Tyk2 inhibitors and uses thereof

Abstract

The present invention provides compounds, compositions thereof, and methods of using the same to inhibit TYK2 and treat TYK2-mediated disorders. The compounds provided by the present invention can also be used to study TYK2 enzymes in biological and pathological phenomena; to study intracellular signal transduction pathways present in cells of the body; and to comparatively evaluate new TYK2 inhibitors or other kinase, signaling pathway, and cytokine level modulators in vitro or in vivo.

Description

[0001] Cross-references to related applications

[0002] This application claims priority to U.S. Provisional Application Serial No. 62 / 745,642, filed October 15, 2018; U.S. Provisional Application Serial No. 62 / 795,869, filed January 23, 2019; and U.S. Provisional Application Serial No. 62 / 820,509, filed March 19, 2019, the entire contents of each of which are incorporated herein by reference. Technical Field

[0003] 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

[0004] In recent years, a better understanding of the structures of disease-related enzymes and other biomolecules has greatly aided research into new therapeutic agents. One important class of enzymes that has been extensively studied is the protein kinase family.

[0005] Protein kinases constitute a large family of structure-associated enzymes responsible for controlling various intracellular signal transduction processes. Due to the conservation of their structure and catalytic function, protein kinases are believed to have evolved from a common ancestral gene. Almost all kinases contain similar catalytic domains of 250-300 amino acids. Kinases can be classified into families based on their phosphorylated substrates (e.g., protein-tyrosine, protein-serine / threonine, lipids, etc.).

[0006] Typically, protein kinases mediate intracellular signaling by influencing the transfer of phosphoryl groups from nucleosides (NPs) to protein receptors involved in signal transduction pathways. These phosphorylation events act as molecular on / off switches that can regulate or modulate the biological functions of target proteins. These phosphorylation events are ultimately triggered in response to a variety of extracellular and other stimuli. Examples of such stimuli include environmental and chemical stress signals (e.g., osmotic shock, heat shock, ultraviolet radiation, bacterial endotoxins, and H2O2), cytokines (e.g., interleukin-1 (IL-1), interleukin-8 (IL-8), and tumor necrosis factor-α (TNF-α)), and growth factors (e.g., granulocyte-macrophage colony-stimulating factor (GM-CSF) and fibroblast growth factor (FGF)). Extracellular stimuli can affect one or more cellular responses related to cell growth, migration, differentiation, hormone secretion, transcription factor activation, muscle contraction, glucose metabolism, protein synthesis control, and cell cycle regulation.

[0007] 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

[0008] It has now been found that the compounds of the present invention and their pharmaceutically acceptable compositions are effective as TYK2 kinase inhibitors.

[0009] The compounds of this invention and their pharmaceutically acceptable compositions may be used to treat a variety of diseases, conditions, or symptoms associated with the regulation of signaling pathways involving TYK2 kinases. Such diseases, conditions, or symptoms include those described herein.

[0010] The compounds provided by this invention can also be used for: the study of TYK2 enzymes in biological and pathological phenomena; the study of intracellular signal transduction pathways present in body tissues; and the in vitro or in vivo comparative evaluation of new TYK2 inhibitors or other kinases, signal transduction pathways and cytokine level regulators. Detailed Implementation

[0011] 1. General description of certain embodiments of the present invention:

[0012] The compounds and compositions thereof of the present invention can be used as TYK2 protein kinase inhibitors.

[0013] The pseudokinase binding pocket of TYK2 contains multiple hydration sites, each occupied by a single water molecule. Each of these water molecules has an associated stability grade. As used herein, the term "stability grade" refers to a numerical calculation incorporating the enthalpy, entropy, and free energy values ​​associated with each water molecule. This stability grade allows for a measurable determination of the relative stability of the water molecules occupying the hydration sites within the TYK2 binding pocket.

[0014] Water molecules with a stability level >2.5 kcal / mol that occupy hydration sites in the binding pocket of TYK2 are called "unstable water".

[0015] Without being bound by any particular theory, it is believed that the substitution or disruption of unstable water molecules (i.e., water molecules with a stability class > 2.5 kcal / mol) or the replacement of stable water molecules (i.e., water molecules with a stability class < 1 kcal / mol) by the inhibitor leads to a more tightly bound inhibitor. Therefore, inhibitors designed to replace one or more unstable water molecules (i.e., those unstable water molecules not replaced by any known inhibitor) will be tighter binders and thus more potent inhibitors compared to those that do not replace unstable water molecules.

[0016] 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.

[0017] In some embodiments, the present invention provides a compound of formula I:

[0018]

[0019] Or a pharmaceutically acceptable salt thereof, wherein R 1 R 2 R 3 and R 4 Each of these is defined below and described individually and in combination in the embodiments herein.

[0020] In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable carrier, adjuvant, or diluent.

[0021] In some embodiments, the present invention provides a method for treating TYK2-mediated diseases, conditions, or symptoms, the method comprising administering a compound of formula I or a pharmaceutically acceptable salt thereof to a patient in need.

[0022] 2. Compounds and definitions:

[0023] The compounds of this invention comprise those generally described herein and further illustrated by the categories, subclasses, and species disclosed herein. Unless otherwise indicated, the following definitions as used herein shall apply. 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. Additionally, the general principles of organic chemistry are described in the following: “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.

[0024] As used herein, the term "aliphatic" or "aliphatic group" means a fully saturated or branched, substituted or unsubstituted, straight-chain (i.e., unbranched) or branched hydrocarbon chain containing one or more unsaturated units, or a fully saturated or aromatic monocyclic or bicyclic hydrocarbon (also referred to herein as "carbocyclic," "alicyclic," or "cycloalkyl") containing one or more unsaturated units but not having a single connection point with the rest of the molecule. Unless otherwise stated, an aliphatic group contains 1-6 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1-5 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1-4 aliphatic carbon atoms. In still other embodiments, an aliphatic group contains 1-3 aliphatic carbon atoms, and in yet another embodiment, an aliphatic group contains 1-2 aliphatic carbon atoms. In some embodiments, "alicyclic" (or "carbocyclic" or "cycloalkyl") means a fully saturated or aromatic monocyclic C3-C6 hydrocarbon containing one or more unsaturated units but not having a single connection point with 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 their hybrids, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0025] As used herein, the term "bridged bicyclic" refers to any bicyclic system having at least one bridge, i.e., a carbocyclic or heterocyclic system, saturated or partially unsaturated. As defined by IUPAC, a "bridge" is an unbranched chain of atoms or an atom or valence bond connecting two bridgeheads, wherein a "bridgehead" is any skeletal atom of the ring system bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, the bridged bicyclic group has 7-12 ring members and 0-4 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 connected to the remainder of the molecule at any substituted carbon or nitrogen atom. Unless otherwise stated, the bridged bicyclic group is optionally substituted with one or more substituents set forth for aliphatic groups. Additionally or alternatively, any substituted nitrogen atom in the bridged bicyclic group is optionally substituted. Exemplary bridged bicyclics comprise:

[0026]

[0027] The term "lower alkyl" refers to C 1-4 Straight-chain or branched alkyl groups. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0028] The term "lower haloalkyl" refers to a C-aryl group that has been substituted with one or more halogen atoms. 1-4 Straight-chain or branched alkyl groups.

[0029] The term "heteroatom" refers to 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).

[0030] As used in this article, the term "unsaturated" means that a part has one or more unsaturated units.

[0031] As used in this article, the term "divalent C" 1-8 (or C) 1-6 "Saturated or unsaturated straight or branched hydrocarbon chains" refers to straight or branched divalent alkylene, alkenylene, and ynylene chains as defined herein.

[0032] 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 the substituted aliphatic group.

[0033] 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 for substituted aliphatic groups.

[0034] The term "halogen" refers to F, Cl, Br, or I.

[0035] The term "aryl," used alone or as part of a larger part, as in "aralkyl," "arylalkoxy," or "aryloxyalkyl," refers to a monocyclic or bicyclic system having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic, and wherein each ring in the system contains three to seven ring members. The term "aryl" may be used interchangeably with the term "aryl ring." In some embodiments of the invention, "aryl" refers to an aromatic ring system comprising, but not limited to, phenyl, biphenyl, naphthyl, anthracene, etc., which may carry one or more substituents. As used herein, the scope of the term "aryl" also includes groups fused with an aromatic ring to one or more non-aromatic rings, such as indanyl, phthalimide, naphthalimide, phenanthridine, or tetrahydronaphthyl.

[0036] The terms "heteroaryl" and "heteroary-" used alone or as part of a larger group, such as "heteroarylalkyl" or "heteroarylalkoxy," refer to a group having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; sharing 6, 10, or 14π electrons in the ring array; and having one to five heteroatoms in addition to carbon atoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur and includes any oxidized form of nitrogen or sulfur, as well as any quaternized form of basic nitrogen. Heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrroleyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indenyl, purine, diazanaphthyl, and pteridinyl. As used herein, the terms "heteroaryl" and "heteroary-" also include groups fused with one or more aryl, alicyclic, or heterocyclic rings of a heteroaromatic ring, wherein, unless otherwise specified, the group or connecting point is located on the heteroaromatic ring or on one of the rings fused with the heteroaromatic ring. Non-limiting examples include indolyl, isoindolyl, benzothiamyl, benzofuranyl, dibenzofuranyl, indazoleyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, terpineyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinazinyl, carbazoleyl, acridineyl, phenazinyl, phenothiazinyl, phenotoxazinyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl. Heteroaryl groups can be monocyclic or bicyclic. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaryl aromatic," any of which includes an optionally substituted ring. The term "heteroarylalkyl" refers to an alkyl group substituted with a heteroaryl group, wherein the alkyl and heteroaryl portions are optionally substituted independently.

[0037] As used herein, the terms “heterocycle,” “heterocyclic group,” “heterocyclic ring,” and “heterocyclic ring” are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moiety that is saturated or partially unsaturated and has one or more, preferably one to four, heteroatoms in addition to a carbon atom, as defined above. When referring to the ring atom of the heterocycle, the term “nitrogen” includes substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur, or nitrogen, nitrogen can be N (e.g., in 3,4-dihydro-2H-pyrrole), NH (e.g., in pyrrolealkyl), or + NR (e.g., in N-substituted pyrroleyl groups).

[0038] The heterocycle can be attached to its side group at any heteroatom or carbon atom that produces a stable structure, and any ring atom in the ring atom can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic groups include, but are not limited to, tetrahydrofuranyl, tetrahydrophenylthiopyrrolyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazine, dioxacyclohexyl, dioxopentyl, diazaphenyl, oxazanyl, thioazanyl, morpholinyl, 2-oxa-6-azaspiro[3.3]heptane, and quininecycloyl. The terms “heterocyclic,” “heterocyclyl,” “heterocyclic ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic group” are used interchangeably herein and also include groups fused with one or more aryl, heteroaryl, or alicyclic rings, such as dihydroindolyl, 3H-indolyl, benzodihydropyranyl, phenanthridineyl, or tetrahydroquinolinyl. Heterocyclic groups can be monocyclic or bicyclic. The term “heterocyclic alkyl” refers to an alkyl group substituted with a heterocyclic group, wherein the alkyl and heterocyclic moiety are optionally substituted independently.

[0039] As used herein, the term "partially unsaturated" refers to a ring moiety containing 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 moietyes as defined herein.

[0040] As described herein, the compounds of the present invention may contain an "optionally substituted" portion. Whether or not the term "optionally" is preceding it, the term "substituted" generally 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 the group, and at each position, the substituents may be the same or different when more than one position in any given structure can be substituted by more than one substituent selected from the specified group. The substituent combinations contemplated in the present invention are preferably combinations that result in stable or chemically viable compounds. As used herein, the term "stable" means a compound that remains substantially unchanged when subjected to conditions that allow it to be produced, detected, and, in some embodiments, recovered, purified, and used for one or more of the purposes disclosed herein.

[0041] The suitable monovalent substituent on the substituted carbon atom of the "optionally substituted" group is independently: halogen; -(CH2). 0-4 R°;-(CH2) 0-4 OR°;-O(CH2) 0-4 R°;-O-(CH2) 0-4 C(O)OR;-(CH2)0-4 CH(OR°)2;-(CH2) 0- 4SR°;-(CH2) 0-4 Ph, which can be replaced by R°; -(CH2) 0-4 O(CH2) 0-1 Ph can be substituted by R°; -CH=CHPh can be substituted by R°; -(CH2) 0-4 O(CH2) 0-1 -Pyridyl group, which can be substituted by R°; -NO2; -CN; -N3; ​​-(CH2) 0-4 N(R°)2;-(CH2) 0-4 N(R°)C(O)R°;-N(R°)C(S)R°;-(CH2) 0-4 N(R°)C(O)NR°2;-N(R°)C(S)NR°2;-(CH2) 0-4 N(R°)C(O)OR°; -N(R°)N(R°)C(O)R°; -N(R°)N(R°)C(O)NR°2; -N(R°)N(R°)C(O)OR°; -N(R°)C(NR°)N(R°)2; -(CH2) 0-4 C(O)R°;-C(S)R°;-(CH2) 0-4 C(O)OR°;-(CH2) 0-4 C(O)SR°;-(CH2) 0-4 C(O)OSiR°3;-(CH2) 0-4 OC(O)R°;-OC(O)(CH2) 0-4 SR°;-SC(S)SR°;-(CH2) 0-4 SC(O)R°;-(CH2) 0-4 C(O)NR°2;-C(S)NR°2;-C(S)SR°;-SC(S)SR;-(CH2) 0-4 OC(O)NR°2; -C(O)N(OR°)R°; -C(O)C(O)R°; -C(O)CH2C(O)R°; -C(NOR°)R°; -(CH2) 0-4 SSR°;-(CH2) 0-4 S(O)2R°;-(CH2) 0-4 S(O)₂OR°;-(CH₂) 0-4 OS(O)2R°;-S(O)2NR°2;-(CH2) 0-4S(O)R°; -N(R°)S(O)2NR°2; -N(R°)S(O)2R°; -N(OR°)R°; -C(NH)NR°2; -P(O)2R°; -P(O)R°2; -OP(O)R°2; -OP(O)(OR°)2; -SiR°3; -(C 1-4 (linear or branched alkylene)ON(R°)2; or -(C 1-4 (straight-chain or branched alkylene)C(O)ON(R°)2, wherein each R° can be substituted as defined below and is independently hydrogen, C 1-6 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, -CH2- (5-6 membered heteroaryl ring) or a 5-6 membered saturated ring, partially unsaturated ring or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or, although defined above, two independently occurring R° together with one or more intermediate atoms to form a 3-12 membered saturated, partially unsaturated or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, said ring may be substituted as defined below.

[0042] A suitable monovalent substituent on R° (or a ring formed by two independently occurring R° atoms together with their intermediate atom) is independently a halogen, -(CH2). 0-2 R · -(halogenated R) · -(CH2) 0-2 OH, -(CH2) 0-2 OR · -(CH2) 0-2 CH(OR · )2、-O(halogenated R · -CN, -N3, -(CH2) 0-2 C(O)R · -(CH2) 0-2 C(O)OH, -(CH2) 0-2 C(O)OR · -(CH2) 0-2 SR · -(CH2) 0-2 SH, -(CH2) 0-2 NH2、-(CH2) 0-2 NHR · -(CH2) 0-2 NR · 2, -NO2, -SiR · 3. -OSiR · 3. -C(O)SR · -(C 1-4(straight-chain or branched alkylene)C(O)OR · or -SSR · , where each R · It is either unsubstituted or, in the case of being preceded by "halogenated," substituted by only one or more halogens and independently selected from C. 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph or a 5-6 membered saturated ring, partially unsaturated ring, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on the saturated carbon atom of R° include =O and =S.

[0043] 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; C that can be substituted as defined below. 1-6 Aliphatic; or an unsubstituted 5-6 membered saturated ring, partially unsaturated ring, or aryl ring having 0-4 independent heteroatoms selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents attached to the ortho-substituted carbon of the "optionally substituted" group include: -O(CR * 2) 2- 3O-, where each independently occurring R * Selected from: hydrogen; C that can be substituted as defined below. 1-6 Aliphatic; or an unsubstituted 5-6 membered saturated ring, partially unsaturated ring, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0044] R * Suitable substituents on aliphatic groups include halogens, -R · -(halogenated R) · -OH, -OR · -O (halogenated R) · -CN, -C(O)OH, -C(O)OR · -NH2, -NHR · -NR · 2. or -NO2, where each R ·It is either unsubstituted or, in the case of "halogenation" preceding it, substituted by only one or more halogens and is independently C. 1-4 Aliphatic, -CH2Ph, -O(CH2) 0- 1Ph or a 5-6 membered saturated ring, partially unsaturated ring, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0045] Suitable substituents on the substituted nitrogen of the "optionally substituted" group include or Each of them Independently: hydrogen; C that can be substituted as defined below. 1-6 Aliphatic; unsubstituted -OPh; or an unsubstituted 5-6 membered saturated ring, partially unsaturated ring, or aryl ring having 0-4 independently selected heteroatoms chosen from nitrogen, oxygen, or sulfur, or, although defined above, two independently occurring... Together with one or more intermediate atoms, it forms a 3-12 saturated, partially unsaturated, or aryl monocyclic or bicyclic ring with 0-4 independent heteroatoms selected from nitrogen, oxygen, or sulfur.

[0046] 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, -NR · 2. -NR2 or -NO2, where each R · It is either unsubstituted or, in the case of "halogenation" preceding it, substituted by only one or more halogens and is independently C. 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph or a 5-6 membered saturated ring, a partially unsaturated ring, or an aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0047] As used herein, the term "pharmaceutically acceptable salt" means those salts that, within reasonable medical judgment, are suitable for contact with tissues of humans and lower animals without excessive toxicity, irritation, anaphylactic response, etc., 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. describe 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 comprise salts derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, non-toxic acid addition salts are those that form with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or are formed by other methods used in the art, such as ion exchange, and have an amino group. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentylpropionate, disaccharide, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucono-p-glucose, glyceryl phosphate, gluconate, hemisulfate, heptaate, hexanoate, hydroiodate, 2-hydroxy-ethanesulfonate, lacturonate, lactate, laurate, dodecyl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, dihydroxynaphthalate, pectate, persulfate, 3-phenylpropionate, phosphate, neopentanoate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc.

[0048] 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, magnesium, etc. Where appropriate, other pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations that resist the formation of counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0049] Unless otherwise stated, the structures described herein also imply all isomers (e.g., enantiomers, diastereomeric, and geometric (or conformational) forms of the structures; for example, R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers of the compounds of the present invention, as well as mixtures of enantiomers, diastereomeric, and geometric (or conformational) forms, 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, compounds containing hydrogen replaced by deuterium or tritium, or... 13 C- or 14 Compounds with the structure of the present invention, which are C-enriched carbon replacing carbon, are within the scope of this invention. According to the present invention, such compounds can be used, for example, as analytical tools, probes in bioassays, or therapeutic agents. In some embodiments, the warhead portion R of the provided compound... 1 It includes one or more deuterium atoms. In some embodiments, the B ring of the provided compound may be substituted with one or more deuterium atoms.

[0050] 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.

[0051] The compounds of the present invention can be tethered to a detectable moiety. It should be understood that such compounds can be used as imaging agents. Those skilled in the art will recognize that the detectable moiety can be linked to the provided compound via suitable substituents. As used herein, the term "suitable substituent" refers to a moiety capable of covalently linking to the detectable moiety. Such moieties are well known to those skilled in the art and comprise groups containing, to name a few, groups containing, for example, a carboxylate moiety, an amino moiety, a thiol moiety, or a hydroxyl moiety. It should be understood that such moieties can be linked to the provided compound directly or via tethering groups such as divalent saturated or unsaturated hydrocarbon chains. In some embodiments, such moieties can be linked via click chemistry. In some embodiments, such moieties can optionally be linked via a 1,3-cycloaddition of an azide to an alkyne in the presence of a copper catalyst. The use of click chemistry methods is known in the art and includes the methods described in Rostovtsev et al., Angew. Chem. Int. Ed. 2002, 41, 2596-99 and Sun et al., Bioconjugate Chem. 2006, 17, 52-57.

[0052] As used herein, the term "detectable portion" and the term "marking" are used interchangeably and refer to any portion that can be detected, such as primary and secondary markings. Examples include radioactive isotopes (e.g., tritium, etc.). 32 P, 33 P, 35 S or 14 C) Primary markers such as quality labels and fluorescent markers are signal-generating reporter groups that can be detected without further modification. The detectable portion also includes luminescent and phosphorescent groups.

[0053] As used herein, the term "secondary label" refers to the portion, such as biotin and various protein antigens, that requires the presence of a second intermediate to generate a detectable signal. For biotin, the second intermediate may comprise a streptavidin-enzyme conjugate. For antigen labels, the second intermediate may comprise 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 the detected signal.

[0054] 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, BODIPY dyes (BODIPY FL, BODIPY R6G, BODIPY TMR, BODIPY TR, BODIPY530 / 550, BODIPY 558 / 568, BODIPY 564 / 570, BODIPY 576 / 589, BODIPY 581 / 591, BODIPY630 / 650, BODIPY 650 / 665), carboxyrhodamine 6G, carboxy-X-rhodamine (ROX), and Cascade Blue. Blue), Cascade Yellow, Coumarin 343, Cyanide Dyes (Cy3, Cy5, Cy3.5, Cy5.5), Danshenyl, Dapoxyl, Dialkylaminocoumarin, 4',5'-Dichloro-2',7'-Dimethoxyfluorescein, DM-NERF, Eosin, Erythrosine, Fluorescein, FAM, Hydroxycoumarin, IRDye (IRD40, IRD700, IRD800), JOE, Lissaminerhodamine B, Marina Blue, Methoxycoumarin, Naphthylfluorescein, Oregon Green 488, Oregon Green 500, Oregon Green 514, Pacific Blue Rhodamine B, Rhodamine 6G, Rhodamine Green, Rhodamine Red, Rhodol Green, 2',4',5',7'-tetra-bromosulfone-fluorescein, Tetramethyl-Rhodamine (TMR), CarboxytetramethylRhodamine (TAMRA), Texas Red, Texas Red-X.

[0055] As used herein, the term "quality tag" refers to any part that can be uniquely detected by mass spectrometry (MS) using a mass spectrometry (MS) detection technique. Examples of quality tags include electrophoretic release tags such as N-[3-[4'-[(p-methoxytetrafluorobenzyl)oxy]phenyl]-3-methylglycerol]isopiperidinic acid, 4'-[2,3,5,6-tetrafluoro-4-(pentafluorophenoxy)]methylacetophenone, and derivatives thereof. The synthesis and use of these quality tags are described in U.S. Patents 4,650,750, 4,709,016, 5,360,8191, 5,516,931, 5,602,273, 5,604,104, 5,610,020, and 5,650,270. Other examples of quality labels include, but are not limited to, nucleotides, dideoxynucleotides, oligonucleotides of varying lengths and base compositions, oligopeptides, oligosaccharides, and other synthetic polymers of varying lengths and monomer compositions. Large quantities of neutral and charged organic molecules (biomolecules or synthetic compounds) in appropriate mass ranges (100–2000 Daltons) can also be used as quality labels.

[0056] As used herein, the terms “measurable affinity” and “measurable inhibition” mean a measurable change in TYK2 protein kinase activity between a sample comprising the compound or composition thereof of the present invention and TYK2 protein kinase and an equivalent sample comprising TYK2 protein kinase in the absence of said compound or composition thereof.

[0057] 3. Description of exemplary embodiments:

[0058] As described above, in some embodiments, the present invention provides a compound of formula I:

[0059]

[0060] R 1 Yes -L 1 -R 1A ;

[0061] L 1 It is a covalent bond; or C 1-6 Divalent saturated or unsaturated straight-chain or branched hydrocarbon chains, wherein one or two methylene units in the chain are optionally and independently substituted with: -C(R)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)-; -S(O)2-; or -Cy-;

[0062] Cy is a divalent 5-6 membered monocyclic heteroaryl ring having 1-4 independently selected heteroatoms of nitrogen, oxygen and sulfur, optionally substituted; a divalent 8-10 membered bicyclic heteroaryl ring having 1-4 independently selected heteroatoms of nitrogen, oxygen and sulfur, optionally substituted; a divalent 3-7 membered saturated or partially unsaturated carbon ring; or a divalent 7-12 membered saturated or partially unsaturated bicyclic heterocycle having 1-4 independently selected heteroatoms of nitrogen, oxygen and sulfur, optionally substituted;

[0063] R 1A It is oxo; halogen; -CN; -NO2; -OR; -SR; -NR2; -S(O)2R; -S(O)2NR2; -S(O)R; -S(O)NR2; -C(O)R; -C(O)OR; -C(O)NR2; -C(O)N(R)OR; -OC(O)R; -OC(O)NR2; -N(R)C(O)OR; -N(R)C(O)R; -N(R)C(O)NR2; -N(R)C(NR)NR2; -N(R)S(O)2NR2; -N(R)S(O)2R; optionally substituted C 1-6 Aliphatic group; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, optionally substituted; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, optionally substituted; a 3-7 membered saturated or partially unsaturated carbocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, optionally substituted; or a 7-12 membered saturated or partially unsaturated bicyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, optionally substituted;

[0064] R 2 It is -C(O)NH2; -C(O)NHR 2A ;-C(O)N(R 2A )2; or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0065] The heteroaryl ring is divided by m R 2B Instance replacement;

[0066] R 2A It is C 1-6Aliphatic group; phenyl; 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; 3-7 membered saturated or partially unsaturated carbocyclic ring; 3-7 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or 7-12 membered saturated or partially unsaturated bicyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0067] Where R 2A by n R 2C Instance replacement,

[0068] Two Rs on the same carbon 2C The substituents may optionally be combined to form a 3-6 membered saturated or partially unsaturated spirofused heterocycle having 1-4 independent heteroatoms selected from nitrogen, oxygen, and sulfur, or

[0069] The two R on adjacent carbons 2C The substituents may optionally be combined to form a 3-6 membered saturated or partially unsaturated fused heterocycle having 1-4 independent heteroatoms selected from nitrogen, oxygen and sulfur;

[0070] R 2B is oxo; halogen; -CN; -NO2; -R; -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;

[0071] Each R 2C Examples independently include oxo; halogen; -CN; -NO2; -OR; -SR; -NR2; -S(O)2R; -S(O)2NR2; -S(O)R; -S(O)NR2; -C(O)R; -C(O)OR; -C(O)NR2; -C(O)N(R)OR; -OC(O)R; -OC(O)NR2; -N(R)C(O)OR; -N(R)C(O)R; -N(R)C(O)NR2; -N(R)C(NR)NR2; -N(R)S(O)2NR2; -N(R)S(O)2R; or optionally substituted groups selected from the following: C 1-6Aliphatic; phenyl; 3-7 membered saturated or partially unsaturated heterocycles having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and 5-6 membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0072] Two optional substituents on the same carbon atom may optionally together form a 3-6 membered saturated or partially unsaturated spirofused heterocycle having 1-4 independent heteroatoms selected from nitrogen, oxygen, and sulfur, or

[0073] The two optional substituents on adjacent carbons may optionally form together a 3- to 6-membered saturated or partially unsaturated fused heterocycle having 1 to 4 independent heteroatoms selected from nitrogen, oxygen and sulfur;

[0074] R 3 It is hydrogen; halogen; -NH2; -NHR 3A ; or -NHC(O)R 3A ;

[0075] R 3A It is C 1-6 Aliphatic group; phenyl; 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; 3-7 membered saturated or partially unsaturated carbocyclic ring; 3-7 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or 7-12 membered saturated or partially unsaturated bicyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0076] Where R 3A be p a R 3B Instance replacement,

[0077] Two Rs on the same carbon 3B The substituents optionally combine to form a 3-6 membered saturated or partially unsaturated spirofused heterocycle having 1-4 independent heteroatoms selected from nitrogen, oxygen, and sulfur; or

[0078] The two R on adjacent carbons 3B The substituents may optionally be combined to form a 3-6 membered saturated or partially unsaturated fused heterocycle having 1-4 independent heteroatoms selected from nitrogen, oxygen and sulfur;

[0079] Each R 3BExamples independently include oxo; halogen; -CN; -NO2; -OR; -SR; -NR2; -S(O)2R; -S(O)2NR2; -S(O)R; -S(O)NR2; -C(O)R; -C(O)OR; -C(O)NR2; -C(O)N(R)OR; -OC(O)R; -OC(O)NR2; -N(R)C(O)OR; -N(R)C(O)R; -N(R)C(O)NR2; -N(R)C(NR)NR2; -N(R)S(O)2NR2; -N(R)S(O)2R; or optionally substituted groups selected from the following: C 1-6 Aliphatic; phenyl; 3-7 membered saturated or partially unsaturated heterocycles having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and 5-6 membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0080] Two optional substituents on the same carbon atom may optionally together form a 3-6 membered saturated or partially unsaturated spirofused heterocycle having 1-4 independent heteroatoms selected from nitrogen, oxygen, and sulfur; or

[0081] The two optional substituents on adjacent carbons may optionally form together a 3- to 6-membered saturated or partially unsaturated fused heterocycle having 1 to 4 independent heteroatoms selected from nitrogen, oxygen and sulfur;

[0082] R 4 It's R.

[0083] Or R 1 and R 4 Together with its intermediate atom, it forms a 4-7 membered partially unsaturated ring or heteroaryl ring having 0-3 independent heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the ring is R 1A replace;

[0084] Each R is independently hydrogen; or selected from the following optionally substituted groups: C 1-6 Aliphatic; phenyl; a 3-7 membered saturated or partially unsaturated heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or

[0085] Two R groups on the same nitrogen atom, together with their intermediate atom, form a 4-7 membered saturated ring, a partially unsaturated ring, or a heteroaryl ring having 0-3 independent heteroatoms selected from nitrogen, oxygen, or sulfur in addition to the nitrogen atom.

[0086] Each hydrogen atom bonded to carbon can be optionally and independently replaced by deuterium;

[0087] m is 0, 1, or 2;

[0088] n is 0, 1, or 2; and

[0089] p is 0, 1, or 2.

