TYK2 inhibitors and their uses

Abstract

The present invention provides compounds, compositions thereof, and methods of using the same to inhibit TYK2 and treat TYK2-mediated disorders.

Description

[0001] Cross - reference to related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 62 / 795,735, filed on January 23, 2019, and U.S. Provisional Application No. 62 / 880,754, filed on July 31, 2019, under 35 U.S.C. § 119(e), the contents of which are incorporated herein by reference in their entireties. Field of the Invention

[0003] The present invention relates to compounds and methods useful for inhibiting non-receptor tyrosine-protein kinase 2 (“TYK2”, also known as tyrosine kinase 2). The present invention also provides pharmaceutically acceptable compositions comprising the compounds of the present invention and methods of using such compositions to treat various disorders. Background of the Invention

[0004] In recent years, a better understanding of the structures of enzymes and other biomolecules associated with diseases has greatly assisted the search for new therapeutic agents. One important class of enzymes that has been widely studied is the protein kinase family.

[0005] Protein kinases constitute a large family of structurally related enzymes responsible for controlling various signal transduction processes within cells. Because of the conservation of their structures and catalytic functions, protein kinases are thought to have evolved from a common ancestral gene. Almost all kinases contain a similar catalytic domain of 250-300 amino acids. Enzymes can be classified into families according to the substrates they phosphorylate (e.g., protein-tyrosine, protein-serine / threonine, lipids, etc.).

[0006] Typically, protein kinases mediate intracellular signal transduction by affecting the transfer of phosphoryl groups from nucleoside triphosphates to protein receptors involved in signal transduction pathways. These phosphorylation events act as molecular on / off switches that can regulate or modulate the biological functions of target proteins. These phosphorylation events are ultimately triggered in response to various extracellular and other stimuli. Examples of such stimuli include environmental and chemical stress signals (e.g., osmotic shock, heat shock, ultraviolet radiation, bacterial endotoxin, and H2O2), cytokines (e.g., interleukin-1 (IL-1), interleukin-8 (IL-8), and tumor necrosis factor α (TNF-α)), and growth factors (e.g., granulocyte macrophage-colony stimulating factor (GM-CSF) and fibroblast growth factor (FGF)). Extracellular stimuli can affect one or more cellular responses related to cell growth, migration, differentiation, hormone secretion, transcription factor activation, muscle contraction, glucose metabolism, protein synthesis control, and cell cycle regulation.

[0007] Many diseases are associated with abnormal cellular responses triggered by kinase-mediated events. These diseases include, but are not limited to, autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer's disease, and hormone-related diseases. Accordingly, there remains a need to find protein kinase inhibitors that can be used as therapeutic agents. SUMMARY OF THE INVENTION

[0008] It has now been found that the compounds of the present invention and their pharmaceutically acceptable compositions are effective as TYK2 kinase inhibitors.

[0009] The compounds of the present invention and their pharmaceutically acceptable compositions can be used to treat various diseases, disorders, or conditions related to the regulation of signal transduction pathways involving the TYK2 kinase. Such diseases, disorders, or conditions include those described herein.

[0010] The compounds provided by the present invention can also be used for: the study of the TYK2 enzyme in biological and pathological phenomena; the study of intracellular signal transduction pathways present in body tissues; and the in vitro or in vivo comparative evaluation of new TYK2 inhibitors or other kinase, signal transduction pathway, and cytokine level modulators. DETAILED DESCRIPTION OF THE INVENTION

[0011] 1. General description of certain embodiments of the present invention:

[0012] The compounds of the present invention and their compositions can be used as TYK2 protein kinase inhibitors.

[0013] The pseudokinase binding pocket of TYK2 contains multiple hydrated sites, each of which is occupied by a single water molecule. Each of these water molecules has an associated stability rank. As used herein, the term "stability rank" refers to a numerical calculation incorporating the enthalpy, entropy, and free energy values associated with each water molecule. This stability rank allows for a measurable determination of the relative stability of the water molecules occupying the hydrated sites in the binding pocket of TYK2.

[0014] Water molecules occupying hydrated sites in the binding pocket of TYK2 with a stability rank > 2.5 kcal / mol are referred to as "unstable water".

[0015] Without wishing to be bound by any particular theory, it is believed that replacement or disruption of labile water molecules (i.e., water molecules with a stability level > 2.5 kcal / mol) or displacement of stable water (i.e., water molecules with a stability level < 1 kcal / mol) by an inhibitor results in tighter binding of the inhibitor. Thus, an inhibitor designed to replace one or more labile water molecules (i.e., those labile water molecules not replaced by any known inhibitor) will be a tighter binder and thus a more potent inhibitor compared to an inhibitor that does not replace labile water molecules.

[0016] Surprisingly, it has been found that the provided compounds replace or disrupt one or more labile water molecules. In some embodiments, the provided compounds replace or disrupt at least two labile water molecules.

[0017] In certain embodiments, the present invention provides a compound of formula I,

[0018]

[0019] or a pharmaceutically acceptable salt thereof, wherein R 3 、R 5 、R 6 and R 7 each is as defined below and is described individually and in combination in the examples herein.

[0020] In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable carrier, adjuvant or diluent.

[0021] In some embodiments, the present invention provides a method of treating a TYK2-mediated disease, disorder or condition, the method comprising administering to a patient in need thereof a compound of formula I or a pharmaceutically acceptable salt thereof.

[0022] 2. Compounds and Definitions:

[0023] The compounds of the present invention include the compounds generally described herein and are further illustrated by the classes, subclasses, and species disclosed herein. Unless otherwise indicated, the following definitions shall apply as used herein. For the purposes of the present invention, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Edition. Additionally, general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999 and "March's Advanced Organic Chemistry", 5th Edition, Editors: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

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

[0025] As used herein, the term "bridged bicyclic" refers to any bicyclic system having at least one bridge, i.e., a carbocyclic or heterocyclic ring, saturated or partially unsaturated. As defined by IUPAC, a "bridge" is an unbranched chain of atoms or an atom or valence bond connecting two bridgeheads, where a "bridgehead" is any skeletal atom of the ring system that is bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, the bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include those set forth below, where each group is attached to the remainder of the molecule at any replaceable carbon or nitrogen atom. Unless otherwise specified, the bridged bicyclic group is optionally substituted with one or more of the substituents described for aliphatic groups. Additionally or alternatively, any replaceable nitrogen of the bridged bicyclic group is optionally substituted. Exemplary bridged bicyclics include:

[0026]

[0027] The term "lower alkyl" refers to a C 1-4 straight or branched chain alkyl. Exemplary lower alkyls are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0028] The term "lower haloalkyl" refers to a C 1-4 straight or branched chain alkyl substituted with one or more halogen atoms.

[0029] The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including any oxidized form of nitrogen, sulfur, phosphorus, or silicon; any quaternized form of any basic nitrogen; or a replaceable nitrogen of a heterocycle, e.g., N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR + (as in an N-substituted pyrrolidinyl)).

[0030] As used herein, the term "unsaturated" means that a moiety has one or more unsaturation units.

[0031] As used herein, the term "divalent C 1-8 (or C 1-6 ) saturated or unsaturated straight or branched hydrocarbon chain" refers to a straight or branched divalent alkylene, alkenylene, and alkynylene chain as defined herein.

[0032] The term "alkylene" refers to a divalent alkyl. An "alkylene chain" is polymethylene, i.e., -(CH2) n-, where n is a positive integer, preferably from 1 to 6, 1 to 4, 1 to 3, 1 to 2 or 2 to 3. The substituted alkylene chain is a polymethylene in which one or more methylene hydrogen atoms are replaced by substituents. Suitable substituents include those described below for substituted aliphatic groups.

[0033] The term "alkenylene" refers to a divalent alkenyl group. The substituted alkenylene chain is a polymethylene containing at least one double bond in which one or more hydrogen atoms are replaced by substituents. Suitable substituents include those described below for substituted aliphatic groups.

[0034] The term "halogen" means F, Cl, Br or I.

[0035] The term "aryl", used alone or as part of a larger moiety such as in "aralkyl", "aralkoxy" or "aryloxyalkyl", refers to a monocyclic or bicyclic system having a total of five to fourteen ring members, where at least one of the rings in the system is aromatic and where 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 including but not limited to phenyl, biphenyl, naphthyl, anthracenyl, etc. which may carry one or more substituents. As used herein, the scope of the term "aryl" also includes groups in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimido, naphthalimido, phenanthridinyl or tetrahydronaphthyl, etc.

[0036] The terms "heteroaryl" and "heteroar-" when used alone or as part of a larger moiety such as "heteroalkyl" or "heteroalkoxy" refer to groups having from 5 to 10 ring atoms, preferably 5, 6 or 9 ring atoms; sharing 6, 10 or 14 π electrons in a ring array; and having from one to five heteroatoms in addition to carbon atoms. The term "heteroatom" refers to nitrogen, oxygen or sulfur and includes any oxidized form of nitrogen or sulfur and any quaternized form of basic nitrogen. Heteroaryl includes but is not limited to thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, phthalazinyl and pteridinyl. As used herein, the terms "heteroaryl" and "heteroar-" also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic or heterocyclic rings, where unless otherwise specified, the group or point of attachment is on the heteroaromatic ring or on one of the rings to which the heteroaromatic ring is fused. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl and tetrahydroisoquinolinyl. Heteroaryl can be monocyclic or bicyclic. The term "heteroaryl" can be used interchangeably with the terms "heteroaryl ring", "heteroaryl group" or "heteroaromatic", any of which terms includes an optionally substituted ring. The term "heteroalkyl" refers to an alkyl group substituted with a heteroaryl group, where the alkyl and heteroaryl moieties are independently optionally substituted.

[0037] As used herein, the terms "heterocycle", "heterocyclic group", "heterocyclic moiety" and "heterocyclic ring" are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moiety that is saturated or partially unsaturated and has one or more, preferably one to four, heteroatoms in addition to carbon atoms, as defined above. When used with reference to the ring atoms of a heterocycle, the term "nitrogen" includes substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0 - 3 heteroatoms selected from oxygen, sulfur or nitrogen, nitrogen can be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or + NR (as in an N-substituted pyrrolidinyl).

[0038] The heterocycle can be attached to its side group at any heteroatom or carbon atom that results in a stable structure, and any of the ring atoms in the ring can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic groups include, but are not limited to, tetrahydrofuranyl, tetrahydrobenzothienyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, 2-oxa-6-aza-spiro[3.3]heptane, and quinuclidinyl. The terms "heterocycle", "heterocyclyl", "heterocyclic ring", "heterocyclic group", "heterocyclic moiety", and "heterocyclic radical" are used interchangeably herein and also include groups in which a heterocyclic ring is fused to one or more aryl rings, heteroaryl rings, or alicyclic rings, such as dihydroindolyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. The heterocyclic group can be monocyclic or bicyclic. The term "heteroalkyl" refers to an alkyl group substituted by a heterocyclic group, wherein the alkyl and heterocyclic moieties are independently optionally substituted.

[0039] As used herein, the term "partially unsaturated" refers to a ring moiety that contains at least one double bond 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 moieties, as defined herein.

[0040] As described herein, the compounds of the present invention can contain "optionally substituted" moieties. Whether or not preceded by the term "optionally", the term "substituted" generally means that one or more hydrogens of the designated moiety are replaced by a suitable substituent. Unless otherwise indicated, an "optionally substituted" group can have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted by more than one substituent selected from the designated group, at each position, the substituents can be the same or different. Combinations of substituents contemplated by the present invention are preferably combinations of substituents that result in the formation of stable or chemically feasible compounds. As used herein, the term "stable" refers to a compound that does not substantially change when subjected to conditions that allow it to be produced, detected, and in some embodiments, recovered, purified, and used for one or more of the purposes disclosed herein.

[0041] Suitable monovalent substituents on a substitutable carbon atom of an "optionally substituted" group are independently: halogen; -(CH2) 0-4 R o ; -(CH2) 0-4 OR o ; -O(CH2) 0-4 R o; -O-(CH2) 0-4 C(O)OR; -(CH2) 0-4 CH(OR o )2; -(CH2) 0-4 SR o ; -(CH2) 0-4 Ph, which may be substituted by R o ; -(CH2) 0-4 O(CH2) 0-1 Ph, which may be substituted by R o ; -CH=CHPh, which may be substituted by R o ; -(CH2) 0-4 O(CH2) 0-1 -pyridyl, which may be substituted by R o ; -NO2; -CN; -N3; -(CH2) 0-4 N(R o )2; -(CH2) 0- 4N(R o )C(O)R o ; -N(R o )C(S)R o ; -(CH2) 0-4 N(R o )C(O)NR o 2; -N(R o )C(S)NR o 2; -(CH2) 0-4 N(R o )C(O)OR o ; -N(R o )N(R o )C(O)R o ; -N(R o )N(R o )C(O)NR o 2; -N(R o )N(R o )C(O)OR o ; -N(R o )C(NR o )N(R o )2; -(CH2) 0-4 C(O)R o ; -C(S)R o ; -(CH2) 0-4 C(O)OR o ; -(CH2) 0-4 C(O)SR o ; -(CH2) 0-4 C(O)OSiR o3; -(CH2) 0- 4OC(O)R o ; -OC(O)(CH2) 0-4 SR o ; -SC(S)SR o ; -(CH2) 0-4 SC(O)R o ; -(CH2) 0-4 C(O)NR o 2; -C(S)NR o 2; -C(S)SR o ; -SC(S)SR; -(CH2) 0-4 OC(O)NR o 2; -C(O)N(OR o )R o ; -C(O)C(O)R o ; -C(O)CH2C(O)R o ; -C(NOR o )R o ; -(CH2) 0-4 SSR o ; -(CH2) 0-4 S(O)2R o ; -(CH2) 0-4 S(O)2OR o ; -(CH2) 0-4 OS(O)2R o ; -S(O)2NR o 2; -(CH2) 0-4 S(O)R o ; -N(R o )S(O)2NR o 2; -N(R o )S(O)2R o ; -N(OR o )R o ; -C(NH)NR o 2; -P(O)2R o ; -P(O)R o 2; -OP(O)R o 2; -OP(O)(OR o )2; -SiR o 3; -(C 1-4 linear or branched alkylene)O-N(R o )2; or -(C 1-4 linear or branched alkylene)C(O)O-N(R o )2, where each R o may be substituted as defined below and is independently hydrogen, C1-6 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, -CH2-(5- or 6-membered heteroaryl ring), or a 5- or 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the foregoing definition, two independently occurring R o together with one or more intervening atoms form a 3- to 12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and the ring may be substituted as defined hereinbelow.

[0042] R o suitable monovalent substituents thereon (or the ring formed by joining two independently occurring R o with their intervening atoms) are independently halogen, -(CH2) 0-2 R · , -(halo-R · ), -(CH2) 0-2 OH, -(CH2) 0-2 OR · , -(CH2) 0-2 CH(OR · )2, -O(halo-R · ), -CN, -N3, -(CH2) 0-2 C(O)R · , -(CH2) 0-2 C(O)OH, -(CH2) 0-2 C(O)OR · , -(CH2) 0-2 SR · , -(CH2) 0-2 SH, -(CH2) 0-2 NH2, -(CH2) 0-2 NHR · , -(CH2) 0-2 NR · 2, -NO2, -SiR · 3, -OSiR · 3, -C(O)SR · , -(C 1-4 linear or branched alkylene)C(O)OR · or -SSR · , where each R · is unsubstituted or, when preceded by "halo-", is substituted only by one or more halogens and is independently selected from C 1-4 aliphatic, -CH2Ph, -O(CH2) 0-1Ph or a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. R o Suitable divalent substituents on the saturated carbon atoms of R

[0043] include =O and =S. Suitable divalent substituents on the saturated carbon atoms of an "optionally substituted" group include the following: =O, =S, =NNR * 2, =NNHC(O)R * , =NNHC(O)OR * , =NNHS(O)2R * , =NR * , =NOR * , -O(C(R * 2)) 2-3 O- or -S(C(R * 2)) 2-3 S-, where each independently occurring R * is selected from: hydrogen; C 1-6 aliphatic which may be substituted as defined hereinafter; or an unsubstituted 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Suitable divalent substituents attached to an ortho-substitutable carbon of an "optionally substituted" group include: -O(CR * 2) 2- 3O-, where each independently occurring R * is selected from: hydrogen; C 1-6 aliphatic which may be substituted as defined hereinafter; or an unsubstituted 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0044] R * Suitable substituents on the aliphatic group of · include halogen, -R · , -(haloR · ), -OH, -OR · ), -CN, -C(O)OH, -C(O)OR · , -NH2, -NHR · , -NR · 2 or -NO2, where each R · is unsubstituted or, in the case where preceded by "halo", is substituted by only one or more halogens and is independently C 1-4 aliphatic, -CH2Ph, -O(CH2) 0-1 Ph or a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0045] Suitable substituents on the substitutable nitrogen of an “optionally substituted” group include or where each is, independently: hydrogen; a substituted C 1-6 aliphatic as defined below; unsubstituted -OPh; or an unsubstituted 5- or 6-membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or, notwithstanding the foregoing definition, two independently occurring together with one or more intervening atoms form a 3- to 12-membered saturated, partially unsaturated or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0046] Suitable substituents on an aliphatic group of · are, independently, halogen, -R · , -(haloR · ), -OH, -OR · , -O(haloR · ), -CN, -C(O)OH, -C(O)OR · , -NH2, -NHR · 2 or -NO2, where each R · is unsubstituted or, in the case where preceded by “halo”, is substituted only by one or more halogens and is independently C 1-4 aliphatic, -CH2Ph, -O(CH2) 0-1 Ph or a 5- or 6-membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0047] As used herein, the term "pharmaceutically acceptable salts" refers to those salts that are suitable, within the scope of sound medical judgment, for contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al. described pharmaceutically acceptable salts in detail in the Journal of Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include salts derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts having an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or formed by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, citrates, cyclopentanepropionates, digluconates, dodecyl sulfates, ethanesulfonates, formates, fumarates, glucoheptanoates, glycerophosphates, gluconates, hemisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxyethanesulfonates, lactobionates, lactates, laurates, dodecyl sulfates, malates, maleates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectates, persulfates, 3-phenylpropionates, phosphates, pivalates, propionates, stearates, succinates, sulfates, tartrates, thiocyanates, p-toluenesulfonates, undecanoates, valerates, etc.

[0048] Salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N + (C 1-4 alkyl)4 salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Where appropriate, additional pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0049] Unless otherwise specified, the structures depicted herein also mean to encompass all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structures; for example, the R and S configurations of each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Thus, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the compounds of the invention are within the scope of the invention. Unless otherwise specified, all tautomeric forms of the compounds of the invention are within the scope of the invention. In addition, unless otherwise stated, the structures depicted herein also intend to encompass compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the structures of the invention with hydrogen replaced by deuterium or tritium or carbon replaced by 13 C- or 14 C-enriched carbon are within the scope of the invention. According to the invention, such compounds can be used, for example, as analytical tools, probes in biological assays, or therapeutic agents. In certain embodiments, the warhead portion R 1 of the provided compounds includes one or more deuterium atoms. In certain embodiments, the B ring of the provided compounds can be substituted with one or more deuterium atoms.

[0050] As used herein, the term "inhibitor" is defined as a compound that binds to TYK2 and / or inhibits TYK2 with a measurable affinity. In certain embodiments, the IC 50 and / or binding constant of the inhibitor is less than about 50 μM, less than about 1 μM, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM.

[0051] The compounds of the invention can be tethered to a detectable moiety. It should be understood that such compounds can be used as imaging agents. One of ordinary skill in the art will recognize that the detectable moiety can be linked to the provided compound through a suitable substituent. As used herein, the term "suitable substituent" refers to a moiety capable of covalently linking to the detectable moiety. Such moieties are well known to those of ordinary skill 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 should be understood that such moieties can be linked to the provided compound directly or through a tethering group such as a divalent saturated or unsaturated hydrocarbon chain. In some embodiments, such moieties can be linked by click chemistry. In some embodiments, such moieties can optionally be linked by the 1,3-cycloaddition of an azide and an alkyne 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 , pp. 52 - 57 as described in

[0052] As used herein, the term "detectable moiety" is used interchangeably with the term "label" and refers to any moiety capable of being detected, such as primary labels and secondary labels. Primary labels, such as radioisotopes (e.g., tritium, 32 P, 33 P, 35 S or 14 C), mass tags, and fluorescent labels, are signal - generating reporter groups that can be detected without further modification. Detectable moieties also include luminescent and phosphorescent groups.

[0053] As used herein, the term "secondary label" refers to moieties such as biotin and various protein antigens that require the presence of a second intermediate to generate a detectable signal. For biotin, the secondary intermediate can include streptavidin - enzyme conjugates. For antigen labels, the secondary intermediate can include antibody - enzyme conjugates. Some fluorescent groups act as secondary labels because they transfer energy to another group during the process of non - radiative fluorescence resonance energy transfer (FRET), and the second group generates the detected signal.

[0054] As used herein, the terms "fluorescent label", "fluorescent dye", and "fluorophore" refer to a moiety that absorbs light energy at a defined excitation wavelength and emits light energy at a different wavelength. Examples of fluorescent labels include, 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 dyes (BODIPY FL, BODIPY R6G, BODIPY TMR, BODIPY TR, BODIPY 530 / 550, BODIPY 558 / 568, BODIPY 564 / 570, BODIPY 576 / 589, BODIPY 581 / 591, BODIPY 630 / 650, BODIPY 650 / 665), carboxyrhodamine 6G, carboxy-X-rhodamine (ROX), Cascade Blue, Cascade Yellow, coumarin 343, cyanine dyes (Cy3, Cy5, Cy3.5, Cy5.5), dansyl, Dapoxyl, dialkylaminocoumarin, 4',5'-dichloro-2',7'-dimethoxy-fluorescein, DM-NERF, eosin, erythrosin, fluorescein, FAM, hydroxycoumarin, IRDye (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'-tetrabromosulfone-fluorescein, tetramethyl-rhodamine (TMR), carboxytetramethylrhodamine (TAMRA), Texas Red, Texas Red-X.

[0055] As used herein, the term "mass tag" refers to any moiety that can be uniquely detected by mass using mass spectrometry (MS) detection techniques. Examples of mass tags include electrophoretically releasable tags such as N-[3-[4'-[(p-methoxytetrafluorobenzyl)oxy]phenyl]-3-methylglyceryl]isopiperidinecarboxylic acid, 4'-[2,3,5,6-tetrafluoro-4-(pentafluorophenoxy)]acetophenone, and derivatives thereof. The synthesis and use of these mass tags are described in U.S. Pat. Nos. 4,650,750, 4,709,016, 5,360,8191, 5,516,931, 5,602,273, 5,604,104, 5,610,020, and 5,650,270. Other examples of mass tags include, but are not limited to, nucleotides, dideoxynucleotides, oligonucleotides of different lengths and base compositions, oligopeptides, oligosaccharides, and other synthetic polymers of different lengths and monomer compositions. A wide variety of neutral and charged organic molecules (biomolecules or synthetic compounds) in the appropriate mass range (100 - 2000 daltons) can also be used as mass tags.

[0056] As used herein, the terms "measurable affinity" and "measurably inhibit" mean to include a measurable change in the TYK2 protein kinase activity between a sample of a compound or composition of the invention and the TYK2 protein kinase and an equivalent sample of the TYK2 protein kinase in the absence of the compound or composition.

[0057] 3. Description of Exemplary Embodiments:

[0058] In certain embodiments, the present invention provides a compound of Formula I,

[0059]

[0060] or a pharmaceutically acceptable salt thereof, wherein:

[0061] R 3 is -C(O)NH2, -C(O)NHR 3A , -C(O)N(R 3A )2, -C(O)OR, -C(O)NHOR or a 5 - 6 membered monocyclic heteroaryl ring having 1 - 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said ring is substituted with m R 3B instances;

[0062] R 5 is hydrogen or -L 1 -R 5A ;

[0063] R 6 is hydrogen, R A or R B ;

[0064] or R 5 and R 6 together with its intervening atom form a 4- to 7-membered partially unsaturated ring or heteroaryl ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said ring is substituted by R 5A and n R C instances;

[0065] R 7 is hydrogen, halogen, -NH2, -NHR 7A or -NHC(O)R 7A ;

[0066] or R 6 and R 7 together with its intervening atom form a 4- to 7-membered partially unsaturated ring or heteroaryl ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said ring is substituted by p R C instances;

[0067] L 1 is a covalent bond or a divalent saturated or unsaturated straight-chain or branched hydrocarbon chain, wherein one or two methylene units of said chain are optionally and independently replaced by: -C(R 1-4 )2-, -CH(R 5B )-, -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2-; 5B )-、-CH(R

[0068] R 3A 、R 3B and R 7A are each independently R B and each is substituted by q R C instances, wherein two R C substituents on the same carbon optionally together form a 3- to 6-membered saturated or partially unsaturated spiro-fused heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or wherein two R C substituents on adjacent carbons optionally together form a 3- to 6-membered saturated or partially unsaturated fused heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

[0069] R 5A and each R 5B instance are each independently R A or R B and each is independently substituted by r R C instances;

[0070] Each R A independently is an oxo group, a 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;

[0071] Each R B independently is C 1-6 aliphatic; phenyl; a 5- or 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

[0072] a 3- to 7-membered saturated or partially unsaturated carbocyclic ring; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7- to 12-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

[0073] Each R C independently is an oxo group, a 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: C 1-6 aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- or 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein two optional substituents on the same carbon optionally together form a 3- to 6-membered saturated or partially unsaturated spiro-fused heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or wherein two optional substituents on adjacent carbons optionally together form a 3- to 6-membered saturated or partially unsaturated fused heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

[0074] Each R is independently hydrogen or an optionally substituted group selected from: C1-6 aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:

[0075] two R groups on the same nitrogen, together with the intervening atom, form a 4- to 7-membered saturated ring, partially unsaturated ring, or heteroaryl ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur in addition to the said nitrogen,

[0076] wherein each hydrogen bonded to carbon may optionally and independently be replaced by deuterium; and

[0077] each instance of m, n, p, q, and r is independently 0, 1, 2, 3, or 4, provided that the compound is not

[0078] as generally defined above, R 3 is -C(O)NH2, -C(O)NHR 3A , -C(O)N(R 3A )2, -C(O)OR, -C(O)NOR, -C(O)NHOR, or a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring is substituted with m instances of R 3B . In some embodiments, R 3 is -C(O)NH2, -C(O)NHR 3A , -C(O)N(R 3A )2, or a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring is substituted with m instances of R 3B . In some embodiments, R 3 is -C(O)NH2 or -C(O)NHR 3A . In some embodiments, R 3 is -C(O)NOR. In some embodiments, R 3 is -C(O)OR.

[0079] In some embodiments, R 3 is -C(O)N(R 3A )2. In some embodiments, R 3 is -C(O)NHOR. In some embodiments, R 3 is a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring is substituted with m instances of R 3B .

[0080] In some embodiments, R 3is -C(O)NH2. In some embodiments, R 3 is -C(O)NHR 3A 。In some embodiments, R 3 is -C(O)NHOR or -C(O)OR. In some embodiments, R 3 is -C(O)NH2, -C(O)NHR 3A 、-C(O)NHOR or -C(O)OR. In some embodiments, R 3 is -C(O)NH2, C(O)NHR 3A or -C(O)NHOR.

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

[0082]

[0083] In some embodiments, R 3 is selected from the following:

[0084]

[0085] In some embodiments, R 3 is selected from the following:

[0086]

[0087] In some embodiments, R 3 is selected from the following:

[0088] In some embodiments, R 3 is selected from those depicted in Table 1 below.

[0089] As generally defined above, R 5 is hydrogen or -L 1 -R 5A ; or R 5 and R 6 together with the intervening atom form a 4-7 membered partially unsaturated ring or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein said ring is substituted by R 5A and n R C instances. In some embodiments, R 5 is hydrogen. In some embodiments, R 5 is -L 1 -R 5A .

[0090] In some embodiments, R5 and R 6 forms, together with its intervening atom, a 4- to 7-membered partially unsaturated ring or heteroaryl ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said ring is substituted by R 5A and n R C Examples. In some embodiments, R 5 is hydrogen or -L 1 -R 5A .

[0091] In some embodiments, R 5 is selected from the following:

[0092]

[0093]

[0094]

[0095]

[0096]

[0097]

[0098]

[0099]

[0100] In some embodiments, R 5 is selected from the following:

[0101] In some embodiments, R 5 is

[0102] In some embodiments, R 5 is selected from those depicted in Table 1 below.

[0103] As generally defined above, R 6 is hydrogen, R A or R B , or R 5 and R 6 forms, together with its intervening atom, a 4- to 7-membered partially unsaturated ring or heteroaryl ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said ring is substituted by R 5A and n R C Examples. In some embodiments, R 6 is hydrogen.

[0104] In some embodiments, R 6 is R A 。In some embodiments, R 6 is R B 。In some embodiments, R 5 and R 6 together with the intervening atom form a 4- to 7-membered partially unsaturated ring or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring is substituted with R 5A and n R C instances. In some embodiments, R 6 is hydrogen, R A or R B 。

[0105] In some embodiments, R 6 is methyl.

[0106] In some embodiments, R 6 is selected from those depicted in Table 1 below.

[0107] As generally defined above, R 7 is hydrogen, halogen, -NH2, -NHR 7A or -NHC(O)R 7A ; or R 6 and R 7 together with the intervening atom form a 4- to 7-membered partially unsaturated ring or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring is substituted with p R C instances. In some embodiments, R 7 is -NH2 or -NHR 7A 。In some embodiments, R 7 is -NHMe. In some embodiments, R 7 is -NHCD3.

[0108] In some embodiments, R 7 is hydrogen. In some embodiments, R 7 is halogen. In some embodiments, R 7 is -NH2. In some embodiments, R 7 is -NHR 7A 。In some embodiments, R 7 is -NHC(O)R 7A 。In some embodiments, R 6 and R 7 together with the intervening atom form a 4- to 7-membered partially unsaturated ring or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring is substituted with p R CReplaced by examples.

[0109] In some embodiments, R 7 is selected from the following:

[0110]

[0111] In some embodiments, R 7 is selected from those depicted in Table 1 below.

[0112] As generally defined above, L 1 is a covalent bond or a C 1-4 divalent saturated or unsaturated straight or branched hydrocarbon chain, wherein one or two methylene units of said chain are optionally and independently replaced by: -C(R 5B )2-, -CH(R 5B )-, -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2-. In some embodiments, L 1 is -N(R)-. In some embodiments, L 1 is -N(H)-.

[0113] In some embodiments, L 1 is a covalent bond. In some embodiments, L 1 is a C 1-4 divalent saturated or unsaturated straight or branched hydrocarbon chain, wherein one or two methylene units of said chain are optionally and independently replaced by: -C(R 5B )2-, -CH(R 5B )-, -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2-.

[0114] In some embodiments, L 1 is -N(R)- or a covalent bond. In some embodiments, L 1 is -N(H)- or a covalent bond.

[0115] In some embodiments, L 1 is selected from those depicted in Table 1 below.

[0116] As generally defined above, R 3A is R B and is substituted with q R Cis replaced with two Rs on the same carbon C The substituents optionally together form a 3-6 membered saturated or partially unsaturated spiro-fused heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two Rs on adjacent carbons C The substituents optionally together form a 3-6 membered saturated or partially unsaturated fused heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 3A is C C aliphatic substituted with q Rs 1-6 In some embodiments, R 3A is a 3-7 membered saturated or partially unsaturated carbocycle substituted with q Rs C In some embodiments, R 3A is cyclopropyl or cyclobutyl; each is substituted with q Rs C In some embodiments, R 3A is cyclopropyl substituted with q Rs C In some embodiments, R 3A is cyclobutyl substituted with q Rs C In some embodiments, R 3A is R B and is substituted with q Rs C provided that R 3A is not phenyl.

[0117] In some embodiments, R 3A is R B and is substituted with q Rs C wherein two Rs on the same carbon C The substituents optionally together form a 3-6 membered saturated or partially unsaturated spiro-fused heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two Rs on adjacent carbons C The substituents optionally together form a 3-6 membered saturated or partially unsaturated fused heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0118] In some embodiments, R 3A is C C aliphatic substituted with q Rs or a 3-7 membered saturated or partially unsaturated carbocycle substituted with q Rs 1-6 In some embodiments, R C is selected from the following:

[0119] In some embodiments, R 3A is selected from the following:

[0120]

[0121] In some embodiments, R3A Selected from those depicted in Table 1 below.

[0122] As defined generally above, R 3B is R B and is replaced by q R C instances, where two R C substituents on the same carbon optionally together form a 3-6 membered saturated or partially unsaturated spiro-fused heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or where two R C substituents on adjacent carbons optionally together form a 3-6 membered saturated or partially unsaturated fused heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 3B is C C aliphatic substituted by q R 1-6 instances. In some embodiments, R 3B is a 3-7 membered saturated or partially unsaturated carbocycle substituted by q R C instances. In some embodiments, R 3B is cyclopropyl or cyclobutyl; each substituted by q R C instances. In some embodiments, R 3B is cyclopropyl substituted by q R C instances. In some embodiments, R 3B is cyclobutyl substituted by q R C instances. In some embodiments, R 3B is R B and is replaced by q R C instances, provided that R 3B is not phenyl.

