TYK2 inhibitors and their use

Abstract

To provide compounds, compositions thereof, and methods for using these compounds and compositions for the inhibition of TYK2 and the treatment of TYK2-mediated disorders. [Solution] The present invention relates to compounds and methods useful for inhibiting non-receptor tyrosine protein kinase 2 ("TYK2") (also known as tyrosine kinase 2). The present invention also provides pharmaceutically acceptable compositions containing the compounds of the present invention, and methods for using these compositions in the treatment of various disorders.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Patent Application No. 62 / 773,620, filed on November 30, 2018, which is incorporated herein by reference in its entirety.

[0002] Technical field of inventions The present invention relates to compounds and methods useful for inhibiting non-receptor tyrosine protein kinase 2 ("TYK2") (also known as tyrosine kinase 2). The present invention also provides pharmaceutically acceptable compositions containing the compounds of the present invention, and methods for using these compositions in the treatment of various disorders. [Background technology]

[0003] Background of the Invention In recent years, the search for new therapeutic agents has been greatly aided by a better understanding of the structures of disease-related enzymes or other biomolecules. One important class of enzymes that is the subject of extensive research is the protein kinase family.

[0004] Protein kinases constitute a large family of structurally related enzymes that regulate various intracellular signaling processes. It is believed that protein kinases evolved from a common ancestral gene due to the conservation of their structure and catalytic function. Almost all kinases contain a similar catalytic domain of 250–300 amino acids. These kinases can be categorized into families based on the substrates they phosphorylate (e.g., protein-tyrosine, protein-serine / threonine, lipids, etc.).

[0005] Generally, protein kinases mediate intracellular signaling by inducing phosphoryl translocation from nucleoside triphosphates to protein acceptors involved in signaling pathways. These phosphorylation events act as molecular on / off switches that can modulate or regulate the biological function of target proteins. These phosphorylation events are ultimately induced in response to various 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 influence one or more cellular responses related to cell proliferation, migration, differentiation, hormone secretion, transcription factor activation, muscle contraction, glucose metabolism, regulation of protein synthesis, and regulation of the cell cycle.

[0006] Many diseases are associated with abnormal cellular responses triggered by kinase-mediated events. These diseases include, but are not limited to, autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer's disease, and hormone-related disorders. Therefore, there remains a need to find protein kinase inhibitors that are useful as therapeutic agents. [Overview of the project] [Means for solving the problem]

[0007] Summary of the Invention The compounds of the present invention and their pharmaceutically acceptable compositions are found to be effective as inhibitors of TYK2 kinase.

[0008] The compounds of the present invention and their pharmaceutically acceptable compositions are useful for treating various diseases, disorders, or conditions related to the modulation of signaling pathways involving TYK2 kinase. Such diseases, disorders, or conditions are listed herein.

[0009] The compounds provided by the present invention are also useful for studying TYK2 enzymes in biological and pathological phenomena; studying intracellular signaling pathways occurring in body tissues; and for comparative evaluation of novel TYK2 inhibitors or kinases, signaling pathways, and other regulators of cytokine levels, either in vitro or in vivo. [Modes for carrying out the invention]

[0010] Detailed description of a specific embodiment 1. General description of specific embodiments of the present invention: The compounds and compositions of the present invention are useful as inhibitors of TYK2 protein kinase.

[0011] The pseudokinase binding pocket of TYK2 contains multiple hydration sites, each of which is occupied by one molecule of water. Each of these water molecules has an associated stability rating. As used herein, the term “stability rating” refers to a numerical calculation including the enthalpy, entropy, and free energy values ​​associated with each water molecule. This stability rating allows for a measurable determination of the relative stability of the water molecules occupying the hydration sites in the binding pocket of TYK2.

[0012] Water molecules that occupy the hydration site in the binding pocket of TYK2 and have a stability rating greater than 2.5 kcal / mol are called "unstable water."

[0013] While we do not wish to be constrained by any particular theory, the movement or disruption of unstable water molecules (i.e., water molecules with a stability rating greater than 2.5 kcal / mol), or the replacement of stable water (i.e., water molecules with a stability rating less than 1 kcal / mol) by an inhibitor, is thought to result in a tighter bond of that inhibitor. Therefore, an inhibitor designed to move one or more unstable water molecules (i.e., unstable water molecules that cannot be moved by any known inhibitor) is a tighter binder and, consequently, a more potent inhibitor compared to an inhibitor that does not move unstable water molecules.

[0014] Surprisingly, the provided compounds were found to move or destroy one or more unstable water molecules. In some embodiments, the provided compounds move or destroy at least two unstable water molecules.

[0015] In a particular embodiment, the present invention relates to formula I: [ka] The present invention provides a compound or a pharmaceutically acceptable salt thereof, in formula I, X, L 1 , R 1 , R 2 , and R 3 Each of these, both individually and in combination, is defined below and described in the embodiments herein.

[0016] In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable carrier, adjuvant, or diluent.

[0017] In some embodiments, the present invention provides a method for treating a TYK2-mediated disease, disorder, or condition, the method comprising the step of administering a compound of formula I or a pharmaceutically acceptable salt thereof to a patient in need thereof. 2. Compounds and Definitions:

[0018] The compounds of the present invention include those generally described herein and are further described by the classes, subclasses, and species disclosed herein. Where used herein, the following definitions apply unless otherwise indicated. For the purposes of the present invention, chemical elements are identified according to the Periodic Table of the Elements, CAS, Handbook of Chemistry and Physics, 75th edition. Furthermore, the general principles of organic chemistry are described in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry," 5th edition, edited by Smith, MB and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

[0019] The terms “aliphatic” or “aliphatic group,” as used herein, mean a linear (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain containing one or more fully saturated or unsaturated units, or a monocyclic or bicyclic hydrocarbon (also referred herein as “carbocyclic,” “alicyclic,” or “cycloalkyl”) that is fully saturated or contains one or more unsaturated units but is not aromatic, and has one bond site to the remainder of the molecule. Unless otherwise specified, an aliphatic group contains one to six aliphatic carbon atoms. In some embodiments, an aliphatic group contains one to five aliphatic carbon atoms. In other embodiments, an aliphatic group contains one to four aliphatic carbon atoms. In yet another embodiment, an aliphatic group contains one to three aliphatic carbon atoms, and in yet another embodiment, an aliphatic group contains one to two aliphatic carbon atoms. In some embodiments, “alicyclic” (or “carbocyclic” or “cycloalkyl”) refers to a monocyclic C3-C6 hydrocarbon that is fully saturated or contains one or more unsaturated units, is not aromatic, and has one bond site to the remainder of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, saturated or unsaturated alkyl groups, alkenyl groups, alkynyl groups, and hybrids thereof (e.g., (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl).

[0020] As used herein, the term “bridged bicyclic” means any bicyclic ring system (i.e., carbocyclic or heterocyclic) having at least one bridge, whether saturated or partially unsaturated. As defined by IUPAC, a “bridge” is a multi-atom unbranched chain, or a single atom, or a valence bond connecting two bridgeheads, where “bridgehead” is any skeletal atom of the ring system bonded to three or more skeletal atoms (other than hydrogen). In some embodiments, a bridged bicyclic group has 7 to 12 ring members and 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include the groups described below, where each group is bonded to the remainder of the molecule at any suitable carbon or nitrogen atom. Unless otherwise specified, bridged bicyclic groups are optionally substituted with one or more substituents, as described for aliphatic groups. In addition, or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. An example of a bridged double-ring type is: [ka] These are some examples.

[0021] The term "lower alkyl" refers to C 1~4 This refers to linear or branched alkyl groups. Exemplary lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0022] The term "lower haloalkyl" refers to a C atom that is substituted with one or more halogen atoms. 1~4 This refers to a linear or branched alkyl group.

[0023] The term "heteroatom" refers to oxygen, sulfur, nitrogen, phosphorus, or silicon (any oxidation form of nitrogen, sulfur, phosphorus, or silicon; any quaternary form of basic nitrogen; or a substituteable nitrogen in a heterocyclic ring (e.g., N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR) +(such as in an N-substituted pyrrolidinyl)) to mean one or more of (including).

[0024] The term "unsaturated", as used herein, means a moiety having one or more unsaturated units.

[0025] As used herein, the term "divalent C 1~8 (or C 1~6 ) saturated or unsaturated, straight-chain or branched hydrocarbon chain" means a straight-chain or branched divalent alkylene chain, alkenylene chain, and alkynylene chain as defined herein.

[0026] The term "alkylene" means 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. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogens are replaced by substituents. Suitable substituents include those described below for substituted aliphatic groups.

[0027] The term "alkenylene" means a divalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond and in which one or more hydrogen atoms are replaced by substituents. Suitable substituents include those described below for substituted aliphatic groups.

[0028] The term "halogen" means F, Cl, Br, or I.

[0029] The term “aryl,” used alone or as part of a larger term such as “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” means a monocyclic or bicyclic ring system having a total of 5 to 14 ring members, with at least one ring in the system being aromatic, and each ring in the system containing 3 to 7 ring members. The term “aryl” may be used interchangeably with the term “aryl ring.” In certain embodiments of the present invention, “aryl” means an aromatic ring system, including, but not limited to, phenyl, biphenyl, naphthyl, and anthracyl, which may have one or more substituents. When the term “term” is used herein, and is included within its scope, it refers to a group in which an aromatic ring is condensed with one or more non-aromatic rings (e.g., indanyl, phthalimidyl, naphthoimidyl, phenantridinyl, or tetrahydronaphthyl).

[0030] The terms “heteroaryl” and “heteroaryl,” used alone or as part of a larger term (e.g., “heteroarylkyl” or “heteroaralkoxy”), mean a group having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; 6, 10, or 14 π electrons shared in a cyclic configuration; and 1 to 5 heteroatoms in addition to carbon atoms. The term “heteroatom” means nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of basic nitrogen. Examples of heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridadinyl, pyrimidinyl, pyrazinyl, indolidinyl, prinyl, naphthilidinyl, and pteridinyl. The terms “heteroaryl” and “hetero-arra-” also, as used herein, encompass groups in which a heteroaromatic ring is fused to one or more aryl, alicyclic, or heterocyclic rings, and unless otherwise specified, its radical or bond is on the heteroaromatic ring or on one of the rings to which the heteroaromatic ring is fused. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolidinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxadinyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl. Heteroaryl groups may be monocyclic or bicyclic. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," any of which may include a ring that is substituted as necessary. The term "heteroaralkyl" refers to an alkyl group substituted with a heteroaryl group, where the alkyl and heteroaryl moieties are substituted independently as necessary.

[0031] As used herein, the terms “heterocyclic,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are interchangeable and stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic rings, which are either saturated or partially unsaturated and have one or more, preferably 1 to 4, heteroatoms in addition to the carbon atoms, as defined above. As used in reference to the ring atoms of a heterocyclic ring, the term “nitrogen” includes substituted nitrogen. For example, in a saturated or partially unsaturated ring having 0 to 3 heteroatoms selected from oxygen, sulfur, or nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl) or NH (as in pyrrolidinyl), + It may also be NR (as in N-substituted pyrrolidinyl).

[0032] Heterocyclic rings can be bonded to their parent group at any heteroatom or carbon atom that results in a stable structure, and any of these ring atoms can be substituted as needed. Examples of such saturated or partially unsaturated heterocyclic radicals include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenylpyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, 2-oxa-6-azaspiro[3.3]heptane, and quinuclidinyl. The terms “heterocyclic,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical” are interchangeable herein and also encompass groups in which the heterocyclyl ring is fused to one or more aryl rings, heteroaryl rings, or alicyclic rings (e.g., indolinyl, 3H-indolyl, chromanyl, phenantridinyl, or tetrahydroquinolinyl). The heterocyclyl group may be monocyclic or bicyclic. The term “heterocyclylalkyl” means an alkyl group substituted with a heterocyclyl, where the alkyl moiety and the heterocyclyl moiety are substituted independently as needed.

[0033] As used herein, the term “partially unsaturated” means a ring portion containing at least one double or triple bond. The term “partially unsaturated” is intended to encompass rings having multiple unsaturated sites, but not to encompass aryl or heteroaryl moies as defined herein.

[0034] As described herein, the compounds of the present invention may include “optionally substituted” moieties. Generally, the term “substituted” means that one or more hydrogens of a designated moiety are replaced with appropriate substituents, whether preceded or not by the term “optionally”. Unless otherwise indicated, an “optionally substituted” group may have appropriate substituents on each of its substituted moieties, and if one or more positions in any given structure can be replaced with one or more substituents selected from a particular group, the substituents may be the same or different at each position. The substituent combinations envisioned by the present invention are preferably combinations that result in the formation of stable compounds or chemically possible compounds. The term “stable,” as used herein, means a compound that remains substantially unchanged when produced, detected, and, in particular embodiments, subjected to conditions that enable their recovery, purification, and use for one or more of the purposes disclosed herein.

[0035] A suitable monovalent substituent on the substitutable carbon atom of the "substituted as needed" group is, independently, a halogen;-(CH2) 0~4 R ○ ;CH2) 0~4 Ure ○ ;-O(CH2) 0~4 R ○ -O-(CH2) 0~4 C(O)OR ○ ;-(CH2) 0~4 CH(OR ○ )2;-(CH2) 0~4 SR ○ ;-(CH2) 0~4 Ph (This is R ○ It can be replaced by (CH2) 0~4 O(CH2) 0~1 Ph (This is R ○ It can be substituted with);-CH=CHPh(this is R ○ It can be replaced by (CH2) 0~4 O(CH2) 0~1 -Pyridyl (This is R ○which may be replaced by); -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) 0~4 S(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 of a linear or branched alkylene)O-N(R ○ )2; or -(C 1~4 of a linear or branched alkylene)C(O)O-N(R ○ )2, wherein each R ○ may be substituted as defined below and independently is hydrogen, C 1~6 aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, -CH2-(5- to 6-membered heteroaryl ring), or independently a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms selected from nitrogen, oxygen, or sulfur, or regardless of the above definition, R ○Two independent entities of these, together with an atom(s) between them, form a 3- to 12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring, each containing 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which can be substituted as defined below.

[0036] R ○ (R ○ The appropriate monovalent substituents on the ring formed by the two independent entities of these atoms joining together with the atom between them are halogens, -(CH2) 0~2 R ● ,-(HaroR ● ), -(CH2) 0~2 OH, -(CH2) 0~2 Ure ● ,-(CH2) 0~2 CH(OR ● )2;-O(HaroR ● ), -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 ● And here each R ● It is either not substituted, or if preceded by "halo", it is substituted by only one or more halogens, and independently, C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1Ph, or selected from 5- to 6-membered saturated, partially unsaturated, or aryl rings having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. ○ Suitable divalent substituents on the saturated carbon atom include =O and =S.

[0037] Suitable divalent substituents on the saturated carbon atoms of the "substituted as needed" groups include: =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-. Here's R * Each independent entity is a hydrogen, which can be substituted as defined below. 1~6 Selected from aliphatic, or unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl rings having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents bonded to the substituteable carbon of the vicinal of the "optionally substituted" group include -O(CR * 2) 2~3 O- is mentioned, and here R * Each independent entity is a hydrogen, which can be substituted as defined below. 1~6 Selected from aliphatic or unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl rings having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0038] R * Suitable substituents on the aliphatic group include halogens, -R ● ,-(HaroR ● ), -OH, -OR ● ,-O(HaroR ● ), -CN, -C(O)OH, -C(O)OR ● -NH2, -NHR● , -NR ● 2, or -NO2, where each R ● It is either not substituted, or if preceded by "halo", it is substituted by only one or more halogens, and independently, C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1 It is a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms, or independently selected from nitrogen, oxygen, or sulfur.

[0039] A suitable substitutionable substituent on the nitrogen of the "substituted as needed" group is -R † , -NR † 2, -C(O)R † , -C(O)OR † ,-C(O)C(O)R † -C(O)CH2C(O)R † -S(O)2R † -S(O)2NR † 2, -C(S)NR † 2, -C(NH)NR † 2, or -N(R † )S(O)2R † These are listed; here each R † C can be substituted independently of hydrogen, as defined below. 1~6 Aliphatic, unsubstituted -OPh, or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or notwithstanding the above definition, R † Two independent entities of these elements, together with an atom(s) between them, form an unsubstituted 3- to 12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring, each containing 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0040] R † Suitable substituents on the aliphatic group are, independently, halogens, -R ● ,-(HaroR ● ), -OH, -OR● ,-O(HaroR ● ), -CN, -C(O)OH, -C(O)OR ● -NH2, -NHR ● , -NR ● 2, or -NO2, where each R ● It is either not substituted, or if preceded by "halo", it is substituted by only one or more halogens, and independently, C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1 It is a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms, or independently selected from nitrogen, oxygen, or sulfur.

[0041] As used herein, the term “pharmaceutically acceptable salt” means a salt that, within reasonable medical judgment, is appropriate for use in contact with human and lower animal tissues without excessive toxicity, irritation, and allergic reactions, and that is balanced by a reasonable benefit / risk ratio. pharmaceutically acceptable salts are well known in the art. For example, SMBerge et al., in J. Pharmaceutical Sciences, 1977, 66, 1-19, describe pharmaceutically acceptable salts in detail, which are incorporated herein by reference. Examples of pharmaceutically acceptable salts of the compounds of the present invention include salts derived from suitable inorganic acids, inorganic bases, organic acids, and organic bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or organic acids (e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or by other methods used in the field, such as ion exchange. Other pharmaceutically acceptable salts include adipines, alginates, ascorbic acid, aspartates, benzenesulfons, benzoates, bisulfates, borates, butyrates, camphorates, camphor sulfons, citrates, cyclopentanepropionates, diglucons, dodecyl sulfates, ethanesulfons, formates, fumarates, glucoheptons, glycerophosphates, glucons, hemisulfates, heptanoates, hexanoates, hydroiodides, and 2-hydroxyethanesulfonates. Examples include nitrates, lactobionates, lactates, laurates, lauryl sulfates, malates, maleates, malons, methanesulfons, 2-naphthalenesulfons, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectins, persulfates, 3-phenylpropionates, phosphates, pivalates, propions, stearates, succinates, sulfates, tartrates, thiocyans, p-toluenesulfons, undecanoates, and valersates.

[0042] Examples of salts derived from suitable bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N + (C 1~4 Examples include alkyl)4 salts. Typical alkali metal salts or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Further pharmaceutically acceptable salts, where appropriate, include non-toxic ammonium, quaternary ammonium, and amine cations formed with counterions such as halide ions, hydroxide ions, carbonate ions, sulfate ions, phosphate ions, nitrate ions, lower alkyl sulfonate ions, and aryl sulfonate ions.

[0043] Unless otherwise stated, the structures illustrated herein also mean that all isomers (e.g., enantiomers, diastereomers, and geometric (or conformational) forms) of that structure, such as the R and S configurations for each chiral center, the Z and E double bond isomers, and the Z and E conformational isomers. Thus, single stereochemical isomers of the compounds of the present invention, as well as enantiomers, diastereomers, and geometric (or conformational) mixtures, are within the scope of the present invention. Unless otherwise stated, all tautomer forms of the compounds of the present invention are within the scope of the present invention. Furthermore, unless otherwise stated, the structures illustrated herein also mean that all compounds differ only in the presence of one or more isotope-enriched atoms. For example, the structures of the present invention in which hydrogen is replaced by deuterium or tritium, or carbon 13 C or 14 Compounds having the present invention in which C is replaced with enriched carbon are within the scope of the present invention. Such compounds are useful, for example, as analytical tools according to the present invention, as probes in biological assays, or as therapeutic agents. In a particular embodiment, the warhead portion R of a given compound 1 It contains one or more deuterium atoms. In certain embodiments, ring B of the provided compound may be substituted with one or more deuterium atoms.

[0044] As used herein, the term “inhibitor” is defined as a compound that binds to and / or inhibits TYK2 with a measurable affinity. In certain embodiments, the inhibitor is an IC2 with an IC2 of 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. 50 It has and / or coupling constants.

[0045] The compounds of the present invention can be anchored to a detectable moiety. It is understood that such compounds are useful as imaging agents. Those skilled in the art will recognize that the detectable moiety may be bonded to the provided compound via a suitable substituent. In this specification, the term “suitable substituent” means a moiety that can be covalently bonded to the detectable moiety. Such moieties are well known to those skilled in the art and include, for example, groups containing a carbonate moiety, an amino moiety, a thiol moiety, or a hydroxyl moiety. It is understood that such moieties may be bonded directly to the provided compound or via a anchoring group such as a divalent saturated or unsaturated hydrocarbon chain. In some embodiments, such moieties may be bonded by click chemistry. In some embodiments, such moieties may be bonded by 1,3-cycloaddition of an azide with an alkyne, optionally in the presence of a copper catalyst. Methods using click chemistry are publicly known in the art, including those described by Rostovtsev et al., Angew. Chem. Int. Ed. 2002, 41, 2596-99 and Sun et al., Bioconjugate Chem., 2006, 17, 52-57.

[0046] In this specification, the term “detectable portion” is used interchangeably with the term “label” and refers to any portion that can be detected, e.g., primary and secondary labels. Radioactive isotopes (e.g., tritium, 32 P, 33 P, 35 S, or 14C) Primary labels such as mass tags and fluorescent labels are signal-generating reporter groups that can be detected without further modification. Other detectable parts include luminescent groups and phosphorescent groups.

[0047] In this specification, the term “secondary label” refers to a portion of a protein, such as biotin and various protein antigens, that requires the presence of a secondary intermediate to generate a detectable signal. For biotin, the secondary intermediate may include a streptavidin-enzyme conjugate. For antigen labeling, the secondary intermediate may include an antibody-enzyme conjugate. Some fluorescent groups act as secondary labels because they transfer energy to another group in a non-radioactive fluorescence resonance energy transfer (FRET) process, producing a signal in which the second group is detectable.

[0048] In this specification, the terms "fluorescent label," "fluorescent dye," and "fluorescent phosphone" refer to a portion that absorbs light energy at a specified excitation wavelength and emits light energy at a different wavelength. Examples of fluorescent labels include Alexa Fluor dyes (Alexa Fluor350, Alexa Fluor488, Alexa Fluor532, Alexa Fluor546, Alexa Fluor568, Alexa Fluor594, Alexa Fluor633, Alexa Fluor660, and Alexa Fluor680), AMCA, AMCA-S, and BODIPY dyes (BODIPY FL, BODIPY R6G, BODIPY TMR, BODIPY TR, BODIPY530 / 550, BODIPY558 / 568, BODIPY564 / 570, BODIPY576 / 589, BODIPY581 / 591, BODIPY630 / 650, BODIPY650 / 665), Carboxyrhodamine 6G, Carboxy-X-Rhodamine (ROX), Cascade Blue, Cascade Yellow, Coumarin 343, Cyanine dye (Cy3, Cy5, Cy3.5, Cy5.5), Dansyl, Dapoxyl, Dialkylaminocoumarin, 4',5'-Dichloro-2',7'-Dimethoxy-Fluorescein, DM-NERF, Eosin, Erythrosine, Fluorescein, FAM, Hid Examples include, but are not limited to, roxycoumarin, IRDyes (IRD40, IRD700, IRD800), JOE, Lisamin Rhodamine B, Marina Blue, Methoxycoumarin, Naphthofluorescein, Oregon Green 488, Oregon Green 500, Oregon Green 514, Pacific Blue, PyMPO, Pyrene, Rhodamine B, Rhodamine 6G, Rhodamine Green, Rhodamine Red, Rhodol Green, 2',4',5',7'-Tetra-bromosulfone-fluorescein, Tetramethyl-Rhodamine (TMR), Carboxytetramethylrhodamine (TAMRA), Texas Red, and Texas Red-X.

[0049] In this specification, the term “mass tag” means any portion that can be uniquely detected by its mass using mass spectrometry (MS) detection techniques. Examples of mass tags include electrophore-emitting tags such as N-[3-[4'-[(p-methoxytetrafluorobenzyl)oxy]phenyl]-3-methylglyceronyl]isonipeconic acid, 4'-[2,3,5,6-tetrafluoro-4-(pentafluorophenoxyl)]methylacetophenone and their derivatives. The synthesis and utility of these mass 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 mass tags include, but are not limited to, nucleotides, dideoxynucleotides, oligonucleotides, oligopeptides, oligosaccharides, and other synthetic polymers of various lengths and monomer compositions. A wide variety of organic molecules (biomolecules or synthetic compounds), both neutral and charged, within a suitable mass range (100–2000 daltons) may be used as mass tags.

[0050] The terms “measurable affinity” and “measurable inhibition,” as used herein, mean a measurable change in TYK2 protein kinase activity between a sample containing the compound or its composition and TYK2 protein kinase of the present invention and an equivalent sample containing TYK2 protein kinase in which neither the compound nor its composition is present. 3. Description of exemplary embodiments:

[0051] As described above, in certain embodiments, the present invention relates to formula I: [ka] Provides a compound or a pharmaceutically acceptable salt thereof, in formula I: X is either N or CH; L 1 is a covalent bond or C1~4 A divalent saturated or unsaturated, straight or branched hydrocarbon chain, where one or two methylene units in the chain are independently -C(R) as needed. 4 ) is replaced by -2-, -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-; R 4 R is independent of R A or R B and; R A Each example is independently halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)(NR)R, -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 -P(O)R2; or R in two examples A They combine as needed to form oxo; R B Each example is independent of C 1~6 Aliphatic; phenyl; 5-6 member monocyclic heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 8-10 member bicyclic heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 3-7 member saturated or partially unsaturated monocyclic carbocyclic rings; 3-7 member saturated or partially unsaturated monocyclic heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or 7-12 member saturated or partially unsaturated bicyclic heterocyclic rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is q examples of R C It is replaced by; R CEach example is independently 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)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -N=S(O)R2, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -P(O)(R)NR2, -P(O)(R)OR or -P(O)R2, or C 1~6 Aliphatic; phenyl; naphthalenyl; 8-10 membered bicyclic heteroaryl rings having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 5-8 membered saturated or partially unsaturated bridged bicyclic rings having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 6-10 membered saturated or partially unsaturated spirocyclic rings having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 6-11 membered saturated or partially unsaturated bicyclic heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 3-7 membered saturated or partially unsaturated monocyclic heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, phosphorus, silicon, and sulfur; and 5-6 membered monocyclic heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or R B For each example, as needed: Two R atoms on the same atom C The group, together with the atoms, forms a 4-7 member saturated spirocyclic heterocyclic ring, which may be substituted as needed, and independently has 1-2 heteroatoms selected from nitrogen, oxygen, and sulfur; 2 R C The groups, together with the atoms between them, form a 4-7 member saturated or partially unsaturated condensed ring which has 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and which are optionally substituted; or 2 R C The groups, together with the atoms between them, form a 5-6 membered fused aryl ring which may be substituted as needed, and which independently has 0-3 heteroatoms selected from nitrogen, oxygen, and sulfur; Each R is independently either hydrogen or C 1~6 Aliphatic; phenyl; naphthalenyl; 8-10 membered bicyclic heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 3-7 membered saturated or partially unsaturated monocyclic heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 7-12 membered saturated or partially unsaturated bicyclic heterocyclic rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and 5-6 membered monocyclic heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or optionally substituted groups; or: Two R groups on the same nitrogen atom, together with the nitrogen, form a 4-7 membered monocyclic saturated, partially unsaturated, or heteroaryl ring, optionally substituted with 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur in addition to the nitrogen; R 1 is Cy 1 and; Cy 1 phenyl; a 5-6 member monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 member bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 member saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 member saturated or partially unsaturated monocyclic carbon ring; or a 7-12 member saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Cy 1 R is p examples 1A It has been replaced with; R 1A Each example is independent, R A or RB and; R 2 C 1~6 Aliphatic; phenyl; 5-6 member monocyclic heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 8-10 member bicyclic heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 3-7 member saturated or partially unsaturated monocyclic carbocyclic rings; 3-7 member saturated or partially unsaturated monocyclic heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or 7-12 member saturated or partially unsaturated bicyclic heterocyclic rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is q examples of R C It is replaced by; R 3 is -C(O)NH2, -C(O)NHCH3, or -C(O)NHCD3; and p and q are independently 0, 1, 2, 3, or 4.

[0052] As described above, in certain embodiments, the present invention relates to formula I': [ka] Provides a compound or a pharmaceutically acceptable salt thereof, in formula I': X is either N or CH; L 1 is a covalent bond or C 1~4 A divalent saturated or unsaturated, straight or branched hydrocarbon chain, where one or two methylene units in the chain are independently -C(R) as needed. 4 ) is replaced by -2-, -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-; R 4 R is independent of R A or R B and; R A Each example is independently halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)(NR)R, -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 -P(O)R2; or R in two examples A They combine as needed to form oxo; R B Each example is independent of C 1~6 Aliphatic; phenyl; 5-6 member monocyclic heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 8-10 member bicyclic heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 3-7 member saturated or partially unsaturated monocyclic carbocyclic rings; 3-7 member saturated or partially unsaturated monocyclic heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or 7-12 member saturated or partially unsaturated bicyclic heterocyclic rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is q examples of R C It is replaced by; R C Each example is independently 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)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -N=S(O)R2, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -P(O)(R)NR2, -P(O)(R)OR or -P(O)R2, or C 1~6Aliphatic; phenyl; naphthalenyl; 8-10 membered bicyclic heteroaryl rings having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 5-8 membered saturated or partially unsaturated bridged bicyclic rings having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 6-10 membered saturated or partially unsaturated spirocyclic rings having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 6-11 membered saturated or partially unsaturated bicyclic heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 3-7 membered saturated or partially unsaturated monocyclic heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, phosphorus, silicon, and sulfur; and 5-6 membered monocyclic heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or R B For each example, as needed: Two R atoms on the same atom C The group, together with the atoms, forms a 4-7 member saturated spirocyclic heterocyclic ring, which may be substituted as needed, and independently has 1-2 heteroatoms selected from nitrogen, oxygen, and sulfur; 2 R C The groups, together with the atoms between them, form a 4-7 member saturated or partially unsaturated condensed ring which has 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and which are optionally substituted; or 2 R C The groups, together with the atoms between them, form a 5-6 membered fused aryl ring which may be substituted as needed, and which independently has 0-3 heteroatoms selected from nitrogen, oxygen, and sulfur; Each R is independently either hydrogen or C 1~6Aliphatic; phenyl; naphthalenyl; 8-10 membered bicyclic heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 3-7 membered saturated or partially unsaturated monocyclic heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 7-12 membered saturated or partially unsaturated bicyclic heterocyclic rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and 5-6 membered monocyclic heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or optionally substituted groups; or: Two R groups on the same nitrogen atom, together with the nitrogen, form a 4-7 membered monocyclic saturated, partially unsaturated, or heteroaryl ring, optionally substituted with 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur in addition to the nitrogen; R 1 is Cy 1 and; Cy 1 phenyl; a 5-6 member monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 member bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 member saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 member saturated or partially unsaturated monocyclic carbon ring; or a 7-12 member saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Cy 1 R is p examples 1A It has been replaced with; R 1A Each example is independent, R A or R B and; R 2 C 1~6Aliphatic; phenyl; 5-6 member monocyclic heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 8-10 member bicyclic heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 3-7 member saturated or partially unsaturated monocyclic carbocyclic rings; 3-7 member saturated or partially unsaturated monocyclic heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or 7-12 member saturated or partially unsaturated bicyclic heterocyclic rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is q examples of R C It is replaced by; R 3 These are -C(O)NH2, -C(O)NHCH3, or -C(O)NHCD3; Each of p and q is independently 0, 1, 2, 3, or 4; and r is either 0 or 1.