[0090] As described above, in some embodiments, the present invention provides a compound of formula I':

[0091]

[0092] R 1 Yes -L 1 -R 1A ;

[0093] L 1 It is a covalent bond; or C 1-6 Divalent saturated or unsaturated straight-chain or branched hydrocarbon chains, wherein one or two methylene units in the chain are optionally and independently substituted with: -C(R)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)-; -S(O)2-; or -Cy-;

[0094] Cy is a divalent 5-6 membered monocyclic heteroaryl ring having 1-4 independently selected heteroatoms of nitrogen, oxygen and sulfur, optionally substituted; a divalent 8-10 membered bicyclic heteroaryl ring having 1-4 independently selected heteroatoms of nitrogen, oxygen and sulfur, optionally substituted; a divalent 3-7 membered saturated or partially unsaturated carbon ring; or a divalent 7-12 membered saturated or partially unsaturated bicyclic heterocycle having 1-4 independently selected heteroatoms of nitrogen, oxygen and sulfur, optionally substituted;

[0095] R 1A It is oxo; halogen; -CN; -NO2; -OR; -SR; -NR2; -S(O)2R; -S(O)2NR2; -S(O)R; -S(O)NR2; -C(O)R; -C(O)OR; -C(O)NR2; -C(O)N(R)OR; -OC(O)R; -OC(O)NR2; -N(R)C(O)OR; -N(R)C(O)R; -N(R)C(O)NR2; -N(R)C(NR)NR2; -N(R)S(O)2NR2; -N(R)S(O)2R; optionally substituted C 1-6Aliphatic group; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, optionally substituted; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, optionally substituted; a 3-7 membered saturated or partially unsaturated carbocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, optionally substituted; or a 7-12 membered saturated or partially unsaturated bicyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, optionally substituted;

[0096] R 2 It is -C(O)OH; -C(O)NH2; -C(O)NHR 2A ;-C(O)N(R 2A )2; or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0097] The heteroaryl ring is divided by m R 2B Instance replacement;

[0098] R 2A It is C 1-6 Aliphatic group; phenyl; 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; 3-7 membered saturated or partially unsaturated carbocyclic ring; 3-7 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or 7-12 membered saturated or partially unsaturated bicyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0099] Where R 2A by n R 2C Instance replacement,

[0100] Two Rs on the same carbon 2C The substituents may optionally be combined to form a 3-6 membered saturated or partially unsaturated spirofused heterocycle having 1-4 independent heteroatoms selected from nitrogen, oxygen, and sulfur, or

[0101] The two R on adjacent carbons 2C The substituents may optionally be combined to form a 3-6 membered saturated or partially unsaturated fused heterocycle having 1-4 independent heteroatoms selected from nitrogen, oxygen and sulfur;

[0102] R 2Bis oxo; halogen; -CN; -NO2; -R; -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;

[0103] Each R 2C Examples independently include oxo; halogen; -CN; -NO2; -OR; -SR; -NR2; -S(O)2R; -S(O)2NR2; -S(O)R; -S(O)NR2; -C(O)R; -C(O)OR; -C(O)NR2; -C(O)N(R)OR; -OC(O)R; -OC(O)NR2; -N(R)C(O)OR; -N(R)C(O)R; -N(R)C(O)NR2; -N(R)C(NR)NR2; -N(R)S(O)2NR2; -N(R)S(O)2R; or optionally substituted groups selected from the following: C 1-6 Aliphatic; phenyl; 3-7 membered saturated or partially unsaturated heterocycles having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and 5-6 membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0104] Two optional substituents on the same carbon atom may optionally together form a 3-6 membered saturated or partially unsaturated spirofused heterocycle having 1-4 independent heteroatoms selected from nitrogen, oxygen, and sulfur, or

[0105] The two optional substituents on adjacent carbons may optionally form together a 3- to 6-membered saturated or partially unsaturated fused heterocycle having 1 to 4 independent heteroatoms selected from nitrogen, oxygen and sulfur;

[0106] R 3 It is hydrogen; halogen; -NH2; -NHR 3A ;-NHC(O)R 3A ; or -NR 3A Boc;

[0107] R 3A It is C 1-6Aliphatic group; phenyl; 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; 3-7 membered saturated or partially unsaturated carbocyclic ring; 3-7 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or 7-12 membered saturated or partially unsaturated bicyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0108] Where R 3A be p a R 3B Instance replacement,

[0109] Two Rs on the same carbon 3B The substituents optionally combine to form a 3-6 membered saturated or partially unsaturated spirofused heterocycle having 1-4 independent heteroatoms selected from nitrogen, oxygen, and sulfur; or

[0110] The two R on adjacent carbons 3B The substituents may optionally be combined to form a 3-6 membered saturated or partially unsaturated fused heterocycle having 1-4 independent heteroatoms selected from nitrogen, oxygen and sulfur;

[0111] Each R 3B Examples independently include oxo; halogen; -CN; -NO2; -OR; -SR; -NR2; -S(O)2R; -S(O)2NR2; -S(O)R; -S(O)NR2; -C(O)R; -C(O)OR; -C(O)NR2; -C(O)N(R)OR; -OC(O)R; -OC(O)NR2; -N(R)C(O)OR; -N(R)C(O)R; -N(R)C(O)NR2; -N(R)C(NR)NR2; -N(R)S(O)2NR2; -N(R)S(O)2R; or optionally substituted groups selected from the following: C 1-6 Aliphatic; phenyl; 3-7 membered saturated or partially unsaturated heterocycles having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and 5-6 membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0112] Two optional substituents on the same carbon atom may optionally together form a 3-6 membered saturated or partially unsaturated spirofused heterocycle having 1-4 independent heteroatoms selected from nitrogen, oxygen, and sulfur; or

[0113] The two optional substituents on adjacent carbons may optionally form together a 3- to 6-membered saturated or partially unsaturated fused heterocycle having 1 to 4 independent heteroatoms selected from nitrogen, oxygen and sulfur;

[0114] R 4 Is it R or -OR?

[0115] Or R 1 and R 4 Together with its intermediate atom, it forms a 4-7 membered partially unsaturated ring or heteroaryl ring having 0-3 independent heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the ring is R 1A replace;

[0116] Or R 3 and R 4 Together with its intermediate atom, it forms a 4-7 membered partially unsaturated ring or heteroaryl ring with 0-3 independent heteroatoms selected from nitrogen, oxygen and sulfur;

[0117] Each R is independently hydrogen; or selected from the following optionally substituted groups: C 1-6 Aliphatic; phenyl; a 3-7 membered saturated or partially unsaturated heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or

[0118] Two R groups on the same nitrogen atom, together with their intermediate atom, form a 4-7 membered saturated ring, a partially unsaturated ring, or a heteroaryl ring having 0-3 independent heteroatoms selected from nitrogen, oxygen, or sulfur in addition to the nitrogen atom.

[0119] Each hydrogen atom bonded to carbon can be optionally and independently replaced by deuterium;

[0120] m is 0, 1, or 2;

[0121] n is 0, 1, or 2; and

[0122] p is 0, 1, or 2.

[0123] As defined above, R 1 Yes -L 1 -R 1A .

[0124] In some embodiments, R 1 Selected from those described in Table 1 below.

[0125] As defined above, L 1 It is a covalent bond; or C 1-6 Divalent saturated or unsaturated straight-chain or branched hydrocarbon chains, wherein one or two methylene units in the chain are optionally and independently substituted with: -C(R)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)-; -S(O)2-; or -Cy-.

[0126] In some embodiments, L 1 It is a covalent bond. In some embodiments, L 1 It is C 1-6 A divalent saturated straight-chain hydrocarbon chain, wherein one or both methylene units of the chain are optionally and independently substituted with: -C(R)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)-, -S(O)2-, or -Cy-. In some embodiments, L 1 It is C 1-6 A divalent unsaturated straight-chain hydrocarbon chain, wherein one or both methylene units of the chain are optionally and independently substituted with: -C(R)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)-, -S(O)2-, or -Cy-. In some embodiments, L 1 It is C 1-6 A divalent saturated branched hydrocarbon chain, wherein one or both methylene units of the chain are optionally and independently substituted with: -C(R)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)-, -S(O)2-, or -Cy-. In some embodiments, L 1 It is C 1-6 Divalent unsaturated branched hydrocarbon chains, wherein one or both methylene units of the chain are optionally and independently substituted with: -C(R)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)-, -S(O)2- or -Cy-.

[0127] In some embodiments, L 1 It is -N(R)-. In some embodiments, L 1 It is -N(H)-. In some embodiments, L 1 It is -Cy-. In some embodiments, L 1 It is -Cy-N(R)-. In some embodiments, L 1 It is -Cy-NH-.

[0128] In some embodiments, L 1 yes In some embodiments, L 1 yes In some embodiments, L 1 yes In some embodiments, L 1 yes In some embodiments, L 1 yes In some embodiments, L 1 yes In some embodiments, L 1 yes In some embodiments, L 1 yes

[0129] In some embodiments, L 1 yes In some embodiments, L 1 yes In some embodiments, L 1 yes In some embodiments, L 1 yes In some embodiments, L 1 yes In some embodiments, L 1 yes In some embodiments, L 1 yes In some embodiments, L 1 yes

[0130] In some embodiments, L 1 yes

[0131] In some embodiments, L 1 yes

[0132] In some embodiments, L 1 Selected from those described in Table 1 below.

[0133] As defined above, Cy is a divalent 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a divalent 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a divalent 3-7 membered saturated or partially unsaturated carbon ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a divalent 7-12 membered saturated or partially unsaturated bicyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0134] In some embodiments, Cy is a divalent 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted. In some embodiments, Cy is a divalent 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted. In some embodiments, Cy is a divalent 3-7 membered saturated carbide ring having optionally substituted. In some embodiments, Cy is a divalent 3-7 membered partially unsaturated carbide ring having optionally substituted. In some embodiments, Cy is a divalent 7-12 membered saturated bicyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted. In some embodiments, Cy is a divalent 7-12 membered partially unsaturated bicyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted.

[0135] In some embodiments, Cy is In some embodiments, Cy is In some embodiments, Cy is In some embodiments, Cy is In some embodiments, Cy is In some embodiments, Cy is In some embodiments, Cy is In some embodiments, Cy is

[0136] In some embodiments, Cy is In some embodiments, Cy is In some embodiments, Cy is In some embodiments, Cy is In some embodiments, Cy is In some embodiments, Cy is In some embodiments, Cy is In some embodiments, Cy is

[0137] In some embodiments, Cy is

[0138] In some embodiments, Cy is

[0139] In some embodiments, Cy is selected from those depicted in Table 1 below.

[0140] As defined above, R 1AIt is oxo; halogen; -CN; -NO2; -OR; -SR; -NR2; -S(O)2R; -S(O)2NR2; -S(O)R; -S(O)NR2; -C(O)R; -C(O)OR; -C(O)NR2; -C(O)N(R)OR; -OC(O)R; -OC(O)NR2; -N(R)C(O)OR; -N(R)C(O)R; -N(R)C(O)NR2; -N(R)C(NR)NR2; -N(R)S(O)2NR2; -N(R)S(O)2R; optionally substituted C 1-6 Aliphatic group; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, optionally substituted; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, optionally substituted; a 3-7 membered saturated or partially unsaturated carbocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, optionally substituted; or a 7-12 membered saturated or partially unsaturated bicyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, optionally substituted.

[0141] In some embodiments, R 1A It is an oxidation. In some embodiments, R 1A It is a halogen. In some embodiments, R 1A Yes -CN. In some embodiments, R 1A It is -NO2. In some embodiments, R 1A Yes - OR. In some embodiments, R 1A It is -SR. In some embodiments, R 1A It is -NR2. In some embodiments, R 1A It is -S(O)2R. In some embodiments, R 1A It is -S(O)2NR2. In some embodiments, R 1A It is -S(O)R. In some embodiments, R 1A It is -S(O)NR2. In some embodiments, R 1A It is -C(O)R. In some embodiments, R 1A It is -C(O)OR. In some embodiments, R 1A It is -C(O)NR2. In some embodiments, R 1A It is -C(O)N(R)OR. In some embodiments, R 1A It is -OC(O)R. In some embodiments, R 1A It is -OC(O)NR2. In some embodiments, R 1A It is -N(R)C(O)OR. In some embodiments, R1A It is -N(R)C(O)R. In some embodiments, R 1A It is -N(R)C(O)NR2. In some embodiments, R 1A It is -N(R)C(NR)NR2. In some embodiments, R 1A It is -N(R)S(O)2NR2. In some embodiments, R 1A It is -N(R)S(O)2R.

[0142] In some embodiments, R 1A It is C that is arbitrarily substituted. 1-6 Aliphatic group. In some embodiments, R 1A It is phenyl. In some embodiments, R 1A It is a 5-6 membered monocyclic heteroaryl ring having 1-4 independently selected heteroatoms chosen from nitrogen, oxygen, and sulfur, optionally substituted. In some embodiments, R 1A It is an 8-10 membered bicyclic heteroaryl ring having 1-4 independently selected heteroatoms chosen from nitrogen, oxygen, and sulfur, optionally substituted. In some embodiments, R 1A It is optionally a substituted 3-7 membered saturated carbon ring. In some embodiments, R 1A It is optionally a substituted 3-7 member partially unsaturated carbon ring. In some embodiments, R 1A It is a 3-7 membered saturated monocyclic heterocycle having 1-2 independently selected heteroatoms chosen from nitrogen, oxygen, and sulfur. In some embodiments, R 1A It is a 3- to 7-membered partially unsaturated monocyclic heterocycle having 1-2 independently selected heteroatoms chosen from nitrogen, oxygen, and sulfur. In some embodiments, R 1A It is a 7-12 membered saturated bicyclic heterocycle having 1-4 independently selected heteroatoms chosen from nitrogen, oxygen, and sulfur. In some embodiments, R 1A It is a 7-12 member partially unsaturated bicyclic heterocycle having 1-4 independently selected heteroatoms chosen from nitrogen, oxygen and sulfur.

[0143] In some embodiments, R 1A Selected from:

[0144]

[0145] In some embodiments, R 1A Selected from:

[0146]

[0147] In some embodiments, R 1A Selected from:

[0148]

[0149] In some embodiments, R 1A Selected from:

[0150] In some embodiments, R 1A yes

[0151] In some embodiments, R 1A Selected from

[0152] In some embodiments, R 1A Selected from:

[0153] In some embodiments, R 1A It is -NR2. In some embodiments, R 1A is -N(H)Me.

[0154] In some embodiments, R 1A Selected from those described in Table 1 below.

[0155] As defined above, R 2 It is -C(O)OH; -C(O)NH2; -C(O)NHR 2A ;-C(O)N(R 2A )2; or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl ring is separated by m R 2B Instance replacement.

[0156] In some embodiments, R 2 It is -C(O)OH. In some embodiments, R 2 It is -C(O)NH2. In some embodiments, R 2 It is -C(O)NHR 2A In some embodiments, R 2 It is -C(O)N(R) 2A )2.

[0157] In some embodiments, R 2 It is a 5-6 membered monocyclic heteroaryl ring having 1-4 independent heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl ring is separated by m R atoms. 2B Instance replacement.

[0158] In some embodiments, R 2 yes In some embodiments, R 2 yes

[0159] In some embodiments, R 2 Selected from those described in Table 1 below.

[0160] As defined above, R 2A It is C 1-6 Aliphatic group; phenyl; 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 3-7 membered saturated or partially unsaturated carbocyclic ring; 3-7 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or 7-12 membered saturated or partially unsaturated bicyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein R 2A by n R 2C Instance replacement; where two Rs on the same carbon 2C The substituents optionally combine to form a 3-6 membered saturated or partially unsaturated spirofused heterocycle having 1-4 independent heteroatoms selected from nitrogen, oxygen, and sulfur; or wherein two R atoms on adjacent carbons form a spirofused heterocycle. 2C The substituents may optionally be combined to form a 3- to 6-membered saturated or partially unsaturated fused heterocycle having 1 to 4 independent heteroatoms selected from nitrogen, oxygen and sulfur.

[0161] In some embodiments, R 2A It is C 1-6 Aliphatic group. In some embodiments, R 2A It is phenyl. In some embodiments, R 2A It is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2A It is an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2A It is a 3-7 ternary saturated carbon ring. In some embodiments, R 2A It is a 3-7 ternary partially unsaturated carbon ring. In some embodiments, R 2A It is a 7-12 member saturated bicyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2A It is a 7-12 member partially unsaturated bicyclic heterocycle with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0162] In some embodiments, R 2A by n R 2C Instance replacement.

[0163] In some embodiments, two R on the same carbon 2CThe substituents optionally combine to form a 3-6 membered saturated spirofused heterocycle having 1-4 independent heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the two R atoms on the same carbon atom... 2C The substituents may optionally be combined to form a 3- to 6-membered partially unsaturated spirofused heterocycle having 1 to 4 independent heteroatoms selected from nitrogen, oxygen, and sulfur.

[0164] In some embodiments, two R on adjacent carbons 2C The substituents optionally combine to form a 3-6 membered saturated fused heterocycle having 1-4 independent heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the two R atoms on adjacent carbons... 2C The substituents may optionally be combined to form a 3- to 6-membered partially unsaturated fused heterocycle having 1 to 4 independent heteroatoms selected from nitrogen, oxygen, and sulfur.

[0165] In some embodiments, R 2A Selected from the following:

[0166]

[0167]

[0168] In some embodiments, R 2A Selected from the following:

[0169] In some embodiments, R 2A Selected from those described in Table 1 below.

[0170] As defined above, R 2B is oxo; halogen; -CN; -NO2; -R; -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.

[0171] In some embodiments, R 2B It is an oxidation. In some embodiments, R 2B Yes -CN. In some embodiments, R 2B It is -NO2. In some embodiments, R 2B Yes -R. In some embodiments, R 2B Yes - OR. In some embodiments, R2B It is -SR. In some embodiments, R 2B It is -NR2. In some embodiments, R 2B It is -S(O)2R. In some embodiments, R 2B It is -S(O)2NR2. In some embodiments, R 2B It is -S(O)R. In some embodiments, R 2B It is -S(O)NR2. In some embodiments, R 2B It is -C(O)R. In some embodiments, R 2B It is -C(O)OR. In some embodiments, R 2B It is -C(O)NR2. In some embodiments, R 2B It is -C(O)N(R)OR. In some embodiments, R 2B It is -OC(O)R. In some embodiments, R 2B It is -OC(O)NR2. In some embodiments, R 2B It is -N(R)C(O)OR. In some embodiments, R 2B It is -N(R)C(O)R. In some embodiments, R 2B It is -N(R)C(O)NR2. In some embodiments, R 2B It is -N(R)S(O)2NR2. In some embodiments, R 2B It is -N(R)S(O)2R.

[0172] In some embodiments, R 2B It is isopropyl.

[0173] In some embodiments, R 2B Selected from those described in Table 1 below.

[0174] As defined above, R 2C It is an oxometalate; halogen; -CN; -NO2; -OR; -SR; -NR2; -S(O)2R; -S(O)2NR2; -S(O)R; -S(O)NR2; -C(O)R; -C(O)OR; -C(O)NR2; -C(O)N(R)OR; -OC(O)R; -OC(O)NR2; -N(R)C(O)OR; -N(R)C(O)R; -N(R)C(O)NR2; -N(R)C(NR)NR2; -N(R)S(O)2NR2; -N(R)S(O)2R; or a optionally substituted group selected from the following: C 1-6Aliphatic; phenyl; a 3-7 membered saturated or partially unsaturated heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein two optional substituents on the same carbon optionally together form a 3-6 membered saturated or partially unsaturated spirofused heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or wherein two optional substituents on adjacent carbons optionally together form a 3-6 membered saturated or partially unsaturated fused heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0175] In some embodiments, R 2C It is an oxidation. In some embodiments, R 2C Yes -CN. In some embodiments, R 2C It is -NO2. In some embodiments, R 2C Yes -R. In some embodiments, R 2C Yes - OR. In some embodiments, R 2C It is -SR. In some embodiments, R 2C It is -NR2. In some embodiments, R 2C It is -S(O)2R. In some embodiments, R 2C It is -S(O)2NR2. In some embodiments, R 2C It is -S(O)R. In some embodiments, R 2C It is -S(O)NR2. In some embodiments, R 2C It is -C(O)R. In some embodiments, R 2C It is -C(O)OR. In some embodiments, R 2C It is -C(O)NR2. In some embodiments, R 2C It is -C(O)N(R)OR. In some embodiments, R 2C It is -OC(O)R. In some embodiments, R 2C It is -OC(O)NR2. In some embodiments, R 2C It is -N(R)C(O)OR. In some embodiments, R 2C It is -N(R)C(O)R. In some embodiments, R 2C It is -N(R)C(NR)NR2. In some embodiments, R 2C It is -N(R)S(O)2NR2. In some embodiments, R 2C It is -N(R)S(O)2R.

[0176] In some embodiments, R 2C It is C that is arbitrarily substituted. 1-6 Aliphatic group. In some embodiments, R2C It is an optionally substituted aryl group. In some embodiments, R 2C It is a 3- to 7-membered saturated heterocycle having 1-2 independently selected heteroatoms chosen from nitrogen, oxygen, and sulfur. In some embodiments, R 2C It is a 3- to 7-membered partially unsaturated heterocycle having 1-2 independently selected heteroatoms chosen from nitrogen, oxygen, and sulfur. In some embodiments, R 2C It is a 5-6 membered heteroaryl ring having 1-4 independently selected heteroatoms chosen from nitrogen, oxygen and sulfur, which are optionally substituted.

[0177] In some embodiments, two optional substituents on the same carbon may optionally together form a 3-6 member saturated or partially unsaturated spirofused heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two optional substituents on adjacent carbons may optionally together form a 3-6 member saturated or partially unsaturated fused heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0178] In some embodiments, R 2C Selected from those described in Table 1 below.

[0179] As defined above, R 3 It is hydrogen, halogen, -NH2, -NHR 3A -NHC(O)R 3A or -NR 3A Boc.

[0180] In some embodiments, R 3 It is hydrogen. In some embodiments, R 3 It is a halogen. In some embodiments, R 3 It is -NH2. In some embodiments, R 3 Yes - NHR 3A In some embodiments, R 3 It is -NHC(O)R 3A In some embodiments, R 3 Yes -NR 3A Boc.

[0181] In some embodiments, R 3 Yes - NHR 3A .

[0182] In some embodiments, R 3 It is -C(O)NHR 3A .

[0183] In some embodiments, R 3 It is -N(Me)Boc.

[0184] In some embodiments, R 3 Selected from those described in Table 1 below.

[0185] As described in general above, R 3A It is C 1-6 Aliphatic group; phenyl; 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 3-7 membered saturated or partially unsaturated carbocyclic ring; 3-7 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or 7-12 membered saturated or partially unsaturated bicyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein R 3A be p a R 3B Instance replacement, where two R on the same carbon 3B The substituents optionally come together to form a 3-6 membered saturated or partially unsaturated spirofused heterocycle having 1-4 independent heteroatoms selected from nitrogen, oxygen, and sulfur, or wherein two R atoms on adjacent carbons form a spirofused heterocycle. 3B The substituents may optionally be combined to form a 3- to 6-membered saturated or partially unsaturated fused heterocycle having 1 to 4 independent heteroatoms selected from nitrogen, oxygen and sulfur.

[0186] In some embodiments, R 3A It is C 1-6 Aliphatic group. In some embodiments, R 3A It is phenyl. In some embodiments, R 3A It is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 3A It is an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 3A It is a 3-7 ternary saturated carbon ring. In some embodiments, R 3A It is a 3-7 ternary partially unsaturated carbon ring. In some embodiments, R 3A It is a 3-7 membered saturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 3A It is a 3- to 7-membered partially unsaturated monocyclic heterocycle having 1-2 independent heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, R 3A It is a 7-12 member saturated bicyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 3A It is a 7-12 member partially unsaturated bicyclic heterocycle with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0187] In some embodiments, R 3Abe p a R 3B Instance replacement.

[0188] In some embodiments, two R on the same carbon 3B The substituents optionally combine to form a 3-6 membered saturated spirofused heterocycle having 1-4 independent heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the two R atoms on the same carbon atom... 3B The substituents optionally combine to form a 3-6 membered partially unsaturated spirofused heterocycle having 1-4 independent heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the two R atoms on adjacent carbons... 3B The substituents optionally combine to form a 3-6 membered saturated fused heterocycle having 1-4 independent heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the two R atoms on adjacent carbons... 3B The substituents may optionally be combined to form a 3- to 6-membered partially unsaturated fused heterocycle having 1 to 4 independent heteroatoms selected from nitrogen, oxygen, and sulfur.

[0189] In some embodiments, R 3A It is methyl. In some embodiments, R 3A It is an ethyl group.

[0190] In some embodiments, R 3A Selected from those described in Table 1 below.

[0191] As described in general above, R 3B It is an oxometalate; halogen; -CN; -NO2; -OR; -SR; -NR2; -S(O)2R; -S(O)2NR2; -S(O)R; -S(O)NR2; -C(O)R; -C(O)OR; -C(O)NR2; -C(O)N(R)OR; -OC(O)R; -OC(O)NR2; -N(R)C(O)OR; -N(R)C(O)R; -N(R)C(O)NR2; -N(R)C(NR)NR2; -N(R)S(O)2NR2; -N(R)S(O)2R; or a optionally substituted group selected from the following: C 1-6 Aliphatic; phenyl; a 3-7 membered saturated or partially unsaturated heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein two optional substituents on the same carbon optionally together form a 3-6 membered saturated or partially unsaturated spirofused heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or wherein two optional substituents on adjacent carbons optionally together form a 3-6 membered saturated or partially unsaturated fused heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0192] In some embodiments, R 3BIt is an oxidation. In some embodiments, R 3B It is a halogen. In some embodiments, R 3B Yes -CN. In some embodiments, R 3B It is -NO2. In some embodiments, R 3B Yes - OR. In some embodiments, R 3B It is -SR. In some embodiments, R 3B It is -NR2. In some embodiments, R 3B It is -S(O)2R. In some embodiments, R 3B It is -S(O)2NR2. In some embodiments, R 3B It is -S(O)R. In some embodiments, R 3B It is -S(O)NR2. In some embodiments, R 3B It is -C(O)R. In some embodiments, R 3B It is -C(O)OR. In some embodiments, R 3B It is -C(O)NR2. In some embodiments, R 3B It is -C(O)N(R)OR. In some embodiments, R 3B It is -OC(O)R. In some embodiments, R 3B It is -OC(O)NR2. In some embodiments, R 3B It is -N(R)C(O)OR. In some embodiments, R 3B It is -N(R)C(O)R. In some embodiments, R 3B It is -N(R)C(O)NR2. In some embodiments, R 3B It is -N(R)C(NR)NR2. In some embodiments, R 3B It is -N(R)S(O)2NR2. In some embodiments, R 3B It is -N(R)S(O)2R.

[0193] In some embodiments, R 3B Yes - OR.

[0194] In some embodiments, R 3B It is C that is arbitrarily substituted. 1-6 Aliphatic group. In some embodiments, R 3B It is an optionally substituted aryl group. In some embodiments, R 3B It is a 3-7 membered saturated heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 3B It is a 3- to 7-membered partially unsaturated heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 3BIt is a 5-6 membered heteroaryl ring having 1-4 independently selected heteroatoms chosen from nitrogen, oxygen and sulfur, which are optionally substituted.

[0195] In some embodiments, two optional substituents on the same carbon atom optionally together form a 3-6 membered saturated spirofused heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two optional substituents on the same carbon atom optionally together form a 3-6 membered partially unsaturated spirofused heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two optional substituents on adjacent carbon atom optionally together form a 3-6 membered saturated fused heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two optional substituents on adjacent carbon atom optionally together form a 3-6 membered partially unsaturated fused heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0196] As defined above, R 4 It is R or -OR; or R 1 and R 4 Together with its intermediate atom, it forms a 4-7 membered partially unsaturated ring or heteroaryl ring having 0-3 independent heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the ring is R 1A Replace; or R 3 and R 4 Together with its intermediate atoms, it forms a 4-7 membered partially unsaturated ring or heteroaryl ring with 0-3 independent heteroatoms selected from nitrogen, oxygen and sulfur.

[0197] In some embodiments, R 4 It is R. In some embodiments, R 4 Yes - OR.

[0198] In some embodiments, R 1 and R 4 Together with its intermediate atom, it forms a 4-7 membered partially unsaturated ring having 0-3 independent heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the ring is R 1A Replacement. In some embodiments, R 1 and R 4 Together with its intermediate atom, it forms a 4-7 membered heteroaryl ring having 0-3 independent heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the ring is R 1A replace.

[0199] In some embodiments, R 3 and R 4 Together with its intermediate atom, it forms a 4-7 membered partially unsaturated ring having 0-3 heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, R 3 and R 4Together with its intermediate atom, it forms a 4-7 membered heteroaryl ring with 0-3 independent heteroatoms selected from nitrogen, oxygen and sulfur.

[0200] In some embodiments, R 4 It's H.

[0201] In some embodiments, R 4 Selected from those described in Table 1 below.

[0202] As defined above in general, each R is independently hydrogen; or selected from the following optionally substituted groups: C 1-6 Aliphatic; phenyl; a 3-7 membered saturated or partially unsaturated heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or a 4-7 membered saturated, partially unsaturated or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur in addition to the nitrogen, formed by two R groups on the same nitrogen and their intermediate atom.

[0203] In some embodiments, R is hydrogen. In some embodiments, R is optionally substituted C. 1-6 Aliphatic group. In some embodiments, R is an optionally substituted aryl group. In some embodiments, R is an optionally substituted 3-7 membered saturated heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 3-7 membered partially unsaturated heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0204] In some embodiments, two R groups on the same nitrogen atom, together with their intermediate atom, form a 4-7 membered saturated ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur in addition to the nitrogen. In some embodiments, two R groups on the same nitrogen atom, together with their intermediate atom, form a 4-7 membered partially unsaturated ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur in addition to the nitrogen. In some embodiments, two R groups on the same nitrogen atom, together with their intermediate atom, form a 4-7 membered heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur in addition to the nitrogen.

[0205] In some embodiments, R is selected from those depicted in Table 1 below.

[0206] As defined in general above, each hydrogen atom bound to carbon can be optionally and independently replaced by deuterium.

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

[0208] In some embodiments, m is selected from those depicted in Table 1 below.

[0209] As generally defined above, n is 0, 1, or 2. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2.

[0210] In some embodiments, n is selected from those depicted in Table 1 below.

[0211] As generally defined above, p is 0, 1, or 2. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2.

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

[0213] In some embodiments, the present invention provides a compound of formula II:

[0214]

[0215] Or a pharmaceutically acceptable salt thereof, wherein R 1A Cy, R 2 R 3 and R 4 Each of these is as defined above and is described individually and in combination in the embodiments herein.

[0216] In some embodiments, the present invention provides a compound of formula III:

[0217]

[0218] Or a pharmaceutically acceptable salt thereof, wherein R 1A R 2 and R 3 Each of these is as defined above and is described individually and in combination in the embodiments herein.

[0219] In some embodiments, the present invention provides a compound of formula IV:

[0220]

[0221] Or a pharmaceutically acceptable salt thereof, wherein R 1A Cy, R 2 R 3 and R 4Each of these is as defined above and is described individually and in combination in the embodiments herein.

[0222] In some embodiments, the present invention provides a compound of formula V:

[0223]

[0224] Or a pharmaceutically acceptable salt thereof, wherein R 1A R 2 R 3 and R 4 Each of these is as defined above and is described individually and in combination in the embodiments herein.

[0225] In some embodiments, the present invention provides a compound of formula VI:

[0226]

[0227] Or a pharmaceutically acceptable salt thereof, wherein R 1 R 2A R 3 and R 4 Each of these is as defined above and is described individually and in combination in the embodiments herein.

[0228] In some embodiments, the present invention provides a compound of formula VII:

[0229]

[0230] Or a pharmaceutically acceptable salt thereof, wherein R 1 R 2B R 3 and R 4 Each of these is as defined above and is described individually and in combination in the embodiments herein.

[0231] In some embodiments, the present invention provides a compound of formula VIII:

[0232]

[0233] Or a pharmaceutically acceptable salt thereof, wherein R 1 R 2 and R 4 Each of these is as defined above and is described individually and in combination in the embodiments herein.

[0234] In some embodiments, the present invention provides a compound of formula IX:

[0235]

[0236] Or a pharmaceutically acceptable salt thereof, wherein R 1A R 2A and R 4 Each of these is as defined above and is described individually and in combination in the embodiments herein.

[0237] In some embodiments, the present invention provides a compound of formula X:

[0238]

[0239] Or a pharmaceutically acceptable salt thereof, wherein R 1A R 2A and R 4 Each of these is as defined above and is described individually and in combination in the embodiments herein.

