TYK2 inhibitors and uses thereof

Abstract

To provide compounds, compositions thereof, and methods of using the same, for the inhibition of TYK2 and the treatment of TYK2-mediated disorders.SOLUTION: Compounds provided by this invention are 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] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 62 / 745,642, filed October 15, 2018, U.S. Provisional Application No. 62 / 795,869, filed January 23, 2019, and U.S. Provisional Application No. 62 / 820,509, filed March 19, 2019, each of which is incorporated by reference in its entirety.

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

[0003] In recent years, the search for new therapeutic agents has been greatly aided by a better understanding of the structure of enzymes and other biomolecules associated with diseases. One important class of enzymes that has been the subject of extensive study is the protein kinase family.

[0004] Protein kinases constitute a large family of structurally related enzymes responsible for the control of various signaling 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. Almost all kinases contain a similar 250-300 amino acid catalytic domain. Kinases can be classified into families according to the substrates they phosphorylate (e.g., protein-tyrosine, protein-serine / threonine, lipids, etc.).

[0005] Generally, protein kinases mediate intracellular signaling by executing phosphoryl transfer from a nucleoside triphosphate to a protein acceptor involved in a signaling pathway. These phosphorylation events act as molecular on / off switches that can modulate or regulate the biological function of the target protein. These phosphorylation events are ultimately triggered in response to a variety of extracellular and other stimuli. Examples of such stimuli include environmental and chemical stress signals (e.g., osmotic shock, heat shock, ultraviolet radiation, bacterial endotoxin, and H 2 O 2 ), cytokines (e.g., interleukin-1 (IL-1), interleukin-8 (IL-8), and tumor necrosis factor alpha (TNF-α)), and growth factors (e.g., granulocyte-macrophage-colony stimulating factor (GM-CSF), and fibroblast growth factor (FGF)). Extracellular stimuli can affect one or more cellular responses related to cell proliferation, migration, differentiation, secretion of hormones, activation of transcription factors, muscle contraction, glucose metabolism, control of protein synthesis, and regulation of the cell cycle.

[0006] Many diseases are associated with abnormal cell response caused by kinase-mediated events.These diseases include, but are not limited to, autoimmune disease, inflammatory disease, bone disease, metabolic disease, neurological disease and neurodegenerative disease, cancer, cardiovascular disease, allergy and asthma, Alzheimer's disease, and hormone-related disease.Therefore, there is still a need to find protein kinase inhibitors that are useful as therapeutic agents. Summary of the Invention [Means for solving the problem]

[0007] Summary of the Invention It has now been found that compounds of the present invention, and pharma- ceutically acceptable compositions thereof, are effective as inhibitors of TYK2 kinase.

[0008] The compounds of the present invention and pharma- ceutically acceptable compositions thereof are useful for treating a variety of diseases, disorders, or conditions associated with the regulation of signal transduction pathways involving TYK2 kinase, including those described herein.

[0009] The compounds provided by the present invention are also useful for the study of the TYK2 enzyme in biological and pathological phenomena; the study of intracellular signaling pathways occurring in body tissues; and the in vitro or in vivo comparative evaluation of new TYK2 inhibitors or other regulators of kinases, signaling pathways, and cytokine levels. In an embodiment of the present invention, for example, the following items are provided: (Item 1) Compound of formula I': [ka] or a pharma- ceutically acceptable salt thereof, R 1 -L 1 -R 1A and L 1 is a covalent bond; or a bivalent saturated or unsaturated linear or branched C 1~6 a hydrocarbon chain, one or two methylene units of said chain being -C(R) 2 -;-N(R)-;-N(R)C(O)-;-C(O)N(R)-;-N(R)S(O) 2 -;-S(O) 2 N(R)-;-O-;-C(O)-;-OC(O)-;-C(O)O-;-S-;-S(O)-;-S(O) 2 or -Cy-, Cy is an optionally substituted 5-6 membered divalent monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an optionally substituted 8-10 membered divalent bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an optionally substituted 3-7 membered saturated or partially unsaturated divalent carbocyclic ring; or an optionally substituted 7-12 membered saturated or partially unsaturated divalent bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 1A is oxo; halogen; -CN; -NO 2 ;-OR;-SR;-NR 2 ;-S(O) 2 R;-S(O) 2 NR 2 ;-S(O)R;-S(O)NR 2 ;-C(O)R;-C(O)OR;-C(O)NR 2 ;-C(O)N(R)OR;-OC(O)R;-OC(O)NR 2 ;-N(R)C(O)OR;-N(R)C(O)R;-N(R)C(O)NR 2 ;-N(R)C(NR)NR 2 ;-N(R)S(O) 2 NR 2 ;-N(R)S(O) 2 R; C substituted as necessary 1~6an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; an optionally substituted 8-10 membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring; an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, R 2 -C(O)OH, -C(O)NH 2 ;-C(O)NHR 2A ;-C(O)N(R 2A ) 2 or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; The heteroaryl ring is selected from m instances of R 2B is replaced by R 2A is C 1~6 an aliphatic group; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 3-7 membered saturated or partially unsaturated carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, R 2A is n examples of R 2C is replaced by Two R on the same carbon 2Cthe substituents, optionally taken 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 R on adjacent carbons 2C the substituents, optionally taken together, form a 3- to 6-membered saturated or partially unsaturated fused heterocyclic ring having from 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; R 2B is oxo; halogen; -CN; -NO 2 ;-R;-OR;-SR;-NR 2 ;-S(O) 2 R;-S(O) 2 NR 2 ;-S(O)R;-S(O)NR 2 ;-C(O)R;-C(O)OR;-C(O)NR 2 ;-C(O)N(R)OR;-OC(O)R;-OC(O)NR 2 ;-N(R)C(O)OR;-N(R)C(O)R;-N(R)C(O)NR 2 ;-N(R)C(NR)NR 2 ;-N(R)S(O) 2 NR 2 ;or -N(R)S(O) 2 R, R 2C Each example is independently oxo; halogen; -CN; -NO 2 ;-OR;-SR;-NR 2 ;-S(O) 2 R;-S(O) 2 NR 2 ;-S(O)R;-S(O)NR 2 ;-C(O)R;-C(O)OR;-C(O)NR 2 ;-C(O)N(R)OR;-OC(O)R;-OC(O)NR 2 ;-N(R)C(O)OR;-N(R)C(O)R;-N(R)C(O)NR 2 ;-N(R)C(NR)NR 2 ;-N(R)S(O) 2 NR 2 ;-N(R)S(O) 2 R; or C 1~6an optionally substituted group selected from aliphatic; phenyl; a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; two optional substituents on the same carbon optionally join together to form a 3-6 membered saturated or partially unsaturated spiro-fused heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or two optional substituents on adjacent carbons optionally joined together form a 3-6 membered saturated or partially unsaturated fused heterocyclic ring having from 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; R 3 is hydrogen; halogen; -NH 2 ;-NHR 3A ; or -NHC(O)R 3A and R 3A is C 1~6 an aliphatic group; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 3-7 membered saturated or partially unsaturated carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, R 3A p examples of R 3B is replaced by Two R on the same carbon 3B the substituents, optionally taken 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 R on adjacent carbons3B the substituents, optionally taken together, form a 3- to 6-membered saturated or partially unsaturated fused heterocyclic ring having from 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; R 3B Each instance of is independently oxo; halogen; -CN; -NO 2 ;-OR;-SR;-NR 2 ;-S(O) 2 R;-S(O) 2 NR 2 ;-S(O)R;-S(O)NR 2 ;-C(O)R;-C(O)OR;-C(O)NR 2 ;-C(O)N(R)OR;-OC(O)R;-OC(O)NR 2 ;-N(R)C(O)OR;-N(R)C(O)R;-N(R)C(O)NR 2 ;-N(R)C(NR)NR 2 ;-N(R)S(O) 2 NR 2 ;-N(R)S(O) 2 R; or C 1~6 an optionally substituted group selected from aliphatic; a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from phenyl, nitrogen, oxygen, and sulfur; and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; two optional substituents on the same carbon optionally join together to form a 3-6 membered saturated or partially unsaturated spiro-fused heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or two optional substituents on adjacent carbons optionally joined together form a 3-6 membered saturated or partially unsaturated fused heterocyclic ring having from 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; R 4 is R or -OR, Or, R 1 and R 4together with the atoms therebetween form a 4-7 membered partially unsaturated ring or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, said ring being selected from R 1A or replaced by Or, R 3 and R 4 together with the atoms therebetween form a 4-7 membered partially unsaturated ring or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; Each R is independently hydrogen; or C 1~6 an optionally substituted group selected from aliphatic; phenyl; 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; and 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or two R groups on the same nitrogen, together with the atoms between them, form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having, in addition to said nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each hydrogen bonded to a carbon can be optionally independently replaced by deuterium; m is 0, 1 or 2; n is 0, 1 or 2; p is 0, 1 or 2). (Item 2) Formula II or IV: [ka] Item 1. The compound according to item 1, or a pharma- ceutically acceptable salt thereof. (Item 3) Formula III or V: [ka] Item 1 or 2, or a pharma- ceutically acceptable salt thereof. (Item 4) Formula VI: [ka] 4. The compound according to any one of items 1 to 3, or a pharma- ceutically acceptable salt thereof. (Item 5) Formula VII: [ka] 4. The compound according to any one of items 1 to 3, or a pharma- ceutically acceptable salt thereof. (Item 6) Formula VIII: [ka] 6. The compound according to any one of items 1 to 5, or a pharma- ceutically acceptable salt thereof. (Item 7) R 1A But the following: [ka] [ka] [ka] 7. The compound according to any one of items 1 to 6, selected from: (Item 8) R 2A But the following: [ka] [ka] 8. The compound according to any one of items 1 to 4, 6 and 7, selected from: (Item 9) A compound according to any one of items 1 to 8 selected from Table 1 or those depicted herein, or a pharma- ceutically acceptable salt thereof. (Item 10) A pharmaceutical composition comprising a compound according to any one of items 1 to 9 or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable carrier, adjuvant or vehicle. (Item 11) A compound according to any one of items 1 to 9 or a pharmaceutical composition according to item 10 for use in the manufacture of a medicament for treating a TYK2-mediated disorder, disease or condition in a patient. (Item 12) A method for inhibiting TYK2 in a biological sample, comprising contacting the sample with a compound described in any one of items 1 to 9, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition described in item 10. (Item 13) A method for treating a TYK2-mediated disorder, disease or condition in a patient, comprising administering to the patient a compound described in any one of items 1 to 9, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition described in item 10. (Item 14) 14. The method of claim 13, wherein the disorder is selected from an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a transplant-related disorder. (Item 15) 15. The method of claim 14, wherein the disorder is an autoimmune disorder. (Item 16) 16. The method of claim 15, wherein the autoimmune disorder is selected from type 1 diabetes, ankylosing spondylitis, cutaneous lupus erythematosus, systemic lupus erythematosus, multiple sclerosis, systemic sclerosis, psoriasis, Crohn's disease, ulcerative colitis, and inflammatory bowel disease. (Item 17) 15. The method of claim 14, wherein the disorder is an inflammatory disorder. (Item 18) 18. The method of claim 17, wherein the inflammatory disorder is selected from rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis, Crohn's disease, ulcerative colitis, and inflammatory bowel disease. (Item 19) 15. The method of item 14, wherein the disorder is a proliferative disorder. (Item 20) 20. The method of claim 19, wherein the proliferative disorder is a hematological cancer. (Item 21) 20. The method of claim 19, wherein the proliferative disorder is leukemia. (Item 22) 22. The method of claim 21, wherein the leukemia is T-cell leukemia. (Item 23) 23. The method of claim 22, wherein the T-cell leukemia is T-cell acute lymphoblastic leukemia (T-ALL). (Item 24) 20. The method of item 19, wherein the proliferative disorder is associated with one or more activating mutations in TYK2. (Item 25) 15. The method of claim 14, wherein the disorder is associated with transplantation. (Item 26) 26. The method of item 25, wherein the disorder is transplant rejection or graft-versus-host disease. (Item 27) 15. The method of claim 14, wherein the disorder is an endocrine disorder. (Item 28) 28. The method of claim 27, wherein the endocrine disorder is polycystic ovary syndrome, Crouzon syndrome, or type 1 diabetes. (Item 29) 15. The method of claim 14, wherein the disorder is a neurological disorder. (Item 30) 30. The method of claim 29, wherein the neurological disorder is Alzheimer's disease. (Item 31) The method of claim 14, wherein the disorder is associated with type I interferon, IL-10, IL-12, or IL-23 signaling. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] Detailed Description of Specific Embodiments 1. General Description of Certain Embodiments of the Invention: The compounds of the present invention and compositions thereof are useful as inhibitors of TYK2 protein kinase.

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

[0012] Water molecules occupying hydration sites in the binding pocket of TYK2 with a stability rating greater than 2.5 kcal / mol are referred to as "labile waters."

[0013] Without wishing to be bound by any particular theory, it is believed that the displacement or disruption of labile water molecules (i.e., water molecules with a stability rating of greater than 2.5 kcal / mol) or the replacement of stable water molecules (i.e., water molecules with a stability rating of less than 1 kcal / mol) by an inhibitor results in tighter binding of the inhibitor. Thus, inhibitors designed to displace one or more labile water molecules (i.e., labile water molecules that are not displaced by any known inhibitor) are tighter binders and therefore more potent inhibitors compared to inhibitors that do not displace labile water molecules.

[0014] Surprisingly, provided compounds have been found to displace or disrupt one or more labile water molecules, hi some embodiments, provided compounds displace or disrupt at least two labile water molecules.

[0015] 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 1 , R 2 , R 3 and R 4 Each of the is as defined below, both alone and in combination, and as described in embodiments herein.

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

[0017] In some embodiments, the present invention provides a method of treating a TYK2-mediated disease, disorder, or condition, comprising administering to a patient in need thereof a compound of formula I, or a pharma- ceutically acceptable salt thereof.

[0018] 2. Compounds and definitions: The compounds of the present invention include those generally described above, and are further illustrated by the classes, subclasses, and species disclosed herein.As used herein, the following definitions shall apply unless otherwise specified.For the purposes of this invention, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Edition.Furthermore, general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science, the entire contents of which are incorporated herein by reference. Books, Sausalito: 1999, and in March's Advanced Organic Chemistry, 5th Edition, eds. Smith, M. B. and March, J., John Wiley & Sons, New York: 2001.

[0019] The term "aliphatic" or "aliphatic group," as used herein, refers to a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted, fully saturated or containing one or more unsaturated units, hydrocarbon chain, or a monocyclic or bicyclic hydrocarbon (also referred to herein as "carbocyclic," "alicyclic," or "cycloalkyl") that is fully saturated or contains one or more unsaturated units, but is not aromatic, having one point of attachment to the remainder of the molecule. Unless otherwise specified, an aliphatic group contains 1-6 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1-5 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1-4 aliphatic carbon atoms. In still other embodiments, an aliphatic group contains 1-3 aliphatic carbon atoms, and in still other embodiments, an aliphatic group contains 1-2 aliphatic carbon atoms. In some embodiments, "alicyclic" (or "carbocycle" or "cycloalkyl") refers to a monocyclic C ring that is fully saturated or contains one or more units of unsaturation, but is not aromatic, and has one point of attachment to the remainder of the molecule. 3 ~C 6 Suitable aliphatic groups include, but are not limited to, straight or branched chain, saturated or unsaturated, alkyl, alkenyl, alkynyl groups, and hybrids thereof (e.g., (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl).

[0020] As used herein, the term "bridged bicyclic" refers to any bicyclic ring system (i.e., carbocyclic or heterocyclic) that has at least one bridge, saturated or partially unsaturated. As defined by IUPAC, a "bridge" is an unbranched chain of atoms, or an atom, or a valence bond, connecting two bridgeheads, where a "bridgehead" is any skeletal atom of the ring system that is attached to three or more skeletal atoms (other than hydrogen). In some embodiments, a bridged bicyclic group has 7 to 12 ring members and 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and each group may be bonded to any suitable carbon or nitrogen atom. The bridged bicyclic groups include the groups described below that are attached to the remainder of the molecule via an aliphatic group. Unless otherwise specified, the bridged bicyclic groups are optionally substituted with one or more substituents as described for aliphatic groups. Additionally, or alternatively, any substitutable nitrogen of the bridged bicyclic group is optionally substituted. Exemplary bridged bicyclic groups include: [ka] Examples include:

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

[0022] The term "lower haloalkyl" refers to a C alkyl group substituted with one or more halogen atoms. 1~4 The term "alkyl" refers to a straight or branched chain alkyl group.

[0023] The term "heteroatom" refers to an atom of oxygen, sulfur, nitrogen, phosphorus, or silicon (any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen; or a substitutable nitrogen of a heterocyclic ring (e.g., N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR +(as in N-substituted pyrrolidinyl)) is meant to include one or more of the following:

[0024] The term "unsaturated," as used herein, means a moiety that has one or more units of unsaturation.

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

[0026] The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH 2 ) n -, where n is a positive integer, preferably 1 to 6, 1 to 4, 1 to 3, 1 to 2, or 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogens are replaced with a substituent. Suitable substituents include those described below for substituted aliphatic groups.

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

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

[0029] The term "aryl", used alone or as part of a larger 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, in which at least one ring in the system is aromatic, and each ring in the system contains 3 to 7 ring members. The term "aryl" may be used interchangeably with the term "aryl ring". In certain embodiments of the invention, "aryl" refers to an aromatic ring system, including, but not limited to, phenyl, biphenyl, naphthyl, and anthracyl, which may bear one or more substituents. Included within the scope of the term "term" as used herein are groups in which an aromatic ring is fused to one or more non-aromatic rings, such as, for example, indanyl, phthalimidyl, naphthoimidyl, phenanthridinyl, or tetrahydronaphthyl.

[0030] The terms "heteroaryl" and "heteroara-", 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 pi electrons shared in a cyclic arrangement; and having 1 to 5 heteroatoms in addition to the carbon atoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. Heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms "heteroaryl" and "heteroara-", as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, alicyclic, or heterocyclic rings, and the radical or point of attachment is on the heteroaromatic ring or on one of the rings to which the heteroaromatic ring is fused, unless otherwise specified.Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl.Heteroaryl groups may be monocyclic or bicyclic. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," any of which includes rings that are optionally substituted. The term "heteroaralkyl" refers to an alkyl group substituted by a heteroaryl, where the alkyl and heteroaryl portions independently are optionally substituted.

[0031] As used herein, the terms "heterocycle", "heterocyclyl", "heterocyclic radical", and "heterocyclic ring" are used interchangeably and refer to a stable 5- to 7-membered monocyclic, or 7- to 10-membered bicyclic, heterocyclic moiety that is either saturated or partially unsaturated and has, in addition to carbon atoms, one or more, preferably one to four, heteroatoms as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes substituted nitrogen. As an example, in a saturated or partially unsaturated ring having zero to three heteroatoms selected from oxygen, sulfur, or nitrogen, the nitrogen can be either N (as in 3,4-dihydro-2H-pyrrolyl) or NH (as in pyrrolidinyl). + It may also be NR (as in N-substituted pyrrolidinyl).

[0032] A heterocyclic ring can be attached to its parent group at any heteroatom or carbon atom that results in a stable structure, and any of these ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, 2-oxa-6-azaspiro[3.3]heptane, and quinuclidinyl. The terms "heterocycle," "heterocyclyl," "heterocyclyl ring," "heterocyclic group," "heterocyclic moiety," and "heterocyclic radical" are used interchangeably herein and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or alicyclic rings (e.g., indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl). Heterocyclyl groups can be monocyclic or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted by heterocyclyl, where the alkyl and heterocyclyl moieties independently are optionally substituted.

[0033] As used herein, the term "partially unsaturated" refers to a ring moiety that contains at least one double or triple bond. The term "partially unsaturated" is intended to include rings with multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as defined herein.

[0034] 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 of the specified moiety are replaced with suitable substituents. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable portion of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a particular group, the substituents may be either the same or different at each position. The combinations of substituents envisioned by the present invention are preferably those that result in the formation of stable compounds, or chemically feasible compounds. The term "stable" as used herein refers to compounds that are substantially unchanged when subjected to conditions that allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0035] Suitable monovalent substituents on a substitutable carbon atom of an "optionally substituted" group are independently: halogen; -(CH 2 ) 0~4 R ○ ;-(CH 2 ) 0~4 OR ○ ;-O(CH 2 ) 0~4 R ○ , -O-(CH 2 ) 0~4 C(O)OR ○ ;-(CH 2 ) 0~4 CH(OR ○ ) 2 ;-(CH 2 ) 0~4 S.R. ○ ;-(CH 2 ) 0~4 Ph (this is R ○ );-(CH 2 ) 0~4 O(CH 2 ) 0~1 Ph (this is R○ -CH=CHPh (which may be substituted with R ○ );-(CH 2 ) 0~4 O(CH 2 ) 0~1 -pyridyl (which is R ○ );-NO 2 ;-CN;-N 3 ;-(CH 2 ) 0~4 N(R ○ ) 2 ;-(CH 2 ) 0~4 N(R ○ )C(O)R ○ ;-N(R ○ )C(S)R ○ ;-(CH 2 ) 0~4 N(R ○ )C(O)NR ○ 2 ;-N(R ○ )C(S)NR ○ 2 ;-(CH 2 ) 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 ;-(CH 2 ) 0~4 C(O)R ○ ;-C(S)R ○ ;-(CH 2 ) 0~4 C(O)OR ○ ;-(CH 2 ) 0~4 C(O)SR ○ ;-(CH 2 ) 0~4C(O)OSiR ○ 3 ;-(CH 2 ) 0~4 OC(O)R ○ ;-OC(O)(CH 2 ) 0~4 SR ○ ;-SC(S)SR ○ ;-(CH 2 ) 0~4 SC(O)R ○ ;-(CH 2 ) 0~4 C(O)NR ○ 2 ;-C(S)NR ○ 2 ;-C(S)SR ○ ;-SC(S)SR ○ 、-(CH 2 ) 0~4 OC(O)NR ○ 2 ;-C(O)N(OR ○ )R ○ ;-C(O)C(O)R ○ ;-C(O)CH 2 C(O)R ○ ;-C(NOR ○ )R ○ ;-(CH 2 ) 0~4 SSR ○ ;-(CH 2 ) 0~4 S(O) 2 R ○ ;-(CH 2 ) 0~4 S(O) 2 OR ○ ;-(CH 2 ) 0~4 OS(O) 2 R ○ ;-S(O) 2 NR ○ 2 ;-(CH 2 ) 0~4 S(O)R ○ ;-N(R ○ )S(O) 2 NR ○ 2 ;-N(R ○ )S(O) 2 R ○;-N(OR ○ )R ○ ;-C(NH)NR ○ 2 ;-P(O) 2 R ○ ;-P(O)R ○ 2 ;-OP(O)R ○ 2 ;-OP(O)(OR ○ ) 2 ;-SiR ○ 3 ;-(C 1~4 A straight or branched alkylene group of R ○ ) 2 ; or -(C 1~4 (R) ○ ) 2 where each R ○ may be substituted as defined below and are independently hydrogen, C 1~6 Aliphatic, -CH 2 Ph, -O(CH 2 ) 0~1 Ph, -CH 2 -(5- to 6-membered heteroaryl ring), or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, regardless of the above definitions, R ○ two independent occurrences of together with the atom(s) between them form a 3- to 12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which can be substituted as defined below.

[0036] R ○ (R ○ Suitable monovalent substituents on the ring formed by two independent occurrences of -(CH 2 ) 0~2 R ● , -(Halo R ● ), -(CH 2 ) 0~2OH, -(CH 2 ) 0~2 OR ● , -(CH 2 ) 0~2 CH(OR ● ) 2 ;-O(HaloR ● ), -CN, -N 3 , -(CH 2 ) 0~2 C(O)R ● , -(CH 2 ) 0~2 C(O)OH, -(CH 2 ) 0~2 C(O)OR ● , -(CH 2 ) 0~2 S.R. ● , -(CH 2 ) 0~2 SH, -(CH 2 ) 0~2 NH 2 , -(CH 2 ) 0~2 NHR ● , -(CH 2 ) 0~2 NR ● 2 , -NO 2 , -SiR ● 3 , -OSiR ● 3 , -C(O)SR ● , -(C 1~4 (straight or branched chain alkylene)C(O)OR ● , or -SSR ● where each R ● is unsubstituted or, if preceded by "halo", is substituted with only one or more halogens, and independently, C 1~4 Aliphatic, -CH 2 Ph, -O(CH 2 ) 0~1 Ph, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. ○ Suitable divalent substituents on a saturated carbon atom of include ═O and ═S.

[0037] Suitable divalent substituents on a saturated carbon atom of an "optionally substituted" group include: ═O, ═S, ═NNR * 2 , =NNHC(O)R * , =NNHC(O)OR * , =NNHS(O) 2 R * , =NR * , =NOR * , -O(C(R * 2 )) 2~3 O-, or -S(C(R * 2 )) 2~3 S-. Here R * Each independent occurrence of 1~6 An optionally substituted group is selected from an aliphatic or unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents attached to a vicinal substitutable carbon of an "optionally substituted" group include -O(CR * 2 ) 2~3 O-, where R * Each independent occurrence of 1~6 It is selected from an aliphatic or unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0038] R * Suitable substituents on the aliphatic group include halogen, -R ● , -(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH 2 , -NHR ● , -NR ● 2 , or -NO 2 where each R● is unsubstituted or, if preceded by "halo", is substituted with only one or more halogens, and independently, C 1~4 Aliphatic, -CH 2 Ph, -O(CH 2 ) 0~1 Ph, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0039] Suitable substituents on a substitutable nitrogen of an "optionally substituted" group include -R † , -NR † 2 , -C(O)R † , -C(O)OR † , -C(O)C(O)R † , -C(O)CH 2 C(O)R † , -S(O) 2 R † , -S(O) 2 NR † 2 , -C(S)NR † 2 , -C(NH)NR † 2 , or -N(R † )S(O) 2 R † where each R † are independently hydrogen, C which may be substituted as defined below 1~6 aliphatic, unsubstituted -OPh, or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or, regardless of the above definitions, R † two independent occurrences of together with the atom(s) between them form an unsubstituted 3- to 12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0040] R †Suitable substituents on the aliphatic group are independently halogen, -R ● , -(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH 2 , -NHR ● , -NR ● 2 , or -NO 2 where each R ● is unsubstituted or, if preceded by "halo", is substituted with only one or more halogens, and independently, C 1~4 Aliphatic, -CH 2 Ph, -O(CH 2 ) 0~1 Ph, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0041] As used herein, the term "pharmaceutically acceptable salts" refers to those salts that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reactions, etc., and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, vol. 66, pp. 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods used in the art, such as ion exchange. Other pharma- ceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, and 2-hydroxy-ethanesulfonate. Examples of the salts include phonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate.

[0042] Salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts and N+ (C 1~4 Alkyl) 4 Representative alkali metal salts or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Further pharma- ceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations, formed, where appropriate, with counterions such as halides, hydroxides, carbonates, sulfates, phosphates, nitrates, lower alkylsulfonates, and arylsulfonates.

[0043] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure, such as the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Thus, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the compounds of the invention are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, structures of the invention in which hydrogen is replaced by deuterium or tritium, or in which carbon is replaced by a tautomeric isomer. 13 C or 14 Compounds having the invention in which C is replaced with an enriched carbon are within the scope of the invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents according to the invention. In certain embodiments, the warhead moiety R of a given compound is 1 contains one or more deuterium atoms. In certain embodiments, ring B of provided compounds can be substituted with one or more deuterium atoms.

[0044] As used herein, the term "inhibitor" is defined as a compound that binds and / or inhibits TYK2 with measurable affinity. In certain embodiments, an inhibitor has an IC of less than about 50 μM, less than about 1 μM, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM. 50 and / or has a binding constant.

[0045] The compounds of the present invention may be tethered to a detectable moiety. It is understood that such compounds are useful as imaging agents. Those skilled in the art will recognize that detectable moieties may be attached to the provided compounds via suitable substituents. As used herein, the term "suitable substituents" refers to moieties that can be covalently attached to detectable moieties. Such moieties are well known to those skilled in the art and include, for example, groups that contain carbonate, amino, thiol or hydroxyl moieties, to name a few. It is understood that such moieties may be attached directly to the provided compounds or via tethering groups such as bivalent saturated or unsaturated hydrocarbon chains. In some embodiments, such moieties may be attached by click chemistry. In some embodiments, such moieties may be attached by 1,3-cycloaddition of azides with alkynes, optionally in the presence of copper catalyst. Methods using click chemistry are known in the art and include those described by Rostovtsev et al., Angew. Chem. Int. Ed. 2002, 41, 2596-99 and Sun et al., Bioconjugate Chem., 2006, 17, 52-57.

[0046] As used herein, the term "detectable moiety" is used interchangeably with the term "label" and refers to any moiety that can be detected, such as primary labels and secondary labels. Radioisotopes (e.g., tritium, 32 P, 33 P, 35 S, or 14C), primary labels, such as mass tags and fluorescent labels, are signal-generating reporter groups that can be detected without further modification. Detectable moieties also include luminescent and phosphorescent groups.

[0047] As used herein, the term "secondary label" refers to moieties such as biotin and various protein antigens that require the presence of a secondary intermediate to generate a detectable signal. For biotin, the secondary intermediate may include streptavidin-enzyme conjugates. For antigen labels, the secondary intermediate may include antibody-enzyme conjugates. Some fluorescent groups act as secondary labels because they transfer energy to another group in the process of non-radioactive fluorescence resonance energy transfer (FRET), and the second group generates the signal that is detected.

