TYK2 inhibitors and uses thereof

Abstract

Compounds, compositions thereof, and methods of using these compounds and compositions for the inhibition of TYK2 and the treatment of TYK2-mediated disorders are provided. The present invention provides compounds, compositions thereof, and methods of using these compounds and compositions for the inhibition of TYK2 and the treatment of TYK2-mediated disorders. The compounds provided by the present invention are also useful for the study of the TYK2 enzyme in biological and pathological phenomena; the study of intracellular signaling pathways occurring in body tissues; and the in vitro or in vivo comparative evaluation of new TYK2 inhibitors or other regulators of kinases, signaling pathways, and cytokine levels.

Description

[Technical Field]

[0001] Technical field of the invention 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 invention, and methods of using these compositions in the treatment of various disorders. [Background technology]

[0002] Background of the Invention The search for new therapeutic agents has been greatly aided in recent years by a better understanding of the structure of enzymes or other biomolecules associated with disease. One important class of enzymes that has been the subject of extensive study is the protein kinase family.

[0003] Protein kinases constitute a large family of structurally related enzymes responsible for regulating various signal transduction processes within cells. Protein kinases are thought to have evolved from a common ancestral gene due to the conservation of their structure and catalytic function. Nearly all kinases contain a similar 250-300 amino acid catalytic domain. These kinases can be categorized into families according to the substrates they phosphorylate (e.g., protein-tyrosine, protein-serine / threonine, lipids, etc.).

[0004] Generally, protein kinases mediate intracellular signaling by effecting phosphoryl transfer from a nucleoside triphosphate to a protein acceptor involved in a signaling pathway. 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 triggered 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 endotoxin, and H2O2), cytokines (e.g., interleukin-1 (IL-1), interleukin-8 (IL-8), and tumor necrosis factor alpha (TNF-α)), and growth factors (e.g., granulocyte-macrophage colony-stimulating factor (GM-CSF) and fibroblast growth factor (FGF)). Extracellular stimuli can affect one or more cellular responses related to cell proliferation, migration, differentiation, hormone secretion, transcription factor activation, muscle contraction, glucose metabolism, control of protein synthesis, and regulation of the cell cycle.

[0005] Many diseases are related to the abnormal cell response caused by kinase-mediated events.These diseases include but are not limited to autoimmune disease, inflammatory disease, bone disease, metabolic disease, neurological disease and neurodegenerative disease, cancer, cardiovascular disease, allergy and asthma, Alzheimer's disease and hormone-related disease.Therefore, there remains a need to find protein kinase inhibitors that are useful as therapeutic agents. Summary of the Invention [Means for solving the problem]

[0006] Summary of the Invention It has now been found that compounds of the present invention, and pharmaceutically acceptable compositions thereof, are effective as inhibitors of TYK2 kinase.

[0007] The compounds of the present invention and pharmaceutically acceptable compositions thereof are useful for treating a variety of diseases, disorders, or conditions associated with the regulation of signal transduction pathways involving TYK2 kinase, including those described herein.

[0008] The compounds provided by the present invention are also useful for studying the TYK2 enzyme in biological and pathological phenomena; studying intracellular signaling pathways occurring in body tissues; and for the in vitro or in vivo comparative evaluation of new TYK2 inhibitors or other regulators of kinases, signaling pathways, and cytokine levels. DETAILED DESCRIPTION OF THE INVENTION

[0009] Detailed Description of Specific Embodiments 1. General Description of Certain Embodiments of the Invention: The compounds of the present invention and compositions thereof are useful as inhibitors of TYK2 protein kinase.

[0010] 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 that includes 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.

[0011] Water molecules occupying hydration sites in the binding pocket of TYK2 with a stability rating greater than 2.5 kcal / mol are referred to as "labile waters."

[0012] While not wishing to be bound by any particular theory, it is believed that the displacement or disruption of labile water molecules (i.e., water molecules with a stability rating of greater than 2.5 kcal / mol) or the replacement of stable water molecules (i.e., water molecules with a stability rating of less than 1 kcal / mol) by an inhibitor results in tighter binding of the inhibitor. Thus, inhibitors designed to displace one or more labile water molecules (i.e., labile water molecules that are not displaced by any known inhibitor) are tighter binders and therefore more potent inhibitors compared to inhibitors that do not displace labile water molecules.

[0013] Surprisingly, provided compounds have been found to displace or disrupt one or more labile water molecules. In some embodiments, provided compounds displace or disrupt at least two labile water molecules.

[0014] In certain embodiments, the present invention provides compounds of formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula I, X, L 1 , R 1 , R 2 , and Cy 1 Each of the is as defined below and described in embodiments herein, both alone and in combination.

[0015] In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable carrier, adjuvant, or diluent.

[0016] In some embodiments, the present invention provides a method of treating a TYK2-mediated disease, disorder, or condition, comprising administering to a patient in need thereof a compound of formula I, or a pharmaceutically acceptable salt thereof.

[0017] In certain embodiments, the present invention provides a compound of formula VIII: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula VIII, X, L 1 , R 1 , R 2 , and Cy 1 Each of the is as defined below and described in embodiments herein, both alone and in combination.

[0018] In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula VIII and a pharmaceutically acceptable carrier, adjuvant, or diluent.

[0019] In some embodiments, the present invention provides a method of treating a TYK2-mediated disease, disorder, or condition, comprising administering to a patient in need thereof a compound of formula VIII or a pharmaceutically acceptable salt thereof.

[0020] In certain embodiments, the present invention provides a compound of formula XVI': [ka] or a pharmaceutically acceptable salt thereof, wherein in formula XVI', Q, X, Y 1 , Y 2 , Z 1 , Z 2 , L 1 , R 1 , R 2 , and Cy 1 Each of the is as defined below and described in embodiments herein, both alone and in combination.

[0021] In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula XVI' and a pharmaceutically acceptable carrier, adjuvant, or diluent.

[0022] In some embodiments, the present invention provides a method of treating a TYK2-mediated disease, disorder, or condition, comprising administering to a patient in need thereof a compound of formula XVI' or a pharmaceutically acceptable salt thereof. 2. Compounds and definitions:

[0023] The compounds of the present invention include those generally described herein and are further described by the classes, subclasses, and species disclosed herein. As used herein, the following definitions apply unless otherwise indicated. For 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.

[0024] The term "aliphatic" or "aliphatic group," as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted, hydrocarbon chain that is fully saturated or contains one or more unsaturated units, or a monocyclic or bicyclic hydrocarbon that is fully saturated or contains one or more unsaturated units, but is not aromatic (also referred to herein as "carbocycle," "alicyclic," or "cycloalkyl"), having one point of attachment to the remainder of the molecule. Unless otherwise specified, an aliphatic group contains 1-6 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1-5 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1-4 aliphatic carbon atoms. In still other embodiments, an aliphatic group contains 1-3 aliphatic carbon atoms, and in still other embodiments, an aliphatic group contains 1-2 aliphatic carbon atoms. In some embodiments, "alicyclic" (or "carbocycle" or "cycloalkyl") refers to a monocyclic C3-C6 hydrocarbon that is fully saturated or contains one or more units of unsaturation, but is not aromatic, and has one point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, straight-chain or branched, saturated or unsaturated, alkyl, alkenyl, alkynyl groups, and hybrids thereof (e.g., (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl).

[0025] As used herein, the term "bridged bicyclic" refers to any bicyclic ring system (i.e., carbocyclic or heterocyclic) that is saturated or partially unsaturated and has at least one bridge. As defined by IUPAC, a "bridge" is an unbranched chain of atoms, or a single atom, or a valence bond connecting two bridgeheads, where a "bridgehead" is any skeletal atom of the ring system that is 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, in which each group is attached to the remainder of the molecule at any suitable carbon or nitrogen atom. Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents, such as those described for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bridged bicyclic rings include: [ka] Examples include:

[0026] The term "lower alkyl" refers to C 1~4 " refers to a straight or branched chain alkyl group of the formula: Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0027] The term "lower haloalkyl" refers to a C alkyl group substituted with one or more halogen atoms. 1~4 The term "alkyl" refers to a straight or branched chain alkyl group.

[0028] The term "heteroatom" refers to oxygen, sulfur, nitrogen, phosphorus, or silicon (any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen; or a substitutable nitrogen of a heterocyclic ring (e.g., N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR +(as in N-substituted pyrrolidinyl)).

[0029] The term "unsaturated," as used herein, means a moiety having one or more units of unsaturation.

[0030] As used herein, the term "divalent C 1~8 (or C 1~6 ) saturated or unsaturated, straight or branched hydrocarbon chains" refers to straight or branched divalent alkylene, alkenylene, and alkynylene chains as defined herein.

[0031] The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH) 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 with a substituent. Suitable substituents include those described below for substituted aliphatic groups.

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

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

[0034] The term "aryl," used alone or as part of a larger moiety, as in "aralkyl," "aralkoxy," or "aryloxyalkyl," refers to a monocyclic or bicyclic ring system having a total of 5 to 14 ring members, in which at least one ring in the system is aromatic, and each ring in the system contains 3 to 7 ring members. The term "aryl" may be used interchangeably with the term "aryl ring." In certain embodiments of the invention, "aryl" refers to an aromatic ring system, including, but not limited to, phenyl, biphenyl, naphthyl, and anthracyl, which may bear one or more substituents. As used herein, and included within its scope, are groups in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl.

[0035] The terms "heteroaryl" and "heteroara-," used alone or as part of a larger moiety (e.g., "heteroaralkyl" or "heteroaralkoxy"), refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 pi electrons shared in a cyclic arrangement; and having 1 to 5 heteroatoms in addition to carbon atoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. Heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms "heteroaryl" and "heteroara-," as used herein, also encompass groups in which a heteroaromatic ring is fused to one or more aryl, alicyclic, or heterocyclic rings, and the radical or point of attachment, unless otherwise specified, 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-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, 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 terms include rings that are optionally substituted. The term "heteroaralkyl" refers to an alkyl group substituted by a heteroaryl, where the alkyl and heteroaryl portions independently are optionally substituted.

[0036] As used herein, the terms "heterocycle," "heterocyclyl," "heterocyclic radical," and "heterocyclic ring" are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated and has, in addition to carbon atoms, one or more, preferably one to four, heteroatoms as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes substituted nitrogen. As an example, in a saturated or partially unsaturated ring having zero to three heteroatoms selected from oxygen, sulfur, or nitrogen, the nitrogen can be N (as in 3,4-dihydro-2H-pyrrolyl) or NH (as in pyrrolidinyl). + It may also be NR (as in N-substituted pyrrolidinyl).

[0037] A heterocyclic ring can be attached to its parent group at any heteroatom or carbon atom that results in a stable structure, and any of these ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, 2-oxa-6-azaspiro[3.3]heptane, and quinuclidinyl. The terms "heterocycle," "heterocyclyl," "heterocyclyl ring," "heterocyclic group," "heterocyclic moiety," and "heterocyclic radical" are used interchangeably herein and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or alicyclic rings (e.g., indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl). Heterocyclyl groups can be monocyclic or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted by a heterocyclyl, where the alkyl and heterocyclyl portions independently are optionally substituted.

[0038] As used herein, the term "partially unsaturated" refers to a ring moiety that contains at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings with multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties as defined herein.

[0039] As described herein, compounds of the invention may contain "optionally substituted" moieties. In general, the term "substituted," whether preceded by the term "optionally" or not, means that one or more hydrogens of the specified moiety have been replaced with a suitable substituent. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituents may be either the same or different at each position. Combinations of substituents envisioned by the present invention are preferably those that result in the formation of stable or chemically feasible compounds. The term "stable," as used herein, refers to compounds that are substantially unchanged when subjected to conditions that permit their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0040] Suitable monovalent substituents on a substitutable carbon atom of an "optionally substituted" group are independently: halogen; -(CH) 0~4 R ○ ;-(CH2) 0~4 OR ○ ;-O(CH2) 0~4 R ○ , -O-(CH2) 0~4 C(O)OR ○ ;-(CH2) 0~4 CH(OR ○ )2;-(CH2) 0~4 SR ○ ;-(CH2) 0~4 Ph (which is R ○ -(CH2) 0~4 O(CH2) 0~1 Ph (which is R ○ -CH=CHPh (which may be substituted with R ○ -(CH2) 0~4 O(CH2) 0~1 -pyridyl (which 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 ○ ; -(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 s OC(O)R ○ ; -OC(O)(CH2) 0~4 SR ○ ; -SC(S)SR ○ ; -(CH2) 0~4 SC(O)R ○ [[ID=8())]]; -(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)NR ○ 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 straight or branched chain alkylene)ON(R ○ )2; or -(C 1~4 straight or branched chain alkylene)C(O)ON(R ○ )2, where each R ○ may be substituted as defined below and independently represent hydrogen, C 1~6 Aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, -CH2- (a 5- to 6-membered heteroaryl ring), or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, regardless of the above definitions, R ○ two independent occurrences of together with the atom(s) between them form a 3- to 12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which can be substituted as defined below.

[0041] R ○ (R ○ Suitable monovalent substituents on the ring formed by two independent occurrences of (a ring formed by two independent occurrences of together with the atom between them) are independently halogen, -(CH2) 0~2 R ● ,-(Halo R ● ), -(CH2) 0~2 OH, -(CH2) 0~2 OR ● , -(CH2) 0~2 CH(OR ● )2;-O(HaloR ● ), -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 or branched chain alkylene)C(O)OR ● , or -SSR ● where each R ● is unsubstituted or, if preceded by "halo", is substituted with only one or more halogens, and independently, C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. ○ Suitable divalent substituents on a saturated carbon atom of include ═O and ═S.

[0042] Suitable divalent substituents on a saturated carbon atom of an "optionally substituted" group 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 R * Each independent occurrence of may be hydrogen, C, which may be substituted as defined below. 1~6 and an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having an aliphatic or 0-4 heteroatom independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents attached to a vicinal substitutable carbon of an "optionally substituted" group include -O(CR * 2) 2~3 O-, where R * Each independent occurrence of may be hydrogen, C, which may be substituted as defined below. 1~6 It is selected from an aliphatic or unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0043] R * Suitable substituents on the aliphatic group include halogen, -R ● ,-(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2, or -NO2, where each R ● is unsubstituted or, if preceded by "halo", is substituted with only one or more halogens, and independently, C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1Ph, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0044] Suitable substituents on a substitutable nitrogen of an "optionally substituted" group include -R † , -NR † 2. -C(O)R † , -C(O)OR † , -C(O)C(O)R † , -C(O)CHC(O)R † , -S(O)2R † , -S(O)NR † 2. -C(S)NR † 2. -C(NH)NR † 2, or -N(R † )S(O)2R † where each R † are independently hydrogen, C which may be substituted as defined below 1~6 an 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, regardless of the above definitions, R † two independent occurrences of together with the atom(s) between them form an unsubstituted 3- to 12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0045] R † Suitable substituents on the aliphatic group are independently halogen, -R ● ,-(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2, or -NO2, where each R ●is unsubstituted or, if preceded by "halo", is substituted with only one or more halogens, and independently, C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0046] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., and commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include salts derived from suitable inorganic 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 formed by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, and the like. Examples of suitable salts include phosphate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate.

[0047] Salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts and N + (C 1~4 Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations, formed where appropriate using counterions such as halides, hydroxides, carbonates, sulfates, phosphates, nitrates, lower alkylsulfonates, and arylsulfonates.

[0048] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure, such as the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Thus, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the compounds of the invention are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Furthermore, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, structures of the invention in which hydrogen is replaced by deuterium or tritium, or in which carbon is replaced by methyl ... 13 C or 14 Compounds having the invention in which C is replaced with an enriched carbon are within the scope of the invention. Such compounds are useful, for example, as analytical tools according to the invention, as probes in biological assays, or as therapeutic agents. In certain embodiments, the warhead moiety R of a given compound is 1 contains one or more deuterium atoms. In certain embodiments, ring B of provided compounds can be substituted with one or more deuterium atoms.

[0049] As used herein, the term "inhibitor" is defined as a compound that binds and / or inhibits TYK2 with measurable affinity. In certain embodiments, an inhibitor has an IC 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 and / or have a binding constant.

[0050] The compounds of the present invention can be tethered to a detectable moiety. It is understood that such compounds are useful as imaging agents. Those skilled in the art will recognize that a detectable moiety can be attached to a provided compound via a suitable substituent. As used herein, the term "suitable substituent" refers to a moiety that can be covalently linked to a detectable moiety. Such moieties are well known to those skilled in the art and include, for example, groups containing carbonate, amino, thiol, or hydroxyl moieties, to name a few. It is understood that such moieties can be attached directly to a provided compound or via a tethering group such as a bivalent saturated or unsaturated hydrocarbon chain. In some embodiments, such moieties can be attached via click chemistry. In some embodiments, such moieties can be attached via 1,3-cycloaddition of an azide with an alkyne, optionally in the presence of a copper catalyst. Methods using click chemistry are known in the art and include those described by Rostovtsev et al., Angew. Chem. Int. Ed. 2002, 41, 2596-99 and Sun et al., Bioconjugate Chem., 2006, 17, 52-57.

[0051] As used herein, the term "detectable moiety" is used interchangeably with the term "label" and refers to any moiety that can be detected, such as primary and secondary labels. Radioisotopes (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. Detectable moieties also include luminescent and phosphorescent groups.

[0052] As used herein, the term "secondary label" refers to moieties such as biotin and various protein antigens that require the presence of a secondary intermediate to generate a detectable signal. For biotin, the secondary intermediate may include a streptavidin-enzyme conjugate. For antigen labels, the secondary intermediate may include an antibody-enzyme conjugate. Some fluorescent groups act as secondary labels because they transfer energy to another group in the process of non-radioactive fluorescence resonance energy transfer (FRET), and the second group generates the signal that is detected.

[0053] As used herein, the terms "fluorescent label," "fluorescent dye," and "fluorophore" refer to a moiety that absorbs light energy at a defined excitation wavelength and emits light energy at a different wavelength. Examples of fluorescent labels include Alexa Fluor dyes (Alexa Fluor 350, Alexa Fluor 488, Alexa Fluor 532, Alexa Fluor 546, Alexa Fluor 568, Alexa Fluor 594, Alexa Fluor 633, Alexa Fluor 660, and Alexa Fluor 680), AMCA, AMCA-S, BODIPY dyes (BODIPY FL, BODIPY R6G, BODIPY TMR, BODIPY TR, BODIPY530 / 550, 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 dyes (Cy3, Cy5, Cy3.5, Cy5.5), dansyl, dapoxyl, dialkylaminocoumarin, 4',5'-dichloro-2',7'-dimethoxy-fluorescein, DM-NERF, eosin, erythrosine, fluorescein, FAM, hydrochloride Examples of suitable dyes include, but are not limited to, roxycoumarin, IRDyes (IRD40, IRD700, IRD800), JOE, Lissamine rhodamine B, Marina Blue, methoxycoumarin, naphthofluorescein, Oregon Green 488, Oregon Green 500, Oregon Green 514, Pacific Blue, PyMPO, pyrene, rhodamine B, rhodamine 6G, rhodamine green, rhodamine red, rhodol green, 2',4',5',7'-tetra-bromosulfone-fluorescein, tetramethyl-rhodamine (TMR), carboxytetramethylrhodamine (TAMRA), Texas Red, and Texas Red-X.

[0054] As used herein, the term "mass tag" refers to any moiety that can be uniquely detected by its mass using mass spectrometry (MS) detection technology.Examples of mass tag include electrophoretic release 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 usefulness of these mass tags are described in U.S. Patent No. 4,650,750, U.S. Patent No. 4,709,016, U.S. Patent No. 5,360,8191, U.S. Patent No. 5,516,931, U.S. Patent No. 5,602,273, U.S. Patent No. 5,604,104, U.S. Patent No. 5,610,020 and U.S. Patent No. 5,650,270. Other examples of mass tags include, but are not limited to, nucleotides of various lengths and base compositions, 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, in the appropriate mass range (100-2000 daltons) may be used as mass tags.

[0055] The terms "measurable affinity" and "measurably inhibit," as used herein, refer to a measurable change in TYK2 protein kinase activity between a sample containing a compound of the present invention or a composition thereof and TYK2 protein kinase and an equivalent sample containing TYK2 protein kinase in the absence of the compound or composition thereof. 3. Description of Exemplary Embodiments:

[0056] As noted above, in certain embodiments, the present invention provides compounds of formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula I: X is N or C(R 3 ) and; R 1is R, R D , or -OR; R 2 H, R C , -N(R)C(O)Cy 2 , -N(R)S(O)2Cy 2 , -N(R)Cy 2 , -OCy 2 , -SCy 2 , or Cy 2 and; R 3 is H, halogen, or C 1~6 Is aliphatic; or R 2 and R 3 together with the atoms therebetween form a 4- to 7-membered partially unsaturated or aromatic ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the ring is one of m examples of R 4 is replaced by; Cy 1 and Cy 2 each independently is phenyl; a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; or a 7- to 12-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy 1 is n examples of R 5 and Cy 2 p examples of R 6 is replaced by; L 1 is a covalent bond, or C 1~4 wherein one or two methylene units of the chain are independently —C(R 7)2-, -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2-, as appropriate; R 4 , R 5 , R 6 , and R 7 Each instance of A or R B and q examples of R C has been replaced by; R A Each example is independently oxo, halogen, -CN, -NO2, -OR, -OR D , -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -O C(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, or -N(R)S(O)2R; R B Each example of C 1~6 aliphatic; phenyl; a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated carbocyclic ring; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7- to 12-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R Cis 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)S(O)2NR2, or -N(R)S(O)2R, or an optionally substituted group, wherein the optionally substituted group is 1~6 selected from aliphatic, phenyl, 3- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R D is a C in which one or more hydrogens have been replaced by deuterium. 1~4 is an aliphatic group; Each R is independently hydrogen or an optionally substituted group, and the optionally substituted group is C 1~6 selected from aliphatic, phenyl, 3- to 7-membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same nitrogen, together with the atoms between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, from 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and m, n, p, and q are independently 0, 1, 2, 3, or 4.

[0057] As generally defined above, X is N or C(R 3 ). In some embodiments, X is N. In some embodiments, X is C(R 3). In some embodiments, X is C(H). In some embodiments, X is C(R 3 ), where R 3 is halogen. In some embodiments, X is C(R 3 ), where R 3 is fluoro.

[0058] As generally defined above, R 1 is R, R D or -OR. In some embodiments, R 1 is R. In some embodiments, R 1 is R D In some embodiments, R 1 In some embodiments, R 1 is replaced by C 1~6 In some embodiments, R 1 is an optionally substituted ethyl group. In some embodiments, R 1 is hydrogen, methyl, or -CD. In some embodiments, R 1 is hydrogen. In some embodiments, R 1 is methyl or -CD3. In some embodiments, R 1 is methyl. In some embodiments, R 1 is -CD3. In some embodiments, R 1 is -OH.

[0059] As generally defined above, R 2 H, R C , -N(R)C(O)Cy 2 , -N(R)Cy 2 , -OCy 2 , -SCy 2 , or Cy 2 In some embodiments, R 2 is H. In some embodiments, R 2 is R C , -N(R)C(O)Cy2 , -N(R)Cy 2 , -OCy 2 , -SCy 2 , or Cy 2 In some embodiments, R 2 is R C In some embodiments, R 2 is —N(R)C(O)R. In some embodiments, R 2 is -N(R)C(O)Cy 2 , -N(R)Cy 2 , or Cy 2 In some embodiments, R 2 is -N(R)C(O)R, -N(R)C(O)Cy 2 , -N(R)Cy 2 , or Cy 2 In some embodiments, R 2 is -N(H)C(O)R, -N(H)C(O)Cy 2 , -N(H)Cy 2 , or Cy 2 In some embodiments, R 2 is -N(H)C(O)R, -N(H)C(O)Cy 2 , or -N(H)Cy 2 In some embodiments, R 2 is —N(H)C(O)R. In some embodiments, R 2 is —N(H)C(O)R, where R is, in this example, an optionally substituted C 1~6 In some embodiments, R 2 is -N(H)C(O)Cy 2 In some embodiments, R 2 -N(H)Cy 2 In some embodiments, R 2 is -N(H)C(O)Cy 2 where Cy 2 is cyclopropyl. In some embodiments, R 2 teeth [ka] is.

[0060] As generally defined above, R 3 is H, halogen, or C 1~6 In some embodiments, R 3 is H. In some embodiments, R 3 is a halogen, or C 1~6 In some embodiments, R 3 is halogen. In some embodiments, R 3 is fluoro. In some embodiments, R 3 is C 1~6 It is aliphatic.

[0061] In some embodiments, R 2 and R 3 together with the atoms therebetween form a 4- to 7-membered partially unsaturated or aromatic ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the ring is one of m examples of R 4 In some embodiments, R 2 and R 3 together with the atoms therebetween form a 5-membered partially unsaturated or aromatic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring is one of m examples of R 4 is replaced by .

[0062] As generally defined above, Cy 1is phenyl; a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; or a 7- to 12-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy is 1 is n examples of R 5 is replaced by .

[0063] In some embodiments, Cy 1 is phenyl. In some embodiments, Cy 1 is a 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1 is a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1 is a 6-membered heteroaryl having 1 to 4 nitrogen atoms. 1 is pyridyl. In some embodiments, Cy 1 is pyrazinyl. In some embodiments, Cy 1 is pyrimidinyl. In some embodiments, Cy 1 is triazinyl. In some embodiments, Cy 1 is pyrrolyl, pyrazolyl, imidazolyl, triazolyl, or tetrazolyl. In some embodiments, Cy1 is furanyl, oxazolyl, isoxazolyl, or oxadiazolyl; in some embodiments, Cy1 is thiophenyl, thiazolyl, isothiazolyl, or thiadiazolyl. In some embodiments, Cy1 is 1is an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy 1 is a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1 is a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring. 1 is a 7- to 12-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0064] In some embodiments, the combined Cy 1 (R 5 ) n is the following: [ka] [ka] [ka] where R, R C Each of q, q, and q, both alone and in combination, is as defined above and described in embodiments herein.

[0065] In some embodiments, the combined Cy 1 (R 5 ) n is the preceding paragraph or the following: [ka] is selected from the group

[0066] In some embodiments, the combined Cy 1 (R 5 ) n the preceding two paragraphs or the following: [ka] [ka] is selected from the group

[0067] As generally defined above, Cy 2 is phenyl; a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; or a 7- to 12-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy is 2 p examples of R 6 is replaced by .

[0068] In some embodiments, Cy 2 is phenyl. In some embodiments, Cy 2 is a 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 is a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 is a 6-membered heteroaryl having 1 to 4 nitrogen atoms. 2 is pyridyl. In some embodiments, Cy 2 is pyrazinyl. In some embodiments, Cy 2 is pyrimidinyl. In some embodiments, Cy 2 is triazinyl. In some embodiments, Cy2 is pyrrolyl, pyrazolyl, imidazolyl, triazolyl, or tetrazolyl. 2 is furanyl, oxazolyl, isoxazolyl, or oxadiazolyl, and in some embodiments, Cy 2 is thiophenyl, thiazolyl, isothiazolyl, or thiadiazolyl. In some embodiments, Cy 2 is an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy 2 is a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 is a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring. 2 is C 3~7 In some embodiments, Cy is cycloalkyl. 2 is cyclopropyl. In some embodiments, Cy 2 is a 7- to 12-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0069] In some embodiments, Cy 2 is selected from the following, each of which is a function of p examples of R 6 has been replaced by: [ka]

[0070] In some embodiments, Cy 2 is selected from the preceding paragraph or the following groups, each of which is selected from p examples of R 6 has been replaced by: [ka]

[0071] In some embodiments, p is 1 or 2 and R 6 At least one example of is -CN, -CH3, -CHF2, or -CF3.

[0072] As generally defined above, L 1 is a covalent bond, or C 1~4 wherein one or two methylene units of the chain are independently —C(R 7 )-, -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)-, -S(O)N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)-. In some embodiments, L 1 is a covalent bond. In some embodiments, L 1 is C 1~4 wherein one or two methylene units of the chain are independently —C(R 7 )-, -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)-, -S(O)N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)-. In some embodiments, L 1 is -N(R)-. In some embodiments, L 1 is -N(H)-.

[0073] As generally defined above, m is 0, 1, 2, 3, or 4. In some embodiments, m is 0. In some embodiments, m is 1, 2, 3, or 4. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.

[0074] As generally defined above, n is 0, 1, 2, 3, or 4. In some embodiments, n is 0. In some embodiments, n is 1, 2, 3, or 4. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0075] 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.

[0076] In some embodiments, the present invention provides a method for treating a cancer comprising administering to a subject a 1 is —N(H)—, thereby providing a compound of formula Ia: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula Ia, X, Cy 1 , R 1 , and R 2 Each of the is as defined above and described in embodiments herein, both alone and in combination.

[0077] In some embodiments, the present invention provides a method for treating rhodium wherein X is N or C(R 3 ) which gives the formula Ib or Ic, respectively: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula Ib and Ic, Cy 1 , L 1 , R 1, R 2 , and R 3 Each of the is as defined above and described in embodiments herein, both alone and in combination.

[0078] In some embodiments, the present invention provides a method for treating a cancer comprising administering to a subject a 1 is N or C(R 3 ) which gives the compound of formula II-a or II-b, respectively: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula II-a and II-b, Cy 1 , R 1 , R 2 , and R 3 Each of the is as defined above and described in embodiments herein, both alone and in combination.

[0079] In some embodiments, the present invention provides a method for the detection of Cy 1 is phenyl, thereby forming a compound of formula III-a or III-b, respectively: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula III-a and III-b, R 1 , R 2 , R 3 , R 5 and each of n, both alone and in combination, is as defined above and described in the embodiments herein.

[0080] In some embodiments, the present invention provides a compound wherein n is 1, 2, or 3 and R 5 At least one example of is ortho to the point of attachment of NH, thereby forming formula IV-a or IV-b, respectively: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula IV-a and IV-b, R 1 , R 2 , R 3 , and R 5 Each of the is as defined above and described in embodiments herein, both alone and in combination.

[0081] In some embodiments, the present invention provides an ortho R 5 The groups are -OR, -S(O)R, -C(O)NR, or -N(R)S(O)R, thereby forming compounds of formula Va, Vb, Vc, Vd, Ve, Vf, Vg, or Vh, respectively: [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein in formulas Va, Vb, Vc, Vd, Ve, Vf, Vg, and Vh, R, R 1 , R 2 , R 3 , and R 5 Each of the is as defined above and described in embodiments herein, both alone and in combination.