[0240] In some embodiments, the present invention provides a compound of formula XI:

[0241]

[0242] Or a pharmaceutically acceptable salt thereof, wherein R 1A R 2A and R 4 Each of these is as defined above and is described individually and in combination in the embodiments herein.

[0243] In some embodiments, the present invention provides a compound of formula XII:

[0244]

[0245] Or a pharmaceutically acceptable salt thereof, wherein R 1A R 2A and R 4 Each of these is as defined above and is described individually and in combination in the embodiments herein.

[0246] In some embodiments, the present invention provides a compound of formula XIII:

[0247]

[0248] Or a pharmaceutically acceptable salt thereof, wherein R 1A R 2A and R 4 Each of these is as defined above and is described individually and in combination in the embodiments herein.

[0249] In some embodiments, the present invention provides a compound of formula XIV:

[0250]

[0251] Or a pharmaceutically acceptable salt thereof, wherein R 1A R 2A and R 4 Each of these is as defined above and is described individually and in combination in the embodiments herein.

[0252] In some embodiments, the present invention provides a compound of formula XV:

[0253]

[0254] Or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 Each of these is as defined above and is described individually and in combination in the embodiments herein.

[0255] In some embodiments, the present invention provides a compound of formula XVI:

[0256]

[0257] Or a pharmaceutically acceptable salt thereof, wherein R 1A R 2A and R 4 Each of these is as defined above and is described individually and in combination in the embodiments herein.

[0258] In some embodiments, the present invention provides a compound of formula XVII:

[0259]

[0260] Or a pharmaceutically acceptable salt thereof, wherein R 1A R 2A and R 4 Each of these is as defined above and is described individually and in combination in the embodiments herein.

[0261] In some embodiments, the present invention provides a compound of formula XVIII:

[0262]

[0263] Or a pharmaceutically acceptable salt thereof, wherein R 1A R 2 R 3 and R 4 Each of these is as defined above and is described individually and in combination in the embodiments herein.

[0264] In some embodiments, the present invention provides a compound of formula XIX:

[0265]

[0266] Or a pharmaceutically acceptable salt thereof, wherein R 1A R 2A and R 4 Each of these is as defined above and is described individually and in combination in the embodiments herein.

[0267] In some embodiments, the present invention provides a compound of formula XX:

[0268]

[0269] Or a pharmaceutically acceptable salt thereof, wherein R 1A R 2A and R 4 Each of these is as defined above and is described individually and in combination in the embodiments herein. Exemplary compounds of the invention are set forth in Table 1 below.

[0270] Table 1: Selected Compounds

[0271]

[0272]

[0273]

[0274]

[0275]

[0276]

[0277]

[0278]

[0279]

[0280]

[0281]

[0282]

[0283]

[0284]

[0285]

[0286]

[0287]

[0288]

[0289]

[0290]

[0291]

[0292]

[0293]

[0294]

[0295]

[0296]

[0297]

[0298]

[0299]

[0300]

[0301]

[0302]

[0303]

[0304]

[0305]

[0306]

[0307]

[0308]

[0309]

[0310]

[0311]

[0312]

[0313]

[0314]

[0315]

[0316]

[0317]

[0318]

[0319]

[0320]

[0321]

[0322]

[0323]

[0324]

[0325]

[0326]

[0327]

[0328]

[0329]

[0330]

[0331]

[0332]

[0333]

[0334]

[0335]

[0336]

[0337]

[0338]

[0339]

[0340]

[0341]

[0342]

[0343]

[0344]

[0345]

[0346]

[0347]

[0348]

[0349]

[0350]

[0351]

[0352]

[0353]

[0354]

[0355]

[0356]

[0357]

[0358]

[0359]

[0360]

[0361]

[0362]

[0363]

[0364]

[0365]

[0366]

[0367]

[0368]

[0369]

[0370]

[0371]

[0372]

[0373]

[0374]

[0375]

[0376]

[0377]

[0378]

[0379]

[0380]

[0381]

[0382]

[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]

[0428]

[0429]

[0430]

[0431]

[0432]

[0433]

[0434]

[0435]

[0436]

[0437]

[0438]

[0439]

[0440]

[0441]

[0442] In some embodiments, the present invention employs compounds described in Table 1 above or pharmaceutically acceptable salts thereof. In some embodiments, the present invention provides compounds described in Table 1 above or pharmaceutically acceptable salts thereof. In some embodiments, the present invention provides a pharmaceutical composition comprising compounds described in Table 1 above or pharmaceutically acceptable salts thereof together with a pharmaceutically acceptable carrier, excipient, or diluent.

[0443] Without being bound by any particular theory, it is believed that proximity of the inhibitor compound or the side group portion of the inhibitor compound to the water of interest favors the replacement or disruption of said water by the inhibitor compound or the side group portion of the inhibitor compound. In some embodiments, the water molecules replaced or disrupted by the inhibitor compound or the side group portion of the inhibitor compound are unstable water molecules.

[0444] In some embodiments, the method employs a complex comprising TYK2 and an inhibitor, wherein at least one unstable water component of TYK2 is replaced or destroyed by the inhibitor. In some embodiments, at least two selected unstable water components are replaced or destroyed by the inhibitor.

[0445] 4. A general method for providing the compounds of the present invention.

[0446] The compounds of the present invention can generally be prepared or isolated by synthetic and / or semi-synthetic methods known to those skilled in the art for similar compounds, as well as by methods described in detail in the examples herein.

[0447] 5. Uses, preparation and application

[0448] Pharmaceutically acceptable compositions

[0449] According to another embodiment, the present invention provides a composition comprising a compound of the present invention or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier, adjuvant, or mediator. The amount of the compound in the composition of the present invention is such that it effectively and measurably inhibits TYK2 protein kinase or a mutant thereof in a biological sample or patient. In some embodiments, the amount of the compound in the composition of the present invention is such that it effectively and measurably inhibits TYK2 protein kinase or a mutant thereof in a biological sample or patient. In some embodiments, the composition of the present invention is formulated for administration to a patient requiring such a composition. In some embodiments, the composition of the present invention is formulated for oral administration to a patient.

[0450] As used herein, the term "patient" refers to an animal, preferably a mammal, and most preferably a human.

[0451] 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 formulated with it. 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 such as human serum albumin, buffering substances such as phosphates, glycine, sorbic acid, potassium sorbate, mixtures of saturated vegetable fatty acids in the form of glycerides, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol, and lanolin.

[0452] "Pharmaceutically acceptable derivative" means any non-toxic salt, ester, ester salt or other derivative of the compound of the present invention that, when administered to a recipient, can directly or indirectly provide the compound of the present invention or its inhibitory metabolites or residues.

[0453] As used herein, the term "its inhibitory active metabolite or residue" means that its metabolite or residue is also an inhibitor of TYK2 protein kinase or its mutants.

[0454] The compositions of the present invention can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implantable receptacle. As used herein, the term "parenterical" includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, 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 the present invention can be an aqueous or oily suspension. These suspensions can be formulated using suitable dispersants or wetting agents and suspending agents according to techniques known in the art. The sterile injectable formulation can also be a sterile injectable solution or suspension in a parenterally acceptable, non-toxic diluent or solvent, such as a solution in 1,3-butanediol. Acceptable mediators and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile, non-volatile oils are conventionally used as solvents or suspension media.

[0455] For this purpose, any mild, non-volatile oil containing synthetic mono- or diglycerides of glycerol can be used. Fatty acids such as oleic acid and their glycerol derivatives can be used to prepare injectable formulations, as can natural, pharmaceutically acceptable oils such as olive oil or castor oil, especially in their polyoxyethylene form. 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). For formulation purposes, 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.

[0456] 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, useful diluents include lactose and dried corn starch. When an aqueous suspension is required for oral use, the active ingredient is combined with an emulsifier and a suspending agent. Sweeteners, flavoring agents, or coloring agents may also be added if desired.

[0457] Alternatively, for rectal administration, the pharmaceutically acceptable compositions of the present invention can be administered in the form of 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.

[0458] The pharmaceutically acceptable compositions of the present invention can also be applied topically, particularly when the therapeutic target comprises an area or organ easily accessible by topical application, including diseases of the eye, skin, or lower intestine. Suitable topical formulations for each of these areas or organs are readily prepared.

[0459] Topical application to the lower intestine can be achieved in the form of rectal suppository formulations (see above) or appropriate enema formulations. Transdermal patches can also be used.

[0460] For topical application, the pharmaceutically acceptable compositions provided can be formulated in suitable ointments containing active ingredients suspended or dissolved in one or more carriers. Carriers for topical application of the compounds of the present invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsified waxes, and water. Alternatively, the pharmaceutically acceptable compositions provided can be formulated in suitable lotions or creams containing active ingredients suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, hexadecyl ester wax, cetearyl alcohol, 2-octyldodecyl alcohol, benzyl alcohol, and water.

[0461] For ophthalmic use, the provided pharmaceutically acceptable composition may be formulated as a micronized suspension in isotonic, pH-adjusted sterile saline, or preferably as a solution in isotonic, pH-adjusted sterile saline (with or without preservatives such as benzalkonium chloride). Alternatively, for ophthalmic use, the pharmaceutically acceptable composition may be formulated in an ointment such as petrolatum.

[0462] The pharmaceutically acceptable compositions of the present invention can also be administered via nasal aerosol or by inhalation. Such compositions are prepared according to techniques well known in the field of pharmaceutical formulation and can be prepared as solutions in saline using benzyl alcohol or other suitable preservatives, absorption enhancers for improving bioavailability, fluorocarbons, and / or other conventional solubilizers or dispersants.

[0463] More 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 administered without food. In other embodiments, the pharmaceutically acceptable compositions of the present invention are administered with food.

[0464] The amount of the compounds of the present invention, which can be combined with carrier materials to produce compositions in a single dosage form, will vary depending on the subject being treated and the specific method of administration. Preferably, the provided compositions should be formulated such that an inhibitor can be administered to patients receiving these compositions at a dose between 0.01 and 100 mg / kg body weight / day.

[0465] It should also be understood that the specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound used, age, weight, general health condition, sex, diet, timing of administration, 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.

[0466] Use of compounds and pharmaceutically acceptable compositions

[0467] The compounds and compositions described herein are generally 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.

[0468] 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 containing TYK2 are essential for cytokine signaling. TYK2 associates with the cytoplasmic domains of type I and type II cytokine receptors, as well as type I and type III interferon receptors, and is activated by these receptors upon cytokine binding. The cytokines involved in TYK2 activation include interferons (e.g., IFN-α, IFN-β, IFN-κ, IFN-δ, IFN-ε, IFN-τ, IFN-ω, and IFN-ζ (also known as restriction factors)) and interleukins (e.g., IL-4, IL-6, IL-10, IL-11, IL-12, IL-13, IL-22, IL-23, IL-27, IL-31, oncokinase 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-Tyk kinase by CNTF-LIF-OSM-IL-6β receptor components", Science (1994) 263:92; Finbloom et al., "IL-10 induces tyrosine phosphorylation of Tyk2 and Jak1 and 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 ( ... "Kinases by IL-2 and IL-12", Journal of Experimental Medicine (J. Exp. Med.) (1995) 181:399; Welham et al., "Interleukin-13 signal transduction in lymphohemopoietic cells: similarities and differences in signal transduction with interleukin-4 and insulin", 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". Subunit (IL-23R)”, Journal of Immunology (2002) 168:5699.Then, the activated TYK2 continues to phosphorylate other signaling proteins, such as members of the STAT family, including STAT1, STAT2, STAT4, and STAT6.

[0469] TYK2 activation by IL-23 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 involved in 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 (2011) 365:1612-1623; Cortes et al., “Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci”, Nature Genetics (2013) 45(7):730-738; Remmers et al., “Genome-wide association study identifies variants in the MHC class I, IL10, and IL23R-IL12RB2 regions associated with Behcet's disease”. IL23R-IL12RB2 regions associated with "Disease", Nature Genetics (2010) 42:698-702. A genome-wide association study of 2,622 individuals with psoriasis identified an association between disease susceptibility and TYK2. Strange et al., "A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1", Nature Genetics (2010) 42:985-992. Knockout of TYK2 or inhibition of tyrosine phosphorylation significantly reduced both IL-23-induced and IL-22-induced dermatitis. Ishizaki et al., "Tyk2 is a therapeutic target for psoriasis-like skin". "inflammation", International Journal of Immunology (Intl. Immunol.) (2013), doi:10.1093 / intimm / dxt062.

[0470] 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," FASEB Journal (FASEB J) (2012) 26:1-11.)

[0471] Decreased 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 inflammatory markers. Ishizaki et al., “Tyk2 deficiency protects joints against destruction in anti-type II collagen antibody-induced arthritis in mice”, International Journal of Immunology (2011) 23(9):575-582.

[0472] Compared to controls, TYK2 knockout mice exhibited complete resistance in experimental autoimmune encephalomyelitis (EAE, an animal model of multiple sclerosis (MS),) with no CD4 T cell invasion in the spinal cord, suggesting that TYK2 is crucial for the pathogenic CD4-mediated disease development in MS. (Oyamada et al., "Tyrosine Kinase 2 Plays Critical Roles in the Pathogenic CD4 T Cell Responses for the Development of Experimental Autoimmune Encephalomyelitis", Journal of Immunology (2009) 183:7539-7546). This confirms 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 TYK2 function due to mutations leads to reduced neuronal demyelination and increased myelin regeneration, further suggesting the role of TYK2 inhibitors in the treatment of MS and other CNS demyelinating diseases.

[0473] TYK2 is the only signaling messenger shared by both IL-12 and IL-23. TYK2 knockout reduced paw pad thickness induced by methylated BSA injection in mice, imiquimod-induced psoriasis-like skin inflammation, and colitis induced by dextran sulfate sodium or 2,4,6-trinitrobenzenesulfonic acid.

[0474] Joint linkage and association studies of various type I IFN signaling genes with systemic lupus erythematosus (SLE, an autoimmune disease) have shown a strong and significant association between loss of function of TYK2 and reduced SLE prevalence in families with affected members. (Sigurdsson et al., "Polymorphisms in the Tyrosine Kinase 2 and Interferon Regulatory Factor 5 Genes Are Associated with Systemic Lupis Erythematosus," *American Journal of Human Genetics* (Am. J. Hum. Genet.) (2005) 76:528-537.) Genome-wide association studies between individuals with SLE and unaffected populations have shown a highly significant association between the TYK2 locus and SLE. Graham et al., “Association of NCF2, IKZF1, IRF8, IFIH1, and TYK2 with Systemic Lupus Erythematosus”, PLoS Genetics (2011) 7(10):e1002341.

[0475] TYK2 has been shown to play an important role in maintaining tumor surveillance, and TYK2 knockout mice exhibit impaired cytotoxic T cell responses and accelerated tumor development. However, these effects are associated with highly efficient suppression of natural killer (NK) cells and cytotoxic T lymphocytes, suggesting that TYK2 inhibitors are 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 is considered a superior target due to its less involvement 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.)

[0476] However, contradicting the reduced tumor surveillance observed by Hima et al., studies on T-cell acute lymphoblastic leukemia (T-ALL) indicate that T-ALL maintains cancer cell survival by upregulating the anti-apoptotic protein BCL2 through STAT1-mediated signal transduction via TYK2 in a highly IL-10-dependent manner. Knockdown of TYK2, rather than other JAK family members, reduced cell growth. TYK2-specific activating mutations that promote cancer cell survival include activating mutations in the FERM domain (G36D, S47N, and R425H), JH2 domain (V731I), and kinase domain (E957D and R1027H). However, TYK2 kinase function was also identified as necessary for enhanced cancer cell survival, as TYK2 enzymes characterized by kinase death mutations (M978Y or M978F), in addition to the activating mutation (E957D), led to transformation failure. Sanda et al., “TYK2-STAT1-BCL2 Pathway Dependence in T-Cell Acute Lymphoblastic Leukemia”, Cancer Disc. (2013) 3(5): 564-577.

[0477] Therefore, selective inhibition of TYK2 is considered a suitable target in 70% of patients with IL-10 and / or BCL2-addicted tumors, such as adult T-cell leukemia cases. (Fontan et al., “Discovering What Makes STAT Signaling TYK in T-ALL”, Cancer Discovery (2013) 3:494-496.)

[0478] 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.)

[0479] Inhibition of the JAK-STAT signaling pathway is also associated with hair growth and reversal of alopecia areata. Xing et al., “Alopecia areata 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.

[0480] Therefore, compounds that inhibit TYK2 activity are beneficial, especially those selective for JAK2. Such compounds should provide a pharmacological response that advantageously treats one or more of the conditions described herein without the side effects associated with JAK2 inhibition.

[0481] Although TYK2 inhibitors are known in the art, there remains a need for novel inhibitors with more potent or advantageous drug-related properties. For example, compounds possessing increased activity, selectivity for other JAK kinases (especially JAK2), and ADMET (absorption, distribution, metabolism, excretion, and / or toxicity) properties. Therefore, in some embodiments, the present invention provides TYK2 inhibitors exhibiting selectivity for JAK2.

[0482] The activity of compounds used as inhibitors of TYK2 or its mutants in this invention can be determined in vitro, in vivo, or in cell lines. In vitro assays include determinations of inhibition of phosphorylation activity and / or subsequent functional outcomes or ATPase activity of activated TYK2 or its mutants. Alternating in vitro assays quantify the ability of an inhibitor to bind to TYK2. Inhibitor binding can be measured by radiolabeling the inhibitor prior to binding, isolating the inhibitor / TYK2 complex, and determining the amount of radiolabeled material bound. Alternatively, inhibitor binding can be determined by running a competition experiment incubating a new inhibitor with TYK2 bound to a known radioligand. Representative in vitro and in vivo assays that can be used to determine TYK2 inhibitors include, for example, those described and disclosed in the literature incorporated herein by reference in its entirety. Details of compounds used to determine inhibitors of TYK2 or its mutants in this invention are set forth in the examples below.

[0483] As used herein, the terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset of a disease or condition or one or more of its symptoms as described herein, or inhibiting its progression. In some embodiments, treatment may be administered after one or more symptoms have occurred. 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 symptom history 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.

[0484] The provided compounds are inhibitors of TYK2 and are therefore useful for treating one or more conditions associated with the activity of TYK2 or its mutants. Thus, in some embodiments, the present invention provides a method for treating TYK2-mediated conditions, the method comprising administering to a patient in need the compound of the present invention or a pharmaceutically acceptable composition thereof.

[0485] As used herein, the term "TYK2-mediated" conditions, diseases, and / or symptoms refer to any disease or other harmful symptom known to be caused by TYK2 or its mutants. Therefore, another embodiment of the invention relates to treating or reducing the severity of diseases caused by one or more known TYK2 or its mutants. Such TYK2-mediated conditions include, but are not limited to, autoimmune diseases, inflammatory diseases, proliferative diseases, endocrine diseases, neurological diseases, and transplant-related diseases.

[0486] 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, nervous system 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.

[0487] In some embodiments, the condition is an autoimmune disease. In some embodiments, the condition is selected from type 1 diabetes, cutaneous lupus erythematosus, systemic lupus erythematosus, multiple sclerosis, psoriasis, Becton's disease, POEMS syndrome, Crohn's disease, ulcerative colitis, and inflammatory bowel disease.

[0488] In some embodiments, the condition is an inflammatory condition. In some embodiments, the inflammatory condition is selected from rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis, hepatomegaly, Crohn's disease, ulcerative colitis, and inflammatory bowel disease.

[0489] In some embodiments, the condition is a proliferative disorder. In some embodiments, the proliferative disorder is a hematologic malignancy. 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.

[0490] 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.

[0491] In some embodiments, the condition is a neurological condition. In some embodiments, the neurological condition is Alzheimer's disease.

[0492] 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.

[0493] In some embodiments, the condition is related to transplantation. In some embodiments, the transplant-related condition is transplant rejection or graft-versus-host disease.

[0494] 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.

[0495] The compounds of this invention can also be used to treat inflammatory or allergic skin conditions, such as psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, herpetic dermatitis, scleroderma, vitiligo, hypersensitivity vasculitis, urticaria, bullous pemphigoid, lupus erythematosus, cutaneous lupus erythematosus, systemic lupus erythematosus, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, acquired bullous epidermolysis bullosa, acne vulgaris, and other inflammatory or allergic skin conditions.

[0496] The compounds of this invention can also be used to treat other diseases or conditions, such as those with inflammatory components, for example, eye diseases and conditions, such as eye allergies, conjunctivitis, dry keratoconjunctivitis, and vernal conjunctivitis; diseases affecting the nose, including allergic rhinitis; and inflammatory diseases involving autoimmune reactions or having autoimmune components or causes, including autoimmune hematologic disorders (e.g., hemolytic anemia, aplastic anemia, pure red cell anemia, and idiopathic thrombocytopenic purpura); cutaneous lupus erythematosus, systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, and Stevens-Johnson syndrome. Syndrome), idiopathic stomatitis diarrhea, autoimmune inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), irritable bowel syndrome, celiac disease, periodontitis, hyaline membrane disease, nephropathy, glomerulonephropathy, alcoholic liver disease, multiple sclerosis, endocrine ophthalmopathy, Graves' disease, sarcoidosis, alveolitis, chronic allergic pneumonia, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), Sjogren's syndrome, keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, cryptothermal protein-related cycle syndrome, nephritis, vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis (with and without nephrotic syndrome),Examples include idiopathic nephrotic syndrome or minimal change disease, chronic granulomatous disease, endometriosis, leptospirosis, glaucoma, retinal disease, aging, headache, pain, complex regional pain syndrome, cardiomegaly, muscular atrophy, catabolism, obesity, fetal growth restriction, hypercholesterolemia, heart disease, chronic heart failure, mesothelioma, anhidrotic ectodermal dysplasia, Becette's disease, pigmentary disorders, and Paget's disease. Diseases, pancreatitis, hereditary periodic fever syndrome, asthma (allergic and non-allergic, mild, moderate, severe, bronchial and exercise-induced asthma), acute lung injury, acute respiratory distress syndrome, eosinophilia, hypersensitivity reactions, 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 associated with 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, localized pneumonia, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendinitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, or vulvitis.

[0497] In some embodiments, the inflammatory diseases that can be treated 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-associated cycle syndrome (CAPS), and osteoarthritis.

[0498] 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, Th 17. The mediated diseases are selected from cutaneous lupus erythematosus, systemic lupus erythematosus, multiple sclerosis, and inflammatory bowel disease (including Crohn's disease or ulcerative colitis).

[0499] In some embodiments, the inflammatory diseases that can be treated according to the method of the present invention are selected from Sjögren's syndrome, allergic conditions, osteoarthritis, ocular conditions such as ocular allergies, conjunctivitis, dry keratoconjunctivitis and vernal conjunctivitis, and diseases affecting the nose such as allergic rhinitis.

[0500] Furthermore, the present invention provides the use of compounds as defined herein, or pharmaceutically acceptable salts, hydrates, or solvates thereof, for the preparation of medicaments for the treatment of autoimmune diseases, inflammatory diseases, or proliferative diseases, or diseases that typically occur in conjunction with transplantation.

[0501] Combination therapy

[0502] Depending on the specific symptom or disease to be treated, additional therapeutic agents typically used to treat said symptom may be used in combination with the compounds and compositions of the present invention. As used herein, additional therapeutic agents typically used to treat a specific disease or symptom are referred to as “the disease or symptom suitable for treatment”.

[0503] In some embodiments, the provided combination or a combination thereof is administered in combination with another therapeutic agent.

[0504] Examples of pharmaceutical agents that can also be combined with the present invention include, but are not limited to: therapeutic agents for Alzheimer's disease, such as... and Treatment agents for HIV, such as ritonavir; treatment agents for Parkinson's disease, such as L-DOPA / carbidopa, entacapone, ropinrole, pramipexole, bromocriptine, pergolide, trihexephendyl, and amantadine; and agents for treating multiple sclerosis (MS), such as beta-interferon (e.g., and ), And mitoxantrone; medications 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, and interferon. Anticonvulsants, ion channel blockers, riluzole, and anti-Parkinson's disease agents; agents for the treatment of cardiovascular diseases, such as beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, and statins; agents for the treatment of liver diseases, such as corticosteroids, cholestyramine, interferon, and antiviral agents; agents for the treatment of hematologic disorders, such as corticosteroids, antileukemic agents, and growth factors; agents that prolong or improve pharmacokinetics, such as cytochrome P450 inhibitors (i.e., inhibitors of metabolic degradation) and CYP3A4 inhibitors (e.g., ketoconazole and ritonavir); and agents for the treatment of immunodeficiency disorders, such as gamma globulin.

[0505] 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.

[0506] These additional agents can be administered separately from the provided combination therapy as part of a multiple-dose regimen. Alternatively, those agents can be a single dosage form mixed with the compounds of the present invention in a single composition. If administered as part of a multiple-dose regimen, the two active agents can be delivered simultaneously, sequentially, or at intervals (typically five hours) between each other.

[0507] As used herein, the terms "combination," "combined," and related terms refer to the simultaneous or sequential administration of therapeutic agents according to the invention. For example, combinations of the invention may be administered simultaneously with another therapeutic agent, or sequentially in individual unit dosage forms, or together in single unit dosage forms.

[0508] The amount of additional therapeutic agent present in the compositions of the present invention will not exceed the amount normally applied in compositions comprising the therapeutic agent as the sole active agent. Preferably, the amount of additional therapeutic agent in the compositions disclosed herein will range from about 50% to 100% of the amount normally present in compositions comprising the pharmaceutical agent as the sole active agent.

[0509] In one embodiment, the present invention provides a composition comprising a compound of formula I and one or more additional therapeutic agents. The therapeutic agent may be administered together with the compound of formula I or may be administered before or after the administration of the compound of formula I. Suitable therapeutic agents are described in further detail below. In some embodiments, the compound of formula I may be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours before the therapeutic agent. In other embodiments, the compound of formula I may be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours after the therapeutic agent.

[0510] In another embodiment, the present invention provides a method for treating an inflammatory disease, condition, or symptom by administering a compound of formula I 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 contain, for example, acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, naproxen, and etodoxacin. (and celecoxib), colchicine Corticosteroids (such as prednisone, prednisolone, methylprednisolone, hydrocortisone, etc.), probenecid, allopurinol, febuxostat sulfasalazine Antimalarial drugs (such as hydroxychloroquine) and chloroquine Methotrexate ), gold salts (such as glucosinolate gold) gold thiomalate And Kinnofen D-Penicillamine or azathioprine Cyclophosphamide Chlorinated nitrogen mustard Cyclosporin Leflunomide and "anti-TNF" drugs (such as etanercept) Infliximab Golimumab Cystuzumab polyethylene glycol and adalimumab ), "anti-IL-1" drugs (such as anakinase) and Linasipu ), cannabinoid 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 tanizine) and anticoagulants (such as heparin) or Warfarin Antidiarrheal medications (such as diphenoxylate) and loperamide Bile acid binders (such as cholestyramine), alosetron Lubiprostone Laxatives (such as magnesium emulsion, polyethylene glycol) and Anticholinergic drugs or anticonvulsants (such as bicyclic amino acids) β-2 agonists (such as salbutamol) L-salbutamol Osinarin Pyrboterol acetate Terbutaline sulfate Salmeterol senna and Formotero Anticholinergic drugs (such as ipratropium bromide) and tiotropium bromide ), inhaled corticosteroids (such as beclomethasone dipropionate) and Triamcinolone Momison Buddyne and flunisulfanil Sodium cromoglycate ), methylxanthine (such as theophylline) And aminophylline), IgE antibodies (such as omalizumab) Nucleoside reverse transcriptase inhibitors (such as zidovudine) Abacave Abacave / Lamivudine Abacavir / Lamivudine / Zidovudine Didano New Enqutabin Lamivudine Lamivudine / Zidovudine Staffidin Hezashitabin ), non-nucleoside reverse transcriptase inhibitors (such as dilavudine) According to Weilen Nevellappi He Yiquweilin Nucleotide reverse transcriptase inhibitors (such as tenofovir) ), protease inhibitors (such as ampravir) Azanavir Darunavir fossavir Indinavir Lopinavir and ritonavir Nefernavir Litonavir Saquinavir or and teranavir ), entry inhibitors (such as entfuvirtide) and Maravero Integrase inhibitors (such as retegvir) Doxorubicin Changchun New Alkali Bortezomib and lenalidomide Combination of dexamethasone (or any one or more combinations thereof).

[0511] In another embodiment, the present invention provides a method for treating rheumatoid arthritis, the method comprising administering to a patient in need a compound of formula I and one or more additional therapeutic agents selected from: nonsteroidal anti-inflammatory drugs (NSAIDs) (such as aspirin, ibuprofen, naproxen, etodoxacin) (and celecoxib), corticosteroids (such as prednisone, prednisolone, methylprednisolone, hydrocortisone, etc.), sulfasalazine Antimalarial drugs (such as hydroxychloroquine) and chloroquine Methotrexate ), gold salts (such as glucosinolate gold) gold thiomalate And Kinnofen D-Penicillamine or azathioprine Cyclophosphamide Chlorinated nitrogen mustard Cyclosporin Leflunomide and "anti-TNF" drugs (such as etanercept) Infliximab Golimumab Cystuzumab polyethylene glycol 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 tocilizumab) ).

[0512] In some embodiments, the present invention provides a method for treating osteoarthritis, the method comprising administering to a patient in need a compound of formula I and one or more additional therapeutic agents selected from: acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs) (such as aspirin, ibuprofen, naproxen, etodoxacin), etc. (and celecoxib), diclofenac, cortisone, hyaluronic acid or And monoclonal antibodies (such as tanidazole).

[0513] In some embodiments, the present invention provides a method for treating cutaneous lupus erythematosus or systemic lupus erythematosus, the method comprising administering to a patient in need a compound of formula I and one or more additional therapeutic agents selected from: acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs) (such as aspirin, ibuprofen, naproxen, etodoxacin), etc. And celecoxib), corticosteroids (such as prednisone, prednisolone, methylprednisolone, hydrocortisone, etc.), antimalarial drugs (such as hydroxychloroquine) and chloroquine Cyclophosphamide Methotrexate ), azathioprine And anticoagulants (such as heparin) or Warfarin

[0514] In some embodiments, the present invention provides a method for treating Crohn's disease, ulcerative colitis, or inflammatory bowel disease, the method comprising administering to a patient in need a compound of formula I and one or more additional therapeutic agents selected from: ammonia salicylic acid sulfasalazine Antidiarrheal medications (such as diphenoxylate) and loperamide Bile acid binders (such as cholestyramine), alosetron Lubiprostone Laxatives (such as magnesium emulsion, polyethylene glycol) and And anticholinergic or anticonvulsant drugs (such as bicyclic amino acids) Anti-TNF therapy, steroids, and antibiotics (such as metronidazole or ciprofloxacin).

[0515] In some embodiments, the present invention provides a method for treating asthma, the method comprising administering to a patient in need a compound of formula I and one or more other therapeutic agents selected from: β-2 agonists (such as salbutamol) L-salbutamol Osinarin Pyrboterol acetate Terbutaline sulfate Salmeterol senna and Formotero Anticholinergic drugs (such as ipratropium bromide) and tiotropium bromide Inhaled corticosteroids (such as prednisone, prednisolone, beclomethasone dipropionate) and Triamcinolone Momison Buddyne and flunisulfanil and Sodium cromoglycate ), methylxanthine (such as theophylline) And aminophylline) and IgE antibodies (such as omalizumab) ).