[0048] As used herein, the terms "fluorescent label", "fluorescent dye" and "fluorophore" refer to a moiety that absorbs light energy at a defined excitation wavelength and emits light energy at a different wavelength. Examples of fluorescent labels include Alexa Fluor dyes (Alexa Fluor350, Alexa Fluor488, Alexa Fluor532, Alexa Fluor546, Alexa Fluor568, Alexa Fluor594, Alexa Fluor633, Alexa Fluor660 and Alexa Fluor680), AMCA, AMCA-S, BODIPY dyes (BODIPY FL, BODIPY R6G, BODIPY TMR, BODIPY TR, BODIPY530 / 550, BODIPY558 / 568, BODIPY564 / 570, BODIPY576 / 589, BODIPY581 / 591, BODIPY630 / 650, BODIPY650 / 665), Carboxyrhodamine 6G, Carboxy-X-rhodamine (ROX), Cascade Blue, Cascade Yellow, Coumarin 343, Cyanine Dyes (Cy3, Cy5, Cy3.5, Cy5.5), Dansyl, Dapoxyl, Dialkylaminocoumarin, 4',5'-Dichloro-2',7'-Dimethoxy-Fluorescein, DM-NERF, Eosin, Erythrosine, Fluorescein, FAM, Hydrogen Examples of suitable fluorescent dyes include, but are not limited to, roxycoumarin, IRDyes (IRD40, IRD700, IRD800), JOE, Lissamine rhodamine B, Marina Blue, methoxycoumarin, naphthofluorescein, Oregon Green 488, Oregon Green 500, Oregon Green 514, Pacific Blue, PyMPO, pyrene, rhodamine B, rhodamine 6G, rhodamine green, rhodamine red, rhodol green, 2',4',5',7'-tetra-bromosulfone-fluorescein, tetramethyl-rhodamine (TMR), carboxytetramethylrhodamine (TAMRA), Texas Red, and Texas Red-X.

[0049] As used herein, the term "mass tag" refers to any moiety that can be uniquely detected by its mass using mass spectrometry (MS) detection technology. Examples of mass tags include electrophoretic release tags such as N-[3-[4'-[(p-methoxytetrafluorobenzyl)oxy]phenyl]-3-methylglyceronyl]isonipeconate, 4'-[2,3,5,6-tetrafluoro-4-(pentafluorophenoxyl)]methylacetophenone and their derivatives. The synthesis and utility of these mass tags are described in U.S. Patent Nos. 4,650,750, 4,709,016, 5,360,8191, 5,516,931, 5,602,273, 5,604,104, 5,610,020 and 5,650,270. Other examples of mass tags include, but are not limited to, nucleotides of various lengths and base compositions, dideoxynucleotides, oligonucleotides, oligopeptides, oligosaccharides and other synthetic polymers of various lengths and monomer compositions.A wide variety of organic molecules (biomolecules or synthetic compounds), both neutral and charged, of the appropriate mass range (100-2000 Daltons) may be used as mass tags.

[0050] The terms "measurable affinity" and "measurably inhibit," as used herein, refer to a measurable change in TYK2 protein kinase activity between a sample containing a compound of the present invention or a composition thereof and TYK2 protein kinase and an equivalent sample containing TYK2 protein kinase in the absence of the compound or composition thereof. 3. Description of Exemplary Embodiments:

[0051] As described above, in certain embodiments, the present invention provides a compound of formula I': [ka] providing R 1 -L 1 -R 1A and L1 is a covalent bond; or a bivalent saturated or unsaturated linear or branched C 1~6 a hydrocarbon chain, one or two methylene units of said chain being -C(R) 2 -;-N(R)-;-N(R)C(O)-;-C(O)N(R)-;-N(R)S(O) 2 -;-S(O) 2 N(R)-;-O-;-C(O)-;-OC(O)-;-C(O)O-;-S-;-S(O)-;-S(O) 2 or -Cy-, Cy is an optionally substituted 5-6 membered divalent monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an optionally substituted 8-10 membered divalent bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an optionally substituted 3-7 membered saturated or partially unsaturated divalent carbocyclic ring; or an optionally substituted 7-12 membered saturated or partially unsaturated divalent bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 1A is oxo; halogen; -CN; -NO 2 ;-OR;-SR;-NR 2 ;-S(O) 2 R;-S(O) 2 NR 2 ;-S(O)R;-S(O)NR 2 ;-C(O)R;-C(O)OR;-C(O)NR 2 ;-C(O)N(R)OR;-OC(O)R;-OC(O)NR 2 ;-N(R)C(O)OR;-N(R)C(O)R;-N(R)C(O)NR 2 ;-N(R)C(NR)NR 2 ;-N(R)S(O) 2 NR 2 ;-N(R)S(O) 2 R; C substituted as necessary 1~6an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; an optionally substituted 8-10 membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring; an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, R 2 is -C(O)NH 2 ;-C(O)NHR 2A ;-C(O)N(R 2A ) 2 or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; The heteroaryl ring is selected from m instances of R 2B is replaced by R 2A is C 1~6 an aliphatic group; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 3-7 membered saturated or partially unsaturated carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, R 2A is n examples of R 2C is replaced by Two R on the same carbon 2Cthe substituents, optionally taken 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 R on adjacent carbons 2C the substituents, optionally taken together, form a 3- to 6-membered saturated or partially unsaturated fused heterocyclic ring having from 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; R 2B is oxo; halogen; -CN; -NO 2 ;-R;-OR;-SR;-NR 2 ;-S(O) 2 R;-S(O) 2 NR 2 ;-S(O)R;-S(O)NR 2 ;-C(O)R;-C(O)OR;-C(O)NR 2 ;-C(O)N(R)OR;-OC(O)R;-OC(O)NR 2 ;-N(R)C(O)OR;-N(R)C(O)R;-N(R)C(O)NR 2 ;-N(R)C(NR)NR 2 ;-N(R)S(O) 2 NR 2 ;or -N(R)S(O) 2 R, R 2C Each example is independently oxo; halogen; -CN; -NO 2 ;-OR;-SR;-NR 2 ;-S(O) 2 R;-S(O) 2 NR 2 ;-S(O)R;-S(O)NR 2 ;-C(O)R;-C(O)OR;-C(O)NR 2 ;-C(O)N(R)OR;-OC(O)R;-OC(O)NR 2 ;-N(R)C(O)OR;-N(R)C(O)R;-N(R)C(O)NR 2 ;-N(R)C(NR)NR 2 ;-N(R)S(O) 2 NR 2 ;-N(R)S(O) 2 R; or C 1~6an optionally substituted group selected from aliphatic; phenyl; a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; two optional substituents on the same carbon optionally join together to form a 3-6 membered saturated or partially unsaturated spiro-fused heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or two optional substituents on adjacent carbons optionally joined together form a 3-6 membered saturated or partially unsaturated fused heterocyclic ring having from 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; R 3 is hydrogen; halogen; -NH 2 ;-NHR 3A ; or -NHC(O)R 3A and R 3A is C 1~6 an aliphatic group; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 3-7 membered saturated or partially unsaturated carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, R 3A p examples of R 3B is replaced by Two R on the same carbon 3B the substituents, optionally taken 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 R on adjacent carbons3B the substituents, optionally taken together, form a 3- to 6-membered saturated or partially unsaturated fused heterocyclic ring having from 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; R 3B Each instance of is independently oxo; halogen; -CN; -NO 2 ;-OR;-SR;-NR 2 ;-S(O) 2 R;-S(O) 2 NR 2 ;-S(O)R;-S(O)NR 2 ;-C(O)R;-C(O)OR;-C(O)NR 2 ;-C(O)N(R)OR;-OC(O)R;-OC(O)NR 2 ;-N(R)C(O)OR;-N(R)C(O)R;-N(R)C(O)NR 2 ;-N(R)C(NR)NR 2 ;-N(R)S(O) 2 NR 2 ;-N(R)S(O) 2 R; or C 1~6 an optionally substituted group selected from aliphatic; a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from phenyl, nitrogen, oxygen, and sulfur; and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; two optional substituents on the same carbon optionally join together to form a 3-6 membered saturated or partially unsaturated spiro-fused heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or two optional substituents on adjacent carbons optionally joined together form a 3-6 membered saturated or partially unsaturated fused heterocyclic ring having from 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; R 4 is R or Or, R 1 and R 4together with the atoms therebetween form a 4-7 membered partially unsaturated ring or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, said ring being selected from R 1A is replaced by Each R is independently hydrogen; or C 1~6 an optionally substituted group selected from aliphatic; phenyl; 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; and 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or two R groups on the same nitrogen, together with the atoms between them, form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having, in addition to said nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each hydrogen bonded to a carbon can be optionally independently replaced by deuterium; m is 0, 1 or 2; n is 0, 1 or 2; p is 0, 1 or 2).

[0052] As described above, in certain embodiments, the present invention provides a compound of formula I': [ka] providing R 1 -L 1 -R 1A and L 1 is a covalent bond; or a bivalent saturated or unsaturated linear or branched C 1~6 a hydrocarbon chain, one or two methylene units of said chain being -C(R) 2 -;-N(R)-;-N(R)C(O)-;-C(O)N(R)-;-N(R)S(O) 2 -;-S(O) 2N(R)-;-O-;-C(O)-;-OC(O)-;-C(O)O-;-S-;-S(O)-;-S(O) 2 or -Cy-, Cy is an optionally substituted 5-6 membered divalent monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an optionally substituted 8-10 membered divalent bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an optionally substituted 3-7 membered saturated or partially unsaturated divalent carbocyclic ring; or an optionally substituted 7-12 membered saturated or partially unsaturated divalent bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 1A is oxo; halogen; -CN; -NO 2 ;-OR;-SR;-NR 2 ;-S(O) 2 R;-S(O) 2 NR 2 ;-S(O)R;-S(O)NR 2 ;-C(O)R;-C(O)OR;-C(O)NR 2 ;-C(O)N(R)OR;-OC(O)R;-OC(O)NR 2 ;-N(R)C(O)OR;-N(R)C(O)R;-N(R)C(O)NR 2 ;-N(R)C(NR)NR 2 ;-N(R)S(O) 2 NR 2 ;-N(R)S(O) 2 R; C substituted as necessary 1~6an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; an optionally substituted 8-10 membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring; an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, R 2 -C(O)OH, -C(O)NH 2 ;-C(O)NHR 2A ;-C(O)N(R 2A ) 2 or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; The heteroaryl ring is selected from m instances of R 2B is replaced by R 2A is C 1~6 an aliphatic group; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 3-7 membered saturated or partially unsaturated carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, R 2A is n examples of R 2C is replaced by Two R on the same carbon 2Cthe substituents, optionally taken 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 R on adjacent carbons 2C the substituents, optionally taken together, form a 3- to 6-membered saturated or partially unsaturated fused heterocyclic ring having from 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; R 2B is oxo; halogen; -CN; -NO 2 ;-R;-OR;-SR;-NR 2 ;-S(O) 2 R;-S(O) 2 NR 2 ;-S(O)R;-S(O)NR 2 ;-C(O)R;-C(O)OR;-C(O)NR 2 ;-C(O)N(R)OR;-OC(O)R;-OC(O)NR 2 ;-N(R)C(O)OR;-N(R)C(O)R;-N(R)C(O)NR 2 ;-N(R)C(NR)NR 2 ;-N(R)S(O) 2 NR 2 ;or -N(R)S(O) 2 R, R 2C Each example is independently oxo; halogen; -CN; -NO 2 ;-OR;-SR;-NR 2 ;-S(O) 2 R;-S(O) 2 NR 2 ;-S(O)R;-S(O)NR 2 ;-C(O)R;-C(O)OR;-C(O)NR 2 ;-C(O)N(R)OR;-OC(O)R;-OC(O)NR 2 ;-N(R)C(O)OR;-N(R)C(O)R;-N(R)C(O)NR 2 ;-N(R)C(NR)NR 2 ;-N(R)S(O) 2 NR 2 ;-N(R)S(O) 2 R; or C 1~6an optionally substituted group selected from aliphatic; phenyl; a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; two optional substituents on the same carbon optionally join together to form a 3-6 membered saturated or partially unsaturated spiro-fused heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or two optional substituents on adjacent carbons optionally joined together form a 3-6 membered saturated or partially unsaturated fused heterocyclic ring having from 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; R 3 is hydrogen; halogen; -NH 2 ;-NHR 3A ;-NHC(O)R 3A , or -NR 3A Boc, R 3A is C 1~6 an aliphatic group; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 3-7 membered saturated or partially unsaturated carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, R 3A p examples of R 3B is replaced by Two R on the same carbon 3B the substituents, optionally taken 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 R on adjacent carbons 3B the substituents, optionally taken together, form a 3- to 6-membered saturated or partially unsaturated fused heterocyclic ring having from 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; R 3B Each instance of is independently oxo; halogen; -CN; -NO 2 ;-OR;-SR;-NR 2 ;-S(O) 2 R;-S(O) 2 NR 2 ;-S(O)R;-S(O)NR 2 ;-C(O)R;-C(O)OR;-C(O)NR 2 ;-C(O)N(R)OR;-OC(O)R;-OC(O)NR 2 ;-N(R)C(O)OR;-N(R)C(O)R;-N(R)C(O)NR 2 ;-N(R)C(NR)NR 2 ;-N(R)S(O) 2 NR 2 ;-N(R)S(O) 2 R; or C 1~6 an optionally substituted group selected from aliphatic; a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from phenyl, nitrogen, oxygen, and sulfur; and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; two optional substituents on the same carbon optionally join together to form a 3-6 membered saturated or partially unsaturated spiro-fused heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or two optional substituents on adjacent carbons optionally joined together form a 3-6 membered saturated or partially unsaturated fused heterocyclic ring having from 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; R 4 is R or -OR, Or, R 1 and R 4together with the atoms therebetween form a 4-7 membered partially unsaturated ring or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, said ring being selected from R 1A or replaced by Or, R 3 and R 4 together with the atoms therebetween form a 4-7 membered partially unsaturated ring or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; Each R is independently hydrogen; or C 1~6 an optionally substituted group selected from aliphatic; phenyl; 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; and 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or two R groups on the same nitrogen, together with the atoms between them, form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having, in addition to said nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each hydrogen bonded to a carbon can be optionally independently replaced by deuterium; m is 0, 1 or 2; n is 0, 1 or 2; p is 0, 1 or 2).

[0053] As generally defined above, R 1 -L 1 -R 1A It is.

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

[0055] As generally defined above, L 1 is a covalent bond; or a bivalent saturated or unsaturated linear or branched C 1~6It is a hydrocarbon chain in which one or two methylene units are -C(R) 2 -;-N(R)-;-N(R)C(O)-;-C(O)N(R)-;-N(R)S(O) 2 -;-S(O) 2 N(R)-;-O-;-C(O)-;-OC(O)-;-C(O)O-;-S-;-S(O)-;-S(O) 2 or -Cy-, optionally independently replaced by -;

[0056] In some embodiments, L 1 is a covalent bond. In some embodiments, L 1 is a divalent saturated linear C 1~6 It is a hydrocarbon chain in which one or two methylene units are -C(R) 2 -, -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O) 2 -, -S(O) 2 N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, -S(O) 2 In some embodiments, L is optionally independently replaced by - or -Cy-. 1 is a divalent unsaturated linear C 1~6 It is a hydrocarbon chain in which one or two methylene units are -C(R) 2 -, -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O) 2 -, -S(O) 2 N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, -S(O) 2 In some embodiments, L is optionally independently replaced by - or -Cy-. 1 is a bivalent saturated branched C 1~6 It is a hydrocarbon chain in which one or two methylene units are -C(R) 2 -, -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O) 2 -, -S(O) 2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, -S(O) 2 In some embodiments, L is optionally independently replaced by - or -Cy-. 1 is a divalent unsaturated branched C 1~6 It is a hydrocarbon chain in which one or two methylene units are -C(R) 2 -, -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O) 2 -, -S(O) 2 N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, -S(O) 2 - or -Cy- are optionally independently replaced.

[0057] In some embodiments, L 1 In some embodiments, L 1 is -N(H)-. In some embodiments, L 1 In some embodiments, L is -Cy-. 1 In some embodiments, L is -Cy-N(R)-. 1 is -Cy-NH-.

[0058] In some embodiments, L 1 teeth, [ka] In some embodiments, L 1 teeth, [ka] In some embodiments, L 1 teeth, [ka] In some embodiments, L 1 teeth, [ka] In some embodiments, L 1 teeth, [ka] In some embodiments, L 1 teeth, [ka] In some embodiments, L 1 teeth, [ka] In some embodiments, L 1 teeth, [ka] It is.

[0059] In some embodiments, L 1 teeth, [ka] In some embodiments, L 1 teeth, [ka] In some embodiments, L 1 teeth, [ka] In some embodiments, L 1 teeth, [ka] In some embodiments, L 1 teeth, [ka] In some embodiments, L 1 teeth, [ka] In some embodiments, L 1 teeth, [ka] In some embodiments, L 1 teeth, [ka] It is.

[0060] In some embodiments, L 1 teeth, [ka] It is.

[0061] In some embodiments, L 1 teeth, [ka] It is.

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

[0063] As generally defined above, Cy is an optionally substituted 5-6 membered divalent monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an optionally substituted 8-10 membered divalent bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an optionally substituted 3-7 membered saturated or partially unsaturated divalent carbocyclic ring; or an optionally substituted 7-12 membered saturated or partially unsaturated divalent bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0064] In some embodiments, Cy is an optionally substituted 5-6 membered divalent monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy is an optionally substituted 8-10 membered divalent bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy is an optionally substituted 3-7 membered divalent saturated carbocyclic ring. In some embodiments, Cy is an optionally substituted 3-7 membered divalent partially unsaturated carbocyclic ring. In some embodiments, Cy is an optionally substituted 7-12 membered saturated divalent bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy is an optionally substituted 7-12 membered divalent partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0065] In some embodiments, Cy is [ka] In some embodiments, Cy is [ka] In some embodiments, Cy is [ka] In some embodiments, Cy is [ka] In some embodiments, Cy is [ka] In some embodiments, Cy is [ka] In some embodiments, Cy is [ka] In some embodiments, Cy is [ka] It is.

[0066] In some embodiments, Cy is [ka] In some embodiments, Cy is [ka] In some embodiments, Cy is [ka] In some embodiments, Cy is [ka] In some embodiments, Cy is [ka] In some embodiments, Cy is [ka] In some embodiments, Cy is [ka] In some embodiments, Cy is [ka] It is.

[0067] In some embodiments, Cy is [ka] It is.

[0068] In some embodiments, Cy is [ka] It is.

[0069] In some embodiments, Cy is selected from those shown in Table 1 below.

[0070] As generally defined above, R 1A is oxo; halogen; -CN; -NO 2 ;-OR;-SR;-NR 2 ;-S(O) 2 R;-S(O) 2 NR 2 ;-S(O)R;-S(O)NR 2 ;-C(O)R;-C(O)OR;-C(O)NR 2 ;-C(O)N(R)OR;-OC(O)R;-OC(O)NR 2 ;-N(R)C(O)OR;-N(R)C(O)R;-N(R)C(O)NR 2 ;-N(R)C(NR)NR 2 ;-N(R)S(O) 2 NR 2 ;-N(R)S(O) 2 R; C substituted as necessary 1~6an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; an optionally substituted 8-10 membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring; an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0071] In some embodiments, R 1A In some embodiments, R 1A is a halogen. In some embodiments, R 1A In some embodiments, R 1A -NO 2 In some embodiments, R 1A is -OR. In some embodiments, R 1A In some embodiments, R 1A -NR 2 In some embodiments, R 1A -S(O) 2 R. In some embodiments, R 1A -S(O) 2 NR 2 In some embodiments, R 1A is -S(O)R. In some embodiments, R 1A is -S(O)NR 2 In some embodiments, R 1A is -C(O)R. In some embodiments, R 1A is -C(O)OR. In some embodiments, R 1A is -C(O)NR 2 In some embodiments, R 1Ais -C(O)N(R)OR. In some embodiments, R 1A is -OC(O)R. In some embodiments, R 1A is -OC(O)NR 2 In some embodiments, R 1A is -N(R)C(O)OR. In some embodiments, R 1A is -N(R)C(O)R. In some embodiments, R 1A is -N(R)C(O)NR 2 In some embodiments, R 1A is -N(R)C(NR)NR 2 In some embodiments, R 1A is -N(R)S(O) 2 NR 2 In some embodiments, R 1A is -N(R)S(O) 2 It's R.

[0072] In some embodiments, R 1A is replaced as necessary 1~6 In some embodiments, R 1A is phenyl. In some embodiments, R 1A is an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1A is an optionally substituted 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1A is an optionally substituted 3- to 7-membered saturated carbocyclic ring. 1A is an optionally substituted 3- to 7-membered partially unsaturated carbocyclic ring. In some embodiments, R 1A is an optionally substituted 3-7 membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1Ais an optionally substituted 3-7 membered partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1A is an optionally substituted 7-12 membered saturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 1A is an optionally substituted 7-12 membered partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0073] In some embodiments, R 1A is the following: [ka] is selected from.

[0074] In some embodiments, R 1A is the following: [ka] [ka] is selected from.

[0075] In some embodiments, R 1A is the following: [ka] is selected from.

[0076] In some embodiments, R 1A is the following: [ka] is selected from.

[0077] In some embodiments, R 1A teeth, [ka] It is.

[0078] In some embodiments, R 1A is the following: [ka] is selected from.

[0079] In some embodiments, R 1A is the following: [ka] is selected from.

[0080] In some embodiments, R 1A -NR 2 In some embodiments, R 1A is -N(H)Me.

[0081] In some embodiments, R 1A is selected from those shown in Table 1 below.

[0082] As generally defined above, R 2 -C(O)OH, -C(O)NH 2 ;-C(O)NHR 2A ;-C(O)N(R 2A ) 2 or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, said heteroaryl ring being selected from m instances of R 2B has been replaced by

[0083] In some embodiments, R 2 is —C(O)OH. In some embodiments, R 2 is -C(O)NH 2 In some embodiments, R 2 is -C(O)NHR 2A In some embodiments, R 2is -C(O)N(R 2A ) 2 It is.

[0084] In some embodiments, R 2 is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, said heteroaryl ring being selected from m instances of R 2B has been replaced by

[0085] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] It is.

[0086] In some embodiments, R 2 is selected from those shown in Table 1 below.

[0087] As generally defined above, R 2A is C 1~6 an aliphatic group; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and R 2A is n examples of R 2C and two R on the same carbon 2CThe substituents, optionally taken 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 R 2C The substituents, optionally taken together, form a 3- to 6-membered saturated or partially unsaturated fused heterocyclic ring having from 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0088] In some embodiments, R 2A is C 1~6 In some embodiments, R 2A is phenyl. In some embodiments, R 2A is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2A is an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2A is a 3-7 membered saturated carbocyclic ring. 2A is a 3- to 7-membered partially unsaturated carbocyclic ring. 2A is a 7-12 membered saturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2A is a 7-12 membered partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0089] In some embodiments, R 2A is n examples of R 2C has been replaced by

[0090] In some embodiments, two R 2C The substituents, optionally taken together, form a 3-6 membered saturated spiro-fused heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, two R2C The substituents, optionally taken together, form a 3- to 6-membered partially unsaturated spiro-fused heterocyclic ring having from 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0091] In some embodiments, two R on adjacent carbons 2C The substituents, optionally taken together, form a 3-6 membered saturated fused heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R 2C The substituents, optionally taken together, form a 3- to 6-membered partially unsaturated fused heterocyclic ring having from 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0092] In some embodiments, R 2A is the following: [ka] [ka] is selected from.

[0093] In some embodiments, R 2A is the following: [ka] is selected from.

[0094] In some embodiments, R 2A is selected from those shown in Table 1 below.

[0095] As generally defined above, R 2B is oxo, halogen; -CN; -NO 2 ;-R;-OR;-SR;-NR 2 ;-S(O) 2 R;-S(O) 2 NR 2 ;-S(O)R;-S(O)NR 2;-C(O)R;-C(O)OR;-C(O)NR 2 ;-C(O)N(R)OR;-OC(O)R;-OC(O)NR 2 ;-N(R)C(O)OR;-N(R)C(O)R;-N(R)C(O)NR 2 ;-N(R)C(NR)NR 2 ;-N(R)S(O) 2 NR 2 ;or -N(R)S(O) 2 It's R.

[0096] In some embodiments, R 2B In some embodiments, R 2B In some embodiments, R 2B -NO 2 In some embodiments, R 2B is -R. In some embodiments, R 2B is -OR. In some embodiments, R 2B In some embodiments, R 2B -NR 2 In some embodiments, R 2B -S(O) 2 R. In some embodiments, R 2B -S(O) 2 NR 2 In some embodiments, R 2B is -S(O)R. In some embodiments, R 2B is -S(O)NR 2 In some embodiments, R 2B is -C(O)R. In some embodiments, R 2B is -C(O)OR. In some embodiments, R 2B is -C(O)NR 2 In some embodiments, R 2B is -C(O)N(R)OR. In some embodiments, R 2B is -OC(O)R. In some embodiments, R 2B is -OC(O)NR 2 In some embodiments, R 2Bis -N(R)C(O)OR. In some embodiments, R 2B is -N(R)C(O)R. In some embodiments, R 2B is -N(R)C(NR)NR 2 In some embodiments, R 2B is -N(R)S(O) 2 NR 2 In some embodiments, R 2B is -N(R)S(O) 2 It's R.

[0097] In some embodiments, R 2B is isopropyl.

[0098] In some embodiments, R 2B is selected from those shown in Table 1 below.

[0099] As generally defined above, R 2C is oxo; halogen; -CN; -NO 2 ;-OR;-SR;-NR 2 ;-S(O) 2 R;-S(O) 2 NR 2 ;-S(O)R;-S(O)NR 2 ;-C(O)R;-C(O)OR;-C(O)NR 2 ;-C(O)N(R)OR;-OC(O)R;-OC(O)NR 2 ;-N(R)C(O)OR;-N(R)C(O)R;-N(R)C(O)NR 2 ;-N(R)C(NR)NR 2 ;-N(R)S(O) 2 NR 2 ;-N(R)S(O) 2 R; or C 1~6an optionally substituted group selected from aliphatic; phenyl; a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, where two optional substituents on the same carbon optionally join together to form a 3- to 6-membered saturated or partially unsaturated spiro-fused heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two optional substituents on adjacent carbons optionally join together to form a 3- to 6-membered saturated or partially unsaturated fused heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0100] In some embodiments, R 2C In some embodiments, R 2C In some embodiments, R 2C -NO 2 In some embodiments, R 2C is -R. In some embodiments, R 2C is -OR. In some embodiments, R 2C In some embodiments, R 2C -NR 2 In some embodiments, R 2C -S(O) 2 R. In some embodiments, R 2C -S(O) 2 NR 2 In some embodiments, R 2C is -S(O)R. In some embodiments, R 2C is -S(O)NR 2 In some embodiments, R 2C is -C(O)R. In some embodiments, R 2C is -C(O)OR. In some embodiments, R 2C is -C(O)NR 2 In some embodiments, R 2Cis -C(O)N(R)OR. In some embodiments, R 2C is -OC(O)R. In some embodiments, R 2C is -OC(O)NR 2 In some embodiments, R 2C is -N(R)C(O)OR. In some embodiments, R 2C is -N(R)C(O)R. In some embodiments, R 2C is -N(R)C(NR)NR 2 In some embodiments, R 2C is -N(R)S(O) 2 NR 2 In some embodiments, R 2C is -N(R)S(O) 2 It's R.

[0101] In some embodiments, R 2C is replaced as necessary 1~6 In some embodiments, R 2C is an optionally substituted phenyl group. In some embodiments, R 2C is an optionally substituted 3-7 membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2C is an optionally substituted 3-7 membered partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2C is an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0102] In some embodiments, two optional substituents on the same carbon optionally join together to form a 3-6 membered saturated or partially unsaturated spiro-fused heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two optional substituents on adjacent carbons optionally join together to form a 3-6 membered saturated or partially unsaturated fused heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0103] In some embodiments, R 2C is selected from those shown in Table 1 below.

[0104] As generally defined above, R 3 is hydrogen, halogen, -NH 2 , -NHR 3A , -NHC(O)R 3A or -NR 3A It is Boc.

[0105] In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is a halogen. In some embodiments, R 3 is -NH 2 In some embodiments, R 3 -NHR 3A In some embodiments, R 3 is -NHC(O)R 3A In some embodiments, R 3 -NR 3A It is Boc.

[0106] In some embodiments, R 3 -NHR 3A It is.

[0107] In some embodiments, R 3 is -C(O)NHR 3A It is.

[0108] In some embodiments, R 3is -N(Me)Boc.

[0109] In some embodiments, R 3 is selected from those shown in Table 1 below.

[0110] As generally described above, R 3A is C 1~6 an aliphatic group; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and R 3A p examples of R 3B and two R on the same carbon 3B The substituents, optionally taken together, form a 3-6 membered saturated or partially unsaturated spiro-fused heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or two R on adjacent carbons. 3B The substituents, optionally taken together, form a 3- to 6-membered saturated or partially unsaturated fused heterocyclic ring having from 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0111] In some embodiments, R 3A is C 1~6 In some embodiments, R 3A is phenyl. In some embodiments, R 3A is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 3Ais an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 3A is a 3-7 membered saturated carbocyclic ring. 3A is a 3- to 7-membered partially unsaturated carbocyclic ring. 3A is a 3-7 membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 3A is a 3-7 membered partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 3A is a 7-12 membered saturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 3A is a 7-12 membered partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0112] In some embodiments, R 3A p examples of R 3B has been replaced by

[0113] In some embodiments, two R 3B The substituents, optionally taken together, form a 3-6 membered saturated spiro-fused heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, two R 3B The substituents, optionally taken together, form a 3-6 membered partially unsaturated spiro-fused heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, two R 3B The substituents, optionally taken together, form a 3-6 membered saturated fused heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R 3BThe substituents, optionally taken together, form a 3- to 6-membered partially unsaturated fused heterocyclic ring having from 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0114] In some embodiments, R 3A is methyl. In some embodiments, R 3A is ethyl.

[0115] In some embodiments, R 3A is selected from those shown in Table 1 below.

