WO2021032582A1 - Pyrazolo[4,3-c]pyridine derivatives and pharmaceutical compositions thereof for the treatment of inflammatory disorders - Google Patents

Pyrazolo[4,3-c]pyridine derivatives and pharmaceutical compositions thereof for the treatment of inflammatory disorders Download PDF

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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
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Prior art keywords
compound
diseases
independently selected
pyrazolo
amino
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PCT/EP2020/072715
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French (fr)
Inventor
Steven Emiel VAN DER PLAS
Sébastien Laurent Xavier MARTINA
Ghjuvanni Petru Diunisu COTI
David Amantini
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Galapagos Nv
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Priority to EP20760394.5A priority Critical patent/EP4017590A1/en
Publication of WO2021032582A1 publication Critical patent/WO2021032582A1/en

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    • 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

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Abstract

The present invention discloses compounds according to Formula (I) wherein R1, R2, and Cy are as defined herein. The present invention relates to compounds, methods for their production, pharmaceutical compositions comprising the same, and methods of treatment using the same, 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 IFNα, IL12 and/or IL23 by administering the compound of the invention.

Description

PYRAZ02L(5f45|-2C]PYRIDINE DERIVATIVES AND PHARMACEUTICAL ^COMPOSIT!ONS THEREOF FOR THE TREATMENT OF INFLAMMATORY DISORDERS
FIELD OF THE INVENTION
[0001] 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. In particular, 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.
BACKGROUND OF THE INVENTION
[0002] Janus kinases (JAKs) are cytoplasmic tyrosine kinases that transduce cytokine signalling from membrane receptors to STAT transcription factors. Four JAK family members are described, JAK1, JAK2, JAK3 and TYK2. 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)
[0003] The combination of genetic models and small molecule JAK inhibitor research revealed the therapeutic potential of JAK inhibitors (JAKinibs) (Babon et ak, 2014). The last decade has seen the development of JAKinibs with various degrees of selectivity profdes versus the JAK family members. In particular, whereas targeting multiple JAK may not be detrimental (Broekman et ak, 2011), developing selective JAKinibs would be very desirable to develop treatment course tailored to the needs of the patient despite the challenge it represents (Fabian et al., 2005). For example, whereas 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.
[0004] Using TYK2 knock out mice, it has been shown that 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. (Schwartz et ak, 2016) However, it has recently been shown that whereas 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). Since the activity of IL12 and IL23 is 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, selective TYK2 inhibition may be particularly advantageous in the treatment of these diseases while avoiding JAK2 dependent erythropoietin (EPO) and thrombopoietin (TPO) signaling (Neubauer et ah, 1998; Parganas et ah, 1998). Additionally, due to its involvement in type I interferons (including IFNa, INRb) signalling, TYK2 inhibition may be particulalryl useful in the treatment of the cytokine storm associated with COVID-19 infections. (Ye et ak, 2020)
[0005] Furthermore, a variant of TYK2 gene decribed in the general human population, with a modification in one amino acid in the kinase domain of TYK2 which invalidates its kinase activity, is associated with the decreased risk of autimmune and inflammatory diseases. (Dendrou et al., 2016)
[0006] Accordingly, there remains a need for new compounds which would effectively and selectively inhibit JAK enzymes, in particular TYK2, thus allowing the design of specific treatments and dosages tailored to the pathology.
SUMMARY OF THE INVENTION
[0007] 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. In particular, 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.
[0008] Accordingly, in a first aspect of the invention, the compounds of the invention are provided having a Formula (I):
Figure imgf000003_0001
wherein
R1 is selected from - -NR3R4,
-C(=0)0-Ci-4 alkyl, and monocyclic, spiropoly cyclic or bridged polycyclic 4-11 membered 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,
O 0X0, o halo, o Ci-4 alkyl unsubstituted or substituted with one or more independently selected halo, -NR5aR5b, or -OH, or o 4-7 membered monocyclic heterocycloalkyl comprising one or more heteroatoms independently selected from N, S, and O,
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;
R2 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 R6 group; each R6 is independently selected from:
- halo,
- -CN,
- -C(=0)0Ci-4 alkyl,
- Ci-4 alkyl unsubstituted or substituted with one or more independently selected halo, C1-4 alkoxy, or OH;
R3 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 -NR7aR7b, or o 4-7 membered monocyclic heterocycloalkyl comprising one or more heteroatoms independently selected from N, O, and S;
R4 is selected from H, and CH alkyl; and each R5a, R5b, R7a and R7b is independently selected from H and CH alkyl.
[0009] In a particular aspect, 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.
[0010] Furthermore, it has also been unexpectedly demonstrated that 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.
[0011] In a further aspect, the present invention provides pharmaceutical compositions comprising a compound of the invention, and a pharmaceutical carrier, excipient or diluent. In a particular aspect, the pharmaceutical composition may additionally comprise further therapeutically active ingredients suitable for use in combination with the compounds of the invention. In a more particular aspect, 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.
[0012] Moreover, the compounds of the invention, useful in the pharmaceutical compositions and treatment methods disclosed herein, are pharmaceutically acceptable as prepared and used.
[0013] In a further aspect of the invention, 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.
[0014] 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. In a particular aspect, 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.
[0015] In additional aspects, this invention provides methods for synthesizing the compounds of the invention, with representative synthetic protocols and pathways disclosed later on herein.
[0016] Other objects and advantages will become apparent to those skilled in the art from a consideration of the ensuing detailed description. DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0017] The following terms are intended to have the meanings presented therewith below and are useful in understanding the description and intended scope of the present invention.
[0018] When describing the invention, which may include compounds, pharmaceutical compositions containing such compounds and methods of using such compounds and compositions, the following terms, if present, have the following meanings unless otherwise indicated. It should also be understood that when described herein any of the moieties defined forth below may be substituted with a variety of substituents, and that the respective definitions are intended to include such substituted moieties within their scope as set out below. Unless otherwise stated, the term “substituted” is to be defined as set out below. It should be further understood that the terms “groups” and “radicals” can be considered interchangeable when used herein.
[0019] The articles ‘a’ and ‘an’ may be used herein to refer to one or to more than one (i.e. at least one) of the grammatical objects of the article. By way of example ‘an analogue’ means one analogue or more than one analogue.
[0020] ‘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. Particular alkyl groups are methyl (-Ctfi), ethyl (-CH2-CH3), n-propyl (-CH2-CH2-CH3), isopropyl (-CH(C]¾)2), n-butyl (- CH2-CH2-CH2-CH3), tert-butyl (-CH2-C(CH3)3), sec-butyl (-CH2-CH(CH3)2), n-pentyl (-CH2-CH2-CH2-CH2-CH3), n-hexyl (-CH2-CH2-CH2-CH2-CH2-CH3), and 1,2-dimethylbutyl (-CHCtfij-C CtUjLb-CLb-CtL). Particular alkyl groups have between 1 and 4 carbon atoms.
[0021] ‘Alkenyl’ refers to monovalent olefinically (unsaturated) hydrocarbon groups with the number of carbon atoms specified. Particular alkenyl has 2 to 8 carbon atoms, and more particularly, from 2 to 6 carbon atoms, which can be straight-chained or branched and having at least 1 and particularly from 1 to 2 sites of olefinic unsaturation. Particular alkenyl groups include ethenyl (-CH=CH2), n-propenyl (-CH2CLUCH2), isopropenyl (-C(CH3)=CH2) and the like.
[0022] ‘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.
[0023] ‘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(CH3)H-CºCH-.
[0024] ‘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.
[0025] ‘Amino’ refers to the radical -Nth.
[0026] As used herein, term ‘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.
[0027] ‘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. In particular aryl refers to an aromatic ring structure, monocyclic or fused polycyclic, with the number of ring atoms specified. Specifically, the term includes groups that include from 6 to 10 ring members. Particular aryl groups include phenyl, and naphthyl.
[0028] ‘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.
[0029] ‘Cyano’ refers to the radical -CN.
[0030] ‘Halo’ or ‘halogen’ refers to fluoro (F), chloro (Cl), bromo (Br) and iodo (I). Particular halo groups are either fluoro or chloro.
[0031] ‘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. [0032] ‘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. In particular, 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. Typically 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. In one embodiment, 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. [0033] 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.
[0034] Examples of six membered monocyclic heteroaryl groups include but are not limited to pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl.
[0035] Particular examples of bicyclic heteroaryl groups containing a five membered ring fused to another five-membered ring include but are not limited to imidazothiazolyl and imidazoimidazolyl.
[0036] Particular examples of 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.
[0037] Particular examples of 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.
[0038] Examples of representative heteroaryls include the following:
Figure imgf000008_0001
wherein each Y is selected from >C=0, NH, O and S.
[0039] ‘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. Typically 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. Examples of 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. 1-piperidinyl, 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), tetrahydropyranyl (e.g. 4- tetrahydropyranyl), tetrahydrothiopyranyl (e.g. 4-tetrahydrothiopyranyl), morpholinyl, thiomorpholinyl, dioxanyl, or piperazinyl. [0040] As used herein, the term ‘heterocycloalkenyl’ means a ‘heterocycloalkyl’, which comprises at least one double bond. Particular examples of heterocycloalkenyl groups are shown in the following illustrative examples: where
Figure imgf000009_0001
and each Z is selected from N and CH.
[0041] Particular examples of monocyclic rings are shown in the following illustrative examples:
Figure imgf000009_0002
wherein each W and Y is independently selected from -CH2-, -NH-, -O- and -S-.
[0042] Particular examples of fused bicyclic rings are shown in the following illustrative examples:
Figure imgf000009_0003
wherein each W and Y is independently selected from -CH2-, -NH-, -O- and -S-.
[0043] Particular examples of bridged bicyclic rings are shown in the following illustrative examples:
Figure imgf000009_0004
wherein each W and Y is independently selected from -CH2-, -NH-, -O- and -S- and each Z is selected from N and CH.
[0044] Particular examples of spirocyclic rings are shown in the following illustrative examples:
C>¾ OO wherein each Y is selected from -CH2-, -NH-, -O- and -S-.
[0045] ‘Hydroxyl’ refers to the radical -OH.
[0046] Oxo’ refers to the radical =0.
[0047] ‘Substituted’ refers to a group in which one or more hydrogen atoms are each independently replaced with the same or different substituent(s).
[0048] ‘Sulfo’ or ‘sulfonic acid’ refers to a radical such as -SO3H.
[0049] ‘Thiol’ refers to the group -SH.
[0050] As used herein, term ‘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. [0051] ‘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.
[0052] One having ordinary skill in the art of organic synthesis will recognize that the maximum number of heteroatoms in a stable, chemically feasible heterocyclic ring, whether it is aromatic or non-aromatic, is determined by the size of the ring, the degree of unsaturation and the valence of the heteroatoms. In general, a heterocyclic ring may have one to four heteroatoms so long as the heteroaromatic ring is chemically feasible and stable.
[0053] ‘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.
[0054] ‘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. In particular, such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts. Specifically, 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 acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-l-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g. an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine and the like. 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. The term ‘pharmaceutically acceptable cation’ refers to an acceptable cationic counter-ion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like. [0055] ‘Pharmaceutically acceptable vehicle’ refers to a diluent, adjuvant, excipient or carrier with which a compound of the invention is administered.
[0056] ‘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.
[0057] ‘ 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.
[0058] ‘Subject’ includes humans. The terms ‘human’, ‘patient’ and ‘subject’ are used interchangeably herein.
[0059] ‘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.
[0060] ‘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. [0061] 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.
[0062] ‘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). In another embodiment ‘treating’ or ‘treatment’ refers to ameliorating at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, ‘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. In a further embodiment, “treating” or “treatment” relates to slowing the progression of the disease. [0063] As used herein the term ‘allergic disease(s)’ 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.
[0064] As used herein the term ‘asthma’ as used herein 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.
[0065] As used herein the term ‘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. complications after bypass surgery or chronic endotoxin states contributing to e.g. chronic cardiac failure), and related diseases involving cartilage, such as that of the joints. Particularly 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.
[0066] As used herein the term ‘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.
[0067] As used herein the term ‘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.
[0068] As used herein the term ‘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. Crohn's disease and ulcerative colitis), interferonopathy, atherosclerosis and amyotrophic lateral sclerosis. Particularly the term refers to COPD, asthma, systemic lupus erythematosus, type I diabetes mellitus, interferonopathy, and inflammatory bowel disease. [0069] As used herein the term ‘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. In particular the term refers to cancer, leukemia, multiple myeloma and psoriasis.
[0070] As used herein, the term ‘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. As used herein the term 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). In particular, the term ‘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, retinoblastoma, gallbladder cancer, gastric (stomach) cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), gastrointestinal stromal cell tumor, germ cell tumor, glioma, hairy cell leukemia, head and neck cancer, hepatocellular (liver) cancer, hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumors (endocrine pancreas), Kaposi sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, Acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, hairy cell leukemia, liver cancer, non-small cell lung cancer, small cell lung cancer, Burkitt lymphoma, cutaneous T- celllymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, lymphoma, Waldenstrom macroglobulinemia, medulloblastoma, medulloepithelioma, melanoma, mesothelioma, mouth cancer, chronic myelogenous leukemia, myeloid leukemia, multiple myeloma, asopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, oral cancer, oropharyngeal cancer, osteosarcoma, malignant fibrous histiocytoma of bone, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, ovarian low malignant potential tumor, pancreatic cancer, papillomatosis, parathyroid cancer, penile cancer, pharyngeal cancer, pineal parenchymal tumors of intermediate differentiation, pineoblastoma and supratentorial primitive neuroectodermal tumors, pituitary tumor, plasma cell neoplasm/multiple myeloma, pleuropulmonary blastoma, primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell (kidney) cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, Ewing sarcoma family of tumors, sarcoma, kaposi, Sezary syndrome, skin cancer, small cell Lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, stomach (gastric) cancer, supratentorial primitive neuroectodermal tumors, T -cell lymphoma, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstrom macroglobulinemia, and Wilms tumor [0071] As used herein the term ‘leukemia’ refers to neoplastic diseases of the blood and blood forming organs. Such diseases can cause bone marrow and immune system dysfunction, which renders the host highly susceptible to infection and bleeding. In particular the term leukemia refers to acute myeloid leukaemia (AML), and acute lymphoblastic leukemia (ALL) and chronic lymphoblastic leukaemia (CLL). [0072] As used herein the term ‘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.
[0073] As used herein 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.
[0074] As used herein the term ‘congenital cartilage malformation(s)’ includes conditions such as hereditary chondrolysis, chondrodysplasias and pseudochondrodysplasias, in particular, but without limitation, microtia, anotia, metaphyseal chondrodysplasia, and related disorders.
[0075] As used herein the term ‘disease(s) associated with hypersecretion 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.
[0076] ‘Compound(s) of the invention’, and equivalent expressions, 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. Similarly, reference to intermediates, whether or not they themselves are claimed, is meant to embrace their salts, and solvates, where the context so permits.
[0077] When ranges are referred to herein, for example but without limitation, Ci-s alkyl, the citation of a range should be considered a representation of each member of said range.
[0078] Other derivatives of the compounds of this invention have activity in both their acid and acid derivative forms, but in the acid sensitive form often offers advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (Bundgard, H, 1985). 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. In some cases it is desirable to prepare 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.
[0079] 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. The term “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.
[0080] An unnatural variant isotopic form of a compound may thus contain one or more artificial or uncommon isotopes such as deuterium (2H or D), carbon-11 (nC), carbon-13 (13C), carbon-14 (14C), nitrogen-13 (13N), nitrogen-15 (15N), oxygen-15 (150), oxygen-17 (170), oxygen-18 (180), phosphorus-32 (32P), sulphur-35 (35S), chlorine-36 (36C1), chlorine-37 (37C1), fluorine-18 (18F) iodine-123 (123I), iodine-125 (125I) 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.
[0081] 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. 3H, and carbon-14, i.e. 14C, 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. 2H 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. Further, unnatural variant isotopic forms may be prepared which incorporate positron emitting isotopes, such as nC, 18F, 150 and 13N, and would be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
[0082] It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed ‘isomers’. Isomers that differ in the arrangement of their atoms in space are termed ‘stereoisomers’. [0083] Stereoisomers that are not mirror images of one another are termed ‘diastereomers’ and those that are non-superimposable mirror images of each other are termed ‘enantiomers’. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. 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’.
[0084] ‘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.
[0085] Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.
[0086] 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.
[0087] Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art.
[0088] It will be appreciated that compounds of the invention may be metabolized to yield biologically active metabolites.
