Kinase modulators and methods of use thereof

Abstract

The invention provides compounds that modulate the activity of protein kinases that are associated with human diseases, disorders, and conditions. In particular, compounds of the invention inhibit TYK2, a member of the Janus Kinase (JAK) family of non-receptor protein kinases.

Description

[0001] Patent Application KINASE MODULATORS AND METHODS OF USE THEREOF Field of the Invention The invention provides compounds that modulate the activity of kinases, such as Tyrosine Kinase 2 (TYK2). Background A variety of medical conditions that affect millions of people are caused or exacerbated by unregulated activity of protein kinases. For example, aberrant kinase activity is associated with autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies, asthma, Alzheimer's disease, Parkinson's disease, multiple sclerosis, skin disorders, eye diseases, infectious diseases and hormone-related diseases. For many such disorders, however, no effective inhibitor or activator exists for the particular kinase that causes the disorder or its symptoms. Consequently, patients continue to suffer from an array of disorders due to the lack of suitable medicaments for their conditions. Summary The invention provides compounds that modulate the activity of protein kinases that are associated with human diseases, disorders, and conditions. In particular, compounds of the invention inhibit TYK2, a member of the Janus Kinase (JAK) family of non-receptor protein kinases. Altered or unregulated activity of TYK2 promotes inflammation and is implicated in autoimmune diseases, such as psoriasis, lupus, multiple sclerosis, and inflammatory bowel disease. Thus, embodiments of the invention are useful as pharmaceutical compositions for treatment of such autoimmune conditions. The invention also provides methods of using the compounds to modulate kinase activity in cells and to treat conditions, such as autoimmune conditions, for which modulation of kinase activity provides a therapeutic benefit. In an aspect, the invention provides compounds of Formula (I), or pharmaceutically acceptable salt, stereoisomer, or solvate thereof, Patent Application (I) wherein: X1, X2, and X3are C, or N, wherein only one of X1, X2, and X3is N; is a single bond or a double bond; Y1is N, or C; Y2is O, or C; n is 0, 1, or 2; m is 0, 1, or 2; R1is selected from the group consisting of hydrogen, deuterium, and optionally substituted C1-C6 alkyl; L is a linker comprising 2-12 atom links, wherein each atom link in L is selected from the group consisting of -CRL1RL2, NRL1, O, and S; wherein: RL1and RL2are independently selected from the group consisting of: hydrogen, deuterium, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C12 cycloalkyl, wherein RL1and RL2on the same or different atoms can be optionally combined to form a 3-12 membered cycloalkyl or heterocycloalkyl, wherein the one or more heteroatoms are N, O, or S; A is selected from the group consisting of 5-12 membered monocyclic or bicyclic aryl and heteroaryl, wherein one or more heteroatoms in said heteroaryl is N, S, or O; Patent Application RA1, RA2, and RBare independently selected from the group consisting of: hydrogen, deuterium, halogen, hydroxy, O-alkyl, alkoxy, cyano, =O, -SRb, -S(=O)Ra, -S(=O)2Ra, -NRcRd, substituted or unsubstituted C1-C6alkyl, C1-C6hydroxyalkyl, C1-C6alkoxyalkyl, C1-C6aminoalkyl, C2-C6alkenyl, wherein one or more substitutions are selected from the group consisting of deuterium, halogen, hydroxy, alkoxy, cyano, =O, 3-12 membered cycloalkyl, oxycycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein one or more heteroatoms in heterocycloalkyl or heteroaryl rings are N, S or O and wherein one or more substitutions are selected from the group consisting of hydrogen, deuterium, halogen, hydroxy, alkoxy, cyano, =O, substituted or unsubstituted C1-C6alkyl, C1-C6hydroxyalkyl, C1-C6alkoxyalkyl, 3-12 membered cycloalkyl, or heterocycloalkyl, aryl, or heteroaryl, wherein optionally RA1and RA2together form a substituted or unsubstituted 3-12 membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl fused with six-membered ring, and the fused ring may be further substituted with alkyl or deuterium alkyl; each Rais independently C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1- C6hydroxyalkyl, C1-C6aminoalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OMe, - NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C1-C6 alkyl, or C1-C6 haloalkyl; each Rbis independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6aminoalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OMe, - NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C1-C6alkyl, or C1-C6haloalkyl; and each Rcand Rdis independently hydrogen, C1-C6alkyl, C1-C6 haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C1-C6 alkyl, or C1-C6 haloalkyl; or Rcand Rdare taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl Patent Application optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OMe, -NH2, - C(=O)Me, -C(=O)OH, -C(=O)OMe, C1-C6 alkyl, or C1-C6 haloalkyl. In certain embodiments, the compound of Formula (I) is of Formula (Ia): (Ia) In certain embodiments, (Ib): In certain (Ic): (Ic) In certain embodiments, in the compounds for Formula (I), (Ia), (Ib), or (Ic), Y1is N. Patent Application In certain embodiments, in the compounds for Formula (I), (Ia), (Ib), or (Ic), Y1is C. In certain embodiments, in the compounds for Formula (I), (Ia), (Ib), or (Ic), Y2is O. In certain embodiments, in the compounds for Formula (I), (Ia), (Ib), or (Ic), Y2is C. In certain embodiments, in the compounds for Formula (I), (Ia), (Ib), or (Ic), R1is H. In certain embodiments, in the compounds for Formula (I), (Ia), (Ib), or (Ic), Ring A is 5- 12 membered aryl or heteroaryl, wherein the one or more heteroatom in the heteroaryl ring is N, S or O. In certain embodiments, in the compounds for Formula (I), (Ia), (Ib), or (Ic), Ring A is 5- 12 membered aryl. In certain embodiments, in the compounds for Formula (I), (Ia), (Ib), or (Ic), Ring A is phenyl. In certain embodiments, in the compounds for Formula (I), (Ia), (Ib), or (Ic), Ring A is 5- 12 membered heteroaryl ring, wherein the one or more heteroatom in the heteroaryl ring is N, S or O. In certain embodiments, in the compounds for Formula (I), (Ia), (Ib), or (Ic), Ring A is pyridine, pyrimidine, pyridazine, pyridone, or pyridazinone. In certain embodiments, in the compounds for Formula (I), (Ia), (Ib), or (Ic), Ring A, RA1, and RA2combine to form a 6,5 or 6,6 fused bicyclic ring. In certain embodiments, the fused bicyclic ring includes further substitutions, wherein the substitutions are selected from the group consisting of hydrogen, deuterium, halogen, C1-C6alkyl, and C1-C6deuterated alkyl. In certain embodiments, one or more substitutions are selected from the group consisting of hydrogen, deuterium, -CH3, or -CD3. In certain embodiments, in the compounds for Formula (I), (Ia), (Ib), or (Ic), RA1, RA2, and RBare independently selected from the group consisting of hydrogen, =O, deuterium, hydroxyl, alkoxy, halogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1- C6 oxyalkyl, substituted or unsubstituted C1-C6 oxycycloalkyl, 3-12 membered substituted or unsubstituted cycloalkyl or heterocycloalkyl wherein one or more heteroatoms are N, S or O, 5-12 Patent Application membered substituted or unsubstituted aryl or heteroaryl wherein one or more heteroatoms are N, S or O; wherein the one or more substitutions are selected from the group consisting of H, deuterium, C1-C6 alkyl, C1-C6 oxyalkyl, halogen, optionally deuterated C1-C6 alkyl, and cyano. In certain embodiments, in the compounds for Formula (I), (Ia), (Ib), or (Ic), RBis selected from the group consisting of hydrogen, deuterium, halogen, -CN, C1-6 alkyl, C1-6 haloalkyl, or C1- 6 deuteroalkyl. In certain embodiments, in the compounds for Formula (I), (Ia), (Ib), or (Ic), RBis H. In certain embodiments, in the compounds for Formula (I), (Ia), (Ib), or (Ic), RA1and RA2are independently selected from the group consisting of alkyl, oxyalkyl, hydrogen, =O, halogen, morpholine and pyridine. In certain embodiments, in the compounds for Formula (I), (Ia), (Ib), or (Ic), RA1is oxyalkyl. In certain embodiments, in the compounds for Formula (I), (Ia), (Ib), or (Ic), RA1is -OCH3. In certain embodiments, in the compounds for Formula (I), (Ia), (Ib), or (Ic), RA1and RA2are independently monocyclic or bicyclic heterocycloalkyl or heteroaryl containing at least one nitrogen, sulfur or oxygen. In certain embodiments, in the compounds for Formula (I), (Ia), (Ib), or (Ic), RA1and RA2are independently substituted or unsubstituted morpholine, 1,4-oxazepane, piperazine, piperidine, pyridine, or pyridazine. In certain embodiments, in the compounds for Formula (I), (Ia), (Ib), or (Ic), RA1and RA2are independently selected from the group consisting of hydrogen, hydroxyl, deuterium, fluoro, chloro, =O, -OCH3, -OCHF2, -O-cyclopropyl, substituted or unsubstituted pyridine, substituted or unsubstituted azetidine, substituted or unsubstituted oxetane, substituted or unsubstituted morpholine, -CH2-cyclopropyl, - - - - - cyclopropyl, cyano, , Patent Application , and 2-10 atom links, wherein each atom link in L is selected from the group consisting of -CRL1RL2, NRL1, O, and S. In certain embodiments, in the compounds for Formula (I), (Ia), (Ib), or (Ic), L comprises between 2 and 8 atom links are -CRL1RL2and between 0 and 2 atom links are NRL1, O, and S. In certain embodiments, in the compounds for Formula (I), (Ia), (Ib), or (Ic), L comprises between 1 and 7 atom links are -CRL1RL2and between 0 and 2 atom links are NRL1, O, and S. In certain embodiments, in the compounds for Formula (I), (Ia), (Ib), or (Ic), L comprises between 1 and 6 atom links are -CRL1RL2and between 0 and 2 atom links are NRL1, O, and S. In certain embodiments, in the compounds for Formula (I), (Ia), (Ib), or (Ic), L comprises between 1 and 10 atom links are -CRL1RL2, and RL1and RL2at different or same atom combine to form an optionally substituted cycloalkyl or heterocycloalkyl. In certain embodiments, one or more optional substitutions are selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, alkoxy, or C1-C4 alkyl. In certain embodiments, in the compounds for Formula (I), (Ia), (Ib), or (Ic), L is selected from the group consisting of: Patent Application , , , , group

[0002] Patent Application , , 5 Patent Application a pharmaceutically acceptable salt, compositions containing one or more compounds of the invention, such as any of the compounds described above. In certain embodiments, pharmaceutical composition comprises a pharmaceutically acceptable carrier or diluent. In another aspect, the invention provides methods of modulating the activity of a kinase by contacting cells containing a kinase with one or more compounds of the invention, such as any of those described above. The compound may inhibit activity of the kinase. The compound may increase activity of the kinase. The kinase may be a JAK family kinase. The kinase may be TYK2. In another aspect, the invention provides methods of treating a condition in a subject by administering to the subject a compound of the invention, such as any of those described above. The condition may be characterized by elevated activity of a kinase. The condition may be characterized by altered activity of a kinase. The kinase may be a JAK family kinase. The kinase may be TYK2. The condition may be an autoimmune disease, inflammatory disease, bone disease, metabolic disease, neurological or neurodegenerative disease, cancer, cardiovascular disease, allergies, asthma, Alzheimer's disease, Parkinson's disease, multiple sclerosis, skin disorder, eye disease, infectious disease, or hormone-related disease. In another aspect, the invention provides use of a compound of the invention, such as any of those described above, for making a medicament. In embodiments of the use, the medicament is useful for treating a condition in a subject. In embodiments of the use the condition is characterized by elevated activity or altered activity of a kinase. In embodiments of the use, the kinase is a JAK family kinase. In embodiments of the use, the kinase isTYK2. Patent Application In embodiments of the use, the condition is an autoimmune disease, inflammatory disease, bone disease, metabolic disease, neurological or neurodegenerative disease, cancer, cardiovascular disease, allergies, asthma, Alzheimer's disease, Parkinson's disease, multiple sclerosis, skin disorder, eye disease, infectious disease, or hormone-related disease. In certain embodiments, the invention provides a pharmaceutical composition comprising a compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, and a pharmaceutically acceptable carrier or diluent. In certain embodiments, the invention provides a method of inhibiting TYK2 activity in a subject in need thereof with a compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof or a pharmaceutical composition. In certain embodiments, the invention provides a method of treating a TYK2-mediated disease or disorder comprising administering to a subject in need thereof a compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof or a pharmaceutical composition. In certain embodiments, the TYK2-mediated disease or disorder is an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a disorder associated with transplantation. In certain embodiments, the TYK2- mediated disease or disorder is multiple sclerosis. Detailed Description: Chemical definitions The expression alkyl refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“C1–20 alkyl”). In some embodiments, an alkyl group has 1 to 12 carbon atoms (“C1–12 alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“C1–10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1–9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C1–8 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C1–7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1–6 alkyl”, also referred to herein as “lower alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1–5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C1–4 alkyl”). In some embodiments, an alkyl group has 1 Patent Application to 3 carbon atoms (“C1–3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1–2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom ("C1 alkyl"). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2–6 alkyl”). Examples of C1-6 alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec- butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2- butanyl (C5), tertiary amyl (C5), and n-hexyl (C6). Additional examples of alkyl groups include n- heptyl (C7), n-octyl (C8) and the like. Unless otherwise specified, each instance of an alkyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents; e.g., from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkyl group is unsubstituted C1-10 alkyl (e.g., -CH3). In certain embodiments, the alkyl group is substituted C1-10 alkyl. Common alkyl abbreviations include Me (-CH3), Et (-CH2CH3), iPr (-CH(CH3)2), nPr (-CH2CH2CH3), n-Bu (- CH2CH2CH2CH3), or i-Bu (-CH2CH(CH3)2). The expression heteroalkyl refers to an alkyl group, as defined herein, which further comprises 1 or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) within the parent chain, wherein the one or more heteroatoms is inserted between adjacent carbon atoms within the parent carbon chain and / or one or more heteroatoms is inserted between a carbon atom and the parent molecule, i.e., between the point of attachment. In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 10 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC1-10 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC1-9 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC1-8 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC1-7 alkyl”). In some embodiments, a heteroalkyl group is a group having 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms (“heteroC1-6 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms (“heteroC1-10 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and lor 2 heteroatoms (“heteroC1-4 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1heteroatom (“heteroC1-3alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom (“heteroC1-2 alkyl”). In some embodiments, a Patent Application heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroC1 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms (“heteroC2-6 alkyl”). The expression alkenyl refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds) (“C2-20 alkenyl”). In some embodiments, an alkenyl group has 2 to 10 carbon atoms (“C2-10 alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms (“C2-9 alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C2-8 alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C2-7 alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2-6alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C2-5 alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C2-4 alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C2-3 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C2 alkenyl”). The one or more carbon-carbon double bonds can be internal (such as in 2- butenyl) or terminal (such as in 1- butenyl). Examples of C2-4 alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each instance of an alkenyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents e.g., from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkenyl group is unsubstituted C2-10 alkenyl. In certain embodiments, the alkenyl group is substituted C2-10 alkenyl. The term “heteroalkenyl,” as used herein, refers to an alkenyl group, as defined herein, which further comprises one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) wherein the one or more heteroatoms is inserted between adjacent carbon atoms within the parent carbon chain and / or one or more heteroatoms is inserted between a carbon atom and the parent molecule, i.e., between the point of attachment. In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 10 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-10 alkenyl”). In some embodiments, a Patent Application heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-9 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-8 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-7 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1, 2, or 3 heteroatoms (“heteroC2-6 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms (“heteroC2-5 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and l or 2 heteroatoms (“heteroC2-4 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom (“heteroC2-3 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms (“heteroCC2-6 alkenyl”). The expression cycloalkyl refers to a saturated or partially unsaturated (for example, a cycloalkenyl group) cyclic group that contains one or more rings, e.g., 2 or 3 rings, and contains from 3 to 14 ring carbon atoms, such as from 3 to 10 (e.g., 3, 4, 5, 6 or 7) ring carbon atoms. The expression cycloalkyl refers furthermore to groups in which one or more hydrogen atoms have been replaced by fluorine, chlorine, bromine or iodine atoms or by OH, =O, SH, =S, NH2, =NH, N3 or NO2 groups, thus, for example, cyclic ketones such as, for cyclohexanone, 2- cyclohexenone or cyclopentanone. Further specific examples of cycloalkyl groups are a cyclopropyl, cyclobutyl, cyclopentyl, spiro[4,5]decanyl, norbornyl, cyclohexyl, cyclopentenyl, cyclohexadienyl, decalinyl, bicyclo[4.3.0]nonyl, tetraline, cyclopentylcyclohexyl, fluorocyclohexyl or cyclohex-2-enyl group. The expression cycloheteroalkyl or heterocycloalkyl refers to a cycloalkyl group as defined above in which one or more (e.g., 1, 2, or 3) ring carbon atoms have been replaced by an oxygen, nitrogen, silicon, selenium, phosphorus or sulfur atom or a SO group or a SO2 group. A cycloheteroalkyl or heterocycloalkyl group may have 1 or 2 rings containing from 3 to 10 (e.g., 3, 4, 5, 6 or 7) ring atoms (e.g., C, O, N or S). Cycloheteroalkyl or heterocycloalkyl groups include cycloheteroalkenyl or heterocycloalkenyl groups. The expression cycloheteroalkyl or heterocycloalkyl refers furthermore to groups that are substituted by fluorine, chlorine, bromine or iodine atoms or by OH, =O, SH, =S, NH2, =NH, N3 or NO2 groups. Examples are a piperidinyl, Patent Application prolinyl, imidazolidinyl, piperazinyl, morpholinyl, urotro pinyl, pyrrolidinyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrofuryl or 2-pyrazolinyl group and also lactams, lactones, cyclic imides and cyclic anhydrides. The expression alkylcycloalkyl refers to groups that contain both cycloalkyl and also alkyl, alkenyl or alkynyl groups in accordance with the above definitions, for example alkylcycloalkyl, cycloalkylalkyl, alkylcycloalkenyl, alkenylcycloalkyl and alkynylcycloalkyl groups. An alkylcycloalkyl group preferably contains a cycloalkyl group that contains one or two rings having from 3 to 10 (e.g., 3, 4, 5, 6 or 7) ring carbon atoms, and one or two alkyl or alkynyl groups having 1 or 2 to 6 carbon atoms. The expression heteroalkylcycloalkyl refers to alkylcycloalkyl groups as defined above in which one or more (e.g., 1, 2 or 3) carbon atoms have been replaced by an oxygen, nitrogen, silicon, selenium, phosphorus or sulfur atom or a SO group or a SO2 group. A heteroalkylcycloalkyl group preferably contains 1 or 2 rings having from 3 to 10 (e.g., 3, 4, 5, 6 or 7) ring atoms, and one or two alkyl, alkenyl, alkynyl or heteroalkyl groups having from 1 or 2 to 6 carbon atoms. Examples of such groups are alkylheterocycloalkyl, alkylheterocycloalkenyl, alkenylheterocycloalkyl, alkynylheterocycloalkyl, heteroalkylcycloalkyl, heteroalkylheterocycloalkyl and heteroalkylheterocycloalkenyl, the cyclic groups being saturated or mono-, di- or tri-unsaturated. The expression aryl refers to an aromatic group that contains one or more rings, e.g., 2 or 3 rings, containing from 6 to 14 ring carbon atoms, such as from 6 to 10 ring carbon atoms. The expression aryl refers furthermore to groups that are substituted by fluorine, chlorine, bromine or iodine atoms or by CH3, OH, SH, NH2, N3 or NO2 groups. Examples are the phenyl, naphthyl, biphenyl, 2-fluorophenyl, anilinyl, 3-nitrophenyl or 4-hydroxyphenyl group. The expression heteroaryl refers to an aromatic group that contains one or more rings, e.g., 2 or 3 rings, containing from 5 to 14 ring atoms, such as from 5 to 10 ring atoms, and contains one or more (e.g., 1, 2, 3 or 4) oxygen, nitrogen, phosphorus or sulfur ring atoms. The expression heteroaryl refers furthermore to groups that are substituted by fluorine, chlorine, bromine or iodine atoms or by CH3, OH, SH, N3, NH2 or NO2 groups. Examples are pyridyl (e.g. 4-pyridyl), imidazolyl (e.g. 2-imidazolyl), phenylpyrrolyl (e.g. 3-phenylpyrrolyl), thiazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl,thiadiazolyl, indolyl, indazolyl, tetrazolyl, pyrazinyl, Patent Application pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, isoxazolyl, indazolyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, pyridazinyl, quinolinyl, isoquinolinyl, pyrrolyl, purinyl, carbazolyl, acridinyl, pyrimidyl, 2,3'-bifuryl, pyrazolyl (e.g. 3- pyrazolyl) and isoquinolinyl groups. The expression aralkyl refers to groups containing both aryl and also alkyl, alkenyl, alkynyl and / or cycloalkyl groups in accordance with the above definitions, such as, for example, aryl- alkyl, arylalkenyl, arylalkynyl, arylcycloalkyl, arylcycloalkenyl, alkylarylcycloalkyl and alkylarylcycloalkenyl groups. Specific examples of aralkyls are toluene, xylene, mesitylene, styrene, benzyl chloride, o-fluorotoluene, lH-indene, tetraline, dihydronaphthalene, indanone, phenylcyclopentyl, cumene, cyclohexylphenyl, fluorene and indane. An aralkyl group preferably contains one or two aromatic ring systems containing from 6 to 10 carbon atoms and one or two alkyl, alkenyl and / or alkynyl groups containing from 1 or 2 to 6 carbon atoms and / or a cycloalkyl group containing 5 or 6 ring carbon atoms. The expression heteroaralkyl refers to an aralkyl group as defined above in which one or more (e.g., 1, 2, 3 or 4) carbon atoms have been replaced by an oxygen, nitrogen, silicon, selenium, phosphorus, boron or sulfur atom, that is to say to groups containing both aryl or heteroaryl, respectively, and also alkyl, alkenyl, alkynyl and / or heteroalkyl and / or cycloalkyl and / or heterocycloalkyl groups in accordance with the above definitions. A heteroaralkyl group preferably contains one or two aromatic ring systems containing from 5 or 6 to 10 ring carbon atoms and one or two alkyl, alkenyl and / or alkynyl groups containing 1 or 2 to 6 carbon atoms and / or a cycloalkyl group containing 5 or 6 ring carbon atoms, wherein 1, 2, 3 or 4 of these carbon atoms have been replaced by oxygen, sulfur or nitrogen atoms. Examples are arylheteroalkyl, arylheterocycloalkyl, arylheterocycloalkenyl, arylalkyl heterocycloalkyl, arylalkenylheterocycloalkyl, arylalkynylheterocycloalkyl, arylalkylhetero cycloalkenyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heteroarylheteroalkyl, heteroarylcycloalkyl, heteroarylcycloalkenyl, heteroarylheterocycloalkyl, hetero arylheterocycloalkenyl, heteroarylalkylcycloalkyl, heteroarylalkylheterocycloalkenyl, hetero arylheteroalkylcycloalkyl, heteroarylheteroalkylcycloalkenyl and heteroarylheteroalkylhetero cycloalkyl groups, the cyclic groups being saturated or mono-, di- or tri-unsaturated. Specific Patent Application examples are a tetrahydroisoquinolinyl, benzoyl, 2- or 3-ethylindolyl, 4-methylpyridino, 2-, 3- or 4-methoxyphenyl, 4-ethoxyphenyl, 2-, 3- or 4-carboxyphenylalkyl group. As stated above, the expressions cycloalkyl, cycloheteroalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl and heteroaralkyl also refer to groups that are substituted by fluorine, chlorine, bromine or iodine atoms or by CH3, OH, =O, SH, =S, NH2, =NH, N3 or NO2 groups. The expression carbocyclyl or carbocyclic refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms (“C3-10 carbocyclyl”) and zero heteroatoms in the nonaromatic ring system. In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms 10 (“C3-8carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“C3-7 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5-10 carbocyclyl”). Exemplary C3-6 carbocyclyl groups include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C3-8 carbocyclyl groups include, without limitation, the aforementioned C3-6 carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (G), cyclooctenyl (G), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (G), and the like. Exemplary C3-10 carbocyclyl groups include, without 20 limitation, the aforementioned G-s carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenvl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or contain a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) and can be saturated or can be partially unsaturated. “Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with Patent Application one or more substituents. In certain embodiments, the carbocyclyl group is unsubstituted C3-10 carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C3-10 carbocyclyl. In some embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 10 ring carbon atoms (“C3-10 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C3-8 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C5-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C5-10 cycloalkyl”). Examples of C5-6 cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3-6 cycloalkyl groups include the aforementioned C5-6 cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3-8cycloalkyl groups include the aforementioned C3-6 cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents. In certain embodiments, the cycloalkyl group is unsubstituted C3-10 cycloalkyl. In certain embodiments, the cycloalkyl group is substituted C3-10 cycloalkyl. The expression heterocyclyl or heterocyclic refers to a radical of a 3- to 14-membered non- aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3-14 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”), and can be saturated or can be partially unsaturated. Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently optionally substituted, i.e., unsubstituted (an “unsubstituted Patent Application heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents. In certain embodiments, the heterocyclyl group is unsubstituted 3-10 membered heterocyclyl. In certain embodiments, the heterocyclyl group is substituted 3-10 membered heterocyclyl. In some embodiments, a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5-10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1¬4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur. Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary 5- membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups 5 containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one Patent Application heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8- membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as a 5,6-bicyclic heterocyclic ring) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6- bicyclic heterocyclic ring) include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like. The expression optionally substituted means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Heteroatoms, such as nitrogen, may have substituents, such as any suitable substituent described herein which satisfies the valencies of the heteroatoms and results in the formation of a stable moiety. For example and without limitation, optional substituents include fluorine, chlorine, bromine, and iodine atoms and CF3, CN, OH, =O, SH, =S, NH2, =NH, N3 and NO2 groups. Optional substituents also include C1-C10 alkyl, C2-C10 alkenyl, C1-C10 heteroalkyl, C3-C16 cycloalkyl, C2-C17 heterocycloalkyl, C4-C20 alkylcycloalkyl, C2-C19 heteroalkylcycloalkyl, C6-C18 aryl, C1-17heteroaryl, C7-C20aralkyl or C2-C19heteroaralkyl, C1-C6alkyl, C2-C6alkenyl, C1-C6heteroalkyl, C3-C10 cycloalkyl, C2-C9 heterocycloalkyl, C7-C12 alkylcycloalkyl, C2-C11 heteroalkylcycloalkyl, C6-C10 aryl, C1-C9 heteroaryl, C7-C12 aralkyl, C2-C11 heteroaralkyl, and C1- C10 haloalkyl groups. Exemplary substituents are F, Cl, Br, OH, SH, =O, NH2, amino, C1-4 alkyl, C1-4 heteroalkyl cyclopropyl, SF5, NO, NO2. Other exemplary substituents are F, Cl, Br, OH, SH, =O, NH2, C1-4 alkyl (e.g. methyl, ethyl, t-butyl), NMe2, CONH2, CH2NMe2, NHSO2Me, C(CH3)2CN, COMe, OMe, SMe, COOMe, COOEt, CH2COOH, OCH2COOH, COOH, SOMe, SO2Me, cyclopropyl, SO2NH2, SO2NHMe, SO2CH2CH2OH, NHCH2CH2OH, CH2CH2OCH3, SF5, SO2NMe2, NO, NO2, OCF3, SO2CF3, CN or CF3. Patent Application Other exemplary substituents are F, Cl, Br, Me, OMe, CN or CF3. The term halogen preferably refers to F, Cl, Br or I. According to certain embodiments, all alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aralkyl and heteroaralkyl groups described herein may optionally be substituted. When an aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl group contains more than one ring, these rings may be bonded to each other via a single or double bond or these rings may be annulated. Other optional substituents include, but are not limited to, halogen, -CN, -NO2, -N3, - SO2H, -SO3H, -OH, -ORaa, -ON(Rbb)2, -N(Rbb)2, -N(Rbb)3+X-, -N(ORcc)Rbb, -SH, -SRaa, - SSRCC, - C - - - - - - - N 2, - C Raa, - 2, - - - C 2Raa, - 2, - 3, - B 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; or two geminal hydrogens on a carbon atom are replaced with the group =O, =S, =NN(Rbb)2, =NNRbbC(O)Raa, =NNRbbC(O)ORaa, =NNRbbS(O)2Raa, =NRbb, or =NORcc; in which: each instance of Raais, independently, selected from C1-10 alkyl, C1-10 heteroalkyl, C1-10 haloalkyl, C2-10 alkenyl, C3-10 cycloalkyl, C3-10 cycloheteroalkyl, C3-10 cycloalkenyl, C3-10 cycloheteroalkenyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two Raagroups are joined to form a 3-14 membered cycloalkyl, 3-14 membered cycloheteroalkyl, 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, heteroalkyl, alkenyl, cycloalkyl, cycloheteroalkyl, cycloalkenyl, cycloheteroalkenyl, Patent Application carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1,2, 3, 4, or 5 Rddgroups; each instance of Rbbis, independently, selected from hydrogen, -OH, -ORaa, - N(Rcc)2, - CN, -C(O)Raa, -C(O)N(Rcc)2, -CO2Raa, -SO2Raa, -C(NRcc)ORaa, -C(NRcc)N(Rcc)2, - SO2N(Rcc)2, -SO2Rcc, -SO2ORcc, -SORaa, -C(S)N(Rcc)2, -C(O)SRcc, -C(S)SRcc, - P(O)2Raa, - P(O)(Raa)2, -P(O)2N(Rcc)2, -P(O)(NRcc)2, C1-10 alkyl, C1-10 heteroalkyl, C1-10 haloalkyl, C2-10 alkenyl, C3-10 cycloalkyl, C3-10 cycloheteroalkyl, C3-10 cycloalkenyl, C3-10 cycloheteroalkenyl, C3- 10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two Raagroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, heteroalkyl, alkenyl, cycloalkyl, cycloheteroalkyl, cycloalkenyl, cycloheteroalkenyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1,2, 3, 4, or 5 Rddgroups; each instance of Rccis, independently, selected from hydrogen, C1-10 alkyl, C1-10 haloalkyl, C2-10 alkenyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two Raagroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; each instance of Rddis, independently, selected from halogen, -CN, -NO2, -N3, - SO2H, - SO3H, -OH, -ORee, -ON(Rff)2, -N(Rff)2, -N(Rn);CX~, -N(ORee)Rff, -SH, -SRee, -SSRee, - C Ree, - 2, - - - P - 2, - 2, - 2, 6 6 6 C2-6 alkenyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, wherein each alkyl, alkenyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups, or two geminal Rddsubstituents can be joined to form =O or =S; each instance of Reeis, independently, selected from C1-6 alkyl, C1-6 haloalkyl, C2-6alkenyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, Patent Application wherein each alkyl, alkenyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1,2, 3, 4, or 5 Rgggroups; each instance of Rffis, independently, selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, or two Rffgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1,2, 3, 4, or 5 Rgggroups; and each instance of Rggis, independently, halogen, -CN, -NO2, -N3, -SO2H, -SO3H, - OH, - OC1-6 alkyl, -ON(C1-6 alkyl)2, -N(C1-6 alkyl)2, -N(C1-6 alkyl)3+X-, -NH(C1-6 alkyl)2+X-, - NH2(C1-6alkyl)+X--MR+X-, -N(OC1-6alkyl)(C1-6alkyl), -N(OH)(C1-6alkyl), - NH(OH), -SH, -SC1-6 alkyl, -SS(C1-6 alkyl), -C(O)(C1-6 alkyl), -CO2H, -CO2(C1-6 alkyl), -OC(O)(C1-6 alkyl), -OCO2(C1- 6 alkyl), -C(O)NH2, -C(O)N(C1-6 alkyl)2, - OC(O)NH(C1-6 alkyl), -NHC(O)(C1-6 alkyl), -N(C1-6 alkyl)C(O)(C1-6 alkyl), - NHCO2(C1-6 alkyl), -NHC(O)N(C1-6 alkyl)2, -NHC(O)NH(C1-6 alkyl), - NHC(O)NH2, -C(NH)O(C1-6 alkyl),-OC(NH)(C1-6 alkyl), -OC(NH)OC1-6 alkyl, -C(NH)N(C1-6 alkyl)2, -C(NH)NH(C1-6 alkyl), -C(NH)NH2, -OC(NH)N(C1-6 alkyl)2, - OC(NH)NH(C1-6 alkyl), - OC(NH)NH2, -NHC(NH)N(C1-6 alkyl)2, -NHC(NH)NH2, - NHSO2(C1-6 alkyl), -SO2N(C1-6 alkyl)2, -SO2NH(C1-6 alkyl), -SO2NH2,-SO2C1-6 alkyl, - SO2OC1-6 alkyl, -OSO2C1-6 alkyl, -SOC1-6 alkyl, -Si(C1-6 alkyl)3, -OSi(C1-6 alkyl)3 - C(S)N(C1-6 alkyl)2, C(S)NH(C1-6 alkyl), C(S)NH2, - C(O)S(C1-6 alkyl), -C(S)SC1-6 alkyl, -SC(S)SC1-6 alkyl, -P(O)2(C1-6 alkyl), -P(O)(C1-6 alkyl)2, - OP(O)(C1-6alkyl)2, -OP(O)(OC1-6alkyl)2, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C3-10carbocyclyl, C3-10 aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal Rggsubstituents can be joined to form =O or =S; wherein X- is a counterion. Janus tyrosine kinase (JAK) family members are regulators of multiple signal transduction pathways initiated by membrane Type I and Type II cytokine receptors. There are 4 JAK family members including JAK1, JAK2, JAK3, and TYK2 (Schwartz et al, 2017). One such association is with signal transducer and activator of transcription (STAT) signal transduction mediated cytokine responses. The JAK-STAT signaling pathway is a chain of interactions between proteins in a cell, and is involved in processes such as immunity, cell division, cell death, and tumor formation (Aaronson et al Science 2002). The binding of Type I and Type II cytokine receptor ligands, such as interferons and interleukins, to cell-surface receptors, causes the Patent Application receptors to dimerize, which brings the receptor-associated JAKs into close proximity (Jalini et al, Genes and Cancer 2011), and sets off a sequence of downstream changes. There is a large body of evidence establishing the contribution of JAK-dependent cytokines to immunopathology, and clinical benefit can be provided by blocking these cytokines with biologics and small-molecule inhibitors. Some examples of this are the blockade of IL-6 in rheumatoid arthritis or IL-12 / IL-23 in inflammatory bowel disease (IBD) (Schwartz et al 2017). The tyrosine kinase 2 (TYK2) member of the JAK family specifically plays a role in the downstream signaling of Interleukin (IL)-12, IL-23, and type I interferons (Baker and Isaacs, Ann Rheum Dis., 2018; Burke et al, Sci Trans Med, 2019). Like other JAK family members, TYK2 heterodimerizes with other JAK family members to provide ligand specificity and regulate downstream signal transduction pathways (Fig 1). Many of these pathways are altered in diseases and drive chronic inflammation in IBD, Psoriasis, and systemic lupus erythematosus (SLE) (Schwartz et al, Nat Rev Drug Dis, 2017). In addition to the role of TYK2 signaling cascades in disease there has been a strong body of genetic evidence of pointing to a role for TYK2. Genetic association studies have linked the TYK2 locus to an impact of the susceptibility in SLE, psoriasis, and multiple sclerosis (MS). This identification has been replicated and expanded in a number of recent analyses, and TYK2 is now recognized as a susceptibility gene in a variety of inflammatory and autoimmune diseases, including type I diabetes (T1D). The common characteristic of these diseases are changes in immunological function and activation, and downstream damage to target organs (Li et al, PLOS One, 2020). The use of small-molecule inhibitors of TYK2 have allowed for the confirmation of several of these hypotheses. Previous work in human derived PBMCs have demonstrated the ability of TYK2 inhibition to reduce IL-12 / IL-23 signaling in rodents and humans TYK2 inhibition has also proven efficacious in preclinical models of disease for psoriasis and ulcerative colitis (Burke et al, Sci Trans Med, 2020). The preclinical effects in rodents have since translated to humans with deucravacitinib demonstrating efficacy in Psoriasis patients (Armstrong et al, Ann of Rheu Dis, 2020). The genetic contribution of TYK2 has also been confirmed preclinically with the use of TYK2 knockout (KO) or transgenic (TG)animals. For example, Type I interferon signaling is reduced in in TYK2 KO animals as compared to WT mice (Karaghiosoff, Immunity, 2000) and Patent Application TG animals with the P1104 protective variant of TYK2 are almost completely protected in the experimental autoimmune encephalitis (EAE) mouse model of MS (Gorman et al, Frnt in Immunology, 2019). Together, this large body of evidence provides supportive data for the role of cytokine signaling, and the support for the development of safe TYK2 inhibitors for a variety of inflammatory disorders. The invention provides compounds that modulate the activity of protein kinases that are associated with human diseases, disorders, and conditions. In particular, compounds of the invention inhibit TYK2, a member of the Janus Kinase (JAK) family of non-receptor protein kinases. Altered or unregulated activity of TYK2 promotes inflammation and is implicated in autoimmune diseases, such as psoriasis, lupus, multiple sclerosis, and inflammatory bowel disease. Thus, embodiments of the invention are useful as pharmaceutical compositions for treatment of such autoimmune conditions. The invention also provides methods of using the compounds to modulate kinase activity in cells and to treat conditions, such as autoimmune conditions, for which modulation of kinase activity provides a therapeutic benefit. Compounds: In an aspect, the invention provides compounds of Formula (I), or pharmaceutically acceptable salt, stereoisomer, or solvate thereof, (I) wherein: X1, X2, and X3are C, or N, wherein only one of X1, X2, and X3is N; is a single bond or a double bond; Y1is N, or C; Patent Application Y2is O, or C; n is 0, 1, or 2; m is 0, 1, or 2; R1is selected from the group consisting of hydrogen, deuterium, and optionally substituted C1- C6 alkyl; L is a linker comprising 2-12 atom links, wherein each atom link in L is selected from the group consisting of -CRL1RL2, NRL1, O, and S; wherein: RL1and RL2are independently selected from the group consisting of: hydrogen, deuterium, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C12 cycloalkyl, wherein RL1and RL2on the same or different atoms can be optionally combined to form a 3-12 membered cycloalkyl or heterocycloalkyl, wherein the one or more heteroatoms are N, O, or S; A is selected from the group consisting of 5-12 membered monocyclic or bicyclic aryl and heteroaryl, wherein one or more heteroatoms in said heteroaryl is N, S, or O; RA1, RA2and RBare independently selected from the group consisting of: hydrogen, deuterium, halogen, hydroxy, O-alkyl, alkoxy, cyano, =O, -SRb, -S(=O)Ra, -S(=O)2Ra, -NRcRd, substituted or unsubstituted C1-C6alkyl, C1-C6hydroxyalkyl, C1-C6alkoxyalkyl, C1-C6aminoalkyl, C2-C6alkenyl, wherein one or more substitutions are selected from the group consisting of deuterium, halogen, hydroxy, alkoxy, cyano, =O, 3-12 membered cycloalkyl, oxycycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein one or more heteroatoms in heterocycloalkyl or heteroaryl rings are N, S or O and wherein one or more substitutions are selected from the group consisting of hydrogen, deuterium, halogen, hydroxy, alkoxy, cyano, =O, substituted or unsubstituted C1-C6alkyl, C1-C6hydroxyalkyl, C1-C6alkoxyalkyl, 3-12 membered cycloalkyl, or heterocycloalkyl, aryl, or heteroaryl, wherein optionally RA1and RA2together form a substituted or unsubstituted 3-12 membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl fused with six-membered ring, and the fused ring may be further substituted with alkyl or deuterium alkyl; Patent Application each Rais independently C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1- C6hydroxyalkyl, C1-C6aminoalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OMe, - NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C1-C6 alkyl, or C1-C6 haloalkyl; each Rbis independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OMe, - NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C1-C6alkyl, or C1-C6haloalkyl; and each Rcand Rdis independently hydrogen, C1-C6alkyl, C1-C6 haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C1-C6 alkyl, or C1-C6 haloalkyl; or Rcand Rdare taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OMe, -NH2, - C(=O)Me, -C(=O)OH, -C(=O)OMe, C1-C6 alkyl, or C1-C6 haloalkyl. In certain embodiments, the compound of Formula (I) is of Formula (Ia): In certain embodiments, the compound of Formula (I) is of Formula (Ib): Patent Application In certain Formula (Ic): In certain (Ia), (Ib), or (Ic), Y1is N. In certain embodiments, in the compounds for Formula (I), (Ia), (Ib), or (Ic), Y1is C. In certain embodiments, in the compounds for Formula (I), (Ia), (Ib), or (Ic), Y2is O. In certain embodiments, in the compounds for Formula (I), (Ia), (Ib), or (Ic), Y2is C. In certain embodiments, in the compounds for Formula (I), (Ia), (Ib), or (Ic), R1is H. In certain embodiments, in the compounds for Formula (I), (Ia), (Ib), or (Ic), Ring A is 5- 12 membered aryl or heteroaryl, wherein the one or more heteroatom in the heteroaryl ring is N, S or O. In certain embodiments, in the compounds for Formula (I), (Ia), (Ib), or (Ic), Ring A is 5- 12 membered aryl. In certain embodiments, in the compounds for Formula (I), (Ia), (Ib), or (Ic), Ring A is phenyl. Patent Application In certain embodiments, in the compounds for Formula (I), (Ia), (Ib), or (Ic), Ring A is 5- 12 membered heteroaryl ring, wherein the one or more heteroatom in the heteroaryl ring is N, S or O. In certain embodiments, in the compounds for Formula (I), (Ia), (Ib), or (Ic), Ring A is pyridine, pyrimidine, pyridazine, pyridone, or pyridazinone. In certain embodiments, in the compounds for Formula (I), (Ia), (Ib), or (Ic), Ring A, RA1, and RA2combine to form a 6,5 or 6,6 fused bicyclic ring. In certain embodiments, the fused bicyclic ring includes further substitutions, wherein the substitutions are selected from the group consisting of hydrogen, deuterium, halogen, C1-C6alkyl, and C1-C6 deuterated alkyl. In certain embodiments, one or more substitutions are selected from the group consisting of hydrogen, deuterium, -CH3, or -CD3. In certain embodiments, in the compounds for Formula (I), (Ia), (Ib), or (Ic), RA1, RA2, and RBare independently selected from the group consisting of hydrogen, =O, deuterium, hydroxyl, alkoxy, halogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1- C6 oxyalkyl, substituted or unsubstituted C1-C6 oxycycloalkyl, 3-12 membered substituted or unsubstituted cycloalkyl or heterocycloalkyl wherein one or more heteroatoms are N, S or O, 5-12 membered substituted or unsubstituted aryl or heteroaryl wherein one or more heteroatoms are N, S or O; wherein the one or more substitutions are selected from the group consisting of H, deuterium, C1-C6 alkyl, C1-C6 oxyalkyl, halogen, optionally deuterated C1-C6 alkyl, and cyano. In certain embodiments, in the compounds for Formula (I), (Ia), (Ib), or (Ic), RBis selected from the group consisting of hydrogen, deuterium, halogen, -CN, C1-6 alkyl, C1-6 haloalkyl, or C1- 6 deuteroalkyl. In certain embodiments, in the compounds for Formula (I), (Ia), (Ib), or (Ic), RBis H. In certain embodiments, in the compounds for Formula (I), (Ia), (Ib), or (Ic), RA1and RA2are independently selected from the group consisting of alkyl, oxyalkyl, hydrogen, =O, halogen, morpholine and pyridine. In certain embodiments, in the compounds for Formula (I), (Ia), (Ib), or (Ic), RA1is oxyalkyl. Patent Application In certain embodiments, in the compounds for Formula (I), (Ia), (Ib), or (Ic), RA1is -OCH3. In certain embodiments, in the compounds for Formula (I), (Ia), (Ib), or (Ic), RA1and RA2are independently monocyclic or bicyclic heterocycloalkyl or heteroaryl containing at least one nitrogen, sulfur or oxygen. In certain embodiments, in the compounds for Formula (I), (Ia), (Ib), or (Ic), RA1and RA2are independently substituted or unsubstituted morpholine, 1,4-oxazepane, piperazine, piperidine, pyridine, or pyridazine. In certain embodiments, in the compounds for Formula (I), (Ia), (Ib), or (Ic), RA1and RA2are independently selected from the group consisting of hydrogen, hydroxyl, deuterium, fluoro, chloro, =O, -OCH3, -OCHF2, -O-cyclopropyl, substituted or unsubstituted pyridine, substituted or unsubstituted azetidine, substituted or unsubstituted oxetane, substituted or unsubstituted morpholine, -CH2-cyclopropyl, -O-CH2-CH3, -CH2-O-CH3, -OCF3, -OCH2CF3, -OCH2- , , and In certain embodiments, in the compounds for Formula (I), (Ia), (Ib), or (Ic), L comprises 2-10 atom links, wherein each atom link in L is selected from the group consisting of -CRL1RL2, NRL1, O, and S. In certain embodiments, in the compounds for Formula (I), (Ia), (Ib), or (Ic), L comprises between 2 and 8 atom links are -CRL1RL2and between 0 and 2 atom links are NRL1, O, and S. Patent Application In certain embodiments, in the compounds for Formula (I), (Ia), (Ib), or (Ic), L comprises between 1 and 7 atom links are -CRL1RL2and between 0 and 2 atom links are NRL1, O, and S. In certain embodiments, in the compounds for Formula (I), (Ia), (Ib), or (Ic), L comprises between 1 and 6 atom links are -CRL1RL2and between 0 and 2 atom links are NRL1, O, and S. In certain embodiments, in the compounds for Formula (I), (Ia), (Ib), or (Ic), L comprises between 1 and 10 atom links are -CRL1RL2, and RL1and RL2at different or same atom combine to form an optionally substituted cycloalkyl or heterocycloalkyl. In certain embodiments, one or more optional substitutions are selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, alkoxy, or C1-C4 alkyl. In certain embodiments, in the compounds for Formula (I), (Ia), (Ib), or (Ic), L is selected from the group consisting of: , , ,

