Tyk2 inhibitors and uses thereof

Abstract

The present invention provides compounds, compositions thereof, and methods of using the same for inhibiting TYK2 and treating TYK2-mediated disorders.

Description

[0001] This application is a divisional application of Chinese patent application No. 201880057821.5, entitled "TYK2 Inhibitor and Its Use", filed on July 26, 2018 (PCT application No. PCT / US2018 / 043917). Technical Field

[0002] This invention relates to compounds and methods for inhibiting non-receptor tyrosine protein kinase 2 (“TYK2”; also known as tyrosine kinase 2). The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods for treating various conditions using said compositions. Background Technology

[0003] In recent years, a better understanding of the structures of disease-related enzymes and other biomolecules has greatly aided the search for novel therapeutics. One important class of enzymes that has become a subject of in-depth research is the protein kinase family.

[0004] Protein kinases constitute a large group of structurally related enzymes responsible for controlling various intracellular signal transduction processes. Because their structure and catalytic function are conserved, they are believed to have evolved from a common ancestral gene. Almost all kinases contain similar catalytic domains of 250-300 amino acids. Kinases can be divided into several families based on their phosphorylation acceptors (e.g., protein-tyrosine, protein-serine / threonine, lipids, etc.).

[0005] Generally, protein kinases mediate intracellular signaling by facilitating the transfer of phosphoryl groups from nucleoside triphosphates to protein receptors involved in signal transduction pathways. These phosphorylation events act as molecular on / off converters that regulate or modulate the biological functions of target proteins. These phosphorylation events are ultimately triggered in response to a variety of extracellular and other stimuli. Examples of such stimuli include environmental and chemical stress signals (e.g., osmotic shock, heat shock, ultraviolet radiation, bacterial endotoxins, and H2O2), cytokines (e.g., interleukin-1 (IL-1), interleukin-8 (IL-8), and tumor necrosis factor-α (TNF-α)), and growth factors (e.g., granulocyte-macrophage community-stimulating factor (GM-CSF) and fibroblast growth factor (FGF)). Extracellular stimuli can affect one or more cellular responses associated with cell growth, migration, differentiation, hormone secretion, transcription factor activation, muscle contraction, glucose metabolism, protein synthesis control, and cell cycle regulation.

[0006] Many diseases are associated with abnormal cellular responses triggered by kinase-mediated events. These diseases include (but are not limited to) autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer's disease, and hormone-related diseases. Therefore, the search for protein kinase inhibitors that can be used as therapeutic agents remains. Summary of the Invention

[0007] It has now been discovered that the compounds of the present invention and their pharmaceutically acceptable compositions are effective as TYK2 kinase inhibitors.

[0008] The compounds of this invention and pharmaceutically acceptable compositions thereof may be used to treat a variety of diseases, symptoms, or conditions associated with the regulation of signal transduction pathways involving TYK2 kinases. These diseases, symptoms, or conditions include those described herein.

[0009] The compounds provided by this invention can also be used to study TYK2 enzymes in biological and pathological phenomena; to study intracellular signal transduction pathways in body tissues; and to comparatively evaluate novel TYK2 inhibitors, or other regulatory factors of kinases, signal transduction pathways and cytokines in vitro or in vivo. Detailed Implementation

[0010] 1. A general description of certain embodiments of the present invention:

[0011] The compounds and compositions thereof of the present invention can be used as inhibitors of TYK2 protein kinase.

[0012] The pseudokinase binding pocket of TYK2 contains multiple hydration sites, each occupied by a single water molecule. Each of these water molecules possesses an associated stability grade. As used herein, the term "stability grade" refers to a numerical calculation incorporating the enthalpy, entropy, and free energy associated with each water molecule. This stability grade allows for measurable determination of the relative stability of the water molecules occupying the hydration sites within the TYK2 binding pocket.

[0013] Water molecules occupying hydration sites in the TYK2 binding bag with a stability level >2.5 kcal / mol are called "unstable water".

[0014] Without being bound by any particular theory, it is believed that using inhibitors to replace or disrupt unstable water molecules (i.e., water molecules with a stability level > 2.5 kcal / mol) or to displace stable water (i.e., water molecules with a stability level < 1 kcal / mol) results in a tighter binding. Therefore, inhibitors designed to replace one or more unstable water molecules (i.e., unstable water molecules not replaced by any known inhibitors) will be tighter binders and thus more potent inhibitors compared to inhibitors that do not replace unstable water molecules.

[0015] It was unexpectedly discovered that the provided compound replaces or destroys one or more unstable water molecules. In some embodiments, the provided compound replaces or destroys at least two unstable water molecules.

[0016] In some embodiments, the present invention provides a compound of formula I:

[0017]

[0018] Or a pharmaceutically acceptable salt thereof, wherein R 3 R 5 R 6 and R 7 Each individually and in combination is defined below and described in the embodiments herein.

[0019] In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable carrier, adjuvant, or diluent.

[0020] In some embodiments, the present invention provides a method for treating TYK2-mediated diseases, symptoms, or conditions, comprising administering a compound of formula I or a pharmaceutically acceptable salt thereof to a patient in need.

[0021] 2. Compounds and their definitions:

[0022] The compounds of this invention include those generally described herein and further illustrated by the classes, subclasses and species disclosed herein. Unless otherwise specified, the following definitions apply as used herein. For the purposes of this invention, chemical elements are identified according to the Periodic Table of the Elements, CAS edition, Handbook of Chemistry and Physics, 75th edition. Additionally, the general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999; and “March's Advanced Organic Chemistry”, 5th edition, edited by Smith, MB and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

[0023] As used herein, the term "aliphatic group" or "aliphatic group" means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more unsaturated units, or a monocyclic or bicyclic hydrocarbon (also referred to herein as "carbocyclic", "cycloaliphatic group" or "cycloalkyl") that is fully saturated or contains one or more unsaturated units but is not an aromatic group, having a single connection point to the rest of the molecule. Unless otherwise stated, an aliphatic group contains 1 to 6 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1 to 5 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1 to 4 aliphatic carbon atoms. In still other embodiments, an aliphatic group contains 1 to 3 aliphatic carbon atoms, and in still other embodiments, an aliphatic group contains 1 to 2 aliphatic carbon atoms. In some embodiments, "cycloaliphatic group" (or "carbocyclic" or "cycloalkyl") means a monocyclic C3-C6 hydrocarbon that is fully saturated or contains one or more unsaturated units but is not an aromatic group, having a single connection point to the rest of the molecule. Suitable aliphatic groups include (but are not limited to) straight-chain or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl and mixtures thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0024] As used herein, the term "bridged bicyclic" refers to any bicyclic ring system having at least one bridging bond, i.e., a carbocyclic or heterocyclic, saturated or partially unsaturated group. As defined by IUPAC, a "bridging bond" is a non-branched or single-atom valence bond connecting two bridgeheads, wherein a "bridgehead" is any skeletal atom bonded to a ring system of three or more skeletal atoms (other than hydrogen). In some embodiments, the bridged bicyclic group has 7 to 12 ring members and 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. The bridged bicyclic group is well known in the art and includes the groups set forth below, wherein each group is attached to the remainder of the molecule at any substituted carbon or nitrogen atom. Unless otherwise stated, the bridged bicyclic group is optionally substituted with one or more substituents as set forth with respect to aliphatic groups. Additionally or alternatively, any substituted nitrogen atom in the bridged bicyclic group is optionally substituted. Exemplary bridged bicyclics include:

[0025]

[0026] The term "low carbon number alkyl" refers to C 1-4 Straight-chain or branched alkyl groups. Exemplary low-carbon alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0027] The term "low-carbon haloalkyl" refers to a C14 alkyl group substituted with one or more halogen atoms. 1-4 Straight-chain or branched alkyl groups.

[0028] The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including any oxidized form of nitrogen, sulfur, phosphorus, or silicon; any quaternized form of basic nitrogen; or a substituted nitrogen of a heterocycle, such as N (as in 3,4-dihydro-2H-pyrrole), NH (as in pyrrolealkyl), or NR. + (e.g., in N-substituted pyrroleyl groups).

[0029] As used in this article, the term "unsaturated" means that a part has one or more unsaturated units.

[0030] As used in this article, the term "divalent C" 1-8 (or C) 1-6 "Saturated or unsaturated, straight or branched hydrocarbon chains" refers to straight or branched divalent alkylene, alkenyl, and ynylene chains as defined herein.

[0031] The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH2). n- where n is a positive integer, preferably 1 to 6, 1 to 4, 1 to 3, 1 to 2, or 2 to 3. The substituted alkylene chain is a polymethylene with one or more methylene hydrogen atoms replaced by substituents. Suitable substituents include those described below with respect to substituted aliphatic groups.

[0032] The term "alkenyl" refers to a divalent alkenyl group. A substituted alkenyl chain is a polymethylene chain containing at least one double bond, wherein one or more hydrogen atoms are substituted by substituents. Suitable substituents include those described below with respect to substituted aliphatic groups.

[0033] The term "halogen" refers to F, Cl, Br, or I.

[0034] When used alone or as part of a larger part, the term "aryl" as used in "aralkyl," "aralkyloxy," or "aryloxyalkyl" refers to a monocyclic or bicyclic ring system having a total of five to fourteen ring members, wherein at least one ring in the system is an aromatic ring and wherein each ring in the system contains three to seven ring members. The term "aryl" may be used interchangeably with the term "aryl ring." In some embodiments of the invention, "aryl" refers to an aromatic ring system including (but not limited to) phenyl, biphenyl, naphthyl, anthracene, etc., which may have one or more substituents. As used herein, the scope of the term "aryl" also includes groups fused with an aromatic ring to one or more non-aromatic rings, such as dihydroindenyl, phthalimide, naphthimide, phenidyl, or tetrahydronaphthyl.

[0035] The terms "heteroaryl" and "heteroary-" used alone or as part of a larger portion, such as "heteroarylalkyl" or "heteroarylalkoxy," refer to a group having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having a total of 6, 10, or 14 π electrons in the ring array; and having 1 to 5 heteroatoms in addition to carbon atoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of basic nitrogen. Heteroaryl groups include (but are not limited to) thiophene, furanyl, pyrrole, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indazinyl, purinyl, pyridinyl, and pteridinyl. As used herein, the terms "heteroaryl" and "heteroary-" also include groups fused with one or more aryl, cycloaliphatic, or heterocyclic rings, wherein, unless otherwise stated, the linking group or connection point is on the heteroaryl ring or on one of the rings fused with the heteroaryl ring. Non-limiting examples include indolyl, isoindolyl, benzothiopheneyl, benzofuranyl, dibenzofuranyl, indazoleyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinazinyl, carbazoleyl, acridineyl, benziazinyl, benziazinyl, benziazinyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl. Heteroaryl groups can be monocyclic or bicyclic. The term "heteroaryl" is used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," any of which includes an optionally substituted ring. The term "heteroarylalkyl" refers to a heteroaryl-substituted alkyl group, wherein the alkyl and heteroaryl portions are optionally substituted independently.

[0036] As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic portion that is saturated or partially unsaturated and has one or more, preferably one to four, heteroatoms as defined above, in addition to a carbon atom. When referring to the ring atom of a heterocycle, the term “nitrogen” includes substituted nitrogen. For example, in a saturated or partially unsaturated ring having 0 to 3 heteroatoms selected from oxygen, sulfur, or nitrogen, nitrogen may be N (as in 3,4-dihydro-2H-pyrrole), NH (as in pyrrolidinyl), or... + NR (e.g., in N-substituted pyrroleyl groups).

[0037] Heterocycles can be attached to their side groups at any heteroatom or carbon atom, thereby producing a stable structure, and any ring atom can optionally be substituted. Examples of such saturated or partially unsaturated heterocyclic groups include (but are not limited to) tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazine, dioxane, dioxanecyclopentane, diazapyryl, oxazapyryl, thiacyclohexadieneyl, morpholinyl, 2-oxa-6-azaspiro[3.3]heptane, and quininecycloyl. The terms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical” are used interchangeably herein and also include groups fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indololinyl, 3H-indolyl, alkyl, phenidyl, or tetrahydroquinolinyl. Heterocyclyl groups can be monocyclic or bicyclic. The term “heterocyclyl alkyl” refers to an alkyl group substituted with a heterocyclyl group, wherein the alkyl group and the heterocyclyl moiety are optionally substituted independently.

[0038] As used herein, the term "partially unsaturated" refers to a ring moiety comprising at least one double or triple bond. The term "partially unsaturated" is intended to cover rings having multiple unsaturated sites, but is not intended to include aryl or heteroaryl moiety as defined herein.

[0039] As described herein, the compounds of the present invention may contain an "optionally substituted" portion. Generally, the term "substituted," whether or not preceded by the term "optionally," means that one or more hydrogens of the specified portion are replaced by a suitable substituent. Unless otherwise indicated, the "optionally substituted" group may have a suitable substituent at each substituted position of the group, and the substituents at each position may be the same or different when more than one position in any given structure is substituted by more than one substituent selected from the specified group. The combinations of substituents contemplated in this invention are preferably combinations that result in stable or chemically viable compounds. As used herein, the term "stable" means that the compound does not undergo substantial change when subjected to conditions that allow it to be made, detected, and, in some embodiments, recovered, purified, and used for one or more purposes disclosed herein.

[0040] The suitable monovalent substituent on the substituted carbon atom of the "optionally substituted" group is independently a halogen; -(CH2) 0-4 R°;-(CH2) 0-4 OR°;-O(CH2) 0-4 Ro , -O-(CH2) 0-4 C(O)OR°;-(CH2) 0-4 CH(OR°)2;-(CH2) 0- 4SR°;-(CH2) 0-4 Ph, which can be substituted by R°; -(CH2) 0-4 O(CH2) 0-1 Ph, which can be substituted by R°; -CH=CHPh, which can be substituted by R°; -(CH2) 0-4 O(CH2) 0-1 -Pyridyl group, which can be substituted via R°; -NO2; -CN; -N3; ​​-(CH2) 0-4 N(R°)2;-(CH2) 0-4 N(R°)C(O)R°;-N(R°)C(S)R°;-(CH2) 0-4 N(R°)C(O)NR°2;-N(R°)C(S)NR°2;-(CH2) 0-4 N(R°)C(O)OR°; -N(R°)N(R°)C(O)R°; -N(R°)N(R°)C(O)NR°2; -N(R°)N(R°)C(O)OR°; -N(R°)C(NR°)N(R°)2; -(CH2) 0-4 C(O)R°;-C(S)R°;-(CH2) 0-4 C(O)OR°;-(CH2) 0-4 C(O)SR°;-(CH2) 0-4 C(O)OSiR°3;-(CH2) 0-4 OC(O)R°;-OC(O)(CH2) 0-4 SR°;-SC(S)SR°;-(CH2) 0-4 SC(O)R°;-(CH2) 0-4 C(O)NR°2;-C(S)NR°2;-C(S)SR°;-SC(S)SR°;-(CH2) 0-4 OC(O)NR°2; -C(O)N(OR°)R°; -C(O)C(O)R°; -C(O)CH2C(O)R°; -C(NOR°)R°; -(CH2) 0-4 SSR°;-(CH2) 0-4 S(O)2R°;-(CH2) 0-4 S(O)₂OR°;-(CH₂) 0-4 OS(O)2R°;-S(O)2NR°2;-(CH2) 0-4S(O)R°; -N(R°)S(O)2NR°2; -N(R°)S(O)2R°; -N(OR°)R°; -C(NH)NR°2; -P(O)2R°; -P(O)R°2; -OP(O)R°2; -OP(O)(OR°)2; -SiR°3; -(C 1-4 (linear or branched alkylene)ON(R°)2; or -(C 1-4 (straight-chain or branched alkylene)C(O)ON(R°)2, wherein each R° may be substituted and independently hydrogen, C as defined below. 1-6 Aliphatic groups, -CH2Ph, -O(CH2) 0-1 Ph, -CH2- (5 to 6-membered heteroaryl ring), or a 5 to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, despite the above definition, two independently occurring R° linked together with their inserted atoms to form a 3 to 12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0041] Suitable monovalent substituents on R° (or a ring formed by two independently occurring R° linked to their inserted atoms) are independently halogens, -(CH2). 0-2 R ● -(halogenated R) ● -(CH2) 0-2 OH, -(CH2) 0-2 OR ● -(CH2) 0-2 CH(OR ● 2. -O(halogenated R) ● -CN, -N3, -(CH2) 0-2 C(O)R ● -(CH2) 0-2 C(O)OH, -(CH2) 0-2 C(O)OR ● -(CH2) 0-2 SR ● -(CH2) 0-2 SH, -(CH2) 0-2 NH2、-(CH2) 0-2 NHR ● -(CH2) 0-2 NR ● 2, -NO2, -SiR ● 3. -OSiR ● 3. -C(O)SR ● -(C 1-4 (straight-chain or branched alkylene)C(O)OR● or -SSR ● , where each R ● It is either unsubstituted or, in the case of a preceding "halogen group," substituted with only one or more halogens, and independently selected from C. 1-4 Aliphatic groups, -CH2Ph, -O(CH2) 0-1 Ph or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 independent heteroatoms selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on the saturated carbon atom of R° include =O and =S.

[0042] Suitable divalent substituents on the saturated carbon atom of the "optionally substituted" group include the following: =O, =S, =NNR. * 2、=NNHC(O)R * =NNHC(O)OR * =NNHS(O)2R * =NR * =NOR * -O(C(R) * 2)) 2-3 O- or -S(C(R) * 2)) 2- 3S-, where R * Each time it appears, it is independently selected from hydrogen, and can be defined as a substituted C as shown below. 1-6 Aliphatic group, or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 independent heteroatoms selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents attached to the adjacent substituted carbon of the "optionally substituted" group include: -O(CR * 2) 2-3 O-, where R * Each time it appears, it is independently selected from hydrogen, and the substituted C can be defined as follows. 1-6 Aliphatic group, or unsubstituted 5 to 6-membered saturated, partially unsaturated or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0043] R * Suitable substituents on aliphatic groups include halogens, -R ● -(halogenated R) ● -OH, -OR ● -O(halogenated R) ● -CN, -C(O)OH, -C(O)OR ● -NH2, -NHR ● -NR ● 2 or -NO2, where each R ●It is formed by substitution with one or more halogens without substitution or with a preceding "halogen group", and is independently C. 1-4 Aliphatic groups, -CH2Ph, -O(CH2) 0-1 Ph or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0044] Suitable substituents on the substituted nitrogen of the "optionally substituted" group include -R † -NR † 2. -C(O)R † -C(O)OR † -C(O)C(O)R † -C(O)CH2C(O)R † -S(O)2R † -S(O)2NR † 2. -C(S)NR † 2. -C(NH)NR † 2 or -N(R) † )S(O)2R † ; where each R † Independently, hydrogen, substituted C can be defined as follows: 1-6 Aliphatic group, unsubstituted -OPh, or unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 independently selected heteroatoms chosen from nitrogen, oxygen, or sulfur, or, despite the above definitions, two independently occurring R groups. † Together with its inserted atoms, it forms an unsubstituted 3 to 12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring with 0 to 4 independent heteroatoms selected from nitrogen, oxygen, or sulfur.

[0045] R † Suitable substituents on the aliphatic group are independently halogens, -R ● -(halogenated R) ● -OH, -OR ● -O(halogenated R) ● -CN, -C(O)OH, -C(O)OR ● -NH2, -NHR ● -NR ● 2 or -NO2, where each R ● It is formed by substitution with one or more halogens without substitution or with a preceding "halogen group", and is independently C. 1-4 Aliphatic groups, -CH2Ph, -O(CH2) 0- 1Ph or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0046] As used herein, the term "pharmaceutically acceptable salt" means a salt that, within reasonable medical judgment, is suitable for use in contact with human and lower animal tissues without undue toxicity, irritation, allergic reactions, etc., and is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. described pharmaceutically acceptable salts in detail in the Journal of Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include salts derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed with amino groups and inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or salts formed by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphor sulfonate, citrate, cyclopentanepropionate, disglucuronate, dodecyl sulfate, ethanesulfonate, formate, transbutenedioic acid, glucono-heptahydrate, glyceryl phosphate, gluconate, hemisulfate, heptahydrate, hexanoate, hydroiodate, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, dihydroxynaphthalate, pectate, persulfate, 3-phenylpropionate, phosphate, p-pentanoate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc.

[0047] Salts derived from suitable bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N salts. + (C 1-4 Alkyl)4 salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium salts. Where appropriate, other pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cation salts formed using relative ions such as halide, hydroxide, carboxyl, sulfate, phosphate, nitrate, low-carbon alkyl sulfonates, and aryl sulfonates.

[0048] Unless otherwise stated, the structures described herein are also intended to include all isomers (e.g., enantiomers, diastereomers, and geometric isomers (or configurational isomers) of said structures; for example, R and S configurations of each asymmetric center, Z and E double bond isomers, and Z and E configurational isomers. Therefore, single stereochemical isomers of the compounds of the present invention, as well as mixtures of enantiomers, diastereomers, and geometric isomers (or configurational isomers), are within the scope of the present invention. Unless otherwise stated, all tautomers of the compounds of the present invention are within the scope of the present invention. Furthermore, unless otherwise stated, the structures described herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, this includes hydrogen replaced by deuterium or tritium, or carbon replaced by... 13 C or 14 Compounds with C-enriched carbon-substituted structures having the structure of this invention are within the scope of this invention. Such compounds can be used, for example, as analytical tools, probes in bioanalysis, or therapeutic agents according to the invention. In some embodiments, the warhead portion R of the provided compound... 1 It contains one or more deuterium atoms. In some embodiments, ring B of the provided compound may be substituted with one or more deuterium atoms.

[0049] As used herein, the term "inhibitor" is defined as a compound that binds to and / or inhibits TYK2 with measurable affinity. In some embodiments, the IC50 of the inhibitor is... 50 And / or the binding constant is less than about 50 μM, less than about 1 μM, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM.

[0050] The compounds of this invention can be tethered to a detectable portion. It should be understood that the compounds can be used as developing agents. Those skilled in the art will recognize that the detectable portion can be linked to the provided compound via suitable substituents. As used herein, the term "suitable substituent" refers to a portion capable of covalently linking to the detectable portion. Such portions are well known to those skilled in the art and include the group containing, for example, carboxylic acid ester moieties, amino moieties, thiol moieties, or hydroxyl moieties, etc. It should be understood that such portions can be directly linked or linked to the provided compound via tethering groups, such as divalent saturated or unsaturated hydrocarbon chains. In some embodiments, such portions can be linked via click chemistry. In some embodiments, the portions can be linked via a 1,3-cycloaddition reaction of an azide compound with an alkyne, optionally in the presence of a copper catalyst. The use of click chemistry methods is known in the field and includes those described by Rostovtsev et al., Angew. Chem. Int. Ed. 2002, 41, 2596-99, and Sun et al., Bioconjugate Chem. 2006, 17, 52-57.

[0051] As used herein, the terms "detectable portion" and "marking" are used interchangeably and refer to any portion that can be detected, such as primary and secondary markings. Primary markings include radioactive isotopes (e.g., tritium, etc.). 32 P, 33 P, 35 S or 14 C) Quality tags and fluorescent markers are reporter groups that generate signals and can be detected without further modification. Detectable components also include luminescent and phosphorescent groups.

[0052] As used herein, the term "secondary label" refers to the portion that requires the presence of a second intermediate to generate a detectable signal, such as biotin and various protein antigens. In the case of biotin, secondary intermediates may include streptavidin-enzyme conjugates. In the case of antigen labels, secondary intermediates may include antibody-enzyme conjugates. Some fluorescent groups act as secondary labels because they transfer energy to another group during non-radiofluorescence resonance energy transfer (FRET), and the second group generates a detection signal.

[0053] As used herein, the terms “fluorescent label,” “fluorescent dye,” and “fluorophore” refer to the portion that absorbs light energy at a specified excitation wavelength and emits light energy at a different wavelength. Examples of fluorescent labels include (but are not limited to): Alexa Fluor dyes (Alexa Fluor 350, Alexa Fluor 488, Alexa Fluor 532, Alexa Fluor 546, Alexa Fluor 568, Alexa Fluor 594, Alexa Fluor 633, Alexa Fluor 660, and Alexa Fluor 680), AMCA, AMCA-S, BODIPY dyes (BODIPY FL, BODIPY R6G, BODIPY TMR, BODIPY TR, BODIPY 530 / 550, BODIPY 558 / 568, BODIPY 564 / 570, BODIPY 576 / 589, BODIPY 581 / 591, BODIPY 630 / 650, BODIPY 650 / 665), and carboxyrhodamine. 6G, Carboxy-X-Rhodamine (ROX), Cascade Blue, Cascade Yellow, Coumarin 343, Anthocyanin Dyes (Cy3, Cy5, Cy3.5, Cy5.5), Dansyl Acetate, Dapoxyl, DialkylaminoCoumarin, 4',5'-Dichloro-2',7'-Dimethoxyfluorescein, DM-NERF, Eosin, Erythrosin, Fluorescein, FAM, Hydroxycoumarin, IRDye (IRD40, IRD700, IRD800), JOE, Lissamine, Rhodamine B, Marina Blue, Methoxycoumarin, Naphthofluorescein, Oregon Green 488, Oregon Green 500, Oregon Green 514, Pacific Blue, PyMPO, Pyrene, Rhodamine B, Rhodamine 6G, Rhodamine Green, Rhodamine Red, Rhodol Green, 2',4',5',7'-Tetra-bromosulfone-fluorescein, Tetramethyl-Rhodamine (TMR), CarboxytetramethylRhodamine (TAMRA), Texas Red, Texas Red-X.

[0054] As used herein, the term "quality tag" refers to any fraction that can be uniquely detected based on its quality using mass spectrometry (MS) detection techniques. Examples of quality tags include electrophoretic release tags such as N-[3-[4'-[(p-methoxytetrafluorobenzyl)oxy]phenyl]-3-methyldihydroxyacetone]isopiperidinecarboxylic acid, 4'-[2,3,5,6-tetrafluoro-4-(pentafluorophenoxy)]methylacetophenone, and derivatives thereof. The synthesis and utility of these quality tags are described in U.S. Patents 4,650,750, 4,709,016, 5,360,8191, 5,516,931, 5,602,273, 5,604,104, 5,610,020, and 5,650,270. Other examples of quality labels include (but are not limited to) nucleotides, dideoxynucleotides, oligonucleotides of varying lengths and base compositions, oligopeptides, oligosaccharides, and other synthetic polymers of varying lengths and monomer compositions. A variety of neutral and charged organic molecules (biomolecules or synthetic compounds) with appropriate mass ranges (100-2000 Daltons) can also be used as quality labels.

[0055] As used herein, the terms “measurable affinity” and “measurable inhibition” mean a measurable change in TYK2 protein kinase activity between a sample containing the compound or a combination thereof of the present invention and TYK2 protein kinase and an equivalent sample containing TYK2 protein kinase but without the compound or the combination thereof.

[0056] 3. Description of exemplary embodiments:

[0057] As described above, in some embodiments, the present invention provides a compound of formula I:

[0058]

[0059] Or its pharmaceutically acceptable salt, wherein:

[0060] R 3 -C(O)NH2; -C(O)NHR 3A ;-C(O)N(R 3A )2; or a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 independently selected heteroatoms chosen from nitrogen, oxygen, and sulfur, wherein the ring is connected by m R 3B replace;

[0061] R 5 For hydrogen or -L 1 -R 5A ;

[0062] R 6 For hydrogen, R A Or R B ;

[0063] Or R 5 and R 6 It is bonded together with the inserted atoms to form a 4- to 7-membered partially unsaturated or heteroaryl ring having 0 to 3 independent heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the ring is R 5A and n R C replace;

[0064] R 7 Hydrogen, halogen, -NH2, -NHR 7A or -NHC(O)R 7A ;

[0065] Or R 6 and R 7 It is bonded together with the inserted atoms to form a 4- to 7-membered partially unsaturated or heteroaryl ring having 0 to 3 independent heteroatoms selected from nitrogen, oxygen, and sulfur; wherein the ring is connected to p R C replace;

[0066] L 1 For covalent bonds or C 1-4 Divalent saturated or unsaturated, straight or branched hydrocarbon chains, wherein one or both methylene units of the chain are optionally and independently substituted with: -C(R 5B )2-、-CH(R 5B )-, -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2-;

[0067] R 3A and R 7A Each independently as R B And each through q R C replace;

[0068] R 5A and R in each case 5B Each independently as R A Or R B And each through r R C replace;

[0069] R AIndependently in each case, it is oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2 or -N(R)S(O)2R;

[0070] R B C is independent in each case. 1-6 Aliphatic group; phenyl; 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 3- to 7-membered saturated or partially unsaturated carbon ring; 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or 7- to 12-membered saturated or partially unsaturated bicyclic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

[0071] R C In each case, the group is independently oxo, halogenated, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2 or -N(R)S(O)2R or optionally substituted, selected from the group: C 1-6 Aliphatic group; phenyl group; a 3- to 7-membered saturated or partially unsaturated heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur; and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0072] Each R is independently hydrogen or optionally substituted with a group selected from the following: C 1-6 Aliphatic group; phenyl; a 3- to 7-membered saturated or partially unsaturated heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:

[0073] Two R groups on the same nitrogen atom are bonded together with their intermediate atom to form a 4- to 7-membered saturated, partially unsaturated or heteroaryl ring having 0-3 independent heteroatoms selected from nitrogen, oxygen or sulfur, in addition to nitrogen.

[0074] Each hydrogen atom bound to carbon can optionally and independently undergo deuteration substitution; and

[0075] m, n, p, q, and r are independently 0, 1, 2, 3, or 4 in each case.

[0076] In some embodiments, the present invention provides a compound of formula I:

[0077]

[0078] Or its pharmaceutically acceptable salt, wherein:

[0079] R 3 -C(O)NH2; -C(O)NHR 3A ;-C(O)N(R 3A )2; -C(O)OR; -C(O)NOR; or a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring is via m R 3B replace;

[0080] R 5 For hydrogen or -L 1 -R 5A ;

[0081] R 6 For hydrogen, R A Or R B ;

[0082] Or R 5 and R 6 It is bonded together with the inserted atoms to form a 4- to 7-membered partially unsaturated or heteroaryl ring having 0 to 3 independent heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the ring is R 5A and n R C replace;

[0083] R 7 Hydrogen, halogen, -NH2, -NHR 7A or -NHC(O)R 7A ;

[0084] Or R 6 and R 7 It is bonded together with the inserted atoms to form a 4- to 7-membered partially unsaturated or heteroaryl ring having 0 to 3 independent heteroatoms selected from nitrogen, oxygen, and sulfur; wherein the ring is connected to p R C replace;

[0085] L 1 For covalent bonds or C 1-4 Divalent saturated or unsaturated, straight or branched hydrocarbon chains, wherein one or both methylene units of the chain are optionally and independently substituted with: -C(R 5B )2-、-CH(R 5B )-, -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2-;

[0086] R 3A and R 7A Each independently as R B And each through q R C replace;

[0087] R 5A and R in each case 5B Each independently as R A Or R B And each through r R C replace;

[0088] R A Independently in each case, it is oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2 or -N(R)S(O)2R;

[0089] R B C is independent in each case. 1-6 Aliphatic group; phenyl; 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 3- to 7-membered saturated or partially unsaturated carbon ring; 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or 7- to 12-membered saturated or partially unsaturated bicyclic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

[0090] R CIn each case, it is independently an oxo, halogenated, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2 or -N(R)S(O)2R, or optionally substituted with a group selected from the following: C 1-6 Aliphatic group; phenyl group; a 3- to 7-membered saturated or partially unsaturated heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur; and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0091] Each R is independently hydrogen or optionally substituted with a group selected from the following: C 1-6 Aliphatic group; phenyl; a 3- to 7-membered saturated or partially unsaturated heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:

[0092] Two R groups on the same nitrogen atom are attached together with their inserted atoms to form a 4 to 7 saturated, partially unsaturated or heteroaryl ring having 0 to 3 independent heteroatoms selected from nitrogen, oxygen and sulfur, in addition to nitrogen.

[0093] Each hydrogen atom bound to carbon can optionally and independently undergo deuteration substitution; and

[0094] m, n, p, q, and r are independently 0, 1, 2, 3, or 4 in each case.

