The obtained compound was again purified by reverse phase C18 column chromatography eluting with a gradient of CH3CN in H2O containing 0.1% FA (0-50%). The pure fractions were concentrated and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to provide 22 g of ethyl (6-(benzyloxy)-3-bromo-2-fluorophenyl)glycinate.
  • Step-5 To a stirred solution of chlorosulfonyl isocyanate (9.54 g, 109.8 mmol) in DCM (150 mL) was added tBuOH (10.42 mL, 109.9 mmol) dropwise at 0°C. The reaction mixture was stirred for 30 min at the same temperature under N2 atmosphere.
  • This pre-reagent mixture was added to a stirred solution of ethyl (6-(benzyloxy)-3-bromo-2-fluorophenyl)glycinate (21 g, 54.94 mmol) and triethylamine (23 mL,164.8 mmol) in DCM (150 mL) at 0°C.
  • the resulting reaction mixture was allowed to RT. After completion of the reaction (TLC monitoring), the reaction mixture was diluted with water (150 mL) and extracted with DCM (2 x 200 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure.
  • the resulting reaction mixture was then stirred at RT. After completion of the reaction (TLC monitoring), the reaction mixture was concentrated under reduced pressure, quenched with a saturated NaHCO3 aqueous solution and extracted with DCM (3 x 100 mL). The organic layer was dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient of EtOAc in PE (0-50%). The pure fractions were combined and concentrated under reduced pressure. The obtained residue was dissolved in DCM (40 mL) and PE (80 mL) was slowly added.
  • the white precipitated solid was filtered and dried under vacuum to provide 12 g of ethyl N-(6-(benzyloxy)-3-bromo-2-fluorophenyl)-N-sulfamoylglycinate as a white solid.
  • Step-7 To a stirred solution of ethyl N-(6-(benzyloxy)-3-bromo-2-fluorophenyl)-N- sulfamoylglycinate (12 g, 26.0 mmol, 1.0 eq) in THF (120 mL), was added sodium methoxide (25% solution in methanol, 8.43 mL, 39.0 mmol, 1.5 eq) at 0°C.
  • reaction mixture was further cooled to -78°C, treated with a solution of bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methane (3.10 g, 11.6 mmol, 1.1 eq) in THF (30 mL) and stirred for another 30 min at -78°C.
  • a solution of tert-butyl 3-oxoazetidine-1-carboxylate (1.8 g, 10.5 mmol) in THF (30 mL) was then added at the same temperature.
  • the resulting reaction mixture was then allowed to warm to RT. After completion of the reaction (TLC monitoring), the reaction mixture was cooled to 0°C, quenched with a sat.
  • reaction mixture was quenched with water (50 mL) and extracted with DCM (2 x 25 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient of DCM in PE (0-10%) to yield 2.1 g of 3-ethynyl-5-methylisoxazole as a pale-yellow liquid.
  • Step-2 A stirred solution of 5-methyl-2-((trimethylsilyl)ethynyl) thiazole (1.0 g, 5.12 mmol, 1.0 eq) in MeOH (10 mL) at RT, was treated portionwise with K2CO3 (1.41 g, 10.24 mmol, 2.0 eq) at 0°C. The resulting reaction mixture was then stirred at RT. After completion of the reaction (TLC monitoring), the reaction mixture was quenched with water (100 mL) and extracted with DCM (2 x 20 mL).
  • reaction mixture was stirred at -78°C for 20 min and a solution of oxetane-3-one (2 g, 27.75 mmol, 1 eq) in THF (5 mL) was then added at the same temperature.
  • the reaction mixture was stirred at -78°C.
  • TLC monitoring After completion of the reaction (TLC monitoring), the reaction mixture was concentrated under reduced pressure to yield 4.5 g of crude 3- ((trimethylsilyl)ethynyl)oxetane as a pale-yellow solid, which is used in the next step without any further purification.
  • Step-2 To a stirred solution of 3-((trimethylsilyl)ethynyl)oxetan-3-ol (4.50 g, 26.4 mmol, 1 eq) in DMF (50 mL), was added sodium hydride (60% in mineral oil, 1.32 g, 33.0 mmol, 1.25 eq) at 0°C. After 15 min, CH3I (1.97 mL, 31.7 mmol, 1.2 eq) was added at 0°C.
  • reaction mixture was then allowed to reach RT. After completion of the reaction (TLC monitoring), the reaction mixture was cooled to 0°C, quenched with ice cold water (30 mL) and extracted with diethyl ether (3 x 50 mL). The combined organic layers were washed with brine (25 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient of EtOAc in PE (3-5%). Combined pure fractions were then concentrated under reduced pressure at low temperature (20°C) to yield 550 mg of 3-ethynyl-3-methoxyoxetane as a pale-yellow liquid.
  • Step-2 To a stirred solution of 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carbaldehyde (600 mg, 1.04 mmol, 1 eq) in MeOH (5 mL) at 0°C, were added K2CO3 (918 mg, 6.66 mmol, 2 eq) followed by dimethyl(1-diazo-2-oxopropyl)phosphonate (960 mg, 4.99 mmol, 1.5 eq). The reaction mixture was slowly allowed to reach RT. After completion of the reaction (TLC monitoring), the reaction mixture was quenched with water (50 mL) and extracted with DCM (2x100 mL).
  • reaction mixture was diluted with water (200 mL) and extracted with DCM (2 x 150 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient of EtOAc in hexane (0-30%) to yield 8 g of 1-(2,2-dibromovinyl)-2,3-difluorobenzene as a pale-yellow liquid.
  • Step-2 To a stirred solution of diisopropylamine (5.67 mL, 40.3 mmol, 4.0 eq) in THF (10 mL) at 0°C, was added n-BuLi (2.5 M in hexane, 16.11 mL, 40.3 mmol, 4.0 eq) dropwise under an N 2 atmosphere. The reaction was stirred at 0°C for 1 h.
  • This freshly prepared lithium diisopropylamide (LDA) solution was added dropwise to a stirred solution of 1-(2,2-dibromovinyl)- 2,3-difluorobenzene (10.1 mmol, 1 eq) in THF (10 mL) at -78°C. The reaction mixture was then allowed to reach RT. After completion of the reaction (TLC monitoring), the reaction mixture was quenched with saturated NH 4 Cl solution (50 mL) and extracted with diethyl ether (2 x 50 mL). The combined organic layers were concentrated under reduced pressure.
  • LDA lithium diisopropylamide
  • Step-1 Product Synthesis of Int-10: synthesis of 1-trityl-1H-1,2,4-triazole-5-carbaldehyde (Int-10) Step-1: To a stirred solution of methyl 1H-1,2,4-triazole-3-carboxylate (5.0 g, 39.4 mmol, 1.0 eq) in DCM (50 mL), were added triphenylmethyl chloride (10.94 g, 39.4 mmol, 1 eq) followed by Et3N (16.42 mL, 118.2 mmol, 3 eq) dropwise at 0 °C.
  • reaction mixture was diluted with ice cold water (500 mL) and extracted with DCM (2 x 250 mL). The combined organic layers were washed with a brine solution (2 ⁇ 300 mL) and concentrated. The residue was purified by column chromatography on silica gel eluting with a gradient of MeOH in DCM (0-10%) to yield 7.0 g of methyl 1-trityl-1H-1,2,4-triazole-5-carboxylate as a white solid.
  • Step-2 To a stirred solution of methyl 1-trityl-1H-1,2,4-triazole-3-carboxylate (5.0 g, 13.54 mmol, 1 eq) in THF:MeOH (1:1, 200 mL), was added NaBH 4 (1.54 g, 40.60 mmol, 3 eq) at 0 °C portion- wise.
  • reaction mixture was quenched with ice-cold water (25 mL) at 0 °C and extracted with DCM (2 x 50 mL). The combined organic layers were washed with a brine solution (2 ⁇ 30 mL) and concentrated. The residue was purified by column chromatography on silica gel eluting with a gradient of MeOH in DCM (0-10%) to yield 4.0 g of 1-trityl-1H-1,2,4-triazol-5-yl) methanol as a white solid.
  • Step-3 To a stirred solution of 1-trityl-1H-1,2,4-triazol-5-yl) methanol (2 g, 5.86 mmol, 1 eq) in DCM (20 mL) at 0 °C, was added Dess–Martin periodinane (3.74 g, 8.79 mmol, 1.5 eq) portion- wise.
  • reaction mixture was cooled to 0°C and quenched with a saturated Na2SO3 solution (100 mL), extracted with DCM (2 X 100 mL) and washed with a NaHCO3 solution (100 mL). The organic layer was separated and concentrated to get 900 mg of 1-trityl-1H-1,2,4-triazole-5-carbaldehyde as a white solid. The crude compound was used as such in the next step without further purification.
  • Step-2 A stirred solution of 3-hydroxy-2-methylpropyl 4-methylbenzenesulfonate (50 g, 204.6 mmol, 1 eq) in DMF (500 mL) was treated portionwise with NaN3 (66.5 g, 1023.3 mmol, 5 eq) at 0 °C and the resulting reaction mixture was then stirred at 60 °C.
  • Step-3 To a stirred solution of 3-azido-2-methylpropan-1-ol (18 g, 156.4 mmol, 1 eq) in MeOH (200 mL) were added 10% Pd/C (800 mg) and Boc 2 O (51.2 g, 234.6 mmol, 1.5 eq) at RT under a N 2 atmosphere. The resulting reaction mixture was then stirred at RT under an hydrogen balloon atmosphere.
  • Step-4 A solution of tert-butyl (3-hydroxy-2-methylpropyl) carbamate (10 g, 48.93 mmol, 1 eq) in DCM (100 mL) was treated portion-wise with Dess-Martin periodinane (31.1 g, 73.4 mmol, 1.5 eq) at 0°C and stirred 30 minutes at 0°C.
  • reaction mixture was then stirred at RT. After completion of the reaction (TLC monitoring), the reaction mixture was quenched with a saturated NaHCO3 solution (50 mL) at 0 °C. The reaction mixture was filtered through a celite bed, which was further washed with DCM (500 mL). The organic layer was separated, washed with brine (10 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient of EtOAc in PE (4-6%) to yield 6 g of tert-butyl (2-methyl-3-oxopropyl) carbamate as a colorless liquid.
  • reaction mixture was used as such in the next step as a 0.25M solution of tert-butyl(1S,5R,6S)-6-[(E)-2- (9-borabicyclo[3.3.1]nonan-9-yl)vinyl]-3-azabicyclo[3.1.0] hexane-3-carboxylate in THF.
  • reaction mixture was cooled again to -17 °C, treated dropwise with a solution of tert-butyl (R)-2-methyl-4- oxopyrrolidine-1-carboxylate (0.20 g, 1.00 mmol, 1.0 eq) in toluene (10 mL), stirred for 1.5 h at - 17°C and then allowed to stir at RT. After completion of the reaction (TLC monitoring), the reaction mixture was quenched with a sat. NH4Cl solution. The medium was filtered through a celite bed, the filtrate was dried over Na2SO4 and concentrated. Similarly, four more batches were conducted on the same scale (4 x 0.20 g) following the same procedure.
  • Step-2 A stirred solution of tert-butyl (R)-4-(bromomethylene)-2-methylpyrrolidine-1-carboxylate (as a E/Z mixture) (500 mg, 1.81 mmol, 1 eq), bis(pinacolato)diboron (1.15 g, 4.53 mmol, 2.5 eq) and KOAc (444 mg, 4.53 mmol, 2.5 eq) in dioxane (30 mL) was degassed with Ar for 10 min.
  • Step-1 A stirred solution of 2,2,6,6-tetramethylpiperidine (4.00 g, 28.37 mmol, 1 eq) in THF (80 mL), at -78°C, was treated with n-BuLi (2.5M solution in hexane, 13.62 mL, 34.04 mmol, 1.2 eq) and then allowed to room temperature over 30 min. The reaction medium, at 0°C, was then treated with a solution of bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methane (8.0 g, 28.37 mmol, 1 eq) in THF (50 mL) and stirred for 10 min.
  • Step-2 A stirred solution of 2,2,6,6-tetramethylpiperidine (4.41 g, 31.21 mmol, 1 eq) in THF (50 mL) was cooled down to -78°C, treated with n-BuLi (2.5M solution in hexane, 13.00 mL, 34.04 mmol, 1.2 eq) and allowed to room temperature over 30 min.
  • reaction mixture was cooled to -30°C, treated with above reaction mixture from step 1 (i.e. crude 2,2'-(ethane-1,1-diyl) bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolane), stirred for 30 minutes and then treated with a solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (5.26 g, 28.37 mmol, 1 eq) in THF (30 mL), still at -30 °C. Reaction mixture was then allowed to RT. After completion of the reaction (TLC monitoring), the reaction mixture was cooled to 0 °C and quenched with a sat. NH 4 Cl solution.
  • Step-2 A solution of methyl rel-(1S,2S)-2-[(4-methoxyphenyl)methylcarbamoyl]cyclopropane carboxylate (735 mg, 2.79 mmol) in THF (12 mL) was cooled to 0°C and treated dropwise with a 2.4 M LiAlH4 solution in THF (3.5 mL, 8.40 mmol, 3 eq). The mixture was stirred at 0 °C for 30 min and then at 66°C. In total, 3 batches were run following the same conditions and amounts. After completion of the reaction (TLC monitoring), the reaction mixture of the three vials were cooled down and diluted with 100 mL of THF.
