TYK2 inhibitors and uses thereof

Abstract

To provide a compound, a composition thereof, and methods of using them, for inhibiting TYK2 and for treating a TYK2-mediated disorder.SOLUTION: The pseudokinase binding pocket of TYK2 contains a plurality of hydration sites, and each of these hydration sites is occupied by a single molecule of water. Each of these water molecules has a stability rating associated with it. As used herein, the term "stability rating" refers to a numerical calculation which includes enthalpy value, entropy value, and free energy value associated with each water molecule. This stability rating enables a measurable determination of the relative stability of water molecules that occupy hydration sites in the binding pocket of TYK2.SELECTED DRAWING: None

Description

Technical Field

[0001] Cross - reference to Related Applications 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, each of which is hereby incorporated by reference in its entirety.

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

Background Art

[0003] In recent years, the search for new therapeutic agents has been greatly aided by a more thorough understanding of the structures of disease - related enzymes and other biomolecules. One important class of enzymes that has been the subject of extensive research is the protein kinase family.

[0004] Protein kinases constitute a large family of structurally related enzymes that are responsible for controlling various intracellular signal transduction processes. Protein kinases are thought to have evolved from a common ancestral gene due to the conservation of their structure and catalytic function. Almost all kinases contain a similar catalytic domain of 250 - 300 amino acids. Kinases can be classified into families based on the substrates they phosphorylate (e.g., protein - tyrosine, protein - serine / threonine, lipids, etc.).

[0005] Generally, protein kinases mediate intracellular signal transduction by performing phosphorylation transfer from nucleoside triphosphates to protein acceptors involved in signal transduction pathways. These phosphorylation events act as molecular on / off switches that can modulate or regulate the biological functions of target proteins. These phosphorylation events are ultimately induced in response to various extracellular and other stimuli. Examples of such stimuli include environmental stress signals and chemical stress signals (e.g., osmotic shock, heat shock, ultraviolet irradiation, bacterial endotoxin, and H2O2), cytokines (e.g., interleukin-1 (IL-1), interleukin-8 (IL-8), and tumor necrosis factor α (TNF-α)), and growth factors (e.g., granulocyte macrophage-colony stimulating factor (GM-CSF) and fibroblast growth factor (FGF)). Extracellular stimuli can affect one or more cellular responses related to cell proliferation, migration, differentiation, hormone secretion, activation of transcription factors, muscle contraction, glucose metabolism, regulation of protein synthesis, and regulation of the cell cycle.

[0006] Many diseases are associated with abnormal cellular responses induced by kinase-mediated events. These diseases include, but are not limited to, autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer's disease, and hormone-related diseases. Therefore, there remains a need to find protein kinase inhibitors useful as therapeutic agents. SUMMARY OF THE INVENTION MEANS FOR SOLVING THE PROBLEM

[0007] GIST OF THE INVENTION It has now been found that the compounds of the present invention and their pharmaceutically acceptable compositions are effective as inhibitors of TYK2 kinase.

[0008] The compounds of the present invention and their pharmaceutically acceptable compositions are useful for treating 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.

[0009] The compounds provided by the present invention are also useful for the study of the TYK2 enzyme in biological and pathological phenomena; the study of intracellular signal transduction pathways occurring in body tissues; and the in vitro or in vivo comparative evaluation of new TYK2 inhibitors or other regulators of kinases, signal transduction pathways, and cytokine levels. In embodiments of the present invention, for example, the following items are provided. (Item 1) Formula I: [Chemical formula] A compound of, or a pharmaceutically acceptable salt thereof, wherein 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- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, said ring being substituted with m examples of R 3B , R 5 is hydrogen or -L 1 -R 5A , R 6 is hydrogen, R A , or R B , or R 5 and R 6 together with the atoms between them form a 4- to 7-membered partially unsaturated or heteroaryl ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, said ring being substituted with R 5A or n examples of R C , R 7 is hydrogen, halogen, -NH2, -NHR 7A , or -NHC(O)R 7A and either R 6 and R 7 together with the atoms between them form a 4- to 7-membered partially unsaturated or heteroaryl ring having from 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, said ring being substituted by p instances of R C ; L 1 is a covalent bond or a divalent saturated or unsaturated straight-chain or branched hydrocarbon chain of C 1~4 , where one or two methylene units of said chain are optionally 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-; R 3A , R 3B , and R 7A are each independently R B and are each substituted by q instances of R C ; 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 from 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R C substituents on adjacent carbons optionally together form a 3- to 6-membered saturated or partially unsaturated fused heterocyclic ring having from 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R 5A , and R 5B is independently either R A or R B and is each substituted by r instances of R C ; R A Each instance of R is, independently, oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, or -N(R)S(O)2R, and R B each instance of R is, independently, C 1~6 a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from carbon, phenyl, 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, and R C each instance of R is, independently, oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, or -N(R)S(O)2R, or C 1~6A group selected from a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which is an optionally substituted group, and two optional substituents on the same carbon may, optionally, together form a 3- to 6-membered saturated or partially unsaturated spiro-fused heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two optional substituents on adjacent carbons may, optionally, together form a 3- to 6-membered saturated or partially unsaturated fused heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, Each R is independently hydrogen or C 1~6 A group selected from a 3- to 7-membered saturated or partially unsaturated heterocycle having 1 to 2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which is an optionally substituted group, or: Two R groups on the same nitrogen, together with the atom between them, form, in addition to said nitrogen, a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, Each hydrogen bonded to carbon may optionally be independently replaced by deuterium, Each of m, n, p, q, and r is independently 0, 1, 2, 3, or 4, Provided that the compound is [Chemical formula] none of). (Item 2) Formula II or III: [Chemical formula] The compound according to item 1 of the above, or a pharmaceutically acceptable salt thereof. (Item 3) Formula V or VI: [Chemical formula] The compound according to any one of Items 1 or 2 thereof, or a pharmaceutically acceptable salt thereof. (Item 4) Formula V-a or VI-a: [Chemical formula] The compound according to any one of Items 1 to 3 thereof, or a pharmaceutically acceptable salt thereof. (Item 5) R 7 is -NH2 or -NHR 7A The compound according to any one of Items 1 to 4 thereof, or a pharmaceutically acceptable salt thereof. (Item 6) Formula V-c or VI-c: [Chemical formula] The compound according to any one of Items 1 to 5 of one of them, or a pharmaceutically acceptable salt thereof. (Item 7) R 3A and R 7A are each independently R B and are substituted by q examples of R C provided that R 3A and R 7A are not phenyl, the compound according to any one of Items 1 to 6. (Item 8) R 7A is C 1~6 aliphatic, the compound according to any one of Items 1 to 7. (Item 9) R 7A is methyl, the compound according to any one of Items 1 to 8. (Item 10) Selected from one of those shown in Table 1 of this specification, the compound according to any one of Items 1 to 9, or a pharmaceutically acceptable salt thereof. (Item 11) A pharmaceutical composition comprising a compound according to any one of items 1 to 10 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle. (Item 12) A compound according to any one of items 1 to 10 or the pharmaceutical composition according to item 11 for use as a medicine. (Item 13) A method for inhibiting TYK2 in a biological sample, the method comprising contacting the sample with a compound according to any one of items 1 to 10, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to item 11. (Item 14) A method for treating a TYK2-mediated disorder, disease or condition in a patient, the method comprising administering to the patient the pharmaceutical composition according to item 11 or a compound according to any one of items 1 to 10, or a pharmaceutically acceptable salt thereof. (Item 15) The method according to item 14, wherein the disorder is selected from an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a disorder related to transplantation. (Item 16) The method according to item 15, wherein the disorder is an autoimmune disorder. (Item 17) The method according to item 16, wherein the autoimmune disorder is selected from type 1 diabetes, ankylosing spondylitis, cutaneous lupus erythematosus, systemic lupus erythematosus, multiple sclerosis, systemic sclerosis, psoriasis, Crohn's disease, ulcerative colitis, and inflammatory bowel disease. (Item 18) The method according to item 15, wherein the disorder is an inflammatory disorder. (Item 19) The method according to item 18, wherein the inflammatory disorder is selected from rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis, Crohn's disease, ulcerative colitis, and inflammatory bowel disease. (Item 20) The method according to item 15, wherein the disorder is a proliferative disorder. (Item 21) The method according to item 20, wherein the proliferative disorder is a hematological cancer. (Item 22) The method according to item 20, wherein the proliferative disorder is leukemia. (Item 23) The method according to item 22, wherein the leukemia is T-cell leukemia. (Item 24) The method according to item 23, wherein the T-cell leukemia is T-cell acute lymphoblastic leukemia (T-ALL). (Item 25) The method according to item 20, wherein the proliferative disorder is related to one or more activating mutations in TYK2. (Item 26) The method according to item 15, wherein the disorder is related to transplantation. (Item 27) The method according to item 26, wherein the disorder is transplant rejection or graft-versus-host disease. (Item 28) The method according to item 15, wherein the disorder is an endocrine disorder. (Item 29) The method according to item 28, wherein the endocrine disorder is polycystic ovary syndrome, Cushing's syndrome, or type 1 diabetes. (Item 30) The method according to item 15, wherein the disorder is a neurological disorder. (Item 31) The method according to item 30, wherein the neurological disorder is Alzheimer's disease. (Item 32) The method according to item 14, wherein the disorder is related to type I interferon, IL-10, IL-12, or IL-23 signaling.

Mode for Carrying Out the Invention

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

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

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

[0013] While not wishing to be bound by any particular theory, it is believed that the movement or disruption of unstable water molecules (i.e., water molecules having a stability rating greater than 2.5 kcal / mol) or the replacement of stable water (i.e., water molecules having a stability rating of less than 1 kcal / mol) by an inhibitor results in a stronger binding of this inhibitor. Thus, inhibitors designed to move one or more unstable water molecules (i.e., unstable water molecules that cannot be moved by any known inhibitor) are stronger binders and thus more potent inhibitors compared to inhibitors that do not move unstable water molecules.

[0014] Surprisingly, the provided compounds have been found to move or disrupt one or more unstable water molecules. In some embodiments, the provided compounds move or disrupt at least two unstable water molecules.

[0015] In certain embodiments, the invention provides a compound of formula I:

Chemical formula

[0016] In some embodiments, the invention provides a pharmaceutical composition comprising a compound of Formula I and a pharmaceutically acceptable carrier, adjuvant, or diluent.

[0017] In some embodiments, the 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.

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

[0019] As used herein, the term "aliphatic" or "aliphatic group" means a straight-chain (i.e., unbranched) or branched-chain, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more unsaturated units, or a monocyclic or bicyclic hydrocarbon that is fully saturated or contains one or more unsaturated units but is not aromatic (also referred to herein as "carbocyclic", "alicyclic" or "cycloalkyl") and has one point of attachment to the remainder of the molecule. Unless otherwise specified, an aliphatic group contains from 1 to 6 aliphatic carbon atoms. In some embodiments, the aliphatic group contains from 1 to 5 aliphatic carbon atoms. In other embodiments, the aliphatic group contains from 1 to 4 aliphatic carbon atoms. In still other embodiments, the aliphatic group contains from 1 to 3 aliphatic carbon atoms, and in still other embodiments, the aliphatic group contains from 1 to 2 aliphatic carbon atoms. In some embodiments, "alicyclic" (or "carbocyclic" or "cycloalkyl") means a monocyclic C3-C6 hydrocarbon that is fully saturated or contains one or more unsaturated units but is not aromatic and has one point of attachment to the remainder of the molecule. Suitable aliphatic groups include, but are not limited to, straight-chain or branched-chain, saturated or unsaturated, alkyl groups, alkenyl groups, alkynyl groups and hybrids thereof (e.g., (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl).

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

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

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

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

[0024] The term "unsaturated", as used herein, means a moiety having one or more unsaturated units.

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

[0026] The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH2) n -, where n is a positive integer, preferably 1 to 6, 1 to 4, 1 to 3, 1 to 2, or 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogens are replaced by substituents. Suitable substituents include those described below for substituted aliphatic groups.

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

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

[0029] The term "aryl", used alone or as part of a larger moiety such as in "aralkyl", "aralkoxy" or "aryloxyalkyl", refers to a monocyclic or bicyclic ring system having a total of 5 to 14 ring members, at least one ring in the system being aromatic and each ring in the system containing 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, examples of which include, but are not limited to, phenyl, biphenyl, naphthyl, and anthracyl, which may have one or more substituents. When the term "term" is used herein, and what is included within its scope are groups in which an aromatic ring is fused to one or more non-aromatic rings (e.g., indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, etc.).

[0030] As used alone or as part of a larger moiety (e.g., "heteroalkyl" or "heteroalkoxy"), the terms "heteroaryl" and "heteroar-" refer to a group having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 π electrons shared in a cyclic arrangement; and having 1 to 5 heteroatoms in addition to carbon atoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of basic nitrogen. Heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms "heteroaryl" and "heteroar-" also, as used herein, include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclic rings, and the radical or point of attachment thereof is, unless otherwise specified, on the heteroaromatic ring or on one of the rings to which the heteroaromatic ring is fused. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl. Heteroaryl groups may be monocyclic or bicyclic. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring", "heteroaryl group" or "heteroaromatic", and any of these terms includes rings that are optionally substituted. The term "heteroalkyl" refers to an alkyl group substituted by heteroaryl, where the alkyl portion and the heteroaryl portion are each independently optionally substituted.

[0031] As used herein, the terms "heterocyclic ring", "heterocyclyl", "heterocyclic radical", and "heterocyclic ring" are used interchangeably and are stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moieties that are either saturated or partially unsaturated and that, in addition to carbon atoms, have one or more, preferably one to four, heteroatoms as defined above. When used with respect to the ring atoms of a heterocyclic ring, the term "nitrogen" includes substituted nitrogen. By way of example, in a saturated or partially unsaturated ring having from 0 to 3 heteroatoms selected from oxygen, sulfur or nitrogen, this nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), + NR (as in N-substituted pyrrolidinyl).

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

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

[0034] As described herein, the compounds of the present invention may contain "optionally substituted" moieties. In general, the term "substituted" means that one or more hydrogens of the designated moiety are replaced with a suitable substituent, whether or not the term "optionally" precedes. Unless otherwise indicated, an "optionally substituted" group may have suitable substituents at each substitutable portion of the group, and if more than one position in any given structure may be substituted with more than one substituent selected from a particular group, the substituents may be the same or different at each position. Combinations of substituents envisioned by the present invention are preferably combinations that result in the formation of stable compounds or chemically possible compounds. The term "stable" as used herein refers to compounds that do not substantially change when subjected to the conditions for their generation, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0035] Suitable monovalent substituents on a substitutable carbon atom of an "optionally substituted" group are, independently, halogen; -(CH2) 0~4 R ○ ; -(CH2) 0~4 OR ○ ; -O(CH2) 0~4 R ○ , -O-(CH2) 0~4 C(O)OR ○ ; -(CH2) 0~4 CH(OR ○ )2; -(CH2) 0~4 SR ○ ; -(CH2) 0~4 Ph (which may be substituted with R ○ ); -(CH2) 0~4 O(CH2) 0~1 Ph (which may be substituted with R ○ ); -CH=CHPh (which may be substituted with R ○ ); -(CH2) 0~4 O(CH2) 0~1 -pyridyl (which may be substituted with R ○which may be replaced by); -NO2; -CN; -N3; -(CH2) 0~4 N(R ○ )2; -(CH2) 0~4 N(R ○ )C(O)R ○ ; -N(R ○ )C(S)R ○ ; -(CH2) 0~4 N(R ○ )C(O)NR ○ 2; -N(R ○ )C(S)NR ○ 2; -(CH2) 0~4 N(R ○ )C(O)OR ○ ; -N(R ○ )N(R ○ )C(O)R ○ ; -N(R ○ )N(R ○ )C(O)NR ○ 2; -N(R ○ )N(R ○ )C(O)OR ○ ; -N(R ○ )C(NR ○ )N(R ○ )2; -(CH2) 0~4 C(O)R ○ ; -C(S)R ○ ; -(CH2) 0~4 C(O)OR ○ ; -(CH2) 0~4 C(O)SR ○ ; -(CH2) 0~4 C(O)OSiR ○ 3; -(CH2) 0~4 OC(O)R ○ ; -OC(O)(CH2) 0~4 SR ○ ; -SC(S)SR ○ ; -(CH2) 0~4 SC(O)R ○ ; -(CH2) 0~4 C(O)NR ○ 2; -C(S)NR ○ 2; -C(S)SR ○ ; -SC(S)SR ○ , -(CH2) 0~4 OC(O)NR ○ 2; -C(O)N(OR○ )R ○ ;-C(O)C(O)R ○ ;-C(O)CH2C(O)R ○ ;-C(NOR ○ )R ○ ;-(CH2) 0~4 SSR ○ ;-(CH2) 0~4 S(O)2R ○ ;-(CH2) 0~4 S(O)2OR ○ ;-(CH2) 0~4 OS(O)2R ○ ;-S(O)2NR ○ 2;-(CH2) 0~4 S(O)R ○ ;-N(R ○ )S(O)2NR ○ 2;-N(R ○ )S(O)2R ○ ;-N(OR ○ )R ○ ;-C(NH)NR ○ 2;-P(O)2R ○ ;-P(O)R ○ 2;-OP(O)R ○ 2;-OP(O)(OR ○ )2;-SiR ○ 3;-(C 1~4 of a straight-chain or branched-chain alkylene)O-N(R ○ )2; or -(C 1~4 of a straight-chain or branched-chain alkylene)C(O)O-N(R ○ )2, where each R ○ may be substituted as defined below and is independently hydrogen, C 1~6 aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, -CH2-(5- to 6-membered heteroaryl ring), or independently a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms selected from nitrogen, oxygen, or sulfur, or regardless of the above definition, R ○Two independent entities, together with the atom(s) between them, form a 3- to 12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having from 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0036] R ○ (R ○ The suitable monovalent substituents on the ring) formed by the two independent entities coming together with the atom between them are independently halogen, -(CH2) 0~2 R ● ,-(haloR ● ),-(CH2) 0~2 OH,-(CH2) 0~2 OR ● ,-(CH2) 0~2 CH(OR ● )2;-O(haloR ● ),-CN,-N3,-(CH2) 0~2 C(O)R ● ,-(CH2) 0~2 C(O)OH,-(CH2) 0~2 C(O)OR ● ,-(CH2) 0~2 SR ● ,-(CH2) 0~2 SH,-(CH2) 0~2 NH2,-(CH2) 0~2 NHR ● ,-(CH2) 0~2 NR ● 2,-NO2,-SiR ● 3,-OSiR ● 3,-C(O)SR ● ,-(C 1~4 The linear or branched alkylene of)C(O)OR ● or-SSR ● where each R ● is unsubstituted or, when preceded by "halo", is substituted by only one or more halogens, and independently, C 1~4 aliphatic,-CH2Ph,-O(CH2) 0~1Ph, or is independently selected from a 5- to 6-membered saturated ring, partially unsaturated ring, or aryl ring having 0 to 4 heteroatoms selected from nitrogen, oxygen, or sulfur. R ○ Suitable divalent substituents on the saturated carbon atoms of R include =O and =S.

[0037] Suitable divalent substituents on the saturated carbon atoms of a "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-. Here, each independent occurrence of R * is hydrogen, C 1~6 aliphatic which may be substituted as defined below, or is independently selected from an unsubstituted 5- to 6-membered saturated ring, partially unsaturated ring, or aryl ring having 0 to 4 heteroatoms selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents bonded to the vicinal substitutable carbons of a "optionally substituted" group include -O(CR * 2) 2~3 O-, where each independent occurrence of R * is hydrogen, C 1~6 aliphatic which may be substituted as defined below, or is independently selected from an unsubstituted 5- to 6-membered saturated ring, partially unsaturated ring, or aryl ring having 0 to 4 heteroatoms selected from nitrogen, oxygen, or sulfur.

[0038] R * Suitable substituents on the aliphatic group of R include halogen, -R ● , -(haloR ● ), -OH, -OR ● , -O(haloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR● 、 -NR ● 2, or -NO2, and each R ● is unsubstituted or, when preceded by "halo", is substituted with only one or more halogens, and independently, C 1~4 aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, or independently a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms selected from nitrogen, oxygen, or sulfur.

[0039] Suitable substituents on the nitrogen of the "optionally substituted" group include -R † , -NR[[ID=1\6]] † 2, -C(O)R † , -C(O)OR † , -C(O)C(O)R † , -C(O)CH2C(O)R † , -S(O)2R † , -S(O)2NR † 2, -C(S)NR † 2, -C(NH)NR † 2, or -N(R † )S(O)2R † are included; where each R † is independently hydrogen, C 1~6 aliphatic which may be substituted as defined below, unsubstituted -OPh, or independently an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms selected from nitrogen, oxygen, or sulfur, or regardless of the above definition, two independent occurrences of R † together with the atom(s) between them form, independently, an unsubstituted 3- to 12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0 to 4 heteroatoms selected from nitrogen, oxygen, or sulfur.

[0040] R † Suitable substituents on the aliphatic group of R are independently halogen, -R ● , -(haloR ● ), -OH, -OR● , -O(halo R ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2, or -NO2, where each R ● is unsubstituted or, when "halo" precedes, substituted with only one or more halogens, and independently, C 1~4 aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, or independently a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms selected from nitrogen, oxygen, or sulfur.

[0041] As used herein, the term "pharmaceutically acceptable salts" refers to salts that, within the scope of sound medical judgment, are free of excessive toxicity, irritation, allergic response, etc., are suitable for use in contact with the tissues of humans and lower animals, and exhibit 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 J. Pharmaceutical Sciences, 1977, Vol. 66, pp. 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, non-toxic acid addition salts are salts of amino groups formed by using inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods commonly used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like.

[0042] Salts derived from suitable bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N+ (C 1~4 alkyl)4 salts are mentioned. Representative alkali metal salts or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium, etc. Further pharmaceutically acceptable salts, when appropriate, are formed using counterions such as halide ions, hydroxide ions, carbonate ions, sulfate ions, phosphate ions, nitrate ions, lower alkyl sulfonate ions and aryl sulfonate ions, and include non-toxic ammonium, quaternary ammonium, and amine cations.