[0082] In some embodiments, the present invention provides a second R 5 Group (R 5b ) is meta to the point of attachment of NH, thereby forming the compound of formula VI-a, or VI-b, respectively: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula VI-a and VI-b, R, R 1 , R2 , R 3 , and R 5 Each of the is as defined above and described in embodiments herein, both alone and in combination.

[0083] In some embodiments, the present invention provides a method for treating a cancer comprising administering to a subject a cancer-causing agent comprising: 5 R B In some embodiments, the present invention provides a compound of formula VI-a or VI-b, wherein R 5 is —C(O)NR2 or a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and this ring is C The present invention provides a compound of formula VI-a or VI-b, wherein

[0084] In some embodiments, the invention provides compounds of formula VI-a or VI-b, where —OR is methoxy, fluoromethoxy, or difluoromethoxy.

[0085] In some embodiments, the present invention provides a method for the detection of Cy 1 is pyridyl, n is 2, and R 5 One example of is oxo, which results in a group of formula VII-a or VII-b, respectively: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula VII-a and VII-b, R 1 , R 2 , R 3 , and R 5 Each of the is as defined above and described in embodiments herein, both alone and in combination.

[0086] As noted above, in certain embodiments, the present invention provides a compound of formula VIII: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula VIII: X is N or C(R 3 ) and; Y is N or C(R 1 ) and; R 1 is H, D, or halogen; R, R D , OR; R 2 H, R C , -N(R)C(O)Cy 2 , -N(R)S(O)2Cy 2 , -N(R)Cy 2 , -OCy 2 , -SCy 2 , or Cy 2 and; R 3 is H, halogen, or C 1~6 Is aliphatic; or R 2 and R 3 together with the atoms therebetween form a 4- to 7-membered partially unsaturated or aromatic ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the ring is one of m examples of R 4 is replaced by; Cy 1 and Cy 2 each independently is phenyl; a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; or a 7- to 12-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 1 is n examples of R 5and Cy 2 p examples of R 6 is replaced by; Cy 3 is a 5- to 6-membered monocyclic partially unsaturated or heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 3 is r examples 8 is replaced by; L 1 is a covalent bond, or C 1~4 wherein one or two methylene units of the chain are independently —C(R 7 )2-, -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -OC(O)N(R)-, -N(R)C(O)O-, -S-, -S(O)- or -S(O)2-, as appropriate; R 4 , R 5 , R 6 , R 7 and R 8 Each instance of A or R B and q examples of R C has been replaced by; R A Each example is independently oxo, halogen, -CN, -NO2, -OR, -OR D , -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -O C(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, or -N(R)S(O)2R; R B Each example of C 1~6aliphatic; phenyl; a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated carbocyclic ring; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7- to 12-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R C 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)S(O)2NR2, or -N(R)S(O)2R, or an optionally substituted group, wherein the optionally substituted group is 1~6 selected from aliphatic, phenyl, 3- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R D is a C in which one or more hydrogens have been replaced by deuterium. 1~4 is an aliphatic group; Each R is independently hydrogen or an optionally substituted group, and the optionally substituted group is C 1~6 selected from aliphatic, phenyl, 3- to 7-membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same nitrogen, together with the atoms between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, from 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and Each of m, n, p, q, and r is independently 0, 1, 2, 3, or 4.

[0087] As generally defined above, X is N or C(R 3 ). In some embodiments, X is N. In some embodiments, X is C(R 3 ). In some embodiments, X is C(H). In some embodiments, X is C(R 3 ), where R 3 is halogen. In some embodiments, X is C(R 3 ), where R 3 is fluoro.

[0088] As generally defined above, Y is N or C(R 1 ). In some embodiments, Y is N. In some embodiments, Y is C(R 1 In some embodiments, Y is C(H). In some embodiments, Y is C(D). In some embodiments, Y is C(R 1 ), where R 1 is halogen. In some embodiments, X is C(R 1 ), where R 3 is fluoro.

[0089] As generally defined above, R 1 is H, D, or halogen. In some embodiments, R 1 is H. In some embodiments, R 1 is D. In some embodiments, R 1 is halogen. In some embodiments, R 1 is fluoro.

[0090] As generally defined above, R 2 H, R C , -N(R)C(O)Cy 2 , -N(R)Cy 2 , -OCy 2 , -SCy 2 , or Cy 2 In some embodiments, R 2 is H. In some embodiments, R 2 is R C , -N(R)C(O)Cy 2 , -N(R)Cy 2 , -OCy 2 , -SCy 2 , or Cy 2 In some embodiments, R 2 is R C In some embodiments, R 2 is —N(R)C(O)R. In some embodiments, R 2 is -N(R)C(O)Cy 2 , -N(R)Cy 2 , or Cy 2 In some embodiments, R 2 is -N(R)C(O)R, -N(R)C(O)Cy 2 , -N(R)Cy 2 , or Cy 2 In some embodiments, R 2 is -N(H)C(O)R, -N(H)C(O)Cy 2 , -N(H)Cy 2 , or Cy 2 In some embodiments, R 2 is -N(H)C(O)R, -N(H)C(O)Cy 2 , or -N(H)Cy 2 In some embodiments, R 2 is —N(H)C(O)R. In some embodiments, R 2 is —N(H)C(O)R, where R is, in this example, an optionally substituted C 1~6In some embodiments, R 2 is -N(H)C(O)Cy 2 In some embodiments, R 2 -N(H)Cy 2 In some embodiments, R 2 is -N(H)C(O)Cy 2 where Cy 2 is cyclopropyl. In some embodiments, R 2 teeth [ka] is.

[0091] In some embodiments, R 2 and R 3 together with the atoms therebetween form a 4- to 7-membered partially unsaturated or aromatic ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the ring is one of m examples of R 4 In some embodiments, R 2 and R 3 together with the atoms therebetween form a 5-membered partially unsaturated or aromatic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring is one of m examples of R 4 is replaced by .

[0092] As generally defined above, Cy 1is phenyl; a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; or a 7- to 12-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy is 1 is n examples of R 5 is replaced by .

[0093] In some embodiments, Cy 1 is phenyl. In some embodiments, Cy 1 is a 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1 is a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1 is a 6-membered heteroaryl having 1 to 4 nitrogen atoms. 1 is pyridyl. In some embodiments, Cy 1 is pyrazinyl. In some embodiments, Cy 1 is pyrimidinyl. In some embodiments, Cy 1 is triazinyl. In some embodiments, Cy 1 is pyrrolyl, pyrazolyl, imidazolyl, triazolyl, or tetrazolyl. In some embodiments, Cy1 is furanyl, oxazolyl, isoxazolyl, or oxadiazolyl; in some embodiments, Cy1 is thiophenyl, thiazolyl, isothiazolyl, or thiadiazolyl. In some embodiments, Cy1 is 1is an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy 1 is a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1 is a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring. 1 is a 7- to 12-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0094] In some embodiments, the combined Cy 1 (R 5 ) n is the following: [ka] [ka] where R, R C Each of q, q, and q, both alone and in combination, is as defined above and described in embodiments herein.

[0095] As generally defined above, Cy 2 is phenyl; a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; or a 7- to 12-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy is 2p examples of R 6 is replaced by .

[0096] In some embodiments, Cy 2 is phenyl. In some embodiments, Cy 2 is a 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 is a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 is a 6-membered heteroaryl having 1 to 4 nitrogen atoms. 2 is pyridyl. In some embodiments, Cy 2 is pyrazinyl. In some embodiments, Cy 2 is pyrimidinyl. In some embodiments, Cy 2 is triazinyl. In some embodiments, Cy 2 is pyrrolyl, pyrazolyl, imidazolyl, triazolyl, or tetrazolyl. 2 is furanyl, oxazolyl, isoxazolyl, or oxadiazolyl, and in some embodiments, Cy 2 is thiophenyl, thiazolyl, isothiazolyl, or thiadiazolyl. In some embodiments, Cy 2 is an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy 2 is a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 is a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring. 2 is C 3~7In some embodiments, Cy is cycloalkyl. 2 is cyclopropyl. In some embodiments, Cy 2 is a 7- to 12-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0097] In some embodiments, Cy 2 is selected from the following, each of which is a function of p examples of R 6 has been replaced by: [ka] [ka]

[0098] In some embodiments, Cy 2 is selected from the preceding paragraph or the following group, which is 6 has been replaced by: [ka]

[0099] As generally defined above, Cy 3 is a 5- to 6-membered monocyclic partially unsaturated or heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 3 is r examples 8 In some embodiments, Cy is substituted with 3 is a 5-membered monocyclic partially unsaturated or heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy 3 is a 5-membered monocyclic partially unsaturated ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy 3is a 5-membered monocyclic heteroaromatic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0100] In some embodiments, Cy 3 is selected from the following, each of which is a set of r examples 8 has been replaced by: [ka] [ka]

[0101] As generally defined above, L 1 is a covalent bond, or C 1~4 wherein one or two methylene units of the chain are independently —C(R 7 )-, -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)-, -S(O)N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)-. In some embodiments, L 1 is a covalent bond. In some embodiments, L 1 is C 1~4 wherein one or two methylene units of the chain are independently —C(R 7 )-, -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)-, -S(O)N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)-. In some embodiments, L 1 is -N(R)-. In some embodiments, L 1 is -N(H)-.

[0102] As generally defined above, R 8 are independent, R A or R B and q examples of R C In some embodiments, R 8 is halogen or 1 to 2 R C C is replaced by 1~6 In some embodiments, R 8 is halogen. In some embodiments, R 8 is 0 to 2 R C C is replaced by 1~6 In some embodiments, R 8 is chloro or fluoro. In some embodiments, R 8 is hydroxymethyl. In some embodiments, R 8 is chloro, fluoro, methyl, cyclopropyl, or hydroxymethyl. 8 is chloro, fluoro, or hydroxymethyl.

[0103] As generally defined above, m is 0, 1, 2, 3, or 4. In some embodiments, m is 0. In some embodiments, m is 1, 2, 3, or 4. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.

[0104] As generally defined above, n is 0, 1, 2, 3, or 4. In some embodiments, n is 0. In some embodiments, n is 1, 2, 3, or 4. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0105] 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.

[0106] As generally defined above, r is 0, 1, 2, 3, or 4. In some embodiments, r is 0. In some embodiments, r is 1, 2, 3, or 4. In some embodiments, r is 1. In some embodiments, r is 2. In some embodiments, r is 3. In some embodiments, r is 4.

[0107] In some embodiments, the present invention provides a method for treating a cancer comprising administering to a subject a 1 is —N(H)—, thereby providing a compound of formula VIII-a: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula VIII-a, X, Cy 1 , R 1 , and R 2 Each of the is as defined above and described in embodiments herein, both alone and in combination.

[0108] In some embodiments, the present invention provides a compound wherein X is C(R 3 ) and Y is C(R 1 ), or X is C(R3) and Y is N, or X is N and Y is C(R1), or both X and Y are N; thereby providing compounds of formula IX-a, IX-b, IX-c, or IX-d, respectively: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula IX-a, IX-b, IX-c, and IX-d, Cy 1 , Cy 3 , L 1 , R 1 , R 2 , and R 3 Each of the is as defined above and described in embodiments herein, both alone and in combination.

[0109] In some embodiments, the present invention provides a method for treating a cancer comprising administering to a subject a 1 is —N(H)—, thereby forming a compound of formula Xa or Xb, Xc, or Xd, respectively: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula Xa, Xb, Xc, and Xd, Cy 1 , Cy 3 , R 1 , R 2 , and R 3 Each of the is as defined above and described in embodiments herein, both alone and in combination.

[0110] In some embodiments, the present invention provides a method for the detection of Cy 1 is phenyl, thereby providing a compound of formula XI-a: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula XI-a, X, Y, R 2 , R 5 and each of n, both alone and in combination, is as defined above and described in the embodiments herein.

[0111] In some embodiments, the present invention provides a method for the detection of Cy 1is phenyl, thereby forming a compound of formula XI-b, XI-c, XI-d, or XI-e, respectively: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula XI-b, XI-c, XI-d, and XI-e, R 1 , R 2 , R 3 , R 5 and each of n, both alone and in combination, is as defined above and described in the embodiments herein.

[0112] In some embodiments, the present invention provides a method for preparing a compound having a hydroxyl group containing 1, 2, or 3, wherein n is 1, 2, or 3, and R 5 At least one example of the formula XII-a: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula XII-a, X, Y, Cy form a compound of formula XI-a: 3 , R 2 , and R 5 Each of the is as defined above and described in embodiments herein, both alone and in combination.

[0113] In some embodiments, the present invention provides a compound wherein n is 1, 2, or 3 and R 5 At least one example of XII-b, XII-c, XII-d, or XII-e: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula XII-b, XII-c, XII-d, and XII-e, Cy 3, R 1 , R 2 , R 3 , and R 5 Each of the is as defined above and described in embodiments herein, both alone and in combination.

[0114] In some embodiments, the present invention provides an ortho R 5 The groups are -OR, -S(O)R, -C(O)NR, or -N(R)S(O)R, thereby forming the compounds of formula XII-ai, XII-a-ii, XII-a-iii, or XII-a-iv, respectively: [ka] or a pharmaceutically acceptable salt thereof, wherein in formulas XII-ai, XII-a-ii, XII-a-iii, and XII-a-iv, X, Y, Cy 3 , R, R 1 , R 2 , R 3 , and R 5 Each of the is as defined above and described in embodiments herein, both alone and in combination.

[0115] In some embodiments, the present invention provides an ortho R 5 The groups are -OR, -S(O)R, -C(O)NR, or -N(R)S(O)R, thereby forming compounds of formula XII-bi, XII-b-ii, XII-b-iii, or XII-b-iv, respectively: [ka] or a pharmaceutically acceptable salt thereof, wherein in Formulas XII-bi, XII-b-ii, XII-b-iii, and XII-b-iv, Cy 3 , R, R 1 , R 2 , R 3 , and R 5Each of the is as defined above and described in embodiments herein, both alone and in combination.

[0116] In some embodiments, the present invention provides an ortho R 5 The groups are -OR, -S(O)R, -C(O)NR, or -N(R)S(O)R, thereby forming compounds of formula XII-ci, XII-c-ii, XII-c-iii, or XII-c-iv, respectively: [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein in Formulas XII-ci, XII-c-ii, XII-c-iii, and XII-c-iv, Cy 3 , R, R 2 , R 3 , and R 5 Each of the is as defined above and described in embodiments herein, both alone and in combination.

[0117] In some embodiments, the present invention provides an ortho R 5 The groups are -OR, -S(O)R, -C(O)NR, or -N(R)S(O)R, thereby forming compounds of formula XII-di, XII-d-ii, XII-d-iii, or XII-d-iv, respectively: [ka] or a pharmaceutically acceptable salt thereof, wherein in Formulas XII-di, XII-d-ii, XII-d-iii, and XII-d-iv, Cy 3 , R, R 1 , R 2 , and R 5 Each of the is as defined above and described in embodiments herein, both alone and in combination.

[0118] In some embodiments, the present invention provides an ortho R 5 The groups are -OR, -S(O)R, -C(O)NR, or -N(R)S(O)R, thereby forming compounds of formula XII-ei, XII-e-ii, XII-e-iii, or XII-e-iv, respectively: [ka] or a pharmaceutically acceptable salt thereof, wherein in formulas XII-ei, XII-e-ii, XII-e-iii, and XII-e-iv, Cy 3 , R, R 2 , and R 5 Each of the is as defined above and described in embodiments herein, both alone and in combination.

[0119] In some embodiments, the present invention provides a method for treating a cancer cell comprising administering to a patient a second R 5 The group is meta to the point of attachment of the NH, thereby providing a compound of formula XIII-a: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula XIII-a, X, Y, Cy form a compound of formula XII-ai or a pharmaceutically acceptable salt thereof. 3 , R, R 2 , and R 5 Each of the is as defined above and described in embodiments herein, both alone and in combination.

[0120] In some embodiments, the present invention provides a method for treating a cancer cell comprising administering to a patient a second R 5 The group is meta to the point of attachment of the NH, thereby forming a compound of formula XIII-b, XIII-c, XIII-d, or XIII-e: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula XIII-b, XIII-c, XIII-d, and XIII-e, Cy 3 , R, R 1 , R 2 , R 3 , and R 5 Each of the is as defined above and described in embodiments herein, both alone and in combination.

[0121] In some embodiments, the present invention provides a method for treating a cancer comprising administering to a subject a cancer-causing agent comprising: 5 R B In some embodiments, the present invention provides a compound of formula XIII-a, XIII-b, XIII-c, XIII-d, or XIII-e, wherein R 5 is —C(O)NR2 or a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and this ring is C

[0013] The present invention provides a compound of formula XIII-a, XIII-b, XIII-c, XIII-d, or XIII-e, wherein the compound is substituted by:

[0122] In some embodiments, the invention provides a compound of formula XIII-a, XIII-b, XIII-c, XIII-d, or XIII-e, where —OR is methoxy, fluoromethoxy, or difluoromethoxy.

[0123] In some embodiments, the present invention provides a method for the detection of Cy 1 is pyridyl, n is 2, and R 5 One example is oxo, which gives the compound of formula XIV-a: [ka] or a pharmaceutically acceptable salt thereof, wherein X, Y, Cy are each independently substituted or unsubstituted, and X, Y, Cy are each independently substituted or unsubstituted, and X, Y, Cy are each independently substituted or unsubstituted, and 3 , R 2, and R 5 Each of the is as defined above and described in embodiments herein, both alone and in combination.

[0124] In some embodiments, the present invention provides a method for the detection of Cy 1 is pyridyl, n is 2, and R 5 One example is oxo, which results in a group of formula XV-a, XV-b, XV-c, or XV-d: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula XV-a, XV-b, XV-c, and XV-d, Cy 3 , R 1 , R 2 , R 3 , and R 5 Each of the is as defined above and described in embodiments herein, both alone and in combination.

[0125] As noted above, in certain embodiments, the present invention provides a compound of formula XVI': [ka] or a pharmaceutically acceptable salt thereof, wherein in formula XVI': Q is CH or N; X is N or C(R X ) and; Y 1 , Y 2 , Z 1 , and Z 2 one of which is N and the other three are C; R 1 D, R, R D , -NR2, -NRR D , -N(R D )2, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)C(O)NRR D, -N(R)C(NR)NRR D , -OR, or -OR D and; R 2 H, R C , -N(R)C(O)Cy 2 , -N(R)S(O)2Cy 2 , -N(R)Cy 2 , -OCy 2 , -SCy 2 , or Cy 2 and; R 3 is H, halogen, or C 1~6 Is aliphatic; or R 2 and R 3 together with the atoms therebetween form a 4- to 7-membered partially unsaturated or aromatic ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the ring is one of m examples of R 4 is replaced by; Cy 1 and Cy 2 each independently is phenyl; a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; or a 7- to 12-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy 1 is n examples of R 5 and Cy 2 p examples of R 6 is replaced by; L 1 is a covalent bond, or C 1~4 wherein one or two methylene units of the chain are independently —C(R7 )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-, as appropriate; R 4 , R 5 , R 6 , and R 7 Each instance of A or R B and q examples of R C has been replaced by; R A Each example is independently oxo, halogen, -CN, -NO2, -OR, -OR D , -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -O C(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, or -N(R)S(O)2R; R B Each example of C 1~6 aliphatic; phenyl; a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated carbocyclic ring; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7- to 12-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R Cis 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)S(O)2NR2, or -N(R)S(O)2R, or an optionally substituted group, wherein the optionally substituted group is 1~6 selected from aliphatic, phenyl, 3- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R D is a C in which one or more hydrogens have been replaced by deuterium. 1~4 is an aliphatic group; R X is H, halogen, or C 1~6 is aliphatic, Each R is independently hydrogen or an optionally substituted group, and the optionally substituted group is C 1~6 selected from aliphatic, phenyl, 3- to 7-membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same nitrogen, together with the atoms between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, from 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and m, n, p, and q are independently 0, 1, 2, 3, or 4.

[0126] As generally defined above, Q is CH or N. In some embodiments, Q is CH. In some embodiments, Q is N.

[0127] As generally defined above, X is N or C(R X ). In some embodiments, X is N. In some embodiments, X is C(R X ). In some embodiments, X is C(H). In some embodiments, X is C(R X ), where R X is halogen. In some embodiments, X is C(R X ), where R X is fluoro.

[0128] As generally defined above, R 1 D, R, R D , -NR2, -NRR D , -N(R D )2, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)C(O)NRR D , -N(R)C(NR)NRR D , -OR, or -OR D In some embodiments, R 1 is D. In some embodiments, R 1 is R. In some embodiments, R 1 is R D In some embodiments, R 1 is -NR2. In some embodiments, R 1 Ha-NRR D In some embodiments, R 1 -N(R D )2. In some embodiments, R 1 In some embodiments, R 1 HA-OR D In some embodiments, R 1 is replaced by C 1~6In some embodiments, R 1 is an optionally substituted ethyl group. In some embodiments, R 1 is hydrogen, methyl, or -CD. In some embodiments, R 1 is hydrogen. In some embodiments, R 1 is methyl or -CD3. In some embodiments, R 1 is methyl. In some embodiments, R 1 is -CD3. In some embodiments, R 1 is —OCH. In some embodiments, R 1 D, R, R D , -NR2, -NRR D , -N(R D )2, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)C(O)NRR D , -N(R)C(NR)NRR D , -OR, or -OR D where R 1 is not hydrogen. In some embodiments, R 1 -NR2, -NRR D , -N(R D )2, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)C(O)NRR D , -N(R)C(NR)NRR D , -OR, or -OR D In some embodiments, R 1 -NR2, -NRR D , -N(R D )2, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)C(O)NRR D , -N(R)C(NR)NRR D In some embodiments, R 1 -NR2 or -NRR D In some embodiments, R 1 is replaced by C 1~6 Aliphatic, -NR2, or -NRR DIn some embodiments, R 1 -NHR or NHR D In some embodiments, R 1 is -NHCH3 or NHCD3.

[0129] As generally defined above, R 2 H, R C , -N(R)C(O)Cy 2 , -N(R)Cy 2 , -OCy 2 , -SCy 2 , or Cy 2 In some embodiments, R 2 is H. In some embodiments, R 2 is R C , -N(R)C(O)Cy 2 , -N(R)Cy 2 , -OCy 2 , -SCy 2 , or Cy 2 In some embodiments, R 2 is R C In some embodiments, R 2 is —N(R)C(O)R. In some embodiments, R 2 is -N(R)C(O)Cy 2 , -N(R)Cy 2 , or Cy 2 In some embodiments, R 2 is -N(R)C(O)R, -N(R)C(O)Cy 2 , -N(R)Cy 2 , or Cy 2 In some embodiments, R 2 is -N(H)C(O)R, -N(H)C(O)Cy 2 , -N(H)Cy 2 , or Cy 2 In some embodiments, R 2 is -N(H)C(O)R, -N(H)C(O)Cy 2 , or -N(H)Cy 2 In some embodiments, R2 is —N(H)C(O)R. In some embodiments, R 2 is —N(H)C(O)R, where R is, in this example, an optionally substituted C 1~6 In some embodiments, R 2 is -N(H)C(O)Cy 2 In some embodiments, R 2 -N(H)Cy 2 In some embodiments, R 2 is -N(H)C(O)Cy 2 where Cy 2 is cyclopropyl. In some embodiments, R 2 teeth [ka] is.

[0130] As generally defined above, R 3 is H, halogen, or C 1~6 In some embodiments, R 3 is H. In some embodiments, R 3 is a halogen, or C 1~6 In some embodiments, R 3 is halogen. In some embodiments, R 3 is fluoro. In some embodiments, R 3 is C 1~6 It is aliphatic.

[0131] In some embodiments, R 2 and R 3 together with the atoms therebetween form a 4- to 7-membered partially unsaturated or aromatic ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the ring is one of m examples of R 4 In some embodiments, R 2 and R 3together with the atoms therebetween form a 5-membered partially unsaturated or aromatic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring is one of m examples of R 4 is replaced by .

[0132] As generally defined above, Cy 1 is phenyl; a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; or a 7- to 12-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy is 1 is n examples of R 5 is replaced by .

[0133] In some embodiments, Cy 1 is phenyl. In some embodiments, Cy 1 is a 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1 is a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1 is a 6-membered heteroaryl having 1 to 4 nitrogen atoms. 1 is pyridyl. In some embodiments, Cy 1 is pyrazinyl. In some embodiments, Cy 1 is pyrimidinyl. In some embodiments, Cy 1 is triazinyl. In some embodiments, Cy 1is pyrrolyl, pyrazolyl, imidazolyl, triazolyl, or tetrazolyl. In some embodiments, Cy1 is furanyl, oxazolyl, isoxazolyl, or oxadiazolyl; in some embodiments, Cy1 is thiophenyl, thiazolyl, isothiazolyl, or thiadiazolyl. In some embodiments, Cy1 is 1 is an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy 1 is a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1 is a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring. 1 is a 7- to 12-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0134] In some embodiments, the combined Cy 1 (R 5 ) n is the following: [ka] [ka] [ka] where R, R C Each of q, q, and q, both alone and in combination, is as defined above and described in embodiments herein.

[0135] As generally defined above, Cy 2is phenyl; a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; or a 7- to 12-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy is 2 p examples of R 6 is replaced by .

[0136] In some embodiments, Cy 2 is phenyl. In some embodiments, Cy 2 is a 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 is a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 is a 6-membered heteroaryl having 1 to 4 nitrogen atoms. 2 is pyridyl. In some embodiments, Cy 2 is pyrazinyl. In some embodiments, Cy 2 is pyrimidinyl. In some embodiments, Cy 2 is triazinyl. In some embodiments, Cy 2 is pyrrolyl, pyrazolyl, imidazolyl, triazolyl, or tetrazolyl. 2 is furanyl, oxazolyl, isoxazolyl, or oxadiazolyl, and in some embodiments, Cy 2is thiophenyl, thiazolyl, isothiazolyl, or thiadiazolyl. In some embodiments, Cy 2 is an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy 2 is a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 is a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring. 2 is C 3~7 In some embodiments, Cy is cycloalkyl. 2 is cyclopropyl. In some embodiments, Cy 2 is a 7- to 12-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0137] In some embodiments, Cy 2 is selected from the following, each of which is a function of p examples of R 6 has been replaced by: [ka]

[0138] As generally defined above, L 1 is a covalent bond, or C 1~4 wherein one or two methylene units of the chain are independently —C(R 7 )-, -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)-, -S(O)N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)-. In some embodiments, L 1is a covalent bond. In some embodiments, L 1 is C 1~4 wherein one or two methylene units of the chain are independently —C(R 7 )2-, -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2-, as appropriate.

[0139] As generally defined above, m is 0, 1, 2, 3, or 4. In some embodiments, m is 0. In some embodiments, m is 1, 2, 3, or 4. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.

[0140] As generally defined above, n is 0, 1, 2, 3, or 4. In some embodiments, n is 0. In some embodiments, n is 1, 2, 3, or 4. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0141] 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.

[0142] In some embodiments, the present invention provides compounds wherein Q is N, thereby providing compounds of formula XVI: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula XVI: X is N or C(R X ) and; Y 1 , Y 2 , Z 1 , and Z 2 one of which is N and the other three are C; R 1 D, R, R D , -NR2, -NRR D , -N(R D )2, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)C(O)NRR D , -N(R)C(NR)NRR D , -OR, or -OR D and; R 2 H, R C , -N(R)C(O)Cy 2 , -N(R)S(O)2Cy 2 , -N(R)Cy 2 , -OCy 2 , -SCy 2 , or Cy 2 and; R 3 is H, halogen, or C 1~6 Is aliphatic; or R 2 and R 3 together with the atoms therebetween form a 4- to 7-membered partially unsaturated or aromatic ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the ring is one of m examples of R 4 is replaced by; Cy 1 and Cy 2each independently is phenyl; a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; or a 7- to 12-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy 1 is n examples of R 5 and Cy 2 p examples of R 6 is replaced by; L 1 is a covalent bond, or C 1~4 wherein one or two methylene units of the chain are independently —C(R 7 )2-, -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2-, as appropriate; R 4 , R 5 , R 6 , and R 7 Each instance of A or R B and q examples of R C has been replaced by; R A Each example is independently oxo, halogen, -CN, -NO2, -OR, -OR D, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -O C(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, or -N(R)S(O)2R; R B Each example of C 1~6 aliphatic; phenyl; a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated carbocyclic ring; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7- to 12-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R C 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)S(O)2NR2, or -N(R)S(O)2R, or an optionally substituted group, wherein the optionally substituted group is 1~6 selected from aliphatic, phenyl, 3- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R D is a C in which one or more hydrogens have been replaced by deuterium. 1~4is an aliphatic group; R X is H, halogen, or C 1~6 is aliphatic, Each R is independently hydrogen or an optionally substituted group, and the optionally substituted group is C 1~6 selected from aliphatic, phenyl, 3- to 7-membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same nitrogen, together with the atoms between them, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, from 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and m, n, p, and q are independently 0, 1, 2, 3, or 4.

[0143] In some embodiments, the present invention provides a method for treating a cancer comprising administering to a subject a 1 is a covalent bond, thereby forming a compound of formula XVI-a: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula XVI-a, X, Y 1 , Y 2 , Z 1 , Z 2 , Cy 1 , R 1 , R 2 , and R 3 Each of the is as defined above and described in embodiments herein, both alone and in combination.

[0144] In some embodiments, the present invention provides a method for treating cancer in which X is N or C(R X ) which gives the compounds of formula XVI-b or XVI-c, respectively: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula XVI-b and XVI-c, L 1 , Y 1 , Y 2 , Z 1 , Z 2 , Cy 1 , R X , R 1 , R 2 , and R 3 Each of the is as defined above and described in embodiments herein, both alone and in combination.

[0145] In some embodiments, the present invention provides a method for treating a cancer comprising administering to a subject a cancer-causing agent comprising: X and R 3 and XVII-b are both H, thereby forming a compound of formula XVII-a or XVII-b, respectively: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula XVII-a and XVII-b, Y 1 , Y 2 , Z 1 , Z 2 , Cy 1 , R 1 , R 2 , and R 3 Each of the is as defined above and described in embodiments herein, both alone and in combination.

[0146] In some embodiments, the present invention provides a method for treating a cancer comprising administering to a subject a 1 is a covalent bond, thereby forming a compound of formula XVIII-a or XVIII-b, respectively: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula XVIII-a and XVIII-b, Y 1 , Y2 , Z 1 , Z 2 , Cy 1 , R 1 , and R 2 Each of the is as defined above and described in embodiments herein, both alone and in combination.