  • reaction mixture was stirred at 0 °C for 10 minutes and then allowed to RT. After completion of the reaction (TLC monitoring), the reaction mixture was diluted with DCM and washed with an aq. saturated solution of NaHCO3. The organic layer was then dried over MgSO 4 , filtered and concentrated. The residue was purified by column chromatography on silica gel eluting with a gradient of EtOAc in heptane (10-100%) to yield 1.23 g of tert-butyl N-[[rel-(1S,2S)-2-formylcyclopropyl]methyl]carbamate as an oily residue.
  • the mixture was stirred at 0 °C for 30 min and then allowed to RT. After completion of the reaction (TLC monitoring), the mixture was diluted with 100 mL of THF and quenched by addition of Na2SO4.10H2O sodium (30.82 g, 94.69 mmol, 5 eq). The mixture was stirred for 2 hours at RT, solids were filtered off and the filtrate was concentrated under reduced pressure.
  • Step-2 To a solution of [rel-(1S,2S)-2-(hydroxymethyl)cyclopropyl]methanol (0.93 g, 9.11 mmol, 1 eq) in THF (9 mL), cooled in an ice bath, was added NaH (60% w/w in mineral oil, 437 mg, 10.93 mmol, 1.2 eq). The mixture was stirred at 0°C for 30 min then treated dropwise with CH3I (1.1 mL, 18.21 mmol, 2 eq). The mixture was stirred at 0°C for 30 min and then overnight at RT. The reaction mixture was then diluted with water and extracted three times with EtOAc.
  • Step-1 A solution of dimethyl rel-(1S,2S)-cyclopropane-1,2-dicarboxylate (3.17 g, 19.42 mmol, 1 eq) in THF (12 mL), cooled in an ice bath, was treated dropwise over 10 minutes with a 2.4 M solution of LiAlH4 in THF (4.0 mL, 9.71 mmol, 0.5 eq).
  • the mixture was stirred at 0 °C for 30 min and then allowed to RT. After completion of the reaction (TLC monitoring), the mixture was diluted with 100 mL of THF and quenched by addition of Na2SO4.10H2O (31.60 g, 97.09 mmol, 5 eq). The mixture was stirred for 2 hours at RT, solids were filtered off and the filtrate was concentrated under reduced pressure.
  • reaction mixture was stirred at 0 °C for 10 minutes and then allowed to RT. After completion of the reaction (TLC monitoring), the reaction mixture was filtered on celite. The filtrate was washed with a 1M aq. solution of Na2CO3 and concentrated under reduced pressure.
  • Step-3 To a stirred solution methyl rel-(1S,2S)-2-formylcyclopropanecarboxylate (703 mg, 5.49 mmol, 1 eq) and dimethyl(1-diazo-2-oxopropyl)phosphonate (0.953 mL, 6.22 mmol, 1.13 eq) in MeOH (20 mL), cooled to 0°C, was added K2CO3 (1.53 g, 11.04 mmol, 2 eq). The mixture was stirred at 0°C for 1 hour and then allowed to warm to RT.
  • Step-4 A solution of methyl rel-(1S,2S)-2-ethynylcyclopropanecarboxylate (271 mg, 2.18 mmol, 1 eq) and a 9 M methanolic solution of methylamine (10.0 mL, 20.00 mmol, 9.2 eq) was stirred at RT for 24 hours and then was concentrated under reduced pressure to afford 196 mg of crude rel-(1S,2S)-2-ethynyl-N-methyl-cyclopropanecarboxamide as a brown solid, which was used as such in the next step.1H NMR (400 MHz, DMSO-d6) ⁇ ppm.8.18 (m, 1 H), 2.76 (d, 1 H), 2.60 (d, 3 H), 1.84 (ddd, 1 H), 1.59-1.52 (m, 1 H), 1.10 (m, 1 H), 0.98 (m, 1 H).
  • Step-5 A solution of rel-(1S,2S)-2-ethynyl-N-methyl-cyclopropanecarboxamide (190 mg, 1.54 mmol, 1 eq) in THF (8 mL) was cooled to 0°C and treated dropwise with a 2.4M solution of LiAlH 4 in THF (1.0 mL, 2.40 mmol, 1.55 eq). The mixture was stirred at 0 °C for 30 min and then stirred at 66°C. After completion of the reaction (TLC monitoring), the mixture was cooled down to RT, diluted with 30 mL of THF and quenched by addition of Na2SO4.10H2O sodium (7.00 g, 21.51 mmol, 14 eq).
  • Step-6 A solution of rel-tert-butyl N-methyl-N-[[(1S,2S)-2-ethynylcyclopropyl] methyl]carbamate (270 mg, 1.29 mmol) in THF (8 mL) was cooled to 0°C and treated dropwise with a 2.4M solution of LiAlH4 in THF (1.5 mL, 3.60 mmol, 2.8 eq).
  • Step-1 To a - mg, 1 eq) in DCM (12 mL), cooled at 0°C, were added sequentially Et 3 N (0.96 mL, 6.87 mmol, 1.5 eq) and mesyl chloride (0.375 mL, 4.81 mmol, 1.05 eq). The mixture was stirred at 0 °C for 2 hours and then was diluted in DCM. The mixture was washed with a 1N aq.
  • Step-2 A mixture of rel-(1S,2S)-2-ethynylcyclopropyl]methyl methanesulfonate (236 mg, 1.35 mmol), pyrrolidine (0.337 mL, 4.06 mmol, 3 eq) and K2CO3 (187 mg, 1.35 mmol, 1 eq) in CH3CN (8 mL) was stirred at 60 °C.
  • Step-2 To a stirred solution of tert-butyl-3-cyclopropyl-4-hydroxypyrrolidine-1-carboxylate (6.0 g, 26.40 mmol, 1.0 eq) in DCM (90 mL) was added Dess-Martin periodinane (16.80 g, 39.60 mmol, 1.5 eq) portion-wise at 0°C. The resulting reaction mixture was then stirred at RT. After completion of the reaction (TLC monitoring), the reaction mixture was filtered through a celite be and the bed was washed with DCM (100 mL). The filtrate was washed with a sat. aq. NaHCO3 solution (2x150 mL) and extracted with DCM.
  • Step-1 To a stirred solution of tert-butyl (3S,4S)-3-hydroxy-4-(hydroxymethyl) pyrrolidine-1- carboxylate (2.0 g, 9.21mmol, 1.0 eq) and Et3N (5.12 mL, 36.82 mmol, 4.0 eq) in DCM (30 mL), cooled at 0°C, was added tert-butylchlorodimethylsilane (2.78 g, 18.41 mmol, 2.0 eq). After addition, the resulting reaction mixture was allowed to stir at RT.
  • Step-2 To a stirred solution of tert-butyl (3S,4S)-3-(((tert-butyldimethylsilyl)oxy)methyl)-4- hydroxypyrrolidine-1-carboxylate (2.1 g, 6.33 mmol, 1.0 eq) in DCM (30 mL), cooled at 0 °C, was added Dess-Martin periodinane (6.72 g, 15.84 mmol, 2.5 eq) portionwise. After addition, the resulting reaction mixture was allowed to stir at RT. After completion (TLC monitoring), the reaction mixture was diluted with an aq. sat. NaHCO3 solution and extracted with DCM (3x30 mL).
  • Step-1 To a stirred solution of tert-butyl (3-oxopropyl)carbamate (10 g, 57.7 mmol, 1.0 eq) in THF (150 mL) was added methyl (triphenylphosphoranylidene)acetate (23.17 g, 69.3 mmol, 1.2 eq) and the resulting reaction mixture was stirred at RT. After completion of the reaction (TLC monitoring), the reaction mixture was filtered and the filtrate was concentrated.
  • Step-2 To a stirred solution of methyl (E)-5-((tert-butoxycarbonyl)amino)pent-2-enoate ( 4.0 g, 17.45 mmol, 1.0 eq) in DCM (60 mL) was added trifluoroacetic acid (13.35 mL, 174.46 mmol, 10.0 eq) at 0°C. The resulting reaction mixture was then left stirring at RT. After completion of the reaction (TLC monitoring), the reaction mixture was concentrated under reduced pressure and the residue was triturated with PE. The solid material was collected by filtration and dried to afford 4.30 g of methyl (E)-5-aminopent-2-enoate 2,2,2-trifluoroacetate.
  • Step-3 A stirred solution of methyl (E)-5-aminopent-2-enoate 2,2,2-trifluoroacetate (4.30 g, 17.68 mmol, 1.0 eq) and Et3N (12.3 mL, 88.41 mmol, 5.0 eq) in DCM (60 mL) at 0°C were treated with methanesulfonyl chloride (2.74 mL, 35.34 mmol, 2.0 eq).
  • reaction mixture was stirred at RT. After completion of the reaction (TLC monitoring), the reaction mixture was diluted with water (30 mL) and extracted with DCM (2 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated.
  • Step-4 To a stirred solution of (2-bromoethyl)diphenylsulfonium trifluoromethanesulfonate (5.08 g, 11.46 mmol, 1.25 eq) in DCM (30 mL), cooled to 0 °C, was added NaH (60% w/w in mineral oil, 770 mg, 32.09 mmol, 3.5 eq). The resulting reaction mixture was stirred at 0°C for 15 min and then treated dropwise with a solution of methyl (E)-5-(methylsulfonamido)pent-2-enoate (1.90 g, 9.17 mmol, 1.0 eq) in DCM (8 mL).
  • reaction mixture was allowed to warm up and stirred at RT. After completion of the reaction (TLC monitoring), the reaction mixture was cooled to 0°C, quenched with AcOH (5 mL), diluted with water (30 mL) and extracted with DCM (2 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated.
  • Step-5 To a stirred solution of rel-methyl (1R,6S,7R)-3-(methylsulfonyl)-3- azabicyclo[4.1.0]heptane-7-carboxylate (6, 700 mg, 3.0 mmol, 1.0 eq) in THF (15 mL), was added dropwise at 0°C a 2M THF solution of LiAlH 4 (3 mL, 6.0mmol, 2.0 eq) and the resulting reaction mixture was stirred at 0°C. After completion of the reaction, the reaction mixture was quenched by dropwise addition of a sat. NH4Cl aq. solution, stirred for 30 min at RT, and then filtered on celite.
  • Step-1 A stirred solution of methyl (E)-5-((tert-butoxycarbonyl)amino)pent-2-enoate (15 g, 65.42 mmol, 1.0 eq) in DCM (150 mL), cooled to 0°C, was treated with a 4M HCl solution in dioxane (164 mL, 656 mmol, 10.0 eq). The resulting reaction mixture was allowed to warm up and was stirred at RT. After completion of the reaction (TLC monitoring), the reaction mixture was concentrated under reduced pressure. The residue was triturated with Et 2 O to yield 10.0 g of methyl (E)-5-aminopent-2-enoate hydrochloride as a pale yellow solid.
  • Step-2 To a stirred solution of methyl (E)-5-aminopent-2-enoate hydrochloride (10.0 g, 60.38 mmol, 1.0 eq.) in THF (200 mL), cooled at 0°C, were added sequentially Et 3 N (42.2 mL, 301.9 mmol, 5.0 eq) and 4-nitrobenzenesulfonyl chloride (14.72 g, 66.42 mmol, 1.10 eq). The resulting mixture was then warm up and stirred at RT. After completion of the reaction (TLC monitoring), the resulting reaction mixture was diluted with water and extracted with EtOAc (2x200 mL).
  • Step-3 To a stirred solution of (2-bromoethyl)diphenylsulfonium trifluoromethanesulfonate (17.63 g, 39.77 mmol, 1.25 eq) in DCM (100 mL), cooled to 0°C, was added NaH (60% in mineral oil, 4.45 g, 111.35 mmol, 3.5 eq). After 15 min, a solution of methyl (E)-5-((4- nitrophenyl)sulfonamido)pent-2-enoate (10.0 g, 31.82 mmol, 1.0 eq) in DCM (50 mL) was added dropwise at 0°C.
  • Step-4 To a stirred solution of rel-methyl (1R,6S,7R)-3-((4-nitrophenyl)sulfonyl)-3- azabicyclo[4.1.0]heptane-7-carboxylate (7.0 g, 20.57 mmol, 1.0 eq) in CH3CN (105 mL), were added K2CO3 (11.37 g, 82.27 mmol, 4.0 eq) and thiophenol (4.20 mL, 41.13 mmol, 2.0 eq). The resulting mixture was stirred at RT for 16 h and then Boc 2 O (6.73 g, 30.85 mmol, 1.5 eq) was added. The resulting mixture was stirred at RT.
  • reaction mixture was diluted with water and extracted twice with EtOAc. The combined organic layers were washed with an aq. sat. sodium thiosulfate solution, brine, dried over anhydrous Na2SO4 and concentrated.
  • Step-5 A stirred solution of rel-3-(tert-butyl) 7-methyl (1R,6S,7R)-3-azabicyclo[4.1.0]heptane-3,7- dicarboxylate (4.0 g, 15.67 mmol, 1.0 eq) in THF (60 mL) was treated dropwise with a 1M THF solution of BH3-THF complex (47.0 mL, 47.0 mmol, 3 eq). After addition, the resulting reaction mixture was stirred at 65°C. After completion of the reaction (TLC monitoring), the reaction mixture was cooled to 0°C and quenched with EtOH (10 mL).