[0116] As generally described above, R 3B is oxo; halogen; -CN; -NO 2 ;-OR;-SR;-NR 2 ;-S(O) 2 R;-S(O) 2 NR 2 ;-S(O)R;-S(O)NR 2 ;-C(O)R;-C(O)OR;-C(O)NR 2 ;-C(O)N(R)OR;-OC(O)R;-OC(O)NR 2 ;-N(R)C(O)OR;-N(R)C(O)R;-N(R)C(O)NR 2 ;-N(R)C(NR)NR 2 ;-N(R)S(O) 2 NR 2 ;-N(R)S(O) 2 R; or C 1~6An optionally substituted group selected from a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein two optional substituents on the same carbon optionally join together to 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 optional substituents on adjacent carbons optionally join together to 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.

[0117] In some embodiments, R 3B In some embodiments, R 3B is a halogen. In some embodiments, R 3B In some embodiments, R 3B -NO 2 In some embodiments, R 3B is -OR. In some embodiments, R 3B In some embodiments, R 3B -NR 2 In some embodiments, R 3B -S(O) 2 R. In some embodiments, R 3B -S(O) 2 NR 2 In some embodiments, R 3B is -S(O)R. In some embodiments, R 3B is -S(O)NR 2 In some embodiments, R 3B is -C(O)R. In some embodiments, R 3B is -C(O)OR. In some embodiments, R 3B is -C(O)NR 2 In some embodiments, R 3Bis -C(O)N(R)OR. In some embodiments, R 3B is -OC(O)R. In some embodiments, R 3B is -OC(O)NR 2 In some embodiments, R 3B is -N(R)C(O)OR. In some embodiments, R 3B is -N(R)C(O)R. In some embodiments, R 3B is -N(R)C(O)NR 2 In some embodiments, R 3B is -N(R)C(NR)NR 2 In some embodiments, R 3B is -N(R)S(O) 2 NR 2 In some embodiments, R 3B is -N(R)S(O) 2 It's R.

[0118] In some embodiments, R 3B is -OR.

[0119] In some embodiments, R 3B is replaced as necessary 1~6 In some embodiments, R 3B is an optionally substituted phenyl group. In some embodiments, R 3B is a 3-7 membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 3B is a 3-7 membered partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 3B is an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0120] In some embodiments, two optional substituents on the same carbon optionally join together to form a 3-6 membered saturated spiro-fused heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two optional substituents on the same carbon optionally join together to form a 3-6 membered partially unsaturated spiro-fused heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two optional substituents on adjacent carbons optionally join together to form a 3-6 membered saturated fused heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two optional substituents on adjacent carbons optionally join together to form a 3-6 membered partially unsaturated fused heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0121] As generally defined above, R 4 is R or -OR; or R 1 and R 4 together with the atoms therebetween form a 4-7 membered partially unsaturated ring or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, said ring being selected from R 1A or R 3 and R 4 together with the atoms between them form a 4-7 membered partially unsaturated ring or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0122] In some embodiments, R 4 is R. In some embodiments, R 4 is -OR.

[0123] In some embodiments, R 1 and R 4together with the atoms therebetween form a 4-7 membered partially unsaturated ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, said ring being 1A In some embodiments, R 1 and R 4 together with the atoms therebetween form a 4-7 membered heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, said ring being selected from R 1A has been replaced by

[0124] In some embodiments, R 3 and R 4 together with the atoms between them form a 4-7 membered partially unsaturated ring having 0-3 heteroatoms selected from nitrogen, oxygen, and sulfur. 3 and R 4 together with the atoms between them form a 4-7 membered heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0125] In some embodiments, R 4 is H.

[0126] In some embodiments, R 4 is selected from those shown in Table 1 below.

[0127] Each R is independently hydrogen or C, as generally defined above. 1~6an optionally substituted group selected from aliphatic, phenyl, 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R groups on the same nitrogen, taken together with the atom between them, form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0128] In some embodiments, R is hydrogen. In some embodiments, R is optionally substituted C 1~6 In some embodiments, R is an optionally substituted phenyl group. In some embodiments, R is an optionally substituted 3-7 membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 3-7 membered partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0129] In some embodiments, two R groups on the same nitrogen, together with the atoms between them, form a 4-7 membered saturated ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R groups on the same nitrogen, together with the atoms between them, form a 4-7 membered partially unsaturated ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R groups on the same nitrogen, together with the atoms between them, form a 4-7 membered heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0130] In some embodiments, R is selected from those shown in Table 1 below.

[0131] As generally defined above, each hydrogen bonded to a carbon can be optionally independently replaced by deuterium.

[0132] As generally defined above, m is 0, 1, or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2.

[0133] In some embodiments, m is selected from those shown in Table 1 below.

[0134] As generally defined above, n is 0, 1, or 2. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, m is 2.

[0135] In some embodiments, n is selected from those shown in Table 1 below.

[0136] As generally defined above, p is 0, 1, or 2. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2.

[0137] In some embodiments, p is selected from those shown in Table 1 below.

[0138] In some embodiments, the present invention provides a compound of formula II: [ka] or a pharma- ceutically acceptable salt thereof, 1A , Cy, R 2 , R 3 and R 4are each as defined above, both alone and in combination, and as described in embodiments herein.

[0139] In some embodiments, the present invention provides a compound of formula III: [ka] or a pharma- ceutically acceptable salt thereof, 1A , R 2 and R 3 are each as defined above, both alone and in combination, and as described in embodiments herein.

[0140] In some embodiments, the present invention provides a compound of formula IV: [ka] or a pharma- ceutically acceptable salt thereof, 1A , Cy, R 2 , R 3 and R 4 are each as defined above, both alone and in combination, and as described in embodiments herein.

[0141] In some embodiments, the present invention provides a compound of formula V: [ka] or a pharma- ceutically acceptable salt thereof, 1A , R 2 , R 3 and R 4 are each as defined above, both alone and in combination, and as described in embodiments herein.

[0142] In some embodiments, the present invention provides a compound of formula VI: [ka] or a pharma- ceutically acceptable salt thereof, 1 , R 2A , R 3 and R 4 are each as defined above, both alone and in combination, and as described in embodiments herein.

[0143] In some embodiments, the present invention provides a compound of formula VII: [ka] or a pharma- ceutically acceptable salt thereof, 1 , R 2B , R 3 and R 4 are each as defined above, both alone and in combination, and as described in embodiments herein.

[0144] In some embodiments, the present invention provides a compound of formula VIII: [ka] or a pharma- ceutically acceptable salt thereof, 1 , R 2 and R 4 are each as defined above, both alone and in combination, and as described in embodiments herein.

[0145] In some embodiments, the present invention provides a compound of formula IX: [ka] or a pharma- ceutically acceptable salt thereof, 1A , R 2A and R 4 are each as defined above, both alone and in combination, and as described in embodiments herein.

[0146] In some embodiments, the present invention provides a compound of formula X: [ka] or a pharma- ceutically acceptable salt thereof, 1A , R 2A and R 4 are each as defined above, both alone and in combination, and as described in embodiments herein.

[0147] In some embodiments, the present invention provides a compound of formula XI: [ka] or a pharma- ceutically acceptable salt thereof, 1A , R 2A and R 4 are each as defined above, both alone and in combination, and as described in embodiments herein.

[0148] In some embodiments, the present invention provides a compound of formula XII: [ka] or a pharma- ceutically acceptable salt thereof, 1A , R 2A and R 4 are each as defined above, both alone and in combination, and as described in embodiments herein.

[0149] In some embodiments, the present invention provides a compound of formula XIII: [ka] or a pharma- ceutically acceptable salt thereof, 1A , R 2A and R 4 are each as defined above, both alone and in combination, and as described in embodiments herein.

[0150] In some embodiments, the present invention provides a compound of formula XIV: [ka] or a pharma- ceutically acceptable salt thereof, 1A , R 2A and R 4 are each as defined above, both alone and in combination, and as described in embodiments herein.

[0151] In some embodiments, the present invention provides a compound of formula XV: [ka] or a pharma- ceutically acceptable salt thereof, 1 and R 2 are each as defined above, both alone and in combination, and as described in embodiments herein.

[0152] In some embodiments, the present invention provides a compound of formula XVI: [ka] or a pharma- ceutically acceptable salt thereof, 1A , R 2A and R 4 are each as defined above, both alone and in combination, and as described in embodiments herein.

[0153] In some embodiments, the present invention provides a compound of formula XVII: [ka] or a pharma- ceutically acceptable salt thereof, 1A , R 2A and R 4 are each as defined above, both alone and in combination, and as described in embodiments herein.

[0154] In some embodiments, the present invention provides a compound of formula XVIII: [ka] or a pharma- ceutically acceptable salt thereof, 1A , R 2 , R 3 and R 4 are each as defined above, both alone and in combination, and as described in embodiments herein.

[0155] In some embodiments, the present invention provides a compound of formula XIX: [ka] or a pharma- ceutically acceptable salt thereof, 1A , R 2A and R 4 are each as defined above, both alone and in combination, and as described in embodiments herein.

[0156] In some embodiments, the present invention provides a compound of formula XX: [ka]

[0157] or a pharma- ceutically acceptable salt thereof, 1A , R 2A and R 4 are each as defined above, both alone and in combination, and as described in embodiments herein. Exemplary compounds of the invention are set forth in Table 1 below. [Table 1-1] [Table 1-2]

Table 1-3

Table 1-4

Table 1-5

Table 1-6

Table 1-7

Table 1-8

Table 1-9

Table 1-10

Table 1-11

Table 1-12

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

Table 1-23

Table 1-24

Table 1-25

Table 1-26

Table 1-27

Table 1-28

Table 1-29

Table 1-30

Table 1-31

Table 1-32

Table 1-33

Table 1-34

Table 1-35

Table 1-36

Table 1-37

Table 1-38

Table 1-39

Table 1-40

Table 1-41

Table 1-42

Table 1-43

Table 1-44

Table 1-45

Table 1-46

Table 1-47

Table 1-48

Table 1-49

Table 1-50

Table 1-51

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

[0158] In some embodiments, the method employs a compound set forth in Table 1 above, or a pharma- ceutically acceptable salt thereof. In some embodiments, the invention provides a compound set forth in Table 1 above, or a pharma- ceutically acceptable salt thereof. In some embodiments, the invention provides a pharmaceutical composition comprising a compound set forth in Table 1 above, or a pharma- ceutically acceptable salt thereof, together with a pharma- ceutically acceptable carrier, excipient, or diluent.

[0159] Without wishing to be bound by any particular theory, it is believed that the proximity of the inhibitor compound, or the pendant moiety of an inhibitor compound, to the water of interest facilitates the displacement or obstruction of the water by the inhibitor compound or the pendant moiety of an inhibitor compound. In some embodiments, the water molecule displaced or obstructed by the inhibitor compound or the pendant moiety of an inhibitor compound is a labile water molecule.

[0160] In certain embodiments, the method uses a complex comprising TYK2 and an inhibitor, where at least one labile water of TYK2 is replaced or obstructed by the inhibitor, hi some embodiments, at least two selected labile waters are replaced or obstructed by the inhibitor. 4. General Methods of Providing the Compounds

[0161] The compounds of the invention may generally be prepared or isolated by synthetic and / or semi-synthetic methods known to those skilled in the art for similar compounds, as well as by methods detailed in the Examples herein. 5. Use, Prescription and Administration Pharmaceutically acceptable compositions

[0162] According to another embodiment, the present invention provides a composition comprising a compound of the present invention, or a pharma- ceutically acceptable derivative thereof, and a pharma- ceutically 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 a mutant thereof 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 a mutant thereof in a biological sample or in a patient. In certain embodiments, the composition of the present invention is formulated for administration to a patient in need of such a composition. In some embodiments, the composition of the present invention is formulated for oral administration to a patient.

[0163] The term "patient", as used herein, means an animal, preferably a mammal, and most preferably a human.

[0164] 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 with which it is formulated. Pharmaceutically acceptable carriers, adjuvants, or vehicles that can be used in the compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, 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, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat.

[0165] "Pharmaceutically acceptable derivative" means any non-toxic salt, ester, salt of an ester, or other derivative of a compound of this invention which, upon administration to a recipient, is capable of providing, directly or indirectly, a compound of this invention, or an inhibitory active metabolite or residue thereof.

[0166] As used herein, the term "inhibitorily active metabolite or residue thereof" means that a metabolite or residue thereof is also an inhibitor of TYK2 protein kinase or a mutant thereof.

[0167] The compositions of the present invention can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, bucally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously. Sterile injectable forms of the compositions of this invention may be aqueous or oily suspensions. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations may also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, such as, for example, solutions in 1,3-butanediol. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as solvents or suspending media.

[0168] For this purpose, any non-irritating fixed oil can be used, including synthetic mono- or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives, especially in their polyoxyethylated form, are useful for the preparation of injectables, as are natural pharmaceutically acceptable oils such as olive oil or castor oil. These oil solutions or suspensions can also contain long-chain alcohol diluents or dispersants, such as carboxymethylcellulose or similar dispersants, which are commonly used in the formulation of pharmaceutically acceptable dosage forms, including emulsions or suspensions. Other commonly used surfactants, such as Tween, Span, and other emulsifiers or bioavailability enhancers, which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms, can also be used for formulation purposes.

[0169] The pharmaceutically acceptable composition of this invention can be orally administered in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions or liquids.For tablets for oral use, commonly used carriers include lactose and corn starch.Lubricants such as magnesium stearate are also typically added.For oral administration in capsule form, useful diluents include lactose and dried corn starch.When aqueous suspensions are required for oral use, active ingredient is combined with emulsifying and suspending agents.If desired, certain sweeteners, flavorings or colorings can also be added.

[0170] Alternatively, the pharma- ceutically acceptable compositions of this invention can be administered in the form of suppositories for rectal administration. These can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, and therefore melts in the rectum to release the drug. Such materials include cocoa butter, beeswax, and polyethylene glycols.

[0171] The pharma- ceutically acceptable compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0172] Topical application for the lower intestinal tract may be in a rectal suppository formulation (see above) or in a suitable enema formulation. Topical-transdermal patches may also be used.

[0173] For topical application, the provided pharma- ceutically acceptable composition can be formulated into a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers.Carriers for topical administration of the compounds of the present invention include, but are not limited to, mineral oil, liquid paraffin, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax and water.Alternatively, the provided pharma-ceutically acceptable composition can be formulated into a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharma-ceutically acceptable carriers.Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[0174] For ophthalmic use, the pharma- ceutically acceptable compositions provided may be formulated as micronized suspensions in isotonic, pH-adjusted, sterile saline, or, preferably, as solutions in isotonic, pH-adjusted, sterile saline, with or without a preservative, such as benzylalkonium chloride. Alternatively, for ophthalmic use, the pharma-ceutically acceptable compositions may be formulated in an ointment, such as petrolatum.

[0175] The pharma- ceutically acceptable compositions of this invention may also be administered by nasal aerosol or inhalation.Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0176] Most preferably, the pharma- ceutically acceptable compositions of this invention are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, the pharma- ceutically acceptable compositions of this invention are administered without food. In other embodiments, the pharma- ceutically acceptable compositions of this invention are administered with food.

[0177] The amount of the compounds of the present invention that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending on the host treated, the particular mode of administration. Preferably, the compositions provided should be formulated so that a dosage of between 0.01-100 mg of inhibitor per kg of body weight per day can be administered to a patient receiving these compositions.

[0178] It should also be understood that the specific dosage and treatment regimen for any particular patient will vary depending on a variety of factors, including the activity of the specific compound employed, age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, as well as the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound of the invention in a composition will also vary depending on the particular compound in the composition.

[0179] Compounds and Pharmaceutically Acceptable Compositions 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.

[0180] TYK2 is a non-receptor tyrosine kinase member of the Janus kinase (JAK) family of protein kinases. The mammalian JAK family consists of four members: TYK2, JAK1, JAK2, and JAK3. JAK proteins, including TYK2, are essential for cytokine signaling. TYK2 associates with the cytoplasmic domains of type I and type II cytokine receptors and interferon type I and type III receptors and is activated by these receptors upon cytokine 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 limitins) and interleukins (e.g., IL-4, IL-6, IL-10, IL-11, IL-12, IL-13, IL-22, IL-23, IL-27, IL-31, oncostatin M, ciliary neurotrophic factor, cardiotrophin 1, cardiotrophin-like cytokine, and LIF). Velasquez et al., "A protein kinase in the interferon 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 tyrosine phosphorylation of Tyk2 and Jak1 and the differential assembly of Stat1 and Stat3 complexes in human T cells and monocytes," J. Immunol. (1995) 155:1079; Bacon et al., "Interleukin 12 (IL-12) induces tyrosine phosphorylation of Jak2 and Tyk2: differential use of Janus family kinases by IL-2 and IL-12," J. Exp. Med. (1995) 181:399; Welham et al., "Interleukin-13 signal transduction in lymphohemopoietic cells: similarities and differences in signal transduction with interleukin-4 and insulin," J. Biol. Chem. (1995) 270:12286; Parham et al., “A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rβ1 and "A novel cytokine receptor subunit, IL-23R," J. Immunol. (2002) 168:5699. Activated TYK2 then proceeds to phosphorylate additional signaling proteins, such as members of the STAT family, including STAT1, STAT2, STAT4, and STAT6.

[0181] Activation of TYK2 by IL-23 has been linked to inflammatory bowel disease (IBD), Crohn's disease, and ulcerative colitis. Duerr et al., "A Genome-Wide Association Study Identifies IL23R as an Inflammatory Bowel Disease Gene," Science (2006) 314:1461-1463. As a downstream effector of IL-23, TYK2 also plays a role in psoriasis, ankylosing spondylitis, and Behcet's disease. Cho et al., "Genomics and the multifactorial nature of human auto-immune disease," N. Engl. J. Med (2011) 365:1612-1623; Cortes et al., "Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci," Nat. Genet. (2013) 45(7):730-738; Remmers et al., "Genome-wide association study identifies variants in the MHC class I, IL10, and IL23R-IL12RB2 regions associated with Behcet's disease," Nat. Genet. (2010) 42:698-702. A genome-wide association study of 2,622 individuals with psoriasis identified an association between disease susceptibility and TYK2. Strange et al., "A Genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1," Nat. Genet. (2010) 42:985-992. Knockout or tyrphostin inhibition of TYK2 significantly reduces both IL-23- and IL-22-induced dermatitis. Ishizaki et al., "Tyk2 is a therapeutic "target for psoriasis-like skin inflammation", Intl. Immunol. (2013), doi:10.1093 / intimm / dxt062.

[0182] TYK2 also plays a role in respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), lung cancer, and cystic fibrosis. Goblet cell hyperplasia (GCH) and mucus hypersecretion are mediated by IL-13-induced activation of TYK2, which in turn activates STAT6. Zhang et al., "Docking protein Gab2 regulates Mucin expression and goblet cell hyperplasia through TYK2 / STAT6 pathway”, FASEB J. (2012) 26:1-11.

[0183] Reduced TYK2 activity confers protection of joints from collagen antibody-induced arthritis, a model of human rheumatoid arthritis. Mechanistically, reduced Tyk2 activity protects against T h 1 / T h17-related cytokines and matrix metalloproteinases, as well as other key inflammatory markers. Ishizaki et al., "Tyk2 deficiency protects joints against destruction in anti-type II collagen antibody-induced arthritis in mice," Intl. Immunol. (2011) 23(9):575-582.

[0184] TYK2 knockout mice showed complete resistance to experimental autoimmune encephalomyelitis (EAE, an animal model of multiple sclerosis (MS)) and no infiltration of CD4 T cells into the spinal cord compared to controls, suggesting that TYK2 is essential for the development of pathogenic CD4-mediated disease in MS. Oyamada et al., "Tyrosine Kinase 2 Plays Critical Roles in the Pathogenic CD4 T Cell Responses for the Development of Experimental Autoimmune Encephalomyelitis," J. Immunol. (2009) 183:7539-7546. This confirms previous studies linking increased TYK2 expression with MS susceptibility. Ban et al., "Replication analysis identifies TYK2 as a multiple sclerosis susceptibility factor," Eur J. Hum. Genet. (2009) 17:1309-1313. Loss-of-function mutations in TYK2 result in decreased demyelination and increased remyelination of neurons, further suggesting a role for TYK2 inhibitors in the treatment of MS and other CNS demyelinating disorders.

[0185] TYK2 is the only signaling messenger common to IL-12 and IL-23. TYK2 knockout reduced methylated BSA injection-induced footpad thickness, imiquimod-induced psoriasis-like skin inflammation, and dextran sulfate sodium or 2,4,6-trinitrobenzenesulfonic acid-induced colitis in mice.

[0186] Articulation and association studies of various type I IFN signaling genes with systemic lupus erythematosus (SLE, an autoimmune disorder) have shown a strong and significant correlation between loss-of-function mutations for TYK2 and reduced prevalence of SLE in families containing affected members. Sigurdsson et al., "Polymorphisms in the Tyrosine Kinase 2 and Interferon Regulatory Factor 5 Genes Are Associated with Systemic Lupus Erythematosus," Am. J. Hum. Genet. (2005) 76:528-537. A genome-wide association study of individuals with SLE versus an unaffected cohort showed a highly significant correlation between the TYK2 locus and SLE. Graham et al., "Association of NCF2, IKZF1, IRF8, IFIH1, and TYK2 with Systemic Lupus Erythematosus," Am. J. Hum. Genet. (2005) 76:528-537. "Lupus Erythematosus", PLoS Genetics (2011) Vol. 7 (Issue 10): e1002341.

[0187] TYK2 has been shown to play an important role in maintaining tumor surveillance, and TYK2 knockout mice showed impaired cytotoxic T cell responses and accelerated tumor development. However, these effects were linked to efficient suppression of natural killer (NK) and cytotoxic T lymphocytes, suggesting that TYK2 inhibitors are highly suitable for the treatment of autoimmune disorders or transplant rejection. Although other JAK family members, such as JAK3, have similar roles in the immune system, TYK2 has been suggested to be a better target because it is involved in fewer, more closely related signaling pathways, resulting in fewer off-target effects. Simma et al., "Identification of an Indispensable Role for Tyrosine Kinase 2 in CTL-Mediated Tumor Surveillance," Cancer Res. (2009) 69:203-211.

[0188] However, in contradiction to the decreased tumor surveillance observed by Simma et al., studies in T-cell acute lymphoblastic leukemia (T-ALL) indicate that T-ALL is highly dependent on IL-10 via TYK2 through STAT1-mediated signaling to maintain cancer cell survival by upregulating the anti-apoptotic protein BCL2. Knockdown of TYK2, but not other JAK family members, reduced cell proliferation. Specific activating mutations in TYK2 that promote cancer cell survival include activating mutations in the FERM domain (G36D, S47N, and R425H), JH2 domain (V731I), and kinase domain (E957D and R1027H). However, it was also identified that the kinase function of TYK2 is required for increased cancer cell survival. This is because TYK2 enzymes characterized by kinase-dead mutations (M978Y or M978F) in addition to an activating mutation (E957D) led to failure of transformation. Sanda et al., "TYK2-STAT1-BCL2 Pathway Dependence in T-Cell Acute Lymphoblastic Leukemia”, Cancer Disc. (2013) Volume 3 (No. 5): pp. 564-577.

[0189] Thus, selective inhibition of TYK2 has been suggested to be a suitable target for patients with IL-10 and / or BCL2-addicted tumors, e.g., 70% of cases of adult T-cell leukemia. Fontan et al., "Discovering What Makes STAT Signaling TYK in T-ALL," Cancer Disc. (2013) 3:494-496.

[0190] TYK2-mediated STAT3 signaling has also been shown to mediate neuronal cell death caused by amyloid-β (Aβ) peptide. Decreased TYK2 phosphorylation of STAT3 following Aβ administration results in decreased neuronal cell death, and increased phosphorylation of STAT3 has been observed in postmortem brains of Alzheimer's disease patients. Wan et al., "Tyk / STAT3 Signaling Mediates β-Amyloid-Induced Neuronal Cell Death: Implications in Alzheimer's Disease," J. Neurosci. (2010) 30(20):6873-6881.

[0191] Inhibition of the JAK-STAT signaling pathway is also involved in hair growth and reversal of hair loss associated with alopecia areata. Xing et al., "Alopecia areata is driven by "Apoptosis is mediated by cytotoxic T lymphocytes and is reversed by JAK inhibition," Nat. Med. (2014) 20:1043-1049; Harel et al., "Pharmacologic inhibition of JAK-STAT signaling promotes hair growth," Sci. Adv. (2015) 1(9):e1500973.

[0192] Therefore, compounds that inhibit the activity of TYK2 would be beneficial, particularly those that have high selectivity over JAK2. Such compounds should deliver a pharmacological response that favorably treats one or more of the conditions described herein without the side effects associated with inhibition of JAK2.

[0193] Although TYK2 inhibitors are known in the art, there is still a need to provide new inhibitors that have more effective or advantageous pharmacologic properties.For example, compounds that have increased activity, high selectivity over other JAK kinases (particularly JAK2), and ADMET (absorption, distribution, metabolism, excretion, and / or toxicity) properties.Therefore, in some embodiments, the present invention provides inhibitors of TYK2 that show high selectivity over JAK2.

[0194] The activity of the compounds utilized in this invention as inhibitors of TYK2, or a mutant thereof, may be assayed in vitro, in vivo or in a cell line. In vitro assays include assays that determine the inhibition of either the phosphorylation activity and / or subsequent functional consequences or ATPase activity of activated TYK2 or its mutants. Alternative in vitro assays quantitate the ability of inhibitors to bind to TYK2. Inhibitor binding can be measured by radiolabeling the inhibitor prior to binding, isolating the inhibitor / TYK2 complex, and determining the amount of radiolabel bound. Alternatively, inhibitor binding can be determined by performing a competition experiment in which new inhibitors are incubated with TYK2 bound to a known radioligand. Representative in vitro and in vivo assays useful for assaying TYK2 inhibitors include, for example, those described and disclosed in, each of which is incorporated herein by reference in its entirety. Detailed conditions for assaying compounds utilized in this invention as inhibitors of TYK2 or its mutants are described in the Examples below.

[0195] As used herein, the terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset, or inhibiting the progression of a disease or disorder, or one or more symptoms thereof, as described herein. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., taking into account a history of the symptoms and / or taking into account genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, e.g., to prevent or delay the recurrence of the symptoms.

[0196] The compounds provided are inhibitors of TYK2 and are therefore useful for treating one or more disorders associated with the activity of TYK2 or its mutants. Thus, in certain embodiments, the present invention provides a method for treating a TYK2-mediated disorder, comprising administering to a patient in need thereof a compound of the present invention, or a pharma- ceutically acceptable composition thereof.

[0197] As used herein, the term "TYK2-mediated" disorder, disease, and / or condition refers to any disease or other deleterious condition in which TYK2 or its variants are known to play a role.Accordingly, another embodiment of the present invention relates to treating or reducing the severity of one or more diseases in which TYK2 or its variants are known to play a role.Such TYK2-mediated disorders include, but are not limited to, autoimmune disorders, inflammatory disorders, proliferative disorders, endocrine disorders, neurological disorders, and transplant-related disorders.

[0198] In some embodiments, the present invention provides a method for treating one or more disorders, wherein the disorders are selected from an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, and a transplant-related disorder, the method comprising administering to a patient in need thereof a pharmaceutical composition comprising an effective amount of a compound of the present invention, or a pharma- ceutical acceptable salt thereof.

[0199] In some embodiments, the disorder is an autoimmune disorder. In some embodiments, the disorder is selected from type 1 diabetes, cutaneous lupus erythematosus, systemic lupus erythematosus, multiple sclerosis, psoriasis, Behcet's disease, POEMS syndrome, Crohn's disease, ulcerative colitis, and inflammatory bowel disease.

[0200] In some embodiments, the disorder is an inflammatory disorder, hi some embodiments, the inflammatory disorder is rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis, hepatomegaly, Crohn's disease, ulcerative colitis, inflammatory bowel disease.

[0201] In some embodiments, the disorder is a proliferative disorder. In some embodiments, the proliferative disorder is a hematological cancer. In some embodiments, the proliferative disorder is a leukemia. In some embodiments, the leukemia is a T-cell leukemia. In some embodiments, the T-cell leukemia is a T-cell acute lymphoblastic leukemia (T-ALL). In some embodiments, the proliferative disorder is polycythemia vera, myelofibrosis, essential or thrombocytosis.

[0202] In some embodiments, the disorder is an endocrine disorder. In some embodiments, the endocrine disorder is polycystic ovary syndrome, Crouzon syndrome, or type 1 diabetes.

[0203] In some embodiments, the disorder is a neurological disorder, hi some embodiments, the neurological disorder is Alzheimer's disease.

[0204] In some embodiments, the proliferation disorder is associated with one or more activating mutations in TYK2.In some embodiments, the activating mutation in TYK2 is a mutation in FERM domain, JH2 domain, or kinase domain.In some embodiments, the activating mutation in TYK2 is selected from G36D, S47N, R425H, V731I, E957D, and R1027H.

[0205] In some embodiments, the disorder is transplant-related, hi some embodiments, the transplant-related disorder is transplant rejection or graft-versus-host disease.

[0206] In some embodiments, the disorder is associated with type I interferon, IL-10, IL-12, or IL-23 signaling. In some embodiments, the disorder is associated with type I interferon signaling. In some embodiments, the disorder is associated with IL-10 signaling. In some embodiments, the disorder is associated with IL-12 signaling. In some embodiments, the disorder is associated with IL-23 signaling.

[0207] The compounds of the 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, hypersensitivity vasculitis, urticaria, bullous pemphigoid, lupus erythematosus, cutaneous lupus erythematosus, systemic lupus erythematosus, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosa acquisita, acne vulgaris, and other inflammatory or allergic conditions of the skin.