[0003] Patent Application , , 5

[0004] Patent Application , a pharmaceutically acceptable salt, In certain embodiments, the invention provides pharmaceutically acceptable isotopically labeled compounds described herein. In certain embodiments, the isotopically labeled compounds are compounds where one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds of the disclosure include isotopes of hydrogen, such as2H and3H, carbon, such as11C,13C and14C, chlorine, such as36Cl, fluorine, such as18F, iodine, such as123I and125I, nitrogen, such as13N and15N, oxygen, such as15O,17O and18O, phosphorus, such as32P, and sulfur, such as35S. In certain embodiments, the isotopically-labeled compounds of the disclosure, for example, those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotopes tritium, i.e.3H, and carbon-14, i.e.14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Patent Application Substitution with heavier isotopes such as deuterium, i.e.2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. Substitution with positron emitting isotopes, such as11C,18F,15O and13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled compounds of the disclosure can generally be prepared by conventional techniques known to those skilled in the art. In another aspect, the invention provides pharmaceutical compositions containing one or more compounds of the invention, such as any of the compounds described above. In another aspect, the invention provides methods of modulating the activity of a kinase by contacting cells containing a kinase with one or more compounds of the invention, such as any of those described above. The compound may inhibit activity of the kinase. The compound may increase activity of the kinase. The kinase may be a JAK family kinase. The kinase may be TYK2. In another aspect, the invention provides methods of treating a condition in a subject by administering to the subject a compound of the invention, such as any of those described above. The condition may be characterized by elevated activity of a kinase. The condition may be characterized by altered activity of a kinase. The kinase may be a JAK family kinase. The kinase may be TYK2. The condition may be an autoimmune disease, inflammatory disease, bone disease, metabolic disease, neurological or neurodegenerative disease, cancer, cardiovascular disease, allergies, asthma, Alzheimer's disease, Parkinson's disease, multiple sclerosis, skin disorder, eye disease, infectious disease, or hormone-related disease. In another aspect, the invention provides use of a compound of the invention, such as any of those described above, for making a medicament. In embodiments of the use, the medicament is useful for treating a condition in a subject. In embodiments of the use the condition is characterized by elevated activity or altered activity of a kinase. In embodiments of the use, the kinase is a JAK family kinase. In embodiments of the use, the kinase is TYK2. Patent Application In embodiments of the use, the condition is an autoimmune disease, inflammatory disease, bone disease, metabolic disease, neurological or neurodegenerative disease, cancer, cardiovascular disease, allergies, asthma, Alzheimer's disease, Parkinson's disease, multiple sclerosis, skin disorder, eye disease, infectious disease, or hormone-related disease. In certain embodiments, the invention provides a pharmaceutical composition comprising a compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, and a pharmaceutically acceptable carrier or diluent. In certain embodiments, the invention provides a method of inhibiting TYK2 activity in a subject in need thereof with a compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof or a pharmaceutical composition. In certain embodiments, the invention provides a method of treating a TYK2-mediated disease or disorder comprising administering to a subject in need thereof a compound of Formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof or a pharmaceutical composition. In certain embodiments, the TYK2-mediated disease or disorder is an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a disorder associated with transplantation. In certain embodiments, the TYK2- mediated disease or disorder is multiple sclerosis. Pharmaceutical compositions The present invention provides pharmaceutical compositions containing one or more compounds described above, or a pharmaceutically acceptable ester, prodrug, hydrate, solvate or salt of such a compound, optionally in combination with a pharmaceutically acceptable carrier. The invention further provides such compounds for the preparation of a medicament for the treatment of one or more diseases mentioned herein. A pharmaceutical composition may contain one or more compounds of the invention in a therapeutically effective amount. A therapeutically effective amount of a compound in accordance with this invention means an amount of compound that is effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated. Determination of a therapeutically effective amount is within the skill in the art. Patent Application The therapeutically effective amount or dosage of a compound according to this invention can vary within wide limits and may be determined in a manner known in the art. Such dosage may be adjusted to the individual requirements in each particular case including the specific compound being administered, the route of administration, the condition being treated, as well as the patient being treated. Compositions of the invention may include a vehicle for delivery of one or more compounds of the invention. For example, the composition may contain particles, such as nanoparticles, microparticles, liposomes, micelles, and virus particles. Examples of pharmacologically acceptable salts of sufficiently basic compounds of the invention are salts of physiologically acceptable mineral acids like hydrochloric, hydrobromic, sulfuric and phosphoric acid; or salts of organic acids like methanesulfonic, p-toluenesulfonic, lactic, acetic, trifluoroacetic, citric, succinic, fumaric, maleic and salicylic acid. Further, a sufficiently acidic compound of the invention may form alkali or earth alkali metal salts, for example sodium, potassium, lithium, calcium or magnesium salts; ammonium salts; or organic base salts, for example methylamine, dimethylamine, trimethylamine, triethylamine, ethylenediamine, ethanolamine, choline hydroxide, meglumin, piperidine, morpholine, tris-(2- hydroxyethyl)amine, lysine or arginine salts; all of which are also further examples of salts of the invention. Compounds of the invention may be solvated, especially hydrated. The hydratization / hydration may occur during the process of production or as a consequence of the hygroscopic nature of the initially water free compounds of the invention. The solvates and / or hydrates may e.g. be present in solid or liquid form. It should be appreciated that certain compounds of the invention may have tautomeric forms from which only one might be specifically mentioned or depicted in the following description, different geometrical isomers (which are usually denoted as cis / trans isomers or more generally as (E) and (Z) isomers) or different optical isomers as a result of one or more chiral carbon atoms (which are usually nomenclatured under the Cahn-Ingold-Prelog or R / S system). All these tautomeric forms, geometrical or optical isomers (as well as racemates and diastereomers) and polymorphous forms are included in the invention. Since the compounds of the invention may contain asymmetric C-atoms, they may be present either as achiral compounds, mixtures of diastereomers, mixtures of enantiomers or as optically pure compounds. The present invention Patent Application comprises both all pure enantiomers and all pure diastereomers, and also the mixtures thereof in any mixing ratio. According to a further embodiment of the present invention, one or more hydrogen atoms of the compounds of the present invention may be replaced by deuterium. Deuterium modification improves the metabolic properties of a drug with little or no change in its intrinsic pharmacology. Deuterium substitution at specific molecular positions improves metabolic stability, reduces formation of toxic metabolites and / or increases the formation of desired active metabolites. Accordingly, the present invention also encompasses the partially and fully deuterated compounds of the invention. The term hydrogen also encompasses deuterium. The therapeutic use of compounds according to the invention, their pharmacologically acceptable salts, solvates and hydrates, respectively, as well as formulations and pharmaceutical compositions also lie within the scope of the present invention. The pharmaceutical compositions according to the present invention may comprise at least one compound of the invention as an active ingredient and, optionally, carrier substances and / or adjuvants. The present invention also relates to prodrugs which are composed of a compound of the invention and at least one pharmacologically acceptable protective group which will be cleaved off under physiological conditions, such as an alkoxy-, arylalkyloxy-, acyl-, acyloxymethyl group (e.g. pivaloyloxymethyl), an 2-alkyl-, 2-aryl- or 2-arylalkyl oxycarbonyl-2-alkylidene ethyl group or an acyloxy group as defined herein, e.g. ethoxy, benzyloxy, acetyl or acetyloxy or, especially for a compound of the invention, carrying a hydroxy group (-OH): a sulfate, a phosphate (-OPO3or -OCH2OPO3) or an ester of an amino acid. For example, compositions may contain pro-drugs of the hydroxy group of a compound of the invention. As used herein, the term pharmaceutically acceptable ester especially refers to esters which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms. Examples of particular esters include, but are not limited to, formates, acetates, propionates, butyrates, acrylates and ethylsuccinates. Patent Application The present invention also relates to a prodrug, a biohydrolyzable ester, a biohydrolyzable amide, a polymorph, tautomer, stereoisomer, metabolite, N-oxide, biohydrolyzable carbamate, biohydrolyzable ether, physiologically functional derivative, atropisomer, or in vivo-hydrolysable precursor, diastereomer or mixture of diastereomers, chemically protected form, affinity reagent, complex, chelate and a stereoisomer of the compounds of the invention. As mentioned above, therapeutically useful agents that contain compounds of the invention, their solvates, salts or formulations are also comprised in the scope of the present invention. In general, compounds of the invention will be administered by using the known and acceptable modes known in the art, either alone or in combination with any other therapeutic agent. For oral administration such therapeutically useful agents can be administered by one of the following routes: oral, e.g. as tablets, dragees, coated tablets, pills, semisolids, soft or hard capsules, for example soft and hard gelatin capsules, aqueous or oily solutions, emulsions, suspensions or syrups, parenteral including intravenous, intramuscular and subcutaneous injection, e.g. as an injectable solution or suspension, rectal as suppositories, by inhalation or insufflation, e.g. as a powder formulation, as microcrystals or as a spray (e.g. liquid aerosol), transdermal, for example via an transdermal delivery system (TDS) such as a plaster containing the active ingredient or intranasal. For the production of such tablets, pills, semisolids, coated tablets, dragees and hard, e.g. gelatin capsules, the therapeutically useful product may be mixed with pharmaceutically inert, inorganic or organic excipients as are e.g. lactose, sucrose, glucose, gelatine, malt, silica gel, starch or derivatives thereof, talc, stearinic acid or their salts, dried skim milk, and the like. For the production of soft capsules one may use excipients as are e.g. vegetable, petroleum, animal or synthetic oils, wax, fat, polyols. For the production of liquid solutions, emulsions or suspensions or syrups one may use as excipients e.g. water, alcohols, aqueous saline, aqueous dextrose, polyols, glycerin, lipids, phospholipids, cyclodextrins, vegetable, petroleum, animal or synthetic oils. Particularly useful are lipids, such as phospholipids (e.g., natural origin and / or with a particle size between 300 to 350 nm) in phosphate buffered saline (pH = 7 to 8, e.g., 7.4). For suppositories one may use excipients as are e.g. vegetable, petroleum, animal or synthetic oils, wax, fat and polyols. For aerosol formulations one may use compressed gases suitable for this purpose, as are e.g. oxygen, nitrogen and carbon dioxide. The pharmaceutically useful agents may Patent Application also contain additives for conservation, stabilization, e.g. UV stabilizers, emulsifiers, sweetener, aromatizers, salts to change the osmotic pressure, buffers, coating additives and antioxidants. In general, in the case of oral or parenteral administration to adult humans weighing approximately 80 kg, a daily dosage of about 10 mg to about 10,000 mg, or from about 20 mg to about 1,000 mg, should be appropriate, although the upper limit may be exceeded when indicated. The daily dosage can be administered as a single dose or in divided doses, or for parenteral administration, it may be given as continuous infusion or subcutaneous injection. Methods of making compounds The invention also provides methods of making compounds of the invention, such as those described above. Synthesis schemes for making specific compounds of Formula (I), (Ia), (Ib), or (Ic), are provided in the Examples below. Methods of treating conditions The compounds and compositions of the invention modulate activity of one or more protein kinases. The compounds and compositions may inhibit, activate, or otherwise alter kinase activity. Consequently, the compounds and compositions may be used to diagnose, treat, or prevent a condition, such as a disease, disorder, or other condition for which modulation of kinase activity provides therapeutic benefit. Diseases, disorders, and conditions that can be diagnosed and / or treated using compositions and methods of the invention include those associated with aberrant activity, e.g., increased activity or decreased activity, of one or more kinases. The kinase may be a serine-threonine kinase or a tyrosine kinase, e.g., a receptor tyrosine kinase or non-receptor tyrosine kinase. The kinase may be a member of the JAK family. For example and without limitation, the kinase may be non- receptor tyrosine-protein kinase TYK2 (TYK2), including mutants of any of the aforementioned kinases. The disease, disorder, or condition may be associated with aberrant TYK2 activity, such as autoimmune disorders, Crohn's disease, hyperimmunoglobulin E syndrome, inflammatory bowel disease, multiple sclerosis (MS), multiple sclerosis (MS), progressive supranuclear palsy (PSP), Patent Application psoriasis, rheumatoid arthritis, systemic lupus erythematosus (SLE), type 1 diabetes (T1D), or ulcerative colitis. The disease, disorder, or condition may be or include a respiratory tract / obstructive airways disease or disorder, such as rhinorrhea, tracheal constriction, airway contraction, acute-, allergic, atrophic rhinitis or chronic rhinitis (such as rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca), rhinitis medicamentosa, membranous rhinitis (including croupous, fibrinous and pseudomembranous rhinitis), scrofulous rhinitis, perennial allergic rhinitis, seasonal rhinitis (including rhinitis nervosa (hay fever) and vasomotor rhinitis), pollinosis, asthma (such as bronchial, atopic, allergic, intrinsic, extrinsic, exercise-induced, cold air-induced, occupational, bacterial infection-induced, and dust asthma particularly chronic or inveterate asthma (e.g. late asthma and airways hyper-responsiveness)), bronchitis (including chronic, acute, arachidic, catarrhal, croupus, phthinoid and eosinophilic bronchitis), cardiobronchitis, pneumoconiosis, chronic inflammatory disease of the lung which result in interstitial fibrosis, such as interstitial lung disease (ILD) (e.g., idiopathic pulmonary fibrosis, or ILD associated with rheumatoid arthritis, or other autoimmune conditions), acute lung injury (ALI), adult respiratory distress syndrome (ARDS), chronic obstructive pulmonary, airways or lung disease (CORD, COAD, COLD or COPD, such as irreversible COPD), chronic sinusitis, conjunctivitis (e.g. allergic conjunctivitis), cystic fibrosis, extrinsic allergic alveolitis (like farmer's lung and related diseases), fibroid lung, hypersensitivity lung diseases, hypersensitivity pneumonitis, idiopathic interstitial pneumonia, nasal congestion, nasal polyposis, otitis media, and cough (chronic cough associated with inflammation or iatrogenic induced), pleurisy, pulmonary congestion, emphysema, bronchiectasis, sarcoidosis, lung fibrosis, including cryptogenic fibrosing alveolitis, fibrosis complicating anti-neoplastic therapy and chronic infection, including tuberculosis and aspergillosis and other fungal infections, vasculitic and thrombotic disorders of the lung vasculature, and pulmonary hypertension, acute viral infection including the common cold, and infection due to respiratory syncytial virus, influenza, coronavirus (including SARS) and adenovirus, allergic bronchopulmonary mycosis, emphysema, diffuse panbronchiolitis, systemic anaphylaxis or hypersensitivity responses, drug allergies (e.g., to penicillin, cephalosporins), insect sting allergies, and food related allergies which may have effects remote from the gut (such as migraine, rhinitis and eczema), anaphylactic shock, or vascular spasms. Patent Application The disease, disorder, or condition may be or include a bone and joint related disease or disorder, such as osteoporosis, arthritis (including rheumatic, infectious, autoimmune, chronic, malignant), seronegative spondyloarthropathies (such as ankylosing spondylitis, rheumatoid spondylitis, psoriatic arthritis, enthesopathy, Bechet's disease, Marie-Strumpell arthritis, arthritis of inflammatory bowel disease, and Reiter's disease), systemic sclerosis, osteoarthritis, osteoarthrosis, both primary and secondary to e.g. congenital hip dysplasia, cervical and lumbar spondylitis, and low back and neck pain, Still's disease, reactive arthritis and undifferentiated spondarthropathy, septic arthritis and other infection-related arthropathies and bone disorders such as tuberculosis, including Pott's disease and Poncet's syndrome, acute and chronic crystal-induced synovitis including urate gout, calcium pyrophosphate deposition disease, and calcium apatite related tendon, bursar and synovial inflammation, primary and secondary Sjogren's syndrome, systemic sclerosis and limited scleroderma, mixed connective tissue disease, and undifferentiated connective tissue disease, inflammatory myopathies including, polymalgia rheumatica, juvenile arthritis including idiopathic inflammatory arthritides of whatever joint distribution and associated syndromes, other joint disease (such as intervertebral disc degeneration or temporomandibular joint degeneration), rheumatic fever and its systemic complications, vasculitides including giant cell arteritis, Takayasu's arteritis, polyarteritis nodosa, microscopic polyarteritis, and vasculitides to associated with viral infection, hypersensitivity reactions, cryoglobulins, paraproteins, low back pain, Familial Mediterranean fever, Muckle-Wells syndrome, and Familial Hibenian Fever, Kikuchi disease, drug-induced arthalgias, tendonititides, polychondritis, and myopathies, osteoporosis, osteomalacia like osteoporosis, osteopenia, osteogenesis imperfects, osteopetrosis, osteofibrosis, osteonecrosis, Paget's disease of bone, hypophosphatemia, Felty's syndrome, Still's disease, slack of artificial joint implant, sprain or strain of muscle or joint, tendinitis, fasciitis, periarthritis humeroscapularis, cervico-omo-brachial syndrome, or tenosynovitis. The disease, disorder, or condition may be or include a skin or eye related disease or disorder, such as glaucoma, ocular hypertension, cataract, retinal detachment, psoriasis (including psoriasis vulgaris, pustular psoriasis, arthritic psoriasis, erythroderma psoriaticum), palmoplantar pustulosis, xerodoma, eczematous diseases (like atopic dermatitis, ultraviolet radiation dermatitis, contact dermatitis, and seborrheic dermatitis), phytodermatitis, photodermatitis, cutaneous eosinophilias, chronic skin ulcers, cutaneous lupus erythematosus, contact hypersensitivity / allergic contact dermatitis (including sensitivity to poison ivy, sumac, or oak), and Patent Application eosinophilic folliculitis (Ofuji's disease), pruritus, drug eruptions, urticaria (acute or chronic, allergic or non-allergic), acne, erythema, dermatitis herpetiformis, scleroderma, vitiligo, lichen planus, lichen sclerosus et atrophica, pyodenna gangrenosum, skin sarcoid, pemphigus, ocular pemphigus, pemphigoid, epidermolysis bullosa, angioedema, vasculitides, toxic erythemas, cutaneous eosinophilias, alopecia areata, male-pattern baldness, Sweet's syndrome, Stevens- Johnson syndrome, Weber-Christian syndrome, erythema multiforme, cellulitis, both, infective and non infective, panniculitis, cutaneous Lymphomas, nonmelanoma skin cancer and other dysplastic lesions, blepharitis, iritis, anterior and posterior uveitis, choroiditis, autoimmune, degenerative or inflammatory disorders affecting the retina, ophthalmitis including sympathetic ophthalmitis, sarcoidosis, xerosis infections including viral, fungal, and bacterial, allergic conjunctivitis, increased fibrosis, keloids, keloplasty, post surgical scars, epidermolysis bullosa, dry eye, ocular inflammation, allergic conjunctivitis, vernal conjunctivitis, vernal keratoconjunctivitis, and giant papillary conjunctivitis, ocular angiogenesis, cornea damage and scar, all forms of macular degeneration, macular edema, macular dystrophy, abnormal wound healing, scleritis, episcleritis, pachydermia, peripheral ulcerative keratitis, fungal keratitis, herpetic keratitis, invasive aspergillosis; conical cornea, dystorphia epithelialis comeae, or severe intraocular inflammation. The disease, disorder, or condition may be or include a gastrointestinal tract and abdominal related disease or disorder, such as celiac / coeliac disease (e.g. celiac sprue), cholecystitis, enteritis (including infectious, ischemic, radiation, drug-induced, and eosinophilic gastroenteritis), eosinophilic esophagitis, eosinophilic gastrointestinal inflammation, allergen induced diarrhea, enteropathy associated with seronegative arthropathies, gastritis, autoimmune atrophic gastritis, ischemic bowel disease, inflammatory bowel disease (Crohn's disease and ulcerative colitis), colitis, Mooren's ulcer, irritable bowel syndrome, necrotizing enterocolitis, gut ischemia, glossitis, gingivitis, periodontitis, oesophagitis, including reflex, proctitis, fibrosis and cirrhosis of the liver, pancreatitis, both acute and chronic, pancreatic fibrosis, pancreatic sclerosis, pancreatolithiasis, hepatic cirrhosis, hepatitis (congestive, autoimmune, acute, fulminant, chronic, drug-induced, alcoholic, lupoid, steatohepatitis and chronic viral), fatty liver, primary biliary cirrhosis, hepatic porphyria, and gastrointestinal related allergic disorders, spastic colon, diverticulitis, gastroenteric bleeding, Behcet's disease; partial liver resection, acute liver necrosis (e.g. necrosis caused by toxins, viral hepatitis, shock or anoxia), or hemolytic uremic syndrome. Patent Application The disease, disorder, or condition may be or include a hematological disease or disorder, such as anemias, coagulation, myeloproliferative disorders, hemorrhagic disorders, leukopenia, eosinophilic disorders, leukemias (e.g. myelogenous, lymphomas, plasma cell dyscrasias, disorders of the spleen, Band's disease, hemophilia, purpura (including idiopathic thrombocytopenic purpura), or Wiskott-Aldrich syndrome. The disease, disorder, or condition may be or include a metabolic disease or disorder, such as obesity, amyloidosis, disturbances of the amino and acid metabolism like branched chain disease, hyperaminoacidemia, hyperaminoaciduria, disturbances of the metabolism of urea, hyperammonemia, mucopolysaccharidoses e.g. Maroteaux-Lamy syndrome, storage disease like glycogen storage diseases and lipid storage diseases, glycogenosis I diseases like Cori's disease, malabsorption diseases like intestinal carbohydrate malabsorption, oligosaccharidase deficiency like maltase-, lactase-, sucrase-insufficiency, disorders of the metabolism of fructose, disorders of the metabolism of galactose, galactosaemia, disturbances of carbohydrate utilization like diabetes, hypoglycemia, disturbances of pyruvate metabolism, hypolipidemia, hypolipoproteinemia, hyperlipidemia, hyperlipoproteinemia, carnitine or carnitine acyltransferase deficiency, disturbances of the porphyrin metabolism, porphyrins, disturbances of the purine metabolism, lysosomal diseases, metabolic diseases of nerves and nervous systems like gangliosidoses, sphingolipidoses, sulfatidoses, leucodystrophies, or Lesch Nyhan syndrome. The disease, disorder, or condition may be or include a cerebellar dysfunction or disturbance of brain metabolism, such as dementia, Alzheimer's disease, Huntington's chores, Parkinson's disease, Pick's disease, toxic encepha-lopathy, demyelinating neuropathies like inflammatory neuropathy, Guillain-Barre syndrome; Meniere's disease and radiculopathy, primary and secondary metabolic disorders associated with hormonal defects like any disorder stemming from either an hyperfunction or hypofunction of some hormone- secreting endocrine gland and any combination thereof. Sipple's syndrome, pituitary gland dysfunction and its effects on other endocrine glands, such as the thyroid, adrenals, ovaries, and testes, acromegaly, hyper- and hypothyroidism, euthyroid goiter, euthyroid sick syndrome, thyroiditis, and thyroid cancer, over or underproduction of the adrenal steroid hormones, adrenogenital syndrome, Cushing's syndrome, Addison's disease of the adrenal cortex, Addison's pernicious anemia, primary and secondary aldosteronism, diabetes insipidus, diabetes mellitus, carcinoid syndrome, disturbances caused by Patent Application the dysfunction of the parathyroid glands, pancreatic islet cell dysfunction, diabetes, disturbances of the endocrine system of the female like estrogen deficiency, resistant ovary syndrome; muscle weakness, myotonia. Duchenne's and other muscular dystrophies, dystrophia myotonica of Steinert, mitochondrial myopathies like disturbances of the catabolic metabolism in the muscle, carbohydrate and lipid storage myopathies, glycogenoses, myoglobinuria, malignant hyperthermia, polymyalgia rheumatics, dermatomyositis, multiple myositis, primary myocardial disease, cardiomyopathy; disorders of the ectoderm, neurofibromatosis, scleroderma and polyar teritis, Louis-Bar syndrome, von Hippel-Lindau disease, Sturge-Weber syndrome, tuberous sclerosis, amyloidosis, porphyria; sexual dysfunction of the male and female; confused states and seizures due to inappropriate secretion of antidiuretic hormone from the pituitary gland, Liddle's syndrome, Bartter's syndrome, Fanconi's I syndrome, or renal electrolyte wasting. The disease, disorder, or condition may be or include a transplant rejection related condition, such as acute and chronic allograft rejection following solid organ transplant, for example, transplantation of kidney, heart, liver, lung, and cornea, chronic graft versus host disease, skin graft rejection, and bone marrow transplant rejection, or immunosuppression. The disease, disorder, or condition may be or include a genitourinary related condition, such as nephritis (interstitial, acute interstitial (allergic), and glomerulonephritis), nephrotic syndrome, cystitis including acute and chronic (interstitial) cystitis and Hunner's ulcer, acute and chronic urethritis, prostatitis, epididymitis, oophoritis, salpingitis, vulvo vaginitis, vulvovaginal candidiasis, Peyronie's disease, and erectile dysfunction, renal disease, renal fibrosis, nephropyelitis, secondary contracted kidney, steroid dependent and steroid-resistant nephrosis, or Goodpasture's syndrome. The disease, disorder, or condition may be or include a CNS related disease or disorder, such as neurodegenerative diseases, Alzheimer's disease and other cementing disorders including CJD and nvCJD, amyloidosis, and other demyelinating syndromes, cerebral atherosclerosis and vasculitis, temporal arteritis, myasthenia gravis, acute and chronic so pain (acute, intermittent or persistent, whether of central or peripheral origin) including post-operative, visceral pain, headache, migraine, neuralgia (including trigeminal), atypical facial pain, joint and bone pain, pain arising from cancer and tumor invasion, neuropathic pain syndromes including diabetic, post- herpetic, and HIV-associated