[0043] Unless otherwise stated, the structures illustrated in this specification also mean that they include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure, e.g., the R configuration and S configuration for each chiral center, Z and E double bond isomers, as well as Z and E conformational isomers. Thus, single stereochemical isomers of the compounds of the present invention, as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures are within the scope of the present invention. Unless otherwise stated, all tautomeric forms of the compounds of the present invention are within the scope of the present invention. Further, unless otherwise stated, the structures illustrated in this specification also mean that they include compounds that differ only in the presence of one or more isotope-enriched atoms. For example, the structures of the present invention in which hydrogen is replaced by deuterium or tritium, or compounds having the present invention in which carbon is replaced by 13 C or 14 C-enriched carbon are within the scope of the present invention. Such compounds are useful, for example, as analytical tools according to the present invention, as probes in biological assays, or as therapeutic agents. In certain embodiments, the warhead moiety R 1 of a given compound contains one or more deuterium atoms. In certain embodiments, ring B of the provided compound may be substituted with one or more deuterium atoms.

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

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

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

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

[0048] As used herein, the terms "fluorescent label", "fluorescent dye" and "fluorophore" refer to a moiety that absorbs light energy at a defined excitation wavelength and emits light energy at a different wavelength. Examples of fluorescent labels include, 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, IRDyes (IRD40, IRD700, IRD800), JOE, lysamine rhodamine B, marina blue, methoxycoumarin, naphthofluorescein, Oregon Green 488, Oregon Green 500, Oregon Green 514, Pacific Blue, PyMPO, pyrene, rhodamine B, rhodamine 6G, rhodamine green, rhodamine red, rhodol green, 2',4',5',7'-tetra-bromo-sulfone-fluorescein, tetramethyl-rhodamine (TMR), carboxytetramethylrhodamine (TAMRA), Texas Red, Texas Red-X.

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

[0050] As used herein, the terms "measurable affinity" and "measurably inhibits" mean a measurable change in TYK2 protein kinase activity between a sample containing a compound or composition of the invention and TYK2 protein kinase, and an equivalent sample containing TYK2 protein kinase in the absence of the compound or composition. 3. Description of Exemplary Embodiments:

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

Chemical formula

Chemical formula

[0052] 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, said ring being 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, said ring being 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.

[0053] 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, said ring being substituted with m instances of R 3B 1]]

[0054] 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.

[0055] In some embodiments, R 3 is as follows:

Chemical formula

[0056] In some embodiments, R 3 is as follows:

Chemical formula

[0057] In some embodiments, R 3 is as follows:

Chemical formula

Chemical formula

[0058] In some embodiments, R 3 is as follows:

Chemical formula

[0059] In some embodiments, R 3 is selected from those shown in Table 1 below.

[0060] As generally defined above, R 5 is hydrogen or -L 1 -R 5A ; or R 5 and R 6 together with the atoms between them form a 4- to 7-membered partially unsaturated or heteroaryl ring having from 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, said ring being substituted by R 5A and n instances of R C . In some embodiments, R 5 is hydrogen. In some embodiments, R 5 is -L 1 -R 5A .

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

[0062] In some embodiments, R 5 is as follows:

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chem.

Chem.

Chem.

Chem.

[0063] In some embodiments, R 5 is as follows:

Chem.

Chem.

[0064] In some embodiments, R 5 is

Chem.

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

[0066] As generally defined above, R 6 is hydrogen, R A , or R B , or R 5 and R 6 together with the atoms therebetween form a 4- to 7-membered partially unsaturated or heteroaryl ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, said ring being substituted by R 5A and n instances of R C . In some embodiments, R 6 is hydrogen.

[0067] In some embodiments, R 6 is R A In some embodiments, R 6 is R B In some embodiments, R 5 and R 6 together with the atoms therebetween form a 4- to 7-membered partially unsaturated or heteroaryl ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and said ring is substituted by R 5A and n instances of R C In some embodiments, R 6 is hydrogen, R A or R B

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

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

[0070] 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 atoms therebetween form a 4- to 7-membered partially unsaturated or heteroaryl ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and said ring is substituted by p instances of R C In some embodiments, R 7 is -NH2 or -NHR 7A In some embodiments, R 7 is -NHMe. In some embodiments, R 7 is -NHCD3.

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

[0072] In some embodiments, R 7 is as follows:

Chemical formula

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

[0074] As generally defined above, L 1 is a covalent bond, or a divalent saturated or unsaturated straight-chain or branched hydrocarbon chain of C 1~4 , where one or two methylene units of this chain are optionally 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)-.

[0075] In some embodiments, L 1is a covalent bond. In some embodiments, L 1 is a divalent saturated or unsaturated straight-chain or branched hydrocarbon chain of C 1~4 , where one or two methylene units of this chain are -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- and are independently replaced as needed.

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

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

[0078] As generally defined above, R 3A is R B , and is substituted by q examples of R C [[ID= thirty-two ]], and 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 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. In some embodiments, R 3A is C C substituted by q examples of R 1~6 and is aliphatic. In some embodiments, R 3A is a 3- to 7-membered saturated or partially unsaturated carbocyclic ring substituted by q examples of R C . In some embodiments, R 3Ais cyclopropyl or cyclobutyl; each of which is substituted by q instances of R C In some embodiments, R 3A is cyclopropyl substituted by q instances of R C In some embodiments, R 3A is cyclobutyl substituted by q instances of R C In some embodiments, R 3A is R B and is substituted by q instances of R C provided that R 3A is not phenyl.

[0079] In some embodiments, R 3A is R B and is substituted by q instances of R C such that 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 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.

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

[0081] In some embodiments, R 3A is as follows:

Chemical formula

[0082] In some embodiments, R 3Ais selected from those shown in Table 1 below.

[0083] As generally defined above, R 3B is R B and is substituted by q examples of R C and two R C substituents on the same carbon, together if necessary, form a 3- to 6-membered saturated or partially unsaturated spiro-fused heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R C substituents on adjacent carbons, together if necessary, 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. In some embodiments, R 3B is C C substituted by q examples of R 1~6 and is aliphatic. In some embodiments, R 3B is a 3- to 7-membered saturated or partially unsaturated carbocyclic ring substituted by q examples of R C . In some embodiments, R 3B is cyclopropyl or cyclobutyl; each is substituted by q examples of R C . In some embodiments, R 3B is cyclopropyl substituted by q examples of R C . In some embodiments, R 3B is cyclobutyl substituted by q examples of R C . In some embodiments, R 3B is R B and is substituted by q examples of R C , provided that R 3B is not phenyl.

[0084] In some embodiments, R 3B is R B and is substituted by q examples of R C and two R CThe substituent, optionally together, forms a 3- to 6-membered saturated or partially unsaturated spiro-fused heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two Rs on adjacent carbons C The substituent, optionally together, forms a 3- to 6-membered saturated or partially unsaturated fused heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0085] In some embodiments, R 3B is an aliphatic substituted by q examples of R C or a 3- to 7-membered saturated or partially unsaturated carbocyclic ring substituted by q examples of R 1~6 C

[0086] In some embodiments, R 3B is as follows:

Chemical formula

[0087] In some embodiments, R 3B is selected from those shown in Table 1 below.

[0088] As generally shown above, R 5A is R A or R B and is substituted by r examples of R C . In some embodiments, R 5A is phenyl or a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and is substituted by r examples of R C .

[0089] In some embodiments, R 5A is R C substituted by r examples of R A . In some embodiments, R 5A is r examples of R​​C R substituted by B is.

[0090] In some embodiments, R 5A is as follows:

Chemical formula

[0091] In some embodiments, R 5A is selected from those shown in Table 1 below.

[0092] As generally defined above, R 7A is R B and is substituted by q examples of R C . In some embodiments, R 7A is C C substituted by q examples of R 1~6 and is aliphatic. In some embodiments, R 7A is methyl. In some embodiments, R 7A is R B and is substituted by q examples of R C , provided that R 7A is not aromatic. In some embodiments, R 7A is R B and is substituted by q examples of R C , provided that R 7A is not phenyl.

[0093] In some embodiments, R 7A is R B and is substituted by q examples of R C .

[0094] In some embodiments, R 7A is hydrogen. In some embodiments, R 7A is methyl.

[0095] In some embodiments, R 7A is as follows:

Chem.

[0096] In some embodiments, R 7A is selected from those shown in Table 1 below.

[0097] As generally defined above, each instance of R A is independently oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, or -N(R)S(O)2R.

[0098] In some embodiments, R A is oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, or -N(R)S(O)2R.

[0099] In some embodiments, R A is selected from those shown in Table 1 below.

[0100] As generally defined above, each instance of R B is independently C 1~6Aliphatic; phenyl; a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated carbocyclic ring; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7- to 12-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0101] In some embodiments, R B is C 1~6 Aliphatic; phenyl; a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 7-membered saturated or partially unsaturated carbocyclic ring; a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7- to 12-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0102] In some embodiments, R B is methyl.

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

[0104] As generally defined above, R CEach example of is, independently, oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, or -N(R)S(O)2R, or C 1~6 A group, optionally substituted, selected from a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein two optional substituents on the same carbon, optionally together, form a 3- to 6-membered saturated or partially unsaturated spiro-fused heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two 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.

[0105] In some embodiments, R C is, independently, oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, or -N(R)S(O)2R, or C 1~6A group selected from a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which is an optionally substituted group, and two optional substituents on the same carbon may optionally combine together to form a 3- to 6-membered saturated or partially unsaturated spiro-fused heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two optional substituents on adjacent carbons may optionally combine together to form a 3- to 6-membered saturated or partially unsaturated fused heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0106] In some embodiments, R C is oxo. In some embodiments, R C is methyl, ethyl, isopropyl, or n-butyl. In some embodiments, R C is fluoro. In some embodiments, R C is chloro. In some embodiments, R C is phenyl.

[0107] In some embodiments, R C is as follows:

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0108] In some embodiments, R C is as follows:

Chemical formula

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

[0110] As generally defined above, each R is independently hydrogen or a group selected from C 1~6 a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which is an optionally substituted group, or: two R groups on the same nitrogen, together with the atoms between them, form, in addition to that nitrogen, a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur

[0111] In some embodiments, R is hydrogen. In some embodiments, R is a group selected from a 3- to 7-membered saturated or partially unsaturated heterocycle having 1 to 2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which is an optionally substituted group. In some embodiments, two R groups on the same nitrogen, together with the atoms between them, form, in addition to that nitrogen, a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur 1~6 In some embodiments, R is selected from those shown in Table 1 below

[0112] In some embodiments, R is selected from those shown in Table 1 below

[0113] As generally defined above, each hydrogen bonded to carbon can be independently replaced by deuterium as needed

[0114] In some embodiments, the hydrogen bonded to carbon is replaced by deuterium.

[0115] 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.

[0116] 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.

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

[0118] 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.

[0119] 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.

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

[0121] 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.

[0122] 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.

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

[0124] 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.

[0125] 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.

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

[0127] 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.

[0128] 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.

[0129] In some embodiments, r is selected from those shown in Table 1 below.

[0130] In some embodiments, the invention is a compound of formula I, wherein R 3 is -C(O)NH2 or -C(O)NHR 3A and thereby forms a compound of formula II or III:

Chemical formula

[0131] In some embodiments, the invention is a compound of formula I, wherein L 1 is -N(R)- and thereby forms a compound of formula IV: [Chemical formula] A compound, or a pharmaceutically acceptable salt thereof, that forms the compound of (wherein R 3 , R 5A , R 6 , and R 7 are each, both alone and in combination, as defined above and as described in the embodiments herein) is provided.

[0132] In some embodiments, the present invention is a compound of formula II or III, wherein L 1 is -N(R)-, thereby forming formula V or VI: [Chemical formula] A compound, or a pharmaceutically acceptable salt thereof, that forms the compound of (wherein R, R 3A , R 5A , R 6 , and R 7 are each, both alone and in combination, as defined above and as described in the embodiments herein) is provided.

[0133] In some embodiments, the present invention is a compound of formula IV, wherein R 5A is phenyl or pyridin-3-yl each substituted by r examples of R C , thereby forming formula VII or VIII: [Chemical formula] A compound, or a pharmaceutically acceptable salt thereof, that forms the compound of (wherein r, R, R C , R 3 , R 6 , and R 7 are each, both alone and in combination, as defined above and as described in the embodiments herein) is provided.

[0134] In some embodiments, the invention is a compound of formula VIII, wherein R 5A for one of the above examples of R C is oxo, whereby formula IX:

Chemical formula

[0135] In some embodiments, the invention is a compound of formula IV, V, VI, VII, VIII, or IX, wherein R is hydrogen, whereby formula X, XI, XII, XIII, XIV, XV:

Chemical formula

[0136] In some embodiments, the invention is a compound of formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, or XV, wherein R 6 is hydrogen, whereby 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:

Chemical formula

[0137] In some embodiments, the present invention is 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, wherein R 7 is -NH2 or -NHR 7A and provides a compound.

[0138] In some embodiments, the present invention is 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, wherein R 7 is -NHR 7A and thereby 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:

Chemical formula

Chemical formula

[0139] In some embodiments, the present invention provides 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, wherein R 7A is R C substituted by q instances of R B , and R 7A is not phenyl. In some embodiments, the present invention provides 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, wherein R 7A is methyl. In some embodiments, the present invention provides 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, wherein R 7AProvided is a compound which is -CD3.

[0140] 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 by q instances of R C with the proviso that R 3A is not phenyl.

[0141] 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 R 7A are each R B and are substituted by q instances of R C with the proviso that neither R 3A nor R 7A is phenyl.

[0142] In some embodiments, the present invention provides a compound of formula IV, wherein R 5A is pyridin-2-yl substituted by r instances of R C thereby forming a compound of formula XVI:

Chemical formula

[0143] In some embodiments, the invention provides a compound of formula I, wherein R 5 is -L 1 -R 5A wherein 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. In some embodiments, the invention provides a compound of formula I, wherein R 5 is -L 1 -R 5A wherein 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.

[0144] In some embodiments, the invention provides a compound of formula I, wherein R 5 is -L 1 -R 5A wherein L 1 is a covalent bond and R 5A is indol-1-yl, indol-3-yl, 4-azaindol-1-yl, 7-azaindol-3-yl, or 7-azaindazol-3-yl, and each R 5A is substituted by r examples of R C thereby providing a compound of formula XVII, XVIII, XIX, XX, or XXI:

Chemical formula

[0145] In some embodiments, the invention is a compound of formula XVII, XVIII, XIX, XX, or XXI, wherein R 6 is hydrogen, whereby formula XVII-a, XVIII-a, XIX-a, XX-a, or XXI-a:

Chemical formula

[0146] In some embodiments, the invention is a compound of formula XVII-a, XVIII-a, XIX-a, XX-a, or XXI-a, wherein R 7 is -NHR 7A and whereby formula XVII-b, XVIII-b, XIX-b, XX-b, or XXI-b:

Chemical formula

Chemical formula

[0147] In some embodiments, the invention is a compound of formula XVII-b, XVIII-b, XIX-b, XX-b, or XXI-b, wherein R3 is - C(O)NHR 3A and thereby provides a compound of formula XVII - c, XVIII - c, XIX - c, XX - c, or XXI - c:

Chemical formula

[0148] Exemplary compounds of the present invention are described in Table 1 below.

Table 1 - 1

Table 1 - 2

Table 1 - 3

Table 1 - 4

Table 1 - 5

Table 1 - 6

Table 1 - 7

Table 1 - 8

Table 1 - 9

Table 1 - 10

Table 1 - 11

[0149] In some embodiments, the method uses the compounds described in Table 1 above, or pharmaceutically acceptable salts thereof. In some embodiments, the present invention provides the compounds described in Table 1 above, or pharmaceutically acceptable salts thereof. In some embodiments, the present invention provides a pharmaceutical composition comprising the compounds described in Table 1 above, or pharmaceutically acceptable salts thereof, together with a pharmaceutically acceptable carrier, excipient, or diluent.

[0150] In some embodiments, the present invention provides a compound of formula I as defined above, which is designated as "A" when described in Table 2. In some embodiments, the present invention provides a compound of formula I as defined above, which is designated as "B" when described in Table 2. In some embodiments, the present invention provides a compound of formula I as defined above, which is designated as "C" when described in Table 2. In some embodiments, the present invention provides a compound of formula I as defined above, which is designated as "D" when described in Table 2. In some embodiments, the present invention provides a compound of formula I as defined above, which is designated as "A" or "B" when described in Table 2. In some embodiments, the present invention provides a compound of formula I as defined above, which is designated as "A" or "B" or "C" when described in Table 2. In some embodiments, the present invention provides a compound of formula I as defined above, which is designated as "A" or "B" or "C" or "D" when described in Table 2.

[0151] In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula I as defined above or a pharmaceutically acceptable salt thereof, or a compound of formula I as defined above or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle for use as a medicament.

[0152] While not wishing to be bound by any particular theory, the proximity of the inhibitor compound, or a pendant portion of the inhibitor compound, to the water of interest is thought to facilitate replacement or interference with this water by the inhibitor compound or a pendant portion of the inhibitor compound. In some embodiments, the water molecule replaced or interfered with by the inhibitor compound or a pendant portion of the inhibitor compound is a labile water molecule.

[0153] In certain embodiments, the method uses a complex comprising TYK2 and an inhibitor, wherein at least one labile water of TYK2 is replaced or interfered with by the inhibitor. In some embodiments, at least two selected labile waters are replaced or interfered with by the inhibitor. 4. General methods for providing the compounds

[0154] The compounds of the present invention can generally be prepared or isolated by synthetic and / or semi-synthetic methods known to those skilled in the art for similar compounds, as well as by the methods described in detail in the examples herein. 5. Use, formulation and administration Pharmaceutically acceptable compositions

[0155] According to another embodiment, the present invention provides a composition comprising a compound of the present invention, or a pharmaceutically acceptable derivative and a pharmaceutically acceptable carrier, adjuvant, or vehicle thereof. The amount of the compound in the composition of the present invention is an amount effective to measurably inhibit TYK2 protein kinase or a variant thereof in a biological sample or in a patient. In certain embodiments, the amount of the compound in the composition of the present invention is an amount effective to measurably inhibit TYK2 protein kinase or a variant thereof in a biological sample or in a patient. In certain embodiments, the composition of the present invention is formulated for administration to a patient in need of such a composition. In some embodiments, the composition of the present invention is formulated for oral administration to a patient.

[0156] As used herein, the term "patient" means an animal, preferably a mammal, most preferably a human.

[0157] The term "pharmaceutically acceptable carrier, adjuvant, or vehicle" refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound formulated therewith. Pharmaceutically acceptable carriers, adjuvants or vehicles that can be used in the compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated plant fatty acids, water, electrolytes such as salts or protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and lanolin.

[0158] "Pharmaceutically acceptable derivative" means any non-toxic salt, ester, salt of an ester or other derivative of a compound of this invention that can directly or indirectly provide the compound of this invention or its inhibitory active metabolite or residue upon administration to a recipient.

[0159] As used herein, the term "its inhibitory active metabolite or residue" means that the metabolite or residue is also an inhibitor of the TYK2 protein kinase or a variant thereof.

[0160] The composition of the present invention can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, orally, vaginally or by an implantable reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intramedullary, intraliver, intralesional and intracranial injection or infusion techniques. Preferably, the composition is administered orally, intraperitoneally or intravenously. The injectable sterile form of the composition of this invention may be an aqueous or oily suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The injectable sterile preparation may also be an injectable sterile solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as, for example, a solution in 1,3-butanediol. Acceptable vehicles and solvents that can be used include water, Ringer's solution and isotonic sodium chloride solution. Furthermore, sterile fixed oils have conventionally been used as a solvent or suspending medium.

[0161] For this purpose, any non-irritating fixed oil containing synthetic monoglycerides or diglycerides can be used. Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectable substances, especially in their polyoxyethylated forms, because they are natural pharmaceutically acceptable oils such as olive oil or castor oil. Solutions or suspensions of these oils may also contain long-chain alcohol diluents or dispersing agents such as carboxymethylcellulose or similar dispersing agents commonly used in the formulation of pharmaceutically acceptable dosage forms, including emulsions or suspensions. Other commonly used surfactants, such as Tween, Span, 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 formulation purposes.

[0162] The pharmaceutically acceptable compositions of this 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, commonly used carriers include lactose and corn starch. Lubricants such as magnesium stearate are also typically added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When an aqueous suspension is required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents can also be added.

[0163] Alternatively, the pharmaceutically acceptable compositions of this invention can be administered in the form of suppositories for rectal administration. These can be prepared by mixing the drug with suitable non-irritating excipients which are solid at room temperature but liquid at rectal temperature and therefore melt in the rectum to release the drug. Such materials include cocoa butter, hydrogenated vegetable oil and polyethylene glycol.

[0164] The pharmaceutically acceptable compositions of this invention can also be administered topically, particularly when the target of treatment includes areas or organs that are readily accessible by topical application, including diseases of the eye, skin, or lower intestinal tract. Suitable topical formulations can be readily prepared for each of these areas or organs.

[0165] Topical application to the lower intestinal tract may be effected using rectal suppository formulations (see above) or suitable enema formulations. Topical transdermal patches can also be used.

[0166] For topical application, the provided pharmaceutically acceptable composition can be formulated into a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers. As carriers for topical administration of the compounds of this invention, but not limited to these, mineral oil, liquid paraffin, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax and water can be mentioned. Alternatively, the provided pharmaceutically acceptable composition can be formulated into a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[0167] For ophthalmic use, the provided pharmaceutically acceptable composition can be formulated as a micronized suspension in isotonic, pH-adjusted sterile saline or, preferably, as a solution in isotonic, pH-adjusted sterile saline with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutically acceptable composition can be formulated into an ointment such as petrolatum.