[0208] The compounds of the invention may also be used in the treatment of other diseases or conditions, for example diseases or conditions which have an inflammatory component, for example diseases and conditions of the eye such as ocular allergies, conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, diseases affecting the nose including allergic rhinitis, and inflammatory diseases which involve an autoimmune response or have an autoimmune component or etiology, including autoimmune hematological disorders (e.g., hemolytic anemia, aplastic anemia, pure red cell aplasia, and idiopathic thrombocytopenia), cutaneous lupus erythematosus, systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Stevens-Johnson disease. syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g. ulcerative colitis and Crohn's disease), irritable bowel syndrome, celiac disease, periodontitis, pulmonary hyaline membrane disease, renal disease, glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine ophthalmopathy, Graves' disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), Sjogren's syndrome, keratoconjunctivitis sicca and vernal conjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, cryopyrin-associated periodic syndrome, nephritis, vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis (e.g. idiopathic nephrotic syndrome or minimal change nephropathy (minal with or without nephrotic syndrome, including nephrotic change nephropathy, chronic granulomatous disease, endometriosis, leptospirosisRenal disease, glaucoma, retinal disease, aging, headache, pain, complex regional pain syndrome, cardiac hypertrophy, muscle wasting, catabolic disorders, obesity, fetal growth retardation, hyperchlolesterolemia, heart disease, chronic heart failure, mesothelioma, anhidrotic ectodermal dysplasia, Behcet's disease, incontinentia pigmenti, Paget's disease, pancreatitis, hereditary periodic fever syndromes, asthma (allergic and non-allergic, mild, moderate, severe, bronchitic and exercise-induced), acute lung injury, acute respiratory distress syndrome, eosinophilia, hypersensitivity, anaphylaxis, sinusitis, ocular allergies, silica-induced disease, COPD (reduction of damage, airway inflammation, bronchial hyperactivity, remodeling or disease progression), pulmonary disease, cystic fibrosis , acid-induced lung injury, pulmonary hypertension, polyneuropathy, cataracts, muscle inflammation associated with systemic sclerosis, inclusion body myositis, myasthenia gravis, thyroiditis, Addison's disease, lichen planus, type 1 or type 2 diabetes, appendicitis, atopic dermatitis, asthma, allergies, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection Diarrhea, colitis, conjunctivitis, Crohn's disease, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibromyalgia, gastritis, gastroenteritis, Henoch-Schönlein purpura, hepatitis, sweat gland abscess, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis It can be used to treat myocarditis, myositis, nephritis, ovariitis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, or vulvitis.

[0209] In some embodiments, the inflammatory disease that can be treated by the methods of this invention is selected from acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, systemic juvenile idiopathic arthritis (SJIA), cryopyrin-associated periodic syndromes (CAPS), and osteoarthritis.

[0210] In some embodiments, the inflammatory disease that can be treated by the methods of this invention is T h 1 or T h 17-mediated disease. h The 17-mediated disease is selected from cutaneous lupus erythematosus, systemic lupus erythematosus, multiple sclerosis, and inflammatory bowel disease (including Crohn's disease or ulcerative colitis).

[0211] In some embodiments, inflammatory diseases that can be treated by the methods of this invention are selected from Sjogren's syndrome, allergic disorders, osteoarthritis, eye conditions such as ocular allergies, conjunctivitis, keratoconjunctivitis sicca and vernal conjunctivitis, and diseases affecting the nose such as allergic rhinitis.

[0212] Furthermore, the present invention provides the use of a compound as defined herein, or a pharma- ceutically acceptable salt, or hydrate or solvate thereof, for the preparation of a medicament for the treatment of an autoimmune, inflammatory, or proliferative disorder, or a disorder commonly occurring in association with transplantation.

[0213] Combination therapy Depending on the particular condition, or disease, being treated, additional therapeutic agents that are normally administered to treat that condition can be administered in combination with the compounds and compositions of this invention. As used herein, additional therapeutic agents that are normally administered to treat a particular disease, or condition, are known as "appropriate for the disease, or condition, being treated."

[0214] In certain embodiments, the provided combinations, or compositions thereof, are administered in combination with another therapeutic agent.

[0215] Examples of agents with which the combinations of the invention may be combined include, but are not limited to: agents for the treatment of Alzheimer's disease, such as Aricept® and Excelon®; agents for the treatment of HIV, such as ritonavir; agents for the treatment of Parkinson's disease, such as L-DOPA / carbidopa, entacapone, ropinrole, pramipexole, bromocriptine, pergolide, trihexephendyl, and amantadine; agents for the treatment of multiple sclerosis (MS), such as beta interferons (e.g., Avonex® and Rebif®), Copaxone®, and mitoxantrone; agents for the treatment of asthma, such as albuterol and Singulair®; agents for the treatment of schizophrenia, such as Zyprexa, Risperdal, Seroquel, and haloperidol; anti-inflammatory agents, such as corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulators and immunosuppressants, such as cyclosporine, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophophamide, azathioprine, and sulfasalazine; neurotrophic factors, such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anticonvulsants, ion channel blockers, riluzole, and anti-Parkinsonian agents for treating cardiovascular disease, such as beta blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, and statins; agents for treating liver disease, such as corticosteroids, cholestyramine, interferons, and antivirals; agents for treating blood disorders, such as corticosteroids, anti-leukemia agents, and growth factors; agents that prolong or improve pharmacokinetics, such as cytochrome P450 inhibitors (i.e., inhibitors of metabolic degradation) and CYP3A4 inhibitors (e.g., ketokenozole and ritonavir), and agents for treating immune deficiency disorders, such as gamma globulins.

[0216] In certain embodiments, the combination therapy of the invention, or a pharma- ceutically acceptable composition thereof, is administered in combination with a monoclonal antibody or siRNA therapeutic.

[0217] These additional agents may be administered as part of a multiple dose regimen, separate from the combination therapy provided. Alternatively, these agents may be part of a single dosage form, mixed together with the compounds of this invention as a single composition. When administered as part of a multiple dose regimen, the two active agents may be given simultaneously, sequentially, or within a period of each other, usually within 5 hours of each other.

[0218] As used herein, the terms "combination," "in combination," and related terms refer to the simultaneous or sequential administration of therapeutic agents according to the invention. For example, the combination of the invention may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms, or together in a single unit dosage form.

[0219] The amount of additional therapeutic agent present in the compositions of this invention will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Preferably, the amount of additional therapeutic agent in the compositions of the present disclosure will range from about 50% to 100% of the amount that would normally be present in a composition comprising that agent as the only therapeutically active agent.

[0220] In one embodiment, the present invention provides a composition comprising a compound of formula I and one or more additional therapeutic agents. The therapeutic agent can be administered together with the compound of formula I, or before or after the compound of formula I. Suitable therapeutic agents are described in more detail below. In certain embodiments, the compound of formula 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 up to 18 hours before the therapeutic agent. In other embodiments, the compound of formula 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.

[0221] In another embodiment, the present invention provides a method of treating an inflammatory disease, disorder, or condition by administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents. Such additional therapeutic agents may be small molecules or recombinant biological agents, such as acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDS) (e.g., aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib), colchicine (Colcrys®), corticosteroids (e.g., prednisone, prednisolone, methylprednisolone, and hydrocortisone), probenecid, allopurinol, febuxostat, etc. (febuxostat) (Uloric®), sulfasalazine (Azulfidine®), antimalarials (e.g., hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®)), methotrexate (Rheumatrex®), gold salts (e.g., gold thioglucose (Solganal®), gold thiomalate (Myochrysine®), and auranofin (Ridaura®) ), D-penicillamine (Depen® or Cuprimine®), azathioprine (Imuran®), cyclophosphamide (Cytoxan®), chlorambucil (Leukeran®), cyclosporine (Sandimmune®), leflunomide (Arava®) and "anti-TNF" agents (e.g., etanercept (Enbrel®), infliximab (Remicade®), golimumab (Gibco®), sirolimus (Sanvitamin ... Mabs (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 (Actemra®)), diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®), monoclonal antibodies (e.g., tanezumab), anticoagulants (e.g., heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®)), antidiarrheal drugs (e.g., diphenoxylate (Lomotil®) and loperamide (Imodium®), bile acid binders (e.g., cholestyramine), alosetron (Lotronex®), lubiprostone (Amitiza®), laxatives (e.g., milk of magnesia, polyethylene glycols (MiraLax®), Dulcolax®, Correctol®, and Senokot®), anticholinergics or antispasmodics (e.g., dicyclomine (Bentyl®)), Singulair®, beta-2 agonists (e.g., albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®), and formoterol (Foradil®)), anticholinergics (e.g., ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), inhaled corticosteroids (e.g., beclomethasone dipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), and flunisolide (Aerobid®)), Afviar®, Symbicort®, Dulera®,Cromolyn sodium (Intal®), methylxanthines (e.g., theophylline (Theo-Dur®, Theolair®, Slo-bid®, Uniphyl®, Theo-24®) and aminophylline), IgE antibodies (e.g., omalizumab (Xolair®)), nucleoside reverse transcriptase inhibitors (e.g., zidovudine (Retrovir®), abacavir (Ziagen®), abacavir / lamivudine (Epzicom ... vacavir / lamivudine / zidovudine (Trizivir®), didanosine (Videx®), emtricitabine (Emtriva®), lamivudine (Epivir®), lamivudine / zidovudine (Combivir®), stavudine (Zerit®), and zalcitabine (Hivid®), non-nucleoside reverse transcriptase inhibitors (e.g., delavirdine (Rescriptor®), efavirenz (Sustiva®), nevirapine (Viramune®), (R)) and etravirine (Intelence®)), nucleotide reverse transcriptase inhibitors (e.g., tenofovir (Viread®)), protease inhibitors (e.g., amprenavir (Agenerase®), atazanavir (Reyataz®), darunavir (Prezista®), fosamprenavir (Lexiva®), indinavir (Crixivan®), lopinavir and ritonavir (Kaletra®), nelfinavir (Viracep®), t®), ritonavir (Norvir®), saquinavir (Fortovase® or Invirase®), and tipranavir (Aptivus®)), entry inhibitors (e.g., enfuvirtide (Fuzeon®) and maraviroc (Selzentry®)), integrase inhibitors (e.g., raltegravir (Isentress®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®),bortezomib (Velcade®), and dexamethasone (Decadron®) in combination with lenalidomide (Revlimid®), or any combination or combinations thereof.

[0222] In another embodiment, the present invention provides a method of treating rheumatoid arthritis, comprising administering to a patient in need thereof a compound of Formula I and nonsteroidal anti-inflammatory drugs (NSAIDS) (e.g., aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib), corticosteroids (e.g., prednisone, prednisolone, methylprednisolone, and hydrocortisone), sulfasalazine (Azulfidine®), antimalarials (e.g., cefolia, cefolia serovar I, cefolia serovar II, cefolia serovar III, cefolia serovar I, cefolia serovar II ... For example, hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), methotrexate (Rheumatrex®), gold salts (e.g., gold thioglucose (Solganal®), gold thiomalate (Myochrysine®) and auranofin (Ridaura®)), D-penicillamine (Depen® or Cuprimine®), azathioprine (Imuran®), (R), cyclophosphamide (Cytoxan®), chlorambucil (Leukeran®), cyclosporine (Sandimmune®), leflunomide (Arava®) and “anti-TNF” agents such as etanercept (Enbrel®), infliximab (Remicade®), golimumab (Simponi®), certolizumab pegol (Cimzia®) and adalimumab (Humira®)), "anti-IL-1" agents (e.g., anakinra (Kineret®) and rilonacept (Arcalyst®)), antibodies (e.g., rituximab (Rituxan®)), "anti-T cell" agents (e.g., abatacept (Orencia®)), and "anti-IL-6" agents (e.g., tocilizumab (Actemra®)).

[0223] In some embodiments, the present invention provides a method of treating osteoarthritis, comprising administering to a patient in need thereof a compound of Formula I and one or more additional therapeutic agents selected from acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDS) (e.g., aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib), diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®), and monoclonal antibodies (e.g., tanezumab).

[0224] In some embodiments, the present invention provides a method of treating cutaneous or systemic lupus erythematosus, comprising administering to a patient in need thereof a compound of Formula I and a combination of acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDS) (e.g., aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib), corticosteroids (e.g., prednisone, prednisolone, methylprednisolone, and hydrocortisone), antimalarials (e.g., hydroxychloroquine ( and administering one or more additional therapeutic agents selected from cyclosporine (Plaquenil®) and chloroquine (Aralen®), cyclophosphamide (Cytoxan®), methotrexate (Rheumatrex®), azathioprine (Imuran®), and an anticoagulant (e.g., heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®)).

[0225] In some embodiments, the present invention provides a method of treating Crohn's disease, ulcerative colitis, or inflammatory bowel disease by administering to a patient in need thereof a compound of Formula I and mesalamine (Asacol®), sulfasalazine (Azulfidine®), antidiarrheal drugs (e.g., diphenoxylate (Lomotil®) and loperamide (Imodium®)), bile acid binders (e.g., cholestyramine, alosetron (Lotronex®), lubiprostone (Amiti), or combination drugs (e.g., cefolia ... za®), laxatives (e.g., milk of magnesia, polyethylene glycol (MiraLax®), Dulcolax®, Correctol®, and Senokot®), and one or more additional therapeutic agents selected from anticholinergics or antispasmodics (e.g., dicyclomine (Bentyl®), anti-TNF therapeutics, steroids, and antibiotics (e.g., Flagyl or ciprofloxacin).

[0226] In some embodiments, the present invention provides a method of treating asthma by administering to a patient in need thereof a compound of formula I and a combination of Singulair®, beta-2 agonists (e.g., albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®), and formoterol (Foradil®)), anticholinergics (e.g., ipratropium bromide (Atrovent®) and tiotropium (Spiriva®)), inhaled corticosteroids (e.g., prednisone, prednisolone, beclomethasone dipropionate), (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), flunisolide (Aerobid®), Afviar®, Symbicort®, and Dulera®), cromolyn sodium (Intal®), methylxanthines (e.g., theophylline (Theo-Dur®, Theolair®, Slo-bid®, Uniphyl®, Theo-24®), and aminophylline), and IgE antibodies (e.g., omalizumab (Xolair®)).

[0227] In some embodiments, the present invention provides a method of treating COPD, comprising administering to a patient in need thereof a compound of formula I and a beta-2 agonist (e.g., albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®), and formoterol (Foradil®)), an anticholinergic (e.g., ipratropium bromide (Atrovent®), and tiotropium (Spiriva®)), a methylxanthine (e.g., theophylline (Theo and aminophylline), inhaled corticosteroids (e.g., prednisone, prednisolone, beclomethasone dipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), flunisolide (Aerobid®), Afviar®, Symbicort®, and Dulera®).

[0228] In another embodiment, the present invention provides a method of treating a hematological malignancy, comprising administering to a patient in need thereof a compound of Formula I and one or more additional therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, hedgehog signaling inhibitors, BTK inhibitors, JAK / pan-JAK inhibitors, PI3K inhibitors, SYK inhibitors, and combinations thereof.

[0229] In another embodiment, the present invention provides a method of treating a solid tumor, comprising administering to a patient in need thereof a compound of Formula I and one or more additional therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, hedgehog signaling inhibitors, BTK inhibitors, JAK / pan-JAK inhibitors, PI3K inhibitors, SYK inhibitors, and combinations thereof.

[0230] In another embodiment, the invention provides a method of treating a hematological malignancy, comprising administering to a patient in need thereof a compound of Formula I and a hedgehog (Hh) signaling pathway inhibitor. In some embodiments, the hematological malignancy is DLBCL (Ramirez et al., "Defining causative factors contributing in the activation of hedgehog signaling in diffuse large B-cell lymphoma," Leuk. Res. (2012), published online July 17, and incorporated herein by reference in its entirety).

[0231] In another embodiment, the present invention provides a method of treating diffuse large B-cell lymphoma (DLBCL), comprising administering to a patient in need thereof a compound of Formula I and one or more additional therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, and combinations thereof.

[0232] In another embodiment, the present invention provides a method of treating multiple myeloma, comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from bortezomib (Velcade®), and dexamethasone (Decadron®), hedgehog signaling inhibitors, BTK inhibitors, JAK / pan-JAK inhibitors, TYK2 inhibitors, PI3K inhibitors, SYK inhibitors in combination with lenalidomide (Revlimid®).

[0233] In another embodiment, the present invention provides a method of treating or lessening the severity of a disease, comprising administering to a patient in need thereof a compound of Formula I and a BTK inhibitor, wherein the disease is selected from the group consisting of inflammatory bowel disease, arthritis, cutaneous lupus erythematosus, systemic lupus erythematosus (SLE), vasculitis, idiopathic thrombocytopenic purpura (ITP), rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis, and the like. thyroiditis), Graves' disease, autoimmune thyroiditis, Sjogren's syndrome, multiple sclerosis, systemic sclerosis, Lyme neuroborreliosis, Guillain-Barré syndrome, acute disseminated cerebrospinal meningitis, Addison's disease, opsoclonus-myoclonus syndrome, ankylosing spondylitis, antiphospholipid syndrome, aplastic anemia, autoimmune hepatitis, autoimmune gastritis, pernicious anemia, celiac disease, Goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia , Wegener's granulomatosis, psoriasis, alopecia universalis, Behçet's disease, chronic fatigue, autonomic neuropathy, membranous glomerular nephropathy, endometriosis, interstitial cystitis, pemphigus vulgaris, bullous pemphigoid, neuromyotonia, scleroderma, vulvodynia, hyperproliferative disorders, rejection of transplanted organs or tissues, acquired immune deficiency syndrome (AIDS, also known as HIV), type 1 diabetes, graft-versus-host disease, transplants, blood transfusions, anaphylaxis, allergies (e.g., to plant pollen, latex, drugs, foods, insect venom, animal hair, animal dander, house dust mites, or cockroach calyx) calyx), type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, and atopic dermatitis, asthma, appendicitis, atopic dermatitis, asthma, allergy, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection, colitis, conjunctivitis, Crohn's disease, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibromyalgia, gastritis, gastroenteritis, Henoch-Schönlein purpura, hepatitis, sweat gland abscess, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitisMyocarditis, myositis, nephritis, ovariitis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, 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, lymphoplasmocytic lymphoma / Walde Breast cancer, prostate cancer, or cancer of the mast cells (e.g., mastocytoma, mast cell leukemia, thymic leukemia, splenic marginal zone lymphoma, multiple myeloma (also known as plasma cell myeloma), non-Hodgkin's lymphoma, Hodgkin's lymphoma, plasmacytoma, extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, Burkitt's lymphoma / leukemia, or lymphomatoid granulomatosis, breast cancer, prostate cancer, or cancer of the mast cells (e.g., mastocytoma, mast cell leukemia, mast cell myeloma, thymic leukemia ... alveolar sarcoma, systemic mastocytosis), bone cancer, colorectal cancer, pancreatic cancer, bone and joint diseases (including but not limited to rheumatoid arthritis, seronegative spondyloarthritis (including ankylosing spondylitis, psoriatic arthritis and Reiter's disease), Behcet's disease, Sjogren's syndrome, systemic sclerosis, osteoporosis, bone cancer, bone metastases), thromboembolic disorders (e.g., myocardial infarction, angina pectoris, reocclusion after angioplasty, restenosis after angioplasty, reocclusion after aortocoronary bypass, restenosis after aortocoronary bypass, stroke, transient ischemia, peripheral arterial occlusive disorder , pulmonary embolism, deep vein thrombosis), inflammatory pelvic disease, urethritis, sunburn of the skin, sinusitis, pneumonitis, encephalitis, meningitis, myocarditis, nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis, dermatitis, gingivitis, appendicitis, pancreatitis, cholecystitis (cholocystitis), agammaglobulinemia, psoriasis, allergies, Crohn's disease, irritable bowel syndrome, ulcerative colitis, Sjogren's disease, tissue graft rejection, hyperacute rejection of transplanted organs, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), autoimmune polyglandulardisease) (also known as autoimmune polyglandular syndrome), autoimmune alopecia, pernicious anemia, glomerulonephritis, dermatomyositis, multiple sclerosis, scleroderma, vasculitis, autoimmune hemolytic and thrombocytopenic states, Goodpasture's syndrome, atherosclerosis, Addison's disease, Parkinson's disease, Alzheimer's disease, diabetes, septic shock, cutaneous lupus erythematosus, systemic lupus erythematosus (SLE), rheumatoid arthritis, psoriatic arthritis, The method further comprises treating a patient with a chronic idiopathic thrombocytopenic purpura, juvenile arthritis, osteoarthritis, chronic idiopathic thrombocytopenic purpura, Waldenstrom's macroglobulinemia, myasthenia gravis, Hashimoto's thyroiditis, atopic dermatitis, degenerative joint disease, vitiligo, autoimmune hypopituitarism, Guillain-Barre syndrome, Behcet's disease, scleroderma, mycosis fungoides, acute inflammatory responses (e.g., acute respiratory distress syndrome and ischemia / reperfusion injury), and Graves' disease.

[0234] In another embodiment, the invention provides a method of treating or lessening the severity of a disease comprising administering to a patient in need thereof a compound of formula I and a PI3K inhibitor, wherein the disease is selected from cancer, a neurodegenerative disorder, an angiogenic disorder, a viral disease, an autoimmune disease, an inflammatory disorder, a hormone-related disease, a condition associated with organ transplantation, an immunodeficiency disorder, a destructive bone disorder, a proliferative disorder, an infectious disease, a condition associated with cell death, thrombin-induced platelet aggregation, chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), a liver disease, a pathological immune condition involving T-cell activation, a cardiovascular disorder, and a CNS disorder.

[0235] In another embodiment, the invention relates to a method of treating or lessening the severity of a disease, comprising administering to a patient in need thereof a compound of formula I and a PI3K inhibitor, wherein the disease is a benign or malignant tumor, carcinoma or solid tumor of the brain, kidney (e.g., renal cell carcinoma (RCC)), liver, adrenal gland, bladder, breast, stomach, gastric tumor, ovary, colon, rectum, prostate, pancreas, lung, vagina, endometrium, cervix, testis, genitourinary tract, esophagus, larynx, skin, bone or thyroid, sarcoma, glioblastoma, neuroblastoma, multiple myeloma or gastrointestinal cancer, in particular colon cancer or colorectal adenoma or head and neck tumor, epidermal hyperproliferation, psoriasis, prostatic hyperplasia, neoplasm, neoplasia of epithelial character), adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung carcinoma, lymphoma (including, for example, non-Hodgkin's lymphoma (NHL) and Hodgkin's lymphoma (also called Hodgkin or Hodgkin's disease)), breast cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, or leukemia, Cowden syndrome, Lhermitte-Dudos disease Diseases including Banayan-Zonana syndrome or diseases in which the PI3K / PKB pathway is abnormally activated, asthma of any type or occurrence, including both intrinsic (non-allergic) and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchitis asthma, exercise-induced asthma, occupational asthma and asthma induced after bacterial infection, acute lung injury (ALI), adult / acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease, chronic obstructive airway disease or chronic obstructive lung disease.chronic bronchitis or dyspnea associated with it, emphysema, and exacerbations of airway overactivity as a result of other medications, particularly other inhaled medications; bronchitis of any type or occurrence, including but not limited to acute, arachidic, catarrhal, croupus, chronic or tuberculous bronchitis; pneumoconiosis of any type or occurrence, an inflammatory, generally occupational, lung disease caused by repeated inhalation of dust, frequently accompanied by obstruction of the airways, whether chronic or acute, including for example aluminosis, anthraxosis, asbestosis, stone disease, ptilosis, siderosis, silicosis, tabacosis and byssinosis; Loffler's syndrome,syndrome), eosinophilic, pneumonia, parasitic (especially metazoan) infestations (including tropical eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa (including Churg-Strauss syndrome), eosinophil-related disorders affecting the airways caused by eosinophilic granulomas and drug reactions, psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity vasculitis, urticaria, bullous Diseases affecting the nose, including pemphigoid, lupus erythematosus, pemphigus, epidermolysis bullosa acquisita, conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, allergic rhinitis, and inflammatory diseases involving an autoimmune reaction or having an autoimmune component or etiology, including autoimmune hematological disorders (e.g., hemolytic anemia, aplastic anemia, pure red cell aplasia, and idiopathic thrombocytopenia), cutaneous lupus erythematosus, systemic lupus erythematosus, rheumatoid arthritis, multiple myelopathy, rheumatoid arthritis ... Osteitis, scleroderma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Stevens-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g. ulcerative colitis and Crohn's disease), endocrine ophthalmopathy, Graves' disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), keratoconjunctivitis sicca and vernal conjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis and glomerulonephritis. The present invention provides a method for treating a neurodegenerative disease selected from the group consisting of systemic nephritis (with or without nephrotic syndrome (including, for example, idiopathic nephrotic syndrome or minimal change nephropathy)), restenosis, cardiac hypertrophy, atherosclerosis, myocardial infarction, ischemic stroke and congestive heart failure, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and cerebral ischemia, as well as neurodegenerative diseases caused by trauma, glutamate neurotoxicity, and hypoxia.

[0236] In some embodiments, the present invention provides a method of treating or reducing the severity of a disease, comprising administering to a patient in need thereof a compound of formula 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 transplant-related disorder. In some embodiments, the disorder is a proliferative disorder, lupus, or lupus nephritis. In some embodiments, the proliferative disorder is chronic lymphocytic leukemia, diffuse large B-cell lymphoma, Hodgkin's disease, small cell lung cancer, non-small cell lung cancer, myelodysplastic syndrome, lymphoma, hematological neoplasm, or solid tumor.

[0237] In some embodiments, the present invention provides a method of treating or reducing the severity of a disease, comprising administering to a patient in need thereof a TYK2 pseudokinase (JH2) domain binding compound and a TYK2 kinase (JH1) domain binding compound. In some embodiments, the disease is an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a transplant-related disorder. In some embodiments, the JH2 binding compound is a compound of formula I. Other suitable JH2 domain binding compounds include those described in WO2014 / 074660A1, WO2014 / 074661A1, WO2015 / 089143A1, each of which is incorporated herein by reference in its entirety. Suitable JH1 domain binding compounds include those described in WO2015 / 131080A1, each of which is incorporated herein by reference in its entirety.

[0238] The compounds and compositions can be administered in any amount and by any route of administration effective for treating or reducing the severity of autoimmune, inflammatory, proliferative, endocrine, neurological, or transplant-related disorders according to the method of the present invention. The exact amount required varies from subject to subject, depending on the species, age and general condition of the subject, the severity of the infection, the specific drug, its mode of administration, and the like. The compounds of the present invention are preferably formulated into unit dosage form for ease of administration and uniformity of dosage. The expression "unit dosage form" as used herein refers to a physically separate unit of drug suitable for the patient to be treated. However, it is understood that the total daily usage of the compounds and compositions of the present invention will be determined by the attending physician within the scope of sound medical judgment. The effective dose level specific to any particular patient or organism depends on a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the specific compound used; the specific composition used; the age, weight, general health, sex and diet of the patient; the administration time, route of administration and excretion rate of the specific compound used; duration of treatment; drugs used in combination or simultaneously with the specific compound used, and similar factors well known in the medical field. The term "patient" as used herein means an animal, preferably a mammal, most preferably a human.

[0239] The pharma- ceutically 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), bucally, as an oral or nasal spray, etc., depending on the severity of the infection being treated. In certain embodiments, the compounds of this invention can be administered orally or parenterally at dosage levels of about 0.01 mg to about 50 mg, preferably about 1 mg to about 25 mg, per kg of subject body weight per day, one or more times per day to obtain the desired therapeutic effect.

[0240] Liquid dosage forms for oral administration include, but are not limited to, pharma- ceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.In addition to active compounds, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing and emulsifying agents, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, and mixtures thereof.Besides inert diluents, oral compositions may also contain adjuvants, such as wetting agents, emulsifying agents and suspending agents, and sweeteners, flavoring agents, and aromatic agents.

[0241] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, may be formulated by known techniques using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations may be injectable sterile solutions, suspensions, or emulsions in non-toxic parenterally acceptable diluents or solvents, for example, solutions in 1,3-butanediol. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution, USP, and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any non-irritating fixed oil may be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0242] Injectable preparations can be sterilized prior to use, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other injectable sterile medium.

[0243] In order to prolong the effect of the compounds of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This can be accomplished by using a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends on its rate of dissolution, which in turn may depend on the crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsulated matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of the compound to the polymer and the nature of the particular polymer employed, the compound release rate can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0244] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing a compound of this invention with a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol or a suppository wax which is solid at ambient temperature but liquid at body temperature and therefore will melt in the rectum or vaginal cavity and release the active compound.

[0245] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert pharma- ceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or a) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants, such as glycerol, d) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents, such as paraffin, f) absorption accelerators, such as quaternary ammonium compounds, g) 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 glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0246] Solid compositions of a similar type may be used as fillers for soft and hard filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols and the like. Solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the art of pharmaceutical formulation. They may optionally contain opacifying agents and can also be of a composition that releases the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may be used as fillers for soft and hard filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols and the like.

[0247] The active compound may be in microencapsulated form with one or more excipients as mentioned above. The solid dosage forms of tablets, dragees, capsules, pills, and granules may be prepared with coatings and shells, such as enteric coatings, release-controlling coatings, and other coatings well known in the art of pharmaceutical formulation. In such solid dosage forms, the active compound may be mixed with at least one inert diluent, such as sucrose, lactose, or starch. Such dosage forms may contain, as in normal practice, additional substances other than the inert diluent, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage forms may also contain buffering agents. They may optionally contain opacifying agents, and may be of a composition that releases the active ingredient(s) only or preferentially in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0248] The topical or transdermal dosage forms of the compounds of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active ingredient is mixed under sterile conditions with a pharma- ceutically acceptable carrier and any preservatives or buffers that may be required, as appropriate. Ophthalmic formulations, ear drops, and eye drops are also contemplated as being within the scope of this invention. Furthermore, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of the compound to the body. Such dosage forms can be made by dissolving or dispersing the compound in a suitable medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. This rate can be controlled by providing a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0249] According to one embodiment, the present invention relates to a method of inhibiting protein kinase activity in a biological sample, comprising the step of contacting said biological sample with a compound of this invention or a composition comprising said compound.

