Tyk2 inhibitors and uses thereof

Abstract

The present invention provides TYK2 inhibitors and uses thereof, specifically compounds that inhibit TYK2 and methods of using the same for treating TYK2-mediated disorders.

Description

[0001] This application is a divisional application of the invention patent application filed on October 13, 2017, with application number 201780069795.3 and title "TYK2 Inhibitor and Its Use". 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 facilitated the exploration of novel therapeutics. One important class of enzymes that has been the subject of extensive research is the protein kinase family.

[0004] Protein kinases constitute a large class 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 a similar catalytic domain of 250-300 amino acids. Kinases can be classified into several families based on their phosphorylated substrates (e.g., protein-tyrosine, protein-serine / threonine, lipids, etc.).

[0005] Generally, protein kinases mediate intracellular signal transduction 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 by responses 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 colony-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, neurological and 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] The compounds of the present invention and pharmaceutically acceptable compositions thereof have been found to be effective inhibitors of TYK2 kinase.

[0008] The compounds of this invention and pharmaceutically acceptable compositions thereof may be used to treat a variety of diseases, conditions, or symptoms related to the regulation of signaling pathways involving TYK2 kinases. Such diseases, conditions, or symptoms 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 compare and evaluate novel TYK2 inhibitors or other kinase regulators, signal transduction pathways, and in vitro or in vivo cytokine levels. Detailed Implementation

[0010] 1. 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 pouch of TYK2 contains multiple hydration sites, each occupied by a single water molecule. Each of these water molecules has an associated stability rating. As used herein, the term "stability rating" refers to a numerical calculation incorporating the enthalpy, entropy, and free energy values ​​associated with each water molecule. This stability rating allows for a measurable determination of the relative stability of the water molecules occupying the hydration sites within the TYK2 binding pouch.

[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 inhibitors bind more tightly by replacing or disrupting unstable water molecules (i.e., water molecules with a stability rating > 2.5 kcal / mol) or by displacing stable water molecules (i.e., water molecules with a stability rating < 1 kcal / mol). Therefore, inhibitors designed to replace one or more unstable water molecules (i.e., those not replaced by any known inhibitors) will be more tightly bound and thus more potent inhibitors than inhibitors that do not replace unstable water molecules.

[0015] Surprisingly, the provided compound was found to replace or disrupt one or more unstable water molecules. In some embodiments, the provided compound replaces or disrupts at least two unstable water molecules.

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

[0017]

[0018] Or its pharmaceutically acceptable salt, wherein X, L 1 R 1 R 2 and Cy 1 Each of these terms is defined below and described individually and in combination 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, conditions, or symptoms, comprising administering a compound of formula I or a pharmaceutically acceptable salt thereof to a patient in need.

[0021] In some embodiments, the present invention provides a compound of formula VIII:

[0022]

[0023] Or its pharmaceutically acceptable salt, wherein X, L 1 R 1 R 2 and Cy 1 Each of these terms is defined below and described individually and in combination in the embodiments herein.

[0024] In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula VIII and a pharmaceutically acceptable carrier, adjuvant, or diluent.

[0025] In some embodiments, the present invention provides a method for treating TYK2-mediated diseases, conditions, or symptoms, comprising administering a compound of formula VIII or a pharmaceutically acceptable salt thereof to a patient in need.

[0026] In some embodiments, the present invention provides a compound of formula XVI':

[0027]

[0028] Or a pharmaceutically acceptable salt thereof, wherein Q, X, Y 1 Y 2 Z 1 Z 2 L 1 R 1 R 2 and Cy 1 Each of these terms is defined below and described individually and in combination in the embodiments herein.

[0029] In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula XVI' and a pharmaceutically acceptable carrier, adjuvant, or diluent.

[0030] In some embodiments, the present invention provides a method for treating TYK2-mediated diseases, conditions, or symptoms, comprising administering a compound of formula XVI' or a pharmaceutically acceptable salt thereof to a patient in need.

[0031] 2. Compounds and their definitions:

[0032] The compounds of this invention include those generally described herein and further illustrated by the categories, subclasses and species disclosed herein. Unless otherwise indicated, the following definitions shall apply as used herein. For the purposes of this invention, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th edition. Furthermore, 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.

[0033] As used herein, the term "aliphatic" or "aliphatic group" means a fully saturated or branched linear (i.e., unbranched) or branched substituted or unsubstituted hydrocarbon chain containing one or more unsaturated units, or a fully saturated or branched monocyclic or bicyclic hydrocarbon (also referred to herein as "carbocyclic," "cycloaliphatic," or "cycloalkyl") that is not aromatic and has a single connection point to the rest of the molecule. Unless otherwise specified, 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 yet still other embodiments, an aliphatic group contains 1 to 2 aliphatic carbon atoms. In some embodiments, a “cycloaliphatic group” (or “carbocyclic” or “cycloalkyl”) refers to a monocyclic C3-C6 hydrocarbon that is fully saturated or contains one or more unsaturated units but is not aromatic, and has 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.

[0034] 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 ring, saturated or partially unsaturated. As defined by IUPAC, a "bridging bond" is a non-branched or single-atom or valence bond connecting multiple atoms at 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. Such bridged bicyclic groups are well known in the art and include those groups set forth below, wherein each group is attached to the remainder of the molecule at any substituted carbon or nitrogen atom. Unless otherwise specified, the bridged bicyclic group is optionally substituted with one or more substituents as described with respect to aliphatic groups. Alternatively, any substituted nitrogen atom in the bridged bicyclic group is optionally substituted. Illustrative bridged bicyclics include:

[0035]

[0036] The term "low carbon number alkyl" refers to C 1-4 Straight-chain or branched alkyl groups. Examples of low-carbon alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0037] The term "low-carbon alkyl halogroup" refers to a C14 alkyl group substituted with one or more halogen atoms. 1-4 Straight-chain or branched alkyl groups.

[0038] 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 (e.g., in 3,4-dihydro-2H-pyrrole), NH (e.g., in pyrrolealkyl), or NR). + (e.g., in N-substituted pyrroleyl groups).

[0039] As used in this article, the term "unsaturated" means a portion having one or more unsaturated units.

[0040] 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 divalent alkylene, alkenyl, and ynylene chains that are straight or branched as defined herein.

[0041] 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 in which one or more methylene hydrogen atoms are replaced by substituents. Suitable substituents include those described below with respect to substituted aliphatic groups.

[0042] The term "alkenyl" refers to a divalent alkenyl group. A substituted alkenyl chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced by substituents. Suitable substituents include those described below with respect to substituted aliphatic groups.

[0043] The term "halogen" refers to F, Cl, Br, or I.

[0044] When used alone or as part of a larger portion, the term "aryl" as used in "aralkyl," "aralkyloxy," or "aryloxyalkyl" refers to a monocyclic or bicyclic ring system having a total of 5 to 14 ring members, wherein at least one ring in the system is aromatic and each ring in the system contains 3 to 7 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 in which an aromatic ring is fused to one or more non-aromatic rings, such as dihydroindenyl, phthalimide, naphthylimide, phenanthridine, or tetrahydronaphthyl, etc.

[0045] The terms "heteroaryl" and "heteroary-" used alone or as part of a larger portion of, for example, "heteroarylalkyl" or "heteroarylalkoxy," refer to a group having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 shared 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, pyrazinyl, indazinyl, purinyl, naphridinyl, and pteridinyl. As used herein, the terms "heteroaryl" and "heteroary-" also include groups in which a heteroaryl ring is fused to one or more aryl, cycloaliphatic, or heterocyclic rings, wherein, unless otherwise specified, the group or connecting point is on the heteroaryl ring or on one of the rings to which the heteroaryl ring is fused. Non-limiting examples include indolyl, isoindolyl, benzothiopheneyl, benzofuranyl, dibenzofuranyl, indazoleyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, cenolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinazinyl, carbazoleyl, acridineyl, phenazinyl, phenothiazinyl, phenotoxazinyl, 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 group and the heteroaryl moiety are optionally substituted independently.

[0046] 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 (e.g., in 3,4-dihydro-2H-pyrroleyl), NH (e.g., in pyrroleyl), or... + NR (e.g., in N-substituted pyrroleyl groups).

[0047] Heterocycles can be attached to their side groups at any heteroatom or carbon atom to produce a stable structure, and any ring atom can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic groups include (but are not limited to) tetrahydrofuranyl, tetrahydrothiophenylpyrrolyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazine, dioxane, dioxopentyl, diazapyrrolyl, oxazapyrrolyl, thiacyclohexadienyl, 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 whose heterocyclic rings are fused to one or more aryl, heteroaryl, or cyclic aliphatic rings, such as dihydroindolyl, 3H-indolyl, chromyl, phenanthrenediyl, or tetrahydroquinolinyl. Heterocyclic groups can be monocyclic or bicyclic. The term “heterocyclic alkyl” refers to an alkyl group that has been heterocyclically substituted, wherein the alkyl group and the heterocyclic moiety are optionally substituted independently.

[0048] 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 not to include aryl or heteroaryl moiety as defined herein.

[0049] As described herein, the compounds of the present invention may contain an “optionally substituted” portion. Generally, the term “substituted”, whether preceded by the term “optionally” or not, means that one or more hydrogens of the specified portion are replaced by suitable substituents. Unless otherwise indicated, the “optionally substituted” group may have suitable substituents at each substituted position of said 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 those that result in the formation of stable or chemically viable compounds. As used herein, the term “stable” means that the compound remains substantially unchanged when subjected to conditions that allow it to be generated, detected, and (in some embodiments) recovered, purified, and used for one or more of the purposes disclosed herein.

[0050] The suitable monovalent substituent on the substituted carbon atom of the "optionally substituted" group is independently a halogen; -(CH2) 0-4 R o ;-(CH2) 0-4 OR o ;-O(CH2)0-4 R o -O-(CH2) 0-4 C(O)OR o ;-(CH2) 0-4 CH(OR o )2;-(CH2) 0- 4SR o ;-(CH2) 0-4 Ph, which can be transmitted via R o Substitution; -(CH2) 0-4 O(CH2) 0-1 Ph, which can be transmitted via R o Substitution; -CH=CHPh, which can be obtained via R o Substitution; -(CH2) 0-4 O(CH2) 0-1 -pyridyl group, which can be transmitted via R o Substitution; -NO2; -CN; -N3; ​​-(CH2) 0-4 N(R o )2;-(CH2) 0-4 N(R o )C(O)R o ;-N(R o )C(S)R o ;-(CH2) 0-4 N(R o )C(O)NR o 2; -N(R) o )C(S)NR o 2;-(CH2) 0-4 N(R o )C(O)OR o ;-N(R o )N(R o )C(O)R o ;-N(R o )N(R o )C(O)NR o 2; -N(R) o )N(R o )C(O)OR o ;-(CH2) 0-4 C(O)R o ;-C(S)R o ;-(CH2) 0-4 C(O)OR o ;-(CH2) 0-4 C(O)SR o ;-(CH2) 0-4 C(O)OSiR o 3; -(CH2) 0-4 OC(O)Ro ;-OC(O)(CH2) 0-4 SR o ;-SC(S)SR o ;-(CH2) 0-4 SC(O)R o ;-(CH2) 0-4 C(O)NR o 2; -C(S)NR o 2;-C(S)SR o ;-SC(S)SR o ;-(CH2) 0-4 OC(O)NR o 2; -C(O)N(OR) o )R o ;-C(O)C(O)R o ;-C(O)CH2C(O)R o ;-C(NOR) o )R o ;-(CH2) 0-4 SSR o ;-(CH2) 0-4 S(O)2R o ;-(CH2) 0-4 S(O)2OR o ;-(CH2) 0-4 OS(O)2R o ;-S(O)2NR o 2;-(CH2) 0-4 S(O)R o ;-N(R o )S(O)2NR o 2; -N(R) o )S(O)2R o ;-N(OR) o )R o ;-C(NH)NR o 2; -P(O)2R o ;-P(O)R o 2; -OP(O)R o 2; -OP(O)(OR o )2; SiR o 3; -(C 1-4 (linear or branched alkylene)ON(R) o )2; or -(C 1-4 (straight-chain or branched alkylene)C(O)ON(R) o )2, where each R o It can be substituted and independently formed as hydrogen or C as defined below. 1-6Aliphatic 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 independent heteroatoms selected from nitrogen, oxygen or sulfur, or, unrelated to the above definition, two independently occurring R... o It combines with its inserted atoms to form a 3 to 12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0 to 4 independent heteroatoms selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0051] R o (or two independently occurring R) o The suitable monovalent substituents on the ring formed by its insertion 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 · 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. R oSuitable divalent substituents on saturated carbon atoms include =O and =S.

[0052] 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)) 2-3 S-, where each independently occurring R * Selected from hydrogen, and substituted C as defined below. 1-6 An 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 for the adjacent substituted carbon atom attached to the "optionally substituted" group include: -O(CR * 2) 2-3 O-, where each independently occurring R * Selected from hydrogen, and substituted C as defined below. 1-6 It is an aliphatic group or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0053] R * Suitable substituents on the aliphatic group 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 unsubstituted or, in the case of a preceding "halogen group", substituted with only one or more halogens, 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.

[0054] Suitable substituents on the substituted nitrogen of the "optionally substituted" group include or Each of them Independently, hydrogen, or substituted C as defined below 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, unrelated to the above definition, two independently occurring... It combines with its inserted atoms to form a 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.

[0055] 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 unsubstituted or, in the case of a preceding "halogen group", substituted with only one or more halogens, 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.

[0056] As used herein, the term "pharmaceutically acceptable salt" means that salts suitable for contact with human and lower animal tissues without undue toxicity, irritation, allergic reactions, etc., within the bounds of reasonable medical judgment, and in proportion to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S.M. 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 the present invention include salts derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed by amino groups with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or organic acids (e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or salts formed by other methods used in the art (e.g., 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, fumarate, glucono-heptahydrate, glyceryl phosphate, gluconate, hemisulfate, heptahydrate, hexanoate, hydroiodate, 2-hydroxy-ethanesulfonate, 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.

[0057] 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. Other pharmaceutically acceptable salts include (where appropriate) non-toxic ammonium, quaternary ammonium, and amine cations formed using relative ions (e.g., halide, hydroxide, carboxyl, sulfate, phosphate, nitrate, low-carbon alkyl sulfonate, and aryl sulfonate).

[0058] 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, Z and E double bond isomers, and Z and E configurational isomers for each asymmetry center. 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, the ring B of the provided compound may be substituted with one or more deuterium atoms.

[0059] 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.

[0060] The compounds of this invention can be tethered to a detectable portion. It should be understood that such 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 groups containing, for example, carboxylate, amino, mercapto, or hydroxyl moieties (to name only). It should be understood that such portions can be directly linked to the provided compound or linked 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, such portions can be linked via a 1,3-cycloaddition of an azide compound with an alkyne, optionally in the presence of a copper catalyst. Methods using click chemistry are known in the art and include those described in Rostovtsev et al., Angew. Chem. Int. Ed. 2002, 41, 2596-99 and Sun et al., Bioconjugate Chem. 2006, 17, 52-57.

[0061] As used herein, the terms "detectable portion" and "marking" are used interchangeably and refer to any portion that can be detected (e.g., primary and secondary markings). For example, radioactive isotopes (e.g., tritium, etc.). 32 P, 33 P, 35 S or 14 C) The primary labeling for quality tags and fluorescent markers consists of signal-generating reporter groups that can be detected without further modification. The detectable portion also includes luminescent and phosphorescent groups.

[0062] As used herein, the term "secondary label" refers to a 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, a secondary intermediate may include an antibiotic streptavidin-enzyme conjugate. In the case of antigen labeling, a secondary intermediate may include an antibody-enzyme conjugate. Some fluorescent groups act as secondary labels because they transfer energy to another group during nonradiative fluorescence resonance energy transfer (FRET), and the second group generates a detection signal.

[0063] As used herein, the terms “fluorescent label,” “fluorescent dye,” and “fluorophore” refer to the portion that absorbs light energy at a defined excitation wavelength and emits light energy at different wavelengths. 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, and 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 576 / 589, BODIPY 581 / 591, BODIPY 630 / 650, BODIPY 576 / 589, BODIPY 581 / 591, BODIPY 589 / 589, BODIPY 581 ... 650 / 665), carboxy-rhodamine 6G, carboxy-X-rhodamine (ROX), Cascade Blue, Cascade Yellow, coumarin 343, cyanine dyes (Cy3, Cy5, Cy3.5, Cy5.5), dansyl sulfonyl, 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, naphthalene fluorescein, Oregon Green Rhodol 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), Carboxy-Tetramethyl-Rhodamine (TAMRA), Texas Red, Texas Red-X.

[0064] As used herein, the term "quality tag" refers to any fraction that can be specifically detected by mass spectrometry (MS) based on its mass. Examples of quality tags include electrophoretic release tags, such as N-[3-[4'-[(p-methoxytetrafluorobenzyl)oxy]phenyl]-3-methylglycero]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 tags 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 wide variety of organic molecules (neutral and charged (biomolecules or synthetic compounds)) with appropriate mass ranges (100 Daltons to 2000 Daltons) can also be used as quality labels.

[0065] As used herein, the terms “measurable affinity” and “measurable inhibition” refer to a measurable change in TYK2 protein kinase activity between a sample containing the compound or composition thereof of the present invention and TYK2 protein kinase and an equivalent sample containing TYK2 protein kinase but without the compound or composition thereof.

[0066] 3. Description of exemplary embodiments:

[0067] As described above, in some embodiments, the present invention provides a compound of formula I:

[0068]

[0069] Or its pharmaceutically acceptable salt, wherein:

[0070] X is N or C(R) 3 );

[0071] R 1 For R, R D OR;

[0072] R 2 For H, R C -N(R)C(O)Cy 2 -N(R)S(O)2Cy 2 -N(R)Cy 2 -OCy 2 -SCy 2 or Cy 2 ;

[0073] R3 H, halogen or C 1-6 aliphatic group; or

[0074] R 2 and R 3 It combines with its inserting atoms to form a 4- to 7-membered partially unsaturated or aromatic ring having 0 to 3 independent heteroatoms selected from nitrogen, oxygen, and sulfur; wherein the ring is connected to m R 4 Instance replacement;

[0075] Cy 1 and Cy 2 Each of the following is independently a phenyl group; a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; or a 7- to 12-membered saturated or partially unsaturated bicyclic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy 1 After n R 5 Instance replacement; and; where Cy 2 After p R 6 Instance replacement;

[0076] L 1 For covalent bonds or C 1-4 Divalent saturated or unsaturated, straight-chain or branched hydrocarbon chains, wherein one or both methylene units of the chain are optionally and independently substituted with -C(R) 7 )2-, -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- substitution;

[0077] R 4 R 5 R 6 and R 7 R is independent for each occurrence. A Or R B And after q R C Instance replacement;

[0078] R A Each occurrence is independently of oxo, halogen, -CN, -NO2, -OR, -OR. D, -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;

[0079] R B It is C independently each time it appears. 1-6 Aliphatic group; phenyl group; 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;

[0080] R C Each time it appears, 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, 3 to 7-membered saturated or partially unsaturated heterocycles having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5 to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0081] R D C 1-4 Aliphatic group, in which one or more hydrogens are replaced by deuterium;

[0082] Each R is independently hydrogen or optionally substituted with a group selected from the following: C 1-6 Aliphatic group, phenyl group, 3- to 7-membered saturated or partially unsaturated heterocycles having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:

[0083] Two R groups on the same nitrogen atom are bonded 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; and

[0084] Each of m, n, p, and q is independently 0, 1, 2, 3, or 4.

[0085] As generally defined above, X is N or C(R). 3 In some embodiments, X is N. In some embodiments, X is C(R). 3 In some embodiments, X is C(H). In some embodiments, X is C(R). 3 ), where R 3 It is a halogen. In some embodiments, X is C(R) 3 ), where R 3 It is fluorine.

[0086] As generally defined above, R 1 For R, R D OR. In some embodiments, R 1 R. In some embodiments, R 1 For R D In some embodiments, R 1 For -OR. In some embodiments, R 1 C is arbitrarily substituted 1-6 Aliphatic group. In some embodiments, R 1 The ethyl group is optionally substituted. In some embodiments, R 1 It is hydrogen, methyl, or -CD3. In some embodiments, R 1 It is hydrogen. In some embodiments, R is... 1 It is methyl or -CD3. In some embodiments, R 1 methyl. In some embodiments, R 1 For -CD3. In some embodiments, R 1 It is -OH.

[0087] As generally defined above, R 2 For H, R C -N(R)C(O)Cy 2 -N(R)Cy 2 -OCy 2 -SCy 2 or Cy 2 In some embodiments, R 2 For H. In some embodiments, R 2 For R C -N(R)C(O)Cy 2-N(R)Cy 2 -OCy 2 -SCy 2 or Cy 2 In some embodiments, R 2 For R C In some embodiments, R 2 It is -N(R)C(O)R. In some embodiments, R 2 is -N(R)C(O)Cy 2 -N(R)Cy 2 or Cy 2 In some embodiments, R 2 is N(R)C(O)R, -N(R)C(O)Cy 2 -N(R)Cy 2 or Cy 2 In some embodiments, R 2 -N(H)C(O)R, -N(H)C(O)Cy 2 -N(H)Cy 2 or Cy 2 In some embodiments, R 2 -N(H)C(O)R, -N(H)C(O)Cy 2 or -N(H)Cy 2 In some embodiments, R 2 It is -N(H)C(O)R. In some embodiments, R 2 The form is -N(H)C(O)R, where R is, in this case, an optionally substituted C. 1-6 Aliphatic group. In some embodiments, R 2 is -N(H)C(O)Cy 2 In some embodiments, R 2 -N(H)Cy 2 In some embodiments, R 2 is -N(H)C(O)Cy 2 Cy 2 It is cyclopropyl. In some embodiments, R 2 for

[0088] As generally defined above, R 3 H, halogen or C 1-6 Aliphatic group. In some embodiments, R 3 For H. In some embodiments, R 3 Halogen or C 1-6 Aliphatic group. In some embodiments, R 3 It is a halogen. In some embodiments, R 3It is fluorine. In some embodiments, R 3 C 1-6 Aliphatic groups.

[0089] In some embodiments, R 2 and R 3 It combines with its inserting atoms to form a 4- to 7-membered partially unsaturated or aromatic ring having 0 to 3 independent heteroatoms selected from nitrogen, oxygen, and sulfur; wherein the ring is connected to m R 4 Instance replacement. In some embodiments, R 2 and R 3 It combines with its inserting atoms to form a 5-membered partially unsaturated or aromatic ring having 1-3 independent heteroatoms selected from nitrogen, oxygen, and sulfur; wherein the ring is connected to m R 4 Instance replacement.

[0090] As generally defined above, Cy 1 It is a phenyl group; a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; or a 7- to 12-membered saturated or partially unsaturated bicyclic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy 1 After n R 5 Instance replacement.

[0091] In some embodiments, Cy 1 It is phenyl. In some embodiments, Cy 1 It is a 5- to 6-membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy 1 It is a 5-membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy 1 It is a 6-membered heteroaryl group having 1 to 4 nitrogen atoms. In some embodiments, Cy 1 It is pyridyl. In some embodiments, Cy 1 It is pyrazinyl. In some embodiments, Cy 1 It is a pyrimidinyl group. In some embodiments, Cy 1 It is triazine-based. In some embodiments, Cy... 1 It is pyrrole, pyrazolyl, imidazole, triazolyl, or tetrazolyl. In some embodiments, Cy1 is furanyl, oxazolyl, isoxazolyl, or oxadiazolyl; in some embodiments, Cy1 is thiophenyl, thiazolyl, isothiazolyl, or thiadiazolyl. 1It is an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy 1 It is a 3- to 7-membered saturated or partially unsaturated heterocycle having one or two heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy 1 It is a 3- to 7-membered saturated or partially unsaturated monocyclic carbon ring. In some embodiments, Cy 1 It is a 7- to 12-membered saturated or partially unsaturated bicyclic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0092] In some embodiments, Cy 1 (R 5 ) n Combined, the following are selected:

[0093]

[0094]

[0095] Among them, R, R C Each of q is as defined above and described individually and in combination in the embodiments herein.

[0096] In some embodiments, Cy 1 (R 5 ) n Combined together, the groups selected from those in the preceding paragraphs or the following:

[0097]

[0098] In some embodiments, Cy 1 (R 5 ) n Combined together, the groups selected from the preceding two paragraphs or the following:

[0099]

[0100]

[0101] As generally defined above, Cy 2 It is a phenyl group; a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; or a 7- to 12-membered saturated or partially unsaturated bicyclic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy 2 After p R6 Instance replacement.

[0102] In some embodiments, Cy 2 It is phenyl. In some embodiments, Cy 2 It is a 5- to 6-membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy 2 It is a 5-membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy 2 It is a 6-membered heteroaryl group having 1 to 4 nitrogen atoms. In some embodiments, Cy 2 It is pyridyl. In some embodiments, Cy 2 It is pyrazinyl. In some embodiments, Cy 2 It is a pyrimidinyl group. In some embodiments, Cy 2 It is triazine-based. In some embodiments, Cy... 2 It is pyrrole, pyrazolyl, imidazole, triazolyl, or tetrazolyl. In some embodiments, Cy 2 It is furanyl, oxazolyl, isoxazolyl or oxadiazolyl; in some embodiments, Cy 2 It is thienyl, thiazolyl, isothiazolyl, or thiadiazolyl. In some embodiments, Cy 2 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, Cy 2 It is a 3- to 7-membered saturated or partially unsaturated heterocycle having one or two heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Cy 2 It is a 3- to 7-membered saturated or partially unsaturated monocyclic carbon ring. In some embodiments, Cy 2 C 3-7 Cycloalkyl. In some embodiments, Cy 2 Cy is cyclopropyl. In some embodiments, Cy 2 It is a 7- to 12-membered saturated or partially unsaturated bicyclic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0103] In some embodiments, Cy 2 Selected from the following, each of which is processed by p R 6 Instance replacement:

[0104]

[0105]

[0106] In some embodiments, Cy 2 Selected from the groups mentioned in the preceding paragraphs or the following, each of which is derived from p R groups. 6 Instance replacement:

[0107]

[0108] In some embodiments, p is 1 or 2, and R 6 At least one instance is -CN, -CH3, -CHF2, or -CF3.

[0109] As generally defined above, L 1 For covalent bonds or C 1-4 Divalent saturated or unsaturated, straight-chain or branched hydrocarbon chains, wherein one or both methylene units of the chain are optionally and independently substituted with -C(R) 7 -2-, -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- are substituted. In some embodiments, L 1 It is a covalent bond. In some embodiments, L 1 C 1-4 Divalent saturated or unsaturated, straight-chain or branched hydrocarbon chains, wherein one or both methylene units of the chain are optionally and independently substituted with -C(R) 7 -2-, -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- are substituted. In some embodiments, L 1 For -N(R)-. In some embodiments, L 1 It is -N(H)-.

[0110] 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.

[0111] 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.

[0112] 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.

[0113] In some embodiments, the present invention provides a compound of formula I, wherein L 1 The form is -N(H)-, thus forming compounds of formula Ia:

[0114]

[0115] Or a pharmaceutically acceptable salt thereof, wherein X, Cy 1 R 1 and R 2 Each of these terms is as defined above and is described individually and in combination in the embodiments herein.

[0116] In some embodiments, the present invention provides a compound of formula I, wherein X is N or C(R) 3 Thus, compounds of formula Ib or Ic are formed respectively:

[0117]

[0118] Or a pharmaceutically acceptable salt thereof, wherein Cy 1 L 1 R 1 R 2 and R 3 Each of these terms is as defined above and is described individually and in combination in the embodiments herein.

[0119] In some embodiments, the present invention provides a compound of formula Ia, wherein L 1 For N or C(R) 3 Thus, compounds of formula II-a or II-b are formed respectively:

[0120]

[0121] Or a pharmaceutically acceptable salt thereof, wherein Cy 1 R 1 R 2 and R 3 Each of these terms is as defined above and is described individually and in combination in the embodiments herein.

[0122] In some embodiments, the present invention provides a compound of formula II-a or II-b, wherein Cy 1 The phenyl group forms compounds of formula III-a or III-b, respectively:

[0123]

[0124] Or a pharmaceutically acceptable salt thereof, wherein R 1 R 2 R 3 R 5 Each of and n is as defined above and described individually and in combination in the embodiments herein.

[0125] In some embodiments, the present invention provides a compound of formula III-a or III-b, wherein n is 1, 2, or 3 and R 5 At least one instance is located adjacent to the NH junction site, thereby forming compounds of formula IV-a or IV-b, respectively:

[0126]

[0127] Or a pharmaceutically acceptable salt thereof, wherein R 1 R 2 R 3 and R 5 Each of these terms is as defined above and is described individually and in combination in the embodiments herein.

[0128] In some embodiments, the present invention provides a compound of formula IV-a or IV-b, wherein the ortho-R 5 The groups are -OR, -S(O)2R, -C(O)NR2 or -N(R)S(O)2R, thereby forming compounds of formula Va, Vb, Vc, Vd, Ve, Vf, Vg or Vh, respectively:

[0129]

[0130] Or a pharmaceutically acceptable salt thereof, wherein R, R 1 R 2 R 3 and R 5 Each of these terms is as defined above and is described individually and in combination in the embodiments herein.

[0131] In some embodiments, the present invention provides a compound of formula Va or Vb, wherein the second R 5 Group (R) 5b The meta position at the NH junction site forms compounds of formula VI-a or VI-b, respectively:

[0132]

[0133] Or a pharmaceutically acceptable salt thereof, wherein R, R 1 R 2 R3 and R 5 Each of these terms is as defined above and is described individually and in combination in the embodiments herein.

[0134] In some embodiments, the present invention provides a compound of formula VI-a or VI-b, wherein R 5 For R B In some embodiments, the present invention provides a compound of formula VI-a or VI-b, wherein R 5 It is -C(O)NR2 or a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, said ring being connected to q R C Instance replacement.