[0095] In some embodiments, the present invention provides a compound of formula I':

[0096]

[0097] Or its pharmaceutically acceptable salt, wherein:

[0098] R 3 -C(O)NH2; -C(O)NHR 3A ;-C(O)N(R 3A )2; -C(O)OR; -C(O)NHOR; or a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring is via m R 3B replace;

[0099] R 5 For hydrogen or -L1 -R 5A ;

[0100] R 6 For hydrogen, R A Or R B ;

[0101] Or R 5 and R 6 It is bonded together with the inserted atoms to form a 4- to 7-membered partially unsaturated or heteroaryl ring having 0 to 3 independent heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the ring is R 5A and n R C replace;

[0102] R 7 Hydrogen, halogen, -NH2, -NHR 7A or -NHC(O)R 7A ;

[0103] Or R 6 and R 7 It is bonded together with the inserted atoms to form a 4- to 7-membered partially unsaturated or heteroaryl ring having 0 to 3 independent heteroatoms selected from nitrogen, oxygen, and sulfur; wherein the ring is connected to p R C replace;

[0104] L 1 For covalent bonds or C 1-4 Divalent saturated or unsaturated, straight or branched hydrocarbon chains, wherein one or both methylene units of the chain are optionally and independently substituted with: -C(R 5B )2-、-CH(R 5B )-, -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2-;

[0105] R 3A and R 7A Each independently as R B And each through q R C Substitution, in which two R on the same carbon C The substituents are optionally linked together to form a 3- to 6-membered saturated or partially unsaturated spirocyclic fused heterocycle having 1 to 4 independent heteroatoms selected from nitrogen, oxygen, and sulfur, or wherein two R atoms on adjacent carbons are... C The substituents are optionally linked together to form a 3- to 6-membered saturated or partially unsaturated fused heterocycle having 1 to 4 independent heteroatoms selected from nitrogen, oxygen and sulfur;

[0106] R 5Aand R in each case 5B Each independently as R A Or R B And each through r R C replace;

[0107] R A Independently in each case, it is oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2 or -N(R)S(O)2R;

[0108] R B C is independent in each case. 1-6 Aliphatic group; phenyl; 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 3- to 7-membered saturated or partially unsaturated carbon ring; 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or 7- to 12-membered saturated or partially unsaturated bicyclic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

[0109] R C In each case, it is independently an oxo, halogenated, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2 or -N(R)S(O)2R, or optionally substituted with a group selected from the following: C 1-6Aliphatic group; phenyl; a 3- to 7-membered saturated or partially unsaturated heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur; and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein two optional substituents on the same carbon are optionally linked together to form a 3- to 6-membered saturated or partially unsaturated spirocyclic fused heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or wherein two optional substituents on adjacent carbons are optionally linked together to form a 3- to 6-membered saturated or partially unsaturated fused heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0110] Each R is independently hydrogen or optionally substituted with a group selected from the following: C 1-6 Aliphatic group; phenyl; a 3- to 7-membered saturated or partially unsaturated heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:

[0111] Two R groups on the same nitrogen atom are attached together with their inserted atoms to form a 4- to 7-membered saturated, partially unsaturated or heteroaryl ring having 0-3 independent heteroatoms selected from nitrogen, oxygen or sulfur, in addition to nitrogen.

[0112] Each hydrogen atom bound to carbon can optionally and independently undergo deuteration substitution; and

[0113] m, n, p, q, and r are independently 0, 1, 2, 3, or 4 in each case.

[0114] As broadly defined above, R 3 -C(O)NH2; -C(O)NHR 3A ;-C(O)N(R 3A )2; -C(O)OR; -C(O)NOR; -C(O)NHOR; or a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring is via m R 3B Replacement. In some embodiments, R 3 -C(O)NH2; -C(O)NHR 3A ;-C(O)N(R 3A )2; or a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 independently selected heteroatoms chosen from nitrogen, oxygen, and sulfur, wherein the ring is connected by m R 3B Replacement. In some embodiments, R 3 It is -C(O)NH2 or -C(O)NHR 3A In some embodiments, R 3 It is -C(O)NOR. In some embodiments, R 3 It is -C(O)OR.

[0115] In some embodiments, R 3 -C(O)N(R) 3A )2. In some embodiments, R 3 For -C(O)NHOR. In some embodiments, R 3 It is a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 independent heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the ring is connected by m R 3B replace.

[0116] In some embodiments, R 3 It is -C(O)NH2. In some embodiments, R 3 -C(O)NHR 3A In some embodiments, R 3 It is -C(O)NHOR or -C(O)OR. In some embodiments, R 3 -C(O)NH2, -C(O)NHR 3A -C(O)NHOR or -C(O)OR. In some embodiments, R 3 -C(O)NH2, -C(O)NHR 3A Or -C(O)NHOR.

[0117] In some embodiments, R 3 Selected from the following:

[0118]

[0119] and .

[0120] In some embodiments, R 3 Selected from the following:

[0121] and .

[0122] In some embodiments, R 3 Selected from the following:

[0123]

[0124] and .

[0125] In some embodiments, R 3 Selected from the following:

[0126] In some embodiments, R 3 Selected from those described in Table 1 below.

[0127] As broadly defined above, R 5 For hydrogen or -L 1 -R 5A ; or R 5 and R 6 It is bonded together with the inserted atoms to form a 4- to 7-membered partially unsaturated or heteroaryl ring having 0 to 3 independent heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the ring is R 5A and n R C Replacement. In some embodiments, R 5 It is hydrogen. In some embodiments, R is... 5 -L 1 -R 5A .

[0128] In some embodiments, R 5 and R 6 It is bonded together with the inserted atoms to form a 4- to 7-membered partially unsaturated or heteroaryl ring having 0 to 3 independent heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the ring is R 5A and n R C Replacement. In some embodiments, R 5 For hydrogen or -L 1 -R 5A .

[0129] In some embodiments, R 5 Selected from the following:

[0130]

[0131]

[0132]

[0133]

[0134]

[0135]

[0136]

[0137]

[0138]

[0139]

[0140] and

[0141] .

[0142] In some embodiments, R 5 Selected from the following: and .

[0143] In some embodiments, R 5 Selected from those described in Table 1 below.

[0144] As broadly defined above, R 6 For hydrogen, R A Or R B , or R 5 and R 6 It is bonded together with the inserted atoms to form a 4- to 7-membered partially unsaturated or heteroaryl ring having 0 to 3 independent heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the ring is R 5A and n R C Replacement. In some embodiments, R 6 It is hydrogen.

[0145] In some embodiments, R 6 For R A In some embodiments, R 6 For R B In some embodiments, R 5 and R 6 It is bonded together with the inserted atoms to form a 4- to 7-membered partially unsaturated or heteroaryl ring having 0 to 3 independent heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the ring is R 5A and n R C Replacement. In some embodiments, R 6 For hydrogen, R A Or R B .

[0146] In some embodiments, R 6 It is a methyl group.

[0147] In some embodiments, R 6 Selected from those described in Table 1 below.

[0148] As broadly defined above, R 7 Hydrogen, halogen, -NH2, -NHR 7A or -NHC(O)R7A ; or R 6 and R 7 It is bonded together with the inserted atoms to form a 4- to 7-membered partially unsaturated or heteroaryl ring having 0 to 3 independent heteroatoms selected from nitrogen, oxygen, and sulfur; wherein the ring is connected to p R C Replacement. In some embodiments, R 7 -NH2 or -NHR 7A In some embodiments, R 7 For -NHMe. In some embodiments, R 7 It is -NHCD3.

[0149] In some embodiments, R 7 It is hydrogen. In some embodiments, R is... 7 It is a halogen. In some embodiments, R 7 For -NH2. In some embodiments, R 7 -NHR 7A In some embodiments, R 7 -NHC(O)R 7A In some embodiments, R 6 and R 7 It is bonded together with the inserted atoms to form a 4- to 7-membered partially unsaturated or heteroaryl ring having 0 to 3 independent heteroatoms selected from nitrogen, oxygen, and sulfur; wherein the ring is connected to p R C replace.

[0150] In some embodiments, R 7 Selected from the following:

[0151] and .

[0152] In some embodiments, R 7 Selected from those described in Table 1 below.

[0153] As broadly defined above, L 1 For covalent bonds or C 1-4 Divalent saturated or unsaturated, straight or branched hydrocarbon chains, wherein one or both methylene units of the chain are optionally and independently substituted with: -C(R 5B )2-、-CH(R 5B -, -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2-. In some embodiments, L 1 For -N(R)-. In some embodiments, L 1It is -N(H)-.

[0154] In some embodiments, L 1 It is a covalent bond. In some embodiments, L 1 C 1-4 Divalent saturated or unsaturated, straight or branched hydrocarbon chains, wherein one or both methylene units of the chain are optionally and independently substituted with: -C(R 5B )2-、-CH(R 5B )-, -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-.

[0155] In some embodiments, L 1 It is -N(R)- or covalent. In some embodiments, L 1 It is -N(H)- or covalent.

[0156] In some embodiments, L 1 Selected from those described in Table 1 below.

[0157] As broadly defined above, R 3A For R B And after q R C Substitution, in which two R on the same carbon C The substituents are optionally linked together to form a 3- to 6-membered saturated or partially unsaturated spirocyclic fused heterocycle having 1 to 4 independent heteroatoms selected from nitrogen, oxygen, and sulfur, or wherein two R atoms on adjacent carbons are... C The substituents are optionally linked together to form a 3- to 6-membered saturated or partially unsaturated fused heterocycle having 1 to 4 independent heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, R 3A For q R C Replacement C 1-6 Aliphatic group. In some embodiments, R 3A For q R C Replacement of 3- to 7-membered saturated or partially unsaturated carbon rings. In some embodiments, R 3A It is cyclopropyl or cyclobutyl; each via q R C Replacement. In some embodiments, R 3A For q R C Substituted cyclopropyl. In some embodiments, R 3A For q R C Substituted cyclobutyl. In some embodiments, R 3A For R B And after q R CReplacement, provided that R 3A It is not a phenyl group.

[0158] In some embodiments, R 3A For R B And after q R C Substitution, in which two R on the same carbon C The substituents are optionally linked together to form a 3- to 6-membered saturated or partially unsaturated spirocyclic fused heterocycle having 1 to 4 independent heteroatoms selected from nitrogen, oxygen, and sulfur, or wherein two R atoms on adjacent carbons are... C The substituents are optionally linked together to form a 3- to 6-membered saturated or partially unsaturated fused heterocycle having 1 to 4 independent heteroatoms selected from nitrogen, oxygen and sulfur.

[0159] In some embodiments, R 3A For q R C Replacement C 1-6 Aliphatic base or via q R C Replacement of 3 to 7 saturated or partially unsaturated carbon rings.

[0160] In some embodiments, R 3A Selected from the following:

[0161]

[0162] and .

[0163] In some embodiments, R 3A Selected from those described in Table 1 below.

[0164] As broadly defined above, R 5A For R A Or R B And through r R C Replacement. In some embodiments, R 5A It is a phenyl group or a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 nitrogen, oxygen, and sulfur atoms; and via r R... C replace.

[0165] In some embodiments, R 5A For r R C Replacement R A In some embodiments, R 5A For r R C Replacement R B .

[0166] In some embodiments, R 5A Selected from the following:

[0167]

[0168] and .

[0169] In some embodiments, R 5A Selected from those described in Table 1 below.

[0170] As broadly defined above, R 7A For R B And after q R C Replacement. In some embodiments, R 7A For q R C Replacement C 1-6 Aliphatic group. In some embodiments, R 7A methyl. In some embodiments, R 7A For R B And after q R C Replacement, provided that R 7A Not an aromatic group. In some embodiments, R 7A For R B And after q R C Replacement, provided that R 7A It is not a phenyl group.

[0171] In some embodiments, R 7A For R B And after q R C replace.

[0172] In some embodiments, R 7A It is hydrogen. In some embodiments, R is... 7A It is a methyl group.

[0173] In some embodiments, R 7A Selected from the following:

[0174] and .

[0175] In some embodiments, R 7A Selected from those described in Table 1 below.

[0176] As broadly defined above, R AIndependently, in each case, it is oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2 or -N(R)S(O)2R.

[0177] In some embodiments, R A For oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R) OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2 or -N(R)S(O)2R.

[0178] In some embodiments, R A Selected from those described in Table 1 below.

[0179] As broadly defined above, R B C is independent in each case. 1-6 Aliphatic group; phenyl; 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; 3- to 7-membered saturated or partially unsaturated carbon ring; 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or 7- to 12-membered saturated or partially unsaturated bicyclic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0180] In some embodiments, R B C 1-6 Aliphatic group; phenyl; 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; 3- to 7-membered saturated or partially unsaturated carbon ring; 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or 7- to 12-membered saturated or partially unsaturated bicyclic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0181] In some embodiments, R B It is a methyl group.

[0182] In some embodiments, R B Selected from those described in Table 1 below.

[0183] As broadly defined above, R C In each case, it is independently an oxo, halogenated, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2 or -N(R)S(O)2R, or optionally substituted with a group selected from the following: C 1-6 Aliphatic group; phenyl; a 3- to 7-membered saturated or partially unsaturated heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur; and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein two optional substituents on the same carbon are optionally linked together to form a 3- to 6-membered saturated or partially unsaturated spirocyclic fused heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or wherein two optional substituents on adjacent carbons are optionally linked together to form a 3- to 6-membered saturated or partially unsaturated fused heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0184] In some embodiments, R C It is an oxo, halogenated, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2 or -N(R)S(O)2R, or optionally substituted groups selected from the following: C 1-6Aliphatic group; phenyl; a 3- to 7-membered saturated or partially unsaturated heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur; and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein two optional substituents on the same carbon are optionally linked together to form a 3- to 6-membered saturated or partially unsaturated spirocyclic fused heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or wherein two optional substituents on adjacent carbons are optionally linked together to form a 3- to 6-membered saturated or partially unsaturated fused heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0185] In some embodiments, R C For oxidation. In some embodiments, R... C It is methyl, ethyl, isopropyl, or n-butyl. In some embodiments, R C It is fluorine. In some embodiments, R C It is chlorine. In some embodiments, R C It is a phenyl group.

[0186] In some embodiments, R C Selected from the following:

[0187]

[0188]

[0189]

[0190]

[0191] and .

[0192] In some embodiments, R C Selected from those described in Table 1 below.

[0193] As generally defined above, each R is independently hydrogen, or optionally substituted with a group selected from the following: C 1-6 Aliphatic group; phenyl; a 3- to 7-membered saturated or partially unsaturated heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur; and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or: two R groups on the same nitrogen atom and their insertion atoms attached together to form a 4- to 7-membered saturated, partially unsaturated or heteroaryl ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, excluding nitrogen.

[0194] In some embodiments, R is hydrogen. In some embodiments, R is a optionally substituted group selected from the group consisting of: C 1-6Aliphatic group; phenyl; a 3- to 7-membered saturated or partially unsaturated heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R groups on the same nitrogen atom are attached together with their intercalation atoms to form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, excluding nitrogen.

[0195] In some embodiments, R is selected from those depicted in Table 1 below.

[0196] As broadly defined above, each hydrogen atom bound to carbon can be optionally and independently replaced by deuterium.

[0197] In some embodiments, hydrogen bound to carbon is replaced by deuterium.

[0198] As generally defined above, m is 0, 1, 2, 3, or 4. In some embodiments, m is 0. In some embodiments, m is 1, 2, 3, or 4. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.

[0199] In some embodiments, m is 1, 2, or 3. In some embodiments, m is 1 or 2. In some embodiments, m is 1 or 3. In some embodiments, m is 2 or 3. In some embodiments, m is 2 or 4. In some embodiments, m is 1, 2, or 4. In some embodiments, m is 1, 3, or 4. In some embodiments, m is 2, 3, or 4.

[0200] In some embodiments, m is selected from those described in Table 1 below.

[0201] As generally defined above, n is 0, 1, 2, 3, or 4. In some embodiments, n is 0. In some embodiments, n is 1, 2, 3, or 4. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0202] In some embodiments, n is 1, 2, or 3. In some embodiments, n is 1 or 2. In some embodiments, n is 1 or 3. In some embodiments, n is 2 or 3. In some embodiments, n is 2 or 4. In some embodiments, n is 1, 2, or 4. In some embodiments, n is 1, 3, or 4. In some embodiments, n is 2, 3, or 4.

[0203] In some embodiments, n is selected from those described in Table 1 below.

[0204] As generally defined above, p is 0, 1, 2, 3, or 4. In some embodiments, p is 0. In some embodiments, p is 1, 2, 3, or 4. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4.

[0205] In some embodiments, p is 1, 2, or 3. In some embodiments, p is 1 or 2. In some embodiments, p is 1 or 3. In some embodiments, p is 2 or 3. In some embodiments, p is 2 or 4. In some embodiments, p is 1, 2, or 4. In some embodiments, p is 1, 3, or 4. In some embodiments, p is 2, 3, or 4.

[0206] In some embodiments, p is selected from those described in Table 1 below.

[0207] As generally defined above, q is 0, 1, 2, 3, or 4. In some embodiments, q is 0. In some embodiments, q is 1, 2, 3, or 4. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3. In some embodiments, q is 4.

[0208] In some embodiments, q is 1, 2, or 3. In some embodiments, q is 1 or 2. In some embodiments, q is 1 or 3. In some embodiments, q is 2 or 3. In some embodiments, q is 2 or 4. In some embodiments, q is 1, 2, or 4. In some embodiments, q is 1, 3, or 4. In some embodiments, q is 2, 3, or 4.

[0209] In some embodiments, q is selected from those described in Table 1 below.

[0210] As generally defined above, r is 0, 1, 2, 3, or 4. In some embodiments, r is 0. In some embodiments, r is 1, 2, 3, or 4. In some embodiments, r is 1. In some embodiments, r is 2. In some embodiments, r is 3. In some embodiments, r is 4.

[0211] In some embodiments, r is 1, 2, or 3. In some embodiments, r is 1 or 2. In some embodiments, r is 1 or 3. In some embodiments, r is 2 or 3. In some embodiments, r is 2 or 4. In some embodiments, r is 1, 2, or 4. In some embodiments, r is 1, 3, or 4. In some embodiments, r is 2, 3, or 4.

[0212] In some embodiments, r is selected from those depicted in Table 1 below.

[0213] In some embodiments, the present invention provides a compound of formula I or I', wherein R 3It is -C(O)NH2 or -C(O)NHR 3A This leads to the formation of compounds of formula II or III:

[0214]

[0215] Or a pharmaceutically acceptable salt thereof, wherein R 3A R 5 R 6 and R 7 Each individually and in combination as defined above and described in the embodiments herein.

[0216] In some embodiments, the present invention provides a compound of formula I or I', wherein L 1 The form is -N(R)-, thus forming compound IV:

[0217]

[0218] Or a pharmaceutically acceptable salt thereof, wherein R 3 R 5A R 6 and R 7 Each individually and in combination as defined above and described in the embodiments herein.

[0219] In some embodiments, the present invention provides a compound of formula II or III, wherein L 1 The form is -N(R)-, thus forming compounds of formula V or VI respectively:

[0220]

[0221] Or a pharmaceutically acceptable salt thereof, wherein R, R 3A R 5A R 6 and R 7 Each individually and in combination as defined above and described in the embodiments herein.

[0222] In some embodiments, the present invention provides a compound of formula IV, wherein R 5A It is either phenyl or pyridin-3-yl, each via r R C Substitution, thereby forming compounds of formula VII or VIII respectively:

[0223]

[0224] Or a pharmaceutically acceptable salt thereof, wherein r, R, R C R 3 R 6 and R 7 Each individually and in combination as defined above and described in the embodiments herein.

[0225] In some embodiments, the present invention provides a compound of formula VIII, wherein R 5A On an R C Oxytokinesis, thus forming compound IX:

[0226]

[0227] Or a pharmaceutically acceptable salt thereof, wherein r, R, R C R 3 R 6 and R 7 Each individually and in combination as defined above and described in the embodiments herein.

[0228] In some embodiments, the present invention provides a compound of formula IV, V, VI, VII, VIII or IX, wherein R is hydrogen, thereby forming compounds of formula X, XI, XII, XIII, XIV, XV respectively:

[0229]

[0230] Or a pharmaceutically acceptable salt thereof, wherein r, R, R C R 3 R 3A R 5A R 6 and R 7 Each individually and in combination as defined above and described in the embodiments herein.

[0231] In some embodiments, the present invention provides a compound of formula I, I', II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV, wherein R 6 The presence of hydrogen forms compounds of formulas Ia, II-a, III-a, IV-a, Va, VI-a, VII-a, VIII-a, IX-a, Xa, XI-a, XII-a, XIII-a, XIV-a, or XV-a, respectively.

[0232]

[0233] Or a pharmaceutically acceptable salt thereof, wherein r, R, R C R 3 R 3A R 5 R 5A and R 7Each individually and in combination as defined above and described in the embodiments herein.

[0234] In some embodiments, the present invention provides a compound of formula I, I', II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, Ia, II-a, III-a, IV-a, Va, VI-a, VII-a, VIII-a, IX-a, Xa, XI-a, XII-a, XIII-a, XIV-a, or XV-a, wherein R 7 -NH2 or -NHR 7A .

[0235] In some embodiments, the present invention provides a compound of formula I, I', II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, Ia, II-a, III-a, IV-a, Va, VI-a, VII-a, VIII-a, IX-a, Xa, XI-a, XII-a, XIII-a, XIV-a, or XV-a, wherein R 7 -NHR 7A This leads to the formation of compounds with the formulas Ib, II-b, III-b, IV-b, Vb, VI-b, VII-b, VIII-b, IX-b, Xb, XI-b, XII-b, XIII-b, XIV-b, XV-b, Ic, II-c, III-c, IV-c, Vc, VI-c, VII-c, VIII-c, IX-c, Xc, XI-c, XII-c, XIII-c, XIV-c, or XV-c, respectively.

[0236]

[0237]

[0238]

[0239] Or a pharmaceutically acceptable salt thereof, wherein r, R, R C R 3 R 3A R 5 R 5A R 6 and R 7A Each individually and in combination as defined above and described in the embodiments herein.

[0240] In some embodiments, the present invention provides a compound of formula Ib, II-b, III-b, IV-b, Vb, VI-b, VII-b, VIII-b, IX-b, Xb, XI-b, XII-b, XIII-b, XIV-b, XV-b, Ic, II-c, III-c, IV-c, Vc, VI-c, VII-c, VIII-c, IX-c, Xc, XI-c, XII-c, XIII-c, XIV-c, or XV-c, wherein R 7A For q R C Replacement R B , where R 7A Not phenyl. In some embodiments, the present invention provides a compound of formula Ib, II-b, III-b, IV-b, Vb, VI-b, VII-b, VIII-b, IX-b, Xb, XI-b, XII-b, XIII-b, XIV-b, XV-b, Ic, II-c, III-c, IV-c, Vc, VI-c, VII-c, VIII-c, IX-c, Xc, XI-c, XII-c, XIII-c, XIV-c or XV-c, wherein R 7A Methyl. In some embodiments, the present invention provides a compound of formula Ib, II-b, III-b, IV-b, Vb, VI-b, VII-b, VIII-b, IX-b, Xb, XI-b, XII-b, XIII-b, XIV-b, XV-b, Ic, II-c, III-c, IV-c, Vc, VI-c, VII-c, VIII-c, IX-c, Xc, XI-c, XII-c, XIII-c, XIV-c or XV-c, wherein R 7A It is -CD3.

[0241] In some embodiments, the present invention provides a compound of formula Ib, III-b, IV-b, VI-b, VII-b, VIII-b, IX-b, Xb, XII-b, XIII-b, XIV-b, XV-b, Ic, III-c, IV-c, VI-c, VII-c, VIII-c, IX-c, Xc, XII-c, XIII-c, XIV-c, or XV-c, wherein R 3A For R B And after q R C Replacement, provided that R 3A It is not a phenyl group.

[0242] In some embodiments, the present invention provides a compound of formula Ib, III-b, IV-b, VI-b, VII-b, VIII-b, IX-b, Xb, XII-b, XIII-b, XIV-b, XV-b, Ic, III-c, IV-c, VI-c, VII-c, VIII-c, IX-c, Xc, XII-c, XIII-c, XIV-c, or XV-c, wherein R 3A and R 7A Each is R B And after q R C Replacement, provided that R 3A and R 7A None of them are phenyl.

[0243] In some embodiments, the present invention provides a compound of formula IV, wherein R 5A For r R C The substituted pyridin-2-yl group thus forms compounds of formula XVI:

[0244]

[0245] Or a pharmaceutically acceptable salt thereof, wherein r, R, R C R 3 R 6 and R 7 Each individually and in combination as defined above and described in the embodiments herein.

[0246] In some embodiments, the present invention provides a compound of formula I or I', wherein R 5 -L 1 -R 5A L 1 It is a covalent bond, and R 5A It is an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the present invention provides a compound of formula I or I', wherein R 5 -L 1 -R 5A L 1 It is a covalent bond, and R 5A It is an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0247] In some embodiments, the present invention provides a compound of formula I or I', wherein R 5 -L 1 -R 5A L 1 It is a covalent bond, and R 5AIt is indole-1-yl, indole-3-yl, 4-azaindole-1-yl, 7-azaindole-3-yl, or 7-azaindazole-3-yl, each R 5A After r R C Substitution, thereby providing compounds of formula XVII, XVIII, XIX, XX or XXI respectively:

[0248]

[0249] Or a pharmaceutically acceptable salt thereof, wherein r, R C R 3 R 6 and R 7 Each individually and in combination as defined above and described in the embodiments herein.

[0250] In some embodiments, the present invention provides a compound of formula XVII, XVIII, XIX, XX, or XXI, wherein R 6 For hydrogen, compounds of formula XVII-a, XVIII-a, XIX-a, XX-a, or XXI-a are provided respectively:

[0251]

[0252] Or a pharmaceutically acceptable salt thereof, wherein r, R C R 3 and R 7 Each individually and in combination as defined above and described in the embodiments herein.

[0253] In some embodiments, the present invention provides a compound of formula XVII-a, XVIII-a, XIX-a, XX-a, or XXI-a, wherein R 7 -NHR 7A This provides compounds of formula XVII-b, XVIII-b, XIX-b, XX-b, or XXI-b, respectively:

[0254]

[0255] Or a pharmaceutically acceptable salt thereof, wherein r, R C R 3 and R 7A Each individually and in combination as defined above and described in the embodiments herein.

[0256] In some embodiments, the present invention provides a compound of formula XVII-b, XVIII-b, XIX-b, XX-b, or XXI-b, wherein R 3 -C(O)NHR 3AThis provides compounds of formula XVII-c, XVIII-c, XIX-c, XX-c, or XXI-c, respectively:

[0257]

[0258] Or a pharmaceutically acceptable salt thereof, wherein r, R C R 3 and R 7A Each individually and in combination as defined above and described in the embodiments herein.

[0259] Exemplary compounds of the present invention are described in Table 1 below.

[0260] Table 1. Selected Compounds

[0261]

[0262] In some embodiments, the method employs compounds or pharmaceutically acceptable salts thereof as set forth in Table 1 above. In some embodiments, the present invention provides compounds or pharmaceutically acceptable salts thereof as set forth in Table 1 above. In some embodiments, the present invention provides a pharmaceutical composition comprising compounds or pharmaceutically acceptable salts thereof as set forth in Table 1 above, and a pharmaceutically acceptable carrier, excipient, or diluent.

[0263] In some embodiments, the present invention provides compounds of formula I or I' as described above, wherein the compounds are designated as "A" as illustrated in Table 2. In some embodiments, the present invention provides compounds of formula I or I' as described above, wherein the compounds are designated as "B" as illustrated in Table 2. In some embodiments, the present invention provides compounds of formula I or I' as described above, wherein the compounds are designated as "C" as illustrated in Table 2. In some embodiments, the present invention provides compounds of formula I or I' as described above, wherein the compounds are designated as "D" as illustrated in Table 2. In some embodiments, the present invention provides compounds of formula I or I' as described above, wherein the compounds are designated as "A" or "B" as illustrated in Table 2. In some embodiments, the present invention provides compounds of formula I or I' as described above, wherein the compounds are designated as "A", "B", "C", or "D" as illustrated in Table 2.

[0264] In some embodiments, the present invention provides a compound of formula I or I' as defined above, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula I or I' as defined above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or mediator, which is used as a medicament.

[0265] Without being bound by any particular theory, it is believed that the proximity of the inhibitory compound or its side portion to the associated water promotes the substitution or destruction of the water by the inhibitory compound or its side portion. In some embodiments, the water molecules substituted or destroyed by the inhibitory compound or its side portion are unstable water molecules.

[0266] In some embodiments, the method employs a complex comprising TYK2 and an inhibitor, wherein at least one unstable water element of TYK2 is replaced or destroyed by the inhibitor. In some embodiments, at least two selected unstable water elements are replaced or destroyed by the inhibitor.

[0267] 4. A general method for producing the compounds of the present invention.

[0268] The compounds of the present invention can generally be prepared or isolated by methods known to those skilled in the art for the synthesis and / or semi-synthesis of similar compounds, and by methods described in detail in the examples herein.

[0269] 5. Use, preparation and distribution

[0270] Pharmaceutically acceptable compositions

[0271] According to another embodiment, the present invention provides a composition comprising a compound of the present invention or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier, adjuvant, or mediator. The amount of the compound in the composition of the present invention is such that it can effectively and measurably inhibit TYK2 protein kinase or its mutants in a biological sample or a patient. In some embodiments, the amount of the compound in the composition of the present invention is such that it can effectively and measurably inhibit TYK2 protein kinase or its mutants in a biological sample or a patient. In some embodiments, the composition of the present invention is formulated for administration to a patient requiring the composition. In some embodiments, the composition of the present invention is formulated for oral administration to a patient.

[0272] As used herein, the term "patient" refers to an animal, preferably a mammal, and most preferably a human.

[0273] The term "pharmaceutically acceptable carrier, adjuvant, or catalyst" refers to a non-toxic carrier, adjuvant, or catalyst that does not impair the pharmacological activity of the compound formulated with it. Pharmaceutically acceptable carriers, adjuvants, or catalysts that can be used in the compositions of this invention include (but are not limited to) ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffering substances such as phosphates, glycine, sorbic acid, potassium sorbate, mixtures of saturated vegetable fatty acids in the form of glycerides, water, salts, or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol, and lanolin.

[0274] "Pharmaceutically acceptable derivative" means any non-toxic salt, ester, salt of ester or other derivative of the compound of the present invention that can directly or indirectly provide, when given to the recipient, the compound of the present invention or its inhibitory metabolites or residues.

[0275] As used herein, the term "its inhibitory active metabolites or residues" means that its metabolites or residues are also inhibitors of TYK2 protein kinase or its mutants.

[0276] The compositions of this invention can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implantable reservoir. As used herein, the term "parenterally" includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrasheathic, intrahepatic, intralesional, and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally, or intravenously. The sterile injectable form of the compositions of this invention can be an aqueous or oily suspension. These suspensions can be formulated using suitable dispersants or wetting agents and suspending agents according to techniques known in the art. The sterile injectable formulation can also be a sterile injectable solution or suspension in a non-toxic, parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Among acceptable mediators and solvents, water, Ringer's solution, and isotonic sodium chloride solution may be used. In addition, sterile, non-volatile oils are commonly used as solvents or suspension media.

[0277] For this purpose, any mild, non-volatile oil, including synthetic monoglycerides or diglycerides, can be used. Fatty acids, such as oleic acid and its glyceride derivatives, as well as pharmaceutically acceptable natural oils, such as olive oil or castor oil, especially their polyoxyethylene forms, can be used to prepare injectable formulations. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as carboxymethyl cellulose or similar dispersants commonly used in the formulation of pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants, such as Tween, Span, and other emulsifiers, or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms, can also be used for formulation purposes.

[0278] The pharmaceutically acceptable compositions of the present invention can be administered orally in any orally acceptable dosage form, including (but not limited to) capsules, tablets, aqueous suspensions, or solutions. In the case of tablets for oral use, common carriers include lactose and corn starch. Lubricants, such as magnesium stearate, are also commonly added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When an aqueous suspension is required for oral use, the active ingredient is combined with an emulsifier and a suspending agent. If desired, certain sweeteners, flavoring agents, or coloring agents may also be added.

[0279] Alternatively, the pharmaceutically acceptable compositions of the present invention can be administered in the form of rectal suppositories. These suppositories can be prepared by mixing the pharmaceutical preparation with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, and thus melts in the rectum to release the drug. The materials include cocoa butter, beeswax, and polyethylene glycol.

[0280] The pharmaceutically acceptable compositions of the present invention can also be administered topically, particularly when the therapeutic target includes diseases of areas or organs easily accessible by topical application, including the eyes, skin, or lower intestine, making it easy to prepare topical formulations suitable for use in each of these areas or organs.

[0281] Topical application to the lower intestine can be achieved in the form of rectal suppositories (see above) or in a form suitable for enemas. Topical percutaneous patches may also be used.

[0282] For topical application, the pharmaceutically acceptable compositions provided may be formulated into suitable ointment forms containing active ingredients suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of the present invention include (but are not limited to) mineral oils, liquid paraffins, leucocele, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsified waxes, and water. Alternatively, the pharmaceutically acceptable compositions provided may be formulated into suitable lotion or cream forms containing active ingredients suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include (but are not limited to) mineral oils, sorbitan monostearate, polysorbate 60, cetyl wax, cetearyl alcohol, 2-octyldodecyl alcohol, benzyl alcohol, and water.

[0283] For ophthalmic use, the pharmaceutically acceptable composition provided may be formulated as a micron-sized suspension in isotonic pH-adjusted sterile physiological saline, with or without a preservative (such as benzyl chlorobenzyl ammonium), or preferably as a solution in isotonic pH-adjusted sterile physiological saline. Alternatively, for ophthalmic use, the pharmaceutically acceptable composition may be formulated as an ointment (such as paraffin).

[0284] The pharmaceutically acceptable compositions of the present invention can also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in pharmaceutical formulation and can be prepared in the form of a solution in physiological saline using benzyl alcohol or other suitable preservatives, bioavailability-enhancing absorption promoters, fluorocarbons and / or other conventional solubilizers or dispersants.

[0285] Most preferably, the pharmaceutically acceptable compositions of the present invention are formulated for oral administration. Such formulations can be administered with or without food. In some embodiments, the pharmaceutically acceptable compositions of the present invention are administered in the absence of food. In other embodiments, the pharmaceutically acceptable compositions of the present invention are administered in the presence of food.

