Macrocyclic DYRK1a-b inhibitors and methods of their preparation and use

Abstract

Disclosed herein are macrocyclic compounds having the structure of Formula (I): or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof, wherein, X, R1, R2, R2a, R3, and Linker are defined herein. Also provided are pharmaceutical compositions comprising the compounds and methods for inhibiting activity of a dual specificity tyrosine phosphorylation regulated kinase 1A and IB (DYRK1A and DYRK1B) enzyme in a subject in need thereof using the compounds or pharmaceutical compositions disclosed herein.

Description

APRE007-PCT | 106265.000238MACROCYCLIC DYRK1A-B INHIBITORS AND METHODS OF THEIR PREPARATION AND USECROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application Nos. 63 / 748,174 (filed January 22, 2025), 63 / 819,080 (filed June 6, 2025), and 63 / 884,416 (filed September 19, 2025), the disclosures of which are incorporated by reference herein.TECHNICAL FIELD

[0002] The disclosure relates to macrocyclic compounds and their use in methods for inhibiting activity of a dual specificity tyrosine phosphorylation regulated kinase 1A (DYRK1 A) and / or IB (DYRK1B).BACKGROUND

[0003] Dual specificity tyrosine-phosphorylation-regulated kinase 1A and IB (DYRK1A and DYRK1B) are enzymes encoded by the DYRK1A and DYRK1B genes, respectively. DYRK1A syndrome is characterized by intellectual disability including impaired speech development, autism spectrum disorder, anxious and / or stereotypic behavior problems, and microcephaly. DYRK1A syndrome may account for a small percentage of individuals with intellectual disability and / or autism.

[0004] DYRK1A is also thought to play roles in regulating cell proliferation and, thus, may be involved in the development and treatment resistance of certain cancers and HIV-1 replication, among others.

[0005] DYRK1B is associated with overlapping and distinct functions as DYRK1A in cells, and its genomic alteration is linked to early onset Coronary Artery Disease, juvenile -onset truncal obesity, severe hypertension, and type II diabetes mellitus.

[0006] What is needed are compounds that modulate DYRK1A and / or DYRK1B activity.BRIEF DESCRIPTION OF THE DRAWINGS

[0007] The present application is further understood when read in conjunction with the appended drawings. For the purpose of illustrating the subject matter, exemplary embodiments of the subject matter are shown in the drawings; however, the presently disclosed subject matter is not limited to the specific processes or methods disclosed. In addition, the drawings are not necessarily drawn to scale.

[0008] FIG. 1 graphically compares the logioGI50 data and GI50 across cell lines.

[0009] FIG. 2 graphically compares the logioTGI data and TGI across cell lines.APRE007-PCT | 106265.000238

[0010] FIG. 3 graphically compares the logioLC50 data and LC50 across cell lines.

[0011] FIG. 4 graphically compares the hollow fiber and GI50 across cell lines.

[0012] FIG. 5 graphically compares the hollow fiber and TGI across cell lines.

[0013] FIG. 6 graphically compares the hollow fiber and LC50 across cell lines.SUMMARY

[0014] In some embodiments, the disclosure provides macrocyclic compounds having the structure of Formula (I):or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof, wherein, X, R1, R2, R2a, R3, and Linker are defined herein.

[0015] In other embodiments, the disclosure provides pharmaceutical compositions comprising a compound described herein and a pharmaceutically acceptable excipient.

[0016] In further embodiments, the disclosure is useful for methods of inhibiting activity of a dual specificity tyrosine phosphorylation regulated kinase 1A (DYRK1 A) enzyme in a subject in need thereof, comprising administering a compound or pharmaceutical composition disclosed herein to the subject in need thereof.

[0017] In yet other embodiments, the disclosure provides compounds for use in treating, e.g., cancer, diabetes, and neurological disorders. In other embodiments, the disclosure provides compounds for use in treating Down syndrome, Intellectual Developmental Disorder Autosomal Dominant 7, dementia, Alzheimer’s Disease, Fronto-Temporal Degeneration, Huntington’s disease, or Parkinson’s disease in a subject in need thereof, comprising administering a compound or a pharmaceutical composition disclosed herein to the subject in need thereof.

[0018] In still further embodiments, the disclosure provides methods of inhibiting activity of a dual specificity tyrosine phosphorylation regulated kinase IB (DYRK1B) enzyme in a subject in need thereof, comprising administering a compound or a pharmaceutical composition disclosed herein to the subject in need thereof.

[0019] In other embodiments, the disclosure provides compounds for using in treating early-onset coronary artery disease, hypertension, central obesity, or diabetes in a subject in need thereof, comprising administering a compound or a pharmaceutical composition disclosed herein to the subject in need thereof.APRE007-PCT | 106265.000238

[0020] In still further embodiments, the disclosure provides compounds for use in treating cancer, diabetes, or heart disease in a subject in need thereof, comprising administering a compound or pharmaceutical composition disclosed herein to the subject in need thereof.DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

[0021] The disclosure may be more fully appreciated by reference to the following description, including the following glossary of terms and the concluding examples. It is to be appreciated that certain features of the disclosed compositions and methods which are, for clarity, described herein in the context of separate aspects, may also be provided in combination in a single aspect.

[0022] In the following descriptions of exemplary embodiments of the present invention, all references, including publications, patent applications, and patents, cited herein are incorporated by reference into this application to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein.

[0023] Conversely, various features of the disclosed compositions and methods that are, for brevity, described in the context of a single aspect, may also be provided separately or in any subcombination.

[0024] It will be appreciated by those skilled in the art that changes could be made to the exemplary embodiments shown and described above without departing from the broad inventive concept thereof. It is understood, therefore, that this invention is not limited to the exemplary embodiments shown and described, but it is intended to cover modifications within the spirit and scope of the present invention as defined by the claims. For example, specific features of the exemplary embodiments may or may not be part of the claimed invention and features of the disclosed embodiments may be combined. Unless specifically set forth herein, the terms “a,” “an” and “the” are not limited to one element but instead should be read as meaning “at least one.”

[0025] When a range of carbon atoms is used herein, e.g., Ci-6, all ranges, as well as individual numbers of carbon atoms are encompassed. For example, “C1-3” includes C1-3, C1-2, C2-3, Ci, C2, and C3.

[0026] The term “alkyl” refers to a straight- or branched-chain alkyl group having from 1 to 12 carbon atoms (“C1-12”), preferably 1 to 6 carbons atoms (“Ci-e”), in the chain. Examples of alkyl groups include methyl (Me, Cialkyl) ethyl (Et, C2alkyl), n-propyl (CLalkyl). isopropyl (Csalkyl), butyl (C4alkyl), isobutyl (C4alkyl), sec-butyl (C4alkyl), tert-butyl (C4alkyl), pentyl (Cealkyl). isopentyl (Csalkyl), tert-pentyl (Cealkyl). hexyl (Cealkyl), isohexyl (Cealkyl), and groups that in light of the ordinary skill in the art and the teachings provided herein would be considered equivalent to any oneAPRE007-PCT | 106265.000238of the foregoing example. Unless stated otherwise, an alkyl group is optionally substituted by one or more of OH, halo, CN, NO2, Ci-ealkoxy, Cs-scycloalkyl, heterocycloalkyl, aryl, or heteroaryl.

[0027] The term “alkylene” refers to a straight- or branched-chain internal alkyl group that is bound through two carbon atoms. An alkylene has 1 to 12 carbon atoms (“C1-12”), preferably 1 to 6 carbons atoms (“Ci-e”), in the chain. Examples of alkyl groups include methyl (Me, Cialkyl) ethyl (Et, C2alkyl), n-propyl (Cealkyl). isopropyl (Cealkyl). butyl (C4alkyl), isobutyl (C4alkyl), sec-butyl (C4alkyl), tert-butyl (C4alkyl), pentyl (Cealkyl), isopentyl (Cealkyl), tert-pentyl (Cealkyl), hexyl (Cealkyl), isohexyl (Cealkyl), and groups that in light of the ordinary skill in the art and the teachings provided herein would be considered equivalent to any one of the foregoing example. Unless stated otherwise, an alkyl group is optionally substituted by one or more of OH, halo, CN, NO2, Ci-ealkoxy, Cs-scycloalkyl, heterocycloalkyl, aryl, or heteroaryl.

[0028] “Alkenyl” refers to a straight or branched hydrocarbon chain comprising carbon and hydrogen atoms, and at least one double bond. In some embodiments, the alkenyl contains 2 to 12 carbon atoms, e.g., 2 carbon atoms, 3 carbon atoms, 4 carbon atoms etc., up to and including 12 carbon atoms. The alkenyl moiety may be attached to the rest of the molecule by a single bond, such as e.g., ethenyl (i.e., vinyl), prop-l-enyl (i.e., allyl), but-l-enyl, pent-l-enyl and penta- 1,4-dienyl, or by a double bond. Unless stated otherwise, an alkenyl group is optionally substituted by one or more of OH, halo, CN, NO2, Ci-ealkoxy, Cs-scycloalkyl, heterocycloalkyl, aryl, or heteroaryl.

[0029] “Alkynyl” refers to a straight or branched hydrocarbon chain comprising carbon and hydrogen atoms, and at least one triple bond. In some embodiments, the alkynyl contains 2 to 12 carbon atoms, e.g., 2 carbon atoms, 3 carbon atoms, 4 carbon atoms etc., up to and including 12 carbon atoms. Unless stated otherwise, an alkynyl group is optionally substituted by one or more of OH, halo, CN, NO2, Ci-ealkoxy, Cs-scycloalkyl, heterocycloalkyl, aryl, or heteroaryl.

[0030] “Cycloalkyl” refers to a saturated monocyclic or polycyclic radical that contains carbon and hydrogen. In some embodiments, cycloalkyl includes groups having 3 to 12 ring atoms (i.e., (C3-i2)cycloalkyl). Illustrative examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl and the like. Unless stated otherwise, a cycloalkyl group is optionally substituted by one or more of OH, halo, CN, NO2, Ci-ealkyl, Ci-ealkoxy, Ce-scycloalkyl, heterocycloalkyl, aryl, or heteroaryl.

[0031] “Heterocycloalkyl” refers to a saturated monocyclic or polycyclic radical that contains carbon and hydrogen. In some embodiments, heterocycloalkyl includes groups having 3 to 12 ring atoms (i.e., (C3-i2)heterocycloalkyl) and one nitrogen or oxygen atom. Illustrative examples of heterocycloalkyl groups include, but are not limited to azepanyl, azetidinyl, aziridinyl, azocanyl, azolidinyl, dioxanyl, oxetanyl, oxanyl, oxepanyl, oxiranyl, oxocanyl, oxolanyl, piperidinyl, pyranyl, pyrrolidinyl, tetrahydrofuranyl, thianyl, thiepanyl, thietanyl, thiiranyl, thiocanyl, thiolanyl, or the like.APRE007-PCT | 106265.000238In some embodiments, the heterocycloalkyl is pyrrolidinyl, tetrahydrofuranyl, oxetanyl, pyranyl, piperidinyl, or azetidinyl. Unless stated otherwise, a heterocycloalkyl is optionally substituted by one or more of OH, halo, CN, NO2, Ci-ealkyl, Ci-ealkoxy, Cs-scycloalkyl, heterocycloalkyl, aryl, or heteroaryl.

[0032] “Halo” refer to fluoro, chloro, bromo or iodo. In some embodiments, the halo is fluoro. In other embodiments, the halo is chloro. In further embodiments, the halo is bromo. In yet other embodiments, the halo is iodo.

[0033] “Alkoxy” refers to a straight- or branched-chain alkyl group having 1 to 12 carbon atoms (“C1-12”), preferably 1 to 6 carbons atoms (“Ci-e”), and one oxygen atom in the chain. Examples of alkyl groups include methyl (OMe), ethyl (OEt), n-propyl (OnPr), isopropyl (O'Pr), butyl (OBu), isobutyl (O'Bu), sec-butyl (OsBu), tert-butyl (0‘Bu), pentyl (O-pentyl), isopentyl (O-'pcntyl). tertpentyl (O-‘pentyl), hexyl (O-hexyl), isohexyl (O-'hcxyl). and groups that in light of the ordinary skill in the art and the teachings provided herein would be considered equivalent to any one of the foregoing example. Unless stated otherwise, an alkoxy is optionally substituted by one or more of OH, halo, CN, NO2, Ci-ealkyl, Cs-scycloalkyl, heterocycloalkyl, aryl, or heteroaryl.

[0034] “Aryl” refers to an unsaturated ring, having six to ten ring atoms (Ce-ioaryl). In some embodiments, an aryl contains 6-10 ring atoms. In other embodiments, an aryl contains 6-8 ring atoms. Aryl also includes monocyclic or fused-ring polycyclic. Examples of aryl include, without limitation, phenyl, naphthyl, or indolyl. Unless stated otherwise, an aryl is optionally substituted by one or more of OH, halo, CN, NO2, Ci-ealkyl, Cs-scycloalkyl, heterocycloalkyl, aryl, or heteroaryl.

[0035] “Heteroaryl” refers to a 5- to 18-membered aromatic radical (e.g., (C5-i3)heteroaryl) that includes one or more ring heteroatoms (nitrogen, oxygen and / or sulfur) and is a monocyclic, bicyclic, tricyclic or tetracyclic ring system. In some embodiments, a heteroaryl contains 5-12 ring atoms. In further embodiments, a heteroaryl contains 5-10 ring atoms. In other embodiments, a heteroaryl contains 5-8 ring atoms. In still further embodiments, a heteroaryl contains 5-6 ring atoms.A polycyclic heteroaryl may be fused or non-fused. The heteroatom(s) in the heteroaryl are optionally oxidized and nitrogen atoms, if present, are optionally quatemized. The heteroaryl may be attached to the rest of the molecule through any atom of the ring(s). Examples of heteroaryls include, but are not limited to, benzimidazolyl, benzindolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzo[b][l,4]dioxepinyl, benzofl, 4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzoxazolyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzofurazanyl, benzothiazolyl, benzothienyl, benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furazanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, 1,6-APRE007-PCT | 106265.000238naphthyridinonyl, oxadiazolyl, oxoazepinyl, oxazolyl, oxiranyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyridopyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, thiapyranyl, triazolyl, tetrazolyl, triazinyl, or thiophenyl (i.e. thienyl). Unless stated otherwise, heteroaryl is optionally substituted by one or more of OH, halo, CN, NO2, Ci-ealkyl, Cs-scycloalkyl, heterocycloalkyl, aryl, or heteroaryl.

[0036] “Pharmaceutically acceptable” means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.

[0037] “Subject” as used herein refers to a mammalian animal. In one embodiment, the patient or subject is a human. In another embodiment, the patient or subject is a veterinary or farm animal, a domestic animal or pet, or animal normally used for clinical research. In further embodiments, the subject is a canine, feline, or primate. The terms “human,” “patient,” and “subject” are used interchangeably herein.

[0038] “Treating” or “treatment” of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e., arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment “treating” or “treatment” refers to ameliorating at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, “treating” or “treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. In yet another embodiment, “treating” or “treatment” refers to delaying the onset of the disease or disorder.

[0039] Compounds described herein may include one or more chiral centers. Compounds described herein, therefore, may refer to a specific enantiomer or diastereomer. Compounds described herein may also be provided as mixtures of enantiomers or diastereomers.

[0040] Compounds of the disclosure may include all isotopes of any atom present in the compound. For example, one or more hydrogen atoms can be substituted with deuterium or tritium. Synthetic methods for preparing isotopically labeled or enriched compounds are generally known in the art.Compounds

[0041] The disclosure provides, compounds having the structure of Formula (I):APRE007-PCT | 106265.000238

[0042] According to the disclosure, X is a bond, -N(H)-, -C(0)NH-, -NHC(O)-, or -[^(Ci-ealkyl)-. In some embodiments, X is a bond. In other embodiments, X is -N(H)-. In further embodiments, X is -C(O)NH-. In yet other embodiments, X is -NHC(O)-. In still further embodiments, X is -N(Ci-6alkyl)-. Examples of N(Ci-6alkyl)- include -N(Cialkyl)-, -N(C2alkyl)-, -N(C3alkyl)-, -N(C4alkyl)-, -N(C5alkyl)-, or -N(C6alkyl)-.

[0043] According to the disclosure, R1is H, Ci-ealkyl, or NH2. In some embodiments, R1is H. In further embodiments, R1is Ci-ealkyl. Examples of Ci-ealkyl include Cialkyl, CSalkyl. Calkyl. C4alkyl, Cealkyl, or Cealkyl, or CH2OH. In yet other embodiments, R1is NH2.

[0044] According to the disclosure, R2and R2aare each, independently, H or Ci-ealkyl. In some embodiments, R2is H. In other embodiments, R2is Ci-ealkyl. Examples of Ci-ealkyl include Cialkyl, Cealkyl . Csalkyl, C4alkyl, Cealkyl, or Cealkyl. In further embodiments, R2ais H. In yet other embodiments, R2ais Ci-ealkyl. Examples of Ci-ealkyl include Cialkyl, CSalkyl. Cialkyl. C4alkyl, Cealkyl, or Cealkyl. In some aspects, R2and R2aare each H. In other aspects, R2and R2aare each a Ci-ealkyl. In some aspects, R2is H and R2ais a Ci-ealkyl. In some aspects, R2is Ci-ealkyl and R2ais a Ci-ealkyl.

[0045] According to the disclosure, R3is hydrogen, Ci-ealkyl, C2-ealkenyl, C2-ealkynyl, NH2, NH(Ci-ealkyl), N(Ci-ealkyl)2, Ci-ealkoxy, CN, halo, or NHC(O)O(Ci. ealkyl). In some embodiments, R3is hydrogen. In other embodiments, R3is Ci-ealkyl. Examples of Ci-ealkyl include Cialkyl, CSalkyl. Cialkyl. C4alkyl, Cealkyl, or Cealkyl.

[0046] In further embodiments, R3is C2-ealkenyl. Examples of C2-ealkenyl include such as C2alkenyl, Cealkenyl. C4alkenyl, Cealkenyl, or Cealkenyl. In yet other embodiments, R3is C2-ealkynyl. Examples of C2-ealkynyl include such as Cealkynyl. Cealkynyl. C4alkynyl, Cealkynyl, or Cealkynyl.

[0047] In still further embodiments, R3is NH2. In other embodiments, R3is NH(Ci. ealkyl). Examples of NH(Ci. ealkyl) include NH(Cialkyl), NH(C2alkyl), NH(C3alkyl), NH(C4alkyl), NH(Cealkyl), or NH(Cealkyl). In further embodiments, R3is N(Ci-ealkyl)2. Examples of N(Ci-ealkyl)2 include N(Ci.ealkyl)(Ci.ealkyl), or such as N(Cialkyl)2, N(Cialkyl)(C2alkyl), N(Cialkyl)(C3alkyl), N(C2alkyl)2, N(C3alkyl)2, N(C4alkyl)2, N(C5alkyl)2, or N(Cealkyl)2.

[0048] In yet other embodiments, R3is Ci-ealkoxy. Examples of Ci-ealkoxy include Cialkoxy, C2alkoxy, Cialkoxy. C4alkoxy, Cealkoxy, or Cealkoxy.

[0049] In still further embodiments, R3is CN. In other embodiments, R3is halo. Examples of halo include F, Cl, Br, or I.APRE007-PCT | 106265.000238

[0050] In further embodiments, R3is NHC(O)O(Ci. ealkyl). Examples of NHC(O)O(Ci. ealkyl) include NHC(O)O(Cialkyl), NHC(O)O(C2alkyl), NHC(O)O(C3alkyl), NHC(O)O(C4alkyl), NHC(O)O(C5alkyl), or NHC(O)O(C6alkyl).

[0051] In still other embodiments, R3is hydrogen, Cnealkyl, C2-ealkenyl, C2-ealkynyl, NH2, NH(Ci-ealkyl), CN, halo, or NHC(O)O(Ci-ealkyl).

[0052] According to the disclosure, Linker is -(Ce-i4alkylene)-, wherein the alkylene is straight, optionally comprises one or more alkyl substituents, optionally wherein one or more carbons is replaced with O, and / or optionally wherein two adjacent carbon atoms of the alkylene are replaced with an aryl or a heteroaryl. In some embodiments, Linker is -(Cealkylene)-, -(Cealkylene)-, -(C?alkylene)-, -(Csalkylene)-, -(Cgalkylene)-, -(Cioalkylene)-, -(Cnalkylene)-, -(Cealkylene)-, -(Cisalkylene)-, or -(Cnalkylene)-. In other embodiments, Linker comprises one or more alkyl substituents. Lor example, Linker may comprise 1-5, 1-4, 1-3, 2-5, 2-4, or 3-5 alkyl substituents, or one, two, three, four, or five alkyl substituents. In further embodiments, in Linker, one or more carbon atom is replaced with O. Lor example, 1-5, 1-4, 1-3, 2-5, 2-4, or 3-5, or one, two, three, four, or five carbon atoms are replaced with O.

[0053] In some embodiments, Linker is -(CR10R11)m-O-(CR12R13)n-, wherein R10-R13, are independently, H or Cnealkyl for each m and n unit, m is 1-6 and n is 1-6. In some embodiments, R10is H. In other embodiments, R11is H. In further embodiments, R12is H. In yet other embodiments, R13is H. In further embodiments, R10is Cnealkyl, such as Cialkyl, CSalkyl. C3alkyl, C4alkyl, Cealkyl, or Cealkyl. In yet other embodiments, R11is Cnealkyl, such as Cialkyl, Cealkyl. C3alkyl, C4alkyl, Cealkyl, or Cealkyl. In still further embodiments, R12is Cnealkyl, such as Cialkyl, CSalkyl. C3alkyl, C4alkyl, Cealkyl, or Cealkyl. In other embodiments, R13is Cnealkyl, such as Cialkyl, CSalkyl. C3alkyl, C4alkyl, Cealkyl, or Cealkyl. In some embodiments, m is 1, 2, 3, 4, 5, or 6. In other embodiments, m is 1-5, 1-4, 1-3, 2-5, 2-4, or 3-5. In some embodiments, n is 1, 2, 3, 4, 5, or 6. In other embodiments, n is 1-5, 1-4, 1-3, 2-5, 2-4, or 3-5.

[0054] In some embodiments, Linker is -(CR10R11)m-O-(CR12R13)n-O-(CR14R15)p-, wherein R10-R15, are independently, H or Cnealkyl for each m, n, and p unit, m is 1-6, n is 1-6, and p is 1-6. In some embodiments, R10is H. In other embodiments, R11is H. In further embodiments, R12is H. In yet other embodiments, R13is H. In still further embodiments, R14is H. In other embodiments, R15is H. In further embodiments, R10is Cnealkyl, such as Cialkyl, CSalkyl. C3alkyl, C4alkyl, Cealkyl, or Cealkyl. In yet other embodiments, R11is Cnealkyl, such as Cialkyl, CSalkyl. C3alkyl, C4alkyl, Cealkyl, or Cealkyl. In still further embodiments, R12is Cnealkyl, such as Cialkyl, CSalkyl. C3alkyl, C4alkyl, Cealkyl, or Cealkyl. In other embodiments, R13is Cnealkyl, such as Cialkyl, CSalkyl. C3alkyl, C4alkyl, Cealkyl, or Cealkyl. In further embodiments, R14is Cnealkyl, such as Cialkyl, CSalkyl.C3alkyl, C4alkyl, Cealkyl, or Cealkyl. In yet other embodiments, R15is Cnealkyl, such as Cialkyl,APRE007-PCT | 106265.000238C2alkyl, Cealkyl. C4alkyl, Cealkyl, or Cealkyl. In some embodiments, m is 1, 2, 3, 4, 5, or 6. In other embodiments, m is 1-5, 1-4, 1-3, 2-5, 2-4, or 3-5. In some embodiments, n is 1, 2, 3, 4, 5, or 6. In other embodiments, n is 1-5, 1-4, 1-3, 2-5, 2-4, or 3-5. In some embodiments, p is 1, 2, 3, 4, 5, or 6. In other embodiments, p is 1-5, 1-4, 1-3, 2-5, 2-4, or 3-5.

[0055] In some embodiments, two adjacent carbon atoms of the alkylene are replaced with an aryl or a heteroaryl in Linker. In other embodiments, two adjacent carbon atoms of the alkylene are replaced with an aryl in Linker. In further embodiments, Linker is -(CR10Rn)m-phenyl- C(R12R13)n, wherein R10-R13, are independently, H or Ci-ealkyl for each m and n unit, m is 1-6 and n is1-6. For example, in some embodiments, Linkersome embodiments, R10is H. In other embodiments, R11is H. In further embodiments, R12is H. In yet other embodiments, R is H. In further embodiments, R10is Ci-ealkyl, such as Cialkyl, C2alkyl, Csalkyl, C4alkyl, Csalkyl, or Cealkyl. In yet other embodiments, R11is Ci-ealkyl, such as Cialkyl, C2alkyl, Cialkyl. C4alkyl, Cialkyl. or Cealkyl. In still further embodiments, R12is Ci^alkyl, such as Cialkyl, C2alkyl, Cialkyl. C4alkyl, Cealkyl, or Cealkyl. In other embodiments, R13is Ci-ealkyl, such as Cialkyl, C2alkyl, Cialkyl. C4alkyl, Cealkyl, or Cealkyl. In further embodiments, two adjacent carbon atoms of the alkylene are replaced with a heteroaryl in Linker. In some embodiments, m is 1, 2, 3, 4, 5, or 6. In other embodiments, m is 1-5, 1-4, 1-3, 2-5, 2-4, or 3-5. In some embodiments, n is 1, 2, 3, 4, 5, or 6. In other embodiments, n is 1-5, 1-4, 1-3, 2-5, 2-4, or 3-5.

[0056] In yet other embodiments, Linker is -(CR^R11)m-pyridyl-C(R12R13)n, wherein R10- R13, are independently, H or Ci-ealkyl for each m and n unit, m is 1-6 and n is 1-6. For example, inAPRE007-PCT | 106265.000238embodiments, Linkersome embodiments, R10is H. In other embodiments, R11is H. In further embodiments, R12is H. In yet other embodiments, R13is H. In further embodiments, R10is Ci-ealkyl, such as Cialkyl, C2alkyl, Csalkyl, C4alkyl, Csalkyl, or Cealkyl. In yet other embodiments, R11is Ci-ealkyl, such as Cialkyl, C2alkyl, Cialkyl. C4alkyl, Cealkyl, or Cealkyl. In still further embodiments, R12is Ci-ealkyl, such as Cialkyl, C2alkyl, Cialkyl. C4alkyl, Cealkyl, or Cealkyl. In other embodiments, R13is Ci-ealkyl, such as Cialkyl, C2alkyl, Cialkyl. C4alkyl, Cealkyl, or Cealkyl. In further embodiments, two adjacent carbon atoms of the alkylene are replaced with a heteroaryl in Linker. In some embodiments, m is 1, 2, 3, 4, 5, or 6. In other embodiments, m is 1-5, 1-4, 1-3, 2-5, 2-4, or 3-5. In some embodiments, n is 1, 2, 3, 4, 5, or 6. In other embodiments, n is 1- 5, 1-4, 1-3, 2-5, 2-4, or 3-5.

[0057] The disclosure also provides pharmaceutically acceptable salts of the compounds of Formula (I). “Pharmaceutically acceptable salt” refers to a salt of a compound of the disclosure that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3 -(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2 -ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1 -carboxylic acid, glucoheptonic acid, 3 -phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine and the like. Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of nontoxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like. In some embodiments, the compounds are hydrochloride (HC1) salts.APRE007-PCT | 106265.000238

[0058] In some embodiments, the compound is:APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238or a pharmaceutically acceptable salt thereof.

[0059] In other embodiments, the compound is:APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238or a pharmaceutically acceptable salt thereof.APRE007-PCT | 106265.000238Compositions

[0060] The compounds of the disclosure are used, alone or in combination with one or more additional active ingredients, to formulate pharmaceutical compositions of the disclosure. In some embodiments, the pharmaceutical composition comprises: (a) an effective amount of at least one compound in accordance with the disclosure; and (b) a pharmaceutically acceptable excipient.

[0061] The compositions or compounds may be administered by a suitable route of delivery, e.g., oral, parenteral, rectal, topical, or ocular routes, or by inhalation. In some embodiments, the compound or composition containing the compound is administered orally.

[0062] For oral administration, the compounds of the disclosure can be provided in the form of tablets or capsules, or as a solution, emulsion, or suspension. To prepare the oral compositions, the compounds may be formulated to yield a dosage of, e.g., from about 0.05 to about 100 mg / kg daily, or from about 0.05 to about 35 mg / kg daily, or from about 0.1 to about 10 mg / kg daily. For example, a total daily dosage of about 5 mg to 5 g daily may be accomplished by dosing once, twice, three, or four times per day.

[0063] Oral tablets or capsules may include a compound according to the disclosure mixed with pharmaceutically acceptable excipients such as inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservative agents.

[0064] The compounds of this disclosure may also be administered by non -oral routes. For example, the compositions may be formulated for rectal administration as a suppository. For parenteral use, including intravenous, intramuscular, intraperitoneal, or subcutaneous routes, the compounds of the disclosure may be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity or in parenterally acceptable oil. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride.Methods

[0065] According to the disclosure, one or more compounds disclosed herein are dual specificity tyrosine phosphorylation regulated kinase 1A (DYRK1 A) enzyme inhibitors. Thus, they are useful in methods for inhibiting activity of a dual specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A) enzyme in subjects in need thereof. Then methods include administering a compound or pharmaceutical composition described herein to the subject.

[0066] A number diseases / conditions may be treated by inhibiting the DYRK1A enzyme. Such diseases include, without limitation, treating Down syndrome, Intellectual Developmental Disorder Autosomal Dominant 7, dementia, Alzheimer’s Disease, Fronto -Temporal Degeneration, Huntington’s disease, or Parkinson’s disease. In some embodiments, the disease is Down syndrome.APRE007-PCT | 106265.000238In other embodiments, the disease is Intellectual Developmental Disorder Autosomal Dominant 7. In further embodiments, the disease is dementia. In yet other embodiments, the disease is Alzheimer’s Disease. In still further embodiments, the disease is Fronto-Temporal Degeneration. In other embodiments, the disease is Huntington’s disease. In further embodiments, the disease is Parkinson’s disease.

[0067] Other diseases that may be treating with the compounds disclosed herein include, without limitation, cancer, diabetes, or heart disease. In some embodiments, the disease is diabetes. In other embodiments, the disease is heart disease. In further embodiments, the disease is cancer. Examples of cancer that may treated include lung cancer (e.g., non-small cell lung cancer), pancreatic cancer, brain cancer (e.g., glioblastoma), skin cancer (e.g., melanoma), a blood borne cancer (e.g., leukemia), colon cancer, a central nervous system cancer, ovarian cancer, renal cancer, prostate cancer, or breast cancer. In some embodiments, the disease is lung cancer. In other embodiments, the disease is pancreatic cancer. In further embodiments, the disease is a glioblastoma. In yet other embodiments, the disease is melanoma. In still further embodiments, the disease is leukemia. In other embodiments, the disease is colon cancer. In further embodiments, the disease is a central nervous system cancer. In yet other embodiments, the disease is ovarian cancer. In still further embodiments, the disease is renal cancer. In other embodiments, the disease is prostate cancer. In further embodiments, the disease is breast cancer.

[0068] According to the disclosure, one or more compounds disclosed herein are dual specificity tyrosine phosphorylation regulated kinase IB (DYRK1B) enzyme inhibitors. Thus, they are useful in methods for inhibiting activity of a dual specificity tyrosine phosphorylation regulated kinase IB (DYRK1B) enzyme in a subject in need thereof, comprising administering a compound or a pharmaceutical composition disclosed herein to the subject in need thereof.

[0069] In other embodiments, the disclosure provides methods for treating early -onset coronary artery disease, hypertension, central obesity, or diabetes in a subject in need thereof, comprising administering a compound or a pharmaceutical composition disclosed herein to the subject in need thereof.Aspects

[0070] Aspect 1. A compound having the structure of Formula (I):APRE007-PCT | 106265.000238wherein:X is a bond, -N(H)-, -C(O)NH-, -NHC(O)-, or -N(Ci.6alkyl)-;R1is H, Ci-ealkyl, or NIL:R2and R2aare each, independently, H or Ci -ealkyl;R3is hydrogen, Ci-ealkyl, C2-ealkenyl, C2-ealkynyl, NH2, NH(Ci-ealkyl), N(Ci-ealkyl)2, Ci- ealkoxy, CN, halo, or NHC(O)O(Ci-ealkyl); andLinker is -(Ce-i4alkylene)-, wherein the alkylene is straight, optionally comprises one or more alkyl substituents, optionally wherein one or more carbons is replaced with O, and / or optionally wherein two adjacent carbon atoms of the alkylene are replaced with an aryl or a heteroaryl;or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof.

[0071] Aspect 2. The compound of Aspect 1, wherein X is a bond.

[0072] Aspect 3. The compound of Aspect 1, wherein X is -N(H)-.

[0073] Aspect 4. The compound of Aspect 1, wherein X is -C(O)NH-.

[0074] Aspect 5. The compound of Aspect 1, wherein X is -NHC(O)-.

[0075] Aspect 6. The compound of Aspect 1, wherein X is -N(Ci-6alkyl)-, such as - N(Cialkyl)-, -N(C2alkyl)-, -N(C3alkyl)-, -N(C4alkyl)-, -N(C5alkyl)-, or -N(C6alkyl)-;

[0076] Aspect 7. The compound of any one of the preceding Aspects, wherein R1is H.

[0077] Aspect 8. The compound of any one of Aspects 1-6, wherein R1is Ci-ealkyl, such as Cialkyl, C2alkyl, Csalkyl, C4alkyl. Cealkyl, or Cealkyl.

[0078] Aspect 9. The compound of Aspect 8, wherein R1is CH2OH.

[0079] Aspect 10. The compound of any one of Aspects 1-6, wherein R1is NH2.

[0080] Aspect 11. The compound of any one of the preceding Aspects, wherein R2is H.

[0081] Aspect 12. The compound of any one of Aspects 1-10, wherein R2is Ci-ealkyl, such as Cialkyl, C2alkyl, Csalkyl, C4alkyl, Cealkyl, or Cealkyl.

[0082] Aspect 13. The compound of any one of the preceding Aspects, wherein R2ais H.

[0083] Aspect 14. The compound of any one of Aspects 1-12, wherein R2ais Ci-ealkyl, such as Cialkyl, C2alkyl, Cialkyl. C4alkyl, Cealkyl, or Cealkyl.

[0084] Aspect 15. The compound of any one of the preceding Aspects, wherein R3is hydrogen.

[0085] Aspect 16. The compound of any one of Aspects 1-14, wherein R3is Ci-ealkyl, such as Cialkyl, C2alkyl, Cialkyl. C4alkyl, Cealkyl, or Cealkyl.

[0086] Aspect 17. The compound of any one of Aspects 1-14, wherein R3is C2-ealkenyl, such as C2alkenyl, Cialkcnyl. C4alkenyl, Cealkenyl, or Cealkenyl.APRE007-PCT | 106265.000238

[0087] Aspect 18. The compound of any one of Aspects 1-14, wherein R3is C2-ealkynyl, such as C2alkynyl, Galkyn l. C4alkynyl, Csalkynyl, or Cealkynyl.

[0088] Aspect 19. The compound of any one of Aspects 1-14, wherein R3is NH2.

[0089] Aspect 20. The compound of any one of Aspects 1-14, wherein R3is NH(Ci. ealkyl), such as NH(Cialkyl), NH(C2alkyl), NH(C3alkyl), NH(C4alkyl), NH(C5alkyl), or NH(Cealkyl).

[0090] Aspect 21. The compound of any one of Aspects 1-14, wherein R3is N(Ci-ealkyl)2, such as N(Ci-6alkyl)(Ci-6alkyl), or such as N(Cialkyl)2, N(Cialkyl)(C2alkyl), N(Cialkyl)(C3alkyl), N(C2alkyl)2, N(C3alkyl)2, N(C4alkyl)2, N(C5alkyl)2, or N(Cealkyl)2.

[0091] Aspect 22. The compound of any one of Aspects 1-14, wherein R3is Ci-ealkoxy, such as Cialkoxy, C2alkoxy, Galkoxy. C4alkoxy, Calkoxy. or Cealkoxy.

[0092] Aspect 23. The compound of any one of Aspects 1-14, wherein R3is CN.

[0093] Aspect 24. The compound of any one of Aspects 1-14, wherein R3is halo, such as F, Cl, Br, or I.

[0094] Aspect 25. The compound of any one of Aspects 1-14, wherein R3is NHC(O)O(Ci.6alkyl), such as NHC(O)O(Cialkyl), NHC(O)O(C2alkyl), NHC(O)O(C3alkyl), NHC(O)O(C4alkyl), NHC(O)O(C5alkyl), or NHC(O)O(C6alkyl).

[0095] Aspect 26. The compound of any one of Aspects 15-20 or 23-25, wherein R3is hydrogen, Ci-ealkyl, C2-ealkenyl, C2-ealkynyl, NH2, NH(Ci-6alkyl), CN, halo, or NHC(O)O(Ci. ealkyl).

[0096] Aspect 27. The compound of any one of the preceding Aspects, wherein Linker is -(Csalkylene)-, -(Cealkylene)-, -(Cvalkylene)-, -(Csalkylene)-, -(Cgalkylene)-, -(Cioalkylene)-, -(Cnalkylene)-, -(Cealkylene)-, -(Cealkylene)-, or -(Cealkylene)-.

[0097] Aspect 28. The compound of any one of the preceding Aspects, wherein Linker comprises one or more alkyl substituents.

[0098] Aspect 29. The compound of any one of the preceding Aspects, wherein in Linker, one or more carbon atom is replaced with O.

[0099] Aspect 30. The compound of Aspect 29, wherein Linker is -(CR10Rn)m-O-(CR12R13)n-, wherein R10-R13, are independently, H or Ci-ealkyl for each m and n unit, m is 1-6 and n is 1-6.

[0100] Aspect 31. The compound of Aspect 29, wherein Linker is -(CR'^R1 1)m-O-(CR12R13)n-O-(CR14R15)p-, wherein R10-R15, are independently, H or Ci-ealkyl for each m, n, and p unit, m is 1-6, n is 1-6, and p is 1-6.

[0101] Aspect 32. The compound of any one of the preceding Aspects, wherein two adjacent carbon atoms of the alkylene are replaced with an aryl or a heteroaryl in Linker.APRE007-PCT | 106265.000238

[0102] Aspect 33. The compound of Aspect 32, wherein Linker is -(CR10Rn)m-phenyl- C(R12R13)n, wherein R10-R13, are independently, H or Ci-ealkyl for each m and n unit, m is 1-6 and n is 1-6.

[0103] Aspect 34. The compound of Aspect 32, wherein Linker

[0104] Aspect 35. The compound of Aspect 32, wherein Linker is (C R 'R )m-p\ rid\ l-C(R12R13)n, wherein R10-R13, are independently, H or Ci-ealkyl for each m and n unit, m is 1-6 and n is 1-6.

[0105] Aspect 36. The compound of Aspect 32, wherein Linker

[0106] Aspect 37. The compound of Aspect 1 that is:APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238or a pharmaceutically acceptable salt thereof.

[0107] Aspect 38. The compound of Aspect 1 that is:APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238<<APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238><"APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238<>APRE007-PCT | 106265.000238>>"<APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238<APRE007-PCT | 106265.000238>> <<APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238>APRE007-PCT | 106265.000238<> ">APRE007-PCT | 106265.000238<>APRE007-PCT | 106265.000238>>APRE007-PCT | 106265.000238>APRE007-PCT | 106265.000238>>APRE007-PCT | 106265.000238"or a pharmaceutically acceptable salt thereof.

[0108] Aspect 39. A pharmaceutical composition comprising a compound of any one of the preceding Aspects and a pharmaceutically acceptable excipient.

[0109] Aspect 40. A method for inhibiting activity of a dual specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A) enzyme in a subject in need thereof, comprising administering a compound of any one of Aspects 1-38 or a pharmaceutical composition of Aspect 39 to the subject in need thereof.

[0110] Aspect 41. A method for treating Down syndrome, Intellectual Developmental Disorder Autosomal Dominant 7, dementia, Alzheimer’s Disease, Fronto -Temporal Degeneration, Huntington’s disease, or Parkinson’s disease in a subject in need thereof, comprising administering a compound of any one of Aspects 1-38 or a pharmaceutical composition of Aspect 39 to the subject in need thereof.APRE007-PCT | 106265.000238

[0111] Aspect 42. A method for treating cancer, diabetes, or heart disease in a subject in need thereof, comprising administering a compound of any one of Aspects 1-38 or a pharmaceutical composition of Aspect 39 to the subject in need thereof.

[0112] Aspect 43. The method of Aspect 42, wherein the cancer is lung cancer, pancreatic cancer, glioblastoma, melanoma, or leukemia.

[0113] Aspect 44. A method for inhibiting activity of a dual specificity tyrosine phosphorylation regulated kinase IB (DYRK1B) enzyme in a subject in need thereof, comprising administering a compound of any one of Aspects 1-38 or a pharmaceutical composition of Aspect 39 to the subject in need thereof.

[0114] Aspect 45. A method for treating early-onset coronary artery disease, hypertension, central obesity, or diabetes in a subject in need thereof, comprising administering a compound of any one of Aspects 1-38 or a pharmaceutical composition of Aspect 39 to the subject in need thereof.Aspects II

[0115] Aspect II- 1. A compound having the structure of Formula (I):wherein:X is a bond, -N(H)-, -C(O)NH-, -NHC(O)-, or -N(Ci.6alkyl)-;R1is H, Ci-ealkyl, or NFL;R2and R2aare each, independently, H or Ci -ealkyl;R3is hydrogen, Ci-ealkyl, C2-ealkenyl, C2-ealkynyl, NH2, NH(Ci-6alkyl), N(Ci-ealkyl)2, Ci- ealkoxy, CN, halo, or NHC(O)O(Ci-ealkyl); andLinker is -(Ckualkylcnc)-. wherein the alkylene is straight, optionally comprises one or more alkyl substituents, optionally wherein one or more carbons is replaced with O, and / or optionally wherein two adjacent carbon atoms of the alkylene are replaced with an aryl or a heteroaryl;or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof.

[0116] Aspect II-2. The compound of Aspect II- 1, wherein X is a bond.

[0117] Aspect II-3. The compound of Aspect II- 1, wherein X is -N(H)-.

[0118] Aspect II-4. The compound of Aspect II- 1, wherein X is -C(O)NH-.

[0119] Aspect II-5. The compound of Aspect II- 1, wherein X is -NHC(O)-.APRE007-PCT | 106265.000238

[0120] Aspect II-6. The compound of Aspect II- 1, wherein X is -N(Ci-6alkyl)-, such as -N(Cialkyl)-, -N(C2alkyl)-, -N(C3alkyl)-, -N(C4alkyl)-, -N(C5alkyl)-, or -N(C6alkyl)-.

[0121] Aspect II-7. The compound of any one of the preceding Aspects II, wherein R1is H.

[0122] Aspect II-8. The compound of any one of Aspects II- 1 to II-6, wherein R1is Ci-ealkyl, such as Cialkyl, CSalkyl. C3alkyl, C4alkyl, Calkyl. or Cealkyl.

[0123] Aspect II-9. The compound of Aspect II-8, wherein R1is CH2OH.

[0124] Aspect II- 10. The compound of any one of Aspects II- 1 to II-6, wherein R1is NH2.

[0125] Aspect II- 11. The compound of any one of the preceding Aspects II, wherein R2is H.

[0126] Aspect 11-12. The compound of any one of Aspects II- 1 to II- 10, wherein R2is Ci-ealkyl, such as Cialkyl, C2alkyl, C3alkyl, C4alkyl, Cealkyl, or Cealkyl.

[0127] Aspect 11-13. The compound of any one of the preceding Aspects II, wherein R2ais H.

[0128] Aspect 11-14. The compound of any one of Aspects II- 1 to 11-12, wherein R2ais Ci-ealkyl, such as Cialkyl, C2alkyl, Cialkyl. C4alkyl, Cealkyl, or Cealkyl.

[0129] Aspect 11-15. The compound of any one of the preceding Aspects II, wherein R3is hydrogen.

[0130] Aspect 11-16. The compound of any one of Aspects II- 1 to 11-14, wherein R3is Ci-ealkyl, such as Cialkyl, C2alkyl, Cealkyl, C4alkyl, Cealkyl, or Cealkyl.

[0131] Aspect 11-17. The compound of any one of Aspects II- 1 to 11-14, wherein R3is C2. ealkenyl, such as C2alkenyl, C3alkenyl, C4alkenyl, Cealkenyl, or Cealkenyl.

[0132] Aspect 11-18. The compound of any one of Aspects II- 1 to 11-14, wherein R3is C2. ealkynyl, such as C2alkynyl, C3alkynyl, C4alkynyl, Cealkynyl, or Cealkynyl.

[0133] Aspect 11-19. The compound of any one of Aspects II- 1 to 11-14, wherein R3is NH2.

[0134] Aspect 11-20. The compound of any one of Aspects II- 1 to 11-14, wherein R3is NH(Ci-ealkyl), such as NH(Cialkyl), NH(C2alkyl), NH(C3alkyl), NH(C4alkyl), NH(Cealkyl), or NH(C6alkyl).

[0135] Aspect 11-21. The compound of any one of Aspects II- 1 to 11-14, wherein R3is N(Ci-ealkyl)2, such as N(Ci.ealkyl)(Ci.ealkyl), or such as N(Cialkyl)2, N(Cialkyl)(C2alkyl), N(Cialkyl)(C3alkyl), N(C2alkyl)2, N(C3alkyl)2, N(C4alkyl)2, N(C5alkyl)2, or N(C6alkyl)2.

[0136] Aspect 11-22. The compound of any one of Aspects II- 1 to 11-14, wherein R3is Ci-ealkoxy, such as Cialkoxy, C2alkoxy, C3alkoxy, C4alkoxy, Cealkoxy, or Cealkoxy.

[0137] Aspect 11-23. The compound of any one of Aspects II- 1 to 11-14, wherein R3is CN.APRE007-PCT | 106265.000238

[0138] Aspect 11-24. The compound of any one of Aspects II- 1 to 11-14, wherein R3is halo, such as F, Cl, Br, or I.

[0139] Aspect 11-25. The compound of any one of Aspects II- 1 to 11-14, wherein R3is NHC(O)O(Ci.6alkyl), such as NHC(O)O(Cialkyl), NHC(O)O(C2alkyl), NHC(O)O(C3alkyl), NHC(O)O(C4alkyl), NHC(O)O(C5alkyl), or NHC(O)O(C6alkyl).

