WO2024254834A1 - Inhibiteurs de tyk2 et compositions et procédés associés - Google Patents

Inhibiteurs de tyk2 et compositions et procédés associés Download PDF

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Publication number
WO2024254834A1
WO2024254834A1 PCT/CN2023/100518 CN2023100518W WO2024254834A1 WO 2024254834 A1 WO2024254834 A1 WO 2024254834A1 CN 2023100518 W CN2023100518 W CN 2023100518W WO 2024254834 A1 WO2024254834 A1 WO 2024254834A1
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Prior art keywords
compound
alkyl
mmol
substituted
disease
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PCT/CN2023/100518
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English (en)
Inventor
Xiaodong Li
Lin SU
Zhaokui WAN
Gurmit Grewal
Michael Lawrence Vazquez
Weiyu Lin
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Lynk Pharmaceuticals Co Ltd
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Lynk Pharmaceuticals Co Ltd
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Priority to PCT/CN2023/100518 priority Critical patent/WO2024254834A1/fr
Priority to PCT/CN2023/137938 priority patent/WO2024255164A1/fr
Priority to IL325314A priority patent/IL325314A/en
Priority to EP24822832.2A priority patent/EP4727941A1/fr
Priority to TW113122024A priority patent/TW202502755A/zh
Priority to AU2024302699A priority patent/AU2024302699A1/en
Priority to PCT/CN2024/099405 priority patent/WO2024255885A1/fr
Priority to CN202480053861.8A priority patent/CN121773113A/zh
Publication of WO2024254834A1 publication Critical patent/WO2024254834A1/fr
Priority to JOJO/P/2025/0311A priority patent/JOP20250311A1/ar
Anticipated expiration legal-status Critical
Priority to CONC2026/0000331A priority patent/CO2026000331A2/es
Ceased legal-status Critical Current

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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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • 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
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the invention generally relates to novel compounds and methods for their therapeutic use. More particularly, the invention provides a novel class of tyrosine kinase 2 inhibitors as well as pharmaceutical compositions of these compounds and methods of preparation and use thereof against various diseases and conditions.
  • Janus kinase is a family of intracellular, nonreceptor tyrosine kinases that transduce cytokine-mediated signals via the Janus kinase -Signal Transduction Activators of Transcription (JAK-STAT) pathway.
  • JAK1, JAK2, JAK3 and tyrosine kinase 2 TYK2
  • the family is defined by the presence of two adjacent kinase domains, JH1 and JH2, of which JH1 performs the phosphorylation involved in pathway activation whereas JH2 regulates JH1 function.
  • cytoplasmic tyrosine kinases are associated with membrane cytokine receptors such as common gamma-chain receptors and the glycoprotein 130 (gp130) transmembrane proteins.
  • membrane cytokine receptors such as common gamma-chain receptors and the glycoprotein 130 (gp130) transmembrane proteins.
  • gp130 glycoprotein 130
  • TYK2 is a key component of the JAK-STAT signaling pathway. TYK2 regulates INF ⁇ , IL12 and IL23. (Ihle, et al. 1995 Annu Rev Immunol. 13: 369–398; Leonard, et al. 1998 Annu Rev Immunol. 16: 293–322; Liu, et al. 1998 Curr Opin Immunol. 10: 271–278.
  • Cytokines implicated in TYK2 activation include interferons (e.g., IFN-a, IFN-b, IFN-k, IFN-d, IFN-e, IFN-t, IFN-w, and IFN-z, and interleukins (e.g., IL-4, IL-6, IL-10, IL-11, IL-12, IL-13, L-22, IL-23, IL-27, IL-31, oncostatin M, ciliary neurotrophic factor, cardiotrophin 1, cardiotrophin-like cytokine, and LIF) .
  • interferons e.g., IFN-a, IFN-b, IFN-k, IFN-d, IFN-e, IFN-t, IFN-w, and IFN-z
  • interleukins e.g., IL-4, IL-6, IL-10, IL-11, IL-12, IL-13, L-22, IL-23, IL-27,
  • the activated TYK2 goes on to phosphorylate further signaling proteins such as members of the STAT family, including STAT1, STAT2, STAT4, and STAT6.
  • Selective inhibition of TYK2 can be utilized to treat a variety of autoimmune inflammatory diseases, such as psoriasis, systemic lupus erythematosus (SLE) , inflammatory bowel disease (IBD) , rheumatoid arthritis (RA) , as well as cancer and diabetes.
  • the selectivity against other JAK family subtypes is regarded as crucial in order to increase the intended pharmacological effects and to reduce side effects. Identifying kinase inhibitors with a high degree of TYK2 selectivity has posed a significant challenge partly due to the high sequence homology of the active site among the JAK family kinases. TYK2 specificity is critical for clinical application of TYK2 kinase inhibitors, because Tyk2 knockout mice are viable with normal blood cell counts, whereas deficiency of JAK3 results in severe combined immunodeficiency in mice, and JAK1 or JAK2 knockout mice show perinatal lethality. (Ghoreschi, et al. 2009 Immunol Rev.
  • the invention provides novel, selective and potent compounds that are orally available. These therapeutic agents are safe and effective TYK2 inhibitors and exhibit fewer and/or lesser side effects than currently available drugs.
  • the invention also provides pharmaceutical compositions of these compounds and methods of their preparation and use.
  • the invention generally relates to a compound having the structural formula (I) :
  • Y 1 is CH, CF or N
  • Y 2 is CH or N
  • Y 3 is NR, O, CH 2 , CF 2 or O-NH;
  • R 1 is a H, F, C 1 -C 3 alkyl and CD 3 , provided that R 1 is not F when Y 3 is N, O or O-NH;
  • R 2’ wherein R 2’ is a C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 5- C 7 spirocycloalkyl, or C 3 -C 6 heterocycloalkyl, each substituted with 0-2 R 2a , wherein R 2a is selected from the group consisting of halogen, CN, OR, NRR’, alkyl, cycloalkyl, heterocyclic;
  • X 6 is CR 6 or N
  • X 7 is CR 7 or N
  • X 8 is C or N
  • X 9 is CR 9 , O, S, N or NR 9 ;
  • X 10 is CR 9 , O, S, N or NR 10 ;
  • Ring A and Ring B is independently an aryl or heteroaryl group
  • R 2b is a C 1-6 alkyl or C 3-6 cycloalkyl, C 5-7 spirocycloalkyl, aryl or heteroaryl, each substituted with 0-2 R 2c ;
  • R 2c at each occurrence is independently halo, CN, OR, NRR’, OCF 3 , CF 3 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, wherein said alkyl, haloalkyl, alkenyl, alkynyl, R and R’ is substituted with 0-3 R 2a ; and
  • R 4 is a C 1-3 alkyl, substituted with 0-5 R 4a , wherein R 4a is selected from D, F and Cl;
  • each of R 6 , R 7 , R 9 and R 10 is independently selected from H, F, Cl, CN, CD 3 , CH 2 CF 3 , CF 3 , OR, NRR’, C 1 -C 3 alkyl and C 3 -C 5 cycloalkyl, wherein said alkyl, cycloalkyl, R and R’ is substituted with 0-2 R 2a ; and
  • each of R and R’ is independently H or a C 1 -C 6 alkyl or acyl, or R and R’, together with the nitrogen atom to which they are bound, form a 4-to 7-membered ring comprising 0-2 heteroatoms selected from O, NR, S and SO 2 .
  • the invention generally relates to a method for preparing a compound disclosed herein, as exemplified by the synthetic schemes and experimental procedure disclosed herein.
  • the invention generally relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound disclosed herein, effective to treat or reduce one or more diseases or disorders, in a mammal, including a human, and a pharmaceutically acceptable excipient, carrier, or diluent.
  • the invention generally relates to a pharmaceutical composition
  • a pharmaceutical composition comprising an amount of a compound having the structural formula of (I) :
  • Y 1 is CH, CF or N
  • Y 2 is CH or N
  • Y 3 is NR, O, CH 2 , CF 2 or O-NH;
  • R 1 is a H, F, C 1 -C 3 alkyl and CD 3 , provided that R 1 is not F when Y 3 is N, O or O-NH;
  • R 2’ wherein R 2’ is a C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 5- C 7 spirocycloalkyl, or C 3 -C 6 heterocycloalkyl, each substituted with 0-2 R 2a , wherein R 2a is selected from the group consisting of halogen, CN, OR, NRR’, alkyl, cycloalkyl, heterocyclic;
  • X 6 is CR 6 or N
  • X 7 is CR 7 or N
  • X 8 is C or N
  • X 9 is CR 9 , O, S, N or NR 9 ;
  • X 10 is CR 9 , O, S, N or NR 10 ;
  • Ring A and Ring B is independently an aryl or heteroaryl group
  • R 2b is a C 1-6 alkyl or C 3-6 cycloalkyl, C 5-7 spirocycloalkyl, aryl or heteroaryl, each substituted with 0-2 R 2c ;
  • R 2c at each occurrence is independently halo, CN, OR, NRR’, OCF 3 , CF 3 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, wherein said alkyl, haloalkyl, alkenyl, alkynyl, R and R’ is substituted with 0-3 R 2a ; and
  • R 4 is a C 1-3 alkyl, substituted with 0-5 R 4a , wherein R 4a is selected from D, F and Cl;
  • each of R 6 , R 7 , R 9 and R 10 is independently selected from H, F, Cl, CN, CD 3 , CH 2 CF 3 , CF 3 , OR, NRR’, C 1 -C 3 alkyl and C 3 -C 5 cycloalkyl, wherein said alkyl, cycloalkyl, R and R’ is substituted with 0-2 R 2a ; and
  • each of R and R’ is independently H or a C 1 -C 6 alkyl or acyl, or R and R’, together with the nitrogen atom to which they are bound, form a 4-to 7-membered ring comprising 0-2 heteroatoms selected from O, NR, S and SO 2 ,
  • a mammal including a human, and a pharmaceutically acceptable excipient, carrier, or diluent.
  • the invention generally relates to a unit dosage form comprising a pharmaceutical composition disclosed herein.
  • the invention generally relates to a method for treating, reducing or preventing a disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1-61, wherein the disease or disorder is selected from inflammatory diseases, immune-mediated diseases, cancer, or a related disease or disorder thereof, in a mammal, including a human.