[0135] In some embodiments, the present invention provides a compound of formula VI-a or VI-b, wherein -OR is a methoxy, fluoromethoxy, or difluoromethoxy compound.

[0136] In some embodiments, the present invention provides a compound of formula II-a or II-b, wherein Cy 1 It is pyridyl, n is 2, and R 5 One example is oxoation, which results in pyridone compounds of formula VII-a or VII-b, respectively:

[0137]

[0138] Or a pharmaceutically acceptable salt thereof, wherein R 1 R 2 R 3 and R 5 Each of these terms is as defined above and is described individually and in combination in the embodiments herein.

[0139] As described above, in some embodiments, the present invention provides a compound of formula VIII:

[0140]

[0141] Or its pharmaceutically acceptable salt, wherein:

[0142] X is N or C(R) 3 );

[0143] Y is N or C(R) 1 );

[0144] R 1 It is H, D or halogen;

[0145] R 2 For H, R C -N(R)C(O)Cy 2-N(R)S(O)2Cy 2 -N(R)Cy 2 -OCy 2 -SCy 2 or Cy 2 ;

[0146] R 3 H, halogen or C 1-6 aliphatic group; or

[0147] R 2 and R 3 It combines with its inserting atoms to form a 4- to 7-membered partially unsaturated or aromatic ring having 0 to 3 independent heteroatoms selected from nitrogen, oxygen, and sulfur; wherein the ring is connected to m R 4 Instance replacement;

[0148] Cy 1 and Cy 2 Each of the following is independently a phenyl group; a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; or a 7- to 12-membered saturated or partially unsaturated bicyclic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein Cy 1 After n R 5 Instance replacement; and; where Cy 2 After p R 6 Instance replacement;

[0149] Cy 3 It is a 5- to 6-membered monocyclic partially unsaturated or heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein Cy 3 After r R 8 Instance replacement;

[0150] L 1 For covalent bonds or C 1-4 Divalent saturated or unsaturated, straight-chain or branched hydrocarbon chains, wherein one or both methylene units of the chain are optionally and independently substituted with -C(R) 7 )2-, -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-, -OC(O)N(R)-, -N(R)C(O)O-, -S-, -S(O)- or -S(O)2- substitution;

[0151] R4 R 5 R 6 R 7 and R 8 R is independent for each occurrence. A Or R B And after q R C Instance replacement;

[0152] R A Each occurrence is independently of oxo, halogen, -CN, -NO2, -OR, -OR. D , -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;

[0153] R B It is C independently each time it appears. 1-6 Aliphatic group; phenyl group; 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;

[0154] R C Each time it appears, 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, 3 to 7-membered saturated or partially unsaturated heterocycles having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5 to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0155] RD C 1-4 Aliphatic group, in which one or more hydrogens are replaced by deuterium;

[0156] Each R is independently hydrogen or optionally substituted with a group selected from the following: C 1-6 Aliphatic group, phenyl group, 3- to 7-membered saturated or partially unsaturated heterocycles having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:

[0157] Two R groups on the same nitrogen atom are bonded 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; and

[0158] Each of m, n, p, q, and r is independently 0, 1, 2, 3, or 4.

[0159] As generally defined above, X is N or C(R). 3 In some embodiments, X is N. In some embodiments, X is C(R). 3 In some embodiments, X is C(H). In some embodiments, X is C(R). 3 ), where R 3 It is a halogen. In some embodiments, X is C(R) 3 ), where R 3 It is fluorine.

[0160] As generally defined above, Y is N or C(R) 1 In some embodiments, Y is N. In some embodiments, Y is C(R). 1 In some embodiments, Y is C(H). In some embodiments, Y is C(D). In some embodiments, Y is C(R). 1 ), where R 1 It is a halogen. In some embodiments, X is C(R) 1 ), where R 3 It is fluorine.

[0161] As generally defined above, R 1 It is H, D, or a halogen. In some embodiments, R 1 For H. In some embodiments, R 1 For D. In some embodiments, R 1 It is a halogen. In some embodiments, R 1 It is fluorine.

[0162] As generally defined above, R 2 For H, R C -N(R)C(O)Cy2 -N(R)Cy 2 -OCy 2 -SCy 2 or Cy 2 In some embodiments, R 2 For H. In some embodiments, R 2 For R C -N(R)C(O)Cy 2 -N(R)Cy 2 -OCy 2 -SCy 2 or Cy 2 In some embodiments, R 2 For R C In some embodiments, R 2 It is -N(R)C(O)R. In some embodiments, R 2 is -N(R)C(O)Cy 2 -N(R)Cy 2 or Cy 2 In some embodiments, R 2 is N(R)C(O)R, -N(R)C(O)Cy 2 -N(R)Cy 2 or Cy 2 In some embodiments, R 2 -N(H)C(O)R, -N(H)C(O)Cy 2 -N(H)Cy 2 or Cy 2 In some embodiments, R 2 -N(H)C(O)R, -N(H)C(O)Cy 2 or -N(H)Cy 2 In some embodiments, R 2 It is -N(H)C(O)R. In some embodiments, R 2 The form is -N(H)C(O)R, where R is, in this case, an optionally substituted C. 1-6 Aliphatic group. In some embodiments, R 2 is -N(H)C(O)Cy 2 In some embodiments, R 2 -N(H)Cy 2 In some embodiments, R 2 is -N(H)C(O)Cy 2 Cy 2 It is cyclopropyl. In some embodiments, R 2 for

[0163] In some embodiments, R 2 and R 3 It combines with its inserting atoms to form a 4- to 7-membered partially unsaturated or aromatic ring having 0 to 3 independent heteroatoms selected from nitrogen, oxygen, and sulfur; wherein the ring is connected to m R 4 Instance replacement. In some embodiments, R 2 and R 3 It combines with its inserting atoms to form a 5-membered partially unsaturated or aromatic ring having 1-3 independent heteroatoms selected from nitrogen, oxygen, and sulfur; wherein the ring is connected to m R 4 Instance replacement.

[0164] As generally defined above, Cy 1 It is a phenyl group; a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; or a 7- to 12-membered saturated or partially unsaturated bicyclic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy 1 After n R 5 Instance replacement.

[0165] In some embodiments, Cy 1 It is phenyl. In some embodiments, Cy 1 It is a 5- to 6-membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy 1 It is a 5-membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy 1 It is a 6-membered heteroaryl group having 1 to 4 nitrogen atoms. In some embodiments, Cy 1 It is pyridyl. In some embodiments, Cy 1 It is pyrazinyl. In some embodiments, Cy 1 It is a pyrimidinyl group. In some embodiments, Cy 1 It is triazine-based. In some embodiments, Cy... 1 It is pyrrole, pyrazolyl, imidazole, triazolyl, or tetrazolyl. In some embodiments, Cy1 is furanyl, oxazolyl, isoxazolyl, or oxadiazolyl; in some embodiments, Cy1 is thiophenyl, thiazolyl, isothiazolyl, or thiadiazolyl. 1 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, Cy 1It is a 3- to 7-membered saturated or partially unsaturated heterocycle having one or two heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy 1 It is a 3- to 7-membered saturated or partially unsaturated monocyclic carbon ring. In some embodiments, Cy 1 It is a 7- to 12-membered saturated or partially unsaturated bicyclic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0166] In some embodiments, Cy 1 (R 5 ) n Combined, the following are selected:

[0167]

[0168]

[0169] Among them, R, R C Each of q is as defined above and described individually and in combination in the embodiments herein.

[0170] As generally defined above, Cy 2 It is a phenyl group; a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; or a 7- to 12-membered saturated or partially unsaturated bicyclic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy 2 After p R 6 Instance replacement.

[0171] In some embodiments, Cy 2 It is phenyl. In some embodiments, Cy 2 It is a 5- to 6-membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy 2 It is a 5-membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy 2 It is a 6-membered heteroaryl group having 1 to 4 nitrogen atoms. In some embodiments, Cy 2 It is pyridyl. In some embodiments, Cy 2 It is pyrazinyl. In some embodiments, Cy 2 It is a pyrimidinyl group. In some embodiments, Cy 2 It is triazine-based. In some embodiments, Cy... 2It is pyrrole, pyrazolyl, imidazole, triazolyl, or tetrazolyl. In some embodiments, Cy 2 It is furanyl, oxazolyl, isoxazolyl or oxadiazolyl; in some embodiments, Cy 2 It is thienyl, thiazolyl, isothiazolyl, or thiadiazolyl. In some embodiments, Cy 2 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, Cy 2 It is a 3- to 7-membered saturated or partially unsaturated heterocycle having one or two heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Cy 2 It is a 3- to 7-membered saturated or partially unsaturated monocyclic carbon ring. In some embodiments, Cy 2 C 3-7 Cycloalkyl. In some embodiments, Cy 2 Cy is cyclopropyl. In some embodiments, Cy 2 It is a 7- to 12-membered saturated or partially unsaturated bicyclic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0172] In some embodiments, Cy 2 Selected from the following, each of which is processed by p R 6 Instance replacement:

[0173]

[0174] In some embodiments, Cy 2 Groups selected from the preceding paragraphs or the following, which are derived from p R groups 6 Instance replacement:

[0175]

[0176] As generally defined above, Cy 3 It is a 5- to 6-membered monocyclic partially unsaturated or heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein Cy 3 After r R 8 Instance replacement. In some embodiments, Cy 3 It is a 5-membered monocyclic partially unsaturated or heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy 3 It is a 5-membered monocyclic partially unsaturated ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy 3 It is a 5-membered monocyclic heteroaromatic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0177] In some embodiments, Cy 3Selected from the following, each of which is processed by r R 8 Instance replacement:

[0178]

[0179] As generally defined above, L 1 For covalent bonds or C 1-4 Divalent saturated or unsaturated, straight-chain or branched hydrocarbon chains, wherein one or both methylene units of the chain are optionally and independently substituted with -C(R) 7 -2-, -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- are substituted. In some embodiments, L 1 It is a covalent bond. In some embodiments, L 1 C 1-4 Divalent saturated or unsaturated, straight-chain or branched hydrocarbon chains, wherein one or both methylene units of the chain are optionally and independently substituted with -C(R) 7 -2-, -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- are substituted. In some embodiments, L 1 For -N(R)-. In some embodiments, L 1 It is -N(H)-.

[0180] As generally defined above, R 8 Independently for R A Or R B And after q R C Instance replacement. In some embodiments, R 8 Halogen or via 1 to 2 R C Replacement C 1-6 Aliphatic group. In some embodiments, R 8 It is a halogen. In some embodiments, R 8 For 0 to 2 R C Replacement C 1-6 Aliphatic group. In some embodiments, R 8 It is chlorine or fluorine. In some embodiments, R 8 hydroxymethyl. In some embodiments, R 8 It is chlorine, fluorine, methyl, cyclopropyl, or hydroxymethyl. In some embodiments, R 8 It can be chlorine, fluorine, or hydroxymethyl.

[0181] 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.

[0182] 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.

[0183] 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.

[0184] 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.

[0185] In some embodiments, the present invention provides a compound of formula VIII, wherein L 1 The form is -N(H)-, thus forming a compound of formula VIII-a:

[0186]

[0187] Or a pharmaceutically acceptable salt thereof, wherein X, Cy 1 R 1 and R 2 Each of these terms is as defined above and is described individually and in combination in the embodiments herein.

[0188] In some embodiments, the present invention provides a compound of formula VIII, wherein X is C(R) 3 And Y is C(R) 1 ), or X is C(R3) and Y is N, or X is N and Y is C(R1), or both X and Y are N; thereby forming compounds of formula IX-a, IX-b, IX-c or IX-d respectively:

[0189]

[0190] Or a pharmaceutically acceptable salt thereof, wherein Cy 1 Cy 3 L 1 R1 R 2 and R 3 Each of these terms is as defined above and is described individually and in combination in the embodiments herein.

[0191] In some embodiments, the present invention provides a compound of formula IX-a, IX-b, IX-c, or IX-d, wherein L 1 The -N(H)- form compounds of formula Xa or Xb, Xc or Xd, respectively.

[0192]

[0193] Or a pharmaceutically acceptable salt thereof, wherein Cy 1 Cy 3 R 1 R 2 and R 3 Each of these terms is as defined above and is described individually and in combination in the embodiments herein.

[0194] In some embodiments, the present invention provides a compound of formula VIII-a, wherein Cy 1 For phenyl, compounds of formula XI-a are:

[0195]

[0196] Or a pharmaceutically acceptable salt thereof, wherein X, Y, R 2 R 5 Each of and n is as defined above and described individually and in combination in the embodiments herein.

[0197] In some embodiments, the present invention provides a compound of formula Xa, Xb, Xc or Xd, wherein Cy 1 The phenyl group forms compounds of formula XI-b, XI-c, XI-d, or XI-e, respectively:

[0198]

[0199] Or a pharmaceutically acceptable salt thereof, wherein R 1 R 2 R 3 R 5 Each of and n is as defined above and described individually and in combination in the embodiments herein.

[0200] In some embodiments, the present invention provides a compound of formula XI-a, wherein n is 1, 2 or 3 and R 5 At least one instance is located at the ortho position of the NH junction site, thereby forming a compound of formula XII-a:

[0201]

[0202] Or a pharmaceutically acceptable salt thereof, wherein X, Y, Cy 3 R 2 and R 5 Each of these terms is as defined above and is described individually and in combination in the embodiments herein.

[0203] In some embodiments, the present invention provides a compound of formula XI-b, XI-c, XI-d, or XI-e, wherein n is 1, 2, or 3 and R 5 At least one instance is located adjacent to the NH junction site, thereby forming compounds of formula XII-b, XII-c, XII-d, or XII-e, respectively:

[0204]

[0205] Or a pharmaceutically acceptable salt thereof, wherein Cy 3 R 1 R 2 R 3 and R 5 Each of these terms is as defined above and is described individually and in combination in the embodiments herein.

[0206] In some embodiments, the present invention provides a compound of formula XII-a, wherein the ortho-R... 5 The groups are -OR, -S(O)2R, -C(O)NR2 or -N(R)S(O)2R, thereby forming compounds of formula XII-ai, XII-a-ii, XII-a-iii or XII-a-iv, respectively:

[0207]

[0208] Or a pharmaceutically acceptable salt thereof, wherein X, Y, Cy 3 , R, R 1 R 2 R 3 and R 5 Each of these terms is as defined above and is described individually and in combination in the embodiments herein.

[0209] In some embodiments, the present invention provides a compound of formula XII-b, wherein the ortho-R 5 The functional groups are -OR, -S(O)2R, -C(O)NR2 or -N(R)S(O)2R, thereby forming compounds of formula XII-bi, XII-b-ii, XII-b-iii or XII-b-iv, respectively:

[0210]

[0211] Or a pharmaceutically acceptable salt thereof, wherein Cy 3 , R, R 1 R 2 R 3 and R 5 Each of these terms is as defined above and is described individually and in combination in the embodiments herein.

[0212] In some embodiments, the present invention provides a compound of formula XII-c, wherein the ortho-R... 5 The groups are -OR, -S(O)2R, -C(O)NR2 or -N(R)S(O)2R, thereby forming compounds of formula XII-ci, XII-c-ii, XII-c-iii or XII-c-iv, respectively:

[0213]

[0214] Or a pharmaceutically acceptable salt thereof, wherein Cy 3 , R, R 2 R 3 and R 5 Each of these terms is as defined above and is described individually and in combination in the embodiments herein.

[0215] In some embodiments, the present invention provides a compound of formula XII-d, wherein the ortho-R 5 The groups are -OR, -S(O)2R, -C(O)NR2 or -N(R)S(O)2R, thereby forming compounds of formula XII-di, XII-d-ii, XII-d-iii or XII-d-iv respectively:

[0216]

[0217] Or a pharmaceutically acceptable salt thereof, wherein Cy 3 , R, R 1 R 2 and R 5 Each of these terms is as defined above and is described individually and in combination in the embodiments herein.

[0218] In some embodiments, the present invention provides a compound of formula XII-e, wherein the ortho-R 5 The groups are -OR, -S(O)2R, -C(O)NR2 or -N(R)S(O)2R, thereby forming compounds of formula XII-ei, XII-e-ii, XII-e-iii or XII-e-iv, respectively:

[0219]

[0220] Or a pharmaceutically acceptable salt thereof, wherein Cy 3 , R, R 2 and R 5 Each of these terms is as defined above and is described individually and in combination in the embodiments herein.

[0221] In some embodiments, the present invention provides a compound of formula XII-ai, wherein the second R 5 The group is located at the meta position of the NH junction, thus forming a compound of formula XIII-a:

[0222]

[0223] Or a pharmaceutically acceptable salt thereof, wherein X, Y, Cy 3 , R, R 2 and R 5 Each of these terms is as defined above and is described individually and in combination in the embodiments herein.

[0224] In some embodiments, the present invention provides a compound of formula XII-bi, XII-ci, XII-di, or XII-ei, wherein the second R... 5 The group is located at the meta position of the NH junction, thereby forming compounds of formula XIII-b, XIII-c, XIII-d, or XIII-e, respectively:

[0225]

[0226] Or a pharmaceutically acceptable salt thereof, wherein Cy 3 , R, R 1 R 2 R 3 and R 5 Each of these terms is as defined above and is described individually and in combination in the embodiments herein.

[0227] In some embodiments, the present invention provides a compound of formula XIII-a, XIII-b, XIII-c, XIII-d, or XIII-e, wherein R 5 For R B In some embodiments, the present invention provides a compound of formula XIII-a, XIII-b, XIII-c, XIII-d, or XIII-e, wherein R 5 It is -C(O)NR2 or a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, said ring being connected to q R C Instance replacement.

[0228] In some embodiments, the present invention provides a compound of formula XIII-a, XIII-b, XIII-c, XIII-d or XIII-e, wherein -OR is methoxy, fluoromethoxy or difluoromethoxy.

[0229] In some embodiments, the present invention provides a compound of formula Ia, wherein Cy 1 It is pyridyl, n is 2, and R 5 One example is oxoation, which forms a pyridone compound of formula XIV-a:

[0230]

[0231] Or a pharmaceutically acceptable salt thereof, wherein X, Y, Cy 3 R 2 and R 5 Each of these terms is as defined above and is described individually and in combination in the embodiments herein.

[0232] In some embodiments, the present invention provides a compound of formula Xa or Xb, Xc or Xd, wherein Cy 1 It is pyridyl, n is 2, and R 5 One example is oxoation, which forms pyridone compounds of the formula XV-a, XV-b, XV-c, or XV-d:

[0233]

[0234] Or a pharmaceutically acceptable salt thereof, wherein Cy 3 R 1 R 2 R 3 and R 5 Each of these terms is as defined above and is described individually and in combination in the embodiments herein.

[0235] As described above, in some embodiments, the present invention provides a compound of formula XVI':

[0236]

[0237] Or its pharmaceutically acceptable salt, wherein:

[0238] Q is CH or N;

[0239] X is N or C(R) X );

[0240] Y 1 Y 2 Z 1 and Z 2 One of them is N, and the other three are C;

[0241] R 1 For D, R, R D -NR2, -NRR D -N(R) D )2, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)C(O)NRR D -N(R)C(NR)NRR D -OR or -OR D ;

[0242] R 2 For H, R C -N(R)C(O)Cy 2 -N(R)S(O)2Cy 2 -N(R)Cy 2 -OCy 2 -SCy 2 or Cy 2 ;

[0243] R 3 H, halogen or C 1-6 aliphatic group; or

[0244] R 2 and R 3 It combines with its inserting atoms to form a 4- to 7-membered partially unsaturated or aromatic ring having 0 to 3 independent heteroatoms selected from nitrogen, oxygen, and sulfur; wherein the ring is connected to m R 4 Instance replacement;

[0245] Cy 1 and Cy 2 Each of the following is independently a phenyl group; a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; or a 7- to 12-membered saturated or partially unsaturated bicyclic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy 1 After n R 5 Instance replacement; and; where Cy 2 After p R 6 Instance replacement;

[0246] L 1 For covalent bonds or C 1-4 Divalent saturated or unsaturated, straight-chain or branched hydrocarbon chains, wherein one or both methylene units of the chain are optionally and independently substituted with -C(R)7 )2-, -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- substitution;

[0247] R 4 R 5 R 6 and R 7 R is independent for each occurrence. A Or R B And after q R C Instance replacement;

[0248] R A Each occurrence is independently of oxo, halogen, -CN, -NO2, -OR, -OR. D , -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;

[0249] R B It is C independently each time it appears. 1-6 Aliphatic group; phenyl group; 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;

[0250] R CEach time it appears, 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, 3 to 7-membered saturated or partially unsaturated heterocycles having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5 to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0251] R D C 1-4 Aliphatic group, in which one or more hydrogens are replaced by deuterium;

[0252] R X H, halogen or C 1-6 aliphatic group

[0253] Each R is independently hydrogen or optionally substituted with a group selected from the following: C 1-6 Aliphatic group, phenyl group, 3- to 7-membered saturated or partially unsaturated heterocycles having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:

[0254] Two R groups on the same nitrogen atom are bonded 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; and

[0255] Each of m, n, p, and q is independently 0, 1, 2, 3, or 4.

[0256] As generally defined above, Q is CH or N. In some embodiments, Q is CH. In some embodiments, Q is N.

[0257] As generally defined above, X is N or C(R). X In some embodiments, X is N. In some embodiments, X is C(R). X In some embodiments, X is C(H). In some embodiments, X is C(R). X ), where R X It is a halogen. In some embodiments, X is C(R) X ), where R XIt is fluorine.

[0258] As generally defined above, R 1 For D, R, R D -NR2, -NRR D -N(R) D )2, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)C(O)NRR D -N(R)C(NR)NRR D -OR or -OR D In some embodiments, R 1 For D. In some embodiments, R 1 R. In some embodiments, R 1 For R D In some embodiments, R 1 For -NR2. In some embodiments, R 1 -NRR D In some embodiments, R 1 -N(R) D )2. In some embodiments, R 1 For -OR. In some embodiments, R 1 For -OR D In some embodiments, R 1 C is arbitrarily substituted 1-6 Aliphatic group. In some embodiments, R 1 The ethyl group is optionally substituted. In some embodiments, R 1 It is hydrogen, methyl, or -CD3. In some embodiments, R 1 It is hydrogen. In some embodiments, R is... 1 It is methyl or -CD3. In some embodiments, R 1 methyl. In some embodiments, R 1 For -CD3. In some embodiments, R 1 For -OCH3. In some embodiments, R 1 For D, R, R D -NR2, -NRR D -N(R) D )2, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)C(O)NRR D -N(R)C(NR)NRR D -OR or -OR D , where R 1 Not hydrogen. In some embodiments, R 1 -NR2, -NRR D -N(R)D )2, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)C(O)NRR D -N(R)C(NR)NRR D -OR or -OR D In some embodiments, R 1 -NR2, -NRR D -N(R) D )2, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)C(O)NRR D -N(R)C(NR)NRR D In some embodiments, R 1 -NR2 or -NRR D In some embodiments, R 1 C is arbitrarily substituted 1-6 Aliphatic group, -NR2 or -NRR D In some embodiments, R 1 -NHR or NHR D In some embodiments, R 1 It is -NHCH3 or NHCD3.

[0259] As generally defined above, R 2 For H, R C -N(R)C(O)Cy 2 -N(R)Cy 2 -OCy 2 -SCy 2 or Cy 2 In some embodiments, R 2 For H. In some embodiments, R 2 For R C -N(R)C(O)Cy 2 -N(R)Cy 2 -OCy 2 -SCy 2 or Cy 2 In some embodiments, R 2 For R C In some embodiments, R 2 It is -N(R)C(O)R. In some embodiments, R 2 is -N(R)C(O)Cy 2 -N(R)Cy 2 or Cy 2 In some embodiments, R 2 is N(R)C(O)R, -N(R)C(O)Cy 2-N(R)Cy 2 or Cy 2 In some embodiments, R 2 -N(H)C(O)R, -N(H)C(O)Cy 2 -N(H)Cy 2 or Cy 2 In some embodiments, R 2 -N(H)C(O)R, -N(H)C(O)Cy 2 or -N(H)Cy 2 In some embodiments, R 2 It is -N(H)C(O)R. In some embodiments, R 2 The form is -N(H)C(O)R, where R is, in this case, an optionally substituted C. 1-6 Aliphatic group. In some embodiments, R 2 is -N(H)C(O)Cy 2 In some embodiments, R 2 -N(H)Cy 2 In some embodiments, R 2 is -N(H)C(O)Cy 2 Cy 2 It is cyclopropyl. In some embodiments, R 2 for

[0260] As generally defined above, R 3 H, halogen or C 1-6 Aliphatic group. In some embodiments, R 3 For H. In some embodiments, R 3 Halogen or C 1-6 Aliphatic group. In some embodiments, R 3 It is a halogen. In some embodiments, R 3 It is fluorine. In some embodiments, R 3 C 1-6 Aliphatic groups.

[0261] In some embodiments, R 2 and R 3 It combines with its inserting atoms to form a 4- to 7-membered partially unsaturated or aromatic ring having 0 to 3 independent heteroatoms selected from nitrogen, oxygen, and sulfur; wherein the ring is connected to m R 4 Instance replacement. In some embodiments, R 2 and R 3 It combines with its inserting atoms to form a 5-membered partially unsaturated or aromatic ring having 1-3 independent heteroatoms selected from nitrogen, oxygen, and sulfur; wherein the ring is connected to m R 4 Instance replacement.

[0262] As generally defined above, Cy 1 It is a phenyl group; a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; or a 7- to 12-membered saturated or partially unsaturated bicyclic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy 1 After n R 5 Instance replacement.

[0263] In some embodiments, Cy 1 It is phenyl. In some embodiments, Cy 1 It is a 5- to 6-membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy 1 It is a 5-membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy 1 It is a 6-membered heteroaryl group having 1 to 4 nitrogen atoms. In some embodiments, Cy 1 It is pyridyl. In some embodiments, Cy 1 It is pyrazinyl. In some embodiments, Cy 1 It is a pyrimidinyl group. In some embodiments, Cy 1 It is triazine-based. In some embodiments, Cy... 1 It is pyrrole, pyrazolyl, imidazole, triazolyl, or tetrazolyl. In some embodiments, Cy1 is furanyl, oxazolyl, isoxazolyl, or oxadiazolyl; in some embodiments, Cy1 is thiophenyl, thiazolyl, isothiazolyl, or thiadiazolyl. 1 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, Cy 1 It is a 3- to 7-membered saturated or partially unsaturated heterocycle having one or two heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy 1 It is a 3- to 7-membered saturated or partially unsaturated monocyclic carbon ring. In some embodiments, Cy 1 It is a 7- to 12-membered saturated or partially unsaturated bicyclic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0264] In some embodiments, Cy 1 (R 5 ) n Combined, the following are selected:

[0265]

[0266]

[0267] Among them, R, R C Each of q is as defined above and described individually and in combination in the embodiments herein.

[0268] As generally defined above, Cy 2 It is a phenyl group; a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; or a 7- to 12-membered saturated or partially unsaturated bicyclic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy 2 After p R 6 Instance replacement.

[0269] In some embodiments, Cy 2 It is phenyl. In some embodiments, Cy 2 It is a 5- to 6-membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy 2 It is a 5-membered heteroaryl group having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy 2 It is a 6-membered heteroaryl group having 1 to 4 nitrogen atoms. In some embodiments, Cy 2 It is pyridyl. In some embodiments, Cy 2 It is pyrazinyl. In some embodiments, Cy 2 It is a pyrimidinyl group. In some embodiments, Cy 2 It is triazine-based. In some embodiments, Cy... 2 It is pyrrole, pyrazolyl, imidazole, triazolyl, or tetrazolyl. In some embodiments, Cy 2 It is furanyl, oxazolyl, isoxazolyl or oxadiazolyl; in some embodiments, Cy 2 It is thienyl, thiazolyl, isothiazolyl, or thiadiazolyl. In some embodiments, Cy 2 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, Cy 2 It is a 3- to 7-membered saturated or partially unsaturated heterocycle having one or two heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Cy 2 It is a 3- to 7-membered saturated or partially unsaturated monocyclic carbon ring. In some embodiments, Cy2 C 3-7 Cycloalkyl. In some embodiments, Cy 2 Cy is cyclopropyl. In some embodiments, Cy 2 It is a 7- to 12-membered saturated or partially unsaturated bicyclic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0270] In some embodiments, Cy 2 Selected from the following, each of which is processed by p R 6 Instance replacement:

[0271]

[0272] As generally defined above, L 1 For covalent bonds or C 1-4 Divalent saturated or unsaturated, straight-chain or branched hydrocarbon chains, wherein one or both methylene units of the chain are optionally and independently substituted with -C(R) 7 -2-, -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- are substituted. In some embodiments, L 1 It is a covalent bond. In some embodiments, L 1 C 1-4 Divalent saturated or unsaturated, straight-chain or branched hydrocarbon chains, wherein one or both methylene units of the chain are optionally and independently substituted with -C(R) 7 )2-, -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- substitution.

[0273] 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.

[0274] 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.

[0275] 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.

