WO2021032582A1 - Dérivés de pyrazolo [4,3-c] pyridine et leurs compositions pharmaceutiques pour le traitement de troubles inflammatoires - Google Patents

Dérivés de pyrazolo [4,3-c] pyridine et leurs compositions pharmaceutiques pour le traitement de troubles inflammatoires Download PDF

Info

Publication number
WO2021032582A1
WO2021032582A1 PCT/EP2020/072715 EP2020072715W WO2021032582A1 WO 2021032582 A1 WO2021032582 A1 WO 2021032582A1 EP 2020072715 W EP2020072715 W EP 2020072715W WO 2021032582 A1 WO2021032582 A1 WO 2021032582A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
diseases
independently selected
pyrazolo
amino
Prior art date
Application number
PCT/EP2020/072715
Other languages
English (en)
Inventor
Steven Emiel VAN DER PLAS
Sébastien Laurent Xavier MARTINA
Ghjuvanni Petru Diunisu COTI
David Amantini
Original Assignee
Galapagos Nv
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Galapagos Nv filed Critical Galapagos Nv
Priority to EP20760394.5A priority Critical patent/EP4017590A1/fr
Publication of WO2021032582A1 publication Critical patent/WO2021032582A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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

Definitions

  • the present invention relates to compounds which may be useful in the prophylaxis and/or treatment of allergic diseases, inflammatory diseases, metabolic diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformations, and/or diseases associated with hypersecretion of IFNa, IL12 and/or IL23.
  • the compound of the invention inhibits JAK, a family of tyrosine kinases, and more particularly TYK2.
  • the present invention also provides methods for the production of the compound of the invention, pharmaceutical compositions comprising the compound of the invention, and/or methods for the prophylaxis and/or treatment of allergic diseases, inflammatory diseases, metabolic diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformations, and/or diseases associated with hypersecretion of IFNa, IL12 and/or IL23 by administering the compound of the invention.
  • Janus kinases are cytoplasmic tyrosine kinases that transduce cytokine signalling from membrane receptors to STAT transcription factors.
  • JAK family members Four JAK family members are described, JAK1, JAK2, JAK3 and TYK2.
  • JAK family members Upon binding of the cytokine to its receptor, JAK family members auto- and/or transphosphorylate each other, followed by phosphorylation of STATs that then migrate to the nucleus to modulate transcription.
  • JAK-STAT intracellular signal transduction serves the interferons, most interleukins, as well as a variety of cytokines and endocrine factors such as EPO, TPO, GH, OSM, LIF, CNTF, GM-CSF and PRL.(Vainchenker et ak, 2008)
  • JAKinibs JAK inhibitors
  • JAK2 inhibition has proven useful in the treatment of polycythemia and myelofibrosis
  • undesirable effect associated with JAK2 inhibition were observed (O'Shea and Plenge, 2012) thus rendering compounds with JAK2 inhibition components less suitable for the treatment of non-JAK2 mediated diseases.
  • IL-6, IL-10, IL-11, IL12, IL-13, IL-19, IL-20, IL-22, IL-23, IL-27, IL-28, IL-29, IL-31, IL-35 and/or type 1 interferons signaling are dependent on TYK2.
  • JAK1 is a key driver in IFNa, IL6, IL10 and IL22 signaling
  • TYK2 is involved in type I interferons (including IFNa, INRb), IL23 and IL12 signaling (Gillooly et ak, 2016; Sohn et ak, 2013).
  • IL12 and IL23 are particularly increased in patients with auto-immune diseases (O'Shea and Plenge, 2012) such as psoriasis, systemic lupus erythematosus (SLE), psoriatic arthritis, and/or inflammatory bowel disorders
  • auto-immune diseases such as psoriasis, systemic lupus erythematosus (SLE), psoriatic arthritis, and/or inflammatory bowel disorders
  • EPO erythropoietin
  • TPO thrombopoietin
  • TYK2 inhibition may be particulalryl useful in the treatment of the cytokine storm associated with COVID-19 infections. (Ye et ak, 2020)
  • the present invention relates to compounds useful in the prophylaxis and/or treatment of allergic diseases, inflammatory diseases, metabolic diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformations, and/or diseases associated with hypersecretion of IFNa, IL12 and/or IL23.
  • the compound of the invention inhibits JAK, a family of tyrosine kinases, and more particularly TYK2.
  • the present invention also provides methods for the production of the compound of the invention, pharmaceutical compositions comprising the compound of the invention, and/or methods for the prophylaxis and/or treatment of allergic diseases, inflammatory diseases, metabolic diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformations, and/or diseases associated with hypersecretion of IFNa, IL12 and/or IL23 by administering the compound of the invention.
  • R 1 is selected from - -NR 3 R 4 ,
  • heterocycloalkyl comprising one or more heteroatoms independently selected from N, S, and O, which heterocycloalkyl is unsubstituted or substituted with one or more independently selected: o -OH,
  • Ci- 4 alkyl unsubstituted or substituted with one or more independently selected o halo, o -OH, o Ci-4 alkoxy, or o 4-7 membered monocyclic heterocycloalkyl comprising one or more heteroatoms independently selected from N, O, and S;
  • R 2 is H, Ci-4 alkyl, -NH2, or 4-7 membered monocyclic heterocycloalkyl comprising one or more heteroatoms independently selected from N, O, and S;
  • Cy is phenyl or pyridinyl, each of which is substituted with one or more independently selected R 6 group; each R 6 is independently selected from:
  • Ci- 4 alkyl unsubstituted or substituted with one or more independently selected halo, C 1-4 alkoxy, or OH;
  • R 3 is selected from
  • Ci- 6 alkyl unsubstituted or substituted with one or more independently selected: o halo, o -OH, o Ci-4 alkoxy, o -NR 7a R 7b , or o 4-7 membered monocyclic heterocycloalkyl comprising one or more heteroatoms independently selected from N, O, and S;
  • R 4 is selected from H, and C H alkyl; and each R 5a , R 5b , R 7a and R 7b is independently selected from H and C H alkyl.
  • the compounds of the invention are provided for use in the prophylaxis and/or treatment of allergic diseases, inflammatory diseases, metabolic diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformations, and/or diseases associated with hypersecretion of IFNa, IL12 and/or IL23.
  • the compounds of the invention exhibit improved selectivity towards TYK2 versus other JAK family members, which may be advantageous in the treatment of IFNa, IL12 and/or IL23 associated diseases, particularly auto-immune diseases such as psoriasis and/or inflammatory bowel disorders.
  • the present invention provides pharmaceutical compositions comprising a compound of the invention, and a pharmaceutical carrier, excipient or diluent.
  • the pharmaceutical composition may additionally comprise further therapeutically active ingredients suitable for use in combination with the compounds of the invention.
  • the further therapeutically active ingredient is an agent for the prophylaxis and/or treatment of allergic diseases, inflammatory diseases, metabolic diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformations, and/or diseases associated with hypersecretion of IFNa, IL12 and/or IL23.
  • the compounds of the invention useful in the pharmaceutical compositions and treatment methods disclosed herein, are pharmaceutically acceptable as prepared and used.
  • this invention provides a method of treating a mammal, in particular humans, afflicted with a condition selected from among those listed herein, and particularly allergic diseases, inflammatory diseases, metabolic diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformations, and/or diseases associated with hypersecretion of IFNa, IL12 and/or IL23, which method comprises administering an effective amount of the pharmaceutical composition or compounds of the invention as described herein.
  • the present invention also provides pharmaceutical compositions comprising a compound of the invention, and a suitable pharmaceutical carrier, excipient or diluent for use in medicine.
  • the pharmaceutical composition is for use in the prophylaxis and/or treatment of allergic diseases, inflammatory diseases, metabolic diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformations, and/or diseases associated with hypersecretion of IFNa, IL12 and/or IL23.
  • this invention provides methods for synthesizing the compounds of the invention, with representative synthetic protocols and pathways disclosed later on herein.
  • analogue means one analogue or more than one analogue.
  • Alkyl means straight or branched aliphatic hydrocarbon having the specified number of carbon atoms. Particular alkyl groups have 1 to 6 carbon atoms or 1 to 4 carbon atoms. Branched means that one or more alkyl groups such as methyl, ethyl or propyl is attached to a linear alkyl chain.
  • alkyl groups are methyl (-Ctfi), ethyl (-CH 2 -CH3), n-propyl (-CH 2 -CH 2 -CH3), isopropyl (-CH(C]3 ⁇ 4) 2 ), n-butyl (- CH 2 -CH 2 -CH 2 -CH3), tert-butyl (-CH 2 -C(CH3)3), sec-butyl (-CH 2 -CH(CH3) 2 ), n-pentyl (-CH 2 -CH 2 -CH 2 -CH 2 -CH3), n-hexyl (-CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH3), and 1,2-dimethylbutyl (-CHCtfij-C CtUjLb-CLb-CtL).
  • Particular alkyl groups have between 1 and 4 carbon atoms.
  • Alkylene refers to divalent alkene radical groups having the number of carbon atoms specified, in particular having 1 to 6 carbon atoms and more particularly 1 to 4 carbon atoms which can be straight-chained or branched. This term is exemplified by groups such as methylene (-CH2-), ethylene (-CH2-CH2-), or -CH(CH3)- and the like.
  • Alkynylene refers to divalent alkyne radical groups having the number of carbon atoms and the number of triple bonds specified, in particular 2 to 6 carbon atoms and more particularly 2 to 4 carbon atoms which can be straight-chained or branched. This term is exemplified by groups such as -CoC-, -CH2- CoC-, and -C(CH 3 )H-CoCH-.
  • Alkoxy refers to the group O-alkyl, where the alkyl group has the number of carbon atoms specified. In particular the term refers to the group -O-Ci-e alkyl. Particular alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. Particular alkoxy groups are lower alkoxy, i.e. with between 1 and 6 carbon atoms. Further particular alkoxy groups have between 1 and 4 carbon atoms.
  • Amino refers to the radical -Nth.
  • polycyclic refers to chemical groups featuring several closed rings of atoms. In particular it refers to groups featuring two, three or four rings of atoms, more particularly two or three rings of atoms, most particularly two rings of atoms.
  • Aryl refers to a monovalent aromatic hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system.
  • aryl refers to an aromatic ring structure, monocyclic or fused polycyclic, with the number of ring atoms specified.
  • the term includes groups that include from 6 to 10 ring members.
  • Particular aryl groups include phenyl, and naphthyl.
  • Cycloalkyl refers to a non-aromatic hydrocarbyl ring structure, monocyclic, fused polycyclic, bridged polycyclic, or spirocyclic, with the number of ring atoms specified.
  • a cycloalkyl may have from 3 to 12 carbon atoms, in particular from 3 to 10, and more particularly from 3 to 7 carbon atoms.
  • Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • Halo or ‘halogen’ refers to fluoro (F), chloro (Cl), bromo (Br) and iodo (I). Particular halo groups are either fluoro or chloro.
  • Hetero when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described above such as alkyl, e.g. heteroalkyl, cycloalkyl, e.g. heterocycloalkyl, aryl, e.g. heteroaryl, and the like having from 1 to 4, and particularly from 1 to 3 heteroatoms, more typically 1 or 2 heteroatoms, for example a single heteroatom.
  • HeteroaryF means an aromatic ring structure, monocyclic or fused polycyclic, that includes one or more heteroatoms independently selected from O, N and S and the number of ring atoms specified.
  • the aromatic ring structure may have from 5 to 9 ring members.
  • the heteroaryl group can be, for example, a five membered or six membered monocyclic ring or a fused bicyclic structure formed from fused five and six membered rings or two fused six membered rings or, by way of a further example, two fused five membered rings.
  • Each ring may contain up to four heteroatoms typically selected from nitrogen, sulphur and oxygen.
  • the heteroaryl ring will contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more usually up to 2, for example a single heteroatom.
  • the heteroaryl ring contains at least one ring nitrogen atom.
  • the nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non-basic as in the case of an indole or pyrrole nitrogen. In general the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five.
  • Examples of five membered monocyclic heteroaryl groups include but are not limited to pyrrolyl, furanyl, thiophenyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl and tetrazolyl groups.
  • Examples of six membered monocyclic heteroaryl groups include but are not limited to pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl.
  • bicyclic heteroaryl groups containing a five membered ring fused to another five-membered ring include but are not limited to imidazothiazolyl and imidazoimidazolyl.
  • bicyclic heteroaryl groups containing a six membered ring fused to a five membered ring include but are not limited to benzofuranyl, benzothiophenyl, benzoimidazolyl, benzoxazolyl, isobenzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, purinyl (e.g. adenine, guanine), indazolyl, pyrazolopyrimidinyl, triazolopyrimidinyl, and pyrazolopyridinyl groups.
  • bicyclic heteroaryl groups containing two fused six membered rings include but are not limited to quinolinyl, isoquinolinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, and pteridinyl groups.
  • Particular heteroaryl groups are those derived from thiophenyl, pyrrolyl, benzothiophenyl, benzofuranyl, indolyl, pyridinyl, quinolinyl, imidazolyl, oxazolyl and pyrazinyl.