  • the invention generally relates to a method for treating, reducing or preventing a disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound having the structural formula of (I) :
  • Y 1 is CH, CF or N
  • Y 2 is CH or N
  • Y 3 is NR, O, CH 2 , CF 2 or O-NH;
  • R 1 is a H, F, C 1 -C 3 alkyl and CD 3 , provided that R 1 is not F when Y 3 is N, O or O-NH;
  • R 2’ wherein R 2’ is a C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 5- C 7 spirocycloalkyl, or C 3 -C 6 heterocycloalkyl, each substituted with 0-2 R 2a , wherein R 2a is selected from the group consisting of halogen, CN, OR, NRR’, alkyl, cycloalkyl, heterocyclic;
  • X 6 is CR 6 or N
  • X 7 is CR 7 or N
  • X 8 is C or N
  • X 9 is CR 9 , O, S, N or NR 9 ;
  • X 10 is CR 9 , O, S, N or NR 10 ;
  • Ring A and Ring B is independently an aryl or heteroaryl group
  • R 2b is a C 1-6 alkyl or C 3-6 cycloalkyl, C 5-7 spirocycloalkyl, aryl or heteroaryl, each substituted with 0-2 R 2c ;
  • R 2c at each occurrence is independently halo, CN, OR, NRR’, OCF 3 , CF 3 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, wherein said alkyl, haloalkyl, alkenyl, alkynyl, R and R’ is substituted with 0-3 R 2a ; and
  • R 4 is a C 1-3 alkyl, substituted with 0-5 R 4a , wherein R 4a is selected from D, F and Cl;
  • each of R 6 , R 7 , R 9 and R 10 is independently selected from H, F, Cl, CN, CD 3 , CH 2 CF 3 , CF 3 , OR, NRR’, C 1 -C 3 alkyl and C 3 -C 5 cycloalkyl, wherein said alkyl, cycloalkyl, R and R’ is substituted with 0-2 R 2a ; and
  • each of R and R’ is independently H or a C 1 -C 6 alkyl or acyl, or R and R’, together with the nitrogen atom to which they are bound, form a 4-to 7-membered ring comprising 0-2 heteroatoms selected from O, NR, S and SO 2 ,
  • disease or disorder is selected from inflammatory diseases, immune-mediated diseases, cancer, or a related disease or disorder thereof, in a mammal, including a human.
  • the invention generally relates to use of a compound disclosed herein, and a pharmaceutically acceptable excipient, carrier, or diluent, in preparation of a medicament for treating a disease or disorder.
  • Ranges provided herein are understood to be shorthand for all of the values within the range.
  • a range of 1 to 16 is understood to include any number, combination of numbers, or sub-range from the group consisting 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16.
  • “more than one” is understood as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 40, 50, 100, etc., or any value therebetween.
  • the term “about” is understood as within a range of normal tolerance in the art, for example within 2 standard deviations of the mean. About can be understood as within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01%of the stated value. Unless otherwise clear from context, all numerical values provided herein can be modified by the term about.
  • compositions or methods disclosed herein can be combined with one or more of any of the other compositions and methods provided herein.
  • compositions and methods when used to define compositions and methods, is intended to mean that the compositions and methods include the recited elements, but do not exclude other elements.
  • the term “consisting essentially of” when used to define compositions and methods, shall mean that the compositions and methods include the recited elements and exclude other elements of any essential significance to the compositions and methods.
  • “consisting essentially of” refers to administration of the pharmacologically active agents expressly recited and excludes pharmacologically active agents not expressly recited.
  • consisting essentially of does not exclude pharmacologically inactive or inert agents, e.g., pharmaceutically acceptable excipients, carriers or diluents.
  • the term “consisting of” when used to define compositions and methods, shall mean excluding trace elements of other ingredients and substantial method steps. Embodiments defined by each of these transition terms are within the scope of this invention.
  • Certain compounds of the present invention may exist in particular geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis-and trans-isomers, atropisomers, R-and S-enantiomers, diastereomers, (D) -isomers, (L) -isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.
  • each asymmetric atom has at least 50 %enantiomeric excess, at least 60 %enantiomeric excess, at least 70 %enantiomeric excess, at least 80 %enantiomeric excess, at least 90 %enantiomeric excess, at least 95 %enantiomeric excess, or at least 99 %enantiomeric excess of either the R-or S-configuration.
  • Isomeric mixtures containing any of a variety of isomer ratios may be utilized in accordance with the present invention. For example, where only two isomers are combined, mixtures containing 50: 50, 60: 40, 70: 30, 80: 20, 90: 10, 95: 5, 96: 4, 97: 3, 98: 2, 99: 1, or 100: 0 isomer ratios are contemplated by the present invention. Those of ordinary skill in the art will readily appreciate that analogous ratios are contemplated for more complex isomer mixtures.
  • a particular enantiomer of a compound of the present invention may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers.
  • the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic methods well known in the art, and subsequent recovery of the pure enantiomers.
  • a mixture of isomers can be separated on the basis of the physicochemical differences of the constituents, into the pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and/or fractional crystallization.
  • C 1-6 alkyl is intended to encompass, C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 , and C 5-6 alkyl.
  • Structures of compounds of the invention are limited by principles of chemical bonding known to those skilled in the art. Accordingly, where a group may be substituted by one or more of a number of substituents, such substitutions are selected so as to comply with principles of chemical bonding and to give compounds that are not inherently unstable and/or would be known to one of ordinary skill in the art as likely to be unstable under ambient conditions (e.g., aqueous, neutral, and several known physiological conditions) .
  • Solvates and polymorphs of the compounds of the invention are also contemplated herein.
  • Solvates of the compounds of the present invention include, for example, hydrates.
  • alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to ten carbon atoms (e.g., C 1-10 alkyl) .
  • a numerical range such as “1 to 10” refers to each integer in the given range; e.g., "1 to 10 carbon atoms” means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms, although the present definition also covers the occurrence of the term "alkyl” where no numerical range is designated.
  • alkyl can be a C 1-6 alkyl group. In some embodiments, alkyl groups have 1 to 10, 1 to 8, 1 to 6, or 1 to 3 carbon atoms.
  • Representative saturated straight chain alkyls include, but are not limited to, -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, and -n-hexyl; while saturated branched alkyls include, but are not limited to, -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, 2-methylbutyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-dimethylbutyl, and the like.
  • alkyl is attached to the parent molecule by a single bond.
  • an alkyl group is optionally substituted by one or more of substituents which independently include: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfona
  • a substituted alkyl can be selected from fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 3-fluoropropyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, benzyl, and phenethyl.
  • alkoxy refers to the group -O-alkyl, including from 1 to 10 carbon atoms (C 1-10 ) of a straight, branched, saturated cyclic configuration and combinations thereof, attached to the parent molecular structure through an oxygen. Unless stated otherwise in the specification, the term is intended to include both substituted and unsubstituted alkoxy groups. Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentoxy, cyclopropyloxy, cyclohexyloxy and the like. "Lower alkoxy” refers to alkoxy groups containing one to six carbons.
  • C 1-3 alkoxy is an alkoxy group that encompasses both straight and branched chain alkyls of from 1 to 3 carbon atoms.
  • an alkoxy group can be optionally substituted by one or more substituents which independently include: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, si
  • aromatic or “aryl” refer to a radical with 6 to 14 ring atoms (e.g., C 6-14 aromatic or C 6-14 aryl) that has at least one ring having a conjugated pi electron system which is carbocyclic (e.g., phenyl, fluorenyl, and naphthyl) . Unless stated otherwise in the specification, the term is intended to include both substituted and unsubstituted aryl groups. In some embodiments, the aryl is a C 6-10 aryl group. For example, bivalent radicals formed from substituted benzene derivatives and having the free valences at ring atoms are named as substituted phenylene radicals.
  • bivalent radicals derived from univalent polycyclic hydrocarbon radicals whose names end in"-yl" by removal of one hydrogen atom from the carbon atom with the free valence are named by adding "-idene” to the name of the corresponding univalent radical, e.g., a naphthyl group with two points of attachment is termed naphthylidene.
  • a numerical range such as "6 to 14 aryl” refers to each integer in the given range; e.g., "6 to 14 ring atoms” means that the aryl group can consist of 6 ring atoms, 7 ring atoms, etc., up to and including 14 ring atoms.
  • the term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of ring atoms) groups.
  • Polycyclic aryl groups include bicycles, tricycles, tetracycles, and the like. In a multi-ring group, only one ring is required to be aromatic, so groups such as indanyl are encompassed by the aryl definition.
  • Non-limiting examples of aryl groups include phenyl, phenalenyl, naphthalenyl, tetrahydronaphthyl, phenanthrenyl, anthracenyl, fluorenyl, indolyl, indanyl, and the like.
  • an aryl moiety can be optionally substituted by one or more substituents which independently include: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfon
  • cycloalkyl and “carbocyclyl” each refers to a monocyclic or polycyclic radical that contains only carbon and hydrogen, and can be saturated or partially unsaturated.
  • Partially unsaturated cycloalkyl groups can be termed “cycloalkenyl” if the carbocycle contains at least one double bond, or "cycloalkynyl” if the carbocycle contains at least one triple bond.
  • Cycloalkyl groups include groups having from 3 to 13 ring atoms (i.e., C 3-13 cycloalkyl) . Unless stated otherwise in the specification, the term is intended to include both substituted and unsubstituted cycloalkyl groups.
  • a numerical range such as “3 to 10" refers to each integer in the given range; e.g., "3 to 13 carbon atoms” means that the cycloalkyl group can consist of 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, etc., up to and including 13 carbon atoms.
  • the term "cycloalkyl” also includes bridged and spiro-fused cyclic structures containing no heteroatoms.
  • the term also includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of ring atoms) groups.
  • Polycyclic aryl groups include bicycles, tricycles, tetracycles, and the like.
  • cycloalkyl can be a C 3-8 cycloalkyl radical. In some embodiments, “cycloalkyl” can be a C 3-5 cycloalkyl radical.
  • Illustrative examples of cycloalkyl groups include, but are not limited to the following moieties: C 3-6 carbocyclyl groups include, without limitation, cyclopropyl (C 3 ) , cyclobutyl (C 4 ) , cyclopentyl (C 5 ) , cyclopentenyl (C 5 ) , cyclohexyl (C 6 ) , cyclohexenyl (C 6 ) , cyclohexadienyl (C 6 ) and the like.