[0123] In some embodiments, R 3B is R B and is replaced by q R C instances, where two R C substituents on the same carbon optionally together form a 3-6 membered saturated or partially unsaturated spiro-fused heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or where two R C substituents on adjacent carbons optionally together form a 3-6 membered saturated or partially unsaturated fused heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0124] In some embodiments, R 3B is C C aliphatic substituted by q R 1-6 instances or a 3-7 membered saturated or partially unsaturated carbocycle substituted by q R C instances.

[0125] In some embodiments, R 3B is selected from the following:

[0126]

[0127] In some embodiments, R 3B is selected from those depicted in Table 1 below.

[0128] As generally defined above, R 5A is R A or R B and is substituted by r R C instances. In some embodiments, R 5A is phenyl or a 5- or 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and is substituted by r R C instances.

[0129] In some embodiments, R 5A is R C substituted by r R A instances. In some embodiments, R 5A is R C substituted by r R B instances.

[0130] In some embodiments, R 5A is selected from the following:

[0131]

[0132] In some embodiments, R 5A is selected from those depicted in Table 1 below.

[0133] As generally defined above, R 7A is R B and is substituted by q R C instances. In some embodiments, R 7A is C C aliphatic substituted by q R 1-6 instances. In some embodiments, R 7A is methyl. In some embodiments, R 7A is R B and is substituted by q R C instances, provided that R 7A is not aromatic. In some embodiments, R 7A is R B and is substituted by q R C instances, provided that R 7A is not phenyl.

[0134] In some embodiments, R 7A is R B and is substituted by q R C instances.

[0135] In some embodiments, R 7A is hydrogen. In some embodiments, R 7A is methyl.

[0136] In some embodiments, R 7A is selected from the following:

[0137]

[0138] In some embodiments, R 7A is selected from those depicted in Table 1 below.

[0139] As generally defined above, each R A instance is independently an oxo group, a 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.

[0140] In some embodiments, R A is an oxo group, a 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.

[0141] In some embodiments, R A is selected from those depicted in Table 1 below.

[0142] As generally defined above, each R B instance is independently C 1-6Aliphatic; phenyl; a 5- or 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated carbocyclic ring; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7- to 12-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0143] In some embodiments, R B is C 1-6 Aliphatic; phenyl; a 5- or 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated carbocyclic ring; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7- to 12-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0144] In some embodiments, R B is methyl.

[0145] In some embodiments, R B is selected from those depicted in Table 1 below.

[0146] As generally defined above, each R C independently is oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2 or -N(R)S(O)2R or an optionally substituted group selected from: C 1-6 Aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein two optional substituents on the same carbon optionally together form a 3- to 6-membered saturated or partially unsaturated spiro-fused heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or wherein two optional substituents on adjacent carbons optionally together form a 3- to 6-membered saturated or partially unsaturated fused heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0147] In some embodiments, R C is an oxo group, a 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: C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated 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, wherein two optional substituents on the same carbon optionally together form a 3-6 membered saturated or partially unsaturated spiro-fused heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or wherein two optional substituents on adjacent carbons optionally together form a 3-6 membered saturated or partially unsaturated fused heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0148] In some embodiments, R C is an oxo group. In some embodiments, R C is methyl, ethyl, isopropyl or n-butyl. In some embodiments, R C is a fluoro group. In some embodiments, R C is a chloro group. In some embodiments, R C is phenyl.

[0149] In some embodiments, R C is selected from the following:

[0150]

[0151]

[0152]

[0153] In some embodiments, R C is selected from the following:

[0154] In some embodiments, R C is selected from those depicted in Table 1 below.

[0155] As generally defined above, each R is independently hydrogen or an optionally substituted group selected from: C 1-6 aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or: two R groups on the same nitrogen together with the intervening atom form a 4- to 7-membered saturated ring, partially unsaturated ring or heteroaryl ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur in addition to the said nitrogen.

[0156] In some embodiments, R is hydrogen. In some embodiments, R is an optionally substituted group selected from: C 1-6 aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, two R groups on the same nitrogen together with the intervening atom form a 4- to 7-membered saturated ring, partially unsaturated ring or heteroaryl ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur in addition to the said nitrogen.

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

[0158] As generally defined above, each hydrogen bonded to carbon may optionally and independently be replaced by deuterium.

[0159] In some embodiments, the hydrogen bonded to carbon is replaced by deuterium.

[0160] As generally defined above, m is 0, 1, 2, 3 or 4. In some embodiments, m is 0. In some embodiments, m is 1, 2, 3 or 4. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.

[0161] In some embodiments, m is 1, 2 or 3. In some embodiments, m is 1 or 2. In some embodiments, m is 1 or 3. In some embodiments, m is 2 or 3. In some embodiments, m is 2 or 4. In some embodiments, m is 1, 2 or 4. In some embodiments, m is 1, 3 or 4. In some embodiments, m is 2, 3 or 4.

[0162] In some embodiments, m is selected from those depicted in Table 1 below.

[0163] As generally defined above, n is 0, 1, 2, 3, or 4. In some embodiments, n is 0. In some embodiments, n is 1, 2, 3, or 4. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0164] In some embodiments, n is 1, 2, or 3. In some embodiments, n is 1 or 2. In some embodiments, n is 1 or 3. In some embodiments, n is 2 or 3. In some embodiments, n is 2 or 4. In some embodiments, n is 1, 2, or 4. In some embodiments, n is 1, 3, or 4. In some embodiments, n is 2, 3, or 4.

[0165] In some embodiments, n is selected from those depicted in Table 1 below.

[0166] As generally defined above, p is 0, 1, 2, 3, or 4. In some embodiments, p is 0. In some embodiments, p is 1, 2, 3, or 4. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4.

[0167] In some embodiments, p is 1, 2, or 3. In some embodiments, p is 1 or 2. In some embodiments, p is 1 or 3. In some embodiments, p is 2 or 3. In some embodiments, p is 2 or 4. In some embodiments, p is 1, 2, or 4. In some embodiments, p is 1, 3, or 4. In some embodiments, p is 2, 3, or 4.

[0168] In some embodiments, p is selected from those depicted in Table 1 below.

[0169] As generally defined above, q is 0, 1, 2, 3, or 4. In some embodiments, q is 0. In some embodiments, q is 1, 2, 3, or 4. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3. In some embodiments, q is 4.

[0170] In some embodiments, q is 1, 2, or 3. In some embodiments, q is 1 or 2. In some embodiments, q is 1 or 3. In some embodiments, q is 2 or 3. In some embodiments, q is 2 or 4. In some embodiments, q is 1, 2, or 4. In some embodiments, q is 1, 3, or 4. In some embodiments, q is 2, 3, or 4.

[0171] In some embodiments, q is selected from those depicted in Table 1 below.

[0172] 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.

[0173] In some embodiments, r is 1, 2, or 3. In some embodiments, r is 1 or 2. In some embodiments, r is 1 or 3. In some embodiments, r is 2 or 3. In some embodiments, r is 2 or 4. In some embodiments, r is 1, 2, or 4. In some embodiments, r is 1, 3, or 4. In some embodiments, r is 2, 3, or 4.

[0174] In some embodiments, r is selected from those depicted in Table 1 below.

[0175] In some embodiments, the present invention provides a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein R 3 is C(O)NH2 or C(O)NHR 3A , thereby forming a compound of Formula II or III,

[0176]

[0177] wherein R 3A , R 5 , R 6 and R 7 each is as defined above and is described individually and in combination in the embodiments herein.

[0178] In some embodiments, the present invention provides a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein L 1 is -N(R)-, thereby forming a compound of Formula IV,

[0179]

[0180] wherein R 3 , R 5A , R 6 and R 7 each is as defined above and is described individually and in combination in the embodiments herein.

[0181] In some embodiments, the present invention provides a compound of Formula II or III or a pharmaceutically acceptable salt thereof, wherein L 1 is -N(R)-, thereby forming a compound of Formula V or VI, respectively,

[0182]

[0183] wherein each of R, R 3A , R 5A , R 6 , and R 7 is as defined above and is described individually and in combination in the examples herein.

[0184] In some embodiments, the present invention provides a compound of formula IV, wherein R 5A is phenyl or pyridin-3-yl, each of which is substituted with r R C instances, thereby forming a compound of formula VII or VIII, respectively,

[0185]

[0186] wherein each of r, R, R C , R 3 , R 6 , and R 7 is as defined above and is described individually and in combination in the examples herein.

[0187] In some embodiments, the present invention provides a compound of formula VIII or a pharmaceutically acceptable salt thereof, wherein each R 5A instance on R C is an oxo group, thereby forming a compound of formula IX,

[0188]

[0189] wherein each of r, R, R C , R 3 , R 6 , and R 7 is as defined above and is described individually and in combination in the examples herein.

[0190] In some embodiments, the present invention provides a compound of formula IV, V, VI, VII, VIII, or IX or a pharmaceutically acceptable salt thereof, wherein R is hydrogen, thereby forming compounds of formula X, XI, XII, XIII, XIV, XV, respectively,

[0191]

[0192] wherein each of r, R, R C , R 3 , R 3A , R 5A , R 6 , and R 7 is as defined above and is described individually and in combination in the examples herein.

[0193] In some embodiments, the present invention provides a compound of formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV or XV or a pharmaceutically acceptable salt thereof, wherein R 6 is hydrogen, thereby forming a compound of formula I-a, II-a, III-a, IV-a, V-a, VI-a, VII-a, VIII-a, IX-a, X-a, XI-a, XII-a, XIII-a, XIV-a or XV-a, respectively,

[0194]

[0195] wherein r, R, R C , R 3 , R 3A , R 5 , R 5A and R 7 each is as defined above and is described individually and in combination in the embodiments herein.

[0196] In some embodiments, the present invention provides a compound of formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, I-a, II-a, III-a, IV-a, V-a, VI-a, VII-a, VIII-a, IX-a, X-a, XI-a, XII-a, XIII-a, XIV-a or XV-a or a pharmaceutically acceptable salt thereof, wherein R 7 is -NH2 or -NHR 7A .

[0197] In some embodiments, the present invention provides a compound of formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, I-a, II-a, III-a, IV-a, V-a, VI-a, VII-a, VIII-a, IX-a, X-a, XI-a, XII-a, XIII-a, XIV-a or XV-a or a pharmaceutically acceptable salt thereof, wherein R 7 is -NHR 7A, thereby forming compounds of formula I-b, II-b, III-b, IV-b, V-b, VI-b, VII-b, VIII-b, IX-b, X-b, XI-b, XII-b, XIII-b, XIV-b, XV-b, I-c, II-c, III-c, IV-c, V-c, VI-c, VII-c, VIII-c, IX-c, X-c, XI-c, XII-c, XIII-c, XIV-c or Xv-c respectively,

[0198]

[0199]

[0200] wherein each of r, R, R C , R 3 , R 3A , R 5 , R 5A , R 6 and R 7A is as defined above and is described individually and in combination in the examples herein.

[0201] In some embodiments, the present invention provides a compound of formula I-b, II-b, III-b, IV-b, V-b, VI-b, VII-b, VIII-b, IX-b, X-b, XI-b, XII-b, XIII-b, XIV-b, XV-b, I-c, II-c, III-c, IV-c, V-c, VI-c, VII-c, VIII-c, IX-c, X-c, XI-c, XII-c, XIII-c, XIV-c or XV-c, wherein R 7A is substituted by q R C instances, wherein R 7A is not phenyl. In some embodiments, the present invention provides a compound of formula I-b, II-b, III-b, IV-b, V-b, VI-b, VII-b, VIII-b, IX-b, X-b, XI-b, XII-b, XIII-b, XIV-b, XV-b, I-c, II-c, III-c, IV-c, V-c, VI-c, VII-c, VIII-c, IX-c, X-c, XI-c, XII-c, XIII-c, XIV-c or XV-c, wherein R 7Ais methyl. In some embodiments, the present invention provides a compound of formula I-b, II-b, III-b, IV-b, V-b, VI-b, VII-b, VIII-b, IX-b, X-b, XI-b, XII-b, XIII-b, XIV-b, XV-b, I-c, II-c, III-c, IV-c, V-c, VI-c, VII-c, VIII-c, IX-c, X-c, XI-c, XII-c, XIII-c, XIV-c or XV-c, wherein R 7A is -CD3.

[0202] In some embodiments, the present invention provides a compound of formula I-b, III-b, IV-b, VI-b, VII-b, VIII-b, IX-b, X-b, XII-b, XIII-b, XIV-b, XV-b, I-c, III-c, IV-c, VI-c, VII-c, VIII-c, IX-c, X-c, XII-c, XIII-c, XIV-c or XV-c, wherein R 3A is R B and is substituted with q R C instances, provided that R 3A is not phenyl.

[0203] In some embodiments, the present invention provides a compound of formula I-b, III-b, IV-b, VI-b, VII-b, VIII-b, IX-b, X-b, XII-b, XIII-b, XIV-b, XV-b, I-c, III-c, IV-c, VI-c, VII-c, VIII-c, IX-c, X-c, XII-c, XIII-c, XIV-c or XV-c, wherein R 3A and each of R 7A is R B and is substituted with q R C instances, provided that R 3A and R 7A are each not phenyl.

[0204] In some embodiments, the present invention provides a compound of formula IV or a pharmaceutically acceptable salt thereof, wherein R 5A is pyridin-2-yl substituted with r R C instances, thereby forming a compound of formula XVI,

[0205]

[0206] wherein r, R, R C 、R 3 、R 6 and R 7Each of them is as defined above and is described individually and in combination in the embodiments herein.

[0207] In some embodiments, the present invention provides a compound of formula I, wherein R 5 is -L 1 -R 5A , L 1 is a covalent bond, and R 5A is an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0208] In some embodiments, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof, wherein R 5 is -L 1 -R 5A , L 1 is a covalent bond, and R 5A is indol-1-yl, indol-3-yl, 4-azaindol-1-yl, 7-azaindol-3-yl, or 7-azaindazol-3-yl, each R 5A is substituted by r R C instances, thereby providing compounds of formula XVII, XVIII, XIX, XX, or XXI, respectively,

[0209]

[0210] wherein each of r, R C , R 3 , R 6 and R 7 is as defined above and is described individually and in combination in the embodiments herein.

[0211] In some embodiments, the present invention provides a compound of formula XVII, XVIII, XIX, XX, or XXI or a pharmaceutically acceptable salt thereof, wherein R 6 is hydrogen, thereby providing compounds of formula XVII-a, XVIII-a, XIX-a, XX-a, or XXI-a, respectively,

[0212]

[0213] wherein each of r, R C , R 3 and R7 is as defined above and is described individually and in combination in the embodiments herein.

[0214] In some embodiments, the present invention provides a compound of formula XVII-a, XVIII-a, XIX-a, XX-a, or XXI-a or a pharmaceutically acceptable salt thereof, wherein R 7is - NHR 7A , which respectively provide compounds of formula XVII - b, XVIII - b, XIX - b, XX - b or XXI - b,

[0215]

[0216]

[0217] wherein each of r, R C , R 3 and R 7A is as defined above and is described individually and in combination in the examples herein.

[0218] In some embodiments, the present invention provides a compound of formula XVII - b, XVIII - b, XIX - b, XX - b or XXI - b or a pharmaceutically acceptable salt thereof, wherein R 3 is - C(O)NHR 3A , which respectively provide compounds of formula XVII - c, XVIII - c, XIX - c, XX - c or XXI - c,

[0219]

[0220] wherein each of r, R C , R 3 and R 7A is as defined above and is described individually and in combination in the examples herein.

[0221] Exemplary compounds of the present invention are set forth in Table 1 below.

[0222] Table 1: Selected Compounds

[0223]

[0224]

[0225]

[0226]

[0227]

[0228]

[0229]

[0230]

[0231]

[0232]

[0233] In some embodiments, the present invention employs the compounds described in Table 1 above or pharmaceutically acceptable salts thereof. In some embodiments, the present invention provides the compounds described in Table 1 above or pharmaceutically acceptable salts thereof. In some embodiments, the present invention provides a pharmaceutical composition comprising the compounds described in Table 1 above or pharmaceutically acceptable salts thereof together with a pharmaceutically acceptable carrier, excipient or diluent.

[0234] In some embodiments, the present invention provides a compound of Formula I as described above, wherein the compound is represented as "A" as described in Table 2. In some embodiments, the present invention provides a compound of Formula I as described above, wherein the compound is represented as "B" as described in Table 2. In some embodiments, the present invention provides a compound of Formula I as described above, wherein the compound is represented as "C" as described in Table 2. In some embodiments, the present invention provides a compound of Formula I as described above, wherein the compound is represented as "D" as described in Table 2. In some embodiments, the present invention provides a compound of Formula I as described above, wherein the compound is represented as "A" or "B" as described in Table 2. In some embodiments, the present invention provides a compound of Formula I as described above, wherein the compound is represented as "A" or "B" or "C" as described in Table 2. In some embodiments, the present invention provides a compound of Formula I as described above, wherein the compound is represented as "A" or "B" or "C" or "D" as described in Table 2.

[0235] In some embodiments, the present invention provides a compound of Formula I as defined above or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula I as defined above or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, adjuvant or vehicle, for use as a medicament.

[0236] Without wishing to be bound by any particular theory, it is believed that the proximity of the inhibitor compound or a side chain moiety of the inhibitor compound to the water of interest facilitates replacement or disruption of the water by the inhibitor compound or a side chain moiety of the inhibitor compound. In some embodiments, the water molecules replaced or disrupted by the inhibitor compound or a side chain moiety of the inhibitor compound are labile water molecules.

[0237] In certain embodiments, the method employs a complex comprising TYK2 and an inhibitor, wherein at least one labile water of TYK2 is replaced or disrupted by the inhibitor. In some embodiments, at least two selected labile waters are replaced or disrupted by the inhibitor.

[0238] 4. General Methods for Providing the Compounds of the Present Invention

[0239] The compounds of the present invention can generally be prepared or isolated by synthetic and / or semi-synthetic methods known to those skilled in the art for similar compounds and by the methods described in detail in the examples herein.

[0240] 5. Use, formulation, and administration

[0241] Pharmaceutically acceptable compositions

[0242] According to another embodiment, the present invention provides a composition comprising a compound of the present invention or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of the compound in the composition of the present invention is such that it effectively and measurably inhibits the TYK2 protein kinase or its mutant in a biological sample or a patient. In certain embodiments, the amount of the compound in the composition of the present invention is such that it effectively and measurably inhibits the TYK2 protein kinase or its mutant in a biological sample or a patient. In certain embodiments, the composition of the present invention is formulated for administration to a patient in need of such a composition. In some embodiments, the composition of the present invention is formulated for oral administration to a patient.

[0243] As used herein, the term "patient" means an animal, preferably a mammal and most preferably a human.

[0244] The term "pharmaceutically acceptable carrier, adjuvant, or vehicle" refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound formulated therewith. Pharmaceutically acceptable carriers, adjuvants, or vehicles that can be used in the compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffering substances such as phosphates, glycine, sorbic acid, potassium sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polypropylene block polymers, polyethylene glycol, and lanolin.

[0245] "Pharmaceutically acceptable derivative" means any non-toxic salt, ester, salt of an ester, or other derivative of a compound of the present invention that, upon administration to a recipient, is capable of directly or indirectly providing the compound of the present invention or its inhibitory active metabolite or residue.

[0246] As used herein, the term "its inhibitory active metabolite or residue" means a metabolite or residue thereof that is also an inhibitor of the TYK2 protein kinase or its mutant.

[0247] The compositions of the present invention can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or by an implanted reservoir. As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intraliver, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously. The sterile injectable form of the compositions of the present invention can be an aqueous or oleaginous suspension. These suspensions can be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a parenterally acceptable non-toxic diluent or solvent such as a solution in 1,3-butanediol. Acceptable vehicles and solvents that can be employed include water, Ringer's solution, and isotonic sodium chloride solution. In addition, a sterile fixed oil is conventionally employed as a solvent or suspending medium.

[0248] For this purpose, any mild fixed oil can be employed, including synthetic mono- or di-glycerides of fatty acids. Fatty acids such as oleic acid and its glyceride derivatives can be used in the preparation of injectables, as can natural pharmaceutically acceptable oils such as olive oil or castor oil, especially in their polyoxylated forms. These oil solutions or suspensions can also contain long-chain alcohol diluents or dispersing agents such as carboxymethyl cellulose or similar dispersing agents commonly used in formulating pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants such as Tweens, Spans and other emulsifying agents or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solid, liquid or other dosage forms can also be used for formulating purposes.

[0249] The pharmaceutically acceptable compositions of the present invention can be administered orally in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, common carriers include lactose and corn starch. Lubricants such as magnesium stearate are usually also added. For oral administration in capsule form, useful diluents include lactose and dry corn starch. When an aqueous suspension is desired for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents can also be added.

[0250] Alternatively, for rectal administration, the pharmaceutically acceptable compositions of the present invention can be administered in the form of suppositories. These suppositories can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and will thus melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycol.

[0251] The pharmaceutically acceptable compositions of the present invention may also be administered topically, particularly when the therapeutic target includes areas or organs that are readily accessible by topical application, including diseases of the eye, skin, or lower intestine. Suitable topical formulations for each of these areas or organs are readily prepared.

[0252] Topical application to the lower intestine can be achieved with a rectal suppository formulation (see above) or an appropriate enema formulation. Topical transdermal patches may also be used.

[0253] For topical application, the pharmaceutically acceptable compositions provided may be formulated as a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers. Carriers for topical application of the compounds of the present invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax, and water. Alternatively, the pharmaceutically acceptable compositions provided may be formulated as a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0254] For ophthalmic use, the pharmaceutically acceptable compositions provided may be formulated as a micronized suspension in isotonic, pH-adjusted sterile saline, or preferably as a solution in isotonic, pH-adjusted sterile saline (with or without a preservative such as benzalkonium chloride). Alternatively, for ophthalmic use, the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum.

[0255] The pharmaceutically acceptable compositions of the present invention may also be administered by nasal aerosol or by inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline with benzyl alcohol or other suitable preservatives, absorption promoters for enhancing bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0256] More preferably, the pharmaceutically acceptable compositions of the present invention are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, the pharmaceutically acceptable compositions of the present invention are not administered with food. In other embodiments, the pharmaceutically acceptable compositions of the present invention are administered with food.

[0257] The amount of the compounds of the invention that can be combined with a carrier material to produce a single dosage form of the composition will vary depending on the subject being treated and the particular mode of administration. Preferably, the compositions provided should be formulated such that a dose of the inhibitor between 0.01 - 100 mg / kg body weight / day can be administered to a patient receiving these compositions.

[0258] It should also be understood that the specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound employed, age, body weight, general health, gender, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician, as well as the severity of the particular disease being treated. The amount of the compounds of the invention in the composition will also depend on the particular compound in the composition.

[0259] Use of the Compounds and Pharmaceutically Acceptable Compositions

[0260] The compounds and compositions described herein are generally useful for inhibiting the kinase activity of one or more enzymes. In some embodiments, the kinase inhibited by the compounds and methods of the invention is TYK2.

[0261] TYK2 is a non-receptor tyrosine kinase member of the Janus kinase (JAK) family of protein kinases. The mammalian JAK family consists of four members: TYK2, JAK1, JAK2, and JAK3. JAK proteins containing TYK2 are indispensable for cytokine signaling. TYK2 associates with the cytoplasmic domains of type I and type II cytokine receptors as well as type I and type III interferon receptors and is activated by these receptors upon cytokine binding. Cytokines involved in TYK2 activation include interferons (e.g., IFN-α, IFN-β, IFN-κ, IFN-δ, IFN-ε, IFN-τ, IFN-ω, and IFN-ζ (also known as restrictin)) and interleukins (e.g., IL-4, IL-6, IL-10, IL-11, IL-12, IL-13, IL-22, IL-23, IL-27, IL-31, oncostatin M, ciliary neurotrophic factor, cardiotrophin 1, cardiotrophin-like cytokine, and LIF).Velasquez et al., "A protein kinase in the interferon α / β signaling pathway", Cell (1992) 70:313; Stahl et al., "Association and activation of Jak-Tyk kinases by CNTF-LIF-OSM-IL-6β receptor components", Science (1994) 263:92; Finbloom et al., "IL-10 induces tyrosine phosphorylation of Tyk2 and Jak1 and differential assembly of Stat1 and Stat3 complexes in human T cells and monocytes", J. Immunol. (1995) 155:1079; Bacon et al., "Interleukin 12 (IL-12) induces tyrosine phosphorylation of Jak2 and Tyk2: differential use of Janus family kinases by IL-2 and IL-12", J. Exp. Med. (1995) 181:399; Welham et al., "Interleukin-13 signal transduction in lymphohemopoietic cells: similarities and differences in signal transduction with interleukin-4 and insulin", J. Biol. Chem. (1995) 270:12286; Parham et al., "A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rβ1 and a novel cytokine receptor subunit, IL-23R", J. Immunol. (2002) 168:5699.Then, the activated TYK2 continues to phosphorylate additional signal transduction proteins, such as members of the STAT family, including STAT1, STAT2, STAT4, and STAT6.

[0262] Activation of TYK2 by IL-23 is associated with inflammatory bowel disease (IBD), Crohn's disease, and ulcerative colitis. Duerr et al., "A Genome-Wide Association Study Identifies IL23R as an Inflammatory Bowel Disease Gene", Science (2006) 314:1461-1463. As a downstream effector of IL-23, TYK2 also plays a role in psoriasis, ankylosing spondylitis, and Behçet's disease. Cho et al., "Genomics and the multifactorial nature of human auto-immune disease", New England Journal of Medicine (N. Engl. J. Med) (2011) 365:1612-1623; Cortes et al., "Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci", Nature Genetics (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 "disease)", Nature Genetics (2010) 42:698 - 702. A genome-wide association study of 2,622 individuals with psoriasis identified an association between disease susceptibility and TYK2. Strange et al., "A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1", Nature Genetics (2010) 42:985 - 992. Knockout of TYK2 or tyrosine phosphorylation inhibitors significantly reduced both IL-23-induced dermatitis 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.

[0263] TYK2 also plays a role in respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), lung cancer, and cystic fibrosis. Goblet cell hyperplasia (GCH) and mucus hypersecretion are mediated by IL-13-induced activation of TYK2, which in turn activates STAT6. Zhang et al., "Docking protein Gab2 regulates mucin expression and goblet cell hyperplasia through TYK2 / STAT6 pathway", FASEB J (2012) 26:1 - 11.

[0264] Reduced TYK2 activity confers protection against collagen antibody-induced arthritis in a human rheumatoid arthritis model. Mechanistically, reduced Tyk2 activity reduces T h 1 / T hProduction of 17 relevant cytokines, matrix metalloproteinases, and other key inflammatory markers. Ishizaki et al., "Tyk2 deficiency protects joints against destruction in anti-type II collagen antibody-induced arthritis in mice", International Immunology (2011) 23(9):575-582.

[0265] Compared with controls, TYK2 knockout mice showed complete resistance in experimental autoimmune encephalomyelitis (EAE, an animal model of multiple sclerosis (MS)), with no invasion of CD4 T cells in the spinal cord, indicating that TYK2 is crucial for pathogenic CD4-mediated disease development in MS. Oyamada et al., "Tyrosine Kinase2 Plays Critical Roles in the Pathogenic CD4 T Cell Responses for the Development of Experimental Autoimmune Encephalomyelitis", Journal of Immunology (2009) 183:7539-7546. This confirmed earlier studies linking increased TYK2 expression to MS susceptibility. Ban et al., "Replication analysis identifies TYK2 as a multiple sclerosis susceptibility factor", European Journal of Human Genetics (Eur J. Hum. Genet.) (2009) 17:1309-1313. Loss of TYK2 function mutations led to reduced demyelination of neurons and increased myelin regeneration, further indicating the role of TYK2 inhibitors in treating MS and other CNS demyelinating disorders.

[0266] TYK2 is the only signaling messenger common to both IL-12 and IL-23. TYK2 knockout reduced the paw pad thickness in mice induced by methylated BSA injection, imiquimod-induced psoriatic skin inflammation, and dextran sulfate sodium or 2,4,6-trinitrobenzenesulfonic acid-induced colitis.

[0267] Studies of the combined linkage and association of various type I IFN signaling genes with systemic lupus erythematosus (SLE), an autoimmune disorder, have shown a strong and significant correlation between the loss of function mutations of TYK2 and a reduced 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 Lupis Erythematosus", Am. J. Hum. Genet. (2005) 76:528-537. Genome-wide association studies of individuals with SLE compared to unaffected populations have shown a highly significant correlation between the TYK2 locus and SLE. Graham et al., "Association of NCF2, IKZF1, IRF8, IFIH1, and TYK2 with Systemic Lupus Erythematosus", PLoS Genetics (2011) 7(10):e1002341.

[0268] TYK2 has been shown to play an important role in maintaining tumor surveillance, and TYK2 knockout mice show impaired cytotoxic T cell responses and accelerated tumor development. However, these effects are related to the potent inhibition of natural killer (NK) cells and cytotoxic T lymphocytes, suggesting that TYK2 inhibitors are well-suited for the treatment of autoimmune disorders or transplant rejection. While other JAK family members such as JAK3 have similar roles in the immune system, TYK2 is considered a superior target because it is less involved and the signaling pathways are more closely related, resulting in fewer off-target effects. Simma et al., "Identification of an Indispensable Role for Tyrosine Kinase 2 in CTL-Mediated Tumor Surveillance", Cancer Res. (2009) 69:203-211.

[0269] However, in contrast to the reduced tumor surveillance observed by Hima et al., studies on T-cell acute lymphoblastic leukemia (T-ALL) indicate that T-ALL is highly dependent on IL-10 via STAT1-mediated signal transduction by means of TYK2 to maintain cancer cell survival by upregulating the anti-apoptotic protein BCL2. Knockdown of TYK2, but not other JAK family members, reduced cell growth. TYK2-specific activating mutations that promote cancer cell survival include activating mutations in the FERM domain (G36D, S47N, and R425H), JH2 domain (V731I), and kinase domain (E957D and R1027H). However, the kinase function of TYK2 was also identified as required for enhancing cancer cell survival, as TYK2 enzymes with kinase-dead mutations (M978Y or M978F) in addition to the activating mutation (E957D) resulted in failed transformation. Sanda et al., “TYK2-STAT1-BCL2 Pathway Dependence in T-Cell Acute Lymphoblastic Leukemia”, Cancer Disc. (2013) 3(5):564-577.

[0270] Therefore, the selective inhibition of TYK2 is considered a suitable target for patients with IL-10 and / or BCL2-addicted tumors, such as in 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.

[0271] TYK2-mediated STAT3 signaling has also been shown to mediate neuronal cell death induced by amyloid-β (Aβ) peptides. Reduction of TYK2 phosphorylation of STAT3 after Aβ administration results in decreased neuronal cell death, and increased STAT3 phosphorylation has been observed in the postmortem brains of Alzheimer's disease patients. Wan et al., "Tyk / STAT3 Signaling Mediates β-Amyloid-Induced Neuronal Cell Death: Implications in Alzheimer's Disease", J. Neurosci. (2010) 30(20):6873-6881.

[0272] Inhibition of the JAK-STAT signaling pathway has also been associated with hair growth and reversal of hair loss associated with alopecia areata. Xing et al., "Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition", Nat. Med. (2014) 20:1043-1049; Harel et al., "Pharmacologic inhibition of JAK-STAT signaling promotes hair growth", Sci. Adv. (2015) 1(9):e1500973.

[0273] Accordingly, compounds that inhibit TYK2 activity are beneficial, particularly compounds that are selective for JAK2. Such compounds should provide a pharmacological response that advantageously treats one or more of the conditions described herein without the side effects associated with JAK2 inhibition.

[0274] Although TYK2 inhibitors are known in the art, there remains a continuing need to provide novel inhibitors having more effective or favorable drug-related properties. For example, compounds having increased activity, selectivity for other JAK kinases, particularly JAK2, and ADMET (absorption, distribution, metabolism, excretion, and / or toxicity) properties. Accordingly, in some embodiments, the present invention provides TYK2 inhibitors that are selective for JAK2.

[0275] The activity of a compound used as an inhibitor of TYK2 or its mutant in the present invention can be determined in vitro, in vivo, or in cell lines. In vitro assays include assays that determine inhibition of phosphorylation activity and / or subsequent functional outcomes or the ATPase activity of activated TYK2 or its mutant. Alternative in vitro assays quantify the ability of an inhibitor to bind to TYK2. Inhibitor binding can be measured by radiolabeling the inhibitor prior to binding, separating the inhibitor / TYK2 complex, and determining the amount of bound radiolabel. Alternatively, inhibitor binding can be determined by running a competition experiment in which a new inhibitor is incubated with TYK2 that is bound to a known radioligand. Representative in vitro and in vivo assays useful for determining TYK2 inhibitors include, for example, those described and disclosed in the literature, each of which is incorporated herein by reference in its entirety. Details of compounds used as inhibitors of TYK2 or its mutant in the present invention are set forth in the examples below.

