TYK2 inhibitors and uses thereof

Abstract

To provide methods for the treatment of diseases.SOLUTION: The present invention provides compounds, compositions thereof, and methods of using the same for the inhibition of TYK2, and the treatment of TYK2-mediated disorders. Compounds provided by this invention are also useful for the study of TYK2 enzymes in biological and pathological phenomena; the study of intracellular signal transduction pathways occurring in bodily tissues; and the comparative evaluation of new TYK2 inhibitors or other regulators of kinases, signaling pathways, and cytokine levels in vitro or in vivo.SELECTED DRAWING: None

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, also known as tyrosine kinase 2 ("TYK2"). The present invention also relates to pharmaceutically acceptable compositions comprising the compounds of the present invention, and methods of using said compositions in the treatment of various disorders.

Background Art

[0002] Background of the Invention In recent years, the search for new therapeutic agents has been greatly aided by a more thorough understanding of the structure of disease-related enzymes and other biomolecules. One important class of enzymes that has been the subject of extensive research is the protein kinase family.

[0003] Protein kinases constitute a large family of structurally related enzymes that are responsible for controlling 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. Most kinases contain a similar catalytic domain of 250-300 amino acids. Kinases can be classified into families based on the substrates they phosphorylate (e.g., protein-tyrosine, protein-serine / threonine, lipids, etc.).

[0004] Generally, protein kinases mediate intracellular signal transduction by performing phosphoryl transfer from nucleoside triphosphates to protein acceptors involved in signal transduction pathways. These phosphorylation events modulate the biological functions of target proteins. ​​​​​​​​​​​​ acts as a molecular on / off switch that can be turned on or adjusted. These phosphorylation events are ultimately induced in response to various extracellular and other stimuli. Such stimuli include, for example, environmental stress signals and chemical stress signals (e.g., osmotic shock, heat shock, ultraviolet irradiation, bacterial endotoxin, and H2O2), cytokines (e.g., interleukin-1 (IL-1), interleukin-8 (IL- 8), and tumor necrosis factor α (TNF-α)), and growth factors (e.g., granulocyte macrophage colony-stimulating factor (GM-CSF), and fibroblast growth factor (FGF ))). Extracellular stimuli can affect one or more cellular responses related to cell proliferation, migration, differentiation, hormone secretion, activation of transcription factors, muscle contraction, glucose metabolism, regulation of protein synthesis, and regulation of the cell cycle.

[0005] Many diseases are associated with abnormal cellular responses induced by kinase-mediated events. These diseases include, but are not limited to, autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases , neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer's disease, and hormone-related diseases. Therefore, there remains a need to find protein kinase inhibitors useful as therapeutic agents. SUMMARY OF THE INVENTION MEANS FOR SOLVING THE PROBLEM

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

[0007] The compounds of the present invention and their pharmaceutically acceptable compositions are involved in the TYK2 kinase and are useful for treating various diseases, disorders or conditions related to the regulation of signal transduction pathways as described herein. are exemplified.

[0008] 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 signal transduction pathways occurring in body tissues; and the in vitro or in vivo comparative evaluation of new TYK2 inhibitors or other regulators of kinases, signal transduction pathways, and cytokine levels.

BEST MODE FOR CARRYING OUT THE INVENTION

[0009] Detailed Description of Specific Embodiments 1. General Description of Specific Embodiments of the Present Invention: The compounds of the present invention and their compositions are useful as inhibitors of the 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 the enthalpy value, entropy value, and free energy value 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] in the binding pocket of TYK2 with a stability rating of greater than 2.5 kcal / mol The water molecules occupying the hydration sites in the nuclei are called "labile water".

[0012] Without wishing to be bound by any particular theory, it is believed that the unstable water molecule (i.e. the movement or destruction of water molecules (i.e., water molecules with a stability rating greater than 2.5 kcal / mol); or stable water (i.e., water molecules with a stability rating of less than 1 kcal / mol). Displacement by an inhibitor is believed to result in tighter binding of the inhibitor. One or more labile water molecules (i.e., not labile to any known inhibitor) Inhibitors designed to displace the labile water molecules that cannot be displaced form tighter bonds. It is a combination drug and therefore a more potent inhibitor compared to inhibitors that do not displace labile water molecules. It is a drug.

[0013] Surprisingly, the compounds provided are capable of displacing one or more labile water molecules. It has been found that the activating or destroying of the cellular endothelial cell is a cellular endothelial cell. The compound displaces or disrupts at least two labile water molecules.

[0014] In certain embodiments, the present invention provides a compound of formula I: [ka] or a pharma- ceutically acceptable salt thereof, wherein in formula I, R 3 , R 5 , R 6 , and R 7 Each of the above, both alone and in combination, is defined below and is used herein as defined in As described in the embodiments herein.

[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, the method comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof. 2. Compounds and Definitions:

[0017] The compounds of the present invention generally include those described above, and are further exemplified by the classes, subclasses, and species disclosed herein. As used herein, unless otherwise specified, the following definitions shall apply. For the purposes of this invention, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and P hysics, 75th Edition. Further, general principles of organic chemistry are described in "Organic Chem istry", Thomas Sorrell, University Science Books, Sausalito: 1999, the entire contents of which are incorporated herein by reference, and "March’s Adva nced Organic Chemistry", 5th Edition, eds: Smith, M.B . and March, J., John Wiley & Sons, New York : 2001. The term "aliphatic" or "aliphatic group", as used herein, refers to a straight-chain (i.e., unbranched) or branched, saturated or unsaturated hydrocarbon chain, as described herein.

[0018] or branched, saturated or unsaturated hydrocarbon chain, as described herein. a straight-chain (non-branched) or branched-chain, substituted or unsubstituted, fully saturated or having one or more unsaturated units hydrocarbon chain, or a fully saturated or having one or more unsaturated units but non-aromatic monocyclic or bicyclic hydrocarbon (also referred to herein as "carbocyclic", "alicyclic" or "cycloalkyl") having one point of attachment to the remainder of the molecule. Unless otherwise specified, aliphatic groups contain from 1 to 6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain from 1 to 5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain from 1 to 4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain from 1 to 3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain from 1 to 2 aliphatic carbon atoms. In some embodiments, "alicyclic" (or "carbocyclic" or "cycloalkyl") refers to a monocyclic C3-C6 hydrocarbon that is fully saturated or has one or more unsaturated units but is non-aromatic and has one point of attachment to the remainder of the molecule. Suitable aliphatic groups include straight-chain or branched-chain, saturated or unsaturated, alkyl groups, alkenyl groups, alkynyl groups and hybrids thereof (e.g., (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl), but are not limited thereto. or more unsaturated units, or a fully saturated or having one or more unsaturated units but non-aromatic monocyclic or bicyclic hydrocarbon but not aromatic carbocyclic ring (also referred to herein as "carbon ring", "alicyclic" or "cycloalkyl") which means having one point of attachment to the remainder of the molecule. Unless otherwise specified aliphatic groups contain from 1 to 6 aliphatic carbon atoms. In some embodiments aliphatic groups contain from 1 to 5 aliphatic carbon atoms. In other embodiments aliphatic groups contain from 1 to 4 aliphatic carbon atoms. In still other embodiments aliphatic groups contain from 1 to 3 aliphatic carbon atoms, and in yet other embodiments aliphatic groups contain from 1 to 2 aliphatic carbon atoms. In some embodiments "alicyclic" (or "carbon ring" or "cycloalkyl") refers to a fully saturated or having one or more unsaturated units but non-aromatic monocyclic C3-C6 hydrocarbon having one point of attachment to the remainder of the molecule. Suitable aliphatic groups include straight-chain or branched-chain, saturated or unsaturated alkyl groups, alkenyl groups, alkynyl groups and hybrids thereof (e.g., , (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl), but are not limited thereto. For example, (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl )

[0019] 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 Any bicyclic ring system (i.e., carbocyclic or heterocyclic) that is saturated or partially unsaturated and has at least one bridge It means that, as defined by IUPAC, a "bridge" is a non-branched chain of a plurality of atoms connecting two bridgeheads, or one atom, or a valence bond, where a "bridgehead" is any backbone atom of the ring system that is bonded to three or more backbone atoms (other than hydrogen). In some embodiments, the bridged bicyclic group has 7 to 12 ring members and independently 0 to 4 heteroatoms selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art, and examples of groups described below in which each group is bonded to the remainder of the molecule at any suitable carbon atom or nitrogen atom include. Unless otherwise specified, the bridged bicyclic group is substituted with one or more substituents as described for aliphatic groups, as necessary. Further, or alternatively, any substitutable nitrogen of the bridged bicyclic group is substituted as necessary. Exemplary bridged bicyclics include: a non-branched chain of atoms, or one atom, or a valence bond, where a "bridgehead" is any backbone atom of the ring system that is bonded to three or more backbone atoms (other than hydrogen). In some embodiments, the bridged bicyclic group has 7 to 12 ring members and independently 0 to 4 heteroatoms selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art, and examples of groups described below in which each group is bonded to the remainder of the molecule at any suitable carbon atom or nitrogen atom include. Unless otherwise specified, the bridged bicyclic group is substituted with one or more substituents as described for aliphatic groups, as necessary. Further, or alternatively, any substitutable nitrogen of the bridged bicyclic group is substituted as necessary. Exemplary bridged bicyclics include: In some embodiments, the bridged bicyclic group has 7 to 12 ring members and independently 0 to 4 heteroatoms selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art, and examples of groups described below in which each group is bonded to the remainder of the molecule at any suitable carbon atom or nitrogen atom include. Unless otherwise specified, the bridged bicyclic group is substituted with one or more substituents as described for aliphatic groups, as necessary. Further, or alternatively, any substitutable nitrogen of the bridged bicyclic group is substituted as necessary. Exemplary bridged bicyclics include: In some embodiments, the bridged bicyclic group has 7 to 12 ring members and independently 0 to 4 heteroatoms selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art, and examples of groups described below in which each group is bonded to the remainder of the molecule at any suitable carbon atom or nitrogen atom include. Unless otherwise specified, the bridged bicyclic group is substituted with one or more substituents as described for aliphatic groups, as necessary. Further, or alternatively, any substitutable nitrogen of the bridged bicyclic group is substituted as necessary. Exemplary bridged bicyclics include: In some embodiments, the bridged bicyclic group has 7 to 12 ring members and independently 0 to 4 heteroatoms selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art, and examples of groups described below in which each group is bonded to the remainder of the molecule at any suitable carbon atom or nitrogen atom include. Unless otherwise specified, the bridged bicyclic group is substituted with one or more substituents as described for aliphatic groups, as necessary. Further, or alternatively, any substitutable nitrogen of the bridged bicyclic group is substituted as necessary. Exemplary bridged bicyclics include: In some embodiments, the bridged bicyclic group has 7 to 12 ring members and independently 0 to 4 heteroatoms selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art, and examples of groups described below in which each group is bonded to the remainder of the molecule at any suitable carbon atom or nitrogen atom include. Unless otherwise specified, the bridged bicyclic group is substituted with one or more substituents as described for aliphatic groups, as necessary. Further, or alternatively, any substitutable nitrogen of the bridged bicyclic group is substituted as necessary. Exemplary bridged bicyclics include: In some embodiments, the bridged bicyclic group has 7 to 12 ring members and independently 0 to 4 heteroatoms selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art, and examples of groups described below in which each group is bonded to the remainder of the molecule at any suitable carbon atom or nitrogen atom include. Unless otherwise specified, the bridged bicyclic group is substituted with one or more substituents as described for aliphatic groups, as necessary. Further, or alternatively, any substitutable nitrogen of the bridged bicyclic group is substituted as necessary. Exemplary bridged bicyclics include: In some embodiments, the bridged bicyclic group has 7 to 12 ring members and independently 0 to 4 heteroatoms selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art, and examples of groups described below in which each group is bonded to the remainder of the molecule at any suitable carbon atom or nitrogen atom include. Unless otherwise specified, the bridged bicyclic group is substituted with one or more substituents as described for aliphatic groups, as necessary. Further, or alternatively, any substitutable nitrogen of the bridged bicyclic group is substituted as necessary. Exemplary bridged bicyclics include: In some embodiments, the bridged bicyclic group has 7 to 12 ring members and independently 0 to 4 heteroatoms selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art, and examples of groups described below in which each group is bonded to the remainder of the molecule at any suitable carbon atom or nitrogen atom include. Unless otherwise specified, the bridged bicyclic group is substituted with one or more substituents as described for aliphatic groups, as necessary. Further, or alternatively, any substitutable nitrogen of the bridged bicyclic group is substituted as necessary. Exemplary bridged bicyclics include:

Chemical Structure

[0020] The term "lower alkyl" refers to a straight-chain or branched-chain alkyl group of C 1~4 Exemplary lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl. and tert-butyl.

[0021] The term "lower haloalkyl" refers to a straight-chain or branched-chain alkyl group of C substituted with one or more halogen atoms. 1~4 substituted with one or more halogen atoms.

[0022] The term "heteroatom" refers to oxygen, sulfur, nitrogen, phosphorus, or silicon (nitrogen, sulfur, phosphorus or any oxidized form of silicon; any quaternized form of basic nitrogen; or a substitutable nitrogen of a heterocyclic ring (such as in N(3,4-dihydro-2H-pyrrolyl ), NH (such as in pyrrolidinyl), or NR + (such as in N-substituted pyrrolidinyl )) means one or more of these.

[0023] The term "unsaturated", as used herein, means a moiety having one or more unsaturated units.

[0024] As used herein, the term "divalent C 1~8 (or C 1~6 ) saturated or unsaturated, straight-chain or branched-chain hydrocarbon chain" refers to a straight chain or branched-chain, divalent alkylene chain, alkenylene chain, and alkynylene chain as defined herein .

[0025] The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH2) n -, where n is a positive integer, preferably 1 to 6 , 1 to 4, 1 to 3, 1 to 2, or 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogens are replaced by substituents. Suitable substituents include those described below for substituted aliphatic groups.

[0026] The term "alkenylene" refers to a divalent alkenyl group. A substituted alkenylene chain contains at least one double bond and one or more hydrogen atoms are replaced by substituents which is a polymethylene group. Suitable substituents include those described below for substituted aliphatic groups. are exemplified.

[0027] The term "halogen" means F, Cl, Br, or I.

[0028] The term "aryl", used alone or as part of a larger moiety such as in "aralkyl", "aralkoxy" or "aryloxyalkyl", refers to a monocyclic or bicyclic ring system having a total of 5 to 14 ring members, at least 1 ring in the system being aromatic, and each ring in the system containing 3 to 7 ring members. The term "aryl" can be used interchangeably with the term "aryl ring". In certain embodiments of the present invention, "aryl" refers to an aromatic ring system, which includes, but is not limited to, phenyl, biphenyl, naphthyl, and anthracyl, etc., and these may have one or more substituents. When the term "aryl" is used herein, also included within its scope are groups in which an aromatic ring is fused to one or more non-aromatic rings (e.g., indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, etc.). The terms "heteroaryl" and "heteroar-", used alone or as part of a larger moiety (e.g., "heteroaralkyl" or "heteroaralkoxy"), refer to a group having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 π electrons shared in a cyclic arrangement; and in addition to carbon atoms, one or more heteroatoms selected from the group consisting of N, O, and S, and having at least one aromatic ring in the ring system. When the term "aryl" is used in this specification, also included within its scope are groups in which an aromatic ring is fused to one or more non-aromatic rings (e.g., indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, etc.). one or more heteroatoms selected from the group consisting of N, O, and S, and having at least one aromatic ring in the ring system. Examples include, but are not limited to, pyridyl, pyrimidyl, pyrazinyl, pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, benzofuranyl, benzothiophenyl, indolyl, quinolinyl, isoquinolinyl, and these may have one or more substituents.

[0029] The terms "heteroaryl" and "heteroar-", used alone or as part of a larger moiety (e.g., "heteroaralkyl" or "heteroaralkoxy"), refer to a group having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 π electrons shared in a cyclic arrangement; and in addition to carbon atoms, one or more heteroatoms selected from the group consisting of N, O, and S, and having at least one aromatic ring in the ring system. Examples include, but are not limited to, pyridyl, pyrimidyl, pyrazinyl, pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, benzofuranyl, benzothiophenyl, indolyl, quinolinyl, isoquinolinyl, A group having 1 to 5 heteroatoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternary form of 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 "heteroar -", as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl rings, cycloaliphatic rings, or heterocyclic rings, and the radical or point of attachment is, unless otherwise specified, on the heteroaromatic ring or on one of the rings to which this 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 can be monocyclic or bicyclic. The term "heteroaryl" can be used interchangeably with the terms "heteroaryl ring", "heteroaryl group", or "heteroaromatic", and any of these terms includes rings that are optionally substituted. The term "heteroalkyl" refers to hetero ​​ An alkyl group substituted by lower aryl, wherein the alkyl moiety and the heteroaryl moiety are each independently optionally substituted.

[0030] As used herein, the terms "heterocyclic", "heterocyclyl", "heterocyclic radical", and "heterocyclic ring" are used interchangeably and are stable 5- to 7-membered monocyclic rings, or 7- to 10-membered bicyclic heterocyclic moieties that are either saturated or partially unsaturated and that, in addition to carbon atoms, have one or more, preferably 1 to 4 heteroatoms as defined above. When used with respect to the ring atoms of a heterocyclic ring, the term "nitrogen" includes substituted nitrogen. By way of example, a saturated or partially unsaturated ring having 0 to 3 heteroatoms selected from oxygen, sulfur or nitrogen, wherein the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR (as in N-substituted pyrrolidinyl). + NR (as in N-substituted pyrrolidinyl ).

[0031] A heterocyclic ring may be attached to its parent group at any heteroatom or carbon atom that provides a stable structure, and any of these ring atoms may 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, oxa Zepinyl, thiazepinyl, morpholinyl, 2-oxa-6-azaspiro[3.3]hepta ne, and quinuclidinyl. The terms "heterocyclic", "heterocyclyl", "hete rocyclic ring", "heterocyclic group", "heterocyclic moiety", and "heterocyclic radical" are used interchangeably herein and also include groups in which the heterocyclic ring is fused to one or more aryl rings, heteroaryl rings, or alicyclic rings (e.g., indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl). The heterocyclyl group may be monocyclic or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted by a heterocyclyl, where the alkyl moiety and the heterocyclyl moiety are each independently optionally substituted. As used herein, the term "partially unsaturated" refers to a ring moiety containing at least one double bond or triple bond. The term "partially unsaturated" is intended to include rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties as defined herein. As described herein, the 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 on the designated moiety are replaced by an appropriate substituent. Unless otherwise indicated, an "optionally substituted" group may have appropriate substituents at each substitutable position of the group and more than one such substituent may be present in any given structure.

[0032] As used herein, the term "partially unsaturated" refers to a ring moiety containing at least one double bond or triple bond. The term "partially unsaturated" is intended to include rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties as defined herein.

[0033] As described herein, the 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 on the designated moiety are replaced by an appropriate substituent. Unless otherwise indicated, an "optionally substituted" group may have appropriate substituents at each substitutable position of the group and more than one such substituent may be present in any given structure. ​​​​​​​​​​ When more than one position can be substituted with more than one substituent selected from a particular group, The substituents at each position may be the same or different. Combinations of substituents envisioned by the invention preferably result in stable compounds or those that are chemically The term "stable" is used herein to refer to a combination that results in the formation of a compound that is stable. As used herein, their production, detection, and in certain embodiments, Their recovery, purification, and use for one or more of the purposes disclosed. "Polyester" refers to a compound that does not change substantially when subjected to conditions that enable its use.

[0034] Suitable monovalent substituents on a substitutable carbon atom of an "optionally substituted" group are independently , halogen; -(CH2) 0~4 R ○ ;-(CH2) 0~4 OR ○ ;-O(CH2)0 ~4 R ○ , -O-(CH2) 0~4 C(O)OR ○ ;-(CH2) 0~4 CH(OR ○ ) 2;-(CH2) 0~4 S.R. ○ ;-(CH2) 0~4 Ph (this is R ○ can be replaced by );-(CH2) 0~4 O(CH2) 0~1 Ph (this is R ○ );-C H=CHPh (This is R ○ );-(CH2) 0~4 O(CH2) 0~1 -pyridyl (which is R ○ -NO2; -CN; -N3; ​​-(CH2) 0~4 N(R ○ )2;-(CH2) 0~4 N(R ○ )C(O)R ○ ;-N(R ○ )C(S )R ○ ;-(CH2) 0~4 N(R ○ )C(O)NR ○ 2;-N(R ○ )C(S)NR ○ 2;-(CH2) 0~4 N(R ○ )C(O)OR ○ ;-N(R ○ )N(R ○ )C(O)R ○ ;-N(R ○ )N(R ○ )C(O)NR ○ 2;-N(R ○ )N(R ○ )C(O)OR ○ ;-N(R ○ )C(NR ○ )N(R ○ )2;-(CH2) 0~4 C(O)R ○ ;-C(S )R ○ ;-(CH2) 0~4 C(O)OR ○ ;-(CH2) 0~4 C(O)SR ○ ;-( CH2) 0~4 C(O)OSiR ○ 3;-(CH2) 0~4 OC(O)R ○ ;-OC(O )(CH2) 0~4 SR ○ ;-SC(S)SR ○ ;-(CH2) 0~4 SC(O)R ○ ; -(CH2) 0~4 C(O)NR ○ 2;-C(S)NR ○ 2;-C(S)SR ○;-SC (S)SR ○ 、-(CH2) 0~4 OC(O)NR ○ 2;-C(O)N(OR ○ )R ○ ; -C(O)C(O)R ○ ;-C(O)CH2C(O)R ○ ;-C(NOR ○ )R ○ ;-( CH2) 0~4 SSR ○ ;-(CH2) 0~4 S(O)2R ○ ;-(CH2) 0~4 S( O)2OR ○ ;-(CH2) 0~4 OS(O)2R ○ ;-S(O)2NR ○ 2;-(CH 2) 0~4 S(O)R ○ ;-N(R ○ )S(O)2NR ○ 2;-N(R ○ )S(O)2R ○ ;-N(OR ○ )R ○ ;-C(NH)NR ○ 2;-P(O)2R ○ ;-P(O)R ○ 2 ;-OP(O)R ○ 2;-OP(O)(OR ○ )2;-SiR ○ 3;-(C 1~4 of the straight-chain or branched-chain alkylene)O-N(R ○ )2; or -(C 1~4 of the straight-chain or branched chain alkylene)C(O)O-N(R ○ )2, where each R ○ may be substituted as defined below, and independently, is hydrogen, C aliphatic, -CH2Ph, -O(C 1~6 H2) H2) 0~1Ph, -CH2-(5- to 6-membered heteroaryl ring), or independently 0 to 4 heteroatoms selected from nitrogen , oxygen, or sulfur, a 5- to 6-membered saturated ring, partially unsaturated ring, or aryl ring, or regardless of the above definition, R ○ 's two independent occurrences, together with the atom(s) between them, form a single 3- to 12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which can be substituted as defined below.

[0035] R ○ (R ○ formed by the two independent occurrences of which together with the atom between them ring) suitable monovalent substituents on are independently halogen, -(CH2) 0~2 R ● , -(halo R ● ), -(CH2) 0~2 OH, -(CH2) 0~2 OR ● , -(CH2) 0~2 CH (OR ● )2; -O(halo R ● ), -CN, -N3, -(CH2) 0~2 C(O)R ● , -(CH2) 0~2 C(O)OH, -(CH2) 0~2 C(O)OR ● , -(CH2)0 ~2 SR ● , -(CH2) 0~2 SH, -(CH2) 0~2 NH2, -(CH2) 0~2 NHR ● , -(CH2) 0~2 NR ● 2, -NO2, -SiR● 3. -OSiR ● 3. - C(O)SR ● , -(C 1~4 's linear or branched alkylene)C(O)OR ● , or -SSR ● and each R ● is unsubstituted or, when "halo" precedes, is substituted with only one or more halogens, and independently, C aliphatic, -CH2Ph, -O(CH2) 1~4 Ph, or independently a 5- to 6-membered saturated ring, partial 0~1 unsaturated ring, or aryl ring having 0 to 4 heteroatoms selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on the saturated carbon atoms of the R include =O and =S. ○ Suitable divalent substituents on the saturated carbon atoms of the "optionally substituted" group include the following ones: =O, =S, =NNR

[0036] 2, =NNHC(O)R , =NNHC(O * )OR * , =NNHS(O)2R , =NR * , =NOR * , =NR * , =NOR * , -O(C(R * 2)) 2~ 3O-, or -S(C(R * 2)) 2~3 S-. Here each independent occurrence of R * is hydrogen , C 1~6 aliphatic which can be substituted as defined below, or independently an unsubstituted 5- to 6-membered saturated ring having 0 to 4 heteroatoms selected from nitrogen, oxygen, or sulfur. , is selected from a partially unsaturated ring, or an aryl ring. Suitable divalent substituents bonded to vicinal replaceable carbons of the "optionally substituted" group include -O(CR 2) * 2) 2~ 3O-, where each independent occurrence of R * is hydrogen, C aliphatic which may be substituted as defined below, or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 1~6 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. ~4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. is selected from a partially unsaturated ring, or an aryl ring.