[0276] In some embodiments, the present invention provides a compound of formula XVI', wherein Q is N, thereby forming a compound of formula XVI:

[0277]

[0278] Or its pharmaceutically acceptable salt, wherein:

[0279] X is N or C(R) X );

[0280] Y 1 Y 2 Z 1 and Z 2 One of them is N, and the other three are C;

[0281] R 1 For D, R, R D -NR2, -NRR D -N(R) D )2, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)C(O)NRR D -N(R)C(NR)NRR D -OR or -OR D ;

[0282] R 2 For H, R C -N(R)C(O)Cy 2 -N(R)S(O)2Cy 2 -N(R)Cy 2 -OCy 2 -SCy 2 or Cy 2 ;

[0283] R 3 H, halogen or C 1-6 aliphatic group; or

[0284] R 2 and R 3 It combines with its inserting atoms to form a 4- to 7-membered partially unsaturated or aromatic ring having 0 to 3 independent heteroatoms selected from nitrogen, oxygen, and sulfur; wherein the ring is connected to m R 4 Instance replacement;

[0285] Cy 1 and Cy 2 Each of the following is independently a phenyl group; a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; or a 7- to 12-membered saturated or partially unsaturated bicyclic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy 1 After n R 5 Instance replacement; and; where Cy 2 After p R 6 Instance replacement;

[0286] L 1 For covalent bonds or C 1-4 Divalent saturated or unsaturated, straight-chain or branched hydrocarbon chains, wherein one or both methylene units of the chain are optionally and independently substituted with -C(R) 7 )2-, -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- substitution;

[0287] R 4 R 5 R 6 and R 7 R is independent for each occurrence. A Or R B And after q R C Instance replacement;

[0288] R A Each occurrence is independently of oxo, halogen, -CN, -NO2, -OR, -OR. D , -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;

[0289] R B It is C independently each time it appears. 1-6Aliphatic group; phenyl group; 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;

[0290] R C Each time it appears, 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, 3 to 7-membered saturated or partially unsaturated heterocycles having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5 to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0291] R D C 1-4 Aliphatic group, in which one or more hydrogens are replaced by deuterium;

[0292] R X H, halogen or C 1-6 aliphatic group

[0293] Each R is independently hydrogen or optionally substituted with a group selected from the following: C 1-6 Aliphatic group, phenyl group, 3- to 7-membered saturated or partially unsaturated heterocycles having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:

[0294] Two R groups on the same nitrogen atom are bonded 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; and

[0295] Each of m, n, p, and q is independently 0, 1, 2, 3, or 4.

[0296] In some embodiments, the present invention provides a compound of formula XVI, wherein L 1The bonds are covalent, thus forming a compound of formula XVI-a:

[0297]

[0298] Or a pharmaceutically acceptable salt thereof, wherein X, Y 1 Y 2 Z 1 Z 2 Cy 1 R 1 R 2 and R 3 Each of these terms is as defined above and is described individually and in combination in the embodiments herein.

[0299] In some embodiments, the present invention provides a compound of formula XVI, wherein X is N or C(R) X Thus, compounds of formula XVI-b or XVI-c are formed respectively:

[0300]

[0301] Or its pharmaceutically acceptable salt, wherein L 1 Y 1 Y 2 Z 1 Z 2 Cy 1 R X R 1 R 2 and R 3 Each of these terms is as defined above and is described individually and in combination in the embodiments herein.

[0302] In some embodiments, the present invention provides a compound of formula XVI-b or XVI-c, wherein R X and R 3 Both are H, thus forming compounds of formula XVII-a or XVII-b respectively:

[0303]

[0304] Or a pharmaceutically acceptable salt thereof, wherein Y 1 Y 2 Z 1 Z 2 Cy 1 R 1 R 2 and R 3 Each of these terms is as defined above and is described individually and in combination in the embodiments herein.

[0305] In some embodiments, the present invention provides a compound of formula XVII-a or XVII-b, wherein L 1 These are covalent bonds, thus forming compounds of formula XVIII-a or XVIII-b, respectively:

[0306]

[0307] Or a pharmaceutically acceptable salt thereof, wherein Y 1 Y 2 Z 1 Z 2 Cy 1 R 1 and R 2 Each of these terms is as defined above and is described individually and in combination in the embodiments herein.

[0308] In some embodiments, the present invention provides a compound of formula XVIII-a or XVIII-b, wherein Cy 1 The phenyl group forms compounds of formula XIX-a or XIX-b, respectively:

[0309]

[0310] Or a pharmaceutically acceptable salt thereof, wherein Y 1 Y 2 Z 1 Z 2 R 1 R 2 Each of and n is as defined above and described individually and in combination in the embodiments herein.

[0311] In some embodiments, the present invention provides a compound of formula XIX-a or XIX-b, wherein n is 1, 2 or 3 and R 5 At least one instance is located adjacent to the NH junction site, thereby forming compounds of formula XX-a or XX-b, respectively:

[0312]

[0313] Or a pharmaceutically acceptable salt thereof, wherein Y 1 Y 2 Z 1 Z 2 R 1 and R 2 Each of these terms is as defined above and is described individually and in combination in the embodiments herein.

[0314] In some embodiments, the present invention provides a compound of formula XX-a or XX-b, wherein the ortho-R 5The groups are -OR, -S(O)2R, -C(O)NR2, or -N(R)S(O)2R, thereby forming compounds of the formulas XXI-a, XXI-b, XXI-c, XXI-d, XXI-e, XXI-f, XXI-g, or XXI-h, respectively.

[0315]

[0316] Or a pharmaceutically acceptable salt thereof, wherein Y 1 Y 2 Z 1 Z 2 , R, R 1 R 2 and R 5 Each of these terms is as defined above and is described individually and in combination in the embodiments herein.

[0317] In some embodiments, the present invention provides a compound of formula XXI-a or XXI-b, wherein the second R 5 The group is located at the meta position of the NH junction, thereby forming compounds of formula XXII-a or XXII-b, respectively:

[0318]

[0319] Or a pharmaceutically acceptable salt thereof, wherein Y 1 Y 2 Z 1 Z 2 , R, R 1 R 2 and R 5 Each of these terms is as defined above and is described individually and in combination in the embodiments herein.

[0320] In some embodiments, the present invention provides a compound of formula XXII-a or XXII-b, wherein R 5 For R B In some embodiments, the present invention provides a compound of formula XXII-a or XXII-b, wherein R 5 It is a -CN, -C(O)NR2 or a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, said ring being connected to q R C Instance replacement.

[0321] In some embodiments, the present invention provides a compound of formula XXII-a or XXII-b, wherein -OR is a methoxy, fluoromethoxy, or difluoromethoxy compound.

[0322] In some embodiments, the present invention provides a compound of formula XVIII-a or XVIII-b, wherein Cy1 It is pyridyl, n is 2, and R 5 One example is oxoation, which results in pyridone compounds of formula XXIII-a or XXIII-b, respectively:

[0323]

[0324] Or a pharmaceutically acceptable salt thereof, wherein Y 1 Y 2 Z 1 Z 2 R 1 R 2 and R 5 Each of these terms is as defined above and is described individually and in combination in the embodiments herein.

[0325] In some embodiments, the present invention provides compounds of one of the following formulas: XVI-a, XVI-b, XVI-c, XVII-a, XVII-b, XVIII-a, XVIII-b, XIX-a, XIX-b, XX-a, XX-b, XXI-a, XXI-b, XXI-c, XXI-d, XXI-e, XXI-f, XXI-g, XXI-h, XXII-a, XXII-b, XXIII-a or XXIII-b, wherein Z 2 For N and Y 1 Y 2 and Z 1 C. In some embodiments, the present invention provides compounds of one of the following formulas: XVI-a, XVI-b, XVI-c, XVII-a, XVII-b, XVIII-a, XVIII-b, XIX-a, XIX-b, XX-a, XX-b, XXI-a, XXI-b, XXI-c, XXI-d, XXI-e, XXI-f, XXI-g, XXI-h, XXII-a, XXII-b, XXIII-a or XXIII-b, wherein Y 2 For N and Y 1 Z 1 and Z 2 The answer is C.

[0326] In some embodiments, the present invention provides a compound of formula I, wherein Z 2 For N and Y 1 Y 2 and Z 1 For C; or where Y is... 2 For N and Y 1 Z 1 and Z 2 C, thus forming compounds of formula XXIV-a or XXIV-b respectively:

[0327]

[0328] Or its pharmaceutically acceptable salt, wherein X, L 1 Cy 1 R 1 and R 2 Each of these terms is as defined above and is described individually and in combination in the embodiments herein.

[0329] In some embodiments, the present invention provides a compound of formula XXIV-a or XXIV-b, wherein L 1 These are covalent bonds, thus forming compounds of formula XXV-a or XXV-b respectively:

[0330]

[0331] Or a pharmaceutically acceptable salt thereof, wherein X, Cy 1 R 1 and R 2 Each of these terms is as defined above and is described individually and in combination in the embodiments herein.

[0332] In some embodiments, the present invention provides a compound of formula XXV-a or XXV-b, wherein X is C and R X H is used to form compounds of formula XXVI-a or XXVI-b, respectively:

[0333]

[0334] Or a pharmaceutically acceptable salt thereof, wherein Cy 1 R 1 and R 2 Each of these terms is as defined above and is described individually and in combination in the embodiments herein.

[0335] In some embodiments, the present invention provides compounds of one of the following formulas: XVI-a, XVI-b, XVI-c, XVII-a, XVII-b, XVIII-a, XVIII-b, XIX-a, XIX-b, XX-a, XX-b, XXI-a, XXI-b, XXI-c, XXI-d, XXI-e, XXI-f, XXI-g, XXI-h, XXII-a, XXII-b, XXIII-a, XXIII-b, XXIV-a, XXIV-b, XXV-a, XXV-b, XXVI-a, or XXVI-b, wherein R 2 is -N(R)C(O)R, -N(R)C(O)Cy 2 -N(R)Cy 2 or Cy2 In some embodiments, the present invention provides compounds of one of the following formulas: XVI-a, XVI-b, XVI-c, XVII-a, XVII-b, XVIII-a, XVIII-b, XIX-a, XIX-b, XX-a, XX-b, XXI-a, XXI-b, XXI-c, XXI-d, XXI-e, XXI-f, XXI-g, XXI-h, XXII-a, XXII-b, XXIII-a, XXIII-b, XXIV-a, XXIV-b, XXV-a, XXV-b, XXVI-a or XXVI-b, wherein R 2 -N(H)C(O)R, -N(H)C(O)Cy 2 -N(H)Cy 2 or Cy 2 In some embodiments, the present invention provides compounds of one of the following formulas: XVI-a, XVI-b, XVI-c, XVII-a, XVII-b, XVIII-a, XVIII-b, XIX-a, XIX-b, XX-a, XX-b, XXI-a, XXI-b, XXI-c, XXI-d, XXI-e, XXI-f, XXI-g, XXI-h, XXII-a, XXII-b, XXIII-a, XXIII-b, XXIV-a, XXIV-b, XXV-a, XXV-b, XXVI-a or XXVI-b, wherein R 2 -N(H)C(O)R, -N(H)C(O)Cy 2 or -N(H)Cy 2 In some embodiments, the present invention provides compounds of one of the following formulas: XVI-a, XVI-b, XVI-c, XVII-a, XVII-b, XVIII-a, XVIII-b, XIX-a, XIX-b, XX-a, XX-b, XXI-a, XXI-b, XXI-c, XXI-d, XXI-e, XXI-f, XXI-g, XXI-h, XXII-a, XXII-b, XXIII-a, XXIII-b, XXIV-a, XXIV-b, XXV-a, XXV-b, XXVI-a or XXVI-b, wherein R 2The form is -N(H)C(O)R. In some embodiments, the present invention provides compounds of one of the following formulas: XVI-a, XVI-b, XVI-c, XVII-a, XVII-b, XVIII-a, XVIII-b, XIX-a, XIX-b, XX-a, XX-b, XXI-a, XXI-b, XXI-c, XXI-d, XXI-e, XXI-f, XXI-g, XXI-h, XXII-a, XXII-b, XXIII-a, XXIII-b, XXIV-a, XXIV-b, XXV-a, XXV-b, XXVI-a, or XXVI-b, wherein R 2 for In some embodiments, the present invention provides compounds of one of the following formulas: XVI-a, XVI-b, XVI-c, XVII-a, XVII-b, XVIII-a, XVIII-b, XIX-a, XIX-b, XX-a, XX-b, XXI-a, XXI-b, XXI-c, XXI-d, XXI-e, XXI-f, XXI-g, XXI-h, XXII-a, XXII-b, XXIII-a, XXIII-b, XXIV-a, XXIV-b, XXV-a, XXV-b, XXVI-a, or XXVI-b, wherein R 2 -N(H)Cy 2 Cy 2 Selected from the following, each of which is processed by p R 6 Instance replacement:

[0336]

[0337] In some embodiments, the present invention provides a compound of formula XVI', wherein Q is CH, thereby forming a compound of formula XVI”:

[0338]

[0339] Or a pharmaceutically acceptable salt thereof, wherein X, Y 1 Y 2 Z 1 Z 2 Cy 1 R 1 R 2 and R 3 Each of these terms is as defined above and is described individually and in combination in the embodiments herein.

[0340] In some embodiments, the present invention provides a compound of formula XVI”, wherein L 1 The bonds are covalent, thus forming a compound of formula XVI-a':

[0341]

[0342] Or a pharmaceutically acceptable salt thereof, wherein X, Y 1 Y 2 Z 1 Z 2 Cy 1 R 1 R 2 and R 3 Each of these terms is as defined above and is described individually and in combination in the embodiments herein.

[0343] In some embodiments, the present invention provides a compound of formula XVI”, wherein X is N or C(R) X Thus, compounds of formula XVI-b' or XVI-c' are formed respectively:

[0344]

[0345] Or its pharmaceutically acceptable salt, wherein L 1 Y 1 Y 2 Z 1 Z 2 Cy 1 R X R 1 R 2 and R 3 Each of these terms is as defined above and is described individually and in combination in the embodiments herein.

[0346] In some embodiments, the present invention provides a compound of formula XVI-b' or XVI-c', wherein R X and R 3 Both are H, thus forming compounds of formula XVII-a' or XVII-b' respectively:

[0347]

[0348] Or a pharmaceutically acceptable salt thereof, wherein Y 1 Y 2 Z 1 Z 2 Cy 1 R 1 R 2 and R 3 Each of these terms is as defined above and is described individually and in combination in the embodiments herein.

[0349] In some embodiments, the present invention provides a compound of formula XVII-a' or XVII-b', wherein L 1These are covalent bonds, thus forming compounds of formula XVIII-a' or XVIII-b' respectively:

[0350]

[0351] Or a pharmaceutically acceptable salt thereof, wherein Y 1 Y 2 Z 1 Z 2 Cy 1 R 1 and R 2 Each of these terms is as defined above and is described individually and in combination in the embodiments herein.

[0352] In some embodiments, the present invention provides a compound of formula XVIII-a' or XVIII-b', wherein Cy 1 The phenyl group forms compounds of formula XIX-a' or XIX-b', respectively:

[0353]

[0354] Or a pharmaceutically acceptable salt thereof, wherein Y 1 Y 2 Z 1 Z 2 R 1 R 2 Each of and n is as defined above and described individually and in combination in the embodiments herein.

[0355] In some embodiments, the present invention provides a compound of formula XIX-a' or XIX-b', wherein n is 1, 2 or 3 and R... 5 At least one instance is located adjacent to the NH junction site, thereby forming compounds of formula XX-a' or XX-b' respectively:

[0356]

[0357] Or a pharmaceutically acceptable salt thereof, wherein Y 1 Y 2 Z 1 Z 2 R 1 and R 2 Each of these terms is as defined above and is described individually and in combination in the embodiments herein.

[0358] In some embodiments, the present invention provides a compound of formula XX-a' or XX-b', wherein the ortho-R 5Compounds with the following group are -OR, -S(O)2R, -C(O)NR2, or -N(R)S(O)2R, respectively, are formed as XXI-a', XXI-b', XXI-c', XXI-d', XXI-e', XXI-f', XXI-g', or XXI-h':

[0359]

[0360] Or a pharmaceutically acceptable salt thereof, wherein Y 1 Y 2 Z 1 Z 2 , R, R 1 R 2 and R 5 Each of these terms is as defined above and is described individually and in combination in the embodiments herein.

[0361] In some embodiments, the present invention provides a compound of formula XXI-a' or XXI-b', wherein the second R... 5 The group is located at the meta position of the NH junction, thereby forming compounds of formula XXII-a' or XXII-b' respectively:

[0362]

[0363] Or a pharmaceutically acceptable salt thereof, wherein Y 1 Y 2 Z 1 Z 2 , R, R 1 R 2 and R 5 Each of these terms is as defined above and is described individually and in combination in the embodiments herein.

[0364] In some embodiments, the present invention provides a compound of formula XXII-a' or XXII-b', wherein R 5 For R B In some embodiments, the present invention provides a compound of formula XXII-a' or XXII-b', wherein R 5 It is a -CN, -C(O)NR2 or a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, said ring being connected to q R C Instance replacement.

[0365] In some embodiments, the present invention provides a compound of formula XXII-a' or XXII-b', wherein -OR is a methoxy, fluoromethoxy, or difluoromethoxy compound.

[0366] In some embodiments, the present invention provides a compound of formula XVIII-a' or XVIII-b', wherein Cy 1 It is pyridyl, n is 2, and R 5 One example is oxoation, which results in pyridone compounds of the formula XXIII-a' or XXIII-b', respectively:

[0367]

[0368] Or a pharmaceutically acceptable salt thereof, wherein Y 1 Y 2 Z 1 Z 2 R 1 R 2 and R 5 Each of these terms is as defined above and is described individually and in combination in the embodiments herein.

[0369] In some embodiments, the present invention provides compounds of one of the following formulas: XVI-a', XVI-b', XVI-c', XVII-a', XVII-b', XVIII-a', XVIII-b', XIX-a', XIX-b', XX-a', XX-b', XXI-a', XXI-b', XXI-c', XXI-d', XXI-e', XXI-f', XXI-g', XXI-h', XXII-a', XXII-b', XXIII-a', or XXIII-b', wherein Z 2 Let N be the number of elements and Y be the number of elements. 1 Y 2 and Z 1 C. In some embodiments, the present invention provides compounds of one of the following formulas: XVI-a', XVI-b', XVI-c', XVII-a', XVII-b', XVIII-a', XVIII-b', XIX-a', XIX-b', XX-a', XX-b', XXI-a', XXI-b', XXI-c', XXI-d', XXI-e', XXI-f', XXI-g', XXI-h', XXII-a', XXII-b', XXIII-a', or XXIII-b', wherein Y 2 Let N be the number of elements and Y be the number of elements. 1 Z 1 and Z 2 The answer is C.

[0370] In some embodiments, the present invention provides a compound of formula I', wherein Z 2 For N and Y 1 Y 2 and Z 1 For C; or where Y is...2 For N and Y 1 Z 1 and Z 2 C, thus forming compounds of formula XXIV-a' or XXIV-b' respectively:

[0371]

[0372] Or a pharmaceutically acceptable salt thereof, wherein Q, X, L 1 Cy 1 R 1 and R 2 Each of these terms is as defined above and is described individually and in combination in the embodiments herein.

[0373] In some embodiments, the present invention provides a compound of formula XXIV-a' or XXIV-b', wherein L 1 These are covalent bonds, thus forming compounds of formula XXV-a' or XXV-b' respectively:

[0374]

[0375] Or a pharmaceutically acceptable salt thereof, wherein Q, X, Cy 1 R 1 and R 2 Each of these terms is as defined above and is described individually and in combination in the embodiments herein.

[0376] In some embodiments, the present invention provides a compound of formula XXV-a' or XXV-b', wherein X is C and R is R X H is used to form compounds of formula XXVI-a' or XXVI-b', respectively:

[0377]

[0378] Or its pharmaceutically acceptable salts, wherein Q, Cy 1 R 1 and R 2 Each of these terms is as defined above and is described individually and in combination in the embodiments herein.

[0379] In some embodiments, the present invention provides compounds of one of the following formulas: XVI-a, XVI-b, XVI-c, XVII-a, XVII-b, XVIII-a, XVIII-b, XIX-a, XIX-b, XX-a, XX-b, XXI-a, XXI-b, XXI-c, XXI-d, XXI-e, XXI-f, XXI-g, XXI-h, XXII-a, XXII-b, XXIII-a, XXIII-b, XXIV-a, XXIV-b, XXV-a, XXV-b, XXVI-a, XXVI-b, XVI', XVI ”, XVI-a', XVI-b', XVI-c', XVII-a', XVII-b', XVIII-a', XXI-e', XXI-f', XXI-g', XXI-h', XXII-a', XXII-b', XXIII-a', XXIII-b', XXIV-a', XXIV-b', XXV-a', XXV-b', XXVI-a' or XXVI-b', where R 2 is -N(R)C(O)R, -N(R)C(O)Cy 2 -N(R)Cy 2 or Cy 2 In some embodiments, the present invention provides compounds of one of the following formulas: XVI-a, XVI-b, XVI-c, XVII-a, XVII-b, XVIII-a, XVIII-b, XIX-a, XIX-b, XX-a, XX-b, XXI-a, XXI-b, XXI-c, XXI-d, XXI-e, XXI-f, XXI-g, XXI-h, XXII-a, XXII-b, XXIII-a, XXIII-b, XXIV-a, XXIV-b, XXV-a, XXV-b, XXVI-a, XXVI-b, XVI', XVI ”, XVI-a', XVI-b', XVI-c', XVII-a', XVII-b', XVIII-a', XXI-e', XXI-f', XXI-g', XXI-h', XXII-a', XXII-b', XXIII-a', XXIII-b', XXIV-a', XXIV-b', XXV-a', XXV-b', XXVI-a' or XXVI-b', where R 2-N(H)C(O)R, -N(H)C(O)Cy 2 -N(H)Cy 2 or Cy 2 In some embodiments, the present invention provides compounds of one of the following formulas: XVI-a, XVI-b, XVI-c, XVII-a, XVII-b, XVIII-a, XVIII-b, XIX-a, XIX-b, XX-a, XX-b, XXI-a, XXI-b, XXI-c, XXI-d, XXI-e, XXI-f, XXI-g, XXI-h, XXII-a, XXII-b, XXIII-a, XXIII-b, XXIV-a, XXIV-b, XXV-a, XXV-b, XXVI-a, XXVI-b, XVI', XVI ”, XVI-a', XVI-b', XVI-c', XVII-a', XVII-b', XVIII-a', XXI-e', XXI-f', XXI-g', XXI-h', XXII-a', XXII-b', XXIII-a', XXIII-b', XXIV-a', XXIV-b', XXV-a', XXV-b', XXVI-a' or XXVI-b', where R 2 -N(H)C(O)R, -N(H)C(O)Cy 2 or -N(H)Cy 2In some embodiments, the present invention provides compounds of one of the following formulas: XVI-a, XVI-b, XVI-c, XVII-a, XVII-b, XVIII-a, XVIII-b, XIX-a, XIX-b, XX-a, XX-b, XXI-a, XXI-b, XXI-c, XXI-d, XXI-e, XXI-f, XXI-g, XXI-h, XXII-a, XXII-b, XXIII-a, XXIII-b, XXIV-a, XXIV-b, XXV-a, XXV-b, XXVI-a, XXVI-b, XVI', XVI ”, XVI-a', XVI-b', XVI-c', XVII-a', XVII-b', XVIII-a', XXI-e', XXI-f', XXI-g', XXI-h', XXII-a', XXII-b', XXIII-a', XXIII-b', XXIV-a', XXIV-b', XXV-a', XXV-b', XXVI-a' or XXVI-b', where R 2 The form is -N(H)C(O)R. In some embodiments, the present invention provides compounds of one of the following formulas: XVI-a, XVI-b, XVI-c, XVII-a, XVII-b, XVIII-a, XVIII-b, XIX-a, XIX-b, XX-a, XX-b, XXI-a, XXI-b, XXI-c, XXI-d, XXI-e, XXI-f, XXI-g, XXI-h, XXII-a, XXII-b, XXIII-a, XXIII-b, XXIV-a, XXIV-b, XXV-a, XXV-b, XXVI-a, XXVI-b, XVI', XVI ”, XVI-a', XVI-b', XVI-c', XVII-a', XVII-b', XVIII-a', XXI-e', XXI-f', XXI-g', XXI-h', XXII-a', XXII-b', XXIII-a', XXIII-b', XXIV-a', XXIV-b', XXV-a', XXV-b', XXVI-a' or XXVI-b', where R 2 for In some embodiments, the present invention provides compounds of one of the following formulas: XVI-a, XVI-b, XVI-c, XVII-a, XVII-b, XVIII-a, XVIII-b, XIX-a, XIX-b, XX-a, XX-b, XXI-a, XXI-b, XXI-c, XXI-d, XXI-e, XXI-f, XXI-g, XXI-h, XXII-a, XXII-b, XXIII-a, XXIII-b, XXIV-a, XXIV-b, XXV-a, XXV-b, XXVI-a, XXVI-b, XVI', XVI ”, XVI-a', XVI-b', XVI-c', XVII-a', XVII-b', XVIII-a', XXI-e', XXI-f', XXI-g', XXI-h', XXII-a', XXII-b', XXIII-a', XXIII-b', XXIV-a', XXIV-b', XXV-a', XXV-b', XXVI-a' or XXVI-b', where R 2 -N(H)Cy 2 Cy 2 Selected from the following, each of which is processed by p R 6 Instance replacement:

[0380]

[0381] The exemplary compounds of the present invention are described in Table 1 below.

[0382] Table 1. Exemplary Compounds

[0383]

[0384]

[0385]

[0386]

[0387]

[0388]

[0389]

[0390]

[0391]

[0392]

[0393]

[0394]

[0395]

[0396]

[0397]

[0398]

[0399]

[0400]

[0401]

[0402]

[0403]

[0404]

[0405]

[0406]

[0407]

[0408]

[0409]

[0410]

[0411]

[0412]

[0413]

[0414]

[0415]

[0416]

[0417]

[0418]

[0419]

[0420]

[0421]

[0422]

[0423]

[0424]

[0425]

[0426]

[0427] The exemplary compounds of the present invention are described in Table 2 below.

[0428] Table 2. Exemplary Compounds

[0429]

[0430]

[0431]

[0432]

[0433] The exemplary compounds of the present invention are described in Table 3 below.

[0434] Table 3. Exemplary Compounds

[0435]

[0436]

[0437]

[0438] In some embodiments, the present invention provides compounds set forth in Table 1 above, or pharmaceutically acceptable salts thereof. In some embodiments, the present invention provides a pharmaceutical composition comprising compounds set forth in Table 1 above, or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers, excipients, or diluents.

[0439] In some embodiments, the method employs compounds or pharmaceutically acceptable salts thereof as set forth in Table 2 above. In some embodiments, the present invention provides compounds or pharmaceutically acceptable salts thereof as set forth in Table 2 above. In some embodiments, the present invention provides a pharmaceutical composition comprising compounds or pharmaceutically acceptable salts thereof as set forth in Table 2 above, and pharmaceutically acceptable carriers, excipients, or diluents.

[0440] In some embodiments, the method employs compounds or pharmaceutically acceptable salts thereof as described in Table 3 above. In some embodiments, the present invention provides compounds or pharmaceutically acceptable salts thereof as described in Table 3 above. In some embodiments, the present invention provides a pharmaceutical composition comprising compounds or pharmaceutically acceptable salts thereof as described in Table 3 above, and pharmaceutically acceptable carriers, excipients, or diluents.

[0441] 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.

[0442] 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.

[0443] 4. A general method for providing the compounds of the present invention.

[0444] 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, as well as by methods described in detail in the examples herein.

[0445] In some embodiments, Formula I compounds are prepared according to the following general procedure described in Scheme 1.

[0446] Scheme 1. Synthesis of Compound I

[0447]

[0448] In which L 1 In some embodiments of NH, the formula Cy 1 -NH2 intermediates were prepared according to the methods described in WO2014074660A1, WO2014074661A1 and WO2015089143A1, the full text of which is incorporated herein by reference.

[0449] In some embodiments, compound VIIII is prepared according to the following general procedure described in scheme 2.

[0450] Synthesis of compound VIII, scheme 2.

[0451]

[0452] In which L 1 In some embodiments of NH, the formula Cy 1 -NH2 intermediates were prepared according to the methods described in WO2014074660A1, WO2014074661A1 and WO2015089143A1, the full text of which is incorporated herein by reference.

[0453] In some embodiments, the XXIV-b compound is prepared according to the following general procedure described in Scheme 3.

[0454] Scheme 3. Synthesis of compound XXIV-b

[0455]

[0456] Among them, X and L 1 and Cy 1 Each of them is individually and in combination as defined above and in the embodiments herein.

[0457] 5. Use, allocation and distribution

[0458] Pharmaceutically acceptable compositions

[0459] 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. 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 a mutant thereof in a biological sample or in a patient. In some embodiments, the composition of the present invention is formulated for administration to a patient who requires the composition. In some embodiments, the composition of the present invention is formulated for oral administration to a patient.

[0460] As used herein, the term "patient" refers to an animal, preferably a mammal, and most preferably a human.

[0461] The term "pharmaceutically acceptable carrier, adjuvant, or mediator" refers to a non-toxic carrier, adjuvant, or mediator that does not impair the pharmacological activity of the compound it is formulated with. Pharmaceutically acceptable carriers, adjuvants, or mediators that can be used in the compositions of this invention include (but are not limited to) ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffering substances (e.g., phosphates), glycine, sorbic acid, potassium sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes (e.g., 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.

[0462] "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 administered to a recipient, the compound of the present invention or its inhibitory metabolites or residues.

[0463] As used herein, the term "its inhibitory metabolites or residues" means that its metabolites or residues are also inhibitors of TYK2 protein kinase or its mutants.

[0464] The compositions of this invention can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via implantable reservoirs. 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. Sterile injectable formulations can also be sterile injectable solutions or suspensions in non-toxic, parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Water, Ringer's solution, and isotonic sodium chloride solution are among the acceptable media and solvents that can be used. Furthermore, sterile, non-volatile oils are routinely used as solvents or suspension media.

[0465] 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) can be used to prepare injectable formulations, as can pharmaceutically acceptable natural oils (such as olive oil or castor oil, especially their polyoxyethylene forms). 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 may also be used for formulation purposes.

[0466] 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 typically added. For oral administration in capsule form, suitable 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.

[0467] Alternatively, the pharmaceutically acceptable compositions of the present invention can be used for administration in the form of rectal suppositories. These suppositories can be prepared by mixing the pharmaceutical agent 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. Such materials include cocoa butter, beeswax, and polyethylene glycol.