[0286] The amount of the compounds of the present invention that can be combined with carrier materials to produce compositions in a single dosage form will vary depending on the host being treated and the specific administration pattern. Preferably, the provided compositions are formulated such that inhibitors can be administered to patients receiving these compositions at doses between 0.01 mg / kg body weight / day and 100 mg / kg body weight / day.

[0287] It should also be understood that the specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound used, age, weight, general health condition, sex, diet, administration time, excretion rate, drug combination, and the judgment of the treating physician and the severity of the specific disease being treated. The amount of the compounds of the present invention in the composition also depends on the specific compounds in the composition.

[0288] Use of compounds and pharmaceutically acceptable compositions

[0289] The compounds and compositions described herein can generally be used to inhibit the kinase activity of one or more enzymes. In some embodiments, the kinase inhibited by the compounds and methods of the present invention is TYK2.

[0290] TYK2 is a non-receptor tyrosine kinase member of the Janus kinase (JAK) family of protein kinases. The mammalian JAK family consists of four members: TYK2, JAK1, JAK2, and JAK3. JAK proteins, including TYK2, are integrated into cytokine signaling. TYK2 associates with the cytoplasmic domains of type I and type II cytokine receptors, as well as interferon type I and type III receptors, and is activated by these receptors upon cytokine binding. The cytokines involved in TYK2 activation include interferons (e.g., IFN-α, IFN-β, IFN-κ, IFN-δ, IFN-ε, IFN-τ, IFN-ω, and IFN-ζ (also known as restriction factors)) and interleukins (e.g., IL-4, IL-6, IL-10, IL-11, IL-12, IL-13, IL-22, IL-23, IL-27, IL-31, oncosin M, ciliary neurotrophic factor, cardiotrophin 1, cardiotrophin-like cytokines, and LIF). Velasquez et al., “A protein kinase in the interferon α / β signaling pathway,” Cell (1992) 70:313; Stahl et al., “Binding and activation of Jak-Tyk via CNTF-LIF-OSM-IL-6β receptor assembly.” "Association and activation of Jak-Tyk kinases by CNTF-LIF-OSM-IL-6β receptor components", Science (1994) 263:92; Finbloom et al., "IL-10 induces the tyrosine phosphorylation of Tyk2 and Jak1 and the differential assembly of Stat1 and Stat3 complexes in human T cells and monocytes", Journal of Immunology.(1995) 155:1079; Bacon et al., “Interleukin 12 (IL-12) induces tyrosine phosphorylation of Jak2 and Tyk2: differential use of Janus family kinases by IL-2 and IL-12”, J. Exp. Med. (1995) 181:399; Welham et al., “Interleukin-13 signal transduction in lymphohemopoietic cells: similarities and differences in signal transduction with interleukin-4 and insulin”, (J. Biol. Chem.) (1995) 270:12286; Parham et al., “A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rβ1 and a novel cytokine receptor subunit, IL-23R”, Journal of Immunology (2002) 168:5699. Subsequently, activated TYK2 phosphorylates other signaling proteins, such as members of the STAT family, including STAT1, STAT2, STAT4, and STAT6.

[0291] IL-23-induced TYK2 activation is associated with inflammatory bowel disease (IBD), Crohn's disease, and ulcerative colitis. (Duerr et al., "A Genome-Wide Association Study Identifies IL23R as an Inflammatory Bowel Disease Gene," Science (2006) 314:1461-1463.) As a downstream effector of IL-23, TYK2 also plays a role in psoriasis, ankylosing spondylitis, and Behçet's disease. Cho et al., “Genomics and the multifactorial nature of human auto-immune disease”, New England Journal of Medicine (2011) 365:1612-1623; Cortes et al., “Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci”, Nature Genetics (2013) 45(7):730-738; Remmers et al., “Genome-wide association study identifies variants in the MHC class I, IL10, and IL23R-IL12RB2 regions associated with Behcet's disease”. "IL23R-IL12RB2 regions associated with Behçet's disease", Nature Genetics (2010) 42:698-702. A genome-wide association study of 2,622 subjects with psoriasis identified an association between disease susceptibility and TYK2.Strange et al., “A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1”, Nature Genetics (2010) 42:985-992. Knockout of the TYK2 gene or inhibition by the tyrphostin inhibitor significantly reduced IL-23 and IL-22-induced dermatitis. Ishizaki et al., “Tyk2 is a therapeutic target for psoriasis-like skin inflammation”, Intl. Immunol. (2013), doi: 10.1093 / intimm / dxt062.

[0292] TYK2 also plays a role in respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), lung cancer, and cystic fibrosis. Goblet cell proliferation (GCH) and excessive mucus secretion are mediated by IL-13-induced TYK2 activation, which in turn activates STAT6. Zhang et al., “Docking protein Gab2 regulates mucin expression and goblet cell hyperplasia through the TYK2 / STAT6 pathway,” Journal of the Federation of American Societies for Laboratory Biology (FASEBJ.) (2012) 26:1-11.

[0293] Decreased TYK2 activity protects joints from collagen antibody-induced arthritis, a model of rheumatoid arthritis in humans. Mechanistically, decreased Tyk2 activity reduces T... h 1 / T h17. The production of related intercytokines and matrix metalloproteinases, as well as other key markers of inflammation, is reduced. Ishizaki et al., “Tyk2 deficiency protects joints against destruction in anti-type II collagen antibody-induced arthritis in mice”, International Immunology (2011) 23(9):575-582.

[0294] Compared to the control group, TYK2 knockout mice exhibited complete resistance in experimental autoimmune encephalomyelitis (EAE, an animal model of multiple sclerosis (MS)) and showed no CD4 T cell infiltration in the spinal cord, indicating that TYK2 is crucial for pathogenic CD4-mediated disease development in MS. (Oyamada et al., "Tyrosine Kinase 2 Plays Critical Roles in the Pathogenic CD4 T Cell Responses for the Development of Experimental Autoimmune Encephalomyelitis", Journal of Immunology (2009) 183:7539-7546). This confirms early studies that associated increased TYK2 expression with MS susceptibility. Ban et al., “Replication analysis identifies TYK2 as a multiple sclerosis susceptibility factor,” (Eur J. Hum. Genet.) (2009) 17:1309-1313. Loss-of-function mutations in TYK2 lead to reduced demyelination and increased myelination in neurons, further demonstrating the role of TYK2 inhibitors in the treatment of MS and other CNS demyelinating diseases.

[0295] TYK2 is the only signaling messenger shared by IL-12 and IL-23. Knockout of the TYK2 gene reduces footpad thickness induced by BSA injection, psoriatic skin inflammation induced by imiquimod, and colitis induced by sodium dextran sulfate or 2,4,6-trinitrobenzenesulfonic acid in mice.

[0296] Studies on the co-linkage and association between various type I IFN signaling genes and systemic lupus erythematosus (SLE, an autoimmune disease) have shown a strong and significant correlation between loss-of-function mutations in TYK2 and a reduced incidence of SLE in families with infected members. (Sigurdsson et al., “Polymorphisms in the Tyrosine Kinase 2 and Interferon Regulatory Factor 5 Genes Are Associated with Systemic Lupis Erythematosus”, American Journal of Human Genetics (Am. J. Hum. Genet.) (2005) 76:528-537.) Genome-wide association studies between SLE-affected and unaffected subjects have shown a highly significant association between the TYK2 locus and SLE. Graham et al., “Association of NCF2, IKZF1, IRF8, IFIH1, and TYK2 with Systemic Lupus Erythematosus”, PLoS Genetics (2011) 7(10):e1002341.

[0297] Studies have shown that TYK2 plays an important role in maintaining tumor surveillance, and TYK2 knockout mice exhibit impaired cytotoxic T cell responses and accelerated tumor development. However, these effects are associated with effective suppression of natural killer (NK) cells and cytotoxic T lymphocytes, suggesting that TYK2 inhibitors may be particularly suitable for treating autoimmune diseases or transplant rejection. Although other JAK family members, such as JAK3, have similar roles in the immune system, TYK2 has been shown to be a superior target due to its involvement in fewer and more closely related signaling pathways, resulting in smaller off-target effects. (Simma et al., “Identification of an Indispensable Role for Tyrosine Kinase 2 in CTL-Mediated Tumor Surveillance”, Cancer Res. (2009) 69:203-211.)

[0298] However, contradicting the reduced tumor surveillance observed by Sima et al., studies on T-cell acute lymphoblastic leukemia (T-ALL) indicate that T-ALL largely depends on IL-10 via TYK2, through STAT1-mediated signal transduction, to maintain cancer cell survival by upregulating the anti-apoptotic protein BCL2. Blocking TYK2 gene expression, rather than other JAK family members, reduces cell growth. Specific activating mutations in TYK2 that promote cancer cell survival include those in the FERM domain (G36D, S47N, and R425H), JH2 domain (V731I), and kinase domain (E957D and R1027H). However, kinase function of TYK2 has also been identified as necessary for increased cancer cell survival because, in addition to the activating mutation (E957D) leading to transformation failure, the TYK2 enzyme also possesses kinase death mutations (M978Y or M978F). Sanda et al., “TYK2-STAT1-BCL2 Pathway Dependence in T-Cell Acute Lymphoblastic Leukemia”, Cancer Disc. (2013) 3(5):564-577.

[0299] Therefore, selective inhibition of TYK2 has been shown to be a suitable target for patients with IL-10 and / or BCL2-addicted tumors, such as 70% of adult T-cell leukemia cases. (Fontan et al., “Discovering What Makes STAT Signaling TYK in T-ALL”, Cancer Exploration (2013) 3:494-496.)

[0300] It has also been shown that TYK2-mediated STAT3 signaling can mediate neuronal cell death induced by amyloid-β (Aβ) peptide. Decreased TYK2 phosphorylation of STAT3 following Aβ administration resulted in reduced neuronal cell death, and increased STAT3 phosphorylation has been observed in the post-mortem brains of Alzheimer's disease patients. (Wan et al., “Tyk / STAT3 Signaling Mediates β-Amyloid-Induced Neuronal Cell Death: Implications in Alzheimer's Disease”, J. Neurosci. (2010) 30(20):6873-6881.)

[0301] Inhibition of the JAK-STAT signaling pathway is also involved in the reversal of hair growth and alopecia areata-related hair loss. Xing et al., “Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition”, Nature Medicine (2014) 20: 1043-1049; Harel et al., “Pharmacologic inhibition of JAK-STAT signaling promotes hair growth”, Science Advances (2015) 1(9):e1500973.

[0302] Therefore, compounds that inhibit TYK2 activity are beneficial, especially those selective for JAK2. Such compounds should provide a favorable pharmacological response for the treatment of one or more of the conditions described herein without the side effects associated with JAK2 inhibition.

[0303] Although TYK2 inhibitors are known in the art, there is a ongoing need for novel inhibitors with more potent or advantageous pharmaceutically relevant properties. For example, compounds exhibiting increased activity, selectivity for other JAK kinases (especially JAK2), and ADMET (absorption, distribution, metabolism, excretion, and / or toxicity) properties. Therefore, in some embodiments, the present invention provides TYK2 inhibitors exhibiting selectivity for JAK2.

[0304] The activity of compounds used as inhibitors of TYK2 or its mutants in this invention can be analyzed in vitro, in vivo, or in cell lines. In vitro analyses include assays of phosphorylation activity and / or subsequent functional outcomes, or inhibition of ATPase activity of activated TYK2 or its mutants. Alternative in vitro analyses quantify the ability of an inhibitor to bind to TYK2. Inhibitor binding can be measured by radiolabeling the inhibitor prior to binding, isolating the inhibitor / TYK2 complex, and determining the amount of radiolabeled material bound. Alternatively, inhibitor binding can be determined by performing a competition experiment in which a novel inhibitor is incubated with TYK2 bound to a known radioligand. Representative in vitro and in vivo analyses that can be used to analyze TYK2 inhibitors include those described and disclosed below, each of which is incorporated herein by reference in its entirety. Detailed examples of compounds used to analyze compounds used as inhibitors of TYK2 or its mutants in this invention are illustrated below.

[0305] As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing or alleviating a disease or condition or one or more symptoms thereof as described herein, delaying its onset, or inhibiting its progression. In some embodiments, treatment may be given after one or more symptoms have already appeared. In other embodiments, treatment may be given in the absence of symptoms. For example, treatment may be given to susceptible subjects before the onset of symptoms (e.g., based on a history of symptoms and / or based on genetic or other susceptibility factors). Treatment may also continue after symptoms have subsided, for example, to prevent or delay their recurrence.

[0306] The provided compounds are TYK2 inhibitors and are therefore suitable for treating one or more conditions associated with the activity of TYK2 or its mutants. Accordingly, in some embodiments, the present invention provides a method for treating TYK2-mediated conditions comprising the step of administering the compound of the present invention or a pharmaceutically acceptable composition thereof to a patient in need.

[0307] As used herein, the term "TYK2-mediated" conditions, diseases, and / or illnesses are used to refer to any disease or other harmful condition in which TYK2 or its mutants are known to play a role. Therefore, another embodiment of the invention relates to treating one or more diseases in which TYK2 or its mutants are known to play a role, or to reducing their severity. Such TYK2-mediated conditions include (but are not limited to) autoimmune diseases, inflammatory diseases, proliferative diseases, endocrine diseases, neurological diseases, and transplant-related diseases.

[0308] In some embodiments, the present invention provides a method for treating one or more conditions, wherein the conditions are selected from: autoimmune diseases, inflammatory diseases, proliferative diseases, endocrine diseases, neurological diseases, and transplant-related diseases, the method comprising administering to a patient in need a pharmaceutical composition comprising an effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof.

[0309] In some embodiments, the condition is an autoimmune disease. In some embodiments, the condition is selected from type 1 diabetes, cutaneous lupus erythematosus, systemic lupus erythematosus, multiple sclerosis, psoriasis, Becton's disease, POEMS syndrome, Crohn's disease, ulcerative colitis, and inflammatory bowel disease.

[0310] In some embodiments, the condition is an inflammatory condition. In some embodiments, the inflammatory condition is rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis, hepatomegaly, Crohn's disease, ulcerative colitis, or inflammatory bowel disease.

[0311] In some embodiments, the condition is a proliferative disorder. In some embodiments, the proliferative disorder is a blood cancer. In some embodiments, the proliferative disorder is leukemia. In some embodiments, the leukemia is T-cell leukemia. In some embodiments, the T-cell leukemia is T-cell acute lymphoblastic leukemia (T-ALL). In some embodiments, the proliferative disorder is polycythemia vera, myelofibrosis, or idiopathic thrombocytosis.

[0312] In some embodiments, the condition is an endocrine disorder. In some embodiments, the endocrine disorder is polycystic ovary syndrome, Crouzon's syndrome, or type 1 diabetes.

[0313] In some embodiments, the condition is a neurological condition. In some embodiments, the neurological condition is Alzheimer's disease.

[0314] In some embodiments, the proliferative condition is associated with one or more activating mutations in TYK2. In some embodiments, the activating mutation in TYK2 is a mutation in the FERM domain, JH2 domain, or kinase domain. In some embodiments, the activating mutation in TYK2 is selected from G36D, S47N, R425H, V731I, E957D, and R1027H.

[0315] In some embodiments, the condition is related to transplantation. In some embodiments, the transplant-related condition is transplant rejection or graft-versus-host disease.

[0316] In some embodiments, the condition is associated with type I interferon, IL-10, IL-12, or IL-23 signaling. In some embodiments, the condition is associated with type I interferon signaling. In some embodiments, the condition is associated with IL-10 signaling. In some embodiments, the condition is associated with IL-12 signaling. In some embodiments, the condition is associated with IL-23 signaling.

[0317] The compounds of this invention can also be used to treat inflammatory or allergic skin conditions, such as psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, herpetic dermatitis, scleroderma, vitiligo, hypersensitivity vasculitis, urticaria, bullous pemphigoid, lupus erythematosus, systemic lupus erythematosus, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, acquired bullous epidermolysis bullosa, acne vulgaris, and other inflammatory or allergic skin conditions.

[0318] The compounds of this invention can also be used to treat other diseases or conditions, such as those with inflammatory components, for example, eye diseases and conditions such as ocular allergies, conjunctivitis, dry eye, and vernal conjunctivitis; diseases affecting the nose, including allergic rhinitis; and inflammatory diseases involving autoimmune reactions or having autoimmune components or causes, including autoimmune blood disorders (e.g., hemolytic anemia, aplastic anemia, pure red blood cell anemia, and idiopathic thrombocytopenic purpura), cutaneous lupus erythematosus, systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, and Steven-Johnson syndrome. Syndrome), idiopathic stomatitis diarrhea, autoimmune inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), irritable bowel syndrome, celiac disease, periodontitis, hyaline membrane disease, nephropathy, glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine ophthalmopathy, Graves' disease, sarcoidosis, alveolitis, chronic allergic pneumonia, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior uveitis), Sjogren's syndrome, dry eye and vernal keratoconjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, cryptothermal protein-related cycle syndrome, nephritis, vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis (with or without nephrotic syndrome),Examples include idiopathic nephrotic syndrome or minimal change nephropathy, chronic granulomatous diseases, endometriosis, leptospirosis nephropathy, glaucoma, retinopathy, aging, headache, pain, complex regional pain syndrome, cardiomegaly, muscle atrophy, catabolism disorders, obesity, fetal growth retardation, hypercholesterolemia, heart disease, chronic heart failure, mesothelioma, anhidrotic ectodermal dysplasia, Becette's disease, pigmentary disorders, and Paget's disease. Diseases, pancreatitis, hereditary periodic fever syndrome, asthma (allergic and non-allergic, mild, moderate, severe, bronchial and exercise-induced asthma), acute lung injury, acute respiratory distress syndrome, eosinophilia, allergic reactions, systemic allergic reactions, sinusitis, ocular allergies, silica-induced diseases, COPD (damage reduction, airway inflammation, bronchial hyperresponsiveness, remodeling or disease progression), lung diseases, cystic fibrosis, acid-induced lung injury, pulmonary hypertension, polyneuropathy, cataracts, muscle inflammation and systemic sclerosis, inclusion body myositis, myasthenia gravis, thyroiditis, Addison's disease. Diseases, lichen planus, type 1 or type 2 diabetes, appendicitis, atopic dermatitis, asthma, allergies, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection, colitis, conjunctivitis, Crohn's disease, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, Henoch-Schonlein purpura. Purpura), hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, mumps, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, non-infectious pneumonia (pneumonitis), pneumonia (pneumonia), polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendinitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, or vulvitis.

[0319] In some embodiments, the inflammatory diseases treatable according to the method of the present invention are selected from acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, systemic juvenile idiopathic arthritis (SJIA), cryptothermal protein-related cycle syndrome (CAPS), and osteoarthritis.

[0320] In some embodiments, the inflammatory disease that can be treated according to the method of the present invention is T h 1 or Th 17-mediated diseases. In some embodiments, T h 17. The mediated diseases are selected from cutaneous lupus erythematosus, systemic lupus erythematosus, multiple sclerosis, and inflammatory bowel disease (including Crohn's disease or ulcerative colitis).

[0321] In some embodiments, the inflammatory diseases treatable according to the method of the present invention are selected from Hughley's syndrome; allergic conditions; osteoarthritis; eye diseases such as ocular allergies, conjunctivitis, dry eye syndrome and vernal conjunctivitis; and diseases affecting the nose, such as allergic rhinitis.

[0322] Furthermore, the present invention provides the use of compounds as defined herein, or pharmaceutically acceptable salts, hydrates, or solvates thereof, for the preparation of medicaments for the treatment of autoimmune diseases, inflammatory diseases, or proliferative diseases, or diseases commonly associated with transplantation.

[0323] Combination therapy

[0324] Depending on the specific condition or disease to be treated, other therapeutic agents typically used to treat said condition may be administered in combination with the compounds and compositions of the present invention. As used herein, other therapeutic agents typically used to treat a specific disease or condition are referred to as “the disease or condition to be treated”.

[0325] In some embodiments, the provided combination or a combination thereof is administered in combination with another therapeutic agent.

[0326] Examples of pharmaceutical agents that can also be combined with the combinations of the present invention include (but are not limited to): for the treatment of Alzheimer's disease, such as Aricept. ® and Excelon ® Drugs used to treat HIV, such as ritonavir; drugs used to treat Parkinson's disease, such as L-DOPA / carbidopa, entacapone, ropinrole, pramipexole, bromocriptine, pergolide, trihexephendyl, and amantadine; and drugs used to treat multiple sclerosis (MS), such as beta-interferon (e.g., avonex). ® Rebif ® ), Copaxone ® And mitoxantrone; used to treat asthma, such as salbutamol and Singulair. ®Medications used to treat schizophrenia, such as Zyprexa, Risperdal, Seroquel, and Haloperidol; anti-inflammatory agents, such as corticosteroids, TNF blockers, IL-1RAs, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulators and immunosuppressants, such as cyclosporine, tacrolimus, rapamycin, mycophenolate mofetil, interferon, corticosteroids, cyclophosphamide, azathioprine, and sulfasalazine; neurotrophic factors, such as acetylcholinesterase inhibitors, MAO inhibitors, interferon, anticonvulsants, and iontophoresis. Channel blockers, riluzole, and anti-Parkinson's disease agents; agents for the treatment of cardiovascular diseases, such as beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, and statins; agents for the treatment of liver diseases, such as corticosteroids, cholestyramine, interferon, and antiviral agents; agents for the treatment of hematologic disorders, such as corticosteroids, anti-leukemic agents, and growth factors; agents that prolong or improve pharmacokinetics, such as cytochrome P450 inhibitors (i.e., inhibitors of metabolic degradation) and CYP3A4 inhibitors (e.g., ketoconazole and ritonavir); and agents for the treatment of immunodeficiency disorders, such as gamma globulin.

[0327] In some embodiments, the combination therapy of the present invention or a pharmaceutically acceptable composition thereof is administered in combination with a monoclonal antibody or siRNA therapeutic agent.

[0328] The other agents may be administered separately from the provided combination therapy as part of a multiple-dose regimen. Alternatively, the agents may be part of a single dosage form, mixed together with the compounds of the invention in a single composition. If administered as part of a multiple-dose regimen, the two active agents may be administered simultaneously, sequentially, or at intervals between each other, typically at intervals of 5 hours.

[0329] As used herein, the terms "combination" and related terms refer to the simultaneous or sequential administration of therapeutic agents according to the invention. For example, a combination of the invention may be administered simultaneously or sequentially with another therapeutic agent in a single unit dosage form or together in a single unit dosage form.

[0330] The amount of other therapeutic agents present in the compositions of the present invention will not exceed the amount normally given in a composition containing the therapeutic agent as the sole active agent. The amount of other therapeutic agents in the currently disclosed compositions is preferably in the range of about 50% to 100% of the amount normally present in a composition containing the pharmaceutical agent as the sole active agent.

[0331] In one embodiment, the present invention provides a composition comprising a compound of formula I or I' and one or more other therapeutic agents. The therapeutic agent may be administered together with the compound of formula I or I', or may be administered before or after administration of the compound of formula I or I'. Suitable therapeutic agents will be described in more detail below. In some embodiments, the compound of formula I or I' may be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours before the therapeutic agent. In other embodiments, the compound of formula I or I' may be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours after the therapeutic agent.

[0332] In another embodiment, the present invention provides a method for treating an inflammatory disease, condition, or illness by administering a compound of formula I or I' and one or more other therapeutic agents to a patient in need. Other therapeutic agents of this class can be small molecule or recombinant biological agents and include, for example, acetaminophen; nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®), and celecoxib; colchicine (Colcrys®); corticosteroids such as prednisone, prednisolone, methylprednisolone, and hydrocortisone; probenecid; allopurinol; febuxostat (Uloric®); and sulfasalazine (Azulfidine®). Antimalarial drugs, such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®); methotrexate (Rheumatrex®); gold salts, such as gold glucosinolate (Solganal®), gold thiomalate (Myochrysine®), and auranofin (Ridaura®); D-penicillamine. (Depen® or Cuprimine®); azathioprine (Imuran®); cyclophosphamide (Cytoxan®); chlorambucil (Leukeran®); cyclosporine (Sandimmune®); leflunomide (Arava®);And "anti-TNF" agents, such as etanercept (Enbrel®), infliximab (Remicade®), golimumab (Simponi®), pegylated certolizumab pegol (Cimzia®), and adalimumab (Humira®); "anti-IL-1" agents, such as anakinra (Kineret®) and rilonacept (Acalyst®); canakinumab (Ilaris®); anti-Jak inhibitors, such as tofacitinib; antibodies, such as... Rituxan® (rituximab); anti-T cell agents such as abatacept® (Orencia®); anti-IL-6 agents such as tocilizumab® (Actemra®), diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®); monoclonal antibodies such as tanizumab (ta... Nezumab; anticoagulants, such as heparin (calcinparine® or liquaemin®) and warfarin (coumadin®); antidiarrheals, such as diphenoxylate (Lomotil®) and loperamide (Imodium®); bile acid decongestants, such as cholestyramine and alosetron. Lotronex® (ron), Amitiza® (lubiprostone); mild laxatives such as magnesium oxide emulsion, MiraLax® (polyethylene glycol), Dulcolax®, Correctol®, and Senokot®; anticholinergic agents or antispasmodics such as dicyclomine® (Bentyl®) and Singulair®;β-2 agonists, such as salbutamol (Ventolin® HFA, Proventil® HFA), levolbutamol (Xopenex®), isoproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®), and formoterol (Foradil®); anticholinergic agents, such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®); inhaled corticosteroids, such as beclomethasone dipropionate. dipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone furoate (Asthmanex®), budesonide (Pulmocort®), and flunisolide (Aerobid®); Afviar®; Symbicort®; Dulera®; sodium cromoglycate (Intal®); methylxanthines, such as theophylline (Theo-Dur®, Theolair®, Slo-bid®, Uniphyl®, and Theo-24). (Theo-24)® and aminophylline; IgE antibodies, such as omalizumab (Xolair®);Nucleoside reverse transcriptase inhibitors, such as zidovudine (Retrovir®), abacavir (Ziagen®), abacavir / lamivudine (Epzicom®), abacavir / lamivudine / zidovudine (Trizivir®), didanosine (Videx®), emtricitabine (Emtriva®), and lamivudine (Epivir®). Combivir®, stavudine (Zerit®), and zalcitabine (Hivid®); non-nucleoside reverse transcriptase inhibitors, such as delavirdine (Rescriptor®), efavirenz (Sustiva®), nevairapine (Viramune®), and etravirine (Intelence®); nucleotide reverse transcriptase inhibitors, such as tenofovir (tenofovir). Viread® (ir); protease inhibitors, such as amprenavir (Agenerase®), atazanavir (Reyataz®), darunavir (Prezista®), fosamprenavir (Lexiva®), indinavir (Crixivan®), lopinavir, ritonavir (Kaletra®), nelfinavir (nelfinavir). Inavir (Viracept®), ritonavir (Norvir®), saquinavir (Fortovase® or Invirase®), and tipranavir (Aptivus®); enterotropic inhibitors, such as enfuvirtide (Fuzeon®) and maraviroc (Selzentry®); integrase inhibitors, such as raltegravir (Isentress®).The following are combinations of or any combination of doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), bortezomib (Velcade®), dexamethasone (Decadron®), and lenalidomide (Revlimid®).

[0333] In another embodiment, the present invention provides a method for treating rheumatoid arthritis, comprising administering to a patient in need a compound of formula I or I' and one or more other therapeutic agents selected from nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, naproxen, etodoxacin (Lodine®), and senecoxib; corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, etc.; sulfasalazine (Azilfeld®); antimalarial drugs such as hydroxychloroquine (Bifacrol®) and chloroquine (Alaren®); methotrexate (Ampicillin®); gold salts such as gold glucosinolate (Solganal®), gold thiomalate (Malcresen®), and aurenophenone (Lido). D-Penicillamine (Dibben® or Gubimin®); Azathioprine (Imuran®); Cyclophosphamide (Sidefiber®); Chlorobutazone (Lacran®); Cyclosporine (Sandimin®); Leflunomide (Alava®); and "anti-TNF" agents, such as etanercept (Embrer®), infliximab (Remicarb®), golimumab (Simponi®), pegylated cetuzumab (Cermina®) and adalimumab (Humira®); "anti-IL-1" agents, such as anaglycinol (Ginareth®) and linacip (Acarlister®); antibodies, such as rituximab (Rituxi®); "anti-T cell" agents, such as abatacept (Olencia®); and "anti-IL-6" agents, such as tocilizumab (Anti-IL-6®).

[0334] In some embodiments, the present invention provides a method for treating osteoarthritis, comprising administering to a patient in need a compound of formula I or I' and one or more other therapeutic agents selected from acetaminophen; nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, naproxen, etodoxacin (Lodin®), and senecoxib; diclofenac; cortisone; hyaluronic acid (Sinvitro® or Heliotropium®); and monoclonal antibodies such as tanizumab.

[0335] In some embodiments, the present invention provides a method for treating cutaneous lupus erythematosus or systemic lupus erythematosus, comprising administering to a patient in need a compound of formula I or I' and one or more other therapeutic agents selected from acetaminophen; nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, naproxen, etodoxacin (Lodin®), and celecoxib; corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, etc.; antimalarial drugs such as hydroxychloroquine (Bifacrol®) and chloroquine (Alaren®); cyclophosphamide (Cydex®); methotrexate (Ampicillin®); azathioprine (Imuran®); and anticoagulants such as heparin (Caspocaline® or Lequinamine®) and warfarin (Coventry®).

[0336] This invention provides a method for treating Crohn's disease, ulcerative colitis, or inflammatory bowel disease, comprising administering to a patient in need a compound of formula I or I' and one or more other therapeutic agents selected from mesalamine (Asacol®); sulfasalazine (Azil); antidiarrheal agents such as diphenhydramine (Imodium®) and loperamide (Imodium®); bile acid binders such as cholestyramine; alosetron (Lactam®); lubiprostone (Amitiza®); laxatives such as magnesium oxide emulsion, polyethylene glycol (Miralex®), Ducola®, Coritol®, and Santox®; and anticholinergic agents or antispasmodics such as dicyclovir (Benzier®); anti-TNF therapeutic agents; steroids; and antibiotics such as metronidazole (Flagyl) or ciprofloxacin.

[0337] This invention provides a method for treating asthma, comprising administering to a patient in need a compound of formula I or I' and one or more other therapeutic agents selected from Singulair®; β-2 agonists, such as salbutamol (Fandeline® HFA, Salbutamol® HFA), levosalbutamol (Cipnax®), mesoproterenol (Orubent®), pibuterol acetate (McHill®), terbutaline sulfate (terbutaline®), salmeterol hydroxynaphthenic acid (Salinomycin®), and formoterol (Formoterol®); anticholinergic agents, such as ipratropium bromide (Dinosine®) and tiotropium (Spirox®); and inhaled corticosteroids, such as prednisone, prednisolone, and beclomethasone dipropionate (Becavent®). Chiva® and Vansriel®), triamcinolone acetonide (Amacourt®), mometasone furoate (Esmanix®), budesonide (Pulmicort®), flunisolone (Anopet®), Afova®, Ibuprofen® and Durella®; sodium cromoglycate (Inter®); methylxanthines, such as theophylline (Cio-Dul®, Tylo®, Slo-Peter®, Unife®, Cio-24®) and aminophylline; and IgE antibodies, such as omalizumab (Cerebro®).

[0338] In some embodiments, the present invention provides a method for treating COPD, comprising administering to a patient in need a compound of formula I or I' and one or more other therapeutic agents, said one or more other therapeutic agents being selected from β-2 agonists, such as salbutamol (Fandeline® HFA, Salbutamol® HFA), levosalbutamol (Cipnax®), mesoproterenol (Orubent®), pibuterol acetate (McHill®), terbutaline sulfate (terbutaline®), salmeterol hydroxynaphthenate (Srifloxacin®), and formoterol (Formadox®); anticholinergic agents, such as ipratropium bromide (Dinoprox®) and tiotropium (Spirox®); methylxanthines, such as theophylline (Cio-Dur). ®, Tylenol®, Slo-Peter®, Unifi®, CE24® and theophylline; inhaled corticosteroids such as prednisone, prednisolone, beclomethasone dipropionate (Becavent®, Chiva® and Vansriel®), triamcinolone (Amacourt®), mometasone furoate (Esmanix®), budesonide (Pulmicort®), flunisolone (Anopet®), Avova®, Inspirin® and Durex®.

[0339] In another embodiment, the present invention provides a method for treating hematologic malignancies, comprising administering to a patient in need a compound of formula I or I' and one or more other therapeutic agents selected from rituximab (rituximab®), cyclophosphamide (Cydex®), cranberry (hydroxydaunorubicin®), vincristine (Acopine®), prednisone, hedgehog signaling inhibitors, BTK inhibitors, JAK / pan-JAK inhibitors, PI3K inhibitors, SYK inhibitors, and combinations thereof.

[0340] In another embodiment, the present invention provides a method for treating solid tumors, comprising administering to a patient in need a compound of formula I or I' and one or more other therapeutic agents selected from rituximab (rituximab®), cyclophosphamide (Cydex®), cranberry (hydroxydaunorubicin®), vincristine (Acopine®), prednisone, hedgehog signaling inhibitors, BTK inhibitors, JAK / pan-JAK inhibitors, PI3K inhibitors, SYK inhibitors, and combinations thereof.

[0341] In another embodiment, the present invention provides a method for treating hematologic malignancies comprising administering to a patient in need a compound of formula I or I' and an inhibitor of the hedgehog (Hh) signaling pathway. In some embodiments, the hematologic malignancy is DLBCL (Ramirez et al., “Defining causative factors contributing in the activation of hedgehog signaling in diffuse large B-cell lymphoma” Leukemia Research (Leuk. Res.) (2012), published online on July 17, and incorporated herein by reference in its entirety).

