TYK2 INHIBITING COMPOUNDS AND IN VITRO METHOD FOR TYK2 INHIBITION IN A BIOLOGICAL SAMPLE

Abstract

The present application provides compounds, their compositions, and methods of use thereof for the inhibition of TYK2 and the treatment of TYK2-mediated disorders. Claim 1: A compound of formula (1), or one of its pharmaceutically acceptable salts, wherein: X is N or C(R³); R¹ is R, RD, or -OR; R² is H, RC, -N(R)C(O)Cy², -N(R)Cy², -N(R)S(O)₂Cy², -OCy², -SCy², or Cy²; R³ is H, a halogen, or a C₁₋₆ aliphatic; or R² and R³ are taken together with their intervening atoms to form a partially unsaturated or aromatic 4-7-membered ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted with m instances of R⁴; each of Cy¹ and Cy² is independently phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 3-7 membered saturated or partially unsaturated carbocyclic ring; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy¹ is substituted with n instances of R⁵; and wherein Cy² is substituted with p instances of R⁶;L¹ is a covalent bond or a saturated or unsaturated, linear or branched bivalent C₁₋₄ hydrocarbon chain, wherein one or two methylene units of the chain are optionally and independently replaced by -C(R⁷)₂-, -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)₂-, -S(O)₂N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)₂-; each instance of R⁴, R⁵, R⁶ and R⁷ is independently RA or RB and is substituted with q instances of RC; each instance of RA is independently oxo, halogen, -CN, -NO₂, -OR, -ORD, -SR, -NR₂, -S(O)₂R, -S(O)₂NR₂, -S(O)R, -S(O)NR₂, -C(O)R, -C(O)OR, -C(O)NR₂, -C(O)N(R)OR, -OC(O)R, -OC(O)NR₂, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR₂ or -N(R)S(O)₂R; each instance of RB is independently aliphatic C₁₋₆; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Each instance of RC is, independently, oxo, halogen, -CN, -NO₂, -OR, -SR, -NR₂, -S(O)₂R, -S(O)₂NR₂, -S(O)R, -S(O)NR₂, -C(O)R, -C(O)OR, -C(O)NR₂, -C(O)N(R)OR, -OC(O)R, -OC(O)NR₂, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR₂ or -N(R)S(O)₂R or an optionally substituted group selected from C₁₋₆ aliphatic, phenyl, a saturated or partially unsaturated 3-7 membered 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; RD is a C₁₋₄ aliphatic group wherein one or more hydrogens are replaced by deuterium;each R is, independently, hydrogen or an optionally substituted group selected from C₁₋₆ aliphatic, phenyl, a saturated or partially unsaturated 3-7 membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or: two R groups on the same nitrogen are taken together with their intervening atoms to form a saturated or partially unsaturated 4-7 membered heteroaryl ring having 0-3 heteroatoms, in addition to nitrogen, independently selected from nitrogen, oxygen and sulfur; and each of m, n, pyq is, independently, 0, 1, 2, 3 or 4. Claim 11: A compound of formula (2), or one of its pharmaceutically acceptable salts, wherein: X is N or C(R³); Y is N or C(R¹); R¹ is H, D or halogen; R, RD or -OR;R² is H, RC, -N(R)C(O)Cy², -N(R)S(O)₂Cy², -N(R)Cy², -OCy², -SCy² or Cy²; R³ is H, halogen or C₁₋₆ aliphatic; or R² and R³ are taken together with their intervening atoms to form a partially unsaturated or aromatic 4-7 membered ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein said ring is substituted with m instances of R⁴; each of Cy¹ and Cy² is independently phenyl; a monocyclic 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;or a saturated or partially unsaturated carbocyclic ring of 3-7 members; or a saturated or partially unsaturated bicyclic heterocyclic ring of 7-12 members having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein Cy¹ is substituted with n instances of R⁵; and wherein Cy² is substituted with p instances of R⁶; Cy³ is a partially unsaturated monocyclic or heteroaromatic ring of 5-6 members having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein Cy³ is substituted with r instances of R⁸; L¹ is a covalent bond or a saturated or unsaturated, linear or branched bivalent C₁₋₄ hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -C(R⁷)₂-, -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)₂-, -S(O)₂N(R)-, -O-, C(O)-, -OC(O)-, -C(O)O-, -OC(O)N(R)-, -N(R)C(O)O-, -S-, -S(O)-oS(O)₂-;each instance of R⁴, R⁵, R⁶, R⁷ and R⁸ is, independently, RA or RB and is replaced by q instances of RC; each instance of RA is independently oxo, halogen, -CN, -NO₂, -OR, -ORD, -SR, -NR₂, -S(O)₂R, -S(O)₂NR₂, -S(O)R, -S(O)NR₂, -C(O)R, -C(O)OR, -C(O)NR₂, -C(O)N(R)OR, -OC(O)R, -OC(O)NR₂, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR₂, -N(R)C(NR)NR₂, -N(R)S(O)₂NR₂ or -N(R)S(O)₂R; each instance of RB is independently aliphatic C₁₋₆; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated carbocyclic ring;a saturated or partially unsaturated monocyclic heterocyclic ring of 3-7 members having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a saturated or partially unsaturated bicyclic heterocyclic ring of 7-12 members having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;each instance of RC is independently oxo, halogen, -CN, -NO₂, -OR, -SR, -NR₂, -S(O)₂R, -S(O)₂NR₂, -S(O)R, -S(O)NR₂, -C(O)R, -C(O)OR, -C(O)NR₂, -C(O)N(R)OR, -OC(O)R, -OC(O)NR₂, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR₂, -N(R)C(NR)NR₂, -N(R)S(O)₂NR₂ or -N(R)S(O)₂R or an optionally substituted group selected from aliphatic C₁₋₆, phenyl, a saturated heterocyclic ring or partially unsaturated 3-7 membered 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; RD is a C₁₋₄ aliphatic group in which one or more hydrogens are replaced by deuterium;each R is, independently, hydrogen or an optionally substituted group selected from C₁₋₆ aliphatic, phenyl, a saturated or partially unsaturated 3-7 membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or: two R groups on the same nitrogen are taken together with their intervening atoms to form a saturated or partially unsaturated 4-7 membered heteroaryl ring having 0-3 heteroatoms, in addition to nitrogen, independently selected from nitrogen, oxygen and sulfur; and each of m, n, p, qyr is, independently, 0, 1, 2, 3 or 4. Claim 23: A compound of formula (3), or one of its pharmaceutically acceptable salts, wherein: X is N or C(RX); one of Y¹, Y², Z¹ and Z² is N and the other three are C;R¹ is D, R, RD, -NR₂, -NRRD, -N(RD)₂, -N(R)C(O)NR₂, -N(R)C(NR)NR₂, -N(R)C(O)NRRD, -N(R)C(NR)NRRD, -OR or -ORD; R² is H, RC, -N(R)C(O)Cy², -N(R)S(O)₂Cy², -N(R)Cy², -OCy², -SCy² or Cy²; R³ is H, halogen or C₁₋₆ aliphatic; or R² and R³ are taken together with their intervening atoms to form a partially unsaturated or aromatic 4-7 membered ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein said ring is substituted with m instances of R⁴; each of Cy¹ and Cy² is independently phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;a saturated or partially unsaturated heterocyclic ring of 3-7 members having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a saturated or partially unsaturated carbocyclic ring of 3-7 members; or a saturated or partially unsaturated bicyclic heterocyclic ring of 7-12 members having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy¹ is substituted with n instances of R⁵; and wherein Cy² is substituted with p instances of R⁶; L¹ is a covalent bond or a saturated or unsaturated, linear or branched bivalent C₁₋₄ hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -C(R⁷)₂-, -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)₂-, -S(O)₂N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)₂-;each instance of R⁴, R⁵, R⁶ and R⁷ is, independently, RA or RB and is replaced by q instances of RC; each instance of RA is independently oxo, halogen, -CN, -NO₂, -OR, -ORD, -SR, -NR₂, -S(O)₂R, -S(O)₂NR₂, -S(O)R, -S(O)NR₂, -C(O)R, -C(O)OR, -C(O)NR₂, -C(O)N(R)OR, -OC(O)R, -OC(O)NR₂, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR₂, -N(R)C(NR)NR₂, -N(R)S(O)₂NR₂ or -N(R)S(O)₂R; each instance of RB is independently aliphatic C₁₋₆; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated carbocyclic ring;a saturated or partially unsaturated monocyclic heterocyclic ring of 3-7 members having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a saturated or partially unsaturated bicyclic heterocyclic ring of 7-12 members having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;each instance of RC is independently oxo, halogen, -CN, -NO₂, -OR, -SR, -NR₂, -S(O)₂R, -S(O)₂NR₂, -S(O)R, -S(O)NR₂, -C(O)R, -C(O)OR, -C(O)NR₂, -C(O)N(R)OR, -OC(O)R, -OC(O)NR₂, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR₂, -N(R)C(NR)NR₂, -N(R)S(O)₂NR₂ or -N(R)S(O)₂R or an optionally substituted group selected from aliphatic C₁₋₆, phenyl, a saturated heterocyclic ring or partially unsaturated 3-7 member having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur and a 5-6 member heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; RD is a C₁₋₄ aliphatic group in which one or more hydrogens are replaced by deuterium; RX is H, halogen or C₁₋₆ aliphatic;each R is, independently, hydrogen or an optionally substituted group selected from C₁₋₆ aliphatic, phenyl, a saturated or partially unsaturated 3-7 membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or: two R groups on the same nitrogen are taken together with their intervening atoms to form a saturated or partially unsaturated 4-7 membered heteroaryl ring having 0-3 heteroatoms, in addition to nitrogen, independently selected from nitrogen, oxygen and sulfur; and each of m, n, pyq is independently 0, 1, 2, 3 or 4. Claim 33: A compound of formula (4), or one of its pharmaceutically acceptable salts, wherein: Q is CH or N; X is N or C(RX); one of Y¹, Y², Z¹ and Z² is N and the other three are C;R¹ is D, R, RD, -NR₂, -NRRD, -N(RD)₂, -N(R)C(O)NR₂, -N(R)C(NR)NR₂, -N(R)C(O)NRRD, -N(R)C(NR)NRRD, -OR or -ORD; R² is H, RC, -N(R)C(O)Cy², -N(R)S(O)₂Cy², -N(R)Cy², -OCy², -SCy² or Cy²; R³ is H, halogen or C₁₋₆ aliphatic; or R² and R³ are taken together with their intervening atoms to form a partially unsaturated or aromatic 4-7 membered ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein said ring is substituted with m instances of R⁴; each of Cy¹ and Cy² is independently phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;a saturated or partially unsaturated heterocyclic ring of 3-7 members having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a saturated or partially unsaturated carbocyclic ring of 3-7 members; or a saturated or partially unsaturated bicyclic heterocyclic ring of 7-12 members having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy¹ is substituted with n instances of R⁵; and wherein Cy² is substituted with p instances of R⁶; L¹ is a covalent bond or a saturated or unsaturated, linear or branched bivalent C₁₋₄ hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -C(R⁷)₂-, -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)₂-, -S(O)₂N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)₂-;each instance of R⁴, R⁵, R⁶ and R⁷ is, independently, RA or RB and is replaced by q instances of RC; each instance of RA is independently oxo, halogen, -CN, -NO₂, -OR, -ORD, -SR, -NR₂, -S(O)₂R, -S(O)₂NR₂, -S(O)R, -S(O)NR₂, -C(O)R, -C(O)OR, -C(O)NR₂, -C(O)N(R)OR, -OC(O)R, -OC(O)NR₂, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR₂, -N(R)C(NR)NR₂, -N(R)S(O)₂NR₂ or -N(R)S(O)₂R; each instance of RB is independently aliphatic C₁₋₆; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated carbocyclic ring;a saturated or partially unsaturated monocyclic heterocyclic ring of 3-7 members having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a saturated or partially unsaturated bicyclic heterocyclic ring of 7-12 members having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;each instance of RC is independently oxo, halogen, -CN, -NO₂, -OR, -SR, -NR₂, -S(O)₂R, -S(O)₂NR₂, -S(O)R, -S(O)NR₂, -C(O)R, -C(O)OR, -C(O)NR₂, -C(O)N(R)OR, -OC(O)R, -OC(O)NR₂, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR₂, -N(R)C(NR)NR₂, -N(R)S(O)₂NR₂ or -N(R)S(O)₂R or an optionally substituted group selected from aliphatic C₁₋₆, phenyl, a saturated heterocyclic ring or partially unsaturated 3-7 member having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur and a 5-6 member heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; RD is a C₁₋₄ aliphatic group in which one or more hydrogens are replaced by deuterium; RX is H, halogen or C₁₋₆ aliphatic;each R is independently hydrogen or an optionally substituted group selected from C₁₋₆ aliphatic, phenyl, a saturated or partially unsaturated 3-7 membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or: two R groups on the same nitrogen are taken together with their intervening atoms to form a saturated or partially unsaturated 4-7 membered heteroaryl ring having 0-3 heteroatoms, in addition to nitrogen, independently selected from nitrogen, oxygen and sulfur; and each of m, n, pyq is independently 0, 1, 2, 3 or 4.

Description

TYK2 INHIBITORS AND THEIR USES TECHNICAL FIELD OF THE INVENTION The present invention relates to compounds and methods useful for inhibiting non-receptor tyrosine-protein kinase 2 ("TYK2"), also known as tyrosine kinase 2. The invention also provides pharmaceutically acceptable compositions comprising compounds of the present invention and methods of use of said compositions for the treatment of various disorders. 232.231 M.A. BACKGROUND OF THE INVENTION The search for new therapeutic agents has been strongly encouraged in recent years due to a better understanding of the structure of enzymes and other biomolecules linked to diseases. An important class of enzymes that have been the subject of extensive studies are the protein kinase family. Protein kinases constitute a large family of structurally related enzymes that are responsible for the control of a variety of signal transduction processes within the cell. Protein kinases are believed to have evolved from a common ancestral gene due to conservation of their structure and catalytic function. Almost all kinases contain a catalytic domain of 250-300 similar amino acids. Kinases can be categorized into families based on the substrates they phosphorylate (e.g., protein-tyrosine, protein-serine / threonine, lipids, etc.). In general, protein kinases mediate intracellular signaling by effecting a transfer of phosphophosphonyl from a nucleoside triphosphate to an acceptor protein that is 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 signals of environmental stress and chemical stress (e.g., osmotic shock, thermal shock, ultraviolet radiation, bacterial endotoxins, and H2O2), cytokines (e.g., interleukin-1 (IL—1), interleukin-8 ( IL-8) and tumor necrosis factor α (TNF-α)) and growth factors (for example, granulocyte macrophage colony-stimulating factor (GM-CSF) and fibroblast growth factor (FGF)). An extracellular stimulus can affect one or several cellular responses related to cell growth, migration, differentiation, hormone secretion, activation of transcription factors, muscle contraction, glucose metabolism, control of synthesis. of proteins and the regulation of the cell cycle. Many diseases are linked to abnormal cellular responses triggered by kinase-mediated events. These diseases include, but are not limited to, autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer's disease, and hormone-related diseases. Therefore, there remains a need to find protein kinase inhibitors useful as therapeutic agents. Summary of the invention The compounds of this invention and pharmaceutically acceptable compositions thereof have been determined to be effective as inhibitors of TYK2 kinase. The compounds of the present invention and pharmaceutically acceptable compositions thereof are useful for treating a variety of diseases, disorders or conditions, linked to the regulation of signaling pathways involving TYK2 kinases. Such diseases, disorders or conditions include those described herein. The compounds provided by this invention are also useful for the study of TYK2 enzymes in biological and pathological phenomena; the study of intracellular signal transduction pathways that occur in body tissues; and the comparative evaluation of new inhibitors of TYK2 or other regulators of kinases, signaling pathways and cytokine levels in vitro or in vivo. DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS 1. General description of certain embodiments of the invention: The compounds of the present invention and their compositions are useful as inhibitors of TYK2 protein kinase. The pseudokinase binding pocket of TYK2 contains a plurality of hydration sites, each of which is occupied by a single water molecule. Each of these water molecules has a stability score associated with it. As used herein, the term “stability score” refers to a numerical calculation that incorporates the enthalpy, entropy, and free energy values ​​associated with each water molecule. This stability score allows measurable determination of the relative stability of water molecules occupying hydration sites in the TYK2 binding pocket. Water molecules occupying hydration sites in the binding pocket of TYK2 that have a stability score of >2.5 kcal / mol are referred to as “unstable waters.” Without wishing to be bound by any particular theory, it is believed that the displacement or disruption of an unstable water molecule (i.e., a water molecule that has a stability score of >2.5 kcal / mol) or replacement of water unstable (i.e., a water molecule that has a stability score of <1 kcal / mol), by an inhibitor results in tighter binding of that inhibitor. Consequently, inhibitors designed to displace one or more unstable water molecules (i.e., those unstable water molecules not displaced by any known inhibitor) will be a tighter linker and, consequently, a more potent inhibitor compared to an inhibitor. which does not displace unstable water molecules. Surprisingly, the provided compounds were found to displace or disrupt one or more unstable water molecules. In some embodiments, a provided compound displaces or disrupts at least two unstable water molecules. In certain embodiments, the present invention provides a compound of formula I: or one of its pharmaceutically acceptable salts, wherein each of X, L1, R1, R2 and Cy1 is as defined below and described in embodiments herein, both alone and in combination. In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable carrier, adjuvant or diluent. In some embodiments, the present invention provides a method of treating a TYK2-mediated disease, disorder or condition comprising administering to a patient in need thereof a compound of formula I or a pharmaceutically acceptable salt thereof. In certain embodiments, the present invention provides a compound of formula VIII: Cy VIII or a pharmaceutically acceptable salt thereof, wherein each of In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula VIII and a pharmaceutically acceptable carrier, adjuvant or diluent. In some embodiments, the present invention provides a method of treating a TYK2-mediated disease, disorder or condition comprising administering to a patient in need thereof, a compound of formula VIII or a pharmaceutically acceptable salt thereof. In certain embodiments, the present invention provides a compound of formula XVI': XVI' or a pharmaceutically acceptable salt thereof, wherein each of Q, both alone and in combination. In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula XVI' and a pharmaceutically acceptable carrier, adjuvant or diluent. In some embodiments, the present invention provides a method of treating a TYK2-mediated disease, disorder or condition comprising administering to a patient in need thereof a compound of formula XVI' or a pharmaceutically acceptable salt thereof. 2. Compounds and definitions: The compounds of this invention include those described above generally and are further illustrated by classes, subclasses and species disclosed herein. As used herein, the following definitions govern unless otherwise indicated. For the purposes of this invention, chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd. Additionally, general principles of organic chemistry are described in Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry”, 5thEd., ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the contents of which are fully incorporated herein by reference. The term "aliphatic" or "aliphatic group", as used herein, means a linear (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation or a monocyclic hydrocarbon or a bicyclic hydrocarbon that is completely saturated or that contains one or more unsaturation units but which is not aromatic (also referred to herein as "carbocycle", "cycloaliphatic" or "cycloalkyl"), which has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, the aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, the aliphatic groups contain 1-4 aliphatic carbon atoms. In still further embodiments, the aliphatic groups contain 1-3 aliphatic carbon atoms, and in still further embodiments, the aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, "cycloaliphatic" (or "carbocycle" or "cycloalkyl") refers to a C3-C6 monocyclic hydrocarbon that is fully saturated or that contains one or more unsaturation units but that is not aromatic, that has a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl and their hybrids, such as, for example, (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl groups. As used herein, the term "bridged bicyclic" refers to any bicyclic, i.e., carbocyclic or heterocyclic, saturated or partially unsaturated ring system, having at least one bridge. According to the IUPAC definition, a “bridge” is an unbranched chain of atoms or an atom or a valence bond that connects two heads of bridge, where a “bridgehead” is any skeletal atom of the ring system that is bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Such bridging bicyclic groups are widely known in the art and include those groups set forth below where each group is connected to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, a bicyclic bridging group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Example bridge bicyclics include: +=7..+=7 The term "lower alkyl" refers to a straight or branched chain Ci_4 alkyl group. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl. The term "lower haloalkyl" refers to a straight or branched chain Ci_4 alkyl group substituted with one or more halogen atoms. The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus or silicon (including any oxidized form of nitrogen, sulfur, phosphorus or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro—2 / 7pyrrolyl), NH (as in pyrrolidinyl) or NR+ (as in N-substituted pyrrolidinyl)). The term unsaturated, as used herein, means that a fraction has one or more unsaturation units. As used herein, the term “bivalent hydrocarbon chain Ci_e (or Ci_e) saturated or unsaturated, linear or branched,” refers to bivalent alkylene, alkenylene and alkynylene chains that are linear or branched as defined herein. document. The term "alkylene" refers to a divalent alkyl group. An “alkylene chain” is a polymethylene group, i.e. -(CH2)n-, where n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2 or from 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced by a substituent. Suitable substituents include those described below regarding a substituted aliphatic group. The term "alkenylene" refers to a divalent alkenyl group. A substituted alkenylene chain is a group containing at least one double bond in which one or more hydrogen atoms are replaced by a substituent. Suitable substituents include those described below in relation to a substituted aliphatic group. The term "halogen" means F, Cl, Br or I. The term “aryl,” used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic or bicyclic ring systems having a total of five to fourteen ring members. wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. The term “aryl” may be used interchangeably with the term “aryl ring.” In certain embodiments of the present invention, "aryl" refers to an aromatic ring system that includes, but is not limited to, phenyl, biphenyl, naphthyl, anthracite and the like, which may be one or more substituents. Also included within the scope of the term "aryl", as used herein, is a group in which an aromatic ring is fused with one or more non-aromatic rings, such as, for example, indanyl, phthalimidyl, naphthymidyl, phenanthridinyl or tetrahydronaphthyl and the like. The terms "heteroaryl" and "heteroar-", used alone or as part of a larger moiety, for example, "heteroaralkyl" or "heteroaralkoxy" refer to groups having 5 to 10 ring atoms, preferably 5, 6 or 9 atom rings; that have 6, 10 or 14 shared π electrons in a cyclic arrangement; and which have, in addition to carbon atoms, from one to five heteroatoms. 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, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolicinyl, purinyl, naphthyridinyl and pteridinyl. The terms "heteroaryl" and "heteroar-", as used herein, also include groups in which a heteroaromatic ring is fused with one or more aryl, cycloaliphatic or heterocyclyl rings, where, unless specified specify otherwise, the radical or attachment point is on the heteroaromatic ring or on one of the rings with which the heteroaromatic ring is fused. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolicinyl, carbazolyl, acridinyl, phenacinyl, phenothiazinyl, phenoxacinyl , tetrahydroquinolinyl and tetrahydroisoquinolinyl . A heteroaryl group may be mono- or bicyclic. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring", "heteroaryl group" or "heteroaromatic", any of which include optionally substituted rings. The term "heteroaralkyl" refers to an alkyl group substituted with a heteroaryl, wherein the alkyl and heteroaryl moieties, independently, are optionally substituted. 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-membered heterocyclic bicyclic moiety. 10-membered which is either saturated or partially unsaturated and which has, in addition to the carbon atoms, one or more preferably one to four-heteroatoms, as defined above. When used in reference to the ring atom of a heterocycle, the term nitrogen includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen can be N (as in 3,4-dihydro—2Hpyrrolyl), NH (as in pyrrolidinyl) or + NR (as in N-substituted pyrrolidinyl). A heterocyclic ring can be attached to its pendant group on any heteroatom or carbon atom leading to a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, 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 cycloaliphatic rings, such as, for example, indolinyl, 3H-indolyl, chromanyl, phenanthridinyl or tetrahydroquinolinyl. A heterocyclyl group may be mono- or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted with a heterocyclyl, wherein the alkyl and heterocyclyl moieties, independently, are optionally substituted. As used herein, the term “partially unsaturated” refers to a ring moiety that includes at least one double or triple bond. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation but is not intended to include aryl or heteroaryl residues, as defined herein. As described herein, compounds of the invention may contain "optionally substituted" moieties. In general, the term "substituted", whether or not preceded by the term 'Optionally', means that one or more hydrogens of the designated moiety are replaced by a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position in the group and, if there is more than one position in any given structure that can be substituted by more than one substituent selected from a group specified, the substituent can be either the same or different at each position. The Combinations of substituents conceived by this invention are preferably those that are obtained from the formation of stable or chemically viable compounds. The term "stable", as used herein, refers to compounds that are not substantially altered when subjected to states to permit their production, detection and, in certain embodiments, their recovery, purification and use for one or more purposes disclosed herein. Suitable monovalent substituents on a substitutable carbon atom of an 'Optionally Substituted' group are, independently, halogen; -(CH2)0^R°; -(CH2)0^OR°; -O(CH2)0^R°, -O-(CH2)0^C(O)OR°; (CH2)o-4CH(OR°)2; -(CH2)o-4SR°; -(CH2)0^Ph, which can be replaced with R°; -(CH2)o-40(CH2)o-iPh which can be replaced with R°; -CH=CHPh, which can be replaced with R°; -(CH2)o^O(CH2)0_i-pyríd¡lo which can be replaced with R°; -NO2; -CN; -N3; -(CH2)0^N(R°)2; -(CH2)0^N(Ro)C(O)R°; N(R°)C(S)R°; -(CH2)o^N(R°)C(0)NR°2; -N(R°)C(S)NR°2; -(CH2)o_4N(Ro)C(O)OR°; -N(R°)N(R°)C(O)R°; -N(Ro)N(R°)C(O)NR°2; N(R°)N(R°)C(O)OR°; -(CH2)0^C(O)R°; -C(S)R°; -(CH2)0-4C(O)ORo; -(CH2)o_ 4C(O)SR°; -(CH2)0_4C(O)OS¡Ro3; -(CH2)0^OC(O)Ro; -OC(O)(CH2)0^SRo; SC(S)SR°; -(CH2)o^SC(0)R°; -(CH2)q^C(O)NR°2; -C(S)NR°2; -C(S)SR°; SC(S)SR°, -(CH2)0^OC(O)NRo2; -C(O)N(OR°)R°; -C(O)C(O)R°; C(O)CH2C(O)Ro; -C(NOR°)R°; -(CH^SSR0; -(CH2)0^S(O)2Ro; -(CH2)o_4S(0)20Ro; -(CH2)o^OS(0)2R°; -S(0)2NRo2; -( CH2)0^S(O)R°; -N(R°)S(O)2NR°2; -N(Ro)S(0)2R°; -N(OR°)R°; -C(NH )NRo2; -P(O)2R°; -P(O)R°2; -OP(O)R°2; OP(O)(OR°)2; YesR°3; -(linear or branched alkylene) O-N(R°)2; or -(linear or branched C^alkylene)C(O)O-N(R°)2, wherein each R° may be substituted as defined below and is, independently, hydrogen, C1-6 aliphatic, -CH2Ph, -0(CH2)o_iPh, -CH2-(5-6 membered heteroaryl ring) or a saturated, partially unsaturated 5-6 membered aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur or, regardless of the above definition, two independent occurrences of R°, taken together with their The atom(s) involved form a saturated, partially unsaturated, 3-12 5-membered ring or a mono- or bicyclic aryl having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, which may be substituted as defined below. Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with its intervening atoms), are, independently, halogen, -(CH2)o_2Re, -(haloR*), (CH2 )o-2OH, -(CH2)o_2OR·, -(CH2)o_2CH(OR*)2; -O(haloR'), -CN, -N3, -(CH2)0_ 2C(O)R', -(CH2)o_2C(0)OH, -(CH2)0-2C(O)OR·, -( CH2)o-2SR·, -(CH2)o_2SH, (CH2)o_2NH2, -(CH2)o 2NHR·, -(CH2)o-2NR*2, -NO2, -YesR*3, -OSíR*3, - C(O)SR· (linear or branched Ci^ alkylene)C(O)OReo -SSR* wherein each R* is unsubstituted or where preceded by “halo” is substituted only by one or more halogens, and is independently selected from an aliphatic Ci^t, -CH2Ph, -0(CH2)o_iPh or a saturated, partially unsaturated 5-6 membered ring or an aryl having 0-4 heteroatoms independently selected , nitrogen, oxygen or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =0 and =S. Suitable divalent substituents on a saturated carbon atom of an 'Optionally Substituted' group include the following: =0, =S, =NNR*2, =NNHC(O)R, =NNHC(O)OR*, =NNHS( O)2R*, =NR*, =NOR*, -O(C(R*2))2_3O- or S(C(R*2))2_3S-, where each independent occurrence of R* is selected from 25 hydrogen, aliphatic Ci_6 which may be substituted as defined below or a saturated, partially unsaturated 5-6 membered unsubstituted aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Suitable divalent substituents that attach to neighboring substitutable carbons of an “optionally substituted” group include: O(CR*2)2-3O-, where each independent occurrence of R* is selected from hydrogen, aliphatic which can be substituted as defined below 5 or a saturated, partially unsaturated 5-6 membered unsubstituted aryl ring having CM heteroatoms independently selected from nitrogen, oxygen or sulfur. Suitable substituents on the aliphatic group of R* include halogen, -R·, -(haloR·), -OH, -OR·, -O(haloR'), -CN, -C(O)OH, -C( O)OR·, -NH2, 10 NHR·, -NR*2 or -NO2, where each R· is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is, so independent, aliphatic Ci^, -CH2Ph, -0(CH2)o-iPh or a saturated, partially unsaturated 5-6 membered aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include -R1, -NR^, -C(O)Rt, -C(O)ORt, 0(0)0(0^, -0(0) ΟΗ20(0)Ρψ, -S(O)2Rf, -S(O)2NRt2, -CÍSJNR^, -C(NH)NRf2, or -N(Rt)S(O)2Rt; where each RTis, so independent, hydrogen, aliphatic Ci-« which may be substituted as defined below, unsubstituted -OPh or a saturated, partially unsaturated 5-6 membered unsubstituted aryl ring having 0-4 selected heteroatoms, independently , of nitrogen, oxygen or sulfur or, regardless of the above definition, two independent occurrences of Rf, taken together with their intervening atom(s) form a saturated, partially unsaturated 3-12 membered unsubstituted aryl ring mono- or bicyclic having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Suitable substituents on the aliphatic Rf group are, independently, halogen, R·, -(haloR*), -OH, -OR*, -O(haloR·), -CN, -C(O)OH, - C(O)OR*, -NH2, -NHR·, -NR*2, or -NO2ien where each R* is unsubstituted or where it is preceded by “halo” is substituted only with one or more halogens, and is, independently, aliphatic Ci^, -CH2Ph, -0(CH2)o_iPh or a saturated, partially unsaturated 5-6 membered aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. As used herein, the term "pharmaceutically acceptable salt" refers to those salts that are suitable, according to medical judgment, for use in contact with tissues of humans and lower animals without undue toxicity, irritation, response. allergic and similar, and are proportional to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are widely known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of an amino group formed with inorganic acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as, for example , acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or using other methods of the technology such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanpropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, iodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, 5 methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate , valerate salts and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(Ci^alkyl)4 salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium and the like. Additional pharmaceutically acceptable salts include, as appropriate, ammonium, quaternary ammonium and non-toxic amine cations formed with counterions such as, for example, halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate. Unless otherwise noted, the structures depicted herein are also intended to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Accordingly, simple stereochemical isomers, as well as enantiomeric, diastereomeric and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Additionally, unless otherwise indicated, the structures represented herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including the replacement of hydrogen with deuterium or tritium or the replacement of one carbon with a 13C- or 14C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools, as probes in biological tests or as therapeutic agents according to the present invention. In certain embodiments, a warhead moiety, R1, of a provided compound comprises one or more deuterium atoms. In certain embodiments, the B ring of a given compound may be substituted with one or more deuterium atoms. 