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WO2022109580A1 - Inhibition de voies de signalisation dépendantes de tyk2 - Google Patents

Inhibition de voies de signalisation dépendantes de tyk2 Download PDF

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Publication number
WO2022109580A1
WO2022109580A1 PCT/US2021/072483 US2021072483W WO2022109580A1 WO 2022109580 A1 WO2022109580 A1 WO 2022109580A1 US 2021072483 W US2021072483 W US 2021072483W WO 2022109580 A1 WO2022109580 A1 WO 2022109580A1
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Prior art keywords
compound
pharmaceutically acceptable
pyridine
alkyl
methoxytetrahydrofuran
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Inventor
Tami MARRONE
Dale Rudolph
Brock Shireman
Jocelyn WANG
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Janssen Pharmaceutica NV
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Janssen Pharmaceutica NV
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    • 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
    • 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]
    • 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

  • TYK2 a TYK2 mediated inflammatory syndrome, disorder, and/or disease.
  • Tyrosine kinase 2 is a member of the Janus Kinase (JAK) family, which consists of non-receptor tyrosine kinases essential for type I and type II cell-surface cytokine receptors signaling.
  • JAK Janus Kinase
  • JAK1, JAK2, JAK3, and TYK2 There are four JAK family members: JAK1, JAK2, JAK3, and TYK2.
  • JAK1, JAK2, JAK3, and TYK2 There are four JAK family members: JAK1, JAK2, JAK3, and TYK2.
  • Different cytokine receptor families utilize specific JAK isoforms for their signal transduction. Phosphorylation of a JAK when a cytokine binds to its cognate receptor leads to phosphorylation of other intracellular molecules that eventually lead to gene transcription (O’Shea, J. J. et al. Ann
  • TYK2 dependent signaling pathways e.g., interleukin-12 and/or interleukin-23
  • TYK2 dependent signaling pathways e.g., interleukin-12 and/or interleukin-23
  • Ps psoriasis
  • RA rheumatoid arthritis
  • SLE systemic lupus erythematosus
  • T1D type 1 diabetes
  • AS ankylosing spondylitis
  • CD Crohn’s disease
  • UC ulcerative colitis
  • MS multiple sclerosis
  • JIA juvenile idiopathic arthritis
  • PBC primary biliary cirrhosis
  • JAK family members share a high degree of homology between their active sites in the kinase catalytic domain (called Janus Homology Domain 1 or JH1); thus it would be challenging to obtain selectivity for TYK2 over the other JAK family members with ATP- competitive small molecule inhibitors.
  • JH1 the JAK family also has a pseudokinase domain (called Janus Homology Domain 2 or JH2).
  • the TYK2 pseudokinase domain despite its lack of intrinsic kinase activity, has been shown to be important in regulating TYK2 kinase activity (Min, X. et al., J. Biol. Chem. 2015, 290, 27261-27270; Lupardus, P.J.
  • TYK2 a small molecule inhibitor as described herein may provide an opportunity to avoid certain adverse effects observed with certain JAK inhibitors (Gadina, M. etal Rheumatology, 2019, 58, i4— i16), such as the pan- JAK inhibitor Tofacitinib (Xeljanz®), which may have dose-limiting and systemically-mediated adverse events.
  • Z is O, S(O) or SO 2 ; m is 1 or 2;
  • R 1 is -C (1-4) alkyl unsubstituted or substituted with one to six fluorine atoms; -OCH 3 ; -OH;
  • R 1a independently for each occurrence is H or -C (1-2) alkyl
  • R 1b independently for each occurrence is H or -OH; n is 0, 1, 2, or 3;
  • X is -O-, -NH-, -SO 2 -, or -C (1-4) alkyl- that is unsubstituted or substituted with -OH or -CN;
  • Y is -CH 2 -, or -CH(OH)-;
  • U is 0 or 1
  • R 2 is -NH 2 , -NH(CH 3 ), -C 3 -C 6 cycloalkyl or -C (1-4) alkyl that is unsubstituted or substituted with -OH;
  • R 3 is H
  • R 3a independently for each occurrence is -OH, -CN or -C(O)NH 2 ; a 5-membered heterocyclyl having 1 to 2 heteroatoms selected from N and O; or a 5-membered heteroaryl having 1 to 3 heteroatoms selected from N, O, and S; wherein the 5-membered heteroaryl is unsubstituted or substituted with one R 4 group;
  • R 4 is H or -C (1-2) alkyl; and R 5 is -C (1-4) alkyl.
  • the present application also discloses compounds of Formula I. All compounds of Formula I are compounds of Formula I’. Some compounds of Formula I’ are compounds of Formula I.
  • R 1 is -C (1-4) alkyl, -O(CH 2 ) 2 OC (1-4) alkyl, wherein n is 0, 1, 2, or 3 and the -C (1-4) alkyl is unsubstituted or substituted with one to six fluorine atoms;
  • X is O, NH, SO 2 , or -C (1-4) alkyl that is unsubstituted or substituted with -OH or CN;
  • R 2 is -NH 2 or -C (1-4) alkyl
  • R 3 is H, -C (1-4) alkyl or a 5-membered heteroaryl having 1 to 3 heteroatoms selected from N, O, and S, wherein the 5-membered heteroaryl is unsubstituted or substituted with -C (1-4) alkyl.
  • a pharmaceutical composition comprising a compound of Formula I’, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the compounds of Formula I’ disclosed herein selectively bind to the pseudokinase (JH2) domain of TYK2.
  • the compounds disclosed herein are modulators of a TYK2 dependent signaling pathway (e.g., interleukin- 12 and/or interleukin- 23).
  • a method for treating and/or ameliorating a TYK2 dependent signaling pathway e.g., interleukin- 12 and/or interleukin-23.
  • a method for treating and/or ameliorating TYK2 mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I’, or a pharmaceutically acceptable salt thereof.
  • a therapeutically effective amount of compound of Formula I’ for treating and/or ameliorating an Tyk2 mediated inflammatory syndrome, disorder, or disease (e.g., psoriasis, psoriatic arthritis, systemic lupus erythematosus, etc.).
  • an Tyk2 mediated inflammatory syndrome, disorder, or disease e.g., psoriasis, psoriatic arthritis, systemic lupus erythematosus, etc.
  • a compound of Formula I’ or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating and/or ameliorating an Tyk2 mediated inflammatory syndrome, disorder, or disease (e.g., psoriasis, psoriatic arthritis, systemic lupus erythematosus, etc.).
  • an Tyk2 mediated inflammatory syndrome, disorder, or disease e.g., psoriasis, psoriatic arthritis, systemic lupus erythematosus, etc.
  • provided herein are processes and intermediates disclosed herein that are useful for preparing a. compound of Formula I’ or pharmaceutically acceptable salts thereof.
  • a pharmaceutical composition comprising a compound of Formula I, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the compounds of Formula I disclosed herein selectively bind to the pseudokinase (JH2) domain of TYK2.
  • the compounds disclosed herein are modulators of a TYK2 dependent signaling pathway (e.g., interleukin- 12 and/or interleukin- 23).
  • a method for treating and/or ameliorating a TYK2 dependent signaling pathway e.g., interleukin- 12 and/or interleukin-23.
  • a method for treating and/or ameliorating TYK2 mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula. I, or a pharmaceutically acceptable salt thereof.
  • disclosed herein is the use of a therapeutically effective amount of compound of Formula I, or a pharmaceutically acceptable salt thereof, for treating and/or ameliorating an Tyk2 mediated inflammatory syndrome, disorder, or disease (e.g., psoriasis, psoriatic arthritis, systemic lupus erythematosus, etc.).
  • a compound of Formula I, or pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating and/or ameliorating an Tyk2 mediated inflammatory syndrome, disorder, or disease (e.g., psoriasis, psoriatic arthritis, systemic lupus erythematosus, etc.).
  • provided herein are processes and intermediates disclosed herein that are usefill for preparing a compound of Formula I or pharmaceutically acceptable salts thereof.
  • the disclosure also provides a compound or method as described herein.
  • administering means a method for therapeutically or prophylactically preventing, treating or ameliorating a syndrome, disorder or disease as described herein by using a compound of Formula I, or pharmaceutically acceptable salt thereof, composition thereof, or medicament thereof.
  • Such methods include administering a therapeutically effective amount of a compound of Formula I, or pharmaceutically acceptable salt thereof, composition thereof, or medicament thereof, at different times during the course of a therapy or concurrently or sequentially as a combination therapy.
  • subject refers to a patient, which may be an animal, preferably a mammal, most preferably a human, whom will be or has been treated by a method according to an embodiment of the application.
  • mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, non-human primates (NHPs) such as monkeys or apes, humans, etc., more preferably a human.
  • terapéuticaally effective amount means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human, that is being sought by a researcher, veterinarian, medical doctor, or other clinician, which includes preventing, treating or ameliorating the symptoms of a syndrome, disorder or disease being treated.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.
  • the term “treat”, “treating”, or “treatment” of any disease, condition, syndrome or disorder refers, in one embodiment, to ameliorating the disease, condition, syndrome or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof).
  • “treat”, “treating”, or “treatment” refers to alleviating or ameliorating at least one physiological or biochemical parameter associated with or causative of the disease, condition, syndrome or disorder, including those which may not be discernible by the patient.
  • “treat”, “treating”, or “treatment” refers to modulating the disease, condition, syndrome or disorder either physically (e.g. stabilization of a discernible symptom), physiologically, (e.g. stabilization of a physical parameter), or both.
  • “treat'’, “treating”, or “treatment” refers to preventing or delaying the onset or development or progression of the disease, condition, syndrome or disorder.
  • QD means once daily.
  • BID means twice daily.
  • alkyl is a straight or branched saturated hydrocarbon.
  • an alkyl group can have 1 to 12 carbon atoms (i.e., (C 1 -C 12 )alkyl) or 1 to 6 carbon atoms (i.e., (C 1 - C 6 )alkyl).
  • alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), 1 -propyl (n-Pr, n-propyl, -CH 2 CH 2 CH 3 ), isopropyl (i-Pr, i-propyl, -CH(CH 3 ) 2 ), 1- butyl (n-Bu, n-butyl, -CH 2 CH 2 CH 2 CH 3 ), 2-butyl (s-Bu, s-butyl, -CH(CH 3 )CH 2 CH 3 ), tert-butyl (t-Bu, t-butyl, -CH(CH 3 ) 3 ), 1 -pentyl (n-pentyl, -CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 ) CH 2 CH 2 CH 3 ), 1 -hexyl (-CH 2 CH 2 CH 2 CH 3 ),
  • C (a-b) refers to an alkyl, alkenyl, alkynyl, alkoxy or cycloalkyl radical or to the alkyl portion of a radical in which alkyl appears as the prefix root containing from a to b carbon atoms inclusive.
  • C (1-4) denotes a radical containing 1, 2, 3 or 4 carbon atoms.
  • heterocycle refers to a single saturated or partially unsaturated ring that has at least one atom other than carbon in the ring, wherein the atom is selected from the group consisting of oxygen, nitrogen and sulfur.
  • exemplary heterocycles include, but are not limited to oxetanyl, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, and thiomorpholinyl.
  • cycloalkyl refers to a saturated or partially unsaturated all carbon ring system having 3 to 8 carbon atoms (i.e., C (3-8) cycloalkyl), and preferably 3 to 6 carbon atoms (i.e., C (3- 6) cycloalkyl), wherein the cycloalkyl ring system has a single ring or multiple rings in a spirocyclic or bicyclic form.
  • Exemplary cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl .
  • a cycloalkyl group may be unsubstituted or substituted.
  • Some cycloalkyl groups may exist as spirocycloalkyls, wherein two cycloalkyl rings are fused through a single carbon atom; for example and without limitation, an example of a spiropentyl group is for example and without limitation, examples of spirohexyl groups include for example and without limitation examples of cycloheptyl groups .
  • examples of cyclooctyl groups include Unless otherwise stated specifically in the specification, a siprocycloalkyl group may be unsubstituted or substituted.
  • Bicyclic cycloalkyl ring systems also include
  • heteroaryl refers to a single aromatic ring that has at least one atom other than carbon in the ring, wherein the atom is selected from the group consisting of oxygen, nitrogen and sulfur.
  • heteroaryl includes single aromatic rings of from 1 to 6 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur.
  • heteroaryl ring systems include but are not limited to pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrazolyl, oxazolyl, oxadiazolyl, isoxazolyl, triazolyl, imidazolyl, tetrazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, or furyl.
  • halogen refers to bromo (-Br), chloro (-Cl), fluoro (-F) or iodo (-I).
  • “Diastereoisomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror images of each other.
  • Enantiomers are a pair of stereoisomers that are non-superimposable mirror images of each other.
  • a “racemic” mixture is a 1 : 1 mixture of a pair of enantiomers.
  • a “scalemic” mixture of enantiomers is mixture of enantiomers at a ratio other than 1 :1. Where the processes for the preparation of the compounds according to the invention give rise to mixture of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography.
  • the compounds may be prepared in racemic form, a scalemic mixture, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution.
  • the compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (-)-di-p-toluoyl-D-tartaric acid and/or (+)-di-p- toluoyl-L-tartaric acid followed by fractional crystallization and regeneration of the free base.
  • the compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary.
  • the compounds may be resolved using a chiral column vial HPLC or SFC. In some instances retainers of compounds may exist which are observable by 1 H NMR leading to complex multiplets and peak integration in the 1 H NMR spectrum.
  • the absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system. Chiral centers, of which the absolute configurations are known, are labelled by prefixes R and S, assigned by the standard sequence-rule procedure, and preceded when necessary by the appropriate locants (Pure & Appl. Chem. 45, 1976, 11-30). Certain examples contain chemical structures that are depicted or labelled as an (*R) or (*S). When (*R) or (*S) is used in the name of a compound or in the chemical representation of the compound, it is intended to convey that the compound is a pure single isomer at that stereocenter; however, absolute configuration of that stereocenter has not been established.
  • a compound designated as (*R) refers to a compound that is a pure single isomer at that stereocenter with an absolute configuration of either (R) or (S)
  • a compound designated as (*S) refers to a compound that is a pure single isomer at that stereocenter with an absolute configuration of either (R) or (S).
  • Pseudoasymmetric stereogenic centers are treated in the same way as chiral centers, but are given lower-case symbols, r or 5 (Angew. Chem. Int. Ed Engl. 1982, 21, 567-583).
  • any of the processes for preparation of the compounds disclosed herein it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis. John Wiley & Sons, 1991.
  • the protecting groups may be removed at a convenient subsequent stage using methods known from the art.
  • any element in particular when mentioned in relation to a compound of Formula I, or pharmaceutically acceptable salt thereof, shall comprise all isotopes and isotopic mixtures of said element, either naturally occurring or synthetically produced, either with natural abundance or in an isotopically enriched form.
  • a reference to hydrogen includes within its scope 1 H, 2 H (i.e., deuterium or D), and 3 H (i.e., tritium or T).
  • the compounds described herein include a 2 H (i.e., deuterium) isotope.
  • the group denoted -C (1-6) alkyl includes not only -CH 3 , but also CD 3 ; not only CH 2 CH 3 , but also CD 2 CD 3 , etc. .
  • references to carbon and oxygen include within their scope respectively 12 C, 13 C and 14 C and 15 O and 16 O and 17 O and 18 O.
  • the isotopes may be radioactive or non-radioactive.
  • Radiolabelled compounds of Formula I may include a radioactive isotope selected from the group comprising 3H, 11 C, 18 F, 35 S, 122 I, 123 I, 125 I, 131 I, 75 Br, 76 Br, 77 Br and 82 Br.
  • the radioactive isotope is selected from the group of 3 H, 11 C and 18 F.
  • Z is O, S(O) or SO 2 ; m is 1 or 2; R 1 is -C (1-4) alkyl unsubstituted or substituted with one to six fluorine atoms; -OCH 3 ; -OH;
  • R 1a independently for each occurrence is H or -C (1-2) alkyl
  • R 1b independently for each occurrence is H or -OH; n is 0, 1, 2, or 3;
  • X is -O-, -NH-, -SO 2 -, or -C (1-4) alkyl- that is unsubstituted or substituted with -OH or -CN;
  • Y is -CH 2 -, or -CH(OH)-;
  • U is 0 or 1
  • R 2 is -NH 2 , -NH(CH 3 ), -C 3 -C 6 cycloalkyl or -C (1-4) alkyl that is unsubstituted or substituted with -OH;
  • R 3 is H
  • R 3a independently for each occurrence is -OH, -CN or -C(O)NH 2 ; a 5-membered heterocyclyl having 1 to 2 heteroatoms selected from N and O; or a 5-membered heteroaryl having 1 to 3 heteroatoms selected from N, O, and S; wherein the 5-membered heteroaryl is unsubstituted or substituted with one R 4 group;
  • R 4 is H or -C (1-2) alkyl; and R 5 is -C (1-4) alkyl.