[0250] According to another embodiment, the present invention relates to a method for inhibiting the activity of TYK2, or a mutant thereof, in a biological sample, comprising the step of contacting said biological sample with a compound of this invention or a composition comprising said compound. In a particular embodiment, the present invention relates to a method for irreversibly inhibiting the activity of TYK2, or a mutant thereof, in a biological sample, comprising the step of contacting said biological sample with a compound of this invention or a composition comprising said compound.

[0251] In another embodiment, the present invention provides a method of 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 over JAK1 / 2 / 3. In some embodiments, the compounds of the present invention are more than 5-fold selective over JAK1 / 2 / 3. In some embodiments, the compounds of the present invention are more than 10-fold selective over JAK1 / 2 / 3. In some embodiments, the compounds of the present invention are more than 50-fold selective over JAK1 / 2 / 3. In some embodiments, the compounds of the present invention are more than 100-fold selective over JAK1 / 2 / 3.

[0252] The term "biological sample" as used herein includes, but is not limited to, a cell culture or extract thereof; a biopsy or extract thereof obtained from a mammal; and blood, saliva, urine, feces, semen, tears, or other bodily fluids or extracts thereof.

[0253] Inhibition of the activity of TYK2 (or a variant thereof) in a biological sample is useful for a variety of purposes known to those of skill in the art, including, but not limited to, blood transfusion, organ transplantation, biological specimen storage, and biological assays.

[0254] Another embodiment of the invention relates to a method of inhibiting protein kinase activity in a patient, comprising the step of administering to said patient a compound of the invention, or a composition comprising said compound.

[0255] According to another embodiment, the present invention relates to a method of inhibiting the activity of TYK2, or a mutant thereof, in a patient, comprising administering to said patient a compound of the present invention or a composition comprising said compound. According to certain embodiments, the present invention relates to a method of reversibly or irreversibly inhibiting the activity of TYK2, or one or more mutants thereof, in a patient, comprising administering to said patient a compound of the present invention or a composition comprising said compound. In other embodiments, the present invention provides a method of treating a disorder mediated by TYK2, or a mutant thereof, in a patient in need thereof, comprising administering to said patient a compound according to the present invention or a pharma- ceutically acceptable composition thereof. Such disorders are described in detail herein.

[0256] Depending on the particular condition, or disease, being treated, additional therapeutic agents, which are normally administered to treat that condition, may also be present in the compositions of this invention. As used herein, additional therapeutic agents that are normally administered to treat a particular disease, or condition, are known as "appropriate for the disease, or condition, being treated."

[0257] The compounds of the present invention can also be advantageously used in combination with other therapeutic compounds.In some embodiments, the other therapeutic compounds are antiproliferative compounds.Such antiproliferative compounds include, but are not limited to, aromatase inhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule active compounds; alkylating compounds; histone deacetylase inhibitors; compounds that induce cell differentiation processes; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; antitumor antimetabolites; platin compounds; compounds that target / reduce protein kinase activity or lipid kinase activity and further antiangiogenic compounds; compounds that target, reduce or inhibit the activity of protein phosphatases or lipid phosphatases; gonadorelin agonists; antiandrogens; methionine aminopeptides; putidase inhibitors;matrix metalloproteinase inhibitors;bisphosphonates;biological response modifiers;antiproliferative 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, CNF1010, CNF2024, CNF1010 (Conforma Therapeutics); temozolomide (Temodal®); kinesin spindle protein inhibitors (e.g., SB715992 or SB743921 (GlaxoSmithKline), or pentamidine / chlorpromazine (CombinatoRx)); MEK inhibitors (e.g., ARRY142886 (Array BioPharma), AZD6244 (AstraZeneca), PD181461 (Pfizer) and leucovorin).The term "aromatase inhibitors", as used herein, refers to compounds that inhibit estrogen production, for example the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively. This term includes, but is not limited to, steroids, especially atamestane, exemestane and formestane, and nonsteroids, especially aminoglutethimide, rogletimide, pyridoglutethimide, trilostane, testolactone, ketoconazole, vorozole, fadrozole, anastrozole and letrozole. Exemestane is marketed under the trade name Aromasin™. Formestane is marketed under the trade name Lentaron™. Fadrozole is marketed under the trade name Afema™. Anastrozole is marketed under the trade name Arimidex™. Letrozole is marketed under the trade name Femara™ or Femar™. Aminoglutethimide is commercially available under the trade name Orimeten™. The combinations of the present invention which include a chemotherapeutic agent that is an aromatase inhibitor are particularly useful for the treatment of hormone receptor positive tumors, such as breast tumors.

[0258] The term "anti-estrogen" as used herein relates to a compound that antagonizes the effect 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 that includes a chemotherapeutic agent that is an anti-estrogen is particularly useful for treating estrogen receptor positive tumors, such as breast tumors.

[0259] The term "antiandrogen" as used herein relates to any substance capable of inhibiting the biological effects of androgen, 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™.

[0260] The term "topoisomerase I inhibitors" as used herein includes, but is not limited to, topotecan, gimatecan, irinotecan, camptothecin and its analogs, 9-nitrocamptothecin, and the polymeric camptothecin conjugate PNU-166148. Irinotecan can be administered, for example, in the form as it is marketed, for example, under the trademark Camptosar™. Topotecan is marketed under the trade name Hycamptin™.

[0261] The term "topoisomerase II inhibitors" as used herein includes, but is not limited to, anthracyclines (e.g., doxorubicin (including liposomal formulations such as Caelyx™), daunorubicin, epirubicin, idarubicin, and nemorubicin, the anthraquinones mitoxantrone and rosoxantrone, and the podophyllotoxins etoposide and teniposide. Etoposide is commercially available under the trade name Etopophos™. Teniposide is commercially available under the trade name VM 26-Bristol. Doxorubicin is commercially available under the trade name Acriblastin™ or Adriamycin™. Epirubicin is commercially available under the trade name Farmorubicin™. Idarubicin is commercially available under the trade name Zavedos™. Mitoxantrone is commercially available under the trade name Novantron.

[0262] The term "microtubule activator" refers to microtubule stabilizing compounds, microtubule destabilizing compounds and microtubule polymerization inhibitors, including, but not limited to, taxanes, such as paclitaxel and docetaxel; vinca alkaloids, such as vinblastine or vinblastine sulfate, vincristine or vincristine sulfate, and vinorelbine; discodermolide; colchicine and epothilones and their derivatives. Paclitaxel is commercially available under the trade name Taxol™. Docetaxel is commercially available under the trade name Taxotere™. Vinblastine sulfate is commercially available under the trade name Vinblastin RP™. Vincristine sulfate is commercially available under the trade name Farmistin™.

[0263] The term "alkylating agent" as used herein includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan, or nitrosourea (BCNU or Gliadel). Cyclophosphamide is commercially available under the trade name Cyclostin™. Ifosfamide is commercially available under the trade name Holoxan™.

[0264] The term "histone deacetylase inhibitors" or "HDAC inhibitors" relates to compounds which inhibit histone deacetylase and which possess antiproliferative activity, including, but not limited to, suberoylanilide hydroxamic acid (SAHA).

[0265] The term "antitumor antimetabolites" includes, but is not limited to, 5-fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylating compounds (e.g., 5-azacytidine and decitabine), methotrexate and edatrexate, and folate antagonists (e.g., pemetrexed). Capecitabine is commercially available under the trade name Xeloda™. Gemcitabine is commercially available under the trade name Gemzar™.

[0266] The term "platin compound" as used herein includes, but is not limited to, carboplatin, cisplatin, cisplatinum and oxaliplatin. Carboplatin can be administered, e.g., in the form as it is marketed, e.g. under the trademark Carboplat™. Oxaliplatin can be administered, e.g., in the form as it is marketed, e.g. under the trademark Eloxatin™.

[0267] The term "compounds which target / reduce the activity of protein kinases or lipid kinases; or compounds which target / reduce the activity of protein phosphatases or lipid phosphatases; or further anti-angiogenic compounds" as used herein includes, but is not limited to, protein tyrosine kinase and / or serine and / or threonine kinase inhibitors, or lipid kinase inhibitors, such as a) compounds which target, reduce or inhibit the activity of platelet derived growth factor receptors (PDGFRs) (e.g. compounds which target, reduce or inhibit the activity of PDGFRs, in particular compounds which inhibit the PDGF receptor, such as N-phenyl-2-pyrimidine- amine derivatives, e.g. imatinib, SU101, SU6668 and GFB-111; b) compounds which target, reduce or inhibit the activity of fibroblast growth factor receptors (FGFR); c) compounds which target, reduce or inhibit the activity of insulin-like growth factor receptor I (IGF-IR) (e.g. compounds which target, reduce or inhibit the activity of IGF-IR, in particular compounds which inhibit the kinase activity of the IGF-I receptor or antibodies which target the extracellular domain of the IGF-I receptor or its growth factors); d) compounds which target, reduce or inhibit the activity of the Trk receptor tyrosine kinase family or ephrinB4 inhibitors; e) compounds which 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 / SCFR receptor tyrosine kinase, e.g., 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). i) compounds that target, reduce or inhibit the activity of c-Abl family members and their gene fusion products (e.g., BCR-Abl kinase) and mutants (e.g., compounds that target, reduce or inhibit the activity of c-Abl family members and their gene fusion products, e.g., N-phenyl-2-pyrimidine-amine derivatives, e.g., imatinib or nilotinib (AMN107); PD180970; AG957; NSC 680410; PD173955 (from ParkeDavis); or dasatinib (BMS-354825); j) compounds that target, decrease or inhibit the activity of members of the protein kinase C (PKC) and Raf families of serine / threonine kinases, MEK, SRC, JAK / pan-JAK, FAK, PDK1, PKB / Akt, Ras / MAPK, PI3K, SYK, BTK and TEC families, and / or members of the cyclin-dependent kinase family (CDK), including staurosporine derivatives, e.g., midostaurin; further exemplary compounds include UCN-01, safingol, BAY 43-9006, bryostatin 1, perifosine; irmofosine; RO 318220 and RO 320432; GO 6976; Isis 3521; LY333531 / LY379196; isoquinoline compounds; FTIs; PD184352 or QAN697 (P13K inhibitors) or AT7519 (CDK inhibitors);k) Compounds that target, decrease or inhibit the activity of protein-tyrosine kinase inhibitors, for example compounds that target, decrease or inhibit the activity of protein-tyrosine kinase inhibitors are imatinib mesylate (Gleevec™) or tyrphostins (e.g. tyrphostin A23 / RG-50810; AG 99; tyrphostin AG 213; tyrphostin AG 1748; tyrphostin AG 490; tyrphostin B44; tyrphostin B44 (+) enantiomer; tyrphostin AG 555; AG 494; tyrphostin AG 556, AG957) and adahostin (4-{[(2,5-dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester; NSC 680410, adahostin);l) the epidermal growth factor family of receptor tyrosine kinases (as homodimers or heterodimers, EGFR; 1Compounds that target, reduce or inhibit the activity of the epidermal growth factor receptor family, for example compounds that target, reduce or inhibit the activity of members of the EGF receptor tyrosine kinase family, such as EGF receptor, ErbB2, ErbB3 and ErbB4, in particular compounds, proteins or antibodies that inhibit members of the EGF receptor tyrosine kinase family, such as EGF receptor, ErbB2, ErbB3 and ErbB4, or that bind to EGF or EGF-related ligands (e.g. CP 358774, ZD 1839, ZM 105180; trastuzumab (Herceptin™), cetuximab (Erbitux™), Iressa, Tarceva, OSI-774, Cl-1033, EKB-569, GW-2016, E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 or E7.6.3, and 7H-pyrrolo-[2,3-d]pyrimidine derivatives); m) compounds that target, reduce or inhibit the activity of the c-Met receptor, e.g., compounds that target, reduce or inhibit the activity of c-Met, in particular compounds that inhibit the kinase activity of the c-Met receptor, or antibodies that target the extracellular domain of c-Met or bind to HGF; n) compounds that target, reduce or inhibit the kinase activity of one or more JAK family members (JAK1 / JAK2 / JAK3 / TYK2 and / or pan-JAK), including but not limited to PRT-062070, SB-1578, baricitinib, pacritinib, momelotinib, VX-509, AZD-1480, TG-101348, tofacitinib , and ruxolitinib); o) compounds that target, decrease or inhibit the kinase activity of PI3 kinase (PI3K), including but not limited to ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictorelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, and idelalisib; and q) compounds that target, decrease or inhibit the signaling effects of the Hedgehog protein (Hh) or Smoothened receptor (SMO) pathways, including but not limited to cyclopamine, vismodegib, itraconazole, erismodegib, and IPI-926 (salidegib).

[0268] 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, PI3K α, PI3K γ, PI3K δ, PI3K β, PI3K-C2 α, PI3K-C2 β, PI3K-C2 γ, Vps34, p110-α, p110-β, p110-γ, p110-δ, p85-α, p85-β, p55-γ, p150, p101, and p87). Examples of PI3K inhibitors useful in the present invention include, but are not limited to, ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictorelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, and idelalisib.

[0269] The term "BTK inhibitor", as used herein, includes, but is not limited to, compounds that have inhibitory activity against Bruton's tyrosine kinase (BTK), including, but not limited to, AVL-292 and ibrutinib.

[0270] The term "SYK inhibitors" as used herein includes, but is not limited to, compounds having inhibitory activity against spleen tyrosine kinase (SYK), including, but not limited to, PRT-062070, R-343, R-333, Excellair, PRT-062607, and fostamatinib.

[0271] The term "Bcl-2 inhibitors", as used herein, refers to compounds having inhibitory activity against the B-cell lymphoma 2 protein (Bcl-2), including but not limited to ABT-199, ABT-731, ABT-737, apogossypol, Ascenta's pan-Bcl-2 inhibitors, curcumin (and analogs thereof), dual Bcl-2 / Bcl-xL inhibitors (Infinity Pharmaceuticals / Novartis Pharmaceuticals), Genasense (G3139), HA14-1 (and analogs thereof; see WO 2008 / 118802), navitoclax (and analogs thereof, see US 7,390,799), NH-1 (Shenaying Pharmaceuticals), and the like. Pharmaceutical University), obatoclax (and its analogues, see WO2004 / 106328), S-001 (Gloria Pharmaceuticals), the TW series of compounds (Univ. of Michigan), and venetoclax. In some embodiments, the Bcl-2 inhibitor is a small molecule therapeutic. In some embodiments, the Bcl-2 inhibitor is a peptidomimetic.

[0272] Further examples of BTK inhibitor compounds and conditions treatable by such compounds in combination with the compounds of this invention can be found in WO2008 / 039218 and WO2011 / 090760, which are incorporated herein by reference in their entireties.

[0273] Further examples of SYK inhibitor compounds and conditions treatable by such compounds in combination with the compounds of this invention can be found in WO2003 / 063794, WO2005 / 007623, and WO2006 / 078846, which are incorporated herein by reference in their entireties.

[0274] Further examples of PI3K inhibitor compounds and conditions treatable by such compounds in combination with the compounds of this invention can be found in WO2004019973, WO2004 / 089925, WO2007 / 016176, US8,138,347, WO2002 / 088112, WO2007 / 084786, WO2007 / 129161, WO2006 / 122806, WO2005 / 113554, and WO2007 / 044729, which are incorporated by reference in their entireties.

[0275] Further examples of JAK inhibitor compounds and conditions treatable by such compounds in combination with the compounds of this invention can be found in WO2009 / 114512, WO2008 / 109943, WO2007 / 053452, WO2000 / 142246, and WO2007 / 070514, which are incorporated by reference in their entireties.

[0276] Additional anti-angiogenic compounds include compounds that have another mechanism for their activity, such as a mechanism unrelated to protein kinase inhibition or lipid kinase inhibition, such as thalidomide (Thalomid™) and TNP-470.

[0277] Examples of useful proteasome inhibitors for use in combination with the compounds of the invention include, but are not limited to, bortezomib, disulfiram, epigallocatechin-3-gallate (EGCG), salinosporamide A, carfilzomib, ONX-0912, CEP-18770, and MLN9708.

[0278] Compounds which target, decrease or inhibit the activity of protein or lipid phosphatases are for example inhibitors of phosphatase 1, inhibitors of phosphatase 2A or inhibitors of CDC25 (eg okadaic acid or a derivative thereof).

[0279] Compounds that induce cell differentiation processes include, but are not limited to, retinoic acid, α-, γ- or δ-tocopherol, or α-, γ- or δ-tocotrienol.

[0280] The term cyclooxygenase inhibitors as used herein includes, but is not limited to, Cox-2 inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acids and derivatives, 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.

[0281] The term "bisphosphonates" as used herein includes, but is not limited to, etridonic acid, clodronic acid, tiludronic acid, pamidronic acid, alendronic acid, ibandronic acid, risedronic acid and zoledronic acid. Etidronic acid is 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 inhibitors" relates to compounds which inhibit the mammalian target of rapamycin (mTOR) and which have antiproliferative activity, such as sirolimus (Rapamune®), everolimus (Certican™), CCI-779 and ABT578.

[0282] The term "heparanase inhibitor" as used herein refers to a compound that targets, reduces or inhibits heparin sulfate degradation. This term includes, but is not limited to, PI-88. The term "biological response modifier" as used herein refers to lymphokines or interferons.

[0283] The term "inhibitor of Ras oncogenic isoform" (e.g., H-Ras, K-Ras, or N-Ras) as used herein 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™). The term "telomerase inhibitor" as used herein refers to a compound that targets, reduces or inhibits the activity of telomerase. Compounds that target, reduce or inhibit the activity of telomerase are, in particular, compounds that inhibit the telomerase receptor, such as telomestatin.

[0284] The term "methionine aminopeptidase inhibitor" as used herein refers to a compound that targets, reduces or inhibits the activity of methionine aminopeptidase. Compounds that target, reduces or inhibit the activity of methionine aminopeptidase include, but are not limited to, bengamide or its derivatives.

[0285] The term "proteasome inhibitor" as used herein refers to a compound that targets, reduces or inhibits the activity of proteasome. Compounds that target, reduces or inhibit the activity of proteasome include, but are not limited to, bortezomib (Velcade™) and MLN 341.

[0286] The term "matrix metalloproteinase inhibitors" or ("MMP" inhibitors), as used herein, includes, but is not limited to, collagen peptidomimetic and non-peptidomimetic inhibitors, tetracycline derivatives (e.g., the hydroxamate peptidomimetic inhibitor batimastat and its orally bioavailable analogs marimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551) BMS-279251, BAY 12-9566, TAA211, MMI270B or AAJ996).

[0287] The term "compounds used in the treatment of hematological malignancies" as used herein includes, but is not limited to, FMS-like tyrosine kinase inhibitors, which are compounds that target, decrease or inhibit the activity of FMS-like tyrosine kinase receptor (Flt-3R); interferon, 1-β-D-arabinofuransylcytosine (ara-c) and busulfan; ALK inhibitors, which are compounds that target, decrease or inhibit anaplastic lymphoma kinase, and Bcl-2 inhibitors.

[0288] Compounds which target, decrease or inhibit the activity of the FLT-3R-like tyrosine kinase receptor are in particular compounds, proteins or antibodies which inhibit members of the Flt-3R receptor kinase family, such as PKC412, midostaurin, staurosporine derivatives, SU11248 and MLN518.

[0289] The term "HSP90 inhibitor" as used herein includes, but is not limited to, compounds that target, reduce or inhibit the intrinsic ATPase activity of HSP90; compounds that degrade, target, reduce or inhibit HSP90 client proteins via the ubiquitin proteosome pathway. Compounds that target, reduce or inhibit the intrinsic ATPase activity of HSP90 are, in particular, compounds, proteins or antibodies that inhibit the ATPase activity of HSP90, such as 17-allylamino, 17-demethoxygeldanamycin (17AAG), geldanamycin derivatives; other geldanamycin-related compounds; radicicol and HDAC inhibitors.

[0290] The term "antiproliferative antibody" as used herein includes, but is not limited to, trastuzumab (Herceptin™), trastuzumab-DM1, Erbitux, bevacizumab (Avastin™), rituximab (Rituxan®), PRO64553 (anti-CD40) and 2C4 antibodies. By antibody is meant intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least two intact antibodies, and antibody fragments so long as they exhibit the desired biological activity.

[0291] For the treatment of acute myeloid leukemia (AML), the compound of the present invention can be used in combination with standard leukemia therapy, in particular in combination with therapy used for the treatment of AML.In particular, the compound of the present invention can be administered in combination with, for example, farnesyltransferase inhibitors and / or other drugs useful for the treatment of AML, such as daunorubicin, adriamycin, Ara-C, VP-16, teniposide, mitoxantrone, idarubicin, carboplatinum and PKC412.In some embodiments, the present invention provides a method for treating AML associated with ITD and / or D835Y mutation, comprising administering the compound of the present invention together with one or more FLT3 inhibitors. In some embodiments, the FLT3 inhibitor is selected from quizartinib (AC220), staurosporine derivatives (e.g., midostaurin or lestaurtinib), sorafenib, tanzutinib, 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 sunitinib.

[0292] Other anti-leukemia compounds include, for example, Ara-C, a pyrimidine analogue that is a 2'-alpha-hydroxyribose (arabinoside) derivative of deoxycytidine. Also included are the purine analogue of hypoxanthine, 6-mercaptopurine (6-MP) and fludarabine phosphate. Compounds that target, reduce or inhibit the activity of histone deacetylase (HDAC) inhibitors, for example, sodium butyrate and suberoylanilide hydroxamic acid (SAHA), inhibit the activity of enzymes known as histone deacetylases. Specific HDAC inhibitors include MS275, SAHA, FK228 (previously FR901228), trichostatin A, and compounds disclosed in US6,552,065, including but not limited to N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide, or its pharmaceutically acceptable salt, and N-hydroxy-3-[4-[(2-hydroxyethyl){2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide, or its pharmaceutically acceptable salt, especially lactate.Somatostatin receptor antagonist as used herein refers to compounds that target, process or inhibit somatostatin receptor, such as octreotide and SOM230.Tumor cell damage approach refers to approaches such as ionizing radiation. The term "ionizing radiation" referred to above and hereinafter means ionizing radiation occurring as either electromagnetic rays (e.g., X-rays and gamma rays) or particles (e.g., alpha and beta particles). Ionizing radiation is provided in, but not limited to, radiation therapy and is known in the art. See Hellman, Principles of Radiation Therapy, Cancer, in Principles and Practice of Oncology, eds., Devita et al., 4th ed., Vol. 1, pp. 248-275 (1993).

[0293] Also included are EDG binders and ribonucleotide reductase inhibitors.The term "EDG binders" as used herein refers to a class of immunosuppressants that modulate lymphocyte recirculation, such as FTY720.The term "ribonucleotide reductase inhibitors" refers to pyrimidine or purine nucleoside analogs, including but not limited to fludarabine and / or cytosine arabinoside (ara-C), 6-thioguanine, 5-fluorouracil, cladribine, 6-mercaptopurine (particularly in combination with ara-C for ALL) and / or pentostatin.The ribonucleotide reductase inhibitor is in particular hydroxyurea or 2-hydroxy-1H-isoindole-1,3-dione derivative.

[0294] Also included are VEGF compounds, proteins or monoclonal antibodies, such as, in particular, 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharma- ceutically acceptable salt thereof, 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate; Angiostatin™; Endostatin™; anthranilic acid amide; ZD4190; ZD6474; SU5416; SU6668; bevacizumab; or anti-VEGF antibodies or anti-VEGF receptor antibodies (e.g., rhuMAb and RHUFab), VEGF aptamers (e.g., Macugon); FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgGI antibodies, Angiozyme (RPI 4610) and bevacizumab (Avastin™).

[0295] Photodynamic therapy, as used herein, refers to the treatment of using certain chemicals known as photosensitizing compounds to treat or prevent cancer.Examples of photodynamic therapy include treatment with compounds such as Visudyne™ and porfimer sodium.

[0296] Angiogenic antisteroids, as used herein, refer to compounds that block or inhibit angiogenesis, such as anecortave, triamcinolone, hydrocortisone, 11-α-epihydrocortisol, cortexolone, 17α-hydroxyprogesterone, corticosterone, desoxycorticosterone, testosterone, estrone, and dexamethasone.

[0297] Implants containing corticosteroids refer to compounds such as fluocinolone and dexamethasone.

[0298] Other chemotherapeutic compounds include, but are not limited to, plant alkaloids, hormonal compounds and antagonists; biological response modifiers, preferably lymphokines or interferons; antisense oligonucleotides or oligonucleotide derivatives; shRNA or siRNA; or miscellaneous compounds or compounds with other or unknown mechanisms of action.

[0299] The compounds of the present invention are also useful as co-therapeutic compounds for use in combination with other drug substances, such as anti-inflammatory, bronchodilator or antihistamine drug substances, in particular in the treatment of obstructive or inflammatory airway diseases such as those mentioned hereinbefore, e.g. as enhancers of the therapeutic activity of such drugs or as a means of reducing the required dosage or potential side effects of such drugs. The compounds of the present invention may be mixed with other drug substances in a given pharmaceutical composition, or may be administered separately, before, simultaneously with or after the other drug substances. Thus, the present invention includes combinations of the compounds of the present invention as described hereinbefore with anti-inflammatory, bronchodilator, antihistamine or antitussive drug substances, wherein the compounds of the present invention and the drug substances are in the same or different pharmaceutical compositions.

[0300] Suitable anti-inflammatory drugs include steroids, in particular glucocorticosteroids (e.g. budesonide, beclomethasone dipropionate, fluticasone propionate, ciclesonide or mometasone furoate); non-steroidal glucocorticoid receptor agonists; LTB4 antagonists (e.g. LY293111, CGS025019C, CP-195543, SC-53228, BIIL 284, ONO 4057, SB 209247); LTD4 antagonists (e.g. montelukast and zafirlukast); PDE4 inhibitors (e.g. cilomilast (Ariflo® GlaxoSmithKline), roflumilast (Byk Gulden), V-11294A (Napp), BAY19-8004 (Bayer), SCH-351591 (Schering-Plough), Allofilin (Almirall Prodesfarma), PD189659 / PD168787 (Parke-Davis), AWD-12-281 (Asta Medica), CDC-801 (Celgene), SeICID(TM) CC-10004 (Celgene), VM554 / UM565 (Vernalis), T-440 (Tanabe), KW-4490 (Kyowa Hakko Kogyo); A2a agonists; A2b antagonists; and beta-2 adrenoceptor agonists (e.g., albuterol (salbutamol), metaproterenol, terbutaline, salmeterol, Suitable bronchodilator drugs include anticholinergic or antimuscarinic compounds, particularly ipratropium bromide, oxitropium bromide, tiotropium salts and CHF 4226 (Chiesi), and glycopyrrolate.

[0301] Suitable antihistamine drug substances include cetirizine hydrochloride, acetaminophen, clemastine fumarate, promethazine, loratadine, desloratidine, diphenhydramine and fexofenadine hydrochloride, activastine, astemizole, azelastine, ebastine, epinastine, mizolastine and terfenadine.

[0302] Other useful combinations of the compounds of the invention with anti-inflammatory drugs are with antagonists of chemokine receptors, such as CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, CCR-8, CCR-9 and CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, in particular CCR-5 antagonists, such as Schering-Plough antagonists SC-351125, SCH-55700 and SCH-D, and Takeda antagonists, such as N-[[4-[[[6,7-dihydro-2-(4-methylphenyl)-5H-benzo-cyclohepten-8-yl]carbonyl]amino]phenyl]-methyl]tetrahydro-N,N-dimethyl-2H-pyran-4-aminium chloride (TAK-770).

[0303] The structures of the active compounds identified by code number, generic name or trade name can be obtained from the current edition of the standard overview book "The Merck Index" or from databases such as Patents International (eg IMS World Publications).

[0304] The compounds of the present invention may also be used in combination with known therapeutic processes, such as the administration of hormones or radiation. In certain embodiments, provided compounds are used as radiosensitizers, particularly for the treatment of tumors that exhibit poor sensitivity to radiation therapy.

[0305] The compounds of the present invention can be administered alone or in combination with one or more other therapeutic compounds, and possible combination therapy can take the form of a fixed combination, or the compound of the present invention and one or more other therapeutic compounds are administered alternately or independently, or a fixed combination and one or more other therapeutic compounds are administered in combination.The compounds of the present invention can also be administered in combination with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention, or a combination thereof, in particular for tumor treatment.As described above, long-term treatment is possible, as well as adjunctive treatment, in the context of other treatment strategies.Other possible treatments are treatments to maintain the patient's condition after tumor regression, or even chemopreventive treatment, for example in patients at risk.

[0306] These additional agents can be administered as part of a multiple dose regimen, separately from the compound-containing composition 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 dose regimen, the two active agents can be given simultaneously, sequentially or within a period of each other, usually within 5 hours of each other.

[0307] As used herein, the term "combination", "combined" and related terms refer to simultaneous or sequential administration of therapeutic agents according to the present invention.For example, the compound of the present invention can be administered simultaneously or sequentially with another therapeutic agent in separate unit dosage forms or together in a single unit dosage form.Therefore, the present invention provides a single unit dosage form that includes the compound of the present invention, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0308] The amounts of both the compounds of the present invention and additional therapeutic agents (in compositions containing additional therapeutic agents as described above) that can be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Preferably, the compositions of this invention should be formulated so that a dosage of between 0.01-100 mg of the compounds of the present invention per kg of body weight per day can be administered.

[0309] In these compositions containing an additional therapeutic agent, the additional therapeutic agent and the compound of the present invention may act synergistically. Thus, the amount of the additional therapeutic agent in such compositions is less than that required in a monotherapy utilizing only that therapeutic agent. In such compositions, the additional therapeutic agent may be administered at a dosage of between 0.01 and 1,000 μg per kg of body weight per day.

[0310] The amount of additional therapeutic agent present in the compositions of this invention will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Preferably, the amount of additional therapeutic agent in the compositions of the present disclosure will range from about 50% to 100% of the amount that would normally be present in a composition comprising that agent as the only therapeutically active agent.