[0147] In some embodiments, the present invention provides a method for the detection of Cy 1 is phenyl, thereby forming a compound of formula XIX-a or XIX-b, respectively: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula XIX-a and XIX-b, Y 1 , Y 2 , Z 1 , Z 2 , R 1 , R 2 and each of n, both alone and in combination, is as defined above and described in the embodiments herein.

[0148] In some embodiments, the present invention provides a compound wherein n is 1, 2, or 3 and R 5 At least one example of the formula XX-a or XX-b: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula XX-a and XX-b, Y 1 , Y 2 , Z 1 , Z 2 , R 1 , and R 2 Each of the is as defined above and described in embodiments herein, both alone and in combination.

[0149] In some embodiments, the present invention provides an ortho R 5 The groups are -OR, -S(O)R, -C(O)NR, or -N(R)S(O)R, thereby forming a compound of formula XXI-a, XXI-b, XXI-c, XXI-d, XXI-e, XXI-f, XXI-g, or XXI-h, respectively: [ka] or a pharmaceutically acceptable salt thereof, wherein in formulas XXI-a, XXI-b, XXI-c, XXI-d, XXI-e, XXI-f, XXI-g, and XXI-h, Y 1 , Y 2 , Z 1 , Z 2 , R, R 1 , R 2 , and R 5 Each of the is as defined above and described in embodiments herein, both alone and in combination.

[0150] In some embodiments, the present invention provides a method for treating a cancer cell comprising administering to a patient a second R 5 The group is meta to the point of attachment of the NH, thereby forming a compound of formula XXII-a, or XXII-b, respectively: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula XXII-a and XXII-b, Y 1 , Y 2 , Z 1 , Z 2 , R, R 1 , R 2 , and R 5 Each of the is as defined above and described in embodiments herein, both alone and in combination.

[0151] In some embodiments, the present invention provides a method for treating a cancer comprising administering to a subject a cancer-causing agent comprising: 5 R BIn some embodiments, the present invention provides a compound of formula XXII-a or XXII-b, wherein R 5 is -CN, -C(O)NR2, or a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and this ring is C The present invention provides a compound of formula XXII-a or XXII-b, wherein

[0152] In some embodiments, the invention provides compounds of formula XXII-a or XXII-b, where —OR is methoxy, fluoromethoxy, or difluoromethoxy.

[0153] In some embodiments, the present invention provides a method for the detection of Cy 1 is pyridyl, n is 2, and R 5 One example of is oxo, which results in the formation of the groups of formula XXIII-a or XXIII-b, respectively: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula XXIII-a and XXIII-b, Y 1 , Y 2 , Z 1 , Z 2 , R 1 , R 2 , and R 5 Each of the is as defined above and described in embodiments herein, both alone and in combination.

[0154] In some embodiments, the present invention provides a method for treating a cancer comprising administering to a subject a cancer-causing agent ... 2 is N and Y 1 , Y 2 , and Z 1is C. In some embodiments, the present invention provides a compound of one of formulas XVI-a, XVI-b, XVI-c, XVII-a, XVII-b, XVIII-a, XVIII-b, XIX-a, XIX-b, XX-a, XX-b, XXI-a, XXI-b, XXI-c, XXI-d, XXI-e, XXI-f, XXI-g, XXI-h, XXII-a, XXII-b, XXIII-a, or XXIII-b, wherein Y is C. 2 is N and Y 1 , Z 1 , and Z 2 is C.

[0155] In some embodiments, the present invention provides a method for treating a cancer comprising administering to a subject a cancer-causing agent ... 2 is N and Y 1 , Y 2 , and Z 1 is C; or Y 2 is N and Y 1 , Z 1 , and Z 2 is C, which gives the compound of formula XXIV-a or XXIV-b, respectively: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula XXIV-a and XXIV-b, X, L 1 , Cy 1 , R 1 , and R 2 Each of the is as defined above and described in embodiments herein, both alone and in combination.

[0156] In some embodiments, the present invention provides a method for treating a cancer comprising administering to a subject a 1is a covalent bond, thereby forming a compound of formula XXV-a or XXV-b, respectively: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula XXV-a and XXV-b, X, Cy 1 , R 1 , and R 2 Each of the is as defined above and described in embodiments herein, both alone and in combination.

[0157] In some embodiments, the present invention provides a method for treating psoriasis in which X is C and R X is H, thereby forming a compound of formula XXVI-a or XXVI-b, respectively: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula XXVI-a and XXVI-b, Cy 1 , R 1 , and R 2 Each of the is as defined above and described in embodiments herein, both alone and in combination.

[0158] In some embodiments, the present invention provides a method for treating a cancer comprising administering to a subject a cancer-causing agent comprising: 2 is -N(R)C(O)R, -N(R)C(O)Cy 2 , -N(R)Cy 2 , or Cy 2In some embodiments, the present invention provides a compound of one of formula XVI-a, XVI-b, XVI-c, XVII-a, XVII-b, XVIII-a, XVIII-b, XIX-a, XIX-b, XX-a, XX-b, XXI-a, XXI-b, XXI-c, XXI-d, XXI-e, XXI-f, XXI-g, XXI-h, XXII-a, XXII-b, XXIII-a, XXIII-b, XXIV-a, XXIV-b, XXV-a, XXV-b, XXVI-a, or XXVI-b, wherein R 2 is -N(H)C(O)R, -N(H)C(O)Cy 2 , -N(H)Cy 2 , or Cy 2 In some embodiments, the present invention provides a compound of one of formula XVI-a, XVI-b, XVI-c, XVII-a, XVII-b, XVIII-a, XVIII-b, XIX-a, XIX-b, XX-a, XX-b, XXI-a, XXI-b, XXI-c, XXI-d, XXI-e, XXI-f, XXI-g, XXI-h, XXII-a, XXII-b, XXIII-a, XXIII-b, XXIV-a, XXIV-b, XXV-a, XXV-b, XXVI-a, or XXVI-b, wherein R 2 is -N(H)C(O)R, -N(H)C(O)Cy 2 , or -N(H)Cy 2 In some embodiments, the present invention provides a compound of one of formula XVI-a, XVI-b, XVI-c, XVII-a, XVII-b, XVIII-a, XVIII-b, XIX-a, XIX-b, XX-a, XX-b, XXI-a, XXI-b, XXI-c, XXI-d, XXI-e, XXI-f, XXI-g, XXI-h, XXII-a, XXII-b, XXIII-a, XXIII-b, XXIV-a, XXIV-b, XXV-a, XXV-b, XXVI-a, or XXVI-b, wherein R 2is —N(H)C(O)R. In some embodiments, the present invention provides a compound of one of formulas XVI-a, XVI-b, XVI-c, XVII-a, XVII-b, XVIII-a, XVIII-b, XIX-a, XIX-b, XX-a, XX-b, XXI-a, XXI-b, XXI-c, XXI-d, XXI-e, XXI-f, XXI-g, XXI-h, XXII-a, XXII-b, XXIII-a, XXIII-b, XXIV-a, XXIV-b, XXV-a, XXV-b, XXVI-a, or XXVI-b, wherein R 2 but, [ka] In some embodiments, the present invention provides a compound of one of formula XVI-a, XVI-b, XVI-c, XVII-a, XVII-b, XVIII-a, XVIII-b, XIX-a, XIX-b, XX-a, XX-b, XXI-a, XXI-b, XXI-c, XXI-d, XXI-e, XXI-f, XXI-g, XXI-h, XXII-a, XXII-b, XXIII-a, XXIII-b, XXIV-a, XXIV-b, XXV-a, XXV-b, XXVI-a, or XXVI-b, wherein R 2 -N(H)Cy 2 where Cy 2 is selected from the following, each of which is a function of p examples of R 6 has been replaced by: [ka] Formulas XVI-a, XVI-b, XVI-c, XVII-a, XVII-b, XVIII-a, XVIII-b, XIX-a, XIX-b, XX-a, XX-b, XXI-a, XXI-b, XXI-c, XXI-d, XXI-e, XX Provided is a compound of one of I-f, XXI-g, XXI-h, XXII-a, XXII-b, XXIII-a, XXIII-b, XXIV-a, XXIV-b, XXV-a, XXV-b, XXVI-a, or XXVI-b.

[0159] In some embodiments, the present invention provides a compound of formula XVI: [ka] or a pharmaceutically acceptable salt thereof, wherein X, Y 1 , Y 2 , Z 1 , Z 2 , Cy 1 , R 1 , R 2 , and R 3 Each of the is as defined above and described in embodiments herein, both alone and in combination.

[0160] In some embodiments, the present invention provides a method for treating a cancer comprising administering to a subject a 1 is a covalent bond, thereby forming a compound of formula XVI-a': [ka] or a pharmaceutically acceptable salt thereof, wherein in formula XVI-a′, X, Y 1 , Y 2 , Z 1 , Z 2 , Cy 1 , R 1 , R 2 , and R 3 Each of the is as defined above and described in embodiments herein, both alone and in combination.

[0161] In some embodiments, the present invention provides a method for treating cancer in which X is N or C(R X ) which gives the formula XVI-b' or XVI-c', respectively: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula XVI-b′ and XVI-c′, L 1 , Y1 , Y 2 , Z 1 , Z 2 , Cy 1 , R X , R 1 , R 2 , and R 3 Each of the is as defined above and described in embodiments herein, both alone and in combination.

[0162] In some embodiments, the present invention provides a method for treating a cancer comprising administering to a subject a cancer-causing agent comprising: X and R 3 and XVII-b′ are both H, thereby forming a compound of formula XVII-a′ or XVII-b′, respectively: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula XVII-a′ and XVII-b′, Y 1 , Y 2 , Z 1 , Z 2 , Cy 1 , R 1 , R 2 , and R 3 Each of the is as defined above and described in embodiments herein, both alone and in combination.

[0163] In some embodiments, the present invention provides a method for treating a cancer comprising administering to a subject a 1 is a covalent bond, thereby forming a compound of formula XVIII-a′ or XVIII-b′, respectively: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula XVIII-a′ and XVIII-b′, Y 1 , Y 2 , Z 1 , Z 2 , Cy 1 , R 1 , and R2 Each of the is as defined above and described in embodiments herein, both alone and in combination.

[0164] In some embodiments, the present invention provides a method for the detection of Cy 1 is phenyl, thereby forming a compound of formula XIX-a' or XIX-b', respectively: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula XIX-a′ and XIX-b′, Y 1 , Y 2 , Z 1 , Z 2 , R 1 , R 2 and each of n, both alone and in combination, is as defined above and described in the embodiments herein.

[0165] In some embodiments, the present invention provides a compound wherein n is 1, 2, or 3 and R 5 At least one example of XX-a' or XX-b' is ortho to the point of attachment of NH, thereby forming the formula XX-a' or XX-b', respectively: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula XX-a′ and XX-b′, Y 1 , Y 2 , Z 1 , Z 2 , R 1 , and R 2 Each of the is as defined above and described in embodiments herein, both alone and in combination.

[0166] In some embodiments, the present invention provides an ortho R 5The groups are -OR, -S(O)R, -C(O)NR, or -N(R)S(O)R, thereby forming a compound of formula XXI-a', XXI-b', XXI-c', XXI-d', XXI-e', XXI-f', XXI-g', or XXI-h', respectively: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula XXI-a′, XXI-b′, XXI-c′, XXI-d′, XXI-e′, XXI-f′, XXI-g′, and XXI-h′, Y 1 , Y 2 , Z 1 , Z 2 , R, R 1 , R 2 , and R 5 Each of the is as defined above and described in embodiments herein, both alone and in combination.

[0167] In some embodiments, the present invention provides a method for treating a cancer cell comprising administering to a patient a second R 5 The group is meta to the point of attachment of the NH, thereby forming a compound of formula XXII-a', or XXII-b', respectively: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula XXII-a′ and XXII-b′, Y 1 , Y 2 , Z 1 , Z 2 , R, R 1 , R 2 , and R 5 Each of the is as defined above and described in embodiments herein, both alone and in combination.

[0168] In some embodiments, the present invention provides a method for treating a cancer comprising administering to a subject a cancer-causing agent comprising: 5 R BIn some embodiments, the present invention provides a compound of formula XXII-a' or XXII-b', wherein R 5 is —CN, —C(O)NR2, or a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and the ring is C The present invention provides a compound of formula XXII-a' or XXII-b', wherein:

[0169] In some embodiments, the invention provides a compound of Formula XXII-a' or XXII-b', where -OR is methoxy, fluoromethoxy, or difluoromethoxy.

[0170] In some embodiments, the present invention provides a method for the detection of Cy 1 is pyridyl, n is 2, and R 5 One example of is oxo, which results in the formation of the groups of formula XXIII-a' or XXIII-b', respectively: [ka] or a pharmaceutically acceptable salt thereof, which forms a pyridone compound of formula XXIII-a' or XXIII-b', 1 , Y 2 , Z 1 , Z 2 , R 1 , R 2 , and R 5 Each of the is as defined above and described in embodiments herein, both alone and in combination.

[0171] In some embodiments, the present invention provides a method for treating a cancer comprising administering to a subject a cancer-causing agent ... 2 is N and Y 1 , Y 2 , and Z 1is C. In some embodiments, the present invention provides a compound of one of Formulas XVI-a', XVI-b', XVI-c', XVII-a', XVII-b', XVIII-a', XVIII-b', XIX-a', XIX-b', XX-a', XX-b', XXI-a', XXI-b', XXI-c', XXI-d', XXI-e', XXI-f', XXI-g', XXI-h', XXII-a', XXII-b', XXIII-a', or XXIII-b', wherein Y is C. 2 is N and Y 1 , Z 1 , and Z 2 is C.

[0172] In some embodiments, the present invention provides a method for treating a cancer comprising administering to a subject a cancer-causing agent ... 2 is N and Y 1 , Y 2 , and Z 1 is C; or Y 2 is N and Y 1 , Z 1 , and Z 2 is C, thereby forming a compound of formula XXIV-a' or XXIV-b', respectively: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula XXIV-a' and XXIV-b', Q, X, L 1 , Cy 1 , R 1 , and R 2 Each of the is as defined above and described in embodiments herein, both alone and in combination.

[0173] In some embodiments, the present invention provides a method for treating a cancer comprising administering to a subject a 1 is a covalent bond, thereby forming a compound of formula XXV-a' or XXV-b', respectively: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula XXV-a' and XXV-b', Q, X, Cy 1 , R 1 , and R 2 Each of the is as defined above and described in embodiments herein, both alone and in combination.

[0174] In some embodiments, the present invention provides a method for treating psoriasis in which X is C and R X is H, thereby forming a compound of formula XXVI-a′ or XXVI-b′, respectively: [ka] or a pharmaceutically acceptable salt thereof, wherein in formula XXVI-a' and XXVI-b', Q, Cy 1 , R 1 , and R 2 Each of the is as defined above and described in embodiments herein, both alone and in combination.

[0175] In some embodiments, the present invention provides a method for treating a cancer comprising administering to a subject a cancer-causing agent comprising: 2 is -N(R)C(O)R, -N(R)C(O)Cy 2 , -N(R)Cy 2 , or Cy 2XVI-a、XVI-b、XVI-c、XVII-a、XVII-b、XVIII-a、XVIII-b、XIX- a、XIX-b、XX-a、XX-b、XXI-a、XXI-b、XXI-c、XXI-d、XXI-e、XXI-f、XXI -g、XXI-h、XXII-a、XXII-b、XXIII-a、XXIII-b、XXIV-a、XXIV-b、XXV- a、XXV-b、XXVI-a、XXVI-b、XVI'、XVI''、XVI-a'、XVI-b'、XVI-c'、XVII -a'、XVII-b'、XVIII-a'、XVIII-b'、XIX-a'、XIX-b'、XX-a'、XX-b'、X XXI-a'、XXI-b'、XXI-c'、XXI-d'、XXI-e'、XXI-f'、XXI-g'、XXI-h'、XXI I-a'、XXII-b'、XXIII-a'、XXIII-b'、XXIV-a'、XXIV-b'、XXV-a'、XXV -b'、XXVI-a'、またはXXVI-b'のうちの1つのYou cannot have anything else in your life. 2 が、-N(H)C(O)R、-N(H)C(O)Cy 2 、-N(H)Cy 2 、またはCy 2XVI-a、XVI-b、XVI-c、XVII-a、XVII-b、XVIII-a、XVIII-b、XIX- a、XIX-b、XX-a、XX-b、XXI-a、XXI-b、XXI-c、XXI-d、XXI-e、XXI-f、XXI -g、XXI-h、XXII-a、XXII-b、XXIII-a、XXIII-b、XXIV-a、XXIV-b、XXV- a、XXV-b、XXVI-a、XXVI-b、XVI'、XVI''、XVI-a'、XVI-b'、XVI-c'、XVII -a'、XVII-b'、XVIII-a'、XVIII-b'、XIX-a'、XIX-b'、XX-a'、XX-b'、X XXI-a'、XXI-b'、XXI-c'、XXI-d'、XXI-e'、XXI-f'、XXI-g'、XXI-h'、XXI I-a'、XXII-b'、XXIII-a'、XXIII-b'、XXIV-a'、XXIV-b'、XXV-a'、XXV -b'、XXVI-a'、またはXXVI-b'のうちの1つのYou cannot have anything else in your life. 2 が、-N(H)C(O)R、-N(H)C(O)Cy 2 、または-N(H)Cy 2 XVI-a、XVI-b、XVI-c、XVII-a、XVII-b、XVIII-a、XVIII-b、XIX- a、XIX-b、XX-a、XX-b、XXI-a、XXI-b、XXI-c、XXI-d、XXI-e、XXI-f、XXI -g、XXI-h、XXII-a、XXII-b、XXIII-a、XXIII-b、XXIV-a、XXIV-b、XXV- a、XXV-b、XXVI-a、XXVI-b、XVI'、XVI''、XVI-a'、XVI-b'、XVI-c'、XVII -a'、XVII-b'、XVIII-a'、XVIII-b'、XIX-a'、XIX-b'、XX-a'、XX-b'、X XXI-a'、XXI-b'、XXI-c'、XXI-d'、XXI-e'、XXI-f'、XXI-g'、XXI-h'、XXI I-a'、XXII-b'、XXIII-a'、XXIII-b'、XXIV-a'、XXIV-b'、XXV-a'、XXV -b'、XXVI-a'、またはXXVI-b'のうちの1つのYou cannot have anything else in your life.2 Provide a compound of one of formula XVI-a, XVI-b, XVI-c, XVII-a, XVII-b, XVIII-a, XVIII-b, XIX-a, XIX-b, XX-a, XX-b, XXI-a, XXI-b, XXI-c, XXI-d, XXI-e, XXI-f, XXI-g, XXI-h, XXII-a, XXII-b, XXIII-a, XXIII-b, XXIV-a, XXIV-b, XXV-a, XXV-b, XXVI-a, XXVI-b, XVI’, XVI’’, XVI-a’, XVI-b’, XVI-c’, XVII-a’, XVII-b’, XVIII-a’, XVIII-b’, XIX-a’, XIX-b’, XX-a’, XX-b’, XXI-a’, XXI-b’, XXI-c’, XXI-d’, XXI-e’, XXI-f’, XXI-g’, XXI-h’, XXII-a’, XXII-b’, XXIII-a’, XXIII-b’, XXIV-a’, XXIV-b’, XXV-a’, XXV-b’, XXVI-a’, or XXVI-b’ which is -N(H)C(O)R. In some embodiments, the invention relates to R 2 is

Chemical formula

[0176] Exemplary compounds of the present invention are set forth 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 Table 1-23 Table 1-24 Table 1-25 Table 1-26 Table 1-27 Table 1-28 Table 1-29 Table 1-30 Table 1-31 Table 1-32 Table 1-33 Table 1-34 Table 1-35 Table 1-36 Table 1-37 Table 1-38 Table 1-39 Table 1-40 Table 1-41 Table 1-42 Table 1-43 [Table 1-44] [Table 1-45] [Table 1-46] [Table 1-47] [Table 1-48] [Table 1-49] [Table 1-50] [Table 1-51]

[0177] Exemplary compounds of the present invention are set forth in Table 2 below. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5]

[0178] Exemplary compounds of the present invention are set forth in Table 3 below. [Table 3-1] [Table 3-2]

[0179] In some embodiments, the present invention provides a compound set forth in Table 1 above, or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a pharmaceutical composition comprising a compound set forth in Table 1 above, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, excipient, or diluent.

[0180] In some embodiments, the method utilizes a compound set forth in Table 2 above, or a pharmaceutically acceptable salt thereof. In some embodiments, the invention provides a compound set forth in Table 2 above, or a pharmaceutically acceptable salt thereof. In some embodiments, the invention provides a pharmaceutical composition comprising a compound set forth in Table 2 above, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, excipient, or diluent.

[0181] In some embodiments, the method utilizes a compound set forth in Table 3 above, or a pharmaceutically acceptable salt thereof. In some embodiments, the invention provides a compound set forth in Table 3 above, or a pharmaceutically acceptable salt thereof. In some embodiments, the invention provides a pharmaceutical composition comprising a compound set forth in Table 3 above, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, excipient, or diluent.

[0182] Without wishing to be bound by any particular theory, it is believed that the proximity of the inhibitor compound, or the pendant moiety of the inhibitor compound, to the water of interest facilitates the displacement or disruption of the water by the inhibitor compound, or the pendant moiety of the inhibitor compound. In some embodiments, the water molecule displaced or disrupted by the inhibitor compound, or the pendant moiety of the inhibitor compound, is a labile water molecule.

[0183] In certain embodiments, the method uses a complex comprising TYK2 and an inhibitor, in which at least one labile water of TYK2 is displaced or disrupted by the inhibitor, hi some embodiments, at least two selected labile waters are displaced or disrupted by the inhibitor. 4. General Methods of Providing the Compounds

[0184] The compounds of the invention may 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.

[0185] In some embodiments, compounds of Formula I are prepared according to the following general procedure illustrated in Scheme 1. Scheme 1. Synthesis of compounds of formula I. [ka]

[0186] L 1 In some embodiments, wherein 1 The -NH2 intermediate was prepared according to the methods described in WO2014074660A1, WO2014074661A1, and WO2015089143A1, each of which is incorporated herein by reference in its entirety.

[0187] In some embodiments, compounds of Formula VIIII are prepared according to the following general procedure, as illustrated in Scheme 2. Scheme 2. Synthesis of compounds of formula VIII. [ka]

[0188] L 1 In some embodiments, wherein 1The -NH2 intermediate was prepared according to the methods described in WO2014074660A1, WO2014074661A1, and WO2015089143A1, each of which is incorporated herein by reference in its entirety.

[0189] In some embodiments, compounds of Formula XXIV-b are prepared according to the following general procedure, as illustrated in Scheme 3. Scheme 3. Synthesis of compounds of formula XXIV-b. [ka] Here, X and L 1 , and Cy 1 Each of the is as defined above and in the embodiments herein, both alone and in combination. 5. Use, Prescription and Administration Pharmaceutically Acceptable Compositions

[0190] According to another embodiment, the present invention provides a composition comprising a compound of the present invention, or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of compound in the composition of the present invention is an amount effective to measurably inhibit TYK2 protein kinase or a mutant thereof in a biological sample or in a patient. In certain embodiments, the amount of compound in the composition of the present invention is an amount effective to measurably inhibit TYK2 protein kinase or a mutant thereof in a biological sample or in a patient. In certain embodiments, the composition of the present invention is formulated for administration to a patient in need of such a composition. In some embodiments, the composition of the present invention is formulated for oral administration to a patient.

[0191] The term "patient", as used herein, means an animal, preferably a mammal, and most preferably a human.

[0192] The term " pharmaceutically acceptable carrier, adjuvant or vehicle " refers to a non-toxic carrier, adjuvant or vehicle that does not destroy the pharmacological activity of the compound that it is formulated with.The pharmaceutically acceptable carrier, adjuvant or vehicle that can be used in the compositions of the present invention includes but is not limited to ion exchange material, alumina, aluminum stearate, lecithin, serum protein (for example, human serum albumin), buffer substance (for example, phosphate), glycine, sorbic acid, potassium sorbate, glyceride mixture of saturated vegetable fatty acid, water, salt or electrolyte (for example, protamine sulfate, sodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based material, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, wax, polyethylene-polyoxypropylene-block copolymer, polyethylene glycol and wool fat.

[0193] "Pharmaceutically acceptable derivative" means a non-toxic salt, ester, salt of an ester, or other derivative of a compound of the present invention which, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of the present invention or an inhibitory active metabolite or residue thereof.

[0194] As used herein, the term "inhibitorily active metabolite or residue thereof" means that a metabolite or residue thereof is also an inhibitor of TYK2 protein kinase, or a mutant thereof.

[0195] The compositions of the present invention can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir. The term "parenteral," as used herein, includes subcutaneous, intravenous, intramuscular, intraarterial, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. Preferably, these compositions are administered orally, intraperitoneally, or intravenously. Sterile injectable forms of the compositions of the present invention can be aqueous or oily suspensions. These suspensions can be formulated using appropriate dispersing or wetting agents and suspending agents according to techniques known in the art. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, such as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

[0196] For this purpose, any brand of fixed oil can be used, including synthetic monoglycerides or synthetic diglycerides.Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectable substances, as well as natural pharmaceutically acceptable oils (for example, olive oil or castor oil, especially their polyoxyethylated versions).These oil solutions or oil suspensions can also contain long-chain alcohol diluents or dispersants (for example, carboxymethylcellulose or similar dispersants commonly used in the formulation of pharmaceutically acceptable dosage forms, including emulsions and suspensions).Other commonly used surfactants (for example, Tweens, Spans and other emulsifiers or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solid, liquid or other dosage forms) can also be used for formulation purposes.

[0197] The pharmaceutically acceptable composition of the present invention can be orally administered 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 cornstarch.Lubricants such as magnesium stearate are also typically added.For oral administration in capsule form, useful diluents include lactose and dry cornstarch.When aqueous suspension is required for oral use, its active ingredient is combined with emulsifier and suspending agent.If desired, certain sweeteners, flavoring agents or coloring agents can also be added.

[0198] Alternatively, the pharmaceutically acceptable composition of the present invention can be administered in the form of suppositories for rectal administration. These can 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 to release the drug. Such materials include cocoa butter, beeswax, and polyethylene glycol.

[0199] The pharmaceutically acceptable compositions of this invention may also be administered topically, particularly when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0200] Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.

[0201] For topical application, provided pharmaceutically acceptable compositions can be formulated into a suitable ointment, 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 wax and water.Alternatively, provided pharmaceutically acceptable compositions can be formulated into a suitable lotion or cream, 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.

[0202] For ophthalmic use, the provided pharmaceutically acceptable compositions can be formulated as a micronized suspension in isotonic, pH-adjusted sterile saline, or preferably as a solution in isotonic, pH-adjusted sterile saline, either with or without a preservative, such as benzylalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutically acceptable compositions can be formulated in an ointment, such as petrolatum.

[0203] The pharmaceutically acceptable compositions of this invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0204] 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.

[0205] The amount of the compounds of the present invention that can be combined with the carrier materials to produce a formulation in a single dosage form will vary depending upon the host treated, the particular mode of administration, etc. Preferably, the compositions provided should be formulated so that a dosage of 0.01 mg / kg body weight / day to 100 mg / kg body weight / day of the inhibitor can be administered to a patient receiving these compositions.

[0206] It should also be understood that the specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the particular compound used, age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, as well as the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound of the invention in a composition will also depend on the particular compound in that composition. Uses of the Compounds and Pharmaceutically Acceptable Compositions

[0207] 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.

[0208] TYK2 is a non-receptor tyrosine kinase member of the Janus kinase (JAK) family of protein kinases. The mammalian JAK family consists of four members: TYK2, JAK1, JAK2, and JAK3. JAK proteins (including TYK2) are integrated for cytokine signaling. TYK2 associates with the cytoplasmic domains of type I and type II cytokine receptors and interferon type I and type III receptors and is activated by these receptors upon cytokine assembly. 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 cytokine, and LIF). Velasquez et al., "A protein kinase C (TYK2) activation is a key regulator of TYK2 activation," in Proc. 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. Activated TYK2 then proceeds to phosphorylate additional signaling proteins (e.g., members of the STAT family, including STAT1, STAT2, STAT4, and STAT6).

[0209] TYK2 activation by IL-23 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 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 a new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1," Nat. Genet. (2010) 42:985-992. Knockout or tyrphostin inhibition of TYK2 significantly reduces both IL-23- and IL-22-induced dermatitis. Ishizaki et al., "Tyk2 is a therapeutic target for psoriasis-like skin inflammation," Intl. Immunol. (2013), doi: 10.1093 / intimm / dxt062.

[0210] 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.

[0211] Reduced TYK2 activity confers protection of joints from collagen antibody-induced arthritis (a model of human rheumatoid arthritis). Mechanistically, reduced Tyk2 activity protects against T h 1 / T hTyk2 deficiency reduces the production of Tyk2-related cytokines and matrix metalloproteinases, as well as other key 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.

[0212] TYK2 knockout mice showed complete resistance to experimental autoimmune encephalomyelitis (EAE, an animal model of multiple sclerosis (MS)) compared with controls, and lacked 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 with MS susceptibility. Ban et al., "Replication analysis identifies TYK2 as a multiple sclerosis susceptibility factor," Eur J. Hum. Genet. (2009) 17:1309-1313. Loss of function mutations in TYK2 result in decreased demyelination and increased remyelination of neurons, further suggesting a role for TYK2 inhibitors in the treatment of MS and other CNS demyelinating disorders.

[0213] TYK2 is a single signaling messenger shared by IL-12 and IL-23. TYK2 knockout reduced methylated BSA injection-induced footpad thickness, imiquimod-induced psoriasis-like skin inflammation, and dextran sulfate sodium or 2,4,6-trinitrobenzenesulfonic acid-induced colitis in mice.

[0214] Joint linkage and association studies of various type I IFN signaling genes with systemic lupus erythematosus (SLE, an autoimmune disorder) showed a strong and significant correlation between loss of function mutations for TYK2 and reduced prevalence of SLE in families containing affected members. Sigurdsson et al., "Polymorphisms in the Tyrosine Kinase 2 and Interferon Regulatory Factor 5 Genes Are Associated with Systemic Lupus Erythematosus," Am. J. Hum. Genet. (2005) 76:528-537. A genome-wide association study of individuals with SLE in an unaffected cohort showed a highly 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.

