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] 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, 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,

[0002] (I) wherein: X1and X2are independently CH or N; Y is CH2or NH; Z is CH2or NH; R1is alkyl or deuterated alkyl; R2is H, halo or alkyl; m and n are independently 1 or 2; RAis selected from the group consisting of: H, halo, oxyalkyl, substituted or unsubstituted alkyl or alkenyl, substituted or unsubstituted cycloalkyl or heterocycloalkyl, wherein the one or more substitutions are selected from the group consisting of H, alkyl, oxyalkyl, and halo; RBis H or substituted or unsubstituted alkyl; A is selected from the group consisting of 5 – 12 membered heterocycloalkyl, aryl, or heteroaryl ring, wherein said heterocycloalkyl, aryl, or heteroaryl rings are optionally fused, wherein the one or more heteroatoms in the heteroaryl ring are selected from the group consisting of N, O, or S; B is either absent or B is selected from the group consisting of C=O, C6-C10 aryl, or 5-10 membered heteroaryl comprising one more heteroatom, wherein the one or more heteroatom is N, O or S. L1is a linker, wherein L1is a bond, substituted or unsubstituted alkenyl, alkynyl, or alkyl; L2is a linker comprising 3 – 15 atom links, wherein each link is selected from the group consisting of -CRLRL’-, -NRL-, or -O-; wherein each RLand RL’are independently selected from the group consisting of: H, =O, alkyl, C3-C8cycloalkyl, C3-C8heterocycloalkyl, wherein the C3-C8cycloalkyl, C3-C8heterocycloalkyl may be fused with other links; and wherein RLand RL'on different atoms can be taken together to form C3-C10cycloalkyl or heterocycloalkyl rings. In certain embodiments, the compound is a compound of Formula (II): (II), wherein B, X1, X2, Y, Z, R1, R2, RA, RB, L2, m, and n are described above. In certain embodiments, the compound is a compound of Formula (III): (III) wherein B, X1, X2, Y, Z, R1, R2, RA, RB, L2, m, and n are described above. In certain embodiments, the compound is a compound of Formula (IV):

[0003] (IV) wherein B, X1, X2, Y, Z, R1, R2, RA, RB, L2, and n are described above. In certain embodiments, wherein the compound is a compound of Formula (V): (V) wherein A, B, X1, X2, Y, Z, R1, R2, RA, RB, L2, m, and n are described above. In certain embodiments, in the compounds of Formula (I), L1is selected from the groupconsisting of: single bond, -CH2-CH2-, -CH=CH-, and -C C-.In certain embodiments, in the compounds of Formula (I)-(V), R1is methyl or ethyl. In certain embodiments, in the compounds of Formula (I)-(V), Y is NH. In certain embodiments, in the compounds of Formula (I)-(V), Y is NH and R1is methyl. In certain embodiments, in the compounds of Formula (I)-(V), B is absent. In certain embodiments, in the compounds of Formula (I)-(V), Z is NH. In certain embodiments, in the compounds of Formula (I)-(V), X1and X2are CH. In certain embodiments, in the compounds of Formula (I)-(V), X1is CH and X2is N. In certain embodiments, in the compounds of Formula (I)-(V), X1is N and X2is CH. In certain embodiments, in the compounds of Formula (I)-(V), B is pyridine. In certain embodiments, in the compounds of Formula (I)-(V), B is pyrimidine. In certain embodiments, in the compounds of Formula (I)-(V), RAis selected from the group consisting of: H, F, -CH3, -CH2CH=CH2, -OCH3, -CH2-azetidine, -CH2-azetidine- O-CH3, and -CH2-morpholine. In certain embodiments, in the compounds of Formula (I)-(V), RAis -OCH3. In certain embodiments, in the compounds of Formula (I)-(V), RAis methyl. In certain embodiments, in the compounds of Formula (I)-(V), the links in L2are selected from the group consisting of -O-, -C(O)-, -C(O)NRL-, and -CH2-. In certain embodiments, in the compounds of Formula (I)-(V), RLis selected from the group consisting of H, =O, -CH3, and cyclopropyl. In certain embodiments, in the compounds of Formula (I)-(V), R2is H. In certain embodiments, the compound is selected from the group consisting of:

[0004]

[0005] 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, 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. 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, 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) – (V), 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) – (V), 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) – (V), 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. 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 (“C1–10alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1–9alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C1–8alkyl”). 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 (“C1–5alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C1–4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1–3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1–2alkyl”). In some embodiments, an alkyl group has 1 carbon atom ("C1alkyl"). 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 (“heteroC1-6alkyl”). 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 (“heteroC1-4alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom (“heteroC1-3 alkyl”). 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 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) (“C2-20alkenyl”). 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 (“C2-9alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C2-8alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C2-7alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2-6 alkenyl”). 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 (“C2-4alkenyl”). 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 C2-4alkenyl 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 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 (“heteroC2-8alkenyl”). 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 (“heteroC2-6alkenyl”). 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 (“heteroC2-4alkenyl”). 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 example, 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, N3or NO2groups. Examples are a piperidinyl, 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, N3or NO2groups. 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, NH2or NO2groups. 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, 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 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 (“C3-10carbocyclyl”) and zero heteroatoms in the nonaromatic ring system. In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms 10 (“C3-8 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“C3-7carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6carbocyclyl”). 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 one or more substituents. In certain embodiments, the carbocyclyl group is unsubstituted C3-10carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C3-10carbocyclyl. In some embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 10 ring carbon atoms (“C3-10cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C3-8cycloalkyl”). 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 C3-6cycloalkyl groups include the aforementioned C5-6cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3-8 cycloalkyl 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 C3-10cycloalkyl. 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 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 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 C6aryl 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, N3and NO2groups. Optional substituents also include C1-C10alkyl, C2-C10alkenyl, C1-C10heteroalkyl, C3-C16cycloalkyl, C2-C17 heterocycloalkyl, C4-C20 alkylcycloalkyl, C2-C19 heteroalkylcycloalkyl, C6-C18 aryl, C1-17 heteroaryl, C7-C20 aralkyl or C2-C19 heteroaralkyl, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 heteroalkyl, C3-C10cycloalkyl, C2-C9heterocycloalkyl, C7-C12alkylcycloalkyl, C2-C11heteroalkylcycloalkyl, 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, C1-4alkyl, C1-4heteroalkyl 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. 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(O)Raa, -CO2H, -CHO, -C(ORcc)2, -CO2Raa, -OC(O)Raa, -OCO2Raa, -C(O)N(Rbb)2, -C(O)N(Raa)(Rbb), - OC(O)N(Rbb)2, -NRbbC(O)Raa, -NRbbCO2Raa, -NRbbC(O)N(Rbb)2, -C(NRbb)Raa, -C(NRbb)ORaa, - OC(NRbb)Raa, -OC(NRbb)ORaa, -C(NRbb)N(Rbb)2, -OC(NRbb)N(Rbb)2, - NRbbC(NRbb)N(Rbb)2, - C(O)NRbbSO2Raa, -NRbbSO2Raa, -SO2N(Rbb)2, -SO2Raa, -SO2ORaa, - OSO2Raa, -S(O)Raa, e.g.,- S(O)Raa, -OS(O)Raa, -Si(Raa)3, -OSi(Raa)3-C(S)N(Rbb)2, - C(O)SRaa, -C(S)SRaa, -SC(S)SRaa, - SC(O)SRaa, -OC(O)SRaa, -SC(O)ORaa, -SC(O)Raa, -P(O)2Raa, -OP(O)2Raa, -P(O)(Raa)2, - OP(O)(Raa)2, -OP(O)(ORcc)2, -P(O)2N(Rbb)2, - OP(O)2N(Rbb)2, -P(O)(NRbb)2, -OP(O)(NRbb)2, - NRbbP(O)(ORcc)2, -NRbbP(O)(NRbb)2, - P(Rcc)2, -P(Rcc)3, -OP(Rcc)2, -OP(Rcc)3, -B(Raa)2, -B(ORcc)2, -BRaa(ORcc), C1-10alkyl, C1-10haloalkyl, C2-10alkenyl, C3-10carbocyclyl, 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, C2-10alkenyl, C3-10cycloalkyl, C3-10cycloheteroalkyl, C3-10cycloalkenyl, C3-10cycloheteroalkenyl, 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, 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, C1-10alkyl, C1-10heteroalkyl, C1-10haloalkyl, C2-10alkenyl, C3-10cycloalkyl, C3-10cycloheteroalkyl, C3-10cycloalkenyl, C3-10cycloheteroalkenyl, C3-10carbocyclyl, 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, C2-10alkenyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, 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(O)Ree, -CO2H, -CO2Ree, -OC(O)Ree, -OCO2Ree, -C(O)N(Rff)2, -OC(O)N(Rff)2, - NRffC(O)Ree, - NRffCO2Ree, -NRffC(O)N(Rff)2, -C(NRff)ORee, -OC(NRff)Ree, - OC(NRff)ORee, -C(NRff)N(Rff)2, - OC(NRff)N(Rff)2, -NRffC(NRff)N(Rff)2,- NRffSO2Ree, -SO2N(Rff)2, -SO2Ree, -SO2ORee, -OSO2Ree, -S(O)Ree, e.g.,-S(O)Rcc, - Si(Ree)3, -OSi(Ree)3, -C(S)N(Rff)2, -C(O)SRee, -C(S)SRee, -SC(S)SRee, - P(O)2Ree, -P(O)(Ree)2, -OP(O)(Ree)2, -OP(O)(ORee)2, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, 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, C2-6 alkenyl, C3-10carbocyclyl, 3-10 membered heterocyclyl, C6-10aryl, 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; each instance of Rffis, independently, selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C2-6alkenyl, C3-10carbocyclyl, 3-10 membered heterocyclyl, C6-10aryl, 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, -SC1-6alkyl, -SS(C1-6alkyl), -C(O)(C1-6alkyl), -CO2H, -CO2(C1-6alkyl), -OC(O)(C1-6alkyl), -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(C1-6alkyl), -C(NH)NH2, -OC(NH)N(C1-6alkyl)2, - OC(NH)NH(C1-6alkyl), - 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(C1-6alkyl)3, -OSi(C1-6alkyl)3- C(S)N(C1-6alkyl)2, C(S)NH(C1-6alkyl), C(S)NH2, -C(O)S(C1-6alkyl), -C(S)SC1-6alkyl, -SC(S)SC1-6alkyl, -P(O)2(C1-6alkyl), -P(O)(C1-6alkyl)2, -OP(O)(C1-6alkyl)2, -OP(O)(OC1-6 alkyl)2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C3-10 carbocyclyl, 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 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 patirnts (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 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: X1and X2are independently CH or N; Y is CH2or NH; Z is CH2or NH; R1is alkyl or deuterated alkyl; R2is H, halo or alkyl; m and n are independently 1 or 2; RAis selected from the group consisting of: H, halo, oxyalkyl, substituted or unsubstituted alkyl or alkenyl, substituted or unsubstituted cycloalkyl or heterocycloalkyl, wherein the one or more substitutions are selected from the group consisting of H, alkyl, oxyalkyl, and halo; RBis H or substituted or unsubstituted alkyl; A is selected from the group consisting of 5 – 12 membered heterocycloalkyl, aryl, or heteroaryl ring, wherein said heterocycloalkyl, aryl, or heteroaryl rings are optionally fused, wherein the one or more heteroatoms in the heteroaryl ring are selected from the group consisting of N, O, or S; B is either absent or B is selected from the group consisting of C=O, C6-C10 aryl, or 5-10 membered heteroaryl comprising one more heteroatom, wherein the one or more heteroatom is N, O or S. L1is a linker, wherein L1is a bond, substituted or unsubstituted alkenyl, alkynyl, or alkyl; L2is a linker comprising 3 – 15 atom links, wherein each link is selected from the group consisting of -CRLRL’-, -NRL-, or -O-; wherein each RLand RL’are independently selected from the group consisting of: H, =O, alkyl, C3-C8cycloalkyl, C3-C8heterocycloalkyl, wherein the C3-C8cycloalkyl, C3-C8heterocycloalkyl may be fused with other links; and wherein RLand RL’on different atoms can be taken together to form C3-C10cycloalkyl or heterocycloalkyl rings. In certain embodiments, the compound is a compound of Formula (II): (II), wherein B, X1, X2, Y, Z, R1, R2, RA, RB, L2, m, and n are described above. In certain embodiments, the compound is a compound of Formula (III):

[0006] (III) wherein B, X1, X2, Y, Z, R1, R2, RA, RB, L2, m, and n are described above. In certain embodiments, the compound is a compound of Formula (IV): (IV) wherein B, X1, X2, Y, Z, R1, R2, RA, RB, L2, and n are described above. In certain embodiments, wherein the compound is a compound of Formula (V):

[0007] (V) wherein A, B, X1, X2, Y, Z, R1, R2, RA, RB, L2, m, and n are described above. In certain embodiments, in the compounds of Formula (I), L1is selected from the group consisting of: single bond, -CH2-CH2-, -CH=CH-, and -C≡C-. In certain embodiments, in the compounds of Formula (I)-(V), R1is methyl or ethyl. In certain embodiments, in the compounds of Formula (I)-(V), Y is NH. In certain embodiments, in the compounds of Formula (I)-(V), Y is NH and R1is methyl. In certain embodiments, in the compounds of Formula (I)-(V), B is absent. In certain embodiments, in the compounds of Formula (I)-(V), Z is NH. In certain embodiments, in the compounds of Formula (I)-(V), X1and X2are CH. In certain embodiments, in the compounds of Formula (I)-(V), X1is CH and X2is N. In certain embodiments, in the compounds of Formula (I)-(V), X1is N and X2is CH. In certain embodiments, in the compounds of Formula (I)-(V), B is pyridine. In certain embodiments, in the compounds of Formula (I)-(V), B is pyrimidine. In certain embodiments, in the compounds of Formula (I)-(V), RAis selected from the group consisting of: H, F, -CH3, -CH2CH=CH2, -OCH3, -CH2-azetidine, -CH2-azetidine- O-CH3, and -CH2-morpholine. In certain embodiments, in the compounds of Formula (I)-(V), RAis -OCH3. In certain embodiments, in the compounds of Formula (I)-(V), RAis methyl. In certain embodiments, in the compounds of Formula (I)-(V), the links in L2are selected from the group consisting of -O-, -C(O)-, -C(O)NRL-, and -CH2-. In certain embodiments, in the compounds of Formula (I)-(V), RLis selected from the group consisting of H, =O, -CH3, and cyclopropyl. In certain embodiments, in the compounds of Formula (I)-(V), R2is H. In certain embodiments, the compound is selected from the group consisting of:

[0008]

[0009] 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. 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, 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. 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, 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) – (V), 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) – (V), 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) – (V), 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. 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. 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 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 (-OPO3 or -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. 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 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) 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), 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. 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 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. 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 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 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, 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 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; 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). The method may include using a composition of the invention to diagnose a disease, disorder, or condition in a subject. For example, a radiolabeled form of a compound may be used a tracer in positron emission tomography (PET) to identify anatomical locations of aberrant kinase activity. PET is known in the art and described in, for example, Wadsak Wolfgang, Mitterhauser Markus (2010), "Basics and principles of radiopharmaceuticals for PET / CT", European Journal of Radiology, 73 (3): 461–469. doi:10.1016 / j.ejrad.2009.12.022; Bailey, D.L; D.W. Townsend; P.E. Valk; M.N. Maisey (2005), Positron Emission Tomography: Basic Sciences. Secaucus, NJ: Springer-Verlag, ISBN 1-85233-798-2; and Carlson, Neil (January 22, 2012). Physiology of Behavior. Methods and Strategies of Research, 11th edition, Pearson, p.151, ISBN 0205239390, the contents of each of which are incorporated herein by reference. The invention may include administering one or more compositions of the invention for both diagnostic and therapeutic purposes. Examples: Example 1: N-methyl-9,15,33-trioxa-3,21,23,27,31-pentazahexacyclo [20.6.2.12,5.14,8.116,20.025,29]tritriaconta-1(28),2,4,6,8(32),16(31),17,19,22 (30),23,25(29),26- dodecaen-26-amine Step 1: Synthesis of 5-((6-bromopyridin-2-yl)oxy)pentan-1-ol To a solution of pentane-1,5-diol (881 mg, 8.46 mmol) in DMF (15 mL) was added NaH (405 mg, 10.1 mmol, 60% purity in mineral oil) at 0 ℃ over 10 min. After addition, the mixture was stirred at this temperature for 30 min, and then 2,6-dibromopyridine (2.0 g, 8.44 mmol) in DMF (5.0 mL) was added dropwise at 0 ℃. The resulting mixture was stirred at 80 ℃ for 1 h. The reaction mixture was quenched with water (50 mL) at 0 ℃, and then extracted with EtOAc (60 mL × 3). The combined organic layers were washed with brine (100 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 0~45%, flow rate = 30 mL / min, 254 nm). The desired product 5-((6-bromopyridin- 2-yl)oxy)pentan-1-ol (920 mg, 37.7% yield) was obtained as a colorless oil. LCMS (ESI) m / z 260.0 [M+H]+. Step 2: Synthesis of 2-(6-((6-((5-hydroxypentyl)oxy)pyridin-2-yl)amino)-1-(methylamino)- 2,7-naphthyridin-4-yl)benzo[d]oxazol-5-ol

[0010] To a mixture of 2-[6-amino-1-(methylamino)-2,7-naphthyridin-4-yl]-1,3-benzoxazol-5-ol (300 mg, 0.976 mmol), 5-[(6-bromo-2-pyridyl)oxy]pentan-1-ol (381 mg, 1.46 mmol) in dioxane (25 mL) was added RockPhos Pd G3 (82 mg, 97.8 mmol), Cs2CO3 (795 mg, 2.44 mmol) and the mixture was stirred at 100 ℃ for 12 hr under N2 atmosphere. The resulting mixture was quenched with water (60 mL) and extracted with EtOAc (60 mL × 3). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 12 g AgelaFlash® Silica Flash Column, Dichloromethane / Methanol with Methanol from 0~12%, flow rate = 30 mL / min, 254 nm). The desired product 2-(6-((6-((5-hydroxypentyl)oxy)pyridin-2-yl)amino)-1- (methylamino)-2,7-naphthyridin-4-yl)benzo[d]oxazol-5-ol (190 mg, 24.0% yield) was obtained as a yellow solid. LCMS (ESI) m / z 487.2 [M+H]+. Step 3: Synthesis of 2-(6-((6-((5-chloropentyl)oxy)pyridin-2-yl)amino)-1-(methylamino)-2,7- naphthyridin-4-yl)benzo[d]oxazol-5-ol To a mixture of 2-[6-[[6-(5-hydroxypentoxy)-2-pyridyl]amino]-1-(methylamino)-2,7- naphthyridin-4-yl]-1,3-benzoxazol-5-ol (190 mg, 0.195 mmol) in toluene (10 mL) was added SOCl2 (1.56 g, 13.1 mmol) and the mixture was stirred at 50 ℃ for 1 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by flash chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Dichloromethane / Methanol with Methanol from 0~10%, Flow Rate: 30 mL / min, 254 nm). The desired product 2-(6-((6-((5-chloropentyl)oxy)pyridin-2-yl)amino)-1-(methylamino)-2,7- naphthyridin-4-yl)benzo[d]oxazol-5-ol (170 mg, 86.2% yield) was obtained as a yellow solid. LCMS (ESI) m / z 505.2 [M+H]+. Step 4: Synthesis of the title compound (Example 1): N-methyl-9,15,33-trioxa-3,21,23,27,31- pentazahexacyclo[20.6.2.12,5.14,8.116,20.025,29]tritriaconta-1(28),2,4,6,8(32),16(31),17,19, 22(30),23,25(29),26-dodecaen-26-amine To a solution of 2-[6-[[6-(5-chloropentoxy)-2-pyridyl]amino]-1-(methylamino)-2,7-naphthyridin- 4-yl]-1,3-benzoxazol-5-ol (100 mg, 0.198 mmol) in DMF (20 mL) was added Cs2CO3(161 mg, 0.494 mmol) and the mixture was stirred at 80 ℃ for 1 h. The resulting mixture was quenched with water (60 mL) and extracted with EtOAc (60 mL × 3). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 4 g AgelaFlash® Silica Flash Column, Dichloromethane / Methanol with Methanol from 0~6%, flow rate =30 mL / min, 254 nm) and then 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% HCl (v%); Mobile phase B: ACN; Gradient: B from 25% to 55% in 8 min, hold 100% B for 2 min; Flow Rate: 25 mL / min; Column Temperature: 30 ℃; Wavelength: 220 nm). The desired product N-methyl-9,15,33-trioxa-3,21,23,27,31- pentazahexacyclo[20.6.2.12,5.14,8.116,20.025,29]tritriaconta- 1(28),2,4,6,8(32),16(31),17,19,22(30),23,25(29),26-dodecaen-26-amine (24.5 mg, 26.4% yield) was obtained as a yellow solid. LCMS (ESI) m / z 469.0 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ ppm 10.59 (br s, 1 H), 10.47 (s, 1 H), 9.73 (s, 1 H), 9.69 (s, 1 H), 8.32 (s, 1 H), 7.65 - 7.74 (m, 2 H), 7.48 (d, J = 2.3 Hz, 1 H), 7.05 (dd, J = 8.8, 2.4 Hz, 1 H), 6.86 (d, J = 7.9 Hz, 1 H), 6.49 (d, J = 8.0 Hz, 1 H), 4.32 (br t, J = 5.3 Hz, 2 H), 4.03 (br t, J = 5.0 Hz, 2 H), 3.23 (d, J = 4.5 Hz, 3 H), 1.73 - 1.84 (m, 4 H), 1.59 - 1.68 (m, 2 H). Example 2: N-methyl-9,12,15,33-tetraoxa-3,21,23,27,31-pentazahexacyclo[20.6.2. 12,5.14,8.116,20.025,29]tritriaconta-1(28),2,4,6,8(32),16(31),17,19,22(30),23,25(29),26- dodecaen-26-amine Step 1: Synthesis of 2-(2-((6-bromopyridin-2-yl)oxy)ethoxy)ethan-1-ol To a solution of 6-bromopyridin-2-ol (2 g, 11.5 mmol), 2-(2-hydroxyethoxy)ethanol (1.34 g, 12.6 mmol) and PPh3(4.52 g, 17.2 mmol) in THF (20 mL) was added dropwise DIAD (2.79 g, 13.8 mmol) at 0 °C. After addition, the mixture was stirred at 0 °C for 10 min, and stirred at 20 °C for 12 hr. The mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL ´ 3). Thecombined organic phase was washed with brine (30 mĹ 3), 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 = 40 mL / min, 254 nm) to afford 2-(2-((6-bromopyridin-2-yl)oxy)ethoxy)ethan-1-ol (1.2 g, 39.8% yield) as a colorless oil. LCMS (ESI) m / z 264.0262.0 [M+H]+. Step 2: Synthesis of 2-(6-((6-(2-(2-hydroxyethoxy)ethoxy)pyridin-2-yl)amino)-1- (methylamino)-2,7-naphthyridin-4-yl)benzo[d]oxazol-5-ol

[0011] A mixture of 2-[2-[(6-bromo-2-pyridyl)oxy]ethoxy]ethanol (511 mg, 1.95 mmol), 2-[6-amino-1- (methylamino)-2,7-naphthyridin-4-yl]-1,3-benzoxazol-5-ol (500 mg, 1.63 mmol), RockPhos Pd G3 (150 mg, 0.179 mmol) and Cs2CO3 (1.33 g, 4.07 mmol) in dioxane (10 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 100 °C for 12 h under nitrogen atmosphere. The mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, DCM / MeOH with MeOH from 0~10%, flow rate = 40 mL / min, 254 nm) to afford 2-(6-((6-(2-(2- hydroxyethoxy)ethoxy)pyridin-2-yl)amino)-1-(methylamino)-2,7-naphthyridin-4- yl)benzo[d]oxazol-5-ol (180 mg, 22.7% yield) as a yellow solid. LCMS (ESI) m / z 489.0 [M+H]+. Step 3: Synthesis of 2-(6-((6-(2-(2-chloroethoxy)ethoxy)pyridin-2-yl)amino)-1- (methylamino)-2,7-naphthyridin-4-yl)benzo[d]oxazol-5-ol A mixture of 2-[6-[[6-[2-(2-hydroxyethoxy)ethoxy]-2-pyridyl]amino]-1-(methylamino)-2,7- naphthyridin-4-yl]-1,3-benzoxazol-5-ol (100 mg, 0.21 mmol) and toluene (5 mL) / SOCl2 (1 mL) was degassed and purged with nitrogen 3 times, and then the mixture was stirred at 50 °C for 1.5 h under nitrogen atmosphere. The mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, DCM / MeOH with MeOH from 0~20%, flow rate = 40 mL / min, 254 nm) to afford 2-(6-((6-(2-(2- chloroethoxy)ethoxy)pyridin-2-yl)amino)-1-(methylamino)-2,7-naphthyridin-4- yl)benzo[d]oxazol-5-ol (80 mg, crude) as a yellow solid. LCMS (ESI) m / z 507.0 [M+H]+. Step 4: Synthesis of the title compound (Example 2): N-methyl-9,12,15,33-tetraoxa- 3,21,23,27,31-pentazahexacyclo[20.6.2.12,5.14,8.116,20.025,29]tritriaconta- 1(28),2,4,6,8(32),16(31), 17,19,22(30),23,25(29),26-dodecaen-26-amine A mixture of 2-[6-[[6-[2-(2-chloroethoxy)ethoxy]-2-pyridyl]amino]-1-(methylamino)-2,7- naphthyridin-4-yl]-1,3-benzoxazol-5-ol (80 mg, 0.158 mmol) and Cs2CO3(154 mg, 0.473 mmol) in DMF (6 mL) was degassed and purged with nitrogen 3 times, and then the mixture was stirred at 80 °C for 2 h under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (Instrument: Gilson GX-281 Liquid Handler, Gilson 322 Pump, Gilson 156 UV Detector; Column:Phenomenex Gemini-C18 ´ 75 ´40 mḿ 3 um; Mobile phase A: [water(FA)-ACN];Mobile phase B: MeCN; Gradient: B from 25%to 55% in 8 min, hold 100% B for 2 min; Flow Rate: 25 mL / min; Column Temperature: 30 °C; Wavelength: 220 nm) to afford N-methyl-9,12,15,33-tetraoxa-3,21,23,27,31- pentazahexacyclo[20.6.2.12,5.14,8.116,20.025,29]tritriaconta- 1(28),2,4,6,8(32),16(31),17,19,22(30),23,25(29),26-dodecaen-26-amine (35 mg, 47.1% yield) as a yellow solid. LCMS (ESI) m / z 471.0 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ ppm 9.99 (s, 1H), 9.88 (s, 1H), 9.36 (s, 1H), 8.84 (s, 1H), 8.50 (br d, J = 4.5 Hz, 1H), 7.95 (d, J = 2.3 Hz, 1H), 7.64 (t, J = 8.0 Hz, 1H), 7.57 (d, J = 8.8 Hz, 1H), 6.91 (dd, J = 8.7, 2.4 Hz, 1H), 6.82 (d, J = 7.8 Hz, 1H), 6.40 (d, J = 8.0 Hz, 1H), 4.39 (br d, J = 2.8 Hz, 2H), 4.14 - 4.24 (m, 2H), 3.77 - 3.86 (m, 2H), 3.63 - 3.71 (m, 2H), 3.07 (d, J = 4.5 Hz, 3H). Example 3: N-methyl-10,14,31-trioxa-3,20,22,26,30-pentazahexacyclo [19.6.2.12,5.115,19.04,9.024,28]hentriaconta-1(27),2,4,6,8,15(30),16, 18,21(29),22,24(28),25- dodecaen-25-amine Step 1: Synthesis of benzo[d]oxazol-4-ol To a solution of 2-aminobenzene-1,3-diol (5 g, 40.0 mmol) in trimethoxymethane (20 mL) was degassed and purged several times with N2. The mixture was stirred at 100 °C for 2 h under N2atmosphere. The reaction mixture was concentrated under reduced pressure and purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Petroleum ether / Ethyl acetate with Ethyl acetate from 0~30%, flow rate = 80 mL / min, 254 nm) to afford 1,3-benzoxazol- 4-ol (4.1 g, 75.9% yield) as a brown solid. LCMS (ESI) m / z 135.8 [M+H]+. Step 2: Synthesis of 4-((4-methoxybenzyl)oxy)benzo[d]oxazole A mixture of 1,3-benzoxazol-4-ol (2 g, 14.8 mmol), PMB-Cl (2.76 g, 17.6 mmol), K2CO3 (5.1 g, 36.9 mmol) in DMF (20 mL) was degassed and purged several times with N2 for 3 times. The mixture was stirred at 20 °C for 12 h under N2atmosphere. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (60 mL×3). The combined organic layers were washed with brine (20 mL×4), dried over Na2SO4, filtered and concentrated under reduced pressure and purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, DCM / Methanol with Methanol from 0~10%, flow rate = 80 mL / min, 254 nm) to afford 4-[(4- methoxyphenyl)methoxy]-1,3-benzoxazole (3.8 g, 96.5% yield) as a brown solid. LCMS (ESI) m / z 255.8 [M+H]+. Step 3: Synthesis of N-(5-(4-((4-methoxybenzyl)oxy)benzo[d]oxazol-2-yl)-8-(methylamino)- 2,7-naphthyridin-3-yl)cyclopropanecarboxamide A mixture of N-[5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl]cyclopropanecarboxamide (500 mg, 1.56 mmol), 4-[(4-methoxyphenyl)methoxy]-1,3-benzoxazole (440 mg, 1.72 mmol), K3PO4(830 mg, 3.91 mmol), Pd(PPh3)4(180 mg, 0.156 mmol) in DMF (4 mL) was degassed and purged with N2 for several times, and then the mixture was stirred at 120 °C for 3 h under N2 atmosphere using a microwave tube. After completion, the reaction mixture was diluted with water (50 mL) and extracted with DCM mL (30 mL×3). The combined organic layers were washed with brine (50 mL×3), dried over Na2SO4, filtered and concentrated under reduced pressure and purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Petroleum ether / Ethyl acetate with Ethyl acetate from 0~70%, flow rate = 80 mL / min, 254 nm) to afford N- [5-[4-[(4-methoxyphenyl)methoxy]-1,3-benzoxazol-2-yl]-8-(methylamino)-2,7-naphthyridin-3- yl]cyclopropanecarboxamide (750 mg, 97.2% yield) as a light yellow solid. LCMS (ESI) m / z 496.0 [M+H]+. Step 4: Synthesis of 4-(4-((4-methoxybenzyl)oxy)benzo[d]oxazol-2-yl)-N1-methyl-2,7- naphthyridine-1,6-diamine A mixture of N-[5-[4-[(4-methoxyphenyl)methoxy]-1,3-benzoxazol-2-yl]-8-(methylamino)-2,7- naphthyridin-3-yl]cyclopropanecarboxamide (750 mg, 1.51 mmol) and NaOH (600 mg, 15 mmol) in MeOH (20 mL), H2O (2 mL) and DMSO (2 mL) under N2.The reaction mixture was stirred at 80 °C for 12 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure and freeze-dried and washed with water (500 mL) to afford 4-[4-[(4- methoxyphenyl)methoxy]-1,3-benzoxazol-2-yl]-N1-methyl-2,7-naphthyridine-1,6-diamine (650 mg, 94.4% yield) as a yellow solid. LCMS (ESI) m / z 428.0 [M+H]+. Step 5: Synthesis of 2-[6-amino-1-(methylamino)-2,7-naphthyridin-4-yl]-1,3-benzoxazol-4-ol A mixture of 4-[4-[(4-methoxyphenyl)methoxy]-1,3-benzoxazol-2-yl]-N1-methyl-2,7- naphthyridine-1,6-diamine (250 mg, 0.585 mmol) and HBr (8 mL, 70.7 mmol, 48% purity) was degassed and purged with nitrogen 3 times. The mixture was stirred at 20 °C for 1.5 h under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (Instrument: Gilson GX-281 Liquid Handler, Gilson 322 Pump, Gilson 156 UV Detector; Column:Phenomenex Gemini-C18 ´ 75 ´ 40 mm ´ 3 um; Mobile phase A: [water(NH3-H2O)-ACN];Mobile phase B: MeCN; Gradient: B from 30% to 35% in 8 min, hold 100% B for 2 min; Flow Rate: 25 mL / min; Column Temperature: 30 °C; Wavelength: 220 nm) to afford 2-[6-amino-1-(methylamino)-2,7-naphthyridin-4-yl]-1,3-benzoxazol-4-ol (100 mg, 55.6% yield) as a yellow solid. LCMS (ESI) m / z 307.9 [M+H]+. Step 6: Synthesis of 2-[6-[[6-(3-hydroxypropoxy)-2-pyridyl]amino]-1-(methylamino)-2,7- naphthyridin-4-yl]-1,3-benzoxazol-4-ol A mixture of 2-[6-amino-1-(methylamino)-2,7-naphthyridin-4-yl]-1,3-benzoxazol-4-ol (110 mg, 0.358 mmol), 3-[(6-bromo-2-pyridyl)oxy]propan-1-ol (126 mg, 0.543 mmol), RockPhos Pd G3 (33 mg, 0.039 mmol) and Cs2CO3(292 mg, 0.896 mmol) in dioxane (3 mL) was degassed and purged with nitrogen. The mixture was stirred at 100 °C for 12 h under nitrogen atmosphere. The mixture was diluted with water (50 mL) and extracted with DCM / IPA (3:1, 50 mL ´ 3). Thecombined organic phase was washed with brine (30 mĹ 3), dried over anhydrous Na2SO4, filtered,and concentrated under reduced pressure and purified by flash chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, DCM / MeOH with MeOH from 0~10%, flow rate = 40 mL / min, 254 nm) to afford 2-[6-[[6-(3-hydroxypropoxy)-2-pyridyl]amino]-1-(methylamino)-2,7- naphthyridin-4-yl]-1,3-benzoxazol-4-ol (70 mg, 42.7% yield) as a yellow solid. LCMS (ESI) m / z 459.0 [M+H]+. Step 7: Synthesis of 2-[6-[[6-(3-chloropropoxy)-2-pyridyl]amino]-1-(methylamino)-2,7- naphthyridin-4-yl]-1,3-benzoxazol-4-ol A mixture of 2-[6-[[6-(3-hydroxypropoxy)-2-pyridyl]amino]-1-(methylamino)-2,7-naphthyridin- 4-yl]-1,3-benzoxazol-4-ol (70 mg, 0.153 mmol) and toluene (5 mL, 46.9 mmol) / SOCl2 (1 mL, 13.8 mmol) was degassed and purged with nitrogen several times. The mixture was stirred at 50 °C for 2 h under nitrogen atmosphere. The mixture was concentrated under reduced pressure and purified by flash chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Petroleum ether / EtOAc with EtOAc from 0~70%, flow rate = 40 mL / min, 254 nm) to afford 2-[6-[[6-(3- chloropropoxy)-2-pyridyl]amino]-1-(methylamino)-2,7-naphthyridin-4-yl]-1,3-benzoxazol-4-ol (25 mg, 34.3% yield) as a yellow solid. LCMS (ESI) m / z 477.0 [M+H]+. Step 8: Synthesis of title compound (Example 3): N-methyl-10,14,31-trioxa-3,20,22,26,30- pentazahexacyclo[19.6.2.12,5.115,19.04,9.024,28]hentriaconta- 1(27),2,4,6,8,15(30),16,18,21(29),22,24(28),25-dodecaen-25-amine

