Macrocyclic heteroaromatic inhibitors of JAK2

Abstract

The present disclosure provides macrocyclic heteroaromatic compounds and compositions thereof useful for inhibiting JAK2. In some embodiments, the present disclosure provides a compound of formula I: or a pharmaceutically acceptable salt thereof.

Description

Attorney Docket No.: 2013518-0088 MACROCYCLIC HETEROAROMATIC INHIBITORS OF JAK2 CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to United States Provisional Application No. 63 / 650,506, filed May 22, 2024, and United States Provisional Application No.63 / 736,937, filed December 20, 2024, the entirety of which are incorporated herein by reference. BACKGROUND

[0002] Janus kinases (JAK1, JAK2, JAK3, and TYK2) are a family of non-receptor tyrosine kinases that may have important roles in the regulation of hematopoeisis, the immune system, and cellular metabolism. JAKs can interact with certain cytokine receptors and can couple cytokine binding to cytoplasmic signaling cascades, including the signal transducers and activators of transcription (STAT) pathway. In addition to a canonical tyrosine kinase domain (JH1) located in the C-terminal region, JAK proteins also contain a pseudokinase domain (JH2).

[0003] Both JH1 and JH2 contain an ATP binding site, but catalytic activity is believed to come predominantly from JH1, as JH2 lacks essential residues for phosphorylation catalysis. However, JH2 mediates critical regulatory functions in JAKs and is believed to primarily serve to inhibit basal JAK2 activity. Mutations to JH2 may therefore, in some instances, lead to kinase hyperactivity. For example, a V617F mutation to the JH2 domain of JAK2 may promote constitutive activation of the JAK-STAT pathway, and may play a causative role in various myeloproliferative disorders. The V617F mutation is found 95% of patients with polycythemia vera, as well as ~60% of patients with essential thrombocythemia and primary myelofibrosis. JAK2 hyperactivation is also associated with several leukemias and lymphomas. Disruption of ATP binding in JH2 inhibits the hyperactivity of JAK2 V617F and other pathogenic JAK2 mutants (Hammaren, H. et. Al., Proc. Natl. Acad. Sci., 2015, 112 (15), 4642-4647).

[0004] A modulator of JAK2 kinase activity (e.g., a JAK2 inhibitor disclosed herein) may be effective in treating a disease associated with JAK-STAT hyperactivity. Therefore, a JAK2 modulator capable of reducing JH1 activity and / or promoting JH2 regulatory function (e.g., by inhibiting ATP binding to JH2) could be useful in restoring or treating aberrant JAK2-mediated signaling, and in treating diseases associated therewith. Page 1 of 196 12746579v1Attorney Docket No.: 2013518-0088 SUMMARY

[0005] The present disclosure provides compounds useful for inhibiting JAK2. In some embodiments, provided compounds are useful for, among other things, treating and / or preventing diseases, disorders, or conditions associated with JAK2.

[0006] In some embodiments, the present disclosure provides a compound of Formula I:or a pharmaceutically acceptable salt thereof, wherein R1, R2, Q, L, and Z are as defined in classes and subclasses herein, both singly and in combination.

[0007] In some embodiments, the present disclosure provides a compound of Formula I- A:or a pharmaceutically acceptable salt thereof, wherein R1, R2, and L are as defined in classes and subclasses herein, both singly and in combination.

[0008] In some embodiments, the present disclosure provides a compound of Formula I- B: Page 2 of 196 12746579v1Attorney Docket No.: 2013518-0088or a pharmaceutically acceptable salt thereof, wherein Q, L2, and Z are as defined in classes and subclasses herein, both singly and in combination.

[0009] In some embodiments, the present disclosure provides a compound of Formula I- C:or a pharmaceutically acceptable salt thereof, wherein R1, R2and L2are as defined in classes and subclasses herein, both singly and in combination.

[0010] In some embodiments, the present disclosure provides a compound of Formula I- D: Page 3 of 196 12746579v1Attorney Docket No.: 2013518-0088or a pharmaceutically acceptable salt thereof, wherein R1, R2, Q, Z, and L2are as defined in classes and subclasses herein, both singly and in combination.

[0011] In some embodiments, the present disclosure provides a compound of Formula I- E:L2are as defined in classes and subclasses herein, both singly and in combination.

[0012] In some embodiments, the present disclosure provides a compound of Formula I- F: Page 4 of 196 12746579v1Attorney Docket No.: 2013518-0088or a pharmaceutically acceptable salt thereof, wherein and L are as defined in classes and subclasses herein, both singly and in combination.

[0013] In some embodiments, the present disclosure provides a compound of Formula I- G:or a pharmaceutically acceptable salt thereof, wherein R1, R2, Q, Z, and L2are as defined in classes and subclasses herein, both singly and in combination.

[0014] In some embodiments, the present disclosure provides a compound of Formula I- H: Page 5 of 196 12746579v1Attorney Docket No.: 2013518-0088or a pharmaceutically acceptable salt thereof, wherein R1, R2, and L2are as defined in classes and subclasses herein, both singly and in combination.

[0015] In some embodiments, the present disclosure provides a compound of Formula I-J:or a pharmaceutically acceptable salt thereof, wherein R1, R2, Q, and L are as defined in classes and subclasses herein, both singly and in combination.

[0016] In some embodiments, the present disclosure provides a compound of Formula I- K:Page 6 of 196 12746579v1Attorney Docket No.: 2013518-0088 or a pharmaceutically acceptable salt thereof, wherein R1, R2, Z, and L are as defined in classes and subclasses herein, both singly and in combination.

[0017] In some embodiments, the present disclosure provides a compound of Formula I- L:R2, Q, Z, and L are as defined in classes and subclasses herein, both singly and in combination.

[0018] In some embodiments, the present disclosure provides a compound of Formula II:or a pharmaceutically acceptable salt thereof, wherein R1, R2a, Q, L, and Z are as defined in classes and subclasses herein, both singly and in combination.

[0019] In some embodiments, the present disclosure provides a compound of Formula II- A: Page 7 of 196 12746579v1Attorney Docket No.: 2013518-0088 or a pharmaceutically L are as defined in classes andsubclasses herein, both singly and in combination.

[0020] In some embodiments, the present disclosure provides a compound of Formula II- B: or a pharmaceuticallyL2, and Z are as defined in classes and subclasses herein, both singly and in combination.

[0021] In some embodiments, the present disclosure provides a compound of Formula II- C:Page 8 of 196 12746579v1Attorney Docket No.: 2013518-0088 or a pharmaceutically acceptable salt thereof, wherein R1, R2aand L2are as defined in classes and subclasses herein, both singly and in combination.

[0022] In some embodiments, the present disclosure provides a compound of Formula II- D: or a pharmaceutically2a 2or -CD3, and R , Q, Z, and L are as defined in classes and subclasses herein, both singly and in combination..

[0023] In some embodiments, the present disclosure provides a compound of Formula II- E:or a pharmaceutically acceptable salt thereof, wherein R1is -CH3or -CD3,and R2aand L2are as defined in classes and subclasses herein, both singly and in combination. Page 9 of 196 12746579v1Attorney Docket No.: 2013518-0088

[0024] In some embodiments, the present disclosure provides a compound of Formula II- F: or a pharmaceutically or -CD32a,and R and L are as defined in classes and subclasses herein, both singly and in combination.

[0025] In some embodiments, the present disclosure provides a compound of Formula II- G:or a pharmaceutically acceptable salt thereof, wherein R1is -CH3 or -CD3, and R2a, Q, Z, and L2are as defined in classes and subclasses herein, both singly and in combination.

[0026] In some embodiments, the present disclosure provides a compound of Formula II- H: Page 10 of 196 12746579v1Attorney Docket No.: 2013518-0088or a pharmaceutically acceptable salt thereof, wherein R1is -CH3or -CD3,and R2aand L2are as defined in classes and subclasses herein, both singly and in combination.

[0027] In some embodiments, the present disclosure provides a compound of Formula II- J:or a pharmaceutically acceptable salt thereof, wherein R1is -CH3 or -CD3, and R2a, Q, and L are as defined in classes and subclasses herein, both singly and in combination.

[0028] In some embodiments, the present disclosure provides a compound of Formula II- K: Page 11 of 196 12746579v1Attorney Docket No.: 2013518-0088 or a pharmaceutically or -CD3, and R2a, Z, and L are asdefined in classes and subclasses herein, both singly and in combination.

[0029] In some embodiments, the present disclosure provides a compound of Formula III- A:or a pharmaceutically acceptable salt thereof, wherein R1, Q, Z, and L are as defined in classes and subclasses herein, both singly and in combination.

[0030] In some embodiments, the present disclosure provides a compound of Formula III- B:Page 12 of 196 12746579v1Attorney Docket No.: 2013518-0088 or a pharmaceutically acceptable salt thereof, wherein R1is -CH3or -CD3,and L is as defined in classes and subclasses herein, both singly and in combination.

[0031] In some embodiments, the present disclosure provides a compound of Formula III- C:or a pharmaceutically acceptable salt thereof, wherein R1is -CH3or -CD3,and Q, Z, and L2are as defined in classes and subclasses herein, both singly and in combination.

[0032] In some embodiments, the present disclosure provides a compound of Formula III- D:or a pharmaceutically acceptable salt thereof, wherein R1is -CH3or -CD3,and L2is as defined in classes and subclasses herein, both singly and in combination.

[0033] In some embodiments, the present disclosure provides a compound of Formula IV- A: Page 13 of 196 12746579v1Attorney Docket No.: 2013518-0088or a pharmaceutically acceptable Z, and L are as defined in classes and subclasses herein, both singly and in combination.

[0034] In some embodiments, the present disclosure provides a compound of Formula IV- B:or a pharmaceutically acceptable salt thereof, wherein R1and L are as defined in classes and subclasses herein, both singly and in combination.

[0035] In some embodiments, the present disclosure provides a compound of Formula IV- C:Page 14 of 196 12746579v1Attorney Docket No.: 2013518-0088 IV-C or a pharmaceutically acceptable salt thereof, wherein R1, Q, Z, and L2are as defined in classes and subclasses herein, both singly and in combination.

[0036] In some embodiments, the present disclosure provides a compound of Formula IV- D:or a pharmaceutically acceptable salt thereof, wherein R1and L2are as defined in classes and subclasses herein, both singly and in combination.

[0037] In some embodiments, the present disclosure provides a compound of Formula V- A:or a pharmaceutically acceptable salt thereof, wherein R1, Q, Z, and L are as defined in classes and subclasses herein, both singly and in combination.

[0038] In some embodiments, the present disclosure provides a compound of Formula V- B: Page 15 of 196 12746579v1Attorney Docket No.: 2013518-0088or a pharmaceutically L are as defined in classes and subclasses herein, both singly and in combination.

[0039] In some embodiments, the present disclosure provides a compound of Formula V- C: or a pharmaceuticallyZ, and L2are as defined in classes and subclasses herein, both singly and in combination.

[0040] In some embodiments, the present disclosure provides a compound of Formula V- D:Page 16 of 196 12746579v1Attorney Docket No.: 2013518-0088 V-D or a pharmaceutically acceptable salt thereof, wherein R1and L2are as defined in classes and subclasses herein, both singly and in combination.

[0041] In some embodiments, the present disclosure provides a method of inhibiting JAK2 in a subject, comprising administering to the subject a compound described herein (e.g., a compound of any one of Formula I to V-D) or a pharmaceutical composition comprising a compound described herein.

[0042] In some embodiments, the present disclosure provides a method of treating a disease, disorder, or condition associated with JAK2, comprising administering to a subject in need thereof the compound of any one of claims 1-38 or the pharmaceutical composition of claim 39.

[0043] In some embodiments, the present disclosure provides a method of treating cancer, comprising administering to a subject in need thereof a compound described herein (e.g., a compound of any one of Formula I to V-D) or a pharmaceutical composition comprising a compound described herein.

[0044] In some embodiments, the present disclosure provides a method of treating a hematological malignancy, comprising administering to a subject in need thereof a compound described herein (e.g., a compound of any one of Formula I to V-D) or a pharmaceutical composition comprising a compound described herein.

[0045] In some embodiments, the present disclosure provides a method of treating a myeloproliferative neoplasm, comprising administering to a subject in need thereof a compound described herein (e.g., a compound of any one of Formula I to V-D) or a pharmaceutical composition comprising a compound described herein. DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0046] The present disclosure provides, among other things, compounds useful for inhibiting JAK2. In some embodiments, provided compounds are useful for, among other things, treating and / or preventing diseases, disorders, or conditions associated with JAK2. In some embodiments, the present disclosure encompasses the insight that compounds that bind to the JH2 domain of JAK proteins are particularly useful as inhibitors of JAK2. Such compounds are useful Page 17 of 196 12746579v1Attorney Docket No.: 2013518-0088 for treating diseases, disorders, and conditions associated with mutations of the JH2 domain that may lead to hyperactivity. For example, the V617F mutation is a mutation that leads to hyperactivity of JAK2. In some embodiments, the discovery of new compounds described herein provides inhibitors that are useful as therapy for diseases and disorders associated with, for example, a V617F to the JH2 domain of JAK2.

[0047] In some embodiments, the present disclosure provides a compound represented by Formula I:or a pharmaceutically acceptable salt thereof, wherein R1, R2, Q, L, and Z are as defined in classes and subclasses herein, both singly and in combination. Compounds and Definitions

[0048] Compounds of this disclosure include those described generally above and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of Elements, CAS version, Handbook of Chemistry and Physics, 75thEd. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry”, 5thEd., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0049] Unless otherwise stated, structures depicted herein are meant to include all stereoisomeric (e.g., enantiomeric or diastereomeric) forms of the structure, as well as all geometric or conformational isomeric forms of the structure. For example, the R and S configurations of each stereocenter are contemplated as part of the disclosure. Therefore, single Page 18 of 196 12746579v1Attorney Docket No.: 2013518-0088 stereochemical isomers, as well as enantiomeric, diastereomic, and geometric (or conformational) mixtures of provided compounds are within the scope of the disclosure. For example, in some case, Table 1 shows one or more stereoisomers of a compound, and unless otherwise indicated, represents each stereoisomer alone and / or as a mixture. Unless otherwise stated, all tautomeric forms of provided compounds are within the scope of the disclosure.

[0050] Unless otherwise indicated, structures depicted herein are meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including replacement of hydrogen by deuterium or tritium, or replacement of a carbon by13C- or14C-enriched carbon are within the scope of this disclosure.

[0051] About or approximately: As used herein, the term “approximately” or “about,” as applied to one or more values of interest, refers to a value that is similar to a stated reference value. In general, those skilled in the art, familiar within the context, will appreciate the relevant degree of variance encompassed by “about” or “approximately” in that context. For example, in some embodiments, the term “approximately” or “about” may encompass a range of values that are within (i.e., ±) 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less of the referred value.

[0052] Administering: As used herein, the term “administering” or “administration” typically refers to the administration of a composition to a subject to achieve delivery of an agent that is, or is included in, a composition to a target site or a site to be treated. Those of ordinary skill in the art will be aware of a variety of routes that may, in appropriate circumstances, be utilized for administration to a subject, for example a human. For example, in some embodiments, administration may be ocular, oral, parenteral, topical, etc. In some particular embodiments, administration may be bronchial (e.g., by bronchial instillation), buccal, dermal (which may be or comprise, for example, one or more of topical to the dermis, intradermal, interdermal, transdermal, etc.), enteral, intra-arterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous, intraventricular, within a specific organ (e.g., intrahepatic), mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (e.g., by intratracheal instillation), vaginal, vitreal, etc. In some embodiments, administration may be parenteral. In some embodiments, administration may be oral. In some particular embodiments, Page 19 of 196 12746579v1Attorney Docket No.: 2013518-0088 administration may be intravenous. In some particular embodiments, administration may be subcutaneous. In some embodiments, administration may involve only a single dose. In some embodiments, administration may involve application of a fixed number of doses. In some embodiments, administration may involve dosing that is intermittent (e.g., a plurality of doses separated in time) and / or periodic (e.g., individual doses separated by a common period of time) dosing. In some embodiments, administration may involve continuous dosing (e.g., perfusion) for at least a selected period of time. In some embodiments, administration may comprise a prime- and-boost protocol. A prime-and-boost protocol can include administration of a first dose of a pharmaceutical composition (e.g., an immunogenic composition, e.g., a vaccine) followed by, after an interval of time, administration of a second or subsequent dose of a pharmaceutical composition (e.g., an immunogenic composition, e.g., a vaccine). In the case of an immunogenic composition, a prime-and-boost protocol can result in an increased immune response in a patient.

[0053] Aliphatic: The term “aliphatic” refers to a straight-chain (i.e., unbranched) or branched, optionally substituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation but which is not aromatic (also referred to herein as “carbocyclic” or “cycloaliphatic”), that has a single point of attachment or more than one point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-12 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms (e.g., C1-6). In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms (e.g., C1-5). In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms (e.g., C1-4). In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms (e.g., C1-3), and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms (e.g., C1-2). Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof. In some embodiments, “aliphatic” refers to a straight-chain (i.e., unbranched) or branched, optionally substituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation that has a single point of attachment or more than one point of attachment to the rest of the molecule.

[0054] Alkyl: The term “alkyl”, used alone or as part of a larger moiety, refers to a saturated, optionally substituted straight or branched hydrocarbon group having (unless otherwise Page 20 of 196 12746579v1Attorney Docket No.: 2013518-0088 specified) 1-12, 1-10, 1-8, 1-6, 1-4, 1-3, or 1-2 carbon atoms (e.g., C1-12, C1-10, C1-8, C1-6, C1-4, C1-3, or C1-2). Exemplary alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, and heptyl.

[0055] Alkylene: The term “alkylene” is refers to a bivalent alkyl group. In some embodiments, “alkylene” is a bivalent straight or branched alkyl group. In some embodiments, an “alkylene chain” is a polymethylene group, i.e., -(CH2)n-, wherein n is a positive integer, e.g., from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. An optionally substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms is optionally replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group and also include those described in the specification herein. It will be appreciated that two substituents of the alkylene group may be taken together to form a ring system. In certain embodiments, two substituents can be taken together to form a 3- to 7-membered ring. The substituents can be on the same or different atoms. The suffix “-ene” or “-enyl” when appended to certain groups herein are intended to refer to a bifunctional moiety of said group. For example, “-ene” or “-enyl”, when appended to “cyclopropyl” becomes “cyclopropylene” or “cyclopropylenyl” and is intended to refer to a bifunctional cyclopropyl group, .

[0056] Alkenyl: The term “alkenyl”, used alone or as part of a largerto an optionally substituted straight or branched chain or cyclic hydrocarbon group having at least one double bond and having (unless otherwise specified) 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms(e.g., C2-12, C2-10, C2-8, C2-6, C2-4, or C2-3). Exemplary alkenyl groups include ethenyl, propenyl, butenyl, pentenyl, hexenyl, and heptenyl. The term “cycloalkenyl” refers to an optionally substituted non-aromatic monocyclic or multicyclic ring system containing at least one carbon-carbon double bond and having about 3 to about 10 carbon atoms. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl, and cycloheptenyl.

[0057] Alkynyl: The term “alkynyl”, used alone or as part of a larger moiety, refers to an optionally substituted straight or branched chain hydrocarbon group having at least one triple bond and having (unless otherwise specified) 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms (e.g., C2-12, C2-10, C2-8, C2-6, C2-4, or C2-3). Exemplary alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and heptynyl. Page 21 of 196 12746579v1Attorney Docket No.: 2013518-0088

[0058] Aryl: The term “aryl” refers to monocyclic and bicyclic ring systems having a total of six to fourteen ring members (e.g., C6-C14), wherein at least one ring in the system is aromatic and wherein each ring in the system contains three to seven ring members. In some embodiments, an “aryl” group contains between six and twelve total ring members (e.g., C6-C12). The term “aryl” may be used interchangeably with the term “aryl ring”. In certain embodiments, “aryl” refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Unless otherwise specified, “aryl” groups are hydrocarbons. In some embodiments, an “aryl” ring system is an aromatic ring (e.g., phenyl) that is fused to a non-aromatic ring (e.g., cycloalkyl). Examples of aryl rings include that are fused .or “bicyclic ring system” refers to any bicyclic ring system, i.e., carbocyclic or heterocyclic, saturated or having one or more units of unsaturation, having one or more atoms in common between the two rings of the ring system. Thus, the term includes any permissible ring fusion, such as ortho-fused or spirocyclic. As used herein, the term “heterobicyclic” is a subset of “bicyclic” that requires that one or more heteroatoms are present in one or both rings of the bicycle. Such heteroatoms may be present at ring junctions and are optionally substituted, and may be selected from nitrogen (including N-oxides), oxygen, sulfur (including oxidized forms such as sulfones and sulfonates), phosphorus (including oxidized forms such as phosphates), boron, etc. In some embodiments, a bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. As used herein, the term “bridged bicyclic” refers to any bicyclic ring system, i.e., carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge. As defined by IUPAC, a “bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a “bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include those groups set forth below where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more Page 22 of 196 12746579v1Attorney Docket No.: 2013518-0088 substituents as set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bicyclic rings include: Exemplary bridgedNH NH .

[0060] term refers to a sample obtained or derived from a biological source (e.g., a tissue or organism or cell culture) of interest, as described herein. In some embodiments, a source of interest comprises an organism, such as an animal or human. In some embodiments, a biological sample is or comprises biological tissue or fluid. In some embodiments, a biological sample may be or comprise bone marrow; blood; blood cells; ascites; tissue or fine needle biopsy samples; cell-containing body fluids; free Page 23 of 196 12746579v1Attorney Docket No.: 2013518-0088 floating nucleic acids; sputum; saliva; urine; cerebrospinal fluid, peritoneal fluid; pleural fluid; feces; lymph; gynecological fluids; skin swabs; vaginal swabs; oral swabs; nasal swabs; washings or lavages such as a ductal lavages or broncheoalveolar lavages; aspirates; scrapings; bone marrow specimens; tissue biopsy specimens; surgical specimens; feces, other body fluids, secretions, and / or excretions; and / or cells therefrom, etc. In some embodiments, a biological sample is or comprises cells obtained from an individual. In some embodiments, obtained cells are or include cells from an individual from whom the sample is obtained. In some embodiments, a sample is a “primary sample” obtained directly from a source of interest by any appropriate means. For example, in some embodiments, a primary biological sample is obtained by methods selected from the group consisting of biopsy (e.g., fine needle aspiration 24ncubae biopsy), surgery, collection of body fluid (e.g., blood, lymph, feces etc.), etc. In some embodiments, as will be clear from context, the term “sample” refers to a preparation that is obtained by processing (e.g., by removing one or more components of and / or by adding one or more agents to) a primary sample. For example, filtering using a semi-permeable membrane. Such a “processed sample” may comprise, for example, nucleic acids or proteins extracted from a sample or obtained by subjecting a primary sample to techniques such as amplification or reverse transcription of mRNA, isolation and / or purification of certain components, etc.

[0061] Composition: Those skilled in the art will appreciate that the term “composition” may be used to refer to a discrete physical entity that comprises one or more specified components. In general, unless otherwise specified, a composition may be of any form – e.g., gas, gel, liquid, solid, etc.

[0062] Cycloaliphatic: As used herein, the term “cycloaliphatic” refers to a monocyclic C3-8 hydrocarbon or a bicyclic C6-12 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point or more than one points of attachment to the rest of the molecule. In some embodiments, a cycloaliphatic ring can be attached in a spirocyclic manner, .

[0063] Cycloalkyl: As used herein, the term “cycloalkyl” refers to an optionally substituted saturated ring monocyclic or polycyclic system of about 3 to about 10 ring carbon Page 24 of 196 12746579v1Attorney Docket No.: 2013518-0088 atoms. Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0064] Dosage form or unit dosage form: Those skilled in the art will appreciate that the term “dosage form” may be used to refer to a physically discrete unit of an active agent (e.g., a therapeutic or diagnostic agent) for administration to a subject. Typically, each such unit contains a predetermined quantity of active agent. In some embodiments, such quantity is a unit dosage amount (or a whole fraction thereof) appropriate for administration in accordance with a dosing regimen that has been determined to correlate with a desired or beneficial outcome when administered to a relevant population (i.e., with a therapeutic dosing regimen).

[0065] Effective Amount: The term “effective amount” refers to the amount of a compound sufficient to effect beneficial or desired results (e.g., a therapeutic, ameliorative, inhibitory, or preventative result). An effective amount can be administered in one or more administrations, applications, or dosages and is not intended to be limited to a particular formulation or administration route.

[0066] Excipient: As used herein, the term “excipient” refers to a non-therapeutic agent that may be included in a pharmaceutical composition, for example, to provide or contribute to a desired consistency or stabilizing effect. Suitable pharmaceutical excipients include, for example, starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.

[0067] Halogen: The term “halogen” or “halo” means F, Cl, Br, or I.

[0068] Heteroaliphatic: The term “heteroaliphatic” or “heteroaliphatic group”, as used herein, denotes an optionally substituted hydrocarbon moiety having, in addition to carbon atoms, from one to five heteroatoms, that may be straight–chain (i.e., unbranched), branched, or cyclic (“heterocyclic”) and may be completely saturated or may contain one or more units of unsaturation, but which is not aromatic. The term “heteroatom” refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. The term “nitrogen” also includes a substituted nitrogen. Unless otherwise specified, heteroaliphatic groups contain 1–10 carbon atoms wherein 1–3 carbon atoms are optionally and independently replaced with heteroatoms selected from oxygen, nitrogen, and sulfur. In some Page 25 of 196 12746579v1Attorney Docket No.: 2013518-0088 embodiments, heteroaliphatic groups contain 1–4 carbon atoms, wherein 1–2 carbon atoms are optionally and independently replaced with heteroatoms selected from oxygen, nitrogen, and sulfur. In yet other embodiments, heteroaliphatic groups contain 1–3 carbon atoms, wherein 1 carbon atom is optionally and independently replaced with a heteroatom selected from oxygen, nitrogen, and sulfur. Suitable heteroaliphatic groups include, but are not limited to, linear or branched, heteroalkyl, heteroalkenyl, and heteroalkynyl groups. For example, a 1- to 10 atom heteroaliphatic group includes the following exemplary groups: -O-CH3, -CH2-O-CH3, -O-CH2- CH2-O-CH2-CH2-O-CH3, and the like.

[0069] Heteroaryl: The terms “heteroaryl” and “heteroar–”, used alone or as part of a larger moiety, e.g., “heteroaralkyl”, or “heteroaralkoxy”, refer to monocyclic or bicyclic ring groups having 5 to 10 ring atoms (e.g., 5- to 6-membered monocyclic heteroaryl or 9- to 10- membered bicyclic heteroaryl); having 6, 10, or 14 π electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. Exemplary heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridonyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2-a]pyridinyl, thienopyrimidinyl, triazolopyridinyl, and benzoisoxazolyl. The terms “heteroaryl” and “heteroar–”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings (i.e., a bicyclic heteroaryl ring having 1 to 3 heteroatoms). Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzoxazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H– quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, pyrido[2,3–b]–1,4–oxazin–3(4H)–one, and benzoisoxazolyl. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring”, “heteroaryl group”, or “heteroaromatic”, any of which terms include rings that are optionally substituted.

[0070] Heteroatom: The term “heteroatom” as used herein refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. Page 26 of 196 12746579v1Attorney Docket No.: 2013518-0088

[0071] Heterocycle: As used herein, the terms “heterocycle”, “heterocyclyl”, and “heterocyclic ring” are used interchangeably and refer to a stable 3- to 8-membered monocyclic or 4- to 10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, such as one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term “nitrogen” includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0–3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4-dihydro- 2H-pyrrolyl), NH (as in pyrrolidinyl), or NR+(as in N-substituted pyrrolidinyl). A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and thiamorpholinyl. In some embodiments, a heterocycle can be attached in a spirocyclic manner, e.g., or . A heterocyclyl group may be mono-, bi-, tri-, or polycyclic, preferably mono-, bi-, or tricyclic, more preferably mono- or bicyclic. A bicyclic heterocyclic ring also includes groups in which the heterocyclic ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings. Exemplary bicyclic heterocyclic groups include indolinyl, isoindolinyl, benzodioxolyl, 1,3- dihydroisobenzofuranyl, 2,3-dihydrobenzofuranyl, and tetrahydroquinolinyl. A bicyclic heterocyclic ring can also be a spirocyclic ring system (e.g., 6- to 11-membered spirocyclic fused heterocyclic ring having, in addition to carbon atoms, one or more heteroatoms as defined above (e.g., one, two, three or four heteroatoms)). A bicyclic heterocyclic ring can also be a bridged ring system (e.g., 7- to 11-membered bridged heterocyclic ring having one, two, or three bridging atoms.

[0072] Oral: The phrases “oral administration” and “administered orally” as used herein have their art-understood meaning referring to administration by mouth of a compound or composition.

[0073] Parenteral: The phrases “parenteral administration” and “administered parenterally” as used herein have their art-understood meaning referring to modes of Page 27 of 196 12746579v1Attorney Docket No.: 2013518-0088 administration other than enteral and topical administration, usually by injection, and include, without limitation, intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticulare, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion.

[0074] Partially Unsaturated: As used herein, the term “partially unsaturated”, when referring to a ring moiety, means a ring moiety that includes at least one double or triple bond between ring atoms. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic (e.g., aryl or heteroaryl) moieties, as herein defined.

[0075] Patient or subject: As used herein, the term “patient” or “subject” refers to any organism to which a provided composition is or may be administered, e.g., for experimental, diagnostic, prophylactic, cosmetic, and / or therapeutic purposes. Typical patients or subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and / or humans). In some embodiments, a patient is a human. In some embodiments, a patient or a subject is suffering from or susceptible to one or more disorders or conditions. In some embodiments, a patient or subject displays one or more symptoms of a disorder or condition. In some embodiments, a patient or subject has been diagnosed with one or more disorders or conditions. In some embodiments, a patient or a subject is receiving or has received certain therapy to diagnose and / or to treat a disease, disorder, or condition.

[0076] Pharmaceutical composition: As used herein, the term “pharmaceutical composition” refers to an active agent, formulated together with one or more pharmaceutically acceptable carriers. In some embodiments, the active agent is present in unit dose amount appropriate for administration in a therapeutic or dosing regimen that shows a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population. In some embodiments, pharmaceutical compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution Page 28 of 196 12746579v1Attorney Docket No.: 2013518-0088 or suspension, or sustained-release formulation; topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin, lungs, or oral cavity; intravaginally or intrarectally, for example, as a pessary, cream, or foam; sublingually; ocularly; transdermally; or nasally, pulmonary, and to other mucosal surfaces.

[0077] Pharmaceutically acceptable: As used herein, the phrase “pharmaceutically acceptable” refers to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0078] Pharmaceutically acceptable salt: The term “pharmaceutically acceptable salt”, as used herein, refers to salts of such compounds that are appropriate for use in pharmaceutical contexts, i.e., salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977). Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2– hydroxy–ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2–naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3–phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p–toluenesulfonate, undecanoate, valerate salts, and the like.

[0079] Further, acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, Page 29 of 196 12746579v1Attorney Docket No.: 2013518-0088 by P. Stahl et al., Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al., Journal of Pharmaceutical Sciences 1977, 66(1), 1-19; P. Gould, International J. of Pharmaceutics 1986, 33, 201-217; Anderson et al., The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, D.C. on their website). These disclosures are incorporated herein by reference.

[0080] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1–4alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.

[0081] Substituted or optionally substituted: As described herein, compounds of this disclosure may contain “optionally substituted” moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent (i.e., as described below for optionally substituted groups). “Substituted” applies to one or more hydrogens that are either explicit or anthe group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use Page 30 of 196 12746579v1Attorney Docket No.: 2013518-0088 for one or more of the purposes provided herein. Groups described as being “substituted” preferably have between 1 and 4 substituents, more preferably 1 or 2 substituents. Groups described as being “optionally substituted” may be unsubstituted or be “substituted” as described above.

[0082] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; –(CH2)0–4R°; –(CH2)0–4OR°; -O(CH2)0-4Ro, –O– (CH2)0–4C(O)OR°; –(CH2)0–4CH(OR°)2; –(CH2)0–4SR°; –(CH2)0–4Ph, which may be substituted with R°; –(CH2)0–4O(CH2)0–1Ph which may be substituted with R°; –CH=CHPh, which may be substituted with R°; –(CH2)0–4O(CH2)0–1-pyridyl which may be substituted with R°; –NO2; –CN; –N3; -(CH2)0–4N(R°)2; –(CH2)0–4N(R°)C(O)R°; –N(R°)C(S)R°; –(CH2)0–4N(R°)C(O)NR°2; -N(R°)C(S)NR°2; –(CH2)0–4N(R°)C(O)OR°; - N(R°)N(R°)C(O)R°; -N(R°)N(R°)C(O)NR°2; -N(R°)N(R°)C(O)OR°; –(CH2)0–4C(O)R°; – C(S)R°; –(CH2)0–4C(O)OR°; –(CH2)0–4C(O)SR°; -(CH2)0–4C(O)OSiR°3; –(CH2)0–4OC(O)R°; – OC(O)(CH2)0–4SR°; –(CH2)0–4SC(O)R°; –(CH2)0–4C(O)NR°2; –C(S)NR°2; –C(S)SR°; – SC(S)SR°, -(CH2)0–4OC(O)NR°2; -C(O)N(OR°)R°; –C(O)C(O)R°; –C(O)CH2C(O)R°; – C(NOR°)R°; -(CH2)0–4SSR°; –(CH2)0–4S(O)2R°; –(CH2)0–4S(O)2OR°; –(CH2)0–4OS(O)2R°; – S(O)2NR°2; -(CH2)0–4S(O)(NH)R°; -(CH2)0–4S(O)R°; -N(R°)S(O)2NR°2; –N(R°)S(O)2R°; – N(OR°)R°; –C(NH)NR°2; –P(O)2R°; -P(O)R°2; -OP(O)R°2; –OP(O)(OR°)2; –SiR°3; –(C1–4 straight or branched alkylene)O–N(R°)2; or –(C1–4 straight or branched alkylene)C(O)O–N(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, C1– 6 aliphatic, –CH2Ph, –O(CH2)0–1Ph, -CH2-(5- to 6-membered heteroaryl ring), or a 3- to 6- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3- to 12- membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0083] Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms), are independently halogen, –(CH2)0–2R^, –(haloR^), –(CH2)0–2OH, –(CH2)0–2OR^, –(CH2)0–2CH(OR^)2, -O(haloR^), –CN, – Page 31 of 196 12746579v1Attorney Docket No.: 2013518-0088 N3, –(CH2)0–2C(O)R^, –(CH2)0–2C(O)OH, –(CH2)0–2C(O)OR^, –(CH2)0–2SR^, –(CH2)0–2SH, – (CH ) NH , –(CH ) NHR^, –(CH ) NR^ , –NO , –S ^ ^ ^ 2 0–2 2 2 0–2 2 0–2 2 2 iR 3, –OsiR 3, -C(O)SR , –(C1–4 straight or branched alkylene)C(O)OR^, or –SSR^wherein each R^is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =O and =S.