[0140] Aspect 11-26. The compound of any one of Aspects 11-15 to 11-20 or 11-23 to 11-25, wherein R3is hydrogen, Ci-ealkyl, C2-ealkenyl, C2-ealkynyl, NH2, NH(Ci. ealkyl), CN, halo, or NHC(O)O(Ci.6alkyl).

[0141] Aspect 11-27. The compound of any one of the preceding Aspects II, wherein Linker is -(Csalkylene)-, -(Cealkylene)-, -(CTalkylcnc)-. -(Csalkylene)-, -(Cgalkylene)-, -(Cioalkylene)-, -(Cnalkylene)-, -(Cealkylene)-, -(Cisalkylene)-, or -(Cealkylene)-.

[0142] Aspect 11-28. The compound of any one of the preceding Aspects II, wherein Linker comprises one or more alkyl substituents.

[0143] Aspect 11-29. The compound of any one of the preceding Aspects II, wherein in Linker, one or more carbon atom is replaced with O.

[0144] Aspect 11-30. The compound of Aspect 11-29, wherein Linker is -(CR10Rn)m-O-(CR12R13)n-, wherein R10-R13, are independently, H or Ci-ealkyl for each m and n unit, m is 1-6 and n is 1-6.

[0145] Aspect II-31. The compound of Aspect 11-29, wherein Linker is -(CR'^R1 1)m-O-(CR12R13)n-O-(CR14R15)P-, wherein R10-R15, are independently, H or Ci-ealkyl for each m, n, and p unit, m is 1-6, n is 1-6, and p is 1-6.

[0146] Aspect 11-32. The compound of any one of the preceding Aspects II, wherein two adjacent carbon atoms of the alkylene are replaced with an aryl or a heteroaryl in Linker.

[0147] Aspect 11-33. The compound of Aspect 11-32, wherein Linker is -(CR10Rn)m-phenyl-C(R12R13)n, wherein R10-R13, are independently, H or Ci-ealkyl for each m and n unit, m is 1-6 and n is 1-6.

[0148] Aspect 11-34. The compound of Aspect 11-32, wherein Linker

[0149] Aspect 11-35. The compound of Aspect 11-32, wherein Linker is -(CR10Rn)m-pyridyl-C(R12R13)n, wherein R10-R13, are independently, H or Ci-ealkyl for each m and n unit, m is 1-6 and n is 1-6.APRE007-PCT | 106265.000238

[0150] Aspect 11-36. The compound of Aspect 11-32, wherein Linker

[0151] Aspect 11-37. The compound of Aspect II- 1 that is:APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238or a pharmaceutically acceptable salt thereof.

[0152] Aspect 11-38. The compound of Aspect II- 1 that is:APRE007-PCT | 106265.000238>"APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238<<><APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238< >"APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238><APRE007-PCT | 106265.000238>> <APRE007-PCT | 106265.000238<<<APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238>APRE007-PCT | 106265.000238<APRE007-PCT | 106265.000238<>>APRE007-PCT | 106265.000238>>>APRE007-PCT | 106265.000238>>APRE007-PCT | 106265.000238>APRE007-PCT | 106265.000238or a pharmaceutically acceptable salt thereof.

[0153] Aspect 11-39. A pharmaceutical composition comprising a compound of any one of the preceding Aspects II and a pharmaceutically acceptable excipient.

[0154] Aspect 11-40. A method for inhibiting activity of a dual specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A) enzyme in a subject in need thereof, comprising administering a compound of any one of Aspects II- 1 to 11-38 or a pharmaceutical composition of Aspect 11-39 to the subject in need thereof.

[0155] Aspect 11-41. A method for treating Down syndrome, Intellectual Developmental Disorder Autosomal Dominant 7, dementia, Alzheimer’s Disease, Fronto -Temporal Degeneration, Huntington’s disease, or Parkinson’s disease in a subject in need thereof, comprising administering a compound of any one of Aspects II- 1 to 11-38 or a pharmaceutical composition of Aspect 11-39 to the subject in need thereof.

[0156] Aspect 11-42. A method for treating cancer, diabetes, or heart disease in a subject in need thereof, comprising administering a compound of any one of Aspects II- 1 to 11-38 or a pharmaceutical composition of Aspect 11-39 to the subject in need thereof.

[0157] Aspect 11-43. The method of Aspect 11-42, that is for treating diabetes

[0158] Aspect 11-44. The method of Aspect 11-42, that is for treating heart disease.

[0159] Aspect 11-45. The method of Aspect 11-42, that is for treating cancer.

[0160] Aspect 11-46. The method of Aspect 11-45, wherein the cancer is lung cancer, pancreatic cancer, glioblastoma, melanoma, or leukemia.APRE007-PCT | 106265.000238

[0161] Aspect 11-47. The method of Aspect 11-45, wherein the cancer is lung cancer, such as non-small cell lung cancer.

[0162] Aspect 11-48. The method of Aspect 11-45, wherein the cancer is colon cancer, central nervous system cancer, ovarian cancer, renal cancer, prostate cancer, or breast cancer.

[0163] Aspect 11-49. A method for inhibiting activity of a dual specificity tyrosine phosphorylation regulated kinase IB (DYRK1B) enzyme in a subject in need thereof, comprising administering a compound of any one of Aspects II- 1 to 11-38 or a pharmaceutical composition of Aspect 11-39 to the subject in need thereof.

[0164] Aspect 11-50. A method for treating early -onset coronary artery disease, hypertension, central obesity, or diabetes in a subject in need thereof, comprising administering a compound of any one of Aspects II- 1 to 11-38 or a pharmaceutical composition of Aspect 11-39 to the subject in need thereof.Examples

[0165] The following examples describe the preparation of representative compounds of the present invention. Melting points are reported as uncorrected in degrees centigrade. For high resolution mass spectral data, the calculated and experimentally found masses, [M+H]+, for the neutral formulae M are reported. Nuclear magnetic resonance data is reported as 5 in parts per million (ppm) downfield from the standard, tetramethylsilane, along with the solvent, nucleus, and field strength parameters. The spin-spin homonuclear coupling constants are reported as J values in hertz; and the multiplicities are reported as: s, singlet; d, doublet; t, triplet; q, quartet; quintet; or br, broadened, etc.

[0166] Examples 1A, IB and 1CExample 1A Example 1B Example 1C

[0167] Preparation of compound 2.25°C, 12 hrs1 2

[0168] To a solution of 5 -bromopentanoic acid (25 g, 138.10 mmol, 1 eq) and N-methoxymethanamine (9.28 g, 151.91 mmol, 1.1 eq) in DCM (200 mb) was added DIEA (19.63 g,APRE007-PCT | 106265.000238151.91 mmol, 26.46 mL, 1.1 eq) and EDCI (29.12 g, 151.91 mmol, l.l eq) at O°C. The mixture was stirred at 25 °C for 12 hrs. The reaction was quenched by water (100 mL), the organic layers was washed by aq.NaHSCL (100 mL x 3), and then washed with aq.NaHCOs (100 mL x 2). The organic layers were dried over Na2SC>4, fdtered and concentrated under reduced pressure to give 5-bromo-N-methoxy-N-methyl-pentanamide (16 g, 64.26 mmol, 46.53% yield, 90% purity) as a yellow oil. ’H NMR (400MHz, Chloroform-d) 53.67 (s, 3H), 3.58-3.37 (m, 2H), 3.16 (s, 3H), 2.45 (brt, J= 7.0 Hz, 2H), 1.90-1.78 (m, 4H).

[0169] Preparation of compound 3."

[0170] To a solution of 5-bromo-N-methoxy-N-methyl-pentanamide (5 g, 22.31 mmol, 1 eq), tert-butyl N-[(2R)-2-hydroxypropyl]carbamate (4.30 g, 24.54 mmol, 1.1 eq) in Toluene (100 mL) was added NaOH (12 M, 18.59 mL, 10 eq) and TB Al (4.12 g, 11.16 mmol, 0.5 eq). The mixture was stirred at 100°C for 1 hr. The reaction mixture was cooled to room temperature and diluted by water (50 mL), and then extracted with ethyl acetate (50 mL x 2). The combined organics were washed with brine (50 mL), dried over Na2SC>4, fdtered and concentrated under reduced pressure to give tertbutyl N-[(2R)-2-[5-[methoxy(methyl)amino]-5-oxo-pentoxy]propyl]carbamate (4.5 g, 12.72 mmol, 57.01% yield, 90% purity) as a yellow oil. 'H NMR (400MHz, Chloroform-d) 54.97-4.84 (m, 1H), 3.96-3.83 (m, 1H), 3.69 (s, 3H), 3.59-3.54 (m, 1H), 3.42-3.34 (m, 1H), 3.33-3.23 (m, 1H), 3.19 (s, 3H), 3.05-2.96 (m, 1H), 2.51-2.42 (m, 2H), 1.86-1.79 (m, 2H), 1.73-1.66 (m, 2H), 1.45 (s, 8H), 1.18 (d, J = 63 Hz, 3H)

[0171] Preparation of compound 4.

[0172] To a solution of tert-butyl N-[(2R)-2-[5-[methoxy(methyl)amino]-5-oxo-pentoxy]propyl]carbamate (4.5 g, 14.13 mmol, 1 eq) in THL (45 mL) was added MeMgBr (3 M, 14.13 mL, 3 eq) at 0°C. The mixture was stirred at 0°C for 1 hr. The reaction mixture was diluted by saturated solution of NH4CI (20 mL) and extracted with ethyl acetate (50 mL x 2). The combined organics were washed with brine (50 mL), dried over Na2SC>4, fdtered and concentrated under reduced pressure to give tert-butyl N-[(2R)-2-(5-oxohexoxy)propyl]carbamate (3 g, 9.88 mmol, 69.89% yield,APRE007-PCT | 106265.00023890% purity) as a yellow oil. 'H NMR (400MHz, Chloroform-d) 54.97-4.83 (m, 1H), 3.91 (br s, 1H), 3.60-3.50 (m, 2H), 3.33-3.23 (m, 1H), 3.01 (td, J = 6.7, 13.7 Hz, 1H), 2.53-2.45 (m, 2H), 2.20-2.12 (m, 3H), 1.84-1.62 (m, 4H), 1.46 (s, 9H), 1.19 (d, J = 6.4 Hz, 3H).

[0173] Preparation of compound 5.

[0174] The reaction was performed by flow chemistry. Solution 1: {tert-butyl N-[(2R)-2-(5-oxohexoxy) propyl] carbamate (3 g, 10.97 mmol, 1 eq)} in {NtL / McOH (61.38 g, 3.60 mol, 60 mb, 328.42 eq)}. The fixed bed (named FLR1, volume 5 mL) was completely packed with granular catalyst 10%Ru / SiC>2 (2.5 g, 1.00 eq) (WXC1019, 2.5 g). The H2 back pressure regulator was adjusted to 2.5 MPa, and the flow rate of H2 was 30 mL / min. Then the solution SI was pumped by Pump 1 {SI, Pl, 0.3 mL / min}to fixed bed {FLR1,SS, fixed bed, 6.350(l / 4”)mm, 5 mL, 100°C}.Then the reaction mixture was collected from the reactor output. Stop collecting the reaction mixture after 5 hrs. The fixed bed was washed by extra MeOH (300 mL). The organic layer was concentrated to give tert-butyl N-[(2R)-2-(5-aminohexoxy)propyl]carbamate (2 g, 6.56 mmol, 59.77% yield, 90% purity) as a yellow oil. ’H NMR (400MHz, Chloroform-d) 54.94 (br s, 1H), 3.91 (qd, J = 6.3, 9.5 Hz, 1H), 3.49 (d, J = 1.5 Hz, 2H), 3.40-3.22 (m, 2H), 3.11-2.97 (m, 2H), 2.82 (dt, J = 3.4, 12.5 Hz, 1H), 1.96-1.63 (m, 4H), 1.51-1.44 (m, 12H), 1.32-1.25 (m, 1H), 1.18 (d, J = 6.4 Hz, 3H), 1.13-1.02 (m, 1H)

[0175] Preparation of compound 6.

[0176] To a solution of tert-butyl N-[(2R)-2-(5-aminohexoxy)propyl]carbamate (2 g, 7.29 mmol, 1 eq) in THF (20 mL) was added TEA (2.21 g, 21.87 mmol, 3.04 m , 3 eq) and 6-bromo-2-chloro-3 -nitro-pyridine (1.04 g, 4.37 mmol, 0.6 eq). The mixture was stirred at 25 °C for 2 hrs. The reaction mixture was cooled to room temperature and diluted by water (20 mL), and then extracted with ethyl acetate (20 mL x 2). The combined organics were washed with brine (15 mL), dried over ISfeSCL, fdtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0-20% ethyl acetate / petroleum ether gradient @ 100 mL / min) to give tert-butyl N-[(2R)-2-[5-[(6-bromo-3-APRE007-PCT | 106265.000238nitro-2-pyridyl)amino]hexoxy]propyl]carbamate (0.5 g, 999.21 pmol, 13.71% yield, 95% purity) as a yellow oil. 'HNMR (400MHz, Chloroform-d) 58.23-8.16 (m, 2H), 6.75 (d, J= 8.5 Hz, 1H), 4.84 (br d, J= 1.9 Hz, 1H), 4.48-4.37 (m, 1H), 3.56-3.46 (m, 2H), 3.37 (td, J= 6.5, 9.1 Hz, 1H), 3.32-3.25 (m, 1H), 3.01 (ddd, = 5.0, 7.1, 13.7 Hz, 1H), 1.71-1.59 (m, 4H), 1.45 (s, 9H), 1.30 (d, .J = 6.5 Hz, 3H), 1.27-1.24 (m, 1H), 1.12 (dd, J= 2.3, 6.2 Hz, 3H), 0.90-0.85 (m, 1H).

[0177] Preparation of compound 7.

[0178] To a solution of tert-butyl N-[(2R)-2-[5-[(6-bromo-3-nitro-2-pyridyl)amino]hexoxy]propyl]carbamate (0.5 g, 1.05 mmol, 1 eq) in EtOH (5 m ), THF (5 m ) and H2O (1.25 mb) was added Fe (234.95 mg, 4.21 mmol, 4 eq) and NH4CI (225.05 mg, 4.21 mmol, 4 eq). The mixture was stirred at 80°C for 1 hr. The reaction mixture was cooled to room temperature and diluted by water (20 mb), and then extracted with ethyl acetate (20 mb x 2). The combined organics were washed with brine (15 mb), dried over Na2SC>4, fdtered and concentrated under reduced pressure to give tert-butyl N-[(2R)-2-[5-[(3-amino-6-bromo-2-pyridyl)amino]hexoxy]propyl]carbamate (0.45 g, 959.83 pmol, 91.26% yield, 95% purity) as a brown oil. ’H NMR (400MHz, Chloroform-d) 56.69 (d, J = 7.6 Hz, 1H), 6.59 (br d, J = 7.5 Hz, 1H), 4.98-4.85 (m, 1H), 3.59-3.44 (m, 2H), 3.41-3.23 (m, 2H), 3.18-3.08 (m, 1H), 3.06-2.95 (m, 1H), 1.60-1.47 (m, 6H), 1.45 (s, 9H), 1.22 (br d, J = 6.1 Hz, 3H), 1.14-1.07 (m, 3H)

[0179] Preparation of compound 8.

[0180] To a solution of tert-butyl N-[(2R)-2-[5-[(3-amino-6-bromo-2-pyridyl)amino]hexoxy]propyl]carbamate (0.45 g, 1.01 mmol, 1 eq) in MeOH (5 mb) was added sulfamic acid (196.20 mg, 2.02 mmol, 91.21 ph, 2 eq) and 1,1,1 -trimethoxy ethane (606.95 mg, 5.05 mmol, 634.88 ph, 5 eq). The mixture was stirred at 40°C for 1 hr. The reaction mixture was diluted by sodium bicarbonate aqueous solution (20 mb) and extracted with ethyl acetate (20 mb x 2). The combined organics were washed with brine (15 mb), dried over Na2SO4, fdtered and concentratedAPRE007-PCT | 106265.000238under reduced pressure to give a residue. The residue was purified by column chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-20% ethyl acetate / petroleum ether gradient @ 100 mL / min) to give tert-butyl N-[(2R)-2-[5-(5-bromo-2-methyl-imidazo[4,5-b]pyridin-3-yl)hexoxy]propyl]carbamate (0.3 g, 575.18 pmol, 56.93% yield, 90% purity) as a yellow oil. ESI [M+H+] = 469.1 / 471.2.

[0181] Preparation of compound 9.>

[0182] To a solution of tert-butyl N-[(2R)-2-[5-(5-bromo-2-methyl-imidazo[4,5-b]pyridin-3-yl)hexoxy]propyl]carbamate (0.3 g, 639.09 pmol, 1 eq) in THF (4 mL) was added ditert-butyl(cyclopenta-l,4-dien-l-yl)phosphane;dichloropalladium;iron (41.65 mg, 63.91 pmol, 0.1 eq), 2-chloro-4-(4,4,5,5-tetramethyloxaborolan-2-yl)pyridine (159.40 mg, 671.05 pmol, 1.05 eq) and a solution of K3PO4 (406.97 mg, 1.92 mmol, 3 eq) in H2O (1 mL). The mixture was stirred at 80°C for 1 hr under N2 atmosphere. The reaction mixture was diluted by water (20 mL) and extracted with ethyl acetate (20 mL x 2). The combined organics were washed with brine (15 mL), dried over ISfeSCL, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-70% ethyl acetate / petroleum ether gradient @ 100 mL / min) to give tert-butyl N-[(2R)-2-[5-[5-(2-chloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]hexoxy]propyl]carbamate (0.25 g, 448.16 pmol, 70.13% yield, 90% purity) as a brown oil. ESI [M+H+] = 502.3.

[0183] Preparation of compound 10.

[0184] To a solution of tert-butyl N-[(2R)-2-[5-[5-(2-chloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]hexoxy]propyl]carbamate (0.2 g, 398.37 pmol, 1 eq) in EtOAc (1 mL)APRE007-PCT | 106265.000238was added HCl / EtOAc (4 M, 4 mL). The mixture was stirred at 25°C for 1 hr. The reaction mixture was concentrated under reduced pressure to give (2R)-2-[5-[5-(2-chloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]hexoxy]propan-l-amine (0.15 g, crude, HC1 salt) as a yellow oil. ESI [M+H+] = 402.1.

[0185] Example 1 A: Preparation of Example 1 A product.10 Example 1A

[0186] To a solution of (2R)-2-[5-[5-(2-chloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]hexoxy]propan-l-amine (0.1 g, 248.80 pmol, HC1 salt,l eq) in 2-methylbutan-2-ol (5 mL) was added dicyclohexyl-[2-(2,6-diisopropoxyphenyl)phenyl]phosphane (23.22 mg, 49.76 pmol, 0.2 eq), (lE,4E)-l,5-diphenylpenta-l,4-dien-3-one;palladium (22.78 mg, 24.88 pmol, 0.1 eq) and sodium;2-methylpropan-2-olate (71.73 mg, 746.40 pmol, 3 eq). The mixture was stirred at 100°C for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: 3_Phenomenex Luna C18 75 x 30mm x 3um; mobile phase: [H2O (0.1% TFA)-ACN]; gradient: l%-30% B over 8.0 min) to give (9R)-9,15,17-trimethyl-10-oxa-5,7,16,18,22-pentazatetracyclo[14.5.2.12,6.019,23]tetracosa-l(22),2(24),3,5,17,19(23),20-heptaene (27 mg, 73.88 pmol, 29.69% yield, 100% purity, TFA salt) as a white solid. ’H NMR (400 MHz, DMSO-d6) 58.53-8.30 (m, 1H), 8.18-8.08 (m, 3H), 8.06-8.01 (m, 1H), 7.75-7.55 (m, 1H), 4.97-4.69 (m, 1H), 3.50 (br dd, J= 6.3, 9.4 Hz, 2H), 3.37 (br dd, J= 5.8, 14.1 Hz, 1H), 3.29-3.18 (m, 1H), 2.70 (d, J= 7.0 Hz, 4H), 2.31-2.12 (m, 1H), 2.05-1.77 (m, 1H), 1.71-1.34 (m, 7H), 1.22-1.11 (m, 3H). ESI [M+H] = 366.2.

[0187] Preparation of Examples IB and 1C products.Example 1A Example 1B Example 1C

[0188] The diastereomeric mixture was purified by SFC (column: DAICEL CHIRALPAK IC (250mm x 30mm, lOum); mobile phase: [CCE-EtOH (0.1% NH3H2O)]; B%:45%, isocratic elutionAPRE007-PCT | 106265.000238mode) to give (9R,15R)-9,15,17-trimethyl-10-oxa-5,7,16,18,22-pentazatetracyclo[14.5.2.12,6.019,23]tetracosa-l(22),2(24),3,5,17,19(23),20-heptaene (Peak 1, retention time =1.273 min) (17.84 mg, 47.49 pmol, 75.46% yield, 97% purity, ee% =100%) as a white solid. ’HNMR (400 MHz, DMSO-d6) 58.09 (dd, J= 1.8, 5.6 Hz, 1H), 8.00 (dd, J= 2.1, 8.3 Hz, 1H), 7.90 (dd, J= 2.1, 8.3 Hz, 1H), 7.73 (s, 1H), 7.51-7.42 (m, 1H), 7.34 (br d, J= 5.5 Hz, 1H), 4.74-4.63 (m, 1H), 3.69 (br s, 1H), 3.67 (br d, J= 2.6 Hz, 2H), 3.18 (br s, 1H), 3.13-3.08 (m, 1H), 2.88-2.81 (m, 1H), 2.63 (d, J= 2.0 Hz, 3H), 1.89-1.67 (m, 3H), 1.65-1.57 (m, 3H), 1.51-1.36 (m, 2H), 1.19-1.12 (m, 3H), ESI [M+H] = 366.2 and (9R,15S)-9,15,17-trimethyl-10-oxa-5,7,16,18,22-pentazatetracyclo[14.5.2.12,6.019,23]tetracosa-l(22),2(24),3,5,17, 19(23),20-heptaene (Peak 2, retention time =1.545 min) (5.01 mg, 13.62 pmol, 21.64% yield, 99% purity, ee% =97.54%) as yellow solid. 'HNMR (400 MHz, DMSO-d6) 58.09-7.94 (m, 2H), 7.76 (d, J= 8.1 Hz, 1H), 7.46 (s, 1H), 7.15 (br d, J= 5.3 Hz, 1H), 6.79 (br t, J= 5.9 Hz, 1H), 5.02-4.90 (m, 1H), 3.68-3.56 (m, 2H), 3.55-3.48 (m, 2H), 3.07 (td, J= 7.1, 14.4 Hz, 1H), 2.65 (s, 3H), 2.19-2.06 (m, 2H), 1.79 (td, J= 6.9, 13.5 Hz, 1H), 1.69-1.62 (m, 1H), 1.58 (br d, J= 7.0 Hz, 3H), 1.53-1.44 (m, 2H), 1.11 (br d, J= 6.0 Hz, 3H), ESI [M+H] = 366.2. The absolute stereochemistry labels for the position 15 methyl substitution were randomly assigned.Example 2A Example 2B

[0190] Preparation of compound 2.<>

[0191] To a solution of tert-butyl N-[(2S)-2-hydroxypropyl]carbamate (25 g, 142.67 mmol, 1 eq) in DMF (500 mb) was added NaH (14.27 g, 356.68 mmol, 60% purity, 2.5 eq) at 0°C. The mixture was stirred for 0.5 hr at 0°C. Then 2 -bromoethoxymethylbenzene (30.69 g, 142.67 mmol, 22.56 mb, 1 eq) was added and the reaction was stirred at 25°C for 1.5 hr. The reactionAPRE007-PCT | 106265.000238mixture was quenched by ammonium chloride aqueous solution (500 mL) and extracted with ethyl acetate (200 mL x 2). The combined organics were washed with brine (150 mL), dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 200 g SepaFlash® Silica Flash Column, Eluent of 0-20% ethyl acetate / petroleum ether gradient @ 100 mL / min) to give tert -butyl N-[(2S)-2-(2-benzyloxyethoxy)propyl]carbamate (5.5 g, 16.89 mmol, 11.84% yield, 95% purity) as colorless oil. ’H NMR (400 MHz, Chloroform-d) 57.41-7.29 (m, 5H), 5.15 (br s, 1H), 4.62-4.57 (m, 2H), 3.78-3.70 (m, 1H), 3.65-3.53 (m, 4H), 3.39-3.30 (m, 1H), 3.03 (ddd, J = 4.6, 7.4, 13.8 Hz, 1H), 1.44 (s, 8H), 1.15 (d, J = 6.3 Hz, 3H).

[0192] Preparation of compound 3.

[0193] To a mixture of Pd / C (1 g, 939.67 pmol, 10% purity, 5.29e-2 eq) in EtOH (55 mL)was added tert-butyl N-[(2S)-2-(2 -benzyloxyethoxy )propyl] carbamate (5.5 g, 17.78 mmol, 1 eq) under N2 atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (496.08 mmol, 27.91 eq) (50Psi) at 40°C for 12 hrs. The reaction mixture was filtered through a pad of Celite, the Celite was rinsed with ethyl acetate (200 mL). The combined organics were concentrated under reduced pressure to give tert-butyl N-[(2S)-2-(2-hy droxy ethoxy )propyl] carbamate (2.5 g, 10.26 mmol, 57.72% yield, 90% purity) as a colorless oil. ’H NMR (400 MHz, Chloroform-d) 53.76-3.71 (m, 2H), 3.70-3.62 (m, 1H), 3.61-3.48 (m, 2H), 3.33 (br d, J = 11.4 Hz, 1H), 3.05 (dd, J = 6.8, 13.9 Hz, 1H), 1.48-1.44 (m, 9H), 1.16 (d, J = 6.3 Hz, 3H)

[0194] Preparation of compound 4.

[0195] To a solution of tert-butyl N-[(2S)-2-(2-hydroxyethoxy)propyl]carbamate (0.5 g, 2.28 mmol, 1 eq) in THF (10 mL)was added NaH (273.60 mg, 6.84 mmol, 60% purity, 3 eq) at 0°C. The mixture was stirred for 0.5 hr. Then methyl 2 -bromoacetate (348.82 mg, 2.28 mmol, 215.85 pL, 1 eq) was added dropwise and the mixture was stirred at 25 °C for 1.5 hr. The reaction mixture was diluted by ammonium chloride aqueous solution (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined organics were washed with brine (50 mL), dried over Na2SC>4, filtered andAPRE007-PCT | 106265.000238concentrated under reduced pressure to give methyl 2-[2-[(lS)-2-(tert-butoxycarbonylamino)-l-methyl-ethoxy]ethoxy]acetate (2 g, crude, 5 batches) as a colorless oil. ESI [M+H-Boc] = 192.1.

[0196] Preparation of compound 5.

[0197] To a solution of methyl 2- [2- [( 1 S)-2-(tert-butoxycarbonylamino)- 1 -methyl-ethoxy] ethoxy] acetate (2 g, 6.86 mmol, 1 eq) in H2O (20 mL) and MeOH (20 mL) as added Li OH (328.83 mg, 13.73 mmol, 2 eq) at 0°C, the reaction was stirred at 25°C for 1 hr. The reaction mixture was extracted with MTBE (20 mL x 2). The aqueous phase was acidified by adding hydrochloric acid (1 M, 3 mL) dropwise at 0°C to pH = 5 and extracted with ethyl acetate (20 mL x 2). The combined organics were washed with brine (15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give 2-[2-[(lS)-2-(tert-butoxycarbonylamino)-l -methyl -ethoxy] ethoxy] acetic acid (1.5 g, 5.14 mmol, 74.85% yield, 95% purity) as a yellow oil. 'H NMR (400 MHz, Chloroform-d) 54.99 (br s, 1H), 4.17 (s, 2H), 3.80-3.74 (m, 3H), 3.69-3.60 (m, 2H), 3.41-3.28 (m, 1H), 3.13-3.03 (m, 1H), 1.51-1.40 (m, 9H), 1.22-1.12 (m, 3H).

[0198] Preparation of compound 6.<>

[0199] To a solution of 2-[2-[(lS)-2-(tert-butoxycarbonylamino)-l -methylethoxy] ethoxy] acetic acid (1.5 g, 5.41 mmol, 1 eq), N-methoxymethanamine (363.44 mg, 5.95 mmol, 1.1 eq) in DCM (30 mL) was added HATU (4.11 g, 10.82 mmol, 2 eq) and DIEA (2.10 g, 16.23 mmol, 2.83 mL, 3 eq). The reaction was stirred at 25°C for 1 hr. The reaction mixture was diluted by water (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined organics were washed with brine (50 mL), dried over ISfeSCL, fdtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0-60% ethyl acetate / petroleum ether gradient @ 100 mL / min) to give tert-butyl N-[(2S)-2-[2-[2-[methoxy(methyl)amino]-2-oxo-ethoxy]ethoxy]propyl]carbamate (1.3 g, 3.65 mmol, 67.51% yield, 90% purity) as a white gum. 'H NMR (400 MHz, Chloroform-d) 54.35 (s, 2H), 3.75-3.71 (m, 2H), 3.69 (s, 3H), 3.63-3.55 (m, 2H), 3.32 (brdd, J = 3.4, 13.8 Hz, 1H), 3.20 (s, 3H), 3.03 (br dd, J = 7.3, 13.8 Hz, 2H), 1.44 (s, 9H), 1.17-1.12 (m, 3H)APRE007-PCT | 106265.000238

[0200] Preparation of compound 7.

[0201] To a solution of tert-butyl N-[(2S)-2-[2-[2-[methoxy(methyl)amino]-2-oxo-ethoxy]ethoxy]propyl]carbamate (1.3 g, 4.06 mmol, 1 eq) in THF (15 mL) was added MeMgBr (3 M, 4.06 mL, 3 eq) at 0°C under nitrogen atmosphere. The mixture was stirred at 25 °C for 1 hr. The reaction mixture was diluted by ammonium chloride aqueous solution (20 mL) and extracted with ethyl acetate (20 mL x 2). The combined organics were washed with brine (15 mL), dried over ISfeSCL, fdtered and concentrated under reduced pressure to give tert-butyl N-[(2S)-2-(2-acetonyloxyethoxy)propyl]carbamate (0.9 g, 2.94 mmol, 72.50% yield, 90% purity) as a yellow oil.1HNMR (400 MHz, Chloroform-d) 54.12 (s, 2H), 3.78-3.72 (m, 1H), 3.68-3.64 (m, 2H), 3.61-3.54 (m, 2H), 3.37-3.29 (m, 1H), 3.07-2.98 (m, 1H), 2.18 (s, 3H), 1.45 (s, 9H), 1.15 (d, J = 6.3 Hz, 3H)

[0202] Preparation of compound 8.' Boc

[0203] The reaction was performed by flow chemistry. Solution 1: tert-butyl N-[(2S)-2-(2 -acetonyloxyethoxy) propyl] carbamate (0.9 g, 3.27 mmol, 1 eq) in NHs / MeOH (18 mL). The fixed bed (named FLR1, volume 5 mL) was completely packed with granular catalyst 10% Ru / SiCL (3 g, 29.68 mmol, 2.94 mL, 9.08 eq). The H2 back pressure regulator was adjusted to 2.5MPa, and the flow rate of H2 was 30mL / min. Then the solution SI was pumped by Pump 1 {SI, Pl, 0.3 mL / min}to fixed bed {FLR1,SS, fixed bed, 6.350(1 / 4”) mm, 5 mL, 100 °C}. Then the reaction mixture was collected from the reactor output. The reaction mixture was concentrated under reduced pressure to give tert-butyl N-[(2S)-2-[2-(2-aminopropoxy)ethoxy]propyl]carbamate (0.8 g, 2.61 mmol, 79.70% yield, 90% purity) as a yellow oil. 'H NMR (400 MHz, Chloroform-d) 58.38-8.21 (m, 2H), 3.78-3.52 (m, 8H), 3.32-3.21 (m, 1H), 3.11-2.97 (m, 1H), 1.45 (s, 12H), 1.15 (d, J = 6.1 Hz, 3H)

[0204] Preparation of compound 9.APRE007-PCT | 106265.000238

[0205] To a solution of tert-butyl N-[(2S)-2-[2-(2-aminopropoxy)ethoxy]propyl]carbamate (0.8 g, 2.89 mmol, 1 eq) in THF (8 mb)was added 6-bromo-2-chloro-3-nitro-pyridine (343.65 mg, 1.45 mmol, 0.5 eq) and TEA (878.72 mg, 8.68 mmol, 1.21 mb, 3 eq). The mixture was stirred at25 °C for 1 hr. The reaction mixture was diluted by water (20 mb) and extracted with ethyl acetate (20 mb x 2). The combined organics were washed with brine (15 mb), dried over ISfeSCh, fdtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-40% ethyl acetate / petroleum ether gradient @ 50 mb / min) to give tert-butyl N-[(2S)-2-[2-[2-[(6-bromo-3-nitro-2-pyridyl)amino]propoxy]ethoxy]propyl]carbamate (0.6 g, 1.19 mmol, 41.25% yield, 95% purity) as a yellow oil. 'HNMR (400 MHz, Chloroform-d) 5 8.46 (br d, J = 5.9 Hz, 1H), 8.21 (d, J = 8.5 Hz, 1H), 6.76 (d, J = 8.5 Hz, 1H), 5.05 (br d, J = 2.3 Hz, 1H), 4.65-4.56 (m, 1H), 3.78-3.68 (m, 1H), 3.68-3.64 (m, 2H), 3.63-3.53 (m, 4H), 3.38-3.29 (m, 1H), 3.09-2.97 (m, 1H), 1.43 (s, 9H), 1.36 (d, J = 6.6 Hz, 3H), 1.14 (d, J = 6.3 Hz, 3H).

[0206] Preparation of compound 10.

[0207] To a solution of tert-butyl N-[(2S)-2-[2-[2-[(6-bromo-3-nitro-2-pyridyl)amino]propoxy]ethoxy]propyl]carbamate (0.6 g, 1.26 mmol, 1 eq) in EtOH (7 m ), THF (7 m ) and H2O (2 mb) was added Fe (280.78 mg, 5.03 mmol, 4 eq) and NH4CI (268.94 mg, 5.03 mmol, 4 eq). The mixture was stirred at 80°C for 2 hrs. The reaction mixture was cooled to room temperature and diluted by water (20 mb) and extracted with ethyl acetate (20 mb x 2). The combined organics were washed with brine (15 mb), dried over Na2SC>4, fdtered and concentrated under reduced pressure to give tert-butyl N-[(2S)-2-[2-[2-[(3-amino-6-bromo-2-pyridyl)amino]propoxy]ethoxy]propyl]carbamate (0.6 g, 1.21 mmol, 96.03% yield, 90% purity) as a brown oil. ESI [M+ H+] = 447.1 / 449.1.APRE007-PCT | 106265.000238

[0208] Preparation of compound 11.

[0209] To a solution of tert-butyl N-[(2S)-2-[2-[2-[(3-amino-6-bromo-2-pyridyl)amino]propoxy]ethoxy]propyl]carbamate (0.6 g, 1.34 mmol, 1 eq) in MeOH (6 mb) was added sulfamic acid (260.44 mg, 2.68 mmol, 121.08 pL, 2 eq) and 1,1,1 -trimethoxy ethane (805.69 mg, 6.71 mmol, 842.77 pL, 5 eq). The mixture was stirred at 40°C for 2 hrs. The reaction mixture was diluted by sodium bicarbonate aqueous solution (20 mb), extracted with ethyl acetate (20 mb x 2). The combined organics were washed with brine (15 mb), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-30% ethyl acetate / petroleum ether gradient @ 100 mL / min) to give tert-butyl N-[(2S)-2-[2-[2-(5-bromo-2-methyl-imidazo[4,5-b]pyridin-3-yl)propoxy]ethoxy]propyl]carbamate (0.5 g, mmol, 75.13% yield, 95% purity) as a yellow oil. ESI [M+ H+] = 471.1 / 473.1.

[0210] Preparation of compound 12.

[0211] To a solution of tert-butyl N-[(2S)-2-[2-[2-(5-bromo-2-methyl-imidazo[4,5-b]pyridin-3-yl)propoxy]ethoxy]propyl]carbamate (0.5 g, 1.06 mmol, 1 eq) in THF (1 mb) was added ditert-butyl(cyclopenta-l,4-dien-l-yl)phosphane;dichloropalladium; iron (69.13 mg, 106.07 pmol, 0.1 eq), 2-chloro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (266.75 mg, 1.11 mmol, 1.05 eq) and a solution of K3PO4 (675.45 mg, 3.18 mmol, 3 eq) in H2O (0.25 mb). The mixture was stirred at 80°C for 2 hrs under N2 atmosphere. The reaction mixture was diluted by water (20 mb), extracted with ethyl acetate (20 mb x 2). The combined organics were washed with brine (15 mb), dried over Na2SC>4, fdtered and concentrated under reduced pressure to give a residue. The residue was purifiedAPRE007-PCT | 106265.000238by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-90% ethyl acetate / petroleum ether gradient @ 100 mL / min) to give tert -butyl N-[(2S)-2-[2-[2-[5-(2-chloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]propoxy]ethoxy]propyl]carbamate (0.3 g, 535.69 pmol, 50.50% yield, 90% purity) as a brown oil. ESI [M+ H+] = 504.2.

[0212] Preparation of compound 13.

[0213] A solution of tert-butyl N- [(2 S)-2- [2- [2- [5 -(2-chloro-4-pyridyl)-2-methyl-imidazo [4,5-b]pyridin-3-yl]propoxy]ethoxy]propyl]carbamate (0.3 g, 595.21 pmol, 1 eq) in HCl / EtOAc (2 mL) was stirred at 25 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give (2S)-2-[2-[2-[5-(2-chloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]propoxy]ethoxy]propan-l -amine (0.25 g, 510.94 pmol, 85.84% yield, 90% purity, HC1 salt) as brown solid. ESI [M+ H+] = 404.1.

[0214] Preparation of AN_06192024_786.

[0215] To a solution of (2S)-2-[2-[2-[5-(2-chloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]propoxy]ethoxy]propan-l-amine (0.1 g, 247.58 pmol, 1 eq) in 2-methylbutan-2-ol (10 mL) was added dicyclohexyl-[2-(2,6-diisopropoxyphenyl)phenyl]phosphane (23.11 mg, 49.52 pmol, 0.2 eq), (1E,4E)- 1,5 -diphenylpenta- l,4-dien-3 -one palladium (22.67 mg, 24.76 pmol, 0.1 eq) and sodium;2-methylpropan-2-olate (71.38 mg, 742.75 pmol, 3 eq). The mixture was stirred at 100 °C for 1 hr under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: WePure Biotech XP tC18 150 x 40 x 7um; mobile phase: [H2O (10 mM NFLFICO3)-ACN]; gradient: 15%-55% B over 8.0 min) to give a mix of diastereomers (9S)-9, 15, 17-trimethyl-10, 13-dioxa-5,7, 16, 18,22-pentazatetracyclo[14.5.2.12,APRE007-PCT | 106265.0002386.019,23]tetracosa-l(22),2(24),3,5, 17, 19(23), 20-heptaene (30 mg, 80.09 pmol, 32.35% yield, 98% purity) as a white solid. ’HNMR (400 MHz, DMSO-d6) 5 8.08-8.04 (m, 1H), 8.00-7.94 (m, 1H), 7.85-7.73 (m, 1H), 7.66-7.52 (m, 1H), 7.23-7.12 (m, 1H), 6.86-6.68 (m, 1H), 4.88-4.70 (m, 1H), 4.55-4.10 (m, 2H), 3.83-3.57 (m, 4H), 3.50-3.42 (m, 2H), 3.15-3.03 (m, 1H), 2.65-2.59 (m, 3H), 1.62-1.55 (m, 3H), 1.18-1.13 (m, 3H)

[0216] Preparation of Examples 2A and 2B products.Example 2A Example 2B

[0217] The diastereomeric mixture was purified by SFC (column: DAICEL CHIRALCEL OD (250 mm x 30 mm, 10 um); mobile phase: [CCE-MeOH (0.1% NH3H2O)]; gradient: 20%-40% B over 13.0 min) to give (9S,15S)-9,15,17-trimethyl-10,13-dioxa-5,7,16,18,22-pentazatetracyclo[14.5.2.12,6.019,23]tetracosa-l(22),2(24),3,5,17,19(23),20-heptaene (Peak 1, retention time =3.223 min) (4.74 mg, 12.90 pmol, 18.96% yield, ee%=100%) as a white solid. 'H NMR (400 MHz, DMSO-d6) 5 8.05 (d, J= 5.3 Hz, 1H), 7.97 (d, J= 8.3 Hz, 1H), 7.75 (d, J= 8.3 Hz, 1H), 7.53 (s, 1H), 7.13 (dd, J= 1.2, 5.3 Hz, 1H), 6.71 (t, J= 6.4 Hz, 1H), 4.85 (sxt, J= 6.9 Hz, 1H), 4.53 (dd, J= 8.2, 9.7 Hz, 1H), 4.12 (dd, J= 5.7, 9.8 Hz, 1H), 3.84-3.73 (m, 2H), 3.72-3.63 (m, 2H), 3.62-3.55 (m, 1H), 3.39 (ddd, J= 2.4, 6.1, 14.6 Hz, 1H), 3.13 (td, J = 6.9, 14.4 Hz, 1H), 2.63 (s, 3H), 1.57 (d, J= 6.9 Hz, 3H), 1.14 (d, J= 6.0 Hz, 3H), ESI [M+H] = 368.1 and (9S,15R)-9,15,17-trimethyl-10,13-dioxa-5,7,16,18,22-pentazatetracyclo [14.5.2.12, 6.019, 23]etracosa-1(22), 2(24), 3, 5, 17, 19(23), 20-heptaene (Peak 2 retention time =3.450 min) (6.61 mg, 17.99 pmol, 26.44% yield, ee%=95.54%) as a white solid. 'HNMR (400 MHz, DMSO-d6) 58.07 (d, J = 5.3 Hz, 1H), 7.97 (d, J= 8.3 Hz, 1H), 7.83 (d, J= 8.4 Hz, 1H), 7.64 (s, 1H), 7.21 (dd, J = 1.1, 5.3 Hz, 1H), 6.82 (t, J= 6.3 Hz, 1H), 4.73 (sxt, J = 7.0 Hz, 1H), 4.48-4.35 (m, 2H), 3.77-3.57 (m, 3H), 3.50-3.42 (m, 3H), 3.12-3.03 (m, 1H), 2.61 (s, 3H), 1.60 (d, J= 6.8 Hz, 3H), 1.16 (d, J= 6.0 Hz, 3H), ESI [M+H] = 368.1.

[0218] The absolute stereochemistry labels for the position 15 methyl substitution were randomly assigned.

[0219] Example 3A and 3BAPRE007-PCT | 106265.000238Example 3A Example 3B

[0220] Preparation of compound 2., , , 1 2

[0221] To a solution of tert-butyl N-(4-hydroxybutyl)carbamate (8 g, 42.27 mmol, 1 eq) in MeCN (80 mL) was added benzyl(trimethyl)ammonium;hydroxide (2.12 g, 12.68 mol, 2.31 mL, 0.3 eq) and tertbutylprop-2 -enoate (10.84 g, 84.54 mmol, 12.27 mL, 2 eq) at 30°C. The resulting solution was stirred for 12 hrs at 30°C. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 200 g SepaFlash® Silica Flash Column, Eluent of 0-10% ethyl acetate / petroleum ether gradient @ 100 mL / min) to give tert-butyl 3-[4-(tert-butoxycarbonylamino)butoxy]propanoate (9.5 g, 28.43 mmol, 67.26% yield, 95% purity) as a colorless oil. 'H NMR (400 MHz, Chloroform-d) 54.77 (br s, 1H), 3.68-3.63 (m, 2H), 3.45 (t, J = 5.9 Hz, 2H), 3.18-3.09 (m, 2H), 2.52-2.46 (m, 2H), 1.65-1.58 (m, 4H), 1.45 (d, J = 4.4 Hz, 18H).

[0222] Preparation of compound 3.2 3

[0223] To a solution of tert-butyl 3-[4-(tert-butoxycarbonylamino)butoxy]propanoate (9.5 g, 29.93 mmol, 1 eq) in MeOH (95 mL) was added NaOH (6 M, 12.47 mb, 2.5 eq). The reaction was stirred for 1 hr at 60°C. The aqueous layer was cooled to 0°C and adjusted to pH=3.5 with HC1 (1 N). The aqueous layer was extracted with ethyl acetate (2x250 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated to give 3-[4-(tert-butoxycarbonylamino)butoxy]propanoic acid (8.5 g, 29.28 mmol, 97.82% yield, 90% purity) as a colorless oil. 'HNMR (400 MHz, Chloroform-d) 53.76-3.68 (m, 2H), 3.49 (t, J = 5.9 Hz, 2H), 3.13 (brt, J = 6.6 Hz, 2H), 2.65-2.59 (m, 2H), 1.65-1.51 (m, 4H), 1.45 (s, 9H).APRE007-PCT | 106265.000238

[0224] Preparation of compound 4.> "

[0225] To a solution of 3-[4-(tert-butoxycarbonylamino)butoxy]propanoic acid (8.5 g, 32.53 mmol, 1 eq), N-methoxymethanamine (2.98 g, 48.79 mmol, 1.5 eq) in DCM (85 mL) was added HATU (13.60 g, 35.78 mmol, 1.1 eq) and DIEA (8.41 g, 65.06 mmol, 11.33 mL, 2 eq). The reaction was stirred for 1 hr at 25 °C. The reaction mixture was diluted by water (100 mL), extracted with ethyl acetate (200 mL x 2). The combined organics were washed with brine (150 mL), dried over Na2SC>4, fdtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0-50% ethyl acetate / petroleum ether gradient @ 100 mL / min) to give tert-butyl N-[4-[3-[methoxy(methyl)amino]-3-oxo-propoxy]butyl]carbamate (7 g, 21.85 mmol, 67.17% yield, 95% purity) as a colorless oil. ’H NMR (400 MHz, Chloroform-d) 53.70 (s, 3H), 3.47 (t, J = 6.1 Hz, 2H), 3.19 (s, 3H), 3.16-3.10 (m, 2H), 2.71 (br t, J = 6.4 Hz, 2H), 1.87-1.73 (m, 2H), 1.64-1.51 (m, 4H), 1.44 (s, 9H).

[0226] Preparation of compound 5.