[0012] The compound was synthesized using a similar procedure that was previously described in Example 1 by using 3-[(6-bromo-2-pyridyl)oxy]propan-1-ol and 2-[6-amino-1-(methylamino)- 2,7-naphthyridin-4-yl]-1,3-benzoxazol-4-ol as the starting material. A mixture of 2-[6-[[6-(3-chloropropoxy)-2-pyridyl]amino]-1-(methylamino)-2,7- naphthyridin-4-yl]-1,3-benzoxazol-4-ol (45 mg, 0.094 mmol), and Cs2CO3(95 mg, 0.292 mmol) in DMF (4 mL) was degassed and purged with nitrogen. The mixture was stirred at 80 °C for 2 h under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative HPLC (Instrument: Gilson GX- 281 Liquid Handler, Gilson 322 Pump, Gilson 156 UV Detector; Column:Phenomenex Gemini-C18́ 75́ 40 mḿ 3 um; Mobile phase A: [water(HCl)-ACN];Mobile phase B: MeCN; Gradient:B from 20% to 50% in 8 min, hold 100% B for 2 min; Flow Rate: 25 mL / min; Column Temperature: 30 °C; Wavelength: 220 nm) to afford N-methyl-10,14,31-trioxa-3,20,22,26,30- pentazahexacyclo[19.6.2.12,5.115,19.04,9.024,28]hentriaconta- 1(27),2,4,6,8,15(30),16,18,21(29),22,24(28),25-dodecaen-25-amine (37.5 mg, 90.2% yield) as a yellow solid. LCMS (ESI) m / z 441.2 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ ppm 10.64 (br d, J = 1.8 Hz, 1H), 10.56 (s, 1H), 9.76 (s, 1H), 9.67 - 9.72 (m, 1H), 8.46 (s, 1H), 7.68 (t, J = 7.9 Hz, 1H), 7.49 - 7.53 (m, 1H), 7.40 - 7.47 (m, 1H), 7.25 (d, J = 7.9 Hz, 1H), 6.81 (d, J = 7.9 Hz, 1H), 6.49 (d, J = 8.0 Hz, 1H), 4.69 (br t, J = 5.2 Hz, 2H), 4.50 (br t, J = 5.2 Hz, 2H), 3.23 - 3.28 (m, 3H), 1.76 - 1.86 (m, 2H). Example 4: (Z)-N,7-dimethyl-5,8,11-trioxa-3-aza-1(2,5)-benzo[d]oxazola-2(5,3)- naphthyridina-4(2,6)-pyridinacycloundecaphan-28-amine Step 1: Synthesis of 1-(2-(benzyloxy)ethoxy)propan-2-ol A mixture of 2-benzyloxyethanol (10 g, 65.7 mmol), 2-methyloxirane (1.91 g, 32.8 mmol), diethyloxonio(trifluoro) boranuide (46.6 mg, 328 μmol) in DCM (100 mL) was degassed and purged with N2. The mixture was stirred at 0°C for 1 h under N2atmosphere. DCM was evaporated. The residue was purified by prep-HPLC (column: C18 150 × 40 mm; mobile phase: [water (NH3H2O+NH4HCO3)-ACN]; gradient:11% - 51% B over 9 min) to give 1-(2- benzyloxyethoxy)propan-2-ol (4 g, 57.9% yield) as a colorless oil.1H NMR (400 MHz, CDCl3) δ ppm 7.22 - 7.48 (m, 5H), 4.66 (s, 2H), 3.78 - 4.09 (m, 1H), 3.56 - 3.78 (m, 5H), 3.44 - 3.55 (m, 1H), 1.15 (m, 3H); LCMS (ESI) m / z 211.3 [M+H]+. Step 2: Synthesis of 1-(2-hydroxyethoxy)propan-2-ol To a mixture of 1-(2-benzyloxyethoxy)propan-2-ol (2 g, 9.51 mmol) in MeOH (50 mL) was added Pd / C (1.01 g, 951 μmol,10 wt. % loading ) under H2. The suspension was degassed under vacuum and purged with H2several times. The mixture was stirred under H2(19.2 mg, 9.51 mmol) at 25°C for 16 h. The reaction mixture was filtered and the filter was concentrated to give 1-(2- hydroxyethoxy)propan-2-ol (700 mg, 61.2% yield) as a yellow solid.1H NMR (400 MHz, DMSO- d6) δ ppm 4.51 - 4.64 (m, 2H), 3.65 - 3.78 (m, 1H), 3.40 - 3.52 (m, 4H), 3.17 - 3.29 (m, 2H), 0.97 - 1.10 (m, 3H). Step 3: Synthesis of 7-bromo-5-methyl-1H-benzotriazole A mixture of 1-(2-hydroxyethoxy)propan-2-ol (200 mg, 1.66 mmol), 2,6-dibromopyridine (394 mg, 1.66 mmol), NaH (73.2 mg, 1.83 mmol, 60% dispersion in mineral oil) in DMF (10 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 25°C for 2 h under N2atmosphere. DMF was evaporated. 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 @ 20 mL / min) to provide 1-[2-[(6-bromo-2-pyridyl)oxy]ethoxy]propan-2-ol (100 mg, 21.7% yield) as a white solid. LCMS (ESI) m / z 275.9 / 277.9 [M+H]+. Step 4: Synthesis of N-(5-(5-methoxybenzo[d]oxazol-2-yl)-8-(methylamino)-2,7- naphthyridin-3-yl)cyclopropanecarboxamide A mixture of N-[5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl]cyclopropane-carboxamide (4 g, 12.4 mmol), 5-methoxy-1,3-benzoxazole (1.86 g, 12.4 mmol), Pd(PPh3)4(2.88 g, 2.49 mmol), Cs2CO3(12.2 g, 37.3 mmol) in DMF (10 mL) was degassed and purged several times with N2. The mixture was stirred at 110°C for 2 h under N2 atmosphere. The reaction mixture was added water and filtered to give N-(5-(5-methoxybenzo[d]oxazol-2-yl)-8-(methylamino)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide (2.2 g, 45.4% yield) as a yellow solid. LCMS (ESI) m / z 390.1 [M+H]+. Step 5: Synthesis of 4-(5-methoxybenzo[d]oxazol-2-yl)-N1-methyl-2,7-naphthyridine-1,6- diamine A mixture of N-(5-(5-methoxybenzo[d]oxazol-2-yl)-8-(methylamino)-2,7-naphthyridin-3-yl) cyclopropanecarboxamide (2.2 g, 5.65 mmol), NaOH (2.26 g, 56.50 mmol) in MeOH (40 mL) and H2O (14 mL) was degassed and purged with N2. The resulting mixture was stirred at 80°C for 32 h under N2atmosphere. The mixture was filtered and concentrated to give 4-(5- methoxybenzo[d]oxazol-2-yl)-N1-methyl-2,7-naphthyridine-1,6-diamine (1.8 g, 99.2% yield) as a white solid. LCMS (ESI) m / z 322.1 [M+H]+. Step 6: Synthesis of 2-(6-amino-1-(methylamino)-2,7-naphthyridin-4-yl)benzo[d]oxazol-5-ol A mixture of 4-(5-methoxy-1,3-benzoxazol-2-yl)-N1-methyl-2,7-naphthyridine-1,6-diamine (1 g, 3.11 mmol), BBr3 (3.90 g, 15.5 mmol) in DCM (10 mL) was stirred at 25°C for 2 h under N2 atmosphere. After completion, the reaction mixture was quenched with H2O (20 mL) at 0°C, then filtered to give 2-[6-amino-1-(methylamino)-2,7-naphthyridin-4-yl]-1,3-benzoxazol-5-ol (900 mg, 94.1% yield) as a yellow solid, LCMS (ESI) m / z 308.1 [M+H]+. Step 7: Synthesis of 2-(6-((6-(2-(2-hydroxypropoxy)ethoxy)pyridin-2-yl)amino)-1- (methylamino)-2,7-naphthyridin-4-yl)benzo[d]oxazol-5-ol

[0013] A mixture of 2-[6-amino-1-(methylamino)-2,7-naphthyridin-4-yl]-1,3-benzoxazol-5-ol (150 mg, 488 μmol), 1-[2-[(6-bromo-2-pyridyl) oxy] ethoxy] propan-2-ol (100 mg, 362 μmol), Cs2CO3 (477 mg, 1.46 mmol), E phos Pd G4(89.6 mg, 97.6 μmol) in dioxane (10 mL) was degassed and purged with N2.The mixture was stirred at 100°C for 16 h under N2atmosphere. The solvent was evaporated and the residue was purified by prep-HPLC (column: C18150 × 30 mm; mobile phase: [Water (HCl)-MeCN]; gradient:12% - 52% B over 9 min) to give 2-[6-[[6-[2-(2- hydroxypropoxy)ethoxy]-2-pyridyl]amino]-1-(methylamino)-2,7-naphthyridin-4-yl]-1,3- benzoxazol-5-ol (70 mg, 28.5% yield) as a white solid. LCMS (ESI) m / z 503.2 [M+H]+. Step 8: Synthesis of 2-(6-((6-(2-(2-chloropropoxy)ethoxy)pyridin-2-yl)amino)-1- (methylamino)-2,7-naphthyridin-4-yl)benzo[d]oxazol-5-ol A mixture of 2-[6-[[6-[2-(2-hydroxypropoxy)ethoxy]-2-pyridyl]amino]-1-(methylamino)-2,7- naphthyridin-4-yl]-1,3-benzoxazol-5-ol (70 mg, 139 μmol), SOCl2 (165 mg, 1.39 mmol) in toluene (2 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 70°C for 4 h under N2atmosphere. Toluene was evaporated to give 2-[6-[[6-[2-(2-chloropropoxy)ethoxy]- 2-pyridyl]amino]-1-(methylamino)-2,7-naphthyridin-4-yl]-1,3-benzoxazol-5-ol (70 mg, crude) as a white solid. LCMS (ESI) m / z 521.1 [M+H]+. Step 9: Synthesis of (Z)-N,7-dimethyl-5,8,11-trioxa-3-aza-1(2,5)-benzo[d]oxazola-2(5,3)- naphthyridina-4(2,6)-pyridinacycloundecaphan-28-amine

[0014] A mixture of 2-[6-[[6-[2-(2-chloropropoxy)ethoxy]-2-pyridyl]amino]-1-(methylamino)-2,7- naphthyridin-4-yl]-1,3-benzoxazol-5-ol (70 mg, 134 μmol), Cs2CO3 (131 mg, 403 μmol) in DMF (2 mL) was stirred at 80°C for 16 h under N2atmosphere. DMF was removed. The residue was purified by prep-HPLC (column: C18 150 × 30 mm; mobile phase: [Water (HCl)-MeCN]; gradient:16% - 56% B over 9 min) to give a crude mixture which was further purified by SFC (column: Phenomenex-Cellulose-2 (250 mm × 30 mm,10 μm); mobile phase: [CO2- MeOH(0.1%NH3H2O)]; B%: 50%, isocratic elution mode) to provide (Z)-N,7-dimethyl-5,8,11- trioxa-3-aza-1(2,5)-benzo[d]oxazola-2(5,3)-naphthyridina-4(2,6)-pyridinacycloundecaphan-28- amine (1 mg, 25% yield) as a white solid. LCMS (ESI) m / z 485.1 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ ppm 9.97 (s, 1H), 9.84 (s, 1H), 9.36 (s, 1H), 8.85 (s, 1H), 8.39 - 8.59 (m, 1H), 8.00 (d, J = 2.45 Hz, 1H), 7.64 (t, J = 8.01 Hz, 1H), 7.57 (d, J = 8.68 Hz, 1H), 6.90 (dd, J = 8.68, 2.45 Hz, 1H), 6.81 (d, J = 7.83 Hz, 1H), 6.41 (d, J = 7.95 Hz, 1H), 4.31 - 4.48 (m, 3H), 3.90 - 4.03 (m, 2H), 3.53 - 3.63 (m, 2H), 3.08 (d, J = 4.40 Hz, 3H), 1.10 (d, J = 6.24 Hz, 3H). Example 5: (Z)-N,6-dimethyl-5,8,11-trioxa-3-aza-1(2,5)-benzo[d]oxazola-2(5,3)- naphthyridina-4(2,6)-pyridinacycloundecaphan-28-amine Step 1: Synthesis of 2-((1-(2-(benzyloxy)ethoxy)propan-2-yl)oxy)-6-bromopyridine A mixture of 1-(2-benzyloxyethoxy)propan-2-ol (500 mg, 2.38 mmol), 2,6-dibromopyridine (619 mg, 2.62 mmol), NaH (142 mg, 3.57 mmol, 60% dispersion in mineral oil) in DMF (10 mL) was stirred at 0°C for 2 h under N2 atmosphere. DMF was removed. 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 @ 20 mL / min) to provide 2-((1-(2- (benzyloxy)ethoxy)propan-2-yl)oxy)-6-bromopyridine (500 mg, 57.4% yield) as a white solid. LCMS (ESI) m / z 366.3, 368.3 [M+H]+Step 2: Synthesis of 2-(6-((6-((1-(2-(benzyloxy)ethoxy)propan-2-yl)oxy)pyridin-2-yl)amino)- 1-(methylamino)-2,7-naphthyridin-4-yl)benzo[d]oxazol-5-ol A mixture of 2-((1-(2-(benzyloxy)ethoxy)propan-2-yl)oxy)-6-bromopyridine (357 mg, 976 μmol), 2-[6-amino-1-(methylamino)-2,7-naphthyridin-4-yl]-1,3-benzoxazol-5-ol (300 mg, 976 μmol), Cs2CO3 (954 mg, 2.93 mmol), Ephos (104 mg, 195 μmol) and Ephos Pd G4 (89.6 mg, 97.6 μmol) in dioxane (20 mL) was degassed and purged with N2for 3 times. The reaction mixture was stirred at 100°C for 16 h under N2atmosphere. The solvent was evaporated and the residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0 ~ 100% Ethyl acetate / Petroleum ethergradient @ 20 mL / min) to provide 2-(6-((6-((1-(2- (benzyloxy)ethoxy)propan-2-yl)oxy)pyridin-2-yl)amino)-1-(methylamino)-2,7-naphthyridin-4- yl)benzo[d]oxazol-5-ol (300 mg, 51.8% yield) as a brown solid. LCMS (ESI) m / z 593.2 [M+H]+Step 3: Synthesis of 2-(6-((6-((1-(2-hydroxyethoxy)propan-2-yl)oxy)pyridin-2-yl)amino)-1- (methylamino)-2,7-naphthyridin-4-yl)benzo[d]oxazol-5-ol A mixture of 2-(6-((6-((1-(2-(benzyloxy)ethoxy)propan-2-yl)oxy)pyridin-2-yl)amino)-1- (methylamino)-2,7-naphthyridin-4-yl)benzo[d]oxazol-5-ol (200 mg, 337 μmol), Pd / C (35.9 mg, 33.7 μmol, 10% purity), Pd(OH)2 (23.7 mg, 33.7 μmol, 20% purity) in MeOH (10 mL) was degassed and purged several times with nitrogen. The mixture was stirred at 25°C for 16 h under H2 atmosphere. The reaction mixture was filtered, concentrated and purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0 ~ 100% Ethyl acetate / Petroleum ether gradient @ 20 mL / min) to provide 2-(6-((6-((1-(2-hydroxyethoxy)propan- 2-yl)oxy)pyridin-2-yl)amino)-1-(methylamino)-2,7-naphthyridin-4-yl)benzo[d]oxazol-5-ol (40 mg, 23.6% yield) as a white solid. LCMS (ESI) m / z 503.1 [M+H]+Step 4: Synthesis of 2-[6-[[6-[2-(2-chloroethoxy)-1-methyl-ethoxy]-2-pyridyl]amino]-1- (methylamino)-2,7-naphthyridin-4-yl]-1,3-benzoxazol-5-ol A mixture of 2-[6-[[6-[2-(2-hydroxyethoxy)-1-methyl-ethoxy]-2-pyridyl]amino]-1- (methylamino)-2,7-naphthyridin-4-yl]-1,3-benzoxazol-5-ol (12 mg, 23.8 μmol) and SOCl2 (56.8 mg, 477 μmol) in toluene (2 mL) was degassed and purged with N2. The mixture was stirred at 80°C for 2 h under N2atmosphere. Upon completion, toluene was remove to provide 2-[6-[[6-[2- (2-chloroethoxy)-1-methyl-ethoxy]-2-pyridyl]amino]-1-(methylamino)-2,7-naphthyridin-4-yl]- 1,3-benzoxazol-5-ol (12 mg, crude) as a white solid. LCMS (ESI) m / z 521.1 [M+H]+Step 5: Synthesis of (Z)-N,6-dimethyl-5,8,11-trioxa-3-aza-1(2,5)-benzo[d]oxazola-2(5,3)- naphthyridina-4(2,6)-pyridinacycloundecaphan-28-amine

[0015] A mixture of 2-[6-[[6-[2-(2-chloroethoxy)-1-methyl-ethoxy]-2-pyridyl]amino]-1-(methylamino)- 2,7-naphthyridin-4-yl]-1,3-benzoxazol-5-ol (10 mg, 19.2 μmol), Cs2CO3 (18.7 mg, 57.6 μmol) in DMF (5 mL)was stirred at 80 °C for 12 h. The solvent was removed and the residue was purified by prep-HPLC (column: C18150 × 30 mm; mobile phase: [Water (NH4HCO3)-MeCN]; gradient: 48% - 68% B over 9 min) to give (Z)-N,6-dimethyl-5,8,11-trioxa-3-aza-1(2,5)-benzo[d]oxazola- 2(5,3)-naphthyridina-4(2,6)-pyridinacycloundecaphan-28-amine (1 mg, 10.75% yield) as a white solid. LCMS (ESI) m / z 485.2 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ ppm 9.95 (s, 1H), 9.67 (s, 1H), 9.37 (s, 1H), 8.78 (s, 1H), 8.45 - 8.54 (m, 1H), 7.94 (d, J = 2.50 Hz, 1H), 7.53 - 7.66 (m, 2H), 6.93 (dd, J = 8.69, 2.56 Hz, 1H), 6.75 (d, J = 8.00 Hz, 1H), 6.36 (d, J = 7.88 Hz, 1H), 4.84 - 4.95 (m, 1H), 4.61 (br dd, J = 13.95, 7.07 Hz, 1H), 4.24 (dd, J = 13.45, 5.07 Hz, 1H), 3.92 (dd, J = 12.88, 4.63 Hz, 1H), 3.60 - 3.68 (m, 1H), 3.47 - 3.54 (m, 1H), 3.08 (d, J = 4.38 Hz, 3H), 2.90 (br d, J = 8.50 Hz, 1H), 0.84 (d, J = 6.13 Hz, 3H). Example 6: N-methyl-10,15,32-trioxa-3,21,23,27,31- pentazahexacyclo[20.6.2.12,5.116,20.04,9.025,29]dotriaconta- 1(28),2,4,6,8,16(31),17,19,22(30),23,25(29),26-dodecaen-26-amine Step 1: Synthesis of 2-bromo-6-(4-chlorobutoxy)pyridine To a mixture of 6-bromopyridin-2-ol (500.00 mg, 2.87 mmol, 1 eq) in THF (10 mL) was added NaH (137.92 mg, 3.45 mmol, 60% dispersion in mineral oil, 1.2 eq) at 0°C. The mixture was stirred at 0°C for 30 min and 1,4-dichlorobutane (401.49 mg, 3.16 mmol, 1.1 eq) was added into the mixture. The mixture was stirred at 25°C for 16 h. The reaction mixture was quenched with H2O (20 mL) at 0 °C and extracted with EA (15 mL × 3). The combined organic layers were washed with brine 20 mL, dried over Na2SO4, filtered, and concentrated under reduced pressure and further purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~4% Ethyl acetate / Petroleum ether gradient @ 60 mL / min) to afford 2-bromo- 6-(4-chlorobutoxy)pyridine (732 mg, 47.66%) was obtained as a colorless oil. LCMS (ESI) m / z 263.6, 265.6 [M+H]+,1H NMR (400 MHz, CDCl3) δ ppm 7.44 (t, J = 7.8 Hz, 1H), 7.04 (d, J = 7.6 Hz, 1H), 6.68 (d, J = 8.2 Hz, 1H), 4.32 (t, J = 6.0 Hz, 2H), 3.64 (t, J = 6.0 Hz, 2H), 2.00 - 1.88 (m, 4H). Step 2: Synthesis of N-methyl-10,15,32-trioxa-3,21,23,27,31- pentazahexacyclo[20.6.2.12,5.116,20.04,9.025,29]dotriaconta- 1(28),2,4,6,8,16(31),17,19,22(30),23,25(29),26-dodecaen-26-amine To a mixture of 2-[6-amino-1-(methylamino)-2,7-naphthyridin-4-yl]-1,3-benzoxazol-4-ol (25 mg, 0.081 μmol, 1 eq) in dioxane (3 mL) was added 2-bromo-6-(4-chlorobutoxy)pyridine (32.28 mg, 0.122 mmol, 1.5 eq), Pd2(dba)3 (7.45 mg, 0.008 mmol, 0.1 eq), DavePhos (6.40 mg, 0.016 mmol, 0.2 eq) and Cs2CO3(79.52 mg, 0.244 mmol, 3 eq). The mixture was degassed and purged with N2three times. The resulting mixture was stirred at 110 °C for 12 h under N2atmosphere. The residue was diluted with H2O (10 mL) and extracted with EtOAc (15 mL × 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product mixture. This crude product mixture was further purified by flash chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Dichloromethane / Methanol with Methanol from 0~10%, 100 mL / min, 254nm / I2 / KMnO4 / PMA) to provide N-methyl-10,15,32-trioxa-3,21,23,27,31-pentazahexacyclo [20.6.2.12,5.116,20.04,9.025,29]dotriaconta-1(28),2,4,6,8,16(31),17,19,22(30),23,25(29),26- dodecaen-26-amine (6.14 mg, 15.71%) as a red solid. LCMS (ESI) m / z 455.4 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ ppm 9.81 (s, 1H), 9.36 (s, 1H), 9.11 (s, 1H), 8.91 (s, 1H), 8.50 (br d, J = 4.63 Hz, 1H), 7.59 (t, J = 7.8 Hz, 1H), 7.27 - 7.31 (m, 2H), 6.94 (dd, J = 6.0, 2.88 Hz, 1H), 6.69 (d, J = 7.63 Hz, 1H), 6.38 (d, J = 8.0 Hz, 1H), 4.74 (br t, J = 5.2 Hz, 2H), 4.35 (br t, J = 5.2 Hz, 2H), 3.08 (d, J = 4.0 Hz, 3 H), 2.04 (br s, 2H), 1.90 (br s, 2H). Example 7: N-methyl-10,13,16,33-tetraoxa-3,22,24,28,32- pentazahexacyclo[21.6.2.12,5.117,21.04,9.026,30]tritriaconta- 1(29),2,4,6,8,17(32),18,20,23(31),24,26(30),27-dodecaen-27-amine Step 1: Synthesis of N-(5-(4-hydroxybenzo[d]oxazol-2-yl)-8-(methylamino)-2,7- naphthyridin-3-yl)cyclopropanecarboxamide

[0016] A mixture of N-(5-bromo8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (300 mg, 0.9 mmol, 1 eq), 1,3-benzoxazol-4-ol (151.5 mg, 1.1 mmol, 1.2 eq), Pd(PPh3)4 (107.9 mg, 0.09 mmol, 0.1 eq), Cs2CO3(913.0 mg, 2.8 mmol, 3 eq) in DMF (5 mL) was degassed and purged with N23 times. The mixture was stirred at 120 °C for 4 h under N2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a crude product mixture which was further purified by column chromatography ((ISCO®; 12 g SepaFlash® Silica Flash Column, DCM / MeOH with MeOH from 0~2.6%, 30 mL / min, 254 nm) to afford N-(5-(4- hydroxybenzo[d]oxazol-2-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (357 mg, 73.9%) as a yellow solid. LCMS (ESI) m / z 376.6 [M+H]+. Step 2: Synthesis of 2-(6-amino-1-(methylamino)-2,7-naphthyridin-4-yl)benzo[d]oxazol-4-ol To a solution of N-[5-(4-hydroxy-1,3-benzoxazol-2-yl)-8-(methylamino)-2,7-naphthyridin-3- yl]cyclopropanecarboxamide (400 mg, 1.1 mmol, 1 eq) in MeOH (4 mL) and H2O (0.5 mL) was added NaOH (639.3 mg, 16.0 mmol, 15 eq). The mixture was stirred at 80 °C for 16 hr. The reaction mixture was filtered and concentrated under reduced pressure and this crude product mixture was purified by column chromatography ((ISCO®; 12 g SepaFlash® Silica Flash Column, DCM / MeOH with MeOH from 0~7.9%, 30 mL / min, 254 nm) to afford 2-(6-amino-1- (methylamino)-2,7-naphthyridin-4-yl)benzo[d]oxazol-4-ol (45 mg, 11.6%) as a yellow solid. LCMS (ESI) m / z 307.8 [M+H]+. Step 3: Synthesis of N-methyl-10,13,16,33-tetraoxa-3,22,24,28,32- pentazahexacyclo[21.6.2.12,5.117,21.04,9.026,30]tritriaconta- 1(29),2,4,6,8,17(32),18,20,23(31),24,26(30),27-dodecaen-27-amine

[0017] A mixture of 2-[6-amino-1-(methylamino)-2,7-naphthyridin-4-yl]-1,3-benzoxazol-4-ol (40 mg, 0.13 mmol, 1 eq), 2-bromo-6-[2-(2-chloroethoxy)ethoxy]pyridine (73.0 mg, 0.26 mmol, 2 eq), Pd2(dba)3 (23.8 mg, 0.03 mmol, 0.2 eq), DavePhos (20.5 mg, 0.05 mmol, 0.4 eq) and Cs2CO3 (127.2 mg, 0.4 mol, 3 eq) in dioxane (2 mL) was degassed and purged with N2for 3 times. The mixture was stirred at 120 °C for 16 h under N2atmosphere. Upon completion, the reaction mixture was concentrated under reduced pressure and purified by column chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, DCM / MeOH with MeOH from 0~1.9%, 30 mL / min, 254nm) to afford N-methyl-10,13,16,33-tetraoxa-3,22,24,28,32- pentazahexacyclo[21.6.2.12,5.117,21.04,9.026,30]tritriaconta- 1(29),2,4,6,8,17(32),18,20,23(31),24,26(30),27-dodecaen-27-amine (15 mg, 24.2%) as a yellow solid. LCMS (ESI) m / z 471.4 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ ppm 9.92 (s, 1H), 9.37 (s, 1H), 9.24 (s, 1H), 8.89 (s, 1H), 8.54 (br s, 1H), 7.59 (t, J = 8.0 Hz, 1H), 7.31 (br d, J = 3.6 Hz, 2H), 7.00 (br d, J = 4.4 Hz, 1H), 6.71 (d, J = 7.6 Hz, 1H), 6.34 (d, J = 8.0 Hz, 1H), 4.63 (br s, 2H), 4.45 (br s, 2H), 3.92 (br s, 2H), 3.63 (br s, 2H), 3.08 (br d, J = 4.0 Hz, 3H). Example 8: N,10-dimethyl-15,33-dioxa-3,10,21,23,27,31- hexazahexacyclo[20.6.2.12,5.14,8.116,20.025,29]tritriaconta- 1(28),2,4,6,8(32),16(31),17,19,22(30),23,25(29),26-dodecaen-26-amine Step 1: Synthesis of tert-butyl (benzo[d]oxazol-5-ylmethyl)(methyl)carbamate To a stirring mixture of NaH (84.88 mg, 2.12 mmol, 60% dispersion in mineral oil, 0.9 eq) in DMF (5 mL) tert-butyl N-methylcarbamate (773.27 mg, 5.90 mmol, 2.5 eq) at 0 °C was added 5- (bromomethyl)-1,3-benzoxazole (500 mg, 2.36 mmol, 1 eq). The reaction mixture was stirred at 25°C for an additional 3 h. The reaction mixture was quenched with H2O (5 mL) at 0°C. The reaction mixture was partitioned between H2O (10 mL) and EtOAc (10 mL). The water layer was extracted by EtOAc (5 mL × 3). The combined organic layers were washed with H2O (10 mL), brine (10 mL), and dried over Na2SO4. The solvent was removed under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~20% Ethyl acetate / Petroleum ether gradient @ 30 mL / min) to afford tert- butyl (benzo[d]oxazol-5-ylmethyl)(methyl)carbamate (345 mg, 1.32 mmol, 55.78% yield) as a colorless oil. LCMS (ESI) m / z 263.2 [M+H]+. Step 2: Synthesis of tert-butyl ((2-(6-(cyclopropanecarboxamido)-1-(methylamino)-2,7- naphthyridin-4-yl)benzo[d]oxazol-5-yl)methyl)(methyl)carbamate To a mixture of N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (420 mg, 1.31 mmol, 1 eq), tert-butyl (benzo[d]oxazol-5-ylmethyl)(methyl)carbamate (343.02 mg, 1.31 mmol, 1 eq), Pd(PPh3)4 (151.11 mg, 130.77 μmol, 0.1 eq) , CuI (49.81 mg, 261.54 μmol, 0.2 eq) and K3PO4(832.75 mg, 3.92 mmol, 3 eq) in DMF (5 mL).The reaction mixture was heated at 120 °C for 2 h under a microwave irradiation condition. The reaction mixture was quenched with H2O (10 mL) at 0°C. and diluted with EtOAc (10 mL). The aqueous layer was extracted by EtOAc (10 mL × 3). The combined organic layers were washed with H2O (20 mL), brine (20 mL) and dried over Na2SO4. The solvent was removed under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~90% Ethyl acetate / Petroleum ether gradient @ 40 mL / min) to afford tert-butyl ((2-(6- (cyclopropanecarboxamido)-1-(methylamino)-2,7-naphthyridin-4-yl)benzo[d]oxazol-5- yl)methyl)(methyl)carbamate (540 mg, 1.07 mmol, 82.17% yield) as a yellow oil. LCMS (ESI) m / z 503.3 [M+H]+. Step 3: Synthesis of tert-butyl ((2-(6-amino-1-(methylamino)-2,7-naphthyridin-4- yl)benzo[d]oxazol-5-yl)methyl)(methyl)carbamate To a solution of tert-butyl ((2-(6-(cyclopropanecarboxamido)-1-(methylamino)-2,7-naphthyridin- 4-yl)benzo[d]oxazol-5-yl)methyl)(methyl)carbamate (540 mg, 1.07 mmol, 1 eq) in MeOH (9 mL) was added NaOH (859.53 mg, 21.49 mmol, 20 eq) in H2O (1 mL). The reaction mixture was stirred at 80°C for 4 h. The solvent was removed under reduced pressure to give a crude product mixture. This crude product mixture was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~90% Ethyl acetate / Petroleum ether gradient @ 40 mL / min) to afford tert-butyl ((2-(6-amino-1-(methylamino)-2,7-naphthyridin-4- yl)benzo[d]oxazol-5-yl)methyl)(methyl)carbamate (330 mg, 759.51 μmol, 70.69% yield) as a yellow solid. LCMS (ESI) m / z 435.3 [M+H]+. Step 4: Synthesis of tert-butyl ((2-(6-((6-(4-chlorobutoxy)pyridin-2-yl)amino)-1- (methylamino)-2,7-naphthyridin-4-yl)benzo[d]oxazol-5-yl)methyl)(methyl)carbamate

[0018] A mixture of tert-butyl ((2-(6-amino-1-(methylamino)-2,7-naphthyridin-4-yl)benzo[d]oxazol-5- yl)methyl)(methyl)carbamate (160 mg, 368.25 μmol, 1 eq), 2-bromo-6-(4-chlorobutoxy)pyridine (87.68 mg, 331.42 μmol, 0.9 eq), E Phos Pd G4 (67.65 mg, 73.65 μmol, 0.2 eq), E Phos (78.78 mg, 147.30 μmol, 0.4 eq) and Cs2CO3 (359.95 mg, 1.10 mmol, 3 eq) in dioxane (6 mL) was degassed and purged with N2 for 3 times. The reaction mixture was stirred at 90 °C for 2 h under N2atmosphere. The reaction mixture was cooled down to 25°C and was filtered and the filtrate was concentrated under reduced pressure. The crude product was further purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~80% Ethyl acetate / Petroleum ether gradient @ 30 mL / min) to afford tert-butyl ((2-(6-((6-(4- chlorobutoxy)pyridin-2-yl)amino)-1-(methylamino)-2,7-naphthyridin-4-yl)benzo[d]oxazol-5- yl)methyl)(methyl)carbamate (180 mg, 291.20 μmol, 79.08% yield) as a yellow solid. LCMS (ESI) m / z 618.2 [M+H]+. Step 5: Synthesis of N6-(6-(4-chlorobutoxy)pyridin-2-yl)-N1-methyl-4-(5- ((methylamino)methyl)benzo[d]oxazol-2-yl)-2,7-naphthyridine-1,6-diamine To a solution of tert-butyl ((2-(6-((6-(4-chlorobutoxy)pyridin-2-yl)amino)-1-(methylamino)-2,7- naphthyridin-4-yl)benzo[d]oxazol-5-yl)methyl)(methyl)carbamate (90 mg, 145.60 μmol, 1 eq) in DCM (1 mL), CF3COOH (1.66 g, 14.56 mmol, 1.08 mL, 100 eq) was added. The reaction was stirred at 25°C for 2 h. The solvent was removed under reduced pressure. The crude product was taken directly to the next step without further purification. The crude TFA salt of N6-(6-(4- chlorobutoxy)pyridin-2-yl)-N1-methyl-4-(5-((methylamino)methyl)benzo[d]oxazol-2-yl)-2,7- naphthyridine-1,6-diamine (70 mg, 110.75 μmol, 76.07% yield, TFA) was directly taken into the next step as a yellow oil. LCMS (ESI) m / z 518.2 [M+H]+ Step 6: Synthesis of N,10-dimethyl-15,33-dioxa-3,10,21,23,27,31- hexazahexacyclo[20.6.2.12,5.14,8.116,20.025,29]tritriaconta- 1(28),2,4,6,8(32),16(31),17,19,22(30),23,25(29),26-dodecaen-26-amine The suspension of crude TFA salt of N6-(6-(4-chlorobutoxy)pyridin-2-yl)-N1-methyl-4-(5- ((methylamino)methyl)benzo[d]oxazol-2-yl)-2,7-naphthyridine-1,6-diamine (70 mg, 110.75 μmol, 1 eq, TFA) and K2CO3 (306.14 mg, 2.22 mmol, 20 eq) in DMF (10 mL) was heated at 110°C for 6 h. The reaction mixture was cooled down to 25°C and the reaction was filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by reversed-phase HPLC(0.1% HCl condition) to afford N,10-dimethyl-15,33-dioxa-3,10,21,23,27,31- hexazahexacyclo[20.6.2.12,5.14,8.116,20.025,29]tritriaconta- 1(28),2,4,6,8(32),16(31),17,19,22(30),23,25(29),26-dodecaen-26-amine (10 mg, 20.77 μmol, 18.75% yield) as a light green solid. LCMS (ESI) m / z 482.1 [M+H]+,1H NMR (400 MHz, DMSO- d6) δ ppm 9.92 (s, 1H), 9.51 (s, 1H), 9.35 (s, 1H), 8.68 (s, 1H), 8.47 (br d, J = 4.0 Hz, 1H), 7.89 (s, 1H), 7.65 (s, 1H), 7.60 (t, J = 8.0 Hz, 1H), 7.21 - 7.29 (m, 1H), 6.75 (d, J = 8.0 Hz, 1H), 6.34 (d, J = 8.0 Hz, 1H), 3.86 - 3.95 (m, 2H), 3.62 - 3.78 (m, 2H), 3.07 (d, J = 4.4 Hz, 3H), 2.45 - 2.49 (m, 3H), 2.19 - 2.38 (m, 2H), 1.42 - 1.56 (m, 4H).