THE INVENTION
[0089] 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. In particular, 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. [0090] Accordingly, in a first aspect of the invention, the compounds of the invention are provided having a Formula (I):
Figure imgf000017_0001
wherein
R1 is selected from
- -NR3R4,
- -C(=0)0-Ci-4 alkyl, and monocyclic, spiropoly cyclic or bridged polycyclic 4-11 membered 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,
O 0X0, o halo, o Ci-4 alkyl unsubstituted or substituted with one or more independently selected halo, -NR5aR5b, or -OH, or o 4-7 membered monocyclic heterocycloalkyl comprising one or more heteroatoms independently selected from N, S, and O,
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;
R2 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 R6 group; each R6 is independently selected from:
- halo,
- -CN,
- -C(=0)0Ci-4 alkyl,
- Ci-4 alkyl unsubstituted or substituted with one or more independently selected halo, C1-4 alkoxy, or OH;
R3 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 -NR7aR7b, or o 4-7 membered monocyclic heterocycloalkyl comprising one or more heteroatoms independently selected from N, O, and S;
R4 is selected from H, and Cw alkyl; and each R5a, R5b, R7a and R7b is independently selected from H and CH alkyl.
[0091] In one embodiment, the compound of the invention is according to Formula I, wherein R2 is H, -CH3, -NH2, or morpholinyl.
[0092] In embodiment, the compound of the invention is according to Formula I, wherein R2 is H.
[0093] In one embodiment, the compound of the invention is according to Formula I, wherein Cy is phenyl substituted with one, two or three independently selected R6 groups. In a particular embodiment, Cy is phenyl substituted with one, or two independently selected R6 groups. In a more particular embodiment, Cy is phenyl substituted with three independently selected R6 groups.
[0094] In one embodiment, the compound of the invention is according to Formula I, wherein Cy is pyridinyl substituted with one, two or three independently selected R6 groups. In a particular embodiment, Cy is pyridinyl substituted with one, or two independently selected R6 groups.
[0095] In one embodiment, the compound of the invention is according to Formula I, wherein Cy is as previously defined, wherein each R6 is independently selected from F, Cl, -CN, -C(=0)OCH3, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)2OH, -CH2OCH3, -CF3, or -CH2OH. In a particular embodiment, each R6 is independently selected from F, Cl, or -CN.
[0096] In one embodiment, the compound of the invention is according to Formula I, wherein Cy is
Figure imgf000018_0001
Cyl, Cy2, Cy3, Cy4, Cy5, or Cy6 wherein each R6a, R6b, and R6c is independently selected from R6, wherein R6 is as previously defined. [0097] In one embodiment, the compound of the invention is according to Formula I, wherein Cy is Cy2, Cy3, Cy4, Cy5 or Cy6, wherein R6a is halo. In a particular embodiment, R6a is F or Cl.
[0098] In one embodiment, the compound of the invention is according to Formula I, wherein Cy is Cy3, Cy4, Cy5, or Cy6 wherein R6b is halo, CN, Ci-4 alkyl unsubstituted or substituted with one or more independently selected halo, Ci-4 alkoxy or OH. In a particular embodiment, R6b is F, Cl, -CN, -OR, or - CF3.
[0099] In one embodiment, the compound of the invention is according to Formula I, wherein Cy is Cyl, Cy2, Cy4, or Cy6, wherein R6c is halo, -CN, -C(=0)OCi-4 alkyl, and CH alkyl unsubstituted or substituted with one or more independently selected halo, Ci-4 alkoxy and OH. In a particular embodiment, R6c is -CN, -C(=0)OCH3, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)2OH, -CH2OCH3, or -CH2OH. In a particular embodiment, R6c is -CN.
[0100] In one embodiment, the compound of the invention is according to Formula Ila, lib, or He:
Figure imgf000019_0001
Ila, lib, or He wherein R1 is as defined previously.
[0101] In one embodiment, the compound of the invention is according to any one of Formulae I-IIc, wherein R1 is -NR3R4, wherein R4 is as previously defined and R3 is H.
[0102] In one embodiment, the compound of the invention is according to any one of Formulae I-IIc, wherein R1 is -NR3R4, wherein R4 is as previously defined and R3 is Ci-6 alkyl. In a particular embodiment, R3 is -CH3, -CH2CH3, or -CH(CH3)2.
[0103] In one embodiment, the compound of the invention is according to any one of Formulae I-IIc, wherein R1 is -NR3R4, wherein R4 is as previously defined and R3 is Ci-6 alkyl substituted with one or more independently selected halo, -OH, C1-4 alkoxy, -NR7aR7b or 4-7 membered monocyclic heterocycloalkyl comprising one or more heteroatoms independently selected from N, O, and S. In a particular embodiment, R3 is Ci-6 alkyl substituted with one, two or three independently selected halo, -OH, Ci-4 alkoxy, -NR7aR7b or 4-7 membered monocyclic heterocycloalkyl comprising one or more heteroatoms independently selected from N, O, and S. In a particular embodiment, R3 is -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)CH3, -CH2CH(CH3)2, each of which is substituted with one, two or three independently selected halo, -OH, C1-4 alkoxy, -NR7aR7b or 4-7 membered monocyclic heterocycloalkyl comprising one or more heteroatoms independently selected from N, O, and S. In another particular embodiment, R3 is Ci-6 alkyl substituted with one, two or three independently selected F, -OH, -OCH3, -OCH2CH3, oxetanyl, tetrahydrofuranyl, or dioxanyl. In a more particular embodiment, R3 is -CH2CH2-OH, -CH2-dioxanyl, -CH(CH3)CH2-OH, -CH2C(CH3)2-OH, -CH2CF2CH2-OH, -CH2CH(OH)CH3, -CH2CH(OH))CHF2, -CH2CH(OH))CF3, -CH2CH2-N(CH3)2 or -CH2CH2-OCH3. In a most particular embodiment, R3 is -CH2CH2-OH.
[0104] In one embodiment, the compound of the invention is according to any one of Formulae I-IIc, wherein R1 is -NR3R4, wherein R3 is as previously defined and R4 is H, or Cw alkyl. In a particular embodiment, R4 is H, or -CH3. In a more particular embodiment, R4 is H.
[0105] In one embodiment, the compound of the invention is according to any one of Formulae I-IIc, wherein R1 is -NH¾ -NHCH3, -NHCH2CH3, -NH-CH2CH2OH, -NH-CH(CH3)CH2OH, -NH- CH2C(CH3)2OH, -NH-CH2CF2CH2OH, -NH-CH2CH(OH)CHF2, -NH-CH2-dioxanyl,
-NH-CH2CH(OH)CH3, -NH-CH2CH(OH)CF3, -NH-CH2CH2OCH3, or -N(CH3)CH2CH2OH. [0106] In one embodiment, the compound of the invention is according to any one of Formulae I-IIc, wherein R1 is -C(=0)0-Ci-4 alkyl. In a particular embodiment, R1 is -C(=0)0CH3.
[0107] In one embodiment, the compound of the invention is according to any one of Formulae I-IIc, wherein R1 is monocyclic or spiro / bridged polycyclic 4-11 membered heterocycloalkyl comprising one or more heteroatoms independently selected from N, S, and O. In a particular embodiment, R1 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.
[0108] In one embodiment, the compound of the invention is according to any one of Formulae I-IIc, wherein R1 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, CH alkyl unsubstituted or substituted with one or more independently selected halo, -NR5aR5b, or OH, or 4-7 membered heterocycloalkyl comprising one or more heteroatoms independently selected from N, S, and O. In a particular embodiment, R1 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, -NR5aR5b, or OH, or 4-7 membered heterocycloalkyl comprising one or more heteroatoms independently selected from N, S, and O. In a more particular embodiment, R1 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, -CH3, -CH2CH3, -CH2OH, -CH2CH2OH, -CFFCFF-NiCFFri. or oxetanyl. In another more particular embodiment, R1 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, -CH3, -CH2CH3, -CH2OH, -CH2CH2OH, -CH2CH2-N(CH3)2, or oxetanyl.
[0109] In one embodiment, the compound of the invention is according to any one of Formulae I-IIc, wherein R1 is CH alkyl. In a particular embodiment, R1 is -CH3, -CH2CH3, or -CH(CH3)2.
[0110] In one embodiment, the compound of the invention is according to any one of Formulae I-IIc, wherein R1 is CH alkyl substituted with one or more independently selected halo, -OH, C1-4 alkoxy, or 4-7 membered monocyclic heterocycloalkyl comprising one or more heteroatoms independently selected from N, O, and S. In a particular embodiment, R1 is -CH3, -GrhCTl·, -CH(CH3)2, or -CH2CH2CH3, 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. In another particular embodiment, R1 is Cw alkyl substituted with one or more independently selected F, -OH, -OCH3, or -OCH2CH3, or oxetanyl, dioxanyl. In a more particular embodiment, R1 is -CH2OH, -CH2-OCH3, -CHF2, -CF3, -CF2CH2OH, -CH(CH3)CH2OH, or -CH2CF2CH2OH. [0111] In one embodiment, the compound of the invention is selected from:
N-4-(l-(2,6-dichlorophenyl)-lH-pyrazolo[4,3-c]pyridin-6-yl)pyrimidine-4, 6-diamine 4-(6-((6-aminopyrimidin-4-yl)amino)- lH-pyrazolo [4,3 -c]pyridin- 1 -yl)-3 ,5 -dichlorobenzonitrile
2-(6-((6-aminopyrimidin-4-yl)amino)-lH-pyrazolo[4,3-c]pyridin-l-yl)-3-chlorobenzonitrile 4-(6-((6-aminopyrimidin-4-yl)amino)-lH-pyrazolo[4,3-c]pyridin-l-yl)-3-chloro-5-fluorobenzonitrile 4-(6-((6-aminopyrimidin-4-yl)amino)- lH-pyrazolo [4,3 -c]pyridin- 1 -yl)-3 ,5 -difluorobenzonitrile N4-(l-(2,6-difluorophenyl)-lH-pyrazolo[4,3-c]pyridin-6-yl)pyrimidine-4, 6-diamine
2-(6-((6-aminopyrimidin-4-yl)amino)-lH-pyrazolo[4,3-c]pyridin-l-yl)-3-fluorobenzonitrile
3,5 -dichloro-4-(6-((6-methylpyrimidin-4-yl)amino)- lH-pyrazolo [4,3 -c]pyridin- 1 -yl)benzonitrile
3-chloro-5-fluoro-4-(6-((6-methylpyrimidin-4-yl)amino)-lH-pyrazolo[4,3-c]pyridin-l- yl)benzonitrile
4-(6-((6-aminopyrimidin-4-yl)amino)-lH-pyrazolo[4,3-c]pyridin-l-yl)-3-chlorobenzonitrile N4-(l-(2-fluoro-6-(trifluoromethyl)phenyl)-lH-pyrazolo[4,3-c]pyridin-6-yl)pyrimidine-4, 6-diamine 3 -chloro-5 -fluoro-4-(6-((6-morpholinopyrimidin-4-yl)amino)- lH-pyrazolo [4,3 -c]pyridin- 1 - yl)benzonitrile
3,5 -difluoro-4-(6-((6-morpholinopyrimidin-4-yl)amino)- lH-pyrazolo[4,3 -c]pyridin- 1 -yl)benzonitrile
3,5 -dichloro-4-(6-((6-(methylamino)pyrimidin-4-yl)amino)- lH-pyrazolo [4,3 -c]pyridin- 1 - yl)benzonitrile
3-chloro-2-(6-((6-(methylamino)pyrimidin-4-yl)amino)-lH-pyrazolo[4,3-c]pyridin-l-yl)benzonitrile 3 -chloro-5 -fluoro-4-(6-((6-(methylamino)pyrimidin-4-yl)amino)- lH-pyrazolo [4,3 -c]pyridin- 1 - yl)benzonitrile
3,5 -difluoro-4-(6-((6-(methylamino)pyrimidin-4-yl)amino)- lH-pyrazolo[4,3 -c]pyridin- 1 - yl)benzonitrile
4-(6-((6-aminopyrimidin-4-yl)amino)-lH-pyrazolo[4,3-c]pyridin-l-yl)-3-methylbenzonitrile 4-(6-((6-aminopyrimidin-4-yl)amino)- lH-pyrazolo [4,3 -c]pyridin- 1 -yl)-3 - (trifluoromethyl)benzonitrile
N-4-(l-(2-chloro-6-fluorophenyl)-lH-pyrazolo[4,3-c]pyridin-6-yl)pyrimidine-4, 6-diamine
3,5 -dichloro-4-(6-((6-(difluoromethyl)pyrimidin-4-yl)amino)- lH-pyrazolo[4,3 -c]pyridin- 1 - yl)benzonitrile
3-chloro-4-(6-((6-(difluoromethyl)pyrimidin-4-yl)amino)-lH-pyrazolo[4,3-c]pyridin-l-yl)-5- fluorobenzonitrile
6-(6-((6-aminopyrimidin-4-yl)amino)-lH-pyrazolo[4,3-c]pyridin-l-yl)-5-chloronicotinonitrile
4-(6-((6-aminopyrimidin-4-yl)amino)-lH-pyrazolo[4,3-c]pyridin-l-yl)-3-fluorobenzonitrile 3-chloro-4-(6-((6-(methylamino)pyrimidin-4-yl)amino)-lH-pyrazolo[4,3-c]pyridin-l-yl)benzonitrile Cpd 4-(6-((6-aminopyrimidin-4-yl)amino)-lH-pyrazolo[4,3-c]pyridin-l-yl)-3,5-dimethylbenzonitrile 3-chloro-2-(6-((6-methylpyrimidin-4-yl)amino)-lH-pyrazolo[4,3-c]pyridin-l-yl)benzonitrile 3-chloro-5-fluoro-4-(6-((6-(trifluoromethyl)pyrimidin-4-yl)amino)-lH-pyrazolo[4,3-c]pyridin-l- yl)benzonitrile 3-chloro-2-(6-((6-(trifluoromethyl)pyrimidin-4-yl)amino)-lH-pyrazolo[4,3-c]pyridin-l- yl)benzonitrile