  • HeterocycloalkyE means a non-aromatic fully saturated ring structure, monocyclic, fused polycyclic, spirocyclic, or bridged polycyclic, that includes one or more heteroatoms independently selected from O, N and S and the number of ring atoms specified.
  • the heterocycloalkyl ring structure may have from 4 to 12 ring members, in particular from 4 to 10 ring members and more particularly from 4 to 7 ring members.
  • Each ring may contain up to four heteroatoms typically selected from nitrogen, sulphur and oxygen.
  • the heterocycloalkyl ring will contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more usually up to 2, for example a single heteroatom.
  • heterocyclic rings include, but are not limited to azetidinyl, oxetanyl, thietanyl, pyrrolidinyl (e.g. 1-pyrrolidinyl, 2-pyrrolidinyl and 3- pyrrolidinyl), tetrahydrofuranyl (e.g. 1-tetrahydrofuranyl, 2-tetrahydrofuranyl and 3-tetrahydrofuranyl), tetrahydrothiophenyl (e.g. 1-tetrahydrothiophenyl, 2-tetrahydrothiophenyl and 3-tetrahydrothiophenyl), piperidinyl (e.g.
  • heterocycloalkenyl means a ‘heterocycloalkyl’, which comprises at least one double bond. Particular examples of heterocycloalkenyl groups are shown in the following illustrative examples: where and each Z is selected from N and CH.
  • each W and Y is independently selected from -CH2-, -NH-, -O- and -S-.
  • fused bicyclic rings are shown in the following illustrative examples: wherein each W and Y is independently selected from -CH2-, -NH-, -O- and -S-.
  • bridged bicyclic rings are shown in the following illustrative examples: wherein each W and Y is independently selected from -CH2-, -NH-, -O- and -S- and each Z is selected from N and CH.
  • each Y is selected from -CH2-, -NH-, -O- and -S-.
  • Haldroxyl refers to the radical -OH.
  • Substituted refers to a group in which one or more hydrogen atoms are each independently replaced with the same or different substituent(s).
  • ‘Sulfo’ or ‘sulfonic acid’ refers to a radical such as -SO 3 H.
  • Thiol refers to the group -SH.
  • substituted with one or more refers to one to four substituents. In one embodiment it refers to one to three substituents. In further embodiments it refers to one or two substituents. In a yet further embodiment it refers to one substituent.
  • ‘Thioalkoxy’ refers to the group -S-alkyl where the alkyl group has the number of carbon atoms specified. In particular the term refers to the group -S-Ci- 6 alkyl.
  • Particular thioalkoxy groups are thiomethoxy, thioethoxy, n-thiopropoxy, isothiopropoxy, n-thiobutoxy, tert-thiobutoxy, sec-thiobutoxy, n- thiopentoxy, n-thiohexoxy, and 1,2-dimethylthiobutoxy.
  • Particular thioalkoxy groups are lower thioalkoxy, i.e. with between 1 and 6 carbon atoms. Further particular alkoxy groups have between 1 and 4 carbon atoms.
  • heterocyclic ring may have one to four heteroatoms so long as the heteroaromatic ring is chemically feasible and stable.
  • ‘Pharmaceutically acceptable’ means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.
  • ‘Pharmaceutically acceptable salt’ refers to a salt of a compound of the invention that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts.
  • such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzene sulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic
  • salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of non-toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.
  • pharmaceutically acceptable cation refers to an acceptable cationic counter-ion of an acidic functional group.
  • ‘Pharmaceutically acceptable vehicle’ refers to a diluent, adjuvant, excipient or carrier with which a compound of the invention is administered.
  • Prodrugs refers to compounds, including derivatives of the compounds of the invention, which have cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention which are pharmaceutically active in vivo. Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like.
  • Solvate refers to forms of the compound that are associated with a solvent, usually by a solvolysis reaction. This physical association includes hydrogen bonding.
  • Conventional solvents include water, EtOH, acetic acid and the like.
  • the compounds of the invention may be prepared e.g. in crystalline form and may be solvated or hydrated.
  • Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid.
  • Solvate’ encompasses both solution-phase and isolable solvates.
  • Representative solvates include hydrates, ethanolates and methanolates.
  • Subject includes humans.
  • the terms ‘human’, ‘patient’ and ‘subject’ are used interchangeably herein.
  • Effective amount means the amount of a compound of the invention that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease.
  • the “effective amount” can vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated.
  • ‘Preventing’ or ‘prevention’ refers to a reduction in risk of acquiring or developing a disease or disorder (i.e. causing at least one of the clinical symptoms of the disease not to develop in a subject that may be exposed to a disease-causing agent, or predisposed to the disease in advance of disease onset.
  • the term ‘prophylaxis’ is related to ‘prevention’, and refers to a measure or procedure the purpose of which is to prevent, rather than to treat or cure a disease.
  • Non-limiting examples of prophylactic measures may include the administration of vaccines; the administration of low molecular weight heparin to hospital patients at risk for thrombosis due, for example, to immobilization; and the administration of an anti- malarial agent such as chloroquine, in advance of a visit to a geographical region where malaria is endemic or the risk of contracting malaria is high.
  • an anti- malarial agent such as chloroquine
  • ‘Treating’ or ‘treatment’ of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e. arresting the disease or reducing the manifestation, extent or severity of at least one of the clinical symptoms thereof).
  • ‘treating’ or ‘treatment’ refers to ameliorating at least one physical parameter, which may not be discernible by the subject.
  • ‘treating’ or ‘treatment’ refers to modulating the disease or disorder, either physically, (e.g. stabilization of a discernible symptom), physiologically, (e.g. stabilization of a physical parameter), or both.
  • “treating” or “treatment” relates to slowing the progression of the disease.
  • allergic disease refers to the group of conditions characterized by a hypersensitivity disorder of the immune system including, allergic airway disease (e.g. asthma, rhinitis), sinusitis, eczema and hives, as well as food allergies or allergies to insect venom.
  • asthma refers to any disorder of the lungs characterized by variations in pulmonary gas flow associated with airway constriction of whatever cause (intrinsic, extrinsic, or both; allergic or non-allergic).
  • the term asthma may be used with one or more adjectives to indicate the cause.
  • inflammatory disease(s) refers to the group of conditions including, rheumatoid arthritis, osteoarthritis, juvenile idiopathic arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, allergic airway disease (e.g. asthma, rhinitis), chronic obstructive pulmonary disease (COPD), inflammatory liver diseases (e.g. primary biliary cholangitis (PBC), and/or primary sclerosing cholangitis (PSC)), inflammatory bowel diseases (e.g. Crohn’s disease, ulcerative colitis), endotoxin-driven disease states (e.g.
  • the term refers to rheumatoid arthritis, osteoarthritis, allergic airway disease (e.g. asthma), chronic obstructive pulmonary disease (COPD) and inflammatory bowel diseases. More particularly the term refers to rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC) and inflammatory bowel diseases. Most particularly the term refers to rheumatoid arthritis, psoriatic arthritis and inflammatory bowel diseases.
  • metabolic disease(s) refers to the group of conditions involving the body’s ability to process certain nutrients and vitamins. Metabolic disorders include phenylketonuria (PKU), type II diabetes, hyperlipidemia, gout, and rickets. A particular example of metabolic disorders is type II diabetes and/or obesity.
  • autoinflammatory diseases(s) refers to the group of diseases including Cryopyrin-Associated Periodic Syndromes (CAPS), Familial Mediterranean Fever (FMF) and Tumor necrosis factor receptor-associated periodic syndrome (TRAPS), Behcets. Systemic-Onset Juvenile Idiopathic Arthritis (SJIA) or Still’s disease.
  • Cryopyrin-Associated Periodic Syndromes Cryopyrin-Associated Periodic Syndromes
  • FMF Familial Mediterranean Fever
  • TRAPS Tumor necrosis factor receptor-associated periodic syndrome
  • Behcets Behcets.
  • SJIA Systemic-Onset Juvenile Idiopathic Arthritis
  • Still s disease.
  • autoimmune disease(s) refers to the group of diseases including obstructive airways disease, including conditions such as COPD, asthma (e.g intrinsic asthma, extrinsic asthma, dust asthma, infantile asthma) particularly chronic or inveterate asthma (for example late asthma and airway hyperreponsiveness), bronchitis, including bronchial asthma, systemic lupus erythematosus (SLE), cutaneous lupus erythrematosis, lupus nephritis, dermatomyositis, Sjogren’s syndrome, multiple sclerosis, psoriasis, dry eye disease, type I diabetes mellitus and complications associated therewith, atopic eczema (atopic dermatitis), thyroiditis (Hashimoto’s and autoimmune thyroiditis), contact dermatitis and further eczematous dermatitis, inflammatory bowel disease (e.g.
  • COPD chronic or inveterate asthma
  • proliferative disease(s) refers to conditions such as cancer (e.g. uterine leiomyosarcoma or prostate cancer), myeloproliferative disorders (e.g. polycythemia vera, essential thrombocytosis and myelofibrosis), leukemia (e.g.
  • acute myeloid leukaemia acute and chronic lymphoblastic leukemia
  • multiple myeloma psoriasis
  • restenosis scleroderma or fibrosis.
  • the term refers to cancer, leukemia, multiple myeloma and psoriasis.
  • cancer refers to a malignant or benign growth of cells in skin or in body organs, for example but without limitation, breast, prostate, lung, kidney, pancreas, stomach or bowel.
  • a cancer tends to infiltrate into adjacent tissue and spread (metastasise) to distant organs, for example to bone, liver, lung or the brain.
  • cancer includes both metastatic tumour cell types (such as but not limited to, melanoma, lymphoma, leukaemia, fibrosarcoma, rhabdomyosarcoma, and mastocytoma) and types of tissue carcinoma (such as but not limited to, colorectal cancer, prostate cancer, small cell lung cancer and non-small cell lung cancer, breast cancer, pancreatic cancer, bladder cancer, renal cancer, gastric cancer, glioblastoma, primary liver cancer, ovarian cancer, prostate cancer and uterine leiomyosarcoma).
  • metastatic tumour cell types such as but not limited to, melanoma, lymphoma, leukaemia, fibrosarcoma, rhabdomyosarcoma, and mastocytoma
  • types of tissue carcinoma such as but not limited to, colorectal cancer, prostate cancer, small cell lung cancer and non-small cell lung cancer, breast cancer, pancreatic cancer, bladder cancer, renal cancer, gastric cancer, glioblastoma
  • cancer refers to acute lymphoblastic leukemia, acute myeloidleukemia, adrenocortical carcinoma, anal cancer, appendix cancer, astrocytomas, atypical teratoid/rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer (osteosarcoma and malignant fibrous histiocytoma), brain stem glioma, brain tumors, brain and spinal cord tumors, breast cancer, bronchial tumors, Burkitt lymphoma, cervical cancer, chronic lymphocytic leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T -Cell lymphoma, embryonal tumors, endometrial cancer, ependymoblastoma, ependymoma, esophageal cancer, ewing sarcoma family of tumors, eye cancer
  • leukemia refers to acute myeloid leukaemia (AML), and acute lymphoblastic leukemia (ALL) and chronic lymphoblastic leukaemia (CLL).
  • AML acute myeloid leukaemia
  • ALL acute lymphoblastic leukemia
  • CLL chronic lymphoblastic leukaemia
  • transplantation rejection refers to the acute or chronic rejection of cells, tissue or solid organ alio- or xenografts of e.g.
  • pancreatic islets stem cells, bone marrow, skin, muscle, comeal tissue, neuronal tissue, heart, lung, combined heart-lung, kidney, liver, bowel, pancreas, trachea or oesophagus, or graft-versus-host diseases.
  • the term ‘diseases involving impairment of cartilage turnover’ includes conditions such as osteoarthritis, psoriatic arthritis, juvenile rheumatoid arthritis, gouty arthritis, septic or infectious arthritis, reactive arthritis, reflex sympathetic dystrophy, algodystrophy, Tietze syndrome or costal chondritis, fibromyalgia, osteochondritis, neurogenic or neuropathic arthritis, arthropathy, endemic forms of arthritis like osteoarthritis deformans endemica, Mseleni disease and Handigodu disease; degeneration resulting from fibromyalgia, systemic lupus erythematosus, scleroderma and ankylosing spondylitis. In a particular embodiment, the term refers to ankylosing spondylitis.
  • cartilage malformation(s) includes conditions such as hereditary chondrolysis, chondrodysplasias and pseudochondrodysplasias, in particular, but without limitation, microtia, anotia, metaphyseal chondrodysplasia, and related disorders.
  • the term ‘disease(s) associated with hypersecretion of of of IFNa, IL12 and/or IL23 includes conditions such as systemic and cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, Sjogren’s syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, trisomy 21, COVID-19 and/or Crohn’s disease.
  • Compound(s) of the invention are meant to embrace compounds of the Formula(e) as herein described, which expression includes the pharmaceutically acceptable salts, and the solvates, e.g. hydrates, and the solvates of the pharmaceutically acceptable salts where the context so permits.
  • reference to intermediates, whether or not they themselves are claimed, is meant to embrace their salts, and solvates, where the context so permits.
  • Prodrugs include acid derivatives well know to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides and anhydrides derived from acidic groups pendant on the compounds of this invention are particularly useful prodrugs.
  • double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters.