[0227] To a solution of tert-butyl N-[4-[3-[methoxy(methyl)amino]-3-oxo-propoxy]butyl]carbamate (7 g, 23.00 mmol, 1 eq) in THF (70 mL) was added MeMgBr (3 M, 19.16 mb, 2.5 eq) at 0°C under N2 atmosphere. The reaction was stirred at 0°C for 1 hr. The reaction mixture was diluted by ammonium chloride aqueous solution (100 mL), extracted with ethyl acetate (200 mL x 2). The combined organics were washed with brine (150 mL), dried over Na2SO4, fdtered and concentrated under reduced pressure to give tert-butyl N-[4-(3-oxobutoxy)butyl]carbamate (4.5 g, 15.62 mmol, 67.91% yield, 90% purity) as yellow oil. 'H NMR (400 MHz, Chloroform-d) 53.72-3.64 (m, 2H), 3.44 (t, J = 6.0 Hz, 2H), 3.18-3.10 (m, 2H), 2.83 (d, J = 1.0 Hz, 3H), 2.68 (t, J = 6.2 Hz, 2H), 1.60-1.52 (m, 4H), 1.45 (s, 9H)

[0228] Preparation of compound 6.APRE007-PCT | 106265.000238

[0229] The reaction was performed by flow chemistry. Solution 1: {tert-butyl N-[4-(3-oxobutoxy)butyl] carbamate (4.5 g, 17.35 mmol, 1 eq)} in {NHs / MeOH (90 mL)}. The fixed bed (named FLR1, volume 5 mL) was completely packed with granular catalyst 10% Ru / SiCL (3 g, 29.68 mmol, 2.94 mL, 1.71 eq). The LL back pressure regulator was adjusted to 2.5 MPa, and the flow rate of FL was 30mL / min. Then the solution SI was pumped by Pump 1 {SI, Pl, 0.3 mL / min}to fixed bed {FLR1,SS, fixed bed, 6.350 (1 / 4”) mm, 5 mL, 100 °C}. Then the reaction mixture was collected from the reactor output. The reaction mixture was concentrated under reduced pressure to give tertbutyl N-[4-(3-aminobutoxy)butyl]carbamate (4 g, 13.83 mmol, 79.68% yield, 90% purity) as a yellow oil. 'HNMR (400 MHz, Chloroform-d) 53.68 (br t, J = 5.8 Hz, 1H), 3.56-3.47 (m, 2H), 3.43 (br t, J = 5.8 Hz, 1H), 3.21-3.04 (m, 3H), 1.64-1.53 (m, 6H), 1.44 (s, 9H), 1.30-1.08 (m, 3H).

[0230] Preparation of compound 7.

[0231] To a solution of tert-butyl N-[4-(3-aminobutoxy)butyl]carbamate (4 g, 15.36 mmol, 1 eq) in THF (40 mL) was added TEA (4.66 g, 46.09 mmol, 6.41 mL, 3 eq) and 6-bromo-2-chloro-3-nitro-pyridine (1.82 g, 7.68 mmol, 0.5 eq). The mixture was stirred at 25°C for 1 hr. The reaction mixture was cooled to room temperature and diluted by water (50 mL), extracted with ethyl acetate (50 mL x 2). The combined organics were washed with brine (50 mL), dried over Na2SC>4, filtered and concentrated under reduced

[0232] pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0-12% ethyl acetate / petroleum ether gradient @ 100 mL / min) to give tert -butyl N-[4-[3-[(6-bromo-3-nitro-2-pyridyl)amino]butoxy]butyl]carbamate (1.7 g, 3.50 mmol, 22.79% yield, 95% purity) as a yellow oil. ’H NMR (400 MHz, Chloroform-d) 5 8.63 (br d, J = 7.0 Hz, 1H), 8.20 (d, J = 8.5 Hz, 1H), 6.73 (d, J = 8.6 Hz, 1H), 4.64-4.56 (m, 1H), 3.67-3.52 (m, 2H), 3.49-3.40 (m, 2H), 3.14 (q, J = 6.3 Hz, 2H), 1.98 (dq, J = 4.9, 9.3 Hz, 1H), 1.89-1.78 (m, 1H), 1.68-1.61 (m, 2H), 1.59-1.52 (m, 2H), 1.44 (s, 9H), 1.32 (d, J = 6.6 Hz, 3H).

[0233] Preparation of compound 8.APRE007-PCT | 106265.000238

[0234] To a solution of tert-butyl N-[4-[3-[(6-bromo-3-nitro-2-pyridyl)amino]butoxy]butyl]carbamate (0.7 g, 1.52 mmol, 1 eq) in EtOH (8 m ), THF (8 m ) and H2O (2 mb) was added Fe (338.93 mg, 6.07 mmol, 4 eq) and NH4CI (324.65 mg, 6.07 mmol, 4 eq). The mixture was stirred at 80°C for 2 hrs. The reaction mixture was cooled to room temperature and diluted by water (50 mb), extracted with ethyl acetate (50 mb x 2). The combined organics were washed with brine (50 mb), dried over ISfeSCE, fdtered and concentrated under reduced pressure to give tert-butyl N-[4-[3-[(3-amino-6-bromo-2-pyridyl)amino]butoxy]butyl]carbamate (0.7 g, crude) as a brown oil. ESI [M+H] = 431.2 / 433.2.

[0235] Preparation of compound 9.

[0236] To a solution of tert-butyl N-[4-[3-[(3-amino-6-bromo-2-pyridyl)amino]butoxy]butyl]carbamate (0.7 g, 1.62 mmol, 1 eq)in MeOH (7 mb)was added sulfamic acid (157.56 mg, 1.62 mmol, 73.25 pb. 1 eq) and 1,1,1 -trimethoxy ethane (974.84 mg, 8.11 mmol, 1.02 mb, 5 eq). The mixture was stirred at 40°C for 2 hrs. The reaction mixture was cooled to room temperature and diluted by water (50 mb), extracted with ethyl acetate (50 mb x 2). The combined organics were washed with brine (50 mb), dried over ISfeSCE, fdtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-80% ethyl acetate / petroleum ether gradient @ 100 mb / min) to give tert-butyl N-[4-[3-(5-bromo-2-methyl-imidazo[4,5-b]pyridin-3-yl)butoxy]butyl]carbamate (0.3 g, 625.84 pmol, 38.57% yield, 95% purity) as a brown oil. ESI [M+H-Boc] = 455.1 / 457.1.

[0237] Preparation of compound 10.APRE007-PCT | 106265.000238

[0238] To a mixture of tert-butyl N-[4-[3-(5-bromo-2-methyl-imidazo[4,5-b]pyridin-3-yl)butoxy]butyl]carbamate (0.3 g, 658.78 pmol, 1 eq) in THF (1 mb) was added ditert-butyl(cyclopenta-l,4-dien-l-yl)phosphane;dichloropalladium;iron (42.94 mg, 65.88 pmol, 0.1 eq), 2-chloro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (165.67 mg, 691.72 pmol, 1.05 eq) and a solution of K3PO4 (419.51 mg, 1.98 mmol, 3 eq) in H2O (0.25 mb). The mixture was stirred at 80°C for 1 hr under N2 atmosphere. The reaction mixture was cooled to room temperature and diluted by water (50 mb), extracted with ethyl acetate (50 mb x 2). The combined organics were washed with brine (50 mb), dried over ISfeSCE, fdtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-80% ethyl acetate / petroleum ether gradient @ 100 mL / min) to give tert-butyl N-[4-[3-[5-(2-chloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]butoxy]butyl]carbamate (0.2 g, 389.33 pmol, 59.10% yield, 95% purity) as a brown oil. ESI [M+H] = 488.2.

[0240] A solution of tert-butyl N-[4-[3-[5-(2-chloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]butoxy]butyl]carbamate (0.2 g, 409.82 pmol, 1 eq) in HCl / EtOAc (2 mb) was stirred at 25°C for 1 hr. The reaction mixture was concentrated under reduced pressure to give 4-[3-[5-(2-chloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]butoxy]butan-l-amine (0.15 g, 335.79 pmol, 81.94% yield, 95% purity, HC1 salt) as a brown solid. ESI [M+H] = 388.2.

[0241] Preparation of compound 11A, 1 IB.APRE007-PCT | 106265.000238

[0242] The racemic material was purified by SFC (column: DAICEL CHIRALPAK IG (250 mm x 30 mm, 10 um); mobile phase: [CCE-EtOH (0.1% NH3H2O)]; B%:50%, isocratic elution mode) to give 4-[(3R)-3-[5-(2-chloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridine-3-yl]butoxy]butan-1-amine (Peak 1, retention time = 0.744 min) (40 mg, 101.06 pmol, 42.88% yield, ee% = 99.64%) as a yellow oil. ESI [M+H] = 388.1 and 4-[(3S)-3-[5-(2-chloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]butoxy]butan- 1-amine (Peak 2 retention time = 1.188 min) (40 mg, 101.06 pmol, 42.88% yield, ee% = 99.78%) as a yellow oil. ESI [M+H] = 388.1. The absolute stereochemistry labels were randomly assigned.

[0243] Preparation of Example 3 A product.11 A Example 3A

[0244] To a mixture of 4-[(3R)-3-[5-(2-chloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3 -yl]butoxy]butan- 1-amine (40 mg, 103.12 pmol, 1 eq) in 2-methylbutan-2-ol (10 mL) was added dicyclohexyl-[2-(2,6-diisopropoxyphenyl)phenyl]phosphane (9.62 mg, 20.62 pmol, 0.2 eq), (1E,4E)-l,5-diphenylpenta-l,4-dien-3-one;palladium (9.44 mg, 10.31 pmol, 0.1 eq) and sodium;2-methylpropan-2-olate (29.73 mg, 309.35 pmol, 3 eq). The mixture was stirred at 100°C for 2 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 100 x 30 mm x 10 um; mobile phase: [H2O (10 mM NJTJTCOs^ACN]; gradient: 45%-80% B over 8.0 min) to give (15R)-15,17-dimethyl-12-oxa-5,7,16,18,22-pentazatetracyclo[14.5.2.12,6.019,23]tetracosa-l(21),2(24),3,5,17,19,22-heptaene (12.53 mg, 34.75 pmol, 33.70% yield, 97% purity) as a white solid. ’H NMR (400 MHz, DMSO-d6) 58.06-7.94 (m, 2H), 7.73 (d, J = 8.3 Hz, 1H), 7.40 (s, 1H), 7.07 (d, J = 5.1 Hz, 1H), 6.59 (brt, J = 6.1 Hz, 1H), 5.12-5.00 (m, 1H), 3.61-3.37 (m, 4H), 3.26 (br d, J = 6.8 Hz, 1H), 3.18-3.05 (m, 1H), 2.75-2.66 (m, 1H), 2.64 (s, 3H), 2.41-2.31 (m, 1H), 1.79-1.68 (m, 2H), 1.64-1.47 (m, 5H). ESI [M+H] = 352.2.APRE007-PCT | 106265.000238

[0245] Preparation of Example 3B product.11 B Example 3B

[0246] To a mixture of 4-[(3S)-3-[5-(2-chloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]butoxy]butan-l-amine (40.00 mg, 103.12 pmol, 1 eq) in 2-methylbutan-2-ol (10 m ) was added dicyclohexyl-[2-(2,6-diisopropoxyphenyl)phenyl]phosphane (9.62 mg, 20.62 pmol, 0.2 eq), (1E,4E)-l,5-diphenylpenta-l,4-dien-3-one;palladium (9.44 mg, 10.31 pmol, 0.1 eq) and sodium;2-methylpropan-2-olate (29.73 mg, 309.35 pmol, 3 eq). The mixture was stirred at 100°C for 2 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 100 x 30 mm x 10 um; mobile phase: [H2O (10 mM NH4HCOS)-ACN]; gradient: 45%-80% B over 8.0 min) to give (15S)-15,17-dimethyl-12-oxa-5,7,16,18,22-pentazatetracyclo[14.5.2.12,6.019,23]tetracosa-l(21),2(24),3,5,17,19,22-heptaene (14.67 mg, 40.08 pmol, 38.86% yield, 96% purity) as a white solid. ’H NMR (400 MHz, DMSO-d6) 58.10-7.93 (m, 2H), 7.73 (d, J = 8.3 Hz, 1H), 7.40 (s, 1H), 7.07 (d, J = 5.3 Hz, 1H), 6.59 (brt, J = 6.1 Hz, 1H), 5.07 (sxt, J = 6.9 Hz, 1H), 3.60-3.37 (m, 4H), 3.30-3.21 (m, 1H), 3.17-3.06 (m, 1H), 2.75-2.60 (m, 4H), 2.37 (qd, J = 6.6, 13.5 Hz, 1H), 1.78-1.66 (m, 2H), 1.63-1.49 (m, 5H). ESI [M+H] = 352.2. The absolute stereochemistry labels were randomly assigned.

[0247] Example 4APRE007-PCT | 106265.000238

[0249] To a solution of 5 -bromopentanenitrile (10 g, 61.72 mmol, 1 eq), tert-butyl N-(2-hydroxyethyl) carbamate (9.95 g, 61.72 mmol, 9.55 mb, 1 eq) in Toluene (200 mL) was added TEAB (6.49 g, 30.86 mmol, 5.82 mL, 0.5 eq) and NaOH (12 M, 51.43 mL, 10 eq). The mixture was stirred at 100°C for 1 hr. The reaction mixture was cooled to room temperature and diluted by water (50 mL), extracted with ethyl acetate (200 mL x 2). The combined organics were washed with brine (100 mL), dried over ISfeSCL, fdtered and concentrated under reduced pressure to give tert-butyl N-[2-(4-cyanobutoxy)ethyl] carbamate (8 g, 31.36 mmol, 50.82% yield, 95% purity) as a colorless oil. ’H NMR (400 MHz, Chloroform-d) 54.84 (br s, 1H), 3.53-3.39 (m, 4H), 3.36-3.26 (m, 2H), 2.42-2.35 (m, 2H), 1.85-1.66 (m, 4H), 1.45 (s, 9H).

[0250] Preparation of compound 3.2 3

[0251] To a solution of tert-butyl N-[2-(4-cyanobutoxy)ethyl]carbamate (8 g, 33.02 mmol, 1 eq) in EtOAc (50 mL) was added HCI / EtOAc (4 M, 40.00 mL). The mixture was stirred at 25°C for 1 hr. The reaction mixture was concentrated under reduced pressure to give 5 -(2-aminoethoxy)pentanenitrile (6 g, 31.90 mmol, 96.64% yield, 95% purity, HC1) as a yellow oil. ’H NMR (400 MHz, Methanol-d4) 53.66 (t, J = 5.0 Hz, 2H), 3.60-3.54 (m, 2H), 3.13 (t, J = 4.9 Hz, 2H), 2.53-2.46 (m, 2H), 1.82-1.70 (m, 4H).

[0252] Preparation of compound 4.

[0253] To a solution of 5 -(2 -aminoethoxy) pentanenitrile (3 g, 21.10 mmol, 1 eq) in THF (30 mL) was added TEA (6.40 g, 63.29 mmol, 8.81 mL, 3 eq) and 6 -bromo-2-chloro-3 -nitro-pyridine (3.01 g, 12.66 mmol, 0.6 eq). The mixture was stirred at 25°C for 1 hr.

[0254] The reaction mixture was diluted by water (50 mL), extracted with ethyl acetate (50 mL x 2). The combined organics were washed with brine (50 mL), dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0-30% ethyl acetate / petroleum ether gradient @ 100 mL / min) to give 5-[2-[(6-bromo-3-nitro-2-APRE007-PCT | 106265.000238pyridyl)amino]ethoxy]pentanenitrile (3 g, 7.87 mmol, 37.29% yield, 90% purity) as a yellow solid. ’H NMR (400 MHz, Chloroform-d) 5 8.54 (br s, 1H), 8.23 (d, J = 8.5 Hz, 1H), 6.79 (d, J = 8.5 Hz, 1H), 3.83 (q, J = 5.3 Hz, 2H), 3.71-3.64 (m, 2H), 3.56 (t, J = 5.6 Hz, 2H), 2.42 (t, J = 6.7 Hz, 2H), 1.89-1.73 (m, 4H).

[0255] Preparation of compound 5.4 5

[0256] To a solution of 5-[2-[(6-bromo-3-nitro-2-pyridyl)amino]ethoxy]pentanenitrile (3 g, 8.74 mmol, 1 eq) in THF (10 mL)was added BH3.THF (1 M, 17.48 mb, 2 eq) at 0°C. The mixture was stirred at 25 °C for 12 hrs. The reaction mixture was quenched by MeOH (50 mL) at 0°C and stirred for 2 hr at 60°C. The mixture was concentrated under reduced pressure to give N-[2-(5-aminopentoxy)ethyl]-6-bromo-3-nitro-pyridin-2 -amine (4 g, crude) as a yellow oil. ’H NMR (400 MHz, Chloroform-d) 58.62-8.53 (m, 1H), 8.26-8.16 (m, 1H), 6.82-6.73 (m, 1H), 3.84-3.75 (m, 2H), 3.68-3.63 (m, 2H), 3.56-3.51 (m, 2H), 1.92-1.79 (m, 2H), 1.74-1.60 (m, 4H), 1.58-1.48 (m, 2H).

[0257] Preparation of compound 6.

[0258] To a solution of N-[2-(5-aminopentoxy)ethyl]-6-bromo-3-nitro-pyridin-2-amine (4 g, 11.52 mmol, 1 eq) in MeOH (5 mL) was added Na2COs (2.44 g, 23.04 mmol, 2 eq) and BOC2O (3.02 g, 13.82 mmol, 3.18 mL, 1.2 eq). The mixture was stirred at 25°C for 1 hr. The reaction mixture was diluted by water (50 mL), extracted with ethyl acetate (50 mL x 2). The combined organics were washed with brine (50 mL), dried over Na2SO4, fdtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 gAPRE007-PCT | 106265.000238SepaFlash® Silica Flash Column, eluent of 0-20% ethyl acetate / petroleum ether gradient @ 100 mL / min) to give tert-butyl N-[5-[2-[(6-bromo-3-nitro-2-pyridyl)amino]ethoxy]pentyl]carbamate (0.9 g, 1.91 mmol, 16.59% yield, 95% purity) as a yellow oil. 'H NMR (400 MHz, Chloroform-d) 58.56 (br s, 1H), 8.22 (d, J = 8.5 Hz, 1H), 6.78 (d, J = 8.5 Hz, 1H), 4.65-4.53 (m, 1H), 3.82 (q, J = 5.3 Hz, 2H), 3.70-3.62 (m, 2H), 3.51 (t, J = 6.3 Hz, 2H), 3.13 (br d, J = 6.3 Hz, 2H), 1.68-1.61 (m, 2H), 1.58 (s, 2H), 1.55-1.50 (m, 2H), 1.44 (s, 9H).

[0259] Preparation of compound 7.6 7

[0260] To a solution of tert-butyl N-[5-[2-[(6-bromo-3-nitro-2-pyridyl)amino]ethoxy]pentyl]carbamate (0.9 g, 2.01 mmol, 1 eq) in EtOH (10 m ), THF (10 m ) and H2O (2.5 mb) was added Fe (449.43 mg, 8.05 mmol, 4 eq) and NH4CI (430.49 mg, 8.05 mmol, 4 eq). The mixture was stirred at 80°C for 2 hrs. The reaction mixture was cooled to room temperature and diluted by water (50 mb), extracted with ethyl acetate (50 mb x 2). The combined organics were washed with brine (50 mb), dried over ISfeSCE, fdtered and concentrated under reduced pressure to give tert-butyl N-[5-[2-[(3-amino-6-bromo-2-pyridyl)amino]ethoxy]pentyl]carbamate (0.9 g, crude) as a brown oil. ESI [M+H] = 417.1 / 419.1.

[0261] Preparation of compound 8.7 8

[0262] To a solution of tert-butyl N-[5-[2-[(3-amino-6-bromo-2-pyridyl)amino]ethoxy]pentyl]carbamate (0.9 g, 2.16 mmol, 1 eq) in MeOH (10 mb) was added sulfamic acid (209.38 mg, 2.16 mmol, 97.34 pb. 1 eq) and 1,1,1 -trimethoxy ethane (1.30 g, 10.78 mmol, 1.36 mb, 5 eq). The mixture was stirred at 40°C for 1 hr. The reaction mixture was cooled toAPRE007-PCT | 106265.000238room temperature and diluted by water (50 mL), extracted with ethyl acetate (50 mL x 2). The combined organics were washed with brine (50 mL), dried over ISfeSCL, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, eluent of 0-90% ethyl acetate / petroleum ether gradient @ 50 mL / min) to give tert-butyl N-[5-[2-(5-bromo-2-methyl-imidazo[4,5-b]pyridin-3-yl)ethoxy]pentyl]carbamate (0.8 g, 1.63 mmol, 75.65% yield, 90% purity) as brown oil. 1H NMR (400 MHz, Chloroform-d) 57.88 (br d, J = 8.3 Hz, 1H), 7.40 (d, J = 8.3 Hz, 1H), 4.57 (br s, 1H), 4.43 (t, J = 4.9 Hz, 2H), 3.80-3.76 (m, 2H), 3.35 (t, J = 6.4 Hz, 2H), 3.06 (br d, J = 6.3 Hz, 2H), 2.74 (s, 3H), 1.51-1.46 (m, 2H), 1.45-1.44 (m, 9H), 1.42-1.36 (m, 2H), 1.29-1.22 (m, 2H).

[0263] Preparation of compound 9.8 9

[0264] To a solution of tert-butyl N-[5-[2-(5-bromo-2-methyl-imidazo[4,5-b]pyridin-3-yl)ethoxy]pentyl]carbamate (0.6 g, 1.36 mmol, 1 eq) in THF (6 mL) and H2O (1.25 mL) was added 2-chloro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (341.87 mg, 1.43 mmol, 1.05 eq), ditert-butyl(cyclopenta-l,4-dien-l-yl)phosphane; dichloropalladium;iron (88.60 mg, 135.94 pmol, 0.1 eq) and K3PO4 (865.68 mg, 4.08 mmol, 3 eq). The mixture was stirred at 80°C for 1 hr. The reaction mixture was cooled to room temperature and diluted by water (50 mL), extracted with ethyl acetate (50 mL x 2). The combined organics were washed with brine (50 mL), dried over ISfeSCL, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, eluent of 0-90% ethyl acetate / petroleum ether gradient @ 50 mL / min) to give tert-butyl N-[5-[2-[5-(2-chloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]ethoxy]pentyl]carbamate (0.3 g, 379.75 pmol, 27.93% yield, 60% purity) as a brown oil. ESI [M+H] = 474.2.

[0265] Preparation of compound 10.APRE007-PCT | 106265.000238

[0266] A solution of tert-butyl N-[5-[2-[5-(2-chloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]ethoxy]pentyl]carbamate (0.2 g, 421.95 pmol, 1 eq) in HCI / EtOAc (4 mL) was stirred at 25°C for 1 hr. The reaction mixture was concentrated under reduced pressure to give 5-[2-[5-(2-chloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]ethoxy]pentan-l-amine (0.1 g, 240.72 pmol, 57.05% yield, 90% purity, HC1 salt) as a brown solid. ESI [M+H] = 374.2.

[0267] Preparation of Example 4 product.

[0268] To a mixture of 5-[2-[5-(2-chloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]ethoxy]pentan-l -amine (0.1 g, 267.47 pmol, 1 eq) in 2-methylbutan-2-ol (10 mb) was added dicyclohexyl-[2-(2,6-diisopropoxyphenyl)phenyl]phosphane (24.96 mg, 53.49 pmol, 0.2 eq), (1E,4E)-l,5-diphenylpenta-l,4-dien-3-one;palladium (24.49 mg, 26.75 pmol, 0.1 eq) and sodium;2-methylpropan-2-olate (77.11 mg, 802.40 pmol, 3 eq). The mixture was stirred at 100 °C for 2 hrs under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 100 x 25 mm x 10 um; mobile phase: [H2O (10 mM NEEHCOs^ACN]; gradient: 30%-60% B over 8.0 min) to give 17-methyl-13-oxa-5,7,16,18,22-pentazatetracyclo[14.5.2.12,6.019,23]tetracosa-l(21),2,4,6(24),17,19, 22-heptaene (8.02 mg, 22.94 pmol, 8.58% yield, 97% purity) as a white solid. ’H NMR (400 MHz, DMSO-d6) 58.08-7.97 (m, 2H), 7.77 (d, J = 8.3 Hz, 1H), 7.33 (s, 1H), 7.09 (dd, J = 1.1, 5.4 Hz, 1H), 6.63 (t, J = 6.3 Hz, 1H), 4.44 (t, J = 6.6 Hz, 2H), 3.86 (t, J = 6.6 Hz, 2H), 3.74 (t, J = 7.4 Hz, 2H), 3.22-3.13 (m, 2H), 2.61 (s, 3H), 1.72 (quin, J = 7.0 Hz, 2H), 1.67-1.56 (m, 2H), 1.52-1.42 (m, 2H). ESI [M+H] = 338.2.

[0269] Example 5APRE007-PCT | 106265.000238

[0271] To a solution of 6-bromo-2-chloro-3-nitro-pyridine (8 g, 33.69 mmol, 1 eq) in THF (200 mL) was added TEA (10.23 g, 101.08 mmol, 14.07 mL, 3 eq) and tert-butyl N-(8-aminooctyl)carbamate (8.23 g, 33.69 mmol, 1 eq). The mixture was stirred at 25°C for 12 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product was purified by re-crystallization from MTBE(30 mb) at 25 °C to give tert-butyl N-[8-[(6-bromo-3-nitro- 2-pyridyl)amino]octyl]carbamate (14 g, 31.44 mmol, 93.30% yield) as a yellow solid. ESI [M+H- Boc] = 345.0 / 347.0.

[0272] Preparation of compound 3.

[0273] To a solution of tert-butyl N-[8-[(6-bromo-3-nitro-2-pyridyl)amino] octyl] carbamate (4 g, 8.98 mmol, 1 eq) in THF (30 mb), EtOH (30 mL) and H2O (10 mL) was added Fe (1.00 g, 17.96 mmol, 2 eq) and NH4CI (1.44 g, 26.95 mmol, 3 eq). The mixture was stirred at 80°C for 1 hr. The reaction mixture was quenched by addition H2O (30 mL), and then extracted with EtOAc (100 mL x 3). The combined organic layers were dried over ISfeSCL, filteredAPRE007-PCT | 106265.000238and concentrated under reduced pressure to give tert-butyl N-[8-[(3-amino-6-bromo-2-pyridyl)amino] octyl] carbamate (6.6 g, crude) as abrown oil. ESI [M+H] = 415.1 / 417.1.

[0274] Preparation of compound 4.3 4

[0275] To a solution of tert-butyl N-[8-[(3-amino-6-bromo-2-pyridyl)amino] octyl] carbamate (1.3 g, 3.13 mmol, 1 eq) in MeOH (50 m ) was added sulfamic acid (15.19 mg, 156.49 pmol, 7.06 ph, 0.05 eq) and trimethoxymethane (498.20 mg, 4.69 mmol, 514.66 ph, 1.5 eq). The mixture was stirred at 30°C for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCE, petroleum ether / ethyl acetate = 50 / 1 to 0 / 1) to give tert-butyl N-[8-(5-bromoimidazo[4,5-b]pyridin-3-yl)octyl] carbamate (680 mg, 1.60 mmol, 51.08% yield) as a brown oil. 'HNMR (400 MHz, DMSO-d6) 5 8.52 (s, 1H), 8.06 (d, J = 8.3 Hz, 1H), 7.46 (d, J = 8.3 Hz, 1H), 6.74 (br t, J = 5.5 Hz, 1H), 4.23 (t, J = 7.2 Hz, 2H), 2.87 (q, J = 6.7 Hz, 2H), 1.84 (quin, J = 7.1 Hz, 2H), 1.36 (s, 9H), 1.34-1.17 (m, 10H).

[0276] Preparation of compound 5.

[0277] A mixture of tert-butyl N-[8-(5-bromoimidazo[4,5-b]pyridin-3-yl)octyl]carbamate (680 mg, 1.60 mmol, 1 eq), 2,6- dichloro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (525.54 mg, 1.92 mmol, 1.2 eq), ISfeCOs (508.31 mg, 4.80 mmol, 3 eq), Pd(dppf)C12 (116.97 mg, 159.86 pmol, 0.1 eq) in dioxane (20 m ) and H2O (5 mb) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80°C for 1 hr under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue, the reaction mixture was quenched byAPRE007-PCT | 106265.000238addition H2O (10 mL), and then extracted with EtOAc (40 mL x 3). The combined organic layers were dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, petroleum ether / ethyl acetate = 50 / 1 to 0 / 1) to give tert-butyl N-[8-[5-(2,6-dichloro-4-pyridyl)imidazo[4,5-b]pyridin-3-yl]octyl]carbamate (700 mg, 1.42 mmol, 44.46% yield) as a brown oil. ESI [M+H] = 492.2 / 494.1.

[0278] Preparation of compound 6.

[0279] A solution of tert-butyl N-[8-[5-(2,6-dichloro-4-pyridyl)imidazo[4,5-b]pyridin-3-yl] octyl] carbamate (680 mg, 1.38 mmol, 1 eq) in HCl / EtOAc (10 mL, 4M) was stirred at 25°C for 1 hr. The reaction mixture was concentrated under reduced pressure to give 8-[5-(2,6-dichloro-4-pyridyl)imidazo[4,5-b]pyridin-3-yl]octan-l-amine (450 mg, crude, HC1 salt) as a white solid. ESI [M+H] = 392.2 / 394.2.

[0280] Preparation of compound 7.

[0281] A mixture of 8-[5-(2,6-dichloro-4-pyridyl)imidazo[4,5-b]pyridin-3-yl]octan-l-amine (200 mg, 466.43 pmol, 1 eq, HC1), CS2CO3 (759.86 mg, 2.33 mmol, 5 eq), [2-(2-aminophenyl)phenyl]-methylsulfonyloxypalladium;dicyclohexyl-[3,6-dimethoxy-2-(2,4,6-triisopropylphenyl)phenyl]phosphane (42.28 mg, 46.64 pmol, 0.1 eq) and 4A MS (100 mg) in 2-methylbutan-2-ol (50 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100°C for 12 hrs under N2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC: column:Phenomenex Luna C18 100 x 30 mm x 3 um; mobile phase: [H2O (0.04% HC1)-ACN]; gradient:35%-65% B over 8.0 min to give 4-chloro-5,7,16,18,22-pentazatetracyclo[14.5.2.12,6.019,23]tetracosa-APRE007-PCT | 106265.000238l(21),2(24),3,5,17,19,22-heptaene (20 mg, 50.98 pmol, 5.46% yield, HC1) as ayellow solid. ESI [M+H] = 356.1.

[0282] Preparation of compound 8.

[0283] A mixture of 4-chloro-5,7,16,18,22-pentazatetracyclo[14.5.2.12,6.019,23]tetracosa-l(21),2(24),3,5,17,19,22-heptaene (20 mg, 50.98 pmol, 1 eq, HC1), tert-butyl carbamate (17.92 mg, 152.93 pmol, 3 eq), Pd2(dba)s (9.34 mg, 10.20 pmol, 0.2 eq), RuPhos (4.76 mg, 10.20 pmol, 0.2 eq) and CS2CO3 (49.83 mg, 152.93 pmol, 3 eq) and 4A MS (10 mg, 50.98 pmol, 1 eq) in 2-methylbutan-2-ol (2 m ) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 110°C for 12 hrs under N2 atmosphere. The reaction mixture was fdtered and concentrated under reduced pressure to give tert-butyl N-(5,7,16,18,22-pentazatetracyclo[14.5.2.12,6.019,23]tetracosa-l(21),2(24),3,5,17,19,22-heptaen4-yl)carbamate (30 mg, crude) as ayellow oil. ESI [M+H] = 437.3.

[0284] Preparation of Example 5 product.8

[0285] To a solution of tert-butyl N-(5,7,16,18,22-pentazatetracyclo[14.5.2.12,6.019,23]tetracosa-l(21),2(24),3,5,17,19,22-heptaen-4-yl)carbamate (30 mg, 68.72 pmol, 1 eq) in H2O (0.5 m ) was added HC1 (0.5 mb, 12 M). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was fdtered, the residue was purified by prep-HPEC (column: Waters Xbridge BEH C18 100 x 30 mm x 10 um; mobile phase: [H2O (10 mM NHJTCC^-ACN]; gradient: 30%-60% B over 8.0 min) to give 5,7,16,18,22-pentazatetracyclo[14.5.2.12,6.019,23]tetracosa-l(21),2(24),3,5,17,19,22-heptaen-4-amine (1.2 mg, 3.13 pmol, 4.55% yield, 97% purity, HC1) as a yellow solid. ’H NMR (400 MHz, DMSO-d6) 58.49 (s, 1H), 8.12 (d, J = 8.4 Hz, 1H), 7.61 (d, J = 8.5 Hz, 1H), 6.50 (s, 1H), 6.22 (s, 1H), 5.99 (t, J = 6.3 Hz, 1H), 5.50 (s, 2H), 4.31 (t, J = 7.3 Hz, 2H), 3.15-3.01 (m, 2H), 2.01-1.91 (m, 2H), 1.68-1.60 (m, 4H), 1.57-1.49 (m, 2H), 1.47-1.38 (m, 4H). ESI [M+H] = 337.2.APRE007-PCT | 106265.000238

[0286] Example 6

[0288] To a solution of tert-butyl N-[8-[(3-amino-6-bromo-2-pyridyl)amino] octyl] carbamate (2.5 g, 6.02 mmol, 1 eq) in MeOH (50 mL) was added 1,1,1-trimethoxypropane (1.21 g, 9.03 mmol, 1.28 mL, 1.5 eq) and sulfamic acid (29.22 mg, 300.94 pmol, 13.58 pL, 0.05 eq). The mixture was stirred at 30°C for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL, petroleum ether / ethyl acetate = 50 / 1 to 0 / 1) to give tert-butyl N-[8-(5-bromo-2-ethyl-imidazo[4,5-b]pyridin-3-yl)octyl]carbamate (1.4 g, 3.09 mmol, 51.30% yield) as a brown oil. 'H NMR (400 MHz, DMSO-d6) 57.93 (d, J = 8.2 Hz, 1H), 7.39 (d, J = 8.2 Hz, 1H), 6.80-6.70 (m, 1H), 4.18 (t, J = 7.3 Hz, 2H), 2.95-2.91 (m, 2H), 2.91-2.86 (m, 2H), 1.80-1.69 (m, 2H), 1.36 (s, 9H), 1.35-1.32 (m, 4H), 1.31-1.19 (m, 9H).

[0289] Preparation of compound 5.

[0290] A mixture of tert-butyl N-[8-(5-bromo-2-ethyl-imidazo[4,5-b]pyridin-3-yl)octyl] carbamate (1.4 g, 3.09 mmol, 1 eq), 2,6-dichloro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)pyridine (1.02 g, 3.71 mmol, 1.2 eq), Pd(dppf)C12 (225.93 mg, 308.77 pmol, 0.1 eq), Na2COsAPRE007-PCT | 106265.000238(981.78 mg, 9.26 mmol, 3 eq) in dioxane (20 mL) and H2O (5 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80°C for 1 hr under N2 atmosphere. The reaction mixture was quenched by addition H2O (10 mL), and then extracted with EtOAc (40 mL x 3). The combined organic layers were dried over Na2SC>4, fdtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL, petroleum ether / ethyl acetate = 50 / 1 to 0 / 1) to give tert-butyl N-[8-[5-(2,6-dichloro-4-pyridyl)-2-ethyl-imidazo[4,5-b]pyridin-3-yl]octyl]carbamate (800 mg, 1.54 mmol, 49.78% yield) as a brown oil. ESI [M+H] = 520.2 / 522.2.

[0291] Preparation of compound 6.

[0292] A solution of tert-butyl N-[8-[5-(2,6-dichloro-4-pyridyl)-2-ethyl-imidazo[4,5-b]pyridin-3-yl]octyl]carbamate (800 mg, 1.54 mmol, 1 eq) in HCl / EtOAc (20 mL, 4 M) was stirred at 25°C for 1 hr. The reaction mixture was concentrated under reduced pressure to give 8-[5 -(2,6-dichloro-4-pyridyl)-2-ethyl-imidazo[4,5-b]pyridin-3-yl]octan-l-amine (580 mg, crude, HC1 salt) as a white solid. ESI [M+H] = 420.2 / 422.2.

[0293] Preparation of compound 7.

[0294] A mixture of 8-[5-(2,6-dichloro-4-pyridyl)-2-ethyl-imidazo[4,5-b]pyridin-3-yl]octan-l -amine (250 mg, 547.24 pmol, 1 eq, HC1), CS2CO3 (891.50 mg, 2.74 mmol, 5 eq), [2-(2-aminophenyl)phenyl]-methylsulfonyloxypalladium;dicyclohexyl-[3,6-dimethoxy-2-(2,4,6-triisopropylphenyl)phenyl]phosphane (49.61 mg, 54.72 pmol, 0.1 eq) and 4A MS (100 mg, 547.24 pmol, 1 eq) in 2-methylbutan-2-ol (100 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100°C for 12 hrs under N2 atmosphere. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC: column: Phenomenex Luna C18 75 x 30 mm x 3 um; mobile phase: [water (0.04%APRE007-PCT | 106265.000238HC1)-ACN]; gradient: 30%-70% B over 8.0 min to give 4-chloro-17-ethyl-5,7, 16, 18,22-pentazatetracyclo[14.5.2.12,6.019,23]tetracosa-l(21),2(24),3,5,17,19, 22-heptaene (35 mg, 83.26 pmol, 15.21% yield, HC1 salt) as a yellow solid. ESI [M+H] = 384.2.

[0295] Preparation of compound 8.

[0296] A mixture of 4-chloro-17-ethyl-5,7, 16, 18,22-pentazatetracyclo[14.5.2.12,6.019,23]tetracosa-l(21),2(24),3,5,17,19,22-heptaene (31 mg, 73.74 pmol, 1 eq, HC1), tert-butyl carbamate (25.92 mg, 221.23 pmol, 3 eq), Pd2(dba)s (13.51 mg, 14.75 pmol, 0.2 eq), CS2CO3 (72.08 mg, 221.23 pmol, 3 eq), RuPhos (6.88 mg, 14.75 pmol, 0.2 eq) and 4A MS (10 mg) in 2-methylbutan-2-ol (6 m ) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 110°C for 12 hrs under N2 atmosphere. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give tert-butyl N-(17-ethyl-5,7, 16, 18,22-pentazatetracyclo[14.5.2.12,6.019,23]tetracosa-l(21),2(24),3,5,17,19,22-heptaen-4-yl)carbamate (30 mg, crude) as a yellow oil. ESI [M+H] = 465.3.8

[0298] A solution oftert-butyl N-(17-ethyl-5,7, 16, 18,22-pentazatetracyclo[14.5.2.12,6.019, 23]tetracosal(21),2(24),3,5,17,19,22-heptaen-4-yl)carbamate (30 mg, 64.57 pmol, 1 eq) in H2O (0.5 m ) and HC1 (0.5 mb) was stirred at 25 °C for 1 hr. The reaction mixture was blow-dried under nitrogen. The residue was purified by prep-HPLC: column:Phenomenex luna C18 100 x 40 mm x 5 urn; mobile phase: [H2O (0.04% HC1)-ACN]; gradient:20%-50% B over 8.0 min to give 17-ethyl-5,7,16,18,22-pentazatetracyclo[14.5.2.12,6.019,23]tetracosa-l(21),2(24),3,5,17,19,22-heptaen-4-amine (9 mg, 21.48 pmol, 33.27% yield, 96% purity, HC1 salt) as a yellow solid. ’H NMR (400 MHz, DMSO-d6) 58.33 (br d, J = 7.4 Hz, 1H), 8.01-7.88 (m, 2H), 7.71APRE007-PCT | 106265.000238(br s, 2H), 6.76 (s, 1H), 6.60 (s, 1H), 4.42 (brt, J = 6.3 Hz, 2H), 3.32 (br s, 2H), 3.22 (br d, J = 7.0 Hz, 2H), 2.02-1.91 (m, 2H), 1.75-1.46 (m, 13H). ESI [M+H] = 365.2.

[0299] Example 7

[0300] Preparation of compound 4.3 4

[0301] To a solution of tert-butyl N-[8-[(3-amino-6-bromo-2-pyridyl)amino] octyl] carbamate (2.5 g, 6.02 mmol, 1 eq) in AcOH (50 m ) was added Cu(OAc)2 (218.64 mg, 1.20 mmol, 0.2 eq) and 2-methylpropanal (650.98 mg, 9.03 mmol, 824.02 pL, 1.5 eq). The mixture was stirred at 25 °C for 12 hrs under N2 atmosphere. The mixture was concentrated under reduced pressure and the residue was diluted with ice cold water, adjusted to pH=9 with aq. NaHCCh and extracted with EtOAc (50 mb x 2). The combined organic layers were dried over sodium sulfate, fdtered and lyophilized. The residue was purified by column chromatography (SiCE, petroleum ether / ethyl acetate = 50 / 1 to 0 / 1) to give tert-butyl N-[8-(5-bromo-2-isopropyl-imidazo[4,5-b]pyridin-3 -yljoctyl] carbamate (1.4 g, 3.00 mmol, 49.76% yield) as a brown oil. 'H NMR (400 MHz, DMSO-d6) 57.93 (d, J = 8.3 Hz, 1H), 7.40 (d, J = 8.3 Hz, 1H), 6.74 (brt, J = 5.1 Hz, 1H), 4.21 (brt, J = 7.4 Hz, 2H), 3.32-3.30 (m, 1H), 2.88 (q, J = 6.5 Hz, 2H), 1.80-1.70 (m, 2H), 1.36 (s, 9H), 1.33 (d, J = 6.6 Hz, 8H), 1.29 (br s, 4H), 1.23 (br s, 4H).

[0302] Preparation of compound 5.APRE007-PCT | 106265.000238

[0303] A mixture of tert-butyl N-[8-(5-bromo-2-isopropyl-imidazo[4,5-b]pyridin-3-yl)octyl] carbamate (1.4 g, 3.00 mmol, 1 eq), 2,6-dichloro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (902.54 mg, 3.29 mmol, 1.1 eq), ISfeCOs (952.32 mg, 8.99 mmol, 3 eq), Pd(dppf)C12 (219.15 mg, 299.50 pmol, 0.1 eq) in dioxane (20 mL) and H2O (5 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80°C for 1 hr under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was added H2O (10 mL), and then extracted with EtOAc (40 mL x 3). The combined organic layers were dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, petroleum ether / ethyl acetate = 50 / 1 to 0 / 1) to give tert-butyl N-[8-[5-(2,6-dichloro-4-pyridyl)-2-isopropyl-imidazo[4,5-b]pyridin-3-yl]octyl]carbamate (750 mg, 1.40 mmol, 46.85% yield) as a brown oil. ESI [M+H] = 534.3 / 536.3.

[0304] Preparation of compound 6.

[0305] To a solution of tert-butyl N-[8-[5 -(2, 6-dichloro-4-pyridyl)-2 -isopropyl -imidazo [4,5-b]pyridin-3-yl]octyl]carbamate (750 mg, 1.40 mmol, 1 eq) in HCl / EtOAc (20 mL, 4M). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue solution was lyophilized to give 8-[5-(2,6-dichloro-4-pyridyl)-2-isopropyl-imidazo[4,5-b]pyridin-3-yl]octan-l-amine (550 mg, crude, HC1) as a yellow solid. ESI [M+H] = 434.2 / 436.2.

[0306] Preparation of 7.APRE007-PCT | 106265.000238

[0307] A mixture of 8-[5-(2,6-dichloro-4-pyridyl)-2-isopropyl-imidazo[4,5-b]pyridin-3-yl]octan-l -amine (220 mg, 467.23 pmol, 1 eq, HC1), CS2CO3 (761.15 mg, 2.34 mmol, 5 eq), [2-(2-aminophenyl)phenyl]-methylsulfonyloxypalladium;dicyclohexyl-[3,6-dimethoxy-2-(2,4,6-triisopropylphenyl)phenyl]phosphane (42.35 mg, 46.72 pmol, 0.1

[0308] eq) and 4A MS (10 mg) in 2-methylbutan-2-ol (40 mb) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100°C for 12 hrs under N2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 100 x 30 mm x 3 um; mobile phase: [H2O (0.04% HC1)-ACN]; gradient: 35 %-65% B over 8.0 min) to give 4-chloro-17-isopropyl-5,7,16,18,22-pentazatetracyclo [14.5.2.12,6.019,23]tetracosa-l(21),2(24),3,5,17,19,22-heptaene (60 mg, 138.12 pmol, 14.78% yield, HC1) as a yellow solid. ESI [M+H] = 398.1.

[0309] Preparation of 8.

[0310] A mixture of 4-chloro-17-isopropyl-5,7,16,18,22-pentazatetracyclo [14.5.2.12,6.019,23]tetracosal(21),2(24),3,5,17,19,22-heptaene (31 mg, 71.36 pmol, 1 eq, HC1), tertbutyl carbamate (25.08 mg, 214.09 pmol, 3 eq), Pd2(dba)s (13.07 mg, 14.27 pmol, 0.2 eq), 4A MS (10 mg, 71.36 pmol, 1 eq), CS2CO3 (69.75 mg, 214.09 pmol, 3 eq) and RuPhos (6.66 mg, 14.27 pmol, 0.2 eq) in 2-methylbutan-2-ol (4 m ) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 110°C for 12 hrs under N2 atmosphere. The reaction mixture was fdtered and concentrated under reduced pressure to give tert-butyl N-(17-isopropyl-5,7, 16, 18,22-pentazatetracyclo[14.5.2.12,6.019,23]tetracosal(21),2(24),3,5,17,19,22-heptaen-4-yl)carbamate (30 mg, crude) as a yellow oil. ESI [M+H] = 479.4.

[0311] Preparation of Example 7 product.APRE007-PCT | 106265.0002388

[0312] To a solution of tert-butyl N-(17-isopropyl-5, 7, 16, 18, 22 -pentazatetracyclo [14.5.2.12,6.019,23]tetracosal(21),2(24),3,5,17,19,22-heptaen-4-yl)carbamate (30 mg, 62.68 pmol, 1 eq) in H2O (0.5 mb) was added HC1 (0.5 mL 12 M). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC: column: Phenomenex luna C18 100 x 40 mm x 5 urn; mobile phase: [H2O (0.04% HC1)-ACN]; gradient: 5 %-45% B over 8.0 min to give 17-isopropyl-5,7, 16, 18,22-pentazatetracyclo[14.5.2.12,6.019,23]tetracosa-l(21),2(24),3,5,17,19,22-heptaen4-amine (7.48 mg, 17.21 pmol, 27.45% yield, 95% purity, HC1 salt) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) 5 8.34-8.28 (m, 1H), 7.94 (d, J = 8.5 Hz, 1H), 7.86 (br s, 1H), 7.64 (br dd, J = 7.2, 8.7 Hz, 2H), 6.83 (s, 1H), 6.61 (s, 1H), 4.48-4.39 (m, 2H), 3.52-3.46 (m, 1H), 3.34 (br s, 2H), 1.98 (br s, 2H), 1.77-1.56 (m, 8H), 1.52-1.45 (m, 8H). ESI [M+H] = 379.3.