[0037] R * Suitable substituents on the aliphatic group of are halogen, -R ● , -(haloR ● ), -O H, -OR ● , -O(haloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH 2, -NHR ● , -NR ● 2, or -NO2, where each R ● is unsubstituted or, when preceded by "halo", is substituted by only one or more halogens, and independently, C aliphatic, -CH2Ph, -O(CH2) 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. 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. is a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0038] Suitable substituents on the replaceable nitrogen of the "optionally substituted" group include -R † , -NR † 2, -C(O)R † , -C(O)OR †, -C(O)C(O)R † , -C(O) CH2C(O)R † , -S(O)2R † , -S(O)2NR † 2, -C(S)NR † 2, -C(NH)NR † 2, or -N(R † )S(O)2R † is exemplified; where each R † is independently hydrogen, C 1~6 aliphatic which may be substituted as defined below, unsubstituted -OPh , or independently a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms selected from nitrogen, oxygen, or sulfur and which is unsubstituted, or notwithstanding the above definition, two independent occurrences of R † together with the atoms (singular or plural) between them independently form a 3- to 12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0 to 4 heteroatoms selected from nitrogen, oxygen, or sulfur and which is unsubstituted.

[0039] R † Suitable substituents on the aliphatic group of are independently halogen, -R ● , -(haloR ● ), -OH, -OR ● , -O(haloR ● ), -CN, -C(O)OH, -C(O)OR ● , - NH2, -NHR ● , -NR ● 2, or -NO2, where each R ● is unsubstituted or, if "halo" precedes, is substituted with only one or more halogens, and independently, C 1~4 ​​Aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, or 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur and is a 5- to 6-membered saturated ring, partially unsaturated ring, or aryl ring having the same.

[0040] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that is within the scope of sound medical judgment and is suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., and that has a reasonable benefit / risk ratio and is a salt. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al. have described pharmaceutically acceptable salts in detail in J. Pharmaceutical Sci ences, 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 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, etc. are mentioned. 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 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, etc. are mentioned. 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 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, etc. are mentioned. 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 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, etc. are mentioned. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, etc. are mentioned. 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 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, Lactate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucohept onate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, la urate, lauryl sulfate, malate, maleate, malonate, methanesulfon ate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate , palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate salt, thiocyanate, p-toluenesulfonate, undecanoate, and valerate, etc. are included.

[0041] Salts derived from suitable bases include alkali metal salts, alkaline earth metal salts, ammo nium salts and N + (C 1~4 alkyl)4 salts. Representative alkali metal salts ma or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium, etc. Further pharmaceutically acceptable salts include, where appropriate, halide ions, hydroxide ions, carbonate ions, sulfate ions, phosphate ions, nitrate ions, lower alkyl sulfonate ions, and aryl sulfonate ions, etc. Counterions used to form non-toxic ammonium, quaternary ammonium, and amine cations containing.

[0042] Unless otherwise stated, the structures illustrated in this specification also include all isomers (e.g., enantiomers, diastereomers, and geometric (or conformational)) forms, such as then, with respect to the various asymmetry centers, the R and S configurations, the Z and E double bond isomers, and it is meant to include the Z and E conformational isomers. Accordingly, a single stereochemical isomer of the compounds of the invention, as well as enantiomers, diastereomers, and geometric (or conformational) mixtures 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. Further, unless otherwise stated, the structures depicted herein also mean compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the structure of the invention in which hydrogen is replaced by deuterium or tritium, or carbon is replaced by carbon enriched with 13C or 14C are within the scope of the invention. Such compounds are, for example, useful as analytical tools according to the invention, as probes in biological assays, or as 13 therapeutic agents. In certain embodiments, the warhead moiety R of a given compound contains one or more deuterium atoms. In certain 14 embodiments, ring B of the provided compounds may be substituted with one or more deuterium atoms. For example, as an analytical tool according to the invention, as a probe in biological assays, or as a therapeutic agent. In certain embodiments, the warhead moiety R of a given compound contains one or more deuterium atoms. In certain embodiments, ring B of the provided compounds may be substituted with one or more deuterium atoms. 1 contains one or more deuterium atoms. In certain embodiments, ring B of the provided compounds may be substituted with one or more deuterium atoms.

[0043] As used herein, the term "inhibitor" is defined as a compound that binds to TYK2 with a measurable affinity and / or inhibits it. In certain embodiments, the inhibitor has an IC and / or binding constant 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. M, or less than about 1 nM. 50 and / or binding constant. ​

[0044] The compounds of the present invention can be tethered to a detectable moiety. Such compounds are understood to be useful as imaging agents. One skilled in the art will recognize that the detectable moiety may be attached to the provided compound via a suitable substituent. As used herein, the term "suitable substituent" refers to a moiety that can be covalently attached to the detectable moiety. Such moieties are well known to those skilled in the art and include, for example, groups containing carbonate moieties, amino moieties, thiol moieties or hydroxyl moieties. Such moieties may be attached directly to the provided compound or via a tethering group such as a divalent saturated or unsaturated hydrocarbon chain. In some embodiments, such moieties can be attached by click chemistry. In some embodiments, such moieties can be attached by 1,3-cycloaddition of an azide with an alkyne, optionally in the presence of a copper catalyst. Methods of 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. One skilled in the art will recognize that the detectable moiety may be attached to the provided compound via a suitable substituent. As used herein, the term "suitable substituent" refers to a moiety that can be covalently attached to the detectable moiety. Such moieties are well known to those skilled in the art and include, for example, groups containing carbonate moieties, amino moieties, thiol moieties or hydroxyl moieties. Such moieties may be attached directly to the provided compound or via a tethering group such as a divalent saturated or unsaturated hydrocarbon chain. In some embodiments, such moieties can be attached by click chemistry. In some embodiments, such moieties can be attached by 1,3-cycloaddition of an azide with an alkyne, optionally in the presence of a copper catalyst. Methods of 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. As used herein, the term "detectable moiety" is used interchangeably with the term "label" and relates to any moiety that can be detected, for example, primary and secondary labels. Radioisotopes (e.g., tritium, P, P, S, or C), mass tags, and fluorescent labels

[0045] As used herein, the term "detectable moiety" is used interchangeably with the term "label" and relates to any moiety that can be detected, for example, primary and secondary labels. Radioisotopes (e.g., tritium, P, 32 P, 33 P, 35 S, or 14 C), mass tags, and fluorescent labels Primary labels, such as, are signal generating reporters that can be detected without further modification. Detectable moieties also include luminescent and phosphorescent groups.

[0046] 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 for the generation of a detectable signal. For biotin, the secondary intermediate can include streptavidin-enzyme conjugates. For antigen labels, the secondary intermediate can include antibody-enzyme conjugates. Some fluorescent groups act as secondary labels because they transfer energy to another group in the process of non-radiative fluorescence resonance energy transfer (FRET), resulting in a signal in which the second group is detected. 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 for the generation of a detectable signal. For biotin, the secondary intermediate can include streptavidin-enzyme conjugates. For antigen labels, the secondary intermediate can include antibody-enzyme conjugates. Some fluorescent groups act as secondary labels because they transfer energy to another group in the process of non-radiative fluorescence resonance energy transfer (FRET), resulting in a signal in which the second group is detected. 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 for the generation of a detectable signal. For biotin, the secondary intermediate can include streptavidin-enzyme conjugates. For antigen labels, the secondary intermediate can include antibody-enzyme conjugates. Some fluorescent groups act as secondary labels because they transfer energy to another group in the process of non-radiative fluorescence resonance energy transfer (FRET), resulting in a signal in which the second group is detected. 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 for the generation of a detectable signal. For biotin, the secondary intermediate can include streptavidin-enzyme conjugates. For antigen labels, the secondary intermediate can include antibody-enzyme conjugates. Some fluorescent groups act as secondary labels because they transfer energy to another group in the process of non-radiative fluorescence resonance energy transfer (FRET), resulting in a signal in which the second group is detected. 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 for the generation of a detectable signal. For biotin, the secondary intermediate can include streptavidin-enzyme conjugates. For antigen labels, the secondary intermediate can include antibody-enzyme conjugates. Some fluorescent groups act as secondary labels because they transfer energy to another group in the process of non-radiative fluorescence resonance energy transfer (FRET), resulting in a signal in which the second group is detected. 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 for the generation of a detectable signal. For biotin, the secondary intermediate can include streptavidin-enzyme conjugates. For antigen labels, the secondary intermediate can include antibody-enzyme conjugates. Some fluorescent groups act as secondary labels because they transfer energy to another group in the process of non-radiative fluorescence resonance energy transfer (FRET), resulting in a signal in which the second group is detected.

[0047] As used herein, the terms "fluorescent label", "fluorescent dye" and "fluorophore" refer to moieties that absorb light energy at a defined excitation wavelength and emit 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, BODIPY 530 / 550, BODIPY 558 / 568, BODIPY 564 / 570, BODIPY 576 / 589, BODIPY 581 / 591, BODIPY 630 / 650, BODIPY 650 / 665). As used herein, the terms "fluorescent label", "fluorescent dye" and "fluorophore" refer to moieties that absorb light energy at a defined excitation wavelength and emit 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, BODIPY 530 / 550, BODIPY 558 / 568, BODIPY 564 / 570, BODIPY 576 / 589, BODIPY 581 / 591, BODIPY 630 / 650, BODIPY 650 / 665). As used herein, the terms "fluorescent label", "fluorescent dye" and "fluorophore" refer to moieties that absorb light energy at a defined excitation wavelength and emit 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, BODIPY 530 / 550, BODIPY 558 / 568, BODIPY 564 / 570, BODIPY 576 / 589, BODIPY 581 / 591, BODIPY 630 / 650, BODIPY 650 / 665). As used herein, the terms "fluorescent label", "fluorescent dye" and "fluorophore" refer to moieties that absorb light energy at a defined excitation wavelength and emit 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, BODIPY 530 / 550, BODIPY 558 / 568, BODIPY 564 / 570, BODIPY 576 / 589, BODIPY 581 / 591, BODIPY 630 / 650, BODIPY 650 / 665). As used herein, the terms "fluorescent label", "fluorescent dye" and "fluorophore" refer to moieties that absorb light energy at a defined excitation wavelength and emit 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, BODIPY 530 / 550, BODIPY 558 / 568, BODIPY 564 / 570, BODIPY 576 / 589, BODIPY 581 / 591, BODIPY 630 / 650, BODIPY 650 / 665). As used herein, the terms "fluorescent label", "fluorescent dye" and "fluorophore" refer to moieties that absorb light energy at a defined excitation wavelength and emit 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, BODIPY 530 / 550, BODIPY 558 / 568, BODIPY 564 / 570, BODIPY 576 / 589, BODIPY 581 / 591, BODIPY 630 / 650, BODIPY 650 / 665). As used herein, the terms "fluorescent label", "fluorescent dye" and "fluorophore" refer to moieties that absorb light energy at a defined excitation wavelength and emit 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, BODIPY 530 / 550, BODIPY 558 / 568, BODIPY 564 / 570, BODIPY 576 / 589, BODIPY 581 / 591, BODIPY 630 / 650, BODIPY 650 / 665). As used herein, the terms "fluorescent label", "fluorescent dye" and "fluorophore" refer to moieties that absorb light energy at a defined excitation wavelength and emit 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, BODIPY 530 / 550, BODIPY 558 / 568, BODIPY 564 / 570, BODIPY 576 / 589, BODIPY 581 / 591, BODIPY 630 / 650, BODIPY 650 / 665). As used herein, the terms "fluorescent label", "fluorescent dye" and "fluorophore" refer to moieties that absorb light energy at a defined excitation wavelength and emit 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, BODIPY 530 / 550, BODIPY 558 / 568, BODIPY 564 / 570, BODIPY 576 / 589, BODIPY 581 / 591, BODIPY 630 / 650, BODIPY 650 / 665). As used herein, the terms "fluorescent label", "fluorescent dye" and "fluorophore" refer to moieties that absorb light energy at a defined excitation wavelength and emit 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, BODIPY 530 / 550, BODIPY 558 / 568, BODIPY 564 / 570, BODIPY 576 / 589, BODIPY 581 / 591, BODIPY 630 / 650, BODIPY 650 / 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, erythrosin, fluorescein, FAM, hydroxycoumarin, IRDyes (IRD40, IRD700, IRD800), JOE, rhodamine B, maroon 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-bromo-sulfo-fluorescein, tetramethyl-rhodamine (TMR), carboxytetramethylrhodamine (TAMRA), Texas red, Texas red-X, and the like, but are not limited thereto. lue, coumarin 343, cyanine dyes (Cy3, Cy5, Cy3.5, Cy5.5), dansyl, dapoxyl, dialkylaminocoumarin, 4’,5’-dichloro-2’,7’-dimethoxy-fluorescein, DM-NERF, eosin, erythrosin, fluorescein, FAM, hydroxycoumarin, IRDyes (IRD40, IRD700, IRD800), JOE, rhodamine B, maroon 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-bromo-sulfo-fluorescein, tetramethyl-rhodamine (TMR), carboxytetramethylrhodamine (TAMRA), Texas red, Texas red-X, and the like, but are not limited thereto. 5, Cy5.5), dansyl, dapoxyl, dialkylaminocoumarin, 4’,5’-dichloro-2’,7’-dimethoxy-fluorescein, DM-NERF, eosin, erythrosin, fluorescein, FAM, hydroxycoumarin, IRDyes (IRD40, IRD700, IRD800), JOE, rhodamine B, maroon 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-bromo-sulfo-fluorescein, tetramethyl-rhodamine (TMR), carboxytetramethylrhodamine (TAMRA), Texas red, Texas red-X, and the like, but are not limited thereto. ine, 4’,5’-dichloro-2’,7’-dimethoxy-fluorescein, DM-NERF, eosin, erythrosin, fluorescein, FAM, hydroxycoumarin, IRDyes (IRD40, IRD700, IRD800), JOE, rhodamine B, maroon 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-bromo-sulfo-fluorescein, tetramethyl-rhodamine (TMR), carboxytetramethylrhodamine (TAMRA), Texas red, Texas red-X, and the like, but are not limited thereto. cein, FAM, hydroxycoumarin, IRDyes (IRD40, IRD700, IRD800), JOE, rhodamine B, maroon 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-bromo-sulfo-fluorescein, tetramethyl-rhodamine (TMR), carboxytetramethylrhodamine (TAMRA), Texas red, Texas red-X, and the like, but are not limited thereto. s (IRD40, IRD700, IRD800), JOE, rhodamine B, maroon 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-bromo-sulfo-fluorescein, tetramethyl-rhodamine (TMR), carboxytetramethylrhodamine (TAMRA), Texas red, Texas red-X, and the like, but are not limited thereto. lue, 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-bromo-sulfo-fluorescein, tetramethyl-rhodamine (TMR), carboxytetramethylrhodamine (TAMRA), Texas red, Texas red-X, and the like, but are not limited thereto. on Green 500, Oregon Green 514, Pacific Blue, PyMPO, pyrene, rhodamine B, rhodamine 6G, rhodamine green, rhodamine red, rhodol green, 2’,4’,5’,7’-tetra-bromo-sulfo-fluorescein, tetramethyl-rhodamine (TMR), carboxytetramethylrhodamine (TAMRA), Texas red, Texas red-X, and the like, but are not limited thereto. amine B, rhodamine 6G, rhodamine green, rhodamine red, rhodol green, 2’,4’,5’,7’-tetra-bromo-sulfo-fluorescein, tetramethyl-rhodamine (TMR), carboxytetramethylrhodamine (TAMRA), Texas red, Texas red-X, and the like, but are not limited thereto. ene, rhodamine B, rhodamine 6G, rhodamine green, rhodamine red, rhodol green, 2’,4’,5’,7’-tetra-bromo-sulfo-fluorescein, tetramethyl-rhodamine (TMR), carboxytetramethylrhodamine (TAMRA), Texas red, Texas red-X, and the like, but are not limited thereto. rhodamine (TMR), carboxytetramethylrhodamine (TAMRA), Texas red, Texas red-X, and the like, but are not limited thereto. Texas red-X, and the like, but are not limited thereto.

[0048] In this specification, 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 tags include electro phore release tags such as N-[3- [4’-[(p-methoxytetrafluorobenzyl)oxy]phenyl]-3-methylg lyceryl]isonipecotic acid, 4’-[2,3,5,6-tetrafluoro-4-(penta fluorophenoxyl)]methylacetophenone, and their derivatives. The synthesis and utility of these mass tags are described in U.S. Patent No. 4, Nos. 650,750, 4,709,016, 5,360,819, 5,516 ,931, 5,602,273, 5,604,104, 5,610,020 are described in Nos. 5,650,270. Other examples of mass tags include various nucleotides, dideoxynucleotides, oligonucleotides, oligopeptides, oligosaccharides and other synthetic polymers of various lengths and monomer compositions but are not limited thereto. A wide variety of organic molecules (biological molecules or synthetic compounds), both neutral and charged, within an appropriate mass range (100 - 2000 daltons) may be used as mass tags.

[0049] As used herein, the terms "measurable affinity" and "measurably inhibit" mean a measurable change in TYK2 protein kinase activity between a sample containing a compound or composition thereof of the invention and a TYK2 protein kinase, and an equivalent sample containing TYK2 protein kinase in the absence of this compound or composition thereof. 3. Description of Exemplary Embodiments:

[0050] As described above, in certain embodiments, the invention provides a compound of formula I:

Chemical formula

[0051] In certain embodiments, the present invention provides a compound of formula I:

Chemical formula

[0052] In certain embodiments, the present invention provides a compound of formula I’:

Chemical formula

[0053] As generally defined above, R 3 is -C(O)NH2; -C(O)NHR 3A ; -C(O)N(R 3A )2; -C(O)OR; -C(O)NOR; -C(O)NHOR; or independently having 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur a 5- to 6-membered monocyclic heteroaryl ring, wherein this ring is substituted with m instances of R 3B substituted therewith. In some embodiments, R 3 is -C(O)NH2; -C(O)NH R 3A ; -C(O)N(R 3A )2; or independently a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur, wherein this ring is substituted with m instances of R therein. In some embodiments, R is 3B -C(O)NH2 or -C(O)NHR 3 is. In some embodiments, R 3A is -C(O)NOR. In some embodiments, R R 3 is -C(O)OR 3 is. In some embodiments, R

[0054] is -C(O)N(R 3 )2. In some embodiments, R 3A is -C(O)NHOR. In some embodiments, R is independently a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur, wherein this ring is substituted with m instances of R 3 therein. 3 In some embodiments, R is -C(O)NH2. In some embodiments, 3B substituted therewith.

[0055] In some embodiments, R 3 is -C(O)NH2. In some embodiments, R 3 is -C(O)NHR 3Ais. In some embodiments, R 3 is - C(O)NHOR or -C(O)OR. In some embodiments, R 3 is -C(O)NH2, -C(O)NHR 3A , -C(O)NHOR or -C(O)OR is. In some embodiments, R 3 is -C(O)NH2, -C(O)NHR 3A , or -C(O)NHOR.

[0056] In some embodiments, R 3 is the following:

Chemical formula

[0057] In some embodiments, R 3 is the following:

Chemical formula

[0058] In some embodiments, R 3 is the following:

Chemical formula

Chemical formula

[0059] In some embodiments, R 3 is the following:

Chemical formula

[0060] In some embodiments, R 3It is selected from those described in Table 1 below.

[0061] As generally defined above, R 5 is hydrogen, or -L 1 -R 5A or; or R 5 and R 6 together with the atoms therebetween independently form a 4- to 7-membered partially unsaturated or heteroaryl ring having from 0 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur, where this ring is substituted by R 5A and n instances of R C In some embodiments, R is hydrogen. In some embodiments 5 R is -L 5 -R 1 -R 5A In some embodiments, R

[0062] and R 5 and R 6 together with the atoms therebetween independently form a 4- to 7-membered partially unsaturated or heteroaryl ring having from 0 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur, where this ring is substituted by R and R 5A and n instances of R C In some embodiments, R 5 is hydrogen or -L 1 -R 5A In some embodiments, R

[0063] is one of the following: 5

Chemical formula

Chemical formula

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

[0064] In some embodiments, R 5 is as follows:

Chem.

Chem.

[0065] In some embodiments, R 5 is selected from those described in Table 1 below.

[0066] As generally defined above, R 6 is hydrogen, R A , or R B , or R 5 and R 6are, together with the atoms between them, independently nitrogen, oxygen, and 4- to 7-membered partially unsaturated or heterocyclic groups having 0 to 3 heteroatoms selected from sulfur and forming a ring of an aryl group, wherein the ring is R 5A and R for n examples C Replaced by In some embodiments, R 6 is hydrogen.

[0067] In some embodiments, R 6 is R A In some embodiments, R 6 is R B In some embodiments, R 5 and R 6 is the atom between these together with 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; forming a 4- to 7-membered partially unsaturated or heteroaryl ring having , R 5A and R for n examples C In some embodiments, R 6 is hydrogen, R A or R B It is.

[0068] In some embodiments, R 6 is methyl.

[0069] In some embodiments, R 6 is selected from those set forth in Table 1 below.

[0070] As generally defined above, R 7 are hydrogen, halogen, -NH2, -NHR 7A , or -NHC(O)R 7A or R 6 and R7 together with the atoms between them, independently form a 4- to 7-membered partially unsaturated or heteroaryl ring having from 0 to 3 hetero atoms selected from nitrogen, oxygen, and sulfur; where this ring is substituted by p instances of R . In some embodiments, R C is - 7 NH2 or -NHR . In some embodiments, R 7A is -NHMe 7 . In some embodiments, R is -NHCD3 7 .

[0071] In some embodiments, R 7 is hydrogen. In some embodiments, R 7 is halogen. In some embodiments, R 7 is -NH2. In some embodiments R 7 is -NHR 7A . In some embodiments, R 7 is -N HC(O)R 7A . In some embodiments, R 6 and R 7 together with the atoms between them, independently form a 4- to 7-membered partially unsaturated or heteroaryl ring having from 0 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur; where here this ring is substituted by p instances of R . C

[0072] In some embodiments, R 7 is one of the following:

Chemical formula

[0073] In some embodiments, R 7 is selected from those set forth in Table 1 below.

[0074] As generally defined above, L 1 is a covalent bond, or C 1~4 The divalent saturation of or unsaturated, linear or branched hydrocarbon chain, where one or two of the chains Each methylene unit is independently -C(R 5B )2-, -CH(R 5B )-, -N(R)- , -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O) 2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S (O)- or -S(O)2- as appropriate. In an embodiment, L 1 In some embodiments, L 1 teeth- N(H)-.

[0075] In some embodiments, L 1 is a covalent bond. In some embodiments, L 1 is C 1~4 A divalent saturated or unsaturated, straight or branched hydrocarbon chain of wherein one or two methylene units of the chain are independently -C(R 5B )2-, -CH(R 5B )-, -N(R)-, -N(R)C(O)-, -C(O)N(R)-, - N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O) -, -C(O)O-, -S-, -S(O)-, or -S(O)2- as required has been replaced by

[0076] In some embodiments, L 1 is -N(R)- or a covalent bond. In some embodiments, L 1 is -N(H)- or a covalent bond.

[0077] In some embodiments, L 1 is selected from those described in Table 1 below.

[0078] As generally defined above, R 3A is R B and is substituted by q examples of R C wherein two R substituents on the same carbon, optionally together, independently form a 3- to 6-membered saturated or partially unsaturated spiro-fused heterocyclic ring having 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur, or two R C substituents on the same carbon, optionally together, independently form a 3- to 6-membered saturated or partially unsaturated fused heterocyclic ring having 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, R is aliphatic substituted by q examples of R In some embodiments, R is a 3- to 7-membered saturated or partially unsaturated carbocyclic ring substituted by q examples of R C In some embodiments, R is cyclopropyl or cyclobutyl ; each being substituted by q examples of R 3A In some embodiments, R C is substituted by q examples of R 1~6 In some embodiments, R 3A is q is substituted by q examples of R C is a 3- to 7-membered saturated or partially unsaturated carbocyclic ring In some embodiments, R 3A is cyclopropyl or cyclobutyl ; each being substituted by q examples of R C In some embodiments, R 3 A is cyclopropyl substituted by q examples of R C In some embodiments, R 3A is cyclobutyl substituted by q examples of R C In some embodiments, R 3A is R B and is substituted by q examples of R C , provided that R is not phenyl. 3A

[0079] In some embodiments, R 3A is R B and is substituted by q examples of R C , where two R substituents on the same carbon, optionally together, C independently form a 3- to 6-membered saturated or partially unsaturated spiro-fused heterocyclic ring having 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur, or two R substituents on the same carbon, optionally together, independently form a 3- to 6-membered saturated or partially unsaturated C condensed heterocyclic ring having 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur.

[0080] In some embodiments, R 3A is C C substituted by q examples of R 1~6 aliphatic, or a 3- to 7-membered saturated or partially unsaturated C carbocyclic ring substituted by q examples of R .

[0081] In some embodiments, R 3A is the following:

Chemical formula

[0082] In some embodiments, R 3A is selected from those described in Table 1 below .

[0083] As generally defined above, R 5A is R A or R B and is substituted by r examples of R C In some embodiments, R 5A is phenyl or independently is a 5-membered - to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur; and is substituted by r examples of C R .

[0084] In some embodiments, R 5A is R C substituted by r examples of A R . In some embodiments, R 5A is R C substituted by r examples of B R .

[0085] In some embodiments, R 5A is the following:

Chemical formula

[0086] In some embodiments, R 5A is selected from those described in Table 1 below .

[0087] As generally defined above, R7A is R B and the R of q examples C is replaced by In some embodiments, R 7A is the R of q examples C replaced by substituted C 1~6 is aliphatic. In some embodiments, R 7A is methyl. In some embodiments, R 7A is R B and the R of q examples C is substituted by however, R 7A is not aromatic. In some embodiments, R 7A is R B and the R of q examples C is substituted, provided that R 7A is not phenyl No.

[0088] In some embodiments, R 7A is R B and the R of q examples C is replaced by In some embodiments, R

[0089] is hydrogen. In some embodiments, R 7A is methyl. In 7A some embodiments, R

[0090] In some embodiments, R 7A is one of the following:

Chemical formula

[0091] In some embodiments, R 7A is selected from those described in Table 1 below .