[0311] The compounds of this invention, or pharmaceutical compositions thereof, may also be incorporated into compositions for coating implantable medical devices, such as prostheses, artificial valves, vascular grafts, stents and catheters. For example, vascular stents are used to overcome restenosis (re-narrowing of the vessel wall after injury). However, patients who use stents or other implantable devices are at risk of clot formation or platelet activation. These unwanted effects can be prevented or reduced by pre-coating the device with a pharma- ceutically acceptable composition that includes a kinase inhibitor. An implantable device coated with the compounds of this invention is another embodiment of the invention.

[0312] The present invention will now be further described by means of non-limiting embodiments 1-31. Embodiment 1:

[0313] Compounds of Formula I: [ka] or a pharma- ceutically acceptable salt thereof, R 1 -L 1 -R 1A and L 1 is a covalent bond; or a bivalent saturated or unsaturated linear or branched C 1~6 A hydrocarbon chain in which one or two methylene units are -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O). 2 -, -S(O) 2 N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, -S(O) 2 and Cy is an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; an optionally substituted 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring; or an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; R 1A is replaced as necessary 1~6an optionally substituted 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; an optionally substituted 3- to 7-membered monocyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or an optionally substituted 6- to 10-membered bridged heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or an optionally substituted 5- to 10-membered monocyclic or bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, R 2 is -C(O)NH 2 ;-C(O)NHR 2A ;-C(O)N(R 2A ) 2 or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, said heteroaryl ring being selected from m instances of R 2B is replaced by R 2A is an optionally substituted 3- to 6-membered saturated or partially unsaturated carbocyclic ring or an optionally substituted 3- to 6-membered heterocyclic ring containing 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur; R 2B is replaced as necessary 1 ~C 6 It is aliphatic, R 3 -NHR 3A and R 3A is Me, Each R is independently hydrogen or C 1~6 an optionally substituted group selected from aliphatic, phenyl, 3-7 membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5-6 membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; each hydrogen bonded to a carbon can be optionally independently replaced by deuterium; m is 0, 1 or 2). Embodiment 2:

[0314] Formula II or IV: [ka] 2. The compound of embodiment 1, or a pharma- ceutically acceptable salt thereof. Embodiment 3:

[0315] Formula III or V: [ka] 3. The compound of embodiment 1 or 2, or a pharma- ceutically acceptable salt thereof. Embodiment 4:

[0316] Formula VI: [ka] Embodiment 5: A compound according to any one of embodiments 1 to 3, or a pharma- ceutically acceptable salt thereof.

[0317] Formula VII: [ka] Embodiment 6: A compound according to any one of embodiments 1 to 3, or a pharma- ceutically acceptable salt thereof.

[0318] Formula VIII: [ka] Embodiment 7: A compound according to any one of embodiments 1 to 5, or a pharma- ceutically acceptable salt thereof.

[0319] R 1A But the following: [ka] 7. The compound according to any one of embodiments 1 to 6, selected from: Embodiment 8:

[0320] R 2A But the following: [ka] The compound according to any one of embodiments 1 to 4, 6 and 7, selected from: Embodiment 9:

[0321] The compound of any one of embodiments 1 to 8, selected from those depicted in Table 1, or a pharma- ceutically acceptable salt thereof. Embodiment 10:

[0322] A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 9 or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable carrier, adjuvant or vehicle. Embodiment 11:

[0323] A compound according to any one of embodiments 1 to 9 or a pharmaceutical composition according to embodiment 10 for use in the manufacture of a medicament for treating a TYK2-mediated disorder, disease or condition in a patient. Embodiment 12:

[0324] A method for inhibiting TYK2 in a biological sample, comprising contacting the sample with a compound described in any one of embodiments 1 to 9, or a pharma- ceutical composition described in embodiment 10. Embodiment 13:

[0325] A method of treating a TYK2-mediated disorder, disease or condition in a patient, comprising administering to the patient a compound described in any one of embodiments 1 to 9, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition described in embodiment 10. Embodiment 14:

[0326] 14. The method of embodiment 13, wherein the disorder is selected from an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a transplant-related disorder. Embodiment 15:

[0327] 15. The method of embodiment 14, wherein the disorder is an autoimmune disorder. Embodiment 16:

[0328] The method of embodiment 15, wherein the autoimmune disorder is selected from type 1 diabetes, ankylosing spondylitis, cutaneous lupus erythematosus, systemic lupus erythematosus, multiple sclerosis, systemic sclerosis, psoriasis, Crohn's disease, ulcerative colitis, and inflammatory bowel disease. Embodiment 17:

[0329] 15. The method of embodiment 14, wherein the disorder is an inflammatory disorder. Embodiment 18:

[0330] The method of embodiment 17, wherein the inflammatory disorder is selected from rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis, Crohn's disease, ulcerative colitis, and inflammatory bowel disease. Embodiment 19:

[0331] 15. The method of embodiment 14, wherein the disorder is a proliferative disorder. Embodiment 20:

[0332] 20. The method of embodiment 19, wherein the proliferative disorder is a hematological cancer. Embodiment 21:

[0333] 20. The method of embodiment 19, wherein the proliferative disorder is leukemia. Embodiment 22:

[0334] 22. The method of embodiment 21, wherein the leukemia is T-cell leukemia. Embodiment 23:

[0335] 23. The method of embodiment 22, wherein said T-cell leukemia is T-cell acute lymphoblastic leukemia (T-ALL). Embodiment 24:

[0336] 21. The method of embodiment 20, wherein the proliferative disorder is associated with one or more activating mutations in TYK2. Embodiment 25:

[0337] 15. The method of embodiment 14, wherein the disorder is associated with transplantation. Embodiment 26:

[0338] 26. The method of embodiment 25, wherein the disorder is transplant rejection or graft-versus-host disease. Embodiment 27:

[0339] 15. The method of embodiment 14, wherein the disorder is an endocrine disorder. Embodiment 28:

[0340] The method of embodiment 27, wherein the endocrine disorder is polycystic ovary syndrome, Crouzon syndrome, or type 1 diabetes. Embodiment 29:

[0341] 15. The method of embodiment 14, wherein the disorder is a neurological disorder. Embodiment 30:

[0342] 30. The method of embodiment 29, wherein the neurological disorder is Alzheimer's disease. Embodiment 31:

[0343] The method of embodiment 14, wherein the disorder is associated with type I interferon, IL-10, IL-12, or IL-23 signaling. EXAMPLES

[0344] As shown in the Examples below, in certain illustrative embodiments, compounds are prepared according to the following general procedures: While the general methods are shown to synthesize certain compounds of the invention, it is understood that the following general methods, and other methods known to those of skill in the art, can be applied to all compounds and each subclass and species of these compounds as described herein. Preparation of Core A: 7-((tert-butoxycarbonyl)(methyl)amino)-5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylic acid [ka]

[0345] Step 1 - Synthesis of Int-1.1: To a solution of Int-1 (50 g, 322.25 mmol, 1.0 equiv.) in ethanol (250 mL), diethyl malonate (103.2 g, 644.51 mmol, 2.0 equiv.) was added, followed by dropwise addition of sodium ethoxide (75 mL, 21% solution in ethanol, 3.0 equiv.). The reaction mixture was stirred for 20 h while heating under reflux. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to give a residue, which was dissolved in water and acidified to pH 3-4 with concentrated hydrochloric acid. The precipitated solid was filtered, washed with water, diethyl ether, and thoroughly dried to obtain pure Int-1.1 (43 g, yield: 59.79%; MS (ES): m / z 224.2 [M+H] + ) was obtained.

[0346] Step 2 - Synthesis of Int-1.2: To a mixture of Int-1.1 (43 g, 192.6 mmol, 1.0 equiv.) in phosphorus oxychloride (191 g, 1251 mmol, 6.5 equiv.), diethylaniline (43 g, 288.9 mmol, 1.5 equiv.) was added. The reaction mixture was stirred at 80° C. for 3 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to give a residue, which was transferred into ice-cold water and extracted with dichloromethane. The organic layers were combined, washed with saturated sodium bicarbonate solution followed by brine solution, dried over sodium sulfate and concentrated under reduced pressure to give the crude material. This was further purified by column chromatography and the compound was eluted with 20% ethyl acetate in hexane to give pure Int1.2 (35 g, yield: 69.85%; MS(ES): m / z 261 [M+H] + ) was obtained.

[0347] Step 3 - Synthesis of Int-1.3: To a solution of Int-1.2 (35 g, 134.58 mmol, 1.0 equiv.) in ethanol (350 mL) at 0 °C, potassium carbonate (18.57 g, 134.58 mmol, 1.0 equiv.) was added followed by methylamine (40% in water) (10.95 mL, 141.3 mmol, 1.05 equiv.) and the reaction mixture was stirred at room temperature for 1 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to give a residue, which was transferred into ice-cold water. The precipitated solid was filtered, washed with water and thoroughly dried under vacuum to give Int-1.3 (30 g, yield: 87.53%; MS (ES): m / z 255.6 [M+H] + ) was obtained.

[0348] Step 4 - Synthesis of Int-1.4: To a solution of Int-1.3 (30 g, 117.8 mmol, 1.0 equiv.) in 1,4-dioxane (300 mL), N,N-dimethylaminopyridine (1.43 g, 11.78 mmol, 0.1 equiv.) was added followed by di-tert-butyl dicarbonate (51.36 g, 235.6 mmol, 2.0 equiv.) and the reaction mixture was stirred at room temperature for 12 h. After the reaction was completed, the reaction mixture was transferred into water and the product was extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure to give the crude material. This was further purified by column chromatography and the compound was eluted with 12% ethyl acetate in hexane to give Int-1.4 (26 g, 62.21%; MS(ES): m / z 355 [M+H] + ) was obtained.

[0349] Step 5 - Synthesis of Core A: To a suspension of Int-1.4 (20 g, 56.37 mmol, 1.0 equiv.) in toluene (200 mL), tributyltin oxide (67.19 g, 112.73 mmol, 2.0 equiv.) was added and the reaction mixture was heated at 120 °C for 12 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to give a residue, which was dissolved in saturated sodium bicarbonate solution and washed with hexane. The aqueous layer was separated, acidified to pH approx. 5-6 with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to give a solid, which was triturated with hexane to give pure Core A (13.2 g, yield: 71.67%; 1 H NMR (DMSO-d6, 400 MHZ): 12.63 (s, 1H), 8.63 (s, 1H), 7.55 (s, 1H), 3.31 (s, 3H), 1.29 (s, 9H)). Preparation of Core B: 7-(benzyl(methyl)amino)-5-chloropyrazolo[1,5-a]pyrimidine-3-carboxamide [ka]

[0350] Step 1 - Synthesis of Int-2.1: To a solution of Int-2 (50 g, 462.5 mmol, 1.0 equiv.) in methanol (400 mL), diethyl malonate (141 mL, 925.06 mmol, 2.0 equiv.) was added, followed by dropwise addition of sodium ethoxide (21% in ethanol; 108 mL, 1387.5 mmol, 3.0 equiv.). The reaction mixture was stirred for 10 h while heating under reflux. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to give a residue, which was dissolved in water and acidified to pH approx. 3-4 with concentrated hydrochloric acid. The precipitated solid was filtered, washed with water, diethyl ether, and thoroughly dried to obtain pure Int-2.1 (50 g, yield: 61.38%; MS (ES): m / z 177.14 [M+H] + ) was obtained.

[0351] Step 2 - Synthesis of Int-2.2: To a mixture of Int-2.1 (50 g, 283.87 mmol, 1.0 equiv.) and phosphorus oxychloride (163 mL, 1704.54 mmol, 6.0 equiv.), diethylaniline (68.26 mL, 426.13 mmol, 1.5 equiv.) was added. The reaction mixture was stirred at 90 °C for 3 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to give a residue, which was transferred into ice-cold water and extracted with dichloromethane. The organic layers were combined, washed with saturated sodium bicarbonate solution, followed by brine solution, dried over sodium sulfate, and concentrated under reduced pressure to give the crude material. This was further purified by column chromatography and the compound was eluted with 20% ethyl acetate in hexane to give pure Int-2.2 (45 g, yield: 74.42%; MS (ES): m / z 214.02 [M+H] + ) was obtained.

[0352] Step 3 - Synthesis of Int-2.3: To a solution of Int-2.2 (10 g, 46.94 mmol, 1.0 equiv.) in ethanol (315 mL) was added potassium carbonate (7.12 g, 51.63 mmol, 1.1 equiv.) followed by benzylamine (5.64 mL, 51.63 mmol, 1.1 equiv.) at 0 °C, and the reaction mixture was stirred at room temperature for 2 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to give a residue, which was transferred into ice-cold water. The precipitated solid was filtered, washed with water, and thoroughly dried under vacuum to give Int2.3 (10 g, yield: 71.54%; MS (ES): m / z 298.75 [M+H] + ) was obtained.

[0353] Step 4 - Synthesis of Core B: To a solution of Int-2.3 (10 g, 33.59 mmol, 1.0 equiv) in toluene:ethanol:water mixture (160 mL, 1.0:0.5:0.25) at 0 °C, triphenylphosphine (1.76 g, 6.72 mmol, 0.2 equiv) was added followed by acetaldoxime (3.96 g, 67.18 mmol, 2.0 equiv) and the reaction mixture was stirred at 110 °C for 5 h. After the reaction was completed, the reaction mixture was transferred into water and the product was extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure to give the crude material. This was further purified by column chromatography and the compound was eluted with 25% ethyl acetate in hexane to give Core B (4.7 g, yield: 44.32%; MS (ES): m / z 315.76 [M+H] + ; 1 H NMR (DMSO-d 6 ,400MHZ): 8.44 (s, 1H), 7.52-7.50 (d, J=8Hz, 1H),7.44 (s, 1H), 7.38-7.29 (m,5H), 6.50 (s, 1H), 5.41 (s, 2H), 3.23 (s, 3H)). Preparation of Core C: 5-chloro-1-(4-methoxybenzyl)-2,3-dihydro-1H-pyrazolo[5',1':2,3]pyrimido[5,4-b][1,4]oxazine-7-carboxylic acid [ka]

[0354] Step 1 - Synthesis of compound Int-3.2: To a solution of Int-3 (50 g, 322.58 mmol, 1.0 equiv.) in ethanol (250 mL), Int-3.1 (104.5 g, 645.16 mmol, 2.0 equiv.) was added, followed by dropwise addition of sodium ethoxide (75 mL, 21% solution in ethanol, 3.0 equiv.). The reaction mixture was stirred for 20 h while heating under reflux. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to give a residue, which was dissolved in water and acidified to pH 3-4 with concentrated hydrochloric acid. The precipitated solid was filtered, washed with water, diethyl ether, and thoroughly dried to obtain pure Int-3.1 (43 g, yield: 52.70%; MS (ES): m / z 254.07 [M+H] + ) was obtained.

[0355] Step 2 - Synthesis of compound Int-3.3: To a mixture of Int-3.2 (43 g, 169.29 mmol, 1.0 equiv.) and phosphorus oxychloride (168.3 g, 1100.38 mmol, 6.5 equiv.), diethylaniline (75.7 g, 507.87 mmol, 3.0 equiv.) was added. The reaction mixture was stirred at 80° C. for 3 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to give a residue, which was transferred into ice-cold water and extracted with dichloromethane. The organic layers were combined, washed with saturated sodium bicarbonate solution followed by brine solution, dried over sodium sulfate and concentrated under reduced pressure to give the crude material. This was further purified by column chromatography and the compound was eluted with 20% ethyl acetate in hexane to give pure Int-3.2 (35 g, yield: 71.05%; MS (ES): m / z 291.00 [M+H] + ) was obtained.

[0356] Step 3 - Synthesis of compound Int-3.5: To a solution of Int-3.3 (20 g, 68.96 mmol, 1.0 equiv.) in isopropyl alcohol (200 mL), Int-3.4 (4.2 g, 68.96 mmol, 1.0 equiv.) and triethylamine (13.9 g, 137.92 mmol, 2.0 equiv.) were added. The reaction mixture was stirred at 80 °C for 6 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to give the crude material, which was purified by column chromatography and the compound was eluted with 3% methanol in dichloromethane to give pure Int-3.5 (10.0 g, yield: 46.09%; MS (ES): m / z 315.08 [M+H] + ) was obtained.

[0357] Step 4 - Synthesis of compound Int-3.6: To a mixture of Int-3.5 (10.0 g, 31.84 mmol, 1.0 equiv.) in dichloromethane (100 mL) was added boron tribromide (39.8 g, 159.2 mmol, 5.0 equiv.) dropwise at -78 °C. The reaction mixture was stirred at room temperature for 2 h. After the reaction was completed, the reaction mixture was transferred into sodium bicarbonate and the product was extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure to give the crude material. This was further purified by column chromatography and the compound was eluted with 10% methanol in dichloromethane to give pure Int-3.6 (6.0 g, yield: 62.80%; MS (ES): m / z 302.06 [M+H] + ) was obtained.

[0358] Step 5 - Synthesis of compound Int-3.7: To a solution of Int-3.6 (6.0 g, 16.62 mmol, 1.0 equiv.) in dichloromethane (80 mL) was added triphenylphosphine (13.06 g, 49.86 mmol, 3.0 equiv.) and diisopropyl azodicarboxylate (10.07 g, 49.86 mmol, 3.0 equiv.) at 0° C. The reaction mixture was stirred at room temperature for 12 h. After the reaction was completed, the reaction mixture was transferred into water and the product was extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure to give Int-3.7 (3.9 g, yield: 83.60%; MS (ES): m / z 283.06 [M+H]+ ) was obtained.

[0359] Step 6 - Synthesis of compound Int-3.8: To a solution of Int-3.7 (3.9 g, 13.82 mmol, 1.0 equiv.) in N,N-dimethylformamide (40 mL) at 0 °C, 4-methoxybenzyl chloride (2.3 g, 15.20 mmol, 1.1 equiv.) and cesium carbonate (8.9 g, 27.84 mmol, 2.0 equiv.) were added. The reaction mixture was stirred at room temperature for 2 h. After the reaction was completed, the reaction mixture was transferred into water and the product was extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material. This was further purified by column chromatography and the compound was eluted with 20% ethyl acetate in hexane to obtain pure Int-3.8 (3.0 g, yield: 53.98%; MS (ES): m / z 403.11 [M+H] + ) was obtained.

[0360] Step 7 - Synthesis of Core C: To a suspension of Int-3.8 (3.0 g, 7.46 mmol, 1.0 equiv.) in toluene (30 mL), tributyltin oxide (8.8 g, 14.92 mmol, 2.0 equiv.) was added and the reaction mixture was refluxed for 12 h. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to give a residue, which was dissolved in saturated sodium bicarbonate solution and washed with hexanes. The aqueous layer was separated, acidified to pH approx. 5-6 with 1N hydrochloric acid and extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure to give a solid, which was triturated with hexanes to give pure Core C (1.9 g, yield: 68.79%, MS(ES): m / z 375.08 [M+H] + ) was obtained. Preparation of Core D: Ethyl 7-(benzyl(methyl)amino)-5-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate [ka]

[0361] Synthesis of compound Int-4. The compound was synthesized using the general procedure for Core A synthesis to give Int-4. (Yield: 45%), MS(ES): m / z 345.10 [M+H] + .

[0362] Synthesis of compound Int-4.2. A stirred solution of 1 (3.5 g, 10.15 mmol, 1.0 equiv.), Int-4.1 (4.5 g, 13.19 mmol, 1.3 equiv.) and sodium carbonate (2.6 g, 25.37 mmol, 2.5 equiv.) in 1,4 dioxane:water (140 mL, 9:1) was purged with argon for 15 min, to which [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (0.738 mg, 1.01 mmol, 0.1 equiv.) was added and purged for an additional 10 min. The reaction was stirred at 110° C. for 6 h. After the reaction was complete, the reaction mixture was poured onto water and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to give Int-4.2. (3.1g, 57.99%). MS(ES):m / z527.24[M+H] +

[0363] Synthesis of compound core D. Int-4.2 (3.1 g, 5.88 mmol, 1.0 equiv.) was added with 4 M hydrochloric acid in 1,4 dioxane (60 mL) and stirred at room temperature for 4 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the residue was stirred with saturated sodium bicarbonate solution and extracted with dichloromethane. The organic layers were combined, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to give a residue which was triturated with diethyl ether to give core D. (2.1 g, 83.64%). MS (ES): m / z 427.18 [M+H] + General Procedure A (acid-amine coupling): [ka]

[0364] Synthesis of Int-5: To a solution of Core A (4 g, 12.26 mmol, 1.0 equiv.) in N,N-dimethylformamide (40 mL), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (9.32 g, 24.53 mmol, 2.0 equiv.) was added and stirred at room temperature for 15 min. To this was added diisopropylethylamine (6.40 mL, 36.78 mmol, 3.0 equiv.) followed by cyclopropanamine (0.699 g, 12.26 mmol, 1.0 equiv.). The reaction mixture was stirred at room temperature for 5 min. After the reaction was completed, 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 over sodium sulfate, and concentrated under reduced pressure to give the crude material. This was further purified by column chromatography, and the compound was eluted with 40% ethyl acetate in hexane to give Int-5 (2.4 g, yield: 53.69%; MS(ES): m / z 366.13 [M+H] + ) was obtained. General Procedure B (Buchwald amination): [ka]

[0365] Synthesis of Int-6.2: To a solution of Int-5 (0.125 g, 0.342 mmol, 1.0 equiv.) in 1,4-dioxane (5 mL) was added Int-6.1 (0.082 g, 0.410 mmol, 1.2 equiv.), sodium carbonate (0.072 g, 0.684 mmol, 2.0 equiv.). The reaction mixture was degassed under argon for 10 min, then tris(dibenzylideneacetone)dipalladium(0) (0.015 g, 0.017 mmol, 0.05 equiv.) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.019 g, 0.034 mmol, 0.1 equiv.) were added and degassed again for 5 min. The reaction was stirred at 100° C. for 4 h. After the reaction was completed, the reaction mixture was cooled to room temperature, transferred into water and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to give the crude material, which was further purified by Combi-Flash using 3% methanol in dichloromethane as eluent to give pure Int-6.2 (0.070 g, yield: 38.6%; MS(ES): m / z 532.23 [M+H] + ) was obtained. General Procedure C (BOC-deprotection): [ka]

[0366] Synthesis of Int-7.1: Int-6.2 (0.070 g, 0.131 mmol, 1.0 equiv) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (0.1 mL) was added to the reaction mixture. The reaction was stirred at room temperature for 1 h. After the reaction was completed, the reaction mixture was transferred into saturated bicarbonate solution and the product was extracted with dichloromethane. The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure to give the crude material. This was further purified by trituration with diethyl ether to give pure Int-7.1 (0.040 g, yield: 70.17%; MS (ES): m / z 432.24 [M+H] + ) was obtained. Preparation of intermediate A: 3-amino-1-(tetrahydro-2H-pyran-4-yl)pyridin-2(1H)-one [ka]

[0367] Synthesis of compound Int-8.2. To a solution of Int-8 (3 g, 14.28 mmol, 1.0 equiv.) and Int-8.1 (2.4 g, 17.14 mmol, 1.2 equiv.) in dioxane (30 mL), copper acetate (2.60 g, 14.28 mmol, 1.0 equiv.) and triethylamine (5.00 mL, 35.7 mmol, 2.5 equiv.) were added under nitrogen. The reaction was stirred at 80° C. for 5 h. After the reaction was completed, the reaction mixture was transferred into ice-cold water and the product was extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure to give the crude material. This was further purified by column chromatography and the compound was eluted with 10% ethyl acetate in hexane to give pure Int-8.2 (0.380 g, 11.98%), MS (ES): m / z 222.20 [M+H] + .

[0368] Synthesis of intermediate A. To a solution of Int-8.1 (0.380 g, 1.71 mmol, 1.0 equiv) in methanol (4 ml) was added palladium on charcoal (0.100 g). Hydrogen was purged through the reaction mixture at room temperature for 3 hours. After the reaction was complete, the reaction mixture was filtered through a celite bed and washed with methanol. The filtrate was concentrated under reduced pressure to give the crude material. This was further purified by column chromatography and the compound was eluted with 1.4% methanol in dichloromethane to give pure intermediate A (0.120 g, 36.13%). MS (ES): m / z 195.23 [M+H] + . Example 1 N-Cyclopropyl-5-((1-(3-hydroxy-3-methylcyclohexyl)-2-oxo-1,2-dihydropyridin-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (I-1). [ka] Scheme 1: [ka]

[0369] Step 1 - Synthesis of compound 1.2: To a cooled solution of 1 (0.260 g, 1.68 mmol, 1.0 equiv.) in N,N-dimethylformamide (4 mL), 1.1 (0.217 g, 1.68 mmol, 1.0 equiv.) was added. The reaction mixture was stirred at 0° C. for 30 min and further stirred at room temperature for 15 min. N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.338 g, 2.18 mmol, 1.3 equiv.) and 4-dimethylaminopyridine (0.040 g, 0.33 mmol, 0.2 equiv.) were added. The reaction mixture was stirred at room temperature for 24 h. After the reaction was completed, 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 over sodium sulfate, and concentrated under reduced pressure to give the crude material. This was further purified by column chromatography and the compound was eluted with 1.7% methanol in dichloromethane to give 1.2. (0.154 g, 34.41% yield; MS(ES): m / z 266.13 [M+H] + ).

[0370] Step 2 - Synthesis of compound 1.3: To a solution of 1.2 (0.140 g, 0.52 mmol, 1.0 equiv) in tetrahydrofuran:water (4 mL, 2:1), lithium hydroxide (0.124 g, 5.2 mmol, 10 equiv) was added. The reaction was stirred at 60 °C for 16 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to give a residue. To this was added water and acidified with 1N hydrochloric acid at 10 °C to adjust the pH to about 6-6.5. The product was extracted with dichloromethane. The organic layers were combined, washed with brine solution, dried over sodium sulfate, and concentrated under reduced pressure to give the crude material. This was further purified by column chromatography and the compound was eluted with 2.1% methanol in dichloromethane to give pure 1.3 (0.130 g, yield: 89.13%; MS (ES): m / z 252.12 [M+H] + ) was obtained.

[0371] Step 3 - Synthesis of compound 1.4: To a solution of 1.3 (0.130 g, 0.51 mmol, 1.0 equiv.) in tert-butanol (3 mL) under nitrogen was added triethylamine (0.087 g, 0.86 mmol, 1.7 equiv.) and diphenylphosphoryl azide (0.182 g, 0.66 mmol, 1.3 equiv.), followed by heating at 80 °C for 16 h. After the reaction was completed, the reaction mixture was cooled to room temperature, transferred into water, and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine solution, dried over sodium sulfate, and concentrated under reduced pressure to obtain the crude material. This was further purified by column chromatography, and the compound was eluted with 22% ethyl acetate in hexane to give pure 1.4 (0.210 g, yield: 95.93%; MS (ES): m / z 323.19 [M+H] + ) was obtained.

[0372] Step 4 - Synthesis of compound 1.5: To a cooled solution of 1.4 (0.210 g, 0.65 mmol, 1 equiv) in dioxane (4 mL), 4N hydrochloric acid in dioxane (6 mL) was added dropwise. The reaction mixture was stirred at room temperature for 2 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to give pure 1.5 (0.170 g, yield: 97.90%; MS (ES): m / z 223.14 [M+H] + ) was obtained.

[0373] Step 5 - Synthesis of compound 1.6: The compound was synthesized using the procedure in the preparation of core A to obtain 1.6 (yield: 57.16%; MS (ES): m / z 366.82 [M+H] + ) was obtained.

[0374] Step 6 - Synthesis of compound 1.7: Use general procedure B to synthesize compound 1.7 (0.130 g, yield: 61.58%; MS(ES): 552.29 [M+H] + ) was obtained.

[0375] Step 7—Synthesis of compound I-1: Compound I-1 was synthesized using general procedure C (0.025 g, yield: 87.27%; MS (ES): 452.42 [M+H] +LCMS purity: 96.18%; HPLC purity: 96.68%; Chiral HPLC: 47.64%, 48.76%; 1 H NMR (DMSO-d 6 , 400MHZ): 8.92 (s,1H), 8.20 (s,1H), 8.12-8.10 (d, J=8Hz, 1H), 7.93-7.92 (d, J=4.8Hz,1H), 7.84-7.83 (d, J=4Hz,1H), 7.47-7.45 (d, J=6.4Hz, 1H), 7.40 (s, 1H), 6.35-6.31 (t, J=7.2Hz, 1H), 6.20(s, 1H), 4.92 (bs,1H), 4.69 (bs, 1H), 2.91-2.90 (d, J=4.8Hz, 3H), 1.78 (bs,3H), 1.67 (bs,2H), 1.45-1.48 (m, 2H), 1.24 (bs, 4H), 0.80-0.79 (d, J=5.6Hz, 2H), 0.51 (bs, 2H)). Example 2 N-Cyclopropyl-5-((1-((1S,3R)-3-hydroxy-3-methylcyclohexyl)-2-oxo-1,2-dihydropyridin-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (I-2) and N-Cyclopropyl-5-((1-((1R,3S)-3-hydroxy-3-methylcyclohexyl)-2-oxo-1,2-dihydropyridin-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (I-3). [ka] Scheme 2: [ka]

[0376] Step 1-Synthesis of compound 2: Compound 2 was synthesized according to the experimental protocol of I-1 (Example 1) to obtain 2 (yield: 61.58%; MS (ES): m / z 552.29 [M+H] + ) was obtained.

[0377] Step 2 - Synthesis of compounds 2.1 and 2.2: The isomers of 2 (0.105 g) were added to a column CHIRALCEL OJ-H (250 mm * 4.6 mm, 5 μm) and a flow rate of 4 mL / min using 0.1% DEA in methanol as co-solvent to give pure fraction-1 (FR-a) and fraction-2 (FR-b).

[0378] FR-a was concentrated under reduced pressure at 30 °C to give pure 2.1 (0.040 g; MS(ES): m / z 552.29 [M+H] + ) was obtained.

[0379] FR-b was concentrated under reduced pressure at 30 °C to give pure 2.2 (0.042 g; MS(ES): m / z 552.29 [M+H] + ) was obtained.

