JAK2 v617f inhibitors and methods of use thereof

Abstract

Described herein are JAK2 V617F inhibitors and pharmaceutical compositions comprising said inhibitors. The subject compounds and compositions are useful for the treatment of JAK2 V617F-mediated disorders or diseases.

Description

JAK2 V617F INHIBITORS AND METHODS OF USE THEREOF CROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application Serial No.63 / 602,163 filed November 22, 2023 and U.S. Provisional Application Serial No.63 / 639,884 filed April 29, 2024; which are hereby incorporated by reference in their entirety. BACKGROUND OF THE INVENTION

[0002] JAK1 and JAK2 are members of the Janus kinase (JAKs) family of non-receptor tyrosine kinases, crucial to blood formation and immune responses. JAK1 and JAK2 play a role in downstream signaling pathways such as the JAK / STAT pathway, involved in cytokine signaling. Members of the JAK family possess seven defined regions of conserved homology denoted JAK homology (JH) domains 1-7. JH5-7 make up the amino terminus of JAKs and contain a predicted FERM (Band-4.1, ezrin, radixin, and moesin)-like motif, which are important in associating JAKs with their receptors and in some cases receptor cell-surface expression. Although the JH3-4 domains display some homology to SH2 domains, their function remains ambiguous. The carboxyl terminus is composed of JH1 and JH2 and contains the kinase and pseudokinase domains, respectively. The JAK2 JH1 domain includes all the features of a catalytic tyrosine kinase, while the JH2 domain, though highly sequence-homologous to JH1, lacks several elements conferring catalytic activity.

[0003] The JAK2 kinase domain exhibits a typical bilobar arrangement, with a secondary structure profile very similar to other solved kinase domains. The N-terminal lobe of JAK2 is composed of β- strands and includes a single helix, αC, while the C-terminal lobe is mostly helical.

[0004] Ubiquitin-Proteasome Pathway (UPP) or Ubiquitin-Proteasome System (UPS) is a critical pathway that regulates key regulator proteins and degrades misfolded or abnormal proteins. UPP is central to multiple cellular processes, and if defective or imbalanced, it leads to pathogenesis of a variety of diseases. The covalent attachment of ubiquitin to specific protein substrates is achieved through the action of E3 ubiquitin ligases.

[0005] The UPP is used to induce selective protein degradation, including use of fusion proteins to artificially ubiquitinate target proteins and synthetic small-molecule probes to induce proteasome- dependent degradation. Bifunctional compounds composed of a target protein-binding ligand and an E3 ubiquitin ligase ligand, induced proteasome-mediated degradation of selected proteins via their recruitment to E3 ubiquitin ligase and subsequent ubiquitination. These drug-like molecules offer the possibility of temporal control over protein expression. Such compounds are capable of inducing the inactivation of a protein of interest upon addition to cells or administration to an animal or human, and could be useful as biochemical reagents and lead to a new paradigm for the treatment of diseases by removing pathogenic or oncogenic proteins.

[0006] The mutant JAK2 V617F is the most common molecular event associated with myeloproliferative neoplasms. Selective targeting of the JAK2 V617F mutant using a small moleculecompound or a degrader may be useful for treating various pathologies, while sparing essential JAK2 functions. SUMMARY OF THE INVENTION

[0007] Disclosed herein is a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:Formula (III) as disclosed herein.

[0008] Also disclosed herein is a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.

[0009] Also disclosed herein is a method of treating a JAK2 V617F-mediated disease in a subject, comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof to the subject. INCORPORATION BY REFERENCE

[0010] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. DETAILED DESCRIPTION OF THE INVENTION Definitions

[0011] In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments. However, one skilled in the art will understand that the invention may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring descriptions of the embodiments. Unless the context requires otherwise, throughout the specification and claims which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, that is, as “including, but not limited to.” Further, headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

[0012] Reference throughout this specification to “some embodiments” or “an embodiment” means that a particular feature, structure, or characteristic described in connection with the embodiment isincluded in at least one embodiment. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Also, as used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise. It should also be noted that the term “or” is generally employed in its sense including “and / or” unless the content clearly dictates otherwise.

[0013] The terms below, as used herein, have the following meanings, unless indicated otherwise:

[0014] “Oxo” refers to =O.

[0015] “Amino” refers to -NH2.

[0016] “Hydroxy” refers to -OH.

[0017] “Carboxyl” refers to -COOH.

[0018] “Alkyl” refers to a straight-chain or branched-chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, more preferably one to six carbon atoms. Examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1- butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3- dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexyl, and longer alkyl groups, such as heptyl, octyl and the like. Whenever it appears herein, a numerical range such as “C1-C6 alkyl”, means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated. In some embodiments, the alkyl is a C1-C10 alkyl. In some embodiments, the alkyl is a C1-C6 alkyl. In some embodiments, the alkyl is a C1-C5 alkyl. In some embodiments, the alkyl is a C1-C4 alkyl. In some embodiments, the alkyl is a C1-C3 alkyl. Unless stated otherwise specifically in the specification, an alkyl group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the alkyl is optionally substituted with one or more oxo, halogen, -CN, - COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkyl is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkyl is optionally substituted with halogen.

[0019] “Alkenyl” refers to a straight-chain or branched-chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms. The group may be in either the cis or trans or Z or E conformation about the double bond(s), and should be understood to include both isomers. Examples include, but are not limited to ethenyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl and the like. Whenever it appears herein, a numerical range such as “C2-C6alkenyl”, means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated. Unless stated otherwise specifically in the specification, an alkenyl group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the alkenyl is optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkenyl is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkenyl is optionally substituted with halogen.

[0020] “Alkynyl” refers to a straight-chain or branched-chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl and the like. Whenever it appears herein, a numerical range such as “C2-C6alkynyl”, means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated. Unless stated otherwise specifically in the specification, an alkynyl group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the alkynyl is optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkynyl is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkynyl is optionally substituted with halogen.

[0021] “Alkylene” refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the alkylene is optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, - NH2, or -NO2. In some embodiments, the alkylene is optionally substituted with one or more halogen, - CN, -OH, or -OMe. In some embodiments, the alkylene is optionally substituted with halogen.

[0022] “Alkoxy” refers to a radical of the formula -Oalkyl where alkyl is defined as above. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the alkoxy is optionally substituted with one or more halogen, -CN, -COOH, -COOMe, - OH, -OMe, -NH2, or -NO2. In some embodiments, the alkoxy is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen.

[0023] “Aryl” refers to a radical derived from a hydrocarbon ring system comprising 6 to 30 carbon atoms and at least one aromatic ring. The aryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring,the aryl is bonded through an aromatic ring atom) or bridged ring systems. In some embodiments, the aryl is a 6- to 10-membered aryl. In some embodiments, the aryl is a 6-membered aryl (phenyl). Aryl radicals include, but are not limited to anthracenyl, naphthyl, phenanthrenyl, azulenyl, phenyl, chrysenyl, fluoranthenyl, fluorenyl, as-indacenyl, s-indacenyl, indanyl, indenyl, phenalenyl, phenanthrenyl, pleiadenyl, pyrenyl, and triphenylenyl. Unless stated otherwise specifically in the specification, an aryl may be optionally substituted, for example, with one or more halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the aryl is optionally substituted with one or more halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the aryl is optionally substituted with one or more halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen.

[0024] “Cycloalkyl” refers to a partially or fully saturated, monocyclic, or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom), spiro, and / or bridged ring systems. In some embodiments, the cycloalkyl is fully saturated. Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (e.g., C3-C15fully saturated cycloalkyl or C3-C15cycloalkenyl), from three to ten carbon atoms (e.g., C3-C10fully saturated cycloalkyl or C3-C10cycloalkenyl), from three to eight carbon atoms (e.g., C3-C8fully saturated cycloalkyl or C3-C8cycloalkenyl), from three to six carbon atoms (e.g., C3-C6fully saturated cycloalkyl or C3-C6cycloalkenyl), from three to five carbon atoms (e.g., C3-C5fully saturated cycloalkyl or C3-C5cycloalkenyl), or three to four carbon atoms (e.g., C3-C4fully saturated cycloalkyl or C3-C4cycloalkenyl). In some embodiments, the cycloalkyl is a 3- to 10-membered fully saturated cycloalkyl or a 3- to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3- to 6-membered fully saturated cycloalkyl or a 3- to 6-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5- to 6-membered fully saturated cycloalkyl or a 5- to 6-membered cycloalkenyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octyl, bicyclo[4.3.0]nonyl, cis-decalinyl, trans-decalinyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, and bicyclo[3.3.2]decyl, bicyclo[1.1.1]pentyl, bicyclo[3.1.0]hexyl, bicyclo[3.1.1]heptyl, 7,7-dimethyl- bicyclo[2.2.1]heptanyl, Spiro[4.2]heptyl, spiro[4.3]octyl, spiro[5.2]octyl, spiro[3.3]heptyl, and spiro[5.3]nonyl. Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless stated otherwise specifically in the specification, a cycloalkyl is optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, a cycloalkyl is optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a cycloalkyl is optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, - CF3, -OH, or -OMe. In some embodiments, the cycloalkyl is optionally substituted with halogen.

[0025] “Halo” or “halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.

[0026] “Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2- trifluoroethyl, 1,2-difluoroethyl, 2-fluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

[0027] “Haloalkoxy” refers to -O-haloalkyl, with haloalkyl as defined above.

[0028] “Hydroxyalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyl includes, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.

[0029] “Aminoalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Aminoalkyl includes, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.

[0030] “Deuteroalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more deuteriums. In some embodiments, the alkyl is substituted with one deuterium. In some embodiments, the alkyl is substituted with one, two, or three deuteriums. In some embodiments, the alkyl is substituted with one, two, three, four, five, or six deuteriums. Deuteroalkyl includes, for example, CD3, CH2D, CHD2, CH2CD3, CD2CD3, CHDCD3, CH2CH2D, or CH2CHD2. In some embodiments, the deuteroalkyl is CD3.

[0031] “Heteroalkyl” refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus, or combinations thereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a C1-C6 heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus, or combinations thereof wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a C1-C6 heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or two atoms selected from the group consisting of oxygen, nitrogen, and sulfur wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyl are, for example, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, - CH(CH3)OCH3, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NHCH3, or -CH2CH2N(CH3)2. Unless stated otherwise specifically in the specification, a heteroalkyl is optionally substituted for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, a heteroalkyl is optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or - NO2. In some embodiments, a heteroalkyl is optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.

[0032] “Heterocycloalkyl” refers to a 3- to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, silicon, and sulfur. In some embodiments, the heterocycloalkyl is fully saturated. In some embodiments, the heterocycloalkyl is C-linked. In some embodiments, the heterocycloalkyl is N-linked. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocycloalkyl comprises one to three nitrogens. In some embodiments, the heterocycloalkyl comprises one or two nitrogens. In some embodiments, the heterocycloalkyl comprises one nitrogen. In some embodiments, the heterocycloalkyl comprises one nitrogen and one oxygen. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom), spiro, or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized. Representative heterocycloalkyls include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (e.g., C2-C15fully saturated heterocycloalkyl or C2-C15heterocycloalkenyl), from two to ten carbon atoms (e.g., C2-C10fully saturated heterocycloalkyl or C2-C10heterocycloalkenyl), from two to eight carbon atoms (e.g., C2-C8fully saturated heterocycloalkyl or C2-C8heterocycloalkenyl), from two to seven carbon atoms (e.g., C2-C7fully saturated heterocycloalkyl or C2-C7heterocycloalkenyl), from two to six carbon atoms (e.g., C2-C6fully saturated heterocycloalkyl or C2-C7heterocycloalkenyl), from two to five carbon atoms (e.g., C2-C5fully saturated heterocycloalkyl or C2-C5heterocycloalkenyl), or two to four carbon atoms (e.g., C2-C4fully saturated heterocycloalkyl or C2-C4heterocycloalkenyl). Examples of such heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl, 3- oxo-1,3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-dioxol-4-yl, and 2-oxo-1,3-dioxol-4-yl. The term heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides, and the oligosaccharides. In some embodiments, heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring). In some embodiments, the heterocycloalkyl is a 3- to 8-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 7-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkyl. In some embodiments,the heterocycloalkyl is a 4- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 8- membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3- to 7-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkenyl. Unless stated otherwise specifically in the specification, a heterocycloalkyl is optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the heterocycloalkyl is optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heterocycloalkyl is optionally substituted with one or more halogen, methyl, ethyl, - CN, -CF3, -OH, or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen.

[0033] “Heteroaryl” refers to a 5- to 14-membered ring system radical comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heteroaryl comprises one to three nitrogens. In some embodiments, the heteroaryl comprises one or two nitrogens. In some embodiments, the heteroaryl comprises one nitrogen. In some embodiments, the heteroaryl is C-linked. In some embodiments, the heteroaryl is N-linked. The heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized. In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl comprising one, two, or three heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. In some embodiments, the heteroaryl is a 5- to 6-membered heteroaryl comprising one, two, or three heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. In some embodiments, the heteroaryl is a 6-membered heteroaryl comprising one, two, or three heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. In some embodiments, the heteroaryl is a 5-membered heteroaryl comprising one, two, or three heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl,indolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1- oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise specifically in the specification, a heteroaryl is optionally substituted, for example, with one or more halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the heteroaryl is optionally substituted with one or more halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heteroaryl is optionally substituted with one or more halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.

[0034] The term “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, “optionally substituted alkyl” means either “alkyl” or “substituted alkyl” as defined above. Further, an optionally substituted group may be un-substituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), mono-substituted (e.g., -CH2CH2F) or substituted at a level anywhere in-between fully substituted and mono-substituted (e.g., -CH2CHF2, - CH2CF3, -CF2CH3, -CFHCHF2, etc.).

[0035] The term “one or more” when referring to an optional substituent means that the subject group is optionally substituted with one, two, three, or four, or more substituents. In some embodiments, the subject group is optionally substituted with one, two, three, or four substituents. In some embodiments, the subject group is optionally substituted with one, two, or three substituents. In some embodiments, the subject group is optionally substituted with one or two substituents. In some embodiments, the subject group is optionally substituted with one substituent. In some embodiments, the subject group is optionally substituted with two substituents. In some embodiments, the subject group is optionally substituted with three substituents.

[0036] An “effective amount” or “therapeutically effective amount” refers to an amount of a compound administered to a mammalian subject, either as a single dose or as part of a series of doses, which is effective to produce a desired therapeutic effect.

[0037] “Treatment” of an individual (e.g. a mammal, such as a human) or a cell is any type of intervention used in an attempt to alter the natural course of the individual or cell. In some embodiments, treatment includes administration of a pharmaceutical composition subsequent to the initiation of a pathologic event or contact with an etiologic agent and includes stabilization of the condition (e.g., condition does not worsen) or alleviation of the condition.

[0038] “Synergy” or “synergize” refers to an effect of a combination that is greater than additive of the effects of each component alone at the same doses.

[0039] As used herein, the term “inhibitor” is defined as a compound that binds to and / or inhibits JAK2 V617F protein with measurable affinity.

[0040] As used herein, the term “degrader” is defined as a heterobifunctional compound that binds to and / or inhibits both JAK2 V617F protein and an E3 ligase with measurable affinity resulting in the ubiquitination and subsequent degradation of the JAK2 V617F protein.

[0041] As used herein, a “disease or disorder associated with JAK2 V617F” or, alternatively, “a JAK2 V617F-mediated disease or disorder” means any disease or other deleterious condition in which JAK2 V617F, or a mutant thereof, is known or suspected to play a role. Compounds

[0042] Described herein are compounds, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof useful in the treatment of a JAK2 V617F-mediated disease or disorder.

[0043] Disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:Formula (I); wherein: X is -O- or -C(RX)2-; each RXis independently hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1- C6haloalkyl, or C1-C6deuteroalkyl; Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R1is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2- C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; and / or two R1on the same atom are taken together to form an oxo; n is 0, 1, 2, 3, or 4; Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R2is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2- C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; and / or two R2on the same atom are taken together to form an oxo; m is 0, 1, 2, 3, or 4; Ring C is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R3is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2- C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; and / or two R3on the same atom are taken together to form an oxo; p is 0, 1, 2, 3, or 4; R4is hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, or C1- C6deuteroalkyl; each Rais independently C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L- aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rbis independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rcand Rdare independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1- C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L- heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl independently optionally substituted with one or more R; and L is absent or C1-C3alkylene optionally substituted with one or more R; each R is independently deuterium, halogen, -CN, -OH, -OC1-C3alkyl, -S(=O)C1-C3alkyl, -S(=O)2C1- C3alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3alkyl, -S(=O)2N(C1-C3alkyl)2, -NH2, -NHC1-C3alkyl, -N(C1- C3alkyl)2, -NHC(=O)OC1-C3alkyl, -C(=O)C1-C3alkyl, -C(=O)OH, -C(=O)OC1-C3alkyl, -C(=O)NH2,-C(=O)N(C1-C3alkyl)2, -C(=O)NHC1-C3alkyl, C1-C3alkyl, C1-C3haloalkyl, C1-C3deuteroalkyl, C1- C3hydroxyalkyl, C1-C3aminoalkyl, C1-C3heteroalkyl, C1-C6cycloalkyl, or 3- to 6-membered heterocycloalkyl; and / or two R on the same atom are taken together to form an oxo.

[0044] Also disclosed herein is a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:Formula (II); wherein: X is -NRX1-, -O-, or -C(RX)2-; RX1is hydrogen, deuterium, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; each RXis independently hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1- C6haloalkyl, or C1-C6deuteroalkyl; Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R1is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2- C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; and / or two R1on the same atom are taken together to form an oxo; n is 0, 1, 2, 3, or 4; Y is C1-C6alkylene, C2-C6alkenylene, or C2-C6alkynylene; each optionally substituted with one or more R; Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R2is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2- C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; and / or two R2on the same atom are taken together to form an oxo; m is 0, 1, 2, 3, or 4; Ring C is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R3is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2- C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; and / or two R3on the same atom are taken together to form an oxo; p is 0, 1, 2, 3, or 4; R4is hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, or C1- C6deuteroalkyl; each Rais independently C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L- aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rbis independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rcand Rdare independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1- C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L- heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl independently optionally substituted with one or more R; and L is absent or C1-C3alkylene optionally substituted with one or more R; each R is independently deuterium, halogen, -CN, -OH, -OC1-C3alkyl, -S(=O)C1-C3alkyl, -S(=O)2C1- C3alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3alkyl, -S(=O)2N(C1-C3alkyl)2, -NH2, -NHC1-C3alkyl, -N(C1- C3alkyl)2, -NHC(=O)OC1-C3alkyl, -C(=O)C1-C3alkyl, -C(=O)OH, -C(=O)OC1-C3alkyl, -C(=O)NH2, -C(=O)N(C1-C3alkyl)2, -C(=O)NHC1-C3alkyl, C1-C3alkyl, C1-C3haloalkyl, C1-C3deuteroalkyl, C1- C3hydroxyalkyl, C1-C3aminoalkyl, C1-C3heteroalkyl, C1-C6cycloalkyl, or 3- to 6-membered heterocycloalkyl;and / or two R on the same atom are taken together to form an oxo.

[0045] Also disclosed herein is a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:Formula (III); wherein: X is -NRX1-, -O-, or -C(RX)2-; RX1is hydrogen, deuterium, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; each RXis independently hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1- C6haloalkyl, or C1-C6deuteroalkyl; Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R11is independently deuterium, halogen, -CN, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2- C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; and / or two R11on the same atom are taken together to form an oxo; n1 is 0, 1, 2, 3, or 4; Z is a C1-C8alkylene, C1-C8alkenylene, or C1-C8alkynylene; each optionally substituted with one or more RZ; wherein one, two, or three carbon atoms of Z are optionally replaced by a heteroatom selected from oxygen, nitrogen, and sulfur; each RZis independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2- C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R; and / or two RZon the same carbon are taken together to form an oxo; and / or two RZon the same carbon are taken together to form a cycloalkyl or a heterocycloalkyl; each independently optionally substituted with one or more R;and / or two RZon the different atoms are taken together to form a cycloalkyl or a heterocycloalkyl; each independently optionally substituted with one or more R; Y is absent, C1-C6alkylene, C2-C6alkenylene, or C2-C6alkynylene; each optionally substituted with one or more R; Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R12is independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1- C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; and / or two R12on the same atom are taken together to form an oxo; m1 is 0, 1, 2, 3, or 4; Ring C is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R3is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2- C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R3; and / or two R3on the same atom are taken together to form an oxo; p is 0, 1, 2, 3, or 4; R4is hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, or C1- C6deuteroalkyl; each Rais independently C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L- aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rbis independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rcand Rdare independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1- C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L- heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl independently optionally substituted with one or more R; and L is absent or C1-C3alkylene optionally substituted with one or more R; each R is independently deuterium, halogen, -CN, -OH, -OC1-C3alkyl, -S(=O)C1-C3alkyl, -S(=O)2C1- C3alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3alkyl, -S(=O)2N(C1-C3alkyl)2, -NH2, -NHC1-C3alkyl, -N(C1- C3alkyl)2, -NHC(=O)OC1-C3alkyl, -C(=O)C1-C3alkyl, -C(=O)OH, -C(=O)OC1-C3alkyl, -C(=O)NH2, -C(=O)N(C1-C3alkyl)2, -C(=O)NHC1-C3alkyl, C1-C3alkyl, C1-C3haloalkyl, C1-C3deuteroalkyl, C1- C3hydroxyalkyl, C1-C3aminoalkyl, C1-C3heteroalkyl, C1-C6cycloalkyl, or 3- to 6-membered heterocycloalkyl; and / or two R on the same atom are taken together to form an oxo.

[0046] In some embodiments of a compound of Formula (II) or (III), X is -NRX1-. In some embodiments of a compound of Formula (I)-(III), X is -O-. In some embodiments of a compound of Formula (I)-(III), X is -C(RX)2-.

[0047] In some embodiments of a compound of Formula (II) or (III), RX1is hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (II) or (III), RX1is C1-C6alkyl. In some embodiments of a compound of Formula (II) or (III), RX1is hydrogen.

[0048] In some embodiments of a compound of Formula (I)-(III), each RXis independently hydrogen.

[0049] In some embodiments of a compound of Formula (II), Y is C2-C6alkenylene or C2- C6alkynylene; each optionally substituted with one or more R. In some embodiments of a compound of Formula (II), Y is C2-C6alkenylene. In some embodiments of a compound of Formula (II), Y is C2- C4alkenylene. In some embodiments of a compound of Formula (II), Y is C2alkenylene. In some embodiments of a compound of Formula (II), Y is C3alkenylene. In some embodiments of a compound of Formula (II), Y is C4alkenylene.

[0050] In some embodiments of a compound of Formula (II), Y is C2-C6alkynylene. In some embodiments of a compound of Formula (II), Y is C2-C4alkynylene. In some embodiments of a compound of Formula (II), Y is C2alkynylene. In some embodiments of a compound of Formula (II), Y is C3alkynylene. In some embodiments of a compound of Formula (II), Y is C4alkynylene.

[0051] In some embodiments of a compound of Formula (I)-(III), Ring A is cycloalkyl or heterocycloalkyl. In some embodiments of a compound of Formula (I)-(III), Ring A is cycloalkyl. In some embodiments of a compound of Formula (I)-(III), Ring A is 4- to 6-membered cycloalkyl. In some embodiments of a compound of Formula (I)-(III), Ring A is cyclopentyl. In some embodiments of a compound of Formula (I)-(III), Ring A is cyclobutyl. In some embodiments of a compound of Formula (I)-(III), Ring A is cyclohexyl. In some embodiments of a compound of Formula (I)-(III), Ring A is heterocycloalkyl. In some embodiments of a compound of Formula (I)-(III), Ring A is 5- to 6-membered heterocycloalkyl. In some embodiments of a compound of Formula (I)-(III), Ring A is 5-membered heterocycloalkyl. In some embodiments of a compound of Formula (I)-(III), Ring A is 6-membered heterocycloalkyl.

[0052] In some embodiments of a compound of Formula (I) or (II), each R1is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1- C6heteroalkyl.

[0053] In some embodiments of a compound of Formula (I) or (II), each R1is independently - OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, - NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd. In some embodiments of a compound of Formula (I) or (II), each R1is independently -NRbC(=O)NRcRd, -NRbC(=O)Ra, or -NRbC(=O)ORb. In some embodiments of a compound of Formula (I) or (II), each R1is independently -NRbC(=O)ORb.

[0054] In some embodiments of a compound of Formula (I) or (II), n is 1 or 2. In some embodiments of a compound of Formula (I) or (II), n is 2. In some embodiments of a compound of Formula (I) or (II), n is 1. In some embodiments of a compound of Formula (I) or (II), n is 0. In some embodiments of a compound of Formula (I) or (II), n is 0, 1, or 2. In some embodiments of a compound of Formula (I) or (II), n is 0 or 1.

[0055] In some embodiments of a compound of Formula (

[0056] In some embodiments of a compound of Formula (I)-(III), Ring B is aryl or heteroaryl. In some embodiments of a compound of Formula (I)-(III), Ring B is heteroaryl. In some embodiments of a compound of Formula (I)-(III), Ring B is a bicyclic heteroaryl. In some embodiments of a compound of Formula (I)-(III), Ring B is a bicyclic heteroaryl comprising one aromatic ring and one non aromatic ring.

[0057] In some embodiments of a compound of Formula (I)-(III), Ring B is a 5- or 6-membered heteroaryl. In some embodiments of a compound of Formula (I)-(III), Ring B is a 5-membered heteroaryl. In some embodiments of a compound of Formula (I)-(III), Ring B is a 5-membered heteroaryl comprising one, two, or three heteroatoms selected from oxygen, nitrogen, and sulfur. In some embodiments of a compound of Formula (I)-(III), Ring B is a 5-membered heteroaryl comprising one or two heteroatoms selected from oxygen, nitrogen, and sulfur. In some embodiments of a compound of Formula (I)-(III), Ring B is aryl. In some embodiments of a compound of Formula (I)-(III), Ring B is phenyl. In some embodiments of a compound of Formula (I)-(III), Ring B is a bicyclic aryl. In some embodiments of a compound of Formula (I)-(III), Ring B is a bicyclic aryl comprising one aromatic ring and one non aromatic ring.

[0058] In some embodiments of a compound of Formula (I) or (II), each R2is independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1- C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl. In some embodiments of a compound of Formula(I) or (II), each R2is independently deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, or C1- C6deuteroalkyl. In some embodiments of a compound of Formula (I) or (II), each R2is independently C1- C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl. In some embodiments of a compound of Formula (I) or (II), each R2is independently C1-C6alkyl or C1-C6deuteroalkyl. In some embodiments of a compound of Formula (I) or (II), each R2is independently C1-C6alkyl.

[0059] In some embodiments of a compound of Formula (I) or (II), m is 0, 1, or 2. In some embodiments of a compound of Formula (I) or (II), m is 1 or 2. In some embodiments of a compound of Formula (I) or (II), m is 0 or 1. In some embodiments of a compound of Formula (I) or (II), m is 1. Insome embodiments of a compound of Formula

[0061] In some embodiments of a compound of Formula.

[0062] In some embodiments of a compound of Formula (III), each R11is independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R.

[0063] In some embodiments of a compound of Formula (III), each R11is independently deuterium, halogen, -CN, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, - S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, - C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, or C2-C6alkynyl.

[0064] In some embodiments of a compound of Formula (III), each R11is independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, C1-C6alkyl, C1- C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl.

[0065] In some embodiments of a compound of Formula (III), each R11is independently deuterium, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, C1-C6alkyl, or C1-C6haloalkyl.

[0066] In some embodiments of a compound of Formula (III), each R11is independently deuterium, halogen, -CN, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, or C1-C6haloalkyl.

[0067] In some embodiments of a compound of Formula (III), each R11is independently -OC(=O)Ra, - OC(=O)ORb, -OC(=O)NRcRd, NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, or -NRbC(=O)ORb.

[0068] In some embodiments of a compound of Formula (III), each R11is independently - NRbC(=O)Raor -NRbC(=O)ORb.

[0069] In some embodiments of a compound of Formula (III), each R11is independently - NRbC(=O)ORb.

[0070] In some embodiments of a compound of Formula (III), each R11is independently deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl. In some embodiments of a compound of Formula (III), each R11is independently halogen or C1-C6alkyl. In some embodiments of a compound of Formula (III), each R11is independently halogen. In some embodiments of a compound of Formula (III), each R11is independently C1-C6alkyl.

[0071] In some embodiments of a compound of Formula (III), n1 is 0. In some embodiments of a compound of Formula (III), n1 is 0 or 1. In some embodiments of a compound of Formula (III), n1 is 1.

[0072] In some embodiments of a compound of Formula (

[0073] In some embodiments of a compound of Formula (,.

[0074] In some embodiments of a compound of Formula (III), each R12is independently deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl. In some embodiments of a compound of Formula (III), each R12is independently halogen or C1-C6alkyl. In some embodiments of a compound of Formula (III), each R12is independently halogen. In some embodiments of a compound of Formula (III), each R12is independently C1-C6alkyl.

[0075] In some embodiments of a compound of Formula (III), m1 is 0. In some embodiments of a compound of Formula (III), m1 is 0 or 1. In some embodiments of a compound of Formula (III), m1 is 1.

[0078] In some embodiments, the compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is of Formula (IIIa):Formula (IIIa).

[0079] In some embodiments, the compound of Formula (IIIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is:.

[0080] In some embodiments, the compound of Formula (IIIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is:.

[0081] In some embodiments of a compound of Formula (III) or (IIIa), Z is a C1-C8alkylene optionally substituted with one or more RZ; wherein one, two, or three carbon atoms of Z are optionally replaced by a heteroatom selected from oxygen, nitrogen, and sulfur.

[0082] In some embodiments of a compound of Formula (III) or (IIIa), Z is a C1-C6alkylene optionally substituted with one or more RZ; wherein one, two, or three carbon atoms of Z are optionally replaced by a heteroatom selected from oxygen, nitrogen, and sulfur.

[0083] In some embodiments of a compound of Formula (III) or (IIIa), Z is a C4-C6alkylene optionally substituted with one or more RZ; wherein one or two carbon atoms of Z are optionally replaced by a heteroatom selected from oxygen, nitrogen, and sulfur.

[0084] In some embodiments of a compound of Formula (III) or (IIIa), Z is a C1-C8alkylene optionally substituted with one or more RZ; wherein one or two carbon atoms of Z are optionally replaced by a heteroatom selected from oxygen, nitrogen, and sulfur.

[0085] In some embodiments of a compound of Formula (III) or (IIIa), Z is a C1-C6alkylene optionally substituted with one or more RZ; wherein one or two carbon atoms of Z are optionally replaced by a heteroatom selected from oxygen, nitrogen, and sulfur.

[0086] In some embodiments of a compound of Formula (III) or (IIIa), Z is a C4-C6alkylene optionally substituted with one or more RZ; wherein one or two carbon atoms of Z are optionally replaced by a heteroatom selected from oxygen, nitrogen, and sulfur.

[0087] In some embodiments of a compound of Formula (III) or (IIIa), Z is a C1-C8alkylene optionally substituted with one or more RZ; wherein one or two carbon atoms of Z are replaced by a heteroatom selected from oxygen, nitrogen, and sulfur.

[0088] In some embodiments of a compound of Formula (III) or (IIIa), Z is a C1-C6alkylene optionallysubstituted with one or more RZ; wherein one or two carbon atoms of Z are replaced by a heteroatom selected from oxygen, nitrogen, and sulfur.

[0089] In some embodiments of a compound of Formula (III) or (IIIa), Z is a C4-C6alkylene optionally substituted with one or more RZ; wherein one or two carbon atoms of Z are replaced by a heteroatom selected from oxygen, nitrogen, and sulfur.

[0090] In some embodiments of a compound of Formula (III) or (IIIa), Z is a C1-C8alkylene optionally substituted with one or more RZ; wherein one or two carbon atoms of Z are replaced by a heteroatom selected from oxygen and nitrogen.

[0091] In some embodiments of a compound of Formula (III) or (IIIa), Z is a C1-C6alkylene optionally substituted with one or more RZ; wherein one or two carbon atoms of Z are replaced by a heteroatom selected from oxygen and nitrogen.

[0092] In some embodiments of a compound of Formula (III) or (IIIa), Z is a C4-C6alkylene optionally substituted with one or more RZ; wherein one or two carbon atoms of Z are replaced by a heteroatom selected from oxygen and nitrogen.

[0093] In some embodiments of a compound of Formula (III) or (IIIa), Z is a C4-C6alkylene optionally substituted with one or more RZ; wherein one carbon atom of Z is replaced by a heteroatom selected from oxygen and nitrogen.

[0094] In some embodiments of a compound of Formula (III) or (IIIa), Z is a C4-C6alkylene optionally substituted with one or more RZ; wherein one or two carbon atoms of Z are replaced by a heteroatom that is oxygen.

[0095] In some embodiments of a compound of Formula (III) or (IIIa), Z is a C4alkylene optionally substituted with one or more RZ; wherein one or two carbon atoms of Z are optionally replaced by a heteroatom selected from oxygen, nitrogen, and sulfur.

[0096] In some embodiments of a compound of Formula (III) or (IIIa), Z is a C4alkylene optionally substituted with one or more RZ; wherein one or two carbon atoms of Z are replaced by a heteroatom selected from oxygen and nitrogen.

[0097] In some embodiments of a compound of Formula (III) or (IIIa), Z is a C4alkylene optionally substituted with one or more RZ; wherein one carbon atom of Z is replaced by a heteroatom selected from oxygen and nitrogen.

[0098] In some embodiments of a compound of Formula (III) or (IIIa), Z is a C4alkylene optionally substituted with one or more RZ; wherein one or two carbon atoms of Z are replaced by a heteroatom that is oxygen.

[0099] In some embodiments of a compound of Formula (III) or (IIIa), Z is a C4alkylene optionally substituted with one or more RZ; wherein one carbon atom of Z is replaced by a heteroatom that is oxygen.

[0100] In some embodiments of a compound of Formula (III) or (IIIa), each RZ is independentlydeuterium, halogen, -CN, -OH, -ORa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -C(=O)Ra, - C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl; and / or two RZon the same carbon are taken together to form an oxo.

[0101] In some embodiments of a compound of Formula (III) or (IIIa), each RZis independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, C1-C6alkyl, C1-C6haloalkyl, or C1- C6deuteroalkyl; and / or two RZon the same carbon are taken together to form an oxo.

[0102] In some embodiments of a compound of Formula (III) or (IIIa), each RZis independently deuterium, halogen, -CN, -OH, -ORa, -C(=O)Ra, or C1-C6alkyl; and / or two RZon the same carbon are taken together to form an oxo.

[0103] In some embodiments of a compound of Formula (III) or (IIIa), each RZis independently -OH, -C(=O)Ra, or C1-C6alkyl; and / or two RZon the same carbon are taken together to form an oxo.

[0104] In some embodiments of a compound of Formula (III) or (IIIa), each RZis independently - C(=O)Raor C1-C6alkyl; and / or two RZon the same carbon are taken together to form an oxo.

[0105] In some embodiments of a compound of Formula (III) or (IIIa), each RZis independently C1- C6alkyl and / or two RZon the same carbon are taken together to form an oxo.

[0106] In some embodiments of a compound of Formula (III) or (IIIa), each RZis independently - C(=O)Raand / or two RZon the same carbon are taken together to form an oxo.

[0107] In some embodiments of a compound of Formula (III) or (IIIa), two RZon the same carbon are taken together to form a cycloalkyl or a heterocycloalkyl; each independently optionally substituted with one or more R.

[0108] In some embodiments of a compound of Formula (III) or (IIIa), two RZon the same carbon are taken together to form a cycloalkyl independently optionally substituted with one or more R.

[0109] In some embodiments of a compound of Formula (III) or (IIIa), two RZon the same carbon are taken together to form a heterocycloalkyl optionally substituted with one or more R.

[0110] In some embodiments of a compound of Formula (III) or (IIIa), two RZon the different atoms are taken together to form a cycloalkyl or a heterocycloalkyl; each independently optionally substituted with one or more R.

[0111] In some embodiments of a compound of Formula (III) or (IIIa), two RZon the different atoms are taken together to form a cycloalkyl independently optionally substituted with one or more R.

[0112] In some embodiments of a compound of Formula (III) or (IIIa), two RZon the different atoms are taken together to form a 3- to 6-membered cycloalkyl independently optionally substituted with one or more R.

[0113] In some embodiments of a compound of Formula (III) or (IIIa), two RZon the different atoms are taken together to form a 4- to 5-membered cycloalkyl independently optionally substituted with one or more R.

[0114] In some embodiments of a compound of Formula (III) or (IIIa), two RZ on the different atomsare taken together to form a 3- to 5-membered cycloalkyl independently optionally substituted with one or more R.

[0115] In some embodiments of a compound of Formula (III) or (IIIa), two RZon the different atoms are taken together to form a 4- to 6-membered cycloalkyl independently optionally substituted with one or more R.

[0116] In some embodiments of a compound of Formula (III) or (IIIa), two RZon the different atoms are taken together to form a heterocycloalkyl independently optionally substituted with one or more R.

[0117] In some embodiments of a compound of Formula (III) or (IIIa), two RZon the different atoms are taken together to form a 4- to 6-membered heterocycloalkyl independently optionally substituted with one or more R.

[0118] In some embodiments of a compound of Formula (III) or (IIIa), two RZon the different atoms are taken together to form a 5- to 6-membered heterocycloalkyl independently optionally substituted with one or more R.