[0215] TYK2 has been shown to play an important role in maintaining tumor surveillance, and TYK2 knockout mice exhibited impaired cytotoxic T cell responses and accelerated tumor development. However, these effects were coupled with sufficient suppression of natural killer (NK) and cytotoxic T lymphocytes, suggesting that TYK2 inhibitors would be highly suitable for the treatment of autoimmune disorders or transplant rejection. While other JAK family members (e.g., JAK3) have similar roles in the immune system, TYK2 has been suggested to be a better target because it participates 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.

[0216] However, in contradiction to the decreased tumor surveillance observed by Simma et al., studies in T-cell acute lymphoblastic leukemia (T-ALL) have shown 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, but not other JAK family members, reduced cell proliferation. Specific activating mutations in TYK2 that promote cancer cell survival include activating mutations in the FERM domain (G36D, S47N, and R425H), JH2 domain (V731I), and kinase domain (E957D and R1027H). However, it has also been identified that the kinase function of TYK2 is required for increased cancer cell survival. This is because TYK2 enzymes characterized by kinase-dead mutations (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.

[0217] Therefore, selective inhibition of TYK2 has been suggested to be a suitable target for IL-10 and / or BCL2-addicted 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.

[0218] TYK2-mediated STAT3 signaling has also been shown to mediate neuronal cell death caused by amyloid-β (Aβ) peptide. Reduced TYK2 phosphorylation of STAT3 after Aβ administration results in reduced neuronal cell death, and increased phosphorylation of STAT3 has been observed in postmortem brains of patients with Alzheimer's disease. 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.

[0219] Inhibition of the JAK-STAT signaling pathway is also involved in hair growth and 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.

[0220] Therefore, compounds that inhibit the activity of TYK2, particularly those with selectivity over JAK2, would be advantageous. Such compounds should induce a pharmacological response that favorably treats one or more of the conditions described herein without the side effects associated with inhibition of JAK2.

[0221] Although TYK2 inhibitors are known in the art, there remains a need to provide novel inhibitors that have more effective or superior pharmaceutically relevant properties, such as compounds with increased activity, selectivity over other JAK kinases (particularly JAK2), and ADMET (absorption, distribution, metabolism, excretion, and / or toxicity) properties. Thus, in some embodiments, the present invention provides inhibitors of TYK2 that exhibit selectivity over JAK2.

[0222] The activity of compounds utilized in the present invention as inhibitors of TYK2 or its mutants can be assayed in vitro, in vivo, or in cell lines. In vitro assays include assays that determine inhibition of either the phosphorylation activity and / or subsequent functional consequences, or the ATPase activity, of activated TYK2 or its mutants. An alternative in vitro assay quantifies the ability of the inhibitor to bind to TYK2. Inhibitor binding can be measured by radiolabeling the inhibitor prior to binding, isolating the inhibitor / TYK2 complex, and determining the amount of bound radiolabel. Alternatively, inhibitor binding can be determined by performing a competition experiment in which new inhibitors are incubated with TYK2 bound to a known radioligand. Representative in vitro and in vivo assays useful in evaluating TYK2 inhibitors include, for example, those described and disclosed in, each of which is incorporated herein by reference in its entirety. Detailed conditions for assaying compounds utilized in the present invention as inhibitors of TYK2 or its mutants are described in the Examples below.

[0223] As used herein, the terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset of, or inhibiting the progression of a disease or disorder, as described herein, or one or more symptoms thereof. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., taking into account a history of the symptoms and / or taking into account genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, e.g., to prevent or delay the recurrence of the symptoms.

[0224] The provided compounds are inhibitors of TYK2 and are therefore useful for treating one or more disorders associated with the activity of TYK2 or its mutants. Accordingly, in certain embodiments, the present invention provides a method of treating a TYK2-mediated disorder, comprising administering to a patient in need thereof a compound of the present invention or a pharmaceutically acceptable composition thereof.

[0225] As used herein, the term "TYK2-mediated" disorder, disease, and / or condition refers to any disease or other deleterious condition in which TYK2 or a variant thereof is known to play a role. Accordingly, another embodiment of the present invention relates to treating or lessening the severity of one or more diseases in which TYK2 or a variant thereof is known to play a role. Such TYK2-mediated disorders include, but are not limited to, autoimmune disorders, inflammatory disorders, proliferative disorders, endocrine disorders, neurological disorders, and transplant-related disorders.

[0226] In some embodiments, the present invention provides a method of treating one or more disorders, wherein the disorders are selected from an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, and a transplant-related disorder, comprising administering to a patient in need of such treatment a pharmaceutical composition containing an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof.

[0227] In some embodiments, the disorder is an autoimmune disorder, hi some embodiments, the disorder is selected from type 1 diabetes, systemic lupus erythematosus, multiple sclerosis, psoriasis, Behcet's disease, POEMS syndrome, Crohn's disease, ulcerative colitis, and inflammatory bowel disease.

[0228] In some embodiments, the disorder is an inflammatory disorder, hi some embodiments, the inflammatory disorder is rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis, hepatomegaly, Crohn's disease, ulcerative colitis, or inflammatory bowel disease.

[0229] In some embodiments, the disorder is a proliferative disorder. In some embodiments, the proliferative disorder is a hematological cancer. In some embodiments, the proliferative disorder is a leukemia. In some embodiments, the leukemia is a T-cell leukemia. In some embodiments, the T-cell leukemia is T-cell acute lymphoblastic leukemia (T-ALL). In some embodiments, the proliferative disorder is polycythemia vera, myelofibrosis, essential or thrombocytosis.

[0230] In some embodiments, the disorder is an endocrine disorder. In some embodiments, the endocrine disorder is polycystic ovary syndrome, Crouzon syndrome, or type 1 diabetes.

[0231] In some embodiments, the disorder is a neurological disorder. In some embodiments, the neurological disorder is Alzheimer's disease.

[0232] In some embodiments, the proliferative disorder is associated with one or more activating mutations in TYK2. In some embodiments, the activating mutation in TYK2 is a mutation in the FERM domain, JH2 domain, or kinase domain. In some embodiments, the activating mutation in TYK2 is selected from G36D, S47N, R425H, V731I, E957D, and R1027H.

[0233] In some embodiments, the disorder is transplant-related. In some embodiments, the transplant-related disorder is transplant rejection or graft-versus-host disease.

[0234] In some embodiments, the disorder is associated with type I interferon, IL-10, IL-12, or IL-23 signaling. In some embodiments, the disorder is associated with type I interferon signaling. In some embodiments, the disorder is associated with IL-10 signaling. In some embodiments, the disorder is associated with IL-12 signaling. In some embodiments, the disorder is associated with IL-23 signaling.

[0235] The compounds of the 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, systemic lupus erythematosus, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosa acquisita, acne vulgaris), and other inflammatory or allergic conditions of the skin.

[0236] The compounds of the invention may also be used in the treatment of other diseases or conditions (e.g., diseases or conditions having an inflammatory component), such as diseases and conditions of the eye (e.g., ocular allergies, conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis), diseases affecting the nose (including allergic rhinitis), and inflammatory diseases involving an autoimmune response or having an autoimmune component or etiology (e.g., autoimmune hematological disorders (e.g., hemolytic anemia, aplastic anemia, pure red cell aplasia, and idiopathic thrombocytopenia), systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome, idiopathic stroke, idiopathic stenosis, idiopathic rheumatoid arthritis, ... Prue, autoimmune inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), irritable bowel syndrome, celiac disease, periodontitis, hyaline membrane disease, kidney disease, glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine ophthalmopathy, Graves' disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), Sjögren's syndrome, keratoconjunctivitis sicca and vernal conjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, cryopyrin-associated periodic syndrome, nephritis, vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis (nephrotic syndrome (e.g., idiopathic nephrotic syndrome or minimal change nephropathy (minal Other conditions include: chronic granulomatous disease, endometriosis, leptospirosis, kidney disease, glaucoma, retinal disease, aging, headache, pain, complex regional pain syndrome, cardiac hypertrophy, muscle wasting, catabolic disorders, and steroid use disorders.disorder), obesity, fetal growth retardation, hypercholesterolemia, heart disease, chronic heart failure, mesothelioma, ahidrotic ectodermal dysplasia, Behçet's disease, incontinentia pigmenti, Paget's disease, pancreatitis, hereditary periodic fever syndromes, asthma (allergic and non-allergic, mild, moderate, severe, bronchitis, and exercise-induced), acute lung injury, acute respiratory distress syndrome, eosinophilia, hypersensitivity, anaphylaxis, sinusitis, ocular allergies, silica-induced disease, COPD (reduction of injury, airway inflammation, bronchial hyperactivity, remodeling, or disease progression), pulmonary disease, cystic fibrosis, acid-induced lung injury, pulmonary hypertension, multiple sclerosis Neuropathy, 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, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, lateral epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, Henoch-Schönlein purpura, hepatitis, hidradenitis abscess, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, and myelitis. myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, eustachian tube inflammation, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, tenosynovitis, vaginal inflammation, vasculitis, or vulvitis).

[0237] In some embodiments, the inflammatory disease that can be treated by the methods of the present invention is 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.

[0238] In some embodiments, the inflammatory disease that can be treated by the methods of the present invention is T h 1 or Th In some embodiments, the T h The 17-mediated disease is selected from systemic lupus erythematosus, multiple sclerosis, and inflammatory bowel disease (including Crohn's disease or ulcerative colitis).

[0239] In some embodiments, the inflammatory disease that can be treated by the methods of the present invention is selected from Sjogren's syndrome, allergic disorders, osteoarthritis, eye conditions (e.g., ocular allergies, conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis), and diseases affecting the nose (e.g., allergic rhinitis).

[0240] The present invention further provides the use of a compound as defined herein, or a pharmaceutically acceptable salt, or hydrate or solvate thereof, for the preparation of a medicament for the treatment of an autoimmune, inflammatory, or proliferative disorder, or a disorder commonly associated with transplantation. Combination therapy

[0241] Depending on the particular condition, or disease, to be treated, additional therapeutic agents, which are normally administered to treat that condition, may be administered in combination with the compounds and compositions of this invention. As used herein, additional therapeutic agents that are normally administered to treat a particular disease or condition are known as "appropriate for the disease, or condition, being treated."

[0242] In certain embodiments, provided combinations or compositions thereof are administered in combination with another therapeutic agent.

[0243] Examples of agents with which the combinations of the present invention may also be combined include, but are not limited to: agents for the treatment of Alzheimer's disease (e.g., Aricept® and Excelon®); agents for the treatment of HIV (e.g., ritonavir); agents for the treatment of Parkinson's disease (e.g., L-DOPA / carbidopa, entacapone, ropinirole, pramipexole, bromocriptine, pergolide, trihexephendyl, and amoxicillin); agents for treating multiple sclerosis (MS) (e.g., beta interferons (e.g., Avonex® and Rebif®), Copaxone®, and mitoxantrone); agents for treating asthma (e.g., albuterol and Singulair®); agents for treating schizophrenia (e.g., zyprexa, Risperdal, Risperdal, and haloperidol); anti-inflammatory agents (e.g., corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulatory and immunosuppressive agents (e.g., cyclosporine, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophosphamide, azathioprine, and sulfasalazine); neurotrophic factors (e.g., acetylcholinesterase inhibitors, MAO inhibitors, interferons, anticonvulsants, ion channel blockers, riluzole, and antiparkinsonian agents); agents for treating cardiovascular disease (e.g., beta-blockers, ACE inhibitors, diuretics, nitrates, , calcium channel blockers, and statins); agents for treating liver disease (e.g., corticosteroids, cholestyramine, interferons, and antivirals); agents for treating blood disorders (e.g., corticosteroids, anti-leukemia agents, growth factors and growth factors); agents that prolong or improve pharmacokinetics (e.g., cytochrome P450 inhibitors (i.e., inhibitors of metabolic degradation) and CYP3A4 inhibitors (e.g., ketokenozole and ritonavir)), and agents for treating immune deficiency disorders (e.g., gamma globulins).

[0244] In certain embodiments, the combination therapy of the invention or a pharmaceutically acceptable composition thereof is administered in combination with a monoclonal antibody or siRNA therapeutic agent.

[0245] These additional agents may be administered as part of a multiple 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 in a single dosage composition. When administered as part of a multiple dose regimen, these two active agents may be given simultaneously, sequentially, or within a period of each other (usually within 5 hours of each other).

[0246] 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 with another therapeutic agent simultaneously, sequentially in separate unit dosage forms, or together in a single unit dosage form.

[0247] The amount of additional therapeutic agent present in the compositions of the invention is no more than the amount that would normally be administered in a composition containing that therapeutic agent as the only active agent. Preferably, the amount of additional therapeutic agent in the compositions of the present disclosure ranges from about 50% to 100% of the amount that would normally be present in a composition containing that agent as the only therapeutically active agent.

[0248] In one embodiment, the present invention provides a composition containing a compound of Formula I, VIII, or XVI' and one or more additional therapeutic agents. The therapeutic agents may be administered together with the compound of Formula I, VIII, or XVI', or may be administered before or after the compound of Formula I, VIII, or XVI'. Suitable therapeutic agents are described in further detail below. In certain embodiments, the compound of Formula I, VIII, or XVI' may be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours before the therapeutic agent. In other embodiments, the compound of Formula I, VIII, or XVI' may be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours after the therapeutic agent.

[0249] In another embodiment, the present invention provides a method of treating an inflammatory disease, disorder, or condition by administering to a patient in need thereof a compound of Formula I, VIII, or XVI' and one or more additional therapeutic agents. Such additional 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®), antimalarials (e.g., hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®)), methotrexate (Rheumatrex®), and the like. (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, etc.). 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., 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., Tane tanezumab), anticoagulants (e.g., heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®)), antidiarrheal drugs (e.g., diphenoxylate (Lomotil®) and loperamide (Imodium®)), bile acid binders (e.g., cholestyramine), alosetron (Lotronex®), lubiprostone (Amitiza®), laxatives (e.g., milk of magnesia, polyethylene glycol (MiraLax®), Dulcolax®, Correctol®, and Senokot®), anticholinergic or antispasmodic drugs (e.g., dicyclomine (Bentyl®)), Singulair®, beta-2 agonists (e.g., albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaprotease inhibitors (e.g., methadone, methadone, methadone), methadone, ... anticholinergics (e.g., ipratropium bromide (Atrovent®) and tiotropium (Spiriva®)), inhaled corticosteroids (e.g., beclomethasone dipropionate (Beclovent®, Qvar®),and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmicort®), and flunisolide (Aerobid®), Afviar®, Symbicort®, Dulera®, cromolyn sodium (Intal®), methylxanthines (e.g., theophylline (Theo-Dur®, Theolair®, Slo-bid®), ®), Uniphyl®, Theo-24®, and aminophylline), IgE antibodies (e.g., omalizumab (Xolair®)), nucleoside reverse transcriptase inhibitors (e.g., zidovudine (Retrovir®), abacavir (Ziagen®), abacavir / lamivudine (Epzicom®), abacavir / lamivudine / zidovudine (Trizivir®), didanosine (Videx®), emtricitabine nucleoside reverse transcriptase inhibitors (e.g., delavirdine (Rescriptor®), efavirenz (Sustiva®), nevirapine (Viramune®), and etravirine (Intelence®)), nucleoside reverse transcriptase 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®),These include ritonavir (Norvir®), saquinavir (Fortvase® or Invirase®), and 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(s) thereof.

[0250] In another embodiment, the present invention provides a method of treating rheumatoid arthritis, comprising the step of administering to a patient in need thereof a compound of Formula I, VIII, or XVI' and one or more additional therapeutic agents, wherein the additional therapeutic agents are nonsteroidal anti-inflammatory drugs (NSAIDS) (e.g., aspirin, ibuprofen, naproxen, etodolac (Lodine®), and celecoxib), corticosteroids (e.g., prednisone, prednisolone, methylprednisolone, benzodiazepines, benzocaine ... antimalarials (e.g., hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®)), methotrexate (Rheumatrex®), gold salts (e.g., gold thioglucose (Solganal®), gold thiomalate (Myochrysine®), and auranofin (Ridaura®)), D-penicillin, Ciramine (Depen® or Cuprimine®), azathioprine (Imuran®), cyclophosphamide (Cytoxan®), chlorambucil (Leukeran®), cyclosporine (Sandimmune®), leflunomide (Arava®), as well as “anti-TNF” agents (e.g., etanercept (Enbrel®), infliximab (Remicade®), golimumab (Simponi®), and adalimumab (Humira®)), "anti-IL-1" agents (e.g., anakinra (Kineret®) and rilonacept (Arcalyst®)), antibodies (e.g., rituximab (Rituxan®)), "anti-T cell" agents (e.g., abatacept (Orencia®)), and "anti-IL-6" agents (e.g., tocilizumab (Actemra®)).

[0251] In some embodiments, the invention provides a method of treating osteoarthritis, comprising administering to a patient in need thereof a compound of Formula I, VIII, or XVI' and one or more additional therapeutic agents, wherein the additional therapeutic agents are 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).

[0252] In some embodiments, the present invention provides a method of treating systemic lupus erythematosus, comprising administering to a patient in need thereof a compound of Formula I, VIII, or XVI' and one or more additional therapeutic agents, wherein the additional therapeutic agents are acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDS) (e.g., aspirin, ibuprofen, naproxen, etodolac (Lodine®), and celecoxib), corticosteroids (e.g., prednisone, prednisolone, methylprednisolone, benzodiazepines, benzocaine ... anticoagulants (such as cyclosporine, cyclohexyl benzoate, and hydrocortisone), antimalarials (such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®)), cyclophosphamide (Cytoxan®), methotrexate (Rheumatrex®), azathioprine (Imuran®), and anticoagulants (such as heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®)).

[0253] In some embodiments, the present invention provides a method of treating Crohn's disease, ulcerative colitis, or inflammatory bowel disease, comprising administering to a patient in need thereof a compound of Formula I, VIII, or XVI' and one or more additional therapeutic agents, including mesalamine (Asacol®), sulfasalazine (Azulfidine®), antidiarrheal drugs (e.g., diphenoxylate (Lomotil®) and loperamide (Imodium®)), bile stimulating agents, and the like. Selected from acid-binding agents (e.g., cholestyramine, alosetron (Lotronex®), lubiprostone (Amitiza®)), laxatives (e.g., milk of magnesia, polyethylene glycol (MiraLax®), Dulcolax®, Correctol®, and Senokot®), and anticholinergics (e.g., antispasmodics such as dicyclomine (Bentyl®)), anti-TNF therapeutics, steroids, and antibiotics (e.g., Flagyl or ciprofloxacin).

[0254] In some embodiments, the present invention provides methods of treating asthma, comprising administering to a patient in need thereof a compound of Formula I, VIII, or XVI' and one or more additional therapeutic agents, including Singulair®, beta-2 agonists (e.g., albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®), and formoterol (Foradil®)), anticholinergics (e.g., ipratropium bromide (Atrovent®) and tiotropium (Spiriva®)), inhalants (e.g., benzodiazepines (Bordeaux®), ... The required corticosteroids are selected from corticosteroids (e.g., prednisone, prednisolone, beclomethasone dipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmicort®), 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®)).

[0255] In some embodiments, the invention provides methods of treating COPD, comprising administering to a patient in need thereof a compound of Formula I, VIII, or XVI' and one or more additional therapeutic agents, wherein the additional therapeutic agents are beta-2 agonists (e.g., albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®), and formoterol (Foradil®)), anticholinergics (e.g., ipratropium bromide (Atrovent®), and tiotropium (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 (Pulmicort®), flunisolide (Aerobid®), Afviar®, Symbicort®, and Dulera®).

[0256] In another embodiment, the invention provides a method of treating a hematological malignancy, comprising administering to a patient in need thereof a compound of Formula I, VIII, or XVI' and one or more additional therapeutic agents, wherein the additional therapeutic agents are selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, a BTK inhibitor, a JAK / pan-JAK inhibitor, a PI3K inhibitor, a SYK inhibitor, and combinations thereof.

[0257] In another embodiment, the invention provides a method of treating a solid tumor, comprising administering to a patient in need thereof a compound of Formula I, VIII, or XVI' and one or more additional therapeutic agents, wherein the additional therapeutic agents are selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, a BTK inhibitor, a JAK / pan-JAK inhibitor, a PI3K inhibitor, a SYK inhibitor, and combinations thereof.

[0258] In another embodiment, the present invention provides a method of treating a hematological malignancy, comprising administering to a patient in need thereof a compound of Formula I, VIII, or XVI' and a hedgehog (Hh) signaling pathway inhibitor. In some embodiments, the 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 July 17, and incorporated herein by reference in its entirety).

[0259] In another embodiment, the invention provides a method of treating diffuse large B-cell lymphoma (DLBCL), comprising administering to a patient in need thereof a compound of Formula I, VIII, or XVI' and one or more additional therapeutic agents, wherein the additional therapeutic agents are selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, and combinations thereof.

[0260] In another embodiment, the invention provides a method of treating multiple myeloma, comprising administering to a patient in need thereof a compound of Formula I, VIII, or XVI' and one or more additional therapeutic agents, wherein the additional therapeutic agents are 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®).

[0261] In another embodiment, the present invention provides a method of treating or lessening the severity of a disease, comprising administering to a patient in need thereof a compound of Formula I, VIII, or XVI′ and a BTK inhibitor, wherein the disease is inflammatory bowel disease, arthritis, systemic lupus erythematosus (SLE), vasculitis, idiopathic thrombocytopenic purpura (ITP), rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis, Graves' disease, autoimmune thyroiditis, Sjogren's syndrome, multiple sclerosis, systemic sclerosis, Lyme neuroborreliosis, Guillain-Barré syndrome, acute disseminated encephalospinal meningitis, Addison's disease, opsoclonus-myoclonus syndrome, or vasculitis. syndrome), ankylosing spondylitis, antiphospholipid syndrome, aplastic anemia, autoimmune hepatitis, autoimmune gastritis, pernicious anemia, celiac disease, Goodbacher's syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia universalis, Behçet's disease, chronic fatigue, autonomic neuropathy, membranous glomerular nephropathyglomerulonephropathy), endometriosis, interstitial cystitis, pemphigus vulgaris, bullous pemphigoid, neuromyotonia, scleroderma, chronic vulvodynia 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-versus-host disease, transplants, blood transfusions, anaphylaxis, allergies (e.g., allergies to plant pollen, latex, drugs, foods, insect venom, animal hair, animal dander, house dust mites, or cockroach calyces) ghee), type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, and atopic dermatitis, asthma, appendicitis, atopic dermatitis, asthma, allergies, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection, colitis, conjunctivitis, Crohn's disease, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, Henoch-Schönlein purpura, hepatitis, hidradenitis abscess, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitisMyocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, eustachian tube inflammation, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, tenosynovitis, sheath inflammation, vasculitis, or vulvitis, B-cell proliferative disorders (e.g., diffuse large B-cell lymphoma), follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma lymphoma / Waldenstrom's macroglobulinemia, splenic marginal zone lymphoma, multiple myeloma (also known as plasma cell myeloma), non-Hodgkin's lymphoma, Hodgkin's lymphoma, plasmacytoma, extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, Burkitt's lymphoma / leukemia, or lymphomatoid granulomatosis, breast cancer, prostate cancer, or cancer of mast cells (e.g., mastocytoma, mast cell leukemia, mast cell sarcoma) tumors, systemic mastocytosis), bone cancer, colorectal cancer, pancreatic cancer, bone and joint diseases (including, but not limited to, rheumatoid arthritis, seronegative spondylitis (including ankylosing spondylitis, psoriatic arthritis, and Reiter's disease), Behcet's disease, Sjogren'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 aortocoronary artery bypass, restenosis after aortocoronary artery bypass, stroke, transient ischemia, peripheral arterial occlusive disease, Disease, 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 (cholocystitis), agammaglobulinemia, psoriasis, allergies, Crohn's disease, irritable bowel syndrome, ulcerative colitis, Sjogren's disease, tissue graft rejection, hyperacute rejection of transplanted organs, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), autoimmune polyglandular diseasedisease) (also known as autoimmune polyendocrine syndrome), autoimmune alopecia, pernicious anemia, glomerulonephritis, dermatomyositis, multiple sclerosis, scleroderma, vasculitis, autoimmune hemolytic and thrombocytopenic states, Goodbaescher's syndrome, atherosclerosis, Addison's disease, Parkinson's disease, Alzheimer's disease, diabetes, septic shock, systemic lupus erythematosus (SLE), rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, osteoarthritis, chronic idiopathic thrombocytopenic purpura, Waldenstrom's macroglobulinemia, myasthenia gravis, Hashimoto's thyroiditis, atopic dermatitis, osteoarthritis, vitiligo, autoimmune hypopituitarism, Guillain-Barré syndrome, Behcet's disease, scleroderma, mycosis fungoides, acute inflammatory responses (e.g., acute respiratory distress syndrome and ischemia / reperfusion injury), and Graves' disease.

[0262] In another embodiment, the present invention provides a method of treating or lessening the severity of a disease, comprising administering to a patient in need thereof a compound of Formula I, VIII, or XVI' and a PI3K inhibitor, wherein the disease is selected from cancer, a neurodegenerative disorder, an angiogenic disorder, a viral disease, an autoimmune disease, an inflammatory disorder, a hormone-related disease, a condition associated with organ transplantation, an immunodeficiency disorder, a destructive bone disorder, a proliferative disorder, an infectious disease, a condition associated with cell death, thrombin-induced platelet aggregation, chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), a liver disease, a pathological immune condition involving T-cell activation, a cardiovascular disorder, and a CNS disorder.

[0263] In another embodiment, the present invention provides a method of treating or lessening the severity of a disease, comprising administering to a patient in need thereof a compound of Formula I, VIII, or XVI' and a PI3K inhibitor, 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, genitourinary tract, esophagus, larynx, skin, bone or thyroid; sarcoma, glioblastoma, Neuroblastoma, multiple myeloma or gastrointestinal cancer (especially colon carcinoma or colon adenoma or head and neck tumors), epidermal hyperproliferation, psoriasis, prostatic hyperplasia, neoplasia, neoplasia of epithelial character, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung carcinoma, lymphoma (including, for example, non-Hodgkin's lymphoma (NHL) and Hodgkin's lymphoma (also called Hodgkin or Hodgkin's disease)), breast cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, or leukemia, Cowden syndrome, Lhermitte-Duclos disease, and Bannayan-Zonana syndrome syndrome) or diseases in which the PI3K / PKB pathway is abnormally activated, asthma of any type or onset, including both intrinsic (non-allergic) and extrinsic (allergic) asthma, mild 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 distress syndrome (ARDS), chronic obstructive pulmonary artery disease, chronic obstructive airway disease or chronic obstructive pulmonary disease (COPD, COAD or COLD) (and related emphysema, and exacerbations of airway overactivity as a result of other medications (especially other inhaled medications); bronchitis of any type or occurrence (including, but not limited to, acute, arachidic, catarrhal, croupus, chronic or tuberculous bronchitis); pneumoconiosis of any type or occurrence (an inflammatory, generally occupational, lung disease, whether chronic or acute, frequently associated with airway obstruction and resulting from repeated inhalation of dust) (e.g., aluminum lung disease, anthraxosis, asbestosis, stone pneumonia, ostrich pneumonitis,eosinophil-related disorders of the respiratory tract, which may be the result of or occur concurrently with: siderosis, silicosis, tobacco poisoning, and byssinosis; Leffler's syndrome; eosinophilic pneumonia; parasitic (especially metazoan) infestations (including tropical eosinophilia); bronchopulmonary aspergillosis; polyarteritis nodosa (including Churg-Strauss syndrome); eosinophilic granulomas; and eosinophil-related disorders affecting the respiratory tract caused by drug reactions; psoriasis; contact dermatitis; atopy dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity vasculitis, urticaria, bullous pemphigoid, lupus erythematosus, pemphigus, epidermolysis bullosa acquisita, conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, diseases affecting the nose (including allergic rhinitis), and inflammatory diseases involving an autoimmune response or having an autoimmune component or etiology (autoimmune hematological disorders (e.g., hemolytic anemia, aplastic anemia, pure red cell aplasia, and idiopathic thrombocytopenia), allergic rhinitis, rheumatoid arthr ... Systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), endocrine ophthalmopathy, Graves' disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), keratoconjunctivitis sicca and vernal conjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis The disease is selected from arthritis and glomerulonephritis (including with or without nephrotic syndrome (including, for example, idiopathic nephrotic syndrome or minimal change nephropathy)), restenosis, cardiac hypertrophy, atherosclerosis, myocardial infarction, ischemic stroke and congestive heart failure, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and cerebral ischemia, as well as neurodegenerative diseases caused by trauma, glutamate neurotoxicity, and hypoxia.

[0264] In some embodiments, the invention provides a method of treating or lessening the severity of a disease, comprising administering to a patient in need thereof a compound of Formula I, VIII, or XVI' and a Bcl-2 inhibitor, wherein the disease is an inflammatory disorder, an autoimmune disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a 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.

[0265] In some embodiments, the present invention provides a method of treating or lessening the severity of a disease, comprising administering to a patient in need thereof a TYK2 pseudokinase (JH2) domain-binding compound and a TYK2 kinase (JH1) domain-binding compound. 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-binding compound is a compound of Formula I, VIII, or XVI'. Other suitable JH2 domain-binding compounds include those described in WO2014074660A1, WO2014074661A1, and WO2015089143A1, each of which is incorporated herein by reference in its entirety. Suitable JH1 domain-binding compounds include those described in WO2015131080A1, each of which is incorporated herein by reference in its entirety.

[0266] These compounds and compositions can be administered in any amount and by any route of administration effective for treating or reducing the severity of autoimmune, inflammatory, proliferative, endocrine, neurological, 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 species, age, and sex of the subject, the severity of the infection, the specific agent, the method of administration, and the like. The compounds of the present invention are preferably formulated into a unit dosage form for ease of administration and uniformity of dosage. As used herein, the term "unit dosage form" refers to a physically separate unit of medication appropriate for the patient being treated. However, it will be understood that the total daily dosage of the compounds and compositions of the present invention will be determined by the attending physician within the scope of sound medical judgment. The effective dosage level specific to any particular patient or organism will depend on a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the particular compound used; the particular composition used; the patient's age, weight, general health, sex, and diet; the time of administration, route of administration, and rate of excretion of the particular compound used; the duration of treatment; drugs used in combination with or concomitantly 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.

[0267] The pharmaceutically acceptable compositions of the present invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (such as by powders, ointments, or drops), bucally, or as an oral or nasal spray, depending on the severity of the infection being treated. In certain embodiments, the compounds of the present invention can be administered orally or parenterally at dosage levels of about 0.01 mg / kg to about 50 mg / kg, preferably about 1 mg / kg to about 25 mg / kg, of subject body weight per day, one or more times daily to achieve the desired therapeutic effect.