neuropathies, neurosarcoidosis, to brain injuries, cerebrovascular Patent Application diseases and their consequences, Parkinson's disease, corticobasal degeneration, motor neuron disease, dementia, including ALS (Amyotrophic-lateral sclerosis), multiple sclerosis, traumatic brain injury, stroke, post-stroke, post- traumatic brain injury, and small-vessel cerebrovascular disease, dementias, vascular dementia, dementia with Lewy bodies, frontotemporal dementia and Parkinsonism linked 1 to chromosome 17, frontotemporal dementias, including Pick's disease, progressive supranuclear palsy, corticobasal degeneration, Huntington's disease, thalamic degeneration, HIV dementia, schizophrenia with dementia, and Korsakoffs psychosis, within the meaning of the definition are also considered to be CNS disorders central and peripheral nervous system complications of malignant, infectious or autoimmune processes, algesia, cerebral infarction, attack, cerebral ischemia, head injury, spinal cord injury, myelopathic muscular atrophy, Shy-Drager syndrome, Reye's syndrome, progressive multifocal leukoencephalopathy, normal pressure hydrocephalus, sclerosing panencephalitis, frontal lobe type dementia, acute anterior poliomyelitis (poliomyelitis), poliomyelitis neurosis, viral encephalitis, allergic encephalomyelitis, epileptic encephalopathies, Creutzfeldt-Jakob disease, Kuru disease, bovine spongiform encephalopathy (mad cow disease), scrapie, epilepsy, cerebral amyloid angiopathy, depression, mania, manic-depressive psychosis, hereditary cerebellar ataxia, peripheral neuropathy, Nasu-Hakola syndrome, or Machado-Joseph disease. The disease, disorder, or condition may be or include an inflammatory or immunological disease or disorder, such as general inflammation (of the ocular, nasal, pulmonary, and gastrointestinal passages), mastocytosis / mast cell disorders (cutaneous, systemic, mast cell activation syndrome, and pediatric mast cell diseases), mastitis (mammary gland), vaginitis, vasculitis (e.g., necrotizing, cutaneous, and hypersensitivity vasculitis), Wegener granulamatosis, myyositis (including polymyositis, dermatomyositis), basophil related diseases including basophilic leukemia and basophilic leukocytosis, and eosinophil related diseases such as Churg- Strauss syndrome, eosinophilic granuloma, lupus erythematosus (such as, systemic lupus erythematosus, subacute cutaneous lupus erythematosus, and discoid lupus erythematosus), chronic thyroiditis, Hashimoto's thyroiditis, Grave's disease, type I diabetes, complications arising from diabetes mellitus, other immune disorders, eosinophilia fasciitis, hyper IgE syndrome, Addison's disease, antiphospholipid syndrome, immunodeficiency disease, acquired immune deficiency syndrome (AIDS), leprosy, Sezary syndrome, paraneoplastic syndromes, and other autoimmune disorders, fervescence, myositis, nervous diseases selected from multiple myositis, Patent Application bursitis, Evans syndrome, leukotriene B4-mediated diseases, idiopathic hypoparathyroidism, nephrotic syndrome lupus, or immunosuppression. The disease, disorder, or condition may be or include a cardiovascular disease or disorder, such as congestive heart failure, myocardial infarction, ischemic diseases of the heart, all kinds of atrial and ventricular arrhythmias, hypertension, cerebral trauma, occlusive vascular disease, stroke, cerebrovascular disorder, atherosclerosis, restenosis, affecting the coronary and peripheral is circulation, pericarditis, myocarditis, inflammatory and auto-immune cardiomyopathies including myocardial sarcoid, endocarditis, valvulitis, and aortitis including infective (e.g. syphilitic), hypertensive vascular diseases, peripheral vascular diseases, and atherosclerosis, vasculitides, disorders of the proximal and peripheral veins including phlebitis and thrombosis, including deep vein thrombosis and complications of varicose veins, aortic aneurism, periarteritis nodosa, cardiac fibrosis, post-myocardial infarction, idiopathic cardiomyopathy, or angioplasty. The disease, disorder, or condition may be or include an oncological disease or disorder, such as common cancers (prostate, breast, lung, ovarian, pancreatic, bowel and colon, abdomen, stomach (and any other digestive system cancers), liver, pancreas, peritoneum, endocrine glands (adrenal, parathyroid, pituitary, testicles, ovary, thymus, thyroid), eye, head, neck, nervous system (central and peripheral), lymphatic system, blood, pelvic, skin, bone, soft tissue, spleen, thoracic, urogenital, and brain tumors), breast cancer, genitourinary cancer, lung cancer, gastrointestinal cancer, epidermoid cancer, melanoma, ovarian cancer, pancreas cancer, neuroblastoma, malignancies affecting the bone marrow (including the leukaemias) and lymphoproliferative systems, such as Hodgkin's and non-Hodgkin's lymphoma, B-cell lymphoma, follicular lymphoma, metastatic disease and tumor recurrences, and paraneoplastic syndromes, as well as hypergammaglobulinemia, lymphoproliferative diseases, disorders, and / or conditions, paraproteinemias, purpura (including idiopathic thrombocytopenic purpura), Waldenstron's Macroglobulinemia, Gaucher's Disease, histiocytosis, retinoblastoma and any other hyperproliferative disease, sarcomata, cachexia, tumor growth, tumor invasion, metastasis, AIDS- related lymphomas, malignant immunoproliferative diseases, multiple myeloma and malignant plasma cell neoplasms, lymphoid leukemia, acute or chronic myeloid leukemia, acute or chronic lymphocytic leukemia, monocytic leukemia, other leukemias of specified cell type, leukemia of unspecified cell type, other and unspecified malignant neoplasms of lymphoid, haematopoietic and Patent Application related tissues, for example diffuse large cell lymphoma, T-cell lymphoma or cutaneous T-cell lymphoma). Myeloid cancer includes e.g. acute or chronic myeloid leukaemia, or keratoleukoma. The disease, disorder, or condition may be or include another disease or disorder, such as pain, migraine, sleep disorders, fever, sepsis, idiopathic thrombocytopenia pupura, post- operative adhesions, flushing, ischemic / reperfusion injury in the heart, brain, peripheral limbs, bacterial infection, viral infection, fungal infection, thrombosis, endotoxin shock, septic shock, thermal regulation including fever, Raynaud's disease, gangrene, diseases requiring anti-coagulation therapy, congestive heart failure, mucus secretion disorders, pulmonary hypotension, prostanoid- induced smooth muscle contract associated with dysmenorrhea and premature labor, premature delivery, reperfusion injury, bum, thermal injury, hemorrhage or traumatic shock, menstrual pain, menstrual cramp, dysmenorrhea, periodontosis, rickettsial infectious disease, protozoal disease, reproduction disease, toothache, pain after tooth extraction, Herpes zoster, Herpes simplex, retroperitoneal fibrosis, or various radiation injuries. In certain embodiments, the disease is selected from the group consisting of an inflammatory disease, an autoimmune disease, an allergic disorder, and an ocular disorder. In certain embodiments, the disease is selected from the group consisting of pruritus, eczema, asthma, rhinitis, dry eye, ocular inflammation, allergic conjunctivitis, vernal conjunctivitis, vernal keratoconjunctivitis, giant papillary conjunctivitis, fungal keratitis and uveitis. The method may include modulating the activity of one or more kinases in a subject, such as any of the kinase described above. The method may include inhibiting a kinase. The method may include activating, e.g., stimulating or enhancing the activity of, a kinase. The method may include modulating activity of a single kinase or preferentially modulating activity of a specific kinase over others. The method may include modulating activity of multiple kinases or preferentially modulating activity of two more specific kinases over others. The method may include providing a compound of the invention. The method may include providing multiple compounds of the invention. The method may include contacting cells containing a kinase with one or more compounds of the invention. For example and without limitation, contacting a cell with a compound may include exposing a cell to a compound, e.g., in a formulation, such as any of those described above; Patent Application delivering a compound inside a cell; providing a compound to a subject and allowing a cell in the subject to become exposed to the compound. Contacting may be performed in vivo or in vitro. In vitro contact may include exposure of cells or tissue isolated from a subject. The method may include contacting cells with a single compound of the invention. The method may include contact cells with multiple compounds of the invention. The method may include administration of a composition to a subject. The compositions may be provided by any suitable route of administration. For example and without limitation, the compositions may be administered buccally, by injection, dermally, enterally, intraarterially, intravenously, intranasally, e.g., by inhalation, intraocularly, orally, parenterally, pulmonarily, rectally, subcutaneously, systemically, topically, e.g., to the skin or eye, transdermally, or with or on an implantable medical device (e.g., stent or drug-eluting stent or balloon equivalents). Examples: The starting materials for the preparation of the compounds and other materials used in the methods described below may be readily obtained from commercial sources or may be prepared from the methods otherwise provided in the pertinent literature. Example 1: (7R)-36-methoxy-7-methyl-11H-5-oxa-2,8-diaza-1(4,7)-imidazo[1,2- b]pyrazolo[3,4-d]pyridazina-3(1,3)-benzenacyclononaphan-9-one Step 1: Synthesis of 4-bromo-6-chloro-5-methyl-pyridazin-3-amine Patent Application To a mixture of 6-chloro-5-methyl-pyridazin-3-amine (23 g, 160 mmol), NaHCO3 (33.6 g, 400 mmol) in MeOH (100 mL) was added Br2 (28.1 g, 176 mmol), and then the mixture was stirred at 25 °C for 2 hrs under N2 atmosphere. The reaction mixture was filtered and the filtrate was concentrated to give a crude product. The residue was dissolved in DCM (500 mL), washed with Na2SO3 aqueous solution (300 mL) and brine (300 mL). The organic layer was concentrated to give 4-bromo-6-chloro-5-methyl-pyridazin-3-amine (24 g, 67.3% yield) as a brown solid.1H NMR (400 MHz, CDCl3) δ ppm 5.46 - 5.88 (m, 2 H), 2.37 - 2.66 (m, 3 H); LCMS (ESI) m / z 221.6 / 223.6 [M+H]+. Step 2: Synthesis of ethyl 8-bromo-6-chloro-7-methyl-imidazo[1,2-b]pyridazine-3- carboxylate A mixture of 4-bromo-6-chloro-5- (24 g, 107 mmol), ethyl 2-chloro-3- oxo-propanoate (19.4 g, 129 mmol) in EtOH (250 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 16 hrs under N2 atmosphere. The solution was concentrated to give a residue. The residue was diluted with water (500 mL) and extracted with DCM (500 mL × 2). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na2SO4, filtered and concentrated to give a brown solid. The residue was purified by flash chromatography (ISCO®; 220 g SepaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0 ~ 30%, 100 mL / min, 254 nm) to give ethyl 8-bromo-6-chloro-7-methyl- imidazo[1,2-b]pyridazine-3-carboxylate (11.36 g, 33.1% yield) as a yellow solid. LCMS (ESI) m / z 317.9 / 319.8 [M+H]+. Step 3: Synthesis of ethyl 8-acetamido-6-chloro-7-methyl-imidazo[1,2-b]pyridazine-3- carboxylate Patent Application A mixture of ethyl 8-bromo-6- [1,2-b]pyridazine-3-carboxylate (11.4 g, 35.6 mmol) and acetamide (3.16 g, , 3 (3.27 g, 3.57 mmol), Xantphos (4.13 g, 7.13 mmol) and Cs2CO3 (23.2 g, 71.3 mmol) in dioxane (40 mL) was stirred at 100 °C for 3 hrs under N2 atmosphere. The reaction mixture was filtered and washed with EtOAc (50 mL). The filtrate was diluted with H2O (50 mL) and extracted with EtOAc (50 mL × 6). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to give a crude product. The residue was purified by flash chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0 ~ 100%, 80 mL / min, 254 nm) to give ethyl 8-acetamido-6-chloro-7-methyl-imidazo[1,2-b]pyridazine-3-carboxylate (3 g, 25.5% yield) as a yellow solid. LCMS (ESI) m / z 252.0 [M+H]+. Step 4: Synthesis of ethyl 7-chloro-3,4,8,9,12-pentazatricyclo[7.3.0.02,6]dodeca- 1(12),2(6),4,7,10 -pentaene-10-carboxylate To a mixture of ethyl 8-acetamido-6-chloro-7-methyl-imidazo[1,2-b]pyridazine-3-carboxylate (2.9 g, 9.77 mmol), KOAc (1.15 g, 11.7 mmol) in toluene (1.5 mL) was added AcOH (704 mg, 671 μL), Ac2O (2.00 g, 1.84 mL) and isopentyl nitrite (2.29 g, 19.5 mmol), and then the mixture was stirred at 80 °C for 16 hrs under N2 atmosphere. The precipitate was filtered to give ethyl 7- chloro-3,4,8,9,12-pentazatricyclo[7.3.0.02,6]dodeca-1(12),2(6),4,7,10-pentaene-10-carboxylate (2.5 g, 96.3% yield) as a yellow solid. LCMS (ESI) m / z 266.0 [M+H]+. Patent Application Step 5: Synthesis of 7-chloro-3,4,8,9,12-pentazatricyclo[7.3.0.02,6]dodeca-1(12),2(6),4,7,10- pentaene-10-carboxylic acid A mixture of ethyl 7-chloro- [7.3.0.02,6]dodeca-1(12),2(6),4,7,10- pentaene-10-carboxylate (3 g, 11.9 , g, 35.7 mmol) in THF (30 mL) and H2O (30 mL) was stirred at 25 °C for 3 hrs under N2 atmosphere. The reaction mixture was diluted with HCl aqueous solution (2 mL) and lyophilized to give 7-chloro-3,4,8,9,12-pentazatricyclo [7.3.0.02,6]dodeca-1(12),2(6),4,7,10-pentaene-10-carboxylic acid (2.5 g, crude) as a yellow solid. LCMS (ESI) m / z 237.8 [M+H]+. Step 6: Synthesis of 4-(bromomethyl)-1-methoxy-2-nitrobenzene To a solution of 1-methoxy-4-methyl-2- (5 g, 29.9 mmol, 1 eq) in CCl4 (50 mL) was added NBS (5.32 g, 29.9 mmol, 1 eq) and AIBN (49.12 mg, 0.29 mmol, 0.01 eq). The mixture was stirred at 75 °C for 16 hrs. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate / Petroleum ether gradient @ 30 mL / min). Compound 4-(bromomethyl)-1-methoxy-2-nitrobenzene (5 g, 67.9%) was obtained as a white solid.1H NMR (400 MHz, DMSO-d6) δ ppm 7.99 - 8.01 (m, 1H), 7.73 - 7.77 (m, 1H), 7.34 - 7.38 (m, 1H), 4.73 - 4.76 (m, 2H), 3.91 - 3.94 (m, 3H). Step 7: Synthesis of tert-butyl (R)-(1-((4-methoxy-3-nitrobenzyl)oxy)propan-2-yl)carbamate Patent Application To a solution of tert-butyl N-[(1R)-2- ethyl]carbamate (2.5 g, 14.3 mmol, 1 eq) and 4-(bromomethyl)-1-methoxy-2- g, 17.1 mmol, 1.2 eq) in DMF (25 mL) was added Cs2CO3 (9.30 g, 28.5 mmol, 2 eq). The mixture was stirred at 80 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethyl acetate / Petroleum ether gradient @ 30 mL / min). Compound tert-butyl (R)-(1-((4-methoxy- 3-nitrobenzyl)oxy)propan-2-yl)carbamate (1.6 g, 26.6%) was obtained as a yellow oil. LCMS (ESI) m / z 341.2 [M+H]+. Step 8: Synthesis of tert-butyl (R)-(1-((3-amino-4-methoxybenzyl)oxy)propan-2- yl)carbamate A mixture of tert-butyl N-[(1R)-2-[(4-methoxy-3-nitro-phenyl)methoxy]-1-methyl- ethyl]carbamate (1.4 g, 4.11 mmol, 1 eq) and Pd / C (437 mg, 0.41mmol, 10 wt% , 0.1 eq) in THF (15 mL) was degassed and purged with H2 for 3 times, and then the mixture was stirred at 25 °C for 16 hrs under H2 atmosphere. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~30% Ethyl acetate / Petroleum ether gradient @ 30mL / min). Compound tert- butyl (R)-(1-((3-amino-4-methoxybenzyl)oxy)propan-2-yl)carbamate (941 mg, 70.8%) was obtained as a yellow oil. LCMS (ESI) m / z 311.3 [M+H]+ Patent Application Step 9: Synthesis of (R)-5-((2-aminopropoxy)methyl)-2-methoxyaniline To a solution of tert-butyl N-[ 4-methoxy-phenyl)methoxy]-1-methyl- ethyl]carbamate (940 mg, 3.03 mmol, 1 eq) in MeOH (2 mL) was added HCl / dioxane (2 M, 3 mL, 1.98 eq). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to remove solvent. Then the residue was diluted with MeOH (10 mL) and adjusted pH to 8 with NaHCO3 aqueous solution (0.5 M). The mixture was filtered and the filtrate was concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~60% MeOH / DCM @ 30 mL / min). Compound 2-methoxy-5-[[(2R)-2-aminopropoxy]methyl]aniline (588 mg, 81.1%) was obtained as a yellow oil. LCMS (ESI) m / z 211.3 [M+H]+,1H NMR (400 MHz, DMSO-d6) δ ppm 7.65 - 8.29 (m, 2H), 6.71 - 6.77 (m, 1H), 6.62 - 6.66 (m, 1H), 6.49 - 6.55 (m, 1H), 4.71 (br s, 2H), 4.32 - 4.36 (m, 2H), 3.75 (s, 3H), 3.41 - 3.47 (m, 2H), 3.27 - 3.31 (m, 1H), 1.16 (d, J = 6.4 Hz, 3H). Step 10: Synthesis of N-[(1R)-2-[(3-amino-4-methoxy-phenyl)methoxy]-1-methyl-ethyl]-7- chloro-3,4,8,9,12-pentazatricyclo[7.3.0.02,6]dodeca-1(12),2(6),4,7,10-pentaene-10- carboxamide A mixture of 7-chloro-3,4,8,9,12-pentazatricyclo[7.3.0.02,6]dodeca-1(12),2(6),4,7,10-pentaene- 10-carboxylic acid (90 mg, 378 μmol), 5-[[(2R)-2-aminopropoxy]methyl]-2-methoxy-aniline (214 Patent Application mg, 757 μmol), HATU (172 mg, 454 μmol), DIEA (391 mg, 3.03 mmol) in DMF (2 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 25 °C for 16 hrs under N2 atmosphere. The reaction mixture was diluted with H2O (10 mL), extracted with EtOAc (10 mL), dried over anhydrous Na2SO4, filtered and concentrated to give a crude product. The residue was purified by flash chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, EtOAc / petroleum ether from 0 ~ 100%, 12 mL / min, 254 nm) to give a N-[(1R)-2-[(3-amino-4-methoxy- phenyl)methoxy]-1-methyl-ethyl]-7-chloro-3,4,8,9,12-pentazatricyclo[7.3.0.02,6]dodeca- 1(12),2(6),4,7,10-pentaene-10-carboxamide (100 mg, 61.4% yield) as a yellow solid. LCMS (ESI) m / z 452.0 [M+Na]+Step 11: Synthesis of (7R)-36-methoxy-7-methyl-11H-5-oxa-2,8-diaza-1(4,7)-imidazo[1,2- b]pyrazolo[3,4-d]pyridazina-3(1,3)-benzenacyclononaphan-9-one A mixture of N-[(1R)-2-[(3- methoxy]-1-methyl-ethyl]-7-chloro- 3,4,8,9,12-pentazatricyclo[7.3.0.02,6]dodeca-1(12),2(6),4,7,10-pentaene-10-carboxamide (100 mg, 232 μmol), [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium;ditert-butyl-[2-(2,4,6- triisopropylphenyl)phenyl]phosphane (36.9 mg, 46.5 μmol), Cs2CO3 (227 mg, 697 μmol) and E Phos (24.8 mg, 46.5 μmol) in DMF (2 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100 °C for 16 hrs under N2 atmosphere. The reaction mixture was concentrated to give a crude product. The crude product was purified by Pre-HPLC (column: C18 150 × 30 mm; mobile phase: [Water (HCl)-MeCN]; gradient: 18% - 58% B over 9 min). The desired fraction was lyophilized to give (7R)-36-methoxy-7-methyl-11H-5-oxa-2,8-diaza-1(4,7)- imidazo[1,2-b]pyrazolo[3,4-d]pyridazina-3(1,3)-benzenacyclononaphan-9-one (5.4 mg, 5.90% yield) as a yellow solid. LCMS (ESI) m / z 394.0 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ ppm 9.14 - 9.35 (m, 1 H), 8.95 - 9.07 (m, 1 H), 8.45 (d, J = 5.4 Hz, 1 H), 8.12 (s, 1 H), 8.01 (s, 1 H), Patent Application 7.07 - 7.15 (m, 2 H), 4.65 (s, 1 H), 4.38 (d, J = 13.1 Hz, 1 H), 3.98 - 4.03 (m, 1 H), 3.92 (s, 3 H), 3.19 (br d, J = 9.5 Hz, 2 H), 1.12 (d, J = 6.5 Hz, 3 H). Example 2: (61R,62R)-31-(methyl-d3)-11H,31H-5-oxa-2,7-diaza-1(4,7)-imidazo[1,2- b]pyrazolo[3,4-d]pyridazina-3(4,6)-benzo[d][1,2,3]triazola-6(1,2)- cyclopentanacyclooctaphan-8-one Step 1: Synthesis of 3-bromo- A mixture of 2-bromo-4-methyl-6-nitro- g, 43.3 mmol), Fe (12.1 g, 216 mmol), and NH4Cl (11.6 g, 216 mmol) in EtOH (50 mL) and H2O (50 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 1 hr under N2 atmosphere. The mixture was diluted with NH4Cl aqueous solution (50 mL) and extracted with EtOAc (50 mL ´ 3). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Petroleum ether / EtOAc with EtOAc from 0 ~ 50%, flow rate = 65 mL / min, 254 nm) to afford 3-bromo-5-methyl-benzene-1,2-diamine (9.30 g, 95.1% yield) as a brown solid. LCMS (ESI) m / z 201.0, 203.0 [M+H]+,1H NMR (400 MHz, DMSO-d6) δ ppm 6.48 (d, J = 1.2 Hz, 1 H), 6.33 (d, J = 1.6 Hz, 1 H), 4.76 (s, 2 H), 4.38 (s, 2 H), 2.05 (s, 3 H). Step 2: Synthesis of 7-bromo-5-methyl-1H-benzo[d][1,2,3]triazole Patent Application To a solution of 3-bromo-5-methyl- (9.30 g, 46.3 mmol) in AcOH (90 mL) and H2O (30 mL) at 0 °C was added 55.5 mmol) in H2O (10 mL). The reaction mixture was stirred at 20 °C for 2 hrs. The precipitate was filtered to afford 7-bromo-5-methyl- 1H-benzo[d][1,2,3]triazole (7.60 g, crude) as a yellow solid. LCMS (ESI) m / z 211.8, 213.8 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ ppm 7.62 (br s, 1 H), 7.51 (s, 1 H), 2.46 (s, 3 H). Step 3: Synthesis of 4-bromo-6-methyl-1-(methyl-d3)-1H-benzo[d][1,2,3]triazole To a mixture of 7-bromo-5-methyl-1H- (7.60 g, 35.8 mmol) in THF (140 mL) at 0 °C was added NaH (2.15 g, 53.8 mmol, 60% in mineral oil). After stirring for 1 hr, trideuterio(iodo)methane (10.5 g, 72.3 mmol) was added to the rection mixture, and then the mixture was stirred at 20 °C for 15 hrs under N2 atmosphere. The reaction mixture was quenched with H2O (100 mL) at 25 °C, extracted with EtOAc (100 mL ´ 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Petroleum ether / EtOAc with EtOAc from 0 ~ 20%, flow rate = 65 mL / min, 254 nm) to afford 4-bromo-6-methyl-1-(methyl-d3)-1H-benzo[d][1,2,3]triazole (5.00 g, 21.8 mmol, 60.9% yield) as a white solid. LCMS (ESI) m / z 229.1, 231.1 [M+H]+,1H NMR (400 MHz, DMSO-d6) δ ppm 7.63 - 7.68 (m, 1 H), 7.53 (d, J = 0.8 Hz, 1 H), 2.49 (br s, 3 H). Step 4: Synthesis of 4-bromo-6-(bromomethyl)-1-(methyl-d3)-1H-benzo[d][1,2,3]triazole Patent Application A mixture of 4-bromo-6-methyl-1-(methyl-d3)-1H-benzo[d][1,2,3]triazole (5.00 g, 21.8 mmol), NBS (5.83 g, 32.7 mmol), AIBN (1.79 g, 10.9 mmol) in CCl4 (50 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 12 hrs under N2 atmosphere. The reaction mixture was quenched with H2O (200 mL) at 25 °C, and extracted with DCM (100 mL ´ 3). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (Instrument: Gilson GX-281 Liquid Handler, Gilson 322 Pump, Gilson 156 UV Detector; Column: Welch Xtimate C18150 × 25 mm × 5 μm; Mobile phase A: H2O with 0.05% NH3 - H2O (v%); Mobile phase B: ACN; Gradient: B from 70% to 100% in 7.8 min, hold 100% B for 2 min; Flow Rate: 25 mL / min; Column Temperature: 30oC; Wavelength: 220 nm) to afford 4-bromo-6- (bromomethyl)-1-(methyl-d3)-1H-benzo[d][1,2,3]triazole (3.80 g, 56.5% yield) as a white solid. LCMS (ESI) m / z 307.1, 309.1, 311.0 [M+H]+. Step 5: Synthesis of tert-butyl ((1R,2R)-2-((4-bromo-1-(methyl-d3)-1H- benzo[d][1,2,3]triazol-6-yl)methoxy)cyclopentyl)carbamate A mixture of 4-bromo-6-(bromomethyl)-1-(methyl-d3)-1H-benzo[d][1,2,3]triazole (1.70 g, 5.52 mmol), tert-butyl N-[(1R,2R)-2-hydroxycyclopentyl]carbamate (1.00 g, 4.97 mmol), TBAI (185 mg, 0.501 mmol), NaH (240 mg, 6.00 mmol, 60% in mineral oil) in THF (10 mL) was stirred at 20 °C for 3 hrs under N2 atmosphere. The reaction mixture was quenched with H2O (100 mL) at 25 °C, and extracted with EtOAc (100 mL ´ 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue The residue was purified by flash chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Petroleum ether / EtOAc with EtOAc from 0 ~ 30%, flow rate = 60 mL / min, 254 nm) to afford tert-butyl ((1R,2R)-2-((4-bromo-1-(methyl-d3)-1H-benzo[d][1,2,3]triazol-6- Patent Application yl)methoxy)cyclopentyl)carbamate (2.05 g, 69.4% yield) as a white solid. LCMS (ESI) m / z 428.3, 430.3 [M+H]+,1H NMR (400 MHz, DMSO-d6) δ ppm 7.79 (s, 1 H), 7.58 (d, J = 0.8 Hz, 1 H), 6.93 (br d, J = 7.2 Hz, 1 H), 4.68 (s, 2 H), 3.77 - 3.85 (m, 1 H), 3.72 - 3.76 (m, 1 H), 1.81 - 1.96 (m, 2 H), 1.50 - 1.67 (m, 4 H), 1.38 (s, 9 H). Step 6: tert-butyl ((1R,2R)-2-((4-((4-methoxybenzyl)amino)-1-(methyl-d3)-1H- benzo[d][1,2,3]triazol-6-yl)methoxy)cyclopentyl)carbamate A mixture of tert-butyl ( d3)-1H-benzo[d][1,2,3]triazol-6- yl)methoxy)cyclopentyl)carbamate (2.00 g, 4.67 mmol), PMBNH2 (800 mg, 5.83 mmol), Pd2(dba)3 (440mg, 0.481 mmol), Xantphos (560 mg, 0.968 mmol), and Cs2CO3 (4.00 g, 12.3 mmol) in dioxane (30 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100 °C for 12 hrs under N2 atmosphere. The mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL ´ 3). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Petroleum ether / EtOAc with EtOAc from 0 ~ 30%, flow rate = 65 mL / min, 254 nm) to afford tert-butyl ((1R,2R)-2-((4-((4-methoxybenzyl)amino)-1-(methyl-d3)-1H-benzo[d][1,2,3]triazol-6- yl)methoxy)cyclopentyl)carbamate (1.40 g, 61.9% yield) as a brown solid. LCMS (ESI) m / z 485.4 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ ppm 7.30 (d, J = 8.8 Hz, 2 H), 7.08 (br t, J = 6.0 Hz, 1 H), 6.81 - 6.91 (m, 3 H), 6.74 (s, 1 H), 6.18 (s, 1 H), 4.36 - 4.54 (m, 4 H), 3.71 - 3.72 (m, 1 H), 3.70 (s, 3 H), 3.66 (br dd, J = 6.0, 3.2 Hz, 1 H), 1.80 - 1.91 (m, 1 H), 1.73 (br dd, J = 12.0, 6.8 Hz, 1 H), 1.45 - 1.64 (m, 3 H), 1.31 - 1.41 (m, 10 H). Step 7: Synthesis of 6-((((1R,2R)-2-aminocyclopentyl)oxy)methyl)-N-(4-methoxybenzyl)-1- (methyl-d3)-1H-benzo[d][1,2,3]triazol-4-amine Patent Application A mixture of tert-butyl amino)-1-(methyl-d3)-1H- benzo[d][1,2,3]triazol-6-yl) (1.40 g, 2.89 mmol) in HCl / dioxane (20 mL, 2M) was stirred at 20 °C for 1 hr under N2atmosphere. The reaction mixture was quenched with water (50 mL) and sodium bicarbonate in aqueous solution until pH ~ 7, then was extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, DCM / MeOH with MeOH from 0 ~ 5%, flow rate: 65 mL / min, 254 nm) to afford 6-((((1R,2R)-2- aminocyclopentyl)oxy)methyl)-N-(4-methoxybenzyl)-1-(methyl-d3)-1H-benzo[d][1,2,3]triazol- 4-amine (920 mg, 82.8% yield) as a white solid. LCMS (ESI) m / z 385.4 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ ppm 7.30 (d, J = 8.4 Hz, 2 H), 7.09 (t, J = 6.4 Hz, 1 H), 6.83 - 6.89 (m, 2 H), 6.76 (s, 1 H), 6.20 (s, 1 H), 4.48 (br d, J = 6.4 Hz, 2 H), 4.43 (d, J = 2.4 Hz, 2 H), 3.70 (s, 3 H), 3.39 - 3.48 (m, 2 H), 3.03 - 3.16 (m, 2 H), 1.72 - 1.88 (m, 2 H), 1.42 - 1.63 (m, 3 H), 1.18 - 1.26 (m, 1 H). Step 8: Synthesis of 7-chloro-N-[(1R,2R)-2-[[7-[(4-methoxyphenyl)methylamino]-3- (trideuteriomethyl)benzotriazol-5-yl]methoxy]cyclopentyl]-3,4,8,9,12-pentazatricyclo [7.3.0.02,6]dodeca-1(12),2(6),4,7,10-pentaene-10-carboxamide A mixture of 7-chloro-3,4,8,9,12-pentazatricyclo[7.3.0.02,6]dodeca-1(12),2(6),4,7,10-pentaene- 10-carboxylic acid (52.5 mg, 221 μmol), 6-[[(1R,2R)-2-aminocyclopentoxy]methyl]-N-[(4- Patent Application methoxyphenyl)methyl]-1-(trideuteriomethyl)benzotriazol-4-amine (85 mg, 221 μmol), HATU (92.4 mg, 243 μmol), and DIEA (85.7 mg, 663 μmol) in DMF (2 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 25 °C for 2 hrs under N2 atmosphere. The reaction mixture was concentrated to give a crude product. The residue was purified by flash chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0 ~ 100%, 12 mL / min, 254 nm) to give 7-chloro-N-[(1R,2R)-2-[[7-[(4- methoxyphenyl)methylamino]-3-(trideuteriomethyl)benzotriazol-5-yl]methoxy]cyclopentyl]- 3,4,8,9,12-pentazatricyclo[7.3.0.02,6]dodeca-1(12),2(6),4,7,10-pentaene-10-carboxamide (70 mg, 52.4% yield) as a yellow solid. LCMS (ESI) m / z 626.2 [M+H]+. Step 9: Synthesis of N-[(1R,2R)-2-[[7-amino-3-(trideuteriomethyl)benzotriazol-5- yl]methoxy]cyclopentyl]-7-chloro-3,4,8,9,12-pentazatricyclo[7.3.0.02,6]dodeca- 1(12),2(6),4,7,10-pentaene-10-carboxamide A mixture of 7-chloro-N-[ - -3-(trideuteriomethyl) benzotriazol-5-yl]methoxy]cyclopentyl]-3,4,8,9,12-pentazatricyclo[7.3.0.02,6]dodeca- 1(12),2(6),4,7, 10-pentaene-10-carboxamide (60 mg, 99.3 μmol) in TFA (2 mL) was stirred at 25 °C for 2 hrs under N2 atmosphere. The reaction mixture was concentrated to give a crude product. The crude product was diluted with NaHCO3 aqueous solution (5 mL), and extracted with 10% of MeOH in EtOAc. The organic layer was washed with brine (5 mL), dried over Na2SO4, filtered and concentrated to give N-[(1R,2R)-2-[[7-amino-3-(trideuteriomethyl)benzotriazol-5- yl]methoxy]cyclopentyl]-7-chloro-3,4,8,9,12-pentazatricyclo[7.3.0.02,6]dodeca- 1(12),2(6),4,7,10-pentaene-10-carboxamide (50 mg, crude) as a light yellow solid. LCMS (ESI) m / z 484.0 [M+H]+. Patent Application Step 10: Synthesis of (61R,62R)-31-(methyl-d3)-11H,31H-5-oxa-2,7-diaza-1(4,7)-imidazo[1,2- b]pyrazolo[3,4-d]pyridazina-3(4,6)-benzo[d][1,2,3]triazola-6(1,2)- cyclopentanacyclooctaphan-8-one A mixture of N-[ benzotriazol-5-yl]methoxy] cyclopentyl]-7-chloro-3,4,8,9,12-pentazatricyclo[7.3.0.02,6]dodeca-1(12),2(6),4,7,10-pentaene- 10-carboxamide (50 mg, 103 μmol), Cs2CO3 (100 mg, 309 μmol), E Phos (11.0 mg, 20.6 μmol) and E Phos Pd G4 (18.9 mg, 20.6 μmol) in DMF (3 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100 °C for 16 hrs under N2 atmosphere. The reaction mixture was concentrated to give a crude product. The crude was purified by Pre-HPLC (column: Boston Prime C18150 × 30 mm × 5 μm; mobile phase: [water(FA)-ACN]; gradient: 20% - 40% B over 11 min), the desired fraction was lyophilized to give (61R,62R)-31-(methyl-d3)-11H,31H-5- oxa-2,7-diaza-1(4,7)-imidazo[1,2-b]pyrazolo[3,4-d]pyridazina-3(4,6)-benzo[d][1,2,3]triazola- 6(1,2)-cyclopentanacyclooctaphan-8-one (1.1 mg, 2.38% yield) as a yellow solid. LCMS (ESI) m / z 448.2 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ ppm 10.58 (s, 1 H), 8.99 - 9.15 (m, 1 H), 8.84 - 8.96 (m, 1 H), 8.19 (s, 1 H), 7.90 (s, 1 H), 7.43 - 7.60 (m, 1 H), 4.93 - 5.00 (m, 1 H), 4.57 - 4.65 (m, 1 H), 3.82 - 3.89 (m, 2 H), 2.21 - 2.29 (m, 1 H), 2.07 - 2.14 (m, 1 H), 1.71 - 1.79 (m, 1 H), 1.46 - 1.58 (m, 3 H). Example 3 and Example 4:

[0005] Patent Application Example 3: (11R)-4-methoxy-11-methyl-9-oxa-2,12,16,19,23,24- hexazapentacyclo[12.8.2.13,7.017,24.018,22]pentacosa-1(23),3,5,7(25),14,16,18(22)-heptaen- 13-one & Example 4 (11R)-4-methoxy-11-methyl-9-oxa-2,12,16,19,23,24- hexazapentacyclo[12.8.2.13,7.017,24.018,22]pentacosa-1(23),3,5,7(25),14,16,18(22),20- octaen-13-one Step 1: Synthesis of ethyl 3-carboxylate A mixture of 4-bromo-6-chloro- g, 47.9 mmol, 1 eq) and ethyl 2-chloro-3- oxo-propanoate (10.8 g, 71.9 mmol, 1.5 eq) in EtOH (150 mL) was stirred at 80 °C for 16 hrs under N2 atmosphere. The reaction mixture was quenched with H2O (200 mL) and extracted with EtOAc (100 mL ´ 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by column chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Petroleum ether / EtOAc with EtOAc from 0~40%, 80 mL / min, 254 nm) to afford ethyl 8-bromo-6-chloroimidazo[1,2- b]pyridazine-3-carboxylate (14 g, 45.52%) as a white solid. LCMS (ESI) m / z 303.9, 305.9, 307.9 [M+H]+. Step 2: Synthesis of ethyl 8-(allyloxy)-6-chloroimidazo[1,2-b]pyridazine-3-carboxylate Patent Application A mixture of ethyl 8-bromo-6- 3-carboxylate (4.1 g, 13.4 mmol, 1 eq), prop-2-en-1-ol (781 mg, 13.4 , g, 17.5 mmol, 1.3 eq) in MeCN (100 mL) was stirred at 70 °C for 16 hrs under N2 atmosphere. The reaction mixture was quenched with H2O (150 mL) and extracted with EtOAc (100 mL ´ 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by column chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Petroleum ether / EtOAc with EtOAc from 0~40%, 60 mL / min, 254 nm) to afford ethyl 8- (allyloxy)-6-chloroimidazo[1,2-b]pyridazine-3-carboxylate (1.49 g, 37.32%) as a white solid. LCMS (ESI) m / z 282.2, 284.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ ppm 8.24 - 8.26 (m, 1H), 7.18 - 7.21 (m, 1H), 6.02 - 6.27 (m, 1H), 5.53 (dd, J = 17.2, 1.5 Hz, 1H), 5.40 (dd, J = 10.4, 1.2 Hz, 1H), 4.96 (d, J = 5.6 Hz, 2H), 4.34 (q, J = 7.2 Hz, 2H), 1.33 (t, J = 7.2 Hz, 3H). Step 3: Synthesis of ethyl 7-allyl-6-chloro-8-hydroxyimidazo[1,2-b]pyridazine-3-carboxylate A solution of ethyl 8-(allyloxy)-6-chloroimidazo[1,2-b]pyridazine-3-carboxylate (1 g, 3.55 mmol, 1 eq) in mesitylene (10 mL) was stirred at 170 °C for 4 hrs under N2 atmosphere. The reaction mixture was quenched with H2O (30 mL) and extracted with EtOAc (30 mL ´ 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by column chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Petroleum ether / EtOAc with EtOAc from 0~100%, 35 mL / min, 254 nm) to Patent Application afford ethyl 7-allyl-6-chloro-8-hydroxyimidazo[1,2-b]pyridazine-3-carboxylate (1 g, crude) as a white solid. LCMS (ESI) m / z 282.2, 284.2 [M+H]+. Step 4: Synthesis of ethyl 7-allyl-6,8-dichloroimidazo[1,2-b]pyridazine-3-carboxylate A mixture of ethyl 7-allyl-6-chloro-8- [1,2-b]pyridazine-3-carboxylate (1 g, 3.55 mmol, 1 eq) and DIEA (1.38 g, 10.6 mmol, 3 eq) in POCl3 (10 mL) was stirred at 100 °C for 16 hrs. The reaction mixture was quenched with H2O (100 mL) and extracted with EtOAc (50 mL ´ 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by column chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Petroleum ether / EtOAc with EtOAc from 0~30%, 35 mL / min, 254 nm) to afford ethyl 7-allyl-6,8-dichloroimidazo[1,2-b]pyridazine-3-carboxylate (630 mg, 56.17%) as a white solid. LCMS (ESI) m / z 300.2, 302.2 [M+H]+. Step 5: Synthesis of ethyl 6,8-dichloro-7-(2-oxoethyl)imidazo[1,2-b]pyridazine-3-carboxylate To a solution of ethyl 7-allyl-6,8-dichloroimidazo[1,2-b]pyridazine-3-carboxylate (630 mg, 2.10 mmol, 1 eq) in MeCN (10 mL) and H2O (2 mL) was added K2OsO4.2H2O (38.6 mg, 0.10 mmol, 0.05 eq) in portion at 0 °C. Then NaIO4 (1.35 g, 6.30 mmol, 3 eq) was added in portion at 0 °C. The reaction mixture was stirred at 25 °C for 16 hrs. It was quenched with H2O (30 mL) and Patent Application extracted with EtOAc (30 mL ´ 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by column chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Petroleum ether / EtOAc with EtOAc from 0~40%, 35 mL / min, 254 nm) to afford ethyl 6,8-dichloro-7-(2- oxoethyl)imidazo[1,2-b]pyridazine-3-carboxylate (209 mg, 26.37%) as a white solid. LCMS (ESI) m / z 302.0, 304.0 [M+H]+. Step 6: Synthesis of ethyl 6-chloro-9-(4-methoxybenzyl)-8,9-dihydro-7H-imidazo[1,2- b]pyrrolo[2,3-d]pyridazine-3-carboxylate To a solution of ethyl 6,8-dichloro- [1,2-b]pyridazine-3-carboxylate (150 mg, 0.49 mmol, 1 eq) and PMBNH2 (68.1 mg, 0.49 mmol, 1 eq) in MeCN (3 mL) was added dropwise AcOH (2.98 mg, 0.04 mmol, 0.1 eq) and NaBH4 (37.5 mg, 0.99 mmol, 2 eq) at 25°C. After addition, the mixture was stirred at this temperature for 2 hrs, and then TEA (502 mg, 4.97 mmol, 10 eq) was added dropwise at 25 °C. The resulting mixture was stirred at 80 °C for 4 hrs. The reaction mixture was quenched with H2O (30 mL) and extracted with EtOAc (30 mL ´ 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by column chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Petroleum ether / EtOAc with EtOAc from 0~40%, 35 mL / min, 254 nm) to afford ethyl 6-chloro-9-(4-methoxybenzyl)-8,9-dihydro-7H-imidazo[1,2- b]pyrrolo[2,3-d]pyridazine-3-carboxylate (141 mg, 69.74%) as a white solid. LCMS (ESI) m / z 387.3, 389.3 [M+H]+. Step 7: Synthesis of 6-chloro-9-(4-methoxybenzyl)-8,9-dihydro-7H-imidazo[1,2- b]pyrrolo[2,3-d]pyridazine-3-carboxylic acid Patent Application A mixture of ethyl 6-chloro-9-(4- dihydro-7H-imidazo[1,2-b]pyrrolo[2,3- d]pyridazine-3-carboxylate (141 mg, NaOH (145 mg, 3.64 mmol, 10 eq) in MeOH (2 mL) was stirred at 80 °C for 2 hrs. The reaction mixture was concentrated under reduced pressure to remove MeOH to afford 6-chloro-9-(4-methoxybenzyl)-8,9-dihydro-7H-imidazo[1,2- b]pyrrolo[2,3-d]pyridazine-3-carboxylic acid (140 mg, crude) as a white solid. LCMS (ESI) m / z 359.0, 361.0 [M+H]+. Step 8: (R)-N-(1-((3-amino-4-methoxybenzyl)oxy)propan-2-yl)-6-chloro-9-(4- methoxybenzyl)-8,9-dihydro-7H-imidazo[1,2-b]pyrrolo[2,3-d]pyridazine-3-carboxamide A mixture of 6-chloro- - 7H-imidazo[1,2-b]pyrrolo[2,3- d]pyridazine-3-carboxylic acid (130 mg, 0.36 mmol, 1 eq), 2-methoxy-5-[[(2R)-2- aminopropoxy]methyl]aniline (76.1 mg, 0.36 mmol, 1 eq), PYBOP (339 mg, 0.65 mmol, 1.8 eq), DBU (165 mg, 1.09 mmol, 3 eq) in DMF (3 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 25 °C for 2 hrs under N2 atmosphere. The reaction mixture was quenched with H2O (30 mL) and extracted with EtOAc (30 mL ´ 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by column chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Petroleum ether / EtOAc with EtOAc from 0~100%, 35 mL / min, 254 nm) to afford (R)- N-(1-((3-amino-4-methoxybenzyl)oxy)propan-2-yl)-6-chloro-9-(4-methoxybenzyl)-8,9-dihydro- Patent Application 7H-imidazo[1,2-b]pyrrolo[2,3-d]pyridazine-3-carboxamide (211 mg, 73.97%) as a white solid. LCMS (ESI) m / z 551.2, 553.2 [M+H]+. Step 9: Synthesis of (11R)-4-methoxy-19-[(4-methoxyphenyl)methyl]-11-methyl-9-oxa- 2,12,16,19,23,24-hexazapentacyclo[12.8.2.13,7.017,24.018,22]pentacosa- 1(23),3,5,7(25),14,16,18(22)-heptaen-13-one A mixture of (R)-N- oxy)propan-2-yl)-6-chloro-9-(4- methoxybenzyl)-8,9-dihydro-7H-imidazo[1,2-b]pyrrolo[2,3-d]pyridazine-3-carboxamide (211 mg, 0.38 mmol, 1 eq), Ephos (41.6 mg, 0.07 mmol, 0.2 eq), Ephos Pd G4 (70.3 mg, 0.07 mmol, 0.2 eq) and Cs2CO3 (374 mg, 1.15 mmol, 3 eq) in DMF (3 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 120 °C for 1 hr under N2 atmosphere. The reaction mixture was quenched with H2O (30 mL) and extracted with EtOAc (30 mL ´ 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by column chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Petroleum ether / EtOAc with EtOAc from 0~100%, 35 mL / min, 254 nm) to afford (11R)-4-methoxy-19-[(4-methoxyphenyl)methyl]-11-methyl-9-oxa-2,12,16,19,23,24- hexazapentacyclo[12.8.2.13,7.017,24.018,22]pentacosa-1(23),3,5,7(25),14,16,18(22)-heptaen- 13-one (130 mg, 62.68%) as a white solid. LCMS (ESI) m / z 515.2 [M+H]+. Step 10: Synthesis of (11R)-4-methoxy-11-methyl-9-oxa-2,12,16,19,23,24- hexazapentacyclo[12.8.2.13,7.017,24.018,22]pentacosa-1(23),3,5,7(25),14,16,18(22)-heptaen- 13-one & (11R)-4-methoxy-11-methyl-9-oxa-2,12,16,19,23,24- hexazapentacyclo[12.8.2.13,7.017,24.018,22]pentacosa-1(23),3,5,7(25),14,16,18(22),20- octaen-13-one Patent Application A solution of methyl]-11-methyl-9-oxa- 2,12,16,19,23,24- 1(23),3,5,7(25),14,16,18(22)-heptaen-13-one (130 mg, 0.25 mmol, 1 eq) in HCl / dioxane (2M, 3 mL) was stirred at 25 °C for 16 hrs. The reaction mixture was concentrated and the residue was purified by prep-HPLC (column: 2_Phenomenex Gemini C1875 ´ 40mm ´ 3um;mobile phase: [water(HCl)-ACN];gradient:17%-47% B over 10 min) to afford Example 3 (11R)-4-methoxy-11- methyl-9-oxa-2,12,16,19,23,24-hexazapentacyclo[12.8.2.13,7.017,24.018,22]pentacosa- 1(23),3,5,7(25),14,16,18(22)-heptaen-13-one (8.05 mg, 7.92%) as a yellow solid and Example 4 (11R)-4-methoxy-11-methyl-9-oxa-2,12,16,19,23,24- hexazapentacyclo[12.8.2.13,7.017,24.018,22]pentacosa-1(23),3,5,7(25),14,16,18(22),20-octaen- 13-one (4.61 mg, 4.56%) as a yellow solid. Analytical data for (11R)-4-methoxy-11-methyl-9-oxa-2,12,16,19,23,24- hexazapentacyclo[12.8.2.13,7.017,24.018,22]pentacosa-1(23),3,5,7(25),14,16,18(22)-heptaen- 13-one: LCMS (ESI) m / z 395.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ ppm 8.57 (br d, J = 5.2 Hz, 1H), 8.27 (s, 1H), 8.01 (s, 1H), 7.72 (s, 1H), 6.96 - 7.08 (m, 2H), 4.59 (br d, J = 13.2 Hz, 1H), 4.35 (br d, J = 13.2 Hz, 1H), 3.98 - 4.03 (m, 1H), 3.96 - 4.03 (m, 1H), 3.97 (br s, 1H), 3.93 (br d, J = 10.0 Hz, 1H), 3.87 (s, 3H), 3.42 (br d, J = 8.4 Hz, 1H), 3.14 - 3.26 (m, 3H), 1.11 (br d, J = 6.4 Hz, 3H). Analytical data for (11R)-4-methoxy-11-methyl-9-oxa-2,12,16,19,23,24- hexazapentacyclo[12.8.2.13,7.017,24.018,22]pentacosa-1(23),3,5,7(25),14,16,18(22),20- octaen-13-one: LCMS (ESI) m / z 393.4 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ ppm 12.88 (br s, 1H), 8.59 (s, 1H), 8.51 (d, J = 5.2 Hz, 1H), 8.13 (d, J = 1.6 Hz, 1H), 7.93 (s, 1H), 7.53 (t, J = 2.4 Hz, 1H), 7.30 - 7.41 (m, 1H), 7.03 - 7.13 (m, 2H), 4.63 (d, J = 13.2 Hz, 1H), 4.37 (d, J = 13.2 Hz, 1H), 3.94 - 4.07 (m, 1H), 3.91 (s, 3H), 3.55 - 3.60 (m, 1H), 3.20 (t, J = 9.2 Hz, 1H), 1.12 (d, J = Patent Application 6.4 Hz, 3H). Example 5: (10R,13R)-5-morpholino-9-oxa-2,14,18,21,26,27- hexazahexacyclo[14.9.2.13,7.010,13.019,27.020,25]octacosa-1(26),3,5,7(28),16,18,20(25)- heptaen-15-one Step 1: Synthesis of chloroimidazo[1,2-b]pyridazine-3- carboxylate and ethyl 6,8-dichloroimidazo[1,2-b]pyridazine-3-carboxylate A mixture of 4-bromo-6-chloro-pyridazin-3-amine (23.0 g, 110.3 mmol, 1.0 eq) and ethyl 2- chloro-3-oxo-propanoate (24.92 g, 165.5 mmol, 1.5 eq) in EtOH (300 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 16 hrs under N2 atmosphere. The reaction mixture was diluted with H2O (300 mL) and extracted with EtOAc (300 mL ´ 3). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ethyl acetate in petroleum ether = 0% to 40%) to afford the product (mixture of ethyl 8-bromo-6-chloroimidazo[1,2-b]pyridazine-3-carboxylate and ethyl 6,8-dichloroimidazo[1,2-b]pyridazine-3-carboxylate) (31.00 g, 43.8% yield) as a white solid. LCMS (ESI) m / z 260.0, 262.0 (Cl); 303.9, 305.9, 307.9 (Br) [M+H]+. Patent Application Step 2: Synthesis of ethyl 6-chloro-8-[(4-methoxyphenyl)methylamino]imidazo[1,2- b]pyridazine-3-carboxylate The mixture of ethyl 8-bromo-6- pyridazine-3-carboxylate and ethyl 6,8- dichloroimidazo[1,2-b]pyridazine-3-carboxylate (11.00 g, 36.1 mmol, 1.0 eq), DIEA (14.01 g, 108.4 mmol, 18.9 mL, 3.0 eq), PMBNH2 (9.91 g, 72.2 mmol, 9.4 mL, 2.0 eq) in EtOH (60 mL) was stirred at 80 °C for 4 hrs. The mixture was concentrated under reduced pressure and triturated with MTBE (100 mL ´ 3). The precipitate was filtered to afford the product of ethyl 6-chloro-8- [(4-methoxyphenyl)methylamino]imidazo[1,2-b]pyridazine-3-carboxylate (13.00 g, 94.7% yield) as a yellow solid. LCMS (ESI) m / z 361.2, 363.2 [M+H]+. Step 3: Synthesis of ethyl 6-chloro-7-iodo-8-[(4-methoxyphenyl)methylamino]imidazo[1,2- b]pyridazine-3-carboxylate A mixture of ethyl 6-chloro-8-[(4-methoxyphenyl)methylamino]imidazo[1,2-b]pyridazine-3- carboxylate (6.50 g, 18.0 mmol, 1.0 eq) and NIS (6.49 g, 28.8 mmol, 1.6 eq) in AcOH (100.0 mL) was stirred at 20 °C for 1 hr under N2. The reaction mixture was quenched with saturated Na2S2O3aqueous solution (100 mL) and concentrated to remove AcOH. The residue was diluted with EtOAc (100 mL) and H2O (100 mL). The aqueous phase was separated and extracted with EtOAc (100 mL ´ 3). The combined organic layers were washed with brine (150 mL), dried over anhydrous Na2SO4, filtered and concentrated to give a residue, which was purified by silica gel Patent Application chromatography (ethyl acetate in petroleum ether = 0% to 20%) to afford the product of ethyl 6- chloro-7-iodo-8-[(4-methoxyphenyl)methylamino]imidazo[1,2-b]pyridazine-3-carboxylate (8.50 g, 95.0% yield) as a yellow solid. LCMS (ESI) m / z 487.1, 489.1 [M+H]+. Step 4: Synthesis of ethyl 6-chloro-8-[(4-methoxyphenyl)methylamino]-7-vinyl-imidazo[1,2- b]pyridazine-3-carboxylate A mixture of ethyl 6- methylamino]imidazo[1,2- b]pyridazine-3-carboxylate (8.50 g, 17.5 mmol, 1.0 eq), potassium;trifluoro(vinyl)boranuide (4.68 g, 34.9 mmol, 2.0 eq), Pd(dppf)Cl2 (1.28 g, 1.8 mmol, 0.1 eq) and K2CO3 (7.24 g, 52.4 mmol, 3.0 eq) in dioxane (300 mL) and H2O (70 mL) was stirred at 95 °C for 12 hrs under N2, The reaction mixture was filtered and the filtrate was concentrated to give a residue, which was purified by silica gel chromatography (ethyl acetate in petroleum ether = 0% to 20%) to afford the product of ethyl 6-chloro-8-[(4-methoxyphenyl)methylamino]-7-vinyl-imidazo[1,2-b]pyridazine-3- carboxylate (3.80 g, 56.3% yield) as a yellow solid. LCMS (ESI) m / z 387.2, 389.2 [M+H]+. Step 5: Synthesis of ethyl 8-[allyl-[(4-methoxyphenyl)methyl]amino]-6-chloro-7-vinyl- imidazo[1,2-b]pyridazine-3-carboxylate To a mixture of ethyl 6-chloro-8-[(4-methoxyphenyl)methylamino]-7-vinyl-imidazo[1,2- b]pyridazine-3-carboxylate (3.80 g, 9.8 mmol, 1.0 eq) and Cs2CO3 (12.80 g, 39.3 mmol, 4.0 eq) in Patent Application ACN (100 mL) was added drop-wise 3-bromoprop-1-ene (3.57 g, 29.5 mmol, 3.0 eq) at 20oC. The mixture was stirred at 20 °C for 12 hrs under N2. The mixture was filtered and the filtrate was concentrated to give a residue, which was purified by silica gel chromatography (ethyl acetate in petroleum ether = 0% to 15%) to afford the product of ethyl 8-[allyl-[(4- methoxyphenyl)methyl]amino]-6-chloro-7-vinyl-imidazo[1,2-b]pyridazine-3-carboxylate (2.80 g, 64.8% yield) as a yellow oil. LCMS (ESI) m / z 427.2, 429.2 [M+H]+. Step 6: Synthesis of ethyl 8-chloro-13-[(4-methoxyphenyl)methyl]-3,6,7,13- tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10-pentaene-5-carboxylate A mixture of ethyl 8-[allyl-[(4- amino]-6-chloro-7-vinyl-imidazo[1,2- b]pyridazine-3-carboxylate (1.80 g, 4.2 mmol, 1.0 eq) and Grubbs catalyst II (286.4 mg, 337.3 μmol, 0.08 eq) in DCM (50 mL) was stirred at 40 °C for 12 hrs under N2. The reaction mixture was concentrated to give a residue, which was purified by silica gel chromatography (ethyl acetate in petroleum ether = 0% to 13%) to afford the product of ethyl 8-chloro-13-[(4- methoxyphenyl)methyl]-3,6,7,13-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10-pentaene-5- carboxylate (350.0 mg, 19.8% yield) as a yellow oil. LCMS (ESI) m / z 399.2, 401.2 [M+H]+. Step 7: Synthesis of ethyl 8-chloro-13-[(4-methoxyphenyl)methyl]-3,6,7,13- tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7-tetraene-5-carboxylate

[0006] Patent Application A mixture of ethyl 8-chloro-13-[(4-methoxyphenyl)methyl]-3,6,7,13- tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10-pentaene-5-carboxylate (350.0 mg, 877.5 μmol, 1.0 eq) and PtO2 (19.9 mg, 87.8 μmol, 0.1 eq) in MeOH (5 mL) and EtOAc (5 mL) was stirred at 20 °C for 1 hr under H2 (15 psi). The mixture was filtered and the filtrate was concentrated to afford the product of ethyl 8-chloro-13-[(4-methoxyphenyl)methyl]-3,6,7,13- tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7-tetraene-5-carboxylate (350.0 mg, 99.5% yield) as a yellow oil. LCMS (ESI) m / z 401.2, 403.2 [M+H]+. Step 8: Synthesis of 8-chloro-13-[(4-methoxyphenyl)methyl]-3,6,7,13- tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7-tetraene-5-carboxylic acid A mixture of 13-[(4-methoxyphenyl)methyl]-3,6,7,13- tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7-tetraene-5-carboxylate (320 mg, 798.3 μmol, 1.0 eq), and LiOH (95.6 mg, 4.0 mmol, 5.0 eq) in H2O (3 mL) and THF (3 mL) was stirred at 20 °C for 8 hrs under N2. The mixture was diluted with EtOAc (30 mL) and H2O (30 mL). The organic layer was separated. The aqueous layer was adjusted to pH = 4 with HCl aqueous solution (4 mL, 2 N) and extracted with EtOAc (30 mL ´ 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated to give the product of 8-chloro-13- [(4-methoxyphenyl)methyl]-3,6,7,13-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7-tetraene-5- carboxylic acid (230.0 mg, 73.4% yield) as a yellow solid. LCMS (ESI) m / z 373.2, 375.2 [M+H]+. Step 9: Synthesis of 3-morpholino-5-nitrobenzoic acid Patent Application To a solution of 3-fluoro-5-nitro-benzoic acid (10 g, 54.02 mmol, 1 eq) in DMSO (100 mL) was added morpholine (23.53 g, 270.11 mmol, 5 eq). The mixture was stirred at 100 °C for 24 hrs. The reaction mixture was quenched with H2O (200 mL) and extracted with EtOAc (100 mL ´ 3). The combined organic layer was washed with brine (100 mL ´ 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The crude product was purified by column chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, DCM / MeOH with MeOH from 0~2%, 35 mL / min, 254 nm) to afford 3-morpholino-5-nitrobenzoic acid (6.2 g, 43.23% yield) as a white solid. LCMS (ESI) m / z 253.1 [M+H]+,1H NMR (400 MHz, DMSO-d6) δ ppm 8.05 (s, 1H), 7.84 (d, J = 1.4 Hz, 1H), 7.73 (t, J = 2.0 Hz, 1H), 3.74 - 3.79 (m, 4H), 3.23 - 3.28 (m, 4H). Step 10: Synthesis of (3-morpholino-5-nitrophenyl)methanol To a solution of 3-morpholino-5- 23.79 mmol, 1 eq) in THF (100 mL) was added dropwise BH3.THF (1 M, 35.68 mL, 1.5 eq) at 0 °C over 30 min. The mixture was then stirred at 25 °C for 12 hrs. The reaction mixture was quenched with saturated NH4Cl aqueous solution (300 mL) and extracted with EtOAc (100 mL ´ 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The crude product was purified by column chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Petroleum ether / EtOAc with EtOAc from 0~80%, 35 mL / min, 254 nm) to afford (3-morpholino-5-nitrophenyl)methanol (720 mg, 12.70% yield) as a white solid. LCMS (ESI) m / z 239.2 [M+H]+. Step 11: Synthesis of 4-(3-(bromomethyl)-5-nitrophenyl)morpholine Patent Application To a solution of (3-morpholino-5-nitrophenyl)methanol (720 mg, 3.02 mmol, 1 eq) in DCM (20 mL) was added CBr4 (2.00 g, 6.04 mmol, 2 eq) and PPh3 (1.59 g, 6.04 mmol, 2 eq). The mixture was stirred at 25 °C for 16 hrs. The reaction mixture was quenched with H2O (30 mL) and extracted with DCM (30 mL ´ 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by column chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Petroleum ether / EtOAc with EtOAc from 0~30%, 35 mL / min, 254 nm) to afford 4-(3-(bromomethyl)-5- nitrophenyl)morpholine (847 mg, 88.41% yield) as a white solid. LCMS (ESI) m / z 301.1, 303.1 [M+H]+. Step 12: Synthesis of tert-butyl ((1R,2R)-2-((3-morpholino-5- nitrobenzyl)oxy)cyclobutyl)carbamate To a solution of tert-butyl ((1R,2R)- carbamate (631 mg, 3.38 mmol, 1.2 eq) in THF (7 mL) was added dropwise t-BuOK solution (1 M, 3.66 mL, 1.3 eq) at 0 °C. The mixture was stirred at 0 °C for 30 min, and then 4-(3-(bromomethyl)-5-nitrophenyl)morpholine (847 mg, 2.81 mmol, 1 eq) was added dropwise at 0 °C. The mixture was stirred at 25 °C for 1.5 hr. The reaction mixture was quenched with H2O (30 mL) and extracted with EtOAc (30 mL ´ 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by column chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Petroleum ether / EtOAc with EtOAc from 0~60%, 35 mL / min, 254 nm) to afford tert-butyl ((1R,2R)-2-((3-morpholino-5- nitrobenzyl)oxy)cyclobutyl)carbamate (823 mg, 68.22% yield) as a yellow oil. LCMS (ESI) m / z 408.3 [M+H]+,1H NMR (400 MHz, DMSO-d6) δ ppm 7.59 (t, J = 2.0 Hz, 1H), 7.53 (s, 1H), 7.30 (s, 1H), 7.20 - 7.27 (m, 1H), 4.41 - 4.61 (m, 2H), 3.77 - 3.85 (m, 2H), 3.72 - 3.77 (m, 4H), 3.21 - 3.26 (m, 4H), 1.81 - 1.99 (m, 2H), 1.44 (br s, 1H), 1.37 (s, 9H), 1.32 (br d, J = 7.6 Hz, 1H). Patent Application Step 13: Synthesis of tert-butyl ((1R,2R)-2-((3-amino-5- morpholinobenzyl)oxy)cyclobutyl)carbamate To a solution of tert-butyl ( nitrobenzyl)oxy)cyclobutyl)carbamate (440 mg, 1.08 mmol, 1 eq) in THF (5 mL) was added Pd / C (229 mg, 0.21 mmol, 10% dispersion in mineral oil, 0.2 eq). The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (15 Psi) at 25 °C for 2 hrs. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to afford tert-butyl ((1R,2R)-2-((3-amino-5- morpholinobenzyl)oxy)cyclobutyl)carbamate (400 mg, crude) as a yellow oil. LCMS (ESI) m / z 378.2 [M+H]+. Step 14: Synthesis of 3-(((1R,2R)-2-aminocyclobutoxy)methyl)-5-morpholinoaniline A solution of tert-butyl ((1R,2R)-2-((3-amino-5-morpholinobenzyl)oxy)cyclobutyl)carbamate (400 mg, 1.06 mmol, 1 eq) in HCl / dioxane (2M, 4 mL) was stirred at 25 °C for 2 hrs. The reaction mixture was concentrated under reduced pressure to remove solvent. Then the mixture was diluted with MeOH (10mL) and was adjusted to pH 8 with NaHCO3 aqueous solution (0.5 M). The mixture was filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~20% DCM / MeOH @ 35 mL / min) to afford 3-(((1R,2R)-2-aminocyclobutoxy)methyl)-5-morpholinoaniline (283 mg, 91.47% yield) as a yellow oil. LCMS (ESI) m / z 278.3 [M+H]+. Patent Application Step 15: Synthesis of N-[(1R,2R)-2-[(3-amino-5-morpholino-phenyl)methoxy]cyclobutyl]-8- chloro-13-[(4-methoxyphenyl)methyl]-3,6,7,13-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7- tetraene-5-carboxamide To a mixture methoxyphenyl)methyl]-3,6,7,13- tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7-tetraene-5-carboxylic acid (210.0 mg, 563.3 μmol, 1.0 eq), 3-[[(1R,2R)-2-aminocyclobutoxy]methyl]-5-morpholino-aniline (187.5 mg, 676.0 μmol, 1.2 eq) and PyBOP (439.7 mg, 845.0 μmol, 1.5 eq) in DMF (5 mL) was added drop-wise DBU (428.8 mg, 2.8 mmol, 424.5 μL, 5.0 eq) at 20oC. The mixture was stirred at 20 °C for 1 hr under N2. The mixture was filtered and the filtrate was purified by Reverse Phase column (ACN in H2O = 0% to 45%) to afford the product of N-[(1R,2R)-2-[(3-amino-5-morpholino- phenyl)methoxy]cyclobutyl]-8-chloro-13-[(4-methoxyphenyl)methyl]-3,6,7,13- tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7-tetraene-5-carboxamide (250.0 mg, 375.7 μmol, 66.7% yield) as a yellow solid. LCMS (ESI) m / z 632.4, 634.4 [M+H]+. Step 16: Synthesis of (10R,13R)-21-[(4-methoxyphenyl)methyl]-5-morpholino-9-oxa- 2,14,18,21,26,27-hexazahexacyclo[14.9.2.13,7.010,13.019,27.020,25]octacosa- 1(26),3,5,7(28),16,18,20(25)-heptaen-15-one A mixture of N-[(1R,2R)-2-[(3-amino-5-morpholino-phenyl)methoxy]cyclobutyl]-8-chloro-13- [(4-methoxyphenyl)methyl]-3,6,7,13-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7-tetraene-5- Patent Application carboxamide (240.0 mg, 379.7 μmol, 1.0 eq), Ephos Pd G4 (34.9 mg, 38.0 μmol, 0.1 eq), Ephos (20.3 mg, 38.0 μmol, 0.1 eq) and K3PO4 (241.8 mg, 1.1 mmol, 3.0 eq) in dioxane (6 mL) was stirred at 100 °C for 3 hrs under N2. The mixture was concentrated to give a residue which was diluted with DMF (8 mL) and then purified by reverse phase column (ACN in H2O = 0% to 80%) to afford the product of (10R,13R)-21-[(4-methoxyphenyl)methyl]-5-morpholino-9-oxa- 2,14,18,21,26,27-hexazahexacyclo[14.9.2.13,7.010,13.019,27.020,25]octacosa- 1(26),3,5,7(28),16,18,20(25)-heptaen-15-one (150.0 mg, 63.0% yield) as a white solid. LCMS (ESI) m / z 596.4 [M+H]+. Step 17: Synthesis of (10R,13R)-5-morpholino-9-oxa-2,14,18,21,26,27- hexazahexacyclo[14.9.2.13,7.010,13.019,27.020,25]octacosa-1(26),3,5,7(28),16,18,20(25)- heptaen-15-one A mixture of (10R,13R)-21-[(4- - morpholino-9-oxa-2,14,18,21,26,27- hexazahexacyclo[14.9.2.13,7.010,13.019,27.020,25]octacosa-1(26),3,5,7(28),16,18,20(25)- heptaen-15-one (110.0 mg, 184.7 μmol, 1.0 eq) in DCM (3 mL) and TFA (1.5 mL) was stirred at 20 °C for 2 hrs under N2. The mixture was concentrated to give a residue, which was diluted with DMF (5 mL) and purified by reverse phase column (ACN in H2O = 0% to 60%) to afford the product of (10R,13R)-5-morpholino-9-oxa-2,14,18,21,26,27- hexazahexacyclo[14.9.2.13,7.010,13.019,27.020,25]octacosa-1(26),3,5,7(28),16,18,20(25)- heptaen-15-one (72.0 mg, 79.5% yield) as a white solid. LCMS (ESI) m / z 476.3 [M+H]+,1H NMR (400 MHz, DMSO-d6) δ ppm 9.32 (d, J = 4.0, 1H), 7.95 (s, 1H), 7.77 (s, 1H), 7.46 (s, 1H), 7.38 (s, 1H), 6.87 (m, 1H), 6.56 (s, 1H), 4.52 (s, 2H), 3.95 - 3.83 (m, 1H), 3.79 - 3.71 (m, 4H), 3.69 - 3.59 (m, 1H), 3.44 - 3.36 (m, 2H), 3.19 - 3.07 (m, 4H), 2.82 - 2.67 (m, 1H), 2.63 - 2.54 (m, 1H), 2.21 - 1.95 (m, 3H), 1.93 - 1.83 (m, 1H), 1.70 - 1.56 (m, 1H), 1.21 - 1.09 (m, 1H). Patent Application Example 6: (61R,62R)-19H-5-oxa-2,7-diaza-1(6,3)-imidazo[1,2-b]pyrrolo[2,3-d]pyridazina- 3(1,3)-benzena-6(1,2)-cyclobutanacyclooctaphan-8-one Step 1: Synthesis of 1- A mixture of (3-nitrophenyl)methanol (2 1 eq), CBr4 (6.50 g, 19.59 mmol, 1.5 eq), PPh3 (5.14 g, 19.59 mmol, 1.5 eq) in DCM (80 mL) at 0 °C was degassed and purged with N2 for 3 times, and then the mixture was stirred at 20 °C for 2 hrs under N2 atmosphere. The mixture was diluted with H2O (100 mL) and extracted with DCM (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Ethyl acetate / Petroleum ether = 0 to 30%). Compound 1-(bromomethyl)-3-nitrobenzene (2.8 g, 99.24% yield) was obtained as a white solid. The desired product showed no mass signal via LCMS. Step 2: Synthesis of tert-butyl ((1R,2R)-2-((3-nitrobenzyl)oxy)cyclobutyl)carbamate Patent Application To a solution of tert-butyl ((1R,2R)-2-hydroxycyclobutyl)carbamate (2.86 g, 15.28 mmol, 1.2 eq) in THF (30 mL) was added dropwise t-BuOK (1 M, 15.28 mL, 1.2 eq) at 0 °C. The mixture was stirred at 0 °C for 1 hr, and then 1-(bromomethyl)-3-nitrobenzene (2.75 g, 12.73 mmol, 1 eq) in THF (30 mL) was added dropwise. The mixture was stirred at 20 °C for 2 hrs. The reaction mixture was quenched with saturated NH4Cl aqueous solution (100 mL) and extracted with EtOAc (50 mL ×3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Ethyl acetate / Petroleum ether = 0 to 50%). Compound tert-butyl ((1R,2R)- 2-((3-nitrobenzyl)oxy)cyclobutyl)carbamate (3.1 g, 75.55% yield) was obtained as a white solid. LCMS (ESI) m / z 223.2 [M+H-100]+. Step 3: Synthesis of tert-butyl ((1R,2R)-2-((3-aminobenzyl)oxy)cyclobutyl)carbamate To a solution of tert-butyl N-[(1R,2R)- methoxy]cyclobutyl]carbamate (810 mg, 2.51 mmol, 1 eq) in THF (10 mL) was added Pd / C (401 mg, 0.37 mmol, 10% dispersion in mineral oil, 0.15 eq). The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (15 Psi) at 25 °C for 2 hrs. The reaction mixture was filtered and concentrated under reduced pressure to remove solvent to afford tert-butyl ((1R,2R)-2-((3- aminobenzyl)oxy)cyclobutyl)carbamate (522 mg, 71.05% yield) as a yellow oil. LCMS (ESI) m / z 293.2 [M+H]+. Step 4: Synthesis of 3-(((1R,2R)-2-aminocyclobutoxy)methyl)aniline