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 IC50y / or binding constant of less than about 50 μΜ, less than about 1 μΜ, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM. A compound of the present invention can bind with a detectable moiety. It will be appreciated that such compounds are useful as imaging agents. One skilled in the art will recognize that a detectable moiety can be attached to a compound provided through an appropriate substituent. As used herein, the term “appropriate substituent” refers to a moiety that is capable of covalent bonding with a detectable moiety. These moieties are well known to one skilled in the art and include groups containing, for example, a carboxylate moiety, an amino moiety, a thiol moiety, or a hydroxyl moiety, to name a few. It will be appreciated that such moieties may be linked with a provided compound or via a linking group, such as a bivalent saturated or unsaturated hydrocarbon chain. In some forms of embodiment, these remains can be joined by means of click chemistry. In some embodiments, these moieties can be linked via a 1,3cycloaddition of an azide with an alkyne, optionally in the presence of a copper catalyst. Methods of using click chemistry are known in the art and include those described by Rostovtsev et al., Angew. Chem. Int. Ed. 2002, 41, 2596-99 and Sun et al., Bioconjugate Chem., 2006, 17, 52-57. As used herein, the term “detectable residue” is used interchangeably with the term label and refers to any residue capable of being detected, for example, primary labels and secondary labels. Primary tags, such as radioisotopes (e.g., tritium, 32P, 33P, 35S or 14C), mass tags, and fluorescent tags are signal-generating reporter groups that can be detected without further modifications. Detectable remains also include luminescent and phosphorescent groups. The term "secondary tag" as used herein refers to residues such as biotin and various protein antigens that require the presence of a second intermediate for the production of a detectable signal. For biotin, the secondary intermediate may include streptavidin-enzyme conjugates. For antigen tags, secondary intermediates 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 fluorescent resonance energy transfer (FRET) and the second group produces the detected signal. The terms "fluorescent label", "fluorescent dye" and "fluorophore" as used herein refer to moieties that absorb light energy at a defined excitation wavelength and emit light energy at a different wavelength. Examples of fluorescent labels include, but are not limited to: Alexa Fluor dyes (Alexa Fluor 350, Alexa Fluor 488, Alexa Fluor 532, Alexa Fluor 546, Alexa Fluor 568, Alexa Fluor 594, Alexa Fluor 633, Alexa Fluor 660 and Alexa Fluor 680), AMCA, AMCA-S, BODIPY tinctures (BODIPY FL, BODIPY R6G, BODIPY TMR, BODIPY TR, BODIPY 530 / 550, BODIPY 558 / 568, BODIPY 564 / 570, BODIPY 576 / 589, BODIPY 581 / 591, BODIPY 630 / 650, BODIPY 650 / 665), Carboxyrhodamine 6G, Carboxy-X-rhodamine (ROX), Cascade Blue, Cascade Yellow, Coumarin 343, Cyanine dyes (Cy3, Cy5, Cy3.5, Cy5.5), Dansyl, Dapoxyl, dialkylaminocoumarin, 4',5'-dichloro-2',7'-dimethoxyfluorescein, DM-NERF, eosin, erythrosine, fluorescein, FAM, hydroxycoumarin, IRDyes (IRD40, IRD 700, IRD 800), 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 , Texas Red-X. The term “mass tag” as used herein refers to any residue that is capable of being detected solely by virtue of its mass using mass spectrometry (MS) detection techniques. Examples of mass labels include electrophore release labels such as N-[3-[4'-[(p-Methoxytetrafluorobenzyl)oxy]phenyl]-3methylglyceronyljisonipecotic acid, 4'-[2,3,5,6-Tetrafluoro -4(pentafluorophenoxyl)]methylacetophenone and its derivatives. The synthesis and utility of these dough labels are described in US Patents 4,650,750, 4,709,016, 5,360,8191, 5,516,931, 5,602,273, 5,604,104, 5,610,020 and 5,650,270. . Other examples of mass tags include, but are not limited to, nucleotides, dideoxynucleotides, oligonucleotides of varying length and base composition, oligopeptides, oligosaccharides and other synthetic polymers of varying length and monomeric composition. A variety of length Organic molecules, both neutral and charged (biomolecules or synthetic compounds) of an appropriate mass range (100-2000 Daltons) can also be used as mass labels. The terms “measurable affinity” and “measurably inhibit,” as used herein, mean a measurable change in a TYK2 protein kinase activity between a sample comprising a compound of the present invention or its composition and a TYK2 protein kinase and an equivalent sample comprising a TYK2 protein kinase, in the absence of said compound or its composition. 3. Description of example embodiments: As described above, in certain embodiments, the present invention provides a compound of formula I: or one of its pharmaceutically acceptable salts, where: X is N or C(R3); R1is R, Rdu -OR; R2is H, Rc, -N(R)C(O)Cy2, -N(R)S(O)2Cy2, -N(R)Cy2, -OCy2, -SCy2o Cy2; R3is H, halogen or aliphatic Ci_6; either R2 and R3 are taken together with their intervening atoms to form a 4-7 membered partially unsaturated or aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein said ring is replaced with m instances of R4; each of Cy1 and Cy2 is, independently, phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 selected heteroatoms, of independent mode, of nitrogen, oxygen and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 3-7 membered saturated or partially unsaturated carbocyclic ring; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein Cy1 is substituted with n instances of R5; and where Cy2 is replaced with p instances of R6; L1 is a covalent bond or a bivalent linear or branched saturated or unsaturated hydrocarbon chain Ci^ wherein one or two methylene units of the chain are optionally and independently replaced by -C(R7)2-, 15 N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, - C(O)-, OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2-; each instance of R4, R5, R6 and R7 is, independently, RA or RBy is replaced with q instances of Rc; each instance of RAis, independently, oxo, halogen, -CN, -NO2, 20 OR, -ORd, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O) R, -S(O)NR2i-C(O)R, C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O )NR2, -N(R)C(O)OR, N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R )S(O)2NR2o -N(R)S(O)2R; each instance of RBes, independently, aliphatic C-i_6; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 3-7 membered saturated or partially unsaturated carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; each instance of Rces, independently, oxo, halogen, -CN, -NO2, OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S (O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2 , -N(R)C(O)OR, 10 N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R) S(O)2NR2o -N(R)S(O)2R or an optionally substituted group selected from aliphatic Ci_6, phenyl, a saturated or partially unsaturated 3-7 membered heterocyclic ring having 1-2 independently selected heteroatoms , of nitrogen, oxygen and sulfur and a 5-6 membered heteroaryl ring having 1^4 15 heteroatoms independently selected from nitrogen, oxygen and sulfur; RDes an aliphatic group Ci^ where one or more hydrogens are replaced by deuterium; each R is independently hydrogen or an optionally substituted group selected from aliphatic Ci_e, phenyl, a saturated or partially unsaturated 3-7 membered heterocyclic 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 are taken together with their intervening atoms to form a saturated or partially unsaturated 4-7 membered heteroaryl ring having 0-3 heteroatoms in addition to the nitrogen, independently selected from nitrogen, oxygen and sulfur; and each of m, η, p and q is, independently, 0, 1.2, 3 or 4. As generally defined above, X is N or C(R3). In some embodiments, X is N. In some embodiments, X is C(R3). In some embodiments, X is C(H). In some embodiments, X is C(R3), where R3 is halogen. In some embodiments, X is C(R3), where R3 is fluoro. As generally defined above, R1 is R, RDu -OR. In some embodiments, R1 is R. In some embodiments, R1 is Rd. In some embodiments, R1 is -OR. In some embodiments, R1 is an optionally substituted Ci_6 aliphatic group. In some embodiments, R1 is an optionally substituted ethyl group. In some embodiments, R1 is hydrogen, methyl or -CD3. In some embodiments, R1 is hydrogen. In some embodiments, R1 is methyl or CD3. In some embodiments, R1 is methyl. In some embodiments, R1 is -CD3. In some embodiments, R1 is -OH. As generally defined above, R2 is H, Rc, -N(R)C(O)Cy2, N(R)Cy2, -OCy2, -SCy2o Cy2. In some embodiments, R2 is H. In some embodiments, R2 is Rc, -N(R)C(O)Cy2, -N(R)Cy2, -OCy2, -SCy2o Cy2. In some embodiments, R2 is Rc. In some embodiments, R2 is -N(R)C(O)R. In some embodiments, R2 is N(R)C(O)Cy2, -N(R)Cy2, or Cy2. In some embodiments, R2 is N(R)C(O)R, -NÍRjCÍOjCy2, -N(R)Cy2or Cy2. In some embodiments, R225 is -N(H)C(O)R, -N(H)C(O)Cy2, -N(H)Cy2, or Cy2. In some embodiments, R2 is -N(H)C(O)R, -N(H)C(O)Cy2 or -N(H)Cy2. In some embodiments, R2 is -N(H)C(O)R. In some embodiments, R2es - N(H)C(O)R, where R in this instance is optionally substituted aliphatic Ci_6. In some embodiments, R2 is -N(H)C(O)Cy2. In some embodiments, R2 is -N(H)Cy2. In some embodiments, R2 is N(H)C(O)Cy2where Cy2 is cyclopropyl. In some embodiments, R2 is Or or Or As generally defined above, R3 is H, halogen or aliphatic Ci_6. In some embodiments, R3 is H. In some embodiments, R3 is halogen or aliphatic C^. In some embodiments, R3 is halogen. In some embodiments, R3 is fluoro. In some embodiments, R3 is aliphatic Ci_6. In some embodiments, R2 and R3 are taken together with their intervening atoms to form a 4-7 membered partially unsaturated or aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; where said ring is replaced with m instances of R4. In some embodiments, R2 and R3 are taken together with their intervening atoms to form a 5-membered partially unsaturated or aromatic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; where said ring is replaced with m instances of R4. As generally defined above, Cy1 is phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a saturated or partially unsaturated carbocyclic ring of 3-7 members; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, where Cy1 is substituted with n instances of R5. In some embodiments, Cy1 is phenyl. In some embodiments, Cy1 is a 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Cy1 is a 5-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Cy1 is a 6-membered heteroaryl having 1-4 nitrogens. In some embodiments, Cy1 is pyridyl. In some embodiments, Cy1 is pyrazinyl. In some embodiments, Cy1 is pyrimidinyl. In some embodiments, Cy1 is triazinyl. In some embodiments, Cy1 is pyrrolyl, pyrazolyl, imidazolyl, triazolyl or tetrazolyl. In some embodiments, Cy1 is furanyl, oxazolyl, isoxazolyl or oxadiazolyl. In some embodiments, Cy1 is thiophenyl, thiazolyl, isothiazolyl or thiadiazolyl. In some embodiments, Cy1 is an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Cy1 is a saturated or partially unsaturated 3-7 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Cy1 is a 3-7 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, Cy1 is a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Cy1(R5)n taken together is selected from defined above and described in the embodiments herein, both alone and in combination. In some embodiments, Cy1(R5)n taken together is selected from the groups in the preceding paragraph or the following: In some embodiments, Cy1(R5)n taken together is selected from the groups in the preceding two paragraphs or the following: As generally defined above, Cy2 is phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a saturated or partially unsaturated 3-7 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 3-7 membered saturated or partially unsaturated carbocyclic ring; or a saturated or partially unsaturated bicyclic heterocyclic ring of 7-12 members having 1-4 selected heteroatoms, so independent, of nitrogen, oxygen and sulfur, where Cy2 is replaced with p instances of R6. In some embodiments, Cy2 is phenyl. In some embodiments, Cy2 is a 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Cy2 is a 5-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Cy2 is a 6-membered heteroaryl having 1-4 nitrogens. In some embodiments, Cy2 is pyridyl. In some embodiments, Cy2 is pyrazinyl. In some embodiments, Cy2 is pyrimidinyl. In some embodiments, Cy2 is triazinyl. In some embodiments, Cy2 is pyrrolyl, pyrazolyl, imidazolyl, triazolyl or tetrazolyl. In some embodiments, Cy2 is furanyl, oxazolyl, isoxazolyl or oxadiazolyl. In some embodiments, Cy2 is thiophenyl, thiazolyl, isothiazolyl or thiadiazolyl. In some embodiments, Cy2 is an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Cy2 is a saturated or partially unsaturated 3-7 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Cy2 is a 3-7 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, Cy2 is C3-7 cycloalkyl. In some embodiments, Cy2 is cyclopropyl. In some embodiments, Cy2 is a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Cy2 is selected from the following, each of which is replaced with p instances of R6: In some embodiments, Cy2 is selected from the groups in the preceding or following paragraph, each of which is replaced with p instances of R6: In some embodiments, p is 1 or 2 and at least one instance of R6 is -CN, -CH3, -CHF2, or -CF3. As generally defined above, L1 is a covalent bond or a bivalent linear or branched saturated or unsaturated hydrocarbon chain Cm, wherein one or two methylene units of the chain are optionally and independently replaced by -C(R7)2- , -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or S(O)2- In some forms of embodiment, L1 is a covalent bond. In some embodiments, L1 is a divalent straight or branched saturated or unsaturated hydrocarbon chain Ci_4 wherein one or two methylene units of the chain are optionally and independently replaced by -C(R7)2-, -N(R), -N(R)C(O)-, -C(O)N(R)-, _N(R)S(O)2-, -S(O)2N(R)-, -O-, -C (O)-, -OC(O)-, C(O)O-, -S-, -S(O)- or -S(O)2- In some embodiments, L1 is -N(R)- . In some embodiments, L1 is -N(H)-. As generally defined above, m is 0, 1.2, 3 or 4. In some embodiments, m is 0. In some embodiments, m is 1.2, 3 or 4. In some embodiments embodiment, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. As generally defined above, n is 0, 1, 2, 3 or 4. In some embodiments, n is 0. In some embodiments, n is 1, 2, 3 or 4. In some embodiments embodiment, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. As generally defined above, p is 0, 1, 2, 3, or 4. In some embodiments, p is 0. In some embodiments, p is 1, 2, 3, or 4. In some embodiments embodiment, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, the present invention provides a compound of formula I, where L1 is -N(H)-, thus forming a compound of formula l-a: or one of its pharmaceutically acceptable salts, wherein each of X, Cy1, R1 and R2 is as defined above and described in the embodiments herein, both alone and in combination. In some embodiments, the present invention provides a compound of formula I, wherein X is N or C(R3), thereby forming a compound of formulas l-b or l-c, respectively: or one of its pharmaceutically acceptable salts, wherein each of Cy1, L1, R1, R2 and R3 is as defined above and described in the embodiments herein, both alone and in combination. In some embodiments, the present invention provides a compound of formula l-a, where L1 is N or C(R3), thus forming a compound of formulas II—a or II—b, respectively: ll-b or one of its pharmaceutically acceptable salts, wherein each of Cy1, R1, R2 and R3 is as defined above and described in the embodiments herein, both alone and in combination. In some embodiments, the present invention provides a compound of formula II—a or ll-b wherein Cy1 is phenyl, thereby forming a compound of formula III—a or III-b, respectively: or one of its pharmaceutically acceptable salts, wherein each of R1, R2, 3 5 R, R and n are as defined above and described in the embodiments herein, both alone and in combination. In some embodiments, the present invention provides a compound of formula III-a or III-b, wherein n is 1, 2 or 3 and at least one instance of R5 is ortho to the point of attachment with NH, forming thus a compound of formulas IV-a or IV-b, respectively: or one of its pharmaceutically acceptable salts, wherein each of R1, R2, R3 and R5 is as defined above and described in the embodiments herein, both alone and in combination. In some embodiments, the present invention provides a compound of formula IV-a or IV-b, wherein the group R5 is -OR, -S(O)2R, C(O)NR2o -N(R)S( O)2R, thus forming a compound of the formulas V-a, V-b, V-c, V-d, V-e, V-f, V-g or V-h, respectively: V-a V-b You V-c V-e V-f V-g V-h or one of its pharmaceutically acceptable salts, where each of R, R1, R2, R3, and R5 are as defined above and described in the embodiments herein, both alone and in combination. In some embodiments, the present invention provides a compound of formula V-a or V-b, wherein a second group R5(R5b) is in meta position with respect to the point of attachment with NH, thus forming a compound of formulas Vl-a or Vl-b, respectively. or one of its pharmaceutically acceptable salts, wherein each of R, R1, R2, R3 and R5 is as defined above and described in the embodiments herein, both alone and in combination. In some embodiments, the present invention provides a compound of the formula Vl-a or Vl-b, wherein R5 is RB. In some forms of embodiment, the present invention provides a compound of the formula Vl-a or Vl-b, where R5 is -C(O)NR2o a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, where said ring is substituted with q instances of In some embodiments, the present invention provides a compound of the formula Vl-a or Vl-b, wherein -OR is methoxy, fluoromethoxy or difluoromethoxy. In some embodiments, the present invention provides a compound of formula II—a or II—b wherein Cy1 is pyridyl, n is 2 and an instance of R5 is oxo, thus forming a pyridone compound of formulas Vil—a or Vil— b, respectively: NO R5 Vll-a N R5 Vll-b or one of its pharmaceutically acceptable salts, wherein each of R1, R2, R3 and R5, is as defined above and described in the embodiments herein, both alone and in combination. As described above, in certain embodiments, the present invention provides a compound of formula VIII: VIII or a pharmaceutically acceptable salt thereof, where: X is N or C(R3); Y is N or C(R1); R1 is H, D or halogen; R, Rdu -OR; R2is H, Rc, -N(R)C(O)Cy2, -N(R)S(O)2Cy2, -N(R)Cy2, -OCy2, -SCy2o Cy2; R3is H, halogen or aliphatic Ci_e; either R2 and R3 are taken together with their intervening atoms to form a 4-7 membered partially unsaturated or aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein said ring is replaced with m instances of R4; each of Cy1 and Cy2 is, independently, phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 3-7 membered saturated or partially unsaturated carbocyclic ring; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; where Cy1 is replaced with n instances of R5; and where Cy2 is replaced with p | instances of R6;I Cy3 is a partially unsaturated or heteroaromatic monocyclic ring of 5-6| members having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; where Cy3 is replaced with r instance of R8; L1 is a covalent bond or a saturated or unsaturated, linear or branched bivalent hydrocarbon chain Ci_4 wherein one or two methylene units of the chain are optionally and independently replaced by -C(R7)2-, N(R)-, -N (R)C(O)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C( O)-, 5 00(0)-, -C(0)0-, -OC(O)N(R)-, -N(R)C(O)O-, -S-, -S(0 )- or -S(0)2-; each instance of R4, R5, R6, R7 and R8 is, independently, RA or RBy is replaced with q instances of Rc; each instance of RAis, independently, oxo, halogen, -CN, -N02, OR, -0Rd, -SR, -NR2, -S(O)2R, -S(O)2NR2i-S(0)R, -S(O)NR2i-C(0)R, 10 C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -0C(0) NR2, -N(R)C(O)OR, N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R) S(O)2NR2o -N(R)S(O)2R; each instance of RBes, independently, aliphatic Ci_e; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 3-7 membered saturated or partially unsaturated carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; each instance of Rces, independently, oxo, halogen, -CN, -NO2, OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S (O)NR2, -C(O)R, -C(O)OR, 25 -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O) NR2, -N(R)C(O)OR, N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R) S(O)2NR2o -N(R)S(O)2R or an optionally substituted group selected from aliphatic Ci_6, 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; Rdes an aliphatic group Ci^ where one or more hydrogens are replaced by deuterium; each R is independently hydrogen or an optionally substituted group selected from aliphatic C^, phenyl, a saturated or partially unsaturated 3-7 membered heterocyclic 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 are taken together with their intervening atoms to form a saturated or partially unsaturated 4-7 membered heteroaryl ring having 0-3 heteroatoms in addition to the nitrogen, independently selected from nitrogen, oxygen and sulfur; and each of m, n, p, q and r is, independently, 0, 1.2, 3 or 4. As generally defined above, X is N or C(R3). In some embodiments, X is N. In some embodiments, X is C(R3). In some embodiments, X is C(H). In some embodiments, X is C(R3), where R3 is halogen. In some embodiments, X is C(R3), where R3 is fluoro. As generally defined above, Y is N or C(R1). In some embodiments, Y is N. In some embodiments, Y is C(R1). In some embodiments, Y is C(H). In some embodiments, Y is CD). In some embodiments, Y is C(R1), where R1 is halogen. In some embodiments, X is C(R1), where R3 is fluoro. As generally defined above, R1 is H, D or halogen. In some embodiments, R1 is H. In some embodiments, R1 is D. In some embodiments, R1 is halogen. In some embodiments, R1 is fluoro. As generally defined above, R2 is H, Rc, -N^CÍOJCy2, NÍRjCy2, -OCy2, -SCy2o Cy2. In some embodiments, R2 is H. In some embodiments, R2 is Rc, -N(R)C(O)Cy2, -N(R)Cy2, -OCy2, -SCy2, or Cy2. In some embodiments, R2 is Rc. In some embodiments, R2 is -N(R)C(O)R. In some embodiments, R2 is N(R)C(O)Cy2, -N(R)Cy2, or Cy2. In some embodiments, R2 is N(R)C(O)R, -N(R)C(O)Cy2, -N(R)Cy2, or Cy2. In some embodiments, R2 is -N(H)C(O)R, -N(H)C(O)Cy2, -N(H)Cy2, or Cy2. In some embodiments, R2 is -N(H)C(O)R, -N(H)C(O)Cy2 or -N(H)Cy2. In some embodiments, R2 is -N(H)C(O)R. In some embodiments, R2 is N(H)C(O)R where R in this instance is optionally substituted aliphatic Ci_6. In some embodiments, R2 is -N(H)C(O)Cy2. In some embodiments, R2 is -N(H)Cy2. In some embodiments, R2 is N(H)C(O)Cy2where Cy2 is cyclopropyl. In some embodiments, R2 is Or or Or In some embodiments, R2 and R3 are taken together with their intervening atoms to form a 4-7 membered partially unsaturated or aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; where said ring is replaced with m instances of R4. In some embodiments, R2 and R3 are taken together with their intervening atoms to form a partially unsaturated or aromatic ring of 5 members having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; where said ring is replaced with m instances of R4. As generally defined above, Cy1 is phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a saturated or partially unsaturated 3-7 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 3-7 membered saturated or partially unsaturated carbocyclic ring; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein Cy1 is substituted with n 15 instances of R5. In some embodiments, Cy1 is phenyl. In some embodiments, Cy1 is a 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Cy1 is a 5-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Cy1 is a 6-membered heteroaryl having 1-4 nitrogens. In some embodiments, Cy1 is pyridyl. In some embodiments, Cy1 is pyrazinyl. In some embodiments, Cy1 is pyrimidinyl. In some embodiments, Cy1 is triazinyl. In some embodiments, Cy1 is pyrrolyl, pyrazolyl, imidazolyl, triazolyl or tetrazolyl. In some embodiments, Cy1 is furanyl, oxazolyl, isoxazolyl or oxadiazolyl, In some embodiments, Cy1 is thiophenyl, thiazolyl, isothiazolyl or thiadiazolyl. In some embodiments, Cy1 is an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Cy1 is a saturated or partially unsaturated 3-7 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Cy1 is a 3-7 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, Cy1 is a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Cy1(R5)n taken together is selected from the following: Yo nr2 ; wherein each of R, Rc and q is as defined above and described in the embodiments herein, both alone and in combination. As generally defined above, Cy2 is phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 3-7 membered saturated or partially unsaturated carbocyclic ring; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein Cy2 is substituted with p instances of R6. In some embodiments, Cy2 is phenyl. In some embodiments, Cy2 is a 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Cy2 is a 5-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Cy2 is a 6-membered heteroaryl having 1-4 nitrogens. In some embodiments, Cy2 is pyridyl. In some embodiments, Cy2 is pyrazinyl. In some embodiments, Cy2 is pyrimidinyl. In some embodiments, Cy2 is triazinyl. In some embodiments, Cy2 is pyrrolyl, pyrazolyl, imidazolyl, triazolyl or tetrazolyl. In some embodiments, Cy2 is furanyl, oxazolyl, isoxazolyl or oxadiazolyl. In some embodiments, Cy2 is thiophenyl, thiazolyl, isothiazolyl or thiadiazolyl. In some embodiments, Cy2 is an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Cy2 is a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms. independently selected from nitrogen, oxygen and sulfur. In some embodiments, Cy2 is a 3-7 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, Cy2 is C3-7 cycloalkyl. In some embodiments, Cy2 is cyclopropyl. In some embodiments, Cy2 is a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Cy2 is selected from the following, each of which is replaced with p instances of R6: N N N=N N=N N=N N N In some embodiments, Cy2 is selected from the groups in the previous paragraph or the following, which is replaced with p instances of R6: As generally defined above, Cy3 is a 5-6 membered partially unsaturated or heteroaromatic monocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; where Cy3 is replaced with r instances of R8. In some embodiments, Cy3 is a 5-membered monocyclic heteroaromatic or partially unsaturated ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Cy3 is a 5-membered monocyclic partially unsaturated ring having 1- independently selected heteroatoms of nitrogen, oxygen and sulfur. In some embodiments, Cy3 is a 5-membered monocyclic heteroaromatic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Cy3 is selected from the following, each of which is replaced with r instances of R8: As generally defined above, L1 is a covalent bond or a bivalent straight or branched saturated or unsaturated hydrocarbon chain Ci_4 wherein one or two methylene units of the chain are optionally and independently replaced by -C(R7)2-, -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R) -, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or S(O)2-. In some embodiments, L1 is a covalent bond. In some embodiments, L1 is a divalent straight or branched saturated or unsaturated hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -C(R7)2-, -N(R), - N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C (O)-, -OC(O)-, 0(0)0-, -S-, —S(0)— or -S(0)2- In some embodiments, L1 is -N(R)-. In some embodiments, L1 is -N(H)-. As generally defined above, R8 is, independently, RA or RBy is replaced with q instances of Rc. In some embodiments, R8 is halogen or aliphatic Ci_6 substituted with 1-2 Rc. In some embodiments, R8 is halogen. In some embodiments, R8 is aliphatic C^ substituted with 0-2 Rc. In some embodiments, R8 is chloro or fluoro. In some embodiments, R8 is hydroxymethyl. In some embodiments, R8 is chloro, fluoro, methyl, cyclopropyl or hydroxymethyl. In some embodiments, R8 is chloro, fluoro or hydroxymethyl. As generally defined above, m is 0, 1, 2, 3, or 4. In some embodiments, m is 0. In some embodiments, m is 1, 2, 3, or 4. In some embodiments, embodiment, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. As generally defined above, n is 0, 1, 2, 3 or 4. In some embodiments, n is 0. In some embodiments, n is 1, 2, 3 or 4. In some embodiments embodiment, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. As generally defined above, p is 0, 1, 2, 3, or 4. In some embodiments, p is 0. In some embodiments, p is 1, 2, 3, or 4. In some embodiments embodiment, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. As generally defined above, r is 0, 1.2, 3, or 4. In some embodiments, r is 0. In some embodiments, r is 1, 2, 3, or 4. In some embodiments, r is 1. In some embodiments, r is 2. In some embodiments, r is 3. In some embodiments, r is 4. In some embodiments, the present invention provides a compound of formula VIII, where L1 is -N(H)-, thus forming a compound of formula Vlll-a: Cy1—NH Vlll-a or one of its pharmaceutically acceptable salts, wherein each of X, Cy1, R1 and R2 is as defined above and described in the embodiments herein, both alone and in combination. In some embodiments, the present invention provides a compound of formula VIII, wherein X is C(R3) and Y is C(R1) or C(R1) or both X and Y are N; thus forming a compound of formulas IX-a, IX-b, IX-c or IX-d, respectively: IX-b Cy IX-d IX-a IX-b or one of its pharmaceutically acceptable salts, wherein each of Cy1, Cy3, L1, R1, R2 and R3 is as defined above and described in the embodiments herein, both alone and in combination. In some embodiments, the present invention provides a compound of formulas IX-a, IX-b, IX-c or IX-d, wherein L1 is -N(H)-, thus forming a compound of formulas X-a or X-b, X-c or X-d, respectively: Ϊ? faith, Cy1—NH For X-c X-D or one of its pharmaceutically acceptable salts, where each of Cy1, Cy3, R1, R2y R3es as defined previously and is described in forms 5 of realization of the present, both alone and in combination. In some embodiments, the present invention provides a compound of formula VIII—a, wherein Cy1 is phenyl, thereby forming a compound of formula Xl-a: X^Cy3 Xl-a or a pharmaceutically acceptable salt thereof, wherein each of X, Y, R2, R5 and n is as defined above and described in the embodiments herein, both alone and in combination. In some embodiments, the present invention provides a compound of the formula X-a, X-b, X-c or , respectively: Xl-b Xl-c Xl-d Xl-e or one of its pharmaceutically acceptable salts, wherein each of R1, R2, R3, R5 and n is as defined above and described in the embodiments herein, both alone and in combination. In some embodiments, the present invention provides a compound of the formula of formula XII—a: XII—a or one of its pharmaceutically acceptable salts, wherein each of In some embodiments, the present invention provides a compound of the formula Xl-b, Xl-c, Xl-d or Xl-e wherein n is 1, 2 or 3 and at least one instance of R5 is in ortho position with respect to the point of union with NH, thus forming a compound of the formula XII-b, XII-c, XII-d or XII-e, respectively: XII—c Xll-e XII—d or one of its pharmaceutically acceptable salts, wherein each of Cy3, R1, R2, R3 and R5 is as defined above and described in the embodiments herein, both alone and in combination. In some embodiments, the present invention provides a compound of formula , thus forming a compound of the formulas XII—a—i, XII—a—ii, XII—a—iii or Xll-a-iv, respectively: XII—a—i C(O)NR2 XII—a—iii Xll-a-iv or one of its pharmaceutically acceptable salts, wherein each of X, Y, Cy3, R, R1, R2, R3 and R5 is as defined above and described in the embodiments herein, both alone and in combination. In some embodiments, the present invention provides a compound of formula , thus forming a compound of the formulas XII—b—i, XII—b—ii, XII—b—iii or Xll-b-iv, respectively: XH-b-iii Xll-b-iv or one of its pharmaceutically acceptable salts, wherein each of Cy3, R, R1, R2, R3 and R5 is as defined above and described in the embodiments herein, both alone and in combination . In some embodiments, the present invention provides a compound of formula , thus forming a compound of the formulas XII—c—i, XII—c—ii, XII—c—iii or Xll-c-iv, respectively: XH-c-iii Xll-c-iv or one of its pharmaceutically acceptable salts, wherein each of Cy3, R, R2, R3 and R5 is as defined above and described in the embodiments herein, both alone and in combination. In some embodiments, the present invention provides a compound of formula 2R, thus forming a compound of the formulas XII—d—i, XII—d—ii, Xll-d-iii or XII Xll-d-i d-iv, respectively: (r5)o-2_CX ^O(O)NR2 Xll-d-iii Xll-d-iv or one of its pharmaceutically acceptable salts, wherein each of Cy3, R, R1, R2 and R5 is as defined above and described in the embodiments herein, both alone and in combination. In some embodiments, the present invention provides a compound of formula , thus forming a compound of the formulas XII—e—i, XII—e—ii, Xll-e-iii or Xll-e-iv, respectively: Xll-e-iii (R5)0-2 Xll-í Xll-e-iv or one of its pharmaceutically acceptable salts, wherein each of Cy3, R, R2 and R5 is as defined above and described in the embodiments herein, both alone and in combination. In some embodiments, the present invention provides a compound of the formula or one of its pharmaceutically acceptable salts, wherein each of X, Y, Cy3, R, R2 and R5 is as defined above and described in the embodiments herein, both alone and in combination. In some embodiments, the