3-(6-((6-aminopyrimidin-4-yl)amino)-lH-pyrazolo[4,3-c]pyridin-l-yl)-4-chlorobenzonitrile l-(2-chloro-6-fluorophenyl)-N-(6-methylpyrimidin-4-yl)-lH-pyrazolo[4,3-c]pyridin-6-amine l-(2-chloro-6-fluorophenyl)-N-(6-morpholinopyrimidin-4-yl)-lH-pyrazolo[4,3-c]pyridin-6-amine
3-chloro-2-(6-((6-morpholinopyrimidin-4-yl)amino)-lH-pyrazolo[4,3-c]pyridin-l-yl)benzonitrile
N4-(l-(3,5-dichloropyridin-4-yl)-lH-pyrazolo[4,3-c]pyridin-6-yl)pyrimidine-4, 6-diamine
3-chloro-2-(6-((6-(4-methylpiperazin-l-yl)pyrimidin-4-yl)amino)-lH-pyrazolo[4,3-c]pyridin-l- yl)benzonitrile l-(2-chloro-6-fluorophenyl)-N-(6-(4-methylpiperazin-l-yl)pyrimidin-4-yl)-lH-pyrazolo[4,3- c]pyridin-6-amine l-(3,5-dichloropyridin-4-yl)-N-(6-methylpyrimidin-4-yl)-lH-pyrazolo[4,3-c]pyridin-6-amine 3-chloro-2-(6-((6-(4-(2-hydroxyethyl)piperazin-l-yl)pyrimidin-4-yl)amino)-lH-pyrazolo[4,3- c]pyridin- 1 -yl)benzonitrile
3 -chloro-2-(6-((6-(4-hydroxypiperidin- 1 -yl)pyrimidin-4-yl)amino)- lH-pyrazolo [4,3 -c]pyridin- 1 - yl)benzonitrile
3-chloro-2-(6-((6-((2-hydroxyethyl)amino)pyrimidin-4-yl)amino)-lH-pyrazolo[4,3-c]pyridin-l- yl)benzonitrile
3-chloro-5-fluoro-4-(6-((6-(4-methylpiperazin-l-yl)pyrimidin-4-yl)amino)-lH-pyrazolo[4,3- c]pyridin- 1 -yl)benzonitrile l-(3,5-difluoropyridin-4-yl)-N-(6-methylpyrimidin-4-yl)-lH-pyrazolo[4,3-c]pyridin-6-amine
(R)-3-chloro-2-(6-((6-(2-(hydroxymethyl)morpholino)pyrimidin-4-yl)amino)-lH-pyrazolo[4,3- c]pyridin- 1 -yl)benzonitrile
(S)-3-chloro-2-(6-((6-(2-(hydroxymethyl)morpholino)pyrimidin-4-yl)amino)-lH-pyrazolo[4,3- c]pyridin- 1 -yl)benzonitrile
3-chloro-2-(6-((6-((methyl-d3)amino)pyrimidin-4-yl)amino)-lH-pyrazolo[4,3-c]pyridin-l- yl)benzonitrile
3-chloro-2-(6-((6-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)amino)-lH-pyrazolo[4,3-c]pyridin-l- yl)benzonitrile
3-chloro-2-(6-((6-((2-methoxyethyl)amino)pyrimidin-4-yl)amino)-lH-pyrazolo[4,3-c]pyridin-l- yl)benzonitrile
3-chloro-2-(6-((6-(ethylamino)pyrimidin-4-yl)amino)-lH-pyrazolo[4,3-c]pyridin-l-yl)benzonitrile 3-chloro-2-(6-((6-((2-(dimethylamino)ethyl)amino)pyrimidin-4-yl)amino)-lH-pyrazolo[4,3- c]pyridin- 1 -yl)benzonitrile
3-chloro-2-(6-((6-(4-(oxetan-3-yl)piperazin-l-yl)pyrimidin-4-yl)amino)-lH-pyrazolo[4,3-c]pyridin-
1-yl)benzonitrile
2-(6-((2-amino-6-morpholinopyrimidin-4-yl)amino)-lH-pyrazolo[4,3-c]pyridin-l-yl)-3- chlorobenzonitrile 3-chloro-2-(6-((6-isopropylpyrimidin-4-yl)amino)-lH-pyrazolo[4,3-c]pyridin-l-yl)benzonitrile methyl 6-((l-(2-chloro-6-cyanophenyl)-lH-pyrazolo[4,3-c]pyridin-6-yl)amino)pyrimidine-4- carboxylate
3-chloro-2-(6-((6-(methoxymethyl)pyrimidin-4-yl)amino)-lH-pyrazolo[4,3-c]pyridin-l- yl)benzonitrile
4-(6-((6-(2-oxa-8-azaspiro[4.5]decan-8-yl)pyrimidin-4-yl)amino)-lH-pyrazolo[4,3-c]pyridin-l-yl)- 3 -chloro-5 -fluorobenzonitrile methyl 3,5-difluoro-4-(6-((6-methylpyrimidin-4-yl)amino)-lH-pyrazolo[4,3-c]pyridin-l-yl)benzoate
(3,5-difluoro-4-(6-((6-methylpyrimidin-4-yl)amino)-lH-pyrazolo[4,3-c]pyridin-l- yl)phenyl)methanol
3-chloro-5-fluoro-4-(6-((6-((2-hydroxyethyl)amino)pyrimidin-4-yl)amino)-lH-pyrazolo[4,3- c]pyridin- 1 -yl)benzonitrile
4-(6-((6-(2-oxa-7-azaspiro[4.4]nonan-7-yl)pyrimidin-4-yl)amino)-lH-pyrazolo[4,3-c]pyridin-l-yl)- 3 -chloro-5 -fluorobenzonitrile
4-(6-((6-(6-oxa-2-azaspiro[3.4]octan-2-yl)pyrimidin-4-yl)amino)-lH-pyrazolo[4,3-c]pyridin-l-yl)-3- chloro-5 -fluorobenzonitrile
4-(6-((6-(2-oxa-9-azaspiro[5.5]undecan-9-yl)pyrimidin-4-yl)amino)-lH-pyrazolo[4,3-c]pyridin-l- yl) -3 -chloro-5 -fluorobenzonitrile
4-(6-((6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyrimidin-4-yl)amino)-lH-pyrazolo[4,3-c]pyridin-l-yl)- 3 -chloro-5 -fluorobenzonitrile
3,5-dichloro-4-(6-((6-((2-hydroxyethyl)amino)pyrimidin-4-yl)amino)-lH-pyrazolo[4,3-c]pyridin-l- yl)benzonitrile
3-chloro-2-(6-((6-(hydroxymethyl)pyrimidin-4-yl)amino)-lH-pyrazolo[4,3-c]pyridin-l- yl)benzonitrile
3-chloro-2-(6-((6-(difluoromethyl)pyrimidin-4-yl)amino)-lH-pyrazolo[4,3-c]pyridin-l- yl)benzonitrile
2-(3,5-difluoro-4-(6-((6-methylpyrimidin-4-yl)amino)-lH-pyrazolo[4,3-c]pyridin-l- yl)phenyl)propan-2-ol
2-(3,5-dichloro-4-(6-((6-methylpyrimidin-4-yl)amino)-lH-pyrazolo[4,3-c]pyridin-l- yl)phenyl)propan-2-ol
(3,5-dichloro-4-(6-((6-methylpyrimidin-4-yl)amino)-lH-pyrazolo[4,3-c]pyridin-l- yl)phenyl)methanol
3-chloro-5-fluoro-4-(6-((6-((2-hydroxyethyl)amino)-2-methylpyrimidin-4-yl)amino)-lH- pyrazolo[4,3 -c]pyridin- 1 -yl)benzonitrile
4-(6-((6-(2-oxa-7-azaspiro[3.5]nonan-7-yl)pyrimidin-4-yl)amino)-lH-pyrazolo[4,3-c]pyridin-l-yl)- 3 -chloro-5 -fluorobenzonitrile
2-(3-chloro-5-fluoro-4-(6-((6-methylpyrimidin-4-yl)amino)-lH-pyrazolo[4,3-c]pyridin-l- yl)phenyl)propan-2-ol (3-chloro-5-fluoro-4-(6-((6-methylpyrimidin-4-yl)amino)-lH-pyrazolo[4,3-c]pyridin-l- yl)phenyl)methanol
4-(6-((6-(((l,4-dioxan-2-yl)methyl)amino)pyrimidin-4-yl)amino)-lH-pyrazolo[4,3-c]pyridin-l-yl)-3- chloro-5 -fluorobenzonitrile
(S)-3-chloro-5-fluoro-4-(6-((6-((2-hydroxypropyl)amino)pyrimidin-4-yl)amino)-lH-pyrazolo[4,3- c]pyridin- 1 -yl)benzonitrile
(R)-3-chloro-5-fluoro-4-(6-((6-((2-hydroxypropyl)amino)pyrimidin-4-yl)amino)-lH-pyrazolo[4,3- c]pyridin- 1 -yl)benzonitrile
(S)-3-chloro-5-fluoro-4-(6-((6-((l-hydroxypropan-2-yl)amino)pyrimidin-4-yl)amino)-lH- pyrazolo[4,3 -c]pyridin- 1 -yl)benzonitrile
2-(4-(6-((6-(difluoromethyl)pyrimidin-4-yl)amino)-lH-pyrazolo[4,3-c]pyridin-l-yl)-3,5- difluorophenyl)propan-2-ol
1-(2,6-difluoro-4-(methoxymethyl)phenyl)-N-(6-methylpyrimidin-4-yl)-lH-pyrazolo[4,3-c]pyridin- 6-amine
(R)-3,5-dichloro-4-(6-((6-(2-(hydroxymethyl)morpholino)pyrimidin-4-yl)amino)-lH-pyrazolo[4,3- c]pyridin- 1 -yl)benzonitrile
(R)-3-chloro-5-fluoro-4-(6-((6-(2-(hydroxymethyl)morpholino)pyrimidin-4-yl)amino)-lH- pyrazolo[4,3 -c]pyridin- 1 -yl)benzonitrile
(R)-3-chloro-5-fluoro-4-(6-((6-((l-hydroxypropan-2-yl)amino)pyrimidin-4-yl)amino)-lH- pyrazolo[4,3 -c]pyridin- 1 -yl)benzonitrile
3-chloro-5-fluoro-4-(6-((6-(3-(hydroxymethyl)pyrrolidm-l-yl)pyrimidm-4-yl)amino)-lH- pyrazolo[4,3 -c]pyridin- 1 -yl)benzonitrile
3-chloro-5-fluoro-4-(6-((6-(4-hydroxypiperidin-l-yl)pyrimidin-4-yl)amino)-lH-pyrazolo[4,3- c]pyridin- 1 -yl)benzonitrile
3-chloro-5-fluoro-4-(6-((6-((2-hydroxy-2-methylpropyl)amino)pyrimidin-4-yl)amino)-lH- pyrazolo[4,3 -c]pyridin- 1 -yl)benzonitrile
2-(3,5-difluoro-4-(6-((6-morpholinopyrimidin-4-yl)amino)-lH-pyrazolo[4,3-c]pyridin-l- yl)phenyl)propan-2-ol
(S)-3-chloro-5-fluoro-4-(6-((6-(3-hydroxypyrrolidin-l-yl)pyrimidin-4-yl)amino)-lH-pyrazolo[4,3- c]pyridin- 1 -yl)benzonitrile
(R)-3-chloro-5-fluoro-4-(6-((6-(3-hydroxypyrrolidin-l-yl)pyrimidin-4-yl)amino)-lH-pyrazolo[4,3- c]pyridin- 1 -yl)benzonitrile
(R)-3-chloro-5-fluoro-4-(6-((6-(3-(hydroxymethyl)piperidin-l-yl)pyrimidin-4-yl)amino)-lH- pyrazolo[4,3 -c]pyridin- 1 -yl)benzonitrile
(S)-3-chloro-5-fluoro-4-(6-((6-(3-(hydroxymethyl)piperidin-l-yl)pyrimidin-4-yl)amino)-lH- pyrazolo[4,3 -c]pyridin- 1 -yl)benzonitrile
3-chloro-5-fluoro-4-(6-((6-(4-(hydroxymethyl)piperidin-l-yl)pyrimidin-4-yl)amino)-lH- pyrazolo[4,3 -c]pyridin- 1 -yl)benzonitrile 3-chloro-5-fluoro-4-(6-((6-(4-hydroxy-4-methylpiperidin-l-yl)pyrimidin-4-yl)amino)-lH- pyrazolo[4,3 -c]pyridin- 1 -yl)benzonitrile l-(2,6-dichloro-4-(methoxymethyl)phenyl)-N-(6-methylpyrimidin-4-yl)-lH-pyrazolo[4,3-c]pyridin-
6-amine
(S)-3-chloro-5-fluoro-4-(6-((6-(3-(hydroxymethyl)morpholino)pyrimidin-4-yl)amino)-lH- pyrazolo[4,3 -c]pyridin- 1 -yl)benzonitrile
(R)-3-chloro-5-fluoro-4-(6-((6-(3-(hydroxymethyl)morpholino)pyrimidin-4-yl)amino)-lH- pyrazolo[4,3 -c]pyridin- 1 -yl)benzonitrile
3-chloro-5-fluoro-4-(6-((6-(3-(hydroxymethyl)azetidin-l-yl)pyrimidin-4-yl)amino)-lH- pyrazolo[4,3 -c]pyridin- 1 -yl)benzonitrile
3-chloro-5-fluoro-4-(6-((6-(4-(oxetan-3-yl)piperazin-l-yl)pyrimidin-4-yl)amino)-lH-pyrazolo[4,3- c]pyridin- 1 -yl)benzonitrile
3-chloro-4-(6-((6-(3,3-difluoro-4-hydroxypiperidin-l-yl)pyrimidin-4-yl)amino)-lH-pyrazolo[4,3- c] pyridin- 1 -yl) -5 -fluorobenzonitrile
3-chloro-5-fluoro-4-(6-((6-(6-hydroxy-6-methyl-2-azaspiro[3.3]heptan-2-yl)pyrimidin-4-yl)amino)- lH-pyrazolo [4,3 -c]pyridin- 1 -yl)benzonitrile
3-chloro-5-fluoro-4-(6-((6-(7-hydroxy-5-azaspiro[2.4]heptan-5-yl)pyrimidin-4-yl)amino)-lH- pyrazolo[4,3 -c]pyridin- 1 -yl)benzonitrile
3-chloro-5-fluoro-4-(6-((6-((2-hydroxyethyl)(methyl)amino)pyrimidin-4-yl)amino)-lH- pyrazolo[4,3 -c]pyridin- 1 -yl)benzonitrile
3-chloro-5-fluoro-4-(6-((6-((lR,3r,5S)-3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl)pyrimidin-4- yl)amino) - 1 H-pyrazolo [4,3 -c] pyridin- 1 -yl)benzonitrile
3-chloro-5-fluoro-4-(6-((6-((3,3,3-trifluoro-2-hydroxypropyl)amino)pyrimidin-4-yl)amino)-lH- pyrazolo[4,3 -c]pyridin- 1 -yl)benzonitrile
3-chloro-5-fluoro-4-(6-((6-(5-hydroxy-2-azabicyclo[2.2.1]heptan-2-yl)pyrimidin-4-yl)amino)-lH- pyrazolo[4,3 -c]pyridin- 1 -yl)benzonitrile
3 -chloro-5 -fluoro-4-(6-((6-(6-hydroxy-3 -azabicyclo [3.1.1 ]heptan-3 -yl)pyrimidin-4-yl)amino)- 1H- pyrazolo[4,3 -c]pyridin- 1 -yl)benzonitrile
3 -chloro-5 -fluoro-4-(6-((6-(3 -hydroxyazetidin- 1 -yl)pyrimidin-4-yl)amino)- lH-pyrazolo [4,3 - c] pyridin- 1 -yl)benzonitrile
(S)-3-chloro-5-fluoro-4-(6-((6-(3-hydroxypiperidin-l-yl)pyrimidin-4-yl)amino)-lH-pyrazolo[4,3- c] pyridin- 1 -yl)benzonitrile
3 -chloro-5 -fluoro-4-(6-((6-(3 -hydroxy-3 -methylpyrrolidin- 1 -yl)pyrimidin-4-yl)amino)- 1H- pyrazolo[4,3 -c]pyridin- 1 -yl)benzonitrile
3-chloro-5-fluoro-4-(6-((6-(6-hydroxy-2-azaspiro[3.3]heptan-2-yl)pyrimidin-4-yl)amino)-lH- pyrazolo[4,3 -c]pyridin- 1 -yl)benzonitrile
3-chloro-5-fluoro-4-(6-((6-(3-fluoro-4-hydroxypyrrolidin-l-yl)pyrimidin-4-yl)amino)-lH- pyrazolo[4,3 -c]pyridin- 1 -yl)benzonitrile (R)-3-chloro-5-fluoro-4-(6-((6-(3-hydroxypiperidin-l-yl)pyrimidin-4-yl)amino)-lH-pyrazolo[4,3- c]pyridin- 1 -yl)benzonitrile
3-chloro-5-fluoro-4-(6-((6-(hydroxymethyl)pyrimidin-4-yl)amino)-lH-pyrazolo[4,3-c]pyridin-l- yl)benzonitrile
3-chloro-5-fluoro-4-(6-((6-(4-hydroxy-3,3-dimethylpiperidin-l-yl)pyrimidin-4-yl)amino)-lH- pyrazolo[4,3 -c]pyridin- 1 -yl)benzonitrile
3-chloro-5-fluoro-4-(6-((2-methyl-6-morpholinopyrimidin-4-yl)amino)-lH-pyrazolo[4,3-c]pyridin- l-yl)benzonitrile
3-chloro-4-(6-((2,6-dimethylpyrimidin-4-yl)amino)-lH-pyrazolo[4,3-c]pyridin-l-yl)-5- fluorobenzonitrile
3-chloro-4-(6-((6-((2,2-difluoro-3-hydroxypropyl)amino)pyrimidin-4-yl)amino)-lH-pyrazolo[4,3- c] pyridin- 1 -yl) -5 -fluorobenzonitrile
(R)-3-chloro-5-fluoro-4-(6-((6-((3,3,3-trifluoro-2-hydroxypropyl)amino)pyrimidin-4-yl)amino)-lH- pyrazolo[4,3 -c]pyridin- 1 -yl)benzonitrile
3-chloro-4-(6-((6-((3,3-difluoro-2-hydroxypropyl)amino)pyrimidin-4-yl)amino)-lH-pyrazolo[4,3- c] pyridin- 1 -yl) -5 -fluorobenzonitrile
(R)-3,5-dichloro-4-(6-((6-((3,3,3-trifluoro-2-hydroxypropyl)amino)pyrimidin-4-yl)amino)-lH- pyrazolo[4,3 -c]pyridin- 1 -yl)benzonitrile
3.5-dichloro-4-(6-((6-((3,3-difluoro-2-hydroxypropyl)amino)pyrimidin-4-yl)amino)-lH- pyrazolo[4,3 -c]pyridin- 1 -yl)benzonitrile
3 -chloro-4-(6-((6-( 1 , 1 -difluoro-2-hydroxyethyl)pyrimidin-4-yl)amino)- lH-pyrazolo [4,3 -c]pyridin- 1 - yl) -5 -fluorobenzonitrile
3.5-dichloro-4-(6-((6-(l,l-difluoro-2-hydroxyethyl)pyrimidin-4-yl)amino)-lH-pyrazolo[4,3- c] pyridin- 1 -yl)benzonitrile
(R)-3,5-dichloro-4-(6-((6-((3,3-difluoro-2-hydroxypropyl)amino)pyrimidin-4-yl)amino)-lH- pyrazolo[4,3 -c]pyridin- 1 -yl)benzonitrile
(S)-3,5-dichloro-4-(6-((6-((3,3-difluoro-2-hydroxypropyl)amino)pyrimidin-4-yl)amino)-lH- pyrazolo[4,3 -c]pyridin- 1 -yl)benzonitrile
[0112] In one embodiment, 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.
[0113] In one embodiment, 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 .
[0114] In one embodiment, the compounds of the invention are provided in a natural isotopic form.
