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

[0002] Field of the Invention

[0003] The invention provides compounds that modulate the activity of kinases, such as Tyrosine Kinase 2 (TYK2).

[0004] Background

[0005] A variety of medical conditions that affect millions of people are caused or exacerbated by unregulated activity of protein kinases. For example, aberrant kinase activity is associated with autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies, asthma, Alzheimer's disease, Parkinson's disease, multiple sclerosis, skin disorders, eye diseases, infectious diseases and hormone- related diseases. For many such disorders, however, no effective inhibitor or activator exists for the particular kinase that causes the disorder or its sy mptoms. Consequently, patients continue to suffer from an array of disorders due to the lack of suitable medicaments for their conditions.

[0006] Summary

[0007] 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 pharmacal 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.

[0008] In an aspect, the invention provides compounds of Formula (I), or pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein:

[0009] X is CR3or N;

[0010] Y is NR4, S, O. SO2, or CH2;

[0011] Z is absent, O, S. or NR5; W is NR6, O, or S;

[0012] R1is selected from the group consisting of hydrogen, deuterium, substituted or unsubstituted C1-C6alkyd, substituted or unsubstituted C3-C6, cycloalkyl, wherein one or more substitutions are selected from the group consisting of deuterium, halo, or C3-C6cycloalkyl;

[0013] R2is selected from the group consisting of hydrogen, deuterium, and optionally substituted C1- C6alkyl;

[0014] R3is selected from the group consisting of hydrogen, deuterium, halogen, and substituted or unsubstituted C1-C6alkyl;

[0015] R4is selected from the group consisting of hydrogen, deuterium, and substituted or unsubstituted C1-C6alkyl;

[0016] R;is selected from the group consisting of hydrogen, deuterium, and substituted or unsubstituted C1-C6alkyl;

[0017] R6is selected from the group consisting of hydrogen, deuterium, and substituted or unsubstituted C1-C6alkyl;

[0018] L is absent or a linker comprising 2-12 atom links, wherein each atom link in L is selected from the group consisting of -CRL1RL2, NRL1. O, and S; wherein:

[0019] RL1and RL2are independently selected from the group consisting of: hydrogen, deuterium, halogen, hydroxy, optionally substituted alkoxy, substituted or unsubstituted C1-C6alky l, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted aryl, or heteroaryl, wherein RL1and RL2on the same or different atoms can be optionally combined to form a 3-12 membered cycloalkyl or heterocycloalkyl, wherein the one or more heteroatoms are N, O, or S;

[0020] A is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein one or more heteroatoms in the heterocycloalkyl or heteroary l is nitrogen, sulfur, or oxygen, and the hctcrocycloalkyl or hctcroaryl may optionally be fused;

[0021] RA1and RA2are independently selected from the group consisting of: hydrogen, deuterium, halogen, hydroxy, optionally substituted alkoxy, optionally substituted heterocycloalkylalkoxy, alkoxy, cyano.

[0022] =0,

[0023] -SRb, -S(=O)Ra, -S(=O)2Ra.-NRcRd. substituted or unsubstituted C1-C6.alkyl. C1-C6hydroxy alkyl. C1-C6alko.xy alkyl. C1- C6aminoalkyl. C2-C6alkenyl. wherein one or more substitutions are selected from the group consisting of deuterium, halogen, hydroxy , optionally substituted alkoxy , optionally substituted cycloalkylalkoxy, cyano, =0, or optionally substituted heterocycloalkyl, substituted or unsubstituted 3-12 membered monocyclic, bicyclic, bridged bicyclic, or spirocyclic cycloalky l, oxycycloalkyl, monocyclic, bicyclic, bridged bicyclic, or spirocyclic heterocycloalkyl, aryl, or heteroaryl, wherein one or more heteroatoms in heterocycloalkyl or heteroaryl rings are N, S, Se, or O and wherein one or more substitutions are selected from the group consisting of hydrogen, deuterium, halogen, hydroxy, optionally substituted alkoxy, cyano, =0, substituted or unsubstituted C1-C6alkyl, C1-C6hydroxy alkyl. C1-C6alkoxyalkyl, 3- 12 membered cycloalkyl, or heterocycloalky l, aryl, or heteroaryl. wherein optionally RA1and RA2together form a substituted or unsubstituted 3-12 membered monocyclic or bicyclic cycloalkyl, heterocycloalkyl, aryl, or heteroaryl fused with Ring A; each Rais independently C1-C6alkyl. C1-C6haloalkyl, C1-C6deuteroalkyl. C1-C6hydroxyalky 1. C1-C6aminoalkyl, C2-C6alkenyl. C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo. deuterium, halogen, -CN, -OH. -OMe, - NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe. C1-C6alkyl, or C1-C6haloalkyl; each Rbis independently hydrogen, C1-C alkvl. C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxy alky 1, C1-C6aminoalkyl, C2-C6alkenyl. C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OMe, - NH2, -C(=O)Me. -C(=O)OH, -C(=O)OMe, C1-C6alkyl. or C1-C6haloalkyl; and each Rcand Rdis independently hydrogen. C1-C6alkyl, C1-C6haloalkyl, C1-Gdeuteroalkyl. C1-C6hydroxyalkyl, C1-C6aininoalkyl, C2-C6, alkenyl. C2-C6alkynyl, cycloalkyd, heterocycloalkyl, aryl, or hctcroaryl; wherein each alky l, alkenyl, alkynyl, cycloalky l, hctcrocycloalky 1, aryl, and hctcroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OMe, - NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C1-C6alkyl, or C1-C6haloalkyl; or Rcand Rdare taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C1-C6alkyl, or C1-C6haloalkyl.

[0024] In certain embodiments, in the compounds of Formula (I), X is CR3. In certain embodiments, when X is CR3, R3is unsubstituted C1-C6alkyl.

[0025] In certain embodiments, R3is hydrogen.

[0026] In certain embodiments, in the compounds of Formula (I), X is N.

[0027] In certain embodiments, in the compounds of Formula (I), Y is NH.

[0028] In certain embodiments, in the compounds of Formula (1), Y is S.

[0029] In certain embodiments, in the compounds of Formula (I), Y is -CH2-.

[0030] In certain embodiments, in the compounds of Formula (I), Z is O. In certain embodiments, in the compounds of Formula (I), Z is NR5. In certain embodiments, when Z is CR5, R5is unsubstituted C1-C6alkyl. In certain embodiments, R5is hydrogen or methyl. In certain embodiments, R5is hydrogen.

[0031] In certain embodiments, in the compounds of Formula (I), Z is absent.

[0032] In certain embodiments, in the compounds of Formula (I), W is NR6. In certain embodiments, wherein W is W is NR6. In certain embodiments, R6is substituted or substituted C1-C6alkyl. In certain embodiments, R6is H.

[0033] In certain embodiments, in the compounds of Formula (I), W is NH.

[0034] In certain embodiments, in the compounds of Formula (I), W is O.

[0035] In certain embodiments, in the compounds of Formula (I), ring A and R AAl1and RA2do not form a fused bicyclic heteroaryl ring. In certain embodiments, in the compounds of Formula (I), ring A and RA1and RA2do not form a fused bicyclic cycloalkyl or heterocycloalkyl ring.

[0036] In certain embodiments, L comprises the linker -(CRL1RL2)-(CRL1RL2)-O-(CRL1RL2)-. In certain embodiments. L comprises the linker In certain embodiments, L comprises the linker

[0037] In certain embodiments, in the compounds of Formula (I), linker L does not comprise a cyclopentyl or cyclohexyl ring.

[0038] In certain embodiments, in the compounds of Formula (I). X is CR3. In certain embodiments, and R3is hydrogen or deuterium. In certain embodiments. R3is substituted or substituted C1-C6alkyl. In certain embodiments, R3is hydrogen. In certain embodiments. R3is deuterium.

[0039] In certain embodiments, in the compounds of Formula (I), R2is selected from the group consisting of hydrogen, deuterium, or C1-6alkyl. In certain embodiments, R2is methyl. In certain embodiments, R2is hydrogen. In certain embodiments. R2is deuterium.

[0040] In certain embodiments, in the compounds of Formula (I), R1is selected from the group consisting of optionally substituted C1-6alkyl, optionally substituted C3-C6cycloalky I. and C1-6deuteroalkyl.

[0041] In certain embodiments, in the compounds of Formula (I), R1is hydrogen.

[0042] In certain embodiments, in the compounds of Formula (I), R1is methyl.

[0043] In certain embodiments, in the compounds of Formula (I), R1is -CD3.

[0044] In certain embodiments, in the compounds of Formula (I), R1is cyclopropyl.

[0045] In certain embodiments, in the compounds of Formula (I), R1is -CH2-cyclopropyl. In certain embodiments, in the compounds of Fonnula (I), R1is ethyl.

[0046] In certain embodiments, in the compounds of Formula (I), Ring A is 5-12 membered aryl or heteroaryl. In certain embodiments, when the Ring A is heteroaryl ring, one or more heteroatoms in Ring A are selected from the group consisting of nitrogen, sulfur, or oxygen.

[0047] In certain embodiments, in the compounds of Formula (I), Ring A is 5-12 membered aryl.

[0048] In certain embodiments, in the compounds of Formula (I), Ring A is phenyl.

[0049] In certain embodiments, in the compounds of Formula (I), Ring A is 5-12 membered heteroaryl ring, wherein the one or more heteroatom in the heteroaryl ring is nitrogen, sulfur or oxygen.

[0050] In certain embodiments. Ring A is a 5-12 membered heteroaryl ring having one or more nitrogen atoms.

[0051] In certain embodiments, in the compounds of Formula (I). Ring A is selected from the group consisting of pyridine, pyrimidine, pyridazine, pyridone. and pyridazinone.

[0052] In certain embodiments, in the compounds of Formula (I), Ring A, RA1. and RA2combine to form a 6,5 or 6,6 fused bicyclic ring. In certain embodiments, the bicyclic ring formed by Ring A, RA1. and RA2include one or more substitutions. In certain embodiments, the substitutions on said bicyclic rings are selected from the group consisting of hydrogen, deuterium, halogen, optionally substituted C1-C6alkyl, and C1-C6deuterated alkyl. In certain embodiments, the substitutions on said bicyclic rings are selected from the group consisting of hydrogen, deuterium, -CH3, or -CD3.

[0053] In certain embodiments, in the compounds of Formula (I), wherein RA1and RA2are independently selected from the group consisting of hydrogen, =0, deuterium, hydroxyl, alkoxy, halogen, cyano, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6oxy alkyl, substituted or unsubstituted C1-C6oxycycloalkyd, 3-12 membered substituted or unsubstituted cycloalkyl or heterocycloalky 1 wherein one or more heteroatoms are nitrogen and oxygen, 3-12 membered substituted or unsubstituted ary 1 or hctcroaryl wherein one or more hctcroatoms arc N or O. In certain embodiment, one or more substitutions are selected from the group consisting of H, deuterium, C1-C6alkyl, C1-C6oxy alkyl, halogen, optionally deuterated C1-C6alkyl, and cyano.

[0054] In certain embodiments, in the compounds of Fonnula (I), RA1and RA2are independently selected from the group consisting of deuterium, halogen, -CN, -ORa. -NRaRa, -C(=O)Ra, -CH2-Ra, C1-6alky 1, C1-6haloalky 1, C1-6deuteroalkyl, cycloalky l, heterocy cloalkyl, aryl, or heteroaryl, wherein; Raand Raare independently C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, Cj-Chydroxyalkyl. C1-C6aminoalkyl. C2-C6alkenyl, C1-C6cycloalkyl. C3-C12heterocycloalkyl, C4-C12aryl, or C4- Ci2heteroaryl; wherein each alkyl, alkenyl, cycloalkyl, heterocycloalkyl, ary l, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen. -CN, -OH, -OMe, - OCF3, - NH2, -C(=O)Me, -C(=O)OH. -C(=O)OMe, C,-C6alkyl, or C,-C6haloalky 1.

[0055] In certain embodiments, in the compounds of Formula (I), RA1and RA2are independently spiro, monocyclic or bicyclic heterocycloalkyl or heteroaryl containing at least one nitrogen or oxygen. In certain embodiments, in the compounds of Formula (I), RA1and / or RA2is substituted or unsubstituted monocyclic heterocycloalkyl, wherein the heterocycloalkyl comprises one or more heteroatoms selected from the group consisting of nitrogen or oxygen. In certain embodiments, in the compounds of Fonnula (I), RA1and / or RA2is substituted or unsubstituted bicyclic heterocycloalkyl, wherein the heterocycloalkyl comprises one or more heleroatoms selected from the group consisting of nitrogen, sulfur or oxygen. In certain embodiments, in the compounds of Formula (I), RA1and / or RA2is substituted or unsubstituted monocyclic heteroaryl, wherein the heterocyaryl comprises one or more heteroatoms selected from the group consisting of nitrogen, sulfur or oxygen. In certain embodiments, in the compounds of Fonnula (I). RA1and / or RA2is substituted or unsubstituted bicyclic heteroaryl, wherein the heteroaryl comprises one or more heteroatoms selected from the group consisting of nitrogen, sulfur or oxygen.

[0056] In certain embodiments, in the compounds of Formula (I), RA1and RA2are independently substituted or unsubstituted morpholine, phenyl morpholine. 1.4-oxazepane, piperazine, piperidine, pyridine, triazole, tetrahyropyrane, pyrazole, oxazole, or pyridazine

[0057] In certain embodiments, in the compounds of Formula (I), RA1and / or RA2are independently substituted or unsubstituted morpholine.

[0058] In certain embodiments, in the compounds of Formula (I), RA1and / or RA2are independently substituted or unsubstituted pyridine.

[0059] In certain embodiments, in the compounds of Formula (I), RA1and / or RA2are independently substituted or unsubstituted pyridazine.

[0060] In certain embodiments, in the compounds of Formula (I), RA1and / or RA2are independently substituted or unsubstituted 1,4-oxazepane.

[0061] In certain embodiments, in the compounds of Formula (I), RA1and / or RA2are independently substituted or unsubstituted piperazine.

[0062] In certain embodiments, in the compounds of Formula (I), RA1and / or RA2are independently substituted or unsubstituted piperidine.

[0063] In certain embodiments, in the compounds of Formula (I). RA1aanndd RRAA22are independently selected from the group consisting of hydrogen, hydroxyl, deuterium, fluoro, chloro, =O, -CN, -OCH3, -OCH2CH3, -OCH2CH3OCH3, -CH(CH3)2OH, -OCHF2, -O-cyclopropyl, substituted or unsubstituted phenyl, substituted or unsubstituted pyridine, substituted or unsubstituted azetidine, substituted or unsubstituted oxetane, substituted or unsubstituted morpholine, -CH2-cyclopropyl, -O-CH2-CH3, -CH2- O-CH3, -CH2-O-CD3, -OCF3, -OCF2H. -OCH2CF3, -OCD3, -OCD2CD3, -OCH2-cyclopropyl, cyano, cyclopropyl, -CF3. -CH3, -CD3,

[0064]

[0065] In certain embodiments, in the compounds of Formula (I), the linker L comprises 2-10 atom links, wherein each atom link in L is selected from the group consisting of -CRL1RL2, NRL1, O, and S. In certain embodiments, L comprises between 2 and 8 atom links, wherein atom links are selected from the group consisting of -CRL1RL2, NRL1, O, and S, and wherein between 0 and 2 atom links arc NRL1, O, and S. In certain embodiments, in the compounds of Formula (I), L comprises betw een 1 and 7 atom links, wherein atom links are selected from the group consisting of are -CRL,1R1 2. NRT 1, O, and S and wherein between 0 and 2 atom links are NRL1. O, and S. In certain embodiments, in the compounds of Fonnula (I), L comprises between 1 and 6 atom links, wherein each atom links are selected from the group consisting of -CRL1RL2, NRL1. O, and S, and wherein between 0 and 2 atom links are NRL1, O, and S.

[0066] In certain embodiments, in the compounds of Formula (I), L comprises between 1 and 10 atom links, wherein the atom links are independently -CRL1RL2and / or RL1and RL2at different or same atom combine to fonn an optionally substituted cycloalkyl or heterocycloalkyl. In certain embodiments, in the compounds of Fonnula (I), the one or more substitutions in said cycloalkyl or heterocycloalkyl, are selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, alkoxy, or C1-C4 alkyl. In certain embodiments, in the compounds of Formula (I). L is selected from the group consisting of:           

[0067]       

[0068] 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 certain embodiments, pharmaceutical composition comprises a pharmaceutically acceptable carrier or diluent.

[0069] 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.

[0070] In another aspect, the invention provides methods of treating a condition in a subject by administering to the subject a compound of the invention, such as any of those described above. The condition may be characterized by elevated activity of a kinase. The condition may be characterized by altered activity of a kinase. The kinase may be a JAK family kinase. The kinase may be TYK2. The condition may be an autoimmune disease, inflammatory disease, bone disease, metabolic disease, neurological or neurodegenerative disease, cancer, cardiovascular disease, allergies, asthma, Alzheimer's disease, Parkinson's disease, multiple sclerosis, skin disorder, eye disease, infectious disease, or hormone-related disease.

[0071] 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.

[0072] 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.

[0073] In embodiments of the use, the condition is an autoiimnune disease, inflammatory' disease, bone disease, metabolic disease, neurological or neurodegenerative disease, cancer, cardiovascular disease, allergies, asthma, Alzheimer's disease, Parkinson's disease, multiple sclerosis, skin disorder, eye disease, infectious disease, or hormone -related disease.

[0074] In certain embodiments, the invention provides a pharmaceutical composition comprising a compound of Formula (I), 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), 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 Fonnula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof or a pharmacal composition.

[0075] In certain embodiments, the TYK.2 -mediated disease or disorder is an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a disorder associated with transplantation. In certain embodiments, the TYK2-mediated disease or disorder is multiple sclerosis.

[0076] Detailed Description:

[0077] Chemical definitions

[0078] The expression alkyl refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“C1-20alkyl”). In some embodiments, an alkyl group has 1 to 12 carbon atoms (“C1-12alky l”). In some embodiments, an alky l group has 1 to 10 carbon atoms (“C1-1 0alky l”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1-9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C1-8alkyl”). In some embodiments, an alky l group has 1 to 7 carbon atoms (“C1-7 alky l”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1-6alky l”, also referred to herein as “lower alky l”). 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 (“C1-3alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (" C1alky"l). In some embodiments, an alkyl group has 2 to 6 carbon atoms ("C2-6alkyl”). Examples of C1-6alkyl 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 C1-10alkyl (e.g., -CH3). In certain embodiments, the alkyl group is substituted Ci.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).

[0079] 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 hctcroalkyl 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 (“heteroC1-9alkyl"’). In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1. 2, 3, or 4 heteroatoms (“heteroC1-8alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1, 2. 3, or 4 heteroatoms (“heteroCi.? alkyl"). In some embodiments, a heteroalkyl group is a group having 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms (“heteroC1-6 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms (“heteroC1-io alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and lor 2 heteroatoms (“heteroC1-4 alky l”). 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 hctcroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroCi alkyl”). In some embodiments, a hctcroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms ('"heteroCi alkyl”).

[0080] 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 carboncarbon double bonds) (“C2-20 alkenyl”). In some embodiments, an alkenyl group has 2 to 10 carbon atoms ("‘C2-10 alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms (“C2-9 alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C2-8 alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C2-7 alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2-6 alkeny l”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C2-5 alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C2-4 alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C2-3 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C2 alkenyl”). The one or more carboncarbon double bonds can be internal (such as in 2 -butenyl) or terminal (such as in 1- butenyl). Examples of C 2-4 alkenyl groups include ethenyl (C2), 1 -propenyl (C3), 2 -propenyl (C3), 1 -butenyl (C4), 2 -butenyl (C4), butadienyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C?), octenyl (Cg), octatrienyl (Cg), 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.

[0081] 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 C'hctcroCXi,, 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 C'hclcroCT.j 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 ("hctcroCXx alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1, 2. 3, or 4 heteroatoms ("heteroC2-7 alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1, 2, or 3 heteroatoms ("heteroC2-6 alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms (“heteroC2-s alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms (“heteroC2-4 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom (“heteroC2-3 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms ('"hctcroCC: e alkenyl”).

[0082] 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, =0, 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 arc a cyclopropyl, cyclobutyl, cyclopcntyl, spiro[4,5]decanyl, norbornyl, cyclohexyl, cyclopentenyl, cyclohexadienyl. decalinyl, bicyclo[4.3.0]nonyl, tetraline, cyclopentylcyclohexyl, fluorocyclohexyl or cyclohex-2-enyl group.

[0083] 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. =0. SH, =S. NH2, =NH. N3or NO2 groups. 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.

[0084] 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, alkylcycloalkcnyl. alkcnylcycloalkyl and alkynylcycloalky 1 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.

[0085] The expression heteroalkylcycloalkyl refers to alkylcycloalky l 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 heteroalky lcycloalky l 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 aarree alkylheterocycloalkyl, alkylheterocycloalkenyl, alkenylheterocycloalkyl, alkynylheterocycloalkyl. heteroalkylcy cloalkyl, heteroalkylheterocycloalkyl and heteroalky lheterocycloalkenyl, the cyclic groups being saturated or mono-, di- or tri-unsaturated.

[0086] 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-fhiorophenyl, anilinyl, 3-nitrophenyl or 4-hydroxyphenyl group.

[0087] 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), phcnylpyrrolyl (e.g. 3-phcnylpyrrolyl), thiazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4- triazolyl, oxadiazoly l.thiadiazoly 1, 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.

[0088] The expression aralkyl refers to groups containing both aiyl 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 alkylarylcycloalkeny l groups. Specific examples of aralkyls are toluene, xylene, mesitylene, styrene, benzyl chloride, o-fluorotoluene, IH-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 cycloalky l group containing 5 or 6 ring carbon atoms. The expression hctc roaralky I 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 cycloalky l 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.

[0089] Examples are arylheteroalkyl, arylheterocycloalkyl, arylheterocycloalkenyl, arylalkyl heterocycloalkyl, , aarryyllaallkkeennyyllhheetteerrooccyyccllooaallkkyyll.. 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-carboxj phenylalkyl group.

[0090] 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, =0, SH, =S, NH2, =NH, Ni or NO? groups.

[0091] The expression carbocyclyl or carbocyclic refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms (“C3-10 carbocycly l”) and zero hctcroatoms in the nonaromatic ring system. In some embodiments, a carbocycly l 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 (“C3-7 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5-10 carbocyclyl”). Exemplary C3-6 carbocyclyl groups include, without limitation, cyclopropyl (C3), cyclopropenyl (C3). cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (Cs), 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 (C?), cycloheptenyl (C?), cycloheptadienyl (C?), cycloheptatrienyl (C?), cyclooctyl (G), cyclooctenyl (G), bicyclo[2.2.1]heptanyl (C?), 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- IH-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 heteroaiyl 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 C3-10 carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C3-10 carbocyclyl.

[0092] In some embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 10 ring carbon atoms (“C3-10 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C3-8 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C5- e 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 (Cs) and cyclohexyl (Cs). Examples of C3-6 cycloalkyl groups include the aforementioned Cs-e cycloalkyl 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 (C?) and cyclooctyl (Cs). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents. In certain embodiments, the cycloalkyl group is unsubstituted C3-10 cycloalkyl. In certain embodiments, the cycloalkyl group is substituted C3-10 cycloalkyl.

[0093] The expression heterocyclyl or heterocyclic refers to a radical of a 3- to 14-mcmbcrcd nonaromatic ring sy stem 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.

[0094] 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.

[0095] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, thiorenyl. Exemplar}' 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl. Exemplar} 5- membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuran} 1, 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. Exemplar}' 5-membered heterocyclyl groups containing three hctcroatoms 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 heleroatoms 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.

[0096] 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.

[0097] For example and without limitation, optional substituents include fluorine, chlorine, bromine, and iodine atoms and CF,. CN, OH. =O, SH, =S, NH2, =NH, N3and NO2groups. Optional substituents also include C1-Cw alkyl, C2-Cio alkenyl, C1-Cw heteroalkyl, C3-Cie cycloalkyl, C2-Ci? heterocycloalkyl, C4-C2o alkylcycloalkyl. C2-Ci9 heteroalkylcycloalkyl, C6-Cis aryl, C1-17 heteroaryl, C7-C20aralkyl or C2-Ci9 heteroaralkyl, C1-C6alkyl. C2-C6alkenyl. C1-C6heteroalkyl. C3-C10 cycloalkyl, C2-C9 heterocycloalkyl, C--Cj2alkylcycloalkyl, C2-C11 heteroalkylcycloalkyl, C6-Cio and. C1-C9 heteroaryl, C?-Ci2aralkyl, C2-Cn heteroaralkyl, and C1-C10 haloalkyl groups.

[0098] Exemplary substituents are F, Cl, Br. OH, SH, =0. NH2, amino, C1-4 alkyl. C1-4 heteroalkyl cyclopropyl, SF5, NO, NO2.

[0099] Other exemplary’ substituents are F, Cl, Br. OH, SH, =0, 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, SFS, SO2NMe2, NO. NO2, OCF3. SO2CF3, CN or CF3.

[0100] Other exemplary substituents are F, Cl, Br. Me, OMe, CN or CF3.

[0101] The term halogen preferably refers to F, Cl, Br or I.

[0102] According to certain embodiments, all alkyl, alkenyl, alkynyl, heteroalkyd, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyd, aralky 1 and heteroaralkyl groups described herein may optionally be substituted.

[0103] When an aryl, hctcroaryd, cycloalkyd, alkydcycloalkyd, hctcroalkylcycloalkyl, hctcrocycloalkyd, 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.

[0104] Other optional substituents include, but are not limited to, halogen, -CN, -NO2, -N3, - SO2H, - - P(RCC)2, -P(RCC)3. -OP(RCC)2. -OP(RCC)3, -B(Raa)2. -B(ORCC)2, -BRaa(OR“), CMO alkyl, CMO haloalky l. C2.io alkenyl, C3.io carbocyclyl. 3-14 membered heterocyclyl. C6-i4 aryl, and 5-14 membered heteroary 1. wherein each alkyl, alkenyl, carbocyclyl, heterocyclyl, ary l, and heteroary l 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-io alkyl, CMO heteroalkyl, CMO haloalkyl, C2-10 alkenyl, C3-10 cycloalkyl, C C33--1100 cycloheteroalkyl, C3-10 cycloalkenyl, C3-10 cycloheteroalkenyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-i4 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, heteroalky l, 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. - P(O)(NRCC)2. CMO alkyl, CMO heteroalkyl, CMO haloalkyl, C2-10 alkenyl. C3-10 cycloalkyl, C3-10 cycloheteroalkyl. C3-10 cycloalkenyl. C3-10 cycloheteroalkenyl, C3-10 carbocyclyl. 3-14 membered heterocyclyl. C6n 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, CMO alkyl, C1-io haloalkyl, C2.

[0105] 10 alkenyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-i4 aryl, and 5-14 membered heteroaryl, or two Raagroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; each instance of Rddis, independently, selected from halogen, -CN, -NO2, -N3, -SO2H, - SO3H, OP(O)(R“)2, -OP(O)(ORee)2, Cue alkyl. Cue heteroalkyl. Cue haloalkyl. CM alkenyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, C6-io 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 =0 or =S; each instance of Reeis. independently, selected from C1-6alkyl. Cue haloalkyl. CM alkenyl, C3- 10 carbocyclyl. 3-10 membered heterocyclyl, C6-io aryl, 5-10 membered heteroaryl, wherein each alkyl. alkenyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1,2, 3, 4, or

[0106] 5 Rgggroups; each instance of Rffis, independently, selected from hydrogen, CM alkyl, CM haloalkyl, C2-e alkenyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, C6-io ary l, 5-10 membered heteroaryl, or two Rffgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaiyl ring, wherein each alkyl, alkenyl, carbocyclyl, heterocyclyl. aryl, and heteroary l is independently substituted with 0, 1.2. 3, 4, or 5 R88groups; and each instance of R88is, independently, halogen, -CN, -NO2, -N3, -SO2H, -SO3H. -OH, - OC1.6 alkyl. -0N(CM alkyl)2, -N(CM alkyl)2, -N(CM alkyl)3+X; -NH(CM alkyl)2+X", -NH2(CM alkyl)+X"-MR+X", -N(0CM alkyl)(Ci.6alkyl), -N(0H)(CM alkyl). - NH(OH), -SH. -SCM alkyl. -SS(Ci.

[0107] 6alkyl). -C(O)(C1-6alkyl), -CO2H, -C02(CM alkyl), -0C(0)(CM alkyl), -0C02(CM alkyl), -C(O)NH2, -C(O)N(CI.6 alkyl)2. - 0C(0)NH(CM alkyl). -NHC(0)(CM alkyl), -N(CM alkyl)C(O)(Ci.6alkyl). - NHCO2(CI-6alkyl). -NHC(0)N(CM alkyl)2, -NHC(0)NH(CM alkyl), -NHC(O)NH2, -C(NH)0(CM alkyl), -0C(NH)(CM alkyl), -0C(NH)0CM alkyl, -C(NH)N(CM alkyl)2, -C(NH)NH(CM alkyl), - C(NH)NH2, -OC(NH)N(CI-6alkyl)2. - 0C(NH)NH(CM alkyl), -OC(NH)NH2, -NHC(NH)N(CM alkyl)2, -NHC(NH)NH2, - NHS02(CM alkyl), -S02N(CM alkyl)2, -S02NH(CM alkyl), -SO2NH2.- SO2C1.6 alkyl, - SO2OC1.6 alkyl, -0S02CM alkyl. -SOCM alkyl, -Si(C1 6alkyl)3, -OSi(Ci6alkyl)3- C(S)N(CI.6 alkyl)2. C(S)NH(CM alkyl), C(S)NH2, -C(O)S(CM alkyl), -C(S)SCM alkyl, -SC(S)SCM alkyl, -P(O)2(Ci-6alkyl), -P(0)(CM alkyl)2, -0P(0)(CM alkyl)2, -OP(O)(OCM alkyl)2, CM alky 1, CM haloalkyl, CM alkenyl, C3-10 carbocyclyl, C3-10 aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal Rsgsubstituents can be joined to form =0 or =S; wherein X" is a counterion.

[0108] 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 ct 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 fonnation (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 lire 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 biologies 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).

[0109] 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 (SEE) (Schwartz et al, Nat Rev Drug Dis, 2017).

[0110] 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 SEE, 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, PEGS One. 2020).

[0111] The use of small-molecule inhibitors of TYK2 have allowed for the confirmation of several of these hypotheses. Previous work in human derived PBMCs have demonstrated the ability of TYK2 inhibition to reduce IL-12 / IL-23 signaling in rodents and humans TYK2 inhibition has also proven efficacious in preclinical models of disease for psoriasis and ulcerative colitis (Burke et al. Sci Trans Med. 2020). The preclinical effects in rodents have since translated to humans with deucravacitinib demonstrating efficacy in Psoriasis patients (Armstrong et al, Ann of Rheu Dis, 2020). The genetic contribution of TYK2 has also been confirmed preclinically with the use of TYK2 knockout (KO) or transgenic (TG)animals. For example. Type I interferon signaling is reduced in in TYK2 KO animals as compared to WT mice (Karaghiosoff, Immunity, 2000) and TG animals with the Pl 104 protective variant of TYK2 are almost completely protected in the experimental autoimmune encephalitis (EAE) mouse model of MS (Gorman et al. Fmt in Immunology7, 2019). Together, this large body7of 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.

[0112] The invention provides compounds that modulate tire 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 treatinent 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.

[0113] Compounds;

[0114] In an aspect, the invention provides compounds of Formula (I), or pharmaceutically acceptable salt, stereoisomer, or solvate thereof,

[0115] O

[0116] R2L w

[0117] N

[0118] RA2

[0119] N / A

[0120] R1 RA1

[0121] Y

[0122] (I) wherein:

[0123] X is CR3or N;

[0124] V is NR4, S, O, or CH2;

[0125] Z is absent, O, S. or NR5;

[0126] W is NR6, O, or S;

[0127] R1is selected from the group consisting of hydrogen, deuterium, substituted or unsubstituted C1-C6alkyl, wherein one or more substitutions are selected from the group consisting of deuterium, halo, or Ca-C6cycloalkyl;

[0128] R2is selected from the group consisting of hydrogen, deuterium, and optionally substituted C1- C6alkyl;

[0129] R3is selected from the group consisting of hydrogen, deuterium, and substituted or unsubstituted C1-C6alkyl;

[0130] R4is selected from the group consisting of hydrogen, deuterium, and substituted or unsubstituted C1-C6alkyl;

[0131] R5is selected from the group consisting of hydrogen, deuterium, and substituted or unsubstituted C1-C6alkyl;

[0132] R6is selected from the group consisting of hydrogen, deuterium, and substituted or unsubstituted C1-C6alkyl;

[0133] L is absent or a linker comprising 2-12 atom links, wherein each atom link in L is selected from the group consisting of -CRL1RL2, NRL1. O, and S; wherein:

[0134] RL1and RL2are independently selected from the group consisting of: hydrogen, deuterium, halogen, hy droxy . optionally substituted alkoxy, substituted or unsubstituted C1-C6alky l, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted aryl, or heteroary l. wherein RL1and RL2on the same or different atoms can be optionally combined to form a 3-12 membered cycloalkyl or heterocycloalkyl, wherein the one or more heteroatoms are N, O, or S;

[0135] A is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein one or more heteroatoms in the heterocycloalkyl or heteroary l is nitrogen, sulfur, or oxygen, and the heterocy cloalky l or heteroary l may optionally be fused; RA1and RA2are independently selected from the group consisting of: hydrogen, deuterium, halogen, hydroxy, optionally substituted alkoxy, optionally substituted heterocycloalkylalkoxy, alkoxy, cyano. substituted or unsubstituted C1-C6alkyl, C1-G, hydroxy alkyl, C1-C6alkoxy alkyl, C1- C6aminoalkyl. C2-C6alkenyl. wherein one or more substitutions are selected from the group consisting of deuterium, halogen, hydroxy, optionally substituted alkoxy, optionally substituted cycloalkylalkoxy, cyano, =0, or optionally substituted heterocycloalkyl. substituted or unsubstituted 3-12 membered monocyclic, bicyclic, bridged bicyclic, or spirocyclic cycloalkyl, oxycycloalkyl, monocyclic, bicyclic, bridged bicyclic, or spirocyclic heterocycloalkyl, ary l, or heteroaryl, wherein one or more heteroatoms in heterocycloalkyl or heteroaryl rings are N, S, Se, or O and wherein one or more substitutions are selected from the group consisting of hydrogen, deuterium, halogen, hydroxy, optionally substituted alkoxy, cyano. =0, substituted or unsubstituted C1-C6alkyl, Ch -C, hydroxy alkyl. Ch-G, alkoxyalkyl. 3- 12 membered cycloalkyl, or heterocycloalky l, aryl, or heteroaryl, wherein optionally RA1and RA2together form a substituted or unsubstituted 3-12 membered monocy clic or bicyclic cycloalky l, hctcrocycloalkyl, ary l, or hctcroary 1 fused with Ring A; each Rais independently C1-C6alkyl, G -Ghaloalkyl. G -Gdcutcroalkyl. C1-C6hydroxyalkyl, C1-C6aminoalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, ary l, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN. -OH, -OMe, - NH2, -C(=0)Me, -C(=O)OH, -C(=O)OMe, C1-C6alkyl, or C1-C6haloalky 1; each Rbis independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalky l, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroary l is independently optionally substituted with one or more oxo. deuterium, halogen, -CN, -OH, -OMe. - NH2, -C(=O)Me, -C(=O)OH. -C(=O)OMe, C1-C6alkyl, or C1-C6haloalkyl; and each Rcand Rdis independently hydrogen, C1-C6alkyl. C1-C6haloalky 1, C1-C6deuteroalkyl. C1- C6hydroxyalkyl. C1-C6aminoalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroary l is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OMe, - Nf k -C(=O)Me, -C(=O)OH, -C(=O)OMe, C1-C6alkyl, or C1-C6haloalky 1; or Rcand Rdare taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C1-C6alkyl, or C1-C6haloalkyl.

[0136] In certain embodiments, in the compounds of Formula (I), X is CR3. In certain embodiments, when X is CR3, R3is unsubstituted C1-C6alkyl.

[0137] In certain embodiments, R3is hydrogen.

[0138] In certain embodiments, in the compounds of Formula (I), X is N.

[0139] In certain embodiments, in the compounds of Formula (I), Y is NH.

[0140] In certain embodiments, in the compounds of Formula (I), Y is S.

[0141] In certain embodiments, in the compounds of Formula (I), Y is -CH2-.

[0142] In certain embodiments, in the compounds of Formula (I), Z is O.

[0143] In certain embodiments, in the compounds of Formula (I), Z is NR3. In certain embodiments, when Z is CR3. R5is unsubstituted C1-C6alkyl. In certain embodiments, R3is hydrogen or methyl. In certain embodiments. R5is hydrogen.

[0144] In certain embodiments, in the compounds of Formula (I), Z is absent.

[0145] In certain embodiments, in the compounds of Formula (I), W is NR6. In certain embodiments, wherein W is W is NR6. In certain embodiments. R6is substituted or substituted C1-C6alkyl. In certain embodiments, R6is H.

[0146] In certain embodiments, in the compounds of Formula (I), W is NH.

[0147] In certain embodiments, in the compounds of Formula (I), W is O.

[0148] In certain embodiments, in the compounds of Formula (I), ring A and R' and RA2do not form a fused bicyclic hctcroaryl ring. In certain embodiments, in the compounds of Formula (I), ring A and RA1and RA2do not form a fused bicyclic cycloalkyd or heterocycloalky l ring.