[0119] In some embodiments of a compound of Formula (III) or (IIIa), two RZon the different atoms are taken together to form a 4- to 5-membered heterocycloalkyl independently optionally substituted with one or more R.

[0121] In some embodiments of a compound of Formula (III) or (IIIa), Z is,,

[0122] In some embodiments of a compound of Formula (III) or (IIIa), Z isor.

[0123] In some embodiments of a compound of Formula (III) or (IIIa), Z is, ,.

[0124] In some embodiments of a compound of Formula (III) or (IIIa), Z is,

[0126] In some embodiments of a compound of Formula (III) or (IIIa), Z is,

[0127] In some embodiments of a compound of Formula (III) or (IIIa), Z is,

[0129] In some embodiments of a compound of Formula (III) or (IIIa), Z isembodiments of a compound of Formula (III) or (IIIa), Z is.

[0130] In some embodiments of a compound of Formula (III) or (IIIa), Z is. In someembodiments of a compound of Formula (III) or (IIIa), Z is .

[0131] In some embodiments of a compound of Formula (III) or (IIIa), Z is. In someembodiments of a compound of Formula (III) or (IIIa), Z is .

[0132] In some embodiments of a compound of Formula (III) or (IIIa), Z is. In some embodiments of a compound of Formula (III) or (IIIa), Z is.

[0133] In some embodiments of a compound of Formula (III), Y is absent. In some embodiments of a compound of Formula (III), Y is C1-C6alkylene, C2-C6alkenylene, or C2-C6alkynylene; each optionally substituted with one or more R. In some embodiments of a compound of Formula (III), Y is C1-C6alkylene. In some embodiments of a compound of Formula (III), Y is C2-C6alkenylene. In some embodiments of a compound of Formula (III), Y is C2-C6alkynylene.

[0134] In some embodiments of a compound of Formula (I)-(III) or (IIIa), Ring C is heteroaryl.

[0135] In some embodiments of a compound of Formula (I)-(III) or (IIIa), Ring C is 5- or 6-membered heteroaryl.

[0136] In some embodiments of a compound of Formula (I)-(III) or (IIIa), Ring C is 5-membered heteroaryl. In some embodiments of a compound of Formula (I)-(III) or (IIIa), Ring C is 5-membered heteroaryl comprising one, two, three, or four heteroatoms selected from oxygen, nitrogen, and sulfur. In some embodiments of a compound of Formula (I)-(III) or (IIIa), Ring C is 5-membered heteroaryl comprising one, two, or three heteroatoms selected from oxygen, nitrogen, and sulfur. In some embodiments of a compound of Formula (I)-(III) or (IIIa), Ring C is a thiophenyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, isothiazolyl, isoxazolyl, pyrazolyl, triazolyl, or tetrazolyl. In some embodiments of a compound of Formula (I)-(III) or (IIIa), Ring C is a pyrrolyl, imidazolyl, pyrazolyl, or triazolyl. In some embodiments of a compound of Formula (I)-(III) or (IIIa), Ring C is a imidazolyl or pyrazolyl. In some embodiments of a compound of Formula (I)-(III) or (IIIa), Ring C is a pyrazolyl.

[0137] In some embodiments of a compound of Formula (I)-(III) or (IIIa), Ring C is 6-membered heteroaryl. In some embodiments of a compound of Formula (I)-(III) or (IIIa), Ring C is 6-membered heteroaryl comprising one or two heteroatoms that are nitrogens. In some embodiments of a compound of Formula (I)-(III) or (IIIa), Ring C is 6-membered heteroaryl comprising one heteroatom that are nitrogens.

[0138] In some embodiments of a compound of Formula (I)-(III) or (IIIa), each R3is independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1- C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl.

[0139] In some embodiments of a compound of Formula (I)-(III) or (IIIa), each R3is independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl.

[0140] In some embodiments of a compound of Formula (I)-(III) or (IIIa), each R3is independently halogen, -OH, -ORa, or C1-C6alkyl.

[0141] In some embodiments of a compound of Formula (I)-(III) or (IIIa), each R3is independently halogen or C1-C6alkyl.

[0142] In some embodiments of a compound of Formula (I)-(III) or (IIIa), p is 1 or 2. In some embodiments of a compound of Formula (I)-(III) or (IIIa), p is 2. In some embodiments of a compound of Formula (I)-(III) or (IIIa), p is 1.,. ,

[0145] In some embodiments of a compound of Formula (I)-(III), R4is hydrogen.

[0146] Described herein are degrader compounds, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof useful in the treatment of a JAK2 V617F-mediated disease or disorder.

[0147] Disclosed herein is a compound of Formula (IVa), (IVb), or (IVc), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:wherein: X is -NRX1-, -O-, or -C(RX)2-; RX1is hydrogen, deuterium, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl;each RXis independently hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1- C6haloalkyl, or C1-C6deuteroalkyl; Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R1is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2- C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; and / or two R1on the same atom are taken together to form an oxo; n is 0, 1, 2, 3, or 4; Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R2is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2- C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; and / or two R2on the same atom are taken together to form an oxo; m is 0, 1, 2, 3, or 4; Ring C is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R3is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2- C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; and / or two R3on the same atom are taken together to form an oxo; p is 0, 1, 2, 3, or 4; R4is hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, or C1- C6deuteroalkyl; each L1is independently -O-, -S-, -S(=O)-, -S(=O)2-, -NRb-, -C(=O)-, -OC(=O)-, -C(=O)O-, -C(=O)NRb-, -NRbC(=O)-, -NRbC(=O)NRb-, -S(=O)2NRb-, -NRbS(=O)2-, -NRbS(=O)2NRb-, C1-C10alkylene, C2- C6alkenylene, C2-C6alkynylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene;wherein each alkylene, alkenylene, alkynylene, cycloalkylene, heterocycloalkylene, arylene, and heteroarylene is independently optionally substituted with one or more R; s is 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; M is an E3 ligase targeting agent; each Rais independently C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L- aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rbis independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rcand Rdare independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1- C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L- heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl independently optionally substituted with one or more R; and L is absent or C1-C3alkylene optionally substituted with one or more R; each R is independently deuterium, halogen, -CN, -OH, -OC1-C3alkyl, -S(=O)C1-C3alkyl, -S(=O)2C1- C3alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3alkyl, -S(=O)2N(C1-C3alkyl)2, -NH2, -NHC1-C3alkyl, -N(C1- C3alkyl)2, -NHC(=O)OC1-C3alkyl, -C(=O)C1-C3alkyl, -C(=O)OH, -C(=O)OC1-C3alkyl, -C(=O)NH2, -C(=O)N(C1-C3alkyl)2, -C(=O)NHC1-C3alkyl, C1-C3alkyl, C1-C3haloalkyl, C1-C3deuteroalkyl, C1- C3hydroxyalkyl, C1-C3aminoalkyl, C1-C3heteroalkyl, C1-C6cycloalkyl, or 3- to 6-membered heterocycloalkyl; and / or two R on the same atom are taken together to form an oxo.

[0148] Disclosed herein is a compound of Formula (Va), (Vb), or (Vc), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:Formula (Vb); Formula (Va);Formula (Vc); wherein: X is -NRX1-, -O-, or -C(RX)2-; RX1is hydrogen, deuterium, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; each RXis independently hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1- C6haloalkyl, or C1-C6deuteroalkyl; Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R11is independently deuterium, halogen, -CN, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2- C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; and / or two R11on the same atom are taken together to form an oxo; n1 is 0, 1, 2, 3, or 4; Z is a C1-C8alkylene, C1-C8alkenylene, or C1-C8alkynylene; each optionally substituted with one or more RZ; wherein one, two, or three carbon atoms of Z are optionally replaced by a heteroatom selected from oxygen, nitrogen, and sulfur; each RZis independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2- C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R; and / or two RZon the same carbon are taken together to form an oxo; and / or two RZon the same carbon are taken together to form a cycloalkyl or a heterocycloalkyl; each independently optionally substituted with one or more R; and / or two RZon the different atoms are taken together to form a cycloalkyl or a heterocycloalkyl; each independently optionally substituted with one or more R; Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;each R12is independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1- C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; and / or two R12on the same atom are taken together to form an oxo; m1 is 0, 1, 2, 3, or 4; Ring C is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R3is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2- C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R3; and / or two R3on the same atom are taken together to form an oxo; p is 0, 1, 2, 3, or 4; R4is hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, or C1- C6deuteroalkyl; each L1is independently -O-, -S-, -S(=O)-, -S(=O)2-, -NRb-, -C(=O)-, -OC(=O)-, -C(=O)O-, -C(=O)NRb-, -NRbC(=O)-, -NRbC(=O)NRb-, -S(=O)2NRb-, -NRbS(=O)2-, -NRbS(=O)2NRb-, C1-C10alkylene, C2- C6alkenylene, C2-C6alkynylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene; wherein each alkylene, alkenylene, alkynylene, cycloalkylene, heterocycloalkylene, arylene, and heteroarylene is independently optionally substituted with one or more R; s is 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; M is an E3 ligase targeting agent; each Rais independently C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L- aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rbis independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rcand Rdare independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1- C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L- heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl,cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl independently optionally substituted with one or more R; and L is absent or C1-C3alkylene optionally substituted with one or more R; each R is independently deuterium, halogen, -CN, -OH, -OC1-C3alkyl, -S(=O)C1-C3alkyl, -S(=O)2C1- C3alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3alkyl, -S(=O)2N(C1-C3alkyl)2, -NH2, -NHC1-C3alkyl, -N(C1- C3alkyl)2, -NHC(=O)OC1-C3alkyl, -C(=O)C1-C3alkyl, -C(=O)OH, -C(=O)OC1-C3alkyl, -C(=O)NH2, -C(=O)N(C1-C3alkyl)2, -C(=O)NHC1-C3alkyl, C1-C3alkyl, C1-C3haloalkyl, C1-C3deuteroalkyl, C1- C3hydroxyalkyl, C1-C3aminoalkyl, C1-C3heteroalkyl, C1-C6cycloalkyl, or 3- to 6-membered heterocycloalkyl; and / or two R on the same atom are taken together to form an oxo.

[0149] In some embodiments of a compound of Formula (IVa)-(IVc) or (Va)-(Vc), X is -NRX1-. In some embodiments of a compound of Formula (IVa)-(IVc) or (Va)-(Vc), X is -O-. In some embodiments of a compound of Formula (IVa)-(IVc) or (Va)-(Vc), X is -C(RX)2-.

[0150] In some embodiments of a compound of Formula (IVa)-(IVc) or (Va)-(Vc), RX1is hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (IVa)-(IVc) or (Va)-(Vc), RX1is C1- C6alkyl. In some embodiments of a compound of Formula (IVa)-(IVc) or (Va)-(Vc), RX1is hydrogen.

[0151] In some embodiments of a compound of Formula (IVa)-(IVc) or (Va)-(Vc), each RXis independently hydrogen.

[0152] In some embodiments of a compound of Formula (IVa)-(IVc) or (Va)-(Vc), Ring A is cycloalkyl or heterocycloalkyl.

[0153] In some embodiments of a compound of Formula (IVa)-(IVc) or (Va)-(Vc), Ring A is cycloalkyl. In some embodiments of a compound of Formula (IVa)-(IVc) or (Va)-(Vc), Ring A is 4- to 6- membered cycloalkyl. In some embodiments of a compound of Formula (IVa)-(IVc) or (Va)-(Vc), Ring A is cyclopentyl. In some embodiments of a compound of Formula (IVa)-(IVc) or (Va)-(Vc), Ring A is cyclobutyl. In some embodiments of a compound of Formula (IVa)-(IVc) or (Va)-(Vc), Ring A is cyclohexyl.

[0154] In some embodiments of a compound of Formula (IVa)-(IVc) or (Va)-(Vc), Ring A is heterocycloalkyl. In some embodiments of a compound of Formula (IVa)-(IVc) or (Va)-(Vc), Ring A is 5- to 6-membered heterocycloalkyl. In some embodiments of a compound of Formula (IVa)-(IVc) or (Va)-(Vc), Ring A is 5-membered heterocycloalkyl. In some embodiments of a compound of Formula (IVa)-(IVc) or (Va)-(Vc), Ring A is 6-membered heterocycloalkyl.

[0155] In some embodiments of a compound of Formula (IVa)-(IVc), each R1is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1- C6heteroalkyl.

[0156] In some embodiments of a compound of Formula (IVa)-(IVc), each R1is independently - OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, - NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd.

[0157] In some embodiments of a compound of Formula (IVa)-(IVc), each R1 is independently -NRbC(=O)NRcRd, -NRbC(=O)Ra, or -NRbC(=O)ORb.

[0158] In some embodiments of a compound of Formula (IVa)-(IVc), each R1is independently - NRbC(=O)ORb.

[0159] In some embodiments of a compound of Formula (IVa)-(IVc), n is 1 or 2. In some embodiments of a compound of Formula (IVa)-(IVc), n is 2. In some embodiments of a compound of Formula (IVa)-(IVc), n is 1. In some embodiments of a compound of Formula (IVa)-(IVc), n is 0. In some embodiments of a compound of Formula (IVa)-(IVc), n is 0, 1, or 2. In some embodiments of a compound of Formula (IVa)-(IVc), n is 0 or 1.

[0160] In some embodiments of a compound of Formula (

[0161] In some embodiments of a compound of Formula (IVa)-(IVc) or (Va)-(Vc), Ring B is aryl or heteroaryl. In some embodiments of a compound of Formula (IVa)-(IVc) or (Va)-(Vc), Ring B is heteroaryl. In some embodiments of a compound of Formula (IVa)-(IVc) or (Va)-(Vc), Ring B is a bicyclic heteroaryl. In some embodiments of a compound of Formula (IVa)-(IVc) or (Va)-(Vc), Ring B is a bicyclic heteroaryl comprising one aromatic ring and one non aromatic ring. In some embodiments of a compound of Formula (IVa)-(IVc) or (Va)-(Vc), Ring B is a 5- or 6-membered heteroaryl. In some embodiments of a compound of Formula (IVa)-(IVc) or (Va)-(Vc), Ring B is a 5-membered heteroaryl. In some embodiments of a compound of Formula (IVa)-(IVc) or (Va)-(Vc), Ring B is a 5-membered heteroaryl comprising one, two, or three heteroatoms selected from oxygen, nitrogen, and sulfur. In some embodiments of a compound of Formula (IVa)-(IVc) or (Va)-(Vc), Ring B is a 5-membered heteroaryl comprising one or two heteroatoms selected from oxygen, nitrogen, and sulfur. In some embodiments of a compound of Formula (IVa)-(IVc) or (Va)-(Vc), Ring B is aryl. In some embodiments of a compound of Formula (IVa)-(IVc) or (Va)-(Vc), Ring B is phenyl. In some embodiments of a compound of Formula (IVa)-(IVc) or (Va)-(Vc), Ring B is a bicyclic aryl. In some embodiments of a compound of Formula (IVa)-(IVc) or (Va)-(Vc), Ring B is a bicyclic aryl comprising one aromatic ring and one non aromatic ring.

[0162] In some embodiments of a compound of Formula (IVa)-(IVc), each R2is independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1- C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl. In some embodiments of a compound of Formula (IVa)-(IVc), each R2is independently deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, or C1- C6deuteroalkyl. In some embodiments of a compound of Formula (IVa)-(IVc), each R2is independentlyC1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl. In some embodiments of a compound of Formula (IVa)-(IVc), each R2is independently C1-C6alkyl or C1-C6deuteroalkyl. In some embodiments of a compound of Formula (IVa)-(IVc), each R2is independently C1-C6alkyl.

[0163] In some embodiments of a compound of Formula (IVa)-(IVc), m is 0, 1, or 2. In some embodiments of a compound of Formula (IVa)-(IVc), m is 1 or 2. In some embodiments of a compound of Formula (IVa)-(IVc), m is 0 or 1. In some embodiments of a compound of Formula (IVa)-(IVc), m is 1. In some embodiments of a compound of Formula (IVa)-(IVc), m is 2. some embodiments of a compound of Formula (IVa)-(IVc),is.

[0165] In some embodiments of a compound of Formula (Va)-(Vc), each R11is independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1- C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R.

[0166] In some embodiments of a compound of Formula (Va)-(Vc), each R11is independently deuterium, halogen, -CN, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, - S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1- C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, or C2-C6alkynyl.

[0167] In some embodiments of a compound of Formula (Va)-(Vc), each R11is independently deuterium, halogen, -CN, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, or C1-C6haloalkyl.

[0168] In some embodiments of a compound of Formula (Va)-(Vc), each R11is independently - OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, or -NRbC(=O)ORb.

[0169] In some embodiments of a compound of Formula (Va)-(Vc), each R11is independently - - NRbC(=O)ORb.

[0170] In some embodiments of a compound of Formula (Va)-(Vc), each R11is independently deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl. In some embodiments of a compound of Formula (Va)-(Vc), each R11is independently halogen or C1-C6alkyl. In some embodiments of a compound of Formula (Va)-(Vc), each R11is independently halogen. In some embodiments of a compound of Formula (Va)-(Vc), each R11is independently C1-C6alkyl.

[0171] In some embodiments of a compound of Formula (Va)-(Vc), n1 is 0. In some embodiments of a compound of Formula (Va)-(Vc), n1 is 0 or 1. In some embodiments of a compound of Formula (Va)- (Vc), n1 is 1.

[0172] In some embodiments of a compound of Formula (. some embodiments of a compound of Formula (.

[0173] In some embodiments of a compound of Formula (Va)-(Vc), each R12is independently deuterium, halogen, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl. In some embodiments of a compound of Formula (Va)-(Vc), each R12is independently halogen or C1-C6alkyl. In some embodiments of a compound of Formula (Va)-(Vc), each R12is independently halogen. In some embodiments of a compound of Formula (Va)-(Vc), each R12is independently C1-C6alkyl.

[0174] In some embodiments of a compound of Formula (Va)-(Vc), m1 is 0. In some embodiments of a compound of Formula (Va)-(Vc), m1 is 0 or 1. In some embodiments of a compound of Formula (Va)- (Vc), m1 is 1.

[0175] In some embodiments of a compound of Formula (

[0176] In some embodiments of a compound of Formula (Va)-(Vc), Z is a C1-C8alkylene optionally substituted with one or more RZ; wherein one, two, or three carbon atoms of Z are optionally replaced by a heteroatom selected from oxygen, nitrogen, and sulfur.

[0177] In some embodiments of a compound of Formula (Va)-(Vc), Z is a C1-C6alkylene optionally substituted with one or more RZ; wherein one, two, or three carbon atoms of Z are optionally replaced by a heteroatom selected from oxygen, nitrogen, and sulfur.

[0178] In some embodiments of a compound of Formula (Va)-(Vc), Z is a C4-C6alkylene optionally substituted with one or more RZ; wherein one or two carbon atoms of Z are optionally replaced by a heteroatom selected from oxygen, nitrogen, and sulfur.

[0179] In some embodiments of a compound of Formula (Va)-(Vc), Z is a C1-C8alkylene optionally substituted with one or more RZ; wherein one or two carbon atoms of Z are optionally replaced by a heteroatom selected from oxygen, nitrogen, and sulfur.

[0180] In some embodiments of a compound of Formula (Va)-(Vc), Z is a C1-C6alkylene optionallysubstituted with one or more RZ; wherein one or two carbon atoms of Z are optionally replaced by a heteroatom selected from oxygen, nitrogen, and sulfur.

[0181] In some embodiments of a compound of Formula (Va)-(Vc), Z is a C4-C6alkylene optionally substituted with one or more RZ; wherein one or two carbon atoms of Z are optionally replaced by a heteroatom selected from oxygen, nitrogen, and sulfur.

[0182] In some embodiments of a compound of Formula (Va)-(Vc), Z is a C1-C8alkylene optionally substituted with one or more RZ; wherein one or two carbon atoms of Z are replaced by a heteroatom selected from oxygen, nitrogen, and sulfur.

[0183] In some embodiments of a compound of Formula (Va)-(Vc), Z is a C1-C6alkylene optionally substituted with one or more RZ; wherein one or two carbon atoms of Z are replaced by a heteroatom selected from oxygen, nitrogen, and sulfur.

[0184] In some embodiments of a compound of Formula (Va)-(Vc), Z is a C4-C6alkylene optionally substituted with one or more RZ; wherein one or two carbon atoms of Z are replaced by a heteroatom selected from oxygen, nitrogen, and sulfur.

[0185] In some embodiments of a compound of Formula (Va)-(Vc), Z is a C1-C8alkylene optionally substituted with one or more RZ; wherein one or two carbon atoms of Z are replaced by a heteroatom selected from oxygen and nitrogen.

[0186] In some embodiments of a compound of Formula (Va)-(Vc), Z is a C1-C6alkylene optionally substituted with one or more RZ; wherein one or two carbon atoms of Z are replaced by a heteroatom selected from oxygen and nitrogen.

[0187] In some embodiments of a compound of Formula (Va)-(Vc), Z is a C4-C6alkylene optionally substituted with one or more RZ; wherein one or two carbon atoms of Z are replaced by a heteroatom selected from oxygen and nitrogen.

[0188] In some embodiments of a compound of Formula (Va)-(Vc), Z is a C4-C6alkylene optionally substituted with one or more RZ; wherein one carbon atom of Z are replaced by a heteroatom selected from oxygen and nitrogen.

[0189] In some embodiments of a compound of Formula (Va)-(Vc), Z is a C4-C6alkylene optionally substituted with one or more RZ; wherein one or two carbon atoms of Z are replaced by a heteroatom that is oxygen.

[0190] In some embodiments of a compound of Formula (Va)-(Vc), Z is a C4alkylene optionally substituted with one or more RZ; wherein one or two carbon atoms of Z are optionally replaced by a heteroatom selected from oxygen, nitrogen, and sulfur.

[0191] In some embodiments of a compound of Formula (Va)-(Vc), Z is a C4alkylene optionally substituted with one or more RZ; wherein one or two carbon atoms of Z are replaced by a heteroatom selected from oxygen and nitrogen.

[0192] In some embodiments of a compound of Formula (Va)-(Vc), Z is a C4alkylene optionallysubstituted with one or more RZ; wherein one carbon atom of Z are replaced by a heteroatom selected from oxygen and nitrogen.

[0193] In some embodiments of a compound of Formula (Va)-(Vc), Z is a C4alkylene optionally substituted with one or more RZ; wherein one or two carbon atoms of Z are replaced by a heteroatom that is oxygen.

[0194] In some embodiments of a compound of Formula (Va)-(Vc), Z is a C4alkylene optionally substituted with one or more RZ; wherein one carbon atom of Z are replaced by a heteroatom that is oxygen.

[0195] In some embodiments of a compound of Formula (Va)-(Vc), each RZis independently deuterium, halogen, -CN, -OH, -ORa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -C(=O)Ra, - C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl; and / or two RZon the same carbon are taken together to form an oxo.

[0196] In some embodiments of a compound of Formula (Va)-(Vc), each RZis independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, C1-C6alkyl, C1-C6haloalkyl, or C1- C6deuteroalkyl; and / or two RZon the same carbon are taken together to form an oxo.

[0197] In some embodiments of a compound of Formula (Va)-(Vc), each RZis independently deuterium, halogen, -CN, -OH, -ORa, -C(=O)Ra, or C1-C6alkyl; and / or two RZon the same carbon are taken together to form an oxo.

[0198] In some embodiments of a compound of Formula (Va)-(Vc), each RZis independently -OH, - C(=O)Ra, or C1-C6alkyl; and / or two RZon the same carbon are taken together to form an oxo.

[0199] In some embodiments of a compound of Formula (Va)-(Vc), each RZis independently - C(=O)Raor C1-C6alkyl; and / or two RZon the same carbon are taken together to form an oxo.

[0200] In some embodiments of a compound of Formula (Va)-(Vc), each RZis independently - C(=O)Raand / or two RZon the same carbon are taken together to form an oxo.

[0201] In some embodiments of a compound of Formula (Va)-(Vc), two RZon the same carbon are taken together to form a cycloalkyl or a heterocycloalkyl; each independently optionally substituted with one or more R.

[0202] In some embodiments of a compound of Formula (Va)-(Vc), two RZon the same carbon are taken together to form a cycloalkyl independently optionally substituted with one or more R.

[0203] In some embodiments of a compound of Formula (Va)-(Vc), two RZon the same carbon are taken together to form a heterocycloalkyl optionally substituted with one or more R.

[0204] In some embodiments of a compound of Formula (Va)-(Vc), two RZon the different atoms are taken together to form a cycloalkyl or a heterocycloalkyl; each independently optionally substituted with one or more R.

[0205] In some embodiments of a compound of Formula (Va)-(Vc), two RZ on the different atoms aretaken together to form a cycloalkyl independently optionally substituted with one or more R.

[0206] In some embodiments of a compound of Formula (Va)-(Vc), two RZon the different atoms are taken together to form a 3- to 6-membered cycloalkyl independently optionally substituted with one or more R.

[0207] In some embodiments of a compound of Formula (Va)-(Vc), two RZon the different atoms are taken together to form a 4- to 5-membered cycloalkyl independently optionally substituted with one or more R.

[0208] In some embodiments of a compound of Formula (Va)-(Vc), two RZon the different atoms are taken together to form a 3- to 5-membered cycloalkyl independently optionally substituted with one or more R.

[0209] In some embodiments of a compound of Formula (Va)-(Vc), two RZon the different atoms are taken together to form a 4- to 6-membered cycloalkyl independently optionally substituted with one or more R.

[0210] In some embodiments of a compound of Formula (Va)-(Vc), two RZon the different atoms are taken together to form a heterocycloalkyl independently optionally substituted with one or more R.

[0211] In some embodiments of a compound of Formula (Va)-(Vc), two RZon the different atoms are taken together to form a 4- to 6-membered heterocycloalkyl independently optionally substituted with one or more R.

[0212] In some embodiments of a compound of Formula (Va)-(Vc), two RZon the different atoms are taken together to form a 5- to 6-membered heterocycloalkyl independently optionally substituted with one or more R.

[0213] In some embodiments of a compound of Formula (Va)-(Vc), two RZon the different atoms are taken together to form a 4- to 5-membered heterocycloalkyl independently optionally substituted with one or more R.

[0214] In some embodiments of a compound of Formula (,

[0215] In some embodiments of a compound of Formula (Va)-(Vc), Z is,

[0216] In some embodiments of a compound of Formula (Va)-(Vc), Z isor.

[0217] In some embodiments of a compound of Formula (Va)-(Vc), Z is, ,.

[0220] In some embodiments of a compound of Formula (Va)-(Vc), Z is ,

[0222] In some embodiments of a compound of Formula (IVa)-(IVc) or (Va)-(Vc), Ring C is heteroaryl.

[0223] In some embodiments of a compound of Formula (IVa)-(IVc) or (Va)-(Vc), Ring C is 5- or 6- membered heteroaryl.

[0224] In some embodiments of a compound of Formula (IVa)-(IVc) or (Va)-(Vc), Ring C is 5- membered heteroaryl. In some embodiments of a compound of Formula (IVa)-(IVc) or (Va)-(Vc), Ring C is 5-membered heteroaryl comprising one, two, three, or four heteroatoms selected from oxygen, nitrogen, and sulfur. In some embodiments of a compound of Formula (IVa)-(IVc) or (Va)-(Vc), Ring C is 5-membered heteroaryl comprising one, two, or three heteroatoms selected from oxygen, nitrogen, and sulfur.

[0225] In some embodiments of a compound of Formula (IVa)-(IVc) or (Va)-(Vc), Ring C is 6- membered heteroaryl. In some embodiments of a compound of Formula (IVa)-(IVc) or (Va)-(Vc), Ring C is 6-membered heteroaryl comprising one or two heteroatoms that are nitrogens. In some embodiments of a compound of Formula (IVa)-(IVc) or (Va)-(Vc), Ring C is 6-membered heteroaryl comprising one heteroatom that are nitrogens.

[0226] In some embodiments of a compound of Formula (IVa)-(IVc) or (Va)-(Vc), each R3is independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1- C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl.

[0227] In some embodiments of a compound of Formula (IVa)-(IVc) or (Va)-(Vc), each R3is independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, or C1- C6deuteroalkyl.

[0228] In some embodiments of a compound of Formula (IVa)-(IVc) or (Va)-(Vc), each R3is independently halogen, -OH, -ORa, or C1-C6alkyl.

[0229] In some embodiments of a compound of Formula (IVa)-(IVc) or (Va)-(Vc), each R3is independently halogen or C1-C6alkyl.

[0230] In some embodiments of a compound of Formula (IVa)-(IVc) or (Va)-(Vc), p is 1 or 2. In some embodiments of a compound of Formula (IVa)-(IVc) or (Va)-(Vc), p is 2. In some embodiments of a compound of Formula (IVa)-(IVc) or (Va)-(Vc), p is 1.

[0232] In some embodiments of a compound of Formula (IVa)-(IVc) or (Va)-(Vc), R4is hydrogen.

[0233] In some embodiments of a compound of Formula (IVa)-(IVc) or (Va)-(Vc), each L1is independently -O-, -NRb-, -C(=O)-, -OC(=O)-, -C(=O)O-, -C(=O)NRb-, -NRbC(=O)-, -NRbC(=O)NRb-, C1-C10alkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene; wherein each alkylene, cycloalkylene, heterocycloalkylene, arylene, and heteroarylene is independently optionally substituted with one or more R.

[0234] In some embodiments of a compound of Formula (IVa)-(IVc) or (Va)-(Vc), each L1is independently -O-, -NRb-, -C(=O)-, -C(=O)NRb-, -NRbC(=O)-, -NRbC(=O)NRb-, C1-C10alkylene, cycloalkylene, or heterocycloalkylene; wherein each alkylene, cycloalkylene, and heterocycloalkylene is independently optionally substituted with one or more R.

[0235] In some embodiments of a compound of Formula (IVa)-(IVc) or (Va)-(Vc), each L1is independently -C(=O)-, -C(=O)NRb-, C1-C10alkylene, or heterocycloalkylene; wherein each alkylene and cycloalkylene is independently optionally substituted with one or more R.

[0236] In some embodiments of a compound of Formula (IVa)-(IVc) or (Va)-(Vc), s is 1-15. In some embodiments of a compound of Formula (IVa)-(IVc) or (Va)-(Vc), s is 1-10. In some embodiments of a compound of Formula (IVa)-(IVc) or (Va)-(Vc), s is 1-5. In some embodiments of a compound of Formula (IVa)-(IVc) or (Va)-(Vc), s is 5-10. In some embodiments of a compound of Formula (IVa)- (IVc) or (Va)-(Vc), s is 5-15. In some embodiments of a compound of Formula (IVa)-(IVc) or (Va)-(Vc), s is 5-20. In some embodiments of a compound of Formula (IVa)-(IVc) or (Va)-(Vc), s is 1. In some embodiments of a compound of Formula (IVa)-(IVc) or (Va)-(Vc), s is 2. In some embodiments of a compound of Formula (IVa)-(IVc) or (Va)-(Vc), s is 3. In some embodiments of a compound of Formula (IVa)-(IVc) or (Va)-(Vc), s is 4. In some embodiments of a compound of Formula (IVa)-(IVc) or (Va)- (Vc), s is 5. In some embodiments of a compound of Formula (IVa)-(IVc) or (Va)-(Vc), s is 6. In some embodiments of a compound of Formula (IVa)-(IVc) or (Va)-(Vc), s is 7. In some embodiments of a compound of Formula (IVa)-(IVc) or (Va)-(Vc), s is 8. In some embodiments of a compound of Formula (IVa)-(IVc) or (Va)-(Vc), s is 9. In some embodiments of a compound of Formula (IVa)-(IVc) or (Va)- (Vc), s is 10. In some embodiments of a compound of Formula (IVa)-(IVc) or (Va)-(Vc), s is 11. In some embodiments of a compound of Formula (IVa)-(IVc) or (Va)-(Vc), s is 12. In some embodiments of a compound of Formula (IVa)-(IVc) or (Va)-(Vc), s is 13. In some embodiments of a compound of Formula (IVa)-(IVc) or (Va)-(Vc), s is 14. In some embodiments of a compound of Formula (IVa)-(IVc) or (Va)-(Vc), s is 15.

[0237] In some embodiments of a compound of Formula (IVa)-(IVc) or (Va)-(Vc), the E3 ligase targeting agent is a cereblon E3 ligase. In some embodiments of a compound of Formula (IVa)-(IVc) or (Va)-(Vc), the E3 ligase targeting agent is a VHL E3 ligase.

[0238] In some embodiments of a compound of Formula (IVa)-(IVc) or (Va)-(Vc), the E3 ligase

[0239] In some embodiments of a compound disclosed herein, each Rais independently C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, -L- cycloalkyl, or -L-heterocycloalkyl; wherein each alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosedherein, each Rais independently C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1- C6aminoalkyl, or C1-C6heteroalkyl. In some embodiments of a compound disclosed herein, each Rais independently C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl. In some embodiments of a compound disclosed herein, each Rais independently C1-C6alkyl or C1-C6haloalkyl. In some embodiments of a compound disclosed herein, each Rais independently C1-C6alkyl. In some embodiments of a compound disclosed herein, each Rais independently C1-C6haloalkyl.

[0240] In some embodiments of a compound disclosed herein, each Rbis independently hydrogen, C1- C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, -L- cycloalkyl, or -L-heterocycloalkyl; wherein each alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rbis independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1- C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl. In some embodiments of a compound disclosed herein, each Rbis independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl. In some embodiments of a compound disclosed herein, each Rbis independently hydrogen, C1-C6alkyl, or C1- C6haloalkyl. In some embodiments of a compound disclosed herein, each Rbis independently hydrogen or C1-C6alkyl. In some embodiments of a compound disclosed herein, each Rbis independently hydrogen or C1-C6haloalkyl. In some embodiments of a compound disclosed herein, each Rbis hydrogen. In some embodiments of a compound disclosed herein, each Rbis independently C1-C6alkyl.

[0241] In some embodiments of a compound disclosed herein, each Rcand Rdare independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1- C6heteroalkyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein each alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rcand Rdare independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1- C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl. In some embodiments of a compound disclosed herein, each Rcand Rdare independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl. In some embodiments of a compound disclosed herein, each Rcand Rdare independently hydrogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound disclosed herein, each Rcand Rdare independently hydrogen or C1-C6alkyl. In some embodiments of a compound disclosed herein, each Rcand Rdare independently hydrogen or C1-C6haloalkyl. In some embodiments of a compound disclosed herein, each Rcand Rdare hydrogen. In some embodiments of a compound disclosed herein, each Rcand Rdare independently C1-C6alkyl.

[0242] In some embodiments of a compound disclosed herein, Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl independently optionally substituted with one or more R.

[0243] In some embodiments of a compound disclosed herein, L is absent. In some embodiments of a compound disclosed herein, L is C1-C3alkylene optionally substituted with one or more R. In some embodiments of a compound disclosed herein, L is C1alkylene optionally substituted with one or more R. In some embodiments of a compound disclosed herein, L is C2alkylene optionally substituted with one ormore R. In some embodiments of a compound disclosed herein, L is C3alkylene optionally substituted with one or more R. In some embodiments of a compound disclosed herein, L is absent or -CH2-. In some embodiments of a compound disclosed herein, L is -CH2-. In some embodiments of a compound disclosed herein, L is -CH2CH2-. In some embodiments of a compound disclosed herein, L is - CH2CH2CH2-.

[0244] In some embodiments of a compound disclosed herein, each R is independently deuterium, halogen, -CN, -OH, -OC1-C3alkyl, -NH2, -NHC1-C3alkyl, -N(C1-C3alkyl)2, -NHC(=O)OC1-C3alkyl, - C(=O)C1-C3alkyl, -C(=O)OH, -C(=O)OC1-C3alkyl, -C(=O)NH2, -C(=O)N(C1-C3alkyl)2, -C(=O)NHC1- C3alkyl, C1-C3alkyl, C1-C3haloalkyl, C1-C3deuteroalkyl, C1-C3hydroxyalkyl, C1-C3aminoalkyl, or C1- C3heteroalkyl; and / or two R on the same atom are taken together to form an oxo. In some embodiments of a compound disclosed herein, each R is independently deuterium, halogen, -CN, -OH, -OC1-C3alkyl, - NH2, -NHC1-C3alkyl, -N(C1-C3alkyl)2, C1-C3alkyl, C1-C3haloalkyl, C1-C3deuteroalkyl, C1- C3hydroxyalkyl, C1-C3aminoalkyl, or C1-C3heteroalkyl; and / or two R on the same atom are taken together to form an oxo. In some embodiments of a compound disclosed herein, each R is independently deuterium, halogen, -CN, -OH, -OC1-C3alkyl, -NH2, C1-C3alkyl, or C1-C3haloalkyl; and / or two R on the same atom are taken together to form an oxo. In some embodiments of a compound disclosed herein, each R is independently deuterium, halogen, C1-C3alkyl, or C1-C3haloalkyl; and / or two R on the same atom are taken together to form an oxo.

[0245] Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one skilled in the field to provide stable moieties and compounds.

[0246] In some embodiments, the compound is selected from a compound of table 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.* stereochemistry arbitrarily assigned. ** regiochemistry arbitrarily assigned.

[0247] In some embodiments, the compound is selected from the group consisting of:pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0248] In some embodiments, the compound is selected from the group consisting of:pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0249] In some embodiments, the compound is selected from the group consisting of:pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0251] In some embodiments, the compound is selected from the group consisting of:stereoisomer thereof.