[0342] In another embodiment, the present invention provides a method for treating diffuse large B-cell lymphoma (DLBCL), comprising administering to a patient in need a compound of formula I or I' and one or more other therapeutic agents selected from rituximab (rituximab®), cyclophosphamide (Cydex®), cranberry (hydroxydaunorubicin®), vincristine (Acopine®), prednisone, hedgehog signaling inhibitors, and combinations thereof.

[0343] In another embodiment, the present invention provides a method for treating multiple myeloma, comprising administering to a patient in need a compound of formula I or I' and one or more other therapeutic agents selected from bortezomib (Vanco®) and dexamethasone (Dicton®), hedgehog signaling inhibitors, BTK inhibitors, JAK / pan-JAK inhibitors, TYK2 inhibitors, PI3K inhibitors, SYK inhibitors, and lenalidomide (Levimed®).

[0344] In another embodiment, the present invention provides a method for treating a disease or reducing its severity, comprising administering a compound of formula I or I' and a BTK inhibitor to a patient in need, wherein the disease is selected from inflammatory bowel disease, arthritis, cutaneous lupus erythematosus, systemic lupus erythematosus (SLE), vasculitis, idiopathic thrombocytopenic purpura (ITP), rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis, Graves' disease, autoimmune thyroiditis, Hugh Grant's syndrome, multiple sclerosis, systemic sclerosis, Lyme neuroborreliosis, Guillain-Barre syndrome, acute disseminated encephalomyelitis, Addison's disease. Diseases, strabismus, myoclonic syndrome, ankylosing spondylitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, autoimmune gastritis, pernicious anemia, celiac disease, Goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia universalis, Behcet's disease, chronic fatigue, autonomic nervous system dysfunction, membranous glomerulonephritis, endometriosis, interstitial cystitis, pemphigus vulgaris, bullous pemphigoid, neuromuscular rigidity, vulvar pain due to scleroderma, hyperplastic diseases, rejection of transplanted organs or tissues, acquired immunodeficiency syndrome (AIDS).Also known as HIV, type 1 diabetes, graft-versus-host disease, transplantation, blood transfusion, systemic allergic reactions, allergies (e.g., allergies to plant pollen, latex, drugs, food, insect poisons, animal hair, animal dander, dust mites, or cockroach calyxes), type I allergy, allergic conjunctivitis, allergic rhinitis and atopic dermatitis, asthma, appendicitis, atopic dermatitis, asthma, allergy, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection, colitis, conjunctivitis, Crohn's disease, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, encephalitis, endocarditis, endometritis, enteritis, epididymitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, Henoch-Schonlein purpura. Purpura; hepatitis; hidradenitis suppurativa; immunoglobulin A nephropathy; interstitial lung disease; laryngitis; mastitis; meningitis; myelitis; myocarditis; myositis; nephritis; oophoritis; orchitis; osteitis; otitis; pancreatitis; mumps; pericarditis; peritonitis; pharyngitis; pleurisy; phlebitis; non-infectious pneumonia; pneumonia; polymyositis; proctitis; prostatitis; pyelonephritis; rhinitis; salpingitis; sinusitis; oral... Inflammatory stomatitis; synovitis; tendinitis; tonsillitis; ulcerative colitis; uveitis; vaginitis; vasculitis or vulvitis; B-cell proliferative disorders, such as diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma / Waldenstrom macroglobulinemia. Macroglobulinemia, splenic marginal zone lymphoma, multiple myeloma (also known as plasma cell myeloma), non-Hodgkin's lymphoma, Hodgkin's lymphoma plasmacytoma, extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary exudative lymphoma, Burkitt lymphoma / leukemia or lymphomatoid granuloma, breast cancer, prostate cancer, or mast cell cancer (e.g., obesity cell tumor, mast cell leukemia, mast cell sarcoma, generalized mastocytosis); bone cancer; colorectal cancer; pancreatic cancer; bone and joint diseases.Including (but not limited to) rheumatoid arthritis, seroreactive spondyloarthritis (including ankylosing spondylitis, psoriatic arthritis, and Rett's disease), Behcet's disease, Hughley's syndrome, systemic sclerosis, osteoporosis, bone cancer, bone metastases; thromboembolic conditions (e.g., myocardial infarction, angina pectoris, re-occlusion after angioplasty, restenosis after angioplasty, re-occlusion after aortocoronary artery bypass grafting, restenosis after aortocoronary artery bypass grafting, stroke, transient ischemic attack, peripheral artery disease). Arterial occlusive disease, pulmonary embolism, deep vein thrombosis; inflammatory pelvic diseases; urethritis; sunburn; sinusitis; non-infectious pneumonia; encephalitis; meningitis; myocarditis; nephritis; osteomyelitis; myositis; hepatitis; gastritis; enteritis; dermatitis; gingivitis; appendicitis; pancreatitis; cholecystitis; agammaglobulinemia; psoriasis; allergies; Crohn's disease; irritable bowel syndrome; ulcerative colitis; Hughley's disease; tissue graft rejection; hyperacute rejection of transplanted organs; asthma. Asthma; Allergic rhinitis; Chronic obstructive pulmonary disease (COPD); Autoimmune polyadenosis (also known as autoimmune polyadenosis syndrome); Autoimmune alopecia; Pernicious anemia; glomerulonephritis; Dermatomyositis; Multiple sclerosis; Scleroderma; Vasculitis; Autoimmune hemolytic and thrombocytopenic conditions; Goupard syndrome; Atherosclerosis; Addison's disease; Parkinson's disease; Alzheimer's disease; Diabetes mellitus; Septic shock; Cutaneous lupus erythematosus; Systemic lupus erythematosus (SLE) SLE; rheumatoid arthritis; psoriatic arthritis; juvenile arthritis; osteoarthritis; chronic idiopathic thrombocytopenic purpura; Waldenström macroglobulinemia; myasthenia gravis; Hashimoto's thyroiditis; atopic dermatitis; degenerative joint diseases; vitiligo; autoimmune hypopituitarism; Graves-Barré syndrome; Behcet's disease; scleroderma; mycosis fungoides; acute inflammatory reactions (such as acute respiratory distress syndrome and ischemia / reperfusion injury); and Graves' disease.

[0345] In another embodiment, the present invention provides a method for treating a disease or reducing its severity, comprising administering to a patient in need a compound of formula I or I' and a PI3K inhibitor, wherein the disease is selected from cancer, neurodegenerative diseases, angiogenic diseases, viral diseases, autoimmune diseases, inflammatory diseases, hormone-related diseases, organ transplant-related conditions, immunodeficiency diseases, destructive bone diseases, proliferative diseases, infectious diseases, cell death-related conditions, thrombin-induced platelet aggregation, chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), liver diseases, pathological immune conditions involving T-cell activation, cardiovascular diseases, and CNS diseases.

[0346] In another embodiment, the present invention provides a method for treating a disease or reducing its severity, comprising administering to a patient in need a compound of formula I or I' and a PI3K inhibitor, wherein the disease is selected from benign or malignant tumors, carcinomas, or solid tumors of the brain, kidneys (e.g., renal cell carcinoma (RCC)), liver, adrenal glands, bladder, breast, stomach, gastric tumors, ovaries, colon, rectum, prostate, pancreas, lungs, vagina, endometrium, cervix, testes, genitourinary tract, esophagus, larynx, skin, bone, or thyroid gland; sarcoma; glioblastoma; neuroblastoma. Tumors; multiple myeloma; or gastrointestinal cancer, especially colon cancer or colorectal adenoma; or neck and head tumors; epidermal hyperplasia; psoriasis; benign prostatic hyperplasia; cysts; epithelial cysts; adenomas; adenocarcinomas; keratoacanthoma; epidermoid carcinomas; large cell carcinoma; non-small cell lung cancer; lymphomas (including, for example, non-Hodgkin's lymphoma (NHL) and Hodgkin's lymphoma (also known as Hodgkin's disease)); breast cancer; follicular carcinoma; undifferentiated tumors; papillary carcinoma; seminocyte carcinoma; melanoma; or leukemia; diseases including Cowden syndrome, Lhermitte-Dudos disease, and Bannayan-Zonana syndrome. Syndrome); or diseases with abnormal activation of the PI3K / PKB pathway; asthma of any type or cause, including intrinsic (non-allergic) asthma and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchial asthma, exercise-induced asthma, occupational asthma, and asthma induced by bacterial infection; acute lung injury (ALI); adult / acute respiratory distress syndrome (ARDS); chronic obstructive pulmonary disease, airway or lung disease (COPD, COAD, or COLD), including chronic bronchitis or related dyspnea, emphysema, and asthma caused by other medications. Therapies that exacerbate airway hyperresponsiveness, particularly other inhaled medications; any type or cause of bronchitis, including (but not limited to) acute, peanut, catarrhal, gravid, chronic, or tuberculous bronchitis; any type or cause of pneumoconiosis (a chronic or acute inflammatory, usually occupational lung disease, often accompanied by airway obstruction and caused by repeated inhalation of dust), including, for example, aluminum deposition disease, carbon deposition disease, asbestos deposition disease, stone deposition disease, eyelash loss disease, pulmonary iron deposition disease, silica deposition disease, smoke deposition disease, and cotton wool deposition disease; Loffler's syndrome. Eosinophilic syndrome; eosinophilic disease, pneumonia, parasitic infestation (especially), including tropical eosinophilia; bronchial and pulmonary aspergillosis; polyarteritis nodosa (including Churg-Strauss syndrome); eosinophilic granuloma and eosinophilic-related conditions affecting the airways due to drug reactions; psoriasis; contact dermatitis; atopic dermatitis;Alopecia areata; erythema multiforme; dermatitis herpetiformis; scleroderma; leukoplakia; allergic vasculitis; urticaria; bullous pemphigoid; lupus erythematosus; pemphigus; acquired epidermolysis bullosa; conjunctivitis; dry eye syndrome; and vernal conjunctivitis; diseases affecting the nose, including allergic rhinitis; and inflammatory diseases with autoimmune reactions related to or having autoimmune components or causes, including autoimmune blood disorders (e.g., hemolytic anemia, aplastic anemia, pure red blood cell anemia, and idiopathic thrombocytopenic purpura); cutaneous lupus erythematosus; systemic lupus erythematosus; rheumatoid arthritis; polychondritis; scleroderma; Wegener's granulomatosis; dermatomyositis; chronic active hepatitis; myasthenia gravis; Stevens-Johnson syndrome; idiopathic stomatitis. Diarrhea; autoimmune inflammatory bowel diseases (e.g., ulcerative colitis and Crohn's disease); endocrine ophthalmopathy; Graves' disease; sarcoidosis; alveolitis; chronic allergic pneumonia; multiple sclerosis; primary biliary cirrhosis; uveitis (anterior and posterior uveitis); dry eye syndrome; and vernal keratoconjunctivitis; interstitial pulmonary fibrosis; psoriatic arthritis; and glomerulonephritis (with or without nephrotic syndrome, including idiopathic nephrotic syndrome or minimal change nephropathy); restenosis; cardiac hypertrophy; atherosclerosis; myocardial infarction; ischemic stroke; and congestive heart failure; Alzheimer's disease; Parkinson's disease; amyotrophic lateral sclerosis; Huntington's disease; and cerebral ischemia; and neurodegenerative diseases caused by traumatic injury, glutamate neurotoxicity, and hypoxia.

[0347] In some embodiments, the present invention provides a method for treating a disease or reducing its severity, comprising administering to a patient in need a compound of formula I or I' and a Bcl-2 inhibitor, wherein the disease is an inflammatory condition, an autoimmune condition, a proliferative condition, an endocrine condition, a neurological condition, or a transplant-related condition. In some embodiments, the condition is a proliferative condition, lupus, or lupus nephritis. In some embodiments, the proliferative condition is chronic lymphocytic leukemia, diffuse large B-cell lymphoma, Hodgkin's disease, small cell lung cancer, non-small cell lung cancer, myelodysplastic syndrome, lymphoma, hematologic malignancy, or a solid tumor.

[0348] In some embodiments, the present invention provides a method for treating a disease or reducing its severity, comprising administering to a patient in need a TYK2 pseudokinase (JH2) domain-binding compound and a TYK2 kinase (JH1) domain-binding compound. In some embodiments, the disease is an autoimmune disease, an inflammatory disease, a proliferative disease, an endocrine disease, a neurological disease, or a transplant-related disease. In some embodiments, the JH2-binding compound is a compound of formula I or I'. Other suitable JH2 domain-binding compounds include those described in WO2014074660A1, WO2014074661A1, and WO2015089143A1, the entire contents of which are incorporated herein by reference. Suitable JH1 domain-binding compounds include those described in WO2015131080A1, the entire contents of which are incorporated herein by reference.

[0349] The compounds and compositions according to the method of the present invention can be administered in any dosage and via any route of administration that is effective in treating or reducing the severity of autoimmune diseases, inflammatory diseases, proliferative diseases, endocrine diseases, neurological diseases, or transplant-related diseases. The precise amount required will vary depending on the species, age, and general condition of the subject, the severity of the infection, the specific agent, the administration method, etc., and will vary from subject to subject. The compounds of the present invention are preferably formulated in unit dosage forms to achieve convenience of administration and dose uniformity. As used herein, the term "unit dosage form" refers to a physically discrete unit of the agent suitable for the patient to be treated. However, it should be understood that the total daily dosage of the compounds and compositions of the present invention will be determined by the attending physician within the bounds of reasonable medical judgment. The specific effective dose level for any particular patient or organism will depend on a variety of factors, including the disease to be treated and its severity; the activity of the specific compound used; the specific composition used; the patient's age, weight, general health condition, sex, and diet; the timing, route of administration, and excretion rate of the specific compound used; the duration of treatment; drugs used in combination with or concurrently with the specific compound used; and similar factors well known in medical technology. As used herein, the term "patient" refers to an animal, preferably a mammal, and most preferably a human.

[0350] The pharmaceutically acceptable compositions of the present invention may be administered to humans and other animals, depending on the severity of the infection being treated, via oral, rectal, parenteral, intracerebrospinal, vaginal, intraperitoneal, topical (e.g., by powder, ointment, or drops), buccal, oral or nasal spray, or similar methods. In some embodiments, the compounds of the present invention may be administered once or more daily, orally or parenterally, at dose levels of about 0.01 mg to about 50 mg per kilogram of subject body weight, and preferably about 1 mg to about 25 mg, to achieve the desired therapeutic effect.

[0351] Liquid dosage forms for oral administration include (but are not limited to) pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, liquid dosage forms may also contain inert diluents commonly used in the field, such as water or other solvents; solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, methyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerin, tetrahydrofurfuryl alcohol, polyethylene glycol, and sorbitol fatty acid esters, and mixtures thereof. In addition to inert diluents, oral compositions may also include adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and aromatizers.

[0352] Injectable formulations, such as sterile injectable aqueous or oily suspensions, can be formulated using suitable dispersants, wetting agents, and suspending agents according to known techniques. Sterile injectable formulations can also be sterile injectable solutions, suspensions, or emulsions in non-toxic, parenteral-acceptable diluents or solvents, such as solutions in 1,3-butanediol. Among acceptable mediators and solvents, water, Ringer's solution, USP, and isotonic sodium chloride solution can be used. Furthermore, sterile, non-volatile oils are commonly used as solvents or suspension media. For this purpose, any mild, non-volatile oil can be used, including synthetic monoglycerides or diglycerides. Additionally, fatty acids, such as oleic acid, are used in the preparation of injectable formulations.

[0353] Injectable formulations can be sterilized, for example, by filtration through a bacterial trap or by incorporating a bactericide into a sterile solid composition, which can be dissolved or dispersed in sterile water or other sterile injectable media before use.

[0354] To prolong the effect of the compounds of this invention, it is generally necessary to slow down the absorption of the compounds from subcutaneous or intramuscular injection. This can be achieved by using liquid suspensions of crystalline or amorphous materials with weak water solubility. The absorption rate of the compound depends on its dissolution rate, which in turn may depend on the crystal size and crystal form. Alternatively, delayed absorption of parenteral-administered compounds can be achieved by dissolving or suspending the compound in an oil-based medium. Injectable accumulation forms are prepared by forming microcapsule matrices of the compound in a biodegradable polymer (such as polylactide-polyglycolic acid). The release rate of the compound can be controlled depending on the ratio of compound to polymer and the properties of the specific polymer used. Examples of other biodegradable polymers include poly(orthoester) and poly(anhydride). Accumulated injectable formulations are also prepared by encapsulating the compound in liposomes or microemulsions compatible with body tissues.

[0355] Compositions for rectal or vaginal administration are preferably suppositories, which can be prepared by mixing the compounds of the invention with suitable non-irritating excipients or carriers, such as cocoa butter, polyethylene glycol, or suppository waxes, which are solid at ambient temperature but liquid at body temperature and thus melt in the rectal or vaginal cavity and release the active compound.

[0356] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or the following: a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silica; b) binders, such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; c) humectants, such as glycerin; d) disintegrants, such as agar, calcium carbonate, potato or cassava starch, alginate, certain silicates, and sodium carbonate; e) dissolution delayers, such as paraffin; f) absorption accelerators, such as quaternary ammonium compounds; g) humectants, such as cetyl alcohol and glyceryl monostearate; h) absorbents, such as kaolin and bentonite; and i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms may also contain buffers.

[0357] Similar types of solid compositions can also be used as fillers in soft-filled and hard-filled gelatin capsules, which use excipients such as lactose / milk sugar and high molecular weight polyethylene glycol. Solid dosage forms such as tablets, sugar-coated pills, capsules, pellets, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in pharmaceutical compounding techniques. They may optionally contain emulsifiers and may also have compositions that optionally release the active ingredient in a delayed manner only or preferentially in a portion of the intestine. Examples of encapsulation compositions that can be used include polymeric substances and waxes. Similar types of solid compositions can also be used as fillers in soft-filled and hard-filled gelatin capsules, which use excipients such as lactose / milk sugar and high molecular weight polyethylene glycol.

[0358] The active compound may also be present in microencapsulation form with one or more of the excipients described above. Solid dosage forms such as tablets, sugar-coated pills, capsules, pellets, and granules can be prepared with coatings and shells, such as enteric coatings, controlled-release coatings, and other coatings well known in pharmaceutical compounding techniques. In such solid dosage forms, the active compound may be mixed with at least one inert diluent, such as sucrose, lactose, or starch. In normal practice, such dosage forms may also contain substances other than inert diluents, such as tablet-making lubricants and other tablet-making aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pellets, the dosage form may also contain a buffer. It may optionally contain an emulsifier and may also have a composition that optionally releases the active ingredient in a delayed manner only or preferentially in a portion of the intestine. Examples of encapsulation compositions that can be used include polymers and waxes.

[0359] Dosage forms for topical or transdermal administration of the compounds of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalers, or patches. The active ingredient is blended under sterile conditions with a pharmaceutically acceptable carrier and, if necessary, any desired preservatives or buffers. Ophthalmic formulations, ear drops, and eye drops are also covered within the scope of the present invention. Additionally, the present invention contemplates the use of transdermal patches, which have the added advantage of controlled delivery of the compounds into the body. Such dosage forms can be prepared by dissolving or dispensing the compounds in a suitable medium. Absorption enhancers can also be used to increase the flux of the compounds across the skin. The rate can be controlled by providing a rate-controlled membrane or by dispersing the compounds in a polymer matrix or gel.

[0360] According to one embodiment, the present invention relates to a method for inhibiting the activity of protein kinases in a biological sample, comprising the step of contacting the biological sample with a compound of the present invention or a composition comprising the compound.

[0361] According to another embodiment, the present invention relates to a method for inhibiting the activity of TYK2 or its mutants in a biological sample, comprising the step of contacting the biological sample with a compound of the present invention or a composition comprising the compound. In some embodiments, the present invention relates to a method for irreversibly inhibiting the activity of TYK2 or its mutants in a biological sample, comprising the step of contacting the biological sample with a compound of the present invention or a composition comprising the compound.

[0362] In another embodiment, the present invention provides a method for selectively inhibiting TYK2 relative to one or more of JAK1, JAK2, and JAK3. In some embodiments, the compounds of the present invention have greater than 2-fold selectivity relative to JAK1 / 2 / 3. In some embodiments, the compounds of the present invention have greater than 5-fold selectivity relative to JAK1 / 2 / 3. In some embodiments, the compounds of the present invention have greater than 10-fold selectivity relative to JAK1 / 2 / 3. In some embodiments, the compounds of the present invention have greater than 50-fold selectivity relative to JAK1 / 2 / 3. In some embodiments, the compounds of the present invention have greater than 100-fold selectivity relative to JAK1 / 2 / 3.

[0363] As used herein, the term “biological sample” includes (but is not limited to) cell cultures or extracts thereof; biopsy material or extracts thereof obtained from mammals; and blood, saliva, urine, feces, semen, tears or other bodily fluids or extracts thereof.

[0364] Inhibiting TYK2 (or its mutants) activity in biological samples can be used for a variety of purposes known to those skilled in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ transplantation, biological sample storage, and bioanalysis.

[0365] Another embodiment of the present invention relates to a method for inhibiting protein kinase activity in a patient, comprising the step of administering the compound of the present invention or a composition comprising the compound to the patient.

[0366] According to another embodiment, the present invention relates to a method for inhibiting the activity of TYK2 or its mutants in a patient, comprising the step of administering the compound of the present invention or a composition comprising the compound to the patient. According to some embodiments, the present invention relates to a method for reversibly or irreversibly inhibiting the activity of one or more of TYK2 or its mutants in a patient, comprising the step of administering the compound of the present invention or a composition comprising the compound to the patient. In other embodiments, the present invention provides a method for treating TYK2 or its mutant-mediated conditions in patients in need, comprising the step of administering the compound of the present invention or a pharmaceutically acceptable composition thereof to the patient. Such conditions are described in detail herein.

[0367] Depending on the specific condition or disease to be treated, other therapeutic agents typically used to treat said condition may also be present in the compositions of the present invention. As used herein, other therapeutic agents typically used to treat a specific disease or condition are referred to as “the disease or condition to be treated”.

[0368] The compounds of the present invention can also be advantageously used in combination with other therapeutic compounds. In some embodiments, the other therapeutic compounds are antiproliferative compounds. The antiproliferative compounds include (but are not limited to) aromatase inhibitors; anti-estrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule-active compounds; alkylating compounds; histone deacetylase inhibitors; compounds that induce cell differentiation; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; anti-proliferative antimetabolites; platinum compounds; compounds that target / reduce the activity of protein or lipid kinases and other anti-angiogenic compounds; compounds that target, reduce, or inhibit the activity of protein or lipid phosphatases; gonadorelin agonists; anti-androgens; methionine aminopeptidase inhibitors; matrix metalloproteinase inhibitors; bisphosphonates; biological response modifiers; antiproliferative antibodies; heparinase inhibitors; inhibitors of Ras carcinogenic isoforms; telomerase inhibitors; proteasome inhibitors; compounds used to treat hematologic malignancies; compounds that target, reduce, or inhibit the activity of Flt-3; Hsp90 inhibitors, such as those from Conforma Therapeutics. Therapeutics' 17-AAG (17-allylaminogeldemycin, NSC330507), 17-DMAG (17-dimethylaminoethylamino-17-demethoxy-geldemycin, NSC707545), IPI-504, CNF1010, CNF2024, CNF1010; Temozolomide (Temodal) ®); kinesin inhibitors, such as SB715992 or SB743921 from GlaxoSmithKline, or pentamidine / chlorpromazine from CombinatoRx; MEK inhibitors, such as ARRY142886 from Array BioPharma, AZD6244 from AstraZeneca, PD181461 from Pfizer, and formyltetrahydrofolate. As used herein, the term "aromatase inhibitor" refers to a compound that inhibits estrogen production, such as the conversion of testosterone and androstenedione and testosterone into estrone and estradiol, respectively. The terms include (but are not limited to) steroids, particularly atamestane, exemestane, and formestane; and specifically, nonsteroidal anti-steroids, particularly aminoglutethimide, roglethimide, pyridoglutethimide, trilostane, testolactone, ketoconazole, vorozole, fadrozole, anastrozole, and letrozole. Exemestane is marketed under the brand name Aromasin™. Formestane is marketed under the brand name Lentaron™. Fadrozole is marketed under the brand name Afema™. Anastrozole is marketed under the brand name Arimidex™. Letrozole is marketed under the brand names Femara™ or Femar™. Aminoglutethimide is marketed under the brand name Orimeten™. The combination of the present invention, which includes the chemotherapeutic agent aromatase inhibitor, is particularly suitable for treating hormone receptor-positive tumors, such as breast tumors.

[0369] As used herein, the term "anti-estrogenic" refers to a compound that antagonizes the effects of estrogen at the estrogen receptor level. This term includes, but is not limited to, tamoxifen, fulvestrant, raloxifene, and raloxifene hydrochloride. Tamoxifen is marketed under the brand name Novadex™. Raloxifene hydrochloride is marketed under the brand name Evista™. Fulvestrant, marketed under the brand name Faslodex™, can be administered. The combinations of the present invention containing chemotherapeutic anti-estrogens are particularly suitable for treating estrogen receptor-positive tumors, such as breast tumors.

[0370] As used herein, the term "antiandrogen" means any substance capable of inhibiting the biological effects of androgens and includes (but is not limited to) bicalutamide (Casodex™). As used herein, the term "gonadotropin-releasing hormone agonist" includes (but is not limited to) abalelix, goserelin, and goserelin acetate. Goserelin, marketed under the name Zoladex™, may be administered.

[0371] As used herein, the term "topotecan I inhibitor" includes (but is not limited to) topotecan, gimatecan, irinotecan, camptothecian and their analogues, 9-nitrocamptothecian and the macromolecular camptothecian conjugate PNU-166148. Irinotecan may be given, for example, in its marketing form, such as under the trademark Camptosar™. Topotecan is marketed under the trade name Hycamptin™.

[0372] As used herein, the term "topoisomerase II inhibitor" includes (but is not limited to) anthracyclines such as cranberry (including lipid modulators such as Caelyx™), daunorubicin, epirubicin, idarubicin, and nemorubicin; anthraquinones such as mitoxantrone and losoxantrone; and podophyllotoxins such as etoposide and teniposide. Etoposide is marketed under the brand name Etopophos™. Teniposide is marketed under the brand name VM 26-Bristol. Cranberries are marketed under the brand names Acriblastin™ or Adriamycin™. Epirubicin is marketed under the brand name Farmorubicin™. Idarubicin is marketed under the brand name Zavedos™. Mitoxarubicin is marketed under the brand name Novantron.

[0373] The term "microtubule activator" refers to microtubule stabilizing, microtubule destabilizing, and microtubule polymerization inhibitors, including (but not limited to) taxanes such as paclitaxel and docetaxel; vinca alkaloids such as vincaline or vinca sulfate, vincristine or vinca sulfate, and vinorelbine; discodermolide; colchicine; and epothilone and their derivatives. Paclitaxel is marketed under the trade name Taxol™. Docetaxel is marketed under the trade name Taxotere™. Vinca sulfate is marketed under the trade name Vinblastin RP™. Vinca sulfate is marketed under the trade name Farmistin™.

[0374] As used herein, the term "alkylating agent" includes (but is not limited to) cyclophosphamide, ifosfamide, melphalan, or nitrosourea (BCNU or Gliadel). Cyclophosphamide is marketed under the trade name Cyclostin™. Ifosfamide is marketed under the trade name Holoxan™.

[0375] The term "histone deacetylase inhibitor" or "HDAC inhibitor" refers to compounds that inhibit histone deacetylases and have antiproliferative activity. This includes (but is not limited to) succinyl aniline oxime acid (SAHA).

[0376] The term "anti-metabolic antimetabolite" includes (but is not limited to) 5-fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylating compounds (such as 5-azacytidine and decitabine), methotrexate and edatrexate, and folic acid antagonists (such as pemetrexed). Capecitabine is marketed under the brand name Xeloda™. Gemcitabine is marketed under the brand name Gemzar™.

[0377] As used herein, the term "platinum compound" includes (but is not limited to) carboplatin, cisplatin, cisplatinum, and oxaliplatin. Carboplatin may be given, for example, in its marketing form, such as under the trademark Carboplat™. Oxaliplatin may be given, for example, in its marketing form, such as under the trademark Eloxatin™.

[0378] As used herein, the term “compounds that target / reduce protein or lipid kinase activity; or protein or lipid phosphatase activity; or otherwise anti-angiogenic compounds” includes (but is not limited to) protein tyrosine kinase and / or serine and / or threonine kinase inhibitors or lipid kinase inhibitors, such as a) compounds that target, reduce or inhibit the activity of platelet-derived growth factor receptor (PDGFR), such as compounds that target, reduce or inhibit PDGFR activity, especially compounds that inhibit PDGF receptors, such as N-phenyl-2-pyrimidinamine derivatives, such as imatinib, SU10 1) SU6668 and GFB-111; b) Compounds that target, reduce, or inhibit the activity of fibroblast growth factor receptor (FGFR); c) Compounds that target, reduce, or inhibit the activity of insulin-like growth factor receptor I (IGF-IR), such as compounds that target, reduce, or inhibit the activity of IGF-IR, especially compounds that inhibit the kinase activity of IGF-I receptor, or antibodies that target the extracellular domain of IGF-I receptor or growth factor; d) Compounds that target, reduce, or inhibit the activity of the Trk receptor tyrosine kinase family, or ephrin. B4 inhibitors; e) compounds that target, reduce, or inhibit the activity of the AxI receptor tyrosine kinase family; f) compounds that target, reduce, or inhibit the activity of Ret receptor tyrosine kinases; g) compounds that target, reduce, or inhibit the activity of Kit / SCFR receptor tyrosine kinases, such as imatinib; h) compounds that target, reduce, or inhibit the activity of C-kit receptor tyrosine kinases, which are part of the PDGFR family, such as compounds that target, reduce, or inhibit the activity of the c-Kit receptor tyrosine kinase family, especially compounds that inhibit c-Kit receptors, such as imatinib; i) compounds that target, reduce, or inhibit the activity of members of the c-Abl family, their gene fusion products (e.g., BCR-Abl kinases), and mutants, such as compounds that target, reduce, or inhibit the activity of members of the c-Abl family and their gene fusion products, such as N-phenyl-2-pyrimidinamine derivatives, such as imatinib or nilotinib (AMN107); PD180970; AG957; NSC 680410; PD173955 from Parke Davis; or dasatinib (BMS-354825);j) Compounds that target, reduce, or inhibit the activity of serine / threonine kinases, including protein kinase C (PKC) and Raf family members, MEK, SRC, JAK / pan-JAK, FAK, PDK1, PKB / Akt, Ras / MAPK, PI3K, SYK, BTK, and TEC family members, and / or cyclin-dependent kinase family (CDK) members, such as staurosporine derivatives like midostaurin; other examples include UCN-01, safingol, BAY 43-9006, bryozoxin 1, Perifosine; llmofosine; RO 318220 and RO 320432; GO 6976; lsis 3521; LY333531 / LY379196; isoquinoline compounds; FTI; PD184352 or QAN697 (P13K inhibitor) or AT7519 (CDK inhibitor); k) compounds that target, reduce or inhibit the activity of protein tyrosine kinase inhibitors, such as imatinib mesylate (Gleevec™) or tyrosine phosphorylation inhibitors (tyrphostin) such as tyrosine phosphorylation inhibitor A23 / RG-50810; AG 99; tyrosine phosphorylation inhibitor AG 213; tyrosine phosphorylation inhibitor AG 1748; tyrosine phosphorylation inhibitor AG490; tyrosine phosphorylation inhibitor B44; tyrosine phosphorylation inhibitor B44(+) enantiomer; tyrosine phosphorylation inhibitor AG 555; AG 494; tyrosine phosphorylation inhibitor AG 556, AG957 and adaphostin (4-{[(2,5-dihydroxyphenyl)methyl]amino}-adaphostin; NSC 680410, adaphostin); l) compounds that target, reduce or inhibit the activity of receptor tyrosine kinases of the epidermal growth factor family (EGFR1ErbB2, ErbB3, ErbB4, in homodimer or heterodimer form) and their mutants, such as compounds that target, reduce or inhibit the activity of the epidermal growth factor receptor family, especially those that inhibit members of the EGF receptor tyrosine kinase family, such as EGF receptor, ErbB2, ErbB3 and ErbB4 or compounds, proteins or antibodies that bind to EGF or EGF-related ligands, CP 358774, ZD 1839, ZM 105180;Trastuzumab (Herceptin™), cetuximab (Erbitux™), Iressa, Tarceva, OSI-774, Cl-1033, EKB-569, GW-2016, E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 or E7.6.3, and 7H-pyrrolo-[2,3-d]pyrimidine derivatives; m) compounds that target, reduce or inhibit c-Met receptor activity, such as compounds that target, reduce or inhibit c-Met activity, especially compounds that inhibit the kinase activity of the c-Met receptor, or antibodies that target the extracellular domain of c-Met or bind to HGF; n) compounds that target, reduce or inhibit one or more JAK family members (JAK1 / JAK2 / Compounds that target, reduce, or inhibit the kinase activity of PI3 kinase (PI3K), including (but not limited to) PRT-062070, SB-1578, baricitinib, pacritinib, momelotinib, VX-509, AZD-1480, TG-101348, tofacitinib, and ruxolitinib; and compounds that target, reduce, or inhibit the kinase activity of PI3 kinase (PI3K), including (but not limited to) ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, and bupazine. Buparlisib, pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, and idelalisib; and q) compounds that target, reduce, or inhibit signal transduction along the hedgehog protein (Hh) or smoothed receptor (SMO) pathway, including (but not limited to) cyclopamine, vismodegib, itraconazole, erismodegib, and IPI-926 (saridegib).