[0168] The pharmaceutically acceptable composition of this invention can also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and can be prepared as solutions in saline using benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0169] Most preferably, the pharmaceutically acceptable compositions of this invention are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, the pharmaceutically acceptable compositions of this invention are administered without food. In other embodiments, the pharmaceutically acceptable compositions of this invention are administered with food.

[0170] The amount of the compounds of this invention that may be combined with a carrier material to produce a composition in a single dosage form will vary depending on the host being treated and the particular mode of administration. Preferably, the compositions provided should be formulated so that an inhibitor in a dosage between 0.01 and 100 mg per kg of body weight per day can be administered to a patient receiving these compositions.

[0171] It should also be understood that the specific dosage and treatment regimen for any particular patient will vary depending on a variety of factors, including the activity of the specific compound being used, age, weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of the compounds of this invention in the composition will also vary depending on the particular compound in the composition.

[0172] Compounds and Pharmaceutically Acceptable Compositions The compounds and compositions described herein are generally useful for inhibiting the kinase activity of one or more enzymes. In some embodiments, the kinase inhibited by the compounds and methods of this invention is TYK2.

[0173] TYK2 is a non-receptor tyrosine kinase member of the Janus kinase (JAK) family of protein kinases. The mammalian JAK family consists of four members, namely, TYK2, JAK1, JAK2, and JAK3. JAK proteins, including TYK2, are essential for cytokine signaling. TYK2 associates with the cytoplasmic domains of type I and type II cytokine receptors, as well as interferon type I and type III receptors, and is activated by these receptors upon cytokine binding. Cytokines involved in TYK2 activation include interferons (e.g., IFN-α, IFN-β, IFN-κ, IFN-δ, IFN-ε, IFN-τ, IFN-ω, and IFN-ζ (also known as limitin), as well as interleukins (e.g., IL-4, IL-6, IL-10, IL-11, IL-12, IL-13, IL-22, IL-23, IL-27, IL-31, oncostatin M, ciliary neurotrophic factor, cardiotrophin 1, cardiotrophin-like cytokine, and LIF). Velasquez et al., "A protein kinase in the interferon α / β signaling pathway", Cell (1992) 70:313; Stahl et al., "Association and activation of Jak-Tyk kinases by CNTF-LIF-OSM-IL-6β "receptor components", Science (1994) 263:92; Finbloom et al., "IL-10 induces the tyrosine phosphorylation of Tyk2 and Jak1 and the differential assembly of Stat1 and Stat3 complexes in human T cells and monocytes", J. Immunol. (1995) 155:1079; Bacon et al., "Interleukin 12 (IL-12) induces tyrosine phosphorylation of Jak2 and Tyk2: differential use of Janus family kinases by IL-2 and IL-12", J. Exp. Med. (1995) 181:399; Welham et al., "Interleukin-13 signal transduction in lymphohemopoietic cells: similarities and differences in signal transduction with interleukin-4 and insulin", J. Biol. Chem. (1995) 270:12286; Parham et al., "A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rβ1 and a novel cytokine receptor subunit, IL-23R", J. Immunol. (2002) 168:5699. Subsequently, activated TYK2 proceeds to phosphorylate members of the STAT family of signal transduction proteins, including STAT1, STAT2, STAT4, and STAT6.

[0174] Activation of TYK2 by IL-23 has been linked to inflammatory bowel disease (IBD), Crohn's disease, and ulcerative colitis. Duerr et al., "A Genome-Wide Association Study Identifies IL23R as an Inflammatory Bowel Disease Gene", Science (2006) 314:1461-1463. As a downstream effector of IL-23, TYK2 also plays a role in psoriasis, ankylosing spondylitis, and Behcet's disease. Cho et al., "Genomics and the multifactorial nature of human auto-immune disease", N. Engl. J. Med (2011) 365:1612-1623; Cortes et al., "Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci", Nat. Genet. (2013) 45(7):730-738; Remmers et al., "Genome-wide association study identifies variants in the MHC class I, IL10, and IL23R-IL12RB2 regions associated with Behcet’s disease", Nat. Genet. (2010) 42:698-702. A genome-wide association study of 2,622 individuals with psoriasis identified an association between disease susceptibility and TYK2. Strange et al., "A "Genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1", Nat. Genet. (2010), 42: 985-992. Knockout of TYK2 or inhibition with tyrphostin significantly reduces both IL-23-induced 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.

[0175] 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 the 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.

[0176] Reduced TYK2 activity confers joint protection from collagen antibody-induced arthritis (a model of human rheumatoid arthritis). Mechanistically, reduced Tyk2 activity is T h 1 / T hIt reduced the production of 17 related cytokines and matrix metalloproteases, as well as other major inflammatory markers. Ishizaki et al., "Tyk2 deficiency protects joints against destruction in anti-type II collagen antibody-induced arthritis in mice", Intl. Immunol. (2011) 23(9): 575-582.

[0177] TYK2 knockout mice showed complete resistance and no infiltration of CD4 T cells into the spinal cord in experimental autoimmune encephalomyelitis (EAE, an animal model of multiple sclerosis (MS)) compared to controls. This suggests that TYK2 is essential for the development of pathogenic CD4-mediated diseases in MS. Oyamada et al., "Tyrosine Kinase 2 Plays Critical Roles in the Pathogenic CD4 T Cell Responses for the Development of Experimental Autoimmune Encephalomyelitis", J. Immunol. (2009) 183: 7539-7546. This is confirmation of previous studies linking increased TYK2 expression to MS susceptibility. Ban et al., "Replication analysis identifies TYK2 as a multiple sclerosis susceptibility factor", Eur J. Hum. Genet. (2009) 17: 1309-1313. Loss-of-function mutations in TYK2 result in reduced demyelination and increased remyelination of neurons, further suggesting the role of TYK2 inhibitors in the treatment of MS and other CNS demyelinating disorders.

[0178] TYK2 is the only signaling messenger common to both IL-12 and IL-23. TYK2 knockout reduced methylated BSA injection-induced footpad thickness, imiquimod-induced psoriatic skin inflammation, and dextran sulfate sodium or 2,4,6-trinitrobenzenesulfonic acid-induced colitis in mice.

[0179] Associations and related studies of various type I IFN signaling genes with systemic lupus erythematosus (SLE, an autoimmune disorder) have shown a strong and significant correlation between loss-of-function mutations in TYK2 and a reduced prevalence of SLE in families including affected members. Sigurdsson et al., "Polymorphisms in the Tyrosine Kinase 2 and Interferon Regulatory Factor 5 Genes Are Associated with Systemic Lupus Erythematosus", Am. J. Hum. Genet. (2005) 76:528-537. Genome-wide association studies of affected individuals with SLE against an unaffected cohort 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.

[0180] TYK2 has been shown to play an important role in maintaining tumor surveillance, and TYK2 knockout mice exhibited impaired cytotoxic T cell responses and accelerated tumorigenesis. However, these effects are associated with efficient suppression of natural killer (NK) and cytotoxic T lymphocytes, suggesting that TYK2 inhibitors are highly suitable for the treatment of autoimmune disorders or transplant rejection. Other JAK family members, such as JAK3, have similar roles in the immune system, but TYK2 is suggested to be a superior target because it is involved in fewer, more closely related signaling pathways, resulting in fewer off-target effects. Simma et al., "Identification of an Indispensable Role for Tyrosine Kinase 2 in CTL-Mediated Tumor Surveillance," Cancer Res. (2009) 69:203-211.

[0181] However, in contrast to the decreased tumor surveillance observed by Simma et al., studies in T-cell acute lymphoblastic leukemia (T-ALL) have shown that T-ALL is highly dependent on IL-10 via TYK2 through STAT1-mediated signaling to maintain cancer cell survival by upregulation of the anti-apoptotic protein BCL2. Knockdown of TYK2 reduced cell proliferation, whereas knockdown of other JAK family members did not. Specific activating mutations in TYK2 promoting cancer cell survival include activating mutations in the FERM domain (G36D, S47N, and R425H), JH2 domain (V731I), and kinase domain (E957D and R1027H). However, it was also identified that the kinase function of TYK2 is required for increased cancer cell survival, as a TYK2 enzyme characterized by an activating mutation (E957D) in addition to a kinase-dead mutation (M978Y or M978F) resulted in failed transformation. Sanda et al., "TYK2-STAT1-BCL2 Pathway Dependence in T-Cell Acute Lymphoblastic Leukemia", Cancer Disc. (2013) 3(5):564-577.

[0182] Therefore, selective inhibition of TYK2 is suggested to be a suitable target for patients with IL-10 and / or BCL2-addicted tumors, such as 70% of cases of adult T-cell leukemia. Fontan et al., "Discovering What Makes STAT Signaling TYK in T-ALL", Cancer Disc. (2013) 3:494-496.

[0183] TYK2-mediated STAT3 signaling has also been shown to mediate neuronal cell death induced by amyloid-β (Aβ) peptide. Reduction of TYK2 phosphorylation of STAT3 after Aβ administration results in a decrease in neuronal cell death, and increased phosphorylation of STAT3 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.

[0184] Inhibition of the JAK-STAT signaling pathway is also involved in hair growth and reversal of hair loss associated with alopecia areata. Xing et al., "Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition", Nat. Med. (2014) 20:1043-1049; Harel et al., "Pharmacologic inhibition of JAK-STAT signaling promotes hair growth", Sci. Adv. (2015) 1(9):e1500973.

[0185] Therefore, compounds that inhibit the activity of TYK2, particularly those with high selectivity preferentially over JAK2, are beneficial. Such compounds should deliver a pharmacological response that preferably treats one or more of the conditions described herein without side effects associated with inhibition of JAK2.

[0186] Although TYK2 inhibitors are known in the art, there is still a need to provide novel inhibitors that have more effective or advantageous pharmaceutically relevant properties. For example, compounds having increased activity, high selectivity over other JAK kinases (especially JAK2), and ADMET (absorption, distribution, metabolism, excretion, and / or toxicity) properties. Thus, in some embodiments, the invention provides an inhibitor of TYK2 that exhibits high selectivity over JAK2.

[0187] The activity of the compounds utilized in this invention as inhibitors of TYK2, or variants thereof, can be assayed in vitro, in vivo or within cell lines. In Examples of in vitro assays include assays that determine the inhibition of the phosphorylation activity and / or subsequent functional consequences, or ATPase activity, of activated TYK2, or variants thereof. By alternative in vitro assays, the ability of the inhibitor to bind to TYK2 is quantified. The binding of the inhibitor can be measured by radiolabeling the inhibitor prior to binding, isolating the inhibitor / TYK2 complex, and determining the amount of radiolabel bound. Alternatively, the binding of the inhibitor can be determined by performing a competition experiment in which the novel inhibitor is incubated with TYK2 that has been bound to a known radioligand. Representative in vitro and in vivo assays useful for assaying TYK2 inhibitors are described and disclosed, for example, in, each of which is incorporated herein by reference in its entirety. In this invention, the detailed conditions for assaying compounds utilized as inhibitors of TYK2 or variants thereof are described in the following examples.

[0188] As used herein, the terms "treatment," "treat," and "treating" refer to the reversal, alleviation, delay in the onset, or inhibition of progression of a disease or disorder, or one or more symptoms thereof, as described herein. In some embodiments, treatment can be administered after one or more symptoms have developed. In other embodiments, treatment can be administered in the absence of symptoms. For example, treatment can be administered to a susceptible individual prior to the onset of symptoms (e.g., taking into account the medical history of the symptoms and / or genetic or other susceptibility factors). Treatment may also be continued after the symptoms have resolved, for example, to prevent or delay recurrence of the symptoms.

[0189] The compounds provided are inhibitors of TYK2 and are thus useful for treating one or more disorders associated with the activity of TYK2 or variants thereof. 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 invention, or a pharmaceutically acceptable composition thereof.

[0190] As used herein, the terms "TYK2-mediated" disorder, disease, and / or condition mean any disease or other adverse condition in which TYK2 or a variant thereof is known to play a role as used herein. Accordingly, another embodiment of the invention relates to treating or reducing the severity of one or more diseases in which TYK2, or a variant thereof, is known to play a role. Such TYK2-mediated disorders include, but are not limited to, autoimmune disorders, inflammatory disorders, proliferative disorders, endocrine disorders, neurological disorders, and disorders associated with transplantation.

[0191] In some embodiments, the present invention is a method for treating one or more disorders, wherein the disorder is selected from autoimmune disorders, inflammatory disorders, proliferative disorders, endocrine disorders, neurological disorders, and disorders related to transplantation, and the method comprises 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.

[0192] In some embodiments, the disorder is an autoimmune disorder. In some embodiments, the disorder is selected from type 1 diabetes, cutaneous lupus erythematosus, systemic lupus erythematosus, multiple sclerosis, psoriasis, Behçet's disease, POEMS syndrome, Crohn's disease, ulcerative colitis, and inflammatory bowel disease.

[0193] In some embodiments, the disorder is an inflammatory disorder. In some embodiments, the inflammatory disorder is rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis, hepatomegaly, Crohn's disease, ulcerative colitis, inflammatory bowel disease.

[0194] 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.

[0195] In some embodiments, the disorder is an endocrine disorder. In some embodiments, the endocrine disorder is polycystic ovary syndrome, Cushing's syndrome, or type 1 diabetes.

[0196] In some embodiments, the disorder is a neurological disorder. In some embodiments, the neurological disorder is Alzheimer's disease.

[0197] In some embodiments, the proliferative disorder is associated with one or more activating mutations in TYK2. In some embodiments, the activating mutation in TYK2 is a mutation to the FERM domain, the JH2 domain, or the kinase domain. In some embodiments, the activating mutation in TYK2 is selected from G36D, S47N, R425H, V731I, E957D, and R1027H.

[0198] In some embodiments, the disorder is associated with transplantation. In some embodiments, the disorder associated with transplantation is transplant rejection, or graft-versus-host disease.

[0199] 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.

[0200] The compounds of the invention are also useful in the treatment of inflammatory or allergic conditions of the skin, such as psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity vasculitis, urticaria, bullous pemphigoid, erythema nodosum, cutaneous erythema nodosum, systemic erythema nodosum, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, acquired epidermolysis bullosa, acne vulgaris, and other inflammatory or allergic conditions of the skin.

[0201] The compounds of the present invention are also useful for treating other diseases or conditions, such as diseases or conditions having an inflammatory component, for example, eye diseases and conditions such as eye allergies, conjunctivitis, dry keratoconjunctivitis, and vernal conjunctivitis, nasal 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, erythroblastosis, and idiopathic thrombocytopenia), cutaneous erythematosus, systemic erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Stevens-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), irritable bowel syndrome, celiac disease, periodontitis, pulmonary alveolar proteinosis, kidney diseases, glomerular diseases, alcoholic liver disease, multiple sclerosis, endocrine ophthalmopathy, Graves' disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), Sjogren's syndrome, dry keratoconjunctivitis and vernal catarrh, interstitial lung fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, cryopyrin-associated periodic syndromes, nephritis, vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis (e.g., those with and without nephrotic syndrome including idiopathic nephrotic syndrome or minimal change nephropathy), chronic granulomatous disease, endometriosis, leptospirosisKidney diseases, glaucoma, retinal diseases, aging, headache, pain, complex regional pain syndrome, cardiac hypertrophy, muscle wasting, catabolism disorders, 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, bronchitic, and exercise-induced), acute lung injury, acute respiratory distress syndrome, eosinophilia, hypersensitivity, anaphylaxis, rhinitis, eye allergy, silica-induced diseases, COPD (reduction of injury, airway inflammation, bronchial hyperactivity, remodeling or disease progression), lung diseases, cystic fibrosis, acid-induced lung injury, pulmonary hypertension, polyneuropathy, cataract, muscle inflammation associated with systemic sclerosis, inclusion body myositis, myasthenia gravis, thyroiditis, Addison's disease, lichen planus, type 1 diabetes, 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, connective tissue inflammation, gastritis, gastroenteritis, Henoch-Schönlein 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, pneumonitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendinitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, or vulvitis can be used for treatment.

[0202] In some embodiments, the inflammatory diseases that can be treated by the method of the present invention are selected from acute gout and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, systemic juvenile idiopathic arthritis (SJIA), cryopyrin-associated periodic syndrome (CAPS), and osteoarthritis.

[0203] In some embodiments, the inflammatory diseases that can be treated by the method of the present invention are T h 1 or T h 17-mediated diseases. In some embodiments, the T h 17-mediated diseases are selected from cutaneous erythematosus, systemic erythematosus, multiple sclerosis, and inflammatory bowel diseases (including Crohn's disease or ulcerative colitis).

[0204] In some embodiments, the inflammatory diseases that can be treated by the method of the present invention are selected from Sjogren's syndrome, allergic disorders, osteoarthritis, eye allergies, conjunctivitis, dry keratoconjunctivitis and spring conjunctivitis and other eye conditions, and diseases affecting the nose such as allergic rhinitis.

[0205] Furthermore, the present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt, or hydrate or solvate thereof, for the preparation of a medicament for the treatment of autoimmune disorders, inflammatory disorders, or proliferative disorders, or disorders commonly occurring in connection with transplantation.

[0206] Combination therapy Depending on the particular condition or disease being treated, an additional therapeutic agent that is normally administered to treat that condition can be administered in combination with the compounds and compositions of the present invention. As used herein, an additional therapeutic agent that is normally administered to treat a particular disease or condition is known as "appropriate for the disease or condition being treated".

[0207] In certain embodiments, the combinations or compositions provided are administered in combination with another therapeutic agent.

[0208] Examples of drugs that may be combined with the combination of the present invention include, but are not limited to: Alzheimer's disease treatment agents, such as Aricept® and Excelon®; HIV treatment agents, such as ritonavir; Parkinson's disease treatment agents, such as L-DOPA / carbidopa, entacapone, ropinirole, pramipexole, bromocriptine, pergolide, trihexephendyl, and amantadine; drugs for treating multiple sclerosis (MS), such as beta interferon (e.g., Avonex® and Rebif®), Copaxone®, and mitoxantrone; asthma treatment agents, such as albuterol and Singulair®; drugs for treating schizophrenia, such as ziprasidone, risperidone, quetiapine, and haloperidol; anti-inflammatory agents, such as corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulatory and immunosuppressive agents, such as cyclosporine, tacrolimus, rapamycin, mycophenolate mofetil, interferon, corticosteroids, cyclophosphamide, azathioprine, and sulfasalazine; neurotrophic factors, such as acetylcholinesterase inhibitors, MAO inhibitors, interferon, anticonvulsants, ion channel blockers, riluzole, and anti-Parkinsonian agent); drugs for treating cardiovascular diseases, such as beta blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, and statins; drugs for treating liver diseases, such as corticosteroids, cholestyramine, interferon, and antiviral agents; drugs for treating blood disorders, such as corticosteroids, anti-leukemia agents, and growth factors; drugs for extending or improving pharmacokinetics, such as cytochrome P450 inhibitors (i.e., inhibitors of metabolic degradation) and CYP3A4 inhibitors (e.g., ketoconazole and ritonavir), and drugs for treating immunodeficiency disorders, such as gamma globulin.

[0209] In certain embodiments, the combination therapy of the present invention, or a pharmaceutically acceptable composition thereof, is administered in combination with a monoclonal antibody or an siRNA therapeutic agent.

[0210] These additional agents may be administered as part of a multiple dosing regimen, separate from the combination therapy provided. Alternatively, these agents may be part of a single dosage form, mixed together with a compound of the invention as a single composition. When administered as part of a multiple dosing regimen, the two active agents may be given simultaneously, sequentially or within a period of time from each other, usually within 5 hours of each other.

[0211] As used herein, the terms "combination", "combined" and related terms refer to the simultaneous or sequential administration of the therapeutic agents according to the invention. For example, the combinations of the present invention may be administered simultaneously or sequentially in separate unit dosage forms with another therapeutic agent, or together in a single unit dosage form.

[0212] The amount of additional therapeutic agent present in the compositions of this invention is less than the amount normally administered in a composition containing that therapeutic agent as the sole active agent. Preferably, the amount of additional therapeutic agent in the compositions of the present disclosure ranges from about 50% to 100% of the amount normally present in a composition containing that agent as the sole therapeutically active agent.

[0213] In one embodiment, the present invention provides a composition comprising a compound of formula I and one or more additional therapeutic agents. The therapeutic agent can be administered together with the compound of formula I, or can be administered before or after 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.