  • Z is O, S(O) or SO 2 ; m is 1 or 2;
  • R 1 is -C (1-2) alkyl unsubstituted or substituted with one to three fluorine atoms; -OCH 3 , -
  • R 1a independently for each occurrence is H or -C (1-2) alkyl
  • R 1b independently for each occurrence is H or -OH; n is 0, 1, 2, or 3;
  • X is -O- or -SO 2 -
  • Y is -CH 2 -, or -CH(OH)-;
  • U is 0 or 1
  • R 2 is -NH 2 , -NH(CH 3 ), -C 3 -C 5 cycloalkyl or -C (1-4) alkyl that is unsubstituted or substituted with -OH;
  • R 3 is H
  • R 3a independently for each occurrence is -OH, -CN or -C(O)NH 2 ; a 5-membered heterocyclyl having 1 to 2 heteroatoms selected from N and O; or a 5-membered heteroaryl having 1 to 3 heteroatoms selected from N, O, and S; wherein the 5-membered heteroaryl is unsubstituted or substituted with one R 4 group;
  • R 4 is H or -C (1-2) alkyl; and R 5 is -C (1-4) alkyl.
  • R 1 is -C (1-3) alkyl, -O(CH 2 ) 2 OCH 3 , wherein the -C (1-3) alkyl is unsubstituted or substituted with one to three fluorine atoms.
  • R 1 is -CH 3 , -CHF 2 , -CF 3 , -CF 2 CH 3 , -O(CH 2 ) 2 OCH 3 ,
  • R 2 is -NH 2 , -NH(CH 3 ), -C 3 -C 4 cycloalkyl or -C (1-2) alkyl that is unsubstituted or substituted with -OH.
  • R 2 is a compound of Formula I’, or a pharmaceutically acceptable salt thereof, wherein:
  • R 2 is -NH 2 , -NH(CH 3 ), -CH 3 , -CD 3 , -CH 2 OH, or
  • R 3 is H
  • R 3a independently for each occurrence is -OH, -CN or -C(O)NH 2 ; a 5-membered heterocyclyl having 1 to 2 heteroatoms selected from N and O; or a 5-membered heteroaryl having 1 to 2 heteroatoms selected from N, O, and S, wherein the 5-membered heteroaryl is unsubstituted or substituted with one R 4 group; and
  • R 4 is -C (1-2) alkyl.
  • R 3 is H, -CH 3 , -CD 3 , -CF 3 , -C 3 -C 4 cycloalkyl that is unsubstituted or substituted with one or two R 3a groups; a 5-membered heterocyclyl having 1 to 2 heteroatoms selected from N and O; or a 5- membered heteroaryl having 1 to 2 heteroatoms selected from N and O, wherein the 5-membered heteroaryl is unsubstituted or substituted with -C (1-2) alkyl.
  • a compound of Formula I’ or a pharmaceutically acceptable salt thereof, wherein: In some embodiments, disclosed herein is a compound of Formula I’, or a pharmaceutically acceptable salt thereof, wherein: wherein R 3 is H, -CH 3 , -CD 3 , -CF 3 ,
  • R 3 is H, -CH 3 , -CD 3 , -CF 3 ,
  • a compound of Formula I’ or a pharmaceutically acceptable salt thereof which is a compound of Formula I’a: In some embodiments, disclosed herein is a compound of Formula I’, or a pharmaceutically acceptable salt thereof which is a compound of Formula I’b:
  • R 1 is -C (1-4) alkyl, -O(CH 2 ) 2 OC (1-4) alkyl, wherein n is 0, 1, 2, or 3 and the -C (1-4) alkyl is unsubstituted or substituted with one to six fluorine atoms;
  • X is O, NH, SO 2 , or -C (1-4) alkyl that is unsubstituted or substituted with -OH or CN;
  • R 2 is -NH 2 or -C (1-4) alkyl
  • R 3 is H, -C (1-4) alkyl or a 5-membered heteroaryl having 1 to 3 heteroatoms selected from
  • R 1 is -C (1-4) alkyl, -O(CH 2 ) 2 OCH 3 , wherein n is 0, 1, or 2 and the -C (1-4) alkyl is unsubstituted or substituted with one to six fluorine atoms;
  • X is O, SO 2 , or -C (1-4) alkyl that is unsubstituted or substituted with -OH;
  • R 2 is -NH 2 or -C (1-4) alkyl
  • R 3 is H, -C (1-4) alkyl or a 5-membered heteroaryl having 1 to 3 heteroatoms selected from N, O, and S, wherein the 5-membered heteroaryl is unsubstituted or substituted with -C (1-3) alkyl.
  • R 1 is -C (1-4) alkyl, -O(CH 2 ) 2 OCH 3 , wherein the -C (1-4) alkyl is unsubstituted or substituted with one to three fluorine atoms;
  • R 2 is -NH 2 or -C (1-4) alkyl
  • R 3 is H, -C (1-4) alkyl or a 5-membered heteroaryl having 1 to 3 heteroatoms selected from
  • a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein R 1 is -C (1-3) alkyl, -O(CH 2 ) 2 OCH 3 , wherein the -C (1-3) alkyl is unsubstituted or substituted with one to three fluorine atoms.
  • R 1 is -C (1-3) alkyl, -O(CH 2 ) 2 OCH 3 , wherein the -C (1-3) alkyl is unsubstituted or substituted with one to three fluorine atoms.
  • a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein
  • R 1 is -CH 3 , -CHF 2 , -CF 3 , -O(CH 2 ) 2 OCH 3 ,
  • R 1 is -O(CH 2 ) 2 OCH 3 ,
  • R 2 is -NH 2 , -CH 3 , or -CH 2 CH 3 .
  • a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein: R 2 is -NH 2 , or -CH 3 .
  • R 3 is H, -C (1-3) alkyl or a 5-membered heteroaryl having 1 to 3 heteroatoms selected from N, O, and S, wherein the 5-membered heteroaryl is unsubstituted or substituted with -C (1-4) alkyl.
  • R 3 is H, -C (1-3) alkyl or a 5-membered heteroaryl having 1 to 3 heteroatoms selected from N, O, and S, wherein the 5-membered heteroaryl is unsubstituted or substituted with -C (1-4) alkyl.
  • R 3 is H, -C (1-3) alkyl or a 5-membered heteroaryl having 1 to 3 heteroatoms selected from N, O, and S, wherein the 5-membered heteroaryl is unsubstituted or substituted with -C (1-2) alkyl.
  • R 3 is H, -C (1-3) alkyl or a 5-membered heteroaryl having 1 to 3 heteroatoms selected from N or O, wherein the 5-membered heteroaryl is unsubstituted or substituted with - C (1-2) alkyl.
  • R 3 is H, -C (1-3) alkyl, R 4 is H or -C (1-2) alkyl.
  • R 3 is H, -CH 3 ,
  • a compound of Formula I or a pharmaceutically acceptable salt thereof, which is a compound of Formula la:
  • a compound of Formula I or a pharmaceutically acceptable salt thereof, which is a compound of Formula lb:
  • a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of the compounds in Table 1 A.
  • a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
  • a pharmaceutical composition comprising a compound of Formula I’, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition is formulated for oral administration (e.g., a tablet or capsule).
  • a pharmaceutical composition made by mixing a compound of Formula I’, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • a process for making a pharmaceutical composition comprising mixing a compound of Formula I’, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition is formulated for oral administration (e.g., a tablet or capsule).
  • a pharmaceutical composition made by mixing a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • a process for making a pharmaceutical composition comprising mixing a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the present application also describes a method of selectively inhibiting the pseudokinase (JH2) domain of TYK2 for the treatment of multiple autoimmune and inflammatory diseases such as psoriasis (Ps), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), type 1 diabetes (T1D), ankylosing spondylitis (AS), Crohn’s disease (CD), ulcerative colitis (UC), multiple sclerosis (MS), juvenile idiopathic arthritis (JIA), and primary biliary cirrhosis (PBC).
  • Ps psoriasis
  • RA rheumatoid arthritis
  • SLE systemic lupus erythematosus
  • T1D type 1 diabetes
  • AS ankylosing spondylitis
  • CD Crohn’s disease
  • UC ulcerative colitis
  • MS multiple sclerosis
  • JIA juvenile idiopathic arthritis
  • PBC primary bil
  • TYK2 dependent signaling pathways e.g., interleukin-12, interleukin-23, and/or Typel interferons
  • Ps psoriasis
  • RA rheumatoid arthritis
  • SLE systemic lupus erythematosus
  • T1D type 1 diabetes
  • AS ankylosing spondylitis
  • CD ulcerative colitis
  • MS multiple sclerosis
  • JIA juvenile idiopathic arthritis
  • PBC primary biliary cirrhosis
  • described herein is a method for treating and/or ameliorating a TYK2 mediated inflammatory syndrome, disorder or disease comprising administering to a subject in need thereof an effective amount of a compound of Formula I’, or pharmaceutically acceptable salt thereof, composition thereof, or medicament thereof
  • disclosed herein is a method for treating or ameliorating an TYK2 mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I’, or a pharmaceutically acceptable salt thereof.
  • a method for treating and/or ameliorating an TYK2 mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I’, or a pharmaceutically acceptable salt thereof, wherein the TYK2 mediated inflammatory syndrome, disorder, or disease is selected from the group consisting of: psoriasis, psoriatic arthritis, systemic lupus erythematosus, lupus nephritis, inflammatory bowel disease, ulcerative colitis, Crohn’s disease, rheumatoid arthritis, hidradenitis suppurativa, atopic dermatitis, multiple sclerosis, and Sjogren’s syndrome.
  • disclosed herein is a method for treating and/or ameliorating an TYK2 mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I’, or a pharmaceutically acceptable salt thereof, wherein the TYK2 mediated inflammatory syndrome, disorder, or disease is psoriasis.
  • a method for treating and/or ameliorating an TYK2mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I’, or a pharmaceutically acceptable salt thereof, wherein the TYK2 mediated inflammatory syndrome, disorder, or disease is psoriatic arthritis.
  • a method for treating and/or ameliorating an TYK2mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I’, or a pharmaceutically acceptable salt thereof, wherein the TYK2 mediated inflammatory syndrome, disorder, or disease is systemic lupus erythematosus.
  • a method for treating and/or ameliorating an TYK2mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I’, or a pharmaceutically acceptable salt thereof, wherein the TYK2 mediated inflammatory syndrome, disorder, or disease is lupus nephritis.
  • a method for treating and/or ameliorating an TYK2 mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I’, or a pharmaceutically acceptable salt thereof, wherein the TYK2 mediated inflammatory syndrome, disorder, or disease is inflammatory bowel disease, ulcerative colitis or Crohn’s disease.
  • a method for treating and/or ameliorating an TYK2 mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I’, or a pharmaceutically acceptable salt thereof, wherein the TYK2 mediated inflammatory syndrome, disorder, or disease is rheumatoid arthritis.
  • a method for treating and/or ameliorating an TYK2 mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I’, or a pharmaceutically acceptable salt thereof, wherein the TYK2 mediated inflammatory syndrome, disorder, or disease is hidradenitis suppurativa.
  • a method for treating and/or ameliorating an TYK2 mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I’, or a pharmaceutically acceptable salt thereof, wherein the TYK2 mediated inflammatory syndrome, disorder, or disease is atopic dermatitis.
  • a method for treating or ameliorating and/an TYK2 mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I’, or a pharmaceutically acceptable salt thereof, wherein the TYK2 mediated inflammatory syndrome, disorder, or disease is multiple sclerosis.
  • a method for treating and/or ameliorating an TYK2 mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I’, or a pharmaceutically acceptable salt thereof, wherein the TYK2 mediated inflammatory syndrome, disorder, or disease is Sjogren’s syndrome.
  • a method for treating and/or ameliorating an TYK2 mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I’, or a pharmaceutically acceptable salt thereof, wherein the TYK2 mediated inflammatory syndrome, disorder, or disease is selected from the group consisting of: psoriasis, psoriatic arthritis, systemic lupus erythematosus, lupus nephritis, inflammatory bowel disease, ulcerative colitis, Crohn’s disease, rheumatoid arthritis, hidradenitis suppurativa, atopic dermatitis, multiple sclerosis, and Sjogren’s syndrome, wherein the compound of Formula I’ or the pharmaceutically acceptable salt thereof is administered orally (e.g., as a tablet or capsule).
  • a method for treating and/or ameliorating an TYK2 mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I’, or a pharmaceutically acceptable salt thereof, wherein the TYK2 mediated inflammatory syndrome, disorder, or disease is selected from the group consisting of: psoriasis, psoriatic arthritis, systemic lupus erythematosus, lupus nephritis, inflammatory bowel disease, ulcerative colitis, Crohn’s disease, rheumatoid arthritis, hidradenitis suppurativa, atopic dermatitis, multiple sclerosis, and Sjogren’s syndrome, wherein the therapeutically effective amount is a dose of about 10 mg to 300 mg QD. In some embodiments, the therapeutically effective amount is a dose of about 20 mg to 200 mg QD. In some embodiments, the therapeutically effective amount is a
  • a method for treating and/or ameliorating an TYK2 mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I’, or a pharmaceutically acceptable salt thereof, wherein the TYK2 mediated inflammatory syndrome, disorder, or disease is selected from the group consisting of: psoriasis, psoriatic arthritis, systemic lupus erythematosus, lupus nephritis, inflammatory bowel disease, ulcerative colitis, Crohn’s disease, rheumatoid arthritis, hidradenitis suppurativa, atopic dermatitis, multiple sclerosis, and Sjogren’s syndrome, wherein the therapeutically effective amount is a dose of about 20 mg to 200 mg BID. In some embodiments, the therapeutically effective amount is a dose of about 50 mg to 100 mg BID. In some embodiments, the therapeutically effective amount is a
  • a therapeutically effective amount of compound of Formula I’ for treating and/or ameliorating an TYK2 mediated inflammatory syndrome, disorder, or disease selected from the group consisting of: psoriasis, psoriatic arthritis, systemic lupus erythematosus, lupus nephritis, inflammatory bowel disease, ulcerative colitis, Crohn’s disease, rheumatoid arthritis, hidradenitis suppurativa, atopic dermatitis, multiple sclerosis, and Sjogren’s syndrome.
  • an TYK2 mediated inflammatory syndrome, disorder, or disease selected from the group consisting of: psoriasis, psoriatic arthritis, systemic lupus erythematosus, lupus nephritis, inflammatory bowel disease, ulcerative colitis, Crohn’s disease, rheumatoid arthritis, hidradenitis suppurativa, atopic
  • a compound of Formula I’ or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating and/or ameliorating an TYK2 mediated inflammatory syndrome, disorder, or disease selected from the group consisting of: psoriasis, psoriatic arthritis, systemic lupus erythematosus, lupus nephritis, inflammatory bowel disease, ulcerative colitis, Crohn’s disease, rheumatoid arthritis, hidradenitis suppurativa, atopic dermatitis, multiple sclerosis, and Sjogren’s syndrome.
  • an TYK2 mediated inflammatory syndrome, disorder, or disease selected from the group consisting of: psoriasis, psoriatic arthritis, systemic lupus erythematosus, lupus nephritis, inflammatory bowel disease, ulcerative colitis, Crohn’s disease, rheumatoid arthritis, hidradenitis s
  • a method for treating and/or ameliorating an TYK2 mediated inflammatory syndrome, disorder or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I’, or pharmaceutically acceptable salt thereof, a composition thereof, or a medicament thereof.
  • a method of treating and/or ameliorating an TYK2 mediated inflammatory syndrome, disorder or disease wherein the syndrome, disorder or disease is selected from the group consisting of: psoriasis, psoriatic arthritis, systemic lupus erythematosus, lupus nephritis, inflammatory bowel disease, ulcerative colitis, Crohn’s disease, rheumatoid arthritis, hidradenitis suppurativa, atopic dermatitis, multiple sclerosis, and Sjogren’s syndrome, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I’, or pharmaceutically acceptable salt thereof, a composition thereof, or a medicament thereof.