[0516] In some embodiments, the present invention provides a method for treating COPD, the method comprising administering a compound of formula I and one or more additional therapeutic agents selected from: β-2 agonists, such as salbutamol, to a patient in need. L-salbutamol Osinarin Pyrboterol acetate Terbutaline sulfate Salmeterol hydroxynaphthylcarbamate and Formotero Anticholinergic agents, such as ipratropium bromide and tiotropium bromide Methylxanthine, such as theophylline Theophylline; inhaled corticosteroids, such as prednisone, prednisolone, and beclomethasone dipropionate. and Triamcinolone Momison Buddyne Flunipine and

[0517] In another embodiment, the present invention provides a method for treating hematologic malignancies, the method comprising administering a compound of formula I and one or more additional therapeutic agents selected from rituximab to a patient in need. Cyclophosphamide Doxorubicin Changchun New Alkali Prednisone, hedgehog signaling inhibitors, BTK inhibitors, JAK / pan-JAK inhibitors, PI3K inhibitors, SYK inhibitors, and combinations thereof.

[0518] In another embodiment, the present invention provides a method for treating solid tumors, the method comprising administering a compound of formula I and one or more additional therapeutic agents selected from rituximab to a patient in need. Cyclophosphamide Doxorubicin Changchun New Alkali Prednisone, hedgehog signaling inhibitors, BTK inhibitors, JAK / pan-JAK inhibitors, PI3K inhibitors, SYK inhibitors, and combinations thereof.

[0519] In another embodiment, the present invention provides a method for treating hematologic malignancies, the method comprising administering a compound of formula I 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), which was published online on July 17 and is incorporated herein by reference in its entirety.

[0520] In another embodiment, the present invention provides a method for treating diffuse large B-cell lymphoma (DLBCL), the method comprising administering to a patient in need a compound of formula I and one or more additional therapeutic agents selected from: rituximab Cyclophosphamide Dorothy Star Changchun New Alkali Prednisone, hedgehog signaling inhibitors, and combinations thereof.

[0521] In another embodiment, the present invention provides a method for treating multiple myeloma, the method comprising administering to a patient in need a compound of formula I and one or more additional therapeutic agents selected from the group consisting of lenalidomide. The combination: bortezomib And dexamethasone Hedgehog signaling inhibitors, BTK inhibitors, JAK / pan-JAK inhibitors, TYK2 inhibitors, PI3K inhibitors, and SYK inhibitors.

[0522] In another embodiment, the present invention provides a method for treating a disease or reducing its severity, the method comprising administering a compound of formula I and a BTK inhibitor to a patient in need, wherein the disease is selected from inflammatory bowel disease, arthritis, cutaneous lupus erythematosus, systemic lupus erythematosus (SLE), vasculitis, idiopathic thrombocytopenic purpura (ITP), rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis, Graves' disease, autoimmune thyroiditis, Sjögren's syndrome, multiple sclerosis, systemic sclerosis, neurolyme disease, Guillain-Barré syndrome, acute disseminated encephalomyelitis, Addison's disease. Diseases including oculoclonus-myoclonus syndrome, ankylosing spondylitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, autoimmune gastritis, pernicious anemia, celiac disease, Goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, and Wegener's granulomatosis. Granulomatosis, psoriasis, alopecia universalis, Behcet's disease, chronic fatigue, autonomic nervous system disorders, membranous glomerulonephritis, endometriosis, interstitial cystitis, pemphigus vulgaris, bullous pemphigoid, neuromuscular rigidity, scleroderma, vulvar pain, hyperplastic disorders, transplant organ or tissue rejection, acquired immunodeficiency syndrome (AIDS, also known as HIV), type 1 diabetes, graft-versus-host disease, transplantation, blood transfusion, allergic reactions, allergies (e.g.,Allergies to plant pollen, latex, medications, food, insect toxins, animal hair, animal dander, dust mites, or cockroach calyxes; Type I hypersensitivity reactions; allergic conjunctivitis; allergic rhinitis and atopic dermatitis; asthma; appendicitis; atopic dermatitis; 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-Schonleinpurpura; 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, pneumonia, pulmonary infection, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendinitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis or vulvitis, B-cell proliferative disorders such as diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, acute lymphoblastic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma / Waldenstrom macroglobulinemia. Macroglobulinemia, splenic marginal zone lymphoma, multiple myeloma (also known as plasma cell myeloma), non-Hodgkin's lymphoma, Hodgkin's lymphoma, plasma cell tumor, extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary exudative lymphoma, Burkitt lymphoma. Lymphoma / leukemia or lymphomatoid granulomatosis, breast cancer, prostate cancer or mast cell cancer (e.g. mast cell tumor, mast cell leukemia, mast cell sarcoma, systemic mastocytosis), bone cancer, colorectal cancer, pancreatic cancer, bone and joint diseases, including but not limited to rheumatoid arthritis, seronegative spondyloarthritis (including ankylosing spondylitis, psoriatic arthritis and Rett syndrome), Becette's disease, Sjögren's syndrome, systemic sclerosis, osteoporosis, bone cancer, bone metastases, 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 occlusive disease, 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, allergy, Crohn's disease, irritable bowel syndrome, ulcerative colitis, Sjögren's syndrome, tissue graft rejection, hyperacute rejection of transplanted organs, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), autoimmune polyglandular disease (also known as autoimmune polyglandular syndrome), and so on. Autoimmune alopecia, pernicious anemia, glomerulonephritis, dermatomyositis, multiple sclerosis, scleroderma, vasculitis, autoimmune hemolytic anemia and thrombocytopenia, pulmonary hemorrhage and nephritis syndrome, atherosclerosis, Addison's disease, Parkinson's disease, Alzheimer's disease, diabetes, septic shock, cutaneous lupus erythematosus, systemic lupus erythematosus (SLE), rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, osteoarthritis, chronic idiopathic thrombocytopenic purpura, Wardenstone macroglobulinemia, myasthenia gravis, Hashimoto's thyroiditis, atopic dermatitis, degenerative joint diseases, vitiligo, autoimmune hypopituitarism, Guillain-Barré syndrome, Becton's disease, scleroderma, mycosis fungoides, acute inflammatory reactions (such as acute respiratory distress syndrome and ischemia / reperfusion injury), and Grieve's disease.

[0523] In another embodiment, the present invention provides a method for treating a disease or reducing its severity, the method comprising administering a compound of formula I 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 bone diseases, proliferative diseases, infectious diseases, cell death-related conditions, thrombin-induced platelet aggregation, chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), liver diseases, pathoimmune conditions involving T cell activation, cardiovascular diseases, and CNS diseases.

[0524] In another embodiment, the present invention provides a method for treating a disease or reducing its severity, the method comprising administering a compound of formula I 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, or other tumors of the brain, kidneys (e.g., renal cell carcinoma (RCC)), liver, adrenal glands, bladder, breast, stomach, gastric tumors, ovaries, colon, rectum, prostate, pancreas, lungs, vagina, endometrium, cervix, testes, genitourinary tract, esophagus, larynx, skin, bone, or thyroid gland. Cell tumors, multiple myeloma, or gastrointestinal cancer, especially colon cancer or colorectal adenoma or neck and head tumors; epidermal hyperplasia; psoriasis; benign prostatic hyperplasia; tumor formation; epithelial neoplasia; adenoma; adenocarcinoma; keratoacanthoma; epidermoid carcinoma; large cell carcinoma; non-small cell lung cancer; lymphoma (including, for example, non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (also known as Hodgkin's disease)); breast cancer; follicular carcinoma; undifferentiated carcinoma; papillary carcinoma; seminoma; melanoma; or leukemia, including Cowden syndrome and Lhermitte-Dudos disease. Diseases including Bannayan-Zonana syndrome, or diseases with abnormal activation of the PI3K / PKB pathway; asthma of any type or origin, including intrinsic (non-allergic) asthma and extrinsic (allergic) asthma; mild asthma; moderate asthma; severe asthma; bronchitis-related 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; and other related conditions. Lung or bronchial diseases (COPD, COAD, or COLD), including chronic bronchitis or related dyspnea, emphysema, and exacerbations of airway hypersensitivity caused by other medications, especially inhaled medications; bronchitis of any type or origin, including but not limited to acute, peanut-inhaled, catarrhal, gravid, chronic, or tuberculous bronchitis; and pneumoconiosis of any type or origin (inflammatory (usually occupational) lung disease, often accompanied by airway obstruction, whether chronic or acute, and caused by repeated inhalation of dust).This includes conditions such as aluminosilicate pneumoconiosis, coal miner's disease, asbestosis, stone lung, eyelash loss, iron pneumoconiosis, silicosis, smoke pneumoconiosis and cotton dust pneumoconiosis, Loffler's syndrome, eosinophilic pneumonia, parasitic infections (especially in metazoans) (including tropical eosinophilia), bronchopulmonary aspergillosis, and polyarteritis nodosa (including Churg-Strauss syndrome). Eosinophilic granuloma and eosinophilic-associated symptoms affecting the airways caused by drug reactions, psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, herpetic dermatitis, scleroderma, vitiligo, hypersensitivity vasculitis, urticaria, bullous pemphigoid, lupus erythematosus, pemphigus, acquired epidermolysis bullosa, conjunctivitis, keratoconjunctivitis sicca and vernal conjunctivitis, diseases affecting the nose (including allergic rhinitis), and inflammatory diseases involving autoimmune reactions or having autoimmune components or causes, including autoimmune hematologic disorders (e.g., hemolytic anemia, aplastic anemia, pure red cell aplasia, and idiopathic thrombocytopenic purpura), cutaneous lupus erythematosus, systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener's granulomatosis. Nulamatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Stevens-Johnson syndrome, idiopathic steatorrhea, autoimmune inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), endocrine ophthalmological disorders, Grieve's disease, sarcoidosis, alveolar ulceration, chronic allergic pneumonia, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior uveitis), keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis, and glomerulonephritis (with and without nephrotic syndrome), including idiopathic nephrotic syndrome or minimal change disease, restenosis, cardiac hypertrophy, atherosclerosis, myocardial infarction, ischemic stroke and congestive heart failure, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease. Diseases including cerebral ischemia and neurodegenerative diseases caused by traumatic injury, glutamate neurotoxicity, and hypoxia.

[0525] In some embodiments, the present invention provides a method for treating a disease or reducing its severity, the method comprising administering a compound of formula I 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 solid tumor.

[0526] In some embodiments, the present invention provides a method for treating a disease or reducing its severity, the method 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. Other suitable JH2 domain-binding compounds include those described in WO 2014 / 074660A1, WO 2014 / 074661A1, and WO 2015 / 089143A1, the entire contents of each of which are incorporated herein by reference. Suitable JH1 domain-binding compounds include those described in WO 2015 / 131080A1, the entire contents of which are incorporated herein by reference.

[0527] According to the method of the invention, compounds and compositions can be administered in any amount and via any route of administration that is effective in treating or alleviating the severity of the following: autoimmune diseases, inflammatory diseases, proliferative diseases, endocrine diseases, neurological diseases, or transplant-related diseases. The precise amount required will vary depending on the subject, taking into account the subject's type, age, and overall condition, the severity of the infection, the specific agent, the method of administration, etc. The compounds of the invention are preferably formulated in dose units for ease of administration and dosage uniformity. As used herein, the expression "dose unit form" refers to physically discrete units of pharmaceutical preparation suitable for the patient to be treated. However, it should be understood that the total daily dose of the compounds and compositions of the invention will be determined by the attending physician within the bounds of reasonable medical judgment. The specific effective dose level for any particular patient or organism will depend on a variety of factors, including the disease being treated and its severity; the activity of the specific compound used; the specific composition used; the patient's age, weight, overall health condition, sex, and diet; the timing, route of administration, and excretion rate of the specific compound used; the duration of treatment; drugs used in combination with or concurrently with the specific compound used; and similar factors well known in the medical field. As used herein, the term "patient" means animal, preferably mammal and most preferably human.

[0528] The pharmaceutically acceptable compositions of the present invention may be administered to humans and other animals orally, rectally, parenterally, intracerebrospinally, vaginally, intraperitoneally, topically (e.g., by powder, ointment, or drops), buccally, orally as a spray or nasal spray, depending on the severity of the infection being treated. In some embodiments, the compounds of the present invention may be administered orally or parenterally once or more daily at dose levels of about 0.01 mg / kg to about 50 mg / kg, and preferably about 1 mg / kg to about 25 mg / kg of subject body weight per day, to achieve the desired therapeutic effect.

[0529] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, liquid dosage forms may also contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide, oils (specifically, 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 sorbitan, and mixtures thereof. In addition to inert diluents, oral compositions may also contain adjuvants, such as humectants, emulsifiers and suspending agents, sweeteners, flavoring agents, and aroma agents.

[0530] Injectable formulations, such as sterile injectable aqueous or oily suspensions, can be formulated using suitable dispersants or wetting agents and suspending agents according to known techniques. Sterile injectable formulations can also be sterile injectable solutions, suspensions, or emulsions in parenteral-acceptable non-toxic diluents or solvents, such as solutions in 1,3-butanediol. Acceptable mediators and solvents that can be used include water, Ringer's solution, USP, and isotonic sodium chloride solution. Additionally, sterile, non-volatile oils are routinely used as solvents or suspension media. For this purpose, any mild fixed oil containing synthetic monoglycerides or diglycerides can be used. Furthermore, fatty acids such as oleic acid are used to prepare injectables.

[0531] Injectable formulations can be sterilized, for example, by filtering through a bacterial trap or by incorporating a sterilizing agent in the form of a sterile solid composition, which can be dissolved or dispersed in sterile water or other sterile injectable media before use.

[0532] To prolong the effects of the compounds of this invention, it is generally desirable to slow the absorption of compounds from subcutaneous or intramuscular injection. This can be achieved by using liquid suspensions of poorly water-soluble crystals or amorphous materials. Thus, the absorption rate of the compound depends on its dissolution rate, which in turn can depend on crystal size and crystal form. Alternatively, delayed absorption of the parenteral administration of the compound can be achieved by dissolving or suspending the compound in an oily medium. Injectable depot forms are prepared by forming a microcapsule matrix of the compound in a biodegradable polymer such as polylactide-polyglycolic acid. The release rate of the compound can be controlled depending on the ratio of compound to polymer and the properties of the specific polymer used. Examples of other biodegradable polymers include poly(orthoester) and poly(anhydride). Depot-type injectable formulations are also prepared by retaining the compound in liposomes or microemulsions compatible with human tissue.

[0533] Compositions for rectal or vaginal application are preferably suppositories, which can be prepared by mixing the compounds of the invention with suitable non-irritating excipients or carriers (such as cocoa butter, polyethylene glycol, or suppository wax), which are solid at room temperature but liquid at body temperature and thus can melt in the rectal or vaginal cavity and release the active compound.

[0534] 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) fillers or enrichers, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders, such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; c) humectants, such as glycerin; d) disintegrants, such as agar-agar, calcium carbonate, potato or cassava starch, alginate, certain silicates, and sodium carbonate; e) solution blockers, such as paraffin; f) absorption enhancers, such as quaternary ammonium compounds; g) humectants, such as cetyl alcohol and glyceryl monostearate; h) adsorbents, such as kaolin and bentonite; and i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also include a buffer.

[0535] Similar solid compositions can also be used as fillers in soft-filled and hard-filled gelatin capsules, which use excipients such as lactose or toffee and high molecular weight polyethylene glycol. Solid dosage forms of tablets, sugar-coated pills, capsules, pellets, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the field of pharmaceutical formulation. Dosage forms may optionally contain emulsifiers, and their composition may also allow the dosage form to optionally release one or more active ingredients in a delayed manner, either exclusively or preferentially, in a specific portion of the intestine. Examples of encapsulation compositions that can be used include polymeric substances and waxes. Similar solid compositions can also be used as fillers in soft-filled and hard-filled gelatin capsules, which use excipients such as lactose and high molecular weight polyethylene glycol.

[0536] The active compound can also be in microencapsulated form with one or more excipients as described above. Solid dosage forms such as tablets, sugar-coated pills, capsules, pellets, and granules can be prepared using coatings and shells (such as enteric coatings, release-controlled coatings, and other coatings well known in the field of pharmaceutical formulation). In such solid dosage forms, the active compound can be mixed with at least one inert diluent (such as sucrose, lactose, or starch). Under normal circumstances, in addition to inert diluents, such dosage forms may also include other substances, 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 forms may also include buffers. The dosage forms may optionally contain emulsifiers, and their composition may also allow the dosage forms to optionally release one or more active ingredients in a delayed manner, either only or preferentially, in a specific portion of the intestine. Examples of encapsulation compositions that can be used include polymers and waxes.

[0537] Dosage forms for topical or transdermal application of the compounds used in this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalers, or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any desired preservatives or buffers that may be required. Ophthalmic formulations, ear drops, and eye drops are also contemplated within the scope of this invention. Additionally, the invention contemplates the use of transdermal patches, which have the added advantage of delivering the compound to the body in a controlled manner. Such dosage forms can be prepared by dissolving or dispersing the compound in a suitable medium. Absorption enhancers can also be used to increase the flow rate 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.

[0538] According to one embodiment, the present invention relates to a method for inhibiting protein kinase activity in a biological sample, the method comprising the step of contacting the biological sample with a compound of the present invention or a composition comprising the compound.

[0539] According to another embodiment, the present invention relates to a method for inhibiting the activity of TYK2 or its mutant in a biological sample, the method comprising 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 mutant in a biological sample, the method comprising contacting the biological sample with a compound of the present invention or a composition comprising the compound.

[0540] In another embodiment, the present invention provides a method for selectively inhibiting TYK2 by more than one or more of JAK1, JAK2, and JAK3. In some embodiments, the selectivity of the compounds of the present invention is more than 2 times greater than that of JAK1 / 2 / 3. In some embodiments, the selectivity of the compounds of the present invention is more than 5 times greater than that of JAK1 / 2 / 3. In some embodiments, the selectivity of the compounds of the present invention is more than 10 times greater than that of JAK1 / 2 / 3. In some embodiments, the selectivity of the compounds of the present invention is more than 50 times greater than that of JAK1 / 2 / 3. In some embodiments, the selectivity of the compounds of the present invention is more than 100 times greater than that of JAK1 / 2 / 3.

[0541] 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.

[0542] Inhibiting TYK2 (or its mutants) activity in biological samples can be used for a variety of purposes known to those skilled in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ transplantation, biological specimen storage, and bioassay.

[0543] Another embodiment of the present invention relates to a method for inhibiting the activity of a protein kinase in a patient, the method comprising the step of administering the compound of the present invention or a composition comprising the compound to the patient.

[0544] According to another embodiment, the present invention relates to a method for inhibiting the activity of TYK2 or its mutants in a patient, the method comprising 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 TYK2s or their mutants in a patient, the method comprising 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 a condition mediated by TYK2 or its mutants in a patient in need, the method comprising administering to the patient a compound of the present invention or a pharmaceutically acceptable composition thereof. Such conditions are described in detail herein.

[0545] Depending on the specific symptom or disease to be treated, the compositions of the present invention may also contain additional therapeutic agents that are typically administered for treating said symptom. As used herein, additional therapeutic agents that are typically administered for treating a specific disease or symptom are referred to as “the disease or symptom suitable for treatment”.

[0546] The compounds of this invention can also be used in combination with other therapeutic compounds to produce advantages. In some embodiments, the other therapeutic compounds are antiproliferative 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 processes; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; antitumor antimetabolites; platinum compounds; compounds that target / reduce the activity of protein or lipid kinases and additional anti-angiogenic compounds; compounds that target protein or lipid phosphatases, reduce or inhibit their activity; gonadotropin-releasing hormone agonists; anti-androgens; methionine aminopeptidase inhibitors; matrix metalloproteinase inhibitors; diphosphates; biological response modifiers; antiproliferative antibodies; heparanase inhibitors; Ras oncogenic isotype inhibitors; telomerase inhibitors; proteasome inhibitors; compounds for the treatment of hematologic malignancies; compounds that target Flt-3, reduce or inhibit its activity; Hsp90 inhibitors, such as those from Conforma Pharmaceuticals. Therapeutics' 17-AAG (17-allylaminogeldemycin, NSC330507), 17-DMAG (17-dimethylaminoethylamino-17-demethoxy-geldemycin, NSC707545), IPI-504, CNF1010, CNF2024, CNF1010; temozolomide Kinesin spindle protein inhibitors, such as SB715992 or SB743921 from GlaxoSmithKline, or pentamicilin / chlorpromazine from CombinatoRx; MEK inhibitors, such as ARRY142886 from Array BioPharma, AZD6244 from AstraZeneca, PD181461 from Pfizer, and formyltetrahydrofolate. As used herein, the term "aromatase inhibitor" refers to compounds that inhibit estrogen production, such as those that convert substrates androstenedione and testosterone into estrone and estradiol, respectively. The term includes, but is not limited to, steroids, particularly atamestane, exemestane, and formestane, and especially nonsteroids, particularly aminoglutethimide, roglethimide, pyridoglutethimide, trilostane, testolactone, ketoconazole, vorozole, fadrozole, anastrozole, and letrozole. Exemestane is marketed under the trade name Aromasin. TM Sales. Formistan is marketed under the trademark Lentaron. TM Sales. Fazodazole 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. Ammonia luminetin is marketed under the trademark Orimeten. TM Sales. The compositions of the present invention, including chemotherapeutic agents that are aromatase inhibitors, are particularly useful for treating hormone receptor-positive tumors, such as breast tumors.

[0547] As used herein, the term "anti-estrogenic" refers to compounds that antagonize the effects of estrogen at estrogen receptor levels. The 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. TMSales. Fluvestralc is marketed under the brand name Faslodex. TM Sales. The combinations of the present invention, including those used as anti-estrogenic chemotherapeutic agents, are particularly useful for treating estrogen receptor-positive tumors, such as breast tumors.

[0548] As used herein, the term "anti-androgen" refers to any substance capable of inhibiting the biological effects of androgens and includes, but is 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 is marketed under the brand name Zoladex. TM Sale.

[0549] As used herein, the term "topoisomerase I inhibitor" includes, but is not limited to: topotecan, gimatecan, irinotecan, camptothecian and its analogues, 9-nitrocamptothecian and the macromolecular camptothecian conjugate PNU-166148. Irinotecan may be marketed, for example, under the trademark Camptosar. TM Topotecan is administered through a sales channel. It is marketed under the brand name Hycamptin. TM Sale.

[0550] As used herein, the term "topoisomerase II inhibitor" includes, but is not limited to, anthracyclines such as doxorubicin (including liposomal formulations such as Caelyx). TM The drugs include daunorubicin, epirubicin, idarubicin, and nemorubicin; anthraquinones—mitoxantrone and losoxantrone; and podophillotoxine—etoposide and teniposide. Etoposide is marketed under the brand name Etopophos. TM Sales. Teniposide is marketed under the brand name VM 26-Bristol. Doxorubicin is 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. TMSales. Mitoxantrone is sold under the brand name Novantron.

[0551] The term "microtubule activator" encompasses microtubule-stabilizing compounds, microtubule-destabilizing compounds, 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; spongiol; colchicine and epochycin and their derivatives. Paclitaxel is marketed under the trade name Taxol. TM Sales. Dorcetathione is marketed under the trademark 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.

[0552] 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.

[0553] 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 isohydroxamic acid (SAHA).

[0554] The term "antitumor 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.

[0555] As used herein, the term "platinum compound" includes, but is not limited to, carboplatin, cisplatin, cisplatinum, and oxaliplatin. Carboplatin may be marketed, for example, under the trademark Carboplatin TM Oxaliplatin can be administered, for example, under the trademark Eloxatin. TM The form of sales is applied.

[0556] 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 platelet-derived growth factor receptor (PDGFR) activity, 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 fibroblast growth factor receptor (FGFR) activity; c) compounds that target, reduce or inhibit insulin-like growth factor receptor I (IGF-IR) activity, 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 Compounds that target, reduce, or inhibit the activity of the Trk receptor tyrosine kinase family or hepatin B4 inhibitors; e) compounds that target, reduce, or inhibit the activity of the AxI receptor tyrosine kinase family; f) compounds that target, reduce, or inhibit the activity of Ret receptor tyrosine kinases; g) compounds that target, reduce, or inhibit the activity of Kit / SCFR receptor tyrosine kinases, such as imatinib; h) compounds that target, reduce, or inhibit the activity of C-kit receptor tyrosine kinases (which are part of the PDGFR family), such as compounds that target, reduce, or inhibit the activity of c-Kit receptor tyrosine kinases. Compounds containing the activity of the c-amino kinase family, 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 serine / threonine kinases, such as 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 (CDK) family members, such as midostaurin;Other examples of compounds include UCN-01, safingol, BAY 43-9006, bryostatin 1, perifosine; ilmofosine; RO 318220 and RO320432; GO 6976; lsis 3521; LY333531 / LY379196; isoquinoline compounds; FTI; PD184352 or QAN697 (P13K inhibitor) or AT7519 (CDK inhibitor); k) compounds that target, reduce or inhibit the activity of protein-tyrosine kinase inhibitors, such as imatinib mesylate (Gleevec); TM Or tyrosine phosphorylation inhibitors, such as tyrosine phosphorylation inhibitor A23 / RG-50810; AG 99; tyrosine phosphorylation inhibitor AG 213; tyrosine phosphorylation inhibitor AG 1748; tyrosine phosphorylation inhibitor AG 490; tyrosine phosphorylation inhibitor B44; tyrosine phosphorylation inhibitor B44(+) enantiomer; tyrosine phosphorylation inhibitor AG555; AG 494; tyrosine phosphorylation inhibitor AG 556, AG957 and adaphostin (4-{[(2,5-dihydroxyphenyl)methyl]amino}-adamantyl benzoate; NSC 680410, Adafustin); l) compounds that target receptor tyrosine kinases (EGFR1, ErbB2, ErbB3, ErbB4 as homodimers or heterodimers) and their mutants, the epidermal growth factor family, or compounds that reduce or inhibit their activity, such as compounds that target the epidermal growth factor receptor family, or compounds that reduce or inhibit their activity, especially those that inhibit members of the EGF receptor tyrosine kinase family, such as EGF receptor, ErbB2, ErbB3 and ErbB4 or compounds, proteins or antibodies that bind to EGF or EGF-associated ligands, CP 358774, ZD 1839, ZM 105180; trastuzumab (Herceptin) TM ), cetuximab (Erbitux) TM), 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 the activity of c-Met receptors, such as compounds that target, reduce or inhibit the activity of c-Met, especially those that inhibit c- Compounds that activate the kinase activity of the Met receptor, or antibodies that target the extracellular domain of c-Met or bind to HGF; n) compounds that target, reduce, or inhibit the kinase activity of one or more JAK family members (JAK1 / JAK2 / JAK3 / TYK2 and / or pan-JAK), including but not limited to PRT-062070, SB-1578, baricitinib, pacritinib, and momelotinib. (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, and pictrelisib. ), PF-4691502, BYL-719, dactolisib, XL-147, XL-765 and ederanisib; and q) compounds that target, reduce or inhibit signal transduction of the hedgehog protein (Hh) or smooth receptor (SMO) pathway, including but not limited to cycloparamine, vemodigine, itraconazole, erismodegib and IPI-926 (saridegib).

[0557] As used herein, the term "PI3K inhibitor" includes, but is not limited to, compounds that have inhibitory activity against one or more enzymes in the phosphatidylinositol-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 may be used in this invention include, but are not limited to: ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, bupanisic, pictenisic, PF-4691502, BYL-719, datonisic, XL-147, XL-765, and ederanisic.

[0558] As used herein, the term "BTK inhibitor" includes, but is not limited to, compounds that have inhibitory activity against Bruton's tyrosine kinase (BTK), including, but not limited to, AVL-292 and ibrutinib.

[0559] 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.

[0560] As used herein, the term "Bcl-2 inhibitor" includes, but is not limited to, compounds with inhibitory activity against B-cell lymphoma 2 protein (Bcl-2), including, but not limited to, ABT-199, ABT-731, ABT-737, apogossypol, pan-Bcl-2 inhibitors of Ascenta, curcumin (and its analogues), dual Bcl-2 / Bcl-xL inhibitors (Infinity Pharmaceuticals / Novartis Pharmaceuticals), Genasense (G3139), HA14-1 (and its analogues; see WO 2008 / 118802), navitoclax (and its analogues; see U.S. Patent No. 7,390,799), NH-1 (Shenayng Pharmaceutical University), and obatoclax (and its analogues; see WO 2008 / 118802). 2004 / 106328), 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.

[0561] Further examples of BTK inhibitory compounds and conditions that can be treated by combining such compounds with the compounds of the present invention can be found in WO 2008 / 039218 and WO 2011 / 090760, the entire contents of which are incorporated herein by reference.

[0562] Further examples of SYK-inhibiting compounds and conditions that can be treated by combining such compounds with the compounds of the present invention can be found in WO 2003 / 063794, WO 2005 / 007623 and WO 2006 / 078846, the entire contents of which are incorporated herein by reference.

[0563] Further examples of PI3K inhibitory compounds and conditions that can be treated by combining such compounds with the compounds of the present invention can be found in WO2004019973, WO 2004 / 089925, WO 2007 / 016176, U.S. Patent No. 8,138,347, WO 2002 / 088112, WO 2007 / 084786, WO 2007 / 129161, WO 2006 / 122806, WO 2005 / 113554 and WO 2007 / 044729, the entire contents of which are incorporated herein by reference.

[0564] Further examples of JAK inhibitory compounds and symptoms that can be treated by combining such compounds with the compounds of the present invention can be found in WO 2009 / 114512, WO 2008 / 109943, WO 2007 / 053452, WO 2000 / 142246 and WO2007 / 070514, the entire contents of which are incorporated herein by reference.

[0565] Other anti-angiogenic compounds include those with an alternative mechanism of action, such as those unrelated to protein or lipid kinase inhibition, like thalidomide. TM ) and TNP-470.

[0566] 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), salinosporamide A, carfilzomib, ONX-0912, CEP-18770, and MLN9708.

[0567] Compounds that target proteins or lipid phosphatases and reduce or inhibit their activity are, for example, inhibitors of phosphatase 1, phosphatase 2A, or CDC25, such as okadaic acid or its derivatives.

[0568] Compounds that induce cell differentiation include, but are not limited to, retinoic acid, α-γ- or δ-tocopherol, or α-γ- or δ-tocotrienol.

[0569] As used herein, the term cyclooxygenase inhibitor includes, but is not limited to, Cox-2 inhibitors, 5-alkyl-substituted 2-arylaminophenylacetic acid and derivatives, such as celecoxib (Celebrex). TM rofecoxib (Vioxx) TMEtoricoxib, valdecoxib, or 5-alkyl-2-arylaminophenylacetic acid, such as 5-methyl-2-(2'-chloro-6'-fluorophenylamino)phenylacetic acid or lumiracoxib.

[0570] As used herein, the term "bisphosphonate" includes, but is not limited to, etridonic acid, clodronic acid, tiludronic acid, pamidronic acid, alendronic acid, ibandronic acid, risedronic acid, and zoledronic acid. Etidronic acid is marketed under the trade name Didronel. 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 marketed 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 antiproliferative activity, such as sirolimus. everolimus (Certican) TM ), CCI-779 and ABT578.