[0019] Example 9: 9,12-dimethyl-25-(methylamino)-32-oxa-3,9,12,20,22,26,30- heptazahexacyclo[19.6.2.12,5.14,8.115,19.024,28]dotriaconta- 1(27),2,4,6,8(31),15(30),16,18,21,23,25,28-dodecaen-10-one Step 1: Synthesis of 1,3-benzoxazol-5-amine To a solution of 5-nitro-1,3-benzoxazole (10 g, 60.9 mmol) in MeOH (150 mL) was added Pd / C (1 g, 0.940 mmol, 10 wt% Pd with 50 wt% water) and the mixture was stirred at 20 ℃ for 12 hr under H2 atmosphere (15 psi). The reaction mixture was filtered, and the filtrate was concentrated. The desired product 1,3-benzoxazol-5-amine (8 g, crude) was obtained as a brown oil. Step 2: Synthesis of tert-butyl N-(1,3-benzoxazol-5-yl)carbamate To a solution of 1,3-benzoxazol-5-amine (8 g, 59.6 mmol), K2CO3(16.5 g, 119 mmol) in dioxane (80 mL) and H2O (40 mL) was added Boc2O (26.6 g, 122 mmol) and the mixture was stirred at 20 ℃ for 4 h. The resulting mixture was quenched with water (50 mL) and extracted with EtOAc (60 mL × 3). The combined organic layers were washed with brine (100 mL × 3), 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 0~40%, flow rate = 50 mL / min, 254 nm). The desired product tert-butyl N-(1,3- benzoxazol-5-yl)carbamate (9.12 g, 56.1% yield) was obtained as a red solid. LCMS (ESI) m / z 235.0[M+H]+. Step 3: Synthesis of tert-butyl N-(1,3-benzoxazol-5-yl)-N-methyl-carbamate To a solution of tert-butyl N-(1,3-benzoxazol-5-yl)carbamate (9.12 g, 38.9 mmol) in DMF (100 mL) was added NaH (1.87 g, 46.7 mmol, 60% dispersion in mineral oil) at 0 ℃. After addition, the mixture was stirred at this temperature for 30 min, and then MeI (11.1 g, 77.8 mmol) was added dropwise at 0 ℃. The resulting mixture was stirred at 20 ℃ for 3 h. The reaction mixture was quenched with a saturated NH4Cl aqueous solution (40 mL) at 0 ℃, and then extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (100 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 120 g AgelaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0~25%, flow rate = 100 mL / min, 254 nm) to afford tert-butyl N-(1,3-benzoxazol- 5-yl)-N-methyl-carbamate (7.73 g, 75.2% yield) as a white solid. LCMS (ESI) m / z 249.0 [M+H]+. Step 4: Synthesis of tert-butyl N-[2-[6-(cyclopropanecarbonylamino)-1-(methylamino)-2,7- naphthyridin-4-yl]-1,3-benzoxazol-5-yl]-N-methyl-carbamate To a mixture of N-[5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl]cyclopropanecarboxamide (3.0 g, 9.34 mmol), tert-butyl N-(1,3-benzoxazol-5-yl)-N-methyl-carbamate (2.77 g, 11.2 mmol) in DMF (40 mL) were added Cs2CO3 (7.57 g, 23.2 mmol) and Pd(PPh3)4 (1.07 g, 0.930 mmol). The sealed tube was heated at 100 ℃ for 2 h under a microwave irradiation condition. The resulting mixture was cooled to RT and quenched with water (50 mL) and extracted with dichloromethane (60 mL × 3). The combined organic layers were washed with brine (100 mL × 5), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 40 g AgelaFlash® Silica Flash Column, Dichloromethane / Methanol with Methanol from 0~10%, flow rate = 40 mL / min, 254 nm) to afford tert-butyl N-[2-[6-(cyclopropanecarbonylamino)-1-(methylamino)-2,7-naphthyridin-4-yl]-1,3- benzoxazol-5-yl]-N-methyl-carbamate (2.5 g, 52.0% yield) as a red solid. LCMS (ESI) m / z 489.4 [M+H]+. Step 5: Synthesis of tert-butyl N-[2-[6-amino-1-(methylamino)-2,7-naphthyridin-4-yl]-1,3- benzoxazol-5-yl]-N-methyl-carbamate To a stirring mixture of tert-butyl N-[2-[6-(cyclopropanecarbonylamino)-1-(methylamino)-2,7- naphthyridin-4-yl]-1,3-benzoxazol-5-yl]-N-methyl-carbamate (2.5 g, 3.41 mmol) in MeOH (30 mL) at 20 ℃ was added dropwise NaOH (683 mg, 17.1 mmol) in H2O (10 mL) The resulting mixture was stirred at 80 ℃ for 12 h. The resulting mixture was quenched with water (50 mL) and extracted with dichloromethane (60 mL × 3). The combined organic layers were washed with brine (100 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford tert-butyl N-[2-[6-amino-1-(methylamino)-2,7-naphthyridin-4-yl]-1,3-benzoxazol-5-yl]-N- methyl-carbamate (1.7 g, crude) was obtained as a brown solid. LCMS (ESI) m / z 421.5 [M+H]+. Step 6: Synthesis of 2-(6-bromo-2-pyridyl)acetaldehyde To a solution of 2-bromo-6-methyl-pyridine (5.0 g, 29.1 mmol) in THF (60 mL) was added dropwise LDA (2 M in THF, 36.0 mL) at -78 ℃. After addition, the mixture was stirred at this temperature for 30 min, and then DMF (7.41 g, 101 mmol) was added dropwise. After stirring for 1 h at -78 ℃ under N2 atmosphere. The mixture was added to a saturated NH4Cl aqueous solution (100 mL) and extracted with EtOAc (120 mL × 3). The combined organic layers were washed with brine (200 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 0~40%, flow rate = 100 mL / min, 254 nm). The desired product 2-(6-bromo-2-pyridyl)acetaldehyde (2.63 g, 27.1% yield) was obtained as a yellow oil. LCMS (ESI) m / z 201.7, 199.7 [M+H]+. Step 7: Synthesis of tert-butyl 2-[2-(6-bromo-2-pyridyl)ethyl-methyl-amino]acetate To a solution of 2-(6-bromo-2-pyridyl)acetaldehyde (2.60 g, 13.0 mmol), tert-butyl 2- (methylamino)acetate (2.08 g, 11.5 mmol, HCl salt) in DCE (40 mL) was added NaBH(OAc)3 (5.51 g, 26.0 mmol), molecular sieves 4Å and the mixture was stirred at 20 ℃ for 12 h under N2 atmosphere. The reaction mixture was quenched with water (100 mL) at 20 ℃, and then extracted with dichloromethane (100 mL × 3). The combined organic layers were washed with brine (200 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 0~100%, flow rate = 30 mL / min, 254 nm) to afford the desired product tert-butyl 2-[2-(6-bromo-2-pyridyl)ethyl-methyl-amino]acetate (820 mg, 15.3% yield) as a yellow oil. LCMS (ESI) m / z 330.8328.8 [M+H]+. Step 8: Synthesis of tert-butyl 2-[2-[6-[[5-[5-[tert-butoxycarbonyl(methyl)amino]-1,3- benzoxazol-2-yl]-8-(methylamino)-2,7-naphthyridin-3-yl]amino]-2-pyridyl]ethyl-methyl- amino]acetate To a mixture of tert-butyl N-[2-[6-amino-1-(methylamino)-2,7-naphthyridin-4-yl]-1,3- benzoxazol-5-yl]-N-methyl-carbamate (300 mg, 0.714 mmol), tert-butyl 2-[2-(6-bromo-2- pyridyl)ethyl-methyl-amino]acetate (270 mg, 0.820 mmol), Cs2CO3 (581 mg, 1.78 mmol) in dioxane (30 mL) were added Brettphos (77 mg, 0.143 mmol) and BrettPhos Pd G3 (65 mg, 71.7 μmol). The resulting mixture was stirred at 100 ℃ for 1 h under N2atmosphere. The resulting mixture was quenched with water (50 mL) and extracted with dichloromethane (80 mL × 3). The combined organic layers were washed with brine (120 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (ISCO®; 4 g AgelaFlash® Silica Flash Column, Dichloromethane / Methanol with Methanol from 0~5%, flow rate = 30 mL / min, 254 nm) to afford the desired product tert-butyl 2- [2-[6-[[5-[5-[tert-butoxycarbonyl(methyl)amino]-1,3-benzoxazol-2-yl]-8-(methylamino)-2,7- naphthyridin-3-yl]amino]-2-pyridyl]ethyl-methyl-amino]acetate (390 mg, 73.6% yield) as a yellow solid. LCMS (ESI) m / z 669.2 [M+H]+. Step 9: Synthesis of 2-[methyl-[2-[6-[[8-(methylamino)-5-[5-(methylamino)-1,3-benzoxazol- 2-yl]-2,7-naphthyridin-3-yl]amino]-2-pyridyl]ethyl]amino]acetic acid To a mixture of tert-butyl 2-[2-[6-[[5-[5-[tert-butoxycarbonyl(methyl)amino]-1,3-benzoxazol-2- yl]-8-(methylamino)-2,7-naphthyridin-3-yl]amino]-2-pyridyl]ethyl-methyl-amino]acetate (20 mg, 29.9 μmol) in HCl / dioxane (4 M, 2 mL) and the mixture was stirred at 20 ℃ for 2 h. The reaction mixture was concentrated under reduced pressure to remove solvent. The desired product 2-[methyl-[2-[6-[[8-(methylamino)-5-[5-(methylamino)-1,3-benzoxazol-2-yl]-2,7- naphthyridin-3-yl]amino]-2-pyridyl]ethyl]amino]acetic acid (15 mg, crude) was obtained as a yellow solid. LCMS (ESI) m / z 513.0 [M+H]+. Step 10: Synthesis of 9,12-dimethyl-25-(methylamino)-32-oxa-3,9,12,20,22,26,30- heptazahexacyclo[19.6.2.12,5.14,8.115,19.024,28]dotriaconta- 1(27),2,4,6,8(31),15(30),16,18,21,23,25,28-dodecaen-10-one To a solution of 2-[methyl-[2-[6-[[8-(methylamino)-5-[5-(methylamino)-1,3-benzoxazol-2-yl]- 2,7-naphthyridin-3-yl]amino]-2-pyridyl]ethyl]amino]acetic acid (150 mg, 0.293 mmol), was added TCFH (123 mg, 0.439 mmol) and NMI (72.1 mg, 0.878 mmol) in DMF (25 mL). The mixture was stirred at 20 ℃ for 1 h. The reaction mixture was purified by reversed-phase HPLC (Column: SepaFlash® Sphercial C18, 40 g, 40-60 μm, 120Å; MeCN / water with MeCN from 0- 52%, 40mL / min, 254 nm) to afford the desired product 9,12-dimethyl-25-(methylamino)-32-oxa- 3,9,12,20,22,26,30-heptazahexacyclo[19.6.2.12,5.14,8.115,19.024,28]dotriaconta- 1(27),2,4,6,8(31),15(30),16,18,21,23,25,28-dodecaen-10-one (43 mg, 29.5% yield) as a yellow solid. LCMS (ESI) m / z 495.2 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ ppm 10.00 (s, 1H), 9.68 (s, 1H), 9.35 (s, 1H), 8.65 (s, 1H), 8.41 - 8.53 (m, 2H), 7.78 (d, J = 8.8 Hz, 1H), 7.56 (t, J = 7.8 Hz, 1H), 7.38 (dd, J = 8.7, 2.1 Hz, 1H), 6.97 (d, J = 8.3 Hz, 1H), 6.74 (d, J = 7.5 Hz, 1H), 3.34 (br s, 3H), 3.08 (d, J = 4.5 Hz, 3H), 2.95 - 3.04 (m, 4H), 2.53 - 2.60 (m, 2H), 2.50 (s, 3H). Example 10: 9,13-dimethyl-25-(methylamino)-14,32-dioxa-3,9,20,22,26,30- hexazahexacyclo[19.6.2.12,5.14,8.115,19.024,28]dotriaconta- 1(27),2,4,6,8(31),15(30),16,18,21,23,25,28-dodecaen-10-one Step 1: Synthesis of tert-butyl 4-oxopentanoate To a mixture of 4-oxopentanoic acid (5 g, 43.1 mmol), t-BuOH (4.81 g, 64.8 mmol) in DCM (50 mL) was added DMAP (5.26 g, 43.1 mmol), DCC (9.79 g, 47.5 mmol) and the mixture was stirred at 20 ℃ for 12 h. The resulting mixture was quenched with water (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 residue was purified by flash chromatography (ISCO®; 60 gAgelaFlash®Silica Flash Column, petroleumether / EtOAc with EtOAc from 0~50%, flow rate = 80 mL / min, 254 nm) to afford the desired product tert-butyl 4-oxopentanoate (5.2 g, 63.1% yield) as a yellow oil.1H NMR (400 MHz, CDCl3) δ ppm 2.66 - 2.72 (m, 2H), 2.47 - 2.52 (m, 2H), 2.18 (s, 3H), 1.43 (s, 9H). Step 2: Synthesis of tert-butyl 4-hydroxypentanoate To a stirring mixture of tert-butyl 4-oxopentanoate (2 g, 11.6 mmol) in EtOH (20 mL) was added NaBH4 (878 mg, 23.2 mmol). The reaction mixture was stirred at 20 ℃ for 1 h under N2 atmosphere. The mixture was added to a saturated NH4Cl aqueous solution (60 mL) and extracted with EtOAc (60 mL × 3). The combined organic layers were washed with brine (120 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The desired product tert-butyl 4-hydroxypentanoate (1.58 g, crude) was obtained as a yellow oil.1H NMR (400 MHz, CDCl3) δ ppm 3.71 - 3.83 (m, 1H), 2.29 (t, J = 7.2 Hz, 2H), 1.59 - 1.75 (m, 2H), 1.38 (s, 9H), 1.14 (d, J = 6.2 Hz, 3H). Step 3: Synthesis of tert-butyl 4-[(6-bromo-2-pyridyl)oxy]pentanoate To a solution of 6-bromopyridin-2-ol (800 mg, 4.60 mmol), tert-butyl 4-hydroxypentanoate (960 mg, 5.51 mmol), PPh3 (2.41 g, 9.20 mmol) in THF (20 mL) was added DIAD (1.46 g, 7.22 mmol) in THF (5.0 mL) at 0 ℃ and the mixture was stirred at 20 ℃ for 12 h under N2atmosphere. The reaction mixture was quenched with a saturated NH4Cl aqueous solution (50 mL) at 20 ℃, and then extracted with EtOAc (60 mL × 3). The combined organic layers were washed with brine (100 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product mixture was purified by flash chromatography (ISCO®; 20 g AgelaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0~5%, flow rate = 40 mL / min, 254 nm) to afford tert-butyl 4-[(6-bromo-2-pyridyl)oxy]pentanoate (1.7 g, 78.4% yield) as a yellow oil. LCMS (ESI) m / z 331.8, 329.8 [M+H]+. Step 4: Synthesis of Example 10: 9,13-dimethyl-25-(methylamino)-14,32-dioxa-3,9,20,22,26,30- hexazahexacyclo[19.6.2.12,5.14,8.115,19.024,28]dotriaconta- 1(27),2,4,6,8(31),15(30),16,18,21,23,25,28-dodecaen-10-one was synthesized using a similar procedure that was previously described in Example 9 by using tert-butyl 4-[(6-bromo-2- pyridyl)oxy]pentanoate and tert-butyl N-[2-[6-amino-1-(methylamino)-2,7-naphthyridin-4-yl]- 1,3-benzoxazol-5-yl]-N-methyl-carbamate as the starting material. LCMS (ESI) m / z 496.1 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ ppm 10.56 (br d, J = 4.4 Hz, 1H), 10.47 (s, 1H), 9.67 (s, 1H), 9.14 (s, 1H), 8.33 (s, 1H), 7.90 - 7.97 (m, 2H), 7.66 (t, J = 8.1 Hz, 1H), 7.54 (dd, J = 8.8, 2.1 Hz, 1H), 6.80 (d, J = 7.8 Hz, 1H), 6.48 (d, J = 8.4 Hz, 1H), 4.59 - 4.66 (m, 1H), 3.35 (s, 3H), 3.23 (d, J = 4.5 Hz, 3H), 2.47 (br d, J = 5.3 Hz, 1H), 2.28 (td, J = 12.5, 3.8 Hz, 1H), 1.85 - 2.06 (m, 2H), 1.08 (d, J = 6.0 Hz, 3H). Example 11 and 12: (13S)-9,13-dimethyl-25-(methylamino)-14,32-dioxa-3,9,20,22,26,30- hexazahexacyclo[19.6.2.12,5.14,8.115,19.024,28]dotriaconta- 1(27),2,4,6,8(31),15(30),16,18,21,23,25,28-dodecaen-10-one and (13R)-9,13-dimethyl-25- (methylamino)-14,32-dioxa-3,9,20,22,26,30- hexazahexacyclo[19.6.2.12,5.14,8.115,19.024,28]dotriaconta- 1(27),2,4,6,8(31),15(30),16,18,21,23,25,28-dodecaen-10-one and 9,13-dimethyl-25-(methylamino)-14,32-dioxa-3,9,20,22,26,30- hexazahexacyclo[19.6.2.12,5.14,8.115,19.024,28]dotriaconta- 1(27),2,4,6,8(31),15(30),16,18,21,23,25,28-dodecaen-10-one Example 10 was separated by chiral SFC column to afford Example 11 and Example 12. Analytical data for Example 11 (peak a): LCMS (ESI) m / z 496.1 [M+H]+; Chiral purity: 100% ee;1H NMR (400 MHz, DMSO-d6) δ ppm 10.56 (br d, J = 4.4 Hz, 1H), 10.47 (s, 1H), 9.67 (s, 1H), 9.14 (s, 1H), 8.33 (s, 1H), 7.90 - 7.97 (m, 2H), 7.66 (t, J = 8.1 Hz, 1H), 7.54 (dd, J = 8.8, 2.1 Hz, 1H), 6.80 (d, J = 7.8 Hz, 1H), 6.48 (d, J = 8.4 Hz, 1H), 4.59 - 4.66 (m, 1H), 3.35 (s, 3H), 3.23 (d, J = 4.5 Hz, 3H), 2.47 (br d, J = 5.3 Hz, 1H), 2.28 (td, J = 12.5, 3.8 Hz, 1H), 1.85 - 2.06 (m, 2H), 1.08 (d, J = 6.0 Hz, 3H). Analytical data for Example 12 (peak b): LCMS (ESI) m / z 496.1 [M+H]+; Chiral purity: 100% ee;1H NMR (400 MHz, DMSO-d6) δ ppm 10.56 (br d, J = 4.4 Hz, 1H), 10.47 (s, 1H), 9.67 (s, 1H), 9.14 (s, 1H), 8.33 (s, 1H), 7.90 - 7.97 (m, 2H), 7.66 (t, J = 8.1 Hz, 1H), 7.54 (dd, J = 8.8, 2.1 Hz, 1H), 6.80 (d, J = 7.8 Hz, 1H), 6.48 (d, J = 8.4 Hz, 1H), 4.59 - 4.66 (m, 1H), 3.35 (s, 3H), 3.23 (d, J = 4.5 Hz, 3H), 2.47 (br d, J = 5.3 Hz, 1H), 2.28 (td, J = 12.5, 3.8 Hz, 1H), 1.85 - 2.06 (m, 2H), 1.08 (d, J = 6.0 Hz, 3H).

[0020] Example 13: 9-methyl-26-(methylamino)-12,15,33-trioxa-3,9,21,23,27,31- hexazahexacyclo[20.6.2.12,5.14,8.116,20.025,29]tritriaconta- 1(29),2,4,6,8(32),16(31),17,19,22(30),23,25,27-dodecaen-10-one Step 1: Synthesis of tert-butyl 2-[2-[(6-bromo-2-pyridyl)oxy]ethoxy]acetate To a stirring mixture of 6-bromopyridin-2-ol (2 g, 11.5 mmol), tert-butyl 2-(2- hydroxyethoxy)acetate (2.2 g, 12.5 mmol), PPh3 (6.03 g, 23.0 mmol) in THF (30 mL) was added DIAD (3.44 g, 17.0 mmol) in THF (5.0 mL). The resulting mixture was stirred at 20 ℃ for 12 h under N2 atmosphere. The resulting mixture was quenched with water (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic layer was washed with a saturated NH4Cl aqueous solution (100 mL × 2), 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 0~20%, Flow Rate: 50 mL / min, 254 nm). The desired product tert-butyl 2-[2-[(6-bromo-2-pyridyl)oxy]ethoxy]acetate (3.6 g, 84.9% yield) was obtained as yellow oil. LCMS (ESI) m / z 333.9, 331.9 [M+H]+. Step 2: Synthesis of example 13:

[0021] 9-methyl-26-(methylamino)-12,15,33-trioxa-3,9,21,23,27,31- hexazahexacyclo[20.6.2.12,5.14,8.116,20.025,29]tritriaconta- 1(29),2,4,6,8(32),16(31),17,19,22(30),23,25,27-dodecaen-10-one was synthesized using a similar procedure that was previously described in Example 9 by using tert-butyl 2-[2-[(6-bromo-2- pyridyl)oxy]ethoxy]acetate and tert-butyl N-[2-[6-amino-1-(methylamino)-2,7-naphthyridin-4- yl]-1,3-benzoxazol-5-yl]-N-methyl-carbamate as the starting material. LCMS (ESI) m / z 498.1 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ ppm 10.69 (br s, 1H), 10.56 (s, 1H), 9.66 - 9.74 (m, 2H), 8.37 (s, 1H), 7.86 - 7.94 (m, 2H), 7.68 (t, J = 7.9 Hz, 1H), 7.51 (dd, J = 8.5, 2.0 Hz, 1H), 6.81 (d, J = 7.8 Hz, 1H), 6.45 (d, J = 8.0 Hz, 1H), 3.99 (br s, 2H), 3.67 (s, 2H), 3.25 (s, 6H), 3.08 (br s, 2H). Example 14: N,9-dimethyl-15,33-dioxa-3,9,21,23,27,31-hexazahexacyclo [20.6.2.12,5.14,8.116,20.025,29]tritriaconta-1(28),2,4,6,8(32),16(31),17,19,22(30),23,25(29),26- dodecaen-26-amine Step 1: Synthesis of tert-butyl N-[2-[6-[[6-(5-hydroxypentoxy)-2-pyridyl]amino]-1- (methylamino)-2,7-naphthyridin-4-yl]-1,3-benzoxazol-5-yl]-N-methyl-carbamate

[0022] To a stirring mixture of tert-butyl N-[2-[6-amino-1-(methylamino)-2,7-naphthyridin-4-yl]-1,3- benzoxazol-5-yl]-N-methyl-carbamate (300 mg, 0.714 mmol), 5-[(6-bromo-2- pyridyl)oxy]pentan-1-ol (224 mg, 0.859 mmol), Cs2CO3 (582 mg, 1.79 mmol) in dioxane (15.0 mL) was added Brettphos (76.5 mg, 0.143 mmol), BrettPhos Pd G3 (66.0 mg, 72.8 μmol). The mixture was stirred at 100 ℃ for 1 h under N2 atmosphere. Upon completion, the resulting mixture was quenched with water (60 mL) and extracted with EtOAc (80 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®; 12 g AgelaFlash® Silica Flash Column, Dichloromethane / Methanol with Methanol from 0~8%, flow rate =30 mL / min, 254 nm). The desired product tert-butyl N-[2-[6-[[6-(5-hydroxypentoxy)-2- pyridyl]amino]-1-(methylamino)-2,7-naphthyridin-4-yl]-1,3-benzoxazol-5-yl]-N-methyl- carbamate (350 mg, 65.44% yield) was obtained as a yellow solid. LCMS (ESI) m / z 600.3 [M+H]+. Step 2: Synthesis of N6-[6-(5-chloropentoxy)-2-pyridyl]-N1-methyl-4-[5-(methylamino)-1,3- benzoxazol-2-yl]-2,7-naphthyridine-1,6-diamine To a mixture of tert-butyl N-[2-[6-[[6-(5-hydroxypentoxy)-2-pyridyl]amino]-1-(methylamino)- 2,7-naphthyridin-4-yl]-1,3-benzoxazol-5-yl]-N-methyl-carbamate (100 mg, 0.167 mmol) in toluene (5.0 mL) was added SOCl2(1.64 g, 13.8 mmol). The mixture was stirred at 50 ℃ for 1 h under N2atmosphere. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by flash chromatography (ISCO®; 4 g AgelaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0~100%, flow rate =30 mL / min, 254 nm). The desired product N6-[6-(5-chloropentoxy)-2-pyridyl]-N1-methyl-4-[5-(methylamino)-1,3- benzoxazol-2-yl]-2,7-naphthyridine-1,6-diamine (60 mg, 55.6% yield) was obtained as a yellow solid. LCMS (ESI) m / z 518.2 [M+H]+. Step 3: Synthesis of N,9-dimethyl-15,33-dioxa-3,9,21,23,27,31- hexazahexacyclo[20.6.2.12,5.14,8.116,20.025,29]tritriaconta- 1(28),2,4,6,8(32),16(31),17,19,22(30),23,25(29),26-dodecaen-26-amine To a solution of N6-[6-(5-chloropentoxy)-2-pyridyl]-N1-methyl-4-[5-(methylamino)-1,3- benzoxazol-2-yl]-2,7-naphthyridine-1,6-diamine (60 mg, 0.116 mmol), Cs2CO3(189 mg, 0.580 mmol) in DMF (15.0 mL) and the mixture was stirred at 100 ℃ for 12 h. The resulting mixture was quenched with water (60 mL) and extracted with EtOAc (80 mL × 3). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. 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% FA (v%); Mobile phase B: ACN; Gradient: B from 14% to 45% in 8 min, hold 100% B for 2 min; Flow Rate: 25 mL / min; Column Temperature: 30 ℃; Wavelength: 220 nm). The desired product N,9-dimethyl-15,33-dioxa-3,9,21,23,27,31- hexazahexacyclo[20.6.2.12,5.14,8.116,20.025,29]tritriaconta- 1(28),2,4,6,8(32),16(31),17,19,22(30),23,25(29),26-dodecaen-26-amine (4.5 mg, 8.1% yield) was obtained as a yellow solid. LCMS (ESI) m / z 482.1 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ ppm 9.91 (s, 1 H), 9.61 (s, 1 H), 9.35 (s, 1 H), 8.71 (s, 1 H), 8.44 (br d, J = 4.3 Hz, 1 H), 7.61 (t, J = 7.9 Hz, 1 H), 7.51 (d, J = 8.8 Hz, 1 H), 7.15 (d, J = 2.3 Hz, 1 H), 6.78 (d, J = 8.0 Hz, 1 H), 6.74 (dd, J = 9.0, 2.3 Hz, 1 H), 6.38 (d, J = 8.0 Hz, 1 H), 4.05 (br t, J = 5.1 Hz, 2 H), 3.42 (br s, 2 H), 3.07 (d, J = 4.5 Hz, 3 H), 2.94 (s, 3 H), 1.84 (br d, J = 6.3 Hz, 2 H), 1.57 - 1.68 (m, 4 H). Example 15: 10-methyl-25-(methylamino)-14,31-dioxa-3,10,20,22,26,30- hexazahexacyclo[19.6.2.12,5.115,19.04,9.024,28]hentriaconta- 1(28),2,4(9),5,7,15(30),16,18,21(29),22,24,26-dodecaen-11-one Step 1: Synthesis of tert-butyl 3-((6-((5-(4-((tert- butoxycarbonyl)(methyl)amino)benzo[d]oxazol-2-yl)-8-(methylamino)-2,7-naphthyridin-3- yl)amino)pyridin-2-yl)oxy)propanoate A mixture of tert-butyl N-[2-[6-amino-1-(methylamino)-2,7-naphthyridin-4-yl]-1,3-benzoxazol- 4-yl]-N-methyl-carbamate (150 mg, 0.357mmol), tert-butyl 3-[(6-bromo-2- pyridyl)oxy]propanoate (120 mg, 0.397 mmol), Pd2(dba)3 (30.0 mg, 32.8 μmol), DavePhos (30.0 mg, 76.2 μmol) and K2CO3 (120 mg,0.868 mmol) in dioxane (5 mL) was heated into a sealed tube at 110 °C for 3 h under a microwave irradiation condition. The reaction mixture was quenched with H2O (100 mL) at 25 °C, extracted with EtOAc (50 mL ´ 3). The combined organic layers were washed with brine (50 mL ´ 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a crude product mixture. This crude product was further purified by flash chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, DCM / MeOH with MeOH from 0~10%, flow rate: 65 mL / min, 254 nm)to afford, tert-butyl 3-[[6-[[5-[4-[tert- butoxycarbonyl(methyl)amino]-1,3-benzoxazol-2-yl]-8-(methylamino)-2,7-naphthyridin-3- yl]amino]-2-pyridyl]oxy]propanoate (200 mg, 87.4% yield), as a yellow solid. LCMS (ESI) m / z 642.1 [M+H]+. Step 2: Synthesis of 3-((6-((8-(methylamino)-5-(4-(methylamino)benzo[d]oxazol-2-yl)-2,7- naphthyridin-3-yl)amino)pyridin-2-yl)oxy)propanoic acid A mixture of tert-butyl 3-[[6-[[5-[4-[tert-butoxycarbonyl(methyl)amino]-1,3-benzoxazol-2-yl]-8- (methylamino)-2,7-naphthyridin-3-yl]amino]-2-pyridyl]oxy]propanoate (150 mg, 0.234 mmol,), 4M HCl / dioxane (10 mL) was degassed and purged with N2 for 3 times. The resulting mixture was stirred at 20 °C for 2 h under N2atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to afford the crude product, 3-[[6-[[8-(methylamino)-5-[4-(methylamino)- 1,3-benzoxazol-2-yl]-2,7-naphthyridin-3-yl]amino]-2-pyridyl]oxy]propanoic acid, (120 mg, crude), as a white solid.. LCMS (ESI) m / z 486.0 [M+H]+. Step 3: Synthesis of 10-methyl-25-(methylamino)-14,31-dioxa-3,10,20,22,26,30- hexazahexacyclo[19.6.2.12,5.115,19.04,9.024,28]hentriaconta- 1(28),2,4(9),5,7,15(30),16,18,21(29),22,24,26-dodecaen-11-one A mixture of 3-[[6-[[8-(methylamino)-5-[4-(methylamino)-1,3-benzoxazol-2-yl]-2,7- naphthyridin-3-yl]amino]-2-pyridyl]oxy]propanoic acid (100 mg, 0.206 mmol), EDCI (82.0 mg, 0.428 mmol), pyridine (360 mg, 4.55 mmol) in DCM (30 mL) was stirred at 20 °C for 12 h under N2 atmosphere. The reaction mixture was quenched with H2O (50 mL) at 25 °C, extracted with EtOAc (50 mL ´ 3). The combined organic layers were washed with brine (50 mL ´ 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a crude product mixture which was further 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% HCl (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: 30 ºC; Wavelength: 220 nm) to afford 10-methyl-25-(methylamino)-14,31-dioxa-3,10,20,22,26,30- hexazahexacyclo[19.6.2.12,5.115,19.04,9.024,28]hentriaconta- 1(28),2,4(9),5,7,15(30),16,18,21(29),22,24,26-dodecaen-11-one (3.30 mg 3.4% yield) as a yellow solid. LCMS (ESI) m / z 468.0 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ ppm 10.09 (s, 1H), 9.56 (s, 1H), 9.37 (s, 1H), 8.77 (s, 1H), 8.56 (br d, J = 4.5 Hz, 1H), 7.81 (br d, J = 7.9 Hz, 1H), 7.52 - 7.67 (m, 1H), 7.47 (br t, J = 7.7 Hz, 1H), 7.36 (br d, J=7.6 Hz, 1H), 6.72 (d, J = 8.0 Hz, 1H), 6.28 (br d, J = 8.0 Hz, 1H), 4.88 - 5.04 (m, 1H), 3.90 - 4.09 (m, 1H), 3.18 (br s, 3H), 3.08 (d, J = 4.4 Hz, 3H), 2.54 - 2.62 (m, 1H), 2.34 - 2.44 (m, 1H). Example 16: (Z)-N,10-dimethyl-5,8,11-trioxa-3-aza-1(2,5)-benzo[d]oxazola-2(5,3)- naphthyridina-4(2,6)-pyridinacycloundecaphan-28-amine Step 1: Synthesis of [2-(2-benzyloxyethoxy)-1-methyl-ethyl] 4-methylbenzenesulfonate A mixture of 1-(2-benzyloxyethoxy)propan-2-ol (2 g, 9.51 mmol), 4-methylbenzenesulfonyl chloride (2.18 g, 11.4 mmol), TEA (2.89 g, 3.97 mL) and DMAP (116 mg, 951 μmol) in DCM (50 mL) was degassed and purged with N23 times.. The resulting mixture was stirred at 20°C for 2 h under N2 atmosphere. The resulting mixture was concentrated and. further purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0 ~ 50% Ethyl acetate / Petroleum ether gradient @ 12 mL / min) to give [2-(2-benzyloxyethoxy)-1-methyl-ethyl] 4-methylbenzenesulfonate (2 g, 57.69% yield) as a white solid. LCMS (ESI) m / z 365.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ ppm 7.67 - 7.89 (m, 2H), 7.20 - 7.54 (m, 7H), 4.50 (s, 1H), 3.99 - 4.08 (m, 1H), 3.86 - 3.94 (m, 1H), 3.61 - 3.69 (m, 1H), 3.51 - 3.58 (m, 1H), 3.41 - 3.51 (m, 3H), 2.34 - 2.46 (m, 3H), 0.92 - 1.07 (m, 3H). Step 2: Synthesis of 2-aminobenzene-1,4-diol To a mixture of 2-nitrobenzene-1,4-diol (5 g, 32.2 mmol) in MeOH (100 mL) was added Pd / C (3.43 g, 3.22 mmol, 10 wt% with 50% water) under N2. The suspension was degassed under vacuum and purged several times with H2. The mixture was stirred under H2(30 psi) at 30°C for 16 h, The reaction mixture was filtered, and the filtrate was concentrated. The crude product was purified by silica gel chromatography eluted with Petroleum ether / Ethyl acetate = 0:1) to give 2- aminobenzene-1,4-diol (3 g, 74.38% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ ppm 8.27 (s, 1H), 8.15 (s, 1H), 6.40 (d, J = 8.31 Hz, 1H), 6.06 (d, J = 2.81 Hz, 1H), 5.79 (dd, J = 8.31, 2.93 Hz, 1H), 4.41 (s, 2H). Step 3: Synthesis of 1,3-benzoxazol-5-ol A mixture of 2-aminobenzene-1,4-diol (3 g, 24.0 mmol) in diethoxymethoxyethane (50 mL) was degassed and purged with N23 times. The reaction mixture was stirred at 100°C for 2 h under N2atmosphere. Upon completion, the resulting mixture was concentrated under reduced pressure and the crude mixture was further purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate / Petroleum ether gradient @ 25 mL / min) to give 1,3-benzoxazol-5-ol (2 g, 61.74% yield) as a brown solid. LCMS (ESI) m / z 136.1 [M+H]+Step 4: Synthesis of 5-[(4-methoxyphenyl)methoxy]-1,3-benzoxazole A mixture of 1,3-benzoxazol-5-ol (2 g, 14.8 mmol), PMB-Cl (2.55 g, 2.21 mL), K2CO3(5.11 g, 37.0 mmol) in DMF (10 mL) was degassed and purged with N2. The reaction mixture was stirred at 20°C for 12 h under N2 atmosphere. To this reaction mixture was added water and filtered to give product to give 5-[(4-methoxyphenyl)methoxy]-1,3-benzoxazole (3.5 g, 92.6% yield) as a white solid. LCMS (ESI) m / z 256.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ ppm 8.68 (s, 1H), 7.66 (d, J = 9.01 Hz, 1H), 7.36 - 7.44 (m, 3H), 7.03 - 7.12 (m, 1H), 6.95 (d, J = 8.63 Hz, 2H), 5.08 (s, 2H), 3.76 (s, 3H). Step 5: Synthesis of N-[5-[5-[(4-methoxyphenyl)methoxy]-1,3-benzoxazol-2-yl]-8- (methylamino)-2,7-naphthyridin-3-yl]cyclopropanecarboxamide A mixture of N-[5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl]cyclopropanecarboxamide (2 g, 6.23 mmol), 5-[(4-methoxyphenyl)methoxy]-1,3-benzoxazole (1.67 g, 6.54 mmol), Pd(PPh3)4 (1.44 g, 1.25 mmol), Cs2CO3(6.09 g, 18.7 mmol) in DMF (2 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 110°C for 16 h under N2atmosphere. The solvent was removed. The crude product mixture was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0 ~ 100% Ethyl acetate / Petroleum ether, gradient @ 30 mL / min) to give N-[5-[5-[(4-methoxyphenyl)methoxy]-1,3-benzoxazol-2-yl]-8- (methylamino)-2,7-naphthyridin-3-yl]cyclopropanecarboxamide (2 g, 64.8% yield) as a white solid. LCMS (ESI) m / z 496.2 [M+H]+. Step 6: Synthesis of N-(5-(5-hydroxybenzo[d]oxazol-2-yl)-8-(methylamino)-2,7- naphthyridin-3-yl)cyclopropanecarboxamide

[0023] A mixture of N-(5-(5-((4-methoxybenzyl)oxy)benzo[d]oxazol-2-yl)-8-(methylamino)-2,7- naphthyridin-3-yl)cyclopropanecarboxamide (2 g, 4.04 mmol) in TFA (10 mL) was degassed and purged with N23 times. The resulting mixture was stirred at 50°C for 4 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0 ~ 15% DCM / MeOH gradient @ 20 mL / min). to give N-(5-(5-hydroxybenzo[d]oxazol-2-yl)-8- (methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (1 g, 66% yield) as a white solid. LCMS (ESI) m / z 376.1 [M+H]+. Step 7: Synthesis of N-(5-(5-((1-(2-(benzyloxy)ethoxy)propan-2-yl)oxy)benzo[d]oxazol-2-yl)- 8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide A mixture of N-[5-(5-hydroxy-1,3-benzoxazol-2-yl)-8-(methylamino)-2,7-naphthyridin-3- yl]cyclopropanecarboxamide (900 mg, 2.40 mmol), [2-(2-benzyloxyethoxy)-1-methyl-ethyl] 4- methylbenzenesulfonate (961 mg, 2.64 mmol), K2CO3 (994 mg, 7.19 mmol) in DMF (20 mL) was stirred at 80°C for 16 h under N2atmosphere The solvent was removed. The crude product mixture was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0 ~ 100% Ethyl acetate / Petroleum ether gradient @ 20 mL / min) to give N-(5-(5-((1-(2- (benzyloxy)ethoxy)propan-2-yl)oxy)benzo[d]oxazol-2-yl)-8-(methylamino)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide (900 mg, 66.13% yield) as a yellow solid. LCMS (ESI) m / z 568.0 [M+H]+. Step 8: Synthesis of N-(5-(5-((1-(2-hydroxyethoxy)propan-2-yl)oxy)benzo[d]oxazol-2-yl)-8- (methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide To a stirring mixture of N-(5-(5-((1-(2-(benzyloxy)ethoxy)propan-2-yl)oxy)benzo[d]oxazol-2-yl)- 8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (700 mg, 1.23 mmol) in MeOH (20 mL) was added Pd / C (131 mg, 10 wt% Pd with ~50 wt% water) and Pd(OH)2 (86.5 mg, 20 wt% Pd(OH) 2 with ~50 wt% water) under N2. The suspension was degassed under vacuum and purged several times with H2. The mixture was stirred under H2(50 psi) at 50°C for 16 h. The reaction mixture was filtered, and the filtrate was concentrated. The crude product was purified by silica gel chromatography eluted with Petroleum ether / Ethyl acetate = 0:1) to give N-(5-(5-((1-(2- hydroxyethoxy)propan-2-yl)oxy)benzo[d]oxazol-2-yl)-8-(methylamino)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide (90 mg, 15.28% yield) as a yellow solid, LCMS (ESI) m / z 478.0 [M+H]+. Step 9: Synthesis of N-(5-(5-((1-(2-((6-bromopyridin-2-yl)oxy)ethoxy)propan-2- yl)oxy)benzo[d]oxazol-2-yl)-8-(methylamino)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide A mixture of N-(5-(5-((1-(2-hydroxyethoxy)propan-2-yl)oxy)benzo[d]oxazol-2-yl)-8- (methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (70 mg, 146 μmol), 6- bromopyridin-2-ol (25.5 mg, 146 μmol), 2-(tributyl-phosphanylidene)acetonitrile (106 mg, 439 μmol) in toluene (10 mL) was degassed and purged with N23 times.. The reaction mixture was stirred at 80°C for 2 h under N2 atmosphere. The solvent was removed. The crude product mixture was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate / Petroleum ether gradient @ 20 mL / min) to give N-(5-(5-((1-(2- ((6-bromopyridin-2-yl)oxy)ethoxy)propan-2-yl)oxy)benzo[d]oxazol-2-yl)-8-(methylamino)-2,7- naphthyridin-3-yl)cyclopropanecarboxamide (70 mg, 75.38% yield) as a white solid. LCMS (ESI) m / z 633.1, 635.1 [M+H]+. Step 10: Synthesis of 4-(5-((1-(2-((6-bromopyridin-2-yl)oxy)ethoxy)propan-2- yl)oxy)benzo[d]oxazol-2-yl)-N1-methyl-2,7-naphthyridine-1,6-diamine A mixture of N-(5-(5-((1-(2-((6-bromopyridin-2-yl)oxy)ethoxy)propan-2-yl)oxy)benzo[d]oxazol- 2-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (70 mg, 110 μmol) NaOH (44.2 mg, 1.10 mmol) in MeOH (10 mL) was degassed and purged with N23 times. The resulting mixture was stirred at 80°C for 2 h under N2 atmosphere. Upon completion, the reaction mixture was concentrated under reduced pressure and the crude product mixture was further purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0 ~ 10% MeOH / DCM gradient @ 12 mL / min) to give 4-(5-((1-(2-((6-bromopyridin-2- yl)oxy)ethoxy)propan-2-yl)oxy)benzo[d]oxazol-2-yl)-N1-methyl-2,7-naphthyridine-1,6-diamine (45 mg, 72.03% yield) as a yellow oil. LCMS (ESI) m / z 565.1, 567.1 [M+H]+. Step 11: Synthesis of (Z)-N,10-dimethyl-5,8,11-trioxa-3-aza-1(2,5)-benzo[d]oxazola-2(5,3)- naphthyridina-4(2,6)-pyridinacycloundecaphan-28-amine

[0024] A mixture of 4-(5-((1-(2-((6-bromopyridin-2-yl)oxy)ethoxy)propan-2-yl)oxy)benzo[d]oxazol-2- yl)-N1-methyl-2,7-naphthyridine-1,6-diamine (45 mg, 79.6 μmol), Ephos Pd G4 (7.31 mg, 7.96 μmol), EPhos (8.51 mg, 15.9 μmol) and Cs2CO3 (77.8 mg, 238 μmol) in dioxane (2 mL) was degassed and purged with N23 times. The resulting mixture was stirred at 100°C for 2 h under N2atmosphere. Upon completion, the reaction mixture was concentrated under reduced pressure. The crude mixture was purified by prep-HPLC (column: C18150 × 30 mm; mobile phase: [Water (HCl)-MeCN]; gradient: 20% - 60% B over 9 min) and further purification by prep-HPLC (column: C18150 × 30 mm; mobile phase: [Water (NH3H2O-NH4HCO3)-MeCN]; gradient: 49% - 89% B over 9 min) to afford,(Z)-N,10-dimethyl-5,8,11-trioxa-3-aza-1(2,5)-benzo[d]oxazola-2(5,3)- naphthyridina-4(2,6)-pyridinacycloundecaphan-28-amine (1 mg, 2.59% yield) as a white solid. LCMS (ESI) m / z 485.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ ppm 10.00 (s, 1H), 9.90 (s, 1H), 9.36 (s, 1H), 8.82 (s, 1H), 8.50 (br d, J = 4.75 Hz, 1H), 7.95 (d, J = 2.38 Hz, 1H), 7.47 - 7.69 (m, 2H), 6.92 (dd, J = 8.69, 2.44 Hz, 1H), 6.83 (d, J = 8.00 Hz, 1H), 6.41 (d, J = 8.00 Hz, 1H), 4.20 - 4.34 (m, 3H), 4.13 (br dd, J = 10.19, 6.32 Hz, 1H), 3.66 - 3.79 (m, 3H), 3.08 (d, J = 4.38 Hz, 3H), 1.24 (d, J = 6.50 Hz, 3H).