[0092] As generally defined above, R in each example A 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.

[0093] In some embodiments, R A is oxo, halogen, -CN, -NO2, -OR , -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O) NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R , -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR 2, or -N(R)S(O)2R.

[0094] In some embodiments, R A is selected from those described in Table 1 below.

[0095] As generally defined above, R in each example B is independently 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; a 5- to An 8- to 10-membered bicyclic heteroaryl ring having 4 heteroatoms; a 3- to 7-membered saturated or partially unsaturated carbocyclic ring; independently a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms selected from nitrogen, oxygen, and sulfur; or an 8- to 12-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, R is C

[0096] 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 an 8- to 12-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. B is 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 an 8- to 12-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is methyl. In some embodiments, R is selected from those described in Table 1 below. As generally defined above, each R is independently oxo, halogen, -CN, is independently oxo, halogen, -CN,

[0097] In some embodiments, R B is methyl.

[0098] In some embodiments, R B is selected from those described in Table 1 below.

[0099] As generally defined above, each 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, and this optionally substituted group is C 1~6 aliphatic, phenyl, independently nitrogen , oxygen, and a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms selected from sulfur, as well as a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur, where two optional substituents on the same carbon, optionally, together, form a 3- to 6-membered saturated or partially unsaturated spiro-fused heterocyclic ring having 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur, or two optional substituents on adjacent carbons, optionally, together, form a 3- to 6-membered saturated or partially unsaturated condensed heterocyclic ring having 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, R is oxo, halogen, -CN, -NO2, -OR

[0100] In some embodiments, R C is oxo, halogen, -CN, -NO2, -OR , -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O) NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R , -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR 2, or -N(R)S(O)2R, or a group optionally substituted, and this must group optionally substituted is C 1~6 aliphatic, phenyl, independently nitrogen, oxygen, and sulfur selected from 1 to 2 heteroatoms having a 3- to 7-membered saturated or partially unsaturated heterocyclic ring, and independently selected from nitrogen, oxygen, and sulfur 1 to 4 he selected from a 5- to 6-membered heteroaryl ring having a teroatom, where two optional substituents on the same carbon, optionally, together, independently nitrogen, oxygen, and sulfur selected from 1 to 4 heteroatoms having a 3- to 6-membered saturated or partially unsaturated spiro-fused heterocyclic ring, or two optional substituents on adjacent carbons, optionally, together, independently nitrogen, oxygen, and sulfur selected from 1 selected from 1 to 4 heteroatoms having a 3- to 6-membered saturated or partially unsaturated fused heterocyclic ring to form.

[0101] In some embodiments, R C is oxo. In some embodiments, R C is methyl, ethyl, isopropyl, or n-butyl. In some embodiments In, R C is fluoro. In some embodiments, R C is chloro. In several embodiments, R C is phenyl.

[0102] In some embodiments, R Cis as follows:

Chem.

Chem.

Chem.

Chem.

[0103] In some embodiments, R C is selected from those described in Table 1 below.

[0104] As generally defined above, each R is independently hydrogen or an optionally substituted group, and this optionally substituted group is a C 1~6 aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated heterocyclic having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same nitrogen, together with the atoms between them, add to this nitrogen to form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0105] In some embodiments, R is hydrogen. In some embodiments, R is a C aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated heterocyclic having 1 to 2 1~6 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and independently ​​​a 5- to 6-membered heteroaryl ring having from 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur is a group selected from, optionally substituted, and in some embodiments, two R groups on the same nitrogen, together with the atoms between them, in addition to this nitrogen, independently form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having from 0 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur In some embodiments, R is selected from those described in Table 1 below As generally defined above, each hydrogen bonded to carbon can optionally and independently be replaced by deuterium In some embodiments, the hydrogen bonded to carbon is replaced by deuterium

[0106] 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. In some embodiments, m is 1, 2, or 3. In some embodiments, m is 1 or 2. In some embodiments, m is 1 or 3. In some embodiments, m is 2 or 3. In some embodiments, m is 1, 2, or 3

[0107] As generally defined above, each hydrogen bonded to carbon can optionally and independently be replaced by deuterium can be replaced by deuterium

[0108] In some embodiments, the hydrogen bonded to carbon is replaced by deuterium is replaced by deuterium

[0109] 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. In some embodiments, m is 1, 2, or 3. In some embodiments, m is 1 or 2. In some embodiments, m is 1 or 3. In some embodiments, m is 2 or 3. In some embodiments, m is 1, 2, or 3 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. In some embodiments, m is 1, 2, or 3. In some embodiments, m is 1 or 2. In some embodiments, m is 1 or 3. In some embodiments, m is 2 or 3. In some embodiments, m is 1, 2, or 3 In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 1, 2, or 3. In some embodiments, m is 1 or 2. In some embodiments, m is 1 or 3. In some embodiments, m is 2 or 3. In some embodiments, m is 1, 2, or 3 In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 1, 2, or 3. In some embodiments, m is 1 or 2. In some embodiments, m is 1 or 3. In some embodiments, m is 2 or 3. In some embodiments, m is 1, 2, or 3 In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 1, 2, or 3. In some embodiments, m is 1 or 2. In some embodiments, m is 1 or 3. In some embodiments, m is 2 or 3. In some embodiments, m is 1, 2, or 3

[0110] In some embodiments, m is 1, 2, or 3. In some embodiments, m is 1 or 2. In some embodiments, m is 1 or 3. In some embodiments, m is 2 or 3. In some embodiments, m is 1, 2, or 3 In some embodiments, m is 1 or 2. In some embodiments, m is 1 or 3. In some embodiments, m is 2 or 3. In some embodiments, m is 1, 2, or 3 In some embodiments, m is 1 or 3. In some embodiments, m is 2 or 3. In some embodiments, m is 1, 2, or 3 Here, m is 2 or 4. In some embodiments, m is 1, 2, or 4. In some embodiments, m is 1, 3, or 4. In some embodiments m is 2, 3, or 4.

[0111] In some embodiments, m is selected from those described in Table 1 below.

[0112] 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.

[0113] In some embodiments, n is 1, 2, or 3. In some embodiments n is 1 or 2. In some embodiments, n is 1 or 3. In some embodiments, n is 2 or 3. In some embodiments n is 2 or 4. In some embodiments, n is 1, 2, or 4. In some embodiments, n is 1, 3, or 4. In some embodiments n is 2, 3, or 4.

[0114] In some embodiments, n is selected from those described in Table 1 below.

[0115] 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 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.

[0116] In some embodiments, p is 1, 2, or 3. In some embodiments p is 1 or 2. In some embodiments, p is 1 or 3 . In some embodiments, p is 2 or 3. In some embodiments p is 2 or 4. In some embodiments, p is 1, 2 or 4 . In some embodiments, p is 1, 3 or 4. In some embodiments p is 2, 3 or 4.

[0117] In some embodiments, p is selected from those described in Table 1 below.

[0118] As generally defined above, q is 0, 1, 2, 3, or 4. In some embodiments, q is 0. In some embodiments, q is 1, 2, 3, or 4. In some embodiments, q is 1. In some embodiments q is 2. In some embodiments, q is 3. In some embodiments q is 4.

[0119] In some embodiments, q is 1, 2, or 3. In some embodiments q is 1 or 2. In some embodiments, q is 1 or 3 . In some embodiments, q is 2 or 3. In some embodiments where q is 2 or 4. In some embodiments, q is 1, 2, or 4. In some embodiments, q is 1, 3, or 4. In some embodiments q is 2, 3, or 4.

[0120] In some embodiments, q is selected from those listed in Table 1 below.

[0121] 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.

[0122] In some embodiments, r is 1, 2, or 3. In some embodiments r is 1 or 2. In some embodiments, r is 1 or 3. In some embodiments, r is 2 or 3. In some embodiments r is 2 or 4. In some embodiments, r is 1, 2, or 4. In some embodiments, r is 1, 3, or 4. In some embodiments r is 2, 3, or 4.

[0123] In some embodiments, r is selected from those listed in Table 1 below.

[0124] In some embodiments, the present invention provides that R 3 is -C(O)NH2 or -C(O)N HR 3A and thereby formula II or III: [Chemical formula] Provided are compounds of formula I or I' or pharmaceutically acceptable salts thereof that form the compounds of wherein R 3A , R 5 , R 6 , and R 7 each, both alone and in combination, are as defined above and as described in the embodiments herein.

[0125] In some embodiments, the invention provides compounds of formula I or I' or pharmaceutically acceptable salts thereof that form the compounds of 1 wherein L is -N(R)-, whereby formula IV: [Chemical formula] wherein R , R 3 , R 5A , R 6 , and R 7 each, both alone and in combination, are as defined above and as described in the embodiments herein.

[0126] In some embodiments, the invention provides compounds of formula II or III or pharmaceutically acceptable salts thereof that form the compounds of 1 wherein L is -N(R)-, whereby they are respectively of formula V or VI: [Chemical formula] wherein R, R , R 3A , R 5A , R 6 , and R 7 each, both alone and in combination are as defined above and as described in the embodiments herein.

[0127] In some embodiments, the present invention provides a compound of formula IV or a pharmaceutically acceptable salt thereof, wherein R 5A is phenyl or pyridin-3-yl and each R of r instances is C substituted by, thereby forming a compound of formula VII or VIII:

Chemical formula

[0128] In some embodiments, the present invention provides a compound of formula VIII or a pharmaceutically acceptable salt thereof, wherein one instance of R 5A is oxo, thereby forming a compound of formula IX C :

Chemical formula

Chemical formula

[0129] In some embodiments, the present invention provides a compound of formula X, XI, XII, XIII, XIV, or XV, wherein R is hydrogen, thereby forming a compound of formula X , XI, XII, XIII, XIV, XV:

Chemical formula

[0130] In some embodiments, the invention provides compounds of formula I, I’, II, III, IV, V, VI, VII, VIII, 6 wherein R is hydrogen, thereby forming compounds of formulae I-a, II-a, III-a, IV-a, V-a, VI-a, VII-a, VIII- a, IX-a, X-a XI-a, XII-a, XIII-a, XIV-a, or XV

Chemical formula

[0131] wherein R 7 is -NH2 or -NHR 7A , formulae I, I’, II, III, IV, V, VI, VII, VIII, IX, X, XI, XI I, XIII, XIV, XV, I-a, II-a, III-a, IV-a, V-a, VI -a, VII-a, VIII-a, IX-a, X-a XI-a, XII-a, XIII -a, XIV-a, or a compound of XV-a is provided.

[0132] In some embodiments, the present invention is R 7 is -NHR 7A and thereby the respective compounds of formulas I-b, II-b, III-b, IV-b, V-b, VI-b, VII-b, V III-b, IX-b, X-b, XI-b, XII-b, XIII-b, XIV-b, X V-b, I-c, II-c, III-c, IV-c, V-c, VI-c, VII-c, V III-c, IX-c, X-c XI-c, XII-c, XIII-c, XIV-c, or XV-c:

Chemical formula

Chemical formula

Chemical formula

[0133] In some embodiments, the invention provides a compound of formula I-b, II-b, III-b, IV-b, V-b, VI-b, VII-b, VIII-b, IX-b, X-b, XI-b, XII-b, XIII-b, XIV-b, XV-b, I-c, II-c, III-c, IV-c, V-c, VI-c, VII-c, VIII-c, IX-c, X-c, XI-c, XII-c, XIII-c, XIV-c, or XV-c, wherein R is replaced by R of q examples, and R is not phenyl. 7A where R is replaced by R of q examples C and R B is such that 7A R is not phenyl. V-b, V-b, VI-b, VII-b, VIII-b, IX-b, X-b, XI-b, XII-b, XIII-b, XIV-b, XV-b, I-c, II-c, III-c, I V-c, V-c, VI-c, VII-c, VIII-c, IX-c, X-c XI-c, XII-c, XIII-c, XIV-c, or XV-c. In some embodiments, the invention provides a compound of formula I-b, II-b, III-b, IV-b, V-b, VI-b, VII-b, VIII-b, IX-b, X-b, XI-b, XII-b, XIII-b, XIV-b, XV-b, I-c, II-c, III-c, IV-c, V-c, VI-c, VII-c, VIII-c, IX-c, X-c, XI-c, XII-c, XIII-c, XIV-c, or XV-c, wherein R is methyl. In some embodiments, the invention provides a compound of formula I-b, II-b, III- 7A b, IV-b, V-b, VI-b, VII-b, VIII-b, IX-b, X-b, XI -b, XII-b, XIII-b, XIV-b, XV-b, I-c, II-c, III- c, IV-c, V-c, VI-c, VII-c, VIII-c, IX-c, X-c XI -c, XII-c, XIII-c, XIV-c, or XV-c, wherein R is CD3. In some embodiments, the invention provides a compound of formula I-b, II-b, III-b, IV-b, V-b, VI-b, VII-b, VIII-b, IX-b, X-b, XI-b, XII-b, XIII-b, XIV-b, XV-b, I-c, II-c, III-c, IV-c, V-c, VI-c, VII-c, VIII-c, IX-c, X-c, XI-c, XII-c, XIII-c, XIV-c, or XV-c, wherein R is CD3. In some embodiments, the invention provides a compound of formula I-b, II-b, III-b, IV-b, V-b, VI-b, VII-b, VIII-b, IX-b, X-b, XI-b, XII-b, XIII-b, XIV-b, XV-b, I-c, II-c, III-c, IV-c, V-c, VI-c, VII-c, VIII-c, IX-c, X-c, XI-c, XII-c, XIII-c, XIV-c, or XV-c, wherein R is CD3. 7A wherein R is CD3. III-b, IV-b, V-b, VI-b, VII-b, VIII-b, IX-b, X- b, XI-b, XII-b, XIII-b, XIV-b, XV-b, I-c, II-c, III-c, IV-c, V-c, VI-c, VII-c, VIII-c, IX-c, X- Provide a compound of XI-c, XII-c, XIII-c, XIV-c, or XV-c Do.

[0134] In some embodiments, the present invention provides a compound of formula I-b, III-b, IV-b, VI-b, VII-b, VIII-b, IX-b, X-b, XII-b, XIII-b, XIV-b, XV-b, I-c, III-c, IV-c, VI-c, VII-c, VIII-c, IX-c, X-c, XII-c, XIII-c, XIV-c, or XV-c, wherein R is R, and q instances of R are substituted by, provided that R is not phenyl. 3A R is R B and q instances of R C are substituted by, provided that R 3A is not phenyl. V-b, VI-b, VII-b, VIII-b, IX-b, X-b, XII-b, XIII I-b, XIV-b, XV-b, I-c, III-c, IV-c, VI-c, VII-c VIII-c, IX-c, X-c, XII-c, XIII-c, XIV-c, or XV -c.

[0135] In some embodiments, the present invention provides a compound of formula I-b, III-b, IV-b, VI-b, VII-b, VIII-b, IX-b, X-b, XII-b, XIII-b, XIV-b, XV-b, I-c, II-c, IV-c, VI-c, VII-c, VIII-c, IX-c, X-c, XII 3A -c, XIII-c, XIV-c, or XV-c, wherein each of R and R is R, and q instances of R are substituted by, provided that neither R nor R is phenyl. 7A Each of R and R is R B and q instances of R are substituted by, provided that C neither R 3A nor R 7A is phenyl. b, IX-b, X-b, XII-b, XIII-b, XIV-b, XV-b, I-c, I II-c, IV-c, VI-c, VII-c, VIII-c, IX-c, X-c, XII -c, XIII-c, XIV-c, or XV-c.

[0136] In some embodiments, the present invention provides a compound of formula XVI, wherein R is pyridin-2-yl substituted by r instances of R. 5A R is pyridin-2-yl substituted by r instances of R C such that the following formula XVI is obtained:

Chemical formula

[0137] In some embodiments, the present invention provides a compound of formula I or I' wherein R 5 is -L 1 -R 5A where L 1 is a covalent bond, and R 5A is an 8- to 10-membered bicyclic heteroaryl ring having from 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the present invention provides a compound of formula I or I' wherein R 5 is -L 1 -R 5A where L is a covalent bond, and R 1 is an 8- to 10-membered bicyclic heteroaryl ring having from 1 to 4 5A heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the present invention provides a compound of formula I or I'.

[0138] In some embodiments, the present invention provides a compound of formula I or I' wherein R 5 is -L 1 -R 5A where L 1 is a covalent bond, and R 5A is indol-1-yl, indol-3-yl, 4-azaindol-1-yl, 7-azaindol-3-yl, or 7-azaindazol-3 -yl, and each R is r examples of R 5A is Cis replaced thereby, whereby that each of the compounds of formula XVII, XVIII, XIX, XX, or XXI: [Chemical formula] [Chemical formula] provides a compound of formula I or I' or a pharmaceutically acceptable salt thereof, which provides a compound of formula XVII, XVIII, XIX, XX, or XXI or a pharmaceutically acceptable salt thereof, where r, R , R C , R 3 , R 6 , and R 7 each, both alone and in combination, is defined above and is as described in the embodiments herein.

[0139] In some embodiments, the invention provides a compound of formula XVII, XVIII, XIX, XX, or XXI or a pharmaceutically acceptable salt thereof, wherein R 6 is hydrogen, whereby each of the compounds of formula XVII-a, XVIII-a, XIX-a, XX-a, or XXI-a: [Chemical formula] where r, R , R C , R 3 , and R 7 each, both alone and in combination, is defined above and is as described in the embodiments herein. as described.

[0140] In some embodiments, the invention provides a compound of formula XVII, XVIII, XIX, XX, or XXI or a pharmaceutically acceptable salt thereof, wherein R 7 is -NHR 7A , whereby each of the compounds of formula XVII-b, XVIII-b, XIX-b, XX-b, or XXI-b: [Chemical formula] To provide a compound of formula XVII-a, XVIII-a, XIX-a, XX-a, or a compound of XXI-a or a pharmaceutically acceptable salt thereof, wherein r, R C , R 3 , and R 7A each, both alone and in combination, are as defined above and as described in the embodiments herein .

[0141] In some embodiments, the present invention provides a compound of formula XVII-b, XVIII-b, XIX-b, XX-b, or 3 XXI-b, wherein R 3A is -C(O)NHR and accordingly, each of the formulas XVII-c, XVIII-c, XIX-c, XX-c, or XXI -c:

Chemical Formula

Chemical Formula

[0142] Exemplary compounds of the present invention are described 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

Table 1-52

Table 1-53

Table 1-54

Table 1-55

Table 1-56

Table 1-57

Table 1-58

Table 1-59

Table 1-60

Table 1-61

Table 1-62

Table 1-63

Table 1-64

Table 1-65

Table 1-66

Table 1-67

Table 1-68

Table 1-69

Table 1-70

Table 1-71

Table 1-72

Table 1-73

Table 1-74

Table 1-75

Table 1-76

Table 1-77

Table 1-78

Table 1-79

Table 1-80

Table 1-81

Table 1-82

Table 1-83

Table 1-84

Table 1-85

Table 1-86

Table 1-87

Table 1-88

Table 1-89

Table 1-90

Table 1-91

Table 1-92

Table 1-93

Table 1-94

Table 1-95

Table 1-96

Table 1-97

Table 1-98

Table 1-99

Table 1-100

Table 1-101

Table 1-102

Table 1-103

Table 1-104

Table 1-105

Table 1-106

Table 1-107

Table 1-108

Table 1-109

Table 1-110

Table 1-111

Table 1-112

Table 1-113

Table 1-114

Table 1-115

Table 1-116

Table 1-117

Table 1-118

Table 1-119

Table 1-120

Table 1-121

Table 1-122

Table 1-123

Table 1-124

Table 1-125

Table 1-126

Table 1-127

Table 1-128

Table 1-129

Table 1-130

Table 1-131

Table 1-132

Table 1-133

Table 1-134

Table 1-135

Table 1-136

Table 1-137

Table 1-138

Table 1-139

Table 1-140

Table 1-141

Table 1-142

Table 1-143

Table 1-144

Table 1-145

Table 1-146

Table 1-147

Table 1-148

Table 1-149

Table 1-150

Table 1-151

Table 1-152

Table 1-153

Table 1-154

Table 1-155

Table 1-156

Table 1-157

Table 1-158

Table 1-159

Table 1-160

Table 1-161

Table 1-162

Table 1-163

Table 1-164

Table 1-165

Table 1-166

Table 1-167

Table 1-168

Table 1-169

Table 1-170

Table 1-171

Table 1-172

Table 1-173

Table 1-174

Table 1-175

Table 1-176

Table 1-177

Table 1-178

Table 1-179

Table 1-180

Table 1-181

Table 1-182

Table 1-183

Table 1-184

Table 1-185

Table 1-186

Table 1-187

Table 1-188

Table 1-189

Table 1-190

Table 1-191

Table 1-192

Table 1-193

Table 1-194

Table 1-195

Table 1-196

Table 1-197

Table 1-198

Table 1-199

Table 1-200

Table 1-201

Table 1-202

Table 1-203

Table 1-204

Table 1-205

Table 1-206

Table 1-207

Table 1-208

Table 1-209

Table 1-210

Table 1-211

Table 1-212

Table 1-213

Table 1-214

Table 1-215

Table 1-216

Table 1-217

Table 1-218

Table 1-219

Table 1-220

Table 1-221

Table 1-222

Table 1-223

Table 1-224

Table 1-225

Table 1-226

Table 1-227

Table 1-228

Table 1-229

Table 1-230

Table 1-231

Table 1-232

Table 1-233

Table 1-234

Table 1-235

Table 1-236

Table 1-237

Table 1-238

Table 1-239

Table 1-240

Table 1-241

Table 1-242

Table 1-243

Table 1-244

Table 1-245

Table 1-246

Table 1-247

Table 1-248

Table 1-249

Table 1-250

Table 1-251

Table 1-252

Table 1-253

Table 1-254

Table 1-255

Table 1-256

Table 1-257

Table 1-258

Table 1-259

Table 1-260

Table 1-261

Table 1-262

Table 1-263

Table 1-264

Table 1-265

Table 1-266

Table 1-267

Table 1-268

Table 1-269

Table 1-270

Table 1-271

Table 1-272

Table 1-273

Table 1-274

Table 1-275

Table 1-276

Table 1-277

Table 1-278

Table 1-279

Table 1-280

Table 1-281

Table 1-282

Table 1-283

Table 1-284

Table 1-285

Table 1-286

Table 1-287

Table 1-288

Table 1-289

Table 1-290

Table 1-291

Table 1-292

Table 1-293

Table 1-294

Table 1-295

Table 1-296

Table 1-297

Table 1-298

Table 1-299

Table 1-300

Table 1-301

Table 1-302

Table 1-303

Table 1-304

Table 1-305

Table 1-306

Table 1-307

Table 1-308

Table 1-309

Table 1-310

Table 1-311

Table 1-312

Table 1-313

Table 1-314

Table 1-315

Table 1-316

Table 1-317

Table 1-318

Table 1-319

Table 1-320

Table 1-321

Table 1-322

Table 1-323

Table 1-324

Table 1-325

Table 1-326

Table 1-327

Table 1-328

Table 1-329

Table 1-330

Table 1-331

Table 1-332

Table 1-333

Table 1-334

Table 1-335

Table 1-336

Table 1-337

Table 1-338

Table 1-339

Table 1-340

Table 1-341

Table 1-342

Table 1-343

[0143] In some embodiments, the method uses the compounds described in Table 1 above, or pharmaceutically acceptable salts thereof. In some embodiments, the present invention provides the compounds described in Table 1 above, or pharmaceutically acceptable salts thereof. In some embodiments, the present invention provides a pharmaceutical composition comprising the compounds described in Table 1 above, or pharmaceutically acceptable salts thereof, together with a pharmaceutically acceptable carrier, excipient, or diluent. In some embodiments, the present invention provides a compound of formula I or I' wherein the compound is designated "A" as described in Table 2. In some embodiments, the present invention provides a compound of formula I or I' wherein the compound is designated "B" as described in Table 2. In some embodiments, the present invention provides a compound of formula I or I' wherein the compound is designated "C" as described in Table 2. In some embodiments, the present invention provides a compound of formula I or I' wherein the compound is designated "D" as described in Table 2. In some embodiments, the present invention provides a compound of formula I or I' wherein the compound is designated "A" as described in Table 2. In some embodiments, the present invention provides a compound of formula I or I' wherein the compound is designated "B" as described in Table 2. In some embodiments, the present invention provides a compound of formula I or I' wherein the compound is designated "C" as described in Table 2. In some embodiments, the present invention provides a compound of formula I or I' wherein the compound is designated "D" as described in Table 2. In some embodiments, the present invention provides a compound of formula I or I' wherein the compound is designated "A" as described in Table 2. In some embodiments, the present invention provides a compound of formula I or I' wherein the compound is designated "B" as described in Table 2. In some embodiments, the present invention provides a compound of formula I or I' wherein the compound is designated "C" as described in Table 2. In some embodiments, the present invention provides a compound of formula I or I' wherein the compound is designated "D" as described in Table 2. In some embodiments, the present invention provides a compound of formula I or I' wherein the compound is designated "A" as described in Table 2. In some embodiments, the present invention provides a compound of formula I or I' wherein the compound is designated "B" as described in Table 2. In some embodiments, the present invention provides a compound of formula I or I' wherein the compound is designated "C" as described in Table 2. In some embodiments, the present invention provides a compound of formula I or I' wherein the compound is designated "D" as described in Table 2. In some embodiments, the present invention provides a compound of formula I or I' wherein the compound is designated "A" as described in Table 2. In some embodiments, the present invention provides a compound of formula I or I' wherein the compound is designated "B" as described in Table 2. In some embodiments, the present invention provides a compound of formula I or I' wherein the compound is designated "C" as described in Table 2. In some embodiments, the present invention provides a compound of formula I or I' wherein the compound is designated "D" as described in Table 2.