present invention provides a compound of formula XII—b—i, XII—c—i, XII—d—i or of union with NH, thus forming a compound of the formula XIII-b, XIII-c, XIII-d or XIII-e, respectively: Xlll-b Xlll-c Xlll-d . In some embodiments, the present invention provides a compound of formula XIII-a, Xlll-b, Xlll-c, Xlll-d or XIII-e wherein R5 is RB. In some embodiments, the present invention provides a compound of formula XIII—a, Xlll-b, Xlll-c, Xlll-d or members having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, where said ring is substituted with q instances of Rc. In some embodiments, the present invention provides a compound of formula XIII-a, XIII-b, XIII-c, XIII-d or XIII-e wherein -OR is methoxy, fluoromethoxy or difluoromethoxy. In some embodiments, the present invention provides a compound of the formula l-a, wherein Cy1 is pyridyl, n is 2 and one instance of R5 is oxo, thus forming a pyridone compound of the formula XlV-a: XlV-a or one of its pharmaceutically acceptable salts, wherein each of X, Y, Cy3, R2 and R5 is as defined above and described in the embodiments herein, both alone and in combination. In some embodiments, the present invention provides a compound of the formula X-a or X-b, X-c or XV-a, XV-b, XV-c or XV-d: XV-a XV-b or one of its pharmaceutically acceptable salts, wherein each of Cy3, R1, R2, R3 and R5 is as defined above and described in the embodiments herein, both alone and in combination. As described above, in certain embodiments, the present invention provides a compound of formula XVI': XVI' or one of its pharmaceutically acceptable salts, where: Q is CH or N; X is N or C(RX); one of Y1, Y2, Z1 and Z2 is N and the other three are C; R1es D, R, Rd, -NR2, -NRRd, -N(Rd)2, -N(R)C(O)NR2i-N(R)C(NR)NR2, N(R)C(O)NRRd , -N(R)C(NR)NRRd,-OR or -ORd; R2is H, Rc, -N(R)C(O)Cy2, -N(R)S(O)2Cy2, -N(R)Cy2, -OCy2, -SCy2o Cy2; R3is H, halogen or aliphatic C^; either R2 and R3 are taken together with their intervening atoms to form a 4-7 membered partially unsaturated or aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein said ring is replaced with m instances of R4; each of Cy1 and Cy2 is, independently, phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 3-7 membered saturated or partially unsaturated carbocyclic ring; or a bicyclic or partially saturated heterocyclic ring 7-12 membered unsaturated having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, where Cy1 is substituted with n instances of R5; and where Cy2 is replaced with p instances of R6; L1 is a covalent bond or a divalent straight or branched saturated or unsaturated hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -C(R7)2-, N(R)_, -N( R)C(O)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O) )-, OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2-; each instance of R4, R5, R6 and R7 is, independently, RA or RBy is replaced with q instances of Rc; each instance of RAis, independently, oxo, halogen, -CN, -NO2, OR, -ORd, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R , -S(O)NR2, -C(O)R, C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O )NR2, -N(R)C(O)OR, 15 N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N( R)S(O)2NR2o -N(R)S(O)2R; each instance of RB is, independently, aliphatic C^; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 3-7 membered saturated or partially unsaturated carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; each instance of Rces, independently, oxo, halogen, -CN, -NO2, OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S (O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2 , -N(R)C(O)OR, N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S (O)2NR2o -N(R)S(O)2R or an optionally substituted group selected from aliphatic C-i_6, phenyl, a saturated or partially unsaturated 3-7 membered heterocyclic ring having 1-2 heteroatoms selected, so independently, from nitrogen, oxygen and sulfur and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Rdes an aliphatic group where one or more hydrogens are replaced by deuterium; Rxes H, halogen or aliphatic Ci_e each R is, independently, hydrogen or an optionally substituted group selected from aliphatic Ci_6, phenyl, a saturated or partially unsaturated 3-7 membered heterocyclic having 1-2 heteroatoms selected, independently , of 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 are taken together with their intervening atoms to form a saturated or partially unsaturated 4-7 membered heteroaryl ring having 0-3 heteroatoms in addition to the nitrogen, independently selected from nitrogen, oxygen and sulfur; and each of m, n, p and q is, independently, 0, 1,2,304. As generally defined above, Q is CH or N. In some embodiments, Q is CH. In some embodiments, Q is N. As generally defined above, X is N or C(RX). In some embodiments, X is N. In some embodiments, X is C(RX). In some embodiments, X is C(H). In some embodiments, X is C(RX), where Rx is halogen. In some embodiments, X is C(RX), where Rx is fluoro. As generally defined above, R1is D, R, R°, -NR2, -NRR°, -N(Rd)2, -N(R)C(O)NR2i-N(R)C(NR)NR2 , -N(R)C(O)NRRd, -N(R)C(NR)NRRd,_ OR or -ORd. In some embodiments, R1 is D. In some embodiments, R1 is R. In some embodiments, R1 is R°. In some embodiments, R1 is -NR2. In some embodiments, R1 is NRRd. In some embodiments, R1 is -N(RD)2. In some embodiments, R1 is -OR. In some embodiments, R1 is -OR°. In some embodiments, R1 is an optionally substituted Ci_6 aliphatic group. In some embodiments, R1 is an optionally substituted ethyl group. In some embodiments, R1 is hydrogen, methyl or -CD3. In some embodiments, R1 is hydrogen. In some embodiments, R1 is methyl or -CD3. In some embodiments, R1 is methyl. In some embodiments, R1 is -CD3. In some embodiments, R1 is OCH3. In some embodiments, R1 is D, R, R°, -NR2, -NRR°, -N(RD)2, -N(R)C(O)NR2, -N(R)C(NR)NR2i-N(R)C(O)NRRd, -N(R)C(NR)NRRd,-OR or ORd, where R1 is not hydrogen. In some embodiments, R1 is NR2, -NRRd, -N(Rd)2, -N(R)C(O)NR2, -N(R)C(NR)NR2i-N(R)C(O)NRRd , -k N(R)C(NR)NRRd,-OR or -ORd. In some embodiments, R1 is -NR2, NRRd, -N(Rd)2, -N(R)C(O)NR2i-N(R)C(NR)NR2, -N(R)C(O)NRRd , 25 N(R)C(NR)NRRd. In some embodiments, R1 is -NR2 or -NRR°. In some embodiments, R1 is optionally substituted aliphatic C-i_6, -NR2 I or -NRR. In some embodiments, R1 is -NHR or NHRDIn some embodiments, R1 is -NHCH3 or NHCD3. As generally defined above, R2 is H, Rc, -N(R)C(O)Cy2, N(R)Cy2, -OCy2, -SCy2o Cy2. In some embodiments, R2 is H. In some embodiments, R2 is Rc, -NíRjCíOjCy2, -N(R)Cy2, -OCy2, -SCy2o Cy2. In some embodiments, R2 is Rc. In some embodiments, R2 is -N(R)C(O)R. In some embodiments, R2 is Ν(Η^(Ο)Ο / , -N(R)Cy2o Cy2. In some embodiments, R2 is N(R)C(O)R, -N(R)C(O )Cy2, -N(R)Cy2o Cy2. In some embodiments, R2 is -N(H)C(O)R, -N(H)C(O)Cy2, -N(H)Cy2o Cy2. embodiments, R2 is -N(H)C(O)R, -N(H)C(O)Cy2 or -N(H)Cy2. In some embodiments, R2 is -N(H)C(O)R. In some embodiments, R2 is N(H)C(O)R where R in this instance is optionally substituted aliphatic Ci_6. In some embodiments, R2 is -N(H)C(O)Cy2. In some embodiments, R2 is -N(H)Cy2. In some embodiments, R2 is N(H)C(O)Cy2, where Cy2 is cyclopropyl. Or or Or As generally defined above, R3 is H, halogen or aliphatic Ci_6. In some embodiments, R3 is H. In some embodiments, R3 is halogen or aliphatic Ci_6. In some embodiments, R3 is halogen. In some embodiments, R3 is fluoro. In some embodiments, R3 is aliphatic C-i_6. In some embodiments, R2 and R3 are taken together with their intervening atoms to form a 4-7 membered partially unsaturated or aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; where said ring is replaced with m instances of R4. In some embodiments, R2 and R3 are taken together with their atoms intervening to form a 5-membered partially unsaturated or aromatic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; where said ring is replaced with m instances of R4. As generally defined above, Cy1 is phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 3-7 membered saturated or partially unsaturated carbocyclic ring; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein Cy1 is substituted with n instances of R5. In some embodiments, Cy1 is phenyl. In some embodiments, Cy1 is a 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Cy1 is a 5-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Cy1 is a 6-membered heteroaryl having 1-4 nitrogens. In some embodiments, Cy1 is pyridyl. In some embodiments, Cy1 is pyrazinyl. In some embodiments, Cy1 is pyrimidinyl. In some embodiments, Cy1 is triazinyl. In some embodiments, Cy1 is pyrrolyl, pyrazolyl, imidazolyl, triazolyl or tetrazolyl. In some embodiments, Cy1 is furanyl, oxazolyl, isoxazolyl or oxadiazolyl, In some embodiments, Cy1 is thiophenyl, thiazolyl, isothiazolyl or thiadiazolyl. In some embodiments, Cy1 is an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Cy1 is a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Cy1 is a 3-7 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, Cy110 is a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Cy1(R5)n taken together is selected from the following: b q is as defined above and described in the embodiments herein, both alone and in combination. As generally defined above, Cy2 is phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 3-7 membered saturated or partially unsaturated carbocyclic ring; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein Cy2 is substituted with p instances of R6. In some embodiments, Cy2 is phenyl. In some embodiments, Cy2 is a 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Cy2 is a 5-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Cy2 is a 6-membered heteroaryl having 1-4 nitrogens. In some embodiments, Cy2 is pyridyl. In some embodiments, Cy2 is pyrazinyl. In some embodiments, Cy2 is pyrimidinyl. In some embodiments, Cy2 is triazinyl. In some embodiments, Cy2 is pyrrolyl, pyrazolyl, imidazolyl, triazolyl or tetrazolyl. In some embodiments, Cy2 is furanyl, oxazolyl, isoxazolyl or oxadiazolyl. In some embodiments, Cy2 is thiophenyl, thiazolyl, isothiazolyl or thiadiazolyl. In some embodiments, Cy2 is an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Cy2 is a saturated or partially unsaturated 3-7 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Cy2 is a 3-7 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, Cy2 is C3-7 cycloalkyl. In some embodiments, Cy2 is cyclopropyl. In some embodiments, Cy2 is a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Cy2 is selected from the following, each of which is replaced with p instances of R6: As generally defined above, L1 is a covalent bond or a bivalent linear or branched saturated or unsaturated hydrocarbon chain F Ci_4 where one or two methylene units of the chain are replaced | optionally and independently by -C(R7)2-, -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O) 2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- either - S(O)2- In some embodiments, L1 is a covalent bond. In some embodiments, L1 is a saturated or unsaturated, straight or branched bivalent C·^ hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -C(R7)2-, -N(R ), -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O- , -C(O)-, -OC(O)-, C(O)O-, -S-, -S(O)- or -S(O)2-, As generally defined above, m is 0, 1, 2, 3 or 4. In some embodiments, m is 0. In some embodiments, m is 1, 2, 3 or 4. In some embodiments embodiment, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. As generally defined above, n is 0, 1, 2, 3 or 4. In some embodiments, n is 0. In some embodiments, n is 1, 2, 3 or 4. In some embodiments embodiment, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. As generally defined above, p is 0, 1, 2, 3, or 4. In some embodiments, p is 0. In some embodiments, p is 1,2, 3, or 4. In some embodiments, embodiment, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, the present invention provides a compound of formula XVI' where Q is N, thus forming a compound of formula XVI: or one of its pharmaceutically acceptable salts, where: X is N or C(RX); one of Y1, Y2, Z1 and Z2 is N and the other three are C; R1es D, R, Rd, -NR2, -NRRd, -N(Rd)2, -N(R)C(O)NR2i-N(R)C(NR)NR2, N(R)C(O)NRRd , -N(R)C(NR)NRRd,-OR or -ORd; R2is H, Rc, -N(R)C(O)Cy2, -N(R)S(O)2Cy2, -N(R)Cy2, -OCy2, -SCy2o Cy2; R3is H, halogen or aliphatic Ci_6¡ or R2 and R3 are taken together with their intervening atoms to form a 4-7 membered partially unsaturated or aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein said ring is replaced with m instances of R4; each of Cy1 and Cy2 is, independently, phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a saturated or partially unsaturated 3-7 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 3-7 membered saturated or partially unsaturated carbocyclic ring; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein Cy1 is replaced with n instances of R5; and where Cy2 is replaced with p instances of R6; L1 is a covalent bond or a divalent straight or branched saturated or unsaturated hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -C(R7)2-, N(R)-, -N (R)C(O)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C( O)-, OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2-; each instance of R4, R5, R6 and R7 is, independently, RA or RBy is replaced with q instances of Rc; each instance of RAis, independently, oxo, halogen, -CN, -NO2, OR, -ORd, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R , -S(O)NR2, -C(O)R, C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O )NR2, -N(R)C(O)OR, N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R )S(O)2NR2o -N(R)S(O)2R; each instance of RB is, independently, aliphatic C^; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 3-7 membered saturated or partially unsaturated carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; each instance of Rces, independently, oxo, halogen, -CN, -NO2, OR, -SR, -NR2, -S(O)2R, -S(O)2NR2i-S(O)R, -S( O)NR2, -C(O)R, -C(O)OR, -C(O)NR2i-C(O)N(R)OR, -OC(O)R, -OC(O)NR2i-N (R)C(O)OR, - N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2o -N(R)S(O )2R or an optionally substituted group selected from aliphatic Ci_6, 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-membered heteroaryl ring -6 members having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Rdes an aliphatic group Ci^ where one or more hydrogens are replaced by deuterium; RXesH, halogen or aliphatic Ci_e each R is, independently, hydrogen or an optionally substituted group selected from aliphatic Ci_6, phenyl, a saturated or partially unsaturated 3-7 membered heterocyclic having 1-2 heteroatoms selected, independently, of 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 are taken together with their intervening atoms to form a saturated or partially unsaturated 4-7 membered heteroaryl ring having 0-3 heteroatoms in addition to the nitrogen, independently selected from nitrogen, oxygen and sulfur; and each of m, n, p and q is, independently, 0, 1, 2, 3 or 4. In some embodiments, the present invention provides a compound of formula XVI, wherein L1 is a covalent bond, thereby forming a compound of formula XVI-a: XVI-a or one of its pharmaceutically acceptable salts, wherein each of alone as well as in combination. In some embodiments, the present invention provides a compound of formula XVI, wherein X is N or C(RX), thereby forming a compound of formula XVI-b or XVI-c, respectively: XVI-b XVI-c or one of its pharmaceutically acceptable salts, wherein each of L1, Y1, Y2, Z1, Z2, Cy1, Rx, R1, R2 and R3 is as defined above and described in the embodiments hereof, both alone and in combination. In some embodiments, the present invention provides a compound of the formula XVI-b or XVI-c, wherein Rx and R3 are both H, thus forming a compound of the formula XVII-a or XVII-b, respectively: or one of its pharmaceutically acceptable salts, wherein each of Y1, Y2, Z1, Z2, Cy1, R1, R2 and R3 are as defined above and described in the embodiments herein, both alone and in combination. In some embodiments, the present invention provides a compound of the formula XVII-a or XVII-b, wherein L1 is a covalent bond, thereby forming a compound of the formula XVIII—a or XVIII-b, respectively: Cy1 X°'y’ VÓ>1'r1 zz2-n cy1 XVIII-a XVIII-b or one of its pharmaceutically acceptable salts, wherein each of Y1, Y2, Z1, Z2, Cy1, R1 and R2 is as defined above and described in the embodiments herein, both alone and in combination. In some embodiments, the present invention provides a compound of the formula XVIII-a or XVIII-b where Cy1 is phenyl, thus forming a compound of the formula ΧΙΧ-a or ΧΙΧ-b, respectively: R3 / Nx Y2rvzl'R1 G’N ^(R5)n TOY1 vo>1'r1 qz2'n M]R5)n XIX-a XIX-b or one of its pharmaceutically acceptable salts, wherein each of Y1, Y2, Z1, Z2, R1, R2 and n is as defined above and described in the embodiments herein, both alone and in combination. In some embodiments, the present invention provides a compound of the formula ΧΙΧ-a or ΧΙΧ-b, where n is 1, 2 or 3 and at least one instance of R5 is ortho to the point of attachment with NH, forming thus a compound of the formula XX-a or XX-b, respectively: or one of its pharmaceutically acceptable salts, wherein each of Y1, Y2, Z1, Z2, R1 and R2 is as defined above and described in the embodiments herein, both alone and in combination. In some embodiments, the present invention provides a compound of formula XX-a or XX-b, wherein the ortho group R5 is -OR,S(O)2R, -C(O)NR2o -N(R)S (O)2R, thus forming a compound of the formula XXI-a, XXI-b, XXI-c, XXI-d, XXI-e, XXI-f, XXI-g or XXI-h, respectively: XXI-a XXI-b XXI-g XXI-h or one of its pharmaceutically acceptable salts, wherein each of Y1, Y2, Z1, Z2, R, R1, R2 and R5 is as defined above and described in the embodiments herein, both alone and in combination. In some embodiments, the present invention provides a compound of the formula XXI-a or XXI-b, wherein a second group R5 is in meta position with respect to the point of attachment with NH, thus forming a compound of the formula XXII-a or XXII-b, respectively: XXII-a XXII-b or a pharmaceutically acceptable salt thereof, wherein each of Y1, Y2, Z1, Z2, R, R1, R2 and R5 is as defined above and described in the embodiments herein, both alone and in combination. In some embodiments, the present invention provides a compound of formula XXII-a or XXII-b, wherein R5 is RB. In some embodiments, the present invention provides a compound of formula XXII-a or XXII-b, wherein R5 is -CN, -C(O)NR2o a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, where said ring is substituted with q instances of Rc. In some embodiments, the present invention provides a compound of formula XXII-a or XXII-b, wherein -OR is methoxy, fluoromethoxy or difluoromethoxy. In some embodiments, the present invention provides a compound of the formula XVIII—a or XVIII—b wherein Cy1 is pyridyl, n is 2 and an instance of R5 is oxo, thus forming a pyridone compound of the formula XXIII-a XXIII-a or XXIII-b, respectively: XXIII-b or one of its pharmaceutically acceptable salts, wherein each of Y1, Y2, Z1, Z2, R1, R2 and R5, is as defined above and described in the embodiments herein, both alone and in combination. In some embodiments, the present invention provides a compound of one of the formulas XVI-a, XVI-b, XVI-c, XVII-a, XVII-b, XVIII—a, XVIII-b, XlX-a, ΧΙΧ-b, XX-a, XX-b, XXI-a, XXI-b, XXI-c, XXI-d, XXI-e, XXI-f, XXI-g, XXI- h, XXII-a, XXII-b, XXIII-a or XXIII-b where Z2 is N and Y1, Y2 and Z1 are C. In some embodiments, the present invention provides a compound of one of the formulas XVI-a, XVI -b, XVI-c, XVII-a, XVII-b, XVIII-a, XVIII-b, XlX-a, ΧΙΧ-b, XX-a, XX-b, XXI-a, XXI-b, XXI-c , XXI-d, XXI-e, XXI-f, XXI-g, XXI-h, XXII-a, XXII-b, XXIII-a or XXIII-b where Y2 is N and Y1, Z1 and Z2 are C. In some embodiments, the present invention provides a compound of formula I wherein Z2 is N and Y1, Y2 and Z1 are C; or where Y2es N and Y1, Z1 and Z2 are C, thus forming a compound of the formula XXIV-a or XXIVb, respectively: XXIV-a XXIV-b or one of its pharmaceutically acceptable salts, wherein each of X, L1, Cy1, R1 and R2, are as defined above and described in the embodiments herein, both alone and in combination. In some embodiments, the present invention provides a compound of formula XXIV-a or XXIV-b wherein L1 is a covalent bond, thereby forming a compound of formula XXV-a or XXV-b, respectively: XXV-a XXV-b or one of its pharmaceutically acceptable salts, wherein each of X, Cy1, R1 and R2 is as defined above and described in the embodiments herein, both alone and in combination. In some embodiments, the present invention provides a compound of formula XXV-a or XXV-b wherein X is C and Rx is H, thereby forming a compound of formula XXVI-a or XXVI-b, respectively: Cy1Cy1 XXVI-a XXVI-b or a pharmaceutically acceptable salt thereof, wherein each of Cy1, R1 and R2 is as defined above and described in the embodiments herein, both alone and in combination. In some embodiments, the present invention provides a compound of one of the formulas XVI-a, XVI-b, XVI-c, XVII-a, XVII-b, XVIII—a, XVIII-b, XlX-a, ΧΙΧ -b, XX-a, XX-b, XXI-a, XXI-b, XXI-c, XXI-d, XXI-e, XXI-f, XXI-g, XXI-h, XXII-a, XXII-b , XXIII-a, XXIII-b, XXIV-a, XXIV-b, XXV-a, XXVb, XXVI-a or XXVI-b where R2 is -N(R)C(O)R, -N(R)C (O)Cy2, -N(R)Cy2o Cy2. In some embodiments, the present invention provides a compound of one of the formulas XVI-a, XVI-b, XVI-c, XVII-a, XVII-b, XVIII-a, XVIII-b, XlX-a, ΧΙΧ -b, XX-a, XX-b, XXI-a, XXI-b, XXI-c, XXI-d, XXI-e, XXI-f, XXI-g, XXI-h, XXII-a, XXII-b , XXIII-a, XXIII-b, XXIV-a, XXIV-b, XXV-a, XXVb, XXVI-a or XXVI-b where R2 is -N(H)C(O)R, -N(H)C (O)Cy2, -N(H)Cy2o Cy2. In some embodiments, the present invention provides a compound of one of the formulas XVI-a, XVI-b, XVI-c, XVII-a, XVII-b, XVIII-a, XVIII-b, XlX-a, ΧΙΧ -b, XX-a, XX-b, XXI-a, XXI-b, XXI-c, XXI-d, XXI-e, XXI-f, XXI-g, XXI-h, XXII-a, XXII-b , XXIII-a, XXIII-b, XXIV-a, XXIV-b, XXV-a, XXVb, XXVI-a or XXVI-b where R2 is -N(H)C(O)R, -N(H)C (O)Cy2o -N(H)Cy2. In some embodiments, the present invention provides a compound of one of the formulas XVI-a, XVI-b, XVI-c, XVII-a, XVII-b, XVIII-a, XVIII-b, XlX-a, ΧΙΧ-b, XX-a, XX-b, XXI-a, XXI-b, XXI-c, XXI-d, XXI-e, XXI-f, XXI-g, XXI-h, XXII- a, XXII-b, XXIII-a, XXIII-b, XXIV-a, XXIV-b, XXV-a, XXV-b, XXVIa or XXVI-b where R2 is -N(H)C(O)R. In some embodiments, the present invention provides a compound of one of the formulas XVI-a, XVI-b, XVI-c, XVII-a, XVII-b, XVIII-a, XVIII-b, XlX-a, ΧΙΧ -b, XX-a, XX-b, XXIa, XXI-b, XXI-c, XXI-d, XXI-e, XXI-f, XXI-g, XXI-h, XXII-a, XXII-b, XXIII -a, XXIII-b, XXIV-a, XXIV-b, XXV-a, XXV-b, XXVI-a or XXVI-b where R2es Or or Or. In some embodiments, the present invention provides a compound of one of the formulas XVI-a, XVI-b, XVIc, XVII-a, XVII-b, XVIII-a, XVIII-b, XlX-a, ΧΙΧ-b , XX-a, XX-b, XXI-a, XXI-b, XXI-c, XXI-d, XXI-e, XXI-f, XXI-g, XXI-h, XXII-a, XXII-b, XXIII-a, XXIII-b, XXIV-a, XXIV-b, XXV-a, XXV-b, XXVI-a or XXVI-b where R2 is -Ν(Η)θ / , where Cy2 is selected from the following, each of which is In some embodiments, the present invention provides a compound of the formula XVI', where Q is CH, thus forming a compound of the formula XVI": XVI” or one of its pharmaceutically acceptable salts, wherein each of as in combination. In some embodiments, the present invention provides a compound of the formula XVI", where L1 is a covalent bond, thus forming a compound of the formula XVI-a': XVI-a' or one of its pharmaceutically acceptable salts, wherein each of both alone and in combination. In some embodiments, the present invention provides a compound of the formula XVI", where X is N or C(RX), thus forming a compound of the formula XVI-b' or XVI-c', respectively: XVI-b' XVI-c' or one of its pharmaceutically acceptable salts, wherein each of L1, Y1, Y2, Z1, Z2, Cy1, Rx, R1, R2 and R3 is as defined above and described in the forms of the present, both alone and in combination. In some embodiments, the present invention provides a compound of the formula XVI-b' or XVI-c', wherein Rx and R3 are both H, thus forming a compound of the formula XVII-a' or XVII-b', respectively : XVII-a' XVII-b' or one of its pharmaceutically acceptable salts, wherein each of Y1, Y2, Z1, Z2, Cy1, R1, R2 and R3 is as defined above and described in the embodiments of the present, both alone and in combination. In some embodiments, the present invention provides a compound of the formula XVII-a' or XVII-b', wherein L1 is a covalent bond, thereby forming a compound of the formula XVIII-a' or XVIII—b', respectively. : or one of its pharmaceutically acceptable salts, wherein each of Y1, Y2, Z1, Z2, Cy1, R1 and R2 is as defined above and described in the embodiments herein, both alone and in combination. In some embodiments, the present invention provides a compound of the formula XVIII—a' or XVIII—b' wherein Cy1 is phenyl, thus forming a compound of the formula XIX-a' or XIX-b', respectively: XIX-a' XIX-b' or one of its pharmaceutically acceptable salts, wherein each of Y1, Y2, Z1, Z2, R1, R2 and n is as defined above and described in the embodiments herein , both alone and in combination. In some embodiments, the present invention provides a compound of formula XIX-a' or XIX-b', wherein n is 1.2 or 3 and at least one instance of R5 is ortho to the point of attachment with NH, thus forming a compound of the formula XX-a' or XX-b', respectively: Yo XX- a' XX-b' or one of its pharmaceutically acceptable salts, wherein each of Y1, Y2, Z1, Z2, R1 and R2 is as defined above and described in the embodiments of the present, both alone as well as in combination. In some embodiments, the present invention provides a compound of the formula XX-a' or XX-b', wherein the ortho group R5 is -ORS(O)2R, -C(O)NR2o -N(R)S (O)2R, thus forming a compound of the formula XXI- a', XXI-b', XXI-c', XXI-d', XXI-e', XXI-f', XXI-g' or XXI-h', 10 respectively: XXI-b' XXI-g' XXI-h' or one of its pharmaceutically acceptable salts, wherein each of Y1, Y2, Z1, Z2, R, R1, R2 and R5 is as defined above and described in the embodiments of the present, both alone and in combination. In some embodiments, the present invention provides a compound of formula XXI-a' or XXI-b', wherein a second group R5 is in meta position with respect to the point of union with NH, thus forming a compound of the formula XXII-a' or XXII-b', respectively: XXII-a' XXII-b' or one of its pharmaceutically acceptable salts, wherein each of Y1, Y2, Z1, Z2, R, R1, R2 and R5 is as defined above and described in the embodiments of the present, both alone and in combination. In some embodiments, the present invention provides a compound of the formula XXII-a' or XXII-b', wherein R5 is RB. In some embodiments, the present invention provides a compound of formula XXII-a' or XXII-b', wherein R5 is -CN, -C(O)NR2o a 5-6 membered monocyclic heteroaryl ring having 1- 4 heteroatoms selected, independently, from nitrogen, oxygen and sulfur, where said ring is substituted with q instances of Rc. In some embodiments, the present invention provides a "compound of formula XXII-a' or XXII-b', wherein -OR is methoxy, fluoromethoxy or difluoromethoxy. In some embodiments, the present invention provides a compound of the formula XVIII-a' or XVIII-b' where Cy1 is pyridyl, n is 2 and an instance of R5 is oxo, thus forming a pyridone compound of the formula XXIII- a' or XXIII—b', respectively: XXIII-a or one of its pharmaceutically acceptable salts, wherein each of Y1, Y2, Z1, Z2, R1, R2 and R5, is as defined above and described in the embodiments herein, both alone and in combination. In some embodiments, the present invention provides a compound of one of the formulas XVI-a', XVI-b', XVI-c', XVII-a', XVII-b', XVIII-a', XVIII-b', XIX-a', XIX-b', XX-a', XX-b', XXI-a', XXI-b', XXI-c', XXI-d', XXI-e', XXI-f', XXI-g', XXI-h', XXII-a', XXII-b', XXIII-a' or XXIII-b' where Z2 is N and Y1, Y2 and Z1 are C. In some embodiments, the present invention provides a compound of one of the formulas XVI-a', XVI-b', XVI-c', XVII-a', XVII-b', XVIII-a', XVIII-b ', XIX-a', XIX-b'(XX-a', XX-b', XXI-a', XXI-b', XXI-c', XXI-d', XXI-e', XXI-f', XXI-g', XXI-h', XXII-a', XXII-b', XXIII-a' or XXIIIb' where Y2es N and Y1, Z1 and Z2 are C. In some embodiments, the present invention provides a compound of formula I' wherein Z2 is N and Y1, Y2 and Z1 are C; or where Y2 is N and Y1, Z1 and Z2 are C, thus forming a compound of the formula XXIV-a' or XXIV-b', respectively: or one of its pharmaceutically acceptable salts, wherein each of Q, In some embodiments, the present invention provides a compound of formula XXIV-a' or XXIV-b' wherein L1 is a covalent bond, thus forming a compound of formula XXV-a' or XXV-b', respectively: XXV-a' XXV-b' or one of its pharmaceutically acceptable salts, wherein each of Q, X, Cy1, R1 and R2 is as defined above and described in the embodiments herein, both alone and in combination. In some embodiments, the present invention provides a compound of the formula XXV-a' or XXV-b' wherein X is C and Rx is H, thus forming a compound of the formula XXVI-a' or XXVI-b', respectively: XXVI-a' XXVI-b' or one of its pharmaceutically acceptable salts, wherein each of Q, Cy1, R1 and R2 is as defined above and described in the embodiments herein, both alone and in combination. In some embodiments, the present invention provides a compound of one of the formulas XVI-a, XVI-b, XVI-c, XVII-a, XVII-b, XVIII—a, XVIII—b, XlX-a, ΧΙΧ -b, XX-a, XX-b, XXI-a, XXI-b, XXI-c, XXI-d, XXI-e, XXI-f, XXI-g, XXI-h, XXII-a, XXII-b , XXIII-a, XXIII—b, XXIV-a, XXIV-b, XXV-a, XXV- b, XXVI-a, XXVI-b, XVI', XVI”, XVI-a', XVI-b', XVI-c', XVII-a', XVII-b', XVIII-a', XVIII-b' , XIX-a', XIX-b', XX-a', XX-b', XXI-a', XXI-b', XXI-c', XXI-d', XXI-e', XXI-f' , XXI-g', XXI-h', XXII-a', XXII-b', XXIII-a', XXIII-b', XXIV-a', XXIV-b', XXV- a', XXV-b', XXVI-a' or XXVI-b' where R2 is -N(R)C(O)R, N(R)C(O)Cy2, -N(R)Cy2o Cy2 . In some embodiments, the present invention provides a compound of one of the formulas XVI-a, XVI-b, XVI-c, XVII-a, XVII-b, XVIII-a, XVIII—b, XIX-a, XIX -b, XX-a, XX-b, XXI-a, XXI-b, XXI-c, XXI-d, XXI-e, XXI-f, XXI-g, XXI-h, XXII-a, XXII-b, XXIII-a, XXIII-b, XXIV-a, XXIV-b, XXV- a, XXV-b, XXVI-a, XXVI-b, XVI', XVI”, XVI-a', XVI-b', XVI-c', XVII-a', XVII-b', XVIII-a', XVIII-b', XIX-a', XIX-b', XX-a', XX-b', XXIa', XXI-b', XXI-c', XXI-d', XXI-e', XXI- f', XXI-g', XXI-h', XXII-a', XXII-b', XXIII-a', XXIII-b', XXIV-a', XXIV-b', XXV-a', XXV- b', XXVI-a' or XXVI-b' where R2 is -N(H)C(O)R, -N(H)C(O)Cy2, -NÍHjCy2o Cy2. In some embodiments, the present invention provides a compound of one of the formulas XVI-a, XVI-b, XVI-c, XVII-a, XVII-b, XVIII-a, XVIII-b, XIX-a, XIX -b, XX- a, XX-b, XXI-a, XXI-b, XXI-c, XXI-d, XXI-e, XXI-f, XXI-g, XXI-h, XXII-a, XXII-b, XXIII-a, XXIII-b, XXIV-a, XXIV-b, XXV-a, XXV-b, XXVI-a, XXVI-b, XVI', XVI”, XVI-a', XVI-b ', XVI-c', XVII-a', XVII-b', XVIII-a', XVIII-b', XIX-a', XIX-b', XX-a', XX-b', XXI-a ', XXI-b', XXI-c', XXI-d', XXI-e', XXI-f', XXI-g', XXI- h’, XXII-a’, XXII-b’, XXIII-a’, XXIII-b’, XXIV-a’, XXIV-b’, XXV-a’, XXV-b’, XXVI- a' or XXVI-b' where R2 is -N(H)C(O)R, -N(H)C(O)Cy2o -NíHJCy2. In some embodiments, the present invention provides a compound of one of the formulas XVI-a, XVI-b, XVI-c, XVII-a, XVII-b, XVIII-a, XVIII-b, XIX-a, XIX -b, XX-a, XX-b, XXI-a, XXI-b, XXI-c, XXI-d, XXI-e, XXI-f, XXI-g, XXI-h, XXII-a, XXII-b , XXIII-a, XXIII-b, XXIV-a, XXIV-b, XXV-a, XXV-b, XXVIa, XXVI-b, XVI', XVI”, XVI-a', XVI-b', XVI-c ', XVII-a', XVII-b', XVIII-a', XVIIIb', XIX-a', XIX-b', XX-a', XX-b', XXI-a', XXI-b', XXI-c', XXI-d', XXI-e', XXI-f', XXI-g', XXI-h', XXII-a', XXII-b', XXIII-a', XXIII-b', XXIV-a', XXIV-b', XXV-a', XXV-b', XXVI-a' or XXVI-b' where R2 is -N(H)C(O)R. In some embodiments, the present invention provides a compound of one of the formulas XVI-a, XVI-b, XVI-c, XVII-a, XVII-b, XVIII-a, XVIII-b, ΧΙΧ-a, XlX -b, XX-a, XX-b, XXI-a, XXI-b, XXI-c, XXI-d, XXI-e, XXI-f, XXI-g, XXI-h, XXII-a, XXII-b, XXIII- a, XXIII-b, XXIV-a, XXIV-b, XXV-a, XXV-b, XXVI-a, XXVI-b, XVI’, XVI”, XVI-a’, XVI-b’, XVI-c’, XVII-a’, XVII-b’, XVIII—a’, XVIII-b’, XIX-a’, XIX-b’, XX-a’, XX-b’, XXI-a’, XXI-b’, XXI-c’, XXI-d’, XXI-e’, XXI-f’, XXI-g’, XXI-h’, XXII-a’, XXII-b’, XXIII-a’, XXIII-b’, XXIV-a’, XXIV-b’, XXV-a’, XXV-b’, XXVI-a' or XXVI-b' where R2 is O or O. In some embodiments, the present invention provides a compound of one of the formulas XVI-a, XVI-b, XVI-c, XVII-a, XVII -b, XVIII-a, XVIII-b, XIX-a, XIXb, XX-a, XX-b, XXI-a, XXI-b, XXI-c, XXI-d, XXI-e, XXI-f, XXI -g, XXI-h, XXIIa, XXII-b, XXIII-a, XXIII-b, XXIV-a, XXIV-b, XXV-a, XXV-b, XXVI-a, XXVI-b, XVI’, XVI”, XVI-a’, XVI-b’, XVI-c’, XVII-a’, XVII-b’, XVIII-a’, XVIII-b’, XIX-a’, XIX-b’, XX-a’, XX-b’, XXI-a’, XXI-b’, XXI-c’, XXI-d’, XXI-e’, XXI-f’, XXI-g’, XXI-h’, XXII-a’, XXII-b’, XXIII-a’, XXIII-b’, XXIV-a’, XXIV-b’, XXV-a’, XXV-b’, XXVI-a' or XXVI-b' where R2 is -N(H)Cy2, where Cy2 is selected from the Exemplary compounds of the invention are set out in Table 1 below. Table 1. Example compounds Compound 1-1 Structure EITHER / N-N \ I-2 \\ / N-N \ I-3 EITHER / N-N \ I-4 / N-N \ 1-6 1-7 1-8 / Ν-Ν \ Ν-Ν \ ζ Ν-Ν \ Ν-Ν \ Yo 1-10 1-11 1-12 Ν-Ν Ν-Ν Ν-Ν Ν-Ν \ 1-14 1-15 1-16 Yo 1-21 Ι-22 Ι-23 Ι-24 1-25 1-26 1-27 EITHER / N-N \ 1-28 1' / N-N \ 1-29 1-30 1-31 Ι-32 Ι-33 1-34 1-35 1-36 1-37 1-38 1-39 1-40 1-41 I—42 I—43 I—44 EITHER I—45 1-46 1-47 1-48 1-49 1-50 1-51 Ι-52 Ν=Ν Ι-53 Ι-54 Ν-Ν / Ι-55 100 Ι-56 Ι-57 / Ν-Ν / Ι-58 Ν-Ν / Ι-59 101 Ι-60 1-61 Ι-62 Ι-63 N-N / N-N Ι-64 102 Ι-65 Ι-66 1-67 1-68 1-69 Ν-Ν \ 103 1-70 1-71 1-72 1-73 1-74 1-75 i i 104 EITHER 1-81 105 Ι-82 Ι-83 1-84 1-85 1-86 1-87 106 Ι-88 Ι-89 Ι-90 1-91 Ι-92 Ό Ι-93 107 Ι-94 Ι-95 Ι-96 Ι-97 Ι-98 1-99 108 1-100 1-101 1-102 1-103 1-104 109 1-105 1-106 1-107 1-108 1-109 1-110 110 Γ 1-111 1-112 1-113 1-114 1-115 1-116 111 φ 1-118 1-119 112 1-122 1-123 1-124 1-125 1-126 113 1-127 1-128 1-129 1-130 1-131 Yo 114 1-132 1-133 1-134 1-135 1-136 1-137 1-138 1-139 1-140 1-142 115 1-143 116 1-144 1-145 1-146 1-147 1-148 117 1-149 1-150 1-151 1-152 1-153 Γ118 1-154 1-155 1-156 1-157 1-158 V / 1-159 N-N \ Yo 119 1-160 1-161 1-162 1-163 1-164 CL 1-165 120 1-166 1-167 1-168 1-169 1-170 1-171 121 1-172 1-173 1-174 1-175 1-176 \ 122 1-177 1-178 1-179 1-180 1-181 Yo 123 1-182 1-183 1-184 1-185 1-186 1-187 124 1-188 1-189 1-190 1-191 1-192 1-193 125 1-194 1-195 1-196 1-197 1-198 1-199 £126 I—200 1-201 I—202 Ι-203 I—204 I—205 Γ; 127 I—206 1-207 1-208 1-209 1-210 1-211 128 1-212 1-213 1-214 1-215 1-216 Yo 1-217 129 1-218 1-219 I-220 1-221 I-222 Ό I-223 130 Ι-224 Ι-225 Ι-226 Ι-227 Ι-228 CL 131 Yo Ι-229 Ι-230 1-231 Ι-232 Ι-234 132 Ι-235 Ι-236 Ι-237 Ι-238 Ι-239 Ι-240 133 1-241 Exemplary compounds of the invention are set out in Table 2 below. Table 2. Example compounds 134 VIII—3 VIII—4 VIII-5 VIII—6 135 VIII—7 VIII—8 VIII—9 VIII-10 136 VIII—11 VIII—12 \ VIII—13 VIII—14 137 VIII—15 VIII—16 you Exemplary compounds of the invention are set out in Table 3 below. Yo 138 Table 3. Example compounds Compound XVI-1 XVI-2 XVI—3 XVI—4 Structure Or faith |g. Yo 139 In some embodiments, the present invention provides a compound set forth in Table 1 above or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a pharmaceutical composition comprising a compound set forth in Table 1 above or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, excipient or diluent. In some embodiments, the method employs a compound set forth in Table 2 above or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a compound set forth in Table 2 above or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a pharmaceutical composition comprising a compound set forth in Table 2 above or a salt thereof. 