[0025] Example 17: 9-methyl-25-(methylamino)-14,32-dioxa-3,9,20,22,26,30- hexazahexacyclo[19.6.2.12,5.14,8.115,19.024,28]dotriaconta- 1(27),2,4,6,8(31),15(30),16,18,21(29),22,24(28),25-dodecaen-10-one Step 1: Synthesis of methyl 4-[(6-bromo-2-pyridyl)oxy]butanoate To a mixture of NaH (172 mg, 4.30 mmol, 60% dispersion in mineral oil) in DMF (5.0 mL) was added 6-bromopyridin-2-ol (0.50 g, 2.87 mmol) in DMF (3.0 mL) at 0℃. After addition, the mixture was stirred at this temperature for 30 min, and methyl 4-chlorobutanoate (500 mg, 3.66 mmol) in DMF (3.0 mL) was added dropwise at 0℃. The resulting mixture was stirred at 120 ℃ for 4 h. The reaction mixture was quenched with water (10 mL) at 0 ℃, and was extracted with EtOAc (15 mL × 3). The combined organic layers were washed with brine (30 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0~20%, Flow Rate: 30 mL / min, 254 nm) to give methyl 4-[(6- bromo-2-pyridyl)oxy]butanoate (336 mg, 42.4% yield) as a yellow oil. LCMS (ESI) m / z 274.0 [M+H]+. Step 2: Synthesis of methyl 4-[[6-[[5-[5-[tert-butoxycarbonyl(methyl)amino]-1,3-benzoxazol- 2-yl]-8-(methylamino)-2,7-naphthyridin-3-yl]amino]-2-pyridyl]oxy]butanoate

[0026] Dissolved tert butyl N-[2-[6-amino-1-(methylamino)-2,7-naphthyridin-4-yl]-1,3-benzoxazol-5- yl]-N-methyl-carbamate (200 mg, 0.476 mmol), methyl 4-[(6-bromo-2-pyridyl)oxy]butanoate (160 mg, 0.584 mmol), Pd2(dba)3(44.0 mg, 48.1 μmol), Cs2CO3(465 mg, 1.43 mmol) and DavePhos (37.0 mg, 94.0 μmol) in dioxane (10 mL) in a sealed tube. The sealed tube was heated at 120 ℃ for 2 h under a microwave irradiation condition. The resulting mixture was quenched with water(20 mL) and extracted with dichloromethane (30 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 chromatography (ISCO®; 4 g AgelaFlash® Silica Flash Column, Dichloromethane / Methanol with Methanol from 0~5%, flow rate =30 mL / min, 254 nm) to give methyl 4-[[6-[[5-[5-[tert-butoxycarbonyl(methyl)amino]-1,3- benzoxazol-2-yl]-8-(methylamino)-2,7-naphthyridin-3-yl]amino]-2-pyridyl]oxy]butanoate (160 mg, 45.0% yield) as a yellow solid. LCMS (ESI) m / z 614.3 [M+H]+. Step 3: Synthesis of methyl 4-[[6-[[8-(methylamino)-5-[5-(methylamino)-1,3-benzoxazol-2- yl]-2,7-naphthyridin-3-yl]amino]-2-pyridyl]oxy]butanoate The solution of methyl 4-[[6-[[5-[5-[tert-butoxycarbonyl(methyl)amino]-1,3-benzoxazol-2-yl]-8- (methylamino)-2,7-naphthyridin-3-yl]amino]-2-pyridyl]oxy]butanoate (350 mg, 0.570 mmol) in 4M HCl / MeOH (10 mL) was stirred at 20℃ for 1 h. The reaction mixture was concentrated under reduced pressure to provide methyl 4-[[6-[[8-(methylamino)-5-[5-(methylamino)-1,3-benzoxazol- 2-yl]-2,7-naphthyridin-3-yl]amino]-2-pyridyl]oxy]butanoate (280 mg, crude) as a yellow solid. LCMS (ESI) m / z 514.3 [M+H]+. Step 4: Synthesis of 4-[[6-[[8-(methylamino)-5-[5-(methylamino)-1,3-benzoxazol-2-yl]-2,7- naphthyridin-3-yl]amino]-2-pyridyl]oxy]butanoic acid To a solution of methyl 4-[[6-[[8-(methylamino)-5-[5-(methylamino)-1,3-benzoxazol-2-yl]-2,7- naphthyridin-3-yl]amino]-2-pyridyl]oxy]butanoate (280 mg, 0.545 mmol) in THF (5.0 mL) and H2O (1.0 mL) was added LiOH-H2O (114 mg, 2.72 mmol). The mixture was stirred at 20℃ for 3 h. An additional amount of HCl solution (2N, 5.0 mL) was added to the stirring mixture. The reaction mixture was concentrated under reduced pressure to remove solvent. The crude product was purified by reversed-phase HPLC (Column: SepaFlash®Sphercial C18, 25 g,40-60 μm, 120Å;MeCN / water (0.5%NH3-H2O) with MeCN from 0-25%, 25mL / min, 254 nm). to provide 4- [[6-[[8-(methylamino)-5-[5-(methylamino)-1,3-benzoxazol-2-yl]-2,7-naphthyridin-3-yl]amino]- 2-pyridyl]oxy]butanoic acid (250 mg, 75.3% yield) as a yellow solid. LCMS (ESI) m / z 500.2 [M+H]+. Step 5: Synthesis of 9-methyl-25-(methylamino)-14,32-dioxa-3,9,20,22,26,30- hexazahexacyclo[19.6.2.12,5.14,8.115,19.024,28]dotriaconta- 1(27),2,4,6,8(31),15(30),16,18,21(29),22,24(28),25-dodecaen-10-one

[0027] A solution of 4-[[6-[[8-(methylamino)-5-[5-(methylamino)-1,3-benzoxazol-2-yl]-2,7- naphthyridin-3-yl]amino]-2-pyridyl]oxy]butanoic acid (100 mg, 0.200 mmol), TCFH (90.0 mg, 0.321 mmol), NMI (51.5 mg, 0.627 mmol) in DMF (4.0 mL) was stirred at 20 ℃ for 2 h under N2atmosphere. The resulting mixture was quenched with water (50 mL) and extracted with dichloromethane (60 mL × 3). The combined organic layers were washed with brine (100 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. 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 33% to 36% in 7.8 min, hold 100% B for 2 min; Flow Rate: 25 mL / min; Column Temperature: 30 ℃; Wavelength: 220 nm); to provide 9-methyl-25-(methylamino)-14,32-dioxa-3,9,20,22,26,30- hexazahexacyclo[19.6.2.12,5.14,8.115,19.024,28]dotriaconta- 1(27),2,4,6,8(31),15(30),16,18,21(29),22,24(28),25-dodecaen-10-one (7.5 mg, 7.78% yield) as a yellow solid. LCMS (ESI) m / z 482.1 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ ppm 9.97 (s, 1H), 9.44 (s, 1H), 9.35 (s, 1H), 8.61 (s, 1H), 8.49 (br d, J = 3.9 Hz, 1H), 7.94 - 7.74 (m, 2H), 7.61 (t, J = 8.0 Hz, 1H), 7.44 (dd, J = 8.5, 2.1 Hz, 1H), 6.79 (d, J = 7.9 Hz, 1H), 6.33 (d, J = 8.1 Hz, 1H), 4.10 – 3.97 (m, 2H), 3.08 (d, J = 3.4 Hz, 3H), 2.43 - 2.36 (m, 2H), 2.23 - 2.15 (m, 2H), 3.37 (s, 3H). Example 18: (Z)-9-methyl-28-(methylamino)-5-oxa-3,9-diaza-1(2,5)-benzo[d]oxazola-2(5,3)- naphthyridina-4(2,6)-pyridinacyclodecaphan-10-one Step 1: Synthesis of methyl 2-(6-(cyclopropanecarboxamido)-1-(methylamino)-2,7- naphthyridin-4-yl)benzo[d]oxazole-5-carboxylate

[0028] A mixture of methyl 1,3-benzoxazole-5-carboxylate (500 mg, 2.82 mmol), N-[5-bromo-8- (methylamino)-2,7-naphthyridin-3-yl]cyclopropanecarboxamide (650 mg, 2.02 mmol), Pd(PPh3)4 (650 mg, 0.563 mmol), Cs2CO3 (2.76 g, 8.47 mmol) in DMF (10 mL) was degassed and purged with N23 times. The mixture was stirred at 110 °C for 12 h under N2atmosphere. The reaction mixture was cooled to RT and quenched with water (100 mL) at 25℃, and then extracted with EtOAc (100 mL ´ 3). The combined organic layers were washed with brine (100 mL ´ 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, DCM / MeOH with MeOH from 0 ~ 10%, flow rate: 45 mL / min, 254 nm); to provide methyl 2-[6- (cyclopropanecarbonylamino)-1-(methylamino)-2,7-naphthyridin-4-yl]-1,3-benzoxazole-5- carboxylate (350 mg, 29.7% yield) as a brown solid. LCMS (ESI) m / z 418.0 [M+H]+. Step 2: Synthesis of 2-(6-amino-1-(methylamino)-2,7-naphthyridin-4-yl)benzo[d]oxazole-5- carboxylic acid A mixture of methyl 2-[6-(cyclopropanecarbonylamino)-1-(methylamino)-2,7-naphthyridin-4-yl]- 1,3-benzoxazole-5-carboxylate (200 mg, 0.479 mmol), NaOH (200 mg, 5.00 mmol) in MeOH (10 mL) and H2O (10 mL) was degassed and purged with N23 times. The mixture was stirred at 60 °C for 12 h under N2atmosphere. The reaction mixture was filtered and concentrated under reduced pressure. The crude product was purified by reversed-phase HPLC (Column: SepaFlash® Sphercial C18, 25 g, 40 - 60 μm, 120 Å; MeCN / water (0.5% NH3-H2O) with MeCN from 0 - 29%, 25 mL / min, 254 nm), to provide 2-[6-amino-1-(methylamino)-2,7-naphthyridin-4-yl]-1,3- benzoxazole-5-carboxylic acid (50.0 mg, 41.5% yield) as a yellow solid. LCMS (ESI) m / z 336.0 [M+H]+. Step 3: Synthesis of 2-(6-amino-1-(methylamino)-2,7-naphthyridin-4-yl)-N-(3-((6- bromopyridin-2-yl)oxy)propyl)-N-methylbenzo[d]oxazole-5-carboxamide A mixture of 2-[6-amino-1-(methylamino)-2,7-naphthyridin-4-yl]-1,3-benzoxazole-5-carboxylic acid (120 mg, 0.358 mmol), 3-[(6-bromo-2-pyridyl)oxy]-N-methyl-propan-1-amine (150 mg, 0.533 mmol, HCl salt), HOBt (60.0 mg, 0.444 mmol), EDCI (80.0 mg, 0.417 mmol), pyridine (15.0 mg, 0.190 mmol) in DMF (10 mL) was degassed and purged with N2 for 3 times. The reaction mixture was stirred at 20°C for 2 h under N2atmosphere. The reaction mixture was quenched with H2O (100 mL) at 25 ℃, and extracted with EtOAc (100 mL ´ 3). The combined organic layers were washed with brine (100 mL ´ 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product mixture was purified by flash chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, DCM / MeOH with MeOH from 0 ~ 5%, flow rate: 85 mL / min, 254 nm); to provide 2-[6-amino-1-(methylamino)-2,7-naphthyridin- 4-yl]-N-[3-[(6-bromo-2-pyridyl)oxy]propyl]-N-methyl-1,3-benzoxazole-5-carboxamide (90 mg, 44.7% yield) as a yellow solid. LCMS (ESI) m / z 564.1 [M+H]+. Step 4: Synthesis of (Z)-9-methyl-28-(methylamino)-5-oxa-3,9-diaza-1(2,5)-benzo[d]oxazola- 2(5,3)-naphthyridina-4(2,6)-pyridinacyclodecaphan-10-one A mixture of 2-[6-amino-1-(methylamino)-2,7-naphthyridin-4-yl]-N-[3-[(6-bromo-2- pyridyl)oxy]propyl]-N-methyl-1,3-benzoxazole-5-carboxamide (30.0 mg, 53.3 μmol), Cs2CO3 (36.0 mg, 0.110 mmol), EPhos (4.20 mg, 7.85 μmol), EPhos Pd G4 (5.40 mg, 5.88 μmol) in dioxane (20 mL) was degassed and purged with N23 times. The mixture was stirred at 120 °C for 2 h under N2 atmosphere. The reaction mixture was quenched with H2O (20 mL) at 25 ℃, and then extracted with EtOAc (20 mL ´ 3). The combined organic layers were washed with brine (20 mL ´ 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. 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% HCl (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 provide compound (Z)-9-methyl-28-(methylamino)-5-oxa-3,9-diaza-1(2,5)- benzo[d]oxazola-2(5,3)-naphthyridina-4(2,6)-pyridinacyclodecaphan-10-one (1.00 mg, 3.89% yield) as a yellow solid. LCMS (ESI) m / z 482.1 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ ppm 10.43 (br s, 1H), 9.65 - 9.59 (m, 2H), 8.42 (s, 1H), 8.15 (s, 1H), 7.90 (d, J = 8.5 Hz, 1H), 7.63 - 7.72 (m, 2H), 6.88 (d, J = 8.1 Hz, 1H), 6.45 (d, J = 8.2 Hz, 1H), 4.09 - 4.04 (m, 2H), 3.20 (br d, J = 4.3 Hz, 3H), 3.07 (s, 3H), 2.54 (s, 2H), 2.46 - 2.40 (m, 2H). Example 19: (Z)-28-(methylamino)-11-oxa-3-aza-1(2,5)-benzo[d]oxazola-2(5,3)- naphthyridinacycloundecaphan-4-one Step 1: Synthesis of 7-((tert-butyldimethylsilyl)oxy)-N-(5-(5-hydroxybenzo[d]oxazol-2-yl)-8- (methylamino)-2,7-naphthyridin-3-yl)heptanamide

[0029] To a mixture of 4-(5-methoxy-1,3-benzoxazol-2-yl)-N1-methyl-2,7-naphthyridine-1,6-diamine (130 mg, 404 μmol),7-[tert-butyl(dimethyl)silyl]oxyheptanoic acid (105 mg, 404 μmol) in pyridine (5 mL) was added POCl3(186 mg, 1.21 mmol) at 0 °C. The mixture was stirred at 25°C for 3 h under N2atmosphere. The reaction was diluted with EtOAc (10 mL) and washed with brine (20 mL × 2), dried over Na2SO4, filtered, and then concentrated under reduced pressure, and purified by flash chromatography (ISCO®; 10 g SepaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0~100%, 12 mL / min, 254 nm) to give 7-[tert- butyl(dimethyl)silyl]oxy-N-[5-(5-methoxy-1,3-benzoxazol-2-yl)-8-(methylamino)-2,7- naphthyridin-3-yl]heptanamide (80 mg, 35.1% yield) as a yellow solid. LCMS (ESI) m / z 564.3 [M+H]+. Step 2: Synthesis of 7-bromo-N-(5-(5-hydroxybenzo[d]oxazol-2-yl)-8-(methylamino)-2,7- naphthyridin-3-yl)heptanamide To a mixture of 7-[tert-butyl(dimethyl)silyl]oxy-N-[5-(5-methoxy-1,3-benzoxazol-2-yl)-8- (methylamino)-2,7-naphthyridin-3-yl]heptanamide (80 mg, 141 μmol) in DCM (10 mL) was added BBr3(355 mg, 1.42 mmol).The mixture was stirred at 25 °C for 3 h under N2atmosphere. The reaction was diluted with DCM (20 mL), quenched with MeOH (10 mL) and a saturated NaHCO3 aqueous solution (10 mL), extracted with EtOAc (20 mL) and washed with brine (20 mL × 2), dried over Na2SO4, filtered and then concentrated under reduced pressure to give 7-bromo- N-[5-(5-hydroxy-1,3-benzoxazol-2-yl)-8-(methylamino)-2,7-naphthyridin-3-yl]heptanamide (70 mg, crude). The crude product mixture was taken directly to the next reaction without further purification. LCMS (ESI) m / z 498.1 [M+H]+. Step 3: Synthesis of example 19: (Z)-28-(methylamino)-11-oxa-3-aza-1(2,5)- benzo[d]oxazola-2(5,3)-naphthyridinacycloundecaphan-4-one To a mixture of 7-bromo-N-[5-(5-hydroxy-1,3-benzoxazol-2-yl)-8-(methylamino)-2,7- naphthyridin-3-yl]heptanamide (70 mg, 140 μmol) in CH3CN (100 mL) was added Cs2CO3 (91.5 mg, 280 μmol). The reaction mixture was stirred at 80°C for 2 h under N2 atmosphere. The solution was filtered and concentrated to give a crude product. The crude product was further purified by pre-HPLC (column: Boston Green ODS 150 × 30 mm × 5 μm; mobile phase: [water(HCl)-ACN]; gradient: 21% - 61% B over 9 min) to give 22-(methylamino)-9,28-dioxa-3,17,19,23- tetrazapentacyclo [16.6.2.12,5.14,8.021,25]octacosa-1(24),2,4,6,8(27),18(26),19,21(25),22- nonaen-16-one (6.5 mg, 11.1% yield, HCl salt) as a white solid. LCMS (ESI) m / z 418.2 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ ppm 10.91 (br s, 1H), 9.76 (s, 1H), 9.56 (s, 2H), 8.66 (br s, 1H), 7.57 (d, J = 8.8 Hz, 1H), 7.11 (d, J = 2.0 Hz, 1H), 6.86 (dd, J = 8.6, 2.4 Hz, 1H), 5.45 (s, 1H), 3.54 - 3.55 (m, 2H), 3.16 (br d, J = 4.0 Hz, 3H), 2.53 - 2.60 (m, 2H), 2.45 - 2.50 (m, 2H), 1.97 - 2.13 (m, 2H), 1.58 - 1.72 (m, 4H). Example 20: 9,12-dimethyl-25-(methylamino)-14,32-dioxa-3,9,20,22,26,30- hexazahexacyclo[19.6.2.12,5.14,8.115,19.024,28]dotriaconta- 1(27),2,4,6,8(31),15(30),16,18,21(29),22,24(28),25-dodecaen-10-one

[0030] Step 1: Synthesis of 4-methoxy-2-methyl-4-oxo-butanoic acid To a mixture of 4-methoxy-2-methylene-4-oxo-butanoic acid (5 g, .0.034 mmol) in MeOH (10 mL) was added Pd / C (500 mg, 0.469 mmol, 10 wt% of Pd with 50 wt% water). The mixture was stirred at 20 °C for 12 h under H2. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to afford 4-methoxy-2-methyl-4-oxo-butanoic acid (5 g, crude) as a colorless oil. LCMS (ESI) m / z 146.8 [M+H]+. Step 2: Synthesis of methyl 4-hydroxy-3-methyl-butanoate To a solution of 4-methoxy-2-methyl-4-oxo-butanoic acid (500 mg, 3.42 mmol) in THF (5 mL) was added BH3-DMS (10 M, 0.43 mL) at -30 °C and the mixture was stirred at 0 °C for 1.5 h. The reaction solution is quenched by pouring into MeOH solution, and then with water (30 mL) at 20 °C. The solution was extracted with EtOAc (50 mL ´ 3). The combined organic layers were washed with brine (50 mL ´ 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure and purify to provide methyl 4-hydroxy-3-methyl-butanoate (400 mg, 88.5% yield) as a colorless oil.1H NMR (500 MHz, CDCl3) δ ppm 3.64 - 3.70 (m, 3 H), 3.50 - 3.57 (m, 1 H), 3.43 - 3.48 (m, 2 H), 2.40 - 2.49 (m, 1 H), 2.08 - 2.25 (m, 2 H), 0.90 - 0.98 (m, 3 H). Step 3: Synthesis to methyl 4-[(6-bromo-2-pyridyl)oxy]-3-methyl-butanoate To a solution of methyl 4-hydroxy-3-methyl-butanoate (400 mg, 3.03 mmol), 6-bromopyridin-2- ol (550 mg, 3.16 mmol), PPh3(1.6 g, 6.10 mmol) in THF (20 mL) was added DIAD (900 mg, 4.45 mmol). The reaction mixture was stirred at 20 °C for 12 h under N2. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with water (20 mL) and extracted with EtOAc (40 mL ´ 2). The combined organic layers were washed with brine (40 mL ´ 2), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0~20%, flow rate: 40 mL / min, 254 nm). Methyl 4-[(6- bromo-2-pyridyl)oxy]-3-methyl-butanoate (600 mg, 68.8% yield) as a colorless oil. LCMS (ESI) m / z 287.9 [M+H]+. Example 20: 9,12-dimethyl-25-(methylamino)-14,32-dioxa-3,9,20,22,26,30- hexazahexacyclo[19.6.2.12,5.14,8.115,19.024,28]dotriaconta- 1(27),2,4,6,8(31),15(30),16,18,21(29),22,24(28),25-dodecaen-10-one was synthesized using a similar procedure that was previously described in Example 17 by using tert-butyl N-[2-[6-amino- 1-(methylamino)-2,7-naphthyridin-4-yl]-1,3-benzoxazol-5-yl]-N-methyl-carbamate and methyl 4-((6-bromopyridin-2-yl)oxy)-3-methylbutanoate as the starting material. Analytical data for Example 20 (9,12-dimethyl-25-(methylamino)-14,32-dioxa- 3,9,20,22,26,30-hexazahexacyclo[19.6.2.12,5.14,8.115,19.024,28]dotriaconta- 1(27),2,4,6,8(31),15(30),16,18,21(29),22,24(28),25-dodecaen-10-one): LCMS (ESI) m / z 496.1 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ ppm 9.93 (s, 1H), 9.34 (s, 1H), 9.29 (s, 1H), 8.56 (s, 1H), 8.45 (br d, J = 4.52 Hz, 1H), 7.88 - 7.81 (m, 2H), 7.59 (t, J = 8.03 Hz, 1H), 7.42 (dd, J = 8.66, 2.13 Hz, 1H), 6.77 (d, J = 8.03 Hz, 1H), 6.35 (d, J = 8.03 Hz, 1H), 3.79 (br d, J = 3.26 Hz, 2H), 3.35 (br s, 3H), 3.07 (d, J = 4.52 Hz, 3H), 2.92 (dd, J = 13.30, 4.77 Hz, 1H), 2.16 (br s, 1H), 1.87 (dd, J = 13.68, 9.91 Hz, 1H), 1.00 (d, J = 7.03 Hz, 3H).

[0031] Example 21 and 22: (12R)-9,12-dimethyl-25-(methylamino)-14,32-dioxa-3,9,20,22,26,30- hexazahexacyclo[19.6.2.12,5.14,8.115,19.024,28]dotriaconta- 1(27),2,4,6,8(31),15(30),16,18,21(29),22,24(28),25-dodecaen-10-one and (12S)-9,12-dimethyl- 25-(methylamino)-14,32-dioxa-3,9,20,22,26,30- hexazahexacyclo[19.6.2.12,5.14,8.115,19.024,28]dotriaconta- 1(27),2,4,6,8(31),15(30),16,18,21(29),22,24(28),25-dodecaen-10-one and Example 20 was separated by chiral SFC to give Example 21 and Example 22. Example 21 (FR-a): LCMS (ESI) m / z 496.1 [M+H]+; Chiral purity: 100.0%;1H NMR (400 MHz, DMSO-d6) δ ppm 9.93 (s, 1H), 9.34 (s, 1H), 9.29 (s, 1H), 8.56 (s, 1H), 8.45 (br d, J = 4.52 Hz, 1H), 7.88 - 7.81 (m, 2H), 7.59 (t, J = 8.03 Hz, 1H), 7.42 (dd, J = 8.66, 2.13 Hz, 1H), 6.77 (d, J = 8.03 Hz, 1H), 6.35 (d, J = 8.03 Hz, 1H), 3.79 (br d, J = 3.26 Hz, 2H), 3.35 (br s, 3H), 3.07 (d, J = 4.52 Hz, 3H), 2.92 (dd, J = 13.30, 4.77 Hz, 1H), 2.16 (br s, 1H), 1.87 (dd, J = 13.68, 9.91 Hz, 1H), 1.00 (d, J = 7.03 Hz, 3H). Example 22 (FR-b): LCMS (ESI) m / z 496.1 [M+H]+; Chiral purity: 99.4%;1H NMR (400 MHz, DMSO-d6) δ ppm 9.93 (s, 1H), 9.34 (s, 1H), 9.29 (s, 1H), 8.56 (s, 1H), 8.45 (br d, J = 4.52 Hz, 1H), 7.88 - 7.81 (m, 2H), 7.59 (t, J = 8.03 Hz, 1H), 7.42 (dd, J = 8.66, 2.13 Hz, 1H), 6.77 (d, J = 8.03 Hz, 1H), 6.35 (d, J = 8.03 Hz, 1H), 3.79 (br d, J = 3.26 Hz, 2H), 3.35 (br s, 3H), 3.07 (d, J = 4.52 Hz, 3H), 2.92 (dd, J = 13.30, 4.77 Hz, 1H), 2.16 (br s, 1H), 1.87 (dd, J = 13.68, 9.91 Hz, 1H), 1.00 (d, J = 7.03 Hz, 3H). Example 23: 9-methyl-24-(methylamino)-13,31-dioxa-3,9,19,21,25,29- hexazahexacyclo[18.6.2.12,5.14,8.114,18.023,27]hentriaconta- 1(26),2,4,6,8(30),14(29),15,17,20(28),21,23(27),24-dodecaen-10-one Synthesis of Example 23: 9-methyl-24-(methylamino)-13,31-dioxa-3,9,19,21,25,29- hexazahexacyclo[18.6.2.12,5.14,8.114,18.023,27]hentriaconta- 1(26),2,4,6,8(30),14(29),15,17,20(28),21,23(27),24-dodecaen-10-one was synthesized using a similar procedure that was previously described in Example 17 by using tert-butyl N-[2-[6-amino- 1-(methylamino)-2,7-naphthyridin-4-yl]-1,3-benzoxazol-5-yl]-N-methyl-carbamate and methyl 3- [(6-bromo-2-pyridyl)oxy]propanoate as the starting material. LCMS (ESI) m / z 468.0 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ ppm 10.52 (s, 1H), 10.51 - 10.40 (m, 1H), 10.07 (s, 1H), 9.63 (s, 1H), 8.40 (s, 1H), 7.94 (d, J = 8.8 Hz, 1H), 7.76 (d, J = 2.3 Hz, 1H), 7.71 (t, J = 8.0 Hz, 1H), 7.54 (dd, J = 8.7, 2.1 Hz, 1H), 6.85 (d, J = 8.0 Hz, 1H), 6.52 (d, J = 8.0 Hz, 1H), 4.27 (br s, 2H), 3.33 (s, 3H), 3.22 (br d, J = 4.0 Hz, 3H), 2.30 (br s, 2H). Example 24: 25-(methylamino)-14,32-dioxa-3,9,20,22,26,30- hexazahexacyclo[19.6.2.12,5.14,8.115,19.024,28]dotriaconta- 1(27),2,4,6,8(31),15(30),16,18,21(29),22,24(28),25-dodecaen-10-one Step 1: Synthesis of methyl 4-((6-((5-(5-((tert-butoxycarbonyl)amino)benzo[d]oxazol-2-yl)-8- (methylamino)-2,7-naphthyridin-3-yl)amino)pyridin-2-yl)oxy)butanoate

[0032] Methyl 4-((6-((5-(5-((tert-butoxycarbonyl)amino)benzo[d]oxazol-2-yl)-8-(methylamino)-2,7- naphthyridin-3-yl)amino)pyridin-2-yl)oxy)butanoate was synthesized using a similar procedure that was previously described in Example 17 by using tert-butyl N-[2-[6-amino-1-(methylamino)- 2,7-naphthyridin-4-yl]-1,3-benzoxazol-5-yl]carbamate and methyl 4-[(6-bromo-2-pyridyl)oxy] butanoate as the starting material. LCMS (ESI) m / z 600.1 [M+H]+. Step 2: Synthesis of methyl 4-((6-((5-(5-aminobenzo[d]oxazol-2-yl)-8-(methylamino)-2,7- naphthyridin-3-yl)amino)pyridin-2-yl)oxy)butanoate A solution of methyl 4-[[6-[[5-[5-(tert-butoxycarbonylamino)-1,3-benzoxazol-2-yl]-8- (methylamino)-2,7-naphthyridin-3-yl]amino]-2-pyridyl]oxy]butanoate (370 mg, 0.62 mmol, 1 eq) in HCl / MeOH (5 mL) was stirred at 25 °C for 2 h. The progress of the reaction was monitored via LCMS.The reaction mixture was concentrated under reduced pressure to give methyl 4-[[6-[[5-(5- amino-1, 3-benzoxazol-2-yl)-8-(methylamino)-2,7-naphthyridin-3-yl]amino]-2- pyridyl]oxy]butanoate (300 mg, crude), as a yellow solid. LCMS (ESI) m / z 500.1 [M+H]+. Step 3: Synthesis of 4-((6-((5-(5-aminobenzo[d]oxazol-2-yl)-8-(methylamino)-2,7- naphthyridin-3-yl)amino)pyridin-2-yl)oxy)butanoic acid