[0053] As generally defined above, X is N or CH. In some embodiments, X is N. In some embodiments, X is CH.

[0054] In some embodiments, X is selected from those shown in Table 1 below.

[0055] As generally defined above, L 1 is a covalent bond or C 1~4 A divalent saturated or unsaturated, straight or branched hydrocarbon chain, where one or two methylene units in the chain are independently -C(R) as needed. 4 It is replaced by -2-, -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-.

[0056] In some embodiments, L 1 It is a covalent bond.

[0057] In some embodiments, L 1 C 1~4 A divalent saturated or unsaturated, straight or branched hydrocarbon chain, where one or two methylene units in the chain are independently -C(R) as needed. 4 It is replaced by -2-, -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-.

[0058] In some embodiments, L 1 C 1~4 A divalent, saturated, straight or branched hydrocarbon chain, where one or two methylene units in the chain are independently -C(R) as needed. 4 ) is replaced by -2-, -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-. In some embodiments, L 1 C 1~4 A divalent unsaturated, straight or branched hydrocarbon chain, where one or two methylene units in the chain are independently -C(R) as needed. 4 It is replaced by -2-, -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-.

[0059] In some embodiments, L 1 C 1~4 A divalent, saturated, straight or branched hydrocarbon chain, where one methylene unit in the chain is, if necessary, -C(R 4) is replaced by -2-, -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-. In some embodiments, L 1 C 1~4 A divalent unsaturated, straight or branched hydrocarbon chain, where one methylene unit in the chain is, if necessary, -C(R 4 It is replaced by -2-, -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-.

[0060] In some embodiments, L 1 C 1~4 A divalent, saturated or unsaturated, linear or branched hydrocarbon chain. In some embodiments, L 1 C 1~4 It is a divalent, saturated, straight or branched hydrocarbon chain. In some embodiments, L 1 C 1~4 It is a divalent, unsaturated, straight or branched hydrocarbon chain.

[0061] In some embodiments, L 1 is a covalent bond, -C(R 4 )2-, -N(R)-, or -O-. In some embodiments, L 1 is a covalent bond or -N(R)-. In some embodiments, L 1 -C(R 4 )2-, -N(R)-, or -O-. In some embodiments, L 1 The bond is covalent, -C(H)2-, -N(H)-, or -O-. In some embodiments, L 1 is a covalent bond or -N(H)-. In some embodiments, L 1 These are -C(H)2-, -N(H)-, or -O-.

[0062] In some embodiments, L 1 The selection is made from those shown in Table 1 below.

[0063] As generally defined above, R 4 Each example is independent, R A or R B In some embodiments, R 4 is R A In some embodiments, R 4 is R B That is the case.

[0064] In some embodiments, R 4 R is a halogen;-OR;q examples C C is replaced as needed by 1~6 Is it aliphatic; or R in two examples 4 They come together to form an oxo. In some embodiments, two examples of R 4 They come together to form an oxo. In some embodiments, R 4 is a halogen. In some embodiments, R 4 is -OR. In some embodiments, R 4 R for q examples C C is replaced as needed by 1~6 It is aliphatic. In some embodiments, R 4 is C 1~3 It is an aliphatic.

[0065] In some embodiments, R 4 The option is selected from those shown in Table 1 below.

[0066] As generally defined above, R AEach example is independently halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)(NR)R, -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 -P(O)R2, or R of two examples. A They combine as needed to form oxoplasm.

[0067] In some embodiments, R A Each example is, independently, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)(NR)R, -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)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, or -P(O)R2. In some embodiments, two examples of R A They come together to form an oxo.

[0068] In some embodiments, R A is a halogen. In some embodiments, R A is -CN. In some embodiments, R A is -NO2. In some embodiments, R A is -OR. In some embodiments, R A is -SR. In some embodiments, R A is -NR2. In some embodiments, R A is -S(O)2R. In some embodiments, R A is -S(O)(NR)R. In some embodiments, R Ais -S(O)2NR2. In some embodiments, R A is -S(O)R. In some embodiments, R A is -S(O)NR2. In some embodiments, R A is -C(O)R. In some embodiments, R A is -C(O)OR. In some embodiments, R A is -C(O)NR2. In some embodiments, R A is -C(O)N(R)OR. In some embodiments, R A is -OC(O)R. In some embodiments, R A is -OC(O)NR2. In some embodiments, R A is -N(R)C(O)OR. In some embodiments, R A is -N(R)C(O)NR2. In some embodiments, R A is -N(R)C(NR)NR2. In some embodiments, R A is -N(R)S(O)2NR2. In some embodiments, R A is -N(R)S(O)2R. In some embodiments, R A is -P(O)R2.

[0069] In some embodiments, R A is a halogen, -CN, or -NO2. In some embodiments, R A is -OR, -SR, or -NR2. In some embodiments, R A is -S(O)2R, -S(O)(NR)R, -S(O)2NR2, -S(O)R, or -S(O)NR2. In some embodiments, R A is -C(O)R, -C(O)OR, -C(O)NR2, or -C(O)N(R)OR. In some embodiments, R A is -OC(O)R or -OC(O)NR2. In some embodiments, R Ais -N(R)C(O)OR, -N(R)C(O)NR2, or -N(R)C(NR)NR2. In some embodiments, R A This is -N(R)S(O)2NR2 or -N(R)S(O)2R.

[0070] In some embodiments, R A is -S(O)2R, -S(O)2NR2, -S(O)R, or -S(O)NR2. In some embodiments, R A This is -N(R)C(O)OR or -N(R)C(O)NR2.

[0071] In some embodiments, R A is either halogen, -CN, -OR, -SR, -NR2, -OC(O)R, -OC(O)NR2, or R in two examples. A They come together to form an oxo. In some embodiments, R A is halogen, -OR, or R in the two examples A They come together to form an oxo.

[0072] In some embodiments, R A is either halogen, -CN, -OR, -SR, -NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, or R in two examples. A They come together to form an oxo. In some embodiments, R A is either halogen, -CN, -OR, -NR2, -C(O)NR2, or R in the two examples. A They come together to form an oxo.

[0073] In some embodiments, R A The option is selected from those shown in Table 1 below.

[0074] As generally defined above, R B Each example is independent of C 1~6Aliphatic; phenyl; 5-6 member monocyclic heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 8-10 member bicyclic heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 3-7 member saturated or partially unsaturated monocyclic carbocyclic rings; 3-7 member saturated or partially unsaturated monocyclic heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or 7-12 member saturated or partially unsaturated bicyclic heterocyclic rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is q examples of R C It has been replaced by.

[0075] In some embodiments, R B R for q examples C C is replaced by 1~6 It is aliphatic. In some embodiments, R B is C 1~6 It is aliphatic. In some embodiments, R B R is q of the examples C C is replaced as needed by 1~3 It is aliphatic. In some embodiments, R B is C 1~3 It is an aliphatic.

[0076] In some embodiments, R B R is a phenyl ring; a 5-6 member monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 member bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 member saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 member saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 member saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is q examples of R C It has been replaced by.

[0077] In some embodiments, R B R for q examples C It is a phenyl substituted with R. In some embodiments, B R for q examples C It is a 5-6 member monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which are substituted with R. In some embodiments, R B R for q examples C It is an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which are substituted with R. In some embodiments, R B R for q examples C A 3-7 member saturated or partially unsaturated monocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which are substituted with R. In some embodiments, R B R for q examples C It is a 3- to 7-membered saturated or partially unsaturated monocyclic carbon ring that is substituted with R. In some embodiments, B R for q examples C It is a 7-12 member saturated or partially unsaturated bicyclic or heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which are substituted with .

[0078] In some embodiments, R B R is a phenyl or 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic; each of which has q examples. C It is replaced by R BR is a 5-6 member monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 member bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 member saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 member saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is q examples of R C It is replaced by R B R is a 5-6 member monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8-10 member bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which has q examples of R C It is replaced by R B R is a 3-7 member saturated or partially unsaturated monocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 member saturated or partially unsaturated bicyclic or heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which has q examples of R C It has been replaced with.

[0079] In some embodiments, R B R is a phenyl ring; a 5-6 member monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 member saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 member saturated or partially unsaturated monocyclic carbon ring; each of which has q examples. C It is replaced by R BR is an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which has q examples of R C It has been replaced with.

[0080] In some embodiments, R B R for q examples C It is a 3- to 7-membered saturated monocyclic carbon ring substituted by R. In some embodiments, R B R for q examples C It is a 3- to 7-membered partially unsaturated monocyclic carbon ring substituted by R. In some embodiments, B R is a 3- to 7-membered saturated or partially unsaturated monocyclic carbon ring. In some embodiments, R B It is cyclopropyl.

[0081] In some embodiments, R B C 1~6 Aliphatic; phenyl; 5-6 member monocyclic heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 3-7 member saturated or partially unsaturated monocyclic carbocyclic rings; or 3-7 member saturated or partially unsaturated monocyclic heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which has q examples of R C It has been replaced with.

[0082] In some embodiments, R B C 1~6 Aliphatic; phenyl; or 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic rings; each of which has q examples of R C It is replaced by R BR is a 5-6 member monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 3-7 member saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which has q examples of R C It has been replaced with.

[0083] In some embodiments, R B R is a 5-6 member monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 member saturated or partially unsaturated monocyclic carbon ring; or a 3-7 member saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which has q examples C It has been replaced with.

[0084] In some embodiments, R B The option is selected from those shown in Table 1 below.

[0085] As generally defined above, R C These are independently 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)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -N=S(O)R2, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -P(O)(R)NR2, -P(O)(R)OR or -P(O)R2, or C 1~6Aliphatic; phenyl; naphthalenyl; 8-10 membered bicyclic heteroaryl rings having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 5-8 membered saturated or partially unsaturated bridged bicyclic rings having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 6-10 membered saturated or partially unsaturated spirocyclic rings having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 6-11 membered saturated or partially unsaturated bicyclic heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 3-7 membered saturated or partially unsaturated monocyclic heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, phosphorus, silicon, and sulfur; and 5-6 membered monocyclic heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or R B For each example, as needed: Two R atoms on the same atom C The group, together with the atoms, forms a 4-7 member saturated spirocyclic heterocyclic ring, which may be substituted as needed, and independently has 1-2 heteroatoms selected from nitrogen, oxygen, and sulfur; 2 R C The groups, together with the atoms between them, form a 4-7 member saturated or partially unsaturated condensed ring which has 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and which are optionally substituted; or 2 R C The groups, together with the atoms between them, form a 5-6 membered fused aryl ring which may be substituted as needed and has 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0086] In some embodiments, R CThese are 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)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -N=S(O)R2, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -P(O)(R)NR2, -P(O)(R)OR or -P(O)R2, or C 1~6 Aliphatic; phenyl; naphthalenyl; 8-10 membered bicyclic heteroaryl rings having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 5-8 membered saturated or partially unsaturated bridged bicyclic rings having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 6-10 membered saturated or partially unsaturated spirocyclic rings having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 6-11 membered saturated or partially unsaturated bicyclic heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 3-7 membered saturated or partially unsaturated monocyclic heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, phosphorus, silicon, and sulfur; and optionally substituted groups selected from 5-6 membered monocyclic heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0087] In some embodiments, two R atoms on the same atom C The group, together with the atom, forms a 4-7 member saturated spirocyclic heterocyclic ring, which may be substituted as needed and may have 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0088] In some embodiments, two R CThe groups, together with the atoms between them, form a 4-7 member saturated or partially unsaturated condensed ring, which may be substituted as needed and contains 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0089] In some embodiments, two R C The groups, together with the atoms between them, form a 5-6 membered fused aryl ring which may be substituted as needed and has 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0090] In some embodiments, R C These are 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)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -N=S(O)R2, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -P(O)(R)NR2, -P(O)(R)OR or -P(O)R2, or C as needed. 1~6 It is aliphatic. In some embodiments, R CThe group is optionally substituted from phenyl; naphthalenyl; an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-8 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-10 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-11 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, phosphorus, silicon, and sulfur; and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0091] In some embodiments, R C C is either 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 -N(R)S(O)R, or substituted as necessary. 1~6 It is aliphatic. In some embodiments, R C C 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, or substituted as needed. 1~6 It is aliphatic. In some embodiments, R CC is oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, or substituted as needed. 1~6 It is aliphatic. In some embodiments, R C C is oxo, halogen, -CN, -OR, -SR, -S(O)2R, -S(O)R, or substituted as needed. 1~6 It is aliphatic. In some embodiments, R C C is oxo, -OR, -S(O)2R, or substituted as needed. 1~6 It is an aliphatic.

[0092] In some embodiments, R C It is methyl.

[0093] In some embodiments, R C The selection is made from those shown in Table 1 below.

[0094] As generally defined above, each R is independently either hydrogen or C 1~6 Aliphatic; phenyl; naphthalenyl; 8-10 membered bicyclic heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 3-7 membered saturated or partially unsaturated monocyclic heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 7-12 membered saturated or partially unsaturated bicyclic heterocyclic rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and 5-6 membered monocyclic heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or optionally substituted groups; or: Two R groups on the same nitrogen atom, together with the nitrogen, form a 4-7 membered monocyclic saturated, partially unsaturated, or heteroaryl ring, which may be substituted as needed, and which also contains 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, in addition to the nitrogen atom.

[0095] In some embodiments, R is hydrogen or C 1~6 Aliphatic; phenyl; naphthalenyl; 8-10 membered bicyclic heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 3-7 membered saturated or partially unsaturated monocyclic heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 7-12 membered saturated or partially unsaturated bicyclic heterocyclic rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and optionally substituted groups selected from 5-6 membered monocyclic heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0096] In some embodiments, two R groups on the same nitrogen atom, together with the nitrogen, form a optionally substituted 4-7 member monocyclic saturated, partially unsaturated, or heteroaryl ring having, in addition to this nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0097] In some embodiments, R is hydrogen. In some embodiments, R is C 1~6 Aliphatic; phenyl; naphthalenyl; 8-10 membered bicyclic heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 3-7 membered saturated or partially unsaturated monocyclic heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 7-12 membered saturated or partially unsaturated bicyclic heterocyclic rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and optionally substituted groups selected from 5-6 membered monocyclic heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0098] In some embodiments, R is C 1~6The group is optionally substituted, selected from aliphatic, phenyl, and naphthalenyl groups. In some embodiments, R is optionally substituted, selected from an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0099] In some embodiments, R is hydrogen, and C is substituted as needed. 1~6 The aliphatic or two R groups on the same nitrogen combine with the nitrogen to form a 4-7 membered monocyclic saturated, partially unsaturated, or heteroaryl ring, which, in addition to the nitrogen, has 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and which are optionally substituted. In some embodiments, R is hydrogen, optionally substituted with C 1~6 The aliphatic or two R groups on the same nitrogen combine with the nitrogen to form a 4-7 membered monocyclic saturated ring, which, in addition to this nitrogen, has 0-1 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and is optionally substituted. In some embodiments, R is hydrogen or optionally substituted C 1~6 It is aliphatic. In some embodiments, R is hydrogen or C is substituted as needed. 1~3 It is an aliphatic.

[0100] In some embodiments, R is selected from those shown in Table 1 below.

[0101] As generally defined above, R 1 is Cy 1 That is the case.

[0102] In some embodiments, R 1 The selection is made from those shown in Table 1 below.

[0103] As generally defined above, Cy 1 phenyl; a 5-6 member monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 member bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 member saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 member saturated or partially unsaturated monocyclic carbon ring; or a 7-12 member saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Cy 1 R is p examples 1A It has been replaced with.

[0104] In some embodiments, Cy 1 R for p examples 1A It is a phenyl substituted with Cy. In some embodiments, Cy 1 R for p examples 1A It is a 5-6 member monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which are substituted with . In some embodiments, Cy 1 R for p examples 1A It is an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which are substituted with. In some embodiments, Cy 1 R for p examples 1A A 3-7 member saturated or partially unsaturated monocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which are substituted with . In some embodiments, Cy 1 R for p examples 1A It is a 3- to 7-membered saturated or partially unsaturated monocyclic carbon ring that is substituted with Cy. In some embodiments, Cy 1R for p examples 1A It is a 7-12 member saturated or partially unsaturated bicyclic or heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which are substituted with .

[0105] In some embodiments, Cy 1 Cy 1 R is p examples 1A It is replaced by Cy 1 This is a 5-6 member monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 member bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 member saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 member saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Cy 1 R is p examples 1A It is replaced by Cy 1 is a 5-6 member monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8-10 member bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Cy 1 R is p examples 1A It is replaced by Cy 1 is a 3-7 member saturated or partially unsaturated monocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 member saturated or partially unsaturated bicyclic or heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Cy 1 R is p examples 1A It has been replaced with.

[0106] In some embodiments, Cy1 phenyl; a 5-6 member monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 member saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 member saturated or partially unsaturated monocyclic carbocyclic ring; Cy 1 R is p examples 1A It is replaced by Cy 1 is an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Cy 1 R is p examples 1A It has been replaced with.

[0107] In some embodiments, Cy 1 phenyl; a 5-6 member monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 member bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 3-7 member saturated or partially unsaturated monocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Cy 1 R is p examples 1A It is replaced by Cy 1 phenyl; a 5-6 member monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 3-7 member saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Cy 1 R is p examples 1A It is replaced by Cy 1 Cy 1R is p examples 1A It has been replaced with.

[0108] In some embodiments, Cy 1 phenyl is a six-membered monocyclic heteroaryl ring having one or two nitrogen atoms; or a six-membered saturated or partially unsaturated monocyclic or heterocyclic ring having one or two nitrogen atoms; Cy 1 R is p examples 1A It is replaced by Cy 1 Cy 1 R is p examples 1A It is replaced by Cy 1 R for p examples 1A It is a phenyl or pyridyl substituted with Cy 1 R for p examples 1A It is pyridyl that has been substituted with [another compound].

[0109] In some embodiments, Cy 1 The following can be selected: [ka]

[0110] In some embodiments, Cy 1 The following can be selected: [ka]

[0111] In some embodiments, Cy 1 teeth, [ka] That is the case.

[0112] In some embodiments, Cy 1 teeth, [ka] That is the case.

[0113] In some embodiments, Cy 1 teeth, [ka] That is the case.

[0114] In some embodiments, Cy 1 teeth, [ka] That is the case.

[0115] In some embodiments, Cy 1 teeth, [ka] That is the case.

[0116] In some embodiments, Cy 1 teeth, [ka] That is the case.

[0117] In some embodiments, Cy 1 teeth, [ka] That is the case.

[0118] In some embodiments, Cy 1 teeth, [ka] That is the case.

[0119] In some embodiments, Cy 1 teeth, [ka] That is the case.

[0120] In some embodiments, Cy 1 teeth, [ka] That is the case.

[0121] In some embodiments, Cy 1 teeth, [ka] That is the case.

[0122] In some embodiments, Cy 1 teeth, [ka] That is the case.

[0123] In some embodiments, Cy 1 R has 0 to 2 examples. A and one example of R B It is replaced by Cy 1 R has 0 to 1 example A and one example of R B It has been replaced with.

[0124] In some embodiments, the R 1A Cy with substituent 1 The following can be selected: [ka] [ka]

[0125] In some embodiments, the R 1A Cy with substituent1 The following can be selected: [ka] [ka]

[0126] In some embodiments, Cy 1 The selection is made from those shown in Table 1 below.

[0127] As generally defined above, R 1A Each example is independent, R A or R B In some embodiments, R 1A is R A In some embodiments, R 1A is R B That is the case.

[0128] In some embodiments, R 1A is C 1~6 Aliphatic; phenyl; 5-6 member monocyclic heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 3-7 member saturated or partially unsaturated monocyclic carbocyclic rings; and R selected from 3-7 member saturated or partially unsaturated monocyclic heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. A or R B and; each R B R is q of the examples C It is replaced by; or R in two examples 1A They come together to form an oxo.

[0129] In some embodiments, two examples of R 1A They come together to form an oxo. In some embodiments, R 1A C 1~6Aliphatic; phenyl; 5-6 member monocyclic heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 3-7 member saturated or partially unsaturated monocyclic carbocyclic rings; and R selected from 3-7 member saturated or partially unsaturated monocyclic heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. A or R B and; each R B R is q of the examples C It has been replaced with.

[0130] In some embodiments, R 1A C 1~6 Aliphatic; phenyl; and R selected from 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic rings A or R B and; each R B R is q of the examples C It is replaced by R 1A R is a 5-6 member monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and R is selected from a 3-7 member saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. A or R B and; each R B R is q of the examples C It has been replaced with.

[0131] In some embodiments, R 1A is halogen;-CN;-OR;-NR2;-C(O)NR2; or C 1~6 Aliphatic; phenyl; 5-6 member monocyclic heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 3-7 member saturated or partially unsaturated monocyclic carbocyclic rings; and R selected from 3-7 member saturated or partially unsaturated monocyclic heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. B and; each R B R is q of the examples C It has been replaced with.

[0132] In some embodiments, R 1A is halogen;-CN;-OR;-NR2;-C(O)NR2; or C 1~6 Aliphatic; phenyl; and R selected from 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic rings B and; each R B R is q of the examples C It is replaced by R 1A R is selected from halogens;-CN;-OR;-NR2;-C(O)NR2; or 5-6 member monocyclic heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and 3-7 member saturated or partially unsaturated monocyclic heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. B and; each R B R is q of the examples C It has been replaced with.

[0133] In some embodiments, at least one example of R 1A is -C(O)NR2 or R B In some embodiments, at least one example of R 1A is -C(O)NR2. In some embodiments, at least one example of R 1A is R B That is the case.

[0134] In some embodiments, at least one example of R 1A R is selected from -C(O)NR2 or a 5-6 member monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 member saturated or partially unsaturated monocyclic carbon ring; and a 3-7 member saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. B and; each R B R is q of the examples C It is replaced by R in some embodiments.1A R is a 5-6 member monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 member saturated or partially unsaturated monocyclic carbon ring; or a 3-7 member saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which has q examples C It has been replaced with.

[0135] In some embodiments, at least one example of R 1A is -C(O)NR2 or R B Here, the two R groups, together with nitrogen, form a 4-7 member monocyclic saturated, partially unsaturated, or heteroaryl ring, optionally substituted, having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, in addition to this nitrogen. In some embodiments, at least one example of R 1A The compound is -C(O)NR2, where the two R groups, together with the nitrogen, form a optionally substituted 4-7 member monocyclic saturated, partially unsaturated, or heteroaryl ring, which has 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur in addition to the nitrogen.

[0136] In some embodiments, at least one example of R 1A is -C(O)NR2 or R B Here, the two R groups, together with nitrogen, form a 4- to 7-membered monocyclic saturated ring which optionally has one heteroatom selected from nitrogen, oxygen, and sulfur in addition to this nitrogen. In some embodiments, at least one example of R 1A The compound is -C(O)NR2, where the two R groups, together with the nitrogen, form a 4- to 7-membered monocyclic saturated ring that optionally has one heteroatom selected from nitrogen, oxygen, and sulfur in addition to the nitrogen.

[0137] In some embodiments, at least one example of R1A R is selected from -C(O)NR2 or a 5-6 member monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 member saturated or partially unsaturated monocyclic carbon ring; and a 3-7 member saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. B and; each R B R is q of the examples C The two R groups are substituted together with nitrogen to form an optionally substituted 4- to 7-membered monocyclic saturated ring, which optionally has one heteroatom selected from nitrogen, oxygen, and sulfur in addition to this nitrogen.

[0138] In some embodiments, R 1A The following can be selected: [ka] [ka] Or two examples of R 1A They come together to form an oxo.

[0139] In some embodiments, R 1A The following can be selected: [ka]

[0140] In some embodiments, R 1A The selection is made from those shown in Table 1 below.

[0141] As generally defined above, R 2 C 1~6Aliphatic; phenyl; 5-6 member monocyclic heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 8-10 member bicyclic heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 3-7 member saturated or partially unsaturated monocyclic carbocyclic rings; 3-7 member saturated or partially unsaturated monocyclic heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or 7-12 member saturated or partially unsaturated bicyclic heterocyclic rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is q examples of R C It has been replaced by.

[0142] In a particular embodiment, R 2 R for q examples C C is replaced by 1~6 It is aliphatic. In certain embodiments, R 2 R for q examples C It is a phenyl substituted with R. In certain embodiments, R 2 R for q examples C It is a 5-6 member monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which are substituted by R. In certain embodiments, R 2 R for q examples C It is an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which are substituted by R. In certain embodiments, R 2 R for q examples C A 3- to 7-membered saturated or partially unsaturated monocyclic carbon ring substituted by R. In certain embodiments, R 2 R for q examples C A 3-7 member saturated or partially unsaturated monocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which are substituted by R. In certain embodiments, R 2 R for q examples CIt is a 7-12 member saturated or partially unsaturated bicyclic or heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which are substituted by [substances].

[0143] In some embodiments, R 2 R for q examples C It is a 3- to 7-membered saturated or partially unsaturated monocyclic carbon ring substituted by R. In some embodiments, R 2 R for q examples C It is a 3- to 7-membered saturated monocyclic carbon ring that is substituted by R. In some embodiments, 2 R for q examples C It is a 3- to 7-membered partially unsaturated monocyclic carbon ring that is substituted by R. In some embodiments, 2 These are 3- to 7-membered saturated or partially unsaturated monocyclic carbon rings.

[0144] In some embodiments, R 2 These are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl; each of them independently has q examples of R C It has been replaced by.

[0145] In some embodiments, R 2 It is cyclopropyl.

[0146] In some embodiments, R 2 teeth, [ka] That is the case.

[0147] In some embodiments, the R C R together with substituents 2 teeth, [ka] That is the case.

[0148] In some embodiments, R 2 The selection is made from those shown in Table 1 below.

[0149] As generally defined above, R 3 These are -C(O)NH2, -C(O)NHCH3, or -C(O)NHCD3.

[0150] In some embodiments, R 3 is -C(O)NH2. In some embodiments, R 3 is -C(O)NHCH3 or -C(O)NHCD3. In some embodiments, R 3 is -C(O)NHCH3. In some embodiments, R 3 It is -C(O)NHCD3.

[0151] In some embodiments, R 3 The selection is made from those shown in Table 1 below.

[0152] As generally defined above, p is 0, 1, 2, 3, or 4. In some embodiments, p is 0. In some embodiments, p is 1, 2, 3, or 4. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4.

[0153] In some embodiments, p is 1, 2, or 3. In some embodiments, p is 1 or 2. In some embodiments, p is 1 or 3. In some embodiments, p is 2 or 3. In some embodiments, p is 2 or 4. In some embodiments, p is 1, 2, or 4. In some embodiments, p is 1, 3, or 4. In some embodiments, p is 2, 3, or 4.

[0154] In some embodiments, p is selected from those shown in Table 1 below.

[0155] As generally defined above, q is 0, 1, 2, 3, or 4. In some embodiments, q is 0. In some embodiments, q is 1, 2, 3, or 4. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3. In some embodiments, q is 4.

[0156] In some embodiments, q is 1, 2, or 3. In some embodiments, q is 1 or 2. In some embodiments, q is 1 or 3. In some embodiments, q is 2 or 3. In some embodiments, q is 2 or 4. In some embodiments, q is 1, 2, or 4. In some embodiments, q is 1, 3, or 4. In some embodiments, q is 2, 3, or 4.

[0157] In some embodiments, q is selected from those shown in Table 1 below.

[0158] As generally defined above, r is either 0 or 1. In some embodiments, r is 0. In some embodiments, r is 1.

[0159] In some embodiments, r is selected from those shown in Table 1 below.

[0160] In some embodiments, the present invention is L 1 Since it is a covalent bond and r is 1, equation II: [ka] We provide a compound of formula I' which forms a compound of or a pharmaceutically acceptable salt thereof, where X, R 1 , R 2 , and R 3Each of these, both alone and in combination, is as defined above and described in the embodiments herein.

[0161] In some embodiments, the present invention is R 1 but, [ka] Therefore, equations III, IV, or V respectively: [ka] We provide a compound of formula II that forms a compound or a pharmaceutically acceptable salt thereof, where X, R 1A , R 2 , R 3 Each of , and p, both individually and in combination, is as defined above and described in the embodiments herein.

[0162] In some embodiments, the present invention is such that r is 1 and X is CH, thereby formulas Ia, II-a, III-a, IV-a, or Va: [ka] We provide compounds of formula I', II, III, IV, or V that form a compound of or a pharmaceutically acceptable salt thereof, where L 1 , R 1 , R 1A , R 2 , R 3 Each of , and p, both individually and in combination, is as defined above and described in the embodiments herein.

[0163] In some embodiments, the present invention is R 3 The present invention provides compounds of formula I', II, III, IV, V, Ia, II-a, III-a, IV-a, or Va, wherein -C(O)NH2.

[0164] In some embodiments, the present invention is R 3 The present invention provides compounds of formula I', II, III, IV, V, Ia, II-a, III-a, IV-a, or Va, wherein the compound is -C(O)NHCH3 or -C(O)NHCD3.

[0165] In some embodiments, the present invention is L 1 Since it is a covalent bond and r is 0, we have equation VI: [ka] We provide a compound of formula I' which forms a compound of or a pharmaceutically acceptable salt thereof, where X, R 1 , R 2 , and R 3 Each of these, both alone and in combination, is as defined above and described in the embodiments herein.

[0166] In some embodiments, the present invention is R 1 but, [ka] And so, equations VII, VIII, or IX, respectively: [ka] We provide a compound of formula VI that forms a compound or a pharmaceutically acceptable salt thereof, where X, R 1A , R 2 , R 3 Each of , and p, both individually and in combination, is as defined above and described in the embodiments herein.