[0252] In some embodiments, the compound is selected from the group consisting of:stereoisomer thereof.

[0253] In some embodiments, the compound is selected from the group consisting of:,, , , ,pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0254] In some embodiments, the compound is selected from the group consisting of:, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0255] In some embodiments, the compound is selected from the group consisting of:, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0256] In some embodiments, the compound is selected from the group consisting of:pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0257] In some embodiments, the compound is selected from the group consisting of:, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0258] In some embodiments, the compound is selected from the group consisting of:pharmaceutically acceptable salt, solvate, or, , .

[0259] In some embodiments, the compound is selected from the group consisting of:,, ,,pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0260] In some embodiments, the compound is selected from the group consisting of:solvate, or stereoisomer thereof. Further Forms of Compounds Disclosed Herein Isomers / Stereoisomers

[0261] In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compoundspresented herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the corresponding mixtures thereof. In some situations, the compounds described herein possess one or more chiral centers and each center independently exists in the R configuration or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation / resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization. Labeled compounds

[0262] In some embodiments, the compounds described herein exist in their isotopically-labeled forms. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chlorine, such as2H,3H,13C,14C,l5N,18O,17O,31P,32P,35S,18F, and36Cl, respectively. Compounds described herein, and the pharmaceutically acceptable salts, solvates, or stereoisomers thereof which contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds, for example those into which radioactive isotopes such as3H and14C are incorporated, are useful in drug and / or substrate tissue distribution assays. Tritiated, i.e.,3H and carbon-14, i.e.,14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavy isotopes such as deuterium, i.e.,2H, produces certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. In some embodiments, one or more hydrogen in a compound disclosed herein has been replaced by a deuterium atom. In some embodiments, one or more alkyl substituents in a compound disclosed herein has been replaced by a deuteroalkyl substituents.

[0263] In some embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels. Pharmaceutically acceptable salts

[0264] In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[0265] In some embodiments, the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or a solvate, or stereoisomer thereof, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.

[0266] Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid or inorganic base, such salts including, but not limited to, acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, gluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate, γ-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate metaphosphate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-napthalenesulfonate, 2-napthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylate, undecanoate, and xylenesulfonate.

[0267] Further, the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and 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, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4’-methylenebis-(3-hydroxy-2-ene-1- carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid and muconic acid. In some embodiments, other acids, such as oxalic, while not in themselves pharmaceutically acceptable, are employed in the preparation of salts useful as intermediates in obtaining the compounds disclosed herein, solvate, or stereoisomer thereof and their pharmaceutically acceptable acid addition salts.

[0268] In some embodiments, those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts and the like. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N+(C1-C4alkyl)4hydroxide, and the like.

[0269] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quaternization. Solvates

[0270] In some embodiments, the compounds described herein exist as solvates. The invention provides for methods of treating diseases by administering such solvates. The invention further provides for methods of treating diseases by administering such solvates as pharmaceutical compositions.

[0271] Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, are formed with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein can be conveniently prepared from an aqueous / organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofuran or methanol. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein. Method of Treatment

[0272] Disclosed herein are methods of treating diseases or disorders in a subject, the method comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0273] Disclosed herein are methods of treating diseases or disorders mediated by JAK2 V617F comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0274] Myeloproliferative diseases (MPD) are multipotent hematopoietic stem cell disorders characterized by excess production of various blood cells. MPNs include polycythemia vera (PV), essential thrombocythemia (ET), and idiopathic myelofibrosis (IMF). JAK2 V617F mutation is reported in about 95% of patients with PV, in 35% to 70% of patients with ET, and 50% of patients with IMF. Also, JAK2 exon 12 mutations are detected in some of the V617F-negative PV patients. In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are useful in the treatment of myeloproliferative disorders (e.g., myeloproliferative neoplasms) in a patient in need thereof, such as polycythemia vera, essential thrombocythemia, myelofibrosis with myeloid metaplasia (MMM), primary myelofibrosis (PMF), chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), hypereosinophilic syndrome (HES), systemic mast cell disease (SMCD), and the like. In some embodiments, the myeloproliferative disorder is a myeloproliferative neoplasm. In some embodiments, the myeloproliferative disorder is myelofibrosis (e.g., primary myelofibrosis (PMF) or post polycythemia vera / essential thrombocythemia myelofibrosis (Post-PV / ET MF)). In some embodiments, the myeloproliferative disorder is primary myelofibrosis (PMF). In some embodiments, the myeloproliferative disorder is post-essential thrombocythemia myelofibrosis (Post-ET MF). In some embodiments, the myeloproliferative disorder is post polycythemia vera myelofibrosis (Post-PV MF). In some embodiments, the myeloproliferative disorder is selected from primary myelofibrosis (PMF), polycythemia vera (PV), and essential thrombocythemia (ET). In some embodiments, the myeloproliferative neoplasm is primary myelofibrosis (PMF). In some embodiments, the myeloproliferative neoplasm is polycythemia vera (PV). In some embodiments, the myeloproliferative neoplasm is essential thrombocythemia (ET). Myeloproliferative diseases include disorders of a bone marrow or lymph node-derived cell type, such as a white blood cell. A myeloproliferative disease can manifest by abnormal cell division resulting in an abnormal level of a particular hematological cell population. The abnormal cell division underlying a proliferative hematological disorder is typically inherent in the cells and not a normal physiological response to infection or inflammation. Leukemia is a type of myeloproliferative disease. Exemplary myeloproliferative diseases include, but are not limited to, acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), myelodysplastic syndrome (MDS), chronic myeloid leukemia (CML), hairy cell leukemia, leukemic manifestations of lymphomas, multiple myeloma, polycythemia vera (PV), essential thrombocythemia (ET), idiopathic myelofibrosis (IMF), hypereosinophilic syndrome (HES), chronic neutrophilic leukemia (CNL), myelofibrosis with myeloid metaplasia (MMM), chronic myelomonocytic leukemia (CMML), juvenile myelomonocytic leukemia, chronic basophilic leukemia, chronic eosinophilic leukemia, systemic mastocytosis (SM), and unclassified myeloproliferative diseases (UMPD or MPD-NC). Lymphoma is a type of proliferative disease that mainly involves lymphoid organs, such as lymph nodes, liver, and spleen. Exemplaryproliferative lymphoid disorders include lymphocytic lymphoma (also called chronic lymphocytic leukemia), follicular lymphoma, large cell lymphoma, Burkitt's lymphoma, marginal zone lymphoma, lymphoblastic lymphoma (also called acute lymphoblastic lymphoma). In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are useful in the treatment of cancer. Example cancers include bladder cancer (e.g., urothelial carcinoma, squamous cell carcinoma, adenocarcinoma), breast cancer (e.g., hormone R positive, triple negative), cervical cancer, colorectal cancer, cancer of the small intestine, colon cancer, rectal cancer, cancer of the anus, endometrial cancer, gastric cancer (e.g., gastrointestinal stromal tumors), head and neck cancer (e.g., cancers of the larynx, hypopharynx, nasopharynx, oropharynx, lips, and mouth, squamous head and neck cancers), kidney cancer (e.g., renal cell carcinoma, urothelial carcinoma, sarcoma, Wilms tumor), liver cancer (e.g., hepatocellular carcinoma, cholangiocellular carcinoma (e.g., intrahepatic, hilar or perihilar, distal extrahepatic), liver angiosarcoma, hepatoblastoma), lung cancer (e.g., adenocarcinoma, small cell lung cancer and non-small cell lung carcinomas, parvicellular and non-parvicellular carcinoma, bronchial carcinoma, bronchial adenoma, pleuropulmonary blastoma), ovarian cancer, prostate cancer, testicular cancer, uterine cancer, vulvar cancer, esophageal cancer, gall bladder cancer, pancreatic cancer (e.g. exocrine pancreatic carcinoma), stomach cancer, thyroid cancer, parathyroid cancer, neuroendocrine cancer (e.g., pheochromocytoma, Merkel cell cancer, neuroendocrine carcinoma), skin cancer (e.g., squamous cell carcinoma, Kaposi sarcoma, Merkel cell skin cancer), and brain cancer (e.g., astrocytoma, medulloblastoma, ependymoma, neuro- ectodermal tumors, pineal tumors). Further example cancers include hematopoietic malignancies such as leukemia or lymphoma, multiple myeloma, chronic lymphocytic lymphoma, adult T cell leukemia, acute myeloid leukemia (AML), B-cell lymphoma, cutaneous T-cell lymphoma, acute myelogenous leukemia, Hodgkin’s or non-Hodgkin’s lymphoma, myeloproliferative neoplasms (e.g., 8p11 myeloproliferative syndrome, polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF)), myelodysplastic syndrome, chronic eosinophilic leukemia, Waldenstrom's Macröglobulinemia (WM), hairy cell lymphoma, chronic myelogenous lymphoma, acute lymphoblastic lymphoma, AIDS-related lymphomas, and Burkitt's lymphoma. In some embodiments, the cancer is selected from T lymphoblastic lymphoma, glioblastoma, melanoma, rhabdosarcoma, lymphosarcoma, and osteosarcoma. Other cancers treatable with the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, include tumors of the eye, glioblastoma, melanoma, leiomyosarcoma, and urothelial carcinoma (e.g., ureter, urethra, bladder, urachus). The compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, can also be useful in the inhibition of tumor metastases. In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, can be used to treat Alzheimer’s disease, HIV, or tuberculosis. In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are useful in the treatment of myelodysplastic syndrome (MDS) in a patient in need thereof. In some embodiments, said patient having the myelodysplastic syndrome (MDS) is red blood cell transfusion dependent. As used herein, myelodysplastic syndromes are intended to encompassheterogeneous and clonal hematopoietic disorders that are characterized by ineffective hematopoiesis on one or more of the major myeloid cell lineages. Myelodysplastic syndromes are associated with bone marrow failure, peripheral blood cytopenia, and a propensity to progress to acute myeloid leukemia (AML). Moreover, clonal cytogenetic abnormalities can be detected in about 50% of cases with MDS.

[0275] In some embodiments, the myelodysplastic syndrome is refractory cytopenia with unilineage dysplasia (RCUD). In some embodiments, the myelodysplastic syndrome is refractory anemia with ring sideroblasts (RARS). In some embodiments, the myelodysplastic syndrome is refractory anemia with ring sideroblasts associated with thrombocytosis (RARS-T). In some embodiments, the myelodysplastic syndrome is refractory cytopenia with multilineage dysplasia. In some embodiments, the myelodysplastic syndrome is refractory anemia with excess blasts-1 (RAEB-1). In some embodiments, the myelodysplastic syndrome is refractory anemia with excess blasts-2 (RAEB-2). In some embodiments, the myelodysplastic syndrome is myelodysplastic syndrome, unclassified (MDS-U). In some embodiments, the myelodysplastic syndrome is myelodysplastic syndrome associated with isolated del(5q). In some embodiments, the myelodysplastic syndrome is refractory to erythropoiesis-stimulating agents. In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are useful in the treatment of myeloproliferative disorder / myelodysplastic overlap syndrome (MPD / MDS overlap syndrome). In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are useful in the treatment of leukemia. In some embodiments, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are useful in the treatment of acute myeloid leukemia (AML). In addition to oncogenic neoplasms, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are useful in the treatment of skeletal and chondrocyte disorders including, but not limited to, achondroplasia, hypochondroplasia, dwarfism, thanatophoric dysplasia (TD) (clinical forms TD I and TD II), Apert syndrome, Crouzon syndrome, Jackson-Weiss syndrome, Beare-Stevenson cutis gyrate syndrome, Pfeiffer syndrome, and craniosynostosis syndromes. The compounds provided herein may further be useful in the treatment of fibrotic diseases, such as where a disease symptom or disorder is characterized by fibrosis. Example fibrotic diseases include liver cirrhosis, glomerulonephritis, pulmonary fibrosis, systemic fibrosis, rheumatoid arthritis, and wound healing. In some embodiments, the compounds provided herein can be used in the treatment of a hypophosphatemia disorder such as, for example, X-linked hypophosphatemic rickets, autosomal recessive hypophosphatemic rickets, and autosomal dominant hypophosphatemic rickets, or tumor-induced osteomalacia. In some embodiments, provided herein is a method of increasing survival or progression-free survival in a patient, comprising administering a compound provided herein to the patient. Dosing

[0276] In certain embodiments, the compositions containing the compound(s) described herein are administered for prophylactic and / or therapeutic treatments. In certain therapeutic applications, thecompositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient’s health status, weight, and response to the drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation and / or dose ranging clinical trial.

[0277] When used in patients, effective amounts for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient’s health status and response to the drugs, and the judgment of the treating physician. In one aspect, prophylactic treatments include administering to a mammal, who previously experienced at least one symptom of or risk factor for the disease being treated and is currently in remission, a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, in order to prevent a return of the symptoms of the disease or condition.

[0278] In certain embodiments wherein the patient’s condition does not improve, upon the doctor’s discretion the compounds are administered chronically, that is, for an extended period of time, including throughout the duration of the patient’s life in order to ameliorate or otherwise control or limit the symptoms of the patient’s disease or condition.

[0279] Once improvement of the patient’s conditions has occurred, a maintenance dose is administered if necessary. Subsequently, in specific embodiments, the dosage, or the frequency of administration, or both, is reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. In certain embodiments, however, the patient requires intermittent or daily treatment on a long-term basis upon any recurrence of symptoms.

[0280] The amount of a given agent that corresponds to such an amount varies depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight, sex) of the subject or host in need of treatment, but nevertheless is determined according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated. Routes of Administration

[0281] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration. In addition, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections.

[0282] In certain embodiments, a compound as described herein is administered in a local rather than systemic manner, for example, via injection of the compound directly into an organ, often in a depot preparation or sustained release formulation. In specific embodiments, long-acting formulations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscularinjection. Furthermore, in other embodiments, the drug is delivered in a targeted drug delivery system, for example, in a liposome coated with organ specific antibody. In such embodiments, the liposomes are targeted to and taken up selectively by the organ. In yet other embodiments, the compound as described herein is provided in the form of a rapid release formulation, in the form of an extended-release formulation, or in the form of an intermediate-release formulation. In some embodiments, the compound described herein is administered topically. Pharmaceutical Compositions / Formulations

[0283] The compounds described herein are administered to a subject, either alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents, in a pharmaceutical composition, according to standard pharmaceutical practice. In one embodiment, the compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, may be administered to animals. The compounds can be administered orally or parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal, and topical routes of administration.

[0284] In another aspect, provided herein are pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and at least one pharmaceutically acceptable excipient. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins1999), herein incorporated by reference for such disclosure. Combination

[0285] Disclosed herein are methods of treating a JAK2 V617F-mediated disorder or disease using a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, in combination with an additional therapeutic agent.

[0286] In some embodiments, the additional therapeutic agent is administered at the same time as the compound disclosed herein. In some embodiments, the additional therapeutic agent and the compound disclosed herein are administered sequentially. In some embodiments, the additional therapeutic agent is administered less frequently than the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered more frequently than the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered prior than the administration of thecompound disclosed herein. In some embodiments, the additional therapeutic agent is administered after the administration of the compound disclosed herein. Example

[0287] In some embodiments, the compounds disclosed herein are synthesized using the scheme below.Step 1: 4-Bromo-3-fluoro-1-methyl-pyrazole

[0288] To a solution of 4-bromo-3-fluoro-1H-pyrazole (5 g, 30.31 mmol) in DMF (50.00 mL) was added NaH (2.42 g, 60.62 mmol) at 0 °C and stirred at 0 °C for 30 min. Then iodomethane (5.59 g, 39.40 mmol, 2.45 mL) was added and the resulting mixture was stirred at 25oC for 2 h. TLC showed that the starting material was consumed and the product was formed. The reaction mixture was quenched with NH4Cl (sat., 50 mL) and extracted with EA (300 mL). The organics were washed with 10% LiCl aqueous(100 ml X 2), 10% brine (100 ml X 2) and saturated brine (70 ml), dried over sodium sulfate, filtered, and evaporated to dryness in vacuo (Note: below 25 °C, low boiling point for product) to give residue. The residue was purified by column chromatography (80 g Silica Flash Column, Eluent of 0~10% Ethyl acetate / Petroleum ether gradient @ 45 mL / min) to give 4-bromo-3-fluoro-1-methyl-pyrazole (5.40 g, 28.66 mmol, 94.56% yield, 95% purity) as yellow oil. LCMS: [M+H]+= 179.1;1H NMR (400 MHz, DMSO-D6) δ 8.07-7.87 (m, 1H), 3.74 (s, 3H) Step 2: 3-Fluoro-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole

[0289] Argon was purged for 10 min through a stirred solution of 4-bromo-3-fluoro-1-methyl- pyrazole (5.4 g, 30.17 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2- dioxaborolane (22.98 g, 90.51 mmol) and KOAc (7.40 g, 75.42 mmol) in dry Dioxane (100 mL) then Pd(dppf)Cl2 (1.10 g, 1.51 mmol) was added to it and further purging done for 10 min. The resulting mixture was stirred at 105 °C for 12 h. LCMS showed the 61.59% desired product was formed. The reaction mixture was filtered, washed with EA and concentrated. The residue was purified by column chromatography column chromatography (80 g Silica Flash Column, Eluent of 0~25% Ethyl acetate / Petroleum ether gradient @ 45 mL / min) followed by trituration with hexane to give 3-fluoro-1- methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (3.10 g, 13.16 mmol, 43.64% yield, 96% purity) as a white solid. LCMS: [M+H]+= 227.1;1H NMR (400 MHz, DMSO-d6) δ 7.97-7.58 (m, 1H), 3.86-3.53 (m, 3H), 1.35-1.08 (m, 12H). Step 3: tert-Butyl N-[(1R,3R)-3-[[1-(benzenesulfonyl)-5-nitro-pyrrolo[2,3-b]pyridin-4- yl]amino]cyclopentyl]carbamate

[0290] A mixture of 1-(benzenesulfonyl)-4-chloro-5-nitro-pyrrolo[2,3-b]pyridine (23.8 g, 70.47 mmol), tert-butyl N-[(1R,3R)-3-aminocyclopentyl]carbamate (14.11 g, 70.47 mmol) and TEA (14.26 g, 140.94 mmol) in CH3CN (200 mL) was stirred at 70 °C for 1 h. LCMS showed that all the starting material was consumed and the product was formed. The solvent was removed under vacuum to give a residue. The residue was triturated with 300 ml water and the precipitated solid was filtered and dried under vacuum to give tert-butyl N-[(1R,3R)-3-[[1-(benzenesulfonyl)-5-nitro-pyrrolo[2,3-b]pyridin-4- yl]amino]cyclopentyl]carbamate (60.00 g, crude) as a yellow solid. LCMS: [M+H]+= 502.00 Step 4: tert-Butyl N-[(1R,3R)-3-[[5-amino-1-(benzenesulfonyl)pyrrolo[2,3-b]pyridin-4- yl]amino]cyclopentyl]carbamate

[0291] To a solution of tert-butyl N-[(1R,3R)-3-[[1-(benzenesulfonyl)-5-nitro-pyrrolo[2,3-b]pyridin-4- yl]amino]cyclopentyl]carbamate (35 g, 69.78 mmol) in THF (80 mL) and EtOH (240 mL) was added Fe (38.97 g, 697.83 mmol) and HCl (1 M, 23 mL), then the mixture was stirred at 70 °C for 4 h. LCMS showed that all the starting material was converted into the product. The reaction was filtered and washed with EA. Then solvent was removed and the residue was diluted with 400 ml EA. The organic layer was washed with 300 ml saturated NaHCO3 and 200 ml brine, dried over Na2SO4, filtered and concentrated to give tert-butyl N-[(1R,3R)-3-[[5-amino-1-(benzenesulfonyl)pyrrolo[2,3-b]pyridin-4- yl]amino]cyclopentyl]carbamate (37.00 g, crude) as a gray solid which was taken into next step without further purification. LCMS: [M+H]+= 472.1.Intermediate 2Step 1: tert-Butyl N-[(1R,3R)-3-[10-(benzenesulfonyl)-4-oxo-3,5,8,10- tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3-yl]cyclopentyl]carbamate

[0292] To a solution of tert-butyl N-[(1R,3R)-3-[[5-amino-1-(benzenesulfonyl)pyrrolo[2,3-b]pyridin- 4-yl]amino]cyclopentyl]carbamate (35 g, 74.22 mmol) in CH3CN (150 mL) was added di(imidazol-1- yl)methanone (36.10 g, 222.66 mmol) and DMAP (13.60 g, 111.33 mmol), then the mixture was stirred at 70 °C for 2 h. LCMS showed that all the starting material was converted into the product. The solvent was removed and diluted with 400 ml EA. The organic layer was washed with 400 ml water, 130 ml 1N HCl, 400 ml water and 200 ml brine. Then organic layer was dried over Na2SO4,filtered and concentrated to give tert-butyl N-[(1R,3R)-3-[10-(benzenesulfonyl)-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca- 1,6,8,11-tetraen-3-yl]cyclopentyl]carbamate (39.00 g, crude) as a yellow solid which was taken into next step without further purification. LCMS: [M+H]+= 498.0 Step 2: tert-Butyl N-[(1R,3R)-3-[10-(benzenesulfonyl)-5-methyl-4-oxo-3,5,8,10- tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3-yl]cyclopentyl]carbamate

[0293] To a solution of tert-butyl N-[(1R,3R)-3-[10-(benzenesulfonyl)-4-oxo-3,5,8,10- tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3-yl]cyclopentyl]carbamate (37 g, 74.36 mmol) in DMF (170 mL) was added K2CO3(30.83 g, 223.08 mmol) and MeI (31.66 g, 223.08 mmol, 13.89 mL) , then the mixture was stirred at 25 °C for 2 h. LCMS showed that all the starting material was converted into the product. The mixture was diluted with 750 ml EA and 750 ml water. The organic layer was washed with 750 ml water twice and 500 ml brine twice. Then organic layer was dried over Na2SO4,filtered and concentrated. The residue was purified by flash silica gel chromatography (120 g, Silica Flash Column, Eluent of 0~30% EA / DCM @ 60 mL / min) to give a tert-butyl N-[(1R,3R)-3-[10-(benzenesulfonyl)-5- methyl-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3-yl]cyclopentyl]carbamate(35.00 g, 61.57 mmol, 82.80% yield, 90% purity) as a yellow solid. LCMS: [M+H]+= 512.0;1H NMR (400 MHz, CHLOROFORM-d) δ 8.24-8.18 (m, 2H), 8.11 (s, 1H), 7.82-7.73 (m, 1H), 7.59-7.55 (m, 1H), 7.50-7.44 (m, 2H), 6.73-6.65 (m, 1H), 5.14-5.05 (m, 1H), 4.68 (s, 1H), 4.36-4.30 (m, 1H), 3.46 (s, 3H), 2.62-2.54 (m, 1H), 2.44 (tt, J = 12.0, 3.9 Hz, 1H), 2.35-2.25 (m, 1H), 2.20-2.10 (m, 1H), 2.04-1.97 (m, 1H), 1.71-1.61 (m, 1H), 1.49-1.42 (m, 10H). Step 3: tert-Butyl N-[(1R,3R)-3-[10-(benzenesulfonyl)-11-bromo-5-methyl-4-oxo-3,5,8,10- tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3-yl]cyclopentyl]carbamate

[0294] To a solution of tert-butyl N-[(1R,3R)-3-[10-(benzenesulfonyl)-5-methyl-4-oxo-3,5,8,10- tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3-yl]cyclopentyl]carbamate (5 g, 9.77 mmol) in THF (110 mL) was added LDA (2 M, 12.71 mL) at -78 °C under N2. The mixture was stirred for 30 min then added dropwise 1,2-dibromo-1,1,2,2-tetrachloro-ethane (4.46 g, 13.68 mmol) dissolved in 10 ml THF. The reaction was stirred at -78 °C for another 1.5 h. LCMS showed the 69.43% desired product was formed. The reaction mixture was quenched by NH4Cl 100 mL at -78 °C, and then diluted with EA 100 ml. The organic layers were washed with water (100 mL X 2), 50 ml brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (80 g Silica Flash Column, Eluent of 0~17% EA / DCM @ 50 mL / min) to give tert-butyl N-[(1R,3R)-3-[10-(benzenesulfonyl)-11-bromo-5-methyl-4-oxo-3,5,8,10- tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3-yl]cyclopentyl]carbamate (4.70 g, 6.37 mmol, 65.15% yield, 80% purity) as a yellow solid. LCMS: [M, M+2]+= 589.9, 591.9;1H NMR (400 MHz, CHLOROFORM-d) δ 8.22-8.20 (m, 2H), 8.13 (s, 1H), 7.79 (d, J = 4.0 Hz, 0H), 7.62-7.57 (m, 1H), 7.50 (t, J = 7.8 Hz, 2H), 6.86 (s, 1H), 6.71 (d, J = 4.3 Hz, 0H), 5.13-5.00 (m, 1H), 4.66 (dd, J = 27.6, 12.6 Hz, 1H), 4.38-4.27 (m, 1H), 3.47 (s, 3H), 2.62-2.29 (m, 3H), 2.19-2.12 (m, 1H), 2.01 (d, J = 9.5 Hz, 1H), 1.72-1.63 (m, 1H), 1.48 (s, 9H). Step 4: tert-Butyl N-[(1R,3R)-3-[10-(benzenesulfonyl)-11-(3-fluoro-1-methyl-pyrazol-4-yl)-5- methyl-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3- yl]cyclopentyl]carbamate

[0295] A mixture of tert-butyl N-[(1R,3R)-3-[10-(benzenesulfonyl)-11-bromo-5-methyl-4-oxo- 3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3-yl]cyclopentyl]carbamate (4.92 g, 7.08 mmol), 3-fluoro-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (3 g, 10.62 mmol), Cs2CO3 (6.92 g, 21.23 mmol) and [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (519.32 mg, 707.79 μmol) in dioxane (36 mL) H2O (9 mL) was evacuated and backfilled with nitrogen (this process was repeated a total of three times), and then the reaction was stirred at 105 °C for 1.5 h. LCMS showed that most of the starting material was converted into the product. The reaction mixture was added H2O (20 mL) and extracted with EA (50 mLX2). The combined organics were dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash silica gel chromatography (80 g Silica Flash Column, Eluent of 50~70% ethyl acetate / petroleum ether @ 50 mL / min) to give tert-butyl N-[(1R,3R)- 3-[10-(benzenesulfonyl)-11-(3-fluoro-1-methyl-pyrazol-4-yl)-5-methyl-4-oxo-3,5,8,10- tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3-yl]cyclopentyl]carbamate (4.34 g, 5.69 mmol, 80.46%yield, 80% purity) as yellow solid. LCMS: [M+H]+= 610.3;1H NMR (400 MHz, DMSO-d6) δ 8.23-8.18 (m, 1H), 8.09 (d, J = 1.9 Hz, 1H), 7.89-7.84 (m, 2H), 7.70-7.64 (m, 1H), 7.57-7.53 (m, 2H), 7.21 (s, 1H), 7.07 (d, J = 7.1 Hz, 1H), 5.07-4.99 (m, 1H), 4.15 (d, J = 3.6 Hz, 1H), 3.85-3.82 (m, 3H), 3.36 (s, 3H), 2.39-2.32 (m, 1H), 2.19-2.03 (m, 3H), 1.85-1.79 (m, 1H), 1.60-1.49 (m, 1H), 1.46-1.34 (m, 11H). Step 5: tert-Butyl N-[(1R,3R)-3-[10-(benzenesulfonyl)-12-bromo-11-(3-fluoro-1-methyl-pyrazol-4- yl)-5-methyl-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3- yl]cyclopentyl]carbamate

[0296] A solution of tert-butyl N-[(1R,3R)-3-[10-(benzenesulfonyl)-11-(3-fluoro-1-methyl-pyrazol-4- yl)-5-methyl-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3- yl]cyclopentyl]carbamate (4.34 g, 7.12 mmol) in DMF (80 mL) was added NBS (1.27 g, 7.12 mmol). The resulting mixture was stirred at 25 °C for 16 h. LCMS showed the 86.16% desired product was formed. The solvent was removed in vacuum. The mixture was diluted with H2O (40 mL) and extracted with EA (80 mLX2). The combined organics were washed with saturated LiCl solution, then dried over sodium sulfate, filtered and concentrated. The residue was purified by flash silica gel chromatography (80 g Silica Flash Column, Eluent of 15~30% dichloromethane / ethyl acetate @ 50 mL / min) to give tert- butyl N-[(1R,3R)-3-[10-(benzenesulfonyl)-12-bromo-11-(3-fluoro-1-methyl-pyrazol-4-yl)-5-methyl-4- oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3-yl]cyclopentyl]carbamate (4.10 g, 5.36 mmol, 75.28% yield, 90% purity) as yellow solid. LCMS: [M+H]+= 688.2;1H NMR (400 MHz, DMSO-d6) δ 8.25 (s, 1H), 8.11 (d, J = 1.9 Hz, 1H), 7.90-7.84 (m, 2H), 7.74-7.67 (m, 1H), 7.58 (t, J = 7.8 Hz, 2H), 6.87 (d, J = 6.3 Hz, 1H), 5.83-5.77 (m, 1H), 4.27-4.10 (m, 1H), 3.89 (s, 3H), 3.38 (s, 3H), 2.43- 2.29 (m, 1H), 2.21-2.03 (m, 3H), 1.95-1.83 (m, 1H), 1.53-1.45 (m, 1H), 1.37 (s, 9H). Intermediate 3: Methyl (3R)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]butanoateStep1: Ethyl (3R)-3-(4-bromophenyl)butanoate

[0297] To a round-bottom flask was charged sequentially with (4-bromophenyl)boronic acid (100.0 g, 497.94 mmol), Rh(NBD)2BF4 (3.64 g, 9.96 mmol), (S)-BINAP (6.20 g, 9.96 mmol) and dioxane (1000 mL) at 30°C and the mixture was degassed with nitrogen and stirred at 30°C under nitrogen for 2 h to give a light pink slurry. Then water (100 mL) was added in one portion and followed by TEA (50.39 g, 497.94 mmol, 69.21 mL). The reaction was heated to 30 °C and neat ethyl (E)-but-2-enoate (68.20 g, 597.53 mmol, 74.30 mL) was added dropwise through addition funnel over 30 min under nitrogenatmosphere. The reaction was stirred at 30°C for a further 16 h. LCMS indicated about 39% conversion from SM to DP. The reaction was diluted with ethyl acetate and water. The two layers were separated, and the aqueous layer was extracted with ethyl acetate again. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. This reaction was repeated two times. The combined residue was purified by silica gel chromatography (Eluent of 0-10 % Ethyl acetate / Petroleum ether) to give ethyl (3R)-3-(4-bromophenyl)butanoate (190.00 g, 700.71 mmol, 70.36% yield) as a yellow oil. LCMS: [M, M+2]+= 271.1, 273.1. Step 2: (3R)-3-(4-Bromophenyl)butanoic acid

[0298] To a solution of ethyl (3R)-3-(4-bromophenyl)butanoate (110.0 g, 405.68 mmol) in EtOH (1100 mL) was added 5 M aq. NaOH (220 mL) at 25 °C, the resulting mixture was stirred at 30 °C for 2 h. LCMS indicated major TM, no SM. The resulting mixture was diluted with H2O and extracted with dichloromethane (3*1000 mL). The pH value of the aqueous layer was adjusted to 1-2 with aqueous HCl (2M). Then it was extracted with DCM. The combined organic layer were washed with brine, dried over Na2SO4, then filtered and concentrated under reduced pressure. Two batches were performed in parallel. The crude product was re-crystallized from Normal heptane (10v) to afford (3S)-3-(4- bromophenyl)butanoic acid (136.00 g, 559.45 mmol, 68.95% yield) as a white solid. LCMS: [M, M+2]+= 243.0, 245.1. Step 3: Methyl (3R)-3-(4-bromophenyl)butanoate

[0299] A solution of (3R)-3-(4-bromophenyl)butanoic acid (71 g, 292.06 mmol) in methanol (710 mL) was added SOCl2(69.51 g, 584.13 mmol, 42.39 mL) at 25 °C, the resulting mixture was stirred at rt for 2 h. LCMS indicated major TM. Two batches were performed in parallel. The reaction mixture was concentrated to dryness and purified by silica gel chromatography eluted with PE: EtOAc=3: 1 to give methyl (3S)-3-(4-bromophenyl)butanoate (128.00 g, 497.82 mmol, 94.69% yield) as colorless oil. LCMS: [M, M+2]+= 257.1, 259.0. Step 4: Methyl (3R)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]butanoate (intermediate 3)

[0300] To a solution of methyl (3R)-3-(4-bromophenyl)butanoate (64.00 g, 248.91 mmol) in dioxane (640.00 mL) was added Pin2B2 (82.17 g, 323.58 mmol) and Pd(dppf)Cl2 (18.21 g, 24.89 mmol) and KOAc (73.28 g, 746.72 mmol) at 25 °C, the resulting mixture was stirred at 100 °C for 2 h under N2. LCMS indicated major TM. Two batches were performed in parallel. The resulting mixture was diluted with EA (3000mL) and washed with brine (2000mLx3). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography eluted with PE: EtOAc=20: 1 to give methyl (3R)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]butanoate (Intermediate 3, 160.00 g, 525.99 mmol, 94.76% yield) as yellow solid. LCMS: [M+H]+= 305.3.1H NMR (400 MHz, CHLOROFORM-D) δ 7.74 (d, J = 8.0 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H), 3.63-3.57 (m, 3H), 3.23-3.30 (m, 1H), 2.65-2.51 (m, 2H), 1.33 (s, 12H), 1.28 (d, J = 6.9 Hz, 3H). Intermediate 4: Methyl (3S)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]butanoateStep1: Ethyl (3S)-3-(4-bromophenyl)butanoate

[0301] To a round-bottom flask was charged sequentially with (4-bromophenyl)boronic acid (50 g, 248.97 mmol), bicyclo[2.2.1]hepta-2,5-diene;rhodium(1+);trifluoroborane;fluoride (911.04 mg, 2.49 mmol), (R)-(+)-2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl (1.55 g, 2.49 mmol) and dioxane (500 mL) at 25°C and the mixture was degassed with nitrogen and stirred at 25°C under nitrogen for 0.5 h to give a light pink slurry. Then water (70 mL) was added in one portion and followed by TEA (25.19 g, 248.97 mmol, 35.99 mL). The reaction was heated to 30 °C and neat ethyl (E)-but-2-enoate (34.10 g, 298.77 mmol) was added through addition funnel over 10 min. The reaction was stirred at 30°C for 16 h. LCMS indicated about 40% conversion from SM to DP. The reaction was diluted with ethyl acetate and water. The two layers were separated and the aqueous layer was extracted with ethyl acetate again. The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by flash silica gel chromatography (Eluent of 5 % Ethyl acetate / Petroleum ether gradient @ 120 mL / min) to give ethyl (3S)-3-(4-bromophenyl)butanoate (25.70 g, 90.90 mmol, 36.51% yield, 95.9% purity) as a colorless oil. LCMS: [M, M+2]+= 271.2, 273. Step 2: (3S)-3-(4-Bromophenyl)butanoic acid

[0302] To a solution of ethyl (3S)-3-(4-bromophenyl)butanoate (40 g, 147.52 mmol) in MeOH (400 mL) was added an aqueous solution of 5 M NaOH (5 M, 59.01 mL) and the mixture was stirred at 25°C for 2 h. LCMS indicated all SM was converted into the product. The reaction was diluted with water (120 mL) and concentrated to remove methanol. The aqueous layer was adjusted pH~1 with 12 M HCl and then extracted with ethyl acetate three times. The combined organic layers were dried over sodium sulfate, filtered and concentrated to give crude (3S)-3-(4-bromophenyl)butanoic acid (35 g, 143.97 mmol) as off-white solid. Chiral HPLC showed that the ee value was about 88.3%.