[0276] As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progression of a disease or disorder or one or more symptoms thereof as described herein. In some embodiments, treatment may be administered after the appearance of one or more symptoms. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., based on a symptom history and / or based on genetic or other predisposing factors). Treatment may also be continued after symptoms have subsided, for example, to prevent or delay their recurrence.

[0277] The provided compounds are inhibitors of TYK2 and are thus useful for treating one or more disorders associated with the activity of TYK2 or its mutant. Accordingly, in certain embodiments, the present invention provides a method for treating a TYK2-mediated disorder, the method comprising administering to a patient in need thereof a compound of the present invention or a pharmaceutically acceptable composition thereof.

[0278] As used herein, the term “TYK2-mediated” disorders, diseases, and / or conditions means any disease or other adverse condition in which TYK2 or its mutant is known to play a role. Accordingly, another embodiment of the present invention relates to treating or reducing the severity of one or more diseases in which TYK2 or its mutant is known to play a role. Such TYK2-mediated disorders include, but are not limited to, autoimmune disorders, inflammatory disorders, proliferative disorders, endocrine disorders, neurological disorders, and transplant-related disorders.

[0279] In some embodiments, the present invention provides a method for treating one or more disorders selected from the group consisting of autoimmune disorders, inflammatory disorders, proliferative disorders, endocrine disorders, neurological disorders, and transplantation-related disorders, the method comprising administering to a patient in need thereof a pharmaceutical composition comprising an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof.

[0280] In some embodiments, the disorder is an autoimmune disorder. In some embodiments, the disorder is selected from the group consisting of type 1 diabetes, cutaneous lupus erythematosus, systemic lupus erythematosus, multiple sclerosis, psoriasis, Behçet's disease, POEMS syndrome, Crohn's disease, ulcerative colitis, and inflammatory bowel disease.

[0281] In some embodiments, the disorder is an inflammatory disorder. In some embodiments, the inflammatory disorder is selected from the group consisting of rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis, hepatomegaly, Crohn's disease, ulcerative colitis, and inflammatory bowel disease.

[0282] In some embodiments, the disorder is a proliferative disorder. In some embodiments, the proliferative disorder is a hematological cancer. In some embodiments, the proliferative disorder is leukemia. In some embodiments, the leukemia is T-cell leukemia. In some embodiments, the T-cell leukemia is T-cell acute lymphoblastic leukemia (T-ALL). In some embodiments, the proliferative disorder is polycythemia vera, myelofibrosis, essential thrombocythemia.

[0283] 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.

[0284] In some embodiments, the disorder is a neurological disorder. In some embodiments, the neurological disorder is Alzheimer's disease.

[0285] In some embodiments, the proliferative disorder is associated with one or more activating mutations in TYK2. In some embodiments, the activating mutation in TYK2 is a mutation in the FERM domain, JH2 domain, or kinase domain. In some embodiments, the activating mutation in TYK2 is selected from the group consisting of G36D, S47N, R425H, V731I, E957D, and R1027H.

[0286] In some embodiments, the disorder is transplantation-related. In some embodiments, the transplantation-related disorder is transplant rejection or graft-versus-host disease.

[0287] In some embodiments, the disorder is associated with type I interferon, IL-10, IL-12 or IL-23 signaling. In some embodiments, the disorder is associated with type I interferon signaling. In some embodiments, the disorder is associated with IL-10 signaling. In some embodiments, the disorder is associated with IL-12 signaling. In some embodiments, the disorder is associated with IL-23 signaling.

[0288] The compounds of the invention can also be used to treat inflammatory or allergic conditions of the skin, such as psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity vasculitis, urticaria, bullous pemphigoid, lupus erythematosus, cutaneous lupus erythematosus, systemic lupus erythematosus, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, acquired epidermolysis bullosa, acne vulgaris and other inflammatory or allergic conditions of the skin.

[0289] The compounds of the present invention can also be used for treating other diseases or conditions, such as diseases or conditions having an inflammatory component, for example, treating eye diseases and conditions, such as eye allergies, conjunctivitis, keratoconjunctivitis sicca and vernal conjunctivitis; diseases affecting the nose, including allergic rhinitis; and inflammatory diseases involving an autoimmune reaction or having an autoimmune component or etiology, including autoimmune hematological disorders (for example, hemolytic anemia, aplastic anemia, pure red cell anemia and idiopathic thrombocytopenia); cutaneous lupus erythematosus, systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener granulamatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel diseases (for example, ulcerative colitis and Crohn's disease), irritable bowel syndrome, celiac disease, periodontitis, hyaline membrane disease, kidney diseases, glomerulopathies, alcoholic liver diseases, multiple sclerosis, endocrine ophthalmopathy, Grave's disease, sarcoidosis, alveolitis, chronic allergic pneumonia, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), Sjogren's syndrome, keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, cryopyrin-associated periodic syndromes, nephritis, vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis (with and without nephrotic syndrome,For example, those including idiopathic nephrotic syndrome or minimal change nephropathy), chronic granulomatous disease, endometriosis, leptospiral nephropathy, glaucoma, retinal diseases, aging, headache, pain, complex regional pain syndrome, cardiac hypertrophy, muscle atrophy, catabolic conditions, obesity, fetal growth retardation, hypercholesterolemia, heart disease, chronic heart failure, mesothelioma, anhidrotic ectodermal dysplasia, Behcet's disease, dyschromatosis, Paget's disease, pancreatitis, hereditary periodic fever syndrome, asthma (allergic and non-allergic, mild, moderate, severe, bronchial and exercise-induced asthma), acute lung injury, acute respiratory distress syndrome, eosinophilia, hypersensitivity, allergic reaction, sinusitis, ocular allergy, silica-induced diseases, COPD (damage reduction, airway inflammation, bronchial hyperreactivity, remodeling or disease progression), lung diseases, cystic fibrosis, acid-induced lung injury, pulmonary hypertension, polyneuropathy, cataract, muscle inflammation combined with systemic sclerosis, inclusion body myositis, myasthenia gravis, thyroiditis, Addison's disease, lichen planus, 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, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, local pneumonia, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendinitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis or vulvitis.,

[0290] In some embodiments, the inflammatory diseases that can be treated according to the methods of the present invention are selected from acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, systemic juvenile idiopathic arthritis (SJIA), cryopyrin-associated periodic syndrome (CAPS), and osteoarthritis.

[0291] In some embodiments, the inflammatory disease that can be treated according to the methods of the present invention is T h 1 or T h 17-mediated diseases. In some embodiments, Th The 17-mediated diseases are selected from cutaneous lupus erythematosus, systemic lupus erythematosus, multiple sclerosis, and inflammatory bowel disease (including Crohn's disease or ulcerative colitis).

[0292] In some embodiments, the inflammatory diseases that can be treated according to the methods of the invention are selected from Sjogren's syndrome, allergic disorders, osteoarthritis, ocular conditions such as ocular allergy, conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, and diseases affecting the nose such as allergic rhinitis.

[0293] In addition, the invention provides the use of a compound or a pharmaceutically acceptable salt or hydrate or solvate thereof as defined herein for the preparation of a medicament for the treatment of an autoimmune disorder, an inflammatory disorder, or a proliferative disorder or a disorder that typically occurs in association with transplantation.

[0294] Combination therapy

[0295] Depending on the particular condition or disease to be treated, additional therapeutic agents that are typically administered for the treatment of the condition may be administered in combination with the compounds and compositions of the invention. As used herein, additional therapeutic agents that are typically administered for the treatment of a particular disease or condition are referred to as "suitable for the disease or condition to be treated".

[0296] In certain embodiments, the provided combination or its composition is administered in combination with another therapeutic agent.

[0297] Examples of agents that can also be combined with the combinations of the invention include, but are not limited to: therapeutic agents for Alzheimer's disease, such as and therapeutic agents for HIV, such as ritonavir; therapeutic agents for Parkinson's Disease, such as L-DOPA / carbidopa, entacapone, ropinrole, pramipexole, bromocriptine, pergolide, trihexephendyl, and amantadine; agents for the treatment of multiple sclerosis (MS), such as beta interferon (e.g., and ), and mitoxantrone; therapeutic agents for asthma, such as albuterol and Agents for treating schizophrenia, such as zyprexa, risperdal, seroquel, and haloperidol; anti-inflammatory agents, such as corticosteroids, TNF blockers, IL-1RA, 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 β-blockers, ACE inhibitors, diuretics, nitrates, calcium ion channel blockers, and statins; agents for treating liver diseases, such as corticosteroids, cholestyramine, interferons, and antiviral agents; agents for treating blood disorders, such as corticosteroids, anti-leukemia agents, and growth factors; agents for prolonging or improving pharmacokinetics, such as cytochrome P450 inhibitors (i.e., inhibitors of metabolic breakdown) and CYP3A4 inhibitors (e.g., ketoconazole and ritonavir), and agents for treating immunodeficiency disorders, such as gamma globulin.

[0298] In certain embodiments, the combination therapy of the invention or a pharmaceutically acceptable composition thereof is administered in combination with a monoclonal antibody or an siRNA therapeutic agent.

[0299] These additional agents can be administered separately from the provided combination therapy as part of a multi-dose regimen. Alternatively, those agents can be part of a single dosage form, which is mixed with the compound of the invention in a single composition. If administered as part of a multi-dose regimen, the two active agents can be delivered simultaneously, sequentially, or at intervals (usually five hours apart) from each other.

[0300] As used herein, the terms "combination", "combined", and related terms refer to the administration of therapeutic agents simultaneously or sequentially according to the invention. For example, the combination of the invention can be administered simultaneously or sequentially with another therapeutic agent in separate unit dosage forms or together in a single unit dosage form.

[0301] The amount of the additional therapeutic agent present in the compositions of the invention will not exceed the amount typically administered in a composition comprising the therapeutic agent as the sole active agent. Preferably, the amount of the additional therapeutic agent in the compositions disclosed herein will be in the range of about 50% to 100% of the amount typically present in a composition comprising the agent as the sole therapeutic active agent.

[0302] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of Formula I and one or more additional therapeutic agents. The therapeutic agent can be administered together with the compound of Formula I or can be administered before or after the administration of the compound of Formula I. Suitable therapeutic agents are described in further detail below. In certain embodiments, the compound of Formula I can be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours before the therapeutic agent. In other embodiments, the compound of Formula I can be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours after the therapeutic agent.

[0303] In another embodiment, the present invention provides a method of treating an inflammatory disease, disorder, or condition by administering a compound of Formula I and one or more additional therapeutic agents to a patient in need thereof. Such additional therapeutic agents can be small molecules or recombinant biopharmaceuticals and include, for example, acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs) (such as aspirin, ibuprofen, naproxen, etodolac and celecoxib), colchicine corticosteroids (such as prednisone, prednisolone, methylprednisolone, hydrocortisone, etc.), probenecid, allopurinol, febuxostat sulfasalazine antimalarial drugs (such as hydroxychloroquine and chloroquine methotrexate ), gold salts (such as aurothioglucose aurothiomalate and auranofin ), D-penicillamine ( or ), azathioprine cyclophosphamide chlorambucil cyclosporine leflunomide and "anti-TNF" agents (such as etanercept infliximab golimumab certolizumab pegol and adalimumab ), "anti-IL-1" agents (such as anakinra Anakinra )、Canakinumab Anti-Jak inhibitors (such as tofacitinib), antibodies (such as rituximab )、“Anti-T cell” agents (such as abatacept )、“Anti-IL-6” agents (such as tocilizumab )、Diclofenac, cortisone, hyaluronic acid( or )、Monoclonal antibodies (such as tanizumab), anticoagulants (such as heparin)( or ) and warfarin Antidiarrheals (such as diphenoxylate and loperamide )、Bile acid binders (such as cholestyramine), alosetron Lubiprostone Laxatives (such as milk of magnesia, polyethylene glycol and )、Anticholinergics or antispasmodics (such as dicyclomine β-2 agonists (such as salbutamol( HFA、 HFA), levalbuterol Orciprenaline Pirbuterol acetate Terbutaline sulfate Salmeterol xinafoate and formoterol )、Anticholinergics (such as ipratropium bromide and tiotropium )、Inhaled corticosteroids (such as beclomethasone dipropionate( and )、Triamcinolone acetonide Mometasone Budesonide and flunisolide Sodium cromoglicate )、Methylxanthines (such as theophylline and aminophylline), IgE antibodies (such as omalizumab )、Nucleoside reverse transcriptase inhibitors (such as zidovudine Abacavir Abacavir / lamivudine Abacavir / lamivudine / zidovudine Didanosine Emtricitabine Lamivudine Lamivudine / zidovudine Stavudine and zalcitabine ) Non-nucleoside reverse transcriptase inhibitors (such as delavirdine efavirenz nevirapine and etravirine ) Nucleotide reverse transcriptase inhibitors (such as tenofovir ) Protease inhibitors (such as amprenavir atazanavir darunavir fosamprenavir indinavir lopinavir and ritonavir nelfinavir ritonavir saquinavir( or ) and tipranavir ) Entry inhibitors (such as enfuvirtide and maraviroc ) Integrase inhibitors (such as raltegravir adriamycin vincristine bortezomib and lenalidomide in combination with dexamethasone ) or any one or more combinations thereof.

[0304] In another embodiment, the present invention provides a method for treating rheumatoid arthritis, the method comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from the following: non-steroidal anti-inflammatory drugs (NSAIDs) (such as aspirin, ibuprofen, naproxen, etodolac and celecoxib), corticosteroids (such as prednisone, prednisolone, methylprednisolone, hydrocortisone, etc.), sulfasalazine antimalarial drugs (such as hydroxychloroquine and chloroquine methotrexate ), gold salts (such as aurothioglucose aurothiomalate and auranofin ), D-penicillamine( or ), azathioprine cyclophosphamide chlorambucil cyclosporine leflunomide and "anti-TNF" agents (such as etanercept infliximab golimumab Certolizumab pegol and adalimumab ), "anti-IL-1" agents (such as anakinra and rilonacept ), antibodies (such as rituximab ), "anti-T cell" agents (such as abatacept ), and "anti-IL-6" agents (such as tocilizumab ).

[0305] In some embodiments, the present invention provides a method for treating osteoarthritis, the method comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from: acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs) (such as aspirin, ibuprofen, naproxen, etodolac and celecoxib), diclofenac, cortisone, hyaluronic acid ( or ), and monoclonal antibodies (such as tanirizumab).

[0306] In some embodiments, the present invention provides a method for treating cutaneous lupus erythematosus or systemic lupus erythematosus, the method comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from: acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs) (such as aspirin, ibuprofen, naproxen, etodolac and celecoxib), corticosteroids (such as prednisone, prednisolone, methylprednisolone, hydrocortisone, etc.), antimalarial drugs (such as hydroxychloroquine and chloroquine cyclophosphamide methotrexate ), azathioprine and anticoagulants (such as heparin) ( or ) and warfarin

[0307] In some embodiments, the present invention provides a method for treating Crohn's disease, ulcerative colitis, or inflammatory bowel disease, the method comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from: aminosalicylic acid sulfasalazine antidiarrheal drugs (such as diphenoxylate and loperamide ), bile acid binders (such as cholestyramine), alosetron lubiprostone laxatives (such as milk of magnesia, polyethylene glycol and ) and an anticholinergic or antispasmodic agent (such as dicyclomine ), anti-TNF therapy, steroids, and antibiotics (such as metronidazole or ciprofloxacin).

[0308] In some embodiments, the present invention provides a method for treating asthma, the method comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from: β-2 agonists (such as albuterol ( HFA, HFA), levalbuterol metaproterenol pirbuterol acetate terbutaline sulfate salmeterol xinafoate and formoterol ), anticholinergics (such as ipratropium bromide and tiotropium bromide ), inhaled corticosteroids (such as prednisone, prednisolone, beclomethasone dipropionate ( and ), triamcinolone acetonide mometasone budesonide and flunisolide and sodium cromoglycate ), methylxanthines (such as theophylline and aminophylline) and IgE antibodies (such as omalizumab ).

[0309] In some embodiments, the present invention provides a method for treating COPD, the method comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from: β-2 agonists, such as albuterol ( HFA, HFA), levalbuterol metaproterenol pirbuterol acetate terbutaline sulfate salmeterol xinafoate and formoterol anticholinergics, such as ipratropium bromide and tiotropium bromide methylxanthines, such as theophylline and aminophylline; inhaled corticosteroids, such as prednisone, prednisolone, beclomethasone dipropionate ( and ), triamcinolone acetonide mometasone budesonide Flunisolide and

[0310] In another embodiment, the present invention provides a method for treating hematological malignancies, the method comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from the following: rituximab cyclophosphamide doxorubicin vincristine prednisone, hedgehog signaling inhibitors, BTK inhibitors, JAK / pan-JAK inhibitors, PI3K inhibitors, SYK inhibitors, and combinations thereof.

[0311] In another embodiment, the present invention provides a method for treating solid tumors, the method comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from the following: rituximab cyclophosphamide doxorubicin vincristine prednisone, hedgehog signaling inhibitors, BTK inhibitors, JAK / pan-JAK inhibitors, PI3K inhibitors, SYK inhibitors, and combinations thereof.

[0312] In another embodiment, the present invention provides a method for treating hematological malignancies, the method comprising administering to a patient in need thereof a compound of formula I and a hedgehog (Hh) signaling pathway inhibitor. In some embodiments, the hematological malignancy is DLBCL (Ramirez et al., "Defining causative factors contributing in the activation of hedgehog signaling in diffuse large B-cell lymphoma," Leuk. Res. (2012), which was published online on July 17 and is incorporated herein by reference in its entirety).

[0313] In another embodiment, the present invention provides a method for treating diffuse large B-cell lymphoma (DLBCL), the method comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from the following: rituximab cyclophosphamide doxorubicin vincristine prednisone, hedgehog signaling inhibitors, and combinations thereof.

[0314] In another embodiment, the present invention provides a method for treating multiple myeloma, the method comprising administering to a patient in need a compound of formula I and one or more additional therapeutic agents selected from the following in combination with lenalidomide : bortezomib and dexamethasone hedgehog signaling inhibitors, BTK inhibitors, JAK / pan-JAK inhibitors, TYK2 inhibitors, PI3K inhibitors, SYK inhibitors.

[0315] In another embodiment, the present invention provides a method for treating a disease or reducing its severity, the method comprising administering a compound of formula I and a BTK inhibitor to a patient in need thereof, wherein the disease is selected from inflammatory bowel disease, arthritis, cutaneous lupus erythematosus, systemic lupus erythematosus (SLE), vasculitis, idiopathic thrombocytopenic purpura (ITP), rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis, Graves'disease, autoimmune thyroiditis, Sjögren's syndrome, multiple sclerosis, systemic sclerosis, neuroborreliosis, Guillain-Barre syndrome, acute disseminated encephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome, ankylosing spondylitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, autoimmune gastritis, pernicious anemia, celiac disease, Goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia totalis, Behcet's disease, chronic fatigue, autonomic disorders, membranous glomerulonephropathy, endometriosis, interstitial cystitis, pemphigus vulgaris, bullous pemphigoid, neuromyotonia, scleroderma, vulvodynia, hyperproliferative diseases, transplant organ or tissue rejection, acquired immunodeficiency syndrome (AIDS, also known as HIV), type 1 diabetes, graft-versus-host disease, transplantation, blood transfusion, allergic reactions, allergies (e.g.,Allergic to plant pollen, latex, drugs, foods, insect venoms, animal hairs, animal dander, dust mites or cockroach frass), type I hypersensitivity reactions, allergic conjunctivitis, allergic rhinitis and atopic dermatitis, asthma, appendicitis, atopic dermatitis, asthma, allergy, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection, colitis, conjunctivitis, Crohn's disease, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, Henoch-Schonlein purpura, hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonia, pulmonary infection, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendinitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis or vulvitis, B cell proliferative disorders such as diffuse large B cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, acute lymphocytic leukemia, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma / Waldenstrom macroglobulinemia, splenic marginal zone lymphoma, multiple myeloma (also known as plasma cell myeloma), non-Hodgkin's lymphoma, Hodgkin's lymphoma, plasmacytoma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, Burkitt lymphoma / leukemia or lymphomatoid granulomatosis, breast cancer, prostate cancer or mast cell carcinoma (e.g., mastocytoma, mast cell leukemia, mast cell sarcoma, systemic mastocytosis), bone cancer, colorectal cancer, pancreatic cancer, bone and joint diseases, including but not limited to rheumatoid arthritis, seronegative spondyloarthropathies (including ankylosing spondylitis, psoriatic arthritis and Reiter's disease), Behcet's disease, Sjogren's syndrome, systemic sclerosis, osteoporosis, bone cancer, bone metastases, thromboembolic disorders (e.g.,Myocardial infarction, angina pectoris, restenosis after angioplasty, reocclusion after angioplasty, restenosis after aortocoronary bypass, reocclusion after aortocoronary bypass, stroke, transient ischemia, peripheral arterial occlusive disease, pulmonary embolism, deep vein thrombosis), inflammatory pelvic disease, urethritis, skin sunburn, sinusitis, pneumonia, encephalitis, meningitis, myocarditis, nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis, dermatitis, gingivitis, appendicitis, pancreatitis, cholecystitis, agammaglobulinemia, psoriasis, allergy, Crohn's disease, irritable bowel syndrome, ulcerative colitis, Sjogren's syndrome, tissue graft rejection, hyperacute rejection of transplanted organs, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), autoimmune polyglandular disease (also known as autoimmune polyglandular syndrome), autoimmune alopecia, pernicious anemia, glomerulonephritis, dermatomyositis, multiple sclerosis, scleroderma, vasculitis, autoimmune hemolytic and thrombocytopenic disorders, Goodpasture's syndrome, atherosclerosis, Addison's disease, Parkinson's disease, Alzheimer's disease, diabetes, septic shock, cutaneous lupus erythematosus, systemic lupus erythematosus (SLE), rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, osteoarthritis, chronic idiopathic thrombocytopenic purpura, Waldenstrom's macroglobulinemia, myasthenia gravis, Hashimoto's thyroiditis, atopic dermatitis, degenerative joint disease, vitiligo, autoimmune hypopituitarism, Guillain-Barré syndrome, Behçet's disease, scleroderma, mycosis fungoides, acute inflammatory responses (such as acute respiratory distress syndrome and ischemia / reperfusion injury) and Grave's disease.,

[0316] In another embodiment, the present invention provides a method of treating a disease or reducing its severity, the method comprising administering to a patient in need a compound of formula I and a PI3K inhibitor, wherein the disease is selected from cancer, neurodegenerative disorders, angiogenic disorders, viral diseases, autoimmune diseases, inflammatory disorders, hormone-related diseases, conditions related to organ transplantation, immunodeficiency disorders, destructive bone disorders, proliferative disorders, infectious diseases, conditions related to cell death, thrombin-induced platelet aggregation, chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), liver diseases, pathological immunological conditions involving T cell activation, cardiovascular disorders and CNS disorders.

[0317] In another embodiment, the present invention provides a method for treating a disease or reducing its severity, the method comprising administering to a patient in need thereof a compound of formula I and a PI3K inhibitor, wherein the disease is selected from benign or malignant tumors, cancers or solid tumors, sarcomas, glioblastomas, neuroblastomas, multiple myelomas or gastrointestinal cancers, especially colon cancer or colorectal adenoma or head and neck tumors, epidermal hyperplasia, psoriasis, prostatic hyperplasia, neoplasia, epithelial neoplasia, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer, lymphoma (including, for example, non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (also known as Hodgkin's disease or Hodgkin disease)), breast cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma or leukemia of the brain, kidney (e.g., renal cell carcinoma (RCC)), liver, adrenal gland, bladder, breast, stomach, gastric tumor, ovary, colon, rectum, prostate, pancreas, lung, vagina, endometrium, cervix, testis, urogenital tract, esophagus, larynx, skin, bone or thyroid, diseases including Cowden syndrome, Lhermitte-Dudos disease and Bannayan-Zonana syndrome, or diseases with abnormal activation of the PI3K / PKB pathway, asthma of any type or origin, including endogenous (non-allergic) asthma and exogenous (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchitic asthma, exercise-induced asthma, occupational asthma and asthma induced after bacterial infection, acute lung injury (ALI), adult / acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease, airway or lung diseases (COPD, COAD or COLD), including chronic bronchitis or dyspnea associated therewith, emphysema and deterioration of airway hyperresponsiveness caused by other drug treatments, especially other drug inhalational treatments, bronchitis of any type or origin, including but not limited to acute, peanut-induced, catarrhal, croupous, chronic or tuberculous bronchitis, pneumoconiosis of any type or origin (inflammatory (usually occupational) lung disease, often accompanied by airway obstruction, whether chronic or acute, and caused by repeated inhalation of dust),including, for example, aluminosis, anthracosis, asbestosis, siderosis, madarosis, siderosis, silicosis, fume fever, and byssinosis, Loffler's syndrome, eosinophilic pneumonia, parasite (especially metazoan) infections (including tropical eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa (including Churg-Strauss syndrome), eosinophilic granuloma, and eosinophil-related conditions affecting the airways caused by drug reactions, psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity vasculitis, urticaria, bullous pemphigoid, lupus erythematosus, pemphigus, epidermolysis bullosa acquisita, conjunctivitis, keratoconjunctivitis sicca and vernal conjunctivitis, diseases affecting the nose (including allergic rhinitis) and inflammatory diseases involving an autoimmune reaction or having an autoimmune component or etiology, including autoimmune hematological disorders (e.g., hemolytic anemia, aplastic anemia, pure red cell aplasia, and idiopathic thrombocytopenia), cutaneous lupus erythematosus, systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener granulamatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Stevens-Johnson syndrome, idiopathic steatorrhea, autoimmune inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), endocrine ophthalmic diseases, Graves' disease, sarcoidosis, alveolitis, chronic allergic pneumonia, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior uvea), keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis, and glomerulonephritis (with and without nephrotic syndrome), such as including idiopathic nephrotic syndrome or minimal change nephropathy, restenosis, cardiac hypertrophy, atherosclerosis, myocardial infarction, ischemic stroke, and congestive heart failure, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and cerebral ischemia, and neurodegenerative diseases caused by traumatic injury, glutamate neurotoxicity, and hypoxia.,

[0318] In some embodiments, the present invention provides a method of treating a disease or reducing its severity, the method comprising administering to a patient in need thereof a compound of formula I and a Bcl-2 inhibitor, wherein the disease is an inflammatory disorder, an autoimmune disorder, a proliferative disorder, an endocrine disorder, a neurological disorder or a transplantation-related disorder. In some embodiments, the disorder is a proliferative disorder, lupus or lupus nephritis. In some embodiments, the proliferative disorder is chronic lymphocytic leukemia, diffuse large B-cell lymphoma, Hodgkin's disease, small cell lung cancer, non-small cell lung cancer, myelodysplastic syndrome, lymphoma, hematopoietic sarcoma or solid tumor.

[0319] In some embodiments, the present invention provides a method of treating a disease or reducing its severity, the method comprising administering to a patient in need thereof a TYK2 pseudokinase (JH2) domain-binding compound and a TYK2 kinase (JH1) domain-binding compound. In some embodiments, the disease is an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder or a transplantation-related disorder. In some embodiments, the JH2-binding compound is a compound of formula I. Other suitable JH2 domain-binding compounds include those described in WO 2014074660A1, WO2014074661A1, WO2015089143A1, the entire contents of each of which are incorporated herein by reference. Suitable JH1 domain-binding compounds include those described in WO 2015131080A1, the entire contents of which are incorporated herein by reference.

[0320] According to the method of the present invention, the compounds and compositions can be administered in any amount and by any route of administration effective to treat or reduce the severity of the following: autoimmune disorders, inflammatory disorders, proliferative disorders, endocrine disorders, neurological disorders, or transplantation-related disorders. The precise amount required will vary depending on the subject and will depend on factors such as the type, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, etc. The compounds of the present invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. As used herein, the expression "dosage unit form" refers to physically discrete units of medicament suitable for the patient to be treated. However, it should be understood that the total daily dosage of the compounds and compositions of the present invention will be determined by the attending physician within the scope of reasonable medical judgment. The specific effective dosage 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 particular compound employed; the particular composition employed; the age, weight, general health, sex, and diet of the patient; the time of administration, route of administration, and excretion rate of the particular compound employed; the duration of the treatment; drugs used in combination with or concurrently with the particular compound employed; and similar factors well known in the medical arts. As used herein, the term "patient" means an animal, preferably a mammal and most preferably a human.

[0321] The pharmaceutically acceptable compositions of the present invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, vaginally, intraperitoneally, topically (such as by powder, ointment, or drops), buccally, in the form of an oral spray, or a nasal spray, etc., depending on the severity of the infection being treated. In certain embodiments, the compounds of the present invention can be administered orally or parenterally once or more times a day at a dosage level of about 0.01 mg / kg to about 50 mg / kg and preferably about 1 mg / kg to about 25 mg / kg of the subject's body weight / day to obtain the desired therapeutic effect.

[0322] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, the liquid dosage forms may also contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents, and emulsifying agents, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide, oils (specifically, cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerin, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan and mixtures thereof. In addition to the inert diluent, the oral compositions may also contain adjuvants such as wetting agents, emulsifying agents, and suspending agents, sweetening agents, flavoring agents, and perfuming agents.

[0323] Injectable preparations such as sterile injectable aqueous or oily suspensions can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparations can also be sterile injectable solutions, suspensions or emulsions in a parenterally acceptable non-toxic diluent or solvent, such as a solution in 1,3-butanediol. Acceptable vehicles and solvents that can be employed include water, Ringer's solution, U.S.P., and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be used, including synthetic mono- or diglycerides of fatty acids. In addition, fatty acids such as oleic acid are used to prepare injectables.

[0324] Injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating a sterilizing agent in the form of a sterile solid composition which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0325] To prolong the effect of the compounds of the present invention, it is generally desirable to slow the absorption of the compounds from subcutaneous or intramuscular injection. This can be accomplished by using a liquid suspension of a poorly water-soluble crystalline or amorphous material. Thus, the rate of absorption of the compound depends upon its rate of dissolution which in turn may depend upon crystal size and form. Alternatively, delayed absorption of a compound form for parenteral administration is achieved by dissolving or suspending the compound in an oily vehicle. Injectable depot forms are prepared by forming microcapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. The rate of compound release can be controlled according to the ratio of the compound to the polymer and the nature of the particular polymer employed. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0326] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of the present invention with a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol or suppository waxes which are solid at room temperature but liquid at body temperature and will therefore melt in the rectal or vaginal cavity and release the active compound.

[0327] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert pharmaceutically acceptable excipient or carrier such as sodium citrate or calcium phosphate dibasic and / or a) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; c) humectants such as glycerol; d) disintegrants such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retarders such as paraffin; f) absorption promoters such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glycerol monostearate; h) adsorbents such as kaolin and bentonite; and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also include buffering agents.

[0328] Solid compositions of a similar type can also be used as fillers in soft and hard gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycol. Solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the art of pharmaceutical formulation. The dosage form may optionally contain emulsifying agents and its composition may also be such that the dosage form releases one or more active ingredients optionally in a delayed manner only or preferentially in a specific part of the intestine. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type can also be used as fillers in soft and hard gelatin capsules using excipients such as lactose and high molecular weight polyethylene glycol.

[0329] The active compound can also be in microencapsulated form with one or more of the excipients as described above. Solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells (such as enteric coatings, release control coatings, and other coatings well known in the art of pharmaceutical formulation). In such solid dosage forms, the active compound can be admixed with at least one inert diluent such as sucrose, lactose, or starch. Under normal circumstances, in addition to the inert diluent, such dosage forms may also include additional substances such as tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage form may also include buffering agents. The dosage form may optionally contain emulsifying agents and its composition may also be such that the dosage form releases one or more active ingredients optionally in a delayed manner only or preferentially in a specific part of the intestine. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0330] Dosage forms for topical or transdermal administration of the compounds of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active ingredient is mixed with a pharmaceutically acceptable carrier and any required preservatives or buffers that may be needed under sterile conditions. Ophthalmic formulations, ear drops, and eye drops are also contemplated within the scope of the present invention. Additionally, the present invention contemplates the use of transdermal patches, which have the additional advantage of delivering the compound to the body in a controlled manner. Such dosage forms can be prepared by dissolving or dispersing the compound in a suitable medium. Penetration enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by providing a rate-controlling membrane or by dispersing the compound in a polymeric matrix or gel.

[0331] According to one embodiment, the present invention relates to a method for inhibiting protein kinase activity in a biological sample, the method comprising the step of contacting the biological sample with a compound of the present invention or a composition comprising the compound.

[0332] According to another embodiment, the present invention relates to a method for inhibiting the activity of TYK2 or a mutant thereof in a biological sample, the method comprising the step of contacting the biological sample with a compound of the present invention or a composition comprising the compound. In certain embodiments, the present invention relates to a method for irreversibly inhibiting the activity of TYK2 or a mutant thereof in a biological sample, the method comprising the step of contacting the biological sample with a compound of the present invention or a composition comprising the compound.