[0167] In some embodiments, the present invention is such that r is 1 and X is CH, thereby formulas I'-a, VI-a, VII-a, VIII-a, or IX-a, respectively: [ka] We provide compounds of formula I', VI, VII, VIII, or IX that form a compound of or a pharmaceutically acceptable salt thereof, where L 1 , R 1 , R 1A , R 2 , R 3 Each of , and p, both individually and in combination, is as defined above and described in the embodiments herein.

[0168] In some embodiments, the present invention is R 3 The present invention provides compounds of formula I'-a, VI-a, VII-a, VIII-a, or IX-a, wherein -C(O)NH2.

[0169] In some embodiments, the present invention is R 3 The present invention provides compounds of formula I'-a, VI-a, VII-a, VIII-a, or IX-a, wherein the integral is -C(O)NHCH3 or -C(O)NHCD3.

[0170] In some embodiments, the present invention is L 1 The bond is covalent, and r is 0, R 2 but [ka] And thus, equation X: [ka] We provide a compound of formula I' which forms a compound of or a pharmaceutically acceptable salt thereof, where X, R 1 , R 2 , R 3 , R C Each of q, and q, both individually and in combination, is as defined above and described in the embodiments herein.

[0171] In some embodiments, the present invention is R 1 but, [ka] Thus, equations XI, XII, or XIII are derived respectively: [ka] We provide a compound of formula X that forms a compound or a pharmaceutically acceptable salt thereof, where X, R 1A , R 2 , R 3 , R C Each of p and q, both individually and in combination, is as defined above and described in the embodiments herein.

[0172] In some embodiments, the present invention is such that r is 1 and X is CH, thereby formulas I''-a, Xa, XI-a, XII-a, or XIII-a, respectively: [ka] We provide compounds of formula I', X, XI, XII, or XIII that form a compound of or a pharmaceutically acceptable salt thereof, where L 1 , R 1 , R 1A , R 2 , R 3 , R C Each of p and q, both individually and in combination, is as defined above and described in the embodiments herein.

[0173] In some embodiments, the present invention is R 3 The present invention provides compounds of formula I''-a, Xa, XI-a, XII-a, or XIII-a, wherein -C(O)NH2.

[0174] In some embodiments, the present invention is R 3 The present invention provides compounds of formula I''-a, Xa, XI-a, XII-a, or XIII-a, wherein the integral is -C(O)NHCH3 or -C(O)NHCD3.

[0175] Exemplary compounds of the present invention are listed in Table 1 below. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] [Table 1-15] [Table 1-16] [Table 1-17] [Table 1-18] [Table 1-19] [Table 1-20] [Table 1-21] [Table 1-22]

[0176] In some embodiments, the present invention provides compounds listed in Table 1 above, or pharmaceutically acceptable salts thereof. In some embodiments, the present invention provides compounds listed in Table 1 above. In some embodiments, the present invention provides a pharmaceutical composition containing a compound listed in Table 1 above, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, excipient, or diluent.

[0177] In some embodiments, the present invention provides a compound of formula I or I' as described above, which is represented as "A" as shown in Table 2. In some embodiments, the present invention provides a compound of formula I or I' as described above, which is represented as "B" as shown in Table 2. In some embodiments, the present invention provides a compound of formula I or I' as described above, which is represented as "C" as shown in Table 2. In some embodiments, the present invention provides a compound of formula I or I' as described above, which is represented as "D" as shown in Table 2. In some embodiments, the present invention provides a compound of formula I or I' as described above, which is represented as "A" or "B" as shown in Table 2. In some embodiments, the present invention provides a compound of formula I or I' as described above, which is represented as "A" or "B" or "C" as shown in Table 2. In some embodiments, the present invention provides a compound of formula I or I' as described above, which is represented as "A" or "B" or "C" as shown in Table 2.

[0178] In some embodiments, the present invention provides a compound of formula I or I' as defined above, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use as a pharmaceutical, comprising a compound of formula I or I' as defined above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0179] While we do not wish to be bound by any particular theory, it is believed that the proximity of the inhibitor compound, or the pendant portion of the inhibitor compound, to the target water facilitates the movement or destruction of this water by the inhibitor compound, or the pendant portion of the inhibitor compound. In some embodiments, the water molecules that are moved or destroyed by the inhibitor compound, or the pendant portion of the inhibitor compound, are unstable water molecules.

[0180] In certain embodiments, the method uses a complex comprising TYK2 and an inhibitor, in which at least one unstable water molecule of TYK2 is moved or destroyed by the inhibitor. In some embodiments, at least two selected unstable water molecules are moved or destroyed by the inhibitor. 4. A general method for providing the compound of the present invention

[0181] 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. 5. Use, prescription, and administration Pharmacologically acceptable compositions

[0182] In another embodiment, the present invention provides compositions containing the compound of the present invention, or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of the compound in the composition of the present invention is such that it is effective in measurably inhibiting TYK2 protein kinase or its variants in a biological sample or in a patient. In certain embodiments, the amount of the compound in the composition of the present invention is such that it is effective in measurably inhibiting TYK2 protein kinase or its variants in a biological sample or in a patient. In certain 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.

[0183] The term “patient” as used herein means an animal, preferably a mammal, and most preferably a human.

[0184] The term “pharmaceutically acceptable carrier, adjuvant, or vehicle” means a non-toxic carrier, adjuvant, or vehicle that does not disrupt the pharmacological activity of the compound it is formulated with. Examples of pharmaceutically acceptable carriers, adjuvants, or vehicles that may be used in the compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffers (e.g., phosphates), glycine, sorbic acid, potassium sorbate, glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (e.g., protamine sulfate, sodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block copolymers, polyethylene glycol, and lanolin tallow.

[0185] "Pharmacologically acceptable derivative" means a 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 metabolite or residue.

[0186] As used herein, the term “its inhibitory metabolite or residue” means that the metabolite or residue is also an inhibitor of TYK2 protein kinase or its variants.

[0187] The compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir. The term “parenteral,” as used herein, encompasses injection or infusion techniques for subcutaneous, intravenous, intramuscular, intraarterial, intrabursal, intrasternal, intrastellar, intrahepatic, intralesional, and intracranial administration. Preferably, these compositions are administered orally, intraperitoneally, or intravenously. The sterile injectable forms of the compositions of the present invention may be aqueous or oily suspensions. These suspensions may be formulated using appropriate dispersants or wetting agents and suspending agents according to techniques known in the art. The sterile injectable preparations may also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents (e.g., solutions in 1,3-butanediol). Among the acceptable vehicles and solvents that may be used are, in particular, water, Ringer's solution, and isotonic sodium chloride solution. Furthermore, sterile fixative oils have conventionally been used as solvents or suspension media.

[0188] For this purpose, any brand of fixed oil, including synthetic monoglycerides or synthetic diglycerides, may be used. Fatty acids, such as oleic acid and its glyceride derivatives, as well as naturally pharmaceutically acceptable oils (e.g., olive oil or castor oil, especially their polyoxyethylene versions), are useful in the preparation of injectable substances. These oil solutions or suspensions may also contain diluents or dispersants of long-chain alcohols (e.g., carboxymethylcellulose, or similar dispersants commonly used in the formulation of pharmaceutically acceptable dosage forms (emulsions and suspensions, among others)). Other commonly used surfactants (e.g., Tweens, Spans, and other emulsifiers or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solids, liquids, or other dosage forms) may also be used for formulation purposes.

[0189] 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). For tablets for oral use, commonly used 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 aqueous suspensions are required for oral use, the active ingredient is combined with emulsifiers and suspending agents. Specific sweeteners, flavoring agents, or colorants may also be added, if desired.

[0190] Alternatively, the pharmaceutically acceptable compositions of the present invention may be administered in the form of suppositories for rectal administration. These may be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, thereby melting in the rectum and releasing the drug. Examples of such substances include cocoa butter, beeswax, and polyethylene glycol.

[0191] The pharmaceutically acceptable compositions of the present invention may also be administered topically, particularly when the target of treatment includes areas or organs that are easily accessible by topical application (such as diseases of the eyes, skin, or lower intestines). Appropriate topical formulations can be readily prepared for each of these areas or organs.

[0192] Topical application for the lower bowel can be performed with rectal suppositories (see above) or appropriate enema formulations. Topical transdermal patches may also be used.

[0193] For topical application, the pharmaceutically acceptable compositions provided may be formulated into suitable ointments containing the active ingredient suspended or dispersed in one or more carriers. Carriers for topical administration of the compounds of the present invention include, but are not limited to, mineral oil, liquid petroleum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying waxes, and water. Alternatively, the pharmaceutically acceptable compositions provided may be formulated into suitable lotions or creams containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0194] For ophthalmic use, the pharmaceutically acceptable compositions provided may be formulated as a finely granulated suspension in isotonic pH-adjusted sterile saline, or preferably as a solution in isotonic pH-adjusted sterile saline, with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum.

[0195] The pharmaceutically acceptable compositions of the present invention may also be administered by nasal aerosol or inhalation. Such compositions may be prepared according to techniques well known in the field of pharmaceutical formulation and, as a solution in physiological saline, using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other conventional solubilizers or dispersants.

[0196] Most preferably, the pharmaceutically acceptable compositions of the present invention are formulated for oral administration. Such formulations may be administered with or without 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.

[0197] The amount of the compound of the present invention that can be combined with a carrier substance to produce a single-dose formulation varies depending on the host being treated and the specific mode of administration. Preferably, the compositions provided should be formulated so that inhibitors in dosages of 0.01 mg / kg body weight / day to 100 mg / kg body weight / day can be administered to patients receiving these compositions.

[0198] It should also be understood that the specific dosage and treatment plan for any particular patient will depend on various factors, including the activity of the specific compound used, age, weight, general health, sex, diet, timing of administration, rate of elimination, drug combinations, and the judgment of the treating physician and the severity of the specific disease being treated. The amount of the compound of the present invention in a composition will also depend on the specific compound in that composition. Use of compounds and pharmaceutically acceptable compositions

[0199] The compounds and compositions described herein are highly useful for inhibiting 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.

[0200] 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, JAK3, and JAK3. JAK proteins (including TYK2) are integrated for cytokine signaling. TYK2 associates with the cytoplasmic domains of type I and type II cytokine receptors, as well as interferon type I and type III receptors, and is activated by these receptors during cytokine construction. 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 limitin)) and interleukins (e.g., IL-4, IL-6, IL-10, IL-11, IL-12, IL-13, IL-22, IL-23, IL-27, IL-31, oncostatin M, ciliary neurotrophic factor, cardiotrophin 1, cardiotrophin-like cytokines, and LIF). Velasquez et al., "A protein kinase in the interferon α / β signaling pathway」,Cell(1992)70:313; Stahlら,「Association and activation of Jak-Tyk kinases by CNTF-LIF-OSM-IL-6β receptor components」, Science (1994) 263:92; Finbloomら,「IL-10 induces the tyrosine phosphorylation of Tyk2 and Jak1 and the differential assembly of Stat1 and Stat3 complexes in human T cells and monocytes」,J. Immunol. (1995) 155:1079; Baconら, 「Interleukin 12 (IL-12) induces tyrosine phosphorylation of Jak2 and Tyk2: differential use of Janus family kinases by IL-2 and IL-12」, J. Exp. Med. (1995) 181:399; Welhamら, 「Interleukin-13 signal transduction in lymphohemopoietic cells: similarities and differences in signal transduction with interleukin-4 and insulin」, J. Biol. Chem. (1995) 270:12286; Parhamら, 「A receptor for The heterodimeric cytokine IL-23 is composed of IL-12Rβ1 and a novel cytokine receptor subunit, IL-23R," J. Immunol. (2002) 168:5699. Subsequently, activated TYK2 proceeds to phosphorylation of further signaling proteins (e.g., members of the STAT family, including STAT1, STAT2, STAT4, and STAT6).

[0201] IL-23-mediated TYK2 activation has been linked to inflammatory bowel disease (IBD), Crohn's disease, and ulcerative colitis. (Duerr et al., "A Genome-Wide Association Study Identifies IL23R as an Inflammatory Bowel Disease Gene," Science) (2006) 314:1461-1463. As a downstream effector of IL-23, TYK2 also plays a role in psoriasis, ankylosing spondylitis, and Behçet's disease. Cho et al., "Genomics and the multifactorial nature of human auto-immune disease," N. Engl. J. Med (2011) 365:1612-1623; Cortes et al., "Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci," Nat. Genet. (2013) 45(7):730-738; Remmers et al., "Genome-wide association "A study identifies variants in the MHC class I, IL10, and IL23R-IL12RB2 regions associated with Behcet's disease," Nat. Genet. (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," Nat. Genet. (2010) 42:985-992. Knockout of TYK2 or inhibition of tilphostin significantly reduces both IL-23-induced and IL-22-induced dermatitis. Ishizaki et al., “Tyk2 is a therapeutic target for psoriasis-like skin inflammation,” Intl. Immunol. (2013), doi: 10.1093 / intimm / dxt062.

[0202] 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 mucus hypersecretion are mediated by IL-13-induced activation of TYK2, which in turn activates STAT6. (Zhang et al., "Docking protein Gab2 regulates") "mucin expression and goblet cell hyperplasia through TYK2 / STAT6 pathway", FASEB J. (2012) 26:1-11.

[0203] Reduced TYK2 activity provides protection for joints from collagen antibody-induced arthritis (a model of human rheumatoid arthritis). Mechanistically, reduced Tyk2 activity leads to T h 1 / T hIt reduced the production of 17 related cytokines and matrix metalloproteinases, as well as other major inflammatory markers. Ishizaki et al., "Tyk2 deficiency protects joints against destruction in anti-type II collagen antibody-induced arthritis in mice", Intl. Immunol. (2011) 23(9):575-582.

[0204] TYK2 knockout mice showed complete resistance to experimental autoimmune encephalomyelitis (EAE, an animal model of multiple sclerosis (MS)) compared to controls, and there was no CD4 T cell infiltration into the spinal cord. This suggests that TYK2 is essential for the development of pathogenic CD4-mediated disease 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," J. Immunol. (2009) 183:7539-7546. This confirms previous studies linking increased TYK2 expression to MS susceptibility. Ban et al., "Replication analysis identifies TYK2 as a multiple sclerosis susceptibility factor," Eur J. Hum. Genet. (2009) 17:1309-1313. Loss of functional mutations in TYK2 results in reduced demyelination and increased myelin regeneration of neurons, further suggesting a role for TYK2 inhibitors in the treatment of MS and other CNS demyelinating disorders.

[0205] TYK2 is a single signaling messenger common to IL-12 and IL-23. TYK2 knockout reduced methylated BSA injection-induced footpad thickness, imiquimod-induced psoriasis-like dermatitis, and dextran sulfate sodium or 2,4,6-trinitrobenzenesulfonic acid-induced colitis in mice.

[0206] Joint linkage and association studies of various type I IFN signaling genes using systemic lupus erythematosus (SLE, an autoimmune disorder) have shown a strong and significant correlation between loss of functional mutations in TYK2 and a reduction in the prevalence of SLE in families including affected members. Sigurdsson et al., "Polymorphisms in the Tyrosine Kinase 2 and Interferon Regulatory Factor 5 Genes Are Associated with Systemic Lupis Erythematosus, Am. J. Hum. Genet. (2005) 76:528-537. Genome-wide association studies of individuals with SLE against a cohort of individuals without SLE showed a very significant correlation 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.

[0207] TYK2 has been shown to play a crucial role in maintaining tumor surveillance, and TYK2 knockout mice exhibited impaired cytotoxic T cell responses and accelerated tumor development. However, these effects were linked to sufficient suppression of natural killer (NK) and cytotoxic T lymphocytes, suggesting that TYK2 inhibitors are highly suitable for treating autoimmune disorders or transplant rejection. While other JAK family members (e.g., JAK3) have similar roles in the immune system, TYK2 is suggested to be a superior target because it is involved in fewer, 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.

[0208] However, contrary to the reduced tumor surveillance observed by Simma et al., studies in T-cell acute lymphoblastic leukemia (T-ALL) indicate that T-ALL is highly dependent on IL-10 via TYK2 through STAT1-mediated signaling to maintain cancer cell survival by upregulating the anti-apoptotic protein BCL2. Knockdown of TYK2 reduced cell proliferation, while knockdown of other JAK family members did not. Specific activating mutations in TYK2 that promote cancer cell survival include activating mutations in the FERM domain (G36D, S47N, and R425H), the JH2 domain (V731I), and the kinase domain (E957D and R1027H). However, kinase function of TYK2 was also identified as being required for enhanced cancer cell survival. This is because TYK2 enzymes characterized by a kinase-dead mutation (M978Y or M978F) in addition to an activating mutation (E957D) resulted in transformation failure. Sanda et al. "TYK2-STAT1-BCL2 Pathway Dependence in T-Cell Acute Lymphoblastic Leukemia", Cancer Disc. (2013) 3(5):564-577.

[0209] Therefore, selective inhibition of TYK2 is suggested to be an appropriate target for IL-10 and / or BCL2-toxic tumors (e.g., 70% of cases of adult T-cell leukemia). Fontan et al. "Discovering What Makes STAT Signaling TYK in T-ALL", Cancer Disc. (2013) 3:494-496.

[0210] TYK2-mediated STAT3 signaling has also been shown to mediate amyloid-β (Aβ) peptide-induced neuronal cell death. Reduced TYK2 phosphorylation of STAT3 after Aβ administration leads to reduced neuronal cell death, while increased STAT3 phosphorylation has been observed in the postmortem brains of Alzheimer's disease patients. Wan et al. "Tyk / STAT3 Signaling Mediates β-Amyloid-Induced Neuronal Cell Death: Implications in Alzheimer's Disease," J. Neurosci. (2010) 30(20):6873-6881.

[0211] Inhibition of the JAK-STAT signaling pathway is also involved in hair growth and the reversal of hair loss associated with alopecia areata. (Xing et al., "Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition," Nat. Med. (2014)) 20: 1043-1049; Harel et al., "Pharmacologic inhibition of JAK-STAT signaling promotes hair growth," Sci. Adv. (2015) 1(9):e1500973.

[0212] Therefore, compounds that inhibit TYK2 activity (especially those with greater selectivity than JAK2) are advantageous. Such compounds should induce pharmacological responses that favorably treat one or more of the conditions described herein without the side effects associated with JAK2 inhibition.

[0213] Despite the fact that TYK2 inhibitors are well known in the art, there is still a need to provide novel inhibitors that are more effective or possess superior pharmaceutically relevant properties. For example, compounds with increased activity, selectivity exceeding that of other JAK kinases (particularly JAK2), and ADMET (absorption, distribution, metabolism, excretion, and / or toxicity) properties. Therefore, in some embodiments, the present invention provides TYK2 inhibitors exhibiting selectivity exceeding that of JAK2.

[0214] The inhibitory activity of the compounds used in the present invention against TYK2 or its variants can be assayed in vitro, in vivo, or in cell lines. In vitro assays include those that determine the inhibition of either the phosphorylation activity and / or subsequent functional consequences, or ATPase activity, of activated TYK2 or its variants. Alternative in vitro assays quantify the ability of the inhibitor to bind to TYK2. Inhibitor binding can be measured by radiolabeling the inhibitor before binding, isolating the inhibitor / TYK2 complex, and determining the amount of radiolabeled material bound. Alternatively, inhibitor binding can be determined by performing competitive experiments in which a novel inhibitor is incubated with TYK2 bound to a known radioligand. Representative in vitro and in vivo assays useful for evaluating TYK2 inhibitors are described and disclosed, for example, in [reference], each of which is incorporated herein by reference in whole. Detailed conditions for assaying the compounds used in the present invention as inhibitors of TYK2 or its variants are described in the following examples.

[0215] As used herein, the terms “treatment,” “treat,” and “treating” mean the reversal, reduction, delay of onset, or inhibition of progression of a disease or disorder, or one or more of its symptoms, as described herein. In some embodiments, treatment may be administered after the onset of one or more symptoms. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual before the onset of symptoms (e.g., taking into account a medical history of the symptoms and / or genetic or other susceptibility factors). Treatment may also be continued after the symptoms have subsided, for example, to prevent or delay the recurrence of those symptoms.

[0216] Since the compounds provided are inhibitors of TYK2, they are useful for treating one or more disorders related to the activity of TYK2 or its variants. Accordingly, in certain embodiments, the present invention provides a method for treating a TYK2-mediated disorder, the method comprising the step of administering the compounds of the present invention or a pharmaceutically acceptable composition thereof to a patient in need.

[0217] As used herein, the terms “TYK2-mediated” disorder, disease, and / or condition mean, as used herein, any disease or other adverse condition in which TYK2 or its variants are known to play a role. Accordingly, another embodiment of the present invention relates to treating one or more diseases in which TYK2 or its variants are known to play a role, or to reducing the severity of such diseases. Such TYK2-mediated disorders include, but are not limited to, autoimmune disorders, inflammatory disorders, proliferative disorders, endocrine disorders, neurological disorders, and transplant-related disorders.

[0218] In some embodiments, the present invention provides a method for treating one or more disorders, where these disorders are selected from autoimmune disorders, inflammatory disorders, proliferative disorders, endocrine disorders, neurological disorders, and transplant-related disorders, and the method comprises the step of administering to a patient in need of this treatment a pharmaceutical composition containing an effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof.

[0219] In some embodiments, the disorder is an autoimmune disorder. In some embodiments, the disorder is selected from type 1 diabetes, cutaneous lupus erythematosus, systemic lupus erythematosus, multiple sclerosis, psoriasis, Behçet's disease, POEMS syndrome, Crohn's disease, ulcerative colitis, and inflammatory bowel disease.

[0220] In some embodiments, this disorder is an inflammatory disorder. In some embodiments, this inflammatory disorder is rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis, hepatomegaly, Crohn's disease, ulcerative colitis, or inflammatory bowel disease.

[0221] In some embodiments, this disorder is a proliferative disorder. In some embodiments, this proliferative disorder is a hematological cancer. In some embodiments, this proliferative disorder is a leukemia. In some embodiments, this leukemia is a T-cell leukemia. In some embodiments, this T-cell leukemia is T-cell acute lymphoblastic leukemia (T-ALL). In some embodiments, this proliferative disorder is polycythemia vera, myelofibrosis, essential thrombocytosis, or thrombocytosis.

[0222] In some embodiments, this disorder is an endocrine disorder. In some embodiments, this endocrine disorder is polycystic ovary syndrome, Curzon syndrome, or type 1 diabetes.

[0223] In some embodiments, this disorder is a neurological disorder. In some embodiments, this neurological disorder is Alzheimer's disease.

[0224] In some embodiments, this proliferative disorder is associated with one or more activating mutations in TYK2. In some embodiments, the activating mutations in TYK2 are mutations in the FERM domain, the JH2 domain, or the kinase domain. In some embodiments, the activating mutations in TYK2 are selected from G36D, S47N, R425H, V731I, E957D, and R1027H.

[0225] In some embodiments, this disorder is related to transplantation. In some embodiments, this transplant-related disorder is transplant rejection or host-versus-graft disease.

[0226] In some embodiments, this impairment is related to type I interferon, IL-10, IL-12, or IL-23 signaling. In some embodiments, this impairment is related to type I interferon signaling. In some embodiments, this impairment is related to IL-10 signaling. In some embodiments, this impairment is related to IL-12 signaling. In some embodiments, this impairment is related to IL-23 signaling.

[0227] The compounds of the present invention are also useful in the treatment of inflammatory or allergic conditions of the skin (e.g., psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity vasculitis, urticaria, bullous pemphigoid, lupus erythematosus, cutaneous lupus erythematosus, systemic lupus erythematosus, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, acquired epidermolysis bullosa, acne vulgaris), and other inflammatory or allergic conditions of the skin.

[0228] The compounds of the present invention are also used to treat other diseases or conditions (e.g., diseases or conditions having inflammatory components) (e.g., eye diseases and conditions (e.g., allergies to the eyes, conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis)), diseases affecting the nose (including allergic rhinitis), and inflammatory diseases involving autoimmune reactions or having autoimmune components or etiologies (e.g., autoimmune hematological disorders (e.g., hemolytic anemia, aplastic anemia, pure red cell adenomatosis, and idiopathic thrombocytopenia), cutaneous lupus erythematosus, systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Stevens-Johnson syndrome). Idiopathic sprue, autoimmune inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), irritable bowel syndrome, celiac disease, periodontitis, hyaline membrane disease, kidney disease, glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine eye disorders, Graves' disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), Sjögren's syndrome, keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, cryopyrin-associated periodic syndromes, nephritis, vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis (nephrotic syndrome (e.g., idiopathic nephrotic syndrome or minimal change nephropathy (minal change) Nephropathy (with and without it), chronic granulomatous disease, endometriosis, leptospirosis, kidney disease, glaucoma, retinal disease, aging, headache, pain, complex regional pain syndrome, cardiac hypertrophy, muscle wasting, catabolic disorders (disorder), obesity, fetal growth retardation, hypercholesterolemia, heart disease, chronic heart failure, mesothelioma, anhidrotic ectodermal dysplasia, Behçet's disease, incontinentia pigmenti, Paget's disease, pancreatitis, hereditary periodic fever syndromes, asthma (allergic and non-allergic, moderate, severe, bronchitis, and exercise-induced), acute lung injury, acute respiratory distress syndrome, eosinophilia, hypersensitivity, anaphylaxis, sinusitis, ocular allergies, silica-induced diseases, COPD (reduction of injury, airway inflammation, bronchial hyperactivity, regeneration or disease progression), lung diseases, cystic fibrosis, acid-induced lung injury, pulmonary hypertension, multiple Neuropathies, cataracts, muscle inflammation associated with systemic sclerosis, inclusion body myositis, myasthenia gravis, thyroiditis, Addison's disease, 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, dacryodenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, lateral epicondylitis, epididymitis, fasciitis, connective tissue inflammation, gastritis, gastroenteritis, Henof-Schönlein purpura, hepatitis, sweat gland abscess, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis It may be used for the treatment of (including, but not limited to) myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, mumps, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, eustitis, sinusitis, stomatitis, synovitis, tendinitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, tenosynovitis, tunica vaginalis, vasculitis, or vulvitis.

[0229] In some embodiments, the inflammatory diseases that can be treated by the methods 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), cryopyrin-associated periodic syndromes (CAPS), and osteoarthritis.

[0230] In some embodiments, the inflammatory diseases that can be treated by the method of the present invention are T h 1 or T h 17 It is a disease mediated by 17. In some embodiments, this T h 17 The mediated diseases are selected from cutaneous lupus erythematosus, systemic lupus erythematosus, multiple sclerosis, and inflammatory bowel disease (including Crohn's disease or ulcerative colitis).

[0231] In some embodiments, inflammatory diseases that can be treated by the method of the present invention are selected from Sjögren's syndrome, allergic disorders, osteoarthritis, eye conditions (e.g., allergic ophthalmos, conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis), and diseases affecting the nose (e.g., allergic rhinitis).

[0232] Furthermore, the present invention provides for the preparation of pharmaceuticals for the treatment of autoimmune disorders, inflammatory disorders, proliferative disorders, or disorders commonly associated with transplantation, using compounds as defined herein, or pharmaceutically acceptable salts thereof, or hydrates or solvates thereof. Combination therapy

[0233] Depending on the specific condition or disease to be treated, additional therapeutic agents that are typically administered to treat that condition may be administered in combination with the compounds and compositions of the present invention. When used herein, additional therapeutic agents that are typically administered to treat a particular disease or condition are known as “appropriate for the disease or condition to be treated.”

[0234] In certain embodiments, the combination or composition provided is administered in combination with another therapeutic agent.

[0235] Examples of agents that may be combined with the combinations of the present invention include, but are not limited to,: treatment agents for Alzheimer's disease (e.g., Aricept® and Excelon®); treatment agents for HIV (e.g., ritonavir); treatment agents for Parkinson's disease (e.g., L-DOPA / carbidopa, entacapone, ropinirole, pramipexole, bromocriptine, pergolide, trihexyphenidyl, and ama). Ntadine; agents for treating multiple sclerosis (MS) (e.g., β-interferon (e.g., Avonex® and Rebif®), Copaxone®, and mitozantrone); agents for treating asthma (e.g., albuterol and Singulair®); agents for treating schizophrenia (e.g., Zyprexa, Risperdal, and haloperidol); anti-inflammatory agents (e.g., corticosteroids, TNF blockers, IL-1) RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulatory and immunosuppressant agents (e.g., cyclosporine, tacrolimus, rapamycin, mycophenolate mofetil, interferon, corticosteroids, cyclophosphamide, azathioprine, and sulfasalazine); neurotrophic factors (e.g., acetylcholinesterase inhibitors, MAO inhibitors, interferon, anticonvulsants, ion channel blockers, riluzole, and antiparkinson's disease agents); agents for treating cardiovascular diseases (e.g., beta-blockers, ACE inhibitors, diuretics, nitrates) Examples include calcium channel blockers and statins; agents for treating liver diseases (e.g., corticosteroids, cholestyramine, interferons, and antivirals); agents for treating blood disorders (e.g., corticosteroids, antileukemia agents, growth factors and growth factors); agents for prolonging or improving pharmacokinetics (e.g., cytochrome P450 inhibitors (i.e., inhibitors of metabolic degradation) and CYP3A4 inhibitors (e.g., ketoconazole and ritonavir)); and agents for treating immunodeficiency disorders (e.g., gamma globulin).

[0236] In certain 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.

[0237] These additional agents may be administered as part of a multi-dose regimen, separate from the combination therapy provided. Alternatively, these agents may be part of a single dosage form, mixed with the compounds of the present invention as a single-dose composition. When administered as part of a multi-dose regimen, these two activators may be administered simultaneously, sequentially, or within a certain time interval from each other (usually within 5 hours from each other).

[0238] As used herein, the terms “combination,” “combined,” and related terms refer to the simultaneous or sequential administration of multiple therapeutic agents according to the present invention. For example, a combination of the present invention may be administered simultaneously, sequentially in separate unit dosage forms, or together in a single unit dosage form with another therapeutic agent.

[0239] The amount of further therapeutic agent present in the composition of the present invention is not greater than the amount typically administered in a composition containing that therapeutic agent as the sole active agent. Preferably, the amount of further therapeutic agent in the composition of the present disclosure is in the range of about 50% to 100% of the amount typically present in a composition containing that agent as the sole therapeutically active agent.

[0240] In one embodiment, the present invention provides a composition containing a compound of formula I or I' and one or more further therapeutic agents. These therapeutic agents may be administered together with the compound of formula I or I', or may be administered before or after the administration of the compound of formula I or I'. Suitable therapeutic agents are described in further detail below. In certain embodiments, the compound of formula I or I' may be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours before the administration of the therapeutic agent. In other embodiments, compounds of formula I or I' may be administered 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.