[0214] In another embodiment, the present invention provides a method of treating an inflammatory disease, disorder or condition in a patient in need thereof by administering a compound of Formula I and one or more additional therapeutic agents. Such additional therapeutic agents may be small molecules or recombinant biological agents, for example, acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs) (e.g., aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib), colchicine (Colcrys®), corticosteroids (e.g., prednisone, prednisolone, methylprednisolone, and hydrocortisone, etc.), probenecid, allopurinol, febuxostat (Uloric®), sulfasalazine (Azulfidine®), anti-malarial drugs (e.g., hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®)), methotrexate (Rheumatrex®), gold salts (e.g., aurothioglucose (Solganal®), aurothiomalate (Myochrysine®) and auranofin (Ridaura®)), D-penicillamine (Depen® or Cuprimine®), azathioprine (Imuran®), cyclophosphamide (Cytoxan®), chlorambucil (Leukeran®), cyclosporine (Sandimmune®), leflunomide (Arava®) and "anti-TNF" agents (e.g., etanercept (Enbrel®), infliximab (Remicade®), golimumab (Simponi®), certolizumab pegol (Cimzia®) and adalimumab (Humira®)), "anti-IL-1" agents (e.g., anakinra (Kineret®) and rilonacept (Arcalyst®)), canakinumab (Ilaris®), anti-Jak inhibitors (e.g., tofacitinib), antibodies (e.g., rituximab (Rituxan®)), "anti-T cell" agents (e.g.,Abatacept (Orencia®), “anti-IL-6” agents (e.g., tocilizumab (Actemra®)), diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®), monoclonal antibodies (e.g., tanezumab), anticoagulants (e.g., heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®)), antidiarrheal agents (e.g., diphenoxylate (Lomotil®) and loperamide (Imodium®)), bile acid binders (e.g., cholestyramine), alosetron (Lotronex®), lubiprostone (Amitiza®), laxatives (e.g., magnesium milk, polyethylene glycol (MiraLax®), Dulcolax®, Correctol®, and Senokot®), anticholinergic or antispasmodic agents (e.g., dicyclomine (Bentyl®)), Singulair®, beta-2 agonists (e.g., albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®), and formoterol (Foradil®)), anticholinergic agents (e.g., ipratropium bromide (Atrovent®) and tiotropium (Spiriva®)), inhaled corticosteroids (e.g., beclomethasone dipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), and flunisolide (Aerobid®)), Afviar®, Symbicort®, Dulera®,Cromolyn sodium (Intal®), methylxanthines (e.g., theophylline (Theo-Dur®, Theolair®, Slo-bid®, Uniphyl®, Theo-24®) and aminophylline), IgE antibodies (e.g., omalizumab (Xolair®)), nucleoside reverse transcriptase inhibitors (e.g., zidovudine (Retrovir®), abacavir (Ziagen®), abacavir / lamivudine (Epzicom®), abacavir / lamivudine / zidovudine (Trizivir®), didanosine (Videx®), emtricitabine (Emtriva®), lamivudine (Epivir®), lamivudine / zidovudine (Combivir®), stavudine (Zerit®), and zalcitabine (Hivid®)), non-nucleoside reverse transcriptase inhibitors (e.g., delavirdine (Rescriptor®), efavirenz (Sustiva®), nevirapine (Viramune®) and etravirine (Intelence®)), nucleotide reverse transcriptase inhibitors (e.g., tenofovir (Viread®)), protease inhibitors (e.g., amprenavir (Agenerase®), atazanavir (Reyataz®), darunavir (Prezista®), fosamprenavir (Lexiva®), indinavir (Crixivan®), lopinavir and ritonavir (Kaletra®), nelfinavir (Viracept®), ritonavir (Norvir®), saquinavir (Fortovase® or Invirase®), and tipranavir (Aptivus®)), entry inhibitors (e.g., enfuvirtide (Fuzeon®) and maraviroc (Selzentry®)), integrase inhibitors (e.g., raltegravir (Isentress®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®),Bortezomib (Velcade®), and dexamethasone (Decadron®), in combination with lenalidomide (Revlimid®), or any combination (s) thereof may be mentioned.

[0215] In another embodiment, the invention is a method of treating rheumatoid arthritis, comprising administering to a patient in need thereof one or more additional therapeutic agents selected from the group consisting of a compound of formula I and non-steroidal anti-inflammatory drugs (NSAIDs) (e.g., aspirin, ibuprofen, naproxen, etodolac (Lodine®), and celecoxib), corticosteroids (e.g., prednisone, prednisolone, methylprednisolone, and hydrocortisone, etc.), sulfasalazine (Azulfidine®), anti-malarial drugs (e.g., hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®)), methotrexate (Rheumatrex®), gold salts (e.g., aurothioglucose (Solganal®), aurothiomalate (Myochrysine®), and auranofin (Ridaura®)), D-penicillamine (Depen® or Cuprimine®), azathioprine (Imuran®), cyclophosphamide (Cytoxan®), chlorambucil (Leukeran®), cyclosporine (Sandimmune®), leflunomide (Arava®), and "anti-TNF" agents (e.g., etanercept (Enbrel®), infliximab (Remicade®), golimumab (Simponi®), certolizumab pegol (Cimzia®), and adalimumab (Humira®)), "anti-IL-1" agents (e.g., anakinra (Kineret®) and rilonacept (Arcalyst®)), antibodies (e.g., rituximab (Rituxan®)), "anti-T cell" agents (e.g., abatacept (Orencia®)), and "anti-IL-6" agents (e.g., tocilizumab (Actemra®)).

[0216] In some embodiments, the invention provides a method of treating osteoarthritis, comprising administering to a patient in need thereof a compound of Formula I and one or more additional therapeutic agents selected from acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs) (e.g., aspirin, ibuprofen, naproxen, etodolac (Lodine®), and celecoxib), diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®), and monoclonal antibodies (e.g., tanezumab).

[0217] In some embodiments, the invention provides a method of treating cutaneous or systemic erythematosus, 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) (e.g., aspirin, ibuprofen, naproxen, etodolac (Lodine®), and celecoxib), corticosteroids (e.g., prednisone, prednisolone, methylprednisolone, and hydrocortisone), anti-malarial drugs (e.g., hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®)), cyclophosphamide (Cytoxan®), methotrexate (Rheumatrex®), azathioprine (Imuran®), and anticoagulants (e.g., heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®)).

[0218] In some embodiments, the invention is a method of treating Crohn's disease, ulcerative colitis, or inflammatory bowel disease, comprising administering to a patient in need thereof a compound of Formula I and one or more additional therapeutic agents selected from mesalamine (Asacol®), sulfasalazine (Azulfidine®), antidiarrheal agents (e.g., diphenoxylate (Lomotil®) and loperamide (Imodium®)), bile acid binders (e.g., cholestyramine, alosetron (Lotronex®), lubiprostone (Amitiza®)), laxatives (e.g., magnesium milk, polyethylene glycol (MiraLax®), Dulcolax®, Correctol®, and Senokot®), and anticholinergic or antispasmodic agents (e.g., dicyclomine (Bentyl®)), anti-TNF therapeutic agents, steroids, and antibiotics (e.g., Flagyl or ciprofloxacin).

[0219] In one embodiment, the invention provides a method of treating asthma, comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from Singulair®, beta-2 agonists (e.g., albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®), and formoterol (Foradil®)), anticholinergic agents (e.g., ipratropium bromide (Atrovent®) and tiotropium (Spiriva®)), inhaled corticosteroids (e.g., prednisone, prednisolone, beclomethasone dipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), flunisolide (Aerobid®), Afviar®, Symbicort®, and Dulera®), cromolyn sodium (Intal®), methylxanthines (e.g., theophylline (Theo-Dur®, Theolair®, Slo-bid®, Uniphyl®, Theo-24®) and aminophylline), and IgE antibodies (e.g., omalizumab (Xolair®)).

[0220] In one embodiment, the present invention is a method of treating COPD, comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from beta-2 agonists (e.g., albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®), and formoterol (Foradil®)), anticholinergic agents (e.g., ipratropium bromide (Atrovent®) and tiotropium (Spiriva®)), methylxanthines (e.g., theophylline (Theo-Dur®, Theolair®, Slo-bid®, Uniphyl®, Theo-24®) and aminophylline), and inhaled corticosteroids (e.g., prednisone, prednisolone, beclomethasone dipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), flunisolide (Aerobid®), Afviar®, Symbicort®, and Dulera®).

[0221] In another embodiment, the present invention provides a method of treating a hematological malignancy, the method comprising administering to a patient in need thereof a compound of Formula I and one or more additional therapeutic agents selected from Rituxan®, Cytoxan®, Hydrodaunorubicin®, Oncovin®, prednisone, a hedgehog signaling inhibitor, a BTK inhibitor, a JAK / pan-JAK inhibitor, a PI3K inhibitor, a SYK inhibitor, and combinations thereof.

[0222] In another embodiment, the present invention provides a method of treating a solid tumor, the method comprising administering to a patient in need thereof a compound of Formula I and one or more additional therapeutic agents selected from Rituxan®, Cytoxan®, Hydrodaunorubicin®, Oncovin®, prednisone, a hedgehog signaling inhibitor, a BTK inhibitor, a JAK / pan-JAK inhibitor, a PI3K inhibitor, a SYK inhibitor, and combinations thereof.

[0223] In another embodiment, the present invention provides a method of treating a hematological malignancy, 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), published online Jul. 17, incorporated herein by reference in its entirety).

[0224] In another embodiment, the present invention provides a method of treating diffuse large B-cell lymphoma (DLBCL), comprising administering to a patient in need thereof a compound of Formula I and one or more additional therapeutic agents selected from Rituxan®, Cytoxan®, Hydrodaunorubicin®, Oncovin®, prednisone, a hedgehog signaling inhibitor, and combinations thereof.

[0225] In another embodiment, the present invention provides a method of treating multiple myeloma, comprising administering to a patient in need thereof a compound of Formula I and one or more additional therapeutic agents selected from Velcade®, and Decadron®, a hedgehog signaling inhibitor, a BTK inhibitor, a JAK / pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, a SYK inhibitor, in combination with Revlimid®.

[0226] In another embodiment, the present invention is a method of treating a disease or reducing its severity, comprising administering to a patient in need thereof a compound of formula I and a BTK inhibitor, wherein the disease is inflammatory bowel disease, arthritis, cutaneous erythematosus, systemic lupus erythematosus (SLE), vasculitis, idiopathic thrombocytopenic purpura (ITP), rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis, Graves' disease, autoimmune thyroiditis, Sjogren's syndrome, multiple sclerosis, systemic sclerosis, Lyme neuroborreliosis, Guillain - Barré syndrome, acute disseminated encephalomyelitis, Addison's disease, opsoclonus - myoclonus syndrome, ankylosing spondylitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, autoimmune gastritis, pernicious anemia, celiac disease, Goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia universalis, Behçet's disease, chronic fatigue, autonomic neuropathy, membranous glomerulonephritis, endometriosis, interstitial cystitis, pemphigus vulgaris, bullous pemphigoid, neuromyotonia, scleroderma, vulvodynia, proliferative disorders, rejection of transplanted organs or tissues, acquired immunodeficiency syndrome (AIDS, also known as HIV), type 1 diabetes, graft - versus - host disease, transplantation, transfusion, anaphylaxis, allergy (e.g., allergy to plant pollen, latex, drugs, food, insect venom, animal hair, animal dander, house dust mites, or cockroach calyx), type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, and atopic dermatitis, asthma, appendicitis, atopic dermatitis, asthma, allergy, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection, colitis, conjunctivitis, Crohn's disease, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, Henoch - Schönlein purpura, hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitisMyocarditis, myositis, nephritis, ovaritis, orchitis, osteitis, otitis, pancreatitis, mumps, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendinitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, or vulvitis, B-cell proliferative disorders (e.g., diffuse large B-cell lymphoma), follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma / Waldenström macroglobulinemia, splenic marginal zone lymphoma, multiple myeloma (also known as plasma cell myeloma), non-Hodgkin lymphoma, Hodgkin lymphoma, 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 cancer of mast cells (e.g., mastocytoma, mast cell leukemia, mast cell sarcoma, systemic mastocytosis), bone cancer, colorectal cancer, pancreatic cancer, diseases of bones and joints (including but not limited to rheumatoid arthritis, seronegative spondyloarthritis (including ankylosing spondylitis, psoriatic arthritis, and Reiter's disease), Behçet's disease, Sjögren's syndrome, systemic sclerosis, osteoporosis, bone cancer, bone metastasis), thromboembolic disorders (e.g., myocardial infarction, angina pectoris, restenosis after angioplasty, re-stenosis after angioplasty, re-occlusion after coronary artery bypass grafting, re-stenosis after coronary artery bypass grafting, stroke, transient ischemia, peripheral arterial occlusive disease, pulmonary embolism, deep vein thrombosis), inflammatory pelvic disease, urethritis, sunburn of the skin, sinusitis, pneumonitis, encephalitis, meningitis, myocarditis, nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis, dermatitis, gingivitis, appendicitis, pancreatitis, cholecystitis, agammaglobulinemia, psoriasis, allergy, Crohn's disease, irritable bowel syndrome, ulcerative colitis, Sjögren's disease, tissue graft rejection, hyperacute rejection of transplanted organs, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), polyglandular autoimmune diseasedisease) (also known as polyglandular autoimmune syndrome), autoimmune alopecia, pernicious anemia, glomerulonephritis, dermatomyositis, multiple sclerosis, scleroderma, vasculitis, autoimmune hemolytic state and autoimmune thrombocytopenic state, Goodpasture syndrome, atherosclerosis, Addison's disease, Parkinson's disease, Alzheimer's disease, diabetes, septic shock, cutaneous erythematosus, systemic lupus erythematosus (SLE), rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, osteoarthritis, chronic idiopathic thrombocytopenic purpura, Waldenström macroglobulinemia, myasthenia gravis, Hashimoto's thyroiditis, atopic dermatitis, osteoarthritic disease, vitiligo, autoimmune hypopituitarism, Guillain-Barré syndrome, Behçet's disease, scleroderma, fungating polyp, acute inflammatory response (e.g., acute respiratory distress syndrome and ischemia / reperfusion injury), and Graves' disease, a method is provided.

[0227] In another embodiment, the present invention is a method of treating a disease or reducing its severity, comprising administering to a patient in need thereof a compound of Formula I and a PI3K inhibitor, wherein the disease is selected from cancer, neurodegenerative disorder, angiogenesis disorder, viral disease, autoimmune disease, inflammatory disorder, hormone-related disease, condition related to organ transplantation, immunodeficiency disorder, destructive bone disorder, proliferative disorder, infectious disease, condition related to cell death, thrombin-induced platelet aggregation, chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), liver disease, pathological immune state involving T cell activation, cardiovascular disorder, and CNS disorder, a method is provided.

[0228] In another embodiment, the present invention is a method of treating a disease or reducing its severity, comprising administering to a patient in need thereof a compound of formula I and a PI3K inhibitor, wherein the disease is a benign or malignant tumor, carcinoma or solid tumor, sarcoma, glioblastoma, neuroblastoma, multiple myeloma or gastrointestinal cancer 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, particularly colon cancer or colorectal adenoma or head and neck tumor, epidermal hyperplasia, psoriasis, prostatic hyperplasia, neoplasm, neoplasia of epithelial character, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer, lymphoma (e.g., including non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (also called Hodgkin or Hodgkin disease)), breast cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, or leukemia, a disease including Cowden syndrome, Lhermitte-Duclos disease and Bannayan-Zonana syndrome, or a disease in which the PI3K / PKB pathway is abnormally activated, any type or occurrence of asthma including both intrinsic (non-allergic) asthma and extrinsic (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, chronic obstructive airway disease or chronic obstructive lungdisease) (COPD, COAD or COLD) (including chronic bronchitis or dyspnea associated therewith), emphysema, and exacerbation of airway hyperactivity as a result of other drug treatments (in particular, other inhaled drug treatments), bronchitis of any type or occurrence (including, but not limited to, acute, arachidonic acid, catarrhal, croupus, chronic or tuberculous bronchitis), pneumoconiosis of any type or occurrence (inflammatory, generally occupational lung diseases, whether chronic or acute, frequently accompanied by airway obstruction and caused by repeated inhalation of dust) (e.g., aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis), Löffler's syndromesyndrome), eosinophilic, pneumonia, parasitic (especially metazoan) infestations (including tropical eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa (including Churg-Strauss syndrome), eosinophilic granuloma and eosinophil-related disorders affecting the airway caused by drug reactions, psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity vasculitis, urticaria, bullous pemphigoid, dermatitis herpetiformis, pemphigus, acquired epidermolysis bullosa, conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, diseases affecting the nose including allergic rhinitis, and inflammatory diseases in which an autoimmune reaction is involved or which have an autoimmune component or etiology (including autoimmune hematological disorders (e.g., hemolytic anemia, aplastic anemia, erythroblastosis and idiopathic thrombocytopenia)), cutaneous dermatitis herpetiformis, systemic dermatitis herpetiformis, rheumatoid arthritis, polychondritis, scleroderma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Stevens-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), endocrine ophthalmopathy, Graves' disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), keratoconjunctivitis sicca and vernal catarrh, interstitial pulmonary fibrosis, psoriatic arthritis and glomerulonephritis (with or without nephrotic syndrome (e.g., including idiopathic nephrotic syndrome or minimal change nephropathy)), restenosis, cardiac hypertrophy, atherosclerosis, myocardial infarction, ischemic attack and congestive heart failure, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and neurodegenerative diseases caused by trauma, glutamate neurotoxicity and hypoxia, and provides a method selected from.

[0229] In some embodiments, the present invention provides a method of treating a disease or reducing its severity, comprising administering to a patient in need thereof a compound of Formula I and a Bcl-2 inhibitor, wherein the disease is an inflammatory disorder, an autoimmune disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a disorder associated with transplantation. In some embodiments, the disorder is a proliferative disorder, lupus, or lupus nephritis. In some embodiments, the proliferative disorder is chronic lymphocytic leukemia, diffuse large B-cell lymphoma, Hodgkin's disease, small cell lung cancer, non-small cell lung cancer, myelodysplastic syndrome, lymphoma, hematological neoplasm, or solid tumor.

[0230] In some embodiments, the present invention provides a method of treating a disease or reducing its severity, comprising administering to a patient in need thereof a TYK2 pseudokinase (JH2) domain-binding compound and a TYK2 kinase (JH1) domain-binding compound. In some embodiments, the disease is an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a disorder associated with transplantation. In some embodiments, the JH2-binding compound is a compound of Formula I. Other suitable JH2 domain-binding compounds include those described in WO2014074660A1, WO2014074661A1, WO2015089143A1, each of which is incorporated herein by reference in its entirety. Suitable JH1 domain-binding compounds include those described in WO2015131080A1, which is incorporated herein by reference in its entirety.

[0231] Compounds and compositions can be administered in any amount and by any route of administration effective to treat or reduce the severity of an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a disorder associated with transplantation, according to the methods of the present invention. The exact amount required will vary for each subject, depending on the subject's species, age and general condition, the severity of the infection, the particular agent, the mode of its administration, and the like. The compounds of the present invention are preferably formulated into unit dosage forms to facilitate administration and to uniformize the dosage. As used herein, the expression "unit dosage form" refers to physically discrete units of the agent suitable for the patient to be treated. However, it is understood that the total daily usage of the compounds and compositions of the present invention will be determined by the attending physician within the scope of sound medical judgment. The effective dosage level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination with or concurrently with the specific compound employed, as well as other factors well known in the medical arts. As used herein, the term "patient" means an animal, preferably a mammal, most preferably a human.

[0232] The pharmaceutically acceptable compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), sublingually, as an oral spray or nasal spray, etc., depending on the severity of the infection to be treated. In certain embodiments, the compounds of the present invention can be administered orally or parenterally at a dosage level of about 0.01 mg to about 50 mg, preferably about 1 mg to about 25 mg per kg of the subject's body weight per day, one or more times a day, to obtain the desired therapeutic effect.

[0233] Examples of 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 contain, for example, inert diluents commonly used in the art such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof. In addition to the inert diluent, the oral compositions may also contain adjuvants such as wetting agents, emulsifiers, and suspending agents, as well as sweetening agents, flavoring agents, and perfuming agents.

[0234] Injectable preparations, for example, aqueous or oily sterile suspensions for injection, may be formulated by known techniques using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may be a sterile injectable solution, suspension, or emulsion in a non-toxic parenterally acceptable diluent or solvent, for example, a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution, U.S.P., and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as a solvent or suspending medium. For this purpose, any bland fixed oil containing synthetic monoglycerides or diglycerides may be used. In addition, fatty acids such as oleic acid are used in the preparation of injectable substances.

[0235] Injectable formulations can be sterilized, prior to use, for example, by filtration through a bacteria-retaining filter or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable medium.

[0236] [[ID=!1]] To extend the effect of the compounds of the present invention, it is often desirable to slow the absorption of the compounds from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of a poorly water-soluble crystalline or amorphous material. The absorption rate of the compound then depends on its dissolution rate, while the dissolution rate can depend on the crystal size and crystal form. Alternatively, delayed absorption of the parenterally administered compound form is achieved by dissolution or suspension of the compound in an oil vehicle. Depot injection forms are prepared by forming a microencapsulation matrix of the compound within a biodegradable polymer such as polylactide-polyglycolide. Depending on the ratio of the compound to the polymer and the nature of the particular polymer used, the compound release rate can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound within liposomes or microemulsions that are compatible with body tissues.

[0237] Compositions for rectal or vaginal administration are preferably suppositories prepared by mixing the compounds of this invention with a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol or suppository wax, which are solid at ambient temperature but liquid at body temperature and thus melt in the rectal or vaginal cavity to release the active compound.

[0238] Examples of solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is combined with at least one inert pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate, and / or a) fillers or bulking agents such as starch, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrants such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) dissolution retardants such as paraffin, f) absorption promoters such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may contain a buffering agent.

[0239] Solid compositions of the same type may also be used as fillers in soft and hard gelatin capsules using excipients such as lactose and lactulose and high molecular weight polyethylene glycols. Solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings and other coatings well known in the art of pharmaceutical formulation. These may optionally contain opacifying agents and can also be made into compositions that release the active ingredient(s) only in or preferentially in a particular part of the intestinal tract in a delayed manner. Examples of implantable compositions that can be used include polymeric materials and waxes. Solid compositions of the same type may also be used as fillers in soft and hard gelatin capsules using excipients such as lactose or lactulose and high molecular weight polyethylene glycols.

[0240] The active compound can be in microencapsulated form with one or more of the excipients described above. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using 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 may be mixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may, as in the normal practice, contain additional substances other than inert diluents, 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 contain buffering agents. These may contain opacifying agents, if desired, and may also be compositions that release the active ingredient(s) only or preferentially in a specific part of the intestinal tract in a delayed manner, if desired. Examples of implantable compositions that can be used include polymeric substances and waxes.

[0241] Dosage forms for topical or transdermal administration of the compounds of the invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active ingredient is optionally mixed with a pharmaceutically acceptable carrier and any necessary preservative or buffer under sterile conditions. Ophthalmic formulations, ear drops, and eye drops are also contemplated to be within the scope of the present invention. Further, the present invention contemplates the use of transdermal patches which have the additional advantage of providing controlled delivery of the compound to the body. Such dosage forms can be prepared by dissolving or dispersing the compound in a suitable medium. Penetration enhancers can also be used to increase the flux of the compound across the skin. This rate can be controlled by providing a rate controlling membrane or by dispersing the compound in a polymeric matrix or gel.

[0242] According to one embodiment, the present invention relates to a method for inhibiting protein kinase activity in a biological sample, the method comprising contacting the biological sample with a compound of the present invention or a composition comprising the compound.