[0313] Example 8

[0314] Preparation of compound 2.

[0315] To a solution of 6-bromo-2 -methyl- IH-indole (600 mg, 2.86 mmol, 1 eq) in DMSO (10 mL) was added NaOH (342.72 mg, 8.57 mmol, 3 eq) and tert -butyl N-(7-bromoheptyl)carbamateAPRE007-PCT | 106265.000238(1.01 g, 3.43 mmol, 1.2 eq). The mixture was stirred at 25°C for 1 hr. The reaction mixture was quenched by addition H2O (20 mL), and then extracted with EtOAc (40 mL x 3). The combined organic layers were dried over Na2SC>4, fdtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, petroleum ether / ethyl acetate = 50 / 1 to 0 / 1) to give tert-butyl N-[7-(6-bromo-2-methyl-indol-l-yl)heptyl]carbamate (1.2 g, 2.83 mmol, 99.23% yield) as a white solid. ESI [M+H] = 423.1 / 425.1.

[0316] Preparation of compound 3.

[0317] A mixture of tert-butyl N-[7-(6-bromo-2-methyl-indol-l-yl)heptyl]carbamate (1.2 g, 2.83 mmol, 1 eq), 2,6-dichloro4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (931.75 mg, 3.40 mmol, 1.2 eq), Pd(dppf)C12 (207.39 mg, 283.43 pmol, 0.1 eq), Na2COs (600.81 mg, 5.67 mmol, 2 eq) in dioxane (20 mL) and H2O (5 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80°C for 1 hr under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue, the residue was quenched by addition H2O (30 mL), and then extracted with EtOAc (40 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 0 / 1) to give tert-butyl N-[7-[6-(2,6-dichloro-4-pyridyl)-2-methyl-indol-l-yl]heptyl]carbamate (1.3 g, 2.65 mmol, 93.52% yield) as a white solid. ESI [M+H] = 490.2 / 492.1.

[0318] Preparation of compound 4.3 4APRE007-PCT | 106265.000238

[0319] A solution of tert-butyl N-[7-[6-(2, 6-dichloro-4-pyridyl)-2 -methyl -indol-1-yl]heptyl]carbamate (1.3 g, 2.65 mmol, 1 eq) in HCl / EtOAc (20 mb, 4M) was stirred at 25°C for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was lyophilized to give 7-[6-(2,6-dichloro-4-pyridyl)-2-methyl-indol-l-yl]heptan-l-amine (900 mg, crude, HC1 salt) as a white solid. ESI [M+H] = 390.2 / 392.3.

[0320] Preparation of compound 5.Brettphos Pd G3, Cs2CO3t-AmylOH, 100°C, 12 hrs

[0321] A mixture of 7-[6-(2,6-dichloro-4-pyridyl)-2-methyl-indol-l-yl]heptan-l-amine (100 mg, 234.30 pmol, 1 eq, HC1), dicesiunpcarbonate (229.01 mg, 702.89 pmol, 3 eq), [2-(2-aminophenyl)phenyl]-methylsulfonyloxypalladium;dicyclohexyl-[3,6-dimethoxy-2-(2,4,6-triisopropylphenyl)phenyl]phosphane (21.24 mg, 23.43 pmol, 0.1 eq) and 4A MS (10 mg, 234.30 pmol, 1 eq) in 2-methylbutan-2-ol (4 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100°C for 12 hrs under N2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC: column: Phenomenex Luna C18 100 x 30 mm x 3 um; mobile phase: [H2O (0.04% HC1)-ACN]; gradient: 65 %-95% B over 8.0 min to give 4-chloro-16-methyl-5,7,15-triazatetracyclo[13.5.2.12,6.018,22]tricosa-l(20),2,4,6(23),16,18,21-heptaene (100 mg, 256.18 pmol, 27.34% yield, HC1 salt) as a white solid. ESI [M+Na+] = 354.2.

[0322] Preparation of compound 6.5 6

[0323] A mixture of 4-chloro-16-methyl-5,7,15-triazatetracyclo[13.5.2.12,6.018,22]tricosa-l(20),2,4,6(23),16,18,21-heptaene (60 mg, 169.55 pmol, 1 eq), tert-butyl carbamate (59.58 mg, 508.64 pmol, 3 eq), CS2CO3 (165.72 mg, 508.64 pmol, 3 eq), RuPhos (15.82 mg, 33.91 pmol, 0.2 eq), Pd2(dba)s (31.05 mg, 33.91 pmol, 0.2 eq) and 4A MSAPRE007-PCT | 106265.000238(169.55 pmol, 1 eq) in 2-methylbutan-2-ol (3 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 110°C for 12 hrs under N2 atmosphere. The reaction mixture was fdtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150 x 40 mm x 10 um; mobile phase: [H2O (10 mM NH4HCC>3)-ACN]; gradient: 75 %-95% B over 8.0 min) to give tert-butyl N-(16-methyl-5,7,15-triazatetracyclo[13.5.2.12,6.018,22]tricosa-l(20),2,4,6(23),16,18,21-heptaen4-yl)carbamate (20 mg, 46.02 pmol, 13.57% yield) as a yellow solid. ESI [M+H] = 435.4.

[0324] Preparation of Example 8 product.6

[0325] To a solution of tert-butyl N-(16-methyl-5,7,15-triazatetracyclo[13.5.2.12,6.018,22]tricosa-l(20),2,4,6(23),16,18,21-heptaen-4-yl)carbamate (10 mg, 23.01 pmol, 1 eq) in H2O (0.5 mL) was added HC1 (0.5 mL, 12 M). The mixture was stirred at 25°C for 12 hrs. The reaction solution is lyophilized and purified by prep-HPLC: column: Phenomenex luna C18 100 x 40 mm x 5 um; mobile phase: [H2O (0.04% HC1)-ACN]; gradient: 35 %-55% B over 8.0 min to give 16-methyl-5,7,15-triazatetracyclo[13.5.2.12,6.018,22]tricosa-l(20),2,4,6(23),16,18,21-heptaen-4-amine (1.34 mg, 2.44 pmol, 10.62% yield, 91% purity, HC1 salt) as a red solid. ’H NMR (400 MHz, DMSO-d6) 5 12.60-12.31 (m, 1H), 7.67-7.57 (m, 2H), 7.54 (d, J = 8.1 Hz, 1H), 7.36 (br s, 2H), 7.27-7.19 (m, 1H), 6.27 (d, J = 10.3 Hz, 2H), 5.96 (s, 1H), 4.16 (br t, J = 7.4 Hz, 2H), 3.29 (br s, 2H), 2.45 (s, 3H), 1.87-1.62 (m, 6H), 1.59-1.41 (m, 4H). ESI [M+H] = 335.2.

[0326] Example 9

[0327] Preparation of compound 2.APRE007-PCT | 106265.000238

[0328] To a solution of 6-bromo-2-chloro-3-nitro-pyridine (5 g, 21.06 mmol, 1 eq) in THF (50 mL) was added TEA (6.39 g, 63.17 mmol, 8.79 mL, 3 eq) and tert -butyl N-[2-[2-(2-aminoethoxy)ethoxy] ethyl] carbamate (5.23 g, 21.06 mmol, 1 eq). The mixture was stirred at 25°C for 12 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC petroleum ether / ethyl acetate = 50 / 1 to 0 / 1) to give tert-butyl N-[2-[2-[2-[(6-bromo-3-nitro-2-pyridyl)amino]ethoxy]ethoxy]ethyl]carbamate (8.5 g, 18.92 mmol, 89.84% yield) as a yellow oil. ESI [M+H-Boc] = 349.0 / 351.1.

[0329] Preparation of compound 3.

[0330] To a solution of tert-butyl N-[2-[2-[2-[(6-bromo-3-nitro-2-pyridyl)amino] ethoxy] ethoxy] ethyl] carbamate (5.1 g, 11.35 mmol, 1 eq) in THF (30 mL) and EtOH (30 mL) and H2O (10 mL) was added Fe (1.27 g, 22.70 mmol, 2 eq) andlSTLCl (1.82 g, 34.05 mmol, 3 eq). The mixture was stirred at 70°C for 2 hrs. The reaction mixture was quenched by addition H2O (100 mL), and then extracted with EtOAc (200 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give tert-butyl N-[2-[2-[2-[(3-amino-6-bromo-2 -pyridyl) amino]ethoxy]ethoxy]ethyl]carbamate (4.7 g, crude) as a brown oil. ESI [M+H-Boc] = 419.1 / 421.1.

[0331] Preparation of compound 4.APRE007-PCT | 106265.000238

[0332] To a solution of tert-butyl N-[2-[2-[2-[(3-amino-6-bromo-2-pyridyljamino] ethoxy] ethoxy] ethyl] carbamate (4.7 g, 11.21 mmol, 1 eq) in AcOH (60 mL) was added 1,1,1 -trimethoxyethane (2.69 g, 22.42 mmol, 2.82 mL, 2 eq). The mixture was stirred at 70°C for 1 hr. The mixture was concentrated under reduced pressure. The residue was diluted with ice cold water and adjusted to pH=9 with aq.NaHCOs, extracted with EtOAc (50 mL x 2). The combined organic layers were dried over sodium sulfate, fdtered and concentrated to give a residue. The residue was purified by column chromatography (SiC petroleum ether / ethyl acetate = 50 / 1 to 0 / 1) to give tert-butyl N-[2-[2-[2-(5-bromo-2-methyl-imidazo[4,5-b]pyridin-3-yl)ethoxy]ethoxy]ethyl]carbamate (4.2 g, 9.47 mmol, 84.52% yield) as a black oil. ESI [M+H] = 443.2 / 445.1.

[0333] Preparation of compound 5.4 5

[0334] A mixture of tert-butyl N-[2-[2-[2-(5-bromo-2-methyl-imidazo[4,5-b]pyridin-3-yl)ethoxy] ethoxy] ethyl] carbamate (3.6 g, 8.12 mmol, 1 eq), 2,6-dichloro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (2.67 g, 9.74 mmol, 1.2 eq), Pd(dppf)C12 (594.17 mg, 812.03 pmol, 0.1 eq), Na2COs (1.72 g, 16.24 mmol, 2 eq) in dioxane (120 mL) and H2O (30 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80°C for 1 hr under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue, the residue wasAPRE007-PCT | 106265.000238quenched by addition H2O (30 mL), and then extracted with EtOAc (40 mL x 3). The combined organic layers were dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, petroleum ether / ethyl acetate = 50 / 1 to 0 / 1) to give tert-butyl N-[2-[2-[2-[5-(2,6-dichloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3 -yl] ethoxy] ethoxy] ethyl] carbamate (4 g, 7.84 mmol, 96.51% yield) as a black oil. ESI [M+H] = 510.2 / 512.2.

[0335] Preparation of compound 6.5 6

[0336] A solution of tert-butyl N-[2-[2-[2-[5 -(2, 6-dichloro-4-pyridyl)-2 -methyl -imidazo [4,5-b]pyridin-3-yl]ethoxy]ethoxy]ethyl]carbamate (2.5 g, 4.90 mmol, 1 eq) in HCl / EtOAc (10 mL, 4M) was stirred at 25 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 100 x 40 mm x 3 um; mobile phase: [H2O (0.1% TFA)-ACN]; gradient: 5%-35% B over 8.0 min) to give 2-[2-[2-[5-(2,6-dichloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]ethoxy]ethoxy]ethanamine (1.8 g, 3.43 mmol, 70.09% yield, TFA salt) as a white solid. ESI [M+H] = 410.1 / 412.1.

[0337] Preparation of compound 7.

[0338] A mixture of 2-[2-[2-[5-(2,6-dichloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3 -yl] ethoxy] ethoxy] ethanamine (50.01 mg, 121.89 pmol, 1 eq), dicesium; carbonate (59.57 mg,APRE007-PCT | 106265.000238182.83 pmol, 1.5 eq), 4A MS (10 mg, 121.89 pmol, 1 eq), RuPhos (11.37 mg, 24.38 pmol, 0.2 eq) and (lE,4E)-l,5-diphenylpenta-l,4-dien-3-one;palladium (22.32 mg, 24.38 pmol, 0.2 eq) in 2-methylbutan-2-ol (3 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 110°C for 12 hrs under N2 atmosphere. The reaction mixture was fdtered and concentrated under reduced pressure to give tert-butyl N-(17-methyl-10,13-dioxa-5,7,16,18,22-pentazatetracyclo[14.5.2.12,6.019,23]tetracosal(21),2,4,6(24),17,19,22-heptaen-4-yl)carbamate (150 mg, crude) as a yellow oil. ESI [M+H] = 455.2.

[0339] Preparation of Example 9 product.

[0340] A solution of tert-butyl N-(17-methyl-10,13-dioxa-5,7,16,18,22-pentazatetracyclo [14.5.2.12,6.019,23]tetracosal(21),2,4,6(24),17,19,22-heptaen-4-yl)carbamate (150 mg, 330.02 pmol, 1 eq) in H2O (1 mL) was added HC1 (3 mL, 3M). The mixture was stirred at 25°C for 1 hr. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 100 x 40 mm x 5 um; mobile phase: [H2O (0.04% HC1)-ACN]; gradient: l%-30% B over 8.0 min) to give 17-methyl-10,13-dioxa-5,7,16,18,22-pentazatetracyclo[14.5.2.12,6.019,23]tetracosal(21),2,4,6(24),17,19,22-heptaen-4-amine (10 mg, 25.58 pmol, 7.75% yield, 100% purity, HC1) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) 5 8.26 (d, J = 8.4 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.72 (brt, J = 5.1 Hz, 1H), 7.60 (br s, 2H), 7.04 (d, J = 0.6 Hz, 1H), 6.57 (d, J = 0.8 Hz, 1H), 4.55 (brt, J = 5.4 Hz, 2H), 3.98 (brt, J = 5.5 Hz, 2H), 3.71-3.67 (m, 4H), 3.50-3.47 (m, 4H), 2.80 (s, 3H). ESI [M+H] = 355.2.

[0341] Example 10

[0342] Preparation of compound 2.APRE007-PCT | 106265.000238

[0343] A mixture of 5 -bromopentanenitrile (4.85 g, 29.96 mmol, 3.50 mb, 1.05 eq), tertbutyl N-(2-hydroxypropyl)carbamate (5 g, 28.53 mmol, 1 eq), TEAB (899.53 mg, 4.28 mmol, 806.75 pL, 0.15 eq), NaOH (12 M, 23.07 mb, 9.7 eq) in Toluene (100 mb) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100°C for 1 hr under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=50 / l to 1 / 1) to give tert-butyl N-[2-(4-cyanobutoxyjpropyl] carbamate (2 g, crude) as a colorless oil. ESI [M+H] = 257.3.

[0344] Preparation of compound 3.

[0345] Solution 1: {tert-butyl N-[2-(4-cyanobutoxy)propyl]carbamate (2 g, 7.80 mmol, 1 eq)} in {NHs / MeOH (20 mb)}. The fixed bed (named FLR1, volume 5 mb) was completely packed with granular catalyst 14%Co / A12C>3 (4 g). The H2 back pressure regulator was adjusted to 1.5 MPa, and the flow rate of H2 was 30 mL / min. Then the solution SI was pumped by Pump 1 {SI, Pl, 0.7 mL / min} to fixed bed {FLR1, SS, fixed bed, 6.350(l / 4”)mm, 1 mb, 80 °C}. The solution SI was flowing through {FLR1, 3.3 min} to leave the reactor zone, then the reaction mixture was collected from the reactor output. Stop collecting the reaction mixture after 0.5 hr. The fixed bed was washed by extra MeOH (100 mb). The organic layer was concentrated to give tert-butyl N-[2-(5-aminopentoxyjpropyl] carbamate (2 g, crude) as a colorless oil.

[0346] Preparation of compound 4.APRE007-PCT | 106265.000238

[0347] To a solution of tert-butyl N-[2-(5-aminopentoxy)propyl]carbamate (1.8 g, 6.91 mmol, 1 eq) in THF (30 mL) was added TEA (2.10 g, 20.74 mmol, 2.89 m , 3 eq) and 6-bromo-2-chloro-3 -nitro-pyridine (984.87 mg, 4.15 mmol, 0.6 eq). The mixture was stirred at 25°C for 12 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCE, Petroleum ether / Ethyl acetate=50 / l to 5 / 1) to give tertbutyl N-[2-[5-[(6-bromo-3-nitro-2-pyridyl)amino]pentoxy]propyl]carbamate (2 g, 4.34 mmol, 62.71% yield) as a yellow solid. ESI [M+H] = 461.3.

[0349] A mixture of tert-butyl N-[2-[5-[(6-bromo-3-nitro-2-pyridyl)amino]pentoxy]propyl]carbamate (1.8 g, 3.90 mmol, 1 eq), Fe (871.62 mg, 15.61 mmol, 4 eq), NH4CI (834.79 mg, 15.61 mmol, 4 eq) in EtOH (10 mL),THF (10 mL) and H2O (2.5 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80°C for 2 hrs under N2 atmosphere. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give tert-butyl N-[2-[5-[(3-amino-6-bromo-2-pyridyl)amino]pentoxy]propyl]carbamate (1.5 g, crude) as a black oil. ESI [M+H] = 431.3 / 433.3.

[0350] Preparation of compound 6.

[0351] To a solution of tert-butyl N-[2-[5-[(3-amino-6-bromo-2-pyridyl)amino]pentoxy]propyl]carbamate (1.5 g, 3.48 mmol, 1 eq) in MeOH (30 mL) was added sulfamic acid (675.25 mg, 6.95 mmol, 313.92 pL, 2 eq) and 1,1,1 -trimethoxy ethane (2.09 g, 17.39 mmol, 2.19 mL, 5 eq). The mixture was stirred at 30°C for 1 hr. The reaction mixture was addedAPRE007-PCT | 106265.000238saturated solution of NaHCC>3(20ml) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (50mL), dried over ISfeSCL, fdtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCE, Petroleum ether / Ethyl acetate=50 / l to 1 / 3) to give tert-butyl N-[2-[5-(5-bromo-2-methyl-imidazo[4,5-b]pyridin-3-yl)pentoxy]propyl]carbamate (1.6 g, crude) as a black oil. ESI [M+H] = 455.3 / 457.3.

[0352] Preparation of compound 7.

[0353] A mixture of tert-butyl N-[2-[5-(5-bromo-2-methyl-imidazo[4,5-b]pyridin-3-yl)pentoxy]propyl]carbamate (530.00 mg, 1.16 mmol, 1 eq), ditert -butyl (cyclopenta- 1,4-dien-l-yl)phosphane;dichloropalladium;iron (75.85 mg, 116.38 pmol, 0.1 eq), K3PO4 (741.13 mg, 3.49 mmol, 3 eq) and 2,6-dichloro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (334.78 mg, 1.22 mmol, 1.05 eq) in THF (10 mL) and H2O (2.5 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80°C for 1 hr under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC Petroleum ether / Ethyl acetate=50 / l to 1 / 1) to give tert-butyl N-[2-[5-[5-(2,6-dichloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]pentoxy]propyl]carbamate (500 mg, 957.00 pmol, 82.23% yield) as a yellow oil. ESI [M+H] = 522.2.

[0354] Preparation of compound 8.

[0355] A solution of tert-butyl N-[2-[5-[5-(2,6-dichloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]pentoxy]propyl]carbamate (500.00 mg, 957.00 pmol, 1 eq) in HCl / EtOAc (4M, 10 mL) was stirred at 25 °C for 1 hr. The reaction mixture was concentrated under reduced pressure toAPRE007-PCT | 106265.000238give 2-[5-[5-(2,6-dichloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]pentoxy]propan-l-amine (350 mg, crude, HC1 salt) as a pink solid. ESI [M+H] = 422.4.

[0356] Preparation of compound 9.

[0357] A mixture of 2-[5-[5-(2,6-dichloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]pentoxy]propan-l -amine (150 mg, 355.16 pmol, 1 eq, HC1, salt), tert-butyl carbamate (124.81 mg, 1.07 mmol, 3 eq), CS2CO3 (347.15 mg, 1.07 mmol, 3 eq), dicyclohexyl-[2-(2,6-diisopropoxyphenyl)phenyl]phosphane (8.29 mg, 17.76 pmol, 0.05 eq) and (1E,4E)-1,5-diphenylpenta-l,4-dien-3-one;palladium (16.26 mg, 17.76 pmol, 0.05 eq) in 2-methylbutan-2-ol (5 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100°C for 1 hr under N2 atmosphere. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give tert-butyl N-(9,17-dimethyl-10-oxa-5, 7,16,18,22-pentazatetracyclo[14.5.2.12,6.019,23]tetracosa-l(22),2(24),3,5,17,19(23),20-heptaen-4-yl)carbamate (150 mg, crude) as a yellow oil. ESI [M+H] = 466.5.

[0358] Preparation of Example 10 product.

[0359] A solution oftert-butyl N-(9,17-dimethyl-10-oxa-5,7, 16, 18,22-pentazatetracyclo[14.5.2.12,6.019,23]tetracosa-l(22),2(24),3,5,17,19(23),20-heptaen-4-yl)carbamate (100 mg, 214.33 pmol, 1 eq) in TFA (5 mL). The mixture was stirred at 25°C for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: WePure Biotech XP tC18 150*40*7um;mobile phase: [H20(0.05% NH3H2O+ 1 OmM NELHCO3)-ACN] gradient: 25 %-55% B over 8.0 min) to give 9,17-dimethyl-10-oxa-5,7,16,18,22-pentazatetracyclo[14.5.2.12,6.019,23]tetracosa-l(22),2(24),3,5,17,19(23),20-heptaen-4-amine (2 mg, 5.39 pmol, 2.52% yield, 99% purity) as a white solid. ’H NMR (400 MHz, DMSO-d6) 57.95 (d, J =APRE007-PCT | 106265.0002388.3 Hz, 1H), 7.61-7.54 (m, 1H), 6.76-6.69 (m, 1H), 6.31-6.27 (m, 1H), 6.18 (br t, J = 5.4 Hz, 1H), 5.65-5.47 (m, 2H), 4.29-4.19 (m, 2H), 3.76-3.67 (m, 1H), 3.62-3.53 (m, 1H), 3.42-3.37 (m, 2H), 2.96-2.85 (m, 1H), 2.60 (s, 3H), 2.02-1.90 (m, 1H), 1.81-1.65 (m, 3H), 1.57-1.44 (m, 2H), 1.12 (d, J = 6.0 Hz, 3H). ESI [M+H] = 366.4.

[0360] Examples HA, 11B and 11C1 2

[0362] A mixture of tert-butyl N-[2-[5-(5-bromo-2-methyl-imidazo[4,5-b]pyridin-3-yl)pentoxy]propyl]carbamate (550 mg, 1.21 mmol, 1 eq), 2-chloro-4-(4, 4, 5, 5 -tetramethyl- 1,3,2-dioxaborolan-2-yl)pyridine (303.73 mg, 1.27 mmol, 1.05 eq), ditert -butyl (cyclopenta- 1,4-dien-l-yl)phosphane;dichloropalladium;iron (78.72 mg, 120.78 pmol, 0.1 eq), K3PO4 (769.10 mg, 3.62 mmol, 3 eq) in THF (2 m ) and H2O (0.5 m ) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80°C for 1 hr under N2 atmosphere. The mixture was added water (20 mb) and extracted with EtOAc (10 mb x 3). The organic layer was dried over MgSO4 and concentrated under reduced pressure to give tert-butyl N-[2-[5-[5-(2-chloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]pentoxy]propyl]carbamate (600 mg, crude) as a yellow oil. ESI [M+H] = 488.0

[0363] Preparation of compound 3.APRE007-PCT | 106265.000238

[0364] A solution of tert-butyl N-[2-[5-[5-(2-chloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]pentoxy]propyl]carbamate (600 mg, 1.23 mmol, 1 eq) in HCl / EtOAc (5 mL) was stirred at 25°C for 1 hr. The reaction mixture was concentrated under reduced pressure to give 2-[5-[5-(2-chloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]pentoxy]propan-l-amine (450 mg, crude, HC1 salt) as a yellow solid. ESI [M+H] = 387.9

[0365] Preparation of Example HA product.Example 11A

[0366] A mixture of 2-[5-[5-(2-chloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]pentoxy]propan-l -amine (50 mg, 128.90 pmol, 1 eq, HC1 salt), dicyclohexyl-[2-(2,6-diisopropoxyphenyl)phenyl]phosphane (6.01 mg, 12.89 pmol, 0.1 eq), (lE,4E)-l,5-diphenylpenta-l,4-dien-3-one;palladium (11.80 mg, 12.89 pmol, 0.1 eq) and t-BuONa (37.16 mg, 386.69 pmol, 3 eq) in 2-methylbutan-2-ol (5 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100°C for 12 hrs under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 75*30mm*3um;mobile phase: [H2O(0.1%TFA)-ACN] gradient: 10%-40% B over 8.0 min) to give 9,17-dimethyl-10-oxa-5,7,16,18,22-pentazatetracyclo[14.5.2.12,6.019,23]tetracosa-1(22), 2(24), 3, 5, 17, 19(23), 20-heptaene (5.78 mg, 16.29 pmol, 12.64% yield, 99% purity) as awhite solid. ’H NMR (400 MHz, DMSO-d6) 58.28 (br s, 1H), 8.15-8.09 (m, 2H), 8.06-8.01 (m, 1H), 7.98 (s, 1H), 7.58 (d, J = 6.5 Hz, 1H), 4.29 (quin, J = 7.0 Hz, 2H), 3.51-3.40 (m, 5H), 2.66 (s, 3H), 2.05-1.94 (m, 1H), 1.89-1.74 (m, 2H), 1.73-1.64 (m, 1H), 1.60 (q, J = 6.6 Hz, 2H), 1.17 (d, J = 5.9 Hz, 3H). ESI [M+H] = 352.4.APRE007-PCT | 106265.000238

[0367] Preparation of Examples 1 IB and 11C products.Example 11AExample 11 B Example 11 C

[0368] The racemic material was purified by SFC (column: DAICEL CHIRALPAK AD(250mm x 30mm,10um);mobile phase: [C02-IPA(0.1%NH3H20)];B%:40%, isocratic elution mode) to give arbitrarily assigned: (9R)-9,17-dimethyl-10-oxa-5, 7, 16,18,22-pentazatetracyclo[14.5.2.12,6.019,23]tetracosa-l(21),2(24),3,5,17,19,22-heptaene (Peak 1, retention time =1.545_min) (30.77 mg, 84.84 pmol, 74.54% yield, 97% purity, ee% =100%) as a white solid and (9S)-9,17-dimethyl-10-oxa-5,7,16,18,22-pentazatetracyclo[14.5.2.12,6.019,23]tetracosa-l(21),2(24),3,5,17,19,22-heptaene (Peak 2, retention time =1.933_min) (27.35 mg, 75.46 pmol, 66.30% yield, 97% purity, ee% =98.7%) as a white solid.

[0369] Example 1 IB: ’H NMR (400 MHz, DMSO-d6) 59.00 (br s, 1H), 8.43-8.38 (m, 1H), 8.36-8.27 (m, 1H), 8.22 (d, J = 6.6 Hz, 1H), 7.97 (s, 1H), 7.64 (br d, J = 6.5 Hz, 1H), 4.42 (br d, J = 2.4 Hz, 2H), 3.69-3.54 (m, 3H), 3.53-3.38 (m, 2H), 2.93 (s, 3H), 2.11-1.75 (m, 3H), 1.73-1.54 (m, 3H), 1.16 (br d, J = 5.8 Hz, 3H) ESI [M+H] = 352.2

[0370] Example 11C: ’H NMR (400 MHz, DMSO-d6) 58.96 (br s, 1H), 8.39-8.32 (m, 1H), 8.30-8.24 (m, 1H), 8.21 (br d, J = 6.6 Hz, 1H), 7.97 (s, 1H), 7.62 (br d, J = 6.5 Hz, 1H), 4.39 (br s, 2H), 3.68-3.56 (m, 3H), 3.50-3.37 (m, 2H), 2.87 (s, 3H), 2.06-1.75 (m, 3H), 1.73-1.55 (m, 3H), 1.16 (br d, J = 5.5 Hz, 3H) ESI [M+H] = 352.2

[0371] Example 12

[0372] Preparation of compound 2.APRE007-PCT | 106265.000238

[0373] To a solution of tert-butyl N-(4-hydroxybutyl)carbamate (25 g, 132.10 mmol, 1 eq) and prop-2 -enenitrile (14.02 g, 264.20 mmol, 17.52 mb, 2 eq) in THF (200 mb) was added NaOMe (713.60 mg, 13.21 mmol, 0.1 eq). The mixture was stirred at 25°C for 12 hrs. The reaction mixture was fdtered. The fdtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, Petroleum ether / THF=50 / l to 0 / 1) to give tert-butyl N-[4-(2-cyanoethoxy)butyl]carbamate (20 g, 82.54 mmol, 62.48% yield) as a colorless oil. ESI [M+H] = 243.2.

[0374] Preparation of compound 3.

[0375] The reaction was performed by flow chemistry. Solution 1: {tert-butyl N-[4-(2-cyanoethoxy)butyl] carbamate (7.5 g, 30.95 mmol, 1 eq)} in {NHs / MeOH (140 mb)}. The fixed bed (named FLR1, volume 5 mb) was completely packed with granular catalyst 14%Co / AhO3 (4 g). The H2 back pressure regulator was adjusted to 2.5 MPa, and the flow rate of H2 was 30 mL / min. Then the solution SI was pumped by Pump 1 {SI, Pl, 2.3 mL / min} to fixed bed {FLR1, SS, fixed bed, 6.350(l / 4”)mm, 1 mb, 80 °C}. The solution SI was flowing through {FLR1, 3.3 min} to leave the reactor zone, then the reaction mixture was collected from the reactor output. Stop collecting the reaction mixture after 1 hr. The fixed bed was washed by extra MeOH (100 mb). The organic layer was concentrated to give tert-butyl N-[4-(3-aminopropoxy)butyl]carbamate (7 g, crude) as a colorless oil. ESI [M+H] = 247.2.

[0376] Preparation of compound 4.

[0377] To a solution of 6-bromo-2-chloro-3-nitro-pyridine (5.40 g, 22.73 mmol, 0.8 eq) in THF (100 mL) was added TEA (8.63 g, 85.25 mmol, 11.87 mL, 3 eq) and tert -butyl N-[4-(3-APRE007-PCT | 106265.000238aminopropoxy )butyl] carbamate (7 g, 28.42 mmol, 1 eq). The mixture was stirred at 25°C for 1 hr. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, Petroleum ether / Ethyl acetate=50 / l to 83 / 17) to give tert-butyl N-[4-[3-[(6-bromo-3-nitro-2-pyridyl)amino]propoxy]butyl]carbamate (6 g, 13.41 mmol, 47.20% yield) as a yellow solid. ’H NMR (400 MHz, Chloroform-d) 5 8.81-8.65 (m, 1H), 8.29-8.19 (m, 1H), 6.81-6.74 (m, 1H), 4.75 (br s, 1H), 3.77 (q, J = 5.9 Hz, 2H), 3.61 (t, J = 5.6 Hz, 2H), 3.51 (t, J = 6.2 Hz, 2H), 3.25-3.11 (m, 2H), 2.03-1.94 (m, 2H), 1.75-1.56 (m, 4H), 1.47 (s, 9H). ESI [M+H] = 447.3 / 449.3.

[0378] Preparation of compound 5.4 5

[0379] A mixture of tert-butyl N-[4-[3-[(6-bromo-3-nitro-2-pyridyl)amino]propoxy]butyl]carbamate (6 g, 13.41 mmol, 1 eq), Fe (3.00 g, 53.65 mmol, 4 eq) and NH4CI (2.87 g, 53.65 mmol, 4 eq) in THF (40 m ), EtOH (40 m ) and H2O (10 m ) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80°C for 2 hrs under N2 atmosphere. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give tert-butyl N-[4-[3-[(3-amino-6-bromo-2-pyridyl)amino]propoxy]butyl]carbamate (5.5 g, crude) as a black oil. ESI [M+H] = 417.3 / 419.2.

[0380] Preparation of compound 6.5 6

[0381] To a solution of tert-butyl N-[4-[3-[(3-amino-6-bromo-2-pyridyl)amino]propoxy]butyl]carbamate (5.5 g, 13.18 mmol, 1 eq) in MeOH (50 mb) was addedAPRE007-PCT | 106265.000238sulfamic acid (2.56 g, 26.36 mmol, 1.19 mL, 2 eq) and 1,1,1 -trimethoxyethane (7.92 g, 65.89 mmol, 8.28 mL, 5 eq). The mixture was stirred at 40°C for 1 hr. The reaction mixture was quenched by addition saturated solution of ISfeCOs (30 mL) at 0°C, and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (50 mL), dried over ISfeSCL, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC Petroleum ether / Ethyl acetate=50 / l to 0 / 1) to give tert-butyl N-[4-[3-(5-bromo-2-methyl-imidazo[4,5-b]pyridin-3-yl)propoxy]butyl]carbamate (4.8 g, 10.88 mmol, 82.52% yield) as a brown oil. ’H NMR (400 MHz, Chloroform-d) 57.77 (d, J = 8.3 Hz, 1H), 7.32 (d, J = 8.3 Hz, 1H), 4.76-4.61 (m, 1H), 4.33 (t, J = 6.8 Hz, 2H), 3.38 (q, J = 5.9 Hz, 4H), 3.19-3.08 (m, 2H), 2.67-2.58 (m, 3H), 2.12 (quin, J = 6.3 Hz, 2H), 1.63-1.51 (m, 4H), 1.44 (s, 9H). ESI [M+H] = 441.3 / 443.1.

[0383] A mixture of tert-butyl N-[4-[3-(5-bromo-2-methyl-imidazo[4,5-b]pyridin-3-yl)propoxy]butyl]carbamate (2.3 g, 5.21 mmol, 1 eq), 2, 6-dichloro-4-(4, 4, 5, 5 -tetramethyl- 1,3,2-dioxaborolan-2-yl)pyridine (1.50 g, 5.47 mmol, 1.05 eq), ditert-butyl (cyclopenta- 1,4-dien-l-yl)phosphane;dichloropalladium;iron (339.63 mg, 521.11 pmol, 0.1 eq), K3PO4 (3.32 g, 15.63 mmol, 3 eq) in THF (50 mL), H2O (10 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80°C for 1 hr under N2 atmosphere. The reaction mixture was added water (100ml) and extracted with EtOAc (80 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=50 / l to 0 / 1) to give tert-butyl N-[4-[3-[5-(2,6-dichloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]propoxy]butyl]carbamate (2.5 g, 4.92 mmol, 94.36% yield) as a brown oil. ’HNMR (400 MHz, Chloroform-d) 58.01 (d, J = 8.2 Hz, 1H), 7.95 (s, 2H), 7.70 (d, J = 8.2 Hz, 1H), 4.43 (t, J = 6.7 Hz, 2H), 3.47-3.35 (m, 4H), 3.19-3.08 (m, 2H), 2.70 (s, 3H), 2.19 (quin, J = 6.1 Hz, 2H), 1.61-1.51 (m, 4H), 1.44 (s, 9H). ESI [M+H] = 508.4.

[0384] Preparation of compound 8.APRE007-PCT | 106265.000238

[0385] A solution of tert-butyl N-[4-[3-[5-(2,6-dichloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]propoxy]butyl]carbamate (2.5 g, 4.92 mmol, 1 eq) in HCl / EtOAc (100 mb) was stirred at 25°C for 1 hr. The reaction mixture was concentrated under reduced pressure to give 4-[3-[5-(2,6-dichloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]propoxy]butan-l-amine (3 g, crude, HC1 salt) as a white solid. ESI [M+H] = 408.1.

[0386] Preparation of compound 9.

[0387] A mixture of 4-[3-[5-(2,6-dichloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]propoxy]butan-l -amine (30 mg, 73.47 pmol, 1 eq, HC1 salt), tert-butyl N-methylcarbamate (28.91 mg, 220.41 pmol, 3 eq), dicyclohexyl-[2-(2,6-diisopropoxyphenyl)phenyl]phosphane (1.71 mg, 3.67 pmol, 0.05 eq), (lE,4E)-l,5-diphenylpenta-l,4-dien-3-one;palladium (3.36 mg, 3.67 pmol, 0.05 eq) and t-BuONa (21.18 mg, 220.41 pmol, 3 eq) in 2-methylbutan-2-ol (5 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100°C for 12 hrs under N2 atmosphere. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give tert -butyl N-methyl-N-(17-methyl-12-oxa-5,7,16,18,22-pentazatetracyclo[14.5.2.12,6.019,23]tetracosa-1(22), 2(24), 3, 5, 17, 19(23), 20-heptaen-4-yl)carbamate (30 mg, crude) as a yellow oil. ESI [M+H] = 467.3.

[0388] Preparation of Example 12 product.APRE007-PCT | 106265.000238

[0389] A solution oftert-butyl N-methyl-N-(17-methyl-12-oxa-5,7, 16, 18,22-pentazatetracyclo[14.5.2.12,6.019,23]tetracosa-l(22),2(24),3,5,17,19(23),20-heptaen-4-yl)carbamate (30 mg, 64.30 pmol, 1 eq) in TFA (2 m ) was stirred at 25°C for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 75*30mm*3um;mobile phase: [H2O(0.1%TFA)-ACN] gradient: 10%-35% B over 8.0 min) to give N,17-dimethyl-12-oxa-5,7, 16, 18,22-pentazatetracyclo[14.5.2.12,6.019,23]tetracosa-l(22),2(24),3,5,17,19(23),20-heptaen-4-amine (4.86 mg, 13.17 pmol, 20.48% yield, 99% purity, TFA salt) as a yellow solid. ’H NMR (400 MHz, DMSO-d6) 57.98-7.90 (m, 1H), 7.63 (d, J = 8.3 Hz, 1H), 6.77 (s, 1H), 6.19 (s, 1H), 6.08-6.03 (m, 1H), 6.00 (q, J = 4.5 Hz, 1H), 4.43-4.34 (m, 2H), 3.54 (t, J = 5.5 Hz, 2H), 3.49 (brt, J = 5.0 Hz, 2H), 3.14-3.03 (m, 2H), 2.76 (d, J = 4.8 Hz, 3H), 2.60 (s, 3H), 2.08-1.99 (m, 2H), 1.86-1.76 (m, 2H), 1.66-1.57 (m, 2H). ESI [M+H] = 367.2.

[0390] Example 13

[0391] A mixture of 4-[3-[5-(2,6-dichloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]propoxy]butan-l -amine (20 mg, 48.98 pmol, 1 eq), (lE,4E)-l,5-diphenylpenta-l,4-dien-3-one;palladium (4.49 mg, 4.90 pmol, 0.1 eq), t-BuONa (14.12 mg, 146.94 pmol, 3 eq) and dicyclohexyl-[2-(2,6-diisopropoxyphenyl)phenyl]phosphane (2.29 mg, 4.90 pmol, 0.1 eq), dimethylamine hydrochloride (11.9 mg, 146.94 pmol, 3 eq) in 2-methylbutan-2-ol (5 mb) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100°C for 12 hr under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. TheAPRE007-PCT | 106265.000238residue was purified by prep-HPLC (column: Phenomenex Luna C18 75*30mm*3um;mobile phase:[H2O(0.1%TFA)-ACN] gradient: 10%-40% B over 8.0 min) to give N,N,17-trimethyl-12-oxa-5,7,16,18,22-pentazatetracyclo[14.5.2.12,6.019,23]tetracosa-l(22),2(24),3,5,17,19(23),20-heptaen-4-amine (33 mg, 86.73 pmol, 59.02% yield, 3 batches) as a white solid. 'H NMR (400 MHz, DMSO-d6) 5 8.20-8.10 (m, 2H), 7.66-7.40 (m, 1H), 7.13 (s, 1H), 6.70 (s, 1H), 4.44 (brt, J = 7.3 Hz, 2H), 3.53 (td, J = 5.3, 13.3 Hz, 4H), 3.37-3.30 (m, 2H), 3.21 (s, 6H), 2.70 (s, 3H), 2.10-2.01 (m, 2H), 1.91-1.81 (m, 2H), 1.70-1.60 (m, 2H). ESI [M+H] = 381.2.

[0392] Example 14

[0393] Preparation of compound 10

[0394] A mixture of 4-[3-[5-(2,6-dichloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]propoxy]butan-l -amine (1 g, 2.45 mmol, 1 eq), CS2CO3 (2.39 g, 7.35 mmol, 3 eq), (1E,4E)-1,5-diphenylpenta-l,4-dien-3-one;palladium (224.26 mg, 244.90 pmol, 0.1 eq) and (5-diphenylphosphanyl-9,9-dimethyl-xanthen-4-yl)-diphenyl-phosphane (141.71 mg, 244.90 pmol, 0.1 eq) in 2-methylbutan-2-ol (50 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100°C for 12 hrs under N2 atmosphere. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Welch Xtimate C18 250*70mm*10um;mobile phase: [H2O(0.2%FA)-ACN];gradient: 10%-40% B over 20.0 min) to give 4-chloro-17-methyl-12-oxa-5,7,16,18,22-pentazatetracyclo[14.5.2.12,6.019,23]tetracosa-l(22),2(24),3,5,17,19(23),20-heptaene (60 mg, 161.35 pmol, 6.59% yield) as a white solid. ESI [M+H] = 372.2.

[0395] Preparation of Example 14 product.APRE007-PCT | 106265.000238

[0396] To a solution of 4-chloro-17-methyl-12-oxa-5,7,16,18,22-pentazatetracyclo[14.5.2.12,6.019,23]tetracosa-l(22),2(24),3,5,17,19(23),20-heptaene (30 mg, 80.67 pmol, 1 eq) in DMF (2 mL) was added K2CO3 (33.45 mg, 242.02 pmol, 3 eq), cyclopentyl(diphenyl)phosphane;dichloropalladium;iron (5.90 mg, 8.07 pmol, 0.1 eq) and triethylborane (23.72 mg, 242.02 pmol, 35.03 pL, 3 eq). The mixture was stirred at 80°C for 12 hrs. The reaction mixture was added water (10 mL) and extracted with EtOAc (8 mL x 3). The combined organic layers were washed with brine (5 mL), dried overlSfeSCL, fdtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 75*30mm*3um;mobile phase: [LLC O.1%TFA)-ACN] gradient: 1 %-30% B over 8.0 min) to give 4-ethyl-17-methyl-12-oxa-5,7,16,18,22-pentazatetracyclo[14.5.2.12,6.019,23]tetracosa-1(22), 2(24), 3, 5, 17, 19(23), 20-heptaene (12.51 mg, 33.15 pmol, 41.09% yield, 97% purity, TFA salt) as a white solid. ’HNMR (400 MHz, DMSO-d6) 58.19-8.11 (m, 2H), 8.09-7.99 (m, 1H), 7.97 (s, 1H), 7.51 (s, 1H), 4.51-4.41 (m, 2H), 3.58 (br s, 2H), 3.54 (br d, J = 5.1 Hz, 2H), 3.45 (br dd, J = 4.2, 7.3 Hz, 2H), 2.83 (q, J = 7.4 Hz, 2H), 2.70 (s, 3H), 2.15-2.03 (m, 2H), 1.95-1.82 (m, 2H), 1.77-1.64 (m, 2H), 1.37-1.31 (m, 3H). ESI [M+H] = 366.2.

[0397] Example 15

[0398] A mixture of 4-chloro-17-methyl-12-oxa-5,7,16,18,22-pentazatetracyclo[14.5.2.12,6.019,23]tetracosa-l(22),2(24),3,5,17,19(23),20-heptaene (170 mg, 457.16 pmol, 1 eq), MeOH (87.89 mg, 2.74 mmol, 6 eq), Pd2(dba)s (41.86 mg, 45.72 pmol, 0.1 eq), t-BuXPhos (36.32 mg, 45.72 pmol, 0.1 eq) and t-BuONa (131.80 mg, 1.37 mmol, 3 eq) in Toluene (2 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80°C for 12 hrsAPRE007-PCT | 106265.000238under N2 atmosphere. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: 3_Phenomenex Luna C18 75*30mm*3um;mobile phase: [H2O(0.1% TFA)-ACN] gradient: 10%-40% B over 8.0 min) to give 4-methoxy- 17 -methyl- 12-oxa-5 ,7, 16, 18, 22 -pentazatetracyclo [14.5.2.12,6.019,23]tetracosa-1(22), 2(24), 3, 5, 17, 19(23), 20-heptaene (8.00 mg, 15.46 pmol, 3.38% yield, 93% purity, TFA salt) as a white solid. ’H NMR (400 MHz, DMSO-d6) 58.14 (d, J = 8.4 Hz, 1H), 8.04 (s, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.17 (s, 1H), 6.61 (s, 1H), 4.49 (brt, J = 7.4 Hz, 2H), 3.83 (s, 3H), 3.54 (td, J = 5.3, 12.8 Hz, 4H), 3.25-3.08 (m, 2H), 2.75 (s, 3H), 2.14-2.05 (m, 2H), 1.89-1.78 (m, 2H), 1.71-1.58 (m, 2H) ESI [M+H] =368.2.

[0399] Example 16

[0400] Preparation of compound 2.

[0401] A mixture of tert-butyl N-[4-[3-(5-bromo-2-methyl-imidazo[4,5-b]pyridin-3-yl)propoxy]butyl]carbamate (300 mg, 679.72 pmol, 1 eq), 2-chloro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (162.80 mg, 679.72 pmol, 1 eq), ISfeCOs (216.13 mg, 2.04 mmol, 3 eq) and Pd(dppf)C12 (49.74 mg, 67.97 pmol, 0.1 eq) in dioxane (4 m ) and H2O (2 m ) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80°C for 1 hr under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue, and then the residue was added H2O (2 mb), extracted with EtOAc (2 mb x 3). The combined organic layers were dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, Petroleum ether : THF=50 / l to 0 / 1) to give tert-butyl N-APRE007-PCT | 106265.000238[4-[3-[5-(2-chloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]propoxy]butyl]carbamate (280 mg, 590.72 pmol, 86.91% yield) as a brown oil. ESI [M+H] =474.2

[0402] Preparation of compound 3.

[0403] A solution of tert-butyl N-[4-[3-[5-(2-chloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]propoxy]butyl]carbamate (280 mg, 590.72 pmol, 1 eq) in HCl / EtOAc (4M, 2 mL) was stirred at 25°C for 1 hr. The reaction mixture was concentrated under reduced pressure to give 4-[3-[5-(2-chloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]propoxy]butan-l-amine (220 mg, crude, HC1 salt) as a white solid. ESI [M+H] =374.2

[0404] Preparation of Example 16 product.