[0333] In another embodiment, the present invention provides a method for selectively inhibiting TYK2 over one or more of JAK1, JAK2, and JAK3. In some embodiments, the selectivity of the compounds of the present invention is more than 2-fold greater than JAK1 / 2 / 3. In some embodiments, the selectivity of the compounds of the present invention is more than 5-fold greater than JAK1 / 2 / 3. In some embodiments, the selectivity of the compounds of the present invention is more than 10-fold greater than JAK1 / 2 / 3. In some embodiments, the selectivity of the compounds of the present invention is more than 50-fold greater than JAK1 / 2 / 3. In some embodiments, the selectivity of the compounds of the present invention is more than 100-fold greater than JAK1 / 2 / 3.

[0334] As used herein, the term "biological sample" includes, but is not limited to, cell cultures or extracts thereof; biopsy material obtained from a mammal or an extract thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.

[0335] Inhibiting the activity of TYK2 (or a mutant thereof) in a biological sample can be used for various purposes known to those skilled in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ transplantation, biological specimen storage, and bioassays.

[0336] Another embodiment of the present invention relates to a method of inhibiting the protein kinase activity in a patient, the method comprising the step of administering to the patient a compound of the present invention or a composition comprising the compound.

[0337] According to another embodiment, the present invention relates to a method of inhibiting the activity of TYK2 or a mutant thereof in a patient, the method comprising the step of administering to the patient a compound of the present invention or a composition comprising the compound. According to certain embodiments, the present invention relates to a method of reversibly or irreversibly inhibiting the activity of one or more of TYK2 or a mutant thereof in a patient, the method comprising the step of administering to the patient a compound of the present invention or a composition comprising the compound. In other embodiments, the present invention provides a method for treating a disorder mediated by TYK2 or a mutant thereof in a patient in need thereof, the method comprising the step of administering to the patient a compound of the present invention or a pharmaceutically acceptable composition thereof. Such disorders are described in detail herein.

[0338] Depending on the particular condition or disease to be treated, additional therapeutic agents typically administered for treating the condition may also be present in the compositions of the present invention. As used herein, additional therapeutic agents typically administered for treating a particular disease or condition are referred to as "disease or condition suitable for treatment".

[0339] The compounds of the present invention can also be used in combination with other therapeutic compounds to produce advantages. In some embodiments, the other therapeutic compounds are anti-proliferative compounds. Such anti-proliferative compounds include but are not limited to: aromatase inhibitors; anti-estrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule-active compounds; alkylating compounds; histone deacetylase inhibitors; compounds that induce the process of cell differentiation; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; anti-tumor antimetabolites; platinum compounds; compounds that target / reduce protein or lipid kinase activity and additional anti-angiogenic compounds; compounds that target protein or lipid phosphatases, reduce or inhibit their activity; gonadotropin-releasing hormone agonists; anti-androgens; methionine aminopeptidase inhibitors; matrix metalloproteinase inhibitors; bisphosphonates; biological response modifiers; anti-proliferative antibodies; heparanase inhibitors; inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasome inhibitors; compounds for the treatment of hematological malignancies; compounds that target Flt-3, reduce or inhibit its activity; Hsp90 inhibitors, such as 17-AAG (17-allylamino geldanamycin, NSC330507), 17-DMAG (17-dimethylaminoethylamino-17-demethoxy-geldanamycin, NSC707545), IPI-504, CNF1010, CNF2024, CNF1010 from Conforma Therapeutics; temozolomide Kinesin spindle protein inhibitors, such as SB715992 or SB743921 from GlaxoSmithKline, or pentamidine / chlorpromazine from CombinatoRx; MEK inhibitors, such as ARRY142886 from Array BioPharma, AZD6244 from AstraZeneca, PD181461 from Pfizer, and folinic acid. As used herein, the term "aromatase inhibitor" refers to a compound that inhibits estrogen production, such as a compound that converts the substrates androstenedione and testosterone into estrone and estradiol, respectively. The term includes, but is not limited to: steroids, especially atamestane, exemestane, and formestane, and especially non-steroids, especially aminoglutethimide, roglethimide, pyridoglutethimide, trilostane, testolactone, ketoconazole, vorozole, fadrozole, anastrozole, and letrozole. Exemestane is sold under the trade name Aromasin TM and formestane is sold under the trade name Lentaron TM and fadrozole is sold under the trade name Afema TM and anastrozole is sold under the trade name Arimidex TM and letrozole is sold under the trade name Femara TM or Femar TM and aminoglutethimide is sold under the trade name Orimeten TM The compositions of the invention, including chemotherapeutic agents that are aromatase inhibitors, are particularly useful for treating hormone receptor-positive tumors, such as breast tumors.

[0340] As used herein, the term "antiestrogen" refers to a compound that antagonizes the action of estrogen at the estrogen receptor level. The term includes, but is not limited to, tamoxifen, fulvestrant, raloxifene, and raloxifene hydrochloride. Tamoxifen is sold under the trade name Nolvadex TM and raloxifene hydrochloride is sold under the trade name Evista TMis sold under the trade name Faslodex TM is sold. The combination according to the invention, as a chemotherapeutic agent acting as an antiestrogen, can in particular be used for treating estrogen receptor-positive tumors, such as breast tumors.

[0341] As used herein, the term "antiandrogen" relates to any substance capable of inhibiting the biological action of androgens and includes, but is not limited to, bicalutamide (Casodex TM ). As used herein, the term "gonadotropin-releasing hormone agonist" includes, but is not limited to, abarelix, goserelin and goserelin acetate. Goserelin is sold under the trade name Zoladex TM is sold.

[0342] As used herein, the term "topoisomerase I inhibitor" includes, but is not limited to: topotecan, gimatecan, irinotecan, camptothecian and its analogs, 9-nitro-camptothecin and the macromolecular camptothecin conjugate PNU-166148. Irinotecan can be administered, for example, in a form sold, for example, under the trade name Camptosar TM Topotecan is sold under the trade name Hycamptin TM is sold.

[0343] As used herein, the term "topoisomerase II inhibitor" includes, but is not limited to, anthracyclines such as doxorubicin (including liposomal formulations such as Caelyx TM ), daunorubicin, epirubicin, idarubicin and nemorubicin, anthraquinones - mitoxantrone and losoxantrone, and podophillotoxine - etoposide and teniposide. Etoposide is sold under the trade name Etopophos TM is sold. Teniposide is sold under the trade name VM 26 - Bristol. Doxorubicin is sold under the trade name Acriblastin TM or Adriamycin TM is sold. Epirubicin is sold under the trade name Farmorubicin TM is sold. Idarubicin is sold under the trade name Zavedos TMSales. Mitoxantrone is sold under the trade name Novantron.

[0344] The term "microtubule - active agent" refers to microtubule - stabilizing compounds, microtubule - destabilizing compounds, and microtubulin polymerization inhibitors, including but not limited to: taxanes, such as paclitaxel and docetaxel; vinca alkaloids, such as vinblastine or vinblastine sulfate, vincristine or vincristine sulfate, and vinorelbine; discodermolide; colchicine and epothilones and their derivatives. Paclitaxel is sold under the trade name Taxol TM Sales. Docetaxel is sold under the trade name Taxotere TM Sales. Vinblastine sulfate is sold under the trade name Vinblastin R.P TM Sales. Vincristine sulfate is sold under the trade name Farmistin TM Sales.

[0345] As used herein, the term "alkylating agent" includes but is not limited to cyclophosphamide, ifosfamide, melphalan, or nitrosoureas (BCNU or Gliadel). Cyclophosphamide is sold under the trade name Cyclostin TM Sales. Ifosfamide is sold under the trade name Holoxan TM Sales.

[0346] The term "histone deacetylase inhibitor" or "HDAC inhibitor" refers to compounds that inhibit histone deacetylases and have anti - proliferative activity. This includes but is not limited to suberoylanilide hydroxamic acid (SAHA).

[0347] The term "antineoplastic antimetabolite" includes but is not limited to 5 - fluorouracil or 5 - FU, capecitabine, gemcitabine, DNA demethylating compounds, such as 5 - azacytidine and decitabine, methotrexate, and edatrexate, and folate antagonists, such as pemetrexed. Capecitabine is sold under the trade name Xeloda TM Sales. Gemcitabine is sold under the trade name Gemzar TM Sales.

[0348] As used herein, the term "platinum compound" includes but is not limited to carboplatin, cis - platin, cisplatinum, and oxaliplatin. Carboplatin can be administered, for example, in a form sold under the trade name Carboplat TM Sales. Oxaliplatin can be administered, for example, in a form sold under the trade name Eloxatin TM Sales.

[0349] As used herein, the term "compound that targets / reduces protein or lipid kinase activity or protein or lipid phosphatase activity or additional anti-angiogenic compound" includes, but is not limited to: protein tyrosine kinases and / or serine and / or threonine kinase inhibitors or lipid kinase inhibitors, such as a) compounds that target, reduce or inhibit platelet-derived growth factor-receptor (PDGFR) activity, such as compounds that target, reduce or inhibit PDGFR activity, especially compounds that inhibit the PDGF receptor, such as N-phenyl-2-pyrimidinamine derivatives, such as imatinib, SU101, SU6668 and GFB-111; b) compounds that target, reduce or inhibit fibroblast growth factor-receptor (FGFR) activity; c) compounds that target, reduce or inhibit insulin-like growth factor receptor I (IGF-IR) activity, such as compounds that target, reduce or inhibit IGF-IR activity, especially compounds that inhibit the kinase activity of the IGF-I receptor or antibodies that target the extracellular domain of the IGF-I receptor or its growth factor; d) compounds that target, reduce or inhibit the activity of the Trk receptor tyrosine kinase family or ephrin B4 inhibitors; e) compounds that target, reduce or inhibit the activity of the AxI receptor tyrosine kinase family; f) compounds that target, reduce or inhibit Ret receptor tyrosine kinase activity; g) compounds that target, reduce or inhibit Kit / SCFR receptor tyrosine kinase activity, such as imatinib; h) compounds that target, reduce or inhibit the activity of the C-kit receptor tyrosine kinase (which is part of the PDGFR family), such as compounds that target, reduce or inhibit the activity of the c-Kit receptor tyrosine kinase family, especially compounds that inhibit the c-Kit receptor, such as imatinib; i) compounds that target, reduce or inhibit the activity of c-Abl family members, their gene fusion products (such as the BCR-Abl kinase) and mutants, such as compounds that target, reduce or inhibit the activity of c-Abl family members and their gene fusion products, such as N-phenyl-2-pyrimidinamine derivatives, such as imatinib or nilotinib (AMN107); PD180970; AG957; NSC 680410; PD173955 from Parke Davis; or dasatinib (BMS-354825); j) compounds that target, reduce or inhibit the activity of protein kinase C (PKC) and Raf family members of serine / threonine kinases; MEK, SRC, JAK / pan-JAK, FAK, PDK1, PKB / Akt, Ras / MAPK, PI3K, SYK, BTK and TEC family members; and / or cyclin-dependent kinase (CDK) family members, such as midostaurin;Examples of additional compounds include UCN-01, safingol, BAY 43-9006, Bryostatin 1, Perifosine; Ilmofosine; RO 318220 and RO320432; GO 6976; Lsis 3521; LY333531 / LY379196; isoquinoline compounds; FTI; PD184352 or QAN697 (PI3K inhibitor) or AT7519 (CDK inhibitor); k) compounds that target, reduce or inhibit the activity of protein-tyrosine kinase inhibitors, such as compounds that target, reduce or inhibit the activity of protein-tyrosine kinase inhibitors include imatinib mesylate (Gleevec; TM ) or tyrosine phosphorylation inhibitors, such as tyrosine phosphorylation inhibitor A23 / RG-50810; AG 99; tyrosine phosphorylation inhibitor AG 213; tyrosine phosphorylation inhibitor AG 1748; tyrosine phosphorylation inhibitor AG 490; tyrosine phosphorylation inhibitor B44; tyrosine phosphorylation inhibitor B44 (+) enantiomer; tyrosine phosphorylation inhibitor AG555; AG 494; tyrosine phosphorylation inhibitors AG 556, AG957 and adaphostin (4-{[(2,5-dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester; NSC680410, adaphostin); l) compounds that target the epidermal growth factor family of receptor tyrosine kinases (EGFR1, ErbB2, ErbB3, ErbB4 as homodimers or heterodimers) and their mutants, reduce or inhibit their activity, such as compounds that target the epidermal growth factor receptor family, reduce or inhibit its activity, especially compounds that inhibit members of the EGF receptor tyrosine kinase family such as the EGF receptor, ErbB2, ErbB3 and ErbB4 or compounds, proteins or antibodies that bind to EGF or the EGF-related ligand CP 358774, ZD 1839, ZM 105180; trastuzumab (Herceptin TM ) cetuximab (Erbitux TM) Iressa, Tarceva, OSI-774, Cl-1033, EKB-569, GW-2016, E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 or E7.6.3; and 7H-pyrrolo-[2,3-d]pyrimidine derivatives; m) a compound that targets, reduces or inhibits the activity of the c-Met receptor, such as a compound that targets, reduces or inhibits the activity of c-Met, especially a compound that inhibits the kinase activity of the c-Met receptor, or an antibody that targets the extracellular domain of c-Met or binds to HGF; n) a compound that targets, reduces or inhibits the kinase activity of one or more JAK family members (JAK1 / JAK2 / JAK3 / TYK2 and / or pan-JAK), including but not limited to PRT-062070, SB-1578, baricitinib, pacritinib, momelotinib, VX-509, AZD-1480, TG-101348, tofacitinib and ruxolitinib; o) a compound that targets, reduces or inhibits the kinase activity of PI3 kinase (PI3K), including but not limited to ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765 and idelalisib; and q) a compound that targets, reduces or inhibits the signal transduction of the hedgehog (Hh) or smoothened receptor (SMO) pathway, including but not limited to cyclopamine, vismodegib, itraconazole, erismodegib and IPI-926 (saridegib).

[0350] As used herein, the term "PI3K inhibitor" includes, but is not limited to, compounds having inhibitory activity against one or more enzymes in the phosphatidylinositol-3-kinase family, said enzymes including, but not limited to, PI3Kα, PI3Kγ, PI3Kδ, PI3Kβ, PI3K-C2α, PI3K-C2β, PI3K-C2γ, Vps34, p110-α, p110-β, p110-γ, p110-δ, p85-α, p85-β, p55-γ, p150, p101, and p87. Examples of PI3K inhibitors that can be used in the present invention include, but are not limited to: ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, Buparlisib, Pictilisib, PF-4691502, BYL-719, Dactolisib, XL-147, XL-765, and Idelalisib.

[0351] As used herein, the term "BTK inhibitor" includes, but is not limited to, compounds having inhibitory activity against Bruton's tyrosine kinase (BTK), including, but not limited to, AVL-292 and Ibrutinib.

[0352] As used herein, the term "SYK inhibitor" includes, but is not limited to, compounds having inhibitory activity against spleen tyrosine kinase (SYK), including, but not limited to, PRT-062070, R-343, R-333, Excellair, PRT-062607, and Fostamatinib.

[0353] As used herein, the term "Bcl-2 inhibitor" includes, but is not limited to, compounds having inhibitory activity against B-cell lymphoma 2 protein (Bcl-2), including, but not limited to, ABT-199, ABT-731, ABT-737, apogossypol, Ascenta's pan-Bcl-2 inhibitor, curcumin (and its analogs), dual Bcl-2 / Bcl-xL inhibitor (Infinity Pharmaceuticals / Novartis Pharmaceuticals), Genasense (G3139), HA14-1 (and its analogs; see WO2008118802), navitoclax (and its analogs, see US7390799), NH-1 (Shenyang Pharmaceutical University), obatoclax (and its analogs, see WO 2004106328), S-001 (Gloria Pharmaceuticals), TW series compounds (Univ. of Michigan), and venetoclax. In some embodiments, the Bcl-2 inhibitor is a small molecule therapeutic agent. In some embodiments, the Bcl-2 inhibitor is a peptidomimetic.

[0354] Additional examples of BTK inhibitory compounds and conditions treatable by combining such compounds with the compounds of the present invention can be found in WO 2008039218 and WO 2011090760, the entire contents of which are incorporated herein by reference.

[0355] Additional examples of SYK inhibitory compounds and conditions treatable by combining such compounds with the compounds of the present invention can be found in WO 2003063794, WO 2005007623, and WO 2006078846, the entire contents of which are incorporated herein by reference.

[0356] Additional examples of PI3K inhibitory compounds and conditions treatable by combination of such compounds with the compounds of the present invention can be found in WO 2004019973, WO 2004089925, WO 2007016176, US8138347, WO2002088112, WO 2007084786, WO 2007129161, WO 2006122806, WO 2005113554 and WO2007044729, the entire contents of which are incorporated herein by reference.

[0357] Additional examples of JAK inhibitory compounds and conditions treatable by combination of such compounds with the compounds of the present invention can be found in WO 2009114512, WO 2008109943, WO 2007053452, WO 2000142246 and WO2007070514, the entire contents of which are incorporated herein by reference.

[0358] Additional anti-angiogenic compounds include compounds having another mechanism for their activity, such as compounds unrelated to protein or lipid kinase inhibition, such as thalidomide (Thalomid TM ) and TNP-470.

[0359] Examples of proteasome inhibitors useful for combination with the compounds of the present invention include, but are not limited to, bortezomib, disulfiram, epigallocatechin-3-gallate (EGCG), salinosporamide A, carfilzomib, ONX-0912, CEP-18770 and MLN9708.

[0360] Compounds that target protein or lipid phosphatases and reduce or inhibit their activity are inhibitors of, for example, phosphatase 1, phosphatase 2A or CDC25, such as okadaic acid or its derivatives.

[0361] Compounds that induce the process of cell differentiation include, but are not limited to, retinoic acid, α-, γ- or δ-tocopherol or α-, γ- or δ-tocotrienol.

[0362] As used herein, the term cyclooxygenase inhibitor includes, but is not limited to, Cox-2 inhibitors, 5-alkyl-substituted 2-aryl aminophenylacetic acids and derivatives, such as celecoxib (Celebrex TM ) and rofecoxib (Vioxx TM) etoricoxib, valdecoxib, or 5-alkyl-2-aryl aminophenylacetic acid, such as 5-methyl-2-(2'-chloro-6'-fluorophenylamino)phenylacetic acid, lumiracoxib.

[0363] As used herein, the term "bisphosphonate" includes, but is not limited to, etridonic acid, clodronic acid, tiludronic acid, pamidronic acid, alendronic acid, ibandronic acid, risedronic acid, and zoledronic acid. Etridonic acid is sold under the trade name Didronel TM Clodronic acid is sold under the trade name Bonefos TM Tiludronic acid is sold under the trade name Skelid TM Pamidronic acid is sold under the trade name Aredia TM Alendronic acid is sold under the trade name Fosamax TM Ibandronic acid is sold under the trade name Bondranat TM Risedronic acid is sold under the trade name Actonel TM Zoledronic acid is sold under the trade name Zometa TM The term "mTOR inhibitor" refers to a compound that inhibits mammalian target of rapamycin (mTOR) and has antiproliferative activity, such as sirolimus everolimus (Certican TM ), CCI-779, and ABT578.

[0364] As used herein, the term "heparanase inhibitor" refers to a compound that targets, reduces, or inhibits heparan sulfate degradation. The term includes, but is not limited to, PI-88. As used herein, the term "biological response modifier" refers to lymphokines or interferons.

[0365] As used herein, the term "inhibitor of Ras oncogenic isoforms" such as H-Ras, K-Ras, or N-Ras refers to a compound that targets Ras, reduces, or inhibits the oncogenic activity of Ras; for example, "farnesyltransferase inhibitors" such as L-744832, DK8G557, or R115777 (Zarnestra TM)。As used herein, the term "telomerase inhibitor" refers to a compound that targets telomerase and reduces or inhibits its activity. Compounds that target telomerase and reduce or inhibit its activity are, in particular, compounds that inhibit the telomerase receptor, such as telomestatin.

[0366] As used herein, the term "methionine aminopeptidase inhibitor" refers to a compound that targets methionine aminopeptidase and reduces or inhibits its activity. Compounds that target methionine aminopeptidase and reduce or inhibit its activity include, but are not limited to, bengamide or its derivatives.

[0367] As used herein, the term "proteasome inhibitor" refers to a compound that targets the proteasome and reduces or inhibits its activity. Compounds that target the proteasome and reduce or inhibit its activity include, but are not limited to, bortezomib (Velcade TM ) and MLN 341.

[0368] As used herein, the term "matrix metalloproteinase inhibitor" or ("MMP" inhibitor) includes, but is not limited to: peptidomimetic and non-peptidomimetic inhibitors of collagen, tetracycline derivatives, such as the hydroxamate peptidomimetic inhibitor batimastat and its orally bioavailable analogue marimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551), BMS-279251, BAY 12-9566, TAA211, MMI270B or AAJ996.

[0369] As used herein, the term "compound for treating hematological malignancies" includes, but is not limited to, FMS-like tyrosine kinase inhibitors, which are compounds that target the FMS-like tyrosine kinase receptor (Flt-3R) and reduce or inhibit its activity; interferons, 1-β-D-arabinofuranosylcytosine (ara-c) and bisulfan; ALK inhibitors, which are compounds that target, reduce or inhibit anaplastic lymphoma kinase and Bcl-2 inhibitors.

[0370] Compounds that target the FMS-like tyrosine kinase receptor (Flt-3R) and reduce or inhibit its activity are, in particular, compounds, proteins or antibodies that inhibit members of the Flt-3R receptor kinase family, such as PKC412, midostaurin, staurosporine derivatives, SU11248 and MLN518.

[0371] As used herein, the term "HSP90 inhibitor" includes, but is not limited to, compounds that target HSP90 and reduce or inhibit its intrinsic ATPase activity; compounds that degrade, target, reduce or inhibit HSP90 client proteins through the ubiquitin proteasome pathway. Compounds that target HSP90 and reduce or inhibit its intrinsic ATPase activity are especially compounds, proteins or antibodies that inhibit the ATPase activity of HSP90, such as 17 - allylamino, 17 - demethoxygeldanamycin (17AAG), geldanamycin derivatives; other geldanamycin - related compounds; radicicol and HDAC inhibitors.

[0372] As used herein, the term "anti - proliferative antibody" includes, but is not limited to, trastuzumab (Herceptin TM ), trastuzumab - DM1, cetuximab (erbitux), bevacizumab (Avastin TM ), rituximab PRO64553 (anti - CD40) and 2C4 antibody. Antibodies refer to intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed by at least two intact antibodies, and antibody fragments, as long as they exhibit the desired biological activity.

[0373] For the treatment of acute myeloid leukemia (AML), the compounds of the present invention can be used in combination with standard leukemia therapies, particularly in combination with therapies for treating AML. Specifically, the compounds of the present invention can be administered in combination with, for example, farnesyl transferase inhibitors and / or other drugs such as daunorubicin, doxorubicin, Ara-C, VP-16, teniposide, mitoxantrone, idarubicin, carboplatinum, and PKC412 that can be used to treat AML. In some embodiments, the present invention provides a method for treating AML associated with ITD and / or D835Y mutations, the method comprising administering a compound of the present invention together with one or more FLT3 inhibitors. In some embodiments, the FLT3 inhibitor is selected from quizartinib (AC220), staurosporine derivatives (such as midostaurin or lestaurtinib), sorafenib, tandutinib, LY-2401401, LS-104, EB-10, famitinib, NOV-110302, NMS-P948, AST-487, G-749, SB-1317, S-209, SC-110219, AKN-028, fedratinib, tozasertib, and sunitinib. In some embodiments, the FLT3 inhibitor is selected from quizartinib, midostaurin, lestaurtinib, sorafenib, and sunitinib.

[0374] Other anti-leukemia compounds include, for example, the pyrimidine analogue Ara-C, which is a 2'-α-hydroxyribose (arabinoside) derivative of deoxycytidine. Also included are purine analogues of hypoxanthine, 6-mercaptopurine (6-MP), and fludarabine phosphate. Compounds that target histone deacetylase (HDAC) inhibitors and reduce or inhibit their activity, such as sodium butyrate and suberoylanilide hydroxamic acid (SAHA), inhibit the activity of an enzyme called histone deacetylase. Specific HDAC inhibitors include MS275, SAHA, FK228 (formerly known as FR901228), trichostatin A, and the compounds disclosed in US 6,552,065, including but not limited to N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide or a pharmaceutically acceptable salt thereof and N-hydroxy-3-[4-[(2-hydroxyethyl){2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide or a pharmaceutically acceptable salt thereof, especially the lactate salt. As used herein, a somatostatin receptor antagonist refers to a compound that targets, treats, or inhibits a somatostatin receptor, such as octreotide and SOM230. Methods of tumor cell damage refer to methods such as ionizing radiation. The term "ionizing radiation" as referred to above and below refers to ionizing radiation generated as electromagnetic rays (such as X-rays and γ-rays) or particles (such as α and β particles). Ionizing radiation is provided in radiation therapy, but is not limited thereto, and is known in the art. See Hellman, Principles of Radiation Therapy, Cancer: Principles and Practice of Oncology, edited by Devita et al., 4th Edition, Volume 1, pp. 248-275 (1993).

[0375] Also included are EDG binders and ribonucleotide reductase inhibitors. As used herein, the term "EDG binder" refers to a class of immunosuppressive agents that regulate lymphocyte recirculation, such as FTY720. The term "ribonucleotide reductase inhibitor" refers to a pyrimidine or purine nucleoside analogue, including but not limited to: fludarabine and / or cytosine arabinoside (ara-C), 6-thioguanine, 5-fluorouracil, cladribine, 6-mercaptopurine (especially for use in combination with ara-C in ALL) and / or pentostatin. Ribonucleotide reductase inhibitors are especially hydroxyurea or 2-hydroxy-1H-isoindole-1,3-dione derivatives.

[0376] Those compounds, proteins or monoclonal antibodies that also specifically contain VEGF, such as 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceutically acceptable salt thereof, 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate; Angiostatin TM ; Endostatin TM ; anthranilic acid amide; ZD4190; ZD6474; SU5416; SU6668; bevacizumab; or an anti-VEGF antibody or an anti-VEGF receptor antibody, such as rhuMAb and RHUFab, a VEGF aptamer such as Macugon; an FLT-4 inhibitor, an FLT-3 inhibitor, a VEGFR-2IgGI antibody, an angiogenic ribozyme (Angiozyme) (RPI 4610) and bevacizumab (Avastin TM ).

[0377] As used herein, photodynamic therapy refers to a therapy for treating or preventing cancer using certain chemical substances called photosensitizing compounds. Examples of photodynamic therapy include treatments with compounds such as Visudyne TM and porfimer sodium.

[0378] As used herein, angiogenesis-inhibiting steroids refer to compounds that block or inhibit angiogenesis, such as anecortave, triamcinolone, hydrocortisone, 11-α-epihydrocotisol, cortexolone, 17α-hydroxyprogesterone, corticosterone, desoxycorticosterone, testosterone, estrone and dexamethasone.

[0379] Implants containing corticosteroids refer to compounds such as fluocinonide and dexamethasone.

[0380] Other chemotherapeutic compounds include, but are not limited to: plant alkaloids, hormonal compounds and antagonists; biological response modifiers, preferably lymphokines or interferons; antisense oligonucleotides or oligonucleotide derivatives; shRNA or siRNA; or other compounds or compounds with other or unknown mechanisms of action.

[0381] The compounds of the present invention can also be used as co-therapeutic compounds for use in combination with other medicaments such as anti-inflammatory agents, bronchodilator drugs or antihistamine drugs, particularly for the treatment of obstructive or inflammatory airway diseases as mentioned above, for example as a therapeutic activity enhancer of such drugs or as a method of reducing the required dosing or potential side effects of such drugs. The compounds of the present invention can be mixed with other drugs in the form of a fixed pharmaceutical composition or they can be administered separately before, simultaneously with or after other drugs. Accordingly, the present invention encompasses combinations of the compounds of the present invention as described above with anti-inflammatory agents, bronchodilator drugs, antihistamine drugs or antitussive drugs, the said compounds and the said drugs of the present invention being in the same or different pharmaceutical compositions.

[0382] Suitable anti-inflammatory agents include steroids, especially glucocorticosteroids such as budesonide, beclomethasone dipropionate, fluticasone propionate, ciclesonide or mometasone furoate; non-steroidal glucocorticoid receptor agonists; LTB4 antagonists such as LY293111, CGS025019C, CP-195543, SC-53228, BIIL 284, ONO 4057, SB 209247; LTD4 antagonists such as montelukast and zafirlukast; PDE4 inhibitors such as cilomilast ( GlaxoSmithKline, Roflumilast (Byk Gulden), V-11294A (Napp), BAY 19-8004 (Bayer), SCH-351591 (Schering-Plough), Arofylline (Almirall Prodesfarma), PD189659 / PD168787 (Parke-Davis), AWD-12-281 (Asta Medica), CDC-801 (Celgene), SeICID(TM) CC-10004 (Celgene), VM554 / UM565 (Vernalis), T-440 (Tanabe), KW-4490 (Kyowa Hakko Kogyo); A2a agonists; A2b antagonists; and β-2 adrenergic receptor agonists such as salbutamol (albuterol), orciprenaline, terbutaline, salmeterol, fenoterol, procaterol and especially formoterol and pharmaceutically acceptable salts thereof. Suitable bronchodilator agents include anticholinergic or antimuscarinic compounds, especially ipratropium bromide, oxitropium bromide, tiotropium salts and CHF 4226 (Chiesi) and glycopyrrolate.

[0383] Suitable antihistamine agents include cetirizine hydrochloride, paracetamol, clemastine fumarate, promethazine, loratidine, desloratidine, diphenhydramine and fexofenadine hydrochloride, activastine, astemizole, azelastine, ebastine, epinastine, mizolastine and terfenadine.

[0384] Other useful combinations of the compounds of the present invention with anti-inflammatory agents are combinations with antagonists of chemokine receptors such as, 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, especially CCR-5 antagonists such as Schering-Plough antagonists SC-351125, SCH-55700 and SCH-D and Takeda antagonists such as N-[[4-[[[6,7-dihydro-2-(4-methylphenyl)-5H-benzo-cyclohepten-8-yl]carbonyl]amino]phenyl]-methyl]tetrahydro-N,N-dimethyl-2H-pyran-4-ammonium chloride (TAK-770).

[0385] The structures of the active compounds identified by code name, common name or trade name may be taken from the actual version of the standard compendium "The Merck Index" or databases such as Patents International (e.g., IMS World Publications).

[0386] The compounds of the present invention may also be used in combination with known therapeutic methods such as, for example, the administration of hormones or radiation. In certain embodiments, the provided compounds are used as radiosensitizers, particularly for treating tumors that exhibit poor sensitivity to radiotherapy.

[0387] The compounds of the present invention may be administered alone or in combination with one or more other therapeutic compounds. The possible combination therapies may take the form of a fixed combination or the administration of the compounds of the present invention and one or more other therapeutic compounds may be staggered or given independently of each other or in combination with a fixed combination and one or more other therapeutic compounds. In addition or alternatively, the compounds of the present invention may be administered in combination with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention or combinations thereof, particularly for tumor therapy. Long-term therapies are also possible, such as adjuvant therapies in the context of other therapeutic strategies as described above. Other possible treatments are therapies for maintaining the patient's condition after tumor regression or even chemoprevention therapies, for example, in patients at risk.

[0388] These additional agents may be administered separately from the composition containing the compound of the present invention as part of a multi-dose regimen. Alternatively, those agents may be part of a single dosage form that is mixed with the compound of the present invention in a single composition. If administered as part of a multi-dose regimen, the two active agents may be delivered simultaneously, sequentially or at intervals (usually five hours apart) from each other.

[0389] As used herein, the terms "combination", "combined", and related terms refer to the administration of therapeutic agents simultaneously or sequentially in accordance with the present invention. For example, a compound of the present invention can be administered simultaneously or sequentially with another therapeutic agent in separate unit dosage forms or in a single unit dosage form together. Accordingly, the present invention provides a single unit dosage form that includes a compound of the present invention, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0390] The amounts of both the compound of the present invention and the additional therapeutic agent (in those compositions that include an additional therapeutic agent as described above) that can be combined with a carrier material to produce a single dosage form will vary depending on the subject being treated and the particular mode of administration. Preferably, the compositions of the present invention should be formulated such that a dose of 0.01 - 100 mg / kg body weight / day of the compound of the present invention can be administered.

[0391] In those compositions that include an additional therapeutic agent, the additional therapeutic agent and the compound of the present invention can act synergistically. Accordingly, the amount of the additional therapeutic agent in such compositions will be less than the amount required in a single therapy using only the therapeutic agent. In such compositions, a dose of the additional therapeutic agent between 0.01 - 1,000 μg / kg body weight / day can be administered.

[0392] The amount of the additional therapeutic agent present in the compositions of the present invention will not exceed the amount typically administered in compositions that include the therapeutic agent as the sole active agent. Preferably, the amount of the additional therapeutic agent in the compositions disclosed herein will be in the range of about 50% to 100% of the amount typically present in compositions that include the agent as the sole therapeutic active agent.