[0084] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =O (“oxo”), =S, =NNR*2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O) R*, =NR*, =NOR* ** 2 , –O(C(R 2))2–3O–, or –S(C(R 2))2–3S–, wherein each independent occurrence of R*is selected from hydrogen, C1–6aliphatic which may be substituted as defined below, or an unsubstituted 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: –O(CR*2)2–3O–, wherein each independent occurrence of R*is selected from hydrogen, C1–6aliphatic which may be substituted as defined below, or an unsubstituted 5– 6–membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0085] Suitable substituents on the aliphatic group of R*include halogen, – R^, -(haloR^), -OH, –OR^, –O(haloR^), –CN, –C(O)OH, –C(O)OR^, –NH2, –NHR^, –NR^2, or – NO2, wherein each R^is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 3- to 6- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0086] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include –R†, –NR†2, –C(O)R†, –C(O)OR†, –C(O)C(O)R†, – C(O)CH2C(O)R†, -S(O)2R†, -S(O)2NR† 2, –C(S)NR† 2, –C(NH)NR† 2, or –N(R†)S(O)2R†; wherein each R†is independently hydrogen, C1–6aliphatic which may be substituted as defined below, or an unsubstituted 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the Page 32 of 196 12746579v1Attorney Docket No.: 2013518-0088 definition above, two independent occurrences of R†, taken together with their intervening atom(s) form an unsubstituted 3- to 12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0087] Suitable substituents on the aliphatic group of R†are independently halogen, – R^, -(haloR^), –OH, –OR^, –O(haloR^), –CN, –C(O)OH, –C(O)OR^, –NH2, –NHR^, –NR^2, or -NO2, wherein each R^is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 3- to 6- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0088] Small molecule: As used herein, the term “small molecule” means a low molecular weight organic and / or inorganic compound. In general, a “small molecule” is a molecule that is less than about 5 kilodaltons (kD) in size. In some embodiments, a small molecule is less than about 4 kD, 3 kD, about 2 kD, or about 1 kD. In some embodiments, the small molecule is less than about 800 daltons (D), about 600 D, about 500 D, about 400 D, about 300 D, about 200 D, or about 100 D. In some embodiments, a small molecule is less than about 2000 g / mol, less than about 1500 g / mol, less than about 1000 g / mol, less than about 800 g / mol, or less than about 500 g / mol. In some embodiments, a small molecule is not a polymer.

[0089] In some embodiments, a small molecule does not include a polymeric moiety. In some embodiments, a small molecule is not and / or does not comprise a protein or polypeptide (e.g., is not an oligopeptide or peptide). In some embodiments, a small molecule is not and / or does not comprise a polynucleotide (e.g., is not an oligonucleotide). In some embodiments, a small molecule is not and / or does not comprise a polysaccharide; for example, in some embodiments, a small molecule is not a glycoprotein, proteoglycan, glycolipid, etc.). In some embodiments, a small molecule is not a lipid.

[0090] In some embodiments, a small molecule is a modulating agent (e.g., is an inhibiting agent or an activating agent). In some embodiments, a small molecule is biologically active. In some embodiments, a small molecule is detectable (e.g., comprises at least one detectable moiety). In some embodiments, a small molecule is a therapeutic agent.

[0091] Those of ordinary skill in the art, reading the present disclosure, will appreciate that certain small molecule compounds described herein may be provided and / or utilized in any of a Page 33 of 196 12746579v1Attorney Docket No.: 2013518-0088 variety of forms such as, for example, crystal forms (e.g., polymorphs, solvates, etc), salt forms, protected forms, pro-drug forms, ester forms, isomeric forms (e.g., optical and / or structural isomers), isotopic forms, etc.

[0092] Those of ordinary skill in the art will appreciate that certain small molecule compounds have structures that can exist in one or more steroisomeric forms. In some embodiments, such a small molecule may be utilized in accordance with the present disclosure in the form of an individual enantiomer, diastereomer or geometric isomer, or may be in the form of a mixture of stereoisomers; in some embodiments, such a small molecule may be utilized in accordance with the present disclosure in a racemic mixture form.

[0093] Those of skill in the art will appreciate that certain small molecule compounds have structures that can exist in one or more tautomeric forms. In some embodiments, such a small molecule may be utilized in accordance with the present disclosure in the form of an individual tautomer, or in a form that interconverts between tautomeric forms.

[0094] Those of skill in the art will appreciate that certain small molecule compounds have structures that permit isotopic substitution (e.g.,2H or3H for H;11C,13C or14C for12C;13N or15N for14N;17O or18O for16O;36Cl for35Cl or37Cl;18F for19F;131I for127I; etc.). In some embodiments, such a small molecule may be utilized in accordance with the present disclosure in one or more isotopically modified forms, or mixtures thereof.

[0095] In some embodiments, reference to a particular small molecule compound may relate to a specific form of that compound. In some embodiments, a particular small molecule compound may be provided and / or utilized in a salt form (e.g., in an acid-addition or base-addition salt form, depending on the compound); in some such embodiments, the salt form may be a pharmaceutically acceptable salt form.

[0096] In some embodiments, where a small molecule compound is one that exists or is found in nature, that compound may be provided and / or utilized in accordance in the present disclosure in a form different from that in which it exists or is found in nature. Those of ordinary skill in the art will appreciate that, in some embodiments, a preparation of a particular small molecule compound that contains an absolute or relative amount of the compound, or of a particular form thereof, that is different from the absolute or relative (with respect to another component of the preparation including, for example, another form of the compound) amount of Page 34 of 196 12746579v1Attorney Docket No.: 2013518-0088 the compound or form that is present in a reference preparation of interest (e.g., in a primary sample from a source of interest such as a biological or environmental source) is distinct from the compound as it exists in the reference preparation or source. Thus, in some embodiments, for example, a preparation of a single stereoisomer of a small molecule compound may be considered to be a different form of the compound than a racemic mixture of the compound; a particular salt of a small molecule compound may be considered to be a different form from another salt form of the compound; a preparation that contains only a form of the compound that contains one conformational isomer ((Z) or I) of a double bond may be considered to be a different form of the compound from one that contains the other conformational isomer (E) or (Z)) of the double bond; a preparation in which one or more atoms is a different isotope than is present in a reference preparation may be considered to be a different form; etc.

[0097] Those skilled in the art will further appreciate that, in small molecule structures, the symbol , as used herein, and drawn across a bond, refers to a point of attachment between two atoms. Additionally or alternatively, the symbol refers to a point of attachment ring in a spirocyclic manner. Alternatively, the symbol , when drawn adjacent to a double bond, is intended to encompass both a cis alkene and a trans alkene, e.g.: .in small molecule structures, the symbol , as used herein, represents a single or double bond between two atoms in a ring structure. For .

[0099] Treat: As used herein, the term “treat” (also “treatment” or “treating”) refers to any administration of a therapy that partially or completely alleviates, ameliorates, relives, inhibits, delays onset of, reduces severity of, and / or reduces incidence of one or more symptoms, features, and / or causes of a particular disease, disorder, and / or condition. In some embodiments, such treatment may be of a subject who does not exhibit signs of the relevant disease, disorder and / or condition and / or of a subject who exhibits only early signs of the disease, disorder, and / or Page 35 of 196 12746579v1Attorney Docket No.: 2013518-0088 condition. Alternatively or additionally, such treatment may be of a subject who exhibits one or more established signs of the relevant disease, disorder and / or condition. In some embodiments, treatment may be of a subject who has been diagnosed as suffering from the relevant disease, disorder, and / or condition. Provided Compounds

[0100] In some embodiments, the present disclosure provides a compound of Formula I:or a pharmaceutically acceptable salt thereof, wherein: R1is hydrogen or optionally substituted C1-C6 aliphatic; R2is C1-C6 aliphatic, C1-C6 heteroaliphatic, C3-C12 cycloaliphatic, 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, or C6-C10 aryl, wherein R2is optionally substituted with one or more instances of R2a; each R2ais independently selected from the group consisting of optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 heteroaliphatic, halogen, oxo, -CN, -NO2, - C(O)N(Ra)2, -OC(O)Ra, -OC(O)N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)C(O)ORa, -N(Ra)C(O)N(Ra)2, -aliphatic; each Rais independently selected from hydrogen, optionally substituted C1-C6 aliphatic, optionally substituted C1-C6heteroaliphatic, optionally substituted 5- to 12- membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, and optionally substituted 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S; Page 36 of 196 12746579v1Attorney Docket No.: 2013518-0088 each Rbis independently selected from optionally substituted C3-C12cycloaliphatic, optionally substituted 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, optionally substituted 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, and optionally substituted C6-C10aryl; Q is selected from optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 heteroaliphatic, optionally substituted C3-C12 cycloaliphatic, optionally substituted 4- to 10- membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, optionally substituted 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, and optionally substituted C6-C10 aryl; Z is selected from optionally substituted C1-C6aliphatic, optionally substituted C1-C6heteroaliphatic, optionally substituted C3-C12cycloaliphatic, optionally substituted 4- to 10- membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, optionally substituted 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, and optionally substituted C6-C10aryl; L is *-L1-L2-L3-**, where * represents a point of attachment to Q and ** represents a point of attachment to Z; L1is a bond, -C(O)N(Ra)-, -OC(O)-, -OC(O)N(Ra)-, -N(Ra)C(O)-, -N(Ra)C(O)O-, - N(Ra)C(O)N(Ra)-, -S(O)2N(Ra)-, -N(Ra)S(O)2-, -S(O)2-, -C(Ra)2O-, -N(Ra)-, -S-, or -O-; L3is a bond, -C(O)N(Ra)-, -OC(O)-, -OC(O)N(Ra)-, -N(Ra)C(O)-, -N(Ra)C(O)O-, - N(Ra)C(O)N(Ra)-, -S(O)2N(Ra)-, -N(Ra)S(O)2-, -S(O)2-, -C(Ra)2O-, -N(Ra)-, -S-, or -O-; and L2is optionally substituted C1-C6aliphatic, optionally substituted 2- to 6-membered heteroaliphatic, optionally substituted 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, or optionally substituted C3-C10 cycloaliphatic.

[0101] In some embodiments, the present disclosure provides a compound of Formula I- A:Page 37 of 196 12746579v1Attorney Docket No.: 2013518-0088 I-A or a pharmaceutically acceptable salt thereof, wherein R1, R2, and L are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.

[0102] In some embodiments, the present disclosure provides a compound of Formula I- B:or a pharmaceutically acceptable salt thereof, wherein R1, R2, Q, Z, and L2are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.

[0103] In some embodiments, the present disclosure provides a compound of Formula I- C:or a pharmaceutically acceptable salt thereof, wherein R1, R2, and L2are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.

[0104] In some embodiments, the present disclosure provides a compound of Formula I- D: Page 38 of 196 12746579v1Attorney Docket No.: 2013518-0088or a pharmaceutically acceptable salt thereof, wherein R1, R2, Q, Z, and L2are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.

[0105] In some embodiments, the present disclosure provides a compound of Formula I- E:L2are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.

[0106] In some embodiments, the present disclosure provides a compound of Formula I- F: Page 39 of 196 12746579v1Attorney Docket No.: 2013518-0088or a pharmaceutically acceptable salt thereof, wherein and L are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.

[0107] In some embodiments, the present disclosure provides a compound of Formula I- G:or a pharmaceutically acceptable salt thereof, wherein R1, R2, Q, Z, and L2are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.

[0108] In some embodiments, the present disclosure provides a compound of Formula I- H: Page 40 of 196 12746579v1Attorney Docket No.: 2013518-0088or a pharmaceutically acceptable salt thereof, wherein R1, R2, and L2are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.

[0109] In some embodiments, the present disclosure provides a compound of Formula I-J:or a pharmaceutically acceptable salt thereof, wherein R1, R2, Q, and L are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.

[0110] In some embodiments, the present disclosure provides a compound of Formula I- K:Page 41 of 196 12746579v1Attorney Docket No.: 2013518-0088 or a pharmaceutically acceptable salt thereof, wherein R1, R2, Z, and L are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.

[0111] In some embodiments, the present disclosure provides a compound of Formula I- L:R2, Q, Z, and L are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.

[0112] In some embodiments, the present disclosure provides a compound of Formula II: or a pharmaceuticallyor -CD3, and R2a, Q, Z, and L are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.

[0113] In some embodiments, the present disclosure provides a compound of Formula II- A: Page 42 of 196 12746579v1Attorney Docket No.: 2013518-0088 or a pharmaceutically or -CD3, and R2aand L are asdefined above for Formula I and described in classes and subclasses herein, both singly and in combination.

[0114] In some embodiments, the present disclosure provides a compound of Formula II- B:or a pharmaceutically acceptable salt thereof, wherein R1is -CH3 or -CD3, and R2a, Q, Z, and L2are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.

[0115] In some embodiments, the present disclosure provides a compound of Formula II- C: Page 43 of 196 12746579v1Attorney Docket No.: 2013518-0088 or a pharmaceutically or -CD3, and R2aand L2are asdefined above for Formula I and described in classes and subclasses herein, both singly and in combination.

[0116] In some embodiments, the present disclosure provides a compound of Formula II- D:or a pharmaceutically acceptable salt thereof, wherein R1is -CH3or -CD3,and R2a, Q, Z, and L2are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.

[0117] In some embodiments, the present disclosure provides a compound of Formula II- E: Page 44 of 196 12746579v1Attorney Docket No.: 2013518-0088 or a pharmaceutically or -CD3,and R2a 2and L are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.

[0118] In some embodiments, the present disclosure provides a compound of Formula II- F:or a pharmaceutically acceptable salt thereof, wherein R1is -CH3 or -CD3, and R2aand L are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.

[0119] In some embodiments, the present disclosure provides a compound of Formula II- G: Page 45 of 196 12746579v1Attorney Docket No.: 2013518-0088 or a pharmaceutically or -CD3, and R2a, Q, Z, and L2are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.

[0120] In some embodiments, the present disclosure provides a compound of Formula II- H:or a pharmaceutically acceptable salt thereof, wherein R1is -CH3or -CD3,and R2aand L2are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.

[0121] In some embodiments, the present disclosure provides a compound of Formula II- J: Page 46 of 196 12746579v1Attorney Docket No.: 2013518-0088 Or a pharmaceutically or -CD3, and R2a, Q, and L areas defined above for Formula I and described in classes and subclasses herein, both singly and in combination.

[0122] In some embodiments, the present disclosure provides a compound of Formula II- K:Or a pharmaceutically acceptable salt thereof, wherein R1is -CH3or -CD3,and R2a, Z, and L are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.

[0123] In some embodiments, the present disclosure provides a compound of Formula III- A:Page 47 of 196 12746579v1Attorney Docket No.: 2013518-0088 or a pharmaceutically acceptable salt thereof, wherein R1, Q, Z, and L are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.

[0124] In some embodiments, the present disclosure provides a compound of Formula III- B:or a pharmaceutically acceptable salt thereof, wherein R1is -CH3or -CD3,and L is as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.

[0125] In some embodiments, the present disclosure provides a compound of Formula III- C:or a pharmaceutically acceptable salt thereof, wherein R1is -CH3or -CD3,and Q, Z, and L2are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.

[0126] In some embodiments, the present disclosure provides a compound of Formula III- D: Page 48 of 196 12746579v1Attorney Docket No.: 2013518-0088or a pharmaceutically acceptable salt thereof, wherein R1is -CH3or -CD3,and L2is as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.

[0127] In some embodiments, the present disclosure provides a compound of Formula IV- A:or a pharmaceutically acceptable salt thereof, wherein R1, Q, Z, and L are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.

[0128] In some embodiments, the present disclosure provides a compound of Formula IV- B: Page 49 of 196 12746579v1Attorney Docket No.: 2013518-0088or a pharmaceutically acceptable salt thereof, wherein and L are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.

[0129] In some embodiments, the present disclosure provides a compound of Formula IV- C:or a pharmaceutically acceptable salt thereof, wherein R1, Q, Z, and L2are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.

[0130] In some embodiments, the present disclosure provides a compound of Formula IV- D: Page 50 of 196 12746579v1Attorney Docket No.: 2013518-0088or a pharmaceutically acceptable salt thereof, wherein R1and L2are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.

[0131] In some embodiments, the present disclosure provides a compound of Formula V- A:or a pharmaceutically acceptable salt thereof, wherein R1, Q, Z, and L are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.

[0132] In some embodiments, the present disclosure provides a compound of Formula V- B:Page 51 of 196 12746579v1Attorney Docket No.: 2013518-0088 V-B or a pharmaceutically acceptable salt thereof, wherein R1and L are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.

[0133] In some embodiments, the present disclosure provides a compound of Formula V- C: or a pharmaceutically Z, and L2are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.

[0134] In some embodiments, the present disclosure provides a compound of Formula V- D: or a pharmaceuticallyL2are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.

[0135] As described herein, with respect to any formula provided herein, R1is hydrogen or optionally substituted C1-C6aliphatic. In some embodiments, R1is hydrogen. In some embodiments, R1is optionally substituted C1-C6aliphatic. In some embodiments, R1is optionally Page 52 of 196 12746579v1Attorney Docket No.: 2013518-0088 substituted C1-C3aliphatic. In some embodiments, R1is C1-C6aliphatic. In some embodiments, R1is methyl or deuterated methyl (e.g., one or more H atoms of methyl have been replaced with deuterium). In some embodiments, R1is -CH3 or -CD3. In some embodiments, R1is -CH3. In some embodiments, R1is -CD3.

[0136] As described with respect to any formula provided herein, R2is selected from C1- C6 aliphatic, C1-C6 heteroaliphatic, C3-C12 cycloaliphatic, 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, C6-C10 aryl, and wherein R2is optionally substituted with one or more instance of R2a.

[0137] In some embodiments, R2is C1-C6aliphatic optionally substituted with one or more instances of R2a. In some embodiments, R2is methyl, ethyl, propyl, butyl, pentyl, or hexyl, wherein R2is optionally substituted with one or more instances of R2a. In some embodiments, R2is C1-C6 aliphatic optionally substituted with one to three instances of R2a. In some embodiments, R2is C1-C6aliphatic optionally substituted with two instances of R2a, wherein one R2ais -ORaand one R2ais -La-Rb, wherein Lais a bond and Rbis optionally substituted C3-C12 cycloaliphatic. In some embodiments, R2is C1-C6 aliphatic optionally substituted with one instance of R2awherein R2ais -ORa. In some embodiments, R2is C1-C6aliphatic optionally substituted with two instances of R2a, wherein one R2ais La-Rb, wherein Lais a bond, and Rbis C3 cycloaliphatic, and one R2ais -OH. In some embodiments, R2is methyl substituted with two instances of R2a, wherein one R2ais -OH, and one R2ais cyclopropyl.

[0138] In some embodiments, R2is C1-C6heteroaliphatic optionally substituted with one or more instances of R2a.

[0139] In some embodiments, R2is 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S optionally substituted with one or more instances of R2a. In some embodiments, R2is 4- to 6-membered monocyclic heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R2is 4- to 6-membered monocyclic heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S optionally substituted with one or more instances of R2a. In some embodiments, R2is 4- to 6-membered monocyclic heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S substituted with one or more instances of R2a, wherein R2ais -CH3or -CD3. In some embodiments, R2is piperidine or pyran Page 53 of 196 12746579v1Attorney Docket No.: 2013518-0088 optionally substituted with one or more instances of R2a. In some embodiments, R2is piperidine or pyran. In some embodiments, R2is 6-membered heterocycle comprising an oxygen atom. In some embodiments, R2is .

[0140] In2R is 6- to 10-membered bicyclic heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, R2is 6- to 10-membered bicyclic heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S optionally substituted with one or more instances of R2a. In some embodiments, R2is 8- to 10-membered bicyclic heterocycle comprising 1 to 4 heteroatoms selected from N and O, optionally substituted with one or more instances of R2a.

[0141] In some embodiments, R2is 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, and is optionally substituted with one or more instances of R2a. In some embodiments, R2is monocyclic 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, and is optionally substituted with one or more instances of R2a. In some embodiments, R2is 5- to 6-membered monocyclic heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, and is substituted with one instance of R2a. In some embodiments, R2is 5- to 6-membered monocyclic heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, and is substituted with two instances of R2a. In some embodiments, R2is 5- to 6-membered monocyclic heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, and wherein R2is optionally substituted with R2awherein R2ais selected from optionally substituted C1-C6aliphatic and -ORa. In some embodiments, R2is 5- to 6-membered monocyclic heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, and wherein R2is substituted with one or more instances of R2awherein R2ais selected from optionally substituted C1-C6 aliphatic and -ORa. In some embodiments, R2is 5- to 6-membered monocyclic heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, and wherein R2is optionally substituted with R2awherein R2ais selected from -CH3 or -CD3. In some embodiments, R2is 5- to 6-membered monocyclic heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, and wherein R2is optionally substituted with R2awherein R2ais selected from -CD3, and halogen. In some embodiments, R2is 5- to 6-membered monocyclic heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, and wherein R2is optionally substituted with R2awherein R2ais selected from -CD3, and -F. In some embodiments, R2is pyrrole, pyrazole, imidazole, triazole, thiazole, Page 54 of 196 12746579v1Attorney Docket No.: 2013518-0088 optionally substituted with R2a. In some embodiments, R2is pyrazole optionally substituted with R2a. In some embodiments, R2is pyrazole optionally substituted with R2a, and wherein R2ais - CH3 or -CD3. In some embodiments, R2is pyrazole substituted with two instances of R2a, and wherein R2ais -CD3and halogen. In some embodiments, R2is pyrazole substituted with two instances of R2a, and wherein R2ais -CD3 and -F. In some embodiments, R2is pyrazole or thiazole, optionally substituted with R2a. ,substituted with one or more instances of In some embodiments, is bicyclic 7- to 10- membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R2is bicyclic 7- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, and is optionally substituted with R2a. In some embodiments, R2is bicyclic 7- to 10-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S optionally substituted with one or more instances of R2a. In some embodiments, R2is 8- to 10- membered bicyclic heteroaryl having 1 to 4 heteroatoms selected from N and O, and is optionally substituted with one or more instances of R2a. In some embodiments, R2is 8- to 10- membered bicyclic heteroaryl having 1 to 3 heteroatoms selected from N and O. In some embodiments, R2is 8- to 10- membered bicyclic heteroaryl having 1 to 3 heteroatoms selected from N and O. In some .

[0143] C10aryl, and wherein R2is optionally substituted with one or more instances of R2a. In some embodiments, R2is C6-C10aryl. In some embodiments, R2is phenyl optionally substituted with one or more instances of R2a. In some embodiments, R2is phenyl. In some embodiments, R2is naphthyl. In some embodiments, R2is phenyl, and wherein R2is optionally substituted with one or more instances of R2aselected from -La-Rband -ORa. In some embodiments, R2is C6-C10 aryl optionally substituted with one or more instances of R2a, and Page 55 of 196 12746579v1Attorney Docket No.: 2013518-0088 wherein R2ais -La-Rb, wherein Lais C1-C6aliphatic and Rbis 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, and optionally substituted with (CH2)0– 4S(O)2R°, wherein R° is C1–6 aliphatic.

[0144] In some embodiments, R2is C3-C12 cycloaliphatic optionally substituted with one or more instances of R2a. In some embodiments, R2is C3-C6cycloaliphatic. In some embodiments, R2is monocyclic 3- to 7-membered cycloaliphatic optionally substituted with one or more instances of R2a. In some embodiments, R2is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. In some embodiments, R2is cyclopropyl.

[0145] In some embodiments, R2is substituted with 0 to 4 instances of R2a. In some embodiments, R2is substituted with 0 to 3 instances of R2a. In some embodiments, R2is substituted with 1 to 3 instances of R2a. In some embodiments, R2is substituted with 1 to 2 instances of R2a. In some embodiments, R2is substituted with 1 instance of R2a. In some embodiments, R2is substituted with 2 instances of R2a. In some embodiments, R2is substituted with 3 instances of R2a. In some embodiments, R2is substituted with 4 instances of R2a.

[0146] In some embodiments, R2is selected ,, wherein each Y is independently CH, CH2, O, N, NH, and S, as valency permits., ,Page 56 of 196 12746579v1Attorney Docket No.: 2013518-0088

[0148] In some embodiments, R2is selected , and.

[0149] In some embodiments, R2is selected .As described with respect to any formula provided herein, R2ais selected from optionally substituted C1-C6aliphatic, optionally substituted C1-C6heteroaliphatic, halogen, oxo, -CN, -NO2, -C(O)N(Ra)2, -OC(O)Ra, -OC(O)N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)C(O)ORa, - N(Ra)C(O)N(Ra)2, -S(O)2N(Ra)2, -N(Ra)S(O)2Ra, -S(O)2Ra, -ORa, and -La-Rb.

[0151] In some embodiments, R2ais selected from oxo, -CN, -NO2, -C(O)N(Ra)2, - OC(O)Ra, -OC(O)N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)C(O)ORa, -N(Ra)C(O)N(Ra)2, -S(O)2N(Ra)2, - N(Ra)S(O)2Ra, -S(O)2Ra, and -ORa. In some embodiments, R2ais selected from oxo, -C(O)N(Ra)2, -OC(O)Ra, -S(O)2Ra, and -ORa. In some embodiments, R2ais selected from optionally substituted C1-C6 aliphatic and halogen. In some embodiments, R2ais selected from -CD3 and -F.

[0152] In some embodiments, R2ais optionally substituted C1-C6 aliphatic. In some embodiments, R2ais methyl or deuterated methyl (e.g., one or more H atoms of methyl have been replaced with deuterium). In some embodiments, R2ais a branched C1-C6 aliphatic. In some embodiments, R2ais C1-C6 aliphatic optionally substituted with –(CH2)0–4OR°, wherein R° is hydrogen or C1-C6 aliphatic.

[0153] In some embodiments, R2ais optionally substituted C1-C3aliphatic. In some embodiments, R2ais optionally substituted C3-C12cycloaliphatic. In some embodiments, R2ais optionally substituted C3-C6 cycloaliphatic.

[0154] In some embodiments, R2ais optionally substituted C1-C6 heteroaliphatic. In some embodiments, R2ais methoxy. In some embodiments, R2ais ethoxy. Page 57 of 196 12746579v1Attorney Docket No.: 2013518-0088

[0155] In some embodiments, R2ais halogen. In some embodiments, R2ais fluoro. In some embodiments, R2ais chloro.

[0156] In some embodiments, R2ais oxo. In some embodiments, R2ais -CN. In some embodiments, R2ais -NO2. In some embodiments, R2ais -C(O)N(Ra)2. In some embodiments, R2ais -C(O)NH2. In some embodiments, R2ais -C(O)N(CH3)2. In some embodiments, R2ais - OC(O)Ra. In some embodiments, R2ais -OC(O)CH3. In some embodiments, R2ais -OC(O)N(Ra)2. In some embodiments, R2ais -OC(O)NH2. In some embodiments, R2ais -OC(O)N(CH3)2. In some embodiments, R2ais -N(Ra)C(O)Ra. In some embodiments, R2ais -NHC(O)CH3. In some embodiments, R2ais -N(CH3)C(O)CH3. In some embodiments, R2ais -N(Ra)C(O)ORa. In some embodiments, R2ais -NHC(O)OH. In some embodiments, R2ais -NHC(O)OCH3. In some embodiments, R2ais -N(Ra)C(O)N(Ra)2. In some embodiments, R2ais -NHC(O)NH2. In some embodiments, R2ais -NHC(O)N(CH3)2. In some embodiments, R2ais -S(O)2N(Ra)2. In some embodiments, R2ais -S(O)2NH2. In some embodiments, R2ais -S(O)2N(CH3)2. In some embodiments, R2ais -N(Ra)S(O)2Ra. In some embodiments, R2ais -NHS(O)2CH3. In some embodiments, R2ais-S(O)2Ra. In some embodiments, R2ais -ORa. In some embodiments, R2ais - OH. In some embodiments, R2ais -CH3. In some embodiments, R2ais -CD3.

[0157] In some embodiments, R2ais -La-Rb.

[0158] As described with respect to any formula provided herein, Lais selected from a bond and optionally substituted C1-C6 aliphatic. In some embodiments, Lais a bond. In some embodiments, Lais optionally substituted C1-C6aliphatic. In some embodiments, Lais C1-C3aliphatic. In some embodiments, Lais methylene or ethylene. In some embodiments, Lais methylene.

[0159] As described with respect to any formula provided herein, Rbis selected from optionally substituted C3-C12cycloaliphatic, optionally substituted 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, optionally substituted 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, and optionally substituted C6- C10aryl.

[0160] In some embodiments, Rbis optionally substituted C3-C12 cycloaliphatic. In some embodiments, Rbis optionally substituted C3-C6 cycloaliphatic. In some embodiments, Rbis cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. Page 58 of 196 12746579v1Attorney Docket No.: 2013518-0088

[0161] In some embodiments, Rbis optionally substituted 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, Rbis optionally substituted monocyclic 5- to 6-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, Rbis optionally substituted pyran. In some embodiments, Rbis optionally substituted piperidine. In some embodiments, Rbis optionally substituted morpholine. In some embodiments, Rbis monocyclic 5- to 6-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S, and optionally substituted with (CH2)0–4S(O)2R°, wherein R° is C1–6aliphatic.

[0162] In some embodiments, Rbis optionally substituted 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, Rbis optionally substituted 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, Rbis optionally substituted pyrazole, pyrrole, imidazole, triazole, oxazole, isoxazole, oxadiazole, isothiazole, thiazole, or thiadiazole. In some embodiments, Rbis optionally substituted pyridine, pyridazine, pyrazine, or pyrimidine.

[0163] In some embodiments, Rbis optionally substituted C6-C10 aryl. In some embodiments, Rbis optionally substituted phenyl. In some embodiments, Rbis optionally substituted naphthyl.

[0164] In some .In some embodiments, R2ais . In some embodiments, R2a. In someembodiments, R2ais . In some embodiments, R2a.

[0165] As to any formula provided Rais independently selected from hydrogen, optionally substituted C1-C6aliphatic, optionally substituted C1-C6heteroaliphatic, optionally substituted 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, and optionally substituted 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, each Rais Page 59 of 196 12746579v1Attorney Docket No.: 2013518-0088 independently selected from optionally substituted 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, optionally substituted 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, optionally substituted C6-C12 aryl, optionally substituted C3-C12cycloaliphatic, or optionally substituted C1-C6aliphatic.

[0166] In some embodiments, Rais hydrogen. In some embodiments, Rais optionally substituted C1-C6 aliphatic. In some embodiments, Rais -CH3. In some embodiments, Rais -CD3. In some embodiments, Rais optionally substituted 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, Rais a 4- to 6-membered heterocycle comprising at least 1 oxygen. In some embodiments, Rais tetrahydrofuran. In some embodiments, Rais pyran. In some embodiments, Rais optionally substituted 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S.

[0167] As described with respect to any formula provided herein, Q is selected from optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 heteroaliphatic, optionally substituted C3-C12cycloaliphatic, optionally substituted 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, optionally substituted 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, and optionally substituted C6- C10aryl. In some embodiments, Q is optionally substituted C3-C6cycloaliphatic, optionally substituted C6-C12 aryl, or optionally substituted 4- to 6-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S.

[0168] In some embodiments, Q is optionally substituted C1-C6aliphatic. In some embodiments, Q is optionally substituted C1-C3aliphatic. In some embodiments, Q is - C(H)(CH3)-. In some embodiments, Q is optionally substituted C2-C6 alkynylene. In some embodiments, Q is C2-C4 alkynylene. In some embodiments, Q is a C2 alkynyl group. In some embodiments, Q is optionally substituted C1-C6heteroaliphatic.

[0169] In some embodiments, Q is optionally substituted C3-C12 cycloaliphatic. In some embodiments, Q is optionally substituted C3-C7 cycloaliphatic. In some embodiments, Q is optionally substituted C3-C6cycloaliphatic. In some embodiments, Q is optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. In some embodiments, Q is optionally substituted cyclopentyl or cyclobutyl. In some embodiments, Q is unsubstituted cyclopentyl or cyclobutyl. Page 60 of 196 12746579v1Attorney Docket No.: 2013518-0088 or

[0171] In some embodiments, Q is selected * representsa point of attachment to L1.

[0172] In some embodiments, Q is optionally substituted 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, Q is optionally substituted 4- to 8-membered monocyclic heterocycle comprising 1 to 2 heteroatoms selected from N, O, and S. In some embodiments, Q is optionally substituted pyran, piperidine, or morpholine. In some embodiments, Q is optionally substituted pyran. In some embodiments, Q is optionally substituted piperidine. In some embodiments, Q is optionally substituted morpholine.