[0144] In some embodiments, the present invention provides a compound of formula I or I' wherein the compound is designated "A" as described in Table 2. In some embodiments, the present invention provides a compound of formula I or I' wherein the compound is designated "B" as described in Table 2. In some embodiments, the present invention provides a compound of formula I or I' wherein the compound is designated "B" as described in Table 2. In some embodiments, the present invention provides a compound of formula I or I' wherein the compound is designated "C" as described in Table 2. In some embodiments, the present invention provides a compound of formula I or I' wherein the compound is designated "C" as described in Table 2. In some embodiments, the present invention provides a compound of formula I or I' wherein the compound is designated "D" as described in Table 2. In some embodiments, the present invention provides a compound of formula I or I', The compound is represented by formula I or denoted as "A" or "B" as set forth in Table 2. In some embodiments, the present invention provides a compound of formula I', wherein the compound is of formula I or I', designated "A" or "B" or "C" as described In some embodiments, the present invention provides a compound, wherein the compound is listed in Table 2. Formula I or Compound I' is provided.

[0145] In some embodiments, the present invention provides a method for the treatment of a pulmonary artery disease, comprising administering to a patient a therapeutically effective amount of a pulmonary artery disease as defined above for use as a medicament. The compound of formula I or I' or a pharma- ceutically acceptable salt thereof, or The compounds of formula I or I' as described above, or pharma- ceutically acceptable salts thereof, and Provide a pharmaceutical composition containing an acceptable carrier, adjuvant, or vehicle. .

[0146] Without wishing to be bound by any particular theory, inhibitor compounds, or inhibitors, The proximity of the pendant moiety of the inhibitor compound to the target water allows the inhibitor compound or inhibitory ligand to It is believed that the pendant moieties of the compound facilitate this displacement or interception of water. In some embodiments, the inhibitor compound or a pendant moiety of the inhibitor compound The water molecule that is displaced or disturbed is the unstable water molecule.

[0147] In certain embodiments, the method uses a complex comprising TYK2 and an inhibitor, Here, at least one labile water in TYK2 is replaced by the inhibitor. is replaced or inhibited. In some embodiments, at least two selected labile waters are replaced or inhibited by this inhibitor. 4. General methods for providing the compounds

[0148] The compounds of the present invention can generally be prepared or isolated by synthetic and / or semi-synthetic methods known to those skilled in the art for similar compounds, as well as by the methods described in detail in the examples herein. and by the methods described in detail in the examples herein. 5. Use, formulation and administration Pharmaceutically acceptable compositions

[0149] According to another embodiment, the present invention provides a composition containing a compound of the present invention, or a pharmaceutically acceptable derivative or salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of the compound in the composition of the present invention is an amount effective to measurably inhibit TYK2 protein kinase or its variant in a biological sample or in a patient. In certain embodiments, the amount of the compound in the composition of the present invention is an amount effective to measurably inhibit TYK2 protein kinase or its variant 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.

[0150] As used herein, the term "patient" means an animal, preferably a mammal, most preferably a human.

[0151] 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 formulated therewith. Pharmaceutically acceptable carriers, adjuvants or vehicles that can be used in the compositions of this invention include ion exchangers, alumina, aluminum stearate, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, electrolytes such as salts or protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, carboxymethylcellulose sodium, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and lanolin. "Pharmaceutically acceptable derivative" means any non-toxic salt, ester, salt of an ester or other derivative of a compound of this invention that can directly or indirectly provide the compound of this invention or its inhibitory active metabolite or residue upon administration to a recipient. As used herein, the term "its inhibitory active metabolite or residue" means that the metabolite or residue is also an inhibitor of TYK2 protein kinase or a variant thereof. The compositions of the present invention can be administered orally, parenterally, by inhalation spray, topically, rectally,

[0152]

[0153]

[0154] ​​​​​​​​​​​​​​​ It can be administered into the nasal cavity, into the oral cavity, into the vagina or by an implantable reservoir. " The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular , intra-synovial, intrasternal, intramedullary, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the composition is administered orally, intraperitoneally or intravenously. The injectable sterile form of the composition of the present invention may be an aqueous or oily suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing agents or wetting agents and suspending agents. The injectable sterile preparation may also be, for example, a sterile solution or suspension in a non-toxic parenterally acceptable diluent or solvent such as a solution in 1,3-butanediol. Acceptable vehicles and solvents that can be used include water, Ringer's solution and isotonic sodium chloride solution. Furthermore, sterile fixed oils have conventionally been used as solvents or suspending media.

[0155] For this purpose, any non-irritating solid fixed oil containing synthetic monoglycerides or diglycerides can be used. Fatty acids such as oleic acid and its glyceride derivatives are particularly pharmaceutically acceptable oils such as olive oil or castor oil in their polyoxyethylated forms and are useful in the preparation of injectable substances. Solutions or suspensions of these oils may also contain long-chain alcohol diluents or dispersing agents such as carboxymethylcellulose or similar dispersing agents commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions or suspensions. Pharmaceutically acceptable solids, liquids, or ​​​​​Other commonly used surfactants, such as those commonly used in the manufacture of other dosage forms, for example, Tween, Span, and other emulsifiers or bioavailability enhancers can also be used for formulation purposes.

[0156] The pharmaceutically acceptable compositions of this invention can be orally administered in any orally acceptable dosage form, including but not limited to capsules, tablets , aqueous suspensions or solutions. In the case of tablets for oral use, commonly used carriers include lactose and corn starch. Lubricants such as magnesium stearate are also typically added. For oral administration in capsule form, useful diluents include lact ose and dried corn starch. When an aqueous suspension is required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring, or coloring agents may also be added. Alternatively, the pharmaceutically acceptable compositions of this invention can be administered in the form of suppositories for rectal administration . These are solid at room temperature but liquid at rectal temperature and can therefore be prepared by mixing a suitable non-irritating excipient with the drug so that it melts in the rectum to release the drug

[0157] . Such materials include cocoa butter, beeswax, and polyethylene glycol. . The pharmaceutically acceptable compositions of this invention can also be topically applied, particularly when the target of treatment includes areas or organs that are readily accessible by topical application, including diseases of the eye, skin, or lower intestinal tract.

[0158] It can be administered locally. Suitable topical formulations can be readily prepared for each of these regions or organs. For

[0159] Local application to the lower intestine may be made with rectal suppository formulations (see above) or suitable enemas. Topical transdermal patches can also be used.

[0160] For topical application, the provided pharmaceutically acceptable compositions can be formulated into suitable ointments containing the active ingredient suspended or dissolved in one or more carriers. As carriers for the topical administration of the compounds of this invention, but not limited to these, mineral oil, liquid paraffin, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying waxes and water can be mentioned. Alternatively, the provided pharmaceutically acceptable compositions can be formulated into suitable lotions or creams containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to these, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[0161] 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 with or without a preservative such as benzalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutically ically acceptable compositions can be formulated as a solution in isotonic, pH-adjusted, sterile saline with or without a preservative such as benzalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutically The acceptable composition can be formulated into an ointment such as petrolatum.

[0162] The pharmaceutically acceptable composition of the present invention can also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulations and can be prepared as a solution in saline using benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents. Preferably, the pharmaceutically acceptable composition of the present invention is formulated for oral administration. Such formulations may be administered with or without food. In some

[0163] embodiments, the pharmaceutically acceptable composition of the present invention is administered without food. In other embodiments, the pharmaceutically acceptable composition of the present invention is administered with food. The amount of the compound of the present invention that may be combined with a carrier material to produce a single dosage form will vary depending on the host to be treated and the particular mode of administration. Preferably, the composition provided should be formulated such that an inhibitor in a dosage of between 0.01 and 100 mg per kg of body weight per day can be administered to a patient receiving these compositions.

[0164] The specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound used, age, weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated.

[0165] ​​​​​​It should also be understood that it may vary depending on the child. The amount of the compound of the present invention in the composition will also vary depending on the specific compound in the composition. It will vary depending on the specific compound in the composition. Use of the compound and the pharmaceutically acceptable composition

[0166] The compounds and compositions described herein are generally 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. The kinase inhibited by the compounds and methods of the present invention is TYK2. is TYK2.

[0167] 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, namely, TYK2, JAK1, JAK2, and JAK3. JAK proteins, including TYK2, are essential for cytokine signaling. TYK2 associates with the cytoplasmic domains of type I and II cytokine receptors, as well as interferon type I and type III receptors, and is activated by these receptors upon cytokine binding. The mammalian JAK family consists of four members, namely, TYK2, JAK1, JAK2, and JAK3. That is, it consists of TYK2, JAK1, JAK2, and JAK3. JAK proteins, including TYK2, are essential for cytokine signaling. are essential for cytokine signaling. TYK2 associates with the cytoplasmic domains of type I and II cytokine receptors, as well as interferon type I and type III receptors, and is activated by these receptors upon cytokine binding. cytoplasmic domains of type I and II cytokine receptors, as well as interferon type I and type III receptors, and is activated by these receptors upon cytokine binding. and is activated by these receptors upon cytokine binding. 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), as well as interleukins (e.g., IL-4 , IL-6, IL-10, IL-11, IL-12, IL-13, IL-22, IL-2 3, IL-27, IL-31, oncostatin M, ciliary neurotrophic factor, cardiotrophin 1, cardiotrophin-like cytokine, and LIF). 1, cardiotrophin-like cytokine, and LIF). Velasquez et al., "A protein kinase in the interfero "n α / β signaling pathway", Cell (1992), 70: 313; Stahl et al., "Association and activation of Jak-Tyk kinases by CNTF-LIF-OSM-IL-6β receptor components", Science (1994), 263 :92; Finbloom et al., "IL-10 induces the tyrosi ne phosphorylation of Tyk2 and Jak1 and the differential assembly of Stat1 and S tat3 complexes in human T cells and mono cytes", J. Immunol. (1995), 155:1079; Baco n et al., "Interleukin 12 (IL-12) induces tyros ine phosphorylation of Jak2 and Tyk2: di fferential use of Janus family kinases b y IL-2 and IL-12", J. Exp. Med. (1995), 181 :399; Welham et al., "Interleukin-13 signal tr ansduction in lymphohemopoietic cells: s imilarities and differences in signal tr ansduction with interleukin-4 and insuli n", J. Biol. Chem. (1995), 270:12286; Parh am et al., "A receptor for the heterodimeric cy The cytokine IL-23 is composed of IL-12Rβ1 and a novel cytokine receptor subunit, IL-2 3R」, J. Immunol. (2002) 168: 5699. Subsequently, the activated TYK2 proceeds to phosphorylate members of the STAT family of further signal transduction proteins, such as STAT1, STAT2, S TAT4, and STAT6.

[0168] Activation of TYK2 by IL-23 is associated with inflammatory bowel disease (IBD), Crohn's disease, and ulcerative colitis. Duerr et al., "A Genome-Wide A ssociation 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 n ature of human auto-immune disease", N. E ngl. J. Med (2011) 365: 1612 - 1623; Cortes et al., "Identification of multiple risk varia nts for ankylosing spondylitis through h igh-density genotyping of immune-related loci", Nat. Genet. (2013) 45(7): 730 - 738 Page; Remmers et al., "Genome-wide association stud y identifies variants in the MHC class I , IL10, and IL23R-IL12RB2 regions associ ated with Behcet’s disease", Nat. Genet.( 2010), 42: 698-702. Genome-wide association studies of 2,622 individuals with psoriasis identified an association between disease susceptibility and TYK2. Strange et al., "A genome-wide association study identifie s new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1", Nat. Genet. (2010), 42: 985-992. Knockdown of TYK2 or inhibition of tofacitinib significantly reduces both IL-23-induced and IL-22-induced skin inflammation. Ishizaki et al., "Tyk2 is a therapeut ic target for psoriasis-like skin inflam mation", Intl. Immunol. (2013), doi:10.109 3 / intimm / dxt062.

[0169] 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 regulate​​​​ mucin expression and goblet cell hyper plasia through the TYK2 / STAT6 pathway」, FASEB J. (2012) 26: 1 - 11.

[0170] Reduced TYK2 activity confers protection of joints from collagen antibody-induced arthritis (a model of human rheumatoid arthritis). Mechanistically, reduced Tyk2 activity reduces the production of T1 / T h 1 / T h 17 related cytokines and matrix metalloproteinases, as well as other major inflammatory markers. Ishizaki et al., "Tyk2 deficiency pro tects joints against destruction in anti -type II collagen antibody-induced arthr itis in mice", Intl. Immunol. (2011) 23(9 ): 575 - 582.

[0171] TYK2 knockout mice show complete resistance in experimental autoimmune encephalomyelitis (EAE, an animal model of multiple sclerosis (MS)) compared to controls, with no infiltration of CD4 T cells into the spinal cord. This suggests that TYK2 is essential for the development of pathogenic CD4-mediated diseases in MS. Oyamada et al., "Tyrosine Kinase 2 Plays Critical Roles in the Pa thogenic CD4 T Cell Responses for the De velopment of Experimental Autoimmune Enc ephalomyelitis", ​"encephalomyelitis", J. Immunol. (2009) 183:7 pp. 539 - 7546. This is confirmation of previous research linking increased TYK2 expression to MS susceptibility. Ban et al., "Replication analysis ide ntifies TYK2 as a multiple sclerosis sus ceptibility factor", Eur J. Hum. Genet. (2 009) 17:1309 - 1313. Loss - of - function mutations in TYK2 result in decreased demyelination and increased remyelination of neurons, further suggesting the role of TYK2 inhibitors in the treatment of MS and other CNS demyelinating disorders.

[0172] TYK2 is the only signaling messenger common to both IL - 12 and IL - 23. TYK2 knockout reduces methylated BSA injection - induced foot pad thickness, imiquimod - induced psoriasiform skin inflammation, and dextran sulfate sodium or 2 ,4,6 - trinitrobenzenesulfonic acid - induced colitis in mice.

[0173] Associations and linkage studies of various type I IFN signaling transduction genes with systemic lupus erythematosus (SLE, an autoimmune disorder) showed a strong and significant correlation between loss - of - function mutations in TYK2 and a decreased prevalence of SLE in families containing affected members. Sigurdsson et al., "Polymorphisms in the Tyros ine Kinase 2 and Interferon Regulatory F actor 5 Genes Are Associated with System ic Lupus Erythematosus", Am J. Hum. Genet. (2009) 85:558 - 568. ​​​"ic Lupis Erythematosus", Am. J. Hum. Gene t. (2005) 76: 528-537. Genome-wide association studies in individuals with SLE against an unaffected cohort showed a highly significant correlation between the TYK2 locus and SLE. Graham et al., "Association of NCF2, IK ZF1, IRF8, IFIH1, and TYK2 with Systemic Lupus Erythematosus", PLoS Genetics (2011 year) 7(10): e1002341.

[0174] TYK2 has been shown to play an important role in the maintenance of tumor surveillance, and TYK2 knockout mice showed impaired cytotoxic T cell responses and accelerated tumorigenesis. However, these effects are associated with efficient suppression of natural killer (NK) and cytotoxic T lymphocytes, suggesting that TYK2 inhibitors are very suitable for the treatment of autoimmune disorders or transplant rejection. JAK3 and any other JAK family members have similar roles in the immune system, but TYK2 is involved in fewer, more closely related signaling pathways and is suggested to be a better target for producing fewer off-target effects. Simma et al. "I dentification of an Indispensable Role f or Tyrosine Kinase 2 in CTL-Mediated Tum or Surveillance", Cancer Res. (2009) 69: 2 03-211.

[0175] However, in contrast to the decreased tumor surveillance observed by Simma et al., studies in T-cell acute lymphoblastic leukemia (T-ALL) have shown that T-ALL highly depends on IL-10 through TYK2 via STAT1-mediated signaling to maintain cancer cell survival by upregulation of the anti-apoptotic protein BCL2. Knockdown of TYK2 reduced cell proliferation, while knockdown of other JAK family members did not. Specific activating mutations in TYK2 promoting cancer cell survival include activating mutations in the FERM domain (G36D, S47N, and R425H), JH2 domain (V731I), and kinase domain (E957D and R1027H). However, the kinase function of TYK2 was also found to be required for increased cancer cell survival, since in addition to the activating mutation (E957D), a TYK2 enzyme characterized by a kinase-dead mutation (M978Y or M978F) resulted in failed transformation. Sanda et al., "TYK2-STAT1- BCL2 Pathway Dependence in T-Cell Acute Lymphoblastic Leukemia", Cancer Disc. (20 13), Vol. 3(5): 564-577.

[0176] Therefore, the selective inhibition of TYK2 is a suitable target for patients with tumors that are IL-10 and / or BCL2 addicted, such as 70% of cases of has been suggested. Fontan et al., "Discovering What Mak es STAT Signaling TYK in T-ALL", Cancer D isc. (2013) 3:494-496.

[0177] TYK2-mediated STAT3 signaling has also been shown to mediate neuronal cell death induced by amyloid-β (Aβ) peptide. Decrease in TYK2 phosphorylation of STAT3 after Aβ administration results in a decrease in neuronal cell death, and an increase in phosphorylation of STAT3 has been observed in the postmortem brains of Alzheimer's disease patients. Wan et al., "Tyk / STAT3 Signaling Me diates β-Amyloid-Induced Neuronal Cell D eath: Implications in Alzheimer’s Diseas e", J. Neurosci. (2010) 30(20):6873-6881 p. eath: Implications in Alzheimer’s Diseas e", J. Neurosci. (2010) 30(20):6873-6881 p.

[0178] Inhibition of the JAK-STAT signaling pathway is also involved in the reversal of hair growth and hair loss associated with alopecia areata. Xing et al., "Alopecia areata is driven by cytotoxic T lymphocytes and is rever sed by JAK inhibition", Nat. Med. (2014) 2 0:1043-1049; Harel et al., "Pharmacologic inhi bition of JAK-STAT signaling promotes ha ir growth", Sci. Adv. (2015) 1(9):e15009 4. Page 73.

[0179] Thus, compounds that inhibit the activity of TYK2, particularly those with high selectivity preferentially over JAK2 are beneficial. Such compounds should preferably deliver a pharmacological response that treats one or more of the conditions described herein without side effects associated with JAK2 inhibition.

[0180] Despite the fact that TYK2 inhibitors are known in the art, there is still a need to provide novel inhibitors with more effective or advantageous pharmaceutically relevant properties. For example, increased activity, high selectivity preferentially over other JAK kinases (particularly JAK2), and ADMET (absorption, distribution, metabolism, excretion, and / or toxicity) properties. Thus, in some embodiments, the invention provides inhibitors of TYK2 that exhibit high selectivity preferentially over JAK2.

[0181] The activity of the compounds utilized in this invention as inhibitors of TYK2, or variants thereof, can be assayed in vitro, in vivo, or within cell lines. Examples of in vitro assays include assays that determine the inhibition of the phosphorylation activity and / or subsequent functional consequences, or the ATPase activity, of activated TYK2, or variants thereof. Alternatively, in vitro assays can quantify the ability of an inhibitor to bind to TYK2. The binding of an inhibitor can be measured by radiolabeling the inhibitor prior to binding, isolating the inhibitor / TYK2 complex, and determining the amount of bound radiolabel. Alternatively, the binding of an inhibitor can be measured by incubating the novel inhibitor It can be determined by conducting a competitive experiment to be performed. Representative in vitro assays and in vivo assays useful for assaying a TYK2 inhibitor are, for example, those described and disclosed in, for example, and each of them is incorporated herein by reference in its entirety. In this invention, the compounds utilized as inhibitors of TYK2 or its variants are assayed under the detailed conditions described in the following examples. When used herein, the terms "treatment", "treat", and "treating" refer to the reversal, alleviation, delay in the onset, or inhibition of progression of a disease or disorder, or one or more symptoms thereof, as described herein. In some embodiments, treatment can be administered after one or more symptoms have developed. In other embodiments, treatment can be administered in the absence of symptoms. For example, treatment can be administered to a susceptible individual prior to the onset of symptoms (e.g., taking into account the medical history of symptoms and / or genetic or other susceptibility factors). Treatment can also be continued after the symptoms have resolved, for example, to prevent or delay recurrence of the symptoms. The compounds provided are inhibitors of TYK2 and are thus useful for treating one or more disorders associated with the activity of TYK2 or its variants. Thus, in certain embodiments, the present invention provides a method for treating a TYK2-mediated disorder, the method comprising administering to a patient in need thereof a compound of the present invention, or a pharmaceutically acceptable composition thereof.

[0182] As used herein, the terms "treatment", "treat", and "treating" refer to the reversal, alleviation, delay in the onset, or inhibition of progression of a disease or disorder, or one or more symptoms thereof, as described herein. In some embodiments, treatment can be administered after one or more symptoms have developed. In other embodiments, treatment can be administered in the absence of symptoms. For example, treatment can be administered to a susceptible individual prior to the onset of symptoms (e.g., taking into account the medical history of symptoms and / or genetic or other susceptibility factors). Treatment can also be continued after the symptoms have resolved, for example, to prevent or delay recurrence of the symptoms. be continued after the symptoms have resolved, for example, to prevent or delay recurrence of the symptoms. In some embodiments, treatment can be administered after one or more symptoms have developed. In other embodiments, treatment can be administered in the absence of symptoms. For example, treatment can be administered to a susceptible individual prior to the onset of symptoms (e.g., taking into account the medical history of symptoms and / or genetic or other susceptibility factors). Treatment can also be continued after the symptoms have resolved, for example, to prevent or delay recurrence of the symptoms. In some embodiments, treatment can be administered after one or more symptoms have developed. In other embodiments, treatment can be administered in the absence of symptoms. For example, treatment can be administered to a susceptible individual prior to the onset of symptoms (e.g., taking into account the medical history of symptoms and / or genetic or other susceptibility factors). Treatment can also be continued after the symptoms have resolved, for example, to prevent or delay recurrence of the symptoms. be continued after the symptoms have resolved, for example, to prevent or delay recurrence of the symptoms. be continued after the symptoms have resolved, for example, to prevent or delay recurrence of the symptoms.

[0183] The compounds provided are inhibitors of TYK2 and are thus useful for treating one or more disorders associated with the activity of TYK2 or its variants. Thus, in certain embodiments, the present invention provides a method for treating a TYK2-mediated disorder, the method comprising administering to a patient in need thereof a compound of the present invention, or a pharmaceutically acceptable composition thereof. be continued after the symptoms have resolved, for example, to prevent or delay recurrence of the symptoms. In certain embodiments, the present invention provides a method for treating a TYK2-mediated disorder, the method comprising administering to a patient in need thereof a compound of the present invention, or a pharmaceutically acceptable composition thereof. In certain embodiments, the present invention provides a method for treating a TYK2-mediated disorder, the method comprising administering to a patient in need thereof a compound of the present invention, or a pharmaceutically acceptable composition thereof. In certain embodiments, the present invention provides a method for treating a TYK2-mediated disorder, the method comprising administering to a patient in need thereof a compound of the present invention, or a pharmaceutically acceptable composition thereof.

[0184] As used herein, the term "TYK2-mediated" disorder, disease, and / or condition means, as used herein, any disease or other adverse condition in which TYK2 or a variant thereof is known to play a role. Thus, another embodiment of the invention relates to treating or reducing 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 disorders associated

[0185] with transplantation. In some embodiments, the invention is a method for treating one or more disorders, wherein the disorder is selected from autoimmune disorders, inflammatory disorders, proliferative disorders, endocrine disorders, neurological disorders, and disorders associated with transplantation, and the method comprises administering to a patient in need thereof a pharmaceutical composition comprising

[0186] an effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof. In some embodiments, the disorder is an autoimmune disorder. In some embodiments, the disorder is selected from type 1 diabetes, cutaneous erythematosus, systemic erythematosus, multiple sclerosis, psoriasis, Behcet's

[0187] disease, POEMS syndrome, Crohn's disease, ulcerative colitis, and inflammatory bowel disease. In some embodiments, the disorder is an inflammatory disorder. In some embodiments, the inflammatory disorder is rheumatoid arthritis, asthma,

[0188] 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 leukemia. In some embodiments, the leukemia is T cell leukemia. In some embodiments, the T cell leukemia is T cell acute lymphoblastic leukemia (T-ALL). In some embodiments, the proliferative disorder is polycythemia vera, myelofibrosis, essential or thrombocythemia.

[0189] In some embodiments, the disorder is an endocrine disorder. In some embodiments, the endocrine dis order is polycystic ovary syndrome, Cushing's syndrome, or type 1 diabetes.

[0190] In some embodiments, the disorder is a neurological disorder. In some embodiments, the neurological dis order is Alzheimer's disease.

[0191] 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 to the FERM domain, J H2 domain, or kinase domain. In some embodiments, the activating mutation in TY K2 is selected from G36D, S47N, R425H, V731I, E957D , and R1027H.

[0192] In some embodiments, the disorder is related to transplantation. In some embodiments, the disorder related to transplantation is transplant rejection, or graft-versus-host disease.

[0193] In some embodiments, the disorder is type I interferon, IL-10, IL-12, or is related to IL-23 signaling. In some embodiments, the disorder is related to type I interferon signaling. In some embodiments, the disorder is related to IL-10 signaling. In some embodiments, the disorder is related to IL-12 signaling. In some embodiments, the disorder is related to IL-23 signaling.

[0194] The compounds of the present invention are also useful in the treatment of inflammatory or allergic conditions of the skin, such as psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, allergic vasculitis, urticaria, bullous pemphigoid, erythema nodosum, cutaneous erythema nodosum, systemic erythema nodosum, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, acquired epidermolysis bullosa, acne vulgaris, and other inflammatory or allergic conditions of the skin.