  • Particular such prodrugs are the Ci-s alkyl, C2-8 alkenyl, G,-io optionally substituted aryl, and (CV aryl)-(Ci-4 alkyl) esters of the compounds of the invention.
  • the present disclosure includes all isotopic forms of the compounds of the invention provided herein, whether in a form (i) wherein all atoms of a given atomic number have a mass number (or mixture of mass numbers) which predominates in nature (referred to herein as the “natural isotopic form”) or (ii) wherein one or more atoms are replaced by atoms having the same atomic number, but a mass number different from the mass number of atoms which predominates in nature (referred to herein as an “unnatural variant isotopic form”). It is understood that an atom may naturally exists as a mixture of mass numbers.
  • unnatural variant isotopic form also includes embodiments in which the proportion of an atom of given atomic number having a mass number found less commonly in nature (referred to herein as an “uncommon isotope”) has been increased relative to that which is naturally occurring e.g. to the level of >20%, >50%, >75%, >90%, >95% or> 99% by number of the atoms of that atomic number (the latter embodiment referred to as an "isotopically enriched variant form").
  • the term “unnatural variant isotopic form” also includes embodiments in which the proportion of an uncommon isotope has been reduced relative to that which is naturally occurring.
  • Isotopic forms may include radioactive forms (i.e. they incorporate radioisotopes) and non-radioactive forms. Radioactive forms will typically be isotopically enriched variant forms.
  • An unnatural variant isotopic form of a compound may thus contain one or more artificial or uncommon isotopes such as deuterium ( 2 H or D), carbon-11 ( n C), carbon-13 ( 13 C), carbon-14 ( 14 C), nitrogen-13 ( 13 N), nitrogen-15 ( 15 N), oxygen-15 ( 15 0), oxygen-17 ( 17 0), oxygen-18 ( 18 0), phosphorus-32 ( 32 P), sulphur-35 ( 35 S), chlorine-36 ( 36 C1), chlorine-37 ( 37 C1), fluorine-18 ( 18 F) iodine-123 ( 123 I), iodine-125 ( 125 I) in one or more atoms or may contain an increased proportion of said isotopes as compared with the proportion that predominates in nature in one or more atoms.
  • an artificial or uncommon isotopes such as deuterium ( 2 H or D), carbon-11 ( n C), carbon-13 ( 13 C), carbon-14 ( 14 C), nitrogen-13 ( 13 N), nitrogen-15 ( 15 N), oxygen-15 ( 15
  • Unnatural variant isotopic forms comprising radioisotopes may, for example, be used for drug and/or substrate tissue distribution studies.
  • the radioactive isotopes tritium, i.e. 3 H, and carbon-14, i.e. 14 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • Unnatural variant isotopic forms which incorporate deuterium i.e. 2 H or D 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.
  • unnatural variant isotopic forms may be prepared which incorporate positron emitting isotopes, such as n C, 18 F, 15 0 and 13 N, and would be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
  • PET Positron Emission Topography
  • An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e. as (+) or (-)-isomers respectively).
  • a chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a ‘racemic mixture’.
  • Tautomers refer to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of p electrons and an atom (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the aci- and nitro- forms of phenylnitromethane, that are likewise formed by treatment with acid or base.
  • Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.
  • the compounds of the invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)- stereoisomers or as mixtures thereof.
  • the present invention relates to compounds which may be useful in the prophylaxis and/or treatment of allergic diseases, inflammatory diseases, metabolic diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformations, and/or diseases associated with hypersecretion of IFNa, IL12 and/or IL23.
  • the compound of the invention inhibits JAK, a family of tyrosine kinases, and more particularly TYK2.
  • the present invention also provides methods for the production of the compound of the invention, pharmaceutical compositions comprising the compound of the invention, and/or methods for the prophylaxis and/or treatment of allergic diseases, inflammatory diseases, metabolic diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformations, and/or diseases associated with hypersecretion of IFNa, IL12 and/or IL23 by administering the compound of the invention.
  • the compounds of the invention are provided having a Formula (I): wherein
  • R 1 is selected from
  • heterocycloalkyl comprising one or more heteroatoms independently selected from N, S, and O, which heterocycloalkyl is unsubstituted or substituted with one or more independently selected: o -OH,
  • Ci-4 alkyl unsubstituted or substituted with one or more independently selected o halo, o -OH, o Ci-4 alkoxy, or o 4-7 membered monocyclic heterocycloalkyl comprising one or more heteroatoms independently selected from N, O, and S;
  • R 2 is H, Ci-4 alkyl, -NH2, or 4-7 membered monocyclic heterocycloalkyl comprising one or more heteroatoms independently selected from N, O, and S;
  • Cy is phenyl or pyridinyl, each of which is substituted with one or more independently selected R 6 group; each R 6 is independently selected from:
  • Ci-4 alkyl unsubstituted or substituted with one or more independently selected halo, C 1-4 alkoxy, or OH;
  • R 3 is selected from:
  • - H - Ci- 6 alkyl unsubstituted or substituted with one or more independently selected: o halo, o -OH, o Ci- 4 alkoxy, o -NR 7a R 7b , or o 4-7 membered monocyclic heterocycloalkyl comprising one or more heteroatoms independently selected from N, O, and S;
  • R 4 is selected from H, and Cw alkyl; and each R 5a , R 5b , R 7a and R 7b is independently selected from H and C H alkyl.
  • the compound of the invention is according to Formula I, wherein R 2 is H, -CH 3 , -NH2, or morpholinyl.
  • the compound of the invention is according to Formula I, wherein R 2 is H.
  • the compound of the invention is according to Formula I, wherein Cy is phenyl substituted with one, two or three independently selected R 6 groups.
  • Cy is phenyl substituted with one, or two independently selected R 6 groups.
  • Cy is phenyl substituted with three independently selected R 6 groups.
  • the compound of the invention is according to Formula I, wherein Cy is pyridinyl substituted with one, two or three independently selected R 6 groups. In a particular embodiment, Cy is pyridinyl substituted with one, or two independently selected R 6 groups.
  • each R 6 is independently selected from F, Cl, or -CN.
  • the compound of the invention is according to Formula I, wherein Cy is
  • R 6a , R 6b , and R 6c is independently selected from R 6 , wherein R 6 is as previously defined.
  • the compound of the invention is according to Formula I, wherein Cy is Cy2, Cy3, Cy4, Cy5 or Cy6, wherein R 6a is halo. In a particular embodiment, R 6a is F or Cl.
  • the compound of the invention is according to Formula I, wherein Cy is Cy3, Cy4, Cy5, or Cy6 wherein R 6b is halo, CN, Ci-4 alkyl unsubstituted or substituted with one or more independently selected halo, Ci-4 alkoxy or OH.
  • R 6b is F, Cl, -CN, -OR, or - CF 3 .
  • R 6c is -CN.
  • the compound of the invention is according to Formula Ila, lib, or He:
  • the compound of the invention is according to any one of Formulae I-IIc, wherein R 1 is -NR 3 R 4 , wherein R 4 is as previously defined and R 3 is H.
  • the compound of the invention is according to any one of Formulae I-IIc, wherein R 1 is -NR 3 R 4 , wherein R 4 is as previously defined and R 3 is Ci- 6 alkyl.
  • R 3 is -CH 3 , -CH 2 CH3, or -CH(CH 3 ) 2 .
  • the compound of the invention is according to any one of Formulae I-IIc, wherein R 1 is -NR 3 R 4 , wherein R 4 is as previously defined and R 3 is Ci- 6 alkyl substituted with one or more independently selected halo, -OH, C 1-4 alkoxy, -NR 7a R 7b or 4-7 membered monocyclic heterocycloalkyl comprising one or more heteroatoms independently selected from N, O, and S.
  • R 3 is Ci- 6 alkyl substituted with one, two or three independently selected halo, -OH, Ci-4 alkoxy, -NR 7a R 7b or 4-7 membered monocyclic heterocycloalkyl comprising one or more heteroatoms independently selected from N, O, and S.
  • R 3 is -CH 3 , -CH 2 CH 3 , -CH 2 CH2CH 3 , -CH(CH 3 )CH 3 , -CH 2 CH(CH 3 ) 2 , each of which is substituted with one, two or three independently selected halo, -OH, C 1-4 alkoxy, -NR 7a R 7b or 4-7 membered monocyclic heterocycloalkyl comprising one or more heteroatoms independently selected from N, O, and S.
  • R 3 is Ci- 6 alkyl substituted with one, two or three independently selected F, -OH, -OCH 3 , -OCH 2 CH 3 , oxetanyl, tetrahydrofuranyl, or dioxanyl.
  • R 3 is -CH 2 CH 2 -OH, -CH 2 -dioxanyl, -CH(CH 3 )CH 2 -OH, -CH 2 C(CH 3 ) 2 -OH, -CH 2 CF 2 CH 2 -OH, -CH 2 CH(OH)CH 3 , -CH 2 CH(OH))CHF 2 , -CH 2 CH(OH))CF 3 , -CH 2 CH 2 -N(CH 3 ) 2 or -CH 2 CH 2 -OCH 3 .
  • R 3 is -CH 2 CH 2 -OH.
  • the compound of the invention is according to any one of Formulae I-IIc, wherein R 1 is -NR 3 R 4 , wherein R 3 is as previously defined and R 4 is H, or Cw alkyl. In a particular embodiment, R 4 is H, or -CH 3 . In a more particular embodiment, R 4 is H.
  • the compound of the invention is according to any one of Formulae I-IIc, wherein R 1 is -NH 3 ⁇ 4 -NHCH 3 , -NHCH 2 CH 3 , -NH-CH 2 CH 2 OH, -NH-CH(CH 3 )CH 2 OH, -NH- CH 2 C(CH 3 ) 2 OH, -NH-CH 2 CF 2 CH 2 OH, -NH-CH 2 CH(OH)CHF 2 , -NH-CH 2 -dioxanyl,
  • the compound of the invention is according to any one of Formulae I-IIc, wherein R 1 is monocyclic or spiro / bridged polycyclic 4-11 membered heterocycloalkyl comprising one or more heteroatoms independently selected from N, S, and O.
  • R 1 is morpholinyl, tetrahydropyranyl, 2-oxa-8-azaspiro[4.5]decanyl, 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-7- azaspiro[4.4]nonanyl, or 6-oxa-2-azaspiro[3.4]octanyl.
  • the compound of the invention is according to any one of Formulae I-IIc, wherein R 1 is monocyclic or spiro / bridged polycyclic 4-11 membered heterocycloalkyl comprising one or more heteroatoms independently selected from N, S, and O, which heterocycloalkyl is substituted with one or more independently selected OH, oxo, halo, C H alkyl unsubstituted or substituted with one or more independently selected halo, -NR 5a R 5b , or OH, or 4-7 membered heterocycloalkyl comprising one or more heteroatoms independently selected from N, S, and O.
  • R 1 is azetidinyl, pyrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azabicyclo[3.2.1]octanyl, azabicyclo[2.2.1]heptanyl, azaspiro[3.3]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, or 5- azaspiro[2.4]heptanyl, each of which is substituted with one or more independently selected OH, oxo, halo, Ci- 4 alkyl unsubstituted or substituted with one or more independently selected halo, -NR 5a R 5b , or OH, or 4-7 membered heterocycloalkyl comprising one or more heteroatoms independently selected from N, S, and O.
  • R 1 is monocyclic or spiro / bridged polycyclic 4-11 membered heterocycloalkyl comprising one or more heteroatoms independently selected from N, S, and O., which heterocycloalkyl is substituted with one or more independently selected OH, oxo, F, Cl, -CH 3 , -CH 2 CH 3 , -CH 2 OH, -CH 2 CH 2 OH, -CFFCFF-NiCFFri. or oxetanyl.
  • R 1 is azetidinyl, pyrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azabicyclo[3.2.1]octanyl, azabicyclo[2.2.1]heptanyl, azaspiro[3.3]heptanyl, 2-oxa-6- azaspiro[3.3]heptanyl, or 5-azaspiro[2.4]heptanyl, each of which is substituted with one or more independently selected OH, oxo, F, Cl, -CH 3 , -CH 2 CH 3 , -CH 2 OH, -CH 2 CH 2 OH, -CH2CH2-N(CH 3 )2, or oxetanyl.
  • the compound of the invention is according to any one of Formulae I-IIc, wherein R 1 is C H alkyl.
  • R 1 is -CH 3 , -CH2CH 3 , or -CH(CH 3 )2.
  • the compound of the invention is according to any one of Formulae I-IIc, wherein R 1 is C H alkyl substituted with one or more independently selected halo, -OH, C 1-4 alkoxy, or 4-7 membered monocyclic heterocycloalkyl comprising one or more heteroatoms independently selected from N, O, and S.
  • R 1 is -CH 3 , -GrhCTl ⁇ , -CH(CH 3 )2, or -CH2CH2CH 3 , each of which is substituted with one or more independently selected halo, -OH, Cw alkoxy, or 4-7 membered monocyclic heterocycloalkyl comprising one or more heteroatoms independently selected from N, O, and S.
  • R 1 is Cw alkyl substituted with one or more independently selected F, -OH, -OCH 3 , or -OCH 2 CH 3 , or oxetanyl, dioxanyl.
  • R 1 is -CH2OH, -CH2-OCH 3 , -CHF 2 , -CF 3 , -CF2CH2OH, -CH(CH 3 )CH 2 OH, or -CH 2 CF 2 CH 2 OH.
  • the compound of the invention is selected from:
  • the compounds of the invention is 3-chloro-5-fluoro-4-(6-((6-((2- hydroxyethyl)amino)pyrimidin-4-yl)amino)-lH-pyrazolo[4,3-c]pyridin-l-yl)benzonitrile.
  • the compounds of the invention is not 3-chloro-5-fhioro-4-(6-((6-((2- hydroxyethyl)amino)pyrimidin-4-yl)amino)- lH-pyrazolo [4,3 -c]pyridin- 1 -yl)benzonitrile .
  • the compounds of the invention are provided in a natural isotopic form.
  • the compounds of the invention are provided in an unnatural variant isotopic form.
  • the unnatural variant isotopic form is a form in which deuterium (i.e. 2 H or D) is incorporated where hydrogen is specified in the chemical structure in one or more atoms of a compound of the invention.
  • the atoms of the compounds of the invention are in an isotopic form which is not radioactive.
  • one or more atoms of the compounds of the invention are in an isotopic form which is radioactive.
  • radioactive isotopes are stable isotopes.
  • the unnatural variant isotopic form is a pharmaceutically acceptable form.
  • a compound of the invention whereby a single atom of the compound exists in an unnatural variant isotopic form. In another embodiment, a compound of the invention is provided whereby two or more atoms exist in an unnatural variant isotopic form.
  • Unnatural isotopic variant forms can generally be prepared by conventional techniques known to those skilled in the art or by processes described herein e.g. processes analogous to those described in the accompanying Examples for preparing natural isotopic forms. Thus, unnatural isotopic variant forms could be prepared by using appropriate isotopically variant (or labelled) reagents in place of the normal reagents employed in the Examples.