[0241] In another embodiment, the present invention provides a method for treating an inflammatory disease, disorder, or condition by administering a compound of formula I or I' and one or more further therapeutic agents to a patient in need. Such further therapeutic agents may be small molecules or recombinant biological agents, and include, for example, acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDS) (e.g., aspirin, ibuprofen, naproxen, etodolac (Lodine®), and celecoxib), colchicine (Colcrys®), corticosteroids (e.g., prednisone, prednisolone, methylprednisolone, and hydrocortisone), probenecid, allopurinol, febuxostat (Uloric®), sulfasalazine (Azulfidine®), antimalarial drugs (e.g., hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®)), methotrexate (Rheumatrex®) (Registered trademarks), gold salts (e.g., gold thioglucose (Solganal®), gold thiomalate (Myochrysine®), and auranofin (Ridaura®)), D-penicillamine (Depen® or Cuprimine®), azathioprine (Imuran®), cyclophosphamide (Cytoxan®), chlorambucil (Leukeran®), cyclosporine (Sandimmune®), leflunomide (Arava®), and "anti-TNF" agents (e.g., etanercept (Enbrel®), infliximab (Remicade®), golimumab (Simponi®), certolizumab pegol) pegol) (Cimzia®) and adalimumab (Humira®), "anti-IL-1" agents (e.g., anakinra (Kineret®) and rilonacept (Arcalyst®)), canakinumab (Ilaris®),Anti-Jak inhibitors (e.g., tofacitinib), antibodies (e.g., rituximab (Rituxan®)), "anti-T cell" agents (e.g., abatacept (Orencia®)), "anti-IL-6" agents (e.g., tocilizumab (Actemra®)), diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®), monoclonal antibodies (e.g., tanezumab), anticoagulants (e.g., heparin) Calcinparine (registered trademark) or Liquaemin (registered trademark) and warfarin (Coumadin (registered trademark)), antidiarrheal agents (e.g., diphenoxylate (Lomotil (registered trademark)) and loperamide (Imodium (registered trademark))), bile acid binders (e.g., cholestyramine), alosetron (Lotronex (registered trademark)), lubiprostone (Amitiza (registered trademark)), laxatives (e.g., magnesia milk, polyethylene glycol ( MiraLax®, Dulcolax®, Correctol®, and Senokot®, anticholinergics or antispasmodics (e.g., dicyclomine (Bentyl®)), Singulair®, β-2 agonists (e.g., albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), acetate) Pirbuterol (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®), and formoterol (Foradil®), anticholinergic agents (e.g., ipratropium bromide (Atrovent®) and tiotropium (Spiriva®)), inhaled corticosteroids (e.g., beclomethasone dipropionate (Beclovent®, Qvar®, and Vanceril®),Triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), and flunisolide (Aerobid®), Afviar®, Symbicort®, Dulera®, cromolyn sodium (Intal®), methylxanthine (e.g., theophylline (Theo-Dur®, Theolair®, Slo-bid®, Uniphyl®)) , Theo-24(registered trademark) and aminophylline), IgE antibodies (e.g., omalizumab (Xolair(registered trademark))), nucleoside reverse transcription inhibitors (e.g., zidovudine (Retrovir(registered trademark)), abacavir (Ziagen(registered trademark)), abacavir / lamivudine (Epzicom(registered trademark)), abacavir / lamivudine / zidovudine (Trizivir(registered trademark)), didanosine (Videx(registered trademark)), emtricitabine (Emtriva(registered trademark)), lamivudine (Epivir®), lamivudine / zidovudine (Combivir®), stavudine (Zelit®), and zalcitabine (Hyvid®)), non-nucleoside reverse transcription inhibitors (e.g., delavirudine (Rescriptor®), efavirenz (Sustiva®), nevirapine (Viramune®) and etravirine (Intelence®)), nucleotide reverse transcription inhibitors (e.g., , tenofovir (Viread®), protease inhibitors (e.g., amprenavir (Agenerase®), atazanavir (Reyataz®), darunavir (Prezista®), fosamprenavir (Lexiva®), indinavir (Crixivan®), lopinavir and ritonavir (Kaletra®), nelfinavir (Viracept®), ritonavir (Norvir®),Examples include saquinavir (Fortbase® or Invirase®), tipranavir (Aptivus®), entry inhibitors (e.g., enfuvirtide (Fuzeon®) and maraviroc (Selzentry®)), integrase inhibitors (e.g., raltegravir (Isentress®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), bortezomib (Velcade®), and dexamethasone (Decadron®) in combination with lenalidomide (Revlimid®), or any combination thereof (one or more).

[0242] In another embodiment, the present invention provides a method for treating rheumatoid arthritis, the method comprising the step of administering to a patient in need a compound of formula I or I' and one or more further therapeutic agents, the further therapeutic agents being nonsteroidal anti-inflammatory drugs (NSAIDS) (e.g., aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib), corticosteroids (e.g., prednisone, prednisolone, methylprednisolone, etc.) (and hydrocortisone, etc.), sulfasalazine (Azulfidine®), antimalarial drugs (e.g., hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®)), methotrexate (Rheumatrex®), gold salts (e.g., gold thioglucose (Solganal®), gold thiomalate (Myochrysine®) and auranofin (Ridaura®)), D-penicillamine (Depen (registered trademark) or Cuprimine registered trademark), azathioprine (Imuran (registered trademark)), cyclophosphamide (Cytoxan (registered trademark)), chlorambucil (Leukeran (registered trademark)), cyclosporine (Sandimmune (registered trademark)), leflunomide (Arava (registered trademark)), and "anti-TNF" agents (e.g., etanercept (Enbrel (registered trademark)), infliximab (Remicade (registered trademark)), golimumab (Simponi (registered trademark)), etc.) The following are selected: certolizumab pegol (Cimzia®) and adalimumab (Humira®), "anti-IL-1" agents (e.g., anakinra (Kineret®) and lilonacept (Arcalyst®)), antibodies (e.g., rituximab (Rituxan®)), "anti-T cell" agents (e.g., abatacept (Orencia®)), and "anti-IL-6" agents (e.g., tocilizumab (Actemra®)).

[0243] In some embodiments, the present invention provides a method for treating osteoarthritis, the method comprising the step of administering to a patient in need a compound of formula I or I' and one or more further therapeutic agents, the further therapeutic agents being selected from acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDS) (e.g., aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib), diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®)), and monoclonal antibodies (e.g., tanezumab).

[0244] In some embodiments, the present invention provides a method for treating cutaneous lupus erythematosus or systemic lupus erythematosus, the method comprising the step of administering to a patient in need a compound of formula I or I' and one or more further therapeutic agents, the further therapeutic agents being acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDS) (e.g., aspirin, ibuprofen, naproxen, etodolac (Lodine®), and celecoxib), corticosteroids (e.g., prednisone, prednisolone, methyl ester), The following are selected: rednisolone and hydrocortisone, antimalarial drugs (e.g., hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®)), cyclophosphamide (Cytoxan®), methotrexate (Rheumatrex®), azathioprine (Imuran®), and anticoagulants (e.g., heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®)).

[0245] In some embodiments, the present invention provides a method for treating Crohn's disease, ulcerative colitis, or inflammatory bowel disease, the method comprising the step of administering to a patient in need a compound of formula I or I' and one or more further therapeutic agents, the further therapeutic agents being mesalamine (Asacol®), sulfasalazine (Azulfidine®), antidiarrheal agents (e.g., diphenoxylate (Lomotil®) and loperamide (Imodium®)), and bile acid binders. (For example, cholestyramine, alosetron (Lotronex®), lubiprostone (Amitiza®)), laxatives (for example, magnesia milk, polyethylene glycol (MiraLax®), Dulcolax®, Correctol®, and Senokot®), as well as anticholinergics (for example, antispasmodics such as dicyclomine (Bentyl®)), anti-TNF agents, steroids, and antibiotics (for example, Flagyl or ciprofloxacin).

[0246] In some embodiments, the present invention provides a method for treating asthma, the method comprising the step of administering to a patient in need a compound of formula I or I' and one or more further therapeutic agents, the further therapeutic agents being Singulair®, β-2 agonists (e.g., albuterol (Ventolin® HFA, Proventil® HFA), revalbuterol (Xopenex®), metaproterenol (Alupent®), pyrbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®), and formoterol (Foradil®)), anticholinergic agents (e.g., ipratropium bromide (Atrovent®) and tiotropium (Spiriva®)), inhaled colcolone The following are selected from tycosteroids (e.g., prednisone, prednisolone, beclomethasone dipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), flunisolide (Aerobid®, Afviar®, Symbicort®, and Dulera®), cromolyn sodium (Intal®), methylxanthines (e.g., theophylline (Theo-Dur®, Theolair®, Slo-bid®, Uniphyl®, Theo-24®), and aminophylline), and IgE antibodies (e.g., omalizumab (Xolair®)).

[0247] In some embodiments, the present invention provides a method for treating COPD, the method comprising the step of administering to a patient in need a compound of formula I or I' and one or more further therapeutic agents, the further therapeutic agents being β-2 agonists (e.g., albuterol (Ventolin® HFA, Proventil® HFA), revalbuterol (Xopenex®), metaproterenol (Alupent®), pyrbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®), and formoterol (Foradil®)), anticholinergic agents (e.g., ipratropium bromide (Atrovent®)) and thiotropin The following are selected: pium (Spiriva®), methylxanthines (e.g., theophylline (Theo-Dur®, Theolair®, Slo-bid®, Uniphyl®, Theo-24®), and aminophylline), inhaled corticosteroids (e.g., prednisone, prednisolone, beclomethasone dipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), flunisolide (Aerobid®), Afviar®, Symbicort®, and Dulera®).

[0248] In another embodiment, the present invention provides a method for treating hematological malignancies, the method comprising administering to a patient in need a compound of formula I or I' and one or more further therapeutic agents, the further therapeutic agents being selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, hedgehog signaling inhibitors, BTK inhibitors, JAK / pan-JAK inhibitors, PI3K inhibitors, SYK inhibitors, and combinations thereof.

[0249] In another embodiment, the present invention provides a method for treating a solid tumor, the method comprising the step of administering to a patient in need a compound of formula I or I' and one or more further therapeutic agents, the further therapeutic agents being selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, hedgehog signaling inhibitors, BTK inhibitors, JAK / pan-JAK inhibitors, PI3K inhibitors, SYK inhibitors, and combinations thereof.

[0250] In another embodiment, the present invention provides a method for treating hematological malignancies, the method comprising the step of administering a compound of formula I or I' and a Hedgehog (Hh) signaling pathway inhibitor to a patient in need. In some embodiments, this hematological malignancy is DLBCL (Ramirez et al. "Defining causative factors contributing in the activation"). "of hedgehog signaling in diffuse large B-cell lymphoma" Leuk.Res. (2012), published online on July 17, is incorporated herein by reference in its entirety.

[0251] In another embodiment, the present invention provides a method for treating diffuse large B-cell lymphoma (DLBCL), the method comprising the step of administering to a patient in need a compound of formula I or I' and one or more further therapeutic agents, the further therapeutic agents being selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, hedgehog signaling inhibitors, and combinations thereof.

[0252] 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 or I' and one or more further therapeutic agents, the further therapeutic agents being selected from bortezomib (Velcade®) and dexamethasone (Decadron®), a hedgehog signaling inhibitor, a BTK inhibitor, a JAK / pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, a SYK inhibitor, in combination with lenalidomide (Revlimid®).

[0253] In another embodiment, the present invention provides a method for treating or reducing the severity of a disease, the method comprising the step of administering a compound of formula I or I' and a BTK inhibitor to a patient in need, wherein the disease is 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 mellitus, myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis, Graves' disease, autoimmune thyroiditis, Sjögren's syndrome, multiple sclerosis, systemic sclerosis, Lyme neuroborreliosis, Guyan-Barré syndrome, acute disseminated meningitis, Addison's disease, opsoclonus-myoclonus syndrome Syndrome, ankylosing spondylitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, autoimmune gastritis, pernicious anemia, celiac disease, Goodbasture syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia generalis, Behçet's disease, chronic fatigue, autonomic neuropathy, membranous glomerulonephropathyGlomerulonephropathy), endometriosis, interstitial cystitis, pemphigus vulgaris, bullous pemphigoid, neurogenic myotonia, scleroderma, chronic vulvodynia presenting with superficial irritation or burning, hyperproliferative disorders, rejection of transplanted organs or tissues, acquired immunodeficiency syndrome (AIDS, also known as HIV), type 1 diabetes, graft disease, transplantation, blood transfusion, anaphylaxis, allergies (e.g., allergies to plant pollen, latex, drugs, food, insect venom, animal hair, animal dander, house dust mites, or cockroach renal calyces) Ghee, type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, and atopic dermatitis, asthma, appendicitis, atopic dermatitis, asthma, allergy, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection, colitis, conjunctivitis, Crohn's disease, cystitis, dacryodenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, lateral epicondylitis, epididymitis, fasciitis, connective tissue inflammation, gastritis, gastroenteritis, Henof-Schönlein purpura, hepatitis, sweat gland abscess, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitisMyocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, mumps, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, pneumonitis, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, eustitis, sinusitis, stomatitis, synovitis, tendinitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, tenosynovitis, tunitis, vasculitis, or vulvitis, B-cell proliferative disorders (e.g., diffuse large B-cell lymphoma), follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, acute lymphoblastic leukemia, B-cell prelymphocytic leukemia, lymphoplasmacytic lymphoma Lymphoma / Waldenström macroglobulinemia, splenic marginal layer lymphoma, multiple myeloma (also known as plasma cell myeloma), non-Hodgkin lymphoma, Hodgkin lymphoma, plasma cell tumor, extranodal marginal layer B cell lymphoma, nodular marginal layer B cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary exudative lymphoma, Burkitt lymphoma / leukemia, or lymphomatoid granulomatosis, breast cancer, prostate cancer, or mast cell cancer (e.g., mast cell tumor, mast cell leukemia, mast cell tumor). (e.g., tumors, systemic mastocytosis), bone cancer, colorectal cancer, pancreatic cancer, diseases of bone and joints (including, but not limited to, rheumatoid arthritis, seronegative spondyloarthritis (ankylosing spondylitis, psoriatic arthritis, and Reiter's disease), Behçet's disease, Sjögren's syndrome, systemic sclerosis, osteoporosis, bone cancer, bone metastases), thromboembolic disorders (e.g., myocardial infarction, angina pectoris, reocclusion after angioplasty, restenosis after angioplasty, reocclusion after coronary artery bypass, restenosis after coronary artery bypass, stroke, transient ischemia, peripheral artery occlusion) Diseases (pulmonary embolism, deep vein thrombosis), inflammatory pelvic disease, urethritis, sunburn, sinusitis, pneumonitis, encephalitis, meningitis, myocarditis, nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis, dermatitis, gingivitis, appendicitis, pancreatitis, cholecystitis (cholocystitus), agammaglobulinemia, psoriasis, allergies, Crohn's disease, irritable bowel syndrome, ulcerative colitis, Sjögren's disease, tissue graft rejection, hyperacute rejection of transplanted organs, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), autoimmune polyglandular disease(also known as autoimmune polyendocrine syndrome), autoimmune alopecia, pernicious anemia, glomerulonephritis, dermatomyositis, multiple sclerosis, scleroderma, vasculitis, autoimmune hemolysis and autoimmune thrombocytopenia, Goodbasture syndrome, atherosclerosis, Addison's disease, Parkinson's disease, Alzheimer's disease, diabetes mellitus, septic shock, cutaneous lupus erythematosus, systemic lupus erythematosus (SLE), rheumatoid arthritis, psoriasis The following conditions are selected: arthritis, juvenile arthritis, osteoarthritis, chronic idiopathic thrombocytopenic purpura, Waldenström macroglobulinemia, myasthenia gravis, Hashimoto's thyroiditis, atopic dermatitis, osteoarthritis, vitiligo, autoimmune hypopituitarism, Guyen-Barré syndrome, Behçet's disease, scleroderma, mycosis fungoides, acute inflammatory responses (e.g., acute respiratory distress syndrome and ischemia / reperfusion injury), and Graves' disease.

[0254] In another embodiment, the present invention provides a method for treating or reducing the severity of a disease, the method comprising the step of administering a compound of formula I or I' and a PI3K inhibitor to a patient in need, wherein the disease is selected from cancer, neurodegenerative disorders, vascular disorders, viral diseases, autoimmune diseases, inflammatory disorders, hormone-related disorders, organ transplant-related conditions, immunodeficiency disorders, destructive bone disorders, proliferative disorders, infectious diseases, cell death-related conditions, thrombin-induced platelet aggregation, chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), liver diseases, pathological immune conditions involving T cell activation, cardiovascular disorders, and CNS disorders.

[0255] In another embodiment, the present invention provides a method for treating or reducing the severity of a disease, the method comprising the step of administering a compound of formula I or I' and a PI3K inhibitor to a patient in need, wherein the disease is a benign or malignant tumor, carcinoma or solid tumor of the brain, kidney (e.g., renal cell carcinoma (RCC)), liver, adrenal gland, bladder, breast, stomach, gastric tumor, ovary, colon, rectum, prostate, pancreas, lung, vagina, endometrium, cervix, testis, urogenital tract, esophagus, larynx, skin, bone or thyroid; sarcoma, gliablastoma, neuroblastoma Cystomas, multiple myeloma or gastrointestinal cancer (especially colon cancer or colon adenoma or head and neck tumors), epidermal hyperplasia, psoriasis, prostatic hyperplasia, neoplasia, neoplasia of epithelial features, adenoma, adenocarcinoma, keratoacanocyte, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer, lymphoma (e.g., non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (also called Hodgkin or Hodgkin's disease)), breast cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, or leukemia, Cowden syndrome, Lhermitte-Dudos disease, and Bannayan-Zonana syndrome Diseases including syndrome, or diseases in which the PI3K / PKB pathway is abnormally activated, asthma of any type or onset, including both endogenous (non-allergic) and exogenous (allergic) asthma, moderate asthma, severe asthma, bronchitis asthma, exercise-induced asthma, occupational asthma and asthma induced after bacterial infection, acute lung injury (ALI), adult / acute respiratory-promoting syndrome (ARDS), chronic obstructive pulmonary artery disease, chronic obstructive airway disease or chronic obstructive pulmonary disease (COPD, COAD or COLD) (and related chronic , including bronchitis or dyspnea), emphysema, and exacerbation of airway hyperactivity as a result of other drug treatments (in particular other inhaled drug treatments), bronchitis of any type or development (including, but not limited to, acute, arachidic, catarrhal, croup, chronic or tuberculous bronchitis), pneumoconiosis of any type or development (inflammatory, generally occupational lung diseases, whether chronic or acute, that frequently involve airway obstruction and develop as a result of repeated inhalation of dust) (e.g., aluminum pneumonitis, anthrax, asbestos disease, olichoconiosis, ostrich pneumonitis, iron disease, silicosis,Eosinophil-related airway disorders, which are either a result of or coexist with (such as tobacco poisoning and cotomatosis), Loeffler syndrome, eosinophilic, pneumonia, parasitic (especially metazoan) infection (such as tropical eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa (such as Churg-Strauss syndrome), eosinophilic granuloma, and eosinophil-related airway disorders affecting the airways caused by drug reactions), psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, polymorphisms Erythema, herpetiform 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 etiologies (autoimmune hematological disorders (e.g., hemolytic anemia, aplastic anemia, pure red cell adenomatosis, and idiopathic thrombocytopenia), cutaneous lupus erythematosus). Systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma (sclerodoma), Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Stevens-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), endocrine eye disorders, Graves' disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial lung disease The following are selected from neurodegenerative diseases caused by trauma, glutamate neurotoxicity, and hypoxia: fibrosis, psoriatic arthritis, and glomerulonephritis (with or without nephrotic syndrome, e.g., idiopathic nephrotic syndrome or minimal change nephropathy), restenosis, cardiac hypertrophy, atherosclerosis, myocardial infarction, ischemic attack and congestive heart failure, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and cerebral ischemia.

[0256] In some embodiments, the present invention provides a method for treating or reducing the severity of a disease, the method comprising the step of administering a compound of formula I or I' and a Bcl-2 inhibitor to a patient in need, wherein the disease is an inflammatory disorder, autoimmune disorder, proliferative disorder, endocrine disorder, neurological disorder, or transplant-related disorder. In some embodiments, the disorder is a proliferative disorder, lupus, or lupus nephritis. In some embodiments, the proliferative disorder is chronic lymphocytic leukemia, diffuse large B-cell lymphoma, Hodgkin's disease, small cell lung cancer, non-small cell lung cancer, myelodysplastic syndrome, lymphoma, hematological neoplasm, or solid tumor.

[0257] In some embodiments, the present invention comprises the step of treating a disease or administering a tyk2 domain-conjugating compound and a tyk2 kinase (JH1) domain-conjugating compound of the disease. In some embodiments, the disease is an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a transplant-related disorder. In some embodiments, the JH2-conjugating compound is a compound of formula I or I'. Other suitable JH2 domain-conjugating compounds are those described in WO2014074660A1, WO2014074661A1, and WO2015089143A1, each of which is incorporated herein by reference in whole. Suitable JH1 domain-conjugating compounds are those described in WO2015131080A1, which is incorporated herein by reference in whole.

[0258] These compounds and compositions may be administered in any amount and via any route of administration that is effective in treating or reducing the severity of autoimmune disorders, inflammatory disorders, proliferative disorders, endocrine disorders, neurological disorders, or transplant-related disorders, according to the methods of the present invention. The exact amount required will vary from subject to subject, depending on the subject's species, age and sex, the severity of the infection, the specific agent, and the method of administration. The compounds of the present invention are preferably formulated into unit dosage forms to facilitate administration and ensure uniformity of dosage. As used herein, the term “unit dosage form” refers to a physically separated unit of the drug appropriate for the patient being treated. However, it should be understood that the total daily dose of the compounds and compositions of the present invention will be determined by the attending physician within the bounds of sound medical judgment. The effective dose level specific to any particular patient or organism depends on a variety of factors, including the disorder being treated and its severity; the activity of the particular compound used; the particular composition used; the patient's age, weight, overall health, sex, and diet; the timing of administration, route of administration, and elimination rate of the particular compound used; the duration of treatment; drugs used in combination with or concurrently with the particular compound used; and similar factors well known in the medical field. The term “patient” as used herein means an animal, preferably a mammal, and most preferably a human.

[0259] The pharmaceutically acceptable compositions of the present invention can be administered to humans and other animals orally, rectally, parenterally, intracisionally, vaginally, intraperitoneally, topically (as powders, ointments, or drops, etc.), buccally, or as oral or nasal sprays, etc., 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 multiple times a day at a dosage level of about 0.01 mg / kg to about 50 mg / kg, preferably about 1 mg / kg to about 25 mg / kg, relative to the subject's daily body weight, to obtain the desired therapeutic effect.

[0260] 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, the liquid dosage form may contain inert diluents, solubilizers, and emulsifiers commonly used in the art, such as water or other solvents, including ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, as well as mixtures thereof. In addition to inert diluents, the oral composition may also contain adjuvants such as humectants, emulsifiers, and suspending agents, as well as sweeteners, flavoring agents, and fragrances.

[0261] Injectable formulations, such as aqueous or oily suspensions for sterile injection, can be formulated by known techniques using appropriate dispersing or wetting and suspending agents. Sterile injectable formulations may be sterile injection solutions, suspensions, or emulsions in non-toxic, parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable vehicles and solvents that can be used include water, Ringer's solution, USP, and isotonic sodium chloride solutions. Furthermore, sterile non-volatile oils are conventionally used as solvents or suspension media. For this purpose, any brand of non-volatile oil, including synthetic monoglycerides or synthetic diglycerides, can be used. Additionally, fatty acids such as oleic acid are used in the preparation of injectable substances.

[0262] Injectable preparations can be sterilized before use, for example, by filtration through a bacterial-retaining filter, or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injection medium.

[0263] To prolong the effects of the compounds of the present invention, it is often desirable to slow down the absorption of the compounds from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of a crystalline or amorphous material with poor water solubility. Thus, the absorption rate of the compound depends on its dissolution rate, which may depend on the crystal size and crystalline form. Alternatively, delayed absorption of parenterally administered compound forms is achieved by dissolving or suspending the compound in an oil vehicle. Injectable depot formulations are prepared by forming a microencapsulation matrix of the compound within a biodegradable polymer, such as polylactide-polyglycolide. The compound release rate can be controlled depending on the ratio of compound to polymer and the properties of the specific polymer used. Other examples of biodegradable polymers include poly(orthoesters) and poly(acid anhydrides). Depot injection formulations can also be prepared by capturing the compound within liposomes or microemulsions that conform to body tissues.

[0264] The composition for rectal or vaginal administration is preferably a suppository that can be prepared by mixing the compound of the present invention with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol, or suppository wax, which is solid at ambient temperature but liquid at body temperature and therefore dissolves in the rectum or vaginal cavity to release the active compound.

[0265] 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 bulking agents such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and acacia; c) humectants such as glycerol; d) disintegrants such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) dissolution retarders such as paraffin; f) absorption enhancers such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite clay; 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 include a buffering agent.

[0266] Similar types of solid compositions may be used as fillers in soft and rigid gelatin capsules using excipients such as lactose and high molecular weight polyethylene glycol. Solid dosage forms of tablets, sugar-coated tablets, capsules, pills, and granules can be prepared using coatings and shells, such as enteric coatings and other coatings well known in the art of pharmaceutical formulation. These may optionally contain opacifying agents and may be compositions that release (one or more) active ingredients to only or preferentially to a portion of the intestinal tract, in a manner that may be delayed as needed. Examples of embedding compositions that can be used include polymeric substances and waxes. Similar types of solid compositions may be used as fillers in soft and rigid gelatin capsules using excipients such as lactose and high molecular weight polyethylene glycol.

[0267] The active compound may also be in microencapsulated form having one or more of the excipients described above. Solid dosage forms of tablets, sugar-coated tablets, capsules, pills, and granules can be prepared using coatings and shells, such as enteric coatings, controlled-release coatings, and other coatings well known in the field of pharmaceutical formulation. In such solid dosage forms, the active compound may be mixed with at least one inert diluent, such as sucrose, lactose, or starch. Such dosage forms may also contain further substances other than the inert diluent, such as tablet forming lubricants and other tablet forming aids, such as magnesium stearate or microcrystalline cellulose, as is common practice. In the case of capsules, tablets, and pills, the dosage form may contain buffers. These may optionally contain opacifying agents and may also be compositions that release (one or more) the active ingredient to only or preferentially to a certain portion of the intestinal tract, in a manner that may be delayed as needed. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0268] Topical or transdermal dosage forms of the compounds of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives or buffers, as needed. Ophthalmic formulations, ear drops, and eye drops are also considered to be within the scope of the present invention. Furthermore, the present invention intends to utilize transdermal patches, which have the additional advantage of enabling controlled delivery of the compound to the body. 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 of the compound across the skin. Its rate can be controlled by providing a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0269] According to one embodiment, the present invention relates to a method for inhibiting protein kinase activity in a biological sample, comprising the step of contacting the biological sample with a compound of the present invention or a composition containing the compound.

[0270] In another embodiment, the present invention relates to a method for inhibiting the activity of TYK2 or its variants in a biological sample, the method comprising the step of contacting the biological sample with the compound of the present invention or a composition containing the compound. In a particular embodiment, the present invention relates to a method for irreversibly inhibiting the activity of TYK2 or its variants in a biological sample, the method comprising the step of contacting the biological sample with the compound of the present invention or a composition containing the compound.

[0271] In another embodiment, the present invention provides a method for selectively inhibiting TYK2 beyond one or more of JAK1, JAK2, and JAK3. In some embodiments, the compounds of the present invention are more than twice as selective as JAK1 / 2 / 3. In some embodiments, the compounds of the present invention are more than five times as selective as JAK1 / 2 / 3. In some embodiments, the compounds of the present invention are more than ten times as selective as JAK1 / 2 / 3. In some embodiments, the compounds of the present invention are more than fifty times as selective as JAK1 / 2 / 3. In some embodiments, the compounds of the present invention are more than one hundred times as selective as JAK1 / 2 / 3.

[0272] The term “biological sample” as used herein includes, but is not limited to, cell cultures or their extracts; biopsy material obtained from mammals or its extracts; and blood, saliva, urine, feces, semen, tears, or other bodily fluids or their extracts.

[0273] Inhibition of TYK2 (or its variants) activity in biological samples is useful 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, preservation of biological specimens, and biological assays.

[0274] Another embodiment of the present invention relates to a method for inhibiting protein kinase activity in a patient, the method comprising the step of administering to the patient a compound of the present invention or a composition containing the compound.

[0275] In another embodiment, the present invention relates to a method for inhibiting the activity of TYK2 or its variants in a patient, the method comprising administering to the patient a compound of the present invention or a composition containing the compound. In a particular embodiment, the present invention relates to a method for reversibly or irreversibly inhibiting the activity of one or more of the TYK2 or its variants in a patient, the method comprising administering to the patient a compound of the present invention or a composition containing the compound. In another embodiment, the present invention provides a method for treating a disorder mediated by TYK2 or its variants in a patient requiring treatment of such disorder, the method comprising administering to the patient a compound of the present invention or a pharmaceutically acceptable composition thereof. Such disorders are described in detail herein.

[0276] Depending on the specific condition or disease to be treated, further therapeutic agents that are typically administered to treat that condition may also be present in the composition of the present invention. In this specification, further therapeutic agents that are typically administered to treat a particular disease or condition are referred to as "appropriate for the disease or condition being treated."