[0243] According to another embodiment, the present invention relates to a method for inhibiting the activity of TYK2 or a variant thereof in a biological sample, the method comprising contacting the biological sample with a compound of the present invention or a composition comprising the compound. In certain embodiments, the present invention relates to a method for irreversibly inhibiting the activity of TYK2 or a variant thereof in a biological sample, the method comprising contacting the biological sample with a compound of the present invention or a composition comprising the compound.

[0244] In another embodiment, the present invention provides a method for selectively inhibiting TYK2 over one or more of JAK1, JAK2, and JAK3. In some embodiments, the compounds of the present invention are more than 2-fold selective over JAK1 / 2 / 3. In some embodiments, the compounds of the present invention are more than 5-fold selective over JAK1 / 2 / 3. In some embodiments, the compounds of the present invention are more than 10-fold selective over JAK1 / 2 / 3. In some embodiments, the compounds of the present invention are more than 50-fold selective over JAK1 / 2 / 3. In some embodiments, the compounds of the present invention are more than 100-fold selective over JAK1 / 2 / 3.

[0245] As used herein, the term "biological sample" includes, but is not limited to, cell cultures or extracts thereof; biopsy materials or extracts thereof obtained from mammals; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.

[0246] Inhibition of the activity of TYK2 (or a variant thereof) in a biological sample is useful for a variety of purposes known to those of skill in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ transplantation, preservation of biological specimens, and biological assays.

[0247] Another embodiment of the present invention relates to a method of inhibiting protein kinase activity in a patient, which method comprises administering to the patient a compound of the present invention or a composition comprising said compound.

[0248] According to another embodiment, the present invention relates to a method of inhibiting the activity of TYK2 or a variant thereof in a patient, which method comprises administering to the patient a compound of the present invention or a composition comprising said compound. According to certain embodiments, the present invention relates to a method of reversibly or irreversibly inhibiting the activity of one or more of TYK2 or a variant thereof in a patient, which method comprises administering to the patient a compound of the present invention or a composition comprising said compound. In other embodiments, the present invention provides a method of treating a disorder mediated by TYK2 or a variant thereof in a patient in need thereof, which method comprises administering to the patient a compound according to the present invention or a pharmaceutically acceptable composition thereof. Such disorders are described in detail herein.

[0249] Depending on the particular condition or disease being treated, additional therapeutic agents that are normally administered to treat that condition may also be present in the compositions of this invention. As used herein, additional therapeutic agents that are normally administered to treat a particular disease or condition are known as being "appropriate for the disease or condition being treated".

[0250] The compounds of the present invention can also be advantageously used in combination with other therapeutic compounds. In some embodiments, the other therapeutic compound is an anti-proliferative compound. Such anti-proliferative compounds include, but are not limited to, aromatase inhibitors; anti-estrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule-active compounds; alkylating compounds; histone deacetylase inhibitors; compounds that induce the cell differentiation process; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; antitumor antimetabolites; platinum compounds; compounds that target / reduce protein kinase activity or lipid kinase activity and additional anti-angiogenic compounds; compounds that target, reduce or inhibit the activity of protein phosphatase or lipid phosphatase; gonadorelin agonists; anti-androgens; methionine aminopeptidase inhibitors; matrix metalloproteinase inhibitors; bisphosphonates; biological response modifiers; anti-proliferative antibodies; heparanase inhibitors; inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasome inhibitors; compounds used in the treatment of hematological malignancies; compounds that target, reduce or inhibit the activity of Flt-3; Hsp90 inhibitors (e.g., 17-AAG (17-allylaminogeldanamycin, NSC330507), 17-DMAG (17-dimethylaminoethylamino-17-demethoxy-geldanamycin, NSC707545), IPI-504, CNF1010, CNF2024, CNF1010 (manufactured by Conforma Therapeutics)); temozolomide (Temodal®); kinesin spindle protein inhibitors (e.g., SB715992 or SB743921 (manufactured by GlaxoSmithKline), or pentamidine / chlorpromazine (manufactured by CombinatoRx)); MEK inhibitors (e.g., ARRY142886 (manufactured by Array BioPharma), AZD6244 (manufactured by AstraZeneca), PD181461 (manufactured by Pfizer) and leucovorin).As used herein, the term "aromatase inhibitor" relates to a compound that inhibits estrogen production, for example, the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively. This term includes, but is not limited to, steroids, especially exemestane, formestane and vorozole, and in particular non-steroids, especially aminoglutethimide, logestimide, pyridoglutethimide, trilostane, testolactone, ketoconazole, borozole, fadrozole, anastrozole and letrozole. Exemestane is marketed under the trade name Aromasin™. Formestane is marketed under the trade name Lentaron™. Faslodex is marketed under the trade name Femara™ or Femar™. Aminoglutethimide is marketed under the trade name Orimeten™. The combination of the invention comprising a chemotherapeutic agent that is an aromatase inhibitor is particularly useful for the treatment of hormone receptor positive tumors, such as breast tumors.

[0251] As used herein, the term "antiestrogen" relates to a compound that antagonizes the effects of estrogen at the estrogen receptor level. This term includes, but is not limited to, tamoxifen, fulvestrant, raloxifene and raloxifene hydrochloride. Tamoxifen is marketed under the trade name Nolvadex™. Raloxifene hydrochloride is marketed under the trade name Evista™. Fulvestrant can be administered under the trade name Faslodex™. The combination of the invention comprising a chemotherapeutic agent that is an antiestrogen is particularly useful for the treatment of estrogen receptor positive tumors, such as breast tumors.

[0252] As used herein, the term "antiandrogen" relates to any substance capable of inhibiting the biological effects of androgens, including but not limited to bicalutamide (Casodex (trademark)). As used herein, the term "gonadorelin agonist" includes but is not limited to abarelix, goserelin and goserelin acetate. Goserelin can be administered under the trade name Zoladex (trademark).

[0253] As used herein, the term "topoisomerase I inhibitor" includes but is not limited to topotecan, gemitecan, irinotecan, camptothecin and its analogs, 9-nitrocamptothecin and the macromolecular camptothecin conjugate PNU-166148. Irinotecan can be administered, for example, under the trademark of Camptosar (trademark) in a commercially available form. Topotecan is commercially available under the trade name Hycamptin (trademark).

[0254] As used herein, the term "topoisomerase II inhibitor" includes but is not limited to anthracyclines (e.g., doxorubicin (including liposomal formulations such as Caelyx (trademark)), daunorubicin, epirubicin, idarubicin and nemorubicin), mitoxantrone and losoxantrone which are anthraquinones, and etoposide and teniposide which are podophyllotoxins. Etoposide is commercially available under the trade name Etopophos (trademark). Teniposide is commercially available under the trade name VM 26-Bristol. Doxorubicin is commercially available under the trade name Acriblastin (trademark) or Adriamycin (trademark). Epirubicin is commercially available under the trade name Farmorubicin (trademark). Idarubicin is commercially available under the trade name Zavedos (trademark). Mitoxantrone is commercially available under the trade name Novantron.

[0255] The term "microtubule agent" relates to, but is not limited to, microtubule stabilizing compounds, microtubule destabilizing compounds, and microtubule polymerization inhibitors, including but not limited to taxanes such as paclitaxel and docetaxel; vinca alkaloids such as vinblastine or vinblastine sulfate, vincristine or vincristine sulfate, and vinorelbine; discodermolide; colchicine and epothilone and derivatives thereof. Paclitaxel is commercially available under the trade name Taxol®. Docetaxel is commercially available under the trade name Taxotere®. Vinblastine sulfate is commercially available under the trade name Vinblastin R.P®. Vincristine sulfate is commercially available under the trade name Farmistin®.

[0256] The term "alkylating agent" as used herein includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan or nitrosourea (BCNU or Gliadel). Cyclophosphamide is commercially available under the trade name Cyclostin®. Ifosfamide is commercially available under the trade name Holoxan®.

[0257] The term "histone deacetylase inhibitor" or "HDAC inhibitor" relates to compounds that inhibit histone deacetylases and have antiproliferative activity. This includes, but is not limited to, suberoylanilide hydroxamic acid (SAHA).

[0258] The term "antineoplastic antimetabolite" includes, but is not limited to, 5-fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylating compounds (such as 5-azacitidine and decitabine), methotrexate and edatrexate, and folic acid antagonists (such as pemetrexed). Capecitabine is commercially available under the trade name Xeloda®. Gemcitabine is commercially available under the trade name Gemzar®.

[0259] The term "platin compound" as used herein includes, but is not limited to, carboplatin, cisplatin, cisplatinum and oxaliplatin. Carboplatin can be administered, for example, under the trademark Carboplat(™) in a commercially available form. Oxaliplatin can be administered, for example, under the trademark Eloxatin(™) in a commercially available form.

[0260] The term "compound that targets / reduces the activity of a protein kinase or a lipid kinase; or a compound that targets / reduces the activity of a protein phosphatase or a lipid phosphatase; or a further anti-angiogenic compound", as used herein, includes, but is not limited to, protein tyrosine kinase and / or serine and / or threonine kinase inhibitors, or lipid kinase inhibitors, for example, a) a compound that targets, reduces or inhibits the activity of the platelet-derived growth factor receptor (PDGFR) (for example, a compound that targets, reduces or inhibits the activity of the PDGFR, particularly a compound that inhibits the PDGF receptor, for example, an N-phenyl-2-pyrimidine-amine derivative, for example, imatinib, SU101, SU6668 and GFB-111); b) a compound that targets, reduces or inhibits the activity of the fibroblast growth factor receptor (FGFR); c) a compound that targets, reduces or inhibits the activity of the insulin-like growth factor receptor I (IGF-IR) (for example, a compound that targets, reduces or inhibits the activity of the IGF-IR, particularly a compound that inhibits the kinase activity of the IGF-I receptor, or an antibody that targets the extracellular domain of the IGF-I receptor or its growth factor); d) a compound that targets, reduces or inhibits the activity of the Trk receptor-type tyrosine kinase family, or an Ephrin B4 inhibitor; e) a compound that targets, reduces or inhibits the activity of the AxI receptor-type tyrosine kinase family; f) a compound that targets, reduces or inhibits the activity of the Ret receptor-type tyrosine kinase; g) a compound that targets, reduces or inhibits the activity of the Kit / SCFR receptor-type tyrosine kinase, for example, imatinib; h) a compound that targets, reduces or inhibits the activity of the C-kit receptor-type tyrosine kinase, which is part of the PDGFR family (for example, a compound that targets, reduces or inhibits the activity of the c-Kit receptor-type tyrosine kinase family, particularly a compound that inhibits the c-Kit receptor, for example, imatinib);i) Compounds that target, reduce or inhibit the activity of members of the c-Abl family, their gene fusion products (e.g., BCR-Abl kinase) and variants (e.g., compounds that target, reduce or inhibit the activity of c-Abl family members and their gene fusion products, such as N-phenyl-2-pyrimidine-amine derivatives, such as imatinib or nilotinib (AMN107); PD180970; AG957; NSC 680410; PD173955 (manufactured by Parke Davis); or dasatinib (BMS-354825)); j) Compounds that target, reduce or inhibit the activity of members of the protein kinase C (PKC) of serine / threonine kinases and the Raf family, MEK, SRC, JAK / pan-JAK, FAK, PDK1, PKB / Akt, Ras / MAPK, PI3K, SYK, BTK and TEC families, and / or members of the cyclin-dependent kinase family (CDK) (including staurosporine derivatives such as midostaurin); Examples of further compounds include UCN-01, safingol, BAY 43-9006, bryostatin 1, perifosine; ilmofosine; RO 318220 and RO 320432; GO 6976; Isis 3521; LY333531 / LY379196; isoquinoline compounds; FTI; PD184352 or QAN697 (a PI3K inhibitor) or AT7519 (a CDK inhibitor); k) Compounds that target, reduce or inhibit the activity of protein-tyrosine kinase inhibitors, e.g., compounds that target, reduce or inhibit the activity of protein-tyrosine kinase inhibitors are imatinib mesylate (Gleevec (trademark)) or tyrphostin (e.g., tyrphostin A23 / RG-50810; AG 99; tyrphostin AG 213; tyrphostin AG 1748; tyrphostin AG 490; tyrphostin B44; tyrphostin B44 (+) enantiomer; tyrphostin AG 555; AG 494; tyrphostin AG 556, AG957) and adaphostin (4-{[(2,5-dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester;including NSC 680410, adafostin; l) a compound that targets, reduces or inhibits the activity of receptor tyrosine kinases of the epidermal growth factor family (EGFR1, ErbB2, ErbB3, ErbB4 as homodimers or heterodimers) and their variants, for example, a compound that targets, reduces or inhibits the activity of the epidermal growth factor receptor family, in particular, a compound that inhibits members of the EGF receptor tyrosine kinase family, such as the EGF receptor, ErbB2, ErbB3 and ErbB4, or a compound, protein or antibody that binds to EGF or an EGF-related ligand (for example, CP 358774, ZD 1839, ZM 105180; trastuzumab (Herceptin™), cetuximab (Erbitux™), Iressa, Tarceva, OSI-774, Cl-1033, EKB-569, GW-2016, E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 or E7.6.3, and 7H-pyrrolo-[2,3-d]pyrimidine derivatives); m) a compound that targets, reduces or inhibits the activity of the c-Met receptor, for example, a compound that targets, reduces or inhibits the activity of c-Met, in particular, a compound that inhibits the kinase activity of the c-Met receptor, or an antibody that targets the extracellular domain of c-Met or binds to HGF; n) a compound that targets, reduces or inhibits the kinase activity of one or more JAK family members (JAK1 / JAK2 / JAK3 / TYK2 and / or pan-JAK) (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, pictilisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, and idelalisib);and compounds that target, reduce or inhibit the signaling effects of the Hedgehog protein (Hh) or Smoothened receptor (SMO) pathway (including, but not limited to, cyclopamine, vismodegib, itraconazole, erismodegib, and IPI-926 (saridegib)).;

[0261] As used herein, the term "PI3K inhibitor" includes compounds having inhibitory activity against one or more enzymes of the phosphatidylinositol-3-kinase family (including, but not limited to, PI3Kα, PI3Kγ, PI3Kδ, PI3Kβ, PI3K-C2α, PI3K-C2β, PI3K-C2γ, Vps34, p110-α, p110-β, p110-γ, p110-δ, p85-α, p85-β, p55-γ, p150, p101, and p87). Examples of PI3K inhibitors useful in this 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, duvelisib, XL-147, XL-765, and idelalisib.

[0262] As used herein, the term "BTK inhibitor" includes compounds having inhibitory activity against Bruton tyrosine kinase (BTK) (including, but not limited to, AVL-292 and ibrutinib).

[0263] As used herein, the term "SYK inhibitor" includes 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).

[0264] 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 inhibitors (Infinity Pharmaceuticals / Novartis Pharmaceuticals), Genasense (G3139), HA14-1 (and its analogs; see WO2008118802), navitoclax (and its analogs; see US7390799), NH-1 (Shenayng Pharmaceutical University), obatoclax (and its analogs; see WO2004106328), 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.

[0265] Further examples of BTK inhibitory compounds and conditions treatable with such compounds in combination with the compounds of the invention can be found in WO2008039218 and WO2011090760, which are hereby incorporated by reference in their entirety.

[0266] Further examples of SYK inhibitory compounds and conditions treatable with such compounds in combination with the compounds of the invention can be found in WO2003063794, WO2005007623, and WO2006078846, which are hereby incorporated by reference in their entirety.

[0267] Examples of additional PI3K inhibitory compounds and conditions treatable by such compounds in combination with the compounds of the present invention can be found in WO2004019973, WO2004089925, WO2007016176, US8,138,347, WO2002088112, WO2007084786, WO2007129161, WO2006122806, WO2005113554, and WO2007044729, which are hereby incorporated by reference in their entirety.

[0268] Examples of additional JAK inhibitory compounds and conditions treatable by such compounds in combination with the compounds of the present invention can be found in WO2009114512, WO2008109943, WO2007053452, WO2000142246, and WO2007070514, which are hereby incorporated by reference in their entirety.

[0269] Additional anti - angiogenic compounds include, for example, compounds having a different mechanism of action for their activity, such as a mechanism not related to protein kinase inhibition or lipid kinase inhibition, for example, thalidomide (Thalomid (trademark)) and TNP - 470.

[0270] Examples of proteasome inhibitors useful for use in combination with the compounds of the present invention include, but are not limited to, bortezomib, disulfiram, epigallocatechin - 3 - gallate (EGCG), salinosporamide A, carfilzomib, ONX - 0912, CEP - 18770, and MLN9708.

[0271] Compounds that target, reduce or inhibit the activity of protein phosphatase or lipid phosphatase are, for example, inhibitors of phosphatase 1, inhibitors of phosphatase 2A, or inhibitors of CDC25 (e.g., okadaic acid or its derivatives).

[0272] Examples of compounds that induce the cell differentiation process include, but are not limited to, retinoic acid, α-tocopherol, γ-tocopherol or δ-tocopherol, or α-tocotrienol, γ-tocotrienol or δ-tocotrienol.

[0273] As used herein, the term "cyclooxygenase inhibitor" includes, but is not limited to, Cox-2 inhibitors, 5-alkyl-substituted 2-arylaminophenylacetic acids and derivatives, such as celecoxib (Celebrex™), rofecoxib (Vioxx™), etoricoxib, valdecoxib, or 5-alkyl-2-arylaminophenylacetic acids, such as 5-methyl-2-(2'-chloro-6'-fluoroanilino)phenylacetic acid, lumiracoxib.

[0274] 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 commercially available under the trade name Didronel™. Clodronic acid is commercially available under the trade name Bonefos™. Tiludronic acid is commercially available under the trade name Skelid™. Pamidronic acid is commercially available under the trade name Aredia™. Alendronic acid is commercially available under the trade name Fosamax™. Ibandronic acid is commercially available under the trade name Bondranat™. Risedronic acid is commercially available under the trade name Actonel™. Zoledronic acid is commercially available under the trade name Zometa™. The term "mTOR inhibitor" relates to compounds that inhibit the mammalian target of rapamycin (mTOR) and have antiproliferative activity, such as sirolimus (Rapamune®), everolimus (Certican™), CCI-779 and ABT578.

[0275] As used herein, the term "heparanase inhibitor" refers to a compound that targets, reduces or inhibits heparan sulfate degradation. This term includes, but is not limited to, PI-88. As used herein, the term "biological response modifier" refers to a lymphokine or interferon.

[0276] As used herein, the term "inhibitor of Ras oncogenic isoform" (e.g., H-Ras, K-Ras, or N-Ras) refers to a compound that targets, reduces or inhibits the oncogenic activity of Ras; for example, a "farnesyl transferase inhibitor" such as L-744832, DK8G557 or R115777 (Zarnestra™). As used herein, the term "telomerase inhibitor" refers to a compound that targets, reduces or inhibits the activity of telomerase. A compound that targets, reduces or inhibits the activity of telomerase is, in particular, a compound that inhibits the telomerase receptor, such as, for example, telomestatin.

[0277] As used herein, the term "methionine aminopeptidase inhibitor" refers to a compound that targets, reduces or inhibits the activity of methionine aminopeptidase. Examples of compounds that target, reduce or inhibit the activity of methionine aminopeptidase include, but are not limited to, benagmid or its derivatives.

[0278] As used herein, the term "proteasome inhibitor" refers to a compound that targets, reduces or inhibits the activity of proteasome. Examples of compounds that target, reduce or inhibit the activity of proteasome include, but are not limited to, bortezomib (Velcade™) and MLN 341.

[0279] The term "matrix metalloproteinase inhibitor" or ("MMP" inhibitor), as used herein, includes, but is not limited to, collagen peptide mimetics and non-peptide mimetic inhibitors, tetracycline derivatives (e.g., batimastat, which is a hydroxamate peptide mimetic inhibitor, and marimastat (BB-2516), its orally bioavailable analog, prinomastat (AG3340), metastat (NSC 683551), BMS-279251, BAY 12-9566, TAA211, MMI270B or AAJ996).

[0280] The term "compound used in the treatment of hematological malignancies", as used herein, includes, but is not limited to, FMS-like tyrosine kinase inhibitors, which are compounds that target, reduce or inhibit the activity of the FMS-like tyrosine kinase receptor (Flt-3R); interferon, 1-β-D-arabinofuransylcytosine (ara-c) and bisulfan; ALK inhibitors, which are compounds that target, reduce or inhibit undifferentiated lymphoma kinase; and Bcl-2 inhibitors.

[0281] Compounds that target, reduce or inhibit the activity of the FMS-like tyrosine kinase receptor (Flt-3R) are, in particular, compounds, proteins or antibodies that inhibit members of the Flt-3R receptor-type kinase family, such as PKC412, midostaurin, staurosporine derivatives, SU11248 and MLN518.

[0282] The term "HSP90 inhibitor", as used herein, includes, but is not limited to, compounds that target, reduce or inhibit the endogenous ATPase activity of HSP90; compounds that target, reduce or inhibit the degradation of HSP90 client proteins via the ubiquitin proteasome pathway. Compounds that target, reduce or inhibit the endogenous ATPase activity of HSP90 include, in particular, compounds, proteins or antibodies that inhibit the ATPase activity of HSP90, such as 17-allylamino,17-demethoxygeldanamycin (17AAG), geldanamycin derivatives; other geldanamycin-related compounds; radicicol and HDAC inhibitors.

[0283] The term "antiproliferative antibody", as used herein, includes, but is not limited to, trastuzumab (Herceptin™), trastuzumab-DM1, Erbitux, bevacizumab (Avastin™), rituximab (Rituxan®), PRO64553 (anti-CD40) and 2C4 antibody. Antibody means intact monoclonal antibody, polyclonal antibody, multispecific antibody formed from at least two intact antibodies, and antibody fragments as long as they exhibit the desired biological activity.