[0268] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers, such as 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, and mixtures thereof. In addition to inert diluents, oral compositions may also contain adjuvants such as wetting agents, emulsifying agents, and suspending agents, as well as sweeteners, flavoring agents, and fragrances.

[0269] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, can be formulated by known techniques using appropriate dispersing or wetting agents and suspending agents. Sterile injectable preparations can also be sterile injectable solutions, suspensions, or emulsions in non-toxic parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution, USP, and isotonic sodium chloride solution. Additionally, sterile, fixed oils are conventionally used as solvents or suspending media. For this purpose, any bland, fixed oil, including synthetic monoglycerides or diglycerides, can be used. Additionally, fatty acids, such as oleic acid, are used in the preparation of injectables.

[0270] Injectable formulations can be sterilized prior to use, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium.

[0271] To prolong the effects of a compound of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound therefore depends on its rate of dissolution, which may depend on crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form can be achieved by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsulated matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. The compound release rate can be controlled depending on the ratio of compound to polymer and the nature of the particular polymer used. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations can also be prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0272] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing a compound of the invention with a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol, or a suppository wax which is solid at ambient temperature but liquid at body temperature and therefore melts in the rectum or vaginal cavity and releases the active compound.

[0273] 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 extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; c) humectants such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retarding agents such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) humectants such as, for example, 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 glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0274] Solid compositions of a similar type may also be used as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical compounding art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be used as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like.

[0275] The active compound may also be in microencapsulated form with one or more of the excipients described above. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings, release-controlling coatings, and other coatings well known in the pharmaceutical compounding art. In such solid dosage forms, the active compound may be mixed with at least one inert diluent, such as sucrose, lactose, or starch. As is common practice, such dosage forms may contain additional substances other than inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate or microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage forms may also contain buffering agents. They may optionally contain opacifying agents, and may be of a composition that releases the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0276] Dosage forms for topical or transdermal administration 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 needed preservatives or buffers, as needed. Ophthalmic formulations, ear drops, and eye drops are also contemplated within the scope of the present invention. The present invention also contemplates the use of transdermal patches, which have the added advantage of providing controlled compound delivery to the body. Such dosage forms can be made by dissolving or dispersing the compound in a suitable medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by providing a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0277] According to one embodiment, the present invention relates to a method of 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 comprising said compound.

[0278] According to another embodiment, the present invention relates to a method for inhibiting the activity of TYK2, or a mutant thereof, in a biological sample, comprising contacting the biological sample with a compound of the present invention or a composition containing the compound. In certain embodiments, the present invention relates to a method for irreversibly inhibiting the activity of TYK2, or a mutant thereof, in a biological sample, comprising contacting the biological sample with a compound of the present invention or a composition containing the compound.

[0279] In another embodiment, the present invention provides a method for selectively inhibiting TYK2 over one or more of JAK1, JAK2, and JAK3. In some embodiments, compounds of the present invention are more than 2-fold selective over JAK1 / 2 / 3. In some embodiments, compounds of the present invention are more than 5-fold selective over JAK1 / 2 / 3. In some embodiments, compounds of the present invention are more than 10-fold selective over JAK1 / 2 / 3. In some embodiments, compounds of the present invention are more than 50-fold selective over JAK1 / 2 / 3. In some embodiments, compounds of the present invention are more than 100-fold selective over JAK1 / 2 / 3.

[0280] The term "biological sample," as used herein, includes, but is not limited to, cell cultures or extracts thereof; biopsies or extracts thereof obtained from mammals; and blood, saliva, urine, feces, semen, tears, or other bodily fluids or extracts thereof.

[0281] Inhibition of TYK2 (or a variant thereof) activity in a biological sample is useful for a variety of purposes known to those skilled in the art, including, but not limited to, blood transfusion, organ transplantation, biological specimen storage, and biological assays.

[0282] Another embodiment of the invention relates to a method of inhibiting protein kinase activity in a patient, comprising administering to the patient a compound of the invention, or a composition containing the compound.

[0283] According to another embodiment, the present invention relates to a method of inhibiting the activity of TYK2, or a mutant thereof, in a patient, comprising administering to the patient a compound of the present invention or a composition containing the compound. According to certain embodiments, the present invention relates to a method of reversibly or irreversibly inhibiting the activity of TYK2, or one or more mutants thereof, in a patient, comprising administering to the patient a compound of the present invention or a composition containing the compound. In other embodiments, the present invention provides a method of treating a disorder mediated by TYK2, or a mutant thereof, in a patient in need thereof, comprising administering to the patient a compound according to the present invention or a pharmaceutically acceptable composition thereof. Such disorders are described in detail herein.

[0284] Depending on the particular condition, or disease, to be treated, additional therapeutic agents, which are normally administered to treat that condition, may also be present in the compositions of this invention. Additional therapeutic agents that are normally administered to treat a particular disease, or condition, are known herein as "appropriate for the disease, or condition, being treated."

[0285] 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; antiestrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule-active compounds; alkylating compounds; histone deacetylase inhibitors; compounds that induce cell differentiation processes; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; antitumor antimetabolites; platin compounds; compounds that target / reduce protein or lipid kinase activity and further antiangiogenic compounds; compounds that target, reduce or inhibit protein or lipid phosphatase activity; gonadorelin agonists; antiandrogens; methionine aminopeptidase inhibitors; matrix metalloproteinase inhibitors; compounds used in the treatment of hematological malignancies; compounds that target, decrease, or inhibit the activity of Flt-3; Hsp90 inhibitors (e.g., 17-AAG (17-allylaminogeldanamycin, NSC330507), 17-DMAG (17-dimethylaminoethylamino-17-dimethoxy-geldanamycin, NSC707545), IPI-504, CNF1010, CNF2024, CNF1010 (Conforma Therapeutics); temozolomide (Temodar®); kinesin spindle protein inhibitors (e.g., SB715992 or SB743921 (GlaxoSmithKline), or pentamidine / chlorpromazine (CombinatoRx)); MEK inhibitors (e.g., ARRY142886 (Array BioPharma), AZD6244 (AstraZeneca), PD181461 (Pfizer) and leucovorin). The term "aromatase inhibitor", as used herein, relates to a compound that inhibits estrogen production (e.g., the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively).The term includes, but is not limited to, steroids (particularly atamestane, exemestane, and formestane), and particularly non-steroids (particularly aminoglutethimide, roglethimide, pyridoglutethimide, trilostane, testolactone, ketoconazole, vorozole, fadrozole, anastrozole, and letrozole). Exemestane is sold under the trade name Aromasin. TM Formestane is marketed under the trade name Lentaron. TM Fadrozole is marketed under the brand name Afema. TM Anastrozole is marketed under the brand name Arimidex. TM Letrozole is marketed under the brand name Femara. TM or Femar TM Aminoglutethimide is marketed under the trade name Orimeten. TM Combinations of the present invention which contain a chemotherapeutic agent that is an aromatase inhibitor are particularly useful for the treatment of hormone receptor positive tumors (eg, breast tumors).

[0286] 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 sold under the trade name Novaldex. TM Raloxifene hydrochloride is marketed under the brand name Evista. TM Fulvestrant is marketed under the trade name Faslodex. TM The combinations of this invention which contain a chemotherapeutic agent that is an anti-estrogen are particularly useful for the treatment of estrogen receptor positive tumors (eg, breast tumors).

[0287] The term "antiandrogenic" as used herein relates to any substance that can inhibit the biological effects of androgenic hormones, and includes bicalutamide (Casodex). TM The term "gonadorelin agonist" as used herein includes, but is not limited to, abarelix, goserelin, and goserelin acetate. Goserelin is sold under the trade name Zoladex. TM It can be administered under

[0288] The term "topoisomerase I inhibitors" as used herein includes, but is not limited to, topotecan, gimatecan, irinotecan, camptothecin and its analogs, 9-nitrocamptothecin, and the polymeric camptothecin conjugate PNU-166148. Irinotecan is known, for example, from Camptosar TM Topotecan can be administered in the form in which it is marketed under the trade name Hycamptin. TM It is on the market under the

[0289] The term "topoisomerase II inhibitors," as used herein, refers to anthracyclines (e.g., doxorubicin (Caelyx) TM These include, but are not limited to, the anthraquinones mitoxantrone and losoxantrone, and the podophyllotoxins etoposide and teniposide. Etoposide is sold under the trade name Etopophos. TM Teniposide is marketed under the trade name VM 26-Bristol. Doxorubicin is marketed under the trade name Acriblastin. TM or Adriamycin TM Epirubicin is marketed under the trade name Farmorubicin. TMIdarubicin is marketed under the trade name Zavedos. TM Mitoxantrone is marketed under the trade name Novantrone.

[0290] The term "microtubule active agent" refers to microtubule stabilizing compounds, microtubule destabilizing compounds and microtubule polymerization inhibitors, including, but not limited to, taxanes (e.g., paclitaxel and docetaxel); vinca alkaloids (e.g., vinblastine or vinblastine sulfate, vincristine or vincristine sulfate, and vinorelbine); discodermolide; colchicine and epothilone and their derivatives. Paclitaxel is sold under the trade name Taxol. TM Docetaxel is marketed under the trade name Taxotere. TM Vinblastine sulfate is marketed under the trade name Vinblastine RP. TM Vincristine sulfate is marketed under the trade name Farmistin. TM It is on the market under the

[0291] The term "alkylating agent" as used herein includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan, or nitrosourea (BCNU or Gliadel). Cyclophosphamide is sold under the trade name Cyclostin. TM Ifosfamide is marketed under the trade name Holoxan. TM It is on the market under the

[0292] The term "histone deacetylase inhibitors" or "HDAC inhibitors" relates to compounds which inhibit histone deacetylase and which possess antiproliferative activity, including, but not limited to, suberoylanilide hydroxamic acid (SAHA).

[0293] The term "antineoplastic antimetabolites" includes, but is not limited to, 5-fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylating compounds (e.g., 5-azacytidine and decitabine), methotrexate and edatrexate, and folate antagonists (e.g., pemetrexed). Capecitabine is sold under the trade name Xeloda. TM Gemcitabine is marketed under the brand name Gemzar. TM It is on the market under the

[0294] The term "platin compound" as used herein includes, but is not limited to, carboplatin, cisplatin, cisplatinum, and oxaliplatin. Carboplatin is, for example, Carboplat TM Oxaliplatin can be administered in the form as it is marketed under the trademark Eloxatin. TM It can be administered in the form as it is marketed under the trademark EP160626.

[0295] The term "compounds which target / reduce protein or lipid kinase activity; or compounds which target / reduce protein or lipid phosphatase activity; or further anti-angiogenic compounds", as used herein, refers to protein tyrosine kinase and / or serine and / or threonine kinase inhibitors, or lipid kinase inhibitors, such as a) compounds which target, reduce or inhibit the activity of platelet-derived growth factor receptors (PDGFRs) (e.g. compounds which target, reduce or inhibit the activity of PDGFRs, in particular compounds which inhibit PDGF receptors, for example N-phenyl-2-pyrimidine-amine derivatives, such as imatinib, SU101, SU6668 and GFB-111); b) compounds which target, reduce or inhibit the activity of fibroblast growth factor receptors (FGFRs); c) compounds which target, reduce or inhibit the activity of insulin-like growth factor receptor I (IGF-IR) (e.g. compounds which reduce the activity of IGF-IR). compounds that target, reduce or inhibit, in particular 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 factors; 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 Axl receptor tyrosine kinase family; f) compounds that target the activity of the Ret receptor tyrosine kinase, g) compounds that target, reduce or inhibit the activity of Kit / SCFR receptor tyrosine kinases (e.g., imatinib); h) compounds that target, reduce or inhibit the activity of C-kit receptor tyrosine kinases (which are part of the PDGFR family) (e.g., compounds that target, reduce or inhibit the activity of the c-Kit receptor tyrosine kinase family, in particular compounds that inhibit the c-Kit receptor, e.g., imatinib);i) Compounds that target, reduce or inhibit the activity of c-Abl family members, their gene fusion products (e.g., BCR-Abl kinase) and mutants (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, e.g., imatinib or nilotinib (AMN107); PD180970; AG957; NSC 680410; PD173955 (ParkeDavis); or dasatinib (BMS-354825); j) compounds that target, decrease, or inhibit the activity of protein kinase C (PKC) and members of the Raf family of serine / threonine kinases, MEK, SRC, JAK / pan-JAK, FAK, PDK1, PKB / Akt, and Ras / MAPK, members of the PI3K, SYK, BTK, and TEC families, and / or members of the cyclin-dependent kinase family (CDK), including staurosporine derivatives (e.g., midostaurin); further exemplary compounds include UCN-01, safingol, BAY 43-9006, Bryostatin 1, Perifosine; ilmofosine; RO 318220 and RO 320432; GO 6976; Isis 3521; LY333531 / LY379196; isoquinoline compounds; FTIs; PD184352 or QAN697 (P13K inhibitors) or AT7519 (CDK inhibitors); k) compounds that target, decrease or inhibit the activity of protein-tyrosine kinase inhibitors (e.g., compounds that target, decrease or inhibit the activity of protein-tyrosine kinase inhibitors, such as imatinib mesylate (Gleevec); TM) or tyrphostins (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, AG957) and adaphostin (4-{[(2,5-dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester; NSC 680410, Adafostin); l) compounds that target, decrease or inhibit the activity of the epidermal growth factor family of receptor tyrosine kinases (EGFR1, ErbB2, ErbB3, ErbB4, as homodimers or heterodimers) and their mutants (e.g., compounds that target, decrease or inhibit the activity of the epidermal growth factor receptor family are, in particular, 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, decrease or inhibit the activity of the c-Met receptor (e.g., compounds that target, decrease 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). n) compounds that target, decrease, 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, momelotinib, VX-509, AZD-1480, TG-101348, tofacitinib, and ruxolitinib (r uxolitinib); o) compounds that target, decrease, 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 idelalisib). lalisib); and q) compounds that target, decrease, or inhibit the signaling effects of the Hedgehog (Hh) or Smoothened receptor (SMO) pathways, including, but not limited to, cyclopamine, vismodegib, itraconazole, erismodegib, and IPI-926 (saridegib).

[0296] The term "PI3K inhibitor," as used herein, includes, but is not limited to, compounds that have 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, pictorelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, and idelalisib.

[0297] The term "BTK inhibitor," as used herein, includes, but is not limited to, compounds that have inhibitory activity against Bruton's tyrosine kinase (BTK), including, but not limited to, AVL-292 and ibrutinib.

[0298] The term "SYK inhibitors," as used herein, includes, but is not limited to, compounds that have inhibitory activity against spleen tyrosine kinase (SYK), including, but not limited to, PRT-062070, R-343, R-333, Excellair, PRT-062607, and fostamatinib.

[0299] The term "Bcl-2 inhibitors", as used herein, includes, but is not limited to, compounds having inhibitory activity against B-cell lymphoma 2 protein (Bcl-2), such as, but not limited to, ABT-199, ABT-731, ABT-737, apogossypol, Ascenta's pan-Bcl-2 inhibitors, curcumin (and analogs thereof), dual Bcl-2 / Bcl-xL inhibitors (Infinity Pharmaceuticals / Novartis Pharmaceuticals), Genasense (G3139), HA14-1 (and analogs thereof; see WO2008118802), navitoclax (and analogs thereof, see US7390799), NH-1 (Shenayng Pharmaceutical University), obatoclax (and analogs thereof, see WO2004106328), S-001 (Gloria In some embodiments, the Bcl-2 inhibitor is a small molecule therapeutic agent. In some embodiments, the Bcl-2 inhibitor is a peptidomimetic.

[0300] Further examples of BTK inhibitor compounds and conditions treatable by such compounds in combination with the compounds of the present invention can be found in WO2008039218 and WO2011090760, the entireties of which are incorporated herein by reference.

[0301] Further examples of SYK inhibitor 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 entireties of which are incorporated herein by reference.

[0302] Further examples of PI3K inhibitor 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 entireties of which are incorporated by reference herein).

[0303] Further examples of JAK inhibitor 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 entireties of which are incorporated herein by reference.

[0304] Additional anti-angiogenic compounds include compounds that have an alternative mechanism for their activity (e.g., unrelated to protein or lipid kinase inhibition) (e.g., thalidomide (Thalomid)). TM ) and TNP-470).

[0305] Examples of proteasome inhibitors that are useful in combination with the compounds of the invention include, but are not limited to, bortezomib, disulfiram, epigallocatechin-3-gallate (EGCG), salinosporamide A, carfilzomib, ONX-0912, CEP-18770, and MLN9708.

[0306] Compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase are eg inhibitors of phosphatase 1, inhibitors of phosphatase 2A or inhibitors of CDC25 (eg okadaic acid or a derivative thereof).

[0307] Compounds that induce cell differentiation processes include, but are not limited to, retinoic acid, α-, γ- or δ-tocopherol, or α-, γ- or δ-tocotrienol.

[0308] The term cyclooxygenase inhibitors, as used herein, includes Cox-2 inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acids and derivatives (e.g., celecoxib (Celebrex) TM ), rofecoxib (Vioxx TM ), etoricoxib, valdecoxib), or 5-alkyl-2-arylaminophenylacetic acid (e.g., 5-methyl-2-(2'-chloro-6'-fluoroanilino)phenylacetic acid), lumiracoxib.

[0309] The term "bisphosphonates" as used herein includes, but is not limited to, etridonic acid, clodronic acid, tiludronic acid, pamidronic acid, alendronic acid, ibandronic acid, risedronic acid, and zoledronic acid. Etidronic acid is available under the trade name Didronel. TM Clodronic acid is marketed under the trade name Bonefos. TM Tiludronic acid is marketed under the trade name Skelid. TM Pamidronic acid is marketed under the brand name Aredia. TM Alendronate is marketed under the brand name Fosamax. TM Ibandronic acid is marketed under the trade name Bondranat. TM Risedronic acid is marketed under the brand name Actonel. TM Zoledronic acid is marketed under the brand 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 ), CCI-779 and ABT578).

[0310] The term "heparanase inhibitor" as used herein refers to a compound that targets, decreases, or inhibits heparin sulfate degradation. This term includes, but is not limited to, PI-88. The term "biological response modifier" as used herein refers to a lymphokine or interferon.

[0311] The term "inhibitor of a Ras oncogene isoform" (e.g., H-Ras, K-Ras, or N-Ras), as used herein, refers to a compound that targets, reduces, or inhibits the oncogene activity of Ras (e.g., L-744832, DK8G557, or R115777 (Zarnestra)). TM The term "telomerase inhibitor" as used herein refers to a compound that targets, reduces, or inhibits the activity of telomerase. Compounds that target, reduce, or inhibit the activity of telomerase are, in particular, compounds that inhibit the telomerase receptor (e.g., telomestatin).

[0312] The term "methionine aminopeptidase inhibitor" as used herein refers to a compound that targets, decreases or inhibits the activity of methionine aminopeptidase. Compounds that target, decrease or inhibit the activity of methionine aminopeptidase include, but are not limited to, bengamide or a derivative thereof.

[0313] The term "proteasome inhibitor," as used herein, refers to a compound that targets, decreases, or inhibits the activity of the proteasome. Compounds that target, decrease, or inhibit the activity of the proteasome include bortezomib (Velcade), TM ) and MLN 341.

[0314] The term "matrix metalloproteinase inhibitors" or ("MMP" inhibitors), as used herein, includes, but is not limited to, collagen peptidomimetic and non-peptidomimetic inhibitors, tetracycline derivatives (e.g., the hydroxamate peptidomimetic inhibitor batimastat and its orally bioavailable analogs marimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551) BMS-279251, BAY 12-9566, TAA211, MMI270B, or AAJ996).

[0315] The term "compounds used in the treatment of hematological malignancies," as used herein, includes, but is not limited to, FMS-like tyrosine kinase inhibitors (which are compounds that target, decrease or inhibit the activity of FMS-like tyrosine kinase receptor (Flt-3R)); interferon, 1-β-D-arabinofuranosylcytosine (ara-c) and bisulfan; ALK inhibitors (which are compounds that target, decrease or inhibit anaplastic lymphoma kinase), and Bcl-2 inhibitors.

[0316] Compounds that target, decrease or inhibit the activity of 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).

[0317] The term "HSP90 inhibitor," as used herein, includes, but is not limited to, compounds that target, reduce, or inhibit the intrinsic ATPase activity of HSP90; and compounds that degrade, target, reduce, or inhibit proteins to which HSP90 family proteins bind (HSP90 client proteins) via the ubiquitin proteosome pathway. Compounds that target, reduce, or inhibit the intrinsic ATPase activity of HSP90 are, in particular, compounds, proteins, or antibodies that inhibit the ATPase activity of HSP90 (e.g., 17-allylamino,17-desmethoxygeldanamycin (17AAG), geldanamycin derivatives; other geldanamycin-related compounds; radicicol, and HDAC inhibitors).

[0318] The term "antiproliferative antibody" as used herein includes trastuzumab (Herceptin TM ), trastuzumab-DM1, Erbitux, bevacizumab (Avastin) TM ), rituximab (Rituxan®), PRO64553 (anti-CD40), and 2C4 antibody. By antibody is meant intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least two intact antibodies, and antibody fragments so long as they exhibit the desired biological activity.

[0319] For the treatment of acute myeloid leukemia (AML), the compound of the present invention can be used in combination with standard leukemia therapy, particularly in combination with the therapy used for the treatment of AML.Specifically, the compound of the present invention can be administered in combination with, for example, farnesyltransferase inhibitors and / or other drugs useful for the treatment of AML (for example, daunorubicin, adriamycin, Ara-C, VP-16, teniposide, mitoxantrone, idarubicin, carboplatinum and PKC412).In some embodiments, the present invention provides a method for treating AML associated with ITD and / or D835Y mutation, the method comprises administering the compound of the present invention together with one or more FLT3 inhibitors. In some embodiments, the FLT3 inhibitors are selected from quizartinib, (AC220), staurosporine derivatives (e.g., midostaurin or lestaurtinib), sorafenib, tandutinib, LY-2401401, LS-104, EB-10, famitinib, NOV-110302, NMS-P948, AST-487, G-749, SB-1317, S-209, SC-110219, AKN-028, fedratinib, tozasertib, and sunitinib. In some embodiments, the FLT3 inhibitors are selected from quizartinib, midostaurin, lestaurtinib, sorafenib, and sunitinib.

[0320] Other anti-leukemia compounds include, for example, Ara-C, a pyrimidine analog (which is a derivative of deoxycytidine) ’

[0003] Also included are the purine analog of hypoxanthine, 6-mercaptopurine (6-MP), and fludarabine phosphate. Compounds that target, decrease, 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 deacetylases. Specific HDAC inhibitors include MS275, SAHA, FK228 (formerly FR901228), Trichostatin A, and compounds disclosed in U.S. Patent No. 6,552,065 (N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide or a pharmaceutically acceptable salt thereof, and N-hydroxy-3-[4-[(2-hydroxyethyl){2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide or a pharmaceutically acceptable salt thereof (particularly the lactate salt), but are not limited to these. As used herein, somatostatin receptor antagonist refers to a compound that targets, treats, or inhibits somatostatin receptors (e.g., octreotide and SOM230). Tumor cell damaging approaches refer to approaches such as ionizing radiation. As described above and hereinafter, the term "ionizing radiation" refers to ionizing radiation that occurs either as electromagnetic rays (e.g., X-rays and gamma rays) or particles (e.g., alpha particles and beta particles). Ionizing radiation is provided in, but not limited to, radiation therapy and is known in the art. See Hellman, Principles of Radiation Therapy, Cancer, Principles and Practice of Oncology, edited by Devita et al., 4th Edition, Vol. 1, pp. 248-275 (1993).

[0321] Also included are EDG binders and ribonucleotide reductase inhibitors. The term "EDG binder" as used herein refers to a class of immunosuppressants that regulate lymphocyte recirculation (e.g., FTY720). The term "ribonucleotide reductase inhibitor" refers to 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 (especially in combination with ara-C for ALL) and / or pentostatin. Ribonucleotide reductase inhibitors are particularly hydroxyurea or 2-hydroxy-1H-isoindole-1,3-dione derivatives.

[0322] In particular, 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceutically acceptable salt thereof, 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate; Angiostatin TM Endostatin TM anthranilamide; ZD4190; ZD6474; SU5416; SU6668; bevacizumab; or anti-VEGF antibodies or anti-VEGF receptor antibodies (e.g., rhuMAb and RHUFab), VEGF aptamers (e.g., Macugon); FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgGI antibodies, Angiozyme (RPI 4610), and bevacizumab (Avastin TM Also included are compounds, proteins or monoclonal antibodies of VEGF, such as VEGF-1, VEGF-2, VEGF-3, VEGF-4, VEGF-5, VEGF-6, VEGF-7, VEGF-8, VEGF-9, VEGF-10, VEGF-11, VEGF-12, VEGF-13, VEGF-14, VEGF-15, VEGF-16, VEGF-17

[0323] Photodynamic therapy, as used herein, refers to treatments that use certain chemicals known as photosensitizing compounds to treat or prevent cancer. Examples of photodynamic therapy include Visudyne. TM and treatment with compounds such as porfimer sodium.

[0324] 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, desoxycorticosterone, testosterone, estrone, and dexamethasone).

[0325] Corticosteroid-containing implants refer to compounds such as fluocinolone and dexamethasone.

[0326] Other chemotherapeutic compounds include, but are not limited to, plant alkaloids, hormonal compounds and antagonists; biological response modifiers (preferably lymphokines or interferons); antisense oligonucleotides or oligonucleotide derivatives; shRNA or siRNA; or miscellaneous compounds or compounds with other or unknown mechanisms of action.

[0327] 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, bronchodilator, or antihistamine drug substances) (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), particularly in the treatment of obstructive or inflammatory airway diseases such as those described hereinabove. The compounds of the present invention can be mixed with the other drug substances in a given pharmaceutical composition, or can be administered separately from, before, simultaneously with, or after the other drug substances. Thus, the present invention encompasses combinations of compounds of the present invention as described hereinabove with anti-inflammatory, bronchodilator, antihistamine, or antitussive drug substances, wherein the compounds of the present invention and the drug substances are in the same or different pharmaceutical compositions.

[0328] Suitable anti-inflammatory agents include steroids (particularly glucocorticosteroids such as budesonide, beclomethasone propionate, fluticasone propionate, ciclesonide, or mometasone furoate); non-steroidal glucocorticoid receptor agonists; LTB antagonists (e.g., LY293111, CGS025019C, CP-195543, SC-53228, BIIL 284, ONO 4057, SB 209247); LTD antagonists (e.g., montelukast and zafirlukast); 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 Kogyo); A2a agonists; A2b antagonists; and beta-2 adrenergic receptor agonists (e.g., albuterol (salbutamol), metaproterenol, terbutaline, salmeterol, fenoterol, procaterol, and, particularly, formoterol and its pharmaceutically acceptable salts). Suitable bronchodilator drugs include anticholinergic or antimuscarinic compounds, particularly ipratropium bromide, oxitropium bromide, tiotropium salts, and CHF 4226 (Chiesi), and glycopyrrolate.

[0329] Suitable antihistamine substances include cetirizine hydrochloride, acetaminophen, clemastine fumarate, promethazine, loratadine, desloratidine, diphenhydramine and fexofenadine hydrochloride, activastine, astemizole, azelastine, ebastine, epinastine, mizolastine and terfenadine.

[0330] Other useful combinations of compounds of the 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), particularly CCR-5 antagonists (e.g., Schering-Plough antagonists). and combinations with agonists SC-351125, SCH-55700, and SCH-D, and Takeda's antagonists (e.g., N-[[4-[[[6,7-dihydro-2-(4-methylphenyl)-5H-benzo-cyclohepten-8-yl]carbonyl]amino]phenyl]-methyl]tetrahydro-N,N-dimethyl-2H-pyran-4-aminium chloride (TAK-770)).

[0331] The structures of the active compounds identified by code numbers, generic names or trade names can be obtained from the current edition of the standard compendium "The Merck Index" or from databases such as Patents International (e.g. IMS World Publications).

[0332] The compounds of the present invention can also be used in combination with known therapeutic processes (e.g., administration of hormones or radiation). In certain embodiments, provided compounds are used as radiosensitizers, particularly for the treatment of tumors that exhibit poor sensitivity to radiation therapy.

[0333] The compound of the present invention can be administered alone or in combination with one or more other therapeutic compounds, and possible combination therapy can be in the form of a fixed combination, or in the form of alternating or independent administration of the compound of the present invention and one or more other therapeutic compounds, or in the form of a fixed combination administered in combination with one or more other therapeutic compounds.Otherwise, or in addition, the compound of the present invention can be administered in combination with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention, or a combination thereof, particularly for tumor treatment.As described above, in view of other treatment strategies, long-term treatment is possible, as well as adjunctive treatment.Other possible treatments are treatments to maintain the patient's condition after tumor relapse, or even chemoprevention treatment, for example, in patients at risk.

[0334] These additional agents may be administered as part of a multiple dose regimen, separate from the individual compound-containing compounds. 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 multiple dose regimen, these two active agents may be given simultaneously, sequentially, or within a period of each other (usually within 5 hours of each other).

[0335] As used herein, the terms "combination," "concomitant use," and related terms refer to the simultaneous or sequential administration of multiple therapeutic agents in accordance with the present invention. For example, a compound of the present invention can be administered simultaneously or sequentially with another therapeutic agent, either in separate unit dosage forms or together in a single unit dosage form. Thus, the present invention provides a single dosage form containing a compound of the present invention, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0336] The amounts of both the compounds of the present invention and additional therapeutic agents (in compositions containing such additional therapeutic agents) that can be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Preferably, the compositions of the present invention should be formulated so that a dosage of 0.01 mg / kg body weight / day to 100 mg / kg body weight / day of the compounds of the present invention can be administered.

[0337] In a composition containing an additional therapeutic agent, the additional therapeutic agent and the compound of the present invention may act synergistically. Thus, the amount of the additional therapeutic agent in such a composition is less than the amount required in a monotherapy utilizing only the therapeutic agent. In such a composition, the additional therapeutic agent may be administered in a dosage of 0.01 μg / kg body weight / day to 1,000 μg / kg body weight / day.

[0338] The amount of additional therapeutic agent present in the compositions of the invention will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Preferably, the amount of additional therapeutic agent in the compositions of the present disclosure ranges from about 50% to 100% of the amount that would normally be present in a composition comprising that agent as the only therapeutically active agent.