[0393] The compound of the present invention or its pharmaceutical composition can also be incorporated into compositions for coating implantable medical devices such as prostheses, artificial valves, vascular grafts, stents, and catheters. For example, vascular stents have been used to overcome restenosis (the re - narrowing of the blood vessel wall after injury). However, patients using stents or other implantable devices are at risk of clot formation or platelet activation. These undesirable effects can be prevented or mitigated by pre - coating the device with a pharmaceutically acceptable composition that includes a kinase inhibitor. An implantable device coated with a compound of the present invention is another embodiment of the present invention.

[0394] The present invention is further described now by non - limiting Examples 1 to 32:

[0395] Example 1:

[0396] A compound of formula I

[0397]

[0398] or a pharmaceutically acceptable salt thereof, wherein:

[0399] R 3 is -C(O)NH2, -C(O)NHR 3A , -C(O)N(R 3A )2, -C(O)OR, -C(O)NHOR or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein said ring is substituted with m R 3B instances;

[0400] R 5 is hydrogen or -L 1 -R 5A ;

[0401] R 6 is hydrogen, R A or R B ;

[0402] or alternatively R 5 and R 6 together with the intervening atom form a 4-7 membered partially unsaturated ring or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein said ring is substituted with R 5A and n R C instances;

[0403] R 7 is hydrogen, halogen, -NH2, -NHR 7A or -NHC(O)R 7A ;

[0404] or alternatively R 6 and R 7 together with the intervening atom form a 4-7 membered partially unsaturated ring or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein said ring is substituted with p R C instances;

[0405] L 1 is a covalent bond or a C 1-4 divalent saturated or unsaturated straight or branched hydrocarbon chain, wherein one or two methylene units of said chain are optionally and independently replaced by: -C(R 5B )2-, -CH(R 5B )-, -N(R)-, -N(R)C(O)-, -C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2-;

[0406] R 3A , R 3B and R 7A Each is independently R B And each is q R C Example substitution, where two R on the same carbon C The substituents are optionally taken together to form a 3-6 membered saturated or partially unsaturated spiro-fused heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or wherein two R on adjacent carbons are C The substituents are optionally taken together to form a 3-6 membered saturated or partially unsaturated fused heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0407] R 5A and each R 5B The instances are each independently R A or R B and are independently represented by r R C Instance replacement;

[0408] Each R A Examples are independently oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, or -N(R)S(O)2R;

[0409] Each R B The instance is independently C 1-6 aliphatic; 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;

[0410] Each R CAn instance is independently an oxo group, a 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: C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated 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, where two optional substituents on the same carbon optionally together form a 3-6 membered saturated or partially unsaturated spiro-fused heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or where two optional substituents on adjacent carbons optionally together form a 3-6 membered saturated or partially unsaturated fused heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0411] Each R is independently hydrogen or an optionally substituted group selected from: C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated 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:

[0412] two R groups on the same nitrogen together with the intervening atom form a 4-7 membered saturated ring, partially unsaturated ring or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur in addition to the said nitrogen,

[0413] wherein each hydrogen bonded to carbon may optionally and independently be replaced by deuterium; and

[0414] each instance of m, n, p, q and r is independently 0, 1, 2, 3 or 4, provided that the compound is not

[0415] Example 2:

[0416] a compound according to Example 1 or a pharmaceutically acceptable salt thereof having one of formula II or III:

[0417]

[0418] Example 3:

[0419] A compound or a pharmaceutically acceptable salt thereof according to any one of Embodiment 1 or 2, which has Formula V or VI,

[0420]

[0421] Example 4:

[0422] A compound or a pharmaceutically acceptable salt thereof according to any one of Embodiments 1 to 3, which has Formula V-a or VI-a,

[0423]

[0424] Example 5:

[0425] A compound or a pharmaceutically acceptable salt thereof according to any one of Embodiments 1 to 4, wherein R 7 is -NH2 or -NHR 7A .

[0426] Example 6:

[0427] A compound or a pharmaceutically acceptable salt thereof according to any one of Embodiments 1 to 5, which has one of Formula V-c or VI-c,

[0428]

[0429] Example 7:

[0430] A compound according to any one of Embodiments 1 to 6, wherein R 3A and R 7A among them are not independently R B and are substituted by q R C instances, provided that neither R 3A nor R 7A is phenyl.

[0431] Example 8:

[0432] A compound according to any one of Embodiments 1 to 7, wherein R 7A is C 1-6 aliphatic.

[0433] Example 9:

[0434] A compound according to any one of Embodiments 1 to 8, wherein R 7A is methyl.

[0435] Example 10:

[0436] A compound according to any one of Examples 1 to 9 or a pharmaceutically acceptable salt thereof, which is selected from those depicted in Table 1 of the present specification.

[0437] Example 11:

[0438] A pharmaceutical composition comprising a compound according to any one of Examples 1 to 10 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, adjuvant or vehicle.

[0439] Example 12:

[0440] A compound according to any one of Examples 1 to 10 or a pharmaceutical composition according to Example 11, which is used as a medicament.

[0441] Example 13:

[0442] A method of inhibiting TYK2 in a biological sample, optionally an in vitro method, the method comprising contacting the sample with a compound according to any one of Examples 1 to 10 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to Example 11.

[0443] Example 14:

[0444] A compound according to any one of Examples 1 to 10 or a pharmaceutical composition according to Example 11, which is used for treating a TYK2-mediated disorder, disease or condition in a patient, including administering to the patient a compound according to any one of Examples 1 to 10 or a pharmaceutical composition according to Example 11.

[0445] Example 15:

[0446] A compound according to any one of Examples 1 to 10 or a pharmaceutical composition according to Example 11 for use according to Example 14, wherein the disorder is selected from autoimmune disorders, inflammatory disorders, proliferative disorders, endocrine disorders, neurological disorders or transplantation-related disorders.

[0447] Example 16:

[0448] A compound according to any one of Examples 1 to 10 or a pharmaceutical composition according to Example 11 for use according to Example 15, wherein the disorder is an autoimmune disorder.

[0449] Example 17:

[0450] The compound according to any one of Embodiments 1 to 10 or the pharmaceutical composition according to Embodiment 11 for use according to Embodiment 16, wherein the autoimmune disease is selected from type 1 diabetes, ankylosing spondylitis, cutaneous lupus erythematosus, systemic lupus erythematosus, multiple sclerosis, systemic sclerosis, psoriasis, Crohn's disease, ulcerative colitis, and inflammatory bowel disease.

[0451] Example 18:

[0452] The compound according to any one of Embodiments 1 to 10 or the pharmaceutical composition according to Embodiment 11 for use according to Embodiment 15, wherein the disease is an inflammatory disease.

[0453] Example 19:

[0454] The compound according to any one of Embodiments 1 to 10 or the pharmaceutical composition according to Embodiment 11 for use according to Embodiment 18, wherein the inflammatory disease is selected from rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis, Crohn's disease, ulcerative colitis, and inflammatory bowel disease.

[0455] Example 20:

[0456] The compound according to any one of Embodiments 1 to 10 or the pharmaceutical composition according to Embodiment 11 for use according to Embodiment 15, wherein the disease is a proliferative disease.

[0457] Example 21:

[0458] The compound according to any one of Embodiments 1 to 10 or the pharmaceutical composition according to Embodiment 11 for use according to Embodiment 20, wherein the proliferative disease is a hematological cancer.

[0459] Example 22:

[0460] The compound according to any one of Embodiments 1 to 10 or the pharmaceutical composition according to Embodiment 11 for use according to Embodiment 20, wherein the proliferative disease is leukemia.

[0461] Example 23:

[0462] The compound according to any one of Embodiments 1 to 10 or the pharmaceutical composition according to Embodiment 11 for use according to Embodiment 22, wherein the leukemia is T-cell leukemia.

[0463] Example 24:

[0464] The compound according to any one of embodiments 1 to 10 or the pharmaceutical composition according to embodiment 11 for use according to embodiment 23, wherein the T cell leukemia is T cell acute lymphoblastic leukemia (T-ALL).

[0465] Example 25:

[0466] The compound according to any one of embodiments 1 to 10 or the pharmaceutical composition according to embodiment 11 for use according to embodiment 20, wherein the proliferative disorder is associated with one or more activating mutations of TYK2.

[0467] Example 26:

[0468] The compound according to any one of embodiments 1 to 10 or the pharmaceutical composition according to embodiment 11 for use according to embodiment 15, wherein the disorder is associated with transplantation.

[0469] Example 27:

[0470] The compound according to any one of embodiments 1 to 10 or the pharmaceutical composition according to embodiment 11 for use according to embodiment 26, wherein the disorder is transplant rejection or graft-versus-host disease.

[0471] Example 28:

[0472] The compound according to any one of embodiments 1 to 10 or the pharmaceutical composition according to embodiment 11 for use according to embodiment 15, wherein the disorder is an endocrine disorder.

[0473] Example 29:

[0474] The compound according to any one of embodiments 1 to 10 or the pharmaceutical composition according to embodiment 11 for use according to embodiment 28, wherein the endocrine disorder is polycystic ovary syndrome, Crouzon syndrome or type 1 diabetes.

[0475] Example 30:

[0476] The compound according to any one of embodiments 1 to 10 or the pharmaceutical composition according to embodiment 11 for use according to embodiment 15, wherein the disorder is a neurological disorder.

[0477] Example 31:

[0478] The compound according to any one of embodiments 1 to 10 or the pharmaceutical composition according to embodiment 11 for use according to embodiment 30, wherein the neurological disorder is Alzheimer's disease.

[0479] Example 32:

[0480] The compound according to any one of embodiments 1 to 10 or the pharmaceutical composition according to embodiment 11 for use according to embodiment 14, wherein the disorder is related to type I interferon, IL-10, IL-12 or IL-23 signaling.

[0481] Illustrative

[0482] As depicted in the examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures. It should be understood that although the general methods depict the synthesis of certain compounds of the invention, the following general methods and other methods known to those of ordinary skill in the art can be applied to all compounds described herein and to subclasses and species of each of these compounds. Additional compounds of the invention are prepared by methods substantially similar to the methods described in the examples herein and methods known to those skilled in the art.

[0483] Example 1: General synthetic procedure and synthesis of N-((1R,2S)-2-fluorocyclopropyl)-6-(1-isopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-8-(methylamino)imidazo[1,2-b]pyridazine-3-carboxamide (I-5).

[0484] General synthetic procedure A (Buchwald amination):

[0485]

[0486] Synthesis of Compound 1.2: To a solution of 1 (0.5 g, 1.33 mmol, 1.0 equiv) in 1,4-dioxane (8 mL) was added 1.1 (0.193 g, 1.59 mmol, 1.2 equiv), cesium carbonate (0.866 g, 2.66 mmol, 2.0 equiv). The reaction mixture was degassed under an argon atmosphere for 10 minutes, then tris(dibenzylideneacetone)dipalladium(0) (0.060 g, 0.066 mmol, 0.05 equiv) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.076 g, 0.13 mmol, 0.1 equiv) were added, and it was degassed again for 5 minutes. The reaction mixture was stirred at 115 °C for 4 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, transferred to water, and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material. This crude material was further purified by combi flash using 3% methanol / dichloromethane (DCM or MDC) as the eluent to obtain pure 1.2 (0.140 g, yield: 22.84%). MS(ES): m / z = 460.23 [M+H] + 。

[0487] General Procedure B: (Suzuki Coupling):

[0488]

[0489] Synthesis of Compound 1.4: Argon was bubbled through a stirred solution of 2 (1.5 g, 4.36 mmol, 1.0 equiv), 1.3 (1.9 g, 5.66 mmol, 1.3 equiv) and potassium acetate (1.0 g, 10.9 mmol, 2.5 equiv) in 1,4-dioxane:water (75 mL, 9:1) for 15 minutes, and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.318 g, 0.43 mmol, 0.1 equiv) was added thereto, and it was further bubbled for 10 minutes. The reaction mixture was stirred at 110 °C for 5 hours. After completion of the reaction, the reaction mixture was transferred to water, and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to obtain 1.4 (0.8 g, yield: 34.86%). MS(ES): m / z 527.24 [M+H] + 。

[0490] General Procedure C (Acid-Amine Coupling):

[0491]

[0492] Synthesis of Compound 1.5: To a solution of 3 (0.060 g, 0.13 mmol, 1.0 equiv) in N,N-dimethylformamide (1 mL) was added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridine 3-oxide hexafluorophosphate (0.098 g, 0.26 mmol, 2.0 equiv) and the mixture was stirred at room temperature for 15 minutes. Diisopropylethylamine (0.06 mL, 0.39 mmol, 3.0 equiv) was added thereto, and then (1S,2R)-2-fluorocyclopropan-1-amine (0.010 g, 0.13 mmol, 1.0 equiv) was added. The reaction mixture was stirred at room temperature for 5 minutes. After completion of the reaction, the reaction mixture was transferred to water and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material. This crude material was further purified by column chromatography and the compound was eluted in 40% ethyl acetate / hexane to obtain 1.5 (0.055 g, yield: 81.15%). MS(ES): m / z 498.24 [M+H] + 。

[0493] General Procedure D (deprotection by trifluoromethanesulfonic acid):

[0494]

[0495] Synthesis of Compound 1.6 (Compound I-5): To a cooled solution of 1.5 (0.055 g, 0.11 mmol, 1.0 equiv) in dichloromethane (DCM or MDC) (1 mL) at 0 °C was added trifluoromethanesulfonic acid (0.5 mL). The reaction mixture was stirred at the same temperature for 10 minutes. After completion of the reaction, the reaction mixture was transferred to 1N sodium hydroxide solution and the product was extracted with dichloromethane. The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material. This crude material was further purified by trituration with diethyl ether to obtain 1.6 (Compound I-5) (0.030 g, yield: 66.61%); MS(ES): m / z 408.19 [M+H] + 。

[0496] General Procedure: Synthesis of ethyl 8-(benzyl(methyl)amino)-6-chloroimidazo[1,2-b]pyridazine-3-carboxylate, applicable to related compounds containing benzyl protecting group.

[0497]

[0498] Synthesis of Compound 1.7: Bromine (12.4 g, 77.51 mmol, 1.0 eq) was added to a mixture of 5 (10.0 g, 77.51 mmol, 1.0 eq) and sodium bicarbonate (13.0 g, 155 mmol, 2.0 eq) in ethanol (150 mL) at 0 °C. The reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, the reaction mixture was transferred to water, and the precipitated solid was collected by filtration and dried thoroughly to obtain 1.7 (7.0 g, yield: 43.50%). MS (ES): m / z 208.92 [M+H] + 。

[0499] Synthesis of Compounds 1.9 and 1.10: A mixture of Compound 1.7 (5.0 g, 24.03 mmol, 1.0 eq) and 1.8 (3.9 g, 26.43 mmol, 1.1 eq) was heated at 90 °C for 18 h. After completion of the reaction, the reaction mixture was transferred to water, and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material. This crude material was further purified by column chromatography, and the compounds were eluted in 2% methanol / dichloromethane to obtain 1.9 and 1.10 (1.3 g, yield: 20.84%). MS (ES): m / z 260.99 [M+H] + 。

[0500] Synthesis of Compound 1.3: 1.11 (0.665 g, 5.5 mmol, 1.1 eq) and triethylamine (0.858 g, 8.5 mmol, 1.7 eq) were added to a mixture of 1.9 + 1.10 (1.3 g, 5.0 mmol, 1.0 eq) in 1,4-dioxane (15 mL). The reaction mixture was stirred at 90 °C for 3 h. After completion of the reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain a residue, which was triturated with water to obtain a solid. The solid was filtered, washed with water and dissolved in dichloromethane. The solution was dried over sodium sulfate and concentrated under reduced pressure to obtain 1.3 (1.28 g, yield: 86.96%). MS (ES): m / z 345.11 [M+H] + 。

[0501] General Procedure: Synthesis of Ethyl 6-chloro-8-((4-methoxybenzyl)(methyl)amino)imidazo[1,2-b]pyridazine-3-carboxylate and Related Compounds Containing the PMB (p-methoxybenzyl) Protecting Group.

[0502]

[0503] Synthesis of Compound 1.12: Bromine (12.4 g, 77.51 mmol, 1.0 equiv) was added to a mixture of 6 (10.0 g, 77.51 mmol, 1.0 equiv) and sodium bicarbonate (13.0 g, 155 mmol, 2.0 equiv) in ethanol (150 mL) at 0 °C. The reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, the reaction mixture was transferred to water, and the precipitated solid was collected by filtration and dried thoroughly to obtain 1.12 (7.0 g, yield: 43.50%). MS (ES): m / z 208.92 [M+H] + 。

[0504] Synthesis of Compounds 1.14a and 1.14b: A mixture of Compound 1.12 (5.0 g, 24.03 mmol, 1.0 equiv) and 1.13 (3.9 g, 26.43 mmol, 1.1 equiv) was heated at 90 °C for 18 h. After completion of the reaction, the reaction mixture was transferred to water, and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material. This crude material was further purified by column chromatography, and the compounds were eluted in 2% methanol / dichloromethane to obtain 1.14a and 1.14b (1.3 g, yield: 20.84%). MS (ES): m / z 260.99 [M+H] + 。

[0505] Synthesis of Compound 1: 1.15 (0.573 g, 3.80 mmol, 1.1 equiv) and triethylamine (0.593 g, 5.88 mmol, 1.7 equiv) were added to a mixture of 1.14a + 1.14b (0.9 g, 3.46 mmol, 1.0 equiv) in 1,4-dioxane (10 mL). The reaction mixture was stirred at 90 °C for 3 h. After completion of the reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain a crude residue, which was triturated with water to obtain a solid. The solid was then filtered, washed with water and dissolved in dichloromethane. The solution was dried over sodium sulfate and concentrated under reduced pressure to obtain 1 (0.7 g, yield: 53.97%). MS (ES): m / z 375.12 [M+H] + 。

[0506] Synthesis of N-((1R,2S)-2-fluorocyclopropyl)-6-(1-isopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-8-(methylamino)imidazo[1,2-b]pyridazine-3-carboxamide (I-5).

[0507]

[0508] Synthesis of Compound 1.3: The compound was synthesized using the general procedure for nuclear synthesis to obtain 1.3. (Yield: 86.96%); MS(ES): m / z 345.11 [M+H] + .

[0509] Synthesis of Compound 1.4: Argon purge was passed through a stirred mixture of 2 (1.5 g, 4.36 mmol, 1.0 equiv), 1.3 (1.9 g, 5.66 mmol, 1.3 equiv) and potassium acetate (1.0 g, 10.9 mmol, 2.5 equiv) in 1,4-dioxane (35 mL) for 15 minutes, then [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.318 g, 0.43 mmol, 0.1 equiv) was added thereto and purged further for 10 minutes. The reaction was stirred at 100 °C for 5 hours. After completion of the reaction, the reaction mixture was transferred to water and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to obtain 1.4 (0.8 g, yield: 34.86%). MS(ES): m / z 527.24 [M+H] + .

[0510] Synthesis of Compound 1.16: Compound 1.4 (0.8 g, 1.52 mmol, 1.0 equiv) was dissolved in dichloromethane (15 mL) and trifluoroacetic acid (1 mL) was added to the reaction mixture. The reaction was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was transferred to saturated bicarbonate solution and the product was extracted with dichloromethane. The organic layers were combined and dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material. This crude material was further purified by trituration with diethyl ether to obtain 1.16 (0.6 g, yield: 92.61%). MS(ES): m / z 427.18 [M+H] + .

[0511] Synthesis of Compound 1.17: To a suspension of sodium hydride (0.043 g, 1.82 mmol, 2 equiv) in dimethylformamide (4 mL) at 0 °C was added 1.16 (0.39 g, 0.91 mmol, 1.0 equiv), and the mixture was stirred for 15 minutes, then 2-iodopropane (0.170 g, 1.00 mmol, 1.1 equiv) was added. The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was diluted with water and extracted with diethyl ether. The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure to obtain a solid. This crude material was further purified by distillation to obtain pure 1.17 (0.250 g, yield: 58.35%). MS(ES): m / z 469.23 [M+H] + .

[0512] Synthesis of Compound 3: Lithium hydroxide (0.127 g, 5.3 mmol, 10 eq) was added to a solution of 1.17 (0.250 g, 0.53 mmol, 1.0 eq) in methanol:tetrahydrofuran:water (8 mL, 2:2:1). The reaction was stirred at a certain temperature for 24 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain a residue. Water was added to this residue at 10 °C and then the mixture was acidified with 1 N hydrochloric acid to adjust to pH ca. 6 - 6.5. The product was extracted with dichloromethane. The organic layers were combined, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material. This crude material was further purified by column chromatography and the compound was eluted in 2.1% methanol / dichloromethane to obtain pure 3 (0.210 g, yield: 89.35%). MS (ES): m / z 441.20 [M+H] + 。

[0513] Synthesis of Compound 1.5: 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridine 3-oxide hexafluorophosphate (0.098 g, 0.26 mmol, 2.0 eq) was added to a solution of 3 (0.060 g, 0.13 mmol, 1.0 eq) in N,N-dimethylformamide (2 mL), and the mixture was stirred at room temperature for 15 min. Diisopropylethylamine (0.06 mL, 0.39 mmol, 3.0 eq) was added to this mixture, then 1.18 (0.011 g, 0.15 mmol, 1.2 eq) was added. The reaction mixture was stirred at room temperature for 5 min. After completion of the reaction, the reaction mixture was transferred to water and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material. This crude material was further purified by column chromatography and the compound was eluted in 40% ethyl acetate / hexane to obtain 1.5 (0.055 g, yield: 81.15%). MS (ES): m / z 498.24 [M+H] + 。

[0514] Synthesis of Compound 1.6 (I-5): A solution of 1.5 (0.055 g, 0.11 mmol, 1.0 eq) in dichloromethane (1 mL) was cooled to 0 °C and trifluoromethanesulfonic acid (1 mL) was added. The reaction mixture was stirred at the same temperature for 10 min. After completion of the reaction, the reaction mixture was transferred to 1 N sodium hydroxide solution and the product was extracted with dichloromethane. The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material. This crude material was further purified by trituration with diethyl ether to obtain I-5 (0.030 g, yield: 66.61%). MS (ES): m / z 408.27 [M+H] +; LCMS purity: 97.21%; HPLC purity: 99.34%; 1 1H NMR (DMSO-d6, 400 MHz): 9.09 - 9.08 (d, J = 4.4 Hz, 1H), 8.59 (bs, 1H), 8.51 - 8.49 (d, J = 8 Hz, 1H), 8.40 - 8.39 (d, J = 4.8 Hz, 1H), 8.06 (s, 1H), 7.79 - 7.78 (d, J = 4.8 Hz, 1H), 7.29 - 7.26 (m, 1H), 6.73 (s, 1H), 5.23 - 5.20 (m, 1H), 5.02 (bs, 1H), 4.86 (bs, 1H), 3.06 - 3.05 (d, J = 4.8 Hz, 3H), 1.59 - 1.57 (d, J = 6.4 Hz, 6H), 1.31 - 1.24 (m, 1H), 1.06 - 1.00 (m, 1H).

[0515] Example 2: Synthesis of N-((1R,2S)-2-fluorocyclopropyl)-8-(methylamino)-6-((2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)imidazo[1,2-b]pyridazine-3-carboxamide (I-3).

[0516]

[0517] Synthesis of Compound 3.1: The compound was synthesized according to the experimental protocol for preparing the intermediate in the synthesis of Compound I-4 described below in Example 3 (yield: 65.23%); MS (ES): m / z 468.17 [M+H] + .

[0518] Synthesis of Compound 3.2: To a solution of 3.1 (0.1 g, 0.21 mmol, 1.0 equiv) in N,N-dimethylformamide (2 mL) was added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridine 3-oxide hexafluorophosphate (0.159 g, 0.42 mmol, 2.0 equiv), and the mixture was stirred at room temperature for 15 minutes. Diisopropylethylamine (0.1 mL, 0.63 mmol, 3.0 equiv) was added to this mixture, and then 3.1 (0.018 g, 0.25 mmol, 1.2 equiv) was added. The reaction mixture was stirred at room temperature for 5 minutes. After completion of the reaction, the reaction mixture was transferred to water, and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material. This crude material was further purified by column chromatography, and the compound was eluted in 40% ethyl acetate / hexane to obtain 3.2 (0.086 g, yield: 76.64%). MS(ES): m / z 425.21 [M+H] + .

[0519] Synthesis of Compound I-3: A solution of 3.2 (0.086 g, 0.20 mmol, 1.0 equiv) in dichloromethane (1 mL) was cooled to 0 °C, and trifluoromethanesulfonic acid (1 mL) was added. The reaction mixture was stirred at the same temperature for 10 minutes. After completion of the reaction, the reaction mixture was transferred to 1 M sodium hydroxide solution, and the product was extracted with dichloromethane. The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material. This crude material was further purified by trituration with diethyl ether to obtain I-3 (0.042 g, yield: 58.97%). MS(ES): m / z 435.52 [M+H] + ; LCMS purity: 98.97%; HPLC purity: 97.10%; 1 1H NMR (DMSO-d6, 400 MHz): 8.66 (bs, 3H), 8.06 - 8.03 (t, J = 6.8 Hz, 2H), 7.92 (s, 1H), 7.85 - 7.83 (d, J = 8 Hz, 1H), 7.54 (bs, 3H), 6.40 (bs, 2H), 4.96 (bs, 1H), 4.80 (bs, 1H), 2.99 (bs, 1H), 2.87 - 2.86 (d, J = 4.8 Hz, 1H), 1.24 (bs, 2H), 1.02 - 0.96 (m, 1H).

[0520] Example 3: Synthesis of N-cyclopropyl-8-(methylamino)-6-((2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)imidazo[1,2-b]pyridazine-3-carboxamide (I-4).

[0521]

[0522] Synthesis of Compound 4.3: 4.2 (7.2 g, 45.45 mmol, 2.5 equivalents) was added to a solution of 4.1 (2 g, 18.18 mmol, 1.0 equivalent) in 1,4-dioxane (40 mL). The reaction mixture was degassed for 10 minutes under an argon atmosphere, and then potassium carbonate (7.5 g, 54.54 mmol, 3.0 equivalents), N,N-dimethylethylenediamine (0.640 g, 7.27 mmol, 0.4 equivalent), and copper(I) iodide (0.692 g, 3.636 mmol, 0.2 equivalent) were added. The reaction mixture was heated at 110 °C for 12 hours. After completion of the reaction, the reaction mixture was transferred to ice-cold water, and the product was extracted with ethyl acetate. The organic layers were combined, washed with an aqueous sodium chloride solution, dried over sodium sulfate, and concentrated under reduced pressure to obtain the crude material. This crude material was further purified by 3% methanol / dichloromethane to obtain 4.3 (2 g, yield: 58.82%). MS (ES): m / z 188.20 [M+H] + 。

[0523] Synthesis of Compound 1.3: The compound was synthesized using the general procedure for nuclear synthesis to obtain 1.3 (yield: 86.96%). MS (ES): m / z 345.11 [M+H] + 。

[0524] Synthesis of Compound 4.4: 4.3 (0.779 g, 4.17 mmol, 1.2 equivalents), cesium carbonate (2.2 g, 6.96 mmol, 2.0 equivalents) were added to a solution of 1.3 (1.2 g, 3.48 mmol, 1.0 equivalent) in 1,4-dioxane (20 mL). The reaction mixture was degassed for 10 minutes under an argon atmosphere, and then copper(I) iodide (I) (0.132 g, 4.17 mmol, 0.2 equivalent), tris(dibenzylideneacetone)dipalladium(0) (0.159 g, 0.69 mmol, 0.05 equivalent), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.201 g, 0.34 mmol, 0.1 equivalent) were added, and then further degassed for 5 minutes. The reaction was stirred at 100 °C for 4 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, transferred to water, and the product was extracted with ethyl acetate. The organic layers were combined, washed with an aqueous sodium chloride solution, dried over sodium sulfate, and concentrated under reduced pressure to obtain the crude material. This crude material was further purified by combi flash using 3% methanol / dichloromethane as the eluent to obtain pure 4.4 (0.650 g, 37.69%). MS (ES): m / z 496.21 [M+H] + 。

[0525] Synthesis of Compound 3.1: Lithium hydroxide (0.314 g, 13.1 mmol, 10 eq) was added to a solution of 4.4 (0.260 g, 1.31 mmol, 1.0 eq) in methanol:tetrahydrofuran:water (12 mL, 2:2:1). The reaction was stirred at room temperature for 24 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain a residue. Water was added to this residue at 10 °C and acidified with 1 N hydrochloric acid to adjust the pH to about 6 - 6.5. The product was extracted with dichloromethane. The organic layers were combined, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material. This crude material was further purified by column chromatography and the compound was eluted in 2.1% methanol / dichloromethane to obtain pure 3.1 (0.4 g, yield: 65.23%). MS(ES): m / z 468.17 [M+H] + 。

[0526] Synthesis of Compound 4.6: 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridine 3-oxide hexafluorophosphate (0.159 g, 0.42 mmol, 2.0 eq) was added to a solution of 3.1 (0.1 g, 0.21 mmol, 1.0 eq) in N,N-dimethylformamide (2 mL), and the mixture was stirred at room temperature for 15 min. Diisopropylethylamine (0.1 mL, 0.63 mmol, 3.0 eq) was added to this mixture, followed by 4.5 (0.015 g, 0.25 mmol, 1.2 eq). The reaction mixture was stirred at room temperature for 5 min. After completion of the reaction, the reaction mixture was transferred to water and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material. This crude material was further purified by column chromatography and the compound was eluted in 40% ethyl acetate / hexane to obtain 4.6 (0.080 g, yield: 73.83%). MS(ES): m / z 507.22 [M+H] + 。

[0527] Synthesis of Compound I-4: A solution of 4.6 (0.080 g, 0.15 mmol, 1.0 eq) in dichloromethane (1 mL) was cooled to 0 °C and trifluoromethanesulfonic acid (1 mL) was added. The reaction mixture was stirred at the same temperature for 10 min. After completion of the reaction, the reaction mixture was transferred to 1 N sodium hydroxide solution and the product was extracted with dichloromethane. The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material. This crude material was further purified by trituration with diethyl ether to obtain I-4 (0.030 g, yield: 45.62%). MS(ES): m / z 417.60 [M+H] +; LCMS purity: 98.89%; HPLC purity: 99.38%; 1 1H NMR (DMSO-d6, 400 MHz): δ 8.67 - 8.66 (d, J = 4 Hz, 2H), 8.61 (bs, 1H), 8.05 - 8.00 (d, J = 12.4 Hz, 2H), 7.86 (bs, 1H), 7.84 (bs, 1H), 7.56 - 7.49 (m, 3H), 6.46 - 6.45 (t, J = 7.2 Hz, 1H), 6.38 (bs, 1H), 3.17 (bs, 1H), 2.86 - 2.85 (d, J = 4.4 Hz, 3H), 0.81 - 0.80 (d, J = 5.6 Hz, 2H), 0.57 (bs, 2H).

[0528] Example 4: Synthesis of N-((1R,2S)-2-fluorocyclopropyl)-8-(methylamino)-6-(1-(2-morpholinoethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)imidazo[1,2-b]pyridazine-3-carboxamide (I-6).

[0529]

[0530] Synthesis of Compound 1.3: The compound was synthesized according to the experimental protocol described above for Compound I-5 in Example 1 to obtain 1.3 (yield: 92.61%); MS (ES): m / z 427.18 [M+H] + .

[0531] Synthesis of Compound 5.2: 1.3 (0.250 g, 0.58 mmol, 1.0 equivalent) was added to a suspension of sodium hydride (0.027 g, 1.16 mmol, 2.0 equivalents) in dimethylformamide (3 mL) at 0 °C, and the mixture was stirred for 15 minutes, then 5.1 (0.095 g, 0.63 mmol, 1.1 equivalents) was added. The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was diluted with water and extracted with diethyl ether. The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure to obtain a solid. This crude material was further purified by distillation to obtain pure 5.2 (0.260 g, yield: 82.19%). MS (ES): m / z 540.27 [M+H] + .

[0532] Synthesis of Compound 5.3: Lithium hydroxide (0.115 g, 4.8 mmol, 10 eq) was added to a solution of 5.2 (0.260 g, 0.48 mmol, 1.0 eq) in methanol:tetrahydrofuran:water (6 mL, 2:2:1). The reaction was stirred at room temperature for 24 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain a residue. Water was added to this residue at 10 °C and the mixture was acidified with 1 N hydrochloric acid to adjust to pH ca. 6 - 6.5. The product was extracted with dichloromethane. The organic layers were combined, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material. This crude material was further purified by column chromatography and the compound was eluted in 2.1% methanol / dichloromethane to obtain pure 5.3 (0.190 g, yield: 77.08%). MS (ES): m / z 512.24 [M+H] + .