[0379] As used herein, the term "PI3K inhibitor" includes (but is not limited to) compounds having inhibitory activity against one or more enzymes in the phosphatidylcyclohexanehexol-3-kinase family, said enzymes including (but not limited to) PI3Kα, PI3Kγ, PI3Kδ, PI3Kβ, PI3K-C2α, PI3K-C2β, PI3K-C2γ, Vps34, p110-α, p110-β, p110-γ, p110-δ, p85-α, p85-β, p55-γ, p150, p101, and p87. Examples of PI3K inhibitors suitable for use in this invention include (but are not limited to) ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, bupacoxib, piticoxib, PF-4691502, BYL-719, dartoxib, XL-147, XL-765, and edoxib.

[0380] As used herein, the term “BTK inhibitor” includes (but is not limited to) compounds that have inhibitory activity against Bruton's tyrosine kinase (BTK), including (but not limited to) AVL-292 and ibrutinib.

[0381] As used herein, the term “SYK inhibitor” includes (but is not limited to) compounds that have inhibitory activity against spleen tyrosine kinase (SYK), including (but not limited to) PRT-062070, R-343, R-333, Excellair, PRT-062607, and fostamatinib.

[0382] As used herein, the term "Bcl-2 inhibitor" includes (but is not limited to) compounds with inhibitory activity against B-cell lymphoma 2 protein (Bcl-2), including (but not limited to) ABT-199, ABT-731, ABT-737, apogossypol, pan-Bcl-2 inhibitors of Ascenta, curcumin (and its analogues), Bcl-2 / Bcl-xL dual inhibitors (Infinity Pharmaceuticals / Novartis Pharmaceuticals), Genasense (G3139), HA14-1 (and its analogues; see WO2008118802), navitoclax (and its analogues; see US7390799), NH-1 (Shenayng Pharmaceutical University), obatoclax (and its analogues; see WO2004106328), S-001 (Gloria Pharmaceuticals), and TW series compounds (Univ. of Michigan and venetoclax. In some embodiments, Bcl-2 inhibitors are small molecule therapeutic agents. In some embodiments, Bcl-2 inhibitors are peptide mimics.

[0383] Other examples of BTK inhibitory compounds and conditions that can be treated by combination of said compounds with compounds of the present invention can be found in WO2008039218 and WO2011090760, the entire contents of which are incorporated herein by reference.

[0384] Other examples of SYK inhibitory compounds and conditions that can be treated by combination of said compounds with compounds of the present invention can be found in WO2003063794, WO2005007623 and WO2006078846, the entire contents of which are incorporated herein by reference.

[0385] Other examples of PI3K inhibitory compounds and conditions that can be treated by combination of such compounds with the compounds of the present invention can be found in WO2004019973, WO2004089925, WO2007016176, US8138347, WO2002088112, WO2007084786, WO2007129161, WO2006122806, WO2005113554 and WO2007044729, the entire contents of which are incorporated herein by reference.

[0386] Other examples of JAK inhibitory compounds and conditions that can be treated by combination of such compounds with the compounds of the present invention can be found in WO2009114512, WO2008109943, WO2007053452, WO2000142246 and WO2007070514, the entire contents of which are incorporated herein by reference.

[0387] Other anti-angiogenic compounds include those with a different mechanism of activity (e.g., independent of protein or lipid kinase inhibition), such as thalidomide (Thalomid™) and TNP-470.

[0388] Examples of proteasome inhibitors that can be used in combination with the compounds of the present invention include (but are not limited to) bortezomib, disulfiram, epigallocatechin-3-gallate (EGCG), halosporin A, carfilzomib, ONX-0912, CEP-18770, and MLN9708.

[0389] Compounds that target, reduce, or inhibit the activity of protein or lipid phosphatases include, for example, phosphatase 1 inhibitors, phosphatase 2A inhibitors, or CDC25 inhibitors, such as okadaic acid or its derivatives.

[0390] Compounds that induce cell differentiation include (but are not limited to) retinoic acid, α-γ- or δ-tocopherol, or α-γ- or δ-tocotrienol.

[0391] As used herein, the term cyclooxygenase inhibitor includes (but is not limited to) Cox-2 inhibitors, 5-alkyl-substituted 2-arylaminophenylacetic acid and their derivatives, such as celecoxib (Celebrex™), rofecoxib (Vioxx™), etoricoxib, valdecoxib, or 5-alkyl-2-arylaminophenylacetic acid, such as 5-methyl-2-(2'-chloro-6'-fluorophenylamino)phenylacetic acid, lumiracoxib.

[0392] As used herein, the term "bisphosphonate" includes (but is not limited to) etridonic acid, clodronic acid, tiludronic acid, pamidronic acid, alendronic acid, ibandronic acid, risedronic acid, and zoledronic acid. Etidronic acid is marketed under the trade name Didronel™. Clodronic acid is marketed under the trade name Bonefos™. Tiludronic acid is marketed under the trade name Skelid™. Pamidronic acid is marketed under the trade name Aredia™. Alendronic acid is marketed under the trade name Fosamax™. Ibandronic acid is marketed under the trade name Bondranat™. Risedronic acid is marketed under the trade name Actonel™. Zoledronic acid is marketed under the trade name Zometa™. The term "mTOR inhibitor" refers to compounds that inhibit mammalian target of rapamycin (mTOR) and have antiproliferative activity, such as sirolimus (Rapamune®) and everolimus (Certicane®). TM ), CCI-779 and ABT578.

[0393] As used herein, the term "heparinase inhibitor" refers to a compound that targets, reduces, or inhibits the degradation of heparin sulfate. This term includes (but is not limited to) PI-88. As used herein, the term "biological response modifier" refers to lymphokines or interferons.

[0394] As used herein, the term "inhibitor of Ras carcinogenic isoforms, such as H-Ras, K-Ras, or N-Ras" refers to compounds that target, reduce, or inhibit the carcinogenic activity of Ras; for example, "farnesyltransferase inhibitors," such as L-744832, DK8G557, or R115777 (Zarnestra™). As used herein, the term "telomerase inhibitor" refers to compounds that target, reduce, or inhibit telomerase activity. Compounds that target, reduce, or inhibit telomerase activity are particularly compounds that inhibit telomerase receptors, such as telomestatin.

[0395] As used herein, the term "methionine aminopeptidase inhibitor" refers to a compound that targets, reduces, or inhibits the activity of methionine aminopeptidase. Compounds that target, reduce, or inhibit the activity of methionine aminopeptidase include (but are not limited to) bengamide or its derivatives.

[0396] As used herein, the term "proteasome inhibitor" refers to a compound that targets, reduces, or inhibits proteasome activity. Compounds that target, reduce, or inhibit proteasome activity include (but are not limited to) bortezomib (Vanco™) and MLN341.

[0397] As used herein, the term “matrix metalloproteinase inhibitor” or (“MMP” inhibitor) includes (but is not limited to) collagen peptide mimicry and non-peptide mimicry inhibitors, tetracycline derivatives such as isohydroxamic acid ester peptide mimicry inhibitors, batimastat and its orally bioavailable analogues marimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551), BMS-279251, BAY12-9566, TAA211, MMI270B or AAJ996.

[0398] As used herein, the term "compound for the treatment of hematological malignancies" includes (but is not limited to) FMS-like tyrosine kinase inhibitors, which are compounds that target, reduce or inhibit the activity of the FMS-like tyrosine kinase receptor (Flt-3R); interferon, 1-β-D-arasulfuran cytosine (ara-c) and bisulfan; and ALK inhibitors, which are compounds that target, reduce or inhibit polymorphic lymphoma kinase; and Bcl-2 inhibitors.

[0399] Compounds that target, reduce, or inhibit the activity of FMS-like tyrosine kinase receptor (Flt-3R) are particularly compounds, proteins, or antibodies that inhibit members of the Flt-3R receptor kinase family, such as PKC412, midostaurin, astrocytocin derivatives, SU11248, and MLN518.

[0400] As used herein, the term "HSP90 inhibitor" includes (but is not limited to) compounds that target, reduce, or inhibit the intrinsic ATPase activity of HSP90; compounds that degrade, target, reduce, or inhibit HSP90 client proteins via the ubiquitin-proteasome pathway. Compounds that target, reduce, or inhibit the intrinsic ATPase activity of HSP90 are particularly compounds, proteins, or antibodies that inhibit the ATPase activity of HSP90, such as 17-allylamino-17-demethoxygeldmycin (17AAG) (a geldmycin derivative); other geldmycin-related compounds; radicicol; and HDAC inhibitors.

[0401] As used herein, the term "antiproliferative antibody" includes (but is not limited to) trastuzumab (Herceptin™), trastuzumab-DM1, erbitux, bevacizumab (Avastin™), and rituximab (rituximab). ® ), PRO64553 (anti-CD40) and 2C4 antibody. Antibody refers to complete monoclonal antibody, polyclonal antibody, multispecific antibody formed by at least two complete antibodies, and antibody fragment, as long as it exhibits the desired biological activity.

[0402] For the treatment of acute myeloid leukemia (AML), the compounds of the present invention can be used in combination with standard leukemia therapies, particularly with therapies used to treat AML. Specifically, the compounds of the present invention can be administered in combination with, for example, farnesyltransferase inhibitors and / or other drugs used to treat AML, such as donomycin, adriamycin, Ara-C, VP-16, teniposide, mitoxantrone, idarubicin, carboplatin, and PKC412. In some embodiments, the present invention provides a method for treating AML associated with ITD and / or D835Y mutations, comprising administering the compounds of the present invention together with one or more FLT3 inhibitors. In some embodiments, the FLT3 inhibitor is selected from quizartinib (AC220), astrocytocin derivatives (e.g., midotulin or lestaurtinib), sorafenib, tandutinib, LY-2401401, LS-104, EB-10, famitinib, NOV-110302, NMS-P948, AST-487, G-749, SB-1317, S-209, SC-110219, AKN-028, fedratinib, tozasertib, and sunitinib. In some embodiments, the FLT3 inhibitor is selected from quizartinib, midotulin, lestaurtinib, sorafenib, and sunitinib.

[0403] Other anti-leukemia compounds include, for example, Ara-C, a pyrimidine analogue that is a 2-hydroxycytidine derivative of deoxycytidine. '-α-hydroxyribose (arabinoside) derivatives. Also includes purine analogs such as inosine, 6-mercaptopurine (6-MP), and fludarabine phosphate. Compounds that target, reduce, or inhibit the activity of histone deacetylase (HDAC) inhibitors such as sodium butyrate and succinyl aniline oxime acid (SAHA) inhibit the activity of enzymes known as histone deacetylases. Specific HDAC inhibitors include MS275, SAHA, FK228 (formerly FR901228), Trichostatin A, and compounds disclosed in US 6,552,065, including (but not limited to) N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-acrylamide or pharmaceutically acceptable salts thereof, and N-hydroxy-3-[4-[(2-hydroxyethyl){2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-acrylamide or pharmaceutically acceptable salts thereof, especially lactate. As used herein, somatostatin receptor antagonists refer to compounds that target, treat, or inhibit somatostatin receptors, such as octreotide and SOM230. Tumor cell damage methods refer to methods such as ionizing radiation. The term "ionizing radiation" as used above and below refers to ionizing radiation occurring in the form of electromagnetic rays (such as X-rays and gamma rays) or particles (such as alpha particles and beta particles). Ionizing radiation is provided in (but not limited to) radiation therapy and is known in the field. See Hellman, Principles of Radiation Therapy, Cancer, in Principles and Practice of Oncology, eds. Devita et al., 4th ed., Vol. 1, pp. 248-275 (1993).

[0404] This also includes EDG binders and ribonucleotide reductase inhibitors. As used herein, the term "EDG binder" refers to a class of immunosuppressants that regulate lymphocyte recirculation, such as FTY720. The term "ribonucleotide reductase inhibitor" refers to pyrimidine or purine nucleoside analogs, including (but not limited to) fludarabine and / or cytosine arabinoside (ara-C), 6-thioguanine, 5-fluorouracil, cladribine, 6-mercaptopurine (especially in combination with ara-C for ALL), and / or pentostatin. Ribonucleotide reductase inhibitors are particularly hydroxyurea or 2-hydroxy-1H-isoindole-1,3-dione derivatives.

[0405] It also includes, in particular, compounds, proteins, or monoclonal antibodies against VEGF, such as 1-(4-chlorophenylamino)-4-(4-pyridylmethyl)phthalazine or a pharmaceutically acceptable salt thereof; 1-(4-chlorophenylamino)-4-(4-pyridylmethyl)phthalazine succinate; Angiostatin™; Endostatin™; o-aminobenzoic acid amide; ZD4190; ZD6474; SU5416; SU6668; bevacizumab; or anti-VEGF antibodies or anti-VEGF receptor antibodies, such as rhuMAb and RHUFab; VEGF aptamers, such as Macugon; FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgGI antibodies, Angiozyme (RPI 4610), and bevacizumab (Avastin™).

[0406] As used in this article, photodynamic therapy refers to the treatment or prevention of cancer using certain chemicals called photosensitizing compounds. Examples of photodynamic therapy include treatments using compounds such as Visudyne™ and porfimer sodium.

[0407] As used in this article, angiostatic steroids are compounds that block or inhibit angiogenesis, such as anecocave, triamcinolone, hydrocortisone, 11-α-epihydrocotisol, cortexolone, 17α-hydroxyprogesterone, corticosterone, desoxycorticosterone, testosterone, estrone, and dexamethasone.

[0408] Implants containing corticosteroids refer to compounds such as fluocinolone and dexamethasone.

[0409] Other chemotherapeutic compounds include (but are not limited to) alkaloids, hormone compounds and antagonists; biological response modifiers, preferably lymphokines or interferons; antisense oligonucleotides or oligonucleotide derivatives; shRNA or siRNA; or hybrid compounds or compounds with other or unknown mechanisms of action.

[0410] The compounds of this invention can also be used as adjunctive therapeutic compounds in combination with other drugs such as anti-inflammatory drugs, bronchodilators, or antihistamines, particularly for the treatment of obstructive or inflammatory tracheal diseases as mentioned above, for example, as a therapeutic enhancer of the drugs or as a means of reducing the required dosage or potential side effects of the drugs. The compounds of this invention can be mixed with other drugs in a fixed pharmaceutical composition or can be administered separately from other drugs, before, simultaneously with, or after the other drugs. Therefore, this invention includes combinations of the compounds of this invention as described above with anti-inflammatory drugs, bronchodilators, antihistamines, or antitussive active pharmaceutical ingredients, wherein the compounds of this invention and the drugs are in the same or different pharmaceutical compositions.

[0411] Suitable anti-inflammatory drugs include steroids, especially glucocorticoids, such as budesonide, beclomethasone dipropionate, fluticasone propionate, ciclesonide, or mometasone furoate; nonsteroidal glucocorticoid receptor agonists; LTB4 antagonists, such as LY293111, CGS025019C, CP-195543, SC-53228, BIIL 284, ONO 4057, and SB 209247; LTD4 antagonists, such as montelukast and zafirlukast; and PDE4 inhibitors, such as cilomilast (Ariflo® GlaxoSmithKline) and roflumilast (Byk Gulden), V-11294A (Napp), BAY19-8004 (Bayer), SCH-351591 (Schering-Plough), Arofylline (Almirall Prodesfarma), PD189659 / PD168787 (Parke-Davis), AWD-12-281 (Asta Medica), CDC-801 (Celgene), SeICID(TM) CC-10004 (Celgene), VM554 / UM565 (Vernalis), T-440 (Tanabe), KW-4490 (Kyowa Hakko Kogyo; A2a agonists; A2b antagonists; and β-2 adrenergic receptor agonists, such as salbutamol, metoprolol, terbutaline, salmeterol, fenoterol, procaterol, and especially formoterol and its pharmaceutically acceptable salts. Suitable bronchodilators include anticholinergic or antimuscarinic compounds, particularly ipratropium bromide, oxytropium bromide, tiotropium salts, and CHF 4226 (Chiesi) and glycopyrrolate.

[0412] Suitable antihistamines include cetirizine hydrochloride, acetaminophen, clemastine fumarate, promethazine, loratidine, desloratidine, diphenhydramine, fexofenadine hydrochloride, activastine, astemizole, azelastine, ebastine, epinastine, mizolastine, and tefenadine.

[0413] Other useful combinations of the compounds of the present invention with anti-inflammatory drugs are combinations with antagonists of chemokine receptors, such as CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, CCR-8, CCR-9 and CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, especially CCR-5 antagonists, such as Schering-Plough antagonists SC-351125, SCH-55700 and SCH-D, and Takeda antagonists, such as N-[[4-[[[6,7-dihydro-2-(4-methylphenyl)-5H-benzo-cycloheptene-8-yl]carbonyl]amino]phenyl]-methyl]tetrahydro-N,N-dimethyl-2H-pyran-4-ammonium chloride (TAK-770).

[0414] The structures of active compounds identified by coded serial numbers, categories, or trade names can be obtained from the official standard summary "The Merck Index" or from databases such as Patents International (e.g., IMS WorldPublications).

[0415] The compounds of this invention can also be used in combination with known treatment methods (e.g., administration of hormones or radiation). In some embodiments, the provided compounds are used as radiosensitizers, particularly for treating tumors that exhibit poor sensitivity to radiation therapy.

[0416] The compounds of this invention can be administered alone or in combination with one or more other therapeutic compounds. Possible combination therapies may be in a fixed combination form, or the compounds of this invention and one or more other therapeutic compounds may be administered alternately or independently, or in combination with a fixed combination and one or more other therapeutic compounds. The compounds of this invention may be administered separately or additionally, particularly in combination with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention, or combinations thereof for the treatment of tumors. As described above, long-term therapy is also possible, as in the case of other treatment strategies, as adjunctive therapy. Other possible treatments include therapies to maintain the patient's condition after tumor regression, or even chemopreventive therapy, for example, for at-risk patients.

[0417] The other agents may be administered separately from the composition containing the compounds of the present invention as part of a multiple-dosing regimen. Alternatively, the agents may be part of a single dosage form, mixed together with the compounds of the present invention in a single composition. If administered as part of a multiple-dosing regimen, the two active agents may be administered simultaneously, sequentially, or at intervals between each other, typically at intervals of 5 hours.

[0418] As used herein, the terms "combination" and related terms refer to the simultaneous or sequential administration of therapeutic agents according to the invention. For example, the compounds of the invention may be administered simultaneously or sequentially with another therapeutic agent in an independent unit dosage form or together in a single unit dosage form. Therefore, the present invention provides a single unit dosage form comprising the compounds of the invention, other therapeutic agents, and pharmaceutically acceptable carriers, adjuvants, or mediators.

[0419] The amounts of the compounds of the present invention that can be combined with carrier substances to produce a single dosage form, as well as other therapeutic agents (in the compositions comprising other therapeutic agents as described above), will vary depending on the host being treated and the specific administration pattern. Preferably, the compositions of the present invention are formulated such that the administered dose is between 0.01 and 100 mg / kg body weight / day.

[0420] In compositions containing other therapeutic agents, the other therapeutic agents and the compounds of the present invention can act synergistically. Therefore, the amount of the other therapeutic agents in such compositions will be less than that required in monotherapy using only the therapeutic agents. In such compositions, the other therapeutic agents can be administered at doses between 0.01 and 1,000 micrograms / kg body weight / day.

[0421] The amount of other therapeutic agents present in the compositions of the present invention will not exceed the amount normally given in a composition containing the therapeutic agent as the sole active agent. The amount of other therapeutic agents in the currently disclosed compositions is preferably in the range of about 50% to 100% of the amount normally present in a composition containing the pharmaceutical agent as the sole active agent.

[0422] The compounds of the present invention or pharmaceutical compositions thereof may also be incorporated into compositions for coating implantable medical devices, such as prostheses, artificial valves, vascular grafts, stents, and catheters. Vascular stents have been used, for example, to overcome restenosis (re-narrowing of the vessel wall after injury). However, patients using vascular stents or other implantable devices are at risk of clot formation or platelet activation. These undesirable effects can be prevented or mitigated by pre-coating the devices with a pharmaceutically acceptable composition containing a kinase inhibitor. Implantable devices coated with the compounds of the present invention are another embodiment of the invention.

[0423] This invention also relates to the following:

[0424] Item 1. A compound of formula I,

[0425]

[0426] Or its pharmaceutically acceptable salt, wherein:

[0427] R 3 -C(O)NH2; -C(O)NHR 3A ;-C(O)N(R 3A )2; or a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 independently selected heteroatoms chosen from nitrogen, oxygen, and sulfur, wherein the ring is connected by m R 3B replace;

[0428] R 5 For hydrogen or -L 1 -R 5A ;

[0429] R 6 For hydrogen, R A Or R B ;

[0430] Or R 5 and R 6 It is bonded together with the inserted atoms to form a 4- to 7-membered partially unsaturated or heteroaryl ring having 0 to 3 independent heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the ring is R 5A and n R C replace;

[0431] R 7 Hydrogen, halogen, -NH2, -NHR 7Aor -NHC(O)R 7A ;

[0432] Or R 6 and R 7 It is bonded together with the inserted atoms to form a 4- to 7-membered partially unsaturated or heteroaryl ring having 0 to 3 independent heteroatoms selected from nitrogen, oxygen, and sulfur; wherein the ring is connected to p R C replace;

[0433] L 1 For covalent bonds or C 1-4 Divalent saturated or unsaturated, straight or branched hydrocarbon chains, wherein one or both methylene units of the chain are optionally and independently substituted with: -C(R 5B )2-、-CH(R 5B )-, -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2-;

[0434] R 3A and R 7A Each independently as R B And each through q R C replace;

[0435] R 5A and R in each case 5B Each independently as R A Or R B And each through r R C replace;

[0436] R A Independently in each case, it is oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2 or -N(R)S(O)2R;

[0437] R B C is independent in each case. 1-6Aliphatic group; phenyl; 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 3- to 7-membered saturated or partially unsaturated carbon ring; 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or 7- to 12-membered saturated or partially unsaturated bicyclic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

[0438] R C In each case, it is independently an oxo, halogenated, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2 or -N(R)S(O)2R, or optionally substituted with a group selected from the following: C 1-6 Aliphatic group; phenyl group; a 3- to 7-membered saturated or partially unsaturated heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur; and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0439] Each R is independently hydrogen or optionally substituted with a group selected from the following: C 1-6 Aliphatic group; phenyl; a 3- to 7-membered saturated or partially unsaturated heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:

[0440] Two R groups on the same nitrogen atom are attached together with their inserted atoms to form a 4- to 7-membered saturated, partially unsaturated or heteroaryl ring having 0 to 3 independent heteroatoms selected from nitrogen, oxygen and sulfur, in addition to the nitrogen atom.

[0441] Each hydrogen atom bound to carbon can optionally and independently undergo deuteration substitution; and

[0442] m, n, p, q, and r are independently 0, 1, 2, 3, or 4 in each case.

[0443] Item 2. The compound according to Item 1, having one of Formula II or III:

[0444]

[0445] Or its pharmaceutically acceptable salt.

[0446] Item 3. The compound according to any one of items 1 or 2, having formula V or VI:

[0447]

[0448] Or its pharmaceutically acceptable salt.

[0449] Item 4. The compound according to item 1 or 2, having the formula Va or VI-a:

[0450]

[0451] Or its pharmaceutically acceptable salt.

[0452] Item 5. The compound according to item 1 or 2, wherein R 7 -NH2 or -NHR 7A Or, or a pharmaceutically acceptable salt thereof.

[0453] Item 6. The compound according to item 1 or 2, having one of the formulas Vc or VI-c:

[0454]

[0455] Or its pharmaceutically acceptable salt.

[0456] Item 7. The compound according to item 1 or 2, wherein R 3A and R 7A Each independently as R B And after q R C Replacement, provided that R 3A and R 7A None of them are phenyl.

[0457] Item 8. The compound according to item 1 or 2, wherein R 7A C 1-6 Aliphatic groups.

[0458] Item 9. The compound according to item 1 or 2, wherein R 7A It is a methyl group.

[0459] Item 10. The compound according to item 1 or 2, selected from the compounds described in Table 1 of this specification, or pharmaceutically acceptable salts thereof.

[0460] Item 11. A pharmaceutical composition comprising a compound according to any one of items 1 to 10 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant or mediator.

[0461] Item 12. The compound according to item 1 or 2 or the pharmaceutical composition according to item 11, used as a medicine.

[0462] Item 13. Use of a compound according to any one of items 1 to 10 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to item 11, wherein the manufacture is a medicament for inhibiting TYK2 in a biological sample.

[0463] Item 14. The use of a pharmaceutical composition according to Item 11 or a compound according to any one of Items 1 to 10 or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a patient with TYK2-mediated symptoms, diseases, or conditions.

[0464] Item 15. The use according to Item 14, wherein the condition is selected from autoimmune diseases, inflammatory diseases, proliferative diseases, endocrine diseases, neurological diseases or transplant-related diseases.

[0465] Item 16. The use according to Item 15, wherein the condition is an autoimmune disease.

[0466] Item 17. The use according to Item 16, wherein the autoimmune disease is selected from type 1 diabetes, ankylosing spondylitis, cutaneous lupus erythematosus, systemic lupus erythematosus, multiple sclerosis, systemic sclerosis, psoriasis, Crohn's disease, ulcerative colitis, and inflammatory bowel disease.

[0467] Item 18. The use according to Item 15, wherein the condition is an inflammatory condition.

[0468] Item 19. The use according to Item 18, wherein the inflammatory condition is selected from rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis, Crohn's disease, ulcerative colitis, and inflammatory bowel disease.

[0469] Item 20. The use according to Item 15, wherein the condition is a proliferative condition.

[0470] Item 21. According to the use described in Item 20, wherein the proliferative condition is a blood cancer.

[0471] Item 22. According to the use described in Item 20, the proliferative condition is leukemia.

[0472] Item 23. The use according to Item 22, wherein the leukemia is T-cell leukemia.

[0473] Item 24. The use according to Item 23, wherein the T-cell leukemia is T-cell acute lymphoblastic leukemia (T-ALL).

[0474] Item 25. The use according to Item 20, wherein the proliferative condition is associated with one or more activating mutations in TYK2.

[0475] Item 26. The use as described in Item 15, wherein the condition is related to transplantation.

[0476] Item 27. The use according to Item 26, wherein the condition is transplant rejection or graft-versus-host disease.

[0477] Item 28. The use according to Item 15, wherein the condition is an endocrine disorder.

[0478] Item 29. The use according to Item 28, wherein the endocrine disorder is polycystic ovary syndrome, Kruzon syndrome or type 1 diabetes.

[0479] Item 30. The use according to Item 15, wherein the condition is a neurological condition.

[0480] Item 31. The use according to Item 30, wherein the neurological condition is Alzheimer's disease.

[0481] Item 32. The use according to Item 14, wherein the condition is associated with type I interferon, IL-10, IL-12 or IL-23 signaling.

[0482] The invention will now be further described with reference to non-limiting embodiments 1-32:

[0483] Example 1:

[0484] A compound of formula I'

[0485]

[0486] Or its pharmaceutically acceptable salt, wherein:

[0487] R 3 -C(O)NH2; -C(O)NHR 3A ;-C(O)N(R 3A )2; -C(O)OR; -C(O)NHOR; or a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring is via m R 3B replace;

[0488] R 5 For hydrogen or -L 1 -R 5A ;

[0489] R 6 For hydrogen, R A Or R B ;

[0490] Or R 5 and R 6It is bonded together with the inserted atoms to form a 4- to 7-membered partially unsaturated or heteroaryl ring having 0 to 3 independent heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the ring is R 5A and n R C replace;

[0491] R 7 Hydrogen, halogen, -NH2, -NHR 7A or -NHC(O)R 7A ;

[0492] Or R 6 and R 7 It is bonded together with the inserted atoms to form a 4- to 7-membered partially unsaturated or heteroaryl ring having 0 to 3 independent heteroatoms selected from nitrogen, oxygen, and sulfur; wherein the ring is connected to p R C replace;

[0493] L 1 For covalent bonds or C 1-4 Divalent saturated or unsaturated, straight or branched hydrocarbon chains, wherein one or both methylene units of the chain are optionally and independently substituted with: -C(R 5B )2-、-CH(R 5B )-, -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2-;

[0494] R 3A and R 7A Each independently as R B And each through q R C Substitution, in which two R on the same carbon C The substituents are optionally linked together to form a 3- to 6-membered saturated or partially unsaturated spirocyclic fused heterocycle having 1 to 4 independent heteroatoms selected from nitrogen, oxygen, and sulfur, or wherein two R atoms on adjacent carbons are... C The substituents are optionally linked together to form a 3- to 6-membered saturated or partially unsaturated fused heterocycle having 1 to 4 independent heteroatoms selected from nitrogen, oxygen and sulfur;

[0495] R 5A and R in each case 5B Each independently as R A Or R B And each through r R C replace;

[0496] R AIndependently in each case, it is oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2 or -N(R)S(O)2R;

[0497] R B C is independent in each case. 1-6 Aliphatic group; phenyl; 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 3- to 7-membered saturated or partially unsaturated carbon ring; 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or 7- to 12-membered saturated or partially unsaturated bicyclic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

[0498] R C In each case, it is independently an oxo, halogenated, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2 or -N(R)S(O)2R, or optionally substituted with a group selected from the following: C 1-6 Aliphatic group; phenyl; a 3- to 7-membered saturated or partially unsaturated heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur; and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein two optional substituents on the same carbon are optionally linked together to form a 3- to 6-membered saturated or partially unsaturated spirocyclic fused heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or wherein two optional substituents on adjacent carbons are optionally linked together to form a 3- to 6-membered saturated or partially unsaturated fused heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0499] Each R is independently hydrogen or optionally substituted with a group selected from the following: C 1-6Aliphatic group; phenyl; a 3- to 7-membered saturated or partially unsaturated heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:

[0500] Two R groups on the same nitrogen atom are attached together with their inserted atoms to form a 4- to 7-membered saturated, partially unsaturated or heteroaromatic ring with 0-3 independent heteroatoms selected from nitrogen, oxygen or sulfur, in addition to nitrogen.

[0501] Each hydrogen atom bound to carbon can optionally and independently undergo deuteration substitution; and

[0502] m, n, p, q, and r are independently 0, 1, 2, 3, or 4 in each case.

[0503] Example 2:

[0504] The compound of Example 1 has one of Formula II or III:

[0505]

[0506] Or its pharmaceutically acceptable salt.

[0507] Example 3:

[0508] The compound of any one of Examples 1 or 2 has formula V or VI:

[0509]

[0510] Or its pharmaceutically acceptable salt.

[0511] Example 4:

[0512] The compound of any one of Examples 1 to 3 has the formula Va or VI-a:

[0513]

[0514] Or its pharmaceutically acceptable salt.

[0515] Example 5:

[0516] The compound of any one of Examples 1 to 4, wherein R 7 -NH2 or -NHR 7A Or, or a pharmaceutically acceptable salt thereof.

[0517] Example 6:

[0518] The compound of any one of Examples 1 to 5 has one of the formulas Vc or VI-c:

[0519]

[0520] Or its pharmaceutically acceptable salt.

[0521] Example 7:

[0522] The compound of any one of Examples 1 to 6, wherein R 3A and R 7A Each independently as R B And after q R C Replacement, provided that R 3A and R 7A None of them are phenyl.

[0523] Example 8:

[0524] The compound of any one of Examples 1 to 7, wherein R 7A C 1-6 Aliphatic groups.

[0525] Example 9:

[0526] The compound of any one of Examples 1 to 8, wherein R 7A It is a methyl group.

[0527] Example 10:

[0528] The compound of any one of Examples 1 to 9 is selected from the compounds described in Table 1 of this specification or their pharmaceutically acceptable salts.

[0529] Example 11:

[0530] A pharmaceutical composition comprising a compound as described in any one of Examples 1 to 10 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or mediator.

[0531] Example 12:

[0532] The compound of any one of Examples 1 to 10 or the pharmaceutical composition of Example 11 is used as a medicine.

[0533] Example 13:

[0534] A method for inhibiting TYK2 in a biological sample, optionally an in vitro method, comprising contacting the sample with a compound as described in any one of Examples 1 to 10 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described in Example 11.

[0535] Example 14:

[0536] The pharmaceutical composition of Example 11, as described by any one of the compounds in Examples 1 to 10, is used to treat a patient with TYK2-mediated symptoms, diseases, or conditions, the treatment comprising administering to the patient a compound as described by any one of Examples 1 to 10 or a pharmaceutical composition as described in Example 11.

[0537] Example 15:

[0538] The compound of any one of Examples 1 to 10 or the pharmaceutical composition of Example 11, used according to the purpose of Example 14, wherein the condition is selected from autoimmune diseases, inflammatory diseases, proliferative diseases, endocrine diseases, neurological diseases or transplant-related diseases.

[0539] Example 16:

[0540] The compound of any one of Examples 1 to 10 or the pharmaceutical composition of Example 11, used according to the purpose of Example 15, wherein the condition is an autoimmune disease.