[0173] In some embodiments, Q is optionally substituted 6- to 8-membered bridged or bicyclic heterocycle comprising 1 to 2 heteroatoms selected from N, O, and S. In some embodiments, Q is optionally substituted 6- to 8-membered monocyclic heterocycle comprising 1 to 2 heteroatoms selected from N and O. In some orrepresents a point of attachment to L1.embodiments, Q is optionally substituted 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, Q is optionally substituted 5- to 6-membered monocyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, Q is optionally substituted and selected from pyrazole, pyrrole, Page 61 of 196 12746579v1Attorney Docket No.: 2013518-0088 imidazole, triazole, oxazole, isoxazole, oxadiazole, isothiazole, thiazole, and thiadiazole. In some embodiments, Q is optionally substituted pyrazole or thiazole. In some embodiments, ,or , wherein * represents a point of attachment to L1.In some embodiments, Q is optionally substituted bicyclic 8- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, Q is optionally substituted bicyclic 8- to 10-membered heteroaryl comprising 1 to 2 heteroatoms selected from N and S. In some or, where * represents a point of attachment to L1.In some embodiments, Q is optionally substituted C6-C10 aryl. In some embodiments, Q is optionally substituted phenyl. In some embodiments, Q is optionally substituted naphthyl. , orrepresents a point of attachment to L1.Page 62 of 196 12746579v1Attorney Docket No.: 2013518-0088

[0178] As described with respect to any formula provided herein, Z is selected from optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 heteroaliphatic, optionally substituted C3-C12 cycloaliphatic, optionally substituted 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, optionally substituted 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, and optionally substituted C6- C10 aryl. In some embodiments, Z is optionally substituted C1-C6 aliphatic, optionally substituted C1-C6heteroaliphatic, optionally substituted C3-C12cycloaliphatic, and optionally substituted C6- C10 aryl.

[0179] In some embodiments, Z is optionally substituted C1-C6 aliphatic. In some embodiments, Z is optionally substituted C1-C3aliphatic. In some embodiments, Z is -C(H)(CH3)-. In some embodiments, Z is optionally substituted C2-C6alkynylene. In some embodiments, Z is C2-C4 alkynylene. In some embodiments, Z is a C2 alkynyl group. In some embodiments, Z is optionally substituted C1-C6 heteroaliphatic.

[0180] In some embodiments, Z is optionally substituted C3-C12cycloaliphatic. In some embodiments, Z is optionally substituted C3-C7 cycloaliphatic. In some embodiments, Z is optionally substituted C3-C6 cycloaliphatic. In some embodiments, Z is optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.

[0181] In some embodiments, Z is orrepresents a point of attachment to L3.embodiments, Z is optionally substituted 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, Z is optionally substituted 4- to 8-membered monocyclic heterocycle comprising 1 to 2 heteroatoms selected from N, O, and S. In some embodiments, Z is optionally substituted pyran, piperidine, or morpholine. In some embodiments, Z is optionally substituted pyran. In some embodiments, Z is optionally substituted piperidine. In some embodiments, Z is optionally substituted morpholine. Page 63 of 196 12746579v1Attorney Docket No.: 2013518-0088

[0183] In some embodiments, Z is optionally substituted 6- to 8-membered bridged or bicyclic heterocycle comprising 1 to 2 heteroatoms selected from N, O, and S. In some embodiments, Z is optionally substituted 6- to 8-membered monocyclic heterocycle comprising 1 to 2 heteroatoms selected from N and O. In some or5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, Z is optionally substituted 5- to 6-membered monocyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, Z is optionally substituted and selected from pyrazole, pyrrole, imidazole, triazole, oxazole, isoxazole, oxadiazole, isothiazole, thiazole, and thiadiazole. In some embodiments, Z is optionally substituted pyrazole or thiazole. In some embodiments, Z is unsubstituted pyrazolyl or thiazolyl. In some , wherein **represents a point of attachment to L3. In some** represents a point of attachment to L3.

[0185] In some embodiments, Z is optionally substituted bicyclic 8- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, Z is optionally substituted bicyclic 8- to 10-membered heteroaryl comprising 1 to 2 heteroatoms selected from N and S. In some embodiments, Z is optionally substituted indazolyl. In some Page 64 of 196 12746579v1Attorney Docket No.: 2013518-0088 embodiments, Z is unsubstituted indazolyl. In some ,represents a point of attachment to L3.

[0186] ** representsa point of attachment to L3. In some ** represents a point of attachment to L3.Page 65 of 196 12746579v1Attorney Docket No.: 2013518-0088

[0187] In some embodiments, Z is optionally substituted C6-C10aryl. In some embodiments, Z is optionally substituted phenyl. In some embodiments, Z is optionally substituted naphthyl. In some embodiments, Z is unsubstituted phenyl. In some ., **

[0189] In some embodiments, Z is phenyl, alkynyl, pyrazolyl, thiazolyl, or indazolyl,

[0190] In some embodiments, Z is selected ,** represents a point of attachment to L3. embodiments, Z is selected ,represents a point of attachment to L3.Page 66 of 196 12746579v1Attorney Docket No.: 2013518-0088

[0192] As described with respect to any formula provided herein, L is *-L1-L2-L3-**, where * represents a point of attachment to Q and ** represents a point of attachment to Z.

[0193] As described with respect to any formula provided herein, L1is a bond, a 4- to 6- membered heterocycle having 1 to 2 heteroatoms independently selected from N, O, and S, - C(O)N(Ra)-, -OC(O)-, -OC(O)N(Ra)-, -N(Ra)C(O)-, -N(Ra)C(O)O-, -N(Ra)C(O)N(Ra)-, - S(O)2N(Ra)-, -N(Ra)S(O)2-, -S(O)2-, -C(Ra)2O-, -N(Ra)-, -S-, or -O-. In some embodiments, L1is -N(Ra)C(O)-, -N(Ra)C(O)O-, -N(Ra)C(O)N(Ra)-, or -O-. In some embodiments, L1is -OC(O)-, - OC(O)N(Ra)-, -C(Ra)2O-, -N(Ra)-, -S-, or -O-. In some embodiments, L1is -N(Ra)C(O)O- or - N(Ra)C(O)N(Ra)-. In some embodiments, L1is -C(Ra)2O- or -O-.

[0194] In some embodiments, L1is a bond.

[0195] In some embodiments, L1is a 4- to 6-membered heterocycle having 1 to 2 heteroatoms independently selected from N, O, and S. In some embodiments, L1is azetidine. In some embodiments, L1is -C(O)N(Ra)-. In some embodiments, L1is -C(O)NH-. In some embodiments, L1is -OC(O)-. In some embodiments, L1is -OC(O)N(Ra)-. In some embodiments, L1is -OC(O)NH-. In some embodiments, L1is -N(Ra)C(O)-. In some embodiments, L1is - NHC(O)-. In some embodiments, L1is -N(Ra)C(O)O-. In some embodiments, L1is -NHC(O)O-. In some embodiments, L1is -N(Ra)C(O)N(Ra)-. In some embodiments, L1is -NHC(O)NH-. In some embodiments, L1is -S(O)2N(Ra)-. In some embodiments, L1is -S(O)2NH-. In some embodiments, L1is -N(Ra)S(O)2-. In some embodiments, L1is -NHS(O)2-. In some embodiments, L1is -S(O)2-. In some embodiments, L1is -C(Ra)2O-. In some embodiments, L1is -CH2O-. In some embodiments, L1is -N(Ra)-. In some embodiments, L1is -NH-. In some embodiments, L1is -S-. In some embodiments, L1is -O-. In some embodiments, L1is -N(CH3)-. In some embodiments, L1is -OC(O)N(Ra)- or -N(Ra)C(O)O-. In some embodiments, L1is -OC(O)NH- or -NHC(O)O-.

[0196] As described with respect to any formula provided herein, L3is a bond, a 4- to 6- membered heterocycle having 1 to 2 heteroatoms independently selected from N, O, and S, - C(O)N(Ra)-, -OC(O)-, -OC(O)N(Ra)-, -N(Ra)C(O)-, -N(Ra)C(O)O-, -N(Ra)C(O)N(Ra)-, - S(O)2N(Ra)-, -N(Ra)S(O)2-, -S(O)2-, -C(Ra)2O-, -N(Ra)-, -S-, or -O-. In some embodiments, L3is -N(Ra)C(O)-, -N(Ra)C(O)O-, -N(Ra)C(O)N(Ra)-, or -O-. In some embodiments, L3is -OC(O)-, - OC(O)N(Ra)-, -C(Ra)2O-, -N(Ra)-, -S-, or -O-. In some embodiments, L3is -N(Ra)C(O)O- or - Page 67 of 196 12746579v1Attorney Docket No.: 2013518-0088 N(Ra)C(O)N(Ra)-. In some embodiments, L3is -C(Ra)2O- or -O-. In some embodiments, L3is a bond, a 4- to 6-membered heterocycle having 1 to 2 heteroatoms independently selected from N, O, and S, -C(Ra)2O-, -N(Ra)-, or -O-. In some embodiments, L3is a bond, azetidinyl, -CH2O-, - N(CH3)-, or -O-.

[0197] In some embodiments, L3is a bond. In some embodiments, L3is a 4- to 6- membered heterocycle having 1 to 2 heteroatoms independently selected from N, O, and S. In some embodiments, L3is azetidinyl. In some embodiments, L3is -C(O)N(Ra)-. In some embodiments, L3is -C(O)NH-. In some embodiments, L3is -OC(O)-. In some embodiments, L3is -OC(O)N(Ra)-. In some embodiments, L3is -OC(O)NH-. In some embodiments, L3is - N(Ra)C(O)-. In some embodiments, L3is -NHC(O)-. In some embodiments, L3is -N(Ra)C(O)O-. In some embodiments, L3is -NHC(O)O-. In some embodiments, L3is -N(Ra)C(O)N(Ra)-. In some embodiments, L3is -NHC(O)NH-. In some embodiments, L3is -S(O)2N(Ra)-. In some embodiments, L3is -S(O)2NH-. In some embodiments, L3is -N(Ra)S(O)2-. In some embodiments, L3is -NHS(O)2-. In some embodiments, L3is -S(O)2-. In some embodiments, L3is -C(Ra)2O-. In some embodiments, L3is -CH2O-. In some embodiments, L3is -N(Ra)-. In some embodiments, L3is -NH-. In some embodiments, L3is -N(CH3)-. In some embodiments, L3is -S-. In some embodiments, L3is -O-. In some embodiments, L3is -N(CH3)-.

[0198] In some embodiments, L1is -N(Ra)C(O)O- or -N(Ra)C(O)N(Ra)-, and L3is - C(Ra)2O- or -O-. In some embodiments, L1is -N(Ra)C(O)O- and L3is -O-. In some embodiments, L1is -NHC(O)O- and L3is -O-. In some embodiments, L1is -NHC(O)O- and L3is -CH2O-. In some embodiments, L1is -NHC(O)O- and L3is a bond.

[0199] As described with respect to any formula provided herein, L2is optionally substituted C1-C6 aliphatic, optionally substituted 2- to 6-membered heteroaliphatic, optionally substituted 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, or optionally substituted C3-C10 cycloaliphatic. In some embodiments, L2is optionally substituted C1-C6 aliphatic or optionally substituted 2- to 6-membered heteroaliphatic. In some embodiments, L2is optionally substituted C1-C6aliphatic. In some embodiments, L2is optionally substituted C1-C4 aliphatic. In some embodiments, L2is unsubstituted C1-C4 aliphatic. In some embodiments, L2is an optionally substituted methyl, ethyl, propyl, butyl, or pentyl group. In some embodiments, L2is optionally substituted ethylene, propylene, butylene, or pentylene. In some Page 68 of 196 12746579v1Attorney Docket No.: 2013518-0088 embodiments, L2is optionally substituted C1-C6aliphatic, optionally substituted 2- to 6-membered heteroaliphatic, or optionally substituted 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, L2is unsubstituted C1-C6 aliphatic, unsubstituted 2- to 6-membered heteroaliphatic, or unsubstituted 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S.

[0200] In some embodiments, L2is optionally substituted 2- to 6-membered heteroaliphatic. In some embodiments, L2is optionally substituted 2- to 6-membered heteroaliphatic selected from -CH2-O-CH2-, -CH2-CH2-O-CH2-, -CH2-CH2-O-CH2-CH2-, or - CH2-CH2-CH2-O-CH2-CH2-CH2-. In some embodiments, L2is optionally substituted -CH2-CH2- O-CH2-CH2-. In some embodiments, L2is optionally substituted 5-membered heteroaliphatic. In some embodiments, L2is unsubstituted 5-membered heteroaliphatic. In some embodiments, L2is -CH2-CH2-O-CH2-CH2-.

[0201] In some embodiments, L2is an optionally substituted 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, L2is an optionally substituted 4- to 6-membered heterocycle comprising 1 to 2 heteroatoms selected from N, O, and S. In some embodiments, L2is an optionally substituted tetrahydrofuran. In some embodiments, L2is an optionally substituted pyran. In some embodiments, L2is an optionally substituted oxetane. In some embodiments, L2is an optionally substituted 4- to 10- membered heterocycle comprising 1 to 2 heteroatoms selected from N, O, and S, and is attached in a spirocyclic manner. In some embodiments, L2is an optionally substituted 4- to 7-membered heterocycle comprising 1 to 2 heteroatoms selected from N, O, and S, and is attached in a spirocyclic manner. In some In some embodiments, L2is . In some embodiments, L2is . In some embodiments, L2is an optionally substituted 4- to 6-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, L2is tetrahydrofuran. In some .Page 69 of 196 12746579v1Attorney Docket No.: 2013518-0088

[0202] In some embodiments, L2is an optionally substituted C3to C10cycloaliphatic. In some embodiments, L2is an optionally substituted monocyclic C3 to C7 cycloaliphatic. In some embodiments, L2is optionally substituted and selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In some embodiments, L2is an optionally substituted C3to C10cycloaliphatic that is attached in a spirocyclic manner. In some embodiments, L2is an optionally substituted monocyclic C3 to C7 cycloaliphatic that is attached in a spirocyclic manner. , or, ,

[0205] In some embodiments, a compound represented by formula I, wherein: R1is optionally substituted C1-C6aliphatic; R2is selected from C3-C12 cycloaliphatic, 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, or C6-C10aryl, wherein R2is optionally substituted with one or more instances of R2a; each R2ais independently selected from the group consisting of optionally substituted C1-C6aliphatic, halogen, -S(O)2Ra, -ORa, and -La-Rb; Page 70 of 196 12746579v1Attorney Docket No.: 2013518-0088 each Lais independently selected from a bond and optionally substituted C1-C6aliphatic; each Rbis independently selected from optionally substituted C3-C12 cycloaliphatic, optionally substituted 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, optionally substituted 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, and optionally substituted C6-C10 aryl; each Rais independently selected from hydrogen, optionally substituted C1-C6aliphatic, optionally substituted C1-C6 heteroaliphatic, optionally substituted 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, and optionally substituted 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S; Q is selected from optionally substituted C1-C6aliphatic, optionally substituted C1-C6heteroaliphatic, optionally substituted C3-C12 cycloaliphatic, and optionally substituted C6-C10 aryl; Z is selected from optionally substituted C1-C6aliphatic, optionally substituted C1-C6heteroaliphatic, optionally substituted C3-C12 cycloaliphatic, and optionally substituted C6-C10 aryl; L is *-L1-L2-L3-**, where * represents a point of attachment to Q and ** represents a point of attachment to Z; L1is a bond, -C(O)N(Ra)-, -OC(O)N(Ra)-, -N(Ra)C(O)-, -C(Ra)2O-, -N(Ra)C(O)O-, - N(Ra)-, or -O-; L3is a bond, -C(O)N(Ra)-, -OC(O)N(Ra)-, -N(Ra)C(O)-, -C(Ra)2O-, -N(Ra)C(O)O-, - N(Ra)-, or -O-; and L2is optionally substituted C1-C6 aliphatic, or optionally substituted 2- to 6-membered heteroaliphatic.

[0206] In some embodiments, R2is 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, or C6-C10 aryl, wherein R2is optionally substituted with one or more instances of R2a; and each R2ais independently selected from the group consisting of optionally substituted C1-C6 aliphatic, -ORa, and -La-Rb. In some embodiments, R1is -CD3 and R2is 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S optionally substituted with one or more instances of R2a. Page 71 of 196 12746579v1Attorney Docket No.: 2013518-0088

[0207] In some embodiments, Q is selected from optionally substituted C1-C6aliphatic, optionally substituted C3-C12 cycloaliphatic, and optionally substituted C6-C10 aryl, and Z is selected from optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 heteroaliphatic, optionally substituted C3-C12cycloaliphatic, and optionally substituted C6-C10aryl. In some embodiments, Q is optionally substituted C3-C12 cycloaliphatic and Z is optionally substituted C6- C10 aryl.

[0208] In some embodiments, L1is N(Ra)C(O)O-, -N(Ra)-, or -O-; L2is optionally substituted C1-C6 aliphatic, and L3is N(Ra)C(O)O-, -N(Ra)-, or -O-. In some embodiments, L1is N(Ra)C(O)O- or -N(Ra)-; L2is optionally substituted C1-C6 aliphatic or optionally substituted 2- to 6-membered heteroaliphatic, and L3is -C(Ra)2O- or -O-.

[0209] In some embodiments, a compound is of formula I, wherein R1is optionally substituted C1-C6 aliphatic; R2is 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, wherein R2is optionally substituted with one or more instances of R2a; each R2ais independently selected from the group consisting of optionally substituted C1-C6 aliphatic, halogen, and -ORa; each Rais independently selected from hydrogen and optionally substituted C1-C6aliphatic; Q is selected from optionally substituted C3-C12 cycloaliphatic, optionally substituted 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, and optionally substituted C6-C10aryl; Z is selected from optionally substituted C1-C6 aliphatic, optionally substituted 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, and optionally substituted C6-C10aryl; L is *-L1-L2-L3-**, where * represents a point of attachment to Q and ** represents a point of attachment to Z; L1is a bond, -N(Ra)C(O)O-, -N(Ra)-, or -O-; L3is a bond, -C(Ra)2O-, -N(Ra)-, -S-, or -O-; and L2is optionally substituted C1-C6 aliphatic, or optionally substituted 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S. Page 72 of 196 12746579v1Attorney Docket No.: 2013518-0088

[0210] In some embodiments, the present disclosure provides a compound selected from Table 1, or a pharmaceutically acceptable salt thereof. Table 1 Compoun Compoun d Structure d StructurePage 73 of 196 12746579v1Attorney Docket No.: 2013518-0088Page 74 of 196 12746579v1Attorney Docket No.: 2013518-0088 3Page 75 of 196 12746579v1Attorney Docket No.: 2013518-0088 F H NNN 33Page 76 of 196 12746579v1Attorney Docket No.: 2013518-0088 3Page 77 of 196 12746579v1Attorney Docket No.: 2013518-0088Page 78 of 196 12746579v1Attorney Docket No.: 2013518-0088Page 79 of 196 12746579v1Attorney Docket No.: 2013518-0088

[0211] In some embodiments, the present disclosure encompasses the recognition that provided compounds display certain desirable characteristics, e.g., as compared to other known compounds. For example, in some embodiments, provided compounds are more potent in one or more biochemical or cellular assays (e.g., the JAK2 Binding Assay or SET2-pSTAT5 Cellular Assay described herein) and / or have one or more other characteristics that make them more suitable for drug development, such as better selectivity over other kinases (e.g., over JAK1, JAK3, and / or TYK2), better selectivity over other pseudokinases (e.g., over JAK1-JH2 and / or Tyk2- JH2), and / or better ADME (absorption, distribution, metabolism, and excretion) properties including but not limited to better permeability, cytotoxicity, hepatocyte stability, solubility, and / or plasma protein binding profiles (e.g., based on assays described in the ensuing examples), than other known compounds. Selectivity over other pseudokinases can be assessed using assays analogous to JAK2 JH2 Domain Binding Assay described in the ensuing examples, utilizing other pseudokinase constructs (e.g., over JAK1-JH2 and / or Tyk2-JH2) in place of JAK2-JH2. In some embodiments, provided compounds display certain desirable characteristics in one or more assays described herein, e.g., compared to other known compounds.

[0212] In some embodiments, provided compounds are provided and / or utilized in a salt form (e.g., a pharmaceutically acceptable salt form). Reference to a compound provided herein is understood to include reference to salts thereof, unless otherwise indicated. Pharmaceutically acceptable salt forms are known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66:1-19(1977). Page 80 of 196 12746579v1Attorney Docket No.: 2013518-0088

[0213] It will be appreciated that throughout the present disclosure, unless otherwise indicated, reference to a compound of Formula I is intended to also include I-A, I-B, I-C, II, II-A, II-B, II-C, and compound species of such formulas disclosed herein. Compositions

[0214] The present disclosure also provides compositions comprising a compound provided herein with one or more other components. In some embodiments, provided compositions comprise and / or deliver a compound described herein (e.g., compounds of Formulae I-A–I-L, II-A–II-K, III-A–III-D, IV-A–IV-D, and V-A–V-D).

[0215] In some embodiments, a provided composition is a pharmaceutical composition that comprises and / or delivers a compound provided herein (e.g., compounds of Formulae I-A–I- L, II-A–II-K, III-A–III-D, IV-A–IV-D, and V-A–V-D), and further comprises a pharmaceutically acceptable carrier. Pharmaceutical compositions typically contain an active agent (e.g., a compound described herein) in an amount effective to achieve a desired therapeutic effect while avoiding or minimizing adverse side effects. In some embodiments, provided pharmaceutical compositions comprise a compound described herein and one or more fillers, disintegrants, lubricants, glidants, anti-adherents, and / or anti-statics, etc. Provided pharmaceutical compositions can be in a variety of forms including oral dosage forms, topical creams, topical patches, iontophoresis forms, suppository, nasal spray and / or inhaler, eye drops, intraocular injection forms, depot forms, as well as injectable and infusible solutions. Methods of preparing pharmaceutical compositions are well known in the art.

[0216] In some embodiments, provided compounds are formulated in a unit dosage form for ease of administration and uniformity of dosage. The expression “unit dosage form” as used herein refers to a physically discrete unit of an active agent (e.g., a compound described herein) for administration to a subject. Typically, each such unit contains a predetermined quantity of active agent. In some embodiments, a unit dosage form contains an entire single dose of the agent. In some embodiments, more than one unit dosage form is administered to achieve a total single dose. In some embodiments, administration of multiple unit dosage forms is required, or expected to be required, in order to achieve an intended effect. A unit dosage form may be, for example, a liquid pharmaceutical composition containing a predetermined quantity of one or more active Page 81 of 196 12746579v1Attorney Docket No.: 2013518-0088 agents, a solid pharmaceutical composition (e.g., a tablet, a capsule, or the like) containing a predetermined amount of one or more active agents, a sustained release formulation containing a predetermined quantity of one or more active agents, or a drug delivery device containing a predetermined amount of one or more active agents, etc.

[0217] Provided compositions may be administered using any amount and any route of administration effective for treating or lessening the severity of any disease or disorder described herein. Uses

[0218] The present disclosure provides uses for compounds and compositions described herein. In some embodiments, provided compounds and compositions are useful in medicine (e.g., as therapy). In some embodiments, provided compounds and compositions are useful in research as, for example, analytical tools and / or control compounds in biological assays.

[0219] In some embodiments, the present disclosure provides methods of administering provided compounds or compositions to a subject in need thereof. In some embodiments, the present disclosure provides methods of administering provided compounds or compositions to a subject suffering from or susceptible to a disease, disorder, or condition associated with JAK2.

[0220] In some embodiments, provided compounds are useful as JAK2 inhibitors. In some embodiments, provided compounds are useful as JAK2 inhibitors that bind the pseudokinase (JH2) domain of JAK2. In some embodiments, the present disclosure provides methods of inhibiting JAK2 in a subject comprising administering a provided compound or composition. In some embodiments, the present disclosure provides methods of inhibiting JAK2 in a biological sample comprising contacting the sample with a provided compound or composition.

[0221] JAK (e.g., JAK2) has been implicated in various diseases, disorders, and conditions, such as myeloproliferative neoplasms (Vainchenker, W. et al., F1000Research 2018, 7(F1000 Faculty Rev):82), atopic dermatitis (Rodrigues, M. A. and Torres, T. J. Derm. Treat. 2019, 31(1), 33-40) and acute respiratory syndrome, hyperinflammation, and / or cytokine storm syndrome (The Lancet. doi:10.1016 / S0140-6736(20)30628-0). Accordingly, in some embodiments, the present disclosure provides methods of treating a disease, disorder or condition Page 82 of 196 12746579v1Attorney Docket No.: 2013518-0088 associated with JAK2 in a subject in need thereof comprising administering to the subject a provided compound or composition. In some embodiments, a disease, disorder, or condition is associated with overexpression of JAK2.

[0222] In some embodiments, the present disclosure provides methods of treating cancer, comprising administering a provided compound or composition to a subject in need thereof. In some embodiments, the present disclosure provides methods of treating proliferative diseases, comprising administering a provided compound or composition to a subject in need thereof.

[0223] In some embodiments, the present disclosure provides methods of treating a hematological malignancy, comprising administering a provided compound or composition to a subject in need thereof. In some embodiments, a hematological malignancy is leukemia (e.g., chronic lymphocytic leukemia, acute lymphoblastic leukemia, T-cell acute lymphoblastic leukemia, chronic myelogenous leukemia, acute myelogenous leukemia, or acute monocytic leukemia). In some embodiments, a hematological malignancy is lymphoma (e.g., Burkitt’s lymphoma, Hodgkin’s lymphoma, or non-Hodgkin’s lymphoma). In some embodiments, a non- Hodgkin’s lymphoma is a B-cell lymphoma. In some embodiments, a non-Hodgkin’s lymphoma is a NK / T-cell lymphoma (e.g., cutaneous T-cell lymphoma). In some embodiments, a hematological malignancy is myeloma (e.g., multiple myeloma). In some embodiments, a hematological malignancy is myeloproliferative neoplasm (e.g., polycythemia vera, essential thrombocytopenia, or myelofibrosis). In some embodiments, a hematological malignancy is myelodysplastic syndrome.

[0224] In some embodiments, the present disclosure provides methods of treating an inflammatory disease, disorder, or condition (e.g., acute respiratory syndrome, hyperinflammation, and / or cytokine storm syndrome (including those associated with COVID-19) or atopic dermatitis), comprising administering a provided compound or composition to a subject in need thereof.

[0225] In some embodiments, a provided compound or composition is administered as part of a combination therapy. As used herein, the term “combination therapy” refers to those situations in which a subject is simultaneously exposed to two or more therapeutic or prophylactic regimens (e.g., two or more therapeutic or prophylactic agents). In some embodiments, the two or more regimens may be administered simultaneously; in some embodiments, such regimens may be Page 83 of 196 12746579v1Attorney Docket No.: 2013518-0088 administered sequentially (e.g., all “doses” of a first regimen are administered prior to administration of any doses of a second regimen); in some embodiments, such agents are administered in overlapping dosing regimens. In some embodiments, “administration” of combination therapy may involve administration of one or more agent(s) or modality(ies) to a subject receiving the other agent(s) or modality(ies) in the combination. For clarity, combination therapy does not require that individual agents be administered together in a single composition (or even necessarily at the same time), although in some embodiments, two or more agents, or active moieties thereof, may be administered together in a combination composition.

[0226] For example, in some embodiments, a provided compound or composition is administered to a subject who is receiving or has received one or more additional therapies (e.g., an anti-cancer therapy and / or therapy to address one or more side effects of such anti-cancer therapy, or otherwise to provide palliative care). Exemplary additional therapies include BCL2 inhibitors (e.g., venetoclax), HDAC inhibitors (e.g., vorinostat), BET inhibitors (e.g., mivebresib), proteasome inhibitors (e.g., bortezomib), LSD1 inhibitors (e.g., IMG-7289), and CXCR2 inhibitors. Useful combinations of a JAK2 inhibitor with BCL2, HDAC, BET, and proteasome inhibitors have been demonstrated in cells derived from cutaneous T-cell lymphoma patients (Yumeen, S., et al., Blood Adv.2020, 4(10), 2213-2226). A combination of a JAK2 inhibitor with a LSD1 inhibitor demonstrated good efficacy in a mouse model of myeloproliferative neoplasms (Jutzi, J.S., et al., HemaSphere 2018, 2(3), http: / / dx.doi.org / 10.1097 / HS9.0000000000000054). CXCR2 activity has been shown to modulate signaling pathways involved in tumor growth, angiogenesis, and / or metastasis, including the JAK-STAT3 pathway (Jaffer, T., Ma, D. Transl. Cancer Res.2016, 5(Suppl.4), S616-S628). Exemplary Embodiments