  • a compound of the invention is not an isotopic variant.
  • a compound of the invention according to any one of the embodiments herein described is a pharmaceutically acceptable salt.
  • a compound of the invention according to any one of the embodiments herein described is a solvate of the compound.
  • a compound of the invention according to any one of the embodiments herein described is a solvate of a pharmaceutically acceptable salt of a compound.
  • a compound of the invention may be one for which one or more variables (for example, R groups) is selected from one or more embodiments according to any of the Formula(e) listed above. Therefore, the present invention is intended to include all combinations of variables from any of the disclosed embodiments within its scope.
  • the present invention provides prodrugs and derivatives of the compounds according to the formulae above.
  • Prodrugs are derivatives of the compounds of the invention, which have metabolically cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention, which are pharmaceutically active, in vivo.
  • Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like.
  • Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides and anhydrides derived from acidic groups pendant on the compounds of this invention are preferred prodrugs.
  • double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters.
  • Particularly useful are the Ci to Cs alkyl, C 2 -C 8 alkenyl, aryl, C 7 -C 12 substituted aryl, and C 7 -C 12 arylalkyl esters of the compounds of the invention.
  • a compound of the invention according to Formula I may be admixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio.
  • a minor amount of magnesium stearate may be added as a lubricant.
  • the mixture may be formed into 240-270 mg tablets (80-90 mg of active compound of the invention according to Formula I per tablet) in a tablet press.
  • a compound of the invention according to Formula I may be admixed as a dry powder with a starch diluent in an approximate 1:1 weight ratio.
  • the mixture may be filled into 250 mg capsules (125 mg of active compound of the invention according to Formula I per capsule).
  • a compound of the invention according to Formula I may be admixed with sucrose (1.75 g) and xanthan gum (4 mg) and the resultant mixture may be blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of microcrystalline cellulose and sodium carboxymethyl cellulose (11:89, 50 mg) in water.
  • Sodium benzoate (10 mg) flavor, and color may be diluted with water and added with stirring. Sufficient water may then be added with stirring. Further sufficient water may be then added to produce a total volume of 5 mL.
  • a compound of the invention according to Formula I may be admixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio.
  • a minor amount of magnesium stearate may be added as a lubricant.
  • the mixture may be formed into 450-900 mg tablets (150-300 mg of active compound of the invention according to Formula I) in a tablet press.
  • a compound of the invention according to Formula I may be dissolved or suspended in a buffered sterile saline injectable aqueous medium to a concentration of approximately 5 mg/mL.
  • Stearyl alcohol (250 g) and a white petrolatum (250 g) may be melted at about 75°C and then a mixture of A compound of the invention according to Formula I (50 g) methylparaben (0.25 g), propylparaben (0.15 g), sodium lauryl sulfate (10 g), and propylene glycol (120 g) dissolved in water (about 370 g) may be added and the resulting mixture may be stirred until it congeals.
  • the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention, for use in medicine.
  • the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and/or treatment of allergic diseases, inflammatory diseases, metabolic diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformations, and/or diseases associated with hypersecretion of IFNa, IL12 and/or IL23.
  • the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention for use in the manufacture of a medicament for use in the prophylaxis and/or treatment of allergic diseases, inflammatory diseases, metabolic diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformations, and/or diseases associated with hypersecretion of IFNa, IL12 and/or IL23.
  • this invention provides methods of prophylaxis and/or treatment of a mammal afflicted with allergic diseases, inflammatory diseases, metabolic diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformations, and/or diseases associated with hypersecretion of IFNa, IL12 and/or IL23, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition.
  • the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent.
  • the other therapeutic agent is an allergic diseases, inflammatory diseases, metabolic diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformations, and/or diseases associated with hypersecretion of IFNa, IL12 and/or IL23 treatment agent.
  • the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention, for use in medicine.
  • the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and/or treatment of allergic diseases.
  • the allergic disease is asthma.
  • the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention for use in the manufacture of a medicament for use in the prophylaxis and/or treatment of allergic diseases.
  • the allergic disease is asthma.
  • this invention provides methods of prophylaxis and/or treatment of a mammal afflicted with allergic diseases, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition.
  • the allergic disease is asthma.
  • the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent.
  • the other therapeutic agent is an allergic diseases treatment agent.
  • the allergic disease is asthma.
  • the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention, for use in medicine.
  • the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and/or treatment of inflammatory diseases.
  • the inflammatory disease is rheumatoid arthritis, psoriatic arthritis, chronic obstructive pulmonary disease (COPD), primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC) and inflammatory bowel diseases.
  • COPD chronic obstructive pulmonary disease
  • PBC primary biliary cholangitis
  • PSC primary sclerosing cholangitis
  • the inflammatory disease is rheumatoid arthritis, psoriatic arthritis and inflammatory bowel diseases.
  • the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention for use in the manufacture of a medicament for use in the prophylaxis and/or treatment of inflammatory diseases.
  • the inflammatory disease is rheumatoid arthritis, psoriatic arthritis, chronic obstructive pulmonary disease (COPD), primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC) and inflammatory bowel diseases.
  • the inflammatory disease is rheumatoid arthritis, psoriatic arthritis and inflammatory bowel diseases.
  • this invention provides methods of prophylaxis and/or treatment of a mammal afflicted with inflammatory diseases, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition.
  • the inflammatory disease is rheumatoid arthritis, psoriatic arthritis, chronic obstructive pulmonary disease (COPD), primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC) and inflammatory bowel diseases.
  • COPD chronic obstructive pulmonary disease
  • PBC primary biliary cholangitis
  • PSC primary sclerosing cholangitis
  • the inflammatory disease is rheumatoid arthritis, psoriatic arthritis and inflammatory bowel diseases.
  • the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent.
  • the other therapeutic agent is inflammatory diseases treatment agent.
  • the inflammatory disease is rheumatoid arthritis, psoriatic arthritis, chronic obstructive pulmonary disease (COPD), primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC) and inflammatory bowel diseases.
  • the inflammatory disease is rheumatoid arthritis, psoriatic arthritis and inflammatory bowel diseases.
  • the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention, for use in medicine.
  • the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and/or treatment of metabolic diseases.
  • the metabolic disease is type II diabetes and/or obesity.
  • the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention for use in the manufacture of a medicament for use in the prophylaxis and/or treatment of metabolic diseases.
  • the metabolic disease is type II diabetes and/or obesity.
  • this invention provides methods of prophylaxis and/or treatment of a mammal afflicted with metabolic diseases, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition.
  • the metabolic disease is type II diabetes and/or obesity.
  • the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent.
  • the other therapeutic agent is metabolic diseases treatment agent.
  • the metabolic disease is type II diabetes and/or obesity.
  • the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention, for use in medicine.
  • the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and/or treatment of autoimmune diseases.
  • the autoimmune disease is COPD, asthma, systemic lupus erythematosus, type I diabetes mellitus, interferonopathy, and inflammatory bowel disease.
  • the autoimmune disease is systemic lupus erythematosus.
  • the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention for use in the manufacture of a medicament for use in the prophylaxis and/or treatment of autoimmune diseases.
  • the autoimmune disease is COPD, asthma, systemic lupus erythematosus, type I diabetes mellitus, interferonopathy, and inflammatory bowel disease.
  • the autoimmune disease is systemic lupus erythematosus.
  • this invention provides methods of prophylaxis and/or treatment of a mammal afflicted with autoimmune diseases, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition.
  • the autoimmune disease is COPD, asthma, systemic lupus erythematosus, type I diabetes mellitus, interferonopathy, and inflammatory bowel disease.
  • the autoimmune disease is systemic lupus erythematosus.
  • the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent.
  • the other therapeutic agent is an autoimmune diseases treatment agent.
  • the autoimmune disease is COPD, asthma, systemic lupus erythematosus, type I diabetes mellitus, interferonopathy, and inflammatory bowel disease.
  • the autoimmune disease is systemic lupus erythematosus.
  • the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention, for use in medicine.
  • the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and/or treatment of autoinflammatory diseases.
  • the autoimmune disease is Cryopyrin-Associated Periodic Syndromes (CAPS), Familial Mediterranean Fever (FMF) and Tumor necrosis factor receptor-associated periodic syndrome (TRAPS), Behcets. Systemic-Onset Juvenile Idiopathic Arthritis (SJIA) or Still’s disease.
  • the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention for use in the manufacture of a medicament for use in the prophylaxis and/or treatment of autoinflammatory diseases.
  • the autoimmune disease is Cryopyrin-Associated Periodic Syndromes (CAPS), Familial Mediterranean Fever (FMF) and Tumor necrosis factor receptor-associated periodic syndrome (TRAPS), Behcets, Systemic-Onset Juvenile Idiopathic Arthritis (SJIA) or Still’s disease.
  • this invention provides methods of prophylaxis and/or treatment of a mammal afflicted with autoinflammatory diseases, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition.
  • the autoimmune disease is Cryopyrin-Associated Periodic Syndromes (CAPS), Familial Mediterranean Fever (FMF) and Tumor necrosis factor receptor-associated periodic syndrome (TRAPS), Behcets, Systemic-Onset Juvenile Idiopathic Arthritis (SJIA) or Still’s disease.
  • the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent.
  • the other therapeutic agent is an autoinflammatory diseases treatment agent.
  • the autoimmune disease is Cryopyrin-Associated Periodic Syndromes (CAPS), Familial Mediterranean Fever (FMF) and Tumor necrosis factor receptor-associated periodic syndrome (TRAPS), Behcets, Systemic-Onset Juvenile Idiopathic Arthritis (SJIA) or Still’s disease.
  • CPS Cryopyrin-Associated Periodic Syndromes
  • FMF Familial Mediterranean Fever
  • TRAPS Tumor necrosis factor receptor-associated periodic syndrome
  • Behcets Behcets
  • SJIA Systemic-Onset Juvenile Idiopathic Arthritis
  • Still Still
  • the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention, for use in medicine.
  • the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and/or treatment of proliferative diseases.
  • the proliferative disease is cancer, leukemia, multiple myeloma and psoriasis.
  • the proliferative disease is psoriasis.
  • the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention for use in the manufacture of a medicament for use in the prophylaxis and/or treatment of proliferative diseases.
  • the proliferative disease is cancer, leukemia, multiple myeloma and psoriasis.
  • the proliferative disease is psoriasis.
  • this invention provides methods of prophylaxis and/or treatment of a mammal afflicted with proliferative diseases, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition.
  • the proliferative disease is cancer, leukemia, multiple myeloma and psoriasis. In a more particular embodiment, the proliferative disease is psoriasis.
  • the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent.
  • the other therapeutic agent is a proliferative diseases treatment agent.
  • the proliferative disease is cancer, leukemia, multiple myeloma and psoriasis.
  • the proliferative disease is psoriasis.
  • the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention, for use in medicine.
  • the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and/or treatment of transplantation rejection.
  • the transplantation rejection is graft versus host disease.
  • the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention for use in the manufacture of a medicament for use in the prophylaxis and/or treatment of transplantation rejection.