[0195] The compounds of the present invention are also useful in the treatment of other diseases or conditions, such as diseases or conditions having an inflammatory component, such as eye allergies, conjunctivitis, dry keratoconjunctivitis, and spring conjunctivitis, diseases and conditions of the eye, diseases affecting the nose, including allergic rhinitis, and autoimmune hematological disorders (e.g., hemolytic anemia, aplastic anemia, erythroblastosis, and idiopathic thrombocytopenia), inflammatory diseases in which an autoimmune reaction is involved or which have an autoimmune component or etiology, such as cutaneous erythema nodosum, systemic erythema nodosum, rheumatoid arthritis, relapsing polychondritis, scleroderma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Stevens-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel diseases (e.g., ulcerative colitis and Crohn's disease), irritable bowel syndrome, celiac disease, periodontitis, pulmonary fibrosis, kidney diseases, Glomerular diseases, alcoholic liver diseases, multiple sclerosis, endocrine ophthalmopathy, Graves' disease, sar coidosis, pneumonia, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, pu ditis (anterior and posterior), Sjogren's syndrome, dry keratoconjunctivitis and vernal catarrh, interstitial pulmonary fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, cryopyrin-associated periodic syndrome, nephritis, vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis (e.g., nephrotic syndro me with or without minimal change nephropathy), chronic granulomatous disease, endometriosis, leptospir osis, renal diseases, glaucoma, retinal diseases, aging, headache, pain, complex regional pain syndrome, hea rt hypertrophy, muscle wasting, catabolism disorders, obesity, fetal growth retardation, hypercholesterol emia, heart disease, chronic heart failure, mesothelioma, anhidrotic ectodermal dysplasia, Behcet's disea se, dyschromatosis, Paget's disease, pancreatitis, hereditary periodic fever syndrome, asthma (allergic an d non-allergic, mild, moderate, severe, bronchitic, and exercise-induced), acute lung injury, acute respirato ry distress syndrome, eosinophilia, hypersensitivity, anaphylaxis, rhinitis, eye allergy, silica-induced dise ases, COPD (reduction of injury, airway inflammation, bronchial hyperactivity, remodeling or disease progre ssion), lung diseases, cystic fibrosis, acid-induced lung injury, pulmonary hypertension, polyneuropathy, cataract, muscle inflammation associated with systemic sclerosis, inclusion body myositis, myasthenia gra vis, thyroiditis, Addison's disease, lichen planus, type 1 diabetes, or type 2 diabetes, appendicitis, atopic dermatitis, asthma, allergy, blepharitis, bronchiolitis ​, bronchitis, synovitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection, colitis, conjunctivitis , Crohn's disease, cystitis, dacryadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis , enterocolitis, epicondylitis, epiploitis, fasciitis, connective tissue inflammation, gastritis, gastroenteritis, Henoch-Schönlein purpura, hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, ovarian itis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis , pneumonitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendinitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, or external vaginitis for treatment.

[0196] In some embodiments, the inflammatory diseases that can be treated by the method of the present invention are acute gout and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, systemic juvenile idiopathic arthritis (SJIA), cryopyrin associated periodic syndrome (CAPS), and osteoarthritis.

[0197] In some embodiments, the inflammatory diseases that can be treated by the method of the present invention are T h 1 or T h 17-mediated diseases. In some embodiments, the T h 17-mediated diseases are skin erythematosus, systemic lupus erythematosus, multiple sclerosis, and inflammatory bowel disease (including Crohn's disease or ulcerative colitis).

[0198] In one embodiment, the inflammatory diseases that can be treated by the method of the present invention include Sjögren's syndrome, allergic disorders, osteoarthritis, eye allergies, conjunctivitis, dry eye conditions such as keratoconjunctivitis and vernal conjunctivitis, and diseases affecting the nose such as allergic rhinitis selected from.

[0199] Furthermore, the present invention 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 disorder, inflammatory disorder, or proliferative disorder , or a disorder commonly occurring in relation to transplantation. Combination therapy

[0200] Depending on the particular condition or disease being treated, an additional therapeutic agent that is normally administered to treat that condition can be administered in combination with the compounds and compositions of the present invention. As used herein, an additional therapeutic agent that is normally administered to treat a particular disease or condition is known as "being appropriate for the disease or condition being treated".

[0201] In certain embodiments, the provided combination or composition thereof is administered in combination with another therapeutic agent.

[0202] Examples of agents with which the combinations of the present invention may be combined include, but are not limited to: agents for treating Alzheimer's disease, such as Aricept® and Excelon® ; agents for treating HIV, such as ritonavir; agents for treating Parkinson's disease, such as L -DOPA / carbidopa, entacapone, ropinrole, prami pexole; Pexol, bromocriptine, pergolide, trihexyphenidyl, and amantadine; beta interferon (e.g., Avonex (R) and Rebif(R)), Copaxone(R), and mitoxantrone, etc., drugs for treating multiple sclerosis (MS); agents for treating asthma, e.g., albuterol and Singulair(R); drugs for treating schizophrenia, e.g., ziprasidone, risperidone, quetiapine, 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, interferon, corticosteroids, cyclophosphamide, azathioprine, and sulfasalazine; neurotrophic factors, e.g., acetylcholinesterase inhibitors, MAO inhibitors, interferon, anticonvulsants, ion channel blockers, riluzole, and anti-Parkinsonian agents; drugs for treating cardiovascular diseases, e.g., beta blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, and statins; drugs for treating liver diseases, e.g., corticosteroids, cholestyramine, interferon, and antiviral agents; drugs for treating blood disorders, e.g., corticosteroids, anti-leukemia agents, and growth factors; drugs for prolonging or improving pharmacokinetics, e.g., cytochrome P 450 inhibitors (i.e., inhibitors of metabolic degradation) and CYP3A4 inhibitors (e.g., keto conazole); conazole);​ Ketoconazole and ritonavir, and agents for treating immunodeficiency disorders, such as gamma globulin. are mentioned.

[0203] In certain embodiments, the combination therapy of the present invention, or a pharmaceutically acceptable composition thereof, is administered in combination with a monoclonal antibody or an siRNA therapeutic agent.

[0204] These additional agents may be administered as part of a multiple dosing regimen, separately from the combination therapy provided. Alternatively, these agents may be part of a single dosage form, mixed together with the compounds of this invention in a single composition. When administered as part of a multiple dosing regimen, the two active agents may be administered simultaneously, sequentially, or within a period of time from each other, usually within 5 hours of each other. are given.

[0205] As used herein, the terms "combination", "combined", and related terms refer to the simultaneous or sequential administration of the therapeutic agents according to this invention. For example, the combination of this invention may be administered simultaneously or sequentially, in separate unit dosage forms, with another therapeutic agent, or together in a single unit dosage form.

[0206] The amount of additional therapeutic agent present in the composition of this invention is less than the amount normally administered in a composition containing that therapeutic agent as the sole active agent. Preferably, the amount of additional therapeutic agent in the composition of the present disclosure is in the range of about 50% to 100% of the amount normally present in a composition containing that agent as the sole therapeutically active agent.

[0207] In one embodiment, the present invention provides a compound of formula I or I' and one or more additional therapeutic To provide a composition comprising a therapeutic agent. The therapeutic agent can be administered together with a compound of formula I or I', or can be administered before or after the administration of a compound of formula I or I'. Suitable therapeutic agents are described in more detail below. In certain embodiments, the compound of formula I or I' can be administered 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours before the therapeutic agent. In other embodiments, the compound of formula I or I' can 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. In another embodiment, the present invention provides a method of treating an inflammatory disease, disorder or condition in a patient in need thereof by administering a compound of formula I or I' and one or more additional therapeutic agents. Such additional therapeutic agents can be small molecules or recombinant biological agents, for example, acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs) (e.g., aspirin, ibuprofen, naproxen, etodolac (Lodine (registered trademark)) and celecoxib), colchicine (Colcrys (registered trademark)), corticosteroids (e.g., prednisone, prednisolone, methylprednisolone,

[0208] DS) (e.g., aspirin, ibuprofen, naproxen, etodolac (Lodine (registered trademark)) and celecoxib), colchicine (Colcrys (registered trademark)), corticosteroids (e.g., prednisone, prednisolone, methylprednisolone, ​​​​​​​​​​​​​​​and hydrocortisone, etc.), probenecid, allopurinol, febuxostat ( Uloric®), sulfasalazine ( Azulfidine®), antimalarial drugs (e.g., hydroxychloroquine ( Plaquenil®) and chloroquine (Aralen®)), methotrexate ( Rheumatrex®), gold salts (e.g., aurothioglucose ( Solganal®), aurothiomalate (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 ( Cimzia®) and adalimumab (Humira®)), "anti-IL-1" agents (e.g., anakinra (Kineret®) and rilonacept ( Arcalyst®)), canakinumab ( Ilaris®), anti-Jak inhibitors (e.g., tofacitinib), antibodies (e.g., rituximab (Rituxan®)), "anti-T cell" agents (e.g., abatacept ( Orencia®)), "anti-IL-6" agents (e.g., tocilizumab (Act emra (registered trademark)), diclofenac, cortisone, hyaluronic acid (Synvis c (registered trademark) or Hyalgan (registered trademark)), monoclonal antibody (e.g., ta nezumab), anticoagulant (e.g., heparin (Calcinparine (registered trademark) or Liquaemin (registered trademark)) and warfarin (Coumadin (registered trademark ))), antidiarrheal (e.g., diphenoxylate (Lomotil (registered trademark)) and loperamide (Imodium (registered trademark))), bile acid binder (e.g., cholestyrami ne), alosetron (Lotronex (registered trademark)), lubiprostone (Amitiz a (registered trademark)), laxative (e.g., magnesium milk, polyethylene glycol (Mi raLax (registered trademark)), Dulcolax (registered trademark), Correctol (registered trademark) and Senokot (registered trademark)), anticholinergic or antispasmodic (e.g., dicyclomine (Bentyl (registered trademark))), Singulair (registered trademark), be ta-2 agonist (e.g., albuterol (Ventolin (registered trademark) HFA, P roventil (registered trademark) HFA), levalbuterol (Xopenex (registered trademark )), metaproterenol (Alupent (registered trademark)), pirbuterol acetate (Ma xair (registered trademark)), terbutaline sulfate (Brethaire (registered trademark))), xy salmetrol xinafoate (Serevent (registered trademark)) and formoterol (Fo radil (registered trademark))), anticholinergic (e.g., ipratropium bromide (Atr ovent (registered trademark)) and tiotropium (Spiriva (registered trademark))), inhal Inhaled corticosteroids (e.g., beclomethasone dipropionate (Beclovent (trademark), Qvar (trademark), and Vanceril (trademark)), triam cinolone acetonide (Azmacort (trademark)), mometasone (Asthman ex (trademark)), budesonide (Pulmocort (trademark)), and fluni solide (Aerobid (trademark)), Afviar (trademark), Symbico rt (trademark), Dulera (trademark), cromolyn sodium (Intal (reg istered trademark)), methylxanthines (e.g., theophylline (Theo-Dur (registered trademark) , Theolair (trademark), Slo-bid (trademark), Uniphyl (reg istered trademark), Theo-24 (trademark)) and aminophylline), IgE antibodies (e.g., omalizumab (Xolair (trademark)), nucleoside reverse transcriptase inhibitors (e.g., , zidovudine (Retrovir (trademark)), abacavir (Ziagen (registered trademark )), abacavir / lamivudine (Epzicom (trademark)), abacavir / lamivudi ne / zidovudine (Trizivir (trademark)), didanosine (Videx (registered trademark )), emtricitabine (Emtriva (trademark)), lamivudine (Epivir( registered trademark)), lamivudine / zidovudine (Combivir (trademark)), stavudine (Zerit (trademark)), and zalcitabine (Hivid (trademark))), non-nu cleoside reverse transcriptase inhibitors (e.g., delavirdine (Rescriptor (registered trademark )), efavirenz (Sustiva (trademark)), nevirapine (nevairap ine) (Viramune (trademark)) and etravirine (Intelence( Registered trademark), nucleotide reverse transcriptase inhibitors (e.g., tenofovir (Viread( Registered trademark)), protease inhibitors (e.g., amprenavir (Agenerase( Registered trademark)), atazanavir (Reyataz (Registered trademark)), darunavir (Prezi sta (Registered trademark)), fosamprenavir (Lexiva (Registered trademark)), indinavir l (Crixivan (Registered trademark)), lopinavir and ritonavir (Kaletra( Registered trademark)), nelfinavir (Viracept (Registered trademark)), ritonavir (Nor vir (Registered trademark)), saquinavir (Fortovase (Registered trademark) or Invir ase (Registered trademark)), and tipranavir (Aptivus (Registered trademark))), entry inhibitors (e.g., enfuvirtide (Fuzeon (Registered trademark)) and maraviroc (Se lzentry (Registered trademark))), integrase inhibitors (e.g., raltegravir (I sentress (Registered trademark)), doxorubicin (Hydrodaunorubici n (Registered trademark)), vincristine (Oncovin (Registered trademark)), bortezomib (V elcade (Registered trademark)), and dexamethasone (Decadron (Registered trademark)) in combination with lenalidomide (Revlimid (Registered trademark)), or these any combination (s) thereof may be mentioned.

[0209] In another embodiment, the present invention is a method of treating rheumatoid arthritis, which is necessary for patients, a compound of formula I or I' and a non-steroidal anti-inflammatory drug (NSAIDS)( e.g., aspirin, ibuprofen, naproxen, etodolac (Lodine (Registered Trademarks)) and celecoxib, corticosteroids (e.g., prednisone, predni solone, methylprednisolone, and hydrocortisone, etc.), sulfasalazine (A zulfidine (registered trademark)), antimalarial drugs (e.g., hydroxychloroquine (P laquenil (registered trademark)) and chloroquine (Aralen (registered trademark))), me thotrexate (Rheumatrex (registered trademark)), gold salts (e.g., aurothiogluc ose (Solganal (registered trademark)), aurothiomalate (Myochrysine (registered trademark)) and auranofin (Ridaura (registered trademark))), D-penicillamine ( Depen (registered trademark) or Cuprimine (registered trademark)), azathioprine (I muran (registered trademark)), cyclophosphamide (Cytoxan (registered trademark)), clo rambucil (Leukeran (registered trademark)), cyclosporine (Sandimmune (registered trademark)), leflunomide (Arava (registered trademark)) and "anti-TNF" agents (e.g such as, etanercept (Enbrel (registered trademark)), infliximab (Remicad e (registered trademark)), golimumab (Simponi (registered trademark)), certolizumab pegol (Cimzia (registered trademark)) and adalimumab (Humira (registered trademark))), "anti-IL-1" agents (e.g., anakinra (Kineret (registered trademark)) and rilonace pt (Arcalyst (registered trademark))), antibodies (e.g., rituximab (Rituxa n (registered trademark))), "anti-T cell" agents (e.g., abatacept (Orencia (registered trademark))) and "anti-IL-6" agents (e.g., tocilizumab (Actemra (registered trademark) )) comprising the step of administering one or more additional therapeutic agents selected from, a method is provided to be used.

[0210] In some embodiments, the invention is a method of treating osteoarthritis, comprising administering to a patient in need thereof a compound of formula I or I' and one or more additional therapeutic agents selected from acetaminophen, non-steroidal 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). In some embodiments, the invention is a method of treating cutaneous erythematosus or systemic erythematosus, comprising administering to a patient in need thereof a compound of formula I or I' and one or more additional therapeutic agents selected from acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs) (e.g., aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib), corticosteroids (e.g., prednisone, prednisolone, methylprednisolone, and hydrocortisone, etc.), anti-malarial drugs (e.g., hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®)), cyclophosphamide (Cytoxan®), methotrexate (Rheumatrex®), azathioprine (Imuran®) and anticoagulants (e.g., heparin (Calcinparine® or Liquemin®) and warfarin (Coumadin®)). hyaluronic acid (Synvisc® or Hyalgan®) and monoclonal antibodies (e.g., tanezumab). In some embodiments, the invention provides a method comprising the step of administering to a patient in need thereof a compound of formula I or I' and one or more additional therapeutic agents selected from acetaminophen, non-steroidal 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).

[0211] In some embodiments, the invention is a method of treating cutaneous erythematosus or systemic erythematosus, comprising administering to a patient in need thereof a compound of formula I or I' and one or more additional therapeutic agents selected from acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs) (e.g., aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib), corticosteroids (e.g., prednisone, prednisolone, methylprednisolone, and hydrocortisone, etc.), anti-malarial drugs (e.g., hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®)), cyclophosphamide (Cytoxan®), methotrexate (Rheumatrex®), azathioprine (Imuran®) and anticoagulants (e.g., heparin (Calcinparine® or Liquemin®) and warfarin (Coumadin®)). In some embodiments, the invention is a method of treating cutaneous erythematosus or systemic erythematosus, comprising administering to a patient in need thereof a compound of formula I or I' and one or more additional therapeutic agents selected from acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs) (e.g., aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib), corticosteroids (e.g., prednisone, prednisolone, methylprednisolone, and hydrocortisone, etc.), anti-malarial drugs (e.g., hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®)), cyclophosphamide (Cytoxan®), methotrexate (Rheumatrex®), azathioprine (Imuran®) and anticoagulants (e.g., heparin (Calcinparine® or Liquemin®) and warfarin (Coumadin®)). corticosteroids (e.g., prednisone, prednisolone, methylprednisolone, and hydrocortisone, etc.), anti-malarial drugs (e.g., hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®)), cyclophosphamide (Cytoxan®), methotrexate (Rheumatrex®), azathioprine (Imuran®) and anticoagulants (e.g., heparin (Calcinparine® or Liquemin®) and warfarin (Coumadin®)). (Plaquenil®) and chloroquine (Aralen®)) cyclophosphamide (Cytoxan®), methotrexate (Rheumatrex®), azathioprine (Imuran®) and anticoagulants (e.g., heparin (Calcinparine® or Liquemin®) and warfarin (Coumadin®)). from. In some embodiments, the invention provides a method comprising the step of administering to a patient in need thereof a compound of formula I or I' and one or more additional therapeutic agents selected from acetaminophen, non-steroidal 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). Provided is a method comprising the step of administering one or more additional therapeutic agents.

[0212] In some embodiments, the invention is 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 or I' and mesalamine (Asacol®), sulfasalazine (Azulfidine® ), antidiarrheal agents (e.g., diphenoxylate (Lomotil®) and loperamide (Imodium®)), bile acid binders (e.g., cholestyramine ), alosetron (Lotronex®), lubiprostone (Amitiza® ), laxatives (e.g., magnesium milk, polyethylene glycol (Mira Lax®), Dulcolax®, Correctol® and Senokot®) and anticholinergic or antispasmodic agents (e.g., dicyclomine (Bentyl®), anti-TNF therapeutic agents, steroids, and antibiotics (e.g., Flagyl or ciprofloxacin) selected from one or more additional therapeutic agents. Provided is a method comprising the step of administering one or more additional therapeutic agents.

[0213] In some embodiments, the invention is a method of treating asthma, comprising administering to a patient in need thereof a compound of formula I or I' and Singulair®, beta-2 agonists (e.g., albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair® ), Registered Trademark)), Terbutaline Sulfate (Brethaire (registered trademark)), Sal Meterol (Serevent (registered trademark)) and Formoterol (Foradil (registered trademark))), an anticholinergic agent (e.g., Ipratropium Bromide (Atrovent (registered trademark)) and Tiotropium (Spiriva (registered trademark))), an inhaled cort icosteroid (e.g., Prednisone, Prednisolone, Beclomethasone Dipropionate (Beclovent (registered trademark), Qvar (registered trademark), and Vanceril( registered trademark)), Triamcinolone Acetonide (Azmacort (registered trademark)), Momet zone (Asthmanex (registered trademark)), Budesonide (Pulmocort (registered trademark ))), Flunisolide (Aerobid (registered trademark)), Afviar (registered trademark), Sy mbicort (registered trademark), and Dulera (registered trademark)), Cromolyn Sodium (Intal (registered trademark)), Methylxanthine (e.g., Theophylline (Theo- Dur (registered trademark), Theolair (registered trademark), Slo-bid (registered trademark), U niphyl (registered trademark), Theo-24 (registered trademark)) and Aminophylline), and also IgE antibodies (e.g., Omalizumab (Xolair (registered trademark))) selected from administering one or more additional therapeutic agents. A method is provided that includes the step of

[0214] In some embodiments, the present invention is a method for treating COPD, comprising, in a patient in need thereof a compound of formula I or I' and a beta-2 agonist (e.g., Albuterol l (Ventolin (registered trademark) HFA, Proventil (registered trademark) HFA), Levalbuterol (Xopenex®), metaproterenol (Alupen t®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent (®)), and formoterol (Foradil®)), an anticholinergic agent (e.g., ipratropium bromide (Atrovent®) and tiotropium ium (Spiriva®)), a methylxanthine (e.g., theophylline( Theo-Dur®, Theolair®, Slo-bid®, Uniphyl®, Theo-24®)) and aminophylline), an inhaled corticosteroid (e.g., prednisone, prednisolone, beclomethasone dipropionate (Beclovent®, Qvar®, and also Vanceril®), triamcinolone acetonide (Azmacort( ®)), mometasone (Asthmanex®), budesonide (Pulm ocort®), flunisolide (Aerobid®), Afvia r®), Symbicort®), and Dulera®)) administering one or more additional therapeutic agents selected from comprising the step of providing a method .

[0215] In another embodiment, the present invention is a method for treating a hematological malignancy, which comprises administering to a patient in need thereof a compound of formula I or I' and rituximab (Rituxan (®)), cyclophosphamide (Cytoxan®), doxorubicin (Hyd ®), daunorubicin (registered trademark), vincristine (Oncovin (registered trademark)), prednisone, hedgehog signaling inhibitor, BTK inhibitor, JAK / pan-JAK inhibitor, PI3K inhibitor, SYK inhibitor, and one or more additional therapeutic agents selected from combinations thereof,

[0216] In another embodiment, the present invention is a method of treating a solid tumor, comprising administering to a patient in need thereof a compound of Formula I or I' and rituximab (Rituxan (registered trademark)), cyclophosphamide (Cytoxan (registered trademark)), doxorubicin (Hydroda unorubicin (registered trademark)), vincristine (Oncovin (registered trademark)) prednisone, hedgehog signaling inhibitor, BTK inhibitor, JAK / pan-JAK inhibitor, PI3K inhibitor, SYK inhibitor, and one or more additional therapeutic agents selected from combinations thereof. In another embodiment, the present invention is a method of treating a

[0217] hematological malignancy, comprising administering to a patient in need thereof a compound of Formula I or I' and a hedgehog (Hh) signaling pathway inhibitor. In some embodiments, the hematological malignancy is DLBCL (Ramirez et al., "Defining causative fac tors contributing in the activation of h edgehog signaling in diffuse large B-cel l lymphoma", Leuk. Res. (2012), July 17, online which is published and incorporated herein by reference in its entirety).