  • Step-1 a - (10 g, 59.46 mmol, 1.0 eq) and benzylamine (7.14 mL, 65.40 mmol, 1.1 eq) in EtOH (100 mL), cooled at 0°C, was added AcOH (14.28 mL, 249.72 mmol, 4.2 eq). After 30 min stirring at 0°C, NaCNBH3 (3.74 g, 59.46 mmol, 1.0 eq) was added.
  • Step-2 To a stirred solution of rel-ethyl (1S,5R,6S)-2-(benzylamino)bicyclo[3.1.0]hexane-6- carboxylate (6.0 g, 23.14 mmol, 1.0 eq) in MeOHl (100 mL) was added 10% Pd/C (6.03 g, 50.9 mmol, 2.2 eq) at RT and under an inert atmosphere. The resulting reaction mixture was degassed and then was stirred under H2 atmosphere at RT. After completion of the reaction (TLC monitoring), the reaction mixture was filtered through celite and the celite pad was washed with MeOH.
  • Step-3 A stirred solution of rel-ethyl (1S,5R,6S)-2-aminobicyclo[3.1.0]hexane-6-carboxylate (3.6 g, 21.27 mmol, 1.0 eq) and Et3N (9 mL, 63.82 mmol, 3.0 eq) in DCM (40 mL), cooled at 0°C, was treated dropwise with mesylchloride (2.47 mL, 31.91 mmol, 1.5 eq). The resulting reaction mixture was then allowed to stir at RT. After completion of the reaction (TLC monitoring), the reaction mixture was diluted with water and extracted with dichloromethane (3x50 mL).
  • Step-2 To a stirred mixture of tert-butyl(cyclopent-3-en-1-yloxy)dimethylsilane (35.0 g, 176.4 mmol, 1.0 eq) and copper powder (1.12 g, 17.6 mmol, 0.1 eq.), heated to 100°C, was added ethyl diazoacetate (37.28 mL, 352.86 mmol, 2.0 eq) via a syringe pump over a period of 4 h and stirring was then continued at 100 °C. After completion of the reaction (TLC monitoring), the reaction mixture was cooled to RT and concentrated.
  • ethyl diazoacetate 37.28 mL, 352.86 mmol, 2.0 eq
  • Step-3 A stirred solution of rel-ethyl (1R,5S,6R)-3-((tert-butyldimethylsilyl) oxy)bicyclo[3.1.0]hexane-6-carboxylate (35 g, 123.04 mmol, 1.0 eq) in THF (700 mL), cooled at 0°C, was treated dropwise with a 2M THF solution of LiAlH4 (123 mL, 246.0 mmol, 2.0 eq) and stirring was continued at 0°C. After completion of the reaction (TLC monitoring), the reaction mixture was carefully quenched with a sat. NH4Cl aq. solution.
  • Step-1 To a stirred solution of 2-(5-bromopyridin-3-yl)acetic acid (3.0 g, 13.89 mmol, 1.0 eq) and dimethylamine hydrochloride (3.40 g, 41.66 mmol, 3.0 eq) in DCM (40 mL), cooled at 0°C, were sequentially added N,N-diisopropylethylamine (4.89 mL, 27.77 mmol, 2.0 eq), 1-hydroxybenzotriazole monohydrate (4.25 g, 27.77 mmol, 2.0 eq) and 1-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (5.32 g, 27.77 mmol, 2.0 eq).
  • the resulting reaction mixture was allowed to warm up and was stirred at RT. After completion of the reaction (TLC monitoring), the reaction mixture was diluted with DCM and a 1N aq. solution of HCl (10 mL) was added. The organic layer was separated and the aqueous solution was neutralized with an aq. sat. NaHCO3 solution and extracted with DCM (3x50 mL). The combined organic layers were washed with water, brine, dried over anhydrous Na2SO4 and concentrated to afford 2.1 g of the crude 2-(5-bromopyridin-3-yl)-N,N-dimethylacetamide which was used as such in the next step.
  • Step-2 A stirred solution of 2-(5-bromopyridin-3-yl)-N,N-dimethylacetamide (1.8 g, 7.40 mmol, 1.0 eq) in THF (30 mL) was treated dropwise with a 2M solution of BH3-S(CH3)2 in THF (19.51 mL, 39.02 mmol, 5.27 eq) at RT. The resulting reaction mixture was then stirred at 55°C.
  • Step-1 To a stirred solution of 4-iodo-1H-imidazole (5 g, 25.78 mmol, 1.0 eq) in DMF (50 mL), cooled at 0°C, was added NaH (60% dispersion in mineral oil, 1.54 g, 38.66 mmol, 1.5 eq), followed by ethyl bromoacetate (3.13 mL, 28.35 mmol, 1.1 eq). The resulting reaction mixture was allowed to warm up and was stirred at RT. After completion of the reaction (TLC monitoring), the reaction mixture was quenched with ice cold water and extracted with EtOAc.
  • Step-2 To a stirred solution of ethyl 2-(4-iodo-1H-imidazol-1-yl)acetate (2.5 g, 8.93 mmol, 1 eq) in MeOH (50 mL), cooled at 0°C, was added NaBH 4 (1.35 g, 35.71 mmol, 4 eq). The resulting reaction mixture was then stirred at RT. After completion of the reaction (TLC monitoring), the reaction mixture was quenched with ice cold water (10 mL) and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated.
  • Step-1 To a stirred acetate g, 7.14 mmol, 1.0 eq) in MeOH (30 mL) was added a 2N methanolic solution of Me2NH (7.85 mL, 35.7 mmol, 5.0 eq) at RT and the resulting reaction mixture was then stirred at reflux.
  • Step-2 To a stirred solution of 2-(4-iodo-1H-imidazol-1-yl)-N,N-dimethylacetamide (1.5 g, 5.38 mmol, 1.0 eq) in THF (20 mL) was added a 1M THF solution of BH3-THF complex (28.33 mL, 28.33 mmol, 5.27 eq) at RT. The resulting reaction mixture was then stirred at 55°C. After completion of the reaction (TLC monitoring), the reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated.
  • Step-1 To a stirred solution of tert-butyl (2-hydroxyethyl)(methyl)carbamate (15 g, 85.6 mmol, 1.0 eq) in THF (200 mL) were added sequentially PPh 3 (33.68 g, 128.40 mmol, 1.5 eq) and CBr 4 (42.58 g, 128.40 mmol, 1.5 eq) at RT. The resulting reaction mixture was stirred at RT for 1 h, solids were filtered off and the filtrate was concentrated.
  • Step-2 To a stirred solution of 4-iodo-1H-pyrazole (4.0 g, 20.62 mmol, 1.0 eq) and Cs 2 CO 3 (16.79 g, 51.55 mmol, 2.5 eq) in DMF (60 mL) was added tert-butyl(2-bromoethyl) (methyl)carbamate (5.40 g, 22.68 mmol, 1.1 eq) at RT and the resulting reaction mixture was then stirred at 80°C.
  • reaction mixture was cooled to RT, quenched with ice cold water and the mixture was then extracted twice with EtOAc. The combined organic layers were washed with water, brine, dried over anhydrous Na 2 SO 4 and concentrated.
  • Step-1 A stirred solution of tert-butyl (3-hydroxy-2-methylpropyl)carbamate (6 g, 31.70 mmol, 1 eq) and imidazole (4.32 g, 63.41 mmol, 2 eq) in THF (100 mL), cooled at 0°C, was treated dropwise with tert-TBDS-Cl (7.17g, 47.56 mmol, 1.5 eq.). After addition, the resulting reaction mixture was stirred at RT. After completion of the reaction (TLC monitoring), the reaction mixture was diluted with EtOAc, washed with a sat. aq. NaHCO3 solution and concentrated.
  • Step-2 To a stirred solution of tert-butyl (3-((tert-butyldimethylsilyl)oxy)-2-methylpropyl) carbamate (8.0 g, 26.36 mmol, 1 eq) in DMF (50 mL), cooled at 0°C, was added NaH (60% w/w in mineral oil, 1.27g, 31.63 mmol, 1.2 eq). The mixture was stirred at 0°C for 5 min and CH3I (7.48 g, 52.72 mmol, 2 eq) was then added. The resulting reaction mixture was then stirred at 50°C.
  • Step-3 To a stirred solution of tert-butyl (3-((tert-butyldimethylsilyl)oxy)-2-methylpropyl) (methyl)carbamate (6.0 g, 18.90 mmol, 1 eq) in THF (100 mL) cooled at 0 °C was added a 1M THF solution of TBAF (56.70 mL, 56.69 mmol, 3 eq). After addition, the reaction mixture was stirred at RT. After completion of the reaction (TLC monitoring), the reaction mixture was diluted with DCM (100 mL), washed with water, brine and the organic layer was concentrated.
  • Step-1 To a stirred solution of 2-ethylpropane-1,3-diol (16 g, 153.63 mmol, 1.0 eq) in DCM (200 mL), cooled at 0°C, were added pyridine (6.2 mL, 76.81 mmol, 0.5 eq) and TsCl (29.29 g, 153.63 mmol, 1.0 eq). After addition, the reaction mixture was stirred at RT. After completion of the reaction (TLC monitoring), the reaction mixture was washed with a 1N aq.
  • Step-2 To a stirred solution of 2-(hydroxymethyl)butyl 4-methylbenzenesulfonate (26 g, 100.65 mmol, 1.0 eq) in DMF (300 mL) was added NaN3 (65.43 g, 1.00 mol, 10 eq) at 0 °C.
  • Step-3 To a stirred solution of 2-(azidomethyl) butan-1-ol (14 g, 108.39 mmol, 1.0 eq) in MeOH (140 mL) were added 10% Pd/C (9.23 g, 86.71 mmol, 0.8 eq) and Boc2O (37.35 g, 162.59 mmol, 1.5 eq) at RT. The resulting reaction mixture was stirred at RT under a H2 atmosphere. After completion of the reaction (TLC monitoring), the reaction mixture was filtered through celite and concentrated.
  • Step-1 To a stirred solution of 3-methyldihydrofuran-2(3H)-one (25 g, 249.71 mmol, 1.0 eq) in DCM (250 mL), cooled at -78°C, was added a 1M toluene solution of DIBAL-H (216.42 mL, 324.62 mmol, 1.3 eq) under nitrogen atmosphere. The resulting reaction mixture was stirred at -78°C for 1 h and then was quenched with a sat. aq.
  • Step-2 To a stirred solution of 3-methyltetrahydrofuran-2-ol (6 g, 58.75 mmol, 1 eq) in MeOH (50 mL) were added K 2 CO 3 (16.21 g, 117.50 mmol, 2.0 eq) and dimethyl diazo-2- oxopropylphosphonate (13.47 g, 70.50 mmol, 1.2 eq. The resulting reaction mixture was stirred at RT. After completion of the reaction, the reaction mixture was quenched with water and extracted twice with Et 2 O and the combined organic extracts were concentrated.
  • Step-3 To a stirred solution of 3-methylpent-4-yn-1-ol (4 g, 40.76 mmol, 1.0 eq) and (Boc) 2 NH (10.61 g, 48.91 mmol, 1.2 eq) in THF (40 mL) were added PPh 3 (16.03 g, 61.13 mmol, 1.5 eq) and diethylazodicarboxylate (26.62 mL, 61.13 mmol, 1.5 eq) at 0 °C. The resulting reaction mixture was stirred at RT. After completion of the reaction (TLC monitoring), the reaction mixture was quenched with water and extracted twice with EtOAc.
  • Step- a - (531 mg, 4.08 mmol) in DMF (6 mL), cooled to 0°C, was added NaH (60% w/w in mineral oil, 180 mg, 4.49 mmol). The mixture was stirred at 0°C for 30 min and 2-bromo-N,N-dimethyl-acetamide (0.520 mL, 4.28 mmol, 1.05 eq) was added. The mixture was stirred at 0°C for 30 min and then overnight at RT.
  • Step-2 A stirred solution of rel-methyl (1S,2S)-2-((2-(dimethylamino)-2-oxoethoxy)methyl) cyclopropane-1-carboxylate (565 mg, 2.62 mmol) in THF (12 mL), cooled to 0°C, was treated dropwise with a 2.4M THF solution of LiAlH 4 (3.5 mL, 8.40 mmol, 3.2 eq). The mixture was stirred at 0°C for 30 min and then refluxed. After completion of the reaction, the reaction mixture was cooled down to RT, diluted with THF and quenched by addition of Na 2 SO 4 .10H 2 O (8.0 g).
  • Step-2 A stirred mixture of 5-bromo-1-fluoro-3-methoxy-2-nitrobenzene (25 g, 99.99 mmol, 1 eq), ethylboronic acid (9.24 g, 124.99 mmol, 1.25 eq), Cs2CO3 (120.54 g, 369.97mmol, 3.7 eq) and Pd(dppf)Cl2 (4.08 g, 5.00 mmol, 0.05 eq) in dioxane (200 mL) and water (20 mL), at RT, was degassed and put under an inert atmosphere, then stirred at 100 °C.