140 pharmaceutically acceptable, together with a pharmaceutically acceptable carrier, excipient or diluent. In some embodiments, the method employs a compound set forth in Table 3 above or one of its pharmaceutically acceptable salts. In some embodiments, the present invention provides a compound set forth in Table 3 above or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a pharmaceutical composition comprising a compound set forth in Table 3 above or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, excipient or diluent. Without wishing to be bound by any particular theory, it is believed that the proximity of an inhibitory compound or pendant moiety of an inhibitory compound to the water of interest facilitates the displacement or disruption of that water by the inhibitory compound or pendant moiety of a compound. inhibitor. In some embodiments, a water molecule displaced or disrupted by an inhibitory compound or pendant moiety of an inhibitory compound is an unstable water molecule. In certain embodiments, the method employs a complex comprising TYK2 and an inhibitor, wherein at least one unstable water of TYK2 is displaced or disrupted by the inhibitor. In some embodiments, at least two selected unstable waters are displaced or disrupted by the inhibitor. 4. General methods of delivery of the present compounds The compounds of this invention can be prepared or isolated by synthetic and / or semisynthetic methods known to those skilled in the art. 141 for analogous compounds and by methods described in detail in the examples herein. In some embodiments, compounds of formula I are prepared according to the following general procedure, depicted in Scheme 1. Scheme 1. Synthesis of compounds of formula I. In some embodiments, where L1 is NH, the intermediates of the formula Cy1-NH2 are prepared according to the methods described in WO 2014074660A1, WO 2014074661A1 and WO 2015089143A1, each of which is incorporated herein by reference. In some embodiments, compounds of formula Vllll are prepared according to the following general procedure, depicted in Scheme 2. Scheme 2. Synthesis of compounds of formula VIII. V-T Br Cl n-BuLi B(OiPr)3 ν··ϊ Br—Cy3 Pd (cat.) Υχ S-1 ΧΥ^Β(ΟΗ)2 Cl S-2 Cy1-[_1-H S-3 Y YXYkCy3 Cy1-L1 In some embodiments, where L1 is NH, the intermediates of the formula Cy1-NH2 are prepared according to the methods described in the 142 documents WO 2014074660A1, WO 2014074661A1 and WO 2015089143A1, each of which is incorporated herein by reference. In some embodiments, compounds of formula XXIV-b are prepared according to the following general procedure, represented in the Scheme 3. Scheme 3. Synthesis of compounds of formula XXIV-b. wherein each of X, L1 and Cy1 is as defined above and in the present embodiments, alone and in combination. 5. Uses, formulation and administration Pharmaceutically acceptable compositions According to another embodiment, the invention provides a composition comprising a compound of this invention or one of its pharmaceutically acceptable derivatives or a pharmaceutically acceptable carrier, adjuvant or vehicle. The amount of compound in compositions of this invention is effective to measurably inhibit a TYK2 protein kinase or one of its mutants, in a biological sample or in a patient. In certain embodiments, the amount of compound in the compositions of this invention is such that it is effective to measurably inhibit a TYK2 protein kinase or one of its mutants, in a 143 biological sample or in a patient. In certain embodiments, a composition of this invention is formulated for administration to a patient in need of such composition. In some embodiments, a composition of this invention is formulated for oral administration to a patient. The term "patient" as used herein means an animal, preferably a mammal and, more preferably, a human. 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 may be used in the compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as, for example, human serum albumin, buffering substances such as, for example, phosphates, glycine, sorbic acid, potassium sorbate, mixtures of partial glycerides, mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as, for example, protamine sulfate, disodium hydrogen phosphate, hydrogen phosphate potassium, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene block polymers—polyoxypropylene, polyethylene glycol and lanolin. A "pharmaceutically acceptable derivative" means any salt, ester, salt of an ester or other non-toxic derivative of a compound of this invention after administration to a patient, is capable of providing, either directly or indirectly, a compound of this invention. invention or one of its metabolites or residues of inhibitory action. 144 As used herein, the term one of its metabolites or residues of inhibitory action means that one of its metabolites or residues is also an inhibitor of a TYK2 protein kinase or one of its mutants. The compositions of the present invention can be administered orally, parenterally, by inhaled spray, topically, rectally, nasally, buccally, 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 an aqueous or oleaginous suspension. These suspensions can be formulated according to techniques known in the art using appropriate dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a parenterally acceptable non-toxic diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution. Furthermore, sterile fixed oils are conventionally used as a solvent or suspension medium. For this purpose, any soft fixed oil can be used including synthetic mono- or di-glycerides. Fatty oils, such as oleic acid and its glyceride derivatives, are useful in the preparation of injectables, as are pharmaceutically acceptable natural oils, such as olive oil or castor oil, especially their versions. polyoxyethylated. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as, for example, 145 carboxymethylcellulose or similar dispersing agents frequently used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other frequently used surfactants, such as, for example, Tweens, Spans and other emulsifying agents or bioavailability enhancers frequently used in the manufacture of solid, liquid or other pharmaceutically acceptable dosage forms may serve the purposes of the formulation. The pharmaceutically acceptable compositions of this invention may be administered orally in any orally acceptable dosage form including, but not limited to, capsules, tablets, suspensions or aqueous solutions. In the case of tablets for oral use, frequently used carriers include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in capsule form, useful diluents include lactose and dehydrated corn starch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents can be added as well. Alternatively, the pharmaceutically acceptable compositions of this invention may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritant excipient that is solid at room temperature but liquid at rectal temperature and will consequently melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols. The pharmaceutically acceptable compositions of this invention can also be administered topically, especially when the goal of the 146 Treatment includes areas or organs easily accessible by topical application, including diseases of the eye, skin or lower intestinal tract. Suitable topical formulations are easily prepared for each of these areas or organs. Topical application to the lower intestinal tract can be effected via a rectal suppository formulation (see text above) or with an appropriate enema formulation. Topical transdermal patches may also be used. For topical applications, the pharmaceutically acceptable compositions can be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Topically administered carriers of compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the provided pharmaceutically acceptable compositions may be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. As for ophthalmic use, the provided pharmaceutically acceptable compositions may be formulated as micronized suspensions in sterile, pH-adjusted, isotonic saline or, preferably, as solutions in sterile, pH-adjusted, isotonic saline, or with or without preservatives such as, for example, example, benzalkonium chloride. Alternatively, for ophthalmic uses, pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum. 147 φ The pharmaceutically acceptable compositions of this invention may further be administered by nasal spray or inhalation. Said compositions are prepared according to techniques widely known in pharmaceutical formulation technology and can be prepared as solutions in saline, using benzyl alcohol or other suitable preservatives, absorption promoters to improve bioavailability, fluorocarbons and / or other conventional agents. solubilization or dispersion. Most preferably, the pharmaceutically acceptable compositions of this invention are formulated for oral administration. These formulations can be administered with or without food. In some embodiments, the pharmaceutically acceptable compositions of this invention are administered without food. In other embodiments, the pharmaceutically acceptable compositions of this invention are administered with food. The amount of compounds of the present invention that can be combined with the carrier materials to produce a composition in a single dose form will vary depending on the host treated, the particular mode of administration. Preferably, the compositions provided should be formulated so that a dose of between 0.01 - 100 mg / kg body weight / day of the inhibitor can be administered to a patient receiving these compositions. It should also be understood that a specific dosage and treatment regimen for any particular patient will depend 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 and the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound of the present invention in the composition will also depend on the particular compound in the composition. 148 Uses of pharmaceutically acceptable compounds and compositions The compounds and compositions described herein are generally useful for the inhibition of the kinase activity of one or more enzymes. In some embodiments, the kinase inhibited by the compounds and methods of the invention is TYK2. TYK2 is a member of the nonreceptor tyrosine kinase 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 integral to cytokine signaling. TYK2 associates with the cytoplasmic domain of type I and II cytokine receptors, as well as with type I and II interferon receptors, and is activated by biological receptors upon cytokine binding. Cytokines involved in TYK2 activation include interferons (e.g., IFN-α, IFN-β, IFN-κ, IFN-δ, IFN-ε, IFN-t, IFN-ω, and IFN-ζ (also known as limitin) and interleukins (e.g., IL-4, IL-6, IL-10, IL-11, IL-12, IL-13, IL-22, IL-23, IL-27, IL-31 , oncostatin M, neutrophil ciliary factor, cardiotrophin 1, cardiotrophin-like cytokine and LIF). Velásquez 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-^ receptor components”, Science (1994) 263:92; Finbloom et al., “IL-10 induces the tyrosine phosphorylation of Tyk2 and Jak1 and the differential assembly of Statl 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 Kak2 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 149 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—12Rp1 and a novel cytokine receptor subunit, IL-23R,” J. Immunol. (2002) 168:5699. Activated TYK2 then goes on to phosphorylate other signaling proteins such as members of the STAT family, which includes STAT1, STAT2, STAT4 and STAT6. Activation of TYK2 by IL-23 has been linked to inflammatory bowel disease (IBD), Crohn's Disease, and Ulcercans Colitis. Duerr et al., “A Genome-Wide 10 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 Behpet'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 trough 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 Behpet's disease", Nat. Genet. (2010) 42:698-702. A genome-wide association study of 2,622 individuals 20 with psoriasis identified associations 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. 150 TYK2 also plays a role in respiratory diseases such as asthma, COPD (Chronic Obstructive Pulmonary Disease), lung cancer and cystic fibrosis. GCH (Goblet cell hyperplasia) and mucosal hypersecretion are mediated by IL-13-mediated 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. Decreased TYK2 activity leads to protection of joints against collagen antibody-induced arthritis, which is a model of human rheumatoid arthritis. Mechanistically, decreased Tyk2 activity reduced the production of Th1 / Th17-related proteins and matrix metalloproteases and other markers of inflammation. 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. TYK2 knockout mice showed complete resistance to experimental autoimmune encephalitis (EAE, an animal model of multiple sclerosis (MS)), without CD4 T cell infiltration in the spinal cord, compared with controls, suggesting that TYK2 is essential for the development of CD4-mediated pathogenic disease in multiple sclerosis. 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) 183:75397546. This corroborates previous studies linking increased TYK2 expression with vulnerability to multiple sclerosis. Ban et al., “Replication analysis identifies TYK2 as a multiple sclerosis susceptibility factor,” Eur J. Hum. Genet. (2009) 17:1309-1313. Loss of functional mutation in TYK2 leads to 151 © decreased demyelination and increased remyelination of neurons, which also suggests an important role for TYK2 inhibitors in the treatment of MS and other CNS demyelination disorders. TYK2 is the only common signaling messenger for both IL-12 5 and IL-23. TYK2 knockout reduced BSA-mediated footpad thickness infection, imiquimoda-induced psoriasis-like skin inflammation, and colitis induced by dextran sulfate sodium or 2,4,6-trinitrobenzenesulfonic acid. in mice. Joint linkage studies and association studies of various type I IFN signaling genes with systemic lupus erythematosus (SLE, an autoimmune disease), showed a strong and significant correlation between loss of function mutations with respect to TYK2 and a decreased prevalence of SLE in families with 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. Genome-wide association studies 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”, PLoS Genetics (2011)7(10):e 1002341. TYK2 has been shown to play an important role in maintaining tumor surveillance and TYK2 knockout mice show a compromised cytotoxic response to T cells and accelerated tumor development. However, these effects were linked to efficient suppression of natural killer (NK) and cytotoxic T lymphocytes, suggesting that TYK2 inhibitors would be highly suitable for the treatment of autoimmune disorders or immune rejection. transplants. Yeah 152 While other members of the JAK family such as JAK3 have been suggested to have similar roles in the immune system, TYK2 has been suggested to be a superior target due to its involvement in a smaller and more closely related number of immune pathways. signaling, which leads to 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. However, and paradoxically with respect to the reduced surveillance of tumors observed by Simma et al., studies in T-cell acute lymphoblastic leukemia (T-ALL) indicate that T-cell ALL is highly dependent on IL-10 via TYK2 via STAT1-mediated signal transduction to maintain cancer cell survival through upregulation of the anti-apoptotic protein BCL2. Knockdown of TYK2, but not other JAK family members, reduced cell growth. Specific activating mutations corresponding to TYK2 that promote cancer cell survival include those corresponding to the FERM domain (G36D, S47N and R425H), the JH2 domain (V7311) and the kinase domain (E957D and R1027H). However, it was also identified that the kinase function of TYK2 is necessary for greater survival of cancer cells, since TYK2 enzymes that present kinase-dead mutations (M978Y or M978F) in addition to an activating mutation (E957D) resulted in an inability to transform. Sanda et al. “TYK2-STAT1-BCL2 Pathway Dependence in T-Cell Acute Lymphoblastic Leukemia”, Cancer Disc. (2013) 3(5):564-577. Therefore, it has been suggested that selective inhibition of TYK2 is a suitable target for patients with tumors addicted to IL-10 and / or BCL2, such as 153φ such as 70% of adult T-cell leukemia cases. Fontan et al. “Discovering What Makes STAT Signaling TYK in T-ALL”, Cancer Disc. (2013) 3:494-496. TYK2-mediated signaling from STAT3 has also been shown to mediate neuronal cell death caused by amyloid-β peptide (Αβ). Decreased TYK2 phosphorylation of STAT3 after Αβ administration led to decreased neuronal cell death and increased STAT3 phosphorylation observed in the postmortem brains of Alzheimer's patients. Wan et al. “Tyk / STAT3 Signaling Mediates β10 Amyloid-induced Neuronal Cell Death: Implications in Alzheimer’s Disease”, J. Neurosci. (2010) 30(20):6873-6881. Inhibition of JAK-STAT signaling pathways also mediates hair growth and reversal of hair loss associated with alopecia areata. Xing et al., “Alopecia areata is driven by cytotoxic T 15 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. Therefore, compounds that inhibit TYK2 activity are beneficial, especially those with selectivity toward JAK2. Such compounds should provide a pharmacological response that pharmacologically treats one or more of the conditions described herein without the side effects associated with JAK2 inhibition. While TYK2 inhibitors are known in the art, there is a continuing need to provide novel inhibitors having more effective or pharmacologically relevant properties. For example, compounds provided with increased activity, selectivity with respect to other JAK kinases (especially JAK2) and ADMET 154 © (absorption, distribution, metabolism, excretion and / or toxicity properties). Therefore, in some embodiments, the present invention provides TYK2 inhibitors that exhibit selectivity with respect to JAK2. The activity of a compound used in this invention as an inhibitor of TYK2, or one of its mutants, can be taught in vitro, in vivo or in a cell line. In vitro assays include assays that determine the inhibition of either phosphorylation activity and / or the subsequent functional consequences of the ATPase activity of activated TYK2 or one of its mutants. Alternatively, in vitro assays quantify the ability of the inhibitor to bind to TYK2. Inhibitor binding can be measured by radiolabeling the inhibitor before binding, isolating the inhibitor / TYK2 complex, and determining the amount of bound radiolabel. Alternatively, inhibitor binding can be determined by running a competition experiment in which new inhibitors are incubated with TYK2 bound to known radioligands. Representative in vitro and in vivo assays useful for testing a TYK2 inhibitor include those described and disclosed, for example, each of which is incorporated herein by reference in its entirety. Detailed conditions for testing a compound used in this invention as an inhibitor of TYK2 or one of its mutants are set out in the following examples. 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 of its symptoms, as described in the present. In some embodiments, the treatment may be administered after the development of one or more symptoms. In some embodiments, the term "treatment" includes preventing or stopping the progression of a disease or disorder. In other embodiments, the treatment may be 155 administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of genetic or other susceptibility factors). Treatment can also be continued after the elimination of symptoms, for example to prevent or delay their recurrence. 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. Therefore, in certain embodiments, the present invention provides a method of treating a TYK2-mediated disorder comprising the step of administering to a patient in need thereof a compound of the present invention or a pharmaceutically acceptable composition of the compound. . As used herein, the term “TYK2-mediated disorders, diseases and / or conditions, as used herein, refers to any disease or other deleterious condition in which TYK2 or one of its mutants is known to They have a role. Accordingly, another embodiment of the present invention relates to the treatment or reduction of the severity of one or more diseases in which TYK2 or one of its mutants is known to play an important role. Such TYK2-mediated disorders include without limitation: autoimmune disorders, inflammatory disorders, proliferative disorders, endocrine disorders, neurological disorders, and transplant-associated disorders. In some embodiments, the present invention provides a method of treating one or more disorders, wherein the disorders are selected from autoimmune disorders, inflammatory disorders, proliferative disorders, endocrine disorders, neurological disorders, and disorders associated with the 156 transplant, said method comprising administering to a patient in need thereof, a pharmaceutical composition comprising an effective amount of a compound of the present invention or one of its pharmaceutically acceptable salts. In some embodiments, the disorder is an autoimmune disorder. In some embodiments, the disorder is selected from type 1 diabetes, systemic lupus erythematosus, multiple sclerosis, psoriasis, Behpet's disease, POEMS syndrome, Crohn's disease, ulcerative colitis and inflammatory bowel disease. In some embodiments, the disorder is an inflammatory disorder. In some embodiments, the inflammatory disease is rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis, hepatomegaly, Crohn's disease, ulcerative colitis, inflammatory bowel disease. 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 review is T-cell leukemia. In some embodiments, the T-cell leukemia is T-cell acute lymphoblastic leukemia (T-ALL). In some embodiments the proliferative disorder is polycythemia vera, essential myelofibrosis, or thrombocytosis. 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. 157 In some embodiments, the disorder is a neurological disorder. In some embodiments, the neurological disorder is Alzheimer's disease. In some embodiments the proliferative disorder is associated with one or more activating mutations of TYK2. In some embodiments, the activating mutation in TYK2 is a mutation corresponding to the FERM domain, the JH2 domain, or the kinase domain. In some embodiments the activating mutation in TYK2 is selected from G36D, S47N, R425H, V731I, E957D and R1027H. In some embodiments, the disorder is associated with a transplant. In some embodiments the transplant-associated disorder is transplant rejection or graft vs. graft disease. host. 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 related to 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. The inversion compounds are also useful in the treatment of inflammatory or allergic skin conditions, for example, psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis, urticaria , bullous pemphigus, lupus erythematosus, systemic lupus erythematosus, pemphigus vulgaris, pemphigus 25 foliaceus, paraneoplastic pemphigus, pydermolysis hullosa acquisita, acne vulgaris and other inflammatory or allergic skin conditions. 158 The compounds of the invention can also be used for the treatment of other diseases or conditions, such as diseases or conditions that have an inflammatory component, for example, the treatment of 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 disease in which autoimmune reactions are involved or which have an autoimmune component or etiology, including autoimmune hematological disorders (for example, hemolytic anemia, aplastic anemia, pure erythrocyte anemia and idiopathic thrombocytopenia), systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome, idiopathic sputum, autoimmune inflammatory bowel disease (e.g. , ulcerative colitis and Crohn's disease), irritable bowel syndrome, celiac disease, periodontitis, hyaline membrane disease, kidney disease, glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine ophthalmopathy, Grave's disease, sarcoidosis, alveolitis, chronic hypersensitive pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), Sjógren's syndrome, keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, cryopyrin-associated periodic syndrome, nephritis, vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis (with and without nephrotic syndrome, for example, including idiopathic nephrotic syndrome or nephropathic change), chronic granulomatous disease, endometriosis, leptospirosis kidney disease, glaucoma, retinal disease, aging, headache, complex regional pain, pain syndrome, cardiac hypertrophy, loss of muscle mass, catabolic disorders, obesity, delayed 159 fetal growth, hypercholesterolemia, heart disease, chronic heart failure, mesothelioma, anhydrous ecodermal dysplasia, Behget's disease, pigmentary incontinence, Paget's disease, pancreatitis, hereditary periodic fever, asthma (allergic and non-allergic, mild, moderate, severe, bronchial and exercise-induced), acute lung injury, acute respiratory syndrome, eosinophilia, hypersensitivity, anaphylaxis, nasal sinusitis, ocular allergy, silica-induced diseases, COPD (damage reduction, airway inflammation, bronchial hyperreactivity, remodeling or progression of the disease), lung disease, cystic fibrosis, acid-induced lung injury, pulmonary hypertension, polyneuropathy, cataracts, muscle inflammation in conjunction with systemic sclerosis, inclusion of myomasitis corporis, myasthenia gravis, thyroiditis, Addison's disease, lichen planus, diabetes type 1 or type 2 diabetes, 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, fibrositis, gastritis, gastroenteritis, Henoch-Schonlein purpura, hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myocarditis myelitis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, mumps, 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. In some embodiments, the inflammatory disease that can be treated according to the methods of this invention is selected acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, 160 juvenile rheumatoid arthritis, systemic juvenile idiopathic arthritis (SJIA), cryopyrin-associated periodic syndrome (CAPS) and osteoarthritis. In some embodiments, the inflammatory disease that can be treated according to the methods of this invention is a disease mediated by Th1 or Th17. In some embodiments the Th17-mediated disease is selected from systemic lupus erythematosus, multiple sclerosis and inflammatory bowel disease (including Crohn's disease and sedative colitis). In some embodiments the inflammatory disease that can be treated according to the methods of this invention is selected from Sjogren's syndrome, allergic disorders, osteoarthritis, eye conditions such as ocular allergy, conjunctivitis, keratoconjunctivitis sicca and vernal conjunctivitis and diseases that affect the nose such as allergic rhinitis. On the other hand, the invention provides the use of a compound according to the definitions given herein or of a pharmaceutically acceptable salts, hydrates or formats, for the preparation of a medicament for the treatment of an autoimmune disorder, a disorder inflammatory disorder, a proliferative disorder, or a disorder that commonly occurs in connection with transplants. Combined therapies Depending on the particular condition or disease to be treated, additional therapeutic agents, which are normally administered to treat said condition, may be administered in combination with the compounds and compositions of this invention. As used herein. Additional therapeutic agents that are normally administered to treat a disease or 161 conditions, in particular, are known to be appropriate for the disease or condition being treated. In certain embodiments, a provided combination or composition thereof is administered in combination with another therapeutic agent. Examples of agents with which the combinations of this invention may be combined include without limitation: treatments for Alzheimer's disease such as Aricept® and Excelon®; HIV treatments such as ritonavir; treatments for Parkinson's disease such as LDOPA / carbidopa, entacapone, ropinrol, pramipexole, bromocriptine, pergolide, trihexependyl and amantadine; agents to treat multiple sclerosis (MS) such as beta interferon (e.g., Avonex® and Rebif®), Copaxone® and mitoxantrone; asthma treatments such as albuterol and Singulair®; agents for treating schizophrenia such as ziprexa, risperdal, seroquel and haloperidol; anti-inflammatory agents such as corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide and sulfasalazine; immunomodulatory and immunosuppressive agents such as cyclosporine, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophosphamide, azathioprine and sulfasalazine; neurotrophic factors such as acetylcholinesterase inhibitors; MAO inhibitors, interferons, anticonvulsants, ion channel blockers, riluzole and anti-Parkinson's agents, agents for treating cardiovascular diseases such as beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers and statins; agents for treating liver diseases such as corticosteroids, cholestyramine, interferons and antiviral agents; agents to treat blood disorders such as corticosteroids, antileukemic agents and growth factors; agents that prolong or improve pharmacokinetic properties such as cytochrome P450 inhibitors (i.e. 162 φ i.e. metabolic breakdown inhibitors) and CYP3A4 inhibitors (e.g. ketokenozole and ritonavir) and agents to treat immunodeficiency disorders such as gamma globulin. In certain embodiments, the combination therapies of the present invention or one of its pharmaceutically acceptable compositions are administered in combination with a monoclonal antibody or an siRNA therapeutic agent. These additional agents may be administered separately from a combination therapy provided, as part of a multiple dosing regimen. Alternatively, those agents may be part of a single dosage form, mixed together with a compound of this invention in a single composition. If supported as part of a multiple dosing region, the two active agents may be delivered simultaneously, sequentially, or within a time interval separated from each other typically within five hours of each other. As used herein, the terms combination, combined, and related terms refer to the simultaneous or sequential administration of therapeutic agents in accordance with this invention. For example, a combination of the present invention may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together so as to form a single unit dosage form. The amount of additional therapeutic agent present in the compositions of this invention will not be greater than the amount that would normally be administered in a composition comprising said therapeutic agent as an active agent. It is preferable that the amount of the additional therapeutic agent in which the compositions described herein will vary from about 163 50% to 100% of the amount normally present in a composition comprising said agent as the only therapeutically active agent. In one embodiment, the present invention provides a composition comprising a compound of formula I, VIII or XVI' and one or more additional therapeutic agents. The therapeutic agent may be administered concomitantly with a compound of formula I, VIII or XVI' or may be administered before or after administration of a compound of formula I, VIII or XVI'. Suitable therapeutic agents are described in detail below. In certain embodiments, a compound of formula I, VIII or XVI' may be administered for up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5, hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours or 18 hours before the therapeutic agent. In other embodiments, a compound of formula I, VIII or XVI' may be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5, hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours or 18 hours after the therapeutic agent. In another embodiment, the present invention provides a method of treating an inflammatory disease, disorder or condition whereby a compound of formula I, VIII or XVI' and one or more additional therapeutic agents are administered to the patient in need. Such additional therapeutic agents may be small molecules or recombinant biological agents and include, for example, acetaminophen, non-spheroid anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, colchicine (Colcrys®), corticosteroids. such as prednisone, prednisolone, methylprednisolone, hydrocortisone and the like, probenecid, allopurinol, febuxostat (Uloric®), sulfasalazine (Azulfidine®), antimalarial agents 164 © such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), methotrexate (Rheumatrex®), gold salts such as gold thioglucose (Solganal®), gold thiomalate (Myochrysine®) and auranofin (Ridaura®), D-penicillamine (Depen® or Cuprimina®), azathioprine (Imuran®), cyclophosphamide (Cytoxan®), chlorambucil 5 (Leukeran®), cyclosporine (Sandimmune®), leflunomide (Arava®) and “anti-agents” TNF” such as etanercept (Enbrel®), infliximab (Remicade®), golimumab (Simponi®), certolizumab pegol (Cimzia®) and adalimumab (Humira®), “anti-IL-1 agents” such as anakinra (Kineret®) and rilonacept (Arcalyst®), canakinumab (llaris®), anti-Jak inhibitors such as tofacitinib, antibodies such as rituximab (Rituxan®), “anti-T cell agents” such as abatacept (Orencia®), “anti-IL” agents -6” such as tocilizumab (Actemra®), diclofenac, cortisone, hyaluronic acid (Sinvisc® or Hialgan®), monoclonal antibodies such as tanezumab, anticoagulants such as heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®), agents antidiarrhea such as diphenoxylate (Lomotil®) and loperamide (Imodium®), bile binding agents such as cholestyramine, alosetron (Lotronex®), lubiprostone (Amitiza®), laxatives such as Milk of Magnesia, polyethylene glycol (MiraLax®), Dulcolax®, Correctol® and Senokot®, anticholinergics or antispasmodics such as dicyclomine (Bentyl®), Singulair®, beta-2 agonists such as albuterol (Ventolín® HFA, Proventil® 20 HFA), levalbuterol (Xopenex®), metaproterenol ( Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®) and formoterol (Foradil®), anticholinergic agents such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), corticosteroids inhaled drugs such as beclomethasone dipropionate (Beclovent®, Qvar® and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmicort®) and flunisolide (Aerobid®), Afviar®, Symbicort®, Dulera® ,cromolin sodium (Intal®), methylxanthines such as theophylline (Theo-Dur®, Theolair®, Slo-bid®, Uniphyl®, 165 Theo-24®) and aminophylline, IgE antibodies such as omalizumab (Xolair®), nucleoside reverse transcriptase inhibitors such as zidovudine (Retrovir®), abacavir (Ziagen®), abacavir / lamivudine (Epzicom®), abacavir / lamivudine / zidovudine (Trizivir®), didanosine (Videx®), emtricitabine (Emtriva®), lamivudine (Epivir®), lamivudine / zidovudine (Combivir®), stavudine (Zerit®), and zalcitabine (Hivid®), non-nucleoside reverse transcriptase inhibitors such as delavirdine (Rescriptor®), efavirenz (Sustiva®), nevirapine (Viramune®) and etravirine (Intelence®), nucleoside reverse transcriptase inhibitors such as tenofovir (Viread®), protease inhibitors such as amprenavir (Agenerase®), atazanavir (Reiataz®), darunavir (Prezista®), fosamprenavir (Lexiva®), indinavir (Crixivan®), lopinavir and ritonavir (Kaletra®), nelfinavir (Viracept®), ritonavir (Norvir®), saquinavir (Fortovase® or Invirase ®) and tipranavir (Aptivus®), entry inhibitors such as enfuvirtide (Fuzeon®) and maraviroc (Selzentry®), integrase inhibitors such as raltegravir (Isentress®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), bortezomib (Velcade®) and dexamethasone (Decadron®) in combination with lenalidomide (Revlimid ®) or any of their combinations. 