[0303] To the crude (3S)-3-(4-bromophenyl)butanoic acid (35 g, 143.97 mmol) was added heptane (250 mL), and this mixture is heated in an oil bath until complete dissolution of all the solids (60-65 °C). The hot solution was transferred to a 1-L round-bottomed flask. Additional warm heptane (200 mL) was used to rinse the residual product into the 1-L flask. The mixture was allowed to cool slowly to 20 °C over the course of 4-5 h. As the temperature reaches 25-30 °C, as determined by an inserted thermometer,crystals begin to form on the side of the flask. The liquid phase was decanted, concentrated to dryness, and placed under reduced pressure (0.25 mmHg) for 2 h to give (3S)-3-(4-bromophenyl)butanoic acid (31.00 g, 127.52 mmol, 86.44% yield) as an white solid. Chiral HPLC showed that the ee value was increased to 96.7%. LCMS: [M, M+2]+= 243.0, 245.1. Step 3: Methyl (3S)-3-(4-bromophenyl)butanoate

[0304] To a solution of (3S)-3-(4-bromophenyl)butanoic acid (30.6 g, 125.88 mmol) in MeOH (200 mL) was added H2SO4 (4 mL) at 25°C and the mixture was stirred at 85°C for 16 h. LCMS indicated all SM was converted into product. The reaction was concentrated and diluted with ethyl acetate. The organic layer was washed with NaHCO3 (aq) and brine, dried over sodium sulfate, filtered and concentrated to give methyl (3S)-3-(4-bromophenyl)butanoate (30.00 g, 116.68 mmol, 92.69% yield) as a colorless oil which was pure enough for next step. LCMS: [M, M+2]+= 257.1, 259.1. Step 4: Methyl (3S)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]butanoate

[0305] To a solution of methyl (3S)-3-(4-bromophenyl)butanoate (30 g, 116.68 mmol) in dioxane (500 mL) was added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2- dioxaborolane (38.52 g, 151.68 mmol), 1,1'-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (4.83 g, 5.83 mmol), potassium acetate (34.35 g, 350.03 mmol) at 25°C under N2and the mixture was degassed with nitrogen three times and stirred at 90 °C for 16 h. LCMS indicated the SM was consumed and DP was formed. The reaction was filtered and concentrated. The residue was purified by flash silica gel chromatography (Eluent of 0~10% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) to give the intermediate 4, methyl (3S)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]butanoate (31.00 g, 91.72 mmol, 78.61% yield, 90% purity) as a white solid. LCMS: [M+H]+= 305.3.1H NMR (400 MHz, DMSO-D6) δ 7.68-7.59 (m, 2H), 7.27-7.22 (m, 2H), 3.54 (s, 3H), 3.22-3.13 (m, 1H), 2.64-2.56 (m, 2H), 1.30 (s, 12H), 1.20 (d, J = 6.9 Hz, 3H). Intermediate 5: tert-Butyl N-[(1S,2R,4S)-4-[10-(benzenesulfonyl)-12-bromo-11-(3-fluoro-1-methyl- pyrazol-4-yl)-5-methyl-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3-yl]-2- [tert-butyl(dimethyl)silyl]oxy-cyclopentyl]carbamateStep 1: Methyl (1R,4S)-4-aminocyclopent-2-ene-1-carboxylate hydrochloride

[0306] To a solution of (1S,4R)-2-azabicyclo [2.2.1] hept-5-en-3-one (92.00 g, 843.07 mmol) in MeOH (300 mL) was added thionyl chloride (61.13 g, 513.86 mmol) dropwise at 0 °C and stirred at 0°C for 2 h. TLC (PE / EA = 1 / 1) showed the starting material was consumed. The reaction was concentratedto remove the solvent. The crude was triturated with ethyl acetate to obtain methyl (1R,4S)-4- aminocyclopent-2-ene-1-carboxylate hydrochloride (150.00 g, quant.) as white solid which 1H NMR showed it was pure enough for next step. LCMS: [M+H]+= 142.1;1H NMR (400 MHz, DMSO-d6) δ 8.43 (s, 3H), 6.08-6.07 (m, 1H), 5.91-5.89 (m, 1H), 4.17 (s, 1H), 3.72-3.65 (m, 4H), 2.60-2.54 (m, 1H), 1.99-1.92 (m, 1H). Step 2: Methyl (1R,4S)-4-((tert-butoxycarbonyl) amino) cyclopent-2-ene-1-carboxylate

[0307] To a solution of methyl (1R,4S)-4-aminocyclopent-2-ene-1-carboxylate hydrochloride (150.00 g, 844.46 mmol) in THF (800 mL) and water (160 mL) was added sodium carbonate (98.45 g, 928.91 mmol), Boc2O (184.30 g, 844.46 mmol) at 0 °C and stirred at 25°C for 16 h. LCMS showed that the title compound was formed. The reaction was diluted with 1000 mL EtOAc and washed with 500 mL water and 500 mL brine. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was triturated with MTBE to obtain methyl (1R,4S)-4-((tert-butoxycarbonyl) amino) cyclopent-2-ene-1- carboxylate (185.00 g, crude, 88% yield over 2 steps) as white solid which was taken into next step without further purification. LCMS: [M+Na]+= 264.1;1H NMR (400 MHz, CHLOROFORM-D) δ 5.87 (q, J = 5.5 Hz, 2H), 4.93 (d, J = 8.2 Hz, 1H), 4.79 (s, 1H), 3.72 (s, 3H), 3.48 (q, J = 4.2 Hz, 1H), 2.55- 2.47 (m, 1H), 1.86 (dt, J = 13.9, 4.1 Hz, 1H), 1.44 (s, 9H). Step 3: Methyl (3aS,5S,6S,6aS)-6-iodo-2-oxohexahydro-2H-cyclopenta[d]oxazole-5-carboxylate

[0308] To a solution of methyl (1R,4S)-4-((tert-butoxycarbonyl) amino) cyclopent-2-ene-1- carboxylate (185.00 g, 766.74 mmol) in THF (1000 mL) and water (100 mL) was added N- Iodosuccinimide (258.75 g, 1.15 mol) at 0 °C and stirred at 25°C for 16 h. LCMS showed that the starting material was consumed. The reaction was concentrated to remove solvent and diluted with 2000 mL EtOAc and washed with 1000 mL 1 M HCl, 1000 mL Sat. sodium bicarbonate solution, 1000 mL Sat. Sodium thiosulfate and 1000 mL brine. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was triturated with MTBE to give methyl (3aS,5S,6S,6aS)-6-iodo-2- oxohexahydro-2H-cyclopenta[d]oxazole-5-carboxylate (174.00 g, crude, 72.9 %yield) as a white solid which was taken into next step without further purification. LCMS: [M+H]+= 312.2;1H NMR (400 MHz, CHLOROFORM-d) δ 6.46 (s, 1H), 5.27 (dd, J = 7.4, 2.2 Hz, 1H), 4.81-4.77 (m, 1H), 4.39 (td, J = 7.1, 2.2 Hz, 1H), 3.75 (s, 3H), 3.16-3.12 (m, 1H), 2.58-2.51 (m, 1H), 2.42-2.37 (m, 1H). Step 4: Methyl (3aS,5R,6aR)-2-oxohexahydro-2H-cyclopenta[d]oxazole-5-carboxylate

[0309] To a solution of methyl (3aS,5S,6S,6aS)-6-iodo-2-oxohexahydro-2H-cyclopenta[d]oxazole-5- carboxylate (168.00 g, 540.07 mmol) in MeOH (1700 mL) was added TEA (54.5 g, 540.07 mol) and 10%Pd / C (20%w / w) at 25 °C and stirred at 25°C under H2 atmosphere for 16 h. The reaction was filtered and concentrated. The residue, combined with the crude of last batch, was purified by flash silica gel chromatography (1000 g Silica Flash Column, Eluent of 0~100% EtOAc / PE gradient @ 200 mL / min) to obtain methyl (3aS,5R,6aR)-2-oxohexahydro-2H-cyclopenta[d]oxazole-5-carboxylate (59.80 g, 57.5% yield) as a white solid.1H NMR (400 MHz, CHLOROFORM-d) δ 6.19 (s, 1H), 5.08-5.01 (m, 1H), 4.26- 4.25 (m, 1H), 3.72 (s, 3H), 2.93-2.87 (m, 1H), 2.51 (d, J = 14.6 Hz, 1H), 2.32-2.17 (m, 2H), 2.12-2.05 (m, 1H).Step 5: Methyl (3aS,5S,6aR)-2-oxo-3,3a,4,5,6,6a-hexahydrocyclopenta[d]oxazole-5- carboxylate

[0310] To a solution of methyl (3aS,5R,6aR)-2-oxo-3,3a,4,5,6,6a-hexahydrocyclopenta[d]oxazole-5- carboxylate (45.6 g, 246.25 mmol) in MeOH (185 mL) was added NaOCH3 (5.4 M, 45.60 mL) under N2. The resulting mixture was stirred at 50 °C for 16 h. TLC (PE / THF = 1 / 1) indicated a new spot was formed with about 30% starting material was remained. The reaction mixture was quenched by pouring into aqueous HCl (2M, 123 mL, 1 eq.) to adjust pH value to 5-6 and then diluted with H2O (100 mL). Then the mixture was extracted with ethyl acetate / MeOH=10:1(200 mLX3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (50X600 mm, 100 -200 silica gel, 50-60% THF in petroleum ether) to give methyl (3aS,5S,6aR)-2-oxo-3,3a,4,5,6,6a-hexahydrocyclopenta[d]oxazole-5- carboxylate (26.70 g, 144 mmol, 58.5% yield) as white solid.1H NMR (400 MHz, CHLOROFORM-d) δ 6.02 (s, 1H), 5.14 (t, J = 6.6 Hz, 1H), 4.39 (t, J = 6.6 Hz, 1H), 3.71 (s, 3H), 3.18-3.09 (m, 1H), 2.24 (m, 2H), 2.04-1.86 (m, 2H). Step 6: O3-tert-Butyl O5-methyl (3aS,5S,6aR)-2-oxo-4,5,6,6a-tetrahydro-3aH- cyclopenta[d]oxazole-3,5-dicarboxylate

[0311] To a solution of methyl (3aS,5S,6aR)-2-oxo-3,3a,4,5,6,6a-hexahydrocyclopenta[d]oxazole-5- carboxylate (26.8 g, 144.73 mmol) in THF (800 mL) was added TEA (73.22 g, 723.63 mmol), DMAP (884.06 mg, 7.24 mmol) and Boc2O (33.17 g, 151.97 mmol) at 0°C. The resulting mixture was stirred at 25°C for 2h. LCMS showed that all the starting material was converted into product. The reaction mixture was poured into saturated NH4C1 (200 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with saturated NaHCO3(100 mL) and brine (100 mL), dried over Na2SO4, filtered and concentrated. The residue was triturated with cold MTBE (50 mL) to give O3-tert- butyl O5-methyl (3aS,5S,6aR)-2-oxo-4,5,6,6a-tetrahydro-3aH-cyclopenta[d]oxazole-3,5-dicarboxylate (28.63 g, 100.35 mmol, 69.3% yield) as a white solid.1H NMR (400 MHz, CHLOROFORM-d) δ 4.98 (t, J = 6.4 Hz, 1H), 4.69 (t, J = 6.8 Hz, 1H), 3.75-3.71 (m, 3H), 3.09-2.99 (m, 1H), 2.41-2.24 (m, 2H), 2.22- 1.99 (m, 2H), 1.53 (s, 9H). Step 7: Ethyl (1S,3S,4R)-3-(tert-butoxycarbonylamino)-4-hydroxy-cyclopentanecarboxylate

[0312] To a solution of O3-tert-butyl O5-methyl (3aS,5S,6aR)-2-oxo-4,5,6,6a-tetrahydro-3aH- cyclopenta[d]oxazole-3,5-dicarboxylate (28 g, 98.14 mmol) in EtOH (500 mL) was added dicesium carbonate (6.40 g, 19.63 mmol). The reaction was stirred at 25°C for 16 h. LCMS showed that the starting material was consumed and the desired product was formed. The reaction mixture was adjusted pH to 6~7 with 5% Citric Acid solution. Then the mixture was extracted with EA (500 mL). The organic layers were washed with water (500 mL X 2), brine (500 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (120 g Silica Flash Column, Eluent of 0~50% EA / PE @ 60 mL / min) to give ethyl (1S,3S,4R)-3-(tert-butoxycarbonylamino)-4- hydroxy-cyclopentanecarboxylate (20.00 g, 73.17 mmol, 74.56% yield) as a colorless oil. LCMS: [M+H- 100]+= 174.2. Step 8: (1S,3S,4R)-3-(tert-Butoxycarbonylamino)-4-hydroxy-cyclopentanecarboxylic acid

[0313] To a solution of ethyl (1S,3S,4R)-3-(tert-butoxycarbonylamino)-4-hydroxy- cyclopentanecarboxylate (20 g, 73.17 mmol) in MeOH / H2O=1:1 (135 mL) was added lithium hydroxide (2.10 g, 87.81 mmol, 1.2 eq.). The reaction was stirred at 25°C for 2 h. LCMS showed that all the starting material was converted into the product. Most of methanol was removed under vacuum and the resulting solution was adjusted pH to 4 with 5% citric acid solution. The mixture was extracted with ethyl acetate (500 mLX3). The combined organic layers were washed with water and brine (500 mL), dried over Na2SO4, filtered and concentrated to give (1S,3S,4R)-3-(tert-butoxycarbonylamino)-4-hydroxy- cyclopentanecarboxylic acid (16.30 g, 66.46 mmol, 90.82% yield) as a colorless oil which was taken into next step without further purification. LCMS: [M+H-100]+= 146.2. Step 9: [tert-Butyl(dimethyl)silyl] (1S,3S,4R)-3-(tert-butoxycarbonylamino)-4-[tert- butyl(dimethyl)silyl]oxy-cyclopentanecarboxylate

[0314] To a solution of (1S,3S,4R)-3-(tert-butoxycarbonylamino)-4-hydroxy-cyclopentanecarboxylic acid (16.3 g, 66.46 mmol) in DMF (160 mL) was added imidazole (27.15 g, 398.74 mmol) and TBSCl (27.36 g, 332.28 mmol), then stirred at 25 °C for 20 h. LCMS showed the starting material was consumed and desired product was formed. The reaction was diluted with 300 ml EA and washed with 160 ml water, 160 ml sat. NH4Cl aqueous, 160 ml sat. NaHCO3aqueous and 160 ml brine. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (120 g Silica Flash Column, Eluent of 0~25% ethyl acetate / PE gradient @ 80 mL / min) to give [tert-butyl(dimethyl)silyl] (1S,3S,4R)-3-(tert-butoxycarbonylamino)-4-[tert- butyl(dimethyl)silyl]oxy-cyclopentanecarboxylate (25.70 g) as a colorless oil. LCMS: [M+Na]+= 496.5 Step 10: (1S,3S,4R)-3-(tert-Butoxycarbonylamino)-4-[tert-butyl(dimethyl)silyl]oxy- cyclopentanecarboxylic

[0315] To a solution of [tert-butyl(dimethyl)silyl] (1S,3S,4R)-3-(tert-butoxycarbonylamino)-4-[tert- butyl(dimethyl)silyl]oxy-cyclopentanecarboxylate (25.7 g, 54.24 mmol) in EtOH (300 mL) and THF (80 mL) was added K2CO3 (1 M, 244.09 mL) , then stirred at 25 °C for 1 h. LCMS showed the starting material was consumed and desired product was formed. The solvent was removed and diluted with 200 ml water. The mixture was extracted with 200 ml EA twice. The combined organic layers were adjusted pH to 1~2 with 0.7N HCl under ice-bath and extracted with 100 ml EA twice. Combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give a (1S,3S,4R)-3-(tert- butoxycarbonylamino)-4-[tert-butyl(dimethyl)silyl]oxy-cyclopentanecarboxylic acid (19.70 g, crude) as a colorless oil which was taken into next step without further purification. LCMS: [M+Na]+= 382.3. Step 11: tert-Butyl N-[(1S,2R,4S)-4-(benzyloxycarbonylamino)-2-[tert-butyl(dimethyl)silyl]oxy- cyclopentyl]carbamate

[0316] To a solution of (1S,3S,4R)-3-(tert-butoxycarbonylamino)-4-[tert-butyl(dimethyl)silyl]oxy- cyclopentanecarboxylic acid (18.7 g, 52.01 mmol) in Toluene (200.07 mL) was added TEA (5.79 g, 57.21 mmol) and DPPA (12.97 g, 53.31 mmol) under N2, then stirred at 90 °C for 0.5 h. The BnOH (4.67 g, 104.02 mmol, 4.46 mL) was added and the reaction was heated at 90 °C for additional 16 h. LCMS showed the starting material was consumed and desired product was formed. The solvent wasquenched by water 200 mL at 25 °C, and then diluted with EA 200 mL. The aqueous layer was separated and extracted with EA (100 mL X 2). The combined organic layers were washed with brine 100 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (80 g Silica Flash Column, Eluent of 0~15% Ethyl acetate / Petroleum ether gradient @ 50 mL / min) followed by trituration with 150 ml hexane to give tert- butyl N-[(1S,2R,4S)-4-(benzyloxycarbonylamino)-2-[tert-butyl(dimethyl)silyl]oxy- cyclopentyl]carbamate (12.00 g, 24.53 mmol, 47.17% yield, 95% purity) as a white solid. LCMS: [M+H]+= 487.5;1H NMR (400 MHz, CHLOROFORM-d) δ 7.38-7.29 (m, 5H), 5.08 (s, 2H), 4.80-4.72 (m, 2H), 4.26 (d, J = 3.8 Hz, 1H), 4.08-4.00 (m, 1H), 2.15 (dd, J = 13.9, 7.8 Hz, 1H), 2.04-1.96 (m, 1H), 1.84-1.74 (m, 1H), 1.55 (d, J = 7.1 Hz, 1H), 1.43 (s, 9H), 0.91 (d, J = 15.1 Hz, 9H), 0.07 (d, J = 11.3 Hz, 6H). Step 12: tert-Butyl N-[(1S,2R,4S)-4-amino-2-[tert-butyl(dimethyl)silyl]oxy-cyclopentyl]carbamate

[0317] To a solution of tert-butyl N-[(1S,2R,4S)-4-(benzyloxycarbonylamino)-2-[tert- butyl(dimethyl)silyl]oxy-cyclopentyl]carbamate (12 g, 25.82 mmol) in MeOH (100 mL) was added Pd / C (1 g, 8.23 mmol), then stirred under H2at 25 °C for 2 h. LCMS showed the starting material was consumed and desired product was formed. The mixture was filtered and concentrated to give tert-butyl N-[(1S,2R,4S)-4-amino-2-[tert-butyl(dimethyl)silyl]oxy-cyclopentyl]carbamate (8.54 g, crude) as a colorless oil which was taken into next step directly. LCMS: [M-56]+= 274.2. Step 13: tert-Butyl N-[(1S,2R,4S)-4-[[1-(benzenesulfonyl)-5-nitro-pyrrolo[2,3-b]pyridin-4- yl]amino]-2-[tert-butyl(dimethyl)silyl]oxy-cyclopentyl]carbamate

[0318] A mixture of 1-(benzenesulfonyl)-4-chloro-5-nitro-pyrrolo[2,3-b]pyridine (8.7 g, 25.76 mmol) , tert-butyl N-[(1S,2R,4S)-4-amino-2-[tert-butyl(dimethyl)silyl]oxy-cyclopentyl]carbamate (8.54 g, 25.84 mmol) and TEA (3.40 g, 33.59 mmol) in CH3CN (150 mL) was stirred at 70 °C for 1 h. LCMS showed the starting material was consumed and desired product was formed. The reaction was quenched by 150 ml water and triturated for 10 min. Then mixture was filtered and filter cake was dried in vacuum to give tert-butyl N-[(1S,2R,4S)-4-[[1-(benzenesulfonyl)-5-nitro-pyrrolo[2,3-b]pyridin-4-yl]amino]-2- [tert-butyl(dimethyl)silyl]oxy-cyclopentyl]carbamate (15.40 g, 23.40 mmol, 90.57% yield, 96% purity) as a yellow solid which was taken into next step without further purification. LCMS: [M+H]+= 632.5. Step 14: tert-Butyl N-[(1S,2R,4S)-4-[[5-amino-1-(benzenesulfonyl)pyrrolo[2,3-b]pyridin-4- yl]amino]-2-[tert-butyl(dimethyl)silyl]oxy-cyclopentyl]carbamate

[0319] To a solution of tert-butyl N-[(1S,2R,4S)-4-[[1-(benzenesulfonyl)-5-nitro-pyrrolo[2,3- b]pyridin-4-yl]amino]-2-[tert-butyl(dimethyl)silyl]oxy-cyclopentyl]carbamate (15.4 g, 24.37 mmol) in MeOH (160 mL) and EA (160 mL) was added Pd / C (1.46 g, 12.04 mmol), and the reaction was stirred under H2 at 25 °C for 16 h. LCMS showed the starting material was consumed and desired product was formed. The mixture was filtered and concentrated to give tert-butyl N-[(1S,2R,4S)-4-[[5-amino-1- (benzenesulfonyl)pyrrolo[2,3-b]pyridin-4-yl]amino]-2-[tert-butyl(dimethyl)silyl]oxy- cyclopentyl]carbamate (14.60 g, crude) as a yellow solid which was taken into next step directly without further purification. LCMS: [M+H]+= 602.5.Step 15: tert-Butyl N-[(1S,2R,4S)-4-[10-(benzenesulfonyl)-4-oxo-3,5,8,10- tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3-yl]-2-[tert-butyl(dimethyl)silyl]oxy- cyclopentyl]carbamate

[0320] To a solution of tert-butyl N-[(1S,2R,4S)-4-[[5-amino-1-(benzenesulfonyl)pyrrolo[2,3- b]pyridin-4-yl]amino]-2-[tert-butyl(dimethyl)silyl]oxy-cyclopentyl]carbamate (9.2 g, 15.29 mmol) in DMF (120 mL) was added DMAP (2.80 g, 22.93 mmol) and CDI (6.60 g, 45.86 mmol), the mixture was stirred at 100°C for 2 h. LC-MS showed starting material was consumed completely and desired product was formed. Water (360 mL) was added and the mixture was extracted with ethyl acetate (200 mLX3). The combined organic layers were washed with brine (200 mLX2), dried over Na2SO4, filtered and concentrated to give tert-butyl N-[(1S,2R,4S)-4-[10-(benzenesulfonyl)-4-oxo-3,5,8,10- tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3-yl]-2-[tert-butyl(dimethyl)silyl]oxy- cyclopentyl]carbamate (9.60 g, crude) as a yellow solid which was taken into next step without further purification. LCMS: [M+H]+= 628.5. Step 16: tert-Butyl N-[(1S,2R,4S)-4-[10-(benzenesulfonyl)-5-methyl-4-oxo-3,5,8,10- tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3-yl]-2-[tert-butyl(dimethyl)silyl]oxy- cyclopentyl]carbamate

[0321] To a solution of tert-butyl N-[(1S,2R,4S)-4-[10-(benzenesulfonyl)-4-oxo-3,5,8,10- tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3-yl]-2-[tert-butyl(dimethyl)silyl]oxy- cyclopentyl]carbamate (9.6 g, 15.29 mmol) in DMF (120 mL) was added MeI (4.34 g, 30.58 mmol) and K2CO3(4.22 g, 30.58 mmol), the mixture was stirred at 25°C for 2 h. LC-MS showed all the starting material was converted into the product. Water (360 mL) was added and the mixture was extracted with ethyl acetate (200 mlX3). The combined organic layers were washed with brine (100 mLX2), dried over Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (80 g Silica Flash Column, Eluent of 50~60% Ethyl acetate / Petroleum ether gradient @ 50 mL / min) to give tert-butyl N-[(1S,2R,4S)-4-[10-(benzenesulfonyl)-5-methyl-4-oxo-3,5,8,10- tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3-yl]-2-[tert-butyl(dimethyl)silyl]oxy- cyclopentyl]carbamate (6 g, 9.34 mmol, 61.1% yield over 2 steps) as a yellow solid. LCMS: [M+H]+= 642.6. Step 17: tert-Butyl N-[(1S,2R,4S)-4-[10-(benzenesulfonyl)-11-bromo-5-methyl-4-oxo-3,5,8,10- tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3-yl]-2-[tert-butyl(dimethyl)silyl]oxy- cyclopentyl]carbamate

[0322] LDA (2 M, 12.15 mL) was added dropwise (about 1 h) to a solution of tert-butyl N- [(1S,2R,4S)-4-[10-(benzenesulfonyl)-5-methyl-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca- 1,6,8,11-tetraen-3-yl]-2-[tert-butyl(dimethyl)silyl]oxy-cyclopentyl]carbamate (6 g, 9.35 mmol) in THF (100 mL) at -78°C. The mixture was stirred for 1 h and 1,2-dibromo-l ,I ,2,2- tetrachloroethane (4.25 g, 13.09 mmol) in THF (16 mL) was added dropwise (about 0.5 h ) to the reaction mixture. After addition, the reaction was stirred at -78°C for an additional 2 h. LCMS showed most of the starting material was converted into the product. The reaction was quenched by adding saturated NH4Cl solution and warmedto room temperature. The mixture was diluted with ethyl acetate and washed with water, and the organic phase was dried and concentrated. The resulting residue was purified by flash silica gel chromatography (120 g Silica Flash Column, Eluent of 0~25% ethyl acetate / dichloromethane gradient @ 50 mL / min) to give tert-butyl N-[(1S,2R,4S)-4-[10-(benzenesulfonyl)-11-bromo-5-methyl-4-oxo-3,5,8,10- tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3-yl]-2-[tert-butyl(dimethyl)silyl]oxy- cyclopentyl]carbamate (4.80 g, 6.66 mmol, 71.24% yield) as a yellow solid. LCMS: [M+H]+= 722.0;1H NMR (400 MHz, DMSO-d6) δ 8.15 (s, 1H), 7.99-7.97 (m, 2H), 7.66 (t, J = 7.4 Hz, 1H), 7.56 (t, J = 7.8 Hz, 2H), 7.27 (s, 1H), 6.58 (d, J = 8.8 Hz, 1H), 5.03-4.95 (m, 1H), 4.42 (q, J = 5.1 Hz, 1H), 4.13-4.08 (m, 1H), 3.31 (s, 3H), 2.27-2.21 (m, 2H), 1.95-1.86 (m, 2H), 1.35 (d, J = 6.3 Hz, 9H), 0.84 (s, 9H), 0.00 (d, J = 2.5 Hz, 6H). Step 18: tert-Butyl N-[(1S,2R,4S)-4-[10-(benzenesulfonyl)-11-(3-fluoro-1-methyl-pyrazol-4-yl)-5- methyl-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3-yl]-2-[tert- butyl(dimethyl)silyl]oxy-cyclopentyl]carbamate

[0323] A mixture of tert-butyl N-[(1S,2R,4S)-4-[10-(benzenesulfonyl)-11-bromo-5-methyl-4-oxo- 3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3-yl]-2-[tert-butyl(dimethyl)silyl]oxy- cyclopentyl]carbamate (4.8 g, 6.66 mmol) , 3-fluoro-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)pyrazole (1.66 g, 7.33 mmol), Cs2CO3(6.47 g, 19.98 mmol) and Pd(PPh3)4(769.87 mg, 665.97 μmol) in dioxane (80 mL) / H2O (20 mL) was evacuated and backfilled with nitrogen (this process was repeated a total of three times), and then the reaction was stirred at 105 °C for 6 h under nitrogen. LCMS showed the product was formed. The reaction mixture was quenched with H2O (20 mL) and extracted with EA (50 mLX2). The combined organics were dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash silica gel chromatography (80 g Silica Flash Column, Eluent of 0~50% ethyl acetate / dichloromethane gradient @ 40 mL / min) to give tert-butyl N-[(1S,2R,4S)-4-[10- (benzenesulfonyl)-11-(3-fluoro-1-methyl-pyrazol-4-yl)-5-methyl-4-oxo-3,5,8,10- tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3-yl]-2-[tert-butyl(dimethyl)silyl]oxy- cyclopentyl]carbamate (3.40 g, 4.60 mmol, 69.00% yield) as yellow solid. LCMS: [M+H]+= 740.6;1H NMR (400 MHz, DMSO-d6) δ 8.17-8.14 (m, 1H), 8.03 (d, J = 1.9 Hz, 1H), 7.85-7.80 (m, 2H), 7.64-7.60 (m, 1H), 7.53-7.49 (m, 2H), 7.03-6.97 (m, 1H), 6.59 (d, J = 8.5 Hz, 1H), 5.09-5.01 (m, 1H), 4.44 (q, J = 4.9 Hz, 1H), 4.15-4.08 (m, 1H), 3.82 (s, 3H), 3.32 (s, 3H), 2.29-2.20 (m, 2H), 1.95-1.88 (m, 3H), 1.35 (s, 9H), 0.84 (d, J = 10.7 Hz, 9H), 0.01 (d, J = 11.5 Hz, 6H). Step 19:

[0324] A solution of tert-butyl N-[(1S,2R,4S)-4-[10-(benzenesulfonyl)-11-(3-fluoro-1-methyl- pyrazol-4-yl)-5-methyl-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3-yl]-2-[tert- butyl(dimethyl)silyl]oxy-cyclopentyl]carbamate (3.2 g, 4.32 mmol) in DMF (30 mL) was added NBS (692.74 mg, 3.89 mmol)resulting mixture was stirred at 25 °C for 3 h. LCMS showed DP was formed. The reaction mixture was quenched with H2O (100 mL) and extracted with EA (50 mLX2). The combined organics were washed with saturated LiCl solution, then dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash silica gel chromatography (80 g Silica Flash Column,Eluent of 0~30% ethyl acetate / dichloromethane gradient @ 40 mL / min) to give tert-butyl N- [(1S,2R,4S)-4-[10-(benzenesulfonyl)-12-bromo-11-(3-fluoro-1-methyl-pyrazol-4-yl)-5-methyl-4-oxo- 3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3-yl]-2-[tert-butyl(dimethyl)silyl]oxy- cyclopentyl]carbamate (INT5, 3.10 g, 3.79 mmol, 87.54% yield) as yellow solid. LCMS: [M, M+2]+= 818.5, 820.7. Intermediate 6: tert-Butyl N-[(1S,2R,4S)-4-[10-(benzenesulfonyl)-12-bromo-11-(3-methoxy-1- methyl-pyrazol-4-yl)-5-methyl-4-oxo-3,5,8,10-tetrazatricyclo [7.3.0.02,6] dodeca-1,6,8,11-tetraen-3- yl]-2-[tert-butyl(dimethyl)silyl]oxy-cyclopentyl]carbamateStep 1: 3-methoxy-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole

[0325] To a solution of 4-bromo-3-methoxy-1-methyl-pyrazole (36 g, 188.46 mmol) in dry toluene (360 mL) was added n-BuLi (123 mL, 244.99 mmol) dropwise under nitrogen atmosphere at -78°C, and the reaction mixture was stirred at -78°C for 30 min. Then a solution of 2-isopropoxy-4,4,5,5- tetramethyl-1,3,2-dioxaborolane (105.19 g, 565.37 mmol) in dry THF (200 mL) was added and the mixture stirred for a further 1 h. LCMS indicated major TM was formed.

[0326] The reaction mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, then filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluted with PE: EtOAc=2: 1 to give 3-methoxy-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (34.00 g, 142.80 mmol, 75.78% yield) as white solid. LCMS: [M+H]+= 239.3. Step 2: tert-Butyl N-[(1S,2R,4S)-4-[10-(benzenesulfonyl)-11-(3-methoxy-1-methyl-pyrazol-4-yl)-5- methyl-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3-yl]-2-[tert- butyl(dimethyl)silyl]oxy-cyclopentyl]carbamate

[0327] A solution of tert-butyl N-[(1S,2R,4S)-4-[10-(benzenesulfonyl)-11-bromo-5-methyl-4-oxo- 3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3-yl]-2-[tert-butyl(dimethyl)silyl]oxy- cyclopentyl]carbamate (5.00 g, 6.94 mmol) and 3-methoxy-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyrazole (4.96 g, 20.81 mmol) in dioxane (150 mL), H2O (35 mL) was added Pd(dppf)Cl2 (507.81 mg, 693.72 μmol) and Cs2CO3 (6.78 g, 20.81 mmol) at 25 °C, the resulting mixturewas stirred at 105 °C for 4 h in N2. LCMS indicated major TM. The reaction mixture was diluted with H2O extracted with ethyl acetate, The combined organic layer were washed with brine, dried over Na2SO4 ,then filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluted with PE: EA=1: 1 to give tert-butyl N-[(1S,2R,4S)-4-[10-(benzenesulfonyl)- 11-(3-methoxy-1-methyl-pyrazol-4-yl)-5-methyl-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca- 1,6,8,11-tetraen-3-yl]-2-[tert-butyl (dimethyl)silyl]oxy-cyclopentyl]carbamate (4.30 g, 5.72 mmol, 82.43% yield) as yellow solid. Step 3: tert-Butyl N-[(1S,2R,4S)-4-[10-(benzenesulfonyl)-12-bromo-11-(3-methoxy-1-methyl- pyrazol-4-yl)-5-methyl-4-oxo-3,5,8,10-tetrazatricyclo [7.3.0.02,6] dodeca-1,6,8,11-tetraen-3-yl]-2- [tert-butyl(dimethyl)silyl]oxy-cyclopentyl]carbamate

[0328] A solution of tert-butyl N-[(1S,2R,4S)-4-[10-(benzenesulfonyl)-11-(3-methoxy-1-methyl- pyrazol-4-yl)-5-methyl-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3-yl]-2-[tert- butyl(dimethyl)silyl]oxy-cyclopentyl]carbamate (4.30 g, 5.72 mmol) in DMF (43 mL) was added NBS (1.02 g, 5.72 mmol) at 25 °C, the resulting mixture was stirred at 25 °C for 2 h. LCMS indicated major TM. The reaction mixture was diluted with H2O extracted with ethyl acetate. The combined organic layer were washed with brine, dried over Na2SO4,filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluted with PE: EA=1: 1 to give tert-butyl N- [(1S,2R,4S)-4-[10-(benzenesulfonyl)-12-bromo-11-(3-methoxy-1-methyl-pyrazol-4-yl)-5-methyl-4-oxo- 3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3-yl]-2-[tert-butyl(dimethyl)silyl]oxy- cyclopentyl]carbamate (intermediate 6, 4.10 g, 4.93 mmol, 86.29% yield) as yellow solid. LCMS: [M+H]+= 752.2. Intermediate 7: 3-methoxy-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]butan-1-olStep 1: 2-(4-Bromophenyl)-2-methyl-oxetane

[0329] To a solution of KOBut (4.51 g, 40.19 mmol) and trimethylsulfoxonium iodide (8.85 g, 40.19 mmol) in t-BuOH (30 mL) was stirred at 50 °C for 1 h. Then, a solution of the 1-(4- bromophenyl)ethanone (2 g, 10.05 mmol) in 10 mL of dry t-BuOH was added, and the new mixture was heated at 50 °C for 24 h. TLC (PE : EA = 6:1) showed the starting material was consumed completelyand a new point was formed in TLC.30 mL saturated ammonium chloride solution was added to the mixture and extracted with EA (3*20mL). The combined organic layers were washed with brine (3*15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a crude. The residue was purified by flash silica gel chromatography (Eluent of 0~10% Ethyl acetate / Petroleum ether gradient @ 30 mL / min) to give 2-(4-bromophenyl)-2-methyl-oxetane (1.50 g, crude) as a colorless oil.1H NMR (400 MHz, CHLOROFORM-D) δ 7.49 (d, J = 8.5 Hz, 2H), 7.27 (d, J = 8.5 Hz, 2H), 4.64-4.59 (m, 1H), 4.53-4.48 (m, 1H), 2.84-2.77 (m, 1H), 2.72-2.65 (m, 1H), 1.70 (s, 3H). Step 2: 3-(4-Bromophenyl)-3-methoxy-butan-1-ol

[0330] To a solution of the 2-(4-bromophenyl)-2-methyl-oxetane (1.3 g, 5.72 mmol) in MeOH (32.5 mL) was added dropwise a solution of CAN (1.37 g, 2.58 mmol) in MeOH (65 mL). The reaction mixture was stirred at 25 °C for 1 h. LCMS showed the starting material was consumed. The mixture was added 50 mL water and extracted with EA (5*40 mL).