[0033] To a stirred mixture of methyl 4-[[6-[[5-(5-amino-1,3-benzoxazol-2-yl)-8-(methylamino)-2,7- naphthyridin-3-yl]amino]-2-pyridyl]oxy]butanoate (300 mg, 0.60 mmol, 1 eq) in THF (5 mL) and H2O (5 mL) was added LiOH (43.15 mg, 1.80 mmol, 3.0 eq). The mixture was stirred at 25°C for 2 h. The mixture was acidified at 0oC with a solution of HCl (2N) to pH = 2-3 and concentrated under reduced pressure to give, 4-[[6-[[5-(5-amino-1,3-benzoxazol-2-yl)-8-(methylamino)-2,7- naphthyridin-3-yl]amino]-2-pyridyl]oxy]butanoic acid, (500 mg, crude) as a yellow solid. LCMS (ESI) m / z 486.0 [M+H]+. Step 4: Synthesis of 25-(methylamino)-14,32-dioxa-3,9,20,22,26,30- hexazahexacyclo[19.6.2.12,5.14,8.115,19.024,28]dotriaconta- 1(27),2,4,6,8(31),15(30),16,18,21(29),22,24(28),25-dodecaen-10-one: To a solution of 4-[[6-[[5-(5-amino-1,3-benzoxazol-2-yl)-8-(methylamino)-2,7-naphthyridin-3- yl]amino]-2-pyridyl]oxy]butanoic acid (500 mg, 0.51 mmol, 1 eq) in DMF (5 mL) was added TCFH (173.38 mg, 0.62 mmol, 1.2 eq) and NMI (147.97 mg, 1.80 mmol, 3.5 eq). The mixture was stirred at 25°C for 2 h. The reaction was monitored by LCMS. The reaction mixture was concentrated under reduced pressure to give a crude product, which was further purified by prep- HPLC (column: Phenomenex Synergi C18100 ´ 30 mm ´ 4 μm; mobile phase: [water (HCl)- ACN]; gradient:6%-36% B over 10 min) to give, 25-(methylamino)-14,32-dioxa-3,9,20,22,26,30- hexazahexacyclo[19.6.2.12,5.14,8.115,19.024,28]dotriaconta- 1(27),2,4,6,8(31),15(30),16,18,21(29),22,24(28),25-dodecaen-10-one (2.26 mg, 0.90% yield), as a yellow solid. LCMS (ESI) m / z 468.1 [M+H]+,1H NMR (400 MHz, DMSO-d6) δ ppm 10.14- 10.38 (m, 1H), 9.89 (d, J = 4.2 Hz, 2H), 9.39-9.63 (m, 1H), 8.32-8.64 (m, 1H), 7.80-7.88 (m, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.67 (t, J = 8.0 Hz, 1H), 7.14 (brd, J = 9.6 Hz, 1H), 6.88 (d, J = 8.0 Hz, 1H), 6.39-6.49 (m, 1H), 4.11 (br s, 2H), 3.17 (br d, J = 3.2 Hz, 3H), 2.58-2.61 (m, 2H), 2.27 (br d, J = 5.27 Hz, 2H). Example 25: (Z)-N-methyl-5,10-dioxa-3-aza-1(2,5)-benzo[d]oxazola-2(5,3)-naphthyridina- 4(2,6)-pyridinacyclodecaphan-28-amine Step 1: Synthesis of N-(5-(5-methoxybenzo[d]oxazol-2-yl)-8-(methylamino)-2,7- naphthyridin-3-yl)cyclopropanecarboxamide A mixture of N-[5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl]cyclopropanecarboxamide (1.5 g, 4.67 mmol), 5-methoxy-1,3-benzoxazole (836 mg, 5.60 mmol), Pd(PPh3)4(1.08 g, 934 µmol) and Cs2CO3 (4.57 g, 14.0 mmol) in DMF (50 mL) was transferred in a microwave tube. The resulting mixture was stirred at 110 °C for 16 h under N2 atmosphere. The reaction mixture was filtered under reduced pressure to give a crude product. The crude product was triturated with EA at 25 °C for 60 min to give N-[5-(5-methoxy-1,3-benzoxazol-2-yl)-8-(methylamino)-2,7- naphthyridin-3-yl]cyclopropanecarboxamide (1.4 g, 77.0% yield) as a yellow solid; LCMS (ESI) m / z 390.3 [M+H]+. Step 2: Synthesis of 4-(5-methoxybenzo[d]oxazol-2-yl)-N1-methyl-2,7-naphthyridine-1,6- diamine A solution of N-[5-(5-methoxy-1,3-benzoxazol-2-yl)-8-(methylamino)-2,7-naphthyridin-3- yl]cyclopropanecarboxamide (1.4 g, 3.60 mmol), NaOH (2.16 g, 53.9 mmol) in MeOH (70 mL), H2O (30 mL) and DMSO (10 mL) was stirred at 80 °C for 16 h under N2 atmosphere. The reaction mixture was filtered and concentrated to give a crude product. The crude product was triturated with H2O at 25 °C for 60 min to give 4-(5-methoxy-1,3-benzoxazol-2-yl)-N1-methyl-2,7- naphthyridine-1,6-diamine (1.1 g, 3.42 mmol, 95.2% yield) as a yellow solid. LCMS (ESI) m / z 322.4 [M+H]+. Step 3: Synthesis of 2-(6-amino-1-(methylamino)-2,7-naphthyridin-4-yl)benzo[d]oxazol-5-ol To a solution of 4-(5-methoxy-1,3-benzoxazol-2-yl)-N1-methyl-2,7-naphthyridine-1,6-diamine (1.1 g, 3.42 mmol) in DCM (10 mL) was added BBr3(2.57 g, 10.3 mmol). The mixture was stirred at 0 °C for 2 h under N2 atmosphere. The reaction mixture was filtered and concentrated to give a crude product. The crude product was triturated with MeOH at 25 °C for 60 min to give 2-[6- amino-1-(methylamino)-2,7-naphthyridin-4-yl]-1,3-benzoxazol-5-ol (2.2 g, crude) as a yellow solid; LCMS (ESI) m / z 308.1 [M+H]+. Step 4: Synthesis of 2-(6-((6-(4-hydroxybutoxy)pyridin-2-yl)amino)-1-(methylamino)-2,7- naphthyridin-4-yl)benzo[d]oxazol-5-ol A mixture of 2-[6-amino-1-(methylamino)-2,7-naphthyridin-4-yl]-1,3-benzoxazol-5-ol (300 mg, 976 μmol), 4-[(6-bromo-2-pyridyl)oxy]butan-1-ol (185 mg, 751 μmol), Cs2CO3 (734 mg, 2.25 mmol), RockPhos Pd G3(63.0 mg, 75.1 μmol) in dioxane (20 mL) was stirred at 100°C for 16 h under N2 atmosphere. The reaction mixture was filtered and concentrated to give a crude product. The crude was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash ® Silica Flash Column, Eluent of 0 ~ 20% Ethyl acetate / Petroleum ether gradient @ 12 mL / min) to give 2-[6- [[6-(4-hydroxybutoxy)-2-pyridyl]amino]-1-(methylamino)-2,7-naphthyridin-4-yl]-1,3- benzoxazol-5-ol (40 mg, 11.3% yield) as a yellow solid. LCMS (ESI) m / z 473.4 [M+H]+. Step 5: Synthesis of 2-(6-((6-(4-chlorobutoxy)pyridin-2-yl)amino)-1-(methylamino)-2,7- naphthyridin-4-yl)benzo[d]oxazol-5-ol A mixture of 2-[6-[[6-(4-hydroxybutoxy)-2-pyridyl]amino]-1-(methylamino)-2,7-naphthyridin-4- yl]-1,3-benzoxazol-5-ol (20 mg, 42.3 μmol) and SOCl2(5.04 mg, 42.3 μmol) in toluene (2 mL) was stirred at 50°C for 1 h under N2 atmosphere. The reaction mixture was filtered and concentrated to give 2-[6-[[6-(4-chlorobutoxy)-2-pyridyl]amino]-1-(methylamino)-2,7- naphthyridin-4-yl]-1,3-benzoxazol-5-ol (30 mg, 72.2% yield) as a yellow solid. LCMS (ESI) m / z 491.3 [M+H]+. Step 6: Synthesis of (Z)-N-methyl-5,10-dioxa-3-aza-1(2,5)-benzo[d]oxazola-2(5,3)- naphthyridina-4(2,6)-pyridinacyclodecaphan-28-amine A mixture of 2-[6-[[6-(4-chlorobutoxy)-2-pyridyl]amino]-1-(methylamino)-2,7-naphthyridin-4- yl]-1,3-benzoxazol-5-ol (30 mg, 61.1 μmol), Cs2CO3 (59.7 mg, 183 μmol) in DMF (2 mL) was stirred at 80 °C for 16 h under N2 atmosphere. The reaction mixture was filtered and concentrated to give a crude product. The crude product was purified by prep-HPLC (column: C18150 × 30 mm; mobile phase: [Water(HCl)-MeCN]; gradient: 21% - 61% B over 9 min) to give (Z)-N- methyl-5,10-dioxa-3-aza-1(2,5)-benzo[d]oxazola-2(5,3)-naphthyridina-4(2,6)- pyridinacyclodecaphan-28-amine (9 mg, 32.4% yield) as a yellow solid. LCMS (ESI) m / z 455.2 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ ppm 10.60 (s, 1H), 10.46 (s, 1H), 9.69 (br s, 2H), 8.30 (s, 1H), 7.68 - 7.75 (m, 2H), 7.58 - 7.63 (m, 1H), 7.03 - 7.09 (m, 1H), 6.85 - 6.90 (m, 1H), 6.50 - 6.57 (m, 1H), 4.30 - 4.37 (m, 2H), 4.15 (br s, 2H), 3.21 - 3.25 (m, 3H), 1.87 - 1.94 (m, 2H), 1.77 (br s, 2H). Example 26: (Z)-N-methyl-5,8,11,14-tetraoxa-3-aza-1(2,5)-benzo[d]oxazola-2(5,3)- naphthyridina-4(2,5)-pyridinacyclotetradecaphan-28-amine Step 1: 2-(2-(2-((6-bromopyridin-3-yl)oxy)ethoxy)ethoxy)ethan-1-ol To a mixture of 6-bromopyridin-3-ol (500.0 mg; 2.874 mmol; 1.00 eq.), K2CO3 (992.8 mg; 7.184 mmol; 2.50 eq.) and LiBr (249.5 mg; 2.873 mmol; 1.00 eq.) in DMF (25 mL) was added a solution of 2-(2-(2-chloroethoxy)ethoxy)ethan-1-ol (1.07 g; 6.323 mmol; 2.20 eq.) in DMF (10 mL). The mixture was stirred at 100 ℃ overnight. The desired product was detected via LCMS. The reaction solution was diluted with EtOAc (100 mL), washed with brine (3 × 20 mL), dried over Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on pre-packed C18 column using 40-60% of MeCN in water (10 mmol / L NH4HCO3) as eluent to provide 2-(2-(2-((6-bromopyridin-3-yl)oxy)ethoxy)ethoxy)ethan-1-ol as a light yellow oil (704.8 mg, 80.1%). LCMS (ESI) m / z 306.0, [M+H]+. Step 2: 2-(2-(2-((6-bromopyridin-3-yl)oxy)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate To a stirred solution of 2-(2-(2-((6-bromopyridin-3-yl)oxy)ethoxy)ethoxy)ethan-1-ol (650.0 mg; 2.123 mmol; 1.00 eq.), TEA (1.07 g; 10.615 mmol; 5.00 eq.) and DMAP (25.9 mg; 0.212 mmol; 0.10 eq.) in dichloroethane (20 mL) was added a solution of 4-methylbenzenesulfonyl chloride (1.01 g; 5.308 mmol; 2.50 eq.) in dichloroethane (10 mL) dropwise at 0 ℃. The resulting solution was stirred at 0 ℃ for 2 hours. The desired product was detected via LCMS. The reaction solution was diluted with CH2Cl2(150 mL), washed with brine (3 × 15 mL), dried over Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel column using 10-30% of EtOAc in petroleum ether as eluent to provide 2-(2-(2-((6-bromopyridin-3-yl)oxy)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate as a light yellow oil (904.8 mg, 92.5%). LCMS (ESI) m / z 460.0, [M+H]+. Step 3: N-(5-(5-hydroxybenzo[d]oxazol-2-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclop ropanecarboxamide To a solution of N-(5-(5-(benzyloxy)benzo[d]oxazol-2-yl)-8-(methylamino)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide (1.36 g; 2.922 mmol; 1.00 eq.) in a mixture solvent of DMA / MeOH (1:1, 40 mL) was added 10% Pd / C (3.40 g, 250% w / w) under nitrogen atmosphere. The mixture was hydrogenated at room temperature for 1 hour under hydrogen atmosphere (2 atm). The desired product was detected via LCMS. The mixture was filtered through a celite pad, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on pre- packed C18 column using 70-90% of MeOH in water (10 mmol / L NH4HCO3) as eluent to provide N-(5-(5-hydroxybenzo[d]oxazol-2-yl)-8-(methylamino)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide as a brown solid (800.0 mg, 72.1%). LCMS (ESI) m / z 376.1, [M+H]+. Step 4: N-(5-(5-(2-(2-(2-((6-bromopyridin-3-yl)oxy)ethoxy)ethoxy)ethoxy)benzo[d]oxazol-2- yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide A mixture of N-(5-(5-hydroxybenzo[d]oxazol-2-yl)-8-(methylamino)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide (140.0 mg; 0.373 mmol; 1.00 eq.), 2-(2-(2-((6-bromopyridin-3- yl)oxy)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (171.6 mg; 0.373 mmol; 1.00 eq.) and Cs2CO3 (243.1 mg; 0.746 mmol; 2.00 eq.) in DMF (6 mL) was stirred at 100 ℃ for 1 hour. The desired product was detected via LCMS. The mixture was purified by flash chromatography on pre-packed C18 column using 20-50% of MeOH in water (10 mmol / L NH4HCO3) as eluent to provide N-(5-(5-(2-(2-(2-((6-bromopyridin-3-yl)oxy)ethoxy)ethoxy)ethoxy)benzo[d]oxazol-2- yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a yellow solid (124.5 mg, 50.0%). LCMS (ESI) m / z 663.1, [M+H]+. Step 5: 4-(5-(2-(2-(2-((6-bromopyridin-3-yl)oxy)ethoxy)ethoxy)ethoxy)benzo[d]oxazol-2-yl)- N1-methyl-2,7-naphthyridine-1,6-diamine To a stirred solution of N-(5-(5-(2-(2-(2-((6-bromopyridin-3- yl)oxy)ethoxy)ethoxy)ethoxy)benzo[d]oxazol-2-yl)-8-(methylamino)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide (120.0 mg; 0.181 mmol; 1.00 eq.) in a mixture solvent of DMSO / MeOH (1:5, 7.2 mL) was added a solution of NaOH (72.5 mg; 1.813 mmol; 10.00 eq.) in water (1.8 mL) at 0 ℃. The resulting solution was stirred at 60 ℃ overnight. The desired product was detected via LCMS. The mixture was allowed to cool to room temperature, the precipitated solids were collected by filtration and washed with water (3 × 5 mL). The solids were dried under vacuum to afford 4-(5-(2-(2-(2-((6-bromopyridin-3- yl)oxy)ethoxy)ethoxy)ethoxy)benzo[d]oxazol-2-yl)-N1-methyl-2,7-naphthyridine-1,6-diamine as a yellow solid (76.4 mg, 48.2%). LCMS (ESI) m / z 595.1, [M+H]+. Step 6: (Z)-N-methyl-5,8,11,14-tetraoxa-3-aza-1(2,5)-benzo[d]oxazola-2(5,3)-naphthyridina- 4(2,5)-pyridinacyclotetradecaphan-28-amine A mixture of 4-(5-(2-(2-(2-((6-bromopyridin-3-yl)oxy)ethoxy)ethoxy)ethoxy)benzo[d]oxazol-2- yl)-N1-methyl-2,7-naphthyridine-1,6-diamine (76.4 mg; 0.128 mmol; 1.00 eq.), EPhos Pd G4 (11.8 mg; 0.013 mmol; 0.10 eq.), EPhos (13.7 mg; 0.026 mmol; 0.20 eq.) and Cs2CO3(83.2 mg; 0.255 mmol; 1.99 eq.) in 1,4-dioxane (8 mL) was stirred at 120 ℃ for 2 hours under nitrogen atmosphere. The desired product was detected via LCMS. The solvent was concentrated under vacuum. The residue was purified by flash chromatography on silica gel column using 10-30% of MeOH in CH2Cl2as eluent to provide (Z)-N-methyl-5,8,11,14-tetraoxa-3-aza-1(2,5)-benzo[d]oxazola- 2(5,3)-naphthyridina-4(2,5)-pyridinacyclotetradecaphan-28-amine as a yellow solid (21.2 mg, 32%). LCMS (ESI) m / z 515.2, [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.08 (s, 1H), 9.84 (s, 1H), 9.32 (s, 1H), 8.78 (s, 1H), 8.48 - 8.45 (m, 1H), 8.25 (d, J = 2.8 Hz, 1H), 7.61 (d, J = 8.8 Hz, 1H), 7.46 (dd, J = 8.8, 2.8 Hz, 1H), 7.35 (d, J = 2.4 Hz, 1H), 7.14 (d, J = 8.4 Hz, 1H), 6.96 (dd, J = 8.4, 2.4 Hz, 1H), 4.30 - 4.25 (m, 4H), 3.85 - 3.50 (m, 8H), 3.07 (d, J = 4.4 Hz, 3H). Example 27: (12Z,42E)-N-methyl-41H-8-oxa-3-aza-1(2,4)-benzo[d]oxazola-2(5,3)- naphthyridina-4(3,1)-pyrazolacyclooctaphan-28-amine Step 1: Synthesis of 3-(3-bromo-1H-pyrazol-1-yl)propan-1-ol To a stirred solution of 3-bromo-1H-pyrazole (2 g; 13.6 mmol; 1.00 eq.) and Cs2CO3 (13.5 g; 41.4 mmol; 3.00 eq.) in DMF (30 mL) was added 3-bromopropan-1-ol (3.8 g; 27.3 mmol; 2.00 eq.) at 0 ℃. The reaction was stirred at room temperature for 14 hours. The mixture was diluted with EtOAc (200 mL) and washed brine (3 × 50 mL). The organic phase was separated, dried over Na2SO4, concentrated under reduced pressure and purified by flash chromatography on silica gel column using 30-60% of EtOAc in petroleum ether as eluent to provide a mixture of 3-(3-bromo- 1H-pyrazol-1-yl)propan-1-ol and 3-(5-bromo-1H-pyrazol-1-yl)propan-1-ol. The mixture was separated by Prep-Achiral-SFC (5 μM GreenSep basic column, 3 × 15 cm, Mobile Phase A: CO2, Mobile Phase B: MeOH (0.1% 2 M NH3-MeOH); Flow rate: 75 mL / min; Gradient: isocratic 9% B.) to provide 3-(3-bromo-1H-pyrazol-1-yl)propan-1-ol as a yellow oil (313 mg, 22.4%). LCMS (ESI) m / z 205.0, [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 7.74 (d, J = 2.3 Hz, 1H), 6.35 (d, J = 2.3 Hz, 1H), 4.60 (t, J = 5.1 Hz, 1H), 4.18 - 4.09 (m, 2H), 3.39 - 3.36 (m, 1H), 3.18 - 3.16 (m, 1H), 1.92 - 1.84 (m, 2H). Step 2: 3-(3-bromo-1H-pyrazol-1-yl)propyl 4-methylbenzenesulfonate To a solution of 3-(3-bromo-1H-pyrazol-1-yl)propan-1-ol (140.0 mg; 0.686 mmol; 1.00 eq.) and Et3N (207.8 mg; 2.05 mmol; 3.00 eq.) and DMAP (12.5 mg; 0.1 mmol; 0.15 eq.) in CH2Cl2 (8 mL) was added 4-methylbenzenesulfonyl chloride (143.4 mg; 0.754 mmol; 1.1 eq.) at 0 ℃. The resulting mixture was stirred at 0 ℃ for 1.5 hours. The desired product was detected via LCMS. The reaction mixture was diluted with CH2Cl2 (30 mL) and washed with brine (2 × 10 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to provide 3-(3-bromo-1H-pyrazol-1-yl)propyl 4-methylbenzenesulfonate as a yellow oil (184 mg, crude). This crude product was taken directly to the next reaction without further purification. LCMS (ESI) m / z 358.0, [M+H]+. Step 3: N-(5-(4-hydroxybenzo[d]oxazol-2-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclop ropanecarboxamide A solution of N-(5-formyl-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (300 mg; 1.11 mmol; 1.00 eq.) and 2-aminobenzene-1,3-diol (138.8 mg; 1.11 mmol; 1.00 eq.) in a mixed solvent of toluene / DMSO (5:1, 30 mL) was stirred at 110 ℃ for 14 hours. The resulting mixture was concentrated under reduced pressure to remove toluene. To the above mixture were added CH2Cl2 (25 mL) and DDQ (277.2 mg; 1.22 mmol; 1.10 eq.). The resulting solution was stirred at room temperature for 2 hours. The desired product was detected via LCMS. The solvent was concentrated under reduced pressure. The remaining DMSO mixture was purified by flash chromatography on pre-packed C18 column using 20-100% of MeCN in water (10 mmol / L NH4HCO3) to provide the crude product. The crude product was further purified by flash chromatography on silica gel column using 2-6% of MeOH in CH2Cl2as eluent to provide N-(5- (4-hydroxybenzo[d]oxazol-2-yl)-8-(methylamino)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide as a yellow solid (130 mg, 32.1%). LCMS (ESI) m / z 376.1, [M+H]+. Step 4: N-(5-(4-(3-(3-bromo-1H-pyrazol-1-yl)propoxy)benzo[d]oxazol-2-yl)-8-(methylamin o)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide To a solution of N-(5-(4-hydroxybenzo[d]oxazol-2-yl)-8-(methylamino)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide (88.0 mg; 0.234 mmol; 1.00 eq.) and 3-(3-bromo-1H-pyrazol-1- yl)propyl 4-methylbenzenesulfonate (184.0 mg; 0.51 mmol; 2.20 eq.) in DMF (5 mL) was added Cs2CO3 (306.0 mg; 0.93 mmol; 4.00 eq.) under nitrogen atmosphere. The reaction was stirred at 100 ℃ for 14 hours. The desired product was detected via LCMS. The mixture was diluted with EtOAc (80 mL) and washed with brine (3 × 10 mL). The organic layer was dried over anhydrous Na2SO4,and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel column using 2-6% of MeOH in CH2Cl2 as eluent to provide N-(5- (4-(3-(3-bromo-1H-pyrazol-1-yl)propoxy)benzo[d]oxazol-2-yl)-8-(methylamino)-2,7- naphthyridin-3-yl)cyclopropanecarboxamide as a yellow solid (130 mg, 68.0%). LCMS (ESI) m / z 562.1, [M+H]+. Step 5: 4-(4-(3-(3-bromo-1H-pyrazol-1-yl)propoxy)benzo[d]oxazol-2-yl)-N1-methyl-2,7- naphthyridine-1,6-diamine To a stirred solution of N-(5-(4-(3-(3-bromo-1H-pyrazol-1-yl)propoxy)benzo[d]oxazol-2-yl)-8- (methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (110.0 mg; 0.19 mmol; 1.00 eq.) in MeOH (3 mL) was added dropwise a solution of NaOH (78.0 mg; 1.95 mmol; 9.97 eq.) in water (1 mL) at 0 ℃ under nitrogen atmosphere. The resulting mixture was stirred at 60 ℃ for 5 hours. The desired product was detected via LCMS. The mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel column using 2-6 % of MeOH in CH2Cl2 as eluent to provide 4-(4-(3-(3-bromo-1H-pyrazol-1- yl)propoxy)benzo[d]oxazol-2-yl)-N1-methyl-2,7-naphthyridine-1,6-diamine as a yellow solid (57 mg, 58.1%). LCMS (ESI) m / z 494.1, [M+H]+. Step 6: (12Z,42E)-N-methyl-41H-8-oxa-3-aza-1(2,4)-benzo[d]oxazola-2(5,3)-naphthyridina- 4(3,1)-pyrazolacyclooctaphan-28-amine To a mixture of 4-(4-(3-(3-bromo-1H-pyrazol-1-yl)propoxy)benzo[d]oxazol-2-yl)-N1-methyl-2,7- naphthyridine-1,6-diamine (30.0 mg; 0.06 mmol; 1.00 eq.) in 1,4-dioxane (3 mL) were added Cs2CO3(40.0 mg; 0.12 mmol; 2.02 eq.), EPhos (3.0 mg; 0.01 mmol; 0.09 eq.) and EPhos Pd G4(6.0 mg; 0.01 mmol; 0.11 eq.) under nitrogen atmosphere. The resulting solution was stirred at 120 ℃ for 2 hours. The desired product was detected via LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel column using 2-6% of MeOH in CH2Cl2as eluent to provide (12Z,42E)-N-methyl-41H-8-oxa- 3-aza-1(2,4)-benzo[d]oxazola-2(5,3)-naphthyridina-4(3,1)-pyrazolacyclooctaphan-28-amine as a yellow solid (20.0 mg, 79.0%). LCMS (ESI) m / z 414.2, [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 9.54 (s, 1H), 9.46 (s, 1H), 9.27 (s, 1H), 8.86 (s, 1H), 8.45 - 8.39 (m, 1H), 7.68 (d, J = 2.0 Hz, 1H), 7.33 - 7.28 (m, 1H), 7.25 - 7.18 (m, 1H), 6.89 - 6.83 (m, 1H), 5.94 (d, J = 2.0 Hz, 1H), 5.24 - 5.17 (m, 2H), 4.29 - 4.23 (m, 2H), 3.07 (d, J = 4.4 Hz, 3H), 2.23 - 2.15 (m, 2H). Example 28: 9,13-dimethyl-25-(methylamino)-14-oxa-3,4,9,20,22,26,30,32 octazahexacyclo[19.6.2.12,5.14,8.115,19.024,28]dotriaconta- 1(27),2,5(32),6,8(31),15(30),16,18,21,23,25,28-dodecaen-10-one Step 1: Synthesis of tert-butyl N-(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-N-methyl- carbamate To a mixture of 6-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (2 g, 8.60 mmol), tert-butyl N- methylcarbamate (1.24 g, 9.46 mmol), Cs2CO3(7.01 g, 21.5 mmol) in dioxane (40 mL) was added Xantphos Pd G4 (414 mg, 0.430 mmol), XPhos (410 mg, 0.860 mmol) and the mixture was stirred at 120 ℃ for 12 hr under N2 atmosphere. The resulting mixture was quenched with water (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0~50%, Flow Rate: 30 mL / min, 254 nm). to provide tert-butyl N-(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-N-methyl-carbamate (800 mg, 28.0% yield) as a white solid. LCMS (ESI) m / z 282.8 [M+H]+. Step 2: Synthesis of tert-butyl N-[2-[6-(cyclopropanecarbonylamino)-1-(methylamino)-2,7- naphthyridin-4-yl]-[1,2,4]triazolo[1,5-a]pyridin-6-yl]-N-methyl-carbamate

[0034] To a stirring mixture of N-[8-(methylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,7- naphthyridin-3-yl]cyclopropanecarboxamide (900 mg, 2.44 mmol), tert-butyl N-(2-chloro- [1,2,4]triazolo[1,5-a]pyridin-6-yl)-N-methyl-carbamate (770 mg, 2.72 mmol) in dioxane (10 mL) and H2O (2 mL) was added XPhos Pd G3 (207 mg, 0.245 mmol), XPhos (233 mg, 0.488 mmol), K3PO4 (1.30 g, 6.11 mmol) and the mixture was stirred at 100 ℃ for 12 h under N2 atmosphere. The resulting mixture was quenched with water (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Dichloromethane / Methanol with Methanol from 0~6%, Flow Rate: 30 mL / min, 254 nm). The desired product tert-butyl N-[2- [6-(cyclopropanecarbonylamino)-1-(methylamino)-2,7-naphthyridin-4-yl]-[1,2,4]triazolo[1,5- a]pyridin-6-yl]-N-methyl-carbamate (600 mg, 45.2% yield) was obtained as a yellow solid. LCMS (ESI) m / z 489.0 [M+H]+. Step 3: Synthesis of tert-butyl N-[2-[6-amino-1-(methylamino)-2,7-naphthyridin-4-yl]- [1,2,4]triazolo[1,5-a]pyridin-6-yl]-N-methyl-carbamate To a solution of tert-butyl N-[2-[6-(cyclopropanecarbonylamino)-1-(methylamino)-2,7- naphthyridin-4-yl]-[1,2,4]triazolo[1,5-a]pyridin-6-yl]-N-methyl-carbamate (600 mg, 1.23 mmol) in MeOH (15 mL) was added NaOH (245 mg, 6.13 mmol) in H2O (3.0 mL) and the mixture was stirred at 80 ℃ for 18 h. The reaction mixture was concentrated under a reduced pressure to remove solvent. The residue was diluted with water (100 mL) and extracted with dichloromethane (100 mL × 3). The combined organic layers were washed with brine (150 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The desired product tert-butyl N-[2-[6- amino-1-(methylamino)-2,7-naphthyridin-4-yl]-[1,2,4]triazolo[1,5-a]pyridin-6-yl]-N-methyl- carbamate (500 mg, crude) was obtained as a yellow solid. LCMS (ESI) m / z 421.0 [M+H]+. Step 4: Synthesis of tert-butyl 4-[[6-[[5-[6-[tert-butoxycarbonyl(methyl)amino]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]-8-(methylamino)-2,7-naphthyridin-3-yl]amino]-2- pyridyl]oxy]pentanoate To a reaction mixture of tert-butyl N-[2-[6-amino-1-(methylamino)-2,7-naphthyridin-4-yl]- [1,2,4]triazolo[1,5-a]pyridin-6-yl]-N-methyl-carbamate (300 mg, 0.713 mmol), tert-butyl 4-[(6- bromo-2-pyridyl)oxy]pentanoate (259 mg, 0.784 mmol), Cs2CO3 (581 mg, 1.78 mmol) in dioxane (25 mL) was added Brettphos (77 mg, 0.143 mmol), BrettPhos Pd G3 (65 mg, 71.7 μmol) and the mixture was stirred at 100 ℃ for 1 hr under N2atmosphere. The resulting mixture was quenched with water (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Dichloromethane / Methanol with Methanol from 0~8%, Flow Rate: 30 mL / min, 254 nm). The desired product tert-butyl 4-[[6-[[5-[6-[tert- butoxycarbonyl(methyl)amino]-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-8-(methylamino)-2,7- naphthyridin-3-yl]amino]-2-pyridyl]oxy]pentanoate (390 mg, 65.3% yield) was obtained as a yellow solid. LCMS (ESI) m / z 670.2 [M+H]+. Step 5: Synthesis of 4-[[6-[[8-(methylamino)-5-[6-(methylamino)-[1,2,4]triazolo[1,5- a]pyridin-2-yl]-2,7-naphthyridin-3-yl]amino]-2-pyridyl]oxy]pentanoic acid The solution of tert-butyl 4-[[6-[[5-[6-[tert-butoxycarbonyl(methyl)amino]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]-8-(methylamino)-2,7-naphthyridin-3-yl]amino]-2-pyridyl]oxy]pentanoate (370 mg, 0.552 mmol) in 4M HCl / dioxane (20 mL) was stirred at 20 ℃ for 1 hr. The reaction mixture was concentrated under reduced pressure to remove solvent. The crude desired product 4-[[6-[[8- (methylamino)-5-[6-(methylamino)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-2,7-naphthyridin-3- yl]amino]-2-pyridyl]oxy]pentanoic acid (280 mg, crude) was obtained as a yellow solid. LCMS (ESI) m / z 514.0 [M+H]+. Step 6: Synthesis of 9,13-dimethyl-25-(methylamino)-14-oxa-3,4,9,20,22,26,30,32 octazahexacyclo[19.6.2.12,5.14,8.115,19.024,28]dotriaconta- 1(27),2,5(32),6,8(31),15(30),16,18,21,23,25,28-dodecaen-10-one To a solution of 4-[[6-[[8-(methylamino)-5-[6-(methylamino)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]- 2,7-naphthyridin-3-yl]amino]-2-pyridyl]oxy]pentanoic acid (80 mg, 0.156 mmol), TCFH (70.0 mg, 0.249 mmol) in DMF (10 mL) was added NMI (41.2 mg, 0.502 mmol) and the mixture was stirred at 20 ℃ for 0.5 h. The residue was purified by preparative HPLC (Instrument: Gilson GX- 281 Liquid Handler, Gilson 322 Pump, Gilson 156 UV Detector; Column: Welch Xtimate C18 150 × 25 mm × 5 μm; Mobile phase A: H2O with 0.05% HCl (v%); Mobile phase B: ACN; Gradient: B from 5% to 35% in 10 min, hold 100% B for 2 min; Flow Rate: 25 mL / min; Column Temperature: 30 ℃; Wavelength: 220 nm) to afford the desired product 9,13-dimethyl-25- (methylamino)-14-oxa-3,4,9,20,22,26,30,32 octazahexacyclo[19.6.2.12,5.14,8.115,19.024,28]dotriaconta- 1(27),2,5(32),6,8(31),15(30),16,18,21,23,25,28-dodecaen-10-one (34.6 mg, 44.8% yield) as a yellow solid. LCMS (ESI) m / z 496.0 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ ppm 10.52 (br d, J = 4.9 Hz, 1H), 10.46 (s, 1H), 9.71 (s, 1H), 9.37 (s, 1H), 9.08 (s, 1H), 7.99 - 8.12 (m, 2H), 7.93 (dd, J = 9.4, 1.9 Hz, 1H), 7.65 (t, J = 8.0 Hz, 1H), 6.79 (d, J = 7.9 Hz, 1H), 6.44 (d, J = 8.4 Hz, 1H), 4.55 (br s, 1H), 3.31 (s, 3H), 3.22 (d, J = 4.6 Hz, 3H), 2.77 - 2.91 (m, 1H), 2.32 (td, J = 12.9, 3.6 Hz, 1H), 1.80 - 1.90 (m, 1H), 1.63 - 1.75 (m, 1H), 1.05 (d, J = 6.0 Hz, 3H). Example 29 and Example 30: (13R)-9,13-dimethyl-25-(methylamino)-14-oxa- 3,4,9,20,22,26,30,32-octazahexacyclo[19.6.2.12,5.14,8.115,19.024,28]dotriaconta- 1(27),2,5(32),6,8(31),15(30),16,18,21,23,25,28-dodecaen-10-one and (13S)-9,13-dimethyl-25- (methylamino)-14-oxa-3,4,9,20,22,26,30,32- octazahexacyclo[19.6.2.12,5.14,8.115,19.024,28]dotriaconta- 1(27),2,5(32),6,8(31),15(30),16,18,21,23,25,28-dodecaen-10-one and 9,13-dimethyl-25-(methylamino)-14-oxa-3,4,9,20,22,26,30,32- octazahexacyclo[19.6.2.12,5.14,8.115,19.024,28]dotriaconta- 1(27),2,5(32),6,8(31),15(30),16,18,21,23,25,28-dodecaen-10-one (Example 28) was separated by chiral SFC column to afford Example 29 (peak a) and Example 30 (peak b). Analytical data for Example 29 (FR-a): LCMS (ESI) m / z 496.0 [M+H]+; Chiral purity: 100% ee;1H NMR (400 MHz, DMSO-d6) δ ppm 10.52 (br d, J = 4.9 Hz, 1H), 10.46 (s, 1H), 9.71 (s, 1H), 9.37 (s, 1H), 9.08 (s, 1H), 7.99 - 8.12 (m, 2H), 7.93 (dd, J = 9.4, 1.9 Hz, 1H), 7.65 (t, J = 8.0 Hz, 1H), 6.79 (d, J = 7.9 Hz, 1H), 6.44 (d, J = 8.4 Hz, 1H), 4.55 (br s, 1H), 3.31 (s, 3H), 3.22 (d, J = 4.6 Hz, 3H), 2.77 - 2.91 (m, 1H), 2.32 (td, J = 12.9, 3.6 Hz, 1H), 1.80 - 1.90 (m, 1H), 1.63 - 1.75 (m, 1H), 1.05 (d, J = 6.0 Hz, 3H). Analytical data for Example 30 (FR-b): LCMS (ESI) m / z 496.0 [M+H]+; Chiral purity: 87.3% ee;1H NMR (400 MHz, DMSO-d6) δ ppm 10.52 (br d, J = 4.9 Hz, 1H), 10.46 (s, 1H), 9.71 (s, 1H), 9.37 (s, 1H), 9.08 (s, 1H), 7.99 - 8.12 (m, 2H), 7.93 (dd, J = 9.4, 1.9 Hz, 1H), 7.65 (t, J = 8.0 Hz, 1H), 6.79 (d, J = 7.9 Hz, 1H), 6.44 (d, J = 8.4 Hz, 1H), 4.55 (br s, 1H), 3.31 (s, 3H), 3.22 (d, J = 4.6 Hz, 3H), 2.77 - 2.91 (m, 1H), 2.32 (td, J = 12.9, 3.6 Hz, 1H), 1.80 - 1.90 (m, 1H), 1.63 - 1.75 (m, 1H), 1.05 (d, J = 6.0 Hz, 3H). Example 31: N-methyl-9,12,15-trioxa-3,4,21,23,27,31,33- heptazahexacyclo[20.6.2.12,5.14,8.116,20.025,29]tritriaconta- 1(28),2,5(33),6,8(32),16(31),17,19,22(30),23,25(29),26-dodecaen-26-amine Step 1: Synthesis of ethyl N-[(5-methoxy-2-pyridyl)carbamothioyl]carbamate To a solution of 5-methoxypyridin-2-amine (3 g, 24.17 mmol, 1 eq) in dioxane (30 mL) was added O-ethyl carbonisothiocyanatidate (3.49 g, 26.58 mmol, 1.1 eq). The mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give ethyl N-[(5- methoxy-2-pyridyl)carbamothioyl]carbamate (6 g,97.2%) as a red solid. LCMS (ESI) m / z 256.0 [M+H]+. Step 2: Synthesis of 6-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-amine To ethyl N-[(5-methoxy-2-pyridyl)carbamothioyl]carbamate (6 g, 23.50 mmol, 1 eq) in MeOH (30 mL) and EtOH (30 mL) was added NH2OH.HCl (8.17 g, 117.51 mmol, 5 eq) and DIEA (9.11 g, 70.51 mmol, 3 eq). The mixture was stirred at 25°C for 2 h, and then heated at 60° C for 4 h. The reaction mixture was added H2O (100 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure, and purified by flash chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0~30%, 40 mL / min, 254nm). to afford 6-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-amine (3.5 g, 87.0%) as a white solid. LCMS (ESI) m / z 165.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ ppm 8.29 (d, J = 2.00 Hz, 1H), 7.24 - 7.31 (m, 1H), 7.17 - 7.23 (m, 1H), 5.82 (br s, 2H), 3.75 - 3.83 (m, 3H). Step 3: Synthesis of 2-chloro-6-methoxy-[1,2,4]triazolo[1,5-a]pyridine To a stirring mixture of 6-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-amine (3.5 g, 21.32 mmol, 1 eq) and CuCl2 (859.95 mg, 6.40 mmol, 0.3 eq) in HCl (12 M, 40 mL, 22.51 eq) at 5℃ was added dropwise a solution of NaNO2 (2.21 g, 31.98 mmol, 1.5 eq) in H2O (10 mL). The mixture was stirred for 30 minutes at 5 ℃ then at 25°C for 16 hr. The yellow mixture was diluted with water (200 mL) and filtered, the cake was washed with water and concentrated under reduced pressure to give, 2-chloro-6-methoxy-[1,2,4]triazolo[1,5-a]pyridine (2.8 g, 68.6%) was obtained as a yellow solid. LCMS (ESI) m / z 184.0 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ ppm 8.69 (d, J = 2.26 Hz, 1H), 7.74 (d, J = 9.76 Hz, 1H), 7.53 (dd, J = 9.64, 2.38 Hz, 1H), 3.80-3.90 (m, 3H). Step 4: Synthesis of N-(5-(6-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-8-(methylamino)- 2,7-naphthyridin-3-yl)cyclopropanecarboxamide A mixture of N-(8-(methylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,7- naphthyridin-3-yl)cyclopropanecarboxamide (1.63 g, 3.54 mmol, 1.3 eq), 2-chloro-6-methoxy- [1,2,4]triazolo[1,5-a]pyridine (500 mg, 2.72 mmol, 1 eq), XPhos (389.48 mg, 0.817 mmol, 0.3 eq), XPhos Pd G3(691.56 mg, 0.817 mmol, 0.3 eq) and K3PO4(1.73 g, 8.17 mmol, 3 eq) in dioxane (12 mL) and H2O (2 mL) was degassed and purged several times with N2, and then the mixture was stirred at 100 °C for 2 h under N2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure, and purified by flash chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, DCM / MeOH with MeOH from 0~5%, 40 mL / min, 254nm) to give N-[5-(6-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-8-(methylamino)-2,7-naphthyridin-3- yl]cyclopropanecarboxamide (620 mg, 54.9%) as a white solid. LCMS (ESI) m / z 389.9 [M+H]+. Step 5: Synthesis of 4-(6-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-N1-methyl-2,7- naphthyridine-1,6-diamine To a solution of N-[5-(6-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-8-(methylamino)-2,7- naphthyridin-3-yl]cyclopropanecarboxamide (520 mg, 1.34 mmol, 1 eq) in MeOH (5 mL) and dioxane (5 mL) was added NaOH (534.10 mg, 13.35 mmol, 10 eq). The mixture was stirred at 80 °C for 16 hr. The reaction mixture was concentrated under reduced pressure to give a crude product mixture which was further purified by flash chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, DCM / MeOH with MeOH from 0~10%, 40 mL / min, 254nm).to afford 4-(6-methoxy- [1,2,4]triazolo[1,5-a]pyridin-2-yl)-N1-methyl-2,7-naphthyridine-1,6-diamine (420 mg, 77.4%) as a yellow solid. LCMS (ESI) m / z 321.7 [M+H]+. Step 6: Synthesis of 2-(6-amino-1-(methylamino)-2,7-naphthyridin-4-yl)-[1,2,4]triazolo[1,5- a]pyridin-6-ol To a solution of 4-(6-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-N1-methyl-2,7-naphthyridine- 1,6-diamine (200 mg, 0.622 mmol, 1 eq) in DCM (10 mL) was added BBr3 (311.85 mg, 1.24 mmol, 2 eq). The mixture was stirred at 0-25 °C for 48 h. The reaction mixture was quenched with H2O (10 mL) and extracted with DCM (20 mL × 3). The combined organic layers were washed with brine (20 mL), dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure, and purified by flash chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0~15%, 40 mL / min, 254nm). This product was further purified by prep-HPLC (column: Phenomenex Synergi C18100 × 30mm × 4um;mobile phase: [water(HCl)-ACN];gradient:0%-20% B over 8 min) to afford 2-[6-amino-1-(methylamino)-2,7- naphthyridin-4-yl]-[1,2,4]triazolo[1,5-a]pyridin-6-ol (110 mg, 57.5%) as a yellow solid. LCMS (ESI) m / z 308.0[M+H]+. Step 7: Synthesis of N-methyl-9,12,15-trioxa-3,4,21,23,27,31,33- heptazahexacyclo[20.6.2.12,5.14,8.116,20.025,29]tritriaconta- 1(28),2,5(33),6,8(32),16(31),17,19,22(30),23,25(29),26-dodecaen-26-amine

[0035] To a reaction mixture of 2-[6-amino-1-(methylamino)-2,7-naphthyridin-4-yl]-[1,2,4]triazolo[1,5- a]pyridin-6-ol (90 mg, 0.292 mmol, 1 eq) and 2-bromo-6-[2-(2-chloroethoxy)ethoxy]pyridine (82.16 mg, 0.292 mmol, 1 eq) in dioxane (8 mL) was added Cs2CO3 (381.68 mg, 1.17 mmol, 4 eq), Ephos Pd G4(29.59 mg, 32.2 μmol, 0.11 eq) and Ephos (15.66 mg, 29.2 μmol, 0.1 eq). The mixture was stirred at 110 °C for 16 h under N2. The reaction mixture was filtered and concentrated under reduced pressure, and purified by prep-HPLC (column: 2_Phenomenex Gemini C1875 × 40mm × 3um; mobile phase: [water(HCl)-ACN];gradient:15%-45% B over 8 min) to provide N- methyl-9,12,15-trioxa-3,4,21,23,27,31,33- heptazahexacyclo[20.6.2.12,5.14,8.116,20.025,29]tritriaconta- 1(28),2,5(33),6,8(32),16(31),17,19,22(30),23,25(29),26-dodecaen-26-amine (5.03 mg, 3.6%) as a yellow solid. LCMS (ESI) m / z 470.9 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ ppm 10.48 (s, 1H), 10.40 (br s, 1H), 9.74 (s, 1H), 9.67 (d, J = 4.64 Hz, 1H), 8.99 (s, 1H), 8.44 (s, 1H), 7.80 (d, J = 9.64 Hz, 1H), 7.71 (t, J = 7.94 Hz, 1H), 7.52- .59 (m, 1H), 6.86 (d, J = 8.00 Hz, 1H), 6.51 (d, J = 8.12 Hz, 1H), 4.42 (br d, J = 3.76 Hz, 2H), 4.06-4.23 (m, 2H), 3.82-3.92 (m, 2H), 3.71-3.80 (m, 2H), 3.22 (d, J = 4.50 Hz, 3H).