[0468] The pharmaceutically acceptable compositions of the present invention can also be administered topically, especially when the therapeutic target includes areas or organs easily accessible by topical application (including diseases of the eyes, skin, or lower intestine). Suitable topical formulations for each of these areas or organs are readily prepared.

[0469] Topical application for the lower intestine can be achieved via rectal suppository formulation (see above) or via a suitable enema formulation. Topical percutaneous patches may also be used.

[0470] 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, white paraffins, 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, hexadecyl wax, hexadecyl stearyl alcohol, 2-octyldodecyl alcohol, benzyl alcohol, and water.

[0471] For ophthalmic use, the pharmaceutically acceptable composition provided may be formulated as a micron-sized suspension, with or without a preservative (e.g., benzylalkonium chloride), in sterile physiological saline with an isotonic pH adjusted, or preferably as a solution in sterile physiological saline with an isotonic pH adjusted. Alternatively, for ophthalmic use, the pharmaceutically acceptable composition may be formulated as an ointment (e.g., paraffin).

[0472] The pharmaceutically acceptable compositions of the present invention can also be administered via nasal aerosol or inhaler. Such compositions are prepared according to techniques well known in pharmaceutical formulation and can be prepared as solutions in physiological saline using benzyl alcohol or other suitable preservatives, bioavailability enhancers, fluorocarbons, and / or other conventional solubilizers or dispersants.

[0473] Most preferably, the pharmaceutically acceptable compositions of the present invention are formulated for oral administration. Such formulations may or may not be administered with food. In some embodiments, the pharmaceutically acceptable compositions of the present invention are not administered with food. In other embodiments, the pharmaceutically acceptable compositions of the present invention are administered with food.

[0474] 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 modality. Preferably, the provided compositions should be 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.

[0475] 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, sex, diet, administration time, excretion rate, drug combination, 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 will also depend on the specific compounds in the composition.

[0476] Use of compounds and pharmaceutically acceptable compositions

[0477] 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.

[0478] 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 involved in cytokine signaling. TYK2 associates with the cytoplasmic domains of type I and type II cytokine receptors, as well as interferon type I and III receptors, and is activated by those receptors after binding to cytokines. Cytokines involved in TYK2 activation include interferons (such as IFN-α, IFN-β, IFN-κ, IFN-δ, IFN-ε, IFN-τ, IFN-ω, and IFN-ζ (also known as limitins)) and interleukins (such as 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..." "pathway", Cell (1992) 70:313; Stahl et al., "Association and activation of Jak-Tykkinases 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”, Journal of Experimental Medicine (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. Exp. Med. (1995)181:399. "Insulin," Journal of Biochemistry (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. Activated TYK2 then continues to phosphorylate other signaling proteins, such as the STAT family, including STAT1, STAT2, STAT4, and STAT6.

[0479] IL-23-activated TYK2 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 is also associated with psoriasis, ankylosing spondylitis, and Becton's disease. It plays a role in disease. Cho et al., “Genomics and the multifactorial nature of human auto-immune disease”, New England Journal of Medicine (N. Engl. J. Med) (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 (Nat. Genet.) (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 "Disease", Nature Genetics (2010) 42:698-702. A genome-wide association study of 2,622 individuals with psoriasis identified the 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. Gene knockout of TYK2 or inhibition by tyrphostin significantly reduced IL-23 and IL-22-induced dermatitis. Ishizaki et al., "Tyk2 is a therapeutic target for psoriasis-like skin". "inflammation", International Immunology (Intl. Immunol.) (2013), doi:10.1093 / intimm / dxt062.

[0480] TYK2 also plays a role in respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), lung cancer, and cystic fibrosis. Goblet cell hyperplasia (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," FASEBJ (2012) 26:1-11.)

[0481] Reduced TYK2 activity protects joints from collagen antibody-induced arthritis in a human rheumatoid arthritis model. Mechanistically, reduced Tyk2 activity decreases T... h 1 / T h17. Production of related cytokines, matrix metalloproteinases, and other key markers of inflammation. 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.

[0482] Compared to the control group, TYK2 knockout mice exhibited complete resistance to 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 progression 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 earlier studies linking increased TYK2 expression to MS susceptibility. Ban et al., "Replication analysis identifies TYK2 as a multiple sclerosis susceptibility factor," European Journal of Human Genetics (Eur J. Hum. Genet.) (2009) 17:1309-1313. Loss of function due to mutations in TYK2 leads to decreased demyelination and increased myelination of neurons, further suggesting the role of TYK2 inhibitors in the treatment of MS and other CNS demyelinating diseases.

[0483] TYK2 is the only signaling messenger shared by IL-12 and IL-23. TYK2 gene knockout reduces paw thickness induced by BSA injection in mice, psoriatic skin inflammation induced by imiquimod, and colitis induced by sodium dextran sulfate or 2,4,6-trinitrobenzenesulfonic acid.

[0484] 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 association between loss of function of TYK2 mutations 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 Lupus Erythematosus," *American Journal of Human Genetics* (Am. J. Hum. Genet.) (2005) 76:528-537.) Genome-wide association studies between individuals with SLE and uninfected populations have shown a very 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.

[0485] TYK2 has been shown to play a crucial 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 would be well-suited for treating autoimmune diseases or transplant rejection. While other JAK family members, such as JAK3, have similar roles in the immune system, TYK2 has shown to be a superior target due to its involvement in fewer and more closely related signaling pathways, resulting in fewer 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.)

[0486] However, contradicting the reduced tumor surveillance observed by Shima et al., studies in T-cell acute lymphoblastic leukemia (T-ALL) indicate that T-ALL relies heavily on IL-10 for TYK2-mediated signal transduction via STAT1 to maintain cancer cell survival through the upregulation of the anti-apoptotic protein BCL2. Blocking TYK2 (but not other JAK family members) gene expression reduces cell growth. Specific TYK2 activation mutations 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, TYK2 kinase function has also been identified as essential for improved cancer cell survival because TYK2 enzymes with kinase death mutations (M978Y or M978F), in addition to activation mutations (E957D), result in transformation failure. Sanda et al., “TYK2-STAT1-BCL2 Pathway Dependence in T-Cell Acute Lymphoblastic Leukemia”, Cancer Disc. (2013) 3(5): 564-577.

[0487] Therefore, selective inhibition of TYK2 has been shown to be a suitable target for patients with tumors addicted to IL-10 and / or BCL2 (e.g., 70% of adult T-cell leukemia cases). Fontan et al., “Discovering What Makes STAT Signaling TYK in T-ALL,” Cancer Discovery (2013) 3:494-496.

[0488] TYK2-mediated STAT3 signaling has also been shown to 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”, Journal of Neuroscience (2010) 30(20): 6873-6881.)

[0489] Inhibition of the JAK-STAT signaling pathway is also involved in hair growth and reversal of alopecia areata-related hair loss. Xing et al., “Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition”, Nat. Med. (2014) 20:1043-1049; Harel et al., “Pharmacologic inhibition of JAK-STAT signaling promotes hair growth”, Sci. Adv. (2015) 1(9):e1500973.

[0490] Therefore, compounds that inhibit TYK2 activity are advantageous, especially those that are selective for JAK2. Such compounds should provide advantageous treatment of one or more of the pharmacological responses to the conditions described herein without the side effects associated with JAK2 inhibition.

[0491] Although TYK2 inhibitors are known in the art, there remains a need for novel inhibitors with more potent or advantageous pharmaceutically relevant properties. For example, compounds exhibiting enhanced 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.

[0492] 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 analyses that determine phosphorylation activity and / or subsequent functional outcomes or inhibition of ATPase activity activating 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 binding. Alternatively, inhibitor binding can be determined by running 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 herein, each of which is incorporated herein by reference in its entirety. Detailed conditions for analyzing compounds used as inhibitors of TYK2 or its mutants in this invention are set forth in the following examples.

[0493] As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing or alleviating a disease or condition or one or more of its symptoms as described herein, delaying its onset, or inhibiting its progression. In some embodiments, treatment may be administered after one or more symptoms have already appeared. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to susceptible individuals 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.

[0494] The provided compounds are inhibitors of TYK2 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 to a patient in need a compound of the present invention or a pharmaceutically acceptable composition thereof.

[0495] As used herein, the term "TYK2-mediated" condition, disease, and / or symptom means any disease or other harmful symptom in which TYK2 or its mutants are known to play a role. Therefore, another embodiment of the invention relates to treating or reducing the severity of one or more diseases in which TYK2 or its mutants are known to play a role. Such TYK2-mediated conditions include (but are not limited to) autoimmune diseases, inflammatory diseases, proliferative diseases, endocrine diseases, neurological diseases, and transplant-related diseases.

[0496] 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.

[0497] In some embodiments, the condition is an autoimmune disease. In some embodiments, the condition is selected from type 1 diabetes, systemic lupus erythematosus, multiple sclerosis, psoriasis, Becton's disease, POEMS syndrome, Crohn's disease, ulcerative colitis, and inflammatory bowel disease.

[0498] 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.

[0499] 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, idiopathic, or thrombocytosis.

[0500] 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.

[0501] In some embodiments, the condition is a neurological condition. In some embodiments, the neurological condition is Alzheimer's disease.

[0502] 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.

[0503] In some embodiments, the condition is related to transplantation. In some embodiments, the transplant-related condition is transplant rejection or graft-versus-host disease.

[0504] 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.

[0505] The compounds of this invention are also suitable for treating 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.

[0506] The compounds of this invention can also be used to treat other diseases or conditions, such as diseases or conditions with inflammatory components, such as eye diseases and conditions, such as eye allergies, conjunctivitis, dry eye syndrome, 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), systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, and Steven-Johnson syndrome. Sjogren's 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, kidney disease, glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine ophthalmopathy, Grave's disease, sarcoidosis, alveolitis, chronic allergic pneumonia, multiple sclerosis, primary biliary cirrhosis, uveitis (pre- and post-inflammatory hyperplasia), Sjogren's syndrome Syndrome), dry eye and vernal keratoconjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, cryptothermal protein-related periodic syndrome, nephritis, vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis (with or without nephrotic syndrome, including idiopathic nephrotic syndrome or minimal change nephropathy), chronic granulomatous disease, endometriosis, leptospirosis nephropathy, glaucoma, retinaldehyde disease, aging, headache, pain, complex regional pain syndrome, cardiomegaly, muscle atrophy, catabolism disorder, obesity, fetal growth retardation, hypercholesterolemia, heart disease, chronic heart failure, mesothelioma, anhidrotic ectodermal dysplasia, Becette's disease, pigmentary disorders, Paget's disease, pancreatitis, hereditary periodic fever syndrome, asthma (allergic and non-allergic, mild, moderate, severe),Bronchial and exercise-induced 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, pneumonitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendinitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, or vulvitis.

[0507] 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.

[0508] In some embodiments, the inflammatory disease that can be treated according to the method of the present invention is T h 1 or T h 17-mediated diseases. In some embodiments, T h 17. The mediated diseases are selected from systemic lupus erythematosus, multiple sclerosis, and inflammatory bowel disease (including Crohn's disease or ulcerative colitis).

[0509] 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 conditions such as ocular allergies, conjunctivitis, dry keratoconjunctivitis and vernal conjunctivitis; and diseases affecting the nose, such as allergic rhinitis.

[0510] 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 treating autoimmune diseases, inflammatory diseases, or proliferative diseases, or diseases commonly associated with transplantation.

[0511] Combination therapy

[0512] Depending on the specific symptom or disease to be treated, additional therapeutic agents typically administered to treat said symptom may be administered in combination with the compounds and compositions of the present invention. As used herein, additional therapeutic agents typically administered to treat a specific disease or symptom are referred to as “the disease or symptom to be treated”.

[0513] In some embodiments, the provided combination, or a combination thereof, is administered in combination with another therapeutic agent.

[0514] Examples of pharmaceutical agents that can also be combined with the present invention include (but are not limited to): for the treatment of Alzheimer's disease, for example... and 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., interferon-β). and ), And mitoxantrone; used to treat asthma, such as salbutamol and 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 agents. Drugs used to treat cardiovascular diseases, such as beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, and statins; drugs used to treat liver diseases, such as corticosteroids, cholestyramine, interferon, and antiviral agents; drugs used to treat blood disorders, such as corticosteroids, antileukemic agents, and growth factors; drugs that prolong or improve pharmacokinetics, such as cytochrome P450 inhibitors (i.e., inhibitors of metabolic breakdown) and CYP3A4 inhibitors (e.g., ketokenozole and ritonavir); and drugs used to treat immunodeficiency disorders, such as gamma globulin.

[0515] 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.

[0516] These additional agents can be administered separately from the provided combination therapy as part of a multi-dose regimen. Alternatively, these agents can be part of a single dosage form, mixed with the compounds of the present invention in a single composition. If administered as part of a multi-dose regimen, the two active agents can be provided simultaneously, sequentially, or at intervals (typically within 5 hours of each other).

[0517] As used herein, the terms "combination" and related terms refer to the simultaneous or sequential administration of a therapeutic agent according to the invention. For example, a combination of the invention may be administered simultaneously or sequentially with another therapeutic agent in individual unit dosage forms or together in a single unit dosage form.

[0518] The amount of additional therapeutic agent present in the compositions of the present invention will not exceed the amount typically administered in a composition comprising the therapeutic agent as the sole active agent. Preferably, the amount of additional therapeutic agent in the currently disclosed compositions will be in the range of about 50% to 100% of the amount typically present in a composition comprising the pharmaceutical agent as the sole active agent.

[0519] In one embodiment, the present invention provides a composition comprising a compound of formula I, VIII, or XVI' and one or more additional therapeutic agents. The therapeutic agent may be administered together with the compound of formula I, VIII, or XVI', or may be administered before or after administration of the compound of formula I, VIII, or XVI'. Suitable therapeutic agents are described in further detail below. In some embodiments, the compound of formula I, VIII, or XVI' 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, compounds of formula I, VIII, or XVI' may be administered up to 5, 10, 15, 30, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 hours after the treatment.

[0520] In another embodiment, the present invention provides a method for treating inflammatory diseases, conditions, or symptoms by administering a compound of formula I, VIII, or XVI' and one or more additional therapeutic agents to a patient in need. Such additional therapeutic agents may be small molecule or recombinant biological agents and include, for example, acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, naproxen, and etodolac. And celecoxib and colchicine. Corticosteroids, such as prednisone, prednisolone, methylprednisolone, hydrocortisone, probenecid, allopurinol, and febuxostat. sulfasalazine Antimalarial drugs, such as hydroxychloroquine. and chloroquine Methotrexate Gold salts, such as glucose thiogold gold thiomalate and Jin Nofen D-Penicillamine ( or ), azathioprine Cyclophosphamide Chlorinated nitrogen mustard Cyclosporine Leflunomide And "anti-TNF" drugs, such as etanercept. Infliximab golimumab Pegylated certolizumab (pegol) and adalimumab Anti-IL-1 drugs, such as anakinra. Rilonacept Canakinumab Anti-Jak inhibitors, such as tofacitinib; antibodies, such as rituximab. Anti-T cell drugs, such as abatacept. Anti-IL-6 drugs, such as tocilizumab. Diclofenac, cortisone, hyaluronic acid or Monoclonal antibodies, such as tanezumab; anticoagulants, such as heparin. or and warfarin Antidiarrheal medications, such as diphenhydramine and loperamide Bile acid binders, such as cholestyramine and alosetron. Lubiprostone Mild laxatives, such as magnesium oxide emulsion and polyethylene glycol. and Anticholinergic agents or antispasmodics, such as dicyclomine. β-2 agonists, such as salbutamol. HFA, HFA, levalbuterol Metaproterenol pirbuterol acetate terbutaline sulfate Salmeterol xinafoate and formoterol Anticholinergic agents, such as ipratropium bromide. and tiotropium Inhaled corticosteroids, such as beclomethasone dipropionate. and triamcinolone acetonide Mometasone furoate budesonide and flunisulfanil Sodium cromoglycate Methylxanthine, such as theophylline And theophylline; IgE antibodies, such as omalizumab. Nucleoside reverse transcriptase inhibitors, such as zidovudine. Abacavir Abacavir / lamivudine Abacavir / lamivudine / zidovudine didanosine emtricitabine Lamivudine Lamivudine / zidovudine Stavudine and zalcitabine Non-nucleoside reverse transcriptase inhibitors, such as delavirdine. According to Efavirenz Nevirapine and etravirine Nucleotide reverse transcriptase inhibitors, such as tenofovir. Protease inhibitors, such as ampranavir. Atazanavir Darunavir Fosamprenavir indinavir Lopinavir and ritonavir Nefinavir ritonavir Saquinavir or and tipranavir Inhibitors, such as enfuvirtide. and Maraviroc Integrase inhibitors, such as raltegravir. doxorubicin (small cranberry) Vincristine Bortezomib and dexamethasone And lenalidomide Or any combination thereof.

[0521] 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, VIII, or XVI' and one or more additional therapeutic agents selected from: nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin, ibuprofen, naproxen, etodoxacin. and senecoxib; corticosteroids, such as prednisone, prednisolone, methylprednisolone, hydroxycorticosterone, etc.; sulfasalazine Antimalarial drugs, such as hydroxychloroquine and chloroquine Methotrexate Gold salts, such as glucose thiogold gold thiomalate and Jin Nofen D-Penicillamine or azathioprine Cyclophosphamide Chlorinated nitrogen mustard Cyclosporine Leflunomide and "anti-TNF" drugs; such as etanercept. Infliximab Golimumab Pegylated cerutuzumab and adalimumab Anti-IL-1 drugs, such as anakinase and Linasipu Antibodies, such as rituximab Anti-T cell drugs, such as abatacept and "anti-IL-6" drugs, such as tocilimab

[0522] In some embodiments, the present invention provides a method for treating osteoarthritis, comprising administering to a patient in need a compound of formula I, VIII, or XVI' and one or more additional therapeutic agents selected from: acetaminophen; nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin, ibuprofen, naproxen, etodoxacin. And senecoxib; diclofenac; cortisone; hyaluronic acid or And monoclonal antibodies, such as tanizumab.

[0523] In some embodiments, the present invention provides a method for treating systemic lupus erythematosus, comprising administering to a patient in need a compound of formula I, VIII, or XVI' and one or more additional therapeutic agents selected from: acetaminophen; nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin, ibuprofen, naproxen, etodoxacin. And senecoxib; corticosteroids, such as prednisone, prednisolone, methylprednisolone, hydroxycorticosteroids, etc.; antimalarial drugs, such as hydroxychloroquine and chloroquine Cyclophosphamide Methotrexate azathioprine and anticoagulants, such as heparin or and warfarin

[0524] In some embodiments, the present 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, VIII, or XVI' and one or more additional therapeutic agents selected from mesalamine. sulfasalazine Antidiarrheal medications, such as diphenhydramine and loperamide Bile acid binders, such as cholestyramine; alosetron Lubiprostone Mild laxatives, such as magnesium oxide emulsion, polyethylene glycol and And anticholinergic agents or antispasmodics, such as dicyclovir. Anti-TNF therapy agents; steroids; and antibiotics, such as metronidazole (Flagyl) or ciprofloxacin.

[0525] In some embodiments, the present invention provides a method for treating asthma, comprising administering to a patient in need a compound of formula I, VIII, or XVI' and one or more additional therapeutic agents selected from: β-2 agonists, such as salbutamol ( HFA, HFA), L-salbutamol metoprolol Pyrboterol Acetate Terbutaline sulfate Salmeterol hydroxynaphthylcarbamate and Formotero Anticholinergic agents, such as ipratropium bromide and tiotropium Inhaled corticosteroids, such as prednisone, prednisolone, and beclomethasone dipropionate. and Triamcinolone Mometasone furoate Buddyne Flunipine and Sodium cromoglycate Methylxanthine, such as theophylline And theophylline; and IgE antibodies, such as omalizumab.

[0526] In some embodiments, the present invention provides a method for treating COPD comprising administering to a patient in need a compound of formula I, VIII, or XVI' and one or more additional therapeutic agents selected from: β-2 agonists, such as salbutamol ( HFA, HFA), L-salbutamol metoprolol Pyrboterol Acetate Terbutaline sulfate Salmeterol hydroxynaphthylcarbamate and Formotero Anticholinergic agents, such as ipratropium bromide and tiotropium Methylxanthine, such as theophylline Theophylline; inhaled corticosteroids, such as prednisone, prednisolone, and beclomethasone dipropionate. and ), Triamcinolone Mometasone furoate Buddyne Flunipine and

[0527] In another embodiment, the present invention provides a method for treating hematological malignancies, comprising administering to a patient in need a compound of formula I, VIII, or XVI' and one or more additional therapeutic agents selected from: rituximab Cyclophosphamide cranberries Changchun New Alkali Prednisone, hedgehog signal transduction inhibitors, BTK inhibitors, JAK / pan-JAK inhibitors, PI3K inhibitors, SYK inhibitors, and combinations thereof.

[0528] 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, VIII, or XVI' and one or more additional therapeutic agents selected from: rituximab Cyclophosphamide cranberries Changchun New Alkali Prednisone, hedgehog signal transduction inhibitors, BTK inhibitors, JAK / pan-JAK inhibitors, PI3K inhibitors, SYK inhibitors, and combinations thereof.

[0529] In another embodiment, the present invention provides a method for treating a hematologic malignancy comprising administering a compound of formula I, VIII, or XVI' and an inhibitor of the hedgehog (Hh) signaling pathway to a patient in need. 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).

[0530] 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, VIII, or XVI' and one or more additional therapeutic agents selected from: rituximab Cyclophosphamide cranberries Changchun New Alkali Prednisone, hedgehog signal transduction inhibitors, and combinations thereof.

[0531] 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, VIII, or XVI' and one or more additional therapeutic agents selected from bortezomib. and dexamethasone Hedgehog signaling inhibitors, BTK inhibitors, JAK / pan-JAK inhibitors, TYK2 inhibitors, PI3K inhibitors, SYK inhibitors, and lenalidomide

[0532] In another embodiment, the present invention provides a method for treating or reducing the severity of a disease, comprising administering a compound of formula I, VIII, or XVI' and a BTK inhibitor to a patient in need, wherein the disease is selected from inflammatory bowel disease, arthritis, 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 including strabismus, myoclonic syndrome, ankylosing spondylitis, antiphospholipid 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, and Wegener's granulomatosis.Granulomatosis, psoriasis, alopecia universalis, Behcet's disease, chronic fatigue, autonomic nervous system dysfunction, membranous glomerulonephritis, endometriosis, interstitial cystitis, pemphigus vulgaris, bullous pemphigoid, neuromuscular rigidity, scleroderma, vulvar pain, hyperplastic diseases, rejection of transplanted organs or tissues, acquired immunodeficiency syndrome (AIDS, also known as HIV), type 1 diabetes, graft-versus-host disease, transplantation, infusion, systemic allergic reactions, allergies (e.g., to plant pollen, latex, drugs, food, insect toxins, animal hair, animal dander). Allergies to dust mites or cockroach calyxes, type I allergies, allergic conjunctivitis, allergic rhinitis and atopic dermatitis, asthma, 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, pneumonitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendinitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis or vulvitis, B-cell proliferative disorders (e.g., diffuse large B-cell lymphoma), follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, acute lymphoblastic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma. Lymphoma / Waldenström 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, intranodal 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, diseases of the bone and joints (including (but not limited to) rheumatoid arthritis), serologically negative spondyloarthritis (including ankylosing spondylitis, psoriatic arthritis and Reiter's disease).Diseases including: Bessett's disease, Hughley's syndrome, systemic sclerosis, osteoporosis, bone cancer, metastatic bone cancer, thromboembolic diseases (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 occlusion, pulmonary embolism, deep vein thrombosis), inflammatory pelvic diseases, urethritis, sunburn, sinusitis, 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, allergic rhinitis, and chronic obstructive pulmonary disease (COPD). Autoimmune polyglandular disease (also known as autoimmune polyglandular syndrome), autoimmune alopecia, pernicious anemia, glomerulonephritis, dermatomyositis, multiple sclerosis, scleroderma, vasculitis, autoimmune hemolytic and thrombocytopenic symptoms, Gupasde syndrome, atherosclerosis, Addison's disease, Parkinson's disease, Alzheimer's disease, diabetes, septic shock, systemic lupus erythematosus (SLE), rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, osteoarthritis, chronic idiopathic thrombocytopenic purpura, Waldenström macroglobulinemia, myasthenia gravis, Hashimoto's thyroiditis, atopic dermatitis, degenerative arthritis, leukoplakia, autoimmune hypopituitarism, G. Bartholomew's syndrome, Bessett's disease, scleroderma, mycosis fungoides, acute inflammatory reactions (e.g., acute respiratory distress syndrome and ischemia / reperfusion injury), and Graves' disease.

[0533] In another embodiment, the present invention provides a method for treating or reducing the severity of a disease, comprising administering a compound of formula I, VIII, or XVI' and a PI3K inhibitor to a patient in need, 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 osteopathies, 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.

[0534] In another embodiment, the present invention provides a method for treating or reducing the severity of a disease, comprising administering a compound of formula I, VIII, or XVI' and a PI3K inhibitor to a patient in need, wherein the disease is selected from benign or malignant tumors, carcinomas, or solid tumors, sarcomas, glioblastomas, neuroblastomas, multiple myeloma, or gastrointestinal cancers 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, bones, or thyroid gland. Symptoms, especially colon cancer or colorectal adenoma or neck tumors, epidermal hyperplasia, psoriasis, benign prostatic hyperplasia, tumor formation, epithelial-characteristic tumor formation, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung lymphoma (including (e.g.) non-Hodgkin's lymphoma (NHL) and Hodgkin's lymphoma (also known as Hodgkin's or Hodgkin's disease)), breast cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, or leukemia; including Cowden syndrome, Lhermitte-Duclos disease, and Bannayan-Zonana syndrome. Diseases including: PI3K / PKB pathway abnormal activation; 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). Treatment, especially exacerbation of airway hyperresponsiveness caused by other inhaled medications; bronchitis of any type or cause, including (but not limited to) acute, eicosanoid, catarrhal, croupus, chronic or tuberculous bronchitis; pneumoconiosis of any type or cause (inflammatory, general occupational lung disease, usually accompanied by chronic or acute airway obstruction and caused by repeated inhalation of dust), including, for example, aluminum deposition, carbon deposition, asbestos deposition, stone deposition, eyelash loss, iron deposition, silica deposition, tobacco poisoning and cotton wool deposition;Loffler's syndrome, eosinophilic pneumonia, parasitic infections (especially in metazoans) (including tropical eosinophilia), bronchopulmonary aspergillosis, and polyarteritis nodosa (including Church-Strauss syndrome). eosinophilic granuloma and eosinophilic-related conditions affecting the airways caused by drug reactions; psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, herpetic dermatitis, scleroderma, vitiligo, allergic vasculitis, rubella, 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 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); systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome. Nephrotic syndrome), idiopathic stomatitis, autoimmune inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), endocrine ophthalmopathy, Grave's disease, sarcoidosis, alveolitis, chronic allergic pneumonia, multiple sclerosis, primary biliary cirrhosis, uveitis (pre- and post-), ​​dry eye and vernal keratoconjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis and glomerulonephritis (with or without nephrotic syndrome, such as including idiopathic nephrotic syndrome or minimally invasive nephropathy, restenosis, cardiomegaly, 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.

[0535] In some embodiments, the present invention provides a method for treating or reducing the severity of a disease, comprising administering a compound of formula I, VIII, or XVI' and a Bcl-2 inhibitor to a patient in need, 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.

[0536] In some embodiments, the present invention provides a method for treating or reducing the severity of a disease, 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, VIII, or XVI'. Other suitable JH2 domain-binding compounds include those described in WO2014074660A1, WO2014074661A1, and WO2015089143A1, each of which is incorporated herein by reference in its entirety. Suitable JH1 domain-binding compounds include those described in WO2015131080A1, which is incorporated herein by reference in its entirety.

[0537] The compounds and compositions according to the method of the present invention can be administered in any effective dosage and via any effective route of administration for treating or reducing the severity of autoimmune diseases, inflammatory diseases, proliferative diseases, endocrine diseases, neurological diseases, or transplant-related diseases. The required precise amount will vary for each subject, depending on the subject's species, age and general condition, severity of infection, specific drug, administration pattern, etc. Preferably, the compounds of the present invention are formulated in unit dosage forms to achieve ease of administration and dosage uniformity. As used herein, "unit dosage form" refers to a physically discrete unit of the drug 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 scope of a reasonable medical diagnosis. The specific effective dose for any particular patient or organism will depend on a number of factors, including the condition to be treated and its severity; the activity of the specific compound used; the specific composition used; the patient's age, weight, general health, sex, and diet; the time of administration, route of administration, and the rate of excretion of the specific compound used; the duration of treatment; drugs used in combination with or concurrently with the specific compound used; and factors well known in the medical field. As used herein, the term "patient" means animal, preferably a mammal, and most preferably a human.

[0538] 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, or as an oral or nasal spray. In some embodiments, the compounds of the present invention may be administered orally or parenterally at the following dosage levels to achieve the desired therapeutic effect: about 0.01 mg to about 50 mg per kilogram of subject body weight per day, preferably about 1 mg to about 25 mg, once or more daily.

[0539] 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 contain inert diluents commonly used in the art, 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 fatty acid esters of sorbitol, and mixtures thereof. In addition to inert diluents, oral compositions may also include adjuvants, such as humectants, emulsifiers and suspending agents, sweeteners, flavoring agents, and aromatizers.

[0540] Injectable formulations can be formulated using suitable dispersants, wetting agents, and suspending agents according to known techniques, such as sterile injectable aqueous or oily suspensions. 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. Acceptable mediators and solvents include water, Ringer's solution, USP, and isotonic sodium chloride solution. Furthermore, sterile non-volatile oils are routinely used as solvents or suspension media. For this purpose, any mild, non-volatile oil, including synthetic monoglycerides or diglycerides, can be used. Additionally, fatty acids (e.g., oleic acid) are used in the preparation of injectable formulations.