[0218] In another embodiment, the present invention is a method for treating diffuse large B-cell lymphoma (DLBCL), comprising administering to a patient in need thereof a compound of formula I or I' and rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, and one or more additional therapeutic agents selected from the group consisting of these and combinations thereof. In another embodiment, the present invention is a method for treating multiple myeloma, comprising administering to a patient in need thereof a compound of formula I or I' and bortezomib (Velcade®), and dexamethasone (Decadron®), a hedgehog signaling inhibitor, a BTK inhibitor, a JAK / pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor,

[0219] a SYK inhibitor, alone or in combination with lenalidomide (Revlimid®). In another embodiment, the present invention is a method for treating a disease or reducing its severity, comprising administering to a patient in need thereof a compound of formula I or I' and a BTK inhibitor, wherein the disease is inflammatory bowel disease, arthritis, cutaneous erythematosus, systemic lupus erythematosus (SLE), vasculitis, idiopathic thrombocytopenic purpura (ITP), rheumatoid arthritis

[0220] . In another embodiment, the present invention is a method for treating a disease or reducing its severity, comprising administering to a patient in need thereof a compound of formula I or I' and a BTK inhibitor, wherein the disease is inflammatory bowel disease, arthritis, cutaneous erythematosus, systemic lupus erythematosus (SLE), vasculitis, idiopathic thrombocytopenic purpura (ITP), rheumatoid arthritis (SLE), vasculitis, idiopathic thrombocytopenic purpura (ITP), rheumatoid arthritis , psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis, Graves' disease, autoimmune thyroiditis, Sjögren's syndrome, multiple sclerosis, systemic sclerosis, Lyme neuroborreliosis, Guillain - Barré syndrome, acute disseminated encephalomyelitis, Addison's disease, opsoclonus - myoclonus syndrome, ankylosing spondylitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, autoimmune gastritis, pernicious anemia, celiac disease, Goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia universalis, Behçet's disease, chronic fatigue, autonomic neuropathy, membranous glomerulonephritis, endometriosis, interstitial cystitis, pemphigus vulgaris, bullous pemphigoid, neuromyotonia, scleroderma, vulvodynia, hyperproliferative disorders, rejection of transplanted organs or tissues, acquired immunodeficiency syndrome (AIDS, also known as HIV), type 1 diabetes, graft - versus - host disease, transplantation, transfusion, anaphylaxis, allergies (e.g., to plant pollen, latex, drugs, food, insect venom, animal hair, animal dandruff, mites, or cockroach calyx), type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, and atopic dermatitis, asthma, appendicitis, atopic dermatitis, asthma, allergies, blepharitis, bronchiolitis, bronchitis, synovitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection, colitis, conjunctivitis, Crohn's disease, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, Enterocolitis, epicondylitis, epiploitis, fasciitis, connective tissue inflammation, gastritis, gastroenteritis, Henoch-Schönlein purpura -linear purpura, hepatitis, sweat gland abscess, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis , meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis , pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis , prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendinitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, or vulvitis, B cell proliferative disorders (e.g., diffuse large B cell lymphoma), follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, acute lymphocytic leukemia, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma / Waldenström macroglobulinemia, splenic marginal zone lymphoma, multiple myeloma (also known as plasma cell myeloma), non-Hodgkin lymphoma, Hodgkin lymphoma, plasma cell tumor, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, mantle cell lymphoma , mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, Burkitt lymphoma / leukemia, or lymphomatoid granulomatosis, breast cancer, prostate cancer , or cancer of mast cells (e.g., mastocytoma, mast cell leukemia, mast cell sarcoma, systemic mastocytosis), bone cancer, colorectal cancer, pancreatic cancer, diseases of bone and joints (including, but not limited to, rheumatoid arthritis, seronegative spondyloarthritis (including ankylosing spondylitis, psoriatic arthritis, and Reiter's disease), Behçet's disease, Sjögren's syndrome, systemic sclerosis, osteoporosis , bone cancer, including bone metastases), thromboembolic disorders (e.g., myocardial infarction, angina pectoris, restenosis after angioplasty, reocclusion after coronary artery bypass grafting, reocclusion after coronary artery bypass grafting , restenosis after coronary artery bypass grafting, restenosis after coronary artery bypass grafting, restenosis after coronary artery bypass grafting , restenosis after coronary artery bypass grafting, restenosis after coronary artery bypass grafting, restenosis after coronary artery bypass grafting , restenosis after coronary artery bypass grafting, restenosis after coronary artery bypass grafting, restenosis after coronary artery bypass grafting , restenosis after coronary artery bypass grafting, restenosis after coronary artery bypass grafting, restenosis after coronary artery bypass grafting , but not limited to, rheumatoid arthritis, seronegative spondyloarthritis (including ankylosing spondylitis, psoriatic arthritis, and Reiter's disease), Behçet's disease, Sjögren's syndrome, systemic sclerosis, osteoporosis , including bone cancer, bone metastases), thromboembolic disorders (e.g., myocardial infarction, angina pectoris, restenosis after angioplasty, reocclusion after coronary artery bypass grafting, reocclusion after coronary artery bypass grafting , restenosis after coronary artery bypass grafting, restenosis after coronary artery bypass grafting, restenosis after coronary artery bypass grafting , restenosis after coronary artery bypass grafting, restenosis after coronary artery bypass grafting, restenosis after coronary artery bypass grafting Post-pass restenosis, stroke, transient ischemia, peripheral arterial occlusive disease, pulmonary embolism, deep venous blood thrombosis), inflammatory pelvic disease, urethritis, sunburn of the skin, sinusitis, pneumonitis, encephalitis, meningitis, heart disease Myositis, nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis, dermatitis, gingivitis, appendicitis, pancreatitis, gallbladder cholocystitus, agammaglobulinemia, psoriasis, allergies, cloaca Sjogren's disease, irritable bowel syndrome, ulcerative colitis, Sjogren's disease, tissue graft rejection, transplanted Hyperacute rejection of transplanted organs, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), autoimmune polyglandular disea se) (also known as polyglandular autoimmune syndrome), autoimmune alopecia, pernicious anemia, glomerular nephropathy inflammation, dermatomyositis, multiple sclerosis, scleroderma, vasculitis, autoimmune hemolytic states and autoimmune hematologic conditions Thrombocytopenic conditions, Goodpasture's syndrome, atherosclerosis, Addison's disease, Kinesiology, Alzheimer's disease, diabetes, septic shock, cutaneous lupus erythematosus, Systemic lupus erythematosus (SLE), rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, osteoarthritis Arthropathy, chronic idiopathic thrombocytopenic purpura, Waldenström's macroglobulinemia, Myasthenia gravis, Hashimoto's thyroiditis, atopic dermatitis, degenerative joint disease, vitiligo, autoimmune disorders Hypopituitarism, Guillain-Barré syndrome, Behcet's disease, scleroderma ma), mycosis fungoides, acute inflammatory responses (e.g., acute respiratory distress syndrome and ischemia / reperfusion injury), and Graves' disease.

[0221] In another embodiment, the present invention provides a method for treating or lessening the severity of a disease. administering to a patient in need thereof a compound of formula I or I' and a PI3K inhibitor comprising the step of, wherein the disease is cancer, neurodegenative disorder , angiogenesis disorder, viral disease, autoimmune disease, inflammatory disorder, hormone-related disease, organ transplantation-related condition, immunodeficiency disorder, destructive bone disorder, proliferative disorder, infectious disease, related to cell death condition, thrombin-induced platelet aggregation, chronic myelogenous leukemia (CML), chronic lymphocytic white blood disease (CLL), liver disease, pathological immune condition involving T cell activation, cardiovascular disorder, and CNS disorder, a method is provided.

[0222] In another embodiment, the present invention is a method of treating a disease or reducing its severity comprising the step of administering to a patient in need thereof a compound of formula I or I' and a PI3K inhibitor wherein the disease is 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 uteri, testis, urogenital tract, esophagus, larynx, skin, bone or thyroid, benign or malignant tumor, carcinoma or solid tumor, sarcoma, glioblastoma, neuroblastoma, multiple myeloma or gastrointestinal cancer, in particular, colon cancer or colorectal adenoma or head and neck tumor, epidermal hyperplasia, psoriasis, prostatic hyperplasia plasia, neoplasm, neoplasia of epithelial character racter), adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer, lymphoma (e.g., including non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (also called Hodgkin disease)), breast cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma , melanoma, or leukemia, Cowden syndrome, Lhermitte-Duclos disease (Lhermi ​ diseases including tte-Dudos disease and the Bannayan-Zonana syndrome, and also diseases in which the PI3K / PKB pathway is abnormally activated, all types or occurrences of asthma including both endogenous (non-allergic) asthma and exogenous (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchitic asthma, exercise-induced asthma, occupational asthma and asthma induced after bacterial infection, acute lung injury (ALI), adult / acute respiratory distress syndrome (ARDS S), chronic obstructive pulmonary disease, chronic obstructive airway disease or chronic obstructive lung disease (COPD, COAD or CO LD) (including chronic bronchitis or dyspnea associated therewith), emphysema, and exacerbation of airway hyperactivity as a result of other drug treatment (in particular, other inhaled drug treatments), all types or occurrences of bronchitis (including, but not limited to, acute, arachidonic acid, catarrhal, croupous (cr oupus), chronic or tuberculous bronchitis), all types or occurrences of pneumoconiosis (inflammatory, generally occupational lung diseases, whether chronic or acute, frequently accompanied by airway obstruction and caused by repeated inhalation of dust) (for example, aluminosis, anthracosis, asbestosis, calcinosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis), Löffler's syndrome, eosinophilic pneumonia, parasitic (in particular, metazoan) infestations (including tropical eosinophilia), allergic bronchopulmonary aspergillosis, polyarteritis nodosa (ch oupus), and also all types or occurrences of bronchitis (including, but not limited to, acute, arachidonic acid, catarrhal, croupous (cr oupus), chronic or tuberculous bronchitis), all types or occurrences of pneumoconiosis (inflammatory, generally occupational lung diseases, whether chronic or acute, frequently accompanied by airway obstruction and caused by repeated inhalation of dust) (for example, aluminosis, anthracosis, asbestosis, calcinosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis), Löffler's syndrome, eosinophilic pneumonia, parasitic (in particular, metazoan) infestations (including tropical eosinophilia), allergic bronchopulmonary aspergillosis, polyarteritis nodosa (ch oupus), and Eosinophilic granuloma and drug reaction (including Churg-Strauss syndrome), eosinophil-related disorders affecting the respiratory tract, psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity vasculitis, urticaria, bullous pemphigoid, lupus erythematosus, pemphisus, acquired epidermolysis bullosa, conjunctivitis, dry keratoconjunctivitis, and vernal conjunctivitis, diseases affecting the nose including allergic rhinitis, and inflammatory diseases in which an immune reaction is involved or which have an autoimmune component or etiology (including autoimmune hematological disorders (e.g., hemolytic anemia, aplastic anemia, erythroblastosis, and idiopathic thrombocytopenic purpura)), cutaneous lupus erythematosus, systemic lupus erythematosus, rheumatoid arthritis, polymyositis, chondritis, sclerodoma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Stevens-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), endocrine ophthalmopathy, Graves' disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), dry keratoconjunctivitis and vernal catarrh, interstitial pulmonary fibrosis, psoriatic arthritis and glomerulonephritis (with or without nephrotic syndrome (e.g., including idiopathic nephrotic syndrome or minimal change disease)), restenosis, cardiac hypertrophy, atherosclerotic arteriosclerosis, myocardial infarction, ischemic attack 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, a method is provided. selected from

[0223] ​In some embodiments, the present invention provides a method of treating a disease or reducing its severity comprising administering to a patient in need thereof a compound of formula I or I' 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 disorder associated with transplantation. 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 a solid tumor.

[0224] In some embodiments, the present invention provides a method of treating a disease or reducing its severity 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 disorder associated with transplantation. In some embodiments, the J H2-binding compound is a compound of formula I or I'. Other suitable JH2 domain-binding compounds include those described in WO2014074660A1, WO2014074661A1, WO2015089143A1, which are incorporated herein by reference in their entireties. Suitable JH1 domain-binding compounds include those described in WO2015131080A1, which is incorporated herein by reference in its entirety.

[0225] Compounds and compositions can be administered, in accordance with the methods of the invention, in any amount and by any route of administration, that is effective for treating or reducing the severity of an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a disorder associated with transplantation. The exact amount required will vary from subject to subject, depending on the species, age and general condition of the subject, the severity of the infection, the particular agent, the mode of its administration, and the like. The compounds of the invention are preferably formulated into unit dosage forms in order to facilitate administration and ensure uniform dosage. As used herein, the expression "unit dosage form" refers to physically discrete units suitable for the patient to be treated. However, it is to be understood that the total daily usage of the compounds and compositions of the invention will be decided by the attending physician within the scope of sound medical judgment. The effective dosage level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination with or concurrently with the specific compound employed, and like factors well known in the medical arts. As used herein, the term "patient" means an animal, preferably a mammal, and most preferably a human. For treating or reducing the severity of an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a disorder associated with transplantation, any amount and any route of administration can be used. The exact amount required will vary from subject to subject, depending on the species, age and general condition of the subject, the severity of the infection, the particular agent, the mode of its administration, and the like. The compounds of the invention are preferably formulated into unit dosage forms in order to facilitate administration and ensure uniform dosage. As used herein, the expression "unit dosage form" refers to physically discrete units suitable for the patient to be treated. However, it is to be understood that the total daily usage of the compounds and compositions of the invention will be decided by the attending physician within the scope of sound medical judgment. The effective dosage level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination with or concurrently with the specific compound employed, and like factors well known in the medical arts. As used herein, the term "patient" means an animal, preferably a mammal, and most preferably a human. The pharmaceutically acceptable compositions of this invention can be administered to humans and other animals, orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), buccally, by oral spray or transdermally, depending on the severity of the infection being treated. For treating or reducing the severity of an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a disorder associated with transplantation, any amount and any route of administration can be used. The exact amount required will vary from subject to subject, depending on the species, age and general condition of the subject, the severity of the infection, the particular agent, the mode of its administration, and the like. The compounds of the invention are preferably formulated into unit dosage forms in order to facilitate administration and ensure uniform dosage. As used herein, the expression "unit dosage form" refers to physically discrete units suitable for the patient to be treated. However, it is to be understood that the total daily usage of the compounds and compositions of the invention will be decided by the attending physician within the scope of sound medical judgment. The effective dosage level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination with or concurrently with the specific compound employed, and like factors well known in the medical arts. As used herein, the term "patient" means an animal, preferably a mammal, and most preferably a human.

[0226] The pharmaceutically acceptable compositions of this invention can be administered to humans and other animals, orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), buccally, by oral spray or transdermally, depending on the severity of the infection being treated. For treating or reducing the severity of an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a disorder associated with transplantation, any amount and any route of administration can be used. The exact amount required will vary from subject to subject, depending on the species, age and general condition of the subject, the severity of the infection, the particular agent, the mode of its administration, and the like. It can be administered as a nasal spray or the like. In certain embodiments, the compound of the present invention is administered once or multiple times a day at a dosage level of about 0.01 mg to about 50 mg, preferably about 1 mg to about 25 mg per kg of the subject's body weight per day in order to obtain the desired therapeutic effect, either orally or parenterally.

[0227] 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, for example, inert diluents commonly used in the art such as water or other solvents, solubilizing agents, and emulsifying agents, for example, 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 the inert diluent, oral compositions may also contain adjuvants such as wetting agents, emulsifying agents, and suspending agents, as well as sweetening agents, flavoring and odor-masking agents, and fragrances.

[0228] Injectable preparations, for example, sterile aqueous or oily suspensions for injection, may be formulated by known techniques using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations are sterile solutions, suspensions, or emulsions in a non-toxic parenterally acceptable diluent or solvent for injection. or an emulsion, for example, it may be in the form of a solution in 1,3 - butanediol. For use Among the acceptable vehicles and solvents that can be used are water, Ringer's solution, U.S .P., and isotonic sodium chloride solution. Furthermore, sterile fixed oils have been conventionally used as solvents or suspension media. For this purpose, any non - irritating fixed oil containing synthetic monoglycerides or diglycerides can be used. Furthermore, any fatty acid such as oleic acid is used in the preparation of injectable substances.

[0229] Injectable preparations can be sterilized before use, for example, by filtration through a bacteria - retaining filter or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable media.

[0230] To prolong the effect of the compounds of the present invention, it is often desirable to slow the absorption of the compounds from subcutaneous or intramuscular injections. This can be achieved by using a liquid suspension of a poorly water - soluble crystalline or amorphous material. Then, the absorption rate of the compound depends on its dissolution rate, while the dissolution rate can depend on the crystal size and crystal form. Alternatively, delayed absorption of the compound in the form administered parenterally is achieved by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are prepared by forming a microcapsule matrix of the compound within a biodegradable polymer such as polylactide - polyglycolide. Depending on the ratio of the compound to the polymer and the properties of the specific polymer used, the compound release rate can be controlled. Examples of other biodegradable polymers include poly(orthoesters ) and poly(anhydrides). Depot injection formulations are also prepared by entrapping the compounds within liposomes or microemulsions that are compatible with body tissues.

[0231] Compositions for rectal or vaginal administration preferably contain the compounds of the invention in a solid form at ambient temperature but liquid at body temperature, and thus melting within the rectum or vaginal cavity to release the active compound Suppositories that can be prepared by mixing with a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol or suppository wax.

[0232] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is combined with at least one inert pharmaceutically acceptable excipient or carrier such as sodium citrate or calcium phosphate, and / or a) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrants such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) dissolution retarders such as paraffin, f) absorption promoters such as quaternary ammonium compounds, g) wetting agents 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 glycol, and la Mix with lubricants such as sodium urilsulfate and mixtures thereof. For capsule formulations, in the case of tablets and pills, the dosage form may contain a buffering agent.

[0233] Similar types of solid compositions can be used as fillers for soft and hard filled gelatin capsules using excipients such as lactose and lactose and high molecular weight polyethyl ene glycol. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings and other coatings well known in the technical field of pharmaceutical formulation. These may contain an opacifying agent if necessary, and can also be made into compositions that release the active ingredient(s) only in or preferentially in a specific part of the intestinal tract in a delayed manner if necessary. Examples of implantable compositions that can be used include polymeric substances and waxes. Similar types of solid compositions can be used as fillers for soft and hard filled gelatin capsules using excipients such as lactose or lactose and high molecular weight polyethylene glycol. The active compound can be obtained in microencapsulated form with one or more of the above excipients. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings, release control coatings and other coatings well known in the technical field of pharmaceutical formulation. In such solid dosage forms, the active compound may be mixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms, as in the case of normal practice, in addition to the inert diluent can be used.

[0234] The active compound is obtained in microencapsulated form with one or more of the above excipients. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings, release control coatings and other coatings well known in the technical field of pharmaceutical formulation. In such solid dosage forms, the active compound may be mixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms, as in the case of normal practice, in addition to the inert diluent can be prepared using coatings and shells. In such solid dosage forms, the active compound may be mixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms, as in the normal practice, in addition to the inert diluent can be used. Additional substances outside, such as tabletting lubricants and magnesium stearate and microcrystalline cellulose and other tabletting aids may be included. In the case of capsules, tablets and pills, the dosage form may contain a buffering agent. These may contain an opacifying agent if necessary, and may also be compositions that release the active ingredient(s) only or preferentially in a specific portion of the intestinal tract in a delayed manner if necessary. Examples of implantable compositions that can be used include polymeric substances and waxes.

[0235] As dosage forms for topical or transdermal administration of the compounds of this invention, ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches are included. The active ingredient is mixed, if necessary, with a pharmaceutically acceptable carrier and any necessary preservative or buffer solution under sterile conditions. Ophthalmic preparations, ear drops, and eye drops are also contemplated to be within the scope of this invention. Further, the invention contemplates the use of transdermal patches, which have the additional advantage of providing controlled delivery of the compound to the body. Such dosage forms can be prepared by dissolving or dispersing the compound in a suitable medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. This rate can be

[0236] According to one embodiment, the invention is a method of inhibiting protein kinase activity in a biological sample, the method comprising contacting the biological sample with a compound A method comprising the step of contacting with a composition comprising

[0237] According to another embodiment, the present invention provides a method for inhibiting the activity of TYK2 or a variant thereof in a biological sample, the method comprising contacting the biological sample with a compound of the present invention or a composition comprising said compound. According to certain embodiments, the present invention provides a method for irreversibly inhibiting the activity of TYK2 or a variant thereof in a biological sample, the method comprising contacting the biological sample with a compound of the present invention or a composition comprising said compound. According to certain embodiments, the present invention provides a method for irreversibly inhibiting the activity of TYK2 or a variant thereof in a biological sample, the method comprising contacting the biological sample with a compound of the present invention or a composition comprising said compound. In certain embodiments, the present invention provides a method for irreversibly inhibiting the activity of TYK2 or a variant thereof in a biological sample, the method comprising contacting the biological sample with a compound of the present invention or a composition comprising said compound. In certain embodiments, the present invention provides a method for irreversibly inhibiting the activity of TYK2 or a variant thereof in a biological sample, the method comprising contacting the biological sample with a compound of the present invention or a composition comprising said compound. In certain embodiments, the present invention provides a method for irreversibly inhibiting the activity of TYK2 or a variant thereof in a biological sample, the method comprising contacting the biological sample with a compound of the present invention or a composition comprising said compound.

[0238] 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, the compounds of the present invention are more than 2-fold selective for TYK2 over JAK1 / 2 / 3. In some embodiments, the compounds of the present invention are more than 5-fold selective for TYK2 over JAK1 / 2 / 3. In some embodiments, the compounds of the present invention are more than 10-fold selective for TYK2 over JAK1 / 2 / 3. In some embodiments, the compounds of the present invention are more than 50-fold selective for TYK2 over JAK1 / 2 / 3. In some embodiments, the compounds of the present invention are more than 10-fold selective for TYK2 over JAK1 / 2 / 3. In some embodiments, the compounds of the present invention are more than 50-fold selective for TYK2 over JAK1 / 2 / 3. In some embodiments, the compounds of the present invention are more than 10-fold selective for TYK2 over JAK1 / 2 / 3. In some embodiments, the compounds of the present invention are more than 50-fold selective for TYK2 over JAK1 / 2 / 3. In some embodiments, the compounds of the present invention are more than 10-fold selective for TYK2 over JAK1 / 2 / 3. In some embodiments, the compounds of the present invention are more than 50-fold selective for TYK2 over JAK1 / 2 / 3. In some embodiments, the compounds of the present invention are more than 10-fold selective for TYK2 over JAK1 / 2 / 3. In some embodiments, the compounds of the present invention are more than 50-fold selective for TYK2 over JAK1 / 2 / 3. In some embodiments, the compounds of the present invention are more than 10-fold selective for TYK2 over JAK1 / 2 / 3. In some embodiments, the compounds of the present invention are more than 50-fold selective for TYK2 over JAK1 / 2 / 3. In some embodiments, the compounds of the present invention are more than 100-fold selective for TYK2 over JAK1 / 2 / 3.

[0239] As used herein, the term "biological sample" includes, but is not limited to, cell cultures or extracts thereof; biopsy materials or extracts thereof obtained from mammals; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof. As used herein, the term "biological sample" includes, but is not limited to, cell cultures or extracts thereof; biopsy materials or extracts thereof obtained from mammals; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof. As used herein, the term "biological sample" includes, but is not limited to, cell cultures or extracts thereof; biopsy materials or extracts thereof obtained from mammals; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.

[0240] Inhibition of the activity of TYK2 (or a variant thereof) in a biological sample is useful for various purposes known to those skilled in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ transplantation, preservation of biological specimens, and biological assays. Another embodiment of the invention is a method of inhibiting protein kinase activity in a patient, comprising administering to the patient a compound of the invention, or a composition comprising said compound. Another embodiment according to the invention is a method of inhibiting the activity of TYK2, or a variant thereof, in a patient, comprising administering to the patient a compound of the invention, or a composition comprising said compound. According to certain embodiments, the invention relates to a method of reversibly or irreversibly inhibiting the activity of one or more of TYK2, or a variant thereof, in a patient, comprising administering to the patient a compound of the invention, or a composition comprising said compound. In other embodiments, the invention provides a method of treating a disorder mediated by TYK2, or a variant thereof, in a patient in need thereof, comprising administering to the patient a compound according to the invention, or a pharmaceutically acceptable composition thereof. Such disorders are described in detail herein.

[0241] Depending on the particular condition or disease being treated, additional therapeutic agents normally administered to treat that condition may also be present in the compositions of this invention. As used herein,

[0242]

[0243] ​​​​​​​​​​​​​​Additional therapeutic agents that are commonly administered to treat a disorder, or condition, are known as being "appropriate for the disorder, or condition being treated."

[0244] The compounds of the invention may also be advantageously used in combination with other therapeutic compounds. In some embodiments, the other therapeutic compound is an anti-proliferative compound. Such anti-proliferative compounds include, but are not limited to, aromatase inhibitors; anti-estrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule-active compounds; alkylating compounds; histone deacetylase inhibitors; compounds that induce cell differentiation processes; cyclooxygenase inhibitors ; MMP inhibitors; mTOR inhibitors; anti-tumor antimetabolites; platinum compounds; compounds that target / reduce protein kinase activity or lipid kinase activity and additional anti-angiogenic compounds; compounds that target, reduce or inhibit the activity of protein phosphatase or lipid phosphatase; gonadorelin agonists; anti-androgens; methionine aminopeptidase inhibitors; matrix metalloproteinase inhibitors; bisphosphonates; biological response modifiers; anti-proliferative antibodies; heparanase inhibitors; inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasome inhibitors; compounds used in the treatment of hematological malignancies; compounds that target, reduce or inhibit the activity of Flt-3; Hsp90 inhibitors (e.g., 17-AAG (17-allylaminogeldanamycin, NSC330507), 17-DMAG (17-dimethylaminoethylamino-17- demethoxy-geldanamycin, NSC707545), IPI-504, CNF101 ​0, CNF2024, CNF1010 (manufactured by Conforma Therapeutics )); Temozolomide (Temodal (registered trademark)); Kinesin spindle protein inhibitor (e.g., SB715992 or SB743921 (manufactured by GlaxoSmithKline ), or pentamidine / chlorpromazine (manufactured by CombinatoRx)); MEK inhibitor (e.g., ARRY142886 (manufactured by Array BioPharma), AZD 6244 (manufactured by AstraZeneca), PD181461 (manufactured by Pfizer) and ro icobolin) are included. The term "aromatase inhibitor" as used in this specification refers to a compound that inhibits estrogen production, e.g., the conversion of the substrates androstenedione and test osterone to estrone and estradiol, respectively. This term includes, but is not limited to, steroids, especially, atamestane, exemestane and formestane, and particularly, non-steroids, especially, amino glutethimide, logestimide, pyridoglutethimide, trilostane, testolactone, ke toconazole, vorozole, fadrozole, anastrozole and letrozole. Exemestane is commercially available under the trade name Aromasin (trademark). Fo lvestane is commercially available under the trade name Lentaron (trademark). Fadrozole is commercially available under the trade name Afema (trademark). Anastrozole is commercially available under the trade name Arimidex (trademark). Letrozole is commercially available under the trade name Femar a (trademark) or Femar (trademark). Aminoglutethimide is commercially available under the trade name Orimeten (trademark). A compound that is an aromatase inhibitor is commercially available under the trade name Orimeten (trademark). A compound that is an aromatase inhibitor is commercially available under the trade name Orimeten (trademark). Compounds that are aromatase inhibitors The combination of the present invention comprising a chemotherapeutic agent is particularly useful for the treatment of hormone receptor positive tumors, such as breast tumors.

[0245] As used herein, the term "anti - estrogen" relates to a compound that antagonizes the effects of estrogen at the estrogen receptor level. This term includes, but is not limited to, tamoxifen, fulvestrant, raloxifene and raloxifene hydrochloride. Tamoxifen is marketed under the trade name Nolvadex™. Raloxifene hydrochloride is marketed under the trade name Evista™. Fulvestrant can be administered under the trade name Faslodex™. The combination of the present invention comprising a chemotherapeutic agent that is an anti - estrogen is particularly useful for the treatment of estrogen receptor positive tumors, such as breast tumors.