  • the transplantation rejection is graft versus host disease.
  • this invention provides methods of prophylaxis and/or treatment of a mammal afflicted with transplantation rejection, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition.
  • the transplantation rejection is graft versus host disease.
  • the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent.
  • the other therapeutic agent is a transplantation rejection treatment agent.
  • the transplantation rejection is graft versus host disease.
  • the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention, for use in medicine.
  • the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and/or treatment of diseases involving impairment of cartilage turnover.
  • the disease involving impairment of cartilage turnover is ankylosing spondylitis.
  • the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention for use in the manufacture of a medicament for use in the prophylaxis and/or treatment of diseases involving impairment of cartilage turnover.
  • the disease involving impairment of cartilage turnover is ankylosing spondylitis.
  • this invention provides methods of prophylaxis and/or treatment of a mammal afflicted with a disease involving impairment of cartilage turnover, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition.
  • the disease involving impairment of cartilage turnover is ankylosing spondylitis.
  • the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent.
  • the other therapeutic agent is a disease involving impairment of cartilage turnover treatment agent.
  • the disease involving impairment of cartilage turnover is ankylosing spondylitis.
  • the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention, for use in medicine.
  • the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and/or treatment of congenital cartilage malformations.
  • the congenital cartilage malformations is selected from microtia, anotia, and/or metaphyseal chondrodysplasia.
  • the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention for use in the manufacture of a medicament for use in the prophylaxis and/or treatment of congenital cartilage malformations.
  • the congenital cartilage malformations is selected from microtia, anotia, and/or metaphyseal chondrodysplasia.
  • this invention provides methods of prophylaxis and/or treatment of a mammal afflicted with congenital cartilage malformations, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition.
  • the congenital cartilage malformations is selected from microtia, anotia, and/or metaphyseal chondrodysplasia.
  • the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent.
  • the other therapeutic agent is a congenital cartilage malformations treatment agent.
  • the congenital cartilage malformations is selected from microtia, anotia, and/or metaphyseal chondrodysplasia.
  • the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention, for use in medicine.
  • the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and/or treatment of diseases associated with hypersecretion of IFNa, IL12 and/or IL23.
  • the disease associated with hypersecretion of IFNa, IL12 and/or IL23 is systemic and cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, Sjogren’s syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, trisomy 21 and/or Crohn’s disease.
  • the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention for use in the manufacture of a medicament for use in the prophylaxis and/or treatment of diseases associated with hypersecretion of IFNa, IL12 and/or IL23.
  • the disease associated with hypersecretion of IFNa, IL12 and/or IL23 is systemic and cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, Sjogren’s syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, trisomy 21 and/or Crohn’s disease.
  • this invention provides methods of prophylaxis and/or treatment of a mammal afflicted with diseases associated with hypersecretion of IFNa, IL12 and/or IL23, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition.
  • the disease associated with hypersecretion of IFNa, IL12 and/or IL23 is systemic and cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, Sjogren’s syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, trisomy 21 and/or Crohn’s disease.
  • the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent.
  • the other therapeutic agent is a diseases associated with hypersecretion of IFNa, IL12 and/or IL23 treatment agent.
  • the disease associated with hypersecretion of IFNa, IL12 and/or IL23 is systemic and cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, Sjogren’s syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, trisomy 21 and/or Crohn’s disease.
  • Injection dose levels range from about 0.1 mg/kg/h to at least 10 mg/kg/h, all for from about 1 to about 120 h and especially 24 to 96 h.
  • a preloading bolus of from about 0.1 mg/kg to about 10 mg/kg or more may also be administered to achieve adequate steady state levels.
  • the maximum total dose is not expected to exceed about 1 g/day for a 40 to 80 kg human patient.
  • the regimen for treatment usually stretches over many months or years so oral dosing is preferred for patient convenience and tolerance.
  • one to four (1-4) regular doses daily especially one to three (1-3) regular doses daily, typically one to two (1-2) regular doses daily, and most typically one (1) regular dose daily are representative regimens.
  • dosage regimen can be every 1-14 days, more particularly 1-10 days, even more particularly 1-7 days, and most particularly 1-3 days.
  • each dose provides from about 1 to about 1000 mg of a compound of the invention, with particular doses each providing from about 10 to about 500 mg and especially about 30 to about 250 mg.
  • Transdermal doses are generally selected to provide similar or lower blood levels than are achieved using injection doses.
  • a compound of the invention When used to prevent the onset of a condition, a compound of the invention will be administered to a patient at risk for developing the condition, typically on the advice and under the supervision of a physician, at the dosage levels described above.
  • Patients at risk for developing a particular condition generally include those that have a family history of the condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the condition.
  • a compound of the invention can be administered as the sole active agent or it can be administered in combination with other therapeutic agents, including other compound of the inventions that demonstrate the same or a similar therapeutic activity and that are determined to be safe and efficacious for such combined administration.
  • co-administration of two (or more) agents allows for significantly lower doses of each to be used, thereby reducing the side effects seen.
  • a compound of the invention or a pharmaceutical composition comprising a compound of the invention is administered as a medicament.
  • said pharmaceutical composition additionally comprises a further active ingredient.
  • a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prophylaxis of a disease involving inflammation
  • therapeutic agents include, but are not limited to, immunoregulatory agents (e.g. azathioprine), corticosteroids (e.g.
  • JAK inhibitors Tofacitinib, Filgotinib, Upadacitinib, Baricitinib, Decemotinib (VX-509), Peficitinib, PF-06651600, Brepocitinib (PF-06700841)
  • cyclophosphamide cyclosporin A, tacrolimus, mycophenolate, mofetil, muromonab-CD3 (OKT3, e.g. Orthocolone®), ATG, aspirin, acetaminophen, ibuprofen, naproxen, and piroxicam.
  • a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prophylaxis of arthritis (e.g. rheumatoid arthritis), particular agents include but are not limited to analgesics, non-steroidal anti-inflammatory drugs (NSAIDS), JAK inhibitors (Tofacitinib, Filgotinib, Upadacitinib, Baricitinib, Decemotinib (VX-509), Peficitinib, PF-06651600, Brepocitinib (PF- 06700841)), steroids, synthetic DMARDS (for example but without limitation methotrexate, leflunomide, sulfasalazine, auranofm, sodium aurothiomalate, penicillamine, chloroquine, hydroxychloroquine, azathioprine, and cyclosporin), and biological DMARDS (for example but without limitation infliximab, e
  • NNSA non-ster
  • a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prophylaxis of proliferative disorders
  • therapeutic agents include but are not limited to: methotrexate, leukovorin, adriamycin, prednisone, bleomycin, cyclophosphamide, 5-fluorouracil, paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine, doxorubicin, tamoxifen, toremifene, megestrol acetate, anastrozole, goserelin, anti-HER 2 monoclonal antibody (e.g.
  • the compound of the invention according to Formula I may be administered in combination with other therapies including, but not limited to, radiotherapy or surgery.
  • the proliferative disorder is selected from cancer, myeloproliferative disease or leukaemia.
  • a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prophylaxis of autoimmune diseases
  • particular agents include but are not limited to: glucocorticoids, JAK inhibitors (Tofacitinib, Filgotinib, Upadacitinib, Baricitinib, Decemotinib (VX- 509), Peficitinib, PF-06651600, Brepocitinib (PF-06700841)), cytostatic agents (e.g.
  • purine analogs include alkylating agents, (e.g nitrogen mustards (cyclophosphamide), nitrosoureas, platinum compound of the inventions, and others), antimetabolites (e.g. methotrexate, azathioprine and mercaptopurine), cytotoxic antibiotics (e.g. dactinomycin anthracyclines, mitomycin C, bleomycin, and mithramycin), antibodies (e.g. anti-CD20, anti-CD25 or anti-CD3 (OTK3) monoclonal antibodies, Atgam® and Thymoglobuline®), cyclosporin, tacrolimus, rapamycin (sirolimus), interferons (e.g. IFN-b), TNF binding proteins (e.g. infliximab, etanercept, or adalimumab), mycophenolate, fingolimod and myriocin..
  • alkylating agents e.
  • a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prophylaxis of transplant rejection
  • particular agents include but are not limited to: calcineurin inhibitors (e.g. cyclosporin or tacrolimus (FK506)), JAK inhibitors (Tofacitinib, Filgotinib, Upadacitinib, Baricitinib, Decemotinib (VX-509), Peficitinib, PF-06651600, Brepocitinib (PF-06700841)), mTOR inhibitors (e.g. sirolimus, everolimus), anti-proliferatives (e.g.
  • azathioprine mycophenolic acid
  • corticosteroids e.g. prednisolone, hydrocortisone
  • antibodies e.g. monoclonal anti-IF-2Ra receptor antibodies, basiliximab, daclizumab
  • polyclonal anti-T-cell antibodies e.g. anti-thymocyte globulin (ATG), anti -lymphocyte globulin (AEG)
  • a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prophylaxis of asthma and/or rhinitis and/or COPD
  • particular agents include but are not limited to: beta2 -adrenoceptor agonists (e.g. salbutamol, levalbuterol, terbutabne and bitolterol), epinephrine (inhaled or tablets), anticholinergics (e.g. ipratropium bromide), glucocorticoids (oral or inhaled).
  • beta2 -adrenoceptor agonists e.g. salbutamol, levalbuterol, terbutabne and bitolterol
  • epinephrine inhaled or tablets
  • anticholinergics e.g. ipratropium bromide
  • glucocorticoids oral or inhaled.
  • Fong -acting b2 -agonists
  • salmeterol, formoterol, bambuterol, and sustained-release oral albuterol combinations of inhaled steroids and long -acting bronchodilators (e.g. fluticasone/salmeterol, budesonide/formoterol), leukotriene antagonists and synthesis inhibitors (e.g. montelukast, zafirlukast and zileuton), inhibitors of mediator release (e.g. cromoglycate and ketotifen), biological regulators of IgE response (e.g. omalizumab), antihistamines (e.g. ceterizine, cinnarizine, fexofenadine) and vasoconstrictors (e.g. oxymethazoline, xylomethazoline, nafazobne and tramazoline).
  • bronchodilators e.g. fluticasone/salmeterol, budesonide/form
  • a compound of the invention may be administered in combination with emergency therapies for asthma and/or COPD, such therapies include oxygen or heliox administration, nebulized salbutamol or terbutaline (optionally combined with an anticholinergic (e.g. ipratropium), systemic steroids (oral or intravenous, e.g. prednisone, prednisolone, methylprednisolone, dexamethasone, or hydrocortisone), intravenous salbutamol, non-specific beta-agonists, injected or inhaled (e.g.
  • oxygen or heliox administration ebulized salbutamol or terbutaline
  • an anticholinergic e.g. ipratropium
  • systemic steroids oral or intravenous, e.g. prednisone, prednisolone, methylprednisolone, dexamethasone, or hydrocortisone
  • intravenous salbutamol e.g. pred
  • epinephrine isoetharine, isoproterenol, metaproterenol
  • anticholinergics IV or nebulized, e.g. glycopyrrolate, atropine, ipratropium
  • methylxanthines theophylline, aminophylline, bamiphylline
  • inhalation anesthetics that have a bronchodilatory effect (e.g. isoflurane, halothane, enflurane), ketamine and intravenous magnesium sulfate.
  • a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prophylaxis of inflammatory bowel disease (IBD), particular agents include but are not limited to: glucocorticoids (e.g. prednisone, budesonide) JAK inhibitors (Tofacitinib, Filgotinib, Upadacitinib, Baricitinib, Decemotinib (VX-509), Peficitinib, PF-06651600, Brepocitinib (PF-06700841)), synthetic disease modifying, immunomodulatory agents (e.g.
  • glucocorticoids e.g. prednisone, budesonide
  • JAK inhibitors Tofacitinib, Filgotinib, Upadacitinib, Baricitinib, Decemotinib (VX-509), Peficitinib, PF-06651600, Brepocitinib (PF
  • methotrexate methotrexate, leflunomide, sulfasalazine, mesalazine, azathioprine, 6-mercaptopurine and cyclosporin
  • biological disease modifying immunomodulatory agents
  • immunomodulatory agents infliximab, adalimumab, rituximab, and abatacept.
  • a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prophylaxis of SLE
  • particular agents include but are not limited to: human monoclonal antibodies (belimumab (Benlysta)), JAK inhibitors (Tofacitinib, Filgotinib, Upadacitinib, Baricitinib, Decemotinib (VX-509), Peficitinib, PF-06651600, Brepocitinib (PF-06700841)), Disease modifying antirheumatic drugs (DMARDs) such as antimalarials (e.g. plaquenil, hydroxychloroquine), immunosuppressants (e.g.
  • methotrexate and azathioprine methotrexate and azathioprine