  • Step-3 To a stirred solution of 5-ethyl-1-fluoro-3-methoxy-2-nitrobenzene (10 g, 50.21mmol, 1 eq) in CH 3 CN (100 mL), were added sequentially at RT N-iodosuccinimide (45.18 g, 200.8 mmol, 4 eq) and TFA (0.77 mL, 10.05 mmol, 0.2 eq). The resulting reaction mixture was stirred at 90 °C. After completion of the reaction (TLC monitoring), the reaction mixture was diluted with DCM and washed with a sat. aq. solution of Na 2 S 2 O 3 .
  • Step-4 To a stirred solution of 1-ethyl-3-fluoro-2-iodo-5-methoxy-4-nitrobenzene (11 g, 33.84 mmol, 1 eq) in DCM (100 mL) was added a 1M DCM solution of BBr 3 (102 mL, 102 mmol, 3 eq) dropwise at 0 °C. The resulting reaction mixture was stirred at 0 °C. After completion of the reaction (TLC monitoring), the reaction mixture was quenched with water and extracted twice with DCM.
  • Step-5 To a stirred solution of 5-ethyl-3-fluoro-4-iodo-2-nitrophenol (8 g, 25.72 mmol, 1 eq) in DMF (80 mL) were added K 2 CO 3 (4.26 g, 30.86 mmol, 1.2 eq.) and (bromomethyl)benzene (3.1 mL, 25.72 mmol, 1.0 eq.) dropwise at 0 °C and the resulting reaction mixture was stirred at 60 °C. After completion of the reaction (TLC monitoring), the reaction mixture was quenched with water.
  • Step-6 To a stirred solution of 1-(benzyloxy)-5-ethyl-3-fluoro-4-iodo-2-nitrobenzene (10 g, 24.93 mmol, 1 eq) in EtOH (100 mL) and water (50 mL) were added at RT NH 4 Cl (13.33 g, 249.27 mmol, 10 eq) followed by iron powder (6.96 g, 124.63 mmol, 5 eq). The resulting reaction mixture was stirred at 80 °C. After completion of the reaction (TLC monitoring), the reaction mixture was filtered through celite. The filtrate was diluted with water and extracted twice with EtOAc and the combined organic extracts were concentrated.
  • Step-7 To a stirred solution of 6-(benzyloxy)-4-ethyl-2-fluoro-3-iodoaniline (8 g, 21.55 mmol, 1 eq) in DMF (80 mL) were added sequentially DIPEA (15.30 mL, 86.21 mmol, 4.0 eq) and ethyl 2- bromoacetate (4.77 mL, 43.10 mmol, 2.0 eq) and the resulting reaction mixture was stirred at 80 °C. After completion of the reaction (TLC monitoring), the reaction mixture was quenched with a sat. aq. solution of NaHCO3 at 0 °C and extracted with EtOAc (3x100 mL).
  • Step-8 To a stirred solution of chlorosulfonyl isocyanate (2.96 mL, 34.12 mmol, 2.0 eq) in DCM (60 mL), cooled at 0 °C, was added dropwise tert-butanol (3.24 mL, 34.12 mmol, 2.0 eq).
  • reaction mixture was stirred at 0°C for 30 min and then was added to a stirred solution of ethyl (6- (benzyloxy)-4-ethyl-2-fluoro-3-iodophenyl)glycinate (7 g, 15.31 mmol, 1.0 eq) and Et3N (7.14 mL, 51.18 mmol, 3.0 eq) in DCM (60 mL) at 0 °C.
  • DCM 60 mL
  • the resulting reaction mixture was allowed to warm up and was and stirred at RT. After completion of the reaction (TLC monitoring), the reaction mixture was diluted with water and extracted with DCM (3x200 mL). Combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated.
  • Step-9 To a stirred solution of ethyl N-(6-(benzyloxy)-4-ethyl-2-fluoro-3-iodophenyl)-N-(N-(tert- butoxycarbonyl) sulfamoyl) glycinate (9 g, 14.14 mmol, 1.0 eq) in DCM (90 mL), cooled at 0 °C, was added TFA (5.41 mL, 70.70 mmol, 5 eq) and the resulting reaction mixture was allowed to stir at RT. After completion of the reaction (TLC monitoring), the reaction mixture was concentrated. The residue was suspended in a sat. aq.
  • Step-10 To a stirred solution of ethyl N-(6-(benzyloxy)-4-ethyl-2-fluoro-3-iodophenyl)-N- sulfamoylglycinate (5 g, 9.32 mmol, 1.0 eq) in THF (40 mL), cooled at 0 °C, was added NaOMe (25% in MeOH, 4.02 mL, 18.64 mmol, 2.0 eq). The resulting reaction mixture was stirred at 0°C and after completion of the reaction (TLC monitoring) was acidified with AcOH (4 mL) at 0°C and was concentrated.
  • Step-1 A - carboxylate (0.50 g, 2.41 mmol, 1 eq) in DCM (10 mL), cooled at 0°C, was treated dropwise with a 4N HCl solution in dioxane (6.0 mL, 24.0 mmol, 9.95 eq) and the reaction mixture was stirred at 0°C. After completion of the reaction (TLC monitoring), the reaction mixture was partitioned between DCM and a 1N aq.
  • Step2 A stirred solution of (1S,5R)-6-ethynyl-3-azabicyclo[3.1.0]hexane (219 mg, 2.04 mmol, 1 eq) in DCM (6 mL), cooled at 0 °C, was treated sequentially with Et 3 N (0.43 mL, 3.07 mmol, 1.5 eq) and 1-Boc-4-chlorosulfonylpiperidine (651 mg, 2.25 mmol, 1.1 eq) and the reaction mixture was then allowed to reach RT.
  • Step3 A stirred solution of tert-butyl 4-[[(1S,5R)-6-ethynyl-3-azabicyclo[3.1.0]hexan-3-yl]sulfonyl] piperidine-1-carboxylate (458 mg, 1.29 mmol, 1 eq) in DCM (6 mL), cooled at 0°C, was treated dropwise with a 4N HCl solution in dioxane (3.0 mL, 12.0 mmol, 9.3 eq) and the reaction mixture was stirred at 0°C.
  • the final debenzylation can be performed by any suitable reagent known to the person skilled in the art (e.g. BBr 3 (neat or as solution in an appropriate solvent), BCl 3, ... ).
  • BBr 3 nitrogen dioxide
  • BCl 3 nitrogen dioxide
  • the reagents are commercially available or synthesized as described in the section “Examples of intermediates and their preparation”.
  • Reagent Step-1 Solvent Step-1 Temp.
  • Step-1 Reagent Step-2 Compound CH3CN RT BBr3 Cpd002 CH3CN 90°C BBr3 Cpd003 CH3CN RT BBr3 Cpd004 CH3CN 80°C BBr3 Cpd005 DMF 90°C BBr3 Cpd006 CH 3 CN 60°C BBr 3 Cpd007 CH 3 CN 90°C BBr 3 Cpd008 CH3CN 90°C BBr3 Cpd009 CH 3 CN 60°C BBr 3 Cpd010 CH3CN RT BBr3 Cpd011 CH3CN RT BBr3 Cpd012 CH3CN 60°C BBr3 Cpd013 CH 3 CN 60°C BBr 3 Cpd014 CH 3 CN 70°C BBr 3 Cpd015 CH3CN RT BBr3 Cpd016 CH 3 CN 60°C BBr 3 Cpd017 CH3CN 80°
  • the final debenzylation (phenol deprotection) and cleavage of labile protecting group when applicable can be performed by any suitable reagent known to the person skilled in the art (e.g. BBr 3 (neat or as solution in an appropriate solvent), BCl 3, ... ).
  • BBr 3 neat or as solution in an appropriate solvent
  • BCl 3 benzyl
  • the reagents are commercially available or synthesized as described in the section “Examples of intermediates and their preparation”.
  • Reagent Step-1 Solvent Step-1 Temp.
  • Step-1 Reagent Step-2 Compound CH3CN 60°C BBr3 Cpd056 CH3CN 60°C BBr3 Cpd064 CH3CN 60°C BBr3 Cpd065 CH 3 CN 90°C BBr 3 Cpd081 CH 3 CN 60°C BBr 3 Cpd117
  • Example 3 Synthesis of 5-(3-(azetidin-3-ylethynyl)-2-fluoro-6-hydroxyphenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide (Cpd019) - - one 1,1-dioxide (800 mg, 1.93 mmol, 1 eq), tert-butyl 3-ethynylazetidine-1-carboxylate (1.04 g, 5.78 mmol, 3 eq) and Cs 2 CO 3 (753 mg, 2.31 mmol, 1.2 eq) in CH 3 CN (20 mL) was degassed
  • Reagent Step-1 Solvent Step-1 Temp. Step-1 Reagent Step-2 Compound CH 3 CN RT BBr 3 Cpd020 CH3CN 90°C BBr3 Cpd079 CH 3 CN 60°C BBr 3 Cpd080 CH3CN 60°C BBr3 Cpd097 CH3CN 60°C BBr3 Cpd101 CH3CN 90°C BCl3 Cpd102 CH3CN 60°C BCl3 Cpd103 CH 3 CN 60°C BCl 3 Cpd104 CH 3 CN 90°C BCl 3 Cpd118 CH3CN 90°C BCl3 Cpd119 CH3CN 90°C BCl3 Cpd140 CH3CN 85°C BCl3 Cpd148 CH3CN 65°C BCl3 Cpd161
  • Example 4 Synthesis of 5-(3-((1-acetylazetidin-3-yl)ethynyl)-2-fluoro-6-hydroxyphenyl)-1,2,5
  • Example 5 Synthesis of 5-(2-fluoro-6-hydroxy-3-(pyrrolidin-3-ylethynyl)phenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide (Cpd022) - - one 1,1-dioxide (1 g, 2.41 mmol), tert-butyl 3-ethynylpyrrolidine-1-carboxylate (1.4 g, 7.23 mmol, 1 eq) in triethylamine (5 mL) and DMSO (5 mL) was degassed for 10 min with Ar.
  • Example 6 Synthesis of 5-(3-(cyclohexylethynyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin- 3-one 1,1-dioxide (Cpd023)
  • Step-1 A stirred solution of 5-(6-(benzyloxy)-3-bromo-2-fluorophenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (300 mg, 0.72 mmol), ethynylcyclohexane (313 mg, 2.89 mmol, 4 eq) and triethylamine (3.02 mL, 21.68 mmol, 30 eq) in DMF (6 mL) was degassed for 20 min with Ar.
  • Step-2 To a stirred solution of tert-butyl 4-((4-(benzyloxy)-3-(1,1-dioxido-4-oxo-1,2,5- thiadiazolidin-2-yl)-2-fluorophenyl)ethynyl)piperidine-1-carboxylate (85 mg, 0.194 mmol, 1 eq) in DCM (1 mL) at -78°C was added 1,2,3,4,5-pentamethylbenzene (86 mg, 0.58 mmol, 3 eq) and BCl3 (0.39 mL, 0.39 mmol, 1M solution in DCM, 2 eq) and the reaction mixture was stirred at - 78°C.
  • Example 8 Synthesis of 5-(3-(but-1-yn-1-yl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3- one 1,1-dioxide (Cpd025) - 3- one (203 mg, 0.49 mmol, 1 eq), CsF (383 mg, 2.44 mmol, 5 eq), Pd(CH3CN)2Cl2 (13 mg, 0.049 mmol, 0.1 eq), Cs2CO3 (193 mg, 0.59 mmol, 1.2 eq), XPhos (35 mg, 0.073 mmol, 0.15 eq) in CH3CN (6.1 mL) and H2O (0.050 mL) was degassed with Ar.1-(trimethylsilyl)-1-butyne (0.35 mL, 2.44 mmol) was then added and the resulting mixture was stirred at RT.
  • Cpd025) 3- one (203 mg, 0.49 mmol
  • reaction mixture was quenched with a 8:2 mixture of DCM/3N ammonia solution in MeOH at -78°C.
  • the reaction mixture was partitioned between water and DCM and the pH of the aq. layer was adjusted to 2 by addition of a 1M solution of NaHSO 4 .
  • the organic phase was separated and the aqueous layer was reextracted 3 times with EtOAc.
  • Combined organic layers were concentrated and the residue was purified by column chromatography on silica gel eluting with MeOH in DCM (2-16%). Obtained compound was further purified by Prep-HPLC (Column: XBridge C18 (19*100 mm, 5 ⁇ m).
  • reaction mixture was quenched with a 8:2 mixture of DCM/3N ammonia solution in MeOH at -78°C.
  • the reaction mixture was partitioned between water and DCM and the pH of the aq. layer was adjusted to 2 by addition of a 1M solution of NaHSO4.
  • the organic phase was separated and the aqueous layer was reextracted 3 times with EtOAc.
  • Combined organic layers were concentrated and the residue was purified by column chromatography on silica gel eluting with a gradient of MeOH in DCM (2-16%) to afford a mixture of the 2 title compounds.
  • This mixture was further purified by Prep-HPLC (Column: XBridge C18 (19*100 mm, 5 ⁇ m).
  • Mobile phase A 25 mM NH4HCO3 in H2O; Mobile phase B: CH3CN:MeOH (50:50).
  • Flow 20 mL/min.