[0533] Synthesis of Compound 5.5: 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridine 3-oxide hexafluorophosphate (0.073 g, 0.19 mmol, 2.0 eq) was added to a solution of 5.3 (0.050 g, 0.097 mmol, 1.0 eq) in N,N-dimethylformamide (1 mL) and the mixture was stirred at room temperature for 15 min. Diisopropylethylamine (0.05 mL, 0.291 mmol, 3.0 eq) was added to this mixture, then 5.4 (0.010 g, 0.11 mmol, 1.2 eq) was added. The reaction mixture was stirred at room temperature for 5 min. After completion of the reaction, the reaction mixture was transferred to water and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material. This crude material was further purified by column chromatography and the compound was eluted in 40% ethyl acetate / hexane to obtain 5.5 (0.050 g, yield: 89.96%). MS (ES): m / z 569.27 [M+H] + .

[0534] Synthesis of Compound I-6: A solution of 5.5 (0.050 g, 0.087 mmol, 1.0 eq) in dichloromethane (1 mL) was cooled to 0 °C and trifluoromethanesulfonic acid (1 mL) was added. The reaction mixture was stirred at the same temperature for 10 min. After completion of the reaction, the reaction mixture was transferred to 1 N sodium hydroxide solution and the product was extracted with dichloromethane. The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material. This crude material was further purified by trituration with diethyl ether to obtain I-6 (0.028 g, yield: 66.55%). MS (ES): m / z 479.56 [M+H] +; LCMS purity: 97.73%; HPLC purity: 95.42%; chiral HPLC: 99.15%; 1 1H NMR (DMSO-d6, 400 MHz): 9.07 (bs, 1H), 8.51 - 8.49 (d, J = 10 Hz, 2H), 8.40 (bs, 1H), 8.07 (s, 1H), 7.82 (bs, 1H), 7.27 (bs, 1H), 6.63 (bs, 1H), 5.02 (bs, 1H), 4.86 (bs, 1H), 4.49 (bs, 3H), 3.55 (bs, 4H), 3.04 - 3.03 (d, J = 4 Hz, 4H), 2.68 (bs, 2H), 1.31 - 1.26 (bs, 2H), 1.10 - 1.06 (bs, 2H).

[0535] Example 5: Synthesis of N-(2-hydroxycyclobutyl)-6-(1-isopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-8-(methylamino)imidazo[1,2-b]pyridazine-3-carboxamide (I-15), N-((1S,2R)-2-hydroxycyclobutyl)-6-(1-isopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-8-(methylamino)imidazo[1,2-b]pyridazine-3-carboxamide (I-10), and N-((1R,2S)-2-hydroxycyclobutyl)-6-(1-isopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-8-(methylamino)imidazo[1,2-b]pyridazine-3-carboxamide (I-7).

[0536]

[0537] Synthesis of Compound 3: Compound 3 was synthesized according to the experimental protocol described above for Compound 3 in Example 1 to obtain 3 (yield: 89.35%); MS (ES): m / z 441.20 [M + H] + .

[0538] Synthesis of Compound 6.2: To a solution of 3 (0.1 g, 0.22 mmol, 1.0 equiv) in N,N-dimethylformamide (1 mL) was added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridine 3-oxide hexafluorophosphate (0.167 g, 0.44 mmol, 2.0 equiv), and the mixture was stirred at room temperature for 15 minutes. Diisopropylethylamine (0.1 mL, 0.66 mmol, 3.0 equiv) was added to this mixture, followed by 6.1 (0.022 g, 0.26 mmol, 1.2 equiv). The reaction mixture was stirred at room temperature for 5 minutes. After completion of the reaction, the reaction mixture was transferred to water, and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material. This crude material was further purified by column chromatography, and the compound was eluted in 40% ethyl acetate / hexane to obtain 6.2 (0.115 g, yield: 99.41%). MS (ES): m / z 510.26 [M+H] + 。

[0539] Synthesis of Compound I-15: A solution of 6.2 (0.115 g, 0.22 mmol, 1.0 equiv) in dichloromethane (1 mL) was cooled to 0 °C, and trifluoromethanesulfonic acid (1 mL) was added. The reaction mixture was stirred at the same temperature for 10 minutes. After completion of the reaction, the reaction mixture was transferred to 1N sodium hydroxide solution, and the product was extracted with dichloromethane. The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material. This crude material was further purified by trituration with diethyl ether to obtain I-15 (0.080 g, yield: 84.51%). MS (ES): m / z 420.27 [M+H] + ; LCMS purity: 97.92%; HPLC purity: 95.0%; chiral HPLC purity: 35%, 62%; 11H NMR (DMSO-d6, 400 MHz): 9.35 - 9.33 (d, J = 8.4 Hz, 1H), 8.75 - 8.74 (d, J = 7.6 Hz, 1H), 8.68 (s, 1H), 8.40 - 8.39 (d, J = 3.2 Hz, 1H), 8.02 (s, 1H), 7.78 - 7.77 (d, J = 4.8 Hz, 1H), 7.31 - 7.28 (m, 1H), 6.72 (s, 1H), 5.51 - 5.50 (d, J = 4 Hz, 1H), 5.26 - 5.21 (m, 1H), 4.63 - 4.60 (t, J = 6.4 Hz, 1H), 4.42 (bs, 1H), 3.08 - 3.06 (d, J = 4.8 Hz, 3H), 1.79 (bs, 1H), 1.59 - 1.57 (d, J = 6.4 Hz, 6H), 1.24 (bs, 1H), 1.06 - 1.04 (d, J = 6 Hz, 2H).

[0540] Synthesis of Compound I-10 and I-7: The isomers of I-15 (0.080 g) were separated using a chiral column (CHIRAL PAK OX-H 250 mm x 4.6 mm, 5 μm) and 0.1% DEA / HEX_IPA-MEOH (50-50) as co-solvent at a flow rate of 4 mL / min to obtain pure fraction-1 (FR-a) and fraction-2 (FR-b). FR-a was concentrated under reduced pressure at 30 °C to obtain pure I-10 (0.024 g). MS (ES): m / z 420.62 [M+H] + ; LCMS purity: 100%; HPLC purity: 97.0%; Chiral HPLC purity: 99.78%; 1 1H NMR (DMSO-d6, 400 MHz): 9.35 - 9.33 (d, J = 8.4 Hz, 1H), 8.75 - 8.74 (d, J = 7.6 Hz, 1H), 8.68 (s, 1H), 8.40 - 8.39 (d, J = 3.2 Hz, 1H), 8.02 (s, 1H), 7.78 - 7.77 (d, J = 4.8 Hz, 1H), 7.31 - 7.28 (m, 1H), 6.72 (s, 1H), 5.51 - 5.50 (d, J = 4 Hz, 1H), 5.26 - 5.21 (m, 1H), 4.63 - 4.60 (t, J = 6.4 Hz, 1H), 4.42 (bs, 1H), 3.08 - 3.06 (d, J = 4.8 Hz, 3H), 1.79 (bs, 1H), 1.59 - 1.57 (d, J = 6.4 Hz, 6H), 1.24 (bs, 1H), 1.06 - 1.04 (d, J = 6 Hz, 2H).

[0541] FR-b was concentrated under reduced pressure at 30 °C to obtain pure I-7 (0.043 g). MS (ES): m / z 420.57 [M+H] + ; LCMS purity: 100%; HPLC purity: 96.86%; chiral HPLC purity: 99.83%; 1 1H NMR (DMSO-d6, 400 MHz): 9.35 - 9.33 (d, J = 8.4 Hz, 1H), 8.75 - 8.74 (d, J = 7.6 Hz, 1H), 8.68 (s, 1H), 8.40 - 8.39 (d, J = 3.2 Hz, 1H), 8.02 (s, 1H), 7.78 - 7.77 (d, J = 4.8 Hz, 1H), 7.31 - 7.28 (m, 1H), 6.72 (s, 1H), 5.51 - 5.50 (d, J = 4 Hz, 1H), 5.26 - 5.21 (m, 1H), 4.63 - 4.60 (t, J = 6.4 Hz, 1H), 4.42 (bs, 1H), 3.08 - 3.06 (d, J = 4.8 Hz, 3H), 1.79 (bs, 1H), 1.59 - 1.57 (d, J = 6.4 Hz, 6H), 1.24 (bs, 1H), 1.06 - 1.04 (d, J = 6 Hz, 2H).

[0542] Example 6: Synthesis of rac-N-((1S,2R)-2-hydroxycyclobutyl)-8-(methylamino)-6-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)imidazo[1,2-b]pyridazine-3-carboxamide (I-31), N-((1S,2R)-2-hydroxycyclobutyl)-8-(methylamino)-6-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)imidazo[1,2-b]pyridazine-3-carboxamide (I-11), and N-((1R,2S)-2-hydroxycyclobutyl)-8-(methylamino)-6-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)imidazo[1,2-b]pyridazine-3-carboxamide (I-8).

[0543]

[0544] Synthesis of Compound 1.16: The compound was synthesized according to the experimental protocol described above in Example 1 to obtain 1.16 (yield: 92.61%). MS (ES): m / z 427.18 [M+H] + .

[0545] Synthesis of Compound 7.2: To a solution of 7.1 (1.1 g, 7.0 mmol, 10.0 equiv) in dimethylformamide (3 mL) was added 1.16 (0.3 g, 0.70 mmol, 1.0 equiv), cesium carbonate (0.682 g, 2.1 mmol, 3.0 equiv) and tetra-n-butylammonium bromide (0.112 g, 0.35 mmol, 0.5 equiv). The reaction mixture was stirred at 80 °C for 16 h. After completion of the reaction, the reaction mixture was transferred to water and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material. This crude material was further purified by column chromatography and the compound was eluted in 1% methanol / dichloromethane to give 7.2 (0.220 g, yield: 61.25%). MS (ES): m / z 511.24 [M+H] + .

[0546] Synthesis of Compound 7.3: To a solution of 7.2 (0.510 g, 0.43 mmol, 1.0 equiv) in tetrahydrofuran:methanol:water (10 mL, 2:1:1) was added lithium hydroxide (0.103 g, 4.3 mmol, 10.0 equiv). The reaction mixture was stirred at 50 °C for 16 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the residue. Water was added to this residue and the mixture was acidified with 1 N hydrochloric acid at 10 °C to adjust to pH about 6 - 6.5. The product was extracted with dichloromethane. The organic layers were combined, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material. This crude material was further purified by column chromatography and the compound was eluted in 2.1% methanol / dichloromethane to give pure 7.3 (0.170 g, yield: 81.77%). MS (ES): m / z 483.21 [M+H] + .

[0547] Synthesis of Compound 7.5: The compound was synthesized using General Procedure C to obtain 7.5 (0.150 g, yield: 77.18%). MS (ES): m / z 552.27 [M+H] + .

[0548] Synthesis of Compound 7.6 (I-31): The compound was synthesized using General Procedure D to obtain 7.6 (0.025 g, yield: 59.76%). MS (ES): m / z 462.32 [M+H]; LCMS purity: 100%; HPLC purity: 98.52%; chiral HPLC: 50.05%, 49.94%; + ; LCMS purity: 100%; HPLC purity: 98.52%; chiral HPLC: 50.05%, 49.94%; 11H NMR (DMSO-d6, 400 MHz): 9.26 - 9.24 (d, J = 8.4 Hz, 1H), 8.78 - 8.77 (d, J = 6.8 Hz, 1H), 8.73 (s, 1H), 8.39 - 8.38 (d, J = 3.6 Hz, 1H), 8.01 (s, 1H), 7.76 - 7.75 (d, J = 4.8 Hz, 1H), 7.31 - 7.28 (m, 1H), 6.74 (s, 1H), 5.11 - 5.05 (m, 1H), 4.64 - 4.60 (d, J = 7.2 Hz, 2H), 3.63 - 3.57 (t, J = 12 Hz, 2H), 3.05 - 3.04 (d, J = 3.6 Hz, 3H), 2.25 - 2.21 (m, 3H), 2.11 - 2.05 (m, 2H), 1.79 (bs, 1H), 1.54 (bs, 2H), 0.88 - 0.80 (m, 3H).

[0549] Synthesis of Compounds 7.5a and 7.5b: The isomers of 7.5 (0.1 g) were separated using a chiral column CHIRALPAK AD-H (250 mm * 4.6 mm, 5 μm) and 0.1% DEA MeOH:ACN (50:50) as a co-solvent at a flow rate of 4 mL / min to obtain pure fraction -1 (FR-a) and fraction -2 (FR-b). FR-a was concentrated under reduced pressure at 30 °C to obtain pure 7.5a (0.045 g). MS (ES): m / z 552.27 [M+H] + . FR-b was concentrated under reduced pressure at 30 °C to obtain pure 7.5b (0.044 g). MS (ES): m / z 552.27 [M+H] + .

[0550] Synthesis of Compound I-11: Compound I-11 (0.032 g, yield: 85%) was obtained using General Procedure D to synthesize the compound. MS (ES): m / z 462.41 [M+H] + ; LCMS purity: 100%; HPLC purity: 99.21%; chiral HPLC: 100%; 11H NMR (DMSO-d6, 400 MHz): 9.26 - 9.24 (d, J = 8.4 Hz, 1H), 8.78 - 8.76 (d, J = 6.8 Hz, 1H), 8.72 (s, 1H), 8.38 - 8.37 (d, J = 3.6 Hz, 1H), 8.00 (s, 1H), 7.76 - 7.75 (d, J = 4.8 Hz, 1H), 7.31 - 7.28 (m, 1H), 6.73 (s, 1H), 5.45 - 5.44 (d, J = 4 Hz, 1H), 5.11 - 5.05 (m, 1H), 4.63 - 4.60 (d, J = 6.4 Hz, 1H), 4.39 (bs, 1H), 3.63 - 3.57 (t, J = 11.6 Hz, 2H), 3.05 - 3.04 (d, J = 3.6 Hz, 3H), 2.23 - 2.21 (m, 3H), 2.11 - 2.05 (m, 3H), 1.78 (bs, 1H), 1.22 (bs, 1H), 0.88 - 0.85 (m, 2H).

[0551] Synthesis of Compound I-8: Using General Procedure D to synthesize the compound to obtain I-8 (0.032 g, yield: 86%). MS (ES): m / z 462.41 [M + H] + ; LCMS purity: 100%; HPLC purity: 100%; chiral HPLC: 100%; 1 1H NMR (DMSO-d6, 400 MHz): 9.26 - 9.24 (d, J = 8.4 Hz, 1H), 8.78 - 8.76 (d, J = 6.8 Hz, 1H), 8.72 (s, 1H), 8.38 - 8.37 (d, J = 3.6 Hz, 1H), 8.00 (s, 1H), 7.76 - 7.74 (d, J = 4.8 Hz, 1H), 7.31 - 7.28 (m, 1H), 6.73 (s, 1H), 5.45 - 5.44 (d, J = 4 Hz, 1H), 5.11 - 5.05 (m, 1H), 4.63 - 4.60 (d, J = 6.4 Hz, 1H), 4.39 (bs, 1H), 3.63 - 3.57 (t, J = 11.6 Hz, 2H), 3.05 - 3.04 (d, J = 3.6 Hz, 3H), 2.23 - 2.21 (m, 3H), 2.11 - 2.03 (m, 3H), 1.78 (bs, 1H), 1.22 (bs, 1H), 0.88 - 0.85 (m, 2H).

[0552] Example 7: Synthesis of N-((1S,2R)-2-hydroxycyclobutyl)-8-(methylamino)-6-(1-(2-morpholinoethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)imidazo[1,2-b]pyridazine-3-carboxamide (I-16), N-((1S,2R)-2-hydroxycyclobutyl)-8-(methylamino)-6-(1-(2-morpholinoethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)imidazo[1,2-b]pyridazine-3-carboxamide (I-12), and N-((1R,2S)-2-hydroxycyclobutyl)-8-(methylamino)-6-(1-(2-morpholinoethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)imidazo[1,2-b]pyridazine-3-carboxamide (I-9).

[0553]

[0554] Synthesis of Compound 5.3: The compound was synthesized according to the experimental protocol in Example 4 to obtain 5.3 (yield: 77.08%); MS (ES): m / z 512.24 [M+H] + 。

[0555] Synthesis of Compound 8.2: 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridine 3-oxide hexafluorophosphate (0.144 g, 0.38 mmol, 2.0 equivalents) was added to a solution of 5.3 (0.1 g, 0.19 mmol, 1.0 equivalent) in N,N-dimethylformamide (1 mL), and the mixture was stirred at room temperature for 15 minutes. Diisopropylethylamine (0.1 mL, 0.57 mmol, 3.0 equivalents) was added to this mixture, followed by 8.1 (0.019 g, 0.22 mmol, 1.2 equivalents). The reaction mixture was stirred at room temperature for 5 minutes. After completion of the reaction, the reaction mixture was transferred to water, and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine solution, dried over sodium sulfate, and concentrated under reduced pressure to obtain the crude material. This crude material was further purified by column chromatography, and the compound was eluted with 40% ethyl acetate / hexane to obtain 8.2. (0.110 g, yield: 96.91%). MS (ES): m / z 581.29 [M+H] + 。

[0556] Synthesis of Compound I-16: 4M hydrochloric acid / 1,4-dioxane (3 mL) was added to Compound 8.2 (0.110 g, 0.18 mmol, 1.0 equivalent), and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was stirred with saturated sodium bicarbonate solution and extracted with dichloromethane. The organic layers were combined, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to obtain a residue, which was triturated with diethyl ether to obtain I-16 (0.075 g, yield: 80.71%). MS (ES): m / z 491.36 [M+H] + ; LCMS purity: 97.26%; HPLC purity: 96.14%; Chiral HPLC purity: 34%, 63%. 1 1H NMR (DMSO-d6, 400 MHz): 9.33 - 9.31 (d, J = 8 Hz, 1H), 8.76 - 8.74 (d, J = 6 Hz, 1H), 8.57 (s, 1H), 8.40 - 8.38 (d, J = 4.4 Hz, 1H), 8.02 (s, 1H), 7.80 - 7.79 (d, J = 4.8 Hz, 1H), 7.31 - 7.28 (m, 1H), 6.65 (s, 1H), 5.54 - 5.53 (d, J = 3.6 Hz, 1H), 4.61 (bs, 1H), 4.51 - 4.48 (t, J = 6.4 Hz, 2H), 4.42 (bs, 1H), 3.52 (s, 4H), 3.06 - 3.05 (d, J = 4.8 Hz, 3H), 2.84 - 2.81 (t, J = 6.4 Hz, 2H), 2.14 - 2.06 (m, 2H), 1.78 (bs, 1H), 1.57 (bs, 1H), 1.24 (bs, 2H), 0.90 (bs, 2H).

[0557] Synthesis of Compounds I-12 and I-9: The isomers of I-16 (0.080 g) were separated using a chiral column (CHIRAL PAK OX-H 250 mm x 4.6 mm, 5 μm) and 0.1% DEA / hexane / i-PrOH-MeOH (50 - 50) as co-solvent at a flow rate of 4 mL / min to obtain pure fraction-1 (FR-a) and fraction-2 (FR-b). FR-a was concentrated under reduced pressure at 30 °C to obtain pure I-12 (0.010 g). MS (ES): m / z 491.52 [M+H] + ; LCMS purity: 95.31%; HPLC purity: 95.00%; Chiral HPLC purity: 95.28%; 11H NMR (DMSO-d6, 400 MHz): 9.33 - 9.31 (d, J = 8 Hz, 1H), 8.76 - 8.74 (d, J = 6 Hz, 1H), 8.57 (s, 1H), 8.40 - 8.38 (d, J = 4.4 Hz, 1H), 8.02 (s, 1H), 7.80 - 7.79 (d, J = 4.8 Hz, 1H), 7.31 - 7.28 (m, 1H), 6.65 (s, 1H), 5.54 - 5.53 (d, J = 3.6 Hz, 1H), 4.61 (bs, 1H), 4.51 - 4.48 (t, J = 6.4 Hz, 2H), 4.42 (bs, 1H), 3.52 (s, 4H), 3.06 - 3.05 (d, J = 4.8 Hz, 3H), 2.84 - 2.81 (t, J = 6.4 Hz, 2H), 2.14 - 2.06 (m, 2H), 1.78 (bs, 1H), 1.57 (bs, 1H), 1.24 (bs, 2H), 0.90 (bs, 2H).

[0558] FR-b was concentrated under reduced pressure at 30 °C to obtain pure I-9 (0.030 g). MS (ES): m / z 491.67 [M+H] + ; LCMS purity: 100%; HPLC purity: 98.71%; chiral HPLC purity: 100%; 1 1H NMR (DMSO-d6, 400 MHz): 9.33 - 9.31 (d, J = 8 Hz, 1H), 8.76 - 8.74 (d, J = 6 Hz, 1H), 8.61 (s, 1H), 8.45 (bs, 2H), 8.39 - 8.38 (d, J = 4 Hz, 1H), 8.02 (s, 1H), 7.80 - 7.79 (d, J = 4.4 Hz, 1H), 7.31 - 7.28 (m, 1H), 6.65 (s, 1H), 4.61 (bs, 1H), 4.50 - 4.48 (t, J = 6.4 Hz, 2H), 4.43 (bs, 1H), 3.55 (s, 4H), 3.06 - 3.05 (d, J = 4.8 Hz, 3H), 2.84 - 2.81 (t, J = 6.4 Hz, 2H), 2.13 - 2.06 (m, 2H), 1.81 (bs, 2H), 1.57 (bs, 1H), 1.24 (bs, 2H).

[0559] Example 8: Synthesis of rac-N-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)-6-(1-isopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-8-(methylamino)imidazo[1,2-b]pyridazine-3-carboxamide (I-32), N-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)-6-(1-isopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-8-(methylamino)imidazo[1,2-b]pyridazine-3-carboxamide (I-14) and N-((3R,4R)-4-hydroxytetrahydrofuran-3-yl)-6-(1-isopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-8-(methylamino)imidazo[1,2-b]pyridazine-3-carboxamide (I-13).

[0560]

[0561] Synthesis of Compound 1.16: The compound was synthesized according to the experimental protocol described in Example 1 above to obtain 1.16 (yield: 92.61%). MS (ES): m / z 427.18 [M+H] + 。

[0562] Synthesis of Compound 1.17: Isopropyl iodide (0.2 mL, 2.05 mmol, 2.5 equivalents) and cesium carbonate (1.3 g, 4.1 mmol, 5.0 equivalents) were added to a solution of 1.16 (0.4 g, 0.82 mmol, 1.0 equivalent) in dimethylformamide (6 mL). The reaction mixture was stirred at 110 °C for 3 hours. After completion of the reaction, the reaction mixture was transferred to water and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material. This crude material was further purified by column chromatography and the compound was eluted in 20% ethyl acetate / hexane to obtain 1.17 (0.3 g, yield: 78.02%). MS (ES): m / z 426.23 [M+H] + 。

[0563] Synthesis of Compound 3: Lithium hydroxide (0.153 g, 6.4 mmol, 10.0 equiv) was added to a solution of 1.17 (0.3 g, 0.64 mmol, 1.0 equiv) in tetrahydrofuran:methanol:water (8 mL, 2:1:1). The reaction was stirred at 50 °C for 16 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain a residue. Water was added to this residue at 10 °C and the mixture was acidified with 1 N hydrochloric acid to adjust to pH about 6 - 6.5. The product was extracted with dichloromethane. The organic layers were combined, washed with an aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material. This crude material was further purified by column chromatography and the compound was eluted in 2.1% methanol / dichloromethane to obtain pure 3 (0.262 g, yield: 92.90%). MS (ES): m / z 441.20 [M+H] + 。

[0564] Synthesis of Compound 9.2: The compound was synthesized using General Procedure C to obtain 9.2 (0.250 g, yield: 79.97%). MS (ES): m / z 526.25 [M+H] + 。

[0565] Synthesis of Compound 9.3 (I-32): The compound was synthesized using General Procedure D to obtain 9.3 (I-32) (0.030 g, yield: 72.42%). MS (ES): m / z 436.41 [M+H] + ; LCMS purity: 100%; HPLC purity: 99.46%; chiral HPLC: 49.39%, 49.28%; 1 1H NMR (DMSO-d6, 400 MHz): 9.20 - 9.18 (d, J = 7.6 Hz, 1H), 8.67 - 8.65 (d, J = 7.6 Hz, 1H), 8.63 (s, 1H), 8.39 - 8.38 (d, J = 3.6 Hz, 1H), 8.05 (s, 1H), 7.80 - 7.79 (d, J = 4.8 Hz, 1H), 7.28 - 7.25 (m, 1H), 6.71 (s, 1H), 5.64 - 5.63 (d, J = 4 Hz, 1H), 5.23 - 5.20 (m, 1H), 4.33 (s, 1H), 4.05 - 3.98 (m, 3H), 3.61 - 3.57 (t, J = 8 Hz, 1H), 3.07 - 3.06 (d, J = 4 Hz, 3H), 1.58 - 1.57 (d, J = 4.8 Hz, 6H), 1.25 (bs, 1H).

[0566] Synthesis of Compounds 9.2a and 9.2b: The isomers of 9.2 (0.2 g) were separated using a column CHIRALPAK AD-H (250 mm * 4.6 mm, 5 μm) and 0.1% DEA MeOH:MeCN (50:50) as the co-solvent at a flow rate of 4 mL / min to obtain pure fraction -1 (FR-a) and fraction -2 (FR-b). FR-a was concentrated under reduced pressure at 30 °C to obtain pure 9.2a (0.070 g). MS(ES): m / z 526.25 [M+H] + FR-b was concentrated under reduced pressure at 30 °C to obtain pure 9.2b (0.072 g). MS(ES): m / z 526.25 [M+H] + .

[0567] Synthesis of Compound I-14: The compound was synthesized using General Procedure D to obtain I-14 (0.030 g, yield: 51.73%). MS(ES): m / z 436.30 [M+H] + ; LCMS purity: 100%; HPLC purity: 100%; chiral HPLC: 100%; 1 1H NMR (DMSO-d6, 400 MHz): 9.18 - 9.16 (d, J = 7.6 Hz, 1H), 8.65 - 8.63 (d, J = 7.6 Hz, 1H), 8.61 (s, 1H), 8.37 - 8.36 (d, J = 3.6 Hz, 1H), 8.03 (s, 1H), 7.78 - 7.76 (d, J = 4.8 Hz, 1H), 7.26 - 7.23 (m, 1H), 6.69 (s, 1H), 5.62 - 5.61 (d, J = 4.4 Hz, 1H), 5.23 - 5.16 (m, 1H), 4.32 (bs, 1H), 4.05 - 3.98 (m, 3H), 3.59 - 3.55 (t, J = 8.4 Hz, 1H), 3.05 - 3.04 (d, J = 4 Hz, 3H), 1.55 - 1.57 (d, J = 4.8 Hz, 6H), 1.22 (bs, 1H).

[0568] Synthesis of Compound I-13: The compound was synthesized using General Procedure D to obtain I-13 (0.031 g, yield: 51.97%). MS(ES): m / z 436.33 [M+H] + ; LCMS purity: 100%; HPLC purity: 99.76%; chiral HPLC: 98.59%; 11H NMR (DMSO-d6, 400 MHz): 9.18 - 9.16 (d, J = 7.6 Hz, 1H), 8.65 - 8.63 (d, J = 7.6 Hz, 1H), 8.61 (s, 1H), 8.37 - 8.36 (d, J = 3.6 Hz, 1H), 8.03 (s, 1H), 7.78 - 7.77 (d, J = 4.8 Hz, 1H), 7.26 - 7.23 (m, 1H), 6.69 (s, 1H), 5.62 - 5.61 (d, J = 4.4 Hz, 1H), 5.23 - 5.16 (m, 1H), 4.32 (bs, 1H), 4.05 - 3.98 (m, 3H), 3.59 - 3.55 (t, J = 8.4 Hz, 1H), 3.05 - 3.04 (d, J = 4 Hz, 3H), 1.55 - 1.57 (d, J = 4.8 Hz, 6H), 1.22 (bs, 1H).

[0569] Example 9: Synthesis of 6 - ((3'-fluoro - 2 - oxo - 2H - [1,2'-bipyridin] - 3 - yl)amino) - N - (2 - methoxycyclobutyl) - 8 - (methylamino)imidazo[1,2 - b]pyridazine - 3 - carboxamide (I - 17).

[0570]

[0571] Synthesis of Compound 10.2: To a solution of 10 (2.5 g, 22.70 mmol, 1.0 equiv) in 1 - methylpyrrolidin - 2 - one (50 mL) was added 10.1 (3.4 g, 29.51 mmol, 1.3 equiv), and then tripotassium phosphate (12.04 g, 56.80 mmol, 2.5 equiv) was added. The reaction mixture was heated at 90 - 100 °C for 22 h. After completion of the reaction, the reaction mixture was cooled to room temperature, transferred to cold water, and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine solution and then with water, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material. This crude material was further purified by column chromatography using 2.0% methanol / dichloromethane as the eluent to obtain 10.2 (2.3 g, 49.37%). MS (ES): m / z 206.02 [M + H] + 。

[0572] Synthesis of Compound 10.3: The compound was synthesized according to the nuclear synthesis experimental protocol described above to obtain 10.3. (Yield: 20.84%); MS (ES): m / z 260.99 [M + H] + 。

[0573] Synthesis of Compound 10.4: Potassium carbonate (8.4 g, 61.52 mmol, 2.0 equiv) was added to a solution of 10.3 (8.0 g, 30.76 mmol, 1.0 equiv) in tetrahydrofuran (100 mL), and then methylamine (2.0 g, 30.76 mmol, 2.0 equiv) was added. The reaction mixture was heated at room temperature for 5 h. After completion of the reaction, the reaction mixture was cooled to room temperature, transferred to cold water, and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine solution and then with water, dried over sodium sulfate and concentrated under reduced pressure to obtain 10.4 (5.0 g, yield: 63.83%). MS(ES): m / z 255.06 [M+H] + .

[0574] Synthesis of Compound 10.5: Di-tert-butyl dicarbonate (0.769 g, 3.52 mmol, 1.8 equiv) and 4-dimethylaminopyridine (0.025 g, 0.19 mmol, 0.1 equiv) were added to a solution of 10.4 (0.5 g, 1.96 mmol, 1.0 equiv) in 1,4-dioxane (8 mL), and the mixture was stirred at room temperature for 8 h. After completion of the reaction, the reaction mixture was cooled to room temperature, transferred to water, and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material. This crude material was further purified by column chromatography, and the compound was eluted in 20% ethyl acetate / hexane to obtain pure 10.5 (0.480 g, yield: 68.91%). MS(ES): m / z 355.11 [M+H] + .

[0575] Synthesis of Compound 10.6: Tributyltin oxide (1.6 g, 2.7 mmol, 2.0 equiv) was added to a suspension of 10.5 (0.480 g, 1.35 mmol, 1.0 equiv) in toluene (5 mL), and the reaction mixture was heated at 120 °C for 12 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain a residue, which was dissolved in saturated sodium bicarbonate solution and washed with hexane. The aqueous layer was separated and acidified to pH about 5 - 6 with 1 N hydrochloric acid and extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure to obtain a residue, which was triturated with hexane to obtain pure 10.6 (0.350 g, yield: 79.18%); MS(ES): m / z 327.08 [M+H] + .

[0576] Synthesis of Compound 10.8: 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridine 3-oxide hexafluorophosphate (4.65 g, 12.26 mmol, 2.0 equiv) was added to a solution of 10.6 (2.0 g, 6.13 mmol, 1.0 equiv) in N,N-dimethylformamide, and the mixture was stirred at room temperature for 15 minutes. Diisopropylethylamine (3.2 mL, 18.39 mmol, 3.0 equiv) was added thereto, and then 10.7 (0.619 g, 6.13 mmol, 1.0 equiv) was added. The reaction mixture was stirred at room temperature for 5 minutes. After completion of the reaction, the reaction mixture was transferred to water, and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material. This crude material was further purified by column chromatography, and the compound was eluted with 40% ethyl acetate / hexane to obtain 10.8 (1.6 g, yield: 63.77%); MS (ES): m / z 410.16 [M+H] + 。

[0577] Synthesis of Compound 10.9: 10.2 (0.103 g, 0.50 mmol, 1.2 equiv) and cesium carbonate (0.088 g, 0.84 mmol, 2.0 equiv) were added to a solution of 10.8 (0.175 g, 0.42 mmol, 1.0 equiv) in 1,4-dioxane (3 mL). The reaction mixture was degassed under an argon atmosphere for 10 minutes, then tris(dibenzylideneacetone)dipalladium(0) (0.019 g, 0.021 mmol, 0.05 equiv) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.024 g, 0.042 mmol, 0.1 equiv) were added, and it was degassed again for 5 minutes. The reaction was stirred at 100 °C for 4 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, transferred to water, and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material. This crude material was further purified by combi flash using 3% methanol / dichloromethane as the eluent to obtain pure 10.9 (0.160 g, 64.77%). MS (ES): m / z 579.24 [M+H] + 。

[0578] Synthesis of Compound I-17: Dissolve Compound 10.9 (0.025 g, 0.043 mmol, 1.0 equivalent) in dichloromethane (1 mL), and add trifluoroacetic acid (0.09 mL) to the reaction mixture. Stir the reaction at room temperature for 1 hour. After completion of the reaction, transfer the reaction mixture to saturated bicarbonate solution and extract the product with dichloromethane. Combine the organic layers, dry over sodium sulfate and concentrate under reduced pressure to obtain the crude material. Further purify this crude material by trituration with diethyl ether to obtain I-17 (0.015 g, 72.55%). MS (ES): m / z 479.56 [M+H] + ; LCMS purity: 100%; HPLC purity: 95.00%; chiral HPLC: 48.97%, 49.70%; 1 1H NMR (DMSO-d6, 400 MHz): 8.87 - 8.85 (d, J = 8.8 Hz, 1H), 8.72 (s, 1H), 8.53 - 8.52 (d, J = 4.4 Hz, 1H), 8.17 - 8.15 (d, J = 6.8 Hz, 1H), 8.10 - 8.06 (d, J = 9.2 Hz, 1H), 7.89 (s, 1H), 7.75 - 7.74 (d, J = 4.4 Hz, 1H), 7.54 - 7.53 (d, J = 4.8 Hz, 1H), 7.45 - 7.44 (d, J = 6.4 Hz, 1H), 6.48 - 6.45 (t, J = 10.8 Hz, 1H), 6.38 (s, 1H), 4.38 - 4.34 (t, J = 8.8 Hz, 1H), 3.18 (s, 3H), 2.88 - 2.87 (d, J = 4 Hz, 3H), 2.15 - 2.07 (m, 3H), 1.57 - 1.51 (m, 2H).