[0277] The compounds of the present invention can also be advantageously used in combination with other therapeutic compounds. In some embodiments, these other therapeutic compounds are other antiproliferative compounds. Such antiproliferative compounds include aromatase inhibitors; anti-estrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule activating 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 kinase activity of proteins or lipids and further anti-angiogenic compounds; compounds that target, reduce or inhibit the activity of protein or lipid phosphatases; gonadrelin agonists; anti-androgens; methionine aminopeptidase inhibitors; matrix Cunx metalloproteinase inhibitors; bisphosphonates; biological reaction modifiers; antiproliferative antibodies; heparanase inhibitors; Ras oncogene isoform inhibitors; telomerase inhibitors; proteasome inhibitors; compounds used in the treatment of hematological malignancies; compounds that target, reduce or inhibit Flt-3 activity; Hsp90 inhibitors (e.g., 17-AAG (17-allylaminogeldanamycin, NSC330507), 17-DMAG (17-dimethylaminoethylamino-17-dimethoxygeldanamycin, NSC707545), IPI-504, CNF1010, CNF2024, CNF1010 (Conforma Examples include, but are not limited to, those of the Therapeutics); temozolomide (Temodal®); kinesin spindle protein inhibitors (e.g., SB715992 or SB743921 (GlaxoSmithKline), or pentamidine / chlorpromazine (CombinatoRx)); and MEK inhibitors (e.g., ARRY142886 (Array BioPharma), AZD6244 (AstraZeneca), PD181461 (Pfizer), and leucovorin). As used herein, the term “aromatase inhibitor” refers to compounds that inhibit estrogen production (e.g., the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively).This term encompasses, but is not limited to, steroids (especially atamethane, exemestane, and formestane), as well as non-steroids (especially aminoglutethimide, roglethimide, pyridoglutethimide, trilostane, testolactone, ketoconazole, vorozole, fadrozole, anastrozole, and letrozole). Exemestane is traded as Aromasin. TM It is on the market under the name Formestan, trade name Lentaron. TM It is on the market under the following conditions. Fadrozol is sold under the trade name Afema TM It is on the market under the brand name Arimidex. Anastrozole is sold under the brand name Arimidex. TM It is on the market under the brand name Femara. Letrozole is sold under the brand name Femara TM Or Femar TM It is on the market under the following conditions. Amino glutetimide is sold under the trade name Orimeten. TM It is marketed under the following conditions. The combination of the present invention, which contains a chemotherapeutic agent that is an aromatase inhibitor, is particularly useful for the treatment of hormone receptor-positive tumors (e.g., breast tumors).

[0278] The term "anti-estrogen," as used herein, refers to compounds that antagonize the effects of estrogen at the estrogen receptor level. This term includes, but is not limited to, tamoxifen, fulvestrant, raloxifene, and raloxifene hydrochloride. Tamoxifen is traded under the name Novaldex. TM It is marketed under the following conditions. Raloxifene hydrochloride is sold under the brand name Evista. TM It is marketed under the name Fulvestrant, trade name Faslodex. TM It can be administered under certain conditions. The combination of the present invention, which contains a chemotherapeutic agent that is an anti-estrogen, is particularly useful for the treatment of estrogen receptor-positive tumors (e.g., breast tumors).

[0279] The term “anti-androgen” as used herein refers to any substance that can inhibit the biological effects of male hormones, and bicalutamide (casodex). TM Examples include, but are not limited to, abarelix, goserelin, and goserelin acetate, as used herein. TM It can be administered under these conditions.

[0280] The term “topoisomerase I inhibitor” as used herein includes, but is not limited to, topotecan, gimatecan, irinotecan, camptothecian and its analogues, 9-nitrocamptothecin, and the high molecular weight camptothecin conjugate PNU-166148. Irinotecan is, for example, camptosar. TM It can be administered in the form available on the market under the brand name Hycamptin. TM It is on the market under that condition.

[0281] The term "topoisomerase II inhibitor" as used herein refers to anthracyclines (e.g., doxorubicin (Caelyx)) TM This includes, but is not limited to, liposomal formulations such as daunorubicin, epirubicin, idarubicin, and nemorubicin, the anthraquinones mitozantrone and losoxantrone, and the podophyllotoxins etoposide and teniposide. Etoposide is traded as Etophos. TM It is marketed under the brand name VM 26-Bristol. Doxorubicin is marketed under the brand name Acriblastin. TM or Adriamycin TM It is on the market under the name Epirubicin, trade name Farmorubicin.TM It is on the market under the name Idarubicin, trade name Zavedos. TM It is marketed under the name [name omitted]. Mitozantron is marketed under the trade name Novantrone.

[0282] The term "microtubule activator" refers to microtubule stabilizing compounds, microtubule destabilizing compounds, and microtubule polymerization inhibitors, and includes, but is not limited to, taxanes (e.g., paclitaxel and docetaxel); vinca alkaloids (e.g., vinblastine or vinblastine sulfate, vincristine or vincristine sulfate, and vinorelbine); discordermolides; cochicine and epothilone, and their derivatives. Paclitaxel is traded as Taxol. TM It is marketed under the following name: Docetaxel, trade name: Taxotere TM It is marketed under the following name: Vinblastine sulfate, trade name Vinblastine RP. TM It is on the market under the following name: Vincristine sulfate, trade name Farmistin. TM It is on the market under that condition.

[0283] The term "alkylating agent," as used herein, includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan, or nitrosourea (BCNU or Gliadel). Cyclophosphamide is traded as Cyclostin. TM It is on the market under the following conditions. Ifosfamide is sold under the trade name Holoxan. TM It is on the market under that condition.

[0284] The term "histone deacetylase inhibitor" or "HDAC inhibitor" refers to compounds that inhibit histone deacetylase and have antiproliferative activity. This includes, but is not limited to, suberoylanilide hydroxamic acid (SAHA).

[0285] The term "antitemolytic antagonist" includes, but is not limited to, 5-fluorouracil (i.e., 5-FU), capecitabine, gemcitabine, DNA demethylated compounds (e.g., 5-azacitidine and decitabine), methotrexate and edatrexate, and folic acid antagonists (e.g., pemetrexed). Capecitabine is traded as Xeloda. TM It is on the market under the name Gemzar. Gemcitabine is sold under the trade name Gemzar. TM It is on the market under that condition.

[0286] The term "platin compound," as used herein, includes, but is not limited to, carboplatin, cisplatin, cisplatinum, and oxaliplatin. Carboplatin is, for example, carboplat. TM It can be administered in the form available on the market under the trade name of oxaliplatin, for example, eloxatin. TM It can be administered in the form available on the market under the brand name.

[0287] The terms “compounds that target / reduce the kinase activity of proteins or lipids; or compounds that target / reduce the phosphatase activity of proteins or lipids; or further anti-angiogenic compounds” are, as used herein, protein tyrosine kinase and / or serine and / or threonine kinase inhibitors, or lipid kinase inhibitors (e.g., a) compounds that target, reduce or inhibit the activity of platelet-derived growth factor receptor (PDGFR) (e.g., compounds that target, reduce or inhibit the activity of PDGFR, in particular compounds that inhibit PDGF receptor, for example, N-phenyl-2-pyrimidine-amine derivatives, for example, imatinib, SU101, SU6668 and GFB-111); b) compounds that target, reduce or inhibit the activity of fibroblast growth factor receptor (FGFR); c) compounds that target, reduce or inhibit the activity of insulin-like growth factor receptor I (IGF-IR) (e.g., compounds that target, reduce or inhibit the activity of IGF-IR) d) Compounds that target, reduce or inhibit the activity of the IGF-I receptor, particularly compounds that inhibit the kinase activity of the IGF-I receptor, or antibodies that target the extracellular domain of the IGF-I receptor or its growth factor; d) Compounds that target, reduce or inhibit the activity of the Trk receptor tyrosine kinase family, or ephrin B4 inhibitors; e) Compounds that target, reduce or inhibit the activity of the AxI receptor tyrosine kinase family; f) Compounds that target the activity of the Ret receptor tyrosine kinase, Compounds that reduce or inhibit the activity of: g) compounds that target, reduce, or inhibit the activity of Kit / SCFR receptor tyrosine kinase (e.g., imatinib); h) compounds that target, reduce, or inhibit the activity of C-kit receptor tyrosine kinase (which is part of the PDGFR family) (e.g., compounds that target, reduce, or inhibit the activity of the c-Kit receptor tyrosine kinase family, and in particular compounds that inhibit the c-Kit receptor, e.g., imatinib);i) Compounds that target, reduce, or inhibit the activity of members of the c-Abl family, their gene fusion products (e.g., BCR-Abl kinase), and mutants (e.g., compounds that target, reduce, or inhibit the activity of c-Abl family members and their gene fusion products, such as N-phenyl-2-pyrimidine-amine derivatives, such as imatinib or nilotinib (AMN107); PD180970; AG957; NSC 680410;PD173955 (manufactured by Parke Davis); or dasatinib (BMS-354825); j) Compounds that target, reduce or inhibit the activity of members of the Raf family of protein kinase C (PKC) and serine / threonine kinases, MEK, SRC, JAK / pan-JAK, FAK, PDK1, PKB / Akt, and members of the Ras / MAPK, PI3K, SYK, BTK, and TEC families, as well as / or members of the cyclin-dependent kinase family (CDK) (e.g., staurosporine derivatives (e.g., midostaurin)); further examples of compounds include UCN-01, safingol, BAY 43-9006, Bryostatin 1, Perifosine; Ilmofosine; RO 318220 and RO 320432;GO 6976; lsis 3521; LY333531 / LY379196; isoquinoline compounds; FTI; PD184352 or QAN697 (P13K inhibitor) or AT7519 (CDK inhibitor) are examples); k) Compounds that target, reduce or inhibit the activity of protein-tyrosine kinase inhibitors (for example, compounds that target, reduce or inhibit the activity of protein-tyrosine kinase inhibitors, such as imatinib mesylate (Gleevec); TM) or tyrphostin (e.g., tyrphostin A23 / RG-50810; AG 99; tyrphostin AG 213; tyrphostin AG 1748; tyrphostin AG 490; tyrphostin B44; tyrphostin B44(+) enantiomer; tyrphostin AG 555; AG 494; tyrphostin AG 556, AG 957) and adaphostin (4-{[(2,5-dihydroxyphenyl)methyl]amino}-adamantyl benzoate; NSC Examples include 680410, adafostin); l) compounds that target, reduce, or inhibit the activity of the epidermal growth factor family of receptor tyrosine kinases (EGFR1, ErbB2, ErbB3, ErbB4 as homodimers or heterodimers) and their variants (e.g., compounds that target, reduce, or inhibit the activity of the epidermal growth factor receptor family are compounds, proteins, or antibodies that inhibit members of the EGF receptor tyrosine kinase family (e.g., EGF receptor, ErbB2, ErbB3, and ErbB4) or bind to EGF or EGF-related 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 the c-Met receptor (e.g., compounds that target, reduce or inhibit the activity of c-Met, in particular compounds that inhibit the kinase activity of the c-Met receptor, or compounds that target the extracellular domain of c-Met) (Antibodies that either convert to 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) (PRT-062070, SB-1578, baricitinib, pacritinib, momerotinib, VX-509, AZD-1480, TG-101348, tofacitinib, and ruxolitinib (r Examples include, but are not limited to, uxolitinib);o) compounds that target, reduce, or inhibit the kinase activity of PI3 kinase (PI3K) (ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, and idelarisib). Examples include, but are not limited to, lalisib); and q) compounds that target, reduce, or inhibit the signaling effect of the Hedgehog protein (Hh) or smoothed receptor (SMO) pathway (examples include, but are not limited to, cyclopamine, vismodegib, itraconazole, erismodegib, and IPI-926 (saridegib)).

[0288] As used herein, the term "PI3K inhibitor" refers to compounds having inhibitory activity against one or more enzymes of the phosphatidylinositol-3-kinase family (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 useful in the present invention include, but are not limited to, ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictrelisib, PF-4691502, BYL-719, dactricib, XL-147, XL-765, and idelalisib.

[0289] As used herein, the term "BTK inhibitor" refers to compounds having inhibitory activity against Bruton's tyrosine kinase (BTK), including but not limited to AVL-292 and ibrutinib.

[0290] As used herein, the term "SYK inhibitor" includes, but is not limited to, compounds having inhibitory activity against spleen tyrosine kinase (SYK), such as PRT-062070, R-343, R-333, Excellair, PRT-062607, and fostamatinib.

[0291] The term "Bcl-2 inhibitor," as used herein, includes, but is not limited to, compounds having inhibitory activity against B-cell lymphoma protein 2 (Bcl-2), including 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 WO2008118802), navitoclax (and its analogues; see US7390799), NH-1 (Shenayng Pharmaceutical University), obatoclax (and its analogues; see WO2004106328), and S-001 (Gloria). Examples include, but are not limited to, Bcl-2 inhibitors (Pharmaceuticals), TW series compounds (Univ. of Michigan), and venetoclax. In some embodiments, the Bcl-2 inhibitor is a small molecule therapeutic agent. In some embodiments, the Bcl-2 inhibitor is a peptide mimetic.

[0292] Further examples of BTK inhibitory compounds and conditions treatable by such compounds in combination with the compounds of the present invention can be found in WO2008039218 and WO2011090760 (these in whole are incorporated herein by reference).

[0293] Further examples of SYK inhibitory compounds and conditions treatable by such compounds in combination with the compounds of the present invention can be found in WO2003063794, WO2005007623, and WO2006078846 (the whole of which is incorporated herein by reference).

[0294] Further examples of PI3K inhibitory compounds and conditions treatable by such compounds in combination with the compounds of the present invention can be found in WO2004019973, WO2004089925, WO2007016176, US8138347, WO2002088112, WO2007084786, WO2007129161, WO2006122806, WO2005113554, and WO2007044729 (the entirety of which is incorporated herein by reference).

[0295] Further examples of JAK inhibitory compounds and conditions treatable by such compounds in combination with the compounds of the present invention can be found in WO2009114512, WO2008109943, WO2007053452, WO2000142246, and WO2007070514 (the whole of which is incorporated herein by reference).

[0296] Further anti-angiogenic compounds include compounds whose activity is due to a different mechanism (e.g., unrelated to protein or lipid kinase inhibition) (e.g., thalidomide (thalomid) TM Examples include ) and TNP-470).

[0297] Examples of proteasome inhibitors useful for use 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.

[0298] Compounds that target, reduce, or inhibit the activity of protein or lipid phosphatases include, for example, phosphatase 1 inhibitors, phosphatase 2A inhibitors, or CDC25 inhibitors (e.g., okadaic acid or its derivatives).

[0299] Compounds that induce cell differentiation processes include, but are not limited to, retinic acid, α-tocopherol, γ-tocopherol or δ-tocopherol, or α-tocotrienol, γ-tocotrienol or δ-tocotrienol.

[0300] The term cyclooxygenase inhibitor, as used herein, refers to Cox-2 inhibitors, 5-alkyl-substituted 2-arylaminophenylacetic acid, and derivatives (e.g., celecoxib (Celebrex)). TM ), rofecoxib (Vioxx) TM This includes, but is not limited to, etoricoxib, valdecoxib, or 5-alkyl-2-arylaminophenylacetic acid (e.g., 5-methyl-2-(2'-chloro-6'-fluoroanilino)phenylacetic acid), lumiracoxib.

[0301] The term "bisphosphonate," as used herein, includes, but is not limited to, etidronic acid, clodronic acid, tydronic acid, pamidronic acid, alendronic acid, ibandronic acid, risedronic acid, and zoledronic acid. Etidronic acid is traded as Didronel. TM It is on the market under the name Bonefos. Clodronic acid is sold under the brand name Bonefos. TM It is on the market under the name of . Childronic acid is sold under the brand name Skelid. TM It is on the market under the name Pamidronic acid, trade name Aredia. TM It is on the market under the name Alendronate, brand name Fosamax. TM It is on the market under the following name: Ibandronate, trade name Bondranat. TM It is marketed under the following conditions. Risedronic acid is sold under the brand name Actonel. TM It is marketed under the following name. Zoledronic acid is sold under the trade name Zometa. TMThe term "mTOR inhibitor" refers to compounds that inhibit the mammalian target of rapamycin (mTOR) and have antiproliferative activity (e.g., sirolimus (Rapamune®), everolimus (Certican)). TM Regarding ), CCI-779 and ABT578).

[0302] The term "heparanase inhibitor," as used herein, refers to a compound that targets, reduces, or inhibits the degradation of heparin sulfate. This term includes, but is not limited to, PI-88. The term "biological reaction modifier," as used herein, refers to a lymphokine or interferon.

[0303] The term “inhibitor of Ras oncogene isoform” (e.g., H-Ras, K-Ras, or N-Ras) as used herein refers to compounds that target, reduce, or inhibit the oncogene activity of Ras (e.g., L-744832, DK8G557, or R115777 (Zarnestra)). TM This refers to "farnesyltransferase inhibitors" such as ). The term "telomerase inhibitor," as used herein, means a compound that targets, reduces, or inhibits telomerase activity. Compounds that target, reduce, or inhibit telomerase activity are, in particular, compounds that inhibit telomerase receptors (e.g., telomestatin).

[0304] The term "methionine aminopeptidase inhibitor," as used herein, refers to a compound that targets, reduces, or inhibits the activity of methionine aminopeptidase. Examples of compounds that target, reduce, or inhibit the activity of methionine aminopeptidase include, but are not limited to, bengamide or its derivatives.

[0305] The term "proteasome inhibitor," as used herein, refers to a compound that targets, reduces, or inhibits the activity of the proteasome. Examples of compounds that target, reduce, or inhibit the activity of the proteasome include bortezomib (Velcade). TM Examples include, but are not limited to, ) and MLN 341.

[0306] The term “matrix metalloproteinase inhibitor” or (“MMP” inhibitor), as used herein, includes, but is not limited to, collagen peptide-mimicking and non-peptide-mimicking inhibitors, tetracycline derivatives (e.g., batimastat, a hydroxamate peptide-mimicking inhibitor, and its orally bioavailable analogs, marimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551), BMS-279251, BAY 12-9566, TAA211, MMI270B, or AAJ996).

[0307] The term “compounds used in the treatment of hematological malignancies” as used herein includes, but is not limited to, FMS-like tyrosine kinase inhibitors (compounds that target, reduce, or inhibit the activity of FMS-like tyrosine kinase receptor (Flt-3R)); interferons, 1-β-D-arabinofuranosilcytosine (ara-c) and busulfan; ALK inhibitors (compounds that target, reduce, or inhibit anaplastic lymphoma kinase); and Bcl-2 inhibitors.

[0308] Compounds that target, reduce, or inhibit the activity of the FMS-like tyrosine kinase receptor (Flt-3R) are, in particular, compounds, proteins, or antibodies that inhibit members of the Flt-3R receptor kinase family (e.g., PKC412, midostaurin, staurosporine derivatives, SU11248, and MLN518).

[0309] The term “HSP90 inhibitor,” as used herein, includes, but is not limited to, compounds that target, reduce, or inhibit the endogenous ATPase activity of HSP90; and compounds that degrade, target, reduce, or inhibit proteins to which HSP90 family proteins bind via the ubiquitin-proteasome pathway (HSP90 client proteins). Compounds that target, reduce, or inhibit the endogenous ATPase activity of HSP90 include, in particular, compounds, proteins, or antibodies that inhibit the ATPase activity of HSP90 (e.g., 17-allylamino,17-demethoxygeldanamycin (17AAG), geldanamycin derivatives; other geldanamycin-related compounds; radicicol and HDAC inhibitors).

[0310] The term "antiproliferative antibody" as used herein refers to trastuzumab (Herceptin) TM ), trastuzumab-DM1, Erbitux, bevacizumab (Avastin) TM This includes, but is not limited to, rituximab (Rituxan®), PRO64553 (anti-CD40), and 2C4 antibodies. Antibodies mean intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least two intact antibodies, and antibody fragments insofar as they exhibit the desired biological activity.

[0311] For the treatment of acute myeloid leukemia (AML), the compounds of the present invention may be used in combination with standard leukemia treatments, and in particular with treatments used for the treatment of AML. Specifically, the compounds of the present invention may be administered in combination with, for example, farnesyltransferase inhibitors and / or other drugs useful for the treatment of AML (e.g., daunorubicin, adriamycin, Ara-C, VP-16, teniposide, mitozantrone, 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 the step of administering the compounds of the present invention together with one or more FLT3 inhibitors. In some embodiments, these FLT3 inhibitors are selected from quizartinib (AC220), staurosporine derivatives (e.g., midostaurin or restaurtinib), 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, these FLT3 inhibitors are selected from quizartinib, midostaurin, restagurtinib, sorafenib, and sunitinib.

[0312] Other anti-leukemia compounds include, for example, Ara-C, a pyrimidine analog (which is a 2-dioxycytidine compound). ’Examples include α-hydroxyribose (arabinoside) derivatives. Also examples include purine analogs of hypoxanthine, 6-mercaptopurine (6-MP), and fludarabine phosphate. Compounds that target, reduce, or inhibit the activity of histone deacetylase (HDAC) inhibitors (e.g., sodium butyrate and suberoylanilide hydroxamic acid (SAHA)) inhibit the activity of enzymes known as histone deacetylase. 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-indole-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide or its pharmaceutically acceptable salts, and N-hydroxy-3-[4-[(2-hydroxyethyl){2-(1H-indole-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide or its pharmaceutically acceptable salts (in particular, lactate)). A somatostatin receptor antagonist, as used herein, means a compound that targets, treats, or inhibits the somatostatin receptor (e.g., octreotide and SOM230). Tumor cell damage approaches refer to approaches such as ionizing radiation. As used above and below in this specification, the term "ionizing radiation" means ionizing radiation that occurs either as electromagnetic radiation (e.g., X-rays and gamma rays) or as particles (e.g., alpha and beta particles). Ionizing radiation is provided in, but is not limited to, radiation therapy and is well known in that field. See Hellman, Principles of Radiation Therapy, Cancer, Principles and Practice of Oncology, Devita et al. (eds.), 4th edition, Vol. 1, pp. 248-275 (1993).

[0313] EDG conjugates and ribonucleotide reductase inhibitors are also included. The term “EDG conjugate” as used herein means a class of immunosuppressants that modulate lymphocyte recirculation (e.g., FTY720). The term “ribonucleotide reductase inhibitor” means pyrimidine nucleoside analogs or purine nucleoside analogs (including, but not limited to, fludarabine and / or cytosine arabinoside (ara-C), 6-thioguanine, 5-fluorouracil, cladribine, 6-mercaptopurine (in particular in combination with ara-C for ALL) and / or pentostatins). Ribonucleotide reductase inhibitors are particularly hydroxyurea or 2-hydroxy-1H-isoindole-1,3-dione derivatives.

[0314] In particular, 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or its pharmaceutically acceptable salts, 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate; angiostatin TM Endostatin TM Anthranilate amides; ZD4190; ZD6474; SU5416; SU6668; bevacizumab; or anti-VEGF antibodies or anti-VEGF receptor antibodies (e.g., rhuMAb and RHUFab), VEGF aptamers (e.g., Macugon); FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgGI antibodies, angiozymes (RPI 4610), and bevacizumab (Avastin). TM This also includes VEGF compounds, proteins, or monoclonal antibodies, such as ) ).

[0315] Photodynamic therapy, as used herein, refers to treatment that uses certain chemical substances known as photosensitizing compounds to treat or prevent cancer. An example of photodynamic therapy is Visudyne. TM Other treatments include those using compounds such as sodium porfimer.

[0316] Hemostatic steroids, as used herein, refer to compounds that block or inhibit angiogenesis (e.g., anecortave, triamcinolone, hydrocortisone, 11-α-epihydrocotisol, cortexolone, 17α-hydroxyprogesterone, corticosterone, deoxycorticosterone, testosterone, estrone, and dexamethasone).

[0317] Grafts containing corticosteroids refer to compounds such as fluocinolone and dexamethasone.

[0318] Other chemotherapeutic compounds include, but are not limited to, plant alkaloids, hormonal compounds and antagonists; biological reaction modifiers (preferably lymphokines or interferons); antisense oligonucleotides or oligonucleotide derivatives; shRNA or siRNA; or a wide variety of other compounds or compounds with unknown mechanisms of action.

[0319] The compounds of the present invention are also useful as co-therapeutic compounds for use in combination with other drug substances (e.g., anti-inflammatory substances, bronchodilators, or antihistamines) in the treatment of obstructive or inflammatory airway diseases, such as those described earlier herein (e.g., as enhancers of the therapeutic activity of such drugs, or as a means of reducing the required dosage or potential side effects of such drugs). The compounds of the present invention may be mixed with other drug substances in a certain pharmaceutical composition, or may be administered separately from other drug substances, either before, simultaneously with, or after them. Accordingly, the present invention encompasses combinations of the compounds of the present invention, as described earlier herein, with anti-inflammatory substances, bronchodilators, antihistamines, or antitussives, where the compounds of the present invention and these drug substances are in the same pharmaceutical composition or in different pharmaceutical compositions.

[0320] Appropriate anti-inflammatory drugs include steroids (especially glucocorticosteroids (e.g., budesonide, beclamethasone dipropionate, fluticasone propionate, ciclesonide, or mometasone furoate)); nonsteroidal glucocorticoid receptor agonists; LTB4 antagonists (e.g., LY293111, CGS025019C, CP-195543, SC-53228, BIIL 284, ONO 4057, SB 209247); LTD4 antagonists (e.g., montelukast and zafilluukast); PDE4 inhibitors (e.g., cilomilast (Ariflo® GlaxoSmithKline), roflumilast (Byk Gulden), V-11294A(Napp), BAY19-8004(Bayer), SCH-351591(Schering-Plough), Allophylline(Almirall Prodesfarma), PD189659 / PD168787(Parke-Davis), AWD-12-281(Asta Medica), CDC-801(Celgene), SeICID(TM)CC-10004(Celgene), VM554 / UM565(Vernalis), T-440(Tanabe), KW-4490(Kyowa Hakko Examples include A2a agonists; A2b antagonists; and β-2 adrenergic receptor agonists (e.g., albuterol (salbutamol), metaproterenol, terbutaline, salmeterol, fenoterol, procaterol, and in particular formoterol and its pharmaceutically acceptable salts). Suitable bronchodilators include anticholinergic or antimuscarinic compounds, in particular ipratropium bromide, oxytropium bromide, tiotropium salts and CHF 4226 (Chiesi), and glycopyrrolates.

[0321] Appropriate antihistamines include cetirizine hydrochloride, acetaminophen, clemastine fumarate, promethazine, loratadine, desloratadine, diphenhydramine and fexofenadine hydrochloride, activastine, astemizole, azelastine, ebastine, epinastine, mizolastine, and terfenadine.

[0322] Other useful combinations of the compounds of the present invention with anti-inflammatory drugs include antagonists of chemokine receptors (e.g., 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), in particular CCR-5 antagonists (e.g., Schering-Plough antagonists). The antagonists are SC-351125, SCH-55700, and SCH-D, as well as Takeda's antagonists (e.g., N-[[4-[[[6,7-dihydro-2-(4-methylphenyl)-5H-benzo-cyclohepten-8-yl]carbonyl]aminophenyl]methyl]tetrahydro-N,N-dimethyl-2H-pyran-4-aminium chloride (TAK-770))).

[0323] The structures of active compounds, identified by their code number, generic name, or trade name, can be obtained from the current edition of the standard reference book "The Merck Index" or from databases (e.g., Patents International (e.g., IMS World Publications)).

[0324] The compounds of the present invention may also be used in combination with known therapeutic processes (e.g., the administration of hormones or radiation). In certain embodiments, the compounds provided are used as radiosensitizers (particularly for the treatment of tumors that show poor sensitivity to radiation therapy).

[0325] The compounds of the present invention may be administered alone or in combination with one or more other therapeutic compounds. Possible combination therapies may take the form of a certain combination, or the administration of the compounds of the present invention and one or more other therapeutic compounds alternately or independently, or a certain combination with one or more other therapeutic compounds. The compounds of the present invention may also be administered, or in addition thereto, particularly for the treatment of tumors, in combination with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention, or a combination thereof. As described above, long-term treatment is possible, as well as adjunctive therapy, in terms of other treatment strategies. Other possible treatments include treatment to maintain the patient's condition after tumor relapse, or further, for example, chemoprotective treatment in patients at risk.

[0326] These additional agents may be administered separately from individual compound-containing compounds as part of a multi-dosage regimen. Alternatively, these agents may be part of a single dosage form, mixed with the compounds of the present invention in a single composition. When administered as part of a multi-dosage regimen, these two activators may be administered simultaneously, sequentially, or within a certain time interval (usually within 5 hours of each other).

[0327] As used herein, the terms “combination,” “combined use,” and related terms refer to the simultaneous or sequential administration of multiple therapeutic agents according to the present invention. For example, the compounds of the present invention may be administered simultaneously or sequentially with another therapeutic agent, either in a separate unit dosage form or together in a single unit dosage form. Accordingly, the present invention provides a single dosage form containing the compounds of the present invention, a further therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0328] The amounts of both the compound of the present invention and the further therapeutic agent (in a composition containing the further therapeutic agent as described above), which can be combined with a carrier material to produce a single dosage form, vary depending on the host being treated and the specific dosage form. Preferably, the composition of the present invention should be formulated so that the compound of the present invention can be administered in doses of 0.01 mg / kg body weight / day to 100 mg / kg body weight / day.

[0329] In a composition containing a further therapeutic agent, the further therapeutic agent and the compound of the present invention may act synergistically. Therefore, the amount of the further therapeutic agent in such a composition is less than the amount required in monotherapy using only that therapeutic agent. In such a composition, the further therapeutic agent may be administered in doses of 0.01 μg / kg body weight / day to 1,000 μg / kg body weight / day.

[0330] The amount of further therapeutic agents present in the composition of the present invention is less than or equal to the amount typically administered in a composition containing the therapeutic agent as the sole active agent. Preferably, the amount of further therapeutic agents in the composition of the present disclosure is about 50% to 100% of the amount typically present in a composition containing the agent as the sole therapeutically active agent.