[0331] The combined organic layers were washed with brine (30*3 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a crude. The residue was purified by flash silica gel chromatography (Eluent of 0~25% ethyl acetate / Petroleum ether gradient @ 30 mL / min) to give 3-(4- bromophenyl)-3-methoxy-butan-1-ol (1.45 g, 5.48 mmol, 95.79% yield, 98% purity) as a light-yellow oil.1H NMR (400 MHz, CHLOROFORM-D) δ 7.52-7.44 (m, 2H), 7.25 (dd, J = 8.7, 2.1 Hz, 2H), 3.76- 3.70 (m, 1H), 3.63-3.58 (m, 1H), 3.12 (s, 3H), 2.79-2.66 (m, 1H), 2.00-1.88 (m, 2H), 1.63 (s, 3H). Step 3: 3-Methoxy-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]butan-1-ol

[0332] The solution of 3-(4-bromophenyl)-3-methoxy-butan-1-ol (1.13 g, 4.34 mmol) , pin2B2 (3.31 g, 13.02 mmol), potassium acetate (1.28 g, 13.02 mmol) and Pd(dppf)Cl2(317.65 mg, 434.13 μmol) in dioxane (20 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 105 °C for 16 h. LCMS showed DP was formed. The reaction mixture was filtered and evaporated to dryness under reduced pressure to give residue. The residue was purified by flash silica gel chromatography (Eluent of 0~25% Ethyl acetate / Petroleum ether gradient @ 30 mL / min) to give 3-methoxy-3-[4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]butan-1-ol (intermediate 7, 2.00 g, 3.23 mmol, 75% yield, 50% purity) as a white solid.1H NMR (400 MHz, CHLOROFORM-D) δ 7.83-7.78 (m, 2H), 7.39-7.34 (m, 2H), 4.12 (q, J = 7.1 Hz, 1H), 3.92-3.58 (m, 2H), 3.18-3.07 (m, 3H), 2.16-2.08 (m, 1H), 2.01-1.90 (m, 1H), 1.61 (d, J = 39.6 Hz, 3H), 1.34 (s, 12H). Intermediate 8: tert-Butyl N-[(1R,2R,4S)-4-[10-(benzenesulfonyl)-12-bromo-11-(3-fluoro-1-methyl- pyrazol-4-yl)-5-methyl-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1(9),2(6),7,11-tetraen-3-yl]- 2-[tert-butyl(dimethyl)silyl]oxy-1-methyl-cyclohexyl]carbamateStep 1: (1S)-4-methylcyclohex-3-ene-1-carboxylate

[0333] To a solution of (1S)-4-methylcyclohex-3-ene-1-carboxylic acid (75 g, 535.03 mmol) in DMF (500 mL) was added K2CO3 (221.50 g, 1.61 mol) at rt. The mixture was stirred at rt for 0.5 h, then Iodoethane (166.89 g, 1.07 mol, 85.58 mL) was added dropwise. The mixture was further stirred at 25 °C for 12 h, TLC showed the desired product was found. The reaction was quenched with H2O (400mL), extracted with EA (400mL*3), washed with NaCl solution(400 mL ), dried over Na2SO4. The mixture was filtered and concentrated. The residue was purified by flash silica gel chromatography (PE:EA=100:1 to 20:1) to obtain ethyl (1S)-4-methylcyclohex-3-ene-1-carboxylate (64.00 g, 380.43 mmol, 71.10% yield) as a colorless oil.1H NMR (400 MHz, CDCl3) δ 5.38-5.34 (m, 1H), 4.19-4.08 (m, 2H), 2.52-2.43 (m, 1H), 2.22-2.16 (m, 2H), 2.05-1.95 (m, 3H), 1.75-1.58 (m, 4H), 1.33-1.24 (t, J = 7.2 Hz, 3H). Step 2: Ethyl (3S)-6-methyl-7-oxabicyclo[4.1.0]heptane-3-carboxylate

[0334] To a solution of ethyl (1S)-4-methylcyclohex-3-ene-1-carboxylate (64 g, 380.43 mmol) in DCM (500 mL) was added m-CPBA (98.47 g, 570.64 mmol) and the resulting mixture was stirred at 25 °C for 12 h. TLC showed SM consumed and the desired product was found. The reaction was quenched with Na2S2O3 / NaHCO3(400 mL:400 mL), extracted with DCM. The organic layer was washed with NaCl solution (400 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography column (PE:EA=100:1-10:1) to obtain the desired product with low polarity (16.5 g).1H NMR (400 MHz, CDCl3) δ 4.16-4.10 (m, 2H), 3.06 (s, 1H), 2.52-2.43 (m, 1H), 2.25-2.13 (m, 1H), 2.10-1.97 (m, 1H), 1.96-1.72 (m, 3H), 1.57-1.38 (m, 1H), 1.32-1.29 (m, 3H), 1.28-1.23 (m, 3H). Step 3: Ethyl (1S,3R,4R)-4-azido-3-hydroxy-4-methyl-cyclohexanecarboxylate

[0335] To a solution of ethyl (3S)-6-methyl-7-oxabicyclo[4.1.0]heptane-3-carboxylate (24.5 g, 132.98 mmol) in EtOH (200 mL) were added NH4Cl (7.11 g, 132.98 mmol) and NaN3(17.29 g, 265.97 mmol), the mixture was stirred at 60 °C for 12 h. TLC&LCMS showed DP was found. The reaction was quenched with water (300 mL), extracted with EA (300mL*3). The combined organic layers were washed with brine (300 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography column (PE:EA=100:1-5:1) to obtain ethyl (1S,3R,4R)-4-azido-3-hydroxy- 4-methyl-cyclohexanecarboxylate (16.00 g, 70.40 mmol, 52.94% yield) as a colorless oil. LCMS: [M+H- N2]+= 200.2;1H NMR (400 MHz, DMSO-d6) δ 5.24 (d, J = 4.7 Hz, 1H), 4.09-4.00 (m, 2H), 3.47 (dd, J = 7.6, 4.5 Hz, 1H), 2.65-2.56 (m, 1H), 1.84-1.42 (m, 6H), 1.29-1.22 (m, 3H), 1.20-1.15 (m, 3H). Chiral: 87%. Step 4: Ethyl (1S,3R,4R)-4-amino-3-hydroxy-4-methyl-cyclohexanecarboxylate

[0336] To a solution of ethyl (1S,3R,4R)-4-azido-3-hydroxy-4-methyl-cyclohexanecarboxylate (16 g, 70.40 mmol) in THF (200 mL) was added Pd / C (3.20 g, 26.35 mmol) at 25 °C, and the resulting mixture was stirred at 25 °C for 12 h under H2 atmosphere. LC-MS showed DP was found. The mixture was filtered and concentrated to give ethyl (1S,3R,4R)-4-amino-3-hydroxy-4-methyl-cyclohexanecarboxylate (14.00 g, crude), which was used directly without further purification. LCMS: [M+H]+= 202.2.Step 5: Ethyl (1S,3R,4R)-4-(tert-butoxycarbonylamino)-3-hydroxy-4-methyl- cyclohexanecarboxylate

[0337] To a solution of ethyl (1S,3R,4R)-4-amino-3-hydroxy-4-methyl-cyclohexanecarboxylate (14 g, 69.56 mmol) in DCM (100 mL) were added TEA (7.04 g, 69.56 mmol, 9.67 mL) and Boc2O (15.16 g, 69.56 mmol) at 25 °C, the resulting mixture was stirred at 25 °C for 3 h. LC-MS showed DP was found. The solvent was removed and the residue was purified by flash silica gel chromatography (eluted with PE:EA=100:1 to 70:30) to obtain ethyl (1S,3R,4R)-4-(tert-butoxycarbonylamino)-3-hydroxy-4-methyl- cyclohexanecarboxylate (19.00 g, 63.04 mmol, 90.63% yield) as a colorless oil. LCMS: [M+H-Boc]+= 202.2;1H NMR (400 MHz, DMSO-d6) δ 6.28 (s, 1H), 4.81 (d, J = 4.7 Hz, 1H), 4.08-4.00 (m, 3H), 3.92- 3.84 (m, 1H), 2.59-2.53 (m, 1H), 1.99 (s, 2H), 1.83-1.46 (m, 6H), 1.38 (d, J = 7.7 Hz, 10H), 1.21-1.11 (m, 8H). Step 6: (1S,3R,4R)-4-(tert-butoxycarbonylamino)-3-hydroxy-4-methyl-cyclohexanecarboxylic acid

[0338] To a solution of ITN10-10 (19 g, 63.04 mmol) in EtOH (60 mL) was added dropwise LiOH (3.02 g, 126.09 mmol) in H2O (60 mL) at 0 °C, and the resulting mixture was stirred at 25 °C for 2 h. LC-MS showed DP was found. Most of EtOH was removed under vacuum and the resulting solution was adjusted pH to 4 with 5% citric acid solution. The mixture was extracted with ethyl acetate (100 mL*3). The combined organic layers were washed with water and brine (100 mL), dried over Na2SO4, filtered and concentrated to give INT10-11(16.00 g, crude) as a colorless oil which was taken into next step without further purification. LCMS: [M+H-56]+= 218.1. Step 7: [tert-Butyl(dimethyl)silyl] (1S,3R,4R)-4-(tert-butoxycarbonylamino)-3-[tert- butyl(dimethyl)silyl]oxy-4-methyl-cyclohexanecarboxylate

[0339] To a solution of (1S,3R,4R)-4-(tert-butoxycarbonylamino)-3-hydroxy-4-methyl- cyclohexanecarboxylic acid (12.3 g, 45.00 mmol) in DMF (120 mL) were added TBSCl (33.91 g, 225.01 mmol) and imidazole (18.38 g, 270.01 mmol) and the mixture was stirred at 25 °C for 16 h. LCMS showed that all the starting material was consumed and the product was formed. The reaction was diluted with 240 ml EA and washed with 120 ml water, 120 ml sat. NH4Cl aqueous, 120 ml sat. NaHCO3 aqueous and 120 ml brine. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (Eluent of 0~25% Ethyl acetate / PE gradient @ 100 mL / min) to give [tert-butyl(dimethyl)silyl] (1S,3R,4R)-4-(tert- butoxycarbonylamino)-3-[tert-butyl(dimethyl)silyl]oxy-4-methyl-cyclohexanecarboxylate (23.16 g, crude) as a colorless oil. LCMS: [M+Na]+= 524.4. Step 8: (1S,3R,4R)-4-(tert-butoxycarbonylamino)-3-[tert-butyl(dimethyl)silyl]oxy-4-methyl- cyclohexanecarboxylic acid

[0340] To a solution of [tert-butyl(dimethyl)silyl] (1S,3R,4R)-4-(tert-butoxycarbonylamino)-3-[tert- butyl(dimethyl)silyl]oxy-4-methyl-cyclohexanecarboxylate (23.16 g, 46.15 mmol) in EtOH (200 mL) and THF (50 mL) was added potassium carbonate solution (2 M, 103.84 mL), the mixture was stirred at 25 °C for 1 h. LCMS showed that all the starting material was consumed and the product was formed. The solvent was removed and diluted with 100 ml water. The mixture was extracted with 100 mlEA twice. The combined organic layers were adjusted pH to 1~2 with 1N HCl under ice-bath and extracted with 100 ml EA twice. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give (1S,3R,4R)-4-(tert-butoxycarbonylamino)-3-[tert- butyl(dimethyl)silyl]oxy-4-methyl-cyclohexanecarboxylic acid (15.60 g, crude) as a colorless oil, which was used directly without further purification. LCMS: [M-100+H]+= 288.3. Step 9: tert-Butyl N-[(1R,2R,4S)-4-(benzyloxycarbonylamino)-2-[tert-butyl(dimethyl)silyl]oxy-1- methyl-cyclohexyl]carbamate

[0341] To a solution of (1S,3R,4R)-4-(tert-butoxycarbonylamino)-3-[tert-butyl(dimethyl)silyl]oxy-4- methyl-cyclohexanecarboxylic acid (15.6 g, 40.25 mmol) in Toluene (150 mL) were added DPPA (10.08 g, 41.46 mmol) and TEA (4.48 g, 44.27 mmol) under N2, then stirred at 90 °C for 0.5 h. Then Benzyl alcohol (4.35 g, 40.25 mmol) was added, the mixture was further stirred for 16 h. LCMS showed that all the starting material was consumed and the product was formed. The solvent was quenched by water 100 mL at 25 °C, and then diluted with EA 200 mL and extracted with EA 200 mL (100 mL * 2). The combined organic layers were washed with brine 400 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (Eluent of 0~15% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to give tert- butyl N-[(1R,2R,4S)-4-(benzyloxycarbonylamino)-2-[tert-butyl(dimethyl)silyl]oxy-1-methyl- cyclohexyl]carbamate (12.34 g, 20.54 mmol, 51.02% yield, 82% purity) as a colorless oil. LCMS: [M- 100+H]+= 393.3. Step 10: tert-Butyl N-[(1R,2R,4S)-4-amino-2-[tert-butyl(dimethyl)silyl]oxy-1-methyl- cyclohexyl]carbamate

[0342] To a solution of tert-butyl N-[(1R,2R,4S)-4-(benzyloxycarbonylamino)-2-[tert- butyl(dimethyl)silyl]oxy-1-methyl-cyclohexyl]carbamate (12.34 g, 25.04 mmol) in MeOH (130 mL) was added Pd / C (2.06 g, 16.93 mmol) , the mixture was stirred under H2at 25 °C for 2 h. LCMS showed that all the starting material was consumed and the product was formed. The mixture was filtered and concentrated to give tert-butyl N-[(1R,2R,4S)-4-amino-2-[tert-butyl(dimethyl)silyl]oxy-1-methyl- cyclohexyl]carbamate (8.98 g, crude) as a colorless oil, which was used directly without further purification. LCMS: [M+H]+= 359.4. Step 11: tert-Butyl N-[(1R,2R,4S)-4-[[1-(benzenesulfonyl)-5-nitro-pyrrolo[2,3-b]pyridin-4- yl]amino]-2-[tert-butyl(dimethyl)silyl]oxy-1-methyl-cyclohexyl]carbamate

[0343] A mixture of 1-(benzenesulfonyl)-4-chloro-5-nitro-pyrrolo[2,3-b]pyridine (7 g, 20.73 mmol) , tert-butyl N-[(1R,2R,4S)-4-amino-2-[tert-butyl(dimethyl)silyl]oxy-1-methyl- cyclohexyl]carbamate (8.98 g, 25.04 mmol) and TEA (3.55 g, 35.06 mmol) in ACN (100 ml) was stirred at 70 °C for 1 h. LCMS showed that all the starting material was consumed and the product was formed. The reaction mixture was quenched by water (150 mL), and then diluted with EA (150 mL) and extracted with EA (150 mL * 2). The combined organic layers were washed with 150 mL brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give tert-butyl N-[(1R,2R,4S)-4-[[1- (benzenesulfonyl)-5-nitro-pyrrolo[2,3-b]pyridin-4-yl]amino]-2-[tert-butyl(dimethyl)silyl]oxy-1-methyl-cyclohexyl]carbamate (15.90 g, 19.28 mmol, 76.98% yield, 80% purity) as a yellow solid. LCMS: [M+H]+= 660.6. Step 12: tert-Butyl N-[(1R,2R,4S)-4-[[5-amino-1-(benzenesulfonyl)pyrrolo[2,3-b]pyridin-4- yl]amino]-2-[tert-butyl(dimethyl)silyl]oxy-1-methyl-cyclohexyl]carbamate

[0344] To a solution of tert-butyl N-[(1R,2R,4S)-4-[[1-(benzenesulfonyl)-5-nitro-pyrrolo[2,3- b]pyridin-4-yl]amino]-2-[tert-butyl(dimethyl)silyl]oxy-1-methyl-cyclohexyl]carbamate (15.9 g, 24.10 mmol) in MeOH (150 mL) and EA (150 mL) was added Pd / C (1.59 g, 13.09 mmol), the mixture was stirred at 25oC under H2 atmosphere for 16 h. LCMS showed the starting material was consumed and desired product was formed. The mixture was filtered and concentrated to give tert-butyl N-[(1R,2R,4S)- 4-[[5-amino-1-(benzenesulfonyl)pyrrolo[2,3-b]pyridin-4-yl]amino]-2-[tert-butyl(dimethyl)silyl]oxy-1- methyl-cyclohexyl]carbamate (15.20 g, crude) as a yellow solid which was taken into next step directly without further purification. LCMS: [M+H]+= 630.5. Step 13: tert-Butyl N-[(1R,2R,4S)-4-[10-(benzenesulfonyl)-4-oxo-3,5,8,10- tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3-yl]-2-[tert-butyl(dimethyl)silyl]oxy-1-methyl- cyclohexyl]carbamate

[0345] To a solution of tert-butyl N-[(1R,2R,4S)-4-[[5-amino-1-(benzenesulfonyl)pyrrolo[2,3- b]pyridin-4-yl]amino]-2-[tert-butyl(dimethyl)silyl]oxy-1-methyl-cyclohexyl]carbamate (14.2 g, 22.54 mmol) in CH3CN (100 mL) were added DMAP (4.13 g, 33.82 mmol) and CDI (9.74 g, 67.63 mmol), the mixture was stirred at 100°C for 2 h. LC-MS showed starting material was consumed completely and desired product was formed. Water (100 mL) was added and the mixture was extracted with ethyl acetate (100 mL*3). The combined organic layers were washed with brine (100 mL*2), dried over Na2SO4, filtered and concentrated to give tert-butyl N-[(1R,2R,4S)-4-[10-(benzenesulfonyl)-4-oxo-3,5,8,10- tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3-yl]-2-[tert-butyl(dimethyl)silyl]oxy-1-methyl- cyclohexyl]carbamate (14.80 g, crude) as a yellow solid which was taken into next step without further purification. LCMS: [M+H]+= 656.6. Step 14: tert-Butyl N-[(1R,2R,4S)-4-[10-(benzenesulfonyl)-5-methyl-4-oxo-3,5,8,10- tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3-yl]-2-[tert-butyl(dimethyl)silyl]oxy-1-methyl- cyclohexyl]carbamate

[0346] To a solution of tert-butyl N-[(1R,2R,4S)-4-[10-(benzenesulfonyl)-4-oxo-3,5,8,10- tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3-yl]-2-[tert-butyl(dimethyl)silyl]oxy-1-methyl- cyclohexyl]carbamate (15.8 g, 24.09 mmol) in DMF (100 mL) were added CH3I (10.26 g, 72.27 mmol, 4.50 mL) and K2CO3 (6.65 g, 48.18 mmol), and the mixture was stirred at 25 °C for 2 h. LC-MS showed the starting material was consumed completely and one main peak with desired mass was detected.600 mL water was added, and extracted with EA (200ml*3). The organic layers were dried by Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (Eluent of 0~46% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) to obtain tert-butyl N-[(1R,2R,4S)-4-[10- (benzenesulfonyl)-5-methyl-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3-yl]-2- [tert-butyl(dimethyl)silyl]oxy-1-methyl-cyclohexyl]carbamate (6.10 g, 9.11 mmol, 37.80% yield) as ayellow solid. LCMS: [M+H]+= 670.6. Step 15: tert-Butyl N-[4-[10-(benzenesulfonyl)-11-bromo-5-methyl-4-oxo-3,5,8,10- tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3-yl]-1-methyl-cyclohexyl]carbamate

[0347] To a solution of tert-butyl N-[4-[10-(benzenesulfonyl)-5-methyl-4-oxo-3,5,8,10- tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3-yl]-1-methyl-cyclohexyl]carbamate (6.1 g, 11.30 mmol) in THF (280 mL) at -78 °C was added LDA (2 M, 14.69 mL) ( about 1 h ), and the reaction was stirred for additional 1 h. Then 1,2-dibromo-l,1,2,2- tetrachloroethane (5.14 g, 15.83 mmol) in THF (30 mL) was added dropwise ( about 0.5 h ) to the reaction mixture. After stirring for an additional 2 h, LCMS showed the product was formed. The reaction was quenched by adding saturated NH4Cl solution. The mixture was diluted with ethyl acetate and washed with water. The organic phase was dried over sodium sulfate, filtered and concentrated. The resulting residue was purified by flash silica gel chromatography (Eluent of 0~50% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to provide tert- butyl N-[4-[10-(benzenesulfonyl)-11-bromo-5-methyl-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca- 1,6,8,11-tetraen-3-yl]-1-methyl-cyclohexyl]carbamate (5.60 g, 9.05 mmol, 80.09% yield) as a yellow solid. LCMS: [M, M+H]+= 748.5, 750.5. Step 16: tert-Butyl N-[(1R,2R,4S)-4-[10-(benzenesulfonyl)-11-(3-fluoro-1-methyl-pyrazol-4-yl)-5- methyl-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3-yl]-2-[tert- butyl(dimethyl)silyl]oxy-1-methyl-cyclohexyl]carbamate

[0348] A mixture of tert-butyl N-[(1R,2R,4S)-4-[10-(benzenesulfonyl)-11-bromo-5-methyl-4-oxo- 3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3-yl]-2-[tert-butyl(dimethyl)silyl]oxy-1- methyl-cyclohexyl]carbamate (3.8 g, 5.07 mmol), 3-fluoro-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyrazole (1.72 g, 7.61 mmol), Cs2CO3(4.93 g, 15.22 mmol) and Pd(PPh3)4(586.64 mg, 507.48 μmol) in dioxane (28 mL) and H2O (7 mL) was evacuated and backfilled with nitrogen (this process was repeated a total of three times), and then the reaction was stirred at 105 °C .for 4 h. LCMS showed the product was formed. The reaction mixture was added H2O (40 mL) and extracted with EA (80 mL*2). The combined organics were dried over sodium sulfate, filtered, and evaporated to dryness in vacuo to give residue. The residue purified by flash silica gel chromatography (Eluent of 0~60% Ethyl acetate / Petroleum ether gradient @ 60 mL / min) to give tert-butyl N-[(1R,2R,4S)-4-[10- (benzenesulfonyl)-11-(3-fluoro-1-methyl-pyrazol-4-yl)-5-methyl-4-oxo-3,5,8,10- tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3-yl]-2-[tert-butyl(dimethyl)silyl]oxy-1-methyl- cyclohexyl]carbamate (2.60 g, 3.39 mmol, 66.71% yield) as yellow solid. LCMS: [M+H]+= 768.7. Step 17: tert-Butyl N-[(1R,2R,4S)-4-[10-(benzenesulfonyl)-12-bromo-11-(3-fluoro-1-methyl- pyrazol-4-yl)-5-methyl-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3-yl]-2-[tert- butyl(dimethyl)silyl]oxy-1-methyl-cyclohexyl]carbamate (Intermediate 8)

[0349] A solution of tert-butyl N-[(1R,2R,4S)-4-[10-(benzenesulfonyl)-11-(3-fluoro-1-methyl- pyrazol-4-yl)-5-methyl-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3-yl]-2-[tert- butyl(dimethyl)silyl]oxy-1-methyl-cyclohexyl]carbamate (2.6 g, 3.39 mmol) in DMF (20 mL) was added NBS (584.47 mg, 3.28 mmol) and resulting mixture was stirred at 25oC for 3 h. LCMS showed DPwas formed. The reaction mixture was quenched with H2O (60mL) and extracted with EA (30 mL*2). The combined organics were washed with saturated LiCl solution, then dried over sodium sulfate, filtered, and evaporated to dryness in vacuo to give tert-butyl N-[(1R,2R,4S)-4-[10-(benzenesulfonyl)- 12-bromo-11-(3-fluoro-1-methyl-pyrazol-4-yl)-5-methyl-4-oxo-3,5,8,10- tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3-yl]-2-[tert-butyl(dimethyl)silyl]oxy-1-methyl- cyclohexyl]carbamate (intermediate 8, 2.60 g, crude) as yellow solid which was used into next step without further purification. Example 1: (31R,33R)-27-(3-fluoro-1-methyl-1H-pyrazol-4-yl)-23-methyl-21,22,23,26-tetrahydro-6- oxa-4-aza-2(8,1)-imidazo[4,5-d]pyrrolo[2,3-b]pyridina-1(1,3)-benzena-3(1,3)- cyclopentanacycloheptaphane-22,5-dioneStep 1: tert-Butyl ((1R,3R)-3-(7-(3-fluoro-1-methyl-1H-pyrazol-4-yl)-8-(3-(hydroxymethyl)phenyl)- 3-methyl-2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)- yl)cyclopentyl)carbamate

[0350] To a solution of the borate ester (350 mg, 508.30 μmol) and the bromo compound (178.49 mg, 762.45 μmol) in dioxane (4 mL) and water (1 mL) was added Pd(dppf)Cl2 (37.19 mg, 50.83 μmol) and Cs2CO3 (496.81 mg, 1.52 mmol), the mixture was degassed and purged with nitrogen and stirred at 105°C for 1.5 h under N2. LC-MS showed INT2-8 was consumed completely and one main peak with desired mass was detected. The mixture was concentrated and the residue was purified by flash silica gel chromatography (20 g Silica Flash Column, Eluent of 0~100% ethyl acetate / petroleum ether gradient @ 20 mL / min) to obtain tert-butyl ((1R,3R)-3-(7-(3-fluoro-1-methyl-1H-pyrazol-4-yl)-8-(3- (hydroxymethyl)phenyl)-3-methyl-2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3- b]pyridin-1(2H)-yl)cyclopentyl)carbamate (250.00 mg, 318.53 μmol, 62.67% yield, 91.2% purity) as yellow solid. LCMS: [M+H]+= 716.2. Step 2: tert-Butyl ((1R,3R)-3-(7-(3-fluoro-1-methyl-1H-pyrazol-4-yl)-3-methyl-8-(3-((((4- nitrophenoxy)carbonyl)oxy)methyl)phenyl)-2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5- d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate

[0351] To a solution of tert-butyl ((1R,3R)-3-(7-(3-fluoro-1-methyl-1H-pyrazol-4-yl)-8-(3- (hydroxymethyl)phenyl)-3-methyl-2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3- b]pyridin-1(2H)-yl)cyclopentyl)carbamate (215 mg, 300.37 μmol) and bis(4-nitrophenyl) carbonate (274.12 mg, 901.10 μmol) in DMF (2 mL) was added TEA (91.18 mg, 901.10 μmol), the mixture was stirred at 25°C for 2h. LC-MS showed the starting material was consumed completely and one main peak with desired mass was detected. Water (5ml ) was added, and extracted with ethyl acetate (10mlX2). The combined organic layers were washed by water and brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash silica gel chromatography (20 g Silica Flash Column, Eluent of 0~100% ethyl acetate / petroleum ether gradient @ 20 mL / min) to obtain tert-butyl ((1R,3R)-3- (7-(3-fluoro-1-methyl-1H-pyrazol-4-yl)-3-methyl-8-(3-((((4-nitrophenoxy)carbonyl)oxy)methyl)phenyl)- 2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)- yl)cyclopentyl)carbamate (186.00 mg, 194.68 μmol, 64.81% yield, 92.2% purity) as white solid. LCMS: [M+H]+= 881.2. Step 3: 3-(1-((1R,3R)-3-Aminocyclopentyl)-7-(3-fluoro-1-methyl-1H-pyrazol-4-yl)-3-methyl-2-oxo- 6-(phenylsulfonyl)-1,2,3,6-tetrahydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-8-yl)benzyl (4- nitrophenyl) carbonate

[0352] To a solution of tert-butyl ((1R,3R)-3-(7-(3-fluoro-1-methyl-1H-pyrazol-4-yl)-3-methyl-8-(3- ((((4-nitrophenoxy)carbonyl)oxy)methyl)phenyl)-2-oxo-6-(phenylsulfonyl)-3,6-dihydroimidazo[4,5- d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclopentyl)carbamate (180 mg, 204.34 μmol) in DCM (1 mL) was added TFA (116.49 mg, 1.02 mmol) , the mixture was stirred at 25°C for 2 h.LC-MS showed the starting material was consumed completely and one main peak with desired mass was formed. The reaction was concentrated to obtain 3-(1-((1R,3R)-3-aminocyclopentyl)-7-(3-fluoro-1-methyl-1H-pyrazol-4-yl)-3- methyl-2-oxo-6-(phenylsulfonyl)-1,2,3,6-tetrahydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-8-yl)benzyl (4- nitrophenyl) carbonate (159.00 mg, crude) as yellow oil which was taken into next step directly without further purification. LCMS: [M+H]+= 781.2Step 4: (31R,33R)-27-(3-fluoro-1-methyl-1H-pyrazol-4-yl)-23-methyl-26-(phenylsulfonyl)- 21,22,23,26-tetrahydro-6-oxa-4-aza-2(8,1)-imidazo[4,5-d]pyrrolo[2,3-b]pyridina-1(1,3)-benzena- 3(1,3)-cyclopentanacycloheptaphane-22,5-dione

[0353] To a solution of 3-(1-((1R,3R)-3-aminocyclopentyl)-7-(3-fluoro-1-methyl-1H-pyrazol-4-yl)-3- methyl-2-oxo-6-(phenylsulfonyl)-1,2,3,6-tetrahydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-8-yl)benzyl (4- nitrophenyl) carbonate (159 mg, 203.64 μmol) in DCM (2 mL) was added TEA (61.82 mg, 610.93 μmol), and the mixture was stirred at 25 °C for 2h. LC-MS showed the starting material was consumed completely and one main peak with desired mass was formed. The reaction was concentrated and the residue was purified by flash silica gel chromatography (20 g Silica Flash Column, Eluent of 0~100% ethyl acetate / petroleum ether gradient @ 20 mL / min) to obtain (31R,33R)-27-(3-fluoro-1-methyl-1H- pyrazol-4-yl)-23-methyl-26-(phenylsulfonyl)-21,22,23,26-tetrahydro-6-oxa-4-aza-2(8,1)-imidazo[4,5- d]pyrrolo[2,3-b]pyridina-1(1,3)-benzena-3(1,3)-cyclopentanacycloheptaphane-22,5-dione (70.00 mg, 100.69 μmol, 49.44% yield, 92.3% purity) as white solid. LCMS: [M+H]+= 642.2. Step 5:

[0354] To a solution of (31R,33R)-27-(3-fluoro-1-methyl-1H-pyrazol-4-yl)-23-methyl-26- (phenylsulfonyl)-21,22,23,26-tetrahydro-6-oxa-4-aza-2(8,1)-imidazo[4,5-d]pyrrolo[2,3-b]pyridina- 1(1,3)-benzena-3(1,3)-cyclopentanacycloheptaphane-22,5-dione (50 mg, 77.92 μmol) in water (2.5 mL) was added NaOH (3.12 mg, 77.92 μmol, 0.5 mL), and the mixture was stirred at 80°C for 10 min. LC- MS showed most of starting material was converted into product along with hydrolyzed byproduct. The reaction was adjusted pH to 6~7 by 2N HCl. The residue was purified by prep-HPLC (Column: Welch Xtimate C1821.2X250mm,10um; Mobile phase: (0.1%FA)H2O-ACN; B%: 30%-55%, 10 min) to give (31R,33R)-27-(3-fluoro-1-methyl-1H-pyrazol-4-yl)-23-methyl-21,22,23,26-tetrahydro-6-oxa-4-aza- 2(8,1)-imidazo[4,5-d]pyrrolo[2,3-b]pyridina-1(1,3)-benzena-3(1,3)-cyclopentanacycloheptaphane-22,5- dione (Example 1) (6.71 mg, 13.10 μmol, 16.81% yield, 97.92% purity) . LCMS: [M+H]+= 502.3;1H NMR (400 MHz, DMSO-d6) δ 12.00 (s, 1H), 8.15 (s, 1H), 7.74-7.33 (m, 4H), 7.17-7.15 (m, 1H), 6.54 (s, 1H), 5.09 (s, 1H), 4.99-4.96 (m, 1H), 4.04-3.82 (m, 1H), 3.64-3.55 (m, 4H), 3.39 (s, 3H), 2.42-2.26 (m, 1H), 2.26-1.93 (m, 1H), 1.93-1.65 (m, 2H), 1.64-1.41 (m, 1H), 1.25-1.08 (m, 1H). Examples 2 and 3: (31R,33R)-27-(3-fluoro-1-methyl-1H- pyrazol-4-yl)-23- methyl-21,22,23,26- tetrahydro-4-oxa-6-aza-2(8,1)-imidazo[4,5-d]pyrrolo[2,3-b]pyridina-1(1,3)-benzena-3(1,3)- cyclopentanacycloheptaphane-22,5-dione and (31R,33S)- 27-(3-fluoro-1-methyl-1H-pyrazol-4-yl)- 23-methyl-21,22,23,26-tetrahydro-4-oxa-6-aza-2(8,1)-imidazo[4,5-d]pyrrolo[2,3b] pyridina-1(1,3)- benzena-3(1,3)-cyclopentanacycloheptaphane-22,5-dioneStep 1: 10-(benzenesulfonyl)-12-bromo-11-(3-fluoro-1-methyl-pyrazol-4-yl)-3- [(1R,3R)-3- hydroxycyclopentyl]-5-methyl-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-4-one

[0355] A solution of 3-[(1R,3R)-3-aminocyclopentyl]-10-(benzenesulfonyl)-12-bromo-11-(3- fluoro- 1-methyl-pyrazol-4-yl)-5-methyl-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8, 11-tetraen-4-one (1.0 g, 1.70 mmol) in 10 mL of glacial acetic acid was treated with 20 mL of water, ten drops of concentrated H2SO4, and a solution of NaNO2 (1.29 g, 18.69 mmol) in H2O (3 mL) at 0oC. The mixture was stirred for 18 h at 25oC and heated at 50oC for 15 min. LCMS showed that all the starting material was consumed and 45% product was formed. The reaction mixture was added H2O (10 mL) and extracted with EA (30 mLX2). The combined organic layers were washed with brine, then dried over sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by flash silica gel chromatography (20 g Silica Flash Column, Eluent of 0~100% ethyl acetate / Petroleum Ether gradient @ 20 mL / min) to give 10-(benzenesulfonyl)-12-bromo-11-(3-fluoro-1-methyl-pyrazol-4-yl)-3- [(1R,3R)-3- hydroxycyclopentyl]-5-methyl-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-4-one (180.00 mg, 213.76 μmol, 12.58% yield, 70 % purity) as light-yellow solid. LCMS showed it was a mixture of diastereomers with a ratio of 2.5 / 1. LCMS: m / z (M, M+2) =589.1, 591.1. Step 2: tert-butyl N-[[3-[10-(Benzenesulfonyl)-11-(3-fluoro-1-methyl-pyrazol -4-yl)-3-[(1R,3R)-3- hydroxycyclopentyl]-5-methyl-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6] dodeca-1,6,8,11-tetraen-12- yl]phenyl]methyl]carbamate

[0356] A mixture of 10-(benzenesulfonyl)-12-bromo-11-(3-fluoro-1-methyl-pyrazol-4-yl)-3- [(1R,3R)-3-hydroxycyclopentyl]-5-methyl-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-4- one (403 mg, 683.70 μmol), tert-butyl N-[[3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2- yl)phenyl]methyl]carbamate (455.66 mg, 1.37 mmol), Cs2CO3 (668.29 mg, 2.05 mmol) and Pd(dppf)Cl2 (50.03 mg, 68.37 μmol) in Dioxane (4 mL) / water (1 mL) was evacuated and backfilled with nitrogen (this process was repeated a total of three times), and then the reaction was stirred at 105 °C for 2 h.LCMS showed that all the starting material was consumed and 46% product formed. The reaction mixture was added H2O (20 mL) and extracted with EA (50 mLX2). The combined organics were dried over sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by flash silica gel chromatography (12 g Silica Flash Column, Eluent of 0~100% ethyl acetate / Petroleum Ether gradient @ 20 mL / min) to give tert-butyl N-[[3-[10-(benzenesulfonyl)-11-(3-fluoro-1-methyl-pyrazol -4-yl)-3- [(1R,3R)-3-hydroxycyclopentyl]-5-methyl-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6] dodeca-1,6,8,11- tetraen-12-yl]phenyl]methyl]carbamate (348.00 mg, 447.28 μmol, 65.42% yield, 92% purity) as yellow solid. LCMS: m / z (M+H) =716.3. Step 3: [(1R,3R)-3-[10-(Benzenesulfonyl)-12-[3-[(tert-butoxycarbonylamino)methyl] phenyl]-11-(3- fluoro-1-methyl-pyrazol-4-yl)-5-methyl-4-oxo-3,5,8,10-tetrazatricyclo [7.3.0.02,6]dodeca-1,6,8,11- tetraen-3-yl]cyclopentyl] (4-nitrophenyl) carbonate

[0357] A solution of tert-butyl N-[[3-[10-(benzenesulfonyl)-11-(3-fluoro-1-methyl-pyrazol-4-yl) -3- [(1R,3R)-3-hydroxycyclopentyl]-5-methyl-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6] dodeca-1,6,8,11- tetraen-12-yl]phenyl]methyl]carbamate (320 mg, 447.06 μmol) in DCM (15 mL) and Pyridine (176.81 mg, 2.24 mmol) was added at 0oC then stirred for 10 min. (4-nitrophenyl) carbonochloridate (180.22 mg, 894.11 μmol) was added to the reaction solution. The resulting mixture was stirred at 40oC for 2 h. LCMS showed that all the starting material was consumed and 55% product formed. The reaction mixture was concentrated to give a residue. The residue was purified by flash silica gel chromatography (12 g Silica Flash Column, Eluent of 0~90% ethyl acetate / Petroleum Ether gradient @ 20 mL / min) to give [(1R,3R)-3-[10-(benzenesulfonyl)-12-[3-[(tert-butoxycarbonylamino)methyl] phenyl]-11-(3-fluoro- 1-methyl-pyrazol-4-yl)-5-methyl-4-oxo-3,5,8,10-tetrazatricyclo [7.3.0.02,6]dodeca-1,6,8,11-tetraen-3- yl]cyclopentyl] (4-nitrophenyl) carbonate (267.00 mg, 287.95 μmol, 64.41% yield, 95% purity) as yellow solid. LCMS: m / z (M+H) =881.6. Step 4: [(1R,3R)-3-[12-[3-(Aminomethyl)phenyl]-10-(benzenesulfonyl)-11-(3-fluoro-1-methyl- pyrazol-4-yl)-5-methyl-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3yl] cyclopentyl] (4-nitrophenyl) carbonate

[0358] To a solution of [(1R,3R)-3-[10-(benzenesulfonyl)-12-[3-[(tert-butoxycarbonylamino) methyl]phenyl]-11-(3-fluoro-1-methyl-pyrazol-4-yl)-5-methyl-4-oxo-3,5,8,10-tetrazatri cyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3-yl]cyclopentyl] (4-nitrophenyl) carbonate (262 mg, 297.42 μmol) in DCM (5 mL) was added TFA (1.70 g, 14.87 mmol, 1.5 mL), the mixture was stirred at 25°C for 2 h. LCMS showed that all the starting material was converted into the product. The reaction mixture was concentrated to obtain [(1R,3R)-3-[12-[3-(aminomethyl)phenyl]-10-(benzenesulfonyl)-11-(3-fluoro-1- methyl-pyrazol-4-yl)-5-methyl-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3yl] cyclopentyl] (4-nitrophenyl) carbonate (232.00 mg, 297.14 μmol, 99.90% yield) as light yellow oil which was used into next step directly without further purification. LCMS: m / z (M+H) =781.5. Step 5: (2R,5R)-17-(Benzenesulfonyl)-16-(3-fluoro-1-methyl-pyrazol-4-yl)-22-methyl-6- oxa-1,8,17,19,22-pentazahexacyclo[13.8.2.12,5.110,14.018,25.021,24]heptacosa- 10(26),11,13,15,18,20,24-heptaene-7,23-dione

[0359] To a solution of [(1R,3R)-3-[12-[3-(aminomethyl)phenyl]-10-(benzenesulfonyl)-11- (3-fluoro- 1-methyl-pyrazol-4-yl)-5-methyl-4-oxo-3,5,8,10tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3- yl]cyclopentyl] (4-nitrophenyl) carbonate (232 mg, 297.14 μmol) in DCM (20 mL) was added N,N- diethylethanamine (902.02 mg, 8.91 mmol), the mixture was stirred at 25°C for 18 h. LCMS showed that all the starting material was consumed and 56% product formed. The reaction mixture was quenched with H2O (10 mL) and extracted with EA(30 mLX2). The combined organics were washed with brine, then dried over Na2SO4, filtered, and concentrated to give a residue. The residue was purified by flash silica gel chromatography (4 g Silica Flash Column, Eluent of 0~99% ethyl acetate / Petroleum Ether gradient @ 15 mL / min) to give (2R,5R)-17-(benzenesulfonyl)-16-(3-fluoro-1-methyl-pyrazol-4-yl)-22- methyl-6-oxa-1,8,17,19,22-pentazahexacyclo[13.8.2.12,5.110,14.018,25.021,24]heptacosa- 10(26),11,13,15,18,20,24-heptaene-7,23-dione (127.00 mg, 168.23 μmol, 56.62% yield, 85% purity) as light yellow solid. LCMS: m / z (M+H) =642.4 in 0.919 min. Step 6:

[0360] To a solution of (2R,5R)-17-(benzenesulfonyl)-16-(3-fluoro-1-methyl-pyrazol-4-yl)-22- methyl-6-oxa-1,8,17,19,22-pentazahexacyclo[13.8.2.12,5.110,14.018,25.021,24] heptacosa- 10(26),11,13,15,18,20,24-heptaene-7,23-dione (122 mg, 190.13 μmol) in MeOH (5 mL) was added NaOH (4 M, 950.64 μL), the mixture was stirred at 50°C for 15 min. LCMS showed that all the starting material was converted into the product. HCl (3N) was adjust pH=5. The residue was purified by prep- HPLC (Column: Nanochrom ChromCore C1821.2X250mm,10um; Mobile phase: (0.1%FA)H2O-ACN; B%: 20%-40%, 10 min) to give (31R,33R)-27-(3-fluoro-1-methyl-1H- pyrazol-4-yl)-23- methyl- 21,22,23,26-tetrahydro-4-oxa-6-aza-2(8,1)-imidazo[4,5-d]pyrrolo[2,3-b]pyridina-1(1,3)-benzena-3(1,3)- cyclopentanacycloheptaphane-22,5-dione(Example 2, 41.05 mg, 79.21 μmol, 41.66% yield, 96.77% purity) and (31R,33S)- 27-(3-fluoro-1-methyl-1H-pyrazol-4-yl)-23-methyl-21,22,23,26-tetrahydro-4- oxa-6-aza-2(8,1)-imidazo[4,5-d]pyrrolo[2,3b] pyridina-1(1,3)-benzena-3(1,3)- cyclopentanacycloheptaphane-22,5-dione (Example 3, 1.18 mg, 2.21 μmol, 1.16% yield, 93.84% purity).