[0571] As used herein, the term "heparinase inhibitor" refers to a compound that targets, reduces, or inhibits the degradation of heparan sulfate. The term includes, but is not limited to, PI-88. As used herein, the term "biological response modulator" refers to lymphokines or interferons.

[0572] As used herein, the term "inhibitor of Ras oncogenic isoforms," ​​such as H-Ras, K-Ras, or N-Ras, refers to compounds that target Ras, reduce, or inhibit its oncogenic activity; for example, "farnesyltransferase inhibitors," such as L-744832, DK8G557, or R115777 (Zarnesyltransferase inhibitors). TMAs used herein, the term "telomerase inhibitor" refers to a compound that targets telomerase, reduces or inhibits its activity. Compounds that target telomerase, reduce or inhibit its activity are particularly compounds that inhibit telomerase receptors, such as telomerostrin.

[0573] As used herein, the term "methionine aminopeptidase inhibitor" refers to a compound that targets methionine aminopeptidase and reduces or inhibits its activity. Compounds that target methionine aminopeptidase and reduce or inhibit its activity include, but are not limited to, bengamide or its derivatives.

[0574] As used herein, the term "proteasome inhibitor" refers to a compound that targets the proteasome and reduces or inhibits its activity. Compounds that target the proteasome and reduce or inhibit its activity include, but are not limited to, bortezomib (Velcade). TM ) and MLN 341.

[0575] As used herein, the term “matrix metalloproteinase inhibitor” or (“MMP” inhibitor) includes, but is not limited to: collagen peptide and non-peptide inhibitors, tetracycline derivatives, such as the isohydroxamic acid peptide inhibitor batimastat and its orally bioavailable analogues marimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551), BMS-279251, BAY 12-9566, TAA211, MMI270B, or AAJ996.

[0576] As used herein, the term "compounds for the treatment of hematologic malignancies" includes, but is not limited to, FMS-like tyrosine kinase inhibitors, which are compounds that target the FMS-like tyrosine kinase receptor (Flt-3R) and reduce or inhibit its activity; interferon, arabinofuransylcytosine (ara-c), and bisulfite; ALK inhibitors, which are compounds that target, reduce, or inhibit anaplastic lymphoma kinase and Bcl-2 inhibitors.

[0577] Compounds that target the FMS-like tyrosine kinase receptor (Flt-3R), reduce or inhibit its activity, especially compounds, proteins or antibodies that inhibit members of the Flt-3R receptor kinase family, such as PKC412, midostaurin, astrocytocin derivatives, SU11248 and MLN518.

[0578] As used herein, the term "HSP90 inhibitor" includes, but is not limited to, compounds that target HSP90, reduce or inhibit its intrinsic ATPase activity; compounds that degrade, target, reduce or inhibit HSP90 client proteins via the ubiquitin-proteasome pathway. Compounds that target HSP90, reduce or inhibit its intrinsic ATPase activity, particularly compounds, proteins or antibodies that inhibit the ATPase activity of HSP90, such as 17-allylamino, 17-demethoxygeldmycin (17AAG), geldmycin derivatives; other geldmycin-related compounds; rhizocarpine and HDAC inhibitors.

[0579] 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. An antibody refers to a complete monoclonal antibody, polyclonal antibody, multispecific antibody formed by at least two complete antibodies, and antibody fragments, as long as they exhibit the desired biological activity.

[0580] For the treatment of acute myeloid leukemia (AML), the compounds of the present invention can be used in combination with standard leukemia therapies, particularly with therapies used to treat AML. Specifically, the compounds of the present invention can be administered in combination with, for example, farnesyltransferase inhibitors and / or other drugs used to treat AML, such as donomycin, adriamycin, Ara-C, VP-16, teniposide, mitoxantrone, idarubicin, carboplatinum, and PKC412. In some embodiments, the present invention provides a method for treating AML associated with ITD and / or D835Y mutations, the method 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.

[0581] Other anti-leukemia compounds include, for example, the pyrimidine analog Ara-C, a 2'-α-hydroxyriboside (arabinoside) derivative of deoxycytidine. Also included are purine analogs of hypoxanthine, 6-mercaptopurine (6-MP), and fludarabine phosphate. Histone deacetylase (HDAC) inhibitors, compounds that reduce or inhibit their activity, such as sodium butyrate and salicylanilide isohydroxamic 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 U.S. Patent No. 6,552,065, including, but not limited to, N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-acrylamide or pharmaceutically acceptable salts thereof, and N-hydroxy-3-[4-[(2-hydroxyethyl){2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-acrylamide or pharmaceutically acceptable salts thereof, especially lactate. As used herein, somatostatin receptor antagonists refer to compounds that target, treat, or inhibit somatostatin receptors, such as octreotide and SOM230. Tumor cell damage methods refer to methods such as ionizing radiation. The term "ionizing radiation" as used above and below refers to ionizing radiation produced as electromagnetic rays (such as X-rays and gamma rays) or particles (such as alpha 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, in Principles and Practice of Oncology, eds. Devita et al., 4th ed., Vol. 1, pp. 248-275 (1993).

[0582] It 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 for use in combination with ara-C for ALL), and / or pentostatin. Ribonucleotide reductase inhibitors are particularly hydroxyurea or 2-hydroxy-1H-isoindole-1,3-dione derivatives.

[0583] It also specifically includes compounds, proteins, or monoclonal antibodies that contain VEGF, such as 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or its pharmaceutically acceptable salts, 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate; 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 macugan; FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgG1 antibodies, angiozyme (RPI 4610) and bevacizumab (Avastin) TM ).

[0584] As used in this article, photodynamic therapy refers to the use of certain chemicals known as photosensitizing compounds to treat or prevent cancer. Examples of photodynamic therapy include the use of compounds such as Visudyne. TM Treatment with compounds such as porfimer sodium.

[0585] As used in this article, angiogenesis-inhibiting steroids refer to compounds that block or inhibit angiogenesis, such as anecortave, triamcinolone, hydrocortisone, 11-α-epihydrocotisol, cortexolone, 17α-hydroxyprogesterone, corticosterone, deoxycorticosterone, testosterone, estrone, and dexamethasone.

[0586] Implants containing corticosteroids refer to compounds such as fluocinolone acetonide and dexamethasone.

[0587] Other chemotherapeutic compounds include, but are not limited to: plant alkaloids, hormone compounds and antagonists; biological response modulators, preferably lymphokines or interferons; antisense oligonucleotides or oligonucleotide derivatives; shRNA or siRNA; or other compounds or compounds with other or unknown mechanisms of action.

[0588] The compounds of the present invention can also be used as co-therapeutic compounds for use in combination with other drugs such as anti-inflammatory drugs, bronchodilators, or antihistamines, particularly for the treatment of obstructive or inflammatory airway diseases as mentioned above, for example, as therapeutic enhancers of such drugs or as a method of reducing the required administration or potential side effects of such drugs. The compounds of the present invention can be mixed with other drugs in a fixed pharmaceutical composition or can be administered alone before, simultaneously with, or after other drugs. Therefore, the present invention comprises combinations of the compounds of the present invention as described above with anti-inflammatory drugs, bronchodilators, antihistamines, or antitussives, wherein the compounds and drugs of the present invention are in the same or different pharmaceutical compositions.

[0589] Suitable anti-inflammatory drugs include steroids, especially glucocorticoids, such as budesonide, beclomethasone dipropionate, fluticasone propionate, ciclesonide, or mometasone furoate; nonsteroidal glucocorticoid receptor agonists; LTB4 antagonists, such as LY293111, CGS025019C, CP-195543, SC-53228, BIIL 284, ONO 4057, and SB 209247; LTD4 antagonists, such as montelukast and zafirlukast; and PDE4 inhibitors, such as cilomilast. GlaxoSmithKline, Roflumilast (BykGulden), V-11294A (Napp), BAY19-8004 (Bayer), SCH-351591 (Schering-Plough), Arofylline (Almirall) Prodesfarma), PD189659 / PD168787 (Parke-Davis), AWD-12-281 (AstaMedica), CDC-801 (Celgene), SeICID(TM)CC-10004 (Celgene), VM554 / UM565 (Vernalis), T-440 (Tanabe), KW-4490 (Kyowa Hakko Kogyo); A2a agonists; A2b antagonists; and β-2 adrenergic receptor agonists, such as salbutamol, osinerol, terbutaline, salmeterol, fenoterol, procaterol, and especially formoterol and its pharmaceutically acceptable salts. Suitable bronchodilators include anticholinergic or antimuscarinic compounds, particularly ipratropium bromide, oxytropium bromide, tiotropium salts and CHF 4226 (Chiesi) and glycopyrrolate.

[0590] Suitable antihistamines include cetirizine hydrochloride, acetaminophen, clemastine fumarate, promethazine, loratidine, desloratidine, diphenhydramine, fexofenadine hydrochloride, activastine, astemizole, azelastine, ebastine, epinastine, mizolastine, and tefenadine.

[0591] Other possible combinations of the compounds of the present invention with anti-inflammatory drugs are combinations with, for example, antagonists of the following chemokine receptors: CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, CCR-8, CCR-9 and CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, especially CCR-5 antagonists, such as Schering-Plough antagonists SC-351125, SCH-55700 and SCH-D, and Takeda antagonists, such as N-[[4-[[[6,7-dihydro-2-(4-methylphenyl)-5H-benzo-cycloheptene-8-yl]carbonyl]amino]phenyl]-methyl]tetrahydro-N,N-dimethyl-2H-pyran-4-ammonium chloride (TAK-770).

[0592] The structure of an active compound identified by its code name, generic name, or trademark name can be taken from the actual version of the standard outline "The Merck Index" or databases such as Patents International (e.g., IMS World Publications).

[0593] The compounds of the present invention can also be used in combination with known treatment methods, such as the administration of hormones or radiation. In some embodiments, the provided compounds are used as radiosensitizers, particularly for treating tumors that exhibit poor sensitivity to radiotherapy.

[0594] The compounds of the present invention can be administered alone or in combination with one or more other therapeutic compounds. Possible combination therapies may take the form of a fixed combination or the administration of the compounds of the present invention with one or more other therapeutic compounds may be interspersed or administered independently of each other, or a fixed combination may be administered in combination with one or more other therapeutic compounds. In addition, the compounds of the present invention may be administered in combination with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention, or combinations thereof for specific purposes in cancer therapy. Long-term therapy is also possible, such as adjuvant therapy in the context of other treatment strategies as described above. Other possible treatments include therapies to maintain the patient's condition after tumor regression, or even chemopreventive therapy, for example, in at-risk patients.

[0595] These additional agents can be administered separately from the composition containing the compounds of the present invention as part of a multi-dosing regimen. Alternatively, those agents can be a single dosage form mixed with the compounds of the present invention in a single composition. If administered as part of a multi-dosing regimen, the two active agents can be delivered simultaneously, sequentially, or at intervals (typically five hours) between each other.

[0596] As used herein, the terms "combination," "combined," and related terms refer to the simultaneous or sequential administration of therapeutic agents according to the invention. For example, compounds of the invention may be administered simultaneously with another therapeutic agent, or sequentially in separate unit dosage forms, or together in a single unit dosage form. Accordingly, the invention provides a single unit dosage form comprising compounds of the invention, additional therapeutic agents, and pharmaceutically acceptable carriers, adjuvants, or mediators.

[0597] The amounts of both the compound of the invention, which can be combined with a carrier material to produce a single dosage form, and additional therapeutic agents (in those compositions including additional therapeutic agents as described above) will vary depending on the subject being treated and the specific mode of administration. Preferably, the compositions of the invention should be formulated such that a dose of the compound of the invention of 0.01-100 mg / kg body weight / day can be administered.

[0598] In compositions that include additional therapeutic agents, the additional therapeutic agents and the compounds of the present invention can work 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 μg / kg body weight / day.

[0599] The amount of additional therapeutic agent present in the compositions of the present invention will not exceed the amount normally applied in compositions comprising the therapeutic agent as the sole active agent. Preferably, the amount of additional therapeutic agent in the compositions disclosed herein will range from about 50% to 100% of the amount normally present in compositions comprising the pharmaceutical agent as the sole active agent.

[0600] The compounds of the present invention or pharmaceutical compositions thereof can also be incorporated into compositions for coating implantable medical devices such as prostheses, artificial valves, vascular grafts, stents, and catheters. For example, vascular stents have been used to overcome restenosis (re-narrowing of the vessel wall after injury). However, patients using 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 including a kinase inhibitor. Implantable devices coated with the compounds of the present invention are another embodiment of the invention.

[0601] The invention will now be further described by way of non-limiting embodiments 1 to 31.

[0602] Example 1:

[0603] A compound of formula I:

[0604]

[0605] Or its pharmaceutically acceptable salt, wherein:

[0606] R 1 Yes -L 1 -R 1A ;

[0607] L 1 Is it a covalent bond or C 1-6 Divalent saturated or unsaturated straight-chain or branched hydrocarbon chains, wherein one or both methylene units of the chain are optionally and independently replaced by: -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)-, -S(O)2- or -Cy-;

[0608] Cy is a 5-6 membered monocyclic heteroaryl ring having 1-4 independently selected heteroatoms chosen from nitrogen, oxygen, and sulfur, optionally substituted; an 8-10 membered bicyclic heteroaryl ring having 1-4 independently selected heteroatoms chosen from nitrogen, oxygen, and sulfur, optionally substituted; a 3-7 membered saturated or partially unsaturated carbocyclic ring; or a 7-12 membered saturated or partially unsaturated bicyclic heterocycle having 1-4 independently selected heteroatoms chosen from nitrogen, oxygen, and sulfur, optionally substituted;

[0609] R 1A It is C that is arbitrarily substituted. 1-6 Aliphatic; optionally substituted 3-7 membered saturated or partially unsaturated monocyclic carbon rings; optionally substituted 3-7 membered monocyclic heterocycles having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or optionally substituted 6-10 membered bridged heterocycles having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or optionally substituted 5-10 membered heteroaryl monocyclic or bicyclic rings having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0610] R 2 It is -C(O)NH2; -C(O)NHR 2A ;-C(O)N(R 2A )2; or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl ring is separated by m R 2B Instance replacement;

[0611] R 2A It is a substituted 3-6 membered saturated or partially unsaturated carbon ring or a substituted 3-6 membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0612] R 2BIt is a C1-C6 aliphatic ...

[0613] R 3 Yes - NHR 3A ;

[0614] R 3A It's me;

[0615] Each R is independently hydrogen or a optionally substituted group selected from the following: C 1-6 Aliphatic; phenyl; 3-7 membered saturated or partially unsaturated heterocycles having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and 5-6 membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur:

[0616] Each hydrogen atom bonded to carbon can optionally and independently be replaced by deuterium; and

[0617] m can be 0, 1, or 2.

[0618] Example 2:

[0619] The compound according to Example 1 has formula II or IV:

[0620]

[0621] Or its pharmaceutically acceptable salt.

[0622] Example 3:

[0623] The compound according to Example 1 or 2 has formula III or V:

[0624]

[0625] Or its pharmaceutically acceptable salt.

[0626] Example 4:

[0627] The compound according to any one of Examples 1 to 3 has Formula VI:

[0628]

[0629] Or its pharmaceutically acceptable salt.

[0630] Example 5:

[0631] The compound according to any one of Examples 1 to 3 has the formula VII:

[0632]

[0633] Or its pharmaceutically acceptable salt.

[0634] Example 6:

[0635] The compound according to any one of Examples 1 to 5 has the formula VIII:

[0636]

[0637] Or its pharmaceutically acceptable salt.

[0638] Example 7:

[0639] According to any one of Examples 1 to 6, the compound wherein R 1A Selected from:

[0640]

[0641]

[0642] Example 8:

[0643] The compound according to any one of Examples 1 to 4, 6 and 7, wherein R 2A Selected from:

[0644]

[0645] Example 9:

[0646] The compound according to any one of Examples 1 to 8 is selected from the compounds depicted in Table 1 or their pharmaceutically acceptable salts.

[0647] Example 10:

[0648] A pharmaceutical composition comprising a compound according to any one of Examples 1 to 9 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or mediator.

[0649] Example 11:

[0650] The compound according to any one of Examples 1 to 9 or the pharmaceutical composition according to Example 10 is used to manufacture an agent for treating TYK2-mediated conditions, diseases, or symptoms in patients.

[0651] Example 12:

[0652] A method for inhibiting TYK2 in a biological sample, the method comprising contacting the sample with a compound according to any one of Examples 1 to 9 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to Example 10.

[0653] Example 13:

[0654] A method for treating a patient with TYK2-mediated conditions, diseases, or symptoms, the method comprising administering to the patient a compound according to any one of Examples 1 to 9 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to Example 10.

[0655] Example 14:

[0656] According to the method described in Example 13, the disease is selected from autoimmune diseases, inflammatory diseases, proliferative diseases, endocrine diseases, nervous system diseases, or transplant-related diseases.

[0657] Example 15:

[0658] The method according to Example 14, wherein the disease is an autoimmune disease.

[0659] Example 16:

[0660] According to the method described in Example 15, the autoimmune disease is selected from type 1 diabetes, ankylosing spondylitis, cutaneous lupus erythematosus, systemic lupus erythematosus, multiple sclerosis, systemic sclerosis, psoriasis, Crohn's disease, ulcerative colitis, and inflammatory bowel disease.

[0661] Example 17:

[0662] According to the method described in Example 14, the condition is an inflammatory condition.

[0663] Example 18:

[0664] According to the method described in Example 17, the inflammatory condition is selected from rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis, Crohn's disease, ulcerative colitis, and inflammatory bowel disease.

[0665] Example 19:

[0666] According to the method described in Example 14, the condition is a proliferative condition.

[0667] Example 20:

[0668] According to the method described in Example 19, the proliferative condition is a hematologic cancer.

[0669] Example 21:

[0670] According to the method described in Example 19, the proliferative condition is leukemia.

[0671] Example 22:

[0672] The method according to Example 21, wherein the leukemia is T-cell leukemia.

[0673] Example 23:

[0674] According to the method described in Example 22, the T-cell leukemia is T-cell acute lymphoblastic leukemia (T-ALL).

[0675] Example 24:

[0676] According to the method described in Example 20, the proliferative condition is associated with one or more activating mutations in TYK2.

[0677] Example 25:

[0678] The method according to Example 14, wherein the condition is related to transplantation.

[0679] Example 26:

[0680] According to the method described in Example 25, the condition is transplant rejection or graft-versus-host disease.

[0681] Example 27:

[0682] The method according to Example 14, wherein the condition is an endocrine disorder.

[0683] Example 28:

[0684] According to the method described in Example 27, the endocrine disorder is polycystic ovary syndrome, Kruzon syndrome, or type 1 diabetes.

[0685] Example 29:

[0686] The method according to Example 14, wherein the condition is a neurological condition.

[0687] Example 30:

[0688] According to the method described in Example 29, the neurological condition is Alzheimer's disease.

[0689] Example 31:

[0690] According to the method described in Example 14, the condition is associated with type I interferon, IL-10, IL-12 or IL-23 signaling.

[0691] illustration

[0692] As depicted in the examples below, in some exemplary embodiments, 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.

[0693] Preparation of nucleus A: 7-((tert-butoxycarbonyl)(methyl)amino)-5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylic acid

[0694]

[0695] Step 1 – Synthesis of Int-1.1: Diethyl malonate (103.2 g, 644.51 mmol, 2.0 equivalent) was added to a solution of Int-1 (50 g, 322.25 mmol, 1.0 equivalent) in ethanol (250 mL), followed by dropwise addition of sodium ethoxide (75 mL, 21% ethanol solution, 3.0 equivalent). The reaction mixture was heated and stirred under reflux for 20 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain a water-soluble residue, which was acidified to pH approximately 3-4 with concentrated hydrochloric acid. The precipitated solid was filtered, washed with water and diethyl ether, and dried thoroughly to obtain pure Int-1.1 (43 g, yield: 59.79%; MS (ES): m / z 224.2 [M+H)). + ).

[0696] Step 2 – Synthesis of Int-1.2: Diethylaniline (43 g, 288.9 mmol, 1.5 equivalent) was added to a mixture of Int-1.1 (43 g, 192.6 mmol, 1.0 equivalent) and phosphorus oxychloride (191 g, 1251 mmol, 6.5 equivalent). The reaction mixture was stirred at 80 °C for 3 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain a residue, which was transferred to ice-cold water and extracted with dichloromethane. The organic layers were combined, washed with a saturated sodium bicarbonate solution, then washed with a brine solution, dried with sodium sulfate, and concentrated under reduced pressure to obtain a crude material. This crude material was further purified by column chromatography, and the compound was eluted in a hexane solution of 20% ethyl acetate to obtain pure Int1.2 (35 g, yield: 69.85%; MS (ES): m / z 261 [M+H)). + ).

[0697] Step 3 – Synthesis of Int-1.3: Potassium carbonate (18.57 g, 134.58 mmol, 1.0 equivalent) was added to an ethanol (350 mL) solution of Int-1.2 (35 g, 134.58 mmol, 1.0 equivalent) at 0 °C, followed by the addition of methylamine (40% aqueous solution) (10.95 mL, 141.3 mmol, 1.05 equivalent), and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain a residue, which was then transferred to ice-cold water. The precipitated solid was filtered, washed with water, and thoroughly dried under vacuum to obtain Int-1.3 (30 g, yield: 87.53%; MS (ES): m / z 255.6 [M+H]). + ).

[0698] Step 4 – Synthesis of Int-1.4: N,N-dimethylaminopyridine (1.43 g, 11.78 mmol, 0.1 equivalence) was added to a solution of Int-1.3 (30 g, 117.8 mmol, 1.0 equivalence) in 1,4-dioxane (300 mL), followed by di-tert-butyl dicarbonate (51.36 g, 235.6 mmol, 2.0 equivalence). The reaction mixture was stirred at room temperature for 12 hours. After the reaction was complete, the reaction mixture was transferred to water, and the product was extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to obtain the crude material. This crude material was further purified by column chromatography, and the compound was eluted in a hexane solution of 12% ethyl acetate to obtain Int-1.4 (26 g; 62.21%; MS (ES): m / z 355 [M+H)). + ).

[0699] Step 5 – Synthesis of Nucleus A: Tributyltin oxide (67.19 g, 112.73 mmol, 2.0 equivalent) was added to a suspension of Int-1.4 (20 g, 56.37 mmol, 1.0 equivalent) in toluene (200 mL), and the reaction mixture was heated at 120 °C for 12 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain a residue, which was dissolved in a saturated sodium bicarbonate solution and washed with hexane. The aqueous layer was separated and acidified with 1N hydrochloric acid to a pH of approximately 5-6 and extracted with ethyl acetate. The organic layers were combined, dried with sodium sulfate, and concentrated under reduced pressure to obtain a solid, which was ground with hexane to obtain pure nucleus A (13.2 g, yield: 71.67%). 1 H NMR(DMSO-d6,400MHZ):12.63(s,1H),8.63(s,1H),7.55(s,1H),3.31(s,3H),1.29(s,9H)).

[0700] Preparation of nucleus B: 7-(benzyl(methyl)amino)-5-chloropyrazolo[1,5-a]pyrimidine-3-carboxamide

[0701]

[0702]

[0703] Step 1 – Synthesis of Int-2.1: Diethyl malonate (141 mL, 925.06 mmol, 2.0 equivalent) was added to a methanol (400 mL) solution of Int-2 (50 g, 462.5 mmol, 1.0 equivalent), followed by dropwise addition of sodium ethoxide (21% ethanol solution; 108 mL, 1387.5 mmol, 3.0 equivalent). The reaction mixture was heated and stirred under reflux for 10 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain a water-soluble residue, which was acidified to pH approximately 3-4 with concentrated hydrochloric acid. The precipitated solid was filtered, washed with water and diethyl ether, and dried thoroughly to obtain pure Int-2.1 (50 g, yield: 61.38%; MS (ES): m / z 177.14 [M+H)). + ).

[0704] Step 2 – Synthesis of Int-2.2: Diethylaniline (68.26 mL, 426.13 mmol, 1.5 equivalent) was added to a mixture of Int-2.1 (50 g, 283.87 mmol, 1.0 equivalent) and phosphorus oxychloride (163 mL, 1704.54 mmol, 6.0 equivalent). The reaction mixture was stirred at 90 °C for 3 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain a residue, which was transferred to ice-cold water and extracted with dichloromethane. The organic layers were combined, washed with a saturated sodium bicarbonate solution, then washed with a brine solution, dried with sodium sulfate, and concentrated under reduced pressure to obtain a crude material. This crude material was further purified by column chromatography, and the compound was eluted in a hexane solution of 20% ethyl acetate to obtain pure Int-2.2 (45 g, yield: 74.42%; MS (ES): m / z 214.02 [M+H)). + ).

[0705] Step 3 – Synthesis of Int-2.3: Potassium carbonate (7.12 g, 51.63 mmol, 1.1 equivalent) was added to an ethanol (315 mL) solution of Int-2.2 (10 g, 46.94 mmol, 1.0 equivalent) at 0 °C, followed by the addition of benzylamine (5.64 mL, 51.63 mmol, 1.1 equivalent), and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain a residue, which was then transferred to ice-cold water. The precipitated solid was filtered, washed with water, and thoroughly dried under vacuum to obtain Int 2.3 (10 g, yield: 71.54%; MS (ES): m / z 298.75 [M+H]). + ).

[0706] Step 4 – Synthesis of Core B: Triphenylphosphine (1.76 g, 6.72 mmol, 0.2 equivalent) was added to a solution of Int-2.3 (10 g, 33.59 mmol, 1.0 equivalent) in a toluene:ethanol:water mixture (160 mL, 1.0:0.5:0.25) at 0 °C, followed by acetaldehyde oxime (3.96 g, 67.18 mmol, 2.0 equivalent). The reaction mixture was stirred at 110 °C for 5 hours. After the reaction was complete, the reaction mixture was transferred to water, and the product was extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to obtain the crude material. This crude material was further purified by column chromatography, and the compound was eluted in a hexane solution of 25% ethyl acetate to obtain core B (4.7 g, yield: 44.32%; MS (ES): m / z 315.76 [M+H)). + ; 1 H NMR (DMSO-d6, 400MHZ): 8.44 (s, 1H), 7.52-7.50 (d, J = 8Hz, 1H), 7.44 (s, 1H), 7.38-7.29 (m, 5H), 6.50 (s, 1H), 5.41 (s, 2H), 3.23 (s, 3H)).

[0707] Preparation of nucleus C: 5-chloro-1-(4-methoxybenzyl)-2,3-dihydro-1H-pyrazolo[5',1':2,3]pyrimidino[5,4-b][1,4]oxazine-7-carboxylic acid

[0708]

[0709] Step 1 – Synthesis of Compound Int-3.2: Int-3.1 (104.5 g, 645.16 mmol, 2.0 equivalent) was added to a solution of Int-3 (50 g, 322.58 mmol, 1.0 equivalent) in ethanol (250 mL), followed by dropwise addition of sodium ethoxide (75 mL, 21% ethanol solution, 3.0 equivalent). The reaction mixture was heated and stirred under reflux for 20 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain a water-soluble residue, which was acidified to pH approximately 3-4 with concentrated hydrochloric acid. The precipitated solid was filtered, washed with water and diethyl ether, and dried thoroughly to obtain pure Int-3.1 (43 g, yield: 52.70%; MS (ES): m / z 254.07 [M+H)). + ).

[0710] Step 2 – Synthesis of Compound Int-3.3: Diethylaniline (75.7 g, 507.87 mmol, 3.0 equivalent) was added to a mixture of Int-3.2 (43 g, 169.29 mmol, 1.0 equivalent) and phosphorus oxychloride (168.3 g, 1100.38 mmol, 6.5 equivalent). The reaction mixture was stirred at 80 °C for 3 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain a residue, which was transferred to ice-cold water and extracted with dichloromethane. The organic layers were combined, washed with a saturated sodium bicarbonate solution, then washed with a brine solution, dried with sodium sulfate, and concentrated under reduced pressure to obtain a crude material. This crude material was further purified by column chromatography, and the compound was eluted in a hexane solution of 20% ethyl acetate to obtain pure Int-3.2 (35 g, yield: 71.05%; MS (ES): m / z 291.00 [M+H)). + ).

[0711] Step 3 – Synthesis of Compound Int-3.5: Int-3.4 (4.2 g, 68.96 mmol, 1.0 equivalent) and triethylamine (13.9 g, 137.92 mmol, 2.0 equivalent) were added to a solution of Int-3.3 (20 g, 68.96 mmol, 1.0 equivalent) in isopropanol (200 mL). The reaction mixture was stirred at 80 °C for 6 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography. The compound was eluted in a 3% methanol solution in dichloromethane to obtain pure Int-3.5 (10.0 g, yield: 46.09%; MS (ES): m / z 315.08 [M+H)). + ).

[0712] Step 4 – Synthesis of Compound Int-3.6: Boron tribromide (39.8 g, 159.2 mmol, 5.0 equivalent) was added dropwise to a mixture of Int-3.5 (10.0 g, 31.84 mmol, 1.0 equivalent) in dichloromethane (100 mL) at -78 °C. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was transferred to sodium bicarbonate and the product was extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to obtain the crude material. This crude material was further purified by column chromatography, and the compound was eluted in a solution of 10% methanol in dichloromethane to obtain pure Int-3.6 (6.0 g, yield: 62.80%; MS (ES): m / z 302.06 [M+H)). + ).

[0713] Step 5 – Synthesis of Compound Int-3.7: Triphenylphosphine (13.06 g, 49.86 mmol, 3.0 equivalent) and diisopropyl azodicarbonate (10.07 g, 49.86 mmol, 3.0 equivalent) were added to a solution of Int-3.6 (6.0 g, 16.62 mmol, 1.0 equivalent) in dichloromethane (80 mL) at 0 °C. The reaction mixture was stirred at room temperature for 12 hours. After the reaction was complete, the reaction mixture was transferred to water, and the product was extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to obtain Int-3.7 (3.9 g, yield: 83.60%; MS (ES): m / z 283.06 [M+H]). + ).

[0714] Step 6 – Synthesis of Compound Int-3.8: 4-Methoxybenzyl chloride (2.3 g, 15.20 mmol, 1.1 equivalent) and cesium carbonate (8.9 g, 27.84 mmol, 2.0 equivalent) were added to a solution of Int-3.7 (3.9 g, 13.82 mmol, 1.0 equivalent) in N,N-dimethylformamide (40 mL) at 0 °C. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was transferred to water, and the product was extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to obtain the crude material. This crude material was further purified by column chromatography, and the compound was eluted in a hexane solution of 20% ethyl acetate to obtain pure Int-3.8 (3.0 g, yield: 53.98%; MS (ES): m / z 403.11 [M+H)). + ).

[0715] Step 7 – Synthesis of Nuclear C: Tributyltin oxide (8.8 g, 14.92 mmol, 2.0 equivalent) was added to a suspension of Int-3.8 (3.0 g, 7.46 mmol, 1.0 equivalent) in toluene (30 mL), and the reaction mixture was refluxed for 12 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain a residue, which was dissolved in a saturated sodium bicarbonate solution and washed with hexane. The aqueous layer was separated and acidified to pH 5-6 with 1 N hydrochloric acid and extracted with ethyl acetate. The organic layers were combined, dried with sodium sulfate, and concentrated under reduced pressure to obtain a solid, which was milled with hexane to obtain pure nuclear C (1.9 g, yield: 68.79%). MS (ES): m / z 375.08 [M+H] + .