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, VIII or XVI' and one or more additional therapeutic agents selected from non-spheroid anti-inflammatory drugs ( NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone and the like, sulfasalazine (Azulfidine®), antimalarial agents such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen ®), methotrexate (Rheumatrex®), gold salts such as gold thioglucose (Solganal®), gold thiomalate (Miochrisine®) and auranofin (Ridaura®), D 166 φ penicillamine (Depen® or Cuprimine®), azathioprine (Imuran®), 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 such as anakinra (Kineret®) and rilonacept (Arcalyst®) , antibodies such as rituximab (Rituxan®), “anti-T cell” agents such as abatacept (Orencia®) and “anti-IL-6” agents such as tocilizumab (Actemra®). 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, VIII or XVI' and one or more additional therapeutic agents selected from acetaminophen, non-inflammatory anti-inflammatory drugs. spheroids (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, diclofenac, cortisone, hyaluronic acid (Synvisc® or 15 Hyalgan®), and monoclonal antibodies such as tanezumab. In some embodiments, the present invention provides a method of treating systemic lupus erythematosus comprising administering to a patient in need thereof a compound of formula I, VIII or XVI' and one or more additional therapeutic agents selected from acetaminophen, drugs 20 non-spheroid anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone and the like, antimalarial agents such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®) , cyclophosphamide (Cytoxan®), methotrexate (Rheumatrex®), azathioprine (Imuran®) and 25 anticoagulants such as heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®). 167 In some embodiments, the present invention provides a method of treating Crohn's disease, ulcerative colitis or inflammatory bowel disease comprising administering to a patient in need thereof a compound of formula I, VIII or XVI' and a or more additional therapeutic agents selected from mesalamine (Asacol®) sulfasalazine (Azulfidine®), antidiarrheal agents such as diphenoxylate (Lomotil®) and loperamide (Imodium®), bile acid binding agents such as cholestyramine, alosetron (Lotronex®) , lubiprostone (Amitiza®), laxative agents such as Milk of Magnesia, polyethylene glycol (MiraLax®), Dulcolax®, Correctol® and Senokot® and anticholinergics or antispasmodics such as dicyclomin (Bentyl®), anti-TNF therapies, spheroids and antibiotics such such as Flagyl or ciprofloxacin. In some embodiments, the present invention provides a method of treating asthma comprising administering to a patient in need thereof a compound of formula I, VIII or XVI' and one or more additional therapeutic agents selected from Singulair®, beta agonists -2 such as albuterol (Ventolín® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®) and formoterol ( Foradil®), anticholinergic agents such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), inhaled corticosteroids such as prednisone, prednisolone, beclomethasone dipropionate (Beclovent®, Qvar® and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmicort®), flunisolide (Aerobid®), Afviar®, Symbicort® and Dulera®,cromolin sodium (Intal®), methylxanthines such as theophylline (Theo-Dur®, Theolair®, Slo-bid ®, Uniphyl®, Theo-24®) and aminophylline and IgE antibodies such as omalizumab (Xolair®). 168 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, VIII or XVI' and one or more additional therapeutic agents selected from beta-2 agonists such such as albuterol 5 (Ventolín® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®) and formoterol (Foradil® ), anticholinergic agents such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), methylxanthines such as theophylline (Theo-Dur®, Theolair®, Slo-bid®, Uniphyl®, Theo-24®) and aminophylline, inhaled corticosteroids such as prednisone, prednisolone, beclomethasone dipropionate (Beclovent®, Qvar® and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmicort®), flunisolide (Aerobid®), Afviar®, Symbicort ® and Dulera®. In another embodiment, the present invention provides a method of treating a malignant hematological condition comprising administering to a patient in need thereof a compound of formula I, VIII or XVI' and one or more additional therapeutic agents selected from rituximab (Rituxan® ), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, a BTK inhibitor, a JAK / pan-JAK inhibitor, a PI3K inhibitor, a SYK inhibitor and its combinations. 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, VIII or XVI' and one or more additional therapeutic agents selected from rituximab (Rituxan® ), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, a 169 © hedgehog signaling inhibitor, a BTK inhibitor, an inhibitor of JAK / pan-JAK, a PI3K inhibitor, a SYK inhibitor and their combinations. In another embodiment, the present invention provides a method of treating a malignant hematological condition comprising administering to a patient in need thereof a compound of formula I, VIII or XVI' and an inhibitor of the hedgehog signaling pathway (Hh , hedgehog). In some embodiments, the hematological malignant condition is DLBCL (Ramírez 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 e 10 incorporated herein in its entirety by reference. In another embodiment, the present invention provides a method of treating DLBCL (diffuse large B cell lymphoma), comprising administering to a patient in need thereof a compound of formula I, VIII or XVI' and one or more therapeutic agents additional selected from rituximab 15 (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, hedgehog signaling inhibitor unit and their combinations. In another embodiment, the present invention provides a method of treating multiple melanoma comprising administering to a patient in need thereof a compound of formula I, VIII or XVI' and one or more additional therapeutic agents selected from bortezomib (Velcade® ) and dexamethasone a (Decadron®), a hedgehog signaling inhibitor, a BTK inhibitor, a JAK / pan-Jak inhibitor, a TYK2 inhibitor, a PI3K inhibitor, a SYK inhibitor combined with lenalidomide (Revlimid® ). In another embodiment, the present invention provides a method of treating or attenuating the severity of a disease comprising administering to a patient in need thereof a compound of formula I, VIII or XVI' and an inhibitor 170 of BTK, wherein the disease is selected from inflammatory bowel disease, arthritis, systemic lupus erythematosus (SLE), vasculitis, IT (idiopathic thrombocytopenia purpura), rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis , s, diabetes, myasthenia gravis, 5 Hashimoto's thyroiditis, Ord's thyroiditis, Graves' disease, autoimmune thyroiditis, Sjógren's syndrome, multiple sclerosis, Lime's neuroborreliosis, Guillain-Barre syndrome, disseminated encephalomyelitis, Addison's disease, syndrome opsoclonus-myoclons, ankylosing spondylitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, gastritis, pernicious anemia 10, celiac disease, Goodpasture syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter syndrome, arteritis Takayasu, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia universalis, Behpet's disease, chronic fatigue, dysautonomia, glomerulonephropathy, 15 endometriosis, interstitial cystitis, pemphigus vulgaris, bullous pemphigoid, neuromyotonia, scleroderma, vulvodynia, a disease hyperproliferative, rejection of transplanted organs or tissues. AIDS (Syndrome Acquired Immunodeficiency (also known as HIV), type I diabetes, graft vs. host, transplant, transfusion, anaphylaxis, allergies 20 (for example, allergies to plant pollen, latex, drugs, foods, insect poisons, animal hair, animal dander, mites or cockroach calyx) type I hypersensitivity, conjunctivitis allergic, 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, fibrositis, gastritis, gastroenteritis, 171 φ Henoch-Schonlein purpura, hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, pulmonary interstitial disease, laryngitis, mastitis, meningitis, myelitis myocarditis, myositis, nephritis, oophoritis, 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, proliferative or cell disorder B, e.g., diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, acute lymphocytic leukemia, prolymphocytic B-cell leukemia B, Plasmacytic / Waldenstrom lymphoma macroglobulinemia, splenic marginal zone lymphoma, multiple myeloma (also known as plasma cell myeloma), non-Hodgkin lymphoma, Hodgkin lymphoma, plasmacytoma, extranodal marginal zone, lymphoma of the spleen mantle, mediastinal (thymic) M-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, Burkitt lymphoma / lymphomatoid leukemia or granulomatosis, breast cancer, prostate cancer, or mast cell cancer (e.g., mast cell , mast cell leukemia, systemic mastocytosis), bone cancer, colorectal cancer, pancreatic cancer, bone and joint cancer including without limitation, rheumatoid arthritis, seronegative spondyloarthropathies (including ankylosing spondylitis, psoriatic arthritis, and Reiter's disease), disease Behget's syndrome, Sjógren's syndrome, systemic sclerosis, osteoporosis, bone cancer, bone metastases, a thromboembolic disorder (for example, myocardial infarction, angina pectoris, reocclusion after angioplasty, restenosis after angioplasty, reocclusion after aortocoronary bypass, restenosis after coronary artery bypass grafting, stroke, transient ischemia, a peripheral arterial occlusive disorder, pulmonary embolism, deep vein thrombosis), pelvic inflammatory disease, urethritis, 172 sunburn, sinusitis, pneumonitis, encephalitis, meningitis, myocarditis, nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis, dermatitis, gingivitis, appendicitis, pancreatitis, colocystitis, agammaglobulinemia, psoriasis, allergy, Crohn's disease, irritable bowel syndrome , ulcerative colitis, Sjógren's disease, rejection of graft tissue, hyperacute rejection of transplanted organs, asthma, allergic rhinitis, COPD (chronic obstructive pulmonary disease), autoimmune polyglandular disease (also known as autoimmune polyglandular syndrome), autoimmune alopecia, pernicious anemia , glomerulonephritis, dermatomyositis, multiple sclerosis, scleroderma, vasculitis, autoimmune hemolytic and thrombocytopenic states, Goodpasture syndrome, atherosclerosis, Addison's disease, Parkinson's disease, Alzheimer's disease, diabetes, septic shock, systemic lupus erythematosus (SLE), rheumatoid arthritis , psoriatic arthritis, chronic idiopathic thrombocytopenic purpura, Waldenstrom macroglobulinemia, myasthenia gravis, Hashimoto's thyroiditis, atopic dermatitis, degenerative joint disease, autoimmune hypopituitarism, Guillain-Barre syndrome, Behpet disease, scleroderma, mycosis fungoides, acute inflammatory responses (such as acute respiratory distress syndrome and ischemia / reperfusion injury), and Graves' god. In another embodiment, the present invention provides a method of treating or attenuating the severity of a disease comprising administering to a patient in need thereof a compound of formula I, VIII or XVI' and a PI3K inhibitor, wherein the disease is selected from a cancer, a neurodegenerative disorder, an angiogenic disorder, a viral disease, an autoimmune disease, an inflammatory disorder, a hormone-related disease, conditions related to organ transplantation, immunodeficiency disorders, a bone destructive disorder , one upset 173 proliferative, an infectious disease, a condition associated with cell death, thrombin-induced platelet aggregation, chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), liver disease, pathological immune conditions involving an activation of T cells, a 5 cardiovascular disorder and a central nervous system disorder. In another embodiment, the present invention provides a method of treating or attenuating the severity of a disease comprising administering to a patient in need thereof a compound of formula I, VIII or XVI' and a PI3K inhibitor, wherein the disease selected from benign or malignant tumor, carcinoma or solid tumor of the brain, kidney (for example, renal cell carcinoma (RCC), liver, adrenal gland, bladder, breast, stomach, gastric tumors, ovaries, colon, rectum, prostate , pancreas, lung, vagina, endometrium, cervix, testicles, genitourinary tract, esophagus, larynx, skin, bone or thyroid, sarcoma, glioblastomas, neuroblastomas, multiple myeloma or gastrointestinal cancer, especially colon carcinoma or colorectal adenoma or a tumor of neck and head, epidermal hyperproliferation, psoriasis, prostate hyperplasia, a neoplasm, a neoplasm of an epithelial nature, adenoma, adenocarcinoma, keratocanthoma, squamous cell carcinoma, large cell carcinoma, non-small cell lung carcinoma, lymphomas (including 20 per example, non-Hodgkin's lymphoma (also called Hodgkin's disease), a breast carcinoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma or a leukemia, diseases including Cowden syndrome, Lhermitte-Duclos disease and Bannaian-Zonana syndrome or diseases in which the PI3K / PKB pathway is aberrantly activated, soul of any type or genesis that includes both intrinsic asthma (non-allergic), extrinsic asthma (allergic), moderate asthma, temperate asthma, moderate asthma, severe asthma, bronchial asthma, asthma induced 174 exercise, occupational asthma and asthma induced after bacterial infection, acute lung injury (ALI), acute / adult respiratory distress syndrome (ARDS), chronic obstructive pulmonary airway or lung disease (COPD, COAD or COLD), which including chronic bronchitis or dyspnea associated with it, emphysema, as well as an exacerbation of airway overactivity as a consequence of therapy with other drugs, in particular therapy with other inhaled drugs, bronchitis of any type and genesis including without limitation: acute, arachidic, catarrhal, croup, chronic or phthynoid bronchitis, pneumoconiosis (an inflammatory disease, commonly occupational, of the lungs, frequently accompanied by chronic or acute airway obstruction, and caused by repeated inhalation of dusts ) of any type or genesis, including, for example, aluminosis, anthracosis, asbestosis, calicosis, ptylosis, siderosis, silicosis, tobaccosis and byssinosis, Loffler's syndrome, eosinophilia, pneumonia, Parasitic infestation (particularly metazoan) (which includes tropical eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa (including Churg-Strauss syndrome), eosinophilic granuloma and eosinophil-related disorders affecting the airways caused by a reaction to drugs, psoriasis, contact dermatitis, dermatitis atopic, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis, urticaria, pemphigoid hollosa, lupus erythematosus, pemphigus, epidermolysis hullosa acquisita, conjunctivitis, keratoconjunctivitis sicca and vernal conjunctivitis, diseases affecting the nose including rhinitis allergic and inflammatory disease involving autoimmune reactions or having an autoimmune component or etiology (e.g., hemolytic anemia, aplastic anemia, pure red cell anemia, and idiopathic thrombocytopenia), systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma , Wegener's granulomatosis, 175 dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g. ulcerative colitis and Crohn's disease), endocrine ophthalmopathy, Grave's disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, sclerosis multiplex, primary biliary cirrhosis, uveitis (anterior and posterior), keratoconjunctivitis sicca and vernal keratoconjunctivitis, fibrosis of the interstices of the lungs, psoriatic arthritis and glomerulonephritis (with and without nephrotic syndrome, for example including idiopathic nephrotic syndrome or nominal change nephropathy , restenosis, cardiomegaly, atherosclerosis, myocardial infarction, stroke and congestive heart failure, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease and cerebral ischemia and neurodegenerative disease caused by traumatic injury, glutamate neurotoxicity and hypoxia. In some embodiments the present invention provides a method of treating or attenuating the severity of a disease comprising administering to a patient in need thereof a compound of formula I, VIII or XVI' and a PIK3 inhibitor, wherein the disease is an inflammatory disorder, a proliferative disorder, a neurological disease or associated with transplant. In some embodiments, the disorder is a proliferative disorder, lupus, or lupus nephritis. In some embodiments, the proliferative disease is chronic lymphocytic leukemia, large B-cell lymphoma, Hodgkin's disease, small cell lung cancer, non-small cell lung cancer, myelodysplastic syndrome, a hematologic neoplasm, or a solid tumor. In some embodiments, the present invention provides a method of treating or attenuating the severity of a disease, comprising administering to a patient in need thereof a compound that binds to the domain of 176 a TYK2 pseudokinase (JH2) and a compound that binds to the domain of a TYK2 kinase (JH1). In some embodiments, the disease is an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a transplant-associated disease. In some embodiments the compound that binds to JH1 is a compound of formula I, VIII or XVI'. Other JH2 domain binding compounds include those described in WO 2014074660A1, WO 2014074661A1, WO 2015089143A1, all of which are incorporated herein by reference. JH1 domain binding compounds include those described in WO 2015131080A1, the entirety of which is incorporated herein by reference. The compounds and compositions, according to the method of the present invention, are administered using any amount and any route of administration effective to treat or reduce the severity of a disorder provided above. The exact amount required would vary from subject to subject, depending on the species, the age and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like. The compounds of the invention are preferably formulated in a dosage unit form to facilitate administration and uniform dosage. The term "dose unit form" as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily use of the compounds and compositions of the present invention will be decided by the treating physician within the scope of good medical judgment. The specific effective dose level for any particular patient or organism will depend on a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound used; the specific composition 177 employee; the patient's age, body weight, general condition, sex and diet; the time of administration, the route of administration and the rate of excretion of the specific compound used; the duration of treatment; the drugs used in combination or coincident with the specific compound used and related factors well known in medical techniques. The term "patient" as used herein means an animal, preferably a mammal and most preferably a human. The pharmaceutically acceptable compositions of the present invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as powders, ointments or drops), buccal, as an oral or nasal spray or similar, depending on the severity of the infection being treated. In certain embodiments, the compounds of the invention can be administered orally or parenterally at dosage levels of about 0.01 mg / kg to about 50 mg / kg and preferably from about 0.1 mg / kg to about 25 mg / kg of body weight of the subject per day, once or several times per day, to obtain the desired therapeutic effect. Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, liquid dosage forms may contain inert diluents frequently used in the technology such as water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, acetate. ethyl, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular cottonseed, peanut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and 178 sorbitan fatty acid esters and their mixtures. In addition to inert diluents, oral compositions may also include adjuvants such as, for example, wetting agents, emulsifiers and suspending agents, sweeteners, flavors and perfumes. Injectable preparations, for example, sterile aqueous or oily injectable suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a parenterally acceptable non-toxic diluent or solvent, for example, as a solution in 1,3-butanediol. Suitable vehicles and solvents that can be used include water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as a solvent or suspension medium. For this purpose, any mild fixed oil can be used, including synthetic mono- or diglycerides. Additionally, fatty acids, such as oleic acid and its glyceride derivatives, are useful in the preparation of injectables. Injectable formulations may be sterilized, for example, by filtration through a bacterial retention filter or by incorporation of sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. use. In order to prolong the effect of a compound of the present invention, it is often desired to slow the absorption of the compound from subcutaneous or intramuscular injection. The above can be achieved using a liquid suspension of crystalline or amorphous material with poor solubility in water. The rate of absorption of the compound subsequently depends on its 179 dissolution rate which, in turn, may depend on crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound is achieved by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by molding microencapsulated matrices of the compound in biodegradable polymers such as polylactide—polyglycolide. Depending on the ratio of compound to polymer and the nature of the particular polymer being used, the rate of compounding can be controlled. Examples of other biodegradable polymers include poly(ortho esters) and poly(anhydrides). Depot injectable formulations are also prepared by immobilizing the compound in liposomes or microemulsions that are compatible with body tissues. Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as, for example, cocoa butter, polyethylene glycol or a suppository wax which is solid at room temperature but liquid at body temperature and consequently melt in the cavity of the rectum or vagina and release the active compound. Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as, for example, sodium citrate or dicalcium phosphate and / or a) fillers or extenders such as, for example, 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, for example, 180 glycerol, d) disintegrating agents such as, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate, e) solution retarding agents, such as, for example, paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin clay and bentonite and i) lubricants such as For example, talc, calcium stearate, magnesium stearate, sodium polyethylene glycols, sodium lauryl sulfate and their mixtures. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. Solid compositions of a similar type can also be used as filling materials in soft and hard gelatin capsules using such excipients as lactose or milk sugar as well as 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, for example, enteric coatings and other coatings widely known in pharmaceutical formulation technology. They may optionally contain opacifying agents and may 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 inclusion compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type can be used as filling materials in soft and hard gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The active compounds may be in microencapsulated form with one or more excipients as highlighted above. Dosage Forms 181 Solid forms of tablets, dragees, capsules, pills and granules can be prepared with shells and shells such as, for example, enteric shells, release control shells and other shells widely known in pharmaceutical formulation technology. In such solid dosage forms the active compound may be mixed with at least one inert diluent such as, for example, sucrose, lactose or starch. Such dosage forms may also comprise, as is the case in practice, additional substances in addition to inert diluents, for example, 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 further comprise buffering agents. They may optionally contain opacifying agents and 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 inclusion compositions that can be used include polymeric substances and waxes. Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, aerosols, inhalers or patches. The active component is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives or buffers as appropriate. The ophthalmic formulation, ear drops and eye drops are also contemplated within the scope of this invention. Additionally, the present invention contemplates the use of transdermal patches, which offer the additional advantage of controlled distribution of a compound to the body. Such dosage forms can be manufactured by dissolving or distributing the compound in the appropriate medium. Absorption enhancers also 182 can be included to increase the circulation of the compound through the skin. The rate can be controlled either by providing a rate control membrane or by dispersing the compound in a polymer matrix or gel. According to one embodiment, the 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. According to one embodiment, the invention relates to a method of inhibiting TYK2 or one of its mutants 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 certain embodiments, the invention relates to a method of irreversible inhibition of the activity of TYK2 or one of its mutants in a biological sample comprising the step of contacting said biological sample with a compound of this invention or a composition that comprises said compound. In another embodiment, the invention provides a method of selectively inhibiting TYK2 relative to one or more of JAK1, JAK2 and JAK3. In some embodiments, a compound of the present invention is more than 2-fold selective for JAK1 / 2 / 3. In some embodiments, a compound of the present invention is more than 5-fold selective for JAK1 / 2 / 3. In some embodiments, a compound of the present invention is more than 10-fold selective for JAK1 / 2 / 3. In some embodiments, a compound of the present invention is more than 50-fold selective I 183 regarding JAK1 / 2 / 3. In some embodiments, a compound of the present invention is more than 100-fold selective for JAK1 / 2 / 3. The term “biological sample” as used herein includes, but is not limited to, cell cultures or their extracts; the biopsied material obtained from a mammal or its extracts; and blood, saliva, urine, feces, semen, tears or other body fluids or their extracts. Inhibiting the activity of TYK2 (or one of its mutants) in a biological sample is useful for a variety of purposes that are known to one skilled in the art. Examples of these purposes include, but are not limited to, blood transfusion, organ transplantation, storage of biological specimens, and biological assays. Another embodiment of the present 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 present invention or a composition comprising said compound. According to another embodiment, the invention relates to a method of inhibiting the activity of TYK2 or one of its mutants, in a patient comprising the step of administering to said patient a compound of the present invention or a composition that comprises said compound. According to certain embodiments, the invention relates to a method of reversible or irreversible inhibition of one or more of TYK2 or one of its mutants, the activity in a patient comprising the step of 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 one of its mutants, in a patient in need thereof, comprising the step of administering to said patient a compound of 184 according to the present invention or its pharmaceutically acceptable composition. These disorders are described herein in detail. Depending on the particular condition or disease to be treated, additional therapeutic agents that are normally administered to treat said condition are administered, which 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. A compound of the present invention can also be used advantageously in combination with other therapeutic compounds. In some embodiments, the other therapeutic compounds are antiproliferative compounds. Such antiproliferative compounds include without limitation: aromatase inhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule active compounds; alkylating compounds, histone deacetylase inhibitors; compounds that induce cellular differentiation processes; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; antineoplastic antimetabolites; platinum compounds; compounds that target / decrease a protein or lipid kinase activity and other anti-angiogenic compounds; compounds targeting, decreasing or inhibiting the activity of a protein or lipid phosphatase; gonadorelin agonists; antiandrogens; methionine aminopeptidase inhibitors; matrix metalloproteinase inhibitors; bisphosphonates; biological response modifiers; antiproliferative antibodies; heparanase inhibitors; inhibitors of oncogenic Ras isoforms; telomerase inhibitors; proteasome inhibitors; compounds used in the treatment of hematological malignancies; compounds that target, decrease or inhibit the activity of 185 Flt-3; Hsp90 inhibitors such as 17-AAG (17-ahlaminogeldanamycin, NSC330507), 17-DMAG (17-dimethylaminoethylamino-17-demethoxy-geldanamycin, NSC707545), IPI-504, CNF1010, CNF2024, CNF1010 from Conforma Therapeutics; temozolomide (Temodal®); kinesin spindle protein inhibitors, such as SB715992 or SB743921 from GlaxoSmithKIine or pentamidine / chlorpromazine from CombinatoRx; MEK inhibitors such as ARRY 142886 from Array BioPharma, AZD6244 from AstraZeneca, PD181461 from Pfizer and leucovorin. The term "aromatase inhibitor" as used herein refers to a compound that inhibits the production of estrogens, for example, the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively. The term includes without limitation, spheroids, especially atamestane, exemestane and formestane and, in particular, non-spheroids, especially aminoglutethimide, roglethimide, pyridoglutethimide, trilostane, testolactone, ketoconazole, vorozole, fadrozole, anastrozole and letrozole. Exemestane is marketed under the trade name Aromasin™. Formestane is marketed under the brand name Lentaron™. Fadrozole is marketed under the trade name Afema™. Anastrozole is marketed under the trade name Arimidex™. Letrozole is marketed under the trade names Femara™ or Femar™. Aminoglutethimide is marketed under the trade name Orimeten™. A combination of the invention comprising a chemotherapeutic agent that is an aromatase inhibitor is particularly useful for the treatment of hormone receptor positive tumors, such as breast tumors. The term antiestrogen, as used herein refers to a compound that antagonizes the effect of estrogens at the level of the estrogen receptor. The term includes, without limitation, tamoxifen, fulvestrant, raloxifene and raloxifene hydrochloride. Tamoxifen is marketed under the trade name 186 Nolvadex™. Raloxifene hydrochloride is marketed under the trade name Evista™. Fulvestrant may be administered under the brand name Faslodex™. A combination of the invention comprising a chemotherapeutic agent that is an antiestrogen is particularly useful for the treatment of tumors that are estrogen receptor positive, such as breast tumors. The term antiandrogen, as used herein, refers to any substance that is capable of inhibiting the biological effects of androgen hormones and includes, without limitation, bicalutamide (Casodex™). The term gonadorelin agonist as used herein includes without limitation abarelix, goserelin and goserelin acetate. Goserelin may be administered under the brand name Zoladex™. The term “topoisomerase I inhibitor as used herein includes without limitation: gimatecane, irinotecan, camptothecin and its analogues, 9-nitrocamptothecin and the macromolecular conjugate of camptothecin, PNU-166148. Irinotecan may be administered, for example, in the form in which it is marketed, for example under the trademark Camptosar™. Topotecan is marketed under the trade name Hycamptin™. The term "topoisomerase II inhibitor" as used herein includes, without limitation, anthracyclines such as doxorubicin (including