[0361] Example 2, LCMS: m / z (M+H)+=502.4;1H NMR (400 MHz, DMSO-d6) δ 11.92 (s, 1H), 8.14 (s, 1H), 7.56-7.54 (m, 1H), 7.43 (s, 1H), 7.40-7.33 (m, 3H), 7.10-7.05 (m, 1H), 4.72 (t, J = 4.7 Hz, 1H), 4.37-4.28 (m, 1H), 4.12-3.99 (m, 2H), 3.64 (s, 3H), 3.36 (s, 3H), 2.63-2.54 (m, 1H), 2.01-1.84 (m, 2H), 1.68-1.61 (m, 1H), 1.23-1.14 (m, 1H), 1.07-0.99 (m, 1H)

[0362] Example 3, LCMS: m / z (M+H)+=502.4;1H NMR (400 MHz, CHLOROFORM-d) δ 7.99-7.96 (m, 1H), 7.53-7.38 (m, 4H), 7.21-7.18 (m, 1H), 6.60 (d, J = 3.0 Hz, 1H), 4.95 (t, J = 4.5 Hz, 1H), 4.33- 4.17 (m, 2H), 3.74 (s, 3H), 3.62-3.60 (m, 1H), 3.46 (s, 3H), 2.23-2.09 (m, 3H), 1.82-1.77 (m, 1H), 1.42- 1.36 (m, 1H), 1.23-1.13 (m, 1H). Example 4: 15-(3-fluoro-1-methyl-pyrazol-4-yl)-21-methyl-7-oxa-1,5,16,18,21- pentazahexacyclo[12.8.2.12,4.19,13.017,24.020,23]hexacosa-9,11,13(25),14,17(24),18,20(23)- heptaene-6,22-dioneStep 1: tert-Butyl N-[3-[10-(benzenesulfonyl)-11-bromo-5-methyl-4-oxo-3,5,8,10- tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3-yl]cyclobutyl]carbamate

[0363] A solution of tert-butyl N-[3-[10-(benzenesulfonyl)-5-methyl-4-oxo-3,5,8,10- tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3-yl]cyclobutyl]carbamate made by a similar procedure to N-[(1R,3R)-3-[10-(benzenesulfonyl)-5-methyl-4-oxo-3,5,8,10- tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3-yl]cyclopentyl]carbamate (5 g, 10.05 mmol) in THF (160 mL) and HMPA (80 mL) at was cooled to -78°C. It was degassed and purged with N2 twice. LDA (2 M, 15.07 mL) was added dropwise and stirred for 0.5 h. Then 1,2-dibromo-l,1,2,2- tetrachloroethane (4.57 g, 14.07 mmol) in THF (10 mL) was added dropwise to the reaction mixture. After stirring for an additional 1 h, LCMS showed the product was formed. The reaction was quenched by adding saturatedNH4Cl solution (100 mL). The mixture was diluted with ethyl acetate (100 mL). The organic layer was washed with brine (50 mL), and the organic phase was dried and concentrated. The resulting residue was purified by flash silica gel chromatography (80 g Silica Flash Column, Eluent of 0~25% ethyl acetate / dichloromethane gradient @ 50 mL / min) to provide tert-butyl N-[3-[10-(benzenesulfonyl)-11-bromo-5- methyl-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3-yl]cyclobutyl]carbamate (3.60 g, 6.24 mmol, 62.15% yield) as a yellow solid. LCMS: [M+H]+= 576.2. Step 2: tert-Butyl N-[3-[10-(benzenesulfonyl)-11-(3-fluoro-1-methyl-pyrazol-4-yl)-5-methyl-4-oxo- 3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3-yl]cyclobutyl]carbamate

[0364] A mixture of tert-butyl ((1r,3r)-3-(7-bromo-3-methyl-2-oxo-6-(phenylsulfonyl)-3,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclobutyl)carbamate (1.6 g, 2.78 mmol), 3- fluoro-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (815.66 mg, 3.61 mmol), Cs2CO3 (2.71 g, 8.33 mmol) and [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (203.65 mg, 277.56 μmol) in dioxane (32 mL) and H2O (8 mL) was degassed and purged with nitrogen (this process was repeated three times), and then the reaction was stirred at 105°C for 3 h. LCMS showed the product was formed. The mixture was diluted with ethyl acetate (50 mL) and washed with water (50 mL). The organic phase was dried and concentrated. The residue was purified by flash silica gel chromatography (40 g Silica Flash Column, Eluent of 0~25% ethyl acetate / dichloromethane gradient @ 20 mL / min) to give tert-butyl N-[3-[10-(benzenesulfonyl)-11-(3-fluoro-1-methyl-pyrazol-4-yl)-5-methyl- 4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3-yl]cyclobutyl]carbamate (780.00 mg, 1.31 mmol, 47.18% yield) as a yellow solid. LCMS: [M+H]+= 596.4. Step 3: tert-Butyl N-[3-[10-(benzenesulfonyl)-12-bromo-11-(3-fluoro-1-methyl-pyrazol-4-yl)-5- methyl-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3-yl]cyclobutyl]carbamate

[0365] To a solution of tert-butyl N-[3-[10-(benzenesulfonyl)-11-(3-fluoro-1-methyl-pyrazol-4-yl)-5- methyl-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3-yl]cyclobutyl]carbamate (830 mg, 1.39 mmol) in DMF (1 mL) was added NBS (235.61 mg, 1.32 mmol) and the resulting mixture was stirred at 25oC for 3 h. LCMS showed DP was formed. The reaction mixture was quenched with H2O (100 mL) and extracted with EA (50 mLX2). The combined organics were washed with saturated LiCl solution, then dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash silica gel chromatography (20 g Silica Flash Column, Eluent of 0~30% ethyl acetate / dichloromethane gradient @ 20 mL / min) to give tert-butyl N-[3-[10-(benzenesulfonyl)-12-bromo-11-(3-fluoro-1-methyl- pyrazol-4-yl)-5-methyl-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3- yl]cyclobutyl]carbamate (700.00 mg, 1.04 mmol, 74.47% yield) as yellow solid. LCMS: [M+H]+=674.4. Step 4: tert-Butyl N-[3-[10-(benzenesulfonyl)-11-(3-fluoro-1-methyl-pyrazol-4-yl)-12-[3- (hydroxymethyl)phenyl]-5-methyl-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen- 3-yl]cyclobutyl]carbamate

[0366] To a solution of tert-butyl N-[3-[10-(benzenesulfonyl)-12-bromo-11-(3-fluoro-1-methyl- pyrazol-4-yl)-5-methyl-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3- yl]cyclobutyl]carbamate (300 mg, 444.75 μmol) and [3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol (156.17 mg, 667.12 μmol) in dioxane (6 mL) and water (1.5 mL) was added Cs2CO3 (434.70 mg, 1.33 mmol) and Pd(dppf)Cl2 (32.54 mg, 44.47 μmol), the mixture was degassed and purged with nitrogen for 3 times and stirred at 105°C for 1.5 h under N2. LC-MS showed the starting material was converted into the product. The reaction was concentrated and purified by flash silica gel chromatography (20 g Silica Flash Column, Eluent of 50~80% ethyl acetate / dichloromethane gradient @ 20 mL / min) to obtain tert-butyl N-[3-[10-(benzenesulfonyl)-11-(3-fluoro-1-methyl-pyrazol-4-yl)-12- [3-(hydroxymethyl)phenyl]-5-methyl-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3- yl]cyclobutyl]carbamate (250.00 mg, 356.24 μmol, 80.10% yield) as yellow solid. LCMS: [M+H]+= 702.6. Step 5: [3-[10-(Benzenesulfonyl)-3-[3-(tert-butoxycarbonylamino)cyclobutyl]-11-(3-fluoro-1- methyl-pyrazol-4-yl)-5-methyl-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-12- yl]phenyl]methyl (4-nitrophenyl) carbonate

[0367] To a solution of tert-butyl N-[3-[10-(benzenesulfonyl)-11-(3-fluoro-1-methyl-pyrazol-4-yl)-12- [3-(hydroxymethyl)phenyl]-5-methyl-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3- yl]cyclobutyl]carbamate (240 mg, 341.99 μmol) in DMF (3 mL) was added Py (108.21 mg, 1.37 mmol), followed by (4-nitrophenyl) carbonochloridate (137.87 mg, 683.99 μmol). The mixture was stirred at 25°C for 3 h. LC-MS showed the desired product was formed. Water was added and extracted with EA (15mlX2). The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash silica gel chromatography (20 g Silica Flash Column, Eluent of 20~50% ethyl acetate / petroleum ether gradient @ 20 mL / min) to obtain [3-[10- (benzenesulfonyl)-3-[3-(tert-butoxycarbonylamino)cyclobutyl]-11-(3-fluoro-1-methyl-pyrazol-4-yl)-5- methyl-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-12-yl]phenyl]methyl (4- nitrophenyl) carbonate (180.00 mg, 207.64 μmol, 60.72% yield) as white solid. LCMS: [M+H]+= 867.6. Step 6: [3-[3-(3-Aminocyclobutyl)-10-(benzenesulfonyl)-11-(3-fluoro-1-methyl-pyrazol-4-yl)-5- methyl-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1(9),2(6),7,11-tetraen-12-yl]phenyl]methyl (4-nitrophenyl) carbonate

[0368] To a solution of [3-[10-(benzenesulfonyl)-3-[3-(tert-butoxycarbonylamino)cyclobutyl]-11-(3- fluoro-1-methyl-pyrazol-4-yl)-5-methyl-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1(9),2(6),7,11- tetraen-12-yl]phenyl]methyl (4-nitrophenyl) carbonate (180 mg, 207.64 μmol) in DCM (3 mL) was added TFA (3 mL). The mixture was stirred at 25°C for 1 h. LC-MS showed the starting material was consumed. The mixture was concentrated to obtain [3-[3-(3-aminocyclobutyl)-10-(benzenesulfonyl)-11- (3-fluoro-1-methyl-pyrazol-4-yl)-5-methyl-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca- 1(9),2(6),7,11-tetraen-12-yl]phenyl]methyl (4-nitrophenyl) carbonate (160.00 mg, crude) as yellow oil which was used into next step directly without further purification. LCMS: [M+H]+= 767.1. Step 7: 16-(Benzenesulfonyl)-15-(3-fluoro-1-methyl-pyrazol-4-yl)-21-methyl-7-oxa-1,5,16,18,21- pentazahexacyclo[12.8.2.12,4.19,13.017,24.020,23]hexacosa-9,11,13(25),14,17(24),18,20(23)- heptaene-6,22-dione

[0369] To a solution of [3-[3-(3-aminocyclobutyl)-10-(benzenesulfonyl)-11-(3-fluoro-1-methyl- pyrazol-4-yl)-5-methyl-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1(9),2(6),7,11-tetraen-12- yl]phenyl]methyl (4-nitrophenyl) carbonate (160 mg, 208.67 μmol) in DCM (100 mL) was added TEA (105.58 mg, 1.04 mmol). The mixture was stirred at 40 °C for 6 h. LCMS showed SM was disappeared and DP was formed. The reaction mixture was concentrated and the residue was purified by flash silica gel chromatography (20 g Silica Flash Column, Eluent of 0~5% methanol / dichloromethane gradient @ 20 mL / min) to give 16-(benzenesulfonyl)-15-(3-fluoro-1-methyl-pyrazol-4-yl)-21-methyl-7-oxa- 1,5,16,18,21-pentazahexacyclo[12.8.2.12,4.19,13.017,24.020,23]hexacosa- 9,11,13(25),14,17(24),18,20(23)-heptaene-6,22-dione (65.00 mg, 103.56 μmol, 49.63% yield) as a yellow solid. LCMS: [M+H]+= 628.1. Step 8:

[0370] A solution of 16-(benzenesulfonyl)-15-(3-fluoro-1-methyl-pyrazol-4-yl)-21-methyl-7-oxa- 1,5,16,18,21-pentazahexacyclo[12.8.2.12,4.19,13.017,24.020,23]hexacosa-9,11,13(25),14,17(24),18,20(23)- heptaene-6,22-dione (65 mg, 103.56 μmol) in MeOH (2 mL) was added NaOH (4 M, 388.36 μL) at 25 °C，and the resulting mixture was stirred at 50 °C for 15 min. LCMS showed the major peak was the DP. The pH value of the solution was adjusted to 5-6 with aqueous HCl (1M). The mixture was purified by HPLC (Nanochrom ChromCore C1821.2X250mm,10um,(0.1%FA)(H2O-ACN 10-35%) to give 15-(3-fluoro-1-methyl-pyrazol-4-yl)-21-methyl-7-oxa-1,5,16,18,21- pentazahexacyclo[12.8.2.12,4.19,13.017,24.020,23]hexacosa-9,11,13(25),14,17(24),18,20(23)-heptaene-6,22- dione (Example 4, 10.44 mg, 21.42 μmol, 20.68% yield). LCMS: [M+H]+= 488.2;1H NMR (400 MHz, DMSO-d6) δ 12.01 (s, 1H), 8.14 (s, 1H), 7.96-7.88 (m, 1H), 7.60-7.53 (m, 1H), 7.42 (d, J = 7.7 Hz, 1H), 7.32 (t, J = 7.6 Hz, 1H), 7.21-7.06 (m, 1H), 6.98 (d, J = 7.7 Hz, 1H), 5.34-5.05 (m, 2H), 3.67 (s, 3H), 3.63-3.47 (m, 2H), 3.37 (s, 3H), 3.20-2.68 (m, 2H), 2.33-2.01 (m, 1H), 1.01-0.56 (m, 1H). Example 5: 15-(3-fluoro-1-methyl-pyrazol-4-yl)-21-methyl-5-oxa-1,7,16,18,21- pentazahexacyclo[12.8.2.12,4.19,13.017,24.020,23]hexacosa-9,11,13(25),14,17(24),18,20(23)- heptaene-6,22-dioneStep 1: 3-[[1-(Benzenesulfonyl)-5-nitro-pyrrolo[2,3-b]pyridin-4-yl]amino]cyclobutanol

[0371] To a solution of 1-(benzenesulfonyl)-4-chloro-5-nitro-pyrrolo[2,3-b]pyridine (12.5 g, 37.01 mmol) in CH3CN (130 mL) was added 3-aminocyclobutanol (4.57 g, 37.01 mmol, HCl) and Et3N (7.49 g, 74.02 mmol) at 25℃ and the reaction was stirred at 75 °C for 1 h. LCMS showed the SM was consumed completely and about 90% of the crude product was formed. Most of the solvent was removed until most of the solid was separated，then the mixture was diluted with 100 mL water and stirred for 10 min, then filtered. The filter cake was washed with 100 mL water, dried under vacuum to give a 3-[[1-(benzenesulfonyl)-5-nitro-pyrrolo[2,3-b]pyridin-4-yl]amino]cyclobutanol (13.14 g, 33.15 mmol, 89.58% yield, 98% purity) as a yellow solid. LCMS: [M-56]+= 389.2. Step 2: 1-(Benzenesulfonyl)-N-[3-[tert-butyl(dimethyl)silyl]oxycyclobutyl]-5-nitro-pyrrolo[2,3- b]pyridin-4-amine

[0372] To a solution of 3-[[1-(benzenesulfonyl)-5-nitro-pyrrolo[2,3-b]pyridin-4- yl]amino]cyclobutanol (12.5 g, 32.18 mmol) in DMF (200 mL) was added imidazole (6.57 g, 96.55 mmol) and TBSCl (9.70 g, 64.37 mmol) at 25℃, the mixture was stirred at 25 ℃ for 2 h. LCMS showed the starting material was consumed completely and about 90% of the desired product was formed.200 mL water was added to the mixture and stirred for 10 min, then filtered. The filter cake was washed with 100 mL water, dried in vacuum to give 1-(benzenesulfonyl)-N-[3-[tert- butyl(dimethyl)silyl]oxycyclobutyl]-5-nitro-pyrrolo[2,3-b]pyridin-4-amine (16.22 g, crude) as a yellow solid which was used into next step without further purification. LCMS: [M+1]+= 503.2;1H NMR (400 MHz, DMSO-d6) δ 8.92 (d, J = 5.5 Hz, 1H), 8.88 (s, 1H), 8.11 (dd, J = 8.2, 1.1 Hz, 2H), 7.76-7.73 (m, 2H), 7.63 (t, J = 7.8 Hz, 2H), 6.89 (d, J = 4.1 Hz, 1H), 4.61-4.54 (m, 1H), 4.48 (t, J = 5.1 Hz, 1H), 2.41 (dd, J = 12.0, 7.0 Hz, 4H), 0.83 (t, J = 2.7 Hz, 9H), -0.00 (t, J = 3.2 Hz, 6H). Step 3: 1-(Benzenesulfonyl)-N4-[3-[tert-butyl(dimethyl)silyl]oxycyclobutyl]pyrrolo[2,3-b]pyridine- 4,5-diamine

[0373] To a solution of 1-(benzenesulfonyl)-N-[3-[tert-butyl(dimethyl)silyl]oxycyclobutyl]-5-nitro- pyrrolo[2,3-b]pyridin-4-amine (16.22 g, 32.27 mmol) in MeOH (200 mL) and THF (200 mL) was added Pd / C (1.62 g, 13.36 mmol) at 25℃，the mixture was stirred at 25℃ for 40 h under 1atm of hydrogen. LCMS showed starting material was consumed completely and about 70% of the desired product was formed. The reaction was filtered through Celite and the filtrate was concentrated under reduced pressure to give 1-(benzenesulfonyl)-N4-[3-[tert-butyl(dimethyl)silyl]oxycyclobutyl]pyrrolo[2,3-b]pyridine-4,5- diamine (14.50 g, crude) as a gray solid which was used into next step without further purification. LCMS: [M+H]+= 473.4. Step 4: 10-(Benzenesulfonyl)-3-[3-[tert-butyl(dimethyl)silyl]oxycyclobutyl]-3,5,8,10- tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-4-one

[0374] To a solution of 1-(benzenesulfonyl)-N4-[3-[tert- butyl(dimethyl)silyl]oxycyclobutyl]pyrrolo[2,3-b]pyridine-4,5-diamine (14.5 g, 30.68 mmol) in ACN (200 mL) was added CDI (14.92 g, 92.03 mmol) and DMAP (5.62 g, 46.01 mmol), then the mixture was stirred at 70 °C for 2 h. LCMS showed the starting material was consumed completely and about 80% of the desired product was formed. The reaction was cooled to room temperature and diluted with 100 mL water and the mixture was stirred at 0℃ for 0.5 hour, then filtered. The filter cake was washed with filtrate and 100 mL water, dried under vacuum to give 10-(benzenesulfonyl)-3-[3-[tert- butyl(dimethyl)silyl]oxycyclobutyl]-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-4-one (14.12 g, 22.65 mmol, 73.84% yield, 80% purity) as a purple solid. LCMS: [M+H]+= 499.3. Step 5: 10-(Benzenesulfonyl)-3-[3-[tert-butyl(dimethyl)silyl]oxycyclobutyl]-5-methyl-3,5,8,10- tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-4-one

[0375] To a solution of 10-(benzenesulfonyl)-3-[3-[tert-butyl(dimethyl)silyl]oxycyclobutyl]-3,5,8,10- tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-4-one (14 g, 28.07 mmol) in DMF (150 mL) was added CH3I (11.95 g, 84.22 mmol) and K2CO3 (11.64 g, 84.22 mmol), then the mixture was stirred at 25 °C for 2 h. LCMS showed the starting material was consumed completely and about 70% of the desired product was formed.150 mL of water was added and the mixture was stirred at 25℃ for 0.5 hour, then filtered. The filter cake was washed with 100 mL of water, dried under vacuum to give 10- (benzenesulfonyl)-3-[3-[tert-butyl(dimethyl)silyl]oxycyclobutyl]-5-methyl-3,5,8,10- tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-4-one (13.70 g, crude) as a gray solid which was used into next step without further purification. LCMS: [M+H]+= 513.4. Step 6: 10-(Benzenesulfonyl)-11-bromo-3-[3-[tert-butyl(dimethyl)silyl]oxycyclobutyl]-5-methyl- 3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-4-one

[0376] To a solution of 10-(benzenesulfonyl)-3-[3-[tert-butyl(dimethyl)silyl]oxycyclobutyl]-5-methyl- 3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-4-one (1 g, 1.95 mmol) in THF (32 mL) and HMPA (16 mL) was added LDA (2 M, 2.93 mL) dropwise at -78 ℃ under N2. After stirring for 0.5 hour, 1,2-Dibromotetrachloroethane (889.21 mg, 2.73 mmol) dissolved in THF (0.5 mL) was added to the mixture, then the mixture was stirred at -78 °C for additional 1 h. LCMS showed the starting material was consumed completely and about 40% of the desired product was formed along with other byproducts. The reaction was quenched with 25 mL NH4Cl solution and extracted with EA (3X20 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (12 g Silica Flash Column, Eluent of 0~40% Ethyl acetate / Petroleum ether gradient @ 25 mL / min) to give 10-(benzenesulfonyl)-11- bromo-3-[3-[tert-butyl(dimethyl)silyl]oxycyclobutyl]-5-methyl-3,5,8,10- tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-4-one (400.00 mg, crude) as a white solid which was used into next step without further purification. LCMS: [M+H]+= 591.3;1H NMR (400 MHz, DMSO- d6) δ 8.18-8.14 (m, 1H), 8.03-7.96 (m, 2H), 7.69-7.65 (m, 1H), 7.59-7.55 (m, 2H), 7.36 (s, 1H), 5.07- 5.00 (m, 1H), 4.85-4.79 (m, 1H), 3.34 (s, 3H), 2.93-2.87 (m, 2H), 2.44-2.39 (m, 2H), 0.85 (t, J = 2.3 Hz, 9H), 0.01--0.01 (m, 6H) Step 7: 10-(Benzenesulfonyl)-3-[3-[tert-butyl(dimethyl)silyl]oxycyclobutyl]-11-(3-fluoro-1-methyl- pyrazol-4-yl)-5-methyl-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-4-one

[0377] To a mixture of 10-(benzenesulfonyl)-11-bromo-3-[3-[tert- butyl(dimethyl)silyl]oxycyclobutyl]-5-methyl-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen- 4-one (570 mg, 963.50 μmol), 3-fluoro-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (239.59 mg, 1.06 mmol), Pd(PPh3)4 (111.34 mg, 96.35 μmol) and Cs2CO3 (941.78 mg, 2.89 mmol) was added the mixture of dioxane (8 mL) and water (1.6 mL) . The resulting mixture was stirred at 105oC for 1.5 h under N2. LCMS showed the starting material was consumed completely and 70% of the desired product was formed. The solvents were removed under vacuum and the residue was purified by flash silica gel chromatography (20 g Silica Flash Column, Eluent of 0~60% Ethyl acetate / Petroleum ether gradient @ 30 mL / min) to give 10-(benzenesulfonyl)-3-[3-[tert-butyl(dimethyl)silyl]oxycyclobutyl]-11-(3-fluoro-1-methyl-pyrazol-4-yl)-5-methyl-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-4- one (430.00 mg, 633.62 μmol, 65.76% yield, 90% purity) as a light-yellow solid. LCMS: [M+H]+= 611.5. Step 8: 10-(Benzenesulfonyl)-12-bromo-3-[3-[tert-butyl(dimethyl)silyl]oxycyclobutyl]-11-(3-fluoro- 1-methyl-pyrazol-4-yl)-5-methyl-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-4-one

[0378] To a solution of 10-(benzenesulfonyl)-3-[3-[tert-butyl(dimethyl)silyl]oxycyclobutyl]-11-(3- fluoro-1-methyl-pyrazol-4-yl)-5-methyl-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-4-one (380 mg, 584.83 μmol) in DMF (8 mL) was added NBS (93.68 mg, 526.35 μmol), then the mixture was stirred at 25 °C for 2 h. LCMS showed the starting material was consumed and about 90% of the desired product was formed.20 mL water was added and the mixture was stirred at 25℃ for 10 min, then filtered. The filter cake was washed with 20 ml of water, dried under vacuum to give 10- (benzenesulfonyl)-12-bromo-3-[3-[tert-butyl(dimethyl)silyl]oxycyclobutyl]-11-(3-fluoro-1-methyl- pyrazol-4-yl)-5-methyl-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-4-one (380.00 mg, crude) as a light-yellow solid which was used into next step without further purification. LCMS: [M+H]+= 689.5. Step 9: N-[[3-[10-(Benzenesulfonyl)-3-[3-[tert-butyl(dimethyl)silyl]oxycyclobutyl]-11-(3-fluoro-1- methyl-pyrazol-4-yl)-5-methyl-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-12- yl]phenyl]methyl]carbamate

[0379] A mixture of 10-(benzenesulfonyl)-12-bromo-3-[3-[tert-butyl(dimethyl)silyl]oxycyclobutyl]- 11-(3-fluoro-1-methyl-pyrazol-4-yl)-5-methyl-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11- tetraen-4-one (410 mg, 475.59 μmol), tert-butyl N-[[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]methyl]carbamate (237.72 mg, 713.39 μmol), Cs2CO3(464.87 mg, 1.43 mmol) and Pd(dppf)Cl2(69.60 mg, 95.12 μmol) in dioxane (16 mL) and water (4 mL) was evacuated and backfilled with nitrogen (this process was repeated a total of three times), and then the reaction was stirred at 105 °C for 1.5 h under N2. LCMS showed the starting material was consumed completely and about 60% of the main peak with desired mass was formed. The reaction was concentrated and purified by flash silica gel chromatography (20 g Silica Flash Column, Eluent of 40~80% Ethyl acetate / Petroleum ether gradient @ 30 mL / min) to give tert-butyl N-[[3-[10-(benzenesulfonyl)-3-[3-[tert- butyl(dimethyl)silyl]oxycyclobutyl]-11-(3-fluoro-1-methyl-pyrazol-4-yl)-5-methyl-4-oxo-3,5,8,10- tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-12-yl]phenyl]methyl]carbamate (380.00 mg, 75% purity, 0.35 mmol, 73.6% yield) as light-yellow solid. LCMS: [M+H]+= 816.6. Step 10: tert-Butyl N-[[3-[10-(benzenesulfonyl)-11-(3-fluoro-1-methyl-pyrazol-4-yl)-3-(3- hydroxycyclobutyl)-5-methyl-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-12- yl]phenyl]methyl]carbamate

[0380] To a solution of tert-butyl N-[[3-[10-(benzenesulfonyl)-3-[3-[tert- butyl(dimethyl)silyl]oxycyclobutyl]-11-(3-fluoro-1-methyl-pyrazol-4-yl)-5-methyl-4-oxo-3,5,8,10- tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-12-yl]phenyl]methyl]carbamate (300 mg, 367.64 μmol in THF (3.00 mL) was added Triethylamine trihydrofluoride (5.93 g, 36.76 mmol, 5.99 mL) and themixture was stirred at 60 °C for 1 h. LCMS showed the starting material was consumed completely and 70% of the desired product was formed. The reaction was cooled to room temperature and 10 mL saturated ammonium chloride solution was added to the mixture and extracted with ethyl acetate (3X10 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated to give tert-butyl N-[[3-[10-(benzenesulfonyl)-11-(3-fluoro-1-methyl-pyrazol-4-yl)-3-(3- hydroxycyclobutyl)-5-methyl-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-12- yl]phenyl]methyl]carbamate (260.00 mg, crude) as a white solid which was used into next step without further purification. LCMS: [M+H]+= 702.6. Step 11: [3-[10-(Benzenesulfonyl)-12-[3-[(tert-butoxycarbonylamino)methyl]phenyl]-11-(3-fluoro- 1-methyl-pyrazol-4-yl)-5-methyl-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3- yl]cyclobutyl] (4-nitrophenyl) carbonate

[0381] To a solution of tert-butyl N-[[3-[10-(benzenesulfonyl)-11-(3-fluoro-1-methyl-pyrazol-4-yl)-3- (3-hydroxycyclobutyl)-5-methyl-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-12- yl]phenyl]methyl]carbamate (190 mg, 270.75 μmol) in DCM (5 mL) was added pyridine (642.48 mg, 8.12 mmol, 656.93 μL) at 0℃，the mixture was stirred at 0 ℃ for 10 min. Then (4-nitrophenyl) carbonochloridate (327.44 mg, 1.62 mmol) was added to the mixture at 0℃. The reaction was stirred at 25℃ for 1 h. LCMS showed the starting material was consumed completely and 50% of the desired product was formed. The solvent was removed and the residue was purified by flash silica gel chromatography (12 g Silica Flash Column, Eluent of 0~55% Ethyl acetate / Petroleum ether gradient @ 30 mL / min) to give [3-[10-(benzenesulfonyl)-12-[3-[(tert-butoxycarbonylamino)methyl]phenyl]-11-(3- fluoro-1-methyl-pyrazol-4-yl)-5-methyl-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11- tetraen-3-yl]cyclobutyl] (4-nitrophenyl) carbonate (120.00 mg, 77.7% purity, 0.138 mmol, 51.1% yield) as a light-yellow solid which was used into next step without further purification. LCMS: [M+H]+= 867.6. Step 12: [3-[12-[3-(Aminomethyl)phenyl]-10-(benzenesulfonyl)-11-(3-fluoro-1-methyl-pyrazol-4-yl)- 5-methyl-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3-yl]cyclobutyl] (4- nitrophenyl) carbonate

[0382] To a solution of [3-[10-(benzenesulfonyl)-12-[3-[(tert-butoxycarbonylamino)methyl]phenyl]- 11-(3-fluoro-1-methyl-pyrazol-4-yl)-5-methyl-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11- tetraen-3-yl]cyclobutyl] (4-nitrophenyl) carbonate (90 mg, 103.82 μmol) in DCM (2.7 ml) was added TFA (2.7 mL), then mixture was stirred at 25°C for 1 h. LCMS showed the starting material was consumed completely and 70% of the desired product was formed. The reaction mixture was concentrated to give [3-[12-[3-(aminomethyl)phenyl]-10-(benzenesulfonyl)-11-(3-fluoro-1-methyl- pyrazol-4-yl)-5-methyl-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3- yl]cyclobutyl] (4-nitrophenyl) carbonate (90.00 mg, crude) as light-yellow solid which was used into next step without further purification. LCMS: [M+H]+= 767.5. Step 13: 16-(Benzenesulfonyl)-15-(3-fluoro-1-methyl-pyrazol-4-yl)-21-methyl-5-oxa-1,7,16,18,21- pentazahexacyclo[12.8.2.12,4.19,13.017,24.020,23]hexacosa-9,11,13(25),14,17(24),18,20(23)-heptaene-6,22-dione

[0383] To a solution of [3-[12-[3-(aminomethyl)phenyl]-10-(benzenesulfonyl)-11-(3-fluoro-1-methyl- pyrazol-4-yl)-5-methyl-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3- yl]cyclobutyl] (4-nitrophenyl) carbonate (90 mg, 117.38 μmol) in DCM (45 mL) was added Et3N (35.63 mg, 352.13 μmol, 2 mL), then the mixture was stirred at 25 °C for 1 h. LCMS showed the starting material was consumed completely and 70% of the desired product was formed. The solvent was removed and the residue was purified by flash silica gel chromatography (12 g Silica Flash Column, Eluent of 0~80% Ethyl acetate / Petroleum ether gradient @ 30 mL / min) to give 16-(benzenesulfonyl)-15- (3-fluoro-1-methyl-pyrazol-4-yl)-21-methyl-5-oxa-1,7,16,18,21- pentazahexacyclo[12.8.2.12,4.19,13.017,24.020,23]hexacosa-9,11,13(25),14,17(24),18,20(23)-heptaene- 6,22-dione (40.00 mg, 63.73 μmol, 54.29% yield, 96% purity) as a white solid. LCMS: [M+H]+= 628.4 Step 14:

[0384] A solution of 16-(benzenesulfonyl)-15-(3-fluoro-1-methyl-pyrazol-4-yl)-21-methyl-5-oxa- 1,7,16,18,21-pentazahexacyclo[12.8.2.12,4.19,13.017,24.020,23]hexacosa- 9,11,13(25),14,17(24),18,20(23)-heptaene-6,22-dione (37 mg, 58.95 μmol) in water (2.6 mL), ACN (2.6 mL) and MeOH (1.3 mL) was added NaOH (4 M, 0.65 mL) at 25 °C the resulting mixture was stirred at 50°C for 1 h. LCMS showed the starting material was consumed completely and 80% of the desired product was formed. The mixture was cooled to room temperature and the pH of the reaction solution was adjusted to be weakly acidic with dilute hydrochloric acid (1N). The mixture was filtered and the filtrate was purified by Pre-HPLC(Column: Welch Xtimate C1821.2X250mm,10um; Mobile phase: (0.1%FA)H2O-ACN; B%: 20%-35%, 10 min) to obtain 15-(3-fluoro-1-methyl-pyrazol-4-yl)-21-methyl- 5-oxa-1,7,16,18,21-pentazahexacyclo[12.8.2.12,4.19,13.017,24.020,23]hexacosa- 9,11,13(25),14,17(24),18,20(23)-heptaene-6,22-dione (Example 5, 5.42 mg, 10.80 μmol, 18.33% yield, 97.17% purity). LCMS: [M+H]+= 488.4;1H NMR (400 MHz, DMSO- d6) δ 11.95 (s, 1H), 8.13 (s, 1H), 7.74 (t, J = 6.2 Hz, 1H), 7.68 (s, 1H), 7.46 (d, J = 1.9 Hz, 1H), 7.43-7.38 (m, 1H), 7.34 (t, J = 7.7 Hz, 1H), 6.93-6.89 (m, 1H), 4.94-4.85 (m, 1H), 4.73 (t, J = 5.6 Hz, 1H), 4.18-4.07 (m, 2H), 3.66 (s, 3H), 3.36 (s, 3H), 3.18-3.11 (m, 1H), 2.90-2.84 (m, 1H), 2.04-1.98 (m, 1H), 0.85-0.78 (m, 1H). Example 6: Methyl N-[(10R,11S,13S)-22-(3-fluoro-1-methyl-pyrazol -4-yl)-16-methyl-15-oxo-9-oxa-14,16,19,21- tetrazahexacyclo[12.8.2.22,5.110,13.017,24.020,23]heptacosa-1(22),2,4,17,19,23,26-heptaen-11- yl]carbamateStep 1: tert-Butyl N-[(1S,2R,4S)-4-[10-(benzenesulfonyl)-11-(3-fluoro-1-methyl-pyrazol-4-yl)- 12-[4-(3-hydroxypropyl)phenyl]-5-methyl-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11- tetraen-3-yl]-2-[tertbutyl(dimethyl)silyl]oxy-cyclopentyl]carbamate