[0149] In certain embodiments, L comprises the linker -(CRL1RL2)-(CRL1RL2)-O-(CRL1RL2)-. In certain embodiments, L comprises the linker . In certain embodiments, L comprises the linker

[0150] In certain embodiments, in the compounds of Formula (I), linker L does not comprise a cyclopentyl or cyclohexyl ring.

[0151] In certain embodiments, in the compounds of Formula (I), X is CR3. In certain embodiments, and R3is hydrogen or deuterium. In certain embodiments, R3is substituted or substituted C1-C6alkyl. In certain embodiments, R3is hydrogen. In certain embodiments, R3is deuterium.

[0152] In certain embodiments, in the compounds of Formula (I), R2is selected from the group consisting of hydrogen, deuterimn, or C1-6alkyl. In certain embodiments, R2is methyl. In certain embodiments, R2is hydrogen. In certain embodiments, R2is deuterium.

[0153] In certain embodiments, in the compounds of Formula (I), R1is selected from the group consisting of optionally substituted C1-6alkyl, optionally substituted C3-C cycloalkyl. and C1-6 deuteroalkyl.

[0154] In certain embodiments, in the compounds of Formula (I), R1is hydrogen.

[0155] In certain embodiments, in the compounds of Formula (I), R1is methyl.

[0156] In certain embodiments, in the compounds of Formula (I), R1is -CD3.

[0157] In certain embodiments, in the compounds of Formula (I), R1is cyclopropyl.

[0158] In certain embodiments, in the compounds of Formula (I), R1is -CH2-cyclopropyl.

[0159] In certain embodiments, in the compounds of Formula (I), R1is ethyl.

[0160] In certain embodiments, in the compounds of Formula (I). Ring A is 5-12 membered aryl or heteroaryl. In certain embodiments, when the Ring A is hctcroaryl ring, one or more heteroatoms in Ring A are selected from the group consisting of nitrogen, sulfur, or oxygen.

[0161] In certain embodiments, in the compounds of Formula (I), Ring A is 5-12 membered aryl.

[0162] In certain embodiments, in the compounds of Formula (I), Ring A is phenyl.

[0163] In certain embodiments, in the compounds of Formula (I), Ring A is 5-12 membered heteroaryl ring, wherein the one or more heteroatom in the heteroaryl ring is nitrogen, sulfur or oxygen.

[0164] In certain embodiments, Ring A is a 5-12 membered heteroaryl ring having one or more nitrogen atoms.

[0165] In certain embodiments, in the compounds of Formula (I), Ring A is selected from the group consisting of pyridine, pyrimidine, pyridazine, pyridone, and pyridazinone.

[0166] In certain embodiments, in the compounds of Formula (I), Ring A, RA1, and RA2combine to fonn a 6,5 or 6,6 fused bicyclic ring. In certain embodiments, the bicyclic ring fonned by Ring A, RA1, and RA2include one or more substitutions. In certain embodiments, the substitutions on said bicyclic rings are selected from the group consisting of hydrogen, deuterium, halogen, optionally substituted Cj-C, alkyl. and C1-C6deuterated alkyl. In certain embodiments, the substitutions on said bicyclic rings are selected from the group consisting of hydrogen, deuterimn, -CH,, or -CD3.

[0167] In certain embodiments, in the compounds of Formula (I), wherein RA1and RA2are independently selected from the group consisting of hydrogen, =0. deuterium, hydroxyl, alkoxy, halogen, cyano, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6oxy alkyl, substituted or unsubstituted C1-C6oxy cycloalkyl, 3-12 membered substituted or unsubstituted cycloalkyl or heterocycloalkyl wherein one or more heteroatoms are nitrogen and oxygen. 3-12 membered substituted or unsubstituted aryl or heteroaryl wherein one or more heteroatoms are N or O. In certain embodiment, one or more substitutions are selected from the group consisting of H, deuterium, C1-C6alkyl, C1-C6oxy alkyl, halogen, optionally deuterated C i -C, alky 1. and cyano.

[0168] In certain embodiments, in the compounds of Formula (I), RA1and RA2are independently selected from the group consisting of deuterium, halogen, -CN, -ORa. -NRaRa, -C(=O)Ra, -CH2-Ra, C1-6alkyl, C1-6haloalky 1, Cue deuteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein; Raand Raare independently C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl. C1- Csaminoalkyl. C2-C6alkenyl, C.-C6cy cloalkyl. Ch-Cizhctcrocycloalkyl. C4-Cizaryl, or C4- Cizheteroaryl; wherein each alkyl, alkenyl, cycloalkyl, heterocycloalkyl, ary l, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen. -CN, -OH, -OMe, - OCF3, - NH2, -C(=O)Me, -C(=O)OH. -C(=O)OMe, C,-C6alkyl, or C,-C6haloalky 1.

[0169] In certain embodiments, in the compounds of Formula (I), RA1and RA2are independently spiro, monocyclic or bicyclic heterocycloalkyl or heteroaryl containing at least one nitrogen or oxygen. In certain embodiments, in the compounds of Formula (I), RA1and / or RA2is substituted or unsubstituted monocyclic heterocycloalkyl, wherein the heterocycloalkyl comprises one or more heteroatoms selected from the group consisting of nitrogen or oxygen. In certain embodiments, in the compounds of Formula (I), RA1and / or RA2is substituted or unsubstituted bicyclic heterocycloalkyl, wherein the heterocycloalkyl comprises one or more heteroatoms selected from the group consisting of nitrogen, sulfur or oxygen. In certain embodiments, in the compounds of Formula (I), RA1and / or RA2is substituted or unsubstituted monocyclic heteroary l. wherein the heterocyaryl comprises one or more heteroatoms selected from the group consisting of nitrogen, sulfur or oxygen. In certain embodiments, in the compounds of Formula (I), RA1and / or RA2is substituted or unsubstituted bicyclic heteroaryl, wherein the heteroaryl comprises one or more heteroatoms selected from the group consisting of nitrogen, sulfur or oxygen.

[0170] In certain embodiments, in the compounds of Formula (I), RA1and RA2are independently substituted or unsubstituted morpholine, phenyl morpholine, 1 ,4-oxazepane, piperazine, piperidine, pyridine, triazole, tetrahyropyrane, pyrazole, oxazole, or pyridazine

[0171] In certain embodiments, in the compounds of Formula (I), RA1and / or RA2are independently substituted or unsubstituted morpholine.

[0172] In certain embodiments, in the compounds of Formula (I), RA1and / or RA2are independently substituted or unsubstituted pyridine.

[0173] In certain embodiments, in the compounds of Formula (I), RA1and / or RA2are independently substituted or unsubstituted pyridazine.

[0174] In certain embodiments, in the compounds of Formula (I), RA1and / or RA2are independently substituted or unsubstituted 1,4-oxazepane.

[0175] In certain embodiments, in the compounds of Formula (I), RA1and / or RA2are independently substituted or unsubstituted piperazine. In certain embodiments, in the compounds of Formula (I), RA1and / or RA2are independently substituted or unsubstituted piperidine.

[0176] In certain embodiments, in the compounds of Formula (I), RA1aanndd RRAA22are independently selected from the group consisting of hydrogen, hydroxyl, deuterium, fluoro, chloro, =O, -CN, -OCH3, -OCFbCFb, -OCH2CH3OCH3, -CH(CH3)2OH, -OCHF2, -O-cyclopropyl, substituted or unsubstituted phenyl, substituted or unsubstituted pyridine, substituted or unsubstituted azetidine, substituted or unsubstituted oxetane, substituted or unsubstituted morpholine, -CH2-cyclopropyl, -O-CH2-CH3, -CH2- O-CH3, -CH2-O-CD3, -OCF3, -OCF2H. -OCH2CF3, -OCD3, -OCD2CD3, -OCHz-cyclopropyl, cyano, cyclopropyl,

[0177] -2-N o

[0178] -<-N O -e-N O -<-N o F

[0179] N

[0180] F

[0181] ,CHF2

[0182] N

[0183] N N N

[0184] O o

[0185] O N O

[0186] N

[0187] N N

[0188] O N

[0189] O O O Se

[0190] N N

[0191] N—

[0192] O 0 I ,0 *-0 N

[0193] N

[0194] N

[0195] ,0 -F

[0196] F F F

[0197] N N

[0198] N N o

[0199] O O O

[0200] 0CF2H

[0201] O 0

[0202] O O

[0203] N

[0204] 0

[0205] O OCD3OCD3and v

[0206] ■N o

[0207] In certain embodiments, in the compounds of Formula (I), the linker L comprises 2-10 atom links, wherein each atom link in L is selected from the group consisting of -CRL1RL2. NRL1, O, and S. In certain embodiments, L comprises between 2 and 8 atom links, wherein atom links are selected from the group consisting of -CRL1RL2, NRL1, O, and S, and wherein between 0 and 2 atom links are NRL1, O, and S. In certain embodiments, in the compounds of Formula (I), L comprises between 1 and 7 atom links, wherein atom links are selected from the group consisting of are -CRL1RL2, NRL1. O, and S and wherein between 0 and 2 atom links are NRL1, O, and S. In certain embodiments, in the compounds of Formula (I), L comprises between 1 and 6 atom links, wherein each atom links are selected from the group consisting of -CRL1RL2, NRL1, O, and S, and wherein between 0 and 2 atom links are NRL1, O, and S.

[0208] In certain embodiments, in the compounds of Formula (I), L comprises betw een 1 and 10 atom links, wherein the atom links are independently -CRL1RL2and / or RL1and RL2at different or same atom combine to form an optionally substituted cycloalkyl or heterocycloalkyl. In certain embodiments, in the compounds of Formula (I), the one or more substitutions in said cycloalkyl or heterocycloalkyl, are selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, alkoxy, or C1-C4 alkyl. In certain embodiments, in the compounds of Formula (I), L is selected from the group consisting of: F

[0209] N O N O N S N

[0210] N N N NS

[0211] °1 °1 optionally substituted with deuterium.

[0212] In certain embodiments, the compotmd of the invention is a compound selected from the compounds listed below, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein the compound is selected from the group consisting of compounds provided in Table A:

[0213] In certain embodiments, the compotmd of the invention is a compound selected from the compounds listed below, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein the compound is selected from the group consisting of compounds provided in Tabic B:

[0214] 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 asnC,13C and14C, chlorine, such as36C1, fluorine, such as18F, iodine, such as123I and125I. nitrogen, such as13N and15N, oxygen, such as15O,17O and18O, phosphorus, such as32P, and sulfur, such as35S.

[0215] 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.

[0216] 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.

[0217] Substitution with positron emitting isotopes, such asnC,18F,15O and13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.

[0218] Isotopically-labeled compounds of the disclosure can generally be prepared by conventional techniques known to those skilled in the art.

[0219] In another aspect, the invention provides pharmaceutical compositions containing one or more compounds of the invention, such as any of the compounds described above.

[0220] 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.

[0221] In another aspect, the invention provides methods of treating a condition in a subject by administering to the subject a compound of the invention, such as any of those described above. The condition may be characterized by elevated activity of a kinase. The condition may be characterized by altered activity of a kinase. The kinase may be a JAK family kinase. The kinase may be TYK2. The condition may be an autoimmune disease, inflammatory disease, bone disease, metabolic disease, neurological or neurodegenerative disease, cancer, cardiovascular disease, allergies, asthma, Alzheimer's disease, Parkinson's disease, multiple sclerosis, skin disorder, eye disease, infectious disease, or hormone-related disease.

[0222] 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.

[0223] 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.

[0224] In embodiments of the use, the condition is an autoimmune disease, inflammatory disease, bone disease, metabolic disease, neurological or neurodegenerative disease, cancer, cardiovascular disease, allergies, asthma, Alzheimer's disease, Parkinson's disease, multiple sclerosis, skin disorder, eye disease, infectious disease, or hormone -related disease.

[0225] In certain embodiments, the invention provides a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, and a pharmaceutically acceptable carrier or diluent.

[0226] In certain embodiments, the invention provides a method of inhibiting TYK2 activity in a subject in need thereof with a compound of Fonnula (I), 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), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof or a pharmaceutical composition.

[0227] In certain embodiments, the TYK2 -mediated disease or disorder is an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a disorder associated with transplantation. In certain embodiments, the TYK2-mediated disease or disorder is multiple sclerosis. Pharmaceutical compositions

[0228] 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.

[0229] 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.

[0230] 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.

[0231] 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.

[0232] 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- hydroxyethyljamine, 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.

[0233] 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.

[0234] 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.

[0235] 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.

[0236] 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-, acvloxymcthyl group (e.g. pivalovloxymcthyl). an 2-alkyl-, 2-ary I- or 2-ary lalkyl oxycarbonyl-2-alkylidene ethyl group or an acyloxy7group as defined herein, e.g. ethoxy, benzyloxy, acetyl or acetyloxy or, especially for a compound of the invention, carry ing a hy droxy 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.

[0237] 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, buty rates, acrylates and ethylsuccinates.

[0238] 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.

[0239] 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.

[0240] 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 mn) 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.

[0241] 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.

[0242] Methods of making compounds

[0243] The invention also provides methods of making compounds of the invention, such as those described above. Synthesis schemes for making specific compounds of Fonnula (I) are provided in the Examples below.

[0244] Methods of treating conditions

[0245] 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.

[0246] 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.

[0247] 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.

[0248] 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 hyperresponsiveness)), 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.

[0249] 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 mate 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, cry oglobulins, 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.

[0250] 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 psoriatiemn), 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, non-' melanoma 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.

[0251] 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), fatty7liver, 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.

[0252] 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.

[0253] 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.

[0254] 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, dennatomyositis, multiple myositis, primary myocardial disease, cardiomyopathy; disorders of the ectoderm, nemofibromatosis, 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, Earner's syndrome, Fanconi's I syndrome, or renal electrolyte wasting.

[0255] 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.

[0256] 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.

[0257] The disease, disorder, or condition may be or include a CNS related disease or disorder, such as neurode generative diseases, Alzheimer's disease and other cementing disorders including CID 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, nemosarcoidosis, 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.

[0258] 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), maslocylosis / 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 1 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, Sezary7syndrome, 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.

[0259] 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.

[0260] 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, ovary7, 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 nonHodgkin'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.

[0261] 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.

[0262] 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.

[0263] 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.

[0264] The method may include providing a compound of the invention. The method may include providing multiple compounds of the invention.

[0265] 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.

[0266] 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, rec tally, 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).

[0267] Examples: Compounds of the invention can be synthesized through the following general synthetic schemes. The starting materials for the preparation of the compounds and other materials used in the methods described below may be readily obtained from commercial sources or may be prepared from the methods otherwise provided in the pertinent literature.

[0268] General Synthetic Scheme I

[0269] In General Synthetic Scheme I, compounds 1-1, II- 1 and III- 1 are purchased from commercial sources or prepared according to the literature methods. A brief description of selected steps listed in the General Scheme I is provided herein.

[0270] The bromination reaction converts compound 1-1 to compound 1-2, followed by a nucleophilic substitution with compound IV- 1 to afford compound 1-3, which is deprotected to obtain compound I- 4.

[0271] Similarly, compound III- 1 is brominated to obtain compound III -2, followed by a nucleophilic substitution with compound IV- 1 to afford compound III-3, which undergoes a C-N coupling reaction to give compound III -4, a subsequent deprotection of compound III -4 then occurs to obtain diamine III- 5.

[0272] Starting from compound II-l, N-protection with SEMC1 obtains compound II-2, followed by an aromatic nucleophilic substitution with compound IV-2 to afford compound II-3, which is deprotected to give compound II -4.

[0273] With compounds 1-4 and II-4, a urea formation mediated by phenyl carbonochloridate is conducted to obtain compound V-l. followed by a reduction to give compound V-2. With the substrates III-5 and II-4. compound V-2 can also be synthesized through a urea formation mediated by phenyl carbonochloridate. The compound of formula A is derived from compound V-2 through an aromatic nucleophilic cyclization. In the case when ¥ is protected nitrogen (N-PG). a deprotection converts compound A to the compound of formula B.

[0274] In General Synthetic Scheme II, primary alcohol VI-1 is purchased from commercial sources or prepared according to the literature methods. A brief description of selected steps listed in the General Scheme II is provided herein.

[0275] Oxidation of alcohol VI- 1 to aldehyde VI -2, followed by an imine formation affords compound VI-3, which is reduced to compound VI-4. Deprotection of compound VI-4 leads to the formation of compound VI-5, which is brominated to obtain compound VI-6. The N protection converts compound VI-6 to compound VI-7, followed by a C-N coupling reaction to afford compound VI-8, which undergoes deprotection to afford diamine VI-9.

[0276] With compounds II-4 and VI-9, a urea formation mediated by pheny l carbonochloridate is conducted to obtain compound V-3, which is then converted to the compound of formula C through an aromatic nucleophilic cyclization. In the case when ¥ is protected nitrogen (N-PG), a further deprotection is needed to convert compound C to the compound of formula D.

[0277] General Synthetic Scheme II

[0278]

[0279] Example 1: 4-methoxy-ll-methyl-18-(methylamino)-9-oxa-2, 12,14,16,20- pentazatetracyclo[12.5.2.13,7.017,21]docosa-l(19),3,5,7(22),15,17,20-heptaen-13-one

[0280] Step 1: Synthesis of 2-[(5,7-dichloroimidazo[4,5-b]pyridin-3-yl)methoxy]ethyl-trimethyl-silane ,SEM ypN N

[0281] N 1?

[0282] Cl Cl

[0283] To a solution of 5,7-dichloro-3H-imidazo[4,5-b]pyridine (14.3 g. 7766..11 mmol) and 2- (chloromethoxy)ethyl-trimethyl-silane (16.5 g, 98.9 mmol) in DMF (150 mL) was added dropwise DIEA (19.7 g, 0.152 mol) at 20 °C. The resulting mixture was stirred at 20 °C for 12 hr. The mixture was diluted with water (50 mL) and extracted with EtOAc (100 mL ' 3). The combined organic phase was washed with brine (30 mL ' 3), dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 220 g Petroleum ether / EtOAc with EtOAc from 0~l 5%, flow rate = 80 mL / min, UV detection 254 nm) to afford 2-[(5,7- dichloroimidazo[4,5-b]pyridin-3-yl)methoxy]ethyl-trimethyl-silane (20 g. 82.6% yield) as a yellow oil. LCMS (ESI) m / z 317.8 [M+H]1.

[0284] Step 2: Synthesis of 5-chloro-N-[(4-methoxyphenyl)methyl]-N-methyl-3-(2- trimethylsilylethoxymethyl)imidazo[4,5-b]pyridin-7-amine

[0285] A mixture of 2-[(5.7-dichloroimidazo[4.5-b]pyridin-3-yl)methoxy]ethyl-trimethyl-silane (20 g, 62.8 mmol), l-(4-methoxyphenyl)-N-methyl-methanamine (14.2 g, 94.3 mmol) and K2CO3 (26 g, 0.188 mmol) in DMSO (200 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 80 °C for 12 h under nitrogen atmosphere. The mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL ' 3). The combined organic phase was washed with brine (30 mL ' 3), dried over anhydrous Na?SO4. filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 220 g Petroleum ether / EtOAc with EtOAc from 0~l 5%, flow rate = 80 mL / min. 254 nm) to afford 5-chloro-N-[(4-methoxyphenyl)methyl]-N-methyl-3-(2- trimethylsilylethoxymethyl)imidazo[4,5-b]pyridin-7-amine (23 g. 84.5% yield) as a brown oil. LCMS (ESI) m / z 433.1 [M+H]+.

[0286] Step 3: Synthesis of 5-chloro-N-[(4-methoxyphenyl)methyI]-N-methyl-3H-imidazo[4,5-b]pyridin- 7- amine

[0287] A mixture of 5 -chloro-N- [(4-methoxypheny l)methylj -N -methyl-3-(2- trimethylsilylethoxymethyl)imidazo[4,5-b]pyridin-7-amine (18 g, 41.6 mmol), and TBAF (1 M, 200 mL) in THF was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 20 °C for 24 h under nitrogen atmosphere. The mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL ' 3). The combined organic phase was washed witlr brine (30 mL ' 3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 220 g SepaFlash® Silica Flash Column, Petroleum ether / EtOAc with EtOAc from 0~20%, flow rate = 80 mL / min, 254 mn) to afford 5-chloro-N-[(4-methoxyphenyl)methyl]-N- methyl-3H-imidazo[4,5-b]pyridin-7-amine (8.1 g, 64.4% yield) as a white solid. LCMS (ESI) m / z 302.9 [M+H]+.

[0288] Step 4: Synthesis of 4-(bromomethyl)-l-methoxy-2-nitro-benzene

[0289] NO2

[0290] Br o

[0291] A mixture of l-methoxy-4-methyl-2 -nitro-benzene (35 g, 0.209 mol), NBS (44.7 g, 0.251 mol), and BPO (5.07 g, 20.9 mmol) in CCL (250 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 80 °C for 12 hr under nitrogen atmosphere. The mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL ' 3). The combmed organic phase was washed with brine (30 mL ' 3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®: 330 g SepaFlash® Silica Flash Column, Petroleum ether / EtOAc with EtOAc from 0~10%. flow rate = 80 mL / min, 254 nm) to afford 4- (bromomethyl)-l -methoxy -2-nitro-benzene (30 g. 34.9% yield, 60% purity) as a yellow solid. LCMS (ESI) m / z 245.6. 247.6 [M+H]+.

[0292] Step 5: Synthesis of tert-butyl N-[2-[(4-methoxy-3-nitro-phenyl)methoxy]-l-methyl- ethyljcarbamate

[0293] NO

[0294] Boe"2

[0295] A mixture of 4-(bromomethyl)-l -methoxy -2 -nitro-benzene (30 g, 0.122 mol), tert-butyl N-(2 -hydroxy - l-methyl-ethyl)carbamate (25.6 g, 0.146 mol) and NaH (7.31 g, 0.183 mol, 60% in mineral oil) in DMF (300 mL) was degassed and purged witlr nitrogen for 3 times, and then the mixture was stirred at 20 °C for 6 h under nitrogen atmosphere. The mixture was diluted witlr a saturated NH iCl aqueous solution (100 mL) and extracted with EtOAc (100 mL ' 3). The combined organic phase was washed with brine (30 mL ' 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 220 g SepaFlash® Silica Flash Column, Petroleum ether / EtOAc with EtOAc from 0~30%, flow rate = 80 mL / min, 254 nm) to afford tert -butyl N-[2-[(4-mcthoxy-3-nitro-phcnyl)mcthoxy]-l-mcthyl-cthyl]carbamatc (22 g, 53.0% yield) as a yellow oil. LCMS (ESI) m / z 340.8 [M+H]+. Step 6: Synthesis of l-[(4-methoxy-3-nitro-phenyl)methoxy]propan-2- amine

[0296] O tert-Butyl N-[2-[(4-methoxy-3-nitro-phenyl)methoxy]-l-methyl-ethyl]carbamate (22 g, 64.6 mmol) was mixed with HC1 in dioxane solution (2N, 60 mL). This resulting mixture was stirred at 20 °C for 12 h under nitrogen atmosphere. The mixture was concentrated under reduced pressure to providel-[(4- methoxy-3-nitro-phenyl)methoxy]propan-2-amine (20 g. crude) as a yellow oil. LCMS (ESI) m / z 241.0 [M+H]+.

[0297] Step 7: Synthesis of phenyl N-[2-[(4-methoxy-3-nitro-phenyl)methoxy]-l-methyl-ethyl]carbamate

[0298] H

[0299] .0. N N02

[0300] O'

[0301] A mixture of l-[(4-methoxy-3-nitro-phenyl)methoxy]propan-2-amine (15 g, 62.4 mmol), phenyl carbonochloridate (10.8 g, 68.7 mmol) and TEA (20.4 g, 0.201 mol) in THE (150 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 20 °C for 12 hrs under nitrogen atmosphere. The mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL ' 3). The combined organic phase was washed with brine (30 mL ' 3), dried over anhydrous NazSO^ filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 330 g SepaFlash® Silica Flash Column, Petroleum ether / EtOAc with EtOAc from 0~20%, flow rate = 60 mL / min, 254 nm) ttoo afford phenyl N-[2-[(4-methoxy-3-nitro-phenyl)methoxy]-l-methyl- ethyl [carbamate (13.4 g, 59.6% yield) as a yellow oil. LCMS (ESI) m / z 360.8 [M+H]+.

[0302] Step 8: Synthesis of 5-chloro-N-[2-[(4-methoxy-3-nitro-phenyI)methoxy]-l-methyI-ethyl]-7-[(4- methoxyphenyl)methyl-methyl-amino]imidazo[4,5-b]pyridinc-3-carboxamidc

[0303] A mixture of 5-chloro-N-[(4-methoxyphenyl)methyl]-N-methyl-3H-imidazo[4,5-b]pyridin-7-amine (5 g, 16.5 mmol), phenyl N-[2-[(4-methoxy-3-nitro-phenyl)methoxy]-l-methyl-ethyl]carbamate (5.95 g, 16.5 mmol) and TEA (5.09 g, 50.3 mmol) in DMSO (50 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 20 °C for 12 hr under nitrogen atmosphere. The mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL ' 3). The combined organic phase was washed with brine (30 mL ' 3), dried over anhydrous Na2SO i. filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (1SCO®; 20 g SepaFlash® Silica Flash Column, Petroleum ether / EtOAc with EtOAc from 0-30%, flow rate = 40 mL / min, 254 nm) to afford 5-chloro-N-[2-[(4-methoxy-3-nitro-phenyl)methoxy]-l-methyl-ethyl]-7-[(4- methoxyphenyl)methyl-methyl-amino]imidazo[4,5-b]pyridine-3-carboxamide (3 g, 31.9% yield) as a yellow oil. LCMS (ESI) m / z 569.0 [M+H]+.

[0304] Step 9: Synthesis of N-[2-[(3-amino-4-methoxy-phenyl)methoxy]-l-methyl-ethyl]-5-chloro-7-[(4- methoxyphenyl)methyl-methyl-amino]imidazo[4,5-b]pyridine-3-carboxamide

[0305] A mixture of 5-chloro-N-[2-[(4-methoxy-3-nitro-phenyl)methoxy]-l-methyl-ethyl] -7-[(4- methoxyphenyl)methyl-methyl-amino]imidazo[4,5-b]pyridine-3-carboxamide (4.5 g, 7.91 mmol), Fe (2.21 g, 39.5 mmol) and NH4CI (4.23 g, 79.1 mmol) in EtOH (40 mL) and H2O (8 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 80 °C for 2 hrs under nitrogen atmosphere. The mixture was filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Petroleum ether / EtOAc with EtOAc from 0-40%. flow rate = 40 mL / min, 254 mn) to afford N-[2-[(3-amino-4- methoxy-phenyl)methoxy]-l-methyl-ethyl]-5-chloro-7-[(4-methoxyphenyl)methyl-methyl- amino]imidazo[4,5-b]pyridine-3-carboxamide (3.8 g, 89.1% yield) as a yellow oil. LCMS (ESI) m / z 539.0 [M+H]+.

[0306] Step 10: Synthesis of 4-methoxy-18-[(4-methoxyphenyl)methyl-methyl-amino]-ll-methyl-9-oxa- 2,12,14,16,20-pentazatetracyclo [12.5.2.13,7.017,21 ] docosa- 1 (19), 3, 5, 7(22), 15,17,20-heptaen-l 3- one

[0307] A mixture of N-[2-[(3-amino-4-methoxy-phenyl)methoxy]-l-methyl-ethyl]-5-chloro-7-[(4- methoxyphenyl)methyl-methyl-amino]imidazo[4,5-b]pyridine-3-carboxamide (3.8 g, 5.64 mmol), EPhos (602 mg, 1.13 mmol). EPhos Pd G4 (650 mg. 0.708 mmol) and K3PO4 (2.99 g, 14.1 mmol) in dioxane (40 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 100 °C for 2 hrs under nitrogen atmosphere. The mixture was diluted with FLO (30 mL) and extracted with EtOAc (50 mL ' 3). The combined organic layer was dried over anhy drous NagSO i. filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Petroleum ether / EtOAc with EtOAc from 0~50%, flow rate = 60 mL / min, 254 mn) to afford 4-methoxy-18-[(4-methoxyphenyl)methyl-methyl-amino]-ll-methyl-9- oxa-2,12,14,16,20-pentazatetracyclo[12.5.2.13,7.017,21]docosa-l(19),3,5,7(22),15,17,20-heptaen-13- one (2.1 g, 74.1% yield) as a white solid. LCMS (ESI) m / z 503.2 [M+H]+.

[0308] Step 11: Synthesis of 4-methoxy-ll-methyl-18-(methylamino)-9-oxa-2,12,14,16,20- pentazatetracyclo[12.5.2.13,7.017,21]docosa-l(19),3,5,7(22),15,17,20-heptaen-13-one

[0309] HN

[0310] O

[0311] O.

[0312] To a solution of 4-methoxy -18- [(4-methoxy pheny l)methy 1-methy 1-amino] -11 -methyl-9-oxa- 2.12,14.16,20-pentazatetracyclo[12.5.2.13,7.017,21]docosa-l(19),3,5,7(22),15,17,20-heptaen-13-one (100 mg, 0.199 mmol) in DCM (40 mL) was added TFA (227 mg, 1.99 mmol) and triethylsilane (232 mg. 2 mmol) in DCM (40 mL). The mixture was stirred at 20 °C for 12 hrs. The mixture was diluted with a saturated NaHCOg aqueous solution (50 mL) and extracted with EtOAc (50 mL ' 3). The combined organic phase was washed with brine (30 mL ' 3), dried over anhydrous Na2SO4. filtered, and 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-ACN]; Mobile phase B: MeCN; Gradient: B from 43% to 73% in 8 min, hold 100% B for 2 min; Flow Rate: 25 mL / min; Column Temperature: 30 °C; Wavelength: 220 nm) to afford 4-methoxy-ll-methyl-18-(methylamino)-9-oxa-2,12.14,16.20- pentazatetracyclo[12.5.2.13,7.017,21]docosa-l(19),3,5,7(22).15,17.20-heptaen-13-one (8.7 mg, 11.4% yield) as a white solid. LCMS (ESI) m / z 383.0 [M+H]+;!H NMR (400 MHz, DMSO-J6) 8 ppm 9.29 (d, .7= 4.8 Hz, 1 H), 8.35 (s, 1 H), 8.17 - 8.23 (m, 2 H), 6.94 (d, J= 8.0 Hz, 1 H), 6.89 (br d. J= 4.8 Hz, 1 H), 6.80 (dd. J = 8.0. 1.8 Hz, 1 H), 6.16 (s, 1 H), 4.59 (d, J = 13.3 Hz, 1 H), 4.35 (d, J = 13.6 Hz, 1 H), 3.88 - 3.95 (m, 1 H), 3.85 (s, 3 H), 3.48 (dd, J = 9.8, 2.3 Hz, 1 H), 3.23 - 3.30 (m, 1 H), 2.85 (d,J = 4.8 Hz, 3 H), 1.18 (d, J = 6.5 Hz, 3 H). Example 2: (llR)-4-methoxy-ll-methyl-18-(methylamino)-9-oxa-2,12,14,16,20- pentazatetracyclo[12.5.2.13,7.017,21]docosa-l(19),3,5,7(22),15,17,20-heptaen-13-one

[0313] 4-methoxy-l 1 -methyl-18-(methy lamino)-9-oxa-2, 12, 14,16,20- pentazatetracyclo[12.5.2.13,7.017,21]docosa-l(19),3,5,7(22),15,17,20-heptaen-13-one (Example 1) was separated by chiral SFC column to afford (HR)-4-methoxy-ll-methyl-18-(methylamino)-9-oxa- 2,12,14,16,20-pentazatetracyclo[12.5.2.13,7.017,21]docosa-l(19),3,5,7(22),15,17,20-heptaen-13-one (Example 2) and (llS)-4-methoxy-ll-methyl-18-(methylamino)-9-oxa-2,12,14,16,20- pentazatetracyclo[12.5.2.13,7.017,21]docosa-l(19),3,5,7(22),15,17,20-heptaen-13-one (Example 3).

[0314] Analytical data for (llR)-4-methoxy-ll-methyl-18-(methylamino)-9-oxa-2,12,14,16,20- pentazatetracyclo[12.5.2.13,7.017,21]docosa-l(19),3,5,7(22),15,17,20-heptaen-13-one: LCMS

[0315] (ESI) m / z 383.0 [M+H]1; Chiral purity: 99.7% ee:1H NMR (400 MHz, DMSO-7.) 3 ppm 9.29 (d. J = 4.8 Hz, 1 H), 8.35 (s, 1 H). 8.17 - 8.23 (m, 2 H). 6.94 (d. 7 = 8.0 Hz, 1 H), 6.89 (br d, J = 4.8 Hz. 1 H), 6.80 (dd, 7= 8.0, 1.8 Hz. 1 H), 6.16 (s, 1 H). 4.59 (d.7 = 13.3 Hz. 1 H), 4.35 (d, J= 13.6 Hz, 1 H), 3.88 - 3.95 (m. 1 H), 3.85 (s, 3 H), 3.48 (dd, J = 9.8, 2.3 Hz, 1 H), 3.23 - 3.30 (m, 1 H), 2.85 (d, J = 4.8 Hz, 3 H), 1.18 (d, 7 = 6.5 Hz, 3 H).

[0316] Example 3: (llS)-4-methoxy-ll-methyl-18-(methylamino)-9-oxa-2,12,14,16,20- pentazatetracyclo[12.5.2.13,7.017,21]docosa-l -heptaen-13-one

[0317] 4-methoxy-ll-methyl-18-(methylamino)-9-oxa-2.12,14.16,20- pentazatetracyclo[12.5.2.13,7.017,21]docosa-l(19),3,5,7(22),15,17,20-heptaen-13-one (example 1) was separated by chiral SFC column to afford (HR)-4-methoxy-l l-methyl-18-(methylamino)-9-oxa- 2,12,14,16,20-pentazatetracyclo[12.5.2.13.7.017.21]docosa-l(19),3.5.7(22).15,17.20-heptaen-13-one (Example 2) and (HS)-4-methoxy-ll-methyl-18-(methylamino)-9-oxa-2,12.14,16.20- pentazatetracyclo[ 12.5.2.13,7.017,21]docosa-l (19),3,5,7(22).15, 17.20-heptaen-13-one (Example 3).

[0318] Analytical data for (llS)-4-methoxy-ll-methyl-18-(methylamino)-9-oxa-2,12,14,16,20- pentazatetracyclo[12.5.2.13,7.017,21]docosa-l(19),3,5,7(22),15,17,20-heptaen-13-one: LCMS

[0319] (ESI) m / z 383.0 [M+H]+; Chiral purity: 96.4% ee; ’H NMR (400 MHz, DMSO-Je) 8 ppm 9.29 (d, J = 4.8 Hz, 1 H), 8.35 (s, 1 H), 8.17 - 8.23 (m, 2 H), 6.94 (d, J= 8.0 Hz, 1 H), 6.89 (br d, J= 4.8 Hz, 1 H), 6.80 (dd,J= 8.0, 1.8 Hz, 1 H), 6.16 (s, 1 H). 4.59 (d,J = 13.3 Hz, 1 H), 4.35 (d, J= 13.6 Hz, 1 H), 3.88 - 3.95 (m, 1 H), 3.85 (s, 3 H), 3.48 (dd, J= 9.8, 2.3 Hz, 1 H), 3.23 - 3.30 (m, 1 H), 2.85 (d, J = 4.8 Hz, 3 H), 1.18 (d, J = 6.5 Hz, 3 H).

[0320] Example 4: 4-(difluoromethoxy)-ll-methyl-18-(methylamino)-9-oxa-2,12,14,16,20- pentazatetracyclo[12.5.2.13’7.017'21]docosa-l(19),3,5,7(22),15,17,20-heptaen-13-one

[0321] Step 1: Synthesis of [4-(difluoromethoxy)-3-nitro-phenyl]methanol

[0322] To a mixture of 4-(hydroxymethyl)-2-nitro-phenol (5.0 g, 29.6 mmol), K2CO3 (8.17 g, 59.1 mmol) in DMF (40.0 mL) was added sodiimi 2-chloro-2,2-difluoro-acetate (5.86 g, 38.4 mmol). The resulting mixture was stirred at 75 °C for 4 hr. The resulting mixture was quenched by addition of water (50 mL) and extracted with EtOAc (60 mL x 3). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na2SOi. fdtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 80 g AgelaFlash® Silica Flash Column, petroleum cthcr / EtOAc with EtOAc from 0—50%, flow rate = 100 mL / min, 254 mn). The desired product [4- (difluoromethoxy)-3-nitro-phenyl]methanol (5.4 g, 75.0% yield) was obtained as a yellow oil. ' l l NMR (400 MHz, DMSO4) 5 ppm 7.97 (d, J= 2.0 Hz, 1 H), 7.70 (dd, J= 8.6, 2.1 Hz, 1 H), 7.50 (d, J = 1.5 Hz, 1 H), 7.13 - 7.47 (m, 1 H), 5.54 (t, J = 5.8 Hz, 1 H), 4.57 (d, J = 5.8 Hz. 2 H).