[0541] Example 17:

[0542] The compound of any one of Examples 1 to 10 or the pharmaceutical composition of Example 11, used according to the purpose of Example 16, wherein the autoimmune disease is selected from type 1 diabetes, ankylosing spondylitis, cutaneous lupus erythematosus, systemic lupus erythematosus, multiple sclerosis, systemic sclerosis, psoriasis, Crohn's disease, ulcerative colitis and inflammatory bowel disease.

[0543] Example 18:

[0544] The compound of any one of Examples 1 to 10 or the pharmaceutical composition of Example 11, used according to the purpose of Example 15, wherein the condition is an inflammatory condition.

[0545] Example 19:

[0546] The compound of any one of Examples 1 to 10 or the pharmaceutical composition of Example 11, used according to the purpose of Example 18, wherein the inflammatory condition is selected from rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis, Crohn's disease, ulcerative colitis and inflammatory bowel disease.

[0547] Example 20:

[0548] The compound of any one of Examples 1 to 10 or the pharmaceutical composition of Example 11, used according to the purpose of Example 15, wherein the condition is a proliferative condition.

[0549] Example 21:

[0550] The compound of any one of Examples 1 to 10 or the pharmaceutical composition of Example 11, used according to the purpose of Example 20, wherein the proliferative condition is a blood cancer.

[0551] Example 22:

[0552] The compound of any one of Examples 1 to 10 or the pharmaceutical composition of Example 11, used according to the purpose of Example 20, wherein the proliferative condition is leukemia.

[0553] Example 23:

[0554] The compound of any one of Examples 1 to 10 or the pharmaceutical composition of Example 11, used according to the purpose of Example 22, wherein the leukemia is T-cell leukemia.

[0555] Example 24:

[0556] The compound of any one of Examples 1 to 10 or the pharmaceutical composition of Example 11, used according to the purpose of Example 23, wherein the T-cell leukemia is T-cell acute lymphoblastic leukemia (T-ALL).

[0557] Example 25:

[0558] The compound of any one of Examples 1 to 10 or the pharmaceutical composition of Example 11, used according to the purpose of Example 20, wherein the proliferative condition is associated with one or more activating mutations in TYK2.

[0559] Example 26:

[0560] The compound of any one of Examples 1 to 10 or the pharmaceutical composition of Example 11, used according to the purpose of Example 15, wherein the condition is related to transplantation.

[0561] Example 27:

[0562] The compound of any one of Examples 1 to 10 or the pharmaceutical composition of Example 11, used according to the purpose of Example 26, wherein the condition is transplant rejection or graft-versus-host disease.

[0563] Example 28:

[0564] The compound of any one of Examples 1 to 10 or the pharmaceutical composition of Example 11, used according to the purpose of Example 15, wherein the condition is an endocrine disorder.

[0565] Example 29:

[0566] The compound of any one of Examples 1 to 10 or the pharmaceutical composition of Example 11, used according to the purpose of Example 28, wherein the endocrine disorder is polycystic ovary syndrome, Kruzon syndrome or type 1 diabetes.

[0567] Example 30:

[0568] The compound of any one of Examples 1 to 10 or the pharmaceutical composition of Example 11, used according to the purpose of Example 15, wherein the condition is a neurological condition.

[0569] Example 31:

[0570] The compound of any one of Examples 1 to 10 or the pharmaceutical composition of Example 11, used according to the purpose of Example 30, wherein the neurological condition is Alzheimer's disease.

[0571] Example 32:

[0572] The compound of any one of Examples 1 to 10 or the pharmaceutical composition of Example 11, used according to the purpose of Example 14, wherein the condition is associated with type I interferon, IL-10, IL-12 or IL-23 signaling.

[0573] Example

[0574] As depicted in the following examples, in some exemplary embodiments, compounds are prepared according to the following general procedure. It should be understood that although the general method described illustrates the synthesis of certain compounds of the present invention, the following general method and other methods known to those skilled in the art can also be applied to all compounds as described herein and their respective subclasses and species. Other compounds of the present invention are prepared by methods substantially similar to those described in the examples herein and methods known to those skilled in the art.

[0575] General Procedure A (Acid-Amine Coupling):

[0576]

[0577]

[0578] Synthesis of Compound 1.1. To a solution of 1 (4 g, 12.26 mmol, 1.0 eq) in N,N-dimethylformamide (40 mL), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (9.32 g, 24.53 mmol, 2.0 eq) was added and stirred at room temperature for 15 min. Diisopropylethylamine (6.40 mL, 36.78 mmol, 3.0 eq) was added, followed by cyclopropylamine (0.699 g, 12.26 mmol, 1.0 eq). The reaction mixture was stirred at room temperature for 5 min. After the reaction was complete, the reaction mixture was transferred to water and the product was extracted with ethyl acetate. The combined organic layers were washed with an aqueous brine solution, dried over sodium sulfate, and concentrated under reduced pressure to give the crude substance. The compound was further purified by column chromatography, and eluted in 40% ethyl acetate / hexane to give 1.1 (2.4 g, 53.69%). MS (ES): m / z 366.13 [M+H] + .

[0579] General Procedure B (Buchwald Amination):

[0580]

[0581]

[0582] Synthesizing Compound 1.2. To a solution of 1 (0.125 g, 0.342 mmol, 1.0 eq) in 1,4-dioxane (5 mL), add 1.1 (0.082 g, 0.410 mmol, 1.2 eq) and sodium carbonate (0.072 g, 0.684 mmol, 2.0 eq). Degas the reaction mixture for 10 min under an argon atmosphere, then add tris(dibenzylacetone)dipalladium(0) (0.015 g, 0.017 mmol, 0.05 eq) and 4,5-bis(diphenylphosphino)-9,9-dimethyldibenzopyran (0.019 g, 0.034 mmol, 0.1 eq), followed by further degassing for 5 min. Stir the reaction mixture at 100 °C for 4 h. After the reaction is complete, cool the reaction mixture to room temperature, transfer it to water, and extract the product with ethyl acetate. Combine the organic layers, wash with a brine solution, dry over sodium sulfate, and concentrate under reduced pressure to obtain the crude substance. It was further purified by combi flash using 3% methanol / dichloromethane as eluent to give pure 1.2 (0.070 g, 38.6%). MS (ES): m / z 532.23 [M+H] + .

[0583] General Program C (BOC Unprotected):

[0584]

[0585] Compound 1.2 was synthesized. Compound 1 (0.070 g, 0.131 mmol, 1.0 eq) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (0.1 mL) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was transferred to a saturated bicarbonate solution, and the product was extracted with dichloromethane. The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to give the crude substance. It was further purified by wet milling with diethyl ether to give pure 1.2 (0.040 g, 70.17%). MS (ES): m / z 432.24 [M+H] + .

[0586] Preparation of core A: 7-((tert-butoxycarbonyl)(methyl)amino)-5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylic acid.

[0587]

[0588] Synthesizing Compound 1.1. Diethyl malonate (103.2 g, 644.51 mmol, 2.0 eq) was added to a solution of 1 (50 g, 322.25 mmol, 1.0 eq) in ethanol (250 mL), followed by dropwise addition of sodium ethoxide (75 mL, 21% ethanol solution, 3.0 eq). The reaction mixture was stirred under reflux for 20 hours under heating. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain a residue, which was dissolved in water and acidified to approximately pH 3–4 with concentrated hydrochloric acid. The precipitated solid was filtered, washed with water and ether, and dried thoroughly to give pure 1.1 (43 g, 59.79%). MS (ES): m / z 224.2 [M+H] + .

[0589] Compound 1.2 was synthesized. Diethylaniline (43 g, 288.9 mmol, 1.5 eq) was added to a mixture of 1.1 (43 g, 192.6 mmol, 1.0 eq) and phosphorus oxychloride (191 g, 1251 mmol, 6.5 eq). The reaction mixture was stirred at 80 °C for 3 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain a residue, which was transferred to ice-cold water and extracted with dichloromethane. The combined organic layers were washed with saturated sodium bicarbonate solution followed by brine, dried over sodium sulfate, and concentrated under reduced pressure to give a crude substance. It was further purified by column chromatography, and the compound was eluted in 20% ethyl acetate / hexane to give pure 1.2 (35 g, 69.85%). MS (ES): m / z 261 [M+H] + .

[0590] Compound 1.3 was synthesized. Potassium carbonate (18.57 g, 134.58 mmol, 1.0 eq) was added to a solution of 1.2 (35 g, 134.58 mmol, 1.0 eq) in ethanol (350 mL) at 0 °C, followed by the addition of methylamine (40% in water) (10.95 mL, 141.3 mmol, 1.05 eq), and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain a residue, which was transferred to ice-cold water. The precipitated solid was filtered, washed with water, and dried thoroughly under vacuum to give 1.3 (30 g, 87.53%). MS (ES): m / z 255.6 [M+H] + .

[0591] Compound 1.4 was synthesized. N,N-dimethylaminopyridine (1.43, 11.78 mmol, 0.1 eq) was added to a solution of 1.3 (30 g, 117.8 mmol, 1.0 eq) in 1,4-dioxane (300 mL), followed by the addition of di-tert-butyl dicarbonate (51.36 g, 235.6 mmol, 2.0 eq), and the reaction mixture was stirred at room temperature for 12 hours. After the reaction was complete, the reaction mixture was transferred to water and the product was extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to give the crude substance. This was further purified by column chromatography, and the compound was eluted in 12% ethyl acetate / hexane to give 1.4 (26 g, 62.21%). MS (ES): m / z 355 [M+H] + .

[0592] To synthesize core A, tributyltin oxide (67.19 g, 112.73 mmol, 2.0 eq) was added to a suspension of 1.4 g (20 g, 56.37 mmol, 1.0 eq) in toluene (200 mL), and the reaction mixture was heated at 120 °C for 12 h. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain a residue, which was dissolved in a saturated sodium bicarbonate solution and washed with hexane. The aqueous layer was separated and acidified to approximately pH 5-6 with 1 N hydrochloric acid and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to obtain a solid, which was wet-milled with hexane to give pure core A (13.2 g, 71.67%). 1 H NMR (DMSO-d6, 400MHZ): 12.63 (s, 1H), 8.63 (s, 1H), 7.55 (s, 1H), 3.31 (s, 3H), 1.29 (s, 9H).

[0593] Preparation of core component B: 5-chloro-7-(diphenylmethylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide

[0594]

[0595] Synthesizing Compound 1.1. Diethyl malonate (141 mL, 925.06 mmol, 2.0 eq) was added to a solution of 1 (50 g, 462.5 mmol, 1.0 eq) in ethanol (400 mL), followed by dropwise addition of sodium ethoxide (21% in ethanol) (108 mL, 1387.5 mmol, 3.0 eq). The reaction mixture was stirred under reflux for 10 hours under heating. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain a residue, which was dissolved in water and acidified to approximately pH 3–4 with concentrated hydrochloric acid. The precipitated solid was filtered, washed with water and ether, and dried thoroughly to give pure 1.1 (50 g, 61.38%). MS (ES): m / z 177.14 [M+H] + .

[0596] Compound 1.2 was synthesized. Diethylaniline (68.26 mL, 426.13 mmol, 1.5 eq) was added to a mixture of 1.1 (50 g, 283.87 mmol, 1.0 eq) and phosphorus oxychloride (163 mL, 1704.54 mmol, 6.0 eq). The reaction mixture was stirred at 90 °C for 3 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain a residue, which was transferred to ice-cold water and extracted with dichloromethane. The organic layers were combined, washed with saturated sodium bicarbonate solution followed by brine, dried over sodium sulfate, and concentrated under reduced pressure to give a crude substance. It was further purified by column chromatography, and the compound was eluted in 20% ethyl acetate / hexane to give pure 1.2 (45 g, 74.42%). MS (ES): m / z 214.02 [M+H] + .

[0597] Compound 1.3 was synthesized. Potassium carbonate (7.12 g, 51.63 mmol, 1.1 eq) was added to a solution of 1.2 (10 g, 46.94 mmol, 1.0 eq) in ethanol (315 mL) at 0 °C, followed by the addition of diphenylmethylamine (9.97 mL, 51.63 mmol, 1.1 eq), and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain a residue, which was transferred to ice-cold water. The precipitated solid was filtered, washed with water, and dried thoroughly under vacuum to give 1.3 (11 g, 62.68%). MS (ES): m / z 374.84 [M+H] + .

[0598] Core B was synthesized by adding triphenylphosphine (1.54 g, 5.88 mmol, 0.2 eq) to a solution of 1.3 g (11 g, 29.42 mmol, 1.0 eq) in a toluene:ethanol:water mixture (160 mL, 1.0:0.5:0.25) at 0 °C, followed by the addition of acetaldehyde oxime (3.47 g, 58.84 mmol, 2.0 eq), and stirring the reaction mixture at 110 °C for 5 hours. After the reaction was complete, the reaction mixture was transferred to water and the product was extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to give the crude substance. This was further purified by column chromatography, and the compound was eluted in 25% ethyl acetate / hexane to give core B (4.3 g, 37.29%). MS (ES): m / z 392.86 [M+H] + , 1 H NMR (DMSO-d6, 400MHZ): 8.48 (s,1H), 7.44-7.28 (m, 10H), 6.46 (s, 1H), 5.19 (s, 4H).

[0599] Preparation of core C: ethyl 5-chloro-7-(diphenylmethylamino)pyrazolo[1,5-a]pyrimidine-3-carboxylate.

[0600]

[0601] 1. The compound was synthesized according to the core synthesis experimental procedure

[0002] .

[0602] To synthesize core C, potassium carbonate (1.06 g, 7.7 mmol, 2.0 eq) was added to a solution of 1 (1.0 g, 3.85 mmol, 1.0 eq) in ethanol (8 mL), followed by dropwise addition of diphenylmethylamine (0.834 g, 4.23 mmol, 1.1 eq). The reaction mixture was stirred at room temperature for 4 hours. After the reaction was complete, the reaction mixture was transferred to ice-cold water, the precipitated solid was filtered off, washed with water followed by diethyl ether, and dried thoroughly to give pure core C (1.0 g, 62%). MS (ES): m / z 421.9 [M+H] + . 1 HNMR (DMSO-d6, 400MHZ): 8.47 (s, 1H), 7.39-7.35(m, 6H), 7.30-7.26 (m, 4H), 6.18 (s, 1H), 5.37 (s, 4H), 4.47-4.42 (q, 2H), 1.46-1.43 (t, 3H).

[0603] Intermediate A: 3-amino-1-(tetrahydro-2H-pyran-3-yl)pyridin-2(1H)-one

[0604]

[0605] Compound A.2 was synthesized. A.1 (0.40 g, 2.86 mmol, 1.0 eq), copper acetate (0.51 g, 2.86 mmol, 1.0 eq), molecular sieve (0.40 g, 2.86 mmol, 1.0 eq), and triethylamine (0.5 g, 5.72 mmol, 2.0 eq) were added to a solution of A (0.60 g, 2.86 mmol, 1.0 eq) in ethanol:acetonitrile (1:1) (1 mL). The reaction mixture was stirred at 80 °C for 3 hours. After the reaction was complete, the reaction mixture was filtered through diatomaceous earth and the product was washed with methanol. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to obtain the crude substance. It was further purified by column chromatography to give pure A.2 (0.19 g, 29.94%). MS (ES): m / z 222.20 [M+H]+.

[0606] To synthesize intermediate A, palladium / charcoal (0.04 g) was added to a solution of A.2 (0.19 g, 0.85 mmol, 1.0 eq) in methanol (3 mL). The reaction mixture was purified by passing hydrogen through it for 24 hours at room temperature. After the reaction was complete, the reaction mixture was filtered through a diatomaceous earth bed and washed with methanol. The filtrate was concentrated under reduced pressure to give intermediate A (0.06 g, 36.13%). MS (ES): m / z 195.23 [M+H] + .

[0607] Intermediates Bi and B-ii: (S)-3-amino-1-(tetrahydro-2H-pyran-3-yl)pyridin-2(1H)-one (Bi) and (R)-3-amino-1-(tetrahydro-2H-pyran-3-yl)pyridin-2(1H)-one (B-ii).

[0608]

[0609] Intermediate A was synthesized according to the experimental protocol for intermediate A, yielding intermediate A (yield: 36.13%). MS (ES): m / z 195.23 [M+H] + .

[0610] Compounds Bi and B-ii were synthesized. The isomer of intermediate A (0.8 g) was separated using a column (CHIRAL PAK AD-H 250 × 4.6 mm, 5 µM) with 0.3% diethylamine / methanol as a co-solvent at a flow rate of 4 mL / min, yielding pure 1a.eluent-1 and 1b.eluent-2 (FR-b). FR-a was evaporated under reduced pressure at 30 °C to give pure eluent-1 (0.3 g). MS (ES): m / z 195.11 [M+H] + FR-b was evaporated under reduced pressure at 30°C to obtain pure eluent-2 (0.3 g). MS (ES): m / z 195.11 [M+H] + .

[0611] Example 1: N-cyclopropyl-5-((3,5-dimethylphenyl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (I-1).

[0612]

[0613] Synthesizing Compound 1.1. Diethyl malonate (20.65 g, 128.9 mmol, 2.0 eq) was added to a solution of 1 (10 g, 64.45 mmol, 1.0 eq) in ethanol (300 mL), followed by dropwise addition of sodium ethoxide (74.97 g, 21% ethanol solution, 3.59 eq). The reaction mixture was stirred under reflux for 18 hours under heating. After the reaction was complete, the mixture was concentrated under reduced pressure to obtain a residue, which was dissolved in water and acidified to approximately pH 3–4 with concentrated hydrochloric acid. The precipitated solid was filtered, washed with water and ether, and dried to give pure 1.1 (10 g, 69.52%). MS (ES): m / z 224.2 [M+H] + .

[0614] Compound 1.2 was synthesized. Diethylaniline (3.37 g, 22.56 mmol, 1.68 eq) was added to a mixture of 1.1 (3 g, 13.44 mmol, 1.0 eq) and phosphorus oxychloride (8.7 mL). The reaction mixture was stirred at 80 °C for 3 hours. After the reaction was complete, the mixture was diluted with ice-cold water, neutralized with saturated sodium bicarbonate solution, and extracted with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to give a crude substance. It was further purified by column chromatography, and the compound was eluted in 15% ethyl acetate / hexane to give pure 1.2 (3.0 g, 85.82%). MS (ES): m / z 261 [M+H] + .

[0615] Compound 1.3 was synthesized. At 0 °C, diisopropylethylamine (4.2 mL, 23 mmol, 2.0 eq) was added to a solution of 1.2 (3.0 g, 11.54 mmol, 1.0 eq) in isopropanol (30 mL), followed by the addition of methylamine (6.9 mL, 13 mmol, 1.2 eq), and the reaction mixture was stirred at 80 °C for 16 hours. After the reaction was complete, the mixture was concentrated under reduced pressure to give a crude residue. Water was added to the residue, and the mixture was extracted with dichloromethane. The combined organic layers were washed with a brine solution, dried over sodium sulfate, and concentrated under reduced pressure to give a crude substance. This crude substance was further purified by column chromatography, and the compound was eluted in 40% ethyl acetate / hexane to give 1.3 (2.9 g, 95.12%). MS (ES): m / z 310 [M+H] + .

[0616] Compound 1.4 was synthesized by adding N,N-dimethylaminopyridine (0.138 g, 1.139 mmol, 0.1 eq) to a solution of 1.3 (2.9 g, 11.39 mmol, 1.0 eq) in 1,4-dioxane (15 mL), followed by the addition of di-tert-butyl dicarbonate (4.79 g, 22.78 g, 2.0 eq), and stirring the reaction mixture at room temperature for 16 hours. After the reaction was complete, the mixture was diluted with water and the product was extracted with dichloromethane. The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to give the crude substance. This crude substance was further purified by column chromatography, and the compound was eluted in 10% ethyl acetate / hexane to give 1.4 (2.9 g, 71.78%). MS (ES): m / z 355 [M+H] + .

[0617] Compound 1.5 was synthesized. A mixture of 1.4 (1.0 g, 2.82 mmol, 1.0 eq) and 3,5-dimethylaniline (2 mL) was stirred at 80-85 °C for 1.5 h. After the reaction was complete, the mixture was diluted with water and the product was extracted with dichloromethane. The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to give the crude substance. It was further purified by column chromatography, and the compound was eluted in 20% ethyl acetate / hexane to give 1.5 (1.0 g, 80.72%). MS (ES): m / z 440.5 [M+H] + .

[0618] Compound 1.6 was synthesized. Lithium hydroxide (0.957 g, 22.8 mmol, 10 eq) was added to a solution of 1.5 (1.0 g, 2.28 mmol, 1.0 eq) in tetrahydrofuran:methanol:water (15 mL, 1:1:1). The reaction was stirred at room temperature for 16 h. After the reaction was complete, the mixture was concentrated under reduced pressure to give a residue. At 10 °C, 1 N hydrochloric acid aqueous solution was added to the residue to adjust the pH to approximately 6–6.5. The product was extracted with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to give 1.6 (0.8 g, 85.45%). MS (ES): m / z 412 [M+H] + .

[0619] Synthesizing Compound 1.7. To a solution of 1.6 (0.110 g, 0.267 mmol, 1.0 eq) in N,N-dimethylformamide (2 mL), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (0.203 g, 0.535 mmol, 2.0 eq) was added, and the mixture was stirred at room temperature for 20 min. Diisopropylethylamine (0.14 mL, 0.801 mmol, 3.0 eq) was added to the mixture, followed by cyclopropylamine (0.030 g, 0.535 mmol, 2.0 eq). The reaction mixture was stirred at room temperature for 1 h. After the reaction was complete, the mixture was diluted with water and the product was extracted with ethyl acetate. The combined organic layers were washed with an aqueous brine solution, dried over sodium sulfate, and concentrated under reduced pressure to give the crude substance. The compound was further purified by column chromatography, and eluted in 25% ethyl acetate / hexane to give 1.7 (0.070 g, 58.12%). MS (ES): m / z 451.5 [M+H] + .

[0620] Synthesis of compound I-1. Compound 1.7 (0.070 g, 0.155 mmol, 1.0 eq) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (0.1 mL) was added to the reaction mixture. The reaction was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was poured into water, alkalized with a saturated bicarbonate solution, and the product was extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to give the crude substance. It was further purified by wet milling with diethyl ether to give pure I-1 (0.025 g, 45.92%). MS (ES): m / z 351.56 [M+H] + LCMS purity: 96.68%, HPLC purity: 96.09%. 1H NMR(DMSO-d6, 400MHZ): 9.32 (s, 1H), 8.14 (s, 1H), 7.97-7.96 (d, J=3.2Hz, 1H), 7.86-7.85 (d, J=5.2Hz, 1H), 7.14(s, 2H), 6.73(s, 1H), 5.50(s, 1H), 2.91(s,3H), 2.77-2.74(m, 1H), 2.30(s, 6H), 0.72-0.67(m, 2H), 0.35(m, 2H).

[0621] Example 2: 5-((3,5-dimethylphenyl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (I-2).

[0622]

[0623] Synthesizing Compound 1.7. To a solution of 1.6 (0.150 g, 0.364 mmol, 1.0 eq) in N,N-dimethylformamide (3 mL), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (0.276 g, 0.728 mmol, 2.0 eq) was added, and the mixture was stirred at room temperature for 20 min. Diisopropylethylamine (0.195 mL, 1.092 mmol, 3.0 eq) was added to the mixture, followed by ammonium chloride (0.058 g, 1.092 mmol, 3.0 eq). The reaction mixture was stirred at room temperature for 1 h. After the reaction was complete, the mixture was diluted with water and the product was extracted with ethyl acetate. The combined organic layers were washed with an aqueous brine solution, dried over sodium sulfate, and concentrated under reduced pressure to give the crude substance. The compound was further purified by column chromatography, and eluted in 40% ethyl acetate / hexane to give 1.7 (0.070 g, 46.78%). MS (ES): m / z 411.5 [M+H] + .

[0624] Synthesis of compound I-2. Compound 1.7 (0.070 g, 0.170 mmol, 1.0 eq) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (0.1 mL) was added to the reaction mixture. The reaction was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was diluted with water, alkalized with a saturated bicarbonate solution, and the product was extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to give the crude substance. It was further purified by wet milling with diethyl ether to give pure I-2 (0.025 g, 94.47%). MS (ES): m / z 311.54 [M+H]+ LCMS purity: 98.61%, HPLC purity: 97.72%. 1 H NMR(DMSO-d6, 400MHZ): 9.37 (s, 1H), 8.13 (s, 1H), 7.85-7.84 (d, J=4.8Hz, 1H), 7.53(s, 1H), 7.34(s, 1H), 6.66(s, 1H), 5.51(s, 1H), 2.91(s, 3H), 2.25(s, 6H).

[0625] Example 3. Analysis of the Combination of TYK2 and JH2 Domains

[0626] The binding constant of the compound of the present invention for the JH2 domain is determined by the following method used in KINOMEscan. ® The assay was performed using the DiscoveRx protocol. A partial-length construct of human TYK2 (JH2 domain-pseudokinase) (amino acids G556 to D888 based on the reference sequence NP_003322.3) was expressed in transiently transfected HEK293 cells as a fusion protein with the DNA-binding domain of NFkB. Extracts were prepared from these HEK 293 cells in the presence of a complete protease inhibitor cocktail (Roche) and a phosphatase inhibitor cocktail set II (Merck) in M-PER extraction buffer (Pierce). The TYK2 (JH2 domain-pseudokinase) fusion protein was tagged with a chimeric double-stranded DNA tag containing an NFkB binding site (5'-GGGAATTCCC-3') fused to the amplicon used for qPCR readout. The tag was added directly to the expression extract (the final concentration of the DNA tag in the binding reaction was 0.1 nM).

[0627] At room temperature, magnetic beads (Dynal M280) coated with streptomycin were treated with biotinylated small molecule ligands and held for 30 minutes to generate affinity resin for binding assays. The beads were then treated with excess biotin-blocking ligands and washed with blocking buffer (SeaBlock, 1% BSA, 0.05% Tween 20, 1 mM DTT) to remove unbound ligands and reduce nonspecific binding.

[0628] The binding reaction was performed by combining 16 µl of DNA-tagged kinase extract, 3.8 µl of ligand-treated affinity beads, and 0.18 µl of the test compound (PBS / 0.05% Tween 20 / 10 mM DTT / 0.1% BSA / 2 µg / ml sonicated salmon sperm DNA). The extract was used directly in the binding assay at a stock solution dilution of ≥10,000 times without any enzymatic purification steps (final DNA-tagged enzyme concentration <0.1 nM). The extract was DNA-tagged and diluted in the binding reaction in a two-step process. The first extract was diluted 1:100 in 1× binding buffer (PBS / 0.05% Tween 20 / 10 mM DTT / 0.1% BSA / 2 µg / ml sonicated salmon sperm DNA) containing 10 nM DNA tag. This dilution was equilibrated for 15 min at room temperature and then diluted 1:100 in 1× binding buffer. The test compound was prepared as a 111× stock solution in 100% DMSO. K was determined using an 11-point, 3-fold compound dilution series and three DMSO control points. d Used for K d All compounds were distributed in 100% DMSO via acoustic transfer (non-contact partitioning). The compounds were then diluted directly into the analytes to a final DMSO concentration of 0.9%. All reactions were performed in polypropylene 384-well plates. Each final volume was 0.02 mL. The analytes were incubated at room temperature with shaking for 1 hour. The beads were then aggregated and washed with wash buffer (1×PBS, 0.05% Tween 20) to remove the substituted kinase and test compounds. The washed beads were resuspended in elution buffer (1×PBS, 0.05% Tween 20, 0.5 μM non-biotinylated affinity ligand) and incubated at room temperature with shaking for 30 minutes. The kinase concentration in the elution buffer was measured by qPCR. The qPCR reaction was performed by adding 2.5 µL of kinase elution buffer to 7.5 µL of a qPCR master mixture containing 0.15 µM amplicon primers and 0.15 µM amplicon probes. The qPCR protocol consists of the following: a hot start at 95°C for 10 minutes, followed by 35 cycles of 95°C for 15 seconds and 60°C for 1 minute.

[0629] The test compound was prepared as a 111× stock solution in 100% DMSO. K was determined using an 11-point, 3-fold compound dilution series and three DMSO control points. d Used for K dAll compounds measured were distributed in 100% DMSO via acoustic transfer (non-contact partitioning). The compounds were then diluted directly into the analyte to a final DMSO concentration of 0.9%. K was determined using the highest concentration of the compound at 30,000 nM. d K d The measurements were taken in duplicate.

[0630] Using standard dose-response curves, the binding constant (K) was calculated using the Hill equation. d ):

[0631] The Hill slope is set to -1. The curve is fitted using the Levenberg-Marquard algorithm (Levenberg, K., A method for the solution of certain non-linear problems in least squares, Q. Appl. Math. 2, 164-168 (1944)).

[0632] The results of the Tyk2 JH2 domain binding analysis are presented in Table 2. The compounds denoted as "A" have a Kd of less than 200 pM; the compounds denoted as "B" have a Kd between 200 pM and 1 nM; the compounds denoted as "C" have a Kd between 1 nM and 10 nM; and the compounds denoted as "D" have a Kd greater than 10 nM.

[0633] Table 2. Results of Tyk2 JH2 domain binding analysis

[0634]

[0635]

[0636]

[0637]

[0638]

[0639]

[0640]

[0641]

[0642]

[0643]

[0644]

[0645]

[0646]

[0647]

[0648]

[0649]

[0650]

[0651]

[0652]

[0653]

[0654]

[0655]

[0656]

[0657]

[0658]

[0659]

[0660]

[0661]

[0662]

[0663] Example 4. Analysis of Tyk2 and JAK2 radiokinases

[0664] Peptide acceptor [KKSRGDYMTMQIG] (20 μM) was prepared in reaction buffer (20 mM Hepes pH 7.5, 10 mM MgCl2, 1 mM EGTA, 0.02% Brij35, 0.02 mg / mL BSA, 0.1 mM Na3PO4, 2 mM DTT, 1% DMSO). TYK2 (Invitrogen) kinase was added, followed by DMSO containing the compound. 10 µM 33PATP was added to initiate the ATP reaction. The kinase reaction was incubated at room temperature for 120 min and spotted onto P81 ion-exchange paper (Whatman # 3698-915), followed by thorough washing in 0.75% phosphate, and then radioactivity counts were read. For JAK2 (Invitrogen) kinase analysis, 0.2 mg / mL peptide acceptor poly[Glu:Tyr] (4:1) was used in the same reaction as for TYK2.

[0665] The Tyk2 and JAK2 radiokinase assays measured the percentage inhibition at the Tyk2 kinase domain (JH1) and the percentage inhibition at the JAK2 kinase domain (JH1). The results are expressed as percentage inhibition at 10 μM.

[0666] The results of the Tyk2 and JAK2 radiokinase analyses are presented in Table 3. Compounds labeled "A" showed an inhibition percentage of less than 50% at 10 μM; compounds labeled "B" showed an inhibition percentage between 50% and 70% at 10 μM; compounds labeled "C" showed an inhibition percentage between 70% and 90% at 10 μM; and compounds labeled "D" showed an inhibition percentage greater than 90% at 10 μM.

[0667] Table 3. Analysis of Tyk2 and JAK2 radiokinases

[0668]

[0669]

[0670]

[0671]

[0672]

[0673]

[0674]

[0675]

[0676]

[0677]

[0678]

[0679]

[0680]

[0681]

[0682]

[0683]

[0684]

[0685]

[0686]

[0687]

[0688]

[0689]

[0690]

[0691]

[0692] Example 5. Analysis of Tyk2 and JAK2 calipers

[0693] The caliper machine employed off-chip mobility variation analysis, using microfluidics to detect phosphorylated peptide acceptors from kinase assays. The analysis was performed at an ATP concentration equivalent to ATP Km and at 1 mM ATP. Compounds were serially diluted in DMSO, followed by further dilution in analysis buffer (25 mM HEPES pH 7.5, 0.01% Brij-35, 0.01% Triton, 0.5 mM EGTA). Initially, 5 μl of the diluted compound was added to each well, followed by 10 μl of the enzyme mixture, and then 10 μL of the acceptor mixture (peptide and ATP in 10 mM MgCl2) to initiate the reaction. The reaction was incubated at 28°C for 25 minutes, followed by the addition of 25 μl of stop buffer (100 mM HEPES, 0.015% Brij-35, 50 mM EDTA), and then read using calipers. 1 nM JAK2 and 9.75 nM TYK2 were derived from Carna, using 20 μM and 16 μM ATP as the reactants, respectively. JAK2 analysis used peptide 22 and TYK2 analysis used peptide 30 (calipers), each at 3 μM.

[0694] Example 6. IL-12-induced pSTAT4 in human PBMCs

[0695] Human PBMCs were isolated from leukocytes and, if necessary, cryopreserved for analysis. Analytical cells were thawed and resuspended in complete medium containing serum, then diluted to 1.67 E6 cells / mL to provide 200,000 cells per 120 μL well. 15 µL of the desired concentration of compound or DMSO was added to each well, and the cells were incubated at 37°C for 1 hour. Prior to pSTAT4 and total STAT4 analysis using the prepared cell lysate, 15 µL of the stimulant (final concentration 1.7 ng / mL IL-12) was added, incubated for 30 minutes, and analyzed using MSD reagents according to the manufacturer's protocol. The final DMSO concentration for the analytical compound was 0.1%.

[0696] IL-12-induced pSTAT4 analysis evaluated the inhibition of IL-12-induced STAT4 phosphorylation mediated by Tyk2 / JAK2 (heterodimeric complex).