the liposomal formulation, such as Caelix™), daunorubicin, epirubicin, idarubicin and nemorubicin, the anthraquinones mitoxantrone and losoxantrone and the podophyllotoxins etoposide and teniposide. Etoposide is marketed under the trade name Etopophos™. Teniposide is marketed under the trade name VM 26—Bristol. Doxorubicin is marketed under the trade name Acriblastin™ or Adriamycin™. Epirubicin is marketed under the c 187 trade name Farmorubicin™. Idarubicin is marketed under the trade name Zavedos™. Mitoxantrone is marketed under the trade name Novantron. The term “microtubule active agent” refers to compounds that stabilize microtubules, destabilize microtubules, and inhibitors of microtubulin polymerization including, without limitation: taxanes, such as paclitaxel and docetaxel; vinca alkaloids, such as vinblastine or vinblastine sulfate, vincristine or vincristine sulfate and vinorelbine; discodermolids; colchicine and epothilones and their derivatives. Paclitaxel is marketed under the trade name Taxol. Docetaxel is marketed under the trade name Taxotere™. Vinblastine sulfate is marketed under the trade name Vinblastina R.P™. Vincristine sulfate is marketed under the trade name Farmistin™. The term alkylating agent as used herein includes, without limitation, cyclophosphamide, ifosfamide, melphalan or nitrosourea (BCNU or Gliadel). Cyclophosphamide is marketed under the trade name Ciclostin™. Ifosfamide is marketed under the trade name Holoxan™. The term “histone deacetylase inhibitors or HDAC inhibitors” refers to compounds that inhibit histone deacetylase and possess antiproliferative activity. This includes, without limitation, suberoylanilide hydroxamic acid (SAHA). The term "antineoplastic antimetabolite" includes, without limitation, 5fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylating compounds, such as 5-azacytidine and decitabine, methotrexate and edatrexate, and folic acid antagonists such as pemetrexed. Capecitabine is marketed under the trade name Xeloda™. Gemcitabine is marketed under the trade name Gemzar™. φ 188 The term platinum compound as used herein includes, without limitation, carboplatin, cisplatin, cisplatin and oxaliplatin. Carboplatin may be administered, for example, in the form as marketed, for example under the trademark Carboplat™. Oxaliplatin may be administered, for example, in the form as marketed, for example under the trademark Eloxatin™. The term "compounds that target / decrease a protein or lipid kinase activity or a protein or lipid phosphatase activity or other antiangiogenic compounds", used herein includes without limitation, protein tyrosine kinase and / or serine inhibitors and / or threonine kinase or lipid kinase, such as: a) compounds that target, decrease or inhibit the activity of platelet-derived growth factor receptors (PDGFR), such as compounds that are direct, decrease or inhibit PDGFR activity, especially compounds that inhibit the PDGF receptor, such as an N—phenyl—derivative 2-pyrimidine-amine, such as imatinib, SU101, SU6668 and GFB-111; b) compounds that target, decrease or inhibit the activity of fibroblast factor receptors (FGFR); c) targeting compounds, which decrease or inhibit the activity of the insulin-like growth factor I receptor (IGF-IR), such as compounds that target, decrease or inhibit the activity of IGF-I or antibodies that target to the extracellular domain of the IGF-I receptor or its growth factors; d) compounds that target, decrease or inhibit the activity of the Trk receptor tyrosine kinase family or ephrin B4 inhibitors; e) compounds targeting, decreasing or inhibiting the activity of the Ax1 receptor tyrosine kinase family; f) compounds targeting, decreasing or inhibiting the activity of the Ret receptor tyrosine kinase; g) compounds targeting, decreasing or inhibiting 189 the activity of the SCFR kit / receptor, tyrosine kinase, such as imatinib; h) compounds that target, decrease or inhibit the activity of C-kit receptor tyrosine kinases of the PDGFR family, such as compounds that target, decrease or inhibit the activity of the c-family receptor tyrosine kinases— Kit, especially compounds that inhibit the c—Kit receptor, such as imatinib; i) compounds targeting, decreasing or inhibiting the activity of c-Abl family members, their gene fusion products (e.g., BCR-Abl kinase) and their mutants, such as compounds that target, or that inhibits the activity of c-Abl family members and their gene fusion products, such as an N-phenyl-2-pyrimidineamine derivative, such as imatinib or nilotinib (AMN107); PD180970; AG957; NSC 680410; PD173955 from ParkeDavis; or dasatinib (BMS-354825); j) compounds targeting, decreasing or inhibiting the activity of members of protein kinase C (PKC) and the Raf family of serine / threonine kinases, members of the MEK family, SRC, JAK / pan-JAK, FAK, PDK1 , PKB / Akt, Ras / MAPK, PI3K, SYK, BTK and TEC, and / or members of the cyclin-dependent kinase (CDK) family, including staurosporine derivatives, such as midostaurin; Examples of other compounds include: UCN-01, safingol, BAY 43-9006, Briostatin 1, Perifosine; ilmofosine; RO 318220 and RO 320432; GO 6976; Isis 3521; LY333531 / LY379196; isoquinoline compounds; FTI; PD184352 or QAN697 (a P13K inhibitor) or AT7519 (a CDK inhibitor); k) compounds that target, decrease or inhibit the activity of protein tyrosine kinase inhibitors, such as compounds that target, decrease or inhibit the activity of protein tyrosine kinase inhibitors, include 25-imatinib mesylate ( Gleevec™) or tyrphostin as Tyrphostin A23 / RG- 50810; AG 99; Tyrphostin AG 213; Tyrphostin AG 1748; Tyrphostin AG 490; Tyrphostin B44; Tyrphostin B44 (+) enantiomer; Tyrphostin AG 555; GA 494; Tyrphostin AG 556, 190 AG957 and adafostine (4-{[(2,5-dihydroxyphenyl)methyl]amino}benzoic acid adamantyl ester; NSC 680410, adafostine); I) compounds targeting, which decrease or inhibit the activity of epidermal growth receptor family tyrosine kinases (EGFR1 ErbB2, ErbB3, ErbB4 as homo- or heterodimers) and their mutants, such as targeting compounds, which decrease or inhibit inhibit the activity of the epidermal growth factor receptor family are especially compounds, proteins or antibodies of the EGF receptor tyrosine kinase family, such as the GF receptor, ErbB2, ErbB3 and ErbB4 or bind to ligands related to EGF or EGF, 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—djpyrimidine derivatives; m) compounds that target, that decrease the activity of the c-Met receptor, such as compounds that target, that decrease, or inhibit, the activity of c-Met, especially compounds that inhibit the kinase activity of c-Met or the antibodies that target the extracellular domain of cMet or bind HGF, n) targeting compounds, which decrease or inhibit the kinase activity of one or more members of the JAK family (JAK1 / JAK2 / JAK3 / TYK2 and / or pan -JAK), including without limitation PRT-062070, SB-1578, baricitinib, pacritinib, momelotinib, VX-509, AZD-1480, TG-101348, tofacitinib and ruxolitinib; o) compounds targeting, decreasing or inhibiting the kinase activity of PI3 kinase (PI3K) including without limitation ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib , pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765 and idelalisib; and; q) compounds that target, decrease or inhibit the signaling effects of the hedgehog (Hh) protein or smoothed receptor pathways (SMO), including, without limitation: cyclopamine, vismodegib, itraconazole, erismodegib and IPI-926 ( saridegib) 191 The term “PI3K inhibitor” used herein refers, without limitation, to compounds that have inhibitory activity against one or more enzymes in the phosphatidylinositol-3-kinase family, including, without limitation, ΡΙ3Κα, ΡΙ3Κγ , ΡΙ3Κδ, ΡΙ3Κβ, ΡΙ3Κ-Ο2α, ΡΙ3Κ-Ο2β, PI3K-C2y, Vps34, ρ110-α, ρ110—β, ρ110—γ, ρ110-δ, ρ85-α, ρ85—β, γ, ρ150, ρ101 and ρ87. Examples of PI3K inhibitors useful in that invention include, without limitation, ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictrelisib, PF-4691502, BYL-719 , dactolisib, XL-147, XL-765 and idelalisib. The term “BTK inhibitor” used herein refers, without limitation, to compounds that have inhibitory activity against Bruton's Tyrosine Kinase (BTK), including, without limitation, AVL-292 and ibrutinib. The term “SYK inhibitor” used herein refers, without limitation, to compounds that have inhibitory activity against spleen tyrosine kinase (SYK), including without limitation PRT-062070, R-343, R-333 , Excellair, PRT-062607 and fostamatinib. The term “BCI-2 inhibitor” as used herein refers, without limitation, to compounds that have inhibitory activity against B cell lymphoma protein 2 (Bel-2), including without limitation ABT-199. , ABT731, ABT-737, apogossypol, pan BCI-2s inhibitor, curcumin (and its analogues), Bcl-2 / Bcl-xL dual inhibitors (Infinity Pharmaceuticals / Novartis Pharmaceuticals), Genasense (G3139), HA14-1 (and its analogues; see WO 2008118802), navitoclax (and its analogues, see US7390799), NH-1 (Shenaing Pharmaceutical University), obatoclax (and its analogues, see WO 2004106328), S-001 (Gloria Pharmaceuticals ), the TW series compounds (Univ. Of Michigan) and venetoclax. In some embodiments the BCI-2 inhibitor is a molecule therapeutic agent. 192 φ small. In some embodiments the BCI-2 inhibitor is a peptidomimetic. Other examples of inhibitors of BTK compounds and conditions treatable by such compounds combined with compounds of this invention can be found in documents WO 2008039218 and WO 2011090760, the entire contents of which are incorporated herein by reference. Other examples of inhibitors of SYK compounds and conditions treatable by such compounds combined with compounds of this invention can be found in WO 2003063794, WO 2005007623 and WO 2006078846, the entire contents of which are incorporated herein by reference. Other examples of PI3K inhibitory compounds and conditions treatable by such compounds combined with compounds of this invention can be found in WO 2004019973, WO 2004089925, WO 2007016176, US8138347, WO 2002088112, WO 2007084786, WO 200712916 1, WO 2006122806, WO 2005113554 and WO 2007044729, the entire contents of which are incorporated herein by reference. Other examples of JAK inhibitor compounds and conditions treatable by such compounds combined with compounds of this invention can be found in documents WO 2009114512, WO 2008109943, WO 2007053452, WO 2000142246 and WO 2007070514, the entire contents of which are incorporated in the present for reference. Other antiangiogenic compounds include compounds that have another mechanism for their activity, for example unrelated to inhibition of lipido kinases, for example thalidomide (Thalomid™) and TNP-470. 193 φ Proteasome inhibitor inhibitors useful for use in combination with compounds of the invention include without limitation bortezomib, disulfiram, epigallocatechin-3-gallate (EGCG), salinosporamide A, carfilzomib, ONX-0912, CEP-18770 and MLN9708. Compounds that target, decrease or inhibit lipid phosphatase activity are for example inhibitors of phosphatase 1, phosphatase 2A or CDC25, such as okadaic acid one of its derivatives. Compounds that induce cellular differentiation processes include, without limitation, retinoic acid, α-γ- or δ-tocopherol or α-y- or δ-tocotrienol. The term “cyclooxygenase inhibitor” used herein refers, without limitation, to Cox-2 inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acid and its derivatives, such as celecoxib (Celebrex™), rofecoxib (Vioxx™) , etoricoxib, valdecoxib or 5-alkyl-2-arylaminophenylacetic acid such as 5-methyl-2-(2-chloro-6'-fluoroanilino)phenyl acetic acid, lumiracoxib. The term "bisphosphonates" used herein refers, without limitation, to etridonic, clodronic, tiludronic, pamidronic, alendronic, ibadronic, risedronic and zoledronic acid. Etridromic acid is marketed under the name commercial Didronel™. Clodronic acid is marketed under the trade name Bonefos™. Tiludronic acid is marketed under the trade name Skelid™. Pamidronic acid is marketed under the trade name Aredia™. Alendronic acid is marketed under the trade name Fosamax™. Ibandronic acid is marketed under the trade name Bondranat™. Risedronic acid is marketed under the trade name Actonel™. Zoledronic acid is marketed under the name Zometa™ commercial. The term mTOR inhibitors refers to compounds that inhibit the mammalian target of rapamycin (mTOR) and that have an activity 194 antiproliferative such as sirolimus (Rapamune®), everolimus (Certican™), CCI779 and ABT578. The term "heparanase inhibitor" as used herein refers to compounds that target, decrease or inhibit the degradation of heparin sulfate. The term includes, without limitation, Pl—88. The term biological response modifier used herein refers to lymphokine or interferons. The term inhibitor of oncogenic Ras isoforms, such as HRas, K-Ras or N-Ras, as used herein refers to compounds that target, decrease or inhibit the oncogenic activity of Ras; for example, a farnesyl transferase inhibitor such as L-744832, DK8G557 or R115777 (Zarnestra™). The term "telomerase inhibitor" as used herein refers to compounds that target, decrease or inhibit the activity of telomerase. Compounds that target, decrease or inhibit telomerase activity are especially compounds that inhibit the telomerase receptor, such as telomestatin. The term "methionine aminopeptide inhibitor" as used herein refers to compounds that target, decrease or inhibit the activity of methionine aminopeptidase. Compounds that target, decrease or inhibit the activity of methionine aminopeptidase include without limitation, bengamia or one of its derivatives. The term "proteasome inhibitor" as used herein refers to compounds that target, decrease or inhibit the activity of the proteasome. Compounds that target, decrease or inhibit proteasome activity include, without limitation, Bortezomib (Velcade™) and MLN 341. The term “matrix metalloproteinase inhibitor” or (“MMP inhibitor”), used herein, refers, without limitation, to inhibitors. 195 Collagen peptidomimetic and non-peptidomimetics, tetracycline derivatives, for example the peptidomimetic inhibitor hydroxamate and its orally bioavailable analog marimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551), BMS-279251, BAY 12-9566, TAA211, MMI270B or AAJ996. The term "compounds used in the treatment of malignant hematological conditions" used herein refers, without limitation, to FMS-like tyrosine kinase inhibitors, which are compounds that target, decrease or inhibit the activity of FMS-like tyrosine kinases. FMS (Flt—3R); interferon, Ι-β-D-arabinofuransylcytosine (ara-c) and bisulfan; ALC inhibitors, which are compounds that target, decrease or inhibit anaplastic lymphoma kinase and BCI-2s Inhibitors. Compounds that target, decrease or inhibit the activity of FMS-like receptor tyrosine kinase (Flt—3R) are especially compounds, proteins or antibodies that inhibit members of the Flt—3R receptor kinase family, such as PKC412 , midostaurin, a staurosporine derivative, SU 11248 and MLN518. The term "HSP90 inhibitors" used herein refers, without limitation, to compounds that target, decrease or inhibit the intrinsic activity of HSP90; that degrade, target, downregulate, or inhibit HSP90 client proteins via the ubiquitin proteasome pathway. Compounds that target, decrease or inhibit the intrinsic ATPase activity of HSP90 are especially compounds, proteins or antibodies that inhibit the ATPase activity of HSP90, such as 17allylamino,17-demethoxygeldanamycin (17AAG), a derivative of geldanamycin, other geldanamycin-related compounds, radicicol and HDAC inhibitors. 196 φ The term "antiproliferative antibodies" used herein refers, without limitation, to, trastuzumab (Herceptin™), Trastuzumab-DM1, erbitux, bevacizumab (Avastin™), rituximab (Rituxan®), PRO64553 (anti-CD40) and antibody 2C4 . The term "antibody" refers to monoclonal antibodies, polyclonal antibodies, intact antibodies, multispecific antibodies formed from at least 2 intact antibodies and antibody fragments as long as they present the desired biological activity. For the treatment of acute myeloid leukemia (AML), the compounds of the present invention can be used in combination with standard leukemia therapies, especially in combination with therapies used for the treatment of AML. In particular, the compounds of the present invention can be administered in combination with, for example, farnesyl transferase inhibitors and / or drugs useful for the treatment of AML, such as Daunorubicin, Adriamycin, Ara-C, VP-16, Teniposide, Mitoxantrone, Idarubicin, Carboplatin 15 and PKC412. In some embodiments, the present invention provides a method of treating AML associated with an ITD and / or D835Y mutation, comprising administering a compound of the present invention together with one or more FLT3 inhibitors. In some embodiments, FLT3 inhibitors are selected from quizartinib (AC220), a staurosporine derivative (e.g. midostaurin or lestaurtinib), sorafenib, tandutinib, LY-2401401, LS104, EB-10, famitinib, NOV-110302 , NMS-P948, AST^87, G-749, SB-1317, S209, SC-110219, AKN-028, fedratinib, tozasertib and sunitinib. In some embodiments, FLT3 inhibitors are selected from quizartinib, midostaurin, lestaurtinib, sorafenib and sunitinib. Other antileukemic compounds include, for example, Ara-C, a pyridine analogue, which is the 2-alpha-hydroxyribose (arabinoside) derivative of deoxycytidine. Also included is the purine analogue of hypoxanthine, 6 197 mercaptopurine (6-MP) and fludarabine phosphate. Compounds that target, decrease, or inhibit the activity of histone inhibitors (HDAC) inhibitors such as sodium butyrate and suberoylanilide hydroxamic acid (SAHA) inhibit the activity of enzymes known as histone deacetylases. Specific HDAC inhibitors include MS275, SAHA, FK228 (formerly FR901228), Trichostatin A and the compounds described in US 6,552,065 which includes, without limitation, N—hydroxy—3—[4—[[[2—( 2—methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide or one of its pharmaceutically acceptable salts and N—hydroxy—3—[4 —[(2—hydroxyethyl){2—(1H— indol-3-íl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide or a pharmaceutically acceptable salt thereof, especially lactate salt. Somatostatin receptor antagonists used herein refer to compounds that target, treat or inhibit the somatostatin receptor such as octreotide and SOM230. The term "damaging tumor cells" refers to approaches such as ionizing radiation. The aforementioned expression “ionizing radiation” hereinafter means ionizing radiation that occurs either as electromagnetic rays (such as X-rays and gamma rays) or as particles (such as alpha and beta particles). Ionizing radiation is provided in, without limitation, radiation therapy known in the art. See: Hellman, Principles of Radiation Therapy, Cancer, in Principles and Practice of Oncology, Devita et al., Eds., 4th Edition, Vol. 248-275 (1993). Also included are EDG binders and ribonucleotide reductase inhibitors. The term “EDG binder” used herein refers to a class of immunosuppressants that modulate lymphocyte recirculation, such as FTY720. The term “ribonucleotide reductase inhibitors” refers to pyrimidine or puncture nucleoside analogs, including, without limitation, 198 fludarabine and / or cytosine arabinoside (ara-C), 6-thioguanine, 5-fluorouracil, cladribine, 6-mercaptopurine (especially combined with ara-C against ALL) and / or pentostatin. Ribonucleotide reductase inhibitors are especially those derived from hydroxyurea or 2-hydroxy-1 H-isoindole-1,3-dione. Also particularly included are those VEGF compounds, proteins or monoclonal antibodies such as 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or one of its pharmaceutically acceptable salts, 1-(4-chloroanilino)-4-(4-pyridylmet). l)phthalazine succinate; Angiostatin™; Endostatin™; anthranilic acid amidase; ZD4190; ZD6474; SU5416; SU6668; bevacizumab; or anti-VEGF antibodies or anti-VEGF receptor antibodies, such as rhuMAb and RHUFab, VEGF aptamer such as Macugon; FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgGl antibody, Angiozyme (RPI 4610) and Bevacizumab (Avastin™). The term “photodynamic therapy” used herein refers to a therapy in which certain chemicals known as photosensitizing compounds are used to treat or prevent cancers. Examples of photodynamic therapy include treatment with compounds such as Visudyne™ and porfimer sodium. The term "angiostatic steroids" used herein refers to compounds that block or inhibit angiogenesis, such as, for example, anecortavo, triamcinolone, hydrocortisone, 11-a-epihydrocotisol, cortexolone, 17ahydroxyprogesterone, corticosterone, deoxycorticosterone, testosterone, estrone and dexamethasone. The term "corticosteroid-containing explants" refers to compounds such as fluocinolone and dexamethasone. Other chemotherapeutic compounds include, without limitation, plant alkaloids, hormonal compounds and antagonists, response modifiers J. 199 biological, preferably lymphokines or interferons; antisense oligonucleotides or oligonucleotide derivatives, shRNA or siRNA; or miscellaneous compounds or compounds with different or unknown mechanisms of action. The compounds of the invention are also useful as co-therapeutic compounds for use in combination with other drug substances such as anti-inflammatory drug substances, bronchodilators or antihistamines, particularly for the treatment of obstructive or inflammatory diseases of the airways, such as those mentioned above. preceding, for example 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. A compound of the 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 substance. Therefore, the invention includes a combination of a compound of the invention described above with an anti-inflammatory, bronchodilator, antihistamine or antitussive pharmacological substance, said compound of the invention and said drug substance being in the same pharmaceutical composition or in another different composition. . Suitable anti-inflammatory drugs include spheroids, in particular glucocorticosteroids such as budesonide, beclomethasone dipropionate, fluticasone propionate, ciclesonide or mometasone furoate; non-spheroid glucorticoid receptor agonists; LTB4 antagonists such as LY293111, CGS025019C, CP-195543, SC-53228, BUL 284, ONO 4057, SB 209247; LTD4 antagonists such as montelukast and zafirlukast; PDE4 inhibitors such as cilomilast (Ariflo® GlaxoSmithKIine), Roflumilast (Byk Gulden),V11294A (Napp), BAY19-8004 (Bayer), SCH-351591 (Schering-Plough), Arofylline (Almirall Prodesfarma), PD189659 / PD168787 (Parke -Davis), AWD-12-281 (Asta 200 Medica), CDC-801 (Celgene), SelCID(TM) CC-10004 (Celgene), VM554 / UM565 (Vernalis), T-440 (Tanabe), KW-4490 (Kyowa Hakko Kogyo); A2a agonists; A2b antagonists; and beta-2-adrenoceptor agonists such as albuterol (salbutamol), metaproterenol, terbutaline, salmeterol fenoterol, procaterol and especially, formoterol and its pharmaceutically acceptable salts. Suitable bronchodilator drugs include anticholinergic or antimuscarinic compounds, in particular ipratropium bromide, oxitropium bromide, salts of tiotropium and CHF 4226 (Chiesi) and glycopyrrolate. Suitable antihistamine drug substances include cetirizine hydrochloride, acetaminophen, clemastine fumarate, promethazine, loratidine, desloratidine, diphenhydramine and fexofenadine hydrochloride, activastin, astemizole, azelastine, ebastine, epinastine, mizolastine and terfenadine. Other useful combinations of compounds of the invention with anti-inflammatory drugs are those with chemokine receptor antagonists, for example CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7 , CCR-8, CCR-9 and CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, particularly CCR-5 antagonists such as Schering-Plough antagonists SC351125, SCH-55700 and SCH-D and Takeda antagonists such as N chloride -[[4-[[[6,7-dihydro-2-(4-methylphenyl)-5H-benzo-cyclohepten-820 l]carbonyl]amino]phenyl]-methyl]tetrahydro -N,N-dimethyl-2H-pyran-4-amnio (TAK770). The structure of active compounds identified by code numbers, generic names or trade names can be taken from the updated edition of the standard compendium The Merck Index or from databases, e.g. international patents (e.g. IMS World Publications). . A compound of the present invention can also be used in combination with known therapeutic processes, for example, the administration 201 of hormones or radiation. In certain embodiments, a provided compound is used as a radiosensitizer, especially for the treatment of tumors that have poor sensitivity to radiotherapy. A compound of the present invention may be administered alone or in combination with one or more other therapeutic compounds; A possible combination therapy takes the form of fixed combinations or the administration of a compound of the invention and one or more other therapeutic compounds is staggered or administered independently of each other or the combined administration of fixed combinations with one or more additional therapeutic compounds. A compound of the present invention may additionally be administered for specific purposes for tumor therapy with chemotherapy, immunotherapy, immunotherapy, phototherapy, surgical intervention or a combination thereof. Long-term treatment in the form of adjuvant therapy is also possible in the context of other strategies, as described above. Other possible treatments include a therapy to maintain the patient's status after tumor regression or even a chemopreventive therapy, for example in patients at risk. These additional agents may be administered separately from an inventive composition containing the compound, as part of a multiple dosing regimen. Alternatively, these agents may be part of an individual dosage form, mixed together with a compound of this invention in an individual composition. If administered as part of a multiple dosage regimen, the two active agents may be administered simultaneously, sequentially, or within a time interval of each other, typically five hours apart. As used herein, the terms "combination", "combined" and related terms refer to the simultaneous or sequential administration of 202 therapeutic agents according to this invention. For example, a compound of the present invention may be administered with another therapeutic agent simultaneously or sequentially in a unit dosage form or together in a single unit dosage form. Therefore, the present invention provides an individual unit dosage form comprising a compound of the present invention, an additional therapeutic agent or a pharmaceutically acceptable vehicle, adjuvant or carrier. The amount of both an inventive compound and an additional therapeutic agent (in those compositions comprising an additional therapeutic agent described above) that can be combined with the carrier materials so as to produce an individual dosage form will vary depending on the host treated and of the particular mode of administration. It is preferable that the compositions of this invention are formulated such that it is possible to administer a dosage of between 0.01 and 100 mg / kg body weight / day of a compound according to the invention. In those compositions comprising an additional therapeutic agent, such additional therapeutic agent and the compound of the invention may act synergistically. Therefore, the amount of additional therapeutic agent in such compositions will be less than that required in monotherapy in which only said therapeutic agent is used. In such compositions, it is possible to administer a dosage of between 0.01 and 1,000 pg / kg body weight / day of the additional therapeutic agent. The amount of additional therapeutic agent present in the compositions of this invention will not be greater than the amount that would normally be administered in a composition comprising said therapeutic agent as the sole active agent. It is preferable that the amount of the additional therapeutic agent in the compositions described herein be in a range of 203 approximately 50% to 100% of the amount that would normally be present in a composition comprising said agent as the sole therapeutically active agent. The compounds of this invention or their pharmaceutical compositions may also be incorporated into compositions for coating an implantable medical device such as prostheses, artificial valves, vascular grafts, stents and catheters. Vascular stents, for example, have been used to overcome stenosis (renarrowing of vascular walls after injury). However, patients using stents or other implantable devices are at risk of clot formation or platelet activation. These undesirable effects can be prevented or mitigated by pre-coating the device with a pharmaceutically acceptable composition comprising a kinase inhibitor. Implantable devices coated with a compound of this invention are another embodiment of the present invention. EXEMPLIFICATION As depicted in the examples below, in certain example embodiments, the compounds are prepared according to the following general procedures. It should be appreciated that, although the general methods represent the synthesis of certain compounds of the present invention, the following general methods and other methods known to those skilled in the art, can be applied to all compounds and subcategories and species of each of these compounds, as described herein. Example 1. Synthesis of N-(4-((2-methoxy-3-(2-methyl-2H-tetrazol-5yl)phenyl)amino)-2-methyl-3-oxo-2,3-dihydro- 1H-pyrazolo[3,4-b]pyridin-6yl)cyclopropanecarboxamide, 1-1 204 O'O StCI.. XX.ACN Here. \H4CH 1.3 1.4 ' SOCI, . Cat DMF, reflux. O / N methylhydrazine NaOH water, reflux 15min 1.7 o'' n-n CU ZN, Ti 'Ί' H ,N ,Λ... ,ann~ X ·:γ- N l JT .NH N Xj O ............... .................... ¡í Ί 1 M LÍHDMS . THF T '{;>nC -until TA N' N N N 2. Silica purification, regioisomers separated ethanol Ps.;C h N.. 'N 1.5 1.6 1Nrb NíJ: OO,. 1 'pentanol ,.N. ...........................* reflux, tShrs 1.8 1.9 Λ II ,N x.J NH? o & , X. l>u 0 . NH O Xantphos. Páqdbah DMAc Cs?COv t J 'T Ό | 130°C. 5h Nz 'N N-N 1.91 1-1 Synthesis of compound 1.2. At a solution of 1.1 (50 g, 253.6 mmol, 1.0 eq) in DMF (500 ml_), K2CO3 (70 g, 507.6 mmol, 2.0 eq) was added at 0 °C and stirred for 15 min. Mel (72 g, 507.6 mmol, 2.0 eq) was added to the suspension dropwise and the reaction mixture was stirred at 60 °C for 2 h. After completion of the reaction, the reaction mixture was transferred to ice water. The precipitated product was filtered, dried to give 1.2 (50.0 g, 93.0%). MS (ES): m / z 212.2 [M+H]+. 205 Synthesis of compound 1.3. To 1.2 (50 g, 236.7 mmol, 1.0 eq) aq. NH4OH was added. (300 mL) followed by methanolic NH3 (1600 mL). The reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the residue was washed with ice water. The precipitate was dried to obtain 1.3 (45.0 g, 96.0%). MS (ES): m / z 197.2 [M+H]+. Synthesis of compound 1.4. To a suspension of NaN3 (21.8 g, 336 mmol, 3.0 eq) in acetonitrile (220 mL) was added SiCI4 (28.6 g, 168 mmol, 1.5 eq). Compound 1.3 (22.0 g, 112 mmol, 1.0 eq) was added to the stirred suspension and the reaction mixture was stirred at 75 °C for 16 h. The reaction mixture was cooled to room temperature and water was added. The precipitated solid was filtered to give 1.4 (18.0 g, 72.5%). MS (ES): m / z 222.2 [M+Hf. Synthesis of compound 1.5. To a stirred solution of 1.4 (15.0 g, 67.8 mmol, 1.0 eq) in DMF (150 mL) K2CO3 (23.4 g, 169.7 mmol, 2.5 eq) was added at 0 °C. To this Mel (19.1 g, 135.7 mmol, 2.0 eq) was added dropwise. The reaction mixture was stirred at room temperature for 24 h. After completion of the reaction, the mixture was transferred to water and extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na2SO4, and concentrated under reduced pressure to obtain crude material. The crude material 20 was purified by column chromatography to provide the desired 1.5 regioisomer (10.0 g, 62.7%). MS (ES): m / z 236.2 [M+H]+. Synthesis of compound 1.6. To a solution of 1.5 (10.0 g, 42.5 mmol, 1.0 eq) in MeOH (100 mL), 10% Pd / C (2.0 g) was added. Hydrogen was purged through the reaction mixture for 4 h. After completion of the reaction, the mixture was filtered through a pad of Celite and washed with MeOH. The filtrate was concentrated under reduced pressure to obtain 1.6 (5.3 g, 60.7%). MS (ES): m / z 206.3 [M+H]+. 206 Synthesis of compound 1.8. At 1.7 (1.0 g, 4.42 mmol, 1.0 eq) SOCI2 (5.0 mL) was added followed by DMF (catalytic) and heated at reflux for 16 h. The reaction mixture was concentrated under reduced pressure to obtain acyl chloride. Methylhydrazine (0.20 g, 42.5 mmol, 1.0 eq) was dissolved in CH2CI2 (20.0 mL) followed by addition of NaOH solution (0.72 g, 177 mmol, 4.0 eq) in water (5.0 mL). Acyl chloride solution previously made in CH2CI2 (20.0 mL) was added to the solution drop by drop. The reaction mixture was heated to reflux for 15 min. After completion of the reaction, the reaction mixture was transferred to water and extracted with CH2CI2. The organic layers were combined, washed with brine, dried over Na2SO4 and concentrated under reduced pressure to obtain crude product which was purified by column chromatography to provide 1.8. (1.1g, 97.0%). MS (ES): m / z 255.5 [M+H]+. Synthesis of compound 1.9. To a suspension of 1.8 (1.0 g, 3.93 mmol, 1.0 eq) in 1-pentanol (15.0 mL) was added Na2CO3 (0.49 g, 3.93 mmol, 1.0 eq) and the reaction mixture was stirred at 120°C for 16 h. After completion of the reaction, the reaction mixture was cooled to room temperature and pH = 6.0 was adjusted using 11N HC. The reaction mixture was concentrated under reduced pressure to obtain the crude product which was purified by preparative HPLC to obtain 1.9. (0.15g, 17.5%). MS (ES): m / z 219.2 [M+H]+. Synthesis of compound 1.91. At a solution of 1.9 (0.1 g, 0.45 mmol, 1.0 eq) and 1.6 (0.188 g, 0.917 mmol, 2.0 eq) in THF (2.0 mL) was added 1.0 M solution of LHMDS (1.6 mL, 1.57 mmol, 3.5 eq) in tetrahydrofuran at -78°C. The reaction mixture was stirred at room temperature for 18 h. After completion of the reaction, the reaction mixture was transferred to water and extracted with EtOAc. The aqueous layer was acidified with 1.0 N HCl and extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na2SO4, and concentrated under reduced pressure to obtain pure 1.91 (0.1 g, 56.37%). M.S. 207 (ES): m / z 387.9 [M+H]+. Synthesis of compound 1-1. To 1.91 (0.020 g, 0.051 mmol, 1.0 eq) in DMA (0.5 mL) cyclopropancarboxamide (0.005 g, 0.062 mmol, 1.2 eq), CS2CO3 (0.033 g, 0.102 mmol, 2.0 eq) was added. ). The reaction mixture was degassed for 10 min under argon atmosphere, then Pd2(dba)3 (0.005 g, 0.005 mmol, 0.1 eq) and Xantphos (0.006 g, 0.01 mmol, 0.2 eq) were added. . The suspension was degassed for a further 5 minutes. The reaction was then heated at 130 °C for 5 hours. After completion of the reaction, the reaction mixture was diluted with CH2CI2 (1 mL) and passed through a silica plug column using 10% methanol in CH2CI2 as eluent. The fractions obtained were combined and concentrated under reduced pressure to obtain crude material. This was then purified by reverse phase HPLC to obtain 1-1 (0.005 g, 22.2%). MS (ES): m / z 436.6 [M+H]+;1H NMR (CDCI3, 400 MHz): 8.92 (s, 1H), 7.79-7.77 (d, 1H), 7 .67-7.66 (d, 1H), 7.45-7.40 (m, 1H), 4.45 (s, 3H), 3.88 (s, 3H), 3.47 (s, 3H) ), 1.69-1.59 (m, 1H), 1.13-1.12 (m, 2H), 0.91-0.90 (m, 2H). Example 2. Synthesis of 4-((2-methoxy-3-(2-methyl-2H-tetrazol-5yl)phenyl)amino)-6-((4-(methoxymethyl)pyridin-2-yl)amino)-2 -methyl-1,2-dihydro3H-pyrazolo[3,4-b]pyridin-3-one I-2 t-Bu X-phos PdG3, K3PO4 , DMF, 50°C, 10-15mins I-2 To compound 1.91 (0.040 g, 0.103 mmol, 1.0 eq) in DMF (1.0 ml) 4-(methoxymethyl)pyridin-2-amine (0.021 g, 0.155 mmol, 1.5 eq) and K3PO4 were added 208 (0.043 g, 0.206 mmol, 2.0 eq). The reaction mixture was degassed for 10 minutes using argon, then [(2—di—tert—butylphosphino—2',4',6'—triisopropyl—1,1biphenyl)—2—(2—amino—) methanesulfonate was added. 