[0246] As used herein, the term "anti - androgen" relates to any substance capable of inhibiting the biological effects of androgens, including but not limited to bicalutamide (Casodex™). The term "gonadorelin agonist" as used herein includes, but is not limited to, abarelix, goserelin and goserelin acetate. Goserelin can be administered under the trade name Zoladex™.

[0247] As used herein, the term "topoisomerase I inhibitor" includes, but is not limited to, topotecan, gemitecan, irinotecan, camptothecin (camp to thecian) and its analogs, 9-nitrocamptothecin and polymeric camptothecin conjugates such as PNU-166148. Irinotecan can be administered, for example, under the trademark of C amptosar (trademark), for example, in a commercially available form. Topotecan is commercially available under the trade name Hycamptin (trademark).

[0248] As used herein, the term "topoisomerase II inhibitor" includes, but is not limited to, anthracyclines (e.g., liposomal formulations such as doxorubicin (Caelyx (trademark))), daunorubicin, epirubicin, idarubicin, and nemorubicin, mitoxantrone and losoxantrone which are anthraquinones, and etoposide and teniposide which are podophyllotoxins. Etoposide is commercially available under the trade name Etopophos (trademark). Teniposide is commercially available under the trade name VM 2 6-Bristol. Doxorubicin is commercially available under the trade name Acribla stin (trademark) or Adriamycin (trademark). Epirubicin is commercially available under the trade name Farmorubicin (trademark). Idarubicin is commercially available under the trade name Zavedos (trademark). Mitoxantrone is commercially available under the trade name Novantron.

[0249] The term "microtubule active agent" relates to, but is not limited to, microtubule stabilizing compounds, microtubule destabilizing compounds, and microtubulin polymerization inhibitors, and includes taxanes such as paclitaxel and docetaxel; vinca alkaloids, ​​​​​​​​​​​​​For example, vincblastine or vinblastine sulfate, vincristine or vincristine sulfate, and vinorelbine; discodermolide; colchicine ; and epothilone and derivatives thereof. Paclitaxel is marketed under the trade name Taxol . Docetaxel is marketed under the trade name Taxotere (trademark). Vinblastine sulfate is marketed under the trade name Vinblastin R.P (trademark). Vincristine sulfate is marketed under the trade name Farmistin (trademark).

[0250] As used herein, the term "alkylating agent" is not limited to these, but includes cyclophosphamide, ifosfamide, melphalan or nitrosourea (BCNU or Gliadel). Cyclophosphamide is marketed under the trade name Cyclostin (trademark). Ifosfamide is marketed under the trade name Holoxan (trademark).

[0251] The term "histone deacetylase inhibitor" or "HDAC inhibitor" relates to a compound that inhibits histone deacetylase and has anti-proliferative activity. This includes, but is not limited to suberoylanilide hydroxamic acid (SAHA).

[0252] The term "antineoplastic antimetabolite" is not limited to these, but includes 5-fluorouracil i.e., 5-FU, capecitabine, gemcitabine, DNA demethylating compounds (e.g., 5-azacitidine and decitabine), methotrexate and edatrexate, and ​​It contains a folic acid antagonist (e.g., pemetrexed). Capecitabine is marketed under the trade name X under the trade name eloda (trademark). Gemcitabine is marketed under the trade name Gemzar (trademark).

[0253] The term "platin compound" as used herein includes, but is not limited to, carboplatin, cisplatin, cisplatinum and oxaliplatin. Carboplatin can be administered, for example, in a commercially available form under the trademark Carboplat (trademark). Oxaliplatin can be administered, for example, in a commercially available form under the trademark Eloxatin (trademark). (trademark). (trademark).

[0254] "Compound that targets / reduces the activity of protein kinase or lipid kinase; or compound that targets / reduces the activity of protein phosphatase or lipid phosphatase; or further anti-angiogenic compound" as used herein includes, but is not limited to, protein tyrosine kinase and / or serine and / or threonine kinase inhibitors, or lipid kinase inhibitors, for example, a) a compound that targets, reduces or inhibits the activity of platelet-derived growth factor receptor (PDGFR) (e.g., a compound that targets, reduces or inhibits the activity of PDGFR, especially a compound that inhibits the PDGF receptor, such as an N-phenyl-2-pyrimidine- amine derivative, such as imatinib, SU101, SU6668 and GFB-111) ; b) a compound that targets, reduces or inhibits the activity of fibroblast growth factor receptor (FGFR) (e.g., a compound that targets, reduces or inhibits the activity of FGFR, especially a compound that inhibits the FGFR, such as an N-phenyl-2-pyrimidine- amine derivative, such as imatinib, SU101, SU6668 and GFB-111) ; c) a compound that targets, reduces or inhibits the activity of vascular endothelial growth factor receptor (VEGFR) (e.g., a compound that targets, reduces or inhibits the activity of VEGFR, especially a compound that inhibits the VEGFR, such as an N-phenyl-2-pyrimidine- amine derivative, such as imatinib, SU101, SU6668 and GFB-111)​ Compounds that are harmful; c) Targeting the activity of insulin-like growth factor receptor I (IGF-IR) Compounds that reduce or inhibit it (e.g., compounds that target, reduce or inhibit the activity of IGF-IR, particularly compounds that inhibit the kinase activity of the IGF-I receptor, or antibodies that target the extracellular domain of the IGF-I receptor or its growth factor); d ) Compounds that target, reduce or inhibit the activity of the Trk receptor tyrosine kinase family, or ephrin B4 inhibitors; e) Compounds that target, reduce or inhibit the activity of the AxI receptor tyrosine kinase family; f) Compounds that target, reduce or inhibit the activity of the Ret receptor tyrosine kinase; g) Compounds that target, reduce or inhibit the activity of the Kit / SC FR receptor tyrosine kinase, for example, imatinib; h) Compounds that target, reduce or inhibit the activity of the C-kit receptor tyrosine kinase, which is part of the PDGFR family (e.g., compounds that target, reduce or inhibit the activity of the c-Kit receptor tyrosine kinase family, particularly compounds that inhibit the c-Kit receptor, for example, imatinib); i) Compounds that target, reduce or inhibit the activity of members of the c-A bl family, their gene fusion products (e.g., BCR-Abl kinase ) and mutants (e.g., compounds that target, reduce or inhibit the activity of c-A bl family members and their gene fusion products, reduce or inhibit compounds, for example, N-phenyl-2-pyrimidin-amine derivatives, for example imatinib or nilotinib (AMN107); PD180970; AG957; NS ) or inhibit compounds, for example, imatinib or nilotinib (AMN107); PD180970; AG957; NS ; ​​C 680410; PD173955 (manufactured by Parke Davis); or dasatinib ( BMS-354825)); j) a compound that targets, reduces or inhibits the activity of members of the serine / threonine kinase protein kinase C ( PKC) and the Raf family, MEK, SRC, JAK / pan-JAK, FA K, PDK1, PKB / Akt, Ras / MAPK, PI3K, SYK, BTK and T EC family members, and / or members of the cyclin-dependent kinase family (C DK), such as compounds that target, reduce or inhibit the activity of staurosporine derivatives, for example, including midostaurin; further examples of compounds include UC N-01, safingol, BAY 43-9006, bryostatin 1, perifosine; ilmofosine; RO 318220 and RO 320432 ; GO 6976; lsis 3521; LY333531 / LY379196; iso quinoline compounds; FTI; PD184352 or QAN6 97 (PI3K inhibitor) or AT7519 (CDK inhibitor); k) a compound that targets, reduces or inhibits the activity of protein -tyrosine kinase inhibitors, for example, compounds that target, reduce or inhibit the activity of protein-tyrosine kinase inhibitors are imatinib mesylate (Gleevec (trademark)) or tyrphostin ( for example, tyrphostin A23 / RG-50810; AG 99; tyrphostin AG 213; tyrphostin AG 1748; tyrphostin AG 490; tyrphostin B4 4; tyrphostin B44 (+) enantiomer; tyrphostin AG 555; AG 494; tyrphostin AG 556, AG957) and adafostin (4-{[(2,5-dih ydroxybenzyl)amino]methyl}-2-methoxyphenol); hydroxybenzyl)amino]methyl}-2-methoxyphenol); {[3-(4-Dimethylaminophenyl)-3-(4-hydroxyphenyl)propyl]amino}-benzoic acid adamantyl ester; NSC 680 410, including adafostin; l) a compound that targets, reduces or inhibits the activity of receptor tyrosine kinases of the epidermal growth factor family -(as a homodimer or heterodimer, EGFR1ErbB2, ErbB3, E rbB4) and their variants, or a compound that reduces or inhibits the activity thereof For example, a compound that targets, reduces or inhibits the activity of the epidermal growth factor receptor family, in particular, a compound that inhibits members of the EGF receptor tyrosine kinase family, such as the EGF receptor, ErbB2, ErbB3 and ErbB4, or a compound, protein or antibody that binds to EGF or an EGF-related ligand (e.g., CP 358774, ZD 1839, ZM 105180; trastuzumab (Hercep tin (trademark)), cetuximab (Erbitux (trademark)), Iressa, Tarc eva, 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) a compound that targets, reduces or inhibits the activity of the c-Met receptor, e.g., a compound that targets, reduces or inhibits the activity of c-Met In particular, a compound that inhibits the kinase activity of the c-Met receptor, or an antibody that targets the extracellular domain of c-Met or binds to HGF, n) a compound that targets, reduces or inhibits the kinase activity of one or more JAK family members (JAK1 / JAK2 / JAK3 / TYK2 and / or pan-JAK) or reduces the same ; or a compound that targets the extracellular domain of c-Met or binds to HGF, n) a compound that targets, reduces or inhibits the kinase activity of one or more JAK family members (JAK1 / JAK2 / JAK3 / TYK2 and / or pan-JAK) and / or reduces the same ; or a compound that targets, reduces or inhibits the kinase activity of one or more JAK family members (JAK1 / JAK2 / JAK3 / TYK2 and / or pan-JAK) or compounds that inhibit (including, but not limited to, PRT-062070, SB-157 8, baricitinib, pacritinib, momelotinib, VX-509, AZD-1480, T G-101348, tofacitinib, and ruxolitinib); o) compounds that target, reduce, or inhibit the kinase activity of phosphatidylinositol 3-kinase (PI3K) (including, but not limited to, ATU-027, SF-1126, DS-7423, PBI-052 04, GSK-2126458, ZSTK-474, buparlisib, pictilisib, P F-4691502, BYL-719, dactolisib, XL-147, XL-765, and idelalisib); and q) compounds that target, reduce, or inhibit the signaling effect of the hedgehog protein (Hh) or smoothened receptor (SMO) pathway (including, but not limited to, cyclopamine, vismodegib, itraconazole, erismodegib, and IPI-926 (saridegib)). The term "PI3K inhibitor" as used herein includes, but is not limited to, compounds having inhibitory activity against one or more enzymes of the phosphatidylinositol-3-kinase family (including, but not limited to, PI3Kα, PI3Kγ, PI3Kδ, PI3Kβ, PI3 K-C2α, PI3K-C2β, PI3K-C2γ, Vps34, p110-α, p11 0-β, p110-γ, p110-δ, p85-α, p85-β, p55-γ, p150 (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 this invention include, but are not limited to, ATU-027, S

[0255] (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 this invention include, but are not limited to, ATU-027, S K-C2α, PI3K-C2β, PI3K-C2γ, Vps34, p110-α, p110-β, p110-γ, p110-δ, p85-α, p85-β, p55-γ, p150 0-β, p110-γ, p110-δ, p85-α, p85-β, p55-γ, p150 F-4691502, BYL-719, dactolisib, XL-147, XL-765, and F-1126, DS-7423, PBI-05204, GSK-2126458, ZST K-474, Buparlisib, Pictilisib, PF-4691502, BYL-719, Dactolisib, XL-147, XL-765, and Idelalisib are included.

[0256] The term "BTK inhibitor", as used herein, is not limited to these but includes compounds having inhibitory activity against Bruton's tyrosine kinase (BTK) (including, but not limited to, AVL-292 and Ibrutinib).

[0257] The term "SYK inhibitor", as used herein, is not limited to these but includes compounds having inhibitory activity against spleen tyrosine kinase (SYK) (including, but not limited to, PRT-062070, R-343, R-333, Excelellair, PRT-062607, and fostamatinib).

[0258] The term "Bcl-2 inhibitor", as used herein, is not limited to these but includes compounds having inhibitory activity against B-cell lymphoma 2 protein (Bcl-2) (including, but not limited to, ABT-199, ABT-731, ABT-737, apogossypol, Ascenta's pan Bcl-2 inhibitor, curcumin (and its analogs), dual Bcl-2 / Bcl-xL inhibitor (Infinity Pharmaceuticals / Novartis Pharmaceuticals), Genasense (G3139), HA14-1 (and its analogs; see WO2008118802), navitoclax (and ) ​ its analog, see US7390799), NH-1 (Shenayng Ph armaceutical University), obatoclax (and its a nalog, see WO2004106328), S-001 (Gloria Pha rmaceuticals), TW series of compounds (Univ.of Michigan) , and venetoclax). In some embodiments, the Bcl-2 inhibitor is a small molecule therapeutic agent. In some embodiments, the Bcl-2 inhibitor is a peptidomimetic .

[0259] Examples of BTK inhibitory compounds and conditions treatable by such compounds in combination with the compounds of this invention can be found in WO200 8039218 and WO2011090760, which are incorporated herein by reference in their entirety.

[0260] Examples of SYK inhibitory compounds and conditions treatable by such compounds in combination with the compounds of this invention can be found in WO200 3063794, WO2005007623, and WO2006078846, which are incorporated herein by reference in their entirety.

[0261] Examples of PI3K inhibitory compounds and conditions treatable by such compounds in combination with the compounds of this invention can be found in WO20 04019973, WO2004089925, WO2007016176, US813 8347, WO2002088112, WO2007084786, WO2007129 161, WO2006122806, WO2005113554, and WO20070 161, which are incorporated herein by reference in their entirety. It can be found in 44729.

[0262] JAK inhibitory compounds, and further examples of conditions treatable by such compounds in combination with the compounds of the present invention are WO200 9114512, WO2008109943, WO2007053452, WO2000 142246, and WO2007070514, which are incorporated herein by reference in their entirety. It can be found in 142246, and WO2007070514.

[0263] As further anti-angiogenic compounds, compounds having a different mechanism of action for their activity, for example, a mechanism not related to protein kinase inhibition or lipid kinase inhibition, such as thalidomide (Thalomid™) and TNP-470 can be mentioned.

[0264] Examples of proteasome inhibitors useful for use in combination with the compounds of the present invention include, but are not limited to, bortezomib, disulfiram, epigallocatechin -3-gallate (EGCG), salinosporamide A, carfilzomib, ONX-091 2, CEP-18770, and MLN9708. It can be found in 2, CEP-18770, and MLN9708.

[0265] Compounds that target, reduce or inhibit the activity of protein phosphatase or lipid phosphatase are, for example, inhibitors of phosphatase 1, inhibitors of phosphatase 2A, or inhibitors of CDC25 (e.g., okadaic acid or its derivatives).

[0266] Compounds that induce the cell differentiation process include, but are not limited to, retinoic acid, α-tocopherol, γ-tocopherol or δ-tocopherol, or α-toco Examples include trienol, γ-tocotrienol, or δ-tocotrienol.

[0267] As used herein, the term "cyclooxygenase inhibitor" includes, but is not limited to, Cox-2 inhibitors, 5-alkyl-substituted 2-arylaminophenylacetic acids and derivatives thereof, such as celecoxib (Celebrex™), rofecoxib (Vioxx™), etoricoxib, valdecoxib, or 5-alkyl-2-arylaminophenylacetic acids, such as 5-methyl-2-(2'-chloro-6'-fluoroanilino)phenylacetic acid, lumiracoxib.

[0268] As used herein, the term "bisphosphonate" includes, but is not limited to, etidronic acid, clodronic acid, tiludronic acid, pamidronic acid, alendronic acid, ibandronic acid, risedronic acid, and zoledronic acid. Etidronic acid is commercially available under the trade name Didronel™. Clodronic acid is commercially available under the trade name Bonefos™. Tiludronic acid is commercially available under the trade name Skelid™. Pamidronic acid is commercially available under the trade name Aredia™. Alendronic acid is commercially available under the trade name Fosamax™. Ibandronic acid is commercially available under the trade name Bondranat™. Risedronic acid is commercially available under the trade name Actonel™. Zoledronic acid is commercially available under the trade name Zometa™. The term "mTOR inhibitor" inhibits the mammalian target of rapamycin (mTOR) and has antiproliferative activity. Compounds such as sirolimus (Rapamune®), everolimus (Certican®), CCI-779, and ABT578 are relevant. rtican®), CCI-779, and ABT578.

[0269] As used herein, the term "heparanase inhibitor" refers to a compound that targets, reduces, or inhibits the degradation of heparan sulfate. This term includes, but is not limited to, PI-88. As used herein, the term "biological response modifier" refers to a lymphokine or interferon. As used herein, the term "inhibitor of Ras oncogenic isoforms" (e.g., H-Ras, K-Ras, or N-Ras) refers to a compound that targets, reduces, or inhibits the oncogenic activity of Ras; for example, "farnesyltransferase inhibitors" such as L-744832, DK8G557, or R115777 (Zarnestra®). As used herein, the term "telomerase inhibitor" refers to a compound that targets, reduces, or inhibits the activity of telomerase.

[0270] Compounds that target, reduce, or inhibit the activity of telomerase include, in particular, compounds that inhibit the telomerase receptor, such as telomestatin. As used herein, the term "methionine aminopeptidase inhibitor" refers to a compound that targets, reduces, or inhibits the activity of methionine aminopeptidase. Examples of compounds that target, reduce, or inhibit the activity of methionine aminopeptidase include, but are not limited to, bengamide or its derivatives. or R115777 (Zarnestra®). As used herein, the term "telomerase inhibitor" refers to a compound that targets, reduces, or inhibits the activity of telomerase. Compounds that target, reduce, or inhibit the activity of telomerase include, in particular, compounds that inhibit the telomerase receptor, such as telomestatin. Compounds that target, reduce, or inhibit the activity of telomerase include, in particular, compounds that inhibit the telomerase receptor, such as telomestatin. Compounds that target, reduce, or inhibit the activity of telomerase include, in particular, compounds that inhibit the telomerase receptor, such as telomestatin.

[0271] As used herein, the term "methionine aminopeptidase inhibitor" refers to a compound that targets, reduces, or inhibits the activity of methionine aminopeptidase. Compounds that target, reduce, or inhibit the activity of methionine aminopeptidase include, in particular, compounds that inhibit the telomerase receptor, such as telomestatin. Compounds that target, reduce, or inhibit the activity of methionine aminopeptidase include, in particular, compounds that inhibit the telomerase receptor, such as telomestatin. Examples of compounds that target, reduce, or inhibit the activity of methionine aminopeptidase include, but are not limited to, bengamide or its derivatives.

[0272] As used herein, the term "proteasome inhibitor" refers to a compound that targets, reduces or inhibits the activity of the proteasome. Examples of compounds that target, reduce or inhibit the activity of the proteasome include, but are not limited to, bortezomib (Velcade (trademark)) and MLN 341. As used herein, the term "matrix metalloproteinase inhibitor" or ("MMP" inhibitor) includes, but is not limited to, collagen peptide mimetics and non-peptide mimetic inhibitors, tetracycline derivatives (e.g., hydroxamate peptide mimetic inhibitors batimastat and its orally bioavailable analog marimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551), BMS-279251, BAY 12-9566, TAA211, MMI270B or AAJ996). As used herein, the term "compound for use in the treatment of hematological malignancies" includes, but is not limited to, FMS-like tyrosine kinase receptor (Flt-3R) inhibitors, which are compounds that target, reduce or inhibit the activity of Flt-3R; interferons, 1-β-D-arabinofuranosylcytosine (ara-c) and busulfan; ALK inhibitors, which are compounds that target, reduce or inhibit the activity of anaplastic lymphoma kinase, and Bcl-2 inhibitors.

[0273]

[0274]

[0275] Compounds that target, reduce or inhibit the activity of the FMS-like tyrosine kinase receptor (Flt-3R) are, in particular, compounds, proteins or antibodies that inhibit members of the Flt-3R receptor-type kinase family, such as PKC412, midostaurin, staurosporine derivatives, SU11248 and MLN518. The term "HSP90 inhibitor", as used herein, includes, but is not limited to, compounds that target, reduce or inhibit the endogenous ATPase activity of HSP90; compounds that target, reduce or inhibit the degradation of HSP90 client proteins via the ubiquitin-proteasome pathway. Compounds that target, reduce or inhibit the endogenous ATPase activity of HSP90 are, in particular, compounds, proteins or antibodies that inhibit the ATPase activity of HSP90, such as 17-allylamino,17-demethoxygeldanamycin (17AAG), geldanamycin derivatives; other geldanamycin-related compounds; radicicol and HDAC inhibitors. The term "anti-proliferative antibody", as used herein, includes, but is not limited to, trastuzumab (Herceptin (trademark)), trastuzumab-DM1, erbitux, bevacizumab (Avastin (trademark)), rituximab (Rituxan (registered trademark)), PRO64553 (anti-CD40) and 2C4 antibody. An antibody refers to an intact monoclonal antibody, a polyclonal antibody, a multispecific antibody formed from at least two intact antibodies, and as long as it exhibits the desired biological activity.

[0276] The term "HSP90 inhibitor", as used herein, includes, but is not limited to, compounds that target, reduce or inhibit the endogenous ATPase activity of HSP90; compounds that target, reduce or inhibit the degradation of HSP90 client proteins via the ubiquitin-proteasome pathway. Compounds that target, reduce or inhibit the endogenous ATPase activity of HSP90 are, in particular, compounds, proteins or antibodies that inhibit the ATPase activity of HSP90, such as 17-allylamino,17-demethoxygeldanamycin (17AAG), geldanamycin derivatives; other geldanamycin-related compounds; radicicol and HDAC inhibitors. The term "HSP90 inhibitor", as used herein, includes, but is not limited to, compounds that target, reduce or inhibit the endogenous ATPase activity of HSP90; compounds that target, reduce or inhibit the degradation of HSP90 client proteins via the ubiquitin-proteasome pathway. Compounds that target, reduce or inhibit the endogenous ATPase activity of HSP90 are, in particular, compounds, proteins or antibodies that inhibit the ATPase activity of HSP90, such as 17-allylamino,17-demethoxygeldanamycin (17AAG), geldanamycin derivatives; other geldanamycin-related compounds; radicicol and HDAC inhibitors. The term "HSP90 inhibitor", as used herein, includes, but is not limited to, compounds that target, reduce or inhibit the endogenous ATPase activity of HSP90; compounds that target, reduce or inhibit the degradation of HSP90 client proteins via the ubiquitin-proteasome pathway. Compounds that target, reduce or inhibit the endogenous ATPase activity of HSP90 are, in particular, compounds, proteins or antibodies that inhibit the ATPase activity of HSP90, such as 17-allylamino,17-demethoxygeldanamycin (17AAG), geldanamycin derivatives; other geldanamycin-related compounds; radicicol and HDAC inhibitors. The term "HSP90 inhibitor", as used herein, includes, but is not limited to, compounds that target, reduce or inhibit the endogenous ATPase activity of HSP90; compounds that target, reduce or inhibit the degradation of HSP90 client proteins via the ubiquitin-proteasome pathway. Compounds that target, reduce or inhibit the endogenous ATPase activity of HSP90 are, in particular, compounds, proteins or antibodies that inhibit the ATPase activity of HSP90, such as 17-allylamino,17-demethoxygeldanamycin (17AAG), geldanamycin derivatives; other geldanamycin-related compounds; radicicol and HDAC inhibitors. The term "HSP90 inhibitor", as used herein, includes, but is not limited to, compounds that target, reduce or inhibit the endogenous ATPase activity of HSP90; compounds that target, reduce or inhibit the degradation of HSP90 client proteins via the ubiquitin-proteasome pathway. Compounds that target, reduce or inhibit the endogenous ATPase activity of HSP90 are, in particular, compounds, proteins or antibodies that inhibit the ATPase activity of HSP90, such as 17-allylamino,17-demethoxygeldanamycin (17AAG), geldanamycin derivatives; other geldanamycin-related compounds; radicicol and HDAC inhibitors. The term "HSP90 inhibitor", as used herein, includes, but is not limited to, compounds that target, reduce or inhibit the endogenous ATPase activity of HSP90; compounds that target, reduce or inhibit the degradation of HSP90 client proteins via the ubiquitin-proteasome pathway. Compounds that target, reduce or inhibit the endogenous ATPase activity of HSP90 are, in particular, compounds, proteins or antibodies that inhibit the ATPase activity of HSP90, such as 17-allylamino,17-demethoxygeldanamycin (17AAG), geldanamycin derivatives; other geldanamycin-related compounds; radicicol and HDAC inhibitors. The term "HSP90 inhibitor", as used herein, includes, but is not limited to, compounds that target, reduce or inhibit the endogenous ATPase activity of HSP90; compounds that target, reduce or inhibit the degradation of HSP90 client proteins via the ubiquitin-proteasome pathway. Compounds that target, reduce or inhibit the endogenous ATPase activity of HSP90 are, in particular, compounds, proteins or antibodies that inhibit the ATPase activity of HSP90, such as 17-allylamino,17-demethoxygeldanamycin (17AAG), geldanamycin derivatives; other geldanamycin-related compounds; radicicol and HDAC inhibitors. The term "HSP90 inhibitor", as used herein, includes, but is not limited to, compounds that target, reduce or inhibit the endogenous ATPase activity of HSP90; compounds that target, reduce or inhibit the degradation of HSP90 client proteins via the ubiquitin-proteasome pathway. Compounds that target, reduce or inhibit the endogenous ATPase activity of HSP90 are, in particular, compounds, proteins or antibodies that inhibit the ATPase activity of HSP90, such as 17-allylamino,17-demethoxygeldanamycin (17AAG), geldanamycin derivatives; other geldanamycin-related compounds; radicicol and HDAC inhibitors.