[0405] A mixture of 4-[3-[5-(2-chloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]propoxy]butan-l -amine (50 mg, 133.73 pmol, 1 eq, HC1 salt), CS2CO3 (130.72 mg, 401.20 pmol, 3 eq), RuPhos (6.24 mg, 13.37 pmol, 0.1 eq) and Pd2(dba)s (12.25 mg, 13.37 pmol, 0.1 eq) in 2-methylbutan-2-ol (7 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100°C for 12 hrs under N2 atmosphere. The reaction mixture was fdtered. The fdtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 75*30mm*3um;mobile phase: [H2O(0.1%TFA)-ACN] gradient: 10%-40% B over 8.0 min) to give 17-methyl-12-oxa-5,7, 16, 18,22-pentazatetracyclo[14.5.2.12,6.019,23]tetracosa-l(22),2(24),3,5,17,19(23),20-heptaene (33.63 mg, 72.85 pmol, 27.24% yield, 98% purity, TFA salt) as a white solid. ’H NMR (400 MHz, DMSO-d6) 5 8.57 (br s, 1H), 8.19-8.08 (m, 4H), 7.59 (dd, J = 1.4, 6.8 Hz, 1H), 4.46 (br t, J = 7.4 Hz, 2H), 3.55 (td,APRE007-PCT | 106265.000238J = 5.3, 15.3 Hz, 4H), 3.43 (brd, J = 3.6 Hz, 2H), 2.70 (s, 3H), 2.16-2.00 (m, 2H), 1.86 (br dd, J = 5.6, 11.1 Hz, 2H), 1.76-1.62 (m, 2H). ESI [M+H] =338.2.

[0406] Example 171 2

[0408] A mixture of tert-butyl N-[4-[3-(5-bromo-2-methyl-imidazo[4,5-b]pyridin-3-yl)propoxy]butyl]carbamate (300 mg, 679.72 pmol, 1 eq), 2-chloro-6-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (172.33 mg, 679.72 pmol, 1 eq), Na2COs (216.13 mg, 2.04 mmol, 3 eq), Pd(dppf)C12 (49.74 mg, 67.97 pmol, 0.1 eq) and H2O (2 m ) in dioxane (4 m ) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80°C for 1 hr under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue and the residue was added H2O (6 mb), extracted with EtOAc (30 mb x 3). The combined organic layers were dried over Na2SC>4, fdtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, Petroleum ether: THb= 50 / 1 to 0 / 1) to give tert-butyl N-[4-[3-[5-(2-chloro-6-methyl-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]propoxy]butyl]carbamate (270 mg, 553.26 pmol, 81.40% yield) as a brown oil. ESI [M+H] =488.2

[0409] Preparation of compound 3.APRE007-PCT | 106265.000238

[0410] A solution of tert-butyl N-[4-[3-[5-(2-chloro-6-methyl-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]propoxy]butyl]carbamate (270 mg, 553.26 pmol, 1 eq) in HCl / EtOAc (4M, 2 mL) was stirred at 25 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give 4-[3-[5-(2-chloro-6-methyl-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]propoxy]butan-l -amine (200 mg, crude, HC1 salt) as a white solid. ESI [M+H] =388.2

[0411] Preparation of Example 17 product.

[0412] A mixture of 4-[3-[5-(2-chloro-6-methyl-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]propoxy]butan-l -amine (50 mg, 128.90 pmol, 1 eq), CS2CO3 (125.99 mg, 386.69 pmol, 3 eq), RuPhos (6.01 mg, 12.89 pmol, 0.1 eq) and Pd2(dba)s (11.80 mg, 12.89 pmol, 0.1 eq) in 2-methylbutan-2-ol (6 mb) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100 °C for 12 hrs under N2 atmosphere. The reaction mixture was fdtered. The fdtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 75*30mm*3um;mobile phase: [H2O(0.1%TFA)-ACN] gradient: 10%-40% B over 8.0 min) to give 4,17-dimethyl-12-oxa-5,7,16,18,22-pentazatetracyclo[14.5.2.12,6.019,23]tetracosa-l(22),2(24),3,5,17,19(23),20-heptaene (24.76 mg, 52.75 pmol, 20.46% yield, 99% purity, TFA salt) as a white solid. ’H NMR (400 MHz, DMSO-d6) 5 8.16 (br d, J = 8.2 Hz, 2H), 8.06 (br d, J = 8.2 Hz, 1H), 7.94 (s, 1H), 7.51 (s, 1H), 4.45 (brt, J = 6.7 Hz, 2H), 3.61-3.50 (m, 4H), 3.42 (br s, 2H), 2.69 (s, 3H), 2.54-2.52 (m, 3H), 2.07 (br s, 2H), 1.86 (br d, J = 2.1 Hz, 2H), 1.69 (br d, J = 5.4 Hz, 2H) ESI [M+H] =352.2.

[0413] Example 18APRE007-PCT | 106265.000238

[0414] Preparation of compound 2.Boc

[0415] A mixture of 3 -bromo-2 -iodo-pyridine (15 g, 52.84 mmol, 1 eq), tert-butyl N-prop-2-ynylcarbamate (8.20 g, 52.84 mmol, 1 eq), Cui (1.01 g, 5.28 mmol, 0.1 eq), TEA (10.69 g, 105.67 mmol, 14.71 m , 2 eq) and dichloropalladium;triphenylphosphane (1.85 g, 2.64 mmol, 0.05 eq) in THF (200 m ) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 60°C for 12 hrs under N2 atmosphere. The reaction mixture was fdtered. The fdtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCE, Petroleum ether / Ethyl acetate=50 / l to 5 / 1) to give tert-butyl N-[3-(3-bromo-2-pyridyl)prop-2-ynyl] carbamate (14.6 g, 46.92 mmol, 88.80% yield) as a yellow oil. ESI [M+H] =311.1 / 313.2.

[0416] Preparation of compound 3.

[0417] A mixture of tert-butyl N-[3-(3-bromo-2-pyridyl)prop-2-ynyl]carbamate (14.4 g, 46.28 mmol, 1 eq), 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoxazole (9.48 g, 48.59 mmol, 1.05 eq), K3PO4 (19.65 g, 92.55 mmol, 2 eq), [2-(2-aminophenyl)phenyl]-chloro-palladium;bis(l-APRE007-PCT | 106265.000238adamantyl)-butyl-phosphane (3.09 g, 4.63 mmol, 0.1 eq) in THF (200 mL) and H2O (50 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 60°C for 1 hr under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, Petroleum ether / Ethyl acetate=50 / l to 3 / 1) to give tert-butyl N-[3-(3-isoxazol-4-yl-2-pyridyl)prop-2-ynyl]carbamate (10 g, 33.41 mmol, 72.19% yield) as a yellow solid. ESI [M+H] =304.2 / 306.2.

[0418] Preparation of compound 4.

[0419] To a solution of tert-butyl N-[3-(3-isoxazol-4-yl-2-pyridyl)prop-2-ynyl]carbamate (10 g, 33.41 mmol, 1 eq) in MeOH (200 mL) was added KF (5 M, 20.05 mL, 3 eq). The mixture was stirred at 70°C for 12 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=50 / l to 3 / 1) to give tert-butyl N-[3-[3-(cyanomethyl)-2-pyridyl]prop-2-ynyl]carbamate (5.4 g, 19.90 mmol, 59.57% yield) as a brown solid. ESI [M+H] =272.3.

[0420] Preparation of compound 5.

[0421] A mixture of Raney Ni (947.33 mg, 11.06 mmol, 1 eq) in EtOH (40 mL) was degassed and purged with Ar2 for 3 times, and then added tert-butyl N-[3-[3-(cyanomethyl)-2-pyridyl]prop-2-ynyl]carbamate (3 g, 11.06 mmol, 1 eq), ammonium;hydroxide (1.16 g, 33.17 mmol, 1.28 mL, 3 eq). The mixture was stirred at 30°C for 12 hrs under H2 (30 Psi) atmosphere. The reaction mixture was concentrated under reduced pressure to give tert-butyl N-[3-[3-(2-aminoethyl)-2-pyridyl]propyl]carbamate (3 g, crude) as a yellow oil. ESI [M+H] =280.2.

[0422] Preparation of compound 6.APRE007-PCT | 106265.000238

[0423] To a solution of tert-butyl N-[3-[3-(2-aminoethyl)-2-pyridyl]propyl]carbamate (3 g, 10.74 mmol, 1 eq) in THF (50 mb) was added TEA (3.26 g, 32.21 mmol, 4.48 m , 3 eq) and 6-bromo-2-chloro-3 -nitro-pyridine (2.04 g, 8.59 mmol, 0.8 eq). The mixture was stirred at 25°C for 12 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC Petroleum ether / Ethyl acetate=50 / l to 1 / 1) to give tert-butyl N-[3-[3-[2-[(6-bromo-3-nitro-2-pyridyl)amino]ethyl]-2-pyridyl]propyl]carbamate (3.3 g, 6.87 mmol, 63.98% yield) as a yellow solid. ESI [M+H] =480.1 / 482.1.

[0424] Preparation of compound 7.

[0425] A mixture of tert-butyl N-[3-[3-[2-[(6-bromo-3-nitro-2-pyridyl)amino]ethyl]-2-pyridyl]propyl]carbamate (3 g, 6.25 mmol, 1 eq), Fe (1.40 g, 24.98 mmol, 4 eq), NH4CI (1.34 g, 24.98 mmol, 4 eq) in EtOH (30 mL),THF (30 mb) and H2O (10 mb) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80°C for 2 hrs under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give tert-butyl N-[3-[3-[2-[(3-amino-6-bromo-2-pyridyl)amino]ethyl]-2-pyridyl]propyl]carbamate (2.8 g, crude) as a black solid. ESI [M+H] =450.2 / 452.2.

[0426] Preparation of compound 8.APRE007-PCT | 106265.000238

[0427] To a solution of tert-butyl N-[3-[3-[2-[(3-amino-6-bromo-2-pyridyl)amino]ethyl]-2-pyridyl]propyl]carbamate (2.8 g, 6.22 mmol, 1 eq) in AcOH (30 mb) was added 1,1,1-trimethoxyethane (2.24 g, 18.65 mmol, 2.34 mb, 3 eq). The mixture was stirred at 80°C for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in EtOAc (20 mb) and washed with saturated solution of ISfeCCE (20 mb x3). The residue was purified by column chromatography (SiC Petroleum ether / Ethyl acetate=50 / l to 0 / 1) to give tert-butyl N-[3-[3-[2-(5-bromo-2-methyl-imidazo[4,5-b]pyridin-3-yl)ethyl]-2-pyridyl]propyl]carbamate (1.9 g, 4.01 mmol, 64.42% yield) as ablack oil. ESI [M+H] =474.1 / 476.2.

[0428] Preparation of compound 9.

[0429] A mixture of tert-butyl N-[3-[3-[2-(5-bromo-2-methyl-imidazo[4,5-b]pyridin-3-yl)ethyl]-2-pyridyl]propyl]carbamate (1.9 g, 4.01 mmol, 1 eq), 2,6-dichloro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (1.15 g, 4.21 mmol, 1.05 eq), K3PO4 (2.55 g, 12.02 mmol, 3 eq), ditert-butyl(cyclopenta-l,4-dien-l-yl)phosphane;dichloropalladium;iron (261.03 mg, 400.51 pmol, 0.1 eq) in THF (40 mL), H2O (10 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80°C for 1 hr under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, DCM / MeOH=l / 0 to 95 / 5) to give tert-butyl N-[3-[3-[2-[5-(2,6-dichloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]ethyl]-2-pyridyl]propyl]carbamate (2.1 g, 3.88 mmol, 96.83% yield) as a brown oil. ESI [M+H] =541.2.

[0430] Preparation of compound 10.APRE007-PCT | 106265.000238

[0431] A solution of tert-butyl N-[3-[3-[2-[5-(2,6-dichloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]ethyl]-2-pyridyl]propyl]carbamate (1 g, 1.85 mmol, 1 eq) in HCl / EtOAc (50 mL) was stirred at 25 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Welch Xtimate C18 250*70mm* 10um;mobile phase: [H2O(0.2%FA)-ACN];gradient: 10%-40% B over 20.0 min) to give 3-[3-[2-[5-(2,6-dichloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]ethyl]-2-pyridyl]propan-l-amine (340 mg, 770.35 pmol, 41.71% yield, FA salt) as a yellow solid. ESI [M+H] =441.2.

[0432] Preparation of compound 11.

[0433] A mixture of 3-[3-[2-[5-(2,6-dichloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]ethyl]-2-pyridyl]propan-l-amine (10 mg, 22.66 pmol, 1 eq), tert-butyl carbamate (2.65 mg, 22.66 pmol, 1 eq), CS2CO3 (22.15 mg, 67.97 pmol, 3 eq), dicyclohexyl-[2-(2,6-diisopropoxyphenyl)phenyl]phosphane (1.06 mg, 2.27 pmol, 0.1 eq) and (lE,4E)-l,5-diphenylpenta-l,4-dien-3-one;palladium (20.75 mg, 22.66 pmol, 1 eq) in 2-methylbutan-2-ol (4 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100°C for 12 hrs under N2 atmosphere. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give tert-butyl N-(20-methyl-5,7,12,19,21,25-hexazapentacyclo[17.5.2.12, 6.011,16.022, 26]heptacosa-l(24), 2, 4, 6(27), 11(16), 12, 14, 20, 22,25-decaen-4-yl)carbamate (30 mg, crude, 5 batches) as a brown oil. ESI [M+H] =486.3.APRE007-PCT | 106265.000238

[0434] Preparation of Example 18 product.

[0435] A solution oftert-butyl N-(20-methyl-5,7,12,19,21,25-hexazapentacyclo[17.5.2.12, 6.011,16.022, 26]heptacosa-l(24), 2, 4, 6(27), 11(16), 12, 14, 20, 22,25-decaen-4-yl)carbamate (10.00 mg, 20.59 pmol, 1 eq) in TFA (3 m ) was stirred at 25°C for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 80*30mm*3um;mobile phase: [H2O(0.1%TFA)-ACN] gradient: 1 %-30% B over 8.0 min) to give 20-methyl-5,7,12,19,21,25-hexazapentacyclo[17.5.2.12, 6.011,16.022, 26]heptacosa-l(24), 2, 4, 6(27), 11(16), 12, 14, 20, 22,25-decaen-4 -amine (17.8 mg, 41.40 pmol, 67.02% yield, 90% purity, TFA salt) as a green solid. ’H NMR (400 MHz, DMSO-d6) 5 8.82-8.55 (m, 1H), 8.38-8.19 (m, 1H), 8.19-8.09 (m, 1H), 7.78 (d, J = 8.2 Hz, 1H), 7.73-7.55 (m, 2H), 7.55-7.37 (m, 2H), 7.01-6.89 (m, 1H), 6.46 (s, 1H), 4.55-4.48 (m, 2H), 3.77-3.64 (m, 2H), 3.55-3.41 (m, 2H), 3.29-3.19 (m, 2H), 2.84-2.72 (m, 3H), 2.21-2.00 (m, 2H). ESI [M+H] =386.2.

[0436] Example 19

[0437] Preparation of compound 2.APRE007-PCT | 106265.000238

[0438] A mixture of tert-butyl N-prop-2-ynylcarbamate (5.74 g, 36.99 mmol, 1.05 eq), 3-bromo-4-iodo-pyridine (10 g, 35.22 mmol, 1 eq), Cui (670.85 mg, 3.52 mmol, 0.1 eq), TEA (7.13 g, 70.45 mmol, 9.81 m , 2 eq) and dichloropalladium;triphenylphosphane (1.24 g, 1.76 mmol, 0.05 eq) in THF (50 m ) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 25 °C for 1 hr under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCE, Petroleum ether / Ethyl acetate=50 / l to 5 / 1) to give tert-butyl N-[3-(3-bromo-4-pyridyl)prop-2-ynyl]carbamate (9.4 g, 30.21 mmol, 85.76% yield) as abrown solid. ESI [M+H] =311.1 / 313.1.

[0439] Preparation of compound 3.

[0440] A mixture of tert-butyl N-[3-(3-bromo-4-pyridyl)prop-2-ynyl]carbamate (8 g, 25.71 mmol, 1 eq), 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoxazole (5.26 g, 26.99 mmol, 1.05 eq), K3PO4 (16.37 g, 77.13 mmol, 3 eq), [2-(2-aminophenyl)phenyl]-chloro-palladium;bis(l-adamantyl)-butyl-phosphane (1.72 g, 2.57 mmol, 0.1 eq) in THF (120 mb) and H2O (30 mb) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 60°C for 1 hr under N2 atmosphere. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCE, Petroleum ether / Ethyl acetate=50 / l to 5 / 1) to give tert-butyl N-[3-(3-isoxazol-4-yl-4-pyridyl)prop-2-ynyl]carbamate (6.5 g, 21.72 mmol, 84.47% yield) as a yellow solid. ESI [M+H] =300.1.

[0441] Preparation of compound 4.APRE007-PCT | 106265.000238

[0442] To a solution of tert-butyl N-[3-(3-isoxazol-4-yl-4-pyridyl)prop-2-ynyl]carbamate (6.50 g, 21.72 mmol, 1 eq) in MeOH (60 mb) was added KF (1.5 M, 57.91 mb, 4 eq). The mixture was stirred at 90°C for 12 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Welch Xtimate C18250*70mm* 10um;mobile phase: [FFOQOmM NH4HCOs)-ACN] gradient: 18%-48% B over 17.0 min) to give tert-butyl N-[3-[3-(cyanomethyl)-4-pyridyl]prop-2-ynyl]carbamate (2.8 g, 10.32 mmol, 47.52% yield) as a yellow solid. ESI [M+H] =272.2.

[0443] Preparation of compound 5.4 5

[0444] A mixture of Raney-Ni (884.18 mg, 10.32 mmol, 1 eq) in EtOH (30 mL) was degassed and purged with Ar2 for 3 times, and then added tert-butyl N-[3-[3-(cyanomethyl)-4-pyridyl]prop-2-ynyl]carbamate (2.8 g, 10.32 mmol, 1 eq) and NH3.H2O (4.34 g, 30.96 mmol, 4.77 mL, 25% purity, 3 eq). The mixture was stirred at 30°C for 12 hrs under H2 (30 Psi) atmosphere. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give tert -butyl N-[3-[3-(2-aminoethyl)-4-pyridyl]propyl]carbamate (3 g, crude) as a brown oil. ESI [M+H] =280.2.

[0445] Preparation of compound 6.APRE007-PCT | 106265.0002385 6

[0446] To a solution of 6-bromo-2-chloro-3-nitro-pyridine (1.97 g, 8.30 mmol, 1 eq) in THF (30 mL) was added TEA (2.52 g, 24.91 mmol, 3.47 mL, 3 eq) and tert -butyl N-[3-[3-(2-aminoethyl)-4-pyridyl]propyl]carbamate (2.9 g, 8.30 mmol, 1 eq). The mixture was stirred at 20°C for 12 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCE, Petroleum ether / Ethyl acetate=50 / l to 5 / 1) to give tert-butyl N-[3-[2-[2-[(6-bromo-3-nitro-2-pyridyl)amino]ethyl]-3-pyridyl]propyl]carbamate (1.8 g, 3.75 mmol, 45.12% yield) as a yellow oil. ESI [M+H] =480.1 / 482.1.

[0447] Preparation of compound 7.6 7

[0448] A mixture of tert-butyl N-[3-[3-[2-[(6-bromo-3-nitro-2-pyridyl)amino]ethyl]-4-pyridyl]propyl]carbamate (1.7 g, 3.54 mmol, 1 eq), Fe (592.97 mg, 10.62 mmol, 3 eq), NH4CI (757.22 mg, 14.16 mmol, 4 eq) and in EtOH (15 mL), THF (15 mL) and H2O (5 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80°C for 2 hrs under N2 atmosphere. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give tertbutyl N-[3-[3-[2-[(3-amino-6-bromo-2-pyridyl)amino]ethyl]-4-pyridyl]propyl]carbamate (1.55 g, crude) as a yellow solid. 'H NMR (400 MHz, Chloroform-d) 58.42-8.31 (m, 2H), 7.12 (br d, J = 4.9 Hz, 1H), 6.74-6.59 (m, 2H), 3.78 (d, J = 11.1 Hz, 1H), 3.60 (brt, J = 7.3 Hz, 2H), 3.21 (brd, J = 6.2 Hz, 3H), 2.97 (brt, J = 7.5 Hz, 2H), 2.82 (brt, J = 7.8 Hz, 2H), 1.90-1.77 (m, 2H), 1.44-1.38 (m, 9H). ESI [M+H] =450.2 / 452.2.

[0449] Preparation of compound 8.APRE007-PCT | 106265.0002387 8

[0450] To a solution of tert-butyl N-[3-[3-[2-[(3-amino-6-bromo-2-pyridyl)amino]ethyl]-4-pyridyl]propyl]carbamate (1.4 g, 3.11 mmol, 1 eq) in AcOH (20 mb) was added 1,1,1-trimethoxyethane (1.87 g, 15.54 mmol, 1.95 mb, 5 eq). The mixture was stirred at 70°C for 2hrs. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=50 / l to 0 / 1) to give tertbutyl N-[3-[3-[2-(5-bromo-2-methyl-imidazo[4,5-b]pyridin-3-yl)ethyl]-4-pyridyl]propyl]carbamate (850 mg, 1.79 mmol, 57.64% yield) as a brown oil. ESI [M+H] =474.1 / 476.1.

[0451] Preparation of compound 9.

[0452] A mixture of tert-butyl N-[3-[3-[2-(5-bromo-2-methyl-imidazo[4,5-b]pyridin-3-yl)ethyl]-4-pyridyl]propyl]carbamate (800 mg, 1.69 mmol, 1 eq), 2,6-dichloro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (485.08 mg, 1.77 mmol, 1.05 eq), ditert-butyl(cyclopentyl)phosphane;dichloropalladium;iron (109.91 mg, 168.64 pmol, 0.1 eq), K3PO4 (1.07 g, 5.06 mmol, 3 eq) in THF (2 mL) and H2O (0.5 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80°C for 1 hr under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCE, Petroleum ether / Ethyl acetate=50 / l to 5 / 1) to give tert-butyl N-[3-[3-[2-[5-APRE007-PCT | 106265.000238(2,6-dichloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]ethyl]-4-pyridyl]propyl]carbamate (470 mg, 868.01 pmol, 51.47% yield) as a yellow oil. ESI [M+H] =541.2 / 543.2.

[0453] Preparation of compound 10.

[0454] A solution of tert-butyl N-[3-[3-[2-[5-(2,6-dichloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]ethyl]-4-pyridyl]propyl]carbamate (470 mg, 868.01 pmol, 1 eq) in HCI / dioxane (4M, 20 mL) was stirred at 25 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 100*40mm*3 um;mobile phase: [H2O(0.1%TFA)-ACN];gradient:5%-35% B over 8.0 min) to give 3-[3-[2-[5-(2,6-dichloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]ethyl]-4-pyridyl]propan-l -amine (200 mg, 418.57 pmol, 48.22% yield, TFA salt) as a brown solid. ESI [M+H] =441.1 / 443.1.

[0455] Preparation of compound 11.

[0456] A mixture of 3-[3-[2-[5-(2,6-dichloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]ethyl]-4-pyridyl]propan-l-amine (12 mg, 27.19 pmol, 1 eq, TFA salt), tert-butyl carbamate (3.19 mg, 27.19 pmol, 1 eq), CS2CO3 (26.58 mg, 81.57 pmol, 3 eq), 4AMS (27.19 pmol, 1 eq), (1E,4E)-1,5-diphenylpenta-l,4-dien-3-one;palladium (24.90 mg, 27.19 pmol, 1 eq) and dicyclohexyl-[2-(2,6-diisopropoxyphenyl)phenyl]phosphane (1.27 mg, 2.72 pmol, 0.1 eq) in 2-methylbutan-2-ol (2 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100°C for 12 hrsAPRE007-PCT | 106265.000238under N2 atmosphere. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give tert-butyl N-(20-methyl-5,7,14,19,21,25-hexazapentacyclo[17.5.2.12, 6.011,16.022, 26]heptacosa-l(24), 2, 4, 6(27), 11(16), 12, 14, 20, 22,25-decaen-4-yl)carbamate (60 mg, crude, 5 batches) as a yellow oil. ESI [M+H] =486.3.

[0457] Preparation of Example 19 product.

[0458] A solution oftert-butyl N-(20-methyl-5,7,14,19,21,25-hexazapentacyclo[17.5.2.12, 6.011,16.022, 26]heptacosa-l(24), 2, 4, 6(27), 11(16), 12, 14, 20, 22,25-decaen-4-yl)carbamate (60 mg, 123.56 pmol, 1 eq) in TFA (5 mL) was stirred at 25°C for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 100*40mm*5 um;mobile phase: [1420(0.04% HC1)-ACN] gradient: 1 %-35% B over 8.0 min) to give 20-methyl-5,7,14,19,21,25-hexazapentacyclo[17.5.2.12, 6.011,16.022, 26]heptacosa-l(24), 2, 4, 6(27), 11(16), 12, 14, 20, 22,25-decaen-4 -amine (7.04 mg, 16.69 pmol, 13.50% yield, HC1 salt) as a green solid. ’H NMR (400 MHz, DMSO-d6) 59.07 (s, 1H), 8.81 (d, J = 5.9 Hz, 1H), 8.24 (d, J = 8.1 Hz, 1H), 8.03 (br d, J = 6.0 Hz, 1H), 8.00-7.93 (m, 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.76-7.60 (m, 2H), 6.97 (s, 1H), 6.57-6.51 (m, 1H), 4.68-4.60 (m, 2H), 3.82 (br dd, J = 4.2, 8.0 Hz, 2H), 3.30 (br d, J = 8.7 Hz, 4H), 2.88 (s, 3H), 2.16-1.97 (m, 2H). ESI [M+H] =371.2.

[0459] Example 20

[0460] Preparation of compound 2.APRE007-PCT | 106265.000238

[0461] To a solution of 6-bromo-2-chloro-3-nitro-pyridine (2 g, 8.42 mmol, 1 eq) in THF (2 mL) was added TEA (1.70 g, 16.85 mmol, 2.34 mL, 2 eq) and tert-butyl 8 -aminooctanoate (1.63 g, 7.58 mmol, 0.9 eq). The mixture was stirred at 20°C for 12 hrs. The reaction mixture was fdtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCE, petroleum ether / ethyl acetate = 1 / 0 to 20 / 1) to give tert-butyl 8-[(6-bromo-3-nitro-2-pyridyl)amino]octanoate (3.3 g, 7.93 mmol, 94.11% yield) as a yellow solid. ESI [M+H] = 416.1 / 418.1

[0462] Preparation of compound 3.

[0463] To a solution of tert-butyl 8-[(6-bromo-3-nitro-2-pyridyl)amino]octanoate (3 g, 7.21 mmol, 1 eq) in EtOH (30 mL) and H2O (15 mL) was added Fe (2.01 g, 36.03 mmol, 5 eq) and NH4CI (1.93 g, 36.03 mmol, 5 eq). The mixture was stirred at 70°C for 2 hrs. The reaction mixture was added water (100 mL) and extracted with EtOAc (80 mL x 3). The combined organic layers were washed with brine (50 mL), dried over ISfeSCL, fdtered and concentrated under reduced pressure to give tert-butyl 8-[(3-amino-6-bromo-2-pyridyl)amino]octanoate (3.5 g, crude) as a black oil. ESI [M+H] = 386.2 / 388.0.

[0464] Preparation of compound 4.APRE007-PCT | 106265.000238

[0465] To a solution of tert-butyl 8-[(3-amino-6-bromo-2-pyridyl)amino]octanoate (3 g, 7.77 mmol, 1 eq) in AcOH (1 mb) was added 1,1,1 -trimethoxy ethane (1.87 g, 15.53 mmol, 1.95 mb, 2 eq). The mixture was stirred at 70°C for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCE, petroleum ether / ethyl acetate = 1 / 0 to 5 / 1) to give tert-butyl 8-(5-bromo-2-methyl-imidazo[4,5-b]pyridin-3-yl) octanoate (2.2 g, 5.36 mmol, 69.04% yield) as a black oil. ESI [M+H] = 410.1 / 412.1.

[0466] Preparation of compound 5.

[0467] To a solution of tert-butyl 8-(5-bromo-2-methyl-imidazo[4,5-b]pyridin-3-yl) octanoate (2 g, 4.87 mmol, 1 eq) in dioxane (20 mb) and H2O (2 mb) was added 2,6-dichloro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (2.00 g, 7.31 mmol, 1.5 eq), Pd(dppf)C12 (713.25 mg, 974.78 pmol, 0.2 eq) and ISfeCOs (1.03 g, 9.75 mmol, 2 eq). The mixture was stirred at 80°C for 1 hr. The reaction mixture was dried over ISfeSCE, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (S i O2- petroleum ether / ethyl acetate = 1 / 0 to 2 / 3) to give tert-butyl 8-[5-(2,6-dichloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]octanoate (2.1 g, 4.40 mmol, 90.25% yield) as a black oil. ESI [M+H] = 477.2 / 479.1.

[0469] To a solution of tert-butyl 8-[5-(2,6-dichloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]octanoate (900 mg, 1.89 mmol, 1 eq) in DCM (10 mL) was added TFA (10 mL). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give 8-[5-(2,6-dichloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]octanoic acid (900 mg, crude, TFA salt) as a black oil. ESI [M+H] = 420.9 / 422.8.

[0470] Preparation of compound 7.APRE007-PCT | 106265.000238

[0471] To a solution of 8-[5-(2,6-dichloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]octanoic acid (800 mg, 1.90 mmol, 1 eq, TFA salt) in DCM (10 mL) was added NFL / MeOH (7 M, 406.89 pL, 1.5 eq), DIEA (736.22 mg, 5.70 mmol, 992.21 pL, 3 eq) and T4P (2.05 g, 2.85 mmol, 50% purity, 1.5 eq). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. Then the residue added water (20 mL) and extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over MgSCL, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18250 x 50 mm x 10 um; mobile phase: [water (NHJTCC^-ACN]; gradient: 32%-62% B over 10 min) to give 8-[5-(2,6-dichloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]octanamide (500 mg, 1.19 mmol, 62.65% yield) as a black oil. ESI [M+H] = 420.1 / 421.8.

[0472] Preparation of compound 8.,

[0473] To a mixture of 8-[5-(2,6-dichloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]octanamide (50 mg, 118.95 pmol, 1 eq), tert-butyl carbamate (41.80 mg, 356.86 pmol, 3 eq), CS2CO3 (116.27 mg, 356.86 pmol, 3 eq), RuPhos (11.10 mg, 23.79 pmol, 0.2 eq), Pd2(dba)s (21.79 mg, 23.79 pmol, 0.2 eq) and 4A MS (118.95 pmol, 1 eq) in 2-methylbutan-2-ol (2 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 110°C for 12 hrs under N2 atmosphere. The reaction mixture was fdtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX 80 x 40 mm x 3 um; mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient: 25 %-55% B over 8.0 min) to give tertbutyl N-(17-methyl-8-oxo-5,7,16,18,22-pentazatetracyclo[14.5.2.12,6.019,APRE007-PCT | 106265.00023823]tetracosal(21),2(24),3,5,17,19, 22-heptaen-4-yl)carbamate (30 mg, 64.6 pmol, 54.5% yield) as a yellow oil. ESI [M+H] = 465.2.

[0474] Preparation of Example 20 product.

[0475] To a solution of tert-butyl N-(17-methyl-8-oxo-5,7,16,18,22-pentazatetracyclo [14.5.2.12,6.019,23]tetracosal(21),2(24),3,5,17,19,22-heptaen-4-yl)carbamate (30 mg, 64.58 pmol, 1 eq) in DCM (1 m ) was added TFA (0.3 m ). The mixture was stirred at 25°C for 1 hr. The reaction mixture was filtered and purified by prep-HPEC (column: 3_Phenomenex buna C18 75 x 30 mm x 3 um; mobile phase: [H2O (0.1% TFA)-ACN]; gradient: 10%-40% B over 8.0 min) to give 4-amino-17-methyl-5,7,16,18,22-pentazatetracyclo[14.5.2.12,6.019,23]tetracosa-l(21),2(24),3,5,17,19,22-heptaen-8-one (18.11 mg, 36.93 pmol, 57.18% yield, 98% purity, TFA salt) as a yellow solid. ’H NMR (400 MHz, Methanol-d4) 5 8.14-7.95 (m, 2H), 7.55 (s, 1H), 7.13 (s, 1H), 4.36-4.21 (m, 2H), 2.73 (s, 3H), 2.43 (br t, J = 7.4 Hz, 2H), 2.03-1.90 (m, 2H), 1.85-1.74 (m, 2H), 1.62-1.48 (m, 6H). ESI [M+H] = 365.2.

[0476] Example 21

[0477] Preparation of compound 2.1 2APRE007-PCT | 106265.000238

[0478] To a solution of 6-bromo-2-chloro-3-nitro-pyridine (2 g, 8.42 mmol, 1 eq) in THF (40 mL) was added TEA (2.56 g, 25.27 mmol, 3.52 mL, 3 eq) and tert-butyl N-[2-[2-(2-aminoethoxy)ethoxy] ethyl] carbamate (2.09 g, 8.42 mmol, 1 eq). The mixture was stirred at 25°C for 12 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCE, petroleum ether / ethyl acetate = 50 / 1 to 0 / 1) to give tert-butyl N-[2-[2-[2-[(6-bromo-3-nitro-2-pyridyl)amino]ethoxy]ethoxy]ethyl]carbamate (3.2 g, 7.12 mmol, 84.55% yield) as a yellow oil. ESI [M+H-Boc] = 349.0 / 351.1.

[0479] Preparation of compound 3.2 3

[0480] To a solution of tert-butyl N-[2-[2-[2-[(6-bromo-3-nitro-2-pyridyl)amino] ethoxy] ethoxy] ethyl] carbamate (6.4 g, 14.24 mmol, 1 eq) in THF (30 mL) and EtOH (30 mL) and H2O (10 mL) was added Fe (1.59 g, 28.49 mmol, 2 eq) andlSTLCl (2.29 g, 42.73 mmol, 3 eq). The mixture was stirred at 70°C for 2 hrs. The reaction mixture was quenched by addition H2O (100 mL), and then extracted with EtOAc (200 mL x 3). The combined organic layers were dried over ISfeSCL, filtered and concentrated under reduced pressure to give tert-butyl N-[2-[2-[2-[(3-amino-6-bromo-2 -pyridyl) amino]ethoxy]ethoxy]ethyl]carbamate (6 g, crude) as a brown oil. ESI [M+H] = 419.1 / 421.1.

[0481] Preparation of compound 4.3 4APRE007-PCT | 106265.000238

[0482] To a solution of tert-butyl N-[2-[2-[2-[(3-amino-6-bromo-2-pyridyl)amino] ethoxy] ethoxy] ethyl] carbamate (5 g, 11.92 mmol, 1 eq) in MeOH (30 mL) was added sulfamic acid (57.89 mg, 596.21 pmol, 26.91 pL, 0.05 eq) and trimethoxymethane (1.90 g, 17.89 mmol, 1.96 mL, 1.5 eq). The mixture was stirred at 30°C for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, petroleum ether / ethyl acetate = 50 / 1 to 5 / 1) to give tert-butyl N-[2-[2-[2-(5-bromoimidazo[4,5-b]pyridin-3-yl) ethoxy] ethoxy] ethyl] carbamate (5 g, 11.65 mmol, 97.67% yield) as a brown oil. ESI [M+H] = 429.1 / 431.1.

[0483] Preparation of compound 5.4 5

[0484] To a mixture of tert-butyl N-[2-[2-[2-(5-bromoimidazo[4,5-b]pyridin-3-yl)ethoxy] ethoxy] ethyl] carbamate (4.8 g, 11.18 mmol, 1 eq), 2,6-dichloro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (3.68 g, 13.42 mmol, 1.2 eq), K3PO4 (7.12 g, 33.54 mmol, 3 eq) and Pd(dtbpf)C12 (728.70 mg, 1.12 mmol, 0.1 eq) in H2O (10 mL) and THF (40 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80°C for 1 hr under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue, and the residue was dissolved in H2O (10 mL), and then extracted with EtOAc (40 mL x 3). The combined organic layers were dried over ISfeSCL, fdtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, petroleum ether / THF = 50 / 1 to 0 / 1) to give tert-butyl N-[2-[2-[2-[5-(2,6-dichloro-4-pyridyl)imidazo[4,5-b]pyridin-3-yl] ethoxy] ethoxy] ethyl] carbamate (4.5 g, 9.07 mmol, 81.08% yield) as a brown oil. ESI [M+H] = 496.2 / 498.1.

[0485] Preparation of compound 6.APRE007-PCT | 106265.0002385 6

[0486] A solution of tert-butyl N-[2-[2-[2-[5-(2,6-dichloro-4-pyridyl)imidazo[4,5-b]pyridin-3-yl]ethoxy]ethoxy]ethyl]carbamate (1.6 g, 3.22 mmol, 1 eq) in HCI / EtOAc (20 mL, 4M) was stirred at 25 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give 2-[2-[2-[5-(2,6-dichloro-4-pyridyl)imidazo[4,5-b]pyridin-3-yl]ethoxy]ethoxy]ethanamine (1 g, 2.31 mmol, 71.69% yield, HC1 salt) as a white solid. ESI [M+H] = 396.1 / 398.1.

[0487] Preparation of compound 7.

[0488] A mixture of 2-[2-[2-[5-(2,6-dichloro-4-pyridyl)imidazo[4,5-b]pyridin-3-yl] ethoxy] ethoxy] ethanamine (80 mg, 184.87 pmol, 1 eq, HC1 salt), CS2CO3 (180.70 mg, 554.62 pmol, 3 eq), RuPhos (17.25 mg, 36.97 pmol, 0.2 eq), 4A MS (184.87 pmol, 1 eq) and Pd2(dba)s (33.86 mg, 36.97 pmol, 0.2 eq) in 2-methylbutan-2-ol (6 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 110°C for 12 hrs under N2 atmosphere. The reaction solution was used directly for next step (4 batches). ESI [M+H] = 360.1.

[0489] Preparation of compound 8.APRE007-PCT | 106265.000238

[0490] A mixture of 4-chloro-10,13-dioxa-5,7,16,18,22-pentazatetracyclo [14.5.2.12,6.019,23]tetracosal(21),2,4,6(24),17,19,22-heptaene (60 mg, 166.75 pmol, 1 eq), tert-butyl carbamate (29.30 mg, 250.13 pmol, 1.5 eq), CS2CO3 (54.33 mg, 166.75 pmol, 1 eq), RuPhos (15.56 mg, 33.35 pmol, 0.2 eq), 4A MS (166.75 pmol, 1 eq) and Pd2(dba)s (30.54 mg, 33.35 pmol, 0.2 eq) in 2-methylbutan-2-ol (6 mb) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 110°C for 12 hrs under N2 atmosphere. The reaction mixture was fdtered and the fdtrate was concentrated under reduced pressure to give tert-butyl N-(10,13-dioxa-5,7,16,18,22-pentazatetracyclo [14.5.2.12,6.019,23]tetracosal(21),2,4,6(24),17,19,22-heptaen-4-yl)carbamate (180 mg, crude, 4 batches) as a black oil. ESI [M+H] = 441.2.

[0491] Preparation of Example 21 product.

[0492] To a solution of tert-butyl N-(10,13-dioxa-5,7,16,18,22-pentazatetracyclo [14.5.2.12,6.019,23]tetracosal(21),2,4,6(24),17,19,22-heptaen-4-yl)carbamate (180 mg, 408.63 pmol, 1 eq) in DCM (3 mL) was added TFA (1 mL). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: 3_Phenomenex Luna C18 75 x 30 mm x 3 um; mobile phase: [H2O (0.1% TFA)-ACN]; gradient: l%-30% B over 8.0 min) to give 10,13-dioxa-5,7, 16, 18,22-pentazatetracyclo [14.5.2.12,6.019,23]tetracosa-l(22),2(24),3,5,17,19(23),20-heptaen-4-amine (11.31 mg, 24.04 pmol, 5.88% yield, 97% purity, TFA salt) as a yellow solid. ’H NMR (400 MHz, Methanol-d4) 58.70 (s, 1H), 8.20 (d, J = 8.4 Hz, 1H), 7.90 (d, J = 8.5 Hz, 1H), 7.35 (d, J = 1.4 Hz, 1H), 6.60 (d, J = 1.3 Hz, 1H), 4.67 (t, J = 5.3 Hz, 3H), 4.09 (t, J = 5.4 Hz, 2H), 3.76-3.71 (m, 2H), 3.69-3.66 (m, 2H), 3.60 (td, J = 4.6, 6.2 Hz, 4H). ESI [M+H] = 341.1.

[0493] Example 22APRE007-PCT | 106265.000238

[0494] Preparation of compound 2.

[0495] A mixture of 4-bromo-3 -iodo-pyridine (9.5 g, 33.46 mmol, 1 eq), tert-butyl N-prop-2-ynylcarbamate (5.19 g, 33.46 mmol, 1 eq), dichloropalladium;triphenylphosphane (1.17 g, 1.67 mmol, 0.05 eq), Cui (637.31 mg, 3.35 mmol, 0.1 eq) and TEA (6.77 g, 66.93 mmol, 9.32 m , 2 eq) in THF (200 m ) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 60°C for 12 hrs under N2 atmosphere. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, petroleum ether / ethyl acetate = 50 / 1 to 0 / 1) to give tert-butyl N-[3-(4-bromo-3-pyridyl)prop-2-ynyl]carbamate (10 g, 32.14 mmol, 96.03% yield) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) 58.63 (s, 1H), 8.40 (br d, J = 5.1 Hz, 1H), 7.81 (d, J = 5.2 Hz, 1H), 7.44 (br s, 1H), 4.15-3.95 (m, 2H), 1.41 (s, 9H). ESI [M+H] = 311.0.

[0496] Preparation of compound 3.APRE007-PCT | 106265.000238

[0497] To a solution of 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoxazole (4.83 g, 24.75 mmol, 1 eq) and tert-butyl N-[3-(4-bromo-3-pyridyl)prop-2-ynyl]carbamate (7.7 g, 24.75 mmol, 1 eq) in THF (100 mb) and H2O (25 mL) was added K3PO4 (10.51 g, 49.49 mmol, 2 eq) and [2-(2-aminophenyl)phenyl]-chloro-palladium;bis(l-adamantyl)-butylphosphane (1.65 g, 2.47 mmol, 0.1 eq). The mixture was stirred at 60°C for 1 hr under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue, the residue was dissolved in H2O (10 mL), and then extracted with EtOAc (40 mL x 3). The combined organic layers were dried over ISfeSCL, fdtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, petroleum ether / ethyl acetate = 50 / 1 to 0 / 1) to give tert-butyl N-[3-(4-isoxazol-4-yl-3-pyridyl)prop-2-ynyl]carbamate (7 g, 23.39 mmol, 94.51% yield) as a brown solid. ESI [M+H] = 300.0.

[0498] Preparation of compound 4.

[0499] To a solution of tert-butyl N-[3-(4-isoxazol-4-yl-3-pyridyl)prop-2-ynyl]carbamate (6 g, 20.05 mmol, 1 eq) in MeOH (60 mL) was added KF (3.49 g, 60.14 mmol, 3 eq). The mixture was stirred at 70°C for 12 hrs. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (S i O2- petroleum ether / ethyl acetate = 50 / 1 to 0 / 1) to give tert-butyl N-[3-[4-(cyanomethyl)-3-pyridyl]prop-2-ynyl]carbamate (5 g, 18.43 mmol, 91.94% yield) as a white solid. ESI [M+Na+] = 272.1.

[0500] Preparation of compound 5.Boc Boc>4 5

[0501] A mixture of tert-butyl N-[3-[4-(cyanomethyl)-3-pyridyl]prop-2-ynyl]carbamate (3.01 g, 11.09 mmol, 1 eq), Raney Ni (950.49 mg, 11.09 mmol, 1 eq) and ammonium ;hydroxide (1.17APRE007-PCT | 106265.000238g, 33.28 mmol, 1.28 mL, 3 eq) in ethanol (30 mL) was degassed and purged with H2 for 3 times, and then the mixture was stirred at 30°C for 12 hrs under H2 (30 psi) atmosphere. The reaction mixture was fdtered and the filtrate was concentrated under reduced pressure to give tert -butyl N-[3-[4-(2-aminoethyl)-3-pyridyl]propyl]carbamate (2.7 g, crude) as a brown oil. ESI [M+H] = 280.1.

[0502] Preparation of compound 6.5 6

[0503] To a solution of tert-butyl N-[3-[4-(2-aminoethyl)-3-pyridyl]propyl]carbamate (2.6 g, 9.31 mmol, 1 eq) in THF (10 mL) was added TEA (2.83 g, 27.92 mmol, 3.89 mL, 3 eq) and 6-bromo-2-chloro-3 -nitro-pyridine (1.33 g, 5.58 mmol, 0.6 eq). The mixture was stirred at 20°C for 12 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC petroleum ether / ethyl acetate = 50 / 1 to 0 / 1) to give tert-butyl N-[3-[4-[2-[(6-bromo-3-nitro-2-pyridyl)amino]ethyl]-3-pyridyl]propyl]carbamate (2.6 g, 5.41 mmol, 58.16% yield) as a brown solid. ESI [M+H] = 480.1 / 482.1.

[0504] Preparation of compound 7.

[0505] To a solution of tert-butyl N-[3-[4-[2-[(6-bromo-3-nitro-2-pyridyl)amino]ethyl]-3-pyridyl]propyl]carbamate (2.6 g, 5.41 mmol, 1 eq) in THF (20 mL), EtOH (20 mL) and H2O (10 mL) was added Fe (604.54 mg, 10.83 mmol, 2 eq) and NH4CI (868.59 mg, 16.24 mmol, 3 eq). The mixture was stirred at 80°C for 2 hrs. The reaction mixture was quenched by addition H2O (50 mL), and then extracted with EtOAc (50 mL x 3). The combined organic layers were dried over ISfeSCL, filtered and concentrated under reduced pressure to give tert-butyl N-[3-[4-[2-[(3-amino-6-bromo-2-pyridyl)amino]ethyl]-3-pyridyl]propyl]carbamate (2.4 g, crude) as a black oil. ESI [M+H] =450.1 / 452.1.APRE007-PCT | 106265.000238

[0506] Preparation of compound 8.