  • C 3-7 carbocyclyl groups include norbornyl (C 7 ) .
  • Examples of C 3-8 carbocyclyl groups include the aforementioned C 3-7 carbocyclyl groups as well as cycloheptyl (C 7 ) , cycloheptadienyl (C 7 ) , cycloheptatrienyl (C 7 ) , cyclooctyl (C 8 ) , bicyclo [2.2.1] heptanyl, bicyclo [2.2.2] octanyl, and the like.
  • C 3-13 carbocyclyl groups include the aforementioned C 3-8 carbocyclyl groups as well as octahydro-1H indenyl, decahydronaphthalenyl, spiro [4.5] decanyl and the like.
  • a cycloalkyl group can be optionally substituted by one or more substituents which independently include: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, s
  • cycloalkenyl and “cycloalkynyl” mirror the above description of “cycloalkyl” wherein the prefix “alk” is replaced with “alken” or “alkyn” respectively, and the parent “alkenyl” or “alkynyl” terms are as described herein.
  • a cycloalkenyl group can have 3 to 13 ring atoms, such as 5 to 8 ring atoms.
  • a cycloalkynyl group can have 5 to 13 ring atoms.
  • halogen refers to fluorine (F) , chlorine (Cl) , bromine (Br) , or iodine (I) .
  • halide or “halo” , means fluoro, chloro, bromo or iodo.
  • haloalkyl, “ “haloalkenyl, “ “haloalkynyl” and “haloalkoxy” include alkyl, alkenyl, alkynyl and alkoxy structures that are substituted with one or more halo groups or with combinations thereof.
  • fluoroalkyl and fluoroalkoxy include haloalkyl and haloalkoxy groups, respectively, in which the halo is fluorine, such as, but not limited to, trifluoromethyl, difluoromethyl, 2, 2, 2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.
  • halo is fluorine, such as, but not limited to, trifluoromethyl, difluoromethyl, 2, 2, 2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.
  • alkyl, alkenyl, alkynyl and alkoxy groups are as defined herein and can be optionally further substituted as defined herein.
  • heteroatom refers to oxygen (O) , nitrogen (N) , sulfur (S) , and phosphorus (P) .
  • heteroalkyl refers to an alkyl radical, which have one or more skeletal chain atoms selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus or combinations thereof. Unless stated otherwise in the specification, the term is intended to include both substituted and unsubstituted heteroalkyl groups.
  • a numerical range can be given, e.g., C 1-4 heteroalkyl, which refers to the chain length in total, which in this example is 4 atoms long.
  • a -CH 2 OCH 2 CH 3 radical is referred to as a "C 4 " heteroalkyl, which includes the heteroatom center in the atom chain length description.
  • an N-containing heteroalkyl moiety refers to a group in which at least one of the skeletal atoms is a nitrogen atom.
  • One or more heteroatom (s) in the heteroalkyl radical can be optionally oxidized.
  • One or more nitrogen atoms, if present, can also be optionally quaternized.
  • heteroalkyl also includes skeletal chains substituted with one or more nitrogen oxide (-O-) substituents.
  • heteroalkyl groups include, without limitation, ethers such as methoxyethanyl (-CH 2 CH 2 OCH 3 ) , ethoxymethanyl (-CH 2 OCH 2 CH 3 ) , (methoxymethoxy) ethanyl (-CH 2 CH 2 OCH 2 OCH 3 ) , (methoxymethoxy) methanyl (-CH 2 OCH 2 OCH 3 ) and (methoxyethoxy) methanyl (-CH 2 OCH 2 CH 2 OCH 3 ) and the like; amines such as (-CH 2 CH 2 NHCH 3 , -CH 2 CH 2 N (CH 3 ) 2 , -CH 2 NHCH 2 CH 3 , -CH 2 N (CH 2 CH 3 ) (CH 3 ) ) and the like.
  • ethers such as methoxyethanyl (-CH 2 CH 2 OCH 3 ) , ethoxymethanyl (-CH 2 OCH 2 CH 3 )
  • heterocycloalkyl refers to a cycloalkyl radical, which have one or more skeletal chain atoms selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus or combinations thereof. Unless stated otherwise in the specification, the term is intended to include both substituted and unsubstituted heterocycloalkyl groups.
  • Illustrative examples of heterocycloalkyl include 2-hydroxy-aziridin-1-yl, 3-oxo-1-oxacyclobutan-2-yl, 2, 2-dimethyl-tetrahydrofuran-3-yl, 3-carboxy-morpholin-4-yl, 1-cyclopropyl-4-methyl-piperazin-2-yl.
  • heteroaryl or, alternatively, “heteroaromatic” refers to a radical of a 5-18 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic, tetracyclic and the like) aromatic ring system (e.g., having 6, 10 or 14 ⁇ electrons shared in a cyclic array) having ring carbon atoms and 1-6 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, phosphorous and sulfur ("5-18 membered heteroaryl” ) . Unless stated otherwise in the specification, the term is intended to include both substituted and unsubstituted heteroaryl groups.
  • Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings.
  • a numerical range such as “5 to 18" refers to each integer in the given range; e.g., "5 to 18 ring atoms” means that the heteroaryl group can consist of 5 ring atoms, 6 ring atoms, etc., up to and including 18 ring atoms.
  • a heteroaryl can have 5 to 14 ring atoms.
  • the heteroaryl has, for example, bivalent radicals derived from univalent heteroaryl radicals whose names end in "-yl” by removal of one hydrogen atom from the atom with the free valence are named by adding "-ene" to the name of the corresponding univalent radical, e.g., a pyridyl group with two points of attachment is a pyridylene.
  • an N-containing “heteroaromatic” or “heteroaryl” moiety refers to an aromatic group in which at least one of the skeletal atoms of the ring is a nitrogen atom.
  • One or more heteroatom (s) in the heteroaryl radical can be optionally oxidized.
  • One or more nitrogen atoms, if present, can also be optionally quaternized.
  • Heteroaryl also includes ring systems substituted with one or more nitrogen oxide (-O-) substituents, such as pyridinyl N-oxides. The heteroaryl is attached to the parent molecular structure through any atom of the ring (s) .
  • Heteroaryl also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment to the parent molecular structure is either on the aryl or on the heteroaryl ring, or wherein the heteroaryl ring, as defined above, is fused with one or more cycloalkyl or heterocycyl groups wherein the point of attachment to the parent molecular structure is on the heteroaryl ring.
  • the point of attachment to the parent molecular structure can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl) .
  • a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, phosphorous, and sulfur ("5-10 membered heteroaryl” ) .
  • a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, phosphorous, and sulfur ( “5-8 membered heteroaryl” ) .
  • a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, phosphorous, and sulfur ("5-6 membered heteroaryl" ) .
  • the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, phosphorous, and sulfur.
  • the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, phosphorous, and sulfur.
  • the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, phosphorous, and sulfur.
  • heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1, 3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo [d] thiazolyl, benzothiadiazolyl, benzo [b] [1, 4] dioxepinyl, benzo [b] [1, 4] oxazinyl, 1, 4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzoxazolyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzopyranonyl, benzofurazanyl, benzothiazolyl, benzothienyl (benzothiophenyl) , benzothieno [3, 2-d] pyrimidinyl
  • a heteroaryl moiety can be optionally substituted by one or more substituents which independently include: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulf
  • administering refers to oral administration, administration as a suppository, topical contact, intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intracranial, intranasal or subcutaneous administration, or the implantation of a slow-release device, e.g., a mini-osmotic pump, to a subject. Suitable routes of administration for a particular patient will depend on the nature and severity of the disease or condition being treated or the nature of the therapy being used and on the nature of the active compound.
  • Administration may be by any suitable route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal) .
  • Parenteral administration includes, e.g., intravenous, intramuscular, intra-arteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial.
  • Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc.
  • composition described herein is administered at the same time, just prior to, or just after the administration of one or more additional therapies.
  • the compound of the invention can be administered alone or can be co-administered to the patient.
  • Co-administration is meant to include simultaneous or sequential administration of the compound individually or in combination (more than one compound or agent) .
  • the preparations can also be combined, when desired, with other active substances (e.g., to reduce metabolic degradation) .
  • compositions of the present invention can be delivered transdermally, by a topical route, formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.
  • Oral preparations include tablets, pills, powder, dragees, capsules, liquids, lozenges, cachets, gels, syrups, slurries, suspensions, etc., suitable for ingestion by the patient.
  • Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
  • Liquid form preparations include solutions, suspensions, and emulsions, gels, for example, water or water/propylene glycol solutions.
  • compositions of the present invention may additionally include components to provide sustained release and/or comfort.
  • Such components include high molecular weight, anionic mucomimetic polymers, gelling polysaccharides and finely-divided drug carrier substrates. These components are discussed in greater detail in U.S. Pat. Nos. 4,911,920; 5,403,841; 5,212,162; and 4,861,760. The entire contents of these patents are incorporated herein by reference in their entirety for all purposes.
  • the compositions of the present invention can also be delivered as microspheres for slow release in the body.
  • microspheres can be administered via intradermal injection of drug-containing microspheres, which slowly release subcutaneously (see Rao, 1995 J. Biomater Sci. Polym. Ed.
  • disease As used herein, the terms “disease, ” “condition, ” and “disorder” are used interchangeably herein and refer to a state of being or health status of a patient or subject capable of being treated with a compound, pharmaceutical composition, or method provided herein.
  • the term “effective amount” of an active agent refers to an amount sufficient to elicit the desired biological response.
  • the effective amount of a compound of the invention may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the patient.
  • the terms “inhibition, ” “inhibit” and “inhibiting” and the like in reference to a biological target (e.g., TYK2) inhibitor interaction refers to negatively affecting (e.g., decreasing) the activity or function of the protein relative to the activity or function of the protein in the absence of the inhibitor.
  • inhibition means negatively affecting (e.g. decreasing) the concentration or levels of the protein relative to the concentration or level of the protein in the absence of the inhibitor.
  • inhibition refers to reduction of a disease or symptoms of disease.
  • inhibition refers to a reduction in the activity of a particular protein target.