[0579] Example 10: Synthesis of N-(2-methoxycyclobutyl)-8-(methylamino)-6-((2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)imidazo[1,2-b]pyridazine-3-carboxamide (I-18).

[0580]

[0581] Synthesis of Compound 11: Synthesize the compound according to the above experimental protocol in Example 9 to obtain 11 (yield: 63.77%). MS (ES): m / z 410.16 [M+H] + .

[0582] Synthesis of Compound 11.1: Synthesize the compound according to the experimental protocol described above in Example 3 to obtain 11.1 (yield: 58.82%). MS (ES): m / z 188.20 [M+H] +。

[0583] Synthesis of Compound 11.2: To a solution of 11 (0.175 g, 0.42 mmol, 1.0 equiv) in 1,4-dioxane (3 mL) was added 11.1 (0.103 g, 0.50 mmol, 1.2 equiv), cesium carbonate (0.088 g, 0.84 mmol, 2.0 equiv). The reaction mixture was degassed under an argon atmosphere for 10 minutes, then tris(dibenzylideneacetone)dipalladium(0) (0.019 g, 0.021 mmol, 0.05 equiv) and 2-dicyclohexylphosphino-2',4',6'-triisopropyldiphenyl (0.020 g, 0.042 mmol, 0.1 equiv) were added, and the mixture was degassed again for 5 minutes. The reaction was stirred at 100 °C for 4 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, transferred to water, and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material. This crude material was further purified by combi flash using 3% methanol / dichloromethane as the eluent to obtain 11.2 (0.170 g, yield: 71.02%). MS(ES): m / z 561.25 [M+H] + 。

[0584] Synthesis of Compound I-18: Compound 11.2 (0.030 g, 0.053 mmol, 1.0 equiv) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (0.09 mL) was added to the reaction mixture. The reaction was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was transferred to a saturated bicarbonate solution, and the product was extracted with dichloromethane. The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material. This crude material was further purified by trituration with diethyl ether to obtain I-18 (0.018 g, yield: 73.04%). MS(ES): m / z 461.77 [M+H] + ; LCMS purity: 99.33%; HPLC purity: 99.59%; chiral HPLC: 47.01%, 48.01%; 11H NMR (DMSO-d6, 400 MHz): δ 8.88 - 8.86 (d, J = 8.8 Hz, 1H), 8.70 (s, 1H), 8.66 - 8.65 (d, J = 3.6 Hz, 1H), 8.13 - 8.11 (d, J = 7.2 Hz, 1H), 8.08 - 8.04 (t, J = 7.6 Hz, 1H), 7.89 (bs, 1H), 7.86 (s, 1H), 7.60 - 7.52 (m, 3H), 6.47 - 6.44 (t, J = 7.2 Hz, 1H), 6.40 (s, 1H), 4.39 - 4.35 (m, 1H), 3.22 (s, 3H), 2.89 - 2.88 (d, J = 4.4 Hz, 3H), 2.14 - 2.07 (m, 2H), 1.57 - 1.51 (m, 3H).

[0585] Example 11: Synthesis of N-(2-methoxycyclobutyl)-6-((6'-methyl-2-oxo-2H-[1,3'-bipyridin]-3-yl)amino)-8-(methylamino)imidazo[1,2-b]pyridazine-3-carboxamide (I-19).

[0586]

[0587] Synthesis of Compound 12.2: To a solution of 12 (3.0 g, 17.44 mmol, 1 equiv) in 1,4-dioxane (150 mL) was added 12.1 (2.30 g, 20.92 mmol, 1.2 equiv). The reaction mixture was degassed for 10 minutes under an argon atmosphere, and then potassium carbonate (6.0 g, 43.6 mmol, 2.5 equiv), N,N-dimethylethylenediamine (0.384 g, 4.36 mmol, 0.25 equiv), and copper(I) iodide (0.497 g, 2.61 mmol, 0.15 equiv) were added. The reaction mixture was heated at 115 °C for 12 h. After completion of the reaction, the reaction mixture was transferred to ice-cold water, and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine solution, dried over sodium sulfate, and concentrated under reduced pressure to give the crude material. This crude material was further purified by 5% methanol / dichloromethane to afford 12.2 (1.56 g, yield: 44.45%). MS (ES): m / z 202.09 [M + H] + .

[0588] Synthesis of Compound 12.3: The compound was synthesized according to the experimental protocol described above in Example 9 to afford 12.3 (yield: 63.77%). MS (ES): m / z 410.16 [M + H] + .

[0589] Synthesis of Compound 12.4: To a solution of 12.3 (0.175 g, 0.42 mmol, 1.0 equiv) in 1,4-dioxane (3 mL) was added 12.2 (0.103 g, 0.50 mmol, 1.2 equiv), cesium carbonate (0.088 g, 0.84 mmol, 2.0 equiv). The reaction mixture was degassed under an argon atmosphere for 10 minutes, then tris(dibenzylideneacetone)dipalladium(0) (0.019 g, 0.021 mmol, 0.05 equiv) and 2-dicyclohexylphosphino-2',4',6'-triisopropyldiphenyl (0.020 g, 0.042 mmol, 0.1 equiv) were added, and the mixture was degassed again for 5 minutes. The reaction was stirred at 100 °C for 4 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, transferred to water, and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material. This crude material was further purified by combi flash using 3% methanol / dichloromethane to obtain pure 12.4. (0.160 g, yield: 65.21%). MS (ES): m / z 575.27 [M+H] + .

[0590] Synthesis of Compound I-19: Compound 12.4 (0.025 g, 0.043 mmol, 1.0 equiv) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (0.09 mL) was added to the reaction mixture. The reaction was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was transferred to saturated bicarbonate solution, and the product was extracted with dichloromethane. The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material. This crude material was further purified by trituration with diethyl ether to obtain I-19 (0.015 g, yield: 72.66%). MS (ES): m / z 475.77 [M+H] + ; LCMS purity: 100%; HPLC purity: 100%; chiral HPLC: 46.44%, 47.34%; 11H NMR (DMSO-d6, 400 MHz): δ 8.85 (s, 1H), 8.83 - 8.81 (d, J = 8.8 Hz, 1H), 8.73 (s, 1H), 8.24 - 8.22 (d, J = 7.2 Hz, 1H), 8.17 - 8.16 (d, J = 6.8 Hz, 1H), 7.94 (bs, 1H), 7.74 - 7.72 (d, J = 8.4 Hz, 1H), 7.49 (bs, 1H), 7.42 - 7.41 (d, J = 6.8 Hz, 1H), 6.47 (s, 1H), 6.45 - 6.43 (t, J = 6 Hz, 1H), 3.80 - 3.77 (m, 1H), 3.22 (s, 3H), 2.87 (s, 3H), 2.66 (bs, 3H), 2.16 - 2.05 (m, 2H), 1.57 - 1.45 (m, 2H), 1.23 (bs, 1H).

[0591] Example 12: Synthesis of N-(2-methoxycyclobutyl)-8-(methylamino)-6-((2-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,2-dihydropyridin-3-yl)amino)imidazo[1,2-b]pyridazine-3-carboxamide (I-20).

[0592]

[0593] Synthesis of Compound 13.2: Under nitrogen, copper(II) acetate (2.60 g, 14.28 mmol, 1.0 equiv) and triethylamine (5.00 mL, 35.7 mmol, 2.5 equiv) were added to a solution of 13 (3.0 g, 14.28 mmol, 1.0 equiv) and 13.1 (2.4 g, 17.14 mmol, 1.2 equiv) in dioxane (30 mL). The reaction was stirred at 80 °C for 5 h. After completion of the reaction, the reaction mixture was transferred to ice-cold water and the product was extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure to give the crude material. This crude material was further purified by column chromatography and the compound was eluted in 10% ethyl acetate / hexane to give 13.2 (0.380 g, 11.98%); MS (ES): m / z 222.20 [M+H] + .

[0594] Synthesis of Compound 13.3: Palladium on carbon (0.100 g) was added to a solution of 13.1 (0.380 g, 1.71 mmol, 1.0 equiv) in methanol (4 ml). Hydrogen was bubbled through the reaction mixture at room temperature for 3 hours. After completion of the reaction, the reaction mixture was filtered through a bed of diatomaceous earth and washed with methanol. The filtrate was concentrated under reduced pressure to obtain the crude material. This crude material was further purified by column chromatography and the compound was eluted in 1.4% methanol / dichloromethane to obtain pure 13.3 (0.120 g, 36.13%). MS (ES): m / z 195.23 [M+H] + 。

[0595] Synthesis of Compound 13.4: The compound was synthesized using the general procedure for nuclear synthesis described above to obtain 13.4. (Yield: 71.67%). MS (ES): m / z 327.08 [M+H] + 。

[0596] Synthesis of Compound 13.6: Propylphosphonic anhydride (3.8 g, 12.22 mmol, 2.0 equiv) was added to a solution of 13.4 (2.0 g, 6.11 mmol, 1.0 equiv) in dichloromethane (30 mL) and stirred at room temperature for 15 minutes. Triethylamine (1.8 g, 18.33 mmol, 3.0 equiv) was added thereto, and then 13.5 (0.740 g, 7.33 mmol, 1.2 equiv) was added. The reaction mixture was stirred at room temperature for 5 minutes. After completion of the reaction, the reaction mixture was transferred to water and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material. This crude material was further purified by column chromatography and the compound was eluted in 40% ethyl acetate / hexane to obtain 13.6 (1.6 g, yield: 63.77%). MS (ES): m / z 410.16 [M+H] + 。

[0597] Synthesis of Compound 13.7: To a solution of 13.6 (0.175 g, 0.42 mmol, 1.0 equiv) in 1,4-dioxane (3 mL) was added 13.3 (0.097 g, 0.50 mmol, 1.2 equiv), cesium carbonate (0.088 g, 0.84 mmol, 2.0 equiv). The reaction mixture was degassed for 10 minutes under an argon atmosphere, then tris(dibenzylideneacetone)dipalladium(0) (0.020 g, 0.021 mmol, 0.05 equiv) and 2-dicyclohexylphosphino-2',4',6'-triisopropyldiphenyl (0.019 g, 0.042 mmol, 0.1 equiv) were added, and the mixture was degassed again for 5 minutes. The reaction mixture was stirred at 100 °C for 4 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, transferred to water, and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material. This crude material was further purified by combi flash using 3% methanol / dichloromethane to obtain 13.7 (0.150 g, yield: 61.89%). MS(ES): m / z 568.28 [M+H] + .

[0598] Synthesis of Compound I-20: Compound 13.7 (0.025 g, 0.044 mmol, 1.0 equiv) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (0.09 mL) was added to the reaction mixture. The reaction was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was transferred to saturated bicarbonate solution, and the product was extracted with dichloromethane. The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material. This crude material was further purified by trituration with diethyl ether to obtain I-20 (0.015 g, 72.85%). MS(ES): m / z 468.77 [M+H] + ; LCMS purity: 100%; HPLC purity: 100%; chiral HPLC purity: 47.30%, 49.03%; 11H NMR (DMSO-d6, 400 MHz): δ 8.83 - 8.80 (d, J = 8.8 Hz, 1H), 8.54 (s, 1H), 7.98 - 7.96 (d, J = 6.4 Hz, 1H), 7.85 (s, 1H), 7.50 - 7.45 (m, 2H), 6.36 - 6.33 (t, J = 6.8 Hz, 1H), 6.31 (s, 1H), 5.76 (s, 1H), 5.03 (bs, 1H), 4.33 - 4.31 (m, 1H), 3.99 (bs, 2H), 3.76 - 3.70 (m, 2H), 3.53 - 3.47 (t, J = 11.2 Hz, 3H), 3.18 (s, 3H), 2.86 - 2.85 (d, J = 4.8 Hz, 3H), 2.10 - 2.03 (m, 3H), 1.76 (bs, 2H).

[0599] Example 13: Synthesis of N-(2-methoxycyclobutyl)-6-((1-((1r,4S)-4-methoxycyclohexyl)-2-oxo-1,2-dihydropyridin-3-yl)amino)-8-(methylamino)imidazo[1,2-b]pyridazine-3-carboxamide (I-21).

[0600]

[0601] Synthesis of Compound 14.1: Imidazole (7 g, 104.19 mmol, 3.0 equiv) and tert-butyldimethylchlorosilane (7.8 g, 52.09 mmol, 1.5 equiv) were added to a solution of 14 (4 g, 34.73 mmol, 1.0 equiv) in dichloromethane (40 mL) at 0 °C. The reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, the reaction mixture was transferred to ice-cold water and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material. This crude material was further purified by combi flash using 5% methanol / dichloromethane to obtain 14.1 (5.2 g, 65.26%). MS (ES): m / z 230.44 [M+H] + 。

[0602] Synthesis of Compound 14.3: 14.2 (3.4 g, 22.66 mmol, 1.0 equiv) was added to a solution of 14.1 (5.2 g, 22.66 mmol, 1.0 equiv) in dimethylformamide (50 mL). The reaction mixture was stirred at room temperature for 1 h, then N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (6.5 g, 33.99 mmol, 1.5 equiv) and 4-dimethylaminopyridine (0.69 g, 5.66 mmol, 0.25 equiv) were added. The reaction was stirred at room temperature for 16 h. After completion of the reaction, the reaction mixture was transferred to ice-cold water and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material. This crude material was further purified by combi flash using 30% ethyl acetate / hexane to obtain 14.3 (1.8 g, 21.73%). MS (ES): m / z 366.55 [M+H] + 。

[0603] Synthesis of Compound 14.4: A solution of hydrochloric acid in 1,4-dioxane (10 mL) was added to 14.3 (1.8 g, 4.92 mmol, 1.0 equiv). The reaction mixture was stirred at room temperature for 1 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain a residue, which was stirred with diethyl ether and filtered to obtain pure 14.4 (1.2 g, 96.98%). MS (ES): m / z 252.28 [M+H] + 。

[0604] Synthesis of Compound 14.5: Sodium hydride (0.10 g, 7.17 mmol, 1.5 equiv) was added to a solution of 14.4 (1.2 g, 4.78 mmol, 1.0 equiv) in tetrahydrofuran (10 mL) at 0 °C, then methyl iodide (0.67 g, 4.78 mmol, 1.0 equiv) was added. The reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, the reaction mixture was transferred to ice-cold water and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material. This crude material was further purified by combi flash using 1.4% methanol / dichloromethane as the eluent to obtain 14.5 (0.78 g, 61.56%). MS (ES): m / z 266.31 [M+H] + 。

[0605] Synthesis of Compound 14.6: Lithium hydroxide (1.2 g, 29.4 mmol, 10 eq) was added to a solution of 14.5 (0.78 g, 2.94 mmol, 1.0 eq) in tetrahydrofuran:methanol:water (5 mL, 1:1:1). The reaction was stirred at 70 °C for 3 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain a residue. Water was added to this residue at 10 °C and then the mixture was acidified with 1 N hydrochloric acid to adjust to pH about 6 - 6.5. The product was extracted with dichloromethane. The organic layers were combined, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to obtain 14.6 (0.65 g, 87.99%). MS (ES): m / z: 252.28 [M+H] + 。

[0606] Synthesis of Compound 14.7: Diphenylphosphoryl azide (1.1 g, 4.14 mmol, 1.6 eq) and trimethylamine (10 mL, 7.7 mmol, 3.0 eq) were added to a solution of 14.6 (0.65 g, 2.59 mmol, 1.0 eq) in tert-butanol (6 mL). The reaction mixture was heated at 80 °C for 18 h. After completion of the reaction, the reaction mixture was transferred to ice-cold water and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to obtain a crude material. This crude material was further purified by combi flash using 5% ethyl acetate / hexane as the eluent to obtain 14.7 (0.38 g, 45.56%). MS (ES): m / z 323.41 [M+H] + 。

[0607] Synthesis of Compound 14.8: A solution of hydrochloric acid in 1,4-dioxane (1 mL) was added to 14.7 (0.38 g, 1.18 mmol, 1.0 eq). The reaction mixture was stirred at room temperature for 1 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain a residue, which was stirred with diethyl ether and filtered to obtain pure 14.8 (0.20 g, 76.34%). MS (ES): m / z 223.29 [M+H] + 。

[0608] Synthesis of Compound 14.9: The compound was synthesized according to the experimental protocol described above in Example 12 to obtain 14.9 (yield: 63.77%). MS (ES): m / z 410.16 [M+H] + 。

[0609] Synthesis of Compound 14.10: To a solution of 14.9 (0.175 g, 0.42 mmol, 1.0 equiv) in 1,4-dioxane (3 mL) was added 14.8 (0.111 g, 0.50 mmol, 1.2 equiv), cesium carbonate (0.088 g, 0.84 mmol, 2.0 equiv). The reaction mixture was degassed under an argon atmosphere for 10 minutes, then tris(dibenzylideneacetone)dipalladium(0) (0.020 g, 0.021 mmol, 0.05 equiv) and 2-dicyclohexylphosphino-2',4',6'-triisopropyldiphenyl (0.019 g, 0.042 mmol, 0.1 equiv) were added, and the mixture was degassed again for 5 minutes. The reaction mixture was stirred at 100 °C for 4 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, transferred to water, and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material. This crude material was further purified by combiflash using 3% methanol / dichloromethane to obtain 14.10 (0.153 g, yield: 60.16%). MS(ES): m / z 596.32 [M+H] + .

[0610] Synthesis of Compound I-21: Compound 14.10 (0.025 g, 0.042 mmol, 1.0 equiv) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (0.09 mL) was added to the reaction mixture. The reaction was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was transferred to a saturated bicarbonate solution, and the product was extracted with dichloromethane. The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material. This crude material was further purified by trituration with diethyl ether to obtain I-21 (0.018 g, 86.55%). MS(ES): m / z 496.61 [M+H] + ; LCMS purity: 100%; HPLC purity: 98.43%; chiral HPLC purity: 47.08%, 48.92%; 11H NMR (DMSO-d6, 400 MHz): δ 8.83 - 8.81 (d, J = 8.8 Hz, 1H), 8.52 (s, 1H), 8.96 - 8.94 (d, J = 6.4 Hz, 1H), 7.85 (s, 1H), 7.49 - 7.48 (d, J = 4.8 Hz, 1H), 7.42 - 7.40 (d, J = 6 Hz, 1H), 6.35 - 6.31 (t, J = 7.2 Hz, 1H), 6.29 (s, 1H), 4.79 (bs, 1H), 4.35 - 4.30 (m, 1H), 3.76 - 3.72 (m, 1H), 3.22 (s, 4H), 3.18 (s, 3H), 2.86 - 2.85 (d, J = 4.8 Hz, 3H), 2.15 - 2.08 (m, 4H), 1.80 (bs, 3H), 1.52 (bs, 2H), 1.23 (bs, 3H).

[0611] Example 14: Synthesis of 6 - ((1 - ((1R,5S,6r)-3 - oxabicyclo[3.1.0]hexan - 6 - yl)-2 - oxo - 1,2 - dihydropyridin - 3 - yl)amino)-N-(2 - methoxycyclobutyl)-8-(methylamino)imidazo[1,2 - b]pyridazine - 3 - carboxamide (I - 22).

[0612]

[0613] Synthesis of Compound 15.1: To a solution of 15 (0.250 g, 1.62 mmol, 1.0 equiv) in N,N - dimethylformamide (12 mL) was added (1R,5S,6r)-3 - oxabicyclo[3.1.0]hexan - 6 - amine hydrochloride (0.218 g, 1.62 mmol, 1.0 equiv). The reaction mixture was stirred at room temperature for 1 hour, then N - ethyl - N'-(3 - dimethylaminopropyl)carbodiimide hydrochloride (0.402 g, 2.10 mmol, 1.3 equiv) and 4 - dimethylaminopyridine (0.049 g, 0.405 mmol, 0.25 equiv) were added. The reaction was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was transferred to ice - cold water and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material. This crude material was further purified by combi flash using 30% ethyl acetate / hexane as the eluent to obtain 15.1 (0.180 g, yield: 47.17%). MS (ES): m / z 236.24 [M + H] + .

[0614] Synthesis of Compound 15.2: Lithium hydroxide (0.160 g, 3.82 mmol, 5.0 equiv) was added to a solution of 15.1 (0.180 g, 0.765 mmol, 1.0 equiv) in tetrahydrofuran:methanol:water (5 mL, 1:1:1). The reaction was stirred at 70 °C for 3 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain a residue. Water was added to this residue at 10 °C and then the mixture was acidified with 1 N hydrochloric acid to adjust to pH about 6 - 6.5. The product was extracted with dichloromethane. The organic layers were combined, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to obtain 15.2 (0.140 g, yield: 82.71%). MS(ES): m / z 222.07 [M+H] + 。

[0615] Synthesis of Compound 15.3: Diphenylphosphoryl azide (0.226 g, 0.821 mmol, 1.3 equiv) and triethylamine (0.108 g, 1.074 mmol, 1.7 equiv) were added to a solution of 15.2 (0.140 g, 0.632 mmol, 1.0 equiv) in tert-butanol. The reaction was stirred at 90 °C for 16 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain a crude material. This crude material was further purified by combi flash using 1.0% MeOH / dichloromethane to obtain 15.3 (0.150 g, yield: 81.08%). MS(ES): m / z 293.34 [M+H] + 。

[0616] Synthesis of Compound 15.4: 4M hydrochloric acid / 1,4-dioxane (7 mL) was added to 15.3 (0.150 g, 0.513 mmol, 1.0 equiv) and the mixture was stirred at room temperature for 4 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the residue was triturated with diethyl ether to obtain 15.4 (0.090 g, 76.70%). MS(ES): m / z 193.09 [M+H] + 。

[0617] Synthesis of Compound 15.5: The compound was synthesized according to the experimental protocol described in Example 12 to obtain 15.5 (yield: 63.77%). MS(ES): m / z 410.16 [M+H] + 。

[0618] Synthesis of Compound 15.6: To a solution of 15.5 (0.175 g, 0.42 mmol, 1.0 equiv) in 1,4-dioxane (3 mL) was added 15.4 (0.096 g, 0.50 mmol, 1.2 equiv), cesium carbonate (0.088 g, 0.84 mmol, 2.0 equiv). The reaction mixture was degassed for 10 min under an argon atmosphere, then tris(dibenzylideneacetone)dipalladium(0) (0.020 g, 0.021 mmol, 0.05 equiv) and 2-dicyclohexylphosphino-2',4',6'-triisopropyldiphenyl (0.019 g, 0.042 mmol, 0.1 equiv) were added, and the mixture was degassed again for 5 min. The reaction mixture was stirred at 100 °C for 4 h. After completion of the reaction, the reaction mixture was cooled to room temperature, transferred to water, and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to give the crude material. This crude material was further purified by combi flash using 3% methanol / dichloromethane to give 15.6 (0.140 g, yield: 57.97%). MS(ES): m / z 566.27 [M+H] + .

[0619] Synthesis of Compound I-22: Compound 15.6 (0.025 g, 0.044 mmol, 1.0 equiv) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (0.09 mL) was added to the reaction mixture. The reaction was stirred at room temperature for 1 h. After completion of the reaction, the reaction mixture was transferred to saturated bicarbonate solution, and the product was extracted with dichloromethane. The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure to give the crude material. This crude material was further purified by trituration with diethyl ether to give I-22 (0.016 g, 77.76%). MS(ES): m / z 466.86 [M+H] + ; LCMS purity: 100%; HPLC purity: 97.40%; chiral HPLC: 49.41%, 49.24%; 11H NMR (DMSO-d6, 400 MHz): δ 8.82 - 8.80 (d, J = 8.8 Hz, 1H), 8.61 (s, 1H), 7.96 - 7.94 (d, J = 6.8 Hz, 1H), 7.85 (s, 1H), 7.50 - 7.48 (d, J = 5.2 Hz, 1H), 7.28 - 7.27 (d, J = 6 Hz, 1H), 6.34 (s, 1H), 6.26 - 6.23 (t, J = 7.2 Hz, 1H), 4.35 - 4.31 (t, J = 8.4 Hz, 1H), 3.98 (bs, 2H), 3.71 (s, 3H), 3.19 (bs, 2H), 3.14 (bs, 2H), 2.86 - 2.84 (d, J = 4.8 Hz, 3H), 2.27 (bs, 2H), 2.13 - 2.00 (m, 2H), 1.55 - 1.50 (m, 1H), 1.42 - 1.37 (m, 1H).

[0620] Example 15: Synthesis of N-((1S,2S)-2-methoxycyclobutyl)-6-((1-((1r,3S)-3-methoxycyclobutyl)-2-oxo-1,2-dihydropyridin-3-yl)amino)-8-(methylamino)imidazo[1,2-b]pyridazine-3-carboxamide (I-23).

[0621]

[0622] Synthesis of Compound 16.2: To a cooled solution of 16 (5.0 g, 32.44 mmol, 1.0 equiv) in N,N-dimethylformamide (50 mL) was added 16.1 (3.99 g, 32.44 mmol, 1.0 equiv). The reaction mixture was stirred at 0 °C for 30 minutes and further stirred at room temperature for 15 minutes. N-Ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (6.5 g, 42.17 mmol, 1.3 equiv) and 4-dimethylaminopyridine (0.790 g, 6.48 mmol, 0.2 equiv) were added. The reaction mixture was stirred at room temperature for 24 hours. After completion of the reaction, the reaction mixture was transferred to water and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material. This crude material was further purified by column chromatography and the compound was eluted in 1.7% methanol / dichloromethane to obtain 16.2 (3.35 g, 46.26%). MS (ES): m / z 224.09 [M+H] + 。

[0623] Synthesis of Compound 16.3: Sodium hydride (1.44 g, 6.08 mmol, 4.0 equivalents) was added portionwise to a cooled solution of 16.2 (3.35 g, 15.02 mmol, 1.0 equivalent) in N,N-dimethylformamide (35 mL) at 0 °C and the mixture was stirred for 30 minutes. Then methyl iodide (2.7 g, 19.52 mmol, 1.3 equivalents) was added dropwise. The reaction mixture was stirred at the same temperature for 20 minutes and then stirred at room temperature for 6 hours. After completion of the reaction, the reaction mixture was transferred to ice water and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography by eluting with 2 - 2.5% methanol / dichloromethane to obtain pure 16.3 (2.85 g, 80.04%). MS(ES): m / z 238.10 [M+H] + .

[0624] Synthesis of Compound 16.4: Lithium hydroxide (2.88 g, 120.2 mmol, 10 equivalents) was added to a solution of 16.3 (2.85 g, 12.02 mmol, 1.0 equivalent) in tetrahydrofuran:water (30 mL, 2:1). The reaction was stirred at 60 °C for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain a residue. Water was added to this residue at 10 °C and then the mixture was acidified with 1N hydrochloric acid to adjust to pH about 6 - 6.5. The product was extracted with dichloromethane. The organic layers were combined, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material. This crude material was further purified by column chromatography and the compound was eluted with 2.1% methanol / dichloromethane to obtain 16.4 (2.4 g, 89.50%). MS(ES): m / z 224.09 [M+H] + .

[0625] Synthesis of Compound 16.5: Triethylamine (1.84 g, 18.29 mmol, 1.7 equivalents) and diphenylphosphoryl azide (3.84 g, 13.98 mmol, 1.3 equivalents) were added to a solution of 16.4 (2.4 g, 10.76 mmol, 1.0 equivalent) in tert-butanol (25 mL) under nitrogen, and then heated at 80 °C for 16 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, transferred to water and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material. This crude material was further purified by column chromatography and the compound was eluted with 22% ethyl acetate / hexane to obtain pure 16.5 (2.0 g, 63.20%). MS(ES): m / z 295.16 [M+H] + .

[0626] Synthesis of Compound 16.6: A dioxane (20 mL) solution of 4N hydrochloric acid (22 mL) was added dropwise to a cooled solution of 16.5 (2.0 g, 6.80 mmol, 1 equivalent) in dioxane. The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain pure 16.6 (1.4 g, 89.32%). MS (ES): m / z 195.11 [M+H] + 。

[0627] Synthesis of Compound 16.7: The compound was synthesized according to the experimental protocol described above in Example 12 to obtain 16.7 (yield: 63.77%). MS (ES): m / z 410.16 [M+H] + 。

[0628] Synthesis of Compound 16.8: To a solution of 16.7 (0.175 g, 0.42 mmol, 1.0 equivalent) in 1,4-dioxane (3 mL) was added 16.6 (0.097 g, 0.50 mmol, 1.2 equivalents), cesium carbonate (0.088 g, 0.84 mmol, 2.0 equivalents). The reaction mixture was degassed under an argon atmosphere for 10 minutes, then tris(dibenzylideneacetone)dipalladium(0) (0.020 g, 0.021 mmol, 0.05 equivalents) and 2-dicyclohexylphosphino-2′,4′,6′-triisopropyldiphenyl (0.019 g, 0.042 mmol, 0.1 equivalents) were added, and the mixture was degassed again for 5 minutes. The reaction mixture was stirred at 100 °C for 4 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, transferred to water, and the product was extracted with ethyl acetate. The organic layers were combined, washed with a brine solution, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material. This crude material was further purified by combi flash using 3% methanol / dichloromethane to obtain 16.8 (0.145 g, yield: 59.83%). MS (ES): m / z 568.28 [M+H] + 。

[0629] Synthesis of Compound I-23: Compound 16.8 (0.025 g, 0.044 mmol, 1.0 equivalent) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (0.09 mL) was added to the reaction mixture. The reaction was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was transferred to a saturated bicarbonate solution, and the product was extracted with dichloromethane. The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material. This crude material was further purified by trituration with diethyl ether to obtain I-23 (0.016 g, 77.70%). MS (ES): m / z 468.91 [M+H]+ ; LCMS purity: 98.64%; HPLC purity: 98.37%; Chiral HPLC purities: 49.08%, 48.92%; 1 H NMR (DMSO-d6, 400 MHz): 8.83 - 8.81 (d, J = 8.8 Hz, 1H), 8.57 (s, 1H), 7.98 - 7.97 (d, J = 6.4 Hz, 1H), 7.85 (s, 1H), 7.50 - 7.49 (d, J = 5.2 Hz, 2H), 6.36 (s, 1H), 6.33 - 6.31 (t, J = 7.2 Hz, 1H), 5.31 - 5.27 (t, J = 8.4 Hz, 1H), 4.35 - 4.31 (t, J = 8 Hz, 1H), 4.05 (bs, 1H), 3.76 - 3.70 (m, 1H), 3.21 (s, 3H), 3.19 (s, 3H), 2.85 - 2.84 (d, J = 4.8 Hz, 3H), 2.13 - 2.01 (m, 2H), 1.55 - 1.50 (m, 1H), 1.45 - 1.40 (m, 1H), 1.22 (bs, 3H), 1.10 - 1.07 (m, 1H).

[0630] Example 16: Synthesis of rac-N-((1S,2S)-2-methoxycyclobutyl)-6-(1-((3R,4S)-3-methoxytetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-8-(methylamino)imidazo[1,2-b]pyridazine-3-carboxamide (I-1), N-((1S,2S)-2-methoxycyclobutyl)-6-(1-((3R,4S)-3-methoxytetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-8-(methylamino)imidazo[1,2-b]pyridazine-3-carboxamide (I-24) and N-((1R,2R)-2-methoxycyclobutyl)-6-(1-((3R,4S)-3-methoxytetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-8-(methylamino)imidazo[1,2-b]pyridazine-3-carboxamide (I-27).

[0631]

[0632] Synthesis of Compound 17: The compound was synthesized according to the experimental protocol described above to obtain 17 (MS(ES): m / z 541.25 [M+H] + .