[0507] To a solution of tert-butyl N-[3-[4-[2-[(3-amino-6-bromo-2-pyridyl)amino]ethyl]-3-pyridyl]propyl]carbamate (2.3 g, 5.11 mmol, 1 eq) in AcOH (20 mL) was added 1,1,1-trimethoxyethane (1.84 g, 15.32 mmol, 1.93 mL, 3 eq). The mixture was stirred at 80°C for 12 hrs. The reaction mixture was fdtered and the fdtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL, petroleum ether / THF = 50 / 1 to 0 / 1) to give tert-butyl N-[3-[4-[2-(5-bromo-2-methyl-imidazo[4,5-b]pyridin-3-yl)ethyl]-3-pyridyl]propyl]carbamate (700 mg, 1.48 mmol, 28.89% yield) as a brown oil. ESI [M+H] = 474.2 / 476.1.

[0508] Preparation of compound 9.

[0509] A mixture of tert-butyl N-[3-[4-[2-(5-bromo-2-methyl-imidazo[4,5-b]pyridin-3-yl)ethyl]-3-pyridyl]propyl]carbamate (650 mg, 1.37 mmol, 1 eq), 2,6-dichloro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (375.36 mg, 1.37 mmol, 1 eq), K3PO4 (872.52 mg, 4.11 mmol, 3 eq) and Pd(dtbpf)C12 (89.30 mg, 137.02 pmol, 0.1 eq) in THF (4 mL) and H2O (1 mL)was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80°C for 1 hr under N2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: 3_Phenomenex Luna C18 75 x 30 mm x 3 um; mobile phase: [H2O (0.1% TFA)-ACN]; gradient: 25 %-55% B over 8.0 min) to give tert-butyl N-[3-[4-[2-[5-(2,6-dichloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]ethyl]-3-pyridyl]propyl]carbamate (100 mg, 152.56 pmol, 11.13% yield, TFA salt) as a white solid. ESI [M+H-tBu] = 541.2 / 543.2.APRE007-PCT | 106265.000238

[0510] Preparation of compound 10.

[0511] A solution of tert-butyl N-[3-[4-[2-[5 -(2, 6-dichloro-4-pyridyl)-2 -methyl -imidazo [4,5-b]pyridin-3-yl]ethyl]-3-pyridyl]propyl]carbamate (90 mg, 166.21 pmol, 1 eq) in HCl / EtOAc (2 mb, 4M) was stirred at 20°C for 1 hr. The reaction mixture was concentrated under reduced pressure to give 3-[4-[2-[5-(2,6-dichloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]ethyl]-3-pyridyl]propan-l -amine (70 mg, crude, HC1 salt) as a white solid. ESI [M+H] = 441.1 / 443.2.

[0512] Preparation of compound 11.10 11

[0513] A mixture of 3-[4-[2-[5-(2,6-dichloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]ethyl]-3-pyridyl]propan-l-amine (12 mg, 27.19 pmol, 1 eq, HC1 salt), tert-butyl carbamate (3.19 mg, 27.19 pmol, 1 eq), CS2CO3 (26.58 mg, 81.57 pmol, 3 eq), RuPhos (1.27 mg, 2.72 pmol, 0.1 eq) and Pd2(dba)s (2.49 mg, 2.72 pmol, 0.1 eq) in 2-methylbutan-2-ol (6 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100°C for 12 hrs under N2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give tert-butyl N-(20-methyl-5,7,13,19,21,25-hexazapentacyclo[17.5.2.12,6.011,16.022,26]heptacosal(24),2,4, 6(27),ll(16),12,14,20,22,25-decaen-4-yl)carbamate (60 mg, crude, 5 batches) as a yellow solid. ESI [M+H] = 486.3.

[0514] Preparation of Example 22 product.APRE007-PCT | 106265.000238

[0515] To a solution of tert-butyl N-(20-methyl-5,7,13,19,21,25-hexazapentacyclo [17.5.2.12, 6.011, 16.022, 26]heptacosal(24), 2, 4, 6(27), 11(16), 12, 14, 20, 22, 25 -decaen-4-yl)carbamate (50 mg, 102.97 pmol, 1 eq) in DCM (1.5 mb) was added TFA (0.5 mL). The mixture was stirred at 20°C for 0.5 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: 3_Phenomenex Luna C18 75 x 30 mm x 3 um; mobile phase: [H2O (0.1% TFA)-ACN]; gradient: l%-20% B over 8.0 min) to give 20-methyl-5,7,13,19,21,25-hexazapentacyclo[17.5.2.12,6.011,16.022,26]heptacosal(24),2,4,6(27), 11(16), 12, 14, 20,22, 25-decaen-4-amine (11.06 mg, 22.14 pmol, 21.50% yield, 100% purity, TFA salt) as a yellow solid. ’H NMR (400 MHz, DMSO-d6) 5 8.73 (s, 1H), 8.67 (d, J = 5.5 Hz, 1H), 8.14 (d, J = 8.3 Hz, 1H), 7.91 (br d, J = 5.4 Hz, 1H), 7.76 (d, J = 8.3 Hz, 1H), 7.73-7.68 (m, 1H), 7.48 (br s, 2H), 6.86 (s, 1H), 6.48 (s, 1H), 4.63-4.51 (m, 2H), 3.97-3.83 (m, 2H), 3.47 (br d, J = 5.6 Hz, 2H), 3.08-3.00 (m, 2H), 2.78 (s, 3H), 2.03 (br s, 2H). ESI [M+H+] = 386.1.APRE007-PCT | 106265.000238

[0518] A mixture of 5 -bromopentanenitrile (25 g, 154.29 mmol, 18.01 mL, 1 eq), tertbutyl N-(2-hydroxyethyl)carbamate (24.87 g, 154.29 mmol, 23.87 mL, 1 eq), TEAB (4.86 g, 23.14 mmol, 4.36 mL, 0.15 eq), NaOH (12 M, 124.72 mL, 9.7 eq) in Tol. (500 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100 °C for 1 hr under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, petroleum ether / ethyl acetate = 50 / 1 to 1 / 1) to give tertbutyl N-[2-(4-cyanobutoxy)ethyl]carbamate (13 g, crude) as a colorless oil. ’H NMR (400 MHz, Chloroform-d) 53.71-3.65 (m, 1H), 3.46 (dt, J = 2.5, 5.3 Hz, 4H), 3.29 (br d, J = 4.8 Hz, 2H), 2.38 (t, J = 6.7 Hz, 2H), 1.83-1.64 (m, 4H), 1.44 (s, 9H). ESI [M+H] = 243.1.

[0519] Preparation of compound 3.25C, 0.5 hr 2 3

[0520] A solution of tert-butyl N- [2 -(4 -cyanobutoxy)ethyl] carbamate (4 g, 16.51 mmol, 1 eq) in HCI / EtOAc (10 mL, 4M) was stirred at 25 °C for 0.5 hr. The reaction mixture was concentrated under reduced pressure to give 5 -(2 -aminoethoxy )pentanenitrile (2 g, crude, HC1 salt) as a white solid. ESI [M+H] = 143.1.

[0521] Preparation of compound 4.

[0522] To a solution of 6-bromo-2-chloro-3-nitro-pyridine (2.13 g, 8.96 mmol, 0.8 eq) in THF (20 mL) was added TEA (3.40 g, 33.58 mmol, 3 eq) and 5 -(2 -aminoethoxy )pentanenitrile (2 g, 11.19 mmol, 1 eq, HC1 salt). The mixture was stirred at 25 °C for 12 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, petroleum ether / ethyl acetate = 50 / 1 to 0 / 1) to give 5-[2-[(6-bromo-3-nitro-2-pyridyl)amino]ethoxy]pentanenitrile (1 g, 2.91 mmol, 26.03% yield) as a yellow oil. ESI [M+H] = 343.1 / 345.1.

[0523] Preparation of compound 5.APRE007-PCT | 106265.000238

[0524] To a solution of 5-[2-[(6-bromo-3-nitro-2-pyridyl)amino]ethoxy]pentanenitrile (1 g, 2.91 mmol, 1 eq) in THF (10 mL) was added BH3.THF (2 M, 7.28 mL, 5 eq) at 0°C. The mixture was stirred at 60°C for 12 hrs under N2 atmosphere. The reaction mixture was quenched by addition MeOH (10 mL) at 0°C. The reaction mixture was concentrated under reduced pressure to give N-[2-(5-aminopentoxy)ethyl]-6-bromo-3-nitro-pyridin-2-amine (1 g, crude) as a yellow oil. ESI [M+H] = 347.0 / 349.0.

[0525] Preparation of compound 6.5 6

[0526] To a solution of N-[2-(5-aminopentoxy)ethyl]-6-bromo-3-nitro-pyridin-2-amine (1 g, 2.88 mmol, 1 eq) in MeOH (6 mL) was added Na2COs (610.52 mg, 5.76 mmol, 2 eq) and tertbutoxycarbonyl tert-butyl carbonate (628.58 mg, 2.88 mmol, 1 eq). The mixture was stirred at 25°C for 12 hrs. The reaction mixture was fdtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / THF = 50 / 1 to 0 / 1) to give tert-butyl N-[5-[2-[(6-bromo-3-nitro-2-pyridyl)amino]ethoxy]pentyl]carbamate (350 mg, 782.43 pmol, 27.17% yield) as a yellow oil. ESI [M+H-Boc] = 347.1 / 349.1.

[0527] Preparation of compound 7.APRE007-PCT | 106265.0002386 7

[0528] To a solution of tert-butyl N-[5-[2-[(6-bromo-3-nitro-2-pyridyl)amino]ethoxy]pentyl]carbamate (350 mg, 782.43 pmol, 1 eq) in EtOH (3 m ), THF (3 m ) and H2O (1 mb) was added Fe (87.39 mg, 1.56 mmol, 2 eq) and NH4CI (125.56 mg, 2.35 mmol, 3 eq). The mixture was stirred at 80°C for 2 hrs. The reaction mixture was quenched by H2O (10 mb), and then extracted with EtOAc (2 mb x 3). The combined organic layers were dried over ISfeSCh, fdtered and concentrated under reduced pressure to give tert-butyl N-[5-[2-[(3-amino-6-bromo-2-pyridyl) amino]ethoxy]pentyl]carbamate (300 mg, crude) as a yellow oil. ESI [M+H] = 417.1 / 419.1.

[0529] Preparation of compound 8.7 8

[0530] To a solution of tert-butyl N-[5-[2-[(3-amino-6-bromo-2-pyridyl)amino]ethoxy]pentyl]carbamate (260 mg, 622.99 pmol, 1 eq) in AcOH (3 mb) was added 1,1,1 -trimethoxyethane (224.55 mg, 1.87 mmol, 234.89 ph, 3 eq). The mixture was stirred at 80°C for 2 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, petroleum ether / ethyl acetate = 50 / 1 to 0 / 1) to give tert-butyl N-[5-[2-(5-bromo-2-methyl-imidazo[4,5-b]pyridin-3-yl)ethoxy]pentyl]carbamate (200 mg, 453.14 pmol, 72.74% yield) as a brown oil. ’H NMR (400 MHz, DMSO-d6) 5 8.05 (d, J = 8.3 Hz, 1H), 7.56 (d, J = 8.3 Hz, 1H), 4.48 (t, J = 5.2 Hz, 2H), 3.77 (t, J = 5.2 Hz, 3H), 3.39 (t, J = 6.4 Hz, 2H), 2.88 (q, J = 6.0 Hz, 2H), 2.75-2.69 (m, 3H), 1.47-1.43 (m, 2H), 1.42 (s, 9H), 1.35-1.30 (m, 2H), 1.24 (t, J = 7.1 Hz, 2H). ESI [M+H] = 441.1 / 443.1.

[0531] Preparation of compound 9.APRE007-PCT | 106265.0002388 9

[0532] A mixture of tert-butyl N-[5-[2-(5-bromo-2-methyl-imidazo[4,5-b]pyridin-3-yl)ethoxy]pentyl]carbamate (200 mg, 453.14 pmol, 1 eq), 2,6-dichloro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (124.14 mg, 453.14 pmol, 1 eq), ISfeCOs (144.09 mg, 1.36 mmol, 3 eq), Pd(dppf)C12 (33.16 mg, 45.31 pmol, 0.1 eq) and H2O (2 mb) in dioxane (6 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80°C for 1 hr under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue and then dissolved in H2O (2 mL), extracted with EtOAc (2 mL x 3). The combined organic layers were dried over ISfeSCL, fdtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, petroleum ether / THF = 50 / 1 to 0 / 1) to give tert-butyl N-[5-[2-[5-(2,6-dichloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]ethoxy]pentyl]carbamate (180 mg, 354.02 pmol, 78.13% yield) as a brown oil. ESI [M+H] = 508.2 / 510.1.

[0533] Preparation of compound 10.

[0534] A solution of tert-butyl N-[5-[2-[5-(2,6-dichloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]ethoxy]pentyl]carbamate (160 mg, 314.69 pmol, 1 eq) in HCl / EtOAc (2 mL, 4M) was stirred at 25 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: 3_Phenomenex Luna C18 75 x 30 mm x 3um; mobile phase: [H2O (0.1% TFA)-ACN]; gradient:! 5 %-45% B over 8.0 min) to give 5-[2-[5-(2,6-dichloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]ethoxy]pentan-l-amine (35 mg, 67.01 pmol, 21.29% yield, TFA salt) as a white solid. ESI [M+H] = 408.1 / 410.0.

[0535] Preparation of compound 11.APRE007-PCT | 106265.000238

[0536] A mixture of 5-[2-[5-(2,6-dichloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]ethoxy]pentan-l -amine (10 mg, 24.49 pmol, 1 eq, TFA salt), tert-butyl carbamate (8.61 mg, 73.47 pmol, 3 eq), CS2CO3 (23.94 mg, 73.47 pmol, 3 eq), RuPhos (1.14 mg, 2.45 pmol, 0.1 eq) and Pd2(dba)s (2.24 mg, 2.45 pmol, 0.1 eq) in 2-methylbutan-2-ol (6 mb) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100°C for 12 hrs under N2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give tert -butyl N-(17-methyl-13-oxa-5,7,16,18,22-pentazatetracyclo[14.5.2.12,6.019,23]tetracosal(22),2(24),3,5,17, 19(23), 20-heptaen-4-yl)carbamate (20 mg, crude, 2 batches) as a yellow oil. ESI [M+H] = 453.4.

[0537] Preparation of Example 23 product.

[0538] To a solution of tert-butyl N-(17-methyl-13-oxa-5,7,16,18,22-pentazatetracyclo [14.5.2.12, 6.019, 23]tetracosal(22), 2(24), 3, 5, 17, 19(23), 20-heptaen-4-yl)carbamate (20 mg, 44.19 pmol, 1 eq) in DCM (1 mL) was added TFA (1 mL). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150 x 40 mm x 10 urn; mobile phase: [H2O (0.05% NH3 H2O + 10 mM NJTJTCC^-ACN]; gradient: 15%-45% B over 8.0 min) to give 17-methyl-13-oxa-5,7,16,18,22-pentazatetracyclo[14.5.2.12,6.019,23]tetracosa-l(22),2(24),3,5,17, 19(23), 20-heptaen-4-amine (2 mg, 5.16 pmol, 11.69% yield, 91% purity) as a yellow solid. ’H NMR (400 MHz, DMSO-d6) 58.02 (d, J = 8.3 Hz, 1H), 7.61 (d, J = 8.4 Hz, 1H), 6.58 (s, 1H), 6.27 (d, J = 0.6 Hz, 1H), 6.06 (brt, J = 6.2 Hz, 1H), 5.55 (s, 2H), 4.48 (brt, J = 6.4 Hz, 2H), 3.92 (t, J = 6.4 Hz, 2H), 3.83 (br t, J = 7.6 Hz, 2H), 3.24-3.07 (m, 2H), 2.66 (s, 3H), 1.77 (quin, J = 6.9 Hz, 2H), 1.71-1.62 (m, 2H), 1.54-1.44 (m, 2H). ESI [M+H] = 353.1.APRE007-PCT | 106265.000238

[0539] Example 24

[0540] Preparation of compound 2.< >25°C, 12 hrs1 2

[0541] To a solution of tert-butyl N-(4-hydroxybutyl)carbamate (25 g, 132.10 mmol, 1 eq) and prop-2 -enenitrile (14.02 g, 264.20 mmol, 17.52 m , 2 eq) in THF (200 m ) was added NaOMe (713.60 mg, 13.21 mmol, 0.1 eq). The mixture was stirred at 25°C for 12 hrs. The reaction mixture was fdtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, petroleum ether / THF = 50 / 1 to 0 / 1) to give tert-butyl N-[4-(2-cyanoethoxy)butyl]carbamate (20 g, 82.54 mmol, 62.48% yield) as a colorless oil. ESI [M+H-Bu ] = 187.1.

[0542] Preparation of compound 3.Raney-NiNH3H2O, H2, EtOH,25°C, 12 hrsw

[0543] A mixture of tert-butyl N-[4-(2-cyanoethoxy)butyl]carbamate (5 g, 20.63 mmol, 1 eq), Raney-Ni (1.77 g, 20.63 mmol, 1 eq) and NFF.FEO (7.23 g, 61.90 mmol, 7.95 mb, 30% purity, 3 eq) in EtOH (50 mb) was degassed and purged with H2 for 3 times, and then the mixture was stirred at 25°C for 12 hrs under H2 (30 psi) atmosphere. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give tert-butyl N-[4-(3-aminopropoxy)butyl]carbamate (4.4 g, crude) as a white solid. ESI [M+H] = 247.1.

[0544] Preparation of compound 4.APRE007-PCT | 106265.000238

[0545] To a solution of tert-butyl N-[4-(3-aminopropoxy)butyl]carbamate (4.15 g, 16.85 mmol, 1 eq) in THF (30 mL) was added TEA (5.11 g, 50.54 mmol, 7.03 mL, 3 eq) and 6-bromo-2-chloro-3 -nitro-pyridine (2.40 g, 10.11 mmol, 0.6 eq). The mixture was stirred at 25°C for 12 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCE, petroleum ether / ethyl acetate = 50 / 1 to 0 / 1) to give tert-butyl N-[4-[3-[(6-bromo-3-nitro-2-pyridyl)amino]propoxy]butyl]carbamate (3 g, 6.71 mmol, 39.81% yield) as a yellow oil. 'HNMR (400 MHz, Chloroform-d) 5 8.13 (d, J = 8.5 Hz, 1H), 6.67 (d, J = 8.5 Hz, 1H), 3.67 (q, J = 5.8 Hz, 2H), 3.51 (t, J = 5.6 Hz, 2H), 3.41 (t, J = 6.1 Hz, 2H), 3.13-3.03 (m, 2H), 1.88 (quin, J = 6.0 Hz, 2H), 1.62-1.55 (m, 2H), 1.54-1.49 (m, 2H), 1.37 (s, 9H). ESI [M+H] = 447.1 / 449.1.

[0546] Preparation of compound 5.4 5

[0547] To a solution of tert-butyl N-[4-[3-[(6-bromo-3-nitro-2-pyridyl)amino]propoxy]butyl]carbamate (2.8 g, 6.26 mmol, 1 eq) in THF (30 mL), EtOH (30 mL) and H2O (10 mL) was added Fe (699.12 mg, 12.52 mmol, 2 eq) and NH4CI (1.00 g, 18.78 mmol, 3 eq). The mixture was stirred at 80°C for 2 hrs. The reaction mixture was quenched by H2O (50 mL), and then extracted with EtOAc (50 mL x 3). The combined organic layers were dried over ISfeSCL, filtered and concentrated under reduced pressure to give tert-butyl N-[4-[3-[(3-amino-6-bromo-2-pyridyl)amino]propoxy]butyl]carbamate (2.6 g, crude) as a brown oil. ESI [M+H] = 417.0 / 419.0.

[0548] Preparation of compound 6.APRE007-PCT | 106265.0002385 6

[0549] To a solution of tert-butyl N-[4-[3-[(3-amino-6-bromo-2-pyridyl)amino]propoxy]butyl]carbamate (2.6 g, 6.23 mmol, 1 eq) in AcOH (30 mb) was added 1,1,1-trimethoxyethane (2.25 g, 18.69 mmol, 2.35 mb, 3 eq). The mixture was stirred at 70°C for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / THF = 50 / 1 to 0 / 1) to give tert -butyl N-[4-[3-(5-bromo-2-methyl-imidazo[4,5-b]pyridin-3-yl)propoxy]butyl]carbamate (1.4 g, 3.17 mmol, 50.92% yield) as a brown oil. ESI [M+H] = 441.0 / 443.0.

[0550] Preparation of compound 7.6 7

[0551] A mixture of tert-butyl N-[4-[3-(5-bromo-2-methyl-imidazo[4,5-b]pyridin-3-yl) propoxy]butyl]carbamate (1.3 g, 2.95 mmol, 1 eq), 2,6-dichloro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (968.28 mg, 3.53 mmol, 1.2 eq), ISfeCOs (936.55 mg, 8.84 mmol, 3 eq) and Pd(dppf)C12 (215.52 mg, 294.54 pmol, 0.1 eq) in dioxane (20 mb) andEEO (5 mb) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80°C for 1 hr under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue and then dissolved in H2O (lOmL), extracted with EtOAc (40 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 0 / 1) to give tert-butyl N-[4-[3-[5-(2,6-dichloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]propoxy]butyl]carbamate (1 g, 1.97 mmol, 66.77% yield) as a yellow oil. ESI [M+H] =508.1 / 510.1.APRE007-PCT | 106265.000238

[0552] Preparation of compound 8.

[0553] A solution of tert-butyl N-[4-[3-[5-(2,6-dichloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]propoxy]butyl]carbamate (1 g, 1.97 mmol, 1 eq) in HCI / dioxane (5 mL, 4M) was stirred at 25 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18250 x 50 mm x 15 um; mobile phase: [H2O (0.1% TFA)-ACN]; gradient: 20%-50% B over 10.0 min) to give 4-[3-[5-(2,6-dichloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]propoxy]butan-l-amine (480 mg, 1.18 mmol, 59.77% yield, TFA salt) as a white solid. ESI [M+H] = 408.1 / 410.1.

[0554] Preparation of compound 9.

[0555] A mixture of 4-[3-[5-(2,6-dichloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]propoxy]butan-l -amine (10 mg, 24.49 pmol, 1 eq, HC1 salt), tert-butyl carbamate (2.87 mg, 24.49 pmol, 1 eq), CS2CO3 (23.94 mg, 73.47 pmol, 3 eq), RuPhos (1.14 mg, 2.45 pmol, 0.1 eq), 4A MS (24.49 pmol, 1 eq) and Pd2(dba)s (2.24 mg, 2.45 pmol, 0.1 eq) in 2-methylbutan-2-ol (1.5 m ) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100°C for 12 hrs under N2 atmosphere. The reaction solution was used directly (5 batches). ESI [M+H] = 453.2.

[0556] Preparation of Example 24 product.APRE007-PCT | 106265.000238

[0557] A solution of tert-butyl N-(17-methyl-12-oxa-5,7,16,18,22-pentazatetracyclo [14.5.2.12,6.019,23]tetracosal(22),2(24),3,5,17,19(23),20-heptaen-4-yl)carbamate (30 mg, 66.29 pmol, 1 eq) in DCM (1.5 mb) was added TFA (0.5 mb). The mixture was stirred at 25°C for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 100 x 40 mm x 5 urn; mobile phase: [H2O (0.04% HC1)-ACN]; gradient: l%-30% B over 8.0 min) to give 17-methyl-12-oxa-5,7, 16, 18,22-pentazatetracyclo[14.5.2.12,6.019,23]tetracosa-l(22),2(24),3,5,17,19(23),20-heptaen-4-amine (1.97 mg, 5.07 pmol, 7.64% yield, 100% purity, HC1 salt) as a yellow solid. ’H NMR (400 MHz, DMSO-d6) 5 8.31-8.25 (m, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.84-7.76 (m, 1H), 7.63-7.47 (m, 2H), 7.02 (s, 1H), 6.58 (s, 1H), 4.51 (br t, J = 7.4 Hz, 2H), 3.44-3.40 (m, 2H), 3.30 (br d, J = 2.5 Hz, 4H), 2.82 (s, 3H), 2.13-2.06 (m, 2H), 1.91-1.79 (m, 2H), 1.65 (quin, J = 5.6 Hz, 2H). [M+H] = 353.2.

[0558] Example 25

[0560] A mixture of 5 -bromopentanenitrile (5 g, 30.86 mmol, 3.60 mb, 1 eq), tert-butyl N-(2-hydroxyethyl)carbamate (4.97 g, 30.86 mmol, 4.77 mb, 1 eq), TEAB (972.80 mg, 4.63 mmol, 872.46 pL, 0.15 eq), NaOH (12 M, 24.94 mb, 9.7 eq) in Tol. (100 mb) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100 °C for 1 hr under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 1 / 1) to give tert-butyl N-[2-(4-APRE007-PCT | 106265.000238cyanobutoxy)ethyl] carbamate (5 g, 20.63 mmol, 66.87% yield) as a colorless oil. ’H NMR (400 MHz, Chloroform-d) 53.71-3.65 (m, 1H), 3.46 (dt, J = 2.5, 5.3 Hz, 4H), 3.29 (br d, J = 4.8 Hz, 2H), 2.38 (t, J = 6.7 Hz, 2H), 1.83-1.64 (m, 4H), 1.44 (s, 9H).

[0561] Preparation of compound 3.NH3.H2O, H2IEtOH,225°C, 12 hrs3

[0562] A mixture of tert-butyl N-[2-(4-cyanobutoxy)ethyl]carbamate (5 g, 20.63 mmol, 1 eq) in EtOH (50 m ) was degassed and purged with Ar2 for 3 times, and then Raney Ni (1.77 g, 20.63 mmol, 1 eq) and NH3.H2O (7.23 g, 61.90 mmol, 7.95 m , 30% purity, 3 eq) was added and the mixture was stirred at 25°C for 12 hrs under H2 (50 Psi) atmosphere. The reaction mixture was fdtered and concentrated under reduced pressure to give tert-butyl N-[2-(5-aminopentoxy)ethyl]carbamate (5 g, crude) as a colorless oil. ESI [M+H] = 247.2.

[0563] Preparation of compound 4.

[0564] To a solution of tert-butyl N-[2-(5-aminopentoxy)ethyl]carbamate (5 g, 8.12 mmol, 1 eq) in THE (50 mb) was added TEA (2.46 g, 24.36 mmol, 3.39 mb, 3 eq), 6-bromo-2-chloro-3-nitro-pyridine (1.93 g, 8.12 mmol, 1 eq). The mixture was stirred at 25 °C for 12 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, petroleum ether / ethyl acetate = 50 / 1 to 5 / 1) to give tert-butyl N-[2-[5-[(6-bromo-3-nitro-2-pyridyl)amino]pentoxy]ethyl]carbamate (2.4 g, 5.37 mmol, 66.09% yield) as a yellow solid. ’H NMR (400 MHz, Chloroform-d) 58.21 (d, J = 8.6 Hz, 1H), 6.80-6.72 (m, 1H), 3.68-3.60 (m, 2H), 3.50-3.44 (m, 4H), 3.31 (br d, J = 4.9 Hz, 2H), 1.76-1.69 (m, 2H), 1.68-1.63 (m, 2H), 1.49 (br d, J = 7.1 Hz, 2H), 1.45 (s, 9H). ESI [M+H] = 447.2 / 449.2.

[0565] Preparation of compound 5.APRE007-PCT | 106265.000238

[0566] A mixture of tert-butyl N-[2-[5-[(6-bromo-3-nitro-2-pyridyl)amino]pentoxy]ethyl]carbamate (2 g, 4.47 mmol, 1 eq), Fe (998.74 mg, 17.88 mmol, 4 eq), NH4C1 (956.65 mg, 17.88 mmol, 4 eq) in EtOH (15 mb), THF (15 mL) and H2O (5 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 80°C for 2 hrs under N2atmosphere. The reaction mixture was fdtered and concentrated under reduced pressure to give tertbutyl N-[2-[5-[(3-amino-6-bromo-2-pyridyl)amino]pentoxy]ethyl]carbamate (1.8 g, crude) as a black oil. ESI [M+H] = 417.2 / 419.2.

[0567] Preparation of compound 6.5 6

[0568] To a solution of tert-butyl N-[2-[5-[(3-amino-6-bromo-2-pyridyl)amino]pentoxy]ethyl]carbamate (1.8 g, 4.31 mmol, 1 eq) in AcOH (20 mL) was added 1,1,1-trimethoxyethane (2.59 g, 21.57 mmol, 2.71 mL, 5 eq). The mixture was stirred at 70°C for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 0 / 1) to give tert-butyl N-[2-[5-(5-bromo-2-methyl-imidazo[4,5-b]pyridin-3-yl)pentoxy]ethyl]carbamate (1.61 g, 3.65 mmol, 84.58% yield) as ayellow oil. ESI [M+H] = 441.1 / 443.1.

[0569] Preparation of compound 7.APRE007-PCT | 106265.000238

[0570] A mixture of tert-butyl N-[2-[5-(5-bromo-2-methyl-imidazo[4,5-b]pyridin-3-yl)pentoxy] ethyl] carbamate (1.5 g, 3.40 mmol, 1 eq), 2,6-dichloro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (977.59 mg, 3.57 mmol, 1.05 eq), K3PO4 (2.16 g, 10.20 mmol, 3 eq) and Pd(dtbpf)C12 (221.50 mg, 339.86 pmol, 0.1 eq) in THF (20 mL) and H2O (4 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80°C for 1 hr under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, petroleum ether / ethyl acetate = 50 / 1 to 0 / 1) to give tertbutyl N-[2-[5-[5-(2,6-dichloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]pentoxy]ethyl]carbamate (1.4 g, 2.75 mmol, 81.02% yield) as a brown oil. ESI [M+H] = 508.3 / 510.2.

[0571] Preparation of compound 8.

[0572] A solution of tert-butyl N-[2-[5-[5-(2,6-dichloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]pentoxy]ethyl]carbamate (600 mg, 1.18 mmol, 1 eq) in HCI / EtOAc (50 mL) was stirred at 25 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 100 x 30 mm x 3 um; mobile phase: [H2O (0.2% FA)-ACN]; gradient: 10%-50% B over 8.0 min) to give 2-[5-[5-(2,6-dichloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]pentoxy]ethanamine (350 mg, 857.16 pmol, 72.64% yield, FA salt) as a white solid.

[0573] Preparation of compound 9.APRE007-PCT | 106265.000238

[0574] A mixture of 2-[5-[5-(2,6-dichloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]pentoxy]ethanamine (20 mg, 48.98 pmol, 1 eq, FA salt), tert-butyl carbamate (5.74 mg, 48.98 pmol, 1 eq), CS2CO3 (47.88 mg, 146.94 pmol, 3 eq), Pd2(dba)s (4.49 mg, 4.90 pmol, 0.1 eq) and RuPhos (2.29 mg, 4.90 pmol, 0.1 eq) in 2-methylbutan-2-ol (6 mb) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100°C for 12 hrs under N2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give tert-butyl N-(17-methyl-10-oxa-5,7,16,18,22-pentazatetracyclo[14.5.2.12,6.019,23]tetracosal(22),2(24),3,5,17, 19(23),20-heptaen-4-yl)carbamate (100 mg, crude, 5 batches) as a yellow oil. ESI [M+H+] = 453.3.

[0575] Preparation of Example 25 product.

[0576] To a solution of tert-butyl N-(17-methyl-10-oxa-5,7,16,18,22-pentazatetracyclo [14.5.2.12, 6.019, 23]tetracosal(22), 2(24), 3, 5, 17, 19(23), 20-heptaen-4-yl)carbamate (100 mg, 220.97 pmol, 1 eq) in DCM (2 mL) was added TFA (1 mL). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150 x 40 mm x 10 urn; mobile phase: [H2O (0.05% NH3H2O+IO mM NFUHCC>3)-ACN]; gradient: 20%-40% B over 8.0 min) to give 17-methyl-10-oxa-5,7 ,16,18,22-pentazatetracyclo[14.5.2.12,6.019,23]tetracosa-l(22),2(24),3,5,17 ,19(23), 20-heptaen-4-amine (26.69 mg, 75.73 pmol, 34.27% yield, 100% purity) as a white solid. ’H NMR (400 MHz, DMSO-d6) 57.95 (d, J = 8.3 Hz, 1H), 7.56 (d, J = 8.3 Hz, 1H), 6.74 (s, 1H), 6.28 (s, 1H), 5.96 (t, J = 6.2 Hz, 1H), 5.52 (s, 2H), 4.22 (br t, J = 7.2 Hz, 2H), 3.49 (t, J = 6.7 Hz, 4H), 3.33-3.27 (m, 2H), 2.59 (s, 3H), 1.88 (quin, J = 7.1 Hz, 2H), 1.75 (quin, J = 6.7 Hz, 2H), 1.56 (quin, J = 7.0 Hz, 2H). ESI [M+H] = 353.2.

[0577] Example 26APRE007-PCT | 106265.000238

[0578] Preparation of compound 2.1 2

[0579] A mixture of 3-bromo-4-iodo-pyridine (9.4 g, 33.11 mmol, 1 eq), tert-butyl N-but-3-ynylcarbamate (5.60 g, 33.11 mmol, 1 eq), Cui (630.60 mg, 3.31 mmol, 0.1 eq), TEA (6.70 g, 66.22 mmol, 9.22 m , 2 eq) and dichloropalladium;triphenylphosphane (1.16 g, 1.66 mmol, 0.05 eq) in THF (100 m ) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 70°C for 12 hrs under N2 atmosphere. The reaction mixture was fdtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, petroleum ether / ethyl acetate = 50 / 1 to 5 / 1) to give tert-butyl N-[4-(3-bromo-4-pyridyl)but-3-ynyl] carbamate (9.4 g, 28.91 mmol, 87.30% yield) as a yellow oil. 'H NMR (400 MHz, Chloroform-d) 59.25-8.18 (m, 2H), 7.33 (br s, 1H), 3.42 (q, J = 6.2 Hz, 2H), 2.70 (t, J = 6.4 Hz, 2H), 1.46 (s, 9H). ESI [M+H] = 325.2 / 327.2.

[0580] Preparation of compound 3.2 3APRE007-PCT | 106265.000238

[0581] A mixture of tert-butyl N-[4-(3-bromo-4-pyridyl)but-3-ynyl]carbamate (9.1 g, 27.98 mmol, 1 eq), 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoxazole (6.00 g, 30.78 mmol, 1.1 eq), K3PO4 (11.88 g, 55.97 mmol, 2 eq) and [2-(2-aminophenyl)phenyl]-chloro-palladium;bis(l-adamantyl)-butyl-phosphane (1.87 g, 2.80 mmol, 0.1 eq) in THF (120 mb) and H2O (40 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 60°C for 1 hr under N2 atmosphere. The reaction mixture was added water (100 mL) and extracted with EtOAc (80 mL x 3). The combined organic layers were washed with brine (50 mL), dried over ISfeSCL, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, petroleum ether / ethyl acetate = 50 / 1 to 1 / 1) to give tert-butyl N-[4-(3-isoxazol-4-yl-4-pyridyl)but-3-ynyl]carbamate (8.7 g, 27.76 mmol, 99.22% yield) as a yellow oil. ESI [M+H] = 314.2.

[0582] Preparation of compound 4.NHBoc NHBoc12 hrs v3 4

[0583] To a solution of tert-butyl N-[4-(3-isoxazol-4-yl-4-pyridyl)but-3-ynyl]carbamate (8.5 g, 27.13 mmol, 1 eq) in MeOH (100 mL) was added KF (15 M, 9.04 mL, 5 eq). The mixture was stirred at 70°C for 12 hrs. The reaction mixture was added water (100 mL) and extracted with EtOAc (80 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 1 / 1) to give tert-butyl N-[4-[3-(cyanomethyl)-4-pyridyl]but-3-ynyl]carbamate (5.8 g, 20.33 mmol, 74.93% yield) as a yellow oil. ESI [M+H] = 286.1.

[0584] Preparation of compound 5.> >4 5APRE007-PCT | 106265.000238

[0585] To a solution of tert-butyl N-[4-[3-(cyanomethyl)-4-pyridyl]but-3-ynyl]carbamate (5.3 g, 18.57 mmol, 1 eq) in NFf / McOH (100 mb) was added Raney Ni (18.57 mmol, 1 eq). The mixture was stirred at 30°C for 12 hrs under H2 (50 Psi). The reaction mixture was fdtered and the fdtrate was concentrated under reduced pressure to give tert-butyl N-[4-[3-(2-aminoethyl)-4-pyridyl]butyl]carbamate (5 g, crude) as a yellow oil. ESI [M+H] = 294.1.

[0586] Preparation of compound 6.

[0587] To a solution of tert-butyl N-[4-[3-(2-aminoethyl)-4-pyridyl]butyl]carbamate (2.1 g, 7.16 mmol, 1 eq) in THF (40 m ) was added TEA (2.17 g, 21.47 mmol, 2.99 mb, 3 eq) and 6-bromo-2-chloro-3 -nitro-pyridine (1.19 g, 5.01 mmol, 0.7 eq). The mixture was stirred at 20°C for 12 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC petroleum ether / ethyl acetate = 50 / 1 to 65 / 35) to give tert-butyl N-[4-[3-[2-[(6-bromo-3-nitro-2-pyridyl)amino]ethyl]-4-pyridyl]butyl]carbamate (2.1 g, 4.25 mmol, 59.35% yield) as a brown oil. ESI [M+H] = 494.2 / 496.2.

[0588] Preparation of compound 7.

[0589] A mixture of tert-butyl N-[4-[3-[2-[(6-bromo-3-nitro-2-pyridyl)amino]ethyl]-4-pyridyl]butyl]carbamate (1.7 g, 3.44 mmol, 1 eq), Fe (768.12 mg, 13.75 mmol, 4 eq) andlSTECl (735.75 mg, 13.75 mmol, 4 eq) in THF (12 mb), EtOH (12 mb) and H2O (3 mb) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80°C for 2 hrs under N2 atmosphere. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give tert-APRE007-PCT | 106265.000238butyl N-[4-[3-[2-[(3-amino-6-bromo-2 -pyridyl) amino]ethyl]-4-pyridyl]butyl]carbamate (1.6 g, crude) as a brown solid. ESI [M+H] = 466.2 / 464.2.

[0590] Preparation of compound 8.

[0591] To a solution of tert-butyl N-[4-[3-[2-[(3-amino-6-bromo-2-pyridyl)amino]ethyl]-4-pyridyl]butyl]carbamate (1.5 g, 3.23 mmol, 1 eq) in MeOH (20 m ) was added 1,1,1-trimethoxyethane (776.14 mg, 6.46 mmol, 811.87 ph, 2 eq), sulfamic acid (627.22 mg, 6.46 mmol, 291.60 ph, 2 eq). The mixture was stirred at 30°C for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Welch Xtimate C18 250 x 70 mm x 10 um; mobile phase: [H2O (0.2% FA)-ACN]; gradient: 15%-45% B over 20.0 min) to give tert-butyl N-[4-[3-[2-(5-bromo-2-methyl-imidazo[4,5-b]pyridin-3-yl)ethyl]-4-pyridyl]butyl]carbamate (1 g, 2.04 mmol, 63.2% yield, FA salt) as a brown solid. ESI [M+H] = 490.2 / 488.2.

[0592] Preparation of compound 9.

[0593] A mixture of tert-butyl N-[4-[3-[2-(5-bromo-2-methyl-imidazo[4,5-b]pyridin-3-yl)ethyl]-4-pyridyl]butyl]carbamate (190 mg, 389.01 pmol, 1 eq), 2,6-dichloro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (111.90 mg, 408.46 pmol, 1.05 eq), K3PO4 (247.72 mg, 1.17 mmol, 3 eq) and Pd(dtbpf)C12 (25.35 mg, 38.90 pmol, 0.1 eq) in THF (8 m ) and H2O (2 mb) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80°C for 1 hr under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. TheAPRE007-PCT | 106265.000238residue was purified by column chromatography (SiCE, petroleum ether / ethyl acetate = 50 / 1 to 0 / 1) to give tert-butyl N-[4-[3-[2-[5-(2, 6-dichloro-4-pyridyl)-2 -methyl -imidazo[4, 5-b]pyridin-3-yl]ethyl]-4-pyridyl]butyl]carbamate (200 mg, 360.04 pmol, 92.55% yield) as a yellow solid. ESI [M+H] = 555.2.

[0594] Preparation of compound 10.

[0595] A solution of tert-butyl N-[4-[3-[2-[5 -(2, 6-dichloro-4-pyridyl)-2 -methyl -imidazo [4,5-b]pyridin-3-yl]ethyl]-4-pyridyl]butyl]carbamate (200 mg, 360.04 pmol, 1 eq) in HCl / EtOAc (2 mL) was stirred at 20°C for 1 hr. The reaction mixture was concentrated under reduced pressure to give 4-[3-[2-[5-(2,6-dichloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]ethyl]-4-pyridyl]butan-1-amine (150 mg, crude, HC1 salt) as a white solid. ESI [M+H] = 455.2.

[0596] Preparation of compound 11.

[0597] A mixture of 4-[3-[2-[5-(2,6-dichloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]ethyl]-4-pyridyl]butan-l-amine (50 mg, 109.80 pmol, 1 eq, HC1 salt), tert-butyl carbamate (38.59 mg, 329.39 pmol, 3 eq), CS2CO3 (107.32 mg, 329.39 pmol, 3 eq), RuPhos (5.12 mg, 10.98 pmol, 0.1 eq) and Pd2(dba)s (10.05 mg, 10.98 pmol, 0.1 eq) in 2-methylbutan-2-ol (6 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100°C for 12 hrs under N2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give tert-butyl N-(21-APRE007-PCT | 106265.000238methyl-5,7,15,20,22,26-hexazapentacyclo[18.5.2.12,6.012,17.023,27]octacosal(25),2,4,6(28), 12(17), 13, 15, 21, 23, 26-decaen-4-yl)carbamate (50 mg, crude) as a yellow oil. ESI [M+H] = 500.4.

[0598] Preparation of Example 26 product.

[0599] A solution oftert-butyl N-(21-methyl-5,7,15,20,22,26-hexazapentacyclo[18.5.2.12, 6.012,17 ,023,27]octacosal(25),2,4,6(28),12(17),13,15,21,23,26-decaen-4-yl) carbamate (45 mg, 90.07 pmol, 1 eq) in DCM (2 mL) was added TFA (1 mL). The mixture was stirred at 25°C for 1 hr. The reaction mixture was fdtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150 x 40 mm x 10 um; mobile phase: [H2O (0.05% NH3H2O+IO mM NFLHCC^-ACN]; gradient: 15%-45% B over 8.0 min) to give 21-methyl-5,7,15,20,22,26-hexazapentacyclo[18.5.2.12,6.012,17.023, 27]octacosal(25),2,4,6(28),12(17),13,15,21,23,26-decaen-4-amine (5.6 mg, 12.99 pmol, 14.42% yield, 93% purity, TFA salt) as a yellow solid. ’H NMR (400 MHz, DMSO-d6) 5 8.57 (s, 1H), 8.41 (d, J = 5.1 Hz, 1H), 7.99 (d, J = 8.3 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.27 (d, J = 5.1 Hz, 1H), 6.90 (s, 1H), 6.33 (s, 1H), 6.06 (t, J = 6.3 Hz, 1H), 5.48 (s, 2H), 4.36-4.23 (m, 2H), 3.23 (br d, J = 3.5 Hz, 4H), 3.18-3.09 (m, 2H), 2.74 (s, 3H), 1.78 (br s, 4H). ESI [M+H] = 400.2.

[0600] Example 27

[0601] Preparation of compound 2.APRE007-PCT | 106265.000238

[0602] To a solution of 2-(2-hydroxyphenyl)acetonitrile (4.9 g, 36.80 mmol, 1 eq) in DMF (20 mL) was added K2CO3 (10.17 g, 73.60 mmol, 2 eq) and tert-butyl N-(4-bromobutyl)carbamate (9.74 g, 38.64 mmol, 7.93 mL, 1.05 eq). The mixture was stirred at 80°C for 2 hrs. The reaction mixture was quenched by addition H2O (200 mL), and then extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (30 mL), dried over ISfeSCL, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, petroleum ether / ethyl acetate = 50 / 1 to 0 / 1) to give tert-butyl N-[4-[2-(cyanomethyl)phenoxy]butyl]carbamate (10 g, 32.85 mmol, 89.27% yield) as a brown oil. ’H NMR (400 MHz, DMSO-d6) 57.36-7.28 (m, 2H), 7.04 (d, J = 8.0 Hz, 1H), 6.96 (dt, J = 0.8, 7.5 Hz, 1H), 6.88-6.80 (m, 1H), 4.03 (t, J = 6.3 Hz, 2H), 3.83 (s, 1H), 3.86-3.79 (m, 1H), 2.99 (q, J = 6.7 Hz, 2H), 1.78-1.69 (m, 2H), 1.57 (td, J = 7.0, 14.5 Hz, 2H), 1.38 (s, 9H).

[0603] Preparation of compound 3.

[0604] The reaction was performed by flow chemistry. Solution 1: {tert-butyl N-[4-[2-(cyanomethyl)phenoxy]butyl]carbamate (3 g, 9.86 mmol, 1 eq)} in {NHs / MeOH (60 mL)}. The fixed bed (named FLR1, volume 5 mL) was completely packed with granular catalyst 14%Co / A12O3 (4 g). The H2 back pressure regulator was adjusted to 2.5 MPa, and the flow rate of H2 was 30 mL / min. Then the solution SI was pumped by Pump 1 {SI, Pl, 0.3 mL / min} to fixed bed {FLR1, SS, fixed bed, 6.350(1 / 4”) mm, 1 mL, 80 °C}. The solution SI was flowing through {FLR1, 3.3 min} to leave the reactor zone, then the reaction mixture was collected from the reactor output. Stop collecting the reaction mixture after 4 hrs. The fixed bed was washed by extra MeOH (300 mL). The organic layerAPRE007-PCT | 106265.000238was concentrated to give tert-butyl N-[4-[2-(2-aminoethyl)phenoxy]butyl]carbamate (3 g, crude) as a yellow oil. ESI [M+H] = 309.2.

[0605] Preparation of compound 4.

[0606] To a solution of 6-bromo-2-chloro-3-nitro-pyridine (1.92 g, 8.11 mmol, 1 eq) in THF (10 m ) was added TEA (2.46 g, 24.32 mmol, 3.38 mb, 3 eq) and tert-butyl N-[4-[2-(2-aminoethyl)phenoxy]butyl]carbamate (2.5 g, 8.11 mmol, 1 eq). The mixture was stirred at 25°C for 2 hrs. The reaction mixture was concentrated under reduced pressure to give tert -butyl N-[4-[2-[2-[(6-bromo-3-nitro-2-pyridyl)amino]ethyl]phenoxy]butyl]carbamate (4 g, crude) as a yellow oil. ’H NMR (400 MHz, DMSO-d6) 58.68 (t, J = 5.6 Hz, 1H), 8.31 (d, J = 8.5 Hz, 1H), 7.28-7.18 (m, 2H), 6.87 (br s, 4H), 4.03 (t, J = 6.4 Hz, 2H), 3.89-3.73 (m, 2H), 3.10-2.92 (m, 4H), 1.85-1.73 (m, 2H), 1.69-1.51 (m, 2H), 1.42 (s, 9H). ESI [M+H] = 509.2 / 511.2.