[0036] Example 32: N-methyl-9,15-dioxa-3,4,21,23,27,31,33-heptazahexacyclo [20.6.2.12,5.14,8.116,20.025,29]tritriaconta-1(28),2,5(33),6,8(32),16(31),17,19,22(30),23,25(29),26- dodecaen-26-amine Step 1: Synthesis of 2-bromo-6-((5-chloropentyl)oxy)pyridine To a solution of 6-bromopyridin-2-ol (1 g, 5.8 mmol, 1 eq) in DMF (10 mL) was added NaH (60% dispersion in mineral oil, 275.8 mg, 6.9 mmol, 1.2 eq) and stirred at 0 °C for 0.5 h, was added 1,5- dichloropentane (891.7 mg, 6.3 mmol, 1.1 eq). The resulting mixture was stirred at 70 °C for 16 h. The reaction mixture was diluted with a saturated NH4Cl aqueous solution (10 mL) and extracted with EtOAc (30 mL ´ 3), dried over Na2SO4, concentrated under reduced pressure, andpurified by column chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, petroleum ether / DCM with DCM from 0~4%, 40 mL / min, 254nm) to afford 2-bromo-6-((5-chloropentyl)oxy)pyridine (640 mg, 34.0%) as a colorless oil. LCMS (ESI) m / z 277.8, 279.8 [M+H]+,1H NMR (400 MHz, DMSO-d6) δ ppm 7.61 - 7.67 (m, 1H), 7.18 - 7.23 (m, 1H), 6.82 - 6.87 (m, 1H), 4.19 - 4.25 (m, 2H), 3.62 - 3.68 (m, 2H), 1.68 - 1.82 (m, 4H), 1.47 - 1.55 (m, 2H). Step 2: Synthesis of N-(5-(6-((5-((6-bromopyridin-2-yl)oxy)pentyl)oxy)-[1,2,4]triazolo[1,5- a]pyridin-2-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0037] To a solution of N-(5-(6-hydroxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-8-(methylamino)-2,7- naphthyridin-3-yl)cyclopropanecarboxamide (290 mg, 0.8 mmol, 1 eq) and 2-bromo-6-(5- chloropentoxy)pyridine (236.7 mg, 0.8 mmol, 1.1 eq) in DMF (5 mL) was added Cs2CO3(251.7 mg, 2.3 mmol, 3 eq). The mixture was stirred at 80 °C for 2 hrs. The reaction mixture was filtered and concentrated under reduced pressure and further purified by column chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, DCM / MeOH with MeOH from 0~5.7%, 30 mL / min, 254nm) to afford N-(5-(6-((5-((6-bromopyridin-2-yl)oxy)pentyl)oxy)-[1,2,4]triazolo[1,5- a]pyridin-2-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (281 mg, 58.3%) as a yellow solid. LCMS (ESI) m / z 617.1, 619.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ ppm 10.93 (s, 1H), 9.40 (d, J = 8.0 Hz, 2H), 8.72 (s, 1H), 8.67 (d, J = 2.4 Hz, 1H), 8.23 - 8.28 (m, 1H), 7.75 (d, J = 9.6 Hz, 1H), 7.64 (t, J = 8.0 Hz, 1H), 7.45 (dd, J = 9.6, 2.4 Hz, 1H), 7.20 (d, J = 7.2 Hz, 1H), 6.85 (d, J = 8.4 Hz, 1H), 4.26 (s, 2H), 4.11 - 4.13 (m, 2H), 3.03 - 3.05 (m, 3H), 2.03 - 2.09 (m, 1H), 1.81 (br dd, J = 14.4, 7.2 Hz, 4H), 1.59 (br d, J = 6.8 Hz, 2H), 0.81 - 0.87 (m, 4H). Step 3: Synthesis of 4-(6-((5-((6-bromopyridin-2-yl)oxy)pentyl)oxy)-[1,2,4]triazolo[1,5- a]pyridin-2-yl)-N1-methyl-2,7-naphthyridine-1,6-diamine

[0038] To a solution of N-(5-(6-((5-((6-bromopyridin-2-yl)oxy)pentyl)oxy)-[1,2,4]triazolo[1,5-a]pyridin- 2-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (265 mg, 0.4 mmol, 1 eq) in MeOH (2 mL) and H2O (0.2 mL) was added NaOH (257.5 mg, 6.4 mmol, 15 eq).The mixture was stirred at 80 °C for 16 h. The reaction mixture was concentrated under reduced pressure and further purified by column chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, DCM / MeOH with MeOH from 0~9%, 30 mL / min, 254nm) to afford 4-(6-((5-((6-bromopyridin- 2-yl)oxy)pentyl)oxy)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-N1-methyl-2,7-naphthyridine-1,6- diamine (168 mg, 57.0%) as a yellow solid. LCMS (ESI) m / z 549.1, 551.1 [M+H]+. Step 4: Synthesis of N-methyl-9,15-dioxa-3,4,21,23,27,31,33- heptazahexacyclo[20.6.2.12,5.14,8.116,20.025,29]tritriaconta- 1(28),2,5(33),6,8(32),16(31),17,19,22(30),23,25(29),26-dodecaen-26-amine A mixture of 4-(6-((5-((6-bromopyridin-2-yl)oxy)pentyl)oxy)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)- N1-methyl-2,7-naphthyridine-1,6-diamine (80 mg, 0.1 mmol, 1 eq), Ephos Pd G4 (13.4 mg, 0.01 mmol, 0.1 eq), Ephos (7.8 mg, 0.01 mmol, 0.1 eq) and Cs2CO3 (142.3 mg, 0.4 mmol, 3 eq) in dioxane (15 mL) was degassed and purged several times with N2. The reaction mixture was stirred at 110 °C for 2 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure and purified by prep-HPLC (column: Welch Xtimate C18150 × 25mm × 5um; mobile phase: [water(NH3H2O)-ACN];gradient:30%-60% B over 9.5 min) to afford N-methyl-9,15- dioxa-3,4,21,23,27,31,33-heptazahexacyclo[20.6.2.12,5.14,8.116,20.025,29]tritriaconta- 1(28),2,5(33),6,8(32),16(31),17,19,22(30),23,25(29),26-dodecaen-26-amine (6 mg, 8.8%) as a yellow solid. LCMS (ESI) m / z 469.1 [M+H]+,1H NMR (400 MHz, DMSO-d6) δ ppm 9.83 (s, 1H), 9.41 (s, 1H), 9.32 (s, 1H), 8.69 (d, J = 2.0 Hz, 1H), 8.67 (s, 1H), 8.10 - 8.16 (m, 1H), 7.80 (d, J = 9.6 Hz, 1H), 7.53 - 7.63 (m, 2H), 6.76 (d, J = 8.0 Hz, 1H), 6.34 (d, J = 8.0 Hz, 1H), 4.34 (br t, J = 5.2 Hz, 2H), 3.95 - 3.99 (m, 2H), 3.03 (d, J = 4.4 Hz, 3H), 1.68 - 1.77 (m, 4H), 1.59 - 1.67 (m, 2H). Example 33: N-methyl-9,12,15-trioxa-3,4,17,21,23,27,31,33- octazahexacyclo[20.6.2.12,5.14,8.116,20.025,29]tritriaconta- 1(28),2,5(33),6,8(32),16(31),17,19,22(30),23,25(29),26-dodecaen-26-amine A mixture of 2-(6-amino-1-(methylamino)-2,7-naphthyridin-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-6- ol (100 mg, 0.3 mmol, 1 eq), 4-bromo-2-(2-(2-chloroethoxy)ethoxy)pyrimidine (91.6 mg, 0.3 mmol, 1 eq), Pd2(dba)3 (59.6 mg, 0.07 mmol, 0.2 eq), DavePhos (51.2 mg, 0.1 mmol, 0.4 eq) and Cs2CO3 (318.1 mg, 1.0 mmol, 3 eq) in dioxane (2 mL) was degassed and purged with N2 several times. The mixture was stirred at 110 °C for 2 h under N2atmosphere. The reaction mixture was concentrated under reduced pressure and purified by prep-HPLC (column: Welch Xtimate C18 150 ´ 25mm ´ 5um; mobile phase: [water(NH3H2O)-ACN]; gradient:24%-54% B over 9.5 min) to afford N-methyl-9,12,15-trioxa-3,4,17,21,23,27,31,33- octazahexacyclo[20.6.2.12,5.14,8.116,20.025,29]tritriaconta- 1(28),2,5(33),6,8(32),16(31),17,19,22(30),23,25(29),26-dodecaen-26-amine (9.38 mg, 5.8%) as a yellow solid. LCMS (ESI) m / z 472.1 [M+H]+,1H NMR (400 MHz, DMSO-d6) δ ppm 10.45 (s, 1H), 10.09 (s, 1H), 9.39 (s, 1H), 8.98 (s, 1H), 8.95 (d, J = 2.0 Hz, 1H), 8.22 - 8.28 (m, 1H), 8.19 (d, J = 5.6 Hz, 1H), 7.74 (d, J = 9.6 Hz, 1H), 7.46 (dd, J = 9.6, 2.4 Hz, 1H), 6.79 (d, J = 5.6 Hz, 1H), 4.43 - 4.47 (m, 2H), 4.38 - 4.42 (m, 2H), 3.85 - 3.90 (m, 2H), 3.80 - 3.84 (m, 2H), 3.05 (d, J = 4.4 Hz, 3H). Example 34: (12Z,15E)-N-methyl-5,8,11-trioxa-3-aza-2(5,3)-pyrido[3,4-c]pyridazina-1(2,6)- [1,2,4]triazolo[1,5-a]pyridina-4(2,6)-pyridinacycloundecaphan-28-amine Step 1: Synthesis of N-(8-(methylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyrido[3,4-c]pyridazin-3-yl)cyclopropanecarboxamide To a stirring mixture of N-[5-bromo-8-(methylamino)pyrido[3,4-c]pyridazin-3- yl]cyclopropanecarboxamide (1 g, 3.10 mmol, 1.0 eq) in 2-methyltetrahydrofuran (8 mL) was added potassium;2,2-dimethylpropanoate (870.5 mg, 6.21 mmol, 2.0 eq) and Pd(PPh3)2Cl2(217.9 mg, 0.31 mmol, 0.1 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1,3,2-dioxaborolane (1.18 g, 4.66 mmol, 1.5 eq). The mixture was degassed and purged with N2 3 times. The mixture was stirred at 85oC for 2 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure and further purified by flash chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0~60%, 60 mL / min, 254nm) to give compound N-[8-(methylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyrido[3,4-c]pyridazin-3-yl]cyclopropanecarboxamide (1 g, 61.08% yield, 70% purity) as a yellow solid. LCMS (ESI) m / z 370.0 [M+H]+. Step 2: Synthesis of N-(5-(6-hydroxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-8- (methylamino)pyrido[3,4-c]pyridazin-3-yl)cyclopropanecarboxamide

[0039] To a stirring mixture of N-[8-(methylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyrido[3,4-c]pyridazin-3-yl]cyclopropanecarboxamide (500 mg, 0.95 mmol, 1.0 eq) in dioxane (10 mL) and H2O (2 mL) was added XPhos Pd G3 (80.2 mg, 0.09 mmol, 0.1 eq), XPhos (90.4 mg, 0.19 mmol, 0.2 eq), 2-chloro-[1,2,4]triazolo[1,5-a]pyridin-6-ol (160.7 mg, 0.95 mmol, 1.0 eq), and K3PO4 (503. mg, 2.37 mmol, 2.5 eq). The mixture was degassed and purged several times with N2. The mixture was stirred at 100oC for 1 h under N2 atmosphere. Upon completion, the reaction mixture was concentrated under reduced pressure and purified by flash chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0~100%, 60 mL / min, 254nm) to give compound N-[5-(6-hydroxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-8- (methylamino)pyrido[3,4-c]pyridazin-3-yl]cyclopropanecarboxamide (40 mg, 11.21% yield, 100% purity) as a yellow solid. LCMS (ESI) m / z 377.1 [M+H]+. Step 3: Synthesis of 2-(3-amino-8-(methylamino)pyrido[3,4-c]pyridazin-5-yl)- [1,2,4]triazolo[1,5-a]pyridin-6-ol To a solution of N-[5-(6-hydroxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-8-(methylamino)pyrido[3,4- c]pyridazin-3-yl]cyclopropanecarboxamide (40 mg, 0.11 mmol, 1.0 eq) in MeOH (1 mL) was added NaOH (42.5 mg, 1.06 mmol, 10.0 eq). The mixture was stirred at 80oC for 2 h. The reaction mixture was concentrated under reduced pressure and purified by flash chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0~100%, 30 mL / min, 254nm) to give compound 2-[3-amino-8-(methylamino)pyrido[3,4-c]pyridazin-5-yl]- [1,2,4]triazolo[1,5-a]pyridin-6-ol (30 mg, 82.40% yield, 90% purity) as a yellow solid. LCMS (ESI) m / z 309.3 [M+H]+. Step 4: Synthesis of (12Z,15E)-N-methyl-5,8,11-trioxa-3-aza-2(5,3)-pyrido[3,4-c]pyridazina- 1(2,6)-[1,2,4]triazolo[1,5-a]pyridina-4(2,6)-pyridinacycloundecaphan-28-amine To a mixture solution of 2-[3-amino-8-(methylamino)pyrido[3,4-c]pyridazin-5-yl]- [1,2,4]triazolo[1,5-a]pyridin-6-ol (30 mg, 0.1 mmol, 1.0 eq) in DMF (1 mL) was added Cs2CO3(95.1 mg, 0.29 mmol, 3.0 eq) and Ephos (10.4 mg, 0.02 mmol, 0.2 eq), 2-bromo-6-(2-(2- chloroethoxy)ethoxy)pyridine (32.8 mg, 0.12 mmol, 1.2 eq), Ephos Pd G4 (8.9 mg, 0.01 mmol, 0.1 eq). The mixture was degassed and purged several times with N2. The mixture was stirred at 110 ºC for 2 h under N2 atmosphere. LCMS showed the desired product mass. The reaction mixture was concentrated under reduced pressure and purified by reversed-phase HPLC (0.3%HCl condition) to give, (12Z,15E)-N-methyl-5,8,11-trioxa-3-aza-2(5,3)-pyrido[3,4-c]pyridazina- 1(2,6)-[1,2,4]triazolo[1,5-a]pyridina-4(2,6)-pyridinacycloundecaphan-28-amine (14.21 mg, 29.7% yield, 95.88% purity) as a yellow solid. LCMS (ESI) m / z 472.1 [M+H]+,1H NMR (400 MHz, DMSO-d6) δ ppm 10.82 - 11.04 (m, 1H), 10.02 (s, 1H), 8.98 (d, J = 1.52 Hz, 1H), 8.64 - 8.85 (m, 1H), 7.72 - 7.80 (m, 2H), 7.48 - 7.54 (m, 1H), 7.17 - 7.37 (m, 1H), 6.96 (brd, J = 8.00 Hz, 1H), 6.52 (brd, J = 7.76 Hz, 1H), 4.43 (brs, 2H), 4.24 (brd, J = 4.78 Hz, 2H), 3.86 (brd, J = 2.76 Hz, 2 H), 3.75 - 3.78 (m, 2H), 3.21 (brs, 3H).

[0040] Example 35: 9-methyl-25-(methylamino)-14-oxa-3,4,9,20,22,26,30,32- octazahexacyclo[19.6.2.12,5.14,8.115,19.024,28]dotriaconta- 1(27),2,5(32),6,8(31),15(30),16,18,21,23,25,28-dodecaen-10-one Step 1: Synthesis of methyl 4-[[6-[[5-[6-[tert-butoxycarbonyl(methyl)amino]- [1,2,4]triazolo[1,5-a]pyridin-2-yl]-8-(methylamino)-2,7-naphthyridin-3-yl]amino]-2- pyridyl]oxy]butanoate Methyl 4-[[6-[[5-[6-[tert-butoxycarbonyl(methyl)amino]-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-8- (methylamino)-2,7-naphthyridin-3-yl]amino]-2-pyridyl]oxy]butanoate was synthesized using a similar procedure that was previously described in example 28 by using tert-butyl N-[2-[6-amino- 1-(methylamino)-2,7-naphthyridin-4-yl]-[1,2,4]triazolo[1,5-a]pyridin-6-yl]-N-methyl-carbamate and methyl 4-[(6-bromo-2-pyridyl)oxy]butanoate as the starting material. LCMS (ESI) m / z 614.1 [M+H]+. Step 2: Synthesis of methyl 4-[[6-[[8-(methylamino)-5-[6-(methylamino)-[1,2,4]triazolo[1,5- a]pyridin-2-yl]-2,7-naphthyridin-3-yl]amino]-2-pyridyl]oxy]butanoate

[0041] To a solution of methyl 4-[[6-[[5-[6-[tert-butoxycarbonyl(methyl)amino]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]-8-(methylamino)-2,7-naphthyridin-3-yl]amino]-2-pyridyl]oxy]butanoate (135 mg, 0.219 mmol, 1eq) in MeOH (1 mL) was added HCl / dioxane (4 M, 2.51 mL). The mixture was stirred at 25°C for 1h. The reaction mixture was concentrated under reduced pressure to remove solvent and provide methyl 4-[[6-[[8-(methylamino)-5-[6-(methylamino)-[1,2,4]triazolo[1,5- a]pyridin-2-yl]-2,7-naphthyridin-3-yl]amino]-2-pyridyl]oxy]butanoate (112 mg) as a yellow solid. LCMS (ESI) m / z 514.3 [M+H]+. Step 3: Synthesis of 4-[[6-[[8-(methylamino)-5-[6-(methylamino)-[1,2,4]triazolo[1,5- a]pyridin-2-yl]-2,7-naphthyridin-3-yl]amino]-2-pyridyl]oxy]butanoic acid To a solution of methyl 4-[[6-[[8-(methylamino)-5-[6-(methylamino)-[1,2,4]triazolo[1,5- a]pyridin-2-yl]-2,7-naphthyridin-3-yl]amino]-2-pyridyl]oxy]butanoate (100 mg, 0.194mmol, 1eq) in THF (1 mL) and H2O (0.1 mL) was added LiOH (23.32 mg, 0.973 mmol, 5eq). The mixture was stirred at 25°C for 16 h. The reaction mixture was concentrated under reduced pressure to provide 4-[[6-[[8-(methylamino)-5-[6-(methylamino)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-2,7- naphthyridin-3-yl]amino]-2-pyridyl]oxy]butanoic acid (97 mg, crude) as a yellow solid. LCMS (ESI) m / z 500.0 [M+H]+. Step 4: Synthesis of 9-methyl-25-(methylamino)-14-oxa-3,4,9,20,22,26,30,32- octazahexacyclo[19.6.2.12,5.14,8.115,19.024,28]dotriaconta- 1(27),2,5(32),6,8(31),15(30),16,18,21,23,25,28-dodecaen-10-one To a solution of 4-[[6-[[8-(methylamino)-5-[6-(methylamino)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]- 2,7-naphthyridin-3-yl]amino]-2-pyridyl]oxy]butanoic acid (5 mg, 0.010 mmol, 1 eq) in DMSO (1 mL) was added TCFH (3.37 mg, 0.012 mmol, 1.2 eq) and NMI (2.88 mg, 0.035 mmol, 3.5 eq). The mixture was stirred at 100 °C for 1h under a microwave irradiation condition. The reaction mixture was purified by prep-HPLC (column: Phenomenex Synergi C18100 ´ 30 mm ´ 4 μm; mobile phase: [water(HCl)-ACN]; gradient:10%-40% B over 10 min), to provide 9-methyl-25- (methylamino)-14-oxa-3,4,9,20,22,26,30,32- octazahexacyclo[19.6.2.12,5.14,8.115,19.024,28]dotriaconta- 1(27),2,5(32),6,8(31),15(30),16,18,21,23,25,28-dodecaen-10-one (2.14 mg, 44.40% yield) as a yellow solid. LCMS (ESI) m / z 482.0 [M+H]+,1H NMR (400 MHz, DMSO-d6) δ 10.48 (s, 1 H), 10.44 (br d, J = 5.6 Hz, 1 H), 9.66 (br s, 1 H), 9.37-9.43 (m, 1 H), 9.23 (d, J = 1.2 Hz, 1 H), 8.14 (s, 1 H), 8.02 (d, J = 9.6 Hz, 1 H), 7.88-7.94 (m, 1 H), 7.70 (br d, J = 1.6 Hz, 1 H), 6.83 (d, J = 8.0 Hz, 1 H), 6.45 (d, J = 8.0 Hz, 1 H), 4.03 - 4.09 (m, 2 H), 3.22 (d, J = 4.4 Hz, 3 H), 2.54 (s, 3 H), 2.44 (br d, J = 7.6 Hz, 2 H), 1.99-2.11 (m, 2 H). Example 36: (12Z,15E)-N,9-dimethyl-5,8,11-trioxa-3-aza-2(5,3)-naphthyridina-1(2,6)- [1,2,4]triazolo[1,5-a]pyridina-4(2,6)-pyridinacycloundecaphan-28-amine

[0042] Step 1: Synthesis of 2-(benzyloxy)ethyl 4-methylbenzenesulfonate A mixture of 2-benzyloxyethanol (10 g, 65.7 mmol, 1 eq), 4-methylbenzenesulfonyl chloride (12.3 g, 65.7 mmol, 1 eq), DMAP (401 mg, 3.29 mmol, 0.1 eq), Et3N (13.3 g, 131 mmol, 2 eq) and in DCM (100 mL) was degassed and purged with N23 times. The mixture was stirred at 25 °C for 2 hr under N2 atmosphere. The residue was diluted with H2O (50 mL) and extracted with EtOAc (50 mL ´ 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~30% Ethyl acetate / Petroleum ether gradient @ 30 mL / min) to afford 2-(benzyloxy)ethyl 4-methylbenzenesulfonate (15 g, 72.3%) as a white oil. LCMS (ESI) m / z 352.2 [M+H]+,1H NMR (400 MHz, DMSO-d6) δ ppm 7.78 (d, J = 8.28 Hz, 2H), 7.46 (d, J = 7.68 Hz, 2H), 7.19 - 7.37 (m, 5H), 4.42 (s, 2H), 4.15 - 4.20 (m, 2H), 3.57 - 3.62 (m, 2H), 2.41 (s, 3H). Step 2: Synthesis of ethyl 2-(2-(benzyloxy)ethoxy)propanoate A mixture of 2-benzyloxyethyl 4-methylbenzenesulfonate (5 g, 16.2 mmol, 1 eq), ethyl 2- hydroxypropanoate (3.86 g, 32.6 mmol, 2 eq), NaH (1.35 mg, 32.6 mmol, 2 eq) in THF (50 mL) at 0°C was stirred at 25 °C for 2 hr under N2 atmosphere. The residue was diluted with H2O (50 mL) and extracted with EtOAc (50 mL ´ 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~10% Ethyl acetate / Petroleum ether gradient @ 30 mL / min) to afford ethyl 2-(2- (benzyloxy)ethoxy)propanoate (2.2 g, 51.8%) as a white solid. LCMS (ESI) m / z 253.2 [M+H]+,1H NMR (400 MHz, DMSO-d6) δ ppm 7.21-7.45 (m, 5H), 4.49 (s, 2H), 4.07-4.15 (m, 2H), 4.02- 4.06 (m, 1H), 3.62-3.67 (m, 1H), 3.50-3.58 (m, 3H), 1.27 (d, J = 6.88 Hz, 3H), 1.16 - 1.20 (m, 3H). Step 3: Synthesis of ethyl 2-(2-hydroxyethoxy)propanoate A mixture of ethyl 2-(2-benzyloxyethoxy)propanoate (2.1 g, 8.32 mmol, 1 eq), Pd / C (886 mg, 0.83 mmol, 0.1 eq) in THF (25 mL) was degassed and purged with H2 for 3 times. The mixture was stirred at 60 °C for 2 hr under H2 atmosphere. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to afford ethyl 2-(2-hydroxyethoxy)propanoate (1.2 g, crude) as a white solid.1H NMR (400 MHz, DMSO-d6) δ ppm 4.58-4.62 (m, 1H), 4.11 (dd, J = 7.24, 1.51 Hz, 2H), 4.03 (d, J = 6.88 Hz, 1H), 3.45-3.51 (m, 3H), 3.34-3.40 (m, 1H), 1.25-1.28 (m, 3H), 1.20 (t, J = 7.03 Hz, 3H). Step 4: Synthesis of ethyl 2-(2-((6-bromopyridin-2-yl)oxy)ethoxy)propanoate A mixture of ethyl 2-(2-hydroxyethoxy)propanoate (1.2 g, 7.4 mmol, 1 eq), 6-bromopyridin-2-ol (1.67 g, 9.62 mmol, 1.3 eq) and PPh3 (2.91 g, 11.1 mmol, 1.5 eq) in THF (20 mL) was added DIAD (2.24 g, 11.1 mmol, 1.5 eq). The reaction mixture was stirred at 25 °C for 1 hr under N2 atmosphere. The residue was diluted with H2O (50 mL) and extracted with EtOAc (50 mL´3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~10% Ethyl acetate / Petroleum ether gradient @ 30 mL / min) to afford ethyl 2-(2-((6-bromopyridin-2-yl)oxy)ethoxy)propanoate (1.6 g, 67.3%) as a white oil. LCMS (ESI) m / z 318.1, 320.1 [M+H]+,1H NMR (400 MHz, DMSO-d6) δ ppm 7.60-7.72 (m, 1H), 7.23 (d, J = 7.48 Hz, 1H), 6.87 (d, J = 8.24 Hz, 1H), 4.29-4.39 (m, 2H), 4.05-4.15 (m, 3H), 3.80 (br dd, J = 5.64, 3.63 Hz, 1H), 3.67-3.74 (m, 1H), 1.27 (d, J = 6.76 Hz, 3H), 1.16-1.20 (m, 3H). Step 5: Synthesis of 2-(2-((6-bromopyridin-2-yl)oxy)ethoxy)propan-1-ol A mixture of ethyl 2-[2-[(6-bromo-2-pyridyl)oxy]ethoxy]propanoate (1 g, 3.14 mmol, 1 eq), MgCl2(29.9 mg, 0.031 mmol, 0.1 eq) in EtOH (10 mL) at 0°C was added NaBH4(357 mg, 9.43 mmol, 3 eq). The resulting mixture was stirred at 25 °C for 2 hr under N2 atmosphere. The residue was diluted with H2O (50 mL) and extracted with EtOAc (50 mL ´ 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~25% Ethyl acetate / Petroleum ether gradient @ 30 mL / min) to afford 2-(2- ((6-bromopyridin-2-yl)oxy)ethoxy)propan-1-ol (800 mg, 91.3%) as a white oil. LCMS (ESI) m / z 276.1, 278.1 [M+H]+,1H NMR (400 MHz, DMSO-d6) δ ppm 7.65 (t, J = 7.88 Hz, 1H), 7.22 (d, J = 7.60 Hz, 1H), 6.87 (d, 8.24 Hz, 1H), 4.56 (t, J = 5.64 Hz, 1H), 4.31 (t, J = 4.84 Hz, 2H), 3.72- 3.80 (m, 2H), 3.37 (s, 2H), 3.25-3.31 (m, 1H), 1.04 (d, J = 6.24 Hz, 3H). Step 6: Synthesis of 2-(2-((6-bromopyridin-2-yl)oxy)ethoxy)propyl 4- methylbenzenesulfonate A mixture of 2-[2-[(6-bromo-2-pyridyl)oxy]ethoxy]propan-1-ol (200 mg, 0.72 mmol, 1 eq) , 4- methylbenzenesulfonyl chloride (152 mg, 0.79 mmol, 1.1 eq), DMAP (8.85 mg, 0.072 mmol, 0.1 eq), Et3N (147 mg, 1.45 mmol, 2 eq) in DCM (5 mL) was stirred at 25 °C for 2 hr under N2 atmosphere. After completion, the reaction mixture was diluted with H2O (20 mL) and extracted with DCM (20 mL ´ 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~5% Ethyl acetate / Petroleum ether gradient @ 30 mL / min) to afford 2-(2-((6-bromopyridin-2- yl)oxy)ethoxy)propyl 4-methylbenzenesulfonate (85 mg, 93.1%) as a white oil. LCMS (ESI) m / z 430.1, 432.1 [M+H]+,1H NMR (400 MHz, DMSO-d6) δ ppm 7.77 (d, J = 8.24 Hz, 2H), 7.66 (t, J = 7.84 Hz, 1H), 7.44 (d, J = 8.13 Hz, 2H), 7.23 (d, J = 7.60 Hz, 1H), 6.84 (d, J = 8.24 Hz, 1H), 4.21 (t, J = 4.84 Hz, 2H), 4.01-4.04 (m, 1H), 3.88-3.94 (m, 1H), 3.66-3.72 (m, 2H), 3.58-3.65 (m, 1H), 2.40 (s, 3H), 1.02 (d, J = 6.40 Hz, 3 H). Step 7: Synthesis of N-(5-(6-(2-(2-((6-bromopyridin-2-yl)oxy)ethoxy)propoxy)- [1,2,4]triazolo[1,5-a]pyridin-2-yl)-8-(methylamino)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide A mixture of N-[5-(6-hydroxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-8-(methylamino)-2,7- naphthyridin-3-yl]cyclopropanecarboxamide (100 mg, 266.39 μmol, 1 eq), 2-(2-((6- bromopyridin-2-yl)oxy)ethoxy)propyl 4-methylbenzenesulfonate (137.56 mg, 319.67 μmol, 1.2 eq), K2CO3 (110.45 mg, 799.18 μmol, 3 eq) in DMF (2 mL) was degassed and purged with N2 . The mixture was stirred at 80 °C for 16 hr under N2 atmosphere. Upon completion, the reaction mixture was cooled to room temperature and concentrated under reduced pressure, and purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~5% Dichloromethane / Methanol gradient @ 30 mL / min) to afford N-(5-(6-(2-(2-((6-bromopyridin-2- yl)oxy)ethoxy)propoxy)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-8-(methylamino)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide (110 mg, 61.9%) as a yellow solid. LCMS (ESI) m / z 633.2, 635.2 [M+H]+. Step 8: Synthesis of 4-(6-(2-(2-((6-bromopyridin-2-yl)oxy)ethoxy)propoxy)- [1,2,4]triazolo[1,5-a]pyridin-2-yl)-N1-methyl-2,7-naphthyridine-1,6-diamine A mixture of N-[5-[6-[2-[2-[(6-bromo-2-pyridyl)oxy]ethoxy]propoxy]-[1,2,4]triazolo[1,5- a]pyridin-2-yl]-8-(methylamino)-2,7-naphthyridin-3-yl]cyclopropanecarboxamide (100 mg, 0.16 mmol, 1 eq), NaOH (126 mg, 3.16 mmol, 20 eq) in MeOH (2 mL) was degassed and purged with N2. The reaction mixture was stirred at 80 °C for 16 hr. The reaction mixture was cooled to room temperature and concentrated under reduced pressure and purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~10% Ethyl acetate / Petroleum ether gradient @ 30 mL / min) to afford 4-(6-(2-(2-((6-bromopyridin-2- yl)oxy)ethoxy)propoxy)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-N1-methyl-2,7-naphthyridine-1,6- diamine (70 mg, 76.7%) as a yellow solid. LCMS (ESI) m / z 565.3, 567.2 [M+H]+. Step 9: Synthesis of (12Z,15E)-N,9-dimethyl-5,8,11-trioxa-3-aza-2(5,3)-naphthyridina- 1(2,6)-[1,2,4]triazolo[1,5-a]pyridina-4(2,6)-pyridinacycloundecaphan-28-amine