[0227] The following numbered embodiments, while non-limiting, are exemplary of certain aspects of the disclosure: Embodiment 1. A compound represented by formula I: Page 84 of 196 12746579v1Attorney Docket No.: 2013518-0088or a pharmaceutically acceptable salt thereof, wherein: R1is hydrogen or optionally substituted C1-C6 aliphatic; R2is C1-C6 aliphatic, C1-C6 heteroaliphatic, C3-C12 cycloaliphatic, 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, 5- to 10- membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, or C6- C10 aryl, wherein R2is optionally substituted with one or more instances of R2a; each R2ais independently selected from the group consisting of optionally substituted C1- C6aliphatic, optionally substituted C1-C6heteroaliphatic, halogen, oxo, -CN, -NO2, - C(O)N(Ra)2, -OC(O)Ra, -OC(O)N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)C(O)ORa, - N(Ra)C(O)N(Ra)2, -S(O)2N(Ra)2, -N(Ra)S(O)2Ra, -S(O)2Ra, -ORa, and -La-Rb; each Lais independently selected from a bond and optionally substituted C1-C6aliphatic; each Rbis independently selected from optionally substituted C3-C12 cycloaliphatic, optionally substituted 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, optionally substituted 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, and optionally substituted C6-C10 aryl; each Rais independently selected from hydrogen, optionally substituted C1-C6aliphatic, optionally substituted C1-C6heteroaliphatic, optionally substituted 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, and optionally substituted 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S; Q is selected from optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 heteroaliphatic, optionally substituted C3-C12 cycloaliphatic, optionally substituted 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and Page 85 of 196 12746579v1Attorney Docket No.: 2013518-0088 S, optionally substituted 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, and optionally substituted C6-C10 aryl; Z is selected from optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 heteroaliphatic, optionally substituted C3-C12cycloaliphatic, optionally substituted 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, optionally substituted 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, and optionally substituted C6-C10aryl; L is *-L1-L2-L3-**, where * represents a point of attachment to Q and ** represents a point of attachment to Z; L1is a bond, a 4- to 6-membered heterocycle having 1 to 2 heteroatoms independently selected from N, O, and S, -C(O)N(Ra)-, -OC(O)-, -OC(O)N(Ra)-, -N(Ra)C(O)-, - N(Ra)C(O)O-, -N(Ra)C(O)N(Ra)-, -S(O)2N(Ra)-, -N(Ra)S(O)2-, -S(O)2-, -C(Ra)2O-, - N(Ra)-, -S-, or -O-; L3is a bond, a 4- to 6-membered heterocycle having 1 to 2 heteroatoms independently selected from N, O, and S, -C(O)N(Ra)-, -OC(O)-, -OC(O)N(Ra)-, -N(Ra)C(O)-, - N(Ra)C(O)O-, -N(Ra)C(O)N(Ra)-, -S(O)2N(Ra)-, -N(Ra)S(O)2-, -S(O)2-, -C(Ra)2O-, - N(Ra)-, -S-, or -O-; and L2is optionally substituted C1-C6 aliphatic, optionally substituted 2- to 6-membered heteroaliphatic, optionally substituted 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, or optionally substituted C3-C10cycloaliphatic. Embodiment 2. The compound of Embodiment 1, wherein R1is optionally substituted C1- C6aliphatic. Embodiment 3. The compound of Embodiments 1 or 2, wherein R1is -CH3 or -CD3. Embodiment 4. The compound of any one of Embodiments 1-3, wherein R2is 5- to 10- membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, C3-C6 cycloaliphatic, or C6-C10aryl, and wherein R2is optionally substituted with one or more instances of R2a. Page 86 of 196 12746579v1Attorney Docket No.: 2013518-0088 Embodiment 5. The compound of Embodiment 1, wherein R2is 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, C3-C6 cycloaliphatic, or 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, and wherein R2is optionally substituted with one or more instances of R2a. Embodiment 6. The compound of any one of Embodiments 1-5, wherein R2is 5- to 10- membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, and wherein R2is optionally substituted with one or more instances of R2a. Embodiment 7. The compound of Embodiment 6, wherein R2is 5- to 6-membered monocyclic heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, and wherein R2is optionally substituted with one or more instance of R2a. Embodiment 8. The compound of Embodiment 7, wherein R2is 5- to 6-membered monocyclic heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, and wherein R2is substituted with one or more instances of R2a, wherein R2ais selected from optionally substituted C1-C6 aliphatic and -ORa. Embodiment 9. The compound of Embodiment 8, wherein R2is 5- to 6-membered monocyclic heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, and wherein R2is substituted with one or more instances of R2a, wherein R2ais selected from optionally substituted C1-C6 aliphatic and halogen. Embodiment 10. The compound of any one of Embodiments 1-4, wherein R2is C6-C10 aryl, and wherein R2is optionally substituted with one or more instances of R2a. Embodiment 11. The compound of any one of Embodiments 1-4, wherein R2is C6 aryl, and wherein R2is optionally substituted with one or more instances of R2a. Page 87 of 196 12746579v1Attorney Docket No.: 2013518-0088 Embodiment 12. The compound Embodiment 11 wherein R2is optionally substituted with one or more instances of R2a, wherein R2ais selected from -La-Rband -ORa. Embodiment 13. The compound of any one of Embodiments 1-3, wherein R2is selected from: ,Embodiment 14. The compound of Embodiment 13, wherein R2is selected from: , ,Embodiment 15. The compound of Embodiment 13, wherein R2is selected from: .Embodiment 16. The compound of any one of Embodiments 1-15, wherein Q is optionally substituted C3-C6 cycloaliphatic, optionally substituted C6-C12 aryl, or optionally substituted 4- to 6-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S. Page 88 of 196 12746579v1Attorney Docket No.: 2013518-0088 Embodiment 17. The compound of Embodiment 16, wherein Q is optionally substituted C1- C6 aliphatic. Embodiment 18. The compound of Embodiment 17, wherein Q is optionally substituted cyclopenyl or cyclobutyl. Embodiment 19. The compound of Embodiment 16, wherein Q is optionally substituted C3- C6 cycloaliphatic. Embodiment 20. The compound of any one of Embodiments 1-15, wherein Q is: ,Embodiment 21. The compound of Embodiment 20, wherein Q is: ,of attachment to L1. Embodiment 22. The compound of any one of Embodiments 1-21, wherein Z is optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 heteroaliphatic, optionally substituted C3- C12cycloaliphatic, and optionally substituted C6-C10aryl. Page 89 of 196 12746579v1Attorney Docket No.: 2013518-0088 Embodiment 23. The compound of any one of Embodiments 1-21, wherein Z is optionally substituted C1-C6 aliphatic, optionally substituted 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, and optionally substituted C6-C10 aryl. Embodiment 24. The compound of Embodiment 23, wherein Z is: ,Embodiment 25. The compound of any one of Embodiments 1-24, wherein Z is optionally substituted C1-C6aliphatic. Embodiment 26. The compound of any one of Embodiments 1-23, wherein Z is optionally substituted C3-C7cycloaliphatic. Embodiment 27. The compound of any one of Embodiments 1-24, wherein Z is optionally substituted C6-C10aryl. Embodiment 28. The compound of any one of Embodiments 1-21, wherein Z is: ,Page 90 of 196 12746579v1Attorney Docket No.: 2013518-0088 Embodiment 29. The compound of any one of Embodiments 1-28, wherein L1is -N(Ra)C(O)- , -N(Ra)C(O)O-, -N(Ra)C(O)N(Ra)-, or -O-. Embodiment 30. The compound of Embodiment 29, wherein L1is -OC(O)N(Ra)- or - N(Ra)C(O)O-. Embodiment 31. The compound of Embodiment 30, wherein L1is -OC(O)NH- or - NHC(O)O-. Embodiment 32. The compound of any one of Embodiments 1-31, wherein L3is -OC(O)-, - OC(O)N(Ra)-, -C(Ra)2O-, -N(Ra)-, -S-, or -O-. Embodiment 33. The compound of any one of Embodiments 1-31, wherein L3is a bond, a 4- to 6-membered heterocycle having 1 to 2 heteroatoms independently selected from N, O, and S, - C(Ra)2O-, -N(Ra)-, or -O-. Embodiment 34. The compound of Embodiment 33, wherein L3is a bond, azetidinyl, -CH2O- , -N(CH3)-, or -O-. Embodiment 35. The compound of any one of Embodiments 1-34, wherein L1is - N(Ra)C(O)O- or -N(Ra)C(O)N(Ra)-, and L3is -C(Ra)2O- or -O-. Embodiment 36. The compound of any one of Embodiments 1-35, wherein L1is - N(Ra)C(O)O- and L3is -O-. Embodiment 37. The compound of any one of Embodiments 1-36, wherein L2is an optionally substituted C1-C6aliphatic. Embodiment 38. The compound of Embodiment 37, wherein L2is C1-C6 alkylene or C2-C6 alkenylene. Page 91 of 196 12746579v1Attorney Docket No.: 2013518-0088 Embodiment 39. The compound of any one of Embodiments 1-36, wherein L2is an optionally substituted 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S. Embodiment 40. The compound of any one of Embodiments 1-36, wherein L2is an optionally substituted 4- to 6-membered heterocycle comprising 1 to 2 heteroatoms selected from N, O, and S. Embodiment 41. The compound of any one of Embodiments 1-36, wherein L2is an optionally substituted 4- to 7-membered heterocycle comprising 1 to 2 heteroatoms selected from N, O, and S, and is attached in a spirocyclic manner. Embodiment 42. The compound of any one of Embodiments 1-36, wherein L2is an optionally substituted monocyclic C3to C7cycloaliphatic. Embodiment 43. The compound of any one of Embodiments 1-36, wherein L2is optionally substituted C1-C6aliphatic, optionally substituted 2- to 6-membered heteroaliphatic, or optionally substituted 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S. Embodiment 44. The compound of any one of Embodiments 1-36, wherein L2is: *-CH2-**, ,where * represents a point of attachment to L1and ** represents a point of attachment to L3. Page 92 of 196 12746579v1Attorney Docket No.: 2013518-0088 Embodiment 45. The compound of Embodiment 43, wherein L2is: *-CH2-,Embodiment 46. The compound of Embodiment 1, wherein the compound is represented by formula I-A–I-L or a pharmaceutically acceptable salt thereof. Embodiment 47. The compound of Embodiment 1, wherein the compound is represented by formula II-A–II-K or a pharmaceutically acceptable salt thereof. Embodiment 48. The compound of Embodiment 1, wherein the compound is represented by formula III-A–III-D or a pharmaceutically acceptable salt thereof. Embodiment 49. The compound of Embodiment 1, wherein the compound is represented by formula IV-A–IV-D or a pharmaceutically acceptable salt thereof. Embodiment 50. The compound of Embodiment 1, wherein the compound is represented by formula V-A–V-D or a pharmaceutically acceptable salt thereof. Embodiment 51. A compound selected from Table 1, or a pharmaceutically acceptable salt thereof. Embodiment 52. A pharmaceutical composition comprising a compound of any one of Embodiments 1-51, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Page 93 of 196 12746579v1Attorney Docket No.: 2013518-0088 Embodiment 53. A method of inhibiting JAK2 in a subject, comprising administering to the subject the compound of any one of Embodiments 1-51 or the pharmaceutical composition of Embodiment 52. Embodiment 54. A method of treating a disease, disorder, or condition associated with JAK2, comprising administering to a subject in need thereof the compound of any one of Embodiments 1-51 or the pharmaceutical composition of Embodiment 52. Embodiment 55. A method of treating cancer, comprising administering to a subject in need thereof the compound of any one of Embodiments 1-51 or the pharmaceutical composition of Embodiment 52. Embodiment 56. A method of treating a hematological malignancy, comprising administering to a subject in need thereof the compound of any one of Embodiments 1-51 or the pharmaceutical composition of Embodiment 52. Embodiment 57. The method of Embodiment 56, wherein the hematological malignancy is leukemia or lymphoma. Embodiment 58. A method of treating a myeloproliferative neoplasm, comprising administering to a subject in need thereof the compound of any one of Embodiments 1-51 or the pharmaceutical composition of Embodiment 52. Embodiment 59. The method of Embodiment 58, wherein the myeloproliferative neoplasm is polycythemia vera, essential thrombocytopenia, or myelofibrosis. EXAMPLES Preparation of Provided Compounds

[0228] As described in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures. It will be appreciated that, although the general methods depict the synthesis of certain compounds of the present Page 94 of 196 12746579v1Attorney Docket No.: 2013518-0088 disclosure, the following general methods and other methods known to one of ordinary skill in the art can be applied to all compounds and subclasses and species of each of these compounds, as described herein.

[0229] Certain abbreviations are utilized in the Examples below: Abbreviation Name EA ethyl acetate - - ePage 95 of 196 12746579v1Attorney Docket No.: 2013518-0088 DIBAL-H diisobutylaluminium hydride Bn benzyl

[0230] Compounds of the present disclosure may be prepared according to the following procedures. Example 1: Synthesis of (31R,33R)-27-(3-fluoro-1-(methyl-d3)-1H-pyrazol-4-yl)-23-(methyl-d3)-21,22,23,26-tetrahydro-6,11-dioxa-4-aza-2(8,1)-imidazo[4,5-d]pyrrolo[2,3-b]pyridina- 1(1,4)-benzena-3(1,3)-cyclopentanacycloundecaphane-22,5-dione (Compound I-1A) Page 96 of 196 12746579v1Attorney Docket No.: 2013518-0088mol, 1.0 equiv) in THF ( 1 L) at 0oC was added sodium hydride (60% in mineral oil, 123.2 g, 3.08 mol, 1.5 equiv) in portions and stirred for 45 min. 2-(trimethylsilyl) ethoxymethyl chloride (511 Page 97 of 196 12746579v1Attorney Docket No.: 2013518-0088 g, 3.08mol, 1.5 equiv) was added dropwise at 0oC and the mixture was stirred at room temperature for 1 h. The reaction mixture was slowly poured into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 1.8% ethyl acetate in hexane) to afford 1.1 (300 g, Yield: 53%).1H NMR (CDCl3, 400 M Hz): δ 7.62 (s,1H), 7.53 (s, 1H), 5.24 (s, 2H), 3.58 (t, 2H), 0.94(t, 2H), 0.06-0.02 (m, 9H).

[0232] Synthesis of compound 1.2. To a stirred solution of 1.1 (100 g, 360.70 mmol, 1.0 equiv) in THF (1000 mL) at-78 °C was added lithium diisopropylamide (2 M in THF, 270 mL, 541.51 mmol, 1.5 equiv) slowly at -78 °C and stirred for 45 min. N-fluorobenzenesulfonimide (170 g, 541.51 mmol, 1.5 equiv) in THF (500 mL) was added slowly at -78 °C and stirred for 45 min. It was transferred into saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 1% ethyl acetate in hexane) to afford 1.2 (12.5 g, Yield: 12%).1H NMR (CDCl3, 400 M Hz): δ 7.62 (s, 1H), 7.53 (s, 1H), 5.24 (s, 2H), 3.58 (t, 2H), 0.94(t, 2H), 0.06-0.02 (m, 9H).

[0233] Synthesis of compound 1.3. To a solution of 1.2 (12.5 g, 42.34 mmol, 1.0 equiv) in THF (125 mL) was added n-butyl lithium (2.5 M in hexane, 50.8 mL, 127 mmol, 3.0 equiv) dropwise at -78 °C and stirred for 45 min. Triisopropylborate (9.5 g, 50.8 mmol, 1.2 equiv) was added dropwise at -78 °C and stirred for 45 min. To the mixture was added 2,3-Dimethylbutane- 2,3-diol (6.49 g, 55.04 mmol, 1.3 equiv) at -78°C and stirred for 45 min. It was transferred into saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 40% ethyl acetate in hexane) to afford 1.3 (1.2 g, Yield: 13%).1H NMR (CDCl3, 400 M Hz): δ 7.62 (s,1H), 7.53 (s, 1H), 5.24 (s, 2H), 3.58 (t, 2H), 0.94 (t, 2H), 0.06-0.02 (m, 9H).

[0234] Synthesis of compound 1.4. A mixture of 1.3 (1.2 g, 5.66 mmol, 1.0 equiv), potassium carbonate (2.34 g, 16.98 mmol, 3.0 equiv) and deuterated iodomethane (2.46 g, mmol, Page 98 of 196 12746579v1Attorney Docket No.: 2013518-0088 3.0 equiv) in DMF (12 mL) was stirred at 80 ℃ for 2 h. It was filtered through a pad of Celite® and concentrated under reduced pressure to afford 1.4 (0.900 g, Yield: 69%).

[0235] Synthesis of compound 1.5. To a stirred solution of 4-chloro-5-nitro-1- (phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (7 g, 20.77 mmol, 1.0 equiv) in THF (140 mL) was added tert-butyl ((1R,3R)-3-aminocyclopentyl)carbamate (4.57 g, 22.84 mmol, 1.1 equiv) and triethylamine (5.78 mL, 41.54 mmol, 2.0 equiv) at room temperature. The reaction mixture was stirred at 70 °C for 1 h. It was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 1.5 (8.1 g, 78%). MS(ES): m / z 502.4 [M+H]+. The residue was used in the next step without purification.

[0236] Synthesis of compound 1.6. To a solution of 1.5 (8.1 g, 16.16 mmol, 1 equiv) in ethanol (63.8 mL) and THF (21.6 mL) was added ammonium chloride (17.46 g, 323.35 mmol, 20 equiv) and iron powder (8.73 g, 161.61 mmol, 10 equiv) at room temperature. The reaction mixture was stirred at 70 °C for 4 h. It was filter through a pad of Celite®, washed with ethyl acetate. This filtrate was concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 1.6 (7.2 g, 95%). MS(ES): m / z 472.3 [M+H]+. The product was used in the next step without purification.

[0237] Synthesis of compound 1.7. To a solution of 1.6 (7.2 g, 15.28 mmol, 1.0 equiv) in acetonitrile (94 mL) was added a solution of 1,1’-carbonyldiimidazole (7.43 g, 45.85 mmol, 3.0 equiv) and 4-dimethylaminopyridine (2.78 mL, 22.93 mmol, 1.5 equiv) at room temperature. The reaction mixture was stirred at 70 °C for 2 h. It was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 1.7 (6.1 g, 80%). MS(ES): m / z 498.4 [M+H]+. It is used in the next step without purification.

[0238] Synthesis of compound 1.8. To a stirred solution of 1.7 (3.0 g, 5.66 mmol, 1.0 equiv) in DMF (30 mL) was added potassium carbonate (2.49 g, 18.10 mmol, 3.0 equiv) and deuterated iodomethane (2.62 g,18.10 mmol, 3.0 equiv) at 0 °C. The reaction mixture was stirred at room temperature for 4 h. It was filtered through a pad of Celite® and the filtrate was concentrated under reduced pressure to afford 1.8 (1.8 g, Yield: 58%). MS(ES): m / z 515.8[M+H]+. Page 99 of 196 12746579v1Attorney Docket No.: 2013518-0088

[0239] Synthesis of compound 1.9. To a solution of 1.8 (1.5 g, 2.91 mmol, 1.0 equiv) in THF (42 mL) at -78oC was slowly added a solution of lithium diisopropylamide in THF (2 M, 3.6 mL, 7.28 mmol, 2.5 equiv) at -78oC and stirred for 1 h. To the mixture was added 1,2- dibromotetrachloroethane (1.94 g, 4.96 mmol, 1.7 equiv) and stirred for 30 min at -78oC. It was transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 55% ethyl acetate in hexane) to afford 1.9 (1.1 g, Yield: 64%) 593.2, 595.2 [M+H]+.

[0240] Synthesis of compound 1.10. A mixture of 1.9 (1.1 g, 1.85 mmol, 1.0 equiv), 1.4 (0.849 g, 3.71 mmol, 2.0 equiv), potassium carbonate (0.767 g, 5.56 mmol, 3.0 equiv) in 1,4- dioxane (15 mL) and water (5 mL) was degassed for 10 min. (1,1'- Bis(diphenylphosphino)ferrocene) palladium(II)dichloride dichloromethane (0.151 g, 0.185 mmol, 0.1 equiv) was added and degassed for 5 min. The reaction mixture was stirred at 110oC for 1 h. It was cooled to rt and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 65% ethyl acetate in hexane) to afford 1.10 (0.440 g, Yield: 39%). MS(ES): m / z 615.92 [M+H]+.

[0241] Synthesis of compound 1.11. To a stirred solution of 1.10 (0.440 g, 0.714 mmol, 1.0 equiv) in DCM (8 mL) was added bromine (0.136 g, 0.859 mmol, 1.2 equiv) at 0 °C. The reaction mixture was stirred at 0 °C for 10 min. It was quenched with saturated sodium bicarbonate and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 1.11 (0.430 g, 87%). MS(ES): m / z 694.5 and 696.5 [M+H]+. The product was used in the next step without purification.

[0242] Synthesis of compound 1.12. A mixture of 1.11 (1.0 g, 1.44 mmol, 1.0 equiv), (4- (allyloxy)phenyl)boronic acid (0.385 g,2.16 mmol, 1.5 equiv) and potassium carbonate (0.596 g, 4.32 mmol, 3.0 equiv) in dioxane (9 mL) and water (1 mL) was degassed for 10 min. [1,1'- Bis(diphenylphosphino)ferrocene]palladium(II) dichloride complex with dichloromethane (0.117 g, 0.144 mmol, 0.1 equiv) was added and the reaction mixture was stirred at 100oC for 1.5 h. It was cooled to room temperature and poured into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered Page 100 of 196 12746579v1Attorney Docket No.: 2013518-0088 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (72% ethyl acetate in hexane) to afford 1.12 (0.8 g, 78%). MS(ES): m / z 708.3 [M+H]+.

[0243] Synthesis of compound 1.13. To a solution of 1.12 (0.8 g, 1.13 mmol, 1.0 equiv) in acetone (50 mL) was slowly added potassium carbonate (0.234 g, 1.69 mmol, 1.5 equiv) and allyl bromide (0.162 g, 1.35 mmol, 1.2 equiv) at room temperature. The reaction mixture was stirred at 60 °C for 5 h. It was concentrated under reduced pressure. The residue was purified by column chromatography (50% ethyl acetate in hexane) to afford 1.13 (0.7 g, Yield: 83%). MS(ES): m / z 748.3 [M+H]+.

[0244] Synthesis of compound 1.14. To a solution of 1.13 (0.7 g, 0.937 mmol, 1.0 equiv) in DCM (10 mL) was slowly added trifluoroacetic acid (5.0 mL) at 0oC. The reaction mixture was stirred at room temperature for 2 h. It was concentrated under reduced pressure. It was diluted with aqueous sodium bicarbonate and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 1.14 (0.57 g, Yield: 94%). MS(ES): m / z 648.3 [M+H]+.

[0245] Synthesis of compound 1.15. To a solution of 1.14 (0.55 g, 0.850 mmol, 1.0 equiv) and triethylamine (0.128 g, 1.27 mmol, 1.5 equiv) in DCM (5 mL) was added a solution of allyl chloroformed (0.122 g, 1.02 mmol, 1.2 equiv) in DCM was added at 0oC. The reaction mixture was stirred at room temperature for 15 min. It was diluted with aqueous sodium bicarbonate and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (55% ethyl acetate in hexane) to afford 1.15 (0.380 g, Yield: 61%). MS(ES): 732.3 m / z [M+H]+.

[0246] Synthesis of compound 1.16. A solution of 1.15 (0.380 g, 0.519 mmol, 1.0 equiv) and Grubbs catalyst 2ndgeneration (0.044 g, 0.051 mmol, 0.1 equiv) in DMF (5 mL) was degassed by bubbling through a stream of argon for 5 min. The reaction mixture was stirred at 70 °C for 2 h. It was concentrated under reduced pressure. The residue was purified by column chromatography (1.5% methanol in DCM) to afford 1.16 (0.110 g, Yield: 30%). MS(ES): 704.3 m / z [M+H]+. Page 101 of 196 12746579v1Attorney Docket No.: 2013518-0088

[0247] Synthesis of compound 1.17. A mixture of 1.16 (0.110 g, 0.156 mmol, 1.0 equiv) and palladium on carbon (0.015 g, 10%) in methanol (5 mL) was stirred under hydrogen atmosphere for 3 h at room temperature. It was filtered through a pad of Celite® and raised with methanol. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (2.0% methanol in DCM) to afford 1.17 (0.070 g, Yield: 64%). MS(ES): 706.3 m / z [M+H]+.

[0248] Synthesis of compound I-1A. To a solution of 1.17 (0.070 g, 0.098 mmol, 1.0 equiv) in methanol (2.0 mL) at room temperature was added 10% aqueous solution of sodium hydroxide (2.0 mL) at room temperature and stirred for 1 h. It was transferred into ice-water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 2.5% methanol in DCM) to afford I-1A (0.012 g, Yield: 21%). MS(ES): 566.3 m / z [M+H]+;1H NMR (DMSO-d6, 400 M Hz): δ 11.90 (s, 1H), 8.12 (s, 1H), 7.33 (s, 1H), 7.27 (s, 1H), 7.18 (d, J = 6.8 Hz, 1H), 6.96 (m, 2H), 5.77 (s, 1H), 4.17 - 4.06 (m, 5H), 3.74 (s, 1H), 2.34-2.17 (m, 2H), 1.90 - 1.69 (m, 6H), 1.53 - 1.50 (m, 1H), 1.30- 1.23 (m, 1H). Example 2: Synthesis of (31R,33R)-27-(3-fluoro-1-(methyl-d3)-1H-pyrazol-4-yl)-23-(methyl-d3)-21,22,23,26-tetrahydro-6,11-dioxa-4-aza-2(8,1)-imidazo[4,5-d]pyrrolo[2,3-b]pyridina- 1(1,4)-benzena-3(1,3)-cyclopentanacycloundecaphane-22,5-dione (Compound I-1A) Page 102 of 196 12746579v1Attorney Docket No.: 2013518-0088Example 3: Synthesis of (31s,33s)-27-(3-fluoro-1-(methyl-d3)-1H-pyrazol-4-yl)-23-(methyl-d3)-21,22,23,26-tetrahydro-6,11-dioxa-4-aza-2(8,1)-imidazo[4,5-d]pyrrolo[2,3-b]pyridina- 1(1,4)-benzena-3(1,3)-cyclobutanacycloundecaphane-22,5-dione (Compound I-2A) Page 103 of 196 12746579v1Attorney Docket No.: 2013518-0088 PhOS PhOS PhOSN NN N H N N NNHBocEtN Fe, NHCl NO NH

[0249] Synthesis of compound 2.1. To a solution of 4-chloro-5-nitro-1-(phenylsulfonyl)- 1H-pyrrolo[2,3-b]pyridine (16 g, 47.37 mmol, 1.0 equiv) in THF (160 mL) was added Page 104 of 196 12746579v1Attorney Docket No.: 2013518-0088 triethylamine (19.81 mL, 142.12 mmol, 3.0) and tert-butyl ((1s,3s)-3-aminocyclobutyl)carbamate (13.24 g, 71.06 mmol, 1.5 equiv) at room temperature. The reaction mixture was stirred at 70 ºC for 3 h. It was added with ice-water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduce pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 30.0% ethyl acetate in hexane) to afford 2.1 (15.6 g, 68%). MS(ES): m / z 488.3 [M+H]+.

[0250] Synthesis of compound 2.2. A mixture of 2.1 (15.6 g, 32.0 mmol, 1.0 equiv), iron (17.87 g, 319.98 mmol, 10.0 equiv) and ammonium chloride (34.23 g, 639.96 mmol, 20.0 equiv) in ethanol: water (100m mL: 50 mL) was stirred at 70 ºC for 2 h. It was filtered through a pad of Celite® and rinsed with ethyl acetate. The filtrate was concentrated under reduce pressure. The residue was added water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under pressure to afford 2.2 (13.8 g, 94%). MS(ES): m / z 458.4 [M+H]+.

[0251] Synthesis of compound 2.3. To a solution of 2.2 (13.8 g, 30.16 mmol, 1.0 equiv) in acetonitrile (150 mL) was added 4-dimethylaminopyridine (5.53 g, 45.24 mmol, 1.5 equiv) and 1,1'-carbonyldiimidazole (14.67 g, 90.48 mmol, 3.0 equiv) at room temperature. The reaction mixture was stirred at 70 ºC for 2 h. It was added water and extracted with ethyl acetate. The combined organic layers were washed with 1 N aqueous hydrochloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduce pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 2% methanol in DCM) to afford 2.3 (7.3 g, 50%). MS(ES): m / z 484.4 [M+H]+.

[0252] Synthesis of compound 2.4. To a solution of 2.3 (7.3 g, 15.10 mmol, 1.0 equiv) in DMF (70 mL) was added potassium carbonate (6.26 g, 45.29 mmol, 3.0 equiv) and iodomethane- d3(1.41 mL, 22.65 mmol, 1.5 equiv) at 0 ºC for 2 h. It was added cooled water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 2% methanol in DCM) to afford 2.4 (4.3 g, Yield: 57%). MS(ES): m / z 501.3 [M+H]+.

[0253] Synthesis of compound 2.5. To a stirred solution of 2.4 (4.3 g, 8.59 mmol, 1.0 equiv) in THF (240 mL) was added lithium diisopropylamide (12.88 mL, 25.77 mmol, 3.0 equiv) Page 105 of 196 12746579v1Attorney Docket No.: 2013518-0088 at -78 ºC and stirred for 45 min. To the mixture was added 1,2-Dibromo-1,1,2,2-tetrachloroethane (4.7 g, 14.12 mmol, 1.7 equiv) in THF (15 mL) at -78 ºC and stirred for 1 h. It was transferred into aqueous solution of ammonium chloride and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 30% ethyl acetate in hexane) to afford 2.5 (4.2 g, Yield: 84%). MS(ES): m / z 579.1 and 581.1 [M+H]+.

[0254] Synthesis of compound 2.6. A mixture of 2.5 (4.2 g, 7.25 mmol, 1.0 equiv), 1.4 (3.0 g, 7.65 mmol, 1.05 equiv) and tetrakis(triphenylphosphine)palladium(0) (0.837 g, 0.725 mmol, 0.1 equiv) in 1,4-dioxane (40 mL) was degassed by bubbling through a stream of argon for 10-15 min. The reaction mixture was stirred at 140oC for 2 h. It was cooled to room temperature. The reaction mixture was added water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 65% ethyl acetate in hexane) to afford 2.6 (2.43 g, Yield: 56%). MS(ES): m / z 602.3 [M+H]+.

[0255] Synthesis of compound 2.7. To a solution of 2.6 (2.43 g, 4.04 mmol, 1.0 equiv) in DCM (30 mL) was added bromine in DCM (0.23 mL, 4.44 mmol, 1.1 equiv) at 0 ºC for 30 min. It was added water and extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduce pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 2% methanol in DCM) to afford 2.7 (1.79 g, Yield: 65%). MS(ES): m / z 680.3 and 682.3 [M+H]+.

[0256] Synthesis of compound 2.8. A mixture of 2.7 (1.79 g, 2.63 mmol, 1.0 equiv), (4- hydroxyphenyl)boronic acid (0.544 g, 3.95 mmol, 1.5 equiv) and cesium carbonate (2.57 g, 7.89 mmol, 3.0 equiv) in dioxane: water (15 mL: 5 mL) was degassed by bubbling through a stream of argon for 10-15 min. To the reaction mixture was added 1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium(II) complex with dichloromethane (0.214 g, 0.263 mmol, 0.1 equiv) at room temperature. The reaction mixture was stirred at 100 ºC for 12 h. It was transferred into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was Page 106 of 196 12746579v1Attorney Docket No.: 2013518-0088 purified by flash column chromatography on silica gel (Combiflash®, 5% methanol in DCM) to afford 2.8 (1.43 g, Yield: 78%). MS(ES): m / z 694.78 [M+H]+.

[0257] Synthesis of compound 2.9. To a stirred solution of 2.8 (1.47 g, 2.12 mmol, 1 equiv) in acetone (20 mL) was added potassium carbonate (0.878 g, 6.36 mmol, 3.0 equiv) and allyl bromide (0.512 g, 4.24 mmol, 2.0 equiv) at 0oC. The reaction mixture was stirred at 50 ºC for 5 h. It was cooled to room temperature and concentrated under reduce pressure. The residue was added water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 70% ethyl acetate in hexane) to afford 2.9 (1.3 g, Yield: 84%). MS(ES): m / z 734.4 [M+H]+.

[0258] Synthesis of compound 2.10. To a stirred solution of 2.9 (1.3 g, 1.77 mmol, 1 equiv) in DCM(15 mL) at 0oC was added trifluoroacetic acid (5.0 mL) and stirred at room temperature for 2 h. It was diluted with DCM and quenched with a saturated aqueous solution of bicarbonate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 4.2% methanol in DCM) to afford 2.10 (0.690 g, Yield: 61%). MS(ES): m / z 634.4 [M+H]+.

[0259] Synthesis of compound 2.11. To a stirred solution of 2.10 (0.690 g, 1.09 mmol, 1 equiv) in DCM (20 mL) was added triethylamine (0.45 mL, 3.27 mmol, 3.0 equiv) and allyl chloroformate (0.262 g, 2.18 mmol, 2.0 equiv) at 0oC. The reaction mixture was stirred at room temperature for 30 min. It was added water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 50% ethyl acetate in hexane) to afford 2.11 (0.419 g, Yield: 54%). MS(ES): m / z 718.5 [M+H]+.

[0260] Synthesis of compound 2.12. To a stirred solution of 2.11 (0.419 g, 0.583 mmol, 1 equiv) in DMF: DCM (5 mL: 5 mL) was added Hoveyda-Grubbs Catalyst (0.049 g, 0.0583 mmol, 0.1 equiv) at room temperature and degassed by bubbling through a stream of argon for 10- 15 min. The reaction mixture was stirred at 60 ºC for 24 h. It was cooled to room temperature and transferred into water and extracted with DCM. The combined organic layers were washed with Page 107 of 196 12746579v1Attorney Docket No.: 2013518-0088 brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 3.2% methanol in DCM) to afford 2.12 (0.132 g, Yield: 33%). MS(ES): m / z 690.3 [M+H]+.

[0261] Synthesis of compound 2.13. A mixture of 2.12 (0.132 g, 0.191 mmol, 1 equiv) and palladium on carbon in methanol (15 mL) was stirred under hydrogen atmosphere (1 atm) for 12 h. It was filtered through a pad of Celite® and rinsed with methanol. The filtrate was concentrated under reduce pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 6.2% methanol in DCM) to afford 2.13 (0.062 g, Yield: 47%). MS(ES): m / z 692.4 [M+H]+.

[0262] Synthesis of I-2A. To a stirred solution of 2.13 (0.062 g, 0.089 mmol, 1 equiv) in methanol (10 mL) was added a solution of sodium hydroxide in water (2 N) at 0 ºC. The reaction mixture was stirred at 80 ºC for 30 min. It was concentrated under reduce pressure. The residue was added water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 4.2% methanol in DCM) to afford I-2A (0.026 g, Yield: 53%). MS(ES): m / z 552.3 [M+H]+,1H NMR (DMSO-d6, 400 M Hz): δ 11.91 (s, 1H), 8.12 (s, 1H), 7.44 (s, 1H), 7.27-(m, 1H), 4.72 (m, 1H), 4.46 (m, 1H), 4.03-3.95 (m, 2H), 2.78 (m, 4H), 1.90 (m, 3H), 1.75 (m, 2H), 1.54-1.50 (m, 1H). Example 4: Synthesis of (31s,33s)-27-(3-fluoro-1-(methyl-d3)-1H-pyrazol-4-yl)-23-(methyl-d3)-21,22,23,26-tetrahydro-6,11-dioxa-4-aza-2(8,1)-imidazo[4,5-d]pyrrolo[2,3-b]pyridina- 1(1,4)-benzena-3(1,3)-cyclobutanacycloundecaphane-22,5-dione (Compound I-2A) Page 108 of 196 12746579v1Attorney Docket No.: 2013518-0088d3)-21,22,23,26-tetrahydro-6,11-dioxa-4-aza-2(8,1)-imidazo[4,5-d]pyrrolo[2,3-b]pyridina- 1(1,4)-benzena-3(1,3)-cyclobutanacycloundecaphan-8-ene-22,5-dione (Compound I-3AC) Page 109 of 196 12746579v1Attorney Docket No.: 2013518-0088

[0263] Synthesis of I-3AC. To a stirred solution of 2.12 (0.032 g, 0.046 mmol, 1 equiv) in methanol (10 mL) was added a solution of sodium hydroxide in water (2 N) at 0 ºC. The reaction mixture was stirred at 80 ºC for 30 min. It was concentrated under reduce pressure. The residue was added water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 4.7% methanol in DCM) to afford I-3AC (0.011 g, Yield: 43%). MS(ES): m / z 550.7 [M+H]+,1H NMR (DMSO- d6, 400 M Hz): δ 11.91 (s, 1H), 8.12 (s, 1H), 7.44 (s, 1H), 7.27-7.25 (d, 2H), 7.08-7.06 (d, 2H), 6.02 (m, 2H), 5.58 (m, 2H), 4.70 (m, 2H), 4.03-2.78 (m, 2H), 1.90 (m, 2H), 1.75 (m, 2H), 1.54- 1.50 (m, 1H). Example 6: Synthesis of (31s,33s)-27-(3-fluoro-1-(methyl-d3)-1H-pyrazol-4-yl)-23-(methyl-d3)-21,22,23,26-tetrahydro-6,11-dioxa-4-aza-2(8,1)-imidazo[4,5-d]pyrrolo[2,3-b]pyridina- 1(1,4)-benzena-3(1,3)-cyclobutanacycloundecaphan-8-ene-22,5-dione (Compound I-3AC)Example 7: Synthesis of (31s,33s)-27-(3-fluoro-1-(methyl-d3)-1H-pyrazol-4-yl)-23-(methyl-d3)-21,22,23,26-tetrahydro-6,9,12-trioxa-4-aza-2(8,1)-imidazo[4,5-d]pyrrolo[2,3-b]pyridina- 1(1,4)-benzena-3(1,3)-cyclobutanacyclododecaphane-22,5-dione (Compound I-4A) Page 110 of 196 12746579v1Attorney Docket No.: 2013518-0088

[0264] Synthesis of compound 4.1. A mixture of 2.7 (1.2 g, 1.76 mmol, 1.0 equiv), (4- (benzyloxy)phenyl)boronic acid (0.522 g, 2.29 mmol, 1.3 equiv) and potassium carbonate (0.728 g, 5.28 mmol, 3.0 equiv) in 1,4-dioxane (25 mL) and water (8 mL) was degassed by bubbling a stream of argon for 10 min. To the mixture was added [1,1'- bis(diphenylphosphino)ferrocene]palladium(II) dichloride complex with dichloromethane (0.138 g, 0.17 mmol, 0.1 equiv) and degassed for 5 min. The reaction mixture was stirred at 100oC for 1.5 h. It was cooled to room temperature, filtered through a pad of Celite®. The filtrate was transferred into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 2.2% methanol in DCM) to afford 4.1 (0.800 g, Yield: 58%). MS(ES): m / z 784.4 [M+H]+.

[0265] Synthesis of compound 4.2. To a solution of 4.1 (0.800 g, 1.02 mmol, 1.0 equiv) in DCM (15 mL) at 0 °C was added trifluoroacetic acid (1 mL). The reaction mixture was stirred at room temperature for 1 h. It was transferred into a saturated solution of sodium bicarbonate and Page 111 of 196 12746579v1Attorney Docket No.: 2013518-0088 extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 2.5% methanol in DCM) to afford 4.2 (0.650 g, Yield: 93%). MS(ES): m / z 684.6 [M+H]+.