[0716] Preparation of nucleus D: ethyl 7-(benzyl(methyl)amino)-5-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate

[0717]

[0718] Synthesis of compound Int-4: The compound Int-4 was synthesized using the general procedure of nuclear A synthesis. (Yield: 45%) MS (ES): m / z 345.10 [M+H] + .

[0719] Synthesis of compound Int-4.2: Argon was purged through a stirred solution of 1 (3.5 g, 10.15 mmol, 1.0 equivalent), Int-4.1 (4.5 g, 13.19 mmol, 1.3 equivalent), and sodium carbonate (2.6 g, 25.37 mmol, 2.5 equivalent) in 1,4-dioxane:water (140 mL, 9:1) for 15 min. [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (0.738 mg, 1.01 mmol, 0.1 equivalent) was added, and the mixture was further purged for 10 min. The reaction was stirred at 110 °C for 6 h. After the reaction was complete, the reaction mixture was poured into water, and the product was extracted with ethyl acetate. The organic layers were combined, washed with a saline solution, dried over sodium sulfate, and concentrated under reduced pressure to obtain Int-4.2 (3.1 g, 57.99%). MS(ES): m / z 527.24 [M+H] +

[0720] Synthesis of compound core D: A solution of 1,4-dioxane in 4M hydrochloric acid (60 mL) was added to Int-4.2 (3.1 g, 5.88 mmol, 1.0 equivalence) and stirred at room temperature for 4 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the residue was stirred with saturated sodium bicarbonate solution and extracted with dichloromethane. The organic layers were combined, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain the residue, which was then ground with diethyl ether to obtain core D (2.1 g, 83.64%). MS (ES): m / z 427.18 [M+H] +

[0721] General procedure A (acid-amine coupling):

[0722]

[0723] Synthesis of Int-5: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridine 3-oxyhexafluorophosphate (9.32 g, 24.53 mmol, 2.0 equivalent) was added to a solution of nucleus A (4 g, 12.26 mmol, 1.0 equivalent) in N,N-dimethylformamide (40 mL) and stirred at room temperature for 15 min. Diisopropylethylamine (6.40 mL, 36.78 mmol, 3.0 equivalent) was added, followed by cyclopropaneamine (0.699 g, 12.26 mmol, 1.0 equivalent). The reaction mixture was stirred at room temperature for 5 min. After the reaction was complete, the reaction mixture was transferred to water, and the product was extracted with ethyl acetate. The organic layers were combined, washed with a brine solution, dried over sodium sulfate, and concentrated under reduced pressure to obtain the crude material. The crude material was further purified by column chromatography, and the compound was eluted in a hexane solution of 40% ethyl acetate to obtain Int-5 (2.4 g, yield: 53.69%; MS (ES): m / z 366.13 [M+H)). + ).

[0724] Standard procedure B (Buchwald amination)

[0725]

[0726] Synthesis of Int-6.2: Int-6.1 (0.082 g, 0.410 mmol, 1.2 equivalence) and sodium carbonate (0.072 g, 0.684 mmol, 2.0 equivalence) were added to a solution of Int-5 (0.125 g, 0.342 mmol, 1.0 equivalence) in 1,4-dioxane (5 mL). The reaction mixture was degassed under an argon atmosphere for 10 min, and then tris(dibenzylacetone)dipalladium(0) (0.015 g, 0.017 mmol, 0.05 equivalence) and 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthracene (0.019 g, 0.034 mmol, 0.1 equivalence) were added, followed by another 5 min of degaussing. The reaction mixture was stirred at 100 °C for 4 h. After the reaction was complete, the reaction mixture was cooled to room temperature, transferred to water, and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried with sodium sulfate, and concentrated under reduced pressure to obtain a crude material. This crude material was further purified by combi flash using a 3% methanol-dichloromethane solution as eluent to obtain pure Int-6.2 (0.070 g, yield: 38.6%; MS (ES): m / z 532.23 [M+H)). + ).

[0727] General procedure C (BOC unprotection)

[0728]

[0729] Synthesis of Int-7.1: Int-6.2 (0.070 g, 0.131 mmol, 1.0 equivalence) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (0.1 mL) was added to the reaction mixture. The reaction was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was transferred to a saturated bicarbonate solution, and the product was extracted with dichloromethane. The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to obtain a crude material. This crude material was further purified by milling with diethyl ether to obtain pure Int-7.1 (0.040 g, yield: 70.17%; MS (ES): m / z 432.24 [M+H)). + ).

[0730] Preparation of intermediate A: 3-amino-1-(tetrahydro-2H-pyran-4-yl)pyridin-2(1H)-one

[0731]

[0732] Synthesis of compound Int-8.2: Copper acetate (2.60 g, 14.28 mmol, 1.0 equivalent) and triethylamine (5.00 mL, 35.7 mmol, 2.5 equivalent) were added to a solution of Int-8 (3 g, 14.28 mmol, 1.0 equivalent) and Int-8.1 (2.4 g, 17.14 mmol, 1.2 equivalent) in dioxane (30 mL) under nitrogen atmosphere. The reaction was stirred at 80 °C for 5 h. After the reaction was complete, the reaction mixture was transferred to ice-cold water and the product was extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to obtain crude material. This crude material was further purified by column chromatography, and the compound was eluted in a hexane solution of 10% ethyl acetate to obtain pure Int-8.2 (0.380 g, 11.98%). MS (ES): m / z 222.20 [M+H] + .

[0733] Synthesis of Intermediate A: Carbon-supported palladium (0.100 g) was added to a methanol (4 mL) solution of Int-8.1 (0.380 g, 1.71 mmol, 1.0 equivalence). The reaction mixture was purged with hydrogen for 3 hours at room temperature. After the reaction was complete, the reaction mixture was filtered through a diatomaceous earth bed and washed with methanol. The filtrate was concentrated under reduced pressure to obtain a crude material. This crude material was further purified by column chromatography, eluting the compound in a 1.4% methanol solution in dichloromethane to obtain pure intermediate A (0.120 g, 36.13%). MS (ES): m / z 195.23 [M+H] + .

[0734] Example 1: N-cyclopropyl-5-((1-(3-hydroxy-3-methylcyclohexyl)-2-oxo-1,2-dihydropyridin-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (I-1).

[0735]

[0736] Option 1:

[0737]

[0738] Step 1 – Synthesis of Compound 1.2: 1.1 (0.217 g, 1.68 mmol, 1.0 equivalent) was added to a cooled solution of 1 (0.260 g, 1.68 mmol, 1.0 equivalent) in N,N-dimethylformamide (4 mL). The reaction mixture was stirred at 0 °C for 30 min and then further stirred at room temperature for 15 min. N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.338 g, 2.18 mmol, 1.3 equivalent) and 4-dimethylaminopyridine (0.040 g, 0.33 mmol, 0.2 equivalent) were added. The reaction mixture was stirred at room temperature for 24 h. After the reaction was complete, the reaction mixture was transferred to water and the product was extracted with ethyl acetate. The organic layers were combined, washed with a brine solution, dried over sodium sulfate, and concentrated under reduced pressure to obtain a crude material. This crude material was further purified by column chromatography, and the compound was eluted in a solution of 1.7% methanol in dichloromethane to obtain 1.2. (0.154 g, yield: 34.41%; MS (ES): m / z 266.13 [M+H]) + ).

[0739] Step 2 – Synthesis of Compound 1.3: Lithium hydroxide (0.124 g, 0.52 mmol, 10 equivalents) was added to a tetrahydrofuran:water (4 mL, 2:1) solution of 1.2 (0.140 g, 0.52 mmol, 1.0 equivalent). The reaction was stirred at 60 °C for 16 h. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain a residue. Water was added to this residue at 10 °C and acidified with 1 N hydrochloric acid to adjust the pH to about 6–6.5. The product was extracted with dichloromethane. The organic layers were combined, washed with brine, dried with sodium sulfate, and concentrated under reduced pressure to obtain a crude material. This crude material was further purified by column chromatography, and the compound was eluted in a 2.1% methanol solution in dichloromethane to obtain pure 1.3 (0.130 g, yield: 89.13%; MS (ES): m / z 252.12 [M+H)). + ).

[0740] Step 3 – Synthesis of Compound 1.4: Triethylamine (0.087 g, 0.86 mmol, 1.7 equivalent) and diphenylphosphoazide (0.182 g, 0.66 mmol, 1.3 equivalent) were added to a solution of 1.3 (0.130 g, 0.51 mmol, 1.0 equivalent) in 3 mL of tert-butanol under nitrogen atmosphere, and the mixture was heated at 80 °C for 16 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, transferred to water, and the product was extracted with ethyl acetate. The organic layers were combined, washed with a brine solution, dried over sodium sulfate, and concentrated under reduced pressure to obtain the crude material. This crude material was further purified by column chromatography, and the compound was eluted in a hexane solution of 22% ethyl acetate to obtain pure 1.4 (0.210 g, yield: 95.93%; MS (ES): m / z 323.19 [M+H)). + ).

[0741] Step 4 – Synthesis of Compound 1.5: A solution of dioxane in 4N hydrochloric acid (6 mL) was added dropwise to a cooled solution of 1.4 (0.210 g, 0.65 mmol, 1 equivalent) in 4 mL of dioxane. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain pure 1.5 (0.170 g, yield: 97.90%; MS (ES): m / z 223.14 [M+H)). + ).

[0742] Step 5 – Synthesis of Compound 1.6: The compound was synthesized using the procedure for preparing nucleus A to obtain 1.6 (yield: 57.16%; MS (ES): m / z 366.82 [M+H)). + ).

[0743] Step 6 – Synthesis of Compound 1.7: The compound was synthesized using general procedure B to obtain 1.7 (0.130 g, yield: 61.58%; MS (ES): 552.29 [M+H)). + ).

[0744] Step 7 – Synthesis of Compound I-1: The compound was synthesized using standard procedure C to obtain I-1 (0.025 g, yield: 87.27%; MS (ES): 452.42 [M+H)). + LCMS purity: 96.18%; HPLC purity: 96.68%; Chiral HPLC: 47.64% and 48.76%; 1H NMR(DMSO-d6,400MHZ):8.92(s,1H),8.20(s,1H),8.12-8.10(d,J=8Hz,1H),7.93-7.92(d,J=4 .8Hz,1H),7.84-7.83(d,J=4Hz,1H),7.47-7.45(d,J=6.4Hz,1H),7.40(s,1H),6.35-6.31(t,J =7.2Hz,1H),6.20(s,1H),4.92(bs,1H),4.69(bs,1H),2.91-2.90(d,J=4.8Hz,3H),1.78(bs,3 H),1.67(bs,2H),1.45-1.48(m,2H),1.24(bs,4H),0.80-0.79(d,J=5.6Hz,2H),0.51(bs,2H)).

[0745] Example 2: N-cyclopropyl-5-((1-((1S,3R)-3-hydroxy-3-methylcyclohexyl)-2-oxo-1,2-dihydropyridin-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (I-2) and N-cyclopropyl-5-((1-((1R,3S)-3-hydroxy-3-methylcyclohexyl)-2-oxo-1,2-dihydropyridin-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (I-3).

[0746]

[0747] Option 2:

[0748]

[0749] Step 1 – Synthesis of Compound 2: Compound 2 was synthesized according to the experimental protocol of I-1 (Example 1) to obtain 2 (yield: 61.58%; MS (ES): m / z 552.29 [M+H]). + ).

[0750] Step 2 – Synthesis of compounds 2.1 and 2.2: The isomers 2 (0.105 g) were separated using a CHIRALCEL OJ-H column (250 mm * 4.6 mm, 5 μm) and a methanol solution of 0.1% DEA as a co-solvent at a flow rate of 4 mL / min to obtain pure fraction-1 (FR-a) and fraction-2 (FR-b).

[0751] FR-a was concentrated under reduced pressure at 30 °C to obtain pure 2.1 (0.040 g; MS (ES): m / z 552.29 [M+H]). + ).

[0752] FR-b was concentrated under reduced pressure at 30°C to obtain pure 2.2 (0.042 g; MS (ES): m / z 552.29 [M+H]). + .

[0753] Step 3 – Synthesis of Compound I-2: The compound was synthesized using standard procedure C to obtain I-2 (0.032 g, yield: 97.74%; MS (ES): m / z 452.2 [M+H]). + LCMS purity: 99.00%; HPLC purity: 99.58%; Chiral HPLC purity: 100%; 1 H NMR(DMSO-d6,400MHZ):8.89(s,1H),8.18(s,1H),8.10-8.08(d,J=6.8Hz,1H),7.91-7.89(d, J=4.8Hz,1H),7.82-7.81(d,J=3.6Hz,1H),7.45-7.43(d,J=6.8Hz,1H),6.33-6.29(t,J=7.2H z,1H),6.16(s,1H),4.67(s,1H),2.89-2.88(d,J=4.4Hz,3H),2.86-2.82(m,1H),1.76(bs,2H ),1.59(bs,2H),1.46-1.40(m,2H),1.23(s,6H),0.78-0.77(d,J=5.2Hz,2H),0.49(bs,2H)).

[0754] Step 4 – Synthesis of Compound I-3: The compound was synthesized using standard procedure C to obtain I-3 (0.032 g, yield: 93.08%; MS (ES): m / z 452.2 [M+H)). + LCMS purity: 100%; HPLC purity: 98.97%; Chiral HPLC purity: 98.25%; 1H NMR(DMSO-d6,400MHZ):8.90(s,1H),8.18(s,1H),8.10-8.08(d,J=6.8Hz,1H),7.90-7.89(d, J=4.8Hz,1H),7.82-7.81(d,J=3.6Hz,1H),7.45-7.43(d,J=6.8Hz,1H),6.33-6.29(t,J=7.2H z,1H),6.16(s,1H),4.67(s,1H),2.89-2.88(d,J=4.4Hz,3H),2.86-2.82(m,1H),1.76(bs,2H ),1.59(bs,2H),1.46-1.40(m,2H),1.22(s,6H),0.78-0.77(d,J=5.2Hz,2H),0.49(bs,2H)).

[0755] Example 3: N-cyclopropyl-5-((1-((1r,3r)-3-methoxycyclobutyl)-2-oxo-1,2-dihydropyridin-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (I-4).

[0756]

[0757] Option 3:

[0758]

[0759] Step 1 – Synthesis of Compound 3.2: Compound 3.1 (3.99 g, 32.44 mmol, 1.0 equivalent) was added to a cooled solution of 3 (5.0 g, 32.44 mmol, 1.0 equivalent) in 50 mL of N,N-dimethylformamide. The reaction mixture was stirred at 0 °C for 30 min and then further stirred at room temperature for 15 min. N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (6.5 g, 42.17 mmol, 1.3 equivalent) and 4-dimethylaminopyridine (0.790 g, 6.48 mmol, 0.2 equivalent) were added. The reaction mixture was stirred at room temperature for 24 h. After the reaction was complete, the reaction mixture was transferred to water and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain the crude material. The crude material was further purified by column chromatography, and the compound was eluted in a 1.7% methanol-dichloromethane solution to obtain 3.2 (3.35 g, yield: 46.26%; MS (ES): m / z 224.09 [M+H]). + ).

[0760] Step 2 – Synthesis of Compound 3.3: Sodium hydride (1.44 g, 6.08 mmol, 4.0 equivalent) was added in portions to a cooled solution of 3.2 (3.35 g, 15.02 mmol, 1.0 equivalent) in 35 mL of N,N-dimethylformamide at 0 °C and stirred for 30 min. Then, methyl iodine (2.7 g, 19.52 mmol, 1.3 equivalent) was added dropwise. The reaction mixture was stirred at the same temperature for 20 min, and then stirred at room temperature for 6 h. After the reaction was complete, the reaction mixture was transferred to ice water, and the product was extracted with ethyl acetate. The organic layers were combined, washed with a brine solution, dried over sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography, eluting the compound in a solution of 2–2.5% methanol in dichloromethane to obtain pure 3.3 (2.85 g, yield: 80.04%; MS (ES): m / z 238.10 [M+H)). + ).

[0761] Step 3 – Synthesis of Compound 3.4: Lithium hydroxide (2.88 g, 120.2 mmol, 10 equivalents) was added to a tetrahydrofuran:water (30 mL, 2:1) solution of 3.3 (2.85 g, 12.02 mmol, 1.0 equivalent). The reaction was stirred at 60 °C for 16 h. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain a residue. Water was added to this residue at 10 °C and acidified with 1 N hydrochloric acid to adjust the pH to about 6–6.5. The product was extracted with dichloromethane. The organic layers were combined, washed with brine, dried with sodium sulfate, and concentrated under reduced pressure to obtain a crude material. This crude material was further purified by column chromatography, and the compound was eluted in a 2.1% methanol solution in dichloromethane to obtain pure 3.4 (2.4 g, yield: 89.50%; MS (ES): m / z 224.09 [M+H)). + ).

[0762] Step 4 – Synthesis of Compound 3.5: Triethylamine (1.84 g, 18.29 mmol, 1.7 equivalent) and diphenylphosphoazide (3.84 g, 13.98 mmol, 1.3 equivalent) were added to a solution of 3.4 (2.4 g, 10.76 mmol, 1.0 equivalent) in 25 mL of tert-butanol under nitrogen atmosphere, and the mixture was heated at 80 °C for 16 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, transferred to water, and the product was extracted with ethyl acetate. The organic layers were combined, washed with a saline solution, dried over sodium sulfate, and concentrated under reduced pressure to obtain the crude material. This crude material was further purified by column chromatography, and the compound was eluted in a hexane solution of 22% ethyl acetate to obtain pure 3.5 (2.0 g, yield: 63.20%; MS (ES): m / z 295.16 [M+H)).+ ).

[0763] Step 5 – Synthesis of Compound 3.6: A solution of dioxane in 4N hydrochloric acid (22 mL) was added dropwise to a cooled solution of 3.5 (2.0 g, 6.80 mmol, 1 equivalent) in 20 mL of dioxane. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain pure 3.6 (1.4 g, yield: 89.32%; MS (ES): m / z 195.11 [M+H)). + ).

[0764] Step 6 – Synthesis of Compound 3.7: Compound 3.7 was synthesized from nucleus A using general method A to obtain 3.7 (yield: 57.16%; MS (ES): m / z 366.82 [M+H)). + ).

[0765] Step 7 – Synthesis of Compound 3.8: Compound 3.8 was synthesized using general procedure B to obtain 0.085 g (yield: 59.39%; MS (ES): m / z 524.26 [M+H)). + ).

[0766] Step 7 – Synthesis of Compound I-4: The compound was synthesized using general procedure C to obtain I-4 (0.060 g, yield: 87.28%; MS (ES): m / z 424.82 [M+H)). + LCMS purity: 100%; HPLC purity: 99.28%; Chiral HPLC purity: 96.77%; 1 H NMR(DMSO-d6,400MHZ):8.92(s,1H),8.20(s,1H),8.14-8.12(d,J=7.2Hz,1H), 7.92-7.91(d,J=4Hz,1H),7.83(bs,1H),7.54-7.53(d,J=6.8Hz,1H),6.37-6.33 (t,J=7.6Hz,1H),6.20(s,1H),4.07(bs,1H),3.21(s,3H),2.90-2.89(d,J=4.8H z, 3H), 2.51 (bs, 4H), 1.24 (bs, 2H), 0.80-0.78 (d, J = 6.8Hz, 2H), 0.50 (bs, 2H)).

[0767] Example 4: N-cyclopropyl-5-((1-((1s,3s)-3-methoxycyclobutyl)-2-oxo-1,2-dihydropyridin-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (I-5).

[0768]

[0769] Option 4:

[0770]

[0771] Step 1 – Synthesis of Compound 5.2: 4.1 (3.99 g, 32.44 mmol, 1.0 equivalent) was added to a cooled solution of 4 (5.0 g, 32.44 mmol, 1.0 equivalent) in 50 mL of N,N-dimethylformamide. The reaction mixture was stirred at 0 °C for 30 min and then further stirred at room temperature for 15 min. N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (6.5 g, 42.17 mmol, 1.3 equivalent) and 4-dimethylaminopyridine (0.790 g, 6.48 mmol, 0.2 equivalent) were added. The reaction mixture was stirred at room temperature for 24 h. After the reaction was complete, the reaction mixture was transferred to water, and the product was extracted with ethyl acetate. The organic layers were combined, washed with a brine solution, dried over sodium sulfate, and concentrated under reduced pressure to obtain the crude material. The crude material was further purified by column chromatography, and the compound was eluted in a 1.7% methanol-dichloromethane solution to obtain 4.2 (3.35 g, yield: 46.26%; MS (ES): m / z 224.09 [M+H]). + ).

[0772] Step 2 – Synthesis of Compound 4.3: Lithium hydroxide (2.88 g, 120.2 mmol, 10 equivalents) was added to a tetrahydrofuran:water (30 mL, 2:1) solution of 4.2 (2.85 g, 12.02 mmol, 1.0 equivalent). The reaction was stirred at 60 °C for 16 h. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain a residue. Water was added to this residue at 10 °C and acidified with 1 N hydrochloric acid to adjust the pH to about 6–6.5. The product was extracted with dichloromethane. The organic layers were combined, washed with brine, dried with sodium sulfate, and concentrated under reduced pressure to obtain a crude material. This crude material was further purified by column chromatography, and the compound was eluted in a 2.1% methanol solution in dichloromethane to obtain pure 4.3 (2.4 g, yield: 89.50%; MS (ES): m / z 224.09 [M+H)). + ).

[0773] Step 3 – Synthesis of Compound 4.4: Triethylamine (1.84 g, 18.29 mmol, 1.7 equivalent) and diphenylphosphoazide (3.84 g, 13.98 mmol, 1.3 equivalent) were added to a solution of 4.3 (2.4 g, 10.76 mmol, 1.0 equivalent) in 25 mL of tert-butanol under nitrogen atmosphere, and the mixture was heated at 80 °C for 16 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, transferred to water, and the product was extracted with ethyl acetate. The organic layers were combined, washed with aqueous brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain the crude material. This crude material was further purified by column chromatography, and the compound was eluted in a hexane solution of 22% ethyl acetate to obtain pure 4.4 (2.0 g, yield: 63.20%; MS (ES): m / z 295.16 [M+H)). + ).

[0774] Step 4 – Synthesis of Compound 4.5: A solution of dioxane in 4N hydrochloric acid (22 mL) was added dropwise to a cooled solution of 4.4 (2.0 g, 6.80 mmol, 1 equivalent) in 20 mL of dioxane. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain pure 4.5 (1.4 g, yield: 89.32%); MS (ES): m / z 195.11 [M+H]. + ).

[0775] Step 5 – Synthesis of compound 4.6: Compound 4.6 was synthesized from nucleus A using general procedure A to obtain 4.6 (yield: 57.16%; MS (ES): m / z 366.82 [M+H)). + ).

[0776] Step 6 – Synthesis of Compound 4.7: The compound was synthesized using general procedure B to obtain 4.7 (0.061 g, yield: 35.52%; MS (ES): 524.26 [M+H)). + ).

[0777] Step 7 – Synthesis of Compound I-5: The compound was synthesized using general procedure C to obtain I-5 (0.038 g, yield: 77.02%; MS (ES): m / z 424.37 [M+H)). + LCMS purity: 100%; HPLC purity: 100%; Chiral HPLC: 95.00%; 1H NMR(DMSO-d6,400MHZ):8.91(s,1H),8.20(s,1H),8.14-8.12(d,J=6.4Hz,1H),7.91 (bs,1H),7.83(bs,1H),7.49-7.47(d,J=6Hz,1H),6.35-6.33(t,J=6.4Hz,1H),6.20( s,1H),4.73-4.69(m,1H),3.79(bs,1H),3.21(s,3H),2.90-2.89(d,J=4.8Hz,3H),2. 83(bs,3H),2.14-2.12(d,J=7.6Hz,2H),0.89-0.79(d,J=5.6Hz,2H),0.50(bs,2H)).

[0778] Example 5: N-((1R,2S)-2-fluorocyclopropyl)-5-((1-(3-hydroxy-3-methylcyclohexyl)-2-oxo-1,2-dihydropyridin-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (I-6).

[0779]

[0780] Option 5:

[0781]

[0782] Step 1 – Synthesis of Compound 5: Compound 5 was synthesized from nucleus A using general method A to obtain 5 (yield: 51.08%; MS (ES): m / z 384.81 [M+H)). + ).

[0783] Step 2 – Synthesis of Compound 5.1: The compound was synthesized according to the experimental protocol of I-1 (Example 1) to obtain 5.1 (yield: 97.90%; MS (ES): m / z 223.14 [M+H)). + ).

[0784] Step 3 – Synthesis of Compound 5.2: Compound 5.2 was synthesized using general procedure B to obtain 5.2 (0.130 g, yield: 62.56%; MS (ES): 570.28 [M+H)). + ).

[0785] Step 4 – Synthesis of Compound I-6: The compound was synthesized using standard procedure C to obtain I-6 (0.034 g, yield: 83.19%; MS (ES): m / z 470.87 [M+H]). +LCMS purity: 96.10%; HPLC purity: 94.95%; Chiral HPLC: 46.44% and 47.34%; 1 H NMR(DMSO-d6,400MHZ):8.88(s,1H),8.23(s,1H),8.11-8.10(d,J=8Hz,1H),7.93-7.92(d, J=4.8Hz, 1H), 7.81-7.79 (d, J=4.4Hz, 1H), 7.42-7.40 (d, J=6.8Hz, 1H), 6.29-6.25 (t, J=7. 2Hz,1H),6.20(s,1H),4.80(bs,2H),4.68(bs,1H),2.98(bs,1H),2.90-2.89(d,J=4.8Hz,3 H), 1.76 (bs, 2H), 1.65 (bs, 1H), 1.47 (bs, 3H), 1.24 (bs, 5H), 0.85-0.84 (d, J = 6.4Hz, 2H)).

[0786] Example 6: 5-((1-((1r,3R)-3-fluorocyclobutyl)-2-oxo-1,2-dihydropyridin-3-yl)amino)-N-((1R,2S)-2-fluorocyclopropyl)-7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (I-7).

[0787]

[0788] Option 6:

[0789]

[0790] Step 1 – Synthesis of Compound 6.2: 6.1 (0.803 g, 6.48 mmol, 1.0 equivalent) was added to a cooled solution of 6 (1.0 g, 6.48 mmol, 1.0 equivalent) in 12 mL of N,N-dimethylformamide. The reaction mixture was stirred at 0 °C for 30 min and then further stirred at room temperature for 15 min. N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.30 g, 8.42 mmol, 1.3 equivalent) and 4-dimethylaminopyridine (0.158 g, 1.29 mmol, 0.2 equivalent) were added. The reaction mixture was stirred at room temperature for 24 h. After the reaction was complete, the reaction mixture was transferred to water, and the product was extracted with ethyl acetate. The organic layers were combined, washed with a brine solution, dried over sodium sulfate, and concentrated under reduced pressure to obtain the crude material. The crude material was further purified by column chromatography, and the compound was eluted in a 1.7% methanol-dichloromethane solution to obtain 6.2 (0.7 g, yield: 47.90%; MS (ES): m / z 226.08 [M+H]).+ ).

[0791] Step 2 – Synthesis of Compound 6.3: Lithium hydroxide (0.746 g, 31.1 mmol, 10 equivalents) was added to a tetrahydrofuran:water (10 mL, 2:1) solution of 6.2 (0.7 g, 3.11 mmol, 1.0 equivalents). The reaction was stirred at 60 °C for 16 h. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain a residue. Water was added to this residue at 10 °C and acidified with 1 N hydrochloric acid to adjust the pH to about 6–6.5. The product was extracted with dichloromethane. The organic layers were combined, washed with a brine solution, dried with sodium sulfate, and concentrated under reduced pressure to obtain a crude material. This crude material was further purified by column chromatography, and the compound was eluted in a 2.1% methanol solution in dichloromethane to obtain pure 6.3 (0.610 g, yield: 92.93%; MS (ES): m / z 212.07 [M+H)). + ).

[0792] Step 3 – Synthesis of Compound 6.4: Triethylamine (0.496 g, 4.91 mmol, 1.7 equivalents) and diphenylphosphoazide (1.0 g, 3.75 mmol, 1.3 equivalents) were added to a solution of 6.3 (0.610 g, 2.89 mmol, 1.0 equivalents) in 8 mL of tert-butanol under nitrogen atmosphere, and then heated at 80 °C for 16 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, transferred to water, and the product was extracted with ethyl acetate. The organic layers were combined, washed with a brine solution, dried over sodium sulfate, and concentrated under reduced pressure to obtain the crude material. This crude material was further purified by column chromatography, and the compound was eluted in a hexane solution of 22% ethyl acetate to obtain pure 6.4 (0.480 g, yield: 58.86%; MS (ES): m / z 283.14 [M+H)). + ).

[0793] Step 4 – Synthesis of Compound 6.5: A solution of dioxane in 4N hydrochloric acid (8 mL) was added dropwise to a cooled solution of 6.4 (0.480 g, 1.70 mmol, 1 equivalent) in 6 mL of dioxane. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain pure 6.5 (0.310 g, yield: 98.46%; MS (ES): m / z 183.09 [M+H)). + ).

[0794] Step 5 – Synthesis of Compound 6.6: Compound 6.6 was synthesized from nucleus A using general method A to obtain 6.6 (yield: 51.08%; MS (ES): m / z 384.81 [M+H)). + ).

[0795] Step 6 – Synthesis of Compound 6.7: Compound 6.7 was synthesized using general procedure B to obtain 6.7 (0.054 g, yield: 39.14%; MS (ES): m / z 530.23 [M+H)). + ).

[0796] Step 7 – Synthesis of Compound I-7: The compound was synthesized using standard procedure C to obtain I-7 (0.038 g, yield: 86.78%; MS (ES): m / z 430.82 [M+H)). + LCMS purity: 100%; HPLC purity: 98.21%; Chiral HPLC: 100%; 1 H NMR(DMSO-d6,400MHZ):8.90(s,1H),8.23(s,1H),8.15-8.13(d,J=6.8Hz,1H),7.93-7. 92(d,J=4.8Hz,1H),7.80-7.79(d,J=4Hz,1H),7.45-7.43(d,J=6.8Hz,1H),6.31-6.27( t,J=7.2Hz,1H),6.23(s,1H),5.44-5.38(m,2H),4.97(bs,1H),4.80(bs,1H),2.98(bs, 1H), 2.90-2.89 (d, J = 4.8Hz, 3H), 2.72-2.67 (m, 3H), 1.27-1.16 (m, 1H), 0.83 (bs, 1H)).

[0797] Example 7: N-((1R,2S)-2-fluorocyclopropyl)-5-((1-((1r,3R)-3-methoxycyclobutyl)-2-oxo-1,2-dihydropyridin-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (I-8).

[0798]

[0799] Option 7:

[0800]

[0801] Step 1 – Synthesis of Compound 7: Compound 8 was synthesized from nucleus A using general method A to obtain compound 8 (yield: 51.08%; MS (ES): m / z 384.81 [M+H)). + ).

[0802] Step 2 – Synthesis of Compound 7.1: Compound 7.1 was synthesized according to the experimental protocol of I-4 (Example 3) to obtain 8.1 (yield: 89.32%; MS (ES): m / z 195.11 [M+H)). + ).

[0803] Step 3 – Synthesis of Compound 7.2: Compound 7.2 was synthesized using general procedure B to obtain 7.2 (0.085 g, yield: 60.24%; MS (ES): m / z 542.25 [M+H)). + ).