[0697] The results of IL-12-induced pSTAT4 in human PBMCs are presented in Table 4. The IC50 values ​​of compounds designated as "A" are listed below. 50 Below 0.1 μM; IC50 of compounds designated as "B" 50 Between 0.1 and 0.5 μM; IC50 of compounds designated as "C" 50The IC50 values ​​for compounds between 0.5 and 1.0 μM and denoted as “D” are within the range of 0.5 to 1.0 μM. 50 Greater than 1.0 μM.

[0698] Table 4. Results of IL-12-induced pSTAT4 analysis in human PBMCs.

[0699]

[0700]

[0701]

[0702]

[0703]

[0704]

[0705]

[0706]

[0707] Example 7. GM-CSF-induced pSTAT5 in human PBMCs

[0708] Cells for analysis were prepared as described above. Before using the prepared cell lysate for pSTAT5 and total STAT5 analysis, 15 μl of GM-CSF (final concentration 5 ng / mL) was added, incubated for 20 minutes, and analyzed using MSD reagents according to the manufacturer's instructions. The final DMSO concentration of the compounds used in the analysis was 0.1%.

[0709] The GM-CSF-induced pSTAT5 assay is a JAK2 cell-selective assay that evaluates the inhibition of GM-CSF-induced STAT5 phosphorylation mediated by the JAK2 / JAK2 homodimer complex.

[0710] The results of GM-CSF-induced pSTAT5 analysis are presented in Table 5. The IC50 values ​​of compounds designated as "A" are listed below. 50 >50 μM; IC50 of compounds designated as "B" 50 Results >12.5 μM, >20 μM, >25 μM, or >30 μM; IC50 of compounds designated as "C" 50 Results >2.5 μM or >10 μM; and the IC50 of compounds indicated by "D" 50 Results >0.3 μM, >0.5 μM, or >1.0 μM.

[0711] Table 5. Results of pSTAT5 analysis induced by GM-CSF.

[0712]

[0713]

[0714]

[0715]

[0716]

[0717]

[0718]

[0719]

[0720] Example 8. Study on IL-12-induced IFNγ in isolated mice

[0721] C57 / BL6 mice were administered a single oral dose of the drug or different doses of the compound at a volume of 10 mL / kg. Animals were euthanized 30 minutes to 1 hour after administration, and blood was collected via the vena cava into heparin sodium blood collection tubes, which were then inverted several times. The blood was then spread onto anti-CD3 plates and stimulated for 24 hours at 37°C in a humidified incubator with 5% CO2 using RPMI medium containing 2 ng / ml mouse IL-12. At the end of the incubation, the blood was centrifuged at 260 g for 5 minutes to collect the supernatant. The IFNγ concentration in the supernatant was determined using a mouse IFNγ MSD kit according to the manufacturer's instructions (Meso Scale Discovery). Plasma was collected during blood collection for drug content analysis by LC-MS / MS.

[0722] Example 9. T-ALL cell proliferation analysis

[0723] T-ALL cells, including KOPT-K1, HPB-ALL, DND-41, PEER, and CCRF-CEM, were cultured in RPMI-1640 medium containing 10% fetal bovine serum and penicillin / streptomycin. Three copies were prepared, with 1 × 10⁶ cells per well. 4 Cells were plated into 96-well plates. T-ALL cells, DU.528, LOUCY, and SUP-T13, were cultured in the same medium at a density of 1.5 × 10⁶ cells per well. 4Cell density was plated. Cells were treated with DMSO or different concentrations of the compounds of this invention. Cell viability after 72 hours of drug exposure was assessed using CellTiter-Glo luminescence cell viability assay (Promega). CellTiter-Glo reagent was added to the wells and incubated for 10 minutes. Luminescence was then measured using a 96-well plate luminescence reader. Cell viability was calculated using the DMSO-treated sample as 100%. IC50 was calculated using nonlinear regression with GraphPadPrism software. 50 value.

[0724] Example 10: N-((1R,2S)-2-fluorocyclopropyl)-5-((2-methoxypyridin-3-yl)amino)-7-((2-(N-morpholino)ethyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide I-388.

[0725]

[0726] Compound 1 was synthesized according to the experimental protocol of I-387, yielding 1 (yield: 64.66%). MS (ES): m / z 426.15 [M+H] + .

[0727] Compound 1.1. was synthesized using general procedure A, yielding 1.1. (0.200 g, 39.19%), MS (ES): 483.19 [M+H]. + .

[0728] Compound 1.2 was synthesized using general procedure B to give 1.2 (0.058 g, 24.54%), MS (ES): 571.27 [M+H). + .

[0729] Synthesis of compound I-388: The compound was synthesized using the general procedure C to give I-388 (0.036 g, 75.28%), MS (ES): m / z 471.56 [M+H] + LCMS purity: 98.38%, HPLC purity: 98.69%. 1H NMR (DMSO-d6,400MHZ): 8.90 (s, 1H), 8.21 (s, 2H), 7.89-7.88 (d, J=3.6Hz 1H), 7.82-7.81 (d,J=4.4Hz, 1H), 7.67 (s, 1H), 6.99-6.96 (m, 1H), 6.05(s, 1H), 4.87-4.71 (m,1H), 3.96 (s, 3H), 3.59 (s, 4H) 3.34 (s, 2H), 2.90-2.89 (d, J=4Hz ,1H), 2.63-2.59 (t, J=13.2Hz, 2H), 2.47 (s, 4H), 1.20-1.10 (m, 1H), 0.76 (bs, 1H).

[0730] Example 11: N-cyclopropyl-7-(cyclopropylamino)-5-((2-methoxypyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide I-336.

[0731]

[0732] Compound 11 was synthesized using the general procedure for synthesis in core A, yielding 11.

[0733] Compound 11.2 was synthesized. Potassium carbonate (2.92 g, 21.15 mmol, 1.1 eq) was added to a solution of 1 (5 g, 19.23 mmol, 1.0 eq) and 11.1 (1.21 g, 21.15 mmol, 1.1 eq) in ethanol (50 mL). The reaction mixture was stirred at room temperature for 2 h. After the reaction was complete, the reaction mixture was transferred to ice-cold water and the product was extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to give the crude substance. It was further purified by column chromatography, and the compound was eluted in 13% ethyl acetate / hexane to give pure 1.2 (4 g, 74.12%). MS (ES): m / z 281.71 [M+H] + .

[0734] Compound 11.3 was synthesized. Di-tert-butyl dicarbonate (4.66 g, 21.37 mmol, 1.5 eq) and 4-dimethylaminopyridine (0.173 g, 1.42 mmol, 0.1 eq) were added to a cold solution of 11.2 (4 g, 14.25 mmol, 1.0 eq) in dioxane (30 mL). The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was transferred to water and the product was extracted with ethyl acetate. The combined organic layers were washed with a saline solution, dried over sodium sulfate, and concentrated under reduced pressure to give the crude substance. This was further purified by column chromatography, and the compound was eluted in 11% ethyl acetate / hexane to give 1.3 (4.2 g, 77.44%). MS (ES): m / z 381.83 [M+H] + .

[0735] Compound 11.5 was synthesized. Potassium tert-butoxide (5.2 mL, 5.26 mmol, 2.5 eq) was added to a cold solution of 11.3 (0.800 g, 2.10 mmol, 1.0 eq) and 11.4 (0.290 g, 2.31 mmol, 1.1 eq) in dimethylformamide (8 mL). The reaction mixture was stirred at room temperature for 30 min. After the reaction was complete, the reaction mixture was transferred to a saturated bicarbonate solution and the product was extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to give the crude substance. This was further purified by column chromatography, and the compound was eluted in 18% ethyl acetate / hexane to give pure 1.5 (0.500 g, 50.80%). MS (ES): m / z 469.51 [M+H] + .

[0736] Compound 11.6 was synthesized. Lithium hydroxide (0.449 g, 10.7 mmol, 10 eq) was added to a solution of 11.5 (0.500 g, 1.07 mmol, 1.0 eq) in tetrahydrofuran:methanol:water (20 mL, 2:1:1). The reaction mixture was stirred at 80 °C for 16 h. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to give a residue. Water was added to the residue at 10 °C and acidified with 1 N hydrochloric acid to adjust the pH to approximately 6–6.5. The product was extracted with dichloromethane. The combined organic layers were washed with a brine solution, dried over sodium sulfate, and concentrated under reduced pressure to give a crude substance. This crude substance was further purified by column chromatography, and the compound was eluted in 2.2% methanol / dichloromethane to give pure 11.6 (0.400 g, 85.10%). MS (ES): m / z 441.46 [M+H] + .

[0737] Compound 11.7 was synthesized using general procedure A to give 11.7 (0.060 g, 55.11%). MS (ES): m / z 480.44 [M+H] + .

[0738] Synthesized compound I-336. The compound was synthesized using the general procedure C to give I-336 (0.025 g, 52.66%). MS (ES): m / z 380.39 [M+H] + LCMS purity: 100%, HPLC purity: 99.13%. 1 H NMR (DMSO-d6,400MHZ): 9.09 (s, 1H), 8.19 (s, 1H), 8.14 (s, 1H), 7.949-7.941 (d, J= 3.2Hz,1H), 7.80 (s, 1H), 7.07-7.04 (m, 1H), 6.84 (m, 1H), 6.23 (s, 1H), 3.96 (s,3H), 1.56 (bs, 1H), 1.24 (m, 1H), 0.84-00.82 (m, 2H), 0.72-0.69 (m, 4H),0.34-0.36 (m, 2H).

[0739] Example 12: 7-(cyclopropylamino)-N-((1R,2S)-2-fluorocyclopropyl)-5-((2-methoxypyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide I-337.

[0740]

[0741] Compound 12. The compound was synthesized according to the experimental protocol of I-336.

[0742] Compound 12.2 was synthesized using general procedure B, yielding 1.2 (0.070 g, 61.97%), MS (ES): m / z 498.53 [M+H]. + .

[0743] Synthesis of compound I-337: The compound was synthesized using the general procedure C to give I-337 (0.050 g, 89.42%), MS (ES): m / z 398.17 [M+H] + LCMS purity: 100%, HPLC purity: 99.62%, chiral HPLC purity: 100%. 1H NMR(DMSO-d6, 400MHZ): 9.07 (s, 1H), 8.22 (s, 1H), 8.20 (s, 1H), 8.18 (s, 1H), 7.91-7.90 (d, J=4Hz, 1H), 7.83-7.82 (d, J=4Hz, 1H), 7.01-6.99 (t, J=8Hz, 1H),6.28 (s, 1H), 4.87-4.69 (m, 1H), 3.96 (s, 3H), 2.91-2.88 (m, 1H), 2.60 (bs,1H), 1.26-1.10 (m, 2H), 0.86-0.82 (m, 2H), 0.79-0.68 (m, 2H).

[0744] Example 13: N-((1R,2S)-2-fluorocyclopropyl)-5-((2-methoxypyridin-3-yl)amino)-7-((methyl-d3)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide I-374.

[0745]

[0746] Compound 13. The compound was synthesized according to the experimental procedure of the core synthesis

[0002] (yield: 69.85%). MS (ES): m / z 261 [M+H] + .

[0747] Compound 13.1 was synthesized. Methyl-D3-amine (0.215 g, 6.33 mmol, 1.1 eq) was added to a solution of 13 (1.5 g, 5.76 mmol, 1.0 eq) in ethanol (20 mL). The reaction mixture was degassed under an argon atmosphere for 10 min, followed by the addition of potassium carbonate (0.873 g, 6.33 mmol, 1.1 eq). The reaction mixture was stirred at room temperature for 5 h. After the reaction was complete, the reaction mixture was transferred to ice-cold water and the product was extracted with ethyl acetate. The combined organic layers were washed with a brine solution, dried over sodium sulfate, and concentrated under reduced pressure to give the crude substance. Further purification with 20% ethyl acetate / hexane gave 13.1 (1.5 g, 100% yield). MS (ES): m / z 258.08 [M+H] + .

[0748] Compound 13.2 was synthesized. N,N-dimethylaminopyridine (0.071 g, 0.58 mmol, 0.1 eq) was added to a solution of 13.1 (1.5 g, 5.82 mmol, 1.0 eq) in 1,4-dioxane (15 mL), followed by di-tert-butyl dicarbonate (2.53 g, 11.64 mmol, 2.0 eq), and the reaction mixture was stirred at room temperature for 12 hours. After the reaction was complete, the reaction mixture was transferred to water and the product was extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to give the crude substance. This was further purified by column chromatography, and the compound was eluted in 12% ethyl acetate / hexane to give 13.2 (1.2 g, 57.62%). MS (ES): m / z 358.13 [M+H] + .

[0749] Compound 13.3 was synthesized by adding tributyltin oxide (3.99 g, 6.7 mmol, 2.0 eq) to a suspension of 13.2 (1.2 g, 3.35 mmol, 1.0 eq) in toluene (20 mL) and heating the reaction mixture at 120 °C for 12 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain a residue, which was dissolved in a saturated sodium bicarbonate solution and washed with hexane. The aqueous layer was separated and acidified to approximately pH 5-6 with 1 N hydrochloric acid and extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to obtain a solid, which was wet-milled with hexane to give pure 13.3 (1 g, 90.42%). MS (ES): m / z 330.10 [M+H] + .

[0750] Compound 13.5 was synthesized using general procedure A to give 13.5 (0.480 g, 40.92%), MS (ES): 387.14 [M+H). + .

[0751] Compound 13.7 was synthesized using general procedure B, yielding 13.7 (0.065 g, 52.99%), MS (ES): 475.23 [M+H]. + .

[0752] Synthesis of compound I-374: The compound was synthesized using the general procedure C to give I-374 (0.028 g, 54.60%), MS (ES): m / z 375.30 [M+H] + LCMS purity: 99.13%, HPLC purity: 98.12%, chiral HPLC purity: 98.42%. 1H NMR(DMSO-d6, 400MHZ): 8.92 (s, 1H), 8.24-8.20 (t, J=7.6Hz, 2H), 7.91-7.89 (m,2H), 7.83-7.82 (d, J=4.4Hz, 1H), 7.00-6.97 (m, 1H), 5.94 (s, 1H), 4.87-4.72 (m, 1H), 2.90 (bs, 1H), 1.24-1.13 (m, 2H), 1.05-1.04 (m, 2H), 0.76-0.70 (m, 1H).

[0753] Example 14: 5-((2-cyclopropoxypyridin-3-yl)amino)-N-((1R,2S)-2-fluorocyclopropyl)-7-((methyl-d3)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide I-375.

[0754]

[0755] Compound 14 was synthesized according to the experimental protocol of I-374, yielding 14 (yield: 40.92%), MS (ES): m / z 387.14 [M+H]. + .

[0756] Compound 14.1 was synthesized according to the experimental protocol of I-366, yielding 14.1 (yield: 79.98%), MS (ES): m / z 151.18 [M+H]. + .

[0757] Compound 14.2 was synthesized using general procedure B, yielding 14.2 (0.070 g, 54.10%), MS (ES): 501.24 [M+H]. + .

[0758] Synthesis of compound I-375: The compound was synthesized using the general procedure C to give I-375 (0.035 g, 62.50%), MS (ES): m / z 401.50 [M+H] + LCMS purity: 96.08%, HPLC purity: 97.25%, chiral HPLC purity: 99.31%. 1H NMR(DMSO-d6, 400MHZ): 8.69 (s, 1H), 8.19 (s, 2H), 7.92 (bs, 2H), 7.81-7.80 (d, J=4.4Hz, 1H), 7.01-6.98 (m, 1H), 5.89 (s, 1H), 2.90 (bs, 1H), 1.19-1.12 (m,1H), 1.24 (bs, 2H), 0.76-0.75 (m, 5H).

[0759] Example 15: N-((1R,2S)-2-fluorocyclopropyl)-5-((2-methoxypyridin-3-yl)amino)-7-((3-(N-morpholino)propyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide I-377.

[0760]

[0761] Compound 15 was synthesized according to the experimental protocol of I-376, yielding 1 (yield: 78.4%), MS (ES): m / z 588.44 [M+H]. + .

[0762] Synthesizing Compound 15.2. To a solution of 1 (0.150 g, 0.284 mmol, 1.0 eq) in N,N-dimethylformamide (2 mL), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (0.216 g, 0.569 mmol, 2.0 eq) was added and stirred at room temperature for 15 min. Diisopropylethylamine (0.3 mL, 1.42 mmol, 5.0 eq) was added, followed by 1 (0.140 g, 0.569 mmol, 2.0 eq). The reaction mixture was stirred at room temperature for 30 min. After the reaction was complete, the reaction mixture was transferred to water and the product was extracted with ethyl acetate. The combined organic layers were washed with a brine solution, dried over sodium sulfate, and concentrated under reduced pressure to give the crude substance. The compound was further purified by column chromatography, and eluted in 1.5% dichloromethane / methanol to give 1.2 (0.130 g, 93.2%). MS (ES): m / z 485.1 [M+H] + .

[0763] Synthesis of compound I-377: The compound was synthesized using the general procedure C to give I-377 (0.050 g, 55.56%), MS (ES): m / z 485.26 [M+H] + LCMS purity: 95.78%, HPLC purity: 96.31%.1 H NMR (DMSO-d6,400MHZ): 8.87 (s, 1H), 8.24-8.23 (m, 3H), 7.90-7.89 (d, J=3.6Hz, 1H), 7.83-7.82 (d, J=4.8Hz, 1H), 7.00-6.97 (m, 1H), 6.02 (s, 1H), 4.87 (s, 2H), 3.96 (s, 3H), 3.63 (s, 3H), 2.92-2.90 (t, J=9.6Hz, 1H) 2.42-2.39 (d, J=12.8Hz, 6H), 1.86-1.83 (t, J=13.2Hz, 2H), 1.21-1.08 (m, 2H), 0.87 (s, 1H), 0.78 (s, 1H).

[0764] Example 16: N-cyclopropyl-5-((2-methoxypyridin-3-yl)amino)-7-((3-(N-morpholino)propyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide I-376.

[0765]

[0766] Compound 16 was synthesized using the core synthesis general procedure

[0002] , yielding 16 (35 g, 69.85%). MS (ES): m / z 261 [M+H] + .

[0767] Compound 16.2 was synthesized. 16.2 (1.3 g, 9.30 mmol, 1.1 eq) was added to a solution of 16 (2.2 g, 8.46 mmol, 1.0 eq) in ethanol (25 mL), and the mixture was stirred at room temperature for 5 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, transferred to water, and the product was extracted with ethyl acetate. The organic layers were combined, washed with a saline solution, dried over sodium sulfate, and concentrated under reduced pressure to give the crude compound. This crude compound was further purified by column chromatography, and the compound was eluted in 1.2% methanol / dichloromethane to give pure 16.2 (1.5 g, 48.21%). MS (ES): m / z 368.83 [M+H] + .

[0768] Compound 16.3 was synthesized. N,N-dimethylaminopyridine (49 mg, 40.8 mmol, 0.1 eq) was added to a solution of 16.2 (1.5 g, 4.08 mmol, 1.0 eq) in 1,4-dioxane (15 mL), followed by the addition of di-tert-butyl dicarbonate (1.7 g, 8.15 mmol, 2.0 eq), and the reaction mixture was stirred at room temperature for 12 hours. After the reaction was complete, the reaction mixture was transferred to water and the product was extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to give the crude substance. This was further purified by column chromatography, and the compound was eluted in 12% ethyl acetate / hexane to give 16.3 (1.5 g, 78.61%). MS (ES): m / z 468.9 [M+H] + .

[0769] Compound 16.5 was synthesized. Potassium tert-butoxide (8.5 mL, 8.52 mmol, 2.0 eq) was added to a suspension of 16.3 (2 g, 4.21 mmol, 1.0 eq) and 1.4 (0.7 g, 5.55 mmol, 1.3 eq) in tetrahydrofuran (40 mL), and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give a solid. This solid was further purified by column chromatography, and the compound was eluted in 50% ethyl acetate / hexane to give pure 16.5 (2 g, 84.42%), MS (ES): m / z 556.28 [M+H]. + .

[0770] Compound 16.6 was synthesized. Lithium hydroxide (1.5 g, 36.01 mmol, 10 eq) was added to a suspension of 16.5 (2 g, 3.60 mmol, 1.0 eq) in tetrahydrofuran:water (20 mL, 2:1). The reaction mixture was stirred at 50 °C for 16 h. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to give the residue. Water was added to the residue at 10 °C and acidified with 1 N hydrochloric acid to adjust the pH to approximately 6–6.5. The product was extracted with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to give 16.6 (1.5 g, 78.4%). MS (ES): m / z 528.44 [M+H] + .

[0771] Compound 16.7 was synthesized using general procedure A, yielding 16.7 (0.480 g, 40.92%), MS (ES): 567.1 [M+H]. + .

[0772] Synthesis of compound I-376: The compound was synthesized using the general procedure C to give I-376 (0.050 g, 60.73%), MS (ES): m / z 467.3 [M+H] + LCMS purity: 100%, HPLC purity: 95.21%. 1 H NMR (DMSO-d6, 400MHZ):8.89 (s, 1H), 8.23-8.19 (m, 2H), 8.15 (s, 1H), 7.93-7.92 (m, 1H), 7.80-7.79(d, J=4.0Hz, 1H), 7.04-7.01 (m, 1H), 5.97 (s, 1H), 3.96 (s, 3H), 3.64-3.62(m, 4H), 3.35-3.33 (m, 2H), 2.81-2.77 (m, 1H), 2.44-2.39 (m, 6H), 1.86-1.82(m, 2H), 0.73-0.69 (m, 2H), 0.38-0.34 (m, 2H).

[0773] Example 17: N-cyclopropyl-5-((2-methoxypyridin-3-yl)amino)-7-((2-(N-morpholino)ethyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide I-387.

[0774]

[0775] Compound 17.2 was synthesized. 17.1 (1.20 g, 9.30 mmol, 1.1 eq) was added to a solution of 17 (2.2 g, 8.46 mmol, 1.0 eq) in ethanol (22 mL). The reaction mixture was degassed under an argon atmosphere for 10 min, followed by the addition of potassium carbonate (1.28 g, 9.3 mmol, 1.1 eq). The reaction mixture was heated at room temperature for 5 h. After the reaction was complete, the reaction mixture was transferred to ice-cold water and the product was extracted with ethyl acetate. The combined organic layers were washed with a brine solution, dried over sodium sulfate, and concentrated under reduced pressure to give the crude compound. Further purification with 20% ethyl acetate / hexane gave 17.2 (1.8 g, yield: 60.14%). MS (ES): m / z 354.13 M+H] + .

[0776] Compound 17.3 was synthesized by adding N,N-dimethylaminopyridine (0.062 g, 0.50 mmol, 0.1 eq) to a solution of 17.2 (1.8 g, 5.09 mmol, 1.0 eq) in 1,4-dioxane (20 mL), followed by the addition of di-tert-butyl dicarbonate (1.66 g, 7.63 g, 1.5 eq), and stirring the reaction mixture at room temperature for 16 hours. After the reaction was complete, the reaction mixture was transferred to water, and the product was extracted with dichloromethane. The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to give the crude substance. This crude substance was further purified by column chromatography, and the compound was eluted in 15% ethyl acetate / hexane to give 17.3 (1.5 g, 64.95%). MS (ES): m / z 454.18 [M+H] + .

[0777] Compound 17.4 was synthesized. Lithium hydroxide (1.39 g, 33.1 mmol, 10 eq) was added to a solution of 17.3 (1.5 g, 3.31 mmol, 1.0 eq) in tetrahydrofuran:methanol:water (10 mL, 2:2:1). The reaction mixture was stirred at 60 °C for 16 h. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to give the residue. Water was added to the residue at 10 °C and acidified with 1 N hydrochloric acid to adjust the pH to approximately 6–6.5. The product was extracted with dichloromethane. The combined organic layers were washed with a brine solution, dried over sodium sulfate, and concentrated under reduced pressure to give the crude substance. This was further purified by column chromatography, and the compound was eluted in 2.1% methanol / dichloromethane to give pure 17.4 (0.910 g, 64.66%). MS (ES): m / z 426.15 [M+H] + .

[0778] Compound 17.5 was synthesized using general procedure A to give 17.5 (0.170 g, 34.60%), MS (ES): 465.20 [M+H]. + .

[0779] Compound 17.6 was synthesized using general procedure B, yielding 17.6 (0.070 g, 45.30%), MS (ES): 553.28 [M+H]. + .

[0780] Synthesis of compound I-387: The compound was synthesized using the general procedure C to give I-387 (0.034 g, 59.32%), MS (ES): m / z 453.51 [M+H] + LCMS purity: 99.67%, HPLC purity: 99.85%. 1H NMR (DMSO-d6,400MHZ): 8.92 (s, 1H), 8.22-8.20 (d, J=6.4Hz, 2H), 7.93-7.92 (d, J=3.6Hz 1H), 7.79-7.78 (d, J=3.6Hz, 1H), 7.64 (s, 1H), 7.04-7.00 (m, 1H), 6.00 (s, 1H), 3.95 (s, 3H), 3.59 (s, 4H), 3.34 (s, 2H), 2.80-2.76 (s, 1H), 2.62-2.60 (d, J=6.8Hz, 2H), 2.59-2.46 (m, 4H), 0.73-0.68 (m, 2H), 0.36 (bs, 2H).

[0781] Example 18: 7-amino-5-((3'-fluoro-2-oxo-2H-[1,2'-bipyridine]-3-yl)amino)-N-((1R,2S)-2-fluorocyclopropyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide I-954.

[0782]

[0783] Compound 18 was synthesized using the core synthesis protocol. MS (ES): m / z 421.14 [M+H] + .

[0784] Compound 18.1 was synthesized according to the experimental protocol of Example 19 (I-144), yielding 18.1 (yield: 80.70%), MS (ES): m / z 206.29 [M+H]. + .

[0785] Synthesis of compound 18.2: Potassium tert-butoxide (1M tetrahydrofuran solution) (0.5 mL, 0.46 mmol, 2.0 eq) was added to a cold solution of 18 (0.1 g, 0.23 mmol, 1.0 eq) in tetrahydrofuran (2 mL) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. After the reaction was complete, the reaction mixture was transferred to water and the product was extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to give the crude substance. It was further purified by column chromatography, and the compound was eluted in 25% ethyl acetate / hexane to give pure 18.2 (0.089 g, 63.53%). MS (ES): m / z 590.23 [M+H]+ .

[0786] Compound 18.3 was synthesized. Lithium hydroxide (0.036 g, 1.5 mmol, 10 eq) was added to a solution of 18.2 (0.089 g, 0.15 mmol, 1.0 eq) in tetrahydrofuran:methanol (2 mL, 1:1). The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to give a residue. Water was added to the residue at 10 °C and acidified with 1 N hydrochloric acid to adjust the pH to approximately 6–6.5. The product was extracted with dichloromethane. The combined organic layers were washed with a brine solution, dried over sodium sulfate, and concentrated under reduced pressure to give 18.3 (0.079 g, 93.20%). MS (ES): m / z 562.20 [M+H] + .

[0787] Compound 18.5 was synthesized using general procedure A to give 18.5 (0.059 g, 67.79%), MS (ES): m / z 619.23 [M+H]. + .

[0788] Synthesis of compound I-954: A mixture of 18.5 g (0.059 g, 0.95 mmol, 1.0 eq) in 1.0 mL of dichloromethane was cooled to 0 °C, and trifluoromethanesulfonic acid (1 mL) was added. The mixture was stirred at the same temperature for 10 min. After the reaction was complete, the reaction mixture was transferred to a 1 N sodium hydroxide solution and the product was extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give a crude substance. It was further purified by wet milling with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give a crude substance. It was further purified by wet milling with diethyl ether to give I-954 (0.033 g, 78.93%), MS (ES): m / z 439.61 [M+H] + LCMS purity: 98.70%, HPLC purity: 98.19%, chiral HPLC purity: 100%. 1H NMR (DMSO-d6, 400MHZ): 9.05 (bs, 1H), 8.51-8.50 (d, J=4.4Hz, 1H), 8.24 (s, 1H), 8.22-8.20 (d, J=7.2Hz, 1H), 8.08-8.03 (t, J=8.4Hz, 1H), 7.85-7.84 (d, J=4.4Hz, 1H), 7.74-7.70 (m, 3H), 4.44-7.43 (d, J=1.2Hz, 1H), 6.43-6.39 (t, J=7.2Hz, 1H), 6.13 (bs, 1H), 4.97-4.95 (m, 1H), 4.80 (bs, 1H), 3.00-2.97 (m, 1H), 1.26-1.18 (m, 1H).

[0789] Example 19: 5-((3'-fluoro-2-oxo-2H-[1,2'-bipyridine]-3-yl)amino)-N-((1R,2S)-2-fluorocyclopropyl)-7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide I-144.

[0790]

[0791] Compound 19.2 was synthesized. 19.1 (7.34 g, 63.79 mmol, 1.1 eq) was added to a solution of 19 (10 g, 57.47 mmol, 1.0 eq) in 1-methylpyrrolidone-2-one (240 mL), followed by the addition of cesium carbonate (46.81 g, 143.67 mmol, 2.5 eq). The reaction mixture was heated at 110 °C for 15 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, transferred to cold water, and the product was extracted with ethyl acetate. The organic layers were combined, washed with a brine solution, dried over sodium sulfate, and concentrated under reduced pressure to give the crude substance. This crude substance was further purified by column chromatography using 50% ethyl acetate / hexane as eluent to give 19.2 (2.6 g, 16.81%). MS (ES): m / z 269.04 [M] + .

[0792] Compound 19.3 was synthesized. Copper powder (0.073 g, 1.15 mmol, 0.12 eq), L-ascorbic acid (0.34 g, 1.93 mmol, 0.2 eq), DL-piperidinic acid (0.37 g, 2.89 mmol, 0.3 eq), and sodium azide (2.26 g, 34.77 mmol, 3.6 eq) were added to a solution of 19.2 (2.6 g, 9.66 mmol, 1.0 eq) in ethanol (26 mL). The reaction mixture was heated at 100 °C for 16 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, transferred to cold water, and extracted with ethyl acetate. The organic layers were combined, washed with a brine solution, dried over sodium sulfate, and concentrated under reduced pressure to give the crude substance. This crude substance was further purified by column chromatography using 55-60% ethyl acetate / hexane as the eluent to give 19.3 (1.6 g, 80.70%). MS(ES): m / z 206.29 [M+H] + .

[0793] Compound 19.4 was synthesized using the general procedure of the core synthesis, yielding 19.4 (yield: 71.67%).

[0794] Synthesizing compound 19.6: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (15.12 g, 39.79 mmol, 1.3 eq) was added to a solution of 19.4 (10 g, 30.61 mmol, 1.0 eq) in N,N-dimethylformamide (300 mL) and stirred at room temperature for 15 min. Then, 19.5 (7.5 g, 30.61 mmol, 1.0 eq) was added, followed by diisopropylethylamine (16 mL, 91.83 mmol, 3.0 eq). The reaction mixture was stirred at room temperature for 5 min. After the reaction was complete, the reaction mixture was transferred to water and the product was extracted with ethyl acetate. The combined organic layers were washed with a brine solution, dried over sodium sulfate, and concentrated under reduced pressure to give the crude substance. The compound was further purified by column chromatography, and eluted in 35% ethyl acetate / hexane to give 19.6 g (6 g, 51.08%). MS (ES): m / z 384.8 [M+H] + .

[0795] Compound 19.7 was synthesized using general procedure B to give 1.7 (yield: 42.78%). MS (ES): m / z 553.47 [M+H] + .

[0796] Synthesis of compound I-144. The compound was synthesized using the general procedure C, yielding I-144 (yield: 91.05%). MS (ES): m / z 453.40 [M+H] + LCMS purity: 100%, HPLC purity: 99.68%, chiral HPLC purity: 99.34%. 1 H NMR(DMSO-d6, 400MHZ): 9.02 (s, 1H), 8.52-8.51 (d, J=4.4Hz, 1H), 8.30-8.27 (m,2H), 8.09-8.05 (t, J=8.8Hz, 1H), 7.99-7.98 (d, J=4.8Hz, 1H), 7.84-7.83 (d, J=4.4Hz, 1H), 7.75-7.71 (m, 1H), 7.44-7.43 (d, J=5.6Hz, 1H), 6.45-6.41 (t, J=7.2Hz, 1H), 6.25 (s, 1H), 5.01-4.83 (m, 1H), 3.03-3.00 (m, 1H), 2.91-2.90 (d,J=4.8Hz, 3H), 1.28-1.22 (m, 1H), 0.96-0.87 (m, 1H).

[0797] In addition, as described below, a modified synthesis method for I-144 has been developed.

[0798] Modify the synthetic route.

[0799]

[0800]

[0801] manufacture

[0802] Unless otherwise instructed, all reactions and processes are carried out under an inert atmosphere of N2 gas.

[0803] Synthesized compound 19.6

[0804]

[0805] Raw materials, solvents and reagents list

[0806] Table 6. Reagents and conditions for preparing 19.6.

[0807]

[0808] Process Description

[0809] 1. Under nitrogen protection, DCM (5.5 L, 10 V), 19.4 (550 g, 1.0 eq.) and TEA (681 g, 4.0 eq.) were added to the reactor.

[0810] 2. At 20-30℃, add T3P (750 g, 1.4 eq.) dropwise into the reactor.

[0811] 3. Stir at 20-30℃ for 20 minutes.

[0812] 4. Compound 19.5 (539 g, 1.3 eq.) was added to the reactor in fractional batches at 20-30 °C.