[0266] Synthesis of compound 4.3. To a solution of 4.2 (0.186 g, 0.95 mmol, 1.0 equiv) in THF (10 mL) was added triethylamine (0.479 g, 4.75 mmol, 5.0 equiv) followed by triphosgene (0.144 g, 0.49mol, 0.5 equiv) at 0 °C. The reaction mixture was stirred at room temperature for 30 min. A solution of 2-(2-(benzyloxy)ethoxy)ethan-1-ol (0.650 g, 0.950 mmol, 1.0 equiv) in THF (10 mL) was added at 0 °C followed by and triethylamine (0.479 g, 4.75 mmol, 5.0 equiv). The reaction mixture was stirred at room temperature for 1 h. It was transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 55% ethyl acetate in hexane) to afford 4.3 (0.450 g, Yield: 52%). MS(ES): m / z 907.4 [M+H]+.

[0267] Synthesis of compound 4.4. To a solution of 4.3 (0.450 g, 0.496 mmol, 1.0 equiv) in DCM (15 mL) at 0 °C was added triflic acid (1.0 mL). The reaction mixture was stirred at room temperature for 5 min. It was diluted with DCM, basified with a saturated solution of sodium bicarbonate and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 3.5% methanol in DCM) to afford 4.4 (0.165 g, Yield: 46%). MS(ES): m / z 726.6 [M+H]+.

[0268] Synthesis of compound 4.5. To a solution of 4.4 (0.165 g, 0.227 mmol, 1.0 equiv) in DMF (6 mL) at 0 °C was added sodium hydride (60% in mineral oil, 0.091 g, 2.27 mmol, 10.0 equiv). The reaction mixture was stirred at 0oC for 10 min. To the mixture was added a solution of tosyl chloride (0.043 g, 0.227 mmol, 1.0 equiv) in DMF dropwise at 0 °C. The reaction mixture was stirred for 1 h. It was poured into crushed ice and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 3.5% methanol in DCM) to afford 4.5 (0.040 g, Yield: 25%). MS(ES): m / z 708.9 [M+H]+. Page 112 of 196 12746579v1Attorney Docket No.: 2013518-0088

[0269] Synthesis of I-4A. To a solution of 4.5 (0.040 g, 0.005 mmol, 1.0 equiv) in methanol: THF (2 mL: 2 mL) was added sodium hydroxide (0.090 g, 2.26 mmol, 40.0 equiv). The reaction mixture was stirred at rt for 1 h. It was poured into crushed ice and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 4.1% methanol in DCM) to afford I-4A (0.014 g, Yield: 44%). MS(ES): m / z 568.3 [M+H]+;1H NMR (DMSO-d6, 400 M Hz): δ 11.85 (s, 1H), 8.10 (s, 1H), 7.47 (s, 1H), 7.29- 1H), 7.10-7.08 (m, 2H),4.22-4.20 (m, 2H), 3.98-3.95 (m, 2H), , 2H), 2.94-2.91 (m, 1H), 2.81-2.79 (m, 3H), 1.87-1.86 (m, 2H). Example 8: Synthesis of (31s,33s)-27-(3-fluoro-1-(methyl-d3)-1H-pyrazol-4-yl)-23-(methyl-d3)-21,22,23,26-tetrahydro-6,9,12-trioxa-4-aza-2(8,1)-imidazo[4,5-d]pyrrolo[2,3-b]pyridina- 1(1,4)-benzena-3(1,3)-cyclobutanacyclododecaphane-22,5-dione (Compound I-4A) B(OH) PhO S Bn F SO Ph F SO Ph FNON N N NCDPage 113 of 196 12746579v1Attorney Docket No.: 2013518-0088 Example 9: Synthesis of (31s,33s)-27-(3-fluoro-1-(methyl-d3)-1H-pyrazol-4-yl)-23-(methyl-d3)-21,22,23,26-tetrahydro-6,10-dioxa-4-aza-2(8,1)-imidazo[4,5-d]pyrrolo[2,3-b]pyridina- 1(1,4)-benzena-3(1,3)-cyclobutanacyclodecaphane-22,5-dione (Compound I-5A)

[0270] Synthesis of compound 5.1. To a stirred solution of 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenol (3.0 g, 18.19 mmol, 1.0 equiv) in DMF (30 mL) was added sodium hydride (60% wt, 1.74 g, 36.36 mmol, 2.0 equiv) and 3-bromopropan-1-ol (3.95 g, 27.27 mmol, 1.5 equiv) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. It was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 35% ethyl acetate in hexane) to afford 5.1 (0.520 g, Yield: 60%). MS(ES): m / z 279.3 [M+H]+.

[0271] Synthesis of compound 5.2. A mixture of 2.7 (2.4 g, 3.53 mmol, 1.0 equiv), 5.1 (2.0 g, 5.29 mmol, 1.5 equiv) and potassium carbonate (1.46 g, 10.59 mmol, 3.0 equiv) in 1,4- dioxane (30 mL) and water (10 mL) was degassed by bubbling through a stream of argon for 10 Page 114 of 196 12746579v1Attorney Docket No.: 2013518-0088 min. [1,1'-Bis(diphenylphosphino)ferrocene]palladium (II) dichloride complex with dichloromethane (0.285 g, 0.35 mmol, 0.1 equiv) was added, and degassed for 5 min. The reaction mixture was stirred at 100oC for 3 h. It was cooled to room temperature, filtered through a pad of Celite®. The filtrate was transferred into water, extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 72% ethyl acetate in hexane) to afford 5.2 (0.90 g, Yield: 30%). MS(ES): m / z 752.4 [M+H]+.

[0272] Synthesis of compound 5.3. To a solution of 5.2 (0.450 g, 0.52 mmol, 1.0 equiv) in DCM (15 mL) at 0 °C was added triflic acid (1.0 mL). The reaction mixture was stirred at 0 °C for 15 min. It was transferred into a saturated solution of sodium bicarbonate and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 7.0% methanolic ammonia in DCM) to afford 5.3 (0.180 g, Yield: 51%). MS(ES): m / z 652.4 [M+H]+.

[0273] Synthesis of compound 5.4. To a stirred solution of 5.3 (0.390 g, 0.482 mmol, 1.0 equiv) in DCM (10 mL) was added a solution of 1,1’-carbonyldiimidazole (0.156 g, 0.965 mmol, 2.0 equiv) at room temperature for 1 h. It was concentrated under reduce pressure. The residue in acetonitrile (10 mL) and added N,N-diisopropylethylamine (0.53 mL, 2.98 mmol, 3.0 equiv) at room temperature. The reaction mixture was stirred at 65 ºC for 16 h. It was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 60% ethyl acetate in hexane) to afford 5.4 (0.520 g, Yield: 60%). MS(ES): m / z 778.5 [M+H]+.

[0274] Synthesis of I-5A. To a stirred solution of 5.4 (0.040 g, 0.059 mmol, 1 equiv) in methanol (10 mL) was added a solution of sodium hydroxide in water (2 N, 3.0 mL) at 0 ºC. The reaction mixture was stirred at 50 ºC for 30 min. It was concentrated under reduce pressure. The residue was added water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 3.8% methanol Page 115 of 196 12746579v1Attorney Docket No.: 2013518-0088 in DCM) to afford I-5S (0.011 g, Yield: 35%). MS(ES): m / z 538.5 [M+H]+,1H NMR (DMSO-d6, 400 M Hz): δ 11.83 (s, 1H), 9.65 (s, 1H), 8.12 (s, 1H), 7.04 (s, 1H), 7.16 (d, J = 8 Hz, 2H), 8.88 (d, J = 8 Hz, 2H), 4.11 (m, 2H), 3.74 (m, 2H), 3.11-3.09 (m, 2H), 2.69 (s, 1H), 1.92 (m, 2H), 1.85 (m, 2H), 1.54-1.50 (m, 1H). Example 10: Synthesis of Compound I-6A

[0275] Synthesis of compound 6.1. To a solution of but-3-yn-1-ol (5 g, 71.34 mmol, 1.0 equiv) in DMF (50 mL) was added sodium hydride (60%wt in mineral oil, 4.24 g, 107.00 mmol, 1.5 equiv) at 0oC. The reaction mixture was stirred for 30 min and added ((2- bromoethoxy)methyl)benzene (18.41 mL, 85.60 mmol, 1.2 equiv) at 0 °C. The reaction mixture was allowed to warm at room temperature and stirred for 1 h. It was poured into crushed ice and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 10% ethyl acetate in hexane) to afford 6.1 (8.3 g, Yield: 57%). MS(ES): m / z 205.5 [M+H]+.

[0276] Synthesis of compound 6.2. A mixture of 2.7 (2 g, 2.94 mmol, 1.0 equiv), 6.1 (1.20 g, 5.88 mmol, 2.0 equiv), copper Iodide (0.056 g, 0.294 mmol, 0.1 equiv) and triethylamine (1.2 mL, 8.82 mmol, 3.0 equiv) in DMF (10 mL) was degassed by argon for 10-15 min. Tetrakis(triphenylphosphine)palladium (0) (0.340 g, 0.294 mmol, 0.1 equiv) was added and degassed for 10 min. The reaction mixture was stirred at 100 ºC for 12 h. It was diluted with water and extracted with ethyl acetate. The organic extract washed with brine, dried over anhydrous Page 116 of 196 12746579v1Attorney Docket No.: 2013518-0088 sodium sulfate, filtered and concentrated under reduce pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 40% ethyl acetate in hexane) to afford 6.2 (1.5 g, 63%). MS(ES): m / z 804.9 [M+H]+.

[0277] Synthesis of compound 6.3. To a stirred solution of 1.4 (1.5 g, 1.87 mmol, 1 equiv) in DCM (10 mL) was added triflic acid (4 mL) at 0oC for 2 h. It was diluted with water and quenched with sodium bicarbonate solution and extracted with DCM. The organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 4.2% methanol in DCM) to afford 6.3 (0.530 g, Yield: 46%). MS(ES): m / z 614.6 [M+H]+.

[0278] Synthesis of compound 6.4. To a stirred solution of 6.3 (0.265 g, 0.431 mmol, 1.0 equiv) in 1,2-dichloroethane (20 mL) was added a solution of 1,1’-carbonyldiimidazole (0.139 g, 0.863 mmol, 2.0 equiv) and N,N-diisopropylethylamine (0.334 g, 2.5 mmol, 6.0 equiv) at room temperature for 1 h. The reaction mixture was stirred at 80 ºC for 12 h. It was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 3.5% methanol in DCM) to afford 6.4 (0.065 g, Yield: 24%). MS(ES): m / z 640.6 [M+H]+.

[0279] Synthesis of I-6A. To a stirred solution of 6.4 (0.065 g, 0.101 mmol, 1 equiv) in methanol (10 mL) was added a solution of sodium hydroxide in water (2N, 5 mL) at 0 ºC for 30 min. It was diluted with water and extracted with DCM. The organic extract washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 4.3% methanol in DCM) to afford I-6A (0.011 g, Yield: 22%). MS(ES): m / z 500.3 [M+H]+,1H NMR (DMSO-d6, 400 M Hz): δ 12.09 (s, 1H), 8.27-8.26 (s, 1H), 7.97 (s, 1H), 7.66-7.58 (m, 1H), 5.31-5.24 (m, 2H), 4.13 (m, 2H), 4.033 (m, 2H), 3.89-3.86 (m, 2H), 2.98-2.94 (m, 2H), 2.89-2.86 (m, 2H), 1.98 (m, 2H). Example 11: Synthesis of Compound I-6A Page 117 of 196 12746579v1Attorney Docket No.: 2013518-0088Example 12: Synthesis of Compound I-7A Page 118 of 196 12746579v1Attorney Docket No.: 2013518-0088

[0280] Synthesis of compound 7.1. To a solution of 2-((tert- butyldimethylsilyl)oxy)ethan-1-ol (5 g, 28.36 mmol, 1.0 equiv) in DMF (50 mL) was added sodium hydride (60%wt in mineral oil, 1.70 g, 42.53 mmol, 1.5 equiv) was added at 0oC. The reaction mixture was stirred for 30 min and added propargyl bromide (80% in toluene, 5.06 mL, 34.02 mmol, 1.2 equiv) at 0 °C. The reaction mixture was allowed to warm at room temperature and stirred for 1 h. It was poured into crushed ice and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 10% ethyl acetate in hexane) to afford 7.1 (5.4 g, Yield: 89%). MS(ES): m / z 215.4 [M+H]+.

[0281] Synthesis of compound 7.2. A mixture of 2.7 (2 g, 2.94 mmol, 1.0 equiv), 7.1 (1.26 g, 5.88 mmol, 2.0 equiv), copper Iodide (0.056 g, 0.294 mmol, 0.1 equiv) and triethylamine (1.2 mL, 8.82 mmol, 3.0 equiv) in DMF (10 mL) was degassed by bubbling through a stream of argon for 10-15 min. Tetrakis(triphenylphosphine)palladium (0) (0.340 g, 0.294 mmol, 0.1 equiv) was added and degassed by argon for 10 min. The reaction mixture was stirred at 100 ºC for 12 h. It was diluted with water and extracted with ethyl acetate. The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduce pressure. The Page 119 of 196 12746579v1Attorney Docket No.: 2013518-0088 residue was purified by flash column chromatography on silica gel (Combiflash®, 50% ethyl acetate in hexane) to afford 7.2 (0.800 g, 33%). MS(ES): m / z 815.2 [M+H]+.

[0282] Synthesis of compound 7.3. To a stirred solution of 7.2 (0.800 g, 0.982 mmol, 1 equiv) in DCM (10 mL) was added triflic acid (2 mL) at 0oC for 2 h. It was diluted with water and quenched with sodium bicarbonate solution. The mixture was extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 3.8% methanol in DCM) to afford 7.3 (0.330 g, Yield: 56%). MS(ES): m / z 600.2 [M+H]+.

[0283] Synthesis of compound I-7A. To a stirred solution of 7.3 (0.070 g, 0.116 mmol, 1.0 equiv) in THF (10 mL) was added a solution of 1,1’-carbonyldiimidazole (0.038 g, 0.233 mmol, 2.0 equiv) and N,N-diisopropylethylamine (0.045 g, 0.350 mmol, 3.0 equiv) at room temperature for 1 h. It was concentrated under reduce pressure. The residue in THF (10 mL) and added sodium hydride (60%wt in mineral oil, 0.012 g, 0.303 mmol, 3 equiv) at room temperature and stirred for 1 h. It was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 4.6% methanol in DCM) to afford I-7A (0.011 g, Yield: 19%). MS(ES): m / z 486.6 [M+H]+;1H NMR (DMSO-d6, 400 M Hz): δ 12.28 (s, 1H), 8.16 (s, 1H), 8.12 (s, 1H), 7.60 (m, 1H), 5.31-5.24 (m, 1H), 4.46 (m, 1H), 4.50 (m, 2H), 3.89-3.86 (m, 2H), 2.98-2.94 (m, 2H), 2.85-2.82 (m, 2H), 1.98 (m, 2H). Example 13: Synthesis of Compound I-7A Page 120 of 196 12746579v1Attorney Docket No.: 2013518-0088 PhO F2S F NN H OTBDPSSO2Ph NNNNN CuI, Pd(PPh3)4, TEAD3CTFA CD3Example 14: Synthesis of (31s,33s,Z)-27-(3-fluoro-1-(methyl-d3)-1H-pyrazol-4-yl)-23- (methyl-d3)-21,22,23,26-tetrahydro-11H-6,9-dioxa-4-aza-2(8,1)-imidazo[4,5-d]pyrrolo[2,3- b]pyridina-1(4,1)-pyrazola-3(1,3)-cyclobutanacycloundecaphane-22,5-dione (Compound I- 8A) Page 121 of 196 12746579v1Attorney Docket No.: 2013518-0088 O B O O CD3

[0284] Synthesis of compound 8.1 To a solution of 2-(2-(benzyloxy)ethoxy)ethan-1-ol (3.0 g, 15.29 mmol, 1.0 equiv), triethylamine (4.6 g, 45.87 mmol, 3.0 equiv) and N,N- dimethylaminopyridine (0.373 g, 3.05 mmol, 0.2 equiv) in DCM (60 mL) at 0 °C was added p- toluenesulphonyl chloride (3.7 g, 19.87 mmol, 1.3 equiv). The reaction mixture was allowed to warm to room temperature and stirred for 1 h, poured into water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 8.1 (3.0 g, Yield: 56%). The product was used in the next step without purification.

[0285] Synthesis of compound 8.2. A mixture of compound 8.1 (1.3 g, 6.70 mmol, 1.0 equiv), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (3.0 g, 8.71 mmol, 1.3 equiv) and potassium carbonate (2.8 g, 20.1 mmol, 3.0 equiv) in DMF (40 mL) was stirred at 80 °C for 16 h. It was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by HPLC (column: Page 122 of 196 12746579v1Attorney Docket No.: 2013518-0088 YMC Acutus Triart C18 (250 * 20mm, 5µm); mobile phase: (a) 0.1% formic acid in water (b) 100% MeCN; flow rate = 20 mL / min) to afford 8.2 (0.50 g, Yield: 20%). MS(ES): m / z 373.4 [M+H]+.

[0286] Synthesis of compound 8.3. A mixture of 2.7 (0.7 g, 1.03 mmol, 1.0 equiv), 8.2 (0.497 g, 1.34 mmol, 1.3 equiv) and potassium carbonate (0.426 g, 3.09 mmol, 3.0 equiv) in 1,4- dioxane (15 mL) and water (3 mL) was degassed by bubbling through a stream of argon 10 min. [1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride complex with dichloromethane (0.084 g, 0.1 mmol, 0.1 equiv) was added and degassed for 5 min. The reaction mixture was stirred at 100oC for 3 h. It was cooled to room temperature, filtered through a pad of Celite®. The filtrate was transferred into water, extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 80% ethyl acetate in hexane) to afford 8.3 (0.217 g, Yield: 25%). MS(ES): m / z 846.8 [M+H]+.

[0287] Synthesis of compound 8.4. To a solution of 8.3 (0.217 g, 0.25 mmol, 1.0 equiv) in DCM (10 mL) at 0 °C was added triflic acid (0.5 mL). The reaction mixture was stirred at 0 °C for 15 min. It was transferred into a saturated solution of sodium bicarbonate and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 7.2% methanolic ammonia in DCM) to afford 8.4 (0.090 g, Yield: 54%). MS(ES): m / z 656.8 [M+H]+.

[0288] Synthesis of compound 8.5. To a solution of 8.4 (0.090 g, 0.13 mmol, 1.0 equiv) in DCM (5 mL) at 0 °C was added triethylamine (0.033 g, 0.32 mmol, 2.5 equiv) and 1,1'- carbonyldiimidazole (0.027 g, 0.17mol, 1.3 equiv) in DCM (1 mL). The reaction mixture was stirred for 15 min. It was transferred into ice-water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure 8.5 (0.090 g). MS(ES): m / z 750.5 [M+H]+. It was used without purification.

[0289] Synthesis of compound 8.6. To a solution of 8.5 (0.090 g, 0.12 mmol, 1.0 equiv) in acetonitrile (5 mL) was added N,N-diisopropylethylamine (0.062 g, 0.48 mmol, 4.0 equiv). The reaction mixture was stirred at 80 °C for 16 h. It was poured into water and extracted with ethyl Page 123 of 196 12746579v1Attorney Docket No.: 2013518-0088 acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 4.8% methanol in DCM) to afford 8.6 (0.035 g, Yield: 43%). MS(ES): m / z 682.8 [M+H]+.

[0290] Synthesis of I-8A. To a solution of 8.6 (0.035 g, 0.05 mmol, 1.0 equiv) in methanol: THF (2 mL: 2 mL) was added sodium hydroxide (0.080 g, 2.0 mmol, 40.0 equiv) and stirred at rt for 1 h. It was poured into crushed ice and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 6.1% methanol in DCM) to afford I-8A (0.012 g, Yield: 43%). MS(ES): m / z 542.4 [M+H]+;1H NMR (DMSO-d6, 400 M Hz): δ 11.92 (s, 1H), 8.11 (s, 1H), 7.81 (s, 1H), 7.56 (s, 1H), 7.46 (d, J = 2.0 Hz, 1H), 7.31 (d, J = 5.6 Hz, 1H), 4.32-4.29 (m, 2H), 4.20-4.11 (m, 2H), 4.10-4.04 (m, 4H), 3.63-3.56 (m, 2H), 3.08-3.02 (m, 2H), 2.01-1.98 (m, 2H). Example 15: Synthesis of (31s,33s,Z)-27-(3-fluoro-1-(methyl-d3)-1H-pyrazol-4-yl)-23- (methyl-d3)-21,22,23,26-tetrahydro-11H-6,9-dioxa-4-aza-2(8,1)-imidazo[4,5-d]pyrrolo[2,3- b]pyridina-13(1,3)-cyclobutanacycloundecaphane-22,5-dione (Compound I- 8A) Page 124 of 196 12746579v1Attorney Docket No.: 2013518-0088Example 16: Synthesis of (31s,33s)-27-(3-fluoro-1-(methyl-d3)-1H-pyrazol-4-yl)-10-methyl- 23-(methyl-d3)-21,22,23,26-tetrahydro-6-oxa-4,10-diaza-1(5,2)-thiazola-2(8,1)-imidazo[4,5- d]pyrrolo[2,3-b]pyridina-3(1,3)-cyclobutanacyclodecaphane-22,5-dione (Compound I-9A) Page 125 of 196 12746579v1Attorney Docket No.: 2013518-0088

[0291] Synthesis of compound 9.1. To a solution of tert-butyl thiazol-2-ylcarbamate (5.0 g, 25.0 mmol, 1.0 equiv) in DMF (50 mL) was added sodium hydride (60%wt in mineral oil, 1.5 g, 37.5 mmol, 1.5 equiv) at 0oC. The reaction mixture was stirred for 30 min. Methyl iodide (5.3 g, 37.5 mmol, 1.5 equiv) was added at 0 °C. The reaction mixture was allowed to warm at room temperature and stirred for 1 h. It was poured into crushed ice and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 10% ethyl acetate in hexane) to afford 9.1 (4.1 g, Yield: 77%). MS(ES): m / z 215.4 [M+H]+.

[0292] Synthesis of compound 9.2 To a solution of 9.1 (4.1 g, 35.9 mmol, 1.0 equiv) in DCM (100 mL) was added trifluoroacetic acid (41 mL, 10Vol.) at 0 °C. The reaction mixture was allowed to warm at room temperature and stirred for 1 h. It was quenched with a saturated solution of sodium bicarbonate and extracted with DCM. The combined organic layers were concentrated Page 126 of 196 12746579v1Attorney Docket No.: 2013518-0088 under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 24% ethyl acetate in hexane) to afford 9.2 (1.1 g, Yield: 50%). MS(ES): m / z 115.2 [M+H]+.

[0293] Synthesis of compound 9.3. To a solution of 9.2 (1.1 g, 6.2 mmol, 1.0 equiv) in DMF (50 mL) was added sodium hydride (60% in mineral oil, 0.62 g, 15.5 mmol, 2.5 equiv) at 0oC. The reaction mixture was stirred for 30 min and added ((3-bromopropoxy)methyl)benzene (2.13 g, 9.3 mmol, 1.5 equiv) at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. It was poured into crushed ice and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 10% ethyl acetate in hexane) to afford 9.3 (0.84 g, Yield: 33%). MS(ES): m / z 263.2 [M+H]+.

[0294] Synthesis of compound 9.4. To a solution of 9.3 (0.64 g, 19.85 mmol, 1.0 equiv) in THF (100 mL) was added N-bromosuccinimide (0.43 g, 2.4 mmol, 1.1 equiv) at 0 °C and stirred for 30 min. It was poured into crushed ice and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 10% ethyl acetate in hexane) to afford 9.4 (0.5 g, Yield: 60%). MS(ES): m / z 341.0 and 343.0[M+H]+.

[0295] Synthesis of compound 9.5. To a solution of 9.4 (0.5 g, 1.7 mmol, 1.0 equiv) and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.0 g, 5.3 mmol, 3.0 equiv) in THF (30 mL) was added n-butyllithium (2.5 M in THF, 2.15 mL, 5.3 mmol, 3.0 equiv) dropwise at -78oC. The reaction mixture was stirred for 1 h. It was transferred into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 9.5 (0.6 g). MS(ES): m / z 307.2 [M+H]+. The product was used in the next step without purification.

[0296] Synthesis of compound 9.6. A mixture of 9.5 (0.6 g, 1.9 mmol, 3.4 equiv), 2.7 (0.4 g, 0.58 mmol, 1.0 equiv) and cesium carbonate (1.28 g, 3.9 mmol, 3.0 equiv) in 1,2- dimethoxyethane (10 mL) and water (1 mL) was degassed by bubbling through a stream of argon 10 min. Bis(di-tert-butyl(4-dimethylaminophenyl) phosphine) dichloropalladium(II) (0.93 g, 0.13 Page 127 of 196 12746579v1Attorney Docket No.: 2013518-0088 mmol, 0.1 equiv) was added and degassed for 5 min. The reaction mixture was stirred at 80oC for 1 h. It was cooled to room temperature, transferred into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 72% ethyl acetate in hexane) to afford 9.6 (0.30 g, Yield: 59%). MS(ES): m / z 862.2 [M+H]+.

[0297] Synthesis of compound 9.7. To a solution of 9.6 (0.3 g, 0.34 mmol, 1.0 equiv) in DCM (15 mL) at 0 °C was added triflic acid (0.6 mL). The reaction mixture was stirred at 0 °C for 15 min. It was transferred into a saturated solution of sodium bicarbonate and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 7.2% methanol (7 M ammonia in MeOH) in DCM) to afford 9.7 (0.13 g, Yield: 56%). MS(ES): m / z 672.8 [M+H]+.

[0298] Synthesis of compound 9.8. To a solution of 9.7 (0.13 g, 0.19 mmol, 1.0 equiv) and triethylamine (0.08 mL, 0.58 mmol, 3.0 equiv) in DCM (15 mL) at 0 °C was added a solution of 1,1’-carbonyldiimidazole (0.040 g, 0.25 mmol, 1.3 equiv) at 0 °C. The reaction mixture was stirred for 15 min. It was transferred into ice-water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 9.8 (0.13 g). MS(ES): m / z 766.4 [M+H]+. The product was used in the next step without purification.

[0299] Synthesis of compound 9.9. A solution of 9.8 (0.13 g, 0.16 mmol, 1.0 equiv) and N,N-diisopropylethylamine (0.11 mL, 0.67 mmol, 4.0 equiv) in acetonitrile (10 mL) was stirred at 80 °C for 16 h. It was poured into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 3.8% methanol in DCM) to afford 9.9 (0.06, Yield: 51%). MS(ES): m / z 698.6 [M+H]+.

[0300] Synthesis of I-9A. To a solution of 9.9 (0.06 g, 0.086 mmol, 1.0 equiv) in methanol: THF (3 mL: 3 mL) was added sodium hydroxide (0.13 g, 3.4 mmol, 40.0 equiv). The reaction mixture was stirred at room temperature for 2 h. It was poured into crushed ice and extracted with Page 128 of 196 12746579v1Attorney Docket No.: 2013518-0088 ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 4.7% methanol in DCM) to afford I-9A (0.021 g, Yield: 44%). MS(ES): m / z 558.4 [M+H]+;1H NMR (DMSO-d6, 400 M Hz): δ 12.09 (s, 1H), 8.12 (s, 1H), 7.67 (s, 1H), 7.27 (d, J = 8.0 Hz, 1H), 7.02 (s, 1H), 4.33 (bs, 1H), 4.31-4.23 (m, 2H), 4.05- 4.03 (m, 1H), 3.29-3.28 (m, 2H),3.05 (s, 3H), 2.97-2.95 (m, 1H), 2.37-2.34 (m, 1H), 2.07 (m, 2H), 1.95-1.83 (m, 2H). Example 17: Synthesis of (31s,33s)-27-(3-fluoro-1-(methyl-d3)-1H-pyrazol-4-yl)-10-methyl- 23-(methyl-d3)-21,22,23,26-tetrahydro-6-oxa-4,10-diaza-1(5,2)-thiazola-2(8,1)-imidazo[4,5- d]pyrrolo[2,3-b]pyridina-3(1,3)-cyclobutanacyclodecaphane-22,5-dione (Compound I-9A) Page 129 of 196 12746579v1Attorney Docket No.: 2013518-0088Page 130 of 196 12746579v1Attorney Docket No.: 2013518-0088 Example 18: Synthesis of (31s,33s)-27-(3-fluoro-1-(methyl-d3)-1H-pyrazol-4-yl)-23-(methyl-d3)-21,22,23,26-tetrahydro-6,10-dioxa-4-aza-1(5,2)-thiazola-2(8,1)-imidazo[4,5- d]pyrrolo[2,3-b]pyridina-3(1,3)-cyclobutanacyclodecaphane-22,5-dione (Compound I-10A)propan-1- ol (2.46 g, 14.82 mmol, 1.2 equiv) in THF (30 mL) at 0 °C was added sodium hydride (60%wt in mineral oil, 0.592 g, 14.82 mmol, 1.2 equiv) and stirred for 30 min. To the mixture was added 2,5- dibromothiazole (3.0 g, 12.35 mmol, 1.0 equiv) in THF (10 mL) dropwise at 0°C. The reaction mixture was stirred at 60 °C for 16 h. It was cooled to room temperature, poured into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 13% ethyl acetate in hexane) to afford 10.1 (3.0 g, Yield: 74%). MS(ES): m / z 328.3 and 330.2 [M+H]+.

[0302] Synthesis of compound 10.2. To a solution of 10.1 (3.0 g, 9.14 mmol, 1.0 equiv) in THF (40 mL) at -78 °C was added n-butyllithium (2.5 M in hexane, 5.48 mL, 13.71 mmol, 1.5 equiv) and stirred for 1 h. To the mixture was added tri-n-butyltin chloride (4.45 g, 13.71 mmol, 1.5 equiv) at -78 °C and stirred for 1 h. It was quenched with a saturated solution of ammonium chloride and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The Page 131 of 196 12746579v1Attorney Docket No.: 2013518-0088 residue was purified by flash column chromatography on silica gel (Combiflash®, 8% ethyl acetate in hexane) to afford 10.3 (2.5 g, Yield: 51%). MS(ES): m / z 540.6 [M+H]+.

[0303] Synthesis of compound 10.3. A mixture of 2.7 (0.7 g, 1.03 mmol, 1.0 equiv) and 10.2 (0.830 g, 1.54 mmol, 1.5 equiv) in 1,4-dioxane (15 mL) was degassed by bubbling through a stream of argon for 10 min. Tetrakis(triphenylphosphine)palladium(0) (0.115 g, 0.1 mmol, 0.1 equiv) was added, and degassed for 5 min. The reaction mixture was stirred at 130oC for 3 h. It was cooled to room temperature and filtered through a pad of Celite®. The filtrate was transferred into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 60% ethyl acetate in hexane) to afford 10.3 (0.500 g, Yield: 57%). MS(ES): m / z 850.3 [M+H]+.

[0304] Synthesis of compound 10.4. To a solution of 10.3 (0.500 g, 0.58 mmol, 1.0 equiv) in DCM (30 mL) at 0 °C was added triflic acid (1.5 mL) and stirred for 15 min. It was transferred into a saturated solution of sodium bicarbonate and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 7% methanolic ammonia in DCM) to afford 10.4 (0.310 g, Yield: 80%). MS(ES): m / z 659.8 [M+H]+.

[0305] Synthesis of compound 10.5. To a solution of 10.4 (0.310 g, 0.47 mmol, 1.0 equiv) and triethylamine (0.118 g, 1.17 mmol, 2.5 equiv) in DCM (30 mL) at 0 °C was added a solution of 1,1’-carbonyldiimidazole (0.099 g, 0.61mol, 1.3 equiv) in DCM (1 mL). The reaction mixture was stirred for 15 min. It was transferred into ice-water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 10.5 (0.150 g). MS(ES): m / z 753.6 [M+H]+. The product was used in the next step without purification.

[0306] Synthesis of compound 10.6. To a solution of 10.5 (0.150 g, 0.19 mmol, 1.0 equiv) and N,N-diisopropylethylamine (0.098 g, 0.76 mmol, 4.0 equiv) in acetonitrile (15 mL) was stirred at 80 °C for 16 h. It was poured into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel Page 132 of 196 12746579v1Attorney Docket No.: 2013518-0088 (Combiflash®, 3.5% methanol in DCM) to afford 10.6 (0.050 g, Yield: 37%). MS(ES): m / z 685.7 [M+H]+.

[0307] Synthesis of I-10A. To a solution of 10.6 (0.050 g, 0.07 mmol, 1.0 equiv) in methanol: THF (2 mL:2 mL) was added sodium hydroxide (0.116 g, 2.9 mmol, 40.0 equiv). The reaction mixture was stirred at rt for 1 h. It was poured into crushed ice and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 4.1% methanol in DCM) to afford I-10A (0.013 g, Yield: 33%). MS(ES): m / z 545.3 [M+H]+;1H NMR (DMSO-d6, 400 M Hz): δ 12.20 (s, 1H), 8.15 (s, 1H), 7.74 (s, 1H), 7.33 (d, J = 8.4 Hz,, 7.13 (s, 1H), 5.08-5.04 (m, 1H), 4.41-4.37 (m, 1H), 4.18-4.15 (m, 1H), 3.98-3.93 (m, 3H), 2.88-2.86 (m, 1H), 2.59-2.56 (m, 1H), 2.21-2.19 (m, 1H), 2.11-2.08 (m, 2H), 1.86-1.83 (m, 1H). Example 19: Synthesis of (31s,33s)-27-(3-fluoro-1-(methyl-d3)-1H-pyrazol-4-yl)-23-(methyl-d3)-21,22,23,26-tetrahydro-6,10-dioxa-4-aza-1(5,2)-thiazola-2(8,1)-imidazo[4,5- d]pyrrolo[2,3-b]pyridina-3(1,3)-cyclobutanacyclodecaphane-22,5-dione (Compound I-10A) Page 133 of 196 12746579v1Attorney Docket No.: 2013518-0088Example 20: Synthesis of (31s,33s)-27-(3-fluoro-1-(methyl-d3)-1H-pyrazol-4-yl)-23-(methyl-d3)-21,22,23,26-tetrahydro-11H-6-oxa-4-aza-2(8,1)-imidazo[4,5-d]pyrrolo[2,3-b]pyridina- 1(5,1)-indazola-3(1,3)-cyclobutanacyclononaphane-22,5-dione (Compound I-11A) Page 134 of 196 12746579v1Attorney Docket No.: 2013518-0088 F SO2Ph NNN N CD3g, 6.02 mmol, 1.0 equiv) and triethylamine (1.8 g, 18.06 mmol, 3.0 equiv) in DCM (20 mL) at 0 °C was added N,N-dimethylamino pyridine (0.146 g, 1.2 mmol, 0.2 equiv) and p-toluenesulphonyl chloride (1.48 g, 7.8 mmol, 1.3 equiv). The reaction mixture was allowed to warm to room temperature and stirred for 1 h. It was poured into water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure 11.1 (1.3 g, Yield: 67%). The product was used without purification.