  • cyclophosphamide mycophenolic acid
  • immunosuppressive drugs and analgesics such as nonsteroidal anti-inflammatory drugs, opiates (e.g. dextropropoxyphene and co-codamol), opioids (e.g. hydrocodone, oxycodone, MS Contin, or methadone) and the fentanyl duragesic transdermal patch.
  • a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prophylaxis of psoriasis
  • particular agents include but are not limited to: topical treatments such as bath solutions, moisturizers, medicated creams and ointments containing coal tar, dithranol (anthralin), corticosteroids like desoximetasone (TopicortTM), fluocinonide, vitamin D3 analogues (for example, calcipotriol), argan oil and retinoids (etretinate, acitretin, tazarotene), systemic treatments such as methotrexate, JAK inhibitors (Tofacitinib, Filgotinib, Upadacitinib, Baricitinib, Decemotinib (VX- 509), Peficitinib, PF-06651600, Brepocitinib (PF-06700841)), cyclosporine
  • a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prophylaxis of allergic reaction
  • therapeutic agents include but are not limited to: antihistamines (e.g. cetirizine, diphenhydramine, fexofenadine, levocetirizine), glucocorticoids (e.g. prednisone, betamethasone, beclomethasone, dexamethasone), epinephrine, theophylline or anti- leukotrienes (e.g. montelukast or zafirlukast), anti-cholinergics and decongestants.
  • antihistamines e.g. cetirizine, diphenhydramine, fexofenadine, levocetirizine
  • glucocorticoids e.g. prednisone, betamethasone, beclomethasone, dexamethasone
  • epinephrine e
  • any means of delivering two or more therapeutic agents to the patient as part of the same treatment regime is included any means of delivering two or more therapeutic agents to the patient as part of the same treatment regime, as will be apparent to the skilled person.
  • the two or more agents may be administered simultaneously in a single formulation, i.e. as a single pharmaceutical composition, this is not essential.
  • the agents may be administered in different formulations and at different times.
  • the compound of the invention can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e. reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
  • a compound of the invention may be prepared from known or commercially available starting materials and reagents by one skilled in the art of organic synthesis.
  • ⁇ NMR spectra were recorded on a Bruker Avance 400 NMR spectrometer (400 MHz), Bruker DPX 300 NMR spectrometer (300 MHz), Bruker AV400 NMR spectrometer (400 MHz), or Bruker DRX 500 NMR spectrometer (500 MHz). Chemical shifts (d) for 1H NMR spectra are reported in parts per million (ppm) relative to tetramethylsilane (d 0.00) or the appropriate residual solvent peak, i.e. CHC1, (d 7.27), as internal reference.
  • Electrospray MS spectra were obtained on a Waters platform LC/MS spectrometer or with Waters Acquity H-Class UPLC coupled to a Waters QDA detector or Waters Acquity UPLC coupled with SQD mass spectrometer.
  • Racemic mixtures were separated on a SFC Basic Sepiatec system with UV detection. Column used: Chiralpak IG (10x250 mm, 5pm). Solvents used: 30 % MeOH in liquid CO2. Enantiomeric purity estimated on a SFC Basic Sepiatec system with UV detection. Column used: Chiralpak IG (10x250 mm, 5pm). Solvents used: 30 % MeOH in liquid CO2.
  • reaction mixture is stirred in sealed tube at 110°C for 18-24h, cooled to room temperature, diluted with a mixture ofMeOH/DCM and filtered through pall-seitz thick paper filter. Obtained filtrate is concentrated under vacuum and purified by flash chromatography on S1O2 (eluting with 2 to 10% 7N N3 ⁇ 4 MeOH solution in DCM) to afford the title compound or Boc protected intermediate.
  • the reaction mixture was stirred in sealed tube at 110°C for 18h, cooled to room temperature, diluted with a mixture of MeOH/DCM and fdtered through pall-seitz thick paper fdter. Obtained fdtrate was coated on S1O2 and purified by flash chromatography on S1O2 (eluting with 2 to 10% MeOH solution in DCM) to afford the Boc protected intermediate.
  • the reaction mixture was stirred in sealed tube at 110°C for 18h, cooled to room temperature, diluted with a mixture of MeOH/DCM and fdtered through pall-seitz thick paper fdter. Obtained fdtrate was coated on S1O2 and purified by flash chromatography on S1O2 (eluting with 2 to 10% MeOH solution in DCM) to afford the Boc protected intermediate.
  • reaction mixture is stirred in sealed tube at 100°C for 18h, cooled to room temperature, diluted with EtOAc and fdtered through a pad of celite.
  • the filtrate is coated on Si0 2 and purified by flash chromatography on Si0 2 (eluting with 1 to 10% MeOH solution in DCM) to afford the SEM protected intermediate.
  • the reaction mixture is stirred in sealed tube at 100-110°C for 3-18h, cooled to room temperature, diluted with EtOAc or DCM and fdtered through pall-itz thick paper fdter.
  • the fdtrate is coated on S1O2 and purified by flash chromatography on S1O2 (eluting with 1 to 10% 7N NH3 MeOH solution in DCM) to afford the SEM protected intermediate.
  • reaction mixture was stirred in sealed tube at 100°C for 18h.
  • the reaction mixture was cooled to room temperature, diluted with DCM and fdtered through pall-seitz thick paper fdter.
  • the fdtrate was coated on S1O2 and purified by flash chromatography on S1O2 (eluting with 1 to 10% 7N NEE MeOH solution in DCM) to afford the SEM protected intermediate.
  • Tr protected intermediate (1 eq) in DCM (0.1-0.3 M) is added TFA (150 eq) or triethysilane (3 eq) and TFA (2-30 eq).
  • TFA 150 eq
  • TFA triethysilane
  • the reaction mixture was degassed and stirred at 120°C for 72h, cooled to room temperature and filtered through a pad of S1O2.
  • the silica pad was washed with EtOAc and combined with the crude product obtained after the dioxane removal.
  • Saturated NEECl solution was added, the organic phase was separated, and the aqueous phase was extracted with EtOAc.
  • the combined organic phases were washed with saturated NaCl solution, dried over Na2S04 and concentrated to dryness under vacuum.
  • the crude mixture was purified by crystallization from EtOAc to afford the Tr protected intermediate.
  • reaction mixture was stirred in sealed tube at 110°C for 18h, cooled to room temperature, diluted with DCM and filtered through pall-seitz thick paper filter. The filtrate was concentrated under vacuum and purified by flash chromatography on Si0 2 (eluting with eluting with 0.5 to 10% 7N NH 3 MeOH solution in DCM) to afford title intermediate.
  • Tr protected intermediate (1 eq) in DCM (0.1 or 0.05 M) are added TFA (110-150 eq) or TFA (30 eq) and triethysilane (1-3 eq).
  • TFA 110-150 eq
  • TFA 30 eq
  • triethysilane 1-3 eq.
  • the reaction mixture is stirred at room temperature for l-2h.
  • the reaction mixture is concentrated to dryness under vacuum to afford the title compound or concentrated to dryness under vacuum and triturated with MTBE to afford the title compound.
  • the reaction mixture was stirred in sealed tube at 110°C for 15h, cooled to room temperature, fdtered through pall-seitz thick paper fdter.
  • the fdtrate was concentrated under vacuum and purified by flash chromatography on S1O2 (eluting with eluting with 2 to 10% 7N NH3 MeOH solution in DCM) to afford Tr proptected intermediate.
  • the filtrate was than acidified by adding 2N aq solution of HC1 (50ml) and the mixture was stirred at room temperature for 10 min. K2CO3 was then added until basic pH and the crude mixture was extracted with DCM. The combined organic layers were dried over MgSCL, filtered, concentrated to dryness and purified by flash chromatography on S1O2 (eluting with 0.5 to 2% MeOH solution in DCM) to afford the title intermediate.
  • the reaction mixture was charged again with Pd 2 dba 3 (116 mg, 0.126 mmol, 0.1 eq) and JohnPhos (44 mg, 0.126 mmol, 0.1 eq) and LiHMDS (1.3 M THF solution, 0.971 mL, 1.263 mmol, 1 eq), degassed and refluxed in microwave reactor at 100°C for 4h.
  • the reaction mixture was quenched with IN HC1 (45 ml) and water (200 ml), concentrated under vacuum and partitioned between DCM and IN NaOH (5 ml).
  • reaction mixture was stirred in sealed tube at 110°C for 20h, diluted with EtOAc and washed with water.
  • the separated organic phase was filtered on phase separator, concentrated under vacuum and purified by flash chromatography on S1O2 (eluting with 2 to 10% 7N N3 ⁇ 4 MeOH solution in DCM) to afford the title intermediate.
  • Recombinant human JAK1 (catalytic domain, amino acids 866-1154; catalog number PV4774) is purchased from Invitrogen. 1 ng of JAKl(or 2 ng of JAK1 depending of the enzyme lot number) is incubated with 20 nM Ulight-JAKl(tyR 1 023) peptide (Perkin Elmer catalog number TRF0121) in kinase reaction buffer (15mM MOPS pH6.8, 0.01% Brij-35, 5mM MgCE, 2mM DTT, 20mM ATP) with or without 4 pL containing test compound or vehicle (DMSO, 1% final concentration), in a total volume of 20 pL, in a white 384 Opti plate (Perkin Elmer, catalog number 6007290).
  • Fluorescent ratio test compound ratio RFU 665/ RFU 615 * 1000 determined for sample with test compound present
  • Fluorescent ratio control ratio RFU 665/ RFU 615 * 1000 determined for sample with positive control inhibitor
  • Fluorescent ratio vehicle ratio RFU 665/ RFU 615 * 1000 determined in the presence of vehicle
  • Dose dilution series were prepared for the compounds enabling the testing of dose-response effects in the JAK1 assay and the calculation of the IC50 for the compound. Each compound is routinely tested at concentration of 20 mM followed by a 1/5 serial dilution, 10 points in a final concentration of 1% DMSO. When potency of compound series increases, more dilutions are prepared and/or the top concentration are lowered (e.g. 5 mM, 1 pM). The data are expressed as the average IC50 from the assays.
  • Recombinant human JAK2 (catalytic domain, amino acids 808-1132; catalog number PV4210) is purchased from Invitrogen. 0.83ng of JAK2 is incubated with 25 nM Ulight-JAKl(tyR 1 023) peptide (Perkin Elmer catalog number TRF0121) in kinase reaction buffer 25mM MOPS pH7.0, 0.01% Triton X- 100, 7.5mM MgCE, 2mM DTT, 0.3mM ATP) with or without 4 pL containing test compound or vehicle (DMSO, 1% final concentration), in a total volume of 20 pL. in a white 384 Opti plate (Perkin Elmer, catalog number 6007290).
  • Fluorescent ratio test compound ratio RFU 665/ RFU 615 * 1000 determined for sample with test compound present
  • Fluorescent ratio control ratio RFU 665/ RFU 615 * 1000 determined for sample with positive control inhibitor
  • Fluorescent ratio vehicle ratio RFU 665/ RFU 615 * 1000 determined in the presence of vehicle
  • Dose dilution series are prepared for compound enabling the testing of dose-response effects in the JAK2 assay and the calculation of the IC50 for the compound. Each compound is routinely tested at concentration of 20 mM followed by a 1/5 serial dilution, 10 points in a final concentration of 1% DMSO. When potency of compound series increases, more dilutions are prepared and/or the top concentration are lowered (e.g. 5 mM, 1 mM). The data are expressed as the average IC50 from the assays.
  • Recombinant human JAK3 catalytic domain (amino acids 781-1124; catalog number PV3855) is purchased from Invitrogen.
  • 0.5 ng JAK3 protein is incubated with 2.5 pg polyGT substrate (Sigma catalog number P0275) in kinase reaction buffer (25 mM Tris pH 7.5, 0.5 mM EGTA, lOmM MgCL 2 , 2.5mM DTT, 0.5 mM Na3V04, 5 mM b-glycerolphosphate, 0.01% Triton X-100, 1 mM non-radioactive ATP, 0.25pCi 33P-gamma-ATP (Perkin Elmer, catalog number NEG602K001MC) final concentrations) with or without 5pL containing test compound or vehicle (DMSO, 1% final concentration), in a total volume of 25 pL, in a polypropylene 96-well plate (Greiner, catalog number 651201).
  • Kinase activity is calculated by subtracting counts per min (cpm) obtained in the presence of a positive control inhibitor (10 mM staurosporine) from cpm obtained in the presence of vehicle. [0277] The ability of a test compound to inhibit this activity (or percentage inhibition) is determined as:
  • cpm control cpm determined for sample with positive control inhibitor
  • cpm vehicle cpm determined in the presence of vehicle
  • Dose dilution series are prepared for the compounds enabling the testing of dose-response effects in the JAK3 assay and the calculation of the IC50 for each compound. Each compound is routinely tested at concentration of 20mM followed by a 1/3 serial dilution, 9 points in a final concentration of 1% DMSO. When potency of compound series increased, more dilutions are prepared and/or the top concentration is lowered (e.g. 5 mM, 1 mM).
  • JAK3 kinase potency was determined by a radiometric assay and performed at Eurofins Cerep SA, Le Bois L'Eveque, BP 30001, F- 86600 Celle-Levescault, cat no 14-629.
  • Recombinant human TYK2 catalytic domain (amino acids 871-1187; catalog number 08-147) is purchased from Cama biosciences. 10 ng of TYK2 is incubated in kinase reaction buffer (25 mM MOPS pH7.2, 50 mM NaCl, 0.01% Brij-35, 0.5 mM EDTA, lOmM MgCl 2 , ImM DTT, 12mM ultra pure ATP (Promega, catalog number V915B) final concentrations) with or without 1 pL containing test compound or vehicle (DMSO, 1 % final concentration), in a total volume of 5 pL, in a white 384 Opti plate (Perkin Elmer, catalog number 6007290).
  • kinase reaction buffer 25 mM MOPS pH7.2, 50 mM NaCl, 0.01% Brij-35, 0.5 mM EDTA, lOmM MgCl 2 , ImM DTT, 12mM ultra pure ATP
  • kinase activity is calculated by subtracting the relative light units (RLU) obtained in the presence of a positive control inhibitor (10 mM staurosporine) from the RLU obtained in the presence of vehicle.
  • RLU relative light units
  • a test compound to inhibit this activity (or percentage inhibition) is determined as:
  • RLU test compound RLU determined for sample with test compound present
  • RLU control RLU determined for sample with positive control inhibitor
  • RLU vehicle RLU determined in the presence of vehicle
  • Dose dilution series were prepared for the compounds enabling the testing of dose-response effects in the TYK2 assay and the calculation of the IC50 for the compound.