  • Step-2 A stirred solution of 5-(6-(benzyloxy)-2-fluoro-3-((1-(methylsulfonyl) azetidin-3-yl) ethynyl) phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (300 mg, 0.60 mmol, 1.0 eq) in DCM (10 mL), cooled to -78°C, was treated dropwise with a BBr3 solution (1M in DCM, 3.64 mL, 3.64 mmol, 6 eq). The resulting reaction mixture was then allowed to warm to RT and stirred at RT.
  • Example 11 Synthesis of 5-(2-fluoro-6-hydroxy-3-((3-methoxyphenyl)ethynyl)phenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide (Cpd029) 3- one 1,1-dioxide (3 g, 7.23 mmol, 1 eq) in DCM (50 mL) was added BBr 3 (1M in DCM, 21.7 mL, 21.7 mmol, 3 eq) dropwise at -78°C and the resulting reaction mixture was stirred at -78°C.
  • reaction mixture was quenched with a 7M NH3 solution in MeOH at -78°C and then concentrated under reduced pressure.
  • the residue was purified by reverse phase column chromatography eluting with a gradient of CH3CN in H2O (10- 20%) to yield 2.2 g of 5-(2-fluoro-6-hydroxy-3-(4-methylpent-1-yn-1-yl)phenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide as an off-white solid.
  • Step-2 A stirred solution of 5-(3-bromo-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1- dioxide (250 mg, 0.77 mmol, 1.0 eq), 1-ethynyl-3-methoxybenzene (305 mg, 2.31 mmol, 3.0 eq) and Cs2CO3 (300 mg, 0.92 mmol, 1.2 eq) in CH3CN (10 mL) was degassed with Ar for 10 min.
  • Reagent Step-2 Solvent Step-2 Temp. Step-2 Compound CH3CN 60°C Cpd030 CH 3 CN 60°C Cpd031 CH 3 CN 60°C Cpd032 DMA 80°C Cpd033 CH 3 CN 60°C Cpd034 CH 3 CN 60°C Cpd049 CH 3 CN 60°C Cpd050 CH3CN 90°C Cpd052 CH3CN 60°C Cpd058 CH 3 CN 60°C Cpd060-IntA O CH3CN 60°C Cpd062 CH3CN 60°C Cpd072 CH3CN 90°C Cpd083 CH 3 CN 50°C Cpd105 Cpd060 can be obtained from Cpd060-IntA following the below procedure : A stirred solution of Cpd060-IntA (225 mg, 0.389 m
  • Example 12 Synthesis of 5-(2-fluoro-6-hydroxy-3-(prop-1-yn-1-yl)phenyl)-1,2,5-thiadiazolidin-3- one 1,1-dioxide
  • Step-1 A - - one 1,1-dioxide (800 mg, 1.83 mmol, 1 eq) and tributyl(1-ethoxyvinyl)stannane (1.30 mL, 3.85 mmol, 2 eq) in 1,4-dioxane (10 mL) was degassed with Ar for 10 min.
  • Pd(PPh3)4 (223 mg, 0.193 mmol, 0.1 eq) was added at RT and the resulting reaction mixture was then stirred at 90°C.
  • reaction mixture was treated with 4M HCl in dioxane (4 mL) at 0°C and then stirred at RT for 2 h.
  • the reaction mixture was filtered through a celite bed and the filtrate was concentrated under reduced pressure.
  • the residue was purified by reverse phase column eluting with a gradient of CH 3 CN in H 2 O (30-36%) to yield 450 mg of 5-(3- acetyl-6-(benzyloxy)-2-fluorophenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide as an off-white solid.
  • reaction mixture was stirred at the same temperature for 10 min and then treated dropwise with a solution of 5-(3-acetyl-6-(benzyloxy)-2-fluorophenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (200 mg, 0.529 mol, 1 eq) in THF (5 mL).
  • THF trifluorofuran
  • the resulting reaction mixture was then allowed to stir at RT. After completion of the reaction (TLC monitoring), the reaction mixture was quenched with ice water (2 mL) and concentrated under reduced pressure.
  • Step-2 To a stirred suspension of ethyl 2-(6-benzyloxy-3-bromo-2-fluoro-4-iodo-anilino)acetate (670 mg, 1.32 mmol, 1 eq) , methylboronic acid (488 mg, 7.91 mmol, 6 eq) and K 2 CO 3 (364 mg, 2.64 mmol, 2 eq) in a previously degassed 5:1 mixture of monoglyme (13.2 mL) and H 2 O (2.7 mL) was added (under Ar atmosphere) PdCl 2 (PPh 3 ) 2 (94 mg, 0.13 mmol, 0.1 eq) and the resulting mixture was heated up to 70°C.
  • Step-3 A stirred solution of 2-methylpropan-2-ol (0.790 mL, 8.33 mmol, 10 eq) in dry DCM (8.3 mL) was slowly treated at 0°C and under an Ar atmosphere with chlorosulfonyl isocyanate (0.740 mL, 8.33 mmol, 10 eq) and the resulting mixture was left under stirring for 30min at 0°C.
  • Step-6 Compound CH 3 CN 90°C Cpd063
  • Example 14 Synthesis of (E)-5-(2-fluoro-6-hydroxy-3-(pyrrolidin-3-ylidenemethyl)phenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide (Cpd037) and (Z)-5-(2-fluoro-6-hydroxy-3-(pyrrolidin-3- ylidenemethyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide - -1,2,5-thiadiazolidin-3-one 1,1-dioxide (400 mg, 0.963 mmol, 1 eq), tert-butyl-3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)methylene)pyrrolidine-1-carboxylate ((E-Z) mixture, 447 mg, 1.45 mmol, 2.4 eq) and K 3 PO 4 (6
  • Step-2 A stirred solution of a E/Z mixture of tert-butyl-3-(4-(benzyloxy)-3-(1,1-dioxido-4-oxo- 1,2,5-thiadiazolidin-2-yl)-2-fluorobenzylidene) pyrrolidine-1-carboxylate from step-1 (400 mg, 0.77 mmol, 1 eq) in DCM (20 mL) was treated with BBr3 (1M in DCM, 2.32 mL, 2.33 mmol, 3 eq) dropwise at 0°C.
  • Step-1 Catalyst/Base/Solvent/Temp.
  • Step-1 Compound Pd(dppf)Cl2/K3PO4/dioxane-H2O/90°C Cpd039 Pd(dtbpf)Cl2/K3PO4/dioxane-H2O/90°C Cpd095, Cpd096 (E/Z mixture) Pd(dtbpf)Cl2/K3PO4/dioxane-H2O/80°C Cpd112
  • Example 15 Synthesis of (E)-5-(2-fluoro-3-(3-fluorostyryl)-6-hydroxyphenyl)-1,2,5-thiadiazolidin- 3-one dioxide a a - mg, eq), 5-(6-benzyloxy-3-bromo-2-fluoro-phenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (220 mg, 0.53 m
  • Step-1 Purification method Compound Supported PS-Pd-PPh 3 /K 2 CO 3 /DME- silica gel column Cpd041 H2O/140°C ( ⁇ W) chromatography Supported PS-Pd-PPh 3 /K 2 CO 3 /DME- silica gel column Cpd042 H2O/140°C ( ⁇ W) chromatography Supported PS-Pd-PPh3/K2CO3/DME- Prep-HPLC Cpd043 H2O/140°C ( ⁇ W) Pd(dtbpf)Cl2/Cs2CO3/dioxane-H2O/90°C Prep-HPLC Cpd044
  • Example 16 Synthesis of (E)-5-(2-fluoro-6-hydroxy-3-styrylphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Cpd045).
  • Step 2 To a stirred solution of (E)-5-(6-(benzyloxy)-2-fluoro-3-styrylphenyl)-1,2,5-thiadiazolidin- 3-one 1,1-dioxide (100 mg, 0.228 mmol, 1 eq) in DCM (2 mL) at -78°C was added 1,2,3,4,5- pentamethylbenzene (101 mg, 0.684 mmol, 3 eq) and BCl 3 (1M solution in DCM , 0.5 mL, 0.456 mmol, 2 eq). After completion of the reaction (TLC monitoring), the reaction mixture quenched with water and volatiles were evaporated.
  • Step-2 To a stirred solution of tert-butyl 4-(4-(benzyloxy)-3-(1,1-dioxido-4-oxo-1,2,5- thiadiazolidin-2-yl)-2-fluorobenzylidene)piperidine-1-carboxylate (200 mg, 0.376 mmol, 1 eq) in DCM (5 mL), cooled to -78°C, was added 1,2,3,4,5-pentamethylbenzene (167 mg, 1.13 mmol, 3 eq) and BCl3 (1 M solution in
  • Step 1 A stirred solution of 5-(6-(benzyloxy)-3-bromo-2-fluorophenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (300 mg, 0.72 mmol, 1 eq), 2-(cyclopentylidenemethyl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (301 mg, 1.45 mmol, 2 eq) and K3PO4 (461 mg, 2.17 mmol, 3.0 eq) in a mix of 1,4- dioxane (10 mL) and water (4 mL) was degassed with Ar for 15 min.
  • Step 2 To a stirred solution of 5-(6-(benzyloxy)-3-(cyclopentylidenemethyl)-2-fluorophenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide (170 mg, 0.4 mmol, 1 eq) in a mixture of MeOH (5 mL) and EtOAc (5 mL) was added 10% Pd/C (125 mg) at RT, under inert atmosphere. The resulting reaction mixture was stirred under 1 atm of H2 (balloon). After completion of the reaction (TLC monitoring), the reaction mixture was filtered through Whatman filter paper and concentrated under reduced pressure.
  • Step-3 A stirred solution of 5-(6-(benzyloxy)-2-fluoro-3-((1-propylpiperidin-4- ylidene)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (275 mg, 0.74 mmol, 1 eq) in DCM (15 mL) was treated with BBr3 (1M in DCM, 1.47 mL, 1.47 mmol, 3 eq) dropwise at 0°C. After completion of the reaction (TLC monitoring), the reaction mixture was quenched with a 7M NH3 solution in MeOH and volatiles were evaporated.
  • Example 20 Synthesis of 5-(2-fluoro-6-hydroxy-3-(pyrazin-2-ylethynyl)phenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide (Cpd067) - - one 1,1-dioxide (500 mg, 1.20 mmol, 1 eq), Cs2CO3 (470 mg, 1.45 mmol, 1.2 eq) in CH3CN (20 mL) was degassed for 10 min with Ar.
  • reaction mixture was again degassed for 10 min with Ar and then treated with Pd(CH3CN)2Cl2 (30 mg, 0.116 mmol, 0.1 eq) followed by XPhos (110 mg, 0.23 mmol, 0.2 eq). The resulting reaction mixture was then stirred at 60 °C in a sealed tube.
  • Step-2 To a stirred solution of 5-(6-(benzyloxy)-2-fluoro-3-(pyridazin-4-ylethynyl) phenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide (300 mg, 1.02 mmol, 1.0 eq) in DCM (10 mL) was added BBr3 (1M in DCM, 6.15 mL, 6.15 mmol, 6.0 eq) dropwise at -78°C and the resulting solution was then stirred at the same temperature.
  • Example 22 Synthesis of 5-(3-(((1R,5S,6S)-3-(ethylsulfonyl)-3-azabicyclo[3.1.0]hexan-6- yl)ethynyl)-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Cpd086) - - one 1,1-dioxide (400 mg, 0.96 mmol, 1 eq), tert-butyl (1S,5R,6S)-6-ethynyl-3-azabicyclo [3.1.0]hexane-3-carboxylate (598 mg, 2.89 mmol, 3 eq) and Cs2CO3 (380 mg, 1.16 mmol, 1.2 eq) in CH3CN (10 mL) was degassed for 20 min with N2.
  • Step-2 A stirred mixture of tert-butyl (1S,5R,6S)-6-[2-[4-benzyloxy-2-fluoro-3-(1,1,4-trioxo-1,2,5- thiadiazolidin-2-yl)phenyl]ethynyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (500 mg, 0.92 mmol) in DCM (6.2 mL) was treated dropwise at 0°C with a 4N HCl solution in dioxane (1.4 mL, 5.54 mmol, 6 eq) and the resulting mixture was then stirred at RT.
  • Step-3 A stirred mixture of 5-[3-[2-[(1S,5R,6S)-3-azabicyclo[3.1.0]hexan-6-yl]ethynyl]-6- benzyloxy-2-fluoro-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (240 mg, 0.54 mmol, 1 eq) and Et3N (0.23 mL, 1.63 mmol, 3 eq) in DCE (5 mL) was cooled down to 0°C and then treated dropwise under inert atmosphere with ethanesulfonyl chloride (0.158 mL, 1.63 mmol, 3 eq) and allowed to stir at RT.
  • reaction mixture was quenched with ice and diluted with DCM.
  • aqueous layer was back extracted again twice with DCM.
  • the combined organic layers were washed with a 1N NaHSO4 aq. solution, then with brine, dried over MgSO4 and concentrated.
  • the final debenzylation can be performed by any suitable reagent known to the skilled in the art (e.g. BBr3 (neat or as solution in an appropriate solvent), BCl3, ).
  • BBr3 nitrogen trioxide
  • BCl3 benzyl reagent
  • the reagents are commercially available or synthesized as described in the section “Examples of intermediates and their preparation”.