[0380] Step 3 - Synthesis of compound I-2: Compound I-2 was synthesized using general procedure C to give I-2 (0.032 g, yield: 97.74%; MS (ES): m / z 452.2 [M+H] + LCMS Purity: 99.00%; HPLC Purity: 99.58%; Chiral HPLC Purity: 100%; 1 HNMR (DMSO-d 6 , 400MHZ): 8.89 (s, 1H), 8.18 (s, 1H),8.10-8.08(d, J=6.8Hz, 1H), 7.91-7.89 (d, J=4.8Hz, 1H), 7.82-7.81 (d,J=3.6Hz,1H), 7.45-7.43 (d, J=6.8Hz, 1H), 6.33-6.29 (t, J=7.2Hz, 1H), 6.16(s,1H), 4.67 (s, 1H),2.89-2.88 (d, J=4.4Hz, 3H), 2.86-2.82 (m, 1H),1.76 (bs, 2H), 1.59 (bs, 2H), 1.46-1.40 (m, 2H), 1.23 (s, 6H), 0.78-0.77 (d,J=5.2Hz, 2H), 0.49 (bs, 2H)).

[0381] Step 4—Synthesis of compound I-3: Compound I-3 was synthesized using general procedure C to give I-3 (0.032 g, yield: 93.08%; MS (ES): m / z 452.2 [M+H] + LCMS Purity: 100%; HPLC Purity: 98.97%, Chiral HPLC Purity: 98.25%; 1 H NMR (DMSO-d 6 , 400MHZ): 8.90 (s, 1H), 8.18 (s, 1H),8.10-8.08 (d, J=6.8Hz, 1H), 7.90-7.89 (d, J=4.8Hz,1H), 7.82-7.81 (d, J=3.6Hz,1H), 7.45-7.43 (d, J=6.8Hz, 1H), 6.33-6.29 (t, J=7.2Hz, 1H), 6.16 (s, 1H), 4.67(s, 1H), 2.89-2.88(d, J=4.4Hz, 3H), 2.86-2.82 (m, 1H), 1.76 (bs, 2H), 1.59 (bs,2H),1.46-1.40 (m, 2H), 1.22 (s, 6H), 0.78-0.77 (d, J=5.2Hz, 2H), 0.49 (bs, 2H)) was obtained. Example 3 N-Cyclopropyl-5-((1-((1r,3r)-3-methoxycyclobutyl)-2-oxo-1,2-dihydropyridin-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (I-4). [ka] Scheme 3: [ka]

[0382] Step 1 - Synthesis of compound 3.2: To a cooled solution of 3 (5.0 g, 32.44 mmol, 1.0 equiv.) in N,N-dimethylformamide (50 mL) was added 3.1 (3.99 g, 32.44 mmol, 1.0 equiv.). The reaction mixture was stirred at 0° C. for 30 min, further stirred at room temperature for 15 min, and N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (6.5 g, 42.17 mmol, 1.3 equiv.) and 4-dimethylaminopyridine (0.790 g, 6.48 mmol, 0.2 equiv.) were added. The reaction mixture was stirred at room temperature for 24 h. After the reaction was completed, 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 over sodium sulfate, and concentrated under reduced pressure to give the crude material. This was further purified by column chromatography, and the compound was eluted with 1.7% methanol in dichloromethane to give 3.2 (3.35 g, yield: 46.26%; MS(ES): m / z 224.09 [M+H] + ) was obtained.

[0383] Step 2 - Synthesis of compound 3.3: To a cooled solution of 3.2 (3.35 g, 15.02 mmol, 1.0 equiv.) in N,N-dimethylformamide (35 mL) at 0 °C, sodium hydride (1.44 g, 6.08 mmol, 4.0 equiv.) was added portionwise and stirred for 30 min, followed by dropwise addition of methyl iodide (2.7 g, 19.52 mmol, 1.3 equiv.). The reaction mixture was stirred at the same temperature for 20 min, and the mixture was stirred at room temperature for 6 h. After the reaction was completed, the reaction mixture was transferred into ice water and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine solution, dried over sodium sulfate, and concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography to elute the pure compound with 2-2.5% methanol in dichloromethane to obtain pure 3.3 (2.85 g, yield: 80.04%; MS (ES): m / z 238.10 [M+H]). + ) was obtained.

[0384] Step 3 - Synthesis of compound 3.4: To a solution of 3.3 (2.85 g, 12.02 mmol, 1.0 equiv) in tetrahydrofuran:water (30 mL, 2:1), lithium hydroxide (2.88 g, 120.2 mmol, 10 equiv) was added. The reaction was stirred at 60 °C for 16 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to give a residue. To this was added water and acidified with 1N hydrochloric acid at 10 °C to adjust the pH to about 6-6.5. The product was extracted with dichloromethane. The organic layers were combined, washed with brine solution, dried over sodium sulfate, and concentrated under reduced pressure to give the crude material. This was further purified by column chromatography and the compound was eluted with 2.1% methanol in dichloromethane to give pure 3.4 (2.4 g, yield: 89.50%; MS (ES): m / z 224.09 [M+H] + ) was obtained.

[0385] Step 4 - Synthesis of compound 3.5: To a solution of 3.4 (2.4 g, 10.76 mmol, 1.0 equiv.) in tert-butanol (25 mL) under nitrogen was added triethylamine (1.84 g, 18.29 mmol, 1.7 equiv.) and diphenylphosphoryl azide (3.84 g, 13.98 mmol, 1.3 equiv.), followed by heating at 80 °C for 16 h. After the reaction was completed, the reaction mixture was cooled to room temperature, transferred into water, and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine solution, dried over sodium sulfate, and concentrated under reduced pressure to obtain the crude material. This was further purified by column chromatography, and the compound was eluted with 22% ethyl acetate in hexane to give pure 3.5 (2.0 g, yield: 63.20%; MS (ES): m / z 295.16 [M+H] + ) was obtained.

[0386] Step 5 - Synthesis of compound 3.6: To a cooled solution of 3.5 (2.0 g, 6.80 mmol, 1 equiv) in dioxane (20 mL), 4N hydrochloric acid in dioxane (22 mL) was added dropwise. The reaction mixture was stirred at room temperature for 2 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to give pure 3.6 (1.4 g, yield: 89.32%; MS (ES): m / z 195.11 [M+H]+ ) was obtained.

[0387] Step 6 - Synthesis of compound 3.7: Compound 3.7 was synthesized from core A using general method A (yield: 57.16%; MS(ES): m / z 366.82 [M+H] + ) was obtained.

[0388] Step 7 - Synthesis of compound 3.8: Compound 3.8 was synthesized using general procedure B to give 3.8 (0.085 g, yield: 59.39%; MS (ES): m / z 524.26 [M+H] + ) was obtained.

[0389] Step 7 - Synthesis of compound I-4: Compound I-4 was synthesized using general procedure C to give I-4 (0.060 g, yield: 87.28%; MS (ES): m / z 424.82 [M+H] + LCMS Purity: 100%; HPLC Purity: 99.28%; Chiral HPLC: 96.77%; 1 H NMR (DMSO-d 6 , 400MHZ): 8.92 (s, 1H), 8.20 (s,1H),8.14-8.12 (d, J=7.2Hz, 1H), 7.92-7.91 (d, J=4Hz,1H), 7.83 (bs, 1H), 7.54-7.53(d, J=6.8Hz, 1H), 6.37-6.33 (t, J=7.6Hz, 1H), 6.20 (s, 1H), 4.07 (bs, 1H),3.21 (s, 3H),2.90-2.89 (d, J=4.8Hz, 3H), 2.51 (bs, 4H), 1.24 (bs, 2H),0.80-0.78 (d, J=6.8Hz,2H), 0.50 (bs, 2H)) was obtained. Example 4 N-Cyclopropyl-5-((1-((1s,3s)-3-methoxycyclobutyl)-2-oxo-1,2-dihydropyridin-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (I-5). [ka] Scheme 4: [ka]

[0390] Step 1 - Synthesis of compound 5.2: To a cooled solution of 4 (5.0 g, 32.44 mmol, 1.0 equiv.) in N,N-dimethylformamide (50 mL) was added 4.1 (3.99 g, 32.44 mmol, 1.0 equiv.). The reaction mixture was stirred at 0° C. for 30 min and further stirred at room temperature for 15 min. N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (6.5 g, 42.17 mmol, 1.3 equiv.) and 4-dimethylaminopyridine (0.790 g, 6.48 mmol, 0.2 equiv.) were added. The reaction mixture was stirred at room temperature for 24 h. After the reaction was completed, 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 over sodium sulfate, and concentrated under reduced pressure to give the crude material. This was further purified by column chromatography, and the compound was eluted with 1.7% methanol in dichloromethane to give 4.2 (3.35 g, yield: 46.26%; MS(ES): m / z 224.09 [M+H] + ) was obtained.

[0391] Step 2 - Synthesis of compound 4.3: To a solution of 4.2 (2.85 g, 12.02 mmol, 1.0 equiv) in tetrahydrofuran:water (30 mL, 2:1), lithium hydroxide (2.88 g, 120.2 mmol, 10 equiv) was added. The reaction was stirred at 60 °C for 16 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to give a residue. To this was added water and acidified with 1N hydrochloric acid at 10 °C to adjust the pH to about 6-6.5. The product was extracted with dichloromethane. The organic layers were combined, washed with brine solution, dried over sodium sulfate, and concentrated under reduced pressure to give the crude material. This was further purified by column chromatography and the compound was eluted with 2.1% methanol in dichloromethane to give pure 4.3 (2.4 g, yield: 89.50%; MS (ES): m / z 224.09 [M+H] + ) was obtained.

[0392] Step 3 - Synthesis of compound 4.4: To a solution of 4.3 (2.4 g, 10.76 mmol, 1.0 equiv.) in tert-butanol (25 mL) under nitrogen was added triethylamine (1.84 g, 18.29 mmol, 1.7 equiv.) and diphenylphosphoryl azide (3.84 g, 13.98 mmol, 1.3 equiv.), followed by heating at 80 °C for 16 h. After the reaction was completed, the reaction mixture was cooled to room temperature, transferred into water, and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine solution, dried over sodium sulfate, and concentrated under reduced pressure to obtain the crude material. This was further purified by column chromatography, and the compound was eluted with 22% ethyl acetate in hexane to give pure 4.4 (2.0 g, yield: 63.20%; MS (ES): m / z 295.16 [M+H] + ) was obtained.

[0393] Step 4 - Synthesis of compound 4.5: To a cooled solution of 4.4 (2.0 g, 6.80 mmol, 1 equiv) in dioxane (20 mL), 4N hydrochloric acid in dioxane (22 mL) was added dropwise. The reaction mixture was stirred at room temperature for 2 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to give pure 4.5. (1.4 g, yield: 89.32%; MS (ES): m / z 195.11 [M+H] + ).

[0394] Step 5 - Synthesis of compound 4.6: Compound 4.6 was synthesized from core A utilizing general procedure A to give compound 4.6 (yield: 57.16%; MS(ES): m / z 366.82 [M+H] + ) was obtained.

[0395] Step 6 - Synthesis of compound 4.7: The compound was synthesized using general procedure B to obtain 4.7 (0.061 g, yield: 35.52%; MS (ES): 524.26 [M+H] + ) was obtained.

[0396] Step 7—Synthesis of compound I-5: Compound I-5 was synthesized using general procedure C (0.038 g, yield: 77.02%; MS (ES): m / z 424.37 [M+H] +LCMS Purity: 100%; HPLC Purity: 100%; Chiral HPLC: 95.00%; 1 H NMR (DMSO-d 6 , 400MHZ): 8.91 (s, 1H), 8.20 (s,1H),8.14-8.12 (d, J=6.4Hz, 1H), 7.91 (bs, 1H), 7.83 (bs, 1H),7.49-7.47 (d, J=6Hz, 1H), 6.35-6.33 (t, J=6.4Hz, 1H), 6.20 (s, 1H), 4.73-4.69 (m, 1H), 3.79(bs,1H), 3.21 (s, 3H), 2.90-2.89 (d, J=4.8Hz, 3H), 2.83 (bs, 3H), 2.14-2.12(d,J=7.6Hz, 2H), 0.89-0.79 (d, J=5.6Hz, 2H), 0.50 (bs, 2H)). Example 5 N-((1R,2S)-2-Fluorocyclopropyl)-5-((1-(3-hydroxy-3-methylcyclohexyl)-2-oxo-1,2-dihydropyridin-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (I-6). [ka] Scheme 5: [ka]

[0397] Step 1 - Synthesis of compound 5: Compound 5 was synthesized from core A using general method A to give 5 (yield: 51.08%; MS(ES): m / z 384.81 [M+H] + ) was obtained.

[0398] Step 2 - Synthesis of compound 5.1: The compound was synthesized according to the experimental protocol of I-1 (Example 1) to obtain 5.1 (yield: 97.90%; MS (ES): m / z 223.14 [M+H] + ) was obtained.

[0399] Step 3 - Synthesis of compound 5.2: Compound 5.2 was synthesized using general procedure B to give compound 5.2 (0.130 g, yield: 62.56%; MS(ES): 570.28 [M+H] + ) was obtained.

[0400] Step 4—Synthesis of compound I-6: The compound was synthesized using general procedure C to obtain I-6 (0.034 g, yield: 83.19%; MS (ES): m / z 470.87 [M+H] + LCMS purity: 96.10%; HPLC purity: 94.95%;Chiral HPLC: 46.44%, 47.34%; 1 H NMR (DMSO-d 6 , 400MHZ): 8.88(s,1H), 8.23 ​​(s, 1H), 8.11-8.10 (d, J=8Hz, 1H), 7.93-7.92 (d, J=4.8Hz,1H),7.81-7.79 (d, J=4.4Hz, 1H), 7.42-7.40 (d, J=6.8Hz, 1H), 6.29-6.25 (t, J=7.2Hz,1H), 6.20 (s, 1H), 4.80 (bs, 2H), 4.68 (bs,1H), 2.98 (bs, 1H), 2.90-2.89 (d,J=4.8Hz, 3H), 1.76 (bs, 2H), 1.65 (bs, 1H), 1.47 (bs, 3H), 1.24 (bs, 5H), 0.85-0.84 (d, J=6.4Hz, 2H)). Example 6 5-((1-((1r,3R)-3-Fluorocyclobutyl)-2-oxo-1,2-dihydropyridin-3-yl)amino)-N-((1R,2S)-2-fluorocyclopropyl)-7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (I-7). [ka] Scheme 6: [ka]

[0401] Step 1 - Synthesis of compound 6.2: To a cooled solution of 6 (1.0 g, 6.48 mmol, 1.0 equiv.) in N,N-dimethylformamide (12 mL) was added 6.1 (0.803 g, 6.48 mmol, 1.0 equiv.). The reaction mixture was stirred at 0° C. for 30 min and further stirred at room temperature for 15 min. N-Ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.30 g, 8.42 mmol, 1.3 equiv.) and 4-dimethylaminopyridine (0.158 g, 1.29 mmol, 0.2 equiv.) were added. The reaction mixture was stirred at room temperature for 24 h. After the reaction was completed, 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 over sodium sulfate, and concentrated under reduced pressure to give the crude material. This was further purified by column chromatography, and the compound was eluted with 1.7% methanol in dichloromethane to give 6.2 (0.7 g, yield: 47.90%; MS(ES): m / z 226.08 [M+H] + ) was obtained.

[0402] Step 2 - Synthesis of compound 6.3: To a solution of 6.2 (0.7 g, 3.11 mmol, 1.0 equiv) in tetrahydrofuran:water (10 mL, 2:1), lithium hydroxide (0.746 g, 31.1 mmol, 10 equiv) was added. The reaction was stirred at 60 °C for 16 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to give a residue. To this was added water and acidified with 1N hydrochloric acid at 10 °C to adjust the pH to about 6-6.5. The product was extracted with dichloromethane. The organic layers were combined, washed with brine solution, dried over sodium sulfate, and concentrated under reduced pressure to give the crude material. This was further purified by column chromatography and the compound was eluted with 2.1% methanol in dichloromethane to give pure 6.3 (0.610 g, yield: 92.93%; MS (ES): m / z 212.07 [M+H] + ) was obtained.

[0403] Step 3 - Synthesis of compound 6.4: To a solution of 6.3 (0.610 g, 2.89 mmol, 1.0 equiv) in tert-butanol (8 mL) under nitrogen was added triethylamine (0.496 g, 4.91 mmol, 1.7 equiv) and diphenylphosphoryl azide (1.0 g, 3.75 mmol, 1.3 equiv) followed by heating at 80 °C for 16 h. After the reaction was completed, the reaction mixture was cooled to room temperature, transferred into water and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material. This was further purified by column chromatography and the compound was eluted with 22% ethyl acetate in hexane to give pure 6.4 (0.480 g, yield: 58.86%; MS (ES): m / z 283.14 [M+H] + ) was obtained.

[0404] Step 4 - Synthesis of compound 6.5: To a cooled solution of 6.4 (0.480 g, 1.70 mmol, 1 equiv) in dioxane (6 mL), 4N hydrochloric acid in dioxane (8 mL) was added dropwise. The reaction mixture was stirred at room temperature for 2 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to give pure 6.5 (0.310 g, yield: 98.46%: MS (ES): m / z 183.09 [M+H] + ) was obtained.

[0405] Step 5 - Synthesis of compound 6.6: Compound 6.6 was synthesized from core A using general method A (yield: 51.08%; MS(ES): m / z 384.81 [M+H] + ) was obtained.

[0406] Step 6 - Synthesis of compound 6.7: Compound 6.7 was synthesized using general procedure B to give compound 6.7 (0.054 g, yield: 39.14%; MS (ES): m / z 530.23 [M+H] + ) was obtained.

[0407] Step 7—Synthesis of compound I-7: Compound I-7 was synthesized using general procedure C (0.038 g, yield: 86.78%; MS (ES): m / z 430.82 [M+H] +LCMS Purity: 100%; HPLC Purity: 98.21%; Chiral HPLC: 100%; 1 H NMR (DMSO-d 6 , 400MHZ):8.90 (s, 1H), 8.23 ​​(s,1H), 8.15-8.13 (d, J=6.8Hz, 1H), 7.93-7.92(d, J=4.8Hz, 1H), 7.80-7.79 (d,J=4Hz, 1H), 7.45-7.43(d, J=6.8Hz, 1H), 6.31-6.27 (t, J=7.2Hz, 1H), 6.23 (s, 1H), 5.44-5.38 (m, 2H),4.97(bs, 1H), 4.80 (bs, 1H), 2.98 (bs, 1H), 2.90-2.89 (d, J=4.8Hz,3H),2.72-2.67 (m, 3H), 1.27-1.16 (m, 1H), 0.83 (bs, 1H)). Example 7 N-((1R,2S)-2-Fluorocyclopropyl)-5-((1-((1r,3R)-3-methoxycyclobutyl)-2-oxo-1,2-dihydropyridin-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (I-8). [ka] Scheme 7: [ka]

[0408] Step 1 - Synthesis of compound 7: Compound 7 was synthesized from core A using general method A to give 8 (yield: 51.08%; MS(ES): m / z 384.81 [M+H] + ) was obtained.

[0409] Step 2 - Synthesis of compound 7.1: The compound was synthesized according to the experimental protocol of I-4 (Example 3) to give 8.1 (yield: 89.32%; MS (ES): m / z 195.11 [M+H] + ) was obtained.

[0410] Step 3 - Synthesis of compound 7.2: Compound 7.2 was synthesized using general procedure B to give compound 7.2 (0.085 g, yield: 60.24%; MS (ES): m / z 542.25 [M+H] + ) was obtained.

[0411] Step 4—Synthesis of compound I-8: Compound I-8 was synthesized using general procedure C (0.060 g, yield: 86.60%; MS (ES): m / z 442.82 [M+H] + LCMS Purity: 100%; HPLC Purity: 99.41%; Chiral HPLC: 96.29%; 1 H NMR (DMSO-d 6 ,400MHZ): 8.89 (s, 1H), 8.24 (s,1H), 8.15-8.13 (d, J=6.4Hz, 1H),7.94-7.93 (d, J=4.4Hz, 1H), 7.81 (bs, 1H),7.50-7.49 (d, J=6Hz, 1H), 6.32-6.29 (t, J=7.2Hz, 1H), 6.24 (s, 1H),5.31-5.27(m, 1H), 4.97 (bs,1H), 4.06 (bs, 1H), 3.23 (s, 3H), 2.99 (s,1H), 2.91-2.90 (d, J=4.8Hz, 3H), 2.51(bs, 4H), 1.12-1.09 (t, J=7.2Hz,1H), 0.86 (bs, 1H)). Example 8 N-((1R,2S)-2-Fluorocyclopropyl)-5-((1-((1s,3S)-3-methoxycyclobutyl)-2-oxo-1,2-dihydropyridin-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (I-9). [ka] Scheme 8: [ka]

[0412] Step 1 - Synthesis of compound 8: Compound 8 was synthesized from core A using general method A to give 8 (yield: 51.08%; MS(ES): m / z 384.81 [M+H] + ) was obtained.

[0413] Step 2 - Synthesis of compound 8.1: The compound was synthesized according to the experimental protocol of I-5 (Example 4) to obtain 8.1 (yield: 89.32%; MS (ES): m / z 195.11 [M+H] + ) was obtained.

[0414] Step 3 - Synthesis of compound 8.2: Compound 8.2 was synthesized using general procedure B to give compound 8.2 (0.054 g, yield: 31.89%; MS(ES): 542.25 [M+H] + ) was obtained.

[0415] Step 4—Synthesis of compound I-9: Compound I-9 was synthesized using general procedure C to give I-9 (0.036 g, yield: 81.79%; MS (ES): m / z 442.37 [M+H] + LCMS Purity: 100%; HPLC Purity: 100%; Chiral HPLC: 95.00%; 1 H NMR (DMSO-d 6 , 400MHZ): 8.89 (s, 1H),8.24 (s, 1H),8.14-8.13 (d, J=6.4Hz, 1H), 7.93 (bs, 1H), 7.81(bs, 1H), 7.49-7.45 (d, J=6Hz,1H), 6.35-6.30 (t, J=6.4Hz, 1H), 6.23 (s, 1H), 4.71 (bs, 1H), 3.80 (bs,1H),3.20 (s, 3H), 3.00 (bs, 1H), 2.90-2.89 (d, J=4.8Hz, 3H), 2.68 (bs,3H),2.13-2.11 (d, J=7.6Hz, 3H), 1.24 (bs, 1H)) was obtained. Example 9 5-((3'-Fluoro-2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)-N-((1S,2R)-2-fluorocyclopropyl)-7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (I-10). [ka] Scheme 9: [ka]

[0416] Step 1 - Synthesis of compound 9.2: To a solution of 9 (10 g, 57.47 mmol, 1.0 equiv.) in 1-methylpyrrolidin-2-one (240 mL), 9.1 (7.34 g, 63.79 mmol, 1.1 equiv.) was added, followed by cesium carbonate (46.81 g, 143.67 mmol, 2.5 equiv.). The reaction mixture was heated at 110° C. for 15 h. After the reaction was completed, the reaction mixture was cooled to room temperature, transferred into cold water, and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine solution, dried over sodium sulfate, and concentrated under reduced pressure to give the crude material. This was further purified by column chromatography using 50% ethyl acetate in hexane as eluent to give 19.2 (2.6 g, yield: 16.81%; MS (ES): m / z 269.04 [M] + ) was obtained.

[0417] Step 2 - Synthesis of compound 9.3: To a solution of 9.2 (2.6 g, 9.66 mmol, 1.0 equiv) in ethanol (26 mL) was added copper powder (0.073 g, 1.15 mmol, 0.12 equiv), L-ascorbic acid (0.34 g, 1.93 mmol, 0.2 equiv), DL-pipecolic acid (0.37 g, 2.89 mmol, 0.3 equiv) and sodium azide (2.26 g, 34.77 mmol, 3.6 equiv). The reaction mixture was heated at 100° C. for 16 h. After the reaction was complete, the reaction mixture was cooled to room temperature, transferred into cold water and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to give the crude material. This was further purified by column chromatography using 55-60% ethyl acetate in hexane as the eluent to give 9.3 (1.6 g, yield: 80.70%; MS(ES): m / z 206.29 [M+H] + ) was obtained.

[0418] Step 3 - Synthesis of compound 9.4: Compound 9.4 was synthesized using the procedure in the preparation of Core A to obtain 9.4 (MS(ES): m / z 355.11 [M+H] + ) was obtained.

[0419] Step 4 - Synthesis of compound 9.2: To a cooled solution of 9.4 (0.2 g, 0.56 mmol, 1.0 equiv.) and 9.3 (0.114 g, 0.67 mmol, 1.2 equiv.) in tetrahydrofuran (4 mL) at 0 °C, potassium tert-butoxide (1 M in tetrahydrofuran; 1.12 mL, 1.12 mmol, 2.0 equiv.) was added. The reaction was stirred at room temperature for 2 h. After the reaction was completed, the reaction mixture was transferred into water and the product was extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure to give the crude material. This was further purified by column chromatography and the compound was eluted with 25% ethyl acetate in hexane to give pure 9.5 (0.120 g, yield: 42.11%; MS (ES): m / z 524.20 [M+H] + ) was obtained.

[0420] Step 6 - Synthesis of compound 9.6: To a solution of 9.5 (0.120 g, 0.22 mmol, 1.0 equiv) in methanol:tetrahydrofuran:water (4 mL, 2:1:1), lithium hydroxide (0.055 g, 2.3 mmol, 10 equiv) was added. The reaction was stirred at 60° C. for 16 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain a residue. To this was added water, followed by hydrochloric acid to adjust the pH to about 1-2, stirred at 10° C. for 1 h, and neutralized with saturated sodium bicarbonate. The product was extracted with dichloromethane. The organic layers were combined, washed with brine solution, dried over sodium sulfate, and concentrated under reduced pressure to obtain the crude material. This was further purified by column chromatography, and the compound was eluted with 2.1% methanol in dichloromethane to give pure 9.6 (0.065 g, yield: 72.56%; MS(ES): m / z 396.12 [M+H] + ) was obtained.

[0421] Step 7—Synthesis of compound I-10: Compound I-10 was synthesized using general procedure A to give I-10 (0.032 g, 27.96%; MS (ES): m / z 453.37 [M+H] + LCMS purity: 95.20%; HPLC purity: 95.01%; Chiral HPLC: 96.00%; 1 H NMR (DMSO-d 6 , 400MHZ): 9.02 (s,1H),8.53-8.52 (d, J=4.8Hz, 1H), 8.30-8.28(d, J=8Hz, 1H), 8.27 (s, 1H),8.10-8.05(d, J=9.2Hz 1H), 7.99-7.98(d, J=4.8Hz, 1H), 7.84-7.83(d, J=4.4Hz, 1H),7.76-7.72(m, 1H), 7.45-7.43 (d, J=6.8Hz, 1H),6.45-6.41 (t, J=6.8Hz, 1H), 6.26(s, 1H),4.83-4.81 (m, 1H), 3.18-3.17 (d, J=5.2Hz, 1H), 3.03-3.01 (m, 1H), 2.91-2.90 (d, J=4.8Hz, 3H), 1.30-1.21 (m, 1H) were obtained. Example 10 5-((1-((1r,3S)-3-Fluorocyclobutyl)-2-oxo-1,2-dihydropyridin-3-yl)amino)-N-(2-hydroxycyclobutyl)-7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (I-11). [ka] Scheme 10: [ka]

[0422] Step 1 - Synthesis of compound 10: Compound 10 was synthesized from core A using general method A (yield: 50.51%; MS(ES): m / z 396.84 [M+H] + ) was obtained.

[0423] Step 2 - Synthesis of compound 10.1: The compound was synthesized according to the experimental protocol of I-7 (Example 6) to obtain 10.1 (yield: 98.46%; MS (ES): m / z 183.09 [M+H] + ) was obtained.

[0424] Step 2 - Synthesis of compound 10.2: Compound 10.2 was synthesized using general procedure B to give compound 10.2 (0.145 g, yield: 70.65%; MS (ES): m / z 542.25 [M+H] + ) was obtained.

[0425] Step 3 - Synthesis of compound I-11: The compound was synthesized using general procedure C to give I-11 (0.028 g, yield: 85.87%; MS (ES): m / z 442.27 [M+H] + LCMS purity: 97.66%; HPLC purity: 97.71%;Chiral HPLC: 48.80%, 49.46%; 1 H NMR (DMSO-d 6, 400MHZ): 8.86(s, 1H),8.54-8.52 (d, J=7.2Hz, 1H), 8.19 (s, 1H), 8.05-8.02 (d, J=8.8Hz,1H),7.89-7.87 (d, J=4.8Hz, 1H), 7.44-7.42 (d, J=6Hz, 1H),6.43-6.40 (t, J=7.2Hz,1H), 6.27 (s, 1H),5.44-5.37 (m, 2H), 4.58-4.55(m, 2H), 4.35 (bs, 1H), 2.90-2.89 (d, J=4.8Hz, 3H),2.83-2.79 (m, 1H),2.73-2.68 (m, 3H), 2.19 (bs, 1H), 2.07-2.02 (m, 1H), 1.99-1.95 (m, 1H), 1.65 (bs, 1H)). Example 11 5-((1-((1S,2S)-2-fluorocyclopropyl)-2-oxo-1,2-dihydropyridin-3-yl)amino)-N-((1S,2R)-2-hydroxycyclobutyl)-7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (I-12) and 5-((1-((1S,2S)-2-fluorocyclopropyl)-2-oxo-1,2-dihydropyridin-3-yl)amino)-N-((1R,2S)-2-hydroxycyclobutyl)-7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (I-13) [ka] Scheme 11: [ka]

[0426] Step 1 - Synthesis of compound 11.2: To a cooled solution of 11 (0.5 g, 3.24 mmol, 1.0 equiv) in acetonitrile (10 mL) was added 11.1 (0.395 g, 3.56 mmol, 1.1 equiv). The reaction mixture was stirred at 0° C. for 30 min and further stirred at room temperature for 15 min. N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.652 g, 4.21 mmol, 1.3 equiv) and molecular sieves were added. The reaction mixture was stirred at room temperature for 24 h. After the reaction was completed, 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 over sodium sulfate, and concentrated under reduced pressure to give the crude material. This was further purified by column chromatography, and the compound was eluted with 1.7% methanol in dichloromethane to give 11.2 (0.320 g, yield: 46.71%; MS(ES): m / z 212.07 [M+H] + ) was obtained.