[0339] The compounds of the present invention or their pharmaceutical compositions can also be incorporated into compositions for coating implantable medical devices, such as prostheses, artificial valves, vascular grafts, stents and catheters.For example, vascular stents are used to overcome restenosis (re-narrowing of the blood vessel wall after injury).However, patients who use stents or other implantable devices are at risk of blood clot formation or platelet activation.These unwanted effects can be prevented or reduced 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. [Example]

[0340] Example As described in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures: While the synthesis of compounds of the present invention is described, it is understood that the following general methods, and other methods known to those of skill in the art, can be applied to all compounds, and each subclass and species of these compounds, as described herein.

[0341] Example 1. Synthesis of N-(4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropanecarboxamide, I-1 [ka] [ka]

[0342] Synthesis of Compound 1.2. To a solution of 1.1 (50 g, 253.6 mmol, 1.0 equiv.) in DMF (500 mL) was added K2CO3 (70 g, 507.6 mmol, 2.0 equiv.) at 0 °C and stirred for 15 min. To this suspension, MeI (72 g, 507.6 mmol, 2.0 equiv.) was added dropwise, and the reaction mixture was stirred at 60 °C for 2 h. After completion of the reaction, the reaction mixture was transferred to ice water. The precipitated product was filtered and dried to give 1.2 (50.0 g, 93.0%). MS (ES): m / z 212.2 [M+H] + .

[0343] Synthesis of Compound 1.3. To 1.2 (50 g, 236.7 mmol, 1.0 equiv.) was added aq. NHOH (300 mL), followed by methanolic NH (1600 mL). The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was washed with ice-cold water. The precipitate was dried to give 1.3 (45.0 g, 96.0%). MS (ES): m / z 197.2 [M+H] + .

[0344] Synthesis of Compound 1.4. To a suspension of NaN3 (21.8 g, 336 mmol, 3.0 equiv.) in acetonitrile (220 mL) was added SiCl4 (28.6 g, 168 mmol, 1.5 equiv.). To this stirred suspension was added compound 1.3 (22.0 g, 112 mmol, 1.0 equiv.), and the reaction mixture was stirred at 75 °C for 16 h. The reaction mixture was cooled to room temperature, and water was added. The precipitate was filtered to give 1.4 (18.0 g, 72.5%). MS (ES): m / z 222.2 [M+H] + .

[0345] Synthesis of Compound 1.5. To a stirred solution of 1.4 (15.0 g, 67.8 mmol, 1.0 equiv.) in DMF (150 mL) was added K2CO3 (23.4 g, 169.7 mmol, 2.5 equiv.) at 0 °C. To this was added MeI (19.1 g, 135.7 mmol, 2.0 equiv.) dropwise. The reaction mixture was stirred at room temperature for 24 hours. After completion of the reaction, the mixture was poured into water and extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give the crude material. The crude material was purified by column chromatography to give the desired regioisomer 1.5 (10.0 g, 62.7%). MS (ES): m / z 236.2 [M+H] + .

[0346] Synthesis of compound 1.6. To a solution of 1.5 (10.0 g, 42.5 mmol, 1.0 equiv) in MeOH (100 mL) was added 10% Pd / C (2.0 g). Hydrogen was purged through the reaction mixture for 4 hours. After completion of the reaction, the mixture was filtered through a celite bed and washed with MeOH. The filtrate was concentrated under reduced pressure to give 1.6 (5.3 g, 60.7%). MS (ES): m / z 206.3 [M+H] + .

[0347] Synthesis of Compound 1.8. SOCl (5.0 mL) was added to 1.7 (1.0 g, 4.42 mmol, 1.0 equiv.), followed by DMF (catalytic) and refluxing for 16 hours. The reaction mixture was concentrated under reduced pressure to give the acyl chloride. Methylhydrazine (0.20 g, 42.5 mmol, 1.0 equiv.) was dissolved in CHCl (20.0 mL), followed by the addition of a solution of NaOH (0.72 g, 177 mmol, 4.0 equiv.) in water (5.0 mL). To this solution was added the previously prepared solution of the acyl chloride in CHCl (20.0 mL) dropwise. The reaction mixture was refluxed for 15 minutes. After completion of the reaction, the reaction mixture was transferred to water and extracted with CHCl. The organic layers were combined, washed with brine, dried over NaSO, and concentrated under reduced pressure to give the crude product, which was purified by column chromatography to give 1.8 (1.1 g, 97.0%). MS(ES): m / z 255.5 [M+H] + .

[0348] Synthesis of Compound 1.9. To a suspension of 1.8 (1.0 g, 3.93 mmol, 1.0 equiv.) in 1-pentanol (15.0 mL), Na2CO3 (0.49 g, 3.93 mmol, 1.0 equiv.) was added, and the reaction mixture was stirred at 120 °C for 16 h. After completion of the reaction, the reaction mixture was cooled to room temperature, and pH = 6.0 was adjusted using 1 N HCl. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC to give 1.9 (0.15 g, 17.5%). MS (ES): m / z 219.2 [M+H] + .

[0349] Synthesis of Compound 1.91. To a solution of 1.9 (0.1 g, 0.45 mmol, 1.0 equiv.) and 1.6 (0.188 g, 0.917 mmol, 2.0 equiv.) in THF (2.0 mL) was added a 1.0 M solution of LHMDS in tetrahydrofuran (1.6 mL, 1.57 mmol, 3.5 equiv.) at −78° C. The reaction mixture was stirred at room temperature for 18 hours. After completion of the reaction, the reaction mixture was transferred to water and extracted with EtOAc. The aqueous layer was acidified with 1.0 N HCl and extracted with EtOAc. The organic layers were combined, washed with brine, dried over NaSO, and concentrated under reduced pressure to give pure 1.91 (0.1 g, 56.37%). MS (ES): m / z 387.9 [M+H] + .

[0350] Synthesis of Compound I-1. To 1.91 (0.020 g, 0.051 mmol, 1.0 equiv.) in DMA (0.5 mL) was added cyclopropanecarboxamide (0.005 g, 0.062 mmol, 1.2 equiv.), Cs2CO3 (0.033 g, 0.102 mmol, 2.0 equiv.). The reaction mixture was degassed under argon for 10 minutes, and then Pd2(dba)3 (0.005 g, 0.005 mmol, 0.1 equiv.) and Xantphos (0.006 g, 0.01 mmol, 0.2 equiv.) were added. The suspension was degassed for an additional 5 minutes. The reaction was then heated at 130 °C for 5 hours. After completion of the reaction, the reaction mixture was diluted with CHCl2 (1 mL) and passed through a silica plug column using 10% methanol in CHCl2 as the eluent. The resulting fractions were combined and concentrated under reduced pressure to give the crude material, which was further purified by reverse-phase HPLC to give I-1 (0.005 g, 22.2%). MS (ES): m / z 436.6 [M+H] + ; 1 H NMR (CDCl3, 400 MHz): 8.92 (s, 1H), 7.79-7.77 (d, 1H), 7.67-7.66 (d, 1H), 7.45-7.40 (m, 1H), 4.45 (s, 3H), 3.88 (s, 3H), 3.47 (s, 3H), 1.69-1.59 (m, 1H), 1.13-1.12 (m, 2H), 0.91-0.90 (m, 2H).

[0351] Example 2. Synthesis of 4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-6-((4-(methoxymethyl)pyridin-2-yl)amino)-2-methyl-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one I-2 [ka]

[0352] To compound 1.91 (0.040 g, 0.103 mmol, 1.0 equiv.) in DMF (1.0 ml) were added 4-(methoxymethyl)pyridin-2-amine (0.021 g, 0.155 mmol, 1.5 equiv.) and KPO (0.043 g, 0.206 mmol, 2.0 equiv.). The reaction mixture was degassed using argon for 10 minutes, and then [(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (0.008 g, 0.01 mmol, 0.1 equiv.) was added. The suspension was degassed for an additional 5 minutes. The reaction was stirred at 50°C for 15 minutes. After completion of the reaction, the mixture was diluted with CHCl (1.0 mL) and passed through a silica plug column using 8% methanol in CHCl as the eluent. The resulting fractions were combined and concentrated under reduced pressure to give the crude product, which was purified by reverse-phase HPLC to give I-2 (0.008 g, 15.84%). MS (ES): m / z 489.75 [M+H] + ; 1 H NMR (CDCl3, 400 MHz): 9.27 (s, 1H), 8.95 (s, 1H), 8.14-8.12 (d, 1H), 7.70-7.68 (d, 1H), 7.41-7.39 (d, 1H), 7.11-7.08 (t, 1H), 7.00 (s, 1H), 6.89-6.88 (d, 1H), 4.43 (s, 3H), 3.78 (s, 3H), 3.65 (s, 2H), 3.57 (s, 3H), 3.43 (s, 3H).

[0353] Example 3. Synthesis of 4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2-methyl-6-((5-methylpyridin-2-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-3 [ka]

[0354] Compound I-3 was prepared from compound 1.91 and 5-methylpyridin-2-amine using the procedure described in Example 2. MS (ES): m / z 459.64 [M+H] + ; 1 H NMR (DMSO-d6, 400 MHz): 10.68 (s,2H), 9.76 (s,1H), 8.93 (s,1H), 8.11 (s,1H), 7.79-7.77 (d,1H), 7.65-7.57 (m,2H), 7.42-7.38 (m,1H), 7.2 (s,1H), 4.47 (s,3H), 3.79 (s,3H), 3.29 (s,3H), 2.24 (s,3H).

[0355] Example 4. Synthesis of 4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2-methyl-6-(pyridin-2-ylamino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-4 [ka]

[0356] Compound I-4 was prepared from compound 1.91 and pyridin-2-amine using the procedure described in Example 2. MS (ES): m / z 445.68 [M+H] + 1 H NMR (DMSO-d6, 400 MHz): 9.97 (s, 1H), 8.95 (s, 1H), 8.27-8.26 (d, 1H), 8.16 (s, 1H), 7.89 (s, 1H), 7.80-7.78 (d, 1H), 7.74-7.71 (m, 1H), 7.65-7.63 (d, 1H), 7.42-7.38 (t, 1H), 6.97-6.94 (t, 1H), 4.47 (s, 3H), 3.79 (s, 3H), 3.29 (s, 3H).

[0357] Example 5. Synthesis of 4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2-methyl-6-((4-methylpyridin-2-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-5 [ka]

[0358] Compound I-5 was prepared from compound 1.91 and 4-methylpyridin-2-amine using the procedure described in Example 2. MS (ES): m / z 459.7 [M+H] + ; 1 H NMR (DMSO-d6, 400 MHz): 9.98 (s, 1H), 8.96 (s, 1H), 8.17 (s, 1H), 8.14-8.13 (d, 1H),7.79-7.77 (d, 1H), 7.65-7.63 (d, 1H), 7.42-7.38 (t, 1H), 6.82-6.81 (d, 1H), 4.47 (s, 3H), 3.79 (s, 3H), 3.30 (s, 3H), 2.30 (s, 3H).

[0359] Example 6. Synthesis of 6-((4-(hydroxymethyl)pyridin-2-yl)amino)-4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2-methyl-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-6 [ka]

[0360] Compound I-6 was prepared from compound 1.91 and (2-aminopyridin-4-yl)methanol using the procedure described in Example 2. MS (ES): m / z 475.58 [M+H] + ; 1 H NMR (DMSO-d6, 400 MHz): 10.01 (s, 1H), 8.97 (s, 1H), 8.20-8.19 (d, 1H),8.17 (s, 1H), 7.79-7.77 (d, 1H), 7.66-7.64 (d, 1H), 7.42-7.38 (t, 1H), 6.92-6.90 (d, 1H), 5.42 (s, 1H), 4.52 (s, 2H), 4.47 (s, 3H), 3.79 (s, 3H), 3.30 (s, 3H).

[0361] Example 7. Synthesis of N-(4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropanecarboxamide, I-14 [ka]

[0362] Compound 1.92 was prepared according to the procedure used for 1.91. Compound I-14 was prepared from compound 1.91 and cyclopropanecarboxamide using the procedure described in Example 2. (Yield: 22.2%). MS (ES): m / z 436.6 [M+H]+ , LCMS purity: 96%, HPLC purity: 91%, 1 H NMR (CDCl3, 400MHZ): 8.92 (s, 1H), 7.79-7.77 (d, J=8Hz, 1H), 7.67-7.66 (d, J=7.2Hz, 1H), 7.45-7.40 (m, 1H), 4.45 (s, 3H), 3.88 (s, 3H), 3.47 (s, 3H), 1.69-1.59 (m, 1H), 1.13-1.12 (m, 2H), 0.91-0.90 (m, 2H).

[0363] Example 13. Synthesis of 4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2-methyl-6-((5-morpholinopyridin-2-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-7 [ka]

[0364] Compound I-7 was prepared from compound 1.91 and 5-morpholinopyridin-2-amine using the procedure described in Example 2 (yield: 8.76%). MS(ES): m / z 530.81 [M+H]+ , LCMS purity: 100%, HPLC purity: 98.59%, 1H NMR (DMSO-d6, 400MHZ): 9.79-9.75 (bs, 2H), 8.94 (s, 1H), 8.14 (s, 1H), 7.98 (s, 1H), 7.78-7.76 (d, J=8Hz,1H), 7.64-7.63(d, J=7.6Hz, 1H), 7.46-7.38 (m, 3H), 4.47 (s, 3H), 3.79 (s, 3H), 3.77-3.74 (t, 4H), 3.29 (s, 3H), 3.10-3.08 (t, 4H).

[0365] Example 14. Synthesis of 6-((5-fluoro-4-methylpyridin-2-yl)amino)-4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2-methyl-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-8 [ka]

[0366] Compound I-8 was prepared from compound 1.91 and 5-fluoro-4-methylpyridin-2-amine using the procedure described in Example 2 (yield: 16.24%). MS (ES): m / z 477.43 [M+H]+, LCMS purity: 99.71%, HPLC purity: 99.14%, 1H NMR (DMSO-d6, 400MHZ): 9.87 (s, 1H), 8.92 (s, 1H), 8.22 (s, 1H), 8.15 (s, 1H), 7.94 (s, 1H), 7.78-7.76 (d, J=8Hz, 1H), 7.64-7.62 (d, J=7.2Hz, 1H), 7.42-7.38 (t, 1H), 6.96 (s, 1H), 4.47 (s, 3H), 3.79 (s, 3H), 3.30 (s, 3H), 2.28 (s, 3H).

[0367] Example 15. Synthesis of 6-((2,6-dimethylpyrimidin-4-yl)amino)-4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2-methyl-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-9 [ka]

[0368] Compound I-9 was prepared from compound 1.91 and 2,6-dimethylpyrimidin-4-amine using the procedure described in Example 2 (yield: 11.98%). MS (ES): m / z 474.58 [M+H]+ , LCMS purity: 99.76%, HPLC purity: 96.42%, 1H NMR (MeOD, 400MHZ): 8.34-8.29 (bs, 2H), 7.86-7.84 (d, J=7.6Hz, 1H), 7.73-7.71(d, J=8Hz, 1H), 7.41-7.37 (t, 1H), 6.89 (s, 1H), 6.25 (s, 1H), 4.48 (s, 3H), 3.85 (s, 3H), 3.53 (s, 3H), 2.64 (s, 3H), 2.42 (s, 3H).

[0369] Example 16. Synthesis of 4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2-methyl-6-((6-methylpyridazin-3-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-10 [ka]

[0370] Compound I-10 was prepared from compound 1.91 and 6-methylpyridazin-3-amine using the procedure described in Example 2 (yield: 14.03%). m / z 460.43 [M+H]+, LCMS purity: 98.69%, HPLC purity: 98.00%, 1H NMR (DMSO-d6, 400MHZ): 10.23 (bs, 1H), 8.93 (s, 1H), 8.29-8.27 (d, J=8.8Hz, 1H), 8.16 (s, 1H), 7.79-7.77 (d, J=8Hz, 1H), 7.65-7.64 (d, J=7.2Hz, 1H), 7.50-7.48 (d, J=9.2Hz, 1H), 7.40-7.36 (t, J=8Hz, 1H), 6.99 (bs, 1H), 4.47 (s, 3H), 3.80 (s, 3H), 3.30 (s, 3H), 2.53 (s, 3H).

[0371] Example 17. Synthesis of 4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2-methyl-6-((5-(piperidin-1-yl)pyridin-2-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-11 [ka]

[0372] Compound I-11 was prepared from compound 1.91 and 5-(piperidin-1-yl)pyridin-2-amine using the procedure described in Example 2 (yield: 9.78%). MS (ES): m / z 528.68 [M+H]+, LCMS purity: 96.10%, HPLC purity: 98.65%, 1H NMR (CDCl3, 400MHZ): 9.76 (bs, 1H), 8.89 (s, 1H), 7.71 (s, 1H), 7.66-7.64 (d, J=7.2Hz, 1H), 7.28 (s, 1H), 7.03-7.00 (m, 2H), 5.72 (s, 1H), 4.40 (s, 3H), 3.77 (s, 3H), 3.54 (s, 3H), 3.17-3.03 (m, 4H), 2.63 (s, 1H), 1.72 (s, 4H), 1.60-1.59 (d, 2H).

[0373] Example 18. Synthesis of 4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2-methyl-6-((5-(pyrrolidin-1-yl)pyridin-2-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-58 [ka]

[0374] Compound I-58 was prepared from compound 1.91 and 5-(pyrrolidin-1-yl)pyridin-2-amine using the procedure described in Example 2 (yield: 11.08%), MS (ES): m / z 514.46 [M+H]+, LCMS purity: 96.44%, HPLC purity: 97.39%, 1H NMR (DMSO-d6, 400MHz): 9.96 (s, 1H), 8.68 (s, 1H), 7.72-7.621 (m, 3H), 7.51 (s, 2H), 7.24-6.98 (m, 2H), 6.40 (s, 1H), 4.50 (s, 3H), 3.68 (s, 4H), 3.45 (s, 3H), 3.25 (s, 3H), 1.98 (s, 4H).

[0375] Example 19. Synthesis of 6-((5-cyclopropylpyridin-2-yl)amino)-4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2-methyl-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-59 [ka]

[0376] Compound I-59 was prepared from compound 1.91 and 5-cyclopropylpyridin-2-amine using the procedure described in Example 2 (yield: 23.28%), MS (ES): m / z 485.53 [M+H]+, LCMS purity: 98.26%, HPLC purity: 97.44%, 1H NMR (DMSO-d6, 400MHz): 10.72 (s, 1H), 9.74 (s, 1H), 8.90 (s, 1H), 8.09 (s, 1H), 7.95-7.93 (d, J=6.8Hz, 1H), 7.81-7.79 (d, J=7.6Hz, 1H), 7.63-7.61 (d, J=7.2Hz, 1H), 7.43-7.36 (m, 2H), 7.18 (s, 1H), 4.48 (s, 3H), 3.79 (s, 3H), 3.16 (s, 3H), 1.89 (s, 1H), 0.94-0.93 (d, J=6.8Hz, 2H), 0.69-0.68 (d, J=6.8Hz, 2H).

[0377] Example 20. Synthesis of 4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2-methyl-6-((6-(trifluoromethyl)pyridin-2-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-60 [ka]

[0378] Compound I-60 was prepared from compound 1.91 and 6-(trifluoromethyl)pyridin-2-amine using the procedure described in Example 2 (yield: 39.25%). MS (ES): m / z 513.43 [M+H]+, LCMS purity: 99.01%, HPLC purity: 98.84%, 1H NMR (DMSO-d6, 400MHz): 10.85 (s, 1H), 10.29 (s, 1H), 9.06 (s, 1H), 8.13-8.11 (d, J=8.8Hz, 1H), 7.98-7.94 (t, J=8.0Hz, 1H), 7.82-7.79 (d, J=8.0Hz, 1H), 7.65-7.64 (d, J=6.8Hz, 1H), 7.48 (s, 1H), 7.40-7.33 (m, 2H), 4.48 (s, 3H), 3.80 (s, 3H), 3.32 (s, 3H).

[0379] Example 21. Synthesis of 4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-6-((6-(3-methoxyazetidin-1-yl)pyridin-2-yl)amino)-2-methyl-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-63 [ka]

[0380] Compound I-63 was prepared from compound 1.91 and 6-(3-methoxyazetidin-1-yl)pyridin-2-amine using the procedure described in Example 2 (yield: 19.48%). MS (ES): m / z 530.40 [M+H]+, LCMS purity: 100.00%, HPLC purity: 98.25%, 1H NMR (CDCl3, 400MHz): 9.49 (bs, 1H), 8.98 (s, 1H), 7.68-7.66 (d, J=6.8Hz, 1H), 7.38-7.34 (t, J=8.0Hz, 2H), 7.05-7.01 (t, J=8.0Hz, 1H), 6.26-6.24 (d, J=7.2Hz, 1H). 5.88-5.86 (d, J=8.0Hz, 1H), 5.73 (bs, 1H), 4.40 (s, 3H), 4.37-4.32 (m, 1H), 4.29-4.25 (m, 2H), 3.96-3.93 (m, 2H), 3.78 (s, 3H), 3.51 (s, 3H), 3.36 (s, 3H).

[0381] Example 22. Synthesis of 6-((4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)amino)pyrazine-2-carbonitrile, I-64 [ka]

[0382] Compound I-64 was prepared from compound 1.91 and 6-aminopyrazine-2-carbonitrile using the procedure described in Example 2 (yield: 20.55%), MS(ES): m / z 471.48 [M+H]+, LCMS purity: 100.00%, HPLC purity: 98.79%, 1H NMR (DMSO-d6, 400MHz): 10.96 (s, 1H), 10.66 (s, 1H), 9.36 (s, 1H), 9.01 (s, 1H), 8.66 (s, 1H), 7.83-7.81 (d, J=8.0Hz, 1H), 7.68-7.66 (dd, J=1.2Hz, 8.0Hz, 1H), 7.44-7.42 (d, J=8.0Hz, 1H), 7.40-7.38 (d, J=8.0Hz, 1H), 4.47 (s, 3H), 3.80 (s, 3H), 3.43 (s, 3H).

[0383] Example 23. Synthesis of 6-((6-cyclopropylpyridin-2-yl)amino)-4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2-methyl-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-65 [ka]

[0384] Compound I-65 was prepared from compound 1.91 and 6-cyclopropylpyridin-2-amine using the procedure described in Example 2 (yield: 7.98%), MS (ES): m / z 485.53 [M+H]+ , LCMS purity: 96.64%, HPLC purity: 96.85%, 1H NMR (DMSO-d6, 400MHz): 11.42 (s, 1H), 9.09 (s, 1H), 7.93 (s, 1H), 7.81-7.79 (d, J=6.4Hz, 1H), 7.66-7.64 (d, J=6.4Hz, 1H), 7.41 (s, 1H), 7.09-7.07 (d, J=7.2Hz, 1H), 6.98-6.96 (d, J=7.2Hz, 1H), 6.02 (s, 1H), 4.44 (s, 3H), 3.74 (s, 3H), 3.48 (s, 3H), 2.28 (s, 1H), 1.26 (s, 2H), 1.09 (s, 2H).

[0385] Example 24. Synthesis of N-ethyl-6-((4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)amino)picolinamide, I-66 [ka]

[0386] Compound I-66 was prepared from compound 1.91 and 6-amino-N-ethylpicolinamide using the procedure described in Example 2 (yield: 12.50%), MS (ES): m / z 516.41 [M+H]+, LCMS purity: 96.85%, HPLC purity: 95.48%, 1H NMR (MeOD, 400MHz): 8.18 (s, 1H), 7.91-7.86 (t, 1H), 7.82-7.80 (d, J=8.0Hz, 1H), 7.74-7.72 (m, 1H), 7.68-7.67 (d, 1H), 7.39-7.35 (t, J=8.0Hz, 1H), 6.19 (s, 1H), 4.48 (s, 3H), 3.84 (s, 3H), 3.53 (s, 3H), 3.52-3.46 (q, J=7.2Hz, 2H), 1.28-1.25 (t, J=7.2Hz, 3H).

[0387] Example 26. Synthesis of 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-2-methyl-6-((5-methylpyridin-2-yl)amino)-1H-pyrazolo[3,4-b]pyridin-3(2H)-one, I-16 [ka]

[0388] Compound I-16 was prepared from compound 1.92 and 5-methylpyridin-2-amine using the procedure described in Example 2 (yield: 19.68%). MS (ES): m / z 458.2 [M+H]+, LCMS purity: 99.65%, HPLC purity: 99.81%, 1H NMR (DMSO-d6, 400MHZ): 10.67 (s, 1H), 9.76 (s, 1H), 8.93 (s, 1H), 8.57 (s, 1H), 8.11 (s, 1H), 7.84 (s, 1H), 7.68-7.66 (d, J=8Hz, 1H), 7.59-7.57 (m, 2H), 7.32-7.18 (m, 1H), 3.96 (s, 3H), 3.78 (s, 3H), 3.29 (s, 3H), 2.23 (s, 3H).

[0389] Example 27. Synthesis of 6-((4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)amino)nicotinonitrile, I-25 [ka]

[0390] Compound I-25 was prepared from compound 1.92 and 6-aminonicotinonitrile using the procedure described in Example 2 (yield: 12.08%). MS (ES): m / z 469.7 [M+H] + , LCMS purity: 99.49%, HPLC purity: 99.22%, 1H NMR (DMSO-d6, 400MHZ): 10.39 (s, 1H), 8.95 (s, 1H), 8.69 (s, 1H), 8.57 (s, 1H), 8.25-8.23 (m, 1H), 8.14-8.11(m, 1H), 7.68-7.66 (d, J=7.2Hz, 1H), 7.60-7.58 (d, J=8Hz, 1H), 7.33-7.29 (m, 1H), 7.10 (s, 1H), 3.96 (s, 3H), 3.78 (s, 3H), 3.31(s, 3H).

[0391] Example 28. Synthesis of 4-((4-chloro-2-methoxyphenyl)amino)-2-methyl-6-((4-methylpyridin-2-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-42 [ka]

[0392] Synthesis of Compound 28.1. Following the procedure used to prepare 1.91, 28.1 was obtained (yield: 24%). MS (ES): m / z 340.2 [M+H]+.

[0393] Compound I-42 was prepared from compound 28.1 and 4-methylpyridin-2-amine using the procedure described in Example 2 (yield: 12.53%). MS (ES): m / z 411.52 [M+H]+, LCMS purity: 100.00%, HPLC purity: 98.32%, 1H NMR (MeOD, 400MHZ): 8.18-8.17 (d, J=5.2Hz, 1H), 7.47-7.45 (d, J=8.4Hz, 1H), 7.19 (s, 1H), 7.08-7.06 (d, J=8.0Hz, 1H), 6.96-6.94 (d, J=4.8Hz, 1H), 6.79 (s, 1H), 5.69 (s, 1H), 3.98 (s, 3H), 3.53 (s, 3H), 2.37 (s, 3H).

[0394] Example 29. Synthesis of N-(4-((4-(hydroxymethyl)-2-methoxyphenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropanecarboxamide, I-42 [ka]

[0395] Synthesis of Compound 29.1. Following the procedure used to prepare 1.91, 29.1 was obtained (yield: 57.32%). MS (ES): m / z 335.8 [M+H]+.

[0396] Compound I-42 was prepared from compound 29.1 and cyclopropanecarboxamide using the procedure described in Example 2 (yield: 17.46%), MS (ES): m / z 384.51 [M+H]+ , LCMS purity: 95.04%, HPLC purity: 93.08%, 1H NMR (DMSO-d6, 400MHZ): 10.67-10.64 (d, J=1.2Hz, 2H), 8.41 (s, 1H), 7.64 (s, 1H), 7.38-7.36 (d, J=8.0Hz, 1H), 7.09 (s, 1H), 6.96-6.94 (d, J=8.0Hz, 1H), 5.24 (t, J=8.0Hz, 1H), 4.51-4.49 (d, J=8.0Hz, 2H), 3.85 (s, 3H), 3.19 (s, 3H), 1.99 (s, 1H), 0.79 (s, 4H).

[0397] Example 30. Synthesis of N-(4-((2-methoxy-4-(methoxymethyl)phenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropanecarboxamide, I-45 [ka]

[0398] Synthesis of Compound 30.1. Following the procedure used to prepare 1.91, 30.1 was obtained (yield: 57.51%). MS (ES): m / z 349.8 [M+H]+.

[0399] Compound I-45 was prepared from compound 30.1 and cyclopropanecarboxamide using the procedure described in Example 2 (yield: 23.4%), MS (ES): m / z 398.38 [M+H]+, LCMS purity: 96.46%, HPLC purity: 95.23%, 1H NMR (DMSO-d6, 400MHZ): 10.70-10.67 (d, J=12.4Hz, 2H), 8.49 (s, 1H), 7.68 (s, 1H), 7.41- 7.39 (d, J=8.0Hz, 1H), 7.07 (s, 1H), 6.96-6.94 (d, J=8.4Hz, 1H), 4.40 (s, 2H), 3.85 (s, 3H), 3.35 (s, 3H), 3.29 (s, 3H), 1.99 (s, 1H), 0.79-0.78 (d, J=3.6Hz, 4H).

[0400] Example 31. Synthesis of N-(4-((3-(1,3-dimethyl-1H-1,2,4-triazol-5-yl)-2-methoxyphenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropanecarboxamide, I-46 [ka]

[0401] Synthesis of Compound 31.1. Following the procedure used to prepare 1.91, 31.1 was obtained (yield: 49.08%). MS (ES): m / z 400.7 [M+H]+.

[0402] Compound I-46 was prepared from compound 31.1 and cyclopropanecarboxamide using the procedure described in Example 2 (yield: 5.45%), MS (ES): m / z 449.37 [M+H]+, LCMS purity: 95.95%, HPLC purity: 97.22%, 1H NMR (MeOD, 400MHZ): 7.79-7.77 (d, J=8.0Hz, 1H), 7.43-7.34 (m, 3H), 3.77 (s, 3H), 3.56 (s, 3H), 3.49 (s, 3H), 2.41 (s, 3H), 1.84 (s, 1H), 1.02-0.90 (m, 4H).

[0403] Example 32. Synthesis of 4-((2-methoxy-3-(5-methylthiazol-2-yl)phenyl)amino)-2-methyl-6-((4-methylpyridin-2-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-47 [ka]

[0404] Synthesis of Compound 32.1. Following the procedure used to prepare 1.91, 32.1 was obtained (yield: 21.10%). MS (ES): m / z 402.7 [M+H]+.