1,1-biphenyl)]palladium (II) (0.008 g, 0.01 mmol, 0.1 eq). The suspension was degassed for a further five minutes. The reaction was stirred at 50 °C for 15 min. After completing the reaction, the mixture was diluted with CH2CI2 (1.0 mL) and passed through a silica plug column using 8% methanol in CH2CI2 as eluent. The obtained fractions were combined and concentrated under reduced pressure to obtain crude product that was purified by reverse phase HPLC to obtain I-2 (0.008 g, 15.84%). MS (ES): m / z 489.75 [M+H]+;1H NMR (CDCI3, 400 MHz): 9.27 (s, 1H), 8.95 (s, 1H), 8.14-8 .12 (d, 1H), 7.70-7.68 (d, 1H), 7.41-7.39 (d, 1H), 7.117.08 (t, 1H), 7.00 (s, 1H) ), 6.89-6.88 (d, 1H), 4.43 (s, 3H), 3.78 (s, 3H), 3.65 (s, 2H), 3.57 (s, 3H) , 3.43 (s, 3H). Example 3. Synthesis of 4-((2-methoxy-3-(2-methyl-2H-tetrazol-5yl)phenyl)amino)-2-methyl-6-((5-methylpyridin-2-yl)amino)- 1,2-dihydro-3H- 1.91 I-3 Compound I-3 was prepared from compound 1.91 and 5—methylpyridine— 2-amine using the procedure described in Example 2. MS (ES): m / z 459.64 [M+H]+;1H NMR (DMSO-d6, 400 MHz): 10.68 (s, 2H), 9.76 (s, 1H), 8.93 (s, 1H), 8.11 (s, 1H), 7.79-7.77 (d, 1H), 7.65-7.57 (m, 2H), 7.42-7.38 (m, 1H), 7, 2 (s, 1H), 209 4.47 (s, 3H), 3.79 (s, 3H), 3.29 (s, 3H), 2.24 (s, 3H). Example 4. Synthesis of 4-((2-methoxy-3-(2-methyl-2H-tetrazol-5yl)phenyl)amino)-2-methyl-6-(pyridin-2-ylamino)-1 ,2-dihydro-3H-pyrazolo[3,4b]pyridin-3-one, I-4 1.91 t-Bu X-phos PdG3, K3PO4, DMF, 50°C, 10-15mins i-4 Compound I-4 was prepared from compound 1.91 and pyridin-2-amine using the procedure described in Example 2. MS (ES): m / z 445.68 [M+Hf1H NMR (DMSO-dg, 400 MHz): 9.97 (s, 1H), 8.95 (s, 1H), 8.27-8.26 (d, 1H), 8.16 (s, 1H), 7.89 (s, 1H), 7.80-7.78 (d, 1H), 7.74-7.71 (m, 1H), 7.65-7.63 (d, 1H), 7, 42- 7.38 (t, 1H), 6.97-6.94 (t, 1H), 4.47 (s, 3H), 3.79 (s, 3H), 3.29 (s, 3H). Example 5. Synthesis of 4-((2-methoxy-3-(2-methyl-2H-tetrazol-5yl)phenyl)amino)-2-methyl-6-((4-methylpyridin-2-yl)amino )-1,2-dihydro-3H15 pyrazolo[3,4-b]pyridin-3-one, 1-5 1.91 I-5 210 Compound I-5 was prepared from compound 1.91 and 4—methylpyridine— 2-amine using the procedure described in Example 2. MS (ES): m / z 459.7 [M+H]+;1H NMR (DMSO-d6, 400 MHz): 9.98 (s, 1H), 8.96 (s, 1H), 8.17 (s, 1H), 8.14-8.13 (d, 1H),7.79-7.77 (d, 1H), 7.65-7.63 (d, 1H), 7.42-7.38 (t, 1H ), 6.82- 6.81 (d, 1H), 4.47 (s, 3H), 3.79 (s, 3H), 3.30 (s, 3H), 2.30 (s, 3H). Example 6. Synthesis of 6-((4-(hydroxymethyl)pyridin-2-yl)amino)-4-((2-methoxy- 3- (2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2-methyl-1,2-dihydro-3Hpyrazolo[3,4-b]pyridin-3-one, I-6 1.91 I-6 Compound I-6 was prepared from compound 1.91 and (2-aminopyridin- 4-yl)methanol using the procedure described in Example 2. MS (ES): m / z 475.58 [M+H]+;1H NMR (DMSO-d6, 400 MHz): 10.01 (s, 1H), 8.97 (s, 1H), 8.20- 8.19 (d, 1H),8.17 (s, 1H), 7.79-7.77 (d, 1H), 7.66-7.64 (d, 1H), 7.42-7 .38 (t, 1H), 6.92-6.90 (d, 1H), 5.42 (s, 1H), 4.52 (s, 2H), 4.47 (s, 3H), 3.79 (s, 3H), 3 .30 (s, 3H). Example 7. Synthesis of N-(4-((2-methoxy-3-(2-methyl-2H-tetrazol-5yl)phenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H- pyrazolo[3,4-b]pyridin-6yl)cyclopropanecarboxamide, 1-14 211 —Ν LÍHMDS 1 Μ in THF, THF, Q°C to ΤΑ ν' ';ν Compound 1.92 was prepared according to the procedure used for 1.91. Compound 1-14 was prepared from compound 1.91 and cyclopropanecarboxamide using the procedure described in Example 2. (yield: 22.2%). MS (ES): m / z 436.6 [M+Hf, LCMS purity: 96%, HPLC purity: 91%, 1H NMR (CDCI3, 400 MHz): 8.92 (s, 1H), 7. 79-7.77 (d, J = 8Hz, 10 1H), 7.67-7.66 (d, J = 7.2Hz, 1H), 7.45-7.40 (m, 1H), 4, 45 (s, 3H), 3.88 (s, 3H), 3.47 (s, 3H), 1.69-1.59 (m, 1H), 1.13-1.12 (m, 2H), 0.91-0.90 (m, 2H). Example 13. Synthesis of 4-((2-methoxy-3-(2-methyl-2H-tetrazol-5¡l)phenyl)amino)-2-methyl-6-((5-morpholinopyridin-2-yl)amino )-1,2-dihydro-3Hpyrazolo[3,4-b]pyridin-3-one, I-7 212 1.91 I-7 Compound I-7 was prepared from compound 1.91 and morpholinopyridin-2-amine using the procedure described in Example 2 (yield: 8.76%). MS (ES): m / z 530.81 [M+H]+, LCMS purity: 100%, HPLC purity: 98.59%, 1H NMR (DMSO-d6, 400 MHz): 9.79-9 .75 (bs, 2H), 8.94 (s, 1H), 8.14 (s, 1H), 7.98 (s, 1H), 7.78-7.76 (d, J = 8Hz, 1H), 7.64-7, 63(d, J = 7.6Hz, 1H), 7.46-7.38 (m, 3H), 4.47 (s, 3H), 3.79 (s, 3H), 3.77-3, 74 (t, 4H), 3.29 (s, 3H), 3.10-3.08 (t,4H). Example 14. Synthesis of 6-((5-fluoro-4-methylplridin-2-yl)amino)-4-((2methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)- 2-methyl-1,2-dihydro-3H- 1.91 I-8 Compound I-8 was prepared from compound 1.91 and 5-fluoro-4methylpyridin-2-amine using the procedure described in Example 2 l 213 (yield: 16.24%). MS (ES): m / z 477.43 [M+HJ+, LCMS purity: 99.71%, HPLC purity: 99.14%, 1H NMR (DMSO-d6, 400 MHz): 9.87 (s) , 1H), 8.92 (s, 1H), 8.22 (s, 1H), 8.15 (s, 1H), 7.94 (s, 1H), 7.78-7.76 (d, J = 8Hz, 1H), 7.647.62(d, J = 7.2Hz, 1H), 7.42-7.38 (t, 1H), 6.96 (s, 1H), 4.47 (s, 3H), 3.79 (s, 3H), 3.30 (s, 3H), 2.28 (s, 3H). Example 15. Synthesis of 6-((2,6-dimethylpyrimidin-4—yl)amino)-4-((2-methoxy- 3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2-methyl-1,2-dihydro-3Hpyrazolo[3,4-b]pyridin-3-one, I-9 1.91 I-9 Compound I-9 was prepared from compound 1.91 and 2,6dimethylpyrimidin-4-amine using the procedure described in Example 2 (yield: 11.98%). MS (ES): m / z 474.58 [M+H]+, LCMS purity: 99.76%, HPLC purity: 96.42%, 1H NMR (MeOD, 400 MHz): 8.34-8 .29 (bs, 2H), 7.86- 7.84 (d, J = 7.6Hz, 1H), 7.73-7.71 (d, J = 8Hz, 1H), 7.41-7.37 (t, 1H), 6.89 (s , 1 HOUR), 6.25 (s, 1H), 4.48 (s, 3H), 3.85 (s, 3H), 3.53 (s, 3H), 2.64 (s, 3H), 2.42 (s , 3H). Example 16. Synthesis of 4-((2-methoxy-3-(2-methyl-2H-tetrazol-5¡l)phenyl)amino)-2-methyl-6-((6-methylpyridazin-3-yl)amino )-1,2-dihydro-3Hpyrazolo[3,4-b]pyridin-3-one, 1-10 214 1.91 1-10 Compound 1-10 was prepared from compound 1.91 and 6methylpyridazin-3-amine using the procedure described in Example 2 (yield: 14.03%). m / z 460.43 [M+H]+, LCMS purity: 98.69%, HPLC purity: 98.00%, 1H NMR (DMSO-d6, 400 MHz): 10.23 (bs, 1H) , 8.93 (s, 1H), 8.29-8.27 (d, J = 8.8Hz, 1H), 8.16 (s, 1H), 7.79-7.77 (d, J = 8Hz, 1H), 7.65-7.64 (d, J = 7.2Hz, 1H), 7.50-7.48 (d, J = 9.2Hz, 1H), 7.40-7.36 (t, J = 8Hz, 1H), 6.99 (bs, 1H), 4.47 (s, 3H), 3.80 (s, 3H), 3.30 (s, 3H), 2.53 ( s, 3H). Example 17. Synthesis of 4-((2-methoxy-3-(2-methyl-2H-tetrazol-5yl)phenyl)amino)-2-methyl-6-((5-(piperidin-1-yl)pyridin- 2-yl)amino)-1,2-dihydro- 1.91 1-11 Compound 1-11 was prepared from compound 1.91 and 5-(piperidin--yl)pyridin-2-amine using the procedure described in Example 2. 215 (yield: 9.78%). MS (ES): m / z 528.68 [M+H]+, LCMS purity: 96.10%, HPLC purity: 98.65%, 1H NMR (CDCI3, 400 MHz): 9.76 (bs , 1H), 8.89 (s, 1H), 7.71 (s, 1H), 7.66-7.64 (d, J = 7.2Hz, 1H), 7.28 (s, 1H), 7.03-7.00 (m, 2H), 5.72 (s, 1H), 4.40 (s, 3H), 3.77 (s, 3H), 3.54 (s, 3H), 3 .17-3.03 (m, 4H), 2.63 (s, 1H), 5 1.72 (s,4H), 1.60-1.59 (d,2H). Example 18. Synthesis of 4-((2-methoxy-3-(2-methyl-2H-tetrazol-5yl)phenyl)amino)-2-methyl-6-((5-(pyrrolidin-1-yl)pyridin- 2-¡l)amino)-1,2-dihydro3H-pyrazolo[3,4-b]pyridin-3-one, I-58 V'l N-N \ 1.91 I-58 Compound I-58 was prepared from compound 1.91 and 5—(pyrrolidin—1—yl)pyridin—2—amine using the procedure described in Example 2 (yield: 11.08%), MS (ES): m / z 514.46 [M+H]+, LCMS purity: 96.44%, HPLC purity: 97.39%, 1H NMR (DMSO-d6, 400 MHz): 9.96 (s, 1H), 8.68 (s, 15 1H), 7.72-7.621 (m, 3H), 7.51 (s, 2H), 7.24-6.98 (m, 2H), 6.40 (s, 1H) ), 4.50 (s, 3H), 3.68 (s, 4H), 3.45 (s, 3H), 3.25 (s, 3H), 1.98 (s, 4H). Example 19. Synthesis of 6-((5-cyclopropylpyridin-2-yl)amino)-4-((2-methoxy-3(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2-methyl -1,2-dihydro-3H-pyrazolo[3,4- b]pyridin-3-one, I-59 216 1.91 Ι-59 Compound I-59 was prepared from compound 1.91 and 5cyclopropylpyridine-2-amine using the procedure described in Example 2 (yield: 23.28%), MS (ES): m / z 485.53 [M+HJ+ , LCMS purity: 98.26%, HPLC purity: 97.44%, 1H NMR (DMSO-d6, 400 MHz): 10.72 (s, 1H), 9.74 (s, 1H), 8.90 (s, 1H), 8.09 (s, 1H), 7.95-7.93 (d, J = 6.8Hz, 1H), 7.81-7.79 (d, J = 7.6Hz, 1H), 7.63-7.61 (d, J = 7.2Hz, 1H), 7.43-7.36 (m, 2H), 7.18 (s, 1H), 4.48 (s, 3H), 3.79 (s, 3H), 3.16 (s, 3H), 1.89 (s, 1H), 0.94-0.93 (d, J = 6, 8Hz, 2H), 0.6910 0.68 (d, J = 6.8Hz, 2H). Example 20. Synthesis of 4-((2-methoxy-3-(2-methyl-2H-tetrazol-5yl)phenyl)amino)-2-methyl-6-((6-(trifluoromethyl)pyridin-2-yl) amino)-1,2-dihydro3H-pyrazolo[3,4-b]pyridin-3-one, I-60 \ 1.91 I-60 Compound I-60 was prepared from compound 1.91 and 6 217 (trifluoromethyl)pyridin-2-amine using the procedure described in Example 2 (yield: 39.25%), MS (ES): m / z 513.43 [M+HJ+, LCMS purity: 99.01%, HPLC purity: 98.84%, 1H NMR (DMSO-d6, 400 MHz): 10.85 (s, 1H), 10.29 (s, 1H), 9.06 (s, 1H), 8.13 -8.11 (d, J = 8.8Hz, 1H), 7.98-7.94 (t, J = 8.0Hz, 1H), 7.82-7.79 (d, J = 8.0Hz , 1H), 7.65-7.64 (d, J = 6.8Hz, 1H), 7.48 (s, 1H), 7.40-7.33 (m, 2H), 4.48 (s , 3H), 3.80 (s, 3H), 3.32 (s, 3H). Example 21. Synthesis of 4—((2-methoxy-3-(2-methyl-2H-tetrazol-5yl)phenyl)amino)-6-((6-(3-methoxyazetidin-1-yl)pyridin-2- yl)amino)-2-methyl-1,2dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-63 \ 1.91 I-63 Compound I-63 was prepared from compound 1.91 and 6-(3methoxyazet¡din-1-¡l)pyridín-2-amine using the procedure described in Example 2 (yield : 19.48%), MS (ES): m / z 530.40 [M+H]+, LCMS purity: 100.00%, HPLC purity: 98.25%, 1H NMR (CDCI3, 400 MHz ): 9.49 (bs, 1H), 8.98 (s, 1H), 7.68-7.66 (d, J = 6.8Hz, 1H), 7.38-7.34 (t, J = 8.0Hz, 2H), 7.05 -7.01 (t, J = 8.0Hz, 1H), 6.26-6.24 (d, J = 7.2Hz, 1H), 5.88-5.86 (d, J = 8.0Hz , 1H), 5.73 (bs, 1H), 4.40 (s, 3H), 4.37^1.32 (m, 1H), 4.29-4.25 (m, 2H), 3, 96-3.93 (m, 2H), 3.78 (s, 3H), 3.51 (s, 3H), 3.36 (s, 3H). Example 22. Synthesis of 6-((4-((2-methoxy-3-(2-methyl-2H-tetrazol-5yl)phenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H -pyrazolo[3,4-b]pyridin-6yl)amino)pyrazin-2-carbonitrile, I-64 218 1.91 Ι-64 Compound I-64 was prepared from compound 1.91 and 6aminopyrazin-2-carbonitrile using the procedure described in Example 2 (yield: 20.55%), MS (ES): m / z 471.48 [M+HJ+ , LCMS purity: 100.00%, HPLC purity: 98.79%, 1H NMR (DMSO-d6, 400 MHz): 10.96 (s, 1H), 10.66 (s, 1H), 9, 36 (s, 1H), 9.01 (s, 1H), 8.66 (s, 1H), 7.83-7.81 (d, J = 8.0Hz, 1H), 7.68- 7.66 (dd, J = 1.2Hz, 8.0Hz, 1H), 7.44-7.42 (d, J = 8.0Hz, 1H), 7.40-7.38 (d, J = 8.0Hz, 1H), 4.47 (s, 3H), 3.80 (s, 3H), 3.43 (s, 3H). Example 23. Synthesis of 6-((6-cyclopropylpyridin-2-yl)amino)-4-((2-methoxy-3(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2-methyl -1,2-dihydro-3H-pyrazolo[3,4b]pyridin-3-one, I-65 1.91 I-65 Compound 1-65 was prepared from compound 1.91 and 6cyclopropylpyridin-2-amine using the procedure described in Example 2 (yield: 7.98%), MS (ES): m / z 485.53 [M+HJ+ , LCMS purity: 96.64%, 219 HPLC purity: 96.85%, 1H NMR (DMSO-d6, 400 MHz): 11.42 (s, 1H), 9.09 (s, 1H), 7.93 (s, 1H), 7.81 -7.79 (d, J = 6.4Hz, 1H), 7.66-7.64 (d, J = 6.4Hz, 1H), 7.41 (s, 1H), 7.09-7, 07 (d, J = 7.2Hz, 1H), 6.98-6.96 (d, J = 7.2Hz, 1H), 6.02 (s, 1H), 4.44 (s, 3H), 3.74 (s, 3H), 3.48 (s, 3H), 2.28 (s, 1H), 1.26 (s, 2H), 1.09 (s , 2H). Example 24. Synthesis of N-ethyl-6-((4-((2-methoxy-3-(2-methyl-2H-tetrazol-5yl)phenyl)amino)-2-methyl-3-oxo-2,3 -dihydro-1H-pyrazolo[3,4-b]pyridin-6- 1.91 I-66 Compound I-66 was prepared from compound 1.91 and 6-amino-A / ethylpicolinamide using the procedure described in Example 2 (yield: 12.50%), MS (ES): m / z 516.41 [M +H]+, LCMS purity: 96.85%, HPLC purity: 95.48%, 1H NMR (MeOD, 400 MHz): 8.18 (s, 1H), 7.91-7.86 (t , 1H), 7.82- 7.80 (d, J = 8.0Hz, 1H), 7.74-7.72 (m, 1H), 7.68-7.67 (d, 1H), 7.39-7.35 (t , J = 8.0Hz, 1H), 6.19 (s, 1H), 4.48 (s, 3H), 3.84 (s, 3H), 3.53 (s, 3H), 3.52-3.46 (q, J = 7.2Hz, 2H), 1.28-1.25 (t, J = 7.2Hz, 3H). Example 26. Synthesis of 4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3yl)phenyl)amino)-2-methyl-6-((5-methylp ¡ridin-2-yl)amino)-1 H-pyrazolo[3,4b]pyridin-3(2H)-one, 1-16 220 1.92 1-16 Compound 1-16 was prepared from compound 1.92 and 55 methylpyridin-2-amine using the procedure described in Example 2 (yield: 19.68%). MS (ES): m / z 458.2 [M+H]+, LCMS purity: 99.65%, HPLC purity: 99.81%, 1H NMR (DMSO-d6, 400 MHz): 10.67 (s, 1H), 9.76 (s, 1H), 8.93 (s, 1H), 8.57 (s, 1H), 8.11 (s, 1H), 7.84 (s, 1H) , 7.68-7.66 (d, J = 8Hz, 1H), 7.59-7.57 (m, 2H), 7.32-7.18 (m, 1H), 3.96 (s, 3H), 3.78 (s, 3H), 3.29 (s, 3H), 2.23 (s, 3H). Example 27. Synthesis of 6-((4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3yl)phenyl)amino)-2-methyl-3-oxo-2 ,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6yl)amino)nicotinonitrile, I-25 Xanthphos, Pd2(dba)3, K2CO3, DMAC, 140°C, M / W, 20min 1.92 I-25 221 Compound 1-25 was prepared from compound 1.92 and 6aminonicotinonitrile using the procedure described in Example 2 (yield: 12.08%). MS (ES): m / z 469.7 [M+H]+, LCMS purity: 99.49%, HPLC purity: 99.22%, 1H NMR (DMSO-d6, 400 MHz): 10.39 (s, 1H), 8.95 (s, 1H), 8.69 (s, 1H), 8.57 (s, 1H), 8.25-8.23 (m, 1H), 8.14- 8.11 (m, 1H), 7.68-7.66 (d, J = 7.2Hz, 1H), 7.60-7.58 (d, J = 8Hz, 1H), 7.33-7 .29 (m, 1H), 7.10 (s, 1H), 3.96 (s, 3H), 3.78 (s, 3H), 3.31 (s, 3H). Example 28. Synthesis of 4-((4-chloro-2-methoxyphenyl)amino)-2-methyl-6-((4methylpyridin-2-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4 -b]pyridin-3-one, I-42 C! VCl ti •N N— -<< b “YOU 1.9 1 M LiHMDS in THF. || THF, 0*C to TA N.H. 28.1 I—42 Synthesis of compound 28.1. According to the procedure used to prepare 1.91, 28.1 was obtained (yield: 24%). MS (ES): m / z 340.2 [M+H]+. Compound I—42 was prepared from compound 28.1 and 4methylpyridin-2-amine using the procedure described in Example 2 (yield: 12.53%), MS (ES): m / z 411.52 [M +H]+, LCMS purity: 100.00%, HPLC purity: 98.32%, 1H NMR (MeOD, 400 MHz): 8.18-8.17 (d, J = 5.2Hz, 1H) , 7.47-7.45 (d, J = 8.4Hz, 1H), 7.19 (s, 1H), 7.08- 7.06 (d, J = 8.0Hz, 1H), 6.96- 6.94 (d, J = 4.8Hz, 1H), 6.79 (s, 1H), 5.69 (s, 1H), 3.98 (s, 3H), 3.53 ( s, 3H), 2.37 (s, 3H). Example 29. Synthesis of N-(4-((4-(hydroxymethyl)-2-methoxyphenyl)amino)-2methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6ylcyclopropancarboxamide , I-42 a., n a ' ζΐ / NH b LiHMDS 1 M in THF,ho THF, 0°C to RT H.O. 222 1.9 29.1 I—42 Synthesis of compound 29.1. According to the procedure used to prepare 1.91, 29.1 was obtained (yield: 57.32%). MS (ES): m / z 335.8 [M+H]-*-. Compound I—42 was prepared from compound 29.1 and cyclopropanecarboxamide using the procedure described in Example 2 (yield: 17.46%), MS (ES): m / z 384.51 [M+H]+, purity LCMS: 95.04%, HPLC purity: 93.08%, 1H NMR (DMSO-d6, 400 MHz): 10.67-10.64 (d, J = 1.2Hz, 2H), 8.41 (s, 1H), 7.64 (s, 1H), 7.38-7.36 (d, J = 8.0Hz, 1H), 7.09 (s, 1H), 6.96-6.94 (d, J = 8.0Hz, 1H), 5.24 (t, J = 8.0Hz, 1H), 4.51-4.49 (d, J = 8.0Hz, 2H), 3.85 (s, 3H), 3.19 (s, 3H), 1.99 (s, 1H), 0.79 (s, 4H). Example 30. Synthesis of N-(4-((2-methoxy-4-(methoxymethyl)phenyl)amino)-2methyl-3-oxo-2,3-dihydro-1 H-pyrazolo[3,4-b]pyridine -6yl)cyclopropanecarboxamide, I-45 , N.H. 1 M LiHMDS in THF, THF, 0*C to TA UC € UN- Qn+n 1.9 30.1 I—45 Synthesis of compound 30.1. According to the procedure used to prepare 1.91, 30.1 was obtained (yield: 57.51%). MS (ES): m / z 349.8 [M+H]+. Compound 1-45 was prepared from compound 30.1 and cyclopropanecarboxamide using the procedure described in Example 2 (yield: 23.4%), MS (ES): m / z 398.38 [M+H]+, purity LCMS: 96.46%, HPLC purity: 95.23%, 1H NMR (DMSO-d6, 400 MHz): 10.70-10.67 (d, J = 12.4Hz, 2H), 8.49 (s, 1H), 7.68 (s, 1H), 7.41-7.39 (d, J = 8.0Hz, 1H), 7.07 (s, 1H), 6.96-6.94 (d, J = 8.4Hz, 1H), 4.40 (s, 2H), 3.85 (s, 3H), 3.35 (s, 3H), 3.29 ( s, 3H), 1.99 (s, 1H), 0.79-0.78 (d, J = 3.6Hz, 4H). Example 31. Synthesis of N-(4-((3-(1,3-dimethyl-l H-1,2,4-triazol-5-yl)-2methoxyphenyl)amino)-2-methyl-3-oxo- 2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6223 il)cyclopropancarboxamide, 1-46 ..,nh2 CA AL T 1 U .A, Y Ό J ,NH χ-Ν 0 Ύ t H < -A Cl- T r N- N—í \ I ° 'N r LÍHMDS1 M in THF, Cl ° THF . 0C to TA 1.9 bA A NH- ir ' o AH IU í U / -· NH ° (1 v i.; Xantophos. Pd- í dbai ΐ i K?CO<. OMAC -Ν' h WO, M / W. N — .1 1-46 Synthesis of compound 31.1. According to the procedure used to prepare 1.91, 5, 31.1 was obtained (yield: 49.08%). MS (ES): m / z 400.7 [M+H]+. Compound I—46 was prepared from compound 31.1 and cyclopropanecarboxamide using the procedure described in Example 2 (yield: 5.45%), MS (ES): m / z 449.37 [M+H]+, purity of LCMS: 95.95%, HPLC purity: 97.22%, 1H NMR (MeOD, 400 MHz): 7.79-7.77 (d, J = 8.0Hz, 1H), 7.43-7.34 (m, 3H), 3.77 (s, 3H), 3.56 (s, 3H), 3.49 (s, 3H), 2.41 (s, 3H) ), 1.84 (s, 1H), 1.02-0.90 (m,4H). Example 32. Synthesis of 4-((2-methoxy-3-(5-methylthiazol-2-yl)phenyl)amino)-2methyl-6-((4-methylpyridin-2-yl)amino)-1,2- dihydro-3H-pyrazolo[3,4-b]pyridin- 3-one, I—47 .-+7 NH. A ANA íA€A- l. A' \\ 'γΥ* LÍHMDS 1 M in THF, or Xamhohox ΓΊ ii-πι i· z ? .·>. .NH θ íí Ύ ' £ N- THF. 0°C to RT .................i--,-···.-..—·.·..·.·.·.·;·· ·····.·:..···—.·.·..... - - '“'A ''i J. ' i DMAC 14Π C \1 !·> 2 'rm Il To you? ¿i A J. 1 A ':'n 1.9 32.1 1-47 Synthesis of compound 32.1. According to the procedure used to prepare 1.91, 32.1 was obtained (yield: 21.10%). MS (ES): m / z 402.7 [M+HJ+. 224 Compound 1-47 was prepared from compound 32.1 and 4methylpyridin-2-amine using the procedure described in Example 2 (yield: 27.88%), MS (ES): m / z 474.48 [M+H ]+, LCMS purity: 97.47%, HPLC purity: 95.33%, 1H NMR (CDCI3, 400 MHz): 8.71 (s, 1H), 8.10-8.09 (d, J = 4.8Hz, 1H), 7.76 (s, 1H), 7.55-7.53 (d, J = 8.0Hz, 1H), 7.46 (s, 1H), 7.35-7 .33 (d, J = 8.0Hz, 1H), 6.96-6.92 (d, J = 8.0Hz, 1H), 6.75 (s, 2H), 3.39 (s, 6H) , 2.55 (s, 3H), 2.37 (s, 3H). Example 33. Synthesis of N-(4-((3-fluoro-2-methoxyphenyl)amino)-2-methyl-3oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl )cyclopropanecarboxamide, I48 X-X ..NH; í j: V o'-é LiHMDS 1 Menu THF. THF, 0*C toTAα·γΜ Ti Ύ % Xanthphos. Ptí, idwj;, K-CO ° DMAC. WC. MAV. 20mm LI.,.. γ Q l· ? V. 1 / Ύ Cl ° 1.9 33.1 I—48 Synthesis of compound 33.1. According to the procedure used to prepare 1.91, 33.1 was obtained (yield: 54.05%). MS (ES): m / z 323.7 [M+HJ+. Compound I-48 was prepared from compound 33.1 and cyclopropanecarboxamide using the procedure described in Example 2 (yield: 18.47%), MS (ES): m / z 372.33 [M+H]+, purity of LCMS: 98.91%, HPLC purity: 95.67%, 1H NMR (DMSO-d6, 400 MHz): 10.79 (s, 1H), 8.83 (s, 1H), 8.17 ( s, 1H), 7.75 (s, 1H), 7.32-7.30 (d, J = 8.0Hz, 1H), 7.21-7.15 (m, 1H), 7.06- 7.03 (d, J = 10.0Hz, 1H), 3.88 (s, 3H), 3.31 (s, 3H), 2.03-2.01 (t, J = 5.6Hz, 1H ), 0.81-0.81 (d, J = 5.6Hz, 4H). Example 34. Synthesis of N-(4-((3-chloro-2-methoxyphenyl)amino)-2-methyl-3oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6 -yl)cyclopropanecarboxamide, I225 LÍHMDS1 M in THF. THF. 0°C to RT JJ ---XΖΗΓΙ· t II Y-0Y “*· Xan:hphO5. & DMAC bin c M N.H. 1.9 34.1 1-49 According to the procedure used to prepare 1.91, 34.1 was obtained (yield: 47.14%). MS (ES): m / z 340.2 [M+H]+. Compound I-49 was prepared from compound 34.1 and cyclopropanecarboxamide using the procedure described in Example 2. (yield: 39.36%), MS (ES): m / z 388.13 [M+H]+, LCMS purity: 99.46%, HPLC purity: 98.93%, 1H NMR (DMSO- d6, 400 MHz): 10.78 (s, 2H), 8.84 (s, 1H), 7.74 (bs, 1H), 7.46- 7.43 (t, J = 4.8Hz, 1H), 7.22-7.20 (d, J = 4.8Hz, 2H), 3.77 (s, 3H), 3.29 (s, 3H), 1.98 (s, 1H), 0.77 (s, 4H). Example 35: Synthesis of N-(4-((4-cyclopropyl-2-methoxyphenyl)amino)-2-methyl- 3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropanecarboxamide, I-50 LIHMDS 1 M in THF, THF, 0°C to RT xwhphrr» □MAL' 1-4Y r* .JJt )ir¡ 1.9 35.1 I-50 According to the procedure used to prepare 1.91, 35.1 was obtained (yield: 54.80%). MS (ES): m / z 345.7 [M+H]+. 226 Compound 1-50 was prepared from compound 35.1 and cyclopropanecarboxamide using the procedure described in Example 2 (yield: 16.18%), MS (ES): m / z 394.61 [M+H]+, purity of LCMS: 94.66%, HPLC purity: 99.76%, 1H NMR (DMSO-d6, 400 MHz): 10.67-10.62 (d, J = 17.6Hz, 2H), 8.36 (s, 1H), 7.58 (bs, 1H), 7.29-7.268 (d, J = 8.0Hz, 1H), 6.83-6.83 ( d, J = 1.6Hz, 1H), 6.72-6.69 (dd, J = 1.6Hz, 8.0Hz, 1H), 3.83 (s, 3H), 3.28 (s, 3H ), 2.01-1.90 (m, 2H), 0.96-0.90 (m, 2H), 0.79-0.77 (d, J = 5.2Hz, 4H), 0.74-0 .72 (dd, J = 3.2Hz, 4.8Hz, 2H). Example 36: Synthesis of N-(4-((4-cyclobutyl-2-methoxyphenyl)amino)-2-methyl-310 oxo-2,3-dihydro-1 H-pyrazolo[3,4-b]pyridin-6 -yl)cyclopropancarboxamide, I51 H vn..... il LÍHMDS 1 M in THF, THF, 0°C to TA CK ,.N._ -N xi- X o Δ ,NH? I <anthphos Pd¿. Appointment; UMAC 140cC, K J ó.....N .. ,|J 3 Γ ιΓ N·, KCOj C ;·2θ,χ rX c Cl θ O' í I . 1.9 36.1 1-51 15 According to the procedure used to prepare 1.91, 36.1 was obtained (yield: 50.64%). MS (ES): m / z 359.8 [M+HJ+. Compound 1-51 was prepared from compound 36.1 and cyclopropanecarboxamide using the procedure described in Example 2 (yield: 42.27%), MS (ES): m / z 408.37 [M+HJ+, LCMS purity : 96.20%, HPLC purity: 96.45%, 1H NMR (DMSO-d6, 400 MHz): 10.67-10.63 (d, J = 17.2Hz, 2H), 8.41 (s , 1H), 7.64 (s, 1H), 7.35-7.33 (d, J = 8.0Hz, 1H), 6.97 (s, 1H), 6.88-6.87 (d, J = 8.0Hz, 1H), 3.85 (s, 3H), 3.54-3.48 (q, J = 8.8Hz, 1H), 3.28 (s, 3H), 2.33-2.25 (m, 2H), 2.19-2.09 (m, 2H), 2.02-1.93 (m, 2H), 1.85-1.80 (m, 1H), 227 0.79-0.78 (d, J = 5.2Hz, 4H). Example 37: Synthesis of N-(4-((2-methoxy-3-(1-methyl-1H-tetrazol-5yl)phenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H- pyrazolo[3,4-b]pyridin-6yljcyclopropanecarboxamide, I-52 o' rv-N. HN 1 A„N CK. -N. Η -N ,A Λ η F i. 1 — LA.. NH- 'V γ.·> U 's T b Y ' 0 τ' Ύ LiHMDS 1 M in THF, ii T XantJ’phos. FM i·4*·.*· rc, ,NH '-γΥ 'γΆ Ϊ ¡f N-- THF, 0°C to TA k Y 0 OMAC. 11Ü i, L! / < -3 π 11 [i , i Yv * ·, i Γ V Γ! ° Ν'' Ν'' N'· --r’ N=N N N 1.9 37.1 1-52 According to the procedure used to prepare 1.91, 37.1 was obtained (yield: 68.77%). MS (ES): m / z 387.7 [M+HJ+. Compound 1-52 was prepared from compound 37.1 and cyclopropanecarboxamide using the procedure described in Example 2 (yield: 22.21%), MS (ES): m / z 436.37 [M+H]+, purity of LCMS: 97.49%, HPLC purity: 94.04%, 1H NMR (DMSO-d6, 400 MHz): 10.78 (s, 1H), 8.82 (s, 1H), 8.19 ( s, 1H), 7.75-7.73 (d, J = 7.6Hz, 1H), 7.65 (s, 1H), 7.4467.40 (t, J 15 7.6Hz, 1H), 7.36-7.34 (d, J = 6.4Hz, 1H), 3.99 (s, 3H), 3.47 (s, 3H), 2.61 (s, 3H), 2.03-2.00 (t, J = 6.0Hz, 1H), 0.81-0.79 (d, J = 6.0Hz, 4H). Example 38: Synthesis of N-(4-((3-(1,5-dimethyl-1H-1,2,4-triazol-3-yl)-2methoxyphenyl)amino)-2-methyl-3-oxo-2 ,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6yl)cyclopropanecarboxamide, I-53 228 LÍHMDS 1 Μ enTHF, THF. 0°C to ΤΑ 1.9 Δ., r Τ π ' ,-¼. .-NH i ;j Xrjnthpncs. Pd- idúal·;., :'.:>·(>' τ o- OMAC. ^rriu X ► Ν '” ‘Ν Ν— / •4 ' Ν Η-4 38.1 Ι-53 According to the procedure used to prepare 1.91, 38.1 was obtained (yield: 68.16%). MS (ES): m / z 400.8 [M+H]+. Compound I-53 was prepared from compound 38.1 and cyclopropanecarboxamide using the procedure described in Example 2 (yield: 30.67%), MS (ES): m / z 449.37 [M+HJ+, LCMS purity : 98.48%, HPLC purity: 95.33%, 1H NMR (CDCI3, 400 MHz): 9.59 (bs, 1H), 8.89 (s, 1H), 7.59-7.57 ( d, J = 7.6Hz, 1H), 7.49-7.47 (d, J = 8.0Hz, 1H), 7.13-7.02 (m, 2H), 10 3.89 (s, 3H), 3.71 (s, 3H), 3.47 (s, 3H), 2.52 (s, 3H), 1.65 (s, 1H), 1.11 (s, 2H), 0.90 (s, 2H). Example 39: Synthesis of N-(4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-5yl)phenyl)amino)-2-methyl-3-oxo-2, 3-dihydro-1 H-pyrazolo[3,4-b]pyridin-6yljcyclopropanecarboxamide, I-54 l J1 Ϊ I ¢0 Il N LÍHMDS 1 M in THF, THF. 0*C to TA ri u H L (. I . I 0 Ν' N Λ NH. V ó X.arifphos. Pd . CS / DMAC. W:C. MW .·' \ 11 i f ' ,N N. m Π ..... / Γ r Y 4, ;o, v ..NH 1 J . T rrz ν' 15 1.9 39.1 I-54 According to the procedure used to prepare 1.91, 39.1 was obtained (yield: 62.17%). MS (ES): m / z 386.6 [M+H]+. 229 Compound 1-54 was prepared from compound 39.1 and cyclopropanecarboxamide using the procedure described in Example 2 (yield: 17.76%), MS (ES): m / z 435.32 [M+H]+, purity of LCMS: 99.53%, HPLC purity: 99.60%, 1H NMR (DMSO-d6, 400 MHz): 10.78 (bs, 1H), 8.84 (s, 1H), 8.08 ( s, 1H), 7.71 (s, 1H), 7.68-7.66 (d, J = 8.0Hz, 1H), 7.38-7.34 (m, 1H), 7.25- 7.23 (d, J = 8.0Hz, 1H), 3.74 (s, 3H), 3.49 (s, 3H), 3.22 (s, 3H), 2.03-2.00 ( m, 1H), 0.81-0.79 (d, J = 5.2Hz, 4H). Example 40: Synthesis of N-(4-((2-methoxy-3-(1-methyl-1H-pyrazol-4¡l)phenyl)amino)-2-methyl-3-oxo-2,3-dihydro- 1H-pyrazolo[3,4-b]pyridin-6yl)cyclopropancarboxamide, I-55. X¿a- s t υ r i * i h a y l n v il y n --n y ' / h lihmds 1 m in thf, íi ϊ a- r i a- thf, 0'c until ta already, · 1 i and cl a 0 a JM-N 1.9 40.1 Depending on the procedure used A Η . H i r ii ñ...... Π Ά-·’ Ά. ru n Y> N-N 1-55 to prepare 1.91, obtained 40.1 (yield: 48.16%). MS (ES): m / z 385.7 [M+HJ+. Compound I-55 was prepared from compound 40.1 and cyclopropanecarboxamide using the procedure described in Example 2 (yield: 20.89%), MS (ES): m / z 434.48 [M+H]+, purity of LCMS: 100.00%, HPLC purity: 100.00%, 1H NMR (DMSO-d6, 400 MHz): 10.76 (bs, 1H), 8.81 (s, 1H), 8.19 ( s, 1H), 7.92 (s, 1H), 7.77 (s, 1H), 7.38-7.33 (t, J = 10.0Hz, 2H), 7.21-7.19 (d, J = 8.0Hz, 1H), 3.90 (s, 3H), 3.61 (s, 3H), 3.32 (s, 3H), 2.02 ( s, 1H), 0.80 (s, 4H). Example 41: Synthesis of N-(4-((2-methoxy-3-(1H-pyrazol-1-yl)phenyl)amino)-2230 methyl-3-oxo-2,3-dihydro-1 H-pyrazolo[3,4-b]pyridin-6yljcyclopropancarboxamide, I-56 .NH, ÍZ,, T° Λ 1 M LiHMDS in THF. THF, 0’C to TA '\o Xanthphos. Fa? ídba CS.CC DMAC. 14LCC. WW. 8üm¡n 1.9 41.1 I-56 According to the procedure used to prepare 1.91, 41.1 was obtained (yield: 58.80%). MS (ES): m / z 371.8 [M+H]+. Compound I-56 was prepared from compound 41.1 and cyclopropanecarboxamide using the procedure described in Example 2 (yield: 22.10%), MS (ES): m / z 420.48 [M+HJ+, LCMS purity : 99.87%, HPLC purity: 99.66%, 1H NMR (DMSO-d6, 400 MHz): 10.80 (bs, 1H), 8.88 7.39-7.31 (m, 2H), 6.57 (s, 1H), 3.45 (s, 3H), 3.32 (s, 3H), 2.02 (s, 1H), 0 .81 (s, 4H). Example 42: Synthesis of N-(4-((2-methoxy-3-(1-methyl-1H-pyrazol-3yl)phenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1 H -pyrazolo[3,4-b]pyridin-6yljcyclopropanecarboxamide, I-57 231 1 M LiHMDS in THF, THF, O’C to TA Zx..„ .nh, J. Xsntnphcn,r’c:. 1 C5-.CO· DMAC. I4frc. rw. hOm π 1.91 42.1 I-57 According to the procedure used to prepare 1.91, 42.1 was obtained (yield: 37.77%). MS (ES): m / z 385.5 [M+HJ+. Compound I-57 was prepared from compound 42.1 and cyclopropanecarboxamide using the procedure described in Example 2 (yield: 31.07%), MS (ES): m / z 434.63 [M+H]+, purity of LCMS: 100.00%, HPLC purity: 96.16%, 1H NMR (DMSO-d6, 400 MHz): 10.76 (bs, 2H), 8.83 (s, 1H), 7.79 ( s, 2H), 7.62-7.60 (d, J = 7.6Hz, 1H), 7.44-7.42 (d, J = 7.6Hz, 1H), 10 7.24-7, 22 (m, 1H), 6.74-6.73 (d, J = 2.4Hz, 1H), 3.91 (s, 3H), 3.61 (s, 3H), 3.31 (s, 3H), 2.02 (s, 1H), 0.81 (s, 4H). Example 46: Synthesis of N-(4-((2-methoxyphenyl)amino)-2-methyl-3-oxo-2,3dihydro-1 H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropanecarboxamide, 1-61. Cl N;. you Ϊ X ,NLiHMDS 1 M in THF, Y T THF. 0°C up to RT or ................................... -EITHER Yo Pd2‘jdbrj / .. CcXCO DMAC, MW. bC-Hin 1.9 46.1 1-61 According to the procedure used to prepare 1.91, 46.1 was obtained 232 (yield: 75.13%). MS (ES): m / z 305.7 [M+H]+. Compound 1-61 was prepared from compound 46.1 and cyclopropanecarboxamide using the procedure described in Example 2 (yield: 19.83%), MS (ES): m / z 354.38 [M+HJ+, LCMS purity : 100.00%, HPLC purity: 98.86%, 1H NMR (DMSO-d6, 400 MHz): 10.69-10.67 (d, J = 10.8Hz, 2H), 8.53 ( s, 1H), 7.69 (s, 1H), 7.45-7.43 (d, J = 8.0Hz, 1H), 7.13-7.12 (d, J = 4.0Hz, 2H ), 7.03-6.99 (m, 1H), 3.85 (s, 3H), 3.29 (s, 3H), 1.99 (s, 1H), 0.78 (s, 4H). Example 51: Synthesis of 4-((2-methoxy-4-(methoxymethyl)phenyl)amino)-2-methyl10 6-((6-(trifluoromethyl)pyridin-2-yl)amino)-1,2-dihydro- 3H-pyrazolo[3,4b]pyridin-3-one, I-67 LÍHMDS1 M in THF, THF, 0*C to TA 1.9 51.1 DMAC, 140 C MfW ?·ΐ''·ηιη I-67 According to the procedure used to prepare 1.91, 51.1 was obtained (yield: 78.14%). MS (ES): m / z 349.7 [M+H]+. Compound i-67 was prepared from compound 51.1 and 6(trifluoromethyl)pyridin-2-amine using the procedure described in Example 2 (yield: 14.70%), MS (ES): m / z 475 .35 [M+H]+, LCMS purity: 100.00%, HPLC purity: 95.73%, 1H NMR (DMSO-d6, 400 MHz): 10.72 (s, 1H), 10.21 (s, 1H), 8.69 (s, 1H), 8.13-8.10 (d, J = 8.4Hz, 1H), 7.96-7.92 (t, J = 8.4Hz, 1 HOUR), 7.54-7.52 (d, J = 8.0Hz, 1H), 7.38-7.36 (d, J = 7.2Hz, 1H), 7.32 (s, 1H), 7.06 (s, 1H), 6.95-6.93 (d, J = 7.6Hz, 1H), 4.42 (s, 2H), 3.88 (s, 3H), 3.31 (s, 3H) ), 3.28 (s, 3H). Example 52: Synthesis of 6-((4-((2-methoxy-4-(methoxymethyl)phenyl)amino)-2233 methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6yl)amino)picolinonitrile, I-68 ..NH-. ί χ Yo 1 M LiHMDS in THF, THF. 0°C to TA '-í 1.9 52.1 Depending on the procedure used Xanthphos. Q:!;· híbai., OS>CO, DMAC. 140'C to prepare 1.91, 52.1 was obtained (yield: 78.14%). MS (ES): m / z 349.7 [M+H]+. Compound I-68 was prepared from compound 52.1 and 6-aminopicolinonitrile using the procedure described in Example 2 (yield: 32.34%), MS (ES): m / z 432.34 [M+H] +, LCMS purity: 97.69%, HPLC purity: 96.47%, 1H NMR (DMSO-d6, 400 MHz): 10.72 (s, 1H), 10.24 (s, 1H), 8 .64 (s, 1H), 8.08 (s, 1H), 7.89 (s, 1H), 7.56-7.53 (d, J = 10.0Hz, 2H), 7.32 (s , 1H), 7.08-7.05 (d, J = 10.4Hz, 2H), 4.41 (s, 2H), 3.88 (s, 3H), 3.33 (s, 3H), 3.28 (s, 3H). Example 53: Synthesis of N-(4-((3-bromo-2-methoxyphenyl)amino)-2-methyl-3oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl )cyclopropanecarboxamide, I69 \H * .. .NH- Y B' L Δ. ί X >- Η η N . ,N.. _f.j 1 j and H LiHMDS 1 M in THF. Y Λ 1.9 53.1 I-69 According to the procedure used to prepare 1.91, 53.1 was obtained 2. 3. 4 (yield: 56.84%). MS (ES): m / z 384.6 [M+H]+. Compound 1-69 was prepared from compound 53.1 and cyclopropanecarboxamide using the procedure described in Example 2 (yield: 15.53%), MS (ES): m / z 434.27 [M+H]+, purity LCMS: 98.62%, HPLC purity: 98.29%, 1H NMR (DMSO-d6, 400 MHz): 10.79-10.78 (d, J = 7.6Hz, 2H), 8.83 (s, 1H), 7.75 (s, 1H), 7.46-7.44 (t, J = 9.6Hz, 1H), 7.22 (s, 1H), 7.21 (s, 1H), 3.78 (s, 3H), 3.32 (s, 3H), 1.98 (s, 1H), 0.79 (s, 4H). Example 54: Synthesis of 4-((4-(hydroxymethyl)-2-methoxyphenyl)amino)-2-methyl- 6-((6-(trifluoromethyl)pyridin-2-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4b]pyridin-3-one, I-72 LÍHMDS 1 M in THF, THF, 0’C to TA HO.. rthpnr.·4·, ícrt.tí· OMAC + π 1.9 54.1 i-72 According to the procedure used to prepare 1.91, 54.1 was obtained (yield: 65.13%). MS (ES): m / z 335.8 [M+H]+. Compound i-72 was prepared from compound 54.1 and 6(trifluoromethyl)pyridin-2-amine using the procedure described in Example 2 (yield: 14.54%), MS (ES): m / z 461 .38 [M+H]+, LCMS purity: 98.86%, HPLC purity: 95.52%, 1H NMR (DMSO-d6, 400 MHz): 10.71 (s, 1H), 10.20 (s, 1H), 8.66 (s, 1H), 8.15-8.13 (d, J = 9.2Hz, 1H), 7.96-7.92 (t, J = 7.6Hz, 1 HOUR), 7.52-7.49 (d, J = 8.0Hz, 1H), 7.38-7.36 (d, J = 7.2Hz, 1H), 7.27 (s, 1H), 7.08 (s, 1H), 6.95-6.94 (d, J = 7.6Hz, 1H), 5.24-5.22 (t, J = 5.6Hz, 1H), 4.51-4, 50 (d, J = 5.6Hz, 2H), 3.87 (s, 3H), 3.28 (s, 3H). 235 Example 55: Synthesis of 4-((3-fluoro-2-methoxyphenyl)amino)-2-methyl-6-((5(piperidin-1-yl)pyridin-2-yl)amino)-1,2-dihydro -3H-pyrazolo[3,4-b]pyridin-3-one, I-77 „NH, lí 1 T '9 F UHMDS 1 M in THF, THF, (PC to TA F 1.9 |TYNH2 Xantphos, Pd2(dba)3, Cs2CO3, DMAC, 140°C, MW According to the procedure used to prepare 1.91, 55.1 10 was obtained (yield: 81.07%). MS (ES): m / z 323.7 [M+H]+. Compound I-77 was prepared from compound 55.1 and 5(piperidin—1 —yl)pyridin—2—amine using the procedure described in Example 2 (yield: 20.89%), MS (ES): m / z 464.53 [M+H]+, LCMS purity: 100.00%, HPLC purity: 98.80%, 1H NMR (DMSO-d6, 400 MHz): 10.67 (s, 1H), 9 .58 (s, 15 1H), 8.90 (s, 1H), 8.02 (s, 2H), 7.40 (s, 2H), 7.22-7.17 (q, J = 8, 4Hz, 1H), 7.01 (s, 2H), 3.89 (s, 3H), 3.27 (s, 3H), 3.08 (s, 4H), 1.64 (s, 4H), 1.23 (s, 2H). Example 56: Synthesis of 4-((3-fluoro-2-methoxyphenyl)amino)-2-methyl-6-((1methyl-1H-pyrazol-3-¡l)amino)-1,2-dihydro- 3H-pyrazolo[3,4-b]pyridin-3-one, I-78 236 55.1 Xantphos, Pd2(dba)3, Cs2CO3, DMAC, 140°C, MW Compound I-78 was prepared from compound 55.1 and 1-methyl-1H5 pyrazole-3-amine using the procedure described in Example 2 (yield: 37.88%), MS (ES): m / z 384, 43 [M+H]+, LCMS purity: 97.80%, HPLC purity: 93.71%, 1H NMR (DMSO-d6, 400 MHz): 10.52 (bs, 1H), 9.52 ( bs, 1H), 8.78 (s, 1H), 7.54 (s, 1H), 7.42-7.39 (d, J = 8.4Hz, 1H), 7.21-7.15 (q, J = 8 ,4Hz, 1H), 7.01-6.97 (d, J = 9.6Hz, 1H), 6.88 (s, 1H), 6.35 (s, 1H), 3.89 (s, 3H ), 3.72 (s, 3H), 3.25 (s, 3H). Example 57: Synthesis of 6-((4-((3-fluoro-2-methoxyphenyl)amino)-2-methyl-3oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6- il)amino)nicotinonitrile, I-79 55.1 I-79 Compound 1-79 was prepared from compound 55.1 and 6aminonicotinonitrile using the procedure described in Example 2 (yield: 39.80%), MS (ES): m / z 406.29 [M+H]+, purity of LCMS: 98.61%, HPLC purity: 99.01%, 1H NMR (DMSO-d6, 400 MHz): 10.99 (s, 1H), 10.44 (s, 1H), 8.88 ( s, 1H), 8.69 (s, 1H), 8.23-8.21 (d, J = 8.8Hz, 1H), 8.15-8.13 (dd, J = 237 7.15 (s, 1H), 7.06-7.01 (d, J = 8.8Hz, 1H), 3.89 (s, 3H), 3.35 (s, 3H). Example 58: Synthesis of 4-((3-fluoro-2-methoxyphenyl)amino)-2-methyl-6(pyridin-2-ylamino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridine -3-one, I-80 55.1 Xanthphos, Pd2(dba)3, CS2CO3, DMAC, 140°C, M / W, 80min Compound I—80 was prepared from compound 55.1 and pyridin—2—amine using the procedure described in Example 2 (yield: 21.21%), MS (ES): m / z 381.28 [M+H ]+, LCMS purity: 97.64%, HPLC purity: >* 97.36%, 1H NMR (DMSO-d6, 400 MHz): 10.78 (s, 1H), 9.85 (s, 1H), 8.85 (s, 1H), 8.26 (s, 1H), 8.03 (s, 1H), 7.71 (s, 1H), 7.44 (s, 1H), 7.21 (s, 2H), 7.06-6 .83 (m, 2H), 3.96 (s, 3H), 3.29 (s, 3H). Example 59: Synthesis of 6-((4-((3-fluoro-2-methoxyphenyl)amino)-2-methyl-3oxo-2,3-dihydro-1 H-pyrazolo[3,4-b]pyridin-6 -yl)amino)picolinonitrile, 1-81 Xantphos, Pd2(dba)3, Cs2CO3, DMAC, 140°C, MW Compound 1-81 was prepared from compound 55.1 and 6aminopicolinonitrile using the procedure described in Example 2 238 (yield: 43.78%), MS (ES): m / z 406.43 [M+H], LCMS purity: 100.00%, HPLC purity: 100.00%, 1H NMR (DMSO-d6 , 400 MHz): 10.84 (s, 1H), 10.32 (s, 1H), 8.95 (s, 1H), 8.05-8.03 (d, J = 8.4Hz, 1H) , 7.93-7.89 (t, J = 8.4Hz, 1H), 7.56-7.49 (m, 3H), 7.26-7.20 (q, J = 8.0Hz, 1H ), 7.06-7.01 (t, J = 9.2Hz, 1H), 3.91 (s, 3H), 3.30 (s, 3H). Example 60: Synthesis of N-(4-((4-(azetidine-1-carbonyl)-2methoxyphenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyrazolo [3,4-b]pyridin-6yl)cyclopropanecarboxamide, I-82 „NH¿ lí ' O ¿A. ,N_ il H ’u— ’v ·. ‘Π ~ υ 0 L £ í V XhíiUífios Cs^CO,. DMAC T o I] Ύ h — ............. ................... O 1 Ί 140' C. MW .. .................................................. ... i or LiHMDS 1 M in THF, THF, 0°C up to TA U-N A xA Y ° .