[0323] Step 2: Synthesis of 4-(bromomethyl)-l-(difluoromethoxy)-2-nitro-benzene

[0324] N02

[0325] Br F

[0326] O' F

[0327] To a solution of [4-(difluoromcthoxy)-3-nitro-phcnyl]mcthanol (5.0 g, 22.8 mmol) in DCM (50 mL) was added CBr4(8.35 g, 25.2 mmol), PPh3(6.60 g, 25.2 mmol) and the mixture was stirred at 20 °C for 12 hrs under N2 atmosphere. The resulting mixture was quenched by addition of water (100 mL) and extracted with EtOAc (100 mL * 3). The combined organic layer was washed with brine (200 mL), dried over anhydrous Na2SC>4, fdtered, 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 = 80 mL / min, 254 nm). The desired product 4- (bromomethyl)-l-(difluoromelhoxy)-2-nitro-benzene (3.64 g, 53.7% yield) was obtained as a yellow oil. ' H NMR (400 MHz, DMSO-ty) 8 ppm 8.20 (d, J= 2.3 Hz, 1 H), 7.87 (dd. J = 8.7. 2.1 Hz, 1 H), 7.18 - 7.57 (in, 2 H). 4.80 (s, 2 H).

[0328] Step 3: Synthesis of tert-butyl A-[2-[[4-(difhioroinethoxy)-3-nitro-phenyl]methoxy]-l-methyl- ethyl]carbamate

[0329] To a solution of tert-butyl / V-(2-hydroxy-l -mcthyl-cthyl)carbamatc (2.35 g. 13.4 mmol) in DMF (30 mL) was added NaH (562 mg, 14.1 mmol, 60% by weight in mineral oil) at 0 °C. After addition, the mixture was stirred at this temperature for 30 min. and then 4-(bromomcthvl)-l-(difluoromcthoxy)-2- nitro-benzene (3.6 g. 12.8 mmol) in DMF (5 mL) was added dropwise at 0 °C. The resulting mixture w as stirred at 20 °C for 1 h. The resulting mixture w as quenched by addition of w ater (50 mL) at 0 °C and extracted with EtOAc (60 mL x 3). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na2S0.4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 40 g AgelaFlash® Silica Flash Column, petroleum ether / EtOAc w ith EtOAc from 0-40%, flow rate = 50 mL / min, 254 nm). The desired product tert-butyl Ar-[2-[[4-(difluoromethoxy)-3-nitro-phenyl]methoxy]-l-methyl-ethyl]carbamate (3.6 g, 63.7% yield) was obtained as a yellow oil. LCMS (ESI) m / z 377.1 [M+H]+.

[0330] Step 4: Synthesis of l-[[4-(difluoromethoxy)-3-nitro-phenyl]methoxy]propan-2-amine

[0331] H2N '2

[0332] F

[0333] F

[0334] Dissolved tert-butyl / V-[2-[[4-(difluoromethoxy)-3-nitro-phenyl]methoxy]-l-methyl-ethyl]carbamate (1.0 g. 2.66 mmol) in a solution of HC1 in dioxane (2N,10 mL) w as stirred at 20 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to remove solvent. The desired product l-[[4- (difluoromethoxy)-3-nitro-phenyl]methoxy]propan-2-amine (700 mg, crude) was obtained as a y ellow solid. LCMS (ESI) m / z 277.1 [M+H]+.

[0335] Step 5: Synthesis of 5-chloro-N-[2-[[4-(difhioromethoxy)-3-nitro-phenyl]methoxy]-l-methyI- ethyl]-7-[(4-methoxyphenyl)methyl-methyl-amino]imidazo[4,5-b]pyridine-3-carboxamide

[0336] To a solution of 5-chloro-N-[(4-methoxyphenyl)methyl]-N-methyl-3H-imidazo[4,5-b]pyridin-7-amine (500 mg. 1.65 mmol), phenyl carbonochloridate (233 mg. 1.49 mmol) in THE (20 mL) was added TEA (509 mg, 5.03 mmol) and the mixture was stirred at 20 °C for 2 hrs. The resulting mixture of phenyl 5- chloro-7-[(4-methoxyphenyl)methyl-methyl-amino]imidazo[4,5-b]pyridine-3-carboxylate (500 mg, crude, in THE solution) as a white liquid was taken directly to the next reaction. To a solution of phenyl 5-chloro-7-[(4-methoxyphenyl)methyl-methyl-amino]imidazo[4,5-b]pyridine-3-carboxylate (500 mg, 1.18 mmol), l-[[4-(difluoromethoxy)-3-nitro-phenyl]methoxy]propan-2 -amine (359 mg, 1.30 mmol) in THF (20 mL) was added TEA (364 mg, 3.59 mmol) and the mixture was stirred at 20 °C for 1.5 hrs. The resulting mixture was quenched by addition of water (50 mL) and extracted with EtOAc (60 mL x 3). The combined organic layer was washed with brine (100 mL), dried over anhy drous Na?SO 1. filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 12 g AgelaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0~50%, flow rate = 30 inL / inin, 254 mn). The desired product 5-chloro-N-[2-[[4-(difluoromethoxy)-3-nitro- phenyl]methoxy]-l-methyl-ethyl]-7-[(4-methoxyphenyl)methyl-methyl-amino]imidazo[4,5- b]pyridine-3-carboxamide (230 mg. 16.1% yield) was obtained as a white solid. LCMS (ESI) m / z 605.2 [M+H]+.

[0337] Step 7: Synthesis of Ar-|2-[|3-amino-4-(difluoromethoxy)phenyl|methoxy]-1-methyl-ethyl|-5- chloro-7-[(4-methoxyphenyl)methyl-methyl-amino]imidazo[4,5-b]pyridine-3-carboxamide

[0338] To a solution of 5-chloro-Ar-[2-[[4-(difluoromethoxy)-3-nitro-phenyl]methoxy]-l-methyl-ethyl]-7-[(4- methoxyphenyl)methyl-methyl-amino]imidazo[4,5-b]pyridine-3-carboxamide (200 mg, 0.331 mmol) in EtOH (6.0 mL) and FLO (2.0 mL) was added NH4CI (89.0 mg, 1.66 mmol), Fe (93.0 mg, 1.67 mmol) and the mixture was stirred at 80 °C for 30 min. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue 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). The desired product Ar-[2-[[3-amino-4-(difluoromethoxy)phenyl]methoxy]-l- methyl-ethyl]-5-chloro-7-[(4-methoxyphenyl)methyl-methyl-amino]imidazo[4,5-b]pyridine-3- carboxamide (150 mg, 55.2% yield) was obtained as a white solid. LCMS (ESI) m / z 597.2 [M+Na]+.

[0339] Step 8: Synthesis of 4-(difluoromethoxy)-18-[(4-methoxyphenyl)methyl-methyl-amino]-ll- methyl-9-oxa-2,12,14,16,20-pentazatetracyclo[12.5.2.13’7.017'21]docosa-l(19),3,5,7(22),15,17,20- heptaen-13-one

[0340] To a mixture of ,M-[2-[[3-amino-4-(difluoromethoxy)phenyl]methoxy]-l-methyl-ethyl]-5-chloro-7-[(4- methoxyphenyl)methyl-methyl-amino]imidazo[4,5-b]pyridine-3-carboxamide (140 mg, 0.243 mmol), K3PO4 (155 mg, 0.730 mmol) in dioxane (30 mL) was added EPhos (26 mg, 48.6 / / mol), EPhos Pd G4 (22 mg, 24.0 / anol). The resulting mixture was stirred at 100 °C for 1 h under N2atmosphere. The resulting mixture was quenched by addition of water (50 mL) and extracted with EtOAc (60 mL x 3). The combined organic layer was washed with brine (80 mL), dried over anhydrous Na2SOi. filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 4 g AgelaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0-70%. flow rate = 20 mL / min, 254 nm). The desired product 4-(difluoromethoxy)-18-[(4-methoxyphenyl)methyl-methyl- amino]-ll-methyl-9-oxa-2,12,14.16,20-pentazatetracyclo[12.5.2.137.017’21]docosa- l(19).3.5,7(22),15,17,20-heptaen-13-one (100 mg. 68.6% yield) was obtained as a colorless oil. LCMS (ESI) m / z 539.2 [M+H]+.

[0341] Step 9: Synthesis of 4-(difluoromethoxy)-ll-methyl-18-(methylamino)-9-oxa-2,12,14,16,20- pentazatetracyclo[12.5.2.13’7.017’21]docosa-l(19),3,5,7(22),15,17,20-heptaen-13-one

[0342] HN o.

[0343] O

[0344] N A

[0345] N

[0346] N N H H O F

[0347] F To a solution of TFA (200 mg, 1.75 mmol), triethylsilane (196 mg, 1.69 mmol) in DCM (36 mL) was added 4-(difluorom ethoxy)- 18- [(4-methoxypheny l)methy 1-methy 1-amino] -11 -methyl-9-oxa-

[0348] 2,12,14,16,20-pentazatetracyclo[12.5.2.137.017 21]docosa-l(19),3,5,7(22),15,17,20-heptaen-13-one (90 mg, 0.167 mmol) and the mixture was stirred at 20 °C for 2 hrs. The resulting mixture was quenched by addition of water (50 mL) and extracted with EtOAc (60 mL x 3). The combined organic layer was washed with a saturated NH4C1 aqueous solution (100 mL x 2), brine (100 mL), dried over anhydrous Na:SO i. 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 0~10%, flow rate = 30 mL / min, 254 nm) and further purified by preparative HPLC (Instrument: Gilson GX-281 Liquid Handler. Gilson 322 Pump, Gilson 156 UV Detector; Column: Welch Xtimate C18 150 x 25 mm x 5 / zm; Mobile phase A: H2O with 0.05% NH4HCO3 (v%): Mobile phase B: ACN; Gradient: B from 41% to 71% in 9.5 min. hold 100% B for 2 min; Flow Rate: 25 mL / min; Column Temperature: 30 °C; Wavelength: 220 nm). The desired product 4 -(difluoromethoxy) - 11 -methyl- 18-(methylamino)-9-oxa-2, 12, 14, 16,20-pentazatetracyclo [ 12.5.2.13 7.017-21] docosa- l(19),3,5,7(22),15.17,20-heptaen-13-one (6.9 mg, 9.9% yield) was obtained as a white solid. LCMS (ESI) m / z 419.1 [M+H]+; ' H NMR (400 MHz, DMSO-Je) <> ppm 9.20 (d. J = 4.8 Hz, 1 H), 8.61 (s, 1 H), 8.38 (d, J= 1.8 Hz, 1 H), 8.24 (s, 1 H). 6.96 - 7.37 (m, 3 H). 6.85 (dd, J= 8.2, 1.9 Hz. 1 H), 6.21 (s, 1 H), 4.63 (d, J = 14.1 Hz, 1 H), 4.41 (d, J = 14.1 Hz, 1 H), 3.87 - 4.02 (m, 1 H), 3.52 (dd, J = 9.8, 2.3 Hz, 1 H), 3.29 (hr s, 1 H), 2.88 (d, J = 4.8 Hz, 3 H), 1.20 (d, J = 6.5 Hz, 3 H).

[0349] Example 5: (llR)-4-(difluoromethoxy)-ll-methyl-18-(methylamino)-9-oxa-2,12,14,16,20- pentazatetracyclo[12.5.2.13'7.017’21]docosa-l(19),3,5,7(22),15,17,20-heptaen-13-one

[0350] 4-(difluoromethoxy)-l l-methyl-18-(methylamino)-9-oxa-2,12.14,16.20- pcntazatclracyclo| 12.5.2. 1 ’ .O1•21]docosa-l(19),3,5,7(22),15,17,20-heptaen-13-one (Example 4) was separated by chiral SFC column to afford (HR)-4-(difluoromethoxy)-ll-methyl-18-(methylamino)-9- oxa-2.12,14.16,20-pentazatetracyclo[12.5.2.13’7.01 ,21]docosa-l(19).3,5,7(22),15.17,20-heptaen-13-one (Example 5) and ( l l S)-4-(difluoromethoxy)-l l -methyl-18-(methylamino)-9-oxa-2,12.14,16.20- pentazatetracyclo[12.5.2.13-7.017-21]docosa-l(19).3,5,7(22),15.17,20-heptaen-13-one (Example 6).

[0351] Analytical data for (HR)-4-(difluoromethoxy)-ll-methyl-18-(methylamino)-9-oxa-2, 12,14,16,20- pentazatetracyclo[12.5.2.13'7.017'21]docosa-l(19),3,5,7(22),15,17,20-heptaen-13-one: LCMS (ESI) m / z 419.1 [M+H]+; Chiral purity: 100% ee; 'H NMR (400 MHz, DMSCM0 8 ppm 9.20 (d, J= 4.8 Hz, 1 H), 8.61 (s, 1 H), 8.38 (d, J = 1.8 Hz, 1 H), 8.24 (s, 1 H), 6.96 - 7.37 (m, 3 H), 6.85 (dd, J = 8.2, 1.9 Hz, 1 H), 6.21 (s, 1 H). 4.63 (d, J= 14.1 Hz. 1 H), 4.41 (d, J= 14.1 Hz, 1 H), 3.87 - 4.02 (m, 1 H), 3.52 (dd. J= 9.8, 2.3 Hz, 1 H), 3.29 (hr s, 1 H), 2.88 (d, J= 4.8 Hz, 3 H), 1.20 (d, J = 6.5 Hz, 3 H).

[0352] Example 6: (llS)-4-(difhioromethoxy)-ll-methyl-18-(methylamino)-9-oxa-2,12,14,16,20- pentazatetracyclo[12.5.2.13’7.017'21]docosa-l(19),3,5,7(22),15,17,20-heptaen-13-one

[0353] 4-(difluoromethoxy)-ll-methyl-18-(methylamino)-9-oxa-2,12,14,16,20- pentazatetracyclo[12.5.2.13’7.017’21]docosa-l(19).3,5,7(22),15,17,20-heptaen-13-one (Example 4) was separated by chiral SFC column to afford (llR)-4-(difluoromethoxy)-ll-methyl-18-(methylamino)-9- oxa-2,12,14,16,20-pcntazatctracyclo[12.5.2.13-7.01721]docosa-l(19),3,5,7(22),15,17,20-hcptacn-13-onc (Example 5) and (11 S)-4-(difluoromethoxy)- 11 -methyl- 18-(methy lamino)-9-oxa-2, 12, 14, 16,20- pentazatetracyclo[12.5.2.137.017 21]docosa-l(19),3,5,7(22),15,17,20-heptaen-13-one (Example 6).

[0354] Analytical data for (llS)-4-(difhioromethoxy)-ll-methyl-18-(methylamino)-9-oxa-2,12,14,16,20- pentazatetracyclo[12.5.2.13,7.017,21]docosa-l(19),3,5,7(22),15,17,20-heptaen-13-one: LCMS

[0355] (ESI) m / z 419.1 [M+H]+; Chiral purity: 100% ee; ’H NMR (400 MHz. DMSO-d6) 8 ppm 9.20 (d, J = 4.8 Hz, 1 H), 8.61 (s, 1 H). 8.38 (d. J = 1.8 Hz, 1 H), 8.24 (s, 1 H), 6.96 - 7.37 (m, 3 H), 6.85 (dd, J = 8.2. 1.9 Hz, 1 H), 6.21 (s, 1 H). 4.63 (d, J= 14.1 Hz. 1 H), 4.41 (d, J = 14.1 Hz, 1 H), 3.87 - 4.02 (m, 1 H), 3.52 (dd, J= 9.8, 2.3 Hz, 1 H), 3.29 (hr s, 1 H), 2.88 (d, J= 4.8 Hz, 3 H), 1.20 (d, J= 6.5 Hz. 3 H). Example 7: (llR)-5-fluoro-ll-methyl-18-(methylamino)-9-oxa-2,12,14,16,20- pentazatetracyclo[12.5.2.13’7.017’21]docosa-l(19),3,5,7(22),15,17,20-heptaen-13-one

[0356] Step 1: Synthesis of l-(bromomethyl)-3-fluoro-5-nitro-benzene NO

[0357] Br2

[0358] F

[0359] To a solution of l-fluoro-3-methyl-5-nitro-benzene (10 g, 64.5 mmol), NBS (17.2 g, 96.7 mmol) in CHCL, (80 mL) was added benzoyl benzenecarboperoxoate (1.56 g, 6.45 mmol) and the mixture was stirred at 80 °C for 12 hr under N2 atmosphere. The reaction mixture was quenched by addition of water (50 mL) at 20 °C and extracted with EtOAc (60 mL x 3). The combined organic layers were washed with brine (100 mL x 3). dried over anhydrous NazSO,. filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 120g AgelaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0—5%, flow rate = 100 niL / min, 254 nm). The desired product l-(bromomethyl)-3-fluoro-5 -nitro-benzene (3 g, 13.9% yield) was obtained as a yellow oil.1H NMR (400 MHz, CDCh) 8 ppm 8.09 (s, 1 H), 7.89 (dt, J = 8.1, 2.1 Hz, 1 H), 7.48 (br d, J = 8.3 Hz, 1 H), 4.51 (s, 2 H).

[0360] Step 2: Synthesis of tert-butyl M|(l R)-2-|(3-fluoro-5-nitro-phenyl)methoxy|-l-methyl- ethyljcarbainate

[0361] H

[0362] Boc J O NO2

[0363] F

[0364] To a solution of tert-butyl Ar-[(lR)-2-hydroxy-l-methyl-ethyl]carbamate (1.50 g. 8.55 mmol) in DMF (20 mL) was added NaH (410 mg. 10.3 mmol. 60% by weight in mineral oil) at 0 °C over 5 min. After addition, the mixture was stirred at this temperature for 30 min. and then l-(bromomethyl)-3-fluoro-5- nitro-benzene (2.0 g, 8.55 mmol) in DMF (1 .0 mL) was added dropwise at 0 °C. The resulting mixture was stirred at 20 °C for 1 hr. The resulting mixture was quenched by addition of water (50 mL) at 0 °C and extracted with EtOAc (60 mL x 3). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na^SOi. filtered, and concentrated under reduced pressure. The desired product tert-butyl A-[(lR)-2-[(3-fluoro-5-nitro-phenyl)methoxy]-l-methyl-ethyl]carbamate (2 g, crude) was obtained as a brown oil. LCMS (ESI) m / z 329.1 [M+H]+.

[0365] Step 3: Synthesis of (2R)-l-[(3-fluoro-5-nitro-phenyI)methoxy]propan-2-amine

[0366] Dissolved tert-butyl A-[(lR)-2-[(3-fluoro-5-nitro-phenyl)methoxy]-l-methyl-ethyl]carbamate (2 g, 6.09 mmol) in a solution of HC1 in dioxane (2N, 10.0 mL). The resulting mixture was stirred at 40 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by flash chromatography (ISCCJ K : 20 g AgelaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0-100%, flow rate = 40 mL / min, 254 mn). The desired product (2R)-1- [(3-fluoro-5-nitro-phenyl)methoxy]propan-2 -amine (290 mg, 17.7% yield) was obtained as a yellow oil. LCMS (ESI) m / z 229.2 [M+H]+.

[0367] Step 4: Synthesis of 5-chloro-7V-[(lR)-2-[(3-fliioro-5-nitro-phenyl)methoxy]-l-methyl-ethyl]-7- [(4-methoxyphenyl)methyl-methyl-amino]imidazo[4,5-b]pyridine-3-carboxamide

[0368] To a solution of 5-chloro-N-[(4-methoxyphenyl)methyl]-N-methyl-3H-imidazo[4,5-b]pyridin-7-amine (500 mg, 1.65 mmol), phenyl carbonochloridate (207 mg. 1.32 mmol) in THE (10 mL) was added TEA (487 mg, 4.81 mmol) and the mixture was stirred at 20 °C for 2 hrs. The resulting mixture of phenyl 5- chloro-7-[(4-methoxyphenyl)methyl-methyl-amino]imidazo[4,5-b]pyridine-3-carboxylate (500 mg, crude.in THE solution) as a yellow liquid was used directly for the next reaction.

[0369] To a solution of phenyl 5-chloro-7-[(4-methoxyphenyl)methyl-methyl-amino]imidazo[4,5-b]pyridine- 3-carboxylate (500 mg, 1.18 mmol), (2R)-l-[(3-fluoro-5-nitro-phenyl)methoxy]propan-2-amine (270 mg, 1.18 mmol) in THE (10 mL) was added TEA (349 mg, 3.45 mmol) and the mixture was stirred at 20 °C for 12 hr. The resulting mixture was quenched by addition of water (60 mL) and extracted with EtOAc (60 mL * 3). The combined organic layers were washed with brine (80 mL). dried over anhydrous NazSO,. filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 12 g AgelaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0-100%. flow rate = 30 mL / min, 254 mn). The desired product 5-chloro-A-[(lR)-2-[(3-fluoro-5- nitro-phenyl)methoxy]-l-methyl-ethyl]-7-[(4-methoxyphenyl)methyl-methyl-amino]imidazo[4,5- b]pyridine-3-carboxamide (460 mg, 55.9% yield) was obtained as a yellow oil. LCMS (ESI) m / z 557.1 [M+H]+.

[0370] Step 5: Synthesis of / V-[(l R)-2-[(3-amino-5-fluoro-phenyl)mcthoxy|-l-methyl-cthyl|-5-chloro-7- [(4-inethoxyphenyl)methyl-methyl-amino]imidazo[4,5-b]pyridine-3-carboxamide

[0371] To a solution of 5-chloro-A-[(lR)-2-[(3-fluoro-5-nitro-phenyl)methoxy]-l-methyl-ethyl]-7-[(4- methoxyphenyl)methyl-methyl-amino]imidazo[4,5-b]pyridine-3-carboxamide (260 mg, 0.467 mmol) in EtOH (10 mL) and H2O (3 mL) was added iron powder (130 mg, 2.33 mmol) and NH4CI (130 mg, 2.43 mmol). The mixture was stirred at 80 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by flash chromatography (ISCO®; 4 g AgelaFlash®Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0~70%, flow rate = 20 mL / min, 254 mn). The desired product A-[(lR)-2-[(3-amino-5-fluoro-phenyl)methoxy]-l-methyl- ethyl]-5-chloro-7-[(4-methoxyphenyl)methyl-methyl-amino]imidazo[4.5-b]pyridine-3-carboxamide (230 mg, 74.8% yield) was obtained as a yellow oil. LCMS (ESI) m / z 527.2 [M+H]1.

[0372] Step 6: Synthesis of (llR)-5-fhioro-18-[(4-methoxyphenyl)methyl-methyl-amino]-ll-inethyl-9- oxa-2,12,14,16,20-pentazatetracyclo[12.5.2.13’7.017’21]docosa-l(19),3,5,7(22),15,17,20-heptaen-13- one

[0373] HN

[0374] O

[0375] / TN o

[0376] N, A

[0377] N

[0378] N N F

[0379] PMB H

[0380] To a stirring mixture of Ar-[(lR)-2-[(3-amino-5-fluoro-phenyl)methoxy]-l-methyl-ethyl]-5-chloro-7- [(4-methoxyphenyl)methyl-methyl-amino]imidazo[4,5-b]pyridine-3-carboxamide (210 mg, 0.398 mmol), K3PO4 (254 mg, 1.20 mmol) in dioxane (30 mb) was added EPhos (43 mg, 80.4 / / mol), EPhos Pd G4 (37 mg, 40.3 / / mol) and the mixture was stirred at 100 °C for 1 h under N2atmosphere. The resulting mixture was quenched by addition of water (50 mL) and extracted with EtOAc (60 mL x 3). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na2SO 1. filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 4 g AgelaFlash® Silica Flash Column, petroleum ether / ElOAc with EtOAc from 0~100%, flow rate = 20 mL / min, 254 mn). The desired product (HR)-5-fluoro-18-[(4-methoxyphenyl)methyl-methyl- amino]-ll-methyl-9-oxa-2,12,14.16,20-pentazatetracyclo[12.5.2.137.017-21]docosa- l(19).3.5,7(22),15,17,20-heptaen-13-one (146 mg, 67.2% yield) was obtained as a white solid. LCMS (ESI) m / z 491.1 [M+H]+.

[0381] Step 7: Synthesis of (HR)-5-fluoro-ll-methyl-18-(methylamino)-9-oxa-2,12,14,16,20- pentazatetracyclo[12.5.2.13’7.017’21]docosa-l(19),3,5,7(22),15,17,20-heptaen-13-one To a solution of TFA (292 mg, 2.56 mmol), triethylsilane (306 mg, 2.63 mmol) in DCM (50 mL) was added ( 1 lR)-5 -fluoro- 18-[(4-methoxy pheny l)methy 1-methyl-amino] -11 -methy l-9-oxa-2, 12,14,16,20- pentazatetracyclo[12.5.2.13 7,01 7-21]docosa-l(19),3,5,7(22),15,17,20-heptaen-13-one (130 mg, 0.265 mmol) and the mixture was stirred at 20 °C for 1 h. The resulting mixture was quenched by addition of water (50 mL) and extracted with EtOAc (60 mL x 3). The combined organic layer was washed with brine (80 mL), dried over anhydrous Na2SO4, fdtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 4 g AgelaFlash® Silica Flash Column, Dichloromethane / Methanol with Methanol from 0~8%, flow rate = 20 mL / min, 254 nm) and then purified by re versed-phase HPLC (Column: SepaFlash® Spherical Cl 8, 25 g, 40-60 / an. 120A; MeCN / water with MeCN from 0-55%. 40 mL / min. 254 nm). The desired product (HR)-5-fluoro-ll- methyl-18-(methylamino)-9-oxa-2.12,14.16,20-pentazatetracyclo[12.5.2.13>7.017-21]docosa- l(19).3.5.7(22),15,17,20-heptaen-13-one (18.3 mg, 18.5% yield) was obtained as a white solid. LCMS (ESI) m / z 371.0 [M+H]+; *H NMR (400 MHz, DMSO-< / 6) § ppm 9.38 (s, 1 H). 9.34 (d, J = 5.0 Hz. 1 H), 8.26 (s, 1 H), 8.23 (s, 1 H), 7.04 (d, J = 4.8 Hz, 1 H), 6.57 - 6.71 (m. 2 H), 5.77 (s, 1 H), 4.63 (d, J = 14.6 Hz. 1 H), 4.45 (d, J= 14.8 Hz, 1 H), 3.87 - 4.02 (m, 1 H), 3.57 (dd. J= 9.8. 2.0 Hz, 1 H), 3.38 - 3.41 (m. 1 H), 2.89 (d, .7= 4.8 Hz. 3 H), 1.23 (d, .7= 6.5 Hz, 3 H).

[0382] Example 88:: (10R,14R)-6-methoxy-21-(methylamino)-9-oxa-2,15,17,19,23- pentazapentacyclo[15.5.2.13’7.01014.02024]pentacosa-l(23),3,5,7(25),18,20(24),21-heptaen-16-one

[0383] Step 11:: Synthesis of tert-butyl N- [(1 R,2R)-2- [(2-methoxy-5-nitro- phenyl) methoxy] cyclopentyl] carbamate

[0384] Boc HN

[0385] To a solution of 2-(bromomethyl)-l -methoxy -4-nitro-benzene (2 g, 8.13 mmol), tert-butyl A-[(1R,2R)- 2-hydroxycyclopentyl |carbamate (1.64 g, 8.13 mmol) in THF (15 mL) was added IM t-BuOK in THF (16.5 mL, 16.5 mmol) at 0 °C and the mixture was stirred at 20 °C for 2 hr. The resulting mixture was quenched by addition of water (100 mL) and extracted with EtOAc (80 mL x 3). The combined organic layer was washed with brine (100 mL), dried over anhydrous NazSCL, 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 0~30%, flow rate = 40 mL / min, 254 nm). The desired product tert-butyl Ar-[(lR,2R)-2-[(2-methoxy-5-nitro-phenyl)methoxy]cyclopentyl]carbamate (2.3 g, 46.3% yield) was obtained as a yellow oil. LCMS (ESI) m / z 389.2 [M+Na]+.

[0386] Step 2: Synthesis of (lR,2R)-2-[(2-methoxy-5-nitro-phenyl)methoxy]cyclopentanamine

[0387] The solution of tert-butyl Af-[(lR,2R)-2-[(2-methoxy-5-nitro-phenyl)methoxy]cyclopentyl]carbamate (2.3 g. 6.28 mmol) in 2M HCl / dioxane (20 mL) was stirred at 20 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to remove solvent. The crude product was purified by reversed- phase HPLC (Column: SepaFlash® Sphercial Cl 8, 25 g, 40-60 «m. 120A; MeCN / water with MeCN from 0-30%, flow rate: 40 mL / min, 254 nm). The desired product (lR,2R)-2-[(2-methoxy-5-nitro- phenyl)methoxy]cyclopentanamine (850 mg, 48.3% yield) was obtained as a yellow oil. LCMS (ESI) m / z 267.3 [M+H]+.

[0388] Step 3: Synthesis of 5-chloro-7V-[(lR,2R)-2-[(2-methoxy-5- nitro-phenyl)methoxy] cyclopentyl] -7- [(4-methoxyphenyl)methyl-methyl-amino]imidazo[4,5-b]pyridine-3-carboxamide

[0389] To a solution of phenyl 5-chloro-7-[(4-methoxyphenyl)methyl-methyl-amino]imidazo[4,5-b]pyridine- 3-carboxylate (300 mg, 0.709 mmol), (lR,2R)-2-[(2-methoxy-5-nitro- phenyl)methoxy]cyclopentanamine (180 mg, 0.676 mmol) in THF (10 mL) was added TEA (218 mg, 2.15 mmol) and the mixture was stirred at 20 °C for 12 hrs. The resulting mixture was quenched by addition of water (50 mL) and extracted with EtOAc (60 mL x 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, petroleum ether / EtOAc with EtOAc from 0~40%, flow rate = 30 mL / min, 254 nm). The desired product 5-chloro-A4(lR,2R)-2-[(2-methoxy-5-nitro-phenyl)methoxy]cyclopentyl]-7-l(4- methoxyphenyl)methyl-methyl-amino]imidazo[4.5-b]pyridine-3-carboxamide (280 mg. 63.0% yield) was obtained as a yellow oil. LCMS (ESI) m / z 617.3 [M+Na]+.

[0390] Step 4: Synthesis of N-[(lR,2R)-2-[(5-amino-2-methoxy-phenyl)methoxy]cyclopentyl]-5-chloro-7-

[0391] [(4-methoxyphenyl)methyl-methyl-amino]imidazo[4,5-b]pyridine-3-carboxamide

[0392] To a solution of 5-chloro-jV-[(lR,2R)-2-[(2-methoxy-5-nitro-phenyl)methoxy]cyclopentyl]-7-[(4- methoxyphenyl)melhyl-methyl-amino]imidazo[4,5-b]pyridine-3-carboxamide (250 mg. 0.420 mmol) in EtOH (10 mL) and H2O (3.0 mL) was added Fe (118 mg, 2.11 mmol) and NH4C1 (113 mg, 2.11 mmol) and the mixture was stirred at 80 °C for 1 h. The reaction mixture was cooled and then concentrated under reduced pressure to remove solvent. The residue 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). Hie desired product jV-[(lR,2R)-2-[(5-amino-2- methoxy-phenyl)methoxy]cyclopentyl]-5-chloro-7-[(4-methoxyphenyl)methyl-methyl- amino]imidazo[4,5-b]pyridine-3-carboxamide (200 mg. 80.0% yield) was obtained as a yellow oil. LCMS (ESI) m / z 587.2 [M+Na]+.

[0393] Step 5: Synthesis of (10R,14R)-6-methoxy-21-[(4-methoxyphenyl)methyl-methyl-amino]-9-oxa- 2,15,17,19,23-pentazapentacyclo[15.5.2.13’7.01014.02024]pentacosa-l(23),3,5,7(25),18,20(24),21- heptaen-16-one

[0394] To a stirred mixture of Ar-[(lR,2R)-2-[(5-amino-2-methoxy-phenyl)methoxy]cyclopentyl]-5-chloro-7- [(4-methoxyphenyl)methyl-methyl-amino]imidazo[4,5-b]pyridine-3-carboxamide (180 mg, 0.319 mmol), K3PO4 (203 mg, 0.956 mmol) in dioxane (15 mb) was added EPhos (34 mg, 63.6 / / mol), EPhos Pd G4 (29 mg, 31.6 / / mol) and the mixture was stirred at 100 °C for 1 h under Nz atmosphere. The resulting mixture was quenched by addition of water (50 mL) and extracted with EtOAc (60 mL * 3). The combined organic layer was washed with brine (80 mL), dried over anhydrous NazSOi. filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCCJ n : 12 g AgelaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0~40%, flow rate = 30 mL / min, 254 run). The desired product (10R,14R)-6-methoxy-21-[(4-methoxyphenyl)methyl- methyl-amino]-9-oxa-2,15,17,19,23-pentazapentacyclo[15.5.2.13 7.010 14.02°-24]pentacosa- l(23).3,5,7(25),18,20(24),21-heptaen-16-one (130 mg, 73.3% yield) was obtained as a white solid. LCMS (ESI) m / z 529.4 [M+H]+.

[0395] Step 6: Synthesis of (10R,14R)-6-methoxy-21-(methylamino)-9-oxa-2,15,17,19,23- pentazapentacyclo[15.5.2.13’7.01014.020'24]pentacosa-l(23),3,5,7(25),18,20(24),21-heptaen-16-one

[0396] To a solution of TFA (259 mg, 2.27 mmol), triethylsilane (264 mg, 2.27 mmol) in DCM (50 mL) was added (10R,14R)-6-methoxy-21-[(4-methoxyphenyl)methyl-methyl-amino]-9-oxa-2,15.17,19.23- pentazapentacyclo[15.5.2.13-7.010 14.020’24]pentacosa-l(23),3,5,7(25),18,20(24).21-heptaen-16-one (120 mg, 0.227 mmol) and the mixture was stirred at 20 °C for 1 h. The resulting mixture was quenched by addition of water (50 mL) and extracted with EtOAc (60 mL x 3). The combined organic layers were washed with brine (80 mL), dried over anhydrous Na?SO i. 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 0~8%, flow rate = 20 mL / min, 254 nm) and then purified by re versed-phase HPLC (Column: SepaFlash® Spherical Cl 8, 25 g. 40-60 «m. 120A; MeCN / water with MeCN from 0-60%, flow rate: 25 mL / min, 254 mn). The desired product (10R.14R)- 6-methoxy-21-(methylamino)-9-oxa-2, 15,17, 19,23- pentazapentacyclo[15.5.2.13’7.010 14.02°’24]pentacosa-l(23),3,5,7(25),18,20(24),21-heptaen-16-one (16.4 mg, 17.6% yield) was obtained as a white solid. LCMS (ESI) m / z 409.4 [M+H]1; *H NMR (400 MHz. DMSO-de) 8 ppm 9.80 (d, J= 1.5 Hz. 1 H), 9.06 (s, 1 H), 8.31 (d. J = 2.3 Hz, 1 H), 8.19 (s. 1 H), 6.86 - 6.95 (m, 3 H). 5.74 (s, 1 H), 4.65 - 4.71 (m, 1 H), 4.53 - 4.58 (m, 1 H), 3.75 (s, 5 H). 2.86 (d. J = 4.8 Hz, 3 H), 2.35 - 2.43 (m, 1 H), 2.07 - 2.14 (m, 1 H), 1.69 - 1.78 (m, 1 H), 1.58 - 1.67 (m, 1 H), 1.48 - 1.57 (m. 1 H), 1.33 (td. J= 9.5. 3.1 Hz, 1 H). Example 99:: (llR)-4-methoxy-ll,15-dimethyl-18-(methylamino)-9-oxa-2,12,14,16,20- pentazatetracyclo[12.5.2.13,7.017,21]docosa-l(19),3,5,7(22),15,17,20-heptaen-13-one

[0397] HN

[0398] N

[0399] N

[0400] H H o

[0401] Step 1: Synthesis of 4,6-dichloropyridine-2,3-diamine

[0402] A mixture of 4,6-dichloro-3-nitro-pyridin-2-amine (5 g, 24.0 mmol), Fe (6.71 g, 120.2 mmol) and NH4CI (6.43 g, 120.2 mmol) in propan-2-ol (50 mL) and H2O (25 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 70 °C for 2 h under nitrogen atmosphere. The mixture was filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Petroleum ether / EtOAc with EtOAc from 0-40%, flow rate = 40 mL / min, 254 nm) to afford 4, 6 -dichloropyridine -2, 3 -diamine (4 g, 93.5% yield) as a brown solid. LCMS (ESI) m / z 177.9 [M+H]+.

[0403] Step 2: Synthesis of 5,7-dichloro-2-methyl-3H-imidazo[4,5-b]pyridine

[0404] V-NH N

[0405] N Ji cr Cl

[0406] A mixture of 4,6-dichloropyridine-2,3-diamine (3.4 g, 19.1 mmol) and AcOH (1.26 g, 21.0 mmol) in Eaton’s reagent (10 rnL) was degassed and purged with nitrogen for 3 times. The mixture was stirred at 100 °C for 3 h under nitrogen atmosphere. The reaction mixture was adjusted to pH- 7 with a saturated NaHCOj aqueous solution and extracted with EtOAc (50 mL ' 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Petroleum elher / EtOAc with EtOAc from 0—100%, flow rate = 60 mL / min, 254 mn) to afford 5.7-dichloro-2-methyl-3H-imidazo[4,5-b]pyridine (2.8 g, 72.6% yield) as a yellow solid. LCMS (ESI) m / z 201.9 [M+HJ+.