[0541] Injectable formulations can be sterilized, for example, by filtration via a bacterial trapping filter or by incorporation of a sterile solid composition in which the sterile agent can be dissolved or dispersed in sterile water or other sterile injectable media before use.

[0542] To prolong the effects of the compounds of this invention, it is generally necessary to slow the absorption of compounds administered subcutaneously or intramuscularly. This can be achieved by using liquid suspensions of crystalline or amorphous materials with poor 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 parenterally administered compounds can be achieved by dissolving or suspending the compound in an oil-based medium. Injectable accumulation forms are prepared by forming microencapsulation matrices of the compound in biodegradable polymers 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 that are compatible with body tissues.

[0543] Compositions for rectal or vaginal administration are preferably suppositories prepared by mixing the compounds of the invention with suitable non-irritating excipients or carriers (e.g., cocoa butter, polyethylene glycol, or suppository waxes); said excipients or carriers are solid at ambient temperature but liquid at body temperature and thus melt in the rectal or vaginal cavity, releasing the active compound.

[0544] 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 a) a filler or extender, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) a binder, such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; c) a humectant, such as glycerin; d) a disintegrant, such as agar-agar, calcium carbonate, potato or cassava starch, alginic acid, certain silicates, and sodium carbonate; e) a solution barrier, such as paraffin; f) an absorption enhancer, such as a quaternary ammonium compound; g) a humectant, such as cetyl alcohol and glyceryl monostearate; h) an absorbent, such as kaolin and bentonite; and i) a lubricant, 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 form may also contain a buffer.

[0545] Similar types of solid compositions can also be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose (or milk sugar) and high molecular weight polyethylene glycol. Solid dosage forms such as tablets, sugar-coated pills, capsules, pellets, and granules with coatings and shells, such as enteric coatings and other coatings well known in pharmaceutical formulation techniques, can be prepared. They may optionally contain light-blocking agents and may also have a composition that optionally releases the active ingredient in a delayed manner only, or preferably in a portion of the intestine. Examples of usable encapsulation compositions include polymeric substances and waxes. Similar types of solid compositions can also be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose (or milk sugar) and high molecular weight polyethylene glycol.

[0546] The active compound may also be microencapsulated with one or more of the excipients described above. Solid dosage forms, such as tablets, sugar-coated pills, capsules, pellets, and granules, with coatings and shells, such as enteric coatings, release-controlled coatings, and other coatings known in pharmaceutical formulation techniques, can be prepared. In such solid dosage forms, the active compound may be mixed with at least one inert diluent (e.g., sucrose, lactose, or starch). As is common practice, such dosage forms may also contain substances other than inert diluents, such as tableting lubricants and other tableting 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 a light-blocking agent and may also have a composition that optionally releases the active ingredient in a delayed manner only or preferably in a portion of the intestine. Examples of encapsulation compositions that can be used include polymers and waxes.

[0547] Dosage forms for topical or transdermal administration of the compounds of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalers, or patches. The active ingredient is infused 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 contemplated within the scope of this invention. Additionally, this invention covers the use of transdermal patches, which have the added advantage of providing controlled delivery of the compound to the body. Such dosage forms can be manufactured by dissolving or dispensing the compound in a suitable medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by providing a rate-controlled membrane or by dispersing the compound in a polymer matrix or gel.

[0548] 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.

[0549] 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.

[0550] In another embodiment, the present invention provides a method for selectively inhibiting TYK2 compared to one or more of JAK1, JAK2, and JAK3. In some embodiments, the compound of the present invention has a selectivity greater than 2 times compared to JAK1 / 2 / 3. In some embodiments, the compound of the present invention has a selectivity greater than 5 times compared to JAK1 / 2 / 3. In some embodiments, the compound of the present invention has a selectivity greater than 10 times compared to JAK1 / 2 / 3. In some embodiments, the compound of the present invention has a selectivity greater than 50 times compared to JAK1 / 2 / 3. In some embodiments, the compound of the present invention has a selectivity greater than 100 times compared to JAK1 / 2 / 3.

[0551] As used herein, the term “biological sample” includes (but is not limited to) cell cultures or extracts thereof; biopsy material obtained from mammals or extracts thereof; and blood, saliva, urine, feces, semen, tears or other bodily fluids or extracts thereof.

[0552] Inhibiting TYK2 (or its mutants) activity in biological samples is suitable 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.

[0553] 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.

[0554] 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 to the patient a compound of the present invention or a composition comprising the compound. 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 to the patient a compound of the present invention or a composition comprising the compound. 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 to the patient a compound of the present invention or a pharmaceutically acceptable composition thereof. Such conditions are described in detail herein.

[0555] Depending on the specific symptom or disease to be treated, additional therapeutic agents typically administered to treat said symptom may also be present in the compositions of the invention. As used herein, additional therapeutic agents typically administered to treat a specific disease or symptom are referred to as “the disease or symptom suitable for treatment”.

[0556] The compounds of this invention can also be used in combination with other therapeutic compounds for an advantageous position. In some embodiments, the other therapeutic compounds are anti-proliferative compounds. Such 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; Ras oncogenic isoform inhibitors; 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 derived from Conforma therapy. Therapeutics' 17-AAG (17-allylaminogeldanamycin, NSC330507), 17-DMAG (17-dimethylaminoethylamino-17-demethoxy-geldanamycin, NSC707545), IPI-504, CNF1010, CNF2024, CNF1010; temozolomide Driver-type spindle protein 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. The term "aromatase inhibitor," as used herein, refers to a compound that inhibits estrogen production, such as the conversion of matrix androstenedione and testosterone to estrone and estradiol, respectively. The terms include (but are not limited to) steroids, particularly atamestane, exemestane, and formestane; and particularly nonsteroids, particularly aminoglutethimide, roglethimide, pyridoglutethimide, trilostane, testolactone, ketoconazole, vorozole, fadrozole, anastrozole, and letrozole. Exemestane is marketed under the brand name Aromasin. TM Sales. Formistan is marketed under the trademark Lentaron. TM Sales. Fadroxil is marketed under the brand name Afema. TM Anastrozole is sold under the brand name Arimidex. TM Sales. Letrozole is marketed under the brand name Femara. TM or Femar TM Sales. Aminolactone is marketed under the trademark Orimeten. TM Sales. Combinations of the present invention containing chemotherapeutic agents that are aromatase inhibitors are particularly suitable for treating hormone receptor-positive tumors, such as breast tumors.

[0557] 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 trade name Novadex. TM Sales. Raloxifene hydrochloride is marketed under the brand name Evista. TM Sales. Fluvestralc can be sold under the brand name Faslodex.TM Application. The combinations of the present invention, comprising anti-estrogenic chemotherapeutic agents, are particularly suitable for treating estrogen receptor-positive tumors, such as breast tumors.

[0558] As used herein, the term "anti-androgen" refers to any substance capable of inhibiting the biological effects of androgens, including (but not limited to) bicalutamide (Casodex). TM As used herein, the term "gonadotropin-releasing hormone agonist" includes (but is not limited to) abarelix, goserelin, and goserelin acetate. Goserelin may be marketed under the brand name Zoladex. TM Invest.

[0559] As used herein, the term "topoisomerase I inhibitor" includes (but is not limited to) topotecan, gimatecan, irinotecan, camptothecin and its analogues, 9-nitrocamptothecin, and the macromolecular camptothecin conjugate PNU-166148. Irinotecan may be marketed, for example, in its marketing form, such as under the trademark Camptosar. TM Topotecan is marketed under the trademark Hycamptin. TM Sale.

[0560] As used herein, the term "topoisomerase II inhibitor" includes (but is not limited to) anthracyclines, such as cranberries (including lipid modulators, such as Caelyx). TM The drug contains daunorubicin, epirubicin, idarubicin, nemorubicin, anthraquinones mitoxantrone and losoxantrone, and podophyllotoxins etoposide and teniposide. Etoposide is marketed under the brand name Etopophos. TM Sales. Teniposide is marketed under the brand name VM 26-Bristol. Cranberries are marketed under the brand name Acriblastin. TM or Adriamycin TM Sales. Farmorubicin is sold under the trademark name Farmorubicin. TM Sales. Itabizin is sold under the trademark name Zavedos. TM Sales. Mitoxantrone is sold under the brand name Novantron.

[0561] 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 vincaine or vinca sulfate, vincristine or vinca sulfate, and vinorelbine; discodermolide; colchicine; and epothilone and their derivatives. Pacific paclitaxel is marketed under the trade name Taxol. TM Sales. Docetaxel is marketed under the brand name Taxotere. TM Sales. Vinblastin sulfate is sold under the brand name Vinblastin RP. TM Sales. Vincristine sulfate is marketed under the brand name Farmistin. TM Sale.

[0562] 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. TM Ifosfamide is sold under the brand name Holoxan. TM Sale.

[0563] 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).

[0564] The term "anti-growth 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. TM Sales. Gemcitabine is marketed under the trademark Gemzar. TM Sale.

[0565] As used herein, the term "platinum compound" includes (but is not limited to) carboplatin, cisplatin, cisplatinum, and oxaliplatin. Carboplatin may be sold, for example, in its form of sale, such as under the trademark CarboplatinTM Oxaliplatin can be sold, for example, through its sales methods, such as under the trademark Eloxatin. TM Invest.

[0566] As used herein, the term “compounds that target / reduce the activity of protein or lipid kinases; or protein or lipid phosphatases; or other 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-pyrimidinylamine derivatives, such as imatinib, SU101, 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 IGF-IR activity, especially compounds that inhibit the kinase activity of IGF-I receptors, or antibodies that target the extracellular domain of IGF-I receptors or their growth factors; d) compounds that target, reduce or inhibit the activity of platelet-derived growth factor receptor I (PDGFR), such as compounds that target, reduce or inhibit PDGF-IR activity, especially compounds that inhibit the kinase activity of IGF-I receptors, or antibodies that target the extracellular domain of IGF-I receptors or their growth factors; Compounds that inhibit the activity of the Trk receptor tyrosine kinase family, or eprilin B4 inhibitors; e) compounds that target, reduce, or inhibit the activity of the Axl receptor tyrosine kinase family; f) compounds that target, reduce, or inhibit the activity of the Ret receptor tyrosine kinase; g) compounds that target, reduce, or inhibit the activity of the Kit / SCFR receptor tyrosine kinase, such as imatinib; h) compounds that target, reduce, or inhibit the activity of the C-kit receptor tyrosine kinase (which is part of the PDGFR family), such as those that target, reduce, or inhibit the activity of the c-kit receptor tyrosine kinase. Compounds with kinase family activity, especially those that inhibit the c-Kit receptor, such as imatinib; i) compounds that target, reduce, or inhibit the activity of c-Abl family members, their gene fusion products (e.g., BCR-Abl kinase), and mutants, 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 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, including astrocytocin derivatives such as midostaurin;Examples of other compounds include UCN-01, safingol, BAY 43-9006, bryostatin 1, perifosine; ilmofosine; RO 318220 and RO 320432; GO 6976; Isis 3521; LY333531 / LY379196; isoquinoline compounds; FTIs; PD184352 or QAN697 (P13K inhibitors) or AT7519 (CDK inhibitors); k) compounds that target, reduce or inhibit the activity of protein-tyrosine kinase inhibitors, such as compounds that target, reduce or inhibit the activity of protein-tyrosine kinase inhibitors, including imatinib mesylate (Gleevec); TM ) or tyrosine phosphorylation inhibitors, such as tyrosine phosphorylation inhibitor A23 / RG-50810; AG 99; tyrosine phosphorylation inhibitor AG213; tyrosine phosphorylation inhibitor AG 1748; tyrosine phosphorylation inhibitor AG 490; tyrosine phosphorylation inhibitor B44; tyrosine phosphorylation inhibitor B44(+) enantiomer; tyrosine phosphorylation inhibitor AG 555; AG 494; tyrosine phosphorylation inhibitors AG 556, AG957 and adamantane phosphorylation inhibitor (4-{[(2,5-dihydroxyphenyl)methyl]amino}-adamantyl benzoate; NSC 680410, adamantane phosphorylation inhibitor); l) Epidermal growth factor family (EGFR1 in homo- or heterodimeric form) that target, reduce or inhibit receptor tyrosine kinases. Compounds that target, reduce, or inhibit the activity of the epidermal growth factor receptor family (EGF receptor tyrosine kinase family members, such as EGF receptor, ErbB2, ErbB3, and ErbB4) or compounds, proteins, or antibodies that inhibit EGF or EGF-related ligands, CP358774, ZD 1839, and ZM 105180; trastuzumab (Herceptin) TM ), cetuximab (Erbitux) TM(i) 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 c-Met receptor kinase activity, or target Compounds that target, reduce, or inhibit the kinase activity of one or more JAK family members (JAK1 / JAK2 / JAK3 / TYK2 and / or pan-JAK) to the extracellular domain of c-Met cells or bound to HGF, including (but not limited to) PRT-062070, SB-1578, baricitinib, pacritinib, molotinib, VX-509, AZD-1480, TG-101348, and tortrol. Tofacitinib and ruxolitinib; o) 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, buparlisib, pictrelisib, PF-4691502, BYL-719, and dartoxib. Actolisib, XL-147, XL-765 and idelalisib; and q) compounds that target, reduce or inhibit signal transduction effects of hedgehog protein (Hh) or smooth receptor (SMO) pathways, including (but not limited to) cyclopamine, vismodegib, itraconazole, erismodegib and IPI-926 (saridegib).

[0567] 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 that can be used in this invention include (but are not limited to) ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, bupazoxib, picotecoxib, PF-4691502, BYL-719, dartoxib, XL-147, XL-765, and edetoxib.

[0568] As used herein, the term "BTK inhibitor" includes (but is not limited to) compounds having inhibitory activity against Bruton's tyrosine kinase (BTK), including (but not limited to) AVL-292 and ibrutinib.

[0569] 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.

[0570] 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 from Ascenta, curcumin (and its analogues), dual Bcl-2 / Bcl-xL inhibitors (Infinity Pharmaceuticals / Novartis Pharmaceuticals), Genasense (G3139), HA14-1 (and its analogues; see WO2008118802), navitoclax (and its analogues; see US7390799), NH-1 (Shenyang Pharmaceutical University). Bcl-2 inhibitors include (University of Michigan), obatoclax (and its analogues, see WO2004106328), S-001 (Gloria Pharmaceuticals), TW series compounds (University of Michigan), and venetoclax. In some embodiments, Bcl-2 inhibitors are small molecule therapeutic agents. In some embodiments, Bcl-2 inhibitors are peptide mimics.

[0571] Other examples of BTK inhibitory compounds and conditions that can be treated by combination of such compounds with the compounds of the present invention can be found in WO2008039218 and WO2011090760, the entire contents of which are incorporated herein by reference.

[0572] Other examples of SYK inhibitory compounds and conditions that can be treated by combination of such 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.

[0573] 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.

[0574] Other examples of JAK inhibitory compounds and conditions that can be treated by combination of such compounds with 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.

[0575] Other anti-angiogenic compounds include those with a different mechanism of activity (e.g., independent of protein or lipid kinase inhibition), such as thalidomide. TM ) and TNP-470.

[0576] 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.

[0577] 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.

[0578] Compounds that induce cell differentiation include (but are not limited to) retinoic acid, α-γ-tocopherol or δ-tocopherol or α-γ-tocotrienol or δ-tocotrienol.

[0579] As used herein, cyclooxygenase inhibitors include (but are not limited to) Cox-2 inhibitors, 5-alkyl-substituted 2-arylaminophenylacetic acid and their derivatives, such as celecoxib. TM rofecoxib (Vioxx) TM etoricoxib, valdecoxib, or 5-alkyl-2-arylaminophenylacetic acid, such as 5-methyl-2-(2'-chloro-6'-fluorophenylamino)phenylacetic acid, lumiracoxib.

[0580] 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 brand name Didronel. TM Sales. Chlorphosphonic acid is marketed under the brand name Bonefos. TM Sales. Tiludronic acid is marketed under the brand name Skelid. TM Sales. Pamidronic acid is marketed under the brand name Aredia. TM Sales. Alendronate is sold under the brand name Fosamax. TM Ibandronic acid is sold under the brand name Bondranat. TM Risedronic acid is sold under the brand name Actonel. TM Sales. Zoledronic acid is marketed under the brand name Zometa. TM Sales. The term "mTOR inhibitor" refers to compounds that inhibit the mammalian target of rapamycin (mTOR) and have anti-proliferative activity, such as sirolimus. everolimus (Certican) TM ), CCI-779 and ABT578.

[0581] 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.

[0582] As used herein, the term "inhibitor of Ras oncogenic isoforms (e.g., H-Ras, K-Ras, or N-Ras)" refers to compounds that target, reduce, or inhibit the oncogenic activity of Ras; for example, "farnesyltransferase inhibitors," such as L-744832, DK8G557, or R115777 (Zarnestra). TM As used herein, the term "telomerase inhibitor" refers to a compound that targets, reduces, or inhibits telomerase activity. Compounds that target, reduce, or inhibit telomerase activity are particularly those that inhibit telomerase receptors, such as telomestatin.

[0583] 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.

[0584] As used herein, the term "proteasome inhibitor" refers to compounds that target, reduce, or inhibit proteasome activity. Compounds that target, reduce, or inhibit proteasome activity include (but are not limited to) bortezomib (Velcade). TM ) and MLN341.

[0585] 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 the hydroxamic acid ester peptide mimicry inhibitor batimastat and its analogues with oral biological availability, marimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551), BMS-279251, BAY 12-9566, TAA211, MMI270B, or AAJ996.

[0586] 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; ALK inhibitors, which are compounds that target, reduce or inhibit polymorphic lymphoma kinase; and Bcl-2 inhibitors.

[0587] Compounds that target, reduce, or inhibit the activity of FMS-like tyrosine kinase receptors (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.

[0588] 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.

[0589] As used herein, the term "antiproliferative antibody" includes (but is not limited to) trastuzumab (Herceptin) TM Trastuzumab-DM1, erbitux, bevacizumab (Avastin) TM ), 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 fragments that only need to exhibit the desired biological activity.

[0590] For the treatment of acute myeloid leukemia (AML), the compounds of the present invention can be used in combination with standard leukemia therapies, particularly those 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, carboplatinum, 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.

[0591] Other anti-leukemia compounds include, for example, Ara-C, a pyrimidine analogue, which is a 2'-α-hydroxyribose (arabinoside) derivative of deoxycytidine. Also included are purine analogues of hypoxanthine, 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 salinomycinoxime 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. Somatostatin receptor antagonists, as used herein, refer to compounds that target, treat, or inhibit somatostatin receptors, such as octreotide and SOM230. Methods of tumor cell destruction include, for example, ionizing radiation. The term "ionizing radiation" as used above and below means ionizing radiation occurring in the form of electromagnetic rays (e.g., X-rays and gamma rays) or particles (e.g., alpha particles and beta particles). Ionizing radiation is provided in (but not limited to) radiation therapy and is known in the art. See Hellman, Principles of Radiation Therapy, Cancer, Principles and Practice of Oncology, eds. Devita et al., 4th ed., Vol. 1, pp. 248-275 (1993).

[0592] 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 anti-ALL), and / or pentostatin. Ribonucleotide reductase inhibitors are particularly hydroxyurea or 2-hydroxy-1H-isoindole-1,3-dione derivatives.

[0593] This also includes, in particular, compounds, proteins, or monoclonal antibodies that react with VEGF, such as 1-(4-chlorophenylamino)-4-(4-pyridylmethyl)phthalazine or a pharmaceutically acceptable salt thereof, 1-(4-chlorophenylamino)-4-(4-pyridylmethyl)phthalazine succinate, and angiostatin. TM Endostatin TM ; anthranilamide; 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 IgG1 antibodies, angiozyme (RPI 4610) and bevacizumab (Avastin) TM ).

[0594] As used in this article, photodynamic therapy refers to the treatment or prevention of cancer using certain chemicals known as photosensitizing compounds. Examples of photodynamic therapy include, for instance, Visudyne. TM Treatment with compounds such as porfimer sodium.

[0595] As used in this article, angiostatic steroids refer to compounds that block or inhibit angiogenesis, such as anecortave, triamcinolone, hydrocortisone, 11-α-epihydrocotisol, cortexolone, 17-hydroxyprogesterone, corticosterone, desoxycorticosterone, testosterone, estrone, and dexamethasone.

[0596] Implants containing corticosteroids refer to compounds such as fluocinolone and dexamethasone.

[0597] Other chemotherapeutic compounds include (but are not limited to) alkaloids, hormonal compounds and antagonists; biological response modifiers, preferably lymphokines or interferons; antisense oligonucleotides or oligonucleotide derivatives; shRNA or siRNA; or mixed compounds or compounds with other or unknown mechanisms of action.

[0598] The compounds of this invention can also be used as co-therapeutic compounds in combination with other active pharmaceutical ingredients, such as anti-inflammatory agents, bronchodilators, or antihistamines, particularly for the treatment of obstructive or inflammatory tracheal diseases mentioned above, for example, as therapeutic enhancers of such drugs or as a method for reducing the required dosage or potential side effects of such drugs. The compounds of this invention can be mixed with other active pharmaceutical ingredients in a fixed pharmaceutical composition or can be administered alone, before, simultaneously with, or after other active pharmaceutical ingredients. Therefore, this invention includes combinations of the compounds of this invention as described above with anti-inflammatory agents, bronchodilators, antihistamines, or antitussive active pharmaceutical ingredients, wherein the pharmaceutical compositions of the compounds and the active pharmaceutical ingredients may be the same or different.

[0599] Suitable anti-inflammatory drugs include steroids, specifically 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, BIIL284, ONO 4057, and SB 209247; LTD4 antagonists such as montelukast and zafirlukast; and PDE4 inhibitors such as cilomilast. GlaxoSmithKline), Roflumilast (Byk Gulden), V-11294A (Napp), BAY19-8004 (Bayer), SCH-351591 (Schering-Plough), Arofylline (Almirall Prodesfarma), PD189659 / PD168787 (Parker Davis), AWD-12-281 (Asta Medica), CDC-801 (Celgene), SeICID™ 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 their pharmaceutically acceptable salts. Suitable bronchodilators include anticholinergic or antimuscarinic compounds, specifically ipratropium bromide, oxytropium bromide, tiotropium salts, and CHF 4226 (Chiesi) and glycopyrrolate.

[0600] Suitable antihistamine active pharmaceutical ingredients include cetirizine hydrochloride, acetaminophen, clemastine fumarate, promethazine, loratidine, desloratidine, diphenhydramine, fexofenadine hydrochloride, activastine, astemizole, azelastine, ebastine, epinastine, mizolastine, and tefenadine.

[0601] Other possible 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 those combinations of 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).

[0602] The structures of active compounds identified by coded serial numbers, categories, or trademarks can be obtained from the official standard summary "The Merck Index" or from databases such as Patents International (e.g., IMS World Publications).

[0603] 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 show poor sensitivity to radiation therapy.

[0604] The compounds of this invention can be administered alone or in combination with one or more other therapeutic compounds. Possible combination therapies may involve administering the compounds of this invention and one or more other therapeutic compounds in a fixed combination, or alternately or independently, or in combination with a fixed combination and one or more other therapeutic compounds. The compounds of this invention may also be administered additionally, particularly in combination with chemotherapy, radiation therapy, immunotherapy, phototherapy, surgical intervention, or combinations thereof, for the treatment of tumors. As described above, this may also be a long-term therapy, or an adjunct therapy in the context of other treatment strategies. Other possible treatments include therapies to maintain the patient's condition after tumor regression or even chemopreventive therapy (e.g., for patients at risk).

[0605] These additional agents may be administered separately from the composition containing the compound of the present invention as part of a multiple-dose regimen. Alternatively, these agents may be part of a single dosage form, mixed together with the compound of the present invention to form a single composition. If administered as part of a multiple-dose regimen, the two active agents may be provided simultaneously, sequentially, or at intervals (typically within 5 hours of each other).

[0606] As used herein, the terms "combination" and related terms refer to the simultaneous or sequential administration of a therapeutic agent according to the invention. For example, the compound of the invention may be administered simultaneously or sequentially with another therapeutic agent in individual unit dosage forms, or co-administered in a single unit dosage form. Therefore, the present invention provides a single unit dosage form comprising the compound of the invention, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or mediator.

[0607] The amounts of the compounds of the present invention that can be combined with carrier materials to produce a single dosage form, and additional therapeutic agents (in those compositions containing additional therapeutic agents as described above), will vary depending on the host being treated and the specific administration modality. Preferably, the compositions of the present invention should be formulated such that the dosage of the compounds of the present invention is between 0.01 and 100 mg / kg body weight / day.

[0608] In those compositions that include an additional therapeutic agent, the additional therapeutic agent and the compound of the present invention can act synergistically. Therefore, the amount of the additional therapeutic agent in such compositions will be less than that required in a single therapy using only the therapeutic agent. In such compositions, the additional therapeutic agent can be administered at a dose between 0.01 and 1,000 micrograms / kg body weight / day.

[0609] The amount of additional therapeutic agent present in the compositions of the present invention will not exceed the amount typically administered in a composition containing the therapeutic agent as the sole active agent. Preferably, the amount of additional therapeutic agent in the currently disclosed compositions will be 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.

[0610] 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 device 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.

[0611] Example

[0612] As depicted in the following examples, in some exemplary embodiments, the compounds are prepared according to the following general procedure. It should be understood that although the general method describes the synthesis of certain compounds of the present invention, the following general method and other methods known to those skilled in the art can be applied to all compounds as described herein and to subclasses and types of each of these compounds.

[0613] Example 1. Synthesis of N-(4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropaneformamide, I-1

[0614]

[0615] Compound 1.2 was synthesized. K₂CO₃ (70 g, 507.6 mmol, 2.0 equivalent) was added to a solution of 1.1 (50 g, 253.6 mmol, 1.0 equivalent) in DMF (500 mL) at 0 °C and stirred for 15 min. MeI (72 g, 507.6 mmol, 2.0 equivalent) was added dropwise to the suspension, and the reaction mixture was stirred at 60 °C for 2 h. After the reaction was complete, the reaction mixture was transferred to ice water. The precipitate was filtered and dried to give 1.2 (50.0 g, 93.0%). MS (ES): m / z 212.2 [M+H] + .

[0616] Compound 1.3 was synthesized. An aqueous solution of NH4OH (300 mL) was added to 1.2 (50 g, 236.7 mmol, 1.0 equivalent), followed by methanol (NH3) (1600 mL). The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the residue was washed with ice-cold water. The precipitate was dried to give 1.3 (45.0 g, 96.0%). MS (ES): m / z 197.2 [M+H] + .

[0617] Compound 1.4 was synthesized. SiCl4 (28.6 g, 168 mmol, 1.5 equivalents) was added to a suspension of NaN3 (21.8 g, 336 mmol, 3.0 equivalents) in acetonitrile (220 mL). Compound 1.3 (22.0 g, 112 mmol, 1.0 equivalents) was added to the stirred suspension, and the reaction mixture was stirred at 75 °C for 16 hours. The reaction mixture was cooled to room temperature, and water was added. The precipitated solid was filtered to give 1.4 (18.0 g, 72.5%). MS (ES): m / z 222.2 [M+H] + .

[0618] Compound 1.5 was synthesized. K₂CO₃ (23.4 g, 169.7 mmol, 2.5 equivalence) was added to a stirred solution of 1.4 (15.0 g, 67.8 mmol, 1.0 equivalence) in 150 mL of DMF at 0 °C. MeI (19.1 g, 135.7 mmol, 2.0 equivalence) was added dropwise to this solution. The reaction mixture was stirred at room temperature for 24 hours. After the reaction was complete, the mixture was transferred to water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated under reduced pressure to obtain the crude compound. The crude compound was purified by column chromatography to give the desired regiomeric isomer 1.5 (10.0 g, 62.7%). MS (ES): m / z 236.2 [M+H] + .

[0619] Compound 1.6 was synthesized. 10% Pd / C (2.0 g) was added to a solution of 1.5 (10.0 g, 42.5 mmol, 1.0 equivalent) in MeOH (100 mL). The reaction mixture was purged with hydrogen for 4 hours. After the reaction was complete, the mixture was filtered through a diatomaceous earth bed and washed with MeOH. The filtrate was concentrated under reduced pressure to give 1.6 (5.3 g, 60.7%). MS (ES): m / z 206.3 [M+H] + .

[0620] Compound 1.8 was synthesized. SOCl2 (5.0 mL) was added to 1.7 (1.0 g, 4.42 mmol, 1.0 equivalent), followed by DMF (catalytic amount), and refluxed for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain the acyl chloride. Methylhydrazine (0.20 g, 42.5 mmol, 1.0 equivalent) was dissolved in CH2Cl2 (20.0 mL), followed by the addition of NaOH (0.72 g, 177 mmol, 4.0 equivalent) in water (5.0 mL). The previously prepared acyl chloride solution in CH2Cl2 was added dropwise to the solution. The reaction mixture was refluxed for 15 minutes. After the reaction was complete, the reaction mixture was transferred to water and extracted with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to obtain the crude substance, which was purified by column chromatography to give 1.8. (1.1g, 97.0%). MS(ES):m / z 255.5[M+H] + .

[0621] Compound 1.9 was synthesized. Na₂CO₃ (0.49 g, 3.93 mmol, 1.0 equivalent) was added to a suspension of 1.8 (1.0 g, 3.93 mmol, 1.0 equivalent) in 1-pentanol (15.0 mL), and the reaction mixture was stirred at 120 °C for 16 h. After the reaction was complete, the reaction mixture was cooled to room temperature, and the pH was adjusted to 6.0 using 1 N HCl. The reaction mixture was concentrated under reduced pressure to obtain a crude substance, which was purified by preparative HPLC to give 1.9 (0.15 g, 17.5%). MS (ES): m / z 219.2 [M+H] + .