[0607] Preparation of compound 5.4 5

[0608] To a solution of tert-butyl N-[4-[2-[2-[(6-bromo-3-nitro-2-pyridyl)amino]ethyl]phenoxy]butyl]carbamate (3.8 g, 7.46 mmol, 1 eq) in THF (30 mb), EtOH (30 mb) and H2O (10 mb) was added Fe (833.19 mg, 14.92 mmol, 2 eq) andlSTECl (1.20 g, 22.38 mmol, 3 eq). The mixture was stirred at 80°C for 2 hrs. The reaction mixture was quenched by H2O (10 mb), and then extracted with EtOAc (20 mb x 3). The combined organic layers were dried over Na2SC>4, fdtered and concentrated under reduced pressure to give tert-butyl N-[4-[2-[2-[(3-amino-6-bromo-2-pyridyl)amino]ethyl]phenoxy]butyl]carbamate (3.5 g, crude) as a yellow oil. ESI [M+H] = 481.1 / 479.1.

[0609] Preparation of compound 6.APRE007-PCT | 106265.000238

[0610] To a solution of tert-butyl N-[4-[2-[2-[(3-amino-6-bromo-2-pyridyl)amino]ethyl]phenoxy]butyl]carbamate (3.5 g, 7.30 mmol, 1 eq) in MeOH (10 mb) was added 1,1,1 -trimethoxyethane (2.63 g, 21.90 mmol, 2.75 mb, 3 eq) and sulfamic acid (70.88 mg, 730.07 pmol, 32.95 pL, 0.1 eq). The mixture was stirred at 30°C for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, petroleum ether / ethyl acetate = 50 / 1 to 0 / 1) to give tert-butyl N-[4-[2-[2-(5-bromo-2-methyl-imidazo[4,5-b]pyridin-3-yl)ethyl]phenoxy]butyl]carbamate (3 g, 5.96 mmol, 81.62% yield) as a brown oil. ESI [M+H] = 505.2 / 503.2.

[0611] Preparation of compound 7.

[0612] A mixture of tert-butyl N-[4-[2-[2-(5-bromo-2-methyl-imidazo[4,5-b]pyridin-3-yl)ethyl]phenoxy]butyl]carbamate (2.8 g, 5.56 mmol, 1 eq), 2,6-dichloro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (1.52 g, 5.56 mmol, 1 eq), ISfeCOs (1.77 g, 16.69 mmol, 3 eq) and Pd(dppf)C12 (406.96 mg, 556.18 pmol, 0.1 eq) in dioxane (20 mb) and FEO (5 mb) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80°C for 1 hr under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue and then dissolved in H2O (10 mb), and then extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCE, petroleum ether / ethyl acetate = 50 / 1 to 0 / 1) to give tert-APRE007-PCT | 106265.000238butyl N-[4-[2-[2-[5-(2,6-dichloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]ethyl]phenoxy]butyl]carbamate (2.5 g, 4.38 mmol, 78.79% yield) as a brown oil. ESI [M+H] =570.2 / 572.3.

[0613] Preparation of compound 8.

[0614] A solution of tert-butyl N-[4-[2-[2-[5 -(2, 6-dichloro-4-pyridyl)-2 -methyl -imidazo[4,5-b]pyridin-3-yl]ethyl]phenoxy]butyl]carbamate (1 g, 1.75 mmol, 1 eq) in HCl / EtOAc (10 m , 4M) was stirred at 20°C for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18250 x 50 mm x 15 um; mobile phase: [H2O (0.1% TFA)-ACN]; gradient: 30%-60% B over 10.0 min) to give 4- [2-[2-[5-(2,6-dichloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]ethyl]phenoxy]butan-l-amine (240 mg, 510.21 pmol, 29.11% yield, TFA salt) as a white solid. ESI [M+H] = 470.2 / 472.2.

[0615] Preparation of compound 9.

[0616] A mixture of 4-[2-[2-[5-(2,6-dichloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]ethyl]phenoxy]butan-l-amine (21 mg, 44.64 pmol, 1 eq, TFA salt), tert-butyl carbamate (15.69 mg, 133.93 pmol, 3 eq), RuPhos (2.08 mg, 4.46 pmol, 0.1 eq), Pd2(dba)s (4.09 mg, 4.46 pmol, 0.1 eq) and t-BuONa (8.58 mg, 89.29 pmol, 2 eq) in 2-methylbutan-2-ol (6 mb) was degassed and purgedAPRE007-PCT | 106265.000238with N2 for 3 times, and then the mixture was stirred at 100°C for 12 hrs under N2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give tert -butyl N-(22-methyl-12-oxa-5,7,21,23,27-pentazapentacyclo[19.5.2.12,6.013,18.024,28]nonacosal(26), 2,4,6(29),13,15,17,22,24,27-decaen-4-yl)carbamate (90 mg, crude, 4 batches) as a yellow oil. ESI [M+H] =515.3.

[0617] Preparation of Example 27 product.

[0618] A solution of tert-butyl N-(22-methyl-12-oxa-5,7,21,23,27-pentazapentacyclo [19.5.2.12,6.013,18.024,28]nonacosal(26),2,4,6(29),13,15,17,22,24,27-decaen-4-yl) carbamate (90 mg, 174.89 pmol, 1 eq) in DCM (1 mL) was added TFA (1 mL). The mixture was stirred at 25°C for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: 3_Phenomenex Luna C18 75 x 30 mm x 3 um; mobile phase:[H2O (0.1% TFA)-ACN]; gradient: 15%-45% B over 8.0 min) to give 22-methyl-12-oxa-5,7,21,23,27-pentazapentacyclo[19.5.2.12,6.013,18.024,28]nonacosal(26),2,4,6(29),13,15,17,22,24,27-decaen-4-amine (5.48 mg, 9.70 pmol, 5.54% yield, 94% purity, TFA salt) as a yellow solid. ’H NMR (400 MHz, DMSO-d6) 58.12 (d, J = 8.3 Hz, 1H), 7.74 (d, J = 8.3 Hz, 1H), 7.57 (br t, J = 5.6 Hz, 1H), 7.39-7.34 (m, 2H), 7.29-7.20 (m, 1H), 7.03 (d, J = 8.1 Hz, 1H), 6.96-6.88 (m, 2H), 6.48 (s, 1H), 4.44-4.38 (m, 2H), 4.16-4.12 (m, 2H), 3.41-3.34 (m, 2H), 3.22-3.14 (m, 2H), 2.75 (s, 3H), 2.06-1.97 (m, 2H), 1.90 (br d, J = 4.3 Hz, 2H). ESI [M+H] = 415.2.

[0619] Example 28APRE007-PCT | 106265.000238

[0620] Preparation of compound 2.

[0621] To a solution of 2-(2-hydroxyphenyl)acetonitrile (3 g, 22.53 mmol, 1 eq) in DMF (40 mL) was added K2CO3 (6.23 g, 45.06 mmol, 2 eq) and tert-butyl N-(3-bromopropyl)carbamate (5.37 g, 22.53 mmol, 1 eq). The mixture was stirred at 80°C for 2 hrs. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by column chromatography (SiCL, petroleum ether / ethyl acetate = 50 / 1) to give tert-butyl N-[3-[2-(cyanomethyl)phenoxy]propyl]carbamate (6 g, 20.66 mmol, 91.71% yield) as a yellow oil. ESI [M+H] = 291.2.

[0622] Preparation of compound 3.

[0623] The reaction was performed by flow chemistry. Solution 1: {tert-butyl N-[3-[2-(cyanomethyl)phenoxy]propyl]carbamate (3 g, 10.33 mmol, 1 eq)} in {NFT / McOH (60 mb)}. The fixed bed (named FLR1, volume 5 mL) was completely packed with granular catalyst 14% Co / AhOs (4 g). The H2 back pressure regulator was adjusted to 2.5 MPa, and the flow rate of H2 was 30 mL / min. Then the solution SI was pumped by Pump 1 {SI, Pl, 0.3 mL / min} to fixed bed {FLR1,APRE007-PCT | 106265.000238SS, fixed bed, 6.350(l / 4”)mm, 1 mL, 80°C}. The solution SI was flowing through {FLR1, 3.3 min} to leave the reactor zone, then the reaction mixture was collected from the reactor output. Stop collecting the reaction mixture after 3.5 hrs. The fixed bed was washed by extra MeOH (300 mL). The organic layer was concentrated to give tert-butyl N-[3-[2-(2-aminoethyl)phenoxy]propyl]carbamate (2.7 g, 9.17 mmol, 88.77% yield) as a colorless oil. ESI [M+H] = 295.2.

[0624] Preparation of compound 4.

[0625] To a solution of tert-butyl N-[3-[2-(2-aminoethyl)phenoxy]propyl]carbamate (2.7 g, 9.17 mmol, 1 eq) in THF (50 mL) was added TEA (1.86 g, 18.34 mmol, 2.55 mL, 2 eq) and 6-bromo-2-chloro-3 -nitro-pyridine (2.18 g, 9.17 mmol, 1 eq). The mixture was stirred at 25°C for 2 hrs. The reaction mixture was concentrated and the residue was purified by column chromatography (SiC>2, petroleum ether / ethyl acetate = 5 / 1) to give tert-butyl N-[3-[2-[2-[(6-bromo-3-nitro-2-pyridyl)amino]ethyl]phenoxy]propyl]carbamate (4.5 g, 9.08 mmol, 99.05% yield) as a yellow oil. ESI [M+H] = 495.2 / 497.2.

[0626] Preparation of compound 5.

[0627] To a solution of tert-butyl N-[3-[2-[2-[(6-bromo-3-nitro-2-pyridyl)amino]ethyl]phenoxy]propyl]carbamate (2.5 g, 5.05 mmol, 1 eq) in EtOH (10 mL), THF (10 mL) and H2O (5 mL) was added Fe (563.67 mg, 10.09 mmol, 2 eq) and NH4CI (809.88 mg, 15.14 mmol, 3 eq). The mixture was stirred at 80°C for 2 hrs. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The reaction mixture was added H2O (20 mL), and then extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (20 mL), dried over ISfeSCL, filtered and concentrated under reduced pressure toAPRE007-PCT | 106265.000238give tert-butyl N-[3-[2-[2-[(3-amino-6-bromo-2-pyridyl)amino]ethyl]phenoxy]propyl]carbamate (2.3 g, crude) as a brown oil. ESI [M+H] = 465.2 / 467.2.

[0628] Preparation of compound 6.

[0629] To a solution of tert-butyl N-[3-[2-[2-[(3-amino-6-bromo-2-pyridyl)amino]ethyl]phenoxy]propyl]carbamate (2 g, 4.30 mmol, 1 eq) in MeOH (10 m ) was added sulfamic acid (417.26 mg, 4.30 mmol, 1 eq) and 1,1,1 -trimethoxy ethane (1.55 g, 12.89 mmol, 1.62 m , 3 eq). The mixture was stirred at 30°C for 1 hr. The reaction mixture was quenched by H2O (10 mb), and then extracted with EtOAc (30 mb x 3). The combined organic layers were dried over Na2SC>4, fdtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, petroleum ether / THb=50 / l to 0 / 1) to give tert-butyl N-[3-[2-[2-(5-bromo-2-methyl-imidazo[4,5-b]pyridin-3-yl)ethyl]phenoxy]propyl]carbamate (1.6 g, 3.27 mmol, 76.07% yield) as a yellow oil. ESI [M+H] = 489.2 / 491.2.

[0630] Preparation of compound 7.

[0631] A mixture of tert-butyl N-[3-[2-[2-(5-bromo-2-methyl-imidazo[4,5-b]pyridin-3-yl)ethyl]phenoxy]propyl]carbamate (500 mg, 1.02 mmol, 1 eq), 2-chloro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (244.69 mg, 1.02 mmol, 1 eq), Pd(dppf)C12 (74.75 mg, 102.17 pmol, 0.1 eq) and ISfeCOs (324.85 mg, 3.06 mmol, 3 eq) in dioxane (5 mb) and H2O (2 mb) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80°C for 1 hr under N2 atmosphere. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was added H2O (6 mb), and then extracted with EtOAc (10 mb x 3). TheAPRE007-PCT | 106265.000238combined organic layers were washed with brine (3 mL), dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, petroleum ether / THF= 50 / 1 to 0 / 1) to give tert-butyl N-[3-[2-[2-[5-(2-chloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]ethyl]phenoxy]propyl]carbamate (300 mg, 574.67 pmol, 56.25% yield) as a brown oil. ESI [M+H] = 522.2.

[0632] Preparation of compound 8.7 8

[0633] A solution of tert-butyl N-[3-[2-[2-[5-(2-chloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]ethyl]phenoxy]propyl]carbamate (300 mg, 574.67 pmol, 1 eq) in HCl / EtOAc (2 mL, 4M) was stirred at 20°C for 1 hr. The reaction mixture was concentrated under reduced pressure to give 3-[2-[2-[5-(2-chloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]ethyl]phenoxy]propan-l-amine (200 mg, crude, HC1 salt) as a white solid. ESI [M+H] = 422.2.

[0634] Preparation of Example 28 product.

[0635] A mixture of 3-[2-[2-[5-(2-chloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]ethyl]phenoxy]propan-l -amine (100 mg, 237.01 pmol, 1 eq, HC1 salt), t-BuONa (68.33 mg, 711.03 pmol, 3 eq), RuPhos (11.06 mg, 23.70 pmol, 0.1 eq) and Pd2(dba)s (21.70 mg, 23.70 pmol, 0.1 eq) in 2-methylbutan-2-ol (5 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100°C for 12 hrs under N2 atmosphere. The residue was purified by prep-HPLC (column: WePure Biotech XPt C18 150 x 40 x 7 um; mobile phase: [H2O (0.05% NH3H2O+IO mM NELHCO3)-ACN]; gradient: 45%-75% B over 8.0 min) to give 21-methyl-l l-oxa-5, 7,20,22,26-APRE007-PCT | 106265.000238pentazapentacyclo [18.5.2.12, 6.012, 17.023, 27]octacosa-l(25), 2, 4, 6(28), 12(17), 13, 15,21,23,26-decaene (7.46 mg, 18.53 pmol, 7.82% yield, 96% purity) as a yellow solid. ’H NMR (400 MHz, DMSO-d6) 58.63 (br d, J = 1.3 Hz, 1H), 8.41 (s, 1H), 8.35-8.29 (m, 2H), 8.17 (d, J = 6.8 Hz, 1H), 7.74-7.69 (m, 1H), 7.49 (dd, J = 1.4, 7.4 Hz, 1H), 7.32-7.27 (m, 1H), 7.08 (d, J = 8.2 Hz, 1H), 7.00 (t, J = 7.3 Hz, 1H), 4.34 (br dd, J = 7.3, 10.3 Hz, 2H), 4.15-4.07 (m, 2H), 3.41 (brdd, J = 5.5, 11.9 Hz, 4H), 2.92 (s, 3H), 2.15 (br d, J = 5.4 Hz, 2H) ESI [M+H] = 386.2.

[0636] Example 29

[0638] A mixture of 6-bromohexanenitrile (4.5 g, 25.56 mmol, 1 eq), tert-butyl N-(2-hydroxyethyl)carbamate (4.12 g, 25.56 mmol, 3.95 m , 1 eq), TEAB (1.61 g, 7.67 mmol, 1.45 mb, 0.3 eq), NaOH (12 M, 21.30 mb, 10 eq) in Toluene (100 mb) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100°C for 1 hr under N2 atmosphere. The reaction mixture was quenched by addition H2O (100 mb), and then extracted with EtOAc (100 mb x 3). The combined organic layers were dried over ISfeSCE, fdtered and concentrated under reduced pressure to give tert-butyl N-[2-(5-cyanopentoxy)ethyl]carbamate (5 g, crude) as a white oil. ESI [M+H] = 257.2.

[0639] Preparation of compound 3.

[0640] The reaction was performed by flow chemistry. Solution 1: {tert-butyl N-[2-(5-cyanopentoxy)ethyl] carbamate (3 g, 11.70 mmol, 1 eq)} in {NFF / McOH (60 mb)}. The fixed bed (named PERI, volume 5 mb) was completely packed with granular catalyst 14% Co / AhOs (4 g). The H2 back pressure regulator was adjusted to 2.5 MPa, and the flow rate of H2 was 30 mb / min. Then the solution SI was pumped by Pump 1 {SI, Pl, 0.3 mb / min} to fixed bed {FERI, SS, fixed bed, 6.350(l / 4”)mm 1 mb, 80°C}. The solution SI was flowing through {FERI, 3.3 min} to leave theAPRE007-PCT | 106265.000238reactor zone, then the reaction mixture was collected from the reactor output. Stop collecting the reaction mixture after 3.5 hrs. The fixed bed was washed by extra MeOH (300 mL). The organic layer was concentrated to give tert-butyl N-[2-(6-aminohexoxy)ethyl]carbamate (2 g, crude) as a colorless oil. ESI [M+H] = 261.2.

[0641] Preparation of compound 4.

[0642] To a solution of tert-butyl N-[2-(6-aminohexoxy)ethyl]carbamate (2 g, 7.68 mmol, 1 eq) in THF (10 mL) was added TEA (2.33 g, 23.04 mmol, 3.21 mL, 3 eq) and 6-bromo-2-chloro-3-nitro-pyridine (911.92 mg, 3.84 mmol, 0.5 eq). The mixture was stirred at 25°C for 1 hr. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCE, petroleum ether / ethyl acetate = 50 / 1 to 0 / 1) to give tert-butyl N-[2-[6-[(6-bromo-3-nitro-2-pyridyl)amino]hexoxy]ethyl]carbamate (0.8 g, 1.73 mmol, 22.57% yield) as ayellow oil. ESI [M+H] = 461.1 / 463.1.

[0643] Preparation of compound 5.Boc Boc2 hrs4 5

[0644] To a solution of tert-butyl N-[2-[6-[(6-bromo-3-nitro-2-pyridyl)amino]hexoxy]ethyl]carbamate (800 mg, 1.73 mmol, 1 eq) in EtOH (3 mL), THF (3 mL) and H2O (1 mL) was added Fe (193.68 mg, 3.47 mmol, 2 eq) and NH4CI (278.27 mg, 5.20 mmol, 3 eq). The mixture was stirred at 80°C for 2 hrs. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give a residue. The reaction mixture was quenched by addition H2O (10 mL), and then extracted with EtOAc (20 mL x 3). The combined organic layers were dried over ISfeSCL, filtered and concentrated under reduced pressure to give tert-butyl N-[2-[6- [(3-amino-6-bromo-2-pyridyl)amino]hexoxy]ethyl]carbamate (700 mg, crude) as a brown oil. ESI [M+H] = 431.1 / 433.1.

[0645] Preparation of compound 6.APRE007-PCT | 106265.000238

[0646] To a solution of tert-butyl N-[2-[6-[(3-amino-6-bromo-2-pyridyl)amino]hexoxy]ethyl]carbamate (700 mg, 1.62 mmol, 1 eq) in MeOH (3 mL) was added sulfamic acid (157.56 mg, 1.62 mmol, 73.25 pL, 1 eq) and 1,1,1 -trimethoxy ethane (584.90 mg, 4.87 mmol, 611.82 pL, 3 eq). The mixture was stirred at 30°C for 1 hr. The reaction mixture was quenched by addition H2O (10 mL), and then extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, fdtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / THF = 50 / 1 to 0 / 1) to give tert-butyl N-[2-[6-(5-bromo-2-methyl-imidazo[4,5-b]pyridin-3-yl)hexoxy] ethyl] carbamate (600 mg, 1.32 mmol, 81.19% yield) as abrown oil. ESI [M+H] = 457.2 / 455.2.

[0647] Preparation of compound 7.

[0648] A mixture of tert-butyl N-[2-[6-(5-bromo-2-methyl-imidazo[4,5-b]pyridin-3-yl)hexoxy] ethyl] carbamate (300 mg, 658.78 pmol, 1 eq), 2-chloro-4-(4, 4, 5, 5 -tetramethyl- 1,3,2-dioxaborolan-2-yl)pyridine (157.78 mg, 658.78 pmol, 1 eq), Pd(dppf)C12 (48.20 mg, 65.88 pmol, 0.1 eq), Na2COs (209.47 mg, 1.98 mmol, 3 eq) in dioxane (4 mL) and H2O (1 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80°C for 1 hr under N2 atmosphere. The reaction mixture was fdtered. The fdtrate was concentrated under reduced pressure to give a residue. The reaction mixture was dissolved in H2O (2 mL), and then extracted with EtOAc (2 mL x 3). The combined organic layers were dried over ISfeSCL, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL, petroleum ether / THF = 50 / 1 to 0 / 1) to give tert-butyl N-[2-[6-[5-(2-chloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]hexoxy]ethyl]carbamate (200 mg, 409.82 pmol, 62.21% yield) as a brown oil. ESI [M+H] = 488.2.

[0649] Preparation of compound 8.APRE007-PCT | 106265.0002387 8

[0650] A solution of tert-butyl N-[2-[6-[5-(2-chloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]hexoxy]ethyl]carbamate (200 mg, 409.82 pmol, 1 eq) in HCl / EtOAc (2 mb, 4M) was stirred at 25°C for 1 hr. The reaction mixture was concentrated under reduced pressure to give 2-[6-[5-(2-chloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]hexoxy]ethanamine (150 mg, crude, HC1 salt) as a white solid. ESI [M+H] = 388.2.

[0651] Preparation of Example 29 product.100°C, 12 hrs8

[0652] A mixture of 2-[6-[5-(2-chloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]hexoxy]ethanamine (100 mg, 257.79 pmol, 1 eq, HC1 salt), RuPhos (12.03 mg, 25.78 pmol, 0.1 eq), Pd2(dba)s (23.61 mg, 25.78 pmol, 0.1 eq) and t-BuONa (74.32 mg, 773.38 pmol, 3 eq) in 2-methylbutan-2-ol (6 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100°C for 12 hrs under N2 atmosphere. The reaction mixture was fdtered. The fdtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: 3_Phenomenex Luna C18 75 x 30 mm x 3 um; mobile phase: [H2O (0.1% TFA)-ACN]; gradient: 5%-35% B over 8.0 min) to give 18-methyl-10-oxa-5,7,17,19,23-pentazatetracyclo[15.5.2.12,6.020,24]pentacosa-l(22),2(25),3,5,18,20,23-heptaene (20 mg, 56.56 pmol, 21.94% yield, 99% purity, TFA salt) as a white solid. ’H NMR (400 MHz, DMSO-d6) 58.25 (s, 1H), 8.23-8.17 (m, 1H), 8.15 (s, 2H), 8.08 (d, J = 6.8 Hz, 1H), 7.64 (dd, J = 1.5, 6.9 Hz, 1H), 4.42 (br t, J = 6.3 Hz, 2H), 3.68 (br d, J = 4.4 Hz, 2H), 3.63-3.59 (m, 2H), 3.43 (br t, J = 5.2 Hz, 2H), 2.69 (s, 3H), 1.88-1.70 (m, 4H), 1.42-1.19 (m, 4H) ESI [M+H] = 352.2.

[0653] Examples 30A, 30B and 30CAPRE007-PCT | 106265.000238Example 30A Example 30C Exmple 30B

[0654] Preparation of compound 2.

[0655] To a solution of 2-[2-(benzyloxycarbonylamino)ethoxy]acetic acid (2 g, 7.90 mmol, 1 eq) and tert-butyl N-(2-hydroxypropyl)carbamate (1.66 g, 9.48 mmol, 1.2 eq) in DCM (20 mb) was added DMAP (192.96 mg, 1.58 mmol, 0.2 eq) and EDCI (1.82 g, 9.48 mmol, 1.2 eq) at 0°C. The mixture was stirred at 25°C for 2 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 0 / 1) to give [2-(tert-butoxycarbonylamino)-l-methyl-ethyl]-2-[2-(benzyloxycarbonylamino)ethoxy]acetate (3.2 g, 7.80 mmol, 98.72% yield) as a yellow oil. ESI [M+H] = 411.2.

[0656] Preparation of compound 3.

[0657] A mixture of [2-(tert-butoxycarbonylamino)-l -methyl -ethyl] 2-[2-(benzyloxycarbonylamino)ethoxy]acetate (3 g, 7.31 mmol, 1 eq), ammonia;borane (563.98 mg, 18.27 mmol, 2.5 eq), TiC’E (2.77 g, 14.62 mmol, 2 eq) in THF (20 mb) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 25 °C for 2 hrs under N2 atmosphere. The reaction mixture was quenched by H2O (20 mb), and then extracted with EtOAc (20 mb x 3). The combined organic layers were washed with brine (20 mb), dried overlS^SCh, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, petroleum ether / ethyl acetate = 50 / 1 to 0 / 1) to give tert-butyl N-[2-[2-[2-(benzyloxycarbonylamino)ethoxy]ethoxy]propyl]carbamate (0.6 g, 1.51 mmol, 20.71%yield) as a colorless oil. ESI [M+H] = 397.2.

[0658] Preparation of compound 4.APRE007-PCT | 106265.000238

[0659] A mixture of tert-butyl N-[2-[2-[2-(benzyloxycarbonylamino)ethoxy]ethoxy]propyl]carbamate (0.6 g, 1.51 mmol, 1 eq), Pd / C (1.61 g, 1.51 mmol, 10% purity, 1 eq) in EtOAc (10 mb) was degassed and purged with H2 for 3 times, and then the mixture was stirred at 25°C for 12 hrs under H2 (50 psi) atmosphere. The reaction mixture was fdtered. The fdtrate was concentrated under reduced pressure to give tert -butyl N-[2-[2-(2-aminoethoxy)ethoxy]propyl]carbamate (380 mg, crude) as a colorless oil. ESI [M+H] = 263.2.

[0660] Preparation of compound 5.

[0661] To a solution of tert-butyl N-[2-[2-(2-aminoethoxy)ethoxy]propyl]carbamate (380 mg, 1.45 mmol, 1 eq) in THF (5 mL) was added TEA (439.71 mg, 4.35 mmol, 604.83 pL, 3 eq) and 6-bromo-2-chloro-3-nitro-pyridine (240.75 mg, 1.01 mmol, 0.7 eq). The mixture was stirred at 25°C for 12 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCE, petroleum ether / ethyl acetate = 50 / 1 to 0 / 1) to give tert-butyl N-[2-[2-[2-[(6-bromo-3-nitro-2-pyridyl)amino]ethoxy]ethoxy]propyl]carbamate (270 mg, 582.75 pmol, 40.23% yield) as a yellow oil. ESI [M+H] = 463.1 / 465.1.

[0662] Preparation of compound 6.

[0663] To a solution of tert-butyl N-[2-[2-[2-[(6-bromo-3-nitro-2-pyridyl)amino]ethoxy]ethoxy]propyl]carbamate (270 mg, 582.75 pmol, 1 eq) in EtOH (2 mL), THF (2 mL) and H2O (1 mL) was added Fe (65.09 mg, 1.17 mmol, 2 eq) and NH4CI (93.52 mg, 1.75 mmol, 3 eq). The mixture was stirred at 80°C for 2 hrs. The reaction mixture was fdtered. The fdtrate was concentrated under reduced pressure to give a residue. The residue was quenched by H2O (2 mL), and then extracted with EtOAc (2 mL x 3). The combined organic layers were dried over Na2SO4, fdtered and concentrated under reduced pressure to give tert-butyl N-[2-[2-[2-[(3-amino-6-APRE007-PCT | 106265.000238bromo-2-pyridyl)amino]ethoxy]ethoxy]propyl]carbamate (230 mg, crude) as a brown oil. ESI [M+H] = 433.1 / 435.1.

[0664] Preparation of compound 7.

[0665] To a solution of tert-butyl N-[2-[2-[2-[(3-amino-6-bromo-2-pyridyl)amino]ethoxy]ethoxy]propyl]carbamate (230 mg, 530.76 pmol, 1 eq) in MeOH (1 mL) was added sulfamic acid (51.53 mg, 530.76 pmol, 23.96 pL, 1 eq) and 1,1,1 -trimethoxy ethane (191.31 mg, 1.59 mmol, 200.11 pL, 3 eq). The mixture was stirred at 30°C for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 0 / 1) to give tert-butyl N-[2-[2-[2-(5-bromo-2-methyl-imidazo[4,5-b]pyridin-3-yl)ethoxy]ethoxy]propyl]carbamate (150 mg, 327.97 pmol, 61.79% yield) as a brown oil. ESI [M+H] = 459.1 / 457.1.

[0666] Preparation of compound 8.

[0667] A mixture of tert-butyl N-[2-[2-[2-(5-bromo-2-methyl-imidazo[4,5-b]pyridin-3-yl)ethoxy]ethoxy]propyl]carbamate (150 mg, 327.97 pmol, 1 eq), 2-chloro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (78.55 mg, 327.97 pmol, 1 eq), Pd(dppf)C12 (24.00 mg, 32.80 pmol, 0.1 eq), Na2COs (104.28 mg, 983.91 pmol, 3 eq) and H2O (1 mL) in dioxane (2 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80°C for 1 hr under N2 atmosphere. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was quenched by addition H2O (2 mL), and then extracted with EtOAc (2 mL x 3). The combined organic layers were dried over ISfeSCL, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL, petroleum ether / THL = 50 / 1 to 0 / 1) to give tert-butyl N-[2-[2-[2-[5-(2-chloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]ethoxy]ethoxy]propyl]carbamate (140 mg, 285.72 pmol, 87.12% yield) as a brown oil. ESI [M+H] = 490.2.

[0668] Preparation of compound 9.APRE007-PCT | 106265.000238

[0669] A solution of tert-butyl N-[2-[2-[2-[5-(2-chloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]ethoxy]ethoxy]propyl]carbamate (140 mg, 285.72 pmol, 1 eq) in HCl / EtOAc (2 mL, 4M) was stirred at 25°C for 1 hr. The reaction mixture was concentrated under reduced pressure to give 2-[2-[2-[5-(2-chloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]ethoxy]ethoxy]propan-l-amine (100 mg, crude, HC1 salt) as a white solid. ESI [M+H] = 390.2.

[0670] Preparation of Example 30A product.xampe

[0671] A mixture of 2-[2-[2-[5-(2-chloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]ethoxy]ethoxy]propan-l -amine (100 mg, 256.49 pmol, 1 eq, HC1 salt), RuPhos (11.97 mg, 25.65 pmol, 0.1 eq), Pd2(dba)s (23.49 mg, 25.65 pmol, 0.1 eq) and t-BuONa (73.95 mg, 769.47 pmol, 3 eq) in 2-methylbutan-2-ol (6 mb) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100°C for 12 hrs under N2 atmosphere. The reaction mixture was fdtered. The fdtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: WePure Biotech XP tC18 150 x 40 x 7 um; mobile phase: [H2O (0.05%NH3H20 + 10 mM NEEHCC^-ACN]; gradient: 15%-45% B over 8.0 min) to give 9,17-dimethyl-10,13-dioxa-5,7,16,18,22-pentazatetracyclo[14.5.2.12,6.019,23]tetracosa-l(22),2(24),3,5,17,19(23),20-heptaene (20 mg, 56.43 pmol, 22.00% yield, -100% purity) as a white solid. 'H NMR (400 MHz, DMSO-d6) 5 8.06 (d, J = 5.3 Hz, 1H), 7.99 (d, J = 8.3 Hz, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.54 (s, 1H), 7.15 (dd, J = 1.2, 5.3 Hz, 1H), 6.75 (t, J = 6.4 Hz, 1H), 4.61-4.32 (m, 2H), 4.01-3.81 (m, 3H), 3.79-3.66 (m, 2H), 3.62-3.49 (m, 2H), 3.41 (br dd, J = 5.0, 14.6 Hz, 1H), 3.07 (td, J = 7.3, 14.5 Hz, 1H), 2.61 (s, 3H), 1.14 (d, J = 6.0 Hz, 3H) ESI [M+H] = 354.2.

[0672] Preparation of Examples 30B and 30C products.APRE007-PCT | 106265.000238Example 30A Example 30C Example 30B

[0673] The racemic material was purified by SFC (column: DAICEL CHIRALPAK AD (250 mm x 30 mm, 10 um); mobile phase: [CCE-MeOH (0.1% NH3H2O)]; B%:35%, isocratic elution mode) to give arbitrarily assigned: (9R)-9,17-dimethyl-10,13-dioxa-5,7,16,18,22-pentazatetracyclo[14.5.2.12,6.019,23]tetracosa-l(22),2(24),3,5,17, 19(23),20-heptaene (Peak 1, retention time = 1.224 min) (4.76 mg, 13.47 pmol, 23.80% yield, 100% purity, ee% = 99.64%) as a white solid and (9S)-9,17-dimethyl-10,13-dioxa-5,7,16,18,22-pentazatetracyclo[14.5.2.12,6.019,23]tetracosa-l(22),2(24),3,5, 17,19(23), 20-heptaene (Peak 2, retention time = 1.317 min) (6.98 mg, 19.75 pmol, 34.90% yield, 100% purity, ee% = 97.12%) as a white solid.

[0674] Example 30C: ’H NMR (400 MHz, DMSO-d6) 58.07 (br d, J = 5.0 Hz, 1H), 7.99 (br d, J= 8.3 Hz, 1H), 7.78 (d, J = 8.1 Hz, 1H), 7.54 (s, 1H), 7.15 (br d, J = 5.1 Hz, 1H), 6.76 (br t, J = 5.7 Hz, 1H), 4.59-4.32 (m, 2H), 4.01-3.81 (m, 3H), 3.80-3.65 (m, 2H), 3.60-3.50 (m, 2H), 3.45-3.42 (m, 1H), 3.07 (td, J = 6.9, 14.2 Hz, 1H), 2.62 (s, 3H), 1.15 (br d, J = 5.8 Hz, 3H). ESI [M+H] = 354.2.

[0675] Example 30B: ’H NMR (400 MHz, DMSO-d6) 58.07 (d, J = 5.3 Hz, 1H), 7.99 (d, J = 8.3 Hz, 1H), 7.79 (d, J = 8.3 Hz, 1H), 7.54 (s, 1H), 7.15 (dd, J = 1.2, 5.3 Hz, 1H), 6.76 (t, J = 6.4 Hz, 1H), 4.58-4.34 (m, 2H), 4.01-3.82 (m, 3H), 3.79-3.66 (m, 2H), 3.62-3.49 (m, 2H), 3.42 (br dd, J = 5.9, 14.3 Hz, 1H), 3.14-3.01 (m, 1H), 2.62 (s, 3H), 1.15 (d, J = 6.0 Hz, 3H). ESI [M+H] = 354.2.

[0676] The absolute stereochemistry labels were randomly assigned.

[0677] Example 31< APRE007-PCT | 106265.000238

[0679] A mixture of 4-bromobutanenitrile (5 g, 33.78 mmol, 1 eq), tert-butyl N-(3-hydroxypropyl)carbamate (5.92 g, 33.78 mmol, 5.78 mb, 1 eq), NaOH (12 M, 27.31 mL, 9.7 eq), TEAB (2.13 g, 10.14 mmol, 1.91 mL, 0.3 eq) in Toluene (50 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100°C for 1 hr under N2 atmosphere. The reaction mixture was quenched by addition H2O (100 mL), and then extracted with EtOAc (100 mL x 3). The combined organic layers were dried over ISfeSCL, filtered and concentrated under reduced pressure to give tert-butyl N- [3 -(3 -cyanopropoxy)propyl] carbamate (3 g, 12.38 mmol, 36.65% yield) as a colourless oil. ESI [M+H] = 243.2.

[0680] Preparation of compound 3.3.5 hrs2 3

[0681] The reaction was performed by flow chemistry. Solution 1: {tert-butyl N-[3-(3-cyanopropoxy)propyl]carbamate (3 g, 12.38 mmol, 1 eq)} in {NHs / MeOH (60 mL)}. The fixed bed (named FLR1, volume 5 mL) was completely packed with granular catalyst 14% Co / AkOs (4 g). The H2 back pressure regulator was adjusted to 2.5 MPa, and the flow rate of H2 was 30 mL / min. Then the solution SI was pumped by Pump 1 {SI, Pl, 0.3 mL / min} to fixed bed {FLR1, SS, fixed bed, 6.350(1 / 4”) mm 1 mL, 80°C}. The solution SI was flowing through {FLR1, 3.3 min} to leave the reactor zone, then the reaction mixture was collected from the reactor output. Stop collecting the reaction mixture after 3.5 hrs. The fixed bed was washed by extra MeOH (300 mL). The organic layer was concentrated to give tert-butyl N-[3-(4-aminobutoxy)propyl]carbamate (2.7 g, 10.96 mmol, 88.53% yield) as a colorless oil. ESI [M+H] = 247.2.

[0682] Preparation of compound 4.

[0683] To a solution of tert-butyl N- [3 -(4 -aminobutoxy jpropyl] carbamate (2.5 g, 10.15 mmol, 1 eq) in THF (20 mL) was added TEA (3.08 g, 30.45 mmol, 4.24 mL, 3 eq) and 6-bromo-2-chloro-3 -nitro-pyridine (1.33 g, 5.58 mmol, 0.55 eq). The mixture was stirred at 25°C for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, petroleum ether / ethyl acetate = 50 / 1 to 0 / 1) to give tert-butyl N-[3-APRE007-PCT | 106265.000238|4-|(6-bromo-3-nitro-2-pyridyl)amino|butoxy Ipropyl |carbamatc (1.5 g, 3.35 mmol, 33.04% yield) as a yellow oil. ESI [M+H] = 447.1 / 449.1.

[0684] Preparation of compound 5.4 5

[0685] To a solution of tert-butyl N-[3-[4-[(6-bromo-3-nitro-2-pyridyl)amino]butoxy]propyl]carbamate (1.5 g, 3.35 mmol, 1 eq) in EtOH (10 mL), THF (10 mL) and H2O (4 mL) was added Fe (374.53 mg, 6.71 mmol, 2 eq) and NH4CI (538.11 mg, 10.06 mmol, 3 eq). The mixture was stirred at 80°C for 2 hrs. The reaction mixture was quenched by H2O (10 mL), and then extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na2SC>4, fdtered and concentrated under reduced pressure to give tert-butyl N-[3-[4-[(3-amino-6-bromo-2-pyridyl) amino]butoxy]propyl]carbamate (1.4 g, crude) as ayellow oil. ESI [M+H] = 417.1 / 419.1.

[0686] Preparation of compound 6., , 5 6

[0687] To a solution of tert-butyl N-[3-[4-[(3-amino-6-bromo-2-pyridyl)amino]butoxy]propyl]carbamate (1.4 g, 3.35 mmol, 1 eq) in MeOH (5 mL) was added sulfamic acid (325.71 mg, 3.35 mmol, 151.42 pL, 1 eq) and 1,1,1 -trimethoxy ethane (1.21 g, 10.06 mmol, 1.26 mL, 3 eq). The mixture was stirred at 30°C for 1 hr. The reaction mixture was quenched by addition H2O (10 mL), and then extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na2SO4, fdtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / THF = 50 / 1 to 0 / 1) to give tert-butyl N-[3-[4-(5-bromo-2-methyl-imidazo[4,5-b]pyridin-3-yl)butoxy]propyl]carbamate (1.2 g, 2.72 mmol, 81.05%yield) as abrown oil. ESI [M+H] = 441.1 / 443.1.

[0688] Preparation of compound 7.APRE007-PCT | 106265.000238

[0689] A mixture of tert-butyl N-[3-[4-(5-bromo-2-methyl-imidazo[4,5-b]pyridin-3-yl)butoxy]propyl]carbamate (300 mg, 679.72 pmol, 1 eq), 2-chloro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (162.80 mg, 679.72 pmol, 1 eq), Pd(dppf)Ch (49.74 mg, 67.97 pmol, 0.1 eq), Na2COs (216.13 mg, 2.04 mmol, 3 eq) in dioxane (5 mL) and H2O (3 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80°C for 1 hr under N2 atmosphere. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was dissolved in H2O (5 mL), and then extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (3 mL), dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, petroleum ether / THF = 50 / 1 to 0 / 1) to give tert-butyl N-[3-[4-[5-(2-chloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]butoxy]propyl]carbamate (220 mg, 464.14 pmol, 68.28% yield) as a brown oil. ESI [M+H] = 474.2.

[0690] Preparation of compound 8.

[0691] A solution of tert-butyl N-[3-[4-[5-(2-chloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]butoxy]propyl]carbamate (220 mg, 464.14 pmol, 1 eq) in HCl / EtOAc (2 mL, 4M) was stirred at 25°C for 1 hr. The reaction mixture was concentrated under reduced pressure to give 3-[4-[5-(2-chloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]butoxy]propan-l-amine (150 mg, crude, HC1 salt) as a brown oil. ESI [M+H] = 374.2.

[0692] Preparation of Example 31 product.APRE007-PCT | 106265.000238

[0693] A mixture of 3-[4-[5-(2-chloro-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]butoxy]propan-l -amine (100 mg, 267.47 pmol, 1 eq, HC1 salt), t-BuONa (77.11 mg, 802.40 pmol, 3 eq), RuPhos (12.48 mg, 26.75 pmol, 0.1 eq) and Pd2(dba)s (24.49 mg, 26.75 pmol, 0.1 eq) in 2-methylbutan-2-ol (6 mb) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100°C for 12 hrs under N2 atmosphere. The reaction mixture was fdtered. The fdtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: 3_Phenomenex Luna C18 75 x 30 mm x 3 um; mobile phase: [H2O (0.1% TFA)-ACN]; gradient: l%-30% B over 8.0 min) to give 17-methyl-ll-oxa-5,7,16,18,22-pentazatetracyclo[14.5.2.12,6.019,23]tetracosa-l(21),2(24),3,5,17,19,22-heptaene (64.15 mg, 141.30 pmol, 52.83% yield, 99% purity, TFA salt) as a white solid. ’H NMR (400 MHz, DMSO-d6) 58.42-8.30 (m, 1H), 8.17-8.10 (m, 2H), 8.04 (d, J = 8.4 Hz, 1H), 7.95 (s, 1H), 7.62-7.54 (m, 1H), 4.29-4.21 (m, 2H), 3.62-3.59 (m, 2H), 3.55 (br dd, J = 1.8, 3.5 Hz, 2H), 3.51-3.47 (m, 2H), 2.68 (s, 3H), 2.22 (quin, J = 7.3 Hz, 2H), 1.87-1.67 (m, 4H) ESI [M+H] = 338.2.

[0694] Example 32

[0695] Preparation of compound 2.

[0696] To a solution of tert-butyl N-(2-hydroxyethyl)carbamate (24.87 g, 154.29 mmol, 23.87 m , 1 eq) and 5 -bromopentanenitrile (25 g, 154.29 mmol, 1 eq) in Toluene (300 m ) was added TEAB (9.73 g, 46.29 mmol, 8.72 mb, 0.3 eq) and NaOH (12 M, 124.72 mb, 9.7 eq). The mixture was stirred at 100°C for 1 hr. The reaction mixture was quenched by H2O (200 mb), and thenAPRE007-PCT | 106265.000238extracted with EtOAc (200 mL x 3). The combined organic layers were dried over Na2SC>4, filtered and concentrated under reduced pressure to give tert-butyl N-[2-(4-cyanobutoxy)ethyl]carbamate (30 g, crude) as a colourless oil. ESI [M+H] = 243.2.

[0697] Preparation of compound 3.>2 3.5 hrs3

[0698] The reaction was performed by flow chemistry. Solution 1: {tert-butyl N-[2-(4-cyanobutoxy)ethyl] carbamate (8 g, 33.02 mmol, 1 eq)} in {NHs / MeOH (160 mL)}. The fixed bed (named FLR1, volume 5 mL) was completely packed with granular catalyst 14% Co / AhOs (4 g). The H2 back pressure regulator was adjusted to 2.5 MPa, and the flow rate of H2 was 30 mL / min. Then the solution SI was pumped by Pump 1 {SI, Pl, 0.8 mL / min} to fixed bed {FLR1, SS, fixed bed, 6.350(1 / 4”) mm 1 mL, 80°C}. The solution SI was flowing through {FLR1, 3.3 min} to leave the reactor zone, then the reaction mixture was collected from the reactor output. Stop collecting the reaction mixture after 3.5 hrs. The fixed bed was washed by extra MeOH (300 mL). The organic layer was concentrated to give tert-butyl N-[2-(5-aminopentoxy)ethyl]carbamate (7 g, crude) as a colorless oil. ESI [M+H] = 247.2.

[0699] Preparation of compound 4.

[0700] To a solution of tert-butyl N-[2-(5-aminopentoxy)ethyl]carbamate (3 g, 12.18 mmol, 1 eq) in THF (40 mL) was added TEA (3.70 g, 36.53 mmol, 5.09 mL, 3 eq) and 6-bromo-2-chloro-3 -nitro-pyridine (1.73 g, 7.31 mmol, 0.6 eq). The mixture was stirred at 25°C for 12 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, petroleum ether / ethyl acetate = 50 / 1 to 0 / 1) to give tert-butyl N-[2-[5-[(6-bromo-3-nitro-2-pyridyl)amino]pentoxy]ethyl]carbamate (3.5 g, 7.82 mmol, 64.25% yield) as a yellow oil. ESI [M+H] = 447.1 / 449.1.

[0701] Preparation of compound 5.APRE007-PCT | 106265.000238

[0702] To a solution of tert-butyl N-[2-[5-[(6-bromo-3-nitro-2-pyridyl)amino]pentoxy]ethyl]carbamate (3.5 g, 7.82 mmol, 1 eq) in THF (10 mb), EtOH (10 m ) and H2O (4 mL) was added Fe (873.90 mg, 15.65 mmol, 2 eq) and NH4CI (1.26 g, 23.47 mmol, 3 eq). The mixture was stirred at 80°C for 2 hrs. The reaction mixture was quenched by H2O (50 mL), and then extracted with EtOAc (100 mL x 3). The combined organic layers were dried over Na2SO4, fdtered and concentrated under reduced pressure to give tert-butyl N-[2-[5-[(3-amino-6-bromo-2-pyridyl)amino]pentoxy]ethyl]carbamate (2.8 g, crude) as a brown oil. ESI [M+H] = 417.1 / 419.1.

[0703] Preparation of compound 6.