[0405] Compound I-47 was prepared from compound 32.1 and 4-methylpyridin-2-amine using the procedure described in Example 2 (yield: 27.88%). MS (ES): m / z 474.48 [M+H]+, LCMS purity: 97.47%, HPLC purity: 95.33%, 1H NMR (CDCl3, 400MHZ): 8.71 (s, 1H), 8.10-8.09 (d, J=4.8Hz, 1H), 7.76 (s, 1H), 7.55-7.53 (d, J=8.0Hz, 1H), 7.46 (s, 1H), 7.35-7.33 (d, J=8.0Hz, 1H), 6.96-6.92. (d, J=8.0Hz, 1H), 6.75 (s, 2H), 3.39 (s, 6H), 2.55 (s, 3H), 2.37 (s, 3H).

[0406] Example 33. Synthesis of N-(4-((3-fluoro-2-methoxyphenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropanecarboxamide, I-48 [ka]

[0407] Synthesis of Compound 33.1. Following the procedure used to prepare 1.91, 33.1 was obtained (yield: 54.05%). MS (ES): m / z 323.7 [M+H]+.

[0408] Compound I-48 was prepared from compound 33.1 and cyclopropanecarboxamide using the procedure described in Example 2 (yield: 18.47%), MS (ES): m / z 372.33 [M+H]+ , LCMS purity: 98.91%, HPLC purity: 95.67%, 1H NMR (DMSO-d6, 400MHZ): 10.79 (s, 1H), 8.83 (s, 1H), 8.17 (s, 1H), 7.75 (s, 1H), 7.32-7.30 (d, J=8.0Hz, 1H), 7.21-7.15 (m, 1H), 7.06-7.03 (d, J=10.0Hz, 1H), 3.88 (s, 3H), 3.31 (s, 3H), 2.03-2.01 (t, J=5.6Hz, 1H), 0.81-0.81 (d, J = 5.6 Hz, 4H).

[0409] Example 34. Synthesis of N-(4-((3-chloro-2-methoxyphenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropanecarboxamide, I-49 [ka]

[0410] Following the procedure used to prepare 1.91, 34.1 was obtained (yield: 47.14%). MS (ES): m / z 340.2 [M+H]+.

[0411] Compound I-49 was prepared from compound 34.1 and cyclopropanecarboxamide using the procedure described in Example 2. (Yield: 39.36%), MS (ES): m / z 388.13 [M+H]+, LCMS purity: 99.46%, HPLC purity: 98.93%, 1H NMR (DMSO-d6, 400MHz): 10.78 (s, 2H), 8.84 (s, 1H), 7.74 (bs, 1H), 7.46-7.43 (t, J=4.8Hz, 1H), 7.22-7.20 (d, J=4.8Hz, 2H), 3.77 (s, 3H), 3.29 (s, 3H), 1.98 (s, 1H), 0.77 (s, 4H).

[0412] Example 35: Synthesis of N-(4-((4-cyclopropyl-2-methoxyphenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropanecarboxamide, I-50 [ka]

[0413] Following the procedure used to prepare 1.91, 35.1 was obtained (yield: 54.80%). MS (ES): m / z 345.7 [M+H]+.

[0414] Compound I-50 was prepared from compound 35.1 and cyclopropanecarboxamide using the procedure described in Example 2 (yield: 16.18%). MS (ES): m / z 394.61 [M+H]+ , LCMS purity: 94.66%, HPLC purity: 99.76%, 1H NMR (DMSO-d6, 400MHz): 10.67-10.62 (d, J=17.6Hz, 2H), 8.36 (s, 1H), 7.58 (bs, 1H), 7.29-7.268 (d, J=8.0Hz, 1H), 6.83-6.83 (d, J=1.6Hz, 1H), 6.72-6.69 (dd, J=1.6Hz, 8.0Hz, 1H), 3.83 (s, 3H), 3.28 (s, 3H), 2.01-1.90 (m, 2H), 0.96-0.90 (m, 2H), 0.79-0.77 (d, J=5.2Hz, 4H), 0.74-0.72 (dd, J=3.2Hz, 4.8Hz, 2H).

[0415] Example 36: Synthesis of N-(4-((4-cyclobutyl-2-methoxyphenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropanecarboxamide, I-51 [ka]

[0416] Following the procedure used to prepare 1.91, 36.1 was obtained (yield: 50.64%). MS (ES): m / z 359.8 [M+H]+.

[0417] Compound I-51 was prepared from compound 36.1 and cyclopropanecarboxamide using the procedure described in Example 2 (yield: 42.27%), MS (ES): m / z 408.37 [M+H]+ , LCMS purity: 96.20%, HPLC purity: 96.45%, 1H NMR (DMSO-d6, 400MHz): 10.67-10.63 (d, J=17.2Hz, 2H), 8.41 (s, 1H), 7.64 (s, 1H), 7.35-7.33 (d, J=8.0Hz, 1H), 6.97 (s, 1H), 6.88-6.87 (d, J=8.0Hz, 1H), 3.85 (s, 3H), 3.54-3.48 (q, J=8.8Hz, 1H), 3.28 (s, 3H), 2.33-2.25 (m, 2H), 2.19-2.09 (m, 2H), 2.02-1.93 (m, 2H), 1.85-1.80 (m, 1H), 0.79-0.78 (d, J=5.2Hz, 4H).

[0418] Example 37: Synthesis of N-(4-((2-methoxy-3-(1-methyl-1H-tetrazol-5-yl)phenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropanecarboxamide, I-52 [ka]

[0419] Following the procedure used to prepare 1.91, 37.1 was obtained (yield: 68.77%). MS (ES): m / z 387.7 [M+H]+.

[0420] Compound I-52 was prepared from compound 37.1 and cyclopropanecarboxamide using the procedure described in Example 2 (yield: 22.21%). MS (ES): m / z 436.37 [M+H]+ , LCMS purity: 97.49%, HPLC purity: 94.04%, 1H NMR (DMSO-d6, 400MHz): 10.78 (s, 1H), 8.82 (s, 1H), 8.19 (s, 1H), 7.75-7.73 (d, J=7.6Hz, 1H), 7.65 (s, 1H), 7.4467.40 (t, J=7.6Hz, 1H), 7.36-7.34 (d, J=6.4Hz, 1H), 3.99 (s, 3H), 3.47 (s, 3H), 2.61 (s, 3H), 2.03-2.00 (t, J=6.0Hz, 1H), 0.81-0.79 (d, J = 6.0 Hz, 4H).

[0421] Example 38: Synthesis of N-(4-((3-(1,5-dimethyl-1H-1,2,4-triazol-3-yl)-2-methoxyphenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropanecarboxamide, I-53 [ka]

[0422] Following the procedure used to prepare 1.91, 38.1 was obtained (yield: 68.16%). MS (ES): m / z 400.8 [M+H]+.

[0423] Compound I-53 was prepared from compound 38.1 and cyclopropanecarboxamide using the procedure described in Example 2 (yield: 30.67%), MS (ES): m / z 449.37 [M+H]+, LCMS purity: 98.48%, HPLC purity: 95.33%, 1H NMR (CDCl3, 400MHz): 9.59 (bs, 1H), 8.89 (s, 1H), 7.59-7.57 (d, J=7.6Hz, 1H), 7.49-7.47 (d, J=8.0Hz, 1H), 7.13-7.02 (m, 2H), 3.89 (s, 3H), 3.71 (s, 3H), 3.47 (s, 3H), 2.52 (s, 3H), 1.65 (s, 1H), 1.11 (s, 2H), 0.90 (s, 2H) .

[0424] Example 39: Synthesis of N-(4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-5-yl)phenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropanecarboxamide, I-54 [ka]

[0425] Following the procedure used to prepare 1.91, 39.1 was obtained (yield: 62.17%). MS (ES): m / z 386.6 [M+H]+.

[0426] Compound I-54 was prepared from compound 39.1 and cyclopropanecarboxamide using the procedure described in Example 2 (yield: 17.76%). MS (ES): m / z 435.32 [M+H]+ , LCMS purity: 99.53%, HPLC purity: 99.60%, 1H NMR (DMSO-d6, 400MHz): 10.78 (bs, 1H), 8.84 (s, 1H), 8.08 (s, 1H), 7.71 (s, 1H), 7.68-7.66 (d, J=8.0Hz, 1H), 7.38-7.34 (m, 1H), 7.25-7.23 (d, J=8.0Hz, 1H), 3.74 (s, 3H), 3.49 (s, 3H), 3.22 (s, 3H), 2.03-2.00 (m, 1H), 0.81-0.79 (d, J=5.2Hz, 4H).

[0427] Example 40: Synthesis of N-(4-((2-methoxy-3-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropanecarboxamide, I-55. [ka]

[0428] Following the procedure used to prepare 1.91, 40.1 was obtained (yield: 48.16%). MS (ES): m / z 385.7 [M+H]+.

[0429] Compound I-55 was prepared from compound 40.1 and cyclopropanecarboxamide using the procedure described in Example 2 (yield: 20.89%). MS (ES): m / z 434.48 [M+H]+ , LCMS purity: 100.00%, HPLC purity: 100.00%, 1H NMR (DMSO-d6, 400MHz): 10.76 (bs, 1H), 8.81 (s, 1H), 8.19 (s, 1H), 7.92 (s, 1H), 7.77 (s, 1H), 7.38-7.33 (t, J=10.0Hz, 2H), 7.21-7.19 (d, J=8.0Hz, 1H), 3.90 (s, 3H), 3.61 (s, 3H), 3.32 (s, 3H), 2.02 (s, 1H), 0.80 (s, 4H).

[0430] Example 41: Synthesis of N-(4-((2-methoxy-3-(1H-pyrazol-1-yl)phenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropanecarboxamide, I-56 [ka]

[0431] Following the procedure used to prepare 1.91, 41.1 was obtained (yield: 58.80%). MS (ES): m / z 371.8 [M+H]+.

[0432] Compound I-56 was prepared from compound 41.1 and cyclopropanecarboxamide using the procedure described in Example 2 (yield: 22.10%), MS (ES): m / z 420.48 [M+H]+ , LCMS purity: 99.87%, HPLC purity: 99.66%, 1H NMR (DMSO-d6, 400MHz): 10.80 (bs, 1H), 8.88 (s, 1H), 8.23-8.22 (d, J=2.0Hz, 1H), 7.79 (s, 2H), 7.52-7.50 (d, J=7.6Hz, 1H), 7.39-7.31 (m, 2H), 6.57 (s, 1H), 3.45 (s, 3H), 3.32 (s, 3H), 2.02 (s, 1H), 0.81 (s, 4H).

[0433] Example 42: Synthesis of N-(4-((2-methoxy-3-(1-methyl-1H-pyrazol-3-yl)phenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropanecarboxamide, I-57 [ka]

[0434] Following the procedure used to prepare 1.91, 42.1 was obtained (yield: 37.77%). MS (ES): m / z 385.5 [M+H]+.

[0435] Compound I-57 was prepared from compound 42.1 and cyclopropanecarboxamide using the procedure described in Example 2 (yield: 31.07%), MS (ES): m / z 434.63 [M+H]+ , LCMS purity: 100.00%, HPLC purity: 96.16%, 1H NMR (DMSO-d6, 400MHz): 10.76 (bs, 2H), 8.83 (s, 1H), 7.79 (s, 2H), 7.62-7.60 (d, J=7.6Hz, 1H), 7.44-7.42 (d, J=7.6Hz, 1H), 7.24-7.22 (m, 1H), 6.74-6.73 (d, J=2.4Hz, 1H), 3.91 (s, 3H), 3.61 (s, 3H), 3.31 (s, 3H), 2.02 (s, 1H), 0.81 (s, 4H).

[0436] Example 46: Synthesis of N-(4-((2-methoxyphenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropanecarboxamide, I-61. [ka]

[0437] Following the procedure used to prepare 1.91, 46.1 was obtained (yield: 75.13%). MS (ES): m / z 305.7 [M+H] + .

[0438] Compound I-61 was prepared from compound 46.1 and cyclopropanecarboxamide using the procedure described in Example 2 (yield: 19.83%), MS (ES): m / z 354.38 [M+H]+ , LCMS purity: 100.00%, HPLC purity: 98.86%, 1H NMR (DMSO-d6, 400MHz): 10.69-10.67 (d, J=10.8Hz, 2H), 8.53 (s, 1H), 7.69 (s, 1H), 7.45-7.43 (d, J=8.0Hz, 1H), 7.13-7.12 (d, J=4.0Hz, 2H), 7.03-6.99 (m, 1H), 3.85 (s, 3H), 3.29 (s, 3H), 1.99 (s, 1H), 0.78 (s, 4H).

[0439] Example 51: Synthesis of 4-((2-methoxy-4-(methoxymethyl)phenyl)amino)-2-methyl-6-((6-(trifluoromethyl)pyridin-2-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-67 [ka]

[0440] Following the procedure used to prepare 1.91, 51.1 was obtained (yield: 78.14%). MS (ES): m / z 349.7 [M+H] + .

[0441] Compound I-67 was prepared from compound 51.1 and 6-(trifluoromethyl)pyridin-2-amine using the procedure described in Example 2 (yield: 14.70%), MS (ES): m / z 475.35 [M+H] + , LCMS purity: 100.00%, HPLC purity: 95.73%, 1H NMR (DMSO-d6, 400MHz): 10.72 (s, 1H), 10.21 (s, 1H), 8.69 (s, 1H), 8.13-8.10 (d, J=8.4Hz, 1H), 7.96-7.92 (t, J=8.4Hz, 1H), 7.54-7.52 (d, J=8.0Hz, 1H), 7.38-7.36 (d, J=7.2Hz, 1H), 7.32 (s, 1H), 7.06 (s, 1H), 6.95-6.93 (d, J=7.6Hz, 1H), 4.42 (s, 2H), 3.88 (s, 3H), 3.31 (s, 3H), 3.28 (s, 3H).

[0442] Example 52: Synthesis of 6-((4-((2-methoxy-4-(methoxymethyl)phenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)amino)picolinonitrile, I-68 [ka]

[0443] Following the procedure used to prepare 1.91, 52.1 was obtained (yield: 78.14%). MS (ES): m / z 349.7 [M+H] + .

[0444] Compound I-68 was prepared from compound 52.1 and 6-aminopicolinonitrile using the procedure described in Example 2 (yield: 32.34%), MS (ES): m / z 432.34 [M+H] + , LCMS purity: 97.69%, HPLC purity: 96.47%, 1H NMR (DMSO-d6, 400MHz): 10.72 (s, 1H), 10.24 (s, 1H), 8.64 (s, 1H), 8.08 (s, 1H), 7.89 (s, 1H), 7.56-7.53 (d, J=10.0Hz, 2H), 7.32 (s, 1H), 7.08-7.05 (d, J=10.4Hz, 2H), 4.41 (s, 2H), 3.88 (s, 3H), 3.33 (s, 3H), 3.28 (s, 3H).

[0445] Example 53: Synthesis of N-(4-((3-bromo-2-methoxyphenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropanecarboxamide, I-69 [ka]

[0446] Following the procedure used to prepare 1.91, 53.1 was obtained (yield: 56.84%). MS (ES): m / z 384.6 [M+H] + .

[0447] Compound I-69 was prepared from compound 53.1 and cyclopropanecarboxamide using the procedure described in Example 2 (yield: 15.53%), MS (ES): m / z 434.27 [M+H] + , LCMS purity: 98.62%, HPLC purity: 98.29%, 1H NMR (DMSO-d6, 400MHz): 10.79-10.78 (d, J=7.6Hz, 2H), 8.83 (s, 1H), 7.75 (s, 1H), 7.46-7.44 (t, J=9.6Hz, 1H), 7.22 (s, 1H), 7.21 (s, 1H), 3.78 (s, 3H), 3.32 (s, 3H), 1.98 (s, 1H), 0.79 (s, 4H).

[0448] Example 54: Synthesis of 4-((4-(hydroxymethyl)-2-methoxyphenyl)amino)-2-methyl-6-((6-(trifluoromethyl)pyridin-2-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-72 [ka]

[0449] Following the procedure used to prepare 1.91, 54.1 was obtained (yield: 65.13%). MS (ES): m / z 335.8 [M+H] + .

[0450] Compound I-72 was prepared from compound 54.1 and 6-(trifluoromethyl)pyridin-2-amine using the procedure described in Example 2 (yield: 14.54%), MS (ES): m / z 461.38 [M+H] + , LCMS purity: 98.86%, HPLC purity: 95.52%, 1H NMR (DMSO-d6, 400MHz): 10.71 (s, 1H), 10.20 (s, 1H), 8.66 (s, 1H), 8.15-8.13 (d, J=9.2Hz, 1H), 7.96-7.92 (t, J=7.6Hz, 1H), 7.52-7.49 (d, J=8.0Hz, 1H), 7.38-7.36 (d, J=7.2Hz, 1H), 7.27 (s, 1H), 7.08 (s, 1H), 6.95-6.94 (d, J=7.6Hz, 1H), 5.24-5.22 (t, J=5.6Hz, 1H), 4.51-4.50 (d, J=5.6Hz, 2H), 3.87 (s, 3H), 3.28 (s, 3H).

[0451] Example 55: Synthesis of 4-((3-fluoro-2-methoxyphenyl)amino)-2-methyl-6-((5-(piperidin-1-yl)pyridin-2-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-77 [ka]

[0452] Following the procedure used to prepare 1.91, 55.1 was obtained (yield: 81.07%). MS (ES): m / z 323.7 [M+H] + .

[0453] Compound I-77 was prepared from compound 55.1 and 5-(piperidin-1-yl)pyridin-2-amine using the procedure described in Example 2 (yield: 20.89%), MS (ES): m / z 464.53 [M+H] + , LCMS purity: 100.00%, HPLC purity: 98.80%, 1H NMR (DMSO-d6, 400MHz): 10.67 (s, 1H), 9.58 (s, 1H), 8.90 (s, 1H), 8.02 (s, 2H), 7.40 (s, 2H), 7.22-7.17 (q, J=8.4Hz, 1H), 7.01 (s, 2H), 3.89 (s, 3H), 3.27 (s, 3H), 3.08 (s, 4H), 1.64 (s, 4H), 1.23 (s, 2H).

[0454] Example 56: Synthesis of 4-((3-fluoro-2-methoxyphenyl)amino)-2-methyl-6-((1-methyl-1H-pyrazol-3-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-78 [ka]

[0455] Compound I-78 was prepared from compound 55.1 and 1-methyl-1H-pyrazol-3-amine using the procedure described in Example 2 (yield: 37.88%), MS (ES): m / z 384.43 [M+H] +, LCMS purity: 97.80%, HPLC purity: 93.71%, 1H NMR (DMSO-d6, 400MHz): 10.52 (bs, 1H), 9.52 (bs, 1H), 8.78 (s, 1H), 7.54 (s, 1H), 7.42-7.39 (d, J=8.4Hz, 1H), 7.21-7.15 (q, J=8.4Hz, 1H), 7.01-6.97 (d, J=9.6Hz, 1H), 6.88 (s, 1H), 6.35 (s, 1H), 3.89 (s, 3H), 3.72 (s, 3H), 3.25 (s, 3H).

[0456] Example 57: Synthesis of 6-((4-((3-fluoro-2-methoxyphenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)amino)nicotinonitrile, I-79 [ka]

[0457] Compound I-79 was prepared from compound 55.1 and 6-aminonicotinonitrile using the procedure described in Example 2 (yield: 39.80%), MS (ES): m / z 406.29 [M+H] + , LCMS purity: 98.61%, HPLC purity: 99.01%, 1H NMR (DMSO-d6, 400MHz): 10.99 (s, 1H), 10.44 (s, 1H), 8.88 (s, 1H), 8.69 (s, 1H), 8.23-8.21 (d, J=8.8Hz, 1H), 8.15-8.13 (dd, J=1.6Hz, 8.8Hz, 1H), 7.43-7.41 (d, J=8.4Hz, 1H), 7.25-7.19 (q, J=8.4Hz, 1H), 7.15 (s, 1H), 7.06-7.01 (d, J=8.8Hz, 1H), 3.89 (s, 3H), 3.35 (s, 3H).

[0458] Example 58: Synthesis of 4-((3-fluoro-2-methoxyphenyl)amino)-2-methyl-6-(pyridin-2-ylamino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-80 [ka]

[0459] Compound I-80 was prepared from compound 55.1 and pyridin-2-amine using the procedure described in Example 2 (yield: 21.21%), MS (ES): m / z 381.28 [M+H] + , LCMS purity: 97.64%, HPLC purity: 97.36%, 1H NMR (DMSO-d6, 400MHz): 10.78 (s, 1H), 9.85 (s, 1H), 8.85 (s, 1H), 8.26 (s, 1H), 8.03 (s, 1H), 7.71 (s, 1H), 7.44 (s, 1H), 7.21 (s, 2H), 7.06-6.83 (m, 2H), 3.96 (s, 3H), 3.29 (s, 3H).

[0460] Example 59: Synthesis of 6-((4-((3-fluoro-2-methoxyphenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)amino)picolinonitrile, I-81 [ka]

[0461] Compound I-81 was prepared from compound 55.1 and 6-aminopicolinonitrile using the procedure described in Example 2 (yield: 43.78%), MS (ES): m / z 406.43 [M+H] +, LCMS purity: 100.00%, HPLC purity: 100.00%, 1H NMR (DMSO-d6, 400MHz): 10.84 (s, 1H), 10.32 (s, 1H), 8.95 (s, 1H), 8.05-8.03 (d, J=8.4Hz, 1H), 7.93-7.89 (t, J=8.4Hz, 1H), 7.56-7.49 (m, 3H), 7.26-7.20 (q, J=8.0Hz, 1H), 7.06-7.01 (t, J=9.2Hz, 1H), 3.91 (s, 3H), 3.30 (s, 3H).

[0462] Example 60: Synthesis of N-(4-((4-(azetidine-1-carbonyl)-2-methoxyphenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropanecarboxamide, I-82 [ka]

[0463] Following the procedure used to prepare 1.91, 60.1 was obtained (yield: 24.74%). MS (ES): m / z 388.8 [M+H] + .

[0464] Compound I-82 was prepared from compound 60.1 and cyclopropanecarboxamide using the procedure described in Example 2 (yield: 21%), MS (ES): m / z 437.37 [M+H] +, LCMS purity: 100.00%, HPLC purity: 98.68%, 1H NMR (MeOD, 400MHz): 7.61-7.59 (d, J=8.0Hz, 2H), 7.39 (s, 1H), 7.34-7.32 (d, J=8.4Hz, 1H), 4.51-4.47 (t, J=6.4Hz, 2H), 4.25-4.21 (t, J=6.4Hz, 2H), 3.99 (s, 3H), 3.49 (s, 3H), 2.45-2.38 (qui, J=6.4Hz, 2H), 1.84 (s, 1H), 1.04-0.96 (m, 4H).

[0465] Example 61: Synthesis of 4-((3-fluoro-2-methoxyphenyl)amino)-2-methyl-6-((4-methylpyridin-2-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-83 [ka]

[0466] Compound I-83 was prepared from compound 55.1 and 4-methylpyridin-2-amine using the procedure described in Example 2 (yield: 30.68%), MS (ES): m / z 395.28 [M+H] + , LCMS purity: 98.12%, HPLC purity: 97.83%, 1H NMR (DMSO-d6, 400MHz): 10.72 (s, 1H), 9.72 (s, 1H), 8.82 (s, 1H), 8.09 (s, 1H), 7.83 (s, 1H), 7.43-7.42 (d, J=7.2Hz, 1H), 7.20-7.14 (m, 2H), 6.98 (s, 1H), 6.76 (s, 1H), 3.87 (s, 3H), 3.26 (s, 3H), 2.28 (s, 3H).

[0467] Example 62: Synthesis of 4-((3-fluoro-2-methoxyphenyl)amino)-2-methyl-6-((5-methylpyridin-2-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-84 [ka]

[0468] Compound I-84 was prepared from compound 55.1 and 5-methylpyridin-2-amine using the procedure described in Example 2 (yield: 20.46%), MS (ES): m / z 395.32 [M+H] + , LCMS purity: 97.72%, HPLC purity: 97.18%, 1H NMR (MeOD, 400MHz): 8.15 (s, 1H), 7.65-7.62 (dd, J=2.0Hz, 8.4Hz, 1H), 7.33-7.31 (d, J=8.0Hz, 1H), 7.18-7.13 (m, 2H), 7.08-7.03 (t, J=8.8Hz, 1H), 6.89-6.87 (d, J=7.6Hz, 1H), 3.97 (s, 3H), 3.54 (s, 3H), 2.31 (s, 3H).

[0469] Example 63: Synthesis of 6-((4-((3-fluoro-2-methoxyphenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)amino)pyrazine-2-carbonitrile, I-85 [ka]

[0470] Compound I-85 was prepared from compound 55.1 and 6-aminopyrazine-2-carbonitrile using the procedure described in Example 2 (yield: 17.87%), MS (ES): m / z 407.27 [M+H] +, LCMS purity: 99.70%, HPLC purity: 99.67%, 1H NMR (DMSO-d6, 400MHz): 10.96 (bs, 1H), 10.67 (bs, 1H), 9.31 (s, 1H), 8.92 (s, 1H), 8.65 (s, 1H), 7.47-7.45 (d, J=8.0Hz, 1H), 7.38 (s, 1H), 7.24-7.18 (q, J=8.0Hz, 1H), 7.08-7.03 (t, J=6.0Hz, 1H), 3.91 (s, 3H), 3.35 (s, 3H).

[0471] Example 64: Synthesis of 4-((3-fluoro-2-methoxyphenyl)amino)-2-methyl-6-((6-(trifluoromethyl)pyridin-2-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-86 [ka]

[0472] Compound I-86 was prepared from compound 55.1 and 6-(trifluoromethyl)pyridin-2-amine using the procedure described in Example 2 (yield: 14.99%), MS (ES): m / z 449.32 [M+H] + , LCMS purity: 99.81%, HPLC purity: 99.80%, 1H NMR (DMSO-d6, 400MHz): 10.80 (bs, 1H), 10.24 (bs, 1H), 8.95 (s, 1H), 8.08-8.06 (d, J=8.0Hz, 1H), 7.95-7.91 (t, J=8.0Hz, 1H), 7.43-7.35 (m, 3H), 7.14-7.09 (q, J=8.0Hz, 1H), 7.03-6.98 (t, J=8.0Hz, 1H), 3.88 (s, 3H), 3.28 (s, 3H).

[0473] Example 65: Synthesis of 6-((6-cyclopropylpyridin-2-yl)amino)-4-((3-fluoro-2-methoxyphenyl)amino)-2-methyl-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-87 [ka]

[0474] Compound I-87 was prepared from compound 55.1 and 6-cyclopropylpyridin-2-amine using the procedure described in Example 2 (yield: 19.19%), MS (ES): m / z 421.32 [M+H] + , LCMS purity: 98.94%, HPLC purity: 94.15%, 1H NMR (DMSO-d6, 400MHz): 11.46 (s, 1H), 8.99 (s, 1H), 7.95-7.91 (t, J=8.0Hz, 1H), 7.29-7.27 (d, J=7.2Hz, 1H), 7.18-7.16 (d, J=8.4Hz, 2H), 7.08-7.06 (d, J=7.2Hz, 1H), 6.99-6.97 (d, J=8.4Hz, 1H), 6.04 (s, 1H), 3.85 (s, 3H), 3.45 (s, 3H), 2.31-2.24 (m, 1H), 1.28-1.23 (m, 2H), 1.11-1.06 (m, 2H).

[0475] Example 66: Synthesis of N-(4-((2-methoxy-3-(2-oxopyrrolidin-1-yl)phenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropanecarboxamide, I-88 [ka]

[0476] Following the procedure used to prepare 1.91, 66.1 was obtained (yield: 56.22%). MS (ES): m / z 388.7 [M+H]+ .

[0477] Compound I-88 was prepared from compound 66.1 and cyclopropanecarboxamide using the procedure described in Example 2 (yield: 17.06%), MS (ES): m / z 437.37 [M+H] + , LCMS purity: 96.29%, HPLC purity: 95.84%, 1H NMR (DMSO-d6, 400MHz): 10.77 (s, 1H), 8.77 (s, 1H), 7.79 (s, 1H), 7.44-7.42 (d, J=7.6Hz, 1H), 7.23-7.19 (t, J=8.0Hz, 1H), 7.06-7.04 (d, J=7.6Hz, 1H), 3.74-3.71 (t, J=6.8Hz, 2H), 3.669 (s, 3H), 3.311 (s, 3H), 2.46-2.42 (d, J=8.0Hz, 2H), 2.17-2.10 (qui, J=6.8Hz, 2H), 2.017 (s, 1H), 0.78 (s, 4H).

[0478] Example 67: 4-((3-fluoro-2-methoxyphenyl)amino)-2-methyl-6-((5-morpholinopyridin-2-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-89 [ka]

[0479] Compound I-89 was prepared from compound 55.1 and 5-morpholinopyridin-2-amine using the procedure described in Example 2 (yield: 13.87%), MS (ES): m / z 466.52 [M+H] +, LCMS purity: 95.70%, HPLC purity: 95.05%, 1H NMR (DMSO-d6, 400MHz): 11.33 (s, 1H), 8.91 (s, 1H), 8.05-8.02 (dd, J=2.4Hz, 9.2Hz, 1H), 7.83-7.82 (d, J=2.4Hz, 1H), 7.32- 7.11 (m, 5H), 6.09 (s, 1H), 3.86 (s, 3H), 3.75 (s, 4H), 3.38 (s, 3H), 3.12 (s, 4H).

[0480] Example 68: Synthesis of 4-((3-fluoro-2-methoxyphenyl)amino)-2-methyl-6-((5-(pyrrolidin-1-yl)pyridin-2-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-90 [ka]

[0481] Compound I-90 was prepared from compound 55.1 and 5-(pyrrolidin-1-yl)pyridin-2-amine using the procedure described in Example 2 (yield: 17.95%), MS (ES): m / z 450.42 [M+H] + , LCMS purity: 97.66%, HPLC purity: 96.95%, 1H NMR (DMSO-d6, 400MHz): 7.61-7.58 (dd, J=2.4Hz, 9.6Hz, 1H), 7.47-7.47 (d, J=2.4Hz, 1H), 7.30-7.28 (d, J=8.4Hz, 1H), 7.22-7.19 (d, J=9.6Hz, 1H), 7.16-7.11 (m, 1H), 7.05-7.00 (d, J=9.6Hz, 1H), 6.15 (s,1H), 3.85 (s, 3H), 3.34 (s, 3H), 3.21 (s, 4H), 1.95 (s, 4H).