[0622] Compound 1.91 was synthesized. A 1.0 M solution (1.6 mL, 1.57 mmol, 3.5 equivalence) of LHMDS in tetrahydrofuran was added to a solution of 1.9 (0.1 g, 0.45 mmol, 1.0 equivalence) and 1.6 (0.188 g, 0.917 mmol, 2.0 equivalence) in THF (2.0 mL) at -78 °C. The reaction mixture was stirred at room temperature for 18 hours. After the reaction was complete, the reaction mixture was transferred to water and extracted with EtOAc. The aqueous layer was acidified with 1.0 N HCl and extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na₂SO₄, and concentrated under reduced pressure to give pure 1.91 (0.1 g, 56.37%). MS (ES): m / z 387.9 [M+H] + .

[0623] Compound I-1 was synthesized. Cyclopropaneformamide (0.005 g, 0.062 mmol, 1.2 equivalent) and Cs₂CO₃ (0.033 g, 0.102 mmol, 2.0 equivalent) were added to 0.5 mL of DMA containing 1.91 g (0.020 g, 0.051 mmol, 1.0 equivalent). The reaction mixture was degassed under an argon atmosphere for 10 min, followed by the addition of Pd₂(dba)₃ (0.005 g, 0.005 mmol, 0.1 equivalent) and Xantphos (0.006 g, 0.01 mmol, 0.2 equivalent). The suspension was degassed again for 5 min. The reaction mixture was then heated at 130 °C for 5 h. After the reaction was complete, the reaction mixture was diluted with CH₂Cl₂ (1 mL) and eluent was obtained by passing CH₂Cl₂ containing 10% methanol through a silica stopper column. The eluates were combined and concentrated under reduced pressure to obtain crude material. Further purification was performed by reversed-phase HPLC to obtain I-1 (0.005 g, 22.2%). MS (ES): m / z 436.6 [M+H] + ; 1HNMR(CDCl3,400MHz):8.92(s,1H),7.79-7.77(d,1H),7.67-7.66(d,1H),7.45-7.40(m,1H),4 .45(s,3H),3.88(s,3H),3.47(s,3H),1.69-1.59(m,1H),1.13-1.12(m,2H),0.91-0.90(m,2H).

[0624] Example 2. Synthesis of 4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-6-((4-(methoxymethyl)pyridin-2-yl)amino)-2-methyl-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one I-2

[0625]

[0626] Add 4-(methoxymethyl)pyridine-2-amine (0.021 g, 0.155 mmol, 1.5 equivalents) and K3PO4 (0.043 g, 0.206 mmol, 2.0 equivalents) to 1.0 mL of DMF containing compound 1.91 (0.040 g, 0.103 mmol, 1.0 equivalents). Degas the reaction mixture under argon for 10 min, then add methanesulfonic acid [(2-di-tert-butylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.008 g, 0.01 mmol, 0.1 equivalents). Degas the suspension again for 5 min. Stir the reaction mixture at 50 °C for 15 min. After the reaction was complete, the mixture was diluted with CH2Cl2 (1.0 mL), and CH2Cl2 containing 8% methanol was used as the eluent to flow through a silica-stopped column. The eluates were combined and concentrated under reduced pressure to obtain a crude substance, which was purified by reversed-phase HPLC to obtain I-2 (0.008 g, 15.84%). MS (ES): m / z 489.75 [M+H] + ; 1 H NMR(CDCl3,400MHz):9.27(s,1H),8.95(s,1H),8.14-8.12(d,1H),7.70-7.68(d,1H),7.41-7.39(d,1H),7.11- 7.08(t,1H),7.00(s,1H),6.89-6.88(d,1H),4.43(s,3H),3.78(s,3H),3.65(s,2H),3.57(s,3H),3.43(s,3H).

[0627] Example 3. Synthesis of 4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2-methyl-6-((5-methylpyridin-2-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-3

[0628]

[0629] Compound I-3 was prepared from compound 1.91 and 5-methylpyridin-2-amine using the procedure described in Example 2. MS (ES): m / z 459.64 [M+H] + ; 1 H NMR(DMSO-d6,400MHz):10.68(s,2H),9.76(s,1H),8.93(s,1H),8.11(s,1H),7.79-7.77(d,1H),7. 65-7.57(m,2H),7.42-7.38(m,1H),7.2(s,1H),4.47(s,3H),3.79(s,3H),3.29(s,3H),2.24(s,3H).

[0630] Example 4. Synthesis of 4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2-methyl-6-(pyridin-2-ylamino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-4

[0631]

[0632] Compound I-4 was prepared from compound 1.91 and pyridine-2-amine using the procedure described in Example 2. MS (ES): m / z 445.68 [M+H] +1 H NMR(DMSO-d6,400MHz):9.97(s,1H),8.95(s,1H),8.27-8.26(d,1H),8.16(s,1H),7.89(s,1H),7.80-7.78(d,1H), 7.74-7.71(m,1H),7.65-7.63(d,1H),7.42-7.38(t,1H),6.97-6.94(t,1H),4.47(s,3H),3.79(s,3H),3.29(s,3H).

[0633] Example 5. Synthesis of 4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2-methyl-6-((4-methylpyridin-2-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-5

[0634]

[0635] Compound I-5 was prepared from compound 1.91 and 4-methylpyridin-2-amine using the procedure described in Example 2. MS (ES): m / z 459.7 [M+H] + ; 1 H NMR(DMSO-d6,400MHz):9.98(s,1H),8.96(s,1H),8.17(s,1H),8.14-8.13(d,1H),7.79-7.77(d,1H),7.6 5-7.63(d,1H),7.42-7.38(t,1H),6.82-6.81(d,1H),4.47(s,3H),3.79(s,3H),3.30(s,3H),2.30(s,3H).

[0636] Example 6. Synthesis of 6-((4-(hydroxymethyl)pyridin-2-yl)amino)-4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2-methyl-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-6

[0637]

[0638] Compound I-6 was prepared from compound 1.91 and (2-aminopyridin-4-yl)methanol using the procedure described in Example 2. MS (ES): m / z 475.58 [M+H] + ; 1 H NMR(DMSO-d6,400MHz):10.01(s,1H),8.97(s,1H),8.20-8.19(d,1H),8.17(s,1H),7.79-7.77(d,1H),7.66-7.6 4(d,1H),7.42-7.38(t,1H),6.92-6.90(d,1H),5.42(s,1H),4.52(s,2H),4.47(s,3H),3.79(s,3H),3.30(s,3H).

[0639] Example 7. Synthesis of N-(4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropaneformamide, I-14

[0640]

[0641] Compound 1.92 was prepared according to the procedure used for 1.91. Compound I-14 was prepared from compound 1.91 and cyclopropaneformamide using the procedure described in Example 2. (Yield: 22.2%). MS (ES): m / z 436.6 [M+H] + LCMS purity: 96%, HPLC purity: 91%. 1 H NMR(CDCl3,400MHZ):8.92(s,1H),7.79-7.77(d,J=8Hz,1H),7.67-7.66(d,J=7.2Hz,1H),7.45-7.40(m ,1H),4.45(s,3H),3.88(s,3H),3.47(s,3H),1.69-1.59(m,1H),1.13-1.12(m,2H),0.91-0.90(m,2H).

[0642] Example 13. Synthesis of 4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2-methyl-6-((5-(N-morpholinyl)pyridin-2-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-7

[0643]

[0644] Compound I-7 was prepared from compound 1.91 and 5-(N-morpholino)pyridine-2-amine using the procedure described in Example 2 (yield: 8.76%). MS (ES): m / z 530.81 [M+H]+, LCMS purity: 100%, HPLC purity: 98.59%, 1H NMR (DMSO-d6, 400MHZ): 9.79-9.75 (bs, 2H), 8.94 (s, 1H), 8.14 (s, 1H), 7.98 (s, 1H), 7.78-7.76 (d, J = 8Hz, 1H), 7.64-7.63 (d, J = 7.6Hz, 1H), 7.46-7.38 (m, 3H), 4.47 (s, 3H), 3.79 (s, 3H), 3.77-3.74 (t, 4H), 3.29 (s, 3H), 3.10-3.08 (t, 4H).

[0645] Example 14. Synthesis of 6-((5-fluoro-4-methylpyridin-2-yl)amino)-4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2-methyl-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-8

[0646]

[0647] Compound I-8 was prepared from compound 1.91 and 5-fluoro-4-methylpyridin-2-amine using the procedure described in Example 2 (yield: 16.24%). MS (ES): m / z 477.43 [M+H]+, LCMS purity: 99.71%, HPLC purity: 99.14%, 1H NMR (DMSO-d6, 400MHZ): 9.87 (s, 1H), 8.92 (s, 1H), 8.22 (s, 1H), 8.15 (s, 1H), 7.94 (s, 1H), 7.78-7.76 (d, J = 8Hz, 1H), 7.64-7.62 (d, J = 7.2Hz, 1H), 7.42-7.38 (t, 1H), 6.96 (s, 1H), 4.47 (s, 3H), 3.79 (s, 3H), 3.30 (s, 3H), 2.28 (s, 3H).

[0648] Example 15. Synthesis of 6-((2,6-dimethylpyrimidin-4-yl)amino)-4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2-methyl-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-9

[0649]

[0650] Compound I-9 was prepared from compound 1.91 and 2,6-dimethylpyrimidin-4-amine using the procedure described in Example 2 (yield: 11.98%). MS (ES): m / z 474.58 [M+H]+, LCMS purity: 99.76%, HPLC purity: 96.42%, 1H NMR (MeOD, 400MHZ): 8.34-8.29 (bs, 2H), 7.86-7.84 (d, J = 7.6Hz, 1H), 7.73-7.71 (d, J = 8Hz, 1H), 7.41-7.37 (t, 1H), 6.89 (s, 1H), 6.25 (s, 1H), 4.48 (s, 3H), 3.85 (s, 3H), 3.53 (s, 3H), 2.64 (s, 3H), 2.42 (s, 3H).

[0651] Example 16. Synthesis of 4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2-methyl-6-((6-methylpyridazin-3-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-10

[0652]

[0653] Compound I-10 was prepared from compound 1.91 and 6-methylpyridazine-3-amine using the procedure described in Example 2 (yield: 14.03%). m / z 460.43 [M+H]+, LCMS purity: 98.69%, HPLC purity: 98.00%, 1H NMR (DMSO-d6, 400MHZ): 10.23 (bs, 1H), 8.93 (s, 1H), 8.29-8.27 (d, J = 8.8 Hz, 1H), 8.16 (s, 1H), 7.79-7.77 (d, J = 8 Hz, 1H), 7.65-7.64 (d, J = 7.2 Hz, 1H), 7.50-7.48 (d, J = 9.2 Hz, 1H), 7.40-7.36 (t, J = 8 Hz, 1H), 6.99 (bs, 1H), 4.47 (s, 3H), 3.80 (s, 3H), 3.30 (s, 3H), 2.53 (s, 3H).

[0654] Example 17. Synthesis of 4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2-methyl-6-((5-(piperidin-1-yl)pyridin-2-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-11

[0655]

[0656] Compound I-11 was prepared from compound 1.91 and 5-(piperidin-1-yl)pyridine-2-amine using the procedure described in Example 2 (yield: 9.78%). MS (ES): m / z 528.68 [M+H]+, LCMS purity: 96.10%, HPLC purity: 98.65%, 1H NMR (CDCl3, 400MHZ): 9.76 (bs, 1H), 8.89 (s, 1H), 7.71 (s, 1H), 7.66-7.64 (d, J = 7.2Hz, 1H), 7.28 (s, 1H), 7.03-7.00 (m, 2H), 5.72 (s, 1H), 4.40 (s, 3H), 3.77 (s, 3H), 3.54 (s, 3H), 3.17-3.03 (m, 4H), 2.63 (s, 1H), 1.72 (s, 4H), 1.60-1.59 (d, 2H).

[0657] Example 18. Synthesis of 4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2-methyl-6-((5-(pyrrolidone-1-yl)pyridin-2-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-58

[0658]

[0659] Compound I-58 was prepared from compound 1.91 and 5-(pyrrolidone-1-yl)pyridine-2-amine using the procedure described in Example 2 (yield: 11.08%). MS (ES): m / z 514.46 [M+H]+, LC-MS purity: 96.44%, HPLC purity: 97.39%, 1H NMR (DMSO-d6, 400MHz): 9.96 (s, 1H), 8.68 (s, 1H), 7.72–7.621 (m, 3H), 7.51 (s, 2H), 7.24–6.98 (m, 2H), 6.40 (s, 1H), 4.50 (s, 3H), 3.68 (s, 4H), 3.45 (s, 3H), 3.25 (s, 3H), 1.98 (s, 4H).

[0660] Example 19. Synthesis of 6-((5-cyclopropylpyridin-2-yl)amino)-4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2-methyl-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-59

[0661]

[0662] Compound I-59 was prepared from compound 1.91 and 5-cyclopropylpyridine-2-amine using the procedure described in Example 2 (yield: 23.28%). MS (ES): m / z 485.53 [M+H]+, LC-MS purity: 98.26%, HPLC purity: 97.44%, 1H NMR (DMSO-d6, 400MHz): 10.72 (s, 1H), 9.74 (s, 1H), 8.90 (s, 1H), 8.09 (s, 1H), 7.95–7.93 (d, J = 6.8 Hz, 1H), 7.81–7.79 (d, J = 7.6 Hz, 1H). Hz,1H),7.63-7.61(d,J=7.2Hz,1H),7.43-7.36(m,2H),7.18(s,1H),4.48(s,3H),3.79(s ,3H),3.16(s,3H),1.89(s,1H),0.94-0.93(d,J=6.8Hz,2H),0.69-0.68(d,J=6.8Hz,2H).

[0663] Example 20. Synthesis of 4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2-methyl-6-((6-(trifluoromethyl)pyridin-2-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-60

[0664]

[0665] Compound I-60 was prepared from compound 1.91 and 6-(trifluoromethyl)pyridine-2-amine using the procedure described in Example 2 (yield: 39.25%). MS (ES): m / z 513.43 [M+H]+, LC-MS purity: 99.01%, HPLC purity: 98.84%, 1H NMR (DMSO-d6, 400MHz): 10.85 (s, 1H), 10.29 (s, 1H), 9.06 (s, 1H), 8.13-8.11 (d, J = 8.8Hz, 1H), 7.98-7.94 (t, J = 8.0Hz, 1H), 7. 82-7.79(d,J=8.0Hz,1H),7.65-7.64(d,J=6.8Hz,1H),7.48(s,1H),7.40-7.33(m,2H),4.48(s,3H),3.80(s,3H),3.32(s,3H).

[0666] Example 21. Synthesis of 4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-6-((6-(3-methoxyazacyclobut-1-yl)pyridin-2-yl)amino)-2-methyl-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-63

[0667]

[0668] Compound I-63 was prepared from compound 1.91 and 6-(3-methoxyazacyclobut-1-yl)pyridine-2-amine using the procedure described in Example 2 (yield: 19.48%). MS (ES): m / z 530.40 [M+H]+, LC-MS purity: 100.00%, HPLC purity: 98.25%, 1H NMR (CDCl3, 400MHz): 9.49 (bs, 1H), 8.98 (s, 1H), 7.68-7.66 (d, J = 6.8Hz, 1H), 7 .38-7.34(t,J=8.0Hz,2H),7.05-7.01(t,J=8.0Hz,1H),6.26-6.24(d,J=7.2Hz ,1H),5.88-5.86(d,J=8.0Hz,1H),5.73(bs,1H),4.40(s,3H),4.37-4.32(m,1H ),4.29-4.25(m,2H),3.96-3.93(m,2H),3.78(s,3H),3.51(s,3H),3.36(s,3H).

[0669] Example 22. Synthesis of 6-((4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)amino)pyrazine-2-carboxynitrile, I-64

[0670]

[0671] Compound I-64 was prepared from compound 1.91 and 6-aminopyrazine-2-carboxynitrile using the procedure described in Example 2 (yield: 20.55%), MS (ES): m / z 471.48 [M+H]+, LCMS purity: 100.00%, HPLC purity: 98.79%, 1H NMR (DMSO-d6, 400MHz): 10.96 (s, 1H), 10.66 (s, 1H), 9.36 (s, 1H), 9.01 (s, 1H), 8.66 (s, 1H), 7.83-7.81 (d, J = 8.0Hz, 1H), 7.68-7.66 (dd, J = 1.2Hz, 8.0Hz, 1H), 7.44-7.42 (d, J = 8.0Hz, 1H), 7.40-7.38 (d, J = 8.0Hz, 1H), 4.47 (s, 3H), 3.80 (s, 3H), 3.43 (s, 3H).

[0672] Example 23. Synthesis of 6-((6-cyclopropylpyridin-2-yl)amino)-4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2-methyl-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-65

[0673]

[0674] Compound I-65 was prepared from compound 1.91 and 6-cyclopropylpyridine-2-amine using the procedure described in Example 2 (yield: 7.98%). MS (ES): m / z 485.53 [M+H]+, LC-MS purity: 96.64%, HPLC purity: 96.85%, 1H NMR (DMSO-d6, 400MHz): 11.42 (s, 1H), 9.09 (s, 1H), 7.93 (s, 1H), 7.81–7.79 (d, J = 6.4 Hz, 1H), 7.66–7.64 (d, J = 6.4 Hz). ,1H),7.41(s,1H),7.09-7.07(d,J=7.2Hz,1H),6.98-6.96(d,J=7.2Hz,1H),6.02(s ,1H),4.44(s,3H),3.74(s,3H),3.48(s,3H),2.28(s,1H),1.26(s,2H),1.09(s,2H).

[0675] Example 24. Synthesis of N-ethyl-6-((4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)amino)pyridinecarboxamide, I-66

[0676]

[0677] Compound I-66 was prepared from compound 1.91 and 6-amino-N-ethylpyridinecarboxamide using the procedure described in Example 2 (yield: 12.50%). MS (ES): m / z 516.41 [M+H]+, LC-MS purity: 96.85%, HPLC purity: 95.48%, 1H NMR (MeOD, 400MHz): 8.18 (s, 1H), 7.91-7.86 (t, 1H), 7.82-7.80 (d, J = 8.0Hz, 1H), 7.74-7.72 (m, 1H), 7.68-7.67 (d, 1H), 7.39-7.3 5(t,J=8.0Hz,1H),6.19(s,1H),4.48(s,3H),3.84(s,3H),3.53(s,3H),3.52-3.46(q,J=7.2Hz,2H),1.28-1.25(t,J=7.2Hz,3H).

[0678] Example 26. Synthesis of 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-2-methyl-6-((5-methylpyridin-2-yl)amino)-1H-pyrazolo[3,4-b]pyridin-3(2H)-one, I-16

[0679]

[0680] Compound I-16 was prepared from compound 1.92 and 5-methylpyridin-2-amine using the procedure described in Example 2 (yield: 19.68%). MS (ES): m / z 458.2 [M+H]+, LCMS purity: 99.65%, HPLC purity: 99.81%, 1H NMR (DMSO-d6, 400MHZ): 10.67 (s, 1H), 9.76 (s, 1H), 8.93 (s, 1H), 8.57 (s, 1H), 8.11 (s, 1H), 7.84 (s, 1H), 7.68-7.66 (d, J=8Hz, 1H), 7.59-7.57 (m, 2H), 7.32-7.18 (m, 1H), 3.96 (s, 3H), 3.78 (s, 3H), 3.29 (s, 3H), 2.23 (s, 3H).

[0681] Example 27. Synthesis of 6-((4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)amino)nicotinonitrile, I-25

[0682]

[0683] Compound I-25 was prepared from compound 1.92 and 6-aminonicotinonitrile using the procedure described in Example 2 (yield: 12.08%). MS (ES): m / z 469.7 [M+H] + LCMS purity: 99.49%, HPLC purity: 99.22%, 1H NMR (DMSO-d6, 400MHZ): 10.39 (s, 1H), 8.95 (s, 1H), 8.69 (s, 1H), 8.57 (s, 1H), 8.25-8.23 (m, 1H), 8.14-8.11 (m, 1H), 7.68-7.66 (d, J = 7.2Hz, 1H), 7.60-7.58 (d, J = 8Hz, 1H), 7.33-7.29 (m, 1H), 7.10 (s, 1H), 3.96 (s, 3H), 3.78 (s, 3H), 3.31 (s, 3H).

[0684] Example 28. Synthesis of 4-((4-chloro-2-methoxyphenyl)amino)-2-methyl-6-((4-methylpyridin-2-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-42

[0685]

[0686] Compound 28.1 was synthesized. Following the procedure used to prepare 1.91, 28.1 was obtained (yield: 24%). MS (ES): m / z 340.2 [M+H]+.

[0687] Compound I-42 was prepared from compound 28.1 and 4-methylpyridin-2-amine using the procedure described in Example 2 (yield: 12.53%). MS (ES): m / z 411.52 [M+H]+, LC-MS purity: 100.00%, HPLC purity: 98.32%, 1H NMR(MeOD,400MHZ):8.18-8.17(d,J=5.2Hz,1H),7.47-7.45(d,J=8.4Hz,1H),7.19(s,1H),7.08-7.06(d,J =8.0Hz,1H),6.96-6.94(d,J=4.8Hz,1H),6.79(s,1H),5.69(s,1H),3.98(s,3H),3.53(s,3H),2.37(s,3H).

[0688] Example 29. Synthesis of N-(4-((4-(hydroxymethyl)-2-methoxyphenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropaneformamide, I-42

[0689]

[0690] Compound 29.1 was synthesized. Following the procedure used to prepare 1.91, 29.1 was obtained (yield: 57.32%). MS (ES): m / z 335.8 [M+H]+.

[0691] Compound I-42 was prepared from compound 29.1 and cyclopropaneformamide using the procedure described in Example 2 (yield: 17.46%). MS (ES): m / z 384.51 [M+H]+, LC-MS purity: 95.04%, HPLC purity: 93.08%, 1H NMR(DMSO-d6,400MHZ):10.67-10.64(d,J=1.2Hz,2H),8.41(s,1H),7.64(s,1H),7.38-7.36(d,J=8.0Hz,1H),7.09(s,1H),6.96 -6.94(d,J=8.0Hz,1H),5.24(t,J=8.0Hz,1H),4.51-4.49(d,J=8.0Hz,2H),3.85(s,3H),3.19(s,3H),1.99(s,1H),0.79(s,4H).

[0692] Example 30. Synthesis of N-(4-((2-methoxy-4-(methoxymethyl)phenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropaneformamide, I-45

[0693]

[0694] Compound 30.1 was synthesized. Following the procedure used to prepare 1.91, 30.1 was obtained (yield: 57.51%). MS (ES): m / z 349.8 [M+H]+.

[0695] Compound I-45 was prepared from compound 30.1 and cyclopropaneformamide using the procedure described in Example 2 (yield: 23.4%). MS (ES): m / z 398.38 [M+H]+, LC-MS purity: 96.46%, HPLC purity: 95.23%, 1H NMR(DMSO-d6,400MHZ):10.70-10.67(d,J=12.4Hz,2H),8.49(s,1H),7.68(s,1H),7.41-7.39(d,J=8.0Hz,1H),7.07(s,1H) ,6.96-6.94(d,J=8.4Hz,1H),4.40(s,2H),3.85(s,3H),3.35(s,3H),3.29(s,3H),1.99(s,1H),0.79-0.78(d,J=3.6Hz,4H).

[0696] Example 31. Synthesis of N-(4-((3-(1,3-dimethyl-1H-1,2,4-triazol-5-yl)-2-methoxyphenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropanecarboxamide, I-46

[0697]

[0698] Compound 31.1 was synthesized. Following the procedure used to prepare 1.91, 31.1 was obtained (yield: 49.08%). MS (ES): m / z 400.7 [M+H]+.

[0699] Compound I-46 was prepared from compound 31.1 and cyclopropaneformamide using the procedure described in Example 2 (yield: 5.45%). MS (ES): m / z 449.37 [M+H]+, LCMS purity: 95.95%, HPLC purity: 97.22%, 1H NMR (MeOD, 400MHZ): 7.79-7.77 (d, J = 8.0 Hz, 1H), 7.43-7.34 (m, 3H), 3.77 (s, 3H), 3.56 (s, 3H), 3.49 (s, 3H), 2.41 (s, 3H), 1.84 (s, 1H), 1.02-0.90 (m, 4H).

[0700] Example 32. Synthesis of 4-((2-methoxy-3-(5-methylthiazolyl-2-yl)phenyl)amino)-2-methyl-6-((4-methylpyridin-2-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-47

[0701]

[0702] Compound 32.1 was synthesized. Following the procedure used to prepare 1.91, 32.1 was obtained (yield: 21.10%). MS (ES): m / z 402.7 [M+H]+.

[0703] Compound I-47 was prepared from compound 32.1 and 4-methylpyridin-2-amine using the procedure described in Example 2 (yield: 27.88%). MS (ES): m / z 474.48 [M+H]+, LC-MS purity: 97.47%, HPLC purity: 95.33%, 1H NMR(CDCl3,400MHZ):8.71(s,1H),8.10-8.09(d,J=4.8Hz,1H),7.76(s,1H),7.55-7.53(d,J=8.0Hz,1H),7.46(s, 1H),7.35-7.33(d,J=8.0Hz,1H),6.96-6.92(d,J=8.0Hz,1H),6.75(s,2H),3.39(s,6H),2.55(s,3H),2.37(s,3H).

[0704] Example 33. Synthesis of N-(4-((3-fluoro-2-methoxyphenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropaneformamide, I-48

[0705]

[0706] Compound 33.1 was synthesized. Following the procedure used to prepare 1.91, 33.1 was obtained (yield: 54.05%). MS (ES): m / z 323.7 [M+H]+.

[0707] Compound I-48 was prepared from compound 33.1 and cyclopropaneformamide using the procedure described in Example 2 (yield: 18.47%). MS (ES): m / z 372.33 [M+H]+, LC-MS purity: 98.91%, HPLC purity: 95.67%, 1H NMR(DMSO-d6,400MHZ):10.79(s,1H),8.83(s,1H),8.17(s,1H),7.75(s,1H),7.32-7.30(d,J=8.0Hz,1H),7.21-7.15(m ,1H),7.06-7.03(d,J=10.0Hz,1H),3.88(s,3H),3.31(s,3H),2.03-2.01(t,J=5.6Hz,1H),0.81-0.81(d,J=5.6Hz,4H).

[0708] Example 34. Synthesis of N-(4-((3-chloro-2-methoxyphenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropaneformamide, I-49

[0709]

[0710] Following the procedure used to prepare 1.91, 34.1 was obtained (yield: 47.14%). MS (ES): m / z 340.2 [M+H]+.

[0711] Compound I-49 was prepared from compound 34.1 and cyclopropaneformamide using the procedure described in Example 2. (Yield: 39.36%), MS (ES): m / z 388.13 [M+H]+, LCMS purity: 99.46%, HPLC purity: 98.93%, 1H NMR (DMSO-d6, 400MHz): 10.78 (s, 2H), 8.84 (s, 1H), 7.74 (bs, 1H), 7.46–7.43 (t, J = 4.8 Hz, 1H), 7.22–7.20 (d, J = 4.8 Hz, 2H), 3.77 (s, 3H), 3.29 (s, 3H), 1.98 (s, 1H), 0.77 (s, 4H).

[0712] Example 35: Synthesis of N-(4-((4-cyclopropyl-2-methoxyphenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropaneformamide, I-50

[0713]

[0714] Following the procedure used to prepare 1.91, 35.1 was obtained (yield: 54.80%). MS (ES): m / z 345.7 [M+H]+.

[0715] Compound I-50 was prepared from compound 35.1 and cyclopropaneformamide using the procedure described in Example 2 (yield: 16.18%). MS (ES): m / z 394.61 [M+H]+, LC-MS purity: 94.66%, HPLC purity: 99.76%, 1H NMR(DMSO-d6,400MHz):10.67-10.62(d,J=17.6Hz,2H),8.36(s,1H),7.58(b s,1H),7.29-7.268(d,J=8.0Hz,1H),6.83-6.83(d,J=1.6Hz,1H),6.72-6.69( dd,J=1.6Hz,8.0Hz,1H),3.83(s,3H),3.28(s,3H),2.01-1.90(m,2H),0.96-0 .90(m,2H),0.79-0.77(d,J=5.2Hz,4H),0.74-0.72(dd,J=3.2Hz,4.8Hz,2H).

[0716] Example 36: Synthesis of N-(4-((4-cyclobutyl-2-methoxyphenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropaneformamide, I-51

[0717]

[0718] Following the procedure used to prepare 1.91, 36.1 was obtained (yield: 50.64%). MS (ES): m / z 359.8 [M+H]+.

[0719] Compound I-51 was prepared from compound 36.1 and cyclopropaneformamide using the procedure described in Example 2 (yield: 42.27%). MS (ES): m / z 408.37 [M+H]+, LC-MS purity: 96.20%, HPLC purity: 96.45%, 1H NMR(DMSO-d6,400MHz):10.67-10.63(d,J=17.2Hz,2H),8.41(s,1H),7.64(s, 1H),7.35-7.33(d,J=8.0Hz,1H),6.97(s,1H),6.88-6.87(d,J=8.0Hz,1H),3.8 5(s,3H),3.54-3.48(q,J=8.8Hz,1H),3.28(s,3H),2.33-2.25(m,2H),2.19-2 .09(m,2H),2.02-1.93(m,2H),1.85-1.80(m,1H),0.79-0.78(d,J=5.2Hz,4H).

[0720] Example 37: Synthesis of N-(4-((2-methoxy-3-(1-methyl-1H-tetrazol-5-yl)phenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropaneformamide, I-52

[0721]

[0722] Following the procedure used to prepare 1.91, 37.1 was obtained (yield: 68.77%). MS (ES): m / z 387.7 [M+H]+.