[0284] For the treatment of acute myeloid leukemia (AML), the compounds of the invention can be used in combination with standard leukemia treatments, in particular in combination with treatments used for the treatment of AML. In particular, the compounds of the invention can be administered, for example, in combination with farnesyl transferase inhibitors and / or other drugs useful for the treatment of AML, such as daunorubicin, adriamycin, Ara-C, VP-16, teniposide, mitoxantrone, idarubicin, carboplatinum and PKC412. In some embodiments, the invention provides a method of treating AML associated with ITD and / or D835Y mutations, the method comprising administering a compound of the invention together with one or more FLT3 inhibitors. In some embodiments, the FLT3 inhibitor is selected from quizartinib (AC220), staurosporine derivatives (e.g., midostaurin or lestaurtinib), sorafenib, 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.

[0285] Other anti-leukemia compounds include, for example, Ara-C, a pyrimidine analog that is a 2'-alpha-hydroxyribose (arabinoside) derivative of deoxycytidine. Also included are purine analogs of hypoxanthine, 6-mercaptopurine (6-MP) and fludarabine phosphate. Compounds that target, reduce or inhibit the activity of histone deacetylase (HDAC) inhibitors, such as sodium butyrate and suberoylanilide hydroxamic acid (SAHA), inhibit the activity of enzymes known as histone deacetylases. Specific HDAC inhibitors include MS275, SAHA, FK228 (formerly FR901228), trichostatin A, and, without limitation, N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide, or a pharmaceutically acceptable salt thereof, and N-hydroxy-3-[4-[(2-hydroxyethyl){2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide, or a pharmaceutically acceptable salt thereof, particularly the lactate salt, compounds disclosed in US 6,552,065. A somatostatin receptor antagonist, as used herein, refers to a compound that targets, treats or inhibits a somatostatin receptor, such as octreotide, and SOM230. A tumor cell damage approach refers to an approach such as ionizing radiation. The term "ionizing radiation" as referred to above and hereinafter in this specification means ionizing radiation generated as either electromagnetic rays (e.g., X-rays and gamma rays) or particles (e.g., alpha particles and beta particles). Ionizing radiation is provided, without limitation, in radiation therapy and is known in the art. See Hellman, Principles of Radiation Therapy, Cancer, in Principles and Practice of Oncology, Devita et al., eds., 4th ed., vol. 1, pp. 248-275 (1993).

[0286] Also included are EDG binders and ribonucleotide reductase inhibitors. As used herein, the term "EDG binder" refers to a class of immunosuppressive drugs that modulate lymphocyte recirculation, such as FTY720. The term "ribonucleotide reductase inhibitor" refers to pyrimidine nucleoside analogs or purine nucleoside analogs including, but not limited to, fludarabine and / or cytosine arabinoside (ara-C), 6-thioguanine, 5-fluorouracil, cladribine, 6-mercaptopurine (especially in combination with ara-C for ALL) and / or pentostatin. Ribonucleotide reductase inhibitors are particularly hydroxyurea or 2-hydroxy-1H-isoindole-1,3-dione derivatives.

[0287] Particularly, 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceutically acceptable salt thereof, 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate; Angiostatin (trademark); Endostatin (trademark); anthranilic acid amide; ZD4190; ZD6474; SU5416; SU6668; bevacizumab; or an anti-VEGF antibody or anti-VEGF receptor antibody (e.g., rhuMAb and RHUFab), VEGF aptamer (e.g., Macugon); compounds, proteins or monoclonal antibodies of VEGF such as FLT-4 inhibitor, FLT-3 inhibitor, VEGFR-2 IgGI antibody, Angiozyme (RPI 4610) and bevacizumab (Avastin (trademark)) are also included.

[0288] As used herein, photodynamic therapy refers to a treatment that uses certain chemicals known as photosensitizing compounds to treat or prevent cancer. Examples of photodynamic therapy include treatments using compounds such as Visudyne (trademark) and porfimer sodium.

[0289] An angiogenesis-inhibiting steroid, as used herein, refers to a compound that blocks or inhibits angiogenesis, such as anecortave, triamcinolone, hydrocortisone, 11-α-epihydrocortisol, cortodoxone, 17α-hydroxyprogesterone, corticosterone, desoxycorticosterone, testosterone, estrone, and dexamethasone.

[0290] A corticosteroid-containing implant refers to compounds such as fluocinolone and dexamethasone.

[0291] Other chemotherapeutic compounds include, but are not limited to, plant alkaloids, hormone compounds and antagonists; biological response modifiers, preferably lymphokines or interferons; antisense oligonucleotides or oligonucleotide derivatives; shRNA or siRNA; or a wide variety of compounds or compounds having other or unknown mechanisms of action.

[0292] The compounds of the present invention are also useful, in particular, as co-therapeutic compounds for use in combination with other drug substances, such as anti-inflammatory drug substances, bronchodilator drug substances or antihistamine drug substances, in the treatment of obstructive or inflammatory airway diseases such as those previously mentioned herein, for example, as enhancers of the therapeutic activity of such drugs or as means for reducing the required dosage or potential side effects of such drugs. The compounds of the present invention may be mixed with other drug substances in a certain pharmaceutical composition, or may be administered separately from, before, simultaneously with, or after other drug substances. Accordingly, the present invention includes combinations of the compounds of the present invention as described previously herein with anti-inflammatory drug substances, bronchodilator drug substances, antihistamine drug substances or antitussive drug substances, and the said compounds and the said drug substances of the present invention are in the same or different pharmaceutical compositions.

[0293] Suitable anti-inflammatory agents include steroids, especially glucocorticosteroids (e.g., budesonide, beclomethasone dipropionate, fluticasone propionate, ciclesonide or mometasone furoate); non-steroidal glucocorticoid receptor agonists; LTB4 antagonists (e.g., LY293111, CGS025019C, CP-195543, SC-53228, BIIL 284, ONO 4057, SB 209247); LTD4 antagonists (e.g., montelukast and zafirlukast); PDE4 inhibitors (e.g., cilomilast (Ariflo® GlaxoSmithKline), roflumilast (Byk Gulden), V-11294A (Napp), BAY19-8004 (Bayer), SCH-351591 (Schering-Plough), theophylline (Almirall Prodesfarma), PD189659 / PD168787 (Parke-Davis), AWD-12-281 (Asta Medica), CDC-801 (Celgene), SeICID(TM) CC-10004 (Celgene), VM554 / UM565 (Vernalis), T-440 (Tanabe), KW-4490 (Kyowa Hakko Kogyo)); A2a agonists; A2b antagonists; and beta-2 adrenergic receptor agonists (e.g., albuterol (salbutamol), metaproterenol, terbutaline, salmeterol, fenoterol, procaterol, and especially formoterol and its pharmaceutically acceptable salts). Suitable bronchodilator drugs include anticholinergic or antimuscarinic compounds, especially ipratropium bromide, oxitropium bromide, tiotropium salts and CHF 4226 (Chiesi), and glycopyrrolate.

[0294] Suitable antihistamine drug substances include cetirizine hydrochloride, acetaminophen, clemastine fumarate, promethazine, loratadine, desloratidine, diphenhydramine and pheniramine maleate, activastine, astemizole, azelastine, ebastine, epinastine, mizolastine and terfenadine.

[0295] Other useful combinations of the compounds of the present invention with anti-inflammatory drugs are antagonists of chemokine receptors such as CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, CCR-8, CCR-9 and CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, in particular CCR-5 antagonists such as the antagonists SC-351125, SCH-55700 and SCH-D of Schering-Plough, and antagonists of Takeda such as N-[[4-[[[6,7-dihydro-2-(4-methylphenyl)-5H-benzo-cyclohepten-8-yl]carbonyl]amino]phenyl]-methyl]tetrahydro-N,N-dimethyl-2H-pyran-4-aminium chloride (TAK-770).

[0296] The structure of the active compounds identified by code number, common name or trade name can be obtained from the current edition of the standard compendium "The Merck Index" or databases such as Patents International (e.g., IMS World Publications).

[0297] The compounds of the present invention can also be used in combination with known therapeutic processes such as the administration of hormones or radiation. In certain embodiments, the compounds provided are used as radiosensitizers, in particular for the treatment of tumors that show poor sensitivity to radiotherapy.

[0298] The compounds of the present invention can be administered alone or in combination with one or more other therapeutic compounds. Possible combination therapies can take the form of a fixed combination, or the administration of the compounds of the present invention and one or more other therapeutic compounds can be alternating or independent of each other, or can take the form of the administration of a fixed combination and one or more other therapeutic compounds in combination. The compounds of the present invention can be administered, in addition or in addition thereto, in particular for the treatment of tumors, in combination with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention, or a combination thereof. As described above, long-term treatment is possible in the context of other treatment strategies, as well as adjuvant treatment. Other possible treatments are treatments for maintaining the condition of the patient after tumor regression, or further, for example, chemopreventive treatment in patients at risk.

[0299] These additional agents can be administered as part of a multiple dosing regimen separately from the composition containing the compound of the present invention. Alternatively, these agents can be part of a single dosage form mixed together with the compound of this invention in a single composition. When administered as part of a multiple dosing regimen, the two active agents may be given simultaneously, sequentially or within a period of time from each other, usually within 5 hours of each other.

[0300] As used herein, the terms "combination", "combined" and related terms refer to the simultaneous or sequential administration of therapeutic agents according to the present invention. For example, the compounds of the present invention can be administered with another therapeutic agent, simultaneously or sequentially in another unit dosage form or together in a single unit dosage form. Accordingly, the present invention provides a single unit dosage form comprising a compound of the present invention, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0301] The amounts of both the compounds of the invention and additional therapeutic agents (in compositions containing such additional therapeutic agents as described above) that can be combined with a carrier material to produce a single dosage form will vary depending on the host being treated and the particular mode of administration. Preferably, the compositions of this invention should be formulated so that a dosage of between 0.01 and 100 mg of the compounds of the invention per kg of body weight per day can be administered.

[0302] In these compositions containing an additional therapeutic agent, the additional therapeutic agent and the compounds of this invention can act synergistically. Thus, the amount of the additional therapeutic agent in such compositions is less than the amount required in a monotherapy utilizing only that therapeutic agent. In such compositions, a dosage of between 0.01 and 1,000 μg of the additional therapeutic agent per kg of body weight per day can be administered.

[0303] The amount of the additional therapeutic agent present in the compositions of this invention is less than or equal to the amount normally administered in a composition containing that therapeutic agent as the sole active agent. Preferably, the amount of the additional therapeutic agent in the compositions of the present disclosure ranges from about 50% to 100% of the amount normally present in a composition containing that agent as the sole therapeutically active agent.

[0304] The compounds of this invention, or pharmaceutical compositions thereof, may also be incorporated into compositions for coating implantable medical devices such as prostheses, artificial valves, graft vessels, stents and catheters. For example, vascular stents are used to overcome restenosis (the re-narrowing of the vessel wall after injury). However, patients using stents or other implantable devices are at risk of blood clot formation or platelet activation. These unwanted effects can be prevented or reduced by pre-coating the device with a pharmaceutically acceptable composition containing a kinase inhibitor. An implantable device coated with a compound of this invention is another embodiment of the present invention.

[0305] The present invention is further described herein by means of non-limiting embodiments 1 to 32. Embodiment 1: Formula I: [Chemical formula] a compound of or a pharmaceutically acceptable salt thereof (wherein, 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- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, said ring being substituted with m examples of R 3B , R 5 is hydrogen or -L 1 -R 5A , R 6 is hydrogen, R A , or R B , or R 5 and R 6 together with the atoms therebetween form a 4- to 7-membered partially unsaturated or heteroaryl ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, said ring being substituted with R 5A or n examples of R C , R 7 is hydrogen, halogen, -NH2, -NHR 7A , or -NHC(O)R 7A , or R 6 and R 7 together with the atoms therebetween form a 4- to 7-membered partially unsaturated or heteroaryl ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, said ring being substituted with p examples of R C , L 1 is a covalent bond or a divalent saturated or unsaturated straight-chain or branched hydrocarbon chain of C 1~4 , wherein one or two methylene units of said chain are -C(R 5B )2-, -CH(R5B )-、-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- are each independently optionally replaced by R 3A 、R 3B 、 and R 7A are each independently R B and are each replaced by q instances of R C where two R substituents on the same carbon optionally combine to form a 3- to 6-membered saturated or partially unsaturated spiro-fused heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R substituents on adjacent carbons optionally combine to form a 3- to 6-membered saturated or partially unsaturated fused heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur C ; C R 5A 、 and R 5B each instance of which is independently R A or R B and are each replaced by r instances of R C ; R A each instance of which is independently oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, or -N(R)S(O)2R; R B each instance of which is independently C 1~6 ​A 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur, an 8- to 10-membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3- to 7-membered saturated or partially unsaturated carbocyclic ring, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 7- to 12-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, R C Each instance of is independently oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, or -N(R)S(O)2R, or C 1~6 A group optionally selected from a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein two optional substituents on the same carbon optionally combine together to form a 3- to 6-membered saturated or partially unsaturated spiro-fused heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two optional substituents on adjacent carbons optionally combine together to form a 3- to 6-membered saturated or partially unsaturated fused heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, Each R is independently hydrogen, or C 1~6A group selected from a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from aliphatic, phenyl, nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which is optionally substituted, or: Two R groups on the same nitrogen, together with the atoms between them, form, in addition to said nitrogen, a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, Each hydrogen bonded to carbon may be independently replaced by deuterium as needed, Each instance of m, n, p, q, and r is independently 0, 1, 2, 3, or 4, provided that the compound is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Examples

[0306] As shown in the following examples, in certain exemplary embodiments, compounds are prepared according to the following general procedures. The general methods illustrate the synthesis of certain compounds of the invention, but it will be recognized that the following general methods and other methods known to those skilled in the art are applicable to all compounds and to each subclass and species of these compounds, as described herein. Additional compounds of the invention were prepared by methods substantially similar to those described herein in the examples and by methods known to those of skill in the art. (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). Synthetic general procedure A (Buchwald amination):

Chemical formula

[0307] 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) were added 1.1 (0.193 g, 1.59 mmol, 1.2 equiv) and cesium carbonate (0.866 g, 2.66 mmol, 2.0 equiv). The reaction mixture was degassed for 10 minutes under an argon atmosphere, 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 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 was further purified by combiflash using 3% methanol in 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] + 。 General Procedure B: (Suzuki Coupling):

Chemical formula

[0308] 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, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (0.318 g, 0.43 mmol, 0.1 equiv) was added thereto, and purging was continued 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]+ 。 General procedure C (acid-amine coupling):

Chem.

[0309] 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), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (0.098 g, 0.26 mmol, 2.0 equiv) was added and the mixture was stirred at room temperature for 15 min. Diisopropylethylamine (0.06 mL, 0.39 mmol, 3.0 equiv) was added thereto, followed by the addition of (1S,2R)-2-fluorocyclopropan-1-amine (0.010 g, 0.13 mmol, 1.0 equiv). The reaction mixture was stirred at room temperature for 5 min. After completion of the reaction, the reaction mixture was transferred into water and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material. This was further purified by column chromatography and the compound was eluted with 40% ethyl acetate in hexane to give 1.5 (0.055 g, yield: 81.15%). MS (ES): m / z 498.24 [M+H] + 。 General procedure D (deprotection with triflic acid):

Chem.

[0310] Synthesis of Compound 1.6 (Compound I-5). Triflic acid (0.5 mL) was added 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. The reaction mixture was stirred at the same temperature for 10 minutes. After completion of the reaction, the reaction mixture was transferred into 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 was further purified by trituration with diethyl ether to give 1.6 (Compound I-5) (0.030 g, yield: 66.61%). MS (ES): m / z 408.19 [M+H] + . General procedure: Synthesis of ethyl-8-(benzyl(methyl)amino)-6-chloroimidazo[1,2-b]pyridazine-3-carboxylate applicable to related compounds containing benzyl protecting groups. [Chemical formula]

[0311] Synthesis of Compound 1.7. Bromine (12.4 g, 77.51 mmol, 1.0 equiv) was added to a mixture of 5 (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 hours. After completion of the reaction, the reaction mixture was transferred into water and the precipitated solid was collected by filtration and dried thoroughly to give 1.7 (7.0 g, yield: 43.50%). MS (ES): m / z 208.92 [M+H] + .

[0312] Synthesis of Compounds 1.9 and 1.10. A mixture of Compound 1.7 (5.0 g, 24.03 mmol, 1.0 equiv) and 1.8 (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 into water, and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine solution, dried over sodium sulfate, and concentrated under reduced pressure to obtain the crude material. This was further purified by column chromatography, eluting the compound in 2% methanol in dichloromethane to obtain 1.9 and 1.10 (1.3 g, yield: 20.84%). MS (ES): m / z 260.99 [M+H] + .

[0313] Synthesis of Compound 1.3. To a mixture of 1.9 and 1.10 (1.3 g, 5.0 mmol, 1.0 equiv) in 1,4-dioxane (15 mL) were added 1.11 (0.665 g, 5.5 mmol, 1.1 equiv) and triethylamine (0.858 g, 8.5 mmol, 1.7 equiv). 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, which 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] + . 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.

Chemical Structure

[0314] 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 into 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] + 。

[0315] 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 into water, and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to obtain a crude material. This was further purified by column chromatography, eluting the compound with 2% methanol in dichloromethane to obtain 1.14a and 1.14b (1.3 g, yield: 20.84%). MS (ES): m / z 260.99 [M+H] + 。

[0316] 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 and 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, which 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] + 。

[0317] 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). [Chemical formula]

[0318] Synthesis of Compound 1.3. The compound was synthesized using the general procedure for the above core synthesis to obtain 1.3. (Yield: 86.96%), MS (ES): m / z 345.11 [M+H] + .

[0319] Synthesis of Compound 1.4. Argon was passed through a stirred mixture of 2 (1.5 g, 4.36 mmol, 1.0 equivalent), 1.3 (1.9 g, 5.66 mmol, 1.3 equivalents) and potassium acetate (1.0 g, 10.9 mmol, 2.5 equivalents) in 1,4-dioxane (35 mL) for 15 minutes, then [bis(diphenylphosphino)ferrocene]palladium(II) dichloride (0.318 g, 0.43 mmol, 0.1 equivalent) was added to it and purging was carried out for an additional 10 minutes. The reaction mixture was stirred at 100 °C for 5 hours. After the reaction was complete, the reaction mixture was transferred into water and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to obtain 1.4 (0.8 g, yield: 34.86%). MS (ES): m / z 527.24 [M+H] + .

[0320] 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 into 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 a crude material. This was further purified by trituration with diethyl ether to obtain pure 1.16 (0.6 g, yield: 92.61%). MS (ES): m / z 427.18 [M+H] + .

[0321] Synthesis of Compound 1.17. To a suspension of sodium hydride (0.043 g, 1.82 mmol, 2 equiv) in dimethylformamide (4 mL) was added 1.16 (0.39 g, 0.91 mmol, 1.0 equiv) at 0 °C, and the mixture was stirred for 15 minutes, followed by the addition of 2-iodopropane (0.170 g, 1.00 mmol, 1.1 equiv). 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 was further purified by distillation to obtain pure 1.17 (0.250 g, yield: 58.35%). MS (ES): m / z 469.23 [M+H] + .

[0322] 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 mixture was stirred at temperature for 24 h. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to give a residue. Water was added thereto, and the mixture was acidified with 1N hydrochloric acid at 10 °C to adjust the pH to about 6 - 6.5. The product was extracted with dichloromethane. The organic layers were combined, washed with brine solution, dried over sodium sulfate, and concentrated under reduced pressure to give the crude material. This was further purified by column chromatography, eluting the compound in 2.1% methanol in dichloromethane to give pure 3 (0.210 g, yield: 89.35%). MS (ES): m / z 441.20 [M+H] + .

[0323] Synthesis of Compound 1.5. 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazol[4,5-b]pyridinium 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 thereto, followed by the addition of 1.18 (0.011 g, 0.15 mmol, 1.2 eq). The reaction mixture was stirred at room temperature for 5 min. After the reaction was complete, the reaction mixture was transferred into water, and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine solution, dried over sodium sulfate, and concentrated under reduced pressure to give the crude material. This was further purified by column chromatography, eluting the compound in 40% ethyl acetate in hexane to give 1.5 (0.055 g, yield: 81.15%). MS (ES): m / z 498.24 [M+H] + .

[0324] Synthesis of Compound 1.6 (I-5). A solution of 1.5 (0.055 g, 0.11 mmol, 1.0 equiv) in dichloromethane (1 mL) was cooled to 0 °C, and triflic acid (1 mL) was added. The reaction mixture was stirred at the same temperature for 10 minutes. After the reaction was complete, the reaction mixture was transferred into 1N sodium hydroxide solution, and the product was extracted with dichloromethane. The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to obtain the crude material. This 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 H 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). (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).

Chemical Structure

[0325] Synthesis of Compound 3.1. The compound was synthesized according to the experimental protocol used to prepare 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] + .

[0326] Synthesis of Compound 3.2. To a solution of 3.1 (0.1 g, 0.21 mmol, 1.0 equivalent) in N,N-dimethylformamide (2 mL) was added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazol[4,5-b]pyridinium 3-oxide hexafluorophosphate (0.159 g, 0.42 mmol, 2.0 equivalents), and the mixture was stirred at room temperature for 15 minutes. Diisopropylethylamine (0.1 mL, 0.63 mmol, 3.0 equivalents) was added thereto, followed by addition of 3.1 (0.018 g, 0.25 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 into water, and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine solution, dried over sodium sulfate, and concentrated under reduced pressure to obtain a crude material. This was further purified by column chromatography, and the compound was eluted with 40% ethyl acetate in hexane to obtain 3.2 (0.086 g, yield: 76.64%). MS (ES): m / z 425.21 [M+H] + .