  • the syndrome, disorder or disease is selected from the group consisting of: psoriasis, psoriatic arthritis, systemic lupus erythematosus, lupus nephritis, inflammatory bowel disease, ulcerative co
  • a method of treating or ameliorating an TYK2 mediated inflammatory syndrome, disorder or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I’, or pharmaceutically acceptable salt thereof, a composition thereof, or a medicament thereof.
  • methods of modulating TYK2 activity in a mammal by administration of a therapeutically effective amount of at least one compound of Formula I’, or pharmaceutically acceptable salt thereof.
  • the present application also describes a method of selectively inhibiting the pseudokinase (JH2) domain of TYK2 for the treatment of multiple autoimmune and inflammatory diseases such as psoriasis (Ps), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), type 1 diabetes (T1D), ankylosing spondylitis (AS), Crohn’s disease (CD), ulcerative colitis (UC), multiple sclerosis (MS), juvenile idiopathic arthritis (JIA), and primary biliary cirrhosis (PBC).
  • Ps psoriasis
  • RA rheumatoid arthritis
  • SLE systemic lupus erythematosus
  • T1D type 1 diabetes
  • AS ankylosing spondylitis
  • CD Crohn’s disease
  • UC ulcerative colitis
  • MS multiple sclerosis
  • JIA juvenile idiopathic arthritis
  • PBC primary bil
  • TYK2 dependent signaling pathways e.g., interleukin- 12, interleukin-23, and/or Typel interferons
  • Ps psoriasis
  • RA rheumatoid arthritis
  • SLE systemic lupus erythematosus
  • T1D type 1 diabetes
  • AS ankylosing spondylitis
  • CD ulcerative colitis
  • MS multiple sclerosis
  • JIA juvenile idiopathic arthritis
  • PBC primary biliary cirrhosis
  • described herein is a method for treating and/or ameliorating a TYK2 mediated inflammatory syndrome, disorder or disease comprising administering to a subject in need thereof an effective amount of a compound of Formula I, or pharmaceutically acceptable salt thereof, composition thereof, or medicament thereof.
  • disclosed herein is a method for treating or ameliorating an TYK2 mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
  • a method for treating and/or ameliorating an TYK2 mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the TYK2 mediated inflammatory syndrome, disorder, or disease is selected from the group consisting of: psoriasis, psoriatic arthritis, systemic lupus erythematosus, lupus nephritis, inflammatory bowel disease, ulcerative colitis, Crohn’s disease, rheumatoid arthritis, hidradenitis suppurativa, atopic dermatitis, multiple sclerosis, and Sjogren’s syndrome.
  • a method for treating and/or ameliorating an TYK2 mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the TYK2 mediated inflammatory syndrome, disorder, or disease is psoriasis.
  • a method for treating and/or ameliorating an TYK2mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the TYK2 mediated inflammatory syndrome, disorder, or disease is psoriatic arthritis.
  • a method for treating and/or ameliorating an TYK2mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the TYK2 mediated inflammatory syndrome, disorder, or disease is systemic lupus erythematosus.
  • a method for treating and/or ameliorating an TYK2mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the TYK2 mediated inflammatory syndrome, disorder, or disease is lupus nephritis.
  • a method for treating and/or ameliorating an TYK2 mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the TYK2 mediated inflammatory syndrome, disorder, or disease is inflammatory bowel disease, ulcerative colitis or Crohn’s disease.
  • a method for treating and/or ameliorating an TYK2 mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the TYK2 mediated inflammatory syndrome, disorder, or disease is rheumatoid arthritis.
  • a method for treating and/or ameliorating an TYK2 mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the TYK2 mediated inflammatory syndrome, disorder, or disease is hidradenitis suppurativa.
  • a method for treating and/or ameliorating an TYK2 mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the TYK2 mediated inflammatory syndrome, disorder, or disease is atopic dermatitis.
  • a method for treating or ameliorating and/an TYK2 mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the TYK2 mediated inflammatory syndrome, disorder, or disease is multiple sclerosis.
  • a method for treating and/or ameliorating an TYK2 mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the TYK2 mediated inflammatory syndrome, disorder, or disease is Sjogren’s syndrome.
  • a method for treating and/or ameliorating an TYK2 mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the TYK2 mediated inflammatory syndrome, disorder, or disease is selected from the group consisting of: psoriasis, psoriatic arthritis, systemic lupus erythematosus, lupus nephritis, inflammatory bowel disease, ulcerative colitis, Crohn’s disease, rheumatoid arthritis, hidradenitis suppurativa, atopic dermatitis, multiple sclerosis, and Sjogren’s syndrome, wherein the compound of Formula I or the pharmaceutically acceptable salt thereof is administered orally (e.g., as a tablet or capsule).
  • a method for treating and/or ameliorating an TYK2 mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the TYK2 mediated inflammatory syndrome, disorder, or disease is selected from the group consisting of: psoriasis, psoriatic arthritis, systemic lupus erythematosus, lupus nephritis, inflammatory bowel disease, ulcerative colitis, Crohn’s disease, rheumatoid arthritis, hidradenitis suppurativa, atopic dermatitis, multiple sclerosis, and Sjogren’s syndrome, wherein the therapeutically effective amount is a dose of about 10 mg to 300 mg QD. In some embodiments, the therapeutically effective amount is a dose of about 20 mg to 200 mg QD. In some embodiments, the therapeutically effective amount is a dose
  • a method for treating and/or ameliorating an TYK2 mediated inflammatory syndrome, disorder, or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the TYK2 mediated inflammatory syndrome, disorder, or disease is selected from the group consisting of: psoriasis, psoriatic arthritis, systemic lupus erythematosus, lupus nephritis, inflammatory bowel disease, ulcerative colitis, Crohn’s disease, rheumatoid arthritis, hidradenitis suppurativa, atopic dermatitis, multiple sclerosis, and Sjogren’s syndrome, wherein the therapeutically effective amount is a dose of about 20 mg to 200 mg BID. In some embodiments, the therapeutically effective amount is a dose of about 50 mg to 100 mg BID. In some embodiments, the therapeutically effective amount is a dose
  • a therapeutically effective amount of compound of Formula I, or a pharmaceutically acceptable salt thereof for treating and/or ameliorating an TYK2 mediated inflammatory syndrome, disorder, or disease selected from the group consisting of: psoriasis, psoriatic arthritis, systemic lupus erythematosus, lupus nephritis, inflammatory bowel disease, ulcerative colitis, Crohn’s disease, rheumatoid arthritis, hidradenitis suppurativa, atopic dermatitis, multiple sclerosis, and Sjogren’s syndrome.
  • an TYK2 mediated inflammatory syndrome, disorder, or disease selected from the group consisting of: psoriasis, psoriatic arthritis, systemic lupus erythematosus, lupus nephritis, inflammatory bowel disease, ulcerative colitis, Crohn’s disease, rheumatoid arthritis, hidradenitis sup
  • a compound of Formula I or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating and/or ameliorating an TYK2 mediated inflammatory syndrome, disorder, or disease selected from the group consisting of: psoriasis, psoriatic arthritis, systemic lupus erythematosus, lupus nephritis, inflammatory bowel disease, ulcerative colitis, Crohn’s disease, rheumatoid arthritis, hidradenitis suppurativa, atopic dermatitis, multiple sclerosis, and Sjogren’s syndrome.
  • an TYK2 mediated inflammatory syndrome, disorder, or disease selected from the group consisting of: psoriasis, psoriatic arthritis, systemic lupus erythematosus, lupus nephritis, inflammatory bowel disease, ulcerative colitis, Crohn’s disease, rheumatoid arthritis, hidradenitis sup
  • a method for treating and/or ameliorating an TYK2 mediated inflammatory syndrome, disorder or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, or pharmaceutically acceptable salt thereof, a composition thereof, or a medicament thereof.
  • a method of treating and/or ameliorating an TYK2 mediated inflammatory syndrome, disorder or disease wherein the syndrome, disorder or disease is selected from the group consisting of: psoriasis, psoriatic arthritis, systemic lupus erythematosus, lupus nephritis, inflammatory bowel disease, ulcerative colitis, Crohn’s disease, rheumatoid arthritis, hidradenitis suppurativa, atopic dermatitis, multiple sclerosis, and Sjogren’s syndrome, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, or pharmaceutically acceptable salt thereof, a composition thereof, or a medicament thereof.
  • the syndrome, disorder or disease is selected from the group consisting of: psoriasis, psoriatic arthritis, systemic lupus erythematosus, lupus nephritis, inflammatory bowel disease, ulcerative colitis
  • a method of treating or ameliorating an TYK2 mediated inflammatory syndrome, disorder or disease wherein the syndrome, disorder or disease is selected from the group consisting of: psoriasis, psoriatic arthritis, and systemic lupus erythematosus, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, or pharmaceutically acceptable salt thereof, a composition thereof, or a medicament thereof.
  • disclosed herein are methods of modulating TYK2 activity in a mammal by administration of a therapeutically effective amount of at least one compound of Formula I, or pharmaceutically acceptable salt thereof.
  • a compound of Formula I’, or pharmaceutically acceptable salt thereof, a composition thereof, or a medicament thereof may also be used in combination with one or more additional therapeutic agents.
  • a compound of Formula I, or pharmaceutically acceptable salt thereof, a composition thereof, or a medicament thereof may also be used in combination with one or more additional therapeutic agents.
  • the one or more additional therapeutic agents is selected from the group consisting of anti-inflammatory agents, immunomodulatory agents, and immunosuppressive agents.
  • the one or more additional therapeutic agents is selected from the group consisting of: (a) anti-TNFalpha agents such as infliximab (Remicade®), adalimumab (Humira®), certolizumab pegol (Cimzia®), golimumab (Simponi®), etanercept (Enbrel®), thalidomide (Immunoprin®), lenalidomide (Revlimid®), and pomalidomide (Pomalyst®/hnnovid®); and
  • anti-TNFalpha agents such as infliximab (Remicade®), adalimumab (Humira®), certolizumab pegol (Cimzia®), golimumab (Simponi®), etanercept (Enbrel®), thalidomide (Immunoprin®), lenalidomide (Revlimid®), and pomalidomide (Pomal
  • anti-pl 9 antibody agents such as tildrakizumab (IlumyaTM/Humetri), risankizumab (SkyriziTM), and mirikizumab.
  • a method of treating and/or ameliorating an TYK2 mediated inflammatory syndrome, disorder or disease, in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the compound of Formula I’, or pharmaceutically acceptable salt thereof, composition thereof, or medicament thereof in a combination therapy with one or more additional therapeutic agents, such as anti-inflammatory agents, immunomodulatory agents, or immunosuppressive agents, wherein said syndrome, disorder or disease is selected from the group consisting of psoriasis, psoriatic arthritis, systemic lupus erythematosus, lupus nephritis, inflammatory bowel disease, ulcerative colitis, Crohn’s disease, rheumatoid arthritis, hidradenitis suppurativa, atopic dermatitis, multiple sclerosis, and Sjogren’s syndrome.
  • additional therapeutic agents such as anti-inflammatory agents, immunomodulatory agents, or immunosuppressive agents
  • a method of treating and/or ameliorating an TYK2 mediated inflammatory syndrome, disorder or disease, in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the compound of Formula I’, or pharmaceutically acceptable salt thereof, composition thereof, or medicament thereof in a combination therapy with one or more additional therapeutic agents, such as anti-inflammatory agents, or immunosuppressive agents, wherein said syndrome, disorder or disease is psoriasis, psoriatic arthritis, or systemic lupus erythematosus.
  • the TYK2 mediated inflammatory syndrome, disorder or disease is psoriasis.
  • the TYK2 mediated inflammatory syndrome, disorder or disease is psoriatic arthritis. In some embodiments, the TYK2 mediated inflammatory syndrome, disorder or disease is systemic lupus erythematosus. In some embodiments, disclosed herein is a method of treating and/or ameliorating an TYK2 mediated inflammatory syndrome, disorder or disease, in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the compound of Formula I, or pharmaceutically acceptable salt thereof, composition thereof, or medicament thereof in a combination therapy with one or more additional therapeutic agents, such as anti-inflammatory agents, immunomodulatory agents, or immunosuppressive agents, wherein said syndrome, disorder or disease is selected from the group consisting of psoriasis, psoriatic arthritis, systemic lupus erythematosus, lupus nephritis, inflammatory bowel disease, ulcerative colitis, Crohn’s disease, rheumatoid arthritis, hidraden
  • a method of treating and/or ameliorating an TYK2 mediated inflammatory syndrome, disorder or disease, in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the compound of Formula I, or pharmaceutically acceptable salt thereof, composition thereof, or medicament thereof in a combination therapy with one or more additional therapeutic agents, such as anti-inflammatory agents, or immunosuppressive agents, wherein said syndrome, disorder or disease is psoriasis, psoriatic arthritis, or systemic lupus erythematosus.
  • the TYK2 mediated inflammatory syndrome, disorder or disease is psoriasis.
  • the TYK2 mediated inflammatory syndrome, disorder or disease is psoriatic arthritis.
  • the TYK2 mediated inflammatory syndrome, disorder or disease is systemic lupus erythematosus.
  • the compounds disclosed herein may be administered in an effective amount within the dosage range of about 0.5 mg to about 1 g, preferably between about 0.5 mg to about 500 mg, in single or divided daily doses.
  • the dosage amount is about 5 mg to 400 mg.
  • the dosage amount is about 10 mg to 300 mg.
  • the dosage amount is about 0.5, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 mg of a compound of Formula I’, or pharmaceutically acceptable salt thereof.
  • the dosage amount is about 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, or 200 mg of a compound of Formula I’, or pharmaceutically acceptable salt thereof.
  • the dosage amount is about 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, or 300 mg of a compound of Formula I’, or pharmaceutically acceptable salt thereof
  • the dosage amount is about 300, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, or 400 mg of a compound of Formula I’, or pharmaceutically acceptable salt thereof.
  • the dosage amount is about 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, or 500 mg of a compound of Formula I’, or pharmaceutically acceptable salt thereof.
  • a compound of Formula I’, or pharmaceutically acceptable salt thereof may be administered in an effective amount within the dosage range of about 10 mg to 300 mg QD. In some embodiments, a compound of Formula I’, or pharmaceutically acceptable salt thereof, may be administered in an effective amount within the dosage range of about 20 mg to 200 mg QD. In some embodiments, a compound of Formula I’, or pharmaceutically acceptable salt thereof, may be administered in an effective amount within the dosage range of about 50 mg to 100 mg QD.
  • a compound of Formula I’, or pharmaceutically acceptable salt thereof may be administered in an effective amount within the dosage range of about 20 mg to 200 mg QD. In some embodiments, a compound of Formula I’, or pharmaceutically acceptable salt thereof, may be administered in an effective amount within the dosage range of about 50 mg to 100 mg QD.
  • the compounds disclosed herein may be administered in an effective amount within the dosage range of about 0.5 mg to about 1 g, preferably between about 0.5 mg to about 500 mg, in single or divided daily doses.
  • the dosage amount is about 5 mg to 400 mg.
  • the dosage amount is about 10 mg to 300 mg.
  • the dosage amount is about 0.5, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 mg of a compound of Formula I, or pharmaceutically acceptable salt thereof.
  • the dosage amount is about 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, or 200 mg of a compound of Formula I, or pharmaceutically acceptable salt thereof. In some embodiments, the dosage amount is about 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, or 300 mg of a compound of Formula I, or pharmaceutically acceptable salt thereof.
  • the dosage amount is about 300, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, or 400 mg of a compound of Formula I, or pharmaceutically acceptable salt thereof. In some embodiments, the dosage amount is about 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, or 500 mg of a compound of Formula I, or pharmaceutically acceptable salt thereof.
  • a compound of Formula I, or pharmaceutically acceptable salt thereof may be administered in an effective amount within the dosage range of about 10 mg to 300 mg QD. In some embodiments, a compound of Formula I, or pharmaceutically acceptable salt thereof, may be administered in an effective amount within the dosage range of about 20 mg to 200 mg QD. In some embodiments, a compound of Formula I, or pharmaceutically acceptable salt thereof, may be administered in an effective amount within the dosage range of about 50 mg to 100 mg QD.
  • a compound of Formula I, or pharmaceutically acceptable salt thereof may be administered in an effective amount within the dosage range of about 20 mg to 200 mg QD. In some embodiments, a compound of Formula I, or pharmaceutically acceptable salt thereof, may be administered in an effective amount within the dosage range of about 50 mg to 100 mg QD.