[0723] Compound I-52 was prepared from compound 37.1 and cyclopropaneformamide using the procedure described in Example 2 (yield: 22.21%). MS (ES): m / z 436.37 [M+H]+, LC-MS purity: 97.49%, HPLC purity: 94.04%, 1H NMR(DMSO-d6,400MHz):10.78(s,1H),8.82(s,1H),8.19(s,1H),7.75-7.73(d,J=7.6Hz,1H),7.65(s,1H),7.4467.40(t,J=7.6Hz, 1H),7.36-7.34(d,J=6.4Hz,1H),3.99(s,3H),3.47(s,3H),2.61(s,3H),2.03-2.00(t,J=6.0Hz,1H),0.81-0.79(d,J=6.0Hz,4H).

[0724] Example 38: Synthesis of N-(4-((3-(1,5-dimethyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropaneformamide, I-53

[0725]

[0726] Following the procedure used to prepare 1.91, 38.1 was obtained (yield: 68.16%). MS (ES): m / z 400.8 [M+H]+.

[0727] Compound I-53 was prepared from compound 38.1 and cyclopropaneformamide using the procedure described in Example 2 (yield: 30.67%). MS (ES): m / z 449.37 [M+H]+, LCMS purity: 98.48%, HPLC purity: 95.33%, 1H NMR (CDCl3, 400MHz): 9.59 (bs, 1H), 8.89 (s, 1H), 7.59–7.57 (d, J = 7.6 Hz, 1H), 7.49–7.47 (d, J = 8.0 Hz, 1H), 7.13–7.02 (m, 2H), 3.89 (s, 3H), 3.71 (s, 3H), 3.47 (s, 3H), 2.52 (s, 3H), 1.65 (s, 1H), 1.11 (s, 2H), 0.90 (s, 2H).

[0728] Example 39: Synthesis of N-(4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-5-yl)phenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropaneformamide, I-54

[0729]

[0730] Following the procedure used to prepare 1.91, 39.1 was obtained (yield: 62.17%). MS (ES): m / z 386.6 [M+H]+.

[0731] Compound I-54 was prepared from compound 39.1 and cyclopropaneformamide using the procedure described in Example 2 (yield: 17.76%). MS (ES): m / z 435.32 [M+H]+, LC-MS purity: 99.53%, HPLC purity: 99.60%, 1H NMR(DMSO-d6,400MHz):10.78(bs,1H),8.84(s,1H),8.08(s,1H),7.71(s,1H),7.68-7.66(d,J=8.0Hz,1H),7.38-7.34(m ,1H),7.25-7.23(d,J=8.0Hz,1H),3.74(s,3H),3.49(s,3H),3.22(s,3H),2.03-2.00(m,1H),0.81-0.79(d,J=5.2Hz,4H).

[0732] Example 40: Synthesis of N-(4-((2-methoxy-3-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropaneformamide, I-55

[0733]

[0734] Following the procedure used to prepare 1.91, 40.1 was obtained (yield: 48.16%). MS (ES): m / z 385.7 [M+H]+.

[0735] Compound I-55 (yield: 20.89%) was prepared from compound 40.1 and cyclopropaneformamide using the procedure described in Example 2. MS (ES): m / z 434.48 [M+H]+, LCMS purity: 100.00%, HPLC purity: 100.00%, 1H NMR (DMSO-d6, 400MHz): 10.76 (bs, 1H), 8.81 (s, 1H), 8.19 (s, 1H), 7.92 (s, 1H), 7.77 (s, 1H), 7.38–7.33 (t, J = 10.0 Hz, 2H), 7.21–7.19 (d, J = 8.0 Hz, 1H), 3.90 (s, 3H), 3.61 (s, 3H), 3.32 (s, 3H), 2.02 (s, 1H), 0.80 (s, 4H).

[0736] Example 41: Synthesis of N-(4-((2-methoxy-3-(1H-pyrazol-1-yl)phenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropaneformamide, I-56

[0737]

[0738] Following the procedure used to prepare 1.91, 41.1 was obtained (yield: 58.80%). MS (ES): m / z 371.8 [M+H]+.

[0739] Compound I-56 was prepared from compound 41.1 and cyclopropaneformamide using the procedure described in Example 2 (yield: 22.10%). MS (ES): m / z 420.48 [M+H]+, LCMS purity: 99.87%, HPLC purity: 99.66%, 1H NMR (DMSO-d6, 400MHz): 10.80 (bs, 1H), 8.88 (s, 1H), 8.23–8.22 (d, J = 2.0 Hz, 1H), 7.79 (s, 2H), 7.52–7.50 (d, J = 7.6 Hz, 1H), 7.39–7.31 (m, 2H), 6.57 (s, 1H), 3.45 (s, 3H), 3.32 (s, 3H), 2.02 (s, 1H), 0.81 (s, 4H).

[0740] Example 42: Synthesis of N-(4-((2-methoxy-3-(1-methyl-1H-pyrazol-3-yl)phenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropaneformamide, I-57

[0741]

[0742] Following the procedure used to prepare 1.91, 42.1 was obtained (yield: 37.77%). MS (ES): m / z 385.5 [M+H]+.

[0743] Compound I-57 was prepared from compound 42.1 and cyclopropaneformamide using the procedure described in Example 2 (yield: 31.07%). MS (ES): m / z 434.63 [M+H]+, LC-MS purity: 100.00%, HPLC purity: 96.16%, 1H NMR(DMSO-d6,400MHz):10.76(bs,2H),8.83(s,1H),7.79(s,2H),7.62-7.60(d,J=7.6Hz,1H),7.44-7.42(d,J=7.6Hz, 1H),7.24-7.22(m,1H),6.74-6.73(d,J=2.4Hz,1H),3.91(s,3H),3.61(s,3H),3.31(s,3H),2.02(s,1H),0.81(s,4H).

[0744] Example 46: Synthesis of N-(4-((2-methoxyphenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropaneformamide, I-61

[0745]

[0746] Following the procedure used to prepare 1.91, 46.1 was obtained (yield: 75.13%). MS (ES): m / z 305.7 [M+H] + .

[0747] Compound I-61 was prepared from compound 46.1 and cyclopropaneformamide using the procedure described in Example 2 (yield: 19.83%). MS (ES): m / z 354.38 [M+H]+, LCMS purity: 100.00%, HPLC purity: 98.86%, 1H NMR (DMSO-d6, 400MHz): 10.69-10.67 (d, J = 10.8 Hz, 2H), 8.53 (s, 1H), 7.69 (s, 1H), 7.45-7.43 (d, J = 8.0 Hz, 1H), 7.13-7.12 (d, J = 4.0 Hz, 2H), 7.03-6.99 (m, 1H), 3.85 (s, 3H), 3.29 (s, 3H), 1.99 (s, 1H), 0.78 (s, 4H).

[0748] Example 51: Synthesis of 4-((2-methoxy-4-(methoxymethyl)phenyl)amino)-2-methyl-6-((6-(trifluoromethyl)pyridin-2-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-67

[0749]

[0750] Following the procedure used to prepare 1.91, 51.1 was obtained (yield: 78.14%). MS (ES): m / z 349.7 [M+H] + .

[0751] Compound I-67 was prepared from compound 51.1 and 6-(trifluoromethyl)pyridine-2-amine using the procedure described in Example 2 (yield: 14.70%), MS (ES): m / z 475.35 [M+H] +LCMS purity: 100.00%, HPLC purity: 95.73%, 1H NMR (DMSO-d6, 400MHz): 10.72 (s, 1H), 10.21 (s, 1H), 8.69 (s, 1H), 8.13-8.10 (d, J = 8.4Hz, 1H), 7.96-7.92 (t, J = 8.4Hz, 1H), 7.54-7.52 (d, J = 8.0Hz, 1H), 7.38-7.36 (d, J = 7.2Hz, 1H), 7.32 (s, 1H), 7.06 (s, 1H), 6.95-6.93 (d, J = 7.6Hz, 1H), 4.42 (s, 2H), 3.88 (s, 3H), 3.31 (s, 3H), 3.28 (s, 3H).

[0752] Example 52: Synthesis of 6-((4-((2-methoxy-4-(methoxymethyl)phenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)amino)pyridinecarboxynitrile, I-68

[0753]

[0754] Following the procedure used to prepare 1.91, 52.1 was obtained (yield: 78.14%). MS (ES): m / z 349.7 [M+H] + .

[0755] Compound I-68 was prepared from compound 52.1 and 6-aminopyridinecarboxynitrile using the procedure described in Example 2 (yield: 32.34%), MS (ES): m / z 432.34 [M+H] + LCMS purity: 97.69%, HPLC purity: 96.47%, 1H NMR (DMSO-d6, 400MHz): 10.72 (s, 1H), 10.24 (s, 1H), 8.64 (s, 1H), 8.08 (s, 1H), 7.89 (s, 1H), 7.56-7.53 (d, J = 10.0 Hz, 2H), 7.32 (s, 1H), 7.08-7.05 (d, J = 10.4 Hz, 2H), 4.41 (s, 2H), 3.88 (s, 3H), 3.33 (s, 3H), 3.28 (s, 3H).

[0756] Example 53: Synthesis of N-(4-((3-bromo-2-methoxyphenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropaneformamide, I-69

[0757]

[0758] Following the procedure used to prepare 1.91, 53.1 was obtained (yield: 56.84%). MS (ES): m / z 384.6 [M+H] + .

[0759] Compound I-69 was prepared from compound 53.1 and cyclopropaneformamide using the procedure described in Example 2 (yield: 15.53%), MS (ES): m / z 434.27 [M+H]. + LCMS purity: 98.62%, HPLC purity: 98.29%, 1H NMR (DMSO-d6, 400MHz): 10.79-10.78 (d, J = 7.6 Hz, 2H), 8.83 (s, 1H), 7.75 (s, 1H), 7.46-7.44 (t, J = 9.6 Hz, 1H), 7.22 (s, 1H), 7.21 (s, 1H), 3.78 (s, 3H), 3.32 (s, 3H), 1.98 (s, 1H), 0.79 (s, 4H).

[0760] Example 54: Synthesis of 4-((4-(hydroxymethyl)-2-methoxyphenyl)amino)-2-methyl-6-((6-(trifluoromethyl)pyridin-2-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-72

[0761]

[0762] Following the procedure used to prepare 1.91, 54.1 was obtained (yield: 65.13%). MS (ES): m / z 335.8 [M+H] + .

[0763] Compound I-72 was prepared from compound 54.1 and 6-(trifluoromethyl)pyridine-2-amine using the procedure described in Example 2 (yield: 14.54%), MS (ES): m / z 461.38 [M+H] +LCMS purity: 98.86%, HPLC purity: 95.52%, 1H NMR(DMSO-d6,400MHz):10.71(s,1H),10.20(s,1H),8.66(s,1H),8.15-8.13(d ,J=9.2Hz,1H),7.96-7.92(t,J=7.6Hz,1H),7.52-7.49(d,J=8.0Hz,1H),7.38-7 .36(d,J=7.2Hz,1H),7.27(s,1H),7.08(s,1H),6.95-6.94(d,J=7.6Hz,1H),5.2 4-5.22(t,J=5.6Hz,1H),4.51-4.50(d,J=5.6Hz,2H),3.87(s,3H),3.28(s,3H).

[0764] Example 55: Synthesis of 4-((3-fluoro-2-methoxyphenyl)amino)-2-methyl-6-((5-(piperidin-1-yl)pyridin-2-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-77

[0765]

[0766] Following the procedure used to prepare 1.91, 55.1 was obtained (yield: 81.07%). MS (ES): m / z 323.7 [M+H] + .

[0767] Compound I-77 was prepared from compound 55.1 and 5-(piperidin-1-yl)pyridin-2-amine using the procedure described in Example 2 (yield: 20.89%), MS (ES): m / z 464.53 [M+H] + LCMS purity: 100.00%, HPLC purity: 98.80%, 1H NMR (DMSO-d6, 400MHz): 10.67 (s, 1H), 9.58 (s, 1H), 8.90 (s, 1H), 8.02 (s, 2H), 7.40 (s, 2H), 7.22-7.17 (q, J = 8.4Hz, 1H), 7.01 (s, 2H), 3.89 (s, 3H), 3.27 (s, 3H), 3.08 (s, 4H), 1.64 (s, 4H), 1.23 (s, 2H).

[0768] Example 56: Synthesis of 4-((3-fluoro-2-methoxyphenyl)amino)-2-methyl-6-((1-methyl-1H-pyrazol-3-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-78

[0769]

[0770] Compound I-78 was prepared from compound 55.1 and 1-methyl-1H-pyrazole-3-amine using the procedure described in Example 2 (yield: 37.88%), MS (ES): m / z 384.43 [M+H]. + LCMS purity: 97.80%, HPLC purity: 93.71%, 1H NMR (DMSO-d6, 400MHz): 10.52 (bs, 1H), 9.52 (bs, 1H), 8.78 (s, 1H), 7.54 (s, 1H), 7.42-7.39 (d, J = 8.4 Hz, 1H), 7.21-7.15 (q, J = 8.4 Hz, 1H), 7.01-6.97 (d, J = 9.6 Hz, 1H), 6.88 (s, 1H), 6.35 (s, 1H), 3.89 (s, 3H), 3.72 (s, 3H), 3.25 (s, 3H).

[0771] Example 57: Synthesis of 6-((4-((3-fluoro-2-methoxyphenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)amino)nicotinonitrile, I-79

[0772]

[0773] Compound I-79 was prepared from compound 55.1 and 6-aminonicotinonitrile using the procedure described in Example 2 (yield: 39.80%), MS (ES): m / z 406.29 [M+H]. + LCMS purity: 98.61%, HPLC purity: 99.01%, 1H NMR (DMSO-d6, 400MHz): 10.99 (s, 1H), 10.44 (s, 1H), 8.88 (s, 1H), 8.69 (s, 1H), 8.23-8.21 (d, J = 8.8 Hz, 1H), 8.15-8.13 (dd, J = 1.6 Hz, 8.8 Hz, 1H), 7.43-7.41 (d, J = 8.4 Hz, 1H), 7.25-7.19 (q, J = 8.4 Hz, 1H), 7.15 (s, 1H), 7.06-7.01 (d, J = 8.8 Hz, 1H), 3.89 (s, 3H), 3.35 (s, 3H).

[0774] Example 58: Synthesis of 4-((3-fluoro-2-methoxyphenyl)amino)-2-methyl-6-(pyridin-2-ylamino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-80

[0775]

[0776] Compound I-80 was prepared from compound 55.1 and pyridine-2-amine using the procedure described in Example 2 (yield: 21.21%), MS (ES): m / z 381.28 [M+H] + LCMS purity: 97.64%, HPLC purity: 97.36%, 1H NMR (DMSO-d6, 400MHz): 10.78 (s, 1H), 9.85 (s, 1H), 8.85 (s, 1H), 8.26 (s, 1H), 8.03 (s, 1H), 7.71 (s, 1H), 7.44 (s, 1H), 7.21 (s, 2H), 7.06-6.83 (m, 2H), 3.96 (s, 3H), 3.29 (s, 3H).

[0777] Example 59: Synthesis of 6-((4-((3-fluoro-2-methoxyphenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)amino)pyridinecarboxynitrile, I-81

[0778]

[0779] Compound I-81 was prepared from compound 55.1 and 6-aminopyridinecarboxynitrile using the procedure described in Example 2 (yield: 43.78%), MS (ES): m / z 406.43 [M+H] + LCMS purity: 100.00%, HPLC purity: 100.00%, 1H NMR (DMSO-d6, 400MHz): 10.84 (s, 1H), 10.32 (s, 1H), 8.95 (s, 1H), 8.05-8.03 (d, J = 8.4Hz, 1H), 7.93-7.89 (t, J = 8.4Hz, 1H), 7.56-7.49 (m, 3H), 7.26-7.20 (q, J = 8.0Hz, 1H), 7.06-7.01 (t, J = 9.2Hz, 1H), 3.91 (s, 3H), 3.30 (s, 3H).

[0780] Example 60: Synthesis of N-(4-((4-(azacyclobutane-1-carbonyl)-2-methoxyphenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropaneformamide, I-82

[0781]

[0782] Following the procedure used to prepare 1.91, 60.1 was obtained (yield: 24.74%). MS (ES): m / z 388.8 [M+H] + .

[0783] Compound I-82 was prepared from compound 60.1 and cyclopropaneformamide using the procedure described in Example 2 (yield: 21%), MS (ES): m / z 437.37 [M+H]. + LCMS purity: 100.00%, HPLC purity: 98.68%, 1H NMR (MeOD, 400MHz): 7.61-7.59 (d, J = 8.0Hz, 2H), 7.39 (s, 1H), 7.34-7.32 (d, J = 8.4Hz, 1H), 4.51-4.47 (t, J = 6.4Hz, 2H), 4.25-4.21 (t, J = 6.4Hz, 2H), 3.99 (s, 3H), 3.49 (s, 3H), 2.45-2.38 (qui, J = 6.4Hz, 2H), 1.84 (s, 1H), 1.04-0.96 (m, 4H).

[0784] Example 61: Synthesis of 4-((3-fluoro-2-methoxyphenyl)amino)-2-methyl-6-((4-methylpyridin-2-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-83

[0785]

[0786] Compound I-83 was prepared from compound 55.1 and 4-methylpyridin-2-amine using the procedure described in Example 2 (yield: 30.68%), MS (ES): m / z 395.28 [M+H]. + LCMS purity: 98.12%, HPLC purity: 97.83%, 1H NMR (DMSO-d6, 400MHz): 10.72 (s, 1H), 9.72 (s, 1H), 8.82 (s, 1H), 8.09 (s, 1H), 7.83 (s, 1H), 7.43-7.42 (d, J = 7.2Hz, 1H), 7.20-7.14 (m, 2H), 6.98 (s, 1H), 6.76 (s, 1H), 3.87 (s, 3H), 3.26 (s, 3H), 2.28 (s, 3H).

[0787] Example 62: Synthesis of 4-((3-fluoro-2-methoxyphenyl)amino)-2-methyl-6-((5-methylpyridin-2-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-84

[0788]

[0789] Compound I-84 was prepared from compound 55.1 and 5-methylpyridin-2-amine using the procedure described in Example 2 (yield: 20.46%), MS (ES): m / z 395.32 [M+H]. + LCMS purity: 97.72%, HPLC purity: 97.18%, 1H NMR (MeOD, 400MHz): 8.15 (s, 1H), 7.65-7.62 (dd, J = 2.0Hz, 8.4Hz, 1H), 7.33-7.31 (d, J = 8.0Hz, 1H), 7.18-7.13 (m, 2H), 7.08-7.03 (t, J = 8.8Hz, 1H), 6.89-6.87 (d, J = 7.6Hz, 1H), 3.97 (s, 3H), 3.54 (s, 3H), 2.31 (s, 3H).

[0790] Example 63: Synthesis of 6-((4-((3-fluoro-2-methoxyphenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)amino)pyrazine-2-carboxynitrile, I-85

[0791]

[0792] Compound I-85 was prepared from compound 55.1 and 6-aminopyrazine-2-carboxynitrile using the procedure described in Example 2 (yield: 17.87%), MS (ES): m / z 407.27 [M+H] + LCMS purity: 99.70%, HPLC purity: 99.67%, 1H NMR (DMSO-d6, 400MHz): 10.96 (bs, 1H), 10.67 (bs, 1H), 9.31 (s, 1H), 8.92 (s, 1H), 8.65 (s, 1H), 7.47–7.45 (d, J = 8.0 Hz, 1H), 7.38 (s, 1H), 7.24–7.18 (q, J = 8.0 Hz, 1H), 7.08–7.03 (t, J = 6.0 Hz, 1H), 3.91 (s, 3H), 3.35 (s, 3H).

[0793] Example 64: Synthesis of 4-((3-fluoro-2-methoxyphenyl)amino)-2-methyl-6-((6-(trifluoromethyl)pyridin-2-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-86

[0794]

[0795] Compound I-86 was prepared from compound 55.1 and 6-(trifluoromethyl)pyridine-2-amine using the procedure described in Example 2 (yield: 14.99%), MS (ES): m / z 449.32 [M+H] + LCMS purity: 99.81%, HPLC purity: 99.80%, 1H NMR (DMSO-d6, 400MHz): 10.80 (bs, 1H), 10.24 (bs, 1H), 8.95 (s, 1H), 8.08-8.06 (d, J = 8.0Hz, 1H), 7.95-7.91 (t, J = 8.0Hz, 1H), 7.43-7.35 (m, 3H), 7.14-7.09 (q, J = 8.0Hz, 1H), 7.03-6.98 (t, J = 8.0Hz, 1H), 3.88 (s, 3H), 3.28 (s, 3H).

[0796] Example 65: Synthesis of 6-((6-cyclopropylpyridin-2-yl)amino)-4-((3-fluoro-2-methoxyphenyl)amino)-2-methyl-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-87

[0797]

[0798] Compound I-87 was prepared from compound 55.1 and 6-cyclopropylpyridine-2-amine using the procedure described in Example 2 (yield: 19.19%), MS (ES): m / z 421.32 [M+H]. + LCMS purity: 98.94%, HPLC purity: 94.15%, 1H NMR (DMSO-d6, 400MHz): 11.46 (s, 1H), 8.99 (s, 1H), 7.95-7.91 (t, J = 8.0Hz, 1H), 7.29-7.27 (d, J = 7.2Hz, 1H), 7.18-7.16 (d, J = 8.0Hz, 1H). .4Hz,2H),7.08-7.06(d,J=7.2Hz,1H),6.99-6.97(d,J=8.4Hz,1H),6.04(s,1H),3 .85(s,3H),3.45(s,3H),2.31-2.24(m,1H),1.28-1.23(m,2H),1.11-1.06(m,2H).

[0799] Example 66: Synthesis of N-(4-((2-methoxy-3-(2-oxopyrrolidone-1-yl)phenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropaneformamide, I-88

[0800]

[0801] Following the procedure used to prepare 1.91, 66.1 was obtained (yield: 56.22%). MS (ES): m / z 388.7 [M+H] + .

[0802] Compound I-88 was prepared from compound 66.1 and cyclopropaneformamide using the procedure described in Example 2 (yield: 17.06%), MS (ES): m / z 437.37 [M+H]. + LCMS purity: 96.29%, HPLC purity: 95.84%, 1H NMR(DMSO-d6,400MHz):10.77(s,1H),8.77(s,1H),7.79(s,1H),7.44-7.42(d,J=7.6Hz,1H),7.23-7.19(t,J=8.0Hz,1H),7.06-7.04(d,J=7.6Hz,1 H),3.74-3.71(t,J=6.8Hz,2H),3.669(s,3H),3.311(s,3H),2.46-2.42(d ,J=8.0Hz,2H),2.17-2.10(qui,J=6.8Hz,2H),2.017(s,1H),0.78(s,4H).

[0803] Example 67: 4-((3-fluoro-2-methoxyphenyl)amino)-2-methyl-6-((5-(N-morpholinyl)pyridin-2-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-89

[0804]

[0805] Compound I-89 was prepared from compound 55.1 and 5-(N-morpholino)pyridine-2-amine using the procedure described in Example 2 (yield: 13.87%), MS (ES): m / z 466.52 [M+H] + LCMS purity: 95.70%, HPLC purity: 95.05%, 1H NMR (DMSO-d6, 400MHz): 11.33 (s, 1H), 8.91 (s, 1H), 8.05-8.02 (dd, J = 2.4Hz, 9.2Hz, 1H), 7.83-7.82 (d, J = 2.4Hz, 1H), 7.32-7.11 (m, 5H), 6.09 (s, 1H), 3.86 (s, 3H), 3.75 (s, 4H), 3.38 (s, 3H), 3.12 (s, 4H).

[0806] Example 68: Synthesis of 4-((3-fluoro-2-methoxyphenyl)amino)-2-methyl-6-((5-(pyrrolidin-1-yl)pyridin-2-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-90

[0807]

[0808] Compound I-90 was prepared from compound 55.1 and 5-(pyrrolidone-1-yl)pyridin-2-amine using the procedure described in Example 2 (yield: 17.95%), MS (ES): m / z 450.42 [M+H + LCMS purity: 97.66%, HPLC purity: 96.95%, 1H NMR (DMSO-d6, 400MHz): 7.61-7.58 (dd, J = 2.4Hz, 9.6Hz, 1H), 7.47-7.47 (d, J = 2.4Hz, 1H), 7.30-7.28 (d, J = 8.4Hz, 1H), 7.22-7.19 (d, J = 9.6Hz, 1H), 7.16-7.11 (m, 1H), 7.05-7.00 (d, J = 9.6Hz, 1H), 6.15 (s, 1H), 3.85 (s, 3H), 3.34 (s, 3H), 3.21 (s, 4H), 1.95 (s, 4H).

[0809] Example 69: Synthesis of 6-((5-cyclopropylpyridin-2-yl)amino)-4-((3-fluoro-2-methoxyphenyl)amino)-2-methyl-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-91

[0810]

[0811] Compound I-91 was prepared from compound 55.1 and 5-cyclopropylpyridine-2-amine using the procedure described in Example 2 (yield: 15.99%), MS (ES): m / z 421.29 [M+H] + LCMS purity: 95.97%, HPLC purity: 95.65%, 1H NMR (DMSO-d6, 400MHz): 11.50 (s, 1H), 8.93 (s, 1H), 8.17 (s, 1H), 7.85-7.83 (d, J = 8.4 Hz, 1H), 7.31-7.29 (d, J = 7.2 Hz, 1H), 7.23-7.12 (m, 3H), 6.14 (s, 1H), 3.85 (s, 3H), 3.38 (s, 3H), 2.04 (s, 1H), 1.02 (s, 2H), 0.72 (s, 2H).

[0812] Example 70: Synthesis of 4-((2-methoxy-4-(methoxymethyl)phenyl)amino)-2-methyl-6-((5-(pyrrolidine-1-carbonyl)-6-(trifluoromethyl)pyridin-2-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-92

[0813]

[0814] Following the procedure used to prepare 1.91, 70.1 was obtained (yield: 78.14%). MS (ES): m / z 349.7 [M+H] + .

[0815] Compound I-92 was prepared from compound 70.1 and (6-amino-2-(trifluoromethyl)pyridin-3-yl)(pyrrolidine-1-yl) methyl ketone using the procedure described in Example 2 (yield: 17.09%), MS (ES): m / z 572.37 [M+H + LCMS purity: 94.64%, HPLC purity: 95.10%, 1H NMR (DMSO-d6, 400MHz): 10.78 (s, 1H), 10.32 (s, 1H), 8.67 (s, 1H), 8.22-8.20 (d, J = 8.8 Hz, 1H), 7.89-7.87 (d, J = 8.8 Hz, 1H), 7.53-7.51 (d, J = 8.0 Hz, 1H), 7.21 (s, 1H), 7. 07(s,1H),6.95-6.93(d,J=8.0Hz,1H),4.42(s,2H),3.88(s,3H),3.47-3.43(t,J=6 .0Hz,2H),3.31(s,3H),3.28(s,3H),3.13-3.10(t,J=6.0Hz,2H),1.89-1.81(m,4H).

[0816] Example 71: Synthesis of 4-((2-methoxy-4-(methoxymethyl)phenyl)amino)-2-methyl-6-((5-methyl-6-(trifluoromethyl)pyridin-2-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-93

[0817]

[0818] Compound I-93 was prepared from compound 70.1 and 5-methyl-6-(trifluoromethyl)pyridine-2-amine using the procedure described in Example 2 (yield: 26.18%), MS (ES): m / z 489.43 [M+H] +LCMS purity: 94.92%, HPLC purity: 99.24%, 1H NMR (DMSO-d6, 400MHz): 10.68 (s, 1H), 10.01 (s, 1H), 8.63 (s, 1H), 8.10-8.08 (d, J = 8.4Hz, 1H), 7.79-7.77 (d, J = 8.4Hz, 1H), 7.52-7.50 (d, J = 7.6Hz, 1H), 7.17 (s, 1H), 7.06 (s, 1H), 6.95-6.93 (d, J = 7.6Hz, 1H), 4.41 (s, 2H), 3.88 (s, 3H), 3.34 (s, 3H), 3.27 (s, 3H), 2.29 (s, 3H).

[0819] Example 72: Synthesis of 4-((3-fluoro-2-methoxyphenyl)amino)-6-((6-(3-methoxyazacyclobut-1-yl)pyridin-2-yl)amino)-2-methyl-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-94

[0820]

[0821] Compound I-94 was prepared from compound 55.1 and 6-(3-methoxyazacyclobut-1-yl)pyridine-2-amine using the procedure described in Example 2 (yield: 11.56%), MS (ES): m / z 466.30 [M+H] + LCMS purity: 99.23%, HPLC purity: 99.29%, 1H NMR (DMSO-d6, 400MHz): 10.66 (s, 1H), 9.51 (s, 1H), 8.82 (s, 1H), 7.45-7.36 (m, 1H), 7.17-7.00 (m, 2H), 5.94-5.92 (d, J = 7.2Hz, 1H), 4.28 (s, 1H), 4.04 (s, 2H), 3.87 (s, 3H), 3.67 (s, 2H), 3.26 (s, 3H), 3.22 (s, 3H).

[0822] Example 73: 4-((3-chloro-2-methoxyphenyl)amino)-6-((5-fluoro-4-methylpyridin-2-yl)amino)-2-methyl-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-95

[0823]

[0824] Following the procedure used to prepare 1.91, 73.1 was obtained (yield: 70.71%). MS (ES): m / z 340.2 [M+H] + .

[0825] Compound I-95 was prepared from compound 73.1 and 5-fluoro-4-methylpyridin-2-amine using the procedure described in Example 2 (yield: 15.82%), MS (ES): m / z 429.27 [M+H] + LCMS purity: 95.01%, HPLC purity: 95.80%, 1H NMR (DMSO-d6, 400MHz): 9.84 (s, 1H), 8.86 (s, 1H), 8.17-8.13 (m, 1H), 7.95 (s, 1H), 7.56-7.54 (d, J = 8.0Hz, 1H), 7.25-7.17 (m, 2H), 6.95 (s, 1H), 3.79 (s, 3H), 3.27 (s, 3H), 2.26 (s, 3H).