[0331] The compounds of the present invention or their pharmaceutically acceptable compositions may also be incorporated into compositions for coating implantable medical devices such as orthoses, artificial valves, grafted blood vessels, stents, and catheters. For example, vascular stents are used to overcome restenosis (narrowing of the blood vessel wall after injury). However, patients using stents or other implantable devices are at risk of clot formation or platelet activation. These unwanted effects can be prevented or mitigated by pre-coating the device with a pharmaceutically acceptable composition containing a kinase inhibitor. An implantable device coated with the compounds of the present invention is another embodiment of the present invention. [Examples]

[0332] Example As described in the following examples, in certain exemplary embodiments, the compounds are prepared according to the following general procedure. While the synthesis of the compounds of the present invention is described, it should be understood that the following general methods and other methods known to those skilled in the art may be applied to all compounds, as well as to each of the subclasses and species of these compounds as described herein. Additional compounds of the present invention were prepared in the examples by methods substantially similar to those described herein and by methods known to those skilled in the art. General procedure A (Suzuki coupling): [ka]

[0333] Synthesis of compound 1.1. Argon was passed through a stirred solution of core A (0.2 g, 0.313 mmol, 1.0 eq), phenylboronic acid (0.049 g, 0.406 mmol, 1.3 eq), and potassium carbonate (0.107 g, 0.782 mmol, 2.5 eq) in 1,4-dioxane:water (10 mL, 9:1) and purged for 15 minutes. [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (0.022 g, 0.0313 mmol, 0.1 eq) was added, and the mixture was purged for another 10 minutes. The reaction mixture was stirred at 100°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, washed with brine, dehydrated with sodium sulfate, and concentrated under reduced pressure to obtain compound 1.1. (0.140g, 75.93%). MS(ES): m / z 588.19[M+H] + . General procedure B (deprotection using trifluic acid): [ka]

[0334] Synthesis of compound 1.2. Trifluic acid (1 mL) was added at 0°C to a cooled solution of 1.1 (0.140 g, 0.238 mmol, 1.0 eq) in dichloromethane (2 mL). The reaction mixture was stirred at the same temperature for 10 minutes. After the reaction was complete, the reaction mixture was transferred to a 1N sodium hydroxide solution, and the product was extracted with dichloromethane. The organic layers were combined, dehydrated with sodium sulfate, and concentrated under reduced pressure to obtain the crude product. This was further purified by grinding with diethyl ether to obtain 1.2 (0.063 g, 98.94%), MS(ES): m / z 268.10[M+H] + . General procedure C (Amide production using acid chlorides): [ka]

[0335] Synthesis of compound 1.3. To a solution of compound 1.2 (0.070 g, 0.26 mmol, 1.0 eq) in tetrahydrofuran (2 mL), triethylamine (0.078 g, 0.78 mmol, 3.0 eq) was added at 0°C and stirred for 10 minutes, followed by the addition of cyclopropane carbonyl chloride (0.041 g, 0.39 mmol, 1.5 eq). The reaction mixture was stirred at 0°C for 30 minutes. 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 saturated sodium bicarbonate solution, followed by brine solution and water, dehydrated with sodium sulfate, and concentrated under reduced pressure to obtain the crude product. This was further purified by column chromatography using 20% ​​ethyl acetate in hexane to obtain 1.3 (0.025 g, yield: 28.46%). MS(ES): m / z 336.13[M+H] + . General procedure D (Amide formation mediated by trimethylaluminum): [ka]

[0336] Synthesis of compound I-1. To a solution of compound 1.3 (0.025 g, 0.074 mmol, 1.0 eq) and methylamine (2 M in THF, 0.11 mL, 0.22 mmol, 3.0 eq) in tetrahydrofuran (2 mL), N,N-diisopropylethylamine (0.028 g, 0.22 mmol, 3.0 eq) followed by trimethylaluminum (2 M, 0.18 mL, 0.37 mmol, 5.0 eq) was added at 0°C. The reaction mixture was stirred at 70°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, washed with brine, dehydrated with sodium sulfate, and concentrated under reduced pressure to obtain the crude product. This was further purified by column chromatography eluting with 2.5% methanol in dichloromethane to obtain I-1 (0.010 g, 40.12%). MS(ES): m / z 335.30[M+H] + . General procedure E (still coupling): [ka]

[0337] Synthesis of compound 10.6. Argon was passed through a stirred mixture of core C (0.9 g, 1.12 mmol, 1.0 eq), compound 10.5 (0.368 g, 1.45 mmol, 1.0 eq), and cesium fluoride (0.338 g, 2.24 mmol, 2.0 eq) in dimethylformamide (10 mL) and purged for 15 minutes. Copper(I) iodide (0.021 g, 1.11 mmol, 0.1 eq) and tetrakis(triphenylphosphine)palladium(O) (0.064 g, 0.056 mmol, 0.05 eq) were added, and the mixture was purged for another 10 minutes. The reaction mixture was stirred at 100 °C for 1 hour. 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 solution, dehydrated with sodium sulfate, and concentrated under reduced pressure to obtain 10.6. (0.120g, 15.57%). MS(ES): m / z 686.19[M+H] + . General procedure F (Boronate ester preparation - Pd2(dba)3 and ligand): [ka]

[0338] Synthesis of compound 7.3. To a solution of 7.2 (1.3 g, 5.48 mmol, 1.0 eq) in 1,4-dioxane (48 mL), bis(pinacolato)diborone (1.6 g, 6.57 mmol, 1.2 eq) and potassium acetate (1.0 g, 10.96 mmol, 2.0 eq) were added. The reaction mixture was degassed under an argon atmosphere for 10 minutes, then tris(dibenzylideneacetone)dipalladium(0) (0.250 g, 0.274 mmol, 0.05 eq) and 4,5-bis(diphenylphosphin)-9,9-dimethylxanthene (0.312 g, 0.54 mmol, 0.1 eq) were added, and the mixture was degassed again for 5 minutes. The reaction mixture was stirred at 110 °C for 4 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, transferred to water, and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine, dehydrated with sodium sulfate, and concentrated under reduced pressure to obtain the crude product. This was further purified by combifl flush using 3% methanol in dichloromethane as the eluate to obtain pure 7.3 (1.0 g, 64.18%). MS(ES): m / z 285.17[M+H] + General procedure G (Boronate ester preparation - Pd(dppf)Cl2): [ka]

[0339] Synthesis of compound 27.1. To a solution of 1-bromo-3-nitrobenzene (1.0 g, 4.95 mmol, 1.0 eq) in dimethyl sulfoxide (20 mL), bis(pinacolato)diborone (1.5 g, 5.94 mmol, 1.2 eq) and potassium acetate (0.970 g, 9.9 mmol, 2.0 eq) were added. The reaction mixture was degassed under an argon atmosphere for 10 minutes, then [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.358 g, 0.49 mmol, 0.1 eq) was added, and the mixture was degassed again for 5 minutes. The reaction mixture was stirred at 90°C for 4 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, transferred to water, and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine, dehydrated with sodium sulfate, and concentrated under reduced pressure to obtain the crude product. This was further purified by combifling with 3% methanol in dichloromethane as the eluate to obtain pure 27.1 (0.32 g, yield: 25.95%). MS(ES): m / z 250.12[M+H] + . General procedure H (Amide coupling using HATU): [ka]

[0340] Synthesis of compound I-24. To a solution of compound 24.9 (0.060 g, 0.13 mmol, 1.0 eq) in N,N-dimethylformamide (2 mL), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxidehexafluorophosphate (0.098 g, 0.26 mmol, 2.0 eq) was added and the mixture was stirred at room temperature for 15 minutes. Diisopropylethylamine (0.050 g, 0.39 mmol, 3.0 eq) was added, followed by methylamine (0.078 mL, 2 M in THF, 0.13 mmol, 1.2 eq). The reaction mixture was stirred at room temperature for 5 minutes. 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, dehydrated with sodium sulfate, and concentrated under reduced pressure to obtain the crude product. This was further purified by column chromatography, and the compound was eluted in 40% ethyl acetate in hexane to obtain I-24 (0.030 g, yield: 48.54%). MS(ES): m / z 448.37[M+H] + . Preparation of core A: Methyl 7-(dibenzylamino)-2-iodo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-c]pyridine-4-carboxylate. [ka]

[0341] Synthesis of compound A.2. To a solution of compound A.1 (25.0 g, 105.48 mmol, 1.0 eq) in tetrahydrofuran (800 mL), N,N-dibenzylamine (33.85 g, 316.44 mmol, 3.0 eq) and triethylamine (31.96 g, 316.44 mmol, 3.0 eq) were added. The reaction mixture was stirred at 60°C for 1 hour. 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, dehydrated with sodium sulfate, and concentrated under reduced pressure to obtain the crude product. This was further purified by column chromatography eluting with 2.5% methanol in dichloromethane to obtain A.2 (32 g, yield: 76.31%). MS(ES): m / z 399.04[M+H] + .

[0342] Synthesis of compound A.3. To a solution of compound A.2 (10.0 g, 25.12 mmol, 1.0 eq) in tetrahydrofuran (200 mL), vinylmagnesium bromide (1 M in THF, 75 mL, 75.36 mmol, 3.0 eq) was added at -78°C. The reaction mixture was stirred at -78°C for 1 hour. 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, dehydrated with sodium sulfate, and concentrated under reduced pressure to obtain the crude product. This was further purified by column chromatography eluting with 10% ethyl acetate in hexane to obtain A.3 (2.5 g, yield: 25.58%). MS(ES): m / z 393.07[M+H] + .

[0343] Synthesis of compound A.4. Carbon monoxide was passed through a stirred solution of compound A.3 (1.5 g, 3.82 mmol, 1.0 eq) in methanol (70 mL) and purged for 15 minutes. Subsequently, triethylamine (1.1 g, 11.46 mmol, 3.0 eq) and a complex of [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride and dichloromethane (0.310 g, 0.38 mmol, 0.1 eq) were added. The mixture was further purged for 10 minutes, and the reaction mixture was stirred at 100°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, washed with brine, dehydrated with sodium sulfate, and concentrated under reduced pressure to obtain A.4 (1.0 g, 73.93%). MS(ES): m / z 372.17[M+H] + .

[0344] Synthesis of compound A.5. To a suspension of sodium hydride (0.131 g, 5.38 mmol, 2.0 eq) in tetrahydrofuran (10 mL), a solution of compound A.4 (1.0 g, 2.69 mmol, 1.0 eq) in tetrahydrofuran (10 mL) (1.0 g, 2.69 mmol, 1.0 eq) was added dropwise at 0°C. The reaction mixture was stirred at 0°C for 30 minutes, and phenylsulfonyl chloride (0.710 g, 4.03 mmol, 1.5 eq) was slowly added dropwise. The reaction mixture was stirred at room temperature for 1 hour. 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, dehydrated with sodium sulfate, and concentrated under reduced pressure to obtain the crude product. This was further purified by column chromatography eluting with 15% ethyl acetate in hexane to obtain A.5 (0.800 g, yield: 58.08%). MS(ES): m / z 512.16[M+H] + .

[0345] Synthesis of Core A. To a solution of compound A.5 (0.8 g, 1.56 mmol, 1.0 eq) in tetrahydrofuran (10 mL), lithium diisopropylamide (2.0 M, 2.34 mL, 4.68 mmol, 3.0 eq) was added at -78°C. The reaction mixture was stirred at -78°C for 1 hour. Then, a solution of iodine (0.475 g, 1.87 mmol, 2.0 eq) in tetrahydrofuran (2 mL) was added to the reaction mixture, and the mixture was stirred at the same temperature for 2 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, dehydrated with sodium sulfate, and concentrated under reduced pressure to obtain the crude product. This was further purified by column chromatography eluting with 7% ethyl acetate in hexane to obtain Core A (0.620 g, yield: 63.39%). MS(ES): m / z 626.06[M+H] + . Preparation of Core B: (7-(dibenzylamino)-4-(methylcarbamoyl)-1H-pyrrolo[2,3-c]pyridin-2-yl)boronic acid. [ka]

[0346] Synthesis of compound B.1. To a solution of compound A.4 (8.0 g, 21.56 mmol, 1.0 eq) in dichloromethane (80 mL), di-tert-butyl dicarbonate (8.4 g, 38.80 mmol, 1.8 eq) and 4-dimethylaminopyridine (0.263 g, 2.15 mmol, 0.1 eq) were added and the mixture was stirred at room temperature for 4 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, washed with brine, dehydrated with sodium sulfate, and concentrated under reduced pressure to obtain the crude product. This was further purified by column chromatography, and the compound was eluted in hexane with 20% ethyl acetate to obtain pure B.1 (7.5 g, 73.85%). MS(ES): m / z 472.22[M+H] + .

[0347] Synthesis of compound B.2. To a solution of compound B.1 (7.0 g, 14.86 mmol, 1.0 eq) in tetrahydrofuran (170 mL), lithium diisopropylamide (2.0 M, 14.8 mL, 29.72 mmol, 3.0 eq) was added at -78°C. The reaction mixture was stirred at -78°C for 1 hour. Then, a solution of triisopropyl borate (5.5 g, 29.72 mmol, 2.0 eq) was added to the reaction mixture. The reaction mixture was stirred at 0°C for 2 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, dehydrated with sodium sulfate, and concentrated under reduced pressure to obtain the crude product. This was further purified by column chromatography eluting with 7% ethyl acetate in hexane to obtain B.2 (4.1 g, 66.51%). MS(ES): m / z 416.17[M+H] + .

[0348] Synthesis of compound B.3. Sodium hydroxide (0.480 g, 12 mmol, 5 eq) was added to a solution of compound B.2 (1.0 g, 2.40 mmol, 1.0 eq) in methanol (10 mL). The reaction mixture was stirred at 60°C for 6 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain a residue. Water was added to this residue, and the pH was adjusted to approximately 6-6.5 by acidification with 1N hydrochloric acid at 10°C. The product was extracted with dichloromethane. The organic layers were combined, washed with brine, dehydrated with sodium sulfate, and concentrated under reduced pressure to obtain the crude product. This was further purified by column chromatography, and the compound was eluted in 2.1% methanol in dichloromethane to obtain pure B.3 (0.650 g, 67.27%). MS(ES): m / z 402.16[M+H] + .

[0349] Synthesis of Core B. To a solution of compound B.3 (0.650 g, 1.62 mmol, 1.0 eq) in N,N-dimethylformamide (7 mL), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (1.2 g, 3.24 mmol, 2.0 eq) was added and the mixture was stirred at room temperature for 15 minutes. Diisopropylethylamine (0.8 mL, 4.86 mmol, 3.0 eq) was added, followed by methylamine (2 M in THF, 1.05 mL, 2.10 mmol, 1.3 eq). The reaction mixture was stirred at room temperature for 5 minutes. 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, dehydrated with sodium sulfate, and concentrated under reduced pressure to obtain the crude product. This was further purified by column chromatography, and the compound was eluted in 40% ethyl acetate in hexane to obtain core B (0.400 g, 59.60%). MS(ES): m / z 415.19[M+H] + . Preparation of Core C: Methyl 7-(dibenzylamino)-1-(phenylsulfonyl)-2-(tributylstannyl)-1H-pyrrolo[2,3-c]pyridine-4-carboxylate [ka]

[0350] Synthesis of Core C. To a solution of compound A.5 (3.0 g, 5.87 mmol, 1.0 eq) in tetrahydrofuran (30 mL), lithium diisopropylamide (2.0 M, 8.8 mL, 17.61 mmol, 3.0 eq) was added dropwise at -78°C. The reaction mixture was stirred at the same temperature for 30 minutes. Tributyltin chloride (1.90 mL, 7.04 mmol, 1.2 eq) was then added dropwise to the reaction mixture, and the mixture was stirred at the same temperature for 1 hour. 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, dehydrated with sodium sulfate, and concentrated under reduced pressure to obtain the crude product. This was further purified by column chromatography eluting with 7% ethyl acetate in hexane to obtain Core C (3.1 g, yield: 66.03%). MS(ES): m / z 801.26[M+H] + . (Example 1) 7-(cyclopropanecarboxamide)-N-methyl-2-phenyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-1). [ka]

[0351] Synthesis of compound 1.1. Compound 1.1 was obtained by synthesizing the compound from core A and phenylboronic acid using general procedure A. (0.140 g, 75.93%). MS(ES): m / z 588.19[M+H] + .

[0352] Synthesis of compound 1.2. Compound 1.2 was obtained by synthesizing compound 1.1 using general procedure B. (0.063g, 98.94%), MS(ES): m / z 268.10[M+H] + .

[0353] Synthesis of compound 1.3. Compound 1.3 was obtained by synthesizing compound 1.2 using general procedure C. (0.025 g, yield: 28.46%). MS(ES): m / z 336.13[M+H] + .

[0354] Synthesis of compound I-1. The compound was synthesized from compound 1.3 and methylamine using general procedure D. Further purification of the substance by column chromatography eluting with 2.5% methanol in dichloromethane yielded I-1 (0.010 g, 40.12%). MS(ES): m / z 335.30[M+H] + LCMS purity: 96.55%, HPLC purity: 97.65%, 1 H NMR (DMSO-d6, 400MHZ): 8.34 (bs, 1H), 8.29 (s, 1H), 7.89 (bs, 1H), 7.87 (bs, 1H), 7.56-7.52 (t, J=7.6Hz, 2H), 7.46-7.42 (t, J=7.6Hz, 1H), 7.36 (s, 1H), 2.85-2.84 (d, J=4.4Hz, 3H), 1.47 (s, 2H), 1.35-1.34 (d, J=7.2Hz, 3H), 0.99 (bs, 2H). (Example 2) 7-(cyclopropanecarboxamide)-N-methyl-2-(3-(1-methyl-1H-1,2,4-triazole-3-yl)phenyl)-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-2). [ka]

[0355] Synthesis of compound 2.2. Methyl iodide (2.0 g, 14.72 mmol, 1.1 eq) was added to a solution of compound 2.1 (3.0 g, 13.39 mmol, 1.0 eq) in dimethylformamide (30 mL). Sodium hydride (0.642 g, 26.78 mmol, 2 eq) was added 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 ice, stirred, and extracted with diethyl ether. The organic layers were combined, dehydrated with sodium sulfate, and concentrated under reduced pressure to obtain the crude product. This was further purified by distillation to obtain pure 2.2 (2.7 g, yield: 84.70%). MS(ES): m / z 237.99[M+H] + .

[0356] Synthesis of compound 2.3. To a solution of compound 2.2 (0.8 g, 3.36 mmol, 1.0 eq) in 1,4-dioxane (30 mL), bis(pinacolato)diborone (1.0 g, 4.03 mmol, 1.2 eq) and potassium acetate (0.659 g, 6.72 mmol, 2.0 eq) were added. The reaction mixture was degassed under an argon atmosphere for 10 minutes, then tris(dibenzylideneacetone)dipalladium(0) (0.153 g, 0.016 mmol, 0.05 eq) and 4,5-bis(diphenylphosphin)-9,9-dimethylxanthene (0.159 g, 0.033 mmol, 0.1 eq) were added, and the mixture was degassed again for 5 minutes. The reaction mixture was stirred at 100 °C for 4 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, transferred to water, and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine, dehydrated with sodium sulfate, and concentrated under reduced pressure to obtain the crude product. This was further purified by a combi-flush using 3% methanol in dichloromethane as the eluate to obtain pure 2.3 (0.7 g, 73.06%). MS(ES): m / z 286.17[M+H] + .

[0357] Synthesis of compound 2.4. Compound 2.4 was obtained by synthesizing compound 2.4 from core A and compound 2.3 using general procedure A. (0.210 g, 84.58%), MS(ES): m / z 528.22[M+H] + .

[0358] Synthesis of compound 2.5. Compound 2.5 was obtained by synthesizing compound 2.4 using general procedure B. (0.1g, 72.12%), MS(ES): m / z 349.14[M+H] + .

[0359] Synthesis of compound 2.6. Compound 2.6 was obtained by synthesizing compound 2.5 using general procedure C. (0.070 g, 58.56%), MS(ES): m / z 417.16[M+H] + .

[0360] Synthesis of compound I-2. The compound was synthesized from compound 2.6 and methylamine using general procedure D. Further purification was performed by column chromatography eluting with 2.5% methanol in dichloromethane to obtain I-2 (0.030 g, 42.96%). MS(ES): m / z 416.38[M+H] + LCMS purity: 100%, HPLC purity: 99.87%, 1 H NMR (DMSO-d6, 400MHZ): 8.61 (bs, 1H), 8.46 (bs, 1H), 8.37-8.36 (d, J=4.4Hz, 1H), 8.33 (s, 1H), 8.07-8.05 (d, J=8Hz, 1H), 7.91-7.89 (d, J=7.6Hz, 1H), 7.67-7.63 (t, J=8Hz, 1H), 7.42 (s, 1H), 3.98 (s, 4H), 3.58 (s, 1H), 2.87-2.86 (d, J=4.4Hz, 4H), 1.01 (bs, 2H), 0.96-0.94 (d, J=7.6Hz, 2H). (Example 3) 7-(cyclopropanecarboxamide)-N-(methyl-d3)-2-phenyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-3). [ka]

[0361] Synthesis of compound I-3. Compound 1.3 (0.050 g, 0.14 mmol, 1.0 eq) and methyl-d3-amine hydrochloride (0.029 g, 0.42 mmol, 3.0 eq) were dissolved in tetrahydrofuran (2 mL) at 0 °C. N,N-diisopropylethylamine (0.054 g, 0.42 mmol, 3.0 eq) followed by trimethylaluminum (2 M, 0.35 mL, 0.7 mmol, 5.0 eq) were added. The reaction mixture was stirred at 70 °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, washed with brine solution, dehydrated with sodium sulfate, and concentrated under reduced pressure to obtain the crude substance. The substance was further purified by column chromatography eluting with 2.5% methanol in dichloromethane to obtain I-3 (0.027 g, 53.67%). MS(ES):338.38[M+H] + LCMS purity: 100%, HPLC purity: 99.52%, 1 H NMR (DMSO-d6, 400MHZ): 11.53 (bs, 1H), 11.10 (bs, 1H), 7.94-7.93 (d, J=5.6Hz, 1H), 7.83 (s, 1H), 7.50-7.49 (d, J=4.4Hz, 4H), 7.41-7.38 (m, 1H), 7.34-7.33 (d, J=5.6Hz, 1H), 2.20 (bs, 1H), 1.92 (s, 2H), 0.97 (bs, 1H), 0.94-0.92 (m, 1H). (Example 4) 7-(cyclopropanecarboxamide)-2-(2-(1,1-dioxideisothiazolidine-2-yl)phenyl)-N-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-4). [ka]

[0362] Synthesis of compound 4.2. Compound 4.2 was synthesized from core A and compound 4.1 using general procedure A to obtain 4.2. (0.160 g, yield: 73.66%), MS(ES): m / z 603.20[M+H] +.

[0363] Synthesis of compound 4.4. Compound 4.3 (0.197 g, 1.11 mmol, 1.2 eq) was added to a solution of 4.2 (0.430 g, 0.93 mmol, 1.0 eq) in pyridine (4 mL) at 0°C. The reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain the crude product. This was further purified by column chromatography eluting with 25% ethyl acetate in hexane to obtain 4.4 (0.320 g, yield: 46.21%). MS(ES): m / z 744.17[M+H] + .

[0364] Synthesis of compound 4.5. Potassium carbonate (0.178 g, 1.29 mmol, 3.0 eq) was added at room temperature to a solution of 4.4 (0.320 g, 0.43 mmol, 1.0 eq) in dimethylformamide (3 mL). The reaction mixture was degassed for 10 minutes and heated at 50°C for 8 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, dehydrated with sodium sulfate, and concentrated under reduced pressure to obtain the crude product. This was further purified by column chromatography eluting with 20% ethyl acetate in hexane to obtain 4.5 (0.260 g, yield: 85.44%). MS(ES): m / z 707.20[M+H] + .

[0365] Synthesis of compound 4.6. Compound 4.6 was obtained by synthesizing compound 4.5 using general procedure B. (0.1g, yield: 70.35%), MS(ES): m / z 387.11[M+H] + .

[0366] Synthesis of compound 4.7. Compound 4.7 was obtained by synthesizing compound 4.6 using general procedure C. (0.064 g, 54.41%), MS(ES): m / z 455.13[M+H] + .

[0367] Synthesis of compound I-4. The compound was synthesized from compound 4.7 and methylamine using general procedure D. Further purification of the substance by column chromatography eluting with 2.5% methanol in dichloromethane yielded I-4 (0.025 g, 39.15%). MS(ES): 454.46[M+H] + LCMS purity: 100%, HPLC purity: 98.36%, 1 H NMR (DMSO-d6, 400MHZ): 11.77 (s, 1H), 11.29 (s, 1H), 8.39-8.36 (m, 3H), 7.98-7.96 (m, 1H), 7.68-7.66 (m, 1H), 7.55-7.52 (m, 1H), 7.40 (s, 1H), 3.68-3.64 (t, J=6.4Hz, 2H), 3.55-3.51 (d, J=7.6Hz, 2H), 3.41-3.36 (m, 1H), 2.85-2.84 (d, J=4Hz, 3H), 2.22 (bs, 1H), 1.11-1.07 (t, J=7.2Hz, 2H), 0.95-0.93 (m, 3H). (Example 5) 7-(cyclopropanecarboxamide)-N-methyl-2-(2-(1-(methylsulfonyl)cyclopropyl)phenyl)-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-5). [ka]

[0368] Synthesis of compound 5.2. Sodium methanesulfinate (5.1 g, 50.91 mmol, 1.1 eq) was added to a solution of compound 5.1 (10.0 g, 46.29 mmol, 1.0 eq) in dimethylformamide (100 mL). The reaction mixture was stirred at 60°C for 1 hour. After the reaction was complete, the reaction mixture was transferred to water to obtain a precipitate, which was filtered and dried to obtain compound 5.2 (8.0 g, yield: 80.30%), MS(ES): m / z 216.03[M+H] + .

[0369] Synthesis of compound 5.3. To a solution of compound 5.2 (8.0 g, 37.20 mmol, 1.0 eq) in toluene (80 mL), 1,2-dibromoethane (10.4 g, 55.8 mmol, 1.5 eq) and tetra-n-butylammonium bromide (1.79 g, 5.58 mmol, 0.15 eq) were added. The reaction mixture was stirred, and aqueous sodium hydroxide solution (10 N) (4.46 g, 111.6 mmol, 3.0 eq) was added. The reaction mixture was stirred at 60°C for 16 hours. After the reaction was complete, the reaction mixture was transferred to water to obtain a precipitate, which was filtered, washed with hexane, and dried to obtain compound 5.3 (2.1 g, yield: 23.42%), MS(ES): m / z 242.04[M+H] + .

[0370] Synthesis of compound 5.4. To a solution of compound 5.3 (2.1 g, 8.71 mmol, 1.0 eq) in methanol (40 ml), 10% palladium-carbon (1.0 g) was added. The reaction mixture was purged with hydrogen at room temperature for 4 hours. After the reaction was complete, the reaction mixture was filtered through a Celite bed and washed with methanol. The filtrate was concentrated under reduced pressure to obtain the crude product. This was further purified by grinding with n-pentane to obtain pure 5.4 (1.6 g, yield: 87.00%). MS(ES): m / z 212.07[M+H] + .

[0371] Synthesis of compound 5.5. Hydrobromic acid (48% aqueous solution, 3.2 mL) was added dropwise to compound 5.4 (1.6 g, 7.58 mmol, 1.0 eq) at 0°C. Then, a solution of sodium nitrite (1.0 g, 15.16 mmol, 2.0 eq) in 5 mL of water, followed by acetone (13 mL), was added at 0°C. The reaction mixture was stirred at 0°C for 5 minutes, and copper(I) bromide (2.1 g, 15.16 mmol, 2.0 eq) was added. The reaction mixture was stirred at 0°C for 1 hour. 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, dehydrated with sodium sulfate, and concentrated under reduced pressure to obtain the crude product. This was further purified by column chromatography, and the compound was eluted in hexane with 7% ethyl acetate to obtain 5.5 (1.3 g, yield: 62.39%). MS(ES): m / z 274.97[M+H] + .

[0372] Synthesis of compound 5.6. To a solution of compound 5.5 (0.5 g, 1.82 mmol, 1.0 eq) in dry tetrahydrofuran (15 mL), n-butyllithium (1.6 M in hexane, 1.25 mL, 2.00 mmol, 1.1 eq) was added dropwise at -78°C. The reaction mixture was then stirred at the same temperature for 15 minutes. Subsequently, tributyltin chloride (1.14 g, 3.64 mmol, 2.0 eq) was added at -78°C. The reaction mixture was stirred at -78°C for 2 hours. After the reaction was complete, 1N hydrochloric acid was added to the reaction mixture, the reaction mixture was brought to room temperature, and extracted with ethyl acetate. The organic layers were combined, washed with brine solution, dehydrated with sodium sulfate, and concentrated under reduced pressure to obtain the crude product. This was further purified by column chromatography, and the compound was eluted in 4% ethyl acetate in hexane to obtain 5.6 (0.1 g, yield: 11.34%). MS(ES): m / z 486.16[M+H] + .

[0373] Synthesis of compound 5.7. Degassed core A (0.8 g, 1.25 mmol, 1.0 eq) and compound 5.6 (0.668 g, 1.37 mmol, 1.1 eq) were dissolved in toluene (40 mL). Tetrakis(triphenylphosphine)palladium(0) (0.144 g, 0.12 mmol, 0.1 eq) was added, and the reaction mixture was heated at 100 °C for 1 hour under an N2 atmosphere. The reaction mixture was cooled to room temperature and purified by column chromatography using 5.0% ethyl acetate in hexane as the eluate to obtain pure 5.7 (0.320 g, yield: 51.85%). MS(ES): m / z 566.21[M+H] + .

[0374] Synthesis of compound 5.8. Compound 5.8 was obtained by synthesizing compound 5.8 from compound 5.7 using general procedure B. (0.1g, 57.23%), MS(ES): m / z 386.11[M+H] + .

[0375] Synthesis of compound 5.9. Compound 5.9 was obtained by synthesizing compound 5.8 using general procedure C. (0.085g, 72.24%), MS(ES): m / z 454.14[M+H] + .

[0376] Synthesis of compound I-5. The compound was synthesized from compound 5.9 and methylamine using general procedure D. Further purification of the substance by column chromatography eluting with 2.5% methanol in dichloromethane yielded I-5 (0.027 g, 31.83%). MS(ES): m / z 453.30[M+H] + LCMS purity: 100%, HPLC purity: 96.44%, 1 H NMR (DMSO-d6, 400MHZ): 11.05 (s, 1H), 10.90 (s, 1H), 8.35-8.33 (m, 2H), 7.84-7.82 (m, 1H), 7.66-7.64 (m, 1H), 7.59-7.56 (m, 2H), 7.06 (bs, 1H), 3.14 (s, 3H), 2.83-2.82 (d, J=4.4Hz, 3H), 2.04 (bs, 1H), 1.60 (s, 2H), 0.96 (bs, 3H), 0.83-0.81 (m, 3H). (Example 6) 7-(cyclopropanecarboxamide)-N-(methyl-d3)-2-(3-(1-methyl-1H-1,2,4-triazole-3-yl)phenyl)-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-6). [ka]

[0377] Synthesis of compound I-6. The compound was synthesized from compound 2.6 and methyl-d3-amine using general procedure D. Further purification of the substance by column chromatography eluting with 2.5% methanol in dichloromethane yielded I-6 (0.025 g, 31.10%). MS(ES): m / z 419.45[M+H] + LCMS purity: 100%, HPLC purity: 99.74%, 1 H NMR (DMSO-d6, 400MHz): 11.92 (s, 1H), 11.15 (s, 1H), 8.62 (s, 1H), 8.46 (s, 1H), 8.35 (s, 1H), 8.32 (s, 1H), 8.06-8.05 (d, J=7.6Hz, 1H), 7.92-7.90 (d, J=7.6Hz, 1H), 7.67-7.63 (t, J=7.6Hz, 1H), 7.41 (s, 1H), 3.98 (s, 3H), 3.44-3.41 (m, 1H), 1.01-0.94 (m, 4H). (Example 7) 7-(cyclopropanecarboxamide)-N-methyl-2-(3-(3-methyl-1H-pyrazole-1-yl)phenyl)-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-7). [ka]

[0378] Synthesis of compound 7.2. Compound 7.1 (3.0 g, 16.04 mmol, 1.0 eq) and buta-3-in-2-one (1.0 g, 16.04 mmol, 1.0 eq) were dissolved in methanol (30 mL), to which hydrochloric acid (4.0 M in water, 0.4 mL, 16.04 mmol, 1.0 eq) was added. The reaction mixture was heated in a microwave at 120°C for 15 minutes. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain a residue. Water was added to this residue, and it was extracted with dichloromethane. The organic layers were combined, washed with brine, dehydrated with sodium sulfate, and concentrated under reduced pressure to obtain the crude product. This was further purified by combiflush using 7% ethyl acetate in hexane as the eluate to obtain pure 7.2 (1.3 g, yield: 34.18%). MS(ES): m / z 237.99[M+H] + .