  • Each compound is routinely tested at concentration of 20 mM followed by a 1/5 serial dilution, 10 points in a final concentration of 1% DMSO.
  • potency of compound series increases, more dilutions are prepared and/or the top concentration are lowered (e.g. 5 pM, 1 pM).
  • the data are expressed as the average IC50 from the assays.
  • a flow cytometry analysis is performed to establish compound selectivity ex vivo using human whole blood by comparing potency (IC50) against each JAK members.
  • Compound is added at different concentrations and incubated at 37°C for 30 min under gentle rocking and subsequently stimulated for 20 30 min at 37°C under gentle rocking with interleukin 6 (IL-6) for JAK 1 -dependent pathway stimulation, Interferon alpha (IFNa) for JAK1/TYK2 pathway stimulation, or GM-CSF for JAK2 -dependent pathway stimulation.
  • IL-6 interleukin 6
  • IFNa Interferon alpha
  • GM-CSF for JAK2 -dependent pathway stimulation.
  • Phospho-STATl for IL-6- and IFNa-stimulated cells
  • phospho-STAT5 for GM-CSF- stimulated cells
  • JAK1 is a key driver in IFNa, IL6, IL10 and IL22 signaling
  • TYK2 is involved in type I interferons (including IFNa, INRb), IL23 and IL12 signaling (Gillooly et ak, 2016; Sohn et ak, 2013).
  • This assay measures the selectivity of a test compound by measuring its potency on IFNa signaling (JAK1 and/or TYK2 mediated) and IL6 signalling (JAK1 mediated only).
  • the 5X Lyse/Fix buffer (BD PhosFlow, Cat. no 558049) was diluted 5-fold with distilled water and pre-warmed at 37°C. The remaining diluted Lyse/Fix buffer was discarded.
  • 10 mg rhIL-6 (R&D Systems, Cat no 206-IL) was dissolved in 1 mL of PBS + 0.1% BSA to obtain a 10 mg/mL stock solution. The stock solution was aliquoted and stored at -80°C.
  • Tubes were centrifuged at 500g for 5 min at room temperature. The pellet was washed with 2 mL of PBS and, after centrifugation the supernatant was removed by inverting the tubes. 900 qL of ice-cold 100% methanol were added in order to permeabilize the cells.
  • PE mouse anti-STATl pY701
  • PE mouse IgG2aK isotype control antibody BD Biosciences, Cat. no 612564 and 559319, respectively
  • 20 qL of APC-conjugated anti-CD4 antibody or control APC-conjugated isotype antibody were added to IL-6-and IFNa-stimulated tubes and mixed, then incubated for 20 min at 4°C, in the dark.
  • 20qL of PE mouse anti-STAT5 pY694
  • PE mouse IgGlK isotype control antibody BD Biosciences, Cat.
  • APC mouse anti CD33 antibody (BD Biosciences #345800) or control APC mouse IgGl isotype antibody (BD Biosciences Cat. no 345818) were added to GM-CSF-stimulated tubes, mixed then incubated for 20 min at 4°C, in the dark.
  • the potencies measured for illustrative compounds of the invention on IL-6 signalling were ranging from 10 to 50 folds lower than on IFNa signaling (JAK1 and/or TYK2 mediated), therefore confirming TYK2 selectivity.
  • the potencies measured for illustrative compounds of the invention on GM-CSF signalling were at least 77 folds lower than on IFNa signaling (JAK1 and/or TYK2 mediated) , therefore confirming TYK2 selectivity.
  • Sterile PBS (Gibco, Cat# 20012027) was obtained from ThermoFisher Scientific (Massachusetts, USA); Brucella Agar (Cat# 211086) was obtained from Becton Dickinson (New Jersy, USA); Brucella Broth Base (Cat# B3051-500g) was obtained from Sigma Aldrich (Missouri, USA). Defibrinated sheep blood (Cat# SR0051) and Campygen (Cat# CN0025) were obtained from ThermoFisher Scientific (Massachusetts, USA). H. bilis ATCC 51360 was obtained from UGC Standards (Molsheim, France) and ComburtestE (Cat# 11896857) was obtained from Roche Diagnostics (Basel, Switzerland).
  • mice Seven to nine week old MDRla (FVB.129P2- AbcblatmlBor N7) female mice were obtained from Taconic (Rensselaer, NY, USA) and seven to nine week old FVB female mice were obtained from Janvier Uabs (Ue Genest-Saint-Isle, France). Mice were kept on a 12 h light/dark cycle. Temperature was maintained at 22 °C, food and water were provided ad libitum.
  • H. bilis culture was diluted in PBS in order to obtain 10 7 cfu/mouse and a second part was put in fresh Brucella Broth and incubated as previously for 7 days.
  • H. bilis culture was diluted in PBS in order to obtain 10 7 cfu/mouse.
  • DAI Disease Activity Index
  • Mouse recombinant IL-23, carrier free (Cat# 14-8231) is provided by e-Bioscience (Frankfurt, Germany).
  • mice female, 18-20 g body weight
  • Mice are kept on a 12 h light/dark cycle. Temperature is maintained at 22 °C, food and water are provided ad libitum.
  • mice On the first day (Dl), the mice were shaved around the two ears. For 4 consecutive days (D1 to D4), the mice received a daily intradermal dose of mouse recombinant IL-23 (1 pg/20 pL in PBS/0.1% BSA) in the right pinna ear and 20 pL of PBS/0.1% BSA in the left pinna ear under anesthesia.
  • mice were dosed with test-compound or with vehicle, 1 h prior IL-23 injection.
  • mice There were 10 mice per group. The results are expressed as mean ⁇ SEM and statistical analysis is performed using one-way ANOVA followed by Dunnett’s post-hoc test versus IL-23 vehicle groups.
  • Half ears are removed from RNAIaler" solution and put in Trizol ® after disruption with 1.4 mm ceramic beads in a Precellys ® device. Total RNA is then purified using NucleoSpin ® RNA kit. cDNA is prepared and quantitative PCR is performed with gene-specific primers from Qiagen using SYBR Green technology in a ViiA7 real-time PCR system (Applied Biosystems). Expression levels of each gene are calculated relative to the cyclophilin A housekeeping gene expression level. Data are expressed as mean ⁇ SEM of the relative quantity. The statistical test used is ANOVA analysis of variance with Dunnett's post- hoc test versus the IL-23 vehicle group.
  • Cpd 58 When tested according to the above-mentioned protocol, Cpd 58 showed a statistically significant effect on preventing ear thickening compared to IL23 group at 3, 10 & 30 mg/kg q.d. p.o. doses.
  • Aldara ® 5% imiquimod cream is obtained from MEDA.
  • Mouse anti-double-stranded DNA antibodies ELISA kits are obtained from Alpha Diagnostic International (Cat# 5120). Mouse urinary albumin ELISA kits are obtained from Abeam (Cat# abl08792). Urine creatinine assay kits are obtained from Abnova (Cat# KA4344).
  • BALB/cJ mice female, 18-20 g body weight
  • Mice are kept on a 12 h light/dark cycle. Temperature is maintained at 22 ⁇ 2 °C, food and water are provided ad libitum.
  • mice On the first day (Dl), the mice are shaved around the right ears. [0330] The mice receive an epicutaneous application of 1.25 mg of imiquimod 3 times per week on the right pinna ear for 12 consecutive weeks (D1 to D86). The control group receives the same quantity of vaseline.
  • mice are dosed with test compound (30 mg/kg, p.o., q.d. in methylcellulose 0.5%) or with vehicle (10 mL/kg).
  • the thickness of the ears is measured once a week with an automatic gage (Mitutoyo, Absolute Digimatic, 547-321).
  • Body weight is assessed at initiation and once a week until sacrifice . At necropsy, the spleen weight is also measured. The mice are sacrificed 2 h after the last dosing.
  • mice are individually placed in a metabolic cage to perform urinalysis and assess proteinuria (albumin to creatinine ratio).
  • Serums are collected at different time points (e.g., on D28, D56 and D86) to assess anti-double stranded-DNA IgG levels.
  • blood samples are also collected from the retro-orbital sinus for PK profiling just before dosing (TO) and 1 h, 3 h, and 6 h post-dosing.
  • mice There are 8-19 mice per group. The results are expressed as mean ⁇ SEM and statistical analysis is performed using one-way ANOVA followed by Dunnett’s post-hoc test versus imiquimod vehicle groups.
  • Plasma concentrations of each test compound are determined by an LC-MS/MS method in which the mass spectrometer is operated in positive or negative electrospray mode.
  • immunohistochemical analysis is performed using image analysis (CaloPix software, TRIBVN Healthcare) on the whole tissue section at a magnification of c 20. Data are expressed as mean ⁇ SEM and statistical analysis is performed using one-way ANOVA followed by Dunnett’s post- hoc test versus imiquimod vehicle group.
  • RNA is then purified with a QIAcube using an RNeasy ® 96 QIAcube ® HT Kit (Qiagen, Cat# 74171).
  • RNA is extracted using a phenol/chloroform process and then purified with a QIAcube using an RNeasy ® 96 QIAcube ® HT Kit (Qiagen, Cat# 74171).
  • cDNA is prepared and quantitative PCR performed with gene-specific primers from Qiagen using SYBR Green technology in a ViiA 7 real-time PCR system (Applied Biosystems) . Expression levels of each gene of interest are calculated relative to the cyclophilin, GAPDH and b-actin housekeeping gene expression levels.
  • Mouse IL-23 enhanced episomal expression vector is obtained from System Biosciences (Cat# EEV651A-1). Mouse IL-23 Quantikine ELISA Kits are obtained from R&D Systems (Cat# M2300). ProSense ® 680 and OsteoSense ® 750EX are obtained from PerkinElmer (Cat# NEV10003 and NEV10053EX). RNAlaler" is obtained from Ambion (Cat# AM7021). Imalgene ® 1000 (Merial) and Rompun ® 2% (Bayer) are obtained from Centravet (Cat# IMA004-6827812 and ROMOOl-6835444).
  • B10.RIII mice male, 8-week old are obtained from Charles River (Ecully, France). Mice are kept on a 12 h light/dark cycle. Temperature is maintained at 22 ⁇ 2 °C, food and water are provided ad libitum.
  • mice undergo a hydrodynamic inj ection of Ringer or IL-23 EEV in Ringer into the tail vein.
  • mice are scored for clinical symptoms until the end of the experiment.
  • blood is collected by puncture in the submandibular vein to assess the serum IL-23 concentration.
  • mice from all groups receive ProSense ® 680 probe (0.8 nmol/10 g, i.p.).
  • the mice are anesthetized.
  • Granulocyte infiltration is then measured using in vivo molecular imaging (Bruker In-Vivo Xtreme imaging system).
  • mice are dosed with test compound or with vehicle.
  • mice from all groups are sacrificed 2 h after last administration of compound.
  • Total blood is collected in a serum blood tube and mixed by gentle inversion 8-10 times. After clotting, blood samples are centrifuged 10 min at 1800 c g. After centrifugation, serum is stored at -80 °C.
  • Body weight is assessed at initiation of the study, then twice a week and at sacrifice.
  • mice from all groups receive ProSense ® 680 probe (0.8 nmol/10 g, i.p.) and OsteoSense ® 750EX probe (0.8 nmol/ 10 g, i.p.).
  • the mice are anesthetized and granulocyte infiltration and bone remodelling are measured using in vivo molecular imaging (Bruker In-Vivo Xtreme imaging system).
  • Methylcellulose 0.5% (Cat# AX021233) is obtained from VWR.
  • MC903 (calcipotriol, Cat# 2700/50) is obtained from Tocris Bioscience (Bristol, UK).
  • ProSense ® 680 (Cat# NEV10003) is obtained from PerkinElmer (Massachusetts, USA).
  • RNA/ /er ® (Cat# AM7021) is obtained from Ambion (California, USA).
  • BALB/cN mice female, 18-20 g body weight
  • CD 1/Swiss mice female, 24-26 g body weight
  • Mice are kept on a 12 h light/dark cycle. Temperature is maintained at 22 ⁇ 2 °C, food and water are provided ad libitum.
  • mice are dosed with test compound (15 or 30 mg/kg, p.o., b.i.d. in methylcellulose 0.5%) or dexamethasone (5 mg/kg. p.o.. q.d. in methylcellulose 0.5%), or with vehicle, until D10, D12, or D16.
  • test compound 15 or 30 mg/kg, p.o., b.i.d. in methylcellulose 0.5%) or dexamethasone (5 mg/kg. p.o.. q.d. in methylcellulose 0.5%), or with vehicle, until D10, D12, or D16.
  • Plasma concentrations of each test compound are determined by an LC-MS/MS method in which the mass spectrometer is operated in positive or negative electrospray mode.
  • each ear is measured immediately before first application of MC903 (baseline), three times a week, and at sacrifice using a thickness gauge (Mitutoyo, Absolute Digimatic, Cat# 547-321).
  • Body weight is assessed at immediately before first application of EtOH (baseline), three times a week and at sacrifice.
  • mice from all groups receive ProSense ® 680 probe (0.8 nmol/10 g, i.p.).
  • D9, D11 or D12 the mice are anesthetized.
  • Granulocyte infiltration is then measured using in vivo molecular imaging (Bruker In-Vivo Xtreme imaging system, excitation wavelength: 630 nm, emission wavelength: 700 nm, acquisition time: 5 seconds).
  • mice are sacrificed, total blood is collected in EDTA-coated tubes and plasma is frozen for further measurements (including circulating compound).
  • the pinnae of the ears are collected. One ear is cut longitudinally into 2 halves. One half is fixed in formaldehyde buffer 3.7% for histology; the other one is immersed in RNAlater'" to assess gene expression.
  • mice There are 8 mice per group. The results are expressed as mean ⁇ SEM and statistical analysis is performed using one-way ANOVA followed by Dunnett’s post-hoc test versus MC903 vehicle groups (MC903 treated mice dosed with vehicle alone) for ear thickness and weight, and/or versus EtOH vehicle group (EtOH treated mice dosed with vehicle alone) for body weight.
  • Ears are removed from RNAlater'" solution and placed in Trizol ® after disruption with 1.4 mm ceramic beads in a Bertin Instruments Precellys ® homogenizer. Total RNA is then extracted using a phenol/chloroform protocol and purified with a QIAcube using an RNeasy ® 96 QIAcube ® HT Kit (Qiagen, Cat# 74171). cDNA is prepared and quantitative PCR performed with gene-specific primers from Qiagen using SYBR Green technology in a ViiA 7 real-time PCR system (Applied Biosystems).
  • the statistical test used is ANOVA analysis of variance with Dunnett's post-hoc test versus the EtOH vehicle group and/or MC903 vehicle group.
  • BMS-986165 Is a Highly Potent and Selective Allosteric Inhibitor of Tyk2, Blocks IL-12, IL-23 and Type I Interferon Signaling and Provides for Robust Efficacy in Preclinical Models of Systemic Lupus Erythematosus and Inflammatory Bowel Disease. ACR Meet. Abstr.
  • Topical vitamin D3 and low- calcemic analogs induce thymic stromal lymphopoietin in mouse keratinocytes and trigger an atopic dermatitis.
  • Jak2 Deficiency Defines an EssentialDevelopmental Checkpoint in DefinitiveHematopoiesis. Cell 93, 397-409. https://doi.org/10.1016/S0092-8674(00)81168-X