[0407] Step 3: Synthesis of 2-[(5,7-dichloro-2-methyl-imidazo[4,5-b]pyridin-3-yl)methoxy]ethyl- trimethyl-silane

[0408] A mixture of 5,7-dichloro-2-methyl-3H-imidazo[4,5-b]pyridine (2.7 g, 13.4 mmol), SEM-C1 (2.23 g, 13.4 mmol) and NaH (588 mg, 14.7 mmol, 60% in mineral oil) in THF (30 mL) was degassed and purged with nitrogen gas for 3 times. The resulting mixture was stirred at 20 °C for 12 h under nitrogen atmosphere. The mixture was diluted with water (50 mL) and extracted with EtOAc (100 mL ' 3). The combined organic phase was washed with brine (30 mL ' 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Petroleum ether / EtOAc with EtOAc from 0~20%, flow rate = 40 mL / min, 254 nm) to afford 2-[(5,7-dichloro-2-methyl-imidazo[4,5-b]pyridin-3-yl)methoxy]ethyl- trimethyl-silane (2.5 g. 56.3% yield) as a yellow oil. LCMS (ESI) m / z 331.9 [M+H]+.

[0409] Step 4: Synthesis of 5-chloro-N-[(4-inethoxyphenyl)methyl]-N,2-dimethyl-3-(2- trimethylsilylethoxymethyl)imidazo[4,5-b]pyridin-7-amine

[0410] A mixture of 2-[(5,7-dichloro-2-methyl-imidazo[4,5-b]pyridin-3-yl)methoxy]ethyl-trimethyl-silane (2.5 g, 7.52mmol), l-(4-methoxyphenyl)-N-methyl-methanamine (1.71 g, 11.3 mmol) and K2CO1 (3.12 g. 22.5 mmol) in DMSO (30 mL) was degassed and purged with nitrogen for 3 times. The mixture was stirred at 120 °C for 8 h under nitrogen atmosphere. The mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL ' 3). The combined organic phase was washed with brine (30 mL ' 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 0~20%, flow rate = 40 mL / min, 254 nm) to afford 5-chloro-N-[(4- methoxyphenyl)methyl]-N,2-dimethyl-3-(2-trimethylsilylethoxymethyl)imidazo[4,5-b]pyridin-7- amine (2 g, 59.5% yield) as a yellow oil. LCMS (ESI) m / z 447.1 [M+H]+.

[0411] Step 5: Synthesis of 5-chloro-N-[(4-methoxyphenyl)methyl]-N,2-dimethyl-3H-imidazo[4,5- b]pyridin-7-amine

[0412] Y-NH

[0413] N

[0414] N

[0415] N 'Cl

[0416] PMB A mixture of 5-chloro-N-[(4-methoxyphenyl)methyl]-N,2-dimethyl-3-(2- trimethylsilylethoxymethyl)imidazo[4,5-b]pyridin-7-amine (1.3 g, 2.91 mmol) and IM TBAF in THF (20 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 20 °C for 12 h under nitrogen atmosphere. The mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL ' 3). The combined organic phase was washed with brine (30 mL ' 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, DCM / MeOH with MeOH from 0-5%, flow rate = 40 mL / min, 254 nm) to afford 5-chloro-N-[(4-methoxyphenyl)methyl]-N,2- dimethyl-3H-imidazo[4,5-b]pyridin-7-amine (650 mg. 70.6% yield) as a white solid. LCMS (ESI) m / z 316.7 [M+H]+.

[0417] Step 6: Synthesis of 5-chloro-N-[(lR)-2-[(4-methoxy-3-nitro-phenyl)methoxy]-l-methyl-ethyl]-7- [(4-methoxyphenyl)methyl-methyl-amino] -2-methyl-imidazo [4,5-b] pyridine-3-carboxamide

[0418] To a solution of 5-chloro-N-[(4-methoxyphenyl)methyl]-N,2-dimethyl-3H-imidazo[4.5-b]pyridin-7- amine (150 mg, 0.474 mmol) and phenyl carbonochloridate (75 mg, 0.479 mmol) in THF (6 mL) was added dropwise TEA (145 mg, 1.44 mmol) at 20 °C. After addition, the mixture was stirred at 20 °C for 2 h. and then (2R)-l-[(4-methoxy-3-nitro-phenyl)methoxy]propan-2-amine (170 mg, 0.708 mmol) was added dropwise at 20 °C. The resulting mixture was stirred at 20 °C for 2 h. The mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL ' 3). The combined organic phase was washed with brine (30 mL ' 3), dried over anhydrous Na2SC>4. filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Petroleum ether / EtOAc with EtOAc from 0-30%, flow rate = 30 mL / min. 254 nm) to afford 5-chloro- N-[(lR)-2-[(4-methoxy-3-nitro-phenyl)methoxy]-l-methyl-ethyl]-7-[(4-methoxyphenyl)methyl- methyl-amino]-2-methyl-imidazo[4,5-b]pyridine-3-carboxamide (40 mg, 14.5% yield) as a yellow oil. LCMS (ESI) m / z 583.0 [M+H]+.

[0419] Step 7: Synthesis of N-[(lR)-2-[(3-amino-4-methoxy-phenyl)methoxy]-l-methyl-ethyI]-5-chloro- 7-[(4-methoxyphenyl)methyl-methyl-amino]-2-methyI-imidazo[4,5-b]pyridine-3-carboxamide

[0420] A mixture of 5-chloro-N-[( 1 R)-2- [(4-methoxy-3 -nitro-pheny l)methoxy ] - 1 -methyl-ethyl] -7-[(4- methoxyphenyl)methyl-methyl-amino]-2-methyl-imidazo[4,5-b]pyridine-3-carboxamide (100 mg, 0.172 mmol), Fe (50 mg, 0.895 mmol) and NH |C1 (91 mg, 1.70 mmol) in EtOH (5 mL) and H2O (1 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 80 °C for 2 h under nitrogen atmosphere. The mixture was fdtered and concentrated under reduced pressure and purified by flash chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Petroleum ether / EtOAc with EtOAc from 0-30%, flow rate = 40 mL / min, 254 run) to affordN-[(lR)-2-[(3-amino- 4-methoxy-phenyl)methoxy]-l-methyl-ethyl]-5-chloro-7-[(4-methoxyphenyl)methyl-methyl-amino]- 2-methyl-imidazo[4,5-b]pyridine-3-carboxamide (90 mg, crude) as a yellow oil. LCMS (ESI) m / z 553.0 [M+H]+.

[0421] Step 8: Synthesis of (llR)-4-methoxy-18-[(4-methoxyphenyl)methyl-methyl-amino]-ll,15- dimethyl-9-oxa-2,l 2,14,16,20-pentazatetracyclo [12.5.2.13,7.017,21] docosa- l(19),3,5,7(22),15,17,20-heptaen-13-one

[0422] HN

[0423] O.

[0424] / / N O N

[0425] N

[0426] N N

[0427] PMB H O.

[0428] A mixture of N-[( 1 R)-2-[(3-amino-4-methoxy -pheny l)methoxy ] - 1 -methyl-ethyl]-5-chloro-7-[(4- methoxyphenyl)methyl-methyl-amino]-2-methyl-imidazo[4,5-b]pyridine-3-carboxamide (80 mg, 0.145 mmol), EPhos (15 mg, 0.028 mmol), EPhos Pd G4 (14 mg, 0.015 mmol) and K3PO4 (77 mg, 0.363 mmol) in dioxane (5 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 100 °C for 2 h under nitrogen atmosphere. The mixture was diluted with water (30 mL) and extracted with EtOAc (50 mL ' 3). The combined organic phase was washed with brine (30 mL ' 3), dried over anhydrous Na2SO4, fdtered. and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column. Petroleum ether / EtOAc with EtOAc from 0-25%, flow rate = 30 mL / min, 254 nm) to afford (HR)-4-methoxy- 18-[(4-methoxyphenyl)methyl-methyl-amino]-l 1, 15-dimethyl-9-oxa-2,12,14,16,20- pentazatetracyclo[12.5.2.13,7.017,21]docosa-l(19),3,5,7(22).15,17.20-heptaen-13-one (35 mg. 46.8% yield) as a y ellow solid. LCMS (ESI) m / z 517.2 [M+H]+.

[0429] Step 9: Synthesis of (llR)-4-methoxy-ll,15-dimethyl-18-(methylamino)-9-oxa-2,12,14,16,20- pentazatetracyclo[12.5.2.13,7.017,21]docosa-l(19),3,5,7(22),15,17,20-heptaen-13-one

[0430] HN

[0431] 0.

[0432] N O

[0433] N

[0434] N N

[0435] H H

[0436] 0.

[0437] To a solution of (llR)-4-methoxy-18-[(4-methoxyphenyl)methyl-methyl-amino]-ll,15-dimethyl-9- oxa-2,12,14,16,20-pentazatetracyclo[12.5.2.13,7.017,21]docosa-l(19),3,5,7(22),15,17,20-heptaen-13- one (25 mg, 0.048 mmol) in THF (10 L) was added Pd / C (25 mg, 0.023 mmol, 10 wt% Pd with 50 wt% water) under nitrogen atmosphere. The suspension was degassed and purged with hydrogen 3 tunes. The mixture was stirred under hydrogen (15 psi) at 20 °C for 12 hrs. The mixture was filtered and concentrated under reduced pressure. The crude 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 (NH4HCO3)-ACN]; Mobile phase B: MeCN; Gradient: B from 43% to 73% in 8 min, hold 100% B for 2 min; Flow Rate: 25 mL / min; Column Temperature: 30 °C; Wavelength: 220 nm) to afford (HR)-4-methoxy-lL15-dimethyl-18- (methylamino)-9-oxa-2,12.14,16.20-pentazatetracyclo[12.5.2.13.7.017.21]docosa- l(19).3.5.7(22),15,17,20-heptaen-13-one (3.7mg, 19.3% yield) as a white solid. LCMS (ESI)m / z396.9 [M+HJ+; 1H NMR (4OO MHz. DMSO-ot) 8 ppm 9.64 (d. J = 4.8 Hz, 1 H), 8.24 (s. 1 H). 8.18 (d. J = 1.5 Hz, 1 H), 6.94 (d, J = 8.3 Hz, 1 H), 6.74 - 6.82 (m, 2 H), 6.16 (s, 1 H), 4.61 (d, J = 13.6 Hz, 1 H), 4.32 (d, J = 13.8 Hz, 1 H), 3.88 - 3.95 (m. 1 H), 3.85 (s, 3 H), 3.43 - 3.46 (m, 1 H), 3.26 (br d, J = 9.5 Hz, 1 H), 2.82 (d, J = 4.8 Hz, 3 H), 2.66 (s, 3 H). 1.14 (d. J = 6.5 Hz, 3 H).

[0438] Example 10: (10R,14R)-5-fluoro-21-(methylamino)-9-oxa-2,15,17,19,23- pentazapentacyclo[15.5.2.13’7.01014.02024]pentacosa-l(23),3,5,7(25),18,20(24),21-heptaen-16-one

[0439] Step 1: Synthesis of tert-butyl 7V-[(lR,2R)-2-[(3-fluoro-5- nitrophenyl)methoxy]cyclopentyl]carbamate

[0440] NO2

[0441] ,Boc HN

[0442] F

[0443] To a solution of l-(bromomethyl)-3-fluoro-5-nitro-benzene (800 mg, 3.42 mmol), tert-butyl N- [(lR,2R)-2-hydroxycyclopenty 11 carbarn ate (688 mg, 3.42 mmol) in THF (15 mL) was added a solution of t-BuOK in THF (IM, 6.80 mL, 6.80 mmol) at 0 °C and the mixture was stirred at 20 °C for 30 min. The resulting mixture was quenched by addition of water (60 mL) and extracted with EtOAc (50 mL x 3). The combined organic layer was washed with brine (100 mL), dried over anhydrous NacSCL, filtered, and concentrated under reduced pressure. The residue 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). The desired product tert-butyl Ar-[(lR,2R)-2-[(3-fluoro-5-nitro- phenyl)methoxy]cyclopentyl]carbamate (380 mg, 28.2% yield) was obtained as a yellow oil. LCMS (ESI) m / z 377.3 [M+Na]+.

[0444] Step 2: Synthesis of (lR,2R)-2-[(3-fluoro-5-nitro-phenyl)methoxy]cyclopentanamine

[0445] NO2

[0446] H2N

[0447] F tert-Butyl A-[(lR,2R)-2-[(3-fluoro-5-nitro-phenyl)methoxy]cyclopentyl]carbamate (380 mg, 1.07 mmol) was dissolved in a solution of HC1 in dioxane (2N, 10 mL) and the resulting mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure to remove solvent. The desired product (lR.2R)-2-[(3-fluoro-5-nitro-phenyl)methoxy]cyclopentanamine (250 mg, crude) was obtained as a brown solid. LCMS (ESI) m / z 255.0 [M+H]+.

[0448] Step 3: Synthesis of 5-chloro-A-[(lR,2R)-2-[(3-fluoro-5-nitro-phenyl)methoxy]cyclopentyl]-7-[(4- methoxyphenyl)methyl-methyl-amino]imidazo[4,5-b]pyridine-3-carboxamide

[0449] To a solution of phenyl 5-chloro-7-[(4-methoxyphenyl)methyl-methyl-amino]imidazo[4,5-b]pyridine- 3-carboxylate (350 mg. 0.828 mmol), (lR,2R)-2-[(3-fluoro-5-nitro-phenyl)methoxy]cyclopentanamine (211 mg, 0.830 mmol) in THF (10 mL) was added TEA (243 mg. 2.40 mmol) and the mixture was stirred at 20 °C for 12 h. The resulting mixture was quenched by addition of water (60 mL) and extracted with EtOAc (50 mL * 3). The combined organic layer was washed with brine (80 mL), dried over anhydrous Na2SO,. filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 12 g AgelaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0-20%, flow rate = 30 mL / min, 254 nm). The desired product 5-chloro-A-[(lR,2R)-2-[(3-fluoro- 5-nitro-phenyl)methoxy]cyclopentyl]-7-[(4-methoxyphenyl)methyl-methyl-amino]imidazo[4,5- b]pyridine-3-carboxamide (340 mg, 49.3% yield) was obtained as a yellow oil. LCMS (ESI) m / z 583.3 [M+H]1.

[0450] Step 4: Synthesis of 7V-[(lR,2R)-2-[(3-amino-5-fhioro-phenyl)inethoxy]cyclopentyl]-5-chloro-7- [(4-methoxyphenyl)methyl-methyl-amino]imidazo[4,5-b]pyridine-3-carboxamide

[0451] To a solution of 5-chloro-A-[(lR,2R)-2-[(3-fluoro-5-nitro-phenyl)methoxylcyclopentyl]-7-[(4- methoxyphenyl)methyl-methyl-amino]imidazo[4.5-b]pyridine-3-carboxamide (340 mg. 0.583 mmol) in EtOH (10 mb) and FLO (2.0 mb) was added Fe (163 mg. 2.92 mmol). NH4CI (156 mg. 2.92 mmol) and the mixture was stirred at 80 °C for 1 h. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue 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). The desired product Ar-[(lR.2R)-2-[(3-amino-5-fluoro- phenyl)methoxy]cyclopentyl]-5-chloro-7-[(4-methoxyphenyl)methyl-methyl-amino]imidazo[4,5- b]pyridine-3-carboxamide (180 mg. 44.7% yield) was obtained as a yellow oil. LCMS (ESI) m / z 575.3 [M+Na]+.

[0452] Step 5: Synthesis of (10R,14R)-5-fluoro-21-[(4-methoxyphenyI)methyI-methyl-amino]-9-oxa- 2,15,17,19,23-pentazapentacyclo[15.5.2.137.01014.02024]pentacosa-l(23),3,5,7(25),18,20(24),21- heptaen-16-one To a stirred mixture of M-[(lR,2R)-2-[(3-amino-5-fluoro-phenyl)methoxy]cyclopentyl]-5-chloro-7-[(4- methoxyphenyl)methyl-methyl-amino]imidazo[4,5-b]pyridine-3-carboxamide (180 mg, 0.325 mmol), K3PO4 (207 mg, 0.975 mmol) in dioxane (30 mL) was added EPhos (35 mg, 65.5 / / mol), EPhos Pd G4 (30 mg, 32.7 / / mol) and the mixture was stirred at 100 °C for 1 h under N2 atmosphere. The resulting mixture was cooled to RT and quenched by addition of waler (50 mL) and extracted with EtOAc (60 mL x 3). The combined organic layer was washed with brine (80 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, petroleum ether / EtOAc with EtOAc from 0-30%, flow rraattee = 30 mL / min, 254 nm). The desired product (10R,14R)-5-fluoro-21-[(4- methoxyphenyl)methyl-methyl-amino] -9-oxa-2.15,17.19,23- pentazapentacyclo[15.5.2.13’7.010 14.020’24]pentacosa-l(23),3,5,7(25),18,20(24),21-heptaen-16-one (120 mg. 64.2% yield) was obtained as a yellow solid. LCMS (ESI) m / z 517.4 [M+H]+.

[0453] Step 6: Synthesis of (10R,14R)-5-fhioro-21-(methylamino)-9-oxa-2,15,17,19,23- pentazapentacyclo[15.5.2.13’7.01014.020’24]pentacosa-l(23),3,5,7(25),18,20(24),21-heptaen-16-one

[0454] To a solution of TFA (199 mg, 1.75 mmol), triethylsilane (203 mg, 1.75 mmol) in DCM (40 mL) was added (1 OR, 14R)-5-fluoro-21 -[(4-methoxyphenyl)methyl-methyl-amino]-9-oxa-2, 15.17, 19.23- pentazapentacyclo[15.5.2.13- .010-14.02°-24]pentacosa-l(23),3,5.7(25).18,20(24).21-heptaen-16-one (90 mg, 0.174 mmol) and the mixture was stirred at 20 °C for 1 h. The resulting mixture was quenched by addition of water (50 mL) and extracted with EtOAc (60 mL x 3). The combined organic layer was washed with brine (80 mL), dried over anhydrous NazSO i. filtered, and concentrated rmder reduced pressure. The residue was purified by flash chromatography (ISCO®; 4 g AgelaFlash® Silica Flash Column, Dichloromethane / Methanol with Methanol from 0-8%, flow rate = 20 mL / min, 254 nm) and then purified by reversed-phase HPLC (Column: SepaFlash® Sphercial C18, 25 g, 40-60 «m. 120A; McCN / watcr with McCN from 0-70%, 40mL / min, 254 nm). The desired product (10R,14R)-5-fluoro- 2 l -(mcthylamino)-9-oxa-2. l 5. 17. l9.23-pcntazapcntacyclo| 15.5.2. 13.0l'l | l.02'l2 l|pcntacosa- l(23),3,5,7(25),18,20(24),21-heptaen-16-one (18.7 mg, 27.1% yield) was obtained as a white solid. LCMS (ESI) m / z 397.4 [M+H]+; ’H NMR (400 MHz, DMSO-t / e) 5 ppm 9.70 (d, J= 2.3 Hz, 1 H), 9.39 (s, 1 H), 8.25 (s, 1 H), 8.18 (s, 1 H), 7.06 (d, J = 4.8 Hz. 1 H), 6.64 (br t, J = 10.5 Hz, 2 H), 5.78 (s, 1 H), 4.78 (d, J = 14.8 Hz. 1 H), 4.42 (d, J = 14.8 Hz. 1 H), 3.72 - 3.80 (m, 2 H), 2.89 (d, J = 4.8 Hz, 3 H), 2.32 - 2.39 (in. 1 H), 2.10 - 2.19 (m, 1 H), 1.69 - 1.80 (m, 1 H), 1.56 - 1.66 (m, 1 H), 1.43 - 1.53 (m, 1 H), 1.28 - 1.41 (m, 1 H).

[0455] Example 1111:: (10R,14R)-21-(methylamino)-5-(2-methyltriazol-4-yl)-9-oxa-2,l 5,17,19,23- pentazapentacyclo [15.5.2.13,7.010,14.020,24] pentacosa-1 (23), 3(25), 4, 6,18, 20(24), 21 -heptaen-16- one

[0456] Step 1: Synthesis of 2-methyl-4-(3-methyl-5-nitro-phenyl)triazoIe

[0457] To a stirring mixture of (2-methyltriazol-4-yl)boronic acid (1.65 g. 13.0 mmol), l-bromo-3-methyl-5- nitro-benzene (2.81 g, 13.0 mmol) in dioxane (20 mL) and H2O (2 mL) was added Pd(dppf)CL (476 mg. 0.650 mmol), K2CO3 (4.49 g, 32.5 mmol) and the mixture was stirred at 100 °C for 12 h under N2atmosphere. The resulting mixture was cooled to RT and quenched by addition of water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layer was washed with brine (200 mL), dried over anhydrous Na2SC>4, filtered, and concentratedunderreduced pressure. The residue was purified by flash chromatography (ISCO®; 20 g AgelaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0~50%, flow rate = 50 mL / min. 254 nm). The desired product 2-methyl- 4-(3-methyl-5-nitro-phenyl)triazole (1.32 g, 41.9% yield) was obtained as a brown solid. LCMS (ESI) m / z 219.2 [M+H]+.

[0458] Step 2: Synthesis of 4-[3-(bromomethyl)-5-nitro-phenyl]-2-methyl-triazole

[0459] To a mixture of 2-methyl-4-(3-methyl-5-nitro-phenyl)triazole (1.3 g, 5.96 mmol), NBS (1.06 g, 5.96 mmol) in CCI4 (15 mL) was added benzoyl benzenecarboperoxoate (145 mg, 0.599 mmol) and the mixture was stirred at 80 °C for 12 h under N2 atmosphere. The resulting mixture was quenched by addition of water (60 mL) and extracted with ElOAc (60 mL x 3). The combined organic layer was washed with brine (80 mL), dried over anhydrous Na2SC>4, 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 0~7%, flow rate = 40 mL / min, 254 run). The desired product 4-[3-(bromomethyl)-5-nitro-phenyl]-2-methyl-triazole (660 mg, 33.6% yield) was obtained as a white solid. LCMS (ESI) m / z 296.6, 298.6 [M+H]+.

[0460] Step 3: Synthesis of tert-butyl N-[(lR,2R)-2-[[3-(2-methyltriazol-4-yl)-5-nitro- phenyl] methoxy] cyclopentyl] carbamate

[0461] To a solution of 4-[3-(bromomethyl)-5-nitro-phenyl]-2-methyl-triazole (640 mg. 2.15 mmol), tert-butyl N-[(lR.2R)-2-hydroxycyclopentyl]carbamate (450 mg, 2.24 mmol) in THF (20 mL) was added a solution of t-BuOK in THF (IM, 3.2 mL, 3.20 mmol) at 0 °C and the mixture was stirred at 20 °C for 1 h. The resulting mixture was quenched by addition of water (100 mL) and extracted with EtOAc (80 mL x 3). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. The residue 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). The desired product tert-butyl N-[(lR,2R)-2-[[3-(2-methyltriazol-4- yl)-5-nitro-phenyl]methoxy]cyclopentyl]carbamate (740 mg, 57.6% yield) was obtained as ayellow oil. LCMS (ESI) m / z 440.3 [M+Na]+.

[0462] Step 4: Synthesis of (lR,2R)-2-[[3-(2-methyltriazol-4-yl)-5-nitro phenyl]methoxy]cyclopentan amine

[0463] Dissolved tert -butyl N-[(lR,2R)-2-[[3-(2-methyltriazol-4-yl)-5-nitro- phenyl]methoxy]cyclopentyl]carbamate (740 mg, 1.24 mmol) in a solution of HC1 in dioxane (2M. 10 mL) . The resulting mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure to remove solvent. The crude product was purified by a reversed-phase HPLC (Column: SepaFlash® Sphercial CIS, 25 g, 40-60 pm, 120A; MeCN / water with MeCN from 0-45%, flow rate: 25 mL / min, 254 nm). The fraction was concentrated under reduced pressure and then lyophilized for overnight. The desired product (lR,2R)-2-[[3-(2-mcthyltriazol-4-yl)-5-nitro- phenyl]methoxy]cyclopentanamine (270 mg, 58.3% yield) was obtained as a yellow oil. LCMS (ESI) m / z 318.4 [M+H]+.

[0464] Step 5: Synthesis of phenyl 5-chloro-7-[(4-methoxyphenyl)methyl-methyl-amino]imidazo[4,5- b] py ridine-3-carboxy late

[0465] To a solution of 5-chloro-N-[(4-methoxyphenyl)methyl]-N-methyl-3H-imidazo[4.5-b]pyridin-7-amine (300 mg, 0.991 mmol), phenyl carbonochloridate (140 mg, 0.894 mmol) in THF (2.0 mL) was added TEA (300 mg. 2.96 mmol) and the mixture was stirred at 20 °C for 2 h. The crude mixture of phenyl 5- chloro-7-|(4-methoxyphenyl)methyl-methyl-amino|imidazo|4.5-b|pyridine-3-carboxylate (400 mg, crude, in solution) was taken directly to the next reaction without further purification. LCMS (ESI) m / z 423.3 [M+HJ+.

[0466] Step 6: Synthesis of 5-chloro-7-[(4-inethoxyphenyl)methyl-methyl-amino]-N-[(lR,2R)-2-[[3-(2- methyltriazol-4-yl)-5-nitro-phenyl]inethoxy]cyclopentyl]imidazo[4,5-b]pyridine-3-carboxamide

[0467] To a solution of phenyl 5-chloro-7-[(4-methoxyphenyl)methyl-methyl-amino]imidazo[4.5-b]pyridine- 3-carboxylate (300 mg, 0.709 mmol). (lR.2R)-2-[[3-(2-methyltriazol-4-yl)-5-nitro- phenyl]methoxy]cyclopentanamine (230 mg, 0.725 mmol) in THF (10 mL) was added TEA (218 mg, 2.16 mmol). The mixture was stirred at 20 °C for 12 h. The resulting mixture was quenched by addition of water (50 mL) and extracted with EtOAc (50 mL * 3). The combined organic layers were washed with brine (80 mL), dried over anhydrous Na^SO,. filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 4 g AgelaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0~30%, flow rate = 30 mL / min, 254 mn). The desired product 5-chloro-7-[(4-methoxyphenyl)methyl-methyl-amino]-N-[(lR,2R)-2-[[3-(2-methyltriazol-4-yl)-5- nitro-phenyl |methoxy |cyclopenty I |imidazo|4.5-b|pyridine-3-carboxamide (250 mg, 27.3% yield) was obtained as a yellow oil. LCMS (ESI) m / z 646.3 [M+H]+.

[0468] Step 7: Synthesis of N-[(lR,2R)-2-[[3-amino-5-(2-methyltriazol-4- yl)phenyl] methoxy]cyclopentyl] -5-chloro-7- [(4-methoxyphenyl)methyl-methyl- amino]imidazo[4,5-b]pyridine-3-carboxamide

[0469] To a solution of 5-chloro-7-[(4-methoxyphenyl)methyl-methyl-amino]-N-[(lR,2R)-2-[[3-(2- methyltriazol-4-yl)-5-nitro-phenyl]methoxy]cyclopentyl]imidazo[4.5-b]pyridine-3-carboxamide (230 mg, 0.356 mmol) in EtOH (10 mL) and H2O (2.0 mL) was added Fe (100 mg. 1.79 mmol). NH4CI (96 mg, 1.79 mmol) and the mixture was stirred at 80 °C for 1 h. The resulting mixture was quenched by addition of water (50 mL) and extracted with EtOAc (60 mL x 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, petroleum ether / EtOAc with EtOAc from 0—60%, flow rate = 20 mL / min, 254 nm) and then purified by reversed-phase HPLC (Column: SepaFlash® Sphercial C18, 25 g, 40-60 pm. 120A; MeCN / water with MeCN from 0-100%, 25 mL / min, 254 nm). The desired product N-[(lR,2R)-2-[[3- amino-5-(2-methyltriazol-4-yl)phenyl]methoxy]cyclopentyl]-5-chloro-7-[(4-methoxyphenyl)methyl- methyl-amino]imidazo[4,5-b]pyridine-3-carboxamide (100 mg, 43.3% yield) was obtained as a white solid. LCMS (ESI) m / z 638.2 [M+Na]+.

[0470] Step 8: Synthesis of (10R,14R)-21-[(4-methoxyphenyl)methyl-methyl-amino]-5-(2-methyltriazol- 4-yl)-9-oxa-2,l 5,17,19,23-pentazapentacyclo[l 5.5.2.13,7.010,14.020, 24]pentacosa- 1 (23), 3(25), 4, 6, 18, 20(24), 21 -heptaen-16-one

[0471] To a stirring mixture ooff N-[(lR,2R)-2-[[3-amino-5-(2-mcthyltriazol-4- yl)phenyl]methoxy]cyclopentyl] -5-chloro-7-[(4-methoxyphenyl)methyl-methyl-amino]imidazo[4,5- b]pyridine-3-carboxamide (90 mg, 0.146 mmol), K3PO4 (93 mg, 0.438 mmol) in dioxane (15 mL) was added EPhos (16 mg, 29.9 pmol), EPhos Pd G4 (14 mg, 15.2 pmol) and the mixture was stirred at 100 °C for 1 h under N2 atmosphere. The resulting mixture was quenched by addition of water (50 mL) and extracted with EtOAc (60 mL x 3). The combined organic layer was washed with brine (80 mL), dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 4 g AgelaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0~40%, flow rate = 20 mL / min, 254 nm). The desired product (10R,14R)-21-[(4- mcthoxy phenyl Jmcthy 1-mcthy 1-amino | -5 -(2-methyltriazol-4-yl)-9-oxa-2, 15,17,19,23- pentazapentacyclo[15.5.2.13,7.010,14.020,24]pentacosa-l(23),3(25),4,6,18,20(24),21-heptaen-l 6-one (80 mg, 85.0% yield) was obtained as a white solid. LCMS (ESI) m / z 580.3 | M+H| .

[0472] Step 9: Synthesis of (10R,14R)-21-(methylamino)-5-(2-methyltriazol-4-yl)-9-oxa-2, 15, 17,19,23- pentazapentacyclo [15.5.2.13,7.010,14.020,24] pentacosa-1 (23), 3(25), 4, 6,18, 20(24), 21 -heptaen-16- one

[0473] To a solution of TEA (138 mg, 1.21 mmol), triethylsilane (140 mg, 1.20 mmol) in DCM (30 mL) was added (10R,14R)-21-[(4-methoxyphenyl)methyl-methyl-amino]-5-(2-methyltriazol-4-yl)-9-oxa- 2.15, 17.19, 23-pentazapentacyclo[15.5.2.13, 7.010, 14.020, 24]pentacosa-l(23), 3(25), 4, 6, 18.20(24), 21- heptaen-16-one (70 mg, 0.121 mmol) and the mixture was stirred at 20 °C for 1 h. The resulting mixture was quenched by addition of water (50 mL) and extracted with EtOAc (60 mL x 3). The combined organic layer was washed with brine (80 mL), dried over anhydrous Na2SC>4, 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 0~8%. flow rate = 30 mL / min, 254 nm) and then purified by reversed-phase HPLC (Column: SepaFlash® Sphercial C18. 25 g, 40-60 pm. 120A; MeCN / water with MeCN from 0-70%, 25 mL / min. 254 nm). The desired product (1 OR.14R)-21 -(methylamino)-5-(2-methy ltriazol-4-yl)-9-oxa-2, 15.17,19.23- pentazapentacyclo[15.5.2.13.7.010,14.020,24]pentacosa-l(23),3(25),4,6,18,20(24),21 -heptaen-16-one (20.3 mg, 36.6% yield) was obtained as a white solid. LCMS (ESI) m / z 460.3 [M+H]+; *H NMR (400 MHz, DMSO-c / ,) 8 ppm 9.69 - 9.80 (m. 1 H), 9.37 (s, 1 H), 8.28 (s, 1 H). 8.23 (s. 1 H), 8.13 (s, 1 H), 7.38 (s, 1 H), 7.25 (s. 1 H), 7.01 (br d. J = 4.8 Hz, 1 H), 5.79 (s, 1 H), 4.84 (d. J= 14.6 Hz, 1 H). 4.46 (d, J= 14.6 Hz, 1 H). 4.20 (s, 3 H), 3.72 - 3.81 (m, 2 H), 2.89 (d, J = 4.8 Hz, 3 H), 2.31 - 2.39 (m, 1 H), 2.09 - 2.21 (m. 1 H), 1.68 - 1.80 (m, 1 H). 1.56 - 1.66 (m, 1 H). 1.44 - 1.55 (m, 1 H), 1.26 - 1.38 (m, 1 H).

[0474] Example 1122:: (11 R)-4-methoxy-ll -methyl- 18-(methylamino)-9-thia-2,12,l 4,16,20- pentazatetracyclo[12.5.2.13'7.017’21]docosa-l(19),3,5,7(22),15,17,20-heptaen-13-one

[0475] Step 1: Synthesis of [(2R)-2-(tert-butoxycarbonylamino)propyl] 4- methylbenzenesulfonate

[0476] H Boc T "OTs

[0477] To a solution of tcrt-butyl N-[(lR)-2-hydroxy-l-mcthyl-cthyl]carbamatc (10 g, 57.1 mmol) in pyridine (100 mL) was added TsCl (10.9 g, 0.154 mol) and the mixture was stirred at 20°C for 12 h. The reaction mixture was quenched by H2O (100 mL) and extracted with DCM (200 mL ' 3). The combined organic layers were washed with brine (200 mL), dried over Na2SCL, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0-25%. flow rate; 50 mL / min, I2) to afford [(2R)-2- (tert-butoxycarbonylamino)propyl] 4-methylbenzenesulfonate (6.6 g, 28.1% yield) as a colorless oil. LCMS (ESI) m / z 330.1 [M+H]+.

[0478] Step 2: Synthesis of S-[(2R)-2-(tert-butoxycarbonylamino)propyl] ethanethioate

[0479] H 0

[0480] Boc T s

[0481] To a solution of [(2R)-2-(tert-butoxycarbonylamino)propyl] 4-methylbenzenesulfonate (6.5 g, 19.3 mmol) in DMF (60 mL) was added potassium ethanethioate (2.58 g, 22.6 mmol) and the mixture was stirred at 20°C for 12 hrs. The reaction mixture was quenched by addition of H2O (100 mL) and extracted with EtOAc (100 mL ' 3). The combined organic layers were washed with brine (100 mL ' 2), dried over Na2SO4. filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0-25%, flow rate: 50 mL / min, I2) to afford S-[(2R)-2-(tert- butoxycarbonylamino)propyl] ethanethioate (2 g, 39.1% yield) as a yellow oil. LCMS (ESI) m / z 234.1 [M+H]+.

[0482] Step 3: Synthesis of tert-butyl N-[(lR)-l-methyl-2-sulfanyl-ethyl]carbamate

[0483] H

[0484] Boc T SH

[0485] To a solution of S-[(2R)-2-(tert-butoxycarbonylamino)propyl] ethanethioate (2 g, 8.57 mmol) in MeOH (20 mb) was added NaOH (400 mg. 10.0 mmol) and the mixture was stirred at 20°C for 1 hr. The reaction mixture was acidified to pH ~ 7 using an aqueous HC1 (2N) solution, and then extracted with EtOAc (100 mL ' 5). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give tert-butyl N-[(1R)-1- methyl-2-sulfanyl-ethyl]carbamate (1.2 g, crude) as a white solid, ' l l NMR (400 MHz, DMSO-ty) 3 ppm 6.71 - 6.80 (m, 1 H), 3.44 - 3.53 (m, 1 H), 2.51 - 2.63 (m, 1 H), 2.39 - 2.46 (m, 1 H), 1.38 (s. 9 H), 1.07 (d, J= 6.8 Hz, 4 H).

[0486] Step 4: Synthesis of tert-butyl N-[(lR)-2-[(4-methoxy-3-nitro-phenyl)methylsulfanyl]-l-methyl- ethyl]carbamate

[0487] Boe"

[0488] To a solution of tert-butyl N-[(lR)-l-methyl-2-sulfanyl-ethyl]carbamate (1.20 g, 6.27 mmol) in DMF (15 mL) was added NaH (268 mg, 60% by weight in mineral oil) at 0 °C. Then 4-(bromomethyl)-l- methoxy-2-nitro-benzene (1.10 g, 4.47 mmol) was added. The mixture was stirred at 20°C for 1 h. The resulting mixture was quenched by addition of NH4C1 aqueous solution (100 mL) and extracted with EtOAc (100 mL ' 3). The combined organic layers were washed with a saturated NH4C1 aqueous solution (100 mL ' 2), brine (100 mL), dried over anhydrous NazSO.,. filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0~30%, flow rate: 30 mL / min, 254 nm) to give tert-butyl N-[(lR)-2-[(4-methoxy-3-nitro-phenyl)methylsulfanyl]-l-methyl- e thy 1 [carbamate (900 mg, 52.5% yield) as a colorless oil. LCMS (ESI) m / z 356.9 [M+H]+.

[0489] Step 5: Synthesis of (2R)-l-[(4-methoxy-3-nitro-phenyl)methylsulfanyl]propan-2-amine

[0490] A solution of tert- buty I N- [( 1 R)-2- [(4-methoxy -3 -nitro-pheny l)methy Isulfany 1] - 1 -methylethyl] carbamate (900 mg, 2.52 mmol) in 2M HCl / dioxane (10 mL) was stirred at 20°C for 2 hrs. The reaction mixture was concentrated under reduced pressure. (2R) -1 -[(4-methoxy -3 -nitro- phenyl)methylsulfanyl]propan-2-amine (750 mg, crude) was obtained as a yellow solid which was taken directly to the next reaction. LCMS (ESI) m / z 257.1 [M+H]+.