  • Inhibition includes, at least in part, partially or totally blocking stimulation, decreasing, preventing, or delaying activation, or inactivating, desensitizing, or down-regulating signal transduction or enzymatic activity or the amount of a protein.
  • inhibition refers to a reduction of activity of a target protein resulting from a direct interaction (e.g., an inhibitor binds to the target protein) .
  • inhibition refers to a reduction of activity of a target protein from an indirect interaction (e.g., an inhibitor binds to a protein that activates the target protein, thereby preventing target protein activation) .
  • isolated or “purified” refer to a material that is substantially or essentially free from components that normally accompany it in its native state. Purity and homogeneity are typically determined using analytical chemistry techniques such as polyacrylamide gel electrophoresis or high-performance liquid chromatography.
  • the term “modulate” refers to the production, either directly or indirectly, of an increase or a decrease, a stimulation, inhibition, interference, or blockage in a measured activity when compared to a suitable control.
  • a “modulator” of a polypeptide or polynucleotide refers to a substance that affects, for example, increases, decreases, stimulates, inhibits, interferes with, or blocks a measured activity of the polypeptide or polynucleotide, when compared to a suitable control.
  • a “modulator” may bind to and /or activate or inhibit the target with measurable affinity, or directly or indirectly affect the normal regulation of a receptor activity.
  • a “pharmaceutically acceptable form” of a disclosed compound includes, but is not limited to, pharmaceutically acceptable salts, esters, hydrates, solvates, isomers, prodrugs, and isotopically labeled derivatives thereof.
  • a “pharmaceutically acceptable form” includes, but is not limited to, pharmaceutically acceptable salts, esters, prodrugs and isotopically labeled derivatives thereof.
  • a “pharmaceutically acceptable form” includes, but is not limited to, pharmaceutically acceptable isomers and stereoisomers, prodrugs and isotopically labeled derivatives thereof.
  • the pharmaceutically acceptable form is a pharmaceutically acceptable salt.
  • pharmaceutically acceptable salt refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of subjects without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66: 1-19.
  • Pharmaceutically acceptable salts of the compounds provided herein include those derived from suitable inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchlorate acid or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchlorate acid
  • organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, besylate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate,
  • organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, lactic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
  • the salts can be prepared in situ during the isolation and purification of the disclosed compounds, or separately, such as by reacting the free base or free acid of a parent compound with a suitable base or acid, respectively.
  • Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like.
  • compositions include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.
  • Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine.
  • the pharmaceutically acceptable base addition salt can be chosen from ammonium, potassium, sodium, calcium, and magnesium salts.
  • the pharmaceutically acceptable form is a “solvate” (e.g., a hydrate) .
  • solvate refers to compounds that further include a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces.
  • the solvate can be of a disclosed compound or a pharmaceutically acceptable salt thereof. Where the solvent is water, the solvate is a “hydrate. ”
  • Pharmaceutically acceptable solvates and hydrates are complexes that, for example, can include 1 to about 100, or 1 to about 10, or 1 to about 2, about 3 or about 4, solvent or water molecules. It will be understood that the term “compound” as used herein encompasses the compound and solvates of the compound, as well as mixtures thereof.
  • the pharmaceutically acceptable form is a prodrug.
  • prodrug refers to compounds that are transformed in vivo to yield a disclosed compound or a pharmaceutically acceptable form of the compound.
  • a prodrug can be inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis (e.g., hydrolysis in blood) .
  • hydrolysis e.g., hydrolysis in blood
  • a prodrug has improved physical and/or delivery properties over the parent compound.
  • Prodrugs can increase the bioavailability of the compound when administered to a subject (e.g., by permitting enhanced absorption into the blood following oral administration) or which enhance delivery to a biological compartment of interest (e.g., the brain or lymphatic system) relative to the parent compound.
  • exemplary prodrugs include derivatives of a disclosed compound with enhanced aqueous solubility or active transport through the gut membrane, relative to the parent compound.
  • the prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985) , pp. 7-9, 21-24 (Elsevier, Amsterdam) .
  • a discussion of prodrugs is provided in Higuchi, T., et al., "Pro-drugs as Novel Delivery Systems, " A.C.S. Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated in full by reference herein.
  • Prodrug forms often offer advantages of solubility, tissue compatibility, or delayed release in the mammalian organism.
  • Prodrugs commonly known in the art include well-known acid derivatives, such as, for example, esters prepared by reaction of the parent acids with a suitable alcohol, amides prepared by reaction of the parent acid compound with an amine, basic groups reacted to form an acylated base derivative, etc.
  • acid derivatives such as, for example, esters prepared by reaction of the parent acids with a suitable alcohol, amides prepared by reaction of the parent acid compound with an amine, basic groups reacted to form an acylated base derivative, etc.
  • Other prodrug derivatives may be combined with other features disclosed herein to enhance bioavailability.
  • Prodrugs include compounds having a carbonate, carbamate, amide or alkyl ester moiety covalently bonded to any of the above substituents disclosed herein.
  • Exemplary advantages of a prodrug can include, but are not limited to, its physical properties, such as enhanced water solubility for parenteral administration at physiological pH compared to the parent compound, or it can enhance absorption from the digestive tract, or it can enhance drug stability for long-term storage.
  • the term “pharmaceutically acceptable” excipient, carrier, or diluent refers to a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body.
  • a pharmaceutically acceptable material, composition or vehicle such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • materials which can serve as pharmaceutically-acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ring
  • wetting agents such as sodium lauryl sulfate, magnesium stearate, and polyethylene oxide-polypropylene oxide copolymer as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
  • the term “subject” refers to any animal (e.g., a mammal) , including, but not limited to humans, non-human primates, rodents, and the like, which is to be the recipient of a particular treatment.
  • a subject to which administration is contemplated includes, but is not limited to, humans (e.g., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult) ) and/or other non-human animals, for example, non-human mammals (e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys) ; commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, and/or dogs) , rodents (e.g., rats and/or mice) , etc.
  • humans e.g., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)
  • non-human mammals
  • the non-human animal is a mammal.
  • the non-human animal may be a male or female at any stage of development.
  • a non-human animal may be a transgenic animal.
  • the terms “subject” and “patient” are used interchangeably herein in reference to a human subject.
  • treatment refers to a method of reducing, delaying or ameliorating such a condition before or after it has occurred. Treatment may be directed at one or more effects or symptoms of a disease and/or the underlying pathology.
  • the treatment can be any reduction and can be, but is not limited to, the complete ablation of the disease or the symptoms of the disease.
  • Treating or treatment thus refers to any indicia of success in the therapy or amelioration of an injury, disease, pathology or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; improving a patient's physical or mental well-being.
  • the treatment or amelioration of symptoms can be based on objective or subjective parameters, for example, the results of a physical examination, neuropsychiatric exams, and/or a psychiatric evaluation. As compared with an equivalent untreated control, such reduction or degree of amelioration may be at least 5%, 10%, 20%, 40%, 50%, 60%, 80%, 90%, 95%, or 100%as measured by any standard technique.
  • Treatment methods include administering to a subject a therapeutically effective amount of a compound described herein.
  • the administering step may be a single administration or may include a series of administrations.
  • the length of the treatment period depends on a variety of factors, such as the severity of the condition, the patient’s age, the concentration of the compound, the activity of the compositions used in the treatment, or a combination thereof.
  • the effective dosage of an agent used for the treatment may increase or decrease over the course of a particular treatment regime. Changes in dosage may result and become apparent by standard diagnostic assays known in the art. In some instances, chronic administration may be required.
  • the compositions are administered to the subject in an amount and for a duration sufficient to treat the patient.
  • the invention is based on an unexpected discovery of novel, selective and potent compounds that are TYK2 inhibitors.
  • the invention also provides pharmaceutical compositions of these compounds and methods of their preparation and use.
  • the compounds are orally available and exhibit fewer and/or lesser side effects than currently available drugs.
  • TYK2 inhibitors disclosed herein exhibit exceptional potency profiles and are useful in treating one or more TYK2-mediated diseases and conditions, such as allergic, autoimmune, inflammatory, metabolic, neurological and proliferative diseases and conditions.
  • compounds of the invention are modulators of interleukins (e.g., IL-12, IL-23) and interferons (e.g., IFN-a) by inhibiting TYK2-mediated signal transduction.
  • the invention also provides pharmaceutical compositions of these compounds and methods of preparation and use thereof.
  • the TYK2 inhibitors disclosed herein exhibit favorable pharmacokinetic profiles and drug properties that are suitable for the target indications.
  • the invention generally relates to a compound having the structural formula (I) :
  • Y 1 is CH, CF or N
  • Y 2 is CH or N
  • Y 3 is NR, O, CH 2 , CF 2 or O-NH;
  • R 1 is a H, F, C 1 -C 3 alkyl and CD 3 , provided that R 1 is not F when Y 3 is N, O or O-NH;
  • R 2’ wherein R 2’ is a C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 5- C 7 spirocycloalkyl, or C 3 -C 6 heterocycloalkyl, each substituted with 0-2 R 2a , wherein R 2a is selected from the group consisting of halogen, CN, OR, NRR’, alkyl, cycloalkyl, heterocyclic;
  • X 6 is CR 6 or N
  • X 7 is CR 7 or N
  • X 8 is C or N
  • X 9 is CR 9 , O, S, N or NR 9 ;
  • X 10 is CR 9 , O, S, N or NR 10 ;
  • Ring A and Ring B is independently an aryl or heteroaryl group
  • R 2b is a C 1-6 alkyl or C 3-6 cycloalkyl, C 5-7 spirocycloalkyl, aryl or heteroaryl, each substituted with 0-2 R 2c ;
  • R 2c at each occurrence is independently halo, CN, OR, NRR’, OCF 3 , CF 3 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, wherein said alkyl, haloalkyl, alkenyl, alkynyl, R and R’ is substituted with 0-3 R 2a ; and
  • R 4 is a C 1-3 alkyl, substituted with 0-5 R 4a , wherein R 4a is selected from D, F and Cl;
  • each of R 6 , R 7 , R 9 and R 10 is independently selected from H, F, Cl, CN, CD 3 , CH 2 CF 3 , CF 3 , OR, NRR’, C 1 -C 3 alkyl and C 3 -C 5 cycloalkyl, wherein said alkyl, cycloalkyl, R and R’ is substituted with 0-2 R 2a ; and
  • each of R and R’ is independently H or a C 1 -C 6 alkyl or acyl, or R and R’, together with the nitrogen atom to which they are bound, form a 4-to 7-membered ring comprising 0-2 heteroatoms selected from O, NR, S and SO 2 .