  • reaction mixture was stirred at 0 °C for 30 minutes and was then concentrated under reduced pressure.
  • the residue was dissolved in EtOH (6 mL), treated with a 2M solution of dimethylamine in THF (4.0 mL, 8.0 mmol, 20 eq) and the mixture was then stirred at RT. After completion of the reaction (LC-MS monitoring), the reaction mixture was concentrated under reduced pressure.
  • Example 25 Synthesis of (1R,5S,6S)-6-((3-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-2-fluoro- 4-hydroxyphenyl)ethynyl)-3-azabicyclo[3.1.0]hexane-3-sulfonamide (Cpd093) was cooled down to 0°C before being treated dropwise with chlorosulfonyl isocyanate (0.145 mL, 1.63 mmol).
  • Example 26 Synthesis of 5-(2-fluoro-6-hydroxy-3-(((1R,5S,6S)-3-methyl-3- azabicyclo[3.1.0]hexan-6-yl)ethynyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Cpd122) - -6- benzyloxy-2-fluoro-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (67 mg, 0.15 mmol) and 37% aq.
  • Formaldehyde 0.094 mL, 1.25 mmol, 8 eq
  • dry MeOH 1.7 mL
  • Example 27 Synthesis of 5-(2-fluoro-6-hydroxy-3-(prop-1-yn-1-yl-d3)phenyl)-1,2,5-thiadiazolidin- 3-one 1,1-dioxide
  • Step-1 To a stirred solution of ethynyltriisopropylsilane (4.0 g, 21.9 mmol, 1.0 eq) in THF (50 mL), under argon atmosphere, was added n-BuLi (2.5M in hexane, 10.53 mL, 26.32 mmol, 1.2 eq) dropwise at -78°C.
  • Step-2 A stirred solution of 5-(6-(benzyloxy)-3-bromo-2-fluorophenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (400 mg, 0.963 mmol, 1.0 eq), Cs 2 CO 3 (470.8 mg, 1.45 mmol, 1.5 eq) and CsF (439 mg, 2.89 mmol, 3.0 eq) in CH3CN (15 mL) was degassed for 10 min with Ar.
  • Step-3 5-(6-(benzyloxy)-2-fluoro-3-(prop-1-yn-1-yl-d3)phenyl)-1,2,5-thiadiazolidin-3-one 1,1- dioxide was then treated with BBr3 according to procedure described in step 2 of Example 1 (phenol deprotection) to yield 5-(2-fluoro-6-hydroxy-3-(prop-1-yn-1-yl-d3)phenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide (Cpd094).
  • Example 28 Synthesis of 5-(3-((1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)ethynyl)-2-fluoro-6- hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Cpd113).
  • Step-2 1.5 g of tert-butyl –(4-(4-(benzyloxy)-3-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-2- fluorophenyl)-2-methylbut-3-yn-1-yl) carbamate were further subjected to chiral SFC purification (Preparative SFC Conditions: Column: Lux Cellulose-4 (30*250 mm, 5 ⁇ m). CO2: 60% - Cosolvent: 40% (0.5% Methanolic ammonia in Methanol). Total Flow: 100 g/min. Back-pressure: 100 bar. Temperature: 30 °C. Wavelength detection: 215 nm.
  • Step-3a Deprotection of 600 mg of Cpd080-en1-IntA according to procedure described in step 2 of Example 3 above afforded 64 mg of final compound Cpd080-en1.
  • Step-3b Deprotection of 700 mg of Cpd080-en2-IntA according to procedure described in step 2 of Example 3 above yielded 80 mg of final compound Cpd080-en2.
  • LC-MS (LC-A): r.t. 1.11 min (99.7%); m/z 328 [M+H] + .
  • Step-1 Compounds PdCl2(CH3CN)2/XPhos/ Cs2CO3/CH3CN/60°C Cpd124-en1 and Cpd124-en2 PdCl2(CH3CN)2/XPhos/ Cs2CO3/CH3CN/RT Cpd125-en1 and Cpd125-en2 PdCl 2 (CH 3 CN) 2 /XPhos/ Cs 2 CO 3 /CH 3 CN/60°C Cpd126-en1 and Cpd126-en2 PdCl2(CH3CN)2/XPhos/ Cs2CO3/CH3CN/60°C Cpd142-en1 and Cpd142-en2 Pd(dtbpf)Cl2/K3PO4/ dioxane-H2O/90°C Cpd149-en1 and Cpd149-en2
  • Example 30 Synthesis of rel-5-(3-(((1R,2R)-2-(
  • reaction mixture was partitioned between EtOAc and water and the aqueous layer was acidified to a pH value of 2 (via addition of a 1M NaHSO4 aq. solution). After separation, the aqueous layer was extracted twice with EtOAc, combined organic extracts were dried over MgSO4 and concentrated.
  • Step-2 A solution of rel-tert-butyl (((1R,2R)-2-((3-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-2- fluoro-4-hydroxyphenyl)ethynyl)cyclopropyl) methyl) carbamate Cpd 128-IntA (63 mg, 0.14 mmol) in DCM (5 mL), cooled at 0°C, was treated with a 4N HCl solution in dioxane (4 mL, 16 mmol). The reaction mixture was then stirred at RT for 2 h and then concentrated.
  • Step-1 A stirred solution of rel-tert-butyl (((1R,2R)-2-((4-(benzyloxy)-3-(1,1-dioxido-4-oxo-1,2,5- thiadiazolidin-2-yl)-2-fluorophenyl)ethynyl)cyclopropyl)methyl) carbamate Cpd129-IntA (95 mg, 0.18 mmol) in DCM (7 mL), cooled at 0°C, was treated with a 4N HCl solution in dioxane (4 mL, 16 mmol). The reaction mixture was stirred at RT for 1 h and concentrated.
  • rel-tert-butyl (((1R,2R)-2-((4-(benzyloxy)-3-(1,1-dioxido-4-oxo-1,2,5- thiadiazolidin-2-yl)-2-fluorophenyl)ethynyl)cyclopropyl
  • reaction mixture was quenched by addition of a 7N solution of NH3 in MeOH.
  • the reaction mixture was partitioned between DCM and water and the aqueous layer was acidified to a pH value of 2 (via addition of a 1M NaHSO4 aq. solution). After separation, the aqueous layer was extracted twice with EtOAc, combined organic extracts were dried over MgSO4 and concentrated.
  • Example 32 Synthesis of (R,Z)-5-(2-fluoro-6-hydroxy-3-((5-methylpyrrolidin-3- ylidene)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Cpd130) and (R,E)-5-(2-fluoro-6- hydroxy-3-((5-methylpyrrolidin-3-ylidene)methyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide .
  • Step-1 A stirred solution of 5-(3-bromo-2-fluoro-6-hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1- dioxide (0.40 g, 1.23 mmol, 1.0 eq), tert-butyl (R)-2-methyl-4-((4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)methylene)pyrrolidine-1-carboxylate (as a E/Z mixture, 0.60 g, 1.85 mmol, 1.5 eq) and K 3 PO 4 (0.78 g, 3.69 mmol, 3.0 eq) in a 9:1 dioxane:water mix (20 mL) was degassed with Ar for 10 min.
  • Step-2 A stirred solution of tert-butyl (R)-4-(3-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-2- fluoro-4-hydroxybenzylidene)-2-methylpyrrolidine-1-carboxylate (as a E/Z mixture) (150 mg, 0.34 mmol, 1.0 eq) in DCM (10 mL) was treated with a 4N HCl solution in dioxane (0.85 mL, 3.40 mmol, 10 eq) at 0°C and the resulting reaction mixture was then allowed to stir at RT.
  • Step-1 A stirred solution of 5-(6-(benzyloxy)-3-bromo-2-fluorophenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (500 mg, 1.20 mmol, 1.0 eq), tert-butyl (S)-pent-4-yn-2-ylcarbamate (662 mg, 3.61 mmol, 3.0 eq) and Cs2CO3 (0.785 g, 2.41 mmol, 2.0 eq) in CH3CN (10 mL) was degassed with Ar for 10 min.
  • Step-2 A stirred solution of tert-butyl (S)-(5-(3-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-2- fluoro-4-hydroxyphenyl)pent-4-yn-2-yl)carbamate (250 mg, 0.585 mmol, 1.0 eq) in dioxane (10 mL) was treated dropwise with a 4N HCl solution in dioxane (5.00 mL, 10.0 mmol, 17.1 eq) at 0 °C and the resulting reaction mixture was stirred at RT.
  • Step-1 A stirred suspension of 5-(6-benzyloxy-3-bromo-2-fluoro-phenyl)-1,1-dioxo-1,2,5- thiadiazolidin-3-one (340 mg, 0.82 mmol, 1 eq), tert-butyl 2-ethynyl-6-azaspiro[2.5]octane-6- carboxylate (231 mg, 0.98 mmol, 1.2 eq), PdCl2(MeCN)2 (21 mg, 0.082 mmol, 0.1 eq), Cs2CO3 (404 mg, 1.23 mmol, 1.5 eq) and Xphos (59 mg, 0.12 mmol, 0.15 eq) in CH3CN (10 mL) was degassed and put under an Ar atmosphere and then stirred at 90 °C.
  • reaction mixture was cooled to room temperature, quenched with water (pH adjusted to 2 by addition of a 1M aq. NaHSO4 solution). The reaction mixture was then extracted three times with EtOAc. Combined organic extracts were dried over MgSO4, filtered and concentrated.
  • Step-2 A stirred solution of tert-butyl 2-[2-[4-benzyloxy-2-fluoro-3-(1,1,4-trioxo-1,2,5- thiadiazolidin-2-yl)phenyl]ethynyl]-6-azaspiro[2.5]octane-6-carboxylate (250 mg, 0.36 mmol, 1 eq) in DCM, cooled to 0 °C, was treated with 2,2,2-trifluoroacetic acid (6.0 mL, 78.4 mmol, 218 eq) and the reaction mixture was stirred at 0°C.
  • reaction mixture was concentrated under reduced pressure. The residue was redissolved in dry DCM (6 mL), the solution was cooled to -78°C, treated with BBr 3 (0.291 mL, 3.03 mmol, 20 eq) and then stirred at -78°C. After completion of the reaction (TLC monitoring), the reaction mixture was quenched by addition of 30 mL of a 8:2 mix of DCM and a 7N solution of NH 3 in MeOH. Ice cold water was added to the reaction mixture and the pH of the mixture was adjusted to 2 by addition of a 1M aq. NaHSO 4 solution. After separation, the aqueous layer was extracted three times with EtOAc and the combined organic extracts were concentrated.
  • Step-4 A mixture of 5-[3-[2-(6-azaspiro[2.5]octan-2-yl)ethynyl]-6-benzyloxy-2-fluoro-phenyl]-1,1- dioxo-1,2,5-thiadiazolidin-3-one (60 mg, 0.13 mmol, 1 eq) and Et3N (0.036 mL, 0.26 mmol, 2 eq) in DCE (3 mL) was sonicated for 15 min and then cooled to 0 °C. To this cooled mixture was added mesyl chloride (0.020 mL, 0.26 mmol, 2 eq).
  • reaction mixture was stirred at 0°C for 25 minutes and an excess of mesyl chloride (0.020 uL, 0.26 mmol, 2 eq) and Et3N (0.036 mL, 0.26 mmol, 2 eq) was added. After completion of the reaction (TLC monitoring), the reaction mixture was diluted with DCM and washed with a sat. aq. NaHCO3 solution of NaHCO3.
  • Step-5 To a stirred solution of 5-[6-benzyloxy-2-fluoro-3-[2-(6-methylsulfonyl-6- azaspiro[2.5]octan-2-yl)ethynyl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (51 mg, 0.088 mmol, 1 eq) in DCM (3 mL), cooled to -78°C, was added BBr3 (0.027 uL, 0.29 mmol, 3.25 eq). The reaction mixture was stirred at -78°C.
  • reaction mixture was quenched by addition of 15 mL of a 8:2 mixture of DCM and a 3N solution of NH 3 in MeOH. Ice cold water was added to the reaction mixture and the pH of the mixture was adjusted to 2 by addition of a 1M aq. NaHSO 4 solution. After separation, the aqueous layer was extracted three times with EtOAc. Combined organic extracts were concentrated under reduced pressure.
  • Example 36 Synthesis of (Z)-5-(2-fluoro-6-hydroxy-4-methyl-3-(pyrrolidin-3- ylidenemethyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Cpd162) and (E)-5-(2-fluoro-6- hydroxy-4-methyl-3-(pyrrolidin-3-ylidenemethyl)phenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Cpd163).
  • Step-1 A stirred solution of 5-(6-(benzyloxy)-3-bromo-2-fluoro-4-methylphenyl)-1,2,5- thiadiazolidin-3-one 1,1-dioxide (3.5 g, 8.154 mmol, 1.0 eq) in DCM (40 mL), at -78°C, was treated dropwise with a 1M solution of BBr 3 in DCM (40.77 mL, 40.77 mmol, 5 eq). After completion of the reaction, the reaction mixture was quenched with a 7N NH 3 solution in MeOH (40 mL) at - 78°C and stirred for 30 min.