  • the dosage administered will be affected by factors such as the route of administration, the health, weight and age of the recipient, the frequency of the treatment and the presence of concurrent and unrelated treatments. It is also apparent to one skilled in the art that the therapeutically effective dose for compounds of the present invention or a pharmaceutical composition thereof will vary according to the desired effect. Therefore, optimal dosages to be administered may be readily determined by one skilled in the art and will vary with the particular compound used, the mode of administration, the strength of the preparation, and the advancement of the disease condition. In addition, factors associated with the particular subject being treated, including subject age, weight, diet and time of administration, will result in the need to adjust the dose to an appropriate therapeutic level. The above dosages are thus exemplary of the average case. There can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.
  • Pharmaceutically acceptable acidic/anionic salts include, and are not limited to acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, glyceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, pamoate, pantothenate, phosphate/diphosphate, polygalacturonate,
  • Organic or inorganic acids also include, and are not limited to, hydriodic, perchloric, sulfuric, phosphoric, propionic, glycolic, methanesulfonic, hydroxyethanesulfonic, oxalic, 2- naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic, saccharinic or trifluoroacetic acid.
  • Pharmaceutically acceptable basic/cationic salts include, and are not limited to aluminum, 2- amino-2-hydroxymethyl-propane-1,3-diol (also known as tris(hydroxymethyl)aminomethane, tromethane or “TRIS”), ammonia, benzathine, t-butylamine, calcium, calcium gluconate, calcium hydroxide, chloroprocaine, choline, choline bicarbonate, choline chloride, cyclohexylamine, diethanolamine, ethylenediamine, lithium, LiOMe, L-lysine, magnesium, meglumine, NH 3 , NH 4 OH, N-methyl-D-glucamine, piperidine, potassium, potassium- t-butoxide, potassium hydroxide (aqueous), procaine, quinine, sodium, sodium carbonate, sodium-2-ethylhexanoate, sodium hydroxide, triethanolamine, or zinc.
  • TMS tris(hydroxymethyl)aminomethane
  • the compounds of Formula I’, or pharmaceutically acceptable salt thereof, may be formulated into pharmaceutical compositions comprising any known pharmaceutically acceptable carriers.
  • exemplary carriers include, but are not limited to, any suitable solvents, dispersion media, coatings, antibacterial and antifungal agents and isotonic agents.
  • exemplary excipients that may also be components of the formulation include fillers, binders, disintegrating agents and lubricants.
  • the pharmaceutically-acceptable salts of the compounds of Formula I’, or pharmaceutically acceptable salt thereof include the conventional non-toxic salts or the quaternary ammonium salts which are formed from inorganic or organic acids or bases.
  • acid addition salts include acetate, adipate, benzoate, benzenesulfonate, citrate, camphorate, dodecylsulfate, hydrochloride, hydrobromide, lactate, maleate, methanesulfonate, nitrate, oxalate, pivalate, propionate, succinate, sulfate and tartrate.
  • Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamino salts and salts with amino acids such as arginine. Also, the basic nitrogen-containing groups may be quatemized with, for example, alkyl halides.
  • compositions of the invention may be administered by any means that accomplish their intended purpose. Examples include administration by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, topical, buccal or ocular routes. Alternatively or concurrently, administration may be by the oral route.
  • Suitable formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form, for example, water-soluble salts, acidic solutions, alkaline solutions, dextrose-water solutions, isotonic carbohydrate solutions and cyclodextrin inclusion complexes.
  • a method of making a pharmaceutical composition comprising mixing a pharmaceutically acceptable carrier with any of the compounds of Formula I’, or pharmaceutically acceptable salt thereof.
  • the present application includes pharmaceutical compositions made by mixing a pharmaceutically acceptable carrier with any of the compounds of the present invention.
  • the compounds of Formula I, or pharmaceutically acceptable salt thereof, may be formulated into pharmaceutical compositions comprising any known pharmaceutically acceptable carriers.
  • exemplary carriers include, but are not limited to, any suitable solvents, dispersion media, coatings, antibacterial and antifungal agents and isotonic agents.
  • exemplary excipients that may also be components of the formulation include fillers, binders, disintegrating agents and lubricants.
  • the pharmaceutically-acceptable salts of the compounds of Formula I, or pharmaceutically acceptable salt thereof include the conventional non-toxic salts or the quaternary ammonium salts which are formed from inorganic or organic acids or bases.
  • acid addition salts include acetate, adipate, benzoate, benzenesulfonate, citrate, camphorate, dodecylsulfate, hydrochloride, hydrobromide, lactate, maleate, methanesulfonate, nitrate, oxalate, pivalate, propionate, succinate, sulfate and tartrate.
  • Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamino salts and salts with amino acids such as arginine. Also, the basic nitrogen-containing groups may be quatemized with, for example, alkyl halides.
  • compositions of the invention may be administered by any means that accomplish their intended purpose. Examples include administration by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, topical, buccal or ocular routes. Alternatively or concurrently, administration may be by the oral route.
  • Suitable formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form, for example, water-soluble salts, acidic solutions, alkaline solutions, dextrose-water solutions, isotonic carbohydrate solutions and cyclodextrin inclusion complexes.
  • a method of making a pharmaceutical composition comprising mixing a pharmaceutically acceptable carrier with any of the compounds of Formula I, or pharmaceutically acceptable salt thereof. Additionally, the present application includes pharmaceutical compositions made by mixing a pharmaceutically acceptable carrier with any of the compounds of the present invention.
  • provided herein are processes and intermediates disclosed herein that are useful for preparing a compound of Formula I or pharmaceutically acceptable salts thereof.
  • a Suzuki reaction or a Suzuki coupling may be performed using the following conditions:
  • One coupling reactant has a boron component that is in the form of, for example, a potassium trifluoroborate, an organoborane, a boronate or a boronic acid.
  • the second coupling reactant is in the form of, for example, an aryl, alkyl, alkenyl or alkynyl halide.
  • a Boc protecting group may be removed using the following conditions: HC1 in dioxane or ethyl acetate or TFA in CH 2 CI 2 .
  • the concentration of the HCl in dioxane or ethyl acetate may be from 1.0 M to 4.0 M, and the reaction may be run in a solvent such as isopropanol or CH 2 CI 2 .
  • a Boc protecting group can be removed by subjecting the compound to microwave irradiation at 120 °C in a solvent such as 1, 1,1, 3,3,3- hexafluoro-2-propanol.
  • the aforementioned conditions are referred to as “Boc deprotection conditions”.
  • a compound of formula VII is prepared in two steps from a compound of formula V.
  • a compound of formula V is reacted with a base such as n-BuLi, in a suitable solvent such as DCM, at a temperature of about -78 °C, followed by the addition of dihydrofuran-3(2H)-one to provide a compound of formula VI.
  • a compound of formula VI is treated with a base such as NaH, LiH, KOH, NaOMe, NaOH, or t- BuOK in a suitable solvent such as DMF, at a temperature of about 0 °C, followed by the addition of an alkyl halide such as CH 3 I, to provide a compound of formula VII.
  • a base such as NaH, LiH, KOH, NaOMe, NaOH, or t- BuOK
  • a suitable solvent such as DMF
  • Scheme 1a As shown in Scheme la, compounds of formula VII-a and Vll-aa, can be prepared in two or three steps from a compound of formula V.
  • a compound of formula V is initially treated with a base such as n-BuLi in a suitable solvent such as DCM, at a temperature of about -78 °C, followed by the addition of a cyclic ketone, such as dihydro-2H-pyran-3(4H)- one or dihydrothi ophen-3(2H)-one to provide a compound of formula Vl-a.
  • a base such as n-BuLi
  • a suitable solvent such as DCM
  • a compound of formula Vl-a is treated with a base such as NaH, LiH, KOH, NaOMe, NaOH, or t- BuOK in a suitable solvent such as THF or DMF, at a temperature of about 0 °C, followed by the addition of an alkyl halide such as CH 3 CH 2 I or CH 3 I, to provide a compound of formula VII-a.
  • a base such as NaH, LiH, KOH, NaOMe, NaOH, or t- BuOK
  • a suitable solvent such as THF or DMF
  • an oxidant such as oxone or 30% aqueous H 2 O 2 in a suitable solvent such as MeOH, H 2 O or 1,1, 1,3,3, 3-hexafluoro- 2-propanol at a temperature of about 0 °C to room temperature for approximately 1 h
  • a compound of formula Vll-aa where R a is NO 2 can be converted to a compound of formula Vll-a where R a is displacement with an amine nucleophile, such as piperidine or 4-(benzyloxy)piperidine, respectively
  • compounds of formula VII-c can be prepared in four steps from a compound of formula VII.
  • a compound of formula VII is treated with an acid, such as concentrated HC1, in a suitable solvent, such as water, to provide an intermediate aldehyde which is then treated with a Grignard reagent, such as MeMgCl in a suitable solvent, such as THF at a temperature of about -78 °C to provide a compound of formula Vll-b.
  • an acid such as concentrated HC1
  • a suitable solvent such as water
  • a Grignard reagent such as MeMgCl
  • THF a suitable solvent
  • a compound of formula VII-b is treated with an oxidant such as Dess-Martin periodinane, in a suitable solvent such as DCM at a temperature around room temperature to provide an intermediate ketone which is then treated with DAST, in a suitable solvent such as DCM at a temperature of about 0 °C to provide a compound of formula VII-c.
  • an oxidant such as Dess-Martin periodinane
  • 2-bromo-6-(3-methoxytetrahydrofuran-3-yl)pyridin-4-ol (a compound of formula VII where R 1 is OH) is alkylated with a compound of formula IX, where and LG 1 is a leaving group such as halo, -OMs, or -OTs, and R bb is -(CH 2 ) 2 OCH 3 , in the presence of a base such as NaH, in a suitable solvent such as DMF, at a temperature ranging from about 0 °C to about 85 °C, to afford a compound of formula VIII.
  • a compound of formula XIII is prepared from a compound of formula X, by reaction with a compound of formula XI, in the presence of a catalyst such as Pd(dppf)Cl 2 , a base such as K 3 PO 4 , in a solvent such as 1,4-dioxane and water, or a combination thereof, at a temperature of about 80 °C for about 3 h.
  • a catalyst such as Pd(dppf)Cl 2
  • a base such as K 3 PO 4
  • solvent such as 1,4-dioxane and water, or a combination thereof
  • a compound of formula XV is prepared from a compound of formula XIII, by reaction with a compound of formula XIV, under Cu- mediated amination conditions using cuprous bromide, in the presence of a ligand, such as 1,2- dimethylethylenediamine, and a base such as K 2 CO 3 , at a temperature of about 105 °C for about 3 h. These conditions are referred to herein as “Cu-mediated amination conditions”.
  • a compound of formula XIII-c can be prepared from 5-bromo- 2,4-dichloropyridine.
  • 5-bromo-2,4-dichloropyridine is reacted with a Grignard reagent such as i-PrMgCl • LiCl, copper (I) bromide, and a compound of formula Xlll-a, in a suitable solvent such as THF, at temperatures ranging from about 0 °C to about 25 °C to provide compound of formula XIII-b.
  • a Grignard reagent such as i-PrMgCl • LiCl, copper (I) bromide
  • a compound of formula Xlll-a in a suitable solvent such as THF
  • a compound of formula Xlll-b is reacted with hydrazine, hydrazine hydrate, hydrazine monohydrochloride, or hydrazine dihydrochloride neat or in a suitable solvent such as EtOH, at temperatures ranging from about -78 °C to about 25 °C to provide a compound of formula XIII-c.
  • Scheme 3b As shown in Scheme 3b, a compound of formula XV-a can be prepared from a compound of formula Xlll-d. , Reaction of compound of formula X-IIId with a compound of formula Vll-a under Cu-mediated amination conditions provides compound of formula XV-a.
  • a compound of formula XXI is prepared from a compound of formula XX and a compound of formula XX is prepared from either a compound of formula XIX or XXIV.
  • ethyl 7-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyrrolo[1,2-c]pyrimidine-3-carboxylate and a compound of formula XII are reacted using Suzuki coupling conditions to afford a compound of formula XVI.
  • a compound of formula XVI is reacted with XVII using Suzuki conditions to provide a compound of formula XVIII.
  • a compound of formula XVI can be reacted with the appropriate boronate ester or boronic acid (structures not shown) to provide a compound of formula XVIII.
  • a compound of formula XIX is prepared from a compound of formula XVIII through hydrolysis. This hydrolysis is accomplished by treatment of the substituent being hydrolyzed (an ester in the compound of formula XVIII) with a suitable base such as lithium hydroxide or sodium hydroxide, in a solvent system such as dioxane or water or combinations thereof, at a suitable temperature such as room temperature. These hydrolysis conditions are referred to as “basic hydrolysis conditions”.
  • a compound of formula XIX undergoes a Curtius rearrangement to provide a compound of formula XX.
  • Curtius rearrangement conditions include a carboxylic acid (as shown in a compound of formula XIX), that is reacted with diphenyl phosphoryl azide (DPPA), in the presence of base such as triethylamine, in a suitable solvent such as tert-butanol, at a temperature of about 85 °C. These conditions are referred to herein as “Curtius rearrangement conditions”.
  • DPPA diphenyl phosphoryl azide
  • ethyl 7-chloropyrrolo[1,2-c]pyrimidine-3- carboxylate is reacted in a Suzuki coupling reaction with a boronic ester XI or suitably substituted 1,3,5,2,4,6-trioxatriborinane XVII
  • a compound of formula XXII is hydrolyzed using basic hydrolysis conditions to provide a compound of formula XXIII.
  • a compound of formula XXIII is subjected to Curtius rearrangement conditions to provide a compound of formula XXIV.
  • a compound of formula XXIV is reacted in a metal-mediated cross coupling reaction with a compound of formula VII under Heck reaction conditions.
  • Heck reaction conditions include a reaction that is run in the presence of a palladium catalyst Pd(OAc) 2 , with or without the addition of a ligand such as tricyclohexyl phosphine, a base such as cesium carbonate, in a suitable solvent such as 1,4-dioxane, at a temperature of about 130 °C to afford a compound of formula XX.
  • a ligand such as tricyclohexyl phosphine
  • a base such as cesium carbonate
  • a suitable solvent such as 1,4-dioxane
  • R 3 When R 3 is an unsaturated heterocycle, it can be converted to a saturated heterocycle using hydrogenation conditions in the presence of a metal such as Pd/C under an atmosphere of hydrogen gas in a solvent such as EtOH, THF or mixtures thereof. These conditions will be known as “hydrogenation conditions”.
  • a compound of formula XXVI is prepared from a compound of formula XXV, by reaction with 1-(4-methoxybenzyl)urea in the presence of a catalyst such as BrettPhos Pd G3 and a base such as such as Cs 2 CO 3 , in a solvent such as THF, at a temperature of about 70 °C for about 2 h.
  • a catalyst such as BrettPhos Pd G3 and a base such as such as Cs 2 CO 3
  • a compound of formula XXVII is prepared from a compound of formula XXVI by heating in a solvent such as TFA at a temperature of about 60 °C for about 2 h.
  • a compound of formula XXVI-a can be prepared from a compound of formula XXV-a, by reaction of compound of formula XXV-a with 1-(4- methoxybenzyl)urea in the presence of a catalyst such as BrettPhos Pd G3 and a base such as such as Cs 2 CO 3 , in a solvent such as THF, at a temperature of about 70 °C for about 2 h.
  • a catalyst such as BrettPhos Pd G3 and a base such as such as Cs 2 CO 3
  • a compound of formula XXVII-a is prepared from a compound of formula XXVI-a by heating a compound of formula XXVI-a in a solvent such as TFA at a temperature of about 60 °C for about 2 h.
  • a compound of formula XXIX is prepared from a compound of formula XXVIII, by treatment with 2,2,2-trichloroacetyl isocyanate in a suitable solvent such as DCM, THF, MeCN, benzene, pyridine or DMF or mixtures thereof, at a temperature of about 0 °C for approximately 2 h.
  • a suitable solvent such as DCM, THF, MeCN, benzene, pyridine or DMF or mixtures thereof.
  • the product of this reaction was then stirred at a temperature of about 0 °C with a base such as saturated aqueous sodium bicarbonate solution in a solvent such as MeOH for a period of about 1 hour to about 4 hours with warming to about room temperature.