[0115] In one embodiment, the compounds of the invention are provided in an unnatural variant isotopic form. In a specific embodiment, the unnatural variant isotopic form is a form in which deuterium (i.e. 2H or D) is incorporated where hydrogen is specified in the chemical structure in one or more atoms of a compound of the invention. In one embodiment, the atoms of the compounds of the invention are in an isotopic form which is not radioactive. In one embodiment, one or more atoms of the compounds of the invention are in an isotopic form which is radioactive. Suitably radioactive isotopes are stable isotopes. Suitably the unnatural variant isotopic form is a pharmaceutically acceptable form.
[0116] In one embodiment, a compound of the invention is provided 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.
[0117] 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.
[0118] In one embodiment a compound of the invention is not an isotopic variant.
[0119] In one aspect a compound of the invention according to any one of the embodiments herein described is present as the free base.
[0120] In one aspect a compound of the invention according to any one of the embodiments herein described is a pharmaceutically acceptable salt.
[0121] In one aspect a compound of the invention according to any one of the embodiments herein described is a solvate of the compound.
[0122] In one aspect 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.
[0123] While specified groups for each embodiment have generally been listed above separately, a compound of the invention includes one in which several or each embodiment in the above Formula, as well as other formulae presented herein, is selected from one or more of particular members or groups designated respectively, for each variable. Therefore, this invention is intended to include all combinations of such embodiments within its scope.
[0124] While specified groups for each embodiment have generally been listed above separately, 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.
[0125] Alternatively, the exclusion of one or more of the specified variables from a group or an embodiment, or combinations thereof is also contemplated by the present invention.
[0126] In certain aspects, 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.
[0127] Other derivatives of the compounds of this invention have activity in both their acid and acid derivative forms, but the acid sensitive form often offers advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (Bundgard, H, 1985). 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. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters. Particularly useful are the Ci to Cs alkyl, C2-C8 alkenyl, aryl, C7-C12 substituted aryl, and C7-C12 arylalkyl esters of the compounds of the invention.
PHARMACEUTICAL COMPOSITIONS Formulation 1 - Tablets
[0128] 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.
Formulation 2 - Capsules
[0129] 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).
Formulation 3 - Liquid
[0130] A compound of the invention according to Formula I (125 mg), 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.
Formulation 4 - Tablets
[0131] 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.
Formulation 5 - Injection
[0132] 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.
Formulation 6 - Topical
[0133] 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.
METHODS OF TREATMENT
[0134] In one embodiment, the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention, for use in medicine. In a particular embodiment, 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.
[0135] In another embodiment, 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.
[0136] In additional method of treatment aspects, 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.
[0137] In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent. In a particular embodiment, 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.
[0138] In one embodiment, the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention, for use in medicine. In a particular embodiment, 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. In a particular embodiment, the allergic disease is asthma.
[0139] In another embodiment, 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. In a particular embodiment, the allergic disease is asthma.
[0140] In additional method of treatment aspects, 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. In a particular embodiment, the allergic disease is asthma.
[0141] In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent. In a particular embodiment, the other therapeutic agent is an allergic diseases treatment agent. In a particular embodiment, the allergic disease is asthma. [0142] In one embodiment, the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention, for use in medicine. In a particular embodiment, 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. In a particular embodiment, 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. In a more particular embodiment, the inflammatory disease is rheumatoid arthritis, psoriatic arthritis and inflammatory bowel diseases.
[0143] In another embodiment, 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. In a particular embodiment, 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. In a more particular embodiment, the inflammatory disease is rheumatoid arthritis, psoriatic arthritis and inflammatory bowel diseases.
[0144] In additional method of treatment aspects, 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. In a particular embodiment, 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. In a more particular embodiment, the inflammatory disease is rheumatoid arthritis, psoriatic arthritis and inflammatory bowel diseases.
[0145] In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent. In a particular embodiment, the other therapeutic agent is inflammatory diseases treatment agent. In a particular embodiment, 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. In a more particular embodiment, the inflammatory disease is rheumatoid arthritis, psoriatic arthritis and inflammatory bowel diseases.
[0146] In one embodiment, the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention, for use in medicine. In a particular embodiment, 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. In a particular embodiment, the metabolic disease is type II diabetes and/or obesity.
[0147] In another embodiment, 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. In a particular embodiment, the metabolic disease is type II diabetes and/or obesity.
[0148] In additional method of treatment aspects, 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. In a particular embodiment, the metabolic disease is type II diabetes and/or obesity.
[0149] In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent. In a particular embodiment, the other therapeutic agent is metabolic diseases treatment agent. In a particular embodiment, the metabolic disease is type II diabetes and/or obesity.
[0150] In one embodiment, the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention, for use in medicine. In a particular embodiment, 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. In a particular embodiment, the autoimmune disease is COPD, asthma, systemic lupus erythematosus, type I diabetes mellitus, interferonopathy, and inflammatory bowel disease. In a more particular embodiment, the autoimmune disease is systemic lupus erythematosus.
[0151] In another embodiment, 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. In a particular embodiment, the autoimmune disease is COPD, asthma, systemic lupus erythematosus, type I diabetes mellitus, interferonopathy, and inflammatory bowel disease. In a more particular embodiment, the autoimmune disease is systemic lupus erythematosus.
[0152] In additional method of treatment aspects, 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. In a particular embodiment, the autoimmune disease is COPD, asthma, systemic lupus erythematosus, type I diabetes mellitus, interferonopathy, and inflammatory bowel disease. In a more particular embodiment, the autoimmune disease is systemic lupus erythematosus.
[0153] In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent. In a particular embodiment, the other therapeutic agent is an autoimmune diseases treatment agent. In a particular embodiment, the autoimmune disease is COPD, asthma, systemic lupus erythematosus, type I diabetes mellitus, interferonopathy, and inflammatory bowel disease. In a more particular embodiment, the autoimmune disease is systemic lupus erythematosus. [0154] In one embodiment, the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention, for use in medicine. In a particular embodiment, 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. In a particular embodiment, 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.
[0155] In another embodiment, 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. In a particular embodiment, 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.
[0156] In additional method of treatment aspects, 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. In a particular embodiment, 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.
[0157] In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent. In a particular embodiment, the other therapeutic agent is an autoinflammatory diseases treatment agent. In a particular embodiment, 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.
[0158] In one embodiment, the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention, for use in medicine. In a particular embodiment, 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. In a particular embodiment, the proliferative disease is cancer, leukemia, multiple myeloma and psoriasis. In a more particular embodiment, the proliferative disease is psoriasis.
[0159] In another embodiment, 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. In a particular embodiment, the proliferative disease is cancer, leukemia, multiple myeloma and psoriasis. In a more particular embodiment, the proliferative disease is psoriasis.
[0160] In additional method of treatment aspects, 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. In a particular embodiment, the proliferative disease is cancer, leukemia, multiple myeloma and psoriasis. In a more particular embodiment, the proliferative disease is psoriasis.
[0161] In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent. In a particular embodiment, the other therapeutic agent is a proliferative diseases treatment agent. In a particular embodiment, the proliferative disease is cancer, leukemia, multiple myeloma and psoriasis. In a more particular embodiment, the proliferative disease is psoriasis.
[0162] In one embodiment, the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention, for use in medicine. In a particular embodiment, 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. In a particular embodiment, the transplantation rejection is graft versus host disease.
[0163] In another embodiment, 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. In a particular embodiment, the transplantation rejection is graft versus host disease.
[0164] In additional method of treatment aspects, 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. In a particular embodiment, the transplantation rejection is graft versus host disease.
[0165] In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent. In a particular embodiment, the other therapeutic agent is a transplantation rejection treatment agent. In a particular embodiment, the transplantation rejection is graft versus host disease.
[0166] In one embodiment, the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention, for use in medicine. In a particular embodiment, 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. In a particular embodiment, the disease involving impairment of cartilage turnover is ankylosing spondylitis.
[0167] In another embodiment, 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. In a particular embodiment, the disease involving impairment of cartilage turnover is ankylosing spondylitis.
[0168] In additional method of treatment aspects, 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. In a particular embodiment, the disease involving impairment of cartilage turnover is ankylosing spondylitis. [0169] In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent. In a particular embodiment, the other therapeutic agent is a disease involving impairment of cartilage turnover treatment agent. In a particular embodiment, the disease involving impairment of cartilage turnover is ankylosing spondylitis.
[0170] In one embodiment, the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention, for use in medicine. In a particular embodiment, 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. In a particular embodiment, the congenital cartilage malformations is selected from microtia, anotia, and/or metaphyseal chondrodysplasia.
[0171] In another embodiment, 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. In a particular embodiment, the congenital cartilage malformations is selected from microtia, anotia, and/or metaphyseal chondrodysplasia.
[0172] In additional method of treatment aspects, 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. In a particular embodiment, the congenital cartilage malformations is selected from microtia, anotia, and/or metaphyseal chondrodysplasia.
[0173] In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent. In a particular embodiment, the other therapeutic agent is a congenital cartilage malformations treatment agent. In a particular embodiment, the congenital cartilage malformations is selected from microtia, anotia, and/or metaphyseal chondrodysplasia.
[0174] In one embodiment, the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention, for use in medicine. In a particular embodiment, 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. In a particular embodiment, 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.
[0175] In another embodiment, 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. In a particular embodiment, 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.
[0176] In additional method of treatment aspects, 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. In a particular embodiment, 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.
[0177] In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent. In a particular embodiment, the other therapeutic agent is a diseases associated with hypersecretion of IFNa, IL12 and/or IL23 treatment agent. In a particular embodiment, 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.
[0178] 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.
[0179] For the prophylaxis and/or treatment of long-term conditions, such as degenerative conditions, the regimen for treatment usually stretches over many months or years so oral dosing is preferred for patient convenience and tolerance. With oral dosing, 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. Alternatively for long lasting effect drugs, with oral dosing, once every other week, once weekly, and once a day are representative regimens. In particular, 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.
[0180] Using these dosing patterns, 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.
[0181] Transdermal doses are generally selected to provide similar or lower blood levels than are achieved using injection doses.
[0182] 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.
[0183] 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. In a specific embodiment, co-administration of two (or more) agents allows for significantly lower doses of each to be used, thereby reducing the side effects seen.
[0184] In one embodiment, a compound of the invention or a pharmaceutical composition comprising a compound of the invention is administered as a medicament. In a specific embodiment, said pharmaceutical composition additionally comprises a further active ingredient.
[0185] In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prophylaxis of a disease involving inflammation, particular agents include, but are not limited to, immunoregulatory agents (e.g. azathioprine), corticosteroids (e.g. prednisolone or dexamethasone), 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.
[0186] In one embodiment, 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, etanercept, adalimumab, rituximab, and abatacept).
[0187] In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prophylaxis of proliferative disorders, particular 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-HER2 monoclonal antibody (e.g. HerceptinTM), capecitabine, raloxifene hydrochloride, EGFR inhibitors (e.g. lressa®, Tarceva™, Erbitux™), VEGF inhibitors (e.g. Avastin™), proteasome inhibitors (e.g. Velcade™), Glivec® and hsp90 inhibitors (e.g. 17-AAG). Additionally, 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. In a specific embodiment the proliferative disorder is selected from cancer, myeloproliferative disease or leukaemia.
[0188] In one embodiment, 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), 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..
[0189] In one embodiment, 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)).
[0190] In one embodiment, 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). Fong -acting b2 -agonists (e.g. 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).
[0191] Additionally, 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. 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.
[0192] In one embodiment, 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. methotrexate, leflunomide, sulfasalazine, mesalazine, azathioprine, 6-mercaptopurine and cyclosporin) and biological disease modifying, immunomodulatory agents (infliximab, adalimumab, rituximab, and abatacept).
[0193] In one embodiment, 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), cyclophosphamide and 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.
[0194] In one embodiment, 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 (Topicort™), 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, retinoids, tioguanine, hydroxyurea, sulfasalazine, mycophenolate mofetil, azathioprine, tacrolimus, fumaric acid esters or biologies such as Amevive™, Enbrel™, Humira™, Remicade™, Raptiva™ and ustekimimab (a IL-12 and IL-23 blocker). Additionally, a compound of the invention may be administered in combination with other therapies including, but not limited to phototherapy, or photochemotherapy (e.g. psoralen and ultraviolet A phototherapy (PUVA)).
[0195] In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prophylaxis of allergic reaction, particular 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.
[0196] By co-administration 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. Whilst 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.
CHEMICAL SYNTHETIC PROCEDURES
General
[0197] 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.
[0198] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The choice of a suitable protecting group for a particular functional group as well as suitable conditions for protection and deprotection are well known in the art (Greene, T W; Wuts, P G M;, 1991).
[0199] The following methods are presented with details as to the preparation of a compound of the invention as defined hereinabove and the comparative examples. 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.
[0200] All reagents were of commercial grade and were used as received without further purification, unless otherwise stated. Commercially available anhydrous solvents were used for reactions conducted under inert atmosphere. Reagent grade solvents were used in all other cases, unless otherwise specified. Column chromatography was performed on silica gel 60 (35-70 pm). Thin layer chromatography was carried out using pre-coated silica gel F-254 plates (thickness 0.25 mm). Ή 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. Multiplicities are given as singlet (s), doublet (d), doublet of doublets (dd), doublet of doublet of doublets (ddd), triplet (t), quartet (q), quintuplet (quin), multiplet (m), pentet (p) and broad (br). 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. Columns used: Waters Acquity UPLC BEH C18 1.7pm, 2.1mm ID x 50mm, Waters Acquity UPLC CSH C18 1.7 pm, 2.1 ID x 50mm and XBridge 5 mih, 30x150 mm. The methods are using either CH3CN/H2O gradients (H2O contains either 0.1% FA, 15 mM NH3 or 10 mM NH4HCO3 pH=10 and CH3CN). Microwave heating was performed with a Biotage Initiator.
[0201] 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.
Table I. List of abbreviations used in the experimental section:
Figure imgf000040_0001
Figure imgf000040_0002
Figure imgf000041_0002
Figure imgf000041_0003
SYNTHETIC PREPARATION OF THE COMPOUND OF THE INVENTION
General synthetic methods
Example 1. Synthetic preparation of the compounds of the invention
1.1. General methods
1.1.1. Method 1: Buchwald coupling and deprotection
1.1.1.1. Method la: Buchwald coupling and Boc deprotection
Figure imgf000041_0001
[0202] To a solution of tert- butyl 6-chloro-lH-pyrazolo[4,3-c]pyridine-l-carboxylate (leq) in dry dioxane (0.2 M) or in dry toluene (0.5 M) are added aminopyrimidine-Rl (1-3 eq), CS2CO3 (1.2-3 eq), catalyst (MorDalPhos Pd G3 or MorDalPhos Pd G4, 0.05-0.1 eq) or catalyst (Pd2(allyl)2Cl2 or Pd(OAc)2, 0.02-0.1 eq) and ligand (MorDalPhos or Xantphos, 0.04-0.3 eq) under N2 atmosphere. The 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 N¾ MeOH solution in DCM) to afford the title compound or Boc protected intermediate.
1.1.1.2. Alternative Boc deprotection with HCl
[0203] To a solution of a Boc protected intermediate (1 eq) in dioxane (0.2-0.3 M) is added 4M HCl in dioxane (5-10 eq). The reaction mixture is stirred at room temperature or 50°C for 1-5 h. If conversion is not complete cone. HCl (10-20 eq) is added. The reaction mixture is stirred at 40-60°C for l-5h and concentrated under vacuum to afford the title compound.
1.1.1.3. Alternative Boc deprotection with TFA
[0204] To a solution of Boc protected intermediate (1 eq) in DCM (0.5 M) or in 1/1 mixture of DCM/dioxane (0.5 M) is added TFA (30 eq). The reaction mixture is stirred at room temperature or at room temperature and then at 60°C for 24h. The reaction mixture is basified with saturated solution of K2CO3, diluted with water and extracted with EtOAc. The combined organic layers are fdtered on phase separator and 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.
1.1.1.4. Illustrative example of method la with in situ deprotection: Synthesis of N4-(1H- pyrazolo[4, 3-c]pyridin-6-yl)pyrimidine-4, 6-diamine
Figure imgf000042_0001
[0205] To a solution of tert-butyl 6-chloro-lH-pyrazolo[4,3-c]pyridine-l-carboxylate (5g, 19.76 mmol, leq) in dry dioxane (100 mL) were added 4,6-pyrimidinediamine (CAS#2434-56-2; 6.52g, 59.29 mmol, 3 eq), Cs2C03 (7.73 g, 23.71 mmol, 1.2 eq) and MorDalPhos Pd G3 (823 mg, 0.988 mmol, 0.05 eq) under N2 atmosphere. The reaction mixture was stirred in sealed tube at 110°C for 24h, cooled to room temperature, diluted in a mixture of MeOH/DCM (1:4) and fdtered through pall-seitz thick paper fdter. Solids were washed with MeOH/DCM (1:4), the fdtrate was coated on S1O2 and purified by flash chromatography on S1O2 (eluting with 2 to 10% 7N NH3 MeOH solution in DCM) to afford the title compound. Illustrative example of method la with HCl Boc deprotection: Synthesis ofN4-methyl-N6-(lH- py razo/of , 3-c/pyridin-6-y/)pyrimidine-4, 6-diamine
Figure imgf000042_0002
Step i)
[0206] To a solution of tert- butyl 6-chloro-lH-pyrazolo[4,3-c]pyridine-l-carboxylate (1.47 g, 5.8 mmol, 1 eq) in dry dioxane (16 mL) were added 4-N-methylpyrimidine-4, 6-diamine (CAS#66131-69-9; 900 mg, 7.25 mmol, 1.25 eq), CS2CO3 (2.83 g, 8.7 mmol, 1.5 eq), Pd2(allyl)2Cl2 (42 mg, 0.11 mmol, 0.02 eq) and MorDalPhos (108 mg, 0.23 mmol, 0.04 eq) under N2 atmosphere. 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.
Step ii)
[0207] To a solution of tert- butyl 6-((6-(methylamino)pyrimidin-4-yl)amino)-lH-pyrazolo[4,3- c]pyridine-l-carboxylate (1.00 g, 2.93 mmol, 1 eq) in dioxane (10 mL) was added 4M HC1 in dioxane (3.7 mL, 29.3 mmol, 10 eq). The reaction mixture was stirred at room temperature for 15h and concentrated under vacuum to afford the title compound.
1.1.1.5. Illustrative example of method la with TFA Boc deprotection: Synthesis of N-(6-
Figure imgf000043_0001
Step i)
[0208] To a solution of tert- butyl 6-chloro-lH-pyrazolo[4,3-c]pyridine-l-carboxylate (500 mg, 1.975 mmol, 1 eq) in dry dioxane (10 mL) were added 6-(difluoromethyl)pyrimidin-4-amine (CAS# 1706464- 15- 4; 286 mg, 1.975 mmol, 1 eq), CS2CO3 (966 mg, 2.96 mmol, 1.5 eq), Pd2(allyl)2Cl2 (15 mg, 0.04 mmol, 0.02 eq) and MorDalPhos (37 mg, 0.08 mmol, 0.04 eq) under N2 atmosphere. 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.
Step ii)
[0209] To a solution of tert- butyl 6-((6-(difluoromethyl)pyrimidin-4-yl)amino)-lH-pyrazolo[4,3- c]pyridine-l-carboxylate (500 mg, 1.38 mmol, 1 eq) in DCM (4 mL) was added TFA (2 mL, 27.6 mmol, 20 eq). The reaction mixture was stirred at room temperature for 24h, concentrated to dryness under vacuum and triturated with MTBE to afford the title compound.
Figure imgf000044_0001
Step i)
[0210] To a solution of 6-chloro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazolo[4,3-c]pyridine (1 eq) in dry dioxane (0.2 M) are added aminopyrimidine-Rl (1.2 eq) and Cs2CC>3 (2 eq). If precipitation of the reagent is observed DMF (0.5-1 mL) is added. The reaction mixture is degassed and MorDalPhos Pd G4 (0.05 eq) is added under N2 atmosphere. The reaction mixture is stirred in sealed tube at 100°C for 3-18h, cooled to room temperature, diluted with EtOAc and filtered through a pad of celite. The filtrate is coated on Si02 and purified by flash chromatography on Si02 (eluting with 1 to 10% 7N NEE MeOH solution in DCM) to afford the SEM protected intermediate.
Step ii)
[0211] To a solution of SEM protected intermediate (1 eq) in DCM (0.2-0.3 M) are added anisole (5 eq) and TFA (30 eq). The reaction mixture is stirred at room temperature for l-3h, concentrated to dryness under vacuum and triturated with MTBE to afford the title compound.
Illustrative example of method lb: Synthesis of 2-(6-((lH-pyrazolo[4,3-c]pyridin-6-yl)amino)pyrimidin-4- yl)-6-methyl-2-azaspiro[3.3 ]heptan-6-ol
Figure imgf000044_0002
Step i)
[0212] To a solution of 6-chloro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazolo[4,3-c]pyridine (408 mg, 1.4 mmol, leq) in dry dioxane (20 mL) were added 2-(6-aminopyrimidin-4-yl)-6-methyl-2- azaspiro[3.3]heptan-6-ol (380 mg, 1.7 mmol, 1.2 eq) and CS2CO3 (937 mg, 2.8 mmol, 2 eq). The reaction mixture is degassed and MorDalPhos Pd G4 (61 mg, 0.072 mmol, 0.05 eq) is added under N2 atmosphere. The 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 Si02 and purified by flash chromatography on Si02 (eluting with 1 to 10% MeOH solution in DCM) to afford the SEM protected intermediate.
Step ii)
To a solution of 6-methyl-2-(6-((l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazolo[4,3-c]pyridin-6- yl)amino)pyrimidin-4-yl)-2-azaspiro[3.3]heptan-6-ol (345mg, 737.3 mmol, 1.0 eq) in DCM (3 mL) were added anisole (0.401 mL, 3.7 mmol, 5 eq) and TFA (1.7 mL, 30 eq). The reaction mixture was stirred at room temperature for 3h, concentrated to dryness under vacuum and triturated with MTBE to afford the title compound.
Figure imgf000045_0001
Step i)
[0213] To a solution of 6-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-pyrazolo[4,3-c]pyridine (1 eq) in dry dioxane (0.2 M) or toluene (0.1 M) are added aminopyrimidine-Rl (1-1.3 eq), CS2CO3 (1.5 -3 eq), catalyst (MorDalPhos Pd G4 , 0.1 eq) or catalyst (Pd2(allyl)2Cl2 or Pd(OAc)2, 0.02-0. leq) and ligand (MorDalPhos or Xantphos, 0.04-0.3 eq) under N2 atmosphere. 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- seitz 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.
Step ii)
[0214] To a solution of SEM protected intermediate (1 eq) in DCM (0.2-0.3 M) are added anisole (5-15 eq) and TFA (30-50 eq). The reaction mixture is stirred at room temperature for 1-6 h, concentrated to dryness under vacuum and triturated with MTBE to afford the title compound.
Illustrative example of method lc: Synthesis of 2-((4-((lH-pyrazolo[4,3-c]pyridin-6-yl)amino)-6- methylpyrimidin-2-yl)amino)ethan-l-ol
Figure imgf000045_0002
Step i)
[0215] To a solution of 6-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-pyrazolo[4,3-c]pyridine (397 mg, 1.399 mmol, leq) in dry toluene (14 mL) were added 2-((6-amino-2-methylpyrimidin-4- yl)amino)ethan-l-ol (306 mg, 1.818 mmol, 1.3 eq), CS2CO3 (1.367 g, 4.196 mmol, 3 eq), Pd(OAc)2 (31 mg, 0.14 mmol, 0.1 eq) and Xantphos (243 mg, 0.420 mmol, 0.3 eq) under N2 atmosphere. The 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. Step ii)
[0216] To a solution of 2-((2-methyl-6-((2-((2-(trimethylsilyl)ethoxy)methyl)-2H-pyrazolo[4,3-c]pyridin- 6-yl)amino)pyrimidin-4-yl)amino)ethan-l-ol (100 mg, 0.241 mmol, 1 eq) in DCM (1 mL) was added anisole (0.131 mL, 1.2 mmol, 5 eq) and TFA (0.482 mL). The reaction mixture was stirred at room temperature for lh30, concentrated to dryness under vacuum and triturated with MTBE to afford the title compound.
Figure imgf000046_0001
Step i)
[0217] To a solution of 6-chloro-l-trityl-lH-pyrazolo[4,3-c]pyridine (1 eq) in dry dioxane (0.2 M) are added aminopyrimidine-Rl (1-1.3 eq), CS2CO3 (1.5-3 eq), catalyst (MorDalPhos Pd G4, 0.1 eq) or catalyst (Pd2(allyl)2Cl2, 0.02-0.05 eq) and ligand (MorDalPhos, 0.04-0.10 eq) under N2 atmosphere. The reaction mixture was degassed and stirred in sealed tube at 110-120°C for l-72h, cooled to room temperature and filtered. The filtrate is coated on S1O2 and purified by flash chromatography on S1O2 (eluting with 1 to 10% MeOH solution in DCM) to afford the Tr protected intermediate.
Step ii)
[0218] To a solution of 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). The reaction mixture is stirred at room temperature for l-3h, concentrated to dryness under vacuum and triturated with MTBE to afford the title compound.
Illustrative example of method Id: Synthesis of 3-((6-((lH-pyrazolo[4,3-c]pyridin-6-yl)amino)pyrimidin- 4-yl)amino)-2,2-difluoropropan-l-ol
Figure imgf000046_0002
Step i)
[0219] To a solution of 6-chloro-l-trityl-lH-pyrazolo[4,3-c]pyridine (420 mg, 1.1 mmol, 1 eq) in dry dioxane (11 mL) were added 3-((6-aminopyrimidin-4-yl)amino)-2,2-difluoropropan-l-ol (260 mg, 1.3 mmol, 1.2 eq), CS2CO3 (692.0 mg, 2.1 mmol, 2 eq) and catalyst (MorDalPhos Pd G4, 90 mg, 0.11 mmol, 0.1 eq) under N2 atmosphere. The reaction mixture was stirred in sealed tube at 110°C for 12h, cooled to room temperature, concentrated under vacuum and purified by flash chromatography on S1O2 (eluting with 1 to 10% MeOH solution in DCM ) to afford the Tr protected intermediate.
Step ii)
[0220] To a solution of 2,2-difluoro-3-((6-((l-trityl-lH-pyrazolo[4,3-c]pyridin-6-yl)amino)pyrimidin-4- yl)amino)propan-l-ol (4.2 g, 7.5 mmol, 1 eq) in DCM (75 mL) were added triethysilane (3.6 mL, 22.5 mmol, 3.0 eq) and TFA (5.8 ml, 75 mmol, 10 eq). The reaction mixture was stirred at room temperature for 40 min, concentrated to dryness under vacuum and triturated with MTBE to afford the title compound.
Figure imgf000047_0001
Step i)
[0221] To a solution of 6-chloro-l-trityl-lH-pyrazolo[4,3-c]pyridine (84 g, 212.3 mmol, 1 eq) in dry dioxane (840 ml) were added 2-((6-aminopyrimidin-4-yl)amino)ethan-l-ol (36 g, 233.5 mmol, 1.1 eq), CS2CO3 (207.5 g, 636.8 mmol, 3 eq), Pd2(allyl)2Cl2 (3.884 g, 10.61 mmol, 0.05 eq) and MorDalPhos (9.842 g, 21.23 mmol, 0.10 eq) under Ar atmosphere. 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.
Step ii)
[0222] To a solution of 2-((6-((l-trityl-lH-pyrazolo[4,3-c]pyridin-6-yl)amino)pyrimidin-4- yl)amino)ethan-l-ol (40.5 g, 78.9 mmol, 1 eq) and triethysilane (38 mL, 237 mmol, 3 eq) in DCM (800 mL) was added dropwise TFA (60.7 mL, 789 mmol, 10 eq) at 0°C. The reaction mixture was stirred at 0°C for 15 min and slowly warmed to room temperature and stirred for 6h. Then, sodium methoxide (51.1 g, 946 mmol, 12 eq) and MeOH (400 mL) were added to the reaction mixture and stirred for 20 min at room temperature. After addition of H2O (300 mL) the mixture was filtrated over a glass filter and the collected solids were washed with MeOH and toluene to afford the title compound. 1.1.2. Method 2: SnAr
Figure imgf000048_0001
[0223] To a solution of N-(pyrimidinyl)pyrazolopyridinamine (1 eq) in NMP (0.1-0.5 M) are added fluoroaryl (1-2 eq) and K2CO3 (1.5-4 eq). The reaction mixture is stirred in sealed tube at 50-80°C for 1- 17h or at room temperature of 72h. The crude mixture is cooled to room temperature, filtered and purified by preparative HPLC to afford the title compound.
Illustrative example of method 2: Synthesis of 3-chloro-4-[6-[[6-(difluoromethyl)pyrimidin-4-
Figure imgf000048_0002
[0224] To a solution of N-[6-(difluoromethyl)pyrimidin-4-yl]-lH-pyrazolo[4,3-c]pyridin-6-amine (55 mg, 0.210 mmol, 1 eq) in NMP (2 mL) were added 3-chloro-4,5-difluoro-benzonitrile (CAS# 103879-29- 4; 40 mg, 0.231 mmol, 1.1 eq) and K2CO3 (43 mg, 0.315 mmol, 1.5 eq). The reaction mixture was stirred in sealed tube at 60°C for lh. The crude mixture was cooled to room temperature, filtered and purified by preparative HPLC to afford the title compound.
Synthesis of 3-chloro-5-fluoro-4-(6-((6-((2-hydroxyethyl)amino)pyrimidin-4-yl)amino)-lH-pyrazolo[4,3- c]pyridin-l-yl)henzonitrile
Figure imgf000048_0003
[0225] To a solution of 2-((6-((lH-pyrazolo[4,3-c]pyridin-6-yl)amino)pyrimidin-4-yl)amino)ethan-l-ol (20.1 g, 52.17 mmol, 1 eq) in NMP (200 mL) were added 3-chloro-4,5-difluoro-benzonitrile (CAS# 103879-29-4; 9.959 g, 57.38 mmol, 1.1 eq) and K2CO3 (21.63 g, 156.5 mmol, 3 eq). The reaction mixture was stirred at room temperature for 72h. After addition of H2O (1 L) and EtOAc (700 mL) the mixture was filtered and the organic phase was separated. The aqueous phase was extracted with EtOAc and the combined organic layers were washed with saturated NaCl solution, dried over Na2S04 and the solvent was removed under vacuum. The crude mixture was purified by reverse phase chromatography (2x C-18 modified S1O2 (880 g), H2O/CH3CN = 5:95 to H2O/CH3CN = 1:2) to afford the title compound.
1.1.3. Method 3: Buchwald coupling and deprotection
1.1.3.1. Method 3a: Buchwald coupling and Boc deprotection
Figure imgf000049_0001
To a solution of tert- butyl 6-amino-lH-pyrazolo[4,3-c]pyridine-l-carboxylate (1 eq) in dry dioxane (0.2 M) are added chloropyrimidine-Rl (1.1 eq), CS2CO3 ( 1.2 eq) and MorDalPhos Pd G3 (0.05 eq) under N2 atmosphere. The reaction mixture is stirred in sealed tube at 110°C for 18-48h, cooled to room temperature, diluted with DCM and filtered through pall-seitz thick paper filter. The filtrate is concentrated under vacuum and purified by flash chromatography on S1O2 (eluting with 3 to 10% MeOH solution in DCM) to afford the deprotected title compound.
Illustrative example of method 3a: Synthesis of N-[6-(difluoromethyl)pyrimidin-4-yl]-lH-pyrazolo[4,3- cjpyridin- 6-amine
Figure imgf000049_0002
[0226] To a solution of tert- butyl 6-amino-lH-pyrazolo[4,3-c]pyridine-l-carboxylate (270 mg, 1.154 mmol, leq) in dry dioxane (5 mL) were added 4-chloro-6-(difluoromethyl)pyrimidine (CAS#1261737-05- 6; 210 mg, 1.269 mmol, 1.1 eq), CS2CO3 (451 mg, 1.385 mmol, 1.2 eq), MorDalPhos Pd G3 (48 mg, 0.058 mmol, 0.05 eq) under N2 atmosphere. The reaction mixture was stirred in sealed tube at 110°C for 36h, 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 S1O2 (eluting with 3 to 10% MeOH solution in DCM) to afford the title compound.
Figure imgf000049_0003
Step i)
[0227] To a solution of 2-((2-(trimethylsilyl)ethoxy)methyl)-2H-pyrazolo[4,3-c]pyridin-6-amine (1 eq) in dry dioxane (0.25 M) are added chloropyrimidine-Rl (1.1 eq), CS2CO3 ( 1.2 eq) and MorDalPhos Pd G4 (0.03 eq) under N2 atmosphere. The reaction mixture is stirred in sealed tube at 110°C for 18h, cooled to room temperature, diluted with DCM and fdtered through pall-seitz thick paper fdter. The fdtrate is concentrated under vacuum and purified by flash chromatography on Si02 (eluting with 0.5 to 10% 7N NH3 MeOH solution in DCM) to afford the title compound.
Step ii)
[0228] To a solution of SEM protected intermediate (1 eq) in DCM (0.15 M) is added TFA (30 eq). The reaction mixture is stirred at room temperature for lh and concentrated under vacuum afford the title compound.
Illustrative example of method 3b: Synthesis of N-[6-(difluoromethyl)pyrimidin-4-yl]-2H-pyrazolo[4,3- cjpyridin- 6-amine
Figure imgf000050_0001
Step i)
[0229] To a solution of 2-((2-(trimethylsilyl)ethoxy)methyl)-2H-pyrazolo[4,3-c]pyridin-6-amine (190 mg, 0.720 mmol, 1.0 eq) in dry dioxane (3 mL) were added 4-chloro-6-(difluoromethyl)pyrimidine (CAS# 1261737-05-6; 130 mg, 0.792 mmol, 1.1 eq), Cs2C03 ( 1.2 eq) and MorDalPhos Pd G4 (18 mg, 0.022 mmol, 0.03 eq) under N2 atmosphere. The 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 Si02 (eluting with eluting with 0.5 to 10% 7N NH3 MeOH solution in DCM) to afford title intermediate.
Step ii)
[0230] To a solution of N-[6-(difluoromethyl)pyrimidin-4-yl]-2-(2- trimethylsilylethoxymethyl)pyrazolo[4,3-c]pyridin-6-amine (169 mg, 0.431 mmol, 1 eq) in DCM (3 mL) was added TFA (1 mL). The reaction mixture was stirred at room temperature for lh and concentrated under vacuum afford the title compound.
Figure imgf000050_0002
Step i)
[0231] To a solution of l-trityl-lH-pyrazolo[4,3-c]pyridin-6-amine (0.1 M) are added chloropyrimidine- R1 (1.05-1.2 eq), CS2CO3 (1.5-3 eq), catalyst (MorDalPhos Pd G4, 0.1 eq) or catalyst (Pd2(allyl)2Cl2 or Pd(OAc)2, 0.02-0.2 eq) and ligand (Xantphos or MorDalPhos 0.04-0.5 eq) under N2 atmosphere. The reaction mixture is stirred in sealed tube at 100-110°C for 3-15h, cooled to room temperature, fdtered through pall-seitz thick paper fdter. The fdtrate is concentrated under vacuum and purified by flash chromatography on S1O2 (eluting with 2 to 10% 7N NH3 MeOH solution in DCM) to afford the Tr protected intermediate.
Step ii)
[0232] To a solution of 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). 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.
Illustrative example of method 3c: Synthesis of l-(6-((lH-pyrazolo[4,3-c]pyridin-6-yl)amino)pyrimidin-4- yl)-4-methylpiperidin-4-ol
Figure imgf000051_0001
Step i)
[0233] To a solution of l-trityl-lH-pyrazolo[4,3-c]pyridin-6-amine (200 mg, 0.53 mmol, 1 eq) in dry dioxane (5 mL) was added l-(6-chloropyrimidin-4-yl)-4-methylpiperidin-4-ol (127 mg, 0.56 mmol, 1.2 eq), CS2CO3 (260 mg, 0.80 mmol, 1.5 eq), Pd2(allyl)2Cl2 (4 mg, 0.011 mmol, 0.02 eq) and MorDalPhos (10 mg, 0.021 mmol, 0.04 eq) under N2 atmosphere. 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.
Step ii)
[0234] To a solution of 4-methyl-l-(6-((l-trityl-lH-pyrazolo[4,3-c]pyridin-6-yl)amino)pyrimidin-4- yl)piperidin-4-ol (250 mg, 0.44 mmol, 1 eq eq) in DCM (5 mL) was added TFA (5 mL, 150 eq). The reaction mixture was stirred at room temperature for lh and concentrated to dryness under vacuum to afford the title compound.
Figure imgf000052_0003
[0235] To a solution of 2-(6-bromo-lH-pyrazolo[4,3-c]pyridin-l-yl)-3-chlorobenzonitrile (1 eq) in dry dioxane (0.1M) are added aminopyrimidine-Rl (1.0-1.5 eq), CS2CO3 (1.2-1.5 eq) and MorDalPhos Pd G4 (0.01 - 0.1 eq) under N2 atmosphere. The reaction mixture is stirred in sealed tube at 65°C for 18-24h, cooled to room temperature, filtered and purified by preparative HPLC to afford the title compound.
Illustrative example of method 4: Synthesis of 3-chloro-2-(6-((6-(hydroxymethyl)pyrimidin-4-yl)amino)- lH-pyrazolo[4,3-c]pyridin-l-yl)henzonitrile
Figure imgf000052_0001
[0236] To a solution of 2-(6-bromo-lH-pyrazolo[4,3-c]pyridin-l-yl)-3-chlorobenzonitrile (100 mg, 0.300 mmol, leq) in dioxane (2 mL) were added (6-aminopyrimidin-4-yl)methanol (38 mg, 0.30 mmol, 1.0 eq), CS2CO3 (117 mg, 0.36 mmol, 1.2 eq) and MorDalPhos Pd G4 (8 mg, 0.01 mmol, 0.03 eq) under N2 atmosphere. The reaction mixture was stirred in sealed tube at 65°C for 18h. The crude mixture is cooled to room temperature, fdtered and purified by preparative HPLC to afford the title compound.
1.1.5. Method 5: SnAr
Figure imgf000052_0002
[0237] To a solution of 6-chloropyrimidin-4-amine (CAS# 5305-59-9; 1 eq) in EtOH (0.6 -1.5 M) or in 1/1 mixture of EtOH/dioxane (0.5 M) are added amine (1 eq) and TEA (1.0-3 eq). The reaction mixture is stirred in sealed tube or in SythWave apparatus for 18-48h or in microwave reactor for 3-5h at 120-150°C. The reaction mixture is diluted with EtOH, sonicated and filtered to afford the title intermediate or concentrated under vacuum and purified by flash chromatography on S1O2 (eluting with 2 to 10% 7N N¾ MeOH solution in DCM) to afford the title intermediate.
Figure imgf000053_0001
[0238] To a solution of 6-chloropyrimidin-4-amine (CAS# 5305-59-9; 840 mg, 6.51 mmol, 1 eq) in EtOH (12 mL) were added (2S)-2-morpholinylmethanol hydrochloride (CAS#1313584-92-7; 1 g, 6.51 mmol, 1 eq) and TEA (1.81 mL, 13.0 mmol, 2 eq). The reaction mixture was stirred in sealed tube at 150°C for 18h. The reaction mixture was diluted with EtOH, sonicated and filtered to afford the title intermediate.
1.1.6. Method 6: SnAr
Figure imgf000053_0003
[0239] To a solution of 4,6-dichloropyrimidine (CAS# 1193-21-1; 1 eq) in THF (0.3-1 M) is added amine (1.1-2 eq) or amine (1.0- 1.1 eq) and TEA (1.05-1.1 eq). The reaction mixture is stirred in sealed tube at room temperature to 80°C for l-17h, cooled to room temperature, diluted with DCM or EtOAc and washed with brine. The separated organic layer is fdtered on phase separator, concentrated under vacuum to afford the title intermediate or concentrated under vacuum and purified by flash chromatography on SiCE (eluting with 30 to 50% EtOAc solution in petroleum ether) to afford the title intermediate.
Figure imgf000053_0002
[0240] To a solution of 4,6-dichloropyrimidine (CAS#1193-21-1; 500 mg, 3.356 mmol, 1 eq) in THF (10 mL) were added 4-piperidylmethanol (CAS#6457-49-4; 387 mg, 3.356 mmol, 1 eq) and TEA (0.491 mL, 3.52 mmol, 1.05 eq). The reaction mixture was stirred in sealed tube at 80°C for 17h, cooled to room temperature, diluted with DCM and washed with brine. The separated organic layer was filtered on phase separator, coated on SiCE and purified by flash chromatography on SiCE (eluting with 30 to 50% EtOAc solution in petroleum ether) to afford the title intermediate.
Figure imgf000054_0001
[0241] To a solution of methylbenzoate (1 eq) in dry THF (0.1 M) is added 3M solution of MeMgBr (4 eq) at 0°C. The reaction mixture is stirred at 0°C to room temperature for 10 min to lh, poured into water and extracted with DCM. The combined organic layers are fdtered on phase separator, concentrated and purified by preparative HPLC to afford the title compound.
Illustrative example of method 7: Synthesis of 2-(3,5-difluoro-4-(6-((6-methylpyrimidin-4-yl)amino)-lH-
Figure imgf000054_0002
[0242] To a solution of methyl 3,5-difluoro-4-(6-((6-methylpyrimidin-4-yl)amino)-lH-pyrazolo[4,3- c]pyridin-l-yl)benzoate (85 mg, 0.214 mmol, 1 eq) in dry THF (2 mL) was added 3M solution of MeMgBr (0.286 mL; 0.86 mmol, 4 eq) at 0°C. Reaction mixture was stirred at 0°C to room temperature for lh, poured into water and extracted with DCM. The combined organic layers were filtered on phase separator, concentrated and purified by preparative HPLC to afford the title compound.
1.1.8. Method 8: Ester reduction
Figure imgf000054_0003
[0243] To a solution of methylbenzoate (1 eq) in dry THF (0.1 M) is added L1AIH4 (1.5 eq) at 0°C. The reaction mixture is stirred at 0°C to room temperature for l-3h, poured into water and extracted with DCM. The combined organic layers are filtered on phase separator, concentrated and purified by preparative HPLC to afford the title compound. Illustrative example of method 8: Synthesis of (3,5-dichloro-4-(6-((6-methylpyrimidin-4-yl)amino)-lH-
Figure imgf000055_0001
[0244] To a solution of methyl 3,5-dichloro-4-(6-((6-methylpyrimidin-4-yl)amino)-lH-pyrazolo[4,3- c]pyridin-l-yl)benzoate (90 mg, 0.209 mmol, 1 eq) in dry THF (2 mL) was added L1AIH4 (1M THF solution , 0.314 ml, 0.314 mmol, 1.5 eq) at 0°C. The reaction mixture was stirred at 0°C to room temperature for lh, poured into water and extracted with DCM. The combined organic layers were fdtered on phase separator, concentrated and purified by preparative HPLC to afford the title compound.
Figure imgf000055_0002
[0245] To a solution of fluorobenzoic acid (1 eq) in 1/1 mixture of DCM/MeOH (0.2-0.3M) is added of (diazomethyl)trimethylsilane (2M Et20 solution, 1.25 eq) at 0°C under N2 atmosphere. The reaction mixture is stirred at room temperature for l-2h, quenched with AcOH and extracted with DCM. The combined organic layers are filtered on phase separator and concentrated under vacuum to afford the title intermediate.
Figure imgf000055_0003
[0246] To a solution of 3-chloro-4,5-difluorobenzoic acid (CAS#150444-95-4; 1 g, 5.19 mmol, 1 eq) in 1/1 mixture of DCM/MeOH (20 mL) was added (diazomethyl)trimethylsilane (2M Et20 solution, 3.24 mL, 6.49 mmol, 1.25 eq) at 0°C under N2 atmosphere. The reaction mixture was stirred at room temperature for lh, quenched with AcOH and extracted with DCM. The combined organic layers were filtered on phase separator, concentrated under vacuum to afford the title intermediate. 1.3. Method 10: Reduction of ester and methylation of alcohol
Figure imgf000056_0001
Step i)
[0247] To a suspension of L1AIH4 (1.5 eq) in dry THF (0.4 M) is added a solution of fluorobenzoate (1 eq) in dry THF (0.3 M) at 0°C. The reaction mixture is stirred at 0°C to room temperature for lh30 and then water (0.04 ml/g of L1AIH4), NaOH (15% solution in water, 0.04 ml/g of L1AIH4) and water (0.1 ml/g of L1AIH4) are sequentially added at 0°C. The crude mixture is stirred at room temperature for 10 min., solid is fdtered and washed with EtOAc. The fdtrate is concentrated under vacuum to afford the title intermediate.
Step ii)
[0248] To a suspension of NaH (60% oil suspension, 1.5 eq) in dry THF (0.6 M) is added a solution of (3- fluorophenyl)methanol (1 eq) at 0°C. The reaction mixture is stirred at 0 °C for 10 min. and then iodomethane (1.5 eq) is added. The reaction mixture is stirred at 0°C to room temperature for 2h30, quenched with saturated solution of NH4CI and extracted with DCM. The combined organic layers are filtered on phase separator and concentrated under vacuum to afford the title intermediate.
Figure imgf000056_0002
Step i)
[0249] To a suspension of L1AIH4 (154 mg , 4.1 mmol, 1.5 eq) in dry THF (10 mL) was added a solution of methyl 3,4,5-trifluorobenzoate (CAS#773873-72-6; 600 mg, 2.7 mmol, 1 eq) in dry THF (10 mL) at 0°C. The reaction mixture was stirred at 0°C to room temperature for lh30 and then water (154 pL), NaOH (15% solution in water, 154 pL) and water (308 pL) were sequentially added at 0°C. The crude mixture was stirred at room temperature for 10 min., solid was filtered and washed with EtOAc. The filtrate was concentrated under vacuum to afford the title intermediate.
Step ii)
[0250] To a suspension of NaH (60% oil suspension, 31 mg, 0.769 mmol , 1.5 eq) in dry THF (1.2 mL) was added a solution of (3,4,5-trifhiorophenyl)methanol (100 mg, 0.513 mmol, 1 eq) at 0°C. The reaction mixture was stirred at 0 °C for 10 min. and then iodomethane (48 pL, 0.769 mmol, 1.5 eq) was added. The reaction mixture was stirred at 0°C to room temperature for 2h30, quenched with saturated solution of NH4CI and extracted with DCM. The combined organic layers were fdtered on phase separator and concentrated under vacuum to afford the title intermediate.
1.4. Intermediates synthesis
Figure imgf000057_0001
[0251] To a solution of 6-chloro-lH-pyrazolo[4,3-c]pyridine (CAS# 1206979-33-0; 17 g , 111.1 mmol, 1 eq) in DCM (400 mL) were added B0C2O ( 24.2 g, 111.1 mmol, leq) and DMAP (1.36 g, 11.1 mmol, 0.1 eq). The reaction mixture was stirred at room temperature for lh, concentrated under vacuum and purified by flash chromatography on SCO (eluting with 30 to 60% of EtOAc in petroleum ether) to afford the title intermediate.
1.4.2. Synthesis of Int. 2 (6-chloro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazolo[4,3-
Figure imgf000057_0002
[0252] To a solution of 6-chloro-lH-pyrazolo[4,3-c]pyridine (CAS# 1206979-33-0; 25 g, 163.4 mmol, 1 eq) in THF (800 mL) were added N,N-Dicyclohexylmethylamine (70 mL, 326.8 mmol, 2 eq) and SEMC1 (57.94 ml, 326.8 mmol, 2 eq). The reaction mixture was refluxed for 3h, cooled to room temperature, quenched with IN solution of NaOH (200 mL) and stirred for 30 min at room temperature. The crude mixture was extracted with EtOAc, combined organic layer were dried over MgS04, filtered, concentrated to dryness and purified by flash chromatography on S1O2 (eluting with 15 to 40% EtOAc solution in petroleum ether) to afford the title intermediates.
Figure imgf000057_0003
[0253] To a solution of 6-chloro-lH-pyrazolo[4,3-c]pyridine (CAS# 1206979-33-0; 4.62 g , 30.104 mmol, 1 eq) in THF (50 mL) was added NaH (60% oil dispersion, 1.81 g, 45.155 mmol, 1.5 eq) at 0°C under N2 atmosphere. The reaction mixture was stirred at 0°C for lh and then trytil chloride (10.07 g, 36.124 mmol, 1.2 eq) was added portion wise. The reaction mixture was left to slowly warm to room temperature and then stirred for 15h, quenched with saturated solution of NH4C1 and extracted with EtOAc. The combined organic layers were dried over MgS04, filtered and concentrated under vacuum. Crude residue was triturated with EtOAc to afford the title intermediate.
Figure imgf000058_0001
[0254] To a solution of tert- butyl 6-chloro-lH-pyrazolo[4,3-c]pyridine-l-carboxylate (1 g, 3.953 mmol, 1 eq) in dry dioxane (20 mL) were added benzophenone imine (0.730 mL, 3.953, 1.1 eq), CS2CO3 ( 1.55 g, 4.744 mmol, 1.2 eq) and XantPhos Pd G3 (187 mg, 0.198 mmol, 0.05 eq) under N2 atmosphere. The reaction mixture was stirred at 110°C for 18h, cooled to room temperature, diluted with DCM and filtered through pall-seitz thick paper filter. 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.
1.4.5. Synthesis of Int. 6 2-((2-(trimethylsilyl)ethoxy)methyl)-2H-pyrazolo[4,3-c]pyridin-6- amine
Figure imgf000058_0002
[0255] To a solution of 6-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-pyrazolo[4,3-c]pyridine (500 mg, 1.767 mmol, leq) in dry toluene (10 ml) were added CS2CO3 (1.15 g, 3.524 mmol, 2 eq), MorDalPhos Pd G4 (112 mg, 0.132 mmol, 0.07 eq) and H2NBoc (413 mg, 3.524 mmol, 2 eq) under N2 atmosphere. The reaction mixture was stirred in sealed tube for 24h at 140°C, 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 S1O2 (eluting with 1 to 5% MeOH solution in DCM) to afford the title intermediate.
Figure imgf000058_0003
[0256] To a solution of 6-chloro-l-trityl-lH-pyrazolo[4,3-c]pyridine (500 mg, 1.263 mmol, 1 eq) in dry THF (7.5 ml) was added Pd2dba3 (116 mg, 0.126 mmol, 0.1 eq) and JohnPhos ( 44 mg, 0.126 mmol, 0.1 eq). The reaction mixture was degassed for 5 min and then LiHMDS (1.3 M THF solution, 1.17 mL, 1.516 mmol, 1.2 eq) was added. The reaction mixture was refluxed in microwave reactor at 100°C for 4h. The reaction mixture was charged again with Pd2dba3 (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). The aqueous layer was extracted with DCM, combined organic layers dried over MgSCL, filtered, concentrated to dryness and purified by flash chromatography on S1O2 (eluting with 0.5 to 5% MeOH solution in DCM) to afford the title intermediate.
1.4.7. Synthesis of Int. 8: 2-(6-bromo-lH-pyrazolo[4,3-c]pyridin-l-yl)-3-chloro benzonitrile
Figure imgf000059_0001
[0257] To a solution of 6-bromo-lH-pyrazolo[4,3-c]pyridine (CAS # 1206973-12-7, 5g, 25.2 mmol, 1 eq) in NMP (125 mL) were added 3-Chloro-2-fluorobenzonitrile (CAS # 94087-40-8, 4.1 g, 26.5 mmol, 1.05 eq) and K2CO3 (7g, 50.5 mmol, 2 eq). The reaction mixture was stirred in sealed tube at 60°C for 2h. 3- Chloro-2-fluorobenzonitrile (590 mg, 3.8 mmol, 0.15 eq) was added again and the reaction mixture was stirred at 60°C for lh30. The crude mixture was cooled to room temperature, diluted with water and filtered to afford the title intermediate.
Figure imgf000059_0002
[0258] To a solution of 6-chloropyrimidin-4-amine (CAS# 5305-59-9; 40g, 308.8 mmol, 1 eq) in ethanolamine (373 mL, 6.175 mol, 20 eq) was added TEA (43 mL, 308.8 mmol, 1.0 eq) and the reaction mixture was stirred at 85°C for 72h. The reaction mixture was concentrated by distillation in Kugelrohr and purified by flash chromatography on S1O2 (eluting with 1 to 10% MeOH solution in DCM) to afford the title intermediate.
Figure imgf000059_0003
Step i)
[0259] To a solution of 4-amino-6-chloropyrimidine (CAS# 5305-59-9, 500 mg, 3.88 mmol, 1 eq) in mixture of dioxane/H20 (12mL/3mL) were added 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (CAS# 287944-16-5, 1 g, 4.84 mmol, 1.25 eq), DIPEA (1.35 mL, 7.75 mmol, 2 eq) and Pd(dppf)Cl2.CH2Cl2 (158 mg, 0.0119 mmol, 0.05 eq). The 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 N¾ MeOH solution in DCM) to afford the title intermediate.
Step ii)
[0260] A degassed suspension of 6-(3,6-dihydro-2H-pyran-4-yl)pyrimidin-4-amine (200 mg, 1.13 mmol, 1.0 eq) in MeOH (1 mL) was added palladium on charcoal, 10 %, Pd/C (119 mg, 0.113 mmol, 0.1 eq) and the reaction mixture was stirred at room temperature under hydrogen atmosphere at room temperature for 48h. The crude mixture was filtered over a celite pad and the pad was washed with MeOH. The filtrate was concentrated under vacuum to afford the title intermediate.
Figure imgf000060_0001
[0261] To a solution of methyl 6-aminopyrimidine-4-carboxylate (CAS#77817-12-0; 200 mg, 1.31 mmol, 1 eq) in dry MeOH (2 mL) was added dropwise LiBH4 (2M THF solution, 1.960 ml, 3.918 mmol, 3 eq). The reaction mixture was stirred at room temperature for lh and then at 60 °C for 18h. The crude mixture was concentrated to dryness and purified by flash chromatography on Si02 (eluting with 10% 7N NH3 MeOH solution in DCM) to afford the title intermediate.
Figure imgf000060_0002
Step i)
[0262] To a solution of 6-bromopyrimidin-4-amine (CAS# 1159818-57-1; 5 g, 28.74 mmol, 1 eq) in THF (150 mL) were added B0C2O (13 g, 60.34 mmol, 1 eq) and DMAP (176 mg, 1.44 mmol, 0.1 eq). The reaction mixture was stirred at room temperature for 6h. B0C2O (13 g, 60.34 mmol, 1 eq) and DMAP (176 mg, 1.44 mmol, 0.1 eq) were added again and the reaction mixture was stirred at room temperature for 20h, concentrated under vacuum and purified by flash chromatography on SCO (eluting with 10 to 100% of EtOAc in petroleum ether) to afford the title intermediate.
Step ii)
[0263] To a suspension of copper (510 mg, 8.02 mmol, 3 eq) in dry DMSO (10 ml) was added ethyl bromodifluoroacetate (CAS# 667-27-6, 0.51 mL, 4.01 mmol, 1.5 eq) and the reaction mixture was stirred at room temperature for lh. Tert- butyl (6-bromopyrimidin-4-yl)(tert-butoxycarbonyl)carbamate (lg, 2.67 mmol, 1 eq) was added portion wise and the reaction mixture was stirred at room temperature for lh30 and then heated at 60°C for 18h. The reaction mixture was diluted with water, filtered and extracted with EtOAc. The combined organic layers were dried over MgSCL, fdtered, concentrated to dryness and purified by flash chromatography on S1O2 (eluting with 10 to 100% EtOAc solution in petroleum ether) to afford the title intermediate.
Step Hi)
[0264] To a solution of ethyl 2-(6-(bis(tert-butoxycarbonyl)amino)pyrimidin-4-yl)-2,2-difluoroacetate (291 mg, 0.70 mmol, 1 eq) in DCM (5 mL) was added TFA (1 mL) and the reaction mixture was stirred at room temperature for lh. The reaction mixture was quenched with saturated solution of NaHCCL and extracted with DCM. The combined organic layers were filtered on phase separator and concentrated to dryness to afford the title intermediate.
Step iv)
[0265] To a solution of tert-butyl 6-(2 -ethoxy- l,l-difluoro-2-oxoethyl)pyrimidine-4-carboxylate (3.46 g, 10.45 mmol, 1 eq) in dry Me OH (50 mL) was added NaBH4 (1.2 g, 31.34 mmol, 3 eq). The reaction mixture was stirred at room temperature for 6h and then NaBH4 (1.2 g, 31.34 mmol, 3 eq) was added again. The reaction mixture was stirred at room temperature for 2h, concentrated to dryness and purified by flash chromatography on Si02 (eluting with 10% 7N NH3 MeOH solution in DCM) to afford the title intermediate.
Table II. Intermediates towards illustrative compounds of the invention
NI: no ionisation
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0002
Table III. Illustrative compounds of the invention
NI: No ionisation
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
Table IV. NMR data of illustrative compounds of the invention
Figure imgf000110_0002
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
BIOLOGICAL EXAMPLES
Example 2. In vitro assays
2.1. JAK1 inhibition assay
[0266] 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(tyR1023) 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). After 60 min at room temperature, reactions are stopped by adding 20 pL/well of detection mixture (l x detection buffer (Perkin Elmer, catalog number CR97-100), 0.5nM Europium-anti-phosphotyrosine (PT66) (Perkin Elmer, catalog number AD0068/AD0069), 10 mM EDTA). Readout is performed after 60 min incubation at room temperature using the Envision with excitation at 320nm and measuring emission at 615 nm and 665nm (Perkin Elmer). The ratio of the relative fluorescence units (RFU) at 665nm and 615nm (RFU 665 / RFU 615 multiplied with a factor 1000) is used to do further calculations. Kinase activity is calculated by subtracting the ratio obtained in the presence of a positive control inhibitor ( 1 mM staurosporine) from the ratio obtained in the presence of vehicle. The ability of a test compound to inhibit this activity (or percentage inhibition) is determined as:
( Fluorescent ratio test compound - Fluorenscent ratio control )
Figure imgf000119_0001
^ (Fluorescent ratio vehicle - Fluorescent ratio control ) ^ wherein
[0267] Fluorescent ratio test compound = ratio RFU 665/ RFU 615 * 1000 determined for sample with test compound present
[0268] Fluorescent ratio control = ratio RFU 665/ RFU 615 * 1000 determined for sample with positive control inhibitor
[0269] Fluorescent ratio vehicle = ratio RFU 665/ RFU 615 * 1000 determined in the presence of vehicle [0270] 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.
2.2. JAK2 inhibition assay
[0271] 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(tyR1023) 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). After 60 min at room temperature, reactions are stopped by adding 20 pL/well of detection mixture (lxdetection buffer (Perkin Elmer, catalog number CR97-100) with 0.5nM Europium- anti -phosphotyrosine (PT66) (Perkin Elmer, catalog number AD0068/AD0069) and 10 mM EDTA). Readout is performed after 60 min incubation at room temperature using the Envision with excitation at 320nm and measuring emission at 615 nm and 665nm (Perkin Elmer). The ratio of the relative fluorescence units (RFU) at 665nm and 615nm (RFU 665 / RFU 615 multiplied with a factor 1000) is used to do further calculations. Kinase activity is calculated by subtracting the ratio obtained in the presence of a positive control inhibitor (1 mM staurosporine) from the ratio obtained in the presence of vehicle. The ability of a test compound to inhibit this activity (or percentage inhibition) is determined as:
(Fluorescent ratio test compound - Fluorescent rationcontrol )
Figure imgf000120_0001
^ (Fluorescent ratio vehicle - Fluorescent ratio control ) ^ wherein
[0272] Fluorescent ratio test compound = ratio RFU 665/ RFU 615 * 1000 determined for sample with test compound present
[0273] Fluorescent ratio control = ratio RFU 665/ RFU 615 * 1000 determined for sample with positive control inhibitor
[0274] Fluorescent ratio vehicle = ratio RFU 665/ RFU 615 * 1000 determined in the presence of vehicle [0275] 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.
2.3. JAK3 inhibition assay
2.3.1. JAK3 inhibition assay 1
[0276] 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 MgCL2, 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). After 45 min at 30 °C, reactions are stopped by adding 25 pL/well of 150 mM phosphoric acid. All of the terminated kinase reaction is transferred to prewashed (75 mM phosphoric acid) 96 well filter plates (Perkin Elmer catalog number 6005177) using a cell harvester (Perkin Elmer). Plates are washed 6 times with 300 pL per well of a 75 mM phosphoric acid solution and the bottom of the plates is sealed. 40 pL/well of Microscint-20 (Perkin Elmer, catalog number 6013621) is added, the top of the plates is sealed and readout is performed using the Topcount (Perkin Elmer). 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 test compound - cpm control )
(1 - ; — 7 - - - tt - -) * 100
(cpm vehicle - cpm control ) cpm test compound = cpm determined for sample with test compound present cpm control = cpm determined for sample with positive control inhibitor cpm vehicle = cpm determined in the presence of vehicle [0278] 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).
2.3.2. JAK3 inhibition assay 2
[0279] 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.
[0280] The following general conditions were used:
- N-terminal His6-tagged, recombinant, human JAK3 amino acids 781-end
- Substrate used: GGEEEEYFELVKKKK
- ATP concentration used: 10 mM (actual Km[ATP] 4 mM; assays are run at Km[ATP] ± 15 mM) [0281] The raw data and % remaining activity were measured and IC50 fitted on % remaining activity. [0282] The following compounds have been tested for their activity against JAK3 and the average IC50 values, as determined using the assays described herein, are given in the table below.
2.4. TYK2 ADPglo™ Kinase assay
[0283] 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 MgCl2, 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). After 120 min at room temperature, reactions were stopped and the remaining ATP is depleted by adding 5 pL/well of ADP Glo Reagent (Promega, catalog number V912B). After 40 min at room temperature, 10 pi Kinase Detection Reagent (Kinase Detection Substrate (Promega, catalog number V914B) dissolved in Kinase Detection Buffer (Promega, catalog number V913B)) is added to convert ADP to ATP and to measure this newly synthesized ATP in a luciferase/luciferin reaction. Readout is performed after 30 min incubation at room temperature using the Envision . 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. The ability of a test compound to inhibit this activity (or percentage inhibition) is determined as:
(RLU test compound - RLU control )
Figure imgf000122_0002
(RLU vehicle - RLU control )
Figure imgf000122_0001
wherein
[0284] RLU test compound = RLU determined for sample with test compound present [0285] RLU control = RLU determined for sample with positive control inhibitor [0286] RLU vehicle = RLU determined in the presence of vehicle
[0287] 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. When 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.
Table V. JAK1/JAK2/JAK3/TYK2 IC50 Values of Illustrative Compounds of the invention
Figure imgf000122_0003
Figure imgf000122_0004
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000125_0001
2.5. Conclusions
[0288] The in vitro assay reported above show the selectivity of the illustrative compounds of the invention towards TYK2 over the remaining JAK family members,
Example 3. Human whole blood assay (hWBA)
3.1. Purpose of the assay
[0289] 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. Phospho-STATl (for IL-6- and IFNa-stimulated cells) and phospho-STAT5 (for GM-CSF- stimulated cells) levels are then evaluated using FACS analysis.
[0290] Whereas 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).
3.2. Protocol
3.2.1. Preparation of reagents
[0291] Blood was taken from human volunteers who gave informed consent and then equilibrated for 30 min at 37°C under gentle rocking, then aliquoted in Eppendorf tubes.
[0292] 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. [0293] 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.
[0294] Universal IFNa (Biomedical Laboratories, Cat no 11200-2) was received at 3.65* 107 units/mL in PBS/BSA. The stock solution was aliquoted and stored at -80°C.
[0295] 10 qg rhGM-CSF (R&D Systems, Cat no 215-GM) was dissolved in 0.1 mL of PBS + 0.1% BSA to obtain a 100 qg/mL stock solution. The stock solution was stored aliquoted at -80°C.
[0296] A 3-fold dilution series of the compound was prepared in DMSO (10 mM stock solution). Control- treated samples received DMSO instead of compound. All samples were incubated with a 1% final DMSO concentration.
3.2.2. Incubation of blood with compound and stimulation with triggers
[0297] Blood was collected from healthy volunteers into Lithium Heparin tubes, and stabilized by incubating the tubes for 30 minutes at 37°C under gentle agitation.
[0298] Then, 100 qL of blood was dispensed into 2 mL-microtubes and incubated with test compounds at different concentrations for 30 min at 37°C under gentle agitation. After this incubation, blood was triggered with either IL-6 (3 ng/mL), IFNa (1000 IU/mL), or GM-CSF (20 pg/mL) or vehicle (PBS + 0.1% BSA) for 20 min at 37°C under gentle agitation.
3.2.3. White blood cell preparation
[0299] At the end of the stimulation period, 2 mL of pre-warmed IX lyse/fix buffer were added to the blood samples, vortexed briefly and incubated for 10 min at 37°C in a water bath in order to lyse red blood cells and fix leukocytes.
[0300] 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.
[0301] Samples were then immediately stored at -20°C until further use. To perform the analysis, cells were washed once with 2 ml of PBS + 3% BSA and centrifuge for 5 minutes at 500 g at room temperature. Supernatant was removed by inverting the tubes.
3.2.4. Cell labeling
[0302] 5 qL of PE mouse anti-STATl (pY701) or PE mouse IgG2aK isotype control antibody (BD Biosciences, Cat. no 612564 and 559319, respectively) and 20 qL of APC-conjugated anti-CD4 antibody or control APC-conjugated isotype antibody (BD Biosciences, Cat. no 555349 and 555751, respectively) were added to IL-6-and IFNa-stimulated tubes and mixed, then incubated for 20 min at 4°C, in the dark. [0303] 20qL of PE mouse anti-STAT5 (pY694) or PE mouse IgGlK isotype control antibody (BD Biosciences, Cat. no 612567 and 554680, respectively) and 5 5qL of 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.
[0304] Cells were then washed once with IX PBS and analyzed on a FACSCanto II flow cytometer (BD Biosciences). 3.2.5. Fluorescence analysis on FACSCanto II [0305] 50,000 total events were counted and Phospho-STATl positive cells were measured after gating on CD4+ cells, in the lymphocyte gate for IL-6- and IFNa-stimulated cells. Phospho-STAT5 positive cells were measured after gating on CD33+ cells. Data were analyzed using the FACSDiva software and the percentage of inhibition of IL-6 or IFNa stimulation calculated is from the percentage of positive cells for phospho-STATl on CD4+ cells. For the GM-CSF stimulated cells, the percentage of inhibition of GM- CSF stimulation was calculated from the percentage of positive cells for phosphor-STAT5 on CD33+ cells.
3.3. Results
[0306] Using the above protocol, the following results are obtained.
Figure imgf000127_0001
3.4. Conclusions
[0307] In this assay, the potencies measured for illustrative compounds of the invention on IL-6 signalling (JAK1) were ranging from 10 to 50 folds lower than on IFNa signaling (JAK1 and/or TYK2 mediated), therefore confirming TYK2 selectivity.
[0308] Similarly, the potencies measured for illustrative compounds of the invention on GM-CSF signalling (JAK2) were at least 77 folds lower than on IFNa signaling (JAK1 and/or TYK2 mediated) , therefore confirming TYK2 selectivity.
Example 4. In vivo assay
4.1. Inflammatory bowel disease
4.1.1. MultiDrug Resistance- la-ablated (MDRal) model (mice)
4.1.1.1. Principle of assay
[0309] Mice deficient in Abcbla (MDRal) develop spontaneous colitis that can be accelerated by infection with Helicobacter bilis. This model is used to evaluate the ability of a compound to treat or prevent colitis(Maxwell et al., 2015) . 4.1.1.2. Materials
[0310] 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).
4.1.1.3. Animals
[0311] 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.
4.1.1.4. H. bilis inoculum preparation
[0312] Frozen vial of H. bilis was thawed, put in Brucella Broth and incubated in Brucella Agar slant containing 5% of defibrinated sheep blood under microaerophily at 37 °C for 4 to 5 days. At Dl, just before administration, a part of H. bilis culture was diluted in PBS in order to obtain 107cfu/mouse and a second part was put in fresh Brucella Broth and incubated as previously for 7 days. At D8, just before administration, H. bilis culture was diluted in PBS in order to obtain 107cfu/mouse.
4.1.1.5. Study design
[0313] After a 10 days acclimatization period, the disease activity index of each MDRla mouse was determined in order to constitue homogene groups regarding the DAI score between groups. All mice (10 mice per group), except for the SHAM group (n= 10), were then administered by oral route with an inoculum of H. bilis ( 107 cfu/mouse) and treatment started accordingly to the protocol for six weeks . Seven days after the start of treatment, a second administration of H. bilis was performed. During the whole treatment period, disease activity index was determined twice a week. Six weeks after the start of treatment, mice were sacrificed, blood was sampled and the complete colon was collected and rinsed with sterile PBS. Collected colons were measured and weighed in order to determine colon weight/length ratio, and histological analysis, gene expression, protein level measurement and/or FACs immunophenotyping analysis were performed on the samples. The results were expressed as mean ± SEM and statistical analysis was performed using one-way ANOVA followed by Dunnett’s post-hoc test versus vehicle groups.
4.1.1.6. Disease Activity Index (DAI) determination [0314] The DAI score of each mouse (sum of scores for weight loss, stool consistency and rectal bleeding) was monitored during the entire treatment period and a DAI score progression curve was obtained.
Figure imgf000128_0001
Figure imgf000129_0001
*A little piece of stool was deposited on a vial containing 1 mL of D-PBS and homogeneized, deposited on a test strip (Combur TestE), a color appears according to the blood intensity in the stool, a score was given according to this intensity, from 0 to 4 points.
4.2. Murine model of psoriatic-like epidermal hyperplasia induced by intradermal injections of IL-23
4.2.1. Materials
[0315] Mouse recombinant IL-23, carrier free (Cat# 14-8231) is provided by e-Bioscience (Frankfurt, Germany).
4.2.2. Animals
[0316] Balb/c mice (female, 18-20 g body weight) are obtained from Janvier Labs (Le Genest-Saint-Isle, France). Mice are kept on a 12 h light/dark cycle. Temperature is maintained at 22 °C, food and water are provided ad libitum.
4.2.3. Study design
[0317] The design of the study is adapted from Rizzo HL. et al. (Rizzo et ah, 2011).
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.
[0318] From Dl to D5, mice were dosed with test-compound or with vehicle, 1 h prior IL-23 injection.
4.2.4. Assessment of disease
[0319] The thickness of both ears is measured daily with an automatic caliper. Body weight was assessed at initiation and at sacrifice. On fifth day, 2 h after the last dosing, the mice were sacrificed. The pinnae of the ear were cut, excluding cartilage. The pinnae, placed in a vial containing 1 mL of RNA/a/er® solution. [0320] At D4, blood samples were also collected from the retro-orbital sinus for PK profiling just before dosing (TO) and 1 h, 3 h, 6 h post-dosing.
[0321] 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.
4.2.5. Gene expression analysis
[0322] 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.
4.2.6. Results
[0323] 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.
Table VI. Ear thickening prevention compared to IL23 group on D5 for illustrative compound of the invention
Figure imgf000130_0001
[0324] One-way ANOVA + Dunnetfs mu tiple comparison post-test vs L23-Veh group *p<0.05,
**p<0.01, ***p<0.001
4.3. Murine model of systemic lupus erythematosus induced by epicutaneous applications of imiquimod
4.3.1. Materials
[0325] Aldara® 5% imiquimod cream is obtained from MEDA.
[0326] 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).
4.3.2. Animals
[0327] BALB/cJ mice (female, 18-20 g body weight) are obtained from Janvier Labs (Le Genest-Saint- Isle, 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.
4.3.3. Study design
[0328] The design of the study is adapted from Yokogawa M. et al. (Yokogawa et ah, 2014).
[0329] 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.
[0331] From D1 to D86, mice are dosed with test compound (30 mg/kg, p.o., q.d. in methylcellulose 0.5%) or with vehicle (10 mL/kg).
4.3.4. Assessment of disease
[0332] The thickness of the ears is measured once a week with an automatic gage (Mitutoyo, Absolute Digimatic, 547-321).
[0333] 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.
[0334] At different time points (e.g., on days D28, D56 and D84), the mice are individually placed in a metabolic cage to perform urinalysis and assess proteinuria (albumin to creatinine ratio).
[0335] Serums are collected at different time points (e.g., on D28, D56 and D86) to assess anti-double stranded-DNA IgG levels.
[0336] At D13, 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.
[0337] 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.
4.3.5. Quantification of compound levels in plasma
[0338] 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.
4.3.5.1. Histopathology
[0339] In each glomerulus, 4 different readouts including mesangioproliferation, endocapillary proliferation, mesangial matrix expansion and segmental sclerosis are graded on a scale of 0 to 2 and then summed. For each kidney, about 50 glomeruli are scored and then averaged giving one glomerular lesion score (Yokogawa et ah, 2014). Data are expressed as mean ± SEM and statistical analysis is performed using the Kruskal-Wallis test followed by Dunn’s post-hoc test versus imiquimod vehicle group.
4.3.5.2. Cellular quantifications
[0340] For each cell type, immunohistochemical analysis is performed using image analysis (CaloPix software, TRIBVN Healthcare) on the whole tissue section at a magnification of c20. 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.
4.3.5.3. Gene expression analysis
[0341] At sacrifice, the second part of the left kidneys is placed in tubes containing 1.4 mm ceramic beads and disrupted in 1% DTT RLT lysis buffer (Qiagen, Cat# 79216) with a Bertin Instruments Precellys® homogenizer. Total RNA is 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 (GOI = CD3, CD68, CD20, OAS1, Mxl, IFIT1, CXCL11 and Uspl8) are calculated relative to the cyclophilin, GAPDH and b-actin housekeeping gene expression levels.
[0342] At sacrifice, one-third of the spleen is placed into tubes containing 1.4 mm ceramic beads and disrupted in Trizol® with a Bertin Instruments Precellys® homogenizer. Total 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.
4.4. Murine model of psoriatic arthritis induced by over expression of IL-23
4.4.1. Materials
[0343] Mouse IL-23 enhanced episomal expression vector (EEV) 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).
4.4.2. Animals
[0344] 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.
4.4.3. Study design
[0345] The design of the study is adapted from Sherlock JP. et al. (Sherlock et ah, 2012).
[0346] On the first day (D 1 ), the mice undergo a hydrodynamic inj ection of Ringer or IL-23 EEV in Ringer into the tail vein.
[0347] As of D5, twice a week, the mice are scored for clinical symptoms until the end of the experiment. [0348] On D5, blood is collected by puncture in the submandibular vein to assess the serum IL-23 concentration.
[0349] On D9, mice from all groups receive ProSense® 680 probe (0.8 nmol/10 g, i.p.). On D10, the mice are anesthetized. Granulocyte infiltration is then measured using in vivo molecular imaging (Bruker In-Vivo Xtreme imaging system).
[0350] On D11, randomization is performed according to ProSense® 680 molecular imaging and scoring. [0351] As of D12, mice are dosed with test compound or with vehicle.
[0352] On D19, blood is sampled at time TO, Tlh, T3h and T6h after last dosing. Plasma is separated and kept at 20 °C until bioanalysis.
[0353] On D36, mice from all groups are sacrificed 2 h after last administration of compound. [0354] 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.
4.4.4. Assessment of disease
[0355] Body weight is assessed at initiation of the study, then twice a week and at sacrifice.
[0356] Twice weekly, clinical signs of inflammation are scored: 0 for normal paw; 1 if swelling of one digit; 2 if swelling of two or more digits; 3 if swelling of the entire paw. The scores of all limbs are summed up to produce a global score.
[0357] On D32, 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.). On D33, the mice are anesthetized and granulocyte infiltration and bone remodelling are measured using in vivo molecular imaging (Bruker In-Vivo Xtreme imaging system). [0358] There are 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 diseased vehicle group for scoring and imaging analysis, versus sham vehicle group for body weight.
4.5. Murine therapeutic model of atopic dermatitis induced by topical application of MC903
4.5.1. Materials
[0359] 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).
4.5.2. Animals
[0360] BALB/cN mice (female, 18-20 g body weight) or CD 1/Swiss mice (female, 24-26 g body weight) are obtained from Janvier Labs (Le Genest-Saint-Isle, 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.
4.5.3. Study design
[0361] The design of the study is adapted from Li M. et al. (Li et ah, 2006). On the first day (Dl), the mice are anesthetized and shaved around the two ears. As of Dl, either 20 pL EtOH or 2 nmol of MC903 (in 20 pL EtOH) are topically applied on each ear of the mice up to D9, Dl l or D15 (except during the weekend).
[0362] From D5, the 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.
4.5.4. Quantification of compound levels in plasma
[0363] 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.
4.5.5. Determination of pharmacokinetic parameters
[0364] Pharmacokinetic parameters are calculated using Phoenix® WinNonlin® (Pharsight®, USA). 4.5.6. Assessment of disease
[0365] The thickness of 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). [0366] Body weight is assessed at immediately before first application of EtOH (baseline), three times a week and at sacrifice.
[0367] On D8, D10 or D11, mice from all groups receive ProSense® 680 probe (0.8 nmol/10 g, i.p.). On the next day (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).
[0368] On D10, D 12, or D 16, 2 h after the last dosing, the mice are sacrificed, total blood is collected in EDTA-coated tubes and plasma is frozen for further measurements (including circulating compound). [0369] 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.
[0370] 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.
4.5.7. Histology
[0371] After sacrifice, half ears are collected and fixed in 3.7% formaldehyde before embedding in paraffin. 4 pm thick sections are immunostained by immunohistochemistry with anti-CD3 antibody. The immunostained cell areas from a whole section per mouse are measured by image analysis (CaloPix software, TRIBVN Healthcare, France). Data are expressed as mean ± SEM and statistical analysis is performed using one-way ANOVA followed by Dunnett’s post-hoc test versus MC903 vehicle group.
4.5.8. Gene expression analysis
[0372] 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). Expression levels of each gene of interest (GOI = IL4, IL5, IL13, TSLP, IL33, ST2, IL25, IL31, IFNy, IL6, IL10, LCN2, S100A8, and S100A9) are calculated relative to the housekeeping gene expression levels (HPRT, GAPDH and b-actin).
All qPCR data are expressed as mean ± SEM of the normalized relative quantity (NRQ) calculated according to the following steps:
1- Calculate the geometric mean of NRQ for each group of animals
2 ~Cq GOI
NRQsampie - Geometric mean(2-Cci hPRT, 2 Cci GADPH 2-cq b-actin) 2- Calculate NRQ-scaled compared to the MC903 vehicle group RQsample
NRQscaled =
Geometric mean (NRQsampies MC903 vehicle group)
[0373] 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.
FINAL REMARKS
[0374] It will be appreciated by those skilled in the art that the foregoing descriptions are exemplary and explanatory in nature, and intended to illustrate the invention and its preferred embodiments. Through routine experimentation, an artisan will recognize apparent modifications and variations that may be made without departing from the spirit of the invention. All such modifications coming within the scope of the appended claims are intended to be included therein. Thus, the invention is intended to be defined not by the above description, but by the following claims and their equivalents.
[0375] All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication are specifically and individually indicated to be incorporated by reference herein as though fully set forth.
[0376] It should be understood that factors such as the differential cell penetration capacity of the various compounds can contribute to discrepancies between the activity of the compounds in the in vitro biochemical and cellular assays.
[0377] At least some of the chemical names of compound of the invention as given and set forth in this application, may have been generated on an automated basis by use of a commercially available chemical naming software program, and have not been independently verified. Representative programs performing this function include the Lexichem naming tool sold by Open Eye Software, Inc. and the Autonom Software tool sold by MDL, Inc. In the instance where the indicated chemical name and the depicted structure differ, the depicted structure will control.
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Claims

1. A compound according to Formula I:
Figure imgf000137_0001
wherein
R1 is selected from - -NR3R4,
-C(=0)0-Ci-4 alkyl, and monocyclic, spiropoly cyclic or bridged polycyclic 4-11 membered 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,
O 0X0, o halo, o Ci-4 alkyl unsubstituted or substituted with one or more independently selected halo, -NR5aR5b, or -OH, or o 4-7 membered monocyclic heterocycloalkyl comprising one or more heteroatoms independently selected from N, S, and O,
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;
R2 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 R6 group; each R6 is independently selected from:
- halo,
- -CN,
- -C(=0)0Ci-4 alkyl,
- Ci-4 alkyl unsubstituted or substituted with one or more independently selected halo, C1-4 alkoxy, or OH;
R3 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 -NR7aR7b, or o 4-7 membered monocyclic heterocycloalkyl comprising one or more heteroatoms independently selected from N, O, and S;
R4 is selected from H, and C14 alkyl; or each R5a, R5b, R7a and R7b is independently selected from H and CH alkyl or a pharmaceutically acceptable, or a a solvate, or the salt of a solvate thereof.
2. A compound of pharmaceutically acceptable salt thereof according to claim 1, wherein R2 is H, -CH3, -NH2, or morpholinyl.
3. A compound of pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein Cy is phenyl or pyridyl, each of which is substituted with one, two or three independently selected R6 groups.
4. A compound of pharmaceutically acceptable salt thereof according to claim 3 wherein each R6 is independently selected from F, Cl, -CN, -C(=0)0CH3, -CH3, -CH2CH3,
-CH(CH3)2, -C(CH3)2OH, -CH2OCH3, -CF3, or -CH2OH.
5. A compound of pharmaceutically acceptable salt thereof according to claim 1 wherein the compound is according to Formula Ila, lib, or He:
Figure imgf000138_0001
Ila, lib, or He
6. A compound of pharmaceutically acceptable salt thereof according to any one of claims 1-5 wherein R1 is -NR3R4.
7. A compound of pharmaceutically acceptable salt thereof according to claim 6 wherein R3 is - CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)CH3, -CH2CH(CH3)2, each of which is substituted with one, two or three independently selected halo, -OH, C1-4 alkoxy, -NR7aR7b or 4-7 membered monocyclic heterocycloalkyl comprising one or more heteroatoms independently selected from N, O, and S.
8. A compound of pharmaceutically acceptable salt thereof according to claim 6 or 7, wherein R4 is H, or -CH3.
9. A compound of pharmaceutically acceptable salt thereof according to any one of claims 1-5 wherein R1 is -NH2, -NHCH3, -NHCH2CH3, -NH-CH2CH2OH, -NH-CH(CH3)CH2OH, -NH- CH2C(CH3)2OH, -NH-CH2CF2CH2OH, -NH-CH2CH(OH)CHF2, -NH-CH2-dioxanyl, -NH-CH2CH(OH)CH3, -NH-CH2CH(OH)CF3, -NH-CH2CH2OCH3, or -N(CH3)CH2CH2OH.
10. A compound of pharmaceutically acceptable salt thereof according to any one of claims 1-5 wherein monocyclic or spiro / bridged polycyclic 4-11 membered heterocycloalkyl comprising one or more heteroatoms independently selected from N, S, and O.
11. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-5 wherein R1 is -CH3, -CH2CH3, or -CH(CH3)2
12. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to anyone of claim 1-11.
13. A pharmaceutical composition according to claim 12 comprising a further therapeutic agent.
14. A compound or pharmaceutically acceptable salt thereof according to any one of claims 1-11, or a pharmaceutically composition according to claim 12 or 13, for use in medicine.
15. A compound or pharmaceutically acceptable salt thereof according to any one of claims 1-11, or a pharmaceutically composition according to claim 12 or 13, 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.
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EP4091449A1 (en) * 2021-05-19 2022-11-23 Syngenta Crop Protection AG Weed control method
WO2023278483A1 (en) * 2021-07-01 2023-01-05 Lomond Therapeutics, Inc. Compounds having 1h-pyrazolo[4,3-c]pyridin-6-aminos as therapeutic agents
WO2023161327A1 (en) * 2022-02-24 2023-08-31 Galapagos Nv Compound for use in and methods of treatment of inflammatory diseases

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