-1- y 1.9 60.1 I-82 According to the procedure used to prepare 1.91, 60.1 was obtained (yield: 24.74%). MS (ES): m / z 388.8 [M+H]+. Compound I-82 was prepared from compound 60.1 and cyclopropanecarboxamide using the procedure described in Example 2 (yield: 21%), MS (ES): m / z 437.37 [M+H]+, LCMS purity : 100.00%, HPLC purity: 98.68%, 1H NMR (MeOD, 400 MHz): 7.61-7.59 (d, J = 8.0Hz, 2H), 7.39 (s, 1H) ), 7.34-7.32 (d, J = 8.4Hz, 1H), 4.51-4.47 (t, J = 6.4Hz, 2H), 4.25- 4.21 (t, J = 6.4Hz, 2H), 3.99 (s, 3H), 3.49 (s, 3H), 2.45-2.38 (qui, J = 6.4Hz, 2H ), 1.84 (s, 1H), 1.04-0.96 (m, 4H). Example 61: Synthesis of 4-((3-fluoro-2-methoxyphenyl)amino)-2-methyl~6-((4methylpyridín-2-yl)amino)-1,2-dihydro-3H-pyrazolo [3,4-b]pyridin-3-one, I-83 239 55.1 Xantphos, Pd2(dba)3, Cs2CO3, DMAC, 140°C, MW Compound I-83 was prepared from compound 55.1 and 4methylpyridin-2-amine using the procedure described in Example 2 5 (yield: 30.68%), MS (ES): m / z 395.28 [M+ H]+, LCMS purity: 98.12%, HPLC purity: 97.83%, 1H NMR (DMSO-d6, 400 MHz): 10.72 (s, 1H), 9.72 (s, 1H) , 8.82 (s, 1H), 8.09 (s, 1H), 7.83 (s, 1H), 7.43-7.42 (d, J = 7.2Hz, 1H), 7.20 - 7.14 (m, 2H), 6.98 (s, 1H), 6.76 (s, 1H), 3.87 (s, 3H), 3.26 (s, 3H), 2.28 (s , 3H). Example 62: Synthesis of 4-((3-fluoro-2-methoxyphenyl)amino)-2-methyl-6-((510 methylpyridin-2-yl)amino)-1,2-dihydro-3H-pyrazolo[ 3,4-b]pyridin-3-one, I-84 55.1 I-84 Compound I-84 was prepared from compound 55.1 and 5methylpyridin-2-amine using the procedure described in Example 2 (yield: 20.46%), MS (ES): m / z 395.32 [M+Hf , LCMS purity: 97.72%, HPLC purity: 97.18%, 1H NMR (MeOD, 400 MHz): 8.15 (s, 1H), 7.65-7.62 (dd, J = 2 ,0Hz, 8.4Hz, 1H), 7.33-7.31 (d, J = 8.0Hz, 1H), 7.18-7.13 (m, 2H), 7.087.03 (t, J = 8.8Hz, 1H), 6.89-6.87 (d, J = 7.6Hz, 1H), 3.97 (s, 3H), 3.54 (s, 3H), 2.31 (s, 3H). 240 Example 63: Synthesis of 6-((4-((3-fluoro-2-methoxyphenyl)amino)-2-methyl-3oxo-2,3-dihydro-1 H-pyrazolo[3,4-b]pyridin-6 -yl)amino)pyrazin-2carbonitrile, I-85 55.1 I-85 Compound I-85 was prepared from compound 55.1 and 6aminopyrazin-2-carbonitrile using the procedure described in Example 2 (yield: 17.87%), MS (ES): m / z 407.27 [M+H ]+, LCMS purity: 99.70%, HPLC purity: 99.67%, 1H NMR (DMSO-d6, 400 MHz): 10.96 (bs, 1H), 10.67 (bs, 1H), 9.31 (s, 1H), 8.92 (s, 1H), 8.65 (s, 1H), 7.47-7.45 (d, J = 8.0Hz, 1H), 7.38 ( s, 1H), 7.24-7.18 (q, J = 8.0Hz, 1H), 7.08-7.03 (t, J = 6.0Hz, 1H), 3.91 (s, 3H ), 3.35 (s, 3H). Example 64: Synthesis of 4-((3-fluoro-2-methoxyphenyl)amino)-2-methyl-6-((6(trifluoromethyl)pyridin-2-yl)amino)-1,2-dihydro-3H-pyrazolo [3,4-b]pyridin-315 one, 1-86 55.1 I-86 Compound I-86 was prepared from compound 55.1 and 6 241 (trifluoromethyl)pyridin—2—amine using the procedure described in Example 2 (yield: 14.99%), MS (ES): m / z 449.32 [M+Hf, LCMS purity: 99.81%, HPLC purity: 99.80%, 1H NMR (DMSO-d6, 400 MHz): 10.80 (bs, 1H), 10.24 (bs, 1H), 8.95 (s, 1H), 8.08 -8.06 (d, J = 8.0Hz, 1H), 7.95-7.91 (t, J = 8.0Hz, 1H), 7.43-7.35 (m, 3H), 7, 14-7.09 (q, J = 8.0Hz, 1H), 7.03-6.98 (t, J = 8.0Hz, 1H), 3.88 (s, 3H), 3.28 (s , 3H). Example 65: Synthesis of 6-((6-cyclopropylpyridin-2-yl)amino)-4-((3-fluoro-2methoxyphenyl)amino)-2-methyl-1,2-dihydro-3H-pyrazolo[3,4 -b]pyridin-3-one, I87 55.1 I-87 Compound I-87 was prepared from compound 55.1 and 6cyclopropylpyridin-2-amine using the procedure described in Example 2 (yield: 19.19%), MS (ES): m / z 421.32 [M+Hf , LCMS purity: 98.94%, HPLC purity: 94.15%, 1H NMR (DMSO-d6, 400 MHz): 11.46 (s, 1H), 8.99 (s, 1H), 7, 95-7.91 (t, J = 8.0Hz, 1H), 7.29-7.27 (d, J = 7.2Hz, 1H), 7.18-7.16 (d, J = 8, 4Hz, 2H), 7.08-7.06 (d, J = 7.2Hz, 1H), 6.99-6.97 (d, J = 8.4Hz, 1H), 6.04 (s, 1H) ), 3.85 (s, 3H), 3.45 (s, 3H), 2.31-2.24 (m, 1H), 1.28-1.23 (m, 2H), 1.11- 1.06 (m, 2H). Example 66: Synthesis of N-(4-((2-methoxy-3-(2-oxopyrrolidin-1yl)phenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3, 4-b]pyridin-6yljcyclopropancarboxamide, I-88 242 ,ΝΗ2 item Ύ 4-X NH;· , Y Y- γ or CK -N. H H X ... M H _.N I i O Π N 1 k . il Η N — i;X ) \_ / 'T ,ÑH o Xantphos. P.S? (d ba) ü ,, NH ® ,N, sj 1 M LiHMDS in THF. l í Ύ Cs2CO<,. DMAC THF. 0*0 up to TA 140¾ MW l , , i N — t o- Ό I x?·., T Cl ° \____ / 1.9 66.1 I- -88 According to the procedure used to prepare 1.91, 66.1 was obtained (yield: 56.22%). MS (ES): m / z 388.7 [M+H]+. Compound I-88 was prepared from compound 66.1 and cyclopropanecarboxamide using the procedure described in Example 2 (yield: 17.06%), MS (ES): m / z 437.37 [M+H]+, purity of LCMS: 96.29%, HPLC purity: 95.84%, 1H NMR (DMSO-d6, 400 MHz): 10.77 (s, 1H), 8.77 (s, 1H), 7.79 ( s, 1H), 7.44-7.42 (d, J = 7.6Hz, 1H), 7.23-7.19 (t, J = 8.0Hz, 1H), 7.06- 3H), (s, 4H). Example 67: 4-((3-fluoro-2-methoxyphenyl)amino)-2-methyl-6-((5-morpholinopyridin-2-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4- b]pyridin-3-one, 1-89 Xanthphos, Pd2(dba)3, CS2CO3, DMAC, 140°C, M / W, 80min 55.1 I-89 Compound I-89 was prepared from compound 55.1 and 5morpholinopyridine-2-amine using the procedure described in Example 2 243 (yield: 13.87%), MS (ES): m / z 466.52 [M+H], LCMS purity: 95.70%, HPLC purity: 95.05%, 1H NMR (DMSO-d6 , 400 MHz): 11.33 (s, 1H), 8.91 (s, 1H), 8.05-8.02 (dd, J = 2.4Hz, 9.2Hz, 1H), 7.83- 7.82 (d, J = 2.4Hz, 1H), 7.32- 7.11 (m, 5H), 6.09 (s, 1H), 3.86 (s, 3H), 3.75 (s, 4H), 3.38 (s, 3H), 3.12 (s , 4H). Example 68: Synthesis of 4-((3-fluoro-2-methoxyphenyl)amino)-2-methyl-6-((5(pyrrolidin-1-yl)pyridin-2-yl)amino)-1,2-dihydro -3H-pyrazolo[3,4-b]pyridin-3- Xanthphos, Pd2(dba)3, CS2CO3DMAC, 140°C, M / W, 80min Compound 1-90 was prepared from compound 55.1 and 5 (pyrrolidin—1—yl)pyridin—2—amine using the procedure described in Example 2 (yield: 17.95%), MS (ES): m / z 450.42 [M+H]+, LCMS purity: 97.66%, HPLC purity: 96.95%, 1H NMR (DMSO-d6, 400 MHz): 7.61-7.58 (dd, J = 2.4Hz, 9.6Hz, 1H), 7.47-7.47 (d, J = 2.4Hz, 1H), 7.30-7.28 (d, J = 8.4Hz, 1H) , 7.22-7.19 (d, J = 9.6Hz, 1H), 7.16-7.11 (m, 1H), 7.05-7.00 (d, J = 9.6Hz, 1H) , 6.15 (s, 1H), 3.85 (s, 3H), 3.34 (s, 3H), 3.21 (s, 4H), 1.95 (s, 4H). Example 69: Synthesis of 6-((5-cyclopropylpyridin-2-yl)amino)-4-((3-fluoro-2methoxyphenyl)amino)-2-methyl-1,2-dihydro-3H-pyrazol[3 ,4-b]pyridin-3-one, I91 244 55.1 Xanthphos, Pd2(dba)3, CS2CO3, DMAC, 140°C, M / W, 80min Compound 1-91 was prepared from compound 55.1 and 5cyclopropylpyridin-2-amine using the procedure described in Example 2 5 (yield: 15.99%), MS (ES): m / z 421.29 [M+ H]+, LCMS purity: 95.97%, HPLC purity: 95.65%, 1H NMR (DMSO-d6, 400 MHz): 11.50 (s, 1H), 8.93 (s, 1H) , 8.17 (s, 1H), 7.85-7.83 (d, J = 8.4Hz, 1H), 7.31-7.29 (d, J = 7.2Hz, 1H), 7.23-7.12 (m, 3H), 6.14 (s, 1H), 3.85 (s, 3H), 3.38 (s, 3H), 2.04 (s, 1H), 1 .02 (s, 2H), 0.72 (s, 2H). Example 70: Synthesis of 4-((2-methoxy-4-(methoxymethyl)phenyl)amino)-2-methyl6-((5-(pyrrolidin-1-carbonyl)-6-(trifluoromethyl)pyridin-2-yl) amino)-1,2dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-92 CL. ,N, i and 1 M LiHMDS in THF. THF. 0'C to TA í-.c, ,N. ,NHz. either Xantphos. Pd^dbah. Cs:?COi, DMAC. 14ÍFC MW 1-92 245 According to the procedure used to prepare 1.91, 70.1 was obtained (yield: 78.14%). MS (ES): m / z 349.7 [M+Hf. Compound I-92 was prepared from compound 70.1 and (6-amino- 2-(trifluoromethyl)pyridin-3-¡l)(pyrrolidin—1-yl)methanone using the procedure described in Example 2 (yield: 17.09%), MS (ES): m / z 572.37 [M +Hf, LCMS purity: 94.64%, HPLC purity: 95.10%, 1H NMR (DMSO-d6, 400 MHz): 10.78 (s, 1H), 10.32 (s, 1H), 8.67 (s, 1H), 8.22-8.20 (d, J = 8.8Hz, 1H), 7.89-7.87 (d, J = 8.8Hz, 1H), 7.53-7.51 (d, J = 8.0Hz, 1H), 7.21 (s, 1H), 7.07 (s, 1H), 6.95-6.93 (d, J = 8.0Hz, 1H), 4.42 (s, 2H), 3.88 (s, 3H), 3.47-3.43 (t, J = 6.0Hz, 2H), 3.31 (s, 3H), 3.28 (s, 3H), 3.13-3.10 (t, J = 6.0Hz, 2H), 1 .89-1.81 (m, 4H). Example 71: Synthesis of 4-((2-methoxy-4-(methoxymethyl)phenyl)amino)-2-methyl- 6-((5-methyl-6-(trifluoromethyl)pyridin-2-yl)amino)-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one, I-93 70.1 I-93 Compound i-93 was prepared from compound 70.1 and 5-methyl-6(trifluoromethyl)pyridin—2—amine using the procedure described in Example 2 (yield: 26.18%), MS (ES): m / z 489.43 [M+Hf, LCMS purity: 94.92%, HPLC purity: 99.24%, 1H NMR (DMSO-d6, 400 MHz): 10.68 (s, 1H), 10.01 (s, 1H), 8.63 (s, 1H), 8.10-8.08 (d, J = 8.4Hz, 1H), 7.79-7.77 (d, J = 8.4Hz, 1 HOUR), 7.52-7.50 (d, J = 7.6Hz, 1H), 7.17 (s, 1H), 7.06 (s, 1H), 6.95-6.93 (d, J = 7 ,6Hz, 1H), 4.41 (s, 2H), 3.88 (s, 3H), 3.34 (s, 3H), 3.27 (s, 3H), 2.29 (s, 3H) . 246 Example 72: Synthesis of 4-((3-fluoro-2-methoxyphenyl)amino)-6-((6-(3-methoxyazetidin-1-yl)pyridin-2-yl)amino)-2-methyl-1, 2-dihydro-3Hpyrazolo[3,4-b]pyridin-3-one, I-94 Xanthphos, Pd2(dba)3, CS2CO3, DMAC, 140°C, M / W, 80min Compound I-94 was prepared from compound 55.1 and 6-(3methoxyazet¡din-1-¡l)pyridín-2-amine using the procedure described in Example 2 (yield: 11.56%), MS (ES): m / z 466.30 [M+H]+, LCMS purity: 99.23%, HPLC purity: 99.29%, 1H NMR (DMSO-d6, 400 MHz): 10.66 (s, 1H), 9.51 (s, 1H), 8.82 (s, 1H), 7.45-7.36 (m, 1H), 7.17-7.00 (m, 2H), 5.94-5, 92 (d, J = 7.2Hz, 1H), 4.28 (s, 1H), 4.04 (s, 2H), 3.87 (s, 3H), 3.67 (s, 2H), 3.26 (s, 3H) ), 3.22 (s, 3H). Example 73: 4-((3-chloro-2-methoxyphenyl)amino)-6-((5-fluoro-4-methylpyridin2-yl)amino)-2-methyl-1,2-dihydro-3H-pyrazolo[3 ,4-b]pyridin-3-one, I-95 ,NH? lí p l! T 1'1 ,O Cl ’ L ,Q~ F' Cl·.. Λ. M Ύ Y UHMDS1 M in THF, T Y Xanthphos. Pd2 (dbal·. CS-.CO THF. 0“C to TA , NH 0 DMAC 14C°C, M / W. 80min 1 || N — rí γ i .A Τ Cl 0 YA Cl 15 1.9 73.1 247 According to the procedure used to prepare 1.91, 73.1 was obtained (yield: 70.71%). MS (ES): m / z 340.2 [M+H]+. Compound I-95 was prepared from compound 73.1 and 5-fluoro-4 methylpyridine-2-amine using the procedure described in Example 2 (yield: 15.82%), MS (ES): m / z 429, 27 [M+H]+, LCMS purity: 95.01%, HPLC purity: 95.80%, 1H NMR (DMSO-d6, 400 MHz): 9.84 (s, 1H), 8.86 ( s, 1H), 8.17-8.13 (m, 1H), 7.95 (s, 1H), 7.56-7.54 (d, J = 8.0Hz, 1H), 7.25- 7.17 (m, 2H), 6.95 (s, 1H), 3.79 (s, 3H), 3.27 (s, 3H), 2.26 (s, 3H). Example 74: Synthesis of 4-((3-chloro-2-methoxyphenyl)amino)-6-((2,6dimethylpyrimidin-4-yl)amino)-2-methyl-1,2-dihydro-3H-pyrazolo[3 ,4-b]pir¡din- 3-on, I-96 73.1 Xanthphos, Pd2(dba)3, CS2CO3, DMAC, 140°C, M / W, 80min Compound I-96 was prepared from compound 73.1 and 2,6dimethylpyrimidin-4-amine using the procedure described in Example 2 (yield: 14.34%), MS (ES): m / z 426.40 [M +H]+, LCMS purity: 96.62%, HPLC purity: 96.51%, 1H NMR (DMSO-d6, 400 MHz): 10.13 (s, 1H), 8.91 (s, 1H), 8.18 (s, 1H), 7.63-7.60 (d, J = 4.8Hz, 1H), 7.49 (s, 1H), 7.45 (s, 1H), 7 .24248 7.23 (d, J = 4.8Hz, 2H), 3.82 (s, 3H), 3.31 (s, 3H), 2.44 (s, 3H), 2.32 (s, 3H) . Example 75: Synthesis of 4-((3-chloro-2-methoxyphenyl)amino)-6-((4(methoxymethyl)pyridin-2-yl)amino)-2-methyl-1,2-dihydro-3H-pyrazolo [3,4b]pyridin-3-one, I-97 73.1 I-97 Compound I-97 was prepared from compound 73.1 and 4(methoxymethyl)pyridin-2-amine using the procedure described in Example 2 (yield: 12.82%), MS (ES ): m / z 441.29 [M+H]+, LCMS purity: 98.70%, HPLC purity: 98.80%, 1H NMR (DMSO-d6, 400 MHz): 10.78 (s , 1H), 9.83 (s, 1H), 8.88 (s, 1H), 8.21 (s, 1H), 7.97 (s, 1H), 7.59 (s, 1H), 7 .25-7.23 (d, J = 7.6Hz, 3H), 6.87 (s, 1H), 4.44 (s, 2H), 3.83 (s, 3H), 3.36 (s , 3H), 3.29 (s, 3H). Example 76: Synthesis of 6-((4-((3-chloro-2-methoxyphenyl)amino)-2-methyl-3oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6- il)amino)nicotinonitrile, I-98 73.1 I-98 Compound I-98 was prepared from compound 73.1 and 6249 aminonicotinonitrile using the procedure described in Example 2 (yield: 13.40%), m / z 422.32 [M+Hf, LCMS purity: 98.00 %, HPLC purity: 97.94%, 1H NMR (DMSO-d6, 400 MHz): 11.01 (s, 1H), 10.44 (s, 1H), 8.91 (s, 1H), 8 .70 (s, 1H), 8.23-8.16 (m, 2H), 7.59-7.57 (d, J = 8.0Hz, 1H), 7.27-7.24 5 (m , 2H), 7.14 (s, 1H), 3.82 (s, 3H), 3.31 (s, 3H). Example 77: Synthesis of 6-((4-((3-chloro-2-methoxyphenyl)amino)-2-methyl-3oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6- il)amino)picolinonitrile, I-99 73.1 I-99 Compound I-99 was prepared from compound 73.1 and 6aminopicolinonitrile using the procedure described in Example 2 (yield: 13.14%), m / z 422.35 [M+Hf, LCMS purity: 95.93% , purity of HPLC: 95.55%, 1H NMR (DMSO-d6, 400 MHz): 10.87 (s, 1H), 10.33 (s, 1H), 8.98 (s, 1H), 8.04 ( s, 1H), 7.91 (s, 1H), 7.67 (s, 1H), 7.56 (s, 1H), 7.50 (s, 1H), 7.27- 7.24 (m, 2H), 3.83 (s, 3H), 3.31 (s, 3H). Example 78: Synthesis of 4-((2-methoxy-4-(methoxymethyl)phenyl)amino)-6-((5methoxy-6-(trifluoromethyl)pyridin-2-yl)amino)-2-methyl-1,2 -dihydro-3Hpyrazolo[3,4-b]pyridin-3-one, 1-104 250 70.1 1-104 Compound 1-104 was prepared from compound 70.1 and 5-methoxy¡6-(trifluoromethyl)pyridin-2-amine using the procedure described in Example 25 (yield: 11.52%), MS (ES): m / z 505.36 [M+H]+, LCMS purity: 97.99%, HPLC purity: 96.46%, 1H NMR (DMSO-d6, 400 MHz): 7.82-7.80 ( d, J = 9.2Hz, 1H), 7.32-7.23 (m, 3H), 7.10 (s, 1H), 6.98-6.96 (d, J = 8.0Hz, 1H ), 4.39 (s, 2H), 3.85 (s, 3H), 3.79 (s, 3H), 3.57 (s, 3H), 3.29 (s, 3H). Example 79: Synthesis of 4-((3-chloro-2-methoxyphenyl)amino)-2-methyl-6-((610 methylpyridazin-3-yl)amino)-1,2-dihydro-3H-pyrazolo[3, 4-b]pyridin-3-one, I105 73.1 1-105 Compound 1-105 was prepared from compound 73.1 and 615 methylpyridazin-3-amine using the procedure described in Example 2 (yield: 5.49%), m / z 412.29 [M+H]+, purity of LCMS: 97.66%, purity HPLC: 95.98%, 1H NMR (DMSO-d6, 400 MHz): 10.21 (s, 1H), 8.87 (s, 1H), 8.29 (s, 1H), 7.56 (s , 1H), 7.48-7.46 (d, J = 9.2Hz, 1H), 7.21-7.20 (d, J = 4.0Hz, 1H), 7.11-7.09 (d, J = 8.8Hz, 1H), 6.69-6.67 (d, J = 9.2Hz, 1H), 6.10 (s, 1H), 3.81 (yes, 251 3Η), 3.27 (s, 3H), 2.34 (s, 3H). Example 80: Synthesis of 6-((4-((3-chloro-2-methoxyphenyl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin- 6-yl)amino)pyrazin-2carbonitrile, 1-117 Xanthphos, Pd2 (dba)3, CS2CO31DMAC, 140°C, M / W, 80min Compound 1-117 was prepared from compound 73.1 and 6methylpyridazin-3-amine using the procedure described in Example 2 (yield: 21.39%), m / z 423.27 [M+Hf, LCMS purity: 96.80%, HPLC purity: 95.08%, 1H NMR (DMSO-d6, 400 MHz): 10.96 (s, 1H), 10.65 (s, 1H), 9.31 (s, 1H), 8.93 (s, 1H), 8.64 (s, 1H), 7.61-7.59 (d, J = 4.0Hz, 1H), 7.35 (s, 1H), 7.277 .23 (m, 2H), 3.86 (s, 3H), 3.30 (s, 3H). Example 81: Synthesis of N-(4-((3,4-difluoro-2-methoxyphenyl)amino)-2-methyl- 3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropanecarboxamide, 1-127 1 M LiHMDS in THF, THF. 0°C to RT -N N — 'f n 1.9 81.1 1-127 According to the procedure used to prepare 1.91, 81.1 was obtained 252 (yield: 63.99%). MS (ES): m / z 341.7 [M+H]+. Compound 1-127 was prepared from compound 81.1 and cyclopropanecarboxamide using the procedure described in Example 2 (yield: 17.5%), m / z 390.27 [M+H]+, LCMS purity: 99. 27%, HPLC purity: 99.63%, 1H NMR (DMSO-d6, 400 MHz): 10.72 (s, 2H), 8.55 (s, 1H), 7.49 (s, 1H) , 7.29-7.20 (m, 2H), 3.89 (s, 3H), 3.28 (s, 3H), 1.99-1.95 (m, 1H), 0.770.75 (d, J = 6 ,4Hz, 4H). Example 82: N-(4-((2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)phenyl)amino)-2 (methyl-d3)-3-oxo-2,3-dihydro -1H-pyrazolo[3,4-b]pyridin-610yl)cyclopropancarboxamide, 1-100 1. SOCI2, Cat DMF. Reflux . 4pm 2. methylhydrazine d3 „ c J ,N. .Cl 1-pcfitanDI, sulfate, NaOH, CH?CI?. 'Γ χ τ NI I Na?CO>. water, reflux I5min L j 'y' L .N. 1' C sealed tube 18hrs D, ........................... Cl O 82.1 O' N=n, h?n^A>>nn~· N-CD, [I J 'Y'· f V’, H . 1 M NH θ -N LiHMDS in THF. (f v u L N-CO, THF. O’C to TA Y '0 A I o o n / Y N-N 82.2 EITHER Xantphos, Pd2(dba)3DMAC, Cs2CO3140°C, 80min 82.3 N-N \ Ό 253 1-100 Synthesis of compound 82.1. To 2,4,6-trichloronicotinic acid (0.25 g, 1.10 mmol, 1.0 eq) was added thionyl chloride (1.2 mL) followed by N,N-dimethylformamide (catalytic) and heated at reflux for 16 h. The reaction mixture was concentrated under reduced pressure to obtain acid chloride. Methylhydrazine sulfate d3 (0.16 g, 1.10 mmol, 1.0 eq) was dissolved in dichloromethane (5 mL) followed by addition of sodium hydroxide solution (0.18 g, 4.40 mmol, 4, 0 eq) in water (1.2 mL). To this, previously prepared acid chloride solution in dichloromethane (5 mL) was added dropwise and the reaction mixture was heated under reflux for 15 min. After completion of the reaction, the reaction mixture was transferred to water and extracted with dichloromethane. The organic layer was combined, washed with brine solution, dried over sodium sulfate, and concentrated under reduced pressure to obtain crude material. This was then purified by column chromatography and the product was eluted in 30% ethyl acetate in hexane to obtain pure 1,1 (0.2 g, 70.35%). MS (ES): m / z 258.5 [M+H]+. Synthesis of compound 82.2. To a suspension of 83.1 (0.2 g, 0.776 mmol, 1.0 eq) in 1-pentanol (5 mL) was added sodium carbonate (0.083 g, 0.776 mmol, 1.0 eq) and the mixture of reaction was stirred at 120 °C for 18 h. After completion of the reaction, the reaction mixture was cooled to room temperature and the pH = 6 was adjusted using 1 N hydrochloric acid. The reaction mixture was concentrated under reduced pressure to obtain crude material. This was then purified by preparative HPLC using 0.1% formic acid in water / acetonitrile in gradient method to obtain pure 1,2 (0.085 g, 49.51%). MS (ES): m / z 222.06 [M+H]+. Synthesis of compound 82.3. According to the procedure used to prepare 1.91, 82.3 was obtained (yield: 30.78%). MS (ES): m / z 390.82 [M+Hf. Compound 1-100 was prepared from compound 82.3 and cyclopropanecarboxamide using the procedure described in Example 2 (0.025 254 g, yield: 23.40%). MS (ES): m / z 439.42 [M+H]+, LCMS purity: 99.10%, HPLC purity: 97.85%, 1H NMR (DMSO-d6, 400 MHz): 10.79 (s, 2H), 8.89 (s, 1H), 7.81 (s, 1H), 7.68-7.64 (t, J = 8.0Hz, 2H), 7.40-7.36 (t, J = 8.0Hz, 1H), 4.47 (s, 3H), 3.77 (s, 3H), 2.02 (s, 1H), 0.81 (s, 4H). Example 83: Synthesis of 3-((6-(cyclopropanecarboxamido)-2-methyl-3-oxo- 2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-4-yl)amino)-2-methoxybenzamide, I102 O?N OH O y- ammonia O...... O Λ A ΓΤ Mel. K2CO., O O ¿ Π methanolic DMF, 0-50'C O?N _. ,A ► γ OMe NH.,OH ac. °7N'- ........ !► 83.1 H?. Pd / C, LtOH 83.2 t t ~Ύ Cl0 LÍHMDS 1 M in THF. THF, 0°C to RT 83.3 nh2o Xantphos, Pd2(dba)3DMAC, CS2CO3140°C, M / W, 80 mins 1.9 1-102 83.4 Synthesis of compound 83.1. To a solution of methyl 2-hydroxy-3-nitrobenzoate (5.0 g, 25.36 mmol, 1.0 eq) in N,N-dimethylformamide (50 mL), potassium carbonate (7.0 g , 50.76 mmol, 2.0 eq) at 0 °C and stirred for 15 min. 255 To this, methyl iodide (7.2 g, 50.76 mmol, 2 eq) was added dropwise and the reaction mixture was stirred at 60 °C for 2 h. After completing the reaction, the reaction mixture was transferred to ice water and the precipitated product was filtered, dried well to obtain 83.1 (5.0 g, 93%). MS (ES): m / z 212.2 [M+Hf. Synthesis of compound 83.2. To 83.1 (5 g, 23.67 mmol, 1.0 eq) aqueous ammonia (30 mL) was added followed by methanolic ammonia (160 mL). The reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the residue was washed with ice water. The solid was dried well to obtain 83.2 (4.5 g, 96%). MS (ES): m / z 197.2 [M+H]+. Synthesis of compound 83.3. To a solution of 83.2 (4.5 g, 22.94 mmol, 1.0 eq) in methanol (45 mL), 10% palladium on carbon (1.0 g) was added. Hydrogen was purged through the reaction mixture for 4 h. After completion of the reaction, the reaction mixture was filtered through a pad of celite and washed with methanol. The filtrate was concentrated under reduced pressure to obtain 83.3. (3.0 g, 78.69%). MS (ES): m / z 167.18 [M+H]+. Synthesis of compound 83.4 According to the procedure used to prepare 1.91, 84.4 was obtained (yield: 62.70%). MS (ES): m / z 348.76 [M+H]+. Compound 1-102 was prepared from compound 83.4 and cyclopropanecarboxamide using the procedure described in Example 2 (yield: 2.63%). MS (ES): m / z 397.41 [M+H]+, LCMS purity: 98.76%, HPLC purity: 98.65%, 1H NMR (DMSO-d6, 400 MHz): 10.81 (s, 1H), 8.56 (s, 1H), 8.12 (s, 1H), 7.69-7.68 (d, J = 6.4Hz, 1H), 7.65-7.63 (d, J = 8.0Hz, 1H), 7.57-7.55 (d, J = 8.0Hz, 1H), 6.95-6.91 (t, J = 8.0Hz, 1H), 3.29 (s, 3H), 3.27 (s, 3H), 1.49-1.46 (m, 1H), 0.78-0.77 (m, 4H). Example 84: Synthesis of 3-((6-((2,6-dimethylpyrimidin-4-yl)amino)-2-methyl-3256 oxo-2,3-dihydro-1 H-pyrazolo[3,4-b]pyridin-4-yl)amino)-2-methoxybenzamide, 1-103 1) H?SO4, 60('C, Ihr 2) NH, ac.(TA Ό 1-103 Compound 84.1 was prepared from compound 84 and 2,6dimethylpyrimidin-4-amine using the procedure described in Example 2 (yield: 19.00%). MS (ES): m / z 417.45 [M+Hf. Synthesis of compound 1-103. To 84.1 (0.120 g, 0.363 mmol, 1 eq) sulfuric acid (2 mL) was added and stirred at 60 °C for 1 h. After completing the reaction, water and aqueous ammonia were added to the reaction mixture and stirred at room temperature for 10 min. The reaction mixture was concentrated under reduced pressure to obtain crude material. This was then purified by preparative HPLC using 0.1% formic acid in water / acetonitrile in gradient method to obtain puree I-84 (0.02 g, yield: 15.98%). MS (ES): m / z 435.46 [M+Hf, LCMS purity: 100.00%, HPLC purity: 95.03%, 1H NMR (DMSO-d6, 400 MHz): 14.19 (s , 1H), 10.15 (s, 1H), 8.61 (s, 2H), 8.15 (s, 1H), 7.73-7.65 (d, J = 7.6Hz, 2H), 7.48 (s, 2H), 6.97-6.93 (t, J = 8.0Hz, 1H), 3.34 257 (s, 3H), 3.29 (s, 3H), 2.43 (s, 3H), 2.34 (s, 3H). Example 85: Synthesis of 4-((2-methoxy-4-(methoxymethyl)phenyl)amino)-6-((5methoxy-6-(trifluoromethyl)pyridin-2-yl)amino)-2-methyl-1 ,2-dihydro-3Hpyrazolo[3,4-b]pyridin-3-one, 1-106 h Cl ·, A. -N -x ..NlbrN — X Y c Nt W FI EITHER * Xantphos, Pd2(dba!3 DMAC Cs,;CO.t 140°C. M / W. 80 mm :;í' Y N. JX. T ¡I Vi H->SOs. 60BC. W Y· A .1 Y 2i NH: ac.TA ,NH or ti Y °· CN L.I. CN1 85.1 Compound 85.1 was prepared from compound 85 and 5-fluoro-4methylpyridine-2-amine using the procedure described in Example 2 (yield: 19.65%). MS (ES): m / z 420.42 [M+H]+. Synthesis of compound 1-106. To 85.1 (0.125 g, 0.298 mmol, 1 eq) sulfuric acid (2 mL) was added and stirred at 60 °C for 1 h. After completing the reaction, water and aqueous ammonia were added to the reaction mixture and stirred at room temperature for 10 min. The reaction mixture was concentrated under reduced pressure to obtain crude material. This was then purified by preparative HPLC using 0.1% formic acid in water / acetonitrile in gradient method to obtain pure 1-106 (0.022 g, yield: 16.88%). MS (ES): m / z 20 438.44 [M+H]+, LCMS purity: 98.97%, HPLC purity: 96.36%, 1H NMR 258 (DMS0-d6, 400 MHz): 14.21 (bs, 1H), 9.84 (s, 1H), 8.64 (s, 1H), 8.56 (s, 1H), 8.15-8.11 (m, 2H), 8.02-8.01 (d, J = 5.6Hz, 1H), 7.66-7.61 (d, J = 8.0Hz, 2H) , 7.00-6.92 (m, 2H), 3.32 (s, 3H), 3.24 (s, 3H), 2.28 (s, 3H). Example 86: Synthesis of 6-((5-fluoro-4-methylpyridin-2-yl)amino)-2-methyl-45 ((2-(methylsulfonyl) phenyl)amino)-1,2-dihydro-3H-pyrazolo [3,4-b]pyridin-3-one, 1-107 LIHMDS 1 M in THF, THF, 0°C to RT · X N , “· OI.., ..N.„ H M I | N f ί N - XX-v í .NH θ H2O2 ac. at 30%. sodium .... NH O í Y tungstate, acetic acid í ...i o 'g Xantphos, Pd2(dba)3,DMAC, CS2CO3,140°C, M / W, 80 mins li According to the procedure used to prepare 1.91, 86.1 was obtained (yield: 76.89%). MS (ES): m / z 321.80 [M+H]+. Synthesis of compound 86.2. To a solution of 86.1 (1.81 g, 5.64 mmol, 1 eq) in acetic acid (2.5 mL) was added 30% hydrogen peroxide (3.83 g, 112.8 mmol, 20 eq) and sodium tungstate dihydrate (1.85 g, 5.64 mmol, 1 eq). The reaction mixture was stirred at room temperature for 2 h. After completing the reaction, the reaction mixture was transferred to ice water and the precipitated product was filtered, washed with 50% ethyl acetate in hexane and dried well to obtain 86.2 (1.25 g, yield: 62. 80%). MS (ES): m / z 353.79 20 [M+H]+, Compound 1-107 was prepared from compound 86.2 and 5-fluoro 259 4-methylpyridin—2-amine using the procedure described in Example 2 (0.060 g, yield: 31.89%). MS (ES): m / z 443.47 [M+H]+, LCMS purity: 99.63%, HPLC purity: 99.37%, 1H NMR (DMSO-d6, 400 MHz): 10.72 (s, 1H), 9.76 (s, 1H), 9.06 (s, 1H), 8.07 (s, 1H), 7.93-7.91 (d, J = 7.2Hz, 2H ), 7.84-7.77 (m, 2H), 7.39-7.36 (t, J = 7.2Hz, 1H), 6.94 (s, 1H), 3.25 (s, 3H), 3.16 (s, 3H), 2.25 ( s, 3H). Example I-87: Synthesis of 6-((2,6-dimethylpyrimidin-4-yl)amino)-2-methyl-4((2-(methylsulfonyl)phenyl)amino)-1,2-dihydro-3H-pyrazolo [3,4-b]pyridin-3-one, 1-109 86.2 1-109 Compound 1-109 was prepared from compound 86.2 and 2,6dimethylpyrimidin-4-amine using the procedure described in Example 2 (yield: 27.52%), MS (ES): m / z 440.40 [M +H]+, LCMS purity: 98.42%, HPLC purity: 95.04%, 1H NMR (DMSO-d6, 400 MHz): 10.84 (bs, 1H), 10.09 (s, 1H) ), 9.15 (s, 1H), 7.94-7.92 (dd, J = 1.2Hz, 8.0Hz, 1H), 7.87-7.85 (d, J = 8.0Hz, 1H), 7.81-7.77(t, J = 8.0Hz, 1H), 7.44-7.34 (m, 3H), 3.27 (s, 3H), 3.16 (s, 3H), 2.37 (s, 3H), 2.29 (s, 3H). Example 88: Synthesis of 2-methyl-6-((6-methylpyridazin-3-yl)amino)-4-((2(methylsulfonyl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4 -b]pyridin-3-one, I109 260 © 86.2 1-109 Compound 1-109 was prepared from compound 86.2 and 6methylpyridazin-3-amine using the procedure described in Example 2 5 (yield: 32.58%), MS (ES): m / z 426.19 [M+ H]+, LCMS purity: 97.90%, HPLC purity: 96.09%, 1H NMR (DMSO-d6, 400 MHz): 10.59 (bs, 1H), 10.17 (s, 1H) , 9.09 (s, 1H), 8.19 (s, 1H), 7.94-7.92 (d, J = 8.0Hz, 1H), 7.84-7.75 (m, 2H) , 7.47-7.38 (m, 2H), 6.95 (s, 1H), 3.171 (s, 3H), 3.059 (s, 3H), 2.314 (s, 3H). Example 89: Synthesis of 6-((4-(methoxymethyl)pyridin-2-yl)amino)-2-methyl-410 ((2-(methylsulfonyl)phenyl)amino)-1,2-dihydro-3H- pyrazolo[3,4-b]pyridin-3-one, 1-110 86.2 1-110 Compound 1-110 was prepared from compound 86.2 and 415 (methoxymethyl)pyridin-2-amine using the procedure described in Example 2 (yield: 14.42%), MS (ES): m / z 455.20 [M+H]+, LCMS purity: 94.46%, HPLC purity: 95.28%, 1H NMR (DMSO-d6, 400 MHz): 11.62 (s, 1H), 9.24 (s , 1H), 8.32-8.30 (d, J = 6.4Hz, 1H), 8.00-7.98 (d, J = 7.2Hz, 1H), 7.84-7.80 ( m, 261 2Η), 7.51 (t, 1H), 7.24-7.19 (m, 2H), 6.21 (s, 1H), 4.59 (s, 2H), 3.39 (s, 3H ), 3.36 (s, 3H), 3.19 (s,3H). Example 90: Synthesis of 2-methyl-6-((5-methylpyridin-2-yl)amino)-4-((2 (methylsulfonyl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4 -b]pyridin-3-one, i5 of the compound Compound 1-111 was prepared from 86.2 and 510 methylpyridin-2-amine using the procedure described in the Example (yield: 20.78%), MS (ES): m / z 425.19 [M+H]+, LCMS purity: 97.76%, fe HPLC purity: 96.61%, 1H NMR (MeOD, 400 MHz): 8.14 (s, 1H), 8.06-8.04 (d, J = 8.0Hz, 1H), 7.82- 7.76 (m, 2H), 7.63-7.61 (d, J = 8.0Hz, 1H), 7.49-7.46 (t, J = 6.8Hz, 1H), 6.90 (s, 1H), 5.81 (s, 1H), 3.56 (s, 3H), 3.34 (s, 1H), 3.11 (s, 3H), 2.30 (s, 3H) . Example 91: Synthesis of 6-((2-methyl-4-((2-(methylsulfonyl)phenyl)amino)-3-oxo- 2,3-dihydro-1 H-pyrazolo[3,4-b]pyridin-6-yl)amino)picolinonitrile, 1-112 NC Xanthphos, Pd2(dba)3, CS2CO3, DMAC, 140°C, M / W, 80min 86.2 NH2fe NC 1-112 262 Compound 1-112 was prepared from compound 86.2 and 6aminopicolinonitrile using the procedure described in Example 2 (yield: 23.15%), MS (ES): m / z 436.35 [M+H]+, purity LCMS: 100.00%, HPLC Purity: 100.00%, 1H NMR (DMSO-d6, 400 MHz): 10.81 (s, 1H), 10.28 5 (s, 1H), 9.18 (s, 1H), 8.05-8.03 (d, J = 8.8Hz, 1H), 7.94-7.80 (m, 4H), 7.52-7.50 (d, J = 7.2Hz, 1H), 7.41-7.38 (t, J = 7.2Hz, 1H), 7.24 (s, 1H), 3.27 (s, 3H), 3.16 (s, 3H). Example 92: Synthesis of 4-((3-chloro-2-methoxyphenyl)amino)-2-methyl-6-((5(pyrrolidin-1-carbonyl)-6-(trifluoromethyl)pyridin-2-yl)amino) -1,2-dihydro-3H10 pyrazolo[3,4-b]pyridin-3-one, 1-128 Zn(CN)2, Tetrakis, DMF, 150°C, M / W F4C\ ,N^ NH T i] Ϊ or pyrrolidine HEY YOU. DIPLA, DMF 92.1 F>C.. _N.. „NH . ' --γ either. ..A J Ύ ~ ,N. \ / 92.2 CL Xantphos, Pd2(dba)3,DMAC, CS2CO3,140°C, M / W, 80 mins CL 263 73.1 1-128 Synthesis of compound 92.1. To 5-bromo-6-(trifluoromethyl)pyridin-2-amine (3.0 g, 12.45 mmol, 1.0 eq) in dimethylformamide (1 mL) was added zinc cyanide (1.456 g, 12.45 mmol , 1.0 eq). The reaction mixture was then heated in 5 microwaves at 150 °C for 15 min. After completion of the reaction, water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was combined, dried over sodium sulfate and concentrated under reduced pressure to obtain crude material. This was then purified by column chromatography and the compound was eluted in 20% ethyl acetate in hexane to obtain 92.1 (yield: 68.69%). MS (ES): m / z 188.13 [M+H]+. Synthesis of compound 92.2. To compound 92.1 (1.6 g, 8.55 mmol, 1.0 eq) and sodium hydroxide (1.0 g, 25.65 mmol, 3.0 eq) was added in water (30 mL). The reaction mixture was stirred at 100 °C for 16 h. After completion of the reaction, the reaction mixture was extracted with ethyl acetate. The aqueous layer was acidified with hydrochloric acid and extracted with ethyl acetate. The organic layer was combined, dried over sodium sulfate and concentrated under reduced pressure to obtain crude material. This was then purified by column chromatography and the compound was eluted in 5% methanol in dichloromethane to obtain 93.2 (yield: 62.41%). MS (ES): m / z 207.12 [M+H]+. Synthesis of compound 92.3. To a cooled solution of 92.2 (0.5 g, 2.43 mmol, 1.0 eq) and pyrrolidine (0.19 g, 2.67 mmol, 1.1 eq) in N,N-dimethylformamide (5 mL) at 0 °C ((1-[Bis(dimethylamino)methylene]-1H-3-oxide hexafluoro-phosphate) was added 1,2,3—triazolo[4,5—bjpyridinium)) (1.846 g, 4.86 mmol, 2.0 eq) followed by N,NDiisopropylethylamine (0.94 g, 7.29 mmol, 3.0 eq) and the reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, the reaction mixture was transferred to water and extracted with ethyl acetate. The organic layer was combined, dried over sodium sulfate and concentrated under pressure 264 reduced to obtain raw material. This was then purified by column chromatography and the compound was eluted in 3% methanol in dichloromethane to obtain pure 92.3 (0.39 g, 62.34%). MS (ES): m / z 260.23 [M+H]+. Compound 1-128 was prepared from compound 73.1 and compound 93.3 using the procedure described in Example 2 (yield: 10.06%). MS (ES): m / z 563.35 [M+H]+, LCMS purity: 90.57%, HPLC purity: 94.43%, 1H NMR (DMSO-d6, 400 MHz): 10.91 (bs, 1H), 10.36 (s, 1H), 8.97 (s, 1H), 8.18-8.16 (d, J = 8.4Hz, 1H), 7.89-7.87 (d, J = 8.4Hz, 1H), 7.58 -7.55 (dd, J = 1.6Hz, 7.6Hz, 1H), 7.30 (s, 1H), 7.21-7.14 (m, 2H), 3.81 (s, 3H) , 3.4510 3.42 (m, 2H), 3.29 (s, 3H), 3.12-3.08 (m, 2H), 1.88-1.79 (m, 4H). Example 93: Synthesis of 4-((3-chloro-2-methoxyphenyl)amino)-2-methyl-6-((5(morpholine-4-carbonyl)-6-(trifluoromethyl)pyridin-2-yl)amino) -1,2-dihydro-3Hpyrazolo[3,4-b]pyridin-3-one, 1-130 FiC.. ..NH? . Ίι 7 morpholine. HATU, DIPFA, '1 DMf ,N-·, CS2CO3,140oC, M / W, 80 mins Xantphos, Pd2(dba)3,DMAC, (trifluoromethyljnicotine (0.5 g, 2.43 mmol, 1.0 eq) and morpholine (0.23 g, 2.67 mmol, 1-130 Synthesis of compound 93.1. To a cooled solution of 6-amino-2265 acid 1.1 eq) in Ν,Ν-dimethylformamide (5 mL) at 0 °C ((1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo3-oxide hexafluorophosphate]-1H-1,2,3-triazolo[4, 5-b]pyridinium)) (1.846 g, 4.86 mmol, 2.0 eq) followed by N,N-Düsopropylethylamine (0.94 g, 7.29 mmol, 3.0 eq) and the reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, the reaction mixture was transferred to water and extracted with ethyl acetate. The organic layer was combined, dried over sodium sulfate and concentrated under reduced pressure to obtain crude material. This was then purified by column chromatography and the compound was eluted in 3% methanol in dichloromethane to obtain pure 93.1 (0.4 g, 59.91%). MS (ES): m / z 10 276.23 [M+H]+. Compound 1-130 was prepared from compound 73.1 and compound 93.1 using the procedure described in Example 2 (yield: 30.52%), MS (ES): m / z 578.41 [M+H]+, LCMS purity: 97.65%, HPLC: 97.61%, 1H NMR (DMSO-d6, 400 MHz): 10.89 (s, 1H), 10.38 (s, 1H), 8.97 (s, 1H), 8.17-8 .15 (d, J = 8....

Claims

1. A TYK2 inhibitor compound of formula Ia: (FORMULA Ia) or one of its pharmaceutically acceptable salts, wherein X is N or C(R3); R1 is C1-6 aliphatic; R2 is -N(H)Cy2 or -N(H)C(O)Cy2; R3 is H; Cy1 is phenyl; Cy2 is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen and oxygen; wherein Cy1 is substituted by n instances of R5; and wherein Cy2 is substituted by p instances of R6; each instance of R5 and R6 is independently RA or RB, and is substituted by p instances of RC; each instance of RA is independently halogen, -CN, -SR, -S(O)2NR 2 , S(O)R, S(O)NR 2 , C(O)R, C(O)OR, -C(O)NR 2 or -N(R)S(O)2R; each instance of RB is independently aliphatic C1-6;a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen and oxygen; a 3-7 membered saturated or partially unsaturated carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen and oxygen; each instance of RC is independently oxo or C1-6 aliphatic; each R is independently hydrogen, or C1-6 aliphatic, or two R groups on the same nitrogen are taken together with their intermediate atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to nitrogen, independently selected from nitrogen, oxygen, and sulfur;and each of n, pyq is independently 0, 1, 2 or 3, characterized in that it consists of a compound selected from the following group: (FORMULAS I-1 to I-240) or one of its pharmaceutically acceptable salts. Claim 1 follows;