[0385] A mixture of tert-butyl N-[(1S,2R,4S)-4-[10-(benzenesulfonyl)-12-bromo-11-(3-fluoro -1-methyl-pyrazol-4-yl)-5-methyl-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3- yl]-2-[tertbutyl(dimethyl)silyl]oxy-cyclopentyl]carbamate (INT5, 500 mg, 610.63 μmol), 3-[4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propan-1-ol (320.16 mg, 1.22 mmol), Pd(PPh3)4 (70.53 mg, 61.06 μmol), Cs2CO3(396.91 mg, 1.22 mmol) in dioxane (15 mL) and water (3 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 105 °C for 2 h under N2atmosphere. LCMS showed that all the starting material was converted into the product. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (20 g Silica Flash Column, Eluent of 0~80% Ethyl acetate / Petroleum ether gradient @ 20 mL / min) to give compound tert-butyl N-[(1S,2R,4S)-4-[10-(benzenesulfonyl)-11-(3-fluoro-1-methyl- pyrazol-4-yl)-12-[4-(3-hydroxypropyl)phenyl]-5-methyl-4-oxo-3,5,8,10- tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3-yl]-2-[tertbutyl(dimethyl)silyl]oxy- cyclopentyl]carbamate (395.00 mg, 451.89 μmol, 74.00% yield) as a yellow solid. LCMS: [M+H]+= 874.7. Step 2: 3-[4-[10-(Benzenesulfonyl)-3-[(1S,3S,4R)-3-(tertbutoxycarbonylamino)-4-[tert- butyl(dimethyl)silyl]oxy-cyclopentyl]-11-(3-fluoro-1-methyl-pyrazol-4-yl)-5-methyl-4-oxo-3,5,8,10- tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-12-yl]phenyl]propyl methanesulfonate

[0386] To a solution of tert-butyl N-[(1S,2R,4S)-4-[10-(benzenesulfonyl)-11-(3-fluoro-1-methyl- pyrazol-4-yl)-12-[4-(3-hydroxypropyl)phenyl]-5-methyl-4-oxo-3,5,8,10- tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3-yl]-2-[tertbutyl(dimethyl)silyl]oxy- cyclopentyl]carbamate (385 mg, 440.45 μmol) in DCM (8 mL) was added MsCl (151.96 mg, 1.32 mmol). The mixture was stirred at 15 °C for 1 h. LCMS showed that all the starting material was converted into the product. The reaction mixture was washed by water (10 mLX3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product 3-[4-[10- (benzenesulfonyl)-3-[(1S,3S,4R)-3-(tertbutoxycarbonylamino)-4-[tert-butyl(dimethyl)silyl]oxy- cyclopentyl]-11-(3-fluoro-1-methyl-pyrazol-4-yl)-5-methyl-4-oxo-3,5,8,10- tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-12-yl]phenyl]propyl methanesulfonate (435.00 mg, crude) was used into the next step without further purification. LCMS: [M+H]+= 952.7. Step 3: tert-Butyl N-[(1S,2R,4S)-4-[10-(benzenesulfonyl)-11-(3-fluoro-1-methyl-pyrazol-4-yl) -12-[4-(3-iodopropyl)phenyl]-5-methyl-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11- tetraen-3-yl]-2-[tertbutyl(dimethyl)silyl]oxy-cyclopentyl]carbamate

[0387] To a solution of 3-[4-[10-(benzenesulfonyl)-3-[(1S,3S,4R)-3-(tertbutoxycarbonylamino)-4- [tert-butyl(dimethyl)silyl]oxy-cyclopentyl]-11-(3-fluoro-1-methyl-pyrazol-4-yl)-5-methyl-4-oxo- 3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-12-yl]phenyl]propyl methanesulfonate (435 mg, 456.84 μmol) in acetone (10 mL) was added LiI (611.46 mg, 4.57 mmol). The mixture was stirred at 50 °C for 2 h. LCMS showed that all the starting material was converted into the product. The reaction mixture was concentrated under reduced pressure to give a residue. Then the residue was dissolved into ethyl acetate (30 mL), washed by water (20 mLX3), dried over Na2SO4, filtered and concentrated to give tert-butyl N-[(1S,2R,4S)-4-[10-(benzenesulfonyl)-11-(3-fluoro-1-methyl-pyrazol-4-yl)-12-[4-(3- iodopropyl)phenyl]-5-methyl-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3-yl]-2- [tertbutyl(dimethyl)silyl]oxy-cyclopentyl]carbamate (515.00 mg, crude) which was used into the next step without further purification. LCMS: [M+H]+= 984.6. Step 4: tert-Butyl N-[(1S,2R,4S)-4-[10-(benzenesulfonyl)-11-(3-fluoro-1-methyl-pyrazol-4-yl)-12-[4- (3-iodopropyl)phenyl]-5-methyl-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3- yl]-2-hydroxycyclopentyl] carbamate

[0388] To a solution of tert-butyl N-[(1S,2R,4S)-4-[10-(benzenesulfonyl)-11-(3-fluoro-1-methyl- pyrazol-4-yl)-12-[4-(3-iodopropyl)phenyl]-5-methyl-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca- 1,6,8,11-tetraen-3-yl]-2-[tertbutyl(dimethyl)silyl]oxy-cyclopentyl]carbamate (515 mg, 523.37 μmol) in THF (10 mL) was added triethylamine trihydrofluoride (421.32 mg, 2.62 mmol). The mixture was stirred at 50 °C for 16 h. LCMS showed that all the starting material was converted into the product. The reaction mixture was concentrated under reduced pressure to give a residue. Then the residue was dissolved into ethyl acetate (25 mg), washed by water (20 mLX3), dried over Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (20 g Silica Flash Column, Eluent of 0~75% ethyl acetate / petroleum ether gradient @ 20 mL / min) to give compound tert-butyl N- [(1S,2R,4S)-4-[10-(benzenesulfonyl)-11-(3-fluoro-1-methyl-pyrazol-4-yl)-12-[4-(3-iodopropyl)phenyl]-5-methyl-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3-yl]-2-hydroxycyclopentyl] carbamate (285.00 mg, 327.68 μmol, 62.61% yield) as a white solid. LCMS: [M+H]+= 870.5. Step 5: tert-Butyl N-[(10R,11S,13S)-21-(benzenesulfonyl)-22-(3-fluoro-1- methyl-pyrazol-4-yl)-16-methyl-15-oxo-9-oxa-14,16,19,21- tetrazahexacyclo[12.8.2.22,5.110,13.017,24.020,23]heptacosa-1(22),2,4,17,19,23,26-heptaen-11- yl]carbamate

[0389] To a solution of tert-butyl N-[(1S,2R,4S)-4-[10-(benzenesulfonyl)-11-(3-fluoro-1-methyl- pyrazol-4-yl)-12-[4-(3-iodopropyl)phenyl]-5-methyl-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca- 1,6,8,11-tetraen-3-yl]-2-hydroxycyclopentyl]carbamate (120 mg, 137.97 μmol) in DMF (120 mL) was added NaH (132.44 mg, 3.31 mmol, 60% purity).The mixture was stirred at 15 °C for 1 h. LCMS showed that all the starting material was converted into the product. The reaction mixture was quenched by addition sat NH4Cl (50 mL) at 0°C, and the solvent was removed under reduced pressure to 50 mL residue, then diluted with ethyl acetate and extracted with ethyl acetate (50 mLX3). The combined organic layers were concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (12 g Silica Flash Column, Eluent of 0~100% ethyl acetate / petroleum ether gradient @ 12 mL / min) to give compound tert-butyl N-[(10R,11S,13S)-21-(benzenesulfonyl)-22- (3-fluoro-1-methyl-pyrazol-4-yl)-16-methyl-15-oxo-9-oxa-14,16,19,21- tetrazahexacyclo[12.8.2.22,5.110,13.017,24.020,23]heptacosa-1(22),2,4,17,19,23,26-heptaen-11- yl]carbamate (38.00 mg, 51.22 μmol, 37.13% yield) as a yellow solid. LCMS: [M+H]+= 742.6. Step 6: (10R,11S,13S)-11-Amino-21-(benzenesulfonyl)-22-(3- fluoro-1-methyl-pyrazol-4-yl)-16-methyl-9-oxa-14,16,19,21- tetrazahexacyclo[12.8.2.22,5.110,13.017,24.020,23]heptacosa-1(22),2,4,17,19,23,26-heptaen-15-one

[0390] To a solution of tert-butyl N-[(10R,11S,13S)-21-(benzenesulfonyl)-22-(3-fluoro-1-methyl- pyrazol-4-yl)-16-methyl-15-oxo-9-oxa-14,16,19,21- tetrazahexacyclo[12.8.2.22,5.110,13.017,24.020,23]heptacosa-1(22),2,4,17,19,23,26-heptaen-11- yl]carbamate (25 mg, 33.70 μmol) in DCM (2 mL) was added TFA (2 mL). The mixture was stirred at 15 °C for 1 h. LCMS showed that all the starting material was converted into the product. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product (10R,11S,13S)-11- amino-21-(benzenesulfonyl)-22-(3-fluoro-1-methyl-pyrazol-4-yl)-16-methyl-9-oxa-14,16,19,21- tetrazahexacyclo[12.8.2.22,5.110,13.017,24.020,23]heptacosa-1(22),2,4,17,19,23,26-heptaen-15-one (30.00 mg, crude) was used into the next step without further purification. LCMS: [M+H]+= 642.2. Step 7: Methyl N-[(10R,11S,13S)-21-(benzenesulfonyl)-22-(3-fluoro-1-methyl-pyrazol-4-yl)-16- methyl-15-oxo-9-oxa-14,16,19,21-tetrazahexacyclo[12.8.2.22,5.110,13.017,24.020,23]heptacosa- 1(22),2,4,17,19,23,26-heptaen-11-yl]carbamate

[0391] To a solution of (10R,11S,13S)-11-amino-21-(benzenesulfonyl)-22-(3-fluoro-1-methyl- pyrazol-4-yl)-16-methyl-9-oxa-14,16,19,21- tetrazahexacyclo[12.8.2.22,5.110,13.017,24.020,23]heptacosa-1(22),2,4,17,19,23,26-heptaen-15-one (30 mg, 46.75 μmol) in DCM (4 mL) and water (2 mL) was added methyl chloroformate (22.21 mg, 233.75μmol). The mixture was stirred at 15 °C for 10 min. LCMS showed that all the starting material was converted into the product. The reaction mixture was partitioned between DCM and water. The organic phase was separated, washed with water (10 mL X3), concentrated under reduced pressure to give a residue. The crude product methyl N-[(10R,11S,13S)-21-(benzenesulfonyl)-22-(3-fluoro-1-methyl- pyrazol-4-yl)-16-methyl-15-oxo-9-oxa-14,16,19,21- tetrazahexacyclo[12.8.2.22,5.110,13.017,24.020,23]heptacosa-1(22),2,4,17,19,23,26-heptaen-11- yl]carbamate (32.00 mg, crude) was used into the next step without further purification. LCMS: [M+H]+= 700.2. Step 8:

[0392] To a solution of methyl N-[(10R,11S,13S)-21-(benzenesulfonyl)-22-(3-fluoro-1-methyl- pyrazol-4-yl)-16-methyl-15-oxo-9-oxa-14,16,19,21- tetrazahexacyclo[12.8.2.22,5.110,13.017,24.020,23]heptacosa-1(22),2,4,17,19,23,26-heptaen-11- yl]carbamate (32 mg, 45.73 μmol) in methanol (5 mL) was added NaOH (4 M, 1 mL). The mixture was stirred at 50 °C for 20 min. LCMS showed that all the starting material was converted into the product. The reaction mixture was adjusted the pH=5-7 by 2M HCl solution and concentrated to remove partial MeOH. The residue was purified by prep-HPLC (Column: Welch Xtimate C1821.2X250mm, 10um; Mobile phase: (0.1%FA)H2O-ACN; B%: 30%-55%, 10 min) to give methyl N-[(10R,11S,13S)-22-(3- fluoro-1-methyl-pyrazol-4-yl)-16-methyl-15-oxo-9-oxa-14,16,19,21- tetrazahexacyclo[12.8.2.22,5.110,13.017,24.020,23]heptacosa-1(22),2,4,17,19,23,26-heptaen-11- yl]carbamate (Example 6, 11.57 mg, 20.65 μmol, 45.16% yield, 99.88% purity). LCMS: [M+H]+= 560.2;1H NMR (400 MHz, DMSO-d6) δ 11.84 (s, 1H), 8.11 (s, 1H), 7.50 (d, J = 1.8 Hz, 1H), 7.34-7.27 (m, 3H), 7.13 (d, J = 7.4 Hz, 1H), 6.55 (d, J = 8.0 Hz, 1H), 4.21-4.06 (m, 1H), 3.67 (s, 3H), 3.63-3.58 (m, 1H), 3.55-3.42 (m, 5H), 3.36 (s, 3H), 2.96-2.92 (m, 1H), 2.67-2.53 (m, 2H), 2.20-2.08 (m, 1H), 2.01-1.86 (m, 2H), 1.66-1.43 (m, 3H). Example 7: Cyclopropyl N-[(10R,11S,13S)-22-(3-fluoro-1-methyl-pyrazol-4-yl)-16-methyl-15-oxo- 9-oxa-14,16,19,21-tetrazahexacyclo[12.8.2.22,5.110,13.017,24.020,23]heptacosa- 1(22),2,4,17,19,23,26-heptaen-11-yl]carbamateStep 1: Ethyl N-[(10R,11S,13S)-21-(benzenesulfonyl)-22-(3-fluoro-1-methyl-pyrazol-4-yl)-16- methyl-15-oxo-9-oxa-14,16,19,21-tetrazahexacyclo[12.8.2.22,5.110,13.017,24.020,23]heptacosa- 1(22),2,4,17,19,23,26-heptaen-11-yl]carbamate

[0393] To a solution of (10R,11S,13S)-11-amino-21-(benzenesulfonyl)-22-(3-fluoro-1-methyl- pyrazol-4-yl)-16-methyl-9-oxa-14,16,19,21- tetrazahexacyclo[12.8.2.22,5.110,13.017,24.020,23]heptacosa-1(22),2,4,17,19,23,26-heptaen-15-one (23 mg, 35.84 μmol), Na2CO3 (14.91 mg, 143.37 μmol) in DCM (4 mL), water (2 mL) was added cyclopropyl carbonochloridate (12.96 mg, 107.52 μmol). The mixture was stirred at 15 °C for 10 min. LCMS showed that all the starting material was converted into the product. The reaction mixture was partitioned between DCM and water. The organic phase was separated, washed with water (10 mL X 3), concentrated to give ethyl N-[(10R,11S,13S)-21-(benzenesulfonyl)-22-(3-fluoro-1-methyl-pyrazol-4-yl)- 16-methyl-15-oxo-9-oxa-14,16,19,21-tetrazahexacyclo[12.8.2.22,5.110,13.017,24.020,23]heptacosa- 1(22),2,4,17,19,23,26-heptaen-11-yl]carbamate (28.00 mg, crude) which was used into the next step without further purification. LCMS: [M+H]+= 726.10. Step 2:

[0394] To a solution of cyclopropyl N-[(10R,11S,13S)-21-(benzenesulfonyl)-22-(3-fluoro-1- methyl- pyrazol-4-yl)-16-methyl-15-oxo-9-oxa-14,16,19,21- tetrazahexacyclo[12.8.2.22,5.110,13.017,24.020,23]heptacosa-1(22),2,4,17,19,23,26-heptaen-11- yl]carbamate (28 mg, 38.58 μmol) in methanol (2.60 mL) was added NaOH (4 M, 396.99 μL). The mixture was stirred at 50 °C for 20 min. LCMS showed that all the starting material was converted into the product. The reaction mixture was adjusted the pH=5-7 by 2M HCl solution and concentrated to remove partial MeOH. The residue was purified by prep-HPLC (Column: Welch Xtimate C18 21.2X250mm, 10um; Mobile phase: (0.1%FA)H2O-ACN; B%: 30%-60%, 10 min) to give cyclopropyl N-[(10R,11S,13S)-22-(3-fluoro-1-methyl-pyrazol-4-yl)-16-methyl-15-oxo-9-oxa-14,16,19,21- tetrazahexacyclo[12.8.2.22,5.110,13.017,24.020,23]heptacosa-1(22),2,4,17,19,23,26-heptaen-11- yl]carbamate (Example 7, 5.11 mg, 8.61 μmol, 22.32% yield, 98.67% purity). LCMS: [M+H]+= 586.15;1H NMR (400 MHz, DMSO-d6) δ 11.83 (s, 1H), 8.10 (s, 1H), 7.49 (d, J = 2.0 Hz, 1H), 7.32-7.25 (m, 3H), 7.11 (d, J = 8.0 Hz, 1H), 6.55 (d, J = 7.8 Hz, 1H), 4.17-4.07 (m, 1H), 3.91-3.85 (m, 1H), 3.67 (s, 3H), 3.65-3.58 (m, 1H), 3.48-3.42 (m, 2H), 3.32 (s, 3H), 2.96-2.86 (m, 1H), 2.61-2.52 (m, 2H), 2.18-2.09 (m, 1H), 2.03-1.86 (m, 2H), 1.67-1.40 (m, 3H), 0.62-0.47 (m, 4H). Example 8: Methyl N-[(10R,11S,13S)-22-(3-fluoro-1-methyl-pyrazol-4-yl)-16-methyl-15-oxo-9-oxa- 14,16,19,21-tetrazahexacyclo[12.8.2.22,5.110,13.017,24.020,23]heptacosa-1(22),2,4,17,19,23,26- heptaen-11-yl]carbamateStep 1: Ethyl N-[(10R,11S,13S)-21-(benzenesulfonyl)-22-(3-fluoro-1-methyl-pyrazol-4-yl)-16- methyl-15-oxo-9-oxa-14,16,19,21-tetrazahexacyclo[12.8.2.22,5.110,13.017,24.020,23]heptacosa- 1(22),2,4,17,19,23,26-heptaen-11-yl]carbamate

[0395] To a solution of (10R,11S,13S)-11-amino-21-(benzenesulfonyl)-22-(3-fluoro-1-methyl- pyrazol-4-yl)-16-methyl-9-oxa-14,16,19,21- tetrazahexacyclo[12.8.2.22,5.110,13.017,24.020,23]heptacosa-1(22),2,4,17,19,23,26-heptaen-15-one (27 mg, 42.07 μmol), Na2CO3 (17.50 mg, 168.30 μmol) in DCM (4 mL) and water (2 mL) was added ethyl chloroformate (13.70 mg, 126.22 μmol). The mixture was stirred at 15 °C for 10 min. LCMS showed that all the starting material was converted into the product. The reaction mixture was partitioned between DCM and water. The organic phase was separated, washed with water (10 mL X 3), concentrated under reduced pressure to give ethyl N-[(10R,11S,13S)-21-(benzenesulfonyl)-22-(3-fluoro-1-methyl-pyrazol-4- yl)-16-methyl-15-oxo-9-oxa-14,16,19,21-tetrazahexacyclo[12.8.2.22,5.110,13.017,24.020,23]heptacosa- 1(22),2,4,17,19,23,26-heptaen-11-yl]carbamate (34.00 mg, crude) which was taken into the next step without further purification. LCMS: [M+H]+= 714.10. Step 2:

[0396] To a solution of methyl N-[(10R,11S,13S)-21-(benzenesulfonyl)-22-(3-fluoro-1-methyl- pyrazol-4-yl)-16-methyl-15-oxo-9-oxa-14,16,19,21- tetrazahexacyclo[12.8.2.22,5.110,13.017,24.020,23]heptacosa-1(22),2,4,17,19,23,26-heptaen-11- yl]carbamate (34 mg, 48.59 μmol) in methanol (2.5 mL) was added NaOH (4 M, 0.5 mL). The mixture was stirred at 50 °C for 20 min. LCMS showed that all the starting material was converted into the product. The reaction mixture was adjusted the pH=5-7 by 2M HCl solution and concentrated to remove partial MeOH. The residue was purified by prep-HPLC (Column: Welch Xtimate C1821.2X250mm, 10um; Mobile phase: (0.1%FA)H2O-ACN; B%: 30%-60%, 10 min) to give methyl N-[(10R,11S,13S)- 22-(3-fluoro-1-methyl-pyrazol-4-yl)-16-methyl-15-oxo-9-oxa-14,16,19,21- tetrazahexacyclo[12.8.2.22,5.110,13.017,24.020,23]heptacosa-1(22),2,4,17,19,23,26-heptaen-11- yl]carbamate (Example 8, 5.57 mg, 9.95 μmol, 20.49% yield). LCMS: [M+H]+= 574.20;1H NMR (400 MHz, DMSO-d6) δ 11.85 (s, 1H), 8.11 (s, 1H), 7.51 (d, J = 1.9 Hz, 1H), 7.37-7.24 (m, 3H), 7.13 (d, J = 7.5 Hz, 1H), 6.49 (d, J = 8.3 Hz, 1H), 4.23-4.05 (m, 1H), 3.97-3.92 (m, 2H), 3.67 (s, 3H), 3.65-3.57 (m, 1H), 3.50-3.43 (m, 2H), 3.36 (s, 3H), 3.01 -2.87 (m, 1H), 2.63-2.52 (m, 2H), 2.20-2.09 (m, 1H), 2.04- 1.88 (m, 2H), 1.71-1.38 (m, 3H), 1.13 (t, J = 7.1 Hz, 3H). Example 9: Methyl N-[(10R,11S,13S)-22-(3-fluoro-1-methyl-pyrazol-4-yl)-16-methyl-8,15-dioxo-9- oxa-14,16,19,21-tetrazahexacyclo[12.8.2.22,5.110,13.017,24.020,23]heptacosa-1(22),2,4,17,19,23,26- heptaen-11-yl]carbamateStep 1: Ethyl 3-[4-[10-(benzenesulfonyl)-3-[(1S,3S,4R)-3-(tert-butoxycarbonylamino)-4-[tert- butyl(dimethyl)silyl]oxy-cyclopentyl]-11-(3-fluoro-1-methyl-pyrazol-4-yl)-5-methyl-4-oxo-3,5,8,10- tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-12-yl]phenyl]propanoate

[0397] To a solution of tert-butyl N-[(1S,2R,4S)-4-[10-(benzenesulfonyl)-12-bromo-11-(3-fluoro-1- methyl-pyrazol-4-yl)-5-methyl-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3-yl]-2- [tert-butyl(dimethyl)silyl]oxy-cyclopentyl]carbamate (INT5, 300 mg, 366.38 μmol) in dioxane / H2O=4:1 (10 mL) was added [4-(3-ethoxy-3-oxo-propyl)phenyl]boronic acid (122.03 mg, 549.57 μmol) , Cesium carbonate (358.12 mg, 1.10 mmol) and cyclopenta-1,3-dien-1- yl(diphenyl)phosphane;iron;palladium(2+);dichloride (26.88 mg, 36.64 μmol), the mixture was degassed with nitrogen three times and stirred at 105 °C for 3 h. The mixture was diluted with 100 ml EA and 100 ml water. The organic layer was separated, washed with 100 ml brine twice, dried over Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (20 g, Silica Flash Column, Eluent of 0~70% EA / PE @ 30 mL / min) to give ethyl 3-[4-[10-(benzenesulfonyl)-3- [(1S,3S,4R)-3-(tert-butoxycarbonylamino)-4-[tert-butyl(dimethyl)silyl]oxy-cyclopentyl]-11-(3-fluoro-1- methyl-pyrazol-4-yl)-5-methyl-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-12- yl]phenyl]propanoate (200.00 mg, 218.31 μmol, 59.59% yield) as a brown solid. LCMS: [M+H]+= 916.7. Step 2: Ethyl 3-[4-[10-(benzenesulfonyl)-3-[(1S,3S,4R)-3-(tert-butoxycarbonylamino)-4-hydroxy- cyclopentyl]-11-(3-fluoro-1-methyl-pyrazol-4-yl)-5-methyl-4-oxo-3,5,8,10- tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-12-yl]phenyl]propanoate

[0398] A solution of ethyl 3-[4-[10-(benzenesulfonyl)-3-[(1S,3S,4R)-3-(tert-butoxycarbonylamino)-4-[tert-butyl(dimethyl)silyl]oxy-cyclopentyl]-11-(3-fluoro-1-methyl-pyrazol-4-yl)-5-methyl-4-oxo- 3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-12-yl]phenyl]propanoate (200 mg, 218.31 μmol) in THF (5 mL) was added Triethylamine trihydrofluoride (0.5 mL), then the mixture was stirred at 50 °C for 1 h. The mixture was diluted with 50 mL EA and 50 mL water. The organic layer was separated, washed with brine (15 mLX2), dried over Na2SO4, filtered and concentrated to give ethyl 3-[4- [10-(benzenesulfonyl)-3-[(1S,3S,4R)-3-(tert-butoxycarbonylamino)-4-hydroxy-cyclopentyl]-11-(3- fluoro-1-methyl-pyrazol-4-yl)-5-methyl-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11- tetraen-12-yl]phenyl]propanoate (100.00 mg, crude) as a brown solid which was used into next step without further purification. LCMS: [M+H]+= 802.6. Step 3: 3-[4-[3-[(1S,3S,4R)-3-(tert-Butoxycarbonylamino)-4-hydroxy-cyclopentyl]-11-(3-fluoro-1- methyl-pyrazol-4-yl)-5-methyl-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-12- yl]phenyl]propanoic acid

[0399] To a solution of ethyl 3-[4-[10-(benzenesulfonyl)-3-[(1S,3S,4R)-3-(tert- butoxycarbonylamino)-4-hydroxy-cyclopentyl]-11-(3-fluoro-1-methyl-pyrazol-4-yl)-5-methyl-4-oxo- 3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-12-yl]phenyl]propanoate (100 mg, 124.71 μmol) in THF / H2O / MeOH=1:1:1 (3 mL) was added NaOH (14.96 mg, 374.12 μmol), then the mixture was stirred at 50 °C for 1 h. The mixture was diluted with 20 mL EA and 20 mL water. The organic layer was separated, washed with brine (10 mLX2) , dried over Na2SO4, filtered and concentrated to give 3-[4- [3-[(1S,3S,4R)-3-(tert-butoxycarbonylamino)-4-hydroxy-cyclopentyl]-11-(3-fluoro-1-methyl-pyrazol-4- yl)-5-methyl-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-12-yl]phenyl]propanoic acid (70.00 mg, crude) as a yellow oil which was used into next step without further purification. LCMS: [M+H]+= 634.6. Step 4: tert-Butyl N-[(10R,11S,13S)-22-(3-fluoro-1-methyl-pyrazol-4-yl)-16-methyl-8,15-dioxo-9- oxa-14,16,19,21-tetrazahexacyclo[12.8.2.22,5.110,13.017,24.020,23]heptacosa-1(22),2,4,17,19,23,26- heptaen-11-yl]carbamate

[0400] To a solution of 3-[4-[3-[(1S,3S,4R)-3-(tert-butoxycarbonylamino)-4-hydroxy-cyclopentyl]- 11-(3-fluoro-1-methyl-pyrazol-4-yl)-5-methyl-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11- tetraen-12-yl]phenyl]propanoic acid (70 mg, 110.47 μmol) in DCM (10 mL) was added DMAP (404.87 mg, 3.31 mmol) and PyBOP (230.39 mg, 441.87 μmol), then the mixture was stirred at rt for 16 h. The mixture was diluted with 20 mL EA and 20 mL water. The organic layer was separated, washed with 20 mL brine twice, dried over Na2SO4, filtered and concentrated. The residue was purified by Pre- TLC (100% EA) to give tert-butyl N-[(10R,11S,13S)-22-(3-fluoro-1-methyl-pyrazol-4-yl)-16-methyl- 8,15-dioxo-9-oxa-14,16,19,21-tetrazahexacyclo[12.8.2.22,5.110,13.017,24.020,23]heptacosa- 1(22),2,4,17,19,23,26-heptaen-11-yl]carbamate (40.00 mg, 64.97 μmol, 58.81% yield) as a yellow oil. LCMS: [M+H]+= 616.5. Step 5 (10R,11S,13S)-11-Amino-22-(3-fluoro-1-methyl-pyrazol-4-yl)-16-methyl-9-oxa-14,16,19,21- tetrazahexacyclo[12.8.2.22,5.110,13.017,24.020,23]heptacosa-1(22),2,4,17,19,23,26-heptaene-8,15- dione

[0401] The solution of tert-butyl N-[(10R,11S,13S)-22-(3-fluoro-1-methyl-pyrazol-4-yl)-16-methyl- 8,15-dioxo-9-oxa-14,16,19,21-tetrazahexacyclo[12.8.2.22,5.110,13.017,24.020,23]heptacosa- 1(22),2,4,17,19,23,26-heptaen-11-yl]carbamate (40 mg, 64.97 μmol) in TFA / DCM=1:1 (2 mL) was stirred at rt for 3 h. The mixture was concentrated to give (10R,11S,13S)-11-amino-22-(3-fluoro-1- methyl-pyrazol-4-yl)-16-methyl-9-oxa-14,16,19,21- tetrazahexacyclo[12.8.2.22,5.110,13.017,24.020,23]heptacosa-1(22),2,4,17,19,23,26-heptaene-8,15- dione (30.00 mg, crude) as a yellow oil which was used into next step directly. LCMS: [M+H]+= 516.4. Step 6:

[0402] To a solution of (10R,11S,13S)-11-amino-22-(3-fluoro-1-methyl-pyrazol-4-yl)-16-methyl-9- oxa-14,16,19,21-tetrazahexacyclo[12.8.2.22,5.110,13.017,24.020,23]heptacosa-1(22),2,4,17,19,23,26- heptaene-8,15-dione (30 mg, 58.19 μmol) in DCM / H2O=1:1 (4 mL) was added disodium carbonate (18.50 mg, 174.57 μmol), and the mixture was stirred at rt for 1 h. The mixture was diluted with 10 mL EA and 10 mL water. Then organic layer was separated, washed with brine (10 mLX2), dried over Na2SO4, filtered and concentrated. The residue was purified by prep-HPLC (Column:Nanochrom ChromCore C1821.2X250mm,10um; Mobile phase: (0.1%FA) H2O-ACN; B%: 20%-50%, 10 min) to give methyl N-[(10R,11S,13S)-22-(3-fluoro-1-methyl-pyrazol-4-yl)-16-methyl-8,15-dioxo-9-oxa- 14,16,19,21-tetrazahexacyclo[12.8.2.22,5.110,13.017,24.020,23]heptacosa-1(22),2,4,17,19,23,26- heptaen-11-yl]carbamate (Example 9, 4.30 mg, 7.50 μmol, 12.88% yield). LCMS: [M+H]+= 574.3;1H NMR (400 MHz, DMSO-d6) δ 11.91 (s, 1H), 8.13 (s, 1H), 7.52 (d, J = 2.4 Hz, 1H), 7.45-7.38 (m, 2H), 7.18-7.04 (m, 3H), 4.79 (t, J = 3.2 Hz, 1H), 4.51-4.39 (m, 1H), 3.67 (s, 3H), 3.56-3.47 (m, 4H), 3.37 (s, 3H), 3.21-3.11 (m, 1H), 2.88-2.75 (m, 1H), 2.71-2.61 (m, 2H), 2.32-2.22 (m, 1H), 1.83-1.74 (m, 1H), 1.67-1.53 (m, 2H). Example 10: Methyl N-[(10R,11S,13S)-22-(3-fluoro-1- methyl-pyrazol-4-yl)-16-methyl-7,15-dioxo- 9-oxa-6,14,16,19,21-pentazahexacyclo [12.8.2.22,5.110,13.017,24.020,23]heptacosa- 1(22),2,4,17,19,23,26-heptaen-11-yl]carbamateStep 1: Ethyl 2-iodoacetate

[0403] To a stirred solution of NaI (9.87 g, 65.87 mmol) in acetone (100 mL) was added ethyl 2- bromoacetate (10 g, 59.88 mmol) at room temperature. Then reaction was stirred at 25 °C for 18 h under darkness. LCMS showed that all the starting material was converted into the product. The suspension was filtrated, and the filtrate was evaporated under reduced pressure. The residue was diluted with water (50 mL) and extracted with hexane (100 mL). The organic layers were washed successively with a 5% sodium thiosulfate solution (50 mL) and water (50 mL), dried over Na2SO4, filtered and concentrated to give ethyl 2-iodoacetate (8.35 g, 33.95 mmol, 56.69% yield, 87% purity) as light-yellow oil. LCMS: m / z [M+H]+=215.0;1H NMR (400 MHz, CHLOROFORM-d) δ 4.25-4.18 (m, 2H), 3.69 (s, 2H), 1.31-1.27 (m, 3H). Step 2: tert-Butyl N-[(1S,2R,4S)-4-[10-(benzenesulfonyl)-12-bromo- 11-(3-fluoro-1- methyl- pyrazol-4-yl)-5-methyl-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6] dodeca-1,6,8,11-tetraen-3-yl]-2- hydroxy-cyclopentyl]carbamate

[0404] To a solution of tert-butyl N-[(1S,2R,4S)-4-[10-(benzenesulfonyl)-12-bromo-11-(3- fluoro-1- methyl-pyrazol-4-yl)-5-methyl-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca -1,6,8,11-tetraen-3-yl]- 2-[tert-butyl(dimethyl)silyl]oxy-cyclopentyl]carbamate (500 mg, 610.63 μmol) in THF (5 mL) was added Triethylamine trihydrofluoride (492.20 mg, 3.05 mmol). Then reaction was stirred at 60 °C for 18 h. LCMS showed that all the starting material was consumed and 70% product formed. The reaction mixture was added NaHCO3 solution (10 mL) and extracted with EA (20 mLX2). The combined organics were washed with saturated NaCl solution, then dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash silica gel chromatography (12 g Silica Flash Column, Eluent of 0~80% ethyl acetate / Petroleum Ether gradient @ 20 mL / min) to give tert-butyl N-[(1S,2R,4S)-4-[10- (benzenesulfonyl)-12-bromo- 11-(3-fluoro-1- methyl-pyrazol-4-yl)-5-methyl-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6] dodeca-1,6,8,11-tetraen-3-yl]-2-hydroxy-cyclopentyl]carbamate (400.00 mg, 567.73 μmol, 92.97% yield) as light-yellow oil. LCMS: m / z [M, M+2]+=704.4, 706.6. Step 3: Ethyl 2-[(1R,2S,4S)-4-[10-(benzenesulfonyl) -12-bromo-11-(3-fluoro-1-methyl-pyrazol-4-yl)- 5-methyl-4-oxo-3,5,8,10-tetrazatricyclo [7.3.0.02,6]dodeca-1,6,8,11-tetraen-3-yl]-2-(tert- butoxycarbonylamino)cyclopentoxy] acetate

[0405] To a mixture of tert-butyl N-[(1S,2R,4S)-4-[10-(benzenesulfonyl)-12-bromo-11 -(3-fluoro-1- methyl-pyrazol-4-yl)-5-methyl-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca -1,6,8,11-tetraen-3-yl]-2- hydroxy-cyclopentyl]carbamate (350 mg, 496.76 μmol) in DCM (5 mL) was added ethyl 2-iodoacetate (318.92 mg, 1.49 mmol) and Ag2O (126.63 mg, 546.44 μmol) at ambient temperature. The resulting mixture was stirred at 25 °C for 2 days. LCMS showed that all the starting material was consumed and 60% product formed. The mixture was filtered through a pad of celite and washed with ethyl acetate. The organic phase concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography (12 g Silica Flash Column, Eluent of 0~60% ethyl acetate / Petroleum Ether gradient @ 20 mL / min) to give ethyl 2-[(1R,2S,4S)-4-[10-(benzenesulfonyl) -12-bromo-11-(3-fluoro-1-methyl- pyrazol-4-yl)-5-methyl-4-oxo-3,5,8,10-tetrazatricyclo [7.3.0.02,6]dodeca-1,6,8,11-tetraen-3-yl]-2-(tert- butoxycarbonylamino)cyclopentoxy] acetate (250.00 mg, 316.19 μmol, 63.65% yield) as colorless oil. LCMS: m / z [M, M+2]+=790.5, 792.5. Step 4: Ethyl 2-[(1R,2S,4S)-4-[12-(4-aminophenyl)-10- (benzenesulfonyl)-11-(3-fluoro-1-methyl- pyrazol-4-yl)-5-methyl-4-oxo-3,5,8,10-tetraza-tricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3-yl]-2- (tert-butoxycarbonylamino)cyc lopentoxy]acetate

[0406] A mixture of ethyl 2-[(1R,2S,4S)-4-[10-(benzenesulfonyl)-12-bromo-11-(3-fluoro-1- methyl- pyrazol-4-yl)-5-methyl-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3-yl]-2-(tert- butoxycarbonylamino)cyclopentoxy]acetate (250 mg, 316.19 μmol), 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)aniline (138.55 mg, 632.39 μmol), Pd(dppf)Cl2(34.70 mg, 47.43 μmol) and Cs2CO3(309.07 mg, 948.58 μmol) in Dioxane (4 mL) / H2O (1 mL) was evacuated and backfilled with nitrogen (this process was repeated a total of three times), and then the reaction was stirred at 105 °C for 2 h. LCMS showed that all the starting material was consumed and 28% product formed. The reaction mixture was concentrated and the residue was purified by flash silica gel chromatography (4 g Silica Flash Column, Eluent of 0~85% ethyl acetate / Petroleum Ether gradient @ 20 mL / min) to give ethyl 2- [(1R,2S,4S)-4-[12-(4-aminophenyl)-10- (benzenesulfonyl)-11-(3-fluoro-1-methyl-pyrazol-4-yl)-5- methyl-4-oxo-3,5,8,10-tetraza-tricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3-yl]-2-(tert- butoxycarbonylamino)cyc lopentoxy]acetate (105.00 mg, 102.01 μmol, 32.26% yield, 78% purity) as yellow solid. LCMS: m / z [M+H]+=803.4. Step 5: 2-[(1R,2S,4S)-4-[12-(4-Aminophenyl)-11-(3-fluoro-1-methyl-pyrazol-4-yl)-5-methyl-4-oxo- 3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3-yl]-2-(tert-butoxycarbonylamino) cyclopentoxy]acetic acid