  • Step-2 A stirred solution of 5-(3-bromo-2-fluoro-6-hydroxy-4-methylphenyl)-1,2,5-thiadiazolidin- 3-one 1,1-dioxide (0.50 g, 1.475 mmol, 1.0 eq), tert-butyl-3-((4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)methylene)pyrrolidine-1-carboxylate (as an E/Z mixture, 0.684 g, 2.21 mmol, 1.5 eq) and K 3 PO 4 (0.939 g, 4.425 mmol, 3.0 eq) in a mix of dioxane (60 mL) and water (10 mL) was degassed with Ar for 15 min.
  • Step-3 A stirred solution of tert-butyl -3-(3-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-2-fluoro- 4-hydroxy-6-methylbenzylidene)pyrrolidine-1-carboxylate (as an E/Z mixture, 450 mg, 1.019 mmol, 1.0 eq) in dioxane (10 mL) was treated with a 4N HCl solution in dioxane (1.274 mL, 5.097 mmol, 5.0 eq) at 0°C and the resulting reaction mixture was then stirred at RT.
  • Example 38 Synthesis of (Z)-5-(3-((1-ethylpyrrolidin-3-ylidene)methyl)-2-fluoro-6- hydroxyphenyl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Cpd167).
  • Example 39 Synthesis of 5-[3-(4-aminopent-4-en-1-ynyl)-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo- 1,2,5-thiadiazolidin-3-one (Cpd138) Step-1: A - (1.50 g, 12.08 mmol, 1 eq) and LiOH monohydrate (1.55 g, 36.25 mmol, 3 eq) in MeOH (50 mL) was stirred at RT. After completion of the reaction (TLC monitoring), the crude reaction mixture was quenched with crushed ice and the pH was adjusted to an acidic value by adding a 1N aq. NaHSO4 solution.
  • Step-2 A stirred mixture of rel-(1R,2R)-2-ethynylcyclopropanecarboxylic acid (800 mg, 7.27 mmol, 1 eq) and Et3N (1.1 mL, 7.63 mmol, 1.05 eq) in tBuOH (7 mL) was treated with diphenyl phosphoryl azide (1.8 mL, 7.99 mmol, 1.1 eq) and the resulting mixture was heated at 65°C. After completion of the reaction (TLC monitoring), the crude reaction mixture was diluted with iced water. The pH was adjusted to ⁇ 7 by adding a 1N NaHSO4 aq. solution and the resulting aqueous layer was extracted several times with Et 2 O.
  • Step-3 To a stirred mixture of rel-tert-butyl N-[(1R,2S)-2-ethynylcyclopropyl]carbamate (655 mg, 3.61 mmol, 3 eq), XPhos (57 mg, 0.12 mmol, 0.1 eq) and PdCl2(MeCN)2 (16 mg, 0.060 mmol, 0.05 eq) in carefully degassed dry CH3CN (72.2 mL) were added under inert atmosphere Cs2CO3 (1.18 g, 3.61 mmol, 3 eq) and 5-(6-benzyloxy-3-bromo-2-fluoro-phenyl)-1,1-dioxo-1,2,5- thiadiazolidin-3-one (Int-01, 0.50 g, 1.20 mmol, 1 eq) and the resulting mixture was then stirred at 65oC.
  • reaction mixture was diluted with EtOAc and filtered through a pad of Celite. Filtering cake was rinsed twice with EtOAc and combined filtrates were partitioned with water. The pH was adjusted to an acidic value adding an aq.1N NaHSO4 solution. The aqueous layer was extracted twice with EtOAc. Combined organic extracts were washed with brine, dried over MgSO 4 and concentrated.
  • Residue was purified by column chromatography over silica gel eluting with a gradient of MeOH (0-10%) in EtOAc to give 335 mg of rel-tert-butyl ((1S,2R)-2-((4-(benzyloxy)-3-(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)- 2-fluorophenyl)ethynyl)cyclopropyl)carbamate.
  • Residue was purified by reverse-phase column chromatography over C18 modified silica gel using a stepwise gradient of MeCN (0-40%) in H 2 O to give 53 mg of 5-[3-(4-aminopent-4-en-1-ynyl)-2-fluoro-6-hydroxy-phenyl]-1,1-dioxo-1,2,5- thiadiazolidin-3-one as a thin white powder.
  • Compound activity was determined using a GST-tagged PTPN2 protein (TC45, accession # NP_002819.2) (Active motif, Cat# 31592) in an in vitro enzymatic reaction.
  • the enzymatic assay used to determine potency was the phosphatase (PTP) activity inhibition assay.
  • the assay is performed using a buffer comprising 50mM HEPES pH7.5, 2mM EDTA, 3mM DTT and 100mM NaCl and as phosphated substrate 10 ⁇ M 6,8-Difluoro-4-Methylumbelliferyl Phosphate (DiFMUP) (ThermoFisher, Cat# D6567) was used.
  • the assay is carried out at room temperature in 384-well plate.
  • the compounds were dispensed on a white 384-well plate at varying concentrations (10 point, 1: 5 dilution).
  • PTPN2 enzyme was added at final concentration of 4 nM and incubated with compound for 10 minutes at room temperature.
  • the reaction is initiated by adding the substrate (DIFMUP) mix to each well of reaction plate to the final concentration of 10 ⁇ M , followed by incubation at room temperature for 30 minutes.
  • a quench solution was added to the reaction plates and the phosphatase activity of the PTPN2 enzyme is assessed by monitoring the appearance of the fluorescent product 6,8-difluoro-7-hydroxyl-4-coumarin (DiFMU) from DiFMUP using the EnVision® multimode plate reader (PerkinElmer, Cat# 2105-0010) with excitation of 360 nm and emission at 450 nm for DiFMU.
  • the % of DIFMU conversion (the amount of phosphorylated substrate which was de-phosphorylated by PTPN2) was plotted against the concentration of the small molecule PTPN2 inhibitor, and the data were fitted using a four-parameter equation.
  • Each plate had a positive control (no PTPN2 enzyme) and a negative control (DMSO + PTPN2 enzyme), which were used to calculate % of inhibition. The % inhibition was then used to determine the IC50 values of the compounds disclosed here for the specific PTPN2 enzyme.
  • Phosphatase activity assay to determine potency against PTPN1. Compound activity was determined using a GST-tagged PTPN1 protein (PTP1B, accession # NP_002818.1) (Active motif, Cat# 81034) in an in vitro enzymatic reaction. The enzymatic assay used to determine potency was the phosphatase (PTP) activity inhibition assay.
  • the assay is performed using a buffer comprising 50mM HEPES pH7.5, 2mM EDTA, 3mM DTT and 100mM NaCl and as phosphated substrate 10 ⁇ M 6,8-Difluoro-4-Methylumbelliferyl Phosphate (DiFMUP) (ThermoFisher, Cat# D6567) was used.
  • the assay is carried out at room temperature in 384-well plate.
  • the compounds were dispensed on a white 384-well plate at varying concentrations (10 point, 1: 5 dilution).
  • PTPN1 enzyme was added at final concentration of 2 nM and incubated with compound for 10 minutes at room temperature.
  • the reaction is initiated by adding the substrate (DIFMUP) mix to each well of reaction plate to the final concentration of 10 ⁇ M, followed by incubation at room temperature for 30 minutes. Finally, a quench solution was added to the reaction plates and the phosphatase activity of the PTPN1 enzyme is assessed by monitoring the appearance of the fluorescent product 6,8-difluoro-7-hydroxyl-4-coumarin (DiFMU) from DiFMUP using the EnVision® multimode plate reader (PerkinElmer, Cat# 2105-0010) with excitation of 360 nm and emission at 450 nm for DiFMU.
  • DiFMU fluorescent product 6,8-difluoro-7-hydroxyl-4-coumarin
  • the % of DIFMU conversion (the amount of phosphorylated substrate which was de-phosphorylated by PTPN2) was plotted against the concentration of the small molecule PTPN1 inhibitor, and the data were fitted using a four-parameter equation. Each plate had a positive control (no PTPN1 enzyme) and a negative control (DMSO + PTPN1 enzyme), which were used to calculate % of inhibition. The % inhibition was then used to determine the IC 50 values of the compounds disclosed here for the specific PTPN1 enzyme. Activities of example compounds of the invention in the PTPN2 and PTPN1 inhibition assays are depicted in the table below. Table 4: PTPN2 and PTPN1 inhibitory activity of compounds of the invention.
  • A represents IC 50 ⁇ 20 nM
  • B represents an IC 50 of 20nM ⁇ IC 50 ⁇ 100 nM
  • C represents IC 50 100nM ⁇ IC 50 ⁇ 1 ⁇ M.
  • PTPN2 PTPN1 IC50 Compounds IC50 Compounds value value Cpd001, Cpd003, Cpd004, Cpd006, Cpd008, Cpd009, Cpd010, Cpd012, Cpd014, Cpd015, Cpd016, Cpd017, Cpd018, Cpd021, Cpd028, Cpd001, Cpd003, Cpd004, Cpd006, Cpd008, Cpd029, Cpd033, Cpd034, Cpd036, Cpd040, Cpd033, Cpd034, Cpd036, Cpd040, Cpd053, Cpd041, Cpd045, Cpd051, C
  • melanoma and colorectal cancer It plays a crucial role in regulating anti-tumor immune responses and it has been shown to have anti-proliferative and anti-tumor effects in various cancer types, including melanoma and colorectal cancer.
  • tumor growth is promoted when IFN ⁇ signaling is impaired, whereas enhancing IFN ⁇ signaling leads to greater inhibition of tumor growth.
  • PTPN2 and PTPN1 act as negative regulators of cytokine signaling, including IFN ⁇ signaling, by dephosphorylating JAK and STAT proteins, the compounds of the invention facilitate tumor growth arrest in the presence of IFN ⁇ .
  • Compounds of the present invention amplify mouse B16F10 melanoma and human T84 colorectal cancer cells growth inhibition in the presence of IFN ⁇ .
  • Mouse B16F10 cells IFN ⁇ -Induced Growth Inhibition Assay B16F10 mouse melanoma cells (ATCC Cat# CRL-6475) were seeded at density of 1500 cells per well in two 96-well white bottom plates (Greiner, Cat# 655083) in 100 ⁇ L total volume of RPMI 1640 + 10% FBS. Cells were allowed to adhere for 3 hours at 37 o C + 5% CO2. Next, compounds resuspended in DMSO at 10 mM were diluted in 1: 3 dilutions in DMSO ranging from 10 mM to 0.0002 mM and DMSO only controls were included.
  • the compound/DMSO dilutions were further diluted 1: 25 in RPMI 1640 + 10% FBS, and 50 ⁇ L of these dilutions were added in duplicates to cells of both plates. Final compound concentration ranged from 100 ⁇ M to 0.002 ⁇ M with a final DMSO concentration of 1%. Compounds were only dosed in the inner 60-wells avoiding the outer 1-well perimeter of the plate to minimize edge effects. Next, 50 ⁇ L of mouse IFN ⁇ (Roche, Cat# 11276905001) was added to the first plate at a concentration of 2 ng/mL for a final assay concentration of 0.5 ng/mL of IFN ⁇ .
  • T84 human colorectal carcinoma cells (ATCC Cat# CCL-248) were seeded in a 96-well format. Before cell seeding, plates were coated with 40ul of 40 ⁇ g/mL rat tail collagen type I (Gibco, Cat# A10483-01) in 20 mM acetic acid and allowed for 1 hour in room temperature for achieving a thin collagen layer. Next, plates were washed 3 times with PBS and T84 cells were seeded at density of 3500 cells per well in two 96-well white bottom plates (Greiner, Cat# 655083) in 100 ⁇ L total volume of DMEM/F12 + 10% FBS.
  • A represents an IC50 ⁇ 10 ⁇ M
  • B represents IC50 of 10 ⁇ M ⁇ IC50 ⁇ 100 ⁇ M
  • C represents IC50 values > 100 ⁇ M.
  • a key target of this signaling is phosphorylation of the transcriptional factor STAT1.
  • STAT1 is also a direct target of PTPN2 and PTPN1 which serve as negative regulators of IFN ⁇ signaling.
  • a PTPN2/N1 inhibitor is expected to increase the phosphorylation of STAT1 upon stimulation with IFN ⁇ .
  • human Jurkat T cells DSMZ, Cat# ACC282 were seeded at a density of 150.000 cells per well in a 96-well U-bottom plate in 25 ⁇ L total volume of RPMI + 1% FCS.
  • Protein tyrosine phosphatases PTPN2 and PTPN1 serve as negative regulators for various cellular pathways, including JAK/STAT-mediated cytokine signaling involving IFN ⁇ , IFN ⁇ , and IL2. Inhibition of PTPN2/N1 is anticipated to enhance STAT phosphorylation by delaying the dephosphorylation of STAT proteins.
  • the phosphorylation of the direct target of PTPN2/N1, STAT1 was measured as proximal translational marker in human Jurkat T cells.
  • the Jurkat T cell line facilitates high-throughput assessment of PTPN2/N1 inhibitors in potentiating the activation of human T cells in a dose dependent manner with determination of half maximal effective concentrations.