[0043] A mixture of 4-[6-[2-[2-[(6-bromo-2-pyridyl)oxy]ethoxy]propoxy]-[1,2,4]triazolo[1,5-a]pyridin- 2-yl]-N1-methyl-2,7-naphthyridine-1,6-diamine (70 mg, 0.12 mmol, 1 eq), Ephos (6.62 mg, 0.012 mmol, 0.1 eq), Ephos Pd G4 (11.4 mg, 0.012 mmol, 0.1 eq) and Cs2CO3 (121 mg, 0.37 mmol, 3 eq) in dioxane (6 mL) was degassed and purged with N23 times. The mixture was stirred at 100 °C for 1 h under N2 atmosphere. After completion, the reaction mixture was cooled to rt, concentrated under reduced pressure, and purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~5% Dichloromethane / Methanol ethergradient @ 30 mL / min) to afford (12Z,15E)-N,9-dimethyl-5,8,11-trioxa-3-aza-2(5,3)-naphthyridina-1(2,6)- [1,2,4]triazolo[1,5-a]pyridina-4(2,6)-pyridinacycloundecaphan-28-amine (30.1 mg, 49.8%) as a yellow solid. LCMS (ESI) m / z 485.2 [M+H]+,1H NMR (400 MHz, DMSO-d6) δ ppm 9.88 (s, 1H), 9.58 (s, 1H), 9.32 (s, 1H), 9.00 (d, J = 2.04 Hz, 1H), 8.82 (s, 1H), 8.13 (br d, J = 4.28 Hz, 1H), 7.73 (d, J = 9.64 Hz, 1H), 7.61 (t, J = 7.60 Hz, 1H), 7.48 (dd, J = 9.64, 2.26 Hz, 1H), 6.78 (d, J = 8.04 Hz, 1H), 6.35 (d, J = 8.04 Hz, 1H), 4.36 (br d, J = 11.60 Hz, 1H), 4.19 (dd, J = 13.24, 6.15 Hz, 1H), 4.09 (br s, 2H), 3.82-3.89 (m, 1H), 3.75 (br s, 2H), 3.04 (d, J = 4.52 Hz, 3H), 1.20 (d, J = 6.52 Hz, 3H). Example 37 and Example 38: (12Z,15E,9R)-N,9-dimethyl-5,8,11-trioxa-3-aza-2(5,3)- naphthyridina-1(2,6)-[1,2,4]triazolo[1,5-a]pyridina-4(2,6)-pyridinacycloundecaphan-28- amine and (12Z,15E,9S)-N,9-dimethyl-5,8,11-trioxa-3-aza-2(5,3)-naphthyridina-1(2,6)- [1,2,4]triazolo[1,5-a]pyridina-4(2,6)-pyridinacycloundecaphan-28-amine

[0044] and The racemic (12Z,15E)-N,9-dimethyl-5,8,11-trioxa-3-aza-2(5,3)-naphthyridina-1(2,6)- [1,2,4]triazolo[1,5-a]pyridina-4(2,6)-pyridinacycloundecaphan-28-amine (Example 36) was purified by SFC (column: DAICEL CHIRALCEL OD(250mm ´ 30mm,10 um); mobile phase: [CO2-i-PrOH(0.1%NH3H2O)]; B%:55%%, isocratic elution mode) to afford Example 37 (peak a, 8.58 mg, 33.9%) as a white solid and Example 38 (peak b, 7.17 mg, 28.4%) as a white solid. Analytical data for Example 37: LCMS (ESI) m / z 485.3 [M+H]+,1H NMR (400 MHz, DMSO-d6) δ ppm 9.87 (s, 1H), 9.58 (s, 1H), 9.32 (s, 1H), 9.00 (s, 1H), 8.82 (s, 1H), 8.12 (br d, J = 3.88 Hz, 1H), 7.73 (br d, J = 9.52 Hz, 1H), 7.61 (br t, J = 7.96 Hz, 1H), 7.48 (dd, J = 9.68, 1.69 Hz, 1H), 6.78 (br d, J = 7.88 Hz, 1H), 6.35 (br d, J = 7.76 Hz, 1H), 4.36 (br d, J = 12.64 Hz, 1H), 4.19 (br dd, J = 13.08, 6.44 Hz, 1H), 4.09 (br s, 2H), 3.86 (br s, 1H), 3.76 (br dd, J = 5.12, 3.00 Hz, 2H), 3.04 (br d, J = 4.12 Hz, 3H), 1.21 (br d, J = 6.48 Hz, 3 H). Analytical data for Example 38: LCMS (ESI) m / z 485.3 [M+H]+,1H NMR (400 MHz, DMSO- d6) δ ppm 9.88 (s, 1H), 9.58 (s, 1H), 9.32 (s, 1H), 9.00 (d, J = 1.76 Hz, 1H), 8.82 (s, 1H), 8.12 (br d, J = 4.12 Hz, 1H), 7.73 (d, J = 9.52 Hz, 1H), 7.61 (t, J = 7.92 Hz, 1H), 7.48 (dd, J = 9.56, 1.94 Hz, 1H), 6.78 (d, J = 7.88 Hz, 1H), 6.35 (d, J = 8.00 Hz, 1H), 4.36 (br d, J = 12.64 Hz, 1H), 4.19 (dd, J = 13.24, 6.13 Hz, 1H), 4.09 (br s, 2H), 3.86 (br t, J = 6.16 Hz, 1H), 3.70-3.80 (m, 2H), 3.04 (d, J = 4.24 Hz, 3H), 1.21 (d, J = 6.36 Hz, 3H). Example 39: N,4-dimethyl-8,11-dioxa-3,4,17,19,23,27-hexazapentacyclo [16.6.2.12,5.112,16.021,25]octacosa-1(24),2,5(28),12(27),13,15,18(26),19,21(25),22-decaen-22- amine

[0045] Step 1: Synthesis of ethyl 3,5-dibromo-1H-pyrazole-4-carboxylate To a solution of ethyl 1H-pyrazole-4-carboxylate (10.0 g, 71.4 mmol), NaOAc (23.4 g, 285 mmol) in EtOH (100 mL) and H2O (150 mL) was added Br2(28.5 g, 179 mmol) and the mixture was stirred at 20 ℃ for 12 h. After addition of Na2S2O3(22.6 g), the reaction mixture was concentrated under reduced pressure to remove EtOH. A normal workup with EtOAc was followed (200 mL × 3). The combined organic layers were washed with brine (300 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to provide ethyl 3,5-dibromo-1H- pyrazole-4-carboxylate (20 g, crude), as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ ppm 14.55 (br s, 1 H), 4.25 (q, J = 7.0 Hz, 2 H),1.29 (t, J = 7.0 Hz, 3 H). Step 2: Synthesis of ethyl 3,5-dibromo-1-methyl-pyrazole-4-carboxylate To a solution of ethyl 3,5-dibromo-1H-pyrazole-4-carboxylate (20.0 g, 67.1 mmol) in THF (200 mL) was added NaH (3.22 g, 80.56 mmol, 60% dispersion in mineral oil) at 0 ℃. After addition, the mixture was stirred at this temperature for 30 min. To this mixture was added MeI (14.4 g, 101 mmol) dropwise at 0 ℃. The resulting mixture was stirred at 20 ℃ for 12 hr. The reaction mixture was quenched with water (200 mL) at 0 ℃, and then extracted with EtOAc (200 mL × 3). The combined organic layers were washed with brine (300 mL × 2), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and futher purified by flash chromatography (ISCO®; 220 g SepaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0~50%, Flow Rate: 100 mL / min, 254 nm) to give ethyl 3,5-dibromo-1-methyl-pyrazole-4- carboxylate (19.16 g, 88.8% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ ppm 4.25 (q, J = 7.0 Hz, 2 H), 3.86 (s, 3 H), 1.29 (t, J = 7.2 Hz, 3 H); LCMS (ESI) m / z 312.4 [M+H]+. Step 3: Synthesis of diethyl 2-(5-bromo-4-ethoxycarbonyl-2-methyl-pyrazol-3- yl)propanedioate To a solution of diethyl propanedioate (10.8 g, 67.2 mmol) in DMF (150 mL) was added NaH (2.95 g, 73.7 mmol, 60% dispersionin mineral oil) at 0 ℃ over 10 min. After addition, the mixture was stirred at this temperature for 30 min. To this mixture was added ethyl 3,5-dibromo-1-methyl- pyrazole-4-carboxylate (19.2 g, 61.4 mmol) in DMF (50 mL) dropwise at 0 ℃. The resulting mixture was stirred at 130 ℃ for 24 hr. The reaction mixture was cooled to room temperature and quenched with water (200 mL) at 0 ℃, and then extracted with EtOAc (200 mL × 3). The combined organic layers were washed with brine (300 mL × 2), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and purified by flash chromatography (ISCO®; 220 g SepaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0~45%, Flow Rate: 30 mL / min, 254 nm). to give the desired product, diethyl 2-(5-bromo-4-ethoxycarbonyl-2-methyl- pyrazol-3-yl)propanedioate (14.7 g, 31.2% yield), as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ ppm 5.88 (s, 1 H), 4.18 - 4.21 (m, 4 H), 4.07 - 4.14 (m, 2 H), 3.81 (s, 3 H), 1.24 (t, J = 7.2 Hz, 3 H), 1.17 - 1.21 (m, 6 H), ; LCMS (ESI) m / z 392.7 [M+H]+. Step 4: Synthesis of 2-(5-bromo-2-methyl-pyrazol-3-yl)acetic acid To a solution of diethyl 2-(5-bromo-4-ethoxycarbonyl-2-methyl-pyrazol-3-yl)propanedioate (11 g, 28.1 mmol) in EtOH (100 mL) and water (50 mL) was added a solution of NaOH (42.2 mL, 8 N, 338 mmol) at 20 ℃. After addition, the mixture was stirred at 60 ℃ for 12 hr. To this reaction mixture was added H2SO4(82.8 g, 844 mmol) dropwise at 0 ℃. The resulting mixture was stirred at 120 ℃ for 12 hr. The reaction mixture was concentrated under reduced pressure to remove EtOH. The residue was diluted with water (50 mL) and extracted with EtOAc (80 mL × 3). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. To the residue was added an aqueous sulfuric acid solution (60 mL, 50% v / v), and the reaction mixture was stirred at 160 ℃ for 2 hr. The reaction mixture was diluted with ice water (50 mL) at 0 ℃ and extracted with EtOAc (100 mL × 3). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the desired product, 2-(5-bromo-2-methyl-pyrazol- 3-yl)acetic acid (6 g, crude), as a white solid.1H NMR (400 MHz, DMSO-d6) δ ppm 12.66 (br s, 1 H), 6.26 (s, 1 H), 3.77 (s, 2 H), 3.69 (s, 3 H); LCMS (ESI) m / z 220.9 [M+H]+. Step 5: Synthesis of 2-(5-bromo-2-methyl-pyrazol-3-yl)ethanol To a solution of 2-(5-bromo-2-methyl-pyrazol-3-yl)acetic acid (3.0 g, 13.7 mmol) in THF (30 mL) was added a solution of BH3.THF (15 mL, 1M, 15 mmol) at 0 ℃ and the mixture was stirred at 0 ℃ for 2 h under N2atmosphere. The reaction mixture was quenched with MeOH (5.0 mL) at 0 ℃ . The resulting mixture was concentrated under reduced pressure to remove solvent. The crude mixture was diluted with water (50 mL) and extracted with EtOAc (60 mL × 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure and further purified by flash chromatography (ISCO®; 40 AgelaFlash® Silica Flash Column, Dichloromethane / Methanol with Methanol from 0~7%, flow rate 50 mL / min, 254 nm) to afford the desired product, 2-(5-bromo-2-methyl-pyrazol-3-yl)ethanol (3.44 g, 55.1% yield), as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ ppm 6.18 (s, 1 H); 4.80 (t, J = 5.3 Hz, 1 H), 3.71 (s, 3 H), 3.58 - 3.63 (m, 2 H), 2.74 (t, J = 6.6 Hz, 2 H); LCMS (ESI) m / z 204.9 [M+H]+. Step 6: Synthesis of 2-[2-(5-bromo-2-methyl-pyrazol-3-yl)ethoxy]acetic acid To a solution of 2-(5-bromo-2-methyl-pyrazol-3-yl)ethanol (1.5 g, 7.32 mmol) in THF (20 mL) was added NaH (450 mg, 11.3 mmol, 60% in mineral oil) and the mixture was stirred at 50 ℃ for 30 min. To this mixture was added dropwise a solution of ethyl 2-bromoacetate (1.51 g, 9.04 mmol) in THF (2.0 mL). The resulting mixture was stirred at 50 ℃ for 12 h. The reaction mixture was quenched with water (50 mL) at 0 ℃, and then extracted with EtOAc (60 mL × 3). The combined organic layers were washed with brine (100 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. To the crude mixture was added a solution of LiOH-H2O (921 mg in THF and water (10 / 5 mL). The reaction mixture was stirred at 50 ℃ for 2 h. The reaction mixture was quenched with water (50 mL) at 20 ℃ and adjusted the pH to ~6 adding a solution of HCl (1N). A normal aqueous workup with EtOAc (60 mL × 3) was followed. The combined organic layers were washed with brine (100 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford, 2-[2-(5-bromo-2-methyl-pyrazol-3- yl)ethoxy]acetic acid (1.8 g, crude), as a yellow oil. LCMS (ESI) m / z 262.9 [M+H]+. Step 7: Synthesis of 2-[2-(5-bromo-2-methyl-pyrazol-3-yl)ethoxy]ethanol To a solution of 2-[2-(5-bromo-2-methyl-pyrazol-3-yl)ethoxy]acetic acid (1.5 g, 5.70 mmol) in THF (20 mL) was added a solution of BH3.THF (8.5 ml, 1M,8.5 mmol) at 0 ℃ and the mixture was stirred at 50 ℃ for 3 h under N2 atmosphere. The reaction mixture was quenched with MeOH (5.0 mL) at 0 ℃ and concentrated under reduced pressure to remove solvents. The crude mixture was purified by flash chromatography (ISCO®; 20 g AgelaFlash® Silica Flash Column, Dichloromethane / Methanol with Methanol from 0~5%, flow rate =40 mL / min, 254 nm) to afford the desired product 2-[2-(5-bromo-2-methyl-pyrazol-3-yl)ethoxy]ethanol (1.3 g, 73.2% yield) as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ ppm 6.21 (s, 1 H), 4.60 (t, J = 5.4 Hz, 1 H), 3.71 (s, 3 H), 3.61 (t, J = 6.4 Hz, 2 H), 3.48 (t, J = 5.1 Hz, 2 H), 3.41 - 3.44 (m, 2 H), 2.84 (t, J = 6.5 Hz, 2H); LCMS (ESI) m / z 250.9 [M+H]+. Step 8: Synthesis of 2-[2-[2-(5-bromo-2-methyl-pyrazol-3-yl)ethoxy]ethoxy]-6-chloro- pyridine

[0046] To a stirred mixture of 2-[2-(5-bromo-2-methyl-pyrazol-3-yl)ethoxy]ethanol (500 mg, 2.01 mmol), 6-chloropyridin-2-ol (390 mg, 3.01 mmol) in toluene (20 mL) was added 2-(tributyl- phosphanylidene)acetonitrile (1.45 g, 6.03 mmol). The resulting mixture was stirred at 110 ℃ for 12 h under N2 atmosphere. The resulting mixture was cooled to rt and quenched with water (50 mL) and extracted with EtOAc (60 mL × 3). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure and further purified by flash chromatography (ISCO®; 12 g AgelaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0~70%, flow rate =30 mL / min, 254 nm) to provide 2- [2-[2-(5-bromo-2-methyl-pyrazol-3-yl)ethoxy]ethoxy]-6-chloro-pyridine (600 mg, 80.4% yield) as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ ppm 7.77 (t, J = 7.9 Hz, 1 H), 7.09 (d, J = 7.3 Hz, 1 H), 6.83 (d, J = 8.0 Hz, 1 H), 6.20 (s, 1 H), 4.31 - 4.41 (m, 2 H), 3.72 - 3.76 (m, 2 H), 3.70 (s, 3 H), 3.68 (t, J = 6.5 Hz, 2 H), 2.86 (t, J = 6.5 Hz, 2 H); LCMS (ESI) m / z 359.8 [M+H]+. Step 9: Synthesis of N-[5-[5-[2-[2-[(6-chloro-2-pyridyl)oxy]ethoxy]ethyl]-1-methyl-pyrazol- 3-yl]-8-(methylamino)-2,7-naphthyridin-3-yl]cyclopropanecarboxamide To a stirring mixture of N-[8-(methylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,7- naphthyridin-3-yl]cyclopropanecarboxamide (300 mg, 0.815 mmol), 2-[2-[2-(5-bromo-2-methyl- pyrazol-3-yl)ethoxy]ethoxy]-6-chloro-pyridine (300 mg, 0.832 mmol) in dioxane (20 mL) and H2O (4.0 mL) was added Pd(dtbpf)Cl2 (60.0 mg, 92.1 μmol), K3PO4 (519 mg, 2.45 mmol). The reaction mixture was stirred at 90 ℃ for 2 h under N2 atmosphere. The resulting mixture was quenched with water (60 mL) and extracted with EtOAc (80 mL × 3). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure and purified by flash chromatography (ISCO®; 12 g AgelaFlash® Silica Flash Column, Dichloromethane / Methanol with Methanol from 0~5%, flow rate =30 mL / min, 254 nm) to afford N-[5-[5-[2-[2-[(6-chloro-2-pyridyl)oxy]ethoxy]ethyl]-1-methyl-pyrazol-3-yl]-8- (methylamino)-2,7-naphthyridin-3-yl]cyclopropanecarboxamide (250 mg, 50.0% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ ppm 10.86 (s, 1 H), 9.34 (s, 1 H), 8.95 (s, 1 H), 8.13 (s, 1 H), 7.89 - 7.97 (m, 1 H), 7.70 (t, J = 7.9 Hz, 1 H), 7.05 (d, J = 7.5 Hz, 1 H), 6.80 (d, J = 8.3 Hz, 1 H), 6.35 (s, 1 H), 4.38 (br dd, J = 5.3, 3.8 Hz, 2 H), 3.80 (s, 3 H), 3.73 - 3.79 (m, 4 H), 3.00 (d, J = 4.3 Hz, 3 H), 2.95 (br d, J = 6.5 Hz, 2 H), 2.01 - 2.08 (m, 1 H), 0.79 - 0.85 (m, 4 H) ; LCMS (ESI) m / z 522.2 [M+H]+. Step 10: Synthesis of 4-[5-[2-[2-[(6-chloro-2-pyridyl)oxy]ethoxy]ethyl]-1-methyl-pyrazol-3- yl]-N1-methyl-2,7-naphthyridine-1,6-diamine To a solution of N-[5-[5-[2-[2-[(6-chloro-2-pyridyl)oxy]ethoxy]ethyl]-1-methyl-pyrazol-3-yl]-8- (methylamino)-2,7-naphthyridin-3-yl]cyclopropanecarboxamide (100 mg, 0.192 mmol) in MeOH (10 mL) was added NaOH (40 mg, 1.00 mmol) in H2O (3.0 mL). The mixture was stirred at 80 ℃ for 12 hr. The reaction mixture was concentrated under reduced pressure to remove MeOH, diluted with water (50 mL) and extracted with EtOAc (60 mL × 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The desired product 4-[5-[2-[2-[(6-chloro-2-pyridyl)oxy]ethoxy]ethyl]-1- methyl-pyrazol-3-yl]-N1-methyl-2,7-naphthyridine-1,6-diamine (80 mg, crude) was obtained as a yellow solid. LCMS (ESI) m / z 454.1 [M+H]+. Step 11: Synthesis of N,4-dimethyl-8,11-dioxa-3,4,17,19,23,27- hexazapentacyclo[16.6.2.12,5.112,16.021,25]octacosa- 1(24),2,5(28),12(27),13,15,18(26),19,21(25),22-decaen-22-amine

[0047] To a mixture of 4-[5-[2-[2-[(6-chloro-2-pyridyl)oxy]ethoxy]ethyl]-1-methyl-pyrazol-3-yl]-N1- methyl-2,7-naphthyridine-1,6-diamine (70 mg, 0.154 mmol), Cs2CO3(126 mg, 0.387 mmol) in DMF (10 mL) was added EPhos (17 mg, 31.8 μmol), EPhos Pd G4 (15 mg, 16.3 μmol) and the mixture was stirred at 100 ℃ for 0.5 h under N2 atmosphere. The resulting mixture was cooled to rt and quenched with water (60 mL) and extracted with EtOAc (80 mL × 3). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and purified by flash chromatography (ISCO®; 12 g AgelaFlash® Silica Flash Column, Dichloromethane / Methanol with Methanol from 0~8%, flow rate =30 mL / min, 254 nm). This product was further 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% HCl (v%); Mobile phase B: ACN; Gradient: B from 5% to 35% in 10 min, hold 100% B for 2 min; Flow Rate: 25 mL / min; Column Temperature: 30 ℃; Wavelength: 220 nm) to afford N,4-dimethyl-8,11-dioxa-3,4,17,19,23,27- hexazapentacyclo[16.6.2.12,5.112,16.021,25]octacosa- 1(24),2,5(28),12(27),13,15,18(26),19,21(25),22-decaen-22-amine (18.2 mg, 27.85% yield)as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ ppm 9.55 (s, 1 H), 8.69 (s, 1 H), 7.67 (t, J = 7.9 Hz, 1 H), 7.59 (s, 1 H), 6.75 (d, J = 8.0 Hz, 1 H), 6.55 (s, 1 H), 6.42 (d, J = 8.0 Hz, 1 H), 4.04 (t, J = 4.8 Hz, 2 H), 3.78 - 3.87 (m, 5 H), 3.73 (br t, J = 4.8 Hz, 2 H), 3.14 (s, 3 H), 2.94 (br t, J = 5.4 Hz, 2 H); LCMS (ESI) m / z 418.1 [M+H]+; HPLC: 98.69%@220 nm, 99.16%@254 nm.

[0048] Example 40: (6E)-N,4-dimethyl-8,11-dioxa-3,4,17,19,23,27-hexazapentacyclo [16.6.2.12,5.112,16.021,25]octacosa-1(24),2,5(28),6,12(27),13,15,18(26),19,21(25),22-undecaen- 22-amine Step 1: Synthesis of 2-[(6-chloro-2-pyridyl)oxy]ethanol To a solution of ethylene glycol (924 mg, 14.9 mmol) in DMF (15.0 mL) was added NaH (648 mg, 16.2 mmol, 60% dispersion in mineral oil) at 0 ℃ over 5 min. After addition, the mixture was stirred at this temperature for 30 min. To this reaction mixture a solution of 2,6-dichloropyridine (2.0 g, 13.5 mmol) in DMF (5.0 mL) was added dropwise at 0 ℃. The resulting mixture was stirred at 80 ℃ for 1 hr. The resulting mixture was quenched with water (50 mL) at 0 ℃. A normal workup with EtOAc (60 mL × 3) was followed. The combined organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (ISCO®; 12 g AgelaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0~30%, flow rate = 30 mL / min, 254 nm) to provide 2-[(6-chloro-2-pyridyl)oxy]ethanol (850 mg, 25.4% yield) as a yellow oil. LCMS (ESI) m / z 173.9 [M+H]+. Step 2: Synthesis of 3,5-dibromo-1-methyl-pyrazole To a solution of 3,5-dibromo-1H-pyrazole (5.0 g, 22.1 mmol), K2CO3 (6.12 g, 44.3 mmol) in DMF (50 mL) was added MeI (3.42 g, 24.1 mmol) and the mixture was stirred at 20 ℃ for 2 hr. The reaction mixture was quenched with water (100 mL) at 0 ℃, and then extracted with EtOAc (120 mL × 3). The combined organic layers were washed with brine (200 mL × 2), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and was purified by flash chromatography (ISCO®; 60 g AgelaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0~30%, flow rate = 80 mL / min, 254 nm) to provide 3,5-dibromo-1-methyl-pyrazole (5.2 g, 88.1% yield)as a yellow oil. LCMS (ESI) m / z 239.0 [M+H]+. Step 3: Synthesis of 2-(5-bromo-2-methyl-pyrazol-3-yl)ethynyl-trimethyl-silane To a stirred mixture of 3,5-dibromo-1-methyl-pyrazole (4.5 g, 18.8 mmol), ethynyl(trimethyl)silane (2.20 g, 22.4 mmol) in DMF (40 mL) was added Pd(dppf)Cl2 (686 mg, 0.938 mmol), CuI (1.07 g, 5.62 mmol), TEA (5.67 g, 56.0 mmol). The reaction mixture was stirred at 100 ℃ for 2 h under N2atmosphere. The resulting mixture was quenched with water (50 mL) and extracted with EtOAc (60 mL × 3). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and purified by flash chromatography (ISCO®; 60 g AgelaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0~20%, flow rate = 80 mL / min, 254 nm) to afford the desired product, 2-(5- bromo-2-methyl-pyrazol-3-yl)ethynyl-trimethyl-silane (3.01 g, 56.2% yield), as a yellow oil. LCMS (ESI) m / z 259.0 [M+H]+. Step 4: Synthesis of 3-bromo-5-ethynyl-1-methyl-pyrazole To a solution of 2-(5-bromo-2-methyl-pyrazol-3-yl)ethynyl-trimethyl-silane (3.0 g, 11.7 mmol) in MeOH (50 mL) was added K2CO3 (1.8 g, 13.0 mmol) and the mixture was stirred at 20 ℃ for 30 min. The resulting mixture was quenched with water (50 mL) and extracted with EtOAc (60 mL × 3). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and was purified by flash chromatography (ISCO®; 40 g AgelaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0~50%, flow rate = 50 mL / min, 254 nm) to provide3-bromo-5-ethynyl-1-methyl-pyrazole (1.2 g, 52.8% yield) as a colorless oil. LCMS (ESI) m / z 185.0 [M+H]+. Step 5: Synthesis of 2-[2-[(E)-2-(5-bromo-2-methyl-pyrazol-3-yl)vinyloxy]ethoxy]-6-chloro- pyridine To a solution of 3-bromo-5-ethynyl-1-methyl-pyrazole (600 mg, 3.24 mmol), 2-[(6-chloro-2- pyridyl)oxy]ethanol (732 mg, 4.22 mmol) in DMSO (10 mL) was added KOH (200 mg, 3.56 mmol) and the mixture was stirred at 70 ℃ for 1 h under N2 atmosphere. The resulting mixture was cooled to rt and quenched with water (30 mL). A normal workup with EtOAc was followed. The crude product was purified by flash chromatography (ISCO®; 12 g AgelaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0~50%, flow rate = 30 mL / min, 254 nm) to afford 2-[2-[(E)-2-(5-bromo-2-methyl-pyrazol-3-yl)vinyloxy]ethoxy]-6-chloro-pyridine (520 mg, 35.8% yield) as a yellow oil. LCMS (ESI) m / z 359.6, 357.6 [M+H]+. Step 6: Synthesis of N-[5-[5-[(E)-2-[2-[(6-chloro-2-pyridyl)oxy]ethoxy]vinyl]-1-methyl- pyrazol-3-yl]-8-(methylamino)-2,7-naphthyridin-3-yl]cyclopropanecarboxamide

[0049] To a stirred mixture of N-[8-(methylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,7- naphthyridin-3-yl]cyclopropanecarboxamide (300 mg, 0.815 mmol), 2-[2-[(E)-2-(5-bromo-2- methyl-pyrazol-3-yl)vinyloxy]ethoxy]-6-chloro-pyridine (380 mg, 1.06 mmol) in dioxane (15 mL) and H2O (3.0 mL) was added ditert-butyl(cyclopentyl)phosphane;dichloropalladium;iron (54 mg, 82.9 μmol), K3PO4(519 mg, 2.44 mmol). The reaction mixture was stirred at 90 ℃ for 2 hr under N2 atmosphere. After completion, the resulting mixture was cooled and quenched with water (60 mL) and extracted with EtOAc (80 mL × 3). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and purified via a flash chromatography (ISCO®; 12 g AgelaFlash® Silica Flash Column, Dichloromethane / Methanol with Methanol from 0~8%, flow rate = 30 mL / min, 254 nm) to give N-[5-[5-[(E)-2-[2-[(6-chloro-2-pyridyl)oxy]ethoxy]vinyl]-1-methyl-pyrazol-3-yl]-8- (methylamino)-2,7-naphthyridin-3-yl]cyclopropanecarboxamide (310 mg, 58.5% yield) as a yellow solid. LCMS (ESI) m / z 520.0 [M+H]+. Step 7: Synthesis of 4-[5-[(E)-2-[2-[(6-chloro-2-pyridyl)oxy]ethoxy]vinyl]-1-methyl-pyrazol- 3-yl]-N1-methyl-2,7-naphthyridine-1,6-diamine To a solution of N-[5-[5-[(E)-2-[2-[(6-chloro-2-pyridyl)oxy]ethoxy]vinyl]-1-methyl-pyrazol-3- yl]-8-(methylamino)-2,7-naphthyridin-3-yl]cyclopropanecarboxamide (120 mg, 0.231 mmol) in MeOH (10 mL) and DMSO (1.0 mL) was added NaOH (46.80 mg, 1.17 mmol) in H2O (2 mL) and the mixture was stirred at 80 ℃ for 12 hr. The resulting mixture was quenched with water (50 mL) and extracted with EtOAc (60 mL × 3). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure to provide 4-[5-[(E)-2-[2-[(6-chloro-2-pyridyl)oxy]ethoxy]vinyl]-1-methyl-pyrazol-3-yl]-N1-methyl-2,7- naphthyridine-1,6-diamine (100 mg, crude) as a yellow solid. LCMS (ESI) m / z 452.1 [M+H]+. Step 8: Synthesis of (6E)-N,4-dimethyl-8,11-dioxa-3,4,17,19,23,27- hexazapentacyclo[16.6.2.12,5.112,16.021,25]octacosa- 1(24),2,5(28),6,12(27),13,15,18(26),19,21(25),22-undecaen-22-amine To a stirring mixture of 4-[5-[(E)-2-[2-[(6-chloro-2-pyridyl)oxy]ethoxy]vinyl]-1-methyl-pyrazol- 3-yl]-N1-methyl-2,7-naphthyridine-1,6-diamine (90 mg, 0.199 mmol), Cs2CO3 (162 mg, 0.497 mmol) in DMF (20 mL) was added EPhos (22 mg, 41.1 μmol) and EPhos Pd G4 (19 mg, 20.7 μmol) and the mixture was stirred at 100 ℃ for 30 min under N2atmosphere. The resulting mixture was quenched with water (50 mL) and extracted with EtOAc (60 mL × 3). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and purified by flash chromatography (ISCO®; 12 g AgelaFlash® Silica Flash Column, Dichloromethane / Methanol with Methanol from 0~8%, flow rate = 30 mL / min, 254 nm) to afford the desired product. The desired product was further 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% HCl (v%); Mobile phase B: ACN; Gradient: B from 5% to 35% in 10 min, hold 100% B for 2 min; Flow Rate: 25 mL / min; Column Temperature: 30 ℃; Wavelength: 220 nm) to provide (6E)-N,4-dimethyl-8,11- dioxa-3,4,17,19,23,27-hexazapentacyclo[16.6.2.12,5.112,16.021,25]octacosa- 1(24),2,5(28),6,12(27),13,15,18(26),19,21(25),22-undecaen-22-amine (11.9 mg, 13.8% yield) as a yellow solid. LCMS (ESI) m / z 416.1 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ ppm 9.85 (br s, 1 H), 9.30 (s, 1 H), 8.37 (s, 1 H), 8.18 (s, 1 H), 7.96 (s, 1 H), 7.66 (t, J = 7.9 Hz, 1 H), 7.14 (s, 1 H), 6.67 (d, J = 7.8 Hz, 1 H), 6.56 (d, J = 6.5 Hz, 1 H), 6.46 (d, J = 7.8 Hz, 1 H), 5.55 (d, J = 6.5 Hz, 1 H), 4.31 (br dd, J = 17.1, 5.0 Hz, 4 H), 3.80 (s, 3 H), 3.01 (d, J = 4.5 Hz, 3 H). Example 41: N,4-dimethyl-9-oxa-3,4,15,17,21,25-hexazapentacyclo[14.6.2.12,5.110,14.019,23] hexacosa-1(22),2,5(26),10(25),11,13,16(24),17,19(23),20-decaen-20-amine Step 1: Synthesis of 3-bromo-1-methyl-5-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1- yl)-1H-pyrazole A mixture of 3,5-dibromo-1-methyl-pyrazole (5 g, 20.8 mmol, 1 eq), 2-prop-2- ynoxytetrahydropyran (2.9 g, 20.8 mmol, 1 eq), CuI (793.9 mg, 4.2 mmol, 0.2 eq), Pd(PPh3)2Cl2 (2.2 g, 3.1 mmol, 0.15 eq) and TEA (6.3 g, 62.5 mmol, 3 eq) in DMF (60 mL) was degassed and purged several times with N2. The reaction mixture was stirred at 80 °C for 2 hr under N2 atmosphere. The reaction mixture was cooled to RT and it was filtered and concentrated under reduced pressure and purified by column chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0~11%, 30 mL / min, 254nm) to afford 3- bromo-1-methyl-5-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)-1H-pyrazole (2.35 g, 37.5%) as a yellow oil. LCMS (ESI) m / z 299.2, 301.2 [M+H]+,1H NMR (400 MHz, DMSO-d6) δ ppm 6.73 (s, 1H), 4.80 (s, 1H), 4.46 - 4.60 (m, 2H), 3.84 (s, 3H), 3.75 (br d, J = 2.76 Hz, 1H), 3.45 - 3.52 (m, 1H), 1.63 - 1.73 (m, 2H), 1.47 - 1.54 (m, 4H). Step 2: Synthesis of N-(5-(1-methyl-5-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)- 1H-pyrazol-3-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide A mixture of 3-bromo-1-methyl-5-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)-1H- pyrazole (600 mg, 2.0 mmol, 1 eq), N-[8-(methylamino)-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-2,7-naphthyridin-3-yl]cyclopropanecarboxamide (1.1 g, 2.6 mmol, 1.3 eq), XPhos Pd G3 (169.8 mg, 0.2 mmol, 0.1 eq), XPhos (95.6 mg, 0.2 mmol, 0.1 eq) and K3PO4 (1.3 g, 6.0 mmol, 3 eq) in dioxane (20 mL) and H2O (0.5 mL) was degassed and purged several times with N2. The mixture was stirred at 100 °C for 2 hr under N2atmosphere. 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, DCM / MeOH with MeOH from 0~5%, 40 mL / min, 254nm) to afford N-(5-(1-methyl-5-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop- 1-yn-1-yl)-1H-pyrazol-3-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (909 mg, 81.2%) as a yellow solid. LCMS (ESI) m / z 461.1 [M+H]+,1H NMR (400 MHz, DMSO- d6) δ ppm 10.93 (s, 1H), 9.35 (s, 1H), 8.86 (s, 1H), 8.19 (s, 1H), 7.99 - 8.05 (m, 1H), 6.79 (s, 1H), 4.82 - 4.87 (m, 1H), 4.49 - 4.64 (m, 2H), 3.93 (s, 3H), 3.79 (s, 1H), 3.47 - 3.56 (m, 1H), 3.00 (d, J = 4.4 Hz, 3H), 2.01 - 2.08 (m, 1H), 1.63 - 1.78 (m, 2H), 1.45 - 1.59 (m, 4H), 0.80 - 0.84 (m, 4H). Step 3: Synthesis of N-(5-(1-methyl-5-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-1H- pyrazol-3-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0050] A mixture of N-(5-(1-methyl-5-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)-1H-pyrazol- 3-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (889 mg, 1.9 mmol, 1 eq), Pd / C (205.4 mg, 0.2 mmol, 10% on carbon, 0.1 eq) in THF (10 mL) was degassed and purged several times with H2, and then the mixture was stirred at 25 °C for 6 hr under H2 atmosphere. The reaction mixture was concentrated under reduced pressure to afford N-(5-(1-methyl-5-(3- ((tetrahydro-2H-pyran-2-yl)oxy)propyl)-1H-pyrazol-3-yl)-8-(methylamino)-2,7-naphthyridin-3- yl)cyclopropanecarboxamide (860 mg, crude) as a yellow solid. LCMS (ESI) m / z 465.1 [M+H]+. Step 4: Synthesis of N-(5-(5-(3-hydroxypropyl)-1-methyl-1H-pyrazol-3-yl)-8-(methylamino)- 2,7-naphthyridin-3-yl)cyclopropanecarboxamide To a solution of N-(5-(1-methyl-5-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-1H-pyrazol-3-yl)- 8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (835 mg, 1.8 mmol, 1 eq) in HCl / EtOAc (10 mL) was stirred at 25 °C for 1 hr. The reaction mixture was diluted with an aqueous solution of NaHCO3 (5 mL) and extracted with EtOAc (30 mL ´ 3), dried over Na2SO4, concentrated under reduced pressure and purified by column chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, DCM / MeOH with MeOH from 0~10%, 40 mL / min, 254 nm) to afford N-(5-(5-(3-hydroxypropyl)-1-methyl-1H-pyrazol-3-yl)-8-(methylamino)-2,7- naphthyridin-3-yl)cyclopropanecarboxamide (510 mg, 73.9%) as a white solid. LCMS (ESI) m / z 381.1 [M+H]+. Step 5: Synthesis of N-(5-(5-(3-((6-bromopyridin-2-yl)oxy)propyl)-1-methyl-1H-pyrazol-3- yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0051] To a solution of N-(5-(5-(3-hydroxypropyl)-1-methyl-1H-pyrazol-3-yl)-8-(methylamino)-2,7- naphthyridin-3-yl)cyclopropanecarboxamide (100 mg, 0.3 mmol, 1 eq) in DMF (4 mL) was added NaH (15.8 mg, 0.4 mmol, 60% purity, 1.5 eq) at 0 °C. The reaction mixture was stirred for 30 min, then 2,6-dibromopyridine (155.7 mg, 0.7 mmol, 2.5 eq) was added in the mixture and stirred at 60 °C for 2 hr. The reaction mixture was diluted with a saturated NH4Cl aqueous solution (5 mL) and extracted with EtOAc (30 mL ´ 3), dried over Na2SO4, concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, DCM / MeOH with MeOH from 0~3%, 40 mL / min, 254 nm) to afford N-(5- (5-(3-((6-bromopyridin-2-yl)oxy)propyl)-1-methyl-1H-pyrazol-3-yl)-8-(methylamino)-2,7- naphthyridin-3-yl)cyclopropanecarboxamide (96 mg, 67.9%) as a yellow solid. LCMS (ESI) m / z 536.3, 538.3 [M+H]+. Step 6: Synthesis of 4-(5-(3-((6-bromopyridin-2-yl)oxy)propyl)-1-methyl-1H-pyrazol-3-yl)- N1-methyl-2,7-naphthyridine-1,6-diamine To a solution of N-(5-(5-(3-((6-bromopyridin-2-yl)oxy)propyl)-1-methyl-1H-pyrazol-3-yl)-8- (methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (100 mg, 0.2 mmol, 1 eq) in MeOH (5 mL) and H2O (1 mL) was added NaOH (111.8 mg, 2.8 mmol, 15 eq).The mixture was stirred at 80 °C for 16 hr. The reaction mixture was cooled to RT and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, DCM / MeOH with MeOH from 0~7.7%, 40 mL / min, 254 nm) to afford 4-(5-(3-((6-bromopyridin-2-yl)oxy)propyl)-1-methyl-1H-pyrazol-3-yl)-N1-methyl-2,7- naphthyridine-1,6-diamine (85 mg, 93.1%) as a yellow solid. LCMS (ESI) m / z 468.0, 470.0 [M+H]+. Step 7: Synthesis of N,4-dimethyl-9-oxa-3,4,15,17,21,25- hexazapentacyclo[14.6.2.12,5.110,14.019,23]hexacosa- 1(22),2,5(26),10(25),11,13,16(24),17,19(23),20-decaen-20-amine A mixture of 4-(5-(3-((6-bromopyridin-2-yl)oxy)propyl)-1-methyl-1H-pyrazol-3-yl)-N1-methyl- 2,7-naphthyridine-1,6-diamine (85 mg, 0.2 mmol, 1 eq), Ephos Pd G4 (16.7 mg, 0.02 mmol, 0.1 eq), Ephos (9.7 mg, 0.02 mmol, 0.1 eq) and Cs2CO3(177.4 mg, 0.5 mmol, 3 eq) in dioxane (6 mL) was degassed and purged 3 times with N2. The mixture was stirred at 100 °C for 1 hr under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, DCM / MeOH with MeOH from 0~6%, 30 mL / min, 254nm) to afford N,4-dimethyl-9-oxa- 3,4,15,17,21,25-hexazapentacyclo[14.6.2.12,5.110,14.019,23]hexacosa- 1(22),2,5(26),10(25),11,13,16(24),17,19(23),20-decaen-20-amine (19.17 mg, 26.7%) as a white solid. LCMS (ESI) m / z 388.4 [M+H]+,1H NMR (400 MHz, DMSO-d6) δ ppm 9.89 (s, 1H), 9.27 (s, 1H), 8.53 (s, 1H), 8.00 (s, 1H), 7.84 - 7.95 (m, 1H), 7.53 (t, J = 7.6 Hz, 1H), 6.71 (d, J = 7.6 Hz, 1H), 6.40 (s, 1H), 6.25 (d, J = 7.6 Hz, 1H), 4.24 - 4.30 (m, 2H), 3.82 (s, 3H), 2.99 (d, J = 4.4 Hz, 3H), 2.89 (br t, J = 6.4 Hz, 2H), 2.00 (br dd, J = 9.2, 6.32 Hz, 2H). Example 42: (Z)-11-allyl-N-methyl-11H-5,8-dioxa-3-aza-2(5,3)-naphthyridina-4(2,6)-pyridin a-1(3,5)-pyrazolacyclodecaphan-28-amine