[0407] To a solution of ethyl 2-[(1R,2S,4S)-4-[12-(4-aminophenyl)-10-(benzenesulfonyl)-11-(3- fluoro-1-methyl-pyrazol-4-yl)-5-methyl-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3-yl]-2-(tert-butoxycarbonylamino)cyclopentoxy]acetate (105 mg, 130.78 μmol) in THF (3 mL) was added NaOH (78.47 mg, 1.96 mmol). The mixture was stirred at 60 °C for 2 h. LCMS showed that all the starting material was consumed and 46% product formed. The solvent was removed and the residue was diluted with water (2 mL) and adjusted pH=3 with 1 M HCl and extracted with EA (30 mLX2). The combined organics were dried over sodium sulfate, filtered, and concentrated to give 2-[(1R,2S,4S)-4- [12-(4-aminophenyl)-11-(3-fluoro-1-methyl-pyrazol-4-yl)-5-methyl-4-oxo-3,5,8,10- tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3-yl]-2-(tert-butoxycarbonylamino) cyclopentoxy]acetic acid (78.00 mg, 104.47 μmol, 79.88% yield, 85% purity) as light-yellow solid. LCMS: m / z [M+H]+= 635.5. Step 6: tert-Butyl N-[(10R,11S,13S)-21-(benzenesulfonyl)-22-(3-fluoro-1-methyl-pyrazol-4-yl)-16- methyl-7,15-dioxo-9-oxa-6,14,16,19,21- pentazahexacyclo[12.8.2.22,5.110,13.017,24.020,23]heptacosa-1(22),2(27),3,5(26),17,19, 23-heptaen- 11-yl]carbamate

[0408] To a solution of 2-[(1R,2S,4S)-4-[12-(4-aminophenyl)-10-(benzenesulfonyl)-11-(3-fluoro -1- methyl-pyrazol-4-yl)-5-methyl-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3-yl]-2- (tert-butoxycarbonylamino)cyclopentoxy]acetic acid (50 mg, 32.27 μmol) in DMF (20 mL) was added DIEA (12.51 mg, 96.80 μmol) and T3P (41.07 mg, 64.53 μmol, 50% purity). The mixture was stirred at 25 °C for 2 h. LCMS showed that all the starting material was consumed and 83% product formed. The solvent was removed in vacuo and the residue was purified by flash silica gel chromatography (4 g Silica Flash Column, Eluent of 0~95% ethyl acetate / Petroleum Ether gradient @ 20 mL / min) to give tert-butyl N-[(10R,11S,13S)-21-(benzenesulfonyl)-22-(3-fluoro-1-methyl-pyrazol-4-yl)-16-methyl-7,15-dioxo-9- oxa-6,14,16,19,21-pentazahexacyclo[12.8.2.22,5.110,13.017,24.020,23]heptacosa- 1(22),2(27),3,5(26),17,19, 23-heptaen-11-yl]carbamate (16.00 mg, 16.91 μmol, 52.42% yield, 80% purity) as yellow oil. LCMS: m / z [M+H]+=757.6. Step 7: (10R,11S,13S)-11- Amino-21-(benzenesulfonyl)-22-(3-fluoro-1-methyl-pyrazol-4-yl)-16- methyl-9-oxa-6,14,16,19,21-pentazahexacyclo[12.8.2.22,5.110,13.017,24.020,23]heptacosa- 1(22),2(27),3,5(26),17,19,23-heptaene-7,15-dione

[0409] To a solution of tert-butyl N-[(10R,11S,13S)-21-(benzenesulfonyl)-22-(3-fluoro-1- methyl- pyrazol-4-yl)-16-methyl-7,15-dioxo-9-oxa-6,14,16,19,21-pentazahexacyclo- [12.8.2.22,5.110,13.017,24.020,23]heptacosa-1(22),2(27),3,5(26),17,19,23-heptaen-11-yl]carbamate (16 mg, 21.14 μmol) in DCM (1 mL) was added TFA (1 mL) and the mixture was stirred at 25°C for 1 h. LCMS showed that all the starting material was converted into the product. The solvent was concentrated in vacuo to give (10R,11S,13S)-11- amino-21-(benzenesulfonyl)-22-(3-fluoro-1-methyl-pyrazol-4-yl)-16- methyl-9-oxa-6,14,16,19,21-pentazahexacyclo[12.8.2.22,5.110,13.017,24.020,23]heptacosa- 1(22),2(27),3,5(26),17,19,23-heptaene-7,15-dione (14.00 mg, crude) as light yellow solid which was taken into next step without further purification. LCMS: m / z [M+H]+=656.8. Step 8: Methyl N-[(10R,11S,13S)-21-(benzenesulfonyl)-22-(3-fluoro-1-methyl-pyrazol-4-yl)-16- methyl-7,15-dioxo-9-oxa-6,14,16,19,21-pentazahexacyclo[12.8.2.22,5.110,13.017,24.020,23]heptacosa-1(22),2(27),3, 5(26),17,19,23-heptaen- 11-yl]carbamate

[0410] A mixture of (10R,11S,13S)-11-amino-21-(benzenesulfonyl)-22-(3-fluoro-1-methyl- pyrazol- 4-yl)-16-methyl-9-oxa-6,14,16,19,21-pentazahexacyclo[12.8.2.22,5.110,13.017,24.020,23]heptacosa- 1(22),2(27),3,5(26),17,19,23-heptaene-7,15-dione (14 mg, 21.32 μmol) in 2-MeTHF (2 mL) was added Na2CO3 (9.04 mg, 85.28 μmol) in H2O (1 mL) followed by ClCOOMe (10.07 mg, 106.60 μmol) and then the mixture was stirred at 25 °C for 20 min. LCMS showed that all the starting material was consumed and 81% product formed. Water was added and extracted with EA (20mL). The organic layer was dried over sodium sulfate, filtered and concentrated to obtain methyl N-[(10R,11S,13S)-21-(benzenesulfonyl)- 22-(3-fluoro-1-methyl-pyrazol-4-yl)-16-methyl-7,15-dioxo-9-oxa-6,14,16,19,21- pentazahexacyclo[12.8.2.22,5.110,13.017,24.020,23]heptacosa-1(22),2(27),3, 5(26),17,19,23-heptaen-11- yl]carbamate (15.00 mg, 20.99 μmol, 98.44% yield) as light-yellow solid. LCMS: m / z [M+H]+=715.6. Step 9: 2-[(1R,2S,4S)-4-[12-(4-Aminophenyl)-11-(3-fluoro-1- methyl-pyrazol-4-yl)-5-methyl-4-oxo- 3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3-yl]-2- (methoxycarbonylamino)cyclopentoxy]acetic acid

[0411] To a solution of methyl N-[(10R,11S,13S)-21-(benzenesulfonyl)-22-(3-fluoro-1-methyl- pyrazol-4-yl)-16-methyl-7,15-dioxo-9-oxa-6,14,16,19,21-pentazahexacyclo[12.8.2.22,5. 110,13.0 .20,23]heptacosa-1(22),2(27),3,5(26),17,19,23-heptaen-11-yl]carbamate (20 mg, 27.98 μmol) in MeOH (5 mL) added NaOH (4 M, 1.05 mL), the mixture was stirred at 50°C for 20 min. LCMS showed that all the starting material was consumed and 77% (254 nm)product formed. The reaction was adjusted pH to 5 with 1 M HCl and the solvent was removed to give 2-[(1R,2S,4S)-4-[12-(4-aminophenyl)-11-(3- fluoro-1- methyl-pyrazol-4-yl)-5-methyl-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11- tetraen-3-yl]-2-(methoxycarbonylamino)cyclopentoxy]acetic acid (16.00 mg, 27.00 μmol, 96.49% yield) as yellow solid which was taken into next step without further purification. LCMS: m / z [M+H]+=593.6. Step 10:

[0412] To a solution of 2-[(1R,2S,4S)-4-[12-(4-aminophenyl)-11-(3-fluoro-1-methyl-pyrazol-4- yl)-5- methyl-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3-yl]-2- (methoxycarbonylamino)cyclopentoxy]acetic acid (16 mg, 27.00 μmol) in DMF (10 mL) was added T3P (34.36 mg, 54.00 μmol, 50% purity) and DIEA (10.47 mg, 81.00 μmol). The mixture was stirred at 25 °C for 1 h. LCMS showed that all the starting material was consumed and 46% product formed. LCMS showed that all the starting material was converted into the product. Partial DMF was removed under vacuum and then purified by prep-HPLC (Column: Welch Xtimate 10um 21.2X250mm Mobile phase: (0.1%FA)H2O-ACN; B%: 10%-70%, 20 min) to give methyl N-[(10R,11S,13S)-22-(3-fluoro-1- methyl- pyrazol-4-yl)-16-methyl-7,15-dioxo-9-oxa-6,14,16,19,21-pentazahexacyclo [12.8.2.22,5.110,13.017,24. 020,23]heptacosa-1(22),2,4,17,19,23,26-heptaen-11-yl]carbamate (Example 10, 6.77 mg, 11.10 μmol, 41.13% yield, 94.24% purity). LCMS: m / z [M+H]+=575.4;1H NMR (400 MHz, DMSO-d6) δ 11.93 (s, 1H), 9.71 (s, 1H), 8.12 (s, 1H), 7.64 (d, J = 1.8 Hz, 1H), 7.50 (dd, J = 8.2, 1.9 Hz, 1H), 7.37 (dd, J = 8.0, 1.8 Hz, 1H), 7.29 (dd, J = 8.0, 1.6 Hz, 1H), 7.21 (dd, J = 7.7, 2.0 Hz, 1H), 6.77 (d, J = 8.3 Hz, 1H), 4.51(d, J = 11.3 Hz, 1H), 4.34 – 4.19 (m, 1H), 3.69 (s, 3H), 3.60 – 3.53 (m, 2H), 3.51 (s, 3H), 3.36 (s, 3H), 3.31 – 3.19 (m, 1H), 2.10 – 1.98 (m, 1H), 1.77 – 1.60 (m, 2H), 1.47 (q, J = 12.1 Hz, 1H). Example 11: Methyl N-[(10R,11S,13S)-22-(3-fluoro-1-methyl-pyrazol-4-yl)-16-methyl-7,15-dioxo-9- oxa-6,14,16,19,21-pentazahexacyclo[12.8.2.22,5.110,13.017,24.020,23]heptacosa- 1(22),2,4,17,19,23,26-heptaen-11-yl]carbamateStep 1: 2-[(1R,2S,4S)-2-(tert-Butoxycarbonylamino)-4-[11-(3-fluoro-1-methyl-pyrazol-4-yl)-5- methyl-12-[4-(methylamino)phenyl]-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11- tetraen-3-yl]cyclopentoxy]acetic acid

[0413] To a solution of 2-[(1R,2S,4S)-4-[12-(4-aminophenyl)-11-(3-fluoro-1-methyl-pyrazol-4-yl)-5- methyl-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3-yl]-2-(tert- butoxycarbonylamino)cyclopentoxy]acetic acid (70 mg, 110.30 μmol) in MeOH (5 mL) was added paraformaldehyde (4.97 mg, 165.44 μmol) and acetic acid (662.35 μg, 11.03 μmol), and the mixture was stirred at 60 °C for 16 h. Then sodium borohydride (20.86 mg, 551.48 μmol) was added to the mixture at 0 °C, and stirred for additional 1 h. LCMS showed the desired product was formed. The mixture was quenched with water and filtered. The residue was purified by Pre-HPLC to give 2-[(1R,2S,4S)-2-(tert- butoxycarbonylamino)-4-[11-(3-fluoro-1-methyl-pyrazol-4-yl)-5-methyl-12-[4-(methylamino)phenyl]-4- oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3-yl]cyclopentoxy]acetic acid (7.00 mg, 10.79 μmol, 9.78% yield) as a white solid. LCMS: [M+H]+= 649.5. Step 2: tert-Butyl N-[(10R,11S,13S)-22-(3-fluoro-1-methyl-pyrazol-4-yl)-6,16-dimethyl-7,15-dioxo- 9-oxa-6,14,16,19,21-pentazahexacyclo[12.8.2.22,5.110,13.017,24.020,23]heptacosa- 1(22),2(27),3,5(26),17,19,23-heptaen-11-yl]carbamate

[0414] To a solution of 2-[(1R,2S,4S)-2-(tert-butoxycarbonylamino)-4-[11-(3-fluoro-1-methyl- pyrazol-4-yl)-5-methyl-12-[4-(methylamino)phenyl]-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca- 1,6,8,11-tetraen-3-yl]cyclopentoxy]acetic acid (7 mg, 10.79 μmol) in DMF (10 mL) was added T3P (6.86 mg, 21.58 μmol) and TEA (3.28 mg, 32.37 μmol), then the mixture was stirred at rt for 1 h. LCMSshowed the desired product was formed. The solvent was removed and the residue was purified by pre- TLC (ethyl acetate) to give tert-butyl N-[(10R,11S,13S)-22-(3-fluoro-1-methyl-pyrazol-4-yl)-6,16- dimethyl-7,15-dioxo-9-oxa-6,14,16,19,21- pentazahexacyclo[12.8.2.22,5.110,13.017,24.020,23]heptacosa-1(22),2(27),3,5(26),17,19,23-heptaen-11- yl]carbamate (6.00 mg, 9.51 μmol, 88.16% yield) as a yellow solid. LCMS: [M+H]+= 631.5. Step 3: (10R,11S,13S)-11-Amino-22-(3-fluoro-1-methyl-pyrazol-4-yl)-6,16-dimethyl-9-oxa- 6,14,16,19,21-pentazahexacyclo[12.8.2.22,5.110,13.017,24.020,23]heptacosa- 1(22),2(27),3,5(26),17,19,23-heptaene-7,15-dione

[0415] The mixture of tert-butyl N-[(10R,11S,13S)-22-(3-fluoro-1-methyl-pyrazol-4-yl)-6,16- dimethyl-7,15-dioxo-9-oxa-6,14,16,19,21- pentazahexacyclo[12.8.2.22,5.110,13.017,24.020,23]heptacosa-1(22),2(27),3,5(26),17,19,23-heptaen-11- yl]carbamate (6 mg, 9.51 µmol) in DCM / TFA=1:1 (2 mL) was stirred at rt for 1 h. LCMS showed the desired product was formed. The mixture was concentrated to give (10R,11S,13S)-11-amino-22-(3- fluoro-1-methyl-pyrazol-4-yl)-6,16-dimethyl-9-oxa-6,14,16,19,21- pentazahexacyclo[12.8.2.22,5.110,13.017,24.020,23]heptacosa-1(22),2(27),3,5(26),17,19,23-heptaene- 7,15-dione (4.00 mg, crude) as a yellow oil which was taken into next step without further purification. LCMS: [M+H]+= 531.4. Step 4:

[0416] To a solution of (10R,11S,13S)-11-amino-22-(3-fluoro-1-methyl-pyrazol-4-yl)-6,16-dimethyl- 9-oxa-6,14,16,19,21-pentazahexacyclo[12.8.2.22,5.110,13.017,24.020,23]heptacosa- 1(22),2(27),3,5(26),17,19,23-heptaene-7,15-dione (4 mg, 7.54 μmol) in DCM / H2O=1:1 (2 mL) was added disodium carbonate (2.40 mg, 22.62 μmol), then the mixture was stirred at rt for 1 h. LCMS showed the desired product was formed. The mixture was diluted with 10 mL EA and 10 mL water. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by Pre-HPLC to give methyl N-[(10R,11S,13S)-22-(3-fluoro-1-methyl-pyrazol-4-yl)-16-methyl-7,15-dioxo-9-oxa- 6,14,16,19,21-pentazahexacyclo[12.8.2.22,5.110,13.017,24.020,23]heptacosa-1(22),2,4,17,19,23,26- heptaen-11-yl]carbamate (Example 11, 1.06 mg, 1.84 μmol, 24.47% yield) as a white solid. LCMS: [M+H]+= 589.3. Example 12: Methyl N-[(10R,11S,13S)-22-(3-fluoro-1-methyl-pyrazol-4-yl)-16-methyl-8,15-dioxo-9- oxa-7,14,16,19,21-pentazahexacyclo[12.8.2.22,5.110,13.017,24.020,23]heptacosa- 1(22),2,4,17,19,23,26-heptaen-11-yl]carbamateStep 1: 3-[(1S,3S,4R)-3-Amino-4-[tert-butyl(dimethyl)silyl]oxy-cyclopentyl]-10-(benzenesulfonyl)- 12-bromo-11-(3-fluoro-1-methyl-pyrazol-4-yl)-5-methyl-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca- 1,6,8,11-tetraen-4-one

[0417] A solution of tert-butyl N-[(1S,2R,4S)-4-[10-(benzenesulfonyl)-12-bromo-11-(3-fluoro-1- methyl-pyrazol-4-yl)-5-methyl-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3-yl]-2- [tert-butyl(dimethyl)silyl]oxy-cyclopentyl]carbamate (INT5, 1 g, 1.22 mmol) in DCM (20 mL) was added TFA (10 mL) and the resulting mixture was stirred at 25oC for 2 h. LCMS showed DP was formed. The reaction mixture was concentrated to give 3-[(1S,3S,4R)-3-amino-4-[tert-butyl(dimethyl)silyl]oxy- cyclopentyl]-10-(benzenesulfonyl)-12-bromo-11-(3-fluoro-1-methyl-pyrazol-4-yl)-5-methyl-3,5,8,10- tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-4-one (880.00 mg, crude) as yellow solid which was taken into next step without further purification. LCMS: [M+H]+= 718.0. Step 2: Methyl N-[(1S,2R,4S)-4-[10-(benzenesulfonyl)-12-bromo-11-(3-fluoro-1-methyl-pyrazol-4- yl)-5-methyl-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3-yl]-2-[tert- butyl(dimethyl)silyl]oxy-cyclopentyl]carbamate

[0418] To a solution of 3-[(1S,3S,4R)-3-amino-4-[tert-butyl(dimethyl)silyl]oxy-cyclopentyl]-10- (benzenesulfonyl)-12-bromo-11-(3-fluoro-1-methyl-pyrazol-4-yl)-5-methyl-3,5,8,10- tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-4-one (880 mg, 1.22 mmol) in DCM (10 mL) and water (5 mL) was added Na2CO3(648.94 mg, 6.12 mmol) and the resulting mixture was stirred at 25oC for 1 h. LCMS showed all starting material was converted into the product. Water (10 mL) was added andextracted with DCM (20 mL). The organic layer was dried over Na2SO4, filtered and concentrated to give methyl N-[(1S,2R,4S)-4-[10-(benzenesulfonyl)-12-bromo-11-(3-fluoro-1-methyl-pyrazol-4-yl)-5- methyl-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3-yl]-2-[tert- butyl(dimethyl)silyl]oxy-cyclopentyl]carbamate (800.00 mg, 1.03 mmol, 84.12% yield) as yellow solid which was taken into next step without further purification. LCMS: [M+H]+= 776.2. Step 3: Methyl N-[(1S,2R,4S)-4-[10-(benzenesulfonyl)-12-bromo-11-(3-fluoro-1-methyl-pyrazol-4- yl)-5-methyl-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3-yl]-2-hydroxy- cyclopentyl]carbamate

[0419] To a solution of methyl N-[(1S,2R,4S)-4-[10-(benzenesulfonyl)-12-bromo-11-(3-fluoro-1- methyl-pyrazol-4-yl)-5-methyl-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3-yl]-2- [tert-butyl(dimethyl)silyl]oxy-cyclopentyl]carbamate (200 mg, 257.48 μmol) in THF (3 mL) was added Triethylamine trihydrofluoride (207.55 mg, 1.29 mmol) and the reaction was stirred at 60 °C for 18 h. LCMS showed SM was consumed completely and desired mass was detected. The reaction mixture was quenched with NaHCO3solution (10 mL) and extracted with EA (20 mLX2). The combined organics were washed with saturated NaCl solution, dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash silica gel chromatography (20 g Silica Flash Column, Eluent of 0~80% Ethyl acetate / Petroleum ether gradient @ 20 mL / min) to give methyl N-[(1S,2R,4S)-4-[10- (benzenesulfonyl)-12-bromo-11-(3-fluoro-1-methyl-pyrazol-4-yl)-5-methyl-4-oxo-3,5,8,10- tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3-yl]-2-hydroxy-cyclopentyl]carbamate (105.00 mg, 158.49 μmol, 61.55% yield) as yellow solid. LCMS: [M+H]+=663.9. Step 4: Methyl N-[(1S,2R,4S)-4-[10-(benzenesulfonyl)-12-[4-[(tert- butoxycarbonylamino)methyl]phenyl]-11-(3-fluoro-1-methyl-pyrazol-4-yl)-5-methyl-4-oxo-3,5,8,10- tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3-yl]-2-hydroxy-cyclopentyl]carbamate

[0420] Nitrogen was purged through of methyl N-[(1S,2R,4S)-4-[10-(benzenesulfonyl)-12-bromo-11- (3-fluoro-1-methyl-pyrazol-4-yl)-5-methyl-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11- tetraen-3-yl]-2-hydroxy-cyclopentyl]carbamate (105 mg, 158.49 μmol), tert-butyl N-[[4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]carbamate (79.22 mg, 237.74 μmol), Cs2CO3 (154.92 mg, 475.48 μmol) and Pd(dppf)Cl2DCM (12.95 mg, 15.85 μmol) and dioxane (2 mL) and H2O (0.5 mL) was added and the resulting mixture was degassed and purged with nitrogen three times and stirred at 105oC for 2 h under N2. LCMS showed DP was formed along with de-bromide byproduct. The reaction was concentrated and purified by flash silica gel chromatography (20 g Silica Flash Column, Eluent of 0~60% Ethyl acetate / Petroleum ether gradient @ 20 mL / min) to give methyl N-[(1S,2R,4S)-4-[10- (benzenesulfonyl)-12-[4-[(tert-butoxycarbonylamino)methyl]phenyl]-11-(3-fluoro-1-methyl-pyrazol-4- yl)-5-methyl-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3-yl]-2-hydroxy- cyclopentyl]carbamate (85.00 mg, 107.75 μmol, 67.99% yield) (EA / PE=2 / 1,Rf=0.62) as a yellow solid. LCMS: [M+H]+= 789.0. Step 5: [(1R,2S,4S)-4-[10-(Benzenesulfonyl)-12-[4-[(tert-butoxycarbonylamino)methyl]phenyl]-11- (3-fluoro-1-methyl-pyrazol-4-yl)-5-methyl-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3-yl]-2-(methoxycarbonylamino)cyclopentyl] (4-nitrophenyl) carbonate

[0421] To a solution of methyl N-[(1S,2R,4S)-4-[10-(benzenesulfonyl)-12-[4-[(tert- butoxycarbonylamino)methyl]phenyl]-11-(3-fluoro-1-methyl-pyrazol-4-yl)-5-methyl-4-oxo-3,5,8,10- tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3-yl]-2-hydroxy-cyclopentyl]carbamate (85 mg, 107.75 μmol) in DCM (2 mL) was added pyridine (426.16 mg, 5.39 mmol) and (4-nitrophenyl) carbonochloridate (108.60 mg, 538.76 μmol) and the mixture was stirred at 25°C for 2h. LCMS showed DP was formed. 10 mL water was added, extracted with DCM (10 mLX2). The combined organic layers were washed by water and brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash silica gel chromatography (20 g Silica Flash Column, Eluent of 0~50% Ethyl acetate / Petroleum ether gradient @ 20 mL / min) to give [(1R,2S,4S)-4-[10-(benzenesulfonyl)-12-[4- [(tert-butoxycarbonylamino)methyl]phenyl]-11-(3-fluoro-1-methyl-pyrazol-4-yl)-5-methyl-4-oxo- 3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3-yl]-2-(methoxycarbonylamino)cyclopentyl] (4-nitrophenyl) carbonate (40.00 mg, 41.93 μmol, 38.91% yield) as a yellow solid. LCMS: [M+H]+= 954.6. Step 6: [(1R,2S,4S)-4-[12-[4-(Aminomethyl)phenyl]-10-(benzenesulfonyl)-11-(3-fluoro-1-methyl- pyrazol-4-yl)-5-methyl-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3-yl]-2- (methoxycarbonylamino)cyclopentyl] (4-nitrophenyl) carbonate

[0422] To a solution of [(1R,2S,4S)-4-[10-(benzenesulfonyl)-12-[4-[(tert- butoxycarbonylamino)methyl]phenyl]-11-(3-fluoro-1-methyl-pyrazol-4-yl)-5-methyl-4-oxo-3,5,8,10- tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3-yl]-2-(methoxycarbonylamino)cyclopentyl] (4- nitrophenyl) carbonate (40 mg, 41.93 μmol) in DCM (1 mL) was added TFA (0.5 mL) and the mixture was stirred at 25°C for 2 h. LCMS showed SM was disappeared and DP was formed. The reaction mixture was concentrated to give [(1R,2S,4S)-4-[12-[4-(aminomethyl)phenyl]-10-(benzenesulfonyl)-11- (3-fluoro-1-methyl-pyrazol-4-yl)-5-methyl-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11- tetraen-3-yl]-2-(methoxycarbonylamino)cyclopentyl] (4-nitrophenyl) carbonate (35.00 mg, crude) as yellow oil which was taken into next step without further purification. LCMS: [M+H]+= 854.6. Step 7: Methyl N-[(10R,11S,13S)-21-(benzenesulfonyl)-22-(3-fluoro-1-methyl-pyrazol-4-yl)-16- methyl-8,15-dioxo-9-oxa-7,14,16,19,21- pentazahexacyclo[12.8.2.22,5.110,13.017,24.020,23]heptacosa-1(22),2,4,17,19,23,26-heptaen-11- yl]carbamate

[0423] To a solution of [(1R,2S,4S)-4-[12-[4-(aminomethyl)phenyl]-10-(benzenesulfonyl)-11-(3- fluoro-1-methyl-pyrazol-4-yl)-5-methyl-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen- 3-yl]-2-(methoxycarbonylamino)cyclopentyl] (4-nitrophenyl) carbonate (35 mg, 40.99 μmol) in DCM (17.5 mL) was added TEA (20.74 mg, 204.96 μmol) and the mixture was stirred at 25 °C for 2 h. LCMS showed SM was disappeared and DP was formed. The reaction mixture was concentrated and the residue was purified by flash silica gel chromatography (20 g Silica Flash Column, Eluent of 0~100% Ethyl acetate / Petroleum ether gradient @ 20 mL / min) to give methyl N-[(10R,11S,13S)-21-(benzenesulfonyl)- 22-(3-fluoro-1-methyl-pyrazol-4-yl)-16-methyl-8,15-dioxo-9-oxa-7,14,16,19,21-pentazahexacyclo[12.8.2.22,5.110,13.017,24.020,23]heptacosa-1(22),2,4,17,19,23,26-heptaen-11-yl]carbamate (20.00 mg, 27.98 μmol, 68.26% yield) as a yellow solid. LCMS: [M+H]+= 715.0. Step 8:

[0424] To a solution of methyl N-[(10R,11S,13S)-21-(benzenesulfonyl)-22-(3-fluoro-1-methyl- pyrazol-4-yl)-16-methyl-8,15-dioxo-9-oxa-7,14,16,19,21- pentazahexacyclo[12.8.2.22,5.110,13.017,24.020,23]heptacosa-1(22),2,4,17,19,23,26-heptaen-11-yl]carbamate (20 mg, 27.98 μmol) in MeOH (0.5 mL), CH3CN (1 mL) and H2O (1 mL) was added NaOH (4 M, 104.94 μL) at 25 °C，and the resulting mixture was stirred at 50 °C for 2 h under N2. LCMS showed the major peak was the DP. The pH value of the solution was adjusted to 5-6 with aqueous HCl (1M). The mixture was purified by HPLC (Nanochrom ChromCore C1821.2X250mm,10um,(0.1%FA)(H2O-ACN 20- 40%) to give methyl N-[(10R,11S,13S)-22-(3-fluoro-1-methyl-pyrazol-4-yl)-16-methyl-8,15-dioxo-9- oxa-7,14,16,19,21-pentazahexacyclo[12.8.2.22,5.110,13.017,24.020,23]heptacosa-1(22),2,4,17,19,23,26- heptaen-11-yl]carbamate (Example 12, 6.65 mg, 11.57 μmol, 41.36% yield). LCMS: [M+H]+= 575.4;1H NMR (400 MHz, DMSO-d6) δ 11.88 (s, 1H), 8.11 (s, 1H), 7.65-7.63 (m, 2H), 7.46 (d, J = 7.4 Hz, 1H), 7.39-7.31 (m, 3H), 7.13 (d, J = 8.8 Hz, 1H), 4.81 (t, J = 3.6 Hz, 1H), 4.51-4.37 (m, 2H), 4.11 (dd, J = 15.7, 6.9 Hz, 1H), 3.69 (s, 3H), 3.55 (s, 3H), 3.38 (s, 3H), 2.82-2.67 (m, 1H), 2.25-2.19 (m, 1H), 1.82- 1.76 (m, 1H), 1.68-1.55 (m, 1H), 1.26 (dd, J = 13.7, 8.8 Hz, 1H). Example 13: Methyl N-[(6R,10R,11S,14S)-22-(3-fluoro-1-methyl-pyrazol-4-yl)-6,16-dimethyl-8,15- dioxo-9-oxa-14,16,19,21-tetrazahexacyclo[12.8.2.22,5.110,13.017,24.020,23]heptacosa- 1(22),2,4,17(24),18,20(23),26-heptaen-11-yl]carbamateStep1: (3R)-3-[4-[10-(Benzenesulfonyl)-3-[(1S,3S,4R)-3-(tert-butoxycarbonylamino)-4-[tert-butyl(dimethyl)silyl]oxy-cyclopentyl]-11-(3-fluoro-1-methyl-pyrazol-4-yl)-5-methyl-4-oxo-3,5,8,10- tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-12-yl]phenyl]butanoate

[0425] To a solution of tert-butyl N-[(1S,2R,4S)-4-[10-(benzenesulfonyl)-12-bromo-11-(3-fluoro-1- methyl-pyrazol-4-yl)-5-methyl-4-oxo-3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-3-yl]-2- [tert-butyl(dimethyl)silyl]oxy-cyclopentyl]carbamate (1 g, 1.22 mmol) in dioxane:H2O=4:1 (15 mL) was added methyl (3R)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]butanoate (1.11 g, 3.66 mmol), cesium fluoride (556.54 mg, 3.66 mmol) and palladium(2+);triphenylphosphane;dichloride (42.86 mg, 61.06 μmol), then the mixture was degassed with nitrogen three times and stirred at 105 °C for 2 h. Parallel reaction*10. LCMS showed the desired product was formed. The mixtures were combined and diluted with 200 mL EA and 200 mL water. Then organic layer was washed with b...

Claims

CLAIMS WHAT IS CLAIMED IS:

1. A compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:Formula (III); wherein: X is -NRX1-, -O-, or -C(RX)2-; RX1is hydrogen, deuterium, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; each RXis independently hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1- C6haloalkyl, or C1-C6deuteroalkyl; Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R11is independently deuterium, halogen, -CN, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2- C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; and / or two R11on the same atom are taken together to form an oxo; n1 is 0, 1, 2, 3, or 4; Z is a C1-C8alkylene, C1-C8alkenylene, or C1-C8alkynylene; each optionally substituted with one or more RZ; wherein one, two, or three carbon atoms of Z are optionally replaced by a heteroatom selected from oxygen, nitrogen, and sulfur; each RZis independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2- C6alkenyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R; and / or two RZon the same carbon are taken together to form an oxo;and / or two RZon the same carbon are taken together to form a cycloalkyl or a heterocycloalkyl; each independently optionally substituted with one or more R; and / or two RZon the different atoms are taken together to form a cycloalkyl or a heterocycloalkyl; each independently optionally substituted with one or more R; Y is absent, C1-C6alkylene, C2-C6alkenylene, or C2-C6alkynylene; each optionally substituted with one or more R; Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R12is independently deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1- C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; and / or two R12on the same atom are taken together to form an oxo; m1 is 0, 1, 2, 3, or 4; Ring C is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R3is independently deuterium, halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2- C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R3; and / or two R3on the same atom are taken together to form an oxo; p is 0, 1, 2, 3, or 4; R4is hydrogen, deuterium, halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, C1-C6haloalkyl, or C1- C6deuteroalkyl; each Rais independently C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1- C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L- aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rbis independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each Rcand Rdare independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1- C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L- heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl,cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl independently optionally substituted with one or more R; and L is absent or C1-C3alkylene optionally substituted with one or more R; each R is independently deuterium, halogen, -CN, -OH, -OC1-C3alkyl, -S(=O)C1-C3alkyl, -S(=O)2C1- C3alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3alkyl, -S(=O)2N(C1-C3alkyl)2, -NH2, -NHC1-C3alkyl, -N(C1- C3alkyl)2, -NHC(=O)OC1-C3alkyl, -C(=O)C1-C3alkyl, -C(=O)OH, -C(=O)OC1-C3alkyl, -C(=O)NH2, -C(=O)N(C1-C3alkyl)2, -C(=O)NHC1-C3alkyl, C1-C3alkyl, C1-C3haloalkyl, C1-C3deuteroalkyl, C1- C3hydroxyalkyl, C1-C3aminoalkyl, C1-C3heteroalkyl, C1-C6cycloalkyl, or 3- to 6-membered heterocycloalkyl; and / or two R on the same atom are taken together to form an oxo.

2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein X is -NRX1-.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein RX1is C1-C6alkyl.

4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 4- to 6-membered cycloalkyl.

5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is cyclopentyl.

6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R11is independently -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, or -NRbC(=O)ORb.

7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R11is independently -NRbC(=O)Raor -NRbC(=O)ORb.

8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R11is independently -NRbC(=O)ORb.

9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein n1 is 1.

10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein.

11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring B is a 5- or 6-membered heteroaryl.

12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein Ring B is phenyl.

13. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R12is independently deuterium, halogen, C1-C6alkyl, C1- C6haloalkyl, or C1-C6deuteroalkyl.

14. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein m1 is 0 or 1.

15. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein m1 is 0.

16. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Y is absent.

17. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R4is hydrogen.

18. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is of Formula (IIIa):Formula (IIIa).

19. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Z is a C1-C6alkylene optionally substituted with one or more RZ; wherein one or two carbon atoms of Z are replaced by a heteroatom selected from oxygen and nitrogen.

20. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Z is a C4-C6alkylene optionally substituted with one or more RZ; wherein one or two carbon atoms of Z are replaced by a heteroatom selected from oxygen and nitrogen.

21. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Z is a C4alkylene optionally substituted with one or more RZ; wherein one or two carbon atoms of Z are replaced by a heteroatom selected from oxygen and nitrogen.

22. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Z is a C4alkylene optionally substituted with one or more RZ; wherein one or two carbon atoms of Z are replaced by a heteroatom that is oxygen.

23. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Z is a C4alkylene optionally substituted with one or more RZ; wherein one carbon atom of Z is replaced by a heteroatom that is oxygen.

24. The compound of any one of claims 1-23, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each RZis independently deuterium, halogen, -CN, -OH, -ORa, - S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl; and / or two RZon the same carbon are taken together to form an oxo.

25. The compound of any one of claims 1-24, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each RZis independently deuterium, halogen, -CN, -OH, -ORa, - NRcRd, -C(=O)Ra, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl; and / or two RZon the same carbon are taken together to form an oxo.

26. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each RZis independently -C(=O)Raor C1-C6alkyl; and / or two RZon the same carbon are taken together to form an oxo.

27. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each RZis independently C1-C6alkyl and / or two RZon the same carbon are taken together to form an oxo.

28. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt, solvate, or.

29. The compound of any one of claims 1-28, or a pharmaceutically acceptable salt, solvate, or3 . The compound of any one of claims 1-29, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Z is, , ,31. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring C is heteroaryl.

32. The compound of any one of claims 1-31, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring C is 5-membered heteroaryl.

33. The compound of any one of claims 1-32, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring C is pyrazolyl.

34. The compound of any one of claims 1-33, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R3is independently deuterium, halogen, -CN, -OH, -ORa, - NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, or C1-C6heteroalkyl.

35. The compound of any one of claims 1-34, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R3is independently deuterium, halogen, -CN, -OH, -ORa, - NRcRd, C1-C6alkyl, C1-C6haloalkyl, or C1-C6deuteroalkyl.

36. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R3is independently halogen, -OH, -ORa, or C1-C6alkyl.

37. The compound of any one of claims 1-36, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R3is independently halogen or C1-C6alkyl.

38. The compound of any one of claims 1-37, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein p is 1 or 2.

39. The compound of any one of claims 1-38, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein p is 2.

40. The compound of any one of claims 1-39, or a pharmaceutically acceptable salt, solvate, or41. The compound of any one of claims 1-40, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein.

42. A compound selected from a compound found in table 1 or in the specification, or a pharmaceutically acceptable salt or solvate thereof.

43. A pharmaceutical composition comprising the compound of any one of claim 1-42, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.

44. A method of treating a JAK2 V617F-mediated disease in a subject, comprising administering a compound of any one of claim 1-42, or a pharmaceutically acceptable salt or solvate thereof to the subject.

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