[0309] Synthesis of compound 11.2 To a solution of compound 5-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1H-indazole (0.82 g, 3.36 mmol, 1.0 equiv) in DMF (20 mL) was added Page 135 of 196 12746579v1Attorney Docket No.: 2013518-0088 11.1 (1.3 g, 4.03 mmol, 1.2 equiv) and potassium carbonate (1.4 g, 10.08 mmol, 3.0 equiv). The reaction mixture was stirred at 80 °C for 16 h. It was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 80% ethyl acetate in hexane) to afford 11.2 (0.750 g, Yield: 57%). MS(ES): m / z 393.4 [M+H]+.

[0310] Synthesis of compound 11.3. A mixture of 2.7 (0.92 g, 1.35 mmol, 1.0 equiv), 11.2 (0.742 g, 1.89 mmol, 1.4 equiv) and potassium carbonate (0.558 g, 4.05 mmol, 3.0 equiv) in 1,4-dioxane (20 mL) and water (5 mL) was degassed by bubbling through a stream of argon for 10 min. [1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride complex with dichloromethane (0.110 g, 0.13 mmol, 0.1 equiv) was added, and degassed for 5 min. The reaction mixture was stirred at 100oC for 3 h. It was cooled to room temperature and filtered through a pad of Celite®. The filtrate was transferred into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 75% ethyl acetate in hexane) to afford 11.3 (0.400 g, Yield: 34%). MS(ES): m / z 867.2 [M+H]+.

[0311] Synthesis of compound 11.4 To a solution of 11.3 (0.400 g, 0.46 mmol, 1.0 equiv) in DCM (15 mL) at 0 °C was added triflic acid (1.0 mL) and stirred at 0 °C for 15 min. It was transferred into a saturated solution of sodium bicarbonate and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 7.5% methanolic ammonia in DCM) to afford 11.4 (0.160 g, Yield: 51%). MS(ES): m / z 676.8 [M+H]+.

[0312] Synthesis of compound 11.5. To a solution of 1.6 (0.160 g, 0.26 mmol, 1.0 equiv) and triethylamine (0.065 g, 0.65 mmol, 2.5 equiv) in DCM (15 mL) at 0 °C was added a solution of 1,1’-carbonyldiimidazole (0.055 g, 0.33 mol, 1.3 equiv) in DCM (2 mL) and stirred for 15 min. It was transferred into ice-water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced Page 136 of 196 12746579v1Attorney Docket No.: 2013518-0088 pressure to afford 11.5 (0.150 g). MS(ES): m / z 770.5 [M+H]+. The product was used in the next step without purification.

[0313] Synthesis of compound 11.6. A solution of 11.5 (0.150 g, 0.19 mmol, 1.0 equiv) and N,N-diisopropylethylamine (0.098 g, 0.76 mmol, 4.0 equiv) in acetonitrile (10 mL) was stirred at 80 °C for 16 h. It was poured into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 4.8% methanol in DCM) to afford 11.6 (0.065 g, Yield: 48%). MS(ES): m / z 702.5 [M+H]+.

[0314] Synthesis of I-11A. To a solution of 11.6 (0.065 g, 0.09 mmol, 1.0 equiv) in methanol: THF (3 mL:3 mL) was added sodium hydroxide (0.144 g, 3.6 mmol, 40.0 equiv) and stirred at rt for 1 h. It was poured into crushed ice and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 4.7% methanol in DCM) to afford I-11A (0.020 g, Yield: 38%). MS(ES): m / z 562.3 [M+H]+.1H NMR (DMSO-d6, 400 M Hz): δ 11.92 (s, 1H), 8.12-8.09 (m, 2H), 7.83-7.82 (m, 2H), 7.43 (s, 1H), 7.34 (d, J = 8.0 Hz, 1H), 6.97 (d, J = 8 Hz, 1H), 4.82-4.79 (m, 1H), 4.53-4.49 (m, 1H), 4.30-4.25 (m, 1H), 4.08-4.03 (m, 1H), 2.66-2.60 (m, 1H), 2.28-2.27 (m, 3H), 2.15-2.13 (m, 1H), 1.59-1.56 (m, 1H), 1.47-1.44 (m, 2H). Example 21: Synthesis of (31s,33s)-27-(3-fluoro-1-(methyl-d3)-1H-pyrazol-4-yl)-23-(methyl-d3)-21,22,23,26-tetrahydro-11H-6-oxa-4-aza-2(8,1)-imidazo[4,5-d]pyrrolo[2,3-b]pyridina- 1(5,1)-indazola-3(1,3)-cyclobutanacyclononaphane-22,5-dione (Compound I-11A) Page 137 of 196 12746579v1Attorney Docket No.: 2013518-0088Page 138 of 196 12746579v1Attorney Docket No.: 2013518-0088 Example 22: Synthesis of Compounds I-12-Isomer 1 and I-12-Isomer 23,4-diol (6.0 g, 57.69 mmol, 1.0 equiv) in THF (9 mL) was added sodium hydride (2.30 g,57.69 mmol, 1.0 equiv) at 0 °C and stirred for 30 min. To the mixture was added 4- methoxy benzyl chloride (9.0 g, 57.69 mmol, 0.1 equiv) and stirred for 1 h. It was quenched into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (22% ethyl acetate in hexane) to afford (±)-12.1 (5.0 g, 39%). MS(ES): m / z 225.3 [M+H]+. Page 139 of 196 12746579v1Attorney Docket No.: 2013518-0088

[0316] Synthesis of compound (±)-12.2. To a solution of (±)-12.1 (5.0 g, 22.32 mmol, 1.0 equiv) in DMF (50 mL) was slowly added sodium hydride (1.78 g, 44.64 mmol, 2.0 equiv) at 0 °C and stirred for 10 min. To the mixture was added propargylic bromide (3.18 g, 26.78 mmol, 1.2 equiv) at 0 °C and stirred for 10 min. It was quenched into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (15% ethyl acetate in hexane) to afford (±)-12.2 (5.0 g, Yield: 86%). MS(ES): m / z 263.4[M+H]+.

[0317] Synthesis of compound (±)-12.3. A mixture of 2.7 (2.0 g, 2.94 mmol, 1.0 equiv) and CuI (0.055 g, 0.29 mmol, 0.1 equiv) in DMF (5 mL) was degassed by bubbling through a stream of argon for 5 min. Triethylamine (1.48 g, 14.7 mmol, 5.0 equiv), tetrakis (triphenylphosphine)palladium (0.340 g, 0.29 mmol, 0.1 equiv) and (±)-12.2 (2.31 g, 8.82 mmol, 3.0 equiv) were added and degassed for 5 min. The reaction mixture was stirred at 50 °C for 16 h. It was concentrated under reduced pressure. The residue was purified by column chromatography (25% ethyl acetate in hexane) to afford (±)-12.3 (0.750 g, Yield: 30%). MS(ES): 862.4 m / z [M+H]+.

[0318] Synthesis of compound (±)-12.4. To a solution of (±)-12.3 (0.750 g, 0.871 mmol, 1.0 equiv) in DCM (30 mL) was slowly added trifluoroacetic acid (7.0 mL) at 0oC and stirred at room temperature for 2 h. It was concentrated under reduced pressure. The residue was diluted with an aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford (±)-12.4 (0.450 g, Yield: 86%). MS(ES): m / z 642.3[M+H]+.

[0319] Synthesis of compound (±)-12.5. To a solution of (±)-12.4 (0.450 g, 0.702 mmol, 1.0 equiv) and triethylamine (0.212 g, 2.10 mmol, 3.0 equiv) in DCM(5 mL) was added a solution of 1,1'-carbonyldiimidazole (0.136 g, 0.842 mmol, 1.2 equiv) in DCM at room temperature. The reaction mixture was stirred at room temperature for 20 min. It was quenched into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was Page 140 of 196 12746579v1Attorney Docket No.: 2013518-0088 purified by column chromatography (50% ethyl acetate in hexane) to afford (±)-12.5 (0.2 g, Yield: 39%). MS(ES): m / z 736.3 [M+H]+.

[0320] Synthesis of compound (±)-12.6. A solution of (±)-12.5 (0.2 g, 0.272 mmol, 1.0 equiv) and N,N-diisopropylamine (0.105 g, 0.816 mmol, 3.0 equiv) in acetonitrile (5 mL) was stirred at 80 °C for 16 h. It was quenched into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (50% ethyl acetate in hexane) to afford (±)-12. (0.070 g, Yield: 39%). MS(ES): m / z 668.3[M+H]+.

[0321] Synthesis of compound I-12-Isomer 1 and I-12-Isomer 2. To a solution of (±)- 12.6 (0.070 g, 0.098 mmol, 1.0 equiv) in methanol (2.0 mL) at room temperature was added 10% aqueous solution of sodium hydroxide (2.0 mL) at room temperature and stirred for 1 h. It was transferred into ice-water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 2.5% methanol in DCM) to afford (±)-I-12 (0.035 g, Yield: 64%). The racemate was purified by SFC (Column: CHIRALPAK IB-N (250 * 30 mm, 5 µm); Mobile Phase: (A) liquid CO2 (B) 0.1% NH3 in isopropanol: MeCN (50: 50); Flow rate: 100 mL / min) to afford first eluting fraction (0.012 g, Yield: 21%) and second eluting fraction (0.010 g, Yield: 21%). I-12-Isomer 1: MS(ES): 528.3 m / z [M+H]+;1H NMR (DMSO-d6, 400 M Hz): δ 12.28 (s, 1H), 8.16 (s, 1H), 8.14 (s, 1H), 7.62 (d, J = 5.2 Hz, 1H), 4.86 - 4.80 (m, 1H), 4.79- 4.77 (m, 1H), 4.72 - 4.68 (m, 1H), 4.56 - 4.52 (m, 1H), 4.13 (s, 1H), 4.00-3.96 (m, 1H), 3.89 - 3.86 (m, 1H), 3.73 – 3.71 (m, 1H), 3.64 – 3.61 (m, 1H), 3.45- 3.39 (m, 3H), 3.33- 3.13 (m, 1H), 2.22- 2.15 (m, 1H). I-12-Isomer 2: MS(ES): 528.3 m / z [M+H]+;1H NMR (DMSO-d6, 400 M Hz): δ 12.28 (s, 1H), 8.17 (s, 1H), 8.14 (s, 1H), 7.62 (d, J = 6.0 Hz, 1H), 4.86 - 4.80 (m, 1H), 4.79- 4.77 (m, 1H), 4.72 - 4.68 (m, 1H), 4.56 - 4.52 (m, 1H), 4.13-4.12 (s, 1H), 4.00-3.96 (m, 1H), 3.89 - 3.85 (m, 1H), 3.71 (m, 1H), 3.63 – 3.61 (m, 1H), 3.46- 3.39 (m, 3H), 3.33- 3.13 (m, 1H), 2.20- 2.18 (m, 1H). Example 23: Synthesis of Compounds I-12-Isomer 1 and I-12-Isomer 2 Page 141 of 196 12746579v1Attorney Docket No.: 2013518-0088Page 142 of 196 12746579v1Attorney Docket No.: 2013518-0088 Example 24: Synthesis of Compounds I-12 Isomer 3 and I-12 Isomer 4Page 143 of 196 12746579v1Attorney Docket No.: 2013518-0088 Example 25: Synthesis of (41s,43s)-37-(3-fluoro-1-(methyl-d3)-1H-pyrazol-4-yl)-33-(methyl-d3)-31,32,33,36-tetrahydro-7-oxa-5-aza-2(2,5)-thiazola-3(8,1)-imidazo[4,5-d]pyrrolo[2,3- b]pyridina-1(1,3)-azetidina-4(1,3)-cyclobutanacyclooctaphane-32,6-dione (Compound I- 13A) N Br S Br N CD3Page 144 of 196 12746579v1Attorney Docket No.: 2013518-0088

[0322] Synthesis of compound 13.1. To a solution of compound tert-butyl 3- (hydroxymethyl)azetidine-1-carboxylate (5.0 g, 26.7 mmol, 1.0 equiv) in DMF (50 mL) was added sodium hydride (60%wt in mineral oil, 1.2 g, 40.1 mmol, 1.5 equiv) at 0oC. and stirred for 30 min. Benzyl bromide (4.99 g, 40.1 mmol, 1.5 equiv) was added at 0oC and the mixture was allowed to warm at room temperature and stirred for 1 h. It was poured into crushed ice and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 10% ethyl acetate in hexane) to afford 13.1 (5.5 g, Yield: 74%). MS(ES): m / z 278.2 [M+H]+.

[0323] Synthesis of compound 13.2 To a solution of 13.1 (5.5 g, 19.85 mmol, 1.0 equiv) in DCM (100 mL) was added a solution of hydrochloric acid in 1,4-dioxane (4 M, 55 mL.) at 0 °C. The reaction mixture was allowed to warm at room temperature and stirred for 1 h. It was concentrated under reduced pressure to afford 13.2 (4.0 g). MS(ES): m / z 178.5 [M+H]+. The product was used in next step without purification.

[0324] Synthesis of compound 13.3. To a solution of 2,5-dibromothiazole (4.0 g, 18.77 mmol, 1.0 equiv) and diisopropylethylamine (15.93 mL, 33.89 mmol, 5.0 equiv) in 1,4-dioxane (60 mL) was added 13.3 (5.45 g, 22.53 mmol, 1.2 equiv) at room temperature. The reaction mixture was stirred at 80oC for 16 h. It was transferred into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 28% ethyl acetate in hexane) to afford 13.3 (3.0 g, Yield: 47%). MS(ES): m / z 340.5 [M+H]+.

[0325] Synthesis of compound 13.4. To a solution of 13.3 (3.0 g, 8.84 mmol, 1.0 equiv) and 2-isobutyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.93 g, 26.5 mmol, 3.0 equiv) in THF (30 mL) was added a solution of n-butyllithium in THF (2.5 M, 10.61 mL, 26.5 mmol, 3.0 equiv) dropwise at -78oC and stirred for 1 h. It was transferred into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 13.4 (4.8 g). MS(ES): m / z 305.2 [M+H]+. The product was used in the next step without purification. Page 145 of 196 12746579v1Attorney Docket No.: 2013518-0088

[0326] Synthesis of compound 13.5. A mixture of 2.7 (2.4 g, 7.7 mmol, 4.0 equiv), 13.4 (1.3 g, 1.9 mmol, 1.0 equiv) and cesium carbonate (1.86 g, 5.7 mmol, 3.0 equiv) in 1,2- dimethoxyethane (30 mL) and water (3 mL) was degassed by bubbling through a stream of argon 10 min. Bis(di-tert-butyl(4-dimethylaminophenyl) phosphine) dichloropalladium (II) (0.135 g, 0.38 mmol, 0.1 equiv) was added and degassed for 5 min. The reaction mixture was stirred at 80oC for 1 h. It was cooled to room temperature, transferred into water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 72% ethyl acetate in hexane) to afford 13.5 (0.50 g, Yield: 31%). MS(ES): m / z 861.2 [M+H]+.

[0327] Synthesis of compound 13.6. To a solution of 13.5 (0.5 g, 0.58 mmol, 1.0 equiv) in DCM (15 mL) at 0 °C was added triflic acid (1.0 mL). The reaction mixture was stirred at 0 °C for 15 min. It was transferred into a saturated solution of sodium bicarbonate and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 7.2% methanol (7M ammonia in MeOH) in DCM) to afford 13.6 (0.2 g, Yield: 49%). MS(ES): m / z 670.8 [M+H]+.

[0328] Synthesis of compound 13.7. A solution of 13.6 (0.2 g, 0.29 mmol, 1.0 equiv) and triethylamine (0.12 mL, 0.87 mmol, 3.0 equiv) in DCM (15 mL) at 0 °C was added a solution of 1,1’-carbonyldiimidazole (0.061 g, 0.37 mmol, 1.3 equiv) in DCM (2 mL) and stirred for 15 min. It was transferred into ice-water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 13.7 (0.21 g). MS(ES): m / z 764.4 [M+H]+. The product was used in the next step without purification.

[0329] Synthesis of compound 13.8. To a solution of 13.7 (0.21 g, 0.27 mmol, 1.0 equiv) and N,N-diisopropylethylamine (0.18 mL, 1.08 mmol, 4.0 equiv) in acetonitrile (10 mL) was stirred at 80 °C for 16 h. It was poured into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography Page 146 of 196 12746579v1Attorney Docket No.: 2013518-0088 on silica gel (Combiflash®, 3.5% methanol in DCM) to afford 13.8 (0.1, Yield: 52%). MS(ES): m / z 696.6 [M+H]+.

[0330] Synthesis of I-13A. To a solution of 13.8 (0.1 g, 0.14 mmol, 1.0 equiv) in methanol: THF (3 mL:3 mL) was added sodium hydroxide (0.23 g, 5.7 mmol, 40.0 equiv). The reaction mixture was stirred at room temperature for 1 h. It was poured into crushed ice and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 4.6% methanol in DCM) to afford I-13A (0.025 g, Yield: 31%). MS(ES): m / z 556.3 [M+H]+.1H NMR (DMSO-d6, 400 M Hz): δ 12.15 (s, 1H), 8.09 (s, 1H), 7.62 (s, 1H), 7.49 (d, J = 7.6 Hz, 1H), 7.11 (s, 1H), 4.30 (t, 1H), 4.21-4.14 (m, 3H), 4.03-4.01 (m, 1H), 3.84-3.82 (m, 2H),3.26 (m, 1H), 3.17-3.09 (m, 2H), 2.45 (s, 1H), 2.18 (m, 1H), 1.97-1.93 (m, 1H). Example 26: Synthesis of (41s,43s)-37-(3-fluoro-1-(methyl-d3)-1H-pyrazol-4-yl)-33-(methyl-d3)-31,32,33,36-tetrahydro-7-oxa-5-aza-2(2,5)-thiazola-3(8,1)-imidazo[4,5-d]pyrrolo[2,3- b]pyridina-1(1,3)-azetidina-4(1,3)-cyclobutanacyclooctaphane-32,6-dione (Compound I- 13A) Page 147 of 196 12746579v1Attorney Docket No.: 2013518-0088Example 27: Synthesis of (31s,33s)-27-(3-fluoro-1-(methyl-d3)-1H-pyrazol-4-yl)-23-(methyl-d3)-21,22,23,26-tetrahydro-6,9-dioxa-4-aza-2(8,1)-imidazo[4,5-d]pyrrolo[2,3-b]pyridina- 1(1,4)-benzena-3(1,3)-cyclobutanacycloundecaphane-22,5-dione (Compound I-14A) Page 148 of 196 12746579v1Attorney Docket No.: 2013518-0088g, 19.89 mmol, 1.0 equiv) in DMF (40 mL) at 0 °C was added sodium hydride (60%wt in mineral oil, 1.2 g, 29.83 mmol, 1.5 equiv) and stirred for 30 min. To the mixture was added 2-(2- bromoethoxy)tetrahydro-2H-pyran (4.99 g, 23.87 mmol, 1.2 equiv) at 0 °C and was allowed to warm at room temperature and stirred for 1 h. It was poured into crushed ice and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 10% ethyl acetate in hexane) to afford 14.1 (3.0 g, Yield: 46%). MS(ES): m / z 329.4 and 331.2 [M+H]+. Page 149 of 196 12746579v1Attorney Docket No.: 2013518-0088

[0332] Synthesis of compound 14.2. A mixture of 14.1 (3.0 g, 9.11 mmol, 1.0 equiv), bis(pinacolato)diborane (3.45 g, 13.66 mmol, 1.5 equiv) and potassium acetate (2.67 g, 27.33 mmol, 3.0 equiv) in 1,4-dioxane (60 mL) was degassed by bubbling through a stream of argon 10 min. [1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride complex with dichloromethane (0.743 g, 0.911 mmol, 0.1 equiv) was added, and degassed for 5 min. The reaction mixture was stirred at 100oC for 3 h. It was cooled to room temperature and filtered through a pad of Celite®. The filtrate was transferred into water, extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 15% ethyl acetate in hexane) to afford 14.2 (2.0 g, Yield: 58%). MS(ES): m / z 377.5 [M+H]+.

[0333] Synthesis of compound 14.3. A mixture of 2.7 (2.4 g, 3.53 mmol, 1.0 equiv), 14.2 (2.0 g, 5.29 mmol, 1.5 equiv) and potassium carbonate (1.46 g, 10.59 mmol, 3.0 equiv) in 1,4- dioxane (30 mL) and water (10 mL) was degassed by bubbling through a stream of argon 10 min. [1,1'-Bis(diphenylphosphino)ferrocene]palladium (II) dichloride complex with dichloromethane (0.285 g, 0.35 mmol, 0.1 equiv) was added, and degassed for 5 min. The reaction mixture was stirred at 100oC for 3 h. It was cooled to room temperature and filtered through a pad of Celite®. The filtrate was transferred into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 72% ethyl acetate in hexane) to afford 14.3 (0.90 g, Yield: 30%). MS(ES): m / z 851.2 [M+H]+.

[0334] Synthesis of compound 14.4. To a solution of 14.3 (0.450 g, 0.52 mmol, 1.0 equiv) in DCM (15 mL) at 0 °C was added triflic acid (1.0 mL). The reaction mixture was stirred at 0 °C for 15 min. It was transferred into a saturated solution of sodium bicarbonate and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 7.0% methanolic ammonia in DCM) to afford 14.4 (0.180 g, Yield: 51%). MS(ES): m / z 666.8 [M+H]+. Page 150 of 196 12746579v1Attorney Docket No.: 2013518-0088

[0335] Synthesis of compound 14.5. To a solution of 14.4 (0.180 g, 0.27 mmol, 1.0 equiv) and triethylamine (0.068 g, 0.67 mmol, 2.5 equiv) in DCM (15 mL) at 0 °C was added a solution of 1,1’-carbonyldiimidazole (0.057 g, 0.35 mmol, 1.3 equiv) in DCM (2 mL) and stirred for 15 min. It was transferred into ice-water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 14.5 (0.160 g). MS(ES): m / z 760.4 [M+H]+. The product was used in the next step without purification.

[0336] Synthesis of compound 14.6. A solution of 14.5 (0.160 g, 0.21 mmol, 1.0 equiv) and N,N-diisopropylethylamine (0.108 g, 0.84 mmol, 4.0 equiv) in acetonitrile (10 mL) was stirred at 80 °C for 16 h. It was poured into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 3.5% methanol in DCM) to afford 14.6 (0.090, Yield: 62%). MS(ES): m / z 692.6 [M+H]+.

[0337] Synthesis of I-14A. To a solution of 14.6 (0.045 g, 0.065 mmol, 1.0 equiv) in methanol: THF (3 mL:3 mL) was added sodium hydroxide (0.104 g, 2.6 mmol, 40.0 equiv). The reaction mixture was stirred at rt for 1 h. It was poured into crushed ice and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 4.2% methanol in DCM) to afford I-14A (0.020 g, Yield: 38%). MS(ES): m / z 552.4 [M+H]+;1H NMR (DMSO-d6, 400 M Hz): δ 11.93 (s, 1H), 8.12 (s, 1H), 7.40 (s, 1H), 7.36 (d, J = 7.6 Hz, 2H), 7.27 (d, J = 7.2 Hz, 2H), 7.19 (d, J = 6.4 Hz, 1H), 4.03-3.99 (m, 2H), 3.82-3.80 (m, 2H), 3.73-3.69 (m, 1H), 3.58-3.56 (m, 2H), 2.89-2.83 (m, 2H), 2.83-2.73 (m, 3H), 1.83-1.81 (m, 2H). Example 28: Synthesis of (31s,33s)-27-(3-fluoro-1-(methyl-d3)-1H-pyrazol-4-yl)-10-methyl- 23-(methyl-d3)-21,22,23,26-tetrahydro-6-oxa-4,10-diaza-2(8,1)-imidazo[4,5-d]pyrrolo[2,3- b]pyridina-1(1,4)-benzena-3(1,3)-cyclobutanacyclodecaphane-22,5-dione (Compound I- 15A) Page 151 of 196 12746579v1Attorney Docket No.: 2013518-0088 Br NHOxalyl Chloride Pd(dppf)Cl2.DCM, TEA STAB, EDCOBn Bispin, KOAc CD3CD31.5 equiv) in DCM (80 mL) at -78 °C was added dimethylsulphoxide (3.75 g, 48.12 mmol, 2.0 equiv) and stirred for 30 min. To the mixture was added 3-(benzyloxy)propan-1-ol (4.0 g, 24.06 mmol, 1.0 equiv) and reaction mixture was stirred at -78°C for 30 min. Triethylamine (9.72 g, 96.24 mmol, 4.0 equiv) was added and reaction mixture was stirred at -78 °C for 1h. It was poured into a saturated solution of ammonium chloride and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 10% ethyl acetate in hexane) to afford 15.1 (1.8 g, Yield: 46%).1H NMR (DMSO- d6, 400 M Hz): δ 9.70 (s, 1H), 7.36-7.26 (m, 5H), 4.51 (s, 2H), 3.81-3.72, 2.67-2.60 (m, 3H). Page 152 of 196 12746579v1Attorney Docket No.: 2013518-0088

[0339] Synthesis of compound 15.2. A solution of 15.1 (0.8 g, 4.87 mmol, 1.0 equiv) and 4-bromo-N-methylaniline (1.0 g, 5.85 mmol, 1.2 equiv) in 1,2-dichloroethane (20 mL) at 0 °C was stirred for 30 min. To the mixture was added sodium triacetoxyborohydride (2.0 g, 9.74 mmol, 2.0 equiv) at 0 °C and stirred at room temperature for 3 h. It was poured into water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 12% ethyl acetate in hexane) to afford 15.2 (1.0 g, Yield: 61%). MS(ES): m / z 334.4 and 336.5 [M+H]+.

[0340] Synthesis of compound 15.3. A mixture of 15.2 (1.0 g, 2.99 mmol, 1.0 equiv), bis(pinacolato)diborane (1.13 g, 4.48 mmol, 1.5 equiv) and potassium acetate (0.88 g, 8.97 mmol, 3.0 equiv) in 1,4-dioxane (30 mL) was degassed by bubbling through a stream of argon 10 min. [1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride complex with dichloromethane (0.236 g, 0.29 mmol, 0.1 equiv) was added, and degassed for 5 min. The reaction mixture was stirred at 100oC for 3 h. It was cooled to room temperature and filtered through a pad of Celite®. The filtrate was transferred into water, extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 25% ethyl acetate in hexane) to afford 15.3 (0.65 g, Yield: 57%). MS(ES): m / z 382.6 [M+H]+.

[0341] Synthesis of compound 15.4. A mixture of 2.7 (0.67 g, 0.98 mmol, 1.0 equiv) ], 15.3 (0.6 g, 1.58 mmol, 1.6 equiv) and sodium carbonate (0.311 g, 2.94 mmol, 3.0 equiv) in 1,4- dioxane (20 mL) and water (5 mL) was degassed by bubbling through a stream of argon 10 min. Tetrakis(triphenylphosphine)palladium(0) (0.103 g, 0.09 mmol, 0.1 equiv) was added, and degassed for 5 min. The reaction mixture was stirred at 100oC for 5 h. It was cooled to room temperature, filtered through a pad of Celite®. The filtrate was transferred into water, extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 65% ethyl acetate in hexane) to afford 15.4 (0.380 g, Yield: 39%). MS(ES): m / z 855.2 [M+H]+. Page 153 of 196 12746579v1Attorney Docket No.: 2013518-0088

[0342] Synthesis of compound 15.5. To a solution of 15.4 (0.325 g, 0.38 mmol, 1.0 equiv) in DCM (20 mL) at 0 °C was added triflic acid (1.0 mL) and stirred for 15 min. It was transferred into a saturated solution of sodium bicarbonate and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 5.2% methanolic ammonia in DCM) to afford 15.5 (0.142 g, Yield: 56%). MS(ES): m / z 665.8 [M+H]+.

[0343] Synthesis of compound 15.6. To a solution of 15.5 (0.142 g, 0.21 mmol, 1.0 equiv) and triethylamine (0.053 g, 0.52 mmol, 2.5 equiv) in DCM (15 mL) at 0 °C was added a solution of 1,1’-carbonyldiimidazole (0.045 g, 0.27 mmol, 1.3 equiv) in DCM (2 mL) and stirred for 15 min. It was transferred into ice-water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 15.6 (0.102 g). MS(ES): m / z 759.5 [M+H]+. The product was used in the next step without purification.

[0344] Synthesis of compound 15.7. To a solution of 15.6 (0.102 g, 0.13 mmol, 1.0 equiv) and N,N-diisopropylethylamine (0.067 g, 0.52 mmol, 4.0 equiv) in acetonitrile (8 mL) was stirred at 80 °C for 16 h. It was poured into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 3.5% methanol in DCM) to afford 15.7 (0.040 g, Yield: 42%). MS(ES): m / z 690.6 [M+H]+.

[0345] Synthesis of I-15A. To a solution of 15.7 (0.040 g, 0.057 mmol, 1.0 equiv) in methanol: THF (3 mL:3 mL) was added sodium hydroxide (0.091 g, 2.2 mmol, 40.0 equiv) and stirred at rt for 1 h. It was poured into crushed ice and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 4.5% methanol in DCM) to afford I-15A (0.019 g, Yield: 60%). MS(ES): m / z 551.4 [M+H]+;1H NMR (DMSO-d6, 400 M Hz): δ 11.75 (s, 1H), 8.09 (d, J = 2.8 Hz, 1H), 7.37 (s, 1H), 7.16-7.11 (m, 3H), 6.77-6.74 (m, 2H), 4.09 (m, 2H), 3.83-3.80 (m, 1H), Page 154 of 196 12746579v1Attorney Docket No.: 2013518-0088 3.64-3.59 (m, 2H), 3.04 (s, 3H), 2.91-2.81 (m, 1H), 2.44-2.47 (m, 2H), 1.97-1.93 (m, 2H), 1.75- 1.74 (m, 2H). Example 29: Synthesis of (31s,33s)-27-(3-fluoro-1-(methyl-d3)-1H-pyrazol-4-yl)-23-(methyl-d3)-21,22,23,26-tetrahydro-6,9-dioxa-4-aza-2(8,1)-imidazo[4,5-d]pyrrolo[2,3-b]pyridina- 1(1,4)-benzena-3(1,3)-cyclobutanacyclononaphane-22,5-dione (Compound I-16A)dioxaborolan-2-yl)phenol (0.8 g, 4.87 mmol, 1.0 equiv), ((2-bromoethoxy)methyl)benzene (1.0 g, 5.85 mmol, 1.2 equiv) and cesium carbonate (2.0 g, 9.74 mmol, 2.0 equiv) in DMF (20 mL) was stirred at 80 °C for 3 h. It was poured into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 15% ethyl acetate in hexane) to afford 16.1 (1.0 g, Yield: 61%).1H NMR (DMSO-d6, 400 M Hz): δ 7.63 (m, 2H), 7.39-7.26 (m, 5H), 7.96-7.94 (m, 2H), 4.56, 4.17-4.15 (m, 2H), 3.78-3.74 (m, 2H), 1.28 (s, 12H).

[0347] Synthesis of compound 16.2. A mixture of 2.7 (1.5 g, 2.20 mmol, 1.0 equiv), 16.1 (1.17 g, 3.31 mmol, 1.5 equiv) and sodium carbonate (0.700 g, 6.60 mmol, 3.0 equiv) in 1,4- Page 155 of 196 12746579v1Attorney Docket No.: 2013518-0088 dioxane (20 mL) and water (5 mL) was degassed by bubbling through a stream of argon 10 min. Tetrakis(triphenylphosphine)palladium(0) (0.254 g, 0.22 mmol, 0.1 equiv) was added, and degassed for 5 min. The reaction mixture was stirred at 100oC for 5 h. It was cooled to room temperature, filtered through a pad of Celite®. The filtrate was transferred into water, extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 65% ethyl acetate in hexane) to afford 16.2 (0.700 g, Yield: 38%). MS(ES): m / z 828.6 [M+H]+.

[0348] Synthesis of compound 16.3. To a solution of 16.2 (0.700 g, 0.84 mmol, 1.0 equiv) in DCM (20 mL) at 0 °C was added triflic acid (1.5 mL) and stirred at 0 °C for 15 min. It was transferred into a saturated solution of sodium bicarbonate and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 5.2% methanolic ammonia in DCM) to afford 16.3 (0.320 g, Yield: 59%). MS(ES): m / z 638.5 [M+H]+.

[0349] Synthesis of compound 16.4. To a solution of 16.3 (0.320 g, 0.50 mmol, 1.0 equiv) and triethylamine (0.126 g, 1.25 mmol, 2.5 equiv) in DMF (25 mL) at 0 °C was added a solution of 1,1’-carbonyldiimidazole (0.105 g, 0.65 mmol, 1.3 equiv) in DMF (5 mL) and stirred for 15 min. The reaction mixture was stirred at 80 °C for 16 h. It was transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 3.5% methanol in DCM) to afford 16.4 (0.125 g, Yield: 38%). MS(ES): m / z 664.8 [M+H]+.