[0379] Synthesis of compound 7.3. Compound 7.3 was obtained by synthesizing compound 7.2 using general procedure F. (1.0 g, 64.18%). MS(ES): m / z 285.17[M+H] + .

[0380] Synthesis of compound 7.4. Compound 7.4 was synthesized from core A and compound 7.3 using general procedure A. (0.160 g, yield: 76.37%), MS(ES): m / z 668.23[M+H] + .

[0381] Synthesis of compound 7.5. Compound 7.5 was obtained by synthesizing compound 7.4 using general procedure B. (0.070 g, yield: 84.10%), MS(ES): m / z 348.14[M+H] + .

[0382] Synthesis of compound 7.6. Compound 7.6 was obtained by synthesizing compound 7.5 using general procedure C. (0.050 g, 59.72%), MS(ES): m / z 416.17[M+H] + .

[0383] Synthesis of compound I-7. The compound was synthesized from compound 7.6 and methylamine using general procedure D. Further purification of the substance by column chromatography eluting with 2.5% methanol in dichloromethane yielded I-7 (0.020 g, 40.09%). MS(ES): m / z 415.27[M+H] + LCMS purity: 96.18%, HPLC purity: 95.44%, 1 H NMR (DMSO-d6, 400MHz): 11.79 (s, 1H), 11.11 (s, 1H), 8.56 (s, 1H), 8.39 (bs, 1H), 8.31 (s, 2H), 7.87-7.85 (d, J=8Hz, 1H), 7.71-7.70 (d, J=7.2Hz, 1H), 7.65-7.61 (t, J=8Hz, 1H), 7.48 (bs, 1H), 6.40 (s, 1H), 2.86-2.85 (d, J=4.4Hz, 3H), 2.32 (s, 3H), 1.23 (bs, 1H), 1.00-0.93 (m, 4H). (Example 8) 2-(3-(2H-1,2,3-triazole-2-yl)phenyl)-7-(cyclopropanecarboxamide)-N-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-8). [ka]

[0384] Synthesis of compound 8.2. Compound 8.1 (0.701 g, 10.16 mmol, 1.2 eq), copper(I) iodide (0.161 g, 0.84 mmol, 0.1 eq), tris(acetylacetonato)ferric(III) (0.896 g, 2.54 mmol, 0.3 eq), and cesium carbonate (5.5 g, 16.94 mmol, 2.0 eq) were added to a solution of 1,3-dibromobenzene (2.0 g, 8.47 mmol, 1.0 eq) in dimethylformamide (20 mL). The reaction mixture was heated at 120 °C for 16 hours under an N2 atmosphere. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain the crude product. This was further purified by combiflapping using 15% ethyl acetate in hexane as the eluate to obtain pure 8.2 (0.450 g, yield: 23.69%). MS(ES): m / z 224.97[M+H] + .

[0385] Synthesis of compound 8.3. Argon was passed through a stirred solution of 8.2 (0.450 g, 2.00 mmol, 1.0 eq) and potassium carbonate (0.828 g, 6.00 mmol, 3.0 eq) in 1,4-dioxane (16 mL) and purged for 15 minutes. Then bis(pinacolato)diborone (0.609 g, 2.4 mmol, 1.2 eq) and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (0.146 g, 0.2 mmol, 0.1 eq) were added, and the mixture was purged for another 10 minutes. 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, washed with brine, dehydrated with sodium sulfate, and concentrated under reduced pressure to obtain 8.3 (0.350 g, 64.28%). MS(ES): m / z 272.15[M+H] + .

[0386] Synthesis of compound 8.4. Compound 8.4 was synthesized from core A and compound 8.3 using general procedure A. (0.220 g, yield: 71.40%), MS(ES): m / z 655.21[M+H] + .

[0387] Synthesis of compound 8.5. Compound 8.5 was obtained by synthesizing compound 8.4 using general procedure B. (0.105 g, yield: 93.47%), MS(ES): m / z 335.12[M+H] + .

[0388] Synthesis of compound 8.6. Compound 8.6 was obtained by synthesizing compound 8.5 using general procedure C. (0.1g, yield: 79.13%), MS(ES): m / z 403.15[M+H] + .

[0389] Synthesis of compound I-8. The compound was synthesized from compound 8.6 and methylamine using general procedure D. Further purification of the substance by column chromatography eluting with 2.5% methanol in dichloromethane yielded I-8 (0.025 g, 25.06%). MS(ES): m / z 402.55[M+H] + LCMS purity: 100%, HPLC purity: 98.21%, 1 H NMR (DMSO-d6, 400MHz): 11.82 (s, 1H), 11.12 (s, 1H), 9.03 (s, 1H), 8.45 (s, 1H), 8.39-8.38 (d, J=4.4Hz, 1H), 8.31 (s, 1H), 8.05 (s, 1H), 7.98-7.94 (m, 2H), 7.79-7.75 (t, J=7.6Hz, 1H), 7.56 (s, 1H), 2.86-2.85 (d, J=4.4Hz, 3H), 2.24 (bs, 1H), 1.00 (bs, 2H), 0.95-0.93 (m, 2H). (Example 9) 7-(cyclopropanecarboxamide)-2-(4-(4,4-dimethyl-4,5-dihydroxazole-2-yl)-2-methoxyphenyl)-N-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-9). [ka]

[0390] Synthesis of compound 9.2. Sodium hydroxide (2.4 g, 61.2 mmol, 5.0 eq) was added to a solution of 9.1 (3.0 g, 12.24 mmol, 1.0 eq) in methanol (25 mL). The reaction mixture was stirred at 60°C for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain a residue. Water was added to this residue, and the pH was adjusted to approximately 6 by acidification with 1N hydrochloric acid at 10°C. The product was extracted with dichloromethane. The organic layers were combined, washed with brine, dehydrated with sodium sulfate, and concentrated under reduced pressure to obtain the crude product. This was further purified by column chromatography, and the compound was eluted in 2.1% methanol in dichloromethane to obtain pure 9.2 (2.4 g, 84.86%). MS(ES): m / z 231.96[M+H] + .

[0391] Synthesis of compound 9.3. To a solution of compound 9.2 (2.4 g, 10.38 mmol, 1.0 eq) in dichloromethane (25 mL), the catalyst dimethylformamide (1 mL) was added, and oxalyl chloride (1.3 mL, 15.57 mmol, 1.5 eq) was added dropwise at 0°C. The reaction mixture was stirred at 0°C for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain the crude product. To this, tetrahydrofuran (10 mL), followed by triethylamine (3.1 g, 31.14 mmol, 3.0 eq) and 2-amino-2-methyl-1-propanol (1.8 g, 20.76 mmol, 2.0 eq) were added at 0°C. The reaction mixture was stirred at room temperature for 2 hours, transferred to ice water, and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine, dehydrated with sodium sulfate, and concentrated under reduced pressure to obtain the crude product. This was further purified by column chromatography using elution with 2.5% methanol in dichloromethane to obtain compound 9.3 (1.6 g, yield: 50.97%). MS(ES): m / z 302.03[M+H] + .

[0392] Synthesis of compound 9.4. To a solution of 9.3 (1.6 g, 5.29 mmol, 1.0 eq) in tetrahydrofuran (20 mL), Burgess's reagent (2.5 g, 10.58 mmol, 2.0 eq) was added at 0°C. The reaction mixture was stirred at 0°C for 4 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, washed with brine, dehydrated with sodium sulfate, and concentrated under reduced pressure to obtain the crude product. This was further purified by combiflapping using 3% methanol in dichloromethane as the eluent to obtain pure 9.4 (0.7 g, 46.52%). MS(ES): m / z 285.02[M+H] + .

[0393] Synthesis of compound 9.5. Compound 9.5 was obtained by synthesizing compound 9.4 using general procedure F. (0.5g, 61.28%). MS(ES): m / z 332.20[M+H] + .

[0394] Synthesis of compound 9.6. Compound 9.6 was obtained by synthesizing the compound from core A and compound 9.5 using general procedure A. (0.140 g, yield: 49.94%), MS(ES): m / z 715.25[M+H] + .

[0395] Synthesis of compound 9.7. Compound 9.7 was obtained by synthesizing compound 9.6 using general procedure B. (0.075 g, yield: 97.09%), MS(ES): m / z 395.17[M+H] + .

[0396] Synthesis of compound 9.8. Compound 9.8 was obtained by synthesizing compound 9.8 from compound 9.7 using general procedure C. (0.070 g, 74.62%), MS(ES): m / z 463.19[M+H] + .

[0397] Synthesis of compound I-9. The compound was synthesized from compound 9.8 and methylamine using general procedure D. Further purification of the substance by column chromatography eluting with 2.5% methanol in dichloromethane yielded I-9 (0.028 g, 40.09%). MS(ES): m / z 462.45[M+H] + LCMS purity: 95.00%, HPLC purity: 95.13%, 1 H NMR (DMSO-d6, 400MHz): 12.59 (s, 1H), 11.35 (s, 1H), 8.34 (bs, 1H), 8.29 (s, 1H), 8.12-8.10 (d, J=8.4Hz, 1H), 7.59-7.58 (d, J=6.4Hz, 2H), 7.53 (s, 1H), 4.17 (s, 2H), 4.07 (s, 2H), 2.87-2.85 (d, J=4.4Hz, 1H), 2.52 (bs, 3H), 2.26 (bs, 1H), 1.33 (s, 6H), 1.02 (bs, 2H), 0.99-0.97 (d, J=7.6Hz, 2H). (Example 10) 7-(cyclopropanecarboxamide)-N-methyl-2-(4-(2-methylthiazole-4-yl)pyridine-2-yl)-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-10). [ka]

[0398] Synthesis of compound 10.2. To a solution of compound 10.1 (2.0 g, 9.90 mmol, 1.0 eq) in dichloromethane (40 mL), N,O-dimethylhydroxylamine hydrochloride (1.4 g, 14.85 mmol, 1.5 eq), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1.6 g, 10.89 mmol, 1.1 eq), hydroxybenzotriazole (1.4 g, 10.89 mmol, 1.1 eq), and triethylamine (3.9 g, 39.6 mmol, 4.0 eq) were added 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 water and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine solution, dehydrated with sodium sulfate, and concentrated under reduced pressure to obtain the crude product. This was further purified by column chromatography, and the compound was eluted in 40% ethyl acetate in hexane to obtain 10.2. (1.8g, 74.18%). MS(ES): m / z 244.9[M+H] + .

[0399] Synthesis of compound 10.3. To a solution of compound 10.2 (1.8 g, 7.37 mmol, 1.0 eq) in tetrahydrofuran (35 mL), methylmagnesium bromide solution (3 M in hexane, 3.68 mL, 11.05 mmol, 1.5 eq) was added dropwise at 0°C. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, 1N hydrochloric acid was added to the reaction mixture and extracted with ethyl acetate. The organic layers were combined, washed with brine, dehydrated with sodium sulfate, and concentrated under reduced pressure to obtain the crude product. This was further purified by column chromatography, and the compound was eluted in 15% ethyl acetate in hexane to obtain 10.3 (1.35 g, 91.89%). MS(ES): m / z 199.97[M+H] + .

[0400] Synthesis of compound 10.4. Compound 10.3 (1.35 g, 6.75 mmol, 1.0 eq) was to be added dropwise with 10 mL of 30% hydrobromide solution in acetic acid, followed by 0.34 mL of bromine (6.75 mmol, 1.0 eq) at 15°C. The reaction mixture was stirred at 60°C for 2 hours. After the reaction was complete, the reaction mixture was cooled to 20°C, diluted with diethyl ether, and stirred for 30 minutes. The precipitated product was filtered, washed with diethyl ether, and vacuum-dried to obtain pure 10.4 (1.1 g, 58.43%). MS(ES): m / z 278.87[M+H] + .

[0401] Synthesis of compound 10.5. Ethanthioamide (0.296 g, 3.95 mmol, 1.0 eq) was added to a solution of compound 10.4 (1.1 g, 3.95 mmol, 1.0 eq) in ethanol (30 mL). The reaction mixture was refluxed for 1 hour. After the reaction was complete, the reaction mixture was cooled to obtain a precipitate, which was filtered and dried to obtain compound 10.5 (0.650 g, 64.60%). MS(ES): m / z 254.95[M+H] + .

[0402] Synthesis of compound 10.6. Compound 10.6 was obtained by synthesizing the compound from core C and compound 10.5 using general procedure E. (0.120 g, 15.57%). MS(ES): m / z 686.19[M+H] + .

[0403] Synthesis of compound 10.7. Compound 10.7 was obtained by synthesizing compound 10.6 using general procedure B. (0.063g, 98.53%), MS(ES): m / z 366.10[M+H] + .

[0404] Synthesis of compound 10.8. Compound 10.8 was obtained by synthesizing compound 10.8 from compound 10.7 using general procedure C. (0.060 g, 72.25%), MS(ES): m / z 434.12[M+H] + .

[0405] Synthesis of compound I-10. The compound was synthesized from compound 10.8 and methylamine using general procedure D. Further purification of the substance by column chromatography eluting with 2.5% methanol in dichloromethane yielded I-10 (0.016 g, 26.73%). MS(ES): m / z 433.32[M+H] + LCMS purity: 100%, HPLC purity: 97.41%, 1 H NMR (DMSO-d6, 400MHz): 12.14 (s, 1H), 11.33 (s, 1H), 8.76-8.74 (d, J=5.2Hz, 1H), 8.63 (bs, 1H), 8.60 (s, 1H), 8.44-8.43 (d, J=4.4Hz, 1H), 8.31 (s, 1H), 7.94-7.93 (d, J=5.2Hz, 1H), 7.77-7.77 (d, J=2Hz, 1H), 2.88-2.87 (d, J=4.4Hz, 3H), 2.80 (s, 3H), 1.35 (bs, 1H), 1.24 (m, 4H). (Example 11) 7-(cyclopropanecarboxamide)-2-(3-(4,4-dimethyl-4,5-dihydrothiazole-2-yl)phenyl)-N-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-11). [ka]

[0406] Synthesis of compound 11.1. To a solution of 3-bromobenzoic acid (3.0 g, 14.92 mmol, 1.0 eq) in dichloromethane (30 mL), the catalyst dimethylformamide (1 mL) and oxalyl chloride (1.9 mL, 22.38 mmol, 1.5 eq) were added dropwise at 0°C. The reaction mixture was stirred at 0°C for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain the crude product. To this, tetrahydrofuran (15 mL), followed by triethylamine (4.5 g, 44.76 mmol, 3.0 eq) and 2-amino-2-methylpropan-1-ol (2.6 g, 29.84 mmol, 2.0 eq) were added at 0°C. The reaction mixture was stirred at room temperature for 2 hours, then transferred to ice-cold water, and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine, dehydrated with sodium sulfate, and concentrated under reduced pressure to obtain the crude product. This was further purified by column chromatography using elution with 2.5% methanol in dichloromethane to obtain 11.1 (2.8g, yield: 68.94%). MS(ES): m / z 273.02[M+H] + .

[0407] Synthesis of compound 11.2. To a solution of 11.1 (2.8 g, 10.29 mmol, 1.0 eq) in toluene (40 mL), phosphorus pentasulfide (1.4 g, 5.14 mmol, 0.5 eq) was added. The reaction mixture was stirred at 120°C for 3 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, washed with brine, dehydrated with sodium sulfate, and concentrated under reduced pressure to obtain the crude product. This was further purified by column chromatography, and the compound was eluted in 3% methanol in dichloromethane to obtain 11.2 (1.0 g, 35.97%). MS(ES): m / z 270.99[M+H] + .

[0408] Synthesis of compound 11.3. Compound 11.3 was obtained by synthesizing compound 11.2 using general procedure F. (0.650 g, 55.36%). MS(ES): m / z 318.17[M+H] + .

[0409] Synthesis of compound 11.4. Compound 11.4 was obtained by synthesizing the compound from core A and compound 11.3 using general procedure A. (0.190 g, yield: 44.39%), MS(ES): m / z 546.22[M+H] + .

[0410] Synthesis of compound 11.5. Compound 11.5 was obtained by synthesizing compound 11.4 using general procedure B. (0.090 g, yield: 67.94%), MS(ES): m / z 381.13[M+H] + .

[0411] Synthesis of compound 11.6. Compound 11.6 was obtained by synthesizing compound 11.5 using general procedure C. (0.070 g, yield: 65.97%), MS(ES): m / z 449.16[M+H] + .

[0412] Synthesis of compound I-11. The compound was synthesized from compound 11.6 and methylamine using general procedure D. Further purification of the substance by column chromatography eluting with 2.5% methanol in dichloromethane yielded I-11 (0.025 g, 35.79%). MS(ES): m / z 448.27[M+H] + LCMS purity: 99.55%, HPLC purity: 95.11%, 1 H NMR (DMSO-d6, 400MHz): 11.92 (s, 1H), 11.14 (s, 1H), 8.40 (bs, 1H), 8.32 (s, 1H), 8.21 (s, 1H), 8.03-8.01 (d, J=8Hz, 1H), 7.79-7.77 (d, J=7.6Hz, 1H), 7.67-7.64 (t, J=7.6Hz, 1H), 7.40 (s, 1H), 2.87-2.85 (d, J=4.4Hz, 3H), 2.51 (s, 2H), 2.27 (bs, 1H), 1.44 (s, 6H), 0.99 (bs, 2H), 0.95-0.93 (d, J=7.6Hz, 2H). (Example 12) 7-(cyclopropanecarboxamide)-2-(3-(1-methyl-1H-1,2,4-triazole-3-yl)phenyl)-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-12). [ka]

[0413] Synthesis of compound 12.1. Sodium hydroxide (0.056 g, 1.4 mmol, 5.0 eq) was added to a solution of compound 2.4 (0.190 g, 0.28 mmol, 1.0 eq) in methanol (3 mL). The reaction mixture was stirred at 70°C for 24 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain a residue. Water was added to this residue, and the pH was adjusted to approximately 6 by acidification with 1N hydrochloric acid at 10°C. The product was extracted with dichloromethane. The organic layers were combined, washed with brine, dehydrated with sodium sulfate, and concentrated under reduced pressure to obtain the crude product. This was further purified by column chromatography, and the compound was eluted in 2.1% methanol in dichloromethane to obtain pure 12.1 (0.110 g, 59.14%). MS(ES): m / z 655.21[M+H] + .

[0414] Synthesis of compound 12.2. To a solution of compound 12.1 (0.080 g, 0.12 mmol, 1.0 eq) in N,N-dimethylformamide (2 mL), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (0.091 g, 0.24 mmol, 2.0 eq) was added and the mixture was stirred at room temperature for 15 minutes. Diisopropylethylamine (0.046 g, 0.36 mmol, 3.0 eq) was added, followed by the addition of 30% aqueous ammonia (0.033 mL, 0.12 mmol, 1.3 eq). The reaction mixture was stirred at room temperature for 5 minutes. 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, dehydrated with sodium sulfate, and concentrated under reduced pressure to obtain the crude product. This was further purified by column chromatography, and the compound was eluted in 40% ethyl acetate in hexane to obtain compound 12.2 (0.070 g, 87.63%). MS(ES): m / z 654.22[M+H] + .

[0415] Synthesis of compound 12.3. Compound 12.3 was obtained by synthesizing compound 12.2 using general procedure B. (0.035g, 98.06%), MS(ES): m / z 334.14[M+H] + .

[0416] Synthesis of compound I-12. Using general procedure C, compound I-12 (0.030 g, 62.28%) was synthesized from compound 12.3. MS(ES): m / z 402.12[M+H] + LCMS purity: 99.30%, HPLC purity: 97.73%, 1 1H NMR (DMSO-d6, 400MHz): 11.90 (s, 1H), 11.13 (s, 1H), 8.61 (s, 1H), 8.46 (s, 1H), 8.41 (s, 1H), 8.07-8.05 (d, J=7.6Hz, 1H), 7.93-7.91 (d, J=7.2Hz, 3H), 7.67-7.63 (t, J=7.6Hz, 2H), 7.47 (bs, 2H), 7.42 (s, 1H), 2.29 (bs, 1H), 1.01 (bs, 2H), 0.96-0.95 (d, J=7.6Hz, 2H). (Example 13) 7-(cyclopropanecarboxamide)-N-methyl-2-(4-(1-methyl-1H-1,2,4-triazole-3-yl)pyridine-2-yl)-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-13). [ka]

[0417] Synthesis of compound 13.2. To a solution of compound 13.1 (2.8 g, 12.44 mmol, 1.0 eq) in dimethylformamide (30 mL), sodium hydride (0.597 g, 24.88 mmol, 2 eq) was added at 0°C and the mixture was stirred for 20 minutes. Methyl iodide (1.9 g, 13.68 mmol, 1.1 eq) was added, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was transferred to ice, stirred, and extracted with diethyl ether. The organic layers were combined, dehydrated with sodium sulfate, and concentrated under reduced pressure to obtain the crude product. This was further purified by distillation to obtain pure 13.2 (1.0 g, yield: 33.62%). MS(ES): m / z 238.99[M+H] + .

[0418] Synthesis of compound 13.3. Compound 13.3 was obtained by synthesizing the compound from core C and compound 13.2 using general procedure E. (0.130 g, 15.54%). MS(ES): m / z 670.22[M+H] + .

[0419] Synthesis of compound 13.4. Compound 13.4 was obtained by synthesizing compound 13.3 using general procedure B. (0.067g, yield: 98.81%), MS(ES): m / z 350.13[M+H] + .

[0420] Synthesis of compound 13.5. Compound 13.5 was obtained by synthesizing compound 13.4 using general procedure C. (0.045g, 50.22%), MS(ES): m / z 418.16[M+H] + .

[0421] Synthesis of compound I-13. The compound was synthesized from compound 13.5 and methylamine using general procedure D. Further purification of the substance by column chromatography eluting with 2.5% methanol in dichloromethane yielded I-13 (0.027 g, 60.14%). MS(ES): m / z 417.47[M+H] + LCMS purity: 98.74%, HPLC purity: 95.00%, 1 H NMR (DMSO-d6, 400MHz): 12.21 (s, 1H), 11.34 (s, 1H), 8.81 (bs, 1H), 8.54 (s, 1H), 8.38 (bs, 1H), 7.94 (bs, 1H), 7.69 (bs, 1H), 7.08 (bs, 1H), 6.84 (bs, 1H), 4.02 (s, 3H), 2.88 (s, 3H), 1.56 (bs, 1H), 1.01-0.97 (m, 4H). (Example 14) 7-(cyclopropanecarboxamide)-N-methyl-2-(4-(thiazole-2-yl)pyridine-2-yl)-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-14). [ka]

[0422] Synthesis of compound 14.2. Argon was passed through a stirred solution of 2-bromo-4-iodopyridine (3.0 g, 10.60 mmol, 1.0 eq), compound 14.1 (5.1 g, 13.78 mmol, 1.3 eq), and copper(I) iodide (0.201 g, 1.06 mmol, 0.1 eq) in 1,4-dioxane (50 mL) and purged for 15 minutes. Bis(triphenylphosphine)palladium(II) dichloride (0.743 g, 1.06 mmol, 0.1 eq) was added, and the mixture was purged for another 10 minutes. The reaction mixture was stirred at 110 °C for 1 hour. 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, dehydrated with sodium sulfate, and concentrated under reduced pressure to obtain compound 14.2 (0.7 g, 27.47%). MS(ES): m / z 241.93[M+H] + .

[0423] Synthesis of compound 14.3. Compound 14.3 was obtained by synthesizing the compound from core C and compound 14.2 using general procedure E. (0.130 g, 15.49%). MS(ES): m / z 672.17[M+H] + .

[0424] Synthesis of compound 14.4. Compound 14.4 was obtained by synthesizing compound 14.3 using general procedure B. (0.067g, yield: 98.53%), MS(ES): m / z 352.08[M+H] + .

[0425] Synthesis of compound 14.5. Compound 14.5 was obtained by synthesizing compound 14.4 using general procedure C. (0.058 g, 63.10%), MS(ES): m / z 420.11[M+H] + .

[0426] Synthesis of compound I-14. The compound was synthesized from compound 14.5 and methylamine using general procedure D. Further purification of the substance by column chromatography eluting with 2.5% methanol in dichloromethane yielded I-14 (0.023 g, 39.75%). MS(ES): m / z 419.80[M+H] +LCMS purity: 97.05%, HPLC purity: 98.91%, 1 H NMR (DMSO-d6, 400MHz): 12.20 (s, 1H), 11.35 (s, 1H), 8.84-8.83 (d, J=5.2Hz, 1H), 8.57 (bs, 1H), 8.41-8.40 (d, J=4.4Hz, 1H), 8.14-8.13 (d, J=3.2Hz, 1H), 7.96-7.95 (m, 1H), 7.81 (d, J=2Hz, 1H), 7.08 (bs, 1H), 6.84 (bs, 1H), 2.89-2.88 (d, J=4.4Hz, 3H), 1.56 (bs, 1H), 1.01-0.96 (m, 4H). (Example 15) 7-(cyclopropanecarboxamide)-N-methyl-2-(4-(oxazol-2-yl)pyridine-2-yl)-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-15). [ka]

[0427] Synthesis of compound 15.3. Triethylamine (5.0 g, 50.49 mmol, 1.7 eq) and carbonyldiimidazole (5.7 g, 35.64 mmol, 1.2 eq) were added to a solution of 15.1 (6.0 g, 29.70 mmol, 1.0 eq) and 15.2 (3.12 g, 29.70 mmol, 1.0 eq) in tetrahydrofuran (70 mL). The reaction mixture was stirred at 100 °C for 2 hours. After the reaction was complete, the reaction mixture was transferred to ice, stirred, and extracted with diethyl ether. The organic layers were combined, dehydrated with sodium sulfate, and concentrated under reduced pressure to obtain the crude product. This was further purified by distillation to obtain pure 15.3 (4.6 g, yield: 53.57%). MS(ES): m / z 290.01[M+H] + .

[0428] Synthesis of compound 15.4. Eaton's reagent (7.7 wt% phosphorus pentoxide solution in methanesulfonic acid) (0.5 mL) was added to compound 15.3 (0.045 g, 0.10 mmol, 1.0 eq). The reaction mixture was then stirred at 80°C for 2 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, dehydrated with sodium sulfate, and concentrated under reduced pressure to obtain compound 15.4 (0.640 g, yield: 17.87%). MS(ES): m / z 225.96[M+H] + .

[0429] Synthesis of compound 15.5. Compound 15.5 was obtained by synthesizing the compound from core C and compound 15.4 using general procedure E. (0.150 g, 18.32%). MS(ES): m / z 656.19[M+H] + .

[0430] Synthesis of compound 15.6. Compound 15.6 was obtained by synthesizing compound 15.5 using general procedure B. (0.076 g, yield: 99.08%), MS(ES): m / z 336.11[M+H] + .

[0431] Synthesis of compound 15.7. Compound 15.7 was obtained by synthesizing compound 15.6 using general procedure C. (0.046 g, 68.46%), MS(ES): m / z 404.13 [M+H] + .

[0432] Synthesis of compound I-15. The compound was synthesized from compound 15.7 and methylamine using general procedure D. Further purification of the substance by column chromatography eluting with 2.5% methanol in dichloromethane yielded I-15 (0.025 g, 35.80%). MS(ES): m / z 403.42[M+H] + LCMS purity: 97.14%, HPLC purity: 95.00%, 1H NMR (DMSO-d6, 400MHz): 12.08 (s, 1H), 10.99 (s, 1H), 8.88-8.87 (d, J=5.2Hz, 1H), 8.51 (s, 1H), 8.34-8.33 (d, J=4.4Hz, 2H), 8.06 (bs, 1H), 7.91-7.90 (d, J=4.2Hz, 1H), 7.73 (s, 1H), 7.53 (s, 1H), 2.92-2.91 (d, J=4.4Hz, 3H), 1.32-1.29 (m, 1H), 1.04-0.95 (m, 4H). (Example 16) 7-(cyclopropanecarboxamide)-N-(methyl-d3)-2-(4-(1-methyl-1H-1,2,4-triazole-3-yl)pyridine-2-yl)-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-16). [ka]

[0433] Synthesis of compound I-16. The compound was synthesized from compound 13.5 and methyl-d3-amine using general procedure D. Further purification of the substance by column chromatography eluting with 2.5% methanol in dichloromethane yielded I-16 (0.025 g, 38.28%). MS(ES): m / z 420.80[M+H] + LCMS purity: 95.11%, HPLC purity: 97.40%, 1 H NMR (DMSO-d6, 400MHz): 12.01 (s, 1H), 10.92 (s, 1H), 8.80-8.78 (d, J=4.8Hz, 1H), 8.62 (s, 1H), 8.51 (s, 1H), 8.33 (s, 1H), 8.02 (bs, 1H), 7.93-7.91 (d, J=4.4Hz, 1H), 7.65 (s, 1H), 4.02 (s, 3H), 1.27 (bs, 1H), 1.04-0.94 (m, 4H). (Example 17) 7-(cyclopropanecarboxamide)-N-methyl-2-(4-(3-methyl-1H-pyrazole-1-yl)pyridine-2-yl)-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-17). [ka]

[0434] Synthesis of compound 17.1. To a solution of 2-chloro-4-iodopyridine (1.0 g, 4.18 mmol, 1.0 eq) and potassium carbonate (1.73 g, 12.54 mmol, 3.0 eq) in toluene (15 mL), 3-methyl-1H-pyrazole (1.0 g, 12.54 mmol, 3.0 eq), trans-1,2-diaminocyclohexane (0.190 g, 1.67 mmol, 0.4 eq), and copper(I) iodide (0.159 g, 0.83 mmol, 0.2 eq) were added. The reaction mixture was heated at 110°C 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, dehydrated with sodium sulfate, and concentrated under reduced pressure to obtain the crude product. This was further purified by column chromatography eluting with 20% ethyl acetate in hexane to obtain compound 17.1. (0.320g, 39.57%), MS(ES): m / z 194.04[M+H] + .