Landscapes

  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne des composés de formule (I) dans laquelle R1, R2, et Cy sont tels que définis dans la description. La présente invention concerne des composés, des procédés pour leur production, des compositions pharmaceutiques les comprenant, et des procédés de traitement l'utilisant, pour la prophylaxie et/ou le traitement de maladies allergiques, de maladies inflammatoires, de maladies métaboliques, de maladies auto-inflammatoires, de maladies auto-immunes, de maladies prolifératives, d'un rejet de transplantation, de maladies impliquant une déficience du renouvellement du cartilage, de malformations congénitales du cartilage et/ou de maladies associées à l'hypersécrétion d'IFNα, IL12 et/ou IL23 par administration du composé de l'invention.
PCT/EP2020/072715 2019-08-19 2020-08-13 Dérivés de pyrazolo [4,3-c] pyridine et leurs compositions pharmaceutiques pour le traitement de troubles inflammatoires WO2021032582A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP20760394.5A EP4017590A1 (fr) 2019-08-19 2020-08-13 Dérivés de pyrazolo [4,3-c] pyridine et leurs compositions pharmaceutiques pour le traitement de troubles inflammatoires

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB1911868.6 2019-08-19
GBGB1911868.6A GB201911868D0 (en) 2019-08-19 2019-08-19 Novel compounds and pharmaceutical compositions thereof for the treatment of inflammatory disorders

Publications (1)

Publication Number Publication Date
WO2021032582A1 true WO2021032582A1 (fr) 2021-02-25

Family

ID=68099572

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2020/072715 WO2021032582A1 (fr) 2019-08-19 2020-08-13 Dérivés de pyrazolo [4,3-c] pyridine et leurs compositions pharmaceutiques pour le traitement de troubles inflammatoires

Country Status (5)

Country Link
EP (1) EP4017590A1 (fr)
AR (1) AR119792A1 (fr)
GB (1) GB201911868D0 (fr)
TW (1) TW202115060A (fr)
WO (1) WO2021032582A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4091449A1 (fr) * 2021-05-19 2022-11-23 Syngenta Crop Protection AG Procédé de désherbage
WO2023278483A1 (fr) * 2021-07-01 2023-01-05 Lomond Therapeutics, Inc. Composés comprenant des 1h-pyrazolo[4,3-c]pyridine-6-aminos en tant qu'agents thérapeutiques
WO2023161327A1 (fr) * 2022-02-24 2023-08-31 Galapagos Nv Procédés de traitement de maladies inflammatoires et composé destiné à être utilisé dans ces procédés

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115557947B (zh) * 2021-07-02 2024-04-02 成都百裕制药股份有限公司 吡唑并[4,3-c]吡啶衍生物及其在医药上的应用

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007140222A2 (fr) * 2006-05-26 2007-12-06 Novartis Ag Composés de pyrrolopyrimidine et leurs utilisations
US20090203688A1 (en) * 2008-02-06 2009-08-13 Novartis Ag Heterocyclic compounds
WO2013017480A1 (fr) * 2011-07-29 2013-02-07 Cellzome Limited Dérivés de pyrazolo[4,3-c]pyridine en tant qu'inhibiteurs de jak

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007140222A2 (fr) * 2006-05-26 2007-12-06 Novartis Ag Composés de pyrrolopyrimidine et leurs utilisations
US20090203688A1 (en) * 2008-02-06 2009-08-13 Novartis Ag Heterocyclic compounds
WO2013017480A1 (fr) * 2011-07-29 2013-02-07 Cellzome Limited Dérivés de pyrazolo[4,3-c]pyridine en tant qu'inhibiteurs de jak

Non-Patent Citations (17)

* Cited by examiner, † Cited by third party
Title
BABON, J.J.LUCET, I.S.MURPHY, J.M.NICOLA, N.A.VARGHESE, L.N.: "The molecular regulation of Janus kinase (JAK) activation", BIOCHEM. J., vol. 462, 2014, pages 1 - 13, Retrieved from the Internet <URL:https://doi.org/10.1042/BJ20140712>
BROEKMAN, F.GIOVANNETTI, E.PETERS, G.J.: "Tyrosine kinase inhibitors: Multi-targeted or single-targeted?", WORLD J. CLIN. ONCOL., vol. 2, 2011, pages 80 - 93, Retrieved from the Internet <URL:https://doi.org/10.5306/wjco.v2.i2.80>
DENDROU, C.A.CORTES, A.SHIPMAN, L.EVANS, H.G.ATTFIELD, K.E.JOSTINS, L.BARBER, T.KAUR, G.KUTTIKKATTE, S.B.LEACH, O.A.: "Resolving TYK2 locus genotype-to-phenotype differences in autoimmunity", SCI. TRANSL. MED., vol. 8, 2016, pages 363ra149, Retrieved from the Internet <URL:https://doi.org/10.1126/scitranslmed.aagl974>
FABIAN, M.A.BIGGS, W.H.TREIBER, D.K.ATTERIDGE, C.E.AZIMIOARA, M.D.BENEDETTI, M.G.CARTER, T.A.CICERI, P.EDEEN, P.T.FLOYD, M.: "A small molecule-kinase interaction map for clinical kinase inhibitors", NAT. BIOTECHNOL., vol. 23, 2005, pages 329 - 336, Retrieved from the Internet <URL:https://doi.org/10.1038/nbtl068>
GILLOOLY, K.ZHANG, Y.YANG, X.ZUPA-FERNANDEZ, A.CHENG, L.STRNAD, J.CUNNINGHAM, M.HEIMRICH, E.ZHOU, X.CHEN, J.: "BMS-986165 Is a Highly Potent and Selective Allosteric Inhibitor of Tyk2, Blocks IL-12, IL-23 and Type I Interferon Signaling and Provides for Robust Efficacy in Preclinical Models of Systemic Lupus Erythematosus and Inflammatory Bowel Disease", ACR MEET, 2016, Retrieved from the Internet <URL:URLhttps://acrabstracts.org/abstract/bms-986165-is-a-highly-potent-and-selective-allosteric-inhibitor-of-tyk2-blocks-il-12-il-23-and-type-i-interferon-signaling-and-provides-for-robust-efficacy-in-preclinical-models-of-systemic-lupus-e>
LI, M.HENER, P.ZHANG, Z.KATO, S.METZGER, D.CHAMBON, P.: "Topical vitamin D3 and low-calcemic analogs induce thymic stromal lymphopoietin in mouse keratinocytes and trigger an atopic dermatitis", PROC. NATL. ACAD. SCI., vol. 103, 2006, pages 11736 - 11741, XP002410505, Retrieved from the Internet <URL:https://doi.org/10.1073/pnas.0604575103> DOI: 10.1073/pnas.0604575103
MAXWELL, J.R.ZHANG, Y.BROWN, W.A.SMITH, C.L.BYRNE, F.R.FIORINO, M.STEVENS, E.BIGLER, J.DAVIS, J.A.ROTTMAN, J.B.: "Differential Roles for Interleukin-23 and Interleukin-17 in Intestinal Immunoregulation", IMMUNITY, vol. 43, 2015, pages 739 - 750, Retrieved from the Internet <URL:https://doi.org/10.1016/j.immuni.2015.08.019>
NEUBAUER, H.CUMANO, A.MULLER, M.WU, H.HUFFSTADT, U.PFEFFER, K.: "Jak2 Deficiency Defines an EssentialDevelopmental Checkpoint in DefinitiveHematopoiesis", CELL, vol. 93, 1998, pages 397 - 409, Retrieved from the Internet <URL:https://doi.org/10.1016/S0092-8674(00)81168-X>
O'SHEA, J.J.PLENGE, R.: "JAKs and STATs in Immunoregulation and Immune-Mediated Disease", IMMUNITY, vol. 36, 2012, pages 542 - 550, Retrieved from the Internet <URL:https://doi.org/10.1016/j.immuni.2012.03.014>
PARGANAS, E.WANG, D.STRAVOPODIS, D.TOPHAM, D.J.MARINE, J.-C.TEGLUND, S.VANIN, E.F.BODNER, S.COLAMONICI, O.R.VAN DEURSEN, J.M.: "Jak2 Is Essential for Signaling through a Variety of Cytokine Receptors", CELL, vol. 93, 1998, pages 385 - 395, XP055573292, Retrieved from the Internet <URL:https://doi.org/10.1016/S0092-8674(00)81167-8> DOI: 10.1016/S0092-8674(00)81167-8
RIZZO, H.L.KAGAMI, S.PHILLIPS, K.G.KURTZ, S.E.JACQUES, S.L.BLAUVELT, A.: "IL-23-Mediated Psoriasis-Like Epidermal Hyperplasia Is Dependent on IL-17A", J. IMMUNOL., vol. 186, 2011, pages 1495 - 1502, Retrieved from the Internet <URL:https://doi.org/10.4049/jimmunol.1001001>
SCHWARTZ, D.M.BONELLI, M.GADINA, M.O'SHEA, J.J.: "Type I/II cytokines, JAKs, and new strategies for treating autoimmune diseases", NAT. REV. RHEUMATOL., vol. 12, 2016, pages 25 - 36, XP055272570, Retrieved from the Internet <URL:https://doi.org/10.1038/nrrheum.2015.167> DOI: 10.1038/nrrheum.2015.167
SHERLOCK, J.P.JOYCE-SHAIKH, B.TURNER, S.P.CHAO, C.-C.SATHE, M.GREIN, J.GORMAN, D.M.BOWMAN, E.P.MCCLANAHAN, T.K.YEARLEY, J.H.: "IL-23 induces spondyloarthropathy by acting on ROR-yt+ CD3+CD4-CD8- entheseal resident T cells", NAT. MED., vol. 18, 2012, pages 1069 - 1076, Retrieved from the Internet <URL:https://doi.org/10.1038/nm.2817>
SOHN, S.J.BARRETT, K.VAN ABBEMA, A.CHANG, C.KOHLI, P.B.KANDA, H.SMITH, J.LAI, Y.ZHOU, A.ZHANG, B.: "A Restricted Role for TYK2 Catalytic Activity in Human Cytokine Responses Revealed by Novel TYK2-Selective Inhibitors", J. IMMUNOL. AUTHOR CHOICE, vol. 191, 2013, pages 2205 - 2216, Retrieved from the Internet <URL:https://doi.org/10.4049/jimmunol.1202859>
VAINCHENKER, W.DUSA, A.CONSTANTINESCU, S.N.: "JAKs in pathology: Role of Janus kinases in hematopoietic malignancies and immunodeficiencies", SEMIN. CELL DEV. BIOL., vol. 19, 2008, pages 385 - 393, XP025885305, Retrieved from the Internet <URL:https://doi.org/10.1016/j.semcdb.2008.07.002> DOI: 10.1016/j.semcdb.2008.07.002
YE, Q.WANG, B.MAO, J.: "The pathogenesis and treatment of the 'Cytokine Storm' in COVID-19", J. INFECT., vol. 80, 2020, pages 607 - 613, XP055695752, Retrieved from the Internet <URL:https://doi.org/10.1016/jjinf.2020.03.037> DOI: 10.1016/j.jinf.2020.03.037
YOKOGAWA, M.TAKAISHI, M.NAKAJIMA, K.KAMIJIMA, R.FUJIMOTO, C.KATAOKA, S.TERADA, Y.SANO, S.: "Epicutaneous Application of Toll-like Receptor 7 Agonists Leads to Systemic Autoimmunity in Wild-Type Mice: A New Model of Systemic Lupus Erythematosus", ARTHRITIS RHEUMATOL., vol. 66, 2014, pages 694 - 706, Retrieved from the Internet <URL:https://doi.org/10.1002/art.38298>

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4091449A1 (fr) * 2021-05-19 2022-11-23 Syngenta Crop Protection AG Procédé de désherbage
WO2023278483A1 (fr) * 2021-07-01 2023-01-05 Lomond Therapeutics, Inc. Composés comprenant des 1h-pyrazolo[4,3-c]pyridine-6-aminos en tant qu'agents thérapeutiques
WO2023161327A1 (fr) * 2022-02-24 2023-08-31 Galapagos Nv Procédés de traitement de maladies inflammatoires et composé destiné à être utilisé dans ces procédés

Also Published As

Publication number Publication date
AR119792A1 (es) 2022-01-12
TW202115060A (zh) 2021-04-16
EP4017590A1 (fr) 2022-06-29
GB201911868D0 (en) 2019-10-02

Similar Documents

Publication Publication Date Title
US20220340581A1 (en) Compounds and pharmaceutical compositions thereof for the treatment of diseases
EP3976189B1 (fr) Nouveaux composés et compositions pharmaceutiques associées pour le traitement de maladies
WO2021032582A1 (fr) Dérivés de pyrazolo [4,3-c] pyridine et leurs compositions pharmaceutiques pour le traitement de troubles inflammatoires
TWI805629B (zh) 用於治療發炎性病症之新穎化合物及其醫藥組合物
US20220402911A1 (en) Novel compounds and pharmaceutical compositions thereof for the treatment of diseases
US20220235048A1 (en) Novel compounds and pharmaceutical compositions thereof for the treatment of diseases
WO2020200900A1 (fr) Nouveaux composés et compositions pharmaceutiques de ceux-ci pour le traitement de troubles inflammatoires
JP2020507612A (ja) Ｉｒａｋ阻害剤及びｊａｋ阻害剤を含む抗炎症組成物
RU2785126C2 (ru) Новые соединения и их фармацевтические композиции для лечения воспалительных заболеваний

Legal Events

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

Ref document number: 20760394

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2020760394

Country of ref document: EP

Effective date: 20220321