[0350] Synthesis of I-16A. To a solution of 16.4 (0.060 g, 0.009 mmol, 1.0 equiv) in methanol: THF (3 mL:3 mL) was added sodium hydroxide (0.015 g, 0.36 mmol, 40.0 equiv) and stirred at rt for 1 h. It was poured into crushed ice and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 4.5% methanol in DCM) to afford I-16A (0.014 g, Yield: 30%). MS(ES): m / z 524.3 [M+H]+;1H NMR (DMSO-d6, 400 M Hz): δ 12.04 (s, 1H), 8.17 (s, 1H), 7.33- Page 156 of 196 12746579v1Attorney Docket No.: 2013518-0088 7.28 (m, 4H), 7.21-7.17 (m, 2H), 4.59-4.58 (m, 2H), 4.10-4.08 (m, 2H), 3.77-3.68 (m, 2H), 2.46- 2.42 (m, 2H), 1.67-1.63 (m, 2H). Example 30: Synthesis of (31s,33s)-27-(3-fluoro-1-(methyl-d3)-1H-pyrazol-4-yl)-23-(methyl-d3)-21,22,23,26-tetrahydro-11H-6-oxa-4-aza-2(8,1)-imidazo[4,5-d]pyrrolo[2,3-b]pyridina- 1(5,1)-indazola-3(1,3)-cyclobutanacyclooctaphane-22,5-dione (Compound I-17A)dioxaborolan-2-yl)-1H-indazole (1.5 g, 6.14 mmol, 1.0 equiv), potassium carbonate (1.69 g,12.2 mmol,2.0 equiv) and ((2-bromoethoxy)methyl)benzene (2.62 g,12.2 mmol, 2.0 equiv) in DMF (10 mL) was stirred at 80oC for 3 h. It was transferred into ice-water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was further purified by column chromatography on silica gel (30% ethyl acetate in hexane) to afford 17.1 (1.0 g, Yield: 43%). MS(ES): m / z 379.21 [M+H]+.

[0352] Synthesis of compound 17.2. A mixture of 2.7 (1.0 g, 1.46 mmol, 1.0 equiv), 1.2 (0.666 g, 1.76 mmol, 1.2 equiv) and sodium carbonate (0.464 g, 4.38 mmol, 3.0 equiv) in 1,4- dioxane (8 mL) and water (2 mL) was degassed by bubbling through a stream of argon for 10 min. Page 157 of 196 12746579v1Attorney Docket No.: 2013518-0088 [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane (0.119 g, 0.0146 mmol, 0.1 equiv) was added and degassed for 5 min and stirred at 100oC for 2 h. It was cooled to room temperature, poured into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0-2.0% methanol in DCM) to afford 17.2 (0.6 g, 48%). MS(ES): m / z 852.3[M+H]+.

[0353] Synthesis of compound 17.3. To a solution of 17.2 (0.6 g, 0.705 mmol, 1.0 equiv) in DCM (12.0 mL) was added triflic acid (4.0 mL) at 0oC dropwise and stirred for 30 min at room temperature. It was poured into ice-water and extract with 10% MeOH / DCM. The crude product was purified by flash column chromatography on silica gel (5-10% methanol (in ammonia) / DCM) to afford 17.3 (0.3 g, 64%) MS(ES): m / z 662.3 [M+H]+.

[0354] Synthesis of compound 17.4. To a stirred solution of 17.3 (0.235 g, 0.355 mmol, 1.0 equiv) in dimethyl sulfoxide(5 mL) at 0oC was added a solution of 1,1’-carbonyldiimidazole (0.069 g, 0.427 mmol, 1.2 equiv) and N,N-diisopropylethylamine (0.137 g, 1.065 mmol, 3.0 equiv). The reaction mixture was stirred at room temperature for 30 min and 80oC overnight. It was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 0-4.6% methanol in DCM) to afford 17.4 (0.060 g, 25%) MS(ES): 688.2 m / z [M+H]+.

[0355] Synthesis of I-17A. To a stirred solution of 17.4 (0.060 g, 0.089 mmol, 1 equiv) in methanol (6 mL) was added an aqueous solution of sodium hydroxide at 0 ºC and stirred at rt for 1 h. It was concentrated under reduce pressure. The residue was added water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 0-4.8% methanol in DCM) to afford I-17A (0.016 g, Yield: 33%). MS(ES): m / z 548.3 [M+H]+;1H NMR (DMSO-d6, 400 M Hz): δ 11.93 (s, 1H), 8.14 (s, 2H), 7.92 (s, 1H), 7.62 (s, 1H), 7.58, 7.43 (s, 1H), 7.13 (d, 1H), 5.11-4.92 (m, 2H), 4.63- 4.60 (m, 1H), 4.27-4.25 (m, 1H), 4.01-3.99 (m, 2H), 2.22-2.10 (m, 2H), 1.96-2.01 (m, 2H). Page 158 of 196 12746579v1Attorney Docket No.: 2013518-0088 Example 31: Synthesis of (31s,33s)-23-(methyl-d3)-27-(thiazol-5-yl)-21,22,23,26-tetrahydro-6,9,12-trioxa-4-aza-2(8,1)-imidazo[4,5-d]pyrrolo[2,3-b]pyridina-1(1,4)-benzena-3(1,3)- cyclobutanacyclododecaphane-22,5-dione (Compound I-18A)a g, 13.9 mmol, 1.0 equiv) in DMF (50 mL) was added sodium hydride (60%wt in mineral oil, 0.84 g, 20.9 mmol, 1.5 equiv) at 0oC and stirred for 30 min. To the mixture was added ((2- bromoethoxy)methyl)benzene (4.5 g, 20.9 mmol, 1.5 equiv) at 0 °C. The reaction mixture was allowed to warm at room temperature and stirred for 1 h. It was poured into crushed ice and Page 159 of 196 12746579v1Attorney Docket No.: 2013518-0088 extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 10% ethyl acetate in hexane) to afford 18.1 (1.78 g, Yield: 37%). MS(ES): m / z 350.4 and 352.4 [M+H]+.

[0357] Synthesis of compound 18.2. A mixture of 18.1 (1.78 g, 5.0 mmol, 1.0 equiv), bis(pinacolato)diboron (1.94 g, 7.6 mmol, 1.5 equiv.) and potassium acetate (1.5 g, 15.2 mmol, 3.0 equiv) in 1,4-dioxane (100 mL) was degassed by bubbling through a stream of argon 15 min. [1,1′- Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.37 g, 0.5 mmol, 0.1 equiv) was added and stirred at 100oC for 2 h. It was cooled to room temperature, transferred into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 32% ethyl acetate in hexane) to afford 18.2 (1.2 g, Yield: 59%). MS(ES): m / z 399.2 [M+H]+.

[0358] Synthesis of compound 18.3. A mixture of 18.2 (4.0 g, 6.8 mmol, 1 equiv) and 5- (tributylstannyl)thiazole (3.1 g, 8.2 mmol, 1.2 equiv) in 1,4-dioxane (20 mL) was degassed by bubbling through a stream of argon 15 min. Tetrakis(triphenylphosphine)palladium(0) (0.77 g, 0.89 mmol, 0.1 equiv) was added. The reaction mixture was stirred at 140oC for 2 h. It was cooled to room temperature, transferred into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 51% ethyl acetate in hexane) to afford 18.3 (2.8 g, Yield: 69%). MS(ES): m / z 584.2 [M+H]+.

[0359] Synthesis of compound 18.4. To a solution of 18.3 (2.8 g, 4.8 mmol, 1.0 equiv) and pyridine (1.13 g, 14.4 mmol, 3.0 equiv) in chloroform (30 mL) was added bromine (0.84 g, 5.2 mmol, 1.1 equiv) dropwise at 0oC for 30 min. It was transferred into water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 40% ethyl acetate in hexane) to afford 18.4 (2.2 g, Yield: 69%). MS(ES): m / z 662.2 and 664.2 [M+H]+. Page 160 of 196 12746579v1Attorney Docket No.: 2013518-0088

[0360] Synthesis of compound 18.5. A mixture of 18.4 (1.1 g, 1.6 mmol, 1 equiv), 18.2 (0.99 g, 2.4 mmol, 1.5 equiv) and cesium carbonate (1.62 g, 4.9 mmol, 3.0 equiv) in 1,2- dimethoxyethane (10 mL) and water (1 mL) was degassed by bubbling through a stream of argon 15 min. Bis(di-tert-butyl(4-dimethylaminophenyl) phosphine) dichloropalladium(II) (0.117 g, 0.16 mmol, 0.1 equiv) was added. The reaction mixture was stirred at 80oC for 2 h. It was cooled to room temperature, transferred into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 72% ethyl acetate in hexane) to afford 18.5 (0.35 g, Yield: 25%). MS(ES): m / z 855.2 [M+H]+.

[0361] Synthesis of compound 18.6. To a solution of 18.5 (0.35 g, 0.41 mmol, 1.0 equiv) in DCM (15 mL) at 0 °C was added triflic acid (0.7 mL). The reaction mixture was stirred at 0 °C for 15 min. It was transferred into a saturated solution of sodium bicarbonate and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 7.2% methanol (7 M ammonia in MeOH) in DCM) to afford 18.6 (0.25 g, Yield: 92%). MS(ES): m / z 664.4 [M+H]+.

[0362] Synthesis of compound 18.7. To a solution of 18.6 (0.25 g, 0.37 mmol, 1.0 equiv) and triethylamine (0.15 mL, 1.1 mmol, 3.0 equiv) in DCM (15 mL) at 0 °C was added a solution of 1,1’-carbonyldiimidazole (0.079 g, 0.49 mmol, 1.3 equiv) in DCM (2 mL) and stirred for 15 min. It was transferred into ice-water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 18.7 (0.22 g). MS(ES): m / z 758.4 [M+H]+. The product was used in the next step without purification.

[0363] Synthesis of compound 18.8. A solution of 18.7 (0.22 g, 0.29 mmol, 1.0 equiv) and N,N-diisopropylethylamine (0.19 mL, 1.1 mmol, 4.0 equiv) in acetonitrile (10 mL) was stirred at 80 °C for 16 h. It was poured into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel Page 161 of 196 12746579v1Attorney Docket No.: 2013518-0088 (Combiflash®, 3.8% methanol in DCM) to afford 18.8 (0.085, Yield: 42%). MS(ES): m / z 690.6 [M+H]+.

[0364] Synthesis of I-18A. To a solution of 18.8 (0.085 g, 0.12 mmol, 1.0 equiv) in methanol: THF (3 mL:3 mL) was added sodium hydroxide (0.2 g, 4.9 mmol, 40.0 equiv). The reaction mixture was stirred at room temperature for 2 h. It was poured into crushed ice and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 4.7% methanol in DCM). The product was repurified by HPLC (column: SUNFIRE C18 (250 * 19 mm, 5 µm); mobile phase: (A) 0.1% TFA in water and (B) MeCN; flow rate: 15 mL / min) to afford I-18A (0.03 g, Yield: 55%). MS(ES): m / z 550.4 [M+H]+;1H NMR (DMSO-d6, 400 M Hz): δ 12.51 (s, 1H), 8.88 (s, 1H), 8.40 (s, 1H), 8.20 (s, 1H), 7.36= 8.4 Hz,2H), 7.23-7.15 (m, 3H), 4.28-4.27 (m, 2H), 4.01-4.00 (m, 2H), 3.68 (m, 2H), 3.76-3.75 (m, 2H), 3.40-3.35 (m, 1H), 2.97-2.95 (m, 1H), 2.85- 2.80 (m, 2H), 1.89-1.87 (m, 2H). Example 32: Synthesis of (31s,33s)-23-(methyl-d3)-27-(thiazol-5-yl)-21,22,23,26-tetrahydro-6,10-dioxa-4-aza-2(8,1)-imidazo[4,5-d]pyrrolo[2,3-b]pyridina-1(1,4)-benzena-3(1,3)- cyclobutanacyclodecaphane-22,5-dione (Compound I-19A) Page 162 of 196 12746579v1Attorney Docket No.: 2013518-0088dioxaborolan-2-yl)phenol (2.0 g, 9.09 mmol, 1.0 equiv) in DMF (50 mL) was added sodium hydride (60%wt in mineral oil, 0.545 g, 13.6 mmol, 1.5 equiv) at 0oC and stirred for 30 min. To the mixture was added ((3-bromopropoxy)methyl)benzene (3.1 g, 13.6 mmol, 1.5 equiv) and stirred at rt for 1 h. It was poured into crushed ice and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 10% ethyl acetate in hexane) to afford 19.1 (1.4 g, Yield: 42%). MS(ES): m / z 369.4 [M+H]+.

[0366] Synthesis of compound 19.2. A mixture of 18.4 (1.1 g, 1.6 mmol, 1 equiv), 19.1 (0.917 g, 2.4 mmol, 1.5 equiv) and cesium carbonate (1.6 g, 4.9 mmol, 3.0 equiv) in 1,2- dimethoxyethane (10 mL) and water (1 mL) was degassed by bubbling through a stream of argon for 15 min. Bis(di-tert-butyl(4-dimethylaminophenyl) phosphine) dichloropalladium(II) (0.117 g, 0.16 mmol, 0.1 equiv) was added. The reaction mixture was stirred at 80oC for 2 h. It was cooled to room temperature, transferred into water and extracted with ethyl acetate. The combined organic Page 163 of 196 12746579v1Attorney Docket No.: 2013518-0088 layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 72% ethyl acetate in hexane) to afford 19.2 (0.42 g, Yield: 20%). MS(ES): m / z 825.2 [M+H]+.

[0367] Synthesis of compound 19.3. To a solution of 19.2 (0.42 g, 0.51 mmol, 1.0 equiv) in DCM (15 mL) at 0 °C was added triflic acid (0.82 mL). The reaction mixture was stirred at 0 °C for 15 min. It was transferred into a saturated solution of sodium bicarbonate and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 7.2% methanol (7M ammonia in MeOH) in DCM) to afford 19.3 (0.28 g, Yield: 87%). MS(ES): m / z 634.4 [M+H]+.

[0368] Synthesis of compound 19.4. To a solution of 19.3 (0.28 g, 0.44 mmol, 1.0 equiv) and triethylamine (0.18 mL, 1.3 mmol, 3.0 equiv) in DCM (15 mL) at 0 °C was added a solution of 1,1’-carbonyldiimidazole (0.093 g, 0.57 mmol, 1.3 equiv) in DCM (2 mL). The reaction mixture was stirred for 15 min. It was transferred into ice-water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 19.4 (0.24 g). MS(ES): m / z 728.4 [M+H]+. The product was used in the next step without purification.

[0369] Synthesis of compound 19.5. A solution of 19.4 (0.24 g, 0.33 mmol, 1.0 equiv) and N,N-diisopropylethylamine (0.22 mL, 1.3 mmol, 4.0 equiv) in acetonitrile (10 mL) was stirred at 80 °C for 16 h. It was poured into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 3.6% methanol in DCM) to afford 19.5 (0.080, Yield: 37%). MS(ES): m / z 660.6 [M+H]+.

[0370] Synthesis of I-19A. To a solution of 19.5 (0.080 g, 0.12 mmol, 1.0 equiv) in methanol: THF (3 mL:3 mL) was added sodium hydroxide (0.2 g, 4.9 mmol, 40.0 equiv). The reaction mixture was stirred at room temperature for 2 h. It was poured into crushed ice and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was Page 164 of 196 12746579v1Attorney Docket No.: 2013518-0088 purified by flash column chromatography on silica gel (Combiflash®, 4.4% methanol in DCM) to afford I-19A (0.06 g, Yield: 95%). MS(ES): m / z 520.6 [M+H]+;1H NMR (DMSO-d6, 400 M Hz): δ 12.46 (s, 1H), 8.87 (s, 1H), 8.42 (s, 1H), 8.18 (s, 1H), 7.35 (d, J = 8.4 Hz, 2H), 7.20-7.18 (m, 3H), 4.36-4.34 (m, 2H), 4.16-4.13 (m, 2H), 3.40-3.37 (m, 1H), 2.88-2.85 (m, 1H), 2.64-2.60 (m, 2H), 2.12-2.09 (m, 2H), 1.73-1.72 (m, 2H). Example 33: Synthesis of (31s,33s)-27-(3-fluoro-1-(methyl-d3)-1H-pyrazol-4-yl)-9-methyl- 23-(methyl-d3)-21,22,23,26-tetrahydro-6-oxa-4,9-diaza-2(8,1)-imidazo[4,5-d]pyrrolo[2,3- b]pyridina-1(1,4)-benzena-3(1,3)-cyclobutanacyclononaphane-22,5-dione (Compound I- 20A)

[0371] a g, 19.98 mmol, 1.0 equiv) in 1,2-dichloroethane (50 mL) at 0 °C was added 4-bromo-N-methylaniline Page 165 of 196 12746579v1Attorney Docket No.: 2013518-0088 (4.46 g, 23.97 mmol, 1.2 equiv) and stirred for 30 min. To the solution was added sodium triacetoxyborohydride (8.43 g, 39.96 mmol, 2.0 equiv) in small portions at 0 °C and reaction mixture was stirred at room temperature for 3 h. It was poured into water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 15% ethyl acetate in hexane) to afford 20.1 (1.8 g, Yield: 28%). MS(ES): m / z 320.4 and 322.5 [M+H]+.

[0372] Synthesis of compound 20.2. A mixture of 20.1 (1.8 g, 5.62 mmol, 1.0 equiv), bis(pinacolato)diborane (2.14 g, 8.43 mmol, 1.5 equiv) and potassium acetate (1.65 g, 16.87 mmol, 3.0 equiv) in 1,4-dioxane (30 mL) was degassed by bubbling through a stream of argon 10 min. [1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride complex with dichloromethane (0.456 g, 0.56 mmol, 0.1 equiv) was added, and degassed for 5 min. The reaction mixture was stirred at 100oC for 3 h. It was cooled to room temperature and filtered through a pad of Celite®. The filtrate was transferred into water, extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 25% ethyl acetate in hexane) to afford 20.2 (1.2 g, Yield: 58%). MS(ES): m / z 368.6 [M+H]+.

[0373] Synthesis of compound 20.3. A mixture of 2.7 (1.4 g, 2.06 mmol, 1.0 equiv), 1.3 (1.2 g, 3.29 mmol, 1.6 equiv) and sodium carbonate (0.655 g, 6.18 mmol, 3.0 equiv) in 1,4-dioxane (30 mL) and water (10 mL) was degassed by bubbling through a stream of argon 10 min. Tetrakis(triphenylphosphine)palladium(0) (0.231 g, 0.2 mmol, 0.1 equiv) was added, and degassed for 5 min. The reaction mixture was stirred at 100oC for 5 h. It was cooled to room temperature and filtered through a pad of Celite®. The filtrate was transferred into water, extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 65% ethyl acetate in hexane) to afford 20.3 (0.500 g, Yield: 29%). MS(ES): m / z 842.2 [M+H]+.

[0374] Synthesis of compound 20.4. To a solution of 20.3 (0.500 g, 0.59 mmol, 1.0 equiv) in DCM (20 mL) at 0 °C was added triflic acid (3.0 mL). The reaction mixture was stirred at 0 °C Page 166 of 196 12746579v1Attorney Docket No.: 2013518-0088 for 15 min. It was transferred into a saturated solution of sodium bicarbonate and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 5.2% methanolic ammonia in DCM) to afford 20.4 (0.190 g, Yield: 49%). MS(ES): m / z 651.6 [M+H]+.

[0375] Synthesis of compound 20.5. A solution of 20.4 (0.190 g, 0.29 mmol, 1.0 equiv) and triethylamine (0.073 g, 0.72 mmol, 2.5 equiv) in DCM (20 mL) at 0 °C was added a solution of 1,1’-carbonyldiimidazole (0.061 g, 0.37 mmol, 1.3 equiv) in DCM (3 mL) and stirred for 15 min. It was transferred into ice-water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 20.5 (0.150 g). MS(ES): m / z 745.6 [M+H]+. The product was used in the next step without purification.

[0376] Synthesis of compound 20.6. A solution of 20.5 (0.150 g, 0.20 mmol, 1.0 equiv) and N,N-diisopropylethylamine (0.103 g, 0.80 mmol, 4.0 equiv) in acetonitrile (10 mL) was stirred at 80 °C for 16 h. It was poured into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 3.5% methanol in DCM) to afford 20.6 (0.080 g, Yield: 59%). MS(ES): m / z 677.7 [M+H]+.

[0377] Synthesis of I-20A. To a solution of 20.6 (0.040 g, 0.059 mmol, 1.0 equiv) in methanol: THF (3 mL:3 mL) was added sodium hydroxide (0.094 g, 2.36 mmol, 40.0 equiv). The reaction mixture was stirred at rt for 1 h. It was poured into crushed ice and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 4.5% methanol in DCM) to afford I-20A (0.013 g, Yield: 41%). MS(ES): m / z 537.4 [M+H]+;1H NMR (DMSO-d6, 400 M Hz): δ 11.77 (s, 1H), 8.09 (s, 1H), 7.28 (s, 1H), 7.20-7.18 (m, 1H),(d, J = 8.8 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 4.00- 3.81 (m, 2H), 3.38-3.36 (m, 2H), 2.87 (s, 3H), 2.66-2.50 (m, 1H), 1,97-1.94 (m, 2H), 1.70-1.67 (m, 2H). Page 167 of 196 12746579v1Attorney Docket No.: 2013518-0088 Example 34: Synthesis of (31s,33s)-27-cyclopropyl-23-(methyl-d3)-21,22,23,26-tetrahydro-11H-6-oxa-4-aza-2(8,1)-imidazo[4,5-d]pyrrolo[2,3-b]pyridina-1(5,1)-indazola-3(1,3)- cyclobutanacyclononaphane-22,5-dione (Compound I-21A) PhO2S PhO2S PhO S NNB(OH)2 N N 2N NBr Pd(dppf)Cl2, K2CO3Br2, CD3, cyclopropylboronic acid (2.97 g, 34.6 mmol, 5.0 equiv) and potassium carbonate (2.8 g, 20.5 mmol, 3.0 equiv) in 1,4-dioxane (20 mL) and water (2 mL) was degassed by bubbling through a stream of argon 15 min. [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.5 g, 0.69mol, 0.1 equiv) was added. The reaction mixture was stirred at 110oC for 2 h. It was cooled to room temperature, transferred into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel Page 168 of 196 12746579v1Attorney Docket No.: 2013518-0088 (Combiflash®, 56% ethyl acetate in hexane) to afford 21.1 (1.8 g, Yield: 48%). MS(ES): m / z 541.2 [M+H]+.

[0379] Synthesis of compound 21.2. To a solution of 21.1 (1.8 g, 3.3 mmol, 1.0 equiv) and pyridine (0.8 mL, 1.0 mmol, 3.0 equiv) in chloroform (30 mL) at 0oC was added bromine (0.572 g, 3.6 mmol, 1.1 equiv) dropwise and stirred for 30 min. It was transferred into water, extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 43% ethyl acetate in hexane) to afford 21.2 (1.4 g, Yield: 68%). MS(ES): m / z 619.2 and 621.2 [M+H]+.

[0380] Synthesis of compound 21.3. A mixture of 21.2 (1.4 g, 2.2 mmol, 1 equiv), 11.2 (1.32 g, 3.3 mmol, 1.5 equiv) and cesium carbonate (2.2 g, 6.7 mmol, 3.0 equiv) in 1,4-dioxane (10 mL) and water (1 mL) was degassed by bubbling through a stream of argon 15 min. [1,1′- Bis(diphenylphosphino)ferrocene]dichloropalladium(II),dichloromethane complex (0.18 g, 0.22 mmol, 0.1 equiv) was added. The reaction mixture was stirred at 110oC for 4 h. It was cooled to room temperature, transferred into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 62% ethyl acetate in hexane) to afford 21.3 (0.80 g, Yield: 44%). MS(ES): m / z 805.2 [M+H]+.

[0381] Synthesis of compound 21.4. To a solution of 21.3 (0.8 g, 0.99 mmol, 1.0 equiv) in DCM (20 mL) at 0 °C was added triflic acid (1.6 mL) and stirred for 15 min. It was transferred into a saturated solution of sodium bicarbonate and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 8.2% methanol (7M ammonia in MeOH) in DCM) to afford 21.3 (0.54 g, Yield: 88%). MS(ES): m / z 615.5 [M+H]+.

[0382] Synthesis of compound 21.5. To a solution of 21.4 (0.54 g, 0.87 mmol, 1.0 equiv) and triethylamine (0.36 mL, 2.6 mmol, 3.0 equiv) in DCM (15 mL) at 0 °C was added a solution of 1,1’-carbonyldiimidazole (0.185 g, 1.1 mmol, 1.3 equiv) in DCM (4 mL). The reaction mixture was stirred for 15 min. It was transferred into ice-water and extracted with DCM. The combined Page 169 of 196 12746579v1Attorney Docket No.: 2013518-0088 organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 21.5 (0.48 g). MS(ES): m / z 709.4 [M+H]+. The product was used in the next step without purification.

[0383] Synthesis of compound 21.6. A solution of 21.5 (0.48 g, 0.67 mmol, 1.0 equiv) and N,N-diisopropylethylamine (0.45 mL, 2.7 mmol, 4.0 equiv) in acetonitrile (10 mL) was stirred at 80 °C for 16 h. It was poured into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 4.2% methanol in DCM). The product was re-purified by reverse phase prep HPLC (column: SUNFIRE C18 (250 * 19 mm, 5 µm); mobile phase: (A) 0.1% formic acid in water, (B) MeCN; flow rate: 16 mL / min) to afford 21.6 (0.05, Yield: 11%). MS(ES): m / z 641.6 [M+H]+.

[0384] Synthesis of I-21A. To a solution of 21.6 (0.05 g, 0.07 mmol, 1.0 equiv) in methanol: THF (3 mL:3 mL) was added sodium hydroxide (0.125 g, 3.1 mmol, 40.0 equiv). The reaction mixture was stirred at room temperature for 2 h. It was poured into crushed ice and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 4.6% methanol in DCM) to afford I-21A (0.02 g, Yield: 44%). MS(ES): m / z 501.4 [M+H]+;1H NMR (DMSO-d6, 400 M Hz): δ 11.33 (s, 1H), 8.09 (s, 1H), 7.99 (s, 1H), 7.87-7.83 (m, 2H)J = 8.4 Hz, 1H), 6.95 (d, J = 8.4 Hz, 1H), 4.81-4.78 (m, 1H), 4.55-4.52 (m, 1H), 4.28-4.24 (m, 1H), 4.10-4.08 (m, 1H), 2.60- 2.58 (m, 1H), 2.38 (bs, 2H), 2.12-2.09 (m, 1H), 1.96-1.93 (m, 1H), 1.76-1.74 (m, 2H), 1.61-1.59 (m, 1H), 1.49-1.41 (m, 2H), 0.94(bs, 2H), 0.83-0.82(m, 2H). Example 35: Synthesis of (31s,33s)-27-cyclopropyl-23-(methyl-d3)-21,22,23,26-tetrahydro-11H-6-oxa-4-aza-2(8,1)-imidazo[4,5-d]pyrrolo[2,3-b]pyridina-1(5,1)-indazola-3(1,3)- cyclobutanacyclooctaphane-22,5-dione (Compound I-22A) Page 170 of 196 12746579v1Attorney Docket No.: 2013518-0088, (1.0 g, 2.6 mmol, 1.5 equiv) and cesium carbonate (1.73 g, 5.2 mmol, 3.0 equiv) in 1,4-dioxane (10 mL) and water (1 mL) was degassed by bubbling through a stream of argon 15 min. [1,1′- Bis(diphenylphosphino)ferrocene]dichloropalladium(II), dichloromethane complex (0.138 g, 0.17 mmol, 0.1 equiv) was added. The reaction mixture was stirred at 110oC for 4 h. It was cooled to room temperature, transferred into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 58% ethyl acetate in hexane). The product was re-purified by reverse phase column chromatography (C18, mobile phase: (A) 0.1% formic acid in water and (B) MeCN) to afford 22.1 (0.17 g, Yield: 12%). MS(ES): m / z 791.2 [M+H]+.

[0386] Synthesis of compound 22.2. To a solution of 22.1 (0.17 g, 0.21 mmol, 1.0 equiv) in DCM (15 mL) at 0 °C was added triflic acid (0.35 mL). The reaction mixture was stirred at 0 °C for 15 min. It was transferred into a saturated solution of sodium bicarbonate and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, Page 171 of 196 12746579v1Attorney Docket No.: 2013518-0088 filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 6.4% methanol (7M ammonia in MeOH) in DCM) to afford 22.2 (0.092 g, Yield: 71%). MS(ES): m / z 600.4 [M+H]+.

[0387] Synthesis of compound 22.3. A solution of 22.2 (0.092 g, 0.15 mmol, 1.0 equiv) and triethylamine (0.063 mL, 0.46 mmol, 3.0 equiv) in DCM (15 mL) at 0 °C was added a solution of 1,1'-carbonyldiimidazole (0.032 g, 0.199 mmol, 1.3 equiv) in DCM (2 mL) and stirred for 15 min. It was transferred into ice-water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 22.3 (0.068 g). MS(ES): m / z 695.4 [M+H]+. The product was used in the next step without purification.

[0388] Synthesis of compound 22.4. A solution of 22.3 (0.068 g, 0.097 mmol, 1.0 equiv) and N,N-diisopropylethylamine (0.066 mL, 0.39 mmol, 4.0 equiv) in acetonitrile (10 mL) was stirred at 80 °C for 16 h. It was poured into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 4.1% methanol in DCM) to afford 22.4 (0.032, Yield: 51%). MS(ES): m / z 627.6 [M+H]+.

[0389] Synthesis of I-22A. To a solution of 22.4 (0.032 g, 0.051 mmol, 1.0 equiv) in methanol: THF (2 mL:2 mL) was added sodium hydroxide (0.081 g, 2.0 mmol, 40.0 equiv). The reaction mixture was stirred at room temperature for 2 h. It was poured into crushed ice and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 4.1% methanol in DCM) to afford I-22A (0.011 g, Yield: 44%). MS(ES): m / z 487.3 [M+H]+;1H NMR (DMSO-d6, 400 M Hz): δ 11.33 (s, 1H), 8.18 (s, 1H), 8.00 (s, 1H), 7.91 (d, J = 8.4, 7.71 (s, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.11 (s, 1H), 5.02-4.99 (m, 1H), 4.63-4.59 (m, 1H), 4.27-4.25 (m, 1H), 3.45(bs, 1H),2.66-2.61 (m, 1H), 2.03 (s, 2H), 1.79 (s, 2H), 0.94 (s, 2H), 0.86-0.81 (m, 2H). Example 36: Synthesis of (31s,33s)-27-(3,6-dihydro-2H-pyran-4-yl)-23-(methyl-d3)- 21,22,23,26-tetrahydro-11H-6-oxa-4-aza-2(8,1)-imidazo[4,5-d]pyrrolo[2,3-b]pyridina- 1(5,1)-indazola-3(1,3)-cyclobutanacyclooctaphane-22,5-dione (Compound I-23A) Page 172 of 196 12746579v1Attorney Docket No.: 2013518-0088 PhO2SPhOS PhO2S PhO2SH2N 2NHBoc NNNNNNNBSNNTEA Fe, NH4ClCD3Page 173 of 196 12746579v1Attorney Docket No.: 2013518-0088

[0390] Synthesis of compound 23.1. To a solution of 4-chloro-5-nitro-1- (phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (10.0 g, 29.61 mmol, 1.0 equiv) in DMF (150 mL) was added N-bromosuccinimide (5.54 g, 31.15 mmol, 1.05 equiv) at 0 ºC. The reaction mixture was stirred at 50 ºC for 1h. It was transfer into water and extracted by ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduce pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 30.0% ethyl acetate in hexane) to afford 23.1 (9.80 g, Yield: 79%). MS(ES): m / z 416.2 and 418.4 [M+H]+.

[0391] Synthesis of compound 23.2. To a solution of 23.1 (9.8 g, 23.52 mmol, 1.0 equiv) and triethylamine (9.9 mL, 70.56 mmol, 3.0) in MeCN (160 mL) was added tert-butyl ((1s,3s)-3- aminocyclobutyl)carbamate (4.82 g, 25.87 mmol, 1.1 equiv) at room temperature. The reaction mixture was stirred at 70 ºC for 3 h. It was added with ice-water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduce pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 35.0% ethyl acetate in hexane) to afford 23.2 (7.9 g, 59%). MS(ES): m / z 566.3 and 568.2 [M+H]+

[0392] Synthesis of compound 23.3. To a solution of 23.2 (7.9 g, 13.950 mmol, 1.0 equiv) in ethanol: water (100 mL: 50 mL) was added iron (7.6 g, 139.50 mmol, 10.0 equiv) and ammonium chloride (14.78 g, 278.94 mmol, 20.0 equiv) at room temperature. The reaction mixture was stirred at 70 ºC for 2 h. It was added filtrate on a pad of Celite® and washed by ethyl acetate. The filtrate was concentrated under reduce pressure. The residue was added water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under pressure to afford compound 23.3 (6.3 g, 84%). MS(ES): m / z 536.4 and 538.4[M+H]+.

[0393] Synthesis of compound 23.4. To a solution of 23.3 (6.3 g, 11.74 mmol, 1.0 equiv) and 4-dimethylaminopyridine (2.1 g, 17.61 mmol, 1.5 equiv) in acetonitrile (100 mL) was added 1,1'-carbonyldiimidazole (5.7 g, 35.23 mmol, 3.0 equiv) at room temperature. The reaction mixture was stirred at 70 ºC for 4 h. It was added water and extracted with ethyl acetate. The combined organic layers were washed with 1N hydrochloride solution, dried over anhydrous sodium sulfate and concentrated under reduce pressure. The residue was purified by flash column chromatography Page 174 of 196 12746579v1Attorney Docket No.: 2013518-0088 on silica gel (Combiflash®, 2% methanol in DCM) to afford 23.4 (4.8 g, 73%). MS(ES): m / z 562.4 and 564.2 [M+H]+.

[0394] Synthesis of compound 23.5. To a solution of 1.5 (4.8 g, 8.53 mmol, 1.0 equiv) in DMF (70 mL) was added potassium carbonate (3.53 g, 25.60 mmol, 3.0 equiv) and iodomethane- d3 (0.8 mL, 12.80 mmol, 1.5 equiv) at 0 ºC for 2 h. It was transferred into cooled water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 2.8% methanol in DCM) to afford 23.5 (4.2 g, Yield: 85%). MS(ES): m / z 579.3 and 581.4 [M+H]+.