  • a compound of formula XXX is reacted with a substituted primary amide XXXI under Pd-catalyzed amination of heteroaryl halide conditions.
  • the Pd- catalyzed amination of heteroaryl halide conditions include a palladium catalyst such as Pd 2 (dba) 3 , Pd(OAc) 2 , or BrettPhos Pd G3, a ligand such as 4,5-bis(diphenylphosphino)-9,9- dimethylxanthene (XantPhos), or 2-(dicyclohexylphosphino)-2',4',6'-triisopropylbiphenyl (XPhos), a base such as Cs 2 CO 3 , LHMDS, NaOtBu, or K 3 PO 4 , in a suitable solvent such as toluene, THF, DMA, dioxane, or mixtures thereof, at temperatures ranging from about 80 °C to
  • a compound of formula XXXIV is prepared from a compound of formula XXXIII, by acylation of the amine moiety.
  • Conditions to acylate the amine include treating the amine with an acylating reagent such as acetic anhydride, acetyl chloride or acetyl-d 3 chloride; in a suitable solvent such as DCM or pyridine or mixtures thereof, at a temperature of about 0 °C to about room temperature, for about 0.5 h to about 24 h. These conditions will be referred to herein as “amine acylation conditions”.
  • a compound of formula XXXVI is prepared from a compound of formula XXXV, by subjecting a compound of formula XXXV to amine acylation conditions.
  • the Pd-catalyzed amination of heteroaryl halide conditions include a palladium catalyst such as Pd 2 (dba) 3 , Pd(OAc) 2 , or BrettPhos Pd G3, a ligand such as 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (XantPhos), or 2- (dicyclohexylphosphino)-2',4',6'-triisopropylbiphenyl (XPhos), a base such as Cs 2 CO 3 , LHMDS, NaOtBu, or K 3 PO 4 , in a suitable solvent such as toluene, THF, DMA, 1,4-dioxane, or mixtures thereof, at temperatures ranging from about 80 °C to about 150 °C.
  • This reaction may employ microwave or conventional heating for a period of about 0.5 h to about 18 h.
  • reaction solutions were stirred at room temperature under a N 2(g) or Ar (g) atmosphere.
  • solutions were “concentrated to dryness”, they were concentrated using a rotary evaporator under reduced pressure, when solutions were dried, they are typically dried over a drying agent such as MgSO 4 or Na 2 SO 4 .
  • Normal phase flash column chromatography was performed on silica gel with prepackaged silica gel columns, such as RediSep®, using ethyl acetate (EtOAc)/petroleum ether, CH 2 Cl 2 /MeOH, or CH 2 Cl 2 /10% 2NNH 3 in MeOH, as eluent, unless otherwise indicated.
  • EtOAc ethyl acetate
  • yield refers to a mass of the entity for which the yield is given with respect to the maximum amount of the same entity that could be obtained under the particular stoichiometric conditions.
  • Reagent concentrations that are given as percentages refer to mass ratios, unless indicated differently.
  • Step A (R,S)-2-Bromo-6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridine.
  • 3-(6-bromo-4-methylpyridin-2-yl)tetrahydrofuran-3-ol ( Intermediate 1, 3.9 g, 15 mmol) in DMF (90 mL) at 0 °C was added NaH (60% dispersion in mineral oil, 435.2 mg, 18.13 mmol) and then CH 3 I (2.146 g, 15.11 mmol).
  • the resulting mixture was stirred at 25 °C for 3 h under N 2 .
  • the reaction was quenched with saturated aq.
  • Step B (R)-2-Bromo-6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridine.
  • the enantiomers of (R,S)-2-bromo-6-(3 -methoxytetrahy drofuran-3-yl)-4-methylpyridine were separated by SFC using an SFC column, such as a Chiralpak IC, 2 x 25cm, 5 ⁇ m column (isocratic elution: 15:85 IP A (containing 0.5% 2 M NH 3 -MeOH): supercritical CO 2 ) yielding as a first eluting enantiomer, (R)-2-bromo-6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridine and as a second eluting enantiomer, (S) -2 -brom 0-6 -(3 -methoxytetrahydrofuran-3-yl)-4-
  • Step A (2,6-Dibromopyridin-4-yl)methanol.
  • 2,6-dibromoisonicotinic acid 100 g, 0.36 mol
  • borane THF-complex 1 M in THF, 537 mL, 0.537 mol
  • the reaction mixture was heated at 50 °C for 3 hours.
  • the reaction was cooled to room temperature and methanol (50 mL) was added dropwise.
  • the reaction mixture was then heated at 50 °C for 20 min.
  • Step B 2,6-Dibromoisonicotinaldehyde.
  • oxalyl chloride 35 mL, 410 mmol
  • dichloromethane 700 mL
  • dichloromethane 200 mL
  • dimethyl sulfoxide 56 mL
  • dichloromethane 200 mL
  • the resulting solution was diluted with di chloromethane (1500 mL) and washed with 400 mL of 5% aqueous hydrogen chloride, 400 mL of saturated aqueous sodium bicarbonate, and 400 mL of saturated aqueous sodium chloride, respectively.
  • the organic layer was dried (Na 2 SO 4 ), filtered, and concentrated to afford the title compound as a colorless oil (100 g).
  • Step C 2,6-Dibromo-4-(1,3-dioxolan-2-yl)pyridine.
  • 2,6- dibromoisonicotinaldehyde 100 g, 0.38 mol
  • toluene 1000 mL
  • ethane-1,2-diol 46.8 g, 0.76 mol
  • 4-methylbenzenesulfonic acid 6.5 g, 0.04 mol
  • the reaction mixture was heated to reflux at 110 °C with a Dean Stark trap for 16 hours.
  • the reaction was quenched with water (10 mL) and the resulting solution was extracted with dichloromethane (3 x 500 mL).
  • Step D 3-(6-Bromo-4-(1,3-dioxolan-2-yl)pyridin-2-yl)tetrahydrofuran-3-ol.
  • the title compound was prepared in a manner analogous to Intermediate 1, using 2,6-dibromo-4-(1,3- dioxolan-2-yl)pyridine instead of 2,6-dibromo-4-methylpyridine.
  • Step A 2-Bromo-6-(3-methoxytetrahydrofuran-3-yl)isonicotinaldehyde.
  • 2-bromo-4-(1,3-dioxolan-2-yl)-6-(3-methoxytetrahydrofuran-3-yl)pyridine (Intermediate 5, 30 g, 0.09 mol) in water (300 mL) was added concentrated hydrochloric acid (300 ml) at room temperature.
  • the reaction mixture was heated at 50 °C for 2 h.
  • the reaction was cooled to room temperature and the pH was adjusted to 7 with 2 N sodium hydroxide.
  • the resulting mixture was extracted with ethyl acetate (3 x 200 mL).
  • Step B (R,S)-2-Bromo-4-(difluoromethyl)-6-(3-methoxytetrahydrofuran-3-yl)pyridine.
  • 2-bromo-6-(3-methoxytetrahydrofuran-3-yl)isonicotinaldehyde 15 g, 0.05 mol
  • dichloromethane 150 mL
  • diethylaminosulfur trifluoride 40 g, 0.25 mol
  • Step B 2-Bromo-6-(3 -methoxy tetrahydrofuran-3-yl)pyridine.
  • the title compound was prepared in a manner analogous to Intermediate 2, Step A, using 3-(6-bromopyridin-2- yl)tetrahydrofuran-3-ol instead of 3-(6-bromo-4-methylpyridin-2-yl)tetrahydrofuran-3-ol (Intermediate 1).
  • Step C 2-Bromo-6-(3-methoxytetrahydrofuran-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridine.
  • Step D (R,S)-2-Bromo-6-(3-methoxytetrahydrofuran-3-yl)pyridin-4-ol.
  • 2-bromo-6-(3-methoxytetrahydrofuran-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridine 25 g, 65 mmol
  • tetrahydrofuran 125 mL
  • potassium peroxymonosulfate (13.1 g, 78.1 mmol
  • Step E (R)-2-Bromo-6-(3-methoxytetrahydrofuran-3-yl)pyridin-4-ol.
  • the enantiomers of (R,S)-2-bromo-6-(3-methoxytetrahydrofuran-3-yl)pyridin-4-ol were separated by SFC using an SFC column, such as a Chiralpak IC, 20 x 250 mm, 5 ⁇ m column (isocratic elution: 5:95 EtOH (containing 1% DEA) supercritical CO 2 ) yielding as a first eluting enantiomer, (R)-2-bromo-6- (3-methoxytetrahydrofuran-3-yl)pyridin-4-ol and as a second eluting enantiomer, (S)-2-bromo-6- (3-methoxytetrahydrofuran-3-yl)pyridin-4-ol (Intermediate 9).
  • Step A (R)-2-Hydroxypropyl 4-methylbenzenesulfonate.
  • 2- propanediol 2.0 g, 26 mmol
  • 4-methylbenzene-1-sulfonyl chloride 5.512 g, 28.91 mmol
  • dichloromethane 50 mL
  • 4- dimethylaminopyridine 0.16 g, 1.3 mmol
  • Step C 2-Bromo-4-((R)-2-((tert-butyldimethylsilyl)oxy)propoxy)-6-((R)-3- methoxytetrahydrofuran-3-yl)pyridine .
  • the title compound was prepared in a manner analogous to Intermediate 10, using (R)-2-((tert-butyldimethylsilyl)oxy)propyl 4-methylbenzenesulfonate instead of 1-bromo-2-methoxyethane.
  • Step A Oxetan-3-ylmethyl 4-methylbenzenesulfonate.
  • the title compound was prepared in a manner analogous to Intermediate 12 A, using oxetan-3-ylmethanol instead of (R)-(+)-1, 2- propanediol.
  • Step B (R)-2-Bromo-6-(3-methoxytetrahydrofuran-3-yl)-4-(oxetan-3- ylmethoxy)pyridine.
  • the title compound was prepared in a manner analogous to Intermediate 10, except the reaction mixture was heated at 85 °C instead of 80 °C, using oxetan-3-ylmethyl 4- methylbenzenesulfonate instead of 1-bromo-2-methoxy ethane.
  • Step B (R)-3-(((2-Bromo-6-(3-methoxytetrahydrofuran-3-yl)pyridin-4- yl)oxy)methyl)thietane 1,1-dioxide.
  • the title compound was prepared in a manner analogous to Intermediate 10, using ( 1,1-dioxidothietan-3-yl)methyl 4-methylbenzenesulfonate instead of 1- bromo-2-methoxyethane.
  • Step B (1s,3s)-3-(Benzyloxy)cyclobutyl methanesulfonate.
  • (1s,3s)-3- (benzyloxy)cyclobutan-1-ol 900 mg, 5.1 mmol
  • triethylamine 664.2 mg, 6.565 mmol
  • dichloromethane 27 mL
  • methanesulfonyl chloride 694.2 mg, 5.565 mmol
  • Step C 4-((1r,3r)-3-(Benzyloxy)cyclobutoxy)-2-bromo-6-((R)-3- methoxytetrahydrofuran-3-yl)pyridine.
  • the title compound was prepared in a manner analogous to Intermediate 10, except the reaction mixture was heated at 85 °C instead of 80 °C, using (1s,3s)-3-(benzyloxy)cyclobutyl methanesulfonate instead of 1-bromo-2-methoxyethane. Purification resulted in isolation of the trans diastereomer.
  • Step A 4,6-Dichloro- N-methoxy- N-methylnicotinamide.
  • 4,6- dichloronicotinic acid 5.0 g, 26 mmol
  • N,N-dimethylformamide 75 mL
  • N,O- dimethyl hydroxylamine 3.81 g, 52.08 mmol
  • hydroxybenzotriazole 7.038 g, 52.08 mmol
  • 1- ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (9.984 g, 52.08 mmol)
  • N- ethyldiisopropylamine (10.078 g, 52.083 mmol) at room temperature.
  • Step B 1-(4,6-Dichloropyridin-3-yl)ethan-1-one.
  • methylmagnesium bromide 3 M in 2-methyltetrahydrofuran, 22.72 mL
  • the reaction mixture was stirred at 0 °C for 2 h.
  • saturated aqueous ammonium chloride 40 mL
  • the mixture was concentrated to ⁇ 20 mL and the remaining residue was extracted with dichloromethane (3 x 200 mL).
  • Step C 6-Chloro-3-methyl-1H-pyrazolo[4,3-c]pyridine.
  • 1-(4,6-Dichloropyridin-3- yl)ethan-1-one (2.3 g, 12 mmol) in hydrazine hydrate (50 mL) was stirred at 20 °C for 4 h.
  • the reaction mixture was diluted with water (50 mL) and extracted with dichloromethane (3 x 150 mL). The combined organic layers were washed with water (2 x 50mL) and saturated aqueous sodium chloride (20 mL), then dried (Na 2 SO 4 ), filtered, and concentrated.
  • Step A (R)-5-(6-(3-Methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-7-(1-methyl- 1H-pyrazol-4-yl)pyrrolo[1,2-c]pyrimidine-3-carboxylic acid.
  • Step B tert-Butyl (R)-(5-(6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-7-(1- methyl-1H-pyrazol-4-yl)pyrrolo[1,2-c]pyrimidin-3-yl)carbamate.
  • Step C (R)-5-(6-(3-Methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-7-(1-methyl- 1H-pyrazol-4-yl)pyrrolo[1,2-c]pyrimidin-3 -amine.
  • Step A tert-Butyl (R)-(5-(4-(difluoromethyl)-6-(3-methoxytetrahydrofuran-3-yl)pyridin- 2-yl)-7-methylpyrrolo[1,2-c]pyrimidin-3-yl)carbamate.
  • Step B (R)-5-(4-(Difluoromethyl)-6-(3-methoxytetrahydrofuran-3-yl)pyridin-2-yl)-7- methylpyrrolo[1,2-c]pyrimidin-3 -amine.
  • Step A tert-Butyl (5-(4-((R)-2-((tert-butyldimethylsilyl)oxy)propoxy)-6-((R)-3- methoxytetrahydrofuran-3-yl)pyridin-2-yl)-7-methylpyrrolo[1,2-c]pyrimidin-3-yl)carbamate.
  • Step B 5-(4-((R)-2-((tert-Butyldimethylsilyl)oxy)propoxy)-6-((R)-3- methoxytetrahydrofuran-3-yl)pyridin-2-yl)-7-methylpyrrolo[1,2-c]pyrimidin-3-amine.
  • Step A tert-Butyl (5-(4-((R)-2-((tert-butyldimethylsilyl)oxy)propoxy)-6-((S)-3- methoxytetrahydrofuran-3-yl)pyridin-2-yl)-7-methylpyrrolo[1,2-c]pyrimidin-3-yl)carbamate.
  • Step B 5-(4-((R)-2-((tert-Butyldimethylsilyl)oxy)propoxy)-6-((S)-3- methoxytetrahydrofuran-3-yl)pyridine-2-yl)-7-methylpyrrolo[1,2-c]pyrimidin-3-amine.
  • Step A N-(4-Chloro-5-nitropyridin-2-yl)acetamide.
  • 4-chloro-5- nitropyridin-2-amine 5 g, 29 mmol
  • acetyl chloride 3.39 g, 43.2 mmol
  • DCM 50 mL
  • pyridine 4.56 g, 57.6 mmol
  • the reaction mixture was stirred for 3 h at room temperature and the solvent was removed under vacuum.
  • Step B (S)-N-(4-((6-(3-Methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)amino)-5- nitropyridin-2-yl)acetamide.
  • Step C (S)- N-(5-Amino-4-((6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridin-2- yl)amino)pyridin-2-yl)acetamide.
  • Step D (S)- N-(4-((6-(3-Methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)amino)-5- (methylamino)pyridin-2-yl)acetamide.
  • Step A 3-Chloro-7-methyl-7H-pyrrolo[2,3-c]pyridazine.
  • DMF dimethyl methyl sulfoxide
  • K 2 CO 3 545.5 mg, 3.947 mmol
  • iodomethane 373.5 mg, 2.631 mmol.
  • the resulting mixture was stirred at room temperature for 1 h.
  • the reaction was quenched with water (20 mL).
  • the resulting mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried (Na 2 SO 4 ), filtered, and concentrated.
  • Step B 5-Bromo-3-chloro-7-methyl-7H-pyrrolo[2,3-c]pyridazine.