[0435] Synthesis of compound 17.2. Sodium iodide (1.2 g, 8.25 mmol, 5 eq) and acetyl chloride (0.194 g, 2.47 mmol, 1.5 eq) were added to a solution of compound 17.1 (0.320 g, 1.65 mmol, 1.0 eq) in acetonitrile (5 mL). The reaction mixture was heated at 70 °C 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, dehydrated with sodium sulfate, and concentrated under reduced pressure to obtain the crude product. This was further purified by column chromatography eluting with 20% ethyl acetate in hexane to obtain 17.2 (0.3 g, 63.68%), MS(ES): m / z 285.97[M+H] + .

[0436] Synthesis of compound 17.3. Compound 17.3 was obtained by synthesizing the compound from core C and compound 17.2 using general procedure E. (0.110 g, 13.17%). MS(ES): m / z 669.22[M+H] + .

[0437] Synthesis of compound 17.4. Compound 17.4 was obtained by synthesizing compound 17.3 using general procedure B. (0.057 g, yield: 99.48%), MS(ES): m / z 349.14[M+H] + .

[0438] Synthesis of compound 17.5. Compound 17.5 was obtained by synthesizing compound 17.4 using general procedure C. (0.056 g, 71.70%), MS(ES): m / z 417.16[M+H] + .

[0439] Synthesis of compound I-17. The compound was synthesized from compound 17.5 and methylamine using general procedure D. Further purification of the substance by column chromatography eluting with 2.5% methanol in dichloromethane yielded I-17 (0.025 g, 38.28%). MS(ES): m / z 416.32[M+H] + LCMS purity: 97.43%, HPLC purity: 98.38%, 1 H NMR (DMSO-d6, 400MHz): 11.97 (s, 1H), 10.92 (s, 1H), 8.69 (s, 2H), 8.43 (s, 1H), 8.30 (s, 1H), 8.08 (s, 1H), 7.81 (s, 1H), 7.75 (s, 1H), 6.47 (bs, 1H), 2.91-2.90 (d, J=4.8Hz, 3H), 2.35 (s, 3H), 1.27 (bs, 1H), 1.03-0.94 (m, 4H). (Example 18) 2-(3-(4H-1,2,4-triazole-4-yl)phenyl)-7-(cyclopropanecarboxamide)-N-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-18). [ka]

[0440] Synthesis of compound 18.2. Compound 18.1 (3.3 g, 23.24 mmol, 2.0 eq) was added to a suspension of 3-bromoaniline (2.0 g, 11.62 mmol, 1.0 eq) in toluene (30 mL), and the reaction mixture was heated at 120 °C for 24 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain a residue, which was dissolved in saturated sodium bicarbonate solution and washed with hexane. The aqueous layer was separated, acidified to approximately pH 5-6 with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layers were combined, dehydrated with sodium sulfate, concentrated under reduced pressure to obtain a solid, which was then ground over hexane to obtain pure 18.2 (0.650 g, yield: 24.95%). MS(ES): m / z 224.97[M+H] + .

[0441] Synthesis of compound 18.3. To a solution of 18.2 (0.650 g, 2.90 mmol, 1.0 eq) in 1,4-dioxane (20 mL), bis(pinacolato)diborone (0.883 g, 3.48 mmol, 1.2 eq) and potassium acetate (0.568 g, 5.8 mmol, 2.0 eq) were added. The reaction mixture was degassed under an argon atmosphere for 10 minutes, then [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.211 g, 0.29 mmol, 0.1 eq) was added, and the mixture was degassed again for 5 minutes. The reaction mixture was stirred at 90°C for 4 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, transferred to water, and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine, dehydrated with sodium sulfate, and concentrated under reduced pressure to obtain the crude product. This was further purified by combifl flush using 3% methanol in dichloromethane as the eluate to obtain pure 18.3 (0.4g, yield: 50.86%). MS(ES): m / z 272.15[M+H]+ .

[0442] Synthesis of compound 18.4. Compound 18.4 was obtained by synthesizing the compound from core A and compound 18.3 using general procedure A. (0.210 g, yield: 40.89%), MS(ES): m / z 655.21[M+H] + .

[0443] Synthesis of compound 18.5. Compound 18.5 was obtained by synthesizing compound 18.4 using general procedure B. (0.106 g, yield: 98.85%), MS(ES): m / z 335.12[M+H] + .

[0444] Synthesis of compound 18.6. Compound 18.6 was obtained by synthesizing compound 18.6 from compound 18.5 using general procedure C. (0.070 g, yield: 67.39%), MS(ES): m / z 403.13[M+H] + .

[0445] Synthesis of compound I-18. The compound was synthesized from compound 18.6 and methylamine using general procedure D. Further purification of the substance by column chromatography eluting with 2.5% methanol in dichloromethane yielded I-18 (0.025 g, 34.55%). MS(ES): m / z 402.79[M+H] + LCMS purity: 100%, HPLC purity: 98.95%, 1 H NMR (DMSO-d6, 400MHz): 11.74 (s, 1H), 11.15 (s, 1H), 9.30 (s, 2H), 8.41-8.40 (d, J=4.8Hz, 1H), 8.31 (s, 2H), 7.89-7.88 (d, J=7.6Hz, 1H), 7.80-7.72 (m, 2H), 7.60 (bs, 1H), 2.87-2.86 (d, J=4.4Hz, 3H), 1.31 (bs, 1H), 1.01-0.94 (m, 4H). (Example 19) 7-(cyclopropanecarboxamide)-2-(2-fluoro-3-(1-methyl-1H-pyrazole-4-yl)phenyl)-N-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-19). [ka]

[0446] Synthesis of compound 19.1. Lithium diisopropylamide (2M) (9.0 mL, 18.0 mmol, 2.0 eq) was added to a solution of 1-fluoro-2-iodobenzene (2.0 g, 9.00 mmol, 1.0 eq) in tetrahydrofuran (20 mL) at -78°C. The reaction mixture was stirred at -78°C for 1 hour. Then, a solution of iodine (2.2 g, 18.0 mmol, 2.0 eq) in tetrahydrofuran (12 mL) was added to the reaction mixture, and the mixture was stirred at the same temperature for 2 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, dehydrated with sodium sulfate, and concentrated under reduced pressure to obtain the crude product. This was further purified by column chromatography eluting with 7% ethyl acetate in hexane to obtain compound 19.1 (1.8 g, yield: 57.43%). MS(ES): m / z 348.83[M+H] + .

[0447] Synthesis of compound 19.3. Argon was passed through a stirred mixture of compound 19.1 (1.6 g, 4.61 mmol, 1.0 eq), compound 19.2 (1.2 g, 5.99 mmol, 1.3 eq), and tripotassium phosphate (2.4 g, 11.52 mmol, 2.5 eq) in 1,4-dioxane (60 mL) and purged for 15 minutes. [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (0.336 mg, 0.46 mmol, 0.1 eq) was added, and the mixture was purged for another 10 minutes. The reaction mixture was stirred at 95°C for 6 hours. After the reaction was complete, the reaction mixture was poured onto water, and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine solution, dehydrated with sodium sulfate, and concentrated under reduced pressure to obtain compound 19.3 (0.650 g, yield: 46.79%). MS(ES): m / z 302.97[M+H] + .

[0448] Synthesis of compound 19.4. Compound 19.4 was obtained by synthesizing compound 19.3 using general procedure F. (0.4g, yield: 61.53%). MS(ES): m / z 303.16[M+H] + .

[0449] Synthesis of compound 19.5. Compound 19.5 was synthesized from core A and compound 19.4 using general procedure A. (0.260 g, yield: 53.71%), MS(ES): m / z 686.22[M+H] + .

[0450] Synthesis of compound 19.6. Compound 19.6 was obtained by synthesizing compound 19.5 using general procedure B. (0.120 g, yield: 86.63%), MS(ES): m / z 366.13[M+H] + .

[0451] Synthesis of compound 19.7. Compound 19.7 was obtained by synthesizing compound 19.6 using general procedure C. (0.110 g, yield: 77.27%), MS(ES): m / z 434.16[M+H] + .

[0452] Synthesis of Compound I-19. Using General Procedure D, the compound was synthesized from Compound 19.7 and methylamine. The substance was further purified by column chromatography eluting with 2.5% methanol in dichloromethane to give I-19 (0.025 g, yield: 22.78%). MS(ES): m / z 433.51[M+H] + LCMS purity: 98.70%, HPLC purity: 97.71%, 1 1H NMR (DMSO-d6, 400 MHz): 12.18 (s, 1H), 11.47 (s, 1H), 8.57 (s, 1H), 8.27 (s, 1H), 8.00 (s, 1H), 7.84 - 7.80 (m, 1H), 7.51 (s, 1H), 7.43 - 7.39 (t, J = 7.6 Hz, 1H), 7.10 (bs, 1H), 6.82 (bs, 1H), 3.95 (bs, 3H), 1.56 (bs, 3H), 1.24 (bs, 1H), 1.03 - 0.97 (m, 4H). (Example 20) 7-(Cyclopropanecarboxamido)-2-(2-cyclopropyl-2H-indazol-6-yl)-N-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide (I-20).

Chemical Structure

[0453] Synthesis of Compound 20.1. Hydrazine hydrate (0.850 g, 26.58 mmol, 1.8 eq) was added to 4-bromo-2-fluorobenzaldehyde (3.0 g, 14.77 mmol, 1.0 eq). The reaction mixture was stirred at room temperature for 20 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 brine solution, dried over sodium sulfate and concentrated under reduced pressure to give the crude material. This was further purified by column chromatography eluting with 2.5% methanol in dichloromethane to give 20.1. (1.9 g, 65.25%), MS(ES): m / z 196.97[M+H]+ .

[0454] Synthesis of Compound 20.2. To a solution of Compound 20.1 (1 g, 5.12 mmol, 1.0 eq) in 1,2-dichloroethane (10 mL) were added cyclopropylboronic acid (0.528 g, 6.14 mmol, 1.8 eq), sodium carbonate (1.3 g, 12.8 mmol, 2.5 eq), cupric acetate (1.3 g, 7.68 mmol, 1.5 eq), and bipyridine (1.5 g, 10.24 mmol, 2.0 eq). The reaction mixture was stirred at room temperature for 6 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 solution, dried over sodium sulfate, and concentrated under reduced pressure to obtain a crude substance. This was further purified by column chromatography eluting with 2% methanol in dichloromethane to obtain 20.2. (0.820 g, 68.14%), MS(ES): m / z 237.99[M+H] + .

[0455] Synthesis of Compound 20.3. Using General Procedure F, a compound was synthesized from Compound 20.2 to obtain 20.3. (0.4 g, 47.68%). MS(ES): m / z 285.17[M+H] + . <x

[0456] Synthesis of Compound 20.4. Using General Procedure A, a compound was synthesized from Core A and Compound 20.3 to obtain 20.4. (0.210 g, 44.55%), MS(ES): m / z 668.23[M+H] + .

[0457] Synthesis of Compound 20.5. Using General Procedure B, a compound was synthesized from Compound 20.4 to obtain 20.5. (0.1 g, 91.54%), MS(ES): m / z 348.14[M+H] + .

[0458] Synthesis of Compound 20.6. Using General Procedure C, a compound was synthesized from Compound 20.5 to obtain 20.6. (0.1 g, 83.61%), MS(ES): m / z 416.17[M+H] +.

[0459] Synthesis of compound I-20. The compound was synthesized from compound 20.6 and methylamine using general procedure D. Further purification of the substance by column chromatography eluting with 2.5% methanol in dichloromethane yielded I-20 (0.032 g, 32.08%). MS(ES): m / z 415.27[M+H] + LCMS purity: 95.82%, HPLC purity: 96.09%, 1 H NMR (DMSO-d6, 400MHz): 11.88 (s, 1H), 11.14 (s, 1H), 8.38-8.37 (d, J=4.4Hz, 1H), 8.30 (s, 1H), 8.19 (s, 1H), 8.07 (s, 1H), 7.92-7.90 (d, J=8.4Hz, 1H), 7.63-7.61 (d, J=8.4Hz, 1H), 7.49-7.48 (d, J=2Hz, 1H), 2.86-2.85 (d, J=4Hz, 3H), 2.26 (bs, 1H), 1.54 (bs, 1H), 1.23-1.17 (m, 4H), 1.01-0.93 (m, 4H). (Example 21) 7-(cyclopropanecarboxamide)-2-(7-fluoro-1-methyl-1H-indole-6-yl)-N-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide (I-21). [ka]

[0460] Synthesis of compound 21.2. To a solution of compound 21.1 (10.0 g, 45.45 mmol, 1.0 eq) in tetrahydrofuran (200 mL), vinylmagnesium bromide (1 M in THF, 136 mL, 136.35 mmol, 3.0 eq) was added at -78°C. The reaction mixture was stirred at -40°C for 1 hour. 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, dehydrated with sodium sulfate, and concentrated under reduced pressure to obtain the crude product. This was further purified by column chromatography eluting with 10% ethyl acetate in hexane to obtain 21.2 (1.5 g, yield: 15.42%). MS(ES): m / z 214.96[M+H] + .

[0461] Synthesis of compound 21.3. To a solution of 21.2 (1.5 g, 7.00 mmol, 1.0 eq) in dimethylformamide (15 mL), sodium hydride (0.336 g, 14.00 mmol, 2 eq) was added at 0°C and the mixture was stirred for 20 minutes. Methyl iodide (1.0 g, 7.7 mmol, 1.1 eq) was added, and the reaction mixture was stirred at 10°C for 2 hours. After the reaction was complete, the reaction mixture was transferred to ice, stirred, and extracted with diethyl ether. The organic layers were combined, dehydrated with sodium sulfate, and concentrated under reduced pressure to obtain the crude product. This was further purified by distillation to obtain pure 21.3 (1.2 g, yield: 75.08%). MS(ES): m / z 228.97[M+H] + .

[0462] Synthesis of compound 21.4. Compound 21.4 was obtained by synthesizing compound 21.4 from compound 21.3 using general procedure F, with 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl used in place of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.6g, 41.45%). MS(ES): m / z 276.15[M+H] + .

[0463] Synthesis of compound 21.5. Compound 21.5 was obtained by synthesizing the compound from core A and compound 21.4 using general procedure A. (0.190g, 40.86%), MS(ES): m / z 659.21[M+H] + .

[0464] Synthesis of compound 21.6. Compound 21.6 was obtained by synthesizing compound 21.5 using general procedure B. (0.090 g, 92.23%), MS(ES): m / z 339.12[M+H] + .

[0465] Synthesis of compound 21.7. Compound 21.7 was obtained by synthesizing compound 21.7 from compound 21.6 using general procedure C. (0.090 g, 83.25%), MS(ES): m / z 407.15[M+H] + .

[0466] Synthesis of compound I-21. The compound was synthesized from compound 21.7 and methylamine using general procedure D. Further purification of the substance by column chromatography eluting with 2.5% methanol in dichloromethane yielded I-21 (0.030 g, 33.41%). MS(ES): m / z 406.20[M+H] + LCMS purity: 98.45%, HPLC purity: 95.07%, 1 H NMR (DMSO-d6, 400MHz): 11.98 (s, 1H), 11.30 (s, 1H), 8.38-8.37 (d, J=4Hz, 1H), 7.53-7.49 (m, 2H), 7.43 (s, 1H), 7.09-7.07 (d, J=8Hz, 1H), 6.84-6.82 (d, J=7.6Hz, 1H), 6.55 (s, 1H), 4.07 (s, 3H), 2.86-2.85 (d, J=4.4Hz, 3H), 1.56 (bs, 1H), 1.01-0.95 (m, 4H). (Example 22) 7-(cyclopropanecarboxamide)-2-(2-fluoro-3-morpholinophenyl)-N-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-22). [ka]

[0467] Synthesis of compound 22.1. To a solution of compound 21.1 (10.0 g, 45.45 mmol, 1.0 eq) in 1,4-dioxane (300 mL), tin(II) chloride (43.0 g, 227.25 mmol, 5.0 eq) was added. The reaction mixture was stirred at room temperature for 3 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, dehydrated with sodium sulfate, and concentrated under reduced pressure to obtain the crude product. This was further purified by column chromatography eluting with 2.5% methanol in dichloromethane to obtain compound 22.1 (5.0 g, 57.89%). MS(ES): m / z 190.96[M+H] + .

[0468] Synthesis of compound 22.3. To a cooled solution of compounds 22.1 (5.0 g, 26.31 mmol, 1.0 eq) and 22.2 (7.2 g, 31.57 mmol, 1.2 eq) in n-butanol (150 mL), potassium carbonate (9.0 g, 65.77 mmol, 2.5 eq) was added at 0°C. The reaction mixture was stirred at 130°C for 48 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, dehydrated with sodium sulfate, and concentrated under reduced pressure to obtain the crude product. This was further purified by column chromatography, and the compound was eluted in hexane with 20% ethyl acetate to obtain pure 22.3 (0.9 g, 13.15%). MS(ES): m / z 261.00[M+H] + .

[0469] Synthesis of compound 22.4. Compound 22.4 was obtained by synthesizing compound 22.4 from compound 22.3 using general procedure F, with 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl used in place of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.650 g, 61.16%). MS(ES): m / z 308.18[M+H] + .

[0470] Synthesis of compound 22.5. Compound 22.5 was obtained by synthesizing the compound from core A and compound 22.4 using general procedure A. (0.220 g, 45.12%), MS(ES): m / z 691.23[M+H] + .

[0471] Synthesis of compound 22.6. Compound 22.6 was obtained by synthesizing compound 22.6 from compound 22.5 using general procedure B. (0.115 g, 97.49%), MS(ES): m / z 371.15 [M+H] + .

[0472] Synthesis of compound 22.7. Compound 22.7 was obtained by synthesizing compound 22.7 from compound 22.6 using general procedure C. (0.110 g, 71.48%), MS(ES): m / z 439.17[M+H] + .

[0473] Synthesis of compound I-22. The compound was synthesized from compound 22.7 and methylamine using general procedure D. Further purification of the substance by column chromatography eluting with 2.5% methanol in dichloromethane yielded I-22 (0.050 g, 45.56%). MS(ES): m / z 438.42[M+H] + LCMS purity: 100%, HPLC purity: 99.42%, 1 H NMR (DMSO-d6, 400MHz): 11.94 (s, 1H), 11.28 (s, 1H), 8.38-8.37 (d, J=4.4Hz, 1H), 8.30 (s, 1H), 7.52-7.49 (t, J=7.2Hz, 1H), 7.41 (bs, 1H), 7.31-7.27 (t, J=8 Hz, 1H), 7.17-7.13 (t, J=7.6Hz, 1H), 3.79 (bs, 4H), 3.06 (bs, 4H), 2.84-2.83 (d, J=4.4Hz, 3H), 2.24 (bs, 1H), 0.98-0.93 (m, 4H). (Example 23) 7-(cyclopropanecarboxamide)-2-(2-fluoro-3-(oxazole-2-yl)phenyl)-N-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-23). [ka]

[0474] Synthesis of compound 23.1. Carbon dioxide was passed through a stirred solution of 1-bromo-2-fluorobenzene (5.0 g, 28.57 mmol, 1.0 eq) in tetrahydrofuran (70 mL) and purged for 15 minutes. Subsequently, lithium diisopropylamide (2 M) (42.8 mL, 85.71 mmol, 3.0 eq) was added at -78°C. The reaction mixture was stirred at -78°C for 1 hour. 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, dehydrated with sodium sulfate, and concentrated under reduced pressure to obtain the crude product. This was further purified by column chromatography eluting with 7% ethyl acetate in hexane to obtain 23.1 (1.3 g, yield: 20.78%). MS(ES): m / z 218.94[M+H] + .

[0475] Synthesis of compound 23.3. To a solution of compound 23.1 (1.3 g, 5.96 mmol, 1.0 eq) in tetrahydrofuran (40 mL), isopropyl carbonyl chloride (1.1 g, 11.92 mmol, 2.0 eq) was added and the mixture was stirred at room temperature for 15 minutes. N-methylmorpholine (1.80 g, 17.88 mmol, 3.0 eq) was added, followed by compound 23.2 (0.625 g, 5.96 mmol, 1.0 eq). The reaction mixture was stirred at room temperature for 5 minutes. 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, dehydrated with sodium sulfate, and concentrated under reduced pressure to obtain the crude product. This was further purified by column chromatography, and the compound was eluted in 40% ethyl acetate in hexane to obtain 23.3 (0.9 g, yield: 49.53%). MS(ES): m / z 307.00[M+H] + .

[0476] Synthesis of compound 23.4. To a solution of 23.3 (0.9 g, 2.94 mmol, 1.0 eq) in toluene (10 mL), phosphorus pentoxide (0.652 g, 1.47 mmol, 0.5 eq) was added. The reaction mixture was stirred at 110°C for 3 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, washed with brine, dehydrated with sodium sulfate, and concentrated under reduced pressure to obtain the crude product. This was further purified by column chromatography, and the compound was eluted in 3% methanol in dichloromethane to obtain 23.4 (0.6 g, yield: 84.32%). MS(ES): m / z 242.95[M+H] + .

[0477] Synthesis of compound 23.5. Compound 23.5 was obtained by synthesizing compound 23.5 from compound 23.4 using general procedure F, with 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl used in place of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.450, yield: 62.79%). MS(ES): m / z 290.13[M+H] + .

[0478] Synthesis of compound 23.6. Compound 23.6 was obtained by synthesizing the compound from core A and compound 23.5 using general procedure A. (0.210 g, yield: 44.22%), MS(ES): m / z 673.19[M+H] + .

[0479] Synthesis of compound 23.7. Compound 23.7 was obtained by synthesizing compound 23.7 from compound 23.6 using general procedure B. (0.115 g, yield: 87.63%), MS(ES): m / z 352.12[M+H] + .

[0480] Synthesis of compound 23.8. Compound 23.8 was obtained by synthesizing compound 23.8 from compound 23.7 using general procedure C. (0.100g, yield: 86.96%), MS(ES): m / z 421.14[M+H] + .

[0481] Synthesis of compound I-23. The compound was synthesized from compound 23.8 and methylamine using general procedure D. Further purification of the substance by column chromatography eluting with 2.5% methanol in dichloromethane yielded I-23 (0.027 g, yield: 27.06%). MS(ES): m / z 420.32[M+H] + LCMS purity: 95.56%, HPLC purity: 97.22%, 1 H NMR (DMSO-d6, 400MHz): 12.14 (s, 1H), 11.33 (s, 1H), 8.40 (s, 1H), 8.34 (s, 1H), 8.16-8.07 (m, 1H), 7.55 (s, 1H), 7.09 (bs, 2H), 6.84 (bs, 2H), 2.87-2.86 (d, J=4.4Hz, 3H), 1.56 (bs, 1H), 1.01-0.95 (m, 4H). (Example 24) 2-(4-(azetidine-1-carbonyl)-2-methoxyphenyl)-7-(cyclopropanecarboxamide)-N-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-24). [ka]

[0482] Synthesis of compound 24.2. Methyl iodide (6.7 g, 47.61 mmol, 1.1 eq) was added to a solution of compound 24.1 (10.0 g, 43.29 mmol, 1.0 eq) in dimethylformamide (100 mL). The reaction mixture was degassed under an argon atmosphere for 10 minutes, followed by the addition of potassium carbonate (17.9 g, 129.87 mmol, 3.0 eq). The reaction mixture was heated at 100 °C for 10 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, dehydrated with sodium sulfate, and concentrated under reduced pressure to obtain the crude product. This was further purified by column chromatography eluting with 5% methanol in dichloromethane to obtain 24.2 (7.2 g, yield: 67.88%). MS(ES): m / z 244.98[M+H] + .

[0483] Synthesis of compound 24.3. To a solution of compound 24.2 (7.2 g, 29.38 mmol, 1.0 eq) in tetrahydrofuran:methanol:water (80 mL, 2:2:1), lithium hydroxide (7.0 g, 293.8 mmol, 10 eq) was added. The reaction mixture was stirred at 60°C for 16 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain a residue. Water was added to this residue, and the pH was adjusted to approximately 6-6.5 by acidification with 1N hydrochloric acid at 10°C. The product was extracted with dichloromethane. The organic layers were combined, washed with brine, dehydrated with sodium sulfate, and concentrated under reduced pressure to obtain the crude product. This was further purified by column chromatography, and the compound was eluted in 2.1% methanol in dichloromethane to obtain pure 24.3 (5.0 g, yield: 73.66%). MS(ES): m / z 231.96[M+H] + .

[0484] Synthesis of compound 24.4. To a solution of compound 24.3 (1.0 g, 4.32 mmol, 1.0 eq) in dimethylformamide (10 mL), azetidine (0.270 g, 4.75 mmol, 1.1 eq) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate (2.77 g, 8.64 mmol, 2.0 eq) were added. The reaction mixture was degassed under an argon atmosphere for 10 minutes, followed by the addition of potassium carbonate (1.78 g, 12.96 mmol, 3.0 eq). The reaction mixture was heated at 100 °C for 10 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, dehydrated with sodium sulfate, and concentrated under reduced pressure to obtain the crude product. This was further purified by column chromatography using elution with 5% methanol in dichloromethane to obtain 24.4 (0.8g, yield: 68.43%). MS(ES): m / z 271.00[M+H] + .

[0485] Synthesis of compound 24.5. Compound 24.5 was obtained by synthesizing compound 24.5 from compound 24.4 using general procedure F, with 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl used in place of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.420 g, yield: 44.71%). MS(ES): m / z 318.18[M+H] + .

[0486] Synthesis of compound 24.6. Compound 24.6 was obtained by synthesizing the compound from core A and compound 24.5 using general procedure A. (0.310 g, yield: 33.41%), MS(ES): m / z 701.24[M+H] + .

[0487] Synthesis of compound 24.7. Compound 24.7 was obtained by synthesizing compound 24.7 from compound 24.6 using general procedure B. (0.150 g, yield: 89.14%), MS(ES): m / z 381.15[M+H] + .

[0488] Synthesis of compound 24.8. Compound 24.8 was obtained by synthesizing compound 24.8 from compound 24.7 using general procedure C. (0.110 g, yield: 62.20%), MS(ES): m / z 449.18[M+H] + .

[0489] Synthesis of compound 24.9. Tributyltin oxide (0.286 g, 0.48 mmol, 2.0 eq) was added to a suspension of compound 24.8 (0.110 g, 0.24 mmol, 1.0 eq) in toluene (2 mL), and the reaction mixture was heated at 100 °C for 16 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain a residue, which was dissolved in saturated sodium bicarbonate solution and washed with hexane. The aqueous layer was separated, acidified to approximately pH 5-6 with 1 N hydrochloric acid, and extracted with ethyl acetate. The organic layers were combined, dehydrated with sodium sulfate, concentrated under reduced pressure to obtain a solid, and ground over hexane to obtain pure 24.9 (0.060 g, yield: 56.31%), MS(ES): m / z 435.16[M+H] + .

[0490] Synthesis of compound I-24. The compound was synthesized from compound 24.9 and methylamine using general procedure H. The substance was further purified by column chromatography, and the compound was eluted in hexane with 40% ethyl acetate to obtain I-24 (0.030 g, yield: 48.54%). MS(ES): m / z 448.37[M+H] + LCMS purity: 99.24%, HPLC purity: 95.14%, 1 H NMR (DMSO-d6, 400MHz): 12.53 (s, 1H), 11.34 (s, 1H), 8.34-8.32 (d, J=4.4Hz, 1H), 8.06-8.04 (d, J=8.4Hz, 1H), 7.51 (s, 1H), 7.35-7.33 (d, J=8Hz, 1H), 7.10 (bs, 1H), 6.82 (bs, 1H), 4.41-4.37 (t, J=7.6Hz, 2H), 4.13-4.08 (m, 2H), 4.05 (s, 3H), 2.86-2.85 (d, J=4.4Hz, 3H), 2.33-2.26 (m, 2H), 1.56 (bs, 1H), 1.01-3.96 (m, 4H). (Example 25) 7-(cyclopropanecarboxamide)-2-(2-methoxy-4-(pyrroridine-1-carbonyl)phenyl)-N-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxamide(I-25). [ka]

[0491] Synthesis of compound 25.1. To a solution of compound 24.3 (1.0 g, 4.32 mmol, 1.0 eq) in dimethylformamide (10 mL), pyrrolidine (0.337 g, 4.75 mmol, 1.1 eq) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate (2.77 g, 8.64 mmol, 2.0 eq) were added. The reaction mixture was degassed under an argon atmosphere for 10 minutes, followed by the addition of potassium carbonate (1.78 g, 12.96 mmol, 3.0 eq). The reaction mixture was heated at 100 °C for 10 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, dehydrated with sodium sulfate, and concentrated under reduced pressure to obtain the crude product. This was further purified by column chromatography using elution with 5% methanol in dichloromethane to obtain 25.1 (0.810 g, yield: 65.86%). MS(ES): m / z 285.02[M+H] + .

[0492] Synthesis of compound 25.2. Compound 25.2 was obtained by synthesizing compound 25.2 from compound 25.1 using general procedure F, with 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl used in place of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.430 g, yield: 45.54%). MS(ES): m / z 332.20[M+H] + .

[0493] Synthesis of compound 25.3. Compound 25.3 was synthesized from core A and compound 25.2 using general procedure A to obtain 25.3. (0.4g, yield: 43.10%), MS(ES): m / z 715.25[M+H] + .

[0494] Synthesis of compound 25.4. Compound 25.4 was obtained by synthesizing compound 25.4 from compound 25.3 using general procedure B. (0.180 g, yield: 81.55%), MS(ES): m / z 395.17[M+H] + .

[0495] Synthesis of compound 25.5. Compound 25.5 was obtained by synthesizing compound 25.4 using general procedure C. (0.140 g, yield: 66.33%), MS(ES): m / z 463.19[M+H] + .

[0496] Synthesis of compound 25.6. Tributyltin oxide (0.357 g, 0.6 mmol, 2.0) was added to a suspension of compound 25.5 (0.140 g, 0.30 mmol, 1.0 eq) in toluene (2 mL), and the reaction mixture was heated at 100 °C for 16 hours. After the reaction was complete, the reac...

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[Claim 1] The object, method, or system described herein.

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