[0327] Synthesis of Compound I-3: A solution of 3.2 (0.086 g, 0.20 mmol, 1.0 equivalent) in dichloromethane (1 mL) was cooled to 0 °C, and triflic 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 into 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 a crude material. This 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%, 11H NMR (DMSO-d6, 400 MHz): δ 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). (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). [Chemical formula]

[0328] Synthesis of Compound 4.3. To a solution of 4.1 (2 g, 18.18 mmol, 1.0 equiv) in 1,4-dioxane (40 mL) was added 4.2 (7.2 g, 45.45 mmol, 2.5 equiv). The reaction mixture was degassed under an argon atmosphere for 10 minutes, followed by the addition of potassium carbonate (7.5 g, 54.54 mmol, 3.0 equiv), N,N-dimethylethylenediamine (0.640 g, 7.27 mmol, 0.4 equiv) and copper(I) iodide (0.692 g, 3.636 mmol, 0.2 equiv). 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 brine solution, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material. This was further purified by 3% methanol in dichloromethane to give 4.3 (2 g, yield: 58.82%). MS (ES): m / z 188.20 [M + H] + .

[0329] Synthesis of Compound 1.3. The compound was synthesized using the general procedure for core synthesis to obtain 1.3 (yield: 86.96%). MS (ES): m / z 345.11 [M+H] + .

[0330] Synthesis of Compound 4.4. To a solution of 1.3 (1.2 g, 3.48 mmol, 1.0 equiv) in 1,4-dioxane (20 mL) was added 4.3 (0.779 g, 4.17 mmol, 1.2 equiv), cesium carbonate (2.2 g, 6.96 mmol, 2.0 equiv). The reaction mixture was degassed under an argon atmosphere for 10 minutes, then copper(I) iodide (0.132 g, 4.17 mmol, 0.2 equiv), tris(dibenzylideneacetone)dipalladium(0) (0.159 g, 0.69 mmol, 0.05 equiv) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.201 g, 0.34 mmol, 0.1 equiv) were added, followed by further degassing 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 was further purified by combiflash using 3% methanol in dichloromethane as the eluent to obtain pure 4.4. (0.650 g, 37.69%). MS (ES): m / z 496.21 [M+H] + .

[0331] Synthesis of Compound 3.1. Lithium hydroxide (0.314 g, 13.1 mmol, 10 equivalents) was added to a solution of 4.4 (0.260 g, 1.31 mmol, 1.0 equivalent) in methanol:tetrahydrofuran:water (12 mL, 2:2:1). The reaction mixture was stirred at room temperature for 24 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give a residue. Water was added thereto, and the mixture was acidified with 1 N hydrochloric acid at 10 °C to adjust the pH to about 6 - 6.5. The product was extracted with dichloromethane. The organic layers were combined, washed with brine solution, dried over sodium sulfate, and concentrated under reduced pressure to give a crude material. This was further purified by column chromatography, and the compound was eluted with 2.1% methanol in dichloromethane to give pure 3.1 (0.4 g, yield: 65.23%). MS (ES): m / z 468.17 [M + H] + .

[0332] Synthesis of Compound 4.6. 1 - [Bis(dimethylamino)methylene]-1H-1,2,3-triazolopyridinium 3-oxide hexafluorophosphate (0.159 g, 0.42 mmol, 2.0 equivalents) was added to a solution of 3.1 (0.1 g, 0.21 mmol, 1.0 equivalent) 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 equivalents) was added thereto, followed by the addition of 4.5 (0.015 g, 0.25 mmol, 1.2 equivalents). The reaction mixture was stirred at room temperature for 5 min. After completion of the reaction, the reaction mixture was transferred into water, and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine solution, dried over sodium sulfate, and concentrated under reduced pressure to give a crude material. This was further purified by column chromatography, and the compound was eluted with 40% ethyl acetate in hexane to give 4.6 (0.080 g, yield: 73.83%). MS (ES): m / z 507.22 [M + H] + .

[0333] 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 triflic acid (1 mL) was added. The reaction mixture was stirred at the same temperature for 10 minutes. After the reaction was complete, the reaction mixture was transferred into 1N sodium hydroxide solution, and the product was extracted with dichloromethane. The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to obtain the crude material. This 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): 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). (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).

Chemical Structure

[0334] Synthesis of Compound 1.3. The compound was synthesized according to the above-described experimental protocol for Compound I-5 in Example 1 to obtain 1.3 (yield: 92.61%). MS(ES): m / z 427.18 [M+H] + .

[0335] Synthesis of Compound 5.2. To a suspension of sodium hydride (0.027 g, 1.16 mmol, 2.0 equiv) in dimethylformamide (3 mL) was added 1.3 (0.250 g, 0.58 mmol, 1.0 equiv) at 0 °C, and the mixture was stirred for 15 minutes, followed by the addition of 5.1 (0.095 g, 0.63 mmol, 1.1 equiv). 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 combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to obtain a solid. This was further purified by distillation to obtain pure 5.2 (0.260 g, yield: 82.19%). MS (ES): m / z 540.27 [M+H] + .

[0336] Synthesis of Compound 5.3. To a solution of 5.2 (0.260 g, 0.48 mmol, 1.0 equiv) in methanol:tetrahydrofuran:water (6 mL, 2:2:1) was added lithium hydroxide (0.115 g, 4.8 mmol, 10 equiv). The reaction was stirred at room temperature for 24 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain a residue. Water was added thereto, and the mixture was acidified with 1 N hydrochloric acid at 10 °C to adjust the pH to about 6 - 6.5. The product was extracted with dichloromethane. The combined organic layers were washed with brine solution, dried over sodium sulfate, and concentrated under reduced pressure to obtain a crude material. This was further purified by column chromatography, eluting the compound in 2.1% methanol in dichloromethane to obtain pure 5.3 (0.190 g, yield: 77.08%). MS (ES): m / z 512.24 [M+H] + .

[0337] Synthesis of Compound 5.5. To a solution of 5.3 (0.050 g, 0.097 mmol, 1.0 equiv) in N,N-dimethylformamide (1 mL) was added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (0.073 g, 0.19 mmol, 2.0 equiv), and the mixture was stirred at room temperature for 15 minutes. Diisopropylethylamine (0.05 mL, 0.291 mmol, 3.0 equiv) was added thereto, followed by the addition of 5.4 (0.010 g, 0.11 mmol, 1.2 equiv). The reaction mixture was stirred at room temperature for 5 minutes. After the reaction was completed, the reaction mixture was transferred into water, and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine solution, dried over sodium sulfate, and concentrated under reduced pressure to obtain a crude material. This was further purified by column chromatography, and the compound was eluted with 40% ethyl acetate in hexane to obtain 5.5 (0.050 g, yield: 89.96%). MS (ES): m / z 569.27 [M+H] + .

[0338] Synthesis of Compound I-6: A solution of 5.5 (0.050 g, 0.087 mmol, 1.0 equiv) in dichloromethane (1 mL) was cooled to 0 °C, and triflic acid (1 mL) was added. The reaction mixture was stirred at the same temperature for 10 minutes. After the reaction was completed, the reaction mixture was transferred into 1N sodium hydroxide solution, and the product was extracted with dichloromethane. The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to obtain a crude material. This was further purified by triturating 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 H 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 = 4Hz, 4H), 2.68 (bs, 2H), 1.31 - 1.26 (bs, 2H), 1.10 - 1.06 (bs, 2H). (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). [Chemical formula]

[0339] Synthesis of Compound 3. The compound was synthesized according to the experimental protocol for Compound 3 in Example 1 to obtain 3 (yield: 89.35%). MS(ES): m / z 441.20 [M + H] + .

[0340] 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]pyridinium 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 thereto, followed by the addition of 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 into water, and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine solution, dried over sodium sulfate, and concentrated under reduced pressure to obtain the crude material. This was further purified by column chromatography, and the compound was eluted with 40% ethyl acetate in hexane to obtain 6.2 (0.115 g, yield: 99.41%). MS (ES): m / z 510.26 [M+H] + .

[0341] 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 triflic 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 into 1N sodium hydroxide solution, and the product was extracted with dichloromethane. The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to obtain the crude material. This 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%, 1 H NMR (DMSO-d6, 400MHZ): 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).

[0342] Synthesis of Compound I - 10 and I - 7. The isomer of I - 15 (0.080 g) was separated using a chiral column (CHIRAL PAK OX - H 250×4.6 mm, 5u) and 0.1% DEA in HEX_IPA - MEOH (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 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 H 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 = 3.2Hz, 1H), 8.02 (s, 1H), 7.78 - 7.77 (d, J = 4.8Hz, 1H), 7.31 - 7.28 (m, 1H), 6.72 (s, 1H), 5.51 - 5.50 (d, J = 4Hz, 1H), 5.26 - 5.21 (m, 1H), 4.63 - 4.60 (t, J = 6.4Hz, 1H), 4.42 (bs, 1H), 3.08 - 3.06 (d, J = 4.8Hz, 3H), 1.79 (bs, 1H), 1.59 - 1.57 (d, J = 6.4Hz, 6H), 1.24 (bs, 1H), 1.06 - 1.04 (d, J = 6Hz, 2H).

[0343] 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 H NMR (DMSO-d6, 400MHZ): 9.35 - 9.33 (d, J = 8.4 Hz, 1H), 8.75 - 8.74 (d, J = 7.6Hz, 1H), 8.68 (s, 1H), 8.40 - 8.39 (d, J = 3.2Hz, 1H), 8.02 (s, 1H), 7.78 - 7.77 (d, J = 4.8Hz, 1H), 7.31 - 7.28 (m, 1H), 6.72 (s, 1H), 5.51 - 5.50 (d, J = 4Hz, 1H), 5.26 - 5.21 (m, 1H), 4.63 - 4.60 (t, J = 6.4Hz, 1H), 4.42 (bs, 1H), 3.08 - 3.06 (d, J = 4.8Hz, 3H), 1.79 (bs, 1H), 1.59 - 1.57 (d, J = 6.4Hz, 6H), 1.24 (bs, 1H), 1.06 - 1.04 (d, J = 6Hz, 2H). (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).

Chem.

Chem.

[0344] 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] + 。

[0345] Synthesis of Compound 7.2. To a solution of 7.2 (0.3 g, 0.70 mmol, 1.0 equiv) in dimethylformamide (3 mL) were added 7.1 (1.1 g, 7.0 mmol, 10.0 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 into water and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material. This was further purified by column chromatography, eluting the compound with 1% methanol in dichloromethane to give 7.2 (0.220 g, yield: 61.25%). MS (ES): m / z 511.24 [M+H] +

[0346] 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 a residue. Water was added thereto and the mixture was acidified with 1N hydrochloric acid at 10 °C to adjust the pH to about 6 - 6.5. The product was extracted with dichloromethane. The organic layers were combined, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material. This was further purified by column chromatography, eluting the compound with 2.1% methanol in dichloromethane to give pure 7.3 (0.170 g, yield: 81.77%). MS (ES): m / z 483.21 [M+H] +

[0347] Synthesis of Compound 7.5. The compound was synthesized using General Procedure C to give 7.5 (0.150 g, yield: 77.18%). MS (ES): m / z 552.27 [M+H] + 。

[0348] 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%, 1 H 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).

[0349] 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, 5u) 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 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] + .

[0350] Synthesis of Compound I-11: The compound was synthesized using General Procedure D to obtain I-11 (0.032 g, yield: 85%). MS (ES): m / z 462.41 [M+H] + LCMS purity: 100%, HPLC purity: 99.21%, 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 - 7.75 (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).

[0351] Synthesis of Compound I-8: The compound was synthesized using General Procedure D 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%; 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 - 7.74 (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). (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). [Chemical Structure] [Chemical Structure]

[0352] 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] + .

[0353] Synthesis of Compound 8.2. To a solution of 5.3 (0.1 g, 0.19 mmol, 1.0 equiv) in N,N-dimethylformamide (1 mL) was added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (0.144 g, 0.38 mmol, 2.0 equiv), and the mixture was stirred at room temperature for 15 minutes. Diisopropylethylamine (0.1 mL, 0.57 mmol, 3.0 equiv) was added thereto, followed by the addition of 8.1 (0.019 g, 0.22 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 into water, and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine solution, dried over sodium sulfate, and concentrated under reduced pressure to obtain a crude material. This was further purified by column chromatography, and the compound was eluted with 40% ethyl acetate in hexane to obtain 8.2. (0.110 g, yield: 96.91%). MS (ES): m / z 581.29 [M+H] + .

[0354] Synthesis of Compound I-16. To Compound 8.2 (0.110 g, 0.18 mmol, 1.0 equiv) was added 4M hydrochloric acid in 1,4-dioxane (3 mL), 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, 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%. 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).

[0355] Synthesis of Compounds I-12 and I-9. An isomer of I-16 (0.080 g) was separated using a column (CHIRAL PAK OX-H 250×4.6 mm, 5u) and a co-solvent of hexane / i-PrOH-MeOH (50 - 50) with 0.1% DEA 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%, 1 H 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 = 3.6Hz, 1H), 4.61 (bs, 1H), 4.51 - 4.48 (t, J = 6.4Hz, 2H), 4.42 (bs, 1H), 3.52 (s, 4H), 3.06 - 3.05 (d, J = 4.8Hz, 3H), 2.84 - 2.81 (t, J = 6.4Hz, 2H), 2.14 - 2.06 (m, 2H), 1.78 (bs, 1H), 1.57 (bs, 1H), 1.24 (bs, 2H), 0.90 (bs, 2H).

[0356] 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 H NMR (DMSO-d6, 400 MHz): 9.33 - 9.31 (d, J = 8Hz, 1H), 8.76 - 8.74 (d, J = 6Hz, 1H), 8.61 (s, 1H), 8.45 (bs, 2H), 8.39 - 8.38 (d, J = 4Hz, 1H), 8.02 (s, 1H), 7.80 - 7.79 (d, J = 4.4Hz, 1H), 7.31 - 7.28 (m, 1H), 6.65 (s, 1H), 4.61 (bs, 1H), 4.50 - 4.48 (t, J = 6.4Hz, 2H), 4.43 (bs, 1H), 3.55 (s, 4H), 3.06 - 3.05 (d, J = 4.8Hz, 3H), 2.84 - 2.81 (t, J = 6.4Hz, 2H), 2.13 - 2.06 (m, 2H), 1.81 (bs, 2H), 1.57 (bs, 1H), 1.24 (bs, 2H). (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). [Chemical formula]

[0357] 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] + .

[0358] Synthesis of compound 1.17. To a solution of 1.16 (0.4 g, 0.82 mmol, 1.0 equivalent) in dimethylformamide (6 mL) were added isopropyl iodide (0.2 mL, 2.05 mmol, 2.5 equivalents) and cesium carbonate (1.3 g, 4.1 mmol, 5.0 equivalents). The reaction mixture was stirred at 110 °C for 3 hours. After the reaction was complete, 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 was further purified by column chromatography and the compound was eluted with 20% ethyl acetate in hexane to obtain 1.17 (0.3 g, yield: 78.02%). MS (ES): m / z 426.23 [M+H] + .

[0359] Synthesis of Compound 3. To a solution of 1.17 (0.3 g, 0.64 mmol, 1.0 equiv) in tetrahydrofuran:methanol:water (8 mL, 2:1:1), lithium hydroxide (0.153 g, 6.4 mmol, 10.0 equiv) was added. 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 give a residue. Water was added thereto, and the mixture was acidified with 1N hydrochloric acid at 10 °C to adjust the pH to about 6 - 6.5. The product was extracted with dichloromethane. The organic layers were combined, washed with brine solution, dried over sodium sulfate, and concentrated under reduced pressure to obtain a crude material. This was further purified by column chromatography, eluting the compound in 2.1% methanol in dichloromethane to give pure 3 (0.262 g, yield: 92.90%). MS (ES): m / z 441.20 [M+H] + .

[0360] Synthesis of Compound 9.2. The compound was synthesized using General Procedure C to give 9.2 (0.250 g, yield: 79.97%). MS (ES): m / z 526.25 [M+H] + .

[0361] Synthesis of Compound 9.3 (I - 32). The compound was synthesized using General Procedure D to give 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 H NMR (DMSO - d6, 400 MHz): 9.20 - 9.18 (d, J = 7.6Hz, 1H), 8.67 - 8.65 (d, J = 7.6Hz, 1H), 8.63 (s, 1H), 8.39 - 8.38 (d, J = 3.6Hz, 1H), 8.05 (s, 1H), 7.80 - 7.79 (d, J = 4.8Hz, 1H), 7.28 - 7.25 (m, 1H), 6.71 (s, 1H), 5.64 - 5.63 (d, J = 4Hz, 1H), 5.23 - 5.20 (m, 1H), 4.33 (s, 1H), 4.05 - 3.98 (m, 3H), 3.61 - 3.57 (t, J = 8Hz, 1H), 3.07 - 3.06 (d, J = 4Hz, 3H), 1.58 - 1.57 (d, J = 4.8Hz, 6H), 1.25 (bs, 1H).

[0362] Synthesis of Compounds 9.2a and 9.2b. The isomers of 9.2 (0.2 g) were separated using column CHIRALPAK AD-H (250 mm * × 4.6 mm, 5 μm) and a flow rate of 4 mL / min with 0.1% DEA MEOH:MeCN (50:50) as the co-solvent 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] + .

[0363] 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).

[0364] 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%; 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 - 7.77 (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). (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).

Chemical Structure

Chemical Structure

[0365] Synthesis of Compound 10.2. To a solution of 10 (2.5 g, 22.70 mmol, 1.0 equivalent) in 1 - methylpyrrolidin - 2 - one (50 mL), 10.1 (3.4 g, 29.51 mmol, 1.3 equivalents) was added, followed by the addition of tripotassium phosphate tribasic acid (12.04 g, 56.80 mmol, 2.5 equivalents). The reaction mixture was heated at 90 - 100 °C for 22 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, transferred to cold water, and the product was extracted with ethyl acetate. The combined organic layers were washed with brine solution followed by water, dried over sodium sulfate, and concentrated under reduced pressure to obtain the crude material. This was further purified by column chromatography using 2.0% methanol in dichloromethane as the eluent to obtain 10.2 (2.3 g, 49.37%). MS(ES): m / z 206.02 [M + H] + 。

[0366] Synthesis of Compound 10.3. The compound was synthesized according to the experimental protocol of the core synthesis described above to obtain 10.3. (Yield: 20.84%), MS(ES): m / z 260.99 [M + H] + 。

[0367] Synthesis of Compound 10.4. To a solution of 10.3 (8.0 g, 30.76 mmol, 1.0 equiv) in tetrahydrofuran (100 mL) was added potassium carbonate (8.4 g, 61.52 mmol, 2.0 equiv), followed by addition of methylamine (2.0 g, 30.76 mmol, 2.0 equiv). 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 followed by water, dried over sodium sulfate, and concentrated under reduced pressure to give 10.4 (5.0 g, yield: 63.83%). MS (ES): m / z 255.06 [M+H] + 。

[0368] Synthesis of Compound 10.5. To a solution of 10.4 (0.5 g, 1.96 mmol, 1.0 equiv) in 1,4-dioxane (8 mL) were added 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), 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 a crude material. This was further purified by column chromatography, eluting the compound in 20% ethyl acetate in hexane to give pure 10.5 (0.480 g, yield: 68.91%). MS (ES): m / z 355.11 [M+H] + 。

[0369] Synthesis of Compound 10.6. To a suspension of 10.5 (0.480 g, 1.35 mmol, 1.0 equiv) in toluene (5 mL) was added tributyltin oxide (1.6 g, 2.7 mmol, 2.0), 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 give a residue, which was dissolved in saturated sodium bicarbonate solution and washed with hexane. The aqueous layer was separated, acidified with 1 N hydrochloric acid to pH about 5 - 6, and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give a solid, which was triturated with hexane to give pure 10.6 (0.350 g, yield: 79.18%). MS (ES): m / z 327.08 [M + H] + .

[0370] Synthesis of Compound 10.8. To a solution of 10.6 (2.0 g, 6.13 mmol, 1.0 equiv) in N,N-dimethylformamide was added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazol[4,5-b]pyridinium 3-oxide hexafluorophosphate (4.65 g, 12.26 mmol, 2.0 equiv), and the mixture was stirred at room temperature for 15 min. To this was added diisopropylethylamine (3.2 mL, 18.39 mmol, 3.0 equiv), followed by 10.7 (0.619 g, 6.13 mmol, 1.0 equiv). The reaction mixture was stirred at room temperature for 5 min. After completion of the reaction, the reaction mixture was poured into water, and the product was extracted with ethyl acetate. The combined organic layers were washed with brine solution, dried over sodium sulfate, and concentrated under reduced pressure to give a crude material. This was further purified by column chromatography, eluting the compound in 40% ethyl acetate in hexane to give 10.8. (1.6 g, yield: 63.77%), MS (ES): m / z 410.16 [M + H] + .

[0371] Synthesis of Compound 10.9. To a solution of 10.8 (0.175 g, 0.42 mmol, 1.0 equiv) in 1,4-dioxane (3 mL) were added 10.2 (0.103 g, 0.50 mmol, 1.2 equiv) and sodium 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) (0.019 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 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 combined organic layers were washed with brine solution, dried over sodium sulfate, and concentrated under reduced pressure to obtain the crude material. This was further purified by combiflash using 3% methanol in dichloromethane as the eluent to give pure 10.9 (0.160 g, 64.77%). MS (ES): m / z 579.24 [M+H] + .

[0372] Synthesis of Compound I-17. Compound 10.9 (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 combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material. This was further purified by trituration with diethyl ether to give pure 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%, 11H 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). (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). [Chemical formula]

[0373] Synthesis of Compound 11. The compound was synthesized according to the above experimental protocol in Example 9 to obtain 11 (yield: 63.77%). MS(ES): m / z 410.16 [M + H] + .

[0374] Synthesis of Compound 11.1. The compound was synthesized 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] + .

[0375] 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) were added 11.1 (0.103 g, 0.50 mmol, 1.2 equiv) and sodium 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′-triisopropylbiphenyl (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 was further purified by combiflash using 3% methanol in dichloromethane as the eluent to obtain pure 11.2 (0.170 g, yield: 71.02%). MS(ES): m / z 561.25 [M+H] + .