  • each of Ring A and Ring B is independently a heteroaryl group.
  • each of Ring A is an aryl group and Ring B is a heteroaryl group.
  • each of Ring A is a heteroaryl group and Ring B is an aryl group.
  • each of Ring A and Ring B is independently an aryl group.
  • X 6 is CH and X 7 is CH, with R 3 having the structure:
  • X 7 is CH and X 8 is C, with R 3 having the structure:
  • X 6 is CH and X 8 is C, with R 3 having the structure:
  • X 7 is CH and X 10 is CH, with R 3 having the structure:
  • R 4 is CH 3 .
  • R 4 is CD 3 .
  • R 3 is selected from:
  • R 3 is:
  • R 3 is:
  • R 7 is H.
  • R 9 is C 1-3 alkyl.
  • R 10 is H.
  • R 10 is C 1-3 alkyl.
  • R 5 is a C 1-4 alkyl, optionally substituted with an OH, alkoxy or ester group.
  • R 5 is:
  • R 5’ is a C 1-3 alkyl, substituted with 0-5 F’s ;
  • R is H, C 1-3 alkyl or acyl.
  • R is CH 3 .
  • R is H and R 5 is:
  • R is CH 3 .
  • Y 3 is NH
  • Y 1 is CH and Y 2 is CH:
  • Y 1 is CH and Y 2 is N:
  • Y 1 is N and Y 2 is CH:
  • Y 1 is N and Y 2 is N:
  • R 2 is R 2’ .
  • R 2b is selected from C 1 -C 6 alkyl, cyclopropyl or cyclobutyl, substituted with 0-2 R 2c .
  • R 2b is cyclopropyl.
  • R 2 is phenyl substituted with 0-2 R 2b .
  • R 2 is pyridinyl substituted with 0-2 R 2c .
  • R 2 is pyrazolyl substituted with 0-2 R 2c .
  • R 2 is pyrimidyl substituted with 0-2 R 2c .
  • R 1 is CH 3 .
  • R 1 is CD 3 .
  • the compound of (I) has the structural formula:
  • X 6 is N or CH.
  • the compound of (I) has the structural formula:
  • the compound of (I) has the structural formula:
  • the compound of (I) has the structural formula:
  • the compound of (I) has the structural formula:
  • the compound of (I) has the structural formula:
  • the compound of (I) has the structural formula:
  • the compound of (I) has the structural formula:
  • the compound of (I) has the structural formula:
  • the compound of (I) has the structural formula:
  • the compound of (I) has the structural formula:
  • the compound of (I) has the structural formula:
  • the compound of (I) has the structural formula:
  • the compound of (I) has the structural formula:
  • the compound of (I) has the structural formula:
  • the compound of (I) has the structural formula:
  • the compound of (I) has the structural formula:
  • each is H.
  • R 2b is C 1 -C 6 alkyl, cyclopropyl or cyclobutyl, substituted with 0-2 R 2c .
  • R 5 is:
  • R 5’ is a C 1-3 alkyl, substituted with 0-5 F’s.
  • R is H, C 1-3 alkyl or acyl.
  • R is H and R 5 is:
  • R is CH 3 .
  • R 1 is CH 3 .
  • R 1 is CD 3 .
  • R 1 is CD 3
  • R 2b is cyclopropyl
  • R 5’ is a C 2-3 alkyl, substituted with 2-5 F’s .
  • Non-limiting examples of compounds of the invention include those listed in Table 1 in the Examples section herein.
  • the invention generally relates to a method for preparing a compound disclosed herein, as exemplified by the synthetic schemes and experimental procedure disclosed herein.
  • the invention generally relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound disclosed herein, effective to treat or reduce one or more diseases or disorders, in a mammal, including a human, and a pharmaceutically acceptable excipient, carrier, or diluent.
  • the invention generally relates to a pharmaceutical composition
  • a pharmaceutical composition comprising an amount of a compound having the structural formula of (I) :
  • Y 1 is CH, CF or N
  • Y 2 is CH or N
  • Y 3 is NR, O, CH 2 , CF 2 or O-NH;
  • R 2’ wherein R 2’ is a C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 5- C 7 spirocycloalkyl, or C 3 -C 6 heterocycloalkyl, each substituted with 0-2 R 2a , wherein R 2a is selected from the group consisting of halogen, CN, OR, NRR’, alkyl, cycloalkyl, heterocyclic;
  • X 6 is CR 6 or N
  • X 7 is CR 7 or N
  • X 8 is C or N
  • X 9 is CR 9 , O, S, N or NR 9 ;
  • X 10 is CR 9 , O, S, N or NR 10 ;
  • Ring A and Ring B is independently an aryl or heteroaryl group
  • R 2b is a C 1-6 alkyl or C 3-6 cycloalkyl, C 5-7 spirocycloalkyl, aryl or heteroaryl, each substituted with 0-2 R 2c ;
  • R 2c at each occurrence is independently halo, CN, OR, NRR’, OCF 3 , CF 3 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, wherein said alkyl, haloalkyl, alkenyl, alkynyl, R and R’ is substituted with 0-3 R 2a ; and
  • R 4 is a C 1-3 alkyl, substituted with 0-5 R 4a , wherein R 4a is selected from D, F and Cl;
  • each of R 6 , R 7 , R 9 and R 10 is independently selected from H, F, Cl, CN, CD 3 , CH 2 CF 3 , CF 3 , OR, NRR’, C 1 -C 3 alkyl and C 3 -C 5 cycloalkyl, wherein said alkyl, cycloalkyl, R and R’ is substituted with 0-2 R 2a ; and
  • each of R and R’ is independently H or a C 1 -C 6 alkyl or acyl, or R and R’, together with the nitrogen atom to which they are bound, form a 4-to 7-membered ring comprising 0-2 heteroatoms selected from O, NR, S and SO 2 ,
  • a mammal including a human, and a pharmaceutically acceptable excipient, carrier, or diluent.
  • the pharmaceutical composition is suitable for oral administration.
  • the pharmaceutical composition is suitable for topical administration.
  • the pharmaceutical composition is suitable for GI-restricted administration.
  • the pharmaceutical composition is useful to treat or reduce one or more of inflammatory diseases, immune-mediated diseases and cancers, or a related disease or disorder.
  • the disease or disorder is an inflammatory disease.
  • the disease or disorder is an immune-mediated disease.
  • the disease or disorder is cancer.
  • the disease or disorder is selected from: inflammatory bowel disease, psoriasis, vitiligo, atopic dermatitis, systemic lupus erythematosus, asthma, diabetic nephropathy, chronic myelogenous leukemia (CML) , essential thrombocythemia (ET) , polycythemia vera (PV) , myelofibrosis (MF) , breast cancer and ovarian cancer.
  • CML chronic myelogenous leukemia
  • ET essential thrombocythemia
  • PV polycythemia vera
  • MF myelofibrosis
  • the invention generally relates to a unit dosage form comprising a pharmaceutical composition disclosed herein.
  • the unit dosage form is a tablet.
  • the unit dosage form is a capsule.
  • the unit dosage form is a topical formulation.
  • the invention generally relates to a method for treating, reducing or preventing a disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1-61, wherein the disease or disorder is selected from inflammatory diseases, immune-mediated diseases, cancer, or a related disease or disorder thereof, in a mammal, including a human.
  • the invention generally relates to a method for treating, reducing or preventing a disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound having the structural formula of (I) :
  • Y 1 is CH, CF or N
  • Y 2 is CH or N
  • Y 3 is NR, O, CH 2 , CF 2 or O-NH;
  • R 1 is a H, F, C 1 -C 3 alkyl and CD 3 , provided that R 1 is not F when Y 3 is N, O or O-NH;
  • R 2’ wherein R 2’ is a C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 5- C 7 spirocycloalkyl, or C 3 -C 6 heterocycloalkyl, each substituted with 0-2 R 2a , wherein R 2a is selected from the group consisting of halogen, CN, OR, NRR’, alkyl, cycloalkyl, heterocyclic;
  • X 6 is CR 6 or N
  • X 7 is CR 7 or N
  • X 8 is C or N
  • X 9 is CR 9 , O, S, N or NR 9 ;
  • X 10 is CR 9 , O, S, N or NR 10 ;
  • Ring A and Ring B is independently an aryl or heteroaryl group
  • R 2b is a C 1-6 alkyl or C 3-6 cycloalkyl, C 5-7 spirocycloalkyl, aryl or heteroaryl, each substituted with 0-2 R 2c ;
  • R 2c at each occurrence is independently halo, CN, OR, NRR’, OCF 3 , CF 3 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, wherein said alkyl, haloalkyl, alkenyl, alkynyl, R and R’ is substituted with 0-3 R 2a ; and
  • R 4 is a C 1-3 alkyl, substituted with 0-5 R 4a , wherein R 4a is selected from D, F and Cl;
  • each of R 6 , R 7 , R 9 and R 10 is independently selected from H, F, Cl, CN, CD 3 , CH 2 CF 3 , CF 3 , OR, NRR’, C 1 -C 3 alkyl and C 3 -C 5 cycloalkyl, wherein said alkyl, cycloalkyl, R and R’ is substituted with 0-2 R 2a ; and
  • each of R and R’ is independently H or a C 1 -C 6 alkyl or acyl, or R and R’, together with the nitrogen atom to which they are bound, form a 4-to 7-membered ring comprising 0-2 heteroatoms selected from O, NR, S and SO 2 ,
  • disease or disorder is selected from inflammatory diseases, immune-mediated diseases, cancer, or a related disease or disorder thereof, in a mammal, including a human.
  • the disease or disorder is an inflammatory disease.
  • the disease or disorder is an immune-mediated disease.
  • the disease or disorder is cancer.
  • the disease or disorder is selected from: inflammatory bowel disease, psoriasis, vitiligo, atopic dermatitis, systemic lupus erythematosus, asthma, diabetic nephropathy, chronic myelogenous leukemia (CML) , essential thrombocythemia (ET) , polycythemia vera (PV) , myelofibrosis (MF) , breast cancer and ovarian cancer.