[0704] To a solution of tert-butyl N-[2-[5-[(3-amino-6-bromo-2-pyridyl)amino]pentoxy]ethyl]carbamate (2.8 g, 6.71 mmol, 1 eq) and methyl 2,2,2 -trimethoxyacetate (3.30 g, 20.13 mmol, 3 eq) in MeOH (10 mL) was added sulfamic acid (651.39 mg, 6.71 mmol, 302.83 pL, 1 eq). The mixture was stirred at 30°C for 1 hr. The reaction mixture was quenched by addition H2O (20 mL), and then extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na2SO4, fdtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 (250 x 70 mm, 15 um); mobile phase: [H2O (0.1%TFA)-ACN]; gradient: 45%-75% B over 20.0 min) to give methyl 5-bromo-3-[5-[2-(tert-butoxycarbonylamino)ethoxy]pentyl]imidazo[4,5-b]pyridine-2 -carboxylate (0.8 g, 1.65 mmol, 24.57% yield, TFA salt) as a brown solid. ESI [M+H] = 485.1 / 487.1.

[0705] Preparation of compound 7.APRE007-PCT | 106265.000238

[0706] To a solution of methyl 5-bromo-3-[5-[2-(tert-butoxycarbonylamino)ethoxy]pentyl]imidazo[4,5-b]pyridine-2 -carboxylate (500 mg, 1.03 mmol, 1 eq) in MeOH (10 mb) was added NaBEL (77.94 mg, 2.06 mmol, 2 eq) at 0°C. The mixture was stirred at 25 °C for 12 hrs under N2 atmosphere. The reaction mixture was quenched by addition H2O (10 mL) at 0°C, and extracted with EtOAc (20 mb x 3). The combined organic layers were dried over Na2SC>4, fdtered and concentrated under reduced pressure to give tert-butyl N-[2-[5-[5-bromo-2-(hydroxymethyl)imidazo[4,5-b]pyridin-3-yl]pentoxy]ethyl]carbamate (450 mg, crude) as a white solid. ESI [M+H] = 459.1 / 457.1.

[0707] Preparation of compound 8.

[0708] A mixture of tert-butyl N-[2-[5-[5-bromo-2-(hydroxymethyl)imidazo[4,5-b]pyridin-3-yl]pentoxy]ethyl]carbamate (450 mg, 983.91 pmol, 1 eq), 2-chloro-4-(4, 4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (235.65 mg, 983.91 pmol, 1 eq), ISfeCCE (312.85 mg, 2.95 mmol, 3 eq), Pd(dppf)C12 (71.99 mg, 98.39 pmol, 0.1 eq) and H2O (2 mL) in dioxane (5 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80°C for 1 hr under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue, the residue was quenched by addition H2O (5 mL), and then extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / THL = 50 / 1 to 0 / 1) to give tert-butyl N-[2-[5-[5-(2-chloro-4-pyridyl)-2-(hydroxymethyl)imidazo[4,5-b]pyridin-3-yl]pentoxy]ethyl]carbamate (400 mg, 816.34 pmol, 82.97% yield) as a brown oil. ESI [M+H] = 490.2.

[0709] Preparation of compound 9.APRE007-PCT | 106265.0002388 9

[0710] A solution of tert-butyl N-[2-[5-[5-(2-chloro-4-pyridyl)-2-(hydroxymethyl)imidazo [4,5-b]pyridin-3-yl]pentoxy]ethyl]carbamate (400 mg, 816.34 pmol, 1 eq) in HCl / EtOAc (5 mb, 4M) was stirred at 25 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give [3 -[5 -(2-aminoethoxy)pentyl] -5 -(2-chloro-4-pyridyl)imidazo [4,5 -b]pyridin-2-yl]methanol (300 mg, crude, HC1 salt) as a yellow solid. ESI [M+H] = 390.2.

[0711] Preparation of Example 32 product.9

[0712] A mixture of [3-[5-(2-aminoethoxy)pentyl]-5-(2-chloro-4-pyridyl)imidazo[4,5-b]pyridin-2-yl]methanol (60 mg, 153.89 pmol, 1 eq, HC1 salt), RuPhos (7.18 mg, 15.39 pmol, 0.1 eq), Pd2(dba)s (14.09 mg, 15.39 pmol, 0.1 eq) and K2CO3 (63.81 mg, 461.68 pmol, 3 eq) in 2-methylbutan-2-ol (6 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100°C for 12 hrs under N2 atmosphere. The reaction mixture was fdtered. The fdtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 100 x 40 mm x 5 urn; mobile phase: [H2O (0.04% HC1)-ACN]; gradient: l%-40% B over 8.0 min) to give 10-oxa-5,7, 16, 18, 22 -pentazatetracyclo [14.5.2.12,6.019,23]tetracosa-l(21),2(24),3,5,17,19,22-heptaen-17-ylmethanol (2 mg, 4.91 pmol, 3.19% yield, 96% purity, HC1 salt) as a yellow solid. ’HNMR (400 MHz, DMSO-d6) 58.31 (br s, 1H), 8.24 (d, J = 8.4 Hz, 1H), 8.16 (d, J = 6.8 Hz, 1H), 8.13-8.07 (m, 2H), 7.61 (br d, J = 6.8 Hz, 1H), 4.85 (s, 2H), 4.38 (br t, J = 6.9 Hz, 2H), 3.65 (br s, 2H), 3.60 (br s, 2H), 3.53 (br s, 2H), 2.04-1.95 (m, 2H), 1.79-1.72 (m, 2H), 1.69-1.62 (m, 2H) ESI [M+H] = 354.2.

[0713] Example 33APRE007-PCT | 106265.000238

[0714] Preparation of compound 2A.2, 80 °C, 12 hrs

[0715] A mixture of 6-chloropyridine-2 -carbonitrile (2 g, 14.43 mmol, 1 eq), HBPin (4.62 g, 36.09 mmol, 5.24 mL, 2.5 eq), chloroiridium;(lZ,5Z)-cycloocta-l,5-diene (969.59 mg, 1.44 mmol, 0.1 eq), 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine (387.43 mg, 1.44 mmol, 0.1 eq) in cyclohexane (30 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80°C for 12 hrs under N2 atmosphere. The reaction mixture was fdtered. The fdtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 (250 x 70 mm, 15 um); mobile phase: [H2O (0.1% TFA)-ACN]; gradient: 15%-45% B over 20.0 min) to give (2-chloro-6-cyano-4-pyridyl)boronic acid (0.4 g, 2.19 mmol, 15.19% yield) as a yellow solid. ESI [M+H] = 183.0.

[0716] Preparation of compound 2.>

[0717] To a solution of tert-butyl N-(2-hydroxyethyl)carbamate (24.87 g, 154.29 mmol, 23.87 mb, 1 eq) and 5 -bromopentanenitrile (25 g, 154.29 mmol, 1 eq) in Toluene (300 mb) was added TEAB (9.73 g, 46.29 mmol, 8.72 mb, 0.3 eq) and NaOH (12 M, 124.72 mb, 9.7 eq). The mixture was stirred at 100°C for 1 hr. The reaction mixture was quenched by addition H2O (200 mb), and then extracted with EtOAc (200 mL x 3). The combined organic layers were dried over ISfeSCE, fdtered and concentrated under reduced pressure to give tert-butyl N-[2-(4-cyanobutoxy)ethyl] carbamate (30 g, crude) as a colourless oil. ESI [M+H] = 243.2.APRE007-PCT | 106265.000238

[0718] Preparation of compound 3.3.5 hrs2 3

[0719] The reaction was performed by flow chemistry. Solution 1: {tert-butyl N-[2-(4-cyanobutoxy)ethyl] carbamate (20 g, 82.54 mmol, 1 eq)} in {NHs / MeOH (600 mL)}. The fixed bed (named FLR1, volume 5 mL) was completely packed with granular catalyst 14% Co / AkOs (4 g). The H2 back pressure regulator was adjusted to 2.5 MPa, and the flow rate of TL was 30 mL / min. Then the solution SI was pumped by Pump 1 {SI, Pl, 3 mL / min} to fixed bed {FLR1, SS, fixed bed, 6.350(1 / 4”) mm, 1 mL, 80°C}. The solution SI was flowing through {FLR1, 3.3 min} to leave the reactor zone, then the reaction mixture was collected from the reactor output. Stop collecting the reaction mixture after 3.5 hrs. The fixed bed was washed by extra MeOH (300 mL). The organic layer was concentrated to give tert-butyl N-[2-(5-aminopentoxy)ethyl]carbamate (11 g, crude) as a colorless oil. ESI [M+H] = 247.2.

[0720] Preparation of compound 4.3 4

[0721] To a solution of tert-butyl N-[2-(5-aminopentoxy)ethyl]carbamate (11.00 g, 44.65 mmol, 1 eq) in THF (200 mL) was added TEA (13.56 g, 133.96 mmol, 18.65 mL, 3 eq) and 6-bromo-2 -chloro-3 -nitro-pyridine (7.42 g, 31.26 mmol, 0.7 eq). The mixture was stirred at 25°C for 12 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL, petroleum ether / ethyl acetate = 50 / 1 to 0 / 1) to give tertbutyl N-[2-[5-[(6-bromo-3-nitro-2-pyridyl)amino]pentoxy]ethyl]carbamate (12 g, 26.83 mmol, 60.08% yield) as a yellow oil. ESI [M+H] = 447.2 / 449.2.

[0722] Preparation of compound 5.APRE007-PCT | 106265.0002384 5

[0723] To a solution of tert-butyl N-[2-[5-[(6-bromo-3-nitro-2-pyridyl)amino]pentoxy]ethyl]carbamate (3 g, 6.71 mmol, 1 eq) in THF (10 mb), EtOH (10 m ) and H2O (3 mL) was added Fe (749.06 mg, 13.41 mmol, 2 eq) and NH4CI (1.08 g, 20.12 mmol, 3 eq). The mixture was stirred at 80°C for 2 hrs. The reaction mixture was quenched by addition H2O (10 mL), and then extracted with EtOAc (20 mL x 3). The combined organic layers were dried over ISfeSCE, fdtered and concentrated under reduced pressure to give tert-butyl N-[2-[5-[(3-amino-6-bromo-2-pyridyl)amino]pentoxy]ethyl]carbamate (2.8 g, crude) as a brown oil. ESI [M+H] = 417.2 / 419.2.

[0724] Preparation of compound 6.5 6

[0725] To a solution of tert-butyl N-[2-[5-[(3-amino-6-bromo-2-pyridyl)amino]pentoxy]ethyl]carbamate (2.8 g, 6.71 mmol, 1 eq) in MeOH (10 mL) was added sulfamic acid (651.42 mg, 6.71 mmol, 302.84 pL, 1 eq) and 1,1,1 -trimethoxy ethane (2.42 g, 20.13 mmol, 2.53 mL, 3 eq). The mixture was stirred at 30°C for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, petroleum ether / ethyl acetate = 50 / 1 to 0 / 1) to give tert-butyl N-[2-[5-(5-bromo-2-methyl-imidazo[4,5-b]pyridin-3-yl)pentoxy]ethyl]carbamate (1.8 g, 4.08 mmol, 60.79% yield) as a yellow oil. ESI [M+H] = 441.2 / 443.2.

[0726] Preparation of compound 7.APRE007-PCT | 106265.000238

[0727] A mixture of tert-butyl N-[2-[5-(5-bromo-2-methyl-imidazo[4,5-b]pyridin-3-yl)pentoxy] ethyl] carbamate (300 mg, 679.72 pmol, 1 eq), (2-chloro-6-cyano-4-pyridyl)boronic acid (123.96 mg, 679.72 pmol, 1 eq), ISfeCOs (216.13 mg, 2.04 mmol, 3 eq), Pd(dppf)C12 (49.74 mg, 67.97 pmol, 0.1 eq) in dioxane (4 mb) and H2O (1 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80°C for 1 hr under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue, the reaction mixture was dissolved in H2O (2 mL), and then extracted with EtOAc (5 mL x 2). The combined organic layers were dried over ISfeSCL, fdtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, petroleum ether / THF = 50 / 1 to 0 / 1) to give tert-butyl N-[2-[5-[5-(2-chloro-6-cyano-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]pentoxy]ethyl]carbamate (200 mg, 400.80 pmol, 58.97% yield) as a brown oil. ESI [M+H] = 499.2.

[0728] Preparation of compound 8.

[0729] A solution of tert-butyl N-[2-[5-[5-(2-chloro-6-cyano-4-pyridyl)-2-methyl-imidazo[4,5-b]pyridin-3-yl]pentoxy]ethyl]carbamate (200 mg, 400.80 pmol, 1 eq) in HCl / EtOAc (2 mL, 4M) was stirred at 25 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give 4 - [3 -[5 -(2 -aminoethoxy )pentyl] -2 -methyl -imidazo [4,5 -b]pyridin-5 -yl] -6-chloro-pyridine-2-carbonitrile (160 mg, crude, HC1 salt) as a white solid. ESI [M+H] = 399.2.

[0730] Preparation of Example 33 product.APRE007-PCT | 106265.000238

[0731] A mixture of 4-[3-[5-(2-aminoethoxy)pentyl]-2-methyl-imidazo[4,5-b]pyridin-5-yl]-6-chloro-pyridine-2-carbonitrile (40 mg, 100.28 pmol, 1 eq, HC1 salt), RuPhos (4.68 mg, 10.03 pmol, 0.1 eq), Pd2(dba)s (9.18 mg, 10.03 pmol, 0.1 eq) and K2CO3 (13.86 mg, 100.28 pmol, 1 eq) in 2-methylbutan-2-ol (6 mb) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100°C for 12 hrs under N2 atmosphere. The reaction mixture was fdtered. The fdtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: WePure Biotech XP tC18 150 x 40 x 7 um; mobile phase: [H2O (0.05%NH3H20 + 10 mM NHJICC^-ACN]; gradient: 25%-55% B over 8.0 min) to give 17-methyl-10-oxa-5,7, 16, 18,22-pentazatetracyclo[14.5.2.12,6.019,23]tetracosa-l(21),2(24),3,5, 17,19,22-heptaene-4-carbonitrile (1.64 mg, 4.50 pmol, 4.49% yield, 99% purity) as a white solid. ’H NMR (400 MHz, DMSO-d6) 5 8.08 (d, J = 8.3 Hz, 1H), 7.97 (d, J = 8.3 Hz, 1H), 7.87 (s, 2H), 7.36 (brt, J = 5.9 Hz, 1H), 4.30 (br t, J = 7.1 Hz, 2H), 3.59-3.53 (m, 4H), 3.51-3.46 (m, 2H), 2.68 (s, 3H), 1.97 (quin, J = 6.9 Hz, 2H), 1.81 (quin, J = 6.5 Hz, 2H), 1.67 (q, J = 6.7 Hz, 2H) ESI [M+H] = 363.2

[0732] Example 34

[0733] Preparation of compound 2.APRE007-PCT | 106265.000238

[0734] A mixture of ethynyl(triisopropyl)silane (2 g, 10.97 mmol, 2.46 mL, 1 eq), 2,6-dichloro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (3.00 g, 10.97 mmol, 1 eq), Cui (208.85 mg, 1.10 mmol, 0.1 eq), TEA (3.33 g, 32.90 mmol, 4.58 mL, 3 eq) and Pd(PPh3)2Cl2(769.72 mg, 1.10 mmol, 0.1 eq) in DMF (40 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 80°C for 4 hrs under N2atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column:Phenomenex luna C18 (250 x 70 mm, 15 um); mobile phase: [H2O (0.1% TFA)-ACN]; gradient: 70%-100% B over 20.0 min) to give [2-chloro-6-(2-triisopropylsilylethynyl)-4-pyridyl]boronic acid (0.8 g, 2.37 mmol, 21.60% yield) as a colourless oil. ESI [M+H] = 338.1.

[0735] Preparation of compound 3.

[0736] A mixture of [2-chloro-6-(2-triisopropylsilylethynyl)-4-pyridyl]boronic acid (400 mg, 1.18 mmol, 1 eq), tert-butyl N-[2-[5-(5-bromo-2-methyl-imidazo[4,5-b]pyridin-3-yl)pentoxy] ethyl] carbamate (522.75 mg, 1.18 mmol, 1 eq), Na2CO3(376.60 mg, 3.55 mmol, 3 eq), Pd(dppf)Cl2(86.66 mg, 118.44 pmol, 0.1 eq) in dioxane (10 mL) and H2O (3 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 80°C for 1 hr under N2atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue, the reaction mixture was dissolved in H2O (20 mL), and then extracted with EtOAc (40 mL x 2). The combined organic layers were dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / THF = 50 / 1 to 0 / 1) to give tert-butyl N-[2-[5-[5-[2-chloro-6-(2-triisopropylsilylethynyl)-4-pyridyl]-2-methyl-imidazo[4,5-b]pyridin-3-yl]pentoxy]ethyl]carbamate (500 mg, 764.11 pmol, 64.51% yield) as a brown oil. ESI [M+H] = 654.4.

[0737] Preparation of compound 4.APRE007-PCT | 106265.000238

[0738] A solution of tert-butyl N-[2-[5-[5-[2-chloro-6-(2-triisopropylsilylethynyl)-4-pyridyl]-2-methyl-imidazo[4,5-b]pyridin-3-yl]pentoxy]ethyl]carbamate (500 mg, 764.11 pmol, 1 eq) in HCI / EtOAc (5 mL, 4M) was stirred at 25 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give 2-[5-[5-[2-chloro-6-(2-triisopropylsilylethynyl)-4-pyridyl]-2-methyl-imidazo[4,5-b]pyridin-3-yl]pentoxy]ethanamine (380 mg, crude, HC1 salt) as a yellow oil. ESI [M+H] = 554.4.

[0739] Preparation of compound 5.

[0740] A mixture of 2-[5-[5-[2-chloro-6-(2-triisopropylsilylethynyl)-4-pyridyl]-2-methyl-imidazo[4,5-b]pyridin-3-yl]pentoxy]ethanamine (75 mg, 135.32 pmol, 1 eq, HC1 salt), RuPhos (6.31 mg, 13.53 pmol, 0.1 eq), Pd2(dba)s (12.39 mg, 13.53 pmol, 0.1 eq) and K2CO3 (56.11 mg, 405.96 pmol, 3 eq) in 2-methylbutan-2-ol (6 mb) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100°C for 12 hrs under N2 atmosphere. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give triisopropyl-[2-(17-methyl-10-oxa-5,7,16,18,22-pentazatetracyclo[14.5.2.12,6.019,23]tetracosa-l(21),2(24),3,5,17,19, 22-heptaen-4-yl)ethynyl] silane (70 mg, crude) as a yellow oil. ESI [M+H] = 518.3.

[0741] Preparation of Example 34 product.APRE007-PCT | 106265.000238

[0742] To a solution of triisopropyl-[2-(17-methyl-10-oxa-5,7,16,18,22-pentazatetracyclo [14.5.2.12,6.019,23]tetracosa-l(21),2(24),3,5,17,19,22-heptaen-4-yl)ethynyl]silane (20 mg, 38.63 pmol, 1 eq) in DMF (1 mL) was added CsF (58.67 mg, 386.27 pmol, 10 eq). The mixture was stirred at 25°C for 1 hr. The reaction mixture was fdtered. The fdtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 80 x 30 mm x 3 um; mobile phase: [FLO (0.1%TFA)-ACN]; gradient: 5 %-35% B over 8.0 min) to give 4-ethynyl-17-methyl-10-oxa-5,7,16,18,22-pentazatetracyclo[14.5.2.12,6.019,23]tetracosa-l(21),2(24),3,5,17,19,22-heptaene (1.07 mg, 2.25 pmol, 5.83% yield, 100% purity, TFA salt) as a white solid. ’H NMR (400 MHz, DMSO-d6) 58.10 (d, J = 8.3 Hz, 1H), 7.98 (d, J = 8.4 Hz, 1H), 7.62 (s, 1H), 7.45 (s, 1H), 7.11-6.90 (m, 1H), 4.37-4.23 (m, 3H), 3.52 (br s, 6H), 2.71-2.66 (m, 3H), 1.93 (quin, J = 7.1 Hz, 2H), 1.75 (quin, J = 6.6 Hz, 2H), 1.65-1.56 (m, 2H) ESI [M+H] = 362.2.

[0743] Example 35

[0745] To a solution of tert-butyl N-[2-[5-[(3-amino-6-bromo-2-pyridyl)amino]pentoxy]ethyl]carbamate (1.8 g, 4.31 mmol, 1 eq) in MeOH (10 mL) was addedAPRE007-PCT | 106265.000238sulfamic acid (418.77 mg, 4.31 mmol, 194.69 pL, 1 eq) and trimethoxymethane (1.37 g, 12.94 mmol, 1.42 mL, 3 eq). The mixture was stirred at 30°C for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, petroleum ether / ethyl acetate = 50 / 1 to 0 / 1) to give tert-butyl N-[2-[5-(5-bromoimidazo[4,5-b]pyridin-3 -yl)pentoxy] ethyl] carbamate (1.5 g, 3.51 mmol, 81.38% yield) as ayellow oil. ESI [M+H] = 427.1 / 429.1.

[0746] Preparation of compound 3B.

[0747] A mixture of tert-butyl N-[2-[5-(5-bromoimidazo[4,5-b]pyridin-3-yl)pentoxy] ethyl] carbamate (300 mg, 702.03 pmol, 1 eq), 2-chloro-4-(4, 4, 5, 5 -tetramethyl- 1,3,2-dioxaborolan-2-yl)pyridine (168.14 mg, 702.03 pmol, 1 eq), ISfeCOs (223.22 mg, 2.11 mmol, 3 eq), Pd(dppf)C12 (51.37 mg, 70.20 pmol, 0.1 eq) in dioxane (4 mL) and H2O (1 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80°C for 1 hr under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue, the residue was dissolved in H2O (2 mL), and then extracted with EtOAc (5 mL x 2). The combined organic layers were dried over ISfeSCL, fdtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, petroleum ether / THL = 50 / 1 to 0 / 1) to give tert-butyl N-[2-[5-[5-(2-chloro-4-pyridyl)imidazo[4,5-b]pyridin-3-yl]pentoxy]ethyl]carbamate (200 mg, 434.81 pmol, 61.94% yield) as a brown oil. ESI [M+H] = 460.2.

[0748] Preparation of compound 4B

[0749] A solution of tert-butyl N-[2-[5-[5-(2-chloro-4-pyridyl)imidazo[4,5-b]pyridin-3-yl]pentoxy]ethyl]carbamate (200 mg, 434.81 pmol, 1 eq) in HCl / EtOAc (3 mL, 4 M) was stirred at 25°C for 1 hr. The reaction mixture was concentrated under reduced pressure to give 2-[5-[5-(2-APRE007-PCT | 106265.000238chloro-4-pyridyl)imidazo[4,5-b]pyridin-3-yl]pentoxy]ethanamine (150 mg, crude, HC1 salt) as a brown oil. ESI [M+H] = 360.2.

[0750] Preparation of Example 35 product.

[0751] A mixture of 2-[5-[5-(2-chloro-4-pyridyl)imidazo[4,5-b]pyridin-3-yl]pentoxy]ethanamine (75 mg, 189.24 pmol, 1 eq, HC1 salt), t-BuONa (54.56 mg, 567.73 pmol, 3 eq), RuPhos (8.83 mg, 18.92 pmol, 0.1 eq) and Pd2(dba)s (17.33 mg, 18.92 pmol, 0.1 eq) in 2-methylbutan-2-ol (6 m ) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100°C for 12 hrs under N2 atmosphere. The reaction mixture was fdtered. The fdtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: WePure Biotech XP tC18 150 x 40 x 7 um; mobile phase: [H2O (0.05%NH3H20 + 10 mM NH4HCO3)-ACN]; gradient: 25%-55% B over 8.0 min) to give 10-oxa-5,7,16,18,22-pentazatetracyclo [14.5.2.12, 6.019, 23]tetracosa-l(21), 2(24), 3, 5, 17, 19, 22-heptaene (30.21 mg, 88.19 pmol, 46.60% yield, 94% purity) as a white solid. ’H NMR (400 MHz, DMSO-d6) 58.50 (s, 1H), 8.15 (d, J = 8.3 Hz, 1H), 8.08 (d, J = 5.2 Hz, 1H), 7.86 (d, J = 8.5 Hz, 1H), 7.56 (s, 1H), 7.19 (d, J = 5.1 Hz, 1H), 6.62 (brt, J = 6.1 Hz, 1H), 4.32 (brt, J = 7.2 Hz, 2H), 3.54-3.46 (m, 4H), 3.42-3.39 (m, 2H), 2.00 (quin, J = 7.2 Hz, 2H), 1.79-1.59 (m, 4H) ESI [M+H] = 324.2.

[0752] Example 36

[0753] Preparation of compound 2.APRE007-PCT | 106265.000238

[0754] To a solution of tert-butyl N-[2-[5-[(3-amino-6-bromo-2-pyridyl)amino]pentoxy]ethyl]carbamate (1.8 g, 4.31 mmol, 1 eq) in EtOH (20 mb) was added carbononitridic bromide (1.310 g, 12.37 mmol, 907.83 pL, 2.87 eq). The mixture was stirred at 25°C for 12 hrs. The reaction quenched by saturated solution of ISfeCCE (50 mb) at 25 °C. The resulting mixture was stirred at 25°C for 0.5 hr. The mixture was concentrated under reduced pressure at 30°C to remove EtOH, the resulting residue was extracted with DCM (50 mb x 3). The combined organic layers were dried over Na2SO4, fdtered and concentrated under reduced pressure at 30°C. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 0 / 1) to give tert-butyl N-[2-[5-(2-amino-5-bromo-imidazo[4,5-b]pyridin-3-yl)pentoxy]ethyl]carbamate (1.5 g, 3.39 mmol, 78.62% yield) as ablack oil. ESI [M+H] = 442.1 / 444.1.

[0755] Preparation of compound 3.2 3

[0756] A mixture of tert-butyl N-[2-[5-(2-amino-5-bromo-imidazo[4,5-b]pyridin-3-yl)pentoxy] ethyl] carbamate (300 mg, 678.20 pmol, 1 eq), 2-chloro-4-(4, 4, 5, 5 -tetramethyl- 1,3,2-dioxaborolan-2-yl)pyridine (170.55 mg, 712.11 pmol, 1.05 eq), ditert-butyl (cyclopenta- 1,4-dien-l-yl)phosphane;dichloropalladium;iron (44.20 mg, 67.82 pmol, 0.1 eq), K3PO4 (431.87 mg, 2.03 mmol, 3 eq) in THF (8 m ), H2O (2 m ) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80°C for 1 hr under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, petroleum ether / ethyl acetate = 50 / 1 to 5 / 1) to give tert-butyl N-[2-[5-[2-amino-5-(2-chloro-4-pyridyl)imidazo[4,5-b]pyridin-3-yl]pentoxy]ethyl]carbamate (300 mg, 631.60 pmol, 93.13% yield) as a black oil. ESI [M+H] = 475.2.APRE007-PCT | 106265.000238

[0757] Preparation of compound 4.3 4

[0758] A solution of tert-butyl N-[2-[5-[2-amino-5-(2-chloro-4-pyridyl)imidazo[4,5-b]pyridin-3-yl]pentoxy]ethyl]carbamate (200 mg, 421.07 pmol, 1 eq) in HCl / EtOAc (10 mL, 4M) was stirred at 25°C for 1 hr. The reaction mixture was concentrated under reduced pressure to give 3-[5-(2-aminoethoxy)pentyl]-5-(2-chloro-4-pyridyl)imidazo[4,5-b]pyridin-2-amine (150 mg, crude, HC1 salt) as a black solid. ESI [M+H] = 375.1.

[0759] Preparation of Example 36 product.4

[0760] A mixture of 3-[5-(2-aminoethoxy)pentyl]-5-(2-chloro-4-pyridyl)imidazo[4,5-b]pyridin-2-amine (75 mg, 200.07 pmol, 1 eq, HC1 salt), RuPhos (18.67 mg, 40.01 pmol, 0.2 eq), Pd2(dba)s (18.32 mg, 20.01 pmol, 0.1 eq) and t-BuONa (57.68 mg, 600.21 pmol, 3 eq) in 2-methylbutan-2-ol (10 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100°C for 12 hrs under N2 atmosphere. The reaction mixture was fdtered. The fdtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: WePure Biotech XP tC18 150 x 40 x 7 um; mobile phase: [H2O (0.05%NH3H20+10 mM NJTJTCC^-ACN]; gradient: 15%-45% B over 8.0 min) to give 13H-6-oxa-3-aza-l(5,3)-imidazo[4,5-b]pyridina-2(4,2)-pyridinacycloundecaphan-12-amine (20 mg, 59.10 pmol, 29.54% yield, 100% purity) as a white solid. ’H NMR (400 MHz, DMSO- d6) 57.99 (d, J = 5.3 Hz, 1H), 7.57 (d, J = 8.1 Hz, 1H), 7.53-7.48 (m, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.10-7.02 (m, 1H), 7.00-6.94 (m, 2H), 6.47 (t, J = 6.1 Hz, 1H), 4.05 (brt, J = 7.3 Hz, 2H), 3.56-3.47 (m, 4H), 3.41-3.37 (m, 2H), 1.89-1.79 (m, 2H), 1.78-1.70 (m, 2H), 1.62-1.50 (m, 2H). ESI [M+H] = 339.1.

[0761] Example 37APRE007-PCT | 106265.000238

[0763] To a solution of tert-butyl N-[2-[5-[(3-amino-6-bromo-2-pyridyl)amino]pentoxy]ethyl]carbamate (1.7 g, 4.07 mmol, 1 eq) in MeOH (10 mb) was added sulfamic acid (395.50 mg, 4.07 mmol, 183.87 pL, 1 eq) and 1,1,1 -trimethoxypentane (1.98 g, 12.22 mmol, 3 eq). The mixture was stirred at 30°C for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCE, petroleum ether / ethyl acetate = 50 / 1 to 0 / 1) to give tert-butyl N-[2-[5-(5-bromo-2-butyl-imidazo[4,5-b]pyridin-3-yl)pentoxy]ethyl]carbamate (1.6 g, 3.31 mmol, 81.25% yield) as a brown oil. ESI [M+H] = 483.2 / 485.2.

[0764] Preparation of 3 C.

[0765] A mixture of tert-butyl N-[2-[5-(5-bromo-2-butyl-imidazo[4,5-b]pyridin-3-yl)pentoxy] ethyl] carbamate (300 mg, 620.55 pmol, 1 eq), 2 -chloro-4-(4, 4, 5, 5 -tetramethyl- 1,3,2-APRE007-PCT | 106265.000238dioxaborolan-2-yl)pyridine (148.63 mg, 620.55 pmol, 1 eq), Na2COs (197.31 mg, 1.86 mmol, 3 eq), Pd(dppf)C12 (45.41 mg, 62.06 pmol, 0.1 eq) in dioxane (3 mL) and H2O (1 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 1 hr under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue, the residue was dissolved in H2O (2 mL), and then extracted with EtOAc (5 mL x 2). The combined organic layers were dried over Na2SC>4, fdtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, petroleum ether / THF = 50 / 1 to 0 / 1) to give tert-butyl N-[2-[5-[2-butyl-5-(2-chloro-4-pyridyl)imidazo[4,5-b]pyridin-3-yl]pentoxy]ethyl]carbamate (200 mg, 387.54 pmol, 62.45% yield) as a yellow oil. ESI [M+H] = 516.3.

[0766] Preparation of 4C

[0767] A solution of tert-butyl N-[2-[5-[2-butyl-5-(2-chloro-4-pyridyl)imidazo[4,5-b]pyridin-3-yl]pentoxy]ethyl]carbamate (200 mg, 387.54 pmol, 1 eq) in HCl / EtOAc (2 mL, 4 M) was stirred at 25°C for 1 hr. The reaction mixture was concentrated under reduced pressure to give 2-[5-[2-butyl-5-(2-chloro-4-pyridyl)imidazo[4,5-b]pyridin-3-yl]pentoxy]ethanamine (160 mg, crude, HC1 salt) as a brown oil. ESI [M+H] = 416.3.

[0768] Preparation of Example 37 product.Buchwald t-BuoNa, RuPhos, Pd2(dba)3, t-AmylOH 100°C, 12 hrs

[0769] A mixture of 2-[5-[2-butyl-5-(2-chloro-4-pyridyl)imidazo[4,5-b]pyridin-3-yl]pentoxy]ethanamine (75 mg, 180.31 pmol, 1 eq, HC1 salt), t-BuONa (51.98 mg, 540.92 pmol, 3 eq), RuPhos (8.41 mg, 18.03 pmol, 0.1 eq) and Pd2(dba)s (16.51 mg, 18.03 pmol, 0.1 eq) in 2-methylbutan-2-ol (6 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100°C for 12 hrs under N2 atmosphere. The reaction mixture was fdtered. The fdtrate wasAPRE007-PCT | 106265.000238concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 80 x 30 mm x 3 um; mobile phase: [H2O (0.1% TFA)-ACN]; gradient: 10%-40% B over 8.0 min) to give 17-butyl-10-oxa-5,7, 16, 18,22-pentazatetracyclo[14.5.2.12,6.019,23]tetracosa-l(21),2(24),3,5,17,19,22-heptaene (42.42 mg, 84.97 pmol, 47.12% yield, 99% purity, TFA salt) as a white solid. ’H NMR (400 MHz, DMSO-d6) 58.40 (br s, 1H), 8.19-8.12 (m, 2H), 8.09-8.02 (m, 2H), 7.60 (dd, J = 1.4, 6.8 Hz, 1H), 4.29 (br t, J = 7.1 Hz, 2H), 3.67-3.57 (m, 4H), 3.53 (t, J = 6.3 Hz, 2H), 2.99 (t, J = 7.6 Hz, 2H), 1.93 (quin, J = 7.1 Hz, 2H), 1.85-1.70 (m, 4H), 1.69-1.60 (m, 2H), 1.45 (sxt, J = 7.4 Hz, 2H), 0.96 (t, J = 7.4 Hz, 3H) ESI [M+H] = 380.2

[0770] Example 38

[0772] To a solution of tert-butyl N-(2-hydroxyethyl)carbamate (4.97 g, 30.86 mmol, 4.77 m , 1 eq) and 5 -bromopentanenitrile (5 g, 30.86 mmol, 1 eq) in Toluene (70 m ) was added TEAB (1.95 g, 9.26 mmol, 1.74 mb, 0.3 eq) and NaOH (12 M, 24.94 mb, 9.7 eq). The mixture was stirred at 100°C for 1 hr. The reaction mixture was quenched by addition H2O (20 mb), and then extracted with EtOAc (20 mb x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give tert-butyl N-[2-(4-cyanobutoxy)ethyl]carbamate (3 g, crude) as a colorless oil. ESI [M+H] = 243.2.

[0773] Preparation of compound 3.3.5 hrs2 3

[0774] The reaction was performed by flow chemistry. Solution 1: {tert-butyl N-[2-(4-cyanobutoxy)ethyl] carbamate (2.5 g, 10.32 mmol, 1 eq)} in {NHJMcOH (60 mb)}. The fixed bed (named FERI, volume 5 mb) was completely packed with granular catalyst 14% Co / ALOs (4 g). TheAPRE007-PCT | 106265.000238H2 back pressure regulator was adjusted to 2.5 MPa, and the flow rate of H2 was 30 mL / min. Then the solution SI was pumped by Pump 1 {SI, Pl, 0.3 mL / min} to fixed bed {FLR1, SS, fixed bed, 6.350(1 / 4”) mm, 1 mL, 80°C}. The solution SI was flowing through {FLR1, 3.3 min} to leave the reactor zone, then the reaction mixture was collected from the reactor output. Stop collecting the reaction mixture after 3.5 hrs. The fixed bed was washed by extra MeOH (300 mL). The organic layer was concentrated to give tert-butyl N-[2-(5-aminopentoxy)ethyl]carbamate (2.5 g, crude) as a colorless oil. ESI [M+H] = 247.2.

[0775] Preparation of compound 4.

[0776] To a solution of tert-butyl N-[2-(5-aminopentoxy)ethyl]carbamate (2.5 g, 10.15 mmol, 1 eq) in THF (20 mL) was added TEA (3.08 g, 30.45 mmol, 4.24 mL, 3 eq) and 6-bromo-2-chloro-3 -nitro-pyridine (1.69 g, 7.10 mmol, 0.7 eq). The mixture was stirred at 25°C for 12 hrs. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiC>2, petroleum ether / ethyl acetate = 50 / 1 to 0 / 1) to give tert-butyl N-[2-[5-[(6-bromo-3-nitro-2-pyridyl)amino]pentoxy]ethyl]carbamate (3 g, 6.71 mmol, 66.09% yield) as a yellow oil. ESI [M+H] = 447.2 / 449.2.

[0777] Preparation of compound 5.4 5

[0778] To a solution of tert-butyl N-[2-[5-[(6-bromo-3-nitro-2-pyridyl)amino]pentoxy]ethyl]carbamate (2.7 g, 6.04 mmol, 1 eq) in EtOH (10 mL), THF (10 mL) and H2O (3 mL) was added Fe (674.15 mg, 12.07 mmol, 2 eq) and NH4CI (968.61 mg, 18.11 mmol, 3 eq). The mixture was stirred at 80°C for 2 hrs. The reaction mixture was quenched by addition H2O (10 mL), and then extracted with EtOAc (20 mL x 3). The combined organic layers were dried overAPRE007-PCT | 106265.000238Na2SC>4, filtered and concentrated under reduced pressure to give tert-butyl N-[2-[5-[(3-amino-6-bromo-2-pyridyl)amino]pentoxy]ethyl]carbamate (2.5 g, crude) as a brown oil. ESI [M+H] = 417.1 / 419.1.

[0779] Preparation of compound 6.5 6

[0780] To a solution of tert-butyl N-[2-[5-[(3-amino-6-bromo-2-pyridyl)amino]pentoxy]ethyl]carbamate (2.5 g, 5.99 mmol, 1 eq) in MeOH (30 m ) was added sulfamic acid (581.62 mg, 5.99 mmol, 270.40 pL, 1 eq) and 1,1,1 -trimethoxy ethane (2.16 g, 17.97 mmol, 2.26 m , 3 eq). The mixture was stirred at 30°C for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, petroleum ether / ethyl acetate = 50 / 1 to 0 / 1) to give tert-butyl N-[2-[5-(5-bromo-2-methyl-imidazo[4,5-b]pyridin-3-yl)pentoxy]ethyl]carbamate (2 g, 4.53 mmol, 75.65% yield) as a brown o...

Claims

1. APRE007-PCT | 106265.000238What is claimed is:

1. A compound having the structure of Formula (I):wherein:X is a bond, -N(H)-, -C(O)NH-, -NHC(O)-, or -N(Ci.6alkyl)-;R1is H, Ci-ealkyl, or NFL;R2and R2aare each, independently, H or Ci -ealkyl;R3is hydrogen, Ci-ealkyl, C2-ealkenyl, C2-ealkynyl, NH2, NH(Ci-ealkyl), N(Ci-ealkyl)2, Ci- ealkoxy, CN, halo, or NHC(O)O(Ci-ealkyl); andLinker is -(Cs-ualkylene)-, wherein the alkylene is straight, optionally comprises one or more alkyl substituents, optionally wherein one or more carbons is replaced with O, and / or optionally wherein two adjacent carbon atoms of the alkylene are replaced with an aryl or a heteroaryl;or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof.

2. The compound of claim 1, wherein X is a bond.

3. The compound of claim 1, wherein X is -N(H)-.

4. The compound of claim 1, wherein X is -C(O)NH-.

5. The compound of claim 1, wherein X is -NHC(O)-.

6. The compound of claim 1, wherein X is -N(Ci -ealkyl)-, such as -N(Cialkyl)-, -N(C2alkyl)-, - N(C3alkyl)-, -N(C4alkyl)-, -N(C5alkyl)-, or -N(C6alkyl)-.

7. The compound of any one of the preceding claims, wherein R1is H.

8. The compound of any one of claims 1-6, wherein R1is Ci-ealkyl, such as Cialkyl, C2alkyl, Csalkyl, CLalkyl. Chalky I. or Cealkyl.APRE007-PCT | 106265.0002389. The compound of claim 8, wherein R1is CH2OH.

10. The compound of any one of claims 1-6, wherein R1is NH2.

11. The compound of any one of the preceding claims, wherein R2is H.

12. The compound of any one of claims 1-10, wherein R2is Ci-ealkyl, such as Cialkyl, C2alkyl, C3alkyl, C4alkyl, Cealkyl. or Cealkyl.

13. The compound of any one of the preceding claims, wherein R2ais H.

14. The compound of any one of claims 1-12, wherein R2ais Ci-ealkyl, such as Cialkyl, C2alkyl, Cialkyl. C4alkyl, Cialkyl. or Cealkyl.

15. The compound of any one of the preceding claims, wherein R3is hydrogen.

16. The compound of any one of claims 1-14, wherein R3is Ci-ealkyl, such as Cialkyl, C2alkyl, Cialkyl. C4alkyl, Cealkyl, or Cealkyl.

17. The compound of any one of claims 1-14, wherein R3is C2-ealkenyl, such as C2alkenyl, Cialkcnyl. C4alkenyl, Cealkenyl, or Cealkenyl.

18. The compound of any one of claims 1-14, wherein R3is C2-ealkynyl, such as C2alkynyl, Cialkynyl. C4alkynyl, Cealkynyl, or Cealkynyl.

19. The compound of any one of claims 1-14, wherein R3is NH2.

20. The compound of any one of claims 1-14, wherein R3is NH(Ci-ealkyl), such as NH(Cialkyl), NH(C2alkyl), NH(C3alkyl), NH(C4alkyl), NH(Cealkyl), or NH(Cealkyl).

21. The compound of any one of claims 1-14, wherein R3is N(Ci-ealkyl)2, such as N(Ci-6alkyl)(Ci.6alkyl), or such as N(Cialkyl)2, N(Cialkyl)(C2alkyl), N(Cialkyl)(C3alkyl), N(C2alkyl)2, N(C3alkyl)2, N(C4alkyl)2, N(C5alkyl)2, or N(Cealkyl)2.

22. The compound of any one of claims 1-14, wherein R3is Ci-ealkoxy, such as Cialkoxy, Ckalkoxy. C3alkoxy, C4alkoxy, Cealkoxy, or Cealkoxy.

23. The compound of any one of claims 1-14, wherein R3is CN.

24. The compound of any one of claims 1-14, wherein R3is halo, such as F, Cl, Br, or I.APRE007-PCT | 106265.00023825. The compound of any one of claims 1-14, wherein R3is NHC(O)O(Ci. ealkyl), such as NHC(O)O(Cialkyl), NHC(O)O(C2alkyl), NHC(O)O(C3alkyl), NHC(O)O(C4alkyl), NHC(O)O(C5alkyl), or NHC(O)O(C6alkyl).

26. The compound of any one of claims 15-20 or 23-25, wherein R3is hydrogen, Ci-ealkyl, C2. ealkenyl, C2.ealkynyl, NH2, NH(Ci. ealkyl), CN, halo, or NHC(O)O(Ci. ealkyl).

27. The compound of any one of the preceding claims, wherein Linker is -(Csalkylene)-, - (Cealkylene)-, -(C?alkylene)-, -(Csalkylene)-, -(Cgalkylene)-, -(Cioalkylene)-, -(Cnalkylene)-, -(Ci2alkylene)-, -(Cisalkylene)-, or -(Cnalkylene)-.

28. The compound of any one of the preceding claims, wherein Linker comprises one or more alkyl substituents.

29. The compound of any one of the preceding claims, wherein in Linker, one or more carbon atom is replaced with O.

30. The compound of claim 29, wherein Linker is -(CR10R11)m-O-(CR12R13)n-, wherein R10-R13, are independently, H or Ci-ealkyl for each m and n unit, m is 1-6 and n is 1-6.

31. The compound of claim 29, wherein Linker is -(CR10R11)m-O-(CR12R13)n-O-(CR14R15)p-, wherein R10-R15, are independently, H or Ci-ealkyl for each m, n, and p unit, m is 1-6, n is 1-6, and p is 1-6.

32. The compound of any one of the preceding claims, wherein two adjacent carbon atoms of the alkylene are replaced with an aryl or a heteroaryl in Linker.

33. The compound of claim 32, wherein Linker is -(CR10R11)m-phenyl-C(R12R13)n, wherein R10- R13, are independently, H or Ci-ealkyl for each m and n unit, m is 1-6 and n is 1-6.

34. The compound of claim 32, wherein Linker35. The compound of claim 32, wherein Linker is -(CR10R11)m-pyridyl-C(R12R13)n, wherein R10- R13, are independently, H or Ci-ealkyl for each m and n unit, m is 1-6 and n is 1-6.APRE007-PCT | 106265.00023837. The compound of claim 1 that is:APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238or a pharmaceutically acceptable salt thereof.

38. The compound of claim 1 that is:APRE007-PCT | 106265.000238>"APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238<<><APRE007-PCT | 106265.000238"APRE007-PCT | 106265.000238< >"APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238><APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238<<><APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238APRE007-PCT | 106265.000238>APRE007-PCT | 106265.000238<APRE007-PCT | 106265.000238<>>APRE007-PCT | 106265.000238>>>APRE007-PCT | 106265.000238>>APRE007-PCT | 106265.000238>APRE007-PCT | 106265.000238or a pharmaceutically acceptable salt thereof.

39. A pharmaceutical composition comprising a compound of any one of the preceding claims and a pharmaceutically acceptable excipient.

40. A compound of any one of claims 1-38 or a pharmaceutical composition of claim 39 for use in inhibiting activity of a dual specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A) enzyme.

41. A compound of any one of claims 1-38 or a pharmaceutical composition of claim 39 for use in treating Down syndrome, Intellectual Developmental Disorder Autosomal Dominant 7, dementia, Alzheimer’s Disease, Fronto-Temporal Degeneration, Huntington’s disease, or Parkinson’s.

42. A compound of any one of claims 1-38 or a pharmaceutical composition of claim 39 for use in treating cancer, diabetes, or heart disease.

43. The compound or pharmaceutical composition of claim 42, that is for treating diabetes.

44. The compound or pharmaceutical composition of claim 42, that is for treating heart disease.

45. The compound or pharmaceutical composition of claim 42, that is for treating cancer.APRE007-PCT | 106265.00023846. The compound or pharmaceutical composition of claim 45, wherein the cancer is lung cancer, pancreatic cancer, glioblastoma, melanoma, or leukemia.

47. The compound or pharmaceutical composition of claim 45, wherein the cancer is lung cancer, such as non-small cell lung cancer.

48. The compound or pharmaceutical composition of claim 45, wherein the cancer is colon cancer, central nervous system cancer, ovarian cancer, renal cancer, prostate cancer, or breast cancer.

49. A compound of any one of claims 1-38 or a pharmaceutical composition of claim 39 for use in inhibiting activity of a dual specificity tyrosine phosphorylation regulated kinase IB (DYRK1B) enzyme.

50. A compound of any one of claims 1-38 or a pharmaceutical composition of claim 39 for use in treating early-onset coronary artery disease, hypertension, central obesity, or diabetes.

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