[0804] Step 4 – Synthesis of Compound I-8: The compound was synthesized using standard procedure C to obtain I-8 (0.060 g, yield: 86.60%; MS (ES): m / z 442.82 [M+H]). + LCMS purity: 100%; HPLC purity: 99.41%; Chiral HPLC purity: 96.29%; 1 H NMR(DMSO-d6,400MHZ):8.89(s,1H),8.24(s,1H),8.15-8.13(d,J=6.4Hz,1H),7.94-7. 93(d,J=4.4Hz,1H),7.81(bs,1H),7.50-7.49(d,J=6Hz,1H),6.32-6.29(t,J=7.2Hz,1H) ,6.24(s,1H),5.31-5.27(m,1H),4.97(bs,1H),4.06(bs,1H),3.23(s,3H),2.99(s,1H) ,2.91-2.90(d,J=4.8Hz,3H),2.51(bs,4H),1.12-1.09(t,J=7.2Hz,1H),0.86(bs,1H)).

[0805] Example 8: N-((1R,2S)-2-fluorocyclopropyl)-5-((1-((1s,3S)-3-methoxycyclobutyl)-2-oxo-1,2-dihydropyridin-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (I-9).

[0806]

[0807] Option 8:

[0808]

[0809] Step 1 – Synthesis of Compound 8: Compound 8 was synthesized from nucleus A using general method A to obtain 8 (yield: 51.08%; MS (ES): m / z 384.81 [M+H)).+ ).

[0810] Step 2 – Synthesis of Compound 8.1: Compound 8.1 was synthesized according to the experimental protocol in I-5 (Example 4) to obtain 8.1 (yield: 89.32%; MS (ES): m / z 195.11 [M+H)). + ).

[0811] Step 3 – Synthesis of Compound 8.2: Compound 8.2 was synthesized using general procedure B to obtain 8.2 (0.054 g, yield: 31.89%; MS (ES): 542.25 [M+H)). + ).

[0812] Step 4 – Synthesis of Compound I-9: The compound was synthesized using standard procedure C to obtain I-9 (0.036 g, yield: 81.79%; MS (ES): m / z 442.37 [M+H]). + LCMS purity: 100%; HPLC purity: 100%; Chiral HPLC: 95.00%; 1 H NMR(DMSO-d6,400MHZ):8.89(s,1H),8.24(s,1H),8.14-8.13(d,J=6.4Hz,1H), 7.93(bs,1H),7.81(bs,1H),7.49-7.45(d,J=6Hz,1H),6.35-6.30(t,J=6.4Hz,1 H),6.23(s,1H),4.71(bs,1H),3.80(bs,1H),3.20(s,3H),3.00(bs,1H),2.90-2 .89(d,J=4.8Hz,3H),2.68(bs,3H),2.13-2.11(d,J=7.6Hz,3H),1.24(bs,1H)).

[0813] Example 9: 5-((3'-fluoro-2-oxo-2H-[1,2'-bipyridine]-3-yl)amino)-N-((1S,2R)-2-fluorocyclopropyl)-7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (I-10).

[0814]

[0815] Option 9:

[0816]

[0817] Step 1 – Synthesis of Compound 9.2: 9.1 (7.34 g, 63.79 mmol, 1.1 equivalent) was added to a solution of 9 (10 g, 57.47 mmol, 1.0 equivalent) in 240 mL of 1-methylpyrrolidone-2-one, followed by the addition of cesium carbonate (46.81 g, 143.67 mmol, 2.5 equivalent). The reaction mixture was heated at 110 °C for 15 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, transferred to cold water, and the product was extracted with ethyl acetate. The organic layers were combined, washed with a brine solution, dried over sodium sulfate, and concentrated under reduced pressure to obtain the crude material. This crude material was further purified by column chromatography using a 50% ethyl acetate solution in hexane as the eluent to obtain 19.2 (2.6 g, yield: 16.81%; MS (ES): m / z 269.04 [M]). + ).

[0818] Step 2 – Synthesis of Compound 9.3: Copper powder (0.073 g, 1.15 mmol, 0.12 equivalents), L-ascorbic acid (0.34 g, 1.93 mmol, 0.2 equivalents), DL-piperidic acid (0.37 g, 2.89 mmol, 0.3 equivalents), and sodium azide (2.26 g, 34.77 mmol, 3.6 equivalents) were added to a 26 mL ethanol solution of 9.2 (2.6 g, 9.66 mmol, 1.0 equivalents). The reaction mixture was heated at 100 °C for 16 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, transferred to cold water, and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain the crude material. The crude material was further purified by column chromatography using a 55%-60% ethyl acetate solution in hexane as the eluent to obtain 9.3 g (1.6 g, yield: 80.70%; MS (ES): m / z 206.29 [M+H]). + ).

[0819] Step 3 – Synthesis of Compound 9.4: The compound was synthesized using the procedure for preparing nucleus A to obtain 9.4 (MS (ES): m / z 355.11 [M+H]). + ).

[0820] Step 4 – Synthesis of Compound 9.2: Potassium tert-butoxide (1M tetrahydrofuran solution; 1.12 mL, 1.12 mmol, 2.0 equivalence) was added to a cooled solution of 9.4 (0.2 g, 0.56 mmol, 1.0 equivalence) and 9.3 (0.114 g, 0.67 mmol, 1.2 equivalence) in tetrahydrofuran (4 mL) at 0 °C. The reaction was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was transferred to water and the product was extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to obtain the crude material. This crude material was further purified by column chromatography, and the compound was eluted in a hexane solution of 25% ethyl acetate to obtain pure 9.5 (0.120 g, yield: 42.11%; MS (ES): m / z 524.20 [M+H)). + ).

[0821] Step 6 – Synthesis of Compound 9.6: Lithium hydroxide (0.055 g, 2.3 mmol, 10 equivalents) was added to a methanol:tetrahydrofuran:water (4 mL, 2:1:1) solution of 9.5 (0.120 g, 0.22 mmol, 1.0 equivalent). The reaction was stirred at 60 °C for 16 h. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain a residue. Water was added to this residue, followed by the addition of hydrochloric acid to adjust the pH to about 1–2, stirring at 10 °C for 1 h, and neutralizing with saturated sodium bicarbonate. The product was extracted with dichloromethane. The organic layers were combined, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain a crude material. This crude material was further purified by column chromatography, eluting the compound in a 2.1% methanol solution in dichloromethane to obtain pure 9.6 (0.065 g, yield: 72.56%; MS (ES): m / z 396.12 [M+H)). + ).

[0822] Step 7 – Synthesis of Compound I-10: The compound was synthesized using general procedure A to obtain I-10 (0.032 g, 27.96%; MS (ES): m / z 453.37 [M+H)). + LCMS purity: 95.20%; HPLC purity: 95.01%; Chiral HPLC: 96.00%; 1H NMR(DMSO-d6,400MHZ):9.02(s,1H),8.53-8.52(d,J=4.8Hz,1H),8.30-8.28(d,J=8Hz,1H),8.27(s,1H),8.10-8.05(d,J=9.2Hz 1H),7.99-7.98(d,J=4.8Hz,1H),7.84-7.83(d,J=4.4Hz,1H),7.76-7.72(m,1H),7.45-7.43(d,J=6.8Hz,1H),6.45-6.41(t,J=6.8Hz, 1H),6.26(s,1H),4.83-4.81(m,1H),3.18-3.17(d,J=5.2Hz,1H),3.03-3.01(m,1H),2.91-2.90(d,J=4.8Hz,3H),1.30-1.21(m,1H)).

[0823] Example 10: 5-((1-((1r,3S)-3-fluorocyclobutyl)-2-oxo-1,2-dihydropyridin-3-yl)amino)-N-(2-hydroxycyclobutyl)-7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (I-11).

[0824]

[0825] Option 10:

[0826]

[0827] Step 1 – Synthesis of Compound 10: Compound 10 was synthesized from nucleus A using general method A to obtain 10 (yield: 50.51%; MS (ES): m / z 396.84 [M+H)). + ).

[0828] Step 2 – Synthesis of Compound 10.1: The compound was synthesized according to the experimental protocol of I-7 (Example 6) to obtain 10.1 (yield: 98.46%; MS (ES): m / z 183.09 [M+H)). + ).

[0829] Step 2 – Synthesis of Compound 10.2: The compound was synthesized using general procedure B to obtain 10.2 (0.145 g, yield: 70.65%; MS (ES): m / z 542.25 [M+H]). + ).

[0830] Step 3 – Synthesis of Compound I-11: The compound was synthesized using standard procedure C to obtain I-11 (0.028 g, yield: 85.87%; MS (ES): m / z 442.27 [M+H]). + LCMS purity: 97.66%; HPLC purity: 97.71%; Chiral HPLC: 48.80% and 49.46%; 1 H NMR (DMSO-d6, 400MHZ): 8.86 (s, 1H), 8.54-8.52 (d, J = 7.2Hz, 1H), 8.19 (s, 1H), 8.05-8.02 (d, J = 8. 8Hz,1H),7.89-7.87(d,J=4.8Hz,1H),7.44-7.42(d,J=6Hz,1H),6.43-6.40(t,J=7.2Hz,1H),6.27 (s,1H),5.44-5.37(m,2H),4.58-4.55(m,2H),4.35(bs,1H),2.90-2.89(d,J=4.8Hz,3H),2.83-2. 79(m,1H),2.73-2.68(m,3H),2.19(bs,1H),2.07-2.02(m,1H),1.99-1.95(m,1H),1.65(bs,1H)).

[0831] Example 11: 5-((1-((1S,2S)-2-fluorocyclopropyl)-2-oxo-1,2-dihydropyridin-3-yl)amino)-N-((1S,2R)-2-hydroxycyclobutyl)-7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (I-12) and 5-((1-((1S,2S)-2-fluorocyclopropyl)-2-oxo-1,2-dihydropyridin-3-yl)amino)-N-((1R,2S)-2-hydroxycyclobutyl)-7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (I-13)

[0832]

[0833] Option 11:

[0834]

[0835] Step 1 – Synthesis of Compound 11.2: 11.1 (0.395 g, 3.56 mmol, 1.1 equivalent) was added to a cooled solution of 11 (0.5 g, 3.24 mmol, 1.0 equivalent) in acetonitrile (10 mL). The reaction mixture was stirred at 0 °C for 30 min and then further stirred at room temperature for 15 min. N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.652 g, 4.21 mmol, 1.3 equivalent) and molecular sieves were added. The reaction mixture was stirred at room temperature for 24 h. After the reaction was complete, the reaction mixture was transferred to water, and the product was extracted with ethyl acetate. The organic layers were combined, washed with a brine solution, dried over sodium sulfate, and concentrated under reduced pressure to obtain the crude material. The crude material was further purified by column chromatography, and the compound was eluted in a 1.7% methanol-dichloromethane solution to obtain 11.2 (0.320 g, yield: 46.71%; MS (ES): m / z 212.07 [M+H]). + ).

[0836] Step 2 – Synthesis of Compound 11.3: Lithium hydroxide (0.362 g, 15.1 mmol, 10 equivalents) was added to a tetrahydrofuran:water (8 mL, 2:1) solution of 11.2 (0.320 g, 1.51 mmol, 1.0 equivalent). The reaction was stirred at 60 °C for 16 h. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain a residue. Water was added to this residue at 10 °C and acidified with 1 N hydrochloric acid to adjust the pH to about 6–6.5. The product was extracted with dichloromethane. The organic layers were combined, washed with brine, dried with sodium sulfate, and concentrated under reduced pressure to obtain a crude material. This crude material was further purified by column chromatography, and the compound was eluted in a 2.1% methanol solution in dichloromethane to obtain pure 11.3 (0.265 g, yield: 88.70%; MS (ES): m / z 198.05 [M+H)). + ).

[0837] Step 3 – Synthesis of Compound 11.4: Triethylamine (0.230 g, 2.27 mmol, 1.7 equivalent) and diphenylphosphoazide (0.478 g, 1.74 mmol, 1.3 equivalent) were added to a solution of 11.3 (0.265 g, 1.34 mmol, 1.0 equivalent) in 6 mL of tert-butanol under nitrogen atmosphere, and the mixture was heated at 80 °C for 16 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, transferred to water, and the product was extracted with ethyl acetate. The organic layers were combined, washed with a brine solution, dried over sodium sulfate, and concentrated under reduced pressure to obtain the crude material. This crude material was further purified by column chromatography, and the compound was eluted in a hexane solution of 22% ethyl acetate to obtain pure 11.4 (0.160 g, yield: 44.37%; MS (ES): m / z 269.13 [M+H)). + ).

[0838] Step 4 – Synthesis of Compound 11.5: A solution of dioxane in 4N hydrochloric acid (10 mL) was added dropwise to a cooled solution of 11.4 (0.160 g, 0.59 mmol, 1 equivalent) in 4 mL of dioxane. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain pure 11.5 (0.125 g, yield: 98.33%; MS (ES): m / z 205.05 [M + HCl)). + ).

[0839] Step 5 – Synthesis of Compound 11.6: Compound 11.6 was synthesized from nucleus A using general method A to obtain 11.6 (yield: 50.51%; MS (ES): m / z 396.84 [M+H)). + ).

[0840] Step 6 – Synthesis of Compound 11.7: Compound 11.7 was synthesized according to general method B to obtain 0.135 g (yield: 67.53%); MS (ES): m / z 527.5 [M+H). + ).

[0841] Step 7 – Synthesis of compounds 11.7a and 11.7b: Isomers of 11.7 (0.1 g) were isolated using a Chiralpak OX-H column (250 mm x 4.6 mm, 5 μm) and 0.1% DEA-HEX-IPA-ACN (70-30) as a co-solvent at a flow rate of 4 mL / min to give pure fraction-1 (FR-a) and fraction-2 (FR-b). FR-a was concentrated under reduced pressure at 30 °C to give pure 11.7a (0.040 g; MS (ES): m / z 527.5 [M+H)). +FR-b was concentrated under reduced pressure at 30°C to obtain pure 11.7b (0.045 g; MS (ES): m / z 527.5 [M+H)). + ).

[0842] Step 8 – Synthesis of Compound I-12: The compound was synthesized using general procedure C to obtain I-12 (0.027 g, yield: 83.31%; MS (ES): m / z 428.18 [M+H]). + LCMS purity: 100%; HPLC purity: 100%; Chiral HPLC purity: 96.10%; 1 H NMR(DMSO-d6,400MHZ):8.87(s,1H),8.51-8.50(d,J=6Hz,1H),8.19(s,1H),8.03-8. 01(d,J=9.2Hz,1H),7.89-7.88(d,J=4.8Hz,1H),7.14-7.12(d,J=5.6Hz,1H),6.35-6. 31(t,J=7.2Hz,1H),6.27(bs,1H),5.40-5.39(d,J=4Hz,1H),4.57-4.54(m,1H),4.34 (bs,1H),3.89-3.81(m,1H),2.91-2.89(d,J=4.8Hz,3H),2.50(s,3H),1.23(bs,4H)).

[0843] Step 9 – Synthesis of Compound I-13: The compound was synthesized using general procedure C to obtain I-13 (0.032 g, 87.77%; MS (ES): m / z 428.18 [M+H]). + LCMS purity: 100%; HPLC purity: 98.81%; Chiral HPLC purity: 99.25%; 1 H NMR(DMSO-d6,400MHZ):8.88(s,1H),8.51-8.50(d,J=6Hz,1H),8.19(s,1H),8.03-8. 01(d,J=9.2Hz,1H),7.89-7.88(d,J=4.8Hz,1H),7.13-7.11(d,J=5.6Hz,1H),6.35-6. 31(t,J=7.2Hz,1H),6.27(bs,1H),5.40-5.39(d,J=4Hz,1H),4.57-4.54(m,1H),4.34 (bs,1H),3.89-3.81(m,1H),2.91-2.89(d,J=4.8Hz,3H),2.50(s,3H),1.24(bs,4H)).

[0844] Example 12: N-((1R,2S)-2-hydroxycyclobutyl)-7-(methylamino)-5-(1-((S)-tetrahydro-2H-pyran-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (I-14) and N-((1S,2R)-2-hydroxycyclobutyl)-7-(methylamino)-5-(1-((S)-tetrahydro-2H-pyran-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (I-15).

[0845]

[0846] Option 12:

[0847]

[0848] Step 1 – Synthesis of Compound 12: The compound was synthesized using the procedure for preparing nucleus B to obtain 12.

[0849] Step 2 – Synthesis of Compound 12.2: Argon gas was purged through a stirred solution of 12 (3.5 g, 10.15 mmol, 1.0 equivalent), 12.1 (4.5 g, 13.19 mmol, 1.3 equivalent), and sodium carbonate (2.6 g, 25.37 mmol, 2.5 equivalent) in 1,4-dioxane:water (140 mL, 9:1) for 15 min. [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (0.738 mg, 1.01 mmol, 0.1 equivalent) was added and the solution was further purged for 10 min. The reaction was stirred at 110 °C for 6 h. After the reaction was complete, the reaction mixture was poured into water and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried with sodium sulfate, and concentrated under reduced pressure to obtain 12.2 g (3.1 g, yield: 57.99%; MS (ES): m / z 527.24 [M+H]). + ).

[0850] Step 3 – Synthesis of Compound 12.3: A solution of 1,4-dioxane in 4M hydrochloric acid (60 mL) was added to 12.2 (3.1 g, 5.88 mmol, 1.0 equivalent) and stirred at room temperature for 4 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the residue was stirred with saturated sodium bicarbonate solution and extracted with dichloromethane. The organic layers were combined, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain the residue, which was then ground with diethyl ether to obtain 12.3 (2.1 g, yield: 83.64%; MS (ES): m / z 427.18 [M+H)). + ).

[0851] Step 4 – Synthesis of Compound 12.5: Potassium carbonate (1.29 g, 9.36 mmol, 2.0 equivalent) was added to a solution of 1,4-dioxane (60 mL) of 12.3 (2.0 g, 4.68 mmol, 1 equivalent) and 12.4 (0.915 g, 5.61 mmol, 1.2 equivalent) and degassed with argon for 15 min. Cuprous iodide (0.178 g, 0.93 mmol, 0.2 equivalent) and 1,2-dimethylethylenediamine (0.165 g, 1.87 mmol, 0.4 equivalent) were added, and the reaction mixture was degassed again with argon for 5 min, then heated at 80 °C for 16 h. After the reaction was complete, the reaction mixture was cooled to room temperature, transferred to water, and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine solution, dried over sodium sulfate, and concentrated under reduced pressure to obtain the crude material. The crude material was further purified by column chromatography, and the compound was eluted in a 1.2% methanol-dichloromethane solution to obtain pure 12.5 (1.0 g, yield: 41.93%; MS (ES): m / z 509.23 [M+H)). + ).

[0852] Step 5 – Synthesis of Compound 12.6: Carbon-supported palladium (0.4 g) was added to a methanol (12 mL) solution of 12.5 (1.0 g, 1.96 mmol, 1.0 equivalent). The reaction mixture was purged with hydrogen for 4 hours at room temperature. After the reaction was complete, the reaction mixture was filtered through a diatomaceous earth bed and washed with methanol. The filtrate was concentrated under reduced pressure to obtain a crude material. This crude material was further purified by milling with pentane to obtain pure 12.6 (0.610 g, yield: 73.78%; MS (ES): m / z 421.19 [M+H)). + ).

[0853] Step 6 – Synthesis of compounds 12.6a and 12.6b: The isomers of 12.6 (0.610 g) were separated using a CHIRALPAK OX-H column (250 mm x 4.6 mm, 5 μm) and 0.1% DEA-HEX-IPA-CAN (70-30) as a co-solvent at a flow rate of 4 mL / min to give pure fraction-1 (FR-a) and fraction-2 (FR-b). FR-a was concentrated under reduced pressure at 30 °C to give pure 12.6a (0.190 g; MS (ES): m / z 421.19 [M+H)). + FR-b was concentrated under reduced pressure at 30°C to obtain pure 12.6b (0.180 g; MS (ES): m / z 421.19 [M+H)). + ).

[0854] Step 7 – Synthesis of Compound 12.7: Lithium hydroxide (0.219 g, 9.56 mmol, 10 equivalents) was added to a methanol:water (8 mL, 2:1) solution of 12.6a (0.4 g, 0.956 mmol, 1.0 equivalent). The reaction was stirred at 60 °C for 16 h. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain a residue. Water was added to this residue at 10 °C and acidified with 1 N hydrochloric acid to adjust the pH to about 6–6.5. The product was extracted with dichloromethane. The organic layers were combined, washed with brine, dried with sodium sulfate, and concentrated under reduced pressure to obtain a crude material. This crude material was further purified by column chromatography, and the compound was eluted in a 2.1% methanol solution in dichloromethane to obtain pure 12.7 (0.350 g, yield: 93.76%; MS (ES): m / z 393.16 [M+H)). + ).

[0855] Step 8 – Synthesis of Compound 12.9: The compound was synthesized using general procedure A to obtain 12.9 (0.125 g, yield: 70.86%; MS (ES): m / z 462.61 [M+H]). + LCMS purity: 97.36%; HPLC purity: 97.32%; Chiral HPLC: 48.06% and 48.35%; 1 H NMR(DMSO-d6,400MHZ):9.04-9.02(d,J=8.4Hz,1H),8.82-8.81(d,J=3.6Hz,1H),8.68-8.64(t,J=7.6Hz ,1H),8.41-8.40(d,J=4Hz,1H),8.37(s,1H),7.27-7.26(d,J=4.4Hz,1H),7.34-7.31(m,1H),6.75(s,1H) ,5.78(s,1H),5.53(bs,1H),4.97(bs,1H),4.60(bs,1H),4.44(bs,1H),4.04(bs,1H),3.98(bs,1H),3.75 -3.72(m,1H),3.52(s,1H),3.15-3.14(d,J=4.4Hz,3H),2.22(bs,3H),1.86(bs,3H),1.28-1.25(m,1H)).

[0856] Step 9: Synthesis of compounds I-14 and I-15: 12.9 g (0.105 g) of isomers were isolated using a chiral PAK OX-H column (250 mm x 4.6 mm, 5 μm) and 0.1% DEA-HEX-IPA-ACN (70-30) to obtain pure fraction-1 (FR-a) and fraction-2 (FR-b).

[0857] FR-a was concentrated under reduced pressure at 30°C to obtain pure I-14 (0.035 g; MS (ES): m / z 462.57 [M+H)). + LCMS purity: 100%; HPLC purity: 97.32%; Chiral HPLC purity: 100%; 1 H NMR(DMSO-d6,400MHZ):9.03-9.01(d,J=8Hz,1H),8.81(s,1H),8.67-8.65(d,J=8Hz,1H),8.40-8.39(d,J=4.4Hz, 1H),8.37(s,1H),8.27-8.26(d,J=4.4Hz,1H),7.33-7.30(m,1H),6.74(s,1H),5.54-5.53(d,J=3.2Hz,1H),4.97( bs,1H),4.60(bs,1H),4.44(bs,1H),4.05-4.03(d,J=8.8Hz,1H),3.98-3.95(d,J=12Hz,1H),3.74-3.69(t,J=10. 4Hz,1H),3.53-3.51(t,J=7.6Hz,1H),3.14-3.13(d,J=4Hz,3H),2.34(bs,3H),2.06-2.02(m,2H),1.86(bs,3H)).

[0858] FR-b was concentrated under reduced pressure at 30°C to obtain pure I-15 (0.035 g; MS (ES): m / z 462.66 [M+H)). + LCMS purity: 100%; HPLC purity: 99.87%; Chiral HPLC purity: 93.05%; 1H NMR(DMSO-d6,400MHZ):9.04-9.03(d,J=8Hz,1H),8.80(s,1H),8.65-8.63(d,J=8Hz,1H),8.40-8.39(d,J=4.4Hz, 1H),8.37(s,1H),8.27-8.26(d,J=4.4Hz,1H),7.33-7.30(m,1H),6.74(s,1H),5.53-5.52(d,J=3.2Hz,1H),4.97( bs,1H),4.60(bs,1H),4.44(bs,1H),4.05-4.03(d,J=8.8Hz,1H),3.98-3.95(d,J=12Hz,1H),3.74-3.69(t,J=10. 4Hz,1H),3.53-3.51(t,J=7.6Hz,1H),3.14-3.13(d,J=4Hz,3H),2.34(bs,3H),2.06-2.02(m,2H),1.86(bs,3H)).

[0859] Example 13: 5-((1-((1r,3S)-3-fluorocyclobutyl)-2-oxo-1,2-dihydropyridin-3-yl)amino)-N-((1S,2R)-2-hydroxycyclobutyl)-7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (I-16) and 5-((1-((1r,3R)-3-fluorocyclobutyl)-2-oxo-1,2-dihydropyridin-3-yl)amino)-N-((1R,2S)-2-hydroxycyclobutyl)-7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (I-17).

[0860]

[0861] Option 13:

[0862]

[0863] Step 1 – Synthesis of Compound 13: The compound was synthesized according to the experimental protocol of I-11 (Example 10) to obtain 13 (yield: 70.65%; MS (ES): 542.25 [M+H)). + ).

[0864] Step 2 – Synthesis of compounds 13a and 13b: Isomers of 13a (0.105 g) were isolated using a Chiralpak OX-H column (250 mm x 4.6 mm, 5 μm) and 0.1% DEA-HEX-IPA-ACN (70-30) as a co-solvent at a flow rate of 4 mL / min to obtain pure fraction-1 (FR-a) and fraction-2 (FR-b). FR-a was concentrated under reduced pressure at 30 °C to give pure 13a (0.042 g; MS (ES): m / z 542.25 [M+H)). + FR-b was concentrated under reduced pressure at 30°C to obtain pure 13b (0.042 g; MS (ES): m / z 542.25 [M+H)). + ).

[0865] Step 3 – Synthesis of Compound I-16: The compound was synthesized using standard procedure C to obtain I-16 (0.030 g, 87.63%; MS (ES): m / z 442.52 [M+H)). + LCMS purity: 100%; HPLC purity: 97.05%; Chiral HPLC purity: 97.29%; 1 H NMR(DMSO-d6,400MHZ):8.87(s,1H),8.55-8.53(d,J=7.2Hz,1H),8.21(s,1H),8.06-8.04(d,J= 8.8Hz,1H),7.90-7.88(d,J=4.8Hz,1H),7.45-7.43(d,J=6.8Hz,1H),6.43-6.41(t,J=7.2Hz,1H) ,6.28(s,1H),5.45-5.37(m,2H),5.31(bs,1H),4.59-4.58(m,1H),4.36(bs,1H),2.92-2.91(d, J=4.8Hz,3H),2.74-2.69(m,3H),2.34(bs,1H),2.21(bs,1H),2.01-1.96(m,2H),1.74(bs,1H)).

[0866] Step 4 – Synthesis of Compound I-17: The compound was synthesized using standard procedure C to obtain I-17 (0.030 g, yield: 87.63%; MS (ES): m / z 442.56 [M+H)). + LCMS purity: 98.00%; HPLC purity: 98.07%; Chiral HPLC purity: 98.29%; 1H NMR(DMSO-d6,400MHZ):8.87(s,1H),8.55-8.53(d,J=7.2Hz,1H),8.21(s,1H),8.06-8.04(d,J= 8.8Hz,1H),7.90-7.88(d,J=4.8Hz,1H),7.45-7.43(d,J=6.8Hz,1H),6.44-6.41(t,J=7.2Hz,1H) ,6.28(s,1H),5.45-5.39(m,2H),5.29(bs,1H),4.60-4.56(m,1H),4.36(bs,1H),2.92-2.91(d, J=4.8Hz,3H),2.74-2.69(m,3H),2.34(bs,1H),2.21(bs,1H),2.01-1.96(m,2H),1.74(bs,1H)).

[0867] Example 14: 5-(5-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-((1S,2S)-2-hydroxycyclobutyl)-7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (I-18) and 5-(5-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-((1R,2R)-2-hydroxycyclobutyl)-7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (I-19).

[0868]

[0869] Option 14:

[0870]

[0871] Step 1 – Synthesis of Compound 14: Compound 14 was synthesized using the general procedure of nuclear B synthesis to obtain 14 (yield: 45%; MS (ES): m / z 345.10 [M+H)). + ).

[0872] Step 2 – Synthesis of Compound 14.2: Argon gas was passed through a stirred solution of 14 (3.5 g, 1.16 mmol, 1.0 equivalent), 14.1 (0.696 g, 1.74 mmol, 1.5 equivalent), and potassium carbonate (0.4 g, 2.9 mmol, 2.5 equivalent) in 1,4-dioxane (8 mL) for 15 min. Cuprous iodide (I) (0.043 g, 0.23 mmol, 0.2 equivalent) and bis(triphenylphosphine)palladium(II) dichloride (II) (0.077 mg, 0.11 mmol, 0.1 equivalent) were added and the mixture was further purged for 10 min. The reaction was stirred at 110 °C for 6 h. After the reaction was complete, the reaction mixture was poured into water and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried with sodium sulfate, and concentrated under reduced pressure to obtain 14.2 g (0.4 g, yield: 63.31%; MS (ES): m / z 545.23 [M+H]). + ).

[0873] Step 3 – Synthesis of Compound 14.3: The compound was synthesized using general procedure C to obtain 14.3 (0.310 g, yield: 94.96%; MS (ES): 445.17 [M+H)). + ).

[0874] Step 4 – Synthesis of Compound 14.5: Cesium carbonate (0.635 g, 1.95 mmol, 2.5 equivalents) was added to a cooled acetonitrile (10 mL) solution of 14.3 (0.350 g, 0.78 mmol, 1.0 equivalent) and 14.4 (0.153 g, 0.93 mmol, 1.2 equivalent) at 0 °C. The reaction was stirred at 70 °C for 2 h. After the reaction was complete, the reaction mixture was transferred to water and the product was extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to obtain the crude material. This crude material was further purified by column chromatography, and the compound was eluted in a hexane solution of 20% ethyl acetate to obtain pure 14.5 (0.3 g, yield: 72.07%; MS (ES): m / z 529.23 [M+H)). + ).

[0875] Step 5 – Synthesis of Compound 14.6: Lithium hydroxide (0.134 g, 5.6 mmol, 10 equivalents) was added to a methanol:tetrahydrofuran (8 mL, 2:1) solution of 14.5 (0.3 g, 0.56 mmol, 1.0 equivalent). The reaction was stirred at 60 °C for 24 h. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain a residue. Water was added to this residue at 10 °C and acidified with 1 N hydrochloric acid to adjust the pH to about 6–6.5. The product was extracted with dichloromethane. The organic layers were combined, washed with a brine solution, dried with sodium sulfate, and concentrated under reduced pressure to obtain a crude material. This crude material was further purified by column chromatography, and the compound was eluted in a 2.1% methanol solution in dichloromethane to obtain pure 14.6 (0.250 g, yield: 88.00%; MS (ES): m / z 501.20 [M+H)). + ).

[0876] Step 6 – Synthesis of Compound 14.8: The compound was synthesized using general procedure A to obtain 14.8 (0.150 g, yield: 52.72%; MS (ES): 570.26 [M+H)). + ).