[0277] The term "anti-proliferative antibody", as used herein, includes, but is not limited to, trastuzumab (Herceptin (trademark)), trastuzumab-DM1, erbitux, bevacizumab (Avastin (trademark)), rituximab (Rituxan (registered trademark)), PRO64553 (anti-CD40) and 2C4 antibody. An antibody refers to an intact monoclonal antibody, a polyclonal antibody, a multispecific antibody formed from at least two intact antibodies, and as long as it exhibits the desired biological activity. The term "anti-proliferative antibody", as used herein, includes, but is not limited to, trastuzumab (Herceptin (trademark)), trastuzumab-DM1, erbitux, bevacizumab (Avastin (trademark)), rituximab (Rituxan (registered trademark)), PRO64553 (anti-CD40) and 2C4 antibody. An antibody refers to an intact monoclonal antibody, a polyclonal antibody, a multispecific antibody formed from at least two intact antibodies, and as long as it exhibits the desired biological activity. The term "anti-proliferative antibody", as used herein, includes, but is not limited to, trastuzumab (Herceptin (trademark)), trastuzumab-DM1, erbitux, bevacizumab (Avastin (trademark)), rituximab (Rituxan (registered trademark)), PRO64553 (anti-CD40) and 2C4 antibody. An antibody refers to an intact monoclonal antibody, a polyclonal antibody, a multispecific antibody formed from at least two intact antibodies, and as long as it exhibits the desired biological activity. The term "anti-proliferative antibody", as used herein, includes, but is not limited to, trastuzumab (Herceptin (trademark)), trastuzumab-DM1, erbitux, bevacizumab (Avastin (trademark)), rituximab (Rituxan (registered trademark)), PRO64553 (anti-CD40) and 2C4 antibody. An antibody refers to an intact monoclonal antibody, a polyclonal antibody, a multispecific antibody formed from at least two intact antibodies, and as long as it exhibits the desired biological activity. The term "anti-proliferative antibody", as used herein, includes, but is not limited to, trastuzumab (Herceptin (trademark)), trastuzumab-DM1, erbitux, bevacizumab (Avastin (trademark)), rituximab (Rituxan (registered trademark)), PRO64553 (anti-CD40) and 2C4 antibody. An antibody refers to an intact monoclonal antibody, a polyclonal antibody, a multispecific antibody formed from at least two intact antibodies, and as long as it exhibits the desired biological activity. The term "anti-proliferative antibody", as used herein, includes, but is not limited to, trastuzumab (Herceptin (trademark)), trastuzumab-DM1, erbitux, bevacizumab (Avastin (trademark)), rituximab (Rituxan (registered trademark)), PRO64553 (anti-CD40) and 2C4 antibody. An antibody refers to an intact monoclonal antibody, a polyclonal antibody, a multispecific antibody formed from at least two intact antibodies, and as long as it exhibits the desired biological activity.​ means an antibody fragment.

[0278] For the treatment of acute myeloid leukemia (AML), the compounds of the present invention are used in combination with standard leukemia treatments and in particular in combination with treatments used for the treatment of AML. In particular, the compounds of the present invention can be administered in combination with, for example, farnesyltransferase inhibitors and / or other drugs useful for the treatment of AML, such as daunorubicin, adriamycin cinc, Ara-C, VP-16, teniposide, mitoxantrone, idarubicin, carbo platinum and PKC412. In some embodiments the present invention provides a method for treating AML associated with the ITD and / or D835Y mutations comprising administering a compound of the present invention together with one or more FLT3 inhibitors . In some embodiments, the FLT3 inhibitor is quizartinib (A C220), a staurosporine derivative (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 inhibitor is selected from quizartinib, midostaurin, lestaurtinib, sorafenib, and suniti nib.

[0279] Other anti-leukemia compounds include, for example, Ara-C, pyrimidine analogs which are 2'-alpha -hydroxyribose (arabinoside) derivatives of deoxycytidine. Purine analogs of hypoxanthine, 6-mercaptopurine (6-MP) and fludarabine are also mentioned. Compounds that target, reduce or inhibit the activity of histone deacetylase (HDAC), such as sodium butyrate and suberoylanilide hydroxamic acid (SAHA), inhibit the activity of enzymes known as histone deacetylases. As specific HDAC inhibitors, MS275, SAHA, FK228 (formerly FR901228), trichostatin A, and, without limitation, 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, include the compounds disclosed in US6,552,065. A somatostatin receptor antagonist, as used in this specification, refers to a compound that targets, treats or inhibits somatostatin receptors, such as octreotide and SOM230. The tumor cell damage approach refers to an approach such as ionizing radiation. The term "ionizing radiation" as used above and hereinafter in this specification means ionizing radiation generated as either electromagnetic rays (e.g., X-rays and gamma rays) or particles (e.g., alpha particles and beta particles). Ionizing radiation is provided in radiation therapy, among other things, and is known in the art. and is known in the art. and is known in the art. and is known in the art. and is known in the art. and is known in the art. and is known in the art. and is known in the art. is well-known. Hellman, Principles of Radiation T herapy, Cancer, in Principles and Practic e of Oncology, Devita et al., 4th ed., vol. 1, pp. 248-275 (1 993) for reference.

[0280] EDG binders and ribonucleotide reductase inhibitors are also included. The term "EDG bind er" as used herein refers to a class of immunosuppressive drugs that modulate lymphocyte recirculation, e.g., FTY720. The term "ribonucleotide reductase inhibitor" refers to pyrimidine nucleoside analogs or purine nucleoside analogs that include, but are 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.

[0281] In particular, 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or its pharmaceutically acceptable salts, 1-(4-chloroanilino)-4-(4-pyridylmethyl)ph thalazine succinate; Angiostatin (trademark); Endostatin (trademark ); anthranilic acid amide; ZD4190; ZD6474; SU5416; SU6668 ; bevacizumab; or an anti-VEGF antibody or an anti-VEGF receptor antibody (e.g., rhu MAb and RHUFab), VEGF aptamers (e.g., Macugon); FLT -4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgGI antibodies, Angiozyme( RPI 4610) and compounds, proteins or monoclonal antibodies such as bevacizumab (Avastin(trademark)) that target VEGF are also included.

[0282] As used herein, photodynamic therapy refers to a treatment that uses certain chemical substances known as photosensitizing compounds to treat or prevent cancer. Examples of photodynamic therapy include treatments using compounds such as Visudyne(trademark) and porfimer sodium.

[0283] As used herein, angiogenesis-inhibiting steroids refer to compounds that block or inhibit angiogenesis, such as anecortave, triamcinolone, hydrocortisone, 11-α-epihydrocortisol, cortisone, 17α-hydroxyprogesterone, corticosterone, desoxycorticosterone, testosterone, estrone and dexamethasone.

[0284] Grafts containing corticosteroids refer to compounds such as fluocinonide and dexamethasone.

[0285] 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 NA or siRNA; or a wide variety of compounds or other mechanisms of action or unknown actions​​​​​​​​​​​ Compounds having a mechanism of action are mentioned.

[0286] The compounds of the present invention are also particularly useful in the treatment of obstructive or inflammatory airway diseases such as those previously mentioned herein, in combination with other drug substances, for example, anti-inflammatory drug substances, bronchodilator drug substances or antihistamine drug substances, as co-therapeutic compounds (co-t herapeutic compound) for use, for example, as enhancers of the therapeutic activity of such drugs or as means for reducing the required dosage or potential side effects of such drugs. The compounds of the present invention may be mixed with other drug substances in a certain pharmaceutical composition, or separately from other drug substances, before, simultaneously, or after which they can be administered. Accordingly, the present invention includes a combination of a compound of the present invention as described hereinbefore with an anti-inflammatory drug substance, a bronchodilator drug substance, an antihistamine drug substance or an antitussive drug substance, wherein the compound and the drug substance of the present invention

[0287] are in the same or different pharmaceutical compositions. suitable anti-inflammatory drugs include steroids, particularly glucocorticosteroids (e.g., budesonide, beclamethasone dipropionate, fluticasone propionate, ciclesonide or mometasone furoate); non- steroidal glucocorticoid receptor agonists; LTB4 antagonists (e.g., L Y293111, CGS025019C, CP-195543, SC-53228, BI IL 284, ONO 4057, SB 209247); LTD4 antagonists (e.g. For example, montelukast and zafirlukast); PDE4 inhibitors (e.g., sirolimus to (Ariflo (registered trademark) GlaxoSmithKline), roflumilast (B yk Gulden), V-11294A (Napp), BAY19-8004 (Bay er), SCH-351591 (Schering-Plough), theophylline (A lmirall Prodesfarma), PD189659 / PD168787 (P arke-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 be ta-2 adrenergic agonists (e.g., albuterol (salbutamol), me taprotenerol, terbutaline, salmeterol fenoterol, procaterol, and, in particular, formoterol and its pharmaceutically acceptable salts) are mentioned. Pre ferably suitable bronchodilator drugs include anticholinergic compounds or antimuscarinic compounds, in particular, ipratropium bromide, oxitropium bromide, tiotropium salts and CHF 4226 (Chiesi), and glycopyrrolate.

[0288] Suitable antihistamine drug substances include cetirizine hydrochloride, acetaminophen, fumar ic acid clemastine, promethazine, loratadine, desloratidine (desloratidi ne), diphenhydramine and phenothiazine hydrochloride, acrivastine (act ivastine), astemizole, azelastine, ebastine, epinastine, mizolastine and terfenadine are included.

[0289] Other useful combinations of the compounds of the present invention with anti-inflammatory drugs are chemokine receptors, such as CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR -7, CCR-8, CCR-9 and CCR10, CXCR1, CXCR2, CXCR3 CXCR4, CXCR5 antagonists, especially CCR-5 antagonists, such as Schering-Plough's antagonist SC-351125, SCH-55 700 and SCH-D, and Takeda's antagonists, such as N-[[4 -[[[6,7-dihydro-2-(4-methylphenyl)-5H-benzo-cyclohept en-8-yl]carbonyl]amino]phenyl]-methyl]tetrahydro-N,N-dime thyl-2H-pyran-4-aminium chloride (TAK-770).

[0290] The structure of the active compound identified by the code number, common name or trade name can be obtained from the current edition of the standard compendium "The Merck Index" or a database (e.g., Pat ents International (e.g., IMS World Publica tions)).

[0291] The compounds of the present invention can also be used in combination with known treatment processes, such as the administration of hormones or radiation. In certain embodiments, the compounds provided are used as radiosensitizers, especially for the treatment of tumors that are poorly sensitive to radiotherapy. ​ .

[0292] The compounds of the present invention can be administered alone or in combination with one or more other therapeutic compounds. Possible combination therapies can be in the form of certain combinations, or the administration of the compounds of the present invention and one or more other therapeutic compounds can be alternating or independent of each other, or in the form of combined administration of certain combinations and one or more other therapeutic compounds. In addition or in addition to that, the compounds of the present invention can be administered, in particular for the treatment of tumors, in combination with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention, or combinations thereof. As described above, in the context of other treatment strategies, long-term treatment is possible, similar to adjuvant treatment. Other possible treatments are treatments for maintaining the condition of patients after tumor regression, or further, for example, chemopreventive treatment in patients at risk. These additional agents can be administered as part of a multiple dosing regimen separately from the composition containing the compound of the present invention. Alternatively, these agents can be part of a single dosage form mixed together with the compound of this invention in a single composition. When administered as part of a multiple dosing regimen, the two active agents can be given simultaneously, sequentially, or within a period from each other, usually within 5 hours from each other. When used herein, the terms "combination", "combined", and related terms refer to the simultaneous or sequential administration of therapeutic agents according to the present invention. For example, the present invention . . . . . . .

[0293] . . . . .

[0294] . . The compounds of the invention can be administered simultaneously, sequentially, or together in a single unit dosage form with another therapeutic agent. Accordingly, the present invention provides a single unit dosage form comprising a compound of the invention, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amounts of both the compound of the invention and the additional therapeutic agent (in a composition comprising an additional therapeutic agent as described above) that can be combined with a carrier material to produce a single dosage form will vary depending on the host being treated and the particular mode of administration. Preferably, the compositions of this invention should be formulated such that a dosage of from 0.01 to 100 mg of the compound of the invention per kg of body weight per day can be administered. In these compositions containing an additional therapeutic agent, the additional therapeutic agent and the compound of this invention can act synergistically. Accordingly, the amount of the additional therapeutic agent in such compositions is less than the amount required in a monotherapy utilizing only that therapeutic agent. In such compositions, a dosage of from 0.01 to 1,000 μg per kg of body weight per day of the additional therapeutic agent can be administered. The amount of the additional therapeutic agent present in the compositions of this invention is less than or equal to the amount normally administered in a composition containing that therapeutic agent as the sole active agent. Preferably, the amount of the additional therapeutic agent in the compositions of the present disclosure ranges from about 50% to 100% of the amount normally present in a composition containing that agent as the sole therapeutically active agent.

[0295] The compound of the invention, or a pharmaceutical composition thereof, can also be used in prostheses, artificial valves, graft vessels, depending on the host being treated and the particular mode of administration. Preferably, the compositions of this invention should be formulated such that a dosage of from 0.01 to 100 mg of the compound of the invention per kg of body weight per day can be administered. In these compositions containing an additional therapeutic agent, the additional therapeutic agent and the compound of this invention can act synergistically. Accordingly, the amount of the additional therapeutic agent in such compositions is less than the amount required in a monotherapy utilizing only that therapeutic agent. In such compositions, a dosage of from 0.01 to 1,000 μg per kg of body weight per day of the additional therapeutic agent can be administered. The amount of the additional therapeutic agent present in the compositions of this invention is less than or equal to the amount normally administered in a composition containing that therapeutic agent as the sole active agent. Preferably, the amount of the additional therapeutic agent in the compositions of the present disclosure ranges from about 50% to 100% of the amount normally present in a composition containing that agent as the sole therapeutically active agent. The compound of the invention, or a pharmaceutical composition thereof, can also be used in prostheses, artificial valves, graft vessels,

[0296] In these compositions containing an additional therapeutic agent, the additional therapeutic agent and the compound of this invention can act synergistically. Accordingly, the amount of the additional therapeutic agent in such compositions is less than the amount required in a monotherapy utilizing only that therapeutic agent. In such compositions, a dosage of from 0.01 to 1,000 μg per kg of body weight per day of the additional therapeutic agent can be administered. The amount of the additional therapeutic agent present in the compositions of this invention is less than or equal to the amount normally administered in a composition containing that therapeutic agent as the sole active agent. Preferably, the amount of the additional therapeutic agent in the compositions of the present disclosure ranges from about 50% to 100% of the amount normally present in a composition containing that agent as the sole therapeutically active agent. The compound of the invention, or a pharmaceutical composition thereof, can also be used in prostheses, artificial valves, graft vessels, In these compositions containing an additional therapeutic agent, the additional therapeutic agent and the compound of this invention can act synergistically. Accordingly, the amount of the additional therapeutic agent in such compositions is less than the amount required in a monotherapy utilizing only that therapeutic agent. In such compositions, a dosage of from 0.01 to 1,000 μg per kg of body weight per day of the additional therapeutic agent can be administered. The amount of the additional therapeutic agent present in the compositions of this invention is less than or equal to the amount normally administered in a composition containing that therapeutic agent as the sole active agent. Preferably, the amount of the additional therapeutic agent in the compositions of the present disclosure ranges from about 50% to 100% of the amount normally present in a composition containing that agent as the sole therapeutically active agent.

[0297] The amount of the additional therapeutic agent present in the compositions of this invention is less than or equal to the amount normally administered in a composition containing that therapeutic agent as the sole active agent. Preferably, the amount of the additional therapeutic agent in the compositions of the present disclosure ranges from about 50% to 100% of the amount normally present in a composition containing that agent as the sole therapeutically active agent. The compound of the invention, or a pharmaceutical composition thereof, can also be used in prostheses, artificial valves, graft vessels, The amount of the additional therapeutic agent present in the compositions of this invention is less than or equal to the amount normally administered in a composition containing that therapeutic agent as the sole active agent. Preferably, the amount of the additional therapeutic agent in the compositions of the present disclosure ranges from about 50% to 100% of the amount normally present in a composition containing that agent as the sole therapeutically active agent. The compound of the invention, or a pharmaceutical composition thereof, can also be used in prostheses, artificial valves, graft vessels,

[0298] The compound of the invention, or a pharmaceutical composition thereof, can also be used in prostheses, artificial valves, graft vessels, Compositions for coating implantable medical devices such as stents and catheters For example, vascular stents may be incorporated into the composition to prevent restenosis (re-narrowing of the blood vessel wall after injury). However, stents or other implantable devices have been used to overcome the Patients using the chair are at risk of blood clot formation or platelet activation. The effect is to pre-coat the device with a pharma- ceutical acceptable composition comprising a kinase inhibitor. This can be prevented or reduced by coating with the compound of the present invention. An implantable device comprising: a first implantable device;

[0299] The present invention will now be further described by non-limiting embodiments 1 to 32: Embodiment 1: Formula I': [ka] or a pharma- ceutically acceptable salt thereof, wherein in formula I': R 3 -C(O)NH2; -C(O)NHR 3A ;-C(O)N(R 3A )2;-C (O)OR; -C(O)NHOR; or independently selected from nitrogen, oxygen, and sulfur is a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms, This ring is a set of m examples R 3B is replaced by; R 5 is hydrogen, or -L 1 -R 5A and; R 6 is hydrogen, R A , or R B Is it; Or R 5 and R 6combines with the atoms between them to form, independently, a 4- to 7-membered partially unsaturated or heteroaryl ring having from 0 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur, where this ring is substituted by R and n instances of R 5A ; C by ; R 7 is hydrogen, halogen, -NH2, -NHR 7A , or -NHC(O)R 7A ; or alternatively R 6 and R 7 combine with the atoms between them to form, independently, a 4- to 7-membered partially unsaturated or heteroaryl ring having from 0 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur; where this ring is substituted by p instances of R ; C ; where this ring is substituted by p instances of R ; 1 L 1~4 is a covalent bond or a divalent saturated or unsaturated, straight-chain or branched hydrocarbon chain of C, where one or two methylene units of this chain are independently replaced, as needed, by - C(R 5B )2-, -CH(R 5B )-, -N(R)-, -N(R)C(O)-, -C( O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O )-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2- ; R 3A and R 7A are each independently R B , and each is substituted by q instances of R C ; where two R substituents on the same carbon are, as needed, combined C together which independently has from 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur forms a 3- to 6-membered saturated or partially unsaturated spiro-fused heterocyclic ring, or the same two Rs on carbon C substituents, optionally together, independently form a 3- to 6-membered saturated or partially unsaturated fused heterocyclic ring having from 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur; and each R and each instance of R is independently R or R 5A and each instance of R 5B is independently R A or R B and each is substituted by r instances of R C ; each instance of R A is independently oxo, halogen, -CN, -NO2, -OR, -SR, -NR 2, -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; each instance of R B is independently C 1~6 aliphatic; phenyl; a 5- to 6-membered monocyclic heteroaryl ring having from 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8- to 10-membered bicyclic heteroaryl ring having from 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 6-membered saturated or partially unsaturated heterocyclic ring having from 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 3- to A 7-membered saturated or partially unsaturated monocyclic heterocyclic ring; or independently a 7- to 12-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur; each R in each instance is independently oxo, halogen, -CN, -NO2, -OR, -SR, -N R2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C( 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 is an optionally substituted group, and this optionally substituted group is selected from C aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, where two optionally present substituents on the same carbon, optionally, together form a 3- to 6-membered saturated or partially unsaturated spiro-fused heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two optionally present substituents on adjacent carbons, optionally, together form a 3- to 6-membered saturated or partially unsaturated fused heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen or an optionally substituted group, and this optionally substituted group 1~6 is selected from C aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, where two optionally present substituents on the same carbon, optionally, together form a 3- to 6-membered saturated or partially unsaturated spiro-fused heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two optionally present substituents on adjacent carbons, optionally, together form a 3- to 6-membered saturated or partially unsaturated fused heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen or an optionally substituted group, and this optionally substituted group is selected from C aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, where two optionally present substituents on the same carbon, optionally, together form a 3- to 6-membered saturated or partially unsaturated spiro-fused heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two optionally present substituents on adjacent carbons, optionally, together form a 3- to 6-membered saturated or partially unsaturated fused heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R is independently hydrogen or an optionally substituted group, and this optionally substituted group is selected from C aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, The substituted group is C 1~6 aliphatic, phenyl, independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms; and 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. or a 5- to 6-membered heteroaryl ring selected from: Two R groups on the same nitrogen, together with the atoms between them, can form an 4, having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; forming a 5-7 membered saturated, partially unsaturated, or heteroaryl ring; where each hydrogen bonded to a carbon can be independently replaced by a deuterium atom, if desired. can be replaced; and m, n, p, q, and r in each instance are independently 0, 1, 2, 3, or 4; A compound or a pharma- ceutically acceptable salt thereof. Embodiment 2: Formula II or III: [ka] or a pharma- ceutically acceptable salt thereof. Embodiment 3: Formula V or VI: [ka] or a pharma- ceutically acceptable salt thereof. . Embodiment 4: Formula Va or VI-a: [ka] 4. The compound according to any one of embodiments 1 to 3, or a pharma- ceutically acceptable salt thereof. Embodiment 5: R7 is -NH2 or -NHR 7A The compound or a pharmaceutically acceptable salt thereof according to any one of Embodiments 1 to 4, wherein the compound is as defined above. Embodiment 6: Formula V - c or VI - c:

Chemical formula

Examples

[0300] Illustration As shown in the following examples, in certain exemplary embodiments, the compound is one of the following prepared according to the general procedure. The general method shows the synthesis of certain compounds of the present invention, but it is understood that the following general methods, as well as other methods known to those skilled in the art, can be applied to all compounds and each subclass and species of these compounds as described in this specification. Additional compounds of the present invention were prepared by methods substantially similar to the methods described herein in the examples and methods known to those skilled in the art. General procedure A (acid - amine coupling):

Chemical formula

[0301] Synthesis of compound 1.1. To a solution of 1 (4 g, 12.26 mmol, 1.0 equivalent) in N,N - dimethyl formamide (40 mL) was added 1 - [bis(dimethylamino)methylene] - 1 H - 1,2,3 - triazolo[4,5 - b]pyridinium 3 - oxide hexafluorophosphate (9.32 g, 24.53 mmol, 2.0 equivalents), and the mixture was stirred at room temperature for 1 5 minutes. Diisopropylethylamine (6.40 mL, 36.78 mmol , 3.0 equivalents) was added thereto, and then cyclopropanamine (0.699 g, 12.26 mmol, 1.0 equivalent) was added. The reaction mixture was stirred at room temperature for 5 minutes. After completion of the reaction, the reaction mixture was transferred into water, and the product was extracted with ethyl acetate. The organic layers were combined , washed with brine solution, dried with sodium sulfate, and concentrated under reduced pressure to obtain a crude product The mass was obtained. This was further purified by column chromatography, and the compound was eluted in ethyl acetate with 40% acetic acid in he xane to obtain 1.1 (2.4 g, 53.69%) . MS(ES): m / z 366.13 [M+H] + . General procedure B (Buchwald amination):

Chemical formula

[0302] Synthesis of compound 1.2. To a solution of 1 (0.125 g, 0.342 mmol, 1.0 equivalent) in 1,4 -dioxane (5 mL), 1.1 (0.082 g, 0.410 mmol, 1. 2 equivalents), sodium carbonate (0.072 g, 0.684 mmol, 2.0 equivalents) were added . The reaction mixture was degassed under an argon atmosphere for 10 minutes, then tris(dibenzylidene acetone)dipalladium(0) (0.015 g, 0.017 mmol, 0.05 equivalent) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.01 9 g, 0.034 mmol, 0.1 equivalent) were added and degassed again for 5 minutes. The reaction was stirred at 100 °C for 4 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, transferred to water, and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine solution, dried with sodium sulfate, and concentrated under reduced pressure to obtain a crude substance. This was further purified by combiflash using 3% methanol in dichloromethane as the eluent to obtain pure 1.2 (0.070 g, 38.6%). MS(ES): m / z 532.2 3 [M+H] + . General procedure C (BOC deprotection): [Chem.]

[0303] Synthesis of Compound 1.2. Compound 1 (0.070 g, 0.131 mmol, 1.0 eq) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (0.1 mL) was added to this reaction mixture. The reaction was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was transferred into saturated bicarbonate solution, and the product was extracted with dichloromethane. The organic layers were combined and dried over sodium sulfate and concentrated under reduced pressure to obtain a crude substance. This was further purified by trituration with diethyl ether to obtain pure 1.2 (0.040 g, 70. 17%). MS (ES): m / z 432.24 [M+H] + . Core A: Preparation of 7-((tert-butoxycarbonyl)(methyl)amino)-5-chloro pyrazolo[1,5-a]pyrimidine-3-carboxylic acid. [Chem.]

[0304] Synthesis of Compound 1.1. To a solution of (50 g, 322.25 mmol, 1.0 eq) in ethanol ( 250 mL), diethyl malonate (103.2 g, 644.51 mmol, 2 .0 eq) was added, and then sodium ethoxide (75 mL, 21% ethanol solution, 3.0 eq) was added dropwise. The reaction mixture was stirred for 20 hours while heating under reflux. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain a residue, which was dissolved in water and acidified to pH about 3 - 4 with concentr...

Claims

[Claim 1] The invention described in the specification.

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