[0395] Synthesis of compound 23.6. A mixture of compound 23.5 (4.2 g, 7.25 mmol, 1.0 equiv), 17.1 (4.11 g, 10.87 mmol, 1.5 equiv) and cesium carbonate (7.06 g, 21.74 mmol, 3.0 equiv) in 1,4-dioxane: water (50 mL: 10 mL) was degassed by bubbling through a stream of argon for 10- 15 min. [1,1′-Bis(diphenylphosphino) ferrocene]dichloropalladium (II) (0.530 g, 0.724 mmol, 0.1 equiv) was added and the reaction mixture was stirred at 100 ºC for 12 h. It was cooled to room temperature and reaction mixture was transferred into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 3.2% methanol in DCM) to afford 23.6 (3.2 g, Yield: 59%). MS(ES): m / z 751. [M+H]+.

[0396] Synthesis of compound 23.7. To a stirred solution of 23.6 (3.2 g, 4.26 mmol, 1.0 equiv) in THF (120 mL) was added a solution of lithium diisopropylamide in THF (2 M, 6.3 mL, 12.78 mmol, 3.0 equiv) at -78 ºC and stirred for 45 min. A solution of 1,2-dibromo-1,1,2,2- tetrachloroethane (2.35 g, 7.24 mmol, 1.7 equiv) in THF (15 mL) was added dropwise to the reaction mixture at -78 ºC and stirred for 1 h. It was transferred into an aqueous solution of ammonium chloride and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 55% ethyl acetate in hexane) to afford 23.7 (0.800 g, Yield: 23%). MS(ES): m / z 829.6 and 831.6 [M+H]+.

[0397] Synthesis of compound 23.8. A mixture of compound 23.7 (0.8 g, 0.964 mmol, 1.0 equiv), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.303 g, 1.45 Page 175 of 196 12746579v1Attorney Docket No.: 2013518-0088 mmol, 1.5 equiv) and sodium carbonate (0.306 g, 2.89 mmol, 3.0 equiv) in 1,4-dioxane: water (15 mL: 4 mL) was degassed by bubbling through a stream of argon for 10-15 min. [1,1′- Bis(diphenylphosphino) ferrocene]dichloropalladium (II) (0.070 g, 0.096 mmol, 0.1 equiv) was added and the reaction mixture was stirred at 110 ºC for 2 h. It was cooled to room temperature and reaction mixture was transferred into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 3.5% methanol in DCM) to afford 23.8 (0.530 g, Yield: 66%). MS(ES): m / z 833.7 [M+H]+.

[0398] Synthesis of compound 23.9. To a solution of 23.8 (0.530 g, 0.636 mmol, 1.0 equiv) in DCM (10 mL) at 0 °C was added triflic acid (1.0 mL). The reaction mixture was stirred at 0 °C for 15 min. It was transferred into a saturated solution of sodium bicarbonate and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 7% methanol in DCM) to afford 23.9 (0.285 g, Yield: 70%). MS(ES): m / z 643.5 [M+H]+.

[0399] Synthesis of compound 23.10. To a solution of 23.9 (0.285 g, 0.443 mmol, 1.0 equiv) and triethylamine (0.112 g, 1.10 mmol, 2.5 equiv) in DCM (10 mL) at 0 °C was added a solution of 1,1'-carbonyldiimidazole (0.093 g, 0.576mol, 1.3 equiv) in DCM (1 mL). The reaction mixture was stirred for 15 min. It was transferred into ice-water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 23.10 (0.210 g). MS(ES): m / z 737.6 [M+H]+. The product was used in the next step without purification.

[0400] Synthesis of compound 23.11. A solution of 23.11 (0.210 g, 0.285 mmol, 1.0 equiv) and N,N-diisopropylethylamine (0.147 g, 1.1 mmol, 4.0 equiv) in acetonitrile (15 mL) was stirred at 80 °C for 6 h. It was poured into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 4.2% methanol in DCM) to afford 23.11 (0.074 g, Yield: 39%). MS(ES): m / z 669.5 [M+H]+. Page 176 of 196 12746579v1Attorney Docket No.: 2013518-0088

[0401] Synthesis of compound I-23A. To a solution of 23.11 (0.074 g, 0.110 mmol, 1.0 equiv) in methanol: THF: H2O (2 mL: 2 mL: 1 mL) was added sodium hydroxide (0.177 g, 4.42 mmol, 40.0 equiv). The reaction mixture was stirred at rt for 1 h. It was poured into crushed ice and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Combiflash®, 4.6% methanol in DCM) to afford I-23A (0.025 g, Yield: 43%). MS(ES): m / z 529.6 [M+H]+;1H NMR (DMSO-d6, 400 M Hz): δ 11.85 (s, 1H), 8.20 (s, 1H), 8.15 (s, 1H), 7.92-7.89 (d, J = Hz, 1H), 7.65 (s, 1H), 7.58-7.56 (d, J = 8.4 Hz, 1H), 7.11-7.09 (d, J = 8.8 Hz, 1H), 6.10-5.99 (m, 1H), 5.05-4.99 (m, 1H), 4.62- 4.59 (d, J = 12 Hz, 1H), 4.26-4.11 (m, 1H), 4.10-3.95 (m, 3H), 3.59-3.43 (m, 2H), 2.75-2.68 (m, 1H), 2.17-2.13 (m, 1H), 2.04-1.96 (m, 2H), 1.95-1.91 (m, 2H), 1.88-1.75 (m, 2H).

[0402] A person of ordinary skill in the art will appreciate that compounds of the present disclosure can be synthesized according to the provided schemes and utilizing various reaction conditions and commercially available reagents. Biological Assays Example 37: JAK2 JH2 Domain Binding Assay

[0403] JAK2 (JH2domain-pseudokinase, NP_004963.1, partial length construct with AA start / stop at R513 / N824) was produced in HEK-293 cells and subsequently tagged with DNA for qPCR detection. Streptavidin-coated magnetic beads were treated with biotinylated small molecule ligands for 30 minutes at room temperature to generate affinity resins for kinase assays. The liganded beads were blocked with excess biotin and washed with blocking buffer (SeaBlock (Pierce), 1% BSA, 0.05% Tween 20, 1 mM DTT) to remove unbound ligand and to reduce non- specific binding. Binding reactions were assembled by combining kinases, liganded affinity beads, and test compounds in 1x binding buffer (20% SeaBlock, 0.17x PBS, 0.05% Tween 20, 6 mM DTT). Test compounds were prepared as 111x stocks in 100% DMSO. Kd values were determined using an 11-point 3-fold compound dilution series with three DMSO control points. All compounds for Kd measurements were distributed by acoustic transfer (non-contact dispensing) in 100% DMSO. The compounds were then diluted directly into the assays such that the final concentration of DMSO was 0.9%. All reactions were performed in polypropylene 384-well plate. Page 177 of 196 12746579v1Attorney Docket No.: 2013518-0088 Each was a final volume of 0.02 mL. The assay plates were incubated at room temperature with shaking for 1 hour and the affinity beads were washed with wash buffer (1x PBS, 0.05% Tween 20). The beads were then re-suspended in elution buffer (1x PBS, 0.05% Tween 20, 0.5 μM non- biotinylated affinity ligand) and incubated at room temperature with shaking for 30 minutes. The kinase concentration in the eluates was measured by qPCR.

[0404] Results of the JAK2 JH2 Domain Binding Assay are presented in Table 2. Compounds denoted as “A” had a Kdless than 10 nM; compounds denoted as “B” had a Kdbetween 10 nM and 50 nM, inclusive; compounds denoted as “C” had a Kd between 50 nM and 1 uM, inclusive; and compounds denoted as “D” had a Kd greater than 1 uM. Table 2 Example number Potency category I-1A AExample 38: JAK Family Selectivity Assays Page 178 of 196 12746579v1Attorney Docket No.: 2013518-0088

[0405] Provided compounds are evaluated for selectivity by comparing their JAK2 binding affinity (Kd) in the above JAK2 Binding Assay with their binding affinity (Kd) for one or more other kinases. Binding affinity for other kinases is determined as follows: Kinase-tagged T7 phage strains are prepared in an E. coli host derived from the BL21 strain. E. coli are grown to log-phase and infected with T7 phage and incubated with shaking at 32 °C until lysis. The lysates are centrifuged and filtered to remove cell debris. The remaining kinases are produced in HEK-293 cells and subsequently tagged with DNA for qPCR detection. Streptavidin-coated magnetic beads are treated with biotinylated small molecule ligands for 30 minutes at room temperature to generate affinity resins for kinase assays. The liganded beads are blocked with excess biotin and washed with blocking buffer (SeaBlock (Pierce), 1% BSA, 0.05% Tween 20, 1 mM DTT) to remove unbound ligand and to reduce non-specific binding. Binding reactions are assembled by combining kinases, liganded affinity beads, and test compounds in 1x binding buffer (20% SeaBlock, 0.17x PBS, 0.05% Tween 20, 6 mM DTT). Test compounds are prepared as 111X stocks in 100% DMSO. Kdvalues are determined using an 11-point 3-fold compound dilution series with three DMSO control points. All compounds for Kd measurements are distributed by acoustic transfer (non-contact dispensing) in 100% DMSO. The compounds are then diluted directly into the assays such that the final concentration of DMSO is 0.9%. All reactions are performed in polypropylene 384-well plate. Each has a final volume of 0.02 ml. The assay plates are incubated at room temperature with shaking for 1 hour and the affinity beads are washed with wash buffer (1x PBS, 0.05% Tween 20). The beads are then re-suspended in elution buffer (1x PBS, 0.05% Tween 20, 0.5 μM non-biotinylated affinity ligand) and incubated at room temperature with shaking for 30 minutes. The kinase concentration in the eluates is measured by qPCR. Compounds that exhibit a better binding affinity for JAK2 compared to one or more other kinases are considered to be JAK2- selective compounds. In some embodiments, provided compounds may be JAK2-selective over one or more of the following kinases: JAK1, JAK3, and Tyk2. Example 39: SET2-pSTAT5 Cellular Assay

[0406] This assay measures inhibition of JAK2-mediated pSTAT5 signaling in constitutively active essential thrombocytopenia cells carrying the V617F mutation. Cells are harvested from a flask into cell culture medium, and the number of cells is counted. The cells are diluted with culture medium and 100 µL of cell suspension (50000 / well) is added into each well Page 179 of 196 12746579v1Attorney Docket No.: 2013518-0088 of a 96-well cell culture plate. A solution of test compound is added to the assay plate. The plates are covered with a lid and placed in a 37 °C 5% CO2 incubator for 4 hours. After 4 hours, the cells are spun, and the cell pellets are re-suspended with 100 µL cold PBS. Then, the cells are spun again at 4 °C and 4000 rpm for 5 min. PBS is aspirated, and 25 µL lysis buffer (with protease and phosphatase inhibitor cocktail) is added to each cell pellet. The cell lysate is shaken at 4 °C for 20 min to fully lyse the cells. The cell lysate is spun at 4 °C and 4000 rpm for 15 min, and then the supernatant is transferred into a new plate and stored at -80 °C. Meso-scale discovery (MSD) is used to analyze plates as follows: a standard MSD plate is coated with capture antibody in PBS (40 µL / well) and is incubated at 4 °C overnight with shaking. The MSD plate is washed three times with 150 µL / well of 1x MSD Wash Buffer (Tris-buffered saline with 0.1% Tween® 20 detergent, TBST). The MSD plates are then blocked with 150 µL of blocking buffer (5% BSA in TBST) and shaken for 1 h at room temperature and 600 rpm. The MSD plate is washed three times with 150 µL / well of 1x MSD Wash Buffer (TBST). Sample lysates are then added to MSD plates (25 µL / well) and shaken for 1 h at room temperature and 600 rpm. The MSD plate is washed three times with 150 µL / well of 1x MSD Wash Buffer (TBST). Detection antibody (prepared in Antibody Detection buffer, 1% BSA in 1xTBST) is then added to the MSD plates, and they are shaken for 1 h at room temperature and 600 rpm. The MSD plate is washed three times with 150 µL / well of 1x MSD Wash Buffer (TBST). A secondary detection antibody (prepared in Antibody Detection buffer, 1% BSA in 1xTBST) is then added to the MSD plates, and they are shaken for 1 h at room temperature and 600 rpm. The MSD plate is washed three times with 150 µL / well of 1x MSD Wash Buffer (TBST). MSD reading buffer (1x) is added to the plates (150 µL / well), and they are diluted from 4x with water. The plates are imaged using an MSD imaging instrument according to the manufacturer’s instructions. Example 40: Caco2 Permeability Assay

[0407] Preparation of Caco-2 Cells: 50 μL and 25 mL of cell culture medium are added to each well of a Transwell® insert and reservoir, respectively. Then, the HTS Transwell® plates are incubated at 37 °C, 5% CO2 for 1 hour before cell seeding. Caco-2 cell cells are diluted to 6.86х105 cells / mL with culture medium, and 50 μL of cell suspension are dispensed into the filter well of the 96-well HTS Transwell® plate. Cells are cultivated for 14-18 days in a cell culture Page 180 of 196 12746579v1Attorney Docket No.: 2013518-0088 incubator at 37 °C, 5% CO2, 95% relative humidity. Cell culture medium is replaced every other day, beginning no later than 24 hours after initial plating.

[0408] Preparation of Stock Solutions: 10 mM stock solutions of test compounds are prepared in DMSO. The stock solutions of positive controls are prepared in DMSO at the concentration of 10 mM. Digoxin and propranolol are used as control compounds in this assay.

[0409] Assessment of Cell Monolayer Integrity: Medium is removed from the reservoir and each Transwell® insert and is replaced with prewarmed fresh culture medium. Transepithelial electrical resistance (TEER) across the monolayer is measured using Millicell Epithelial Volt-Ohm measuring system (Millipore, USA). The Plate is returned to the incubator once the measurement is done. The TEER value is calculated according to the following equation: TEER measurement (ohms) x Area of membrane (cm2) = TEER value (ohm•cm2). A TEER value greater than 230 ohm•cm2indicates a well-qualified Caco-2 monolayer.

[0410] Assay Procedure: The Caco-2 plate is removed from the incubator and washed twice with pre-warmed HBSS (10 mM HEPES, pH 7.4), and then incubated at 37 °C for 30 minutes. The stock solutions of control compounds are diluted in DMSO to get 1 mM solutions and then diluted with HBSS (10 mM HEPES, pH 7.4) to get 5 μM working solutions. The stock solutions of the test compounds are diluted in DMSO to get 1 mM solutions and then diluted with HBSS (10 mM HEPES and 4% BSA, pH 7.4) to get 5 μM working solutions. The final concentration of DMSO in the incubation system is 0.5%. To determine the rate of drug transport in the apical to basolateral direction.75 μL of 5 μM working solutions of test compounds are added to the Transwell® insert (apical compartment) and the wells in the receiver plate (basolateral compartment) are filled with 235 μL of HBSS (10 mM HEPES and 4% BSA, pH 7.4). To determine the rate of drug transport in the basolateral to apical direction, 235 μL of 5 μM working solutions of test compounds are added to the receiver plate wells (basolateral compartment) and then the Transwell® inserts (apical compartment) are filled with 75 μL of HBSS (10 mM HEPES and 4% BSA, pH 7.4). Time 0 samples are prepared by transferring 50 μL of 5 μM working solution to wells of the 96-deepwell plate, followed by the addition of 200 μL cold methanol containing appropriate internal standards (IS). The plates are incubated at 37 °C for 2 hours. At the end of the incubation, 50 μL samples from donor sides (apical compartment for Ap→Bl flux, and basolateral compartment for Bl→Ap) and receiver sides (basolateral compartment for Ap→Bl Page 181 of 196 12746579v1Attorney Docket No.: 2013518-0088 flux, and apical compartment for Bl→Ap) are transferred to wells of a new 96-well plate, followed by the addition of 4 volume of cold acetonitrile or methanol containing appropriate internal standards (IS). Samples are vortexed for 5 minutes and then centrifuged at 3,220 g for 40 minutes. An aliquot of 100 µL of the supernatant is mixed with an appropriate volume of ultra-pure water before LC-MS / MS analysis. To determine the Lucifer Yellow leakage after 2 hour transport period, stock solution of Lucifer yellow is prepared in ultra-pure water and diluted with HBSS (10 mM HEPES, pH 7.4) to reach the final concentration of 100 μM. 100 μL of the Lucifer yellow solution is added to each Transwell® insert (apical compartment), followed by filling the wells in the receiver plate (basolateral compartment) with 300 μL of HBSS (10 mM HEPES, pH 7.4). The plates are incubated at 37 °C for 30 minutes.80 μL samples are removed directly from the apical and basolateral wells (using the basolateral access holes) and transferred to wells of new 96 wells plates. The Lucifer Yellow fluorescence (to monitor monolayer integrity) signal is measured in a fluorescence plate reader at 485 nM excitation and 530 nM emission. Example 41: Cytotoxicity Assay

[0411] HEK293T cells are harvested from flask into cell culture medium, and then the cells are counted. The cells are diluted with culture medium to the desired density, and 40 μL of cell suspension is added into each well of a 384-well cell culture plate. The plates are covered with a lid and spun at room temperature at 1,000 RPM for 1 minute and then transferred into 37 °C 5% CO2incubator overnight. Test compounds are dissolved at 10 mM DMSO stock solution.45 μL of stock solution is then transferred to a 384 PP-plate. A 3-fold, 10-point dilution is performed via transferring 15 μL compound into 30 μL DMSO by using TECAN (EVO200) liquid handler. The plates are spun at room temperature at 1,000 RPM for 1 minute and shaken on a plate shaker for 2 minutes. 40 nL of diluted compound is transferred from compound source plate into the cell plate by using liquid handler Echo550. After compound treatment for 48 hours, CTG detection is performed for compound treatment plates: the plates are removed from incubators and equilibrated at room temperature for 15 minutes.30 μL of CellTiter-Glo reagent is added into each well to be detected. The plates are then placed at room temperature for 30 min followed by reading on EnVision. Inhibition activity is calculated with the following formula: %Inhibition = 100 x (LumHC – LumSample) / (LumHC –LumLC), wherein HC is reading obtained from cells treated Page 182 of 196 12746579v1Attorney Docket No.: 2013518-0088 with 0.1% DMSO only and LC is reading from cells treated with 10 μL staurosporine. IC50values are calculated using XLFit (equation 201). Example 42: Hepatocyte Stability Assay

[0412] 10 mM stock solutions of test compound and positive control are prepared in DMSO. Stock solutions are diluted to 100 μM by combining 198 μL of 50% acetonitrile / 50% water and 2 μL of 10 mM stock solution. Verapamil is used as positive control in the assay. Vials of cryopreserved hepatocytes are thawed in a 37 °C water bath with gently shaking. The contents are poured into the 50 mL thawing medium conical tube. Vials are centrifuged at 100 g for 10 minutes at room temperature. Thawing medium is aspirated and hepatocytes are re-suspended with serum-free incubation medium to yield ~1.5 × 106 cells / mL. Cell viability and density are counted using a Trypan Blue exclusion, and then cells are diluted with serum-free incubation medium to a working cell density of 0.5×106 viable cells / mL. A portion of the hepatocytes at 0.5×106 viable cells / mL are boiled for 5 min prior to adding to the plate as negative control to eliminate the enzymatic activity so that little or no substrate turnover should be observed. Aliquots of 198 μL hepatocytes are dispensed into each well of a 96-well non-coated plate. The plate is placed in the incubator for approximately 10 minutes. Aliquots of 2 μL of the 100 μM test compound and 2 μL positive control are added into respective wells of a non-coated 96-well plate to start the reaction. The final concentration of test compound is 1 μM. This assay is performed in duplicate. The plate is incubated in the incubator for the designed time points. 25 μL of contents are transferred and mixed with 6 volumes (150 μL) of cold acetonitrile with internal standard (100 nM alprazolam, 200 nM labetalol, 200 nM caffeine and 200 nM diclofenac) to terminate the reaction at time points of 0, 15, 30, 60, 90 and 120 minutes. Samples are centrifuged for 25 minutes at 3,220 g and aliquots of 150 μL of the supernatants are used for LC-MS / MS analysis. Example 43: Kinetic Solubility Assay

[0413] Stock solutions of test compounds are prepared in DMSO at the concentration of 10 mM, and a stock solution of control compound is prepared in DMSO at the concentration of 30 mM. Diclofenac is used as positive control in the assay. 30 µL stock solution of each compound is placed into their a 96-well rack, followed by adding 970 µL of PBS at pH 4.0 and pH 7.4 into Page 183 of 196 12746579v1Attorney Docket No.: 2013518-0088 each vial of the cap-less solubility sample plate. This study is performed in duplicate. One stir stick is added to each vial and then vials are sealed using a molded PTDE / SIL 96-Well Plate Cover. The solubility sample plate is transferred to the Thermomixer comfort plate shaker and incubated at RT for 2 hours with shaking at 1100 rpm. After 2 hours incubation, stir sticks are removed using a big magnet and all samples from the solubility sample plate are transferred into the filter plate. All the samples are filtered by vacuum manifold. The filtered samples are diluted with methanol. Samples are analyzed by LC-MS / MS and quantified against a standard of known concentration in DMSO using LC coupled with Mass spectral peak identification and quantitation. The solubility values of the test compounds are calculated as follows, wherein INJ VOL is injection volume, DF is dilution factor, and STD is standard:Example 44: Plasma Protein Binding Assay

[0414] Working solutions of test compounds and control compound are prepared in DMSO at the concentration of 200 μM, and then the working solutions are spiked into plasma. The final concentration of compound is 1 μM. The final concentration of DMSO is 0.5%. Ketoconazole is used as positive control in the assay. Dialysis membranes are soaked in ultrapure water for 60 minutes to separate strips, then in 20% ethanol for 20 minutes, finally in dialysis buffer for 20 minutes. The dialysis set up is assembled according to the manufacturer’s instruction. Each Cell is with 150 μL of plasma sample and dialyzed against equal volume of dialysis buffer (PBS). The assay is performed in duplicate. The dialysis plate is sealed and incubated in an incubator at 37 °C with 5% CO2 at 100 rpm for 6 hours. At the end of incubation, 50 μL of samples from both buffer and plasma chambers are transferred to wells of a 96-well plate. 50 μL of plasma is added to each buffer samples and an equal volume of PBS is supplemented to the collected plasma sample. 400 μL of precipitation buffer acetonitrile containing internal standards (IS, 100 nM alprazolam, 200 nM labetalol, 200 nM imipramine and 2 μM ketoplofen) is added to precipitate protein and release compounds. Samples are vortexed for 2 minutes and centrifuged for 30 minutes at 3,220 g. Aliquot of 50 µL of the supernatant is diluted by 150 µL acetonitrile containing internal standards : ultra- pure H2O = 1 : 1, and the mixture is used for LC-MS / MS analysis. Page 184 of 196 12746579v1Attorney Docket No.: 2013518-0088

[0415] While we have described a number of embodiments of this invention, it is apparent that our basic examples may be altered to provide other embodiments that utilize the compounds and methods of this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims rather than by the specific embodiments that have been represented by way of example. Page 185 of 196 12746579v1

Claims

1. Attorney Docket No.: 2013518-0088 CLAIMS 1. A compound represented by formula I: or a pharmaceutically acceptable salt thereof, wherein: R1is hydrogen or optionally substituted C1-C6aliphatic; R2is C1-C6aliphatic, C1-C6heteroaliphatic, C3-C12cycloaliphatic, 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, 5- to 10- membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, or C6- C10aryl, wherein R2is optionally substituted with one or more instances of R2a; each R2ais independently selected from the group consisting of optionally substituted C1- C6aliphatic, optionally substituted C1-C6heteroaliphatic, halogen, oxo, -CN, -NO2, -C(O)N(Ra)2, -OC(O)Ra, -OC(O)N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)C(O)ORa, -N(Ra)C(O)N(Ra)2, -S(O)2N(Ra)2, -N(Ra)S(O)2Ra, -S(O)2Ra, -ORa, and -La-Rb; each Lais independently selected from a bond and optionally substituted C1-C6 aliphatic; each Rbis independently selected from optionally substituted C3-C12cycloaliphatic, optionally substituted 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, optionally substituted 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, and optionally substituted C6-C10aryl; each Rais independently selected from hydrogen, optionally substituted C1-C6 aliphatic, optionally substituted C1-C6heteroaliphatic, optionally substituted 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, and optionally substituted 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S; Page 186 of 196 12746579v1 Attorney Docket No.: 2013518-0088 Q is selected from optionally substituted C1-C6aliphatic, optionally substituted C1-C6heteroaliphatic, optionally substituted C3-C12 cycloaliphatic, optionally substituted 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, optionally substituted 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, and optionally substituted C6-C10 aryl; Z is selected from optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 heteroaliphatic, optionally substituted C3-C12cycloaliphatic, optionally substituted 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, optionally substituted 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, and optionally substituted C6-C10aryl; L is *-L1-L2-L3-**, where * represents a point of attachment to Q and ** represents a point of attachment to Z; L1is a bond, a 4- to 6-membered heterocycle having 1 to 2 heteroatoms independently selected from N, O, and S, -C(O)N(Ra)-, -OC(O)-, -OC(O)N(Ra)-, -N(Ra)C(O)-, -N(Ra)C(O)O-, -N(Ra)C(O)N(Ra)-, -S(O)2N(Ra)-, -N(Ra)S(O)2-, -S(O)2-, -C(Ra)2O-, -N(Ra)-, -S-, or -O-; L3is a bond, a 4- to 6-membered heterocycle having 1 to 2 heteroatoms independently selected from N, O, and S, -C(O)N(Ra)-, -OC(O)-, -OC(O)N(Ra)-, -N(Ra)C(O)-, -N(Ra)C(O)O-, -N(Ra)C(O)N(Ra)-, -S(O)2N(Ra)-, -N(Ra)S(O)2-, -S(O)2-, -C(Ra)2O-, -N(Ra)-, -S-, or -O-; and L2is optionally substituted C1-C6aliphatic, optionally substituted 2- to 6-membered heteroaliphatic, optionally substituted 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, or optionally substituted C3-C10 cycloaliphatic.

2. The compound of claim 1, wherein R1is optionally substituted C1-C6 aliphatic.

3. The compound of claims 1 or 2, wherein R1is -CH3 or -CD3. Page 187 of 196 12746579v1 Attorney Docket No.: 2013518-0088 4. The compound of any one of claims 1-3, wherein R2is 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, C3-C6 cycloaliphatic, or C6-C10 aryl, and wherein R2is optionally substituted with one or more instances of R2a.

5. The compound of claim 1, wherein R2is 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, C3-C6 cycloaliphatic, or 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, and wherein R2is optionally substituted with one or more instances of R2a.

6. The compound of any one of claims 1-5, wherein R2is 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, and wherein R2is optionally substituted with one or more instances of R2a.

7. The compound of claim 6, wherein R2is 5- to 6-membered monocyclic heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, and wherein R2is optionally substituted with one or more instances of R2a.

8. The compound of claim 7, wherein R2is 5- to 6-membered monocyclic heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, and wherein R2is substituted with one or more instances of R2a, wherein R2ais selected from optionally substituted C1-C6aliphatic and -ORa.

9. The compound of claim 8, wherein R2is 5- to 6-membered monocyclic heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, and wherein R2is substituted with one or more instances of R2a, wherein R2ais selected from optionally substituted C1-C6 aliphatic and halogen.

10. The compound of any one of claims 1-4, wherein R2is C6-C10 aryl, and wherein R2is optionally substituted with one or more instances of R2a. Page 188 of 196 12746579v1 Attorney Docket No.: 2013518-0088 11. The compound of any one of claims 1-4, wherein R2is C6aryl, and wherein R2is optionally substituted with one or more instances of R2a.

12. The compound claim 11 wherein R2is optionally substituted with one or more instances of R2a, wherein R2ais selected from -La-Rband -ORa.

13. The compound of any one of claims 1-3, wherein R2is selected from: , 14. The compound of claim 13, wherein R2is selected from: , , 15. The compound of claim 13, wherein R2is selected from: . Page 189 of 196 12746579v1 Attorney Docket No.: 2013518-0088 16. The compound of any one of claims 1-15, wherein Q is optionally substituted C3-C6cycloaliphatic, optionally substituted C6-C12 aryl, or optionally substituted 4- to 6-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S.

17. The compound of claim 16, wherein Q is optionally substituted C1-C6 aliphatic.

18. The compound of claim 17, wherein Q is optionally substituted cyclopenyl or cyclobutyl.

19. The compound of claim 16, wherein Q is optionally substituted C3-C6 cycloaliphatic.

20. The compound of any one of claims 1-15, wherein Q is: , 21. The compound of claim 20, wherein Q is: , of attachment to L1.

22. The compound of any one of claims 1-21, wherein Z is optionally substituted C1-C6 aliphatic, optionally substituted C1-C6heteroaliphatic, optionally substituted C3-C12cycloaliphatic, and optionally substituted C6-C10aryl. Page 190 of 196 12746579v1 Attorney Docket No.: 2013518-0088 23. The compound of any one of claims 1-21, wherein Z is optionally substituted C1-C6aliphatic, optionally substituted 5- to 10-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, and optionally substituted C6-C10 aryl.

24. The compound of claim 23, wherein Z is: , 25. The compound of any one of claims 1-24, wherein Z is optionally substituted C1-C6aliphatic.

26. The compound of any one of claims 1-23, wherein Z is optionally substituted C3-C7 cycloaliphatic.

27. The compound of any one of claims 1-24, wherein Z is optionally substituted C6-C10 aryl.

28. The compound of any one of claims 1-21, wherein Z is: , Page 191 of 196 12746579v1 Attorney Docket No.: 2013518-0088 29. The compound of any one of claims 1-28, wherein L1is -N(Ra)C(O)-, -N(Ra)C(O)O-, -N(Ra)C(O)N(Ra)-, or -O-.

30. The compound of claim 29, wherein L1is -OC(O)N(Ra)- or -N(Ra)C(O)O-.

31. The compound of claim 30, wherein L1is -OC(O)NH- or -NHC(O)O-.

32. The compound of any one of claims 1-31, wherein L3is -OC(O)-, -OC(O)N(Ra)-, -C(Ra)2O-, -N(Ra)-, -S-, or -O-.

33. The compound of any one of claims 1-31, wherein L3is a bond, a 4- to 6-membered heterocycle having 1 to 2 heteroatoms independently selected from N, O, and S, -C(Ra)2O-, -N(Ra)-, or -O-.

34. The compound of claim 33, wherein L3is a bond, azetidinyl, -CH2O-, -N(CH3)-, or -O-.

35. The compound of any one of claims 1-34, wherein L1is -N(Ra)C(O)O- or -N(Ra)C(O)N(Ra)-, and L3is -C(Ra)2O- or -O-.

36. The compound of any one of claims 1-35, wherein L1is -N(Ra)C(O)O- and L3is -O-.

37. The compound of any one of claims 1-36, wherein L2is an optionally substituted C1-C6 aliphatic.

38. The compound of claim 37, wherein L2is C1-C6 alkylene or C2-C6 alkenylene.

39. The compound of any one of claims 1-36, wherein L2is an optionally substituted 4- to 10- membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S.

40. The compound of any one of claims 1-36, wherein L2is an optionally substituted 4- to 6- membered heterocycle comprising 1 to 2 heteroatoms selected from N, O, and S. Page 192 of 196 12746579v1 Attorney Docket No.: 2013518-0088 41. The compound of any one of claims 1-36, wherein L2is an optionally substituted 4- to 7- membered heterocycle comprising 1 to 2 heteroatoms selected from N, O, and S, and is attached in a spirocyclic manner.

42. The compound of any one of claims 1-36, wherein L2is an optionally substituted monocyclic C3to C7cycloaliphatic.

43. The compound of any one of claims 1-36, wherein L2is optionally substituted C1-C6 aliphatic, optionally substituted 2- to 6-membered heteroaliphatic, or optionally substituted 4- to 10-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S.

44. The compound of any one of claims 1-36, wherein L2is: *-CH2- , , where * represents a point of attachment to L1and ** represents a point of attachment to L3.

45. The compound of claim 43, wherein L2is: *-CH2- , , Page 193 of 196 12746579v1 Attorney Docket No.: 2013518-0088 46. The compound of claim 1, wherein the compound is represented by formula I-A–I-L or a pharmaceutically acceptable salt thereof.

47. The compound of claim 1, wherein the compound is represented by formula II-A–II-K or a pharmaceutically acceptable salt thereof.

48. The compound of claim 1, wherein the compound is represented by formula III-A–III-D or a pharmaceutically acceptable salt thereof.

49. The compound of claim 1, wherein the compound is represented by formula IV-A–IV-D or a pharmaceutically acceptable salt thereof.

50. The compound of claim 1, wherein the compound is represented by formula V-A–V-D or a pharmaceutically acceptable salt thereof.

51. A compound selected from Table 1, or a pharmaceutically acceptable salt thereof.

52. A pharmaceutical composition comprising a compound of any one of claims 1-51, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

53. A method of inhibiting JAK2 in a subject, comprising administering to the subject the compound of any one of claims 1-51 or the pharmaceutical composition of claim 52.

54. A method of treating a disease, disorder, or condition associated with JAK2, comprising administering to a subject in need thereof the compound of any one of claims 1-51 or the pharmaceutical composition of claim 52.

55. A method of treating cancer, comprising administering to a subject in need thereof the compound of any one of claims 1-51 or the pharmaceutical composition of claim 52. Page 194 of 196 12746579v1 Attorney Docket No.: 2013518-0088 56. A method of treating a hematological malignancy, comprising administering to a subject in need thereof the compound of any one of claims 1-51 or the pharmaceutical composition of claim 52.

57. The method of claim 56, wherein the hematological malignancy is leukemia or lymphoma.

58. A method of treating a myeloproliferative neoplasm, comprising administering to a subject in need thereof the compound of any one of claims 1-51 or the pharmaceutical composition of claim 52.

59. The method of claim 58, wherein the myeloproliferative neoplasm is polycythemia vera, essential thrombocytopenia, or myelofibrosis. Page 195 of 196 12746579v1

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