[0007] Patent Application A solution of tert-butyl ((1R,2R)-2-( oxy)cyclobutyl)carbamate (522 mg, 1.79 mmol, 1 eq) in HCl / dioxane (2M, 6 was 25 °C for 2 hrs. The reaction mixture was concentrated under reduced pressure to remove solvent. Then the mixture was diluted with MeOH (10mL) and was adjusted to pH 8 with NaHCO3 aqueous solution (0.5 M). The mixture was filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~20% MeOH / DCM @ 35 mL / min) to afford 3- (((1R,2R)-2-aminocyclobutoxy)methyl)aniline (300 mg, 83.03% yield) as a yellow solid. LCMS (ESI) m / z 193.3 [M+H]+. Step 5: Synthesis of ethyl 6-chloro-8-((4-methoxybenzyl)amino)imidazo[1,2-b]pyridazine-3- carboxylate A mixture of ethyl 8-bromo-6-chloro-imidazo[1,2-b]pyridazine-3-carboxylate (20 g, 65.68 mmol, 1 eq) , PMBNH2 (9.01 g, 65.68 mmol, 1 eq), DIEA (25.46 g, 197.03 mmol, 3 eq) in EtOH (100 mL) was stirred at 80 °C for 16 hrs. The reaction mixture was quenched with H2O (200 mL) and extracted with EtOAc (100 mL ´ 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The crude product was purified by column chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Petroleum ether / EtOAc with EtOAc from 0~50%, 80 mL / min, 254 nm) to afford ethyl 6-chloro- Patent Application 8-((4-methoxybenzyl)amino)imidazo[1,2-b]pyridazine-3-carboxylate (23 g, 87.36% yield) as a white solid. LCMS (ESI) m / z 361.0, 363.0 [M+H]+. Step 6: Synthesis of ethyl 7-bromo-6-chloro-8-((4-methoxybenzyl)amino)imidazo[1,2- b]pyridazine-3-carboxylate A mixture of ethyl 6-chloro-8-((4- imidazo[1,2-b]pyridazine-3-carboxylate (10 g, 27.72 mmol, 1 eq), NBS (4.93 g, 27.72 mmol, 1 eq) in DMF (100 mL) was stirred at 25 °C for 1 hr. The reaction mixture was quenched with H2O (200 mL) and extracted with EtOAc (100 mL ´ 3). The combined organic layer was washed with brine (100 mL ´ 3 ), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Petroleum ether / EtOAc with EtOAc from 0~40%, 60 mL / min, 254 nm) to afford ethyl 7-bromo-6-chloro-8-((4- methoxybenzyl)amino)imidazo[1,2-b]pyridazine-3-carboxylate (7.11 g, 55.43% yield) as a yellow solid. LCMS (ESI) m / z 439.1, 441.1, 443.1 [M+H]+,1H NMR (400 MHz, DMSO-d6) δ ppm 8.18 (s, 1H), 7.88 (t, J = 6.8 Hz, 1H), 7.25 (d, J = 8.8 Hz, 2H), 6.84 (d, J = 8.4 Hz, 2H), 5.40 (d, J = 6.8 Hz, 2H), 4.32 (q, J = 7.2 Hz, 2H), 3.69 (s, 3H), 1.31 (t, J = 7.2 Hz, 3H). Step 7: Synthesis of ethyl 6-chloro-7-(2-ethoxyvinyl)-8-((4- methoxybenzyl)amino)imidazo[1,2-b]pyridazine-3-carboxylate

[0008] Patent Application A mixture of ethyl 7-bromo-6-chloro-8-((4-methoxybenzyl)amino)imidazo[1,2-b]pyridazine-3- carboxylate (1.48 g, 3.37 mmol, 1 eq), 2-[(E)-2-ethoxyvinyl]-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (1 g, 5.05 mmol, 1.5 eq), XPhos Pd G3 (284 mg, 0.33 mmol, 0.1 eq), Cs2CO3 (3.29 g, 10.10 mmol, 3 eq) in toluene (20 mL) and H2O (1 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 110 °C for 16 hrs under N2 atmosphere. The reaction mixture was quenched with H2O (50 mL) and extracted with EtOAc (30 mL ´ 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by column chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Petroleum ether / EtOAc with EtOAc from 0~30%, 35 mL / min, 254 nm) to afford ethyl 6-chloro-7-(2-ethoxyvinyl)-8-((4- methoxybenzyl)amino)imidazo[1,2-b]pyridazine-3-carboxylate (364 mg, 19.58% yield) as a yellow solid. LCMS (ESI) m / z 431.2, 433.2 [M+H]+. Step 8: Synthesis of ethyl 6-chloro-9H-imidazo[1,2-b]pyrrolo[2,3-d]pyridazine-3- carboxylate To a solution of ethyl 6-chloro-7- -8-((4-methoxybenzyl)amino)imidazo[1,2- b]pyridazine-3-carboxylate (200 mg, 0.46 mmol, 1 eq) in DCM (2 mL) was added TFA (52.92 mg, 0.46 mmol, 1 eq). The mixture was stirred at 25 °C for 2 hrs. and then concentrated under reduced pressure to give a residue. The crude product was purified by column chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Petroleum ether / EtOAc with EtOAc from 0~100%, 35 mL / min, 254 nm) to afford ethyl 6-chloro-9H-imidazo[1,2-b]pyrrolo[2,3-d]pyridazine-3- carboxylate (122 mg, 94.34% yield) as a white solid. LCMS (ESI) m / z 265.1, 267.1 [M+H]+,1H NMR (400 MHz, DMSO-d6) δ ppm 13.48 (br s, 1H), 8.23 (s, 1H), 7.71 (d, J = 2.8 Hz, 1H), 6.81 (d, J = 2.8 Hz, 1H), 4.35 (q, J = 7.2 Hz, 2H), 1.34 (t, J = 7.2 Hz, 3H). Step 9: Synthesis of 6-chloro-9H-imidazo[1,2-b]pyrrolo[2,3-d]pyridazine-3-carboxylic acid Patent Application To a solution of ethyl 6-chloro-9H- [2,3-d]pyridazine-3-carboxylate (122 mg, 0.46 mmol, 1 eq) in MeOH (2 mL) (184 mg, 4.61 mmol, 10 eq). The mixture was stirred at 80 °C for 2 hrs. The reaction mixture was concentrated under reduced pressure to remove MeOH to afford 6-chloro-9H-imidazo[1,2-b]pyrrolo[2,3-d]pyridazine-3-carboxylic acid (100 mg, crude) as a white solid. LCMS (ESI) m / z 237.0, 239.0 [M+H]+. Step 8: Synthesis of N-((1R,2R)-2-((3-aminobenzyl)oxy)cyclobutyl)-6-chloro-9H- imidazo[1,2-b]pyrrolo[2,3-d]pyridazine-3-carboxamide To a solution of 6-chloro-9H- 3-carboxylic acid (60 mg, 0.25 mmol, 1 eq) and 3-(((1R,2R)-2-aminocyclobutoxy)methyl)aniline (48.7 mg, 0.25 mmol, 1 eq) in DMF (2 mL) was added PYBOP (237 mg, 0.45 mmol, 1.8 eq) and DBU (115 mg, 0.76 mmol, 3 eq). The mixture was stirred at 25 °C for 2 hrs. The reaction mixture was quenched with H2O (30 mL) and extracted with EtOAc (30 mL ´ 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The crude product was purified by column chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, DCM / MeOH with MeOH from 0~15%, 35 mL / min, 254 nm) to afford N-((1R,2R)-2-((3- aminobenzyl)oxy)cyclobutyl)-6-chloro-9H-imidazo[1,2-b]pyrrolo[2,3-d]pyridazine-3- carboxamide (128 mg, 61.43% yield) as a white solid. LCMS (ESI) m / z 411.2, 413.2 [M+H]+. Step 10: Synthesis of (61R,62R)-19H-5-oxa-2,7-diaza-1(6,3)-imidazo[1,2-b]pyrrolo[2,3- d]pyridazina-3(1,3)-benzena-6(1,2)-cyclobutanacyclooctaphan-8-one Patent Application A mixture of N-((1R,2R)-2- cyclobutyl)-6-chloro-9H-imidazo[1,2- b]pyrrolo[2,3-d]pyridazine-3- mg, mmol, 1 eq), EPhos (33.8 mg, 0.06 mmol, 0.2 eq), EPhos Pd G3 (57.24 mg, 62.31 μmol, 0.2 eq) and K3PO4 (198 mg, 0.93 mmol, 3 eq) in DMF (3 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 110 °C for 1 hr under N2 atmosphere. The reaction mixture was quenched with H2O (30 mL) and extracted with EtOAc (30 mL ´ 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The crude product was purified by prep-HPLC (column: 2_Phenomenex Gemini C18 75 ´ 40mm ´ 3um;mobile phase: [water(HCl)-ACN];gradient:15%-45% B over 10 min) to afford (61R,62R)-19H-5-oxa-2,7- diaza-1(6,3)-imidazo[1,2-b]pyrrolo[2,3-d]pyridazina-3(1,3)-benzena-6(1,2)- cyclobutanacyclooctaphan-8-one (4 mg, 3.36% yield) as a white solid. LCMS (ESI) m / z 375.3 [M+H]+,1H NMR (400 MHz, DMSO-d6) δ ppm 12.94 (br s, 1H), 9.65 (br d, J = 19.2 Hz, 1H), 9.25 (br d, J = 4.4 Hz, 1H), 8.19 (s, 1H), 7.98 - 8.11 (m, 1H), 7.58 - 7.70 (m, 1H), 7.40 - 7.49 (m, 1H), 7.32 (br d, J = 7.2 Hz, 2H), 7.05 (d, J = 7.2 Hz, 1H), 4.58 - 4.74 (m, 2H), 4.03 (br dd, J = 8.0, 4.4 Hz, 1H), 3.74 - 3.76 (m, 1H), 2.03 - 2.21 (m, 2H), 1.66 (br t, J = 9.6 Hz, 1H), 1.19 - 1.26 (m, 1H).

[0009] Patent Application Example 7: (10R,13R)-5-morpholino-9-oxa-2,14,18,21,25,26- hexazahexacyclo[14.8.2.13,7.010,13.019,26.020,24]heptacosa-1(25),3,5,7(27),16,18,20(24),22- octaen-15-one Step 1: Synthesis of N-( oxy)cyclobutyl)-6-chloro- 9H-imidazo[1,2-b]pyrrolo[2,3-d]pyridazine-3-carboxamide To a solution of 6-chloro- 3-carboxylic acid (60 mg, 0.25 mmol, 1 eq) and 3-(((1R,2R)-2-aminocyclobutoxy)methyl)-5-morpholinoaniline (70.3 mg, 0.25 mmol, 1 eq) in DMF (2 mL) was added PYBOP (237 mg, 0.45 mmol, 1.8 eq) and DBU (115 mg, 0.76 mmol, 3 eq). The mixture was stirred at 25 °C for 2 hrs. The reaction mixture was quenched with H2O (30 mL) and extracted with EtOAc (30 mL ´ 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The crude product was purified by column chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, DCM / MeOH with MeOH from 0~20%, 35 mL / min, 254 nm) to afford N- ((1R,2R)-2-((3-amino-5-morpholinobenzyl)oxy)cyclobutyl)-6-chloro-9H-imidazo[1,2- b]pyrrolo[2,3-d]pyridazine-3-carboxamide (143 mg, 79.59% yield) as a white solid. LCMS (ESI) m / z 496.3, 498.3 [M+H]+. Patent Application Step 2: Synthesis of (10R,13R)-5-morpholino-9-oxa-2,14,18,21,25,26- hexazahexacyclo[14.8.2.13,7.010,13.019,26.020,24]heptacosa-1(25),3,5,7(27),16,18,20(24),22- octaen-15-one A mixture of N-((1R,2R)- oxy)cyclobutyl)-6-chloro-9H- imidazo[1,2-b]pyrrolo[2,3-d]pyridazine-3-carboxamide (134 mg, 0.27 mmol, 1 eq), EPhos (29.3 mg, 0.05 mmol, 0.2 eq), EPhos Pd G3 (49.6 mg, 0.05 mmol, 0.2 eq) and Cs2CO3 (264 mg, 0.81 mmol, 3 eq) in DMF (2 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 110 °C for 1 hr under N2atmosphere. The reaction mixture was quenched with H2O (30 mL) and extracted with EtOAc (30 mL ´ 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The crude product was purified by prep-HPLC (column: 2_Phenomenex Gemini C18 75 ´ 40 mm ´ 3um;mobile phase: [water(HCl)-ACN];gradient:15%-45% B over 10 min ) to afford (10R,13R)- 5-morpholino-9-oxa-2,14,18,21,25,26- hexazahexacyclo[14.8.2.13,7.010,13.019,26.020,24]heptacosa-1(25),3,5,7(27),16,18,20(24),22- octaen-15-one (12 mg, 9.47% yield) as a white solid. LCMS (ESI) m / z 460.3 [M+H]+,1H NMR (400 MHz, DMSO-d6) δ ppm 13.00 (br s, 1H), 9.95 (br s, 1H), 9.29 (br d, J = 4.4 Hz, 1H), 8.37 (s, 1H), 7.84 (br s, 1H), 7.68 (s, 1H), 7.49 (br s, 1H), 7.09 (br s, 1H), 6.77 (br s, 1H), 4.52 - 4.66 (m, 2H), 3.99 - 4.10 (m, 1H), 3.79 - 3.87 (m, 4H), 3.72 - 3.78 (m, 1H), 3.21 (br s, 4H), 2.03 - 2.19 (m, 2H), 1.65 (quin, J = 9.6 Hz, 1H), 1.18 - 1.31 (m, 1H).

[0010] Patent Application Example 8: Synthesis of (7R)-7-methyl-31-(pyridin-2-yl)-31,32-dihydro-19H-5-oxa-2,8-diaza- 1(6,3)-imidazo[1,2-b]pyrrolo[2,3-d]pyridazina-3(3,5)-pyridinacyclononaphane-32,9-dione Step 1: Synthesis of 3- A mixture of 3-bromo-5-methyl-1H- g, 53.19 mmol, 1 eq), 2-bromopyridine (8.40 g, 53.19 mmol, 1 eq), CuI (1.52 g, 7.98 mmol, 0.15 eq), DMEDA (1.17 g, 13.30 mmol, 0.25 eq) and K2CO3 (18.38 g, 132.96 mmol, 2.5 eq) in toluene (100 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 110 °C for 16 hrs under N2 atmosphere. The reaction mixture was quenched with H2O (100 mL) and extracted with EtOAc (100 mL ´ 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Petroleum ether / EtOAc with EtOAc from 0~30%, 35 mL / min, 254 nm) to afford 3-bromo-5-methyl-2H-[1,2'-bipyridin]-2-one (12.48 g, 84.09%) as a white solid. LCMS (ESI) m / z 265.1, 267.1 [M+H]+. Step 2: Synthesis of 3-bromo-5-(bromomethyl)-2H-[1,2'-bipyridin]-2-one Patent Application To a solution of 3-bromo-5-methyl-2H-[1,2'-bipyridin]-2-one (12.48 g, 47.08 mmol, 1 eq) in THF (150 mL) was added NBS (8.80 g, 49.43 mmol, 1.05 eq) and AIBN (773.01 mg, 4.71 mmol, 0.1 eq). The mixture was stirred at 80 °C for 2 hrs. The reaction mixture was quenched with H2O (200 mL) and extracted with EtOAc (100 mL ´ 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Petroleum ether / EtOAc with EtOAc from 0~25%, 35 mL / min, 254 nm) to afford 3-bromo-5-(bromomethyl)- 2H-[1,2'-bipyridin]-2-one (6.8 g, 21.00%) as a white solid. LCMS (ESI) m / z 342.9, 344.9, 346.9 [M+H]+. Step 3: Synthesis of (R)-tert-butyl (1-((3-bromo-2-oxo-2H-[1,2'-bipyridin]-5- yl)methoxy)propan-2-yl)carbamate To a solution of tert-butyl (R)-(1- (2.95 g, 16.86 mmol, 1 eq) and TBAI (1.25 g, 3.37 mmol, 0.2 eq) in THF (60 mL) was added in portion NaH (1.35 g, 33.72 mmol, 60% dispersion in mineral oil, 2 eq) at 0 °C. The mixture was stirred at 0 °C for 30 min, and then 3-bromo-5-(bromomethyl)-1-(2-pyridyl)pyridin-2-one (5.8 g, 16.86 mmol, 1 eq) was added in portion at 0 °C. The mixture was stirred at 25 °C for 1.5 hrs. The reaction mixture was quenched with H2O (100 mL) and extracted with EtOAc (100 mL ´ 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Petroleum ether / EtOAc with EtOAc from 0~40%, 35 mL / min, 254 nm) to afford (R)-tert-butyl (1-((3-bromo- 2-oxo-2H-[1,2'-bipyridin]-5-yl)methoxy)propan-2-yl)carbamate (1.76 g, 22.62%) as a white solid. LCMS (ESI) m / z 438.0, 440.0 [M+H]+. Step 4: Synthesis of tert-butyl N-[(1R)-2-[[5-(tert-butoxycarbonylamino)-6-oxo-1-(2- pyridyl)-3-pyridyl]methoxy]-1-methyl-ethyl]carbamate Patent Application A mixture of (R)-tert-butyl bipyridin]-5-yl)methoxy)propan-2- yl)carbamate (1.76 g, 4.02 mmol, , mg, 4.02 mmol, 1 eq), Xantphos (464 mg, 0.80 mmol, 0.2 eq), Pd2(dba)3(367 mg, 0.40 mmol, 0.1 eq) and Cs2CO3(3.92 g, 12.05 mmol, 3 eq) in dioxane (20 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100 °C for 16 hrs under N2 atmosphere. The reaction mixture was quenched with H2O (50 mL) and extracted with EtOAc (50 mL ´ 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Petroleum ether / EtOAc with EtOAc from 0~30%, 35 mL / min, 254 nm) to afford tert-butyl N-[(1R)-2-[[5-(tert- butoxycarbonylamino)-6-oxo-1-(2-pyridyl)-3-pyridyl]methoxy]-1-methyl-ethyl]carbamate (1.7 g, 84.75%) as a white solid. LCMS (ESI) m / z 475.2 [M+H]+. Step 5: Synthesis of (R)-3-amino-5-((2-aminopropoxy)methyl)-2H-[1,2'-bipyridin]-2-one A mixture of tert-butyl N-[(1R)-2-[[5-(tert-butoxycarbonylamino)-6-oxo-1-(2-pyridyl)-3- pyridyl]methoxy]-1-methyl-ethyl]carbamate (1.7 g, 3.58 mmol, 1 eq) in HCl / dioxane (2M, 5 mL) was stirred at 20 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to remove HCl / dioxane. Then the mixture was diluted with MeOH (10mL) and adjusted to pH 8 with NaHCO3 aqueous solution (0.5 M). The mixture was filtered and concentrated in vacuum. The crude product was purified by column chromatography (ISCO®; 12 g SepaFlash® Silica Flash Patent Application Column, DCM / MeOH with MeOH from 0~10%, 35 mL / min, 254 nm) to afford (R)-3-amino-5- ((2-aminopropoxy)methyl)-2H-[1,2'-bipyridin]-2-one (410 mg, 39.64%) as a white solid. LCMS (ESI) m / z 275.1 [M+H]+. Step 6: Synthesis of (R)-N-(1-((3-amino-2-oxo-2H-[1,2'-bipyridin]-5-yl)methoxy)propan-2- yl)-6-chloro-9H-imidazo[1,2-b]pyrrolo[2,3-d]pyridazine-3-carboxamide To a solution of 6-chloro-9H- 3-carboxylic acid (70 mg, 0.29 mmol, 1 eq) and (R)-3-amino-5-((2-aminopropoxy)methyl)-2H-[1,2'-bipyridin]-2-one (81.1 mg, 0.29 mmol, 1 eq) in DMF (2 mL) was added PYBOP (277 mg, 0.53 mmol, 1.8 eq) and DBU (135 mg, 0.88 mmol, 3 eq). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was quenched with H2O (10 mL) and extracted with EtOAc (10 mL ´ 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, DCM / MeOH with MeOH from 0~5%, 35 mL / min, 254 nm) to afford (R)-N-(1-((3-amino-2-oxo- 2H-[1,2'-bipyridin]-5-yl)methoxy)propan-2-yl)-6-chloro-9H-imidazo[1,2-b]pyrrolo[2,3- d]pyridazine-3-carboxamide (171 mg, 91.47%) as a white solid. LCMS (ESI) m / z 493.2, 495.2 [M+H]+. Step 7: Synthesis of (7R)-7-methyl-31-(pyridin-2-yl)-31,32-dihydro-19H-5-oxa-2,8-diaza- 1(6,3)-imidazo[1,2-b]pyrrolo[2,3-d]pyridazina-3(3,5)-pyridinacyclononaphane-32,9-dione Patent Application A mixture of N-[(1R)-2-[[5-amino-6-oxo-1-(2-pyridyl)-3-pyridyl]methoxy]-1-methyl-ethyl]-8- chloro-3,6,7,12-tetrazatricyclo[7.3.0.02,6]dodeca-1(9),2,4,7,10-pentaene-5-carboxamide (131 mg, 0.26 mmol, 1 eq), EPhos (28.9 mg, 0.053 mmol, 0.2 eq), EPhos Pd G4 (48.8 mg, 0.053 mmol, 0.2 eq) and Cs2CO3 (259 mg, 0.79 mmol, 3 eq) in dioxane (3 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 110 °C for 1 hr under N2 atmosphere. The reaction mixture was quenched with H2O (10 mL) and extracted with EtOAc (10 mL ´ 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by prep-HPLC (column: 2_Phenomenex Gemini C18 75´40mm´3um;mobile phase: [water(HCl)-ACN];gradient:15%-45% B over 10 min) to afford (7R)-7-methyl-31-(pyridin-2-yl)-31,32-dihydro-19H-5-oxa-2,8-diaza-1(6,3)-imidazo[1,2- b]pyrrolo[2,3-d]pyridazina-3(3,5)-pyridinacyclononaphane-32,9-dione (17 mg, 13.63%) as a white solid. LCMS (ESI) m / z 457.2 [M+H]+,1H NMR (400 MHz, DMSO-d6) δ ppm 12.95 (br s, 1H), 8.94 (s, 1H), 8.60 - 8.69 (m, 1H), 8.51 (d, J = 6.4 Hz, 1H), 8.30 (d, J = 2.0 Hz, 1H), 8.14 (s, 1H), 8.06 (td, J = 7.6, 2.0 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.73 (d, J = 1.6 Hz, 1H), 7.65 (br s, 1H), 7.55 (ddd, J = 7.6, 4.8, 1.2 Hz, 1H), 7.42 (br s, 1H), 4.55 (d, J = 13.2 Hz, 1H), 4.35 (d, J = 13.2 Hz, 1H), 4.07 - 4.17 (m, 1H), 3.60 - 3.72 (m, 2H), 1.16 (d, J = 6.4 Hz, 3H). Example 9: (11R)-11-methyl-5-(2-pyridyl)-9-oxa-2,5,12,16,19,24,25- heptazapentacyclo[12.9.2.13,7.017,25.018,23]hexacosa-1(24),3(26),6,14,16,18(23)-hexaene-4,13- dione Step 1: (R)-N-(1-((3-amino-2-oxo-2H-[1,2'-bipyridin]-5-yl)methoxy)propan-2-yl)-6-chloro- 10-(4-methoxybenzyl)-7,8,9,10-tetrahydroimidazo[1,2-b]pyrido[2,3-d]pyridazine-3- carboxamide Patent Application To a solution methoxyphenyl)methyl]-3,6,7,13- tetrazatricyclo[7.4.0.02,6] acid (100 mg, 0.268 mmol, 1 eq) in DMF (3 mL) was added 3-amino-5-[[(2R)-2-aminopropoxy]methyl]-1-(2-pyridyl)pyridin- 2-one (73.58 mg, 0.268 mmol, 1 eq) and PYBOP (209.38 mg, 0.402 mmol, 1.5 eq). To the mixture was added drop-wise DBU (204.18 mg, 1.34 mmol, 202.16 μL, 5 eq) at 20oC. The mixture was stirred at 20 °C for 1 hr under N2. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Ethyl acetate / Methanol with Methanol from 0~3%, 40 mL / min, 254 nm / I2 / KMnO4 / PMA). Compound (R)-N-(1-((3-amino-2-oxo-2H-[1,2'-bipyridin]-5- yl)methoxy)propan-2-yl)-6-chloro-10-(4-methoxybenzyl)-7,8,9,10-tetrahydroimidazo[1,2- b]pyrido[2,3-d]pyridazine-3-carboxamide (240 mg, crude) was obtained as a colorless oil. LCMS (ESI) m / z 629.3, 631.2 [M+H]+. Step 2: (11R)-19-[(4-methoxyphenyl)methyl]-11-methyl-5-(2-pyridyl)-9-oxa- 2,5,12,16,19,24,25-heptazapentacyclo[12.9.2.13,7.017,25.018,23]hexacosa- 1(24),3(26),6,14,16,18(23)-hexaene-4,13-dione To a solution of (R)-N-(1-((3-amino-2-oxo-2H-[1,2'-bipyridin]-5-yl)methoxy)propan-2-yl)-6- chloro-10-(4-methoxybenzyl)-7,8,9,10-tetrahydroimidazo[1,2-b]pyrido[2,3-d]pyridazine-3- carboxamide (230 mg, 0.365 mmol, 1 eq) in dioxane (10 mL) was added EPhos (39.10 mg, 0.073 Patent Application mmol, 0.2 eq), EPhos Pd G4 (33.58 mg, 0.036 mmol, 0.1 eq) and K3PO4 (232.81 mg, 1.10 mmol, 3 eq). The mixture was degassed and purged with N2 for three times. The mixture was stirred at 100 °C for 12 hours under N2 atmosphere. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0~100%, 60 mL / min, 254 nm / I2 / KMnO4 / PMA). Compound (11R)-19-[(4- methoxyphenyl)methyl]-11-methyl-5-(2-pyridyl)-9-oxa-2,5,12,16,19,24,25- heptazapentacyclo[12.9.2.13,7.017,25.018,23]hexacosa-1(24),3(26),6,14,16,18(23)-hexaene-4,13- dione (120 mg, 54.28%) was obtained as a yellow solid. LCMS (ESI) m / z 593.3 [M+H]+. Step 3: (11R)-11-methyl-5-(2-pyridyl)-9-oxa-2,5,12,16,19,24,25- heptazapentacyclo[12.9.2.13,7.017,25.018,23]hexacosa-1(24),3(26),6,14,16,18(23)-hexaene-4,13- dione A solution of (11R)- -11-methyl-5-(2-pyridyl)-9-oxa- 2,5,12,16,19,24,25-heptazapentacyclo[12.9.2.13,7.017,25.018,23]hexacosa- 1(24),3(26),6,14,16,18(23)-hexaene-4,13-dione (100 mg, 0.16 mmol, 1 eq) in DCM (4 mL) and TFA (3.07 g, 26.92 mmol, 2 mL, 159.57 eq) was stirred at 20 °C for 1 hour under N2 atmosphere. The mixture was basified at 0 °C with NaHCO3 aqueous solution to pH = 7-8 and extracted with DCM (20 mL ´ 3). Then the combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Dichloromethane / Methanol with methanol from 0~3.4%, 50 mL / min, 254 nm / I2 / KMnO4 / PMA). Compound (11R)-11-methyl-5-(2-pyridyl)-9-oxa-2,5,12,16,19,24,25- heptazapentacyclo[12.9.2.13,7.017,25.018,23]hexacosa-1(24),3(26),6,14,16,18(23)-hexaene-4,13- dione (35.43 mg, 44.20%) was obtained as a white solid. LCMS (ESI) m / z 473.3 [M+H]+,1H NMR Patent Application (400 MHz, DMSO-d6) δ ppm 8.64 (dd, J = 4.8, 1.2 Hz, 1H), 8.58 (d, J = 6.0 Hz, 1H), 8.20 (d, J = 2.0 Hz, 1H), 8.04 (td, J = 7.6, 2.0 Hz, 1H), 7.83 - 7.90 (m, 2H), 7.67 (br s, 1H), 7.59 (s, 1H), 7.51 - 7.56 (m, 1H), 7.42 (s, 1H), 4.53 (d, J = 12.8 Hz, 1H), 4.36 (d, J = 13.2 Hz, 1H), 4.04 - 4.14 (m, 1H), 3.51 - 3.57 (m, 1H), 3.45 (br t, J = 9.2 Hz, 1H), 3.35 - 3.41 (m, 2H), 2.60 - 2.67 (m, 2H), 1.90 - 2.05 (m, 2H), 1.14 (d, J = 6.4 Hz, 3H). Example 10: (7R)-7-methyl-35-morpholino-17,18,19,110-tetrahydro-5-oxa-2,8-diaza-1(6,3)- imidazo[1,2-b]pyrido[2,3-d]pyridazina-3(1,3)-benzenacyclononaphan-9-one Step 1: tert-butyl (R)-(1-((3- propan-2-yl)carbamate To a solution of (3-morpholino-5-nitro-phenyl)methanol (1 g, 4.20 mmol, 1 eq) and TBAI (310.08 mg, 0.839 mmol, 0.2 eq) in THF (20 mL) was added in portion NaH (335.80 mg, 8.39 mmol, 60% dispersion in mineral oil, 2 eq) at 0 °C. After addition, the mixture was stirred at 0 °C for 30 min, and then tert-butyl (4R)-4-methyl-2,2-dioxo-oxathiazolidine-3-carboxylate (1.99 g, 8.39 mmol, 2 eq) was added dropwise at 0 °C. The resulting mixture was stirred at 25 °C for 1.5 hr. The reactionmixture was diluted with H2O (30 mL) and extracted with ethyl acetate (30 mĹ 3). The combinedorganic layers were washed with brine (30 mL ´ 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~50% PE / EA @ 35 Patent Application mL / min). Compound tert-butyl (R)-(1-((3-morpholino-5-nitrobenzyl)oxy)propan-2-yl)carbamate (849 mg, 35.80%) was obtained as a yellow solid. LCMS (ESI) m / z 396.1 [M+H]+,1H NMR (400 MHz, DMSO-d6) δ ppm 7.54 - 7.61 (m, 2H), 7.33 (s, 1H), 6.70 - 6.85 (m, 1H), 4.53 (s, 2H), 3.73 - 3.78 (m, 4H), 3.34 - 3.41 (m, 1H), 3.26 - 3.31 (m, 1H), 3.22 - 3.26 (m, 4H), 2.90 - 3.05 (m, 1H), 1.36 (s, 9H), 1.03 (d, J = 6.8 Hz, 3 H). Step 2: tert-butyl (R)-(1-((3-amino-5-morpholinobenzyl)oxy)propan-2-yl)carbamate To a solution of tert-butyl (R)-(1-( oxy)propan-2-yl)carbamate (800 mg, 2.02 mmol, 1 eq) in EtOH (20 mL) and H2O (1 mL) was added Fe (677.85 mg, 12.14 mmol, 6 eq) and NH4Cl (649.28 mg, 12.14 mmol, 6 eq). The mixture was stirred at 80 °C for 1 hour. The mixture was filtered to collect the solution and the solution was concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0~60%, 60 mL / min, 254 nm / I2 / KMnO4 / PMA). Compound tert-butyl (R)-(1-((3-amino-5- morpholinobenzyl)oxy)propan-2-yl)carbamate (480 mg, 59.73%) was obtained as a yellow oil. LCMS (ESI) m / z 366.4 [M+H]+Step 3: (R)-3-((2-aminopropoxy)methyl)-5-morpholinoaniline