[0826] Example 74: Synthesis of 4-((3-chloro-2-methoxyphenyl)amino)-6-((2,6-dimethylpyrimidin-4-yl)amino)-2-methyl-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-96

[0827]

[0828] Compound I-96 was prepared from compound 73.1 and 2,6-dimethylpyrimidin-4-amine using the procedure described in Example 2 (yield: 14.34%), MS (ES): m / z 426.40 [M+H] + LCMS purity: 96.62%, HPLC purity: 96.51%, 1H NMR (DMSO-d6, 400MHz): 10.13 (s, 1H), 8.91 (s, 1H), 8.18 (s, 1H), 7.63-7.60 (d, J = 4.8 Hz, 1H), 7.49 (s, 1H), 7.45 (s, 1H), 7.24-7.23 (d, J = 4.8 Hz, 2H), 3.82 (s, 3H), 3.31 (s, 3H), 2.44 (s, 3H), 2.32 (s, 3H).

[0829] Example 75: Synthesis of 4-((3-chloro-2-methoxyphenyl)amino)-6-((4-(methoxymethyl)pyridin-2-yl)amino)-2-methyl-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-97

[0830]

[0831] Compound I-97 was prepared from compound 73.1 and 4-(methoxymethyl)pyridine-2-amine using the procedure described in Example 2 (yield: 12.82%), MS (ES): m / z 441.29 [M+H] + LCMS purity: 98.70%, HPLC purity: 98.80%, 1H NMR (DMSO-d6, 400MHz): 10.78 (s, 1H), 9.83 (s, 1H), 8.88 (s, 1H), 8.21 (s, 1H), 7.97 (s, 1H), 7.59 (s, 1H), 7.25-7.23 (d, J = 7.6Hz, 3H), 6.87 (s, 1H), 4.44 (s, 2H), 3.83 (s, 3H), 3.36 (s, 3H), 3.29 (s, 3H).

[0832] Example 76: Synthesis of 6-((4-((3-chloro-2-methoxyphenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)amino)nicotinonitrile, I-98

[0833]

[0834] Compound I-98 was prepared from compound 73.1 and 6-aminonicotinonitrile using the procedure described in Example 2 (yield: 13.40%), m / z 422.32 [M+H]. + LCMS purity: 98.00%, HPLC purity: 97.94%, 1H NMR (DMSO-d6, 400MHz): 11.01 (s, 1H), 10.44 (s, 1H), 8.91 (s, 1H), 8.70 (s, 1H), 8.23–8.16 (m, 2H), 7.59–7.57 (d, J = 8.0 Hz, 1H), 7.27–7.24 (m, 2H), 7.14 (s, 1H), 3.82 (s, 3H), 3.31 (s, 3H).

[0835] Example 77: Synthesis of 6-((4-((3-chloro-2-methoxyphenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)amino)pyridinecarboxylon, I-99

[0836]

[0837] Compound I-99 was prepared from compound 73.1 and 6-aminopyridinecarboxynitrile using the procedure described in Example 2 (yield: 13.14%), m / z 422.35 [M+H]. +LCMS purity: 95.93%, HPLC purity: 95.55%, 1H NMR (DMSO-d6, 400MHz): 10.87 (s, 1H), 10.33 (s, 1H), 8.98 (s, 1H), 8.04 (s, 1H), 7.91 (s, 1H), 7.67 (s, 1H), 7.56 (s, 1H), 7.50 (s, 1H), 7.27-7.24 (m, 2H), 3.83 (s, 3H), 3.31 (s, 3H).

[0838] Example 78: Synthesis of 4-((2-methoxy-4-(methoxymethyl)phenyl)amino)-6-((5-methoxy-6-(trifluoromethyl)pyridin-2-yl)amino)-2-methyl-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-104

[0839]

[0840] Compound I-104 was prepared from compound 70.1 and 5-methoxy-6-(trifluoromethyl)pyridine-2-amine using the procedure described in Example 2 (yield: 11.52%), MS (ES): m / z 505.36 [M+H + LCMS purity: 97.99%, HPLC purity: 96.46%, 1H NMR (DMSO-d6, 400MHz): 7.82-7.80 (d, J = 9.2Hz, 1H), 7.32-7.23 (m, 3H), 7.10 (s, 1H), 6.98-6.96 (d, J = 8.0Hz, 1H), 4.39 (s, 2H), 3.85 (s, 3H), 3.79 (s, 3H), 3.57 (s, 3H), 3.29 (s, 3H).

[0841] Example 79: Synthesis of 4-((3-chloro-2-methoxyphenyl)amino)-2-methyl-6-((6-methylpyridazin-3-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-105

[0842]

[0843] Compound I-105 was prepared from compound 73.1 and 6-methylpyridazine-3-amine using the procedure described in Example 2 (yield: 5.49%), m / z 412.29 [M+H]. +LCMS purity: 97.66%, HPLC purity: 95.98%, 1H NMR (DMSO-d6, 400MHz): 10.21 (s, 1H), 8.87 (s, 1H), 8.29 (s, 1H), 7.56 (s, 1H), 7.48-7.46 (d, J = 9.2Hz, 1H), 7.21-7.20 (d, J = 4.0Hz, 1H), 7.11-7.09 (d, J = 8.8Hz, 1H), 6.69-6.67 (d, J = 9.2Hz, 1H), 6.10 (s, 1H), 3.81 (s, 3H), 3.27 (s, 3H), 2.34 (s, 3H).

[0844] Example 80: Synthesis of 6-((4-((3-chloro-2-methoxyphenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)amino)pyrazin-2-carboxynitrile, I-117

[0845]

[0846] Compound I-117 was prepared from compound 73.1 and 6-methylpyridazine-3-amine using the procedure described in Example 2 (yield: 21.39%), m / z 423.27 [M+H]. + LCMS purity: 96.80%, HPLC purity: 95.08%, 1H NMR (DMSO-d6, 400MHz): 10.96 (s, 1H), 10.65 (s, 1H), 9.31 (s, 1H), 8.93 (s, 1H), 8.64 (s, 1H), 7.61-7.59 (d, J = 4.0 Hz, 1H), 7.35 (s, 1H), 7.27-7.23 (m, 2H), 3.86 (s, 3H), 3.30 (s, 3H).

[0847] Example 81: Synthesis of N-(4-((3,4-difluoro-2-methoxyphenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropanecarboxamide, I-127

[0848]

[0849] Following the procedure used to prepare 1.91, 81.1 was obtained (yield: 63.99%). MS (ES): m / z 341.7 [M+H] + .

[0850] Compound I-127 was prepared from compound 81.1 and cyclopropaneformamide using the procedure described in Example 2 (yield: 17.5%), m / z 390.27 [M+H]. + LCMS purity: 99.27%, HPLC purity: 99.63%, 1H NMR (DMSO-d6, 400MHz): 10.72 (s, 2H), 8.55 (s, 1H), 7.49 (s, 1H), 7.29–7.20 (m, 2H), 3.89 (s, 3H), 3.28 (s, 3H), 1.99–1.95 (m, 1H), 0.77–0.75 (d, J = 6.4 Hz, 4H).

[0851] Example 82: N-(4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2-(methyl-d3)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropanecarboxamide, I-100

[0852]

[0853] Compound 82.1 was synthesized. Thionyl chloride (1.2 mL) was added to 2,4,6-nicotinic acid (0.25 g, 1.10 mmol, 1.0 equivalent), followed by N,N-dimethylformamide (catalytic amount), and refluxed for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain the acid chloride. Methylhydrazine sulfate d3 (0.16 g, 1.10 mmol, 1.0 equivalent) was dissolved in dichloromethane (5 mL), followed by the addition of sodium hydroxide (0.18 g, 4.40 mmol, 4.0 equivalent) in water (1.2 mL). The previously prepared acid chloride solution in dichloromethane was added dropwise to this solution, and the reaction mixture was refluxed for 15 minutes. After the reaction was complete, the reaction mixture was transferred to water and extracted with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain the crude substance. Further purification was performed by column chromatography, with the product eluted in 30% ethyl acetate / hexane to give pure 1.1g (0.2g, 70.35%). MS (ES): m / z 258.5 [M+H] + .

[0854] Compound 82.2 was synthesized. Sodium carbonate (0.083 g, 0.776 mmol, 1.0 equivalent) was added to a suspension of 83.1 (0.2 g, 0.776 mmol, 1.0 equivalent) in 1-pentanol (5 mL), and the reaction mixture was stirred at 120 °C for 18 h. After the reaction was complete, the reaction mixture was cooled to room temperature, and the pH was adjusted to 6 using 1 N hydrochloric acid. The reaction mixture was concentrated under reduced pressure to obtain a crude product. This crude product was further purified by preparative HPLC using a gradient method with water / acetonitrile containing 0.1% formic acid to obtain pure 1.2 (0.085 g, 49.51%). MS (ES): m / z 222.06 [M+H] + .

[0855] Compound 82.3 was synthesized following the procedure used to prepare 1.91, yielding 82.3 (yield: 30.78%). MS (ES): m / z 390.82 [M+H] + .

[0856] Compound I-100 (0.025 g, yield: 23.40%) was prepared from compound 82.3 and cyclopropaneformamide using the procedure described in Example 2. MS (ES): m / z 439.42 [M+H] + LCMS purity: 99.10%, HPLC purity: 97.85%, 1H NMR (DMSO-d6, 400MHz): 10.79 (s, 2H), 8.89 (s, 1H), 7.81 (s, 1H), 7.68-7.64 (t, J = 8.0Hz, 2H), 7.40-7.36 (t, J = 8.0Hz, 1H), 4.47 (s, 3H), 3.77 (s, 3H), 2.02 (s, 1H), 0.81 (s, 4H).

[0857] Example 83: Synthesis of 3-((6-(cyclopropaneformamido)-2-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-4-yl)amino)-2-methoxybenzamide, I-102

[0858]

[0859] Compound 83.1 was synthesized. Potassium carbonate (7.0 g, 50.76 mmol, 2.0 equivalent) was added to a solution of methyl 2-hydroxy-3-nitrobenzene (5.0 g, 25.36 mmol, 1.0 equivalent) in N,N-dimethylformamide (50 mL) at 0 °C, and the mixture was stirred for 15 min. Iodomethane (7.2 g, 50.76 mmol, 2 equivalent) was added dropwise to this solution, and the reaction mixture was stirred at 60 °C for 2 h. After the reaction was complete, the reaction mixture was transferred to ice water, and the precipitate was filtered off and dried thoroughly to give 83.1 (5.0 g, 93%). MS (ES): m / z 212.2 [M+H] + .

[0860] Compound 83.2 was synthesized. Ammonia (30 mL) was added to 83.1 (5 g, 23.67 mmol, 1.0 equivalence), followed by a methanol-ammonia solution (160 mL). The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the residue was washed with ice-cold water. The solid was dried thoroughly to give 83.2 (4.5 g, 96%). MS (ES): m / z 197.2 [M+H] + .

[0861] Compound 83.3 was synthesized. 10% palladium / charcoal (1.0 g) was added to a solution of 83.2 (4.5 g, 22.94 mmol, 1.0 equivalent) in methanol (45 mL). The reaction mixture was purged with hydrogen for 4 hours. 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 83.3 (3.0 g, 78.69%). MS (ES): m / z 167.18 [M+H] + .

[0862] Compound 83.4 was synthesized following the procedure used to prepare 1.91, yielding 84.4 (yield: 62.70%). MS (ES): m / z 348.76 [M+H] + .

[0863] Compound I-102 was prepared from compound 83.4 and cyclopropaneformamide using the procedure described in Example 2 (yield: 2.63%). MS (ES): m / z 397.41 [M+H] +LCMS purity: 98.76%, HPLC purity: 98.65%, 1H NMR (DMSO-d6, 400MHz): 10.81 (s, 1H), 8.56 (s, 1H), 8.12 (s, 1H), 7.69-7.68 (d, J = 6.4 Hz, 1H), 7.65-7.63 (d, J = 8.0 Hz, 1H), 7.57-7.55 (d, J = 8.0 Hz, 1H), 6.95-6.91 (t, J = 8.0 Hz, 1H), 3.29 (s, 3H), 3.27 (s, 3H), 1.49-1.46 (m, 1H), 0.78-0.77 (m, 4H).

[0864] Example 84: Synthesis of 3-((6-((2,6-dimethylpyrimidin-4-yl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-4-yl)amino)-2-methoxybenzamide, I-103

[0865]

[0866] Compound 84.1 was prepared from compound 84 and 2,6-dimethylpyrimidin-4-amine using the procedure described in Example 2 (yield: 19.00%). MS (ES): m / z 417.45 [M+H] + .

[0867] Compound I-103 was synthesized. Sulfuric acid (2 mL) was added to 84.1 (0.120 g, 0.363 mmol, 1 equivalent), and the mixture was stirred at 60 °C for 1 hour. After the reaction was complete, water and ammonia were added to the reaction mixture, and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure to obtain a crude product. Further purification was performed by preparative HPLC using a gradient method with water / acetonitrile containing 0.1% formic acid to obtain pure I-84 (0.02 g, yield: 15.98%). MS (ES): m / z 435.46 [M+H] + LCMS purity: 100.00%, HPLC purity: 95.03%, 1H NMR (DMSO-d6, 400MHz): 14.19 (s, 1H), 10.15 (s, 1H), 8.61 (s, 2H), 8.15 (s, 1H), 7.73-7.65 (d, J = 7.6Hz, 2H), 7.48 (s, 2H), 6.97-6.93 (t, J = 8.0Hz, 1H), 3.34 (s, 3H), 3.29 (s, 3H), 2.43 (s, 3H), 2.34 (s, 3H).

[0868] Example 85: Synthesis of 4-((2-methoxy-4-(methoxymethyl)phenyl)amino)-6-((5-methoxy-6-(trifluoromethyl)pyridin-2-yl)amino)-2-methyl-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-106

[0869]

[0870] Compound 85.1 was prepared from compound 85 and 5-fluoro-4-methylpyridin-2-amine using the procedure described in Example 2 (yield: 19.65%). MS (ES): m / z 420.42 [M+H] + .

[0871] Compound I-106 was synthesized. Sulfuric acid (2 mL) was added to 85.1 mL (0.125 g, 0.298 mmol, 1 equivalent), and the mixture was stirred at 60 °C for 1 hour. After the reaction was complete, water and ammonia were added to the reaction mixture, and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure to obtain a crude product. Further purification was performed by preparative HPLC using a gradient method with water / acetonitrile containing 0.1% formic acid to obtain pure I-106 (0.022 g, yield: 16.88%). MS (ES): m / z 438.44 [M+H] + LCMS purity: 98.97%, HPLC purity: 96.36%, 1H NMR (DMSO-d6, 400MHz): 14.21 (bs, 1H), 9.84 (s, 1H), 8.64 (s, 1H), 8.56 (s, 1H), 8.15-8.11 (m, 2H), 8.02-8.01 (d, J = 5.6Hz, 1H), 7.66-7.61 (d, J = 8.0Hz, 2H), 7.00-6.92 (m, 2H), 3.32 (s, 3H), 3.24 (s, 3H), 2.28 (s, 3H).

[0872] Example 86: Synthesis of 6-((5-fluoro-4-methylpyridin-2-yl)amino)-2-methyl-4-((2-(methanesulfonyl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-107

[0873]

[0874] Following the procedure used to prepare 1.91, 86.1 was obtained (yield: 76.89%). MS (ES): m / z 321.80 [M+H] + .

[0875] Compound 86.2 was synthesized. 30% hydrogen peroxide (3.83 g, 112.8 mmol, 20 equivalents) and sodium tungstate dihydrate (1.85 g, 5.64 mmol, 1 equivalent) were added to a solution of 86.1 (1.81 g, 5.64 mmol, 1 equivalent) in acetic acid (2.5 mL). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was transferred to ice water, and the precipitate was filtered off, washed with 50% ethyl acetate / hexane, and dried thoroughly to give 86.2 (1.25 g, yield: 62.80%). MS (ES): m / z 353.79 [M+H] + .

[0876] Compound I-107 (0.060 g, yield: 31.89%) was prepared from compound 86.2 and 5-fluoro-4-methylpyridin-2-amine using the procedure described in Example 2. MS (ES): m / z 443.47 [M+H] + LCMS purity: 99.63%, HPLC purity: 99.37%, 1H NMR (DMSO-d6, 400MHz): 10.72 (s, 1H), 9.76 (s, 1H), 9.06 (s, 1H), 8.07 (s, 1H), 7.93-7.91 (d, J = 7.2Hz, 2H), 7.84-7.77 (m, 2H), 7.39-7.36 (t, J = 7.2Hz, 1H), 6.94 (s, 1H), 3.25 (s, 3H), 3.16 (s, 3H), 2.25 (s, 3H).

[0877] Example I-87: Synthesis of 6-((2,6-dimethylpyrimidin-4-yl)amino)-2-methyl-4-((2-(methanesulfonyl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-109

[0878]

[0879] Compound I-109 was prepared from compound 86.2 and 2,6-dimethylpyrimidin-4-amine using the procedure described in Example 2 (yield: 27.52%), MS (ES): m / z 440.40 [M+H] +LCMS purity: 98.42%, HPLC purity: 95.04%, 1H NMR (DMSO-d6, 400MHz): 10.84 (bs, 1H), 10.09 (s, 1H), 9.15 (s, 1H), 7.94-7.92 (dd, J = 1.2Hz, 8.0Hz, 1H), 7.87-7.85 (d, J = 8.0Hz, 1H), 7.81-7.77 (t, J = 8.0Hz, 1H), 7.44-7.34 (m, 3H), 3.27 (s, 3H), 3.16 (s, 3H), 2.37 (s, 3H), 2.29 (s, 3H).

[0880] Example 88: Synthesis of 2-methyl-6-((6-methylpyridazin-3-yl)amino)-4-((2-(methanesulfonyl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-109

[0881]

[0882] Compound I-109 was prepared from compound 86.2 and 6-methylpyridazine-3-amine using the procedure described in Example 2 (yield: 32.58%), MS (ES): m / z 426.19 [M+H]. + LCMS purity: 97.90%, HPLC purity: 96.09%, 1H NMR (DMSO-d6, 400MHz): 10.59 (bs, 1H), 10.17 (s, 1H), 9.09 (s, 1H), 8.19 (s, 1H), 7.94–7.92 (d, J = 8.0 Hz, 1H), 7.84–7.75 (m, 2H), 7.47–7.38 (m, 2H), 6.95 (s, 1H), 3.171 (s, 3H), 3.059 (s, 3H), 2.314 (s, 3H).

[0883] Example 89: Synthesis of 6-((4-(methoxymethyl)pyridin-2-yl)amino)-2-methyl-4-((2-(methanesulfonyl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-110

[0884]

[0885] Compound I-110 was prepared from compound 86.2 and 4-(methoxymethyl)pyridine-2-amine using the procedure described in Example 2 (yield: 14.42%), MS (ES): m / z 455.20 [M+H] +LCMS purity: 94.46%, HPLC purity: 95.28%, 1H NMR (DMSO-d6, 400MHz): 11.62 (s, 1H), 9.24 (s, 1H), 8.32-8.30 (d, J = 6.4Hz, 1H), 8.00-7.98 (d, J = 7.2Hz, 1H), 7.84-7.80 (m, 2H), 7.51 (t, 1H), 7.24-7.19 (m, 2H), 6.21 (s, 1H), 4.59 (s, 2H), 3.39 (s, 3H), 3.36 (s, 3H), 3.19 (s, 3H).

[0886] Example 90: Synthesis of 2-methyl-6-((5-methylpyridin-2-yl)amino)-4-((2-(methanesulfonyl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-111

[0887]

[0888] Compound I-111 was prepared from compound 86.2 and 5-methylpyridin-2-amine using the procedure described in Example 2 (yield: 20.78%), MS (ES): m / z 425.19 [M+H]. + LCMS purity: 97.76%, HPLC purity: 96.61%, 1H NMR (MeOD, 400MHz): 8.14 (s, 1H), 8.06-8.04 (d, J = 8.0Hz, 1H), 7.82-7.76 (m, 2H), 7.63-7.61 (d, J = 8.0Hz, 1H), 7.49-7.46 (t, J = 6.8Hz, 1H), 6.90 (s, 1H), 5.81 (s, 1H), 3.56 (s, 3H), 3.34 (s, 1H), 3.11 (s, 3H), 2.30 (s, 3H).

[0889] Example 91: Synthesis of 6-((2-methyl-4-((2-(methanesulfonyl)phenyl)amino)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)amino)pyridinecarboxynitrile, I-112

[0890]

[0891] Compound I-112 was prepared from compound 86.2 and 6-aminopyridinecarboxynitrile using the procedure described in Example 2 (yield: 23.15%), MS (ES): m / z 436.35 [M+H] +LCMS purity: 100.00%, HPLC purity: 100.00%, 1H NMR (DMSO-d6, 400MHz): 10.81 (s, 1H), 10.28 (s, 1H), 9.18 (s, 1H), 8.05-8.03 (d, J = 8.8Hz, 1H), 7.94-7.80 (m, 4H), 7.52-7.50 (d, J = 7.2Hz, 1H), 7.41-7.38 (t, J = 7.2Hz, 1H), 7.24 (s, 1H), 3.27 (s, 3H), 3.16 (s, 3H).

[0892] Example 92: Synthesis of 4-((3-chloro-2-methoxyphenyl)amino)-2-methyl-6-((5-(pyrrolidine-1-carbonyl)-6-(trifluoromethyl)pyridin-2-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-128

[0893]

[0894] Compound 92.1 was synthesized. Zinc cyanide (1.456 g, 12.45 mmol, 1.0 equivalent) was added to dimethylformamide (1 ml) containing 5-bromo-6-(trifluoromethyl)pyridine-2-amine (3.0 g, 12.45 mmol, 1.0 equivalent). The reaction mixture was then heated in a microwave at 150 °C for 15 min. After the reaction was complete, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give the crude compound. Further purification was performed by column chromatography, eluting the compound in 20% ethyl acetate / hexane to give 92.1 (yield: 68.69%). MS (ES): m / z 188.13 [M+H] + .

[0895] Compound 92.2 was synthesized. Water (30 mL) was added to compound 92.1 (1.6 g, 8.55 mmol, 1.0 equivalent) and sodium hydroxide (1.0 g, 25.65 mmol, 3.0 equivalent), and the reaction mixture was stirred at 100 °C for 16 hours. After the reaction was complete, the reaction mixture was extracted with ethyl acetate. The aqueous layer was acidified with hydrochloric acid and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give the crude substance. Further purification was performed by column chromatography, eluting the compound in 5% methanol / dichloromethane to give 93.2 (yield: 62.41%). MS (ES): m / z 207.12 [M+H] + .

[0896] Compound 92.3 was synthesized. A cooled solution of 92.2 (0.5 g, 2.43 mmol, 1.0 equivalent) and pyrrolidine (0.19 g, 2.67 mmol, 1.1 equivalent) in N,N-dimethylformamide (5 mL) was added with ((1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate)) (1.846 g, 4.86 mmol, 2.0 equivalent), followed by N,N-diisopropylethylamine (0.94 g, 7.29 mmol, 3.0 equivalent), and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was transferred to water and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give the crude product. Further purification was performed by column chromatography, eluting the compound in 3% methanol / dichloromethane to give a pure 92.3 g (0.39 g, 62.34%). MS (ES): m / z 260.23 [M+H] + .

[0897] Compound I-128 was prepared from compounds 73.1 and 93.3 using the procedure described in Example 2 (yield: 10.06%). MS (ES): m / z 563.35 [M+H] + LCMS purity: 90.57%, HPLC purity: 94.43%, 1H NMR (DMSO-d6, 400MHz): 10.91 (bs, 1H), 10.36 (s, 1H), 8.97 (s, 1H), 8.18-8.16 (d, J = 8.4Hz, 1H), 7.89-7.87 (d, J = 8.4Hz, 1H), 7.58-7.55 (dd, J = 1.6Hz, 7.6Hz, 1H), 7.30 (s, 1H), 7.21-7.14 (m, 2H), 3.81 (s, 3H), 3.45-3.42 (m, 2H), 3.29 (s, 3H), 3.12-3.08 (m, 2H), 1.88-1.79 (m, 4H).

[0898] Example 93: Synthesis of 4-((3-chloro-2-methoxyphenyl)amino)-2-methyl-6-((5-(morpholin-4-carbonyl)-6-(trifluoromethyl)pyridin-2-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-130

[0899]

[0900] Compound 93.1 was synthesized. A cooled solution of 6-amino-2-(trifluoromethyl)nicotinic acid (0.5 g, 2.43 mmol, 1.0 equivalent) and morpholine (0.23 g, 2.67 mmol, 1.1 equivalent) in N,N-dimethylformamide (5 mL) was added to ((1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate)) (1.846 g, 4.86 mmol, 2.0 equivalent), followed by N,N-diisopropylethylamine (0.94 g, 7.29 mmol, 3.0 equivalent), and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was transferred to water and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to obtain the crude substance. Further purification was performed by column chromatography, eluting the compound in 3% methanol / dichloromethane to give a pure 93.1 g (0.4 g, 59.91%). MS (ES): m / z 276.23 [M+H] + .

[0901] Compound I-130 was prepared from compounds 73.1 and 93.1 using the procedure described in Example 2 (yield: 30.52%), MS (ES): m / z 578.41 [M+H]. + LCMS purity: 97.65%, HPLC purity: 97.61%, 1H NMR (DMSO-d6, 400MHz): 10.89 (s, 1H), 10.38 (s, 1H), 8.97 (s, 1H), 8.17-8.15 (d, J = 8.4 Hz, 1H), 7.87-7.84 (d, J = 8.8 Hz, 1H), 7.57-7.56 (d, J = 7.6 Hz, 1H), 7.32 (s, 1H), 7.22-7.14 (m, 2H), 3.81 (s, 3H), 3.66-3.42 (m, 6H), 3.29 (s, 3H), 3.19-3.15 (m, 2H).

[0902] Example 94: Synthesis of 6-((4-((3-chloro-2-methoxyphenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)amino)-3-methylpyridinecarboxynitrile, I-132

[0903]

[0904] Compound 94.1 was synthesized. Zinc cyanide (1.35 g, 11.56 mmol, 1.0 equivalent) was added to dimethylformamide (1 ml) containing 6-bromopyridin-2-amine (2.0 g, 11.56 mmol, 1.0 equivalent). The reaction mixture was then heated in a microwave at 150 °C for 15 min. After the reaction was complete, the reaction mixture was transferred to water and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give the crude compound. Further purification was performed by column chromatography, eluting the compound in 20% ethyl acetate / hexane to give 94.1 (1.0 g, yield: 72.62%). MS (ES): m / z 120.13 [M+H] + .

[0905] Compound 94.2 was synthesized. N-bromosuccinimide (2.24 g, 12.58 mmol, 1.5 equivalents) was added to acetonitrile containing compound 94.1 (1.0 g, 8.39 mmol, 1.0 equivalent). The reaction mixture was stirred at room temperature for 12 hours. After the reaction was complete, the reaction mixture was transferred to water and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give the crude product. Further purification was performed by column chromatography, eluting the compound in 25% ethyl acetate / hexane to give 94.2 (0.42 g, yield: 25.27%). MS (ES): m / z 199.02 [M+H] + .

[0906] Compound 94.3 was synthesized. A solution of 94.2 (0.42 g, 2.12 mmol, 1.0 equivalent) in a mixture of water (5 mL) and 1,4-dioxane (15 mL) was added with trimethylborooxycyclohexane (0.4 g, 3.18 mmol, 1.5 equivalent), tetrakis (0.073 g, 0.064 mmol, 0.03 equivalent), and potassium carbona...

Claims

1. A compound of formula Xa, Xa Or its pharmaceutically acceptable salt, wherein: R 1 is H or D; R 2 -N(R)C(O)Cy 2 or -N(R)Cy 2 ; R 3 is H or C 1-6 aliphatic; Cy 1 is one of the following: ； Each Cy 2 Independently comprising a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 3- to 7-membered saturated monocyclic carbocyclic ring; wherein Cy 2 After p R 6 Instance replacement; Cy 3 is a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein Cy 3 is substituted by r instances of R 8 is an example substituent; R 6 independently at each occurrence is R A or R B , and q R C instances of substitution; R A independently at each occurrence is halogen, -CN, -OR, -OR D , -C(O)OR; R B independently at each occurrence is C 1-6 aliphatic; R C independently at each occurrence is halogen, -CN, -OR, or C 1-6 aliphatic group; each R is independently hydrogen or C 1-6 aliphatic; Each of p and q is independently 0, 1, 2 or 3; r is 1, 2, or 3; R 8 independently at each occurrence is R A , and q R C instance substitution; or R 8 independently at each occurrence is R B ', and is substituted with q' instances of R C ' R B ’independently at each occurrence is C 1-6 aliphatic; R C ’independently at each occurrence is -CN, -OR’, or C 1-6 aliphatic; each R' is independently C 1-6 aliphatic; q' is 0, 1, 2, or 3; and R D is C 1-4 aliphatic, wherein one or more hydrogens are replaced by deuterium.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Cy 3 is a 5-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein Cy 3 is r R 8 Examples of substitution.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 2 is -N(H)C(O)Cy 2 .

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Cy 2 is selected from the following: ； each of which is p R 6 Example substitutions.

5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 2 is .

6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Cy 3 is selected from the following: each of which is substituted by r R 8 Examples of substitutions.

7. A compound selected from the group consisting of, or a pharmaceutically acceptable salt thereof:

8. A pharmaceutical composition comprising a compound according to any one of claims 1-7 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or mediator.

9. Use of the compound according to any one of claims 1-7 in the preparation of a medicament for treating TYK2-mediated conditions, diseases, or symptoms in patients.

10. The use according to claim 9, wherein the disease is selected from autoimmune diseases, inflammatory diseases, proliferative diseases, endocrine diseases, neurological diseases, or transplant-related diseases.

11. The use according to claim 9, wherein the condition is psoriasis, psoriatic arthritis, Crohn's disease, and ulcerative colitis.

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