[0491] Step 6: Synthesis of 5-chloro-N-[(lR)-2-[(4-methoxy-3-nitro-phenyl)methylsulfanyl]-l-methyl- ethyl]-7-[(4-methoxyphenyl)methyl-methyl-amino]imidazo[4,5-b]pyridine-3-carboxamide To a solution of 5-chloro-N-[(4-methoxyphenyl)methyl]-N-methyl-3H-imidazo[4,5-b]pyridin-7-amine (500 mg, 1.65 mmol) in THF (10 mL) was added TEA (0.690 mL, 4.95 mmol) and phenyl carbonochloridate (310 mg, 1.98 mmol) and the mixture was stirred at 20°C for 2 h. Compound phenyl 5-chloro-7-[(4-methoxyphenyl)methyl-methyl-amino]imidazo[4,5-b]pyridine-3-carboxylate (698 mg, crude in 10 mL THF) was obtained as a colorless liquid. The crude product was taken directly to the next step without any further purification.

[0492] To a solution of phenyl 5-chloro-7-[(4-methoxyphenyl)methyl-methyl-amino]imidazo[4,5-b]pyridine- 3-carboxylate (698 mg, in THF solution) and (2R)-l-[(4-methoxy-3-nitro- phenyl)methylsulfanyl]propan-2-amine (423 mg, 1.65 mmol) in THF (5 mL) was added TEA (0.460 mL, 3.30 mmol). The mixture was stirred at 20 °C for 12 h. Upon completion, the resulting mixture was quenched by addition of H2O (50 mL) and extracted with EtOAc (100 mL ' 3). The combined organic layer was washed with a saturated NH4C1 aqueous solution (100 mL). brine (100 mL), dried over anhydrous Na2SO i. filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0-30%, flow rate: 30 mL / min, 254 nm) to afford 5-chloro-N-[(lR)-2-[(4-methoxy-3-nitro- phenyl)methylsulfanyl]-l-methyl-ethyl]-7-[(4-methoxyphenyl)methyl-methyl-amino]imidazo[4,5- b]pyridine-3-carboxamide (280 mg, 27.5% yield) as a white solid. LCMS (ESI) m / z 585.3 [M+H]+.

[0493] Step 7: Synthesis of N-[(lR)-2-[(3-amino-4-methoxy-phenyl)methylsulfanyl]-l-methyl-ethyl]-5- chloro-7-[(4-methoxyphenyl)methyl-methyl-amino]imidazo[4,5-b]pyridine-3-carboxamide

[0494] To a solution of 5-chloro-N-[(lR)-2-[(4-methoxy-3-nitro-phenyl)methylsulfanyl]-l-methyl-ethyl]-7- [(4-methoxyphenyl)methyl-methyl-amino]imidazo[4,5-b]pyridine-3-carboxamide (280 mg. 0.479 mmol) in H2O (2 mL) and EtOH (10 mL) was added Fe (133 mg, 2.38 mmol) and NH4C1 (154 mg, 2.88 mmol) and the mixture was stirred at 80 °C for 2 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0-30%. flow rate: 35 mL / min, 254 nm) to afford N-[(lR)-2-[(3-amino-4-methoxy-phenyl)methylsulfanyl]-l-methyl-ethyl]- 5-chloro-7-[(4-methoxyphenyl)methyl-methyl-amino]imidazo[4,5-b]pyridine-3-carboxamide (220 mg, 77.9% yield) as a white solid. LCMS (ESI) m / z 555.2 [M+HJ+.

[0495] Step 8: Synthesis of (llR)-4-methoxy-18-[(4-methoxyphenyl)methyl-methyl-amino]-ll-methyl-9- thia-2,12,14,16,20-pentazatetracyclo[12.5.2.13,7.017,21]docosa-l(19),3,5,7(22),15,17,20-heptaen- 13-one

[0496] A mixture of N-[(lR)-2-[(3-amino-4-methoxy-phenyl)methylsulfanyl]-l-methyl-ethyl]-5-chloro-7-[(4- mctho.xyphcnyl)mcthyl-mcthyl-amino|imidazo|4.5-b|pyridiiic-3-carboxaniidc (200 mg, 0.360 mmol), EPhos Pd G4 (165 mg, 0.180 mmol), EPhos (192 mg, 0.359 mmol) and K3PO4 (191 mg, 0.900 mmol) in dioxane (10 mb) was degassed and purged with N2for 3 times, and then the mixture was stirred at 100°C for 2 h under N2atmosphere. The reaction mixture was cooled to room temperature and quenched by H2O (20 mL) and extracted with DCM (50 mL ' 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®: 12 g SepaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0~30%, flow rate: 35 mL / min, 254 nm) to afford (HR)-4-methoxy-18- [(4-methoxyphenyl)methyl-methyl-amino]-l l-methyl-9-thia-2.12,14.16,20- pentazatetracyclo[12.5.2.13,7.017,21]docosa-l(19).3,5,7(22),15.17,20-heptaen-13-one (130 mg. 62.3% yield) as a white solid. LCMS (ESI) m / z 519.2 [M+H]+.

[0497] Step 9: Synthesis of (llR)-4-methoxy-ll-methyl-18-(methylamino)-9-thia-2,12,14,16,20- pentazatetracyclo[12.5.2.13,7.017,21]docosa-l(19),3,5,7(22),15,17,20-heptaen-13-one

[0498] To a solution of (HR)-4-methoxy-18-[(4-methoxyphenyl)methyl-methyl-amino]-l l-methyl-9-thia- 2,12,14,16,20-pentazatetracyclo[12.5.2.13.7.017.21]docosa-l(19),3.5.7(22).15,17.20-heptaen-13-one (100 mg. 0.193 mmol) in DCM (30 mL) was added triethylsilane (224 mg. 1.93 mmol) and TFA (0.140 mL. 1.88 mmol) in DCM (1 mL) at 0 °C. The mixture was stirred at 20°C for 2 h. Upon completion, the reaction mixture was quenched with a saturated NaHCCh aqueous solution (20 mL) and extracted with DCM (50 mL ' 3). The combined organic layers were washed with brine (50 mL). dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by reversed- phase HPLC (column: Welch Xtimate C18 150 ' 25 mm ' 5 urn; mobile phase: [water (NH3-H2O)- ACN]; gradient: 42%-72% B over 9.5 min) to afford (llR)-4-methoxy-ll-methyl-18-(methylamino)- 9-thia-2,12,14,16,20-pentazatetracyclo[12.5.2.13,7.017,21]docosa-l(19),3,5,7(22),15,17,20-heptaen- 13-one (19.4 mg, 25.3% yield) as a white solid. LCMS (ESI) m / z 399.3 [M+H]+;1H NMR (400 MHz, DMSO-de) <? ppin 9.19 (d, J= 5.8 Hz, 1 H), 8.28 (s, 1 H), 8.23 (d, J = 2.0 Hz, 1 H), 8.20 (s, 1 H), 6.86 - 6.96 (in, 2 H), 6.81 (dd, J= 8.3, 2.0 Hz, 1 H), 6.13 (s, 1 H), 3.84 (s, 3 H), 3.68 - 3.80 (m, 3 H), 2.91 (dd. J = 12.3, 2.0 Hz, 1 H), 2.86 (d, J = 4.8 Hz, 3 H), 2.11 (t, J = 11.9 Hz, 1 H), 1.18 (d, J = 6.3 Hz, 3 H).

[0499] Example 1133:: (10R,14R)-5-(5-fluoropyrimidin-2-yl)-21-(methylamino)-9-oxa-2,15,17,19,23- pentazapentacyclo[15.5.2.13’7.01014.020'24]pentacosa-l(23),3(25),4,6,18,20(24),21-heptaen-16-one

[0500] Step 1: Synthesis of 4,4,5,5-tetramethyl-2-(3-methyl-5-nitro-phenyl)-l,3,2-dioxaborolane

[0501] To a solution of l-bromo-3-methyl-5-nitro-benzene (5 g, 23.1 mmol), KOAc (4.54 g, 46.3 mmol) in dioxane (50 mL) was added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-1.3,2- dioxaborolane (6.47 g. 25.5 mmol), Pd(dppf)Cl2(847 mg. 1.16 mmol) and the mixture was stirred at 100 °C for 12 h under N2atmosphere. The resulting mixture was quenched by addition of water (100 mL) and extracted with EtOAc (100 mL * 3). The combined organic layer was washed with brine (200 mL), dried over anhydrous Na2SO i. filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 80 g AgelaFlash® Silica Flash Column, petroleinn ether / EtOAc with EtOAc from 0~30%, flow rate = 80 mL / min. 254 nm). The desired product 4, 4,5,5- tetramethyl-2-(3-methyl-5-nitro-phenyl)-l,3.2-dioxaborolane (5.68 g. 88.6% yield) was obtained as a white solid. LCMS (ESI) m / z 264.1 [M+H]+.

[0502] Step 2: Synthesis of 5-fluoro-2-(3-methyl-5-nitro-phenyl)pyrimidine

[0503] O2N

[0504] F

[0505] To a stirring mixture of 4.4.5, 5-tetramethyl-2-(3-methyl-5-nitro-phenyl)-1.3.2-dioxaborolane (2.5 g, 9.50 mmol), 2-chloro-5-fluoro-pyrimidine (1.39 g, 10.5 mmol). K2CO2(3.28 g, 23.8 mmol) in dioxane (30 mL) and H2O (3.0 mL) was added Pd(dppf)Cl2(348 mg, 0.476 mmol) and the mixture was stirred at 100 °C for 12 h under N2atmosphere. The resulting mixture was quenched by addition of water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na2SO i. filtered, and concentrated imder reduced pressure. The residue was purified by flash chromatography (ISCO®: 40 g AgelaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0~20%, flow rale = 50 mL / min, 254 nm). The desired product 5-fluoro- 2-(3-methyl-5-nitro-phenyl)pyrimidine (1.87 g, 84.0% yield) was obtained as a white solid. LCMS (ESI) m / z 234.2 [M+H]+.

[0506] Step 3: Synthesis of 2-[3-(bromomethyl)-5-nitro-phenyl]-5-fluoro-pyrimidine

[0507] To a solution of 5-fluoro-2-(3-methyl-5-nitro-phenyl)pyrimidine (1.8 g, 7.72 mmol), NBS (1.44 g, 8.10 mmol) in CCL (15 mL) was added benzoyl benzenecarboperoxoate (187 mg. 0.772 mmol) and the mixture was stirred at 80 °C for 12 h under N2atmosphere. The resulting mixture was quenched by addition of water (50 mL) and extracted with EtOAc (50 mL x 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 AgelaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0~5%, flow rate = 40 mL / min, 254 nm). The desired product 2-[3-(bromomethyl)-5-nitro-phenyl]-5-fluoro-pyrimidine (840 mg. 33.2% yield) was obtained as a white solid. LCMS (ESI) m / z 314.0 [M+H]+.

[0508] Step 4: Synthesis of tert-butyl N-[(lR,2R)-2-[[3-(5-fhioropyrimidin-2-yl)-5- nitrophenyl] methoxy] cyclopentyl] carbamate

[0509] To a solution of 2-[3-(bromomethyl)-5-nitro-phenyl]-5-fluoro-pyrimidine (800 mg, 2.56 mmol), tertbutyl N-[(lR,2R)-2-hydroxycyclopentyl]carbamate (516 mg. 2.56 mmol) in THE (10 mL) was added IM t-BuOK in THF (3.9 mL) at 0 °C and the mixture was stirred at 20 °C for 30 min. The resulting mixture was quenched by addition of water (100 mL) and extracted with EtOAc (80 mL x 3). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated imder reduced pressure. The residue was purified by flash chromatography (ISCO®; 20 g AgelaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0~25%, flow rate = 40 mL / min, 254 mn). The desired product tert-butyl N-[(lR,2R)-2-[[3-(5-fluoropyrimidin-2-yl)-5-nitro- phcnyl]mcthoxy]cyclopcntyl]carbamatc (430 mg, 27.2% yield) was obtained as a yellow oil. LCMS (ESI) m / z 455.3 [M+Na]+.

[0510] Step 5: Synthesis of (lR,2R)-2-[[3-(5-fluoropyrimidin-2-yl)-5-nitro- phenyl]methoxy]cyclopentanamine tert-Butyl N-[(lR,2R)-2-[[3-(5-fhioropyrimidin-2-yl)-5-nitro-phenyl]methoxy]cyclopentyl] carbamate (430 mg, 0.994 mmol) was dissolved in a solution of HC1 in dioxane (2M, 15 mL). The resulting mixture was stirred at 20 °C for 1 h under N2atmosphere. The reaction mixture was concentrated under reduced pressure to remove solvent. The desired product (lR,2R)-2-[[3-(5-fluoropyrimidin-2-yl)-5-nitro- phenyl]methoxy]cyclopentanamine (300 mg, crude) was obtained as a yellow oil. LCMS (ESI) m / z 333.2 [M+H]+.

[0511] Step 6: Synthesis ooff 5-chloro-N-[(lR,2R)-2-[[3-(5-fluoropyrimidin-2-yl)-5-nitro- phenyl] methoxy] cyclopentyl] - 7- [ (4-methoxyphenyl)met hyl- methyl- amino] imidazo [ 4,5- b] py ridine-3-carboxamide

[0512] To a solution of 5-chloro-N-[(4-niethoxyphenyl)methyl]-N-methyl-3H-iniidazo[4,5-b]pyridin-7-amine (300 mg, 0.991 mmol), phenyl carbonochloridate (125 mg, 0.798 mmol) in THE (10 mL) was added TEA (300 mg, 2.96 mmol) and the mixture was stirred at 20 °C for 2 h. The resulting mixture of phenyl 5-chloro-7-[(4-methoxyphenyl)methyl-methyl-amino]imidazo[4,5-b]pyridine-3-carboxylate (300 mg, crude in THE solution) was obtained as a yellow liquid, which was used directly to the next reaction.

[0513] To a solution of phenyl 5-chloro-7-[(4-methoxyphenyl)methyl-methyl-amino]imidazo[4,5-b]pyridine- 3-carboxylate (300 mg, 0.709 mmol), (lR,2R)-2-[[3-(5-fluoropyrimidin-2-yl)-5-nitro- phenyl]methoxy]cyclopentanamine (240 mg, 0.722 mmol) in THE (10 mL) was added TEA (218 mg, 2.16 mmol) and die mixture was stirred at 20 °C for 12 h. The resulting mixture was quenched by addition of water (50 mL) and extracted with EtOAc (60 mL x 3). The combined organic layer was washed with brine (80 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, petroleum ether / EtOAc with EtOAc from 0~30%, flow rate = 30 mL / min, 254 nm). The de sired product 5 -chloro-N- [( 1 R.2R)-2- [ [3 -(5 -fluoropy rimidin-2-y l)-5 -nitro- phenyl]methoxy]cyclopentyl]-7-[(4-methoxyphenyl)methyl-methyl-amino]imidazo[4,5-b]pyridine-3- carboxamide (440 mg, 46.9% yield) was obtained as a yellow oil. LCMS (ESI) m / z 661.3 [M+H]+.

[0514] Step 7: Synthesis of N-[(lR,2R)-2-[[3-amino-5-(5-fluoropyrimidin-2- yl)phenyl] methoxy]cyclopentyl] -5-chloro-7- [(4-methoxyphenyl)methyl-methyl- amino]imidazo[4,5-b]pyridine-3-carboxamide

[0515] To a solution of 5-chloro-N-[(lR,2R)-2-[[3-(5-fluoropyrimidin-2-yl)-5-nitro- phenyl]methoxy]cyclopentyl]-7-[(4-methoxyphenyl)methyl-methyl-amino]imidazo[4,5-b]pyridine-3- carboxamide (430 mg, 0.325 mmol) in EtOH (10 mL) and H2O (2 mL) was added Fe (91.0 mg, 1.63 mmol), NH4CI (87.0 mg, 1.63 mmol) and the mixture was stirred at 80 °C for 1 h. 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, Dichloromethane / Methanol with Methanol from 0~20%, flow rate = 20 mL / min, 254 nm). The desired product N-[(lR,2R)-2-[[3-amino- 5-(5-fluoropyrimidin-2-yl)phenyl]methoxy]cyclopentyl]-5-chloro-7-[(4-methoxyphenyl)methyl- methyl-amino]imidazo[4,5-b]pyridine-3-carboxamide (90 mg. 26.3% yield) was obtained as a white solid. LCMS (ESI) m / z 631.3 [M+H]+.

[0516] Step 8: Synthesis of (10R,14R)-5-(5-fluoropyrimidin-2-yl)-21-[(4-inethoxyphenyl)niethyl-methyl- amino | -9-oxa-2,15,l 7,19,23-pentazapentacyclo [15.5.2.13,7.010,14.020, 24]pentacosa- 1 (23), 3(25), 4, 6, 18, 20(24), 21 -heptaen-16-one

[0517] To a stine d mixture of N-[(lR,2R)-2-[[3-amino-5-(5-fluoropyrimidin-2- yl)phenyl]methoxy]cyclopentyl] -5-chloro-7-[(4-methoxyphenyl)methyl-methyl-amino]imidazo[4,5- b]pyridine-3-carboxamide (80 mg, 0.127 mmol), K3PO4 (81 mg, 0.382 mmol) in dioxane (20 mL) was added EPhos (14 mg, 26.2 pmol), EPhos Pd G4 (12 mg, 13.1 pmol) and the mixture was stirred at 100 °C for 1 h under N2atmosphere. The resulting mixture was quenched by addition of water (50 mL) and extracted with EtOAc (60 mL x 3). The combined organic layer was washed with brine (80 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 0-15%, flow rate = 20 mL / min, 254 nm). The desired product (10R,14R)-5-(5- fluoropyrimidin-2-yl)-21-[(4-methoxyphenyl)melhyl-methyl-amino]-9-oxa-2,15,17,19,23- pentazapentacyclo[15.5.2.13.7.010.14.020,24]pentacosa-l(23).3(25),4,6,18,20(24),21-heptaen-16-one (60 mg, 47.8% yield) was obtained as a white solid. LCMS (ESI) m / z 595.3 | M+H| .

[0518] Step 9: Synthesis of (10R,14R)-5-(5-fluoropyrimidin-2-yl)-21-(methylamino)-9-oxa-2,15,17,19,23- pentazapentacyclo[15.5.2.13, 7.010,14.020, 24]pentacosa-l(23), 3(25), 4, 6, 18, 20(24), 21-heptaen-16- one

[0519] To a solution of TFA (96 mg. 0.842 mmol), triethylsilane (98 mg, 0.843 mmol) in DCM (30 mL) was added (10R,14R)-5-(5-fluoropyrimidin-2-yl)-21-[(4-methoxyphenyl)methyl-methyl-amino]-9-oxa- 2,15,17,19,23-pentazapentacyclo[15.5.2.13,7.010,14.020,24]pentacosa-l(23),3(25),4,6,18,20(24),21- heptaen-16-one (50 mg, 84.1 pmol) and the mixture was stirred at 20 °C for 1 h. The resulting mixture was quenched by addition of water (50 mL) and extracted with EtOAc (60 mL x 3). The combined organic layer was washed with brine (80 mL), dried over anhydrous NazSCL, 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—20%, flow rate = 20 inL / min, 254 nm) and then purified by reversed-phase HPLC (Column: SepaFlash® Sphercial Cl 8, 25 g, 40-60 pm, 120A; McCN / watcr with McCN from 0-75%, 25 inL / min, 254 mn). The fraction was concentrated under reduced pressure and then lyophilized overnight. The desired product (10R,14R)-5-(5- fluoropyrimidin-2-y 1) -21 -(methy lamino) -9-oxa-2, 15,17,19,23- pentazapentacyclo[15.5.2.13,7.010,14.020,24]pentacosa-l(23).3(25),4,6,18,20(24),21-heptaen- 16-one (4.6 mg, 11.4% yield) was obtained as a white solid. LCMS (ESI) m / z 475.3 [M+H]+;

[0520] ' H NMR (400 MHz, DMSO-r / ,) d ppm 9.74 (d, J= 2.0 Hz, 1 H), 9.48 (s, 1 H), 8.99 (s, 2 H). 8.43 (s, 1 H), 8.23 (s, 1 H), 7.97 (s, 1 H), 7.76 (s, 1 H). 7.01 (br d, J= 5.0 Hz, 1 H), 5.81 (s. 1 H), 4.87 (d, J= 14.6 Hz, 1 H), 4.54 (d, J = 14.6 Hz, 1 H), 3.73 - 3.80 (m, 2 H), 2.89 (d. J = 4.8 Hz, 3 H), 2.32 - 2.39 (m, 1 H), 2.17 (dt. J = 10.0, 2.9 Hz. 1 H), 1.68 - 1.79 (m. 1 H), 1.56 - 1.66 (m, 1 H), 1.46 - 1.55 (m, 1 H), 1.28 - 1.37 (m. 1 H). Example 14: (13R,16R)-23-(methylamino)-7-(trideuteriomethyl)-12-oxa-2,5,6,7,17,19,21,25- octazahexacyclo[l 7.5.2.13, 10.04, 8.013, 16.022, 26]heptacosa-l(25), 3, 5, 8, 10(27), 20, 22(26), 23- octaen- 18-one

[0521] Step 1: Synthesis of tert-butyl N-[(lR,2R)-2-[[7-bromo-3-(trideuteriomethyl)benzotriazol-5- yl]methoxy]cyclobutyl]carbamate

[0522] To a solution of 4-bromo-6-(bromomethyl)-l-(trideuteriomethyl)benzotriazole (1.50 g, 4.88 mmol) and TBAI (165 mg, 0.447 mmol) in THF (20 mL) was added NaH (213 mg, 5.33 mmol, 60% by weight in mineral oil) in portions at 0 °C. After addition, the mixture was stirred at this temperature for 5 min, and then tert-butyl N-[(lR,2R)-2-hydroxycyclobutyl]carbamate (830 mg, 4.43 mmol) was added dropwise at 0 °C. The resulting mixture was stirred at 20 °C for 12 hrs. The mixture was diluted with a saturated NH4CI aqueous solution (30 mL) and extracted with EtOAc (50 mL ' 3). The combined organic phase was washed with brine (30 mL ' 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, Petroleinn ether / EtOAc with EtOAc from O~35%, flow rate = 30 mL / min, 254 mn) to afford tert-butyl N-[(lR,2R)-2-[[7-bromo-3-(trideuteriomethyl)benzotriazol-5- yl]methoxy]cyclobutyl]carbamate (1.6 g, 87.1% yield) as a white solid: LCMS (ESI) m / z 413.7, 415.7 [M+H1+.

[0523] Step 2: Synthesis of tert-butyl N-[6-[[(lR,2R)-2-(tert-butoxycarbonylamino)cyclobutoxy]methyl]- l-(trideuteriomethyl)benzotriazol-4-yl] carbamate

[0524] A mixture of tert-butyl N-[(lR,2R)-2-[[7-bromo-3-(trideuteriomethyl)benzotriazol-5- yl]methoxy]cyclobutyl]carbamate (300 mg, 0.724 mmol), tert-butyl carbamate (101 mg, 0.862 mmol),

[0525] Pd2(dba)3 (67 mg, 0.073 mmol), Xantphos (84 mg. 0.145 mmol) and CS2CO3 (590 mg, 1.81 mmol) in dioxane (5 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 cooled to room temperature and diluted with H2O (30 mL) and extracted with EtOAc (100 mL ' 3). The combined organic phase was washed with brine (30 mL ' 3), dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 12 g SepaFlash®’ Silica Flash Column, Petroleum ether / EtOAc with EtOAc from 0~40%, flow rate = 40 mL / min, 254 nm) to afford tert -butyl N-[6-[[(lR,2R)-2-(tert-butoxycarbonylamino)cyclobutoxy]methyl]-l-(trideuteriomethyl)benzotriazol- 4-yl] carbamate (270 mg, 82.8% yield) as a yellow solid. LCMS (ESI) m / z 451.1 [M+H]+.

[0526] Step 3: Synthesis of 6-[[(lR,2R)-2-aminocyclobutoxy]methyl]-l-(trideuteriomethyl)benzotriazol- 4- amine tert-Butyl N-[6-[[(lR,2R)-2-(tert-butoxycarbonylamino)cyclobutoxy]methyl]-l-

[0527] (trideuteriomethyl)benzotriazol-4-yl]carbamate (270 mg, 0.599 mmol) was dissolved in a solution of HC1 in dioxane (2N. 6 mL) and stirred at 20 °C for 2 h under nitrogen atmosphere. The mixture was concentrated under reduced pressure. Compound 6-[[(lR,2R)-2-aminocyclobutoxy]methyl]-l- (trideuteriomethyl)benzotriazol-4-amine (250 mg. crude) was obtained as a yellow solid. LCMS (ESI) m / z 250.8 [M+H]+.

[0528] Step 4: Synthesis ooff N-[(lR,2R)-2-[[7-amino-3-(trideuteriomethyl)benzotriazol-5- yl]methoxy]cyclobutyl]-5-chloro-7-[(4-methoxyphenyl)inethyl-methyl-amino]imidazo[4,5- b] py ridine-3-carboxamide

[0529] To a solution of 5-chloro-N-[(4-methoxyphenyl)methyl]-N-methyl-3H-imidazo[4.5-b]pyridin-7-amine (150 mg, 0.495 mmol) and TEA (100 mg, 0.988 mmol) in THF (8 mL) was added dropwise phenyl carbonochloridate (78 mg, 0.498 mmol) at 20 °C. After addition, the mixture was stirred at 20 °C for 2 h. and then 6-[[(lR,2R)-2-aminocyclobutoxy]methyl]-l-(trideuteriomethyl)benzotriazol-4-amine (150 mg. 0.599 mmol) was added dropwise at 20 °C. The resulting mixture was stirred at 20 °C for 3 h. The mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL ' 3). The combined organic phase was washed with brine (30 mL ' 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Petroleum ether / EtOAc with EtOAc from 0~70%, flow rate = 40 mL / min, 254 mn) to afford N-[(lR,2R)-2-[[7-amino-3-(trideuteriomethyl)benzotriazol-5-yl]methoxy]cyclobutyl]-5- chloro-7-[(4-methoxyphenyl)methyl-methyl-amino]imidazo[4,5-b]pyridine-3-carboxamide (90 mg, 31.4% yield) as a white solid. LCMS (ESI) m / z 579.1 [M+H]+.

[0530] Step 5: Synthesis of (13R,16R)-23-[(4-methoxyphenyl)methyl-methyl-amino]-7-

[0531] (trideuteriomethyl)-12-oxa-2,5,6,7,17,19,21,25- octazahexacyclo[17.5.2.13, 10.04, 8.013, 16.022, 26]heptacosa-l(25), 3, 5, 8, 10(27), 20, 22(26), 23- octaen- 18-one

[0532] A mixture of N-[( lR,2R)-2-[[7-amino-3-(trideuteriomethyl)benzotriazol-5-yl]methoxy]cyclobutyl]-5- chloro-7-[(4-methoxyphenyl)methyl-methyl-amino]imidazo[4,5-b]pyridine-3-carboxamide (90 mg, 0.155 mmol), EPhos (17.0 mg, 0.032 mmol). EPhos Pd G4 (15.0 mg. 0.016 mmol) and K3PO4 (83.0 mg, 0.391 mmol) in dioxane (5 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 100 °C for 2 h under nitrogen atmosphere. The mixture was cooled to room temperature, diluted with H2O (30 mL) and extracted with EtOAc (50 mL ' 3). The combined organic layer was 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 0~45%, flow rraattee = 40 mL / min, 254 mn) to afford (13R,16R)-23-[(4- methoxyphenyl)methyl-methyl-amino]-7-(trideuteriomethyl)-12-oxa-2,5,6,7,17.19,21,25- octazahexacyclo[17.5.2.13.10.04,8.013,16.022,26]heptacosa-l(25),3,5,8,10(27),20,22(26).23-octaen- 18-one (40 mg, 47.4% yield) as a yellow solid. LCMS (ESI) m / z 543.1 [M+H]+.

[0533] Step 6: Synthesis of (13R,16R)-23-(methylamino)-7-(trideuteriomethyl)-12-oxa- 2, 5, 6, 7,17,19,21 ,25-octazahexacyclo[l 7.5.2.13,10.04,8.013,16.022, 26]heptacosa- 1(25), 3,: 5,8, 10(27), 20, 22(26), 23-octaen-18-one

[0534] A mixture of (13R,16R)-23-[(4-methoxyphenyl)methyl-methyl-amino]-7-(trideuteriomethyl)-12-oxa- 2,5,6,7,17,19,21,25-octazahexacyclo[17.5.2.13,10.04,8.013,16.022,26]heptacosa- l(25),3,5,8,10(27),20,22(26),23-octaen-18-one (25 mg, 0.046 mmol) and TfOH (21 mg, 0.14 mmol) in DCM (5 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 20 °C for 30 min under nitrogen atmosphere. The mixture was diluted with a NaHCOj aqueous solution (30 mL) and extracted with EtOAc (50 mL ' 3). The combined organic layer was dried over anhydrous Na^SO i. filtered, and 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(NH4HCO3)- ACN]; Mobile phase B: MeCN; Gradient: B from 31% to 61% in 8 min, hold 100% B for 2 min: Flow Rate: 25 mL / min; Column Temperature: 30 °C; Wavelength: 220 mn) to afford (13R,16R)-23- (methylamino)-7-(trideuteriomethyl)-12-oxa-2,5,6,7,17,19,21,25- octazahexacyclo[17.5.2.13,10.04,8.013.16.022,26]heptacosa-l(25),3.5.8.10(27),20,22(26),23-octaen- 18-one (7.5 mg. 38.5% yield) as a white solid. LCMS (ESI) m / z 423.0 [M+H]+; ‘H NMR (400 MHz. DMSO-ds) d ppm 9.95 (d, J= 4.0 Hz, 1 H), 9.78 (s, 1 H), 8.25 (s, 1 H), 8.05 (s, 1 H), 7.20 (s, 1 H), 7.07 (q. J= 4.3 Hz, 1 H), 6.44 (s. 1 H), 4.89 (d, J = 14.6 Hz, 1 H), 4.69 (d, J = 14.8 Hz, 1 H). 3.94 - 4.02 (m, 1 H), 3.85 - 3.92 (m, 1 H), 2.91 (d, .7 = 4.8 Hz. 3 H). 2.07 - 2.16 (m, 2 H). 1.65 (br t. .7 = 9.2 Hz, 1 H), 1.24 - 1.35 (m. 1 H).

[0535] Example 1155:: (llR)-ll-cyclopropyl-4-methoxy-18-(methylamino)-9-oxa-2,12,14,16,20- pentazatetracyclo[12.5.2.13'7.017’21]docosa-l(19),3,5,7(22),15,17,20-heptaen-13-one

[0536] Step 11:: Synthesis of tert-butyl N-[(lR)-l-cyclopropyl-2-[(4-methoxy-3-nitro- phenyl)methoxy] ethyl] carbamate

[0537] .0.

[0538] NO2

[0539] To a solution of tert-butyl N-[(lR)-l-cyclopropyl-2-hydroxy-ethyl]carbamate (980 mg, 4.87 mmol) in DMF (15 mL) was added NaH portion-wise (243 mg, 6.07 mmol, 60% dispersion in mineral oil) at 0 °C, then 4-(bromomethyl)-l -methoxy -2 -nitro-benzene (1 g, 4.06 mmol) was added. The mixture was stirred at 20° C for 1 h. The resulting mixture was quenched by addition of a saturated NH4C1 aqueous solution (100 mL) and extracted with EtOAc (100 mL ' 3). The combined organic layer was washed with a saturated NH4C1 aqueous solution (100 mL ' 2), brine (100 mL), dried over anhy drous Na2SO i. filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0-25%, 30 mL / min, 254 nm) to afford tert-butyl N-[(lR)-l-cyclopropyl-2-[(4-methoxy-3-nitro- phenyl)methoxy]ethyl]carbamate (1 g, 53.7% yield) as a yellow oil. LCMS (ESI) m / z 367.2 [M+H]+.

[0540] Step 2: Synthesis of (1R)-1 -cyclopropyl- 2- [(4-methoxy-3-nitro-phenyl)methoxy] ethanamine tert- Butyl N-[(lR)-l-cyclopropyl-2-[(4-methoxy-3-nitro-phenyl)methoxy]ethyl]carbamate (1.00 g, 2.73 mmol) was dissolved in a solution of HC1 in dioxane (10 mL, 2M) and stirred at 20°C for 2 h. The reaction mixture was adjusted to pH - 8 with a saturated Na2COs aqueous solution, and then extracted with DCM (100 mL ' 5). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4. filtered, and concentrated under reduced pressure to give (lR)-l-cyclopropyl-2-[(4- methoxy-3-nitro-phenyl)methoxy]ethanamine (500 mg, crude) as a yellow solid which was used to the next step without further purification. LCMS (ESI) m / z 267.2 [M+H]+.

[0541] Step 3: Synthesis ooff 5-chloro-N-[(lR)-l-cyclopropyl-2-[(4-methoxy-3-nitro- phenyl)methoxy]ethyl]-7-[(4-methoxyphenyl)methyl-methyl-amino]imidazo[4,5-b]pyridine-3- carboxamide

[0542] To a solution of 5-chloro-N-[(4-methoxyphenyl)methyl]-N-methyl-3H-imidazo[4,5-b]pyridin-7-amine (700 mg, 2.31 mmol) in THF (10 mL) was added TEA (0.960 mL, 6.90 mmol) and phenyl carbonochloridate (434 mg, 2.77 mmol). The mixture was stirred at 20 °C for 2 h. Compound phenyl 5-chloro-7-[(4-methoxyphenyl)methyl-methyl-amino]imidazo[4,5-b]pyridine-3-carboxylate (977 mg, in 10 mL THF) was obtained as a white liquid. The crude product was taken directly to the next step without further purification.

[0543] To a solution of phenyl 5-chloro-7-[(4-methoxyphenyl)methyl-methyl-amino]imidazo[4,5-b]pyridine- 3-carboxylate (977 mg. in 10 mL THF) and (lR)-l-cyclopropyl-2-[(4-methoxy-3-nitro- phenyl)methoxy]ethanamine (500 mg, 1.88 mmol) in THF (10 mL) was added TEA (0.6 mL, 4.31 mmol). The mixture was stirred at 20 °C for 4 h. The resulting mixture was quenched by addition of H2O (50 mL) and extracted with EtOAc (100 mL ' 3). The combined organic layer was washed with a saturated NH4C1 aqueous solution (100 mL), brine (100 mL), dried over anhydrous Na2SOi. 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 0~30%, flow rate: 35 mL / min, 254 mn) ttoo afford 5-chloro-N-[(lR)-l-cyclopropyl-2-[(4-methoxy-3-nitro- phenyl)melhoxy]ethyl]-7-[(4-methoxyphenyl)methyl-methyl-amino]imidazo[4,5-b]pyridine-3- carboxamide (500 mg, 32.7% yield) as a white solid. LCMS (ESI) m / z 595.2 [M+H]+.

[0544] Step 5: Synthesis of N-[(lR)-2-[(3-amino-4-methoxy-phenyl)methoxy]-l-cyclopropyl-ethyl]-5- chloro-7-[(4-methoxyphenyl)methyl-methyl-amino]imidazo[4,5-b]pyridine-3-carboxamide

[0545] To a solution of 5-chloro-N-[(IR)-I-cyclopropyl-2-[(4-methoxy-3-nitro-phenyl)methoxy]ethyl]-7-[(4- methoxyphenyl)methyl-methyl-amino]imidazo[4,5-b]pyridine-3-carboxamide (500 mg. 0.840 mmol) in EtOH (10 mL) and H2O (2 mL) was added Fe (300 mg, 5.37 mmol) and NH4CI (440 mg, 8.23 mmol). The mixture was stirred at 80 °C for 4 h. The resulting mixture was quenched by addition of FLO (50 mL) and extracted with EtOAc (100 mL ' 3). The combined organic layer was washed with a saturated NH4CI aqueous solution (100 mL), brine (100 mL). dried over anhydrous Na-AOi. filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (I SCO": 20 g AgelaFlash®Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0~30%. flow rate = 35 mL / min. 254 nm) to afford N-[(IR)-2-[(3-amino-4-methoxy-phenyl)methoxy]-I-cyclopropyl-ethyl]-5- chloro-7-[(4-methoxyphenyl)methyl-methyl-amino]imidazo[4,5-b]pyridine-3-carboxamide (470 mg, 89.1% yield) was obtained as a white solid. LCMS (ESI) m / z 587.2 [M+Na]+.

[0546] Step 6: Synthesis of (llR)-ll-cycIopropyI-4-methoxy-18-[(4-methoxyphenyl)methyI-methyI- amino]-9-oxa-2,12,14,16,20-pentazatetracyclo[12.5.2.13'7.017’21]docosa-l(19),3,5,7(22),15,17,20- heptaen-13-one

[0547] A mixture of N-[(lR)-2-[(3-amino-4-methoxy-phenyl)methoxy]-l-cyclopropyl-ethyl]-5-chloro-7-[(4- methoxyphenyl)methyl-methyl-amino]imidazo[4,5-b]pyridine-3-carboxamide (200 mg, 0.354 mmol), EPhos Pd G4 (33 mg, 35.9 pmol), EPhos (40 mg, 74.8 pmol) and K3PO4 (188 mg, 0.886 mmol) in dioxane (6 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100 °C for 2 h under N2 atmosphere. Upon completion, the reaction mixture was quenched by H2O (20 mL) and extracted with DCM (50mL ' 3). The combined organic layers were washed with brine (50mL), dried over anhydrous Na2SO4. filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®: 12 g AgelaFlash®Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0-30%, flow rate = 35 mL / min, 254 nm) to afford (HR)-ll-cyclopropyl- 4-methoxy-18-[(4-methoxyphenyl)methyl-methyl-amino]-9-oxa-2.12,14.16,20- pentazatetracyclo[12.5.2.13’7.017’21]docosa-l(19),3.5.7(22),15,17,20-heptaen-13-one (140 mg. 71.1% yield) as a white solid. LCMS (ESI) m / z 529.3 [M+H]+.