  • the title compound was prepared in a manner analogous to Intermediate 48, using 3-chloro-7-methyl-7H- pyrrolo[2,3-c]pyridazine instead of ethyl pyrrolo[1,2-c]pyrimidine-3-carboxylate (Intermediate 47), NBS instead of NCS, and DMF instead of CHCh (100 mL).
  • Step C 3-Chloro-7-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7H- pyrrolo[2,3-c]pyridazine.
  • the title compound was prepared in a manner analogous to Intermediate 50, using 5-bromo-3-chloro-7-methyl-7H-pyrrolo[2,3-c]pyridazine instead of ethyl 5-bromo-7-chloropyrrolo[1,2-c]pyrimidine-3-carboxylate (Intermediate 49) and
  • Step A 6-Chloro-3-iodo-1 -((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3- c]pyridine.
  • Step B 6-Chloro-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrazolo[4,3-c]pyridine.
  • 6-chloro-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-pyrazolo[4,3-c]pyridine (1.15 g, 2.81 mmol) and diphenyl(trifluoromethyl)sulfonium trifluoromethanesulfonate (2.27 g, 5.62 mmol) in DMF (12 mL) under N 2 was added copper (450 mg, 7.0 mmol). The resulting mixture was heated at 80 °C for 16 h.
  • Step C 6-Chloro-3-(trifluoromethyl)-1H-pyrazolo[4,3-c]pyridine.
  • 6- chloro-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridine 800 mg, 2 mmol
  • dichloromethane 8 mL
  • TFA 8 mL
  • the solution was stirred for 2 h at room temperature.
  • the pH of the reaction mixture was adjusted to pH 9 with 2 N NH 3 in water.
  • the resulting mixture was stirred at room temperature for 1 h, then concentrated under reduced pressure.
  • Step A Isoxazole-3 -carbonyl chloride.
  • DCM dimethylethyl sulfoxide
  • Step B (4,6-Dichloropyridin-3-yl)isoxazol-3-yl)methanone.
  • 5-bromo- 2,4-dichloropyridine 0.49 g, 4.18 mmol
  • CuBr 0.15 g, 1.0 mmol
  • i-PrMgCl LiCl 1.3 M in THF, 4.18 mL, 5.44 mmol
  • Step C 3-(6-Chloro-1H-pyrazolo[4,3-c]pyridin-3-yl)isoxazole.
  • 4-,6- dichloropyridin-3-yl)(isoxazol-3-yl)methanone 0.8 g, 3 mmol
  • EtOH 20 mL
  • triethylamine 3.3 g, 33 mmol
  • NH 2 NH 2 HCI 1.1 g, 16 mmol
  • Step A 3-(Benzyloxy)cyclobutanecarbonyl chloride.
  • a mixture of 3- (benzyloxy)cyclobutanecarboxylic acid (7.3 g, 35 mmol) and thionyl chloride (100 mL) was heated to 83 °C for 2 h. The resulting mixture was concentrated to afford the title compound.
  • Step B (3-(Benzyloxy)cyclobutyl)(4,6-dichloropyridin-3-yl)methanone.
  • the title compound was prepared in a manner analogous to Intermediate 85, Step B, using 3- (benzyloxy)cyclobutanecarbonyl chloride instead of isoxazole-3-carbonyl chloride (Intermediate 85A).
  • Step C 3-(3-(Benzyloxy)cyclobutyl)-6-chloro-1H-pyrazolo[4,3-c]pyridine.
  • the title compound was prepared in a manner analogous to Intermediate 27, Step C, using (3- (benzyloxy)cyclobutyl)(4,6-dichloropyridin-3-yl)methanone instead of 1-(4,6-dichloropyridin-3- yl)ethan-1-one (Intermediate 27B).
  • Step A (R)- 1 -(3 -(3 -(Benzyloxy)cyclobutyl)- 1 -(6-(3 -methoxy -tetrahydrofuran-3 -yl)-4- methylpyridin-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(4-methoxybenzyl)urea.
  • Step B (R)- 1 -(3 -(3 -Hydroxy cyclobutyl)- 1 -(6-(3 -methoxy -tetrahy drofuran-3 -yl)-4- methylpyridin-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(4-methoxybenzyl)urea.
  • Interm ediate 90 (R)- 1 -(3 -(3 -Cyanocyclobutyl)- 1 -(6-(3 -methoxytetrahydrofuran-3 -yl)-4- methylpyri din-2 -yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(4-methoxybenzyl)urea.
  • Step A (R)-3 -(6-(3 -(4-Methoxybenzyl)ureido)- 1 -(6-(3 -methoxy tetrahy drofuran-3 -yl)-4- methylpyridin-2-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)cyclobutyl methanesulfonate.
  • Step B (R)- 1 -(3 -(3 -Cyanocyclobutyl)- 1-(6-(3 -methoxytetrahy drofuran-3 -yl)-4- methylpyridin-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(4-methoxybenzyl)urea.
  • Step A (R,S)-2-Bromo-6-(3-ethoxytetrahydrofuran-3-yl)-4-methylpyridine.
  • the title compound was prepared in a manner analogous to Intermediate 2 Step A, except the reaction mixture was heated at 50 °C instead of 25 °C, using iodoethane instead of CH 3 I and THF instead of DMF.
  • Step B (R)-2-Bromo-6-(3-ethoxytetrahydrofuran-3-yl)-4-methylpyridine.
  • Step B 2-Bromo-6-(3-methoxytetrahydro-2H-pyran-3-yl)pyridine.
  • the title compound was prepared in a manner analogous to Intermediate 2, Step A, using 3-(6-bromopyridin-2- yl)tetrahydro-2H-pyran-3-ol instead of 3-(6-bromo-4-methylpyridin-2-yl)tetrahydrofuran-3-ol (Intermediate 1) and THF instead of DMF.
  • Step C 2-Bromo-6-(3 -methoxytetrahy dro-2H-py ran-3 -y l)-4-(4,4, 5 , 5 -tetramethyl- 1,3,2- dioxaborolan-2-yl)pyridine.
  • the title compound was prepared in a manner analogous to Intermediate 8, Step C, using 2-bromo-6-(3-methoxytetrahydro-2H-pyran-3-yl)pyridine instead of 2-bromo-6-(3-methoxytetrahydrofuran-3-yl)pyridine.
  • Step D 2-Bromo-6-(3 -methoxytetrahydro-2H-pyran-3 -yl)pyridin-4-ol.
  • the title compound was prepared in a manner analogous to Intermediate 8, Step D, using 2-bromo-6-(3- methoxytetrahydro-2H-pyran-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine instead of 2-bromo-6-(3-methoxytetrahydrofuran-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridine.
  • Step E 2-Bromo-6-(3 -methoxytetrahydro-2H-pyran-3 -yl)-4-(oxetan-3 - ylmethoxy)pyridine.
  • the title compound was prepared in a manner analogous to Intermediate 14, using 2 -bromo-6-(3 -methoxytetrahydro-2H-pyran-3 -yl)pyridin -4-ol instead of (R)-2-bromo-6-(3- methoxytetrahydrofuran-3-yl)pyridin-4-ol (Intermediate 8).
  • Step A 1-(2-Bromo-6-(3-methoxytetrahydrofuran-3-yl)pyridin-4-yl)ethan-1-ol.
  • 2-bromo-6-(3-methoxytetrahydrofuran-3-yl)isonicotinaldehyde (Intermediate 6A, 2.4 g, 8.4 mmol) in THF (24 mL)
  • CH 3 MgCl 3.0 M in THF, 4.2 mL
  • Step B 1-(2-Bromo-6-(3-methoxytetrahydrofuran-3-yl)pyridin-4-yl)ethan-1-one.
  • 1-(2-bromo-6-(3-methoxytetrahydrofuran-3-yl)pyridin-4-yl)ethan-1-ol 1.7 g, 5.6 mmol
  • Dess-Martin periodinane 3.58 g , 8.46 mmol
  • Step C 2-Bromo-4-(1,1-difluoroethyl)-6-(3-methoxytetrahydrofuran-3-yl)pyridine.
  • 1-(2-bromo-6-(3-methoxytetrahydrofuran-3-yl)pyridin-4-yl)ethan-1-one 1.5 g, 5.0 mmol
  • diethylaminosulfur trifluoride 4.0 g, 25 mmol
  • Step A 4-(4-(Benzyloxy)piperidin-1-yl)-2,6-dibromopyridine.
  • 4- (benzyloxy)piperidine (4.05 g, 17.9 mmol) dropwise maintaining the internal temperature below 0 °C.
  • 2,6-dibromo-4-nitropyridine (5 g, 18 mmol) was added dropwise at 0 °C and the reaction mixture was stirred for 3 hours at room temperature. The reaction was quenched with water (20 mL) and extracted with ethyl acetate.
  • Step B 3-(4-(4-(Benzyloxy)piperidin-1-yl)-6-bromopyridin-2-yl)tetrahydrofuran-3-ol.
  • the title compound was prepared in a manner analogous to Intermediate 1, using 4-(4- (benzyloxy)piperidin-1-yl)-2,6-dibromopyridine instead of 2,6-dibromo-4-methylpyridine.
  • Step C 4-(4-(Benzyloxy)piperidin- 1 -yl)-2-bromo-6-(3-methoxytetrahydrofuran-3 - yl)pyridine.
  • the title compound was prepared in a manner analogous to Intermediate 2, Step A, using 3-(4-(4-(benzyloxy)piperidin-1-yl)-6-bromopyridin-2-yl)tetrahydrofuran-3-ol instead of 3- (6-bromo-4-methylpyridin-2-yl)tetrahydrofuran-3-ol (Intermediate 1).
  • Step A 3-(6-Bromo-4-methylpyridin-2-yl)tetrahydrothiophen-3-ol.
  • the title compound was prepared in a manner analogous to Intermediate 1, using dihydrothiophen-3(2H)-one instead of dihydrofuran-3(2H)-one.
  • Step B 2-Bromo-6-(3 -methoxytetrahydrothiophen-3-yl)-4-methylpyridine.
  • the title compound was prepared in a manner analogous to Intermediate 2, Step A, using 3-(6-bromo-4- methylpyridin-2-yl)tetrahydrothiophen-3-ol instead of 3-(6-bromo-4-methylpyridin-2- yl)tetrahydrofuran-3-ol (Intermediate 1) and THF instead of DMF.
  • Step C 3 -(6-Bromo-4-methylpyridin-2-yl)-3 -methoxytetrahydrothiophene 1,1 -dioxide.
  • 2-bromo-6-(3-methoxytetrahydrothiophen-3-yl)-4-methylpyridine 1.5 g, 5.2 mmol
  • MeOH MeOH
  • potassium peroxymonosulfate 7..99 g, 13.1 mmol, dissolved in 4 mL of water
  • Intermedi ate 106 2-Bromo-6-(3 -methoxytetrahydrofuran-3 -yl)-4-(piperidin- 1 -yl)pyridine.
  • Step A 2,6-Dibromo-4-(piperidin-1-yl)pyridine.
  • the title compound was prepared in a manner analogous to Intermediate 100, Step A, using piperidine instead of 4- (benzyloxy)piperidine.
  • Step B 3-(6-Bromo-4-(piperidin-1-yl)pyridin-2-yl)tetrahydrofuran-3-ol.
  • the title compound was prepared in a manner analogous to Intermediate 1, using 2,6-dibromo-4- (piperidin-1-yl)pyridine instead of 2,6-dibromo-4-methylpyridine.
  • Step C 2-Bromo-6-(3 -methoxytetrahydrofuran-3 -yl)-4-(piperidin-1-yl)pyridine.
  • the title compound was prepared in a manner analogous to Intermediate 2, Step A, using 3-(6-bromo-4- (piperidin-1-yl)pyridin-2-yl)tetrahydrofuran-3-ol instead of 3-(6-bromo-4-methylpyridin-2- yl)tetrahydrofuran-3-ol (Intermediate 1).
  • Intermedi ate 109 2-Bromo-4-((R)-2-methoxypropoxy)-6-((R)-3 -methoxytetrahydrofuran-3 - yl)pyridine.
  • Step A (R)-2-Methoxypropyl 4-methylbenzenesulfonate.
  • Step B 2-Bromo-4-((R)-2-methoxypropoxy)-6-((R)-3 -methoxytetrahy drofuran-3 - yl)pyridine.
  • the title compound was prepared in a manner analogous to Intermediate 10, using (R)-2-methoxypropyl 4-methylbenzenesulfonate instead of 1-bromo-2-methoxy ethane and heating at 85 °C instead of 80 °C.
  • Step A Ethyl (R)-7-(4,5-dihydrofuran-3-yl)-5-(6-(3-methoxytetrahydrofuran-3-yl)-4- methylpyridin-2-yl)pyrrolo[1,2-c]pyrimidine-3 -carboxylate.
  • Step B Ethyl 5-(6-((R)-3-methoxytetrahydrofu ran-3-yl)-4-methylpyridin-2-yl)-7- (tetrahydrofuran-3-yl)pyrrolo[1,2-c]pyrimidine-3-carboxylate.
  • Example 1 (R)-1 -(1-(6-(3-Methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-3-(1-methyl-1H- pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine-6-yl)urea.
  • Step A (R)-1-(4-Methoxybenzyl)-3-(1-(6-(3-methoxytetrahydrofuran-3-y])-4- methylpyridin-2-yl)-3 -( 1 -methyl- 1H-pyrazol-4-yl)- 1H-pyrazolo[4,3-c]pyridine-6-yl)urea.
  • Step B 4. (R)-1-(1-(6-(3-Methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-3-(1- methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine-6-yl)urea.
  • Example 2 (S)- 1 -( 1 -(6-(3 -Methoxy tetrahy drofuran-3 -yl)-4-methylpyridin-2-yl)-3 -( 1 -methyl- 1H- pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine-6-yl)urea.
  • Example 7 (R)-1-(1-(4-(Difluoromethyl)-6-(3-methoxytetrahydrofuran-3-yl)pyridine-2-yl)-3- methyl-1H-pyrazolo[4,3 -c]pyridine-6-yl)urea.
  • Example 8 (S)- 1 -( 1 -(4-(Difluoromethyl )-6-(3 -methoxytetrahy drofuran-3 -y l)pyridine-2-yl)-3 - methyl- 1H-pyrazolo[4,3 -c]pyridine-6-yl)urea.
  • Example 9 (R)- 1 -(1 -(4-(2-Methoxyethoxy)-6-(3 -methoxytetrahy drofuran-3 -yl)pyridine-2-y l)-3 - methyl -1H-pyrazolo[4,3 -c]pyridine-6-yl)urea.
  • Example 10 (S)- 1 -( 1 -(4-(2-Methoxy ethoxy )-6-(3 -methoxytetrahy drofuran-3 -yl)pyridine-2-yl)-3 - methyl- 1H-pyrazolo[4,3-c]pyridine-6-yl)urea.
  • Example 11 1 -(1 -(4-((R)-2-Hydroxypropoxy)-6-((R)-3-methoxytetrahydrofuran-3-yl)pyridine-2- yl)-3-methyl-1H-pyrazolo[4,3-c]pyridine-6-yl)urea.
  • Step A 1 -( 1 -(4-((R)-2-((tert-Butyldimethylsilyl)oxy)propoxy)-6-((R)-3 - methoxytetrahydrofuran-3-yl)pyridine-2-yl)-3-methyl-1H-pyrazolo[4,3-c]pyridine-6-yl)urea.
  • Step B 1 -( 1 -(4-((R)-2-Hy droxypropoxy)-6-((R)-3 -methoxytetrahydrofuran-3 -yl)pyridine- 2-yl)-3-methyl-1H-pyrazolo[4,3-c]pyridine-6-yl)urea.
  • Example 12 1 -( 1 -(4-((R)-2-Hy droxy propoxy )-6-((S)-3 -methoxytetrahydrofuran-3 -yl)pyridine-2- yl)-3 -methyl- 1H-pyrazolo[4,3 -c]pyridine-6-yl)urea.
  • Step A 1-(1-(4-((R)-2-((tert-Butyldimethylsilyl)oxy)propoxy)-6-((S)-3- methoxytetrahy drofuran-3 -yl)pyridin-2-yl)-3 -methyl-1H-pyrazolo[4, 3 -c]pyridin-6-yl)urea.
  • Step B 1-(1-(4-((R)-2-Hydroxypropoxy)-6-((S)-3-methoxytetrahydrofuran-3-yl)pyridine- 2-yl)-3-methyl-1H-pyrazolo[4,3-c]pyridine-6-yl)urea .