[0011] Patent Application A solution of tert-butyl (R)-(1-((3-amino-5-morpholinobenzyl)oxy)propan-2-yl)carbamate (450 mg, 1.23 mmol, 1 eq) in HCl / dioxane (2M, 5 mL) was stirred at 20 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue. The mixture was basified with NaHCO3 aqueous solution to pH =7-8 and concentrated. The residue was purified by flash chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, dichloromethane / Methanol with Methanol from 0~35%, 60 mL / min, 254 nm / I2 / KMnO4 / PMA). Compound (R)-3-((2- aminopropoxy)methyl)-5-morpholinoaniline (200 mg, 55.09%) was obtained as a white solid. LCMS (ESI) m / z 266.3 [M+H]+Step 4: (R)-N-(1-((3-amino-5-morpholinobenzyl)oxy)propan-2-yl)-6-chloro-10-(4- methoxybenzyl)-7,8,9,10-tetrahydroimidazo[1,2-b]pyrido[2,3-d]pyridazine-3-carboxamide To a solution of (R)-3-((2- (71.18 mg, 0.268 mmol, 1 eq) in DMF (3 mL) was added 6-chloro-10-(4-methoxybenzyl)-7,8,9,10-tetrahydroimidazo[1,2- b]pyrido[2,3-d]pyridazine-3-carboxylic acid (100 mg, 0.268 mmol, 1 eq) and PYBOP (209.38 mg, 0.402 mmol, 1.5 eq). To the mixture was added drop-wise DBU (204.18 mg, 1.34 mmol, 202.16 μL, 5 eq) at 20oC. The mixture was stirred at 20 °C for 1 hour under N2. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0~100%, 60 mL / min, 254 nm / I2 / KMnO4 / PMA). Compound (R)-N-(1-((3-amino-5- morpholinobenzyl)oxy)propan-2-yl)-6-chloro-10-(4-methoxybenzyl)-7,8,9,10- tetrahydroimidazo[1,2-b]pyrido[2,3-d]pyridazine-3-carboxamide (180 mg, 90.90%) was obtained as a white solid. LCMS (ESI) m / z 620.3, 622.3 [M+H]+. Step 5: (7R)-110-(4-methoxybenzyl)-7-methyl-35-morpholino-17,18,19,110-tetrahydro-5-oxa- 2,8-diaza-1(6,3)-imidazo[1,2-b]pyrido[2,3-d]pyridazina-3(1,3)-benzenacyclononaphan-9-one Patent Application To a solution of (R)-N-(1- oxy)propan-2-yl)-6-chloro-10-(4- methoxybenzyl)-7,8,9,10- d]pyridazine-3-carboxamide (130 mg, 0.209 mmol, 1 eq) in dioxane (10 mL) was added EPhos (22.42 mg, 0.041 mmol, 0.2 eq), EPhos Pd G4 (19.26 mg, 0.020 mmol, 0.1 eq) and K2CO3 (86.92 mg, 0.628 mmol, 3 eq). The mixture was degassed and purged with N2 for three times. The mixture was stirred at 100 °C for 12 hours under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0~95%, 60 mL / min, 254 nm / I2 / KMnO4 / PMA). Compound (7R)-110-(4-methoxybenzyl)-7-methyl-35-morpholino- 17,18,19,110-tetrahydro-5-oxa-2,8-diaza-1(6,3)-imidazo[1,2-b]pyrido[2,3-d]pyridazina-3(1,3)- benzenacyclononaphan-9-one (100 mg, 78.46%) was obtained as a white solid. LCMS (ESI) m / z 584.4 [M+H]+. Step 6: (7R)-7-methyl-35-morpholino-17,18,19,110-tetrahydro-5-oxa-2,8-diaza-1(6,3)- imidazo[1,2-b]pyrido[2,3-d]pyridazina-3(1,3)-benzenacyclononaphan-9-one To a solution of (7R)-110-(4-methoxybenzyl)-7-methyl-35-morpholino-17,18,19,110-tetrahydro-5- oxa-2,8-diaza-1(6,3)-imidazo[1,2-b]pyrido[2,3-d]pyridazina-3(1,3)-benzenacyclononaphan-9- one (80 mg, 0.137 mmol, 1 eq) in DCM (4 mL) was added TFA (2 mL). The mixture was degassed and purged with N2 for three times. The mixture was stirred at 20 °C for 1 hour under N2 Patent Application atmosphere. The mixture was basified at 0 °C with NaHCO3 aqueous solution to pH = 8 and extracted with DCM (30 mL ´ 3). Then the combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, dichloromethane / Methanol with Methanol from 0~8%, 50 mL / min, 254 nm / I2 / KMnO4 / PMA). Compound (7R)-7-methyl-35-morpholino-17,18,19,110-tetrahydro-5-oxa-2,8-diaza-1(6,3)- imidazo[1,2-b]pyrido[2,3-d]pyridazina-3(1,3)-benzenacyclononaphan-9-one (36.85 mg, 56.87%) was obtained as a white solid. LCMS (ESI) m / z 464.4 [M+H]+,1H NMR (400 MHz, DMSO-d6) δ ppm 8.69 (d, J = 5.2 Hz, 1H), 7.96 (s, 1H), 7.79 (s, 1H), 7.56 (s, 1H), 7.42 (s, 1H), 6.81 (s, 1H), 6.52 (s, 1H), 4.60 (d, J = 13.6 Hz, 1H), 4.28 (d, J = 13.6 Hz, 1H), 3.92 - 4.02 (m, 1H), 3.72 - 3.79 (m, 4H), 3.45 (dd, J = 9.6, 2.4 Hz, 1H), 3.33 - 3.40 (m, 2H), 3.20 (t, J = 9.6 Hz, 1H), 3.06 - 3.15 (m, 4H), 2.58 - 2.74 (m, 2H), 1.85 - 2.04 (m, 2H), 1.10 (d, J = 6.4 Hz, 3H). Example 11: Synthesis of (61R,62R)-35-morpholino-16,17,18,19-tetrahydro-5-oxa-2,7-diaza- 1(5,3)-pyrazolo[1,5-a]pyrido[3,2-e]pyrimidina-3(1,3)-benzena-6(1,2)- cyclobutanacyclooctaphan-8-one Step 1: Synthesis of ethyl 5-chloro-7-((4-methoxybenzyl)amino)pyrazolo[1,5-a]pyrimidine- 3-carboxylate Patent Application A mixture of ethyl 5,7-dichloropyrazolo[1,5-a]pyrimidine-3-carboxylate (20 g, 76.90 mmol, 1 eq), PMBNH2 (10.55 g, 76.90 mmol, 1 eq), DIEA (29.82 g, 230.70 mmol, 3 eq) in EtOH (300 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 16 hrs under N2 atmosphere. The reaction mixture was quenched with H2O (200 mL) and extracted with EtOAc (200 mL ´ 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The crude product was purified by column chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Petroleum ether / EtOAc with EtOAc from 0~50%, 35 mL / min, 254nm) to afford ethyl 5-chloro-7-((4- methoxybenzyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylate (25.52 g, 87.38%) as a white solid. LCMS (ESI) m / z 361.1, 363.1 [M+H]+. Step 2: Synthesis of ethyl 5-chloro-6-iodo-7-((4-methoxybenzyl)amino)pyrazolo[1,5- a]pyrimidine-3-carboxylate A mixture of ethyl 5-chloro- amino)pyrazolo[1,5-a]pyrimidine-3- carboxylate (15 g, 41.57 mmol, 1 eq), NIS (14.97 g, 66.52 mmol, 1.6 eq) in AcOH (100 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 20 °C for 1 hr under N2 atmosphere. The reaction mixture was quenched with H2O (150 mL) and extracted with EtOAc (100 mL ´ 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The crude product was purified by column chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Petroleum ether / EtOAc with EtOAc from 0~50%, 35 mL / min, 254nm) to afford ethyl 5-chloro-6-iodo-7-((4- methoxybenzyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylate (23.2 g, 91.73%) as a white solid. LCMS (ESI) m / z 487.0, 489.0+ . Step 3: Synthesis of ethyl 5-chloro-7-((4-methoxybenzyl)amino)-6-vinylpyrazolo[1,5- a]pyrimidine-3-carboxylate Patent Application A mixture of ethyl 5-chloro-6-iodo- amino)pyrazolo[1,5-a]pyrimidine-3- carboxylate (10 g, 20.55 mmol, 1 eq), (vinyl)boranuide (5.50 g, 41.09 mmol, 2 eq), Pd(dppf)Cl2(1.50 g, 2.05 mmol, 0.1 eq), K2CO3(8.52 g, 61.64 mmol, 3 eq) in dioxane (100 mL) and H2O (20 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 95 °C for 16 hrs under N2 atmosphere. The reaction mixture was quenched with H2O (100 mL) and extracted with EtOAc (100 mL ´ 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The crude product was purified by column chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Petroleum ether / EtOAc with EtOAc from 0~50%, 35 mL / min, 254nm) to afford ethyl 5-chloro-7- ((4-methoxybenzyl)amino)-6-vinylpyrazolo[1,5-a]pyrimidine-3-carboxylate (4 g, 25.16%) as a white solid. LCMS (ESI) m / z 387.1, 389.1 [M+H]+. Step 4: Synthesis of ethyl 7-(allyl(4-methoxybenzyl)amino)-5-chloro-6-vinylpyrazolo[1,5- a]pyrimidine-3-carboxylate To a solution of ethyl 5-chloro-7-((4-methoxybenzyl)amino)-6-vinylpyrazolo[1,5-a]pyrimidine-3- carboxylate (3.58 g, 9.25 mmol, 1 eq) in DMF (40 mL) was added Cs2CO3 (12.06 g, 37.02 mmol, 4 eq) and 3-bromoprop-1-ene (3.36 g, 27.76 mmol, 3 eq). The mixture was stirred at 20 °C for 16 hrs. The reaction mixture was quenched with H2O (60 mL) and extracted with EtOAc (60 mL ´ 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The crude product was purified by column chromatography (ISCO®; Patent Application 40 g SepaFlash® Silica Flash Column, Petroleum ether / EtOAc with EtOAc from 0~20%, 35 mL / min, 254 nm) to afford ethyl 7-(allyl(4-methoxybenzyl)amino)-5-chloro-6-vinylpyrazolo[1,5- a]pyrimidine-3-carboxylate (1 g, 22.53%) as a white solid. LCMS (ESI) m / z 427.3, 429.3 [M+H]+. Step 5: Synthesis of ethyl 5-chloro-9-(4-methoxybenzyl)-8,9-dihydropyrazolo[1,5- a]pyrido[3,2-e]pyrimidine-3-carboxylate A mixture of ethyl 7-(allyl(4- chloro-6-vinylpyrazolo[1,5-a]pyrimidine- 3-carboxylate (1 g, 2.34 mmol, 1 eq), benzylidene-[1,3-bis(2,4,6-trimethylphenyl)imidazolidin-2- ylidene]-dichloro-ruthenium;tricyclohexylphosphane (159 mg, 0.18 mmol, 0.08 eq) in DCM (10 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 40 °C for 16 hrs under N2 atmosphere. The reaction mixture was quenched with H2O (30 mL) and extracted with EtOAc (30 mL ´ 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The crude product was purified by column chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Petroleum ether / EtOAc with EtOAc from 0~30%, 35 mL / min, 254 nm) to afford ethyl 5-chloro-9-(4-methoxybenzyl)-8,9- dihydropyrazolo[1,5-a]pyrido[3,2-e]pyrimidine-3-carboxylate (315 mg, 29.00%) as a white solid. LCMS (ESI) m / z 399.3, 401.3 [M+H]+. Step 6: Synthesis of ethyl 5-chloro-9-(4-methoxybenzyl)-6,7,8,9-tetrahydropyrazolo[1,5- a]pyrido[3,2-e]pyrimidine-3-carboxylate Patent Application To a solution of ethyl 5-chloro-9-(4-methoxybenzyl)-8,9-dihydropyrazolo[1,5-a]pyrido[3,2- e]pyrimidine-3-carboxylate (315 mg, 0.78 mmol, 1 eq) in MeOH (2 mL) and EtOAc (2 mL) was added PtO2 (17.93 mg, 0.078 mmol, 0.1 eq) under N2 atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (15 Psi) at 20 °C for 1 hr. The reaction mixture was filtered to remove the insoluble. The filtrate was concentrated in vacuo to afford ethyl 5-chloro-9-(4-methoxybenzyl)-6,7,8,9-tetrahydropyrazolo[1,5-a]pyrido[3,2- e]pyrimidine-3-carboxylate (300 mg, crude) as a white solid. LCMS (ESI) m / z 401.1, 403.1 [M+H]+. Step 7: Synthesis of 5-chloro-9-(4-methoxybenzyl)-6,7,8,9-tetrahydropyrazolo[1,5- a]pyrido[3,2-e]pyrimidine-3-carboxylic acid To a solution of ethyl 5-chloro-9-(4- tetrahydropyrazolo[1,5-a]pyrido[3,2- e]pyrimidine-3-carboxylate (300 mg, 0.74 mmol, 1 eq) in THF (4 mL) and H2O (2 mL) was added LiOH (89.61 mg, 3.74 mmol, 5 eq). The mixture was stirred at 70 °C for 16hrs. The reaction mixture was quenched with H2O (20 mL) and extracted with EtOAc (20 mL ´ 3). The organic layer was separated. The aqueous layer was adjusted to pH=4 with HCl aqueous solution (4 mL, 2 N) and extracted with EtOAc (30 mL ´ 3). The combined organic layers were washed with brine (30 mL ´ 2), dried over Na2SO4, filtered and concentrated under reduced pressure to afford 5- chloro-9-(4-methoxybenzyl)-6,7,8,9-tetrahydropyrazolo[1,5-a]pyrido[3,2-e]pyrimidine-3- carboxylic acid (171 mg, 42.90%) as a white solid. LCMS (ESI) m / z 373.3, 375.3 [M+H]+. Step 8: Synthesis of N-((1R,2R)-2-((3-amino-5-morpholinobenzyl)oxy)cyclobutyl)-5-chloro- 9-(4-methoxybenzyl)-6,7,8,9-tetrahydropyrazolo[1,5-a]pyrido[3,2-e]pyrimidine-3- carboxamide Patent Application A mixture of 5-chloro- [1,5-a]pyrido[3,2- e]pyrimidine-3-carboxylic mg, 1 eq), 3-(((1R,2R)-2- aminocyclobutoxy)methyl)-5-morpholinoaniline (66.96 mg, 0.24 mmol, 1 eq), PYBOP (226 mg, 0.43 mmol, 1.8 eq), DBU (110 mg, 0.72 mmol, 3 eq) in DMF (2 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 25 °C for 1 hr under N2 atmosphere. The reaction mixture was quenched with H2O (20 mL) and extracted with EtOAc (20 mL ´ 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The crude product was purified by column chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Petroleum ether / EtOAc with EtOAc from 0~100%, 35 mL / min, 254 nm) to afford N-((1R,2R)-2-((3-amino-5-morpholinobenzyl)oxy)cyclobutyl)-5- chloro-9-(4-methoxybenzyl)-6,7,8,9-tetrahydropyrazolo[1,5-a]pyrido[3,2-e]pyrimidine-3- carboxamide (100 mg, 52.42%) as a white solid. LCMS (ESI) m / z 632.2, 633.2 [M+H]+. Step 9: Synthesis of (61R,62R)-19-(4-methoxybenzyl)-35-morpholino-16,17,18,19-tetrahydro-5- oxa-2,7-diaza-1(5,3)-pyrazolo[1,5-a]pyrido[3,2-e]pyrimidina-3(1,3)-benzena-6(1,2)- cyclobutanacyclooctaphan-8-one A mixture of N-((1R,2R)-2-((3-amino-5-morpholinobenzyl)oxy)cyclobutyl)-5-chloro-9-(4- methoxybenzyl)-6,7,8,9-tetrahydropyrazolo[1,5-a]pyrido[3,2-e]pyrimidine-3-carboxamide (100 mg, 0.15 mmol, 1 eq), EPhos (17.20 mg, 0.03 mmol, 0.2 eq), EPhos Pd G4 (29.06 mg, 0.03 mmol, Patent Application 0.2 eq) and K3PO4 (100 mg, 0.47 mmol, 3 eq) in dioxane (3 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 110 °C for 1 hr under N2 atmosphere. The reaction mixture was quenched with H2O (20 mL) and extracted with EtOAc (20 mL ´ 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by column chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Petroleum ether / EtOAc with EtOAc from 0~100%, 35 mL / min, 254 nm) to afford (61R,62R)-19-(4-methoxybenzyl)-35-morpholino-16,17,18,19-tetrahydro-5-oxa- 2,7-diaza-1(5,3)-pyrazolo[1,5-a]pyrido[3,2-e]pyrimidina-3(1,3)-benzena-6(1,2)- cyclobutanacyclooctaphan-8-one (30 mg, 15.92%) as a white solid. LCMS (ESI) m / z 596.4 [M+H]+. - 8- a - - oxa-2,7- diaza-1(5,3)-pyrazolo[1,5-a]pyrido[3,2-e]pyrimidina-3(1,3)-benzena-6(1,2)- cyclobutanacyclooctaphan-8-one (25 mg, 0.04 mmol, 1 eq) in DCM (2 mL) was added TFA (4.79 mg, 0.04 mmol, 1 eq). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was quenchedwith H2O (10 mL) and extracted with EtOAc (10 mĹ 3). The combined organic layers were driedover Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by prep-HPLC (column: Welch Xtimate C18 150´25mm´5um;mobile phase: [water(NH3H2O)-ACN];gradient:28%-58% B over 9.5 min) to afford (61R,62R)-35-morpholino- 16,17,18,19-tetrahydro-5-oxa-2,7-diaza-1(5,3)-pyrazolo[1,5-a]pyrido[3,2-e]pyrimidina-3(1,3)- benzena-6(1,2)-cyclobutanacyclooctaphan-8-one (4.1 mg, 20.26%) as a white solid. LCMS (ESI) m / z 476.3 [M+H]+,1H NMR (400 MHz, DMSO-d6) δ ppm 8.76 (d, J = 3.6 Hz, 1H), 8.35 (s, 1H), Patent Application 8.07 (s, 1H), 7.99 (br s, 1H), 7.59 (s, 1H), 6.84 (s, 1H), 6.55 (s, 1H), 4.62 (d, J = 14.4 Hz, 1H), 4.41 (d, J = 14.0 Hz, 1H), 3.79 - 3.87 (m, 1H), 3.72 - 3.77 (m, 4H), 3.65 (br d, J = 7.2 Hz, 1H), 3.43 (br d, J = 4.0 Hz, 2H), 3.10 - 3.15 (m, 4H), 2.70 - 2.79 (m, 1H), 2.57 - 2.63 (m, 1H), 2.02 - 2.13 (m, 2H), 1.86 - 2.01 (m, 2H), 1.50 - 1.67 (m, 1H), 1.00 - 1.20 (m, 1H). Example 12: Synthesis of (61R,62R)-35-methoxy-19H-5-oxa-2,7-diaza-1(6,3)-imidazo[1,2- b]pyrrolo[2,3-d]pyridazina-3(4,2)-pyridina-6(1,2)-cyclobutanacyclooctaphan-8-one Step 1: Synthesis of (4-bromo-5- To a solution of 4-bromo-5-methoxy- (1 g, 4.63 mmol) in MeOH (15 mL) was added NaBH4 (290 mg, 7.67 mmol) at 0 °C. The mixture was stirred at 20 °C for 1 hr. The reaction mixture was quenched by addition of H2O (50 mL) at 25 °C, and then extracted with DCM (100 mL ´ 3). The combined organic layers were washed with brine (50 mL ´ 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0~50%, flow rate: 35 mL / min, 254 nm) to afford (4-bromo-5- methoxy-2-pyridyl)methanol (900 mg, 89.2% yield) as a white solid. LCMS (ESI) m / z 218.1, 220.1 [M+H]+. Step 2: Synthesis of 4-bromo-2-(bromomethyl)-5-methoxy-pyridine To a solution of (4-bromo-5-methoxy-2-pyridyl)methanol (800 mg, 3.67 mmol) in THF (10 mL) was added CBr4 (1.46 g, 4.40 mmol) and PPh3 (1.44 g, 5.50 mmol) at 0 °C. The mixture was stirred Patent Application at 20 °C for 2 hrs under N2. The reaction mixture was quenched by addition of H2O (50 mL), and then extracted with EtOAc (100 mL ´ 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0~50%, flow rate: 30 mL / min, 254 nm) to afford 4-bromo-2-(bromomethyl)-5-methoxy-pyridine (950 mg, 92.2% yield) as a red solid. LCMS (ESI) m / z 281.9 [M+H]+. Step 3: Synthesis of tert-butyl N-[(1R,2R)-2-[(4-bromo-5-methoxy-2- pyridyl) carbamate To a solution of 4-bromo-2- pyridine (500 mg, 1.78 mmol), tert-butyl N-[(1R,2R)-2-hydroxycyclobutyl]carbamate (370 mg, 1.98 mmol) in THF (10 mL) was added t- BuOK (240 mg, 2.14 mmol). The mixture was stirred at 20 °C for 1 hr under N2 atmosphere. The reaction mixture was quenched by addition of water (20 mL), and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (60 mL × 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 20 g AgelaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0 ~ 40%, flow rate = 40 mL / min, 254 nm). Compound tert-butyl N-[(1R,2R)-2-[(4- bromo-5-methoxy-2-pyridyl)methoxy]cyclobutyl]carbamate (600 mg, 87.1% yield) was obtained as a white solid. LCMS (ESI) m / z 387.3. [M+H]+. Step 4: Synthesis of tert-butyl N-[5-methoxy-2-[[(1R,2R)-2-(tert- butoxycarbonylamino)cyclobutoxy]methyl]-4-pyridyl]carbamate Patent Application To a solution of N-[(1R,2R)-2-[(4-bromo-5-methoxy-2- pyridyl)methoxy]cyclobutyl] mmol) in dioxane (15 mL) was added NH2Boc (230 mg, 1.96 mmol) and Cs2CO3 (1.26 g, 3.87 mmol), Pd2(dba)3 (160 mg, 0.175 mmol), Xantphos (180 mg, 0.311 mmol) and the mixture was stirred at 100 °C for 12 hrs. The reaction mixture was quenched by addition of water (50 mL), and extracted with DCM (30 mL × 3). The combined organic layers were washed with brine (60 mL × 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 20 g AgelaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0 ~ 100%, flow rate = 40 mL / min, 254 nm). Compound tert-butyl N-[5-methoxy-2- [[(1R,2R)-2-(tert-butoxycarbonylamino)cyclobutoxy]methyl]-4-pyridyl]carbamate (550 mg, 83.8% yield) was obtained as a yellow oil. LCMS (ESI) m / z 424.4. [M+H]+. Step 5: Synthesis of 5-methoxy-2-[[(1R,2R)-2-aminocyclobutoxy]methyl]pyridin-4-amine A solution of tert-butyl N-[5-methoxy-2-[[(1R,2R)-2-(tert- butoxycarbonylamino)cyclobutoxy]methyl]-4-pyridyl]carbamate (550 mg, 1.30 mmol) in 2M HCl / dioxane (10 mL) was stirred at 20 °C for 2 hrs. The reaction mixture was concentrated under reduced pressure. Compound 5-methoxy-2-[[(1R,2R)-2-aminocyclobutoxy]methyl]pyridin-4- amine (280 mg, crude) was obtained as a yellow solid. LCMS (ESI) m / z 224.2. [M+H]+. Step 6: Synthesis of N-((1R,2R)-2-((4-amino-5-methoxypyridin-2-yl)methoxy)cyclobutyl)-6- chloro-9H-imidazo[1,2-b]pyrrolo[2,3-d]pyridazine-3-carboxamide Patent Application To a solution of 6-chloro-9H- d]pyridazine-3-carboxylic acid (80 mg, 0.33 mmol, 1 eq) and 2-(((1R,2R)-2- methyl)-5-methoxypyridin-4-amine (113 mg, 0.50 mmol, 1.5 eq) in DMF (2 mL) was added PYBOP (316 mg, 0.60 mmol, 1.8 eq) and DBU (154 mg, 1.01 mmol, 3 eq). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was quenched with H2O (30 mL) and extracted with EtOAc (30 mL ´ 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The crude product was purified by column chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, DCM / MeOH with MeOH from 0~10%, 35 mL / min, 254 nm) to afford N-((1R,2R)-2-((4- amino-5-methoxypyridin-2-yl)methoxy)cyclobutyl)-6-chloro-9H-imidazo[1,2-b]pyrrolo[2,3- d]pyridazine-3-carboxamide (100 mg, 46.85%) as a white solid. LCMS (ESI) m / z 442.2, 444.2 [M+H]+. one A mixture of N-((1R,2R)-2-((4-amino-5-methoxypyridin-2-yl)methoxy)cyclobutyl)-6-chloro-9H- imidazo[1,2-b]pyrrolo[2,3-d]pyridazine-3-carboxamide (100 mg, 0.22 mmol, 1 eq), EPhos (24.61 mg, 0.04 mmol, 0.2 eq), EPhos Pd G4 (41.58 mg, 0.04 mmol, 0.2 eq) and Cs2CO3 (221 mg, 0.67 mmol, 3 eq) in dioxane (5 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100 °C for 1 hr under N2 atmosphere. The reaction mixture was quenched with H2O Patent Application (30 mL) and extracted with EtOAc (30 mL ´ 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by prep-HPLC (column: 2_Phenomenex Gemini C18 75*40mm*3um;mobile phase: [water(HCl)-ACN];gradient:5%-35% B over 10 min) to afford (61R,62R)-35-methoxy-19H-5-oxa- 2,7-diaza-1(6,3)-imidazo[1,2-b]pyrrolo[2,3-d]pyridazina-3(4,2)-pyridina-6(1,2)- cyclobutanacyclooctaphan-8-one (6 mg, 6.21%) as a white solid. LCMS (ESI) m / z 406.2 [M+H]+,1H NMR (400 MHz, DMSO-d6) δ ppm 13.25 (br s, 1H), 9.45 (s, 1H), 8.77 - 8.94 (m, 2H), 8.55 (s, 1H), 7.99 (s, 1H), 7.65 (t, J = 2.6 Hz, 1H), 7.26 (br s, 1H), 4.87 - 4.96 (m, 1H), 4.76 - 4.84 (m, 1H), 4.23 - 4.30 (m, 1H), 4.15 (s, 3H), 3.97 - 4.03 (m, 1H), 2.10 (br t, J = 8.5 Hz, 2H), 1.59 - 1.66 (m, 1H), 1.22 - 1.30 (m, 1H). Example 13: (61R,62R)-35-methoxy-17,18,19,110-tetrahydro-5-oxa-2,7-diaza-1(6,3)- imidazo[1,2-b]pyrido[2,3-d]pyridazina-3(4,2)-pyridina-6(1,2)-cyclobutanacyclooctaphan-8- one Step 1: N-((1R,2R)-2-((4-amino-5- methoxy)cyclobutyl)-6-chloro-10-(4- methoxybenzyl)-7,8,9,10-tetrahydroimidazo[1,2-b]pyrido[2,3-d]pyridazine-3-carboxamide To a solution of 2-[[(1R,2R)-2-aminocyclobutoxy]methyl]-5-methoxy-pyridin-4-amine (77.86 mg, 0.348 mmol, 1.3 eq) in DMF (3 mL) was added 6-chloro-10-(4-methoxybenzyl)-7,8,9,10- Patent Application tetrahydroimidazo[1,2-b]pyrido[2,3-d]pyridazine-3-carboxylic acid (100 mg, 0.268 mmol, 1 eq), PYBOP (209.38 mg, 0.402 mmol, 1.5 eq) and DBU (204.18 mg, 1.34 mmol, 202.16 μL, 5 eq). The mixture was stirred at 20 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0~100%, 60 mL / min, 254 nm / I2 / KMnO4 / PMA). Compound N-((1R,2R)-2-((4-amino-5-methoxypyridin-2- yl)methoxy)cyclobutyl)-6-chloro-10-(4-methoxybenzyl)-7,8,9,10-tetrahydroimidazo[1,2- b]pyrido[2,3-d]pyridazine-3-carboxamide (120 mg, 69.65%) was obtained as a yellow oil. LCMS (ESI) m / z 578.3 [M+H]+. Step 2: (61R,62R)-35-methoxy-110-(4-methoxybenzyl)-17,18,19,110-tetrahydro-5-oxa-2,7-diaza- 1(6,3)-imidazo[1,2-b]pyrido[2,3-d]pyridazina-3(4,2)-pyridina-6(1,2)- cyclobutanacyclooctaphan-8-one To a solution of N-((1R,2R)-2-( 2-yl)methoxy)cyclobutyl)-6-chloro- 10-(4-methoxybenzyl)-7,8,9,10-tetrahydroimidazo[1,2-b]pyrido[2,3-d]pyridazine-3-carboxamide (110 mg, 0.190 mmol, 1 eq) in dioxane (5 mL) was added EPhos (20.35 mg, 0.038 mmol, 0.2 eq), K3PO4 (121.18 mg, .0.572 mmol, 3 eq) and EPhos Pd G4 (17.48 mg, 0.019 mmol, 0.1 eq). The mixture was degassed and purged with N2 for three times. The mixture was stirred at 100 °C for 12 hours under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Dichloromethane / Methanol with methanol from 0~5%, 60 mL / min, 254 nm / I2 / KMnO4 / PMA). Compound (61R,62R)-35-methoxy-110-(4-methoxybenzyl)-17,18,19,110- tetrahydro-5-oxa-2,7-diaza-1(6,3)-imidazo[1,2-b]pyrido[2,3-d]pyridazina-3(4,2)-pyridina-6(1,2)- cyclobutanacyclooctaphan-8-one (90 mg, 76.85%) was obtained as a white solid. LCMS (ESI) m / z 542.3 [M+H]+. Patent Application Step 3: (61R,62R)-35-methoxy-17,18,19,110-tetrahydro-5-oxa-2,7-diaza-1(6,3)-imidazo[1,2- b]pyrido[2,3-d]pyridazina-3(4,2)-pyridina-6(1,2)-cyclobutanacyclooctaphan-8-one A solution of (61R,62R)-35- -17,18,19,110-tetrahydro-5-oxa-2,7- diaza-1(6,3)-imidazo[1,2-b]pyrido[2,3-d]pyridazina-3(4,2)-pyridina-6(1,2)- cyclobutanacyclooctaphan-8-one (80 mg, 0.147 mmol, 1 eq) in DCM (2 mL) and TFA (2 mL) was stirred at 20 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Dichloromethane / Methanol with Methanol from 0~4.7%, 40 mL / min, 254 nm / I2 / KMnO4 / PMA). Compound (61R,62R)-35-methoxy-17,18,19,110-tetrahydro-5-oxa-2,7-diaza- 1(6,3)-imidazo[1,2-b]pyrido[2,3-d]pyridazina-3(4,2)-pyridina-6(1,2)-cyclobutanacyclooctaphan- 8-one (43.72 mg, 69.77%) was obtained as a white solid. LCMS (ESI) m / z 422.3 [M+H]+,1H NMR (400 MHz, DMSO-d6) δ ppm 8.95 (d, J = 5.6 Hz, 1H), 8.25 (s, 1H), 8.16 (s, 1H), 7.82 (s, 1H), 7.72 (br s, 1H), 7.36 (s, 1H), 4.68 (d, J = 15.6 Hz, 1H), 4.43 (d, J = 15.6 Hz, 1H), 4.08 (br dd, J = 8.0, 5.6 Hz, 1H), 4.01 (s, 3H), 3.81 - 3.90 (m, 1H), 3.38 - 3.43 (m, 2H), 2.65 (br t, J = 6.0 Hz, 2H), 1.92 - 2.16 (m, 4H), 1.58 (br t, J = 9.6 Hz, 1H), 1.18 - 1.24 (m, 1H).