[0052] Step 1: ethyl 3,5-dibromo-1-cyclopropyl-1H-pyrazole-4-carboxylate A stirred mixture of ethyl 3,5-dibromo-1H-pyrazole-4-carboxylate (7.50 g; 25.173 mmol; 1.00 eq.), cyclopropylboronic acid (4.32 g; 50.346 mmol; 2.00 eq.), Cu(AcO)2 (4.57 g; 25.173 mmol; 1.00 eq.), 2,2'-bipyridine (3.93 g; 25.173 mmol; 1.00 eq.) and Na2CO3(5.34 g; 50.346 mmol; 2.00 eq.) in DCE (150 mL) was stirred at 70 ℃ for 2 hours under O2atmosphere. The desired product was detected via LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel column using 0-20% of EtOAc in petroleum ether as eluent to provide ethyl 3,5-dibromo-1-cyclopropyl-1H-pyrazole-4-carboxylate as a white solid (3.10 g, 36.4%). LCMS (ESI) m / z 337.0, [M+H]+. Step 2: diethyl 2-(3-bromo-1-cyclopropyl-4-(ethoxycarbonyl)-1H-pyrazol-5-yl)malonate To a stirred solution of NaH (60%) (427.2 mg; 9.792 mmol; 1.10 eq.) in DMF (30 mL) was added a solution of diethyl malonate (1.56 g; 9.792 mmol; 1.10 eq.) in DMF (5 mL) dropwise at 0 ℃ under nitrogen atmosphere. The resulting mixture was stirred for 30 min at 0 ℃. To the above mixture was added dropwise a solution of ethyl 3,5-dibromo-1-cyclopropyl-1H-pyrazole-4- carboxylate (3.00 g; 8.876 mmol; 1.00 eq.) in DMF (5 mL) at 0 ℃. The resulting mixture was stirred at 130 ℃ for 12 hours. The desired product was detected via LCMS. Upon completion, the reaction was cooled to RT and quenched with water (20 mL) at 0 ℃. The reaction mixture was extracted with EtOAc (3 × 80 mL). The combined organic layers were washed with brine (1 × 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel column using 0-20% of EtOAc in petroleum ether as eluent to provide diethyl 2-(3-bromo-1-cyclopropyl-4- (ethoxycarbonyl)-1H-pyrazol-5-yl)malonate as a colorless oil (1.34 g, 36.1%). LCMS (ESI) m / z 417.0, [M+H]+. Step 3: 2-(3-bromo-1-cyclopropyl-1H-pyrazol-5-yl)acetic acid To a solution of diethyl 2-(3-bromo-1-cyclopropyl-4-(ethoxycarbonyl)-1H-pyrazol-5-yl)malonate (1.391 g; 3.331 mmol; 1.00eq.) in EtOH (30 mL) and water (15 mL) was added NaOH (8 M in water; 4.8 mL) at room temperature. The mixture was stirred at 60 ℃ for 12 hours. The reaction mixture was cooled to RT and concentrated under reduced pressure to remove EtOH. To the above mixture was added H2SO4 (9.80 g; 99.700 mmol; 30.00 eq.) dropwise at 0 ℃. The resulting mixture was stirred at 120 ℃ for 12 hours. The resulting mixture was diluted with ice water (10 mL). The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (1 ×20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 2-(3-bromo-1-cyclopropyl-1H-pyrazol-5-yl)acetic acid as a brown oil (1.2 g, crude). LCMS (ESI) m / z 245.0 [M+H]+. Step 4: 2-(3-bromo-1-cyclopropyl-1H-pyrazol-5-yl)ethan-1-ol To a stirred solution of 2-(3-bromo-1-cyclopropyl-1H-pyrazol-5-yl)acetic acid (880.0 mg; 3.591 mmol; 1.00 eq.) in THF (10 mL) was added BH3-THF (7.2 mL; 1 M in THF) dropwise at 0 ℃ under nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight. The desired product was detected via LCMS. The reaction was quenched with MeOH at 0 ℃. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel column using 0-10% of MeOH in CH2Cl2 as eluent to provide 2-(3- bromo-1-cyclopropyl-1H-pyrazol-5-yl)ethan-1-ol as a yellow oil (329.9 mg, 39.7%). LCMS (ESI) m / z 231.0, [M+H]+. Step 5: tert-butyl 2-(2-(3-bromo-1-cyclopropyl-1H-pyrazol-5-yl)ethoxy)acetate A solution of 2-(3-bromo-1-cyclopropyl-1H-pyrazol-5-yl)ethan-1-ol (300.0 mg; 1.298 mmol; 1.00 eq.), tert-butyl 2-bromoacetate (759.6 mg; 3.894 mmol; 3.00 eq.) and t-BuOK (582.6 mg; 5.192 mmol; 4.00 eq.) in THF (5 mL) was stirred at room temperature for 1 hour. The desired product was detected via LCMS. The resulting mixture was concentrated under reduced pressure and purified by flash chromatography on silica gel column using 0-10% of MeOH in CH2Cl2as eluent to provide tert-butyl 2-(2-(3-bromo-1-cyclopropyl-1H-pyrazol-5-yl)ethoxy)acetate as a yellow oil (247.0 mg, 57.7%). LCMS (ESI) m / z 345.1, [M+H]+. Step 6: 2-(2-(3-bromo-1-cyclopropyl-1H-pyrazol-5-yl)ethoxy)ethan-1-ol

[0053] To a stirred solution of tert-butyl 2-(2-(3-bromo-1-cyclopropyl-1H-pyrazol-5-yl)ethoxy)acetate (237.0 mg; 0.686 mmol; 1.00 eq.) in DCM (5 mL) was added DIBAL-H (2 mL, 1 M in CH2Cl2) dropwise at 0 ℃ under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 hours. The desired product was detected via LCMS. The reaction was quenched by the addition of MeOH at 0 ℃. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel column using 0-10% of MeOH in CH2Cl2 as eluent to provide 2-(2-(3-bromo-1-cyclopropyl-1H-pyrazol-5-yl)ethoxy)ethan-1-ol as a colorless oil (147.9 mg, 78.3%). LCMS (ESI) m / z 275.0, [M+H]+. Step 7: 2-(2-(2-(3-bromo-1-cyclopropyl-1H-pyrazol-5-yl)ethoxy)ethoxy)-6-chloropyridine To a stirred mixture of NaH (60% dispersion in mineral oil) (60.2 mg; 3.00 eq.) in THF (5 mL) was added dropwise a solution of 2-(2-(3-bromo-1-cyclopropyl-1H-pyrazol-5-yl)ethoxy)ethan-1- ol (137.9 mg; 0.501 mmol; 1.00 eq.) in THF (1 mL) at 0 ℃ under nitrogen atmosphere. The resulting mixture was stirred at 0 ℃ for 30 min. To the above mixture was added a solution of 2,6- dichloropyridine (74.1 mg; 0.501 mmol; 1.00 eq.) in THF (1 mL) dropwise at 0 ℃. The resulting mixture was stirred at room temperature overnight. The desired product was detected via LCMS. The reaction was quenched by the addition of MeOH at 0 ℃. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel column using 0-20% of MeOH in CH2Cl2 as eluent to provide 2-(2-(2-(3-bromo-1- cyclopropyl-1H-pyrazol-5-yl)ethoxy)ethoxy)-6-chloropyridine as a colorless oil (138.4 mg, 71.4%). LCMS (ESI) m / z 386.0, [M+H]+. Step 8: N-(5-(5-(2-(2-((6-chloropyridin-2-yl)oxy)ethoxy)ethyl)-1-cyclopropyl-1H-pyrazol-3- yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide A stirred mixture of 2-(2-(2-(3-bromo-1-cyclopropyl-1H-pyrazol-5-yl)ethoxy)ethoxy)-6- chloropyridine (133.4 mg; 0.345 mmol; 1.00 eq.), N-(8-(methylamino)-5-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (125.7 mg; 0.345 mmol; 1.00 eq.), Pd(DtBPF)Cl2(24.7 mg; 0.038 mmol; 0.11 eq.) and K3PO4(218.9 mg; 1.031 mmol; 3.00 eq.) in a mixture solvent of dioxane / H2O (5:1, 1.2 mL) was stirred at 90 ℃ for 2 hours under nitrogen atmosphere. The desired product was detected via LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel column using 0-10% of MeOH in CH2Cl2 as eluent to provide N-(5-(5-(2-(2-((6- chloropyridin-2-yl)oxy)ethoxy)ethyl)-1-cyclopropyl-1H-pyrazol-3-yl)-8-(methylamino)-2,7- naphthyridin-3-yl)cyclopropanecarboxamide as a yellow solid (106.0 mg, 56.0%). LCMS (ESI) m / z 548.2, [M+H]+. Step 9: 4-(5-(2-(2-((6-chloropyridin-2-yl)oxy)ethoxy)ethyl)-1-cyclopropyl-1H-pyrazol-3-yl)- N1-methyl-2,7-naphthyridine-1,6-diamine

[0054] To a stirred solution of N-(5-(5-(2-(2-((6-chloropyridin-2-yl)oxy)ethoxy)ethyl)-1-cyclopropyl- 1H-pyrazol-3-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (100.0 mg; 0.182 mmol; 1.00 eq.) in MeOH (5 mL) was added a solution of NaOH (72.0 mg; 1.800 mmol; 10.00 eq.) in H2O (1.5 mL) dropwise at room temperature. The resulting mixture was stirred at 70 ℃ overnight. The desired product was detected via LCMS. The resulting mixture was concentrated under reduced pressure to remove MeOH. The residue was purified by flash chromatography on pre-packed C18 column using 30-100% of MeCN in water (6.5 mmol / L TFA) to afford 4-(5-(2-(2-((6-chloropyridin-2-yl)oxy)ethoxy)ethyl)-1-cyclopropyl-1H-pyrazol-3-yl)- N1-methyl-2,7-naphthyridine-1,6-diamine as a yellow solid (15.3 mg, 17.4%). LCMS (ESI) m / z 480.2, [M+H]+. Step 10: (Z)-11-allyl-N-methyl-11H-5,8-dioxa-3-aza-2(5,3)-naphthyridina-4(2,6)-pyridina- 1(3,5)-pyrazolacyclodecaphan-28-amine

[0055] A mixture of 4-(5-(2-(2-((6-chloropyridin-2-yl)oxy)ethoxy)ethyl)-1-cyclopropyl-1H-pyrazol-3- yl)-N1-methyl-2,7-naphthyridine-1,6-diamine (12.0 mg; 0.025 mmol; 1.00 eq.), EPhos (2.7 mg; 0.005 mmol; 0.20 eq.), EPhos Pd G4 (2.3 mg; 0.003 mmol; 0.10 eq.) and Cs2CO3(16.3 mg; 0.050 mmol; 2.00 eq.) in dioxane (1.8 mL) was stirred at 120 ℃ for 2 hours under nitrogen atmosphere. The desired product was detected via LCMS. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel column using 0-10% of MeOH in CH2Cl2as eluent to provide (Z)- 11-allyl-N-methyl-11H-5,8-dioxa-3-aza-2(5,3)-naphthyridina-4(2,6)-pyridina-1(3,5)- pyrazolacyclodecaphan-28-amine as an off-white solid (2.7 mg, 23.3%). LCMS (ESI) m / z 444.2, [M+H]+.1H NMR (400 MHz, Methanol-d4) δ 9.18 (s, 1H), 8.18 (s, 1H), 7.77 (s, 1H), 7.53 (t, J = 7.9 Hz, 1H), 6.55 (d, J = 7.9 Hz, 1H), 6.37 (s, 1H), 6.28 (d, J = 7.9 Hz, 1H), 5.91 - 5.77 (m, 1H), 5.00 (d, J = 10.4 Hz, 1H), 4.87 (m, 1H), 4.48 (d, J = 5.4 Hz, 2H), 4.00 (t, J = 4.4 Hz, 2H), 3.93 - 3.79 (m, 4H), 3.12 (s, 3H), 2.92 (t, J = 5.4 Hz, 2H). Example 43: N-methyl-8,13-dioxa-2,16,24,28,31-pentazapentacyclo[20.6.2.13,7.014,19.026,30] hentriaconta-1(29),3,5,7(31),14(19),15,17,22,24,26(30),27-undecaen-20-yn-25-amine Step 1: Synthesis of 1,6-dichloro-2,7-naphthyridine A mixture of 6-chloro-2,7-naphthyridin-1-ol (2.00 g, 11.1 mmol), TEA (5.60 g, 55.3 mmol), POCl3 (8.55 g, 55.8 mmol) in toluene (30 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100 °C for 12 hr under N2 atmosphere. The reaction mixture was cooled and quenched with H2O (50 mL) at 25 °C, extracted with EtOAc (50 mL ´ 3). The combined organic layers were washed with brine (50 mL ´ 3), dried over Na2SO4, filtered and concentrated under reduced pressure and 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 provide 1,6-dichloro-2,7-naphthyridine (1.00 g, 45.4% yield) as a white solid. LCMS (ESI) m / z 198.7 [M+H]+. Step 2: Synthesis of 6-chloro-N-methyl-2,7-naphthyridin-1-amine A mixture of 1,6-dichloro-2,7-naphthyridine (1.0 g, 5.02 mmol), methanamine (250 mg, 8.05 mmol) TEA (1.53 g, 15.1 mmol) in butan-1-ol (10 mL) was degassed and purged with N2The mixture was stirred at 110 °C for 12 h under N2atmosphere. The reaction mixture was cooled to room temperature and quenched with H2O (50 mL) at 25 °C, extracted with EtOAc (50 mL ´ 3). The combined organic layers were washed with brine (50 mL ´ 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give 6-chloro-N-methyl-2,7-naphthyridin-1-amine (900 mg, crude) as a white solid. LCMS (ESI) m / z 194.0 [M+H]+. Step 3: Synthesis of tert-butyl (8-(methylamino)-2,7-naphthyridin-3-yl)carbamate A mixture of 6-chloro-N-methyl-2,7-naphthyridin-1-amine (900 mg, 4.65 mmol), tert-butyl carbamate (810 mg, 6.91 mmol), BrettPhos Pd G3 (450 mg, 0.496 mmol), Brettphos (495mg, 0.922 mmol) and Cs2CO3 (4.50 g, 13.8 mmol) in dioxane (20 mL) was degassed and purged several times with N2. The mixture was stirred at 100 °C for 12 h under N2atmosphere. The reaction mixture was cooled to room temperature and quenched with H2O (50 mL) at 25 °C, extracted with EtOAc (50 mL ´ 3). The combined organic layers were washed with brine (50 mL ´ 3), dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by flash chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, DCM / MeOH with MeOH from 0 ~ 5%, flow rate: 65 mL / min, 254 nm). to afford tert-butyl N-[8-(methylamino)-2,7-naphthyridin-3-yl]carbamate (1.15 g, 90.2% yield) as a white solid. LCMS (ESI) m / z 274.9 [M+H]+. Step 4: Synthesis of tert-butyl (5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)carbamate A mixture of tert-butyl N-[8-(methylamino)-2,7-naphthyridin-3-yl]carbamate (1.00 g, 3.65 mmol), NBS (652 mg, 3.66 mmol), in DCM (12 mL) was stirred at 0 °C for 30 min under N2 atmosphere. The reaction mixture was quenched with H2O (50 mL) at 25 °C, extracted with EtOAc (50 mL ´ 3). The combined organic layers were washed with brine (50 mL ´ 3), dried over Na2SO4, filtered, concentrated under reduced pressure and 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 provide tert-butyl N-[5-bromo-8-(methylamino)-2,7-naphthyridin-3- yl]carbamate (650 mg, 50.5% yield) as a white solid. LCMS (ESI) m / z 354.7 [M+H]+. Step 5: Synthesis of tert-butyl N-[8-(methylamino)-5-(2-trimethylsilylethynyl)-2,7- naphthyridin-3-yl]carbamate A mixture of tert-butyl N-[5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl]carbamate (500 mg, 1.42 mmol), ethynyl(trimethyl)silane (1.50 g, 15.27 mmol), CuI (275 mg, 1.44 mmol), DIEA (1.00 g, 7.74 mmol) and Pd(dppf)Cl2-DCM (450 mg, 0.51 mmol) in DMF (10 mL) was degassed and purged several times with N2. The mixture was stirred at 80 °C for 12 h under N2atmosphere. 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 ´ 3), dried over Na2SO4, filtered , concentrated under reduced pressure ,and purified by flash chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 20 ~ 60%, flow rate: 65 mL / min, 254 nm), then the crude product was purified by reversed-phase HPLC (Column: SepaFlash® Sphercial C18, 25 g, 40-60 μm, 120 Å; MeCN / water (0.5% NH3 - H2O) with MeCN from 0 - 29%, 25 mL / min, 254 nm) to afford tert-butyl N-[8-(methylamino)-5-(2- trimethylsilylethynyl)-2,7-naphthyridin-3-yl]carbamate (450 mg 42.9% yield) as a yellow solid. LCMS (ESI) m / z 371.0 [M+H]+. Step 6: Synthesis of tert-butyl (5-ethynyl-8-(methylamino)-2,7-naphthyridin-3- yl)carbamate A mixture of tert-butyl N-[8-(methylamino)-5-(2-trimethylsilylethynyl)-2,7-naphthyridin-3- yl]carbamate (450 mg, 1.21 mmol), K2CO3(675 mg, 4.88 mmol ) in MeOH (10 mL) was degassed and purged with N2. The mixture was stirred at 20 °C for 30 min under N2 atmosphere. The reaction mixture was quenched with H2O (50 mL) at 25 °C, extracted with EtOAc (50 mL ´ 3). The combined organic layers were washed with brine (50 mL ´ 3), 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 from20 ~ 50%, flow rate: 65 mL / min, 254 nm) to provide tert-butyl N-[5-ethynyl-8- (methylamino)-2,7-naphthyridin-3-yl]carbamate (300 mg, 82.8% yield) as a white solid. LCMS (ESI) m / z 299.2 [M+H]+. Step 7: Synthesis of tert-butyl (5-((3-(4-((tert-butyldimethylsilyl)oxy)butoxy)pyridin-4- yl)ethynyl)-8-(methylamino)-2,7-naphthyridin-3-yl)carbamate

[0056] A mixture of tert-butyl N-[5-ethynyl-8-(methylamino)-2,7-naphthyridin-3-yl]carbamate (200 mg, 0.670 mmol), 4-[(4-bromo-3-pyridyl)oxy]butoxy-tert-butyl-dimethyl-silane (320 mg, 0.888 mmol), XPhos Pd G3 (120 mg, 0.142 mmol), CuI (40.0 mg, 0.210 mmol), TEA (200 mg, 1.98 mmol), and XPhos (64.0 mg, 0.134 mmol) in DMF (5 mL) in a sealed tube was heated at 100 °C for 1 h under a microwave irradiation condition. The reaction mixture was quenched with H2O (50 mL) at 25 °C, extracted with EtOAc (50 mL ´ 3). The combined organic layers were washed with brine (50 mL ´ 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a crude product mixture. The crude product 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 provide tert-butyl N-[5-[2-[3-[4-[tert-butyl(dimethyl)silyl]oxybutoxy]-4- pyridyl]ethynyl]-8-(methylamino)-2,7-naphthyridin-3-yl]carbamate (220 mg, 56.8% yield) as a brown solid. LCMS (ESI) m / z 600.1 [M+Na]+. Step 8: Synthesis of tert-butyl (5-((3-(4-hydroxybutoxy)pyridin-4-yl)ethynyl)-8- (methylamino)-2,7-naphthyridin-3-yl)carbamate A mixture of tert-butyl N-[5-[2-[3-[4-[tert-butyl(dimethyl)silyl]oxybutoxy]-4-pyridyl]ethynyl]-8- (methylamino)-2,7-naphthyridin-3-yl]carbamate (220 mg, 0.381 mmol), TBAF (1 M in THF, 0.70 mL) in THF (10 mL) was stirred at 20 °C for 1 h under N2 atmosphere. The reaction mixture was quenched with H2O (20 mL) at 25 °C, extracted with EtOAc (20 mL ´ 3). The combined organic layers were washed with brine (20 mL ´ 3), dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by reversed-phase HPLC (Column: SepaFlash® Sphercial C18, 12 g, 40-60 μm, 120 Å; MeCN / water (0.5% NH3-H2O) with MeCN from 0 - 30%, 25 mL / min, 254 nm) to provide tert-butyl N-[5-[2-[3-(4-hydroxybutoxy)-4-pyridyl]ethynyl]-8-(methylamino)-2,7- naphthyridin-3-yl]carbamate (150 mg, 85.0% yield) as a brown solid. LCMS (ESI) m / z 464.1 [M+H]+. Step 9: Synthesis of tert-butyl (5-((3-(4-((6-bromopyridin-2-yl)oxy)butoxy)pyridin-4- yl)ethynyl)-8-(methylamino)-2,7-naphthyridin-3-yl)carbamate A mixture of tert-butyl N-[5-[2-[3-(4-hydroxybutoxy)-4-pyridyl]ethynyl]-8-(methylamino)-2,7- naphthyridin-3-yl]carbamate (150 mg, 0.324 mmol), 6-bromopyridin-2-ol (75.0 mg, 0.431 mmol), DIAD (195 mg, 0.964 mmol), PPh3 (255 mg, 0.972 mmol) in THF (10 mL) was degassed and purged with N2 . The mixture was stirred at 20 °C for 12 h under N2 atmosphere. The reaction mixture was quenched with H2O (50 mL) at 25 °C, extracted with EtOAc (50 mL ´ 3). The combined organic layers were washed with brine (50 mL ´ 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a crude product. This crude product was purified by flash chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0 ~ 50%, flow rate: 65 mL / min, 254 nm) to provide tert-butyl N-[5-[2-[3-[4-[(6- bromo-2-pyridyl)oxy]butoxy]-4-pyridyl]ethynyl]-8-(methylamino)-2,7-naphthyridin-3- yl]carbamate (150 mg, 74.8% yield) as a yellow solid. LCMS (ESI) m / z 619.2 [M+H]+. Step 10: Synthesis of 4-((3-(4-((6-bromopyridin-2-yl)oxy)butoxy)pyridin-4-yl)ethynyl)-N1- methyl-2,7-naphthyridine-1,6-diamine

[0057] A mixture of tert-butyl N-[5-[2-[3-[4-[(6-bromo-2-pyridyl)oxy]butoxy]-4-pyridyl]ethynyl]-8- (methylamino)-2,7-naphthyridin-3-yl]carbamate (150 mg, 0.242 mmol) in HCl / dioxane (10 mL, 2M) was stirred at 20 °C for 30 min under N2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to afford 4-[2-[3-[4-[(6-bromo-2-pyridyl)oxy]butoxy]-4- pyridyl]ethynyl]-N1-methyl-2,7-naphthyridine-1,6-diamine (100 mg, crude) as a yellow solid. LCMS (ESI) m / z 519.0 [M+H]+. Step 11: Synthesis of N-methyl-8,13-dioxa-2,16,24,28,31- pentazapentacyclo[20.6.2.13,7.014,19.026,30]hentriaconta- 1(29),3,5,7(31),14(19),15,17,22,24,26(30),27-undecaen-20-yn-25-amine A mixture of 4-[2-[3-[4-[(6-bromo-2-pyridyl)oxy]butoxy]-4-pyridyl]ethynyl]-N1-methyl-2,7- naphthyridine-1,6-diamine (100 mg, 0.193 mmol), EP hos Pd G4 (20.0 mg, 21.8 μmol), EPhos (20.0 mg, 37.4 μmol) and Cs2CO3(200 mg, 0.614 mmol) in dioxane (10 mL) was degassed and purged several times with N2. The mixture was stirred at 100 °C for 1 hr under N2atmosphere. After completion, the reaction mixture was cooled to room temperature and quenched with H2O (50 mL) at 25 °C, extracted with EtOAc (50 mL ´ 3). The combined organic layers were washed with brine (50 mL ´ 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (Column: SepaFlash® Sphercial C18, 25 g, 40-60 μm, 120 Å; MeCN / water (0.5% NH3-H2O) with MeCN from 0 - 29%, 25mL / min, 254 nm) to afford N-methyl-8,13-dioxa-2,16,24,28,31- pentazapentacyclo[20.6.2.13,7.014,19.026,30]hentriaconta- 1(29),3,5,7(31),14(19),15,17,22,24,26(30),27-undecaen-20-yn-25-amine (8.50 mg, 10.1% yield) as a white solid. LCMS (ESI) m / z 439.1 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ ppm 9.96 (s, 1 H), 9.31 (s, 1 H), 8.51 (s, 1 H), 8.26 - 8.33 (m, 2 H), 8.17 - 8.23 (m, 2 H), 7.57 (t, J = 7.9 Hz, 1 H), 7.48 (d, J = 4.8 Hz, 1 H), 6.65 (d, J = 7.8 Hz, 1 H), 6.29 (d, J = 8.0 Hz, 1 H), 4.47 (br t, J = 6.6 Hz, 2 H), 4.39 (br t, J=5.1 Hz, 2 H), 3.02 (d, J = 4.4 Hz, 3 H), 1.89 - 1.97 (m, 2 H), 1.79 - 1.87 (m, 2 H). Example 44: N-methyl-8,12-dioxa-2,15,23,27,30- pentazapentacyclo[19.6.2.13,7.013,18.025,29]triaconta- 1(28),3,5,7(30),13(18),14,16,21,23,25(29),26-undecaen-19-yn-24-amine Step 1: Synthesis of 4-bromo-3-(3-((tert-butyldimethylsilyl)oxy)propoxy)pyridine A mixture of 4-bromopyridin-3-ol (500 mg, 2.87 mmol), 3-bromopropoxy-tert-butyl-dimethyl- silane (950 mg, 3.75 mmol), K2CO3(1.00 g, 7.24 mmol), in DMF (10 mL) was stirred at 20 °C for 4 h under N2 atmosphere. The reaction mixture was quenched with H2O (50 mL) at 25 °C, extracted with EtOAc (50 mL ´ 3). The combined organic layers were washed with brine (50 mL ´ 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography (ISCO®; 20 g SepaFlash...

Claims

Claims 1. A compound represented by Formula (I), or pharmaceutically acceptable salt, stereoisomer, or solvate thereof, (I) wherein: X1and X2are independently CH or N; Y is CH2or NH; Z is CH2or NH; R1is alkyl or deuterated alkyl; R2is H, halo or alkyl; m and n are independently 1 or 2; RAis selected from the group consisting of: H, halo, oxyalkyl, substituted or unsubstituted alkyl or alkenyl, substituted or unsubstituted cycloalkyl or heterocycloalkyl, wherein the one or more substitutions are selected from the group consisting of H, alkyl, oxyalkyl, and halo; RBis H or substituted or unsubstituted alkyl; A is selected from the group consisting of 5 – 12 membered heterocycloalkyl, aryl, or heteroaryl ring, wherein said heterocycloalkyl, aryl, or heteroaryl rings are optionally fused, wherein the one or more heteroatoms in the heteroaryl ring are selected from the group consisting of N, O, or S; B is either absent or B is selected from the group consisting of C=O, C6-C10aryl, and 5-10membered heteroaryl comprising one more heteroatom, wherein the one or more heteroatom is N, O or S; L1is a linker, wherein L1is a bond, substituted or unsubstituted alkenyl, alkynyl, or alkyl; L2is a linker comprising 3 – 15 atom links, wherein each link is selected from the group consisting of -CRLRL’-, -NRL-, or -O-; wherein RLand RL’are independently selected from the group consisting of: H, =O, alkyl, C3-C8cycloalkyl, C3-C8heterocycloalkyl, wherein the C3-C8cycloalkyl, C3-C8heterocycloalkyl may be fused with other links; and wherein RLand RL'on different atoms can be taken together to form C3-C10cycloalkyl or heterocycloalkyl rings.

2. The compound of claim 1, wherein the compound is a compound of Formula(II): (II), wherein B, X1, X2, Y, Z, R1, R2, RA, RB, L2, m, and n are described in claim 1.

3. The compound of claim 1, wherein the compound is a compound of Formula(III):(III) wherein B, X1, X2, Y, Z, R1, R2, RA, RB, L2, m, and n are described in claim 1.

4. The compound of claim 1, wherein the compound is a compound of Formula (IV): (IV) wherein B, X1, X2, Y, Z, R1, R2, RA, RB, L2, and n are described in claim 1.

5. The compound of claim 1, wherein the compound is a compound of Formula (V):(V) wherein A, B, X1, X2, Y, Z, R1, R2, RA, RB, L2, m, and n are described in claim 1.

6. The compound of claim 1, wherein L1is selected from the group consisting of: single bond, -CH2-CH2-, -CH=CH-, and -C≡C-.

7. The compound of claim 1, wherein R1is methyl or ethyl.

8. The compound of claim 1, wherein Y is NH.

9. The compound of claim 1, wherein Z is NH.

10. The compound of claim 1, wherein X1and X2are CH.

11. The compound of claim 1, wherein X1is CH and X2is N.

12. The compound of claim 1, wherein X1is N and X2is CH.

13. The compound of claim 1, wherein B is pyridine.

14. The compound of claim 1, wherein B is pyrimidine.

15. The compound of claim 1, wherein RAis selected from the group consisting of: H, F, -CH3, -CH2CH=CH2, -OCH3, -CH2-azetidine, -CH2-azetidine-O-CH3, and -CH2-morpholine.

16. The compound of claim 1, wherein RAis -OCH3.

17. The compound of claim 1, wherein RAis methyl.

18. The compound of claim 1, wherein the links in L2are selected from the group consisting of -O-, -C(O)-, -C(O)NRL-, and -CH2-.

19. The compound of claim 1, wherein RLis selected from the group consisting of H, =O, - CH3, and cyclopropyl.

20. The compound of claim 1, wherein R2is H.

21. The compound of claim 1, wherein the compound is selected from the group consisting of:

22. A method of treating a condition by administration of a compound represented by formula (I), or pharmaceutically acceptable salt, stereoisomer, or solvate thereof,(I) wherein: X1and X2are independently CH or N; Y is CH2or NH; Z is CH2or NH; R1is alkyl or deuterated alkyl; R2is H, halo or alkyl; m and n are independently 1 or 2; RAis selected from the group consisting of: H, halo, oxyalkyl, substituted or unsubstituted alkyl or alkenyl, substituted or unsubstituted cycloalkyl or heterocycloalkyl, wherein the one or more substitutions are selected from the group consisting of H, alkyl, oxyalkyl, and halo; RBis H or substituted or unsubstituted alkyl; A is selected from the group consisting of 5 – 12 membered heterocycloalkyl, aryl, or heteroaryl ring, wherein said heterocycloalkyl, aryl, or heteroaryl rings are optionally fused, wherein the one or more heteroatoms in the heteroaryl ring are selected from the group consisting of N, O, or S; B is either absent or B is selected from the group consisting of C=O, C6-C10aryl, and 5-10 membered heteroaryl comprising one more heteroatom, wherein the one or more heteroatom is N, O or S; L1is a linker, wherein L1is a bond, substituted or unsubstituted alkenyl, alkynyl, or alkyl; L2is a linker comprising 3 – 15 atom links, wherein each link is selected from the group consisting of -CRLRL’-, -NRL-, or -O-;wherein each RLand RL’are independently selected from the group consisting of: H, =O, alkyl, C3-C8cycloalkyl, C3-C8heterocycloalkyl; wherein the C3-C8cycloalkyl, C3-C8heterocycloalkyl may be fused with other links; and wherein RLand RL’on different atoms can be taken together to form C3-C10 cycloalkyl or heterocycloalkyl rings.

23. The method of claim 22, wherein the compound is a compound of Formula (II): (II), wherein B, X1, X2, Y, Z, R1, R2, RA, RB, L2, m, and n are described in claim 1.

24. The method of claim 22, wherein the compound is a compound of Formula (III): (III)wherein B, X1, X2, Y, Z, R1, R2, RA, RB, L2, m, and n are described in claim 1.

25. The method of claim 22, wherein the compound is a compound of Formula (IV): (IV) wherein B, X1, X2, Y, Z, R1, R2, RA, RB, L2, and n are described in claim 1.

26. The method of claim 22, wherein the compound is a compound of Formula (V): (V) wherein A, B, X1, X2, Y, Z, R1, R2, RA, RB, L2, m, and n are described in claim 1.

27. The method of claim 22, wherein L1is selected from the group consisting of: single bond, -CH2-CH2-, -CH=CH-, and -C≡C-.

28. The method of claim 22, wherein R1is methyl or ethyl.

29. The method of claim 22, wherein Y is NH.

30. The method of claim 22, wherein Z is NH.

31. The method of claim 22, wherein X1and X2are CH.

32. The method of claim 22, wherein X1is CH and X2is N.

33. The method of claim 22, wherein X1is N and X2is CH.

34. The method of claim 22, wherein B is pyridine.

35. The method of claim 22, wherein B is pyrimidine.

36. The method of claim 22, wherein RAis selected from the group consisting of: H, F, -CH3, -CH2CH=CH2, -OCH3, -CH2-azetidine, -CH2-azetidine-O-CH3, and -CH2-morpholine.

37. The method of claim 22 wherein RAis -OCH3.

38. The method of claim 22, wherein RAis methyl.

39. The method of claim 22, wherein the links in L2are selected from the group consisting of -O-, -C(O)-, -C(O)NRL-, and -CH2-.

40. The method of claim 22, wherein RLis selected from the group consisting of H, =O, -CH3, and cyclopropyl.

41. The method of claim 22, wherein R2is H.

42. The method of claim 22, wherein the compound is selected from the group consisting of:

43. A pharmaceutical composition comprising a compound of any one of the claims 1-21, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, and a pharmaceutically acceptable carrier or diluent.

44. A method of inhibiting TYK2 activity in a subject in need thereof with a compound of any one of claims 1-21, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof or a pharmaceutical composition according to claim 43.

45. 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 1-21, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof or a pharmaceutical composition according to claim 43.

46. The method of claim 45, 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.

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