[0813] 5. Stir for 2 hours under nitrogen atmosphere at 20-30°C.

[0814] 6. Samples were subjected to IPC (84% purity).

[0815] 7. Add 1.0 N K2CO3 aqueous solution (11 L, 20 V) to the reactor and adjust the pH of the aqueous solution to 9-10 using K2CO3 powder.

[0816] 8. Stir for 30 minutes.

[0817] 9. Separate by adding 1.0 N K2CO3 aqueous solution (4 L, 10 V) to the organic phase.

[0818] 10. Stir for 30 minutes.

[0819] 11. Separate. Repeat steps 10-12 up to 4 times.

[0820] 12. Wash the organic layer with brine (1.4 L, 2.5 V). Concentrate the organic phase to 1 V under vacuum at 40 °C. Add EA (1.65 L, 3 V) to the residue and concentrate the organic phase to 1 V under vacuum at 50 °C.

[0821] 13. Add heptane (2.75 L, 5 V) to the residue, stir for 30 minutes, and filter.

[0822] 14. The filter cake was collected and dried to constant weight at 60°C under vacuum to obtain 494 g of compound 19.6 with a purity of 99.27% ​​and a separation yield of 76.5%.

[0823] Synthesized compound 19.3

[0824]

[0825] Table 7. Reagents and conditions for preparing 19.3.

[0826]

[0827] Process Description

[0828] 1. Under nitrogen protection, DMA (3.0 L, 20 V), compound 19a hydrochloride (150 g, 1.0 eq.), compound 19.1 (152.6 g, 1.3 eq.) and K3PO4 (780 g, 3.6 eq.) were added to the reactor.

[0829] 2. Heat to 90~95℃.

[0830] 3. Stir overnight at 90~95℃.

[0831] 4. Samples were taken for IPC (HPLC showed that compound 19a was 4.1%).

[0832] 5. Cool to 15~25℃.

[0833] 6. Add DCM (3.0 L, 20 V) and water (3.0 L, 20 V) to the reactor and stir for 0.5 hours.

[0834] 7. Filter through a diatomaceous earth pad (300 g, 2 w / w, 15 cm wide and packed to a height of 3-4 cm), and wash the pad with DCM (1.5 L, 10 V). If no diatomaceous earth pad is available, emulsification will occur during extraction.

[0835] 8. Separate by extracting the aqueous phase three times with DCM (3.0 L, 20 V). (Note: Approximately 5% of compound 19.3 is lost in the aqueous phase.)

[0836] 9. Combine the organic phases and wash three times with brine (1.5 L, 10°C). (Note: Approximately 5% of compound 19.3 is lost in the brine.)

[0837] 10. Under vacuum, the organic phase was concentrated at 60°C until no separation occurred, yielding a crude oily substance (analytical yield 75%).

[0838] 11. Add the residue dropwise to heptane (7.5 L, 50 V) and stir at 20-30°C for 2 hours.

[0839] 12. Filter and wash the filter cake with heptane (1.5 L, 10 V).

[0840] 13. Add EA (0.3 L, 2 V) and crude solid (HPLC: 92%) to the reactor and stir for 2 hours. Then add heptane (1.2 L, 8 V) dropwise to the mixture and stir for 2 hours.

[0841] 14. Filter, collect the filter cake and dry it to constant weight at 60°C under vacuum to give 141.2 g of compound 19.3 with a purity of 97.41% and a separation yield of 67.2%.

[0842] Synthesized compound 19.7

[0843]

[0844] Table 8. Reagents and conditions for preparing 19.7.

[0845]

[0846] Process Description

[0847] 1. Under nitrogen protection, DME (2.4 L, 10 V), compound 19.3 (240 g, 1.0 eq.), compound 19.6 (514 g, 1.15 eq.) and Na2CO3 (272 g, 2.2 eq.) were added to the reactor.

[0848] 2. Stir for 15 minutes at room temperature and allow nitrogen to bubble at the liquid level.

[0849] 3. Under nitrogen atmosphere, Pd2(dba)3 (78.4 g, 0.065 eq.) and Xantphos (88.8 g, 0.13 eq.) were added to the reactor.

[0850] 4. Stir for 30 minutes and allow nitrogen to bubble at the liquid level.

[0851] 5. Heat to 80-82℃ and stir under nitrogen for 16 hours.

[0852] 6. Samples were subjected to IPC (90.0% purity).

[0853] 7. Cool to 15~25℃.

[0854] 8. Add EA (7.2 L, 30 V) and water (12 L, 50 V) to the reactor, add the reaction mixture to the reactor, and stir for 2 hours.

[0855] 9. Filter, wash the filter cake with EA (1.2 L, 5 V), and separate the filtrate.

[0856] 10. Separation.

[0857] 11. Extract the aqueous phase twice with EA (2.4 L, 10 V). Combine the organic phases and wash once with water (1.2 L, 5 V).

[0858] 12. Concentrate the organic layer to 6 V under vacuum at 50°C.

[0859] 13. Add the residue to the reactor, and add n-heptane (1.4 L, 6 V) dropwise to the reactor.

[0860] 14. Filter the filter cake and wash it with EA:n-heptane = 1:1 (0.5 L, 2 V). Return the filter cake to the reactor.

[0861] 15. Add EA (1.9 L, 8 V) to the reactor, heat to 77°C and stir at 77°C for 1 hour.

[0862] 16. Cool to 15-25°C, add n-heptane (3.8 L, 12 V) dropwise to the reactor, and stir for 2 hours.

[0863] 17. Filter and wash the filter cake with EA:n-heptane = 1:1 (0.5 L, 2 V).

[0864] 18. The filter cake was collected and dried to constant weight under vacuum at 60°C to give 609 g of compound 19.7 with a purity of 96.23% and a separation yield of 94.7%. (Residual Pd: 10800 ppm)

[0865] 19. Add crude compound 19.7 to the reactor, and add acetone (14.4 L, 60 V) to the reactor. Heat to 55 °C and stir until a clear solution is obtained.

[0866] 20. Concentrate the solution to 9°C and stir at 15-25°C for 2 hours.

[0867] 21. Filter and wash the filter cake with acetone (0.48 L, 2 V).

[0868] 22. The filter cake was collected and dried to constant weight under vacuum at 60°C to give 550 g of compound 19.7 with a purity of 99.51% and a separation yield of 78%. (Residual Pd: 2120 ppm)

[0869] 23. Add pure compound 19.7 to the reactor, and add THF (14.4 L, 60 V) to the reactor. Heat to 65 °C until a clear solution is obtained.

[0870] 24. Add 100 g of activated carbon (0.42 w / w) to the reactor and stir overnight at 65 °C. (Residual Pd: 512 ppm)

[0871] 25. Cool to 20-30℃ and filter.

[0872] 26. Return the filtered material to the reactor and add 50 g of thiol silica gel (0.21 w / w). Heat to 65°C and stir overnight. (Residual Pd: 62 ppm)

[0873] 27. Cool to 20-30℃ and filter.

[0874] 28. Concentrate the filtrate to 4V and stir at 20-30℃ for 2 hours.

[0875] 29. The mixture was filtered, the filter cake was collected, and dried under vacuum at 50°C to constant weight to give 470 g of compound 19.7 with a purity of 99.56% and a separation yield of 73%. (Residual Pd: 13 ppm)

[0876] Synthetic I-144

[0877]

[0878] Table 9. Reagents and conditions for preparing I-144.

[0879]

[0880] Process Description

[0881] 1. Under nitrogen protection, DCM (4.7 L, 10 V), compound 19.7 (468 g, 1.0 eq.), and TFA (940 mL, 2 V) were added to the reactor.

[0882] 2. Stir at room temperature for 4 hours.

[0883] 3. Samples were taken for IPC (HPLC showed that compound 19.7 was 0.5%).

[0884] 4. Filter to remove mechanical mixtures.

[0885] 5. Add the reaction mixture dropwise to 0.5 N K2CO3 (23.5 L, 50 v / w).

[0886] 6. Stir for 2 hours.

[0887] 7. Filter and wash with soft water (2.4 L, 5 V) and DCM (940 mL, 2 V).

[0888] 8. Dry the filter cake to obtain a loose solid. (KF≈15%)

[0889] 9. Use soft water (4.7 L, 10 V) to form a slurry from the crude material and keep it for 3 hours.

[0890] 10. Filter and wash with soft water (940 mL, 2 V).

[0891] 11. Collect the filter cake and dry it under vacuum at 60°C until KF is less than 0.5%, yielding 350 g of I-144 with a purity of 99.1% and a separation yield of 91%. Residual Pd is 15 ppm.

[0892] Analysis section

[0893] Table 10. Analysis methods for IPC 1

[0894]

[0895] Table 11. Gradient of analysis method 1 related to IPC.

[0896]

[0897] Dwell time: 1.5 min

[0898] Table 12. Analysis methods related to IPC 2.

[0899]

[0900] Table 13. Gradients of analysis method 2 related to IPC.

[0901]

[0902] Dwell time: 1.5 min

[0903] Example 20: 7-amino-N-cyclopropyl-5-((2-(trifluoromethoxy)pyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (I-113).

[0904]

[0905] Compound 20 was synthesized using the general procedure of the core synthesis, yielding 20 (yield: 62.0%). MS (ES): m / z 422.0 [M+H] + .

[0906] Compound 20.2 was synthesized. Potassium tert-butoxide (1.80 mL, 1.80 mmol, 2.0 eq) was added to a cold solution of 20 (0.380 g, 0.902 mmol, 1 eq) and 20.1 (0.144 g, 0.812 mmol, 0.9 eq) in tetrahydrofuran (5 mL). The reaction mixture was stirred at room temperature for 30 min. After the reaction was complete, the reaction mixture was transferred to a saturated bicarbonate solution and the product was extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to give the crude substance. It was further purified by column chromatography, and the compound was eluted in 17% ethyl acetate / hexane to give pure 20.2 (0.270 g, 53.16%). MS (ES): m / z 563.55 [M+H] + .

[0907] Compound 20.3 was synthesized. Lithium hydroxide (0.208 g, 4.97 mmol, 10 eq) was added to a solution of 20.2 (0.270 g, 0.497 mmol, 1.0 eq) in tetrahydrofuran:methanol:water (8 mL, 2:2:1). The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to give a residue. Water was added to the residue at 10 °C, and the solution was acidified with 1 N hydrochloric acid to adjust the pH to approximately 6–6.5. The product was extracted with dichloromethane. The combined organic layers were washed with a brine solution, dried over sodium sulfate, and concentrated under reduced pressure to give a crude substance. This crude substance was further purified by column chromatography, and the compound was eluted in 2.4% methanol / dichloromethane to give pure 20.3 (0.210 g, 78.94%). MS (ES): m / z 535.50 [M+H] + .

[0908] Compound 20.4 was synthesized using general procedure A to give 1.4 (0.060 g, 78.87%). MS (ES): m / z 574.58 [M+H] + .

[0909] Synthesizing compound I-113. A mixture of 20.4 g (0.060 g, 0.104 mmol, 1.0 eq) and trifluoromethanesulfonic acid (1 mL) was stirred at room temperature for 30 min. After the reaction was complete, the reaction mixture was transferred to a saturated bicarbonate solution and the product was extracted with dichloromethane. The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to give the crude substance. It was further purified by wet milling with diethyl ether to give I-113 (0.025 g, 60.76%). MS (ES): m / z 394.47 [M+H] + LCMS purity: 96.64%, HPLC purity: 95.18%. 1H NMR (DMSO-d6, 400MHZ): 9.25 (s, 1H), 8.33-8.31 (d, J=8Hz, 1H), 8.16 (s, 1H), 8.13-8.12 (d, J=4Hz, 1H), 7.74 (s, 2H), 7.65-7.64(d, J=4Hz, 1H), 7.47-7.44 (m, 1H), 5.84 (s, 1H), 2.74-2.70 (m, 1H), 0.67-0.62(m, 2H), 0.24-0.20 (m, 2H).

[0910] Example 21: 7-amino-N-(oxetane-3-yl)-5-((6-(2-oxopyrrolidone-1-yl)pyridin-2-yl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (I-101).

[0911]

[0912] Compound 21 was synthesized using the general procedure of the core synthesis, yielding 21 (yield: 62.0%). MS (ES): m / z 422.0 [M+H] + .

[0913] Compound 21.2 was synthesized. Potassium tert-butoxide (1.43 mL, 1.42 mmol, 2.0 eq) was added to a cold solution of 21 (0.300 g, 0.712 mmol, 1 eq) and 21.1 (0.123 g, 0.712 mmol, 1 eq) in tetrahydrofuran (6 mL). The reaction mixture was stirred at room temperature for 30 min. After the reaction was complete, the reaction mixture was transferred to a saturated bicarbonate solution and the product was extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to give the crude substance. Further purification was achieved by column chromatography, and the compound was eluted in 20% ethyl acetate / hexane to give pure 21.2 (0.180 g, 45.30%). MS (ES): m / z 558.45 [M+H] + .

[0914] Compound 21.3 was synthesized. Lithium hydroxide (0.135 g, 3.22 mmol, 10 eq) was added to a solution of 21.2 (0.180 g, 0.322 mmol, 1.0 eq) in tetrahydrofuran:methanol:water (6 mL, 2:1:1). The reaction mixture was stirred at 50 °C for 16 h. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain a residue. Water was added to the residue at 10 °C and acidified with 1 N hydrochloric acid to adjust the pH to approximately 6–6.5. The product was extracted with dichloromethane. The combined organic layers were washed with a brine solution, dried over sodium sulfate, and concentrated under reduced pressure to obtain a crude substance. This crude substance was further purified by column chromatography, and the compound was eluted in 2.2% methanol / dichloromethane to give pure 21.3 (0.165 g, 96.52%). MS (ES): m / z 530.40 [M+H] + .

[0915] Compound 21.5 was synthesized using general procedure A, yielding 21.5 (0.150 g, 82.34%). MS (ES): m / z 585.48 [M+H] + .

[0916] Compound 21.7 was synthesized. Potassium carbonate (0.071 g, 0.513 mmol, 2.0 eq) was added to solutions of 21.5 (0.150 g, 0.256 mmol, 1 eq) and 21.6 (0.043 g, 0.513 mmol, 2.0 eq) in 1,4-dioxane (2 mL), and the mixture was degassed with argon for 15 min. Copper iodide was then added. (0.0073 g, 0.038 mmol, 0.15 eq) and 1,2-dimethylethylenediamine (0.0067 g, 0.076 mmol, 0.3 eq) were added, and the reaction mixture was degassed with argon for 5 minutes, followed by heating at 110 °C for 6 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, transferred to water, and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to give the crude substance. Further purification was achieved by column chromatography, with the compound eluting in 1.8% methanol / dichloromethane to give pure 21.7 (0.062 g, 41.04%). MS (ES): m / z 589.67 [M+H] + .

[0917] Compound I-101 was synthesized. A mixture of 1.7 g (0.062 g, 0.105 mmol, 1.0 eq) and trifluoromethanesulfonic acid (1 mL) was stirred at room temperature for 30 min. After the reaction was complete, the reaction mixture was transferred to a saturated bicarbonate solution and the product was extracted with dichloromethane. The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to give the crude substance. It was further purified by wet milling with diethyl ether to give I-101 (0.027 g, 62.77%). MS (ES): m / z 409.39 [M+H] + LCMS purity: 98.18%, HPLC purity: 95.11%. 1 H NMR (DMSO-d6, 400MHZ): 9.50 (s, 1H), 8.18 (s, 1H), 7.84-7.82 (d, J=8Hz, 1H), 7.67-7.65 (d, J=8Hz, 1H), 7.42 (s, 2H), 7.16 (m,2H), 6.77 (s, 1H), 4.50 (s, 1H), 4.38 (s, 1H), 4.24 (m, 2H), 4.09 (s, 2H), 3.64 (m, 1H), 3.47 (s, 1H), 2.12-2.08 (m, 3H).

[0918] Example 22: 7-amino-N-(oxetane-3-yl)-5-((2-(trifluoromethoxy)pyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (I-103).

[0919]

[0920] Compound 22 was synthesized according to the experimental protocol of Example 20 (I-113) to obtain 22.

[0921] Compound 22.1 was synthesized using general procedure A to give 22.1 (0.055 g, 71.23%). MS (ES): m / z 590.58 [M+H] + .

[0922] Synthesis of compound I-103: A mixture of 22.1 g (0.055 g, 0.093 mmol, 1.0 eq) and trifluoromethanesulfonic acid (1 mL) was stirred at room temperature for 30 minutes. After the reaction was complete, the reaction mixture was transferred to a saturated bicarbonate solution and the product was extracted with dichloromethane. The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to give the crude substance. Further purification was achieved by wet milling with diethyl ether to give I-103 (0.030 g, 78.76%), MS (ES): m / z 410.39 [M+H]. + LCMS purity: 95.74%, HPLC purity: 96.31%. 1 H NMR (DMSO-d6, 400MHZ): 9.49-9.46 (d, J=8.8Hz, 1H),9.03 (s, 1H), 8.20 (s, 1H), 7.92 (s, 1H), 7.61 (s, 2H), 7.38-7.36 (t, J=4Hz,1H), 7.02 (s, 1H), 6.06 (s, 1H), 4.78 (s, 1H), 4.37-4.35 (t, J=8Hz, 1H), 4.17-4.16 (d, J=4Hz, 2H), 3.64-3.63 (d, J=4Hz, 1H).

[0923] Example 23: 7-amino-N-((1R,2S)-2-fluorocyclopropyl)-5-((2-isopropoxypyridin-3-yl)amino)-6-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide (I-206).

[0924]

[0925] Compound 23.2 was synthesized. A mixture of 23 (20 g, 128.90 mmol, 1.0 eq) and 23.1 (22.45 g, 128.90 mmol, 1.0 eq) in tributylamine (48 mL) was stirred for 16 hours at 160 °C. After the reaction was complete, the reaction mixture was cooled to room temperature and transferred to a 1 N sodium hydroxide solution, and the product was extracted with ethyl acetate. The aqueous layer was acidified with 1 M hydrochloric acid. The precipitated solid was filtered and thoroughly dried to give pure 23.2 (13.5 g, 44.15%). MS (ES): m / z 238.22 [M+H] + .

[0926] Compound 23.3 was synthesized. Phosphorus oxychloride (135 mL) was added to a cooled mixture of 23.2 (13.5 g, 56.91 mmol, 1.0 eq) and N,N-diethylaniline (13.67 mL, 85.36 mmol, 1.5 eq) at 0 °C. The reaction mixture was stirred at 85 °C for 3 hours. After the reaction was complete, the reaction mixture was transferred to ice-cold water and the product was extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give the crude substance. It was further purified by column chromatography, and the compound was eluted in 24% ethyl acetate / hexane to give pure 23.3 (8 g, 51.28%). MS (ES): m / z 275.10 [M+H] + .

[0927] Synthesizing compound 23.4. Potassium carbonate (1.10 g, 8.03 mmol, 1.1 eq) was added to a solution of 23.3 (2 g, 7.30 mmol, 1.0 eq) in ethanol (40 mL). The mixture was purified by ammonia through the reaction mixture for 30 minutes at room temperature. After the reaction was complete, the reaction mixture was transferred to ice-cold water. The precipitated solid was filtered and thoroughly dried to give pure 23.4 (1.62 g, 87.18%). MS (ES): m / z 255.67 [M+H] + .

[0928] Compound 23.5 was synthesized. 4-Dimethylaminopyridine (0.076 g, 0.63 mmol, 0.1 eq) was added to a solution of 23.4 (1.62 g, 6.36 mmol, 1.0 eq) in N,N-dimethylformamide (16 mL), followed by the addition of di-tert-butyl dicarbonate (2.77 g, 12.72 mmol, 2 eq). The reaction mixture was stirred at room temperature for 1 h. After the reaction was complete, the reaction mixture was transferred to ice-cold water and the precipitated solid was filtered off and thoroughly dried to give the crude substance. This was further purified by column chromatography, and the compound was eluted in 15% ethyl acetate / hexane to give pure 23.5 (1 g, 34.56%). MS (ES): m / z 455.91 [M+H] + .

[0929] Compound 23.6 was synthesized according to the experimental protocol of I-72.

[0930] Compound 23.7 was synthesized. Potassium tert-butoxide (3.1 mL, 3.08 mmol, 2.0 eq) was added to a cold solution of 23.5 (0.700 g, 1.54 mmol, 1.0 eq) and 23.6 (0.281 g, 1.85 mmol, 1.2 eq) in N,N-dimethylformamide (7 mL). The reaction mixture was stirred at 0 °C for 30 min. After the reaction was complete, the reaction mixture was transferred to a saturated bicarbonate solution and the product was extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to give the crude compound. Further purification was achieved by column chromatography, and the compound was eluted in 18% ethyl acetate / hexane to give pure 23.7 (0.690 g, 78.58%). MS (ES): m / z 571.65 [M+H] + .

[0931] Compound 23.8 was synthesized. Lithium hydroxide (0.508 g, 12.1 mmol, 10 eq) was added to a solution of 23.7 (0.690 g, 1.21 mmol, 1.0 eq) in tetrahydrofuran:methanol:water (12 mL, 1:1:1). The reaction mixture was stirred at 50 °C for 3 h. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain a residue. Water was added to the residue at 10 °C and acidified with 1 N hydrochloric acid to adjust the pH to approximately 6–6.5. The product was extracted with dichloromethane. The combined organic layers were washed with a brine solution, dried over sodium sulfate, and concentrated under reduced pressure to obtain a crude substance. This crude substance was further purified by column chromatography, and the compound was eluted in 1.9% methanol / dichloromethane to give pure 23.8 (0.480 g, 73.16%). MS (ES): m / z 543.59 [M+H] + .

[0932] Compound 23.10 was synthesized using general procedure A, yielding 23.10 (0.104 g, 58.81%). MS (ES): m / z 600.66 [M+H] + .

[0933] Synthesis of compound I-206: The compound was synthesized using the general procedure C to give I-206 (0.065 g, 93.83%), MS (ES): m / z 400.50 [M+H] + LCMS purity: 100%, HPLC purity: 99.61%, chiral HPLC purity: 100%. 1H NMR(DMSO-d6, 400MHZ): 8.17 (s, 1H), 8.02-8.00 (d, J=8Hz, 1H), 7.95-7.94 (d, J=4Hz, 1H), 7.79 (s, 1H), 7.69-7.68 (d, J=4Hz, 1H), 7.49 (s, 2H), 6.99-6.98 (t,J=4Hz, 1H), 5.30-5.24 (m, 1H), 4.80-4.68 (m, 1H), 2.85-2.82 (m, 1H), 2.16 (s,3H), 1.27-1.25 (t, J=8Hz, 6H), 1.10-1.05 (m, 1H), 0.57-0.51 (m, 1H).

[0934] Example 24: 7-amino-N-cyclopropyl-5-((2-isopropoxypyridin-3-yl)amino)-6-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide (I-207).

[0935]

[0936] Compound 24 was synthesized according to the experimental scheme of Example 23, yielding compound 24.

[0937] Compound 24.2 was synthesized using general procedure A, yielding 24.2 (0.089 g, 51.89%). MS (ES): m / z 582.67 [M+H] + .

[0938] Synthesis of compound I-207: The compound was synthesized using the general procedure C to give I-207 (0.055 g, 94.24%), MS (ES): m / z 382.33 [M+H] + LCMS purity: 98.84%, HPLC purity: 98.21%. 1H NMR (DMSO-d6,400MHZ): 8.12 (s, 1H), 7.99-7.98 (d, J=4Hz, 1H), 7.95-7.93 (d, J=8Hz, 1H), 7.84 (s, 1H), 7.63-7.62 (d, J=4Hz, 1H), 7.44 (s, 2H), 7.03-7.00 (m, 1H), 5.28-5.24 (m, 1H), 2.74-2.69 (m, 1H), 2.15 (s, 3H), 1.23-1.22 (d, J=4Hz, 6H), 0.65-0.61 (m, 2H), 0.19-0.15 (m, 2H).

[0939] Example 25: 7-amino-N-cyclobutyl-5-((2-isopropoxypyridin-3-yl)amino)-6-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide (I-208).

[0940]

[0941] Compound 25 was synthesized according to the experimental scheme of Example 23.

[0942] Compound 25.2 was synthesized using general procedure A, yielding 25.2 (0.095 g, 54.08%). MS (ES): m / z 596.70 [M+H] + .

[0943] Synthesis of compound I-208: The compound was synthesized using the general procedure C to give I-208 (0.058 g, 91.96%), MS (ES): m / z 396.53 [M+H] + LCMS purity: 100%, HPLC purity: 99.73%. 1 H NMR (DMSO-d6,400MHZ): 8.09 (s, 1H), 8.02-8.00 (d, J=8Hz, 2H), 7.90 (s, 1H), 7.84-7.82 (d,J=8Hz, 1H), 7.43 (s, 2H), 7.05-7.03 (t, J=8Hz, 1H), 5.35-5.28 (m, 1H), 4.38-4.32 (m, 1H), 2.16 (s, 5H), 1.62-1.55 (m, 4H), 1.24-1.22 (d, J=8Hz, 6H).

[0944] Example 26: 5-((1-(5-(dimethylaminoformyl)pyrazin-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (I-53).

[0945]

[0946] Synthesis of Compound 26.1. To a cold solution of 26 (3 g, 18.92 mmol, 1.0 eq) in N,N-dimethylformamide (30 mL), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (8.65 g, 22.70 mmol, 1.2 eq) was added and the mixture was stirred at room temperature for 20 min. Then, cold diisopropylethylamine (7.32 mL, 56.76 mmol, 3.0 eq) was added to the reaction mixture, followed by dimethylamine (0.851 g, 18.92 mmol, 1.0 eq). The reaction mixture was stirred at room temperature for 2 h. After the reaction was complete, the reaction mixture was transferred to water and the product was extracted with ethyl acetate. The combined organic layers were washed with a brine solution, dried over sodium sulfate, and concentrated under reduced pressure to give the crude substance. The compound was further purified by column chromatography, and eluted in 0.9% methanol / dichloromethane to give 26.1 g (2.5 g, 71.18%). MS (ES): m / z 186.61 [M+H] + .

[0947] Compound 26.3 was synthesized. Potassium carbonate (3.71 g, 26.94 mmol, 2.0 eq) was added to a solution of 26.1 (3 g, 13.47 mmol, 1.2 eq) and 26.2 (0.989 g, 11.22 mmol, 1.0 eq) in 1,4-dioxane (30 mL), and the mixture was degassed with argon for 15 min. Copper iodide (0.371 g, 2.69 mmol, 0.2 eq) and 1,2-dimethylethylenediamine (0.474 g, 5.38 mmol, 0.4 eq) were added, and the reaction mixture was degassed with argon for another 5 min, followed by heating at 110 °C for 16 h. After the reaction was complete, the reaction mixture was cooled to room temperature, transferred to water, and extracted with ethyl acetate. The combined organic layers were washed with a brine solution, dried over sodium sulfate, and concentrated under reduced pressure to give the crude substance. The compound was further purified by column chromatography, and eluted in 1.5% methanol / dichloromethane to give 26.3 g (1.2 g, 41.24%) of pure form. MS (ES): m / z 260.27 [M+H] + .

[0948] Compound 26.4 was synthesized using the general procedure of the core synthesis, yielding 26.4 (yield: 62.0%). MS (ES): m / z 316.76 [M+H] + .

[0949] Compound 26.5 was synthesized. 26.1 (0.147 g, 0.570 mmol, 1.2 eq) and cesium carbonate (0.359 g, 1.53 mmol, 2.0 eq) were added to a solution of 26 (0.150 g, 0.478 mmol, 1.0 eq) in 1,4-dioxane (5 mL). The reaction mixture was degassed for 10 min under an argon atmosphere, followed by the addition of tris(dibenzylacetone)dipalladium(0) (0.023 g, 0.023 mmol, 0.05 eq) and 4,5-bis(diphenylphosphino)-9,9-dimethyldibenzopyran (0.027 g, 0.047 mmol, 0.1 eq), and then degassed for another 5 min. The reaction mixture was stirred at 100 °C for 3 h. After the reaction was complete, the reaction mixture was cooled to room temperature, transferred to water, and extracted with ethyl acetate. The combined organic layers were washed with a brine solution, dried over sodium sulfate, and concentrated under reduced pressure to give the crude product. It was further purified by combi flash using 2% methanol / dichloromethane as eluent to give pure 26.5 (0.090 g, 35.18%). MS (ES): m / z 539.57 [M+H] + .

[0950] Compound I-53 was synthesized. A mixture of 26.5 g (0.090 g, 0.167 mmol, 1.0 eq) and trifluoromethanesulfonic acid (2 mL) was stirred at room temperature for 30 min. After the reaction was complete, the reaction mixture was transferred to a saturated bicarbonate solution and the product was extracted with dichloromethane. The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to give the crude substance. It was further purified by wet milling with diethyl ether to give I-53 (0.025 g, 33.36%). MS (ES): m / z 449.51 [M+H] + LCMS purity: 98.97%, HPLC purity: 97.25%. 1H NMR (DMSO-d6, 400MHZ): 9.21 (s, 1H), 9.06 (s, 1H), 8.91 (s, 1H), 8.33-8.31 (t, J=8Hz, 1H), 8.21 (s, 1H), 7.93 (s, 1H), 7.65-7.63(d, J=8Hz, 1H), 7.33 (s, 1H), 7.24 (bs, 1H), 6.51-6.50 (t, J=4Hz,1H), 6.24(s, 1H), 3.08-3.05 (d, J=12Hz, 6H), 2.92-2.91 (d, J=4Hz, 3H).

[0951] Example 27: N-cyclopropyl-5-((1-(5-(dimethylaminoformyl)pyrazin-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (I-127).

[0952]

[0953] Compound 27 was synthesized using the core synthesis protocol, yielding 27 (yield: 71.67%). MS (ES): m / z 326.74 [M+H] + .

[0954] Compound 27.1 was synthesized using the general procedure of Synthesis A, yielding 27.1 (yield: 57.16%). MS (ES): m / z 366.82 [M+H] + .

[0955] 27.2. The compound was synthesized according to the experimental protocol of Example 26.

[0956] Compound 27.3 was synthesized using general procedure B, yielding 27.3 (yield: 22.37%). MS (ES): m / z 589.63 [M+H] + .

[0957] Synthesis of compound I-127. The compound was synthesized using the general procedure C, yielding I-127 (yield: 66.94%). MS (ES): m / z 489.51 [M+H] + LCMS purity: 100%, HPLC purity: 98.60%. 1H NMR (DMSO-d6,400MHZ): 9.23 (s, 1H), 9.09 (s, 1H), 8.93 (s, 1H), 8.29-8.28 (d, J=7.2Hz,1H), 8.22 (s, 1H), 7.97-7.96 (d, J=4.8Hz, 1H), 7.85-7.84 (d, J=4Hz, 1H), 7.70-7.68 (d, J=6.8Hz, 1H), 6.56-6.52 (t, J=7.2Hz, 1H), 6.24 (s, 1H), 3.09-3.06 (m, 6H), 2.92-2.86 (m, 4H), 1.35-1.33 (d, J=8Hz, 1H), 1.24 (s, 1H), 0.834-0.788 (m, 2H).

[0958] Example 28: N-cyclopropyl-7-(methylamino)-5-((1-(5-methylthiazo-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (I-261).

[0959]

[0960] Synthesizing compound 28.2: Potassium carbonate (2.50 g, 18.16 mmol, 2.0 eq) was added to a solution of 28 (1 g, 9.08 mmol, 1 eq) and 28.1 (1.94 g, 10.90 mmol, 1.2 eq) in 1,4-dioxane (10 mL), and the mixture was degassed with argon for 15 min. Copper iodide (0.345 g, 1.81 mmol, 0.2 eq) and 1,2-dimethylethylenediamine (0.320 g, 3.63 mmol, 0.4 eq) were added, and the reaction mixture was degassed with argon for another 5 min, followed by heating at 110 °C for 16 h. After the reaction was complete, the reactio...

Claims

1. A pharmaceutical composition comprising N-(2-methoxycyclobutyl)-7-(methylamino)-5-((2-oxo-2H-[1,2'-bipyridine]-3-yl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant or mediator.

2. The pharmaceutical composition according to claim 1, comprising a compound ， Or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant or mediator.

3. The pharmaceutical composition according to claim 1, comprising a compound ， Or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant or mediator.

4. The pharmaceutical composition according to claim 1, comprising a compound ， And pharmaceutically acceptable carriers, adjuvants or mediators.

5. The pharmaceutical composition according to claim 1, comprising a compound ， And pharmaceutically acceptable carriers, adjuvants or mediators.

6. Use of the pharmaceutical composition according to any one of claims 1-5 in the preparation of a medicament for treating a patient with a TYK2-mediated symptom, disease, or condition, wherein the symptom, disease, or condition can be treated by inhibiting TYK2.

7. The use according to claim 6, wherein the condition, disease, or illness is psoriasis.

8. The use according to claim 6, wherein the condition, disease, or illness is psoriatic arthritis.

9. The use according to claim 6, wherein the condition, disease, or illness is cutaneous lupus erythematosus.

10. The use according to claim 6, wherein the condition, disease, or illness is systemic lupus erythematosus.

11. The use according to claim 6, wherein the condition, disease, or illness is Crohn's disease.

12. The use according to claim 6, wherein the condition, disease, or illness is ulcerative colitis.

13. The use according to claim 6, wherein the symptom, disease, or condition is inflammatory bowel disease.

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