[0012] Patent Application Example 14: (61R,62R)-35-methoxy-16,17,18,19-tetrahydro-13H-5-oxa-2,7-diaza-1(5,3)- imidazo[4,5-h][1,6]naphthyridina-3(4,2)-pyridina-6(1,2)-cyclobutanacyclooctaphan-8-one Step 1: Synthesis of 5-chloro-N- (2-(trimethylsilyl)ethoxy)methyl)-6- vinyl-3H-imidazo[4,5-b]pyridin-7-amine A mixture of 5-chloro-6-iodo-N-[ methyl]-3-(2-trimethylsilylethoxymethyl) imidazo[4,5-b]pyridin-7-amine (1.7 g, 3.12 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2- dioxaborolane (961 mg, 6.24 mmol), Pd(dppf)Cl2 (228 mg, 311 μmol), Na2CO3 (992 mg, 9.36 mmol) in DMF (60 mL) and H2O (12 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100 °C for 3 hrs under N2 atmosphere. After the starting material was consumed completely, the reaction mixture was diluted with water (5 mL) and extracted with EtOAc (5 mL × 3). The combined organic layers were washed with brine (15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate / Petroleum ether gradient @ 12 mL / min) to give 5-chloro-N-(4- methoxybenzyl)-3-((2-(trimethylsilyl)ethoxy)methyl)-6-vinyl-3H-imidazo[4,5-b]pyridin-7-amine (450 mg, 32.41% yield) as a yellow solid. LCMS (ESI) m / z 445.3 [M+H]+. Step 2: Synthesis of N-allyl-5-chloro-N-(4-methoxybenzyl)-3-((2- (trimethylsilyl)ethoxy)methyl)-6-vinyl-3H-imidazo[4,5-b]pyridin-7-amine Patent Application A mixture of 5-chloro-N-(4- ethoxy)methyl)-6-vinyl-3H- imidazo[4,5-b]pyridin-7-amine (500 mg, 1.12 mmol), 3-bromoprop-1-ene (407 mg, 3.37 mmol), Cs2CO3 (1.46 g, 4.49 mmol) in DMF (10 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 25 °C for 16 hrs under N2 atmosphere. After the starting material was consumed completely and one main peak with desired mass was detected, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (15 mL × 1), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate / Petroleum ether gradient @ 12 mL / min) to give N-allyl-5-chloro-N-(4-methoxybenzyl)-3-((2- (trimethylsilyl)ethoxy)methyl)-6-vinyl-3H-imidazo[4,5-b]pyridin-7-amine (260 mg, 47.71% yield) as a yellow solid. LCMS (ESI) m / z 485.4 [M+H]+. Step 3: Synthesis of 5-chloro-9-(4-methoxybenzyl)-3-((2-(trimethylsilyl)ethoxy)methyl)-8,9- dihydro-3H-imidazo[4,5-h][1,6]naphthyridine To a solution of N-allyl-5-chloro-N-(4-methoxybenzyl)-3-((2-(trimethylsilyl)ethoxy)methyl)-6- vinyl-3H-imidazo[4,5-b]pyridin-7-amine (260 mg, 535 μmol) in DCM (10 mL) was added benzylidene-[1,3-bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene]-dichloro- ruthenium;tricyclohexylphosphane (45.5 mg, 53.6 μmol). The mixture was degassed and purged with N2 for 3 times. The mixture was stirred at 40 °C for 12 hrs under N2 atmosphere. After the Patent Application starting material was consumed and one main new spot formed, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0 ~ 20%, 60 mL / min, 254 nm / I2 / KMnO4 / PMA) to give 5-chloro-9-(4- methoxybenzyl)-3-((2-(trimethylsilyl)ethoxy)methyl)-8,9-dihydro-3H-imidazo[4,5- h][1,6]naphthyridine (150 mg, 61.2% yield) as a black oil. LCMS (ESI) m / z 457.3 [M+H]+. Step 4: Synthesis of 5-chloro-9-(4-methoxybenzyl)-3-((2-(trimethylsilyl)ethoxy)methyl)- 6,7,8,9-tetrahydro-3H-imidazo[4,5-h][1,6]naphthyridine To a solution of 5-chloro-9-(4- ethoxy)methyl)-8,9-dihydro- 3H-imidazo[4,5-h][1,6]naphthyridine (150 mg, 328 μmol) in MeOH (3 mL) and EtOAc (3 mL) was added PtO2 (7.45 mg, 32.8 μmol). The mixture was degassed and purged with H2 for three times. The mixture was stirred at 20 °C for 1 hr under H2 atmosphere. After the reaction was completed, the mixture was filtered to collect the solution and the solution was concentrated under reduced pressure to give 5-chloro-9-(4-methoxybenzyl)-3-((2-(trimethylsilyl)ethoxy)methyl)- 6,7,8,9-tetrahydro-3H-imidazo[4,5-h][1,6]naphthyridine (100 mg, 66.4% yield) as a black oil. LCMS (ESI) m / z 459.3 [M+H]+. Step 5: Synthesis of 5-chloro-9-(4-methoxybenzyl)-6,7,8,9-tetrahydro-3H-imidazo[4,5- h][1,6]naphthyridine Patent Application A solution of 5-chloro-9-(4-methoxybenzyl)-3-((2-(trimethylsilyl)ethoxy)methyl)-6,7,8,9- tetrahydro-3H-imidazo [4,5-h][1,6]naphthyridine (100 mg, 217 μmol) in TBAF (5 mL) was stirred at 50 °C for 2 hrs. The mixture was concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0 ~ 70% Ethyl acetate / Petroleum ether gradient @ 25 mL / min) to give 5-chloro-9-(4-methoxybenzyl)-6,7,8,9- tetrahydro-3H-imidazo[4,5-h][1,6]naphthyridine (30 mg, 41.9% yield) as a white solid. LCMS (ESI) m / z 329.0 [M+H]+. Step 6: Synthesis of phenyl 5-chloro-9-(4-methoxybenzyl)-6,7,8,9-tetrahydro-3H- imidazo[4,5-h][1,6]naphthyridine-3-carboxylate A mixture of 5- -6,7,8,9-tetrahydro-3H-imidazo[4,5- h][1,6]naphthyridine (30 mg, 91.24 μmol), phenyl carbonochloridate (15.7 mg, 100 μmol), TEA (27.7 mg, 273 μmol) in THF (1 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 25 °C for 1 hr under N2 atmosphere. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to remove THF to give crude product. The crude product of phenyl 5-chloro-9-(4-methoxybenzyl)-6,7,8,9-tetrahydro-3H-imidazo[4,5- h][1,6]naphthyridine-3-carboxylate (40 mg, 97.6% yield) as a white liquid was used into the next step without further purification. LCMS (ESI) m / z 449.1 [M+H]+. Step 7: Synthesis of N-((1R,2R)-2-((4-amino-5-methoxypyridin-2-yl)methoxy)cyclobutyl)-5- chloro-9-(4-methoxybenzyl)-6,7,8,9-tetrahydro-3H-imidazo[4,5-h][1,6]naphthyridine-3- carboxamide Patent Application A mixture of phenyl 5- -6,7,8,9-tetrahydro-3H-imidazo[4,5- h][1,6]naphthyridine-3-carboxylate (40 mg, 89.1 μmol), 2-[[(1R,2R)-2- aminocyclobutoxy]methyl]-5-methoxy-pyridin-4-amine (19.9 mg, 76.6 μmol, HCl) , TEA (27.1 mg, 267 μmol) in THF (5 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 20 °C for 16 hrs under N2 atmosphere. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0 ~ 100% Ethyl acetate / Petroleum ether gradient @ 40 mL / min) to give N-((1R,2R)-2-((4-amino-5- methoxypyridin-2-yl)methoxy)cyclobutyl)-5-chloro-9-(4-methoxybenzyl)-6,7,8,9-tetrahydro- 3H-imidazo[4,5-h][1,6]naphthyridine-3-carboxamide (40 mg, 77.6% yield) as a white solid. LCMS (ESI) m / z 578.3 [M+H]+. Step 8: Synthesis of (61R,62R)-35-methoxy-19-(4-methoxybenzyl)-16,17,18,19-tetrahydro-13H- 5-oxa-2,7-diaza-1(5,3)-imidazo[4,5-h][1,6]naphthyridina-3(4,2)-pyridina-6(1,2)- cyclobutanacyclooctaphan-8-one A mixture of N-((1R,2R)-2-((4-amino-5-methoxypyridin-2-yl)methoxy)cyclobutyl)-5-chloro-9- (4-methoxybenzyl)-6,7,8,9-tetrahydro-3H-imidazo[4,5-h][1,6]naphthyridine-3-carboxamide (30 mg, 51.9 μmol), EPhos Pd G4 (4.76 mg, 5.19 μmol), EPhos (5.54 mg, 10.4 μmol) and K3PO4 (33.1 Patent Application mg, 155 μmol) in dioxane (1 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100 °C for 1 hr under N2 atmosphere. After the reaction was completed, the mixture was filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0 ~ 100% Ethyl acetate / Petroleum ether gradient @ 12 mL / min) to afford (61R,62R)-35-methoxy-19-(4- methoxybenzyl)-16,17,18,19-tetrahydro-13H-5-oxa-2,7-diaza-1(5,3)-imidazo[4,5- h][1,6]naphthyridina-3(4,2)-pyridina-6(1,2)-cyclobutanacyclooctaphan-8-one (7 mg, 24.90% yield) as a white solid. LCMS (ESI) m / z 542.1 [M+H]+. Step 9: Synthesis of (61R,62R)-35-methoxy-16,17,18,19-tetrahydro-13H-5-oxa-2,7-diaza-1(5,3)- imidazo[4,5-h][1,6]naphthyridina-3(4,2)-pyridina-6(1,2)-cyclobutanacyclooctaphan-8-one A mixture of (61R,62R)-35 -methoxy- -16,17,18,19-tetrahydro-13H-5-oxa-2,7- diaza-1(5,3)-imidazo[4,5-h][1,6]naphthyridina-3(4,2)-pyridina-6(1,2)- cyclobutanacyclooctaphan-8-one (7 mg, 12.92 μmol) in DCM (10 mL) and TFA (0.1 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 20 °C for 1 hr under N2 atmosphere. After the reaction was completed, the mixture was quenched with 1M NaHCO3 aqueous solution (4 mL). The aqueous phase was extracted with DCM (10 mL × 2). The combined organic phase was washed with brine (10 mL × 2), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: C18150 × 30 mm; mobile phase: [Water (NH3H2O-NH4HCO3)-MeCN]; gradient: 38% - 58% B over 9 mins) to afford (61R,62R)-35-methoxy-16,17,18,19-tetrahydro-13H-5-oxa-2,7-diaza-1(5,3)-imidazo[4,5- h][1,6]naphthyridina-3(4,2)-pyridina-6(1,2)-cyclobutanacyclooctaphan-8-one (1 mg, 18.4% yield) as a yellow solid. LCMS (ESI) m / z 422.1 [M+H]+;1H NMR (400 MHz, CDCl3) δ ppm 9.84 (br d, J = 3.2 Hz, 1H), 8.29 (d, J = 1.6 Hz, 2H), 8.12 (s, 1H), 7.14 (s, 1H), 5.57 (br s, 1 H), 4.52 - Patent Application 4.87 (m, 2 H), 4.16 (qd, J = 8.4, 3.6 Hz, 1H), 4.03 (s, 3H), 3.91 (q, J = 8.0 Hz, 1H), 3.42 - 3.57 (m, 2H), 2.64 - 2.78 (m, 2H), 2.09 - 2.38 (m, 4H), 1.72 - 1.83 (m, 1H), 1.33 (br t, J = 8.8 Hz, 1H). Example 15: (61R,62R)-35-morpholino-16,17,18,19-tetrahydro-13H-5-oxa-2,7-diaza-1(5,3)- imidazo[4,5-h][1,6]naphthyridina-3(1,3)-benzena-6(1,2)-cyclobutanacyclooctaphan-8-one Step 1: Synthesis of (1R,2R)-2-( oxy)cyclobutan-1-amine A mixture of tert-butyl ((1R,2R)- oxy)cyclobutyl)carbamate (550 mg, 1.35 mmol) in 2M HCl / dioxane (10 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 20 °C for 1 hr under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product was used in the next step without further purification. Compound (1R,2R)-2-((3-morpholino-5- nitrobenzyl)oxy)cyclobutan-1-amine (550 mg, crude) was obtained as a yellow solid. LCMS (ESI) m / z 308.2 [M+H]+. Step2: Synthesis of 5-chloro-9-(4-methoxybenzyl)-N-((1R,2R)-2-((3-morpholino-5- nitrobenzyl)oxy)cyclobutyl)-6,7,8,9-tetrahydro-3H-imidazo[4,5-h][1,6]naphthyridine-3- carboxamide Patent Application To a solution of 6,7,8,9-tetrahydro-3H-imidazo[4,5- h][1,6]naphthyridine (130 mg, 395 μmol) in THF (5 mL) were added triphosgene (190 mg, 640 μmol) and TEA (120 mg, 1.19 mmol). The mixture was stirred at 25°C for 12 hrs, then to the reaction mixture was added (1R,2R)-2-((3-morpholino-5-nitrobenzyl)oxy)cyclobutan-1-amine (133 mg, 433 μmol). The mixture was stirred for 2 hrs under N2. After the reaction was completed, the mixture was quenched with H2O (20 ml). The aqueous phase was extracted with ethyl acetate (30 mL × 3). The combined organic phase was washed with brine (50 mL × 1), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate / Petroleum ether gradient @ 40 mL / min) to afford 5-chloro-9-(4-methoxybenzyl)-N- ((1R,2R)-2-((3-morpholino-5-nitrobenzyl)oxy)cyclobutyl)-6,7,8,9-tetrahydro-3H-imidazo[4,5- h][1,6]naphthyridine-3-carboxamide (330 mg, 69.8% yield) as a white solid. LCMS (ESI) m / z 662.2 [M+H]+. Step 3: Synthesis of N-((1R,2R)-2-((3-amino-5-morpholinobenzyl)oxy)cyclobutyl)-5-chloro- 9-(4-methoxybenzyl)-6,7,8,9-tetrahydro-3H-imidazo[4,5-h][1,6]naphthyridine-3- carboxamide A mixture of 5-chloro-9-(4-methoxybenzyl)-N-((1R,2R)-2-((3-morpholino-5- nitrobenzyl)oxy)cyclobutyl)-6,7,8,9-tetrahydro-3H-imidazo[4,5-h][1,6]naphthyridine-3- Patent Application carboxamide (230 mg, 347 μmol), Fe (194 mg, 3.47 mmol), NH4Cl (186 mg, 3.47 mmol) in H2O (2 mL) and EtOH (6 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 50°C for 2 hrs under N2 atmosphere. After the reaction was completed, the mixture was filtered and the filtrate was concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate / Petroleum ether gradient @ 12 mL / min) to afford N-((1R,2R)-2-((3-amino-5- morpholinobenzyl)oxy)cyclobutyl)-5-chloro-9-(4-methoxybenzyl)-6,7,8,9-tetrahydro-3H- imidazo[4,5-h][1,6]naphthyridine-3-carboxamide (180 mg, 81.97% yield) as a white solid. LCMS (ESI) m / z 632.3 [M+H]+. Step 4: Synthesis of (61R,62R)-19-(4-methoxybenzyl)-35-morpholino-16,17,18,19-tetrahydro- 13H-5-oxa-2,7-diaza-1(5,3)-imidazo[4,5-h][1,6]naphthyridina-3(1,3)-benzena-6(1,2)- cyclobutanacyclooctaphan-8-one A mixture of N-((1R,2R)-2-((3-amino-5-morpholinobenzyl)oxy)cyclobutyl)-5-chloro-9-(4- methoxybenzyl)-6,7,8,9-tetrahydro-3H-imidazo[4,5-h][1,6]naphthyridine-3-carboxamide (170 mg, 269 μmol), EPhos Pd G4 (24.7 mg, 26.9 μmol), EPhos (28.7 mg, 53.8 μmol) and K3PO4(171 mg, 807 μmol) in dioxane (15 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100 °C for 0.5 hrs under N2 atmosphere. After the reaction was completed, the mixture was filtered and the filtrate was concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0 ~ 100% Ethyl acetate / Petroleum ether gradient @ 12 mL / min) to afford (61R,62R)-19-(4- methoxybenzyl)-35-morpholino-16,17,18,19-tetrahydro-13H-5-oxa-2,7-diaza-1(5,3)-imidazo[4,5- h][1,6]naphthyridina-3(1,3)-benzena-6(1,2)-cyclobutanacyclooctaphan-8-one (160 mg, 99.88% yield) as a white solid. LCMS (ESI) m / z 596.3 [M+H]+. Patent Application Step 5: Synthesis of (61R,62R)-35-morpholino-16,17,18,19-tetrahydro-13H-5-oxa-2,7-diaza- 1(5,3)-imidazo[4,5-h][1,6]naphthyridina-3(1,3)-benzena-6(1,2)-cyclobutanacyclooctaphan- 8-one A mixture of (61R,62R)-19-(4- 16,17,18,19-tetrahydro-13H-5-oxa- 2,7-diaza-1(5,3)-imidazo[4,5-h][1,6]naphthyridina-3(1,3)-benzena-6(1,2)- cyclobutanacyclooctaphan-8-one (160 mg, 268 μmol) in DCM (3 mL) and TFA (0.3 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 20 °C for 1hr under N2 atmosphere. After the reaction was completed, the mixture was quenched with 1M aqueous solution of NaHCO3 (4 ml). The aqueous phase was extracted with DCM (10 mL × 2). The combined organic phase was washed with brine (10 mL × 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: C18150 × 40 mm; mobile phase: [Water(NH3H2O-NH4HCO3)-MeCN]; gradient: 37% - 57% B over 9 mins) to afford (61R,62R)-35-morpholino-16,17,18,19-tetrahydro-13H-5-oxa-2,7-diaza-1(5,3)- imidazo[4,5-h][1,6]naphthyridina-3(1,3)-benzena-6(1,2)-cyclobutanacyclooctaphan-8-one (36 mg, 28.2% yield) as a white solid. LCMS (ESI) m / z 476.2 [M+H]+;1H NMR (400 MHz, CDCl3) δ ppm 10.01 (br d, J = 1.2 Hz, 1H), 8.23 (s, 1H), 7.63 (s, 1H), 6.48 (s, 1H), 6.42 - 6.38 (m, 1H), 6.14 (s, 1H), 5.56 - 5.47 (m, 1H), 4.78 - 4.48 (m, 2H), 4.06 (dq, J = 3.2, 8.4 Hz, 1H), 3.90 - 3.79 (m, 5H), 3.55 - 3.43 (m, 2H), 3.24 - 3.16 (m, 4H), 2.72 - 2.56 (m, 2H), 2.34 (q, J = 9.2 Hz, 1H), 2.22 - 2.06 (m, 3H), 1.81 - 1.73 (m, 1H), 1.33 - 1.27 (m, 1H).

[0013] Patent Application Example 16: (61R,62R)-36-fluoro-35-morpholino-16,17,18,19-tetrahydro-13H-5-oxa-2,7-diaza- 1(5,3)-imidazo[4,5-h][1,6]naphthyridina-3(1,3)-benzena-6(1,2)-cyclobutanacyclooctaphan- 8-one Step 1: Synthesis of methyl 3- To a solution of methyl 3-bromo-4- (5.00 g, 17.98 mmol) in EtOH (50 mL) and H2O (5 mL) was added NH4Cl (96.0 mg, 1.80 mmol), AcOH (2.16 g, 35.9 mmol) and Fe (5.00 g, 89.5 mmol). The reaction mixture was stirred at 80 °C for 30 min. After filtration, the filtrate was concentrated. The residue was diluted with NaHCO3aqueous solution and extracted with EtOAc (100 mL × 3). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Compound methyl 3-amino-5-bromo-4-fluoro- benzoate (3.50 g, crude) was obtained as a white solid. LCMS (ESI) m / z 289.1, 291.1 [M+H+41]+,1H NMR (400 MHz, DMSO-d6) δ ppm 7.39 (dd, J = 7.6, 2.01 Hz, 1 H), 7.27 (dd, J = 5.6, 2.01 Hz, 1 H), 5.75 - 5.87 (m, 2 H), 3.81 (s, 3 H). Step 2: Synthesis of methyl 3-bromo-4-fluoro-5-morpholino-benzoate To a solution of methyl 3-amino-5-bromo-4-fluoro-benzoate (3.3 g, 13.3 mmol), KI (2.31 g, 13.9 mmol) and K2CO3 (2.81 g, 20.3 mmol) in DMF (30 mL) was added 1-bromo-2-(2- Patent Application bromoethoxy)ethane (31.0 g, 135 mmol). The mixture was stirred at 130 °C for 12 hrs. The reaction mixture was quenched with water (100 mL), and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (60 mL × 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 80 g AgelaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0 ~ 30%, flow rate = 80 mL / min, 254 nm). Compound methyl 3-bromo-4-fluoro-5- morpholino-benzoate (3.20 g, crude) was obtained as a yellow solid. LCMS (ESI) m / z 317.7, 319.7 [M+H]+. Step 3: Synthesis of (3-bromo-4-fluoro-5-morpholino-phenyl)methanol To a solution of methyl 3-bromo-4- benzoate (2.7 g, 8.49 mmol) in THF (50 mL) was added 1M DIBAL-H in toluene (18 mL) at 0 ℃ under N2 atmosphere. The mixture was stirred at 20 °C for 1 hr under N2 atmosphere. The reaction mixture was quenched with saturated potassium sodium tartrate aqueous solution (50 mL) and extracted with EtOAc (100 mL× 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 40 g AgelaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0 ~ 50%, flow rate = 40 mL / min, 254 nm). Compound (3-bromo-4-fluoro-5-morpholino-phenyl)methanol (1.90 g, 77.2% yield) was obtained as a yellow solid. LCMS (ESI) m / z 290.1, 292.1 [M+H]+. Step 4: Synthesis of 4-[3-bromo-5-(bromomethyl)-2-fluoro-phenyl]morpholine To a solution of (3-bromo-4-fluoro-5-morpholino-phenyl)methanol (1.9 g, 6.55 mmol) in MeCN (30 mL) was added PPh3 (2.66 g, 10.1 mmol) and CBr4 (2.66 g, 8.02 mmol). The mixture was stirred at 20 °C for 1 hr. The reaction mixture was quenched with water (60 mL), and extracted Patent Application with EtOAc (60 mL × 3). The combined organic layers were washed with brine (60 mL × 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 40 g AgelaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0 ~ 35%, flow rate = 60 mL / min, 254 nm). Compound 4-[3-bromo- 5-(bromomethyl)-2-fluoro-phenyl]morpholine (1.60 g, 69.2% yield) was obtained as a white solid. LCMS (ESI) m / z 351.5, 353.5355.5 [M+H]+. Step 5: Synthesis of tert-butyl N-[(1R,2R)-2-[(3-bromo-4-fluoro-5-morpholino- phenyl)methoxy]cyclobutyl]carbamate To a solution of 4-[3-bromo-5- morpholine (1.15 g, 2.94 mmol), tert-butyl N-[(1R,2R)-2-hydroxycyclobutyl]carbamate (500 mg, 2.67 mmol) in THF (20 mL) was added t-BuOK (355 mg, 3.16 mmol) and TBAI (98.0 mg, 0.267 mmol). The mixture was stirred at 20 °C for 1 hr. The reaction mixture was quenched with water (30 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 40 g AgelaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0 ~ 35%, flow rate = 40 mL / min, 254 nm). Compound tert-butyl N-[(1R,2R)-2-[(3- bromo-4-fluoro-5-morpholino-phenyl)methoxy]cyclobutyl]carbamate (1.00 g, 81.5% yield) was obtained as a yellow solid. LCMS (ESI) m / z 459.1, 461.1 [M+H]+. Step 6: Synthesis of tert-butyl N-[5-[[(1R,2R)-2-(tert- butoxycarbonylamino)cyclobutoxy]methyl]-2-fluoro-3-morpholino-phenyl]carbamate