[0548] Step 7: Synthesis of (HR)-ll-cyclopropyl-4-methoxy-18-(methylamino)-9-oxa-2,12,14,16,20- pentazatetracyclo[12.5.2.13’7.017’21]docosa-l(19),3,5,7(22),15,17,20-heptaen-13-one

[0549] A mixture of (llR)-l l-cyclopropyl-4-methoxy-18-[(4-methoxyphenyl)methyl-methyl-amino]-9-oxa- 2.12,14.16,20-pentazatetracyclo[12.5.2.13-7.01•21]docosa-l(19).3.5.7(22).15,17.20-heptaen-13-one (140 mg. 0.265 mmol). Pd / C (280 mg. 10 wt% Pd with 50 wt% water) in THF (10 mL) was degassed and purged with H2for 3 times, and then the mixture was stirred at 20 °C for 12 h under H2(15 psi). The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (1SCO®; 12 g AgelaFlash®Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0-65%, flow rate = 30 mL / min, 254 run) and further purified by flash chromatography (Biotage®. Column: SepaFlash® Spherical CIS, 40 g, 40-60 pm. 120A; MeCN / water (0.05 v%NH3-H2O) with MeCN from 0-60%, 30 mL / min, 254 nm) to afford (11R)-11- cyclopropyl-4-methoxy-18-(methylamino)-9-oxa-2,12.14,16.20- pentazatetracyclo[12.5.2.13’7.017’21]docosa-l(19).3,5,7(22),15,17,20-heptaen-13-one (15.3 mg, 14.1% yield) as a white solid. LCMS (ESI) m / z 409.1 [M+H]+; ’H NMR (400 MHz, DMSO-rfc) 8 ppm 9.21 (d, J - 5.9 Hz, 1 H), 8.36 (s, 1 H), 8.28 (d, J = 1.9 Hz, 1 H), 8.22 (s, 1 H), 6.93 (d. J - 8.1 Hz, 1 H), 6.86 - 6.91 (m, 1 H), 6.79 (dd, J= 8.1, 1.9 Hz, 1 H), 6.18 (s, 1 H), 4.58 (s, 1 H), 4.35 (d, J = 13.3 Hz, 1 H), 3.86 (s, 3 H), 3.59 (dd, J= 9.6, 2.3 Hz, 1 H), 3.37 - 3.47 (m, 2 H), 2.86 (d, J = 4.8 Hz, 3 H), 0.76 - 0.90 (m, 1 H), 0.69 (dq, J = 9.6, 4.8 Hz, 1 H), 0.40 - 0.50 (m, 1 H), 0.33 - 0.40 (m, 1 H), 0.24 (dq, J= 9.8, 4.8 Hz, 1 H). Example 16: (llR)-4-methoxy-ll-methyl-18-(methylamino)-2,12,14,16,20- pentazatetracyclo[12.5.2.13,7.017,21]docosa-l(19),3,5,7(22),15,17,20-heptaen-13-one

[0550] HN (R)

[0551] O.

[0552] Step 1: Synthesis of 4-(4-methoxyphenyl)butanal

[0553] O'

[0554] To a solution of 4-(4-methoxyphenyl)butan-l-ol (10 g, 55.48 mmol) in DCM (100 mL) was added DMP (24.7 g, 58.3 mmol) at 0 °C and the mixture was stirred at 20 °C for 1 h. The reaction mixture was quenched by addition of a saturated sodium thiosulfate (100 mL) at 0 °C, and then extracted with dichloromethane (100 mL * 3). The combined organic layers were washed with brine (200 mL * 2), dried over anhydrous Na2SO4, fdtered, 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 0~20%, flow rate = 100 mL / min, 254 nm). The desired product 4-(4- methoxyphenyl)butanal (10 g, 91.0% yield) was obtained as a yellow oil. *H NMR (400 MHz, DMSO- de) 8 ppm 9.65 (t, J= 1.5 Hz, 1 H). 7.10 (d, J = 8.5 Hz, 2 H), 6.84 (d, J= 8.5 Hz, 2 H). 3.71 (s, 3 H), 2.53 (s, 2 H), 2.41 (td, J= 7.3, 1.5 Hz, 2 H). 1.78 (q. J= 7.5 Hz, 2 H).

[0555] Step 2: Synthesis of (E,S)-A'-|4-(4-methoxyphenyl)butylidene|-2-methyl-propane-2-sulfinamide n isi o

[0556] O

[0557] To a solution of 4-(4-methoxyphenyl)butanal (5 g, 28.1 mmol). (S)-2-methylpropane-2-sulfinamide (3.40 g, 28.1 mmol) in THF (50 mL) was added Ti(OEt)4 (9.60 g, 42.1 mmol) and the mixture was stirred at 80 °C for 1 h under N2atmosphere. The resulting mixture was quenched by addition of a saturated NH4CI aqueous solution (60 mL) and extracted with EtOAc (60 mL x 3). The combined organic layer was washed with brine (80 mL), dried over anhydrous Na2SO,. filtered, and concentrated under reduced pressure. The desired product (E.S)-Ar-[4-(4-methoxyphenyl)butylidene]-2-methyl- propane-2-sulfinamide (7.5 g, crude) was obtained as a yellow oil. LCMS (ESI) m / z 282.2 [M+H]+.

[0558] Step 3: Synthesis of (S)-IV-[(lR)-4-(4-methoxyphenyl)-l-methyl-butyl]-2-methyl-propane-2- sulfinamide

[0559] To a solution of (NE,S)-A-[4-(4-methoxyphenyl)butylidene]-2-methyl-propane-2-sulfinamide (7.5 g, 26.7 mmol) in THF (60 mL) was added a solution of MeMgBr in THF (26.7 mL, 3M. 80.1 mmol) at - 78 °C and the mixture was stirred at 0 °C for 1 h under N2atmosphere. The resulting mixture was quenched by addition of water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layer was washed with brine (200 mL), 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 0-30%, flow rate = 100 mL / min, 254 mn). The desired product (S)- / V-[(lR)-4-(4-methoxyphenyl)-l-methyl-butyl]-2-methyl-propane-2- sulfinamide (5.05 g, 63.4% yield) was obtained as a yellow oil. LCMS (ESI) m / z 298.3 [M+H]+.

[0560] Step 4: Synthesis of (2R)-5-(4-methoxyphenyl)pentan-2-amine

[0561] O'

[0562] A solution of (S)-7V-[(lR)-4-(4-methoxyphenyl)-l-methyl-butyl]-2-methyl-propane-2-sulfinamide (3.5 g, 11.8 mmol) in 2M HCl / dioxane (10 mL) was stirred at 20 °C for 30 min. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by flash chromatography (ISCO®; 40 g AgelaFlash® Silica Flash Column, Dichloromethane / Methanol with Methanol from 0—20%, flow rate = 50 mL / min, 254 nm). The desired product (2R)-5-(4- mclho.xyphcnyl)pcntan-2-aminc (2.2 g, 95.2% yield) was obtained as a white solid. LCMS (ESI) m / z 194.2 [M+H]+.

[0563] Step 5: Synthesis of (2R)-5-(3-bromo-4-methoxy-phenyl)pentan-2-amine

[0564] H2N Br o

[0565] To a solution of (2R)-5-(4-methoxyphenyl)pentan-2-amine (2.2 g. 11.4 mmol), AcOH (682 mg, 11.4 mmol) in DCM (30 mL) was added dropwise Br2(1.82 g, 11.4 mmol) in DCM (10 mL) at 0 °C and the mixture was stirred at 20 °C for 10 min. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with a saturated Na2CO2aqueous solution (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (80 mL x 2), dried over anhydrous Na2SCL. filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (I SCO®; 40 g AgelaFlash® Silica Flash Column, Dichloromethane / Methanol with Methanol from 0-10%, flow rate = 50 mL / min. 254 nm). The desired product (2R)-5-(3-bromo-4-methoxy-phenyl)pentan-2-amine (2.19 g. 70.3% yield) was obtained as a white solid. LCMS (ESI) m / z 272.2. 274.2 [M+H]+. Step 6: Synthesis of tert-butyl A-[(l R)-4-(3-bromo-4-methoxv-phenyl)-l-methyl-butyl|carhamatc

[0566] To a solution of (2R)-5-(3-bromo-4-methoxy-phenyl)pentan-2 -amine (2.19 g, 8.05 mmol) in dioxane (20 mL) and H2O (10 mL) was added K2CO3 (2.22 g, 16.1 mmol), Boc2O (3.51 g, 16.1 mmol) and the mixture was stirred at 20 °C for 1 hr. The resulting mixture was quenched by addition of water (100 mL) and extracted with EtOAc (100 mL x 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 chromatograph} (ISCO®: 40 g AgelaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0~20%, flow rate = 50 mL / min. 254 mn). The desired product tert-butyl A-[(lR)-4-(3-bromo-4-methoxy-phenyl)-l-methyl-butyl]carbamate (4.6 g, 92.1% yield) was obtained as a colorless oil. LCMS (ESI) m / z 372.2. 374.2 [M+H]+.

[0567] Step 7: Synthesis of tert-butyl 7V-[2-methoxy-5-[(4R)-4-(tert- butoxycarbonylamino)pentyl]phenyl]carbamate

[0568] BOCHNVRJ NHBoc

[0569] O

[0570] To a mixture of tert-butyl A-[(lR)-4-(3-bromo-4-methoxy-phenyl)-l-methyl-butyl]carbamate (1.0 g, 2.69 mmol), tert-butyl carbamate (378 mg, 3.23 mmol). CS2CO3 (2.19 g, 6.72 mmol) in dioxane (15 mL) was added Pd2(dba)2(246 mg, 0.269 mmol), Xantphos (311 mg, 0.537 mmol) and the mixture was stirred at 100 °C for 12 h under N2atmosphere. The resulting mixture was quenched by addition of water (60 mL) and extracted with EtOAc (80 mL x 3). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na2SO2. filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 12 g AgelaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0~60%, flow rate = 30 mL / min, 254 mn). The desired product tert -butyl / V-[2-methoxy-5-[(4R)-4-(tert-butoxycarbonylamino)pentyl]phenyl]carbamate (460 mg, 37.7% yield) was obtained as a yellow oil. LCMS (ESI) m / z 431.4 [M+Na]+.

[0571] Step 8: Synthesis of 2-methoxy-5-[(4R)-4-aminopentyl]aniline

[0572] H2N N H2

[0573] O tert-Butyl / V-[2-methoxy-5-[(4R)-4-(tert-butoxycarbonylamino)penty IJphenylJcarbamate (460 mg, 1.13 mmol) was dissolved in a solution of HC1 in dioxane (10 mL, 2M) and stirred at 40 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to remove solvent. The desired product 2- methoxy-5-[(4R)-4-aminopentyl]aniline (220 mg. crude) was obtained as a yellow solid. LCMS (ESI) m / z 209.1 [M+H]+.

[0574] Step 9: Synthesis of 5-chloro-7-[(4-methoxyphenyl)methyl-methyl-amino]- / V-[(lR)-4-(3-amino-4- methoxy-phenyl)-! -methyl-butyl] imidazo [4, 5-b]pyridine-3-carboxamide

[0575] To a solution of 5-chloro-AL[(4-methoxyphenyl)methyl]-Ar-methyl-3H-imidazo[4,5-b]pyridin-7-amine (300 mg, 0.991 mmol), phenyl carbonochloridate (128 mg, 0.818 mmol) in THE (10 mL) was added TEA (401 mg, 3.96 mmol) and the mixture was stirred at 20 °C for 1 Im The resulting mixture of phenyl 5-chloro-7-[(4-methoxyphenyl)methyl-methyl-amino]imidazo[4,5-b]pyridine-3-carboxylate (400 mg, crude in solution) as a yellow liquid which was taken directly to the next reaction without any purification. To aa solution of phenyl 5-chloro-7-[(4-methoxyphenyl)methyl-methyl- amino]imidazo[4,5-b]pyridine-3-carboxylate (400 mg, 0.946 mmol), 2-methoxy-5-[(4R)-4- aminopentyljaniline (200 mg, 0.960 mmol) in THE (10 mL) was added TEA (290 mg, 2.87 mmol) and the mixture was stirred at 20 °C for 1 hr. The resulting mixture was quenched by addition of water (80 mL) and extracted with EtOAc (80 mL x 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, petroleum ether / EtOAc with EtOAc from 0~40%, flow rate =30 mL / min, 254 nm). The desired product 5-chloro- 7-[(4-methoxyphenyl)methy l-methyl-amino]-A-[(lR)-4-(3-amino-4-methoxy -phenyl)- 1-methyl- butyl]imidazo[4,5-b]pyridine-3-carboxamide (140 mg, 26.2% yield) was obtained as a colorless oil. LCMS (ESI) m / z 559.3 [M+Na]+.

[0576] Step 10: Synthesis of (llR)-4-methoxy-18-[(4-methoxyphenyl)methyl-methyl-amino]-ll-methyl- 2,12,14,16,20-pentazatetracyclo[12.5.2.13’7.017’21]docosa-l(19),3,5,7(22),15,17,20-heptaen-13-one

[0577] HN (R)

[0578] O

[0579] M l.

[0580] N

[0581] N T N PMB H o.

[0582] To a stirring mixture of 5-chloro-7-[(4-methoxyphenyl)methyl-methyl-amino]-Ar-[(lR)-4-(3-amino-4- methoxy-phenyl)-l-methyl-butyl]imidazo[4,5-b]pyridine-3-carboxamide (130 mg, 0.242 mmol), K3PO4 (155 mg, 0.730 mmol) in dioxane (15 mL) was added EPhos (26.0 mg, 48.6 / zmol), EPhos Pd G4 (26.0 mg, 28.3 / (mol) and the mixture was stirred at 100 °C for 1 h under N2 atmosphere. The resulting mixture was quenched by addition of water (50 mL) and extracted with EtOAc (60 mL x 3). The combined organic layer was washed with brine (80 mL), dried over anhydrous NazSO i. filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 12 g AgelaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0~40%, flow rate = 30 mL / min, 254 nm). The desired product (HR)-4-methoxy-18-[(4-methoxyphenyl)methyl-methyl- amino]-ll-methyl-2.12,14,16,20-pentazatetracyclo[12.5.2.137.01721]docosa-l(19),3,5,7(22),15,17,20- heptaen-13-one (88 mg, 65.4% yield) was obtained as a white solid. LCMS (ESI) m / z 501.3 [M+H]+.

[0583] Step 11: Synthesis of (HR)-4-methoxy-ll-methyl-18-(methylamino)-2,12,14,16,20- pentazatetracyclo[12.5.2.13’7.017’21]docosa-l(19),3,5,7(22),15,17,20-heptaen-13-one

[0584] To a solution of TFA (137 mg, 1.20 mmol), triethylsilane (139 mg, 1.20 mmol) in DCM (30 mL) was added (11 R)-4-methoxy- 18-[(4-methoxypheny l)methy 1-methyl-amino] -11 -methyl-2, 12, 14, 16,20- pentazatetracyclo[12.5.2.13-7.017>21]docosa-l(19), 3.5.7(22), 15,17, 20-heptaen-13-one (60 mg. 0.120 mmol) and the mixture was stirred at 20 °C for 30 min. The resulting mixture was quenched by addition of water (50 mL) and extracted with EtOAc (60 mL x 3). The combined organic layer was washed with brine (80 mL), dried over anhydrous Na2SCL, fdtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 4 g AgelaFlash® Silica Flash Column, Dichloromethane / M ethanol with Methanol from 0—10%, flow rate = 20 mL / min, 254 nm) and which was further purified by reversed-phase HPLC (Column: SepaFlash® Spherical C18, 25 g. 40-60 ,um, 120A; MeCN / water with MeCN from 0-70%, 25mL / min, 254 nm). The desired product (HR)-4- methoxy-ll-methyl-18-(methylamino)-2,12.14,16.20-pentazatetracyclo[12.5.2.13'.017’21]docosa- l(19),3,5,7(22),15.17,20-heptaen-13-one (4.2 mg, 9.21% yield) was obtained as a white solid. LCMS (ESI) m / z 381.4 [M+H]+; ’H NMR (400 MHz, DMSO-t / .) 8 ppm 9.05 (d, J = 5.8 Hz, 1 H), 8.28 (s, 1 H), 8.22 (s, 1 H). 7.91 (d. J = 1.5 Hz, 1 H). 6.85 - 6.94 (m, 2 H). 6.73 (dd, J= 8.2, 1.6 Hz. 1 H), 6.15 (s, 1 H), 3.85 (s, 3 H). 3.59 - 3.75 (m, 1 H). 2.87 (d. J= 4.8 Hz, 3 H), 2.77 - 2.85 (m, 1 H), 2.35 - 2.46 (m, 1 H), 1.82 - 2.01 (m, 2 H), 1.49 - 1.66 (m, 1 H), 1.04 - 1.20 (m, 4 H).

[0585] Example 1177:: (10R,14R)-6-fluoro-4-methoxy-21 -(methylamino)-9-oxa-2,l 5,17,19,23- pentazapentacyclo[15.5.2.13’7.01014.020’24]pcntacosa-l(23),3(25),4,6,18,20(24),21-hcptacn-16-one

[0586] Step 1: Synthesis of (2-fluoro-4-methoxy-5-nitro-phenyl)methanol

[0587] NO2

[0588] F

[0589] To a solution of 2-fluoro-4-methoxy-5-nitro-benzaldehyde (3 g, 15.07 mmol) in MeOH (30 mL) was added NaBtU (627.00 mg, 16.6 mmol) at 0 °C and the mixture was stirred at 0 °C for 1 h. The reaction mixture was quenched by addition of a saturated NH4CI aqueous solution (50 mL) at 0 °C, and then extracted with EtOAc (50mL x 3). The combined organic layers were washed with brine (100 mL x 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 0~70%, flow rate = 40 mL / min, 254 nm). The desired product (2-fluoro- 4-methoxy-5-nitro-phenyl)methanol (2.97 g, 93.1% yield) was obtained as a brown solid. H NMR (400 MHz. DMSO-rfe) ^ ppm 8.01 (d, J= 7.8 Hz, 1 H). 7.29 (d. J = 11.9 Hz. 1 H), 5.45 (t, J = 5.8 Hz. 1 H), 4.51 (d. J = 5.8 Hz, 2 H), 3.93 (s. 3 H).

[0590] Step 2: Synthesis of l-(bromomethyl)-2-fluoro-4-methoxy- 5- nitro-benzene

[0591] NO2

[0592] A

[0593] Br-

[0594] F

[0595] To a solution of (2-fluoro-4-methoxy-5-nitro-phenyl)methanol (2.97 g, 14.8 mmol) in THF (25 mL) was added CBr4(5.39 g, 16.2 mmol), PPh3(4.26 g, 16.2 mmol) and the mixture was stirred at 20 °C for 12 h. The resulting mixture was quenched by addition of water (100 mL) and extracted with EtOAc (100 mL x 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®; 120 g AgelaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0~30%, flow rate = 100 mL / min, 254 nm). The desired product l-(bromomethyl)-2-fluoro- 4-methoxy -5 -nitro-benzene (2.24 g, 54.6% yield) was obtained as a yellow oil. H NMR (400 MHz, DMSO-de) 8 ppm 8.26 (d, J= 7.8 Hz, 1 H), 7.40 (d, J= 12.0 Hz, 1 H), 4.72 (s, 2 H), 3.96 (s, 3 H).

[0596] Step 3: Synthesis of tert-butyl 2V-[(lR,2R)-2-[(2-fluoro-4-niethoxy-5-nitro- phenyl) methoxy] cyclopentyl] carbamate

[0597] NO2

[0598] Boc k TD. HN

[0599] F

[0600] To a solution of tert-butyl Ar-[(lR,2R)-2-hydroxycyclopentyl]carbamate (503 mg. 2.50 mmol) in THE (10 mL) was added NaH (136 mg, 3.40 mmol, 60% by weight in mineral oil) at 0 °C. After addition, the mixture was stirred at this temperature for 30 min, and then l-(bromomethyl)-2-fluoro-4-methoxy- 5 -nitro-benzene (600 mg. 2.27 mmol) in THE (5.0 mL) was added dropwise at 0 °C. The resulting mixture was stirred at 20 °C for 1 h. The resulting mixture was quenched by addition of water (60 mL) at 0 °C and extracted with EtOAc (80 mL x 3). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na2SCL, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 12 g AgelaFlash® Silica Flash Column, petroleum ether / EtOAc from 0~40%, flow rate = 30 mL / min, 254 nm). The desired product tert -butyl A-|(I R.2R)- 2-[(2-fluoro-4-methoxy-5-nitro-phenyl)methoxy]cyclopentyl]carbamate (430 mg, 42.8% yield) was obtained as a yellow oil. LCMS (ESI) m / z 407.3 [M+Na]+.

[0601] Step 4: Synthesis of (lR,2R)-2-[(2-fluoro-4-methoxy-5-nitro-phenyl)methoxy]cyclopentanamine tert-Butyl Ar-[(lR,2R)-2-[(2-fluoro-4-methoxy-5-nitro-phenyl)methoxy]cyclopentyl]carbamate (420 mg. 1.09 mmol) was dissolved in a solution of HC1 in dioxane (2M, 10 mL) and the resulting mixture was stirred at 20 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to remove solvent. The desired product (lR,2R)-2-[(2-fluoro-4-methoxy-5-nitro- phenyl)methoxy]cyclopentanamine (300 mg, crude) was obtained as a yellow oil. LCMS (ESI) m / z 285.2 [M+H]+.

[0602] Step 5: Synthesis of 5-chloro- / V-[(lR,2R)-2-[(2-fluoro-4-methoxy-5-nitro- phenyl)methoxy]cyclopentyI]-7-[(4-methoxyphenyl)methyLmethyI-amino]imidazo[4,5- b] py ridine-3-carboxamide

[0603] VR)

[0604] O Cty

[0605] N F

[0606] N I PMB2I

[0607] O. To a solution of 5-chloro-Ar-[(4-methoxyphenyl)methyl]-Ar-methyl-3H-imidazo[4,5-b]pyridin-7-amine (300 mg, 0.991 mmol), phenyl carbonochloridate (130 mg, 0.830 mmol) in THF (10 mL) was added TEA (401 mg, 3.96 mmol) and the mixture was stirred at 20 °C for 1 h. The resulting mixture of phenyl 5-chloro-7-[(4-methoxyphenyl)methyl-methyl-amino]imidazo[4,5-b]pyridine-3-carboxylate (400 mg, crude in solution) was obtained as a yellow liquid which was taken directly to the next reaction without any purification.

[0608] To a solution of phenyl 5-chloro-7-[(4-methoxyphenyl)methyl-methyl-amino]imidazo[4,5-b]pyridine- 3-carboxylate (400 mg, 0.946 mmol), (lR,2R)-2-[(2-fluoro-4-methoxy-5-nitro- phenyl)methoxy]cyclopentanamine (280 mg, 0.985 mmol) in THF (10 mL) was added TEA (293 mg, 2.90 mmol) and the mixture was stirred at 20 °C for 12 h. The resulting mixture was quenched by addition of water (50 mL) and extracted with EtOAc (60 mL x 3). The combined organic layer was washed with brine (80 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, petroleum ether / EtOAc with EtOAc from 0~40%, flow rate = 30 mL / min, 254 nm). The desired product 5-chloro-A-[(lR,2R)-2-[(2-fluoro-4-methoxy-5-nitro-phenyl)methoxy]cyclopentyl]-7- [(4-methoxyphenyl)methyl-methyl-amino]imidazo[4,5-b]pyridine-3-carboxamide (420 mg, 57.9% yield) was obtained as a yellow oil. LCMS (ESI) m / z 635.3 [M+Na]+.

[0609] Step 6: Synthesis of N- [(lR,2R)-2- [(5- amino- 2-fluoro-4-methoxy-phenyl)methoxy] cyclopentyl] -5- chloro-7-[(4-methoxyphenyl)methyl-methyl-amino]imidazo[4,5-b]pyridine-3-carboxamide

[0610] V(R)

[0611] N > F

[0612] N H2N PMB O.

[0613] To a solution of 5-chloro-Ar-[(lR,2R)-2-[(2-fluoro-4-methoxy-5-nitro-phenyl)methoxy]cyclopentyl]-7- [(4-methoxyphenyl)methyl-methyl-amino]imidazo[4,5-b]pyridine-3-carboxamide (350 mg, 0.571 mmol) in EtOH (20 mL) and H2O (2 mL) was added Fe (160 mg, 2.86 mmol), NH4CI (153 mg, 2.86 mmol) and the mixture was stirred at 80 °C for 1 h. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue 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). The desired product A-[(lR,2R)-2-[(5-amino-2-fluoro-4-methoxy- phenyl)methoxy]cyclopentyl]-5-chloro-7-[(4-methoxyphenyl)methyl-methyl-amino]imidazo[4,5- b]pyridine-3-carboxamide (240 mg, 68.5% yield) was obtained as a y ellow oil. LCMS (ESI) m / z 605.2 [M+Na]+.

[0614] Step 7: Synthesis of (10R,14R)-6-fluoro-4-methoxy-21-[(4-methoxyphenyl)methyl-methyl- amino]-9-oxa-2,15,17,19,23-pentazapentacyclo[15.5.2.13'7.010 14.020'24]pentacosa-

[0615] 1 (23), 3(25), 4, 6, 18, 20(24), 21 -heptaen-16-one

[0616] To a stirred mixture of Ar-[(lR,2R)-2-[(5-amino-2-fluoro-4-methoxy-phenyl)methoxy]cyclopent}4]-5- chloro-7-[(4-methoxyphenyl)methyl-methyl-amino]imidazo[4,5-b]pyridine-3-carboxamide (220 mg, 0.377 mmol), K3PO4 (240 mg, 1.13 mmol) in dioxane (20 mL) was added EPhos (41 mg, 76.7 / / mol). EPhos Pd G4 (35 mg, 38.1 / / mol) and the mixture was stirred at 100 °C until complete by LCMS (1 hour) under N2 atmosphere. The resulting mixture was cooled to room temperature, partitioning with water (50 mL) and EtOAc. The reaction mixture was extracted with EtOAc (50 mL x 3). The combined organic layer was washed with brine (80 mL), dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 12 g AgelaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0~40%, flow rate = 30 mL / min, 254 mn). The desired product (10R,14R)-6-fluoro-4-methoxy-21-[(4-methoxyphenyl)methyl-methyl- amino] -9-oxa-2, 15 , 17, 19,23 -pentazapentacyclo [ 15.5.2.137.01014.02"-24]pentacosa- l(23).3(25).4,6,18,20(24),21-heptaen-16-one (130 mg, 59.9% yield) was obtained as a white solid. LCMS (ESI) m / z 547.4 [M+H]+.

[0617] Step 8: Synthesis of (10R,14R)-6-fluoro-4-methoxy-21-(methylamino)-9-oxa-2,15,17,19,23- pentazapentacyclo[15.5.2.13’7.010 14.020’24]pentacosa-l(23),3(25),4,6,18,20(24),21-heptaen-16-one

[0618] To a solution of TFA (230 mg, 2.02 mmol), triethylsilane (234 mg, 2.01 mmol) in dichloromethane (45 mL) was added ( 1 OR, 14R)-6-fluoro-4-methoxy-21 - [(4-methoxypheny l)methyl-methyl-amino] -9-oxa- 2.15,17.19,23-pentazapentacyclo[15.5.2.13>7.01014.020>24]pentacosa-l(23),3(25),4,6,18,20(24),21- heptaen-16-one (110 mg, 0.201 mmol) and the mixture was stirred at 20 °C for 1 h. Upon completion, the resulting mixture was quenched by addition of water (50 mL) and extracted with DCM (60 mL x 3). The combined organic layer was washed with brine (80 mL), dried over anhydrous Na2SC>4. 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—10%, flow rate = 20 inL / min, 254 mn) and then purified by reversed-phase HPLC (Column: SepaFlash® Spherical CIS, 25 g, 40-60 pm, 120A; MeCN / water with MeCN from 0-79%, 25 mL / min, 254 mn). The desired product ( 1 OR, 14R)-6-H uoro-4-inctho.xy -21 -(methy lamino)-9-oxa-2, 15,17,19,23- pentazapentacyclo[15.5.2.13,7.01014.020-24]penlacosa-l(23),3(25),4,6,18,20(24),21-heptaen-16-one (12.3 mg, 14.3% yield) was obtained as a white solid. LCMS (ESI) m / z 427.3 [M+H]+; *H NMR (400 MHz, DMSO-Je) <5 ppm 9.62 (d, J= 3.4 Hz. 1 H), 8.32 (s, 1 H), 8.20 (s, 1 H), 8.14 (d, J= 8.1 Hz. 1 H), 6.95 (d,J= 11.6 Hz, 1 H), 6.90 - 6.94 (m. 1 H), 6.15 (s, 1 H), 4.56 - 4.69 (m, 2 H), 3.88 (s. 3 H), 3.63 - 3.74 (m, 2 H), 2.86 (d, J = 4.8 Hz, 3 H). 2.31 - 2.39 (m, 1 H), 2.05 - 2.14 (m, 1 H), 1.69 - 1.79 (m. 1 H), 1.57 - 1.66 (m, 1 H). 1.46 - 1.55 (m, 1 H). 1.27 - 1.36 (m, 1 H).

[0619] Example 1188:: (10R,l 4R)-5-tluoro-4-methoxy-21 -(methylamino)-9-oxa-2,l 5,17,19,23- pentazapentacyclo[15.5.2.13’7.01014.020’24]pentacosa-l(23),3(25),4,6,18,20(24),21-heptaen-16-one

[0620] HN

[0621] > <X

[0622] N >

[0623] N if ll

[0624] N N F

[0625] H H o.

[0626] Step 1: Synthesis of 5-(bromomethyl)-l-fluoro-2-methoxy-3-nitro-benzene

[0627] NO2 / k AX

[0628] Br-

[0629] F

[0630] To a solution of l-fluoro-2-methoxy-5-methyl-3-nitro-benzene (3 g, 16.2 mmol) in CCL (30 mL) was added NBS (3.1 g. 17.4 mmol) and AIBN (1.3 g, 7.92 mmol) and the mixture was stirred at 80 °C for 12 h. The resulting mixture was cooled to room temperature and quenched by addition of a saturated Na2SOs aqueous solution (20 mL). Then the mixture was extracted with DCM (50 mL ' 3). The combined organic layer was dried over anhydrous Na2SC>4. filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage®; 20 g AgelaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0-10%. flow rate = 40 mL / min, 254 mn) to give 5- (bromomethyl)-l-fluoro-2-methoxy-3-nitro-benzene (2.4 g, 56.1% yield) as a colorless oil.!H NMR (400 MHz. DMSO-r / s) <5 ppm 7.90 (t, J= 1.8 Hz, 1H). 7.81 (dd, J= 12.0. 2.0 Hz, 1H). 4.73 (s, 2H), 3.99 (d, J = 2.0 Hz, 3H).

[0631] Step 2: Synthesis ooff tert-butyl N-[(lR,2R)-2-[(3-fhioro-4-methoxy-5-nitro- phenyl) methoxy] cyclopentyl] carbamate Boc HN

[0632] To a solution of tert-butyl N-[(lR,2R)-2-hydroxycyclopentyl]carbamate (1 g, 4.97 mmol) in THF (20 mL) was added portion-wise NaH (200 mg, 5.00 mmol, 60% weight in mineral oil) at 0°C. The mixture was stirred at 20 °C for 30 min. Then to the mixture was added 5-(bromomethyl)-l-fluoro-2-methoxy- 3-nitro-bcnzcnc (1.3 g, 4.92 mmol). The mixture was stirred at 20 °C for 1 h Upon completion, the resulting mixture was quenched by addition of water (30 mL) and extracted with EtOAc (30 mL ’ 3). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage®; 20 g AgelaFlash® Silica Flash Column, petroleum elher / ElOAc with EtOAc from 0~10%, flow rate = 40 mL / min, 254 mn) to give tert-butyl N-[(lR,2R)-2-[(3-fluoro-4-methoxy-5-nitro-phenyl)methoxy]cyclopentyl]carbamate (900 mg. 47.56% yield) as a yellow oil. LCMS (ESI) m / z 385.1 [M+H]+.

[0633] Step 3: Synthesis of (lR,2R)-2-[(3-fluoro-4-methoxy-5-nitro-phenyl)methoxy]cyclopentanamine tert-Butyl N-[(lR,2R)-2-[(3-fluoro-4-methoxy-5-nitro-phenyl)methoxy]cyclopentyl]carbamate (900 mg. 2.34 mmol) was dissolved in a solution of HC1 in dioxane (10 mL) and the reaction mixture was stirred at 20 °C for 1 h. The resulting mixture was quenched by addition of a saturated NaHCO;, aqueous solution (20 mL) and extracted with EtOAc (50 mL ' 3). The combined organic layer was dried over anhydrous Na2SO4, fdtered and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage®; 20 g AgelaFlash® Silica Flash Column. DCM / MeOH with MeOH from 0~10%. flow rate = 40 mL / min, 254 mn) to give (lR,2R)-2-[(3-fhioro-4-methoxy-5-nitro- phenyl)methoxy]cyclopentanamine (450 mg. 67.6% yield) as a yellow oil. LCMS (ESI) m / z 285.0 [M+H]+.

[0634] Step 4: Synthesis of 5-chloro-7-[(4-methoxyphenyl)methyl-methyl-amino]-N-[(lR,2R)-2-[(3- fluoro-4-methoxy-5-nitro-phenyl)methoxy]cydopentyl]imidazo[4,5-b]pyridine-3-carboxamide

[0635] A mixture of 5-chloro-N-[(4-methoxyphenyl)methyl]-N-methyl-3H-imidazo[4,5-b]pyridin-7-amine (350 mg, 1.16 mmol), phenyl carbonochloridate (0.14 mL, 1.12 mmol) and TEA (0.66 mL, 4.74 mmol) in THF (15 mL) was stirred at 20 °C for 1 h. To this mixture was added (lR,2R)-2-[(3-fluoro-4- methoxy-5 -nitro-pheny l)methoxy]cyclopentanamine (300 mg, 1.06 mmol) and stirred at 20 °C for 2 h. The resulting mixture was quenched by addition of water (30 mL) and extracted with EtOAc (30 mL ' 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage®; 20 g AgelaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0~20%, flow rate = 40 mL / min. 254 nm) to give 5-chloro-7-[(4-methoxyphenyl)methyl-methyl-amino]-N-[(lR.2R)-2-[(3-fluoro-4-methoxy-5- nitro-phenyl)methoxy]cyclopentyl]imidazo[4.5-b]pyridine-3-carboxamide (450 mg. 63.5% yield) as a yellow oil. LCMS (ESI) m / z 613.2 [M+H]+.

[0636] Step 5: Synthesis of 5-chloro-7-[(4-methoxyphenyl)methyl-methyl-amino]-N-[(lR,2R)-2-[(3- amino-5-fluoro-4-methoxy-phenyl)methoxy]cyclopentyl]imidazo[4,5-b]pyridine-3-carboxamide

[0637] A mixture of 5-chloro-7-[(4-methoxyphenyl)methyl-methyl-amino]-N-[(lR,2R)-2-[(3-fluoro-4- methoxy -5 -nitro-pheny l)methoxy] cyclopentyl] imidazo [4, 5 -b] pyridine -3 -carboxamide (430 m g, 0.701 mmol), Fe (200 mg, 3.58 mmol) and NH4CI (190 mg, 3.55 mmol) in EtOH (4 mL) and H2O (4 mL) was stirred at 80 °C for 1 h. The resulting mixture was filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage®; 20 g AgelaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0~34%, flow rate = 40 mL / min. 254 nm) to give 5-chloro-7- [(4-methoxyphenyl)methyl-methyl-amino]-N-[(lR,2R)-2-[(3-amino-5-fluoro-4-methoxy- phenyl)methoxy]cyclopentyl]imidazo[4,5-b]pyridine-3-carboxamide (270 mg. 66.0% yield) as a yellow oil. LCMS (ESI) m / z 583.2 [M+H]+.

[0638] Step 6: Synthesis of (10R,14R)-5-fluoro-4-methoxy-21-[(4-methoxyphenyl)methyI-methyI- amino]-9-oxa-2,15,17,19,23-pentazapentacyclo[15.5.2.13’7.01014.020’24]pentacosa-

[0639] 1 (23), 3(25), 4, 6, 18, 20(24), 21 -heptaen-16-one A mixture of 5-chloro-7-[(4-methoxyphenyl)methyl-methyl-amino]-N-[(lR,2R)-2-[(3-amino-5-fluoro- 4-mctho.xy-phcnyl)nicthoxy |cyclopcntyl |imidazo|4.5-b|pyridinc-3-carboxamidc (250 mg, 0.429 mmol), EPhos (50 mg. 0.0935 mmol), EPhos Pd G4 (40 mg, 0.0436 mmol) and K3PO4 (280 mg, 1.32 mmol) in dioxane (5 mL) was stirred at 100°C for 2 h under N2. The mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage®; 20 g AgelaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0~30%, flow rate = 40 mL / min. 254 nm) to give (1 OR, 14R)-5 -fluoro-4-methoxy-21 - [(4-methoxypheny l)methyl-methyl-amino] -9-oxa-

[0640] 2.15,17.19,23-pentazapentacyclo[15.5.2.13’7.010 14.020’24]pentacosa-l(23),3(25),4,6,18,20(24).21- heptaen- 16-one (150 mg, 64.0% yield) as a yellow oil. LCMS (ESI) m / z 547.1 [M+H]+.