  • Example 11 The title compound was prepared in a manner analogous to Example 11, Step B, using 1-(1-(4-((R)-2-((tert- butyldimethylsilyl)oxy)propoxy)-6-((S)-3-methoxytetrahydrofuran-3-yl)pyridin-2-yl)-3-methyl- 1H-pyrazolo[4,3-c]pyridin-6-yl)urea instead of 1-(1-(4-((R)-2-((tert- butyldimethylsilyl)oxy)propoxy)-6-((R)-3-methoxytetrahydrofuran-3-yl)pyridine-2-yl)-3-methyl- 1H-pyrazolo[4,3-c]pyridine-6-yl)urea (Example 11, Step A).
  • Example 13 (R)- 1 -(1 -(6-(3 -Methoxytetrahydrofuran-3 -yl)-4-(oxetan-3 -ylmethoxy)pyridine-2- yl)-3-methyl-1H-pyrazolo[4,3-c]pyridine-6-yl)urea.
  • Example 14 (S)- 1 -( 1 -(6-(3 -Methoxytetrahydrofuran-3 -y l)4-(oxetan-3 -ylmethoxy)pyridine-2- yl)-3-methyl-1H-pyrazolo[4,3-c]pyridine-6-yl)urea.
  • Example 15 (R)- 1 -( 1 -(4-(( 1 , 1 -Dioxidothietan-3-yl)methoxy)-6-(3 -methoxytetrahy drofuran-3 - yl)pyridine-2-yl)-3 -methyl- 1 H-pyrazolo[4,3 -c]pyridine-6-yl)urea.
  • Example 16 (S)- 1 -( 1 -(4-(( 1 , 1 -Dioxidothietan-3 -yl)methoxy)-6-(3-methoxytetrahydrofuran-3 - yl)pyridine-2-yl)-3 -methyl- 1 H-pyrazolo[4,3 -c]pyridine-6-yl)urea.
  • Example 17 (R)- 1 -(1 -(6-(3 -Methoxytetrahydrofuran-3 -yl)-4-methylpyridin-2-yl)-3 -methyl- 1H- pyrrolo[3,2-c]pyridine-6-yl)urea.
  • Example 18 (S)-1-(1-(6-(3-Methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-3-methyl-1H- pyrrolo[3,2-c]pyridine-6-yl)urea.
  • Example 19 (R)- 1 -(1 -(6-(3 -Methoxytetrahy drofuran-3 -yl)-4-(oxetan-3 -ylmethoxy)pyridine-2- yl)-3-methyl-1H-pyrrolo[3,2-c]pyridine-6-yl)urea.
  • Example 20 (S)- 1 -( 1 -(6-(3 -Methoxytetrahy drofuran-3 -yl)-4-(oxetan-3 -ylmethoxy)pyridine-2- yl)-3-methyl-1H-pyrrolo[3,2-c]pyridine-6-yl)urea.
  • Example 21 (R)-1-(1-(4-((1,1-Dioxidothietan-3-yl)methoxy)-6-(3-methoxytetrahydrofuran-3- yl)pyridine-2-yl)-3-methyl-1H-pyrrolo[3,2-c]pyridine-6-yl)urea.
  • Example 22 (S)- 1 -( 1 -(4-((l , 1 -Dioxidothietan-3 -yl)methoxy)-6-(3 -methoxytetrahydrofuran-3 - yl)pyridine-2-yl)-3-methyl-1H-pyrrolo[3,2-c]pyridine-6-yl)urea.
  • Example 23 (R)-1-(5-(6-(3-Methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-7-(1-methyl- 1H-pyrazol-4-yl)pyrrolo[1,2-c]pyrimidin-3-yl)urea.
  • Example 24 (S)- 1 -(5-(6-(3 -Methoxytetrahydrofuran-3 -yl)-4-methylpyridin-2-yl)-7-(1-methyl- 1H-pyrazol-4-yl)pyrrolo[1,2-c]pyrimidin-3 -yl)urea.
  • Example 27 (R)-1-(5-(4-(Difluoromethyl)-6-(3-methoxytetrahydrofuran-3-yl)pyridine-2-yl)-7- methylpyrrolo[1,2-c]pyrimidin-3-yl)urea.
  • Example 28 (S)-1-(5-(4-(Difluoromethyl)-6-(3-methoxytetrahydrofuran-3-yl)pyridine-2-yl)-7- methylpyrrolo[1 ,2-c]pyrimidin-3 -yl)urea.
  • Example 29 (R)-1-(5-(4-(2-Methoxyethoxy)-6-(3-methoxytetrahydrofuran-3-yl)pyridine-2-yl)- 7-methylpyrrolo[1,2-c]pyrimidin-3 -yl)urea.
  • Example 30 (S)- 1 -(5-(4-(2-Methoxyethoxy)-6-(3 -methoxytetrahy drofuran-3 -yl)pyridine-2-yl)-7- methylpyrrolo[1,2-c]pyrimidin-3-yl)urea.
  • Example 31 1-(5-(4-((R)-2-Hydroxypropoxy)-6-((R)-3-methoxytetrahydrofuran-3-yl)pyridine-2- yl)-7-methylpyrrolo[1,2-c]pyrimidin-3-yl)urea.
  • Step A 1-(5-(4-((R)-2-((tert-Butyldimethylsilyl)oxy)propoxy)-6-((R)-3- methoxytetrahydrofuran-3-yl)pyridin-2-yl)-7-methylpyrrolo[1,2-c]pyrimidin-3-yl)urea.
  • Step B 1-(5-(4-((R)-2-Hydroxypropoxy)-6-((R)-3-methoxytetrahydrofuran-3-yl)pyridine- 2-yl)-7-methylpyrrolo[1,2-c]pyrimidin-3-yl)urea.
  • Example 11 The title compound was prepared in a manner analogous to Example 11, Step B, using 1-(5-(4-((R)-2-((tert-butyldimethylsilyl)oxy)propoxy)-6- ((R)-3-methoxytetrahydrofuran-3-yl)pyridin-2-yl)-7-methylpyrrolo[1,2-c]pyrimidin-3-yl)urea instead of 1 -( 1 -(4-((R)-2-((tert-butyldimethylsilyl)oxy)propoxy)-6-((R)-3 - methoxytetr ahydrofuran-3-yl)pyridine-2-yl)-3-methyl-1H-pyrazolo[4,3-c]pyridine-6-yl)urea (Example 11, Step A).
  • Example 32 1 -(5-(4-((R)-2-Hydroxypropoxy)-6-((S)-3-methoxytetrahydrofuran-3-yl)pyridine-2- yl)-7-methylpyrrolo[1,2-c]pyrimidin-3-yl)urea.
  • Step A 1 -(5-(4-((R)-2-((tert-Butyldimethylsilyl)oxy)propoxy)-6-((S)-3- methoxytetrahydrofuran-3-yl)pyridin-2-yl)-7-methylpyrrolo[1,2-c]pyrimidin-3-yl)urea.
  • Step B 1-(5-(4-((R)-2-hydroxypropoxy)-6-((S)-3-methoxytetrahydrofuran-3-yl)pyridin- 2-yl)-7-methylpyrrolo[1,2-c]pyrimidin-3-yl)urea.
  • Example 11 The title compound was prepared in a manner analogous to Example 11, Step B, using 1-(5-(4-((R)-2-((tert-butyldiinethylsilyl)oxy)propoxy)-6- ((S)-3-methoxytetrahydrofuran-3-yl)pyridin-2-yl)-7-methylpyrrolo[1,2-c]pyrimidin-3-yl)urea instead of 1 -( 1 -(4-((R)-2-((tert-butyldimethylsilyl)oxy)propoxy)-6-((R)-3 - methoxytetrahydrofuran-3-yl)pyridine-2-yl)-3-methyl-1H-pyrazolo[4,3-c]pyridine-6-yl)urea (Example 11, Step A).
  • Example 33 1-(5-(4-((1r,3r)-3-Hydroxycyclobutoxy)-6-((R)-3-methoxytetrahydrofuran-3- yl)pyridine-2-yl)-7-methylpyrrolo[1,2-c]pyrimidin-3-yl)urea.
  • Step A 1-(5-(4-((1r,3r)-3-(Benzyloxy)cyclobutoxy)-6-((R)-3-methoxytetrahydrofuran-3- yl)pyridin-2-yl)-7-methylpyrrolo[1,2-c]pyrimidin-3-yl)urea.
  • Step B 1-(5-(4-((1r,3r)-3-Hydroxycyclobutoxy)-6-((R)-3-methoxytetrahydrofuran-3- yl)pyridine-2-yl)-7-methylpyrrolo[1,2-c]pyrimidin-3-yl)urea.
  • Example 34 1-(5-(4-((1r,3s)-3-Hydroxycyclobutoxy)-6-((S)-3-methoxytetrahydrofuran-3- yl)pyridine-2-yl)-7-methylpyrrolo[1,2-c]pyrimidin-3-yl)urea.
  • Step A 1-(5-(4-((1r,3s)-3-(Benzyloxy)cyclobutoxy)-6-((S)-3-methoxytetrahydrofuran-3- yl)pyridin-2-yl)-7-methylpyrrolo[1,2-c]pyrimidin-3-yl)urea.
  • Step B 1-(5-(4-((1r,3s)-3-Hydroxycyclobutoxy)-6-((S)-3-methoxytetrahydrofuran-3- yl)pyridine-2-yl)-7-methylpyrrolo[1,2-c]pyrimidin-3-yl)urea.
  • Example 33, Step B The title compound was prepared in a manner analogous to Example 33, Step B, using 1-(5-(4-((1r,3s)-3- (benzyloxy)cyclobutoxy)-6-((S)-3-methoxytetrahydrofuran-3-yl)pyridin-2-yl)-7- methylpyrrolo[1,2-c]pyrimidin-3-yl)urea instead of 1-(5-(4-((1r,3r)-3-(benzyloxy)cyclobutoxy)- 6-((R)-3-methoxytetrahydrofuran-3-yl)pyridin-2-yl)-7-methylpyrrolo[1,2-c]pyrimidin-3-yl)urea (Example 33, Step A).
  • Example 35 (S)-1-(5-(4-((1, 1 -Dioxidothietan-3 -yl)methoxy)-6-(3 -methoxy tetrahydrofuran- 3- yl)pyridine-2-yl)-7-methylpyrrolo[1,2-c]pyrimidin-3-yl)urea.
  • Example 36 1 -(6-(3 -Methoxy tetrahy drofuran-3 -yl)-4-methylpyridin-2-yl)-3 -methyl- 1H- pyrazolo[4,3-c]pyridine-6-yl)acetamide.
  • Example 37 (S)-N-( 1 -(6-(3 -Methoxytetrahydrofuran-3 -yl)-4-methylpyridin-2-yl)-3 -methyl- 1 H- pyrazolo[4,3-c]pyridine-6-yl)acetamide.
  • Example 38 (R)-N-( 1 -(4-(Difluoromethyl)-6-(3 -methoxytetrahydrofuran-3 -y l)pyridine-2-y l)-3 - methyl -1H-pyrazolo[4,3 -c]pyridine-6-yl)acetamide.
  • Example 39 (S)-N-(1-(4-(Difluoromethyl)-6-(3-methoxytetrahydrofuran-3-yl)pyridine-2-yl)-3- methyl- 1H-pyrazolo[4,3 -c]pyridine-6-yl)acetamide.
  • Example 40 (R)-N-( 1 -(4-(2-Methoxy ethoxy )-6-(3 -methoxytetrahydrofuran-3 -yl)pyridine-2-yl)- 3-methyl-1H-pyrazolo[4,3-c]pyridine-6-yl)acetamide.
  • the title compound was prepared in a manner analogous to Example 38, except the reaction mixture was heated at 70 °C instead of 110 °C, using (R)-6-chloro-1 -(4-(2- m ethoxy ethoxy )-6-(3 -methoxytetrahydrofuran-3 -yl)pyridine-2-yl)-3 -methyl- 1H-pyrazolo[4,3 - c]pyridine (Intermediate 33) instead of (R)-6-chloro-1-(4-(difluoromethyl)-6-(3- methoxytetrahy drofuran-3 -yl)pyridine-2-yl)-3 -methyl- 1H-pyrazolo[4, 3 -c]pyridine (Intermediate 31) and THF instead of 1,4-dioxane.
  • Example 41 (S)-N-(1-(4-(2-Methoxyethoxy)-6-(3-methoxytetrahydrofuran-3-yl)pyridine-2-yl)- 3-methyl-1H-pyrazolo[4,3-c]pyridine-6-yl)acetamide.
  • the title compound was prepared in a manner analogous to Example 38, except the reaction mixture was heated at 70 °C instead of 110 °C, using (S)-6-chloro-1-(4-(2- methoxyethoxy)-6-(3 -methoxytetrahydrofuran-3 -yl)pyridine-2-yl)-3 -methyl- 1H-pyrazolo[4,3 - c]pyridine (Intermediate 34) instead of (R)-6-chloro-1-(4-(difluoromethyl)-6-(3- methoxytetrahydrofuran-3 -yl)pyridine-2-yl)-3 -methyl- 1H-pyrazolo[4,3 -c]pyridine (Intermediate 31) and THF instead of 1,4-dioxane.
  • Example 42 N-( 1 -(4-((R)-2-hydroxypropoxy)-6-((R)-3 -methoxytetrahydrofuran-3 -yl)pyridine-2- yl)-3-methyl-1H-pyrazolo[4,3-c]pyridine-6-yl)acetamide.
  • Step A N-(1-(4-((R)-2-((tert-butyldimethylsilyl)oxy)propoxy)-6-((R)-3- methoxytetrahydrofuran-3-yl)pyridine-2-yl)-3-methyl-1H-pyrazolo[4,3-c]pyridine-6- yl)acetamide.
  • Step B N-(1-(4-((R)-2-hydroxypropoxy)-6-((R)-3-methoxytetrahydrofuran-3-yl)pyridine- 2-yl)-3-methyl-1H-pyrazolo[4,3-c]pyridine-6-yl)acetamide.
  • Example 11 The title compound was prepared in a manner analogous to Example 11, Step B, using N-(1-(4-((R)-2-((tert- butyldimethylsilyl)oxy)propoxy)-6-((R)-3-methoxytetrahydrofuran-3-yl)pyridine-2-yl)-3-methyl- 1H-pyrazolo[4,3-c]pyridine-6-yl)acetamide instead of 1-(1-(4-((R)-2-((tert- butyldimethylsilyl)oxy)propoxy)-6-((R)-3-methoxytetrahydrofuran-3-yl)pyridine-2-yl)-3-methyl- 1H-pyrazolo[4,3-c]pyridine-6-yl)urea (Example 11, Step A).
  • Example 43 N-(1-(4-((R)-2-Hydroxypropoxy)-6-( (S)-3-methoxytetrahydrofuran-3-yl)pyridine-2- yl)-3-methyl-1H-pyrazolo[4,3-c]pyridine-6-yl)acetamide.
  • Step A N-(1-(4-((R)-2-((tert-Butyldimethylsilyl)oxy)propoxy)-6-((S)-3- methoxytetrahydrofuran-3-yl)pyridin-2-yl)-3-methyl-1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide.
  • Step B N-(1-(4-((R)-2-Hydroxypropoxy)-6-((S)-3-methoxytetrahydrofuran-3- yl)pyridine-2-yl)-3 -methyl- 1H-pyrazolo[4, 3 -c]pyridine-6-yl)acetamide.
  • Example 11 The title compound was prepared in a manner analogous to Example 11, Step B, using N-(1-(4-((R)-2-((tert- butyldimethylsilyl)oxy)propoxy)-6-((S)-3-methoxytetrahydrofuran-3-yl)pyridin-2-yl)-3-methyl- 1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide instead of 1-(1-(4-((R)-2-((tert- butyldimethylsilyl)oxy)propoxy)-6-((R)-3-methoxytetrahydrofuran-3-yl)pyridine-2-yl)-3-methyl- 1H-pyrazolo[4,3-c]pyridine-6-yl)urea (Example 11, Step A).
  • Example 44 (S)-N-( 1 -(6-(3 -Methoxytetrahy drofuran-3 -yl)-4-methylpyridin-2-yl)- 1H- pyrazolo[4,3-c]pyridine-6-yl)acetamide.