[0482] Example 69: Synthesis of 6-((5-cyclopropylpyridin-2-yl)amino)-4-((3-fluoro-2-methoxyphenyl)amino)-2-methyl-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-91 [ka]

[0483] Compound I-91 was prepared from compound 55.1 and 5-cyclopropylpyridin-2-amine using the procedure described in Example 2 (yield: 15.99%), MS (ES): m / z 421.29 [M+H] + , LCMS purity: 95.97%, HPLC purity: 95.65%, 1H NMR (DMSO-d6, 400MHz): 11.50 (s, 1H), 8.93 (s, 1H), 8.17 (s, 1H), 7.85-7.83 (d, J=8.4Hz, 1H), 7.31-7.29 (d, J=7.2Hz, 1H), 7.23-7.12 (m, 3H), 6.14 (s, 1H), 3.85 (s, 3H), 3.38 (s, 3H), 2.04 (s, 1H), 1.02 (s, 2H), 0.72 (s, 2H).

[0484] Example 70: Synthesis of 4-((2-methoxy-4-(methoxymethyl)phenyl)amino)-2-methyl-6-((5-(pyrrolidine-1-carbonyl)-6-(trifluoromethyl)pyridin-2-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-92 [ka]

[0485] Following the procedure used to prepare 1.91, 70.1 was obtained (yield: 78.14%). MS (ES): m / z 349.7 [M+H] + .

[0486] Compound I-92 was prepared from compound 70.1 and (6-amino-2-(trifluoromethyl)pyridin-3-yl)(pyrrolidin-1-yl)methanone using the procedure described in Example 2 (yield: 17.09%), MS (ES): m / z 572.37 [M+H] + , LCMS purity: 94.64%, HPLC purity: 95.10%, 1H NMR (DMSO-d6, 400MHz): 10.78 (s, 1H), 10.32 (s, 1H), 8.67 (s, 1H), 8.22-8.20 (d, J=8.8Hz, 1H), 7.89-7.87 (d, J=8.8Hz, 1H), 7.53-7.51 (d, J=8.0Hz, 1H), 7.21 (s, 1H), 7.07 (s, 1H), 6.95-6.93 (d, J=8.0Hz, 1H), 4.42 (s, 2H), 3.88 (s, 3H), 3.47-3.43 (t, J=6.0Hz, 2H), 3.31 (s, 3H), 3.28 (s, 3H), 3.13-3.10 (t, J=6.0Hz, 2H), 1.89-1.81 (m, 4H).

[0487] Example 71: Synthesis of 4-((2-methoxy-4-(methoxymethyl)phenyl)amino)-2-methyl-6-((5-methyl-6-(trifluoromethyl)pyridin-2-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-93 [ka]

[0488] Compound I-93 was prepared from compound 70.1 and 5-methyl-6-(trifluoromethyl)pyridin-2-amine using the procedure described in Example 2 (yield: 26.18%), MS (ES): m / z 489.43 [M+H] +, LCMS purity: 94.92%, HPLC purity: 99.24%, 1H NMR (DMSO-d6, 400MHz): 10.68 (s, 1H), 10.01 (s, 1H), 8.63 (s, 1H), 8.10-8.08 (d, J=8.4Hz, 1H), 7.79-7.77 (d, J=8.4Hz, 1H), 7.52-7.50 (d, J=7.6Hz, 1H), 7.17 (s, 1H), 7.06 (s, 1H), 6.95-6.93 (d, J=7.6Hz, 1H), 4.41 (s, 2H), 3.88 (s, 3H), 3.34 (s, 3H), 3.27 (s, 3H), 2.29 (s, 3H).

[0489] Example 72: Synthesis of 4-((3-fluoro-2-methoxyphenyl)amino)-6-((6-(3-methoxyazetidin-1-yl)pyridin-2-yl)amino)-2-methyl-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-94 [ka]

[0490] Compound I-94 was prepared from compound 55.1 and 6-(3-methoxyazetidin-1-yl)pyridin-2-amine using the procedure described in Example 2 (yield: 11.56%), MS (ES): m / z 466.30 [M+H] + , LCMS purity: 99.23%, HPLC purity: 99.29%, 1H NMR (DMSO-d6, 400MHz): 10.66 (s, 1H), 9.51 (s, 1H), 8.82 (s, 1H), 7.45-7.36 (m, 1H), 7.17-7.00 (m, 2H), 5.94-5.92 (d, J=7.2Hz, 1H), 4.28 (s, 1H), 4.04 (s, 2H), 3.87 (s, 3H), 3.67 (s, 2H), 3.26 (s, 3H), 3.22 (s, 3H).

[0491] Example 73: 4-((3-chloro-2-methoxyphenyl)amino)-6-((5-fluoro-4-methylpyridin-2-yl)amino)-2-methyl-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-95 [ka]

[0492] Following the procedure used to prepare 1.91, 73.1 was obtained (yield: 70.71%). MS (ES): m / z 340.2 [M+H] + .

[0493] Compound I-95 was prepared from compound 73.1 and 5-fluoro-4-methylpyridin-2-amine using the procedure described in Example 2 (yield: 15.82%), MS (ES): m / z 429.27 [M+H] + , LCMS purity: 95.01%, HPLC purity: 95.80%, 1H NMR (DMSO-d6, 400MHz): 9.84 (s, 1H), 8.86 (s, 1H), 8.17-8.13 (m, 1H), 7.95 (s, 1H), 7.56-7.54 (d, J=8.0Hz, 1H), 7.25-7.17 (m, 2H), 6.95 (s, 1H), 3.79 (s, 3H), 3.27 (s, 3H), 2.26 (s, 3H).

[0494] Example 74: Synthesis of 4-((3-chloro-2-methoxyphenyl)amino)-6-((2,6-dimethylpyrimidin-4-yl)amino)-2-methyl-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-96 [ka]

[0495] Compound I-96 was prepared from compound 73.1 and 2,6-dimethylpyrimidin-4-amine using the procedure described in Example 2 (yield: 14.34%), MS (ES): m / z 426.40 [M+H] + , LCMS purity: 96.62%, HPLC purity: 96.51%, 1H NMR (DMSO-d6, 400MHz): 10.13 (s, 1H), 8.91 (s, 1H), 8.18 (s, 1H), 7.63-7.60 (d, J=4.8Hz, 1H), 7.49 (s, 1H), 7.45 (s, 1H), 7.24-7.23 (d, J=4.8Hz, 2H), 3.82 (s, 3H), 3.31 (s, 3H), 2.44 (s, 3H), 2.32 (s, 3H).

[0496] Example 75: Synthesis of 4-((3-chloro-2-methoxyphenyl)amino)-6-((4-(methoxymethyl)pyridin-2-yl)amino)-2-methyl-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-97 [ka]

[0497] Compound I-97 was prepared from compound 73.1 and 4-(methoxymethyl)pyridin-2-amine using the procedure described in Example 2 (yield: 12.82%), MS (ES): m / z 441.29 [M+H] + , LCMS purity: 98.70%, HPLC purity: 98.80%, 1H NMR (DMSO-d6, 400MHz): 10.78 (s, 1H), 9.83 (s, 1H), 8.88 (s, 1H), 8.21 (s, 1H), 7.97 (s, 1H), 7.59 (s, 1H), 7.25-7.23 (d, J=7.6Hz, 3H), 6.87 (s, 1H), 4.44 (s, 2H), 3.83 (s, 3H), 3.36 (s, 3H), 3.29 (s, 3H).

[0498] Example 76: Synthesis of 6-((4-((3-chloro-2-methoxyphenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)amino)nicotinonitrile, I-98 [ka]

[0499] Compound I-98 was prepared from compound 73.1 and 6-aminonicotinonitrile using the procedure described in Example 2 (yield: 13.40%), m / z 422.32 [M+H] + , LCMS purity: 98.00%, HPLC purity: 97.94%, 1H NMR (DMSO-d6, 400MHz): 11.01 (s, 1H), 10.44 (s, 1H), 8.91 (s, 1H), 8.70 (s, 1H), 8.23-8.16 (m, 2H), 7.59-7.57 (d, J=8.0Hz, 1H), 7.27-7.24 (m, 2H), 7.14 (s, 1H), 3.82 (s, 3H), 3.31 (s, 3H).

[0500] Example 77: Synthesis of 6-((4-((3-chloro-2-methoxyphenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)amino)picolinonitrile, I-99 [ka]

[0501] Compound I-99 was prepared from compound 73.1 and 6-aminopicolinonitrile using the procedure described in Example 2 (yield: 13.14%), m / z 422.35 [M+H] + , LCMS purity: 95.93%, HPLC purity: 95.55%, 1H NMR (DMSO-d6, 400MHz): 10.87 (s, 1H), 10.33 (s, 1H), 8.98 (s, 1H), 8.04 (s, 1H), 7.91 (s, 1H), 7.67 (s, 1H), 7.56 (s, 1H), 7.50 (s, 1H), 7.27-7.24 (m, 2H), 3.83 (s, 3H), 3.31 (s, 3H).

[0502] Example 78: Synthesis of 4-((2-methoxy-4-(methoxymethyl)phenyl)amino)-6-((5-methoxy-6-(trifluoromethyl)pyridin-2-yl)amino)-2-methyl-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-104 [ka]

[0503] Compound I-104 was prepared from compound 70.1 and 5-methoxy-6-(trifluoromethyl)pyridin-2-amine using the procedure described in Example 2 (yield: 11.52%), MS (ES): m / z 505.36 [M+H] + , LCMS purity: 97.99%, HPLC purity: 96.46%, 1H NMR (DMSO-d6, 400MHz): 7.82-7.80 (d, J=9.2Hz, 1H), 7.32-7.23 (m, 3H), 7.10 (s, 1H), 6.98-6.96 (d, J=8.0Hz, 1H), 4.39 (s, 2H), 3.85 (s, 3H), 3.79 (s, 3H), 3.57 (s, 3H), 3.29 (s, 3H).

[0504] Example 79: Synthesis of 4-((3-chloro-2-methoxyphenyl)amino)-2-methyl-6-((6-methylpyridazin-3-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-105 [ka]

[0505] Compound I-105 was prepared from compound 73.1 and 6-methylpyridazin-3-amine using the procedure described in Example 2 (yield: 5.49%), m / z 412.29 [M+H] + , LCMS purity: 97.66%, HPLC purity: 95.98%, 1H NMR (DMSO-d6, 400MHz): 10.21 (s, 1H), 8.87 (s, 1H), 8.29 (s, 1H), 7.56 (s, 1H), 7.48-7.46 (d, J=9.2Hz, 1H), 7.21-7.20 (d, J=4.0Hz, 1H), 7.11-7.09 (d, J=8.8Hz, 1H), 6.69-6.67 (d, J=9.2Hz, 1H), 6.10 (s, 1H), 3.81 (s, 3H), 3.27 (s, 3H), 2.34 (s, 3H).

[0506] Example 80: Synthesis of 6-((4-((3-chloro-2-methoxyphenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)amino)pyrazine-2-carbonitrile, I-117 [ka]

[0507] Compound I-117 was prepared from compound 73.1 and 6-methylpyridazin-3-amine using the procedure described in Example 2 (yield: 21.39%), m / z 423.27 [M+H] + , LCMS purity: 96.80%, HPLC purity: 95.08%, 1H NMR (DMSO-d6, 400MHz): 10.96 (s, 1H), 10.65 (s, 1H), 9.31 (s, 1H), 8.93 (s, 1H), 8.64 (s, 1H), 7.61-7.59 (d, J=4.0Hz, 1H), 7.35 (s, 1H), 7.27-7.23 (m, 2H), 3.86 (s, 3H), 3.30 (s, 3H).

[0508] Example 81: Synthesis of N-(4-((3,4-difluoro-2-methoxyphenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropanecarboxamide, I-127 [ka]

[0509] Following the procedure used to prepare 1.91, 81.1 was obtained (yield: 63.99%). MS (ES): m / z 341.7 [M+H] + .

[0510] Compound I-127 was prepared from compound 81.1 and cyclopropanecarboxamide using the procedure described in Example 2 (yield: 17.5%), m / z 390.27 [M+H] + , LCMS purity: 99.27%, HPLC purity: 99.63%, 1H NMR (DMSO-d6, 400MHz): 10.72 (s, 2H), 8.55 (s, 1H), 7.49 (s, 1H), 7.29-7.20 (m, 2H), 3.89 (s, 3H), 3.28 (s, 3H), 1.99-1.95 (m, 1H), 0.77-0.75 (d, J=6.4Hz, 4H).

[0511] Example 82: N-(4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2-(methyl-d3)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropanecarboxamide, I-100 [ka]

[0512] Synthesis of Compound 82.1. To 2,4,6-trichloronicotinic acid (0.25 g, 1.10 mmol, 1.0 equiv.), thionyl chloride (1.2 mL) was added, followed by N,N-dimethylformamide (catalyst), and the mixture was refluxed for 16 hours. The reaction mixture was concentrated under reduced pressure to give the acid chloride. Methylhydrazine d3 sulfate (0.16 g, 1.10 mmol, 1.0 equiv.) was dissolved in dichloromethane (5 mL), followed by the addition of a solution of sodium hydroxide (0.18 g, 4.40 mmol, 4.0 equiv.) in water (1.2 mL). To this was added the previously prepared solution of the acid chloride in dichloromethane (5 mL) dropwise, and the reaction mixture was refluxed for 15 minutes. After completion of the reaction, the reaction mixture was transferred to water and extracted with dichloromethane. The organic layers were combined, washed with brine solution, dried over sodium sulfate, and concentrated under reduced pressure to give crude material, which was further purified by column chromatography, and the product was eluted in 30% ethyl acetate in hexane to give pure 1.1 (0.2 g, 70.35%). MS(ES): m / z 258.5 [M+H] + .

[0513] Synthesis of Compound 82.2. To a suspension of 83.1 (0.2 g, 0.776 mmol, 1.0 equiv.) in 1-pentanol (5 mL), sodium carbonate (0.083 g, 0.776 mmol, 1.0 equiv.) was added, and the reaction mixture was stirred at 120° C. for 18 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and pH=6 was adjusted using 1N hydrochloric acid. The reaction mixture was concentrated under reduced pressure to give the crude material, which was further purified by preparative HPLC using 0.1% formic acid in water / acetonitrile in a gradient to give pure 1.2 (0.085 g, 49.51%). MS (ES): m / z 222.06 [M+H] + .

[0514] Synthesis of Compound 82.3 Following the procedure used to prepare 1.91, 82.3 was obtained (yield: 30.78%). MS (ES): m / z 390.82 [M+H] + .

[0515] Compound I-100 was prepared from compound 82.3 and cyclopropanecarboxamide using the procedure described in Example 2 (0.025 g, yield: 23.40%). MS (ES): m / z 439.42 [M+H] + , LCMS purity: 99.10%, HPLC purity: 97.85%, 1H NMR (DMSO-d6, 400MHz): 10.79 (s, 2H), 8.89 (s, 1H), 7.81 (s, 1H), 7.68-7.64 (t, J=8.0Hz, 2H), 7.40-7.36 (t, J=8.0Hz, 1H), 4.47 (s, 3H), 3.77 (s, 3H), 2.02 (s, 1H), 0.81 (s, 4H).

[0516] Example 83: Synthesis of 3-((6-(cyclopropanecarboxamido)-2-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-4-yl)amino)-2-methoxybenzamide, I-102 [ka] [ka]

[0517] Synthesis of Compound 83.1. To a solution of methyl 2-hydroxy-3-nitrobenzoate (5.0 g, 25.36 mmol, 1.0 equiv.) in N,N-dimethylformamide (50 mL), potassium carbonate (7.0 g, 50.76 mmol, 2.0 equiv.) was added at 0° C. and stirred for 15 minutes. Methyl iodide (7.2 g, 50.76 mmol, 2 equiv.) was added dropwise, and the reaction mixture was stirred at 60° C. for 2 hours. After completion of the reaction, the reaction mixture was transferred to ice water, and the precipitated product was filtered and thoroughly dried to give Compound 83.1 (5.0 g, 93%). MS (ES): m / z 212.2 [M+H] + .

[0518] Synthesis of Compound 83.2. To 83.1 (5 g, 23.67 mmol, 1.0 equiv.) was added aqueous ammonia (30 mL), followed by methanolic ammonia (160 mL). The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was washed with ice-cold water. The solid was thoroughly dried to give 83.2 (4.5 g, 96%). MS (ES): m / z 197.2 [M+H] + .

[0519] Synthesis of Compound 83.3. To a solution of 83.2 (4.5 g, 22.94 mmol, 1.0 equiv.) in methanol (45 mL) was added 10% palladium on activated carbon (1.0 g). Hydrogen was purged through the reaction mixture for 4 hours. After completion of the reaction, the reaction mixture was filtered through a bed of celite and washed with methanol. The filtrate was concentrated under reduced pressure to give 83.3 (3.0 g, 78.69%). MS (ES): m / z 167.18 [M+H] + .

[0520] Synthesis of Compound 83.4 Following the procedure used to prepare 1.91, 84.4 was obtained (yield: 62.70%). MS (ES): m / z 348.76 [M+H] + .

[0521] Compound I-102 was prepared from compound 83.4 and cyclopropanecarboxamide using the procedure described in Example 2 (yield: 2.63%). MS (ES): m / z 397.41 [M+H] + , LCMS purity: 98.76%, HPLC purity: 98.65%, 1H NMR (DMSO-d6, 400MHz): 10.81 (s, 1H), 8.56 (s, 1H), 8.12 (s, 1H), 7.69-7.68 (d, J=6.4Hz, 1H), 7.65-7.63 (d, J=8.0Hz, 1H), 7.57-7.55 (d, J=8.0Hz, 1H), 6.95-6.91 (t, J=8.0Hz, 1H), 3.29 (s, 3H), 3.27 (s, 3H), 1.49-1.46 (m, 1H), 0.78-0.77 (m, 4H).

[0522] Example 84: Synthesis of 3-((6-((2,6-dimethylpyrimidin-4-yl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-4-yl)amino)-2-methoxybenzamide, I-103 [ka]

[0523] Compound 84.1 was prepared from compound 84 and 2,6-dimethylpyrimidin-4-amine using the procedure described in Example 2 (yield: 19.00%). MS (ES): m / z 417.45 [M+H] + .

[0524] Synthesis of compound I-103. 84.1 (0.120 g, 0.363 mmol, 1 eq) was added with sulfuric acid (2 mL) and stirred at 60° C. for 1 hour. After completion of the reaction, water and aqueous ammonia were added to the reaction mixture and stirred at room temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure to give the crude material. This was further purified by preparative HPLC using 0.1% formic acid in water / acetonitrile in a gradient method to give pure I-84 (0.02 g, yield: 15.98%). MS (ES): m / z 435.46 [M+H] + , LCMS purity: 100.00%, HPLC purity: 95.03%, 1H NMR (DMSO-d6, 400MHz): 14.19 (s, 1H), 10.15 (s, 1H), 8.61 (s, 2H), 8.15 (s, 1H), 7.73-7.65 (d, J=7.6Hz, 2H), 7.48 (s, 2H), 6.97-6.93 (t, J=8.0Hz, 1H), 3.34 (s, 3H), 3.29 (s, 3H), 2.43 (s, 3H), 2.34 (s, 3H).

[0525] Example 85: Synthesis of 4-((2-methoxy-4-(methoxymethyl)phenyl)amino)-6-((5-methoxy-6-(trifluoromethyl)pyridin-2-yl)amino)-2-methyl-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-106 [ka]

[0526] Compound 85.1 was prepared from compound 85 and 5-fluoro-4-methylpyridin-2-amine using the procedure described in Example 2 (yield: 19.65%). MS (ES): m / z 420.42 [M+H] + .

[0527] Synthesis of compound I-106. To 85.1 (0.125 g, 0.298 mmol, 1 eq.) was added sulfuric acid (2 mL) and stirred at 60° C. for 1 hour. After completion of the reaction, water and aqueous ammonia were added to the reaction mixture and stirred at room temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure to give the crude material. This was further purified by preparative HPLC using 0.1% formic acid in water / acetonitrile in a gradient method to give pure I-106 (0.022 g, yield: 16.88%). MS (ES): m / z 438.44 [M+H] + , LCMS purity: 98.97%, HPLC purity: 96.36%, 1H NMR (DMSO-d6, 400MHz): 14.21 (bs, 1H), 9.84 (s, 1H), 8.64 (s, 1H), 8.56 (s, 1H), 8.15-8.11 (m, 2H), 8.02-8.01 (d, J=5.6Hz, 1H), 7.66-7.61 (d, J=8.0Hz, 2H), 7.00-6.92 (m, 2H), 3.32 (s, 3H), 3.24 (s, 3H), 2.28 (s, 3H).

[0528] Example 86: Synthesis of 6-((5-fluoro-4-methylpyridin-2-yl)amino)-2-methyl-4-((2-(methylsulfonyl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-107 [ka]

[0529] Following the procedure used to prepare 1.91, 86.1 was obtained (yield: 76.89%). MS (ES): m / z 321.80 [M+H] + .

[0530] Synthesis of Compound 86.2. To a solution of 86.1 (1.81 g, 5.64 mmol, 1 equiv.) in acetic acid (2.5 mL), 30% hydrogen peroxide (3.83 g, 112.8 mmol, 20 equiv.) and sodium tungstate dihydrate (1.85 g, 5.64 mmol, 1 equiv.) were added. The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was transferred to ice water, and the precipitated product was filtered, washed with 50% ethyl acetate in hexane, and thoroughly dried to give 86.2 (1.25 g, yield: 62.80%). MS (ES): m / z 353.79 [M+H] + .

[0531] Compound I-107 was prepared from compound 86.2 and 5-fluoro-4-methylpyridin-2-amine using the procedure described in Example 2 (0.060 g, yield: 31.89%). MS (ES): m / z 443.47 [M+H] + , LCMS purity: 99.63%, HPLC purity: 99.37%, 1H NMR (DMSO-d6, 400MHz): 10.72 (s, 1H), 9.76 (s, 1H), 9.06 (s, 1H), 8.07 (s, 1H), 7.93-7.91 (d, J=7.2Hz, 2H), 7.84-7.77 (m, 2H), 7.39-7.36 (t, J=7.2Hz, 1H), 6.94 (s, 1H), 3.25 (s, 3H), 3.16 (s, 3H), 2.25 (s, 3H).

[0532] Example I-87: Synthesis of 6-((2,6-dimethylpyrimidin-4-yl)amino)-2-methyl-4-((2-(methylsulfonyl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-109 [ka]

[0533] Compound I-109 was prepared from compound 86.2 and 2,6-dimethylpyrimidin-4-amine using the procedure described in Example 2 (yield: 27.52%), MS (ES): m / z 440.40 [M+H] + , LCMS purity: 98.42%, HPLC purity: 95.04%, 1H NMR (DMSO-d6, 400MHz): 10.84 (bs, 1H), 10.09 (s, 1H), 9.15 (s, 1H), 7.94-7.92 (dd, J=1.2Hz, 8.0Hz, 1H), 7.87-7.85 (d, J=8.0Hz, 1H), 7.81-7.77(t, J=8.0Hz, 1H), 7.44-7.34 (m, 3H), 3.27 (s, 3H), 3.16 (s, 3H), 2.37 (s, 3H), 2.29 (s, 3H).

[0534] Example 88: Synthesis of 2-methyl-6-((6-methylpyridazin-3-yl)amino)-4-((2-(methylsulfonyl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-109 [ka]

[0535] Compound I-109 was prepared from compound 86.2 and 6-methylpyridazin-3-amine using the procedure described in Example 2 (yield: 32.58%), MS (ES): m / z 426.19 [M+H] +, LCMS purity: 97.90%, HPLC purity: 96.09%, 1H NMR (DMSO-d6, 400MHz): 10.59 (bs, 1H), 10.17 (s, 1H), 9.09 (s, 1H), 8.19 (s, 1H), 7.94-7.92 (d, J= 8.0Hz, 1H), 7.84-7.75 (m, 2H), 7.47-7.38 (m, 2H), 6.95 (s, 1H), 3.171 (s, 3H), 3.059 (s, 3H), 2.314 (s, 3H).

[0536] Example 89: Synthesis of 6-((4-(methoxymethyl)pyridin-2-yl)amino)-2-methyl-4-((2-(methylsulfonyl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-110 [ka]

[0537] Compound I-110 was prepared from compound 86.2 and 4-(methoxymethyl)pyridin-2-amine using the procedure described in Example 2 (yield: 14.42%), MS (ES): m / z 455.20 [M+H] + , LCMS purity: 94.46%, HPLC purity: 95.28%, 1H NMR (DMSO-d6, 400MHz): 11.62 (s, 1H), 9.24 (s, 1H), 8.32-8.30 (d, J= 6.4Hz, 1H), 8.00-7.98 (d, J= 7.2Hz, 1H), 7.84-7.80 (m, 2H), 7.51 (t, 1H), 7.24-7.19 (m, 2H), 6.21 (s, 1H), 4.59 (s, 2H), 3.39 (s, 3H), 3.36 (s, 3H), 3.19 (s, 3H).

[0538] Example 90: Synthesis of 2-methyl-6-((5-methylpyridin-2-yl)amino)-4-((2-(methylsulfonyl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-111 [ka]

[0539] Compound I-111 was prepared from compound 86.2 and 5-methylpyridin-2-amine using the procedure described in Example 2 (yield: 20.78%), MS (ES): m / z 425.19 [M+H] + , LCMS purity: 97.76%, HPLC purity: 96.61%, 1H NMR (MeOD, 400MHz): 8.14 (s, 1H), 8.06-8.04 (d, J= 8.0Hz, 1H), 7.82-7.76 (m, 2H), 7.63-7.61 (d, J=8.0Hz, 1H), 7.49-7.46 (t, J=6.8Hz, 1H), 6.90 (s, 1H), 5.81 (s, 1H), 3.56 (s, 3H), 3.34 (s, 1H), 3.11 (s, 3H), 2.30 (s, 3H).

[0540] Example 91: Synthesis of 6-((2-methyl-4-((2-(methylsulfonyl)phenyl)amino)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)amino)picolinonitrile, I-112 [ka]

[0541] Compound I-112 was prepared from compound 86.2 and 6-aminopicolinonitrile using the procedure described in Example 2 (yield: 23.15%), MS (ES): m / z 436.35 [M+H] +, LCMS purity: 100.00%, HPLC purity: 100.00%, 1H NMR (DMSO-d6, 400MHz): 10.81 (s, 1H), 10.28 (s, 1H), 9.18 (s, 1H), 8.05-8.03 (d, J= 8.8Hz, 1H), 7.94-7.80 (m, 4H), 7.52-7.50 (d, J=7.2Hz, 1H), 7.41-7.38 (t, J=7.2Hz, 1H), 7.24 (s, 1H), 3.27 (s, 3H), 3.16 (s, 3H).

[0542] Example 92: Synthesis of 4-((3-chloro-2-methoxyphenyl)amino)-2-methyl-6-((5-(pyrrolidine-1-carbonyl)-6-(trifluoromethyl)pyridin-2-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-128 [ka] [ka]

[0543] Synthesis of Compound 92.1. To 5-bromo-6-(trifluoromethyl)pyridin-2-amine (3.0 g, 12.45 mmol, 1.0 equivalent) in dimethylformamide (1 ml) was added zinc cyanide (1.456 g, 12.45 mmol, 1.0 equivalent). The reaction mixture was then heated in a microwave at 150° C. for 15 minutes. After completion of the reaction, water was added to the reaction mixture and extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to obtain the crude material. This was further purified by column chromatography, and the compound was eluted in 20% ethyl acetate in hexane to obtain 92.1. (Yield: 68.69%). MS (ES): m / z 188.13 [M+H] + .

[0544] Synthesis of Compound 92.2. Compound 92.1 (1.6 g, 8.55 mmol, 1.0 eq) and sodium hydroxide (1.0 g, 25.65 mmol, 3.0 eq) were added with water (30 mL), and the reaction mixture was stirred at 100° C. for 16 hours. After completion of the reaction, the reaction mixture was extracted with ethyl acetate. The aqueous layer was acidified with hydrochloric acid and extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to obtain the crude material. This was further purified by column chromatography, and the compound was eluted in 5% methanol in dichloromethane to obtain 93.2. (Yield: 62.41%). MS (ES): m / z 207.12 [M+H] + .

[0545] Synthesis of Compound 92.3. To a cold solution of 92.2 (0.5 g, 2.43 mmol, 1.0 equiv.) and pyrrolidine (0.19 g, 2.67 mmol, 1.1 equiv.) in N,N-dimethylformamide (5 mL) was added 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (1.846 g, 4.86 mmol, 2.0 equiv.) at 0° C., followed by N,N-diisopropylethylamine (0.94 g, 7.29 mmol, 3.0 equiv.), and the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to obtain the crude material. This was further purified by column chromatography, and the compound was eluted in 3% methanol in dichloromethane to obtain pure 92.3 (0.39 g, 62.34%). MS (ES): m / z 260.23 [M+H] + .

[0546] Compound I-128 was prepared from compound 73.1 and compound 93.3 using the procedure described in Example 2 (yield: 10.06%). MS (ES): m / z 563.35 [M+H] + , LCMS purity: 90.57%, HPLC purity: 94.43%, 1H NMR (DMSO-d6, 400MHz): 10.91 (bs, 1H), 10.36 (s, 1H), 8.97 (s, 1H), 8.18-8.16 (d, J=8.4Hz, 1H), 7.89-7.87 (d, J=8.4Hz, 1H), 7.58-7.55 (dd, J=1.6Hz, 7.6Hz, 1H), 7.30 (s, 1H), 7.21-7.14 (m, 2H), 3.81 (s, 3H), 3.45-3.42 (m, 2H), 3.29 (s, 3H), 3.12-3.08 (m, 2H), 1.88-1.79 (m, 4H).

[0547] Example 93: Synthesis of 4-((3-chloro-2-methoxyphenyl)amino)-2-methyl-6-((5-(morpholine-4-carbonyl)-6-(trifluoromethyl)pyridin-2-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-130 [ka]

[0548] Synthesis of Compound 93.1. To a cold solution of 6-amino-2-(trifluoromethyl)nicotinic acid (0.5 g, 2.43 mmol, 1.0 equiv.) and morpholine (0.23 g, 2.67 mmol, 1.1 equiv.) in N,N-dimethylformamide (5 mL) was added (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate)) (1.846 g, 4.86 mmol, 2.0 equiv.) at 0 °C, followed by N,N-diisopropylethylamine (0.94 g, 7.29 mmol, 3.0 equiv.), and the reaction mixture was stir...

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[Claim 1] An object, method or system as described in the specification.

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