  • Jurkat- pStat Compounds IC50 value Cpd001, Cpd002, Cpd003, Cpd004, Cpd005, Cpd006, Cpd008, Cpd009, Cpd012, Cpd013, Cpd014, Cpd016, Cpd017, Cpd018, Cpd025, Cpd027, Cpd029, Cpd033, Cpd034, Cpd035, Cpd036, Cpd038, Cpd040, Cpd041, Cpd045, Cpd051, Cpd055, Cpd056, Cpd057, Cpd058, Cpd059, Cpd060, Cpd061, A Cpd063, Cpd065, Cpd066, Cpd067, Cpd068, Cpd073, Cpd074, Cpd075, Cpd077, Cpd082, Cpd086, Cpd087, C
  • T cell activation and function In vitro assays utilizing primary T cells are frequently employed to evaluate the effects of compounds on T cell activation and function.
  • Primary human CD3+ T cells were isolated from PBMCs using a StemCell T cell isolation kit ( StemCell technologies, Grenoble, France) according to manufacturer’s instructions. Isolated T cells (150.00 cell/well) were re-suspended in RPMI 1640 supplemented with 10% FBS and seeded into antiCD28/antiCD3 coated 96-well flat-bottom cell culture wells. Directly after seeding, the compounds were added at 10 and 30 ⁇ M. The same amount of DMSO only was added to controls.
  • Cpd008 was tested at 10 ⁇ M and 30 ⁇ M in the primary human T cell activation assay and significantly enhances T cell activation and antitumor function as reflected by the increased CD8+ T cell cytotoxic activity.
  • elevated levels of the T cell activation marker CD69 as well as increased production of the cytotoxic effector molecule Granzyme B and the antitumor cytokines IFN ⁇ and TNF ⁇ were measured.
  • the activity of Cpd008 is shown in the table below.
  • Table 7 summary of T cell activation effect of Cpd008 (at 10 ⁇ M and 30 ⁇ M). Data for CD69+, Granzyme B+, IFN ⁇ + and TNF ⁇ + cells within CD8+ T cell population in vehicle or compound treated primary, human CD3+ T cells are shown. Data represent the mean ⁇ SD.
  • mice C57Bl/6 female mice were obtained from Janvier Elevages Ldt. (St. Ile, France). The mice were group-housed 5 per cage. Food and water were available ad libitum. Animals were acclimated to the animal facilities for a period of at least two weeks prior to start of the experiments.
  • spleens were excised and dissociated over 100um strainers, red blood cells lysed, and single cell suspensions were prepared.
  • the cells were re-stimulated with PMA (50ng/mL) and Ionomycin (1uM) in the presence of Brefeldin A (3 ug/mL) to stain for cytokines (TNF ⁇ + and IFN ⁇ +), Granzyme B and Perforin levels in T cells.
  • the cells were stained with Zombie NIR Fixable Viability Kit (Biolegend, San Diego, CA) diluted in Dulbecco’s PBS for 10 minutes on ice to exclude dead cells followed by staining for surface markers for 15 minutes on ice using the following flow cytometry antibodies in FACS buffer (PBS, 2% FCS, 2mM EDTA): Brilliant Violet(BV)450-labeled anti-CD45, Brilliant Utraviolet (BUV)661-labeled anti-CD3, BV570-labeled anti CD4 and PE-TexasRed-labeled anti-CD8.
  • Zombie NIR Fixable Viability Kit Biolegend, San Diego, CA
  • Cpd008 of the invention was tested in the model described and exhibited significant in vivo immune activation in splenic CD8+ T cells as assessed by measuring elevated levels of STAT1 and STAT5 phosphorylation upon in vivo administration.
  • Cpd008 The activity of Cpd008 is shown in the table below.
  • Table 8 summary of in vivo target engagement of Cpd008 (oral 10/mg/kg/dose dosed at 10 mL/Kg formulated in 40% PEG-400, 30% PG and 30% water). Data for pSTAT1+ cells within splenic CD8+ T cell population in vehicle or compound treated animals are shown. Data represent the mean ⁇ SD.
  • mice All experiments were conducted in compliance with Swiss animal welfare legislation and the Animal Welfare Commission of the Canton of Switzerland approved all procedures (License ZH179/2019).
  • C57Bl/6 female mice were obtained from Janvier Elevages Ldt. (St. Ile, France). The mice were group-housed 5 per cage. Food and water were available ad libitum. Animals were acclimated to the animal facilities for a period of at least two weeks prior to start of the experiments.
  • Tumor Cell Inoculation and Treatments Cells were grown to passage 3 in vitro.
  • TGI Tumor growth inhibition
  • mice were sacrificed on day 13 of dosing with Cpd008 (2 hours after the 8 th dose) and tumors were excised. Tumors were digested in digestion solution (0.5 mg/mL collagenase type IV (Sigma Aldrich) and 0.05 mg/mL DNAse I) to obtain single cell suspensions. Next, tumor single cell suspensions were re-stimulated with PMA (50ng/mL) and Ionomycin (1uM) in the presence of Brefeldin A (3 ug/mL) to stain for cytokines (TNF ⁇ + and IFN ⁇ +), Granzyme B and Perforin levels in T cells.
  • digestion solution 0.5 mg/mL collagenase type IV (Sigma Aldrich) and 0.05 mg/mL DNAse I
  • PMA 50ng/mL
  • Ionomycin (1uM) in the presence of Brefeldin A (3 ug/mL) to stain for cytokines (TNF ⁇ + and IFN ⁇ +), Granzyme B
  • tumor cells were stained with Zombie NIR Fixable Viability Kit (Biolegend, San Diego, CA) diluted in Dulbecco’s PBS for 10 minutes on ice to exclude dead cells followed by staining for surface markers for 15 minutes on ice using the following flow cytometry antibodies in FACS buffer (PBS, 2% FCS, 2mM EDTA): Brilliant Violet(BV)450-labeled anti-CD45, Brilliant Utraviolet (BUV)661- labeled anti-CD3, BV570-labeled anti CD4 and PE-TexasRed-labeled anti-CD8.
  • Zombie NIR Fixable Viability Kit Biolegend, San Diego, CA
  • Table 10 summary of the anti-tumor effect of Cpd008 (oral 10/mg/kg/dose dosed BID at 5 mL/Kg formulated in 40% PEG-400, 30% PG and 30% water) in the MC38-syngenic tumor model. Maximum tumor growth inhibition was determined over the entire study. Data for pSTAT1+, Granzyme B+ and IFN ⁇ + cells within intratumor CD8+ T cell population on day 13 post tumor inoculation in vehicle or compound treated animals are shown. Data represent the mean ⁇ SD.

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Abstract

La présente invention concerne de nouveaux composés, lesdits composés étant destinés à être utilisés comme médicament, en particulier pour la prévention ou le traitement de maladies médiées par l'activité de PTPN2 et/ou PTPN1 et, plus particulièrement, pour la prévention ou le traitement du cancer ou de maladies métaboliques. La présente invention concerne également une méthode de prévention ou de traitement desdites maladies comprenant l'utilisation des nouveaux composés. La présente invention concerne en outre des compositions pharmaceutiques ou des préparations d'association de nouveaux composés ainsi que lesdites compositions ou préparations destinées à être utilisées en tant que médicament, de préférence pour la prévention ou le traitement de maladies médiées par l'activité de PTPN2 et/ou PTPN1 et, plus particulièrement, pour la prévention ou le traitement du cancer ou de maladies métaboliques. La présente invention concerne par ailleurs des procédés de préparation desdits composés.
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Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996015111A1 (fr) 1994-11-15 1996-05-23 Regents Of The University Of Minnesota Procede et intermediaires de la synthese de korupensamines
WO2007067614A1 (fr) * 2005-12-08 2007-06-14 Novartis Ag L, l, 3-tri0x0-l, 2, 5-thiadiaz0lidines et leur utilisation comme inhibiteurs des ptp-ases
WO2007067612A1 (fr) * 2005-12-08 2007-06-14 Novartis Ag Dérivés de 1-orthofluorophényl substitués 1, 2, 5-thiazolidinédione utilisés comme inhibiteurs de la ptp-ase
WO2020186199A1 (fr) 2019-03-14 2020-09-17 Calico Life Sciences Llc Inhibiteurs de protéine tyrosine phosphatase et leurs procédés d'utilisation
WO2021127499A1 (fr) 2019-12-18 2021-06-24 Calico Life Sciences Llc Inhibiteurs de protéine tyrosine phosphatase et leurs méthodes d'utilisation
WO2021127586A1 (fr) 2019-12-20 2021-06-24 Calico Life Sciences Llc Agents de dégradation de protéine tyrosine phosphatase et leurs méthodes d'utilisation
WO2022192598A1 (fr) 2021-03-11 2022-09-15 Kumquat Biosciences Inc. Hétérocycles et leurs utilisations
WO2023096928A1 (fr) 2021-11-23 2023-06-01 Kumquat Biosciences Inc. Composés contenant des hétéroatomes et leurs utilisations
CN117658947A (zh) * 2022-09-06 2024-03-08 杭州中美华东制药有限公司 蛋白酪氨酸磷酸酶抑制作用的5-(取代芳基)-1,2,5-噻二唑啉-3-酮类化合物

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996015111A1 (fr) 1994-11-15 1996-05-23 Regents Of The University Of Minnesota Procede et intermediaires de la synthese de korupensamines
WO2007067614A1 (fr) * 2005-12-08 2007-06-14 Novartis Ag L, l, 3-tri0x0-l, 2, 5-thiadiaz0lidines et leur utilisation comme inhibiteurs des ptp-ases
WO2007067612A1 (fr) * 2005-12-08 2007-06-14 Novartis Ag Dérivés de 1-orthofluorophényl substitués 1, 2, 5-thiazolidinédione utilisés comme inhibiteurs de la ptp-ase
WO2020186199A1 (fr) 2019-03-14 2020-09-17 Calico Life Sciences Llc Inhibiteurs de protéine tyrosine phosphatase et leurs procédés d'utilisation
WO2021127499A1 (fr) 2019-12-18 2021-06-24 Calico Life Sciences Llc Inhibiteurs de protéine tyrosine phosphatase et leurs méthodes d'utilisation
WO2021127586A1 (fr) 2019-12-20 2021-06-24 Calico Life Sciences Llc Agents de dégradation de protéine tyrosine phosphatase et leurs méthodes d'utilisation
WO2022192598A1 (fr) 2021-03-11 2022-09-15 Kumquat Biosciences Inc. Hétérocycles et leurs utilisations
WO2023096928A1 (fr) 2021-11-23 2023-06-01 Kumquat Biosciences Inc. Composés contenant des hétéroatomes et leurs utilisations
CN117658947A (zh) * 2022-09-06 2024-03-08 杭州中美华东制药有限公司 蛋白酪氨酸磷酸酶抑制作用的5-(取代芳基)-1,2,5-噻二唑啉-3-酮类化合物

Non-Patent Citations (21)

* Cited by examiner, † Cited by third party
Title
"Chiral Liquid Chromatography", 1989, CHAPMAN AND HALL
"McCutcheon's Detergents and Emulsifiers Annual", 1981, CHEMICAL PUBLISHING CO.
"The Chemistry of Heterocyclic Compounds, A series of Monographs", vol. 13, 14, 16, 19, 28, 1950, JOHN WILEY & SONS
E. L. ELIEL: "Stereochemistry of Carbon Compounds", 1962, MCGRAW HILL
ELCHEBLY M. ET AL., SCIENCE, vol. 283, 1999, pages 1544 - 1548
ELIEL, E. AND WILEN, S.: "Stereochemistry of Organic Compounds", 1994, JOHN WILEY & SONS, INC., pages: 322
FLOSBACH, M. ET AL., CELL REP., vol. 32, 2020, pages 107957
J. AM. CHEM. SOC., vol. 82, 1960, pages 5566
J. SONG ET AL., INT. J. MOL. SCI, vol. 23, no. 17, 2022, pages 10025
JACOB ILL., J. ORG. CHEM., vol. 47, 1982, pages 4165
KATRITZKY, ALAN R.REES, C.W.SCRIVEN, E.: "Comprehensive Heterocyclic Chemistry", 1996, PERGAMON PRESS
KENNER K. A. ET AL., J BIOL CHEM, vol. 271, 1996, pages 19810 - 19816
LOCHMULLER, C. H., J. CHROMATOGR., vol. 113, no. 3, 1975, pages 283 - 302
MANGUSO, R.T. ET AL., NATURE, vol. 547, 2017, pages 413 - 418
no. 1279876-13-9
OKAMOTO: "Optical resolution of dihydropyridine enantiomers by High-performance liquid chromatography using phenylcarbamates of polysaccharides as a chiral stationary phase", J. OF CHROMATOGR., vol. 513, 1990, pages 375 - 378, XP026488183, DOI: 10.1016/S0021-9673(01)89459-0
PAQUETTE, LEO A.: "Principles of Modern Heterocyclic Chemistry", 1968, W.A. BENJAMIN
PARDOLL, NATURE REV. CANCER, vol. 12, 2012, pages 252 - 264
RAUTIO J. ET AL.: "Prodrugs: design and clinical applications", NATURE REVIEWS DRUG DISCOVERY, 2008
SCHAPIRA M. ET AL., NAT. REV. DRUG DISCOV., vol. 18, no. 12, 2019, pages 949 - 963
THEODORA W. GREENE: "Protective Groups in Organic Chemistry", 1991, JOHN WILEY & SONS, INC.

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