  • Example 46 (S)-N-(1-(6-(3 -Methoxytetrahydrofuran-3 -yl)-4-methylpyridin-2-yl)-3 -methyl- 1H- pyrrolo[3,2-c]pyridine-6-yl)acetamide.
  • Example 47 (R)-N-(5-(6-(3 -Methoxy tetrahy drofuran-3 -yl)-4-methylpyridin-2-yl)-7-(1 -methyl- 1H-pyrazol-4-yl)pyrrolo[1,2-c]pyrimidin-3-yl)acetamide.
  • Example 48 (S)-N-(5-(6-(3-Methoxytetrahydrofuran-3-yl)-4-rnethylpyridin-2-yl)-7-(1-methyl- 1H-pyrazol-4-yl)pyrrolo[1,2-c]pyrimidin-3-yl)acetamide.
  • Example 50 (R)-N-(5-(4-(Difluoromethyl)-6-(3-methoxytetrahydrofuran-3-yl)pyridine-2-yl)-7- methylpyrrolo[1 ,2-c]pyrimidin-3 -yl)acetamide.
  • Example 51 (S)-N-(5-(4-(Difluoromethyl)-6-(3-methoxytetrahydrofuran-3-yl)pyridine-2-yl)-7- methylpyrrolo[ 1 ,2-c]pyrimidin-3-yl)acetamide.
  • Example 52 (R)-N-(5-(4-(2-Methoxyethoxy)-6-(3-methoxytetrahydrofuran-3-yl)pyridin-2-yl)-7- methylpyrrolo[1,2-c]pyrimidin-3-yl)acetamide.
  • Example 54 N-(5-(4-((R)-2-Hydroxypropoxy)-6-((R)-3 -methoxytetrahydrofuran-3 -yl)pyridin-2- yl)-7-methylpyrrolo[1,2-c]pyrimidin-3-yl)acetamide.
  • Step A N-(5-(4-((R)-2-((tert-Butyldimethylsilyl)oxy)propoxy)-6-((R)-3- methoxytetrahydrofuran-3-yl)pyridin-2-yl)-7-methylpyrrolo[1,2-c]pyrimidin-3-yl)acetamide.
  • Step B N-(5-(4-((R)-2-Hydroxypropoxy)-6-((R)-3-methoxytetrahydrofuran-3-yl)pyridin- 2-yl)-7-methylpyrrolo[1,2-c]pyrimidin-3-yl)acetamide.
  • Example 11 The title compound was prepared in a manner analogous to Example 11, Step B, using N-(5-(4-((R)-2-((tert- butyldimethylsilyl)oxy)propoxy)-6-((R)-3-methoxytetrahydrofuran-3-yl)pyridin-2-yl)-7- methylpyrrolo[1,2-c]pyrimidin-3-yl)acetamide instead of 1-(1-(4-((R)-2-((tert- butyldimethylsilyl)oxy)propoxy)-6-((R)-3-methoxytetrahydrofuran-3-yl)pyridine-2-yl)-3-methyl- 1H-pyrazolo[4,3-c]pyridine-6-yl)urea (Example 11, Step A).
  • Example 55 N-(5-(4-((R)-2-Hydroxypropoxy)-6-((S)-3-methoxytetrahydrofuran-3-yl)pyridin-2- yl)-7-methylpyrrolo[1,2-c]pyrimidin-3-yl)acetamide.
  • Step A N-(1-(4-((R)-2-((tert-Butyldimethylsilyl)oxy)propoxy)-6-((S)-3- methoxytetrahydrofuran-3-yl)pyridin-2-yl)-3-methyl-1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide.
  • Step B N-(5-(4-((R)-2-Hydroxypropoxy)-6-((S)-3-methoxytetrahydrofuran-3-yl)pyridin- 2-yl)-7-methylpyrrolo[1,2-c]pyrimidin-3-yl)acetamide.
  • Example 11 The title compound was prepared in a manner analogous to Example 11, Step B, using N-(1-(4-((R)-2-((tert- butyldimethylsilyl)oxy)propoxy)-6-((S)-3-methoxytetrahydrofuran-3-yl)pyridin-2-yl)-3-methyl- 1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide instead of 1-(1-(4-((R)-2-((tert- butyldimethylsilyl)oxy)propoxy)-6-((R)-3-methoxytetrahydrofuran-3-yl)pyridine-2-yl)-3-methyl- 1H-pyrazolo[4,3-c]pyridine-6-yl)urea (Example 11, Step A).
  • Example 56 (S)-N-( 1 -(6-(3 -Methoxytetrahydrofuran-3 -yl)-4-methylpyridin-2 -yl)-1H- pyrrolo[3,2-c]pyridin-6-yl)acetamide.
  • Example 57 (S)-N-( 1 -(6-(3 -Methoxytetrahy drofuran-3 -yl)-4-methylpyridin-2-yl)-3 -methyl-2- oxo-2, 3 -dihydro- 1H-imidazo[4, 5-c]pyridin-6-yl)acetamide.
  • Example 58 (S)-N-(5-(6-(3-Methoxytetrahydrofuran-3-yl)-4-methylpyridin-2-yl)-7-methyl-7H- pyrrolo[2,3 -c]pyridazin-3 -yl)acetamide.
  • Example 60 (R)-1-(1-(4-(2-Methoxyethoxy)-6-(3-methoxytetrahydrofuran-3-yl)pyridin-2-yl)-3- (methyl-d 3 )- 1H-pyrazolo[4,3-c]pyridin-6-yl)urea.
  • Example 61 (R)-1-(3-Cyclopropyl-1-(4-(2-methoxyethoxy)-6-(3-methoxytetrahydrofuran-3- yl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)urea.
  • Example 62 (R)- 1 -( 1 -(4-(2 -Methoxyethoxy )-6-(3 -methoxytetrahy drofuran-3 -yl)pyridin-2-yl)-3- (trifluoromethyl)-1H-pyrazolo[4,3 -c]pyridin-6-yl)urea.
  • Example 63 (R)- 1 -( 1 -(6-(3 -Methoxytetrahydrofuran-3 -yl)-4-(oxetan-3 -ylmethoxy)pyri din-2-yl)- 3 -(trifluoromethyl)- 1H-pyrazolo[4,3 -c]pyridin-6-yl)urea.
  • Example 64 (R)- 1 -(3 -(Isoxazol-3 -yl)- 1 -(6-(3 -methoxytetrahydrofuran-3 -yl)-4-methylpyridin-2- yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)urea.
  • Example 65 (R)- 1 -(3 -(3 -Hydroxycyclobutyl)- 1 -(6-(3 -methoxytetrahy drofuran-3 -yl)-4- methylpyridin-2-yl)- 1H-pyrazolo[4, 3 -c]pyridin-6-yl)urea.
  • Example 66 (R)- 1 -(3 -(3 -Cyanocyclobutyl)- 1 -(6-(3 -methoxytetrahydrofuran-3 -yl)-4- methylpyridin-2 -yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)urea.
  • Example 68 (S)-3 -( 1 -(6-(3 -Methoxytetrahy drofuran-3 -yl)-4-methylpyridin-2-yl)-6-ureido- 1H- pyrazolo[4,3-c]pyridin-3-yl)cyclobutane- 1 -carboxamide.
  • Example 69 (R)- 1 -(1 -(6-(3 -Ethoxytetrahydrofuran-3 -yl)-4-methylpyri din-2 -yl)-3 -methyl- 1H- pyrazolo[4,3 -c]pyridin-6-yl)urea.
  • Example 70 (*S)- 1 -( 1 -(6-(3 -Methoxytetrahydro-2H-pyran-3-yl)-4-(oxetan-3 -ylmethoxy)pyridin- 2-yl)-3 -methyl -1H-pyrazolo[4,3 -c]pyridin-6-yl)urea.
  • Step A (R,S)-1-(1-(6-(3-Methoxytetrahydro-2H-pyran-3-yl)-4-(oxetan-3- ylmethoxy)pyridin-2-yl)-3-methyl-1H-pyrazolo[4,3-c]pyridin-6-yl)urea.
  • Step B (*S)-1-(1-(6-(3-Methoxytetrahydro-2H-pyran-3-yl)-4-(oxetan-3- ylmethoxy)pyridin-2-yl)-3-methyl-1H-pyrazolo[4,3-c]pyridin-6-yl)urea.
  • Example 71 (*R)- 1 -(1 -(6-(3 -Methoxytetrahydro-2H-pyran-3 -yl)-4-(oxetan-3 - ylmethoxy)pyridin-2-yl)-3-methyl-1H-pyrazolo[4,3-c]pyridin-6-yl)urea.
  • Example 72 (*R)- 1 -(1 -(4-( 1 , 1 -Difluoroethyl)-6-(3 -methoxytetrahydrofuran-3 -yl)pyridin-2-yl)-3 - methyl- 1H-pyrazolo[4,3 -c]pyridin-6-yl)urea.
  • Step A (R,S)-1-(1-(4-(1,1-Difluoroethyl)-6-(3-methoxytetrahydrofuran-3-yl)pyridin-2- yl)-3-methyl-1H-pyrazolo[4,3-c]pyridin-6-yl)urea.
  • Step B (*R)- 1 -( 1 -(4-(l , 1 -Difluoroethyl)-6-(3 -methoxy tetrahydrofuran-3 -yl)pyridin-2-yl)- 3-methyl-1H-pyrazolo[4,3-c]pyridin-6-yl)urea.
  • Example 73 (*S)- 1 -( 1 -(4-( 1 , 1 -Difluoroethyl)-6-(3 -methoxytetrahydrofuran-3 -yl)pyridin-2-yl)-3 - methyl-1H-pyrazolo[4,3-c]pyridin-6-yl)urea.
  • Example 74 (*R)- 1 -(1 -(4-(4-Hy droxypi peridin- 1 -yl)-6-(3 -methoxytetrahydrofuran-3 -yl)pyridin- 2-yl)-3 -methyl-1H-pyrazolo[4, 3 -c]pyridin-6-yl)urea.
  • Step A 1-(1-(4-(4-(Benzyloxy)piperidin-1-yl)-6-(3 -methoxytetrahydrofuran-3 - yl)pyridin-2-yl)-3 -methyl-1H-pyrazolo[4, 3 -c]pyridin-6-yl)urea.
  • Step B 1 -( 1 -(4-(4-Hydroxypiperidin- 1 -yl)-6-(3 -methoxytetrahydrofuran-3 -yl)pyridin-2- yl)-3-methyl-1H-pyrazolo[4,3-c]pyridin-6-yl)urea.
  • Step C (*R)-1-( 1 -(4-(4-Hy droxypiperidin- 1 -yl)-6-(3 -methoxytetrahy drofuran-3 - yl)pyridin-2-yl)-3-methyl-1H-pyrazolo[4,3-c]pyridin-6-yl)urea.
  • Example 75 (*S)-1-(1-(4-(4-Hydroxypiperidin-1-yl)-6-(3-methoxytetrahydrofuran-3-yl)pyridin- 2-yl)-3-methyl-1H-pyrazolo[4,3-c]pyridin-6-yl)urea.
  • Example 74 The chiral separation described for Example 74 provided (*S)- 1 -( 1-(4-(4- hydroxypiperidin- 1 -yl)-6-(3 -methoxytetrahydrofuran-3 -yl)pyridin-2-yl)-3 -methyl- 1H- pyrazolo[4,3-c]pyridin-6-yl)urea (58 mg, 22%) as a white solid.
  • R t 2.42 min
  • Example 76 1-(1 -(6-(3 -Methoxy- 1,1 -dioxidotetrahydrothiophen-3 -yl)-4-methylpyridin-2-yl)-3 - methyl-1H-pyrazolo[4,3 -c]pyridin-6-yl)urea.
  • Example 77 1 -( 1 -(6-(3 -Methoxy- 1 -oxidotetrahydrothiophen-3 -yl)-4-methylpyridin-2-yl)-3 - methyl- 1H-pyrazolo[4,3-c]pyridin-6-yl)urea.
  • Example 78 1-(1 -(6-(3-Methoxytetrahydrofuran-3-yl)-4-(piperidin-1-yl)pyridin-2-yl)-3-methyl- 1H-pyrazolo[4,3-c]pyridin-6-yl)urea.
  • Example 79 1 -(6-(3 -Methoxytetrahy drofuran-3 -yl)-4-(oxetan-3 -ylmethoxy)pyridin-2-yl)-
  • the title compound was prepared in a manner analogous to Example 38, except the reaction mixture was heated at 70 °C instead of 110 °C, using (R)-6-chloro-1-(6-(3- methoxytetrahydrofuran-3 -yl)-4-(oxetan-3 -ylmethoxy )pyridin-2-yl)-3 -methyl-1H-pyrazolo[4, 3 - c]pyridine (Intermediate 37) instead of (R)-6-chloro-1-(4-(difluoromethyl)-6-(3- methoxytetrahydrofuran-3 -yl)pyridine-2-yl)-3 -methyl- 1H-pyrazolo[4, 3 -c]pyridine (Intermediate 31), and THF instead of 1,4-dioxane.
  • Example 80 (R)-N-( 1 -(6-(3 -Methoxytetrahydrofuran-3 -yl)-4-(oxetan-3 -ylmethoxy)pyridin-2-yl)- 3 -methyl-1H-pyrazolo[4, 3 -c]pyridin-6-yl)acetamide-2,2,2-d 3 .
  • Example 81 (R)-N-( 1 -(4-(( 1 , 1 -Dioxidothietan-3 -yl)methoxy)-6-(3 -methoxytetrahydrofuran-3 - yl)pyridin-2-yl)-3-methyl-1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide.
  • Example 82 N-(1-(4-((R)-2-Hydroxypropoxy)-6-((R)-3-methoxytetrahydrofuran-3-yl)pyridin-2- yl)-3 -methyl- 1H-pyrazolo[4,3 -c]pyridin-6-yl)acetamide-2,2,2-d 3 .
  • Step A N-(1-(4-((R)-2-((tert-Butyldimethylsilyl)oxy)propoxy)-6-((R)-3- methoxytetrahydrofuran-3-yl)pyridin-2-yl)-3-methyl-1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide- 2,2,2-d 3 .
  • Step B N-( 1 -(4-((R)-2-Hy droxypropoxy)-6-((R)-3 -methoxytetrahydrofuran-3 -yl)pyridin- 2-yl)-3-methyl-1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide-2,2,2-d 3 .
  • Example 83 (R)-2-Hydroxy-N-(1-(6-(3-methoxytetrahydrofuran-3-yl)-4-(oxetan-3- ylmethoxy)pyridin-2-yl)-3 -methyl-1H-pyrazolo[4,3 -c]pyridin-6-y l)acetamide.

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Abstract

La présente invention concerne des composés de formule (I') ou un sel pharmaceutiquement acceptable de celui-ci, Formule (A), R1, R5, Z et m étant définis dans la description, ainsi que des procédés de fabrication et d'utilisation des composés de l'invention pour traiter ou soulager un syndrome, un trouble et/ou une maladie à médiation par TYK2.
PCT/US2021/072483 2020-11-20 2021-11-18 Inhibition de voies de signalisation dépendantes de tyk2 Ceased WO2022109580A1 (fr)

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WO2023232133A1 (fr) 2022-06-02 2023-12-07 西藏海思科制药有限公司 Composé pour inhiber ou dégrader bcl6 et son utilisation en pharmacie
WO2023250064A1 (fr) * 2022-06-23 2023-12-28 Biogen Ma Inc. Inhibiteurs de tyrosine kinase 2 et leurs utilisations
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US20160222014A1 (en) * 2013-09-10 2016-08-04 Asana Biosciences, Llc Compounds for regulating fak and/or src pathways
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US20200255423A1 (en) * 2018-03-12 2020-08-13 Abbvie Inc. Inhibitors of tyrosine kinase 2 mediated signaling

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WO2023076161A1 (fr) 2021-10-25 2023-05-04 Kymera Therapeutics, Inc. Agents de dégradation de tyk2 et leurs utilisations
WO2023232133A1 (fr) 2022-06-02 2023-12-07 西藏海思科制药有限公司 Composé pour inhiber ou dégrader bcl6 et son utilisation en pharmacie
WO2023250064A1 (fr) * 2022-06-23 2023-12-28 Biogen Ma Inc. Inhibiteurs de tyrosine kinase 2 et leurs utilisations
WO2024015497A1 (fr) * 2022-07-14 2024-01-18 Biogen Ma Inc. Inhibiteurs de tyrosine kinase 2 et leurs utilisations

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