[0641] Step 7: Synthesis of (10R,14R)-5-fluoro-4-methoxy-21-(methylamino)-9-oxa-2,15,17,19,23- pentazapentacyclo[15.5.2.13’7.01014.020’24]pentacosa-l(23),3(25),4,6,18,20(24),21-heptaen-16-one

[0642] To a solution of (10R,14R)-5-fluoro-4-methoxy-21-[(4-methoxyphenyl)methyl-methyl-amino]-9-oxa-

[0643] 2. 15. 17. 19.23-pcntazapcntacyclo| 15.5.2. 13.0l"l1.02l, 24|pcntacosa- l (23).3(25).4.6. 18.20(24).21 - heptaen- 16-one (70 mg, 0.128 mmol) in DCM (5 mL) was added triethylsilane (0.2 mL, 1.25 mmol) and TFA (0.1 mL, 1.35 mmol). The mixture was stirred at 20° C for 1 h. The mixture was 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: 1 Welch Xtimate C18 75 * 40 mm x 3pm; Mobile phase A: H2O with 0.05% NH4HCO3 (v%); Mobile phase B: MeCN; Gradient: B from 55% to 85% in 7.8 min, hold 100% B for 2 min; Flow Rate: 30 mL / min; Column Temperature: 30°C; Wavelength: 220 nm, 254 nm) to give (10R.14R)-5-fluoro-4-methoxy-21-(methylamino)-9-oxa-

[0644] 2.15.17.19.23-pentazapentacyclo[15.5.2.13’7.010 14.020’24]pentacosa-l(23),3(25),4,6,18,20(24).21- heptaen- 16-one (13.7 mg, 24.9% yield) as a white solid. LCMS (ESI) m / z 427.3 [M+H]+;1H NMR (400 MHz. DMSO-rfe) § ppm 9.61 (br s. 1H), 8.67 (s, 1H). 8.24 (s. 1H), 8.13 (s, 1H). 7.00 (q. J = 4.3 Hz, 1H), 6.74 (br d, J = 11.1 Hz, 1H), 6.27 (s. 1H), 4.72 (br d, J = 14.4 Hz. 1H), 4.34 (d, J = 14.4 Hz, 1H). 3.86 (s, 3H). 3.69 - 3.76 (m. 2H), 2.88 (d, J = 4.6 Hz. 3H), 2.30 - 2.38 (m. 1H), 2.12 (br d. J = 3.5 Hz, 1H). 1.69 - 1.79 (m, 1H), 1.56 - 1.65 (m. 1H), 1.42 - 1.52 (m. 1H), 1.28 - 1.39 (m, 1H). Example 19: 19-deuterio-4-methoxy-ll-methyl-18-(methylamino)-9-oxa-2,12,14,16,20- pentazatetracyclo[12.5.2.13,7.017,21]docosa-l(19),3,5,7(22),15,17,20-heptaen-13-one

[0645] Step 1: Synthesis of 19-bromo-4-methoxy-ll-methyl-18-(methylamino)-9-oxa-2,12,14,16,20- pentazatetracyclo[12.5.2.13,7.017,21]docosa-l(19),3,5,7(22),15,17,20-heptaen-13-one

[0646] A mixture of 4-methoxy-l l-methyl-18-(methylamino)-9-oxa-2,12.14,16.20- pentazatetracyclo[12.5.2.13,7.017,21]docosa-l(19),3,5,7(22),15,17.20-heptaen-13-one (100 mg, 0.262 mmol), CBr4(113 mg, 0.341 mmol) and t-BuONa (106 mg, 1.10 mmol) in DMF (5 mL) was degassed and pinged with nitrogen for 3 times, and then the mixture was stirred at 20 °C for 2 hr under nitrogen atmosphere. Upon completion, the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (50 mL ' 3). The combined organic phase was washed with brine (30 mL ' 3), dried over anhydrous Na2SO4, fdtcrcd and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Petroleum ether / EtOAc with EtOAc from 0~30%, flow rate = 40 mL / min, 254 mn) to afford 19-bromo-4-methoxy-ll-methyl-18- (methylamino)-9-oxa-2,12.14,16,20-pentazatetracyclo[12.5.2.13,7.017,21]docosa- l(19).3,5,7(22),15,17,20-heptaen-13-one (12 mg, 10.0% yield) as a yellow solid. LCMS (ESI) m / z 460.8, 462.8 [M+H]*.

[0647] Step 2: Synthesis of 19-deuterio-4-methoxy-ll-methyl-18-(methylamino)-9-oxa-2,12,14,16,20- pentazatetracyclo[12.5.2.13,7.017,21]docosa-l(19),3,5,7(22),15,17,20-heptaen-13-one 19-Bromo-4-methoxy- 11 -methyl- 18-(methylamino)-9-oxa-2, 12,14,16,20- pentazatetracyclo[12.5.2.13,7.017,21]docosa-l(19),3,5,7(22),15,17,20-heptaen-13-one (12 mg, 0.026 mmol), Pd2(dba)2(5 mg, 0.005 mmol), SPhos (7 mg, 0.017 mmol) and K2CO2(8 mg, 0.058 mmol) were taken up into a microwave tube in 2-propanol-D8 (3 mL). The sealed tube was heated at 100 °C for 1 hr under a microwave irradiation reaction condition. The mixture was filtered and concentrated under reduced pressure. The crude 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 urn; Mobile phase A: [water(NH4HCO3)-ACN] ;Mobile phase B: MeCN; Gradient: B from 45% to 75% in 8 min, hold 100% B for 2 min; Flow Rate: 25 mL / min; Column Temperature: 30 °C; Wavelength: 220 nm) ttoo afford 19-deuterio-4-methoxy-ll-methyl-18-(methylamino)-9-oxa- 2.12,14.16,20-pentazatetracyclo[12.5.2.13,7.017,21]docosa-l(19),3,5,7(22),15,17,20-heptaen-13-one (1 mg, 10.0% yield) as a white solid. LCMS (ESI) m / z 384.0 [M+HJ+;!H NMR (400 MHz, DMSO-de) § ppm 9.29 (d, J = 4.8 Hz. 1 H), 8.35 (s, 1 H), 8.20 (s. 1 H). 8.18 (d. J = 1.9 Hz, 1 H), 6.94 (d, J = 8.3 Hz, 1 H), 6.88 (br d, J = 4.9 Hz, 1 H), 6.80 (dd, J = 8.1, 1.8 Hz, 1 H), 4.59 (d, J = 13.5 Hz, 1 H), 4.35 (d. J = 13.5 Hz, 1 H). 3.88 - 3.94 (m, 1 H). 3.85 (s. 3 H), 3.45 - 3.50 (m. 1 H), 3.27 (br s, 1 H), 2.85 (d, J = 4.9 Hz, 3 H). 1 .18 (d, J = 6.5 Hz, 3 H).

[0648] Example 20: (61R,62R)-36-methoxy-17-(methylamino)-13H-5-oxa-2,7-diaza-l(5,3)-imidazo[4,5- b]pyridina-3(l,3)-benzena-6(l,2)-cyclobutanacyclooctaphan-8-one

[0649] (R), HN''V(R)

[0650] O.

[0651] N A

[0652] L n

[0653] N N H H

[0654] O.

[0655] Step 1: Synthesis of 4-(bromomethyI)-l-methoxy-2-nitrobenzene

[0656] NO2

[0657] Br

[0658] O'

[0659] A mixture of l-methoxy-4-methyl-2-nitro-benzene (10.0 g, 59.8 mmol), NBS (12.5 g, 70.2 mmol), AIBN (1.00 g. 6.09 mmol) in CCL (100 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 80 °C for 12 h undcrN2atmosphere. The reaction mixture was cooled to room temperature and quenched by diluting with H2O (200 mL) at 25 °C, extracted with EtOAc (200 mL ' 3). The combined organic lay ers were washed with brine (200 mL ' 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (Instrument; Gilson GX-281 Liquid Handler. Gilson 322 Pump, Gilson 156 UV Detector; Column; Welch Xtimate C18 150 x 25 mm * 5 pm; Mobile phase A; H2O with 0.05% NH3-H2O (v%); Mobile phase B: ACN; Gradient: B from 70% to 100% in 7.8 min, hold 100% B for 2 min; Flow Rate: 25 mL / min; Column Temperature: 30 °C; Wavelength: 220 nm). Compound 4-(bromomethyl)-l-methoxy- 2-nitro-benzene (7.8 g, 53.0% yield) was obtained as a white solid, ' l l NMR (400 MHz, DMSO-< / ,.) 8 ppm 7.99 (d, J = 2.3 Hz, 1 H), 7.74 (dd, J = 8.8, 2.3 Hz, 1 H), 7.36 (d, J = 8.8 Hz, 1 H), 4.74 (s, 2 H), 3.92 (s, 3 H).

[0660] Step 2: Synthesis of tert-butyl ((lR,2R)-2-((4-methoxy-3-nitrobenzyl)oxy)cyclobutyl)carbamate

[0661] H

[0662] Boc

[0663] To a solution of tert-butyl N-[(lR,2R)-2-hydroxycyclobutyl]carbamate (420 mg, 2.24 mmol) in DMF (5 mL) was added NaH (120 mg, 3.00 mmol, 60% dispersion in mineral oil) at 0 °C, then 4- (bromomethyl)-l-methoxy-2-nitro-benzene (600 mg, 2.44 mmol) was added. The mixture was stirred at 20 °C for 30 min. The reaction mixture was diluted 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 overNazSCL, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0 ~ 20%, flow rate: 40 mL / min, 254 nm). Compound tert-butyl N-[(lR,2R)-2-[(4-methoxy-3- nitro-phenyl)methoxy]cyclobutyl]carbamate (400 mg, 46.6% yield) was obtained as a white solid. LCMS (ESI) m / z 375.3 [M+Na]+.

[0664] Step 3: Synthesis of (lR,2R)-2-((4-methoxy-3-nitrobenzyl)oxy)cyclobutan-l-amine tert-Butyl N-[(lR,2R)-2-[(4-methoxy-3-nitro-phenyl)methoxy]cyclobutyl]carbamate (400 mg, 1.14 mmol) was dissolved in a solution of HC1 in dioxane (2N, 10 mL) and the reaction mixture was stirred at 20 °C for 12 h under N2atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. Compound (1R, 2R)-2-((4-methoxy-3-nitrobenzyl)oxy)cyclobutan- 1 -amine (290 mg, crude) was obtained as a white solid. LCMS (ESI) m / z 253.2 [M+H]+.

[0665] Step 4: Synthesis of 5-chloro-N-((lR,2R)-2-((4-methoxy-3-nitrobenzyI)oxy)cyclobutyl)-7-((4- methoxybenzyl)(methyl)amino)-3H-imidazo[4,5-b]pyridine-3-carboxamide

[0666] A mixture of 5-chloro-N-[(4-methoxyphenyl)methyl]-N-methyl-3H-imidazo[4.5-b]pyridin-7-amine (300 mg, 0.793 mmol), phenyl carbonochloridate (110 mg, 0.703 mmol), TEA (320 mg, 3.16 mmol) in THE (5 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 20 °C for 1 h under N2 atmosphere, then (lR,2R)-2-((4-methoxy-3-nitrobenzyl)oxy)cyclobutan-l-amine (240 mg.0.951 mmol) was added, the mixture was stirred at 20 °C for 1 h under N2atmosphere. 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 overNa2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography (ISCO®; 20 g SepaFlash®1Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0 ~ 40%, flow rate: 65 mL / min, 254 nm). Compound 5-chloro-N-((lR,2R)-2-((4-methoxy-3-nitrobenzyl)oxy)cyclobutyl)-7- ((4-methoxybenzyl)(methyl)amino)-3H-imidazo[4.5-b]pyridine-3-carboxamide (440 mg. 43.0% yield) was obtained as a white solid. LCMS (ESI) m / z 581.3 [M+H]+.

[0667] Step 5: Synthesis of N-((lR,2R)-2-((3-amino-4-methoxybenzyl)oxy)cyclobutyl)-5-chloro-7-((4- methoxybenzyl)(methyl)amino)-3H-imidazo[4,5-b]pyridine-3-carboxamide

[0668] A mixture of 5-chloro-N-((lR,2R)-2-((4-methoxy-3-nitrobenzyl)oxy)cyclobutyl)-7-((4- methoxybenzyl)(methyl)amino)-3H-imidazo[4,5-b]pyridine-3-carboxamide (430 mg, 0.740 mmol), Fe (205mg, 3.67 mmol), NH4C1 (205mg, 3.84 mmol) in EtOH (5 mL) and H2O (5 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 80 °C for 30 min under N2atmosphere. 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 from 0 ~ 40%, flow rate: 65 mL / min, 254 nm). Compound N-((1R, 2R)-2-((3-amino-4- methoxybenzyl)oxy)cyclobutyl)-5-chloro-7-((4-methoxybenzyl)(methyl)amino)-3H-imidazo[4.5- b]pyridine-3-carboxamide (400 mg, 55.9% yield) was obtained as a white solid. LCMS (ESI) m / z 573.3 [M+Na]+.

[0669] Step 6: Synthesis of (61R,62R)-36-methoxy-17-((4-methoxybenzyl)(methyl)amino)-13H-5-oxa- 2,7-diaza-l(5,3)-imidazo[4,5-b]pyridina-3(l,3)-benzena-6(l,2)-cyclobutanacyclooctaphan-8-one

[0670] A mixture of N-((lR,2R)-2-((3-amino-4-methoxybenzyl)oxy)cyclobutyl)-5-chloro-7-((4- methoxybenzyl)(methyl)amino)-3H-imidazo[4,5-b]pyridine-3-carboxamide (390 mg, 0.425 mmol), EPhos (24.0 mg, 44.9 pmol). EPlios Pd G4 (46.0 mg, 50.1 pmol) and K3PO4 (175 mg, 0.824 mmol) in dioxane (10 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 100 °C until complete by LCMS (~ 2 h) under N2atmosphere. The reaction mixture was quenched by addition of 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 Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography (ISCO®: 20 g SepaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0 ~ 20%, flow rate: 65 mL / min, 254 nm). Compound (61R, 62R)-36-methoxy-17-((4-methoxybenzyl)(methyl)amino)-13H-5-oxa-2,7- diaza-l(5,3)-imidazo[4,5-b]pyridina-3(l,3)-benzena-6(l,2)-cyclobutanacyclooctaphan-8-one (52 mg, 23.8% yield) was obtained as a white solid. LCMS (ESI) m / z 515.4 [M+H]+.

[0671] Step 7: Synthesis of (61R, 62R)-36-methoxy-17-(methylamino)-13H-5-oxa-2,7-diaza-l(5,3)- imidazo[4,5-b]pyridina-3(l,3)-benzena-6(l,2)-cyclobutanacycIooctaphan-8-one

[0672] (R).

[0673] HN'"V(R)

[0674] N

[0675] N

[0676] H H

[0677] O.

[0678] A mixture of (61R, 62R)-36-methoxy-17-((4-methoxybenzyl)(methyl)amino)-13H-5-oxa-2.7-diaza- l(5.3)-imidazo[4,5-b]pyridina-3(l,3)-benzena-6(l,2)-cyclobutanacyclooctaphan-8-one (50.0 mg, 97.2 pmol), TEA (110 mg, 0.965 mmol), triethylsilane (60.0 mg. 0.516 mmol) in DCM (5 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 20 °C for 30 min under N2atmosphere. The mixture was diluted with water (lOmL) and a sat. sodium bicarbonate aqueous solution was added until pH ~ 7. then extracted with EtOAc (10 mL ' 3). The combined organic layers were washed with brine (10 mL ' 3), dried over anhydrous NazSCL, 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 C18 150 x 25 mm x 5 gm; Mobile phase A: H2O with 0.05% NH4HCO3 (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 °C; Wavelength: 220 mn). Compound (61R, 62R)-36-methoxy-17-(methylamino)-13H-5-oxa-2,7-diaza-l(5,3)-imidazo[4,5- b]pyridina-3(l,3)-benzena-6(l,2)-cyclobutanacyclooctaphan-8-one (5.00 mg, 13.1% yield) was obtained as a white solid. LCMS (ESI) m / z 395.3 [M+H]1; *H NMR (400 MHz, DMSO-<4) 3 ppm 9.96 (d, J = 3.8 Hz, 1 H). 8.28 (s. 1 H), 8.17 (s, 1 H), 7.99 (d, J = 1.8 Hz, 1 H), 7.02 (d, J = 8.3 Hz. 1 H), 6.92 (d. J = 4.8 Hz, 1 H), 6.83 (dd, J = 8.3, 2.0 Hz, 1 H). 6.16 (s, 1 H), 4.63 (d, J= 13.8 Hz, 1 H), 4.45 - 4.52 (m. 1 H), 3.86 (s, 3 H), 3.84 - 3.93 (m, 1 H), 3.71 - 3.79 (m, 1 H), 2.86 (d, J = 4.8 Hz, 3 H), 2.05 - 2.14 (m. 2 H), 1.62 (br t, J= 10.2 Hz, 1 H), 1.25 - 1.30 (m. 1 H).

[0679] Example 21 : (10R,l 4R)-4-methoxy-21 -(methylamino)-9-oxa-2,l 5,17,19,23- pentazapentacyclo [15.5.2.13, 7.010,14.020, 24]pentacosa-l(23), 3, 5, 7(25), 18, 20(24), 21-heptaen-16- one

[0680] N

[0681] N

[0682] H H

[0683] O.

[0684] Step 11:: Synthesis of tert-butyl N- [(lR,2R)-2- [(4-methoxy-3-nitro- phenyl) methoxy] cyclopentyl] carbamate

[0685] To a solution of 4-(bromomethyl)-l-methoxy-2-nitro-benzene (2 g, 8.13 mmol) in DMF (20 mL) was added portion-wise NaH (488 mg, 12.2 mmol, 60% by weight in mineral oil) at 0 °C. After addition, the mixture was stirred aatt 0 °C for 5 min, and then tert-butyl N-[(lR,2R)-2- hydroxycyclopcntyl [carbamate (1.80 g, 8.94 mmol) was added dropwise at 0 °C. The resulting mixture was stirred at 20 °C for 3 h. The mixture was diluted with a sat. NH4C1 aqueous solution (30 mL) and extracted with EtOAc (50 mL ' 3). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCCJ K : 40 g SepaFlash® Silica Flash Column, Petroleum ether / EtOAc with EtOAc from 0~20%, flow rate = 40 mL / min, 254 nm) to afford tert-butyl N-[(lR,2R)-2-[(4-methoxy-3-nitro- phenyl)methoxy]cyclopentyl]carbamate (1 g, 33.6% yield) as a yellow solid. LCMS (ESI) m / z 367.1 [M+H]+.

[0686] Step 2: Synthesis of (lR,2R)-2-[(4-methoxy-3-nitro-phenyl)methoxy]cyclopentanamine

[0687] Dissolved tert-butyl N-[(lR,2R)-2-[(4-methoxy-3-nitro-phenyl)methoxy]cyclopentyl]carbamate (1 g, 2.73 mmol) in a solution of HC1 in dioxane (6 mb), was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 20 °C for 2 h under nitrogen atmosphere. The mixture was concentrated under reduced pressure. Compound (lR,2R)-2-[(4-methoxy-3-nitro- phenyl)methoxy]cyclopentanamine (1 g, crude) was obtained as a yellow oil and was taken directly to the next reaction . LCMS (ESI) m / z 266.9 [M+H]+.

[0688] Step 3: Synthesis of 5-chloro-7-[(4-methoxyphenyl)methyl-methyl-amino]-N-[(lR,2R)-2-[(4- methoxy-3-nitro-phenyl)methoxy]cyclopentyl]imidazo[4,5-b]pyridine-3-carboxamide

[0689] A mixture of 5-chloro-N-[(4-methoxyphenyl)methyl]-N-methyl-3H-imidazo[4,5-b]pyridin-7-amine (800 mg, 2.64 mmol), pheny l carbonochloridate (414 mg, 2.64 mmol) and TEA (560 mg, 5.53 mmol), in THE (15 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 20 °C for 2 h under nitrogen atmosphere. The mixture was concentrated under reduced pressure. Compound pheny l 5-chloro-7-[(4-methoxyphenyl)methyl-methyl-amino]imidazo[4,5-b]pyridine-3- carboxylate (1.2 g. crude) was obtained as a yellow oil.

[0690] A mixture of phenyl 5-chloro-7-[(4-methoxyphenyl)methyl-methyl-amino]imidazo[4,5-b]pyridine-3- carboxylate (1.20 g. 2.84 mmol), (lR,2R)-2-[(4-methoxy-3-nitro-phenyl)methoxy]cyclopentanamine (906 mg, 3.4 mmol) and TEA (601 mg, 5.94 mmol) in THE (10 mL) was degassed and pinged with nitrogen for 3 times, and then the mixture was stirred at 20 °C for 2 h imder nitrogen atmosphere. The mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL ' 3). The combined organic phase was washed with brine (30 mL ' 3), dried over anhydrous Na2SO i. 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 mn) to afford compound 5-chloro-7-[(4-methoxypheny l)methy 1-methy 1-amino] -N-[(1R, 2R)-2-[(4-methoxy-3- nitro-phenyl)methoxy]cyclopentyl]imidazo[4.5-b]pyridine-3-carboxamide (850 mg. 50.3% yield) as a yellow oil. LCMS (ESI) m / z 595.1 [M+H]+.

[0691] Step 4: Synthesis of 5-chloro-7-[(4-methoxyphenyl)methyl-methyl-amino]-N-[(lR,2R)-2-[(3- amino-4-methoxy-phenyl)methoxy]cyclopentyl]imidazo[4,5-b]pyridine-3-carboxamide

[0692] A mixture of 5-chloro-7-[(4-methoxyphenyl)methyl-methyl-amino]-N-[(lR,2R)-2-[(4-methoxy-3- nitro-phenyl)methoxy]cyclopentyl]imidazo[4,5-b]pyridine-3-carboxamide (850 mg, 1.43 mmol), Fe (400 mg, 7.16 mmol) and NH4C1 (765 mg. 14.3 mmol) in EtOH (10 mL) and H2O (2 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 80 °C for 2 h under nitrogen atmosphere. The mixture was 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 0~35%, flow rate = 40 mL / min, 254 mn) to afford 5-chloro-7-[(4- methoxyphenyl)methy 1-methy 1-amino] -N- [(1 R,2R)-2-[(3 -amino-4-methoxy- phenyl)methoxy]cyclopentyl]imidazo[4,5-b]pyridine-3-carboxamide (700 mg, 86.7% yield) as a yellow oil. LCMS (ESI) m / z 565.1 [M+H]+.

[0693] Step 5: Synthesis of (10R,14R)-4-methoxy-21-[(4-methoxyphenyl)methyl-methyl-amino]-9-oxa- 2, 15, 17, 19,23- pentazapentacyclo[15.5.2.13, 7.010, 14.020, 24]pentacosa-

[0694] 1 (23), 3, 5, 7(25), 18, 20(24), 21 -heptaen-16-one

[0695] HN" (R) (R)

[0696] N

[0697] PMB H

[0698] 0.

[0699] A mixture of 5-chloro-7-[(4-methoxyphenyl)methyl-methyl-amino]-N-[(lR,2R)-2-[(3-amino-4- methoxy -phenyl)niethoxy]cyclopentyl]imidazo[4,5-b]pyridine-3-carboxamide (700 mg, 1.24 mmol), EPhos (133 mg, 0.249 mmol), EPhos Pd G4 (114 mg, 0.124 mmol) and K3PO4 (665 mg, 3.13 mmol) in dioxane (10 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 100 °C for 2 h under nitrogen atmosphere. The mixture was diluted with water (50 mL) and extracted with ElOAc (50 mL ' 3). The combined organic phase was washed with brine (30 mL ' 3), dried over anhydrous Na2SC>4, 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 0~40%, flow rate = 40 mL / min. 254 nm) to afford (10R.14R)-4-methoxy-21-[(4- methoxyphenyl)methyl-methyl-amino] -9-oxa-2.15,17.19,23- pentazapentacyclo[15.5.2.13.7.010.14.020,24]pentacosa-l(23).3.5.7(25),18,20(24),21-heptaen-16-one (300 mg, 45.8% yield) as a yellow solid. LCMS (ESI) m / z 529.2 [M+H]+.

[0700] Step 8: Synthesis of (10R,14R)-4-methoxy-21-(methylamino)-9-oxa-2,15,17,19,23- pentazapentacyclo[15.5.2.13, 7.010,14.020, 24]pentacosa-l(23), 3, 5, 7(25), 18, 20(24), 21-heptaen-16- one

[0701] To a solution of (10R,14R)-4-methoxy-21-[(4-methoxyphenyl)methyl-methyl-amino]-9-oxa- 2.15, 17.19, 23-pentazapentacyclo[15.5.2.13.7.010, 14.020, 24]pentacosa-l(23), 3, 5, 7(25), 18.20(24), 21- heptaen- 16-one (130 mg. 0.246 mmol) in THF (30 mL) was added Pd / C (260 mg, 0.244 mmol, 10 wt% Pd with 50wt% water) under nitrogen atmosphere. The suspension was degassed and purged with a hydrogen gas for 3 times. The mixture was stirred under hydrogen (15 psi) at 20 °C until complete by LCMS, f~ 12 h. The mixture was Filtered and concentrated under reduced pressure. The crude product mixture 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(NH4HCO3)-ACN];Mobile phase B: MeCN; Gradient: B from 50% to 80% in 8 min, hold 100% B for 2 min; Flow Rate: 25 mL / min; Column Temperature: 30 °C; Wavelength: 220 nm) to afford (10R,14R)-4-methoxy-21-(methylamino)-9-oxa-2,15,17,19,23- pentazapentacyclo[15.5.2.13,7.010,14.020,24]pentacosa-l (23),3,5,7(25),18.20(24),21 -heptaen-16-one (28.3 mg, 28.2% yield) as a white solid. LCMS (ESI) m / z 409.0 [M+H]+; *H NMR (400 MHz, DMSO- de) 8 ppm 9.68 (d, J = 3.3 Hz, 1 H). 8.33 (s, 1 H), 8.19 (s, 1 H), 8.13 (d, J = 1.4 Hz, 1 H), 6.96 (d, J = 8.1 Hz, 1 H), 6.91 (br d, J= 4.9 Hz, 1 H), 6.82 (dd, J= 8.1, 1.5 Hz, 1 H). 6.17 (s, 1 H), 4.74 (d, J= 13.8 Hz, 1 H), 4.32 (d, J= 13.8 Hz, 1 H), 3.86 (s, 3 H), 3.62 - 3.73 (m, 2 H), 2.86 (d, J = 4.8 Hz, 3 H), 2.27 - 2.37 (in, 1 H), 2.08 (dt, J = 7.9, 3.7 Hz, 1 H), 1.67 - 1.77 (m, 1 H), 1.53 - 1.63 (m, 1 H), 1.40 - 1.50 (m, 1 H), 1.21 - 1.32 (in, 1 H).

[0702] Example 22: (10R,l 5R)-4-methoxy-22-(methylamino)-9-oxa-2,l 6,18,20,24- pentazapentacyclo[16.5.2.137.01015.0212S]hexacosa-l(24),3,5,7(26),19,21(25),22-heptaen-17-one

[0703] N

[0704] N H H

[0705] O

[0706] Step 11:: Synthesis of tert-butyl N-[(lR,2R)-2-[(4-methoxy-3-nitro- phenyl)methoxy] cyclohexyl] carbamate

[0707] To a solution of tert-buty l N-[(lR,2R)-2-hydroxycyclohexyl]carbamate (890 mg, 4.13 mmol) in DMF (10 mL) was added NaH (240 mg, 6.00 mmol, 60% by weight in mineral oil) at 0 °C. Then 4- (bromomethyl)-l -mctlioxy-2-nitro-benzene (1 g, 4.06 mmol) was added. The mixture was stirred at 20 °C for 1 hr. The reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (100 mL ' 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous NazSCL, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 20 g AgclaFlash® Silica Flash Column, petroleum cthcr / EtOAc with EtOAc from 0~30%, flow rate = 35 mL / min, 254 nm) to afford tert-buty l N-[(lR,2R)-2-[(4-methoxy-3-nitro- phenyl)methoxy]cyclohexyl]carbamate (900 mg, 51.2% yield) as a yellow oil. LCMS (ESI) m / z 381.3 [M+H]+.

[0708] Step 2: Synthesis of (lR,2R)-2-[(4-methoxy-3-nitro-phenyl)methoxy]cyclohexanamine O2N

[0709] O

[0710] ADissolved tert-butyl N-[(fR,2R)-2-[(4-methoxy-3-nitro-phenyl)methoxy]cyclohexyl]carbamate (900 mg, 2.37 mmol) in a solution of HC1 in dioxane. The resulting mixture (10 mL) was stirred at 20 °C for 2 h. The reaction mixture was concentrated under reduced pressure to afford (lR.2R)-2-[(4-methoxy- 3-nitro-phenyl)methoxy]cyclohexanamine (700 mg, crude) as a yellow solid which was taken directly to the next step without further purification. LCMS (ESI) m / z 281.3 [M+H]+.

[0711] Step 3: Synthesis of 5-chloro-N-[(lR,2R)-2-[(4-methoxy-3-nitro-phenyI)methoxy]cyclohexyl]-7- [(4-methoxyphenyl)methyI-methyI-amino]imidazo[4,5-b]pyridine-3-carboxamide

[0712] To a solution of 5-chloro-N-[(4-methoxyphenyl)methyl]-N-methyl-3H-imidazo[4,5-b]pyridin-7-amine (400 mg, 1.32 mmol) in THE (5 mL) was added TEA (0.55 mL, 3.95 mmol) and phenyl carbonochloridate (248 mg, 1.59 mmol). The mixture was stirred at 20 °C for 2 h. Compound phenyl 5-chloro-7-[(4-methoxyphenyl)methyl-methyl-amino]imidazo[4,5-b]pyridine-3-carboxylate (558 mg, in 5 mL THF) was obtained as a white liquid. The crude product mixture was used in next step without further purification.

[0713] To a solution of phenyl 5-chloro-7-[(4-mcthoxy phcnyl)mcthyl-mcthyl-amino]imidazo[4,5-b]pyridinc- 3-carboxylate (550 mg, i inn 5 mL THF) and (lR,2R)-2-[(4-methoxy-3-nitro- phenyl)methoxy]cyclohexanamine (364 mg, 1.30 mmol) in THF (5 mL) was added TEA (0.362 mL, 2.60 mmol). The mixture was stirred at 20 °C for 12 h. The resulting mixture was quenched with H2O (50 mL) and extracted with EtOAc (100 mL ' 3). The combined organic layer was washed with a saturated NH4CI aqueous solution (100 mL), brine (100 mL), dried over anhydrous Na?SO i. 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 0~28%, flow rate = 35 mL / inin. 254 nm) ttoo afford 5-chloro-N-[(fR,2R)-2-[(4-methoxy-3-nitro- phenyl)methoxy]cyclohexyl]-7-[(4-methoxyphenyl)methyl-methyl-amino]imidazo[4,5-b]pyridine-3- carboxamide (500 mg, 31.6% yield, 50% purity) as a white solid. LCMS (ESI) m / z 609.1 [M+H]+.

[0714] Step 5: Synthesis of N-[(lR,2R)-2-[(3-amino-4-methoxy-phenyl)methoxy]cyclohexyl]-5-chloro-7-

[0715] [(4-methoxyphenyl)methyl-methyl-amino]imidazo[4,5-b]pyridine-3-carboxamide

[0716] To a mixture of 5-chloro-N-[(lR,2R)-2-[(4-methoxy-3-nitro-phenyl)methoxy]cyclohexyl]-7-[(4- methoxyphenyl)methyl-methyl-amino]imidazo[4,5-b]pyridine-3-carboxamide (400 mg, 0.657 mmol) in EtOH (10 mL) and H2O (2 mL) was added Fe (367 mg, 6.57 mmol) and NHiCl (351 mg, 6.57 mmol). The mixture was stirred at 80 °C for 2 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 20 g AgelaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0~28%, flow rate = 35 mL / min, 254 nm). The crude product was purified by reversed-phase HPLC (column: Welch Xtimate C18 150 ’ 25 mm ' 5 um; mobile phase: [water (NEEFfOl-ACN] ; gradient: 70%- 100% B over 9.5 min) to afford N-[(lR,2R)-2-[(3-amino-4-methoxy-phenyl)methoxy]cyclohexyl]-5-chloro-7-[(4- methoxyphenyl)methyl-methyl-amino|imidazo|4,5-b|pyridine-3-carboxamide (130mg, 33.8% yield) as a white solid. LCMS (ESI) m / z 579.3 [M+H]+.

[0717] Step 6: Synthesis of (10R,15R)-4-methoxy-22-[(4-methoxyphenyl)methyl-methyl-amino]-9-oxa- 2,16,18, 20, 24-pentazapentacyclo[16.5.2.13’7.01015.02125]hexacosa-l(24),3, 5,' 7(26), 19, 21(25), 22- heptaen-17-one

[0718] N

[0719] H PMB O.

[0720] To a stirred mixture of N-[(lR,2R)-2-[(3-amino-4-methoxy-phenyl)methoxy]cyclohexyl]-5-chloro-7- [(4-methoxyphenyl)methyl-methyl-amino]imidazo[4,5-b]pyridine-3-carboxamide (120 mg, 0.207 mmol) in dioxane (5 mL) was added EPhos Pd G4 (19.0 mg, 20.7 pmol), K3PO4 (110 mg, 0.518 mmol) and EPhos (22 mg, 41.1 pmol). The mixture was stirred at 100 °C for 2 h. The reaction mixture was cooled to room temperature and diluted with H2O (50 mL) and extracted with EtOAc (100 mL ' 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO i. filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 12 g AgelaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0~33%, flow rate = 30 mL / min, 254 nm) to afford (10R,15R)-4-methoxy-22-[(4-methoxyphenyl)methyl- methyl-amino]-9-oxa-2,16.18,20,24-pentazapentacyclo[16.5.2.13 7.0l l) 15.021 >25]hexacosa- l(24).3,5,7(26),19,21(25),22-heptaen-17-one (HO mg. 97.8% yield) as a white solid. LCMS (ESI) m / z 543.2 [M+H]+.

[0721] Step 7: Synthesis ooff (10R,15R)-4-methoxy-22-(methylamino)-9-oxa-2,16,18,20,24- pentazapentacyclo[16.5.2.13’7.01015.021'2S]hexacosa-l(24),3,5,7(26),19,21(25),22-heptaen-17-one

[0722] A mixture of (10R.15R)-4-methoxy-22-[(4-methoxyphenyl)methyl-methyl-amino]-9-oxa- 2,16,18,20,24-pentazapentacyclo[16.5.2.13’7.0lci l5.021-25]hexacosa-l(24).3,5,7(26),19,21(25),22- heptaen-17-one (110 mg, 0.203 mmol), Pd / C (240 mg, 10 wt% Pd with 50 wt% water) in THF (8 inL) was degassed and purged with H2for 3 times, and then the mixture was stirred at 20 °C for 12 h under H2(15 psi). The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 12 g AgelaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0~65%, flow rate = 30 mL / min, 254 nm). The residue was purified by flash chromatography (Biotage®, Column; SepaFlash®Sphercial Cis, 40 g, 40-60 pm. 120A; MeCN / water (0.05v%NH3-H20) with MeCN from 0~60%, 30 mL / min, 254 nm) to afford (10R,15R)- 4-methoxy-22-(methylamino)-9-oxa-2,16,18,20,24- pentazapentacyclo[16.5.2.13’7.010 15.021’25]hexacosa-l(24),3,5.7(26),19,21(25),22-heptaen-17-one (15.2 mg. 17.8% yield) as a white solid. LCMS (ESI) m / z 423.2 [M+H] ’H NMR (400 MHz, DMSO-rL) 8 ppm 9.34 (d, J = 5.3 Hz. 1 H), 8.41 (s, 1 H), 8.20 (d, J = 1.8 Hz. 1 H), 8.19 (s, 1 H), 6.86 - 6.94 (m, 2 H), 6.83 (dd, J = 8.1, 1.8 Hz. 1 H). 6.12 (s, 1 H), 4.39 - 4.64 (m. 2 H), 3.85 (s, 3 H), 3.47 - 3.54 (m. 1 H), 3.04 (td. J = 9.9. 3.9 Hz, 1 H), 2.85 (d, J = 4.9 Hz. 3 H), 2.27 - 2.42 (m. 2 H), 1.47 - 1.75 (m. 2 H), 0.77 - 1.35 (m, 4 H).

[0723] Example 23: (llR)-ll-methyl-18-(methylamino)-5-(2-methyltriazoI-4-yl)-9-oxa-2,12,14,16,20- pentazatetracyclo[12.5.2.13’7.017’21]docosa-l(19),3,5,7(22),15,17,20-heptaen-13-one

[0724] Step 1: Synthesis of (2-methyltriazol-4-yl)boronic acid

[0725] To a solution of 4-bromo-2-methyl-triazole (2.0 g, 12.3 mmol) in THF (20 mb) was added dropwise 1.3M i-PrMgCl-LiCl (11.5 mL) at 0 °C. After addition, the mixture was stirred at 0 °C for 2 hrs, and then trimethyl borate (1.95 g, 18.7 mmol) in THF (5.0 mL) was added dropwise at -20 °C. The resulting mixture was stirred at 20 °C for 1 hr under N2atmosphere. The reaction mixture was diluted with a saturated NH4C1 aqueous solution (100 mL). and adjusted to pH ~ 5 with an aqueous HC1 solution, then extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na2SO i. filtered and concentrated under reduced pressure. The desired product (2-methyltriazol-4-yl)boronic acid (935 mg, crude) was obtained as a white solid. LCMS (ESI) m / z 128.0 [M+H]+.