[0376] 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 was further purified by trituration with diethyl ether to obtain pure 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%; 1 1H NMR (DMSO-d6, 400 MHz): 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). (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). [Chemical formula]

[0377] 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 under an argon atmosphere for 10 minutes, followed by the addition of 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). The reaction mixture was heated at 115 °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 brine solution, dried over sodium sulfate and concentrated under reduced pressure to give the crude material. This was further purified by 5% methanol in dichloromethane to give 12.2 (1.56 g, yield: 44.45%). MS (ES): m / z 202.09 [M + H] + .

[0378] Synthesis of Compound 12.3. The compound was synthesized according to the experimental protocol described above in Example 9 to obtain 12.3 (yield: 63.77%). MS (ES): m / z 410.16 [M+H] + .

[0379] 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) were added 12.2 (0.103 g, 0.50 mmol, 1.2 equiv) and sodium 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′-triisopropylbiphenyl (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 was further purified by combiflash using 3% methanol in dichloromethane as the eluent to obtain pure 12.4. (0.160 g, yield: 65.21%). MS (ES): m / z 575.27 [M+H] + .

[0380] 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 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 was further purified by trituration with diethyl ether to obtain pure 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%, 1 1H NMR (DMSO-d6, 400 MHz): 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). (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).

Chemical Structure

[0381] Synthesis of Compound 13.2. 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) was added copper(II) acetate (2.60 g, 14.28 mmol, 1.0 equiv) and triethylamine (5.00 mL, 35.7 mmol, 2.5 equiv) under nitrogen. The reaction mixture was stirred at 80 °C for 5 h. After completion of the reaction, the reaction mixture was transferred into ice-cold water and the product was extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure to give the crude material. This was further purified by column chromatography, eluting the compound in 10% ethyl acetate in hexane to give pure 13.2 (0.380 g, 11.98%). MS (ES): m / z 222.20 [M+H] + .

[0382] Synthesis of Compound 13.3. To a solution of 13.1 (0.380 g, 1.71 mmol, 1.0 equiv) in methanol (4 mL) was added palladium on carbon (0.100 g). The reaction mixture was purged with hydrogen at room temperature for 3 h. After completion of the reaction, the reaction mixture was filtered through a celite bed and washed with methanol. The filtrate was concentrated under reduced pressure to give the crude material. This was further purified by column chromatography, eluting the compound in 1.4% methanol in dichloromethane to give pure 13.3 (0.120 g, 36.13%). MS (ES): m / z 195.23 [M+H] + .

[0383] Synthesis of Compound 13.4. The compound was synthesized using the general procedure for core synthesis described above to give 13.4. (Yield: 71.67%). MS (ES): m / z 327.08 [M+H] + .

[0384] Synthesis of Compound 13.6. To a solution of 13.4 (2.0 g, 6.11 mmol, 1.0 equiv) in dichloromethane (30 mL) was added propylphosphonic anhydride (3.8 g, 12.22 mmol, 2.0 equiv), and the mixture was stirred at room temperature for 15 minutes. Triethylamine (1.8 g, 18.33 mmol, 3.0 equiv) was added thereto, followed by the addition of 13.5 (0.740 g, 7.33 mmol, 1.2 equiv). The reaction mixture was stirred at room temperature for 5 minutes. After the reaction was completed, the reaction mixture was transferred into water, and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine solution, dried over sodium sulfate, and concentrated under reduced pressure to obtain the crude material. This was further purified by column chromatography, eluting the compound with 40% ethyl acetate in hexane to obtain 13.6 (1.6 g, yield: 63.77%). MS (ES): m / z 410.16 [M+H] + .

[0385] 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) were added 13.3 (0.097 g, 0.50 mmol, 1.2 equiv) and sodium 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′-triisopropylbiphenyl (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 the reaction was completed, the reaction mixture was cooled to room temperature, transferred into water, and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine solution, dried over sodium sulfate, and concentrated under reduced pressure to obtain the crude material. This was further purified by combiflash using 3% methanol in dichloromethane as the eluent to obtain pure 13.7 (0.150 g, yield: 61.89%). MS (ES): m / z 568.28 [M+H] + .

[0386] Synthesis of Compound I-20. Compound 13.7 (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 the reaction was completed, the reaction mixture was transferred into 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 was further purified by trituration with diethyl ether to obtain pure 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%; 1 1H NMR (DMSO-d6, 400 MHz): 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). (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).

Chemical Structure

Chemical Structure

[0387] Synthesis of Compound 14.1. To a solution of 14 (4 g, 34.73 mmol, 1.0 equiv) in dichloromethane (40 mL) was added imidazole (7 g, 104.19 mmol, 3.0 equiv) and tert-butyldimethylsilyl chloride (7.8 g, 52.09 mmol, 1.5 equiv) at 0 °C. The reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, the reaction mixture was transferred into 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 was further purified by combiflash using 5% methanol in dichloromethane as the eluent to obtain 14.1 (5.2 g, 65.26%). MS (ES): m / z 230.44 [M+H] + 。

[0388] Synthesis of Compound 14.3. To a solution of 14.1 (5.2 g, 22.66 mmol, 1.0 equiv) in dimethylformamide (50 mL) was added 14.2 (3.4 g, 22.66 mmol, 1.0 equiv). The reaction mixture was stirred at room temperature for 1 h, followed by the addition of N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (6.5 g, 33.99 mol, 1.5 equiv) and 4-dimethylaminopyridine (0.69 g, 5.66 mmol, 0.25 equiv). The reaction was stirred at room temperature for 16 h. After completion of the reaction, the reaction mixture was transferred into 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 was further purified by combiflash using 30% ethyl acetate in hexane as the eluent to obtain 14.3 (1.8 g, 21.73%). MS (ES): m / z 366.55 [M+H] + 。

[0389] Synthesis of Compound 14.4. Hydrochloric acid (10 mL) in 1,4-dioxane was added to 14.3 (1.8 g, 4.92 mmol, 1.0 equivalent). The reaction mixture was stirred at room temperature for 1 hour. 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] + .

[0390] Synthesis of Compound 14.5. Sodium hydride (0.10 g, 7.17 mmol, 1.5 equivalents) was added to a solution of 14.4 (1.2 g, 4.78 mmol, 1.0 equivalent) in tetrahydrofuran (10 mL) at 0 °C, followed by the addition of methyl iodide (0.67 g, 4.78 mmol, 1.0 equivalent). The reaction mixture 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 a crude material. This was further purified by combiflash using 1.4% methanol in dichloromethane as the eluent to obtain 14.5 (0.78 g, 61.56%). MS (ES): m / z 266.31 [M+H] + .

[0391] Synthesis of Compound 14.6. Lithium hydroxide (1.2 g, 29.4 mmol, 10 equivalents) was added to a solution of 14.5 (0.78 g, 2.94 mmol, 1.0 equivalent) in tetrahydrofuran:methanol:water (5 mL, 1:1:1). The reaction was stirred at 70 °C for 3 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain a residue. Water was added thereto and the mixture was acidified with 1N hydrochloric acid at 10 °C to adjust the pH to about 6 - 6.5. The product was extracted with dichloromethane. The organic layers were combined, washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to obtain 14.6 (0.65 g, 87.99%). MS (ES): m / z: 252.28 [M+H] + .

[0392] Synthesis of Compound 14.7. To a solution of 14.6 (0.65 g, 2.59 mmol, 1.0 equiv) in tert-butanol (6 mL) were added diphenylphosphoryl azide (1.1 g, 4.14 mmol, 1.6 equiv) and trimethylamine (10 mL, 7.7 mmol, 3.0 equiv). The reaction mixture was heated at 80 °C for 18 h. After completion of the reaction, the reaction mixture was transferred into 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 was further purified by combi-flash using 5% ethyl acetate in hexane as the eluent to give 14.7 (0.38 g, 45.56%). MS (ES): m / z 323.41 [M+H] + .

[0393] Synthesis of Compound 14.8. Hydrochloric acid (1 mL) in 1,4-dioxane was added to 14.7 (0.38 g, 1.18 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 give a residue, which was stirred with diethyl ether and filtered to give pure 14.8 (0.20 g, 76.34%). MS (ES): m / z 223.29 [M+H] + .

[0394] Synthesis of Compound 14.9. The compound was synthesized according to the experimental protocol described above in Example 12 to give 14.9 (yield: 63.77%). MS (ES): m / z 410.16 [M+H] + .

[0395] 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) were added 14.8 (0.111 g, 0.50 mmol, 1.2 equiv) and sodium 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′-triisopropylbiphenyl (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 combined organic layers were washed with brine solution, dried over sodium sulfate, and concentrated under reduced pressure to obtain the crude material. This was further purified by combiflash using 3% methanol in dichloromethane as the eluent to give pure 14.10 (0.153 g, yield: 60.16%). MS (ES): m / z 596.32 [M+H] + .

[0396] 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 saturated bicarbonate solution, and the product was extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material. This was further purified by trituration with diethyl ether to give pure 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%, 1 1H NMR (DMSO-d6, 400 MHz): 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). (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). [Chemical formula]

[0397] 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 h, followed by the addition of 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). The reaction was stirred at room temperature for 16 h. After completion of the reaction, the reaction mixture was transferred into ice-cold water, and the product was extracted with ethyl acetate. The combined organic layers were washed with brine solution, dried over sodium sulfate, and concentrated under reduced pressure to obtain the crude material. This was further purified by combiflash using 30% ethyl acetate in hexane as the eluent to give 15.1 (0.180 g, yield: 47.17%). MS(ES): m / z 236.24 [M+H] + .

[0398] Synthesis of Compound 15.2. To a solution of 15.1 (0.180 g, 0.765 mmol, 1.0 equiv) in tetrahydrofuran:methanol:water (5 mL, 1:1:1) was added lithium hydroxide (0.160 g, 3.82 mmol, 5.0 equiv). 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 thereto, and the mixture was acidified with 1N hydrochloric acid at 10 °C to adjust the pH to about 6 - 6.5. The product was extracted with dichloromethane. The combined organic layers were washed with brine solution, dried over sodium sulfate, and concentrated under reduced pressure to give 15.2 (0.140 g, yield: 82.71%). MS(ES): m / z 222.07 [M+H] + .

[0399] Synthesis of Compound 15.3. To a solution of 15.2 (0.140 g, 0.632 mmol, 1.0 equiv) in tert-butyl alcohol were added diphenylphosphoryl azide (0.226 g, 0.821 mmol, 1.3 equiv) and triethylamine (0.108 g, 1.074 mmol, 1.7 equiv). The reaction mixture was stirred at 90 °C for 16 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the crude material. This was further purified by combiflash using 1.0% MeOH in dichloromethane as the eluent to give 15.3 (0.150 g, yield: 81.08%). MS (ES): m / z 293.34 [M+H] + .

[0400] Synthesis of Compound 15.4. To 15.3 (0.150 g, 0.513 mmol, 1.0 equiv) was added 4 M hydrochloric acid (7 mL) in 1,4-dioxane, 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 give 15.4 (0.090 g, 76.70%). MS (ES): m / z 193.09 [M+H] + .

[0401] Synthesis of Compound 15.5. The compound was synthesized according to the experimental protocol described in Example 12 to give 15.5 (yield: 63.77%). MS (ES): m / z 410.16 [M+H] +

[0402] 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) were added 15.4 (0.096 g, 0.50 mmol, 1.2 equiv) and sodium 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′-triisopropylbiphenyl (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 was further purified by combiflash using 3% methanol in dichloromethane as the eluent to obtain pure 15.6 (0.140 g, yield: 57.97%). MS(ES): m / z 566.27 [M+H] + .

[0403] 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 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 was further purified by trituration with diethyl ether to obtain pure I-22 (0.016 g, 77.76%). MS(ES): m / z 466.86 [M+H] + LCMS purity: 100%, HPLC purity: 97.40%, CHIRALHPLC: 49.41%, 49.24%, 11H NMR (DMSO-d6, 400 MHz): 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). (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). [Chemical formula]

[0404] 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), 16.1 (3.99 g, 32.44 mmol, 1.0 equiv) was added. The reaction mixture was stirred at 0 °C for 30 minutes and then 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 the reaction was complete, the reaction mixture was transferred into water, and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine solution, dried over sodium sulfate, and concentrated under reduced pressure to obtain the crude material. This was further purified by column chromatography, eluting the compound in 1.7% methanol in dichloromethane to obtain 16.2 (3.35 g, 46.26%). MS(ES): m / z 224.09 [M+H] + .

[0405] Synthesis of Compound 16.3. To a cooled solution of 16.2 (3.35 g, 15.02 mmol, 1.0 equiv) in N,N-dimethylformamide (35 mL), sodium hydride (1.44 g, 6.08 mmol, 4.0 equiv) was added portionwise at 0 °C, stirred for 30 minutes, and then methyl iodide (2.7 g, 19.52 mmol, 1.3 equiv) was added dropwise. The reaction mixture was stirred at the same temperature for 20 minutes and the mixture was stirred at room temperature for 6 hours. After the reaction was complete, the reaction mixture was transferred into ice water, and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine solution, dried over sodium sulfate, and concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography eluting with 2 - 2.5% methanol in dichloromethane to obtain pure 16.3 (2.85 g, 80.04%). MS(ES): m / z 238.10 [M+H] + .

[0406] Synthesis of Compound 16.4. To a solution of 16.3 (2.85 g, 12.02 mmol, 1.0 equiv) in tetrahydrofuran:water (30 mL, 2:1) was added lithium hydroxide (2.88 g, 120.2 mmol, 10 equiv). The reaction mixture was stirred at 60 °C for 16 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give a residue. Water was added thereto, and the mixture was acidified with 1N hydrochloric acid at 10 °C to adjust the pH to about 6 - 6.5. The product was extracted with dichloromethane. The organic layers were combined, washed with brine solution, dried over sodium sulfate, and concentrated under reduced pressure to give a crude material. This was further purified by column chromatography, eluting the compound in 2.1% methanol in dichloromethane to give pure 16.4 (2.4 g, 89.50%). MS (ES): m / z 224.09 [M + H] + .

[0407] Synthesis of Compound 16.5. To a solution of 16.4 (2.4 g, 10.76 mmol, 1.0 equiv) in tert-butanol (25 mL) were added triethylamine (1.84 g, 18.29 mmol, 1.7 equiv) and diphenylphosphoryl azide (3.84 g, 13.98 mmol, 1.3 equiv) under nitrogen, and the mixture was subsequently heated at 80 °C for 16 h. After completion of the reaction, the reaction mixture was cooled to room temperature, transferred into water, and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine solution, dried over sodium sulfate, and concentrated under reduced pressure to give a crude material. This was further purified by column chromatography, eluting the compound in 22% ethyl acetate in hexane to give pure 16.5 (2.0 g, 63.20%). MS (ES): m / z 295.16 [M + H] + .

[0408] Synthesis of Compound 16.6. To a cooled solution of 16.5 (2.0 g, 6.80 mmol, 1 equiv) in dioxane (20 mL) was added dropwise 4N hydrochloric acid in dioxane (22 mL). 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 give pure 16.6 (1.4 g, 89.32%). MS (ES): m / z 195.11 [M + H] + .

[0409] 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] + .

[0410] Synthesis of Compound 16.8. To a solution of 16.7 (0.175 g, 0.42 mmol, 1.0 eq) in 1,4-dioxane (3 mL) were added 16.6 (0.097 g, 0.50 mmol, 1.2 eq) and sodium carbonate (0.088 g, 0.84 mmol, 2.0 eq). 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 eq) and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (0.019 g, 0.042 mmol, 0.1 eq) 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 a crude material. This was further purified by combiflash using 3% methanol in dichloromethane as the eluent to obtain pure 16.8 (0.145 g, yield: 59.83%). MS (ES): m / z 568.28 [M+H] + .

[0411] Synthesis of Compound I-23. Compound 16.8 (0.025 g, 0.044 mmol, 1.0 eq) 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 a crude material. This was further purified by trituration with diethyl ether to obtain pure 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 purity: 49.08%, 48.92%, 1 1H NMR (DMSO-d6, 400 MHz): 8.83-8.81 (d, J=8.8Hz, 1H), 8.57 (s, 1H), 7.98-7.97 (d, J=6.4Hz, 1H), 7.85 (s, 1H), 7.50-7.49 (d, J=5.2Hz, 2H), 6.36 (s, 1H), 6.33-6.31 (t, J=7.2Hz, 1H), 5.31-5.27 (t, J=8.4Hz, 1H), 4.35-4.31 (t, J=8Hz, 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=4.8Hz, 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). (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).

Chemical Structure

Chem.

[0412] Synthesis of Compound 17. The compound was synthesized according to the above-described experimental protocol to obtain 17. MS (ES): m / z 541.25 [M+H] + .

[0413] Synthesis of Compound 17.1. To a solution of 17 (0.250 g, 0.46 mmol, 1.0 equiv) in tetrahydrofuran:methanol:water (4 mL, 2:1:1) was added lithium hydroxide (0.110 g, 4.6 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 give a residue. Water was added thereto, and the mixture was acidified with 1N hydrochloric acid at 10 °C to adjust the pH to about 6 - 6.5. The product was extracted with dichloromethane. The combined organic layers were washed with brine solution, dried over sodium sulfate, and concentrated under reduced pressure to obtain a crude material. This was further purified by column chromatography, eluting the compound in 2.1% methanol in dichloromethane to give pure 17.1 (0.195 g, yield: 82.27%). MS (ES): m / z 513.22 [M+H] + .

[0414] 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] + .

[0415] 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%; 11H 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).

[0416] Synthesis of Compounds 17.3a and 17.3b. The isomer of 17.3 (0.115 g) was separated using column CHIRALCEL OJ-H (250 mm * × 4.6 mm, 5 μm) and 0.1% DEA in 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-b was concentrated under reduced pressure at 30 °C to obtain pure 17.3a (0.046 g). MS (ES): m / z 596.29 [M + H] + .

[0417] 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%, 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 = 6.8 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).

[0418] 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=8.8Hz, 1H), 8.78-8.76 (d, J=7.2Hz, 1H), 8.48 (bs, 2H), 7.97 (s, 1H), 7.64-7.63 (d, J=4.8Hz, 1H), 7.27-7.24 (t, J=6.4Hz, 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=11.2Hz, 1H), 3.22 (s, 3H), 3.13 (s, 3H), 3.02-3.01 (d, J=4.8Hz, 3H), 2.21-2.16 (m, 1H), 2.09-2.05 (m, 1H), 1.54-1.47 (m, 3H), 1.22 (bs, 1H). (Example 17) Synthesis of 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). [Chemical formula] [Chemical formula]

[0419] Synthesis of Compound 18. According to the experimental protocol described above in Example 1, the compound was synthesized to obtain 18 (yield: 92.61%). MS (ES): m / z 427.18 [M+H] + .

[0420] Synthesis of Compound 18.2. To a solution of 18 (1.1 g, 2.58 mmol, 1.0 equivalent) in toluene (15 mL), 18.1 (0.387 g, 3.87 mmol, 1.5 equivalents) and p-toluenesulfonic acid (0.044 g, 0.25 mmol, 0.1 equivalent) were added. The reaction mixture was refluxed at 110 °C for 48 hours. After the reaction was complete, the reaction mixture was transferred to water, and 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 a crude material. This was further purified by column chromatography, and the compound was eluted with 2.1% methanol in dichloromethane to obtain 18.2 (0.8 g, yield: 58.90%). MS (ES): m / z 527.24 [M+H] + .

[0421] Synthesis of Compound 18.3. To a solution of Compound 18.2 (0.8 g, 1.52 mmol, 1.0 equivalent) in dimethylformamide (10 mL), sodium hydride (0.072 g, 3.04 mmol, 2.0 equivalents) was added at 0 °C, and the mixture was stirred for 20 minutes. Methyl iodide (0.237 g, 1.67 mmol, 1.1 equivalents) was added, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, 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 a crude material. This was further purified by column chromatography, and the compound was eluted with 2.0% methanol in dichloromethane to obtain 18.3 (0.640 g, yield: 77.92%). MS (ES): m / z 541.25 [M+H] + .

[0422] Synthesis of Compounds 18.3a and 18.3b. The isomer of 18.3 (0.640 g) was separated using column CHIRALCEL OJ-H (250 mm * × 4.6 mm, 5 µm) and 0.1% DEA in 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 18.3a (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] + .

[0423] Synthesis of Compound 18.4. To a solution of 18.3a (0.242 g, 0.44 mmol, 1.0 equiv) in tetrahydrofuran:methanol:water (4 mL, 2:1:1) was added lithium hydroxide (0.105 g, 4.4 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 a residue. Water was added thereto, and the mixture was acidified with 1 N hydrochloric acid at 10 °C to adjust the pH to about 6 - 6.5. The product was extracted with dichloromethane. The organic layers were combined, washed with brine solution, dried over sodium sulfate, and concentrated under reduced pressure to obtain the crude material. This was further purified by column chromatography, eluting the compound in 2.5% methanol in dichloromethane to obtain pure 18.4 (0.185 g, yield: 80.63%). MS (ES): m / z 513.22 [M+H] + .

[0424] 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] + .

[0425] 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 H NMR (DMSO-d6, 400MHZ): 9.26 - 9.24 (d, J = 8.8Hz, 1H), 8.78 - 8.77 (d, J = 7.2Hz, 1H), 8.49 (bs, 2H), 7.98 (s, 1H), 7.64 - 7.63 (d, J = 4.8Hz, 1H), 7.27 - 7.24 (t, J = 6.8Hz, 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 = 11.2Hz, 1H), 3.22 (s, 3H), 3.13 (s, 3H), 3.02 - 3.01 (d, J = 4.8Hz, 3H), 2.21 - 2.16 (m, 1H), 1.98 (bs, 1H), 1.54 - 1.47 (m, 3H), 1.23 (bs, 1H).

[0426] Synthesis of compounds 18.6a and 18.6b. The isomer of 18.5 (0.110 g) was separated using column CHIRALCEL OJ-H (250 mm * × 4.6 mm, 5u) and 0.1% DEA in MEOH 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 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] + .

[0427] 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 H 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).

[0428] 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%, 1 H 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). (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). [Chemical formula] ...

Claims

【Claim 1】 The invention described in this specification.

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