[0877] Step 5 – Synthesis of compounds 14.8a and 14.8b: The isomers of 14.8 (0.120 g) were separated using a Chiralpak AD-H column (250 mm x 4.6 mm, 5 μm) and a methanol solution of 0.1% DEA as a co-solvent at a flow rate of 4 mL / min to give pure fraction-1 (FR-a) and fraction-2 (FR-b). FR-a was concentrated under reduced pressure at 30 °C to give pure 14.8a (0.032 g; MS (ES): m / z 570.26 [M+H]). + FR-b was concentrated under reduced pressure at 30°C to obtain pure 14.8b (0.033 g; MS (ES): m / z 570.26 [M+H]). + ).

[0878] Step 6 – Synthesis of Compound I-18: A solution of 14.8a (0.032 g, 0.056 mmol, 1.0 equivalent) in dichloromethane (1 mL) was cooled to 0 °C, and trifluoromethanesulfonic acid (0.5 mL) was added. The reaction mixture was stirred at the same temperature for 10 min. After the reaction was complete, the reaction mixture was transferred to a 1 N sodium hydroxide solution, and the product was extracted with dichloromethane. The organic layers were combined, dried with sodium sulfate, and concentrated under reduced pressure to obtain a crude material. This crude material was further purified by grinding with diethyl ether to obtain I-18 (0.021 g, yield: 77.96%; MS (ES): m / z 480.51 [M+H)). +LCMS purity: 99.20%; HPLC purity: 97.20%; Chiral HPLC purity: 99.08%; 1 H NMR(DMSO-d6,400MHZ):8.97(s,1H),8.51(s,1H),8.42(s,1H),8.37-8.36(d,J=6. 8Hz,1H),8.33(s,1H),8.27(bs,1H),6.82(s,1H),5.44(bs,1H),5.05-5.02(m,1H) ,4.38-4.34(t,J=8.4Hz,1H),4.08-4.06(m,4H),3.64-3.58(t,J=11.6Hz,3H),3.1 1-3.10(d,J=3.6Hz,4H),2.11-2.07(m,3H),1.53-1.49(m,1H),1.43-1.38(m,1H)).

[0879] Step 7 – Synthesis of Compound I-19: A solution of 14.8b (0.033 g, 0.056 mmol, 1.0 equivalent) in dichloromethane (1 mL) was cooled to 0 °C, and trifluoromethanesulfonic acid (0.5 mL) was added. The reaction mixture was stirred at the same temperature for 10 min. After the reaction was complete, the reaction mixture was transferred to a 1 N sodium hydroxide solution, and the product was extracted with dichloromethane. The organic layers were combined, dried with sodium sulfate, and concentrated under reduced pressure to obtain the crude material. This crude material was further purified by grinding with diethyl ether to obtain I-19 (0.021 g, yield: 75.60%; MS (ES): m / z 480.51 [M+H)). + LCMS purity: 93.46%; HPLC purity: 96.00%; Chiral HPLC purity: 95.92%; 1 H NMR (DMSO-d6, 400MHZ): 8.99 (s, 1H), 8.53-8.51 (d, J = 8.8Hz, 1H), 8.44 (s, 1H), 8.39-8. 1 H 37(d,J=6.8Hz,1H),8.35(s,1H),8.29(bs,1H),6.83(s,1H),5.45(bs,1H),5.06(bs,1H),4.39-4.35(t,J=8.4Hz,1H),4.0 9-4.07(m,4H),3.65-3.59(t,J=11.6Hz,3H),3.12-3.11(d,J=3.6Hz,4H),2.18(bs,3H),2.10(bs,1H),1.52-1.42(m,1H)).

[0880] Example 15: N-((1S,2S)-2-hydroxycyclobutyl)-5-((1-((1R,2R)-2-methoxycyclobutyl)-2-oxo-1,2-dihydropyridin-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (I-20) and N-((1R,2R)-2-hydroxycyclobutyl)-5-((1-((1R,2R)-2-methoxycyclobutyl)-2-oxo-1,2-dihydropyridin-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (I-21)

[0881]

[0882] Option 15:

[0883]

[0884] Step 1 – Synthesis of Compound 15.2: Compound 15.1 (0.327 g, 3.24 mmol, 1.0 equivalent) was added to a cooled solution of 15 (0.5 g, 3.24 mmol, 1.0 equivalent) in N,N-dimethylformamide (8 mL). The reaction mixture was stirred at 0 °C for 30 min and then further stirred at room temperature for 15 min. N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.653 g, 4.21 mmol, 1.3 equivalent) and 4-dimethylaminopyridine (0.078 g, 0.64 mmol, 0.2 equivalent) were added. The reaction mixture was stirred at room temperature for 24 h. After the reaction was complete, the reaction mixture was transferred to water and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain the crude material. The crude material was further purified by column chromatography, and the compound was eluted in a 1.7% methanol-dichloromethane solution to obtain 15.2 (0.390 g, yield: 50.67%; MS (ES): m / z 238.10 [M+H]). + ).

[0885] Step 2 – Synthesis of Compound 15.3: Lithium hydroxide (0.393 g, 16.4 mmol, 10 equivalents) was added to a tetrahydrofuran:water (5 mL, 2:1) solution of 15.2 (0.390 g, 1.64 mmol, 1.0 equivalent). The reaction was stirred at 60 °C for 16 h. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain a residue. Water was added to this residue at 10 °C and acidified with 1 N hydrochloric acid to adjust the pH to about 6–6.5. The product was extracted with dichloromethane. The organic layers were combined, washed with a brine solution, dried with sodium sulfate, and concentrated under reduced pressure to obtain a crude material. This crude material was further purified by column chromatography, and the compound was eluted in a 2.1% methanol solution in dichloromethane to obtain 15.3 (0.3 g, yield: 81.76%; MS (ES): m / z 224.09 [M+H)). + ).

[0886] Step 3 – Synthesis of Compound 15.4: Triethylamine (0.229 g, 2.27 mmol, 1.7 equivalent) and diphenylphosphoazide (0.478 g, 1.74 mmol, 1.3 equivalent) were added to a solution of 15.3 (0.3 g, 1.34 mmol, 1.0 equivalent) in 5 mL of tert-butanol under nitrogen atmosphere, and the mixture was heated at 80 °C for 16 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, transferred to water, and the product was extracted with ethyl acetate. The organic layers were combined, washed with a brine solution, dried over sodium sulfate, and concentrated under reduced pressure to obtain the crude material. This crude material was further purified by column chromatography, and the compound was eluted in a hexane solution of 22% ethyl acetate to obtain pure 15.4 (0.275 g, yield: 69.52%; MS (ES): m / z 295.16 [M+H)). + ).

[0887] Step 4 – Synthesis of Compound 15.5: A solution of dioxane in 4N hydrochloric acid (10 mL) was added dropwise to a cooled solution of 15.4 (0.275 g, 0.93 mmol, 1 equivalent) in 4 mL of dioxane. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain pure 15.5 (0.2 g, 92.80%; MS (ES): m / z 231.09 [M + HCl)). + ).

[0888] Step 5 – Synthesis of compound 15.6: The compound is synthesized from nucleus A using 15.5 in a manner similar to I-11 (Example 10).

[0889] Step 6 – Synthesis of compounds I-20 and I-21: 15.6 g (0.1 g) of isomers were isolated using a chiral PAK IC-H column (250 mm x 4.6 mm, 5 μm) and 0.1% DEA-HEX-IPA-ACN (70-30) to obtain pure fraction-1 (FR-a) and fraction-2 (FR-b).

[0890] FR-a was concentrated under reduced pressure at 30°C to obtain pure I-20 (0.026 g; MS (ES): m / z 454.2 [M+H)). + LCMS purity: 100%; HPLC purity: 99.00%; Chiral HPLC purity: 99.00%; 1 H NMR(DMSO-d6,400MHZ):8.96(s,1H),8.26-8.24(d,J=7.2Hz,1H),8.20(s,1H),8.03-8.0 1(d,J=8.8Hz,1H),7.94-7.93(d,J=4.4Hz,1H),7.60-7.58(d,J=6.8Hz,1H),6.40-6.37( t,J=6.8Hz,1H),6.24(s,1H),5.46-5.44(m,1H),5.21-5.14(m,1H),4.25-4.18(m,2H),3 .86(bs,1H),3.17(s,3H),2.92-2.90(d,J=4.8Hz,3H),1.69-1.62(m,2H),1.24(bs,6H)).

[0891] FR-b was concentrated under reduced pressure at 30°C to obtain pure I-21 (0.030 g; MS (ES): m / z 454.2 [M+H)). + LCMS purity: 100%; HPLC purity: 99.00%; Chiral HPLC purity: 99.00%; 1H NMR(DMSO-d6,400MHZ):8.97(s,1H),8.26-8.24(d,J=7.2Hz,1H),8.20(s,1H),8.04-8.0 2(d,J=8.8Hz,1H),7.94-7.93(d,J=4.4Hz,1H),7.60-7.58(d,J=6.8Hz,1H),6.41-6.38( t,J=6.8Hz,1H),6.24(s,1H),5.46-5.44(m,1H),5.21-5.14(m,1H),4.25-4.18(m,2H),3 .86(bs,1H),3.17(s,3H),2.92-2.90(d,J=4.8Hz,3H),1.69-1.62(m,2H),1.23(bs,6H)).

[0892] Example 16: N-((1S,2S)-2-hydroxycyclobutyl)-5-((1-((1S,2S)-2-methoxycyclobutyl)-2-oxo-1,2-dihydropyridin-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (I-22) and N-((1R,2R)-2-hydroxycyclobutyl)-5-((1-((1S,2S)-2-methoxycyclobutyl)-2-oxo-1,2-dihydropyridin-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (I-23)

[0893]

[0894] Option 16:

[0895]

[0896] Step 1 – Synthesis of Compound 16: The compound was synthesized according to the experimental protocol of I-20 (Example 15).

[0897] Step 2 – Synthesis of compounds I-22 and I-23: 16 isomers (0.095 g) were isolated using a CHIRALPAK OX-H column (250 mm x 4.6 mm, 5 μm) and 0.1% DEA_HEX_IPA-ACN (70-30) to obtain pure fraction-1 (FR-a) and fraction-2 (FR-b).

[0898] FR-a was concentrated under reduced pressure at 30 °C to obtain pure I-22 (0.028 g; MS (ES): m / z 454.2 [M+H)). + LCMS purity: 100%; HPLC purity: 98.77%; Chiral HPLC purity: 99.00%; 1H NMR(DMSO-d6,400MHZ):8.96(s,1H),8.26-8.24(d,J=7.2Hz,1H),8.20(s,1H),8.03-8.0 1(d,J=8.8Hz,1H),7.94-7.93(d,J=4.4Hz,1H),7.60-7.58(d,J=6.8Hz,1H),6.40-6.37( t,J=6.8Hz,1H),6.24(s,1H),5.46-5.44(m,1H),5.21-5.14(m,1H),4.25-4.18(m,2H),3 .86(bs,1H),3.17(s,3H),2.92-2.90(d,J=4.8Hz,3H),1.69-1.62(m,2H),1.24(bs,6H)).

[0899] FR-b was concentrated under reduced pressure at 30°C to obtain pure I-23 (0.032 g; MS (ES): m / z 454.2 [M+H)). + LCMS purity: 99.00%; HPLC purity: 96.20%; Chiral HPLC purity: 99.00%; 1 H NMR(DMSO-d6,400MHZ)8.95(s,1H),8.25-8.23(d,J=7.2Hz,1H),8.20(s,1H),8.03-8.01 (d,J=8.8Hz,1H),7.94-7.93(d,J=4.4Hz,1H),7.60-7.58(d,J=6.8Hz,1H),6.40-6.37(t ,J=6.8Hz,1H),6.24(s,1H),5.46-5.44(m,1H),5.21-5.14(m,1H),4.25-4.18(m,2H),3. 86(bs,1H),3.17(s,3H),2.92-2.90(d,J=4.8Hz,3H),1.69-1.62(m,2H),1.23s(bs,6H)).

[0900] Example 17: 5-((1-((1R,5S,6r)-3-oxabicyclo[3.1.0]hexane-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)amino)-N-(2-methoxycyclopropyl)-7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (I-24).

[0901]

[0902] Option 17:

[0903]

[0904] Step 1 – Synthesis of Compound 17.2: 17.1 (0.218 g, 1.62 mmol, 1.0 equivalent) was added to a solution of 17 (0.250 g, 1.62 mmol, 1.0 equivalent) in 12 mL of N,N-dimethylformamide. The reaction mixture was stirred at room temperature for 1 hour, followed by the addition of N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.402 g, 2.10 mmol, 1.3 equivalent) and 4-dimethylaminopyridine (0.049 g, 0.405 mmol, 0.25 equivalent). The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was transferred to ice-cold water, and the product was extracted with ethyl acetate. The organic layers were combined, washed with a brine solution, dried over sodium sulfate, and concentrated under reduced pressure to obtain the crude material. The crude material was further purified to 17.2 g (0.180 g, yield: 47.17%) using a combi flash solution of 30% ethyl acetate in hexane as the eluent. MS (ES): m / z 236.24 [M+H] + ).

[0905] Step 2 – Synthesis of Compound 17.3: Lithium hydroxide (0.160 g, 3.82 mmol, 5.0 equivalent) was added to a solution of 17.2 (0.180 g, 0.765 mmol, 1.0 equivalent) in tetrahydrofuran:methanol:water (5 mL, 1:1:1). The reaction was stirred at 70 °C for 3 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain a residue. Water was added to this residue at 10 °C and acidified with 1 N hydrochloric acid to adjust the pH to about 6–6.5. The product was extracted with dichloromethane. The organic layers were combined, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain 17.3 (0.140 g, yield: 82.71%; MS (ES): m / z 222.07 [M+H)). + ).

[0906] Step 3 – Synthesis of Compound 17.4: Diphenylphosphoazide (0.226 g, 0.821 mmol, 1.3 equivalents) and triethylamine (0.108 g, 1.074 mmol, 1.7 equivalents) were added to a solution of 17.3 (0.140 g, 0.632 mmol, 1.0 equivalents) in tert-butanol. The reaction was stirred at 90 °C for 16 h. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain crude material. This crude material was further purified to 17.4 (0.150 g, yield: 81.08%; MS (ES): m / z 293.34 [M+H)) by combi flash using a 1.0% MeOH solution in dichloromethane as the eluent. + ).

[0907] Step 4 – Synthesis of Compound 17.5: A solution of 1,4-dioxane in 4M hydrochloric acid (7 mL) was added to 17.4 (0.150 g, 0.513 mmol, 1.0 equivalent) and stirred at room temperature for 4 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the residue was ground with diethyl ether to obtain 17.5 (0.090 g, yield: 76.70%; MS (ES): m / z 229.68 [M+H]). + ).

[0908] Step 5 – Synthesis of Compound 17.6: Compound 17 was synthesized from nucleus A using general method A to obtain 17 (yield: 56.13%; MS (ES): m / z 396.14 [M+H]). + ).

[0909] Step 6 – Synthesis of Compound 17.7: The compound was synthesized using general procedure B to obtain 17.7 (0.119 g, yield: 56.93%; MS (ES): m / z 552.25 [M+H)). + ).

[0910] Step 7 – Synthesis of Compound I-24: The compound was synthesized using standard procedure C to obtain I-24 (0.017 g, yield: 69.23%; MS (ES): m / z 452.52 [M+H)). + LCMS purity: 98.79%; HPLC purity: 99.36%; Chiral HPLC: 49.51% and 49.74%; 1 H NMR(DMSO-d6,400MHZ):8.89(s,1H),8.22(s,1H),8.15-8.13(d,J=7.2Hz,1H),7.92-7.91(d ,J=4.8Hz,1H),7.67-7.65(d,J=6Hz,1H),7.28-7.27(d,J=6.8Hz,1H),6.26-6.23(t,J=7.2H z,1H),6.10(s,1H),3.98(s,2H),3.74-3.72(d,J=8Hz,2H),3.24(bs,3H),3.14(bs,1H),3.0 8-3.04(m,1H),2.90-2.89(d,J=4.8Hz,3H),2.27(bs,2H).2.22(bs,2H),1.08-1.03(m,1H)).

[0911] Example 18: 5-((1-((1R,5S,6r)-3-oxabicyclo[3.1.0]hexane-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)amino)-N-((1R,2R)-2-methoxycyclopropyl)-7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (I-25) and 5-((1-((1R,5S,6r)-3-oxabicyclo[3.1.0]hexane-6-yl)-2-oxo-1,2-dihydropyridin-3-yl)amino)-N-((1S,2S)-2-methoxycyclopropyl)-7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (I-26)

[0912]

[0913] Option 18:

[0914]

[0915] Synthesis of compounds I-25 and I-26: I-24 (Example 17) (0.070 g) isomers were isolated using a chiral PAK OJ-H column (250 mm x 4.6 mm, 5 μm) and a methanol solution of 0.1% DEA to obtain pure fraction-1 (FR-a) and fraction-2 (FR-b).

[0916] FR-a was concentrated under reduced pressure at 30°C to obtain pure I-25 (0.025 g; MS (ES): m / z 452.87 [M+H)). + LCMS purity: 96.75%; HPLC purity: 95.00%; Chiral HPLC purity: 95.02%; 1 H NMR(DMSO-d6,400MHZ):8.89(bs,1H),8.22(s,1H),8.13-8.12(d,J=7.2Hz,1H),7.72-7. 71(d,J=6Hz,1H),7.29-7.27(d,J=6.8Hz,1H),6.27-6.23(t,J=7.2Hz,1H),6.13(s,1H), 3.99(s,2H),3.73-3.71(d,J=8Hz,2H),3.32(bs,1H),3.23(s,3H),3.11(bs,1H),3.06-3 .03(m,1H),2.90-2.89(d,J=4.8Hz,3H),2.24(bs,2H),2.22(bs,2H),1.08-1.03(m,1H)).

[0917] FR-b was concentrated under reduced pressure at 30°C to obtain pure I-26 (0.025 g; MS (ES): m / z 452.87 [M+H)). + LCMS purity: 97.55%; HPLC purity: 96.10%; Chiral HPLC purity: 99.65%; 1 H NMR(DMSO-d6,400MHZ):8.89(bs,1H),8.22(s,1H),8.14-8.13(d,J=7.2Hz,1H),7.71-7. 69(d,J=6Hz,1H),7.29-7.27(d,J=6.8Hz,1H),6.26-6.23(t,J=7.2Hz,1H),6.16(s,1H), 3.99(s,2H),3.74-3.72(d,J=8Hz,2H),3.32(bs,1H),3.24(s,3H),3.12(bs,1H),3.06-3 .03(m,1H),2.84-2.82(d,J=8.4Hz,3H),2.25(bs,2H),2.22(bs,2H),1.07-1.05(m,1H)).

[0918] Example 19: N-((1R,2R)-2-methoxycyclopropyl)-7-(methylamino)-5-((2-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,2-dihydropyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (I-27) and N-((1S,2S)-2-methoxycyclopropyl)-7-(methylamino)-5-((2-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,2-dihydropyridin-3-yl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (I-28).

[0919]

[0920] Option 19:

[0921]

[0922] Step 1 – Synthesis of Compound 19.2: Copper acetate (2.60 g, 14.28 mmol, 1.0 equivalent) and triethylamine (5.00 mL, 35.7 mmol, 2.5 equivalent) were added to a solution of dioxane (30 mL) of 19 (3 ​​g, 14.28 mmol, 1.0 equivalent) and 19.1 (2.4 g, 17.14 mmol, 1.2 equivalent) under nitrogen atmosphere. The reaction was stirred at 80 °C for 5 hours. After the reaction was complete, the reaction mixture was transferred to ice-cold water and the product was extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to obtain the crude material. This crude material was further purified by column chromatography, and the compound was eluted in a hexane solution of 10% ethyl acetate to obtain pure 19.2 (0.380 g, yield: 11.98%; MS (ES): m / z 222.20 [M+H)). + ).

[0923] Step 2 – Synthesis of Compound 19.3: Carbon-supported palladium (0.100 g) was added to a methanol (4 mL) solution of 19.2 (0.380 g, 1.71 mmol, 1.0 equivalent). The reaction mixture was purged with hydrogen for 3 hours at room temperature. After the reaction was complete, the reaction mixture was filtered through a diatomaceous earth bed and washed with methanol. The filtrate was concentrated under reduced pressure to obtain a crude material. This crude material was further purified by column chromatography, and the compound was eluted in a 1.4% methanol solution in dichloromethane to obtain pure 19.3 (0.120 g, yield: 36.13%; MS (ES): m / z 195.23 [M+H)). + ).

[0924] Step 3 – Synthesis of compound 19.4: Compound 19.4 was synthesized from nucleus A using general method A.

[0925] Step 4 – Synthesis of Compound 19.5: Compound 19.5 was synthesized using general procedure B to obtain 19.5 (yield: 64.35%; MS (ES): m / z 554.27 [M+H)). + ).

[0926] Step 5 – Synthesis of compounds 19.5a and 19.5b: The isomers of 19.5 (0.105 g) were separated using a Chiralpak AD-H column (250 mm x 4.6 mm, 5 μm) and a methanol solution of 0.1% DEA as a co-solvent at a flow rate of 4 mL / min to give pure fraction-1 (FR-a) and fraction-2 (FR-b). FR-a was concentrated under reduced pressure at 30 °C to give pure 19.5a (0.045 g; MS (ES): m / z 554.27 [M+H]). +FR-b was concentrated under reduced pressure at 30°C to obtain pure 19.5b (0.050 g; MS (ES): m / z 554.27 [M+H)). + ).

[0927] Step 5 – Synthesis of Compound I-27: The compound was synthesized using standard procedure C to obtain I-27 (0.030 g, yield: 81.38%; MS (ES): m / z 454.86 [M+H)). + LCMS purity: 100%; HPLC purity: 97.87%; Chiral HPLC purity: 100%; 1 H NMR(DMSO-d6,400MHZ):8.83(s,1H),8.21(bs,1H),8.16-8.14(d,J=6.4Hz,1H),7.91-7.90(d,J=4 .8Hz,1H),7.67-7.66(d,J=7.2Hz,1H),7.46-7.45(d,J=6.4Hz,1H),6.31-6.28(t,J=7.2Hz,1H),6. 22(s,1H),5.03(bs,1H),4.02(bs,2H),3.53-3.47(t,J=11.6Hz,2H),3.24(s,3H),3.07-3.06(m,1 H),2.90-2.89(d,J=4.8Hz,3H),1.97-1.91(m,2H),1.76(bs,2H),1.23(s,2H),1.08-1.02(m,1H)).

[0928] Step 6 – Synthesis of Compound I-28: The compound was synthesized using standard procedure C to obtain I-28 (0.030 g, yield: 73.25%; MS (ES): m / z 454.86 [M+H)). + LCMS purity: 100%; HPLC purity: 98.96%; Chiral HPLC purity: 96.00%; 1H NMR(DMSO-d6,400MHZ):8.82(s,1H),8.21(bs,1H),8.16-8.14(d,J=6.4Hz,1H),7.91-7.89(d,J=4 .8Hz,1H),7.67-7.66(d,J=7.2Hz,1H),7.46-7.44(d,J=6.4Hz,1H),6.31-6.28(t,J=7.2Hz,1H),6. 22(s,1H),5.03(bs,1H),4.02(bs,2H),3.53-3.47(t,J=11.6Hz,2H),3.24(s,3H),3.07-3.06(m,1 H),2.90-2.89(d,J=4.8Hz,3H),1.97-1.91(m,2H),1.76(bs,2H),1.23(s,2H),1.08-1.02(m,1H)).

[0929] Example 20: 5-((1-isopropyl-2-oxo-1,2-dihydropyridin-3-yl)amino)-N-((1R,2R)-2-methoxycyclopropyl)-7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (I-29) and 5-((1-isopropyl-2-oxo-1,2-dihydropyridin-3-yl)amino)-N-((1S,2S)-2-methoxycyclopropyl)-7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (I-30).

[0930]

[0931] Option 20:

[0932]

[0933] Step 1 – Synthesis of Compound 20.1: 2-propyl bromide (1.3 g, 10.71 mmol, 1.5 equivalence) was added to a solution of 20 (1 g, 7.14 mmol, 1.0 equivalence) in 10 mL of dimethylformamide. The reaction mixture was degassed under an argon atmosphere for 10 min, followed by the addition of potassium carbonate (2.9 g, 21.42 mmol, 3.0 equivalence). The reaction mixture was heated at 100 °C for 10 h. After the reaction was complete, the reaction mixture was transferred to ice-cold water, and the product was extracted with ethyl acetate. The organic layers were combined, washed with a brine solution, dried over sodium sulfate, and concentrated under reduced pressure to obtain a crude material. This crude material was further purified with a 5% methanol solution in dichloromethane to obtain 20.1 (0.320 g, yield: 24.61%; MS (ES): m / z 183.07 [M+H]). + ).

[0934] Step 2 – Synthesis of Compound 20.2: Carbon-supported palladium (0.16 g) was added to a solution of 20.1 (0.32 g, 1.75 mmol, 1.0 equivalent) in ethanol (7 mL). The reaction mixture was purged with hydrogen for 4 hours at room temperature. After the reaction was complete, the reaction mixture was filtered through a diatomaceous earth bed and washed with methanol. The filtrate was concentrated under reduced pressure to obtain a crude material. This crude material was further purified by milling with n-pentane to obtain pure 20.2 (0.220 g, yield: 82.29%; MS (ES): m / z 153.10 [M+H)). + ).

[0935] Step 3 – Synthesis of compound 20.3: Compound 20.3 was synthesized from nucleus A using general method A.

[0936] Step 4 – Synthesis of Compound 20.4: Compound 20.4 was synthesized using general procedure B to obtain 20.4 (yield: 72.22%; MS (ES): m / z 512.26 [M+H)). + ).

[0937] Step 5 – Synthesis of compounds 20.4a and 20.4b: The isomers of 20.4 (0.110 g) were separated using a CHIRALCEL OJ-H column (250 mm x 4.6 mm, 5 μm) and a methanol solution of 0.1% DEA as a co-solvent at a flow rate of 4 mL / min to obtain pure fraction-1 (FR-a) and fraction-2 (FR-b). FR-a was concentrated under reduced pressure at 30 °C to give pure 20.4a (0.045 g; MS (ES): m / z 512.26 [M+H]). + FR-b was concentrated under reduced pressure at 30°C to obtain pure 20.4b (0.040 g; MS (ES): m / z 512.26 [M+H)). + ).

[0938] Step 6 – Synthesis of Compound I-29: The compound was synthesized using general procedure C to obtain I-29 (0.030 g, yield: 82.89%; MS (ES): m / z 412.37 [M+H)). + LCMS purity: 100%; HPLC purity: 99.51%; Chiral HPLC purity: 100%; 1H NMR(DMSO-d6,400MHZ):8.86(s,1H),8.23(bs,1H),8.17-8.15(d,J=7.2Hz,1H),7.92-7 .91(d,J=4.8Hz,1H),7.70-7.68(d,J=7.2Hz,1H),7.44-7.42(d,J=6.4Hz,1H),6.33-6.3 0(t,J=7.2Hz,1H),6.24(s,1H),5.22-5.15(m,1H),3.26(s,3H),3.09-3.04(m,1H),2.9 2-2.91(d,J=4.8Hz,3H),1.37-1.35(d,J=6.8Hz,6H),1.10-1.04(m,1H),0.53(bs,2H)).

[0939] Step 7 – Synthesis of Compound I-30: The compound was synthesized using general procedure C to obtain I-30 (0.028 g, 87.03%; MS (ES): m / z 412.42 [M+H)). + LCMS purity: 97.73%; HPLC purity: 98.62%; Chiral HPLC purity: 100%; 1 H NMR(DMSO-d6,400MHZ):8.86(s,1H),8.23(bs,1H),8.16-8.15(d,J=7.2Hz,1H),7.92-7 .91(d,J=4.8Hz,1H),7.69-7.68(d,J=7.2Hz,1H),7.44-7.42(d,J=6.4Hz,1H),6.33-6.3 0(t,J=7.2Hz,1H),6.24(s,1H),5.21-5.15(m,1H),3.26(s,3H),3.09-3.04(m,1H),2.9 2-2.90(d,J=4.8Hz,3H),1.36-1.35(d,J=6.8Hz,6H),1.09-1.04(m,1H),0.52(bs,2H)).

[0940] Example 21: 5-((1-((1r,4R)-4-methoxycyclohexyl)-2-oxo-1,2-dihydropyridin-3-yl)amino)-N-((1R,2R)-2-methoxycyclopropyl)-7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (I-31) and 5-((1-((1r,4S)-4-methoxycyclohexyl)-2-oxo-1,2-dihydropyridin-3-yl)amino)-N-((1S,2S)-2-methoxycyclopropyl)-7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (I-32).

[0941]

[0942] Option 21:

[0943]

[0944] Step 1 – Synthesis of Compound 21.1: Imidazole (7 g, 104.19 mmol, 3.0 equivalent) and tert-butyldimethylsilyl chloride (7.8 g, 52.09 mmol, 1.5 equivalent) were added to a solution of 21 (4 g, 34.73 mmol, 1.0 equivalent) in dichloromethane (40 mL) at 0 °C. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was transferred to ice-cold water and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain the crude material. This crude material was further purified to 21.1 (5.2 g, yield: 65.26%; MS (ES): m / z 230.44 [M+H)) by combi flash using a 5% methanol solution in dichloromethane as the eluent. + ).

[0945] Step 2 – Synthesis of Compound 21.3: 21.2 (3.4 g, 22.66 mmol, 1.0 equivalent) was added to a solution of 21.1 (5.2 g, 22.66 mmol, 1.0 equivalent) in 50 mL of dimethylformamide. The reaction mixture was stirred at room temperature for 1 hour, followed by the addition of N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (6.5 g, 33.99 mol, 1.5 equivalent) and 4-dimethylaminopyridine (0.69 g, 5.66 mmol, 0.25 equivalent). The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was transferred to ice-cold water, and the product was extracted with ethyl acetate. The organic layers were combined, washed with a brine solution, dried over sodium sulfate, and concentrated under reduced pressure to obtain the crude material. The crude material was further purified to 21.3 g (1.8 g, yield: 21.73%) using a combi flash solution of 30% ethyl acetate in hexane as the eluent. MS (ES): m / z 366.55 [M+H] + ).

[0946] Step 3 – Synthesis of Compound 21.4: A solution of 1,4-dioxane in hydrochloric acid (10 mL) was added to 21.3 (1.8 g, 4.92 mmol, 1.0 equivalent). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain a residue, which was then ground with diethyl ether and filtered to obtain pure 21.4 (1.2 g, yield: 96.98%; MS (ES): m / z 252.28 [M+H)). + ).

[0947] Step 4 – Synthesis of Compound 21.5: Sodium hydride (0.10 g, 7.17 mmol, 1.5 equivalent) was added to a solution of 21.4 (1.2 g, 4.78 mmol, 1.0 equivalent)...

Claims

1. A compound of formula III, III Or its pharmaceutically acceptable salt, wherein: R 1A Selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , as well as ; R 2 It is -C(O)NHR 2A ; R 2A Selected from: Selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , as well as ; R 3 Yes - NHR 3A ; R 3A It is C 1-6 Aliphatic groups; R 4 It's hydrogen. Or R 3 and R 4 Together with its intermediate atoms, it forms a 6-membered ring with the following structure: ; The aliphatic group described therein is a fully saturated, straight-chain or branched, unsubstituted hydrocarbon chain; and Each hydrogen atom bonded to carbon is optionally and independently replaced by deuterium.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4 It is H.

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 It is –NHCH3.

4. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from...

5. A pharmaceutical composition comprising the compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or mediator.

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