[0427] Step 2 - Synthesis of compound 11.3: To a solution of 11.2 (0.320 g, 1.51 mmol, 1.0 equiv) in tetrahydrofuran:water (8 mL, 2:1), lithium hydroxide (0.362 g, 15.1 mmol, 10 equiv) was added. The reaction was stirred at 60 °C for 16 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to give a residue. To this was added water and acidified with 1N hydrochloric acid at 10 °C to adjust the pH to about 6-6.5. The product was extracted with dichloromethane. The organic layers were combined, washed with brine solution, dried over sodium sulfate, and concentrated under reduced pressure to give the crude material. This was further purified by column chromatography and the compound was eluted with 2.1% methanol in dichloromethane to give pure 11.3 (0.265 g, yield: 88.70%; MS (ES): m / z 198.05 [M+H] + ) was obtained.

[0428] Step 3 - Synthesis of compound 11.4: To a solution of 11.3 (0.265 g, 1.34 mmol, 1.0 equiv) in tert-butanol (6 mL) under nitrogen was added triethylamine (0.230 g, 2.27 mmol, 1.7 equiv) and diphenylphosphoryl azide (0.478 g, 1.74 mmol, 1.3 equiv) followed by heating at 80 °C for 16 h. After the reaction was completed, the reaction mixture was cooled to room temperature, transferred into water and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material. This was further purified by column chromatography and the compound was eluted with 22% ethyl acetate in hexane to give pure 11.4 (0.160 g, yield: 44.37%; MS (ES): m / z 269.13 [M+H] + ) was obtained.

[0429] Step 4 - Synthesis of compound 11.5: To a cooled solution of 11.4 (0.160 g, 0.59 mmol, 1 equiv) in dioxane (4 mL), 4N hydrochloric acid in dioxane (10 mL) was added dropwise. The reaction mixture was stirred at room temperature for 2 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to give pure 11.5 (0.125 g, yield: 98.33%; MS (ES): m / z 205.05 [M+HCl]). + ) was obtained.

[0430] Step 5 - Synthesis of compound 11.6: Compound 11.6 was synthesized from core A using general method A to give compound 11.6 (yield: 50.51%; MS(ES): m / z 396.84 [M+H] + ) was obtained.

[0431] Step 6 - Synthesis of compound 11.7: The compound was synthesized by general method B to give 11.7 (0.135 g, yield: 67.53%; MS (ES): m / z 527.5 [M+H] + ) was obtained.

[0432] Step 7 - Synthesis of compounds 11.7a and 11.7b: The isomers of 11.7 (0.1 g) were separated using a column CHIRALPAK OX-H (250 mm x 4.6 mm, 5 μm) and 0.1% DEA_HEX_IPA-ACN (70-30) as co-solvent at a flow rate of 4 mL / min to give pure fraction-1 (FR-a) and fraction-2 (FR-b). FR-a was concentrated under reduced pressure at 30 °C to give pure 11.7a (0.040 g; MS (ES): m / z 527.5 [M+H] + ) was obtained. FR-b was concentrated under reduced pressure at 30 °C to give pure 11.7b (0.045 g; MS (ES): m / z 527.5 [M+H] + ) was obtained.

[0433] Step 8—Synthesis of compound I-12: The compound was synthesized using general procedure C to give I-12 (0.027 g, yield: 83.31%; MS (ES): m / z 428.18 [M+H] + LCMS Purity: 100%; HPLC Purity: 100%; Chiral HPLC Purity: 96.10%; 1 H NMR (DMSO-d 6 , 400MHZ): 8.87 (s, 1H), 8.51-8.50(d,J=6Hz, 1H), 8.19 (s, 1H), 8.03-8.01 (d, J=9.2Hz, 1H),7.89-7.88 (d, J=4.8Hz,1H), 7.14-7.12 (d, J=5.6Hz, 1H), 6.35-6.31(t, J=7.2Hz, 1H), 6.27 (bs, 1H),5.40-5.39 (d, J=4Hz, 1H),4.57-4.54 (m, 1H), 4.34 (bs, 1H), 3.89-3.81 (m, 1H), 2.91-2.89 (d,J=4.8Hz,3H), 2.50 (s, 3H), 1.23 (bs, 4H)) were obtained.

[0434] Step 9 - Synthesis of compound I-13: The compound was synthesized using general procedure C to give I-13 (0.032 g, 87.77%; MS (ES): m / z 428.18 [M+H] +LCMS Purity: 100%; HPLC Purity: 98.81%; Chiral HPLC Purity: 99.25%; 1 H NMR (DMSO-d 6 , 400MHZ): 8.88 (s, 1H), 8.51-8.50(d, J=6Hz,1H), 8.19 (s, 1H), 8.03-8.01 (d, J=9.2Hz, 1H),7.89-7.88 (d, J=4.8Hz, 1H),7.13-7.11 (d, J=5.6Hz, 1H), 6.35-6.31(t, J=7.2Hz, 1H), 6.27 (bs, 1H), 5.40-5.39(d, J=4Hz, 1H),4.57-4.54 (m, 1H), 4.34 (bs, 1H), 3.89-3.81 (m, 1H), 2.91-2.89(d, J=4.8Hz, 3H), 2.50 (s, 3H), 1.24 (bs, 4H) were obtained. Example 12 N-((1R,2S)-2-Hydroxycyclobutyl)-7-(methylamino)-5-(1-((S)-tetrahydro-2H-pyran-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (I-14) and N-((1S,2R)-2-Hydroxycyclobutyl)-7-(methylamino)-5-(1-((S)-tetrahydro-2H-pyran-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (I-15). [ka] Scheme 12: [ka]

[0435] Step 1 - Synthesis of compound 12: The compound was synthesized using the procedure in the preparation of core B to give 12.

[0436] Step 2 - Synthesis of compound 12.2: A stirred solution of 12 (3.5 g, 10.15 mmol, 1.0 equiv), 12.1 (4.5 g, 13.19 mmol, 1.3 equiv) and sodium carbonate (2.6 g, 25.37 mmol, 2.5 equiv) in 1,4 dioxane:water (140 mL, 9:1) was purged with argon for 15 min, to which [1,1'-bis(diphenylphospino)ferrocene]palladium(II) dichloride (0.738 mg, 1.01 mmol, 0.1 equiv) was added and purged for an additional 10 min. The reaction was stirred at 110 °C for 6 h. After completion of the reaction, the reaction mixture was poured onto water and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to give 12.2 (3.1 g, yield: 57.99%; MS(ES): m / z 527.24 [M+H] + ) was obtained.

[0437] Step 3 - Synthesis of compound 12.3: 12.2 (3.1 g, 5.88 mmol, 1.0 equiv) was added with 4 M hydrochloric acid in 1,4 dioxane (60 mL) and stirred at room temperature for 4 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure and the residue was stirred with saturated sodium bicarbonate solution and extracted with dichloromethane. The organic layers were combined, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to give a residue which was triturated with diethyl ether to give 12.3 (2.1 g, yield: 83.64%; MS (ES): m / z 427.18 [M+H] + ) was obtained.

[0438] Step 4 - Synthesis of compound 12.5: To a solution of 12.3 (2.0 g, 4.68 mmol, 1 eq.) and 12.4 (0.915 g, 5.61 mmol, 1.2 eq.) in 1,4-dioxane (60 mL), potassium carbonate (1.29 g, 9.36 mmol, 2.0 eq.) was added and degassed with argon for 15 min. Copper iodide (0.178 g, 0.93 mmol, 0.2 eq.) and 1,2-dimethylethylenediamine (0.165 g, 1.87 mmol, 0.4 eq.) were added and the reaction mixture was degassed again with argon for 5 min, followed by heating at 80 °C for 16 h. After the reaction was complete, the reaction mixture was cooled to room temperature, transferred into water, and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine solution, dried over sodium sulfate, and concentrated under reduced pressure to give the crude material. This was further purified by column chromatography, and the compound was eluted with 1.2% methanol in dichloromethane to give pure 12.5 (1.0 g, yield: 41.93%; MS(ES): m / z 509.23 [M+H] + ) was obtained.

[0439] Step 5 - Synthesis of compound 12.6: To a solution of 12.5 (1.0 g, 1.96 mmol, 1.0 equiv) in methanol (12 mL) was added palladium on charcoal (0.4 g). Hydrogen was purged through the reaction mixture at room temperature for 4 h. After the reaction was complete, the reaction mixture was filtered through a celite bed and washed with methanol. The filtrate was concentrated under reduced pressure to give the crude material, which was further purified by trituration with pantane to give pure 12.6. 12.6 (0.610 g, yield: 73.78%; MS (ES): m / z 421.19 [M+H] + ) was obtained.

[0440] Step 6 - Synthesis of compounds 12.6a and 12.6b: The isomers of 12.6 (0.610 g) were separated using a column CHIRALPAK OX-H (250 mm x 4.6 mm, 5 μm) and 0.1% DEA_HEX_IPA-CAN (70-30) as co-solvent at a flow rate of 4 mL / min to give pure fraction-1 (FR-a) and fraction-2 (FR-b). FR-a was concentrated under reduced pressure at 30 °C to give pure 12.6a (0.190 g; MS (ES): m / z 421.19 [M+H] + ) was obtained. FR-b was concentrated under reduced pressure at 30 °C to give pure 12.6b (0.180 g; MS (ES): m / z 421.19 [M+H] + ) was obtained.

[0441] Step 7 - Synthesis of compound 12.7: To a solution of 12.6a (0.4 g, 0.956 mmol, 1.0 equiv) in methanol:water (8 mL, 2:1), lithium hydroxide (0.219 g, 9.56 mmol, 10 equiv) was added. The reaction was stirred at 60 °C for 16 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to give a residue. To this was added water and acidified with 1N hydrochloric acid at 10 °C to adjust the pH to about 6-6.5. The product was extracted with dichloromethane. The organic layers were combined, washed with brine solution, dried over sodium sulfate, and concentrated under reduced pressure to give the crude material. This was further purified by column chromatography and the compound was eluted with 2.1% methanol in dichloromethane to give pure 12.7 (0.350 g, yield: 93.76%; MS (ES): m / z 393.16 [M+H] + ) was obtained.

[0442] Step 8 - Synthesis of compound 12.9: Compound 12.9 was synthesized using general procedure A to give compound 12.9 (0.125 g, yield: 70.86%; MS (ES): m / z 462.61 [M+H] + LCMS purity: 97.36%; HPLC purity: 97.32%;Chiral HPLC: 48.06%, 48.35%; 1 H NMR (DMSO-d 6, 400MHZ):9.04-9.02(d, J=8.4Hz, 1H), 8.82-8.81 (d, J=3.6Hz, 1H), 8.68-8.64 (t,J=7.6Hz,1H), 8.41-8.40 (d, J=4Hz, 1H), 8.37 (s, 1H), 7.27-7.26 (d, J=4.4Hz,1H),7.34-7.31 (m, 1H), 6.75 (s, 1H), 5.78 (s, 1H), 5.53 (bs, 1H), 4.97 (bs,1H),4.60 (bs, 1H), 4.44 (bs, 1H), 4.04 (bs, 1H), 3.98 (bs, 1H), 3.75-3.72 (m,1H), 3.52 (s, 1H), 3.15-3.14 (d, J=4.4Hz, 3H), 2.22 (bs, 3H), 1.86 (bs,3H),1.28-1.25 (m, 1H)).

[0443] Step 9: Synthesis of compounds I-14 and I-15: The isomers of 12.9 (0.105 g) were separated using a column CHIRAL PAK OX-H (250 mm × 4.6 mm, 5 μm) 0.1% DEA_HEX_IPA-ACN (70-30) to obtain pure fraction-1 (FR-a) and fraction-2 (FR-b).

[0444] FR-a was concentrated under reduced pressure at 30 °C to give pure I-14 (0.035 g; MS (ES): m / z 462.57 [M+H] + LCMS Purity: 100%; HPLC Purity: 97.32%; Chiral HPLC Purity: 100%; 1 H NMR (DMSO-d 6 , 400MHZ): 9.03-9.01 (d, J=8Hz,1H), 8.81(s, 1H), 8.67-8.65 (d, J=8Hz, 1H), 8.40-8.39 (d, J=4.4Hz,1H), 8.37 (s, 1H),8.27-8.26 (d, J=4.4Hz, 1H), 7.33-7.30 (m, 1H), 6.74(s,1H), 5.54-5.53 (d, J=3.2Hz, 1H), 4.97 (bs, 1H), 4.60 (bs, 1H),4.44 (bs, 1H),4.05-4.03 (d, J=8.8Hz, 1H), 3.98-3.95 (d, J=12Hz, 1H), 3.74-3.69 (t, J=10.4Hz, 1H),3.53-3.51 (t, J=7.6Hz,1H), 3.14-3.13 (d, J=4Hz, 3H), 2.34 (bs, 3H), 2.06-2.02 (m, 2H), 1.86 (bs, 3H)).

[0445] FR-b was concentrated under reduced pressure at 30 °C to give pure I-15 (0.035 g; MS (ES): m / z 462.66 [M+H] + LCMS Purity: 100%; HPLC Purity: 99.87%; Chiral HPLC Purity: 93.05%; 1 H NMR (DMSO-d 6 , 400MHZ): 9.04-9.03 (d, J=8Hz,1H), 8.80(s, 1H), 8.65-8.63 (d, J=8Hz, 1H), 8.40-8.39 (d, J=4.4Hz,1H), 8.37 (s, 1H),8.27-8.26 (d, J=4.4Hz, 1H), 7.33-7.30 (m, 1H),6.74(s, 1H), 5.53-5.52 (d, J=3.2Hz, 1H), 4.97 (bs, 1H), 4.60 (bs, 1H),4.44 (bs,1H), 4.05-4.03 (d, J=8.8Hz, 1H), 3.98-3.95 (d, J=12Hz, 1H), 3.74-3.69 (t, J=10.4Hz,1H), 3.53-3.51 (t, J=7.6Hz,1H), 3.14-3.13 (d, J=4Hz, 3H), 2.34 (bs, 3H), 2.06-2.02(m, 2H), 1.86 (bs, 3H)). Example 13 5-((1-((1r,3S)-3-fluorocyclobutyl)-2-oxo-1,2-dihydropyridin-3-yl)amino)-N-((1S,2R)-2-hydroxycyclobutyl)-7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (I-16) and 5-((1-((1r,3R)-3-Fluorocyclobutyl)-2-oxo-1,2-dihydropyridin-3-yl)amino)-N-((1R,2S)-2-hydroxycyclobutyl)-7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (I-17). [ka] Scheme 13: [ka]

[0446] Step 1 - Synthesis of compound 13: The compound was synthesized according to the experimental protocol of I-11 (Example 10) to obtain 13 (yield: 70.65%; MS(ES): 542.25 [M+H] + ) was obtained.

[0447] Step 2 - Synthesis of compounds 13a and 13b: The isomers of 13 (0.105 g) were separated using a column CHIRALPAK OX-H (250 mm × 4.6 mm, 5 μm) and 0.1% DEA_HEX_IPA-ACN (70-30) as co-solvent at a flow rate of 4 mL / min to give pure fraction-1 (FR-a) and fraction-2 (FR-b). FR-a was concentrated under reduced pressure at 30 °C to give pure 13a (0.042 g; MS (ES): m / z 542.25 [M+H] + ) was obtained. FR-b was concentrated under reduced pressure at 30 °C to give pure 13b (0.042 g; MS (ES): m / z 542.25 [M+H] + ) was obtained.

[0448] Step 3 - Synthesis of compound I-16: The compound was synthesized using general procedure C to give I-16 (0.030 g, 87.63%; MS (ES): m / z 442.52 [M+H] + LCMS Purity: 100%; HPLC Purity: 97.05%; Chiral HPLC Purity: 97.29%; 1 H NMR (DMSO-d 6 , 400MHZ): 8.87 (s, 1H), 8.55-8.53(d,J=7.2Hz, 1H), 8.21 (s, 1H), 8.06-8.04 (d, J=8.8Hz, 1H),7.90-7.88 (d, J=4.8Hz,1H), 7.45-7.43 (d, J=6.8Hz, 1H), 6.43-6.41(t, J=7.2Hz, 1H), 6.28 (s, 1H),5.45-5.37 (m, 2H), 5.31 (bs, 1H),4.59-4.58 (m, 1H), 4.36 (bs, 1H), 2.92-2.91(d, J=4.8 Hz, 3H), 2.74-2.69 (m, 3H), 2.34 (bs, 1H), 2.21 (bs, 1H), 2.01-1.96 (m, 2H), 1.74 (bs,1H)).

[0449] Step 4—Synthesis of compound I-17: The compound was synthesized using general procedure C to give I-17 (0.030 g, yield: 87.63%; MS (ES): m / z 442.56 [M+H] + LCMS Purity: 98.00%; HPLC Purity: 98.07%; Chiral HPLC Purity: 98.29%; 1 H NMR (DMSO-d 6 , 400MHZ): 8.87 (s, 1H),8.55-8.53(d, J=7.2Hz, 1H), 8.21 (s, 1H), 8.06-8.04 (d, J=8.8Hz, 1H),7.90-7.88 (d, J=4.8Hz,1H), 7.45-7.43 (d, J=6.8Hz, 1H), 6.44-6.41(t, J=7.2Hz, 1H), 6.28 (s, 1H),5.45-5.39 (m, 2H), 5.29 (bs, 1H),4.60-4.56 (m, 1H), 4.36 (bs, 1H), 2.92-2.91(d, J=4.8Hz, 3H), 2.74-2.69(m, 3H), 2.34 (bs, 1H), 2.21 (bs, 1H), 2.01-1.96 (m, 2H), 1.74(bs, 1H)). Example 14 5-(5-Fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-((1S,2S)-2-hydroxycyclobutyl)-7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (I-18) and 5-(5-Fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-((1R,2R)-2-hydroxycyclobutyl)-7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (I-19). [ka] Scheme 14: [ka]

[0450] Step 1 - Synthesis of compound 14: The compound was synthesized using the general procedure for Core B synthesis to give 14 (yield: 45%; MS(ES): m / z 345.10 [M+H] + ) was obtained.

[0451] Step 2 - Synthesis of compound 14.2: A stirred solution of 14 (3.5 g, 1.16 mmol, 1.0 equiv), 14.1 (0.696 g, 1.74 mmol, 1.5 equiv) and potassium carbonate (0.4 g, 2.9 mmol, 2.5 equiv) in 1,4-dioxane (8 mL) was purged with argon for 15 min. Copper(I) iodide (0.043 g, 0.23 mmol, 0.2 equiv) and bis(triphenylphosphine)palladium(II) dichloride (0.077 mg, 0.11 mmol, 0.1 equiv) were added to this and purged further for 10 min. The reaction was stirred at 110° C. for 6 h. After completion of the reaction, the reaction mixture was poured onto water and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to give 14.2 (0.4 g, yield: 63.31%; MS(ES): m / z 545.23 [M+H] + ) was obtained.

[0452] Step 3 - Synthesis of compound 14.3: Compound 14.3 was synthesized using general procedure C to give 14.3 (0.310 g, yield: 94.96%; MS(ES): 445.17 [M+H] + ) was obtained.

[0453] Step 4 - Synthesis of compound 14.5: To a cooled solution of 14.3 (0.350 g, 0.78 mmol, 1.0 equiv) and 14.4 (0.153 g, 0.93 mmol, 1.2 equiv) in acetonitrile (10 mL) at 0 °C, cesium carbonate (0.635 g, 1.95 mmol, 2.5 equiv) was added. The reaction was stirred at 70 °C for 2 h. After the reaction was completed, the reaction mixture was transferred into water and the product was extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure to give the crude material. This was further purified by column chromatography and the compound was eluted with 20% ethyl acetate in hexane to give pure 14.5 (0.3 g, yield: 72.07%; MS (ES): m / z 529.23 [M+H] + ) was obtained.

[0454] Step 5 - Synthesis of compound 14.6: To a solution of 14.5 (0.3 g, 0.56 mmol, 1.0 equiv) in methanol:tetrahydrofuran (8 mL, 2:1), lithium hydroxide (0.134 g, 5.6 mmol, 10 equiv) was added. The reaction was stirred at 60 °C for 24 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to give a residue. To this was added water and acidified with 1N hydrochloric acid at 10 °C to adjust the pH to about 6-6.5. The product was extracted with dichloromethane. The organic layers were combined, washed with brine solution, dried over sodium sulfate, and concentrated under reduced pressure to give the crude material. This was further purified by column chromatography and the compound was eluted with 2.1% methanol in dichloromethane to give pure 14.6 (0.250 g, yield: 88.00%; MS (ES): m / z 501.20 [M+H] + ) was obtained.

[0455] Step 6 - Synthesis of compound 14.8: Compound 14.8 was synthesized using general procedure A to give compound 14.8 (0.150 g, yield: 52.72%; MS(ES): 570.26 [M+H] + ) was obtained.

[0456] Step 5 - Synthesis of compounds 14.8a and 14.8b: The isomers of 14.8 (0.120 g) were separated using a column CHIRALPAK AD-H (250 mm x 4.6 mm, 5 μm) and 0.1% DEA in methanol as co-solvent at a flow rate of 4 mL / min to give pure fraction-1 (FR-a) and fraction-2 (FR-b). FR-a was concentrated under reduced pressure at 30 °C to give pure 14.8a (0.032 g; MS (ES): m / z 570.26 [M+H] + ) was obtained. FR-b was concentrated under reduced pressure at 30 °C to give pure 14.8b (0.033 g; MS (ES): m / z 570.26 [M+H] + ) was obtained.

[0457] Step 6 - Synthesis of compound I-18: A solution of 14.8a (0.032 g, 0.056 mmol, 1.0 equiv) in dichloromethane (1 mL) was cooled to 0 °C, and triflic acid (0.5 mL) was added. The reaction mixture was stirred at the same temperature for 10 min. After the reaction was completed, the reaction mixture was transferred into 1N sodium hydroxide solution, and the product was extracted with dichloromethane. The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to give the crude material. This was further purified by trituration with diethyl ether to give I-18 (0.021 g, yield: 77.96%; MS (ES): m / z 480.51 [M+H]). + LCMS purity: 99.20%; HPLC purity: 97.20%; Chiral HPLC: 99.08%; 1 H NMR (DMSO-d 6 , 400MHZ): 8.97 (s,1H),8.51 (s, 1H), 8.42 (s, 1H), 8.37-8.36 (d, J=6.8Hz, 1H), 8.33 (s,1H), 8.27 (bs,1H), 6.82 (s, 1H), 5.44 (bs, 1H), 5.05-5.02 (m, 1H), 4.38-4.34(t, J=8.4Hz, 1H),4.08-4.06 (m, 4H), 3.64-3.58 (t, J=11.6Hz,3H), 3.11-3.10 (d, J=3.6Hz, 4H),2.11-2.07 (m, 3H), 1.53-1.49 (m, 1H), 1.43-1.38 (m, 1H)).

[0458] Step 7 - Synthesis of compound I-19: A solution of 14.8b (0.033 g, 0.056 mmol, 1.0 equiv) in dichloromethane (1 mL) was cooled to 0 °C, and triflic acid (0.5 mL) was added. The reaction mixture was stirred at the same temperature for 10 min. After the reaction was completed, the reaction mixture was transferred into 1N sodium hydroxide solution, and the product was extracted with dichloromethane. The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to give the crude material. This was further purified by trituration with diethyl ether to give I-19 (0.021 g, yield: 75.60%; MS (ES): m / z 480.51 [M+H]).+ LCMS purity: 93.46%; HPLC purity: 96.00%; Chiral HPLC: 95.92%; 1 H NMR (DMSO-d 6 , 400MHZ): 8.99 (s,1H),8.53-8.51 (d, J=8.8Hz, 1H), 8.44 (s, 1H), 8.39-8. 1 H 37 (d,J=6.8Hz,1H), 8.35 (s, 1H), 8.29 (bs, 1H), 6.83 (s, 1H), 5.45 (bs, 1H), 5.06(bs,1H), 4.39-4.35 (t, J=8.4Hz, 1H), 4.09-4.07 (m, 4H), 3.65-3.59 (t,J=11.6Hz,3H), 3.12-3.11 (d, J=3.6Hz, 4H), 2.18(bs, 3H), 2.10 (bs, 1H), 1.52-1.42 (m,1H)). Example 15 N-((1S,2S)-2-Hydroxycyclobutyl)-5-((1-((1R,2R)-2-Methoxycyclobutyl)-2-oxo-1,2-dihydropyridin-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (I-20) and N-((1R,2R)-2-hydroxycyclobutyl)-5-((1-((1R,2R)-2-methoxycyclobutyl)-2-oxo-1,2-dihydropyridin-3-yl)amino)-7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (I-21) [ka] Scheme 15: [ka]

[0001] Step 1 - Synthesis of compound 15.2: To a cooled solution of 15 (0.5 g, 3.24 mmol, 1.0 equiv) in N,N-dimethylformamide (8 mL) was added 15.1 (0.327 g, 3.24 mmol, 1.0 equiv). The reaction mixture was stirred at 0° C. for 30 min and further stirred at room temperature for 15 min. N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.653 g, 4.21 mmol, 1.3 equiv) and 4-dimethylaminopyridine (0.078 g, 0.64 mmol, 0.2 equiv) were added. The reaction mixture was stirred at room temperature for 24 h. After the reaction was completed, 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 over sodium sulfate, and concentrated under reduced pressure to give the crude material. This was further purified by column chromatography and the compound was eluted with 1.7% methanol in dichloromethane to give 15.2 (0.390 g, yield: 50.67%; MS(ES): m / z 238.10 [M+H] + ) was obtained.

[0459] Step 2 - Synthesis of compound 15.3: To a solution of 15.2 (0.390 g, 1.64 mmol, 1.0 equiv) in tetrahydrofuran:water (5 mL, 2:1), lithium hydroxide (0.393 g, 16.4 mmol, 10 equiv) was added. The reaction was stirred at 60 °C for 16 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to give a residue. To this was added water and acidified with 1N hydrochloric acid at 10 °C to adjust the pH to about 6-6.5. The product was extracted with dichloromethane. The organic layers were combined, washed with brine solution, dried over sodium sulfate, and concentrated under reduced pressure to give the crude material. This was further purified by column chromatography and the compound was eluted with 2.1% methanol in dichloromethane to give pure 15.3. (0.3 g, yield: 81.76%; MS (ES): m / z 224.09 [M+H] + ).

[0460] Step 3 - Synthesis of compound 15.4: To a solution of 15.3 (0.3 g, 1.34 mmol, 1.0 equiv) in tert-butanol (5 mL) under nitrogen was added triethylamine (0.229 g, 2.27 mmol, 1.7 equiv) and diphenylphosphoryl azide (0.478 g, 1.74 mmol, 1.3 equiv) followed by heating at 80 °C for 16 h. After the reaction was completed, the reaction mixture was cooled to room temperature, transferred into water and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material. This was further purified by column chromatography and the compound was eluted with 22% ethyl acetate in hexane to give pure 15.4 (0.275 g, yield: 69.52%; MS (ES): m / z 295.16 [M+H] + ) was obtained.

[0461] Step 4 - Synthesis of compound 15.5: To a cooled solution of 15.4 (0.275 g, 0.93 mmol, 1 equiv) in dioxane (4 mL) was added 4N hydrochloric acid in dioxane (10 mL) dropwise. The reaction mixture was stirred at room temperature for 2 h. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to give pure 15.5 (0.2 g, 92.80%; MS (ES): m / z 231.09 [M+HCl]). + ) was obtained.

[0462] Step 5 - Synthesis of compound 15.6: The compound was synthesized from core A utilizing 15.5 in a similar manner as I-11 (example 10).

[0463] Step 6 - Synthesis of compounds I-20 and I-21: The isomers of 15.6 (0.1 g) were separated using a column CHIRAL PAK IC-H (250 mm × 4.6 mm, 5 μm) 0.1% DEA_HEX_IPA-ACN (70-30) to obtain pure fraction-1 (FR-a) and fraction-2 (FR-b).

[0464] FR-a was concentrated under reduced pressure at 30 °C to give pure I-20 (0.026 g; MS (ES): m / z 454.2 [M+H] +; LCMS purity: 100%; HPLC purity: 99.00%; chiral HPLC purity: 99.00%; 1 H NMR (DMSO-d 6 , 400 MHz): 8.96 (s, 1H), 8.26 - 8.24 (d, J = 7.2 Hz, 1H), 8.20 (s, 1H), 8.03 - 8.01 (d, J = 8.8 Hz, 1H), 7.94 - 7.93 (d, J = 4.4 Hz, 1H), 7.60 - 7.58 (d, J = 6.8 Hz, 1H), 6.40 - 6.37 (t, J = 6.8 Hz, 1H), 6.24 (s, 1H), 5.46 - 5.44 (m, 1H), 5.21 - 5.14 (m, 1H), 4.25 - 4.18 (m, 2H), 3.86 (bs, 1H), 3.17 (s, 3H), 2.92 - 2.90 (d, J = 4.8 Hz, 3H), 1.69 - 1.62 (m, 2H), 1.24 (bs, 6H)) was obtained.

[0465] FR-b was concentrated under reduced pressure at 30 °C to obtain pure I-21 (0.030 g; MS (ES): m / z 454.2 [M+H] + ; LCMS purity: 100%; HPLC purity: 99.00%; chiral HPLC purity: 99.00%; 1 H NMR (DMSO-d 6 , 400 MHz): 8.97 (s, 1H), 8.26 - 8.24 (d, J = 7.2 Hz,...

Claims

[Claim 1] The invention described in this specification.

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