[0633] Synthesis of Compound 17.1: Lithium hydroxide (0.110 g, 4.6 mmol, 10.0 equiv) was added to a solution of 17 (0.250 g, 0.46 mmol, 1.0 equiv) in tetrahydrofuran:methanol:water (4 mL, 2:1:1). The reaction was stirred at 50 °C for 16 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain a residue. Water was added to this residue at 10 °C and acidified with 1 N hydrochloric acid to adjust the pH to about 6 - 6.5. The product was extracted with dichloromethane. The organic layers were combined, washed with an aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material. This crude material was further purified by column chromatography and the compound was eluted in 2.1% methanol / dichloromethane to obtain pure 17.1 (0.195 g, yield: 82.27%). MS (ES): m / z 513.22 [M + H] + .

[0634] Synthesis of Compound 17.3: The compound was synthesized using General Procedure C to obtain 17.3 (0.155 g, yield: 68.39%). MS (ES): m / z 596.29 [M + H] + .

[0635] Synthesis of Compound 17.4 (I - 1): The compound was synthesized using General Procedure D to obtain 17.4 (0.025 g, yield: 65.46%). MS (ES): m / z 506.25 [M + H] + ; LCMS purity: 99.00%; HPLC purity: 97.89%; chiral HPLC: 50.05%, 49.94%; 1 1H NMR (DMSO - d6, 400 MHz): 9.26 - 9.24 (d, J = 8.8 Hz, 1H), 8.80 - 8.78 (d, J = 7.6 Hz, 1H), 8.50 (bs, 2H), 7.99 (s, 1H), 7.72 - 7.70 (d, J = 7.2 Hz, 1H), 7.29 - 7.26 (t, J = 6.8 Hz, 1H), 6.67 (s, 1H), 5.45 (bs, 1H), 4.49 (bs, 1H), 4.42 - 4.38 (m, 1H), 4.13 - 4.04 (m, 3H), 3.84 - 3.80 (m, 1H), 3.66 - 3.60 (t, J = 10.8 Hz, 1H), 3.24 (s, 3H), 3.21 (s, 3H), 3.03 - 3.02 (d, J = 4.8 Hz, 3H), 2.20 - 2.18 (m, 1H), 2.10 - 2.08 (m, 1H), 1.54 (bs, 3H), 1.23 (bs, 1H).

[0636] Synthesis of Compounds 17.3a and 17.3b: The isomers of 17.3 (0.115 g) were separated using a column CHIRALCEL OJ-H (250 mm * 4.6 mm, 5 μm) and 0.1% DEA / MeOH as the co-solvent at a flow rate of 4 mL / min to obtain pure fraction -1 (FR-a) and fraction -2 (FR-b). FR-a was concentrated under reduced pressure at 30 °C to obtain pure 17.3b (0.045 g). MS (ES): m / z 596.29 [M+H] + FR-a was concentrated under reduced pressure at 30 °C to obtain pure 17.3a (0.046 g). MS (ES): m / z 596.29 [M+H] + .

[0637] Synthesis of Compound I-24: The compound was synthesized using General Procedure D to obtain I-24 (0.030 g, yield: 78.55%). MS (ES): m / z 506.64 [M+H] + ; LCMS purity: 100%; HPLC purity: 97.60%; chiral HPLC: 97.55%; 1 1H NMR (DMSO-d6, 400 MHz): 9.25 - 9.22 (d, J = 8.8 Hz, 1H), 8.78 - 8.76 (d, J = 7.2 Hz, 1H), 8.48 (bs, 2H), 7.97 (s, 1H), 7.64 - 7.63 (d, J = 4.8 Hz, 1H), 7.28 - 7.24 (t, J = 6.8 Hz, 1H), 6.65 (s, 1H), 5.44 (bs, 1H), 4.47 (bs, 1H), 4.43 - 4.37 (m, 1H), 4.13 - 4.04 (m, 3H), 3.84 - 3.80 (m, 1H), 3.64 - 3.58 (t, J = 11.2 Hz, 1H), 3.22 (s, 3H), 3.13 (s, 3H), 3.02 - 3.00 (d, J = 4.8 Hz, 3H), 2.19 - 2.16 (m, 1H), 1.98 (bs, 1H), 1.54 - 1.47 (m, 3H), 1.23 (bs, 1H).

[0638] Synthesis of Compound I-27: The compound was synthesized using General Procedure D to obtain I-27 (0.032 g, yield: 81.97%). MS (ES): m / z 506.64 [M+H] + ; LCMS purity: 100%; HPLC purity: 98.98%; chiral HPLC: 100%; 11H NMR (DMSO-d6, 400 MHz): 9.25 - 9.22 (d, J = 8.8 Hz, 1H), 8.78 - 8.76 (d, J = 7.2 Hz, 1H), 8.48 (bs, 2H), 7.97 (s, 1H), 7.64 - 7.63 (d, J = 4.8 Hz, 1H), 7.27 - 7.24 (t, J = 6.4 Hz, 1H), 6.65 (s, 1H), 5.44 (bs, 1H), 4.47 (bs, 1H), 4.43 - 4.37 (m, 1H), 4.13 - 4.04 (m, 3H), 3.84 - 3.80 (m, 1H), 3.64 - 3.59 (t, J = 11.2 Hz, 1H), 3.22 (s, 3H), 3.13 (s, 3H), 3.02 - 3.01 (d, J = 4.8 Hz, 3H), 2.21 - 2.16 (m, 1H), 2.09 - 2.05 (m, 1H), 1.54 - 1.47 (m, 3H), 1.22 (bs, 1H).

[0639] Synthesis of Example 17: rac-N-((1S,2S)-2-Methoxycyclobutyl)-6-(1-((3S,4R)-3-methoxytetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-8-(methylamino)imidazo[1,2-b]pyridazine-3-carboxamide (I-2), N-((1S,2S)-2-Methoxycyclobutyl)-6-(1-((3S,4R)-3-methoxytetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-8-(methylamino)imidazo[1,2-b]pyridazine-3-carboxamide (I-25), and N-((1R,2R)-2-Methoxycyclobutyl)-6-(1-((3S,4R)-3-methoxytetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-8-(methylamino)imidazo[1,2-b]pyridazine-3-carboxamide (I-26).

[0640]

[0641] Synthesis of Compound 18: The compound was synthesized according to the experimental protocol described in Example 1 above to obtain 18 (yield: 92.61%). MS (ES): m / z 427.18 [M+H] + .

[0642] Synthesis of Compound 18.2: To a solution of 18 (1.1 g, 2.58 mmol, 1.0 equiv) in toluene (15 mL) was added 18.1 (0.387 g, 3.87 mmol, 1.5 equiv) and p-toluenesulfonic acid (0.044 g, 0.25 mmol, 0.1 equiv). The reaction mixture was refluxed at 110 °C for 48 h. After completion of the reaction, the reaction mixture was transferred to water, and the product was extracted with dichloromethane. The organic layers were combined, washed with an aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material. This crude material was further purified by column chromatography and the compound was eluted in 2.1% methanol / dichloromethane to obtain 18.2 (0.8 g, yield: 58.90%). MS (ES): m / z 527.24 [M+H] + .

[0643] Synthesis of Compound 18.3: To a solution of Compound 18.2 (0.8 g, 1.52 mmol, 1.0 equiv) in dimethylformamide (10 mL) at 0 °C was added sodium hydride (0.072 g, 3.04 mmol, 2.0 equiv) and stirred for 20 min. Methyl iodide (0.237 g, 1.67 mmol, 1.1 equiv) was added and the reaction mixture was stirred at room temperature for 2 h. After completion of the reaction, the reaction mixture was transferred to ice, stirred and extracted with diethyl ether. The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material. This crude material was further purified by column chromatography and the compound was eluted in 2.0% methanol / dichloromethane to obtain 18.3 (0.640 g, yield: 77.92%). MS (ES): m / z 541.25 [M+H] + .

[0644] Synthesis of Compounds 18.3a and 18.3b: The isomers of 18.3 (0.640 g) were separated using a column CHIRALCEL OJ-H (250 mm * 4.6 mm, 5 μm) and 0.1% DEA / MeOH as a co-solvent at a flow rate of 4 mL / min to obtain pure fraction-1 (FR-a) and fraction-2 (FR-b). FR-a was concentrated under reduced pressure at 30 °C to obtain pure 18.3a (0.242 g). MS (ES): m / z 541.25 [M+H] + . FR-b was concentrated under reduced pressure at 30 °C to obtain pure 18.3b (0.250 g). MS (ES): m / z 541.25 [M+H] + .

[0645] Synthesis of Compound 18.4: Lithium hydroxide (0.105 g, 4.4 mmol, 10.0 eq) was added to a solution of 18.3a (0.242 g, 0.44 mmol, 1.0 eq) in tetrahydrofuran:methanol:water (4 mL, 2:1:1). The reaction was stirred at 50 °C for 16 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain a residue. Water was added to this residue at 10 °C and the mixture was acidified with 1 N hydrochloric acid to adjust to pH ca. 6 - 6.5. The product was extracted with dichloromethane. The organic layers were combined, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material. This crude material was further purified by column chromatography and the compound was eluted in 2.5% methanol / dichloromethane to obtain pure 18.4 (0.185 g, yield: 80.63%). MS (ES): m / z 513.22 [M+H] + 。

[0646] Synthesis of Compound 18.6: The compound was synthesized using General Procedure C to obtain 18.6 (0.150 g, yield: 69.77%). MS (ES): m / z 596.29 [M+H] + 。

[0647] Synthesis of Compound 18.7 (I - 2): The compound was synthesized using General Procedure D to obtain 18.7 (0.025 g, yield: 73.64%). MS (ES): m / z 506.25 [M+H] + ; LCMS purity: 100%; HPLC purity: 98.30%; chiral HPLC: 50.05%, 49.94%; 1 1H NMR (DMSO - d6, 400 MHz): 9.26 - 9.24 (d, J = 8.8 Hz, 1H), 8.78 - 8.77 (d, J = 7.2 Hz, 1H), 8.49 (bs, 2H), 7.98 (s, 1H), 7.64 - 7.63 (d, J = 4.8 Hz, 1H), 7.27 - 7.24 (t, J = 6.8 Hz, 1H), 6.65 (s, 1H), 5.44 (bs, 1H), 4.47 (bs, 1H), 4.43 - 4.37 (m, 1H), 4.13 - 4.04 (m, 3H), 3.84 - 3.80 (m, 1H), 3.64 - 3.59 (t, J = 11.2 Hz, 1H), 3.22 (s, 3H), 3.13 (s, 3H), 3.02 - 3.01 (d, J = 4.8 Hz, 3H), 2.21 - 2.16 (m, 1H), 1.98 (bs, 1H), 1.54 - 1.47 (m, 3H), 1.23 (bs, 1H).

[0648] Synthesis of Compounds 18.6a and 18.6b: The isomers of 18.5 (0.110 g) were separated using a column CHIRALCEL OJ-H (250 mm * 4.6 mm, 5 μm) and 0.1% DEA / MeOH as the co-solvent at a flow rate of 4 mL / min to obtain pure fraction -1 (FR-a) and fraction -2 (FR-b). FR-a was concentrated under reduced pressure at 30 °C to obtain pure 18.6b (0.045 g). MS (ES): m / z 596.29 [M+H] + FR-b was concentrated under reduced pressure at 30 °C to obtain pure 18.6b (0.045 g). MS (ES): m / z 596.29 [M+H] + .

[0649] Synthesis of Compound I-25: The compound was synthesized using General Procedure D to obtain I-25 (0.030 g, yield: 78.55%). MS (ES): m / z 506.37 [M+H] + ; LCMS purity: 100%; HPLC purity: 98.22%; chiral HPLC: 96.41%; 1 1H NMR (DMSO-d6, 400 MHz): 9.25 - 9.22 (d, J = 8.8 Hz, 1H), 8.78 - 8.77 (d, J = 7.2 Hz, 1H), 8.49 (bs, 2H), 7.97 (s, 1H), 7.64 - 7.63 (d, J = 4.8 Hz, 1H), 7.27 - 7.24 (t, J = 6.8 Hz, 1H), 6.65 (s, 1H), 5.44 (bs, 1H), 4.47 (bs, 1H), 4.43 - 4.37 (m, 1H), 4.13 - 4.04 (m, 3H), 3.84 - 3.80 (m, 1H), 3.64 - 3.59 (t, J = 11.2 Hz, 1H), 3.22 (s, 3H), 3.13 (s, 3H), 3.02 - 3.01 (d, J = 4.8 Hz, 3H), 2.21 - 2.16 (m, 1H), 1.98 (bs, 1H), 1.54 - 1.47 (m, 3H), 1.22 (bs, 1H).

[0650] Synthesis of Compound I-26: The compound was synthesized using General Procedure D to obtain I-26 (0.031 g, yield: 81.17%). MS (ES): m / z 506.37 [M+H] + ; LCMS purity: 100%; HPLC purity: 98.92%; chiral HPLC: 100%; 11H NMR (DMSO-d6, 400 MHz): 9.25 - 9.22 (d, J = 8.8 Hz, 1H), 8.78 - 8.76 (d, J = 7.2 Hz, 1H), 8.48 (bs, 2H), 7.97 (s, 1H), 7.64 - 7.63 (d, J = 4.8 Hz, 1H), 7.28 - 7.24 (t, J = 6.4 Hz, 1H), 6.65 (s, 1H), 5.44 (bs, 1H), 4.47 (bs, 1H), 4.43 - 4.37 (m, 1H), 4.13 - 4.04 (m, 3H), 3.84 - 3.80 (m, 1H), 3.64 - 3.59 (t, J = 11.2 Hz, 1H), 3.22 (s, 3H), 3.13 (s, 3H), 3.02 - 3.01 (d, J = 4.8 Hz, 3H), 2.21 - 2.16 (m, 1H), 1.98 (bs, 1H), 1.54 - 1.47 (m, 3H), 1.22 (bs, 1H).

[0651] Example 18: Synthesis of 6 - ((3'-fluoro - 2 - oxo - 2H - [1,2'-bipyridin] - 3 - yl)amino) - N - (2 - (methoxy - d3)cyclobutyl) - 8 - (methylamino)imidazo[1,2 - b]pyridazine - 3 - carboxamide (I - 30).

[0652]

[0653] Synthesis of Compound 19.1: To a cooled solution of 19 (100 g, 434.78 mmol, 1.0 eq) in acetone (300 mL) and water (15.6 mL) was added iron(III) chloride on catalytic silica gel (500 mg). The reaction mixture was stirred at room temperature for 2 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the crude material. This crude material was further purified by column chromatography and the compound was eluted in 60% ethyl acetate / hexane to obtain pure 19.1 (32 g, yield: 85.66%). MS (ES): m / z 87.04 [M + H] + 。

[0654] Synthesis of Compound 19.2: 4-Dimethylaminopyridine (4.53 g, 37.20 mmol, 0.1 equiv) was added to a cooled solution of 19.1 (32 g, 372.09 mmol, 1.0 equiv) in toluene (320 mL). Then dibenzylamine (73.30 g, 372.09 mmol, 1.0 equiv) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the crude material. This crude material was further purified by column chromatography, and the compound was eluted in 5% ethyl acetate / hexane to obtain pure 19.2 (74 g, yield: 75.02%). MS (ES): m / z 266.15 [M+H] + 。

[0655] Synthesis of Compounds 19.2a and 19.2b: Sodium borohydride (10.5 g, 279.24 mmol, 1.0 equiv) was added portionwise to a cooled solution of 19.2 (74 g, 279.24 mmol, 1.0 equiv) in methanol (750 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 2 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the crude material. This crude material was further purified by column chromatography, and Compound 19.2a was eluted in 30% ethyl acetate / hexane, and Compound 19.2b was eluted in 40% ethyl acetate / hexane to obtain 19.2a (32 g, yield: 42.92%) and 19.2b (24.7 g, yield: 33.13%). MS (ES): m / z 268.17 [M+H] + 。

[0656] Synthesis of Compound 19.3: Potassium tert-butoxide (1 M in tetrahydrofuran) (2.68 mL, 2.68 mmol, 1.2 equiv) was added to a cooled solution of 19.2b (0.6 g, 2.24 mmol, 1.0 equiv) in tetrahydrofuran (6 mL). The reaction was stirred at 0 °C for 30 min. Then methyl-d3 iodide (0.357 g, 2.46 mmol, 1.1 equiv) was added to the reaction mixture at 0 °C, and the reaction was stirred at 0 °C for 2 h. After completion of the reaction, the reaction mixture was transferred to water, and the product was extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material. This crude material was further purified by column chromatography, and the compound was eluted in 30% ethyl acetate / hexane to obtain pure 19.3 (0.4 g, yield: 62.67%). MS (ES): m / z 285.20 [M+H] + 。

[0657] Synthesis of Compound 19.4: 10% palladium on carbon (0.2 g) was added to a solution of 19.3 (0.4 g, 1.40 mmol, 1.0 equiv) in methanol (8 mL). Hydrogen was bubbled through the reaction mixture at room temperature for 4 hours. After completion of the reaction, the reaction mixture was filtered through a bed of diatomaceous earth and washed with methanol. The filtrate was concentrated under reduced pressure to obtain the crude material. A dioxane solution of 1N hydrochloric acid (2 mL) was added to this filtrate and stirred at 0 °C for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the crude material. This crude material was further purified by trituration with n-pentane to obtain pure 19.4 (0.1 g, yield: 50.56%); MS (ES): 105.13 [M-HCl] + 。

[0658] Synthesis of Compound 19.5: The compound was synthesized according to the above experimental protocol in Example 9 to obtain 19.5 (yield: 79.18%). MS (ES): m / z 327.08 [M+H] + 。

[0659] Synthesis of Compound 19.6: 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridine 3-oxide hexafluorophosphate (0.228 g, 0.6 mmol, 2.0 equiv) was added to a solution of 19.5 (0.1 g, 0.30 mmol, 1.0 equiv) in N,N-dimethylformamide (1 mL) and stirred at room temperature for 15 minutes. Diisopropylethylamine (0.15 mL, 0.9 mmol, 3.0 equiv) was added thereto, and then 19.4 (0.042 g, 0.30 mmol, 1.0 equiv) was added. The reaction mixture was stirred at room temperature for 5 minutes. After completion of the reaction, the reaction mixture was transferred to water, and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material. This crude material was further purified by column chromatography, and the compound was eluted in 40% ethyl acetate / hexane to obtain 19.6 (0.220 g, yield: 74.93%). MS (ES): m / z 413.17 [M+H] + 。

[0660] Synthesis of Compound 19.7: The compound was synthesized according to the above experimental protocol in Example 9 to obtain 19.7 (yield: 49.37%). MS (ES): m / z 206.02 [M+H] + 。

[0661] Synthesis of Compound 19.8: To a solution of 19.6 (0.220 g, 0.53 mmol, 1.0 equiv) in 1,4-dioxane (4 mL) was added 19.7 (0.130 g, 0.63 mmol, 1.2 equiv), sodium carbonate (0.112 g, 1.06 mmol, 2.0 equiv). The reaction mixture was degassed under an argon atmosphere for 10 minutes, then tris(dibenzylideneacetone)dipalladium(0) (0.023 g, 0.026 mmol, 0.05 equiv) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.030 g, 0.053 mmol, 0.1 equiv) were added, and it was degassed again for 5 minutes. The reaction was stirred at 100 °C for 4 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, transferred to water, and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material. This crude material was further purified by combi flash using 3% methanol / dichloromethane as the eluent to obtain pure 19.8. (0.150 g, yield: 48.40%). MS(ES): m / z 582.26 [M+H] + 。

[0662] Synthesis of Compound I-30: Compound 19.6 (0.040 g, 0.068 mmol, 1.0 equiv) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (0.15 mL) was added to the reaction mixture. The reaction was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was transferred to saturated bicarbonate solution, and the product was extracted with dichloromethane. The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material. This crude material was further purified by trituration with diethyl ether to obtain I-30 (0.025 g, yield: 75.50%). MS(ES): m / z 482.56 [M+H] + ; LCMS purity: 97.46%; HPLC purity: 50.17%; chiral HPLC: 50.17%, 49.46%; 11H NMR (DMSO-d6, 400 MHz): δ 8.86 - 8.83 (d, J = 8.8 Hz, 1H), 8.71 (s, 1H), 8.51 (bs, 1H), 8.15 - 8.13 (d, J = 7.2 Hz, 1H), 8.09 - 8.04 (t, J = 8.8 Hz, 1H), 7.87 (s, 1H), 7.72 (bs, 1H), 7.53 (bs, 1H), 7.44 - 7.42 (d, J = 6.8 Hz, 1H), 6.48 - 6.44 (t, J = 7.2 Hz, 1H), 6.36 (s, 1H), 4.34 (bs, 1H), 3.78 - 3.76 (m, 2H), 2.88 - 2.86 (d, J = 4 Hz, 3H), 2.12 - 2.05 (m, 1H), 1.23 (bs, 2H).

[0663] Example 19: Synthesis of 6 - ((3'-fluoro - 2 - oxo - 2H - [1,2'-bipyridin]-3 - yl)amino)-N - ((1R,2R)-2-(methoxy - d3)cyclobutyl)-8-(methylamino)imidazo[1,2 - b]pyridazine - 3 - carboxamide (I - 28) and 6 - ((3'-fluoro - 2 - oxo - 2H - [1,2'-bipyridin]-3 - yl)amino)-N - ((1S,2S)-2-(methoxy - d3)cyclobutyl)-8-(methylamino)imidazo[1,2 - b]pyridazine - 3 - carboxamide (I - 29).

[0664]

[0665] Separation of compounds I - 28 and I - 29 from the trans - diastereomeric mixture I - 30. The isomers of I - 30 (0.090 g) were separated on a Shimadzu LC - 20AP with a UV detector. The column used was CHIRALCEL OX - H (250 * 21.0) mm, 5 μm; the column flow was 18.0 mL / min. The mobile phases used were (A) 0.1% diethylamine / n - hexane and (B) 0.1% diethylamine / 2 - propanol:acetonitrile (70:30). The UV spectrum was recorded at 275 nm Lambdamax. The isocratic ratio is as described below.

[0666] Time (minutes) A％ B％ 0.01 50 50 28 50 50

[0667] To obtain pure fraction - 1 (FR - a) and fraction - 2 (FR - b).

[0668] FR - a was concentrated under reduced pressure at 30 °C to obtain pure I - 28 (0.030 g). MS (ES): m / z 482.72 [M + H] +; LCMS purity: 100%; HPLC purity: 97.29%; chiral HPLC purity: 99.50%; 1 1H NMR (DMSO-d6, 400 MHz): δ 8.85 - 8.83 (d, J = 8.8 Hz, 1H), 8.70 (s, 1H), 8.51 - 8.50 (d, J = 4.4 Hz, 1H), 8.14 - 8.13 (d, J = 7.2 Hz, 1H), 8.08 - 8.04 (t, J = 8.4 Hz, 1H), 7.87 (s, 1H), 7.74 - 7.70 (m, 1H), 7.52 - 7.51 (t, J = 4.8 Hz, 1H), 7.43 - 7.42 (d, J = 5.6 Hz, 1H), 6.48 - 6.44 (t, J = 7.2 Hz, 1H), 6.36 (s, 1H), 4.36 - 4.32 (m, 1H), 3.80 - 3.74 (m, 1H), 2.86 - 2.85 (d, J = 4.4 Hz, 3H), 2.14 - 2.03 (m, 2H), 1.17 - 1.13 (m, 1H), 1.04 - 1.02 (d, J = 6.4 Hz, 1H).

[0669] FR-b was concentrated under reduced pressure at 30 °C to obtain pure I-29 (0.030 g). MS (ES): m / z 482.67 [M+H] + ; LCMS purity: 100%; HPLC purity: 98.53%; chiral HPLC purity: 96.77%; 1 1H NMR (DMSO-d6, 400 MHz): δ 8.85 - 8.83 (d, J = 8.8 Hz, 1H), 8.70 (s, 1H), 8.51 - 8.50 (d, J = 4.4 Hz, 1H), 8.15 - 8.13 (d, J = 7.2 Hz, 1H), 8.08 - 8.04 (t, J = 8.4 Hz, 1H), 7.87 (s, 1H), 7.74 - 7.70 (m, 1H), 7.52 - 7.51 (t, J = 4.8 Hz, 1H), 7.43 - 7.42 (d, J = 5.6 Hz, 1H), 6.48 - 6.44 (t, J = 7.2 Hz, 1H), 6.36 (s, 1H), 4.36 - 4.32 (m, 1H), 3.80 - 3.74 (m, 1H), 2.86 - 2.85 (d, J = 4.4 Hz, 3H), 1.04 - 1.02 (d, J = 6 Hz, 4H).

[0670] Example 20: 6-((3'-fluoro-2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)-N-((1S,2S)-2-methoxycyclobutyl)-8-(methylamino)imidazo[1,2-b]pyridazine-3-carboxamide (I-33), 6-((3'-fluoro-2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)-N-((1R,2R)-2-methoxycyclobutyl)-8-(methylamino)imidazo[1,2-b]pyridazine-3-carboxamide (I-34).

[0671]

[0672] Synthesis of Compound 20: The compound was synthesized according to the experimental protocol of I-17 to obtain 20. (Yield: 64.77%); MS(ES): 579.24 [M+H] + 。

[0673] Synthesis of Compounds 20a and 20b: The isomers of 20 (0.110 g) were separated using a column CHIRALPAK AD-H (250 mm * 4.6 mm, 5 μm) and 0.1% diethylamine / isopropanol as the co-solvent at a flow rate of 4 mL / min to obtain pure fraction-1 (FR-a) and fraction-2 (FR-b). FR-a was concentrated under reduced pressure at 30 °C to obtain pure 20a. (0.040 g). MS(ES): m / z 579.24 [M+H] + 。FR-b was concentrated under reduced pressure at 30 °C to obtain pure 20b. (0.041 g). MS(ES): m / z579.24 [M+H] + 。

[0674] Synthesis of Compound I-33: Compound 20a (0.040 g, 0.069 mmol, 1.0 equiv) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (0.15 mL) was added to the reaction mixture. The reaction was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was transferred to saturated sodium bicarbonate solution, and the product was extracted with dichloromethane. The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material. This crude material was further purified by trituration with diethyl ether to obtain I-33 (0.025 g, yield: 75.58%). MS(ES): m / z 479.77 [M+H] + ; LCMS purity: 100%; HPLC purity: 100%; chiral HPLC purity: 100%; 11H NMR (DMSO-d6, 400 MHz): δ 8.85 - 8.83 (d, J = 8.4 Hz, 1H), 8.71 (s, 1H), 8.51 - 8.50 (d, J = 4.4 Hz, 1H), 8.15 - 8.13 (d, J = 6.4 Hz, 1H), 8.08 - 8.04 (t, J = 9.2 Hz, 1H), 7.87 (s, 1H), 7.73 - 7.71 (m, 1H), 7.53 - 7.52 (d, J = 5.2 Hz, 1H), 7.44 - 7.42 (d, J = 6.8 Hz, 1H), 6.48 - 6.44 (t, J = 7.2 Hz, 1H), 6.36 (s, 1H), 4.36 - 4.32 (t, J = 8.4 Hz, 1H), 3.78 - 3.76 (d, J = 7.2 Hz, 1H), 3.20 (s, 3H), 2.86 - 2.85 (d, J = 4.4 Hz, 3H), 2.12 - 2.05 (m, 3H), 0.85 (bs, 1H).

[0675] Synthesis of Compound I-34: Dissolve Compound 20b (0.041 g, 0.070 mmol, 1.0 equiv) in dichloromethane (1 mL), and add trifluoroacetic acid (0.15 mL) to the reaction mixture. Stir the reaction at room temperature for 1 hour. After completion of the reaction, transfer the reaction mixture to saturated sodium bicarbonate solution, and extract the product with dichloromethane. Combine the organic layers, dry over sodium sulfate and concentrate under reduced pressure to obtain the crude material. Further purify this crude material by trituration with diethyl ether to obtain I-34 (0.025 g, yield: 73.7%). MS (ES): m / z 479.87 [M+H] + ; LCMS purity: 100%; HPLC purity: 99.44%; chiral HPLC purity: 100%; 11H NMR (DMSO-d6, 400 MHz): δ 8.85 - 8.83 (d, J = 8.4 Hz, 1H), 8.71 (s, 1H), 8.51 - 8.50 (d, J = 4.4 Hz, 1H), 8.15 - 8.13 (d, J = 6.4 Hz, 1H), 8.08 - 8.04 (t, J = 9.2 Hz, 1H), 7.87 (s, 1H), 7.74 - 7.71 (m, 1H), 7.53 - 7.52 (d, J = 5.2 Hz, 1H), 7.43 - 7.42 (d, J = 6.8 Hz, 1H), 6.48 - 6.44 (t, J = 7.2 Hz, 1H), 6.36 (s, 1H), 4.36 - 4.32 (t, J = 8.4 Hz, 1H), 3.78 - 3.74 (m, 1H), 3.20 (s, 3H), 2.85 - 2.84 (d, J = 4.4 Hz, 3H), 2.12 - 2.05 (m, 3H), 0.85 (bs, 1H).

[0676] Example 21: N-((1S,2S)-2-methoxycyclobutyl)-8-(methylamino)-6-((2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)imidazo[1,2-b]pyridazine-3-carboxamide (I-35), N-((1R,2R)-2-methoxycyclobutyl)-8-(methylamino)-6-((2-oxo-2H-[1,2'-bipyridin]-3-yl)amino)imidazo[1,2-b]pyridazine-3-carboxamide (I-36).

[0677]

[0678] Synthesis of Compound 21: The compound was synthesized according to the experimental protocol of I-18 to obtain 21. (Yield: 71.02%); MS (ES): 561.25 [M+H] + 。

[0679] Synthesis of Compounds 21a and 21b: The isomers of 21 (0.120 g) were separated using a column CHIRALCEL OJ-H (250 mm * 4.6 mm, 5 μm) and 0.1% DEA / MeOH:ACN (50:50) as the co-solvent at a flow rate of 4 mL / min to obtain pure fraction -1 (FR-a) and fraction -2 (FR-b). FR-a was concentrated under reduced pressure at 30 °C to obtain pure 21a. (0.042 g). MS (ES): m / z 561.25 [M+H] + 。FR-b was concentrated under reduced pressure at 30 °C to obtain pure 21b. (0.041 g). MS (ES): m / z 561.25 [M+H] + 。

[0680] Synthesis of Compound I-35: Dissolve Compound 21a (0.042 g, 0.074 mmol, 1.0 equiv) in dichloromethane (1 mL), and add trifluoroacetic acid (0.15 mL) to the reaction mixture. Stir the reaction at room temperature for 1 hour. After completion of the reaction, transfer the reaction mixture to saturated sodium bicarbonate solution, and extract the product with dichloromethane. Combine the organic layers, dry over sodium sulfate and concentrate under reduced pressure to obtain the crude material...

Claims

1. A compound of formula XX, or a pharmaceutically acceptable salt thereof, wherein: R 3 is -C(O)NH2, -C(O)NHR 3A or -C(O)N(R 3A )2; R 6 is hydrogen; R 7 is -NH2 or -NHR 7A ; wherein R 7A is C 1-6 aliphatic; R 3A is the R replaced by q R C instances B ; R B independently C 1-6 aliphatic; a 5- or 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- to 7-membered saturated or partially unsaturated carbocyclic ring; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7- to 12-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R C independently is an oxo group, a 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; Each R is independently hydrogen or an optionally substituted group selected from the following: C 1-6 aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur: wherein each hydrogen bonded to carbon may optionally and independently be replaced by deuterium; and each instance of q and r is independently 0, 1, 2, 3, or 4.

2. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 7 is -NHR 7A .

3. The compound or a pharmaceutically acceptable salt thereof according to claim 2, wherein R 7A is methyl.

4. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein r is 1.

5. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from:

6. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from:

7. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from:

8. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from:

9. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is selected from:

10. A pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9 and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

11. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9 or the pharmaceutical composition according to claim 10, for use as a medicament.

12. Use of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9 or a pharmaceutical composition according to claim 10 for the manufacture of a medicament for inhibiting TYK2 in a biological sample.

13. Use of a pharmaceutical composition according to claim 10 or a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9 for the manufacture of a medicament for treating a TYK2-mediated disorder, disease, or condition in a patient.

14. The use according to claim 13, wherein the disorder is selected from autoimmune disorders, inflammatory disorders, proliferative disorders, endocrine disorders, neurological disorders, or transplantation-related disorders.

15. The use according to claim 13, wherein the disorder is selected from type 1 diabetes, ankylosing spondylitis, cutaneous lupus erythematosus, systemic lupus erythematosus, multiple sclerosis, systemic sclerosis, psoriasis, Crohn's disease, ulcerative colitis, and inflammatory bowel disease.

16. The use according to claim 13, wherein the disorder is psoriasis.

17. The use according to claim 13, wherein the disorder is Crohn's disease.

18. The use according to claim 13, wherein the disorder is ulcerative colitis.

19. The use according to claim 13, wherein the disorder is inflammatory bowel disease.

20. The use according to claim 13, wherein the disorder is cutaneous lupus erythematosus or systemic lupus erythematosus.

21. The use according to claim 13, wherein the disease is associated with one or more activating mutations of TYK2.

22. The use according to claim 13, wherein the disease is associated with type I interferon, IL-10, IL-12 or IL-23 signaling.

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