[0726] Step 2: Synthesis of [3-(2-methyItriazol-4-yl)-5-nitro-phenyl]methanol

[0727] To a stirred mixture of (3-bromo-5-nitro-phenyl)methanol (1.4 g, 6.03 mmol). (2 -methyltriazol -4- yljboronic acid (918 mg, 7.23 mmol) in dioxane (20 mL) and H2O (2.0 mL) was added Pd(dppf)C12 (221 mg, 0.302 mmol), K2CO3 (2.08 g, 15.1 mmol) and the mixture was stirred at 100 °C for 3 h under N2atmosphere. The resulting mixture was quenched by addition of water (100 mL) and extracted with EtOAc (100 mL x 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®; 20g AgelaFlash® Silica Flash Column, petroleum elher / EtOAc with EtOAc from 0~40%, flow rate = 40 mL / min. 254 mn). The desired product [3-(2-methyltriazol-4-yl)-5-nitro- phcnyl |mclhanol (640 mg, 40.8% yield) was obtained as a white solid. LCMS (ESI) m / z 235.2 [M+H]+.

[0728] Step 3: Synthesis of 4-[3-(bromomethyl)-5-nitro-phenyl]-2-methyl-triazole

[0729] To a solution of [3-(2-methyltriazol-4-yl)-5-nitro-phenyl]methanol (600 mg, 2.56 mmol) in DCM (20 mL) was added PPI13 (1.01 g, 3.84 mmol), CBr i (1.10 g, 3.33 mmol) and the mixture was stirred at 20 °C for 1 h under N2 atmosphere. The resulting mixture was quenched by addition of water (50 mL) and extracted with EtOAc (60 mL x 3). The combined organic layer was washed with brine (80 mL), dried over anhydrous Na2SC>4, 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 0~30%, flow rate = 30 mL / min. 254 nm). The desired product 4-[3- (bromomethyl) -5 -nitro-phenyl] -2-methyl-triazole (600 mg. 78.8% yield) was obtained as a white solid. ' H NMR (400 MHz. DMSO-de) 8 ppm 8.57 (d, J= 1.8 Hz, 1 H). 8.50 (s, 1 H), 8.40 (s, 1 H). 8.34 (s. 1 H), 4.92 (s, 2 H), 4.26 (s. 3 H).

[0730] Step 4: Synthesis of tert-butyl / V-[(lR)-l-methyl-2-[[3-(2-methyltriazol-4-yl)-5-nitro- phenyl] methoxy] ethyl] carbamate

[0731] To a solution of 4-[3-(bromomethyl)-5-nitro-phenyl]-2-methyl-triazole (580 mg, 1.95 mmol), tert-butyl A-[(lR)-2-hydroxy-l-methyl-ethyl]carbamate (411 mg. 2.35 mmol) in THF (15 mL) was added IM t- BuOK in THF (2.34 mL, 2.34 mmol) at 0 °C and the mixture was stirred at 20 °C for 15 min. The resulting mixture was quenched by addition of water (60 mL) and extracted with EtOAc (60 mL x 3). The combined organic layers were washed with brine (80 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, petroleum ether / EtOAc with EtOAc from 0~40%. flow rate = 30 mL / min, 254 nm). The desired product tert-butyl A-[(lR)-l-methyl-2-[[3-(2-methyltriazol-4-yl)-5- nitro-phenyl]methoxy]ethyl]carbamate (620 mg, 78.6% yield) was obtained as a yellow oil. LCMS (ESI) m / z 414.3 [M+Na]+.

[0732] Step 5: Synthesis of (2R)-l-[[3-(2-methyltriazol-4-yl)-5-nitro-phenyl]methoxy]propan-2-amine

[0733] A mixture of tert-butyl Ar-[(lR)-l-methyl-2-[[3-(2-methyltriazol-4-yl)-5-nitro- phenyl]methoxy]ethyl]carbamate (620 mg, 1.58 mmol) in 2M HO in dioxane (15 mL) was stirred at 20 °C for 30 min. Upon completion, the reaction mixture was concentrated under reduced pressure to remove solvent. The desired product (2R)-l-[[3-(2-methyltriazol-4-yl)-5-nitro- phenyl]methoxy]propan-2-amine (460 mg, crude) was obtained as a yellow solid. LCMS (ESI) m / z 292.3 [M+H]+.

[0734] Step 6: Synthesis of 5-chloro-7-[(4-methoxyphenyl)methyl-methyl-amino|-A'-[(1 R)-l-methyl-2- [[3-(2-methyltriazol-4-yl)-5-nitro-phenyl]methoxy]ethyl]imidazo[4,5-b]pyridine-3-carboxamide

[0735] To a solution of 5-chloro-Ar-[(4-methoxyphenyl)methyl]-Ar-methyl-3H-imidazo[4,5-b]pyridin-7-amine (300 mg, 0.991 mmol), phenyl carbonochloridate (125 mg, 0.798 mmol) in THE (15 mL) was added TEA (401 mg, 3.96 mmol) and the mixture was stirred at 20 °C for 1 hr. The resulting mixture of phenyl 5-chloro-7-[(4-methoxyphenyl)methyl-methyl-amino]imidazo[4,5-b]pyridine-3-carboxylate (400 mg, crude in solution) as yellow liquid was used directly for the next reaction.

[0736] To a solution of phenyl 5-chloro-7-[(4-methoxyphenyl)methyl-methyl-amino]imidazo[4,5-b]pyridine- 3-carboxylate (400 mg, 0.946 mmol), (2R)-l-[[3-(2-methyltriazol-4-yl)-5-nitro- phenyl]methoxy]propan-2 -amine (290 mg, 0.996 mmol) in THE (10 mL) was added TEA (300 mg, 2.96 mmol) and tire mixture was stirred at 20 °C for 12 hrs. The resulting mixture was quenched with water (50 mL) and extracted with EtOAc (60 mL x 3). The combined organic layer was washed with brine (100 mL). dried over anhydrous Na2SCL, filtered and concentrated under reduced pressure. The residue 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 mn). The desired product 5-chloro- 7-[(4-methoxyphenyl)methyl-methyl-amino]-A-[(lR)-l-methyl-2-[[3-(2-methyltriazol-4-yl)-5-nitro- phenylJmethoxy]ethyl]imidazo|4,5-b]pyridine-3-carboxamide (270 mg, 46.0% yield) was obtained as a yellow solid. LCMS (ESI) m / z 620.3 [M+H]+.

[0737] Step 7: Synthesis of 5-chloro-7-[(4-methoxyphenyl)methyl-methyl-amino]-A-[(lR)-2-[[3-amino-

[0738] 5-(2-methyltriazol-4-yl)phenyl]methoxy]-l-methyl-ethyl]imidazo[4,5-b]pyridine-3-carboxamide

[0739] To a solution of 5-chloro-7-[(4-methoxyphenyl)methyl-methyl-amino]-jV-[(lR)-l-methyl-2-[[3-(2- methyltriazol-4-yl)-5-nitro-phenyl]methoxy]ethyl]imidazo[4.5-b]pyridine-3-carboxamide (270 mg, 0.435 mmol) in EtOH (20 mL) and H2O (2.0 mL) was added Fe (122 mg, 2.18 mmol), NH4CI (117 mg, 2.19 mmol) and the mixture was stirred at 80 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by flash chromatography (ISCO®; 12 g AgelaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0~60%, flow rate = 30 mL / min, 254 nm). The desired product 5-chloro-7-|(4-mctlioxyplienyl)metliyl-methyl-ainino|- / V-|(I R)- 2-[[3-amino-5-(2-methyltriazol-4-yl)phenyl]methoxy]-l-methyl-ethyl]imidazo[4,5-b]pyridine-3- carboxamide (220 mg, 82.8% yield) was obtained as a yellow solid. LCMS (ESI) m / z 612.3 [M+Na]+.

[0740] Step 8: Synthesis of (llR)-18-[(4-methoxyphenyl)methyl-methyl-amino]-ll-methyl-5-(2- methyltriazol-4-yl)-9-oxa-2,12,14,16,20-pentazatetracyclo[12.5.2.13'7.017'21]docosa- l(19),3,5,7(22),15,17,20-heptaen-13-one

[0741] To a stirred mixture of 5-chloro-7-[(4-methoxyphenyl)methyl-methyl-amino]- / V-[(lR)-2-[[3-amino-5- (2-methyltriazol-4-yl)phenyl]methoxy]-l-methyl-ethyl]imidazo[4,5-b]pyridine-3-carboxamide (200 mg, 0.339 mmol), K3PO4 (216 mg. 1.02 mmol) in dioxane (30 mL) was added EPhos (37 mg. 69.2 / / mol), EPhos Pd G4 (32 mg. 34.8 / / mol) and the mixture was stirred at 100 °C for 30 min under N2atmosphere. The resulting mixture was cooled to room temperature and quenched with water (50 mL) and extracted with EtOAc (60 mL * 3). The combined organic layer was washed with brine (80 mL), dried over anhydrous Na2SOi. filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 12 g AgelaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0~60%, flow rate = 30 mL / min, 254 mn). The desired product (11R)- 18-[(4-methoxyphenyl)methyl-methyl-amino]-ll -methy l-5-(2 -methy ltriazol-4-yl)-9-oxa-

[0742] 2.12.14.16.20-pentazatetracyclo[12.5.2.137.017 21]docosa-l(19),3,5,7(22),15,17,20-heptaen-13-one (144 mg, 67.9% yield) was obtained as a white solid. LCMS (ESI) m / z 554.4 [M+H]+.

[0743] Step 9: Synthesis of (HR)-ll-methyl-18-(methylamino)-5-(2-methyltriazol-4-yl)-9-oxa-

[0744] 2.12.14.16.20-pentazatetracyclo[12.5.2.13’7.017’21]docosa-l(19),3,5,7(22),15,17,20-heptaen-13-one

[0745] To a solution of TFA (247 mg, 2.17 mmol), triethylsilane (252 mg, 2.17 mmol) in DCM (50 mL) was added (HR)- 18-| (4-methoxy pheny Ijmethy I -methy Lam ino | -11 -methy 1-5 -(2-methyltriazol-4-yl)-9-oxa- 2,12,14,16,20-pentazatetracyclo[12.5.2.13-7.017-21]docosa-l(19),3,5,7(22),15.17,20-heptaen-13-one (120 mg, 0.217 mmol) and the mixture was stirred at 20 °C for 30 min. The resulting mixture was quenched by addition of water (50 mL) and extracted with EtOAc (60 mL x 3). The combined organic layer was washed with brine (80 mL), dried over anhydrous NazSCL, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 4 g AgelaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0~50%, flow rate = 30 mL / min, 254 mn) and then purified by reversed-phase HPLC (Column: SepaFlash® Spherical Cl 8, 25 g. 40-60 pm, 120A; MeCN / water with MeCN from 0-75%, 25mL / min, 254 mn). The fractions were concentrated under reduced pressure and then lyophilized overnight. 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 x 25 mm x 5 om: Mobile phase A: H2O with 0.05% FA(v%); Mobile phase B: ACN; Gradient: B from 35% to 65% in 10 min, hold 100% B for 2 min; Flow Rate; 25 mL / min; Column Temperature: 30 °C; Wavelength: 220 mn). The desired product (llR)-ll-methyl-18-(methylamino)-5- (2-methyltriazol-4-yl)-9-oxa-2.12,14.16,20-pentazatetracyclo[12.5.2.13 7.01 ,-21]docosa- l(19).3.5.7(22),15,17,20-heptaen-13-one (4.7 mg. 5.0% yield) was obtained as a white solid. LCMS (ESI) m / z 434.4 [M+H]+;]H NMR (400 MHz, DMSO-rfc) <5 ppm 9.32 - 9.44 (m, 2 H). 8.31 (s. 1 H). 8.24 (s, 1 H), 8.14 (s, 1 H), 7.36 (s, 1 H), 7.25 (s, 1 H), 6.96 (d, J = 4.9 Hz, 1 H), 5.80 (s. 1 H), 4.68 (d, J = 14.4 Hz, 1 H), 4.51 (d, J = 14.3 Hz, 1 H), 4.20 (s, 3 H). 3.91 - 3.97 (m, 1 H), 3.56 (hr s, 1 H). 3.37 (hr s, 1 H). 2.89 (d. J = 4.8 Hz, 3 H), 1.22 (d, J = 6.5 Hz, 3 H).

[0746] Example 2244:: (llR)-4-(cyclopropoxy)-ll-methyl-18-(methylamino)-9-oxa-2,12,14,16,20- pentazatetracyclo[12.5.2.13'7.017’21]docosa-l(19),3,5,7(22),15,17,20-heptaen-13-one

[0747] Step 1: Synthesis of methyl 4-(cyclopropoxy)-3-nitro-benzoate

[0748] O

[0749] NO

[0750] O'2

[0751] 0^

[0752] A mixture of methyl 4-fluoro-3 -nitro-benzoate (5 g, 25.1 mmol), cyclopropanol (1.5 g, 25.8 mmol) and CS2CO3 (20 g, 61.4 mmol) in DMF (50 mL) was stirred at 20 °C for 6 h. The resulting mixture was quenched by addition of water (50 mL) and extracted with EtOAc (50 mL ' 3). The combined organic layer was dried over anhydrous Na^SO,. fdtered and concentrated tmder reduced pressure. The residue was purified by flash chromatography (Biotagc®; 40 g AgclaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0—25%, flow rate = 40 mL / min, 254 mn) to give methyl 4- (cyclopropoxy) -3 -nitro-benzoate (3.5 g, 58.8% yield) as a yellow solid. LCMS (ESI) m / z 238.2 [M+H]+.

[0753] Step 2: Synthesis of [4-(cyclopropoxy)-3-nitro-phenyl]methanol

[0754] To a solution of methyl 4-(cyclopropoxy)-3-nitro-benzoate (3.4 g, 14.3 mmol) in EtOH (30 mL) was added NaBH4(1.1 g. 29.1 mmol) and CaCL (1.6 g, 14.4 mmol). The mixture was stirred at 20 °C for 4 h. The resulting mixture was quenched with a saturated NH4C1 aqueous solution (30 mL). Then the mixture was concentrated under reduced pressure to removed EtOH and extracted with EtOAc (50 mL ' 3). The combined organic layer was dried over anhydrous Na2SO ,. filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage®; 20 g AgelaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0-27%. flow rate = 40 mL / min, 254 nm) to give [4-(cyclopropoxy)-3-nitro-phenyl]methanol (2.5 g, 83.4% yield) was obtained as a yellow oil. LCMS (ESI) m / z 209.7 [M+H]+.

[0755] Step 3: Synthesis of 4-(bromomethyI)-l-(cyclopropoxv)-2-nitro-benzene To a solution of [4-(cyclopropoxy)-3-nitro-phenyl]methanol (1 g, 4.78 mmol) in THF (10 mL) was added CBr4 (1.8 g, 5.43 mmol) and PPI13 (1.4 g, 5.34 mmol). The mixture was stirred at 20° C for 1 h. The resulting mixture was quenched a saturated Na2SOg aqueous solution (30 mL) and extracted with EtOAc (30 mL ' 3). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage®; 20 g AgelaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0-20%, flow rate = 40 mL / min, 254 nm) to give 4-(bromomethyl)-l-(cyclopropoxy)-2 -nitro-benzene (780 mg, 60.0% yield) as a yellow solid. LCMS (ESI) m / z 272.1, 274.1 [M+H]1.

[0756] Step 4: Synthesis of tert-butyl N-[(lR)-2-[[4-(cyclopropoxy)-3-nitro-phenyl]methoxy]-l-methyl- ethyljcarbamate

[0757] To a solution of tert-butyl N-|( I R)-2-hydro.\y-l -methyl-ctliyl |carbamate (0.5 g, 2.85 mmol) in THF (10 mL) was added NaH (120 mg, 3.00 mmol, 60% in mineral oil) at 0 °C. The mixture was stirred at 20 °C for 30 min. Then to the reaction mixture was added 4-(bromomethyl)-l-(cyclopropoxy)-2 -nitrobenzene (750 mg, 2.76 mmol) and stirred at 20 °C for 1 hr. The resulting mixture was quenched with water (30 mL) and extracted with EtOAc (50 mL ' 3). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage®; 20 g AgelaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0-20%, flow rate = 40 mL / min, 254 nm) to give tert-butyl N-[(lR)-2-[[4-(cyclopropoxy)-3-nitro- phenyl]methoxy]-l-methyl-ethyl]carbamate (600 mg, 59.4% yield) as a yellow oil. LCMS (ESI) m / z 367.2 [M+H]+.

[0758] Step 5: Synthesis of (2R)-l-[[4-(cyclopropoxy)-3-nitro-phenyl]methoxy]propan-2-amine

[0759] H2N^

[0760] Dissolved tert -butyl N-[(lR)-2-[[4-(cyclopropoxy)-3-nitro-phenyl]methoxy]-l-methyl- ethyl] carbamate (560 mg, 1.53 mmol) in 2M HCl / dioxane solution (6 mL). This resulting mixture was stirred at 20 °C for 30 min. The mixture was concentrated under reduced pressure to give (2R)-l-[[4- (cyclopropoxy)-3-nitro-phcnyl |mcthoxy |propan-2-aminc (450 mg, crude) as a yellow oil. The crude product was taken directly to the next step without further purification. LCMS (ESI) m / z 267.2 [M+H]+.

[0761] Step 6: Synthesis of 5-chloro-7-[(4-methoxyphenyl)methyl-methyl-amino]-N-[(lR)-2-[[4- (cyclopropoxy)-3-nitro-phenyl]methoxy] -1 -methyl-ethyl] imidazo [4,5-b] pyridine-3-carboxamide

[0762] A mixture of 5-chloro-N-[(4-methoxyphenyl)methyl]-N-methyl-3H-imidazo[4.5-b]pyridin-7-amine (300 mg, 0.991 mmol), phenyl carbonochloridate (0.14 mL. 1.12 mmol) and TEA(0.72 mL. 5.17 mmol) in THF (10 mL) was stirred at 20 °C for 1 hr. Then to the mixture was added (2R)-l-[[4-(cyclopropoxy)-

[0763] 3-nitro-phenyl]methoxy]propan-2 -amine (450 mg. 1.35 mmol) and stirred at 20 °C for 1 h. The mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage®; 20 g AgelaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0~27%, flow rate = 40 mL / min. 254 nm) to give 5-chloro-7-[(4-methoxyphenyl)methyl-methyl-amino]-N-[(lR)-2-[[4- (cyclopropoxy)-3-nitro-phenyl]methoxy]-l-methyl-ethyl]imidazo[4,5-b]pyridine-3-carboxamide (360 mg, 44.8% yield) as a yellow gum. LCMS (ESI) m / z 595.2 [M+H]+.

[0764] Step 7: Synthesis of 5-chloro-7-[(4-methoxyphenyl)methyl-methyl-amino]-N-[(lR)-2-[[3-amino-

[0765] 4-(cycIopropoxy)phenyl]methoxy]-l-methyl-ethyl]imidazo[4,5-b]pyridine-3-carboxamide

[0766] A mixture of 5-chloro-7-[(4-methoxyphenyl)methyl-methyl-amino]-N-[(lR)-2-[[4-(cyclopropoxy)-3- nitro-phenyl]methoxy]-l-methyl-ethyl]imidazo[4,5-b]pyridine-3-carboxamide (360 mg, 0.605 mmol), Fe (170 mg, 3.04 mmol) and NH4CI (160 mg, 2.99 mmol) in EtOH (3 mL) and H2O (3 mL) was stirred at 80 °C for 1 h. The mixture was filtered, and the fdtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage®; 20 g AgelaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0~30%, flow rate = 40 mL / min, 254 mn) to give 5-chloro-7- [(4-methoxyphenyl)methyl-methyl-amino]-N-[(lR)-2-[[3-amino-4-(cyclopropoxy)phenyl]methoxy]- l-methyl-ethyl]imidazo[4,5-b]pyridine-3-carboxamide (330 mg, 96.5% yield) was obtained as a y ellow gum. LCMS (ESI) m / z 565.1 [M+H]+.

[0767] Step 8: Synthesis of (llR)-4-(cyclopropoxy)-18-[(4-methoxyphenyl)methyl-methyl-amino]-ll- methyl-9-oxa-2,12,14,16,20-pentazatetracyclo[12.5.2.13’7.017'21]docosa-l(19),3,5,7(22),15,17,20- heptaen-13-one

[0768] A mixture of 5-chloro-7-[(4-methoxyphenyl)methyl-methyl-amino]-N-[(lR)-2-[[3-amino-4- (cyclopropoxy)phenyl]methoxy]-l-methyl-ethyl]imidazo[4,5-b]pyridine-3-carboxamide (330 mg, 0.584 mmol), EPhos (64 mg. 0.120 mmol), EPhos Pd G4 (55 mg, 0.0599 mmol) and K3PO4 (370 mg, 1.74 mmol) in dioxane was stirred at 100 °C for 2 h under N2. The mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage®; 20 g AgelaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0~30%, flow rate = 40 mL / min. 254 nm) to give (llR)-4-(cyclopropoxy)-18-[(4-methoxyphenyl)methyl-methyl-amino]-ll-methyl-9-oxa- 2.12,14.16,20-pentazatetracyclol 12.5.2.13-7.017-21|docosa-l(19).3.5.7(22),15,17,20-heptaen-13-one (200 mg, 64.8% yield) as a yellow gum. LCMS (ESI) m / z 529.2 [M+H]+.

[0769] Step 9: Synthesis of (llR)-4-(cyclopropoxy)-ll-methyl-18-(methylamino)-9-oxa-2,12,14,16,20- pentazatetracyclo[12.5.2.13’7.017’21]docosa-l(19),3,5,7(22),15,17,20-heptaen-13-one

[0770] KN

[0771] O.

[0772] / TN O N

[0773] Y N

[0774] N " N

[0775] H H

[0776] O

[0777] Amixture of (l lR)-4-(cyclopropoxy)-18-[(4-methoxyphenyl)methyl-methyl-amino]-l l-methyl-9-oxa- 2, 12.14,16.20-pentazatetracyclo[12.5.2.13-7.01-21]docosa-l(19),3,5,7(22),15.17,20-heptaen-13-one (100 mg. 0.189 mmol). TFA (210 mg. 1.84 mmol) and triethylsilane (220 mg. 1.89 mmol) in DCM (5 mL) was stirred at 20 °C for 1 h. The resulting mixture was quenched by addition of a saturated NaHC'CL aqueous solution ( 10 mL) and extracted with DCM (30 mL ' 3). The combined organic layer was dried over anhydrous Na^SO i. filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage®; 20 g AgelaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0—50%, flow rate = 40 inL / inin, 254 nm) to give (HR)-4-(cyclopropoxy)-l l-methyl-18- (methylamino)-9-oxa-2,12,14,16,20-pentazatetracyclo[12.5.2.13- .017-21]docosa- l(19),3,5,7(22),15,17,20-heptaen-13-one (3.4 mg, 4.3% yield, 96.6% purity) as a white solid. LCMS (ESI) m / z 409.0 [M+H]+;]H NMR (400 MHz, DMSO-cfc) 3 ppm 9.30 (d, J = 4.8 Hz, 1H), 8.50 (br d, J = 2.3 Hz, 1H), 8.25 (s, 1H), 8.19 (s, 1H), 7.97 (d, J = 1.8 Hz, 1H), 6.89 (q, J = 4.4 Hz, 1H). 6.58 (d, J = 1.8 Hz, 1H), 6.02 (s, 1H), 5.89 - 6.00 (m, 1H), 5.00 - 5.12 (m, 2H), 4.54 (d. J = 13.3 Hz, 1H), 4.29 (d, J = 13.3 Hz, 1H), 3.85 - 3.93 (m, 1H), 3.42 - 3.47 (m, 2H), 3.22 - 3.32 (m, 2H), 2.86 (d, J = 4.8 Hz, 3H), 1.18 (d, J = 6.5 Hz, 3H).

[0778] Example 2255:: (10R,14R)-21 -(methylamino)-5-(2-pyridyl)-9-oxa-2,5,l 5,17,19,23- hexazapentacyclo[15.5.2.13’7.01014.020’24]pentacosa-l(23), 3(25), 6, 18, 20(24), 21-hexaene-4, 16-dione

[0779] Step 1: Synthesis of 3-bromo-5-methyl-l-(2-pyridyl)pyridin-2-one

[0780] Br

[0781] ,0

[0782] N N

[0783] A mixture of 3-bromo-5-methyl-lH-pyridin-2-one (2 g, 10.6 mmol). 2 -bromopyridine (1.2 mL. 12.6 mmol.), K2CO3 (4.4 g, 31.8 mmol). Cui (400 mg. 2.10 mmol) and N,N'-dimethylethane-l,2-diamine (0.45 mL, 4.20 mmol) in dioxane (30 mL) was stirred at 110 °C for 12 hrs. The mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage®; 20 g AgelaFlash® Silica Flash Column, petroleum ether / EtOAc with EtOAc from 0-36%, flow rate = 40 mL / min, 254 nm) to give 3-bromo-5-methyl-l-(2-pyridyl)pyridin-2-one (2.3 g, 81.6% yield) as a white solid. LCMS (ESI) m / z 265.0, 267.0 [M+H]+

[0784] Step 2: Synthesis of 3-bromo-5-(bromomethyl)-l-(2-pyridyl)pyridin-2-one

[0785] To a solution of 3-bromo-5-methyl-l-(2-pyridyl)pyridin-2-one (2 g, 7.54 mmol) in CCL (20 mL) was added NBS (1.4 g, 7.87 mmol) and AIBN (0.6 g, 3.65 mmol). The mixture was stirred at 80°C for 12 hrs. The resulting mixture...

Claims

1. Claims1. A compormd of fonnula (I), or pharmaceutically acceptable salt, stereoisomer, or solvate thereof,wherein:X is CR3or N;Y is NR4, S, O, or CH2;Z is absent, O, S, or NR5;W is NR6, O, or S;R1is selected from the group consisting of hydrogen, deuterium, substituted or unsubstituted C1-C6alkyl, wherein one or more substitutions are selected from the group consisting of deuterium, halo, or C3-C6 cycloalkyl;R2is selected from the group consisting of hydrogen, deuterium, and optionally substituted C1- C6alkyl;R3is selected from the group consisting of hydrogen, deuterium, and substituted or unsubstituted C1-C6alkyl;R4is selected from the group consisting of hydrogen, deuterium, and substituted or unsubstituted C1-C6alkyl;R5is selected from the group consisting of hydrogen, deuterium, and substituted or unsubstituted C1-C6alkyl;R6is selected from the group consisting of hydrogen, deuterium, and substituted or unsubstituted C1-C6alkyl;L is a linker comprising 2-12 atom links, wherein each atom link in L is selected from the group consisting of -CRL1RL2. NRL1, O, and S; wherein:RL1and RL2are independently selected from the group consisting of: hydrogen, deuterium, halogen, hydroxy, optionally substituted alkoxy, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C3-C12 cycloalky l, substituted or unsubstituted ary l, or heteroaryl, whereinRL1and RL2on the same or different atoms can be optionally combined to form a 3-12 membered cycloalkyl or hclcrocvcloalkvl. wherein the one or more heteroatoms are N, O, or S;A is selected from the group consisting of cycloalkyl, heterocycloalkyl, ary l, and heteroaryl, wherein one or more heteroatoms in the heterocycloalkyl or heteroaryl is nitrogen, sulfur, or oxygen, and the heterocycloalkyl or heteroaryl may optionally be fused;RA1and RA2are independently selected from the group consisting of: hydrogen, deuterium. halogen. hydroxy, optionally substituted alkoxy. optionally substituted heterocycloalkylalkoxy. cyano.=0.-SRb. -S(=O)Ra, -S(=O)2Ra, -NRcRd, substituted or unsubstituted C1-C6alkyl, C1-C6hydroxy alkyl. C -Cealkoxy alkyl. C1- C6aminoalkyl, Ck-C alkcnvl. wherein one or more substitutions are selected from the group consisting of deuterium, halogen, hydroxy, optionally substituted alkoxy, optionally substituted cycloalkylalkoxy, cyano, =0, or optionally substituted heterocycloalkyl substituted or unsubstituted 3-12 membered monocyclic, bicyclic, bridged bicyclic, or spirocyclic cycloalkyl, oxy cycloalkyl, monocyclic, bicyclic, bridged bicyclic, or spirocyclic heterocycloalkyl, aryl, or heteroary l, wherein one or more heteroatoms in heterocycloalkyl or heteroary l rings are N, S, Se, or O and wherein one or more substitutions are selected from the group consisting of hydrogen, deuterium, halogen, hydroxy7, optionally substituted alkoxy, cyano, =0, substituted or unsubstituted C1-C6alkyl, C1-C6hydroxyalkyl, C1-C6alkoxyalkyl, 3- 12 membered cycloalky l, or heterocycloalky l, ary l, or heteroary l, wherein optionally RA1and RA2together form a substituted or unsubstituted 3-12 membered monocyclic or bicyclic cycloalkyl, heterocycloalkyl, aryl, or heteroaryl fused with Ring A; each Rais independently C1-C6alkyl, C -C>haloalkvl. C1-C6deuteroalkyl, C1-C6hydroxy alkyl, C1-C6aminoalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen. -CN, -OH, -OMe, - NH2. -C(=0)Me, -C(=0)0H, -C(=0)0Me, C1-C6alkyl, or C1-C6haloalky 1; each Rbis independently hydrogen. Ck -Ckalkvl. C1-C6haloalkyl. C1-C6deuteroalkyl, C1-C6hydroxyalkyl. C1-C6aminoalkyl. C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroary l is independently optionally substituted with one or more oxo. deuterium, halogen. -CN, -OH, -OMe. -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C1-C, alkyl. or C1-C haloalkyk and each Rcand Rdis independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1- C6hydroxyalkyl, C1-C6aminoalkyl, C2-Cealkenyl, CS-Cealkynyl. cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OMe, - NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, C1-C6alkyl, or C1-C6haloalkyl; or R° and Rdare taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo. deuterium, halogen, -CN, -OH. -OMe, -NH2, -C(=O)Me. -C(=O)OH, -C(=O)OMe, Ci -Ce alkyl, or C1-C6haloalkyl.

2. The compound of claim 1, wherein X is CR3.

3. The compound of claim 2, wherein R3is hydrogen.

4. The compound of claim 1, wherein X is N.

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

6. The compound of claim 1, wherein ¥ is S.

7. The compound of claim 1, wherein ¥ is -CH2-.

8. The compound of claim 1, wherein Z is O.

9. The compound of claim 1, wherein Z is NR5.

10. The compound of claim 8, wherein R3is hydrogen or methyl.

11. The compound of claim 8, wherein R5is hydrogen.

12. The compound of claim 1, wherein Z is absent.

13. The compound of claim 1, wherein W is NH.

14. The compound of claim 1, wherein W is O.

15. The compormd of claim 1, wherein ring A and Al and RA2do not form a fused bicyclic heteroaryl ring.

16. The compound of claim 1, wherein L does not comprise a cyclopenty l or cyclohexyl ring.

17. The compound of claim 1, wherein L comprises the linker -(CRL1RL2)-(CRL1RL2)-O- (CRL1RL2)-.

18. The compound of claim 1, wherein L comprises the linker19. The compound of claim 18, wherein L comprises the linker20. The compound of claim 1, wherein X is CR3and R3is hydrogen or deuterium.

21. The compound of claim 1, wherein R2is selected from the group consisting of hydrogen, deuterium, or substituted or unsubstituted C1-6alkyl.

22. The compound of claim 1. wherein R2is methyl.

23. The compound of claim 1, wherein R1is optionally substituted Ci^ alkyl, optionally substituted C1-Ccycloalkyl. or C1-6deuteroalkyl.

24. The compound of claim 1, wherein R1is methyl.

25. The compound of claim 1, wherein R1is -CD3.

26. The compound of claim 1, wherein R1is cyclopropyl or -CH2-cyclopropyl.

27. The compound of claim 1, wherein R1is ethyl.

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

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

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

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

32. The compound of claim 31, wherein Ring Ais a 5-12 membered heteroaryl ring having one or more nitrogen atoms.

33. The compound of claim 1, wherein Ring Ais pyridine, pyrimidine, py ridazine, pyridone, or pyridazinone.

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

35. The compound of claim 29, wherein the fused bicyclic ring include further substitutions, wherein the substitutions are selected from the group consisting of hydrogen, deuterium, halogen, C1-C6alkyl, and C1-C6deuterated alkyl.

36. The compound of claim 30, wherein the one or more substitutions are selected from the group consisting of hydrogen, deuterium, -CH3, or -CD3.

37. The compound of claim 1, wherein R .AA11aanndd RRAA22are independently selected from die group consisting of hydrogen, =0, deuterium, hydroxyl, alkoxy, halogen, cyano, substituted or unsubstituted Ci -C6alkyl, substituted or unsubstituted Ci -C6oxy alkyl, substituted or unsubstituted C1-C6oxy cycloalkyl, 3-12 membered substituted or unsubstituted cycloalkyl or heterocycloalkyl wherein one or more heteroatoms are N, S, or O. 5-12 membered substituted or unsubstituted aryl or heteroaryl wherein one or more heteroatoms are N, S, or O; wherein the one or more substitutions are selected from the group consisting of H, deuterium. C1-C, alkyl. C1-C6oxyalkyl, halogen, optionally deuterated C1-C6alkyl. and cyano.

38. The compound of claim 32. wherein RA1and RA2are independently selected from the group consisting of deuterium, halogen, -CN, -0Ra, -NRaRa, -C(=O)Ra, -CH2-Ra, C|.e alkyl. C1-6haloalky 1, Ci -6 deuteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein:Raand Raare independently C1-C6alkyl. C1-C6haloalkvl. C1-C6dciitcroalkvl. C1- C6hydroxyalkyl, C1-C6aminoalkyl, C2-C6alkenyl, C3-C6cycloalkyl, C.-CAheterocycloalkyl. C I-CI zaryl. or C .-Ci 2heteroaryk wherein each alkyl, alkenyl, cycloalky l, heterocycloalkyl, ary 1, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen. -CN, -OH, -OMe, -OCF3, - NH2, -C(=0)Me, -C(=O)OH, -C(=O)OMe, C1-C6alkyl, or C1-C6haloalkyl.

39. The compound of claim 1, wherein RA1and RA2are independently monocyclic or bicy clic heterocycloalkyl or heteroaryl containing at least one nitrogen, sulfur, or oxy gen.

40. The compound of claim 1, wherein R AAl1aanndd RRAA22are independently substituted or unsubstituted phenyl morpholine, 1,4-oxazepane, piperazine, piperidine, pyridine, triazole, tetrahyropyrane, pyrazole, oxazole, or pyridazine.

41. The compound of claim 1, wherein RA1and RA2are independently selected from tire group consisting of hydrogen, hydroxyl, deuterium, fluoro, chloro, =0, -CN, -OCH3, -OCH2CH3. - OCH2CH3OCH3, -CH(CH3)2OH, -OCHF2, -O-cyclopropyl. substituted or unsubstituted phenyl, substituted or unsubstituted pyridine, substituted or unsubstituted azetidine, substituted or unsubstituted oxetane, substituted or unsubstituted morpholine, -CH2- cyclopropyl. -O-CH2-CH3. -CH2-O-CH3, -CH2-O-CD3, -OCF3. -OCF2H, -OCH2CF3. -OCD3, N. —'N-OCD2CD3, -OCFF-cyclopropyl, cyano, cyclopropyl, -CF3. -CH3. -CD3.F,CHF>2>— <-N o F O> N' N -yo >\,— 2-N o ■N>N NON o ONN NO NSe DO O D DN N NOO O'"42. The compound of claim 1, wherein L comprises 2-10 atom links, wherein each atom link in L is selected from the group consisting of -CRL1RL2, NRL1, O, and S.

43. The compound of claim 42. wherein L comprises betw een 2 and 8 atom links are -CRL1RL2and betw een 0 and 2 atom links are NRL1, O, and S.

44. The compound of claim 42, wherein L comprises between 1 and 7 atom links are -CR L1I L2 and betw een 0 and 2 atom links are NRL1, O, and S.

45. The compound of claim 42, wherein L comprises between 1 and 6 atom links are -CRL1RJand between 0 and 2 atom links are NRL1. O, and S.

46. The compound of claim 42. wherein L comprises betw een 1 and 10 atom links are -CRL1RL2, and RL1and RL2at different or same atom combine to form an optionally substituted cycloalkyl or heterocycloalky l.

47. The compound of claim 46, wherein the one or more substitutions are selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, alkoxy, or C1-C4 alky l.

48. The compound of claim 1, wherein L is selected from the group consisting of:, optionally substituted with deuterium.

49. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein the compound is a compound provided in Table A.

50. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein the compound is a compound provided in Table B.

51. A pharmaceutical composition comprising a compound of any one of the claims 1-50, and a pharmaceutically acceptable carrier or diluent.

52. A method of inhibiting TYK2 activity in a subject in need thereof with a compound of any one of claims 1-50 or a pharmaceutical composition of claim 46.

53. 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 1-50, or a pharmaceutical composition according to claim 46.

54. The method of claim 53. 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.

55. The method of claim 54, wherein the TYK2 -mediated disease or disorder is multiple sclerosis.

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