[0014] Patent Application To a solution of tert-butyl N-[(1R,2R)-2-[(3-bromo-4-fluoro-5-morpholino- phenyl)methoxy]cyclobutyl]carbamate (1.00 g, 2.18 mmol) in dioxane (20 mL) was added BocNH2 (310 mg, 2.65 mmol) and Cs2CO3 (1.80 g, 5.52 mmol), Pd2(dba)3 (200 mg, 0.218 mmol) and Xantphos (260 mg, 0.449 mmol). The mixture was stirred at 100 °C for 12 hrs. The reaction mixture was quenched with water (50 mL), and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 40 g AgelaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0 ~ 50%, flow rate = 40 mL / min, 254 nm). Compound tert-butyl N-[5-[[(1R,2R)-2-(tert- butoxycarbonylamino)cyclobutoxy]methyl]-2-fluoro-3-morpholino-phenyl]carbamate (1.00 g, 92.7% yield) was obtained as a red oil. LCMS (ESI) m / z 496.3 [M+H]+. Step 7: Synthesis of 5-[[(1R,2R)-2-aminocyclobutoxy]methyl]-2-fluoro-3-morpholino- aniline A solution of tert-butyl N-[5-[[ cyclobutoxy]methyl]-2- fluoro-3-morpholino-phenyl]carbamate (1.00 g, 2.02 mmol) in 2M HCl / dioxane (60 mL) was stirred at 20 °C for 12 hrs. The reaction mixture was concentrated under reduced pressure. Compound 5-[[(1R,2R)-2-aminocyclobutoxy]methyl]-2-fluoro-3-morpholino-aniline (680 mg, crude) was obtained as a yellow solid. LCMS (ESI) m / z 296.2. [M+H]+. Step 8: Synthesis of N-((1R,2R)-2-((3-amino-4-fluoro-5-morpholinobenzyl)oxy)cyclobutyl)- 5-chloro-9-(4-methoxybenzyl)-6,7,8,9-tetrahydro-3H-imidazo[4,5-h][1,6]naphthyridine-3- carboxamide Patent Application A mixture of phenyl -6,7,8,9-tetrahydro-3H-imidazo[4,5- h][1,6]naphthyridine-3-carboxylate (136 mg, 303 μmol), 5-(((1R,2R)-2-aminocyclobutoxy) methyl)-2-fluoro-3-morpholinoaniline (159 mg, 303 μmol, 2TFA), TEA (91.9 mg, 909 μmol) in THF (5 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 20 °C for 1 hr under N2 atmosphere. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0 ~ 100% Ethyl acetate / Petroleum ether gradient @ 40 mL / min) to give N-((1R,2R)-2-((3-amino-4-fluoro-5-morpholinobenzyl)oxy) cyclobutyl)-5-chloro-9-(4-methoxybenzyl)-6,7,8,9-tetrahydro-3H-imidazo[4,5-h][1,6] naphthyridine-3-carboxamide (40 mg, 20.3% yield) as a white solid, LCMS (ESI) m / z 650.3 [M+H]+. Step 9: Synthesis of (61R,62R)-36-fluoro-19-(4-methoxybenzyl)-35-morpholino-16,17,18,19- tetrahydro-13H-5-oxa-2,7-diaza-1(5,3)-imidazo[4,5-h][1,6]naphthyridina-3(1,3)-benzena- 6(1,2)-cyclobutanacyclooctaphan-8-one A mixture of N-((1R,2R)-2-((3-amino-4-fluoro-5-morpholinobenzyl)oxy)cyclobutyl)-5-chloro-9- (4-methoxybenzyl)-6,7,8,9-tetrahydro-3H-imidazo[4,5-h][1,6]naphthyridine-3-carboxamide (40 mg, 61.5 μmol), EPhos Pd G4 (5.65 mg, 6.15 μmol), EPhos (6.57 mg, 12.3 μmol) and K3PO4 (39.2 mg, 185 μmol) in dioxane (5 mL) was degassed and purged with N2 for 3 times, and then the Patent Application mixture was stirred at 100 °C for 1 hr under N2 atmosphere. After the reaction was completed, the mixture was filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0 ~ 100% Ethyl acetate / Petroleum ether gradient @ 12 mL / min) to afford (61R,62R)-36-fluoro-19-(4- methoxybenzyl)-35-morpholino-16,17,18,19-tetrahydro-13H-5-oxa-2,7-diaza-1(5,3)-imidazo[4,5- h][1,6]naphthyridina-3(1,3)-benzena-6(1,2)-cyclobutanacyclooctaphan-8-one (15 mg, 39.7% yield) as a white solid, LCMS (ESI) m / z 614.3 [M+H]+. Step 10: Synthesis of (61R,62R)-36-fluoro-35-morpholino-16,17,18,19-tetrahydro-13H-5-oxa- 2,7-diaza-1(5,3)-imidazo[4,5-h][1,6]naphthyridina-3(1,3)-benzena-6(1,2)- cyclobutanacyclooctaphan-8-one A mixture of (61R,62R)-36-fluoro-19-(4-methoxybenzyl)-35-morpholino-16,17,18,19-tetrahydro- 13H-5-oxa-2,7-diaza-1(5,3)-imidazo[4,5-h][1,6]naphthyridina-3(1,3)-benzena-6(1,2)-cyclobutanacyclooctaphan-8-one (15 mg, 24.4 μmol) in DCM (10 mL) and TFA (0.1 mL) wasdegassed and purged with N2 for 3 times, and then the mixture was stirred at 20 °C for 1 hr underN2 atmosphere. After the reaction was completed, the mixture was quenched with 1M NaHCO3aqueous solution (4 m ) The aqueous phase was extracted with DCM (10 mL × 2). Thecombined organic phase was washed with brine (10 mL × 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: C18150 × 30 mm; mobile phase: [water(TFA)-ACN];gradient: 35% - 75% B over 9 mins) to afford (61R,62R)-36-fluoro-35-morpholino-16,17,18,19-tetrahydro-13H-5-oxa-2,7-diaza-1(5,3)- imidazo[4,5-h][1,6]naphthyridina-3(1,3)-benzena-6(1,2)-cyclobutanacyclooctaphan-8-one(1.3 mg, 10.78% yield) as a yellow solid. LCMS (ESI) m / z 494.2 [M+H]+;1H NMR (400 MHz, CDCl3) δ ppm 10.00 (br d, J = 3.2 Hz, 1H), 8.64 (s, 1H), 7.77 (br d, J = 5.6 Hz, 1H), 6.54 - 6.46 (m, 2H), Patent Application 4.78 - 4.47 (m, 2H), 4.14 - 4.04 (m, 1H), 3.90 (t, J = 4.4 Hz, 4H), 3.82 (q, J = 8.0 Hz, 1H), 3.62 - 3.45 (m, 2H), 3.18 - 3.07 (m, 4H), 2.71 - 2.63 (m, 2H), 2.27 - 2.05 (m, 4H), 1.85 - 1.75 (m, 1H), 1.42 - 1.31 (m, 1H). Example 17: ((61R,62R)-35-morpholino-13,17,18,19-tetrahydro-5-oxa-2,7-diaza-1(5,3)- imidazo[4',5':5,6]pyrido[3,4-b][1,4]oxazina-3(1,3)-benzena-6(1,2)- cyclobutanacyclooctaphan-8-one Step 1: Synthesis of 6-bromo-5- -3-((2- (trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-7-amine To a solution of 5-chloro-N-(4- - ethoxy)methyl)-3H- imidazo[4,5-b]pyridin-7-amine (7.8 g, 18.7 mmol, 1 eq) in DMF (70 mL) was added NBS (3.7 g, 20.6 mmol, 1.1 eq) at 0 °C and stirred at 25 °C for 1 h. The reaction mixture was diluted with H2O (100 mL) and extracted with EtOAc (100 mL ´ 2). The combined organic layers were washed with brine (100 mL´ 3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was triturated with DMF / H2O at 25oC for 10 min to afford 6-bromo-5-chloro-N-(4-methoxybenzyl)-3-((2-(trimethylsilyl)ethoxy)methyl)- 3H-imidazo[4,5-b]pyridin-7-amine (8.33 g, 87.1%) as a yellow solid. LCMS (ESI) m / z 497.0 / 499.0 / 501.0 [M+H]+Step 2: Synthesis of 2-((6-bromo-5-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-3H- imidazo[4,5-b]pyridin-7-yl)(4-methoxybenzyl)amino)ethyl hydrogen sulfate Patent Application To a solution of 6-bromo-5-chloro-N- -3-((2-(trimethylsilyl)ethoxy)methyl)- 3H-imidazo[4,5-b]pyridin-7-amine (5 g, eq) in THF (60 mL) was added LiHMDS (1 M, 12.1 mL, 1.2 eq) at 0 °C and stirred at 0 °C for 0.5 h, then 1,3,2-dioxathiolane 2,2-dioxide (1.5 g, 12.1 mmol, 1.2 eq) was added to the mixture at 0 °C and stirred at 25 °C for 2 h. The reaction mixture was diluted with NH4Cl aqueous solution (100 mL) and extracted with DCM (50 mL ´ 3). The combined organic layers were washed with brine (100 mL´ 3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, DCM / MeOH with MeOH from 0~4.8%, 60 mL / min, 254 nm) to afford 2-((6-bromo-5- chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-7-yl)(4- methoxybenzyl)amino)ethyl hydrogen sulfate (6.06 g, 89.9%) as a yellow oil. LCMS (ESI) m / z 621.0 / 623.0 / 625.0 [M+H]+Step 3: Synthesis of 2-((6-bromo-5-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-3H- imidazo[4,5-b]pyridin-7-yl)amino)ethanol A solution of 2-((6-bromo-5-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5- b]pyridin-7-yl)(4-methoxybenzyl)amino)ethyl hydrogen sulfate (6.1 g, 9.7 mmol, 1 eq) in EtOH (60 mL) was stirred at 70 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0~50%, 40 mL / min, Patent Application 254 nm) to afford 2-((6-bromo-5-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5- b]pyridin-7-yl)amino)ethanol (2.12 g, 50.6%) as a white solid. LCMS (ESI) m / z 421.0 / 423.0 / 425.0 [M+H]+. Step 4: Synthesis of 5-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-3,7,8,9- tetrahydroimidazo[4',5':5,6]pyrido[3,4-b][1,4]oxazine A mixture of 2-((6-bromo-5-chloro-3-( ethoxy)methyl)-3H-imidazo[4,5- b]pyridin-7-yl)amino)ethanol (2.1 g, 5.0 mmol, 1 eq), Gphos Pd G6 (472.5 mg, 0.5 mmol, 0.1 eq), Cs2CO3 (4.9 g, 15.0 mmol, 3 eq) in dioxane (30 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100 °C for 16 hr under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0~48%, 30 mL / min, 254 nm) to afford 5-chloro-3-((2- (trimethylsilyl)ethoxy)methyl)-3,7,8,9-tetrahydroimidazo[4',5':5,6]pyrido[3,4-b][1,4]oxazine (1.02 g, 55.4%) as a white solid. LCMS (ESI) m / z 341.1 / 343.1 [M+H]+. Step 5: Synthesis of 5-chloro-3,7,8,9-tetrahydroimidazo[4',5':5,6]pyrido[3,4-b][1,4]oxazine A solution of 5-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-3,7,8,9- tetrahydroimidazo[4',5':5,6]pyrido[3,4-b][1,4]oxazine (1.0 g, 3.0 mmol, 1 eq) in 1 M HCl / EtOAc solution (20 mL) was stirred at 50 °C for 1 hr. The reaction mixture was diluted with NaHCO3aqueous solution (30 mL) and extracted with DCM (30 mL ´ 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography Patent Application (ISCO®; 12 g SepaFlash® Silica Flash Column, DCM / MeOH with MeOH from 0~2.5%, 50 mL / min, 254 nm) to afford 5-chloro-3,7,8,9-tetrahydroimidazo[4',5':5,6]pyrido[3,4- b][1,4]oxazine (640 mg, 98.5%) as a white solid. LCMS (ESI) m / z 211.0 / 213.0 [M+H]+. Step 6: Synthesis of N-((1R,2R)-2-((3-amino-5-morpholinobenzyl)oxy)cyclobutyl)-5-chloro- 8,9-dihydroimidazo[4',5':5,6]pyrido[3,4-b][1,4]oxazine-3(7H)-carboxamide To a solution of 5-chloro-3,7,8,9- pyrido[3,4-b][1,4]oxazine (200 mg, 0.9 mmol, 1 eq) in THF (10 mL) was added TEA (288.3 mg, 2.9 mmol, 3 eq) and bis(trichloromethyl) carbonate (93.0 mg, 0.3 mmol, 0.33 eq). The mixture was stirred at 0 °C for 0.5 hr. Then to the mixture was added TEA (287.9 mg, 2.9 mmol, 3 eq) and 3-(((1R,2R)-2- aminocyclobutoxy)methyl)-5-morpholinoaniline (289.4 mg, 1.0 mmol, 1.1 eq) at 0 °C and stirred at 25 °C for 0.5 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, DCM / MeOH with MeOH from 0~1.3%, 50 mL / min, 254 nm) to afford N- ((1R,2R)-2-((3-amino-5-morpholinobenzyl)oxy)cyclobutyl)-5-chloro-8,9- dihydroimidazo[4',5':5,6]pyrido[3,4-b][1,4]oxazine-3(7H)-carboxamide (152 mg, 29.9%) as a white solid. LCMS (ESI) m / z 514.2 / 516.2 [M+H]+. Step 7: Synthesis of (61R,62R)-35-morpholino-13,17,18,19-tetrahydro-5-oxa-2,7-diaza-1(5,3)- imidazo[4',5':5,6]pyrido[3,4-b][1,4]oxazina-3(1,3)-benzena-6(1,2)- cyclobutanacyclooctaphan-8-one Patent Application A mixture of N-((1R,2R)-2-((3- cyclobutyl)-5-chloro-8,9- dihydroimidazo[4',5':5,6]pyrido - (93 mg, 0.2 mmol, 1 eq), EPhos Pd G4 (16.6 mg, 0.02 mmol, 0.1 eq), Ephos (19.4 mg, 0.04 mmol, 0.2 eq) and KHCO3 (54.4 mg, 0.5 mmol, 3 eq) in dioxane (6 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100 °C for 16 hr under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, DCM / MeOH with MeOH from 0~1%, 30 mL / min, 254 nm) to afford (61R,62R)-35-morpholino-13,17,18,19-tetrahydro-5- oxa-2,7-diaza-1(5,3)-imidazo[4',5':5,6]pyrido[3,4-b][1,4]oxazina-3(1,3)-benzena-6(1,2)- cyclobutanacyclooctaphan-8-one (20.50 mg, 22.7%) as a white solid. LCMS (ESI) m / z 478.2 [M+H]+,1H NMR (400 MHz, DMSO-d6) δ ppm 9.95 (br d, J = 3.2 Hz, 1H), 8.20 (s, 1H), 8.08 (s, 1H), 7.51 (s, 1H), 7.25 (br s, 1H), 6.84 (s, 1H), 6.42 (s, 1H), 4.66 (d, J = 14.4 Hz, 1H), 4.43 (d, J = 14.4 Hz, 1H), 4.19 - 4.29 (m, 2H), 3.84 - 3.94 (m, 1H), 3.77 - 3.84 (m, 1H), 3.70 - 3.75 (m, 4H), 3.50 (br s, 2H), 3.07 - 3.12 (m, 4H), 2.11 (br dd, J = 13.2, 9.0 Hz, 2H), 1.57 - 1.65 (m, 1H), 1.28 - 1.38 (m, 1H). Example 18: (61R,62R)-35-methoxy-13,17,18,19-tetrahydro-5-oxa-2,7-diaza-1(5,3)- imidazo[4',5':5,6]pyrido[3,4-b][1,4]oxazina-3(4,2)-pyridina-6(1,2)- cyclobutanacyclooctaphan-8-one-12-d Step 1: Synthesis of 5-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-3,7,8,9- Patent Application tetrahydroimidazo[4',5':5,6]pyrido[3,4-b][1,4]oxazine-2-d To a solution of ((2-(trimethylsilyl)ethoxy)methyl)-3,7,8,9- tetrahydroimidazo[4',5':5,6]pyrido[3,4- (1.4 g, 4.2 mmol. This intermediate was synthesized using similar procedure that was described in Example N-6227) in 2- methyltetrahydrofuran (15 mL) was added t-BuOK (1.9 g, 16.7 mmol) and stirred at 60 °C for 0.5 hr, then CD3OD (275.3 mg, 8.3 mmol) was added in the mixture and stirred at 60 °C for 1 hr. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (30 mL ´ 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0~50%, 30 mL / min, 254 nm) to afford 5-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)- 3,7,8,9-tetrahydroimidazo[4',5':5,6]pyrido[3,4-b][1,4]oxazine-2-d (1.15 g, 79.0% yield) as a white solid. LCMS (ESI) m / z 342.1 [M+H]+. Step 2: Synthesis of 5-chloro-3,7,8,9-tetrahydroimidazo[4',5':5,6]pyrido[3,4-b][1,4]oxazine- 2-d To a solution of 5-chloro-3-( ethoxy)methyl)-3,7,8,9-tetrahydroimidazo [4',5':5,6]pyrido[3,4-b][1,4]oxazine-2-d (1.15 g, 3.4 mmol) in HCl / EtOAc (2M, 20 mL) was stirred at 50 °C for 1 hr. The mixture was basified at 0 °C with an aquoues solution of NaHCO3 to pH = 7-8 and extracted with DCM (20 mL ´ 3). Then the combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, DCM / MeOH with MeOH from 0~2.5%, 50 mL / min, 254 nm) to afford 5- Patent Application chloro-3,7,8,9-tetrahydroimidazo[4',5':5,6]pyrido[3,4-b][1,4]oxazine-2-d (530 mg, 73.6% yield) as a white solid. LCMS (ESI) m / z 212.0 [M+H]+. Step 3: Synthesis of N-((1R,2R)-2-((4-amino-5-methoxypyridin-2-yl)methoxy)cyclobutyl)-5- chloro-8,9-dihydroimidazo[4',5':5,6]pyrido[3,4-b][1,4]oxazine-2-d-3(7H)-carboxamide To a solution of 5-chloro-3,7,8,9- pyrido[3,4-b][1,4]oxazine-2-d (200 mg, 0.9 mmol) in THF (10 mL) was mg, 2.8 mmol) and bis(trichloromethyl) carbonate (84.1 mg, 0.3 mmol). The mixture was stirred at 0 °C for 0.5 hr. Then the mixture was added TEA (286.3 mg, 2.8 mmol) and 2-(((1R,2R)-2-aminocyclobutoxy)methyl)-5- methoxypyridin-4-amine (245 mg, 0.9 mmol) at 0 °C and stirred at 25 °C for 0.5 hr. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (30 mL ´ 3). The combined organic layers were concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, DCM / MeOH with MeOH from 0~2.5%, 30 mL / min, 254 nm) to afford N-((1R,2R)-2-((4-amino- 5-methoxypyridin-2-yl)methoxy)cyclobutyl)-5-chloro-8,9-dihydroimidazo[4',5':5,6]pyrido[3,4- b][1,4]oxazine-2-d-3(7H)-carboxamide (134 mg, 30.8% yield) as a white solid. LCMS (ESI) m / z 461.1 [M+H]+. Step 4: Synthesis of (61R,62R)-35-methoxy-13,17,18,19-tetrahydro-5-oxa-2,7-diaza-1(5,3)- imidazo[4',5':5,6]pyrido[3,4-b][1,4]oxazina-3(4,2)-pyridina-6(1,2)- cyclobutanacyclooctaphan-8-one-12-d A mixture of N-((1R,2R)-2-((4-amino-5-methoxypyridin-2-yl)methoxy)cyclobutyl)-5-chloro-8,9- Patent Application dihydroimidazo[4',5':5,6]pyrido[3,4-b][1,4]oxazine-2-d-3(7H)-carboxamide (90 mg, 0.2 mmol), EPhos Pd G4 (17.9 mg, 0.02 mmol), Ephos (20.9 mg, 0.04 mmol) and KHCO3 (58.7 mg, 0.6 mmol) in dioxane (10 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100 °C for 16 hr under N2 atmosphere. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (30 mL ´ 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Welch Xtimate C18150 ´ 25 mm ´ 5 µm;mobile phase: [water( NH4HCO3)-ACN];gradient:35%-65% B over 9.5 min) to afford (61R,62R)-35-methoxy- 13,17,18,19-tetrahydro-5-oxa-2,7-diaza-1(5,3)-imidazo[4',5':5,6]pyrido[3,4-b][1,4]oxazina-3(4,2)- pyridina-6(1,2)-cyclobutanacyclooctaphan-8-one-12-d (5.87 mg, 6.8% yield) as a white solid. LCMS (ESI) m / z 425.2 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ ppm 9.52 (d, J = 4.4 Hz, 1 H), 8.36 (s, 1 H), 8.19 (s, 1 H), 7.57 (s, 1 H), 7.54 (br s, 1 H), 4.68 (d, J = 16.0 Hz, 1 H), 4.41 (d, J = 15.6 Hz, 1 H), 4.29 (br t, J = 4.0 Hz, 2 H), 3.92 - 4.05 (m, 5 H), 3.51 (br d, J = 2.0 Hz, 2 H), 2.15 - 2.25 (m, 1 H), 2.09 (q, J = 8.8 Hz, 1 H), 1.62 (quin, J = 9.6 Hz, 1 H), 1.32 (quin, J = 9.6 Hz, 1 H). Example 19: (61R,62R)-36-morpholino-13,17,18,19-tetrahydro-5-oxa-2,7-diaza-1(5,3)- imidazo[4',5':5,6]pyrido[3,4-b][1,4]oxazina-3(4,2)-pyridina-6(1,2)- cyclobutanacyclooctaphan-8-one Step 1: Synthesis of tert-butyl 4-yl)carbamate To a solution of 2-bromo-6-methylpyridin-4-amine (22.2 g, 118.7 mmol) in THF (200 mL) was added LiHMDS (1 M, 237.4 mL) and Boc2O (28.5 g, 130.6 mmol) at 0 °C and stirred at 25 °C for 1 hr. The reaction mixture was diluted with H2O (400 mL) and extracted with DCM (200 mL ´ 3). Patent Application The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (ISCO®; 24 g SepaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0~6%, 50 mL / min, 254 nm) to afford tert-butyl (2-bromo-6-methylpyridin-4- yl)carbamate (21.31 g, 60.6% yield) as a yellow solid. LCMS (ESI) m / z 286.9, 288.9 [M+H]+Step 2: Synthesis of tert-butyl (2-bromo-6-(bromomethyl)pyridin-4-yl)carbamate To a solution of tert-butyl (2-bromo- yl)carbamate (3 g, 10.5 mmol) in DCM (30 mL) was added AIBN (171.6 mg, (2.1 g, 11.5 mmol). The mixture was stirred at 80 °C for 16 hrs. The reaction mixture was diluted with H2O (30 mL) and extracted with DCM (30 mL ´ 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0~7%, 50 mL / min, 254 nm) to afford tert-butyl (2- bromo-6-(bromomethyl)pyridin-4-yl)carbamate (1.33 g, 25.2% yield) as a yellow oil. LCMS (ESI) m / z 364.9, 366.9, 368.9 [M+H]+Step 3: Synthesis of tert-butyl (2-bromo-6-(((1R,2R)-2-((tert-butoxycarbonyl)amino) cyclobutoxy)methyl)pyridin-4-yl)carbamate To a solution of tert-butyl ((1R,2R)-2- carbamate (518.5 mg, 2.8 mmol) in THF (20 mL) was added TBAI (186.0 mg, 0.5 mmol) and NaH (201.4 mg, 5.0 mmol) at 0 °C and stirred for 10 mins, then tert-butyl (2-bromo-6-(bromomethyl)pyridin-4-yl)carbamate (1.28 g, 2.52 mmol) was added in the mixture and stirred at 25 °C for 50 mins. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (30 mL ´ 3). The combined organic layers were Patent Application washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0~14%, 50 mL / min, 254 nm) to afford tert-butyl (2-bromo-6-(((1R,2R)-2-((tert-butoxycarbonyl)amino)cyclobutoxy) methyl)pyridin-4-yl)carbamate (1.05 g, 59.8% yield) as a yellow oil. LCMS (ESI) m / z 472.1, 474.1 [M+H]+. Step of tert-butyl (2-(((1R,2R)-2-((tert-butoxycarbonyl)amino)cyclobutoxy) methyl)-6-morpholinopyridin-4-yl)carbamate A mixture of tert-butyl (2- butoxycarbonyl)amino)cyclobutoxy) methyl)pyridin-4-yl)carbamate (1.05 g, 2.2 mmol), morpholine (290.5 mg, 3.3 mmol), Pd2(dba)3 (203.6 mg, 0.2 mmol), Xantphos (257.2 mg, 0.4 mmol) and Cs2CO3 (1.8 g, 5.6 mmol) in dioxane (15 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100 °C for 16 hrs under N2 atmosphere. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (20 mL ´ 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0~14%, 50 mL / min, 254 nm) to afford tert-butyl (2- (((1R,2R)-2-((tert-butoxycarbonyl)amino)cyclobutoxy)methyl)-6-morpholinopyridin-4- yl)carbamate (253 mg, 19.0% yield) as a yellow oil. LCMS (ESI) m / z 479.3 [M+H]+. Step 5: Synthesis of 2-(((1R,2R)-2-aminocyclobutoxy)methyl)-6-morpholinopyridin-4-amine Patent Application To a solution of tert-butyl (2-(( amino)cyclobutoxy)methyl)-6- morpholinopyridin-4-yl)carbamate HCl / dioxane (2M, 6 mL) was stirred at 45 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to afford 2- (((1R,2R)-2-aminocyclobutoxy)methyl)-6-morpholinopyridin-4-amine (200 mg, crude) as a yellow solid. It was used into the next step without further purification. LCMS (ESI) m / z 279.1 [M+H]+. Step 6: Synthesis of N-((1R,2R)-2-((4-amino-6-morpholinopyridin-2- yl)methoxy)cyclobutyl)-5-chloro-8,9-dihydroimidazo[4',5':5,6]pyrido[3,4-b][1,4]oxazine- 3(7H)-carboxamide To a solution of 5-chloro- pyrido[3,4-b][1,4]oxazine (102.8 mg, 0.5 mmol) and TEA (148.2 mg, 1.5 mmol) in THF (5 mL) was added phenyl carbonochloridate (76.4 mg, 0.5 mmol) at 25 °C and stirred for 0.5 hrs, then 2-(((1R,2R)-2- aminocyclobutoxy)methyl)-6-morpholinopyridin-4-amine (167 mg, 0.5 mmol) and TEA (148.2 mg, 1.5 mmol) was added in the mixture and stirred at 25 °C for 0.5 hrs. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL ´ 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, DCM / MeOH with MeOH from 0~3%, 30 mL / min, 254 nm) to afford N-((1R,2R)-2-((4-amino-6-morpholinopyridin-2-yl)methoxy)cyclobutyl)-5-chloro- 8,9-dihydroimidazo[4',5':5,6]pyrido[3,4-b][1,4]oxazine-3(7H)-carboxamide (76 mg, 28.7% yield) Patent Application as a white solid. LCMS (ESI) m / z 515.2 [M+H]+. Step 7: Synthesis of (61R,62R)-36-morpholino-13,17,18,19-tetrahydro-5-oxa-2,7-diaza-1(5,3)- imidazo[4',5':5,6]pyrido[3,4-b][1,4]oxazina-3(4,2)-pyridina-6(1,2)- cyclobutanacyclooctaphan-8-one A mixture of N-((1R,2R)-2-((4- 2-yl)methoxy)cyclobutyl)-5-chloro- 8,9-dihydroimidazo[4',5':5,6] -carboxamide (76 mg, 0.1 mmol), Ephos (15.8 mg, 0.3 mmol), EPhos Pd G4 (13.6 mg, 0.1 mmol) and KHCO3 (44.3 mg, 0.4 mmol) in dioxane (5 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100 °C for 16 hrs under N2 atmosphere. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL ´ 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, DCM / MeOH with MeOH from 0~1%, 30 mL / min, 254 nm) to afford (61R,62R)- 36-morpholino-13,17,18,19-tetrahydro-5-oxa-2,7-diaza-1(5,3)-imidazo[4',5':5,6] b][1,4]oxazina-3(4,2)-pyridina-6(1,2)-cyclobutanacyclooctaphan-8-one (6.02 mg, 8.5% yield) as a white solid. LCMS (ESI) m / z 479.2 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ ppm 9.72 (d, J = 4.4 Hz, 1 H), 8.50 (s, 1 H), 8.27 (s, 1 H), 7.65 (s, 1 H), 7.42 (s, 1 H), 6.67 (s, 1 H), 4.58 (d, J = 16.0 Hz, 1 H), 4.19 - 4.31 (m, 1 H), 3.83 - 4.01 (m, 2 H), 3.69 (t, J = 4.8 Hz, 4 H), 3.51 (br s, 2 H), 3.30 - 3.33 (m, 4 H), 2.14 - 2.24 (m, 1 H), 2.08 (br d, J = 8.8 Hz, 1 H), 1.60 (s, 1 H), 1.21 - 1.36 (m, 1 H). Biological Assays The following assays are used to show the activity of the compounds of the invention. Assay A: TYK2 JH2 binding assay Competitive binding studies using TKY2 JH2-domain fragments were conducted by DiscoverX using the KINOMEscan (KdELECT) platform. Kinase-tagged T7 phage strains were Patent Application prepared in an E. coli host derived from the BL21 strain. E. coli were grown to log-phase and infected with T7 phage and incubated with shaking at 32°C until lysis. The lysates were centrifuged and filtered to remove cell debris. The remaining kinases were produced in HEK-293 cells and subsequently tagged with DNA for qPCR detection. Streptavidin-coated magnetic beads were treated with biotinylated small molecule ligands for 30 minutes at room temperature to generate affinity resins for kinase assays. The liganded beads were blocked with excess biotin and washed with blocking buffer (SeaBlock (Pierce), 1% BSA, 0.05% Tween 20, 1 mM DTT) to remove unbound ligand and to reduce non-specific binding. Binding reactions were assembled by combining kinases, liganded affinity beads, and test compounds in 1x binding buffer (20% SeaBlock, 0.17x PBS, 0.05% Tween 20, 6 mM DTT). Test compounds were prepared as 111X stocks in 100% DMSO. Kds were determined using an 11-point 3-fold compound dilution series with three DMSO control points. All compounds for Kd measurements are distributed by acoustic transfer (non-contact dispensing) in 100% DMSO. The compounds were then diluted directly into the assays such that the final concentration of DMSO was 0.9%. All reactions were performed in polypropylene 384-well plate. Each was a final volume of 0.02 ml. The assay plates were incubated at room temperature with shaking for 1 hour and the affinity beads were washed with wash buffer (1x PBS, 0.05% Tween 20). The beads were then re-suspended in elution buffer (1x PBS, 0.05% Tween 20, 0.5 μM non- biotinylated affinity ligand) and incubated at room temperature with shaking for 30 minutes. The kinase concentration in the eluates was measured by qPCR. Using this data, binding constants (Kds) for test compounds were calculated in Dotmatics using the four- parameter logistic curve regression model with bottom fixed to 0 and Hill Slope fixed to -1. Assay B: JAK1 / TYK2 pSTAT5 (Tyr694 / 699) inhibition IC50 Cellular Assays To evaluate the inhibition effect of compounds disclosed herein against TYK2, an IFNa- stimulated JAK1 / TYK2 pSTAT5 (Tyr694 / 699) quantification assay was conducted in the THP-1 or PBMC cell line using an AlphaLISA detection method (PerkinElmer ALSU-PST5). Compounds in DMSO were serially diluted in a 96-well plate (10 mM starting concentration, 6-fold dilutions, 8 concentrations total) prior to dispensing of 8 nL into a 384-well plate using an I.DOT non-contact liquid handler (Dispendix). Cells were collected via centrifugation at 300 rcf for 5 min and resuspended in Hanks’ Balanced Salt Solution (Gibco 14175-079), and 6 µl containing 2e4 cells was dispensed into each well of the 384-well plate containing test compounds or DMSO alone Patent Application (final concentrations: 10000, 1666.67, 277.78, 46.30, 7.72, 1.29, 0.21 and 0.04 nM). Cells were then incubated for 1 h at 37°C with 5% CO2 prior to the addition of 2 µL IFNa (100 ng / mL; PBL Assay Science 11175-1). Following an additional 30 min incubation at 37°C with 5% CO2, 2 µL of 5x lysis buffer was added to each well using the I.DOT (name / product ID needed). Plates were sealed and incubated at RT for 10 min on a plate shaker set to 400 RPM. Cell lysates were then frozen at -80°C before subsequent detection of pSTAT5 by AlphaLISA. At the time of the detection assay, cell lysates were thawed for 5 min at room temperature and then on a plate shaker set to 400 RPM for an additional 10 min. Following the manufacturer recommended protocol (Perkin Elmer), 5 µL of acceptor bead master mix was added to each well; plates were then resealed and incubated for 2 min at RT on a plate shaker (400 rpm) prior to an additional 2-h incubation without agitation (protected from light). Donor bead master mix, 5 uL per well, was then added to each well before 2 min of shaking (RT, 400 rpm) and 2-h incubation (RT, no shaking, protected from light). Levels of pSTAT5 protein were then measured as fluorescent signal at 615 nm with an EnVision multimode plate reader (Perkin Elmer). IC50 values were calculated in Dotmatics using the four- parameter logistic curve regression model with bottom fixed to 0 and Hill Slope fixed to -1. Table 1: Potency of exemplified compounds Compounds with TYK2 JH2 Kd (as measured in Assay A) equal to or less than 0.1 nM are designated as A, between 0.1 nM and 1 nM as B, between 1 nM and 10 nM as C, larger than 10 nM as D. Compounds with IFNa IC50 in IFNa cellular assay (as measured in Assay B) equal to or less than 100 nM are designated as A, larger than 100 nM as B (aIFNa data was run in THP1 cell line;bIFNa data was run in PBMC cell line). Cellular - Patent Application Cellular Biochemical Example THP1 / PBMC _IFNa- TYK2_JH2__Kd STAT5 IC50 Incorporation by Reference References and citations to other documents, such as patents, patent applications, patent publications, journals, books, papers, web contents, publicly accessible databases, have been made throughout this disclosure. All such documents are hereby incorporated herein by reference in their entirety for all purposes. Equivalents Various modifications of the invention and many further embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art from the full contents of this document, including references to the scientific and patent literature cited herein. The subject matter herein contains important information, exemplification and guidance that can be adapted to the practice of this invention in its various embodiments and equivalents thereof.

Claims

1. Patent Application Claims:

1. A compound of formula (I), or pharmaceutically acceptable salt, stereoisomer, or solvate thereof, (I) wherein: X1, X2, and X3are C, or N, wherein only one of X1, X2, and X3is N; is a single bond or a double bond; Y1is N, or C; Y2is O, or C; n is 0, 1, or 2; m is 0, 1, or 2; R1is selected from the group consisting of hydrogen, deuterium, and optionally substituted C1- C6 alkyl; L is a linker comprising 2-12 atom links, wherein each atom link in L is selected from the group consisting of -CRL1RL2, NRL1, O, and S; wherein: RL1and RL2are independently selected from the group consisting of: hydrogen, deuterium, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C12 cycloalkyl, wherein RL1and RL2on the same or different atoms can be optionally combined to form a 3-12 membered cycloalkyl or heterocycloalkyl, wherein the one or more heteroatoms are N, O, or S; Patent Application A is selected from the group consisting of 5-12 membered monocyclic or bicyclic aryl and heteroaryl, wherein one or more heteroatoms in said heteroaryl is N, S, or O; RA1, RA2, and RBare independently selected from the group consisting of: hydrogen, deuterium, halogen, hydroxy, O-alkyl, alkoxy, cyano, =O, -SRb, -S(=O)Ra, -S(=O)2Ra, -NRcRd, substituted or unsubstituted C1-C6alkyl, C1-C6hydroxyalkyl, C1-C6alkoxyalkyl, C1-C6aminoalkyl, C2-C6alkenyl, wherein one or more substitutions are selected from the group consisting of deuterium, halogen, hydroxy, alkoxy, cyano, =O, 3-12 membered cycloalkyl, oxycycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein one or more heteroatoms in heterocycloalkyl or heteroaryl rings are N, S or O and wherein one or more substitutions are selected from the group consisting of hydrogen, deuterium, halogen, hydroxy, alkoxy, cyano, =O, substituted or unsubstituted C1-C6alkyl, C1-C6hydroxyalkyl, C1-C6alkoxyalkyl, 3-12 membered cycloalkyl, or heterocycloalkyl, aryl, or heteroaryl, wherein optionally RA1and RA2together form a substituted or unsubstituted 3-12 membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl fused with six-membered ring, and the fused ring may be further substituted with alkyl or deuterium alkyl; each Rais independently C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1- C6hydroxyalkyl, C1-C6aminoalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OMe, - NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C1-C6alkyl, or C1-C6haloalkyl; each Rbis independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OMe, - NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C1-C6alkyl, or C1-C6haloalkyl; and each Rcand Rdis independently hydrogen, C1-C6alkyl, C1-C6 haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C1-C6alkyl, or C1-C6haloalkyl; or Rcand Patent Application Rdare taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OMe, -NH2, - C(=O)Me, -C(=O)OH, -C(=O)OMe, C1-C6 alkyl, or C1-C6 haloalkyl.

2. The compound of claim 1, wherein the compound of Formula (I) is of Formula (Ia):

3. The compound of is of Formula (Ib):

4. The compound of claim 1, wherein the compound of Formula (I) is of Formula (Ic):Patent Application (Ic) 5. The compound of6. The compound of claim 1, wherein Y1is C.

7. The compound of claim 1, wherein Y2is O.

8. The compound of claim 1, wherein Y2is C.

9. The compound of claim 1, wherein R1is H.

10. The compound of claim 1, wherein Ring A is 5-12 membered aryl or heteroaryl, wherein the one or more heteroatom in the heteroaryl ring is N, S or O.

11. The compound of claim 1, wherein Ring A is 5-12 membered aryl.

12. The compound of claim 1, wherein Ring A is phenyl.

13. The compound of claim 1, wherein Ring A is 5-12 membered heteroaryl ring, wherein the one or more heteroatom in the heteroaryl ring is N, S or O.

14. The compound of claim 1, wherein Ring A is pyridine, pyrimidine, pyridazine, pyridone, or pyridazinone.

15. The compound of claim 1, wherein Ring A, RA1, and RA2combine to form a 6,5 or 6,6 fused bicyclic ring.

16. The compound of claim 15, wherein the fused bicyclic ring includes further substitutions,Patent Application wherein the substitutions are selected from the group consisting of hydrogen, deuterium, halogen, C1-C6alkyl, and C1-C6 deuterated alkyl.

17. The compound of claim 16, wherein the one or more substitutions are selected from the group consisting of hydrogen, deuterium, -CH3, or -CD3.

18. The compound of claim 1, wherein RA1, RA2and RBare independently selected from the group consisting of hydrogen, =O, deuterium, hydroxyl, alkoxy, halogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 oxyalkyl, substituted or unsubstituted C1-C6 oxycycloalkyl, 3-12 membered substituted or unsubstituted cycloalkyl or heterocycloalkyl wherein one or more heteroatoms are N, S or O, 5-12 membered substituted or unsubstituted aryl or heteroaryl wherein one or more heteroatoms are N, S or O; wherein the one or more substitutions are selected from the group consisting of H, deuterium, C1-C6 alkyl, C1-C6 oxyalkyl, halogen, optionally deuterated C1-C6 alkyl, and cyano.

19. The compound of claim 1, wherein RBis selected from the group consisting of hydrogen, deuterium, halogen, -CN, C1-6 alkyl, C1-6 haloalkyl, or C1-6 deuteroalkyl.

20. The compound of claim 1, wherein RBis H.

21. The compound of claim 1, wherein RA1and RA2are independently selected from the group consisting of alkyl, oxyalkyl, hydrogen, =O, halogen, morpholine and pyridine.

22. The compound of claim 1, wherein RA1is oxyalkyl.

23. The compound of claim 1, wherein RA1is -OCH3.

24. The compound of claim 1, wherein RA1and RA2are independently monocyclic or bicyclic heterocycloalkyl or heteroaryl containing at least one nitrogen, sulfur or oxygen.

25. The compound of claim 1, wherein RA1and RA2are independently substituted or unsubstituted morpholine, 1,4-oxazepane, piperazine, piperidine, pyridine, or pyridazine.

26. The compound of claim 1, wherein RA1and RA2are independently selected from the group consisting of hydrogen, hydroxyl, deuterium, fluoro, chloro, =O, -OCH3, -OCHF2,Patent Application -O-cyclopropyl, substituted or unsubstituted pyridine, substituted or unsubstituted azetidine, substituted or unsubstituted oxetane, substituted or unsubstituted morpholine, - CH2-cyclopropyl, -O-CH2-CH3, -CH2-O-CH3, -OCF3, -OCH2CF3, -OCH2-cyclopropyl, ,, and 27.atom link in L is selected from the group consisting of -CRL1RL2, NRL1, O, and S.

28. The compound of claim 1, wherein L comprises between 2 and 8 atom links are -CRL1RL2and between 0 and 2 atom links are NRL1, O, and S.

29. The compound of claim 1, wherein L comprises between 1 and 7 atom links are -CRL1RL2and between 0 and 2 atom links are NRL1, O, and S.

30. The compound of claim 1, wherein L comprises between 1 and 6 atom links are -CRL1RL2and between 0 and 2 atom links are NRL1, O, and S.

31. The compound of claim 1, wherein L comprises between 1 and 10 atom links are - CRL1RL2, and RL1and RL2at different or same atom combine to form an optionally substituted cycloalkyl or heterocycloalkyl.

32. The compound of claim 31, wherein the one or more substitutions are selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, alkoxy, or C1-C4 alkyl.Patent Application 33. The compound of claim 1, wherein L is selected from the group consisting of: , , , ,34. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein the compound is:Patent Application , ,Patent Application ,35. A pharmaceutical composition comprising a compound of any one of the claims 1-34, and a pharmaceutically acceptable carrier or diluent.

36. A method of inhibiting TYK2 activity in a subject in need thereof with a compound of any one of claims 1-34 or a pharmaceutical composition of claim 35.

37. A method of treating a TYK2-mediated disease or disorder comprising administering to a subject in need thereof a compound of any one of claims 1-34, or a pharmaceutical composition according to claim 35.

38. The method of claim 37, wherein the TYK2-mediated disease or disorder is an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a disorder associated with transplantation.

39. The method of claim 38, wherein the TYK2-mediated disease or disorder is multiple sclerosis.