  • CML chronic myelogenous leukemia
  • ET essential thrombocythemia
  • PV polycythemia vera
  • MF myelofibrosis
  • administration is via oral administration.
  • administration is via topical administration.
  • administration is via GI-restricted administration.
  • the invention generally relates to use of a compound disclosed herein, and a pharmaceutically acceptable excipient, carrier, or diluent, in preparation of a medicament for treating a disease or disorder.
  • the disease or disorder is one or more of inflammatory diseases, immune-mediated diseases and cancer.
  • the disease or disorder is an inflammatory disease.
  • the disease or disorder is an immune-mediated disease.
  • the disease or disorder is cancer.
  • the medicament is for oral administration.
  • the medicament is for topical administration.
  • the medicament is for GI restriction administration.
  • isotope derivative compounds having one or more hydrogen atoms (e.g., 1, 2, 4, 5, 6, 7, 8, 9, 10, etc. ) replaced with deuterium atoms are contemplated in the presented invention.
  • inflammatory disease refers to a disease or condition characterized by aberrant inflammation, e.g. an increased level of inflammation compared to a control such as a healthy person not suffering from a disease.
  • inflammatory diseases include autoimmune diseases, traumatic brain injury, arthritis, rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, multiple sclerosis, systemic lupus erythematosus (SLE) , myasthenia gravis, juvenile onset diabetes, diabetes mellitus type 1, Guillain-Barre syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, Sjogren's syndrome, vasculitis, glomerulonephritis, auto-immune thyroiditis, Behcet's disease, Crohn's disease, ulcerative colitis, bullous pemphigoid
  • inflammatory-related diseases, disorders and conditions which may, for example, be caused by inflammatory cytokines, include, arthritis, kidney failure, lupus, asthma, psoriasis, colitis, pancreatitis, allergies, fibrosis, surgical complications (e.g., where inflammatory cytokines prevent healing) , anemia, and fibromyalgia.
  • diseases and disorders which may be associated with chronic inflammation include Alzheimer's disease, congestive heart failure, stroke, aortic valve stenosis, arteriosclerosis, osteoporosis, Parkinson's disease, infections, inflammatory bowel disease (IBD) , allergic contact dermatitis and other eczemas, systemic sclerosis, transplantation and multiple sclerosis.
  • IBD inflammatory bowel disease
  • autoimmune disease refers to a disease or condition in which a subject's immune system has an aberrant immune response against a substance that does not normally elicit an immune response in a healthy subject.
  • autoimmune diseases that may be treated with a compound, pharmaceutical composition, or method described herein include acne vulgaris, acute disseminated encephalomyelitis, acute necrotizing hemorrhagic leukoencephalitis, Addison's disease, agammaglobulinemia, Aicardi-Goutines syndrome (AGS) , alopecia areata, alopecia totalis, amyloidosis, ankylosing spondylitis, anti-GBM/anti-TBM nephritis, antiphospholipid syndrome, autoimmune angioedema, autoimmune aplastic anemia, autoimmune dysautonomia, autoimmune hepatitis, autoimmune hyperlipidemia, autoimmune immunodeficiency, autoimmune inner ear disease, autoimmune myocarditis, autoimmune o
  • Immune-mediated disease refers to chronic inflammatory diseases perpetuated by antibodies and cellular immunity.
  • Immune-mediated diseases include, for example, but not limited to, asthma, allergies, arthritis (e.g., rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis) , juvenile arthritis, inflammatory bowel diseases (e.g., ulcerative colitis and Crohn's disease) , endocrinopathies (e.g., type 1 diabetes and Graves’ disease) , neurodegenerative diseases (e.g., multiple sclerosis (MS) ) , autistic spectrum disorder, depression, Alzheimer's disease, Guillain-Barre syndrome, obsessive-compulsive disorder, optic neuritis, retinal degeneration, dry eye syndrome DES, Sjogren's syndrome, amyotrophic lateral sclerosis (ALS) , Parkinson's disease, Huntington's Disease, Guillain-Barre syndrome, myasthenia gravis, and
  • Hashimoto's thyroiditis pernicious anemia, Cushing's disease, Addison's disease, chronic active hepatitis, polycystic ovary syndrome (PCOS) , celiac disease, pemphigus, transplant rejection (allograft transplant rejection) , graft-versus-host disease (GVDH) .
  • cancer refers to all types of cancer, neoplasm or malignant tumors found in mammals, e.g., humans, including hematological cancers leukemia, and lymphomas, T-ALL, large B-cell lymphoma , solid cancers such as carcinomas and sarcomas.
  • Exemplary cancers include blood cancer, brain cancer, glioma, glioblastoma, neuroblastoma, prostate cancer, colorectal cancer, pancreatic cancer, cervical cancer, gastric cancer, ovarian cancer, lung cancer, and cancer of the head.
  • Exemplary cancers include cancer of the thyroid, endocrine system, brain, breast, cervix, colon, head &neck, liver, kidney, lung, non-small cell lung, melanoma, mesothelioma, ovary, sarcoma, stomach, uterus, medulloblastoma, colorectal cancer, pancreatic cancer.
  • Additional examples include penile, skin –non-melanoma, anal, hepatobiliary, esophagogastric, uterine sarcoma, gastrointestinal stromal tumor, salivary gland, peripheral nervous system, soft tissue sarcoma, bone, renal, myeloproliferative neoplasms, thyroid carcinoma, cholangiocarcinoma, pancreatic adenocarcinoma, skin cutaneous melanoma, colon adenocarcinoma, rectum adenocarcinoma, stomach adenocarcinoma, esophageal carcinoma, head and neck squamous cell carcinoma, breast invasive carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, Hodgkin's Disease, Non-Hodgkin's Lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, r
  • the disease or disorder is selected from: inflammatory bowel disease, psoriasis, vitiligo, atopic dermatitis, systemic lupus erythematosus, asthma, diabetic nephropathy, chronic myelogenous leukemia (CML) , essential thrombocythemia (ET) , polycythemia vera (PV) , myelofibrosis (MF) , breast cancer and ovarian cancer.
  • CML chronic myelogenous leukemia
  • ET essential thrombocythemia
  • PV polycythemia vera
  • MF myelofibrosis
  • Isotopically-labeled compounds are also within the scope of the present disclosure.
  • an "isotopically-labeled compound” refers to a presently disclosed compound including pharmaceutical salts and prodrugs thereof, each as described herein, in which one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds presently disclosed include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl, respectively.
  • the compounds may be useful in drug and/or substrate tissue distribution assays.
  • Tritiated ( 3 H) and carbon-14 ( 14 C) labeled compounds are particularly preferred for their ease of preparation and detectability.
  • substitution with heavier isotopes such as deuterium ( 2 H) can 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.
  • Isotopically labeled compounds presently disclosed, including pharmaceutical salts, esters, and prodrugs thereof, can be prepared by any means known in the art.
  • Stereoisomers e.g., cis and trans isomers
  • optical isomers of a presently disclosed compound e.g., R and S enantiomers
  • racemic, diastereomeric and other mixtures of such isomers are within the scope of the present disclosure.
  • Compounds of the present invention are, subsequent to their preparation, preferably isolated and purified to obtain a composition containing an amount by weight equal to or greater than 95% ( “substantially pure” ) , which is then used or formulated as described herein. In certain embodiments, the compounds of the present invention are more than 99%pure. Solvates and polymorphs of the compounds of the invention are also contemplated herein. Solvates of the compounds of the present invention include, for example, hydrates.
  • Any appropriate route of administration can be employed, for example, parenteral, intravenous, subcutaneous, intramuscular, intraventricular, intracorporeal, intraperitoneal, rectal, or oral administration. Most suitable means of administration for a particular patient will depend on the nature and severity of the disease or condition being treated or the nature of the therapy being used and on the nature of the active compound.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the compounds described herein or derivatives thereof are admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or
  • fillers or extenders as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid
  • binders as for example, carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone, sucrose, and acacia
  • humectants as for example, glycerol
  • disintegrating agents as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate
  • solution retarders as for example, paraffin
  • absorption accelerators as for example, quaternary
  • the dosage forms may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethyleneglycols, and the like.
  • Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and others known in the art.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents, and emulsifiers, such as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1, 3-butyleneglycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols, and fatty acid esters of sorbitan, or mixtures of these substances, and the like.
  • the composition can also include additional agents, such as
  • Method A NH 4 HCO 3 : Column: Gilson2-Xbridge C18 19*150 mm, 5 ⁇ m; mobile phase: CH 3 CN in water (0.1%NH 4 HCO 3 ) from 20%to 60%, Flow rate: 15 mL/min.
  • Method B TFA: Column: Waters-Xbridge C18 10*190 mm, 5 ⁇ m; mobile phase: CH 3 CN in water (0.1%TFA) from 15%to 40%, Flow rate: 15 mL/min.
  • Method C HCOOH: Column: Waters-Xbridge C18 10*190 mm, 5 ⁇ m; mobile phase: CH 3 CN in water (0.1%formic acid) from 15%to 40%, Flow rate: 15 mL/min.
  • Method D HCOOH: Column: Waters Prep C18 OBDTM (5 micron, 19*150 mm) ; mobile phase: CH 3 CN in water (0.1%formic acid) from 18%to 38%, Flow rate: 20 mL/min.
  • Method E NH 4 HCO 3 : Column: Waters Prep C18 OBD TM (5 micron, 19*150 mm) ; mobile phase: CH 3 CN in water (10 mM NH 4 HCO 3 ) from 20%to 60%, Flow rate: 20 mL/min.
  • Method 1 Analysis was performed on an Agilent 1200_series HPLC-6120MS. UHPLC Long Gradient Equivalent 5%to 95%acetonitrile in water (containing 0.02%NH 4 OAc) run time of 6.5 minutes with a flow rate of 1.5 mL/min. A Waters Xbridge C18 column (18.5 micron, 4.6*50 mm) was used at a temperature of 40 °C.
  • Method 2 Analysis was performed on an Agilent 1200_series HPLC-6120MS. UHPLC Long Gradient Equivalent 5%to 95%acetonitrile in water (containing 0.1%trifluoroacetic acid) run time of 6.5 minutes with a flow rate of 1.5 mL/min. A Waters Xbridge C18 column (18.5 micron, 4.6*50 mm) was used at a temperature of 40 °C.
  • Method 3 Analysis was performed on an Agilent 1260_series HPLC-6120MS. UHPLC Long Gradient Equivalent 5%to 95%acetonitrile in water (containing 0.02%NH 4 OAc) run time of 2.5 minutes with a flow rate of 0.5 mL/min. A Diamonsil Plus C18 column (18.5 micron, 4.6*30 mm) was used at a temperature of 40 °C.
  • Method 4 Analysis was performed on an Agilent 1260_series HPLC-6125C MS. HPLC Long Gradient Equivalent 20%to 100%acetonitrile in water (containing 0.1%FA) run time of 6 minutes with a flow rate of 0.8 mL/min. Agilent ZORBAX SB-C18 column (1.8 micron, 2.1*50 mm) was used at a temperature of 30 °C.
  • Method 5 Analysis was performed on a SHIMADZU 20A HPLC. HPLC Long Gradient Equivalent Hexane/EtOH/DEA (70/30/0.2) run time of 20 minutes with a flow rate of 1 mL/min. CHIRALPAK IE (5 ⁇ m, 4.6*250 mm) was used at a temperature of 30 °C.
  • Method 7 Analysis was performed on a SHIMADZU 20A HPLC. HPLC Long Gradient Equivalent Hexane/IPA/DEA (80/20/0.2) run time of 30 minutes with a flow rate of 1 mL/min. CHIRALPAK IB N-5 (5 ⁇ m, 4.6*250 mm) was used at a temperature of 30 °C.
  • Method 8 Analysis was performed on a SHIMADZU 20A HPLC. HPLC Long Gradient Equivalent Hexane/EtOH (70/30) run time of 30 minutes with a flow rate of 1 mL/min. CHIRALPAK IG (5 ⁇ m, 4.6*250 mm) was used at a temperature of 30 °C.
  • Step 3 4-Chloro-6- ( (1S, 2S) -2-fluorocyclopropane-1-carboxamido) -N- (methyl-d 3 ) nicotinamide (Int. B)
  • Step 4 4- ( (5-Bromo-4-methoxy-1-methyl-1H-indol-3-yl) amino) -6- (cyclopropanecarboxamido) -N- (methyl-d 3 ) nicotinamide hydrochloride (2e)
  • Step 8 4- ( (5-Chloro-4-methoxypyrazolo [1, 5-a] pyridin-3-yl) amino) -6- (cyclopropanecarboxamido) nicotinic acid (3i)
  • Step 9 4- ( (5-Chloro-4-methoxypyrazolo [1, 5-a] pyridin-3-yl) amino) -6- (cyclopropanecarboxamido) -N- (methyl-d 3 ) nicotinamide (3)
  • Step 8 4- (N- (5-chloro-4-methoxypyrazolo [1, 5-a] pyridin-3-yl) cyclopropane carboxamido) -2- (cyclopropanecarboxamido) -N- (methyl-d 3 ) pyrimidine-5-carboxamide (4h)
  • Step 9 4- ( (5-Chloro-4-methoxypyrazolo [1, 5-a] pyridin-3-yl) amino) -2- (cyclopropanecarboxamido) -N- (methyl-d 3 ) pyrimidine-5-carboxamide (4)
  • Step 7 6- (Cyclopropanecarboxamido) -4- ( (4-methoxy-5-methylpyrazolo [1, 5-a] pyridin-3-yl) amino) nicotinic acid (5h)
  • Step 8 6- (Cyclopropanecarboxamido) -4- ( (4-methoxy-5-methylpyrazolo [1, 5-a] pyridin-3-yl) amino) -N- (methyl-d 3 ) nicotinamide (5)
  • Step 7 (S) -6- (cyclopropanecarboxamido) -4- ( (4-methoxy-5- (2, 2, 2-trifluoro-1-hydroxyethyl) pyrazolo [1, 5-a] pyridin-3-yl) amino) -N- (methyl-d 3 ) nicotinamide (7A) and (R) -6- (cyclopropanecarboxamido) -4- ( (4-methoxy-5- (2, 2, 2-trifluoro-1-hydroxyethyl) pyrazolo [1, 5-a] pyridin-3-yl) amino) -N- (methyl-d 3 ) nicotinamide (7B)
  • Step 1 1- (3- ( (2- (Cyclopropanecarboxamido) -5- ( (methyl-d 3 ) carbamoyl) pyridin-4-yl) amino) -4-methoxypyrazolo [1, 5-a] pyridin-5-yl) -2, 2, 2-trifluoroethyl methanesulfonate (8a)
  • Step 7 6- (Cyclopropanecarboxamido) -4- ( (4-methoxy-5- (1, 1, 1-trifluoropropan-2-yl) pyrazolo [1, 5-a] pyridin-3-yl) amino) -N- (methyl-d 3 ) nicotinamide (9)
  • Step 8 (R*) -6- (cyclopropanecarboxamido) -4- ( (4-methoxy-5- (1, 1, 1-trifluoropropan-2-yl) pyrazolo [1, 5-a] pyridin-3-yl) amino) -N- (methyl-d 3 ) nicotinamide (9A) and (S*) -6- (cyclopropanecarboxamido) -4- ( (4-methoxy-5- (1, 1, 1-trifluoropropan-2-yl) pyrazolo [1, 5-a] pyridin-3-yl) amino) -N- (methyl-d 3 ) nicotinamide (9B)
  • Step 1 6- ( (1S, 2S) -2-fluorocyclopropane-1-carboxamido) -4- ( (4-methoxy-5- (trifluoromethyl) pyrazolo [1, 5-a] pyridin-3-yl) amino) -N- (methyl-d 3 ) nicotinamide (11)
  • Step 6 4- ( (5-Cyano-4-methoxypyrazolo [1, 5-a] pyridin-3-yl) amino) -6- (cyclopropanecarboxamido) -N- (methyl-d 3 ) nicotinamide (12)
  • Step 1 4- ( (5-Cyano-4-methoxypyrazolo [1, 5-a] pyridin-3-yl) amino) -6- ( (1S, 2S) -2-fluorocyclopropane-1-carboxamido) -N- (methyl-d 3 ) nicotinamide (13)
  • Step 1 6- (Cyclopropanecarboxamido) -4- ( (4-methoxy-3- (2, 2, 2-trifluoro-1-hydroxyethyl) pyrazolo [1, 5-a] pyridin-5-yl) amino) -N-methylnicotinamide (14)
  • Step 2 (S) -6- (cyclopropanecarboxamido) -4- ( (4-methoxy-3- (2, 2, 2-trifluoro-1-hydroxyethyl) pyrazolo [1, 5-a] pyridin-5-yl) amino) -N-methylnicotinamide (14A) and (R) -6- (cyclopropanecarboxamido) -4- ( (4-methoxy-3- (2, 2, 2-trifluoro-1-hydroxyethyl) pyrazolo [1, 5-a] pyridin-5-yl) amino) -N-methylnicotinamide (14B)
  • Step 1 6- ( (1S, 2S) -2-fluorocyclopropane-1-carboxamido) -4- ( (4-methoxy-5- (2, 2, 2-trifluoro-1-hydroxyethyl) pyrazolo [1, 5-a] pyridin-3-yl) amino) -N- (methyl-d 3 ) nicotinamide (15)
  • Step 2 6- ( (1S, 2S) -2-fluorocyclopropane-1-carboxamido) -4- ( (4-methoxy-5- ( (S) -2, 2, 2-trifluoro-1-hydroxyethyl) pyrazolo [1, 5-a] pyridin-3-yl) amino) -N- (methyl-d 3 ) nicotinamide (15A) and 6- ( (1S, 2S) -2-fluorocyclopropane-1-carboxamido) -4- ( (4-methoxy-5- ( (R) -2, 2, 2-trifluoro-1-hydroxyethyl) pyrazolo [1, 5-a] pyridin-3-yl) amino) -N- (methyl-d 3 ) nicotinamide (15B)
  • Step 1 6- ( (1S, 2S) -2-fluorocyclopropane-1-carboxamido) -4- ( (4-methoxy-5- (methoxymethyl) pyrazolo [1, 5-a] pyridin-3-yl) amino) -N- (methyl-d 3 ) nicotinamide (17)
  • Step 4 4- ( (5- (Cyanomethyl) -4-methoxypyrazolo [1, 5-a] pyridin-3-yl) amino) -6- (cyclopropanecarboxamido) -N- (methyl-d 3 ) nicotinamide (18)
  • Step 1 6- (Cyclopropanecarboxamido) -4- ( (5- (hydroxymethyl) -4-methoxypyrazolo [1, 5-a] pyridin-3-yl) amino) -N- (methyl-d 3 ) nicotinamide (22)
  • Step 5 4- ( (5- (1- ( (Tert-butyldiphenylsilyl) oxy) ethyl) -4-methoxypyrazolo [1, 5-a] pyridin-3-yl) amino) -6- (cyclopropanecarboxamido) -N- (methyl-d 3 ) nicotinamide (23e)
  • Step 4 6- (Cyclopropanecarboxamido) -4- ( (4-methoxy-5- ( (methoxy-d 3 ) methyl) pyrazolo [1, 5-a] pyridin-3-yl) amino) -N- (methyl-d 3 ) nicotinamide (29)
  • Step 1.4- (4-Methoxy-5- ( (S) -2, 2, 2-trifluoro-1-hydroxyethyl) pyrazolo [1, 5-a] pyridin-3-yl) amino) -N- (methyl-d 3 ) -6- (spiro [2.2] pentane-1-carboxamido) nicotinamide (32)
  • Step 7 6- (Cyclopropanecarboxamido) -4- ( (4, 5-dimethoxypyrazolo [1, 5-c] pyrimidin-3-yl) amino) -N- (methyl-d 3 ) nicotinamide (35)
  • Step 1 4- ( (4, 5-Dimethoxypyrazolo [1, 5-c] pyrimidin-3-yl) amino) -6- ( (1S, 2S) -2-fluorocyclopropane-1-carboxamido) -N- (methyl-d 3 ) nicotinamide (36)
  • Step 8 Methyl 4-methoxy-5- (3, 3, 3-trifluoroprop-1-en-2-yl) pyrazolo [1, 5-c] pyrimidine-3-carboxylate (37h)
  • Step 13 6- (Cyclopropanecarboxamido) -4- ( (4-methoxy-5- (1, 1, 1-trifluoropropan-2-yl) pyrazolo [1, 5-c] pyrimidin-3-yl) amino) -N- (methyl-d 3 ) nicotinamide (37)
  • Step 1 6- ( (1S, 2S) -2-fluorocyclopropane-1-carboxamido) -4- ( (4-methoxy-5- (1, 1, 1-trifluoropropan-2-yl) pyrazolo [1, 5-c] pyrimidin-3-yl) amino) -N- (methyl-d 3 ) nicotinamide (38)
  • Step 7 2, 2-Trifluoro-1- (3-iodo-4-methoxypyrazolo [1, 5-c] pyrimidin-5-yl) ethan-1-ol (39g)
  • Step 8 1- (3- ( (Diphenylmethylene) amino) -4-methoxypyrazolo [1, 5-c] pyrimidin-5-yl) -2, 2, 2-trifluoroethan-1-ol (39h)
  • Step 9 6- ( (1S, 2S) -2-fluorocyclopropane-1-carboxamido) -4- ( (4-methoxy-5- (2, 2, 2-trifluoro-1-hydroxyethyl) pyrazolo [1, 5-c] pyrimidin-3-yl) amino) -N- (methyl-d 3 ) nicotinamide (39)
  • Step 4 2, 2-Trifluoro-1- (pyrazolo [1, 5-a] pyridin-5-yl) ethan-1-ol (41e)
  • Step 7 6- (Cyclopropanecarboxamido) -N- (methyl-d 3 ) -4- ( (5- (2, 2, 2-trifluoro-1-hydroxyethyl) pyrazolo [1, 5-a] pyridin-3-yl) amino) nicotinamide (41)
  • the compounds are prepared in DMSO for 200x top dose, then serial dilute it with 27-fold for 3 more points. Add 8 ⁇ L/well in echo source plate, echo will add 75nL/well with 3-fold serial dilution for 11 points in assay plate. 75nL DMSO for high control and low control.
  • RLU_compound the relative light unit of cells treated with test compounds
  • RLU_low control the relative light unit of medium with DMSO only
  • RLU_high control the relative light unit of cells treated with DMSO only
  • the dose-response (percent inhibition) curve was plotted and IC50 values (the concentration that causes 50%growth inhibition) were determined by GraphPad software.
  • IC50 values the concentration that causes 50%growth inhibition
  • Exemplary compounds of the invention showed good selectivity over JAK1. These compounds can be used to reduce or eliminate the side effects caused by JAK1 inhibition in autoimmune disease.
  • JAK activity was determined in the reaction buffer 50 mM HEPES, 0.01%Brij35, 10 mM MgCl 2 , 2 mM DTT by a microfluidic assay.
  • the phosphorylation of a FAM labeled peptide substrate was monitored in the Caliper EZ Reader II (Perkin Elmer) .
  • the assay condition for each batch of enzyme was optimized to obtain 10%conversion rate of peptide substrate.
  • test compounds were dissolved in DMSO to a stock concentration of 10 mM. Three-fold serially diluted compounds with top concentration of 5 ⁇ M were pre-incubated with JAK1, JAK2 or TYK2 for 10 min at ambient temperature. The final DMSO concentration of assay mixture was 1%. FAM labeled peptide substrate (final concentration 3 ⁇ M) and ATP (Km concentration or 1mM) were sequentially added to initiate the kinase reaction at 28°C for 90 min (JAK) , 15 min (JAK2) and 30 min (TYK2) , respectively. The reaction was stopped by adding 50 mM EDTA.
  • the dose-response (percent inhibition) curve was plotted and IC50 values were determined by GraphPad software.
  • the IC50 values of tested compounds were list in Table 3.
  • Exemplary compounds of the invention showed excellent selectivity over JAK1,
  • JAK2 and TYK2 kinase domain inhibition JAK2 and TYK2 kinase domain inhibition.
  • Ba/F3 cells Dimerization domain of Tel protein fused with JAK kinase domain was permanently transduced into Ba/F3 cells, whose proliferation is dependent on JAK activity in the absence of IL-3 induction.
  • These engineered Ba/F3-FL-TYK2-P760L cells were used to monitor JAK inhibitory activities of the compounds in the cellular.
  • Ba/F3 cells were cultured in RPMI-1640 (Corning) containing 10%fetal bovine serum. Cells were seeded at 2000/well of white flat bottom 96-well plates. The well containing medium only was used as background control. After 24h growth, cells were treated with compounds. The test compounds were dissolved in DMSO to a stock concentration of 20 mM.
  • RLU_compound the relative light unit of cells treated with test compounds
  • RLU_blank the relative light unit of medium with DMSO only
  • RLU_control the relative light unit of cells treated with DMSO only
  • the dose-response (percent inhibition) curve was plotted and IC50 values (the concentration that causes 50%growth inhibition) were determined by GraphPad software.
  • IC50 values the concentration that causes 50%growth inhibition
  • Exemplary compounds of the invention showed good TYK2 pathway inhibition activity in cells.
  • test articles in human whole blood assay was evaluated by the method of flow cytometry.
  • IFN-alpha will activate JAK1 and TYK2 kinase in T cells by binding to IFN receptors, and then lead to phosphorylation of STAT1 and STAT2.
  • the phosphorylated STAT1 enter nuclear and promote transcription and expression of IFN-gamma.
  • To evaluate the efficacy of TYK2i in T cells freshly collected human whole blood will be stimulated with certain unit of human IFN-alpha (Universal Type I IFN (1MU) , R&D, 11200-2) for 20 mins in incubator. After stimulation, fix cells with PhosflowTM Fix Buffer I (BD, 557870) , and then collect fixed cells by centrifugation (500 g, 8min) .
  • Microsomes were pre-incubated with test compound or control compounds for 5 min at 37°C in 100 mM potassium phosphate buffer, pH 7.4, 1.0 mM EDTA.
  • the reaction was initiated by addition of 15 ⁇ L of the NADPH regenerating system to 30 ⁇ L of each incubation mixture per time point.
  • the final incubation condition was composed of 0.5 mg/mL microsomal protein, 1 ⁇ M test article/positive control, 2 mM NADPH.
  • the 0-minute samples were prepared by addition of a 30 ⁇ L aliquot of each incubation mixture to 135 ⁇ L quench reagent to precipitate proteins. And then a 15 ⁇ L aliquot of the NADPH regenerating system was added.
  • the reaction will be stopped by the addition of cold acetonitrile solution containing internal standard.
  • the samples taken at all time points were centrifuged at 5000 ⁇ g for 15 minutes. 50 ⁇ L of supernatant are taken into 96-well assay plates pre-added with 50 ⁇ L ultrapure water, and then analyzed by LC/MS/MS.
  • CL int (mic) 0.693/T 1/2 /mg microsome protein per mL.
  • the slope was measured by the natural logarithm of the percentage of the residual compound and time, T1/2 was calculated according to the following formula.
  • Exemplary compounds of the invention showed ideal solubility for further development.
  • PK parameter values including, but not necessarily limited to, the maximum plasma concentrations (Cmax) , and the area under the plasma concentration vs. time curve (AUC) from time zero to 24-hour (AUC0-24h) were determined using WinNonlin program.
  • Example 42 showed good brain exposure in Rats.

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Abstract

L'invention concerne une nouvelle classe d'agents thérapeutiques qui sont des inhibiteurs de TYK2 sûrs et efficaces et des compositions pharmaceutiques à base de ces composés et des procédés de préparation et d'utilisation associés contre diverses maladies et troubles médiés par TYK2.
PCT/CN2023/100518 2023-06-15 2023-06-15 Inhibiteurs de tyk2 et compositions et procédés associés Ceased WO2024254834A1 (fr)

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PCT/CN2023/100518 WO2024254834A1 (fr) 2023-06-15 2023-06-15 Inhibiteurs de tyk2 et compositions et procédés associés
PCT/CN2023/137938 WO2024255164A1 (fr) 2023-06-15 2023-12-11 Inhibiteurs de tyk2 et compositions et procédés associés
AU2024302699A AU2024302699A1 (en) 2023-06-15 2024-06-14 Tyk2 inhibitors and compositions and methods thereof
EP24822832.2A EP4727941A1 (fr) 2023-06-15 2024-06-14 Inhibiteurs de tyk2 et compositions et procédés associés
TW113122024A TW202502755A (zh) 2023-06-15 2024-06-14 酪胺酸激酶2抑制劑及組成物以及其方法
IL325314A IL325314A (en) 2023-06-15 2024-06-14 Tyk2 inhibitors, compositions and methods thereof
PCT/CN2024/099405 WO2024255885A1 (fr) 2023-06-15 2024-06-14 Inhibiteurs de tyk2 et compositions et procédés associés
CN202480053861.8A CN121773113A (zh) 2023-06-15 2024-06-14 Tyk2抑制剂及其组合物和方法
JOJO/P/2025/0311A JOP20250311A1 (ar) 2023-06-15 2025-12-14 مثبطات tyk2 وتركيبات وطرق لها
CONC2026/0000331A CO2026000331A2 (es) 2023-06-15 2026-01-14 Inhibidores de tyk2 y composiciones y métodos de estos

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CN111484480A (zh) * 2019-01-29 2020-08-04 上海翰森生物医药科技有限公司 一种多环类衍生物抑制剂、其制备方法和应用
CN115003667A (zh) * 2020-02-26 2022-09-02 百济神州有限公司 Tyk-2抑制剂
CN115466257A (zh) * 2021-06-11 2022-12-13 爱科诺生物医药(香港)有限公司 具有tyk2抑制活性的化合物，包含其的药物组合物，及其应用

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US20230416225A1 (en) * 2020-11-09 2023-12-28 Merck Sharp & Dohme Llc Diaminopyrimidine carboxamide inhibitors of hpk1

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111484480A (zh) * 2019-01-29 2020-08-04 上海翰森生物医药科技有限公司 一种多环类衍生物抑制剂、其制备方法和应用
CN115003667A (zh) * 2020-02-26 2022-09-02 百济神州有限公司 Tyk-2抑制剂
CN115466257A (zh) * 2021-06-11 2022-12-13 爱科诺生物医药(香港)有限公司 具有tyk